WO1999020614A1 - Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant Download PDF

Info

Publication number
WO1999020614A1
WO1999020614A1 PCT/US1998/022570 US9822570W WO9920614A1 WO 1999020614 A1 WO1999020614 A1 WO 1999020614A1 US 9822570 W US9822570 W US 9822570W WO 9920614 A1 WO9920614 A1 WO 9920614A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethoxy
dihydro
phenyl
benzoxazin
formula
Prior art date
Application number
PCT/US1998/022570
Other languages
English (en)
Inventor
Braj Bhushan Lohray
Vidya Bhushan Lohray
Ashok Channaveerappa Bajji
Shivaramayya Kalchar
Rajagopalan Ramanujam
Ranjan Chakrabarti
Original Assignee
Dr. Reddy's Research Foundation
Reddy-Cheminor, Inc.
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
Priority claimed from US09/085,292 external-priority patent/US6265401B1/en
Priority to PL98341795A priority Critical patent/PL341795A1/xx
Priority to EP98953970A priority patent/EP1082313A1/fr
Priority to JP2000516956A priority patent/JP2002507543A/ja
Priority to AU11206/99A priority patent/AU752059B2/en
Priority to UA2000052997A priority patent/UA72883C2/uk
Application filed by Dr. Reddy's Research Foundation, Reddy-Cheminor, Inc. filed Critical Dr. Reddy's Research Foundation
Priority to BR9812770-5A priority patent/BR9812770A/pt
Priority to IL13583998A priority patent/IL135839A/en
Priority to CA002307068A priority patent/CA2307068C/fr
Priority to HU0101110A priority patent/HUP0101110A3/hu
Priority to NZ504106A priority patent/NZ504106A/xx
Publication of WO1999020614A1 publication Critical patent/WO1999020614A1/fr
Priority to NO20002114A priority patent/NO319208B1/no

Links

Classifications

    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereo-isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
  • the compounds of the present invention lower total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
  • the compounds of general formula (I) are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia. lowering of atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis. nephrotic syndrome, hypertensive nephrosclerosis, retinnopathy and nephropathy.
  • the compounds of general formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS) inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and for the treatment of cancer.
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combination/con-comittant with one or more HMG CoA reductase inhibitors and/or hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyr-amine, colestipol. or probucol.
  • HMG CoA reductase inhibitors and/or hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyr-amine, colestipol. or probucol.
  • Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called "normal” level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum” (or “ideal”) value.
  • CAD coronary artery disease
  • LDL Low density lipo-protein
  • IDL intermediate density lipoprotein
  • HDL High density lipoprotein
  • VLDL Very low density lipoprotein
  • HDL-particles may decrease the number of sites of stenosis in coronary arteries of human, and high level of HDL- cholesterol may protect against the progression of atherosclerosis.
  • Picardo et al (Arteriosclerosis 6 (1986) 434 - 441) have shown by in vitro experiment that HDL is capable of removing cholesterol from cells. They suggest that HDL may deplete tissues of excess free cholesterol and transfer them to liver (Macikinnon et al, J. Biol. chem. 261 (1986), 2548 - 2552). Therefore, agents that increase HDL cholesterol would have therapeutic significance for the treatment of hypercholesterolemia and coronary heart diseases (CHD).
  • CHD coronary heart diseases
  • Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteo-arthritis, reduced fertility and many other psychological and social problems.
  • Diabetes and insulin resistance is yet another disease which severely effects the quality of a large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.
  • diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest, (1985) 75 : 809 - 817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66 : 580 - 583; J. Clin.
  • Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases.
  • High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyper-lipidemia.
  • LDL Low Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • Patients having glucose intolerance/insulin resistance in addition to hyper-lipidemia have higher risk of CVD.
  • Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
  • Peroxisome proliferator activated receptors are members of the nuclear receptor super family.
  • the gamma ( ⁇ ) isoform of PPAR (PPAR ⁇ ) has been implicated in regulating differentiation of adipocytes (Endo-crinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab.. (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618 -621).
  • PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that there exists synergism for the molecules, which are agonists for both PPAR ⁇ and PPAR ⁇ and suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar synergism between the insulin sensitizer (PPAR ⁇ agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma. (EP 0 753 298).
  • PPAR ⁇ plays an important role in adipocyte differentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, (1994) 79, 1147-1156) including cell cycle withdrawal. PPAR ⁇ is consistently expressed in certain cells and activation of this nuclear receptor with PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad.
  • Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardio-vascular diseases and such other interrelated complications.
  • Kallen et al Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression and therefore lower plasma leptin concentrations.
  • compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO/98/02159).
  • R a represents 2- benzoxazolyl or 2-pyridyl and Rb represent CF3, CH2OCH3 or CH3.
  • Rb represent CF3, CH2OCH3 or CH3.
  • a typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (II f).
  • A* represents aromatic heterocycle
  • a ⁇ represents substituted benzene ring
  • formula (Ilh) An example of these compounds is shown in formula (Ilh).
  • the main objective of the present invention is therefore, to provide novel -aryl- - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
  • Another objective of the present invention is to provide novel -aryl- - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPAR ⁇ and/or PPAR ⁇ , and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPAR ⁇ and/or PPAR ⁇ .
  • Another objective of the present invention is to provide novel -ar y 1- - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
  • Yet another objective of the present invention is a process for the preparation of novel -aryl- -oxysubstituted alkylcarboxylic acids of formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
  • Still another objective of the present invention is to provide pharma-ceutical compositions containing compounds of the general formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their poly-mo ⁇ hs, their salts, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • Another objective of the present invention is to provide novel inter-mediates, a process for their preparation and use of the intermediates in processes for preparation of ⁇ -aryl- ⁇ -oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereo-isomers, their polymo ⁇ hs, their salts and their pharmaceutically acceptable solvates.
  • groups R 1 , R 2 , R 3 , R 4 , and the groups R ? and R° when attached to a carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, hetero-cyclyl. heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl.
  • alkoxycarbonyl aryloxycarbonyl. aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryl-oxycarbonylamino, aralkoxycarbonylamino.
  • R ⁇ and R may also represent an oxo group when they are attached to a carbon atom;
  • R ⁇ and R 6 when attached to a nitrogen atom represents hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cyclo-alkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl.
  • alkylthio, thioalkyl groups carboxylic acid derivatives, or sulfonic acid derivatives
  • X represents a heteroatom selected from oxygen, sulfur or NR 1 1 where R 11 is selected from hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups
  • Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group
  • R 7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl.
  • R 8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl or R forms a bond together with R 7 ;
  • R 9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl. alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, aryl-aminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups;
  • R 10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl.
  • Y represents oxygen or NR , where R represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl. or heteroaralkyl groups; R 10 and R 12 together may form a 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by -(CH 2 ) n -(O) m - may be attached either through a nitrogen atom or a carbon atom; n is an integer ranging from 1 -4 and m is an integer 0 or 1.
  • Suitable groups represented by R 1 - R 4 and the groups R ⁇ and R 6 when attached to carbon atom may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, formyl: substituted or unsubstituted ( - C 1 )alkyl group, especially, linear or branched (C
  • n-butyl iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl and the like; cyclo(C 3 -C 6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl.
  • the cycloalkyl group may be substituted; cyclo(C 3 -C 6 )alkoxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; aralkyl such as benzyl or phenethyl.
  • the aralkyl group may be substituted and the substituted aralkyl is a group such as CH 3 C 6 H 4 CH 2 , Hal-C 6 H 4 CH 2 , CH 3 OC 6 H 4 CH 2 , CH 3 OC 6 H 4 CH 2 CH 2 and the like: heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl. oxazolyl, thiazolyl.
  • the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, mo ⁇ holinyl, piperidinyl, piperazinyl and the like, the heterocyclyl group may be substituted; aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkylamino group such as C 6 H 5 CH 2 NH, C 6 H 5 CH 2 CH 2 NH, C 6 H 5 CH 2 NCH 3 and the like, which may be substituted; alkoxy
  • (C r C 6 )alkylamino group such as NHCH 3 , NHC 2 H 5 , NHC 3 H 7. NHC 6 H ⁇ , and the like, which may be substituted; (C ⁇ -C 6 )dialkylamino group such as N(CH 3 ) 2 , NCH 3 (C 2 H 5 ).
  • alkoxyalkyl group such as methoxy-methyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group such as C 6 H 5 OCH2, C6H5OCH2CH2, naphthyloxymethyl and the like, which may be substituted; aralkoxyalkyl group such as C6H 5 CH 2 OCH 2 , C 6 H CH 2 OCH 2 CH 2 and the like, which may be substituted; heteroaryloxy and heteroaralkoxy, wherein heteroaryl moiety is as defined earlier and may be substituted; aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted; arylamino group such as HNC 6 H 5 , NCH 3 (C H 5 ), NHC 6 H 4 CH 3 , NHC 6 H 4 -Hal and the
  • NHCOOC 6 H OCH 3 and the like which may be substituted; alkoxycarbonyl-amino group such as NHCOOC 2 H 5 , NHCOOCH 3 and the like, which may be substituted; carboxylic acid or its derivatives such as amides, like CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh and the like, the carboxylic acid derivatives may be substituted; acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may be substituted; sulfonic acid or its derivatives such as SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , SO 2 NHCF 3 and the like, the sulfonic acid derivatives may be substituted.
  • R 5 and R 6 may also represent an oxo group.
  • the substituents may be selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aralkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl.
  • heteroaralkyl acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives .
  • R 1 - R 6 represent halogen atom such as fluorine, chlorine, bromine; alkyl group such as methyl, ethyl, iso-propyl. n-propyl, n- butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; (C ⁇ -C 3 )alkoxy, benzyloxy, hydroxy group, acyl or acyloxy groups.
  • halogen atom such as fluorine, chlorine, bromine
  • alkyl group such as methyl, ethyl, iso-propyl. n-propyl, n- butyl
  • cycloalkyl group such as cyclopropyl
  • aryl group such as phenyl
  • aralkyl group such as benzyl
  • Suitable R 5 and R 6 when attached to nitrogen atom is selected from hydrogen, hydroxy, formyl; substituted or unsubstituted (C
  • acyl group such as acetyl, propionyl, benzoyl and the like, the acyl group may be substituted; acylamino groups such as NHCOCH 3 , NHCOC 2 H 3 , NHCOC 3 H 7 , NHCOC 6 H 5 and the like, which may be substituted; carboxylic acid derivatives such as amides, like CONH 2 , CONHMe,
  • the carboxylic acid derivatives may be substituted; acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may be substituted; sulfonic acid derivatives such as SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , SO 2 NHCF 3 and the like, the sulfonic acid derivatives may be substituted.
  • preferred substituents may be selected from halogen such as fluorine, chlorine; hydroxy, acyl, acyloxy, or amino groups.
  • Suitable X includes oxygen, sulfur or a group NR 1 ' as defined above, preferably oxygen and sulfur.
  • R 11 represent hydrogen, (C ⁇ -C )alkyl, (C 3 -C 6 )cycloalkyl, aryl group such as phenyl or naphthyl, aralkyl group such as benzyl or phenethyl; acyl group such as acetyl, propanoyl, butyroyl, benzoyl and the like; (C ⁇ -C 6 )alkoxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl, CH 3 OC 6 H OCO, Hal-C 6 H OCO,
  • the group represented by Ar be substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl. benzofuranyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzo-pyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.
  • the substituents on the group represented by Ar may be selected from linear or branched optionally halogenated (C
  • Ar represents a substituted or unsubstituted divalent, phenylene, naphthylene, benzofuranyl, indolyl, indolinyl. quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
  • Ar is represented by divalent phenylene or benzofuranyl, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
  • Suitable R 7 includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, ( -C 3 )alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; aralkyl such as benzyl, phenethyl, which may be optionally substituted or R 7 together with R 8 represents a bond.
  • Suitable R may be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, ( -C 3 )alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; acyl group such as linear or branched (C 2 -C ⁇ o)acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl, which may be optionally substituted or together with R 7 forms a bond.
  • Suitable groups represented by R 9 may be selected from hydrogen, linear or branched (C ⁇ -C J6 )alkyl, preferably (C ⁇ -Ci 2 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C -C 7 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazol-e
  • the substituents may be selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cyclo-alkoxy, aryl, aralkyl. aralkoxyalkyl. heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryl-oxy, alkoxycarbonyl, alkylamino. alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives .
  • Suitable groups represented by R 10 may be selected from hydrogen, linear or branched (C]-Ci 6 )alkyl, preferably (C ⁇ -C ⁇ 2 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C 3 -C 7 )cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazole
  • R 10 may be selected from the same group of R'-R 6 .
  • Suitable groups represented by R 12 may be selected from hydrogen, linear or branched (C]-C 16 )alkyl, preferably (C]-C ⁇ 2 )alkyl; hydroxy
  • (C ⁇ -C 6 )alkyl aryl group such as phenyl, naphthyl and the like; aralkyl group such as benzyl, phenethyl and the like; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl, and the like; heteroaryl group such as pyridyl, thienyl, furyl and the like; and heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl. oxazolethyl and the like.
  • Suitable ring structures formed by R 10 and R 12 together may be selected from pyrrolidinyl, piperidinyl, mo ⁇ holinyl, piperazinyl and the like.
  • Suitable n is an integer ranging from 1 to 4, preferably n represents an integer 1 or 2.
  • salts forming part of this invention include salts of the carboxylic acid moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, and aluminum salts.
  • alkali metal salts like Li, Na, and K salts
  • alkaline earth metal salts like Ca and Mg salts
  • salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, and aluminum salts.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates. salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to the present invention include :
  • the compound of general formula (I) where R 7 and R 8 together represent a bond, Y represents oxygen atom, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , X, n, m and Ar are as defined earlier, can be prepared by any of the following routes shown in Scheme I.
  • Route (1) The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier with a compound of formula (Illb) where R , R 10 are as defined earlier and R , 14 represents (C ⁇ -C 6 )alkyl, to yield compound of general formula (I) where R 7 , R 8 together represent a bond and Y represents an oxygen atom
  • a base such as alkali metal hydrides like NaH, or KH or organolithiums like CH 3 Li, BuLi and the like or alkoxides such as NaOMe, NaOEt, K + BuO " or mixtures thereof.
  • the reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.
  • HMPA may be used as cosolvent.
  • the reaction temperature may range from -78 °C to 50 °C, preferably at a temperature in the range o -10 °C to 30 °C.
  • the reaction is more effective under anhydrous conditions.
  • the compound of general formula (Illb) may be prepared according to the procedure described in the literature (Annalen. Chemie, (1996) 53, 699).
  • Route (2) The reaction of a compound of general formula (IIIc) where all symbols are as defined earlier with a compound of general formula (Hid) where R 7 , R 8 together represent a bond and all symbols are as defined earlier and L 1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethane-sulfonate and the like, preferably a halogen atom to produce a compound of general formula (I) defined above may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He.
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, or potassium hydroxide; alkali metal carbonates like sodium carbonate, or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • Phase transfer catalysts such as tetraalkylammonium halide or hydroxide may be added.
  • the reaction may be carried out at a temperature in the range of 0 °C to 150 °C, preferably at a temperature in the range of 15 °C to 100 °C.
  • the duration of the reaction may range from 0.25 to 48 hours, preferably from 0.25 to 12 hours.
  • the reaction may be carried out in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.
  • HMPA may be used as cosolvent.
  • the reaction temperature may range from -78 °C to 100 °C, preferably at a temperature in the range of -10 °C to 50 °C.
  • the nature of the base is not critical. Any base normally employed for aldol condensation reaction may be employed; bases like metal hydride such as NaH, or
  • KH metal alkoxides such as NaOMe, K + BuO " , or NaOEt
  • metal amides such as LiNH 2 , or LiN(ipr) 2
  • Aprotic solvent such as THF, ether, or dioxane may be used.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He and the reaction is more effective under anhydrous conditions. Temperature in the range of -80 °C to 35 °C may be used.
  • the ⁇ - hydroxy product initially produced may be dehydrated under conventional dehydration conditions such as treating with PTSA in solvents such as benzene or toluene.
  • solvents such as benzene or toluene.
  • the nature of solvent and dehydrating agent is not critical.
  • Temperature in the range of 20 °C to reflux temperature of the solvent used may be employed, preferably at reflux temperature of the solvent by continuous removal of water using a Dean Stark water separator.
  • Route (5) The reaction of compound of formula (Illh) where all symbols are as defined earlier and L 1 represents a leaving group such as as halogen atom, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like with a compound of formula (Hli) where R 7 and R 8 together represent a bond and R 9 .
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof.
  • Acetone may be used as solvent when Na 2 CO 3 or
  • K 2 CO 3 is used as a base.
  • the reaction temperature may range from 0 °C - 120 °C, preferably at a temperature in the range of 30 °C - 100 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the compound of formula (Hli) can be prepared according to known procedures by a Wittig Horner reaction between the hydroxy protected aryl aldehyde such as benzyloxyaryl aldehyde and compound of formula (Illb), followed by deprotection.
  • suitable coupling agents such as dicyclohexyl urea, triaryl- phosphine/dialkylazadicarboxylate such as PPh 3 / DEAD and the like.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHC1 , toluene, acetonitrile, carbontetrachloride and the like.
  • solvents such as THF, DME, CH 2 C1 2 , CHC1 , toluene, acetonitrile, carbontetrachloride and the like.
  • the inert atmosphere may be maintained by using inert gases such as N , Ar, or He.
  • the reaction may be effected in the presence of DMAP, HOBT and they may be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • the reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed.
  • the catalyst may be preferably 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (I) in optically active form.
  • the metal catalyst may contain rhodium, ruthenium, indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as (2S,3S)-bis(diphenyl-phosphino)butane, 1,2- bis(diphenylphosphino)ethane, 1 ,2-bis(2-methoxyphenyl phenylphosphino)ethane, (-)- 2,3-isopropylidene-2,3-dihydroxy-l,4-bis(diphenyl-phosphino) butane and the like.
  • Any suitable chiral catalyst may be employed which would give required optical purity of the product (I) (Ref : Principles of Asymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed. Baldwin J. E.).
  • Route 8 The reaction of compound of formula (IVb) where all symbols are as defined earlier and L 2 is a leaving group such as halogen atom with an alcohol of general formula (IVc), where R is as defined earlier to produce a compound of the formula (I) defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He.
  • the reaction may be effected in the presence of a base such as KOH, NaOH, NaOMe, NaOEt, K + BuO " or NaH or mixtures thereof.
  • Phase transfer catalysts such as tetraalkylammonium halides or hydroxides may be employed.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 100 °C.
  • the duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
  • the compound of general formula (IVb) and its preparation has been disclosed in the copending U.S. Application No. 08/982,910.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 ? NaH or mixtures thereof.
  • Acetone may be used as a solvent when K2CO3 or Na2CO3 is used as a base.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 80
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the compound of formula (Illi) may be prepared by Wittig Horner reaction between the protected hydroxyaryl aldehyde and compound of formula (Illb) followed by reduction of the double bond and deprotection. Alternatively, the compound of formula (Illi) may be prepared by following a procedure disclosed in WO 94/01420.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 CI 2 , CHC1 3 , toluene, acetonitrile, carbon tetrachloride and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, or He.
  • the reaction may be effected in the presence of DMAP. HOBT and they may be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • Route 11 The reaction of compound of formula (IVd) which represents a compound of formula (I) where R 9 represents hydrogen atom and all other symbols are as defined earlier with a compound of formula (IV e) where R 9 is as defined earlier and L 2 is a leaving group such as a halogen atom, may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like.
  • solvents such as THF, DMF, DMSO, DME and the like.
  • the inert atmosphere may be maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as KOH, NaOH, NaOMe, K + BuO " , NaH and the like.
  • Phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be employed.
  • the reaction temperature may range from 20 °C to 150 °C, preferably at a temperature in the range of 30 °C to 100 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
  • Route 12 The reaction of a compound of the general formula (Ilia) as defined above with a compound of formula (Illg) where R . R , and R are as defined earlier may be carried out under conventional conditions.
  • the base is not critical.
  • any base normally employed for aldol condensation reaction may be employed, metal hydride such as NaH, or KH; metal alkoxides such as NaOMe, K l BuO " , or NaOEt; metal amides such as L1NH 2 , or LiN(ipr) 2 .
  • Aprotic solvent such as THF may be used.
  • Inert atmosphere may be employed such as argon and the reaction is more effective under anhydrous conditions.
  • Temperature in the range of -80 °C to 25 °C may be used.
  • the ⁇ -hydroxy aldol product may be dehydroxylated using conventional methods, conveniently by ionic hydrogenation technique such as by treating with a trialkyl silane in the presence of an acid such as trifluoroacetic acid.
  • Solvent such as CH 2 CI 2 may be used.
  • the reaction proceeds at 25 °C. A higher temperature may be employed if the reaction is slow.
  • Route 13 The reaction of a compound of general formula (IIIc) where all symbols are as defined earlier with a compound of general formula (Hid) where L is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethane- sulfonate and the like, preferably L 1 is a halogen atom, and all other symbols are as defined earlier to produce a compound of general formula (I) may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He.
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, or potassium hydroxide, alkali metal carbonates like sodium carbonate, or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium, alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • the reaction may be carried out at a temperature in the range of 0 °C to 150 °C, preferably at a temperature in the range of 15 °C to 100 °C.
  • the duration of the reaction may range from 0.25 to 24 hours, preferably from 0.25 to 12 hours.
  • the conversion of compound of formula (IVf) to a compound of formula (I) may be carried out either in the presence of base or acid and the selection of base or acid is not critical.
  • Any base normally used for hydrolysis of nitrile to acid may be employed, such as metal hydroxides such as NaOH. or KOH in an aqueous solvent or any acid normally used for hydrolysis of nitrile to ester may be employed such as dry HCl in an excess of alcohol such as methanol, ethanol, propanol etc.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent used, preferably at a temperature in the range of 25 °C to reflux temperature of the solvent used.
  • the duration of the reaction may range from 0.25 to 48 hrs.
  • Route 15 The reaction of a compound of formula (IVg) where all symbols are as defined earlier with a compound of formula (IVc) where R 9 is as defined earlier to produce a compound of formula (I) (by a rhodium carbenoid mediated insertion reaction) may be carried out in the presence of rhodium (II) salts such as rhodium (II) acetate.
  • the reaction may be carried out in the presence of solvents such as benzene, toluene, dioxane, ether, THF and the like or a combination thereof or when practicable in the presence of R 9 OH as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as reflux temperature of the solvent.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, or He.
  • the duration of the reaction may range from 0.5 to 24 h, preferably from 0.5 to 6 h.
  • the compound of general formula (I) where Y represents oxygen and R 10 is as defined earlier may be converted to compound of formula (I), where Y represents NR 12 by reaction with appropriate amines of the formