WO2000047568A2 - 1,2-benzothiazepines for the treatment of hyperlipidemic diseases - Google Patents

1,2-benzothiazepines for the treatment of hyperlipidemic diseases Download PDF

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Publication number
WO2000047568A2
WO2000047568A2 PCT/US2000/002503 US0002503W WO0047568A2 WO 2000047568 A2 WO2000047568 A2 WO 2000047568A2 US 0002503 W US0002503 W US 0002503W WO 0047568 A2 WO0047568 A2 WO 0047568A2
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alkyl
heterocyclyl
group
aryl
independently selected
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WO2000047568A3 (en
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Michael B. Tollefson
Steve A. Kolodziej
David B. Reitz
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GD Searle LLC
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GD Searle LLC
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Priority to IL14471600A priority Critical patent/IL144716A0/en
Priority to EP00915720A priority patent/EP1155007A2/en
Priority to KR1020017010201A priority patent/KR20020000139A/en
Priority to AU36946/00A priority patent/AU3694600A/en
Priority to CA002362147A priority patent/CA2362147A1/en
Priority to JP2000598488A priority patent/JP2002536440A/en
Publication of WO2000047568A2 publication Critical patent/WO2000047568A2/en
Publication of WO2000047568A3 publication Critical patent/WO2000047568A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/36—Amides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds

Definitions

  • the present invention relates to novel 1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia, in mammals.
  • the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption ofthe enterohepatic circulation with specific transport inhibitors.
  • Kramer, et al "Intestinal Bile Acid Absorption", The Journal of Biological Chemistry. Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993.
  • Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents ofthe enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents. See, e.g., Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731.
  • Selected benzothiepines are disclosed in world patent application number WO93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
  • benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring ofthe fused bicyclo benzothiepine ring.
  • WO96/16051 published May 30, 1996 describes certain 1,5- benzothiazepines as useful in the treatment of hyperlipidemic conditions.
  • WO96/05188 published February 22, 1996 describes certain 1 ,4- benzothiazepines as useful in the treatment of hyperlipidemic conditions.
  • U.S. Patent No. 5,350,761 describes hydroxylamine derivatives that generically encompass certain benzothiazepine compounds. These derivatives are described as lipoxygenase inhibitors useful in the treatment of inflammatory and allergic conditions.
  • WO98/02432 published January 22, 1998 describes certain 5-(aryl-(N- containing-heterocyclyl)alkyl)benzothiazepines and aralkyl-(N-containing- heterocyclyl)alkyl)-benzothiazepines as useful for controlling micturition.
  • WO97/03953 published February 6, 1997 describes certain sulfonylamino-substituted benzothiazepines as inhibitors ofthe enzyme cyclooxygenase II.
  • WO95/21843 published August 17, 1995 describes certain benzothiazepines substituted with azacyclic condensed piperazines. These compounds are identified as kappa receptor agonists useful as analgesics and diuretics and for the treatment of cerebral ischaemia.
  • EP338331 published October 25, 1989 describes certain 2- benzothiazepine-5-ones useful as muscle relaxants.
  • a first aspect ofthe invention comprises novel 1,2- benzothiazepines that are effective agents for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
  • a second aspect ofthe invention comprises pharmaceutical compositions comprising the novel 1 ,2- benzothiazepines that are suitable for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
  • a third aspect ofthe invention comprises methods for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders comprising administering to a subject a prophylactically or therapeutically effective amount of one ofthe novel 1,2- benzothiazepines.
  • a fourth aspect ofthe invention comprises methods of making the novel 1,2-benzothiazepines ofthe present invention. Additional aspects ofthe invention are discussed throughout the specification of this application.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
  • R and R are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR 9 ; -NR 9 R 10 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -
  • R 9 and R 10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moieties may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and
  • R and R are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR 9 ; -NR 9 R 1 ; -
  • hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or R 11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and
  • R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -SO3R 9 ; wherein the R and R radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -NO2; -CN; oxo; hydrocarbyl; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -
  • 1 T consisting of hydrogen; halogen; -CN; -N ⁇ 2; hydrocarbyl; -OR ; -
  • NR 13 OR 14 ; -NR 13 NR 14 R 15 ; -CO2R 13 ; -OM; -SO2OM; -SO2NR 13 R 14 ; -
  • R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxy alkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocy ley loxy alkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R 1 and R 2 taken together with the carbon to which they are attached form C 3 -C]o cycloalkyl or C 3 -C 10 cycloalkenyl; wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl
  • R , R , and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; or wherein A " is a pharmaceutically acceptable anion; and
  • R and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; -NR R ; - SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -SO3R 9 ; or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R 10 are as defined above; and R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -SO3R 9 ; wherein the R and R alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alky
  • 7 optionally may have one or more carbons replaced by -O-; -NR -; -
  • R 7 R 8 A " -; -S-; -SO-; -SO2-; -S + R 7 A--; -PR 7 -; -P(O)R 7 -; -P + R 7 R 8 A " -; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; amino
  • NR 13 OR 14 ; -NR 13 NR 14 R 15 ; -CO2R 13 ; -OM; -SO2OM; -SO2NR 13 R 14 ; - NR 14 C(O)R 13 ; -C(O)NR 13 R 14 ; -C(O)OM; -COR 13 ; -OR 18 ; - S(O) n NR 13 R 14 ; -NR 13 R 18 ; -NR 18 OR 14 ; -N + R 13 R 14 R 15 A " ; -PR 13 R 14 ; -P(O)R 13 R 14 ; -P + R 13 R 14 R 15 A " ; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the R x alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; hetero
  • R" quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R 13 ; - SO2R 13 ; -S ⁇ 3R 13 ; -NR 13 OR 14 ; -NR 13 NR 14 R 15 ; -CO2R 13 ; OM; - SO2OM; -SO2NR 13 R 14 ; -C(O)NR 13 R 14 ; -C(O)OM
  • R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R 18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO 2 ; oxo; -OR 9 ; -NR 9 R 10 ; -N ⁇ R 1 ⁇ A " ;
  • R 5 and R 6 preferably are independently selected from the group consisting of H; aryl; heterocyclyl; and quaternary heterocyclyl; wherein the R and R aryl; heterocyclyl; and quaternary heterocyclyl; radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R 13 ; - SO2R 13 ; -S ⁇ 3R 13 ; -NR 13 OR 14 ; -NR 13 NR 14 R 15 ; -
  • R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl
  • R 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R n , R 12 , R w , and A " are as previously set forth above for the compounds of Formula I.
  • R 5 or R 6 has the formula -Ar-(R y ) t wherein: t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl; thiophenyl; pyridyl; piperazinyl; piperonyl; pyrrolyl; naphthyl; furanyl; anthracenyl; quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; oxazolyl; isoxazolyl; pyrimidinyl; thiazolyl; triazolyl; isothiazolyl; indolyl; benzoimidazolyl; benzoxazolyl; benzothiazolyl; and benzoisothiazolyl; and one or more R ⁇ are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl;
  • R 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R", R 12 , R w , and A " are as previously set forth above for the compounds of Formula I.
  • At least one of R 5 or R 6 has the formula (II)
  • R y and t are defined as above.
  • Formula I preferably satisfy at least one or more ofthe following additional conditions:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl and (C 3 . 10 )cycloalkyl.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and (C,_ 10 )alkyl. More preferably, R 1 and R 2 are independently selected from the group consisting of (C,., 0 )alkyl. Still more preferably, R 1 and R 2 are independently selected from the group consisting of (C ⁇ . 7 )alkyl. Still more preferably, R 1 and R 2 are independently selected from the group consisting of (C 2 . 4 )alkyl. Still more preferably, R 1 and R 2 are the same (C 2 . 4 )alkyl. Still more preferably, R 1 and R 2 are each n-butyl; and/or
  • R 3 and R 4 are independently selected from the group consisting of hydrogen and -OR 9 wherein R 9 is defined as previously set forth above for the compounds of Formula I.
  • R 3 is hydrogen and R 4 is -OR 9
  • R 3 is hydrogen and R 4 is hydroxy.
  • the hydroxy group is in a syn relationship to the structure of Formula II; and/or
  • R 5 is phenyl substituted with a radical selected from the group consisting of -OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 14 R 15 , - NR 13 CO 2 R 14 , -OC(O)R 13 , -OC(O)NR 13 R 14 , -NR 13 SOR 14 , -NR 13 SO 2 R 14 , - NR 13 SONR 1 R 15 , and -NR 13 SO 2 NR 1 R 15 wherein R 13 , R 14 and R 15 are as previously set forth above for the compounds of Formula I.
  • R 5 is phenyl substituted with -OR 13 or -NR 13 C(O)R 14 . Still more preferably, R 5 is phenyl substituted at the para or meta position with -OR 13 wherein R 13 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl, or R 5 is phenyl substituted at the para or meta position with -NR 13 C(O)R 14 wherein R 13 is hydrogen and R 14 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl; and/or
  • R 6 is hydrogen
  • R N is selected from the group consisting of hydrogen, alkyl and aralkyl.
  • R N is selected from the group consisting of hydrogen, (C 0 )alkyl and aryl(C 1 . 10 )alkyl. More preferably, R N is selected from the group consisting of hydrogen, methyl, ethyl and benzyl. Still more preferably, R N is hydrogen; and/or
  • R x is independently selected from the group consisting of -OR 13 , - NR 13 R 14 , -N + R 13 R 14 R ,5 A ⁇ and polyether. More preferably, R x is selected from the group consisting of -OR 13 and -NR 13 R 14 . Still more preferably, R x is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, R x is selected from the group consisting of methoxy and dimethylamino; and or
  • R x are present at the 7-, 8- or 9-position ofthe benzo ring ofthe structure of Formula I.
  • said R" are present at the 7- and 9-positions ofthe benzo ring ofthe structure of Formula I.
  • R x is present at the 7-position ofthe benzo ring ofthe structure of Formula I; and/or
  • q is 1, 2 or 3.
  • q is 1 or 2, and more preferably q is 1; and/or
  • the compounds of Formula I satisfy at least one or more ofthe above-described conditions and R 5 comprises a carbohydrate residue.
  • a more preferred class of compounds comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or
  • R 1 and R 2 taken together with the carbon to which they are attached form C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9 R 10 ; -
  • R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR ,9" N N ++ RR 99 RR 1100 AA __.. __ ss __.. _ so _. _ s ⁇ 2 _.
  • R , R , and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A " is a pharmaceutically acceptable anion; and
  • R and R are independently selected from the group consisting of
  • 7 optionally may have one or more carbons replaced by -O-; -NR -; -
  • R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R 13 and R 14
  • R 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R 11 , R 12 , R w , and A " are as defined above; and
  • R is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; and aralkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; pojyether; acyloxy; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R 13 ; - S(O)2R 13 ; -SO3R 13 ; -S + R 13 R 14 A-; -NR 13 OR 14 ; -NR 13 NR 14 R 15 ; -
  • R x radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR 13 -; -N + R 13 R 14 A -; -S-; -SO-; -SO2-; -S + R 13 A " -; -PR 13 -; -P(O)R 13 -; -PR 13 -; -P + R 13 R 1 A " -; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and
  • polyalkyl optionally may have one or more carbons replaced by -O-; -NR -;
  • R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R 18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals
  • a class of compounds of interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen; (C,-C 10 )alkyl; (C 3 -C 10 )cycloalkyl; (C 2 -C 10 )alkenyl; (C 2 -
  • R , R , and R w are independently selected from the group consisting of hydrogen; (C r C 10 )alkyl; (C 3 -C 10 )cycloalkyl; (C 2 -C 10 )alkenyl; (C 2 -C 10 )alkynyl; aryl; heterocyclyl; ammonium(C 1 -C 10 )alkyl; (C r C ⁇ o)alkylammonium(C 1 -C 10 )alkyl; aryl(C !
  • R and R are independently selected from the group consisting of hydrogen; (C,-C 10 )alkyl; (C 2 -C )0 )alkenyl; (C 2 -C 10 )alkynyl; aryl; heterocyclyl; -OR 9 ; -NR 9 R 10 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -SO3R 9 ; or
  • R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; (C,-C 10 )alkyl; (C 2 -C 10 )alkenyl; (C 2 -C 10 )alkynyl; aryl; heterocyclyl; aryl(C,-C 10 )alkyl; carboxy(C r C 10 )alkyl; carbo(C 1 -C 10 )alkoxy(C 1 -C 10 )alkyl; (C 3 -C 10 )cycloalkyl; cyano(C,-C 10 )alkyl; - OR 9 ; -NR 9 R 10 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; -SO3R 9 ; -CO2R 9 ; and - CONR 9 R 10 ; or i i 1
  • R and R together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R 10 are as defined above; and
  • R and R are independently selected from the group consisting of hydrogen; (C r C 10 )alkyl; (C 3 -C 10 )cycloalkyl; (C 2 -C, 0 )alkenyl; (C 2 -
  • R 5 and R 6 (C,-C ⁇ 0 )alkyl; (C 3 -C 10 )cycloalkyl; (C 2 -
  • C 10 )alkenyl; (C 2 -C I0 )alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; (C,-C 10 )alkyl; polyalkyl; halo(C,-C 10 )alkyl; (C 3 -C 10 )cycloalkyl; (C 2 - C 10 )alkenyl; (C 2 -C 10 )alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C 10 )alkyl; heterocyclyl(C r C 10 )alkyl; polyether; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R 13 ; -SO2R 13 ; -SO3R
  • 7 + 7 8 may have one or more carbons replaced by -O-; -NR -; -N R R A " -; -S-; -
  • R 7 and R 8 are independently selected from the group consisting of hydrogen and (C r C 10 )alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C,-C 10 )alkyl; halo(C,-C 10 )alkyl; (C 3 -
  • C 10 cycloalkyl; polyalkyl; (C 2 -C 10 )alkenyl; (C 2 -C 10 )alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -C 10 )alkyl; heterocyclyl(C r
  • C 10 alkyl
  • quaternary heterocyclyl(C r C 10 )alkyl quaternary heterocyclyl(C r C 10 )alkyl; (C 1 -C 10 )alkylaryl(C 1 - C 10 )alkyl; (C 1 -C 10 )alkylheterocyclyl(C I -C I0 )alkyl; (C r
  • C 10 alkylaminocarbonyl(C r C I0 )alkyl
  • polyether radicals optionally may have one or more carbons replaced by -O-; -NR 9 -; -N R R A'-; -S-; -SO-; -SO 2 -; -S + R 9 A -; -PR 9 -; -P + R 9 R 10 A " -; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and
  • R and R are independently selected from the group
  • R is selected from the group consisting of hydrogen; (C r C 10 )alkyl; (C 2 -C 10 )alkenyl; (C 2 -C, 0 )alkynyl; and aryl(C,-C 10 )alkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; (C r C 10 )alkyl; (C 3 - C 10 )cycloalkyl; polyalkyl; halo(C r C 10 )alkyl; (C 2 -C 10 )alkenyl; (C 2 - C 10 )alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -C 10 )alkyl; polyether; acyloxy; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R 13 ; -S
  • R 1 is selected from the group consisting of (C,-C 10 )alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C r C 10 )alkyl; acyl; and aryl(C r
  • R 18 (C r C 10 )alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C r C 10 )alkyl; acyl; and aryl(C r C 10 )alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR 9 ; -NR 9 R 10 ; -N ⁇ R 1 ⁇ A " ; -SR 9 ;
  • a class of compounds of particular interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or
  • R 1 and R 2 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R and R are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and
  • R and R 6 are independently selected from the group consisting of hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethy
  • R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more R x radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfmyl, methylsulfonyl, ethylthio, ethylsulfmyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylamrnonium, triethylammonium, N-methyl-
  • a class of compounds of specific interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and (C r C 10 )alkyl; or
  • R 1 and R 2 taken together with the carbon to which they are attached form (C 3 -C 10 )cycloalkyl
  • R and R are independently selected from the group consisting of hydrogen and hydroxy
  • R is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen; hydroxy; -N ⁇ 2; (C,-C 10 )alkyl; halo(C,-C, 0 )alkyl; aryl(C,-C I0 )alkyl; heterocyclyl(C,-C 10 )alkyl; polyether; -OR 13 ; -NR 13 R 14 ; and -NR 13 C(O)R 14 ; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C r C 10 )alkyl; halo(C,-C 10 )alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C r C 10 )alkyl; heterocyclyl(C r C 10 )alkyl; quaternary heterocyclyl(C ,-Cj 0 )alkyl
  • R and R are independently selected from the group consisting of hydrogen; (C r C ⁇ 0 )alkyl; heterocyclyl; ammonium(C r
  • C 10 alkyl; (C 1 -C ⁇ o)alkylammonium(C 1 -C 10 )alkyl; aryl(C 1 -C 10 )alkyl; heterocyclyl(C r C 10 )alkyl; carboxy(C r C 10 )alkyl; carbo(C ] -C 10 )alkoxy(C 1 -
  • R 11 and R 12 are independently selected from the group consisting of hydrogen; (C r C 10 )alkyl; heterocyclyl; aryl(C,-C 10 )alkyl; carboxy(C r C 10 )alkyl; and carbo(C 1 -C ⁇ 0 )alkoxy(C 1 -C 10 )alkyl; or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R and R 16 are as previously set forth above for the compounds of Formula I;
  • R 6 is hydrogen; and R R iiss sseelleecctteedd frfroorm the group consisting of hydrogen; (C 1 -C 10 )alkyl; and aryl(C r C 10 )alkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; -NO2; (C C ⁇ 0 )alkyl; halo(C,-C 10 )alkyl; -OR 13 ; - NR 13 R 14 ; wherein R 13 and R 14 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen
  • R and R taken together with the carbon to which they are attached form cyclopentyl; and one of R and R is hydrogen and the other of R and R is hydroxy;
  • R is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophen
  • R is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more R x radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl- amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a subclass of compounds of high interest comprises those compounds of Formula I wherein: wherein: q is 1 or 2;
  • R 1 and R 2 are each independently alkyl
  • R is hydroxy; R and R are hydrogen;
  • R 5 has the formula (II):
  • t is an integer from 0 to 5; one or more R ⁇ are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R ; - SR 13 ; -S(O)R 13 ; -SO2R 13 ; -SO3R 13 ; -NR 13 OR 14 ; -NR 13 NR 14 R 15 ; - CO2R 13 ; -OM; -SO2OM; -SO2NR 13 R 14 ; -C(O)NR 13 R 14 ; -C(O)OM; - COR 13 ; -NR 13 C(O)R 14 ; -C
  • R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxy
  • R 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R", R 12 , R , and A " are as previously set forth above for the compounds of Formula I; and
  • R is selected from the group consisting of hydrogen; alkyl; and aralkyl; and one or more R radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a family of specific compounds of particular interest within Formula I consists ofthe following compounds:
  • the invention further comprises a compound selected from among:
  • R 19 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue; and wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optionally may have one or more carbon atoms replaced by -O-, -NR 7 -, -N + R 7 R 8 A ' -, -S-, -SO-, -SO 2 -, -S + R 7 N-, - PR 7 -, -PR 7 R 8 A " -, phenylene, heterocyclyl, quaternary heterocyclyl, or aryl; wherein alkane diyl
  • R 19 can further comprise functional linkages by which R 19 is bonded to R 20 and/or R 21 in the compounds of Formula DI; to R 20 , R 21 and/or R 22 in the compounds of Formula DII; and to R 20 , R 21 , R 22 and or R 23 in the compounds of Formula Dili; and wherein each of R 20 , R 21 , or R 22 and R 23 comprises a benzothiazepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
  • R 19 substituents include, but are not limited to, the following:
  • R 25 is selected from the group consisting of carbon and nitrogen; and R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , and R 37 are independently selected from the group consisting of: -CH .
  • R 38 , R 39 , R 40 and R 41 are independently selected from the group consisting of alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl;
  • a " is a pharmaceutically acceptable anion; and h, i, j and k are independently selected from the group consisting of integers from 1 to 10 inclusive.
  • the invention is also directed to a compound selected from among Formula DI, Formula DII and Formula Dili in which each of R 20 , R 21 , R 22 and R 23 comprises a benzothiazepine moiety corresponding to the Formula DIV or Formula DIVA:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N , R ⁇ q, and n are as previously defined above for the compounds of Formula I, and R 55 is either a covalent bond or arylene.
  • R 20 , R 21 , R 22 , and R 23 in Formulae DI, DII and Dili be bonded at its 7- or 8- position to R 19 .
  • R 55 comprise a phenylene moiety bonded at a m- or j9-carbon thereof to R 19 .
  • Formula DI examples include:
  • R 1A , R 2A , R 3A , R 4A , R NA , R yA , R , r and u have the same definitions as stated above for R 1 , R 2 , R 3 , R 4 , R NA , R y , R x , q and t, respectively.
  • R 1 and R 2 can be, among other combinations, ethyl/butyl or butyl/butyl.
  • Illustrative dimeric compounds include the following:
  • a core moiety backbone, R 19 as discussed herein in Formulae DI, DII and Dili can be multiply substituted with more than four pendant active benzothiazepine units, i.e., R 20 , R 21 , R 22 , and R 23 as discussed above, through multiple functional groups within the core moiety backbone.
  • the core moiety backbone unit, R 19 can comprise a single core moiety unit, multimers thereof, and multimeric mixtures ofthe different core moiety units discussed herein, i.e., alone or in combination.
  • the number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25.
  • the number of points of attachment of similar or different pendant active benzothiazepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25.
  • Such points of attachment can include bonds to C, S, O, N, or P within any ofthe groups encompassed by the definition of R 19 .
  • the more preferred benzothiazepine moieties comprising R 20 , R 21 , R 22 and/or R 23 conform to the preferred structures as outlined above for Formula I.
  • the 3 -position carbon on each benzothiazepine moiety can be achiral, and the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R x can be selected from the prefened groups and combinations of substituents as discussed above.
  • the core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).
  • the present invention provides a pharmaceutical composition for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.
  • a bile acid transport inhibitor such as a hyperlipidemic condition, for example, atherosclerosis.
  • Such compositions comprise any ofthe compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, alone or in a composition comprising, for example, one or more pharmaceutically acceptable carriers, excipients, and/or diluents.
  • the benzothiazepine compounds of the present invention can be used alone or in various combinations.
  • the present invention also provides a method of treating a disease, condition and/or disorder in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound ofthe present invention in an effective amount in unit dosage form or in divided doses.
  • the present invention comprises the use ofthe compounds of Formula I and/or the dimeric or multimeric compounds of Formulae DI, DII and/or Dili in the preparation of a medicament useful for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated.
  • the compounds of Formula I are also useful for the prophylaxis and/or treatment of gallstones.
  • the present invention also provides processes for the preparation of compounds ofthe present invention.
  • hydrocarbyl refers to radicals consisting exclusively ofthe elements carbon and hydrogen. These radicals include, for example, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties. These radicals also include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
  • substituted hydrocarbyl refers to a hydrocarbyl radical that is substituted with a group comprising at least one atom other than carbon, such as but not limited to, halogen, oxygen, nitrogen, sulfur and phosphorus.
  • substituted hydrocarbyl include hydrocarbyl radicals substituted with groups such as, but not limited to, lower alkoxy such as methoxy, ethoxy, and butoxy; halogen such as chloro and fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl and thienyl; alkanoxy; . hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.
  • Substituted hydrocarbyl also includes hydrocarbyl radicals in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or a halogen.
  • alkyl is used, either alone or within other terms such as “haloalkyl", and “hydroxyalkyl”, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More prefened alkyl radicals are "lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso- amyl, hexyl and the like. Even more prefened are lower alkyl radicals having one to three carbon atoms.
  • alkenyl is used, either alone or within other terms such as “arylalkenyl”, it embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More prefened alkenyl radicals are "lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl.
  • alkenyl and lower alkenyl embrace radicals having “cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More prefened alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms. Most prefened are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More prefened cycloalkyl radicals are
  • lower cycloalkyl radicals having three to about ten carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring ofthe benzothiazepine.
  • cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl". More prefened cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about ten carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • halo and halogen means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having one to six carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • "Perfluoroalkyl” means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More prefened hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more prefened are lower hydroxyalkyl radicals having one to three carbon atoms.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and anthracenyl. More prefened aryl is phenyl.
  • Said "aryl” group may have one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Prefened heterocyclyl are 3-10 membered ring heterocyclyl, particularly 5-8 membered ring heterocyclyl.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocychc groups containing 1 to 4 nitrogen atoms [e.g. pynolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclyl saturated 3 to 6-membered heteromonocychc groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • unsaturated heterocyclic radicals include unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pynolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H- 1,2,3 -triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridaziny
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said "heterocyclyl” group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.
  • Heterocyclic radicals can include fused or unfused radicals, particularly 3-10 membered fused or unfused radicals.
  • Prefened examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl, and pyrazinyl.
  • More prefened heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
  • heteroaryl means a fully unsaturated heterocyclyl
  • heterocyclyl or "heteroaryl”
  • the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
  • trimazolyl includes all positional isomers. In all other heterocyclyl and heteroaryl which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocyclyl and heteroaryl.
  • quaternary heterocyclyl means a heterocyclyl in which one or more ofthe heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures).
  • the point of attachment ofthe quaternary heterocyclyl to the molecule of interest can be at a heteroatom or elsewhere.
  • quaternary heteroaryl means a heteroaryl in which one or more ofthe heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures).
  • the point of attachment ofthe quaternary heteroaryl to the molecule of interest can be at a heteroatom or elsewhere.
  • diyl means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.
  • oxo means a doubly bonded oxygen.
  • polyalkyl means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
  • polyether means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
  • polyalkoxy means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
  • carbohydrate residue encompasses residues derived from carbohydrates such as, but is not limited to, mono-, di-, tri-, tetra- and polysaccharides wherein the polysaccharides can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan residue; compounds derived from aldoses and ketoses with 3 to 7 carbon atoms and which belong to the D- or L-series; aminosugars; sugar alcohols; and saccharic acids.
  • Nonlimiting specific examples of such carbohydrates include glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannoic acid, glucamine, 3-amino-l,2- propanediol, glucaric acid and galactaric acid.
  • peptide residue means polyamino acid residue containing up to about 100 amino acid units.
  • polypeptide residue means a polyamino acid residue containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, and most preferably from about 100 amino acid units to about 500 amino acid units.
  • alkylammoniumalkyl means an an -NH 2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
  • sulfo means a sulfo group, -SO 3 H, and its salts.
