WO1994029302A1 - Derives heterocycliques et leur utilisation dans les produits pharmaceutiques - Google Patents

Derives heterocycliques et leur utilisation dans les produits pharmaceutiques Download PDF

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Publication number
WO1994029302A1
WO1994029302A1 PCT/EP1994/001448 EP9401448W WO9429302A1 WO 1994029302 A1 WO1994029302 A1 WO 1994029302A1 EP 9401448 W EP9401448 W EP 9401448W WO 9429302 A1 WO9429302 A1 WO 9429302A1
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Prior art keywords
compound
pharmaceutically acceptable
formula
group
alkyl
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PCT/EP1994/001448
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English (en)
Inventor
Andrew Faller
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Smithkline Beecham Plc
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Publication of WO1994029302A1 publication Critical patent/WO1994029302A1/fr

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    • 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

Definitions

  • This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • A* represents a substituted or unsubstituted aromatic heterocyclyl group
  • A-* * * represents a benzene ring having three optional substituents;
  • R! represents an N- linked, substituted or unsubstituted aromatic heterocyclyl group having 5 ring atoms, which ring atoms comprise the said linking N atom and optionally 1, 2 or 3 additional nitrogen atoms
  • R*-*- represents OR-* *1 wherein R--- * represents hydrogen, alkyl, aryl or aralkyl, or R*-** represents-NR ⁇ R ⁇ wherein R" * and R- ⁇ each independently represent hydrogen or alkyl or R4 and R-5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
  • X represents O, S or NR wherein R represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
  • m represents an integer in the range of from 1 to 6; and n represents an integer in the range of from 2 to 6.
  • A* represents a substituted or unsubstituted, single or fused ring aromatic heterocyclyl group comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • A* represents a substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • the A aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable values for A when it represents a 5- membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
  • Suitable values for A when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.
  • a particular pyridyl group is a 2-pyridyl group.
  • A-- represents a moiety of formula (a), (b) or (c):
  • R" and R ' each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R6 and R ⁇ are each attached to adjacent carbon atoms, then R ⁇ and R? together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R - * and R? together may be substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.
  • A* represents a moiety of the abovedefined formula (a).
  • A* represents a moiety of the abovedefined formula (b).
  • A* represents a moiety of the abovedefined formula (c).
  • R° and Rj together represent a moiety of formula (d):
  • R (d) wherein R*--* and R ⁇ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R* ⁇ and R each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ represents hydrogen.
  • R ⁇ represents hydrogen.
  • R and R ⁇ both represent hydrogen.
  • R" and R ⁇ each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R6 and R ⁇ each independently represent hydrogen, alkyl or phenyl.
  • R-*-* and R ⁇ together represent the moiety of formula (d).
  • R ⁇ and R ⁇ both represent hydrogen.
  • Favoured optional substituents for A- are selected from the group consisting of halogen, substituted or unsubstituted alkyl and alkoxy.
  • P - represents a moiety of formula (e):
  • R--0 and R-*- - ⁇ • each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R--0 and R ⁇ each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ and R* * each represent hydrogen.
  • X represents O. In a further aspect, X represents S. In yet a further aspect, and preferably, X represents NR.
  • R represents an N-pyrrolyl group.
  • R-2 represents OR-3 .
  • R2 represents -NR ⁇ R-5 wherein R 4 and R are as defined above.
  • R ⁇ represents hydrogen or alkyl.
  • R-*-' is alkyl it is suitably ⁇ _ ⁇ alkyl, for example methyl or ethyl.
  • R 4 and R-5 each independently represent hydrogen or C ⁇ . alkyl.
  • R 4 and R-5 each independently represent hydrogen or C ⁇ . alkyl.
  • -NR 4 R5 or -NR s R l represents a heterocyclic ring
  • favoured heterocyclic rings are saturated or unsaturated, fused or monocyclic heterocyclic rings comprising 5, 6 or 7 ring atoms and optionally comprising 1 or 2 additional hetero- atoms, selected from O,S or N, in each ring.
  • Favoured rings are saturated rings.
  • Favoured rings are monocyclic rings. Favoured, additional hetero atoms are N or O. Examples of such heterocyclic rings include N- pyrrolidinyl, N-piperidinyl and N- morpholinyl.
  • NR 4 R 5 include NH2 and N(CH3)2.
  • R represents hydrogen or alkyl.
  • suitable acyl groups include acetyl.
  • n 1
  • n 2
  • a compound of formula (I), and the pharmaceutically acceptable salts thereof may exist in one of several tautomeric forms, all of which are encompassed by the present invention as individual tautomeric forms or as mixtures thereof.
  • the compounds of formula (I) may contain at least one chiral carbon, and hence they may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, whether as individual stereoisomers or as mixtures of isomers, including racemates.
  • Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a phenylene group, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • the term 'aryl' includes phenyl and naphthyl; any aryl group mentioned herein may be optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
  • alkyl groups are alkyl groups having straight or branched carbon chains, containing up to 12 carbon atoms.
  • suitable alkyl groups are C ⁇ -12 alkyl groups, especially Cj.g alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl”.
  • Suitable acyl groups include alkylcarbonyl groups
  • Suitable pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine,
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide
  • pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be prepared by reacting a compound of formula (II):
  • a , A- X, m and n are as defined in relation to formula (I) and RP is R3 or a protecting group, with a compound of formula (HI):
  • R! is an N-pyrrolyl. group
  • Y is suitably a moiety, which together with the amine nitrogen of (II) is capable of forming Rl; an example of Y is a 1,4-dimethoxybutane group.
