EP1140849A1 - Amino-alcools et leur utilisation comme agonistes beta-3 adrenergiques - Google Patents

Amino-alcools et leur utilisation comme agonistes beta-3 adrenergiques

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Publication number
EP1140849A1
EP1140849A1 EP99961305A EP99961305A EP1140849A1 EP 1140849 A1 EP1140849 A1 EP 1140849A1 EP 99961305 A EP99961305 A EP 99961305A EP 99961305 A EP99961305 A EP 99961305A EP 1140849 A1 EP1140849 A1 EP 1140849A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
ammo
phenyl
mixture
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99961305A
Other languages
German (de)
English (en)
Inventor
Kiyoshi Taniguchi
Minoru Sakurai
Takeshi Kato
Naoaki Fujii
Kenichi Washizuka
Yasuyo Tomishima
Hisashi Takasugi
Yutaka Kohno
Nobuhiro Yamamoto
Naoko Tanimura
Hirohumi Ishikawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP1140849A1 publication Critical patent/EP1140849A1/fr
Withdrawn legal-status Critical Current

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/62—Benzothiazoles
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    • 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

Definitions

  • This invention relates to new aminoalcohol derivatives and salts thereof.
  • new aminoalcohol derivatives and salts thereof which act as selective j33 adrenergic receptor agonists and therefore have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like;
  • One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence and anti-pollakiuria activities.
  • Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoalcohol derivatives and salts thereof.
  • Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said aminoalcohol derivatives and salts thereof.
  • X ⁇ _ is bond or -OCH 2 - ⁇
  • X 2 is -(CH2- n -, in which n is 1, 2 or 3;
  • X3 is bond, -0-, -S-, -OCH 2 * or -NH-
  • R ,1 x is phenyl or pyridyl, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, halogen, amino, [ (lower) alkylsulfonyl] amino, nitro, benzyloxycarbonylamino and benzyloxy; R is hydrogen, (lower) alkoxycarbonyl, benzyl or benzyloxycarbonyl ;
  • R is hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl or halo (lower ) alkyl;
  • R ⁇ is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo ( lower) alkyl, halogen, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, cyano, carboxy, (lower) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl] carbamoyl, amino, nitro, ureido, [ (lower) alkylcarbonyl] amino, [ (lower ) alkylsulfonyl] amino and (arylsulfonyl) amino, and a salt thereof.
  • substituent selected from the group consisting of hydroxy, lower alkyl, lower alkoxy,
  • the object compound [I] or a salt thereof can be prepared by the following processes.
  • Rfj and R are each ammo protective group, Q is protected hydroxy
  • X is halogen, and is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo (lower) alkyl, halogen, hydroxy (lower) alkyl, (lower ) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl ] carbamoyl, amino nitro, ureido, [ (lower) alkylcarbamoyl ] amino,
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl” moiety in the terms of "[ (lower) alkylsulfonyl] amino” , "hydroxy (lower) - alkyl”, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
  • Suitable "lower alkoxy” and “lower alkoxy” moiety in the terms of " (lower) alkoxycarbonyl” , “ (lower) alkoxy (lower) - alkyl”, etc. may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, 1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in which the preferred one may be C- ⁇ -C ⁇ alkoxy, and the most preferred one may be methoxy.
  • Suitable “lower alkanoyl” may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl and the like.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "aryl” and “aryl” moiety in the term of " (arylsulfonyl ) amino" may include phenyl, naphthyl, anthryl, and the like, in which the preferred one may be phenyl.
  • Suitable "an unsaturated heterocyclic group containing nitrogen” may include an unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. And especially preferable unsaturated heterocyclic group containing nitrogen may be ones such as an unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4- triazolyl, 1H-1, 2 , 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazoly
  • Suitable "hydroxy protective group” in the term “protected hydroxy” may include commonly protective group or the like.
  • Suitable common protective group may include acyl as mentioned below, mono (or di or tri) phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g. benzyl, 4- methoxyphenyl, trityl, etc.), trisubstituented silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl; t-butyldimethylsilyl, etc.], tetrahydropyranyl and the like.
  • suitable substituent e.g. benzyl, 4- methoxyphenyl, trityl, etc.
  • trisubstituented silyl e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl; t-butyldimethylsilyl, etc.]
  • Suitable "acyl” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • acyl may be illustrated as follows; carbamoyl; carboxy; aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl , octadecanoyl, nonadecanoyl, icosanoyl, etc.); cyclo ( lower) alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutyl
  • Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanol, phenylbutanoyl , phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthtyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, naphthylisobutanoyl, etc.); ar (lower) alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phen
  • Heterocyclic acyl such as heterocyclic carbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; and the like.
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, hetero
  • Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry. These include benzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2, 2, 2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, 2, 2, 2-trifluoroacetyl, 2, 2, 2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2, 4-dinitobenzyl, 4-nitrophenyl, 4-methoxyphenyl, triphen
  • Suitable salts of the object aminoalcohol derivatives [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzen
  • Preferred embodiments of the object compound [I] are as follows:
  • X ⁇ is bond or -0CH 2 -;
  • X 2 is -(CH 2 ) n - in which n is 1;
  • X 3 is -0-
  • R-i is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and loweralkylsulfonylamino; or pyridyl which may have amino.
  • R 2 is hydrogen.
  • R is hydroxy (lower) alkyl
  • R4 is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower) - alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [1 , 2-a] pyridyl ; quinoxalinyl which may be substituted with halogen; acridinyl
  • More preferred embodiment of the object compound [I] are llows: X j _ is bond or -OCH 2 -;
  • X 2 is ⁇ (CH 2m- -"- n n i cl1 n i- s 1 ;
  • X 3 is -0-;
  • R is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and lower alkylsulfonylamino;
  • R 2 is hydrogen;
  • R3 is hydroxy (lower) alkyl ; and R ⁇ is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower ) alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [ 1 , 2-a] pyridyl; quinoxalinyl which may be
  • More preferred embodiment of the object compound [I] are as follows:
  • X- ] _ is bond or -OCH 2 ⁇ ;
  • X is ⁇ (CH ) n - in which n is 1;
  • X 3 is -0-;
  • R ⁇ is pyridyl which may have amino;
  • R 2 is hydrogen;
  • R3 is hydroxy ( lower) alkyl
  • R4 is pyridyl which may have hydroxy (lower) alkyl .
  • the object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
  • Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
  • a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethy
  • the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in the manner disclosed in Example 8 or Example 30, or similar manners thereto.
  • the object compound [Ic] or a salt thereof can be prepared by reacting a compound [III] or a salt thereof with a compound [IV] .
  • Suitable salts of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction can be carried out in the presence of the base such as an alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g., magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g., sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g., trimethylamine, triethylamine, etc.], picoline or the like.
  • the base such as an alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g., magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g., sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g., trimethyl
  • the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not have adverse effect on the reaction.
  • a conventional solvent such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not have adverse effect on the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the reaction can also be carried out in the manner disclosed in Example 72 or similar manner thereof.
  • the object compound [Id] or a salt thereof can be prepared by reacting a compound [V] or a salt thereof with a compound [VI ] .
  • Suitable salts of the compound [V] may be the same as those exemplified for the compound [I].
  • reaction can also be carried out in the manner disclosed in Example 78 or similar manners thereto.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
  • the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I] are included within the scope of the present invention.
  • the object compound [I] or a salt thereof possesses gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prost
  • the object compound (I) or a pharmaceutically acceptable salt thereof can be usually administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like.
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, one to four times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of patients or methods of administration.
  • the organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo.
  • the residue was dissolved in ethanol, and treated with aqueous sodium hydrogen sulfite for 10 minutes. After evaporation in vacuo and partition between ethyl acetate and water, the aqueous layer was made basic with aqueous sodium carbonate and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo.
  • N, N-dimethylformamide (10 ml) was stirred at room temperature for 9 hours.
  • the mixture was diluted with ethyl acetate and poured into water.
  • the organic layer was washed with aqueous 10% potassium hydrogensulfate and brine, dried over sodium sulfate and evaporated in vacuo.
  • Example 7 Under nitrogen, to a solution of [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ ( IS) -1- [ 4- ( 3-formylpyr ⁇ dm-2- yloxy) benzyl] -2-hydroxyethyl ] carbamic acid tert-butyl ester (0.24 g) in methanol (4.5 ml) was added sodium borohydride (17 mg) at 5°C, and the mixture was stirred at the same temperature for 10 minutes. The mixture was evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo.
  • Example 8 To a solution of [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethyl] [ (IS) -2-hydroxy-l- [4- ( 3-hydroxymethylpy ⁇ dm-2- yloxy) benzyl] ethyl] carbamic acid tert-butyl ester (0.14 g) in ethyl acetate (5.2 ml) was added 4N hydrogen chloride in ethyl acetate (1.3 ml) and the resulting mixture was allowed to stand at room temperature for 2 hours. The mixture was evaporated in vacuo. To the residue was added aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel
  • Example 11 A mixture of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotinic acid methyl ester dihydrochloride (0.26 g) and aqueous 28% ammonium hydroxide (26 ml) in 1,4-dioxane (5.2 ml) was stirred at room temperature for 1 day. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water.
  • 6- [4- [ (2S) -2- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide was treated with 4N hydrogen chloride in ethyl acetate, followed by crystallization from methanol-ethyl acetate to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide dihydrochloride (57 mg) .
  • Example 13 To a solution of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) - 2-hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotmic acid methyl ester dihydrochloride (0.18 g) in methanol (3.6 ml) was added with aqueous IN sodium hydroxide (1.4 ml), and the mixture was stirred at room temperature for 4.5 hours. To the mixture was added aqueous IN hydrogen chloride (1.2 ml) and evaporated m vacuo.
  • Example 14 Under nitrogen, a solution of (S) -2-am ⁇ no-3- [4- (3, 5- d ⁇ chloropyr ⁇ dm-4-yloxy) phenyl] propan-1-ol hydrochloride (0.39 g) , (R) -3-chlorostyrene oxide (0.50 g) and N,N- dnsopropylethylamme (0.19 ml) in a mixture of methanol (1 ml) and 1,4-dioxane (1 ml) was refluxed for 14.5 nours . The mixture was evaporated in vacuo.
  • Example 16 Under nitrogen, a suspension of (S)-4-[4-(6- chloropy ⁇ dm-2-yloxy) benzyl ] oxazol ⁇ dm-2-one (0.49 g) , (R)- 3-chlorostyrene oxide (0.49 g) and potassium carbonate (0.44 g) in N, N-dimethylformamide (4.9 ml) was stirred at 80°C for 96 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethanol (8 ml) and water (7 ml) .
  • Example 18 To a solution of ( 4S) -3- [ (2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl]-4-[4-(py ⁇ dm-2-yloxy)benzyl]oxazol ⁇ dm-2-one (0.67 g) in ethanol (6.7 ml) was added aqueous 4N sodium hydroxide (4 ml), and the mixture was refluxed for 2 hours. After evaporation in vacuo and partition between water and ethyl acetate, the organic layer was washed with brme, dried over sodium sulfate, and evaporated m vacuo.
  • Example 25 Under nitrogen, a solution of 2- [4- [ (2S) -2- [ (2S) -2- hydroxy-3-phenoxypropylammo] -3-hydroxypropyl ] phenoxy] - nicotmonitrile (3.0 g) , di-tert-butyl dicarbonate (1.8 g) in tetrahydrofuran (20 ml) was stirred at room temperature for 9 hours.
  • Example 34 The following compound was synthesized according to a similar manner to that of Example 33.
  • Example 39 To a solution of (2S) -2- ( (2S) -2-hydroxy-3-pnenoxypropyl- amino) -3- [4- ( 3-n ⁇ tropy ⁇ dm-2-yloxy) phenyl] propanol (100 mg) in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours.
  • Example 42 A mixture of 2- (4- ⁇ 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- ( 4-benzyloxyphenoxy) propylamino] propyl ⁇ phenoxy) nicotmamide (150 mg) , 10% palladium on activated carbon (50% wet, 50 mg) and methanol (10.0 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated m vacuo.
  • Example 55 A mixture of N- [2-benzyloxy-5- (( IR) -l-hydroxy-2- IS) -1- nydroxymethyl-2- [ 4- (qumolm-3-yloxy) phenyl] ethylammo ⁇ - ethyl) phenyl ] methanesulfonamide (20 mg) and 10% palladium on activated carbon (50% wet, 10 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours.
  • Example 60 The following compound was obtained according to a similar manner to that of Example 55.
  • Example 61 The following compounds were obtained according to a similar manner to that of Example 53.
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo.
  • To the residue was added 4N hydrogen chloride in 1,4- dioxane in order to decompose the boran complexes, followed by evaporation in vacuo.
  • the residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and dichloromethane. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo.
  • Potassium hydroxide powder (85% purity, 35.3 mg, 0.535 mmol) was added to dimethyl sulfoxide (5.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour.
  • 4-chloroqu ⁇ nolme (103 mg, 0.203 mmol) in dimethyl sulfoxide (0.5 ml) was added and the mixture was stirred at 100°C for 5 hours.
  • Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide ( 6.0 ml ) at room temperature and the mixture was stirred at the same temperature for 80 minutes.
  • 4- [ (2S) -2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3- hydroxypropyl] phenol 300 mg, 0.736 mmol
  • 4-chloro-7-methoxyqumolme (171 mg, 0.883 mmol) was added and the mixture was stirred at 100°C for 3.5 hours.
  • Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide (6.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour.
  • dimethyl sulfoxide 6.0 ml
  • 4-[(2S)-2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3-hydroxypropyl] phenol 300 mg, 0.736 mmol
  • 4-chloro-6-fluoroqumolme 160 mg, 0.881 mmol was added and the mixture was stirred at 100°C for 24 hours.
  • Example 81 Potassium hydroxide powder (85% purity, 55.0 mg, 0.833 mmol) was added to dimethyl sulfoxide ( 8.0 ml ) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 4-[(2S)-2- [benzyl [ (2R) -2- ( 4-benzyloxy-3-n ⁇ trophenyl ) -2-hydroxyethyl] - ammo] -3-hydroxypropyl] phenol (400 mg, 0.757 mmol) and stirred for 40 minutes. Further, 4-chloro-6-fluoroquinol e (179 mg, 0.986 mmol) was added and the mixture was stirred at 100°C for 96 hours.
  • reaction mixture was warmed to room temperature and stirred for 15 minutes.
  • the reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml x 2), brme (10 ml x 1), dried over magnesium sulfate. Evaporation of the solvent gave an orange foam (97.6 mg) .
  • Example 88 The following compound was obtained by a similar manner to that of Example 94 followed by a reduction of the nitro group as described in Example 88.
  • Example 95 A mixture of 2- ⁇ 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3- phenoxypropylammo) propyl] phenoxy ⁇ qumolme-3-carboxylic acid methyl ester (270 mg) and aqueous 28% ammonium hydroxide (5.0 ml) m 1,4-dioxane (5.0 ml) was stirred at room temperature for 2 days. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water. The organic layer was washed with brme, dried over sodium sulfate and evaporated in vacuo.

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Abstract

L'invention concerne un composé de formule (I), dans laquelle X1 est une liaison ou OCH2; X2 est (CH2)n, où n est 1, 2 ou 3; X3 est une liaison, O, S, OCH2 ou NH; R1 est phényle ou pyridyle, chacun pouvant comporter un ou deux substituants choisis dans le groupe comprenant hydroxy, halogène, etc.; R2 est hydrogène, alcoxycarbonyle (inférieur), etc.; R3 est hydroxyalkyle (inférieur), haloalkyle (inférieur), etc.; R4 est aryle ou un groupe hétérocyclique insaturé, chacun pouvant comporter un ou deux substituants choisis dans le groupe comprenant alkyle inférieur, hydroxy, carbamoyle, halogène, alcoxy inférieur, etc.; ainsi qu'un sel dudit composé, qui est utile comme médicament.
EP99961305A 1998-12-30 1999-12-22 Amino-alcools et leur utilisation comme agonistes beta-3 adrenergiques Withdrawn EP1140849A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPP796798 1998-12-30
AUPP7967A AUPP796798A0 (en) 1998-12-30 1998-12-30 New compound
PCT/JP1999/007203 WO2000040560A1 (fr) 1998-12-30 1999-12-22 Amino-alcools et leur utilisation comme agonistes beta-3 adrenergiques

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JP2002534415A (ja) 2002-10-15
AUPP796798A0 (en) 1999-01-28

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