  • sulfoalkyl means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more prefened are lower aralkyl radicals having phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • arylalkenyl embraces aryl-substituted alkenyl radicals.
  • Preferable arylalkenyl radicals are "lower arylalkenyl” radicals having aryl radicals attached to alkenyl radicals having
  • heterocyclylalkyl means an alkyl radical that is substituted with one or more heterocyclyl groups.
  • Preferable heterocyclylalkyl radicals are "lower heterocyclylalkyl” radicals having one or more heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms.
  • heteroarylalkyl means an alkyl radical that is substituted with one or more heteroaryl groups.
  • Preferable heteroarylalkyl radicals are "lower heteroarylalkyl” radicals having one or more heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
  • quaternary heterocyclylalkyl means an alkyl radical that is substituted with one or more quaternary heterocyclyl groups.
  • Preferable quaternary heterocyclylalkyl radicals are "lower quaternary heterocyclylalkyl” radicals having one or more quaternary heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms.
  • quaternary heteroarylalkyl means an alkyl radical that is substituted with one or more quaternary heteroaryl groups.
  • Preferable quaternary heteroarylalkyl radicals are "lower quaternary heteroarylalkyl” radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
  • alkylheteroarylalkyl means a heteroarylalkyl radical that is substituted with one or more alkyl groups.
  • Preferable alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl” radicals with alkyl portions having one to ten carbon atoms.
  • alkoxy means an alkyl radical which is attached to the molecule of interest by oxygen, such as a methoxy radical. More prefened alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.
  • carboxy means the carboxy group, -CO 2 H, or its salts.
  • carboxyalkyl means an alkyl radical that is substituted with one or more carboxy groups.
  • Preferable carboxyalkyl radicals are "lower carboxyalkyl” radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms.
  • carboxyheterocyclyl means a heterocyclyl radical that is substituted with one or more carboxy groups.
  • carboxyheteroaryl means a heteroaryl radical that is substituted with one or more carboxy groups.
  • carboalkoxyalkyl means an alkyl radical that is substituted with one or more alkoxycarbonyl groups.
  • Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl” radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.
  • Carboxyalkylamino means an amino radical that is mono- or di-substituted When used in combination, for example “alkylaryl” or “arylalkyl,” the individual terms listed above have the meaning indicated above.
  • a bile acid transport inhibitor means a compound capable of inhibiting abso ⁇ tion of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol.
  • Conditions and/or diseases that benefit from the prophylaxis and/or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
  • THF tetrahydrofuran
  • PTC phase transfer catalyst
  • Aliquart 336 means methyltricaprylylammonium chloride
  • MCPBA means m-chloroperbenzoic acid
  • Celite refers to a brand of diatomaceous earth filtering aid
  • DMF means dimethylformamide
  • DME ethylene glycol dimethyl ether
  • Me means methyl
  • Et means ethyl
  • EtOAc means ethyl acetate
  • Et 2 O means diethyl ether
  • LAH lithium aluminum hydride
  • DMSO dimethylsulfoxide
  • KOSiMe 3 means potassium trimethylsilanolate
  • PEG polyethylene glycol
  • MS mass spectrometry
  • HRMS high resolution mass spectrometry
  • ES electrospray
  • MPLC medium pressure liquid chromatography
  • HPLC high pressure liquid chromatography
  • RPHPLC reverse phase high pressure liquid chromatography
  • RT room temperature
  • the compounds ofthe present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture.
  • stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds ofthe present invention.
  • Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds ofthe present invention.
  • the compounds ofthe present invention also include tautomers, salts, solvates and prodrugs of such compounds.
  • the starting materials for use in the preparation ofthe compounds of the invention are commercially available or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
  • the compounds ofthe present invention can be prepared by the procedures described below.
  • Scheme 1 illustrates the preparation of racemic benzothiazepines 9a and 9b.
  • Reaction of benzenesulfonyl chloride 1 with aminoalcohol 2 in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran yields benzenesulfonamide 3 which can be converted to protected benzenesulfonamide 4.
  • Protected benzenesulfonamide 4 optionally can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N- substituted benzenesulfonamide 5.
  • Protected benzenesulfonamide 4 or N- substituted benzenesulfonamide 5 is then successively reacted with (i) a strong base (such as n-butyllithium in hexanes) in a solvent (such as tetrahydrofuran), (ii) an electrophile (such as trimethyl borate), and (iii) a base (such as sodium carbonate), a benzyl halide (such as p-methoxybenzyl chloride), and a catalyst (such as tetrakis(triphenylphosphine)palladium(0)) to yield sulfonamide 6.
  • a strong base such as n-butyllithium in hexanes
  • a solvent such as tetrahydrofuran
  • an electrophile such as trimethyl borate
  • a base such as sodium carbonate
  • a benzyl halide such as p-methoxybenzyl chloride
  • sulfonamide 6 Treatment of sulfonamide 6 with a fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, provides the deprotected sulfonamide alcohol 7.
  • Sulfonamide alcohol 7 is successively oxidized using a method such as Swem Oxidation to yield sulfonamide aldehyde 8.
  • aldehyde 8 is converted to racemic benzothiazepines 9a and 9b.
  • R 1 , R 2 , R 5 , R N , R x and q are as previously defined above for compounds of Formula I.
  • Scheme 2 illustrates an alternative synthetic scheme for the preparation of sulfonamide alcohol 3 used in Scheme 1.
  • Substituent L of benzenesulfonyl chloride 10 is a suitable leaving group such as fluoro, chloro, bromo, nitro, tosyloxy or trifluoromethylsulfonyloxy.
  • Scheme 3 illustrates the preparation of benzothiazepines having 4- position substituents other than hydroxy.
  • benzothiazepine 9a or 9b is first oxidized to benzothiazepine-4-one 13.
  • Conventional oxidizing agents such as PCC, or Swem conditions can be used.
  • Benzothiazepine-4-one 13 is then reacted with Lawesson's Reagent to produce 4-thioxo-benzothiazepine 14.
  • 4-Thioxo- benzothiazepine 14 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-mercapto-benzothiazepine 15.
  • 4-Mercapto-benzothiazepine 15 can be reacted with a suitable alkylating agent, such as an alkyl halide, in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, to yield 4-alkylthio-benzothiazepine 16.
  • 4-Alkylthio- benzothiazepine 16 can be reacted with a suitable oxidizing agent, such as t- butyl hydroperoxide or m-chloroperbenzoic acid, to yield, successively, 4- alkylsulfinyl-benzothiepine 17 and 4-alkylsulfonyl-benzothiazepine 18.
  • a suitable oxidizing agent such as t- butyl hydroperoxide or m-chloroperbenzoic acid
  • 4-amino- or imino-benzothiazepines can be prepared by reacting benzothiazepine-4-one 13 with ammonia or a primary amine in a suitable solvent, such as tetrahydrofuran, to produce 4-imino-benzothiazepine 19.
  • 4-Imino-benzothiazepine 19 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-amino-benzothiazepine 20.
  • Benzothiazepine-4-one 13 also can undergo reductive alkylation by reaction with ammonia, a primary amine or a secondary amine in the presence of an reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as tetrahydrofuran, to produce 4-amino-benzothiazepine 21.
  • an reducing agent such as sodium triacetoxyborohydride
  • a suitable solvent such as tetrahydrofuran
  • Scheme 3 also illustrates the preparation of 4-alkyl-benzothiazepine 23 and 4-alkoxycarbonyl-benzothiazepine 25.
  • the 4-position hydroxy of benzothiazepine 9a or 9b is first converted to a suitable leaving group such as mesyloxy to form protected benzothiazepine 22.
  • Protected benzothiazepine 22 is then reacted with a suitable nucleophile, such as butyl lithium, in a suitable solvent, such as tetrahydrofuran, to yield 4-alkyl-benzothiazepine 23.
  • protected benzothiazepine 22 can be reacted with a suitable cyanidating agent, such as an potassium cyanide, in a suitable solvent, such as dimethylformarnide, to yield 4-cyano-benzothiazepine 24.
  • a suitable cyanidating agent such as an potassium cyanide
  • a suitable solvent such as dimethylformarnide
  • 4-cyano-benzothiazepine 24 4-Cyano- benzothiazepine 24 is converted to 4-alkoxycarbonyl-benzothiazepine 25 by reaction with a suitable alcohol in the presence of a base, such as potassium hydroxide.
  • Scheme 4 illustrates the preparation of benzothiazepine-4-ene 36 and benzothiazepine-4-one 33.
  • Reaction of phenol 26 with a thiocarbamyl chloride, such as dimethylthiocarbamyl chloride, in a solvent, such as methanol-.tetrahydrofuran yields 0-thiocarbamate 27.
  • Heating of O- thiocarbamate 27 in a solvent, such as tetradecane yields S-thiocarbamate 28.
  • Hydrolysis of S-thiocarbamate 28 in the presence of a base, such as sodium hydroxide, in a solvent, such as methanohtetrahydrofuran yields thiophenol 29.
  • Thiophenol 29 can be treated with a sulfonylating agent, such as sulfonyl chloride, in the presence of a oxidant such as potassium nitrate, in a solvent, such as tetrahydrofuran, to yield sulfonyl chloride 30.
  • a sulfonylating agent such as sulfonyl chloride
  • a solvent such as tetrahydrofuran
  • Sulfonyl chloride 30 is then reacted with an aminoalcohol in a solvent, such as tetrahydrofuran, to yield benzenesulfonamide 31.
  • Benzenesulfonamide 31 optionally can be hydroxyl protected with a silylating group agent, such as tert- butyldimethylsilyl chloride, in the presence of a base, such as imidazole, in a solvent, such as tetrahydrofuran, to yield protected benzenesulfonamide 32.
  • a silylating group agent such as tert- butyldimethylsilyl chloride
  • a base such as imidazole
  • a solvent such as tetrahydrofuran
  • N-substituted benzene sulfonamide 33 Deprotection ofthe protected N-substituted benzene sulfonamide 33 with a fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, yields N-substitued benzenesulfonamide 34.
  • Benzenesulfonamide 31 or N-substituted benzenesulfonamide 34 is then oxidized with a suitable oxidizing agent or under Swem conditions to form aldehyde 35.
  • aldehyde 35 Upon treatment with zinc and titanium trichloride aldehyde 35 is converted to a mixture of benzothiazepine-4-ene 36 and benzothiazepine-4-one 37.
  • Another class of compounds of specific interest comprises those compounds of Formula I wherein R 1 and R 2 are selected from among substituted and unsubstituted C,. 10 alkyl wherein substituted C,., 0 alkyl comprises one or more radicals independently selected from among, for example, alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocyclyl joined to the C ]0 alkyl through an ether linkage.
  • Ethyl, n-propyl, n-butyl, and isobutyl are prefened.
  • substituents R 1 and R 2 are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-position carbon. Eliminating optical isomerism at the 3-position carbon simplifies the selection, synthesis, separation, and quality control ofthe compound used as an ileal bile acid transport inhibitor.
  • substituents R on the benzo ring can include, for example, hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)- hydroxy-carbonylalkylamino, haloalkylthio, haloalkylsulfmyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)- alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)- alkylamido
  • the benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds.
  • substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring including, for example, guanidinyl, cycloalkyl, carbohydrate residue (e.g., a 5 or 6 carbon monosaccharide residue), peptide residue, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., -(OCH 2 CH 2 ) x -N+R 13 R 14 R 15 A ⁇ where x is 2 to 10.
  • poly(oxyalkylene) linkages e.g., -(OCH 2 CH 2 ) x -N+R 13 R 14 R 15 A ⁇ where x is 2 to 10.
  • R 5 and R 6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiopene, pyridine, pynole, thiazole, imidazole, pyrazole, pyrimidine, mo ⁇ holine, N-alkylpyridinium, N-alkylpiperazinium, N- alkylmo ⁇ holinium, or furan in which the substituent(s) are selected from among, for example, halo, hydroxyl, trihaloalkyl, alkoxy, amino, N- alkylamino, N,N-dialkylamino, quaternary ammonium salts, a to C alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene, -[O(CH 2 )
  • the species that may constitute the substituents on the aryl ring of R 5 or R 6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)- hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both ofthe aryl ring.
  • R 5 or R 6 is selected from phenyl, p-fluorophenyl, m- fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m- methoxyphenyl, p-N,N-dimethylaminophenyl, m-N, N-dimethylaminophenyl, I- p-(CH 3 ) 3 -N + -phenyl, I " m-(CH 3 ) 3 -N + -phenyl, T m-(CH 3 ) 3 -N + -CH 2 CH 2 -
  • Prefened compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each ofthe above prefened R 5 substituents in combination with the R x substituents shown in Tables 1 , 2 and 3 below. It is particularly prefened that one, but not both, of R 5 and R 6 is hydrogen.
  • R 4 and R 6 be hydrogen, that R 3 and R 5 not be hydrogen, and that R 3 and R 5 be oriented in the same direction relative to the plane ofthe molecule, i.e., both in a- or both in ⁇ -configuration. It is further prefened that, where R 2 is butyl and R 1 is ethyl, then R 1 has the same orientation relative to the plane ofthe molecule as R 3 and R 5 .
  • a class of compounds of particular interest comprises those 1,2- benzothiazepines wherein the R 1 , R 2 , R 3 , R 4 and R 5 radicals are as set forth in Table 1 below; the R 6 radical is hydrogen; the R N radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl and benzyl; and the R x radical or radicals are independently selected from the group of R radicals disclosed in Table 1 below.
  • the first part of Table 1 identifies the R 1 , R 2 , R 3 , R 4 and R 5 radicals for each compound and the second part of Table 1 identifies the R x radical or radicals for those compounds.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N and R x radicals are selected from among the radicals disclosed in Table 2 below.
  • R 6 is hydrogen and R 5 is other than hydrogen; and/or R 3 is hydroxy and R 4 is hydrogen; and/or R 1 and R 2 are alkyl. More preferably, R 1 and R 2 are the same.
  • R 1 , R 2 , R 3 , R 4 and R 5 radicals are as set forth in Table 3 below;
  • R 6 is hydrogen;
  • the R N radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl;
  • the R x radical or radicals are independently selected from the group of R x radicals disclosed in Table 2 above.
  • q is 1 and R x is 7-dimethylamino. ⁇ / ⁇
  • R 1 and R 2 are alkyl, preferably n-butyl; R 3 is hydroxy; R 4 and R 6 are hydrogen; R N is hydrogen; R x radicals are selected from the group consisting of amino, dimethylamino and methoxy; and R 5 is phenyl substituted at the para or meta position with one ofthe following groups:
  • M is selected from the group consisting of Co 11 , Co 111 , Mn 11 , Mn 111 , Fe 11 , Fe 111 , Ni ⁇ , Ni 111 , Cr 111 , Cu ⁇ , Zn 11 , Cd 11 , Ga ⁇ , In 111 , V IV , Ru 11 , Pt IV , Rh m and Ir 1 ".
  • the ileal bile acid transport inhibitor compounds ofthe present invention can be administered for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders by any means, preferably oral, that contacts these compounds with their site of action in the body, for example in the ileum of a mammal such as a human.
  • the compounds ofthe present invention can be used as the compound er se.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • Such salts comprise a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable acid addition salts ofthe compounds ofthe present invention where appropriate include those salts derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • the chloride salt is particularly preferred for medical purposes.
  • Suitable pharmaceutically acceptable base salts where appropriate include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.
  • the anions ofthe definition of A " in the present invention are pharmaceutically acceptable anions such as those anions selected, for example, from the above list.
  • the compounds ofthe present invention also can be administered in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising additional ingredients such as acceptable carriers, diluents, excipients, adjuvants and the like (collectively referred to herein as "carrier materials").
  • Acceptable carrier materials are compatible with the other ingredients ofthe composition and are not deleterious to the recipient.
  • a carrier material can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet or capsule, which can contain from 0.05% to 95% by weight ofthe active compound.
  • Other pharmacologically active substances can also be present, including other compounds ofthe present invention.
  • the pharmaceutical compositions ofthe invention can be prepared by any ofthe well known techniques of pharmacy, consisting essentially of admixing the components.
  • These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as an individual therapeutic compound in a monotherapeutic regimen or as a combination of therapeutic compounds in a combination therapy regimen.
  • the amount of compound that is required to achieve the desired biological effect will depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition ofthe recipient.
  • a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, and more preferably from about 3 to about 10 mg/kg bodyweight/day.
  • This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses.
  • Subdoses can be administered 2 to 6 times per day.
  • Doses can be in sustained release form effective to obtain desired results.
  • Orally administrable unit dose formulations such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiazepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound.
  • the weights indicated above refer to the weight ofthe benzothiazepine ion derived from the salt.
  • Oral delivery of an ileal bile acid transport inhibitor ofthe present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery ofthe drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH ofthe small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties ofthe formulation, bioadhesion ofthe dosage form to the mucosal lining ofthe intestinal tract, or enzymatic release ofthe active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation ofthe dosage form.
  • enteric-coated and enteric-coated controlled release formulations are within the scope ofthe present invention.
  • Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
  • the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, and more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight.
  • This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute.
  • Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, and preferably from about 1 ng to about 10 mg per milliliter.
  • Unit doses can contain, for example, from about 1 mg to about 10 g ofthe compound ofthe present invention.
  • ampoules for injection can contain, for example, from about 1 mg to about 100 mg.
  • compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity ofthe condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.
  • compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound ofthe present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier material (which can constitute one or more accessory ingredients).
  • compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier material, or both, and then, if necessary, shaping the product.
  • a tablet can be prepared by compressing or molding a powder or granules ofthe compound, optionally with one or more assessory ingredients.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
  • compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound ofthe present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound ofthe present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.
  • compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound ofthe present invention with one or more conventional solid carrier materials, for example, cocoa butter, and then shaping the resulting mixture.
  • compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carrier materials that can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound is generally present at a concentration of from 0.1 to 15% w/w ofthe composition, for example, from 0.5 to 2%.
  • compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain a compound ofthe present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer.
  • a suitable concentration ofthe active compound is about 1% to 35%, preferably about 3% to 15%.
  • the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research. 3(6), 318 (1986).
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
  • the solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds ofthe present invention admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions encompass all the foregoing and the like.
  • the dosage regimen to prevent, give relief from, or ameliorate a disease, condition and/or disorder relating to hyperlipemia, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions ofthe present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition ofthe patient, the severity ofthe disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles ofthe particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
  • Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated.
  • Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any ofthe methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification ofthe treatment regimen during therapy so that optimal effective amounts of compounds ofthe present invention are administered at any point in time, and so that the duration of treatment can be determined as well.
  • the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor ofthe present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
  • the reaction mixture was stirred for one hour and warmed to room temperature.
  • the resulting slurry was filtered and washed with 100 mL ethyl acetate.
  • the ethyl acetate solution was washed with water (2x200 mL) and then brine (300 mL).
  • the ethyl acetate layer was dried over magnesium sulfate and concentrated.
  • the resulting yellow oil was dissolved in 300 mL of tetrahydrofuran and concentrated to give 20.61 g of 2-amino-2-butylhexanol as an oil.
  • Step 4 N-[ 1 -Butyl- 1 -[[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]- 4-(dimethylamino)benzenesulfonamide
  • Step 8 N-[l-Butyl-l-(hydroxymethyl) ⁇ entyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide
  • Step 9 N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N-methylbenzenesulfonamide.
  • Step 10 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl- 5-(3-nitrophenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
  • the reaction mixture was stirred for 15 minutes, water was added, and then the mixture was concentrated to yield a residue.
  • the residue was dissolved in 100 mL ethyl acetate.
  • the semi-solid material was crystallized from ethyl acetate and hexane to give 0.51 g of (4R,5R)-5-(3- aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide as colorless crystals.
  • Step 1 N-[ 1 -Butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide
  • Step 8 of Example 1 above was followed except that N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy] methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide.
  • Step 3 N-[ 1 -Butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]-N-methylbenzenesulfonamide
  • Step 9 of Example 1 above was followed except that N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N- [ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
  • Step 10 of Example 1 The procedure of Step 10 of Example 1 above was followed except that N-[ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N- [ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide.
  • Example 10 The procedure of Example 10 was followed except that triethylamine was used in place of pyridine and heating was at 90 °C for 6 hours.
  • 'H ⁇ MR is consistent with the desired product.
  • Step 8 of Example 1 The procedure of Step 8 of Example 1 was followed except that N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide.
  • Example 2 The procedure of Example 2 above was followed except that (4R,5R)- 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide.
  • ⁇ NMR was consistent with the product. MS (M + ) 460.
  • Example 3 The procedure of Example 3 above was followed except that (4R,5R)- 5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-5-(3- aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide.
  • ⁇ NMR was consistent with the product. MS (M+H + ) 623.
  • Step 1 N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2- (phenylmethyl)benzenesulfonamide
  • Steps 1-2 of Example 7 The procedure of Steps 1-2 of Example 7 was followed except that N- [ 1 -butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)benzenesulfonamide and benzyl chloride were used in place of N-[ 1 -butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-N-methylbenzenesulfonamide and /?-methoxybenzyl chloride.
  • Step 3 of Example 13 The procedure of Step 3 of Example 13 was followed except that N-[l- butyl- 1 -(hydroxymethyl)pentyl] -4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[l -butyl- l-(hydroxymethyl) pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
  • Butyl- 1 -formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[l -butyl- l-formylpentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzene- sulfonamide.
  • Step 1 of Example 7 The procedure of Step 1 of Example 7 was followed except that N-[l- butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)benzenesulfonamide was used in place of N-[l-butyl-l- [[[(1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N- methylb enzenesulfonamide.
  • Step 2 N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]benzenesulfonamide
  • Step 8 of Example 1 The procedure of Step 8 of Example 1 was followed except that N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl] pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzene- sulfonamide.
  • Step 3 of Example 13 The procedure of Step 3 of Example 13 was followed except that N-[l- butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
  • Step 10 of Example 1 The procedure of Step 10 of Example 1 was followed except that N-[l- butyl-l-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl] benzenesulfonamide was used in place of N-[ 1 -butyl- 1 -formylpentyl]-4-
  • Example 8 The procedure set forth in Example 8 above was followed except that (4R,5R)- 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide and a reaction temperature of 0 °C was employed.
  • Step 8 of Example 1 The procedure of Step 8 of Example 1 was followed except that N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-(phenylmethyl) benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
  • Step 3 N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
  • Step l N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N- (phenylmethyl)benzenesulfonamide
  • Step 3 N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
  • Step 3 of Example 13 The procedure of Step 3 of Example 13 was followed except that N-[l- butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide.
  • Step 10 of Example 1 The procedure of Step 10 of Example 1 was followed except that N-[l- butyl-l-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- (phenylmethyl)benzenesulfonamide was used in place of N-[l -butyl- 1- formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide.
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was followed except that cycloleucinol was substituted for 2-amino-2-butylhexanol.
  • Step 2-3 N-[ 1 -[[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)benzenesulfonamide
  • Steps 3 and 4 of Example 1 The procedure of Steps 3 and 4 of Example 1 was followed except that N-[l-(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide was used in place of N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide.
  • Step 4 N-[ 1 -[[[( 1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide
  • Step 1 of Example 7 The procedure of Step 1 of Example 7 was followed except that N-[l- [[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)benzenesulfonamide was used in place of N- [1 -butyl- 1- [[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N- methylbenzenesulfonamide.
  • Step 5 N-[ 1 -(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-ethylbenzenesulfonamide
  • Step 6-8 (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4- methoxyphenyl)-spiro[ 1 ,2-benzothiazepine-3 (2H), 1 ' -cyclopentan]-4-ol 1,1- dioxide
  • Baby hamster kidney cells (BHK) transfected with the cD ⁇ A of human IB AT (HI 4 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within 24 hours of seeding; 30,000 cells/well for assays run within 48 hours; and 10,000 cells/well for assays run within 72 hours. On the day of assay, the cell monolayer is gently washed once with
  • assay buffer Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2%o (w/v) fatty acid free bovine serum albumin ((FAF)BSA).
  • assay buffer Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2%o (w/v) fatty acid free bovine serum albumin ((FAF)BSA.
  • FAF fatty acid free bovine serum albumin
  • alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
  • Bile ducts are cannulated with a 10 " length of PEI 0 tubing.
  • the small intestine is exposed and laid out on a gauze pad.
  • a canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction ofthe small intestine and the cecum.
  • a slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum).
  • 20 mL of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment.
  • the distal opening is cannulated with a 20 cm length of silicone tubing (0.02" LD. x 0.037" O.D.).
  • the proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 minutes with warm PBS at 0.25 mL/minute. Temperature of the gut segment is monitored continuously.
  • 2.0 mL of control sample [ 1 C]-taurocholate @ 0.05 mi/mL with 5 mM cold taurocholate) is loaded into the gut segment with a 3 mL syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 mL/minute for 21 minutes.
  • Bile samples fractions are collected every three minutes for the first 27 minutes ofthe procedure. After the 21 minutes of sample infusion, the ileal loop is washed out with 20 mL of warm PBS (using a 30 mL syringe), and then the loop is washed out for 21 minutes with warm PBS at 0.25 mL/minute. A second perfusion is initiated as described above but with the test compound being administered as well (21 minutes administration followed by 21 minutes of wash out) and bile sampled every three minutes for the first 27 minutes. If necessary, a third perfusion is performed as above that typically contains the control sample. Measurement Of Hepatic Cholesterol Concentration (HEPATIC CHOP Liver tissue is weighed and homogenized in chloroform:methanol (2:1).
  • Hepatic HMG CoA-Reductase Activity HMG CO A Hepatic microsomes are prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C in the presence of 14 C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HCl followed by centrifugation.
  • Total serum cholesterol (SER.CHOL) is measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol Cl 1, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) is assayed using this same kit after precipitation of NLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) are assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. NLDL and LDL (VLDL + LDL) cholesterol concentrations are calculated as the difference between total and HDL cholesterol.
  • Hepatic Cholesterol 7- Hvdroxylase Activity 7 -OHase '
  • Hepatic microsomes are prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37° C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/ methanol.
  • the enzymatic product is separated by injecting an aliquot ofthe extract onto a C ]8 reversed phase HPLC column and quantitating the eluted material using UN detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).
