EP1210343A2 - Benzoesaürederivate und deren verwendung als ppar- rezeptor- agonisten - Google Patents

Benzoesaürederivate und deren verwendung als ppar- rezeptor- agonisten

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Publication number
EP1210343A2
EP1210343A2 EP00953320A EP00953320A EP1210343A2 EP 1210343 A2 EP1210343 A2 EP 1210343A2 EP 00953320 A EP00953320 A EP 00953320A EP 00953320 A EP00953320 A EP 00953320A EP 1210343 A2 EP1210343 A2 EP 1210343A2
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EP
European Patent Office
Prior art keywords
optionally substituted
formula
compound
group
alkyl
Prior art date
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Application number
EP00953320A
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English (en)
French (fr)
Inventor
Rodney Brian Hargreaves
Paul Robert Owen Whittamore
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1210343A2 publication Critical patent/EP1210343A2/de
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • 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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to the use of certain benzoic acid derivatives which act as peroxisome proliferator activated receptor (PPAR) agonists, in particular gamma receptors 5 (PPAR ⁇ ), and so are useful in the treatment of states of insulin resistance, including type 2 diabetes mellitus.
  • PPAR peroxisome proliferator activated receptor
  • Novel pharmaceutical compositions and novel compounds are also defined, together with methods of their production.
  • HbAlc haemoglobin
  • FPG fasting blood sugar level
  • insulin resistance syndrome a cluster of other cardiovascular risk factors
  • type B A typical dyslipidemic atherogenic lipoprotein phenotype (referred to as type B) is seen in IRS including frequently in type 2 diabetics, characterised by a modestly raised LDL-C, a more significant increase in VLDL-TG and reduced HDL.
  • VLDL- TG particles changes in the physicochemical properties of VLDL- TG particles result in slower plasma clearance rates and in the generation of small dense LDL particles.
  • the latter permeate the vascular endothelium more readily and are more prone to oxidation and glycation and are considered to play a critical role in atherogenesis in large vessels.
  • improved free fatty acid (IFF A) flux is increasingly considered to play an important role in the IRS affecting metabolic events in muscle, liver, adipose tissue and pancreas.
  • the first generation TZDs e.g. troglitazone, pioglitazone, rosiglitazone were in clinical development before the putative mechanism of action was discovered and published in 1995 (PPAR ⁇ activation). It is clear from experience with these first generation agents that it is difficult to predict from animal pharmacology the safety and efficacy profile these agents will have in the clinic. Thus, knowledge of the putative mechanism of action of this class coupled with concerns regarding safety, offers the opportunity to identify non-TZD activators of PPAR for the treatment of type 2 diabetes and is the subject of this invention. Furthermore, we recognise that agents with a dual action at both ⁇ and g PPAR may have additional benefits in reducing diabetic co-morbidities, particularly raised triglycerides. Such agents may be useful in the treatment of type 2 diabetes, the IRS, dyslipidemia and in reducing risk of cardiovascular disease.
  • the present invention provides the use of a compound of formula (I)
  • X, Y and Z may represent either bonds or atoms or groups of atoms such that X, Y and Z together with the nitrogen atom complete an optionally substituted five or six-membered aromatic or non- aromatic ring; where each R 1 is selected from C ⁇ - alkyl, halo, haloC ⁇ -3 alkyl, C ⁇ . 3 alkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyl and n is 0, 1 or 2;
  • R 2 is selected from R 4 , OQR 4 , C(O) p R 4 , S(O) q R 4 , N(QR 6 ) R 7 , halo, cyano, carboxy, nitro,
  • R is selected from optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups;
  • R ⁇ R 6 and R are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R 6 and R 7 together with the atom to which they are attached form a ring which may be optionally substituted and which may comprise one or more heteroatoms;
  • l is O or 1;
  • each Q is independantly selected from a direct bond, C ⁇ -3 alkylene or C 2-3 alkenylene;
  • each R 3 is independently selected from C ⁇ -3 alkyl, halo, haloC ⁇ -3 alkyl, C ⁇ -3 alkoxy and m is 0, 1 or 2.