  • L is halogen.
  • l is halogen.
  • L-- and L * * represent the same halogen, for example chlorine.
  • RP is R 3 .
  • the reaction between the compound of formula (II) and the compound of formula (III), may be carried out in any suitable inert solvent, for example dichloromethane, at a temperature which provides a suitable rate of formation of the compound of formula (I), such as a low to ambient temperature, suitably in the range from -10°C to +10°C, for example at 4°C, and preferably in the presence of a base such as Amberlyst A-21 resin.
  • a compound of formula (II) may be prepared by reacting a compound of formula (III): H -A - ⁇ CH 2 ) m -(pH-CO-R P
  • A-- * , X and n are as defined in relation to formula (I) and L 3 represents a leaving group, such as a tosylate or mesylate group.
  • the reaction between the compound of formula (HI) and the compound of formula (IV) may be carried out in any suitable solvent, for example dimethylformamide, at a temperature which provides a suitable rate of formation of the compound of formula (II), such as at an elevated temperature, suitably in the range from 50°C to 120°C, for example at 100°C, and preferably in the presence of a base such as sodium hydride; and preferably in an inert, anhydrous atmosphere, for example dry nitrogen.
  • a suitable solvent for example dimethylformamide
  • the compounds of formula (III) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in Tetrahedron Lett., 1971, 4495, in particular the compound wherein RP is OCH3, m is 1 and A-2 is 1,4-phenylene is a commercially available compound.
  • the compounds of formulae (IV) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those disclosed in EP 0306228.
  • the abovementioned conversion of a compound of formula (I) into a further compound of formula (I) includes: a) converting one group R into another group R; and b) converting one group CO.R2 into another group CO.R- ⁇ .
  • the abovementioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.
  • Suitable conversions of one group R into another group R include converting a group R which represents hydrogen into a group R which represents an acyl group; such conversion may be carried out using an appropriate conventional acylation procedure, for example treating an appropriately protected compound of formula (I) with an acylating agent.
  • acetic anhydride may be used to prepare the compound of formula (I) wherein R is acetyl.
  • Suitable conversions of one group CO.R-2 into another group CO.R* ⁇ include:
  • Suitable hydrolysis methods for use in conversion b(i) are conventional ester hydrolysis methods, for example using an alkali hydroxide, for example lithium hydroxide, in aqueous methanol.
  • Suitable amination methods for conversion b(ii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol or treatment with an appropriate dialkylamine in a solvent such as tetrahydrofuran/methanol.
  • any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
  • protecting groups will be used when and as necessary in accordance with conventional procedures.
  • Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art.
  • a suitable hydroxyl protecting group is a benzyl group.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures.
  • the compounds of the invention are indicated as having useful therapeutic properties:
  • the present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.
  • the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia.
  • the present invention also provides a compound of formula (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension, cardiovascular disease and certain eating disorders.
  • a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • a pharmaceutically acceptable carrier for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • compositions of the present invention may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method for the treatment and/or prophylaxis of hyperglycaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof.
  • the present invention further provides a method for the treatment of hyperlipidaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a hyperlipidaemic human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
  • the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.
  • the dosages regimens for the treatment of hypertension, cardiovascular disease and eating disorders will generally be those mentioned above in relation to hyperglycaemia.
  • the present invention provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.
  • the present invention also provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidaemia, hypertension, cardiovascular disease or certain eating disorders.
  • mice C57W1/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice continued on a powdered oxoid diet or were fed powdered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3 g/kg). Blood samples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control groups. 8 mice were used for each treatment.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé selon la formule (I) ou une forme tautomère de ce composé, et/ou un sel pharmaceutiquement acceptable de ce composé et/ou un solvate pharmaceutiquement acceptable de ce composé. Dans cette formule: A1 représente un groupe hétérocyclique aromatique substitué ou non substitué; A2 représente un cycle benzène ayant trois substituants facultatifs; R1 représente un groupe hétérocyclique aromatique lié N, substitué ou non substitué, ayant 5 atomes de cycle y compris ledit atome N de liaison et facultativement 1, 2 ou 3 atomes d'azote supplémentaires; R2 représente OR3 dans lequel R3 représente hydrogène, alkyle, aryle ou aralkyle, ou R2 représente NR4R5 dans lequel R4 et R5 chacun indépendamment représentent hydrogène ou alkyle ou R4 et R5 ensemble avec l'atome d'azote auquel ils sont attachés, forment une chaîne hétérocyclique; X représente O, S ou NR dans lequel R représente un atome d'hydrogène, un groupe alkyle, un groupe acyle, un groupe aralkyle dans lequel la fraction aryle peut être substituée ou non substituée, ou un groupe aryle substitué ou non substitué; m représente un nombre entier entre 1 et 6; et n représente un nombre entier entre 2 et 6. L'invention concerne également un procédé pour préparer un tel composé, une composition comprenant un tel composé et l'utilisation de ce composé et de cette composition en médecine.
PCT/EP1994/001448 1993-06-05 1994-05-03 Derives heterocycliques et leur utilisation dans les produits pharmaceutiques WO1994029302A1 (fr)