  • Rat Gavage Assay Male Wister rats (275-300g) are administered IB AT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:00 a.m.) for four days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours ofthe treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison ofthe increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group. Table 5 describes the results of this assay when the compound of Example 4 was tested. Table 5
  • FBA fecal bile acid
  • Rabbit Ileal brush border membranes are prepared from frozen ileal mucosa by the calcium precipitation method described by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259).
  • the method for measuring taurocholate is essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume is 200 ⁇ L instead of 100 ⁇ L.
  • a 190 ⁇ L solution containing 2 ⁇ M [ 3 H]-taurocholate(0.75 ⁇ Ci), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 is incubated for 5 seconds with 10 ⁇ L of brush border membrane vesicles (60-120 ⁇ g protein).
  • the incubation is initiated by the addition ofthe BBMN while vortexing and the reaction is stopped by the addition of 5 mL of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 ⁇ m pore) and an additional 5 mL wash with stop buffer.
  • Acyl-CoA; cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes are prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme.
  • the assay consists of a 2.0 mL incubation containing 24 ⁇ M Oleoyl-CoA (0.05 ⁇ Ci) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 ⁇ g of microsomal protein. The assay is initiated by the addition of oleoyl-Co A.
  • the reaction proceeds for five minutes at 37° C and is terminated by the addition of 8.0 mL of chloro form/methanol (2:1).
  • 125 ⁇ g of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases ofthe extraction are separated by centrifugation after thorough vortexing.
  • the chloroform phase is taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1).
  • the amount of cholesterol ester formed is determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.
  • the examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

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Abstract

Novel 1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia.

Description

NOVEL 1,2-BENZOTHIAZEPINES HAVING ACTIVITY AS
INHIBITORS OF ILEAL BILE ACID TRANSPORT AND
TAUROCHOLATE UPTAKE
Field ofthe Invention
The present invention relates to novel 1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia, in mammals.
Description of Related Art
It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein ("LDL") cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen ofthe intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, "Interaction Of Bile Acids And Cholesterol With Nonsystemic Agents Having Hypocholesterolemic Properties," Biochimica et Biophvsica Acta, 1210 (1994) 255-287, discusses the biochemistry, physiology and known active agents relating to bile acids and cholesterol. Pathophysiologic alterations are shown to be consistent with interruption ofthe enterohepatic circulation of bile acids in humans in Heubi, J.E., et al., "Primary Bile Acid Malabsorption: Defective In Vitro Heal Active Bile Acid Transport", Gastroenterologv. 1982:83:804-11. In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation. Reihner, E. et al, in "Regulation of Hepatic Cholesterol Metabolism In Humans: Stimulatory Effects Of Cholestyramine On HMG-CoA Reductase Activity And Low Density Lipoprotein Receptor Expression In Gallstone Patients", Journal of Lipid Research. Volume 31, 1990, 2219-2226. This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation ofthe liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels. Suckling el al, "Cholesterol Lowering And Bile Acid Excretion In The Hamster With Cholestyramine Treatment", Atherosclerosis. 89(1991) 183-190), also discloses the results of cholestyramine treatment to lower serum cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption ofthe enterohepatic circulation with specific transport inhibitors. Kramer, et al, "Intestinal Bile Acid Absorption", The Journal of Biological Chemistry. Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993. In a series of patent applications, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents ofthe enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents. See, e.g., Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731.
In vitro bile acid transport inhibition is disclosed to show hypohpidemic activity in The Wellcome Foundation Limited disclosure ofthe world patent application number WO 93/16055 for "Hypohpidemic Benzothiepine Compounds".
Selected benzothiepines are disclosed in world patent application number WO93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Additional benzothiepines for use as hypohpidemic agents are disclosed in WO97/33882 and U.S. Patent 5,994,391.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring ofthe fused bicyclo benzothiepine ring.
WO96/16051 published May 30, 1996 describes certain 1,5- benzothiazepines as useful in the treatment of hyperlipidemic conditions. WO96/05188 published February 22, 1996 describes certain 1 ,4- benzothiazepines as useful in the treatment of hyperlipidemic conditions.
Additional benzothiazepines are discussed in the references set forth below. These references either do not disclose a specific utility or disclose a different utility than the present invention. Orahovats et al., "A Ring Enlargement From Seven- To Ten-
Membered-Ring Sulfonamide Derivatives", Helv. Chim. Acta. vol. 79, pp. 1121-1128 (1996) describes 4,5-dihydro-7,8-dimethoxy-l,2-benzothiazepine- 3 -one- 1,1 -dioxide.
Katrizky et al., "Preparation Of 6-, 7- and 8-Membered Sultams By Friedel-Crafts Cyclization Of δi-Phenylalkanesulfamoyl Chlorides", Org.
Prep. Proced. Int.. vol. 24(4), pp. 463-467 (1992) describes 2,3,4,5-tetrahydro- 1 ,2-benzothiazepine- 1 , 1 -dioxide and 2,3,4,5-tetrahydro-2 -butyl- 1 , 2- benzothiazepine- 1,1 -dioxide for possible use as an anticonvulsant, diuretic or sedative. Beckwith et al., "Iododediazoniation Of Arenediazonium Salts Accompanied By Aryl Radical Ring Closure", J. Org. Chem.. vol. 52, pp. 1922-1930 (1987) describes 2,3,4,5-tetrahydro-2-allyl-l,2-benzothiazepine- 1,1 -dioxide. Stassinopolou et al., "13C NMR Spectra Of Benzothiazepine,
Benzothiazone and Benzosulphonamide N-substituted Derivatives", Org. Magn. Reson.. vol. 21(3), pp. 187-189 (1983), describes certain N-substituted 4,5-dihydro-7,8-dimethoxy- 1 ,2-benzothiazepine-3-one- 1 , 1 -dioxides.
Tamura et al., "Novel Conversions Of Benzo[b]thiophen-3(2H)-ones Into 1,2-Benzisothiazole And Tetrahydro-l,2-benzothiazepin-5-One Systems Via Sulphimide Intermediates", J. Chem. Soc. Perkin Trans. I. vol. 12, pp. 2830-2834 (1980) describes 2,3,4,5-tetrahydro-2-tosyl-4-methyl-l,2- benzothiazepine-5-one- 1 , 1 -dioxide.
Catsoulacos et al., "Synthesis Of Some N-Substituted 4,5-Dihydro-7,8- dimethoxybenzothiazepin-3-one 1.1 -Dioxides. J. Hetero. Chem.. vol. 13(6), pp. 1309-1314 (1976) describes 4,5-dihydro-7,8-dimethoxy-l,2- benzothiazepine-3-one- 1,1 -dioxide and certain 4,5-dihydro-2-(phenyl, substituted phenyl or pyridyl)-7,8-dimethoxy-l,2-benzothiazepine-3-one-l,l- dioxides having anti-inflammatory and central nervous system activity. Pangiotopoulos et al., "N(p-Bromophenyl)-4,5-Dihydro-7,8-
Dimethoxy Benzothiazepine-3-One 1,1 -Dioxide C,7H16BrNO5S", Cryst. Struct. Comm.. vol. 9, pp. 313-320 (1980) describes 4,5-dihydro-2-(4-bromo- phenyl)-7,8-dimethoxy- 1 ,2-benzothiazepine-3-one- 1 , 1 -dioxide.
Catsoulacos et al., "Thiazo Compounds. Derivatives Of 4,5-Dihydro- 7,8-Dimethoxybenzothiazepin-3-one 11 -Dioxides", J. Chem. Eng. Data, vol. 22(3), pp. 353-354 (1977) describes 4,5-dihydro-2-(ethyl, n-propyl or isopropyl)-7, 8-dimethoxy- 1 ,2-benzothiazepine-3-one- 1 , 1 -dioxide.
Camoutsis et al., "N-Substituted 4,5-Dihydro-l,2-benzothiaepin-3-one 1,1-Dioxide", J. Hetero. Chem.. vol. 17(5), pp. 1135-1136 (1980) describes certain 4,5-dihydro-2-(3- or 5-pyridyl)-7,8-dimethoxy-l,2-benzothiazepine-3- one- 1,1 -dioxides.
U.S. Patent No. 5,350,761 describes hydroxylamine derivatives that generically encompass certain benzothiazepine compounds. These derivatives are described as lipoxygenase inhibitors useful in the treatment of inflammatory and allergic conditions.
WO98/02432 published January 22, 1998 describes certain 5-(aryl-(N- containing-heterocyclyl)alkyl)benzothiazepines and aralkyl-(N-containing- heterocyclyl)alkyl)-benzothiazepines as useful for controlling micturition. WO97/03953 published February 6, 1997 describes certain sulfonylamino-substituted benzothiazepines as inhibitors ofthe enzyme cyclooxygenase II.
WO95/21843 published August 17, 1995 describes certain benzothiazepines substituted with azacyclic condensed piperazines. These compounds are identified as kappa receptor agonists useful as analgesics and diuretics and for the treatment of cerebral ischaemia.
EP338331 published October 25, 1989 describes certain 2- benzothiazepine-5-ones useful as muscle relaxants.
Summary of the Invention A first aspect ofthe invention comprises novel 1,2- benzothiazepines that are effective agents for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
A second aspect ofthe invention comprises pharmaceutical compositions comprising the novel 1 ,2- benzothiazepines that are suitable for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
A third aspect ofthe invention comprises methods for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders comprising administering to a subject a prophylactically or therapeutically effective amount of one ofthe novel 1,2- benzothiazepines.
A fourth aspect ofthe invention comprises methods of making the novel 1,2-benzothiazepines ofthe present invention. Additional aspects ofthe invention are discussed throughout the specification of this application.
Detailed Description ofthe Invention
The following detailed description is provided to aid those skilled in the art in practicing the present invention. This detailed description, however, should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope ofthe present inventive discovery. The contents of each ofthe references cited herein, including the contents ofthe references cited within these primary references, are herein incorporated by reference in their entirety.
Accordingly, the present invention provides compounds corresponding to the structure of Formula (I):
Figure imgf000008_0001
(I) wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
R and R are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -
SO3R , or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moieties may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and
1 1 1 7 wherein R and R are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR 9 ; -NR 9 R 1 ; -
SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or R 11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and
R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -NO2; -CN; oxo; hydrocarbyl; -OR13; -NR13R14; -SR13; -
S(O)R13; -Sθ2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; - OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NRi3SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR1 R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A"; -
P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A'; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R13, R14, and R15 are independently selected from hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein A" is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; and wherein R9 is as defined above; or R4 and R6 together represent a bond; and R is selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; one or more Rx radicals are independently selected from the group
1 T consisting of hydrogen; halogen; -CN; -Nθ2; hydrocarbyl; -OR ; -
NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A"; -
NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -
NR1 C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -S(O)nNR13R14; - N+R13R14R15A"; -PR13R14; -P(O)R13R14; -P+R13R14R15 A-; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R13, R14, R15, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and p prroovviiddeedd tthhaatt aatt lleeaasstt oonnee ooff RR1 ,, R R2, R3, R4, R5, and R6 is a radical other than hydrogen or alkyl; and pprroovviiddeedd tthhaatt wwhheenn RR oorr RR is aryl, the other of R and R is a radical other than heterocycylalkyl. A preferred class of compounds comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxy alkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocy ley loxy alkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R 1 and R 2 taken together with the carbon to which they are attached form C3-C]o cycloalkyl or C3-C10 cycloalkenyl; wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcy loxy alkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10R A"; -SR9;
-S+R9R10A-; -PR9R10; -P+R9R10RWA"; -S(O)R9; -SO2R9; -SO3R9; - CO2R9; and -CONR9R! °; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR 9 -; -N + R 9 R 10 A--; -S-; -
SO-; -SO2-; -S+R9A--; -PR9-; -P(O)R9-; -P+R9R10A"-; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; or wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; -NR R ; - SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CRπR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary
1 3 1 3 14 heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -M R ; -
SR13; -S(O)R13; -SO2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR,3C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals
7 optionally may have one or more carbons replaced by -O-; -NR -; -
N+R7R8A"-; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R1 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR ; -NR R ; - N+R9R10RwA-. _SR16. _s(θ)R9; -SO2R9; -SO3R16; -CO2R16; - CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -P9R10; -P+R9R10RnA-; - S R R A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N R R A"-; -S-; -SO-; -SO2-; -S+R9A'-; -PR9-; -P+R9R10A -; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000015_0001
are independently selected from the group o consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R", R12, Rw, and A" are as defined above; and R is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -Nθ2; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR 13 ; - NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A"; -
NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; - S(O)nNR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A"; -PR13R14; -P(O)R13R14; -P+R13R14R15A"; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ; - NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; - CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)ORπ; -P9R10; - P+R9R! ^^A"; -S+R9R10A"; and carbohydrate residue; and wherein the R" quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; - SO2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; - SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - P(O)R13R14; -P13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A" ; -N R R R A"; and carbohydrate residue; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A"-; -S-; -SO-; -SO2-; -S+R13A"-; -PR13-; -P(O)R13-; -PR13R14; -P+R13R14A -; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR -; -N+R9R10A"-; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10A"-; or -
P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N^R1 ^^A";
-SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -
SO2NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR1 ?; and -C(O)OM; and wherein R9, R10, Ru, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In the various embodiments ofthe invention, R5 and R6 preferably are independently selected from the group consisting of H; aryl; heterocyclyl; and quaternary heterocyclyl; wherein the R and R aryl; heterocyclyl; and quaternary heterocyclyl; radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; - SO2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; - SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - NRI3C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NRI3SONR14R15; - NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -PR13R14; -P+R13R14R15A" ; -P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals
7 optionally may have one or more carbons replaced by -O-; -NR -; -
N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A -; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -C02R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; - PR9R10; -P+R9R10RnA-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _S+R9A._. _pR9_. _p+R9R10A._. .p(o)RQ.; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000020_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, Rn, R12, Rw, and A" are as previously set forth above for the compounds of Formula I.
More preferably, R5 or R6 has the formula -Ar-(Ry)t wherein: t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl; thiophenyl; pyridyl; piperazinyl; piperonyl; pyrrolyl; naphthyl; furanyl; anthracenyl; quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; oxazolyl; isoxazolyl; pyrimidinyl; thiazolyl; triazolyl; isothiazolyl; indolyl; benzoimidazolyl; benzoxazolyl; benzothiazolyl; and benzoisothiazolyl; and one or more R^ are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -
S(O)R13; -S02R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; - OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
NR13C(O)R14; -NRI3C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -
OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR1 R15; -
NRI3SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A_; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"-; -S-; - SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA'; -SR16; -S(O)R9; -SO2R9;
-SO3R16; -Cθ2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -
PR9R10;
Figure imgf000022_0001
-S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A -; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10N-; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000022_0002
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R", R12, Rw, and A" are as previously set forth above for the compounds of Formula I.
Still more preferably, at least one of R5 or R6 has the formula (II)
Figure imgf000023_0001
(II)
wherein Ry and t are defined as above.
In the various embodiments ofthe invention, the compounds of
Formula I preferably satisfy at least one or more ofthe following additional conditions:
(1) R1 and R2 are independently selected from the group consisting of hydrogen, alkyl and (C3.10)cycloalkyl. Preferably, R1 and R2 are independently selected from the group consisting of hydrogen and (C,_ 10)alkyl. More preferably, R1 and R2 are independently selected from the group consisting of (C,.,0)alkyl. Still more preferably, R1 and R2 are independently selected from the group consisting of (Cι.7)alkyl. Still more preferably, R1 and R2 are independently selected from the group consisting of (C2.4)alkyl. Still more preferably, R1 and R2 are the same (C2.4)alkyl. Still more preferably, R1 and R2 are each n-butyl; and/or
(2) R3 and R4 are independently selected from the group consisting of hydrogen and -OR9 wherein R9 is defined as previously set forth above for the compounds of Formula I. Preferably, R3 is hydrogen and R4 is -OR9 Still more preferably, R3 is hydrogen and R4 is hydroxy. Still more preferably, the hydroxy group is in a syn relationship to the structure of Formula II; and/or
(3) R5 is phenyl substituted with a radical selected from the group consisting of -OR13, -NR13R14, -NR13C(O)R14, -NR 13C(O)NR14R15, - NR13CO2R14, -OC(O)R13, -OC(O)NR13R14 , -NR13SOR14, -NR13SO2R14, - NR13SONR1 R15, and -NR13SO2NR1 R15 wherein R13, R14 and R15 are as previously set forth above for the compounds of Formula I. Still more preferably, R5 is phenyl substituted with -OR13 or -NR13C(O)R14. Still more preferably, R5 is phenyl substituted at the para or meta position with -OR13 wherein R13 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl, or R5 is phenyl substituted at the para or meta position with -NR13C(O)R14 wherein R13 is hydrogen and R14 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl; and/or
(4) R6 is hydrogen; and/or
(5) RN is selected from the group consisting of hydrogen, alkyl and aralkyl. Preferably, RN is selected from the group consisting of hydrogen, (C 0)alkyl and aryl(C1.10)alkyl. More preferably, RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl. Still more preferably, RN is hydrogen; and/or
(6) Rx is independently selected from the group consisting of -OR13, - NR13R14, -N+R13R14R,5A\ and polyether. More preferably, Rx is selected from the group consisting of -OR13 and -NR13R14. Still more preferably, Rx is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, Rx is selected from the group consisting of methoxy and dimethylamino; and or
(7) One or more Rx are present at the 7-, 8- or 9-position ofthe benzo ring ofthe structure of Formula I. Preferably, said R" are present at the 7- and 9-positions ofthe benzo ring ofthe structure of Formula I. More preferably, Rx is present at the 7-position ofthe benzo ring ofthe structure of Formula I; and/or
(8) q is 1, 2 or 3. Preferably, q is 1 or 2, and more preferably q is 1; and/or
(9) t is 1 or 2.
In still another embodiment ofthe invention, the compounds of Formula I satisfy at least one or more ofthe above-described conditions and R5 comprises a carbohydrate residue.
A more preferred class of compounds comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or
R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9 R 10 ; -
N+R9R10RW A-; -SR9; -S+R9R10N; -PR9R10; -P+R9R10RWA"; -S(O)R9; -
SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR ,9" N N++RR99RR1100AA__.. __ss__.. _so_. _sθ2_. _S+R9A- -PR9-; -P(O)R9- -P+R9R10A- or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of
9 9 10 hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; -NR R ; -
SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRnR12; wherein R 1 1 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or R 11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10are as defined above; and R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -Nθ2; oxo; alkyl; polyalkyl; haloalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -
S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; - OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - NR13C(O)R14; -NRI3C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR,3SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals
7 optionally may have one or more carbons replaced by -O-; -NR -; -
N+R7R8A"-; -S-; -SO-; -SO2S -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA"; -
SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -
SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10RUN; -S+R9R10N
; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _s+R9A-_. _pR9_. _p+R9R10A._. _p(0)R9.; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000028_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, Rw, and A" are as defined above; and
R is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; and aralkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; pojyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; - S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -
CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -S(O)nNR13R14; -NR13R18; -NR18OR14; - N+R13R14R15A-. .PR13R14. _P(0)R13R14. _P 3R14R15A-; aminQ acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ; - NR9R10; -N+R9R10R A"; -SR16; -S(O)R9; -SO2R9; -SO3R16; - CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - P+R9RUR12A"; -S+R9R10A"; and carbohydrate acid residue; and wherein the Rx quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; - SO2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; - SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - P(O)R13R14; -PR13R14; -P+R13R14R15A"; -P(OR13)OR14; -
S+R13R14A-. _N+R13R14R15A-. and car ohydrate acid residue; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A -; -S-; -SO-; -SO2-; -S+R13A"-; -PR13-; -P(O)R13-; -PR13-; -P+R13R1 A"-; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and
9 polyalkyl optionally may have one or more carbons replaced by -O-; -NR -;
-N+R9R10A"-; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10A"-; or - P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9RUR12A"; -SR9; -S(O)R9; -Sθ2R9; -SO3R9; -C02R9; -CONRV °; -SO2OM; -
SO2NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A class of compounds of interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-
C10)alkynyl; aryl(CrC10)alkyl; (C1-C1o)alkoxy(CrC10)alkyl; (Cr
C1o)alkoxy(C2-C1o)alkenyl; (CI-Cιo)alkoxy(C2-C10)alkynyl; (CrC10)alkylaryl; and (polyalkyl)aryl; or R 1 and R 2 taken together with the carbon to which they are attached form (C3-C10)cycloalkyl; and wherein the R1 and R2 (C,-C10)alkyl; (C3-C10)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl(C,-C10)alkyl; (C1-C10)alkoxy(C1-C10)alkyl; (C1-C1o)alkoxy(C2-C1o)alkenyl; (CI-C10)alkoxy(C2-C1o)alkynyl; (C1- C10)alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RWA_; -SR9; -S+R9R10N; -PR9R10; - p+R9R10RwA-. _S(0)R9. _sθ2R9. .so3R9; -CO2R9; and -CONR9R10; and wherein the R1 and R2 (C,-C10)alkyl; (C3-C10)cycloalkyl; (C2-
C10)alkenyl; (C2-C10)alkynyl; aryl(C,-CI0)alkyl; (CrC10)alkoxy(C1-C10)alkyl; (C1-C1o)alkoxy(C2-C1o)alkenyl; (CrC1o)alkoxy(C2-C10)alkynyl; (C1- C10)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R! °A"-; -S-; -SO-; -SO2-; -S+R9A~- ; -PR9; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; (CrC10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; ammonium(C1-C10)alkyl; (Cr Cιo)alkylammonium(C1-C10)alkyl; aryl(C!-C10)alkyl; heterocyclyl(Cι- C10)alkyl; carboxy(CrC10)alkyl; carbo(CI-C10)alkoxy(C1-C10)alkyl; carboxyheterocyclyl; carboxy(CrC10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; (C2-C)0)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; (C,-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C,-C10)alkyl; carboxy(CrC10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl; (C3-C10)cycloalkyl; cyano(C,-C10)alkyl; - OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and - CONR9R10; or i i 1
R and R together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and
R and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; (C3-C10)cycloalkyl; (C2-C,0)alkenyl; (C2-
9 9 C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR ; -SR ; -
S(O)R9; -S02R9; and -SO3R9; wherein the R5 and R6 (C,-Cι0)alkyl; (C3-C10)cycloalkyl; (C2-
C10)alkenyl; (C2-CI0)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; (C,-C10)alkyl; polyalkyl; halo(C,-C10)alkyl; (C3-C10)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(CrC10)alkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the (C,-C10)alkyl, polyalkyl, halo(CrC10)alkyl, hydroxy(Cr CI0)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CrC10)alkyl, heterocyclyl(Cr C10)alkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; (CrC10)alkyl; (C3-C,0)cycloalkyl;
(C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(CrC10)alkyl;
7 7 8 7 heterocyclyl(CrCι0)alkyl; quaternary heterocyclyl; -OR ; -NR R ; -SR ; - S(O)R7; -Sθ2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -
P(O)R7R8; -PR7R8; -P+R7R8R9A"; and -P(O)(OR7)OR8; and wherein the (CrC10)alkyl, polyalkyl, halo(CrC10)alkyl, hydroxy(Cr
Cl0)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CrC10)alkyl, heterocyclyl(Cr C10)alkyl, and polyether substituents ofthe R5 and R6 radicals optionally
7 + 7 8 may have one or more carbons replaced by -O-; -NR -; -N R R A"-; -S-; -
SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A'-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and (CrC10)alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; halo(C,-C10)alkyl; (C3-
C10)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(Cr
C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylaryl(C1- C10)alkyl; (C1-C10)alkylheterocyclyl(CI-CI0)alkyl; (Cr
C I0)alkylammonium(C , -C , 0)alkyl; carboxy (C , -C 10)alkylaminocarbonyl(C j -
C10)alkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 (CrC10)alkyl; halo(C,-C10)alkyl; (C3- C10)cycloalkyl; polyalkyl; (C2-Cι0)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(CrCI0)alkyl; heterocyclyl(Cr C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (CrC10)alkylaryl (Cr C10)alkyl; (CrC10)alkylheterocyclyl(CrC10)alkyl; (C,- C10)alkylammonium(CrC10)alkyl; aminocarbonyl(C,-C10)alkyl; (Cr
C1o)alkylaminocarbonyl(C1-C10)alkyl; carboxy(C,-Cιo)alkylaminocarbonyl (CrC10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; (CrC10)alkyl; sulfo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrCI0)alkyl; carboxy; carboxy(CrC10)alkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; - -SO2NR9R10; -PO(OR16)OR17; - PR9R10; -P+R9R10RπA-;-S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 (CrC10)alkyl; halo(C,-C10)alkyl; (C3- C10)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocycly^C C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C,-C10)alkylaryl(C1- C10)alkyl; (C1-C1o)alkylheterocyclyl(CrC10)alkyl; (C,- C10)alkylammonium(C1-C10)alkyl; aminocarbonyl(C)-C10)alkyl; (Cr C10)alkylaminocarbonyl(CI-C10)alkyl; carboxy(Cr
C10)alkylaminocarbonyl(CrCI0)alkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N R R A'-; -S-; -SO-; -SO2-; -S+R9A -; -PR9-; -P+R9R10A"-; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and
1 zr n wherein R and R are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, Ru, R12, Rw, and A" are as defined above; and
R is selected from the group consisting of hydrogen; (CrC10)alkyl; (C2-C10)alkenyl; (C2-C,0)alkynyl; and aryl(C,-C10)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; (CrC10)alkyl; (C3- C10)cycloalkyl; polyalkyl; halo(CrC10)alkyl; (C2-C10)alkenyl; (C2- C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; - SO3R13; -S+R13R14N; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; - SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; - COR13; -OR18; -S(O)nNR13R14; -NR13R18; -NR18OR14; - N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the Rx (CrC10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(Cr C10)alkyl; hydroxy(CrC10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(CrC10)alkyl; polyether; acyloxy radicals optionally may be further substituted with halogen; -CN; oxo; -OR16; -NR9R10; -N+R9RπR12A"; -SR16; -S(O)R9; -SO2R9; - SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; - PR9R10; -P+R9RHR12A"; or -S+R9R10A"; and wherein the Rx quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; (CrC10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(CrC10)alkyl; hydroxy(CrC10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C,-CI0)alkyl; heterocyclyl(CrC10)alkyl; polyether; - OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; - NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; - p+R13R14R15A-; .p(OR13)OR 1 ; -S+R13R14A-; and -N+R13R14R15 A-; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A"-; -S-; -SO-; -SO2S -S+R13A"-; -PR13-; -P(O)R13-; -PR13-; -P+R13R14A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR 9 -; -N + R 9 R 10 A - -; -S-; -
SO-; -SO2-J -S+R9A--; -PR9-; -P+R9R10N-; or -P(O)R9-; and wherein R 1 is selected from the group consisting of (C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; acyl; and aryl(Cr
C10)alkoxycarbonyl; and wherein the R18 (CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; acyl; and aryl(CrC10)alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N^R1 ^^A"; -SR9;
-S(O)R9; -SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -
SO2NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
A class of compounds of particular interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or
R 1 and R 2 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and
R and R are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and
R and R6 are independently selected from the group consisting of hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, piperazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and
R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfmyl, methylsulfonyl, ethylthio, ethylsulfmyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylamrnonium, triethylammonium, N-methyl-N- carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n- butylcarbonylamino, n-pentylcarbonylamino, n-hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, mo holinyl, N- methyl-morpholinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N- methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N'-dimethyl- piperazinium, piperidinyl, methylpiperidinyl, N-methyl-piperidinium, and thienyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A class of compounds of specific interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen and (CrC10)alkyl; or
R 1 and R 2 taken together with the carbon to which they are attached form (C3-C10)cycloalkyl; and
R and R are independently selected from the group consisting of hydrogen and hydroxy; and
R is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen; hydroxy; -Nθ2; (C,-C10)alkyl; halo(C,-C,0)alkyl; aryl(C,-CI0)alkyl; heterocyclyl(C,-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(C ,-Cj 0)alkyl ; (C rC 10)alky lheterocyclyl(C , - C10)alkyl; (C1-C1o)alkylammonium(CrC10)alkyl; and polyether; or wherein the R13, R14 and R15 (C,-C10)alkyl; halo(C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(Cr C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (Cr C10)alkylheterocyclyl(Cι-C10)alkyl; (C1-Cι0)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(C,-C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -
CONR9R10; and
9 i n wherein R and R are independently selected from the group consisting of hydrogen; (CrCι0)alkyl; heterocyclyl; ammonium(Cr
C10)alkyl; (C1-Cιo)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(CrC10)alkyl; carboxy(CrC10)alkyl; carbo(C]-C10)alkoxy(C1-
C10)alkyl; carboxyheterocyclyl; carboxy(C,-C10)alkylamino; and acyl; or wherein A" is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; aryl(C,-C10)alkyl; carboxy(CrC10)alkyl; and carbo(C1-Cι0)alkoxy(C1-C10)alkyl; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R and R16 are as previously set forth above for the compounds of Formula I; and
R6 is hydrogen; and R R iiss sseelleecctteedd frfroorm the group consisting of hydrogen; (C1-C10)alkyl; and aryl(CrC10)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; -NO2; (C Cι0)alkyl; halo(C,-C10)alkyl; -OR13; - NR13R14; wherein R13 and R14 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
A class of compounds of high interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4; R 1 and R 2 are independently selected from the group consisting of ethyl and n-butyl; or
1
R and R taken together with the carbon to which they are attached form cyclopentyl; and one of R and R is hydrogen and the other of R and R is hydroxy; and
R is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylammophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and R6 is hydrogen;
R is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl- amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A subclass of compounds of high interest comprises those compounds of Formula I wherein: wherein: q is 1 or 2;
R 1 and R 2 are each independently alkyl;
3 R is hydroxy; R and R are hydrogen;
R5 has the formula (II):
Figure imgf000043_0001
wherein t is an integer from 0 to 5; one or more R^ are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R ; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -
NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quatemary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"-; -S-; -
SO-; -SO2-; -S+R7A'-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9;
-SO3R16; -Cθ2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -
PR9R10; -P+R9R10RnA-; -S+R9R10A-; and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _S+R9A._. _pR9_. _p+R9R10A._. _p(o) >_; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000045_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R", R12, R , and A" are as previously set forth above for the compounds of Formula I; and
R is selected from the group consisting of hydrogen; alkyl; and aralkyl; and one or more R radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A family of specific compounds of particular interest within Formula I consists ofthe following compounds:
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3- nitrophenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
5-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]pentanamide;
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N, N-triethyl-5- oxo-pentanaminium trifluoroacetate;
2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2 -methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]acetamide;
2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N, N-triethyl-2- oxoethanaminium chloride;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2- iodoethyoxy)ethoxy)ethoxy)phenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1,1- dioxide;
l-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yljphenoxy] ethoxy] ethoxy] ethyl]pyridinium;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yl]phenoxy]ethoxy]ethoxy]-N)N,N-triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3- methoxyphenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)- l,2-benzothiazepin-4-ol 1,1 -dioxide and (4S,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2-benzothiazepin-4-ol 1,1 -dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl)phenyl]pentanamide; 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo-l - pentanaminium trifluoroacetate;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-l,2- benzothiazepin-4-ol 1,1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N- triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2- (phenylmethyl)-l,2-benzothiazepin-4-ol 1,1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5- tetrahydro-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide; and
(4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)- spiro[ 1 ,2-benzothiazepine-3 (2H), 1 '-cyclopentan]-4-ol 1 , 1 -dioxide; and the pharmaceutically-acceptably salts thereof.
The invention further comprises a compound selected from among:
.20 , 19 .21 ( F o rmu la D I )
,22
.20 ,19 .21 ( F o rmu l a D I I ) ,
and
.22
R20 R19 R21 (Fo rmu la D i l l )
,23
wherein R19 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue; and wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optionally may have one or more carbon atoms replaced by -O-, -NR7-, -N+R7R8A'-, -S-, -SO-, -SO2-, -S+R7N-, - PR7-, -PR7R8A"-, phenylene, heterocyclyl, quaternary heterocyclyl, or aryl; wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optimally can be substituted with one or more radicals independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclyl, arylalkyl, halogen, oxo, -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; - SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; - SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
P(O)R , 1°3Rτ. l4 ; -PR , 113 J-R, 14 ;. -P ARπ 1'3„ 1'4 'Α-; -P(OR13)OR14; -S+R13R14A"; and - N+R13R14R15A-; wherein R13, R14, R15, M and A" are as previously set forth above for the compounds of Formula I; and wherein R19 can further comprise functional linkages by which R19 is bonded to R20 and/or R21 in the compounds of Formula DI; to R20, R21 and/or R22 in the compounds of Formula DII; and to R20, R21, R22 and or R23 in the compounds of Formula Dili; and wherein each of R20, R21, or R22 and R23 comprises a benzothiazepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
Exemplary R19 substituents include, but are not limited to, the following:
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
wherein:
R25 is selected from the group consisting of carbon and nitrogen; and R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, and R37 are independently selected from the group consisting of: -CH .
— c s -N —
— c- o N H — NH-
:NH
-o
NH .
-s o
N HS O 2 ' a n d
-s o
Figure imgf000052_0001
wherein R38 , R39, R40 and R41 are independently selected from the group consisting of alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl;
A" is a pharmaceutically acceptable anion; and h, i, j and k are independently selected from the group consisting of integers from 1 to 10 inclusive. The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula Dili in which each of R20, R21, R22 and R23 comprises a benzothiazepine moiety corresponding to the Formula DIV or Formula DIVA:
Figure imgf000053_0001
o r :
Figure imgf000053_0002
wherein R1, R2, R3, R4, R5, R6, RN, R\ q, and n are as previously defined above for the compounds of Formula I, and R55 is either a covalent bond or arylene. In compounds of Formula DIV, it is particularly preferred that each of R20, R21, R22, and R23 in Formulae DI, DII and Dili be bonded at its 7- or 8- position to R19. In compounds of Formula DIVA, it is particularly prefened that R55 comprise a phenylene moiety bonded at a m- or j9-carbon thereof to R19.
Examples of Formula DI include:
Figure imgf000054_0001
and
Figure imgf000054_0002
and
Figure imgf000055_0001
wherein R1A, R2A, R3A, R4A, RNA, RyA, R , r and u have the same definitions as stated above for R1, R2, R3, R4, RNA, Ry, Rx, q and t, respectively.
In any ofthe compounds ofthe present invention, R1 and R2 can be, among other combinations, ethyl/butyl or butyl/butyl.
Illustrative dimeric compounds include the following:
Figure imgf000056_0001
Figure imgf000056_0002
In another embodiment, a core moiety backbone, R19, as discussed herein in Formulae DI, DII and Dili can be multiply substituted with more than four pendant active benzothiazepine units, i.e., R20, R21, R22, and R23 as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R19, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures ofthe different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiazepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any ofthe groups encompassed by the definition of R19.
The more preferred benzothiazepine moieties comprising R20, R21, R22 and/or R23 conform to the preferred structures as outlined above for Formula I. The 3 -position carbon on each benzothiazepine moiety can be achiral, and the substituents R1, R2, R3, R4, R5 and Rx can be selected from the prefened groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).
Methods of Treatment In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any ofthe compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, alone or in a composition comprising, for example, one or more pharmaceutically acceptable carriers, excipients, and/or diluents. In any of the dimeric or multimeric structures discussed immediately above, for example, the benzothiazepine compounds of the present invention can be used alone or in various combinations.
In a further aspect, the present invention also provides a method of treating a disease, condition and/or disorder in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound ofthe present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention comprises the use ofthe compounds of Formula I and/or the dimeric or multimeric compounds of Formulae DI, DII and/or Dili in the preparation of a medicament useful for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated.
The compounds of Formula I are also useful for the prophylaxis and/or treatment of gallstones. In yet a further aspect, the present invention also provides processes for the preparation of compounds ofthe present invention.
Further scope ofthe applicability ofthe present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating prefened embodiments ofthe invention, are given by way of illustration only since various changes and modifications within the spirit and scope ofthe invention will beomce apparent to those skilled in the art from this detailed description.
Definitions and Abbreviations In order to aid the reader in understanding the following detailed description, the following definitions are provided:
The term "hydrocarbyl" refers to radicals consisting exclusively ofthe elements carbon and hydrogen. These radicals include, for example, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties. These radicals also include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms. The term "substituted hydrocarbyl" refers to a hydrocarbyl radical that is substituted with a group comprising at least one atom other than carbon, such as but not limited to, halogen, oxygen, nitrogen, sulfur and phosphorus. Examples of such substituted hydrocarbyl include hydrocarbyl radicals substituted with groups such as, but not limited to, lower alkoxy such as methoxy, ethoxy, and butoxy; halogen such as chloro and fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl and thienyl; alkanoxy; . hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido. Substituted hydrocarbyl also includes hydrocarbyl radicals in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or a halogen.
Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl", and "hydroxyalkyl", it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More prefened alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso- amyl, hexyl and the like. Even more prefened are lower alkyl radicals having one to three carbon atoms.
Where the term "alkenyl" is used, either alone or within other terms such as "arylalkenyl", it embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More prefened alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl.
The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
The term "alkynyl" denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More prefened alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms. Most prefened are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More prefened cycloalkyl radicals are
"lower cycloalkyl" radicals having three to about ten carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring ofthe benzothiazepine.
The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More prefened cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about ten carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term "halo" and "halogen" means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More prefened hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more prefened are lower hydroxyalkyl radicals having one to three carbon atoms. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and anthracenyl. More prefened aryl is phenyl. Said "aryl" group may have one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Prefened heterocyclyl are 3-10 membered ring heterocyclyl, particularly 5-8 membered ring heterocyclyl. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocychc groups containing 1 to 4 nitrogen atoms [e.g. pynolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. moφholinyl]; saturated 3 to 6-membered heteromonocychc groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pynolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H- 1,2,3 -triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl]; unsaturated 3 to 6- membered heteromonocychc groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocychc groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated 5 to 6- membered heteromonocychc groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 5 -thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.
Heterocyclic radicals can include fused or unfused radicals, particularly 3-10 membered fused or unfused radicals. Prefened examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl, and pyrazinyl. More prefened heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
The term "heteroaryl" means a fully unsaturated heterocyclyl.
In either "heterocyclyl" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring. The term "triazolyl" includes all positional isomers. In all other heterocyclyl and heteroaryl which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocyclyl and heteroaryl. The term "quaternary heterocyclyl" means a heterocyclyl in which one or more ofthe heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment ofthe quaternary heterocyclyl to the molecule of interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a heteroaryl in which one or more ofthe heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment ofthe quaternary heteroaryl to the molecule of interest can be at a heteroatom or elsewhere.
The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.
The term "oxo" means a doubly bonded oxygen. The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000. The term "carbohydrate residue" encompasses residues derived from carbohydrates such as, but is not limited to, mono-, di-, tri-, tetra- and polysaccharides wherein the polysaccharides can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan residue; compounds derived from aldoses and ketoses with 3 to 7 carbon atoms and which belong to the D- or L-series; aminosugars; sugar alcohols; and saccharic acids. Nonlimiting specific examples of such carbohydrates include glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannoic acid, glucamine, 3-amino-l,2- propanediol, glucaric acid and galactaric acid.
The term "peptide residue" means polyamino acid residue containing up to about 100 amino acid units.
The term "polypeptide residue" means a polyamino acid residue containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, and most preferably from about 100 amino acid units to about 500 amino acid units.
The term "alkylammoniumalkyl" means an an -NH2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
The term "sulfo" means a sulfo group, -SO3H, and its salts. The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more prefened are lower aralkyl radicals having phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are "lower arylalkenyl" radicals having aryl radicals attached to alkenyl radicals having
The term "heterocyclylalkyl" means an alkyl radical that is substituted with one or more heterocyclyl groups. Preferable heterocyclylalkyl radicals are "lower heterocyclylalkyl" radicals having one or more heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms.
The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are "lower heteroarylalkyl" radicals having one or more heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
The term "quaternary heterocyclylalkyl" means an alkyl radical that is substituted with one or more quaternary heterocyclyl groups. Preferable quaternary heterocyclylalkyl radicals are "lower quaternary heterocyclylalkyl" radicals having one or more quaternary heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms. The term "quaternary heteroarylalkyl" means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are "lower quaternary heteroarylalkyl" radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
The term "alkylheteroarylalkyl" means a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl" radicals with alkyl portions having one to ten carbon atoms. The term "alkoxy" means an alkyl radical which is attached to the molecule of interest by oxygen, such as a methoxy radical. More prefened alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. The term "carboxy" means the carboxy group, -CO2H, or its salts.
The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are "lower carboxyalkyl" radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms. The term "carboxyheterocyclyl" means a heterocyclyl radical that is substituted with one or more carboxy groups.
The term "carboxyheteroaryl" means a heteroaryl radical that is substituted with one or more carboxy groups.
The term "carboalkoxyalkyl" means an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.
The term "carboxyalkylamino" means an amino radical that is mono- or di-substituted When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.
The term "acyl" means an organic acid group in which the hydroxy of the carboxy group has been removed. Examples of acyl groups include, but are not limited to, acetyl and benzoyl. The term "active compound" means a compound ofthe present invention that inhibits transport of bile acids.
The term "a bile acid transport inhibitor" means a compound capable of inhibiting absoφtion of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions and/or diseases that benefit from the prophylaxis and/or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
The abbreviations used in this application have the following meanings:
The term "THF" means tetrahydrofuran;
The term "PTC" means phase transfer catalyst;
The term "Aliquart 336" means methyltricaprylylammonium chloride;
The term "MCPBA" means m-chloroperbenzoic acid; The term "Celite" refers to a brand of diatomaceous earth filtering aid;
The term "DMF" means dimethylformamide;
The term "DME" means ethylene glycol dimethyl ether;
The term "BOC" means t-butoxycarbonyl;
The term "Me" means methyl; The term "Et" means ethyl;
The term "Bu" means butyl;
The term "EtOAc" means ethyl acetate;
The term "Et2O" means diethyl ether;
The term "LAH" means lithium aluminum hydride; The term "DMSO" means dimethylsulfoxide;
The term "KOSiMe3" means potassium trimethylsilanolate;
The term "PEG" means polyethylene glycol;
The term "MS" means mass spectrometry; The term "HRMS" means high resolution mass spectrometry;
The term "ES" means electrospray;
The term "NMR" means nuclear magnetic resonance spectroscopy;
The term "GC" means gas chromatography;
The term "MPLC" means medium pressure liquid chromatography; The term "HPLC" means high pressure liquid chromatography;
The term "RPHPLC" means reverse phase high pressure liquid chromatography
The term "RT" means room temperature;
The terms "h" or "hr" means hour(s); and The term "min" means minute(s);
Alternate Forms of Compounds
The compounds ofthe present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds ofthe present invention. Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds ofthe present invention.
The compounds ofthe present invention also include tautomers, salts, solvates and prodrugs of such compounds. Compound Syntheses
The starting materials for use in the preparation ofthe compounds of the invention are commercially available or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
Generally, the compounds ofthe present invention can be prepared by the procedures described below.
Scheme
Figure imgf000070_0001
Scheme 1 illustrates the preparation of racemic benzothiazepines 9a and 9b. Reaction of benzenesulfonyl chloride 1 with aminoalcohol 2 in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields benzenesulfonamide 3 which can be converted to protected benzenesulfonamide 4. Protected benzenesulfonamide 4 optionally can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N- substituted benzenesulfonamide 5. Protected benzenesulfonamide 4 or N- substituted benzenesulfonamide 5 is then successively reacted with (i) a strong base (such as n-butyllithium in hexanes) in a solvent (such as tetrahydrofuran), (ii) an electrophile (such as trimethyl borate), and (iii) a base (such as sodium carbonate), a benzyl halide (such as p-methoxybenzyl chloride), and a catalyst (such as tetrakis(triphenylphosphine)palladium(0)) to yield sulfonamide 6. Treatment of sulfonamide 6 with a fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, provides the deprotected sulfonamide alcohol 7. Sulfonamide alcohol 7 is successively oxidized using a method such as Swem Oxidation to yield sulfonamide aldehyde 8. Upon treatment with a base such as potassium tert-butoxide, aldehyde 8 is converted to racemic benzothiazepines 9a and 9b. R1, R2, R5, RN, Rx and q are as previously defined above for compounds of Formula I.
SCHEME 2
Alternative Synthesis of sulfonamide alcohol
Figure imgf000072_0001
Where L = F, Cl, Br, N02, TsO, TfO (Rx)q
Figure imgf000072_0002
Scheme 2 illustrates an alternative synthetic scheme for the preparation of sulfonamide alcohol 3 used in Scheme 1. Reaction of benzenesulfonyl chloride 10 with aminoalcohol 11 in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields sulfonamide 12. Substituent L of benzenesulfonyl chloride 10 is a suitable leaving group such as fluoro, chloro, bromo, nitro, tosyloxy or trifluoromethylsulfonyloxy. Reaction of sulfonamide 12 with a suitable nucleophile in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields benzenesulfonamide 3 which can be further reacted in accordance with Scheme 1. R1, R2, Rx and q are as previously defined above for compounds of Formula I. Substituent M is a metal, preferably an alkali metal, or a hydrogen. SCHEME 3
Figure imgf000073_0001
Scheme 3 illustrates the preparation of benzothiazepines having 4- position substituents other than hydroxy.
In the preparation of 4-thioxo-, thio-, sulfinyl- or sulfonyl- benzothiazepines, benzothiazepine 9a or 9b is first oxidized to benzothiazepine-4-one 13. Conventional oxidizing agents, such as PCC, or Swem conditions can be used. Benzothiazepine-4-one 13 is then reacted with Lawesson's Reagent to produce 4-thioxo-benzothiazepine 14. 4-Thioxo- benzothiazepine 14 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-mercapto-benzothiazepine 15. 4-Mercapto-benzothiazepine 15 can be reacted with a suitable alkylating agent, such as an alkyl halide, in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, to yield 4-alkylthio-benzothiazepine 16. 4-Alkylthio- benzothiazepine 16 can be reacted with a suitable oxidizing agent, such as t- butyl hydroperoxide or m-chloroperbenzoic acid, to yield, successively, 4- alkylsulfinyl-benzothiepine 17 and 4-alkylsulfonyl-benzothiazepine 18.
Alternatively, 4-amino- or imino-benzothiazepines can be prepared by reacting benzothiazepine-4-one 13 with ammonia or a primary amine in a suitable solvent, such as tetrahydrofuran, to produce 4-imino-benzothiazepine 19. 4-Imino-benzothiazepine 19 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-amino-benzothiazepine 20. Benzothiazepine-4-one 13 also can undergo reductive alkylation by reaction with ammonia, a primary amine or a secondary amine in the presence of an reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as tetrahydrofuran, to produce 4-amino-benzothiazepine 21.
Scheme 3 also illustrates the preparation of 4-alkyl-benzothiazepine 23 and 4-alkoxycarbonyl-benzothiazepine 25. The 4-position hydroxy of benzothiazepine 9a or 9b is first converted to a suitable leaving group such as mesyloxy to form protected benzothiazepine 22. Protected benzothiazepine 22 is then reacted with a suitable nucleophile, such as butyl lithium, in a suitable solvent, such as tetrahydrofuran, to yield 4-alkyl-benzothiazepine 23. Alternatively, protected benzothiazepine 22 can be reacted with a suitable cyanidating agent, such as an potassium cyanide, in a suitable solvent, such as dimethylformarnide, to yield 4-cyano-benzothiazepine 24. 4-Cyano- benzothiazepine 24 is converted to 4-alkoxycarbonyl-benzothiazepine 25 by reaction with a suitable alcohol in the presence of a base, such as potassium hydroxide.
Figure imgf000076_0001
Scheme 4 illustrates the preparation of benzothiazepine-4-ene 36 and benzothiazepine-4-one 33. Reaction of phenol 26 with a thiocarbamyl chloride, such as dimethylthiocarbamyl chloride, in a solvent, such as methanol-.tetrahydrofuran yields 0-thiocarbamate 27. Heating of O- thiocarbamate 27 in a solvent, such as tetradecane, yields S-thiocarbamate 28. Hydrolysis of S-thiocarbamate 28 in the presence of a base, such as sodium hydroxide, in a solvent, such as methanohtetrahydrofuran, yields thiophenol 29. Thiophenol 29 can be treated with a sulfonylating agent, such as sulfonyl chloride, in the presence of a oxidant such as potassium nitrate, in a solvent, such as tetrahydrofuran, to yield sulfonyl chloride 30. Sulfonyl chloride 30 is then reacted with an aminoalcohol in a solvent, such as tetrahydrofuran, to yield benzenesulfonamide 31. Benzenesulfonamide 31 optionally can be hydroxyl protected with a silylating group agent, such as tert- butyldimethylsilyl chloride, in the presence of a base, such as imidazole, in a solvent, such as tetrahydrofuran, to yield protected benzenesulfonamide 32. Protected benzenesulfonamide 32 can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N-substituted benzenesulfonamide 33. Deprotection ofthe protected N-substituted benzene sulfonamide 33 with a fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, yields N-substitued benzenesulfonamide 34. Benzenesulfonamide 31 or N-substituted benzenesulfonamide 34 is then oxidized with a suitable oxidizing agent or under Swem conditions to form aldehyde 35. Upon treatment with zinc and titanium trichloride aldehyde 35 is converted to a mixture of benzothiazepine-4-ene 36 and benzothiazepine-4-one 37.
The recovery, isolation and purification ofthe intermediates and the reaction products of this invention, and in particular the intermediates and the reaction products illustrated in Schemes 1, 2, 3 and 4, can be accomplished by conventional methods well known to those skilled in the art, such as precipitation, filtration, extraction, or chromatography. Except where otherwise indicated, conditions, solvents, and reagents are either conventional, not nanowly critical, or both.
Additional Embodiments and Examples Another class of compounds of specific interest comprises those compounds of Formula I wherein R1 and R2 are selected from among substituted and unsubstituted C,.10 alkyl wherein substituted C,.,0 alkyl comprises one or more radicals independently selected from among, for example, alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocyclyl joined to the C ]0 alkyl through an ether linkage. These R1 and R2 substituents include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH2C(=O)C2H5, -CH2OC2H5, and -CH2 O-(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are prefened. In certain particularly prefened compounds ofthe present invention, substituents R1 and R2 are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-position carbon. Eliminating optical isomerism at the 3-position carbon simplifies the selection, synthesis, separation, and quality control ofthe compound used as an ileal bile acid transport inhibitor.
In the compounds ofthe present invention having a chiral 3-position carbon as well as those having an achiral 3-position carbon, substituents R on the benzo ring can include, for example, hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)- hydroxy-carbonylalkylamino, haloalkylthio, haloalkylsulfmyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)- alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)- alkylamido, N,N-dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)- alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamino, hydroxylamino, haloacylamino, carbohydrate residue, thiophene, a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more ofthe alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, -[O(CH2)d ] e-X where e is 2 to 12, d is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocyclyl wherein the nitrogen of said heterocyclyl is optionally quatemized.
Among the prefened species which may constitute Rx are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfmyl, methylsulfonyl, ethylthio, amino, hydroxylamino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)- benzyloxycarbamoyl, trimethylammonium A", -NHC(=O)CH3, - NHC(=O)C5H„ , -NHC(=O)C6H13, carboxyethylamino, (N)-morpholinyl, (N)- azetidinyl, (N)-N-methylazetidinium A-, (N)-pynolidinyl, pynolyl, (N)-N- methylpyridinium A-, (N)-N-methylmoφholinium A-, and N-N1- methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, - N+(CH3)2 CO2 H I", -NCH3 CH2 CO2H, -(N)-N'-dimethylpiperazinium T, (N)- t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpynolidinium, and -(OCH2CH2)3l, where A" is a pharmaceutically acceptable anion. The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring including, for example, guanidinyl, cycloalkyl, carbohydrate residue (e.g., a 5 or 6 carbon monosaccharide residue), peptide residue, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., -(OCH2 CH 2)x -N+R 13R14R15A\ where x is 2 to 10.
In further compounds ofthe present invention, R5 and R6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiopene, pyridine, pynole, thiazole, imidazole, pyrazole, pyrimidine, moφholine, N-alkylpyridinium, N-alkylpiperazinium, N- alkylmoφholinium, or furan in which the substituent(s) are selected from among, for example, halo, hydroxyl, trihaloalkyl, alkoxy, amino, N- alkylamino, N,N-dialkylamino, quaternary ammonium salts, a to C alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene, -[O(CH2)d]eX where e is 2 to 12, d is 2 or 3 and x comprises halo or a quaternary ammonium salt, thiophene, pyridine, pynole, thiazole, imidazole, pyrazole, or furan. The aryl group of R5 or R6 is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono- substituted, or di-substituted.