  • hydrocarbyl refers to alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups.
  • heterocyclyl refers to single or fused ring structures which, unless stated otherwise, may be aromatic or non-aromatic in nature and which suitably contain from 2 to 20 ring atoms, suitably from 5 to 8 ring atoms, at least one of which and suitably up to four of which are heteroatoms.
  • heteroatom includes oxygen, sulphur and nitrogen. Where a heteroatom is nitrogen, it will be further substituted for example by hydrogen or an alkyl group.
  • Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
  • “Heteroaryl” refers to those groups described above which have an aromatic character.
  • aryl refers to phenyl, biphenyl and naphthyl.
  • alkyl when used either alone or as a suffix includes straight chained, branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms.
  • alkenyl and alkynyl refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms.
  • Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms, suitably from 3 to 20 carbon atoms and preferably from 3 to 7 carbon atoms.
  • Terms such as “alkoxy” and “thioalkyl” comprise alkyl groups as is understood in the art.
  • the term “halo” includes fluoro, chloro, bromo and iodo.
  • References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl.
  • aralkyl refers to alkyl groups substituted with aryl, such as benzyl. Preferably 1 is 1.
  • n is 0 or 1.
  • n is 0.
  • m is 0 or 1.
  • m is 0.
  • R 1 is selected from C ⁇ - alkyl, halo, haloC ⁇ - alkyl and C ⁇ -3 alkoxy.
  • (a) is suitably selected from a group of sub-formula (b), (c), (d), (e), (f), (g), (h) or (i).
  • R 17 , R 18 and R 19 are selected from hydrogen and C. -5 alkyl. Preferably R 17 , R 18 and R 19 are all hydrogen.
  • compounds of formula (I) are indoles of formula (II)
  • R 1 , R 2 , R 3 , m and n are as defined above.
  • the carboxyl group of formula (I) is suitably at the ortho position on the phenyl ring.
  • a particular preferred group of compounds are those of formula (HA)
  • R 1 and R 3 are suitably independently selected from halo, methyl and trifluoromethyl, and are preferably halo. Most preferably however, n and m are 0.
  • Suitable optional substitutents for the heterocyclyl group include carboxyalkyl or carboxyalkenyl.
  • a and R 2 are as defined above.
  • R ⁇ , R v and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, any of which may themselves be optionally substituted, a is 1 or 2 and b is 0, 1, 2 or 3.
  • Suitable optional substituents for alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups within R 8 , R 9 and R 10 include halo, nitro cyano, alkanoyl such as acetyl, oxo, carboxy or salts or esters thereof, alkoxy such as methoxy, ethoxy or propoxy, aryloxy such as phenoxy, thioalkyl such as thiomethyl, thioethyl or thiopropyl, sulphate, haloalkyl such as trifluoromethyl, aryl such as phenyl, carbamate, amino, mono- or di-alkyl amino such as methylamino or di-methylamino.
  • Aryl, heterocyclyl or aralkyl groups R 8 , R 9 and R 10 may
  • the group R 2 is preferably selected from R 4 , OQR 4 , C(O) p R 4 , NR 6 R 7 , nitro, C(O)NR 6 R 7 , OC(O)N(QR 6 )R 7 , NR 5 C(O) n R 6 , NR 5 CON(QR 6 )R 7 , NR 5 CSN(QR 6 )R 7 , NR 5 C(O)OR 6 where Q, R 4 , R 5 , R 6 and R 7 are as defined above.
  • R 2 is selected from R 4 , OQR 4 , NR 6 R 7 and C(O)NR 6 R 7 where Q, R 4 , R 5 , R 6 and R 7 are as defined above.
  • R 2 is OR 4 .
  • R 4 is suitably substituted alkyl, in particular substituted methyl, heterocyclyl or carbocyclyl.