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GB939311644A GB9311644D0 (en) 1993-06-05 1993-06-05 Novel compounds
GB9311644.0 1993-06-05

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037970A1 (fr) * 1996-04-04 1997-10-16 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
US6194446B1 (en) 1996-07-01 2001-02-27 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
US6528525B1 (en) 1997-10-02 2003-03-04 Sankyo Company, Limited Amidocarboxylic acid derivatives
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
US7041837B2 (en) 2001-07-26 2006-05-09 Cadilla Healthcare Limited Heterocyclic compounds having hypolipidemic, hypocholesteremic activities process for their preparation and pharmaceutical compositions containing them and their use in medicine
EP2154131A1 (fr) * 2007-04-26 2010-02-17 Pharmafrontier, Co., Ltd. Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992002520A1 (fr) * 1990-08-06 1992-02-20 Beecham Group P.L.C. Derives d'oxazolidine dione
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992002520A1 (fr) * 1990-08-06 1992-02-20 Beecham Group P.L.C. Derives d'oxazolidine dione
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
WO1997037970A1 (fr) * 1996-04-04 1997-10-16 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
EP0916651A1 (fr) * 1996-04-04 1999-05-19 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
US6103907A (en) * 1996-04-04 2000-08-15 Sankyo Company, Limited Phenylalkylcarboxylic acid compounds and compositions for treating hyperglycemia
CN1104413C (zh) * 1996-04-04 2003-04-02 三共株式会社 苯基烷基羧酸衍生物
EP0916651A4 (fr) * 1996-04-04 2001-09-12 Sankyo Co Derives d'acide phenylalkylcarboxylique
US6541497B1 (en) 1996-07-01 2003-04-01 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6353027B1 (en) 1996-07-01 2002-03-05 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6194446B1 (en) 1996-07-01 2001-02-27 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6528525B1 (en) 1997-10-02 2003-03-04 Sankyo Company, Limited Amidocarboxylic acid derivatives
US7041837B2 (en) 2001-07-26 2006-05-09 Cadilla Healthcare Limited Heterocyclic compounds having hypolipidemic, hypocholesteremic activities process for their preparation and pharmaceutical compositions containing them and their use in medicine
US7323491B2 (en) 2001-07-26 2008-01-29 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US8110598B2 (en) 2001-07-26 2012-02-07 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US8558009B2 (en) 2001-07-26 2013-10-15 Cadila Healthcare Limited Pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
EP2154131A1 (fr) * 2007-04-26 2010-02-17 Pharmafrontier, Co., Ltd. Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique
EP2154131A4 (fr) * 2007-04-26 2011-09-21 Pharmafrontier Co Ltd Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique

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