Among the species that may constitute the substituents on the aryl ring of R5 or R6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)- hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both ofthe aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring includes 3, 4-dioxymethylene (5-membered ring) and 3, 4- dioxyethylene (6-membered ring). One group of compounds of interest are those in which R5 or R6 is selected from phenyl, p-fluorophenyl, m- fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m- methoxyphenyl, p-N,N-dimethylaminophenyl, m-N, N-dimethylaminophenyl, I- p-(CH3)3-N+-phenyl, I" m-(CH3)3-N+-phenyl, T m-(CH3)3-N+-CH2CH2-
(OCH2CH2)2-O-phenyl, I" p-(CH3)3-N+-CH2CH2-(OCH2CH2)2-O-phenyl, m- (N,N-dimethylpiperazinium)-(N')-CH2-(OCH2CH2)2-O-phenyl, 3-methoxy-4- fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3, 4-difluorophenyl, I- p- (N,N-dimethylpiperazinium)-(N')-CH2-OCH2CH2)2-O-ρhenyl, 3-fluoro-4- methoxyphenyl, 4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, I" N-methyl-3-pyridinium, 3, 4-dioxymethylenephenyl, 3, 4- dioxyethylenephenyl, and p-methoxycarbonylphenyl.
Prefened compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each ofthe above prefened R5 substituents in combination with the Rx substituents shown in Tables 1 , 2 and 3 below. It is particularly prefened that one, but not both, of R5 and R6 is hydrogen.
It is especially prefened that R4 and R6 be hydrogen, that R3 and R5 not be hydrogen, and that R3 and R5 be oriented in the same direction relative to the plane ofthe molecule, i.e., both in a- or both in β-configuration. It is further prefened that, where R2 is butyl and R1 is ethyl, then R1 has the same orientation relative to the plane ofthe molecule as R3 and R5.
A class of compounds of particular interest comprises those 1,2- benzothiazepines wherein the R1, R2, R3, R4 and R5 radicals are as set forth in Table 1 below; the R6 radical is hydrogen; the RN radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl and benzyl; and the Rx radical or radicals are independently selected from the group of R radicals disclosed in Table 1 below. The first part of Table 1 identifies the R1, R2, R3, R4 and R5 radicals for each compound and the second part of Table 1 identifies the Rx radical or radicals for those compounds.
TABLE 1
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
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Figure imgf000093_0001
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Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
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Figure imgf000104_0001
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Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
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Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0002
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
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Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
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Figure imgf000134_0001
Figure imgf000135_0001
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Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
/^
Figure imgf000191_0001
\cø
Figure imgf000192_0001
1*11
Figure imgf000193_0001
$
Figure imgf000194_0001
Ϊ SS
Figure imgf000195_0001
Figure imgf000196_0001
«
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000199_0002
«N
Figure imgf000200_0001
-S->
Figure imgf000201_0001
o
Figure imgf000202_0001
S
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
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Figure imgf000206_0001
%-5 o
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000208_0001
Figure imgf000208_0002
~3
Figure imgf000209_0001
Another class of compounds of particular interest comprises those 1,2- benzothiazepines wherein the R1, R2, R3, R4, R5, R6, RN and Rx radicals are selected from among the radicals disclosed in Table 2 below. Preferably, R6 is hydrogen and R5 is other than hydrogen; and/or R3 is hydroxy and R4 is hydrogen; and/or R1 and R2 are alkyl. More preferably, R1 and R2 are the same.
Table 2
Figure imgf000210_0001
Figure imgf000211_0001
R!/R2 R3/R R5/R6 (Rx)q RN
4
8-0(iso-propyl)
8-SCH3
8-SOCH3
8-SO2CH3
8-SCH2CH3
8-NH2
8-NHOH
8-NHCH3
8-N(CH3)2
8-N+(CH3)3, I-
8-NHC(0)CH3
8-N(CH2CH3)2
8-NMeCH2Cθ2H
8-N+(Me)2CH2Cθ2H, r
8-(N)-morpholine 8-(N)-azetidine 8-(N)-N- methylazetidinium, I" 8-(N)-pyrrolidine 8-(N)-N-methyl- pyrrolidinium, I" 8-(N)- N-methyl- morpholinium, I" 8-(N)-N'- methylpiperazine 8-(N)-N'- dimethylpiperazinium, r
8-NH-CBZ
Figure imgf000212_0001
8-(2)-thiophene
9-methyl
9-ethyl
9-iso-propyl
9-tert-butyl
9-OH
9-OCH3
9-0(iso-propyl)
9-SCH3
9-SOCH3
9-SO2CH3
9-N+(Me)2CH2Cθ2H,
I" R* R2 R3/R R5/R6 (Rx)q
4 RN
9-SCH2CH3
9-NH2
9-NHOH
9-NHCH3
9-N(CH3)2
9-N+(CH3)3, r
9-NHC(0)CH3
9-N(CH2CH3)2
9-NMeCH2C02H
9-(N)-morpholine
9-(N)-azetidine
9-(N)-N- methylazetidinium,
I-
9-(N)-pyrrolidine
9-(N)-N-methyl- pyrrolidinium, I" 9-(N)-
N- methyl- morpholinium, I" 9-(N)-N'- methylpiperazine 9-(N)-N'-dimethyl- piperazinium, I" 9-NH-CBZ
Figure imgf000213_0001
9-(2)-thiophene 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8- OCH3
Another class of compounds of particular interest comprises those 1,2- benzothiazepines wherein the R1, R2, R3, R4 and R5 radicals are as set forth in Table 3 below; R6 is hydrogen; the RN radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and the Rx radical or radicals are independently selected from the group of Rx radicals disclosed in Table 2 above. In one embodiment ofthe compounds of Table 3, for example, q is 1 and Rx is 7-dimethylamino. Λ/Λ
Figure imgf000214_0001
Compound R1 R2 R3 R4 R5 Number
1452 ethyl n-butyl OH H
OH
"
1453 n-butyl ethyl OH H
Figure imgf000215_0001
1454 n-butyl n-butyl OH H
OH
" V
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Λ(oύ
Figure imgf000262_0001
a x X x o o o
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
a a
o a o a a o
fr fr
3 3 43 43 -g
fr 3 fr 43 >κ 3
43 43
r- OS ro ro ro o o o
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Λ7/
Figure imgf000273_0001
a o
3
-9
fr 3 43
3
m Another group of compounds of interest consists of those compounds of Formula I wherein R1 and R2 are alkyl, preferably n-butyl; R3 is hydroxy; R4 and R6 are hydrogen; RN is hydrogen; Rx radicals are selected from the group consisting of amino, dimethylamino and methoxy; and R5 is phenyl substituted at the para or meta position with one ofthe following groups:
Figure imgf000274_0001
Figure imgf000274_0002
^C02H
N. 02H '
Figure imgf000274_0003
Figure imgf000274_0004
Figure imgf000275_0001
Figure imgf000275_0002
Figure imgf000275_0003
OMWPEG
O' 'R' R= lOO
Figure imgf000275_0004
Figure imgf000275_0005
Figure imgf000276_0001
Figure imgf000276_0002
Figure imgf000276_0003
Λ CA+NEt3 o"
Figure imgf000276_0004
Figure imgf000276_0005
Figure imgf000277_0001
Figure imgf000277_0002
Figure imgf000277_0003
Figure imgf000277_0004
Figure imgf000277_0005
Figure imgf000278_0001
Figure imgf000278_0002
wherein M is selected from the group consisting of Co11, Co111, Mn11, Mn111, Fe11, Fe111, Niπ, Ni111, Cr111, Cuπ, Zn11, Cd11, Gaιπ, In111, VIV, Ru11, PtIV, Rhm and Ir1".
Dosages. Formulations, and Routes of Administration
The ileal bile acid transport inhibitor compounds ofthe present invention can be administered for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders by any means, preferably oral, that contacts these compounds with their site of action in the body, for example in the ileum of a mammal such as a human.
For the prophylaxis and/or treatment ofthe diseases, conditions and/or disorders referred to above, the compounds ofthe present invention can be used as the compound er se. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts comprise a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts ofthe compounds ofthe present invention where appropriate include those salts derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts where appropriate include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts. The anions ofthe definition of A" in the present invention are pharmaceutically acceptable anions such as those anions selected, for example, from the above list.
The compounds ofthe present invention also can be administered in the form of a pharmaceutical composition comprising additional ingredients such as acceptable carriers, diluents, excipients, adjuvants and the like (collectively referred to herein as "carrier materials"). Acceptable carrier materials are compatible with the other ingredients ofthe composition and are not deleterious to the recipient. A carrier material can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet or capsule, which can contain from 0.05% to 95% by weight ofthe active compound. Other pharmacologically active substances can also be present, including other compounds ofthe present invention. The pharmaceutical compositions ofthe invention can be prepared by any ofthe well known techniques of pharmacy, consisting essentially of admixing the components.
These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as an individual therapeutic compound in a monotherapeutic regimen or as a combination of therapeutic compounds in a combination therapy regimen.
The amount of compound that is required to achieve the desired biological effect will depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition ofthe recipient.
In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, and more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.
Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiazepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight ofthe benzothiazepine ion derived from the salt.
Oral delivery of an ileal bile acid transport inhibitor ofthe present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery ofthe drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH ofthe small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties ofthe formulation, bioadhesion ofthe dosage form to the mucosal lining ofthe intestinal tract, or enzymatic release ofthe active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation ofthe dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope ofthe present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, and more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, and preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g ofthe compound ofthe present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg. Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity ofthe condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound ofthe present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier material (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier material, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules ofthe compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound ofthe present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound ofthe present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound ofthe present invention with one or more conventional solid carrier materials, for example, cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carrier materials that can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w ofthe composition, for example, from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound ofthe present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration ofthe active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research. 3(6), 318 (1986).
In any case, the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds ofthe present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable carrier materials encompass all the foregoing and the like.
Treatment Regimen
The dosage regimen to prevent, give relief from, or ameliorate a disease, condition and/or disorder relating to hyperlipemia, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions ofthe present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition ofthe patient, the severity ofthe disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles ofthe particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any ofthe methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification ofthe treatment regimen during therapy so that optimal effective amounts of compounds ofthe present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor ofthe present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
The following non-limiting examples serve to illustrate various aspects ofthe present invention.
Examples of Synthetic Procedures The starting materials used in the preparation ofthe compounds ofthe following examples, as well as other compounds ofthe present invention, are commercially available or can be prepared by conventional methods known to one of ordinary skill in the art or in an analogous manner to conventional methods described in the art. The starting materials ofthe following examples were obtained from commercial sources unless otherwise noted. The ethyl 2- amino-2-butylhexanoate hydrochloride used below was prepared in an analogous manner to the literature method of Stork (J. Org. Chem. 41, 3491 (1976)).
Example 1
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5- (3-nitrophenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000286_0001
Step 1. 2-Amino-2-butylhexanol
NH.
HO
B u B u
To a solution of 29.75 g (0.12 mol) of ethyl 2-amino-2-butylhexanoate hydrochloride in 100 mL of tetrahydrofuran cooled to -20 °C was added 148.8 mL of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran while maintaining a temperature below -15 °C. The reaction mixture was stirred for one hour at -20 °C, warmed to room temperature and stirred for 16 hours. The reaction mixture was then cooled to -20 °C and 6 mL of water was added, followed by 5.6 mL of 3.75 M aqueous sodium hydroxide and 16 mL of water. The reaction mixture was stirred for one hour and warmed to room temperature. The resulting slurry was filtered and washed with 100 mL ethyl acetate. The ethyl acetate solution was washed with water (2x200 mL) and then brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting yellow oil was dissolved in 300 mL of tetrahydrofuran and concentrated to give 20.61 g of 2-amino-2-butylhexanol as an oil.
Step 2. N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide
Figure imgf000287_0001
To a solution of 16.95 g (0.09 mol) of 4-fluorobenzene sulfonyl chloride in 150 mL of tetrahydrofuran was added 36.4 mL of triethylamine. The reaction mixture was cooled to 0 °C and a solution of 19.61 g of 2-amino- 2-butylhexanol (prepared in step 1 above) in 70 mL of tetrahydrofuran was added. The reaction mixture was stirred 30 minutes at 0 °C and then 16 hours at room temperature. The reaction mixture was concentrated and then the residue was dissolved in 250 mL of ethyl acetate. This ethyl acetate solution was washed with water (2 x 200 mL) and brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 29.47 g of N- [1 -butyl- l-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide as an oil. Step 3. N-(l-Butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino) benzenesulfonamide
Figure imgf000288_0001
A solution containing 28.89 g (0.09 mol) ofthe oil prepared in Step 2 above, 872 mL of 2.0 M dimethylamine in tetrahydrofuran and 100 mL of neat dimethylamine was prepared and placed in a bomb. The reaction mixture was heated to 110 °C for 16 hours, cooled, and then concentrated to give 25.46 g of N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)benzenesulfonamide as an solid.
Step 4. N-[ 1 -Butyl- 1 -[[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]- 4-(dimethylamino)benzenesulfonamide
Figure imgf000288_0002
To a solution of 15.51 g (0.10 mol) of t-butyldimethylsilyl chloride in 158 mL of dimethylformamide was added 24.46 g (0.07 mol) ofthe solid prepared in Step 3 and then 14.01 g of imidazole. The reaction mixture was stirred 3 days and then diluted with 1 L of ethyl acetate and 500 mL of water. The ethyl acetate solution was washed with 5% hydrochloric acid solution (2 x 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried with magnesium sulfate and concentrated to an oil. The oil was stirred with hexane and the resulting solid was filtered to give 25.31 g of N-[l- butyl- 1 -[[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)benzenesulfonamide as a white solid.
Step 5. N-[ 1 -Butyl- 1 -[[[(1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]- 4-(dimethylamino)-N-methylbenzenesulfonamide
Figure imgf000289_0001
To a solution of 0.476 g (11.90 mmol) of 60% sodium hydride dispersion in mineral oil in 43 mL of tetrahydrofuran was added 4.0 g (8.50 mmol) ofthe solid prepared in Step 4 above and then 1.6 mL of dimethyl sulfate dropwise. The reaction mixture was heated at reflux for one hour, cooled to 0 °C, and then water was added. The reaction mixture was concentrated and 250 mL ethyl acetate and 250 mL water added. The layers were separated and the ethyl acetate solution was washed with 1 M hydrochloric acid (2 x 200 mL), saturated sodium bicarbonate (2 x 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 4.63 g of a residue. The residue was purified by flash chromatography with 15%) ethyl acetate/hexane as eluent to give 3.35 g of N-[l -butyl- l-[[[(l,ldimethylethyl) dimethylsilyl] oxy]methyl]pentyl]-4-(dimethylamino)-N-methylbenzenesulfonamide as an oil. Step 6.
Figure imgf000290_0001
To a solution of 3.35 g (6.90 mmol) ofthe oil prepared in Step 5 above in 35 mL of tetrahydrofuran cooled to 0 °C was added dropwise 9.66 mL of 1.6 M «-butyllithium in hexanes. The reaction mixture was stirred 30 minutes at 0 °C, warmed to room temperature, and stirred one hour. To the reaction mixture was added 6.5 mL of 5% hydrochloric acid and then the Tetrahydrofuran was evaporated. To the residue was added 200 mL dichloromethane and 200 mL water and the layers separated. The dichloromethane layer was washed with brine (200 mL), dried over magnesium sulfate and concentrated to give 3.12 g of a yellow solid.
Step 7. N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide
Figure imgf000290_0002
To a solution of 130 mg (0.11 mmol) of tetrakis(triphenylphosphine) palladium(O) in 10 mL of toluene was added 825 mg of 3-nitrobenzyl bromide. After the toluene solution was stirred 10 minutes, a degassed solution of 2.02 g (3.82 mmol) ofthe solid prepared in Step 6 above in 8 mL ethanol was added followed by 10 mL of 1 M sodium carbonate. The reaction mixture was heated at reflux 45 minutes and then cooled and concentrated. To the residue was added 250 mL of ethyl acetate. The ethyl acetate mixture was washed with brine (2 x 200 mL), dried over magnesium sulfate and concentrated to give 2.76 g of a residue. To the residue was added 200 mL of 30%) ethyl acetate in hexane, and the mixture was stirred 1.5 hours and then filtered through silica. The ethyl acetate solution was concentrated to give 2.30 g ofN-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]- 4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide as a yellow solid.
Step 8. N-[l-Butyl-l-(hydroxymethyl)ρentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide
Figure imgf000291_0001
To a solution of 2.16 g (3.48 mmol) ofthe solid prepared in Step 7 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 4.4 mL of 1 M tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred 15 minutes at 0 °C and then 12 hours at room temperature. To the reaction mixture was added 250 mL of ethyl acetate. The ethyl acetate solution was washed with water (200 mL) and brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 1.88 g of a brown oil residue. The residue was purified by flash chromatography with 30%) ethyl acetate in hexane as eluent to give 1.49 g of N-[l -butyl- 1- (hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide as a yellow oil.
Step 9. N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N-methylbenzenesulfonamide.
Figure imgf000292_0001
To a solution of 1.49 g (2.95 mmol) ofthe oil prepared in Step 8 above in 10 mL of dimethylsulfoxide was added 1.23 mL of triethylamine and then 1.41 g of sulfur trioxide pyridine complex. The reaction mixture was stirred one hour and then diluted with 200 mL water. The aqueous mixture was washed with ethyl acetate (3 x 100 mL). The combined organic layers were washed with 5%> hydrochloric acid (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 25%> ethyl acetate in hexane as eluent to give 1.31 g ofN-[l-butyl-l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide as a yellow oil.
Step 10. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl- 5-(3-nitrophenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide To a solution of 504 mg (2.60 mmol) ofthe oil prepared in Step 9 above in 50 mL of tetrahydrofuran cooled to 0 °C was added 2.80 mL of 1 M potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 15 minutes, water was added, and then the mixture was concentrated to yield a residue. The residue was dissolved in 100 mL ethyl acetate. The ethyl acetate solution was washed with water (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 1.25 g of a semi-solid. The residue was purified by crystallization with ethyl acetate and hexane to give 737.5 mg of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3-nitrophenyl)-l,2- benzothiazepin-4-ol 1,1 -dioxide as a yellow crystalline solid. 'H NMR (CDC13) δ 0.90-1.00 (m, 6H), 1.05-1.80 (m, 12H), 2.50-2.60 (m, IH), 2.79 (s, 6H), 2.85 (s, 3H), 4.09 (d, J= 9.0 Hz, IH), 5.76 (d, J= 2.0 Hz, IH), 5.88 (s, IH), 6.53 (dd, J= 2.4, 8.9 Hz, IH), 7.59 (t, J= 7.9 Hz, IH), 7.84-7.88 (m, 2H), 8.22 (dd, J= 1.0, 8.1 Hz, IH), 8.47 (s, IH). MS (M+H+) 504.
Example 2
(4R,5R)-5-(3-aminoρhenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5- tetrahydro-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000293_0001
A solution of 737 mg (1.46 mmol) ofthe solid prepared in Step 10 of Example 1 was dissolved in 110 mL of ethanol in a 3 oz. Fisher/Porter vessel, and about 150 mg of 10%o Pd/C catalyst was added. This mixture was hydrogenated at 40 psi H2 for 20 hours and then filtered. The filtrate was concentrated to give 0.82 g of a semi-solid material. The semi-solid material was crystallized from ethyl acetate and hexane to give 0.51 g of (4R,5R)-5-(3- aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide as colorless crystals. Η NMR (CDC13) δ 0.89 (t, J= 6.6 Hz, 3H), 0.92 (t, J= 7.2 Hz, 3H), 1.10-1.45 (m, 8H), 1.60-1.75 (m, 3H), 1.98-2.10 (m, IH), 2.48-2.58 (m, IH), 2.79 (s, 6H), 2.81 (s, 3H), 3.69 (s, 2H), 4.12 (d, J= 7.8 Hz, IH), 5.62 (s, IH), 6.07 (d, J= 2.1 Hz, IH), 6.46 (dd, J= 2.4, 8.7 Hz, IH), 6.61 (br d, J= 7.8 Hz, IH), 6.80 (br s, IH), 6.89 (br d, J = 2.1 Hz, IH), 7.15 (t, J= 7.8 Hz, IH), 7.79 (d, J= 8.7 Hz, IH). MS (M+H+) 474.
Example 3
5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]pentanamide
Figure imgf000294_0001
To a solution of 0.25 g (0.53 mmol) ofthe solid prepared in Example 2 above in 3 mL of tetrahydrofuran was added 153 μL of triethylamine followed by 86 μL of 5-bromovaleryl chloride. The reaction mixture was stirred one hour and then concentrated to form a residue. Water (50 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were washed with 5%> hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL) and brine (25 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 0.29 g of a solid. The solid was purified by crystallization with ethyl acetate and hexane to give 202.3 mg of 5-bromo-N- [3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1,1 -dioxido- l,2-benzothiazepin-5-yl]phenyl]pentanamide as a tan solid. 'H ΝMR (CDC13) δ 0.88 (t, J= 7.2 Hz, 3H), 0.92 (t, J= 6.9 Hz, 3H), 1.20-1.42 (m, 8H), 1.57-2.10 (m, 8H), 2.37 (t, J= 6.9 Hz, 2H), 2.46-2.57 (m, IH), 2.78 (s, 6H), 2.81 (m, 3H), 3.41 (t, J= 6.3 Hz, 2H), 4.10 (d, J= 8.5 Hz, IH), 5.69 (s, IH), 5.97 (s, IH), 6.47 (dd, J= 2.4, 8.9 Hz, IH), 7.24-7.40 (m, 4H), 7.76 (br s, IH), 7.80 (d, J= 8.7 Hz, IH). MS (M+H+) 636, 638.
Example 4
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N, N, N-triethyl-5- oxo-pentanaminium trifluoroacetate
Figure imgf000296_0001
C F 3C02
To a solution of 100 mg (0.16 mmol) ofthe solid prepared in Example 3 above in 1 mL of acetonitrile was added 87 μL of triethylamine. The reaction mixture was heated at 55 °C for 28 hours and then at 75 °C for 16 hours. The reaction mixture was concentrated to form a residue. The residue was purified by reverse phase high pressure liquid chromatography to give 16.2 mg of 5- [[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl-l,l-dioxido-l,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5- oxo-pentanaminium trifluoroacetate as a white solid. ]H ΝMR was consistent with the product. MS (M+) 657.
Example 5
2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]acetamide
Figure imgf000297_0001
To a solution of 100 mg (0.21 mmol) ofthe solid prepared in Example 4 above in 2 mL of tetrahydrofuran was added 29 mg of bromoacetic acid, 29 μL of triethylamine, and then 40 mg of ethyldimethylaminopropylcarbodiimide hydrochloride. The reaction mixture was stirred 16 hours and then 50 mL ethyl acetate was added. The ethyl acetate solution was washed with water, 5%> hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), and then brine (25 mL). The ethyl acetate layer was dried over magnesium sulfate and then concentrated to give 88 mg of an oil. The oil was purified by flash chromatography with 50%> ethyl acetate in hexane as eluent to give 72.0 mg of cw-3,3-dibutyl-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-7-dimethylamino-5-(3- (2-chloroaceamido)phenyl)-l,2-benzothiazepine with a trace of 2-chloro-N-[3- [(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]acetamide present. 'H ΝMR was consistent with the product. MS (M+H+) 550. Example 6
2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N, N-triethyl-2- oxoethanaminium chloride
Figure imgf000298_0001
To a mixture of 63 mg (0.12 mmol) ofthe material prepared in Example 5 above in 1 mL of tetrahydrofuran was added 64 μL of triethylamine. The reaction mixture was heated to reflux for three days and then concentrated. The residue was triturated with ether to give 66.5 mg of 2- [[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2- methyl-l,l-dioxido-l,2-benzothiazepin-5-yl]phenyl]amino]-N)N,N-triethyl-2- oxoethanaminium chloride as a tan solid. ]H ΝMR was consistent with the product. MS (M+) 615.
Example 7
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000299_0001
Step 1. N-[ 1 -Butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide
Figure imgf000299_0002
To a solution of 1.00 g (2.06 mmol) ofthe material from Step 5 of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 2 mL of 1.6 M n-butyllithium in hexanes. The reaction mixture was stirred one hour at 0 °C. To the reaction mixture was added 480 μL of trimethyl borate and the mixture stirred 15 minutes at 0 °C and then one hour at room temperature. The reaction mixture was concentrated to form a residue. The residue was dissolved in 20 mL of toluene and 2.1 mL of 2 M aqueous sodium carbonate. To the mixture was added 300 μL ofp-methoxybenzyl chloride and then 71 mg of tetrakis(triphenylphosphine)palladium(0). The reaction mixture was heated at 100 °C for 16 hours, cooled, and then 50 mL of toluene added. The reaction mixture was washed with water (50 mL) and brine (50 mL), filtered through silica, and concentrated to form a residue. The residue was purified by flash chromatography to give 0.82 g of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide as an oil.
Step 2. N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide
Figure imgf000300_0001
The procedure of Step 8 of Example 1 above was followed except that N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy] methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide. Step 3. N-[ 1 -Butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]-N-methylbenzenesulfonamide
Figure imgf000301_0001
The procedure of Step 9 of Example 1 above was followed except that N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N- [ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
The procedure of Step 10 of Example 1 above was followed except that N-[ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N- [ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide. Η ΝMR (CDC13) δ 0.83-0.96 (m, 6H), 1.15-1.38 (m, 6H), 1.69-1.83 (m, 4H), 2.00-2.08 (m, IH), 2.55-2.59 (m, IH), 2.81 (s, 6H), 2.83 (s, 3H), 3.84 (s, 3H), 4.10-41.6 (m, IH), 5.70 (s, IH), 5.99 (s, IH), 6.52 (s, IH), 6.93 (d, J= 8.6 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.6 Hz).
Example 8
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000302_0001
OH
To a solution of 0.52 g (1.06 mmol) ofthe solid prepared in Step 4 of Example 7 above in 10 mL of dichloromethane cooled to -78 °C was added 300 μL of boron tribromide. The reaction mixture was stirred for one hour at - 78 °C and then 100 mL of water and 100 mL of dichloromethane were added. The dichloromethane solution was washed with 10%o aqueous sodium carbonate(100 mL), 10% hydrochloric acid (100 mL) and brine (100 mL). The dichloromethane layer was dried over magnesium sulfate and concentrated to give 0.46 g of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5- tetrahydro-5-(4-hydroxyphenyl)-2-methyl-l ,2-benzothiazepin-4-ol 1 , 1 -dioxide as a solid. ]H NMR (CDC13) δ 0.82-0.97 (m, 6H), 1.15-1.40 (m, 6H), 1.67- 1.76 (m, 4H), 2.00-2.10 (m, IH), 2.51-2.59 (m, IH), 2.83 (s, 6H), 2.84 (s, 9H), 4.12 (d, J= 8.0 Hz, IH), 4.88 (br s, IH), 5.69 (s, IH), 6.07 (d, J= 2.2 Hz, IH), 6.60 (dd, J= 2.2, 8.6 Hz, IH), 6.88 (d, J= 8.6 Hz, 2H), 7.38 (d, J= 8.3 Hz, 2H), 7.85 (d, J= 8.6 Hz). HRMS (ES) Calc'd for C26H39N2O4S: 475.2631. Found: 475.2649.
Example 9
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2- iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1,1- dioxide
Figure imgf000303_0001
To a solution of 0.38 g (0.80 mmol) ofthe solid prepared in Example 8 in 8 mL dimethylformamide was added 44 mg of 95%> sodium hydride and then 730 μL of l,2-bis(2-iodoethoxy)ethane. The reaction mixture was stirred one hour. To the reaction mixture was added 100 mL of water and 100 mL of ethyl acetate and the reaction mixture extracted with ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 10-25%) ethyl acetate in hexane as eluent to give 0.37 g of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2- iodoethyoxy)ethoxy)ethoxy)phenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1,1- dioxide as a solid. HRMS (ES) Calc'd for C32H50N2O6SI: 717.2434. Found: 717.2419. Η NMR is consistent with the structure ofthe product. Example 10 l-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido-1 ,2-benzothiazepin-5- yljphenoxy ] ethoxy] ethoxy] ethyl]pyridinium
Figure imgf000304_0001
A solution of 75 mg ofthe solid prepared in Example 9 above in 5 mL of pyridine was heated at 70 °C for 16 hours. The reaction mixture was concentrated to form a residue. The residue was triturated with ether to give 56.8 mg of l-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5- tetrahydro-4-hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium as a solid. 'H NMR (CDC13) δ 0.89-0.97 (m, 6H), 1.19-1.40 (m, 6H), 1.70-1.74 (m, 4H), 2.00-2.10 (m, IH), 2.60-2.69 (m, IH), 2.80 (s, 6H), 2.83 (s, 3H), 3.69-3.72 (m, 4H), 3.83-3.87 (m, 2H), 4.09-4.15 (m, 5H), 5.23-5.27 (m, 2H), 5.70 (s, IH), 5.97 (d, J= 2.4 Hz, IH), 6.50 (dd, J= 2.4, 8.8 Hz, IH), 6.93 (d, J= 8.8 Hz, 2H), 7.46 (d, J= 8.7 Hz, 2H), 7.83 (d, J= 8.7 Hz, IH), 7.96-8.01 (m, 2H), 8.63-8.67 (m, 2H), 9.52 (d, J= 6.0 Hz, IH). HRMS (ES) Calc'd for C37H54N3O6S: 668.3733. Found: 668.3762. Example 11
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2 -methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide
Figure imgf000305_0001
The procedure of Example 10 was followed except that triethylamine was used in place of pyridine and heating was at 90 °C for 6 hours. 'H ΝMR is consistent with the desired product. 'H ΝMR (CDC13) δ 0.90-0.97 (m, 6H), 1.12-1.45 (m, 15H), 1.60-1.73 (m, 4H), 2.09-2.11 (m, IH), 2.52-2.55 (m, IH), 2.82 (s, 6H), 2.83 (s, 3H), 3.06-3.15 (m, 2H), 3.53 (q, J= 7.2 Hz, 6H), 3.74- 3.75 (m, 4H), 3.86-3.89 (m, 2H), 4.04-4.16 (m, 5H), 5.70 (s, IH), 5.98 (m, IH), 6.50 (d, J= 3.0 Hz, IH), 6.93 (d, J= 8.7 Hz, 2H), 7.45 (d, J= 8.7 Hz, 2H), 7.83 (d, J= 8.7 Hz, IH). HRMS (ES) Calc'd for C38H64Ν3O6S: 690.4516. Found: 690.4548.
Example 12 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3- methoxyphenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000306_0001
The procedures set forth in Example 1 above were followed except that 3-methoxybenzyl chloride was substituted for 3-nitrobenzyl chloride. JH NMR was consistent with the product. Η NMR (CDC13) δ 0.90-0.97 (m, 6H), 1.17- 1.38 (m, 8H),1.69-1.73 (m, 2H), 2.04-2.08 (m, IH), 2.55-2.62 (m, IH), 2.81 (s, 6H), 2.84 (s, 3H), 3.82 (s, 3H), 4.15 (d, J= 7.8 Hz, IH), 5.72 (s, IH), 6.01 (d, J= 2.4 Hz, IH), 6.50 (dd, J= 2.4, 8.4 Hz, IH), 6.86-6.89 (m, IH), 7.05 (br s, IH), 7.13-7.16 (m, IH), 7.32 (t, J= 8.1 Hz, IH), 7.83 (d, J= 8.7 Hz, IH). MS (M+H+) 489.
Figure imgf000306_0002
Example 13
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)- 1 ,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide
Figure imgf000307_0001
Step 1. N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide
To a solution of 2.0 g (4.25 mmol) ofthe material prepared in Step 4 of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 8.0 mL of 1.6 M n-butyllithium in hexane. The reaction mixture was stirred at 0 °C for 30 minutes. To the reaction mixture was added 1.9 mL of trimethyl borate and the mixture stirred 10 minutes at 0 °C and then one hour at room temperature. To the reaction mixture was added 100 mL of water and 5%> hydrochloric acid to bring the solution to a pH of 6-7 and then the volatiles were evaporated. To the aqueous solution was added 100 mL of ethyl acetate and the solution extracted. The ethyl acetate layer was washed with water
(100 mL) and brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was dissolved in 7 mL of ethanol and degassed with nitrogen. In a separate flask was placed 150 mg of tetrakis(triphenylphosphine)palladium(0), 10 mL of toluene and 918 mg of 3- nitrobenzaldehyde. The ethanol solution was added to the toluene solution followed by 10 mL of 1 M aqueous sodium carbonate. The reaction mixture was heated to reflux for one hour, cooled to room temperature, and then stirred for 16 hours. The reaction mixture was concentrated and dissolved in 100 mL of ethyl acetate. The ethyl acetate solution was washed with water (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography to give 1.72 g of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]benzenesulfonamide.
Step 2. N-[l-Butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]benzenesulfonamide
Figure imgf000308_0001
The procedure of Step 8 of Example 1 was followed except that N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 3. N-[1-Butyl-1 -formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyljbenzenesulfonamide
Figure imgf000309_0001
To a solution of 79 μL of oxalyl chloride in 2 mL of dichloromethane cooled to -78 °C was added 107 μL of dimethylsulfoxide and the mixture stirred 20 minutes. To the cooled reaction mixture was added a solution of 370 mg (0.75 mmol) ofthe alcohol from Step 2 above in 2 mL of dichloromethane and the mixture was stirred one hour at -78 °C. To the cooled reaction mixture was added 660 μL of diisopropylethylamine. The reaction mixture was warmed to room temperature and stirred for 30 minutes. To the reaction mixture was added 100 mL of water and mixture was extracted with dichloromethane (2 x 50 mL). The combined dichloromethane layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated to give 0.47 g of a yellow oil. The residue was dissolved in 25 mL of 25% ethyl acetate in hexane and filtered through silica and concentrated. The residue was crystallized with ethyl acetate and hexane to give 301.6 mg of N-[l -butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]benzenesulfonamide as a yellow solid.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3- nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide
To a solution of 150 mg (0.31 mmol) ofthe material prepared in Step 3 above in 6 mL of tetrahydrofuran cooled to -15 °C was added 0.90 mL 1 M of potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 15 minutes at -15 °C and then water was added. The organics were evaporated and 100 mL of ethyl acetate was added and then extracted. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 30% ethyl acetate in hexane as eluent to give 61.8 mg of (4S,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)- l,2-benzothiazepin-4-ol 1,1-dioxide, and 65.7 mg of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide. Η ΝMR and mass spectra were consistent with the product.
Example 14 (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000311_0001
The procedure of Example 2 above was followed except that (4R,5R)- 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide. Η NMR was consistent with the product. MS (M+) 460.
Example 15
5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl)phenyl]pentanamide
Figure imgf000311_0002
The procedure of Example 3 above was followed except that (4R,5R)- 5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-5-(3- aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide. Η NMR was consistent with the product. MS (M+H+) 623.
Example 16
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- 1,1 -dioxido- l,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo-l- pentanaminium trifluoroacetate
Figure imgf000312_0001
To a solution of 54.1 mg (0.09 mmol) ofthe bromide prepared in Example 15 above in 1 mL of tetrahydrofuran was added 48 μL of triethylamine. The reaction mixture was heated at reflux for three days. The solvent was evaporated and the residue triturated with ether. The solid was purified by reverse phase high pressure liquid chromatography to give 17.9 mg of 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-tri ethyl- 5-oxo-l-pentanaminium trifluoroacetate as a white solid. Η NMR was consistent with the product. MS (M+) 643.
Example 17
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-l,2- benzothiazepin-4-ol 1,1-dioxide
Figure imgf000313_0001
Step 1 -2. N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2- (phenylmethyl)benzenesulfonamide
Figure imgf000313_0002
The procedure of Steps 1-2 of Example 7 was followed except that N- [ 1 -butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)benzenesulfonamide and benzyl chloride were used in place of N-[ 1 -butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-N-methylbenzenesulfonamide and /?-methoxybenzyl chloride.
Step 3. N-[1-Butyl-1 -formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide
Figure imgf000314_0001
The procedure of Step 3 of Example 13 was followed except that N-[l- butyl- 1 -(hydroxymethyl)pentyl] -4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[l -butyl- l-(hydroxymethyl) pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
The procedure Step 4 of Example 7 was followed except that N-[l-
Butyl- 1 -formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[l -butyl- l-formylpentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzene- sulfonamide. 'H ΝMR (CDC13) δ 0.9 (m, 6H), 1-1.7 (m, 13H), 2.3 (m, IH), 2.8 (s, 6H), 4.0 (s, 2H), 5.5 (s, IH), 5.9 (s, IH), 6.5 (m, IH), 7.4 (m, 3H), 7.5 (m, 2H), 7.8 (m, IH). MS (M+H+) 445.0. Example 18
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000315_0001
Step 1. N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide
Figure imgf000315_0002
The procedure of Step 1 of Example 7 was followed except that N-[l- butyl- 1 -[[[( 1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)benzenesulfonamide was used in place of N-[l-butyl-l- [[[(1 , 1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N- methylb enzenesulfonamide. Step 2. N-[ 1 -Butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]benzenesulfonamide
Figure imgf000316_0001
The procedure of Step 8 of Example 1 was followed except that N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl] pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzene- sulfonamide.
Step 3. N-[ 1 -Butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide
Figure imgf000316_0002
The procedure of Step 3 of Example 13 was followed except that N-[l- butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
The procedure of Step 10 of Example 1 was followed except that N-[l- butyl-l-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl] benzenesulfonamide was used in place of N-[ 1 -butyl- 1 -formylpentyl]-4-
(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. 'H ΝMR (CDC13) δ 0.89-1.00 (m, 6H), 1.06-1.73 (m, 11H), 2.36 (t, J= 9.5 Hz, IH), 2.80 (s, 6H), 2.98 (s, IH), 3.85 (s, 3H), 3.97 (s, IH), 4.03 (d, J= 9.0 Hz, IH), 5.47 (s, IH), 6.00 (d, J= 2.4 Hz, IH), 6.50 (dd, J= 2.6, 8.9 Hz, IH), 6.95 (d, J= 8.8 Hz, 2H), 7.44 (d, J= 8.5 Hz, 2H), 7.81 (d, J= 8.7 Hz, IH).
Example 19
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000317_0001
OH The procedure set forth in Example 8 above was followed except that (4R,5R)- 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-l,2- benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-l,2- benzothiazepin-4-ol 1,1-dioxide and a reaction temperature of 0 °C was employed. Η NMR (CDC13) δ 0.86-0.97 (m, 6H), 1.15-1.75 (m, 1 IH), 2.35 (t, J= 9.9 Hz, IH), 2.80 (s, 6H), 3.98 (s, IH), 4.02 (d, J= 8.6 Hz, IH), 5.12 (s, IH), 5.45 (s, IH), 5.98 (d, J= 2.4 Hz, IH), 6.48 (dd, J= 2.6, 8.6 Hz, IH), 6.88 (d, J= 8.8 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.80 (d, J= 8.7 Hz, IH).
Example 20
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N, N- triethylethanaminium iodide
Figure imgf000318_0001
Step l
Figure imgf000319_0001
The procedure set forth in Example 9 above was followed except that (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide was used in place of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2- iodoethyoxy)ethoxy)ethoxy)phenyl)-2 -methyl- 1 ,2-benzothiazepin-4-ol 1,1- dioxide and 3.3 equivalents of 95%> sodium hydride was used instead of 2.2 equivalents. 'H NMR was consistent with the product.
Step 2. 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]- N,N,N-triethylethanaminium iodide
The procedure set forth in Example 10 above was followed except that the benzothiazepine prepared in Step 1 above was used. 'H ΝMR (CDC13) δ 0.88-0.05 (m, 6H), 1.14-1.60 (m, 20H), 2.31-2.39 (m, IH), 2.82 (s, 6H), 3.06- 3.15 (m, 2H), 3.54 (q, J= 7.3 Hz, 6H), 3.75-3.81 (m, 4H), 3.88-4.17 (m, 7H), 5.47 (s, IH), 5.98-6.02 (m, IH), 6.47-6.54 (m, IH), 6.93-6.98 (m, 2H), 7.42- 7.47 (m, 2H), 7.81-7.84 (m, IH).
Example 21 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)- 2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000320_0001
Step l. N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-
(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-(phenylmethyl) benzenesulfonamide
Figure imgf000320_0002
NO . To a solution of 4.24 g (7.0 mmol) ofthe sulfonamide prepared in Step 1 of Example 13 in 30 mL of acetone was added 2.90 g of potassium carbonate, 0.517 g of tetra-w-butylammonium iodide then 2.394 g of benzyl bromide. The reaction mixture was heated at reflux for five days. To the reaction mixture was added 2.394 g of benzyl bromide, 0.517 g of tetra-n- butylammonium iodide, and then 2.90 g of powdered potassium carbonate. The reaction mixture was heated at reflux for one day. To the reaction mixture 250 mL of ethyl acetate was added. The ethyl acetate solution was washed with water (3 x 100 mL) and brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to a residue. The residue was purified by flash chromatography to give 1.82 g of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide.
Step 2. N-[l-Butyl-l-(hydroxymethyl)ρentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
Figure imgf000321_0001
The procedure of Step 8 of Example 1 was followed except that N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-(phenylmethyl) benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 3. N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
Figure imgf000322_0001
The procedure of Step 3 of Example 13 was followed except that N-[l-
Butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N-(phenylmethyl)benzenesulfonamide was used in place of N-[l- butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3- nitrophenyl)-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
The procedure of Step 10 of Example 1 was followed except that N-[l- butyl-l-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- (phenylmethyl)benzenesulfonamide was used in place of N-[l -butyl- 1- formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide. Η ΝMR was consistent with the product. MS (M+H+) 580. Example 22
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5- tetrahydro-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000323_0001
To a solution of 50 mg (0.09 mmol) ofthe compound prepared in Step 4 of Example 21 in 50 mL ethanol was added about 10 mg of Pearlman's Catalyst. This mixture was hydrogenated at 60 psi H2 for 20 hours. To the reaction mixture was added about 10 mg of Pearlman's Catalyst and the mixture was hydrogenated at 60 psi at 60 °C for 20 hours. The reaction mixture was filtered and washed with 50 mL of ethyl acetate. The filtrate was washed with water (2 x 50 mL) and brine (50 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 39.8 mg of a residue. The residue was purified by flash chromatography to give 12.6 mg of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5- tetrahydro-2-(phenylmethyl)-l,2-benzothiazepin-4-ol 1,1-dioxide. 'H NMR (CDC13) δ 0.72 (t, J= 6.6, 3H), 0.90 (t, J= 7.4 Hz), 1.00-1.98 (m, 15H), 2.81 (s, 6H), 3.17 (q, J= 7.2 Hz, 2H), 4.15 (d, J= 7.8 Hz, IH), 4.39 (s, 2H), 5.69 (s, IH), 6.12 (s, IH), 6.47 (dd, J= 2.7, 9.0 Hz, IH), 6.61-6.65 (m, IH), 6.78- 6.83 (m, IH), 6.95-7.00 (m, IH), 7.16-7.31 (m, 5H), 7.40 (d, J= 7.2 Hz, IH), 7.81 (d, J= 8.7 Hz, IH). MS (M+H+) 578. Example 23
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
Figure imgf000324_0001
Step l. N-[l-Butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N- (phenylmethyl)benzenesulfonamide
Figure imgf000324_0002
To a solution of 2.15 g (4.05 mmol) ofthe sulfonamide prepared in Step 1 of Example 7 above in 30 mL of dimethylformamide was added 123 mg of 95%) sodium hydride and then 964 μL of benzyl bromide. The reaction mixture was stirred 18 hours. To the reaction mixture was added 250 mL of ethyl acetate and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and brine (150 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 2.88 g of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide.
Step 2. N-[l-Butyl-l-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
Figure imgf000325_0001
The procedure of Step 8 of Example 1 was followed except that N-[l- butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-
(phenylmethyl)benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l- dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 3. N-[l -Butyl- l-formylpentyl]-4-(dimethylamino)-2-[(3- nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide
Figure imgf000326_0001
The procedure of Step 3 of Example 13 was followed except that N-[l- butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide was used in place of N-[l-butyl-l-[[[(l-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide.
Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide
The procedure of Step 10 of Example 1 was followed except that N-[l- butyl-l-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- (phenylmethyl)benzenesulfonamide was used in place of N-[l -butyl- 1- formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N- methylbenzenesulfonamide. 'H ΝMR (CDC13) δ 0.7 (m, 3H), 0.9 (m, 3H), 1- 1.7 (m, 10H), 1.9 (m, IH), 2.1 (m, IH), 2.8 (s, 6H), 3.8 (s, 3H), 4.1 (s, IH), 4.4 (s, 2H), 5.8 (s, IH), 6.0 (s, IH), 6.5 (m, IH), 7.0 (d, J= 8 Hz, IH), 7.1-7.5 (m, 7H), 7.8 (m, IH). Example 24
(4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)- spiro[l ,2-benzothiazepine-3(2H), 1 '-cyclopentan]-4-ol 1 , 1 -dioxide
Figure imgf000327_0001
Step 1. N-[l-(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide
Figure imgf000327_0002
The procedure of Step 2 of Example 1 was followed except that cycloleucinol was substituted for 2-amino-2-butylhexanol.
Step 2-3. N-[ 1 -[[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)benzenesulfonamide
Figure imgf000327_0003
The procedure of Steps 3 and 4 of Example 1 was followed except that N-[l-(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide was used in place of N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide.
Step 4. N-[ 1 -[[[( 1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide
Figure imgf000328_0001
The procedure of Step 1 of Example 7 was followed except that N-[l- [[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4- (dimethylamino)benzenesulfonamide was used in place of N- [1 -butyl- 1- [[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N- methylbenzenesulfonamide.
Step 5. N-[ 1 -(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-ethylbenzenesulfonamide
Figure imgf000328_0002
To a solution of 0.25 g (0.49 mmol) ofthe sulfonamide prepared in Step 4 above in 5 mL of tetrahydrofuran was added 25 mg of 95% sodium hydride. After 15 minutes, 125 μL of ethyl iodide was added to the reaction mixture. The reaction mixture was stirred 16 hours. To the reaction mixture was added 5 mL ofdimethylformamide and the mixture stirred four hours. To the reaction mixture 100 mL of water was added and the mixture extracted with 100 mL of ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give 0.27g of an oil.
Step 6-8. (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4- methoxyphenyl)-spiro[ 1 ,2-benzothiazepine-3 (2H), 1 ' -cyclopentan]-4-ol 1,1- dioxide
The procedure of Steps 8-10 of Example 1 was followed except that N- [ 1 -(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4- methoxyphenyl)methyl]-N-ethylbenzenesulfonamide was used in place of N- [1 -butyl- 1-[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]ρentyl]-4- (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. *H ΝMR was consistent with product. MS (M+H+) 445.
Biological Assays The utility ofthe compounds ofthe present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility ofthe present invention.
In Nitro Assay Of Compounds That Inhibit IBAT-Mediated Uptake Of r14C]- Taurocholate (TO in HI 4 Cells
Baby hamster kidney cells (BHK) transfected with the cDΝA of human IB AT (HI 4 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within 24 hours of seeding; 30,000 cells/well for assays run within 48 hours; and 10,000 cells/well for assays run within 72 hours. On the day of assay, the cell monolayer is gently washed once with
100 mL assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2%o (w/v) fatty acid free bovine serum albumin ((FAF)BSA). To each well 50 mL of a two-fold concentrate of test compound in assay buffer is added along with 50 mL of 6 mM [14C]-taurocholate in assay buffer (final concentration of 3 mM [14C]-taurocholate). The cell culture plates are incubated two hours at 37° C prior to gently washing each well twice with 100 mL of 4° C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 mL of 4° C PBS without (FAF)BSA. To each 200 mL of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.
In Vitro Assay Of Compounds That Inhibit Uptake Of F14Cl-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
Data from each ofthe noted compounds in this assay is as set forth in Table 4 below: Table 4
Figure imgf000331_0001
In Vivo Assay Of Compounds That Inhibit Rat Ileal Uptake Of I"14C1- Taurocholate into Bile
(See "Metabolism of 3 ,7βdihydroxy-7β-methyl-5β-cholanoic acid and 3 ,7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)
Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10 " length of PEI 0 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction ofthe small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 mL of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" LD. x 0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 minutes with warm PBS at 0.25 mL/minute. Temperature of the gut segment is monitored continuously. At the start ofthe experiment, 2.0 mL of control sample ([1 C]-taurocholate @ 0.05 mi/mL with 5 mM cold taurocholate) is loaded into the gut segment with a 3 mL syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 mL/minute for 21 minutes. Bile samples fractions are collected every three minutes for the first 27 minutes ofthe procedure. After the 21 minutes of sample infusion, the ileal loop is washed out with 20 mL of warm PBS (using a 30 mL syringe), and then the loop is washed out for 21 minutes with warm PBS at 0.25 mL/minute. A second perfusion is initiated as described above but with the test compound being administered as well (21 minutes administration followed by 21 minutes of wash out) and bile sampled every three minutes for the first 27 minutes. If necessary, a third perfusion is performed as above that typically contains the control sample. Measurement Of Hepatic Cholesterol Concentration (HEPATIC CHOP Liver tissue is weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant is separated and dried under nitrogen. The residue is dissolved in isopropanol and the cholesterol content is measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.
Measurement Of Hepatic HMG CoA-Reductase Activity (HMG CO A Hepatic microsomes are prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C in the presence of 14C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HCl followed by centrifugation. An aliquot ofthe supernatant is separated, by thin- layer chromatography, and the spot corresponding to the enzyme product is scraped off the plate, extracted and radioactivity is determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).
Determination Of Serum Cholesterol (SER.CHOL. HDL-CHOL. TGI and NLDL + LDL)
Total serum cholesterol (SER.CHOL) is measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol Cl 1, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) is assayed using this same kit after precipitation of NLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) are assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. NLDL and LDL (VLDL + LDL) cholesterol concentrations are calculated as the difference between total and HDL cholesterol.
Measurement Of Hepatic Cholesterol 7- Hvdroxylase Activity (7 -OHase') Hepatic microsomes are prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37° C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/ methanol. The enzymatic product is separated by injecting an aliquot ofthe extract onto a C]8 reversed phase HPLC column and quantitating the eluted material using UN detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).
Rat Gavage Assay Male Wister rats (275-300g) are administered IB AT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:00 a.m.) for four days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours ofthe treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison ofthe increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group. Table 5 describes the results of this assay when the compound of Example 4 was tested. Table 5
Figure imgf000335_0001
Measurement Of Fecal Bile Acid Concentration (FBA Total fecal output from individually housed hamsters is collected for
24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present is measured enzymatically using the 3α-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).
[3H"|taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMN)
Rabbit Ileal brush border membranes are prepared from frozen ileal mucosa by the calcium precipitation method described by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate is essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume is 200 μL instead of 100 μL. Briefly, at room temperature a 190 μL solution containing 2μM [3H]-taurocholate(0.75 μCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 is incubated for 5 seconds with 10 μL of brush border membrane vesicles (60-120 μg protein). The incubation is initiated by the addition ofthe BBMN while vortexing and the reaction is stopped by the addition of 5 mL of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 μm pore) and an additional 5 mL wash with stop buffer.
Acyl-CoA; cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes are prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consists of a 2.0 mL incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 μg of microsomal protein. The assay is initiated by the addition of oleoyl-Co A. The reaction proceeds for five minutes at 37° C and is terminated by the addition of 8.0 mL of chloro form/methanol (2:1). To the extraction is added 125 μg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases ofthe extraction are separated by centrifugation after thorough vortexing. The chloroform phase is taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed is determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager. The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope ofthe present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope ofthe following claims.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000337_0001
wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consistmg of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
R and R are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -
SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRnR12; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR ; -NR R ; - SR9; -S(O)R9; -SO2R ; and -SO3R9; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and
R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -NO2; -CN; oxo; hydrocarbyl; -OR13; -NR13R14; -SR13; -S(O)R13; - SO2R13; -S03R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; - SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR,4R15; -PR13R14; - P(O)R13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A"; and - N R R R A"; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen or hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein A" is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; and wherein R9 is as defined above; or R4 and R6 together represent a bond; and R is selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -Nθ2; hydrocarbyl; -OR 13 ; -
NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A"; -
NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -S(O)nNR13R14; -
N+R13R14R15A-. _PR13R14. _P(0)R13R14. _P+R13R14R15A-. aminQ ^ residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R13, R14, R15, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and pprroovviiddeedd tthhaatt aatt lleeaasstt oonnee 1 of R , R , R , R , R , and R is a radical other than hydrogen or alkyl; aanndd
C sr r fr pprroovviiddeedd tthhaatt wwhheenn 1 R or R is aryl, the other of R and R is a radical other than heterocycylalkyl.
2. A compound of claim 1 wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or
R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-Cι0 cycloalkenyl; wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -
OR9; -NR9R10; -N+R9R10RWA"; -SR9; -S+R9R10A"; -PR9R10; - p+R9R10RwA-. _S(0)R9. _so2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A"-; - PR9-; -P(O)R9-; -P+R9R! 0A"-; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -
S(O)R9; -Sθ2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRHR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and
R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -Nθ2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R ; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR,3SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"
-S-; -SO-; -SO2-; -S+R7N-; -PR7-; -P(O)R7-; -P+R7R8N-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR ; -NR R ; -
N+R9R10RwA-; _SR16. _S(0)R9 ; -Sθ2R9; -SO3R16; -Cθ2R16; -
CONR9R10; -SO2NR9R10; -PO(OR16)OR1 ?; -P9R10; -P+R9R10RπA-; - S R R A-; and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; 105 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have 110 one or more carbons replaced by -O-; -NR9-; -N+R9R! °N-; -S-; -SO-; -SO2-;
-S+R9A--; -PR9-; -P+R9R10A -; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and group
Figure imgf000343_0001
115 wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, Rw, and A" are as defined above; and R is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx radicals are independently selected from the group 120 consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR 13 ; -
NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A"; -
NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -
125 NR,4C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -
S(O)nNR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A"; -PR13R14; - P(O)R13R14; -P+R13R14R15A"; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl;
130 alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ; - NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; - CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -P9R10; -P+R9RUR12A"; - 35 S R R A"; and carbohydrate residue; and wherein the Rx quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; 140
Figure imgf000344_0001
145 wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14N-; -S-; -SO-; -SO2-; - S+R13A"-; -PR13-; -P(O)R13-; -PR13R14; -P+R13R14N-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide
150 residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally
9 + 9 10 - may have one or more carbons replaced by -O-; -NR -; -N R R A -; -S-; -
SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10A--; or -P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 155 heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may 160 be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9RπR12A"; -SR9; - S(O)R9; -S02R9; -SO3R9; -Cθ2R9; -CONR9R10; -SO2OM; -SO2NR9R10; _pR9R10. _p(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, Rw, A", and M are as 65 defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
3. A compound of claim 1 wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10R A"
; -SR9; -S+R9R!0A-; -PR9R10; -P+R9R10RWA"; -S(O)R9; -SO2R9; -SO3R9; -
CO2R9; and -CONR9R10; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR 9 -; -
N+R9R10A--, -S-; -SO-; -SO2-; -S+RV-, -PR9-; -P(O)R9-; -P+R9R10A--, or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; - S(O)R9; -Sθ2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRnR12; wherein R 1 1 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or
R 1 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10are as defined above; and
R and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R and R alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -Nθ2; oxo; alkyl; polyalkyl; haloalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13;
-Sθ2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -
SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;
-NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR,3SO2NR14R15; -PR13R14; - P(O)R13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A"; and - N+R13R14R15A-. and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A" -; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or 75 wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they 80 are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; 85 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10RWA"; -SR16; - 90 S(O)R9; -S02R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -
PO(OR16)OR17; -PR9R10; -P+R9R10RHN; -S+R9R10A"; and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 95 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _g_. _so_. _SQ2_. _s+R9A-_. _pR9_. _p+R9R10A._. _p(o)RQ
100 phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and
1 17 wherein R and R are independently selected from the group consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and 105 wherein R9, R10, Rπ, R12, R , and A" are as defined above; and
R is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; and aralkyl; and oonnee oorr mmoorree RRx rraadicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; 110 haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; - S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; - C(O)OM; -COR13; -OR18; -S(O)nNR13R14; -NR13R18; -NR18OR14; -
115 N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15 A-; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether;
120 and acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ; - NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; - CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RπR12A"; - S R R A"; and carbohydrate residue; and
125 wherein the Rx quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13;
130 -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; - SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; - PR13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A"; and - N+R13R14R15A"; and carbohydrate residue; and wherein the Rx radicals comprising carbon optionally may have one or
135 more carbons replaced by -O-; -NR13-; -N+R13R14A"-; -S-; -SO-; -SO2-; -
S+R13A"-; -PR13-; -P(O)R13-; -PR13-; -P+R13R14A"-; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl
9 optionally may have one or more carbons replaced by -O-; -NR -; -
140 N+R9R10A"-; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10A'-; or -P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and 145 heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of 150 halogen; -CN ; oxo; -OR9; -NR9R10; -N^R1 ^A"; -SR9; -S(O)R9; -
SO2R9; -SO3R9; -C02R9; -CONR9R10; -SO2OM; -SO2NR9R10; -
PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; or 155 a pharmaceutically acceptable salt, solvate, or prodrug thereof.
4. A compound of claim 1 wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen; (CrC10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
5 aryl(CrC10)alkyl; (C1-C10)alkoxy(C,-C10)alkyl; (CrC,o)alkoxy(C2-C10)alkenyl;
(C1-C10)alkoxy(C2-C10)alkynyl; (C,-C10)alkylaryl; and (polyalkyl)aryl; or
R 1 and R 2 taken together with the carbon to which they are attached form (C3-CI0)cycloalkyl; wherein the R1 and R2 (C,-C10)alkyl; (C3-C10)cycloalkyl; (C2-
10 C10)alkenyl; (C2-C10)alkynyl; aryl(CrC10)alkyl; (CrC10)alkoxy(C1-C10)alkyl; (C1-C1o)alkoxy(C2-C1o)alkenyl; (C1-C1o)alkoxy(C2-C10)alkynyl; (C1- C10)alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RWA"; -SR9; -S+R9R10N; -PR9R10; -
15 P+R9R] °R A"; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CO Al1 °; and wherein the R1 and R2 (CrC,0)alkyl; (C3-C10)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl(C1-C10)alkyl; (C1-C10)alkoxy(C1-C10)alkyl; (C1-C10)alkoxy(C2-C1o)alkenyl; (C1-C1o)alkoxy(C2-C10)alkynyl; (C1- C10)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more
20 carbons replaced by -O-; -NR9-; -N+R9R! °A--; -S-; -SO-; -SO2-; -S+R9A~-; - PR9; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; ammonium(C1-C10)alkyl; (Cr C10)alkylammonium(CrC10)alkyl; aryl(C,-C10)alkyl; heterocyclyl(Cr C10)alkyl; carboxy(CrC10)alkyl; carbo(CrC10)alkoxy(C1-C10)alkyl; carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R and R are independently selected from the group consisting of hydrogen; (CrC]0)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; - OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; (C1-C10)alkyl; (C2-C10)alkenyl;
(C2-Cj0)alkynyl; aryl; heterocyclyl; aryl(CrC10)alkyl; carboxy(CrC10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl; (C3-C10)cycloalkyl; cyano(CrC]0)alkyl; -
OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -
CONR9R10; or R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and
R and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-Cι0)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein the R5 and R6 (CrC10)alkyl; (C3-C10)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; (Cr
C10)alkyl; polyalkyl; halo(C,-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; ary^ -C^alkyl; heterocyclyl(C,-C10)alkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -
SO2R13; -Sθ3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; - NRI3C(O)R14; -NR,3C(O)NR14R15; -NR1 CO2R14; -OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR,3SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; - P(O)R13R14; -PR13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A" ; and -N+R13R14R15A"; and wherein the (CrCI0)alkyl, polyalkyl, halo(CrC10)alkyl, hydroxy(Cr
C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-CI0)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(C1-C10)alkyl, heterocyclyl(C!- C]0)alkyl, and polyether substituents ofthe R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; (CrCι0)alkyl; (C3-C10)cycloalkyl; (C -C10)alkenyl; (C2-C]0)alkynyl; aryl; heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; - S(O)R7; -Sθ2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; - P(O)R7R8; -PR7R8; -P+R7R8R9A"; and -P(O)(OR7)OR8; and wherein the (CrC]0)alkyl, polyalkyl, halo(CrC10)alkyl, hydroxy(Cr
C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CrC10)alkyl, heterocyclyl(C,-
C10)alkyl, and polyether substituents ofthe R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"-; -S-; -SO-; - SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A'-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and (CrC10)alkyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(CrC10)alkyl; (C3-CI0)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C,-C10)alkylaryl(C1-C1o)alkyl; (C,- C10)alkylheterocyclyl(CrC10)alkyl; (C1-Cι0)alkylammonium(C1-CI0)alkyl; carboxy(C,-C10)alkylaminocarbonyl(C1-C,o)alkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 (C,-C10)alkyl; halo(CrC10)alkyl; (C3- C,0)cycloalkyl; polyalkyl; (C2-CI0)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(C,-C10)alkyl; (CrC10)alkylaryl (C,-C10)alkyl; (Cr 95 C10)alkylheterocyclyl(CrC10)alkyl; (C1-C10)alkylammonium(CI-C10)alkyl; aminocarbonyl(CrCI0)alkyl; (C1-C10)alkylaminocarbonyl(C1-C10)alkyl; carboxy(CrC10)alkylaminocarbonyl (CrC10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; (C,-C10)alkyl; sulfo(Cr
100 C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(Cr C10)alkyl; carboxy; carboxy(CrC10)alkyl; guanidinyl; -OR16; -NR9R10; - N+R9R10RwA-. _SR16. .S(0)R9 ; -S02R9; -SO3R16; -CO2R16; - CONR9R10; - -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10RnA- ; -S R R A-; and carbohydrate residue; and
105 wherein the R13, R14, and R15 (C,-C10)alkyl; halo(CrC10)alkyl; (C3-
C10)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylaryl(C1-C10)alkyl; (Cr C10)alkylheterocyclyl(CrC10)alkyl; (Cι-C10)alkylammonium(C1-C10)alkyl;
110 aminocarbonyl(CrC10)alkyl; (C1-C10)alkylaminocarbonyl(CrC)o)alkyl; carboxy(C1-C10)alkylaminocarbonyl(C1-C10)alkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. .S+R9A._. _pR9_. .p+R9R10A._. .p(o)R9.. phenylene; carbohydrate residue; amino acid residue; peptide residue; or 115 polypeptide residue; and wherein
Figure imgf000352_0001
are independently selected from the group 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, Rπ, R12, R , and A" are as defined above; and
120 R is selected from the group consisting of hydrogen; (CrCI0)alkyl;
(C2-C10)alkenyl; (C2-C10)alkynyl; and aryl(CrC10)alkyl; and one or more R radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; (C,-C10)alkyl; (C3-
C10)cycloalkyl; polyalkyl; halo(CrC10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
125 aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-CI0)alkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; - S+R13R14A.. .NRBQRM. .^13^14^5. _cθ2R13; -OM; -SO2OM; -
SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18;
-S(O)nNR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A_; -PR13R14; - 130 P(O)R13R14; -P+R13R14R! 5A"; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the Rx (CrC10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(Cr
CI0)alkyl; hydroxy(CrC10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(C,-C10)alkyl; polyether; and 135 acyloxy radicals optionally may be further substituted with halogen; -CN; oxo;
-OR16; -NR9R10; -N+R9RπR12A"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -
CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -
P+R9RUR12A"; or -S+R9R10A"; and wherein the R" quaternary heterocyclyl radical optionally may be 140 substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; (CrC10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(CrC10)alkyl; hydroxy(CrC10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(CrCι0)alkyl; heterocyclyl(CrC10)alkyl; polyether; -
OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; - 145 NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14;
-C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; -
P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A -; -S-; -SO-; -SO2-; - 150 S+R13A"-; -PR13-; -P(O)R13-; -PR13-; -P+R13R14A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR 9 -; -N + R 9 R 10 A - -; -S-; -
155 SO-; -SO2-; -S+R9A-; -PR9-; -P+R9R10A"-; or -P(O)R9-; and wherein R 18 is selected from the group consisting of (CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; acyl; and aryl(Cr
C10)alkoxycarbonyl; and wherein the R18 (CpC10)alkyl; heterocyclyl; quaternary heterocyclyl;
160 aryl(C1-C10)alkyl; acyl; and aryl(CrC10)alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9R! 1R12A"; -SR9; - S(O)R9; -S02R9; -SO3R9; -Cθ2R9; -CONR9R10; -SO2OM; -SO2NR9R10; _PR9R10. .p(0R13)OR14; -PO(OR16)OR17; and -C(O)OM; and
165 wherein R9, R10, Ru, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and
170 provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
5. A compound of claim 1 wherein: q is an integer from 1 to 4;
R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
5 butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or 1
R and R taken together with the carbon to which they are attached
10 form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and
R and R are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and
R and R6 are independently selected from the group consisting of
15 hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl,
20 dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, piperazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and
R is selected from the group consisting of hydrogen, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n-butylcarbonylamino, n-pentylcarbonylamino, n- hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, morpholinyl, N-methyl-mo holinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N-methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N'- dimethyl-piperazinium, piperidinyl, methylpiperidinyl, N-methyl- piperidinium, and thienyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6. A compound of claim 1 wherein: q is an integer from 1 to 4;
R and R are independently selected from the group consisting of hydrogen and (CrC10)alkyl; or 1 2 R and R taken together with the carbon to which they are attached form (C3-C10)cycloalkyl; and
R and R are independently selected from the group consisting of hydrogen and hydroxy; and
R is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen; hydroxy; -Nθ2; (CrC10)alkyl; halo(CrC10)alkyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrCI0)alkyl; heterocyclyl(C,-C10)alkyl; quaternary heterocyclyl(CrCι0)alkyl; (C,-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-Cιo)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C,-C10)alkyl; halo(C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C,- C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylheterocyclyl(C1- Cιo)alkyl; (C1-C10)alkylammonium(C,-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; ( -C^alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(Cr
C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and wherein R 9 and R 10 are independently selected from the group consisting of hydrogen; (CrCι0)alkyl; heterocyclyl; ammonium(CrC10)alkyl;
(CrC1o)alkylammonium(CI-C10)alkyl; aryl(C!-C10)alkyl; heterocycly^C]- C10)alkyl; carboxy(C,-C10)alkyl; carbo(C1-C1o)alkoxy(CrC10)alkyl; carboxyheterocyclyl; carboxy(CI-C10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; heterocyclyl; aryl(CrCι0)alkyl; carboxy(C,-C10)alkyl; and carbo(C1-C10)alkoxy(CI-C10)alkyl; or
R 1 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein Rw and R16 are as defined in claim 2; and
R6 is hydrogen; and R is selected from the group consisting of hydrogen; (CrC10)alkyl; and aryl(CrC10)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; -NO2; (C,-C10)alkyl; halo(CrC10)alkyl; -OR 13 ; -
NR13R14; wherein R13 and R14 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
7. A compound of claim 1 wherein: q is an integer from 1 to 4; R 1 and R 2 are independently selected from the group consisting of ethyl and n-butyl; or
1 2 R R1 aanndd RR2 ttaaken together with the carbon to which they are attached form cyclopenty yll;; aanndd one of R and R is hydrogen and the other of R and R is hydroxy; and
R is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and R6 is hydrogen; 90 R is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino,
95 trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or 100 a pharmaceutically acceptable salt, solvate, or prodrug thereof.
8. A compound of claim 1 selected from the compounds of the group consisting of:
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3- 5 nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
10 5-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5 -yl]phenyl]pentanamide;
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2- methyl- 1 , 1 -dioxido-1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N, N-triethyl-5- oxo-pentanaminium trifluoroacetate;
2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2 -methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]acetamide;
2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2- methyl-l,l-dioxido-l,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-2- oxoethanaminium chloride; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2- iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1,1- dioxide;
l-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-2-methyl- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5- yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3- methoxyphenyl)-2-methyl- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)- l,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-l,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-l,l-dioxido-l,2-benzothiazepin-5-yl)phenyl]pentanamide;
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- 1 , 1 -dioxido- 1 ,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo- 1 - pentanaminium trifluoroacetate; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-l,2- benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- hydroxyphenyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4- hydroxy-l,l-dioxido-l,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N- triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2- (phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5- tetrahydro-2- (phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4- methoxyphenyl)-2-(phenylmethyl)- 1 ,2-benzothiazepin-4-ol 1 , 1 -dioxide; and
(4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)- spiro[l,2-benzothiazepine-3(2H),l'-cyclopentan]-4-ol 1,1-dioxide; and
their pharmaceutically acceptable salts.
9. A compound of claim 2 wherein R and R are independently selected from the group consisting of H; aryl; heterocyclyl; and quaternary heterocyclyl; wherein the R and R aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CΝ; -ΝO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; - OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; - NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NRI3C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; - OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and Rδ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A"; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R5 and R6 radicals
7 + 7 8 optionally may have one or more carbons replaced by -O-; -NR -; -N R R A"
-; -S-; -SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wwhheerreeiinn RR aamnd R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -
CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - P^R^R1 1 A-; -S+R9R10A-; and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -
N+R9R10A -; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10N-; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000363_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, Ru, R12, Rw, and A" are as defined in claim 2.
10. A compound of claim 2 wherein R or R has the formula
Figure imgf000363_0002
wherein: t is an integer from 0 to 5;
Ar is selected from the group consisting of phenyl; thiophenyl; pyridyl; piperazinyl; piperonyl; pyrrolyl; naphthyl; furanyl; anthracenyl; quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; oxazolyl; isoxazolyl; pyrimidinyl; thiazolyl; triazolyl; isothiazolyl; indolyl; benzoimidazolyl; benzoxazolyl; benzothiazolyl; and benzoisothiazolyl; and one or more R^ are independently selected from the group consisting of halogen; -CN; -Nθ2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13;
-S02R13; -S03R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -
SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
NR13C(O)R14; -NR,3C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;
-NR13SOR14; -NR13SO2R14; -NR,3SONR14R'5; -NR13SO2NR14R'5; - P(O)R13R14; -PR13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl;
7 aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR ;
-NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -
N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may
7 + 7 8 have one or more carbons replaced by -O-; -NR -; -N R R A'-; -S-; -SO-; - SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; - CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - p+R9R10Rl lA_. _S+R9R10A_. and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _s+R9A-_. _pR9_. _p+R9R10A-_. _p(0)R9_. phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000365_0001
are independently selected from the group 9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, Rw, and A" are as defined in claim 2.
11. A compound of claim 2 wherein at least one of R and R has the formula
Figure imgf000366_0001
(II)
wherein Ry and t are defined as in claim 10.
12. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, alkyl and aralkyl.
13. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, (CrCι0)alkyl and aryl(C,-C10)alkyl.
14. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
15. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl.
16. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen and (CrC10)alkyl.
17. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of (CrC^alkyl.
18. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of (C,-C7)alkyl.
19. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of (C2-C4)alkyl.
20. A compound of claim 11 wherein R 1 and R 2 are the same (Cr
C10)alkyl.
21. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
22. A compound of claim 11 wherein R1 and R2 are each n-butyl.
23. A compound of claim 11 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is n-butyl.
24. A compound of claim 11 wherein q is 1, 2, or 3.
25. A compound of claim 11 wherein q is 1 or 2.
26. A compound of claim 11 wherein q is 1.
27. A compound of claim 11 wherein R3 and R4 are independently selected from the group consisting of hydrogen and -OR9.
9 .
28. A compound of claim 27 wherein R is hydrogen.
29. A compound of claim 28 wherein said hydroxy group is in a syn relationship to said stmcture of formula (II).
30. A compound of claim 11 wherein R radicals are present at the 7-, 8- and 9-positions ofthe benzo ring ofthe stmcture of formula (I).
31. A compound of claim 11 wherein an Rx radical is present at one or more ofthe 7-, 8-, or 9-positions ofthe benzo ring ofthe stmcture of formula (I).
32. A compound of claim 11 wherein Rx radicals are present at the 7- and 9-positions ofthe benzo ring ofthe stmcture of formula (I). X
33. A compound of claim 11 wherein an R radical is present at the 7-position ofthe benzo ring ofthe stmcture of formula (I).
34. A compound of claim 32 wherein said one or more R are independently selected from the group consisting of alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR ; -NR R ; - NR13NR14R15; -N+R9RUR12A"; -SR13; -S+R13R14A; -CO2R13; and - NR14C(O)R13; wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; oxo; -CO2R16; -CN; halogen; - CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RUR12A"; or -S+R9R10A"; and wherein in Rx, one or more carbons are optionally replaced by -O-; - NR13-; -N+R13R14A"-; -S-; -SO-; -SO2-; -S+R13N-; -PR13-; -P(O)R13-; - P R R A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons
9 + 9 10 are optionally replaced by -O-; -NR -; -N R R A-; -S-; -SO-; -SO2-; -
S+R9A--; -PR9-; -P+R9R10A"-; or -P(O)R9-.
Y
35. A compound of claim 33 wherein said one or more R are independently selected from the group consisting of alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR ; -NR R ; - NR13NR14R15; -N+R9RUR12A"; -SR13; -S+R13R14A'; -CO2R13; and - NR14C(O)R13; wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; oxo; -CO2R16; -CN; halogen; - CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RUR12A"; or -S+R9R10A"; and wherein in Rx, one or more carbons are optionally replaced by -O-; - NR13-; -N+R13R14AA -S-; -SO-; -SO2-; -S+R13A-; -PR13-; -P(O)R13-; - P +R 13 R 14 A - -; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons are optionally replaced by -O-; -NR9-; -N+R9R10A"-; -S-; -SO-; -SO2-; -
S+R9A -; -PR9-; -P+R9R10A"-; or -P(O)R9-.
36. A compound of claim 34 wherein said one or more R" are independently selected from the group consisting of polyether; -OR 13 ; -
NR13R14; and -N+R9RUR12A".
• • •
37. A compound of the claim 35 wherein said R is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9RUR12A".
38. A compound of claim 36 wherein said one or more Rx are independently selected from the group consisting of -OR and -NR R .
39. A compound of claim 37 wherein said Rx is independently selected from the group consisting of -OR and -NR R .
40. A compound of claim 38 wherein R and R are each methyl.
41. A compound of the claim 39 wherein R and R are each methyl.
42. A compound of claim 11 wherein an R^ substituent is attached at the 3- or the 4-position ofthe phenyl ring ofthe stmcture of formula (II).
43. A compound of claim 11 wherein t is 1 or 2.
44. A compound of claim 42 wherein t is 1 or 2.
45. A compound of claim 11 wherein said one or more R^ are independently selected from the group consisting of hydrogen; halogen; hydroxy; -NO2; (C,-C10)alkyl; halo(CrC10)alkyl; aryl(C,-C10)alkyl; heterocyclyl(CrC,0)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylheterocyclyl(C1-CI0)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R , R , and R (CrCι0)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C10)alkyl; halo(C,-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C]0)alkylammonium(CI-C1o)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(C,-C10)alkyl; -OR16; -NR9R10; -
N+R9R10RwA-. and _CONR9R10; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; ammonium(CrC10)alkyl; (Cι-CI0)alkylammonium(C,-C10)alkyl; aryl(CrC10)alkyl; heterocyclyl(Cr C10)alkyl; carboxy(CrC10)alkyl; carbo(C1-C10)alkoxy(C,-C10)alkyl; carboxyheterocyclyl; carboxy(CrC10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; (C C10)alkyl; heterocyclyl; aryl(CrC10)alkyl; carboxy(CrC10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R
Figure imgf000370_0001
are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
46. A compound of claim 11 wherein said R^ is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methy lcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
47. A compound of claim 11 wherein said one or more R^ are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
48. A compound of claim 11 wherein said one or more R^ are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino , triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
49. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl.
50. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
51. A compound of claim 50 wherein said hydroxy group is in a syn relationship to said stmcture of formula (II).
52. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and
R ,X i ;s sel ιec_t_e_d J fr {■ om t 4hl e group consi ;st ,i;ng of c pol 1y. „et+h1 er; -O"vRπ 1 J .
.14; and -N+R9RUR12A-; wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
53. A compound of claim 11 wherein:
1 2
R and R are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
54. A compound of claim 11 wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and Rx is selected from the group consisting of polyether; -OR ; -NR R ; and -
N+R9RUR12A"; wherein R9, R", R12, R13 and R14 are as defined in claim 2.
55. A compound of claim 11 wherein:
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and x 13
R is selected from the group consisting of polyether; -OR ; - NR13R14; and -N+R9R! ^^A"; wherein R9, R", R12, R13 and R14 are as defined in claim 2.
56. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
57. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R is selected from the group consisting of polyether; -OR ; -NR R ; and -
N+R9RπR12A"; wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
58. A compound of claim 11 wherein:
RN is selected from the group consisting of hydrogen, alkyl and aralkyl; R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and
R x is selected from the group consisting of polyether; -OR 13 ; -
NR13R14; and -N+R9RπR12A-; wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
59. A compound of claim 11 wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl;
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and
R x is selected from the group consisting of polyether; -OR 13 ; -
M13R14; and -N+R9RπR12A ; wherein R9, Ru, R12, R13 and R14 are as defined in claim 2.
60. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and
R x is selected from the group consisting of polyether; -OR 13 ; -
NR13R14; and -N+R9RUR12A"; wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
61. A compound of claim 60 wherein RN is selected from the group consisting of hydrogen, ( -Cit alkyl and
Figure imgf000375_0001
62. A compound of claim 60 wherein RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
63. A compound of claim 60 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen and (CrC10)alkyl.
64. A compound of claim 60 wherein R 1 and R 2 are independently selected from the group consisting of (CrC10)alkyl.
65. A compound of claim 60 wherein R 1 and R 2 are independently selected from the group consisting of (C2-C4)alkyl.
66. A compound of claim 60 wherein R 1 and R 2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
67. A compound of claim 60 wherein R1 and R2 are each n-butyl.
68. A compound of claim 60 wherein one of R 1 and R 2 is ethyl and the other of R 1 and R 2 is n-butyl.
69. A compound of claim 60 wherein q is 1, 2, or 3.
70. A compound of claim 60 wherein q is 1 or 2.
71. A compound of claim 60 wherein q is 1.
72. A compound of claim 60 wherein R radicals are present at the 7-, 8- and 9-positions ofthe benzo ring ofthe stmcture of formula (I).
73. A compound of claim 60 wherein an Rx radical is present at one or more ofthe 7-, 8-, or 9-positions ofthe benzo ring ofthe stmcture of formula (I).
74. A compound of claim 60 wherein Rx radicals are present at the 7- and 9-positions ofthe benzo ring ofthe stmcture of formula (I).
75. A compound of claim 60 wherein an R radical is present at the 7-position ofthe benzo ring ofthe stmcture of formula (I).
76. A compound of claim 60 wherein said one or more Rx are indepen nddeennttllyy sseelleecctteedd frfroomm tthhee ggrroouupp ccoonnssiissiting of -OR and -NR R , wherein R13 and R14 are as defined in claim 2.
77. A compound of claim 76 wherein R and R are each methyl.
78. A compound of claim 60 wherein an R^ substituent is independently attached at the 3- or the 4-position ofthe phenyl ring of formula (II).
79. A compound of claim 60 wherein t is 1 or 2.
80. A compound of claim 60 wherein t is 1.
81. A compound of claim 60 wherein said one or more R^ are independently selected from the group consisting of hydrogen; halogen; hydroxy; -NO2; (C,-C10)alkyl; halo(CrC10)alkyl; aryl(C,-C10)alkyl; heterocyclyl(C,-C10)alkyl; polyether; -OR13; -NR13R14; and -NR,3C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (CrC10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C,-C10)alkyl; halo(C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(C,- C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (CrC10)alkylheterocyclyl(Cr C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(Cr C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; (CrCι0)alkyl; heterocyclyl; ammonium(CrC10)alkyl; (C j -C ]0)alkylammonium(C C 10)alkyl; aryl(C ι -C 10)alkyl; heterocyclyl(C { - C10)alkyl; carboxy(CrC10)alkyl; carbo(CrCιo)alkoxy(C,-C10)alkyl; carboxyheterocyclyl; carboxy(C!-C10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and wherein R 1 1 and R 12 are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; aryl(C1-C10)alkyl; carboxy(C!-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or
R 1 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R
Figure imgf000377_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation.
82. A compound of claim 60 wherein said R^ is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylaniino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
83. A compound of claim 60 wherein said one or more R^ are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
84. A compound of claim 60 wherein said one or more R" are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
85. A compound of claim 60 wherein said hydroxy group is in a syn relationship to said stmcture of formula (II).
86. A compound of formula (I):
Figure imgf000380_0001
wherein: q is 1 or 2;
R 1 and R 2 are each independently alkyl;
R is hydroxy;
R and R are hydrogen;
R has the formula (II):
Figure imgf000380_0002
wherein t is an integer from 0 to 5; one or more R^ are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R ; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR,3C(O)R14; -NR13C(O)NR14R15; -NR13CO2R'4; -OC(O)R13; - OC(O)NR,3R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl;
7 aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR ;
-NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -
N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ radicals optionally may
7 + 7 8 have one or more carbons replaced by -O-; -NR -; -N R R A"-; -S-; -SO-; -
SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8N-; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; 75 hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -
CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - p+R9R10Rl lA_. _S+R9R10A_. and carbohydrate residue; and
80 wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 85 radicals optionally may have one or more carbons replaced by -O-; -NR9-; -
N+R9R10A -; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; -P+R9R10A-; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R
Figure imgf000382_0001
are independently selected from the group 9 90 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R", R12, Rw, and A" are as defined in claim 2; and
R is selected from the group consisting of hydrogen; alkyl; and aralkyl; and
95 one or more R radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
87. A compound of claim 86 wherein R1 and R2 are each the same (Cr C10)alkyl.
88. A compound of claim 86 wherein R1 and R2 are each n-butyl.
89. A compound of claim 86 wherein one or more Rx are independently selected from the group consisting of methoxy and dimethylamino.
90. A compound of claim 86 wherein q is 1.
91. A compound of claim 86 wherein q is 1, and Rx is selected from the group consisting of methoxy and dimethylamino.
92. A compound of claim 86 wherein R is selected from thegroup consisting of hydrogen; methyl, ethyl and benzyl.
93. A compound of claim 86 wherein said hydroxy group is in a syn relationship to said stmcture of formula (II).
94. A compound of claim 86 wherein t is 1.
95. A compound of claim 86 wherein t is 1 and Ry is in the para position.
96. A compound of claim 86 wherein t is 1 and Ry is in the meta position.
97. A compound of claim 86 wherein one or more Ry are independently selected from selected from the group consisting of halogen; hydroxy; -Nθ2; (C,-C10)alkyl; halo(CrC10)alkyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrCιo)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocycly 1(C , -C ] 0)alkyl; (C , -C , 0)alkylheterocyclyl(C j-C, 0)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (CrC10)alkyl; halo(CrCI0)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocyclyl(Cr C10)alkyl; quaternary heterocyclyl(C,-C10)alkyl; (CrC10)alkylheterocyclyl(Cr CI0)alkyl; (C1-C1o)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(Cr C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl; (CI-C10)alkylammonium(CI-C10)alkyl; aryl(CrC10)alkyl; heterocyclyl(Cr C10)alkyl; carboxy(C,-C10)alkyl; carbo(CI-C10)alkoxy(CrC10)alkyl; carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; heterocyclyl; aryl(CrC1())alkyl; carboxy(CrC10)alkyl; and carbo(C,-C1o)alkoxy(C1-C10)alkyl; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R
Figure imgf000384_0001
are independently selected from the group consisting of R and M; and wherein M is a pharmaceutically acceptable cation.
98. A compound of claim 97 wherein:
R1 and R2 are each the same (C1-C10)alkyl; one or more Rx are independently selected from the group consisting of methoxy and dimethylamino; said hydroxy group is in a syn relationship to said stmcture of formula
(ii); t is 1 ; and
Ry is in the meta or para position.
99. A compound of claim 97 wherein R1 and R2 are each n-butyl.
100. A compound of claim 97 wherein q is 1.
101. A compound of claim 97 wherein R is selected from the group consisting of hydrogen; methyl, ethyl and benzyl.
102. A compound of claim 97 wherein Ry is in the para position.
103. A compound of claim 97 wherein Ry is in the meta position.
104. A compound of the formula (III):
Figure imgf000385_0001
wherein : q and r are independently integers from 0 to 4; t and u are independently integers from 0 to 4; R , R , R , and R are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or
R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; or
1 A ^ A
R and R taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-Cl0 cycloalkenyl; wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of - CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RWA"; -SR9; -S+R9R10A"; - PR9R10; -P+R9R10RWA"; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -
CONR9R10; and wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR 9 -; -N + R 9 R 10 A"-; -S-; -SO-; -
SO2-; -S+R9A'-; -PR9-; -P(O)R9-; -P+R9R10N-; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and R 3 , R 4 , R 3A , and R 4A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; -
NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or
-CRHR12; or R3A and R4A together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and
-CONR9R10; or
1 1 12
R and R together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R^ and R^ are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; - R1 ; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR,3R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals
7 + 7 optionally may have one or more carbons replaced by -O-; -NR -; -N R R A"
-; -S-; -SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and
,7 / „„J T, X wherein R and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wwhheerreeiinn RR aann<d R together with the nitrogen atom to which they are attached form a cyclic ring; and 95 wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 100 radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
105
Figure imgf000388_0001
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
110 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _s+R9A-_. _pR9_. _p+R9R10A-_. _p(0)R9_. phenylene; carbohydrate residue; amino acid residue; peptide residue; or 115 polypeptide residue; and wherein R
Figure imgf000388_0002
are independently selected from the group 9 consisting of R and M; and wherein n is 0, 1 or 2; and wherein M is a pharmaceutically acceptable cation; and 120 wherein R9, R10, R", R12, Rw, and A" are as defined above; and
R and RNA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and RXA radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; 125 polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; uaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; - OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; - NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -SOnNR13R18 ; - 130 NR18OR14; -N+R13R14R15A"; -PR13R14; -P(O)R13R14; -
P R R R A"; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; 135 polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ;
-NR9R10; -N+R9R10R A"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -
CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RHR12A"; - S + R 9 R 10 A - ; and carbohydrate residue; and
140 wherein the Rx and RXA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -
145 NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; - C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; - p+R13R14R15A-. _p(OR13)OR14; -S+R13R14A"; -N+R13R14R15A"; and carbohydrate residue; and wherein the Rx and RXA radicals comprising carbon optionally may 150 have one or more carbons replaced by -O-; -NR 13 -; -N + R 13 R 14 A"-; -S-; -SO-;
-SO2-; -S+R13A"-; -PR13-; -P(O)R13-; -P+R13R14A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have
9 + 9 10 - 155 one or more carbons replaced by -O-; -NR -; -N R R A -; -S-; -SO-; -SO2-;
-S+R9A"-; -PR9-; -P+R9R10 -; or -P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and
160 heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of 165 halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R! ^^A"; -SR9; -S(O)R9;
-Sθ2R9; -S03R9; -C02R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10;
-P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, Rπ, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; and 170 R19 is selected from the group consisting of alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and 175 polypeptide residue; can optionally have one or more carbons replaced by -O-;
-NR7-; -N+R7R8A--; -S-; -SO-; -SO2.; -S+R7A"-; -PR7-; -P+R7R8A"-; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; 180 peptide residue; and polypeptide residue can be substituted with one or more substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -
SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -
185 SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14N; and - N+R13R14R15A-. wherein R7, R8, R", R12, R13, R14 R15, and A" are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
105. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
106. A compound of claim 104 wherein R1, RIA, R2, and R2A are independently selected from the group consisting of hydrogen and C,-C10 alkyl.
107. A compound of claim 104 wherein R', R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
108. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
109. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
110. A compound of claim 104 wherein R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 104.
111. A compound of claim 110 wherein R9 is hydrogen.
112. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
113. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, (CrC10)alkyl and aryl(CrCιo)alkyl.
114. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
115. A compound of claim 104 wherein one or more Rx and RxA are independently selected from the group consisting of methoxy and dimethylamino.
116. A compound of claim 104 wherein q and r are each 1.
117. A compound of claim 104 wherein one or more Ry are independently selected from selected from the group consisting of halogen; hydroxy; -Nθ2; (C,-C10)alkyl; halo(CrCI0)alkyl; aryl(CrCI0)alkyl; heterocyclyl(C,-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrCι0)alkyl; heterocyclyl(C,-C10)alkyl; quaternary heterocyclyl(C,-Ci0)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C,-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C,-C10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrC10)alkyl; heterocycly l(Cr C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C1-C10)alkylheterocyclyl(C1- C10)alkyl; (C,-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(Cr C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; ammonium(C,-C10)alkyl; (C1-Cιo)alkylammonium(C1-CIO)alkyl; aryl(C1-C10)alkyl;
Figure imgf000392_0001
C10)alkyl; carboxy(C,-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl; carboxyheterocyclyl; carboxy(CrC10)alkylamino; and acyl; and wherein A is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the groi consisting of hydrogen; (CrC10)alkyl; heterocyclyl; aryl(C1-C10)alkyl; carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C,-C10)alkyl; or
R R1 1 11 aanndd R R 12 together with the carbon atom to which they are attached form a cyclic ring wherein R and R are independently selected from the group g consisting of R and M; and wherein M is a pharmaceutically acceptable cation.
118. A compound of claim 104 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A"-; -S-; -SO-; -SO2-; -S+R7A"-; - PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene, wherein R7 and R8 are defined as in claim 104.
119. A compound of claim 104 wherein R19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O-; -NR7-; -N+R7R8A"-; -S-; -SO-; -SO2 -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R9 and R10 are defined as in claim 104.
120. A compound of claim 104 having the formula:
Figure imgf000393_0001
121. A compound of the formula (IV) :
Figure imgf000394_0001
wherein : q and r are independently integers from 0 to 3; t and u are independently integers from 0 to 5;
R 1 , R 2 , R IA , and R 2 A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or 1
R and R taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; or
R IA and R 2A taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; wherein the R1, R2, R1 A, and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -
CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RWA"; -SR9; -S+R9R10A"; -
PR9R10; -P+R9R10RWA"; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -
CONR9R10; and wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may
9 + 9 10 have one or more carbons replaced by -O-; -NR -; -N R R A -; -S-; -SO-; -
SO2-; -S+R9A"-; -PR9-; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxy alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R 3 , R 4 , R 3A , and R 4A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; -
NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CRπR12;
R3A and R4A together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CRnR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and
-CONR9R10; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R^ and R^ are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R ; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; - COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR,4R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and
75 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl;
80 alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl,
85 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"
-; -S-; -SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; or phenylene; and
90 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
95 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted
100 with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wwhheerreeiinn RR aamnd R together with the nitrogen atom to which they are attached form a cyclic ; ririnngg;; a anndd wwhheerreeiinn tthhee R R13,, R R14,, a and R alkyl; haloalkyl; cycloalkyl; polyalkyl;
105 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from 110 the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9RπR12A"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -
CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - 115 P+R9R! °Rl l A-; -S+R9R! °A-; and carbohydrate residue; and wherein the R , R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
120 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _s+R9A-_. _pR9_. _p+R9R10A-_. _p(0)R9_. phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and
125 wherein R
Figure imgf000397_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein n is 0, 1 or 2; and wherein R9, R10, R11, R12, R , and A" are as defined above; and 130 R and RNA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and R^ radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; 35 quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -
OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; - NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -SOnNR13R14; - NR18OR14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; - P R R R A"; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR
Figure imgf000398_0001
-NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -
CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RnR12A"; -
S R R A"; and carbohydrate residue; and wherein the R and RXA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -
NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; - C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; - p+R13R14R15A-. _p(OR 13)OR14; -S+R13R14A"; -N+R13R14R15A"; and carbohydrate residue; and wherein the Rx and R5^ radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR 13 -; -N + R 13 R 14 A"-; -S-; -SO-; -SO2-; -S+R13A"-; -PR13-; -P(O)R13-; -P+R13R14A-; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A"-; -S-; -SO-; -SO2-; -S+R9A"-; -PR9-; - P+R9R10A--; or -P(O)R9-; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9RnR12A"; -SR9; -S(O)R9; 175 -Sθ2R9; -SO3R9; -Cθ2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10;
-P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; and
R19 is selected from the group consisting of alkane diyl; alkene diyl; 180 alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; can optionally have one or more carbons replaced by -O-;
185 -NR7-; -N+R7R8N-; -S-; -SO-; -SO2-; -S+R7A"-; -PR7-; -P(O)R7-; -
+ 7 8 P R R A"-; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue can be substituted with one or more
190 substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -
SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -
SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
195 P(O)R13R14; -PR13R14; -P+R13R14R15A"; -P(OR,3)OR14; -S+R13R14A"; and -
N+R9RHR12A"; wherein R7, R8, Rn, R12, R13, R14 R15, and A" are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
122. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
123. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and C]-C10 alkyl.
124. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
125. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
126. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
127. A compound of claim 121 wherein R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 121.
128. A compound of claim 126 wherein R9 is hydrogen.
129. A compound of claim 121 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
130. A compound of claim 121 wherein RN and RNA are independently selected from the group consisting of hydrogen, (CrC10)alkyl and aryl(C]-Cιo)alkyl.
131. A compound of claim 121 wherein RN and RNA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
132. A compound of claim 121 wherein one or more Rx and RxAare independently selected from the group consisting of methoxy and dimethylamino.
133. A compound of claim 121 wherein q and r are each 1.
134. A compound of claim 121 wherein one or more Ry are independently selected from selected from the group consisting of halogen; hydroxy; -NO2; (C,-Cι0)alkyl; halo(CrC10)alkyl; aryl(CrC10)alkyl; heterocyclyl(CrC10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C]-C10)alkyl; haloCrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C,-C10)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(C,-C10)alkyl; (C1-C10)alkylheterocyclyl(CI-C10)alkyl; (C]-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C,-C10)alkyl; halo(C,-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CrCι0)alkyl; heterocyclyl(Cr C10)alkyl; quaternary heterocyclyl(C,-C!0)alkyl; (C,-C10)alkylheterocyclyl(Cr C10)alkyl; (C1-C]0)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(Cr C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and wherein R , R and Rw are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl; (CI-C1o)alkylammonium(C,-C10)alkyl; aryl(C,-C10)alkyl; heterocyclyl(Cr C10)alkyl; carboxy(CrC10)alkyl; carbo(CI-Cι0)alkoxy(CI-C10)alkyl; carboxyheterocyclyl; carboxy(CrC10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; aryl(CrC10)alkyl; carboxy(C,-C10)alkyl; and carbo(C]-C10)alkoxy(C1-C10)alkyl; or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclic ring; wherein R
Figure imgf000401_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation.
135. A compound of claim 121 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A"-; -S-; -SO-; -SO2-; -S+R7A'-; - PR7-; -P(O)R7-; -P+R7R8A -; or phenylene, wherein R7 and R8 are defined as in claim 121.
136. A compound of claim 121 wherein R19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O-; -NR7-; -N+R7R8A"-; -S-; -SO-; -SO2S -S+R7A"-; -PR7-; -P(O)R7-; -P+R7R8A"-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R9 and R10 are defined as in claim 121.
137. A compound of claim 121 having the structural formula:
Figure imgf000402_0001
138. A compound of formula (V) :
Figure imgf000403_0001
( R ) ,
wherein : q is an integer from 0 to 4; r is an integer from 0 to 3; t is an integer from 0 to 4; u is an integer from 0 to 5;
R 1 , R 2 , R IA , and R 2A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or
R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C]0 cycloalkenyl; or
R 1 A and R 2A taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -
CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RWA"; -SR9; -S+R9R10A"; - p+R9R10RwA-. .pR9R10. _S(0)R9. .Sθ2R9; -SO3R9; -CO2R9; and - CONR9R10; and wherein the R1 , R2, R1 A and R2A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR 9 -; -N + R 9 R 10 A'-; -S-; -SO-; -
SO2-; -S+R9A"-; -PR9-; -P(O)R9-; -P+R9R10A"-; or phenylene; and wherein R , R , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and
R , R , R , and R are independently selected from the group
9 consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR ; - NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or
R3 and R4 together form O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12;
R3A and R4A together form =O; =NOR9; =S; =NNR9R10; =NR9; or
=CRπR12; wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or
1 1 1 7
R and R together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R^ and R^ are independently selected from the group consistmg of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR ; -NR R14; - SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; - CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -
75 COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; - OC(O)NRI3R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; - NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A"; - P(OR13)OR14; -S+R13R14A"; and -N+R13R14R15A"; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl,
80 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary
85 heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; - CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A"; and - P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl,
90 heterocyclylalkyl, and polyether substituents ofthe R^ and R^ radicals optionally may have one or more carbons replaced by -O-; -NR 7 -; -N + R7 R8 A"
-; -S-; -SO-; -SO2-; -S+R7A -; -PR7-; -P(O)R7-; -P+R7R8A'-; or phenylene; and wherein R 7 and R 8 are independently selected from the group
95 consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R , R , and R are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 100 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, 105 and quaternary salts; or wherein R and R together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R , R , and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
110 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
115 hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9RHR12A"; -SR16; -S(O)R9; -SO2R9; -SO3R16; - CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; - p+R9R10Rl 1A_. _S+R9R10A_. md carbohydrate residue; and
120 wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether
125 radicals optionally may have one or more carbons replaced by -O-; -NR9-; - N+R9R10A._. _s_. _so_. _sθ2_. _S+R9A._. _pR9_. _p+R9R10A._. _p(0)R9_; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein
Figure imgf000406_0001
are independently selected from the group 9 130 consisting of R and M; and wherein M is a pharmaceutically acceptable cation; and wherein n is 0, 1 or 2; and wherein R9, R10, R11, R12, Rw and A" are as defined above; and
R and RNA are independently selected from the group consisting of 135 hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and R radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; - 140 OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; - NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; - NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -S(O)nNR13R14; -NR13R18; -NR18OR14; -N+R13R14R15 A-; -PR13R14; -P(O)R13R14; -
P R R R A"; amino acid residue; peptide residue; polypeptide residue; 145 and carbohydrate residue; wherein the Rx and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR ; 150 -NR9R10; -N+R9R10RWA"; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -
CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9RHR12A"; -
S R R A"; and carbohydrate residue; and wherein the Rx and RXA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of 155 halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -
NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; -
C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; - 160 P+R13R14R15A"; -P(OR13)OR14; -S+R13R14A"; -N+R13R14R15A"; and carbohydrate residue; and wherein the Rx and RXA radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR 13 -; -N + R 13 R 14 A"-; -S-; -SO-;
-SO2-; -S+R13A"-; -PR13-; -P(O)R13-; -P+R13R14A"-; phenylene; amino acid
165 residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have
9 + 9 10 - one or more carbons replaced by -O-; -NR -; -N R^RιυA -; -S-; -SO-; -SO2-;
-S+R9A -; -PR9-; -P+R9R10A -; or -P(O)R9-; and
1 o
170 wherein R is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary 175 heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R! ^^A"; -SR9; -S(O)R9;
-Sθ2R9; -SO3R9; -Cθ2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10; 180 -P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R", R12, R13, R14, R15, R16, R17, Rw, A", and M are as defined above; and
R19 is selected from the group consisting of alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; 185 carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A"-; -S-; -SO-; -SO2-; -S+R7A-; - 190 PR7-; -P(O)R7-; -P+R7R8A"-; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide; and polypeptide residue can be substituted with one or more 195 substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -
SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -
SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -
200 P(O)R13R14; -PR13R14; -P+R13R14R15A"; -P(OR13)OR14; -S+R,3R14A"; and - N+R13R14R15A-. wherein R7, R8, R", R12, R13, R14 R15, and A" are as defined above; or a pharmaceutically acceptable salt, solvate, or prodmg thereof.
139. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
140. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and CrC10 alkyl.
141. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
142. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
143. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
144. A compound of claim 138 wherein R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 138.
145. A compound of claim 144 wherein R9 is hydrogen.
146. A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
147 A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, (C,-C10)alkyl and aryl(CrC10)alkyl.
148. A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
149. A compound of claim 138 wherein one or more Rx and RxAare independently selected from the group consisting of methoxy and dimethylamino.
150. A compound of claim 138 wherein q and r are each 1.
151. A compound of claim 138 wherein one or more Ry are independently selected from selected from the group consisting of halogen; hydroxy; -Nθ2; (C,-C10)alkyl; halo(C,-C10)alkyl; aryl(CrC10)alkyl; heterocyclyl(C,-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R , R , and R are independently selected from the group consisting of hydrogen; (C,-C10)alkyl; halo(CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(Cι-Cι0)alkyl; heterocyclyl(CrC10)alkyl; quaternary heterocyclyl(C , -C !0)alkyl; (C j -C 10)alkylheterocyclyl(C1 -C , 0)alkyl; (CrC10)alkylammonium(CrC]0)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl;halo(C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C1-Cι0)alkyl; heterocyclyl(Cr
C10)alkyl; quaternary heterocyclyl(CrC10)alkyl; (C,-C10)alkylheterocyclyl(Cr
C10)alkyl; (C,-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (CrC10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CrC10)alkyl; carboxy; carboxy(C,-
C10)alkyl; -OR16; -NR9R10; -N+R9R10RWA"; and -CONR9R10; and g i o wherein R and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(CI-C10)alkylammonium(C1-C]0)alkyl; aryl(Cι-C10)alkyl; heterocycly l(Cr
C10)alkyl; carboxy(CrC10)alkyl; carbo(CrC10)alkoxy(CrC10)alkyl; carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A" is a pharmaceutically acceptable anion; and i i o wherein R and R are independently selected from the group consisting of hydrogen; (CrC10)alkyl; heterocyclyl; aryl(CrC10)alkyl; carboxy(CrC10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or 1 1 12
R and R together with the carbon atom to which they are attached form a cyclic ring; wherein R
Figure imgf000410_0001
are independently selected from the group
9 consisting of R and M; and wherein M is a pharmaceutically acceptable cation.
152. A compound of claim 138 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A-; -S-; -SO-; -SO2-; -S+R7A"-; - PR7-; -P(O)R7-; -P+R7R8N-; or phenylene, wherein R7 and R8 are defined as in claim 138.
153. A compound of claim 138 wherein R19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O-; -NR7-; -N+R7R8A'-; -S-; -SO-; -SO2-; -S+R7A -; -PR7-; -P(O)R7-; -P+R7R8A -; phenylene; amino acid; peptide; polypeptide; carbohydrate; or polyalkyl, wherein R9 and R!0 are defined as in claim 138.
154. A compound of claim 138 having the formula:
155. A pharmaceutical composition comprising an anti- hyperlipidemic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
156. A pharmaceutical composition comprising an anti- atherosclerotic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
157. A pharmaceutical composition comprising an anti- hypercholesterolemia effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
158. A pharmaceutical composition comprising an anti- hyperlipidemic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
159. A pharmaceutical composition comprising an anti- atherosclerotic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
160. A pharmaceutical composition comprising an anti- hyp ercholesterolemi a effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
161. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 155 in unit dosage form.
162 A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 156 in unit dosage form.
163. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 157 in unit dosage form.
164. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 158 in unit dosage form.
165. A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 159 in unit dosage form.
166. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 160 in unit dosage form.
PCT/US2000/002503 1999-02-12 2000-02-10 1,2-benzothiazepines for the treatment of hyperlipidemic diseases Ceased WO2000047568A2 (en)

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IL14471600A IL144716A0 (en) 1999-02-12 2000-02-10 Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
EP00915720A EP1155007A2 (en) 1999-02-12 2000-02-10 1,2-benzothiazepines for the treatment of hyperlipidemic diseases
KR1020017010201A KR20020000139A (en) 1999-02-12 2000-02-10 Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
AU36946/00A AU3694600A (en) 1999-02-12 2000-02-10 Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
CA002362147A CA2362147A1 (en) 1999-02-12 2000-02-10 1,2-benzothiazepines for the treatment of hyperlipidemic diseases
JP2000598488A JP2002536440A (en) 1999-02-12 2000-02-10 Novel 1,2-benzothiazepines with activity as inhibitors of ileal bile acid transport and taurocholate uptake

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CN1195748C (en) 2005-04-06
HUP0105409A2 (en) 2002-05-29
EP1155007A2 (en) 2001-11-21
CA2362147A1 (en) 2000-08-17
HUP0105409A3 (en) 2004-11-29
ZA200106252B (en) 2002-07-30
IL144716A0 (en) 2002-06-30
AU3694600A (en) 2000-08-29
KR20020000139A (en) 2002-01-04
CN1346351A (en) 2002-04-24
WO2000047568A3 (en) 2000-12-14

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