  • R 4 is substituted alkyl where the substitutent on the alkyl group is aryl in particular phenyl, which may itself be optionally substituted with one or more groups selected from alkyl such as C ⁇ -3 alkyl, halo such as chloro, alkylsulphonyl such as methylsulphonyl, alkoxy such as methoxy, aryl such as phenyl or aryloxy such as phenoxy.
  • a further preferred group R 2 is a group NR 5 C(O)OR 6 where R 5 is hydrogen and R 6 is alkyl, in particular C ⁇ -6 alkyl, such as butyl or tert-butyl.
  • -CR 17 CR 18 C(O)-, -CHR 17 -CHR 18 -C(O)-, -CHR 17 -CHR 18 -CHR 19 -, where R 17 , R 18 and R 19 are independently selected from hydrogen or C 1-3 alkyl such as methyl; provided that (i) where the group of sub-formula (a) as defined above is a group of sub-formula (h) and R 17 and R are hydrogen, R is other than (2-ethyl-5,7-dimethyl-3H imidazo [4,5-b]pyridin-3-yl)methyl, or methyl substituted with an aromatic heterocyclic ring containing 2 or 3 nitrogen atoms;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (LA) in combination with a pharmaceutically acceptable carrier.
  • Compounds of formula (LA) as defined above are novel and form a further aspect of the invention.
  • Preferred groups and moieties which are present in the compounds of formula (LA) are those preferred groups defined above in relation to formula (I).
  • R is an ester protecting group, in particular an alkyl group, one of R 31 or R 33 is a leaving group and the other is hydrogen or a group which reacts with and eliminates said leaving group,
  • R 32 is a bond or is a precursor to R 2 .
  • R 34 is a group R 2 as defined in relation to formula (I) or a part thereof, such that where R 34 -R 32 forms a group R 2 ; and thereafter if necessary or desired carrying out one or more of the following steps:
  • Suitable leaving groups for R 31 or R 33 include halogen, such as bromine, mesylate or tosylate.
  • Other examples of leaving groups may comprise hydroxy, where for example this forms part of an acid group (e.g. in the case of R 31 , where R 32 comprises a carbonyl group) which may be condensed, for example with amines of formula (TV) to form compounds where R 2 is an amide group.
  • the other may comprise hydrogen, but other reactive groups such as boronic acid, which would react with and eliminate halo groups may also be employed.
  • the reaction is suitably effected in a solvent such as an organic solvent and or water, in the presence of a base such as an alkali metal carbonate such as potassium carbonate. Catalysts such as palladium catalysts and elevated temperatures for example at the reflux temperature of the solvent, may be employed to assist the reaction.
  • Terminal groups such as R 4 and R 7 will then comprise the moiety R 34 above. Examples of such reactions are illustrated hereinafter. Suitable combinations of compounds of formula (HI) and
  • Deprotection to remove the group R 30 can be carried out by conventional methods, for example by acidifying the compound using a mineral acid such as hydrochloric acid.
  • Optional step (ii) above can be carried out using various methods depending upon the nature of the R 2 groups involved and could be derived from the literature.
  • Suitable leaving groups for R , 3 i 6 0 include those listed above for R 31 or R 33 and in particular is halo such as bromo.
  • the reaction is suitably effected in an organic solvent such as butanone or dimethylformamide (DMF), in the presence of a base such as an alkali metal carbonate, for example potassium carbonate or an alkali metal hydride such as sodium hydride. Elevated temperatures, for example the reflux temperature of the solvent may be employed.
  • compounds of formula (I) may be prepared by reacting a compound of formula (VTJ)
  • VH Compounds of formula (VH) may be prepared by reacting a compound of formula (VET)
  • VHT where X, Y, Z, R and m are as defined in relation to formula (I) and R is as defined in relation to formula (LH), which a compound of formula (IV) as defined above.
  • Suitable reaction conditions include those listed above for the reaction between compounds of formula (HI) and (TV).
  • Compounds of formulae (TV), (V), (VI) and (VLH) are either known compounds or they can be prepared from known compounds by conventional methods.
  • Compounds of formula (V) where R 31 -R 32 is a complex moiety may be constructed in stages as would be understood by a chemist, and examples of such procedures are given hereinafter.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • compounds of formula (I) and compositions containing them will be used in the treatment of diabetes.
  • the invention provides a method of treating diabetes which comprises administering to a patient an effective amount of a compound of formula (I) as defined above.
  • Step 4 l-(2-Carboethoxybenzyl)-3-methyl-5-(4-phenylbenzyloxy)indole
  • Step 1 1 -(2-Carboethoxybenzyl)-5-nitroindole
  • Step 3 l-(2-Carboethoxybenzyl)-5-( N (N'-benzyl)thioureido)indole
  • Benzylisothiocyanate (0.135ml lmmol ) in methylene chloride (0.5ml) was added at room temperature to a solution of l-(2-carbethoxybenzyl)-5-aminoindole in methylene chloride (2ml).
  • Step 1 l-(2-Carboethoxybenzyl)-5 -cyano indole.
  • Step 3 5-(Methylamino(N-biphenyl))-l-(2-carbomethoxybenzyl)indole.
  • Step 4 (Compound 52) A mixture of 5-(methylamino(N-biphenyl))-l-(2-carbomethoxybenzyl)indole (140 mg 0.295 mmol) and lithium hydroxide ( 24.8 mg 0.59mmol) in dioxane (5ml) and water (2ml) were stirred together at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in water and acidified with 1.ON hydrochloric acid to give a precipitate. The solid was filtered off, and washed well with water.
  • Trimethylsilyl triflate (0.89ml 4.9mmol ) was added at room temperature to a stirred solution of the t-butyl ester of l-(2-carboethoxybenzyl)-indole-5-oxyacetic acid (550mg 1.35mmol ) and triethylamine (0.75ml 5.4mmol) in dry dioxane(5ml) The mixture was heated at 60° C for three hours . After evaporation the residue was partitioned between water and ether . The combined ether extracts were washed with water brine and then dried over magnesium sulphate. The product was obtained as a crude oil after filtering and evaporating the filtrate.
  • Step 4 l-(2-Carboethoxybenyl)-5-((N- benzyl) oxyacetamido)indole.
  • Benzylamine (0.16ml 1.46mmol ), l-(2-carboethoxybenzyl)-indole-5-oxyacetic acid, (338mg 0.96mmol ), and O-(7-azabenzotriazol-l-yl)-NNN',N'-tetramethyluroniumhexafluorophosphate [ HATU ] (550mg 1.45mmol ) were stirred together at room temperature in NN dimethylformamide (3ml). Diisopropylethylamine (0.67ml 3.85mmol ) was added and the mixture was stirred at room temperature for 1 hour. After pouring into l.ON hydrochloric acid, the mixture was extracted with ether.
  • Methyl- l-(2-carboethoxybenzyl)-indole-5-oxyacetate ) was made using an analogous route to that used above for the preparation of the t-butyl ester of l-(2-carboethoxybenzyl)-indole-5- oxyacetic acid.
  • Step 2 1 -(2-Carboethoxybenzyl)-5-acetoxy-indole
  • Step 4 1 -(2-Carboethoxybenzyl)-5-(4-trifluoromethylbenzyloxy)-indole
  • step 1 was repeated as described above, except 1.5 molar equivalents of sodium hydride (60% dispersion in oil) were used instead of potassium carbonate, and the reaction stirred at room temperature for 16 hours, not 100°C for 48 hours.
  • Example 24 Using a method analogous to that described in Example 23,the following compounds were prepared.
  • Step 3 l-(p-toluenesulfonyl)-5-methyl-(N-methylamino)-pyridine-indole
  • Step 5 l-(2-carboethoxybenzyl)-5-(2-(N-methyl-N-(2-pyridyl)-aminomethyl)-indole
  • Step 6 l-(2-carboxybenzyl)-5-(2-(N-methyl-N-(2-pyridyl)-aminomethyl)-indole (Compound 5)
  • Example 26 Using a method analogous to that described in Example 25, the following compounds were prepared:
  • step 2 To a suspension of product Example 28, step 2 (250 mg, 0.56 mmol) in tetrahydrafuran (7 ml) and methanol (5 ml), was added sufficient sodium hydroxide to cause solvation. The solution was placed in a hydrogen atmosphere overnight in the presence of 10% Pd/C (52 mg). The reaction was filtered through celite® and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5 ml) and acidified to pH 1 with IN HCl . The resulting mixture was stirred for 1 hour at room temperature, then 45 minutes at 40°C, filtered off, washed with water and dried under vacuum at 50°C. The product was obtained (192 mg, 75 %) as a yellow solid, melting point 115-120°C. MS [MH] + 407; required for C 27 H 22 N 2 O 2 .HC1.0.75H 2 O):
  • (a) Ligand binding assay The assay was based on a scintillation proximity assay in which the displacement of radiolabelled [ 3 H] BRL 49653 (rosiglitazone) binding from biotinylated human PPAR ⁇ - recombinant protein was measured.
  • the PPAR ⁇ ligand binding domain (LBD) of human PPAR ⁇ l was expressed in E-Coli as a poly his and c-myc tagged fusion protein.
  • Compounds of the invention were incubated with [ 3 H] BRL 49653, 30nM (O.lmCi), biotinylated human PPARg LBD protein (150 ng) and streptavidin SPA beads, 0.25 mg/well. Compounds were able to displace radiolabel and so have pharmacological potential as PPARg agonists or antagonists.
  • Assays were performed by transient transfection of Hepalclc7 cells in which compounds of the invention were tested for their ability to activate human PPARa, d and g isoforms.
  • Cells were co-transfected with either PPARa, d and g expression vectors (containing the entire ORF sequence) and a reporter construct carrying a PPRE linked Lac Z construct.
  • Cells were transfected using Superfect and cultured in T75 flasks overnight, then plated into 96 well plates and left for 5 hours before the addition of test compound.
  • PPAR activation was quantitated indirectly as ⁇ -Galactosidase activity by hydrolysis of chlorophenol red- ⁇ -D-galactopyranoside (CPRG), measured spectrophotometrically at 580 nm.
  • CPRG chlorophenol red- ⁇ -D-galactopyranoside
  • Compounds of the invention were active in this assay.
  • Compound 3 in Table 1 showed a g transactivation of 79% at a concentration of lO ⁇ M.
  • 3T3L1 preadipocytes were grown in DMEM containing 10% NBCS and 1 day post-confluence cells were cultured in differentiation medium (DMEM containing 5% FCS, 1 ⁇ g/ml insulin,
  • 49653 was used as the positive control and the medium replenished after 3 days. On day 7, cells were lysed and glycerophosphate dehydrogenase activity measured spectrophotometrically at 340nm. Under the conditions of the assay BRL 49653 induces a dose related increase in glycerophosphate dehydrogenase activity.
  • Compounds of the invention were found to activate PPARg in the transactivation assay (vide supra) induce glycerophosphate dehydrogenase activity 0 in 3T3L1 cells in a dose -related manner. For example, Compound 3 in Table 1 showed activity at 81% as compared to the control at a concentration of lO ⁇ M.

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EP00953320A 1999-08-18 2000-08-14 Benzoesaürederivate und deren verwendung als ppar- rezeptor- agonisten Withdrawn EP1210343A2 (de)

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CN1379774A (zh) 2002-11-13
WO2001012187A3 (en) 2001-06-07
NZ517059A (en) 2004-05-28
GB9919411D0 (en) 1999-10-20
NO20020765D0 (no) 2002-02-15
CA2380775A1 (en) 2001-02-22
ZA200200669B (en) 2003-06-25
BR0013368A (pt) 2002-05-07
IL147821A0 (en) 2002-08-14
JP2003507327A (ja) 2003-02-25
MXPA02001598A (es) 2002-07-02
WO2001012187A2 (en) 2001-02-22
AU6583400A (en) 2001-03-13
NO20020765L (no) 2002-04-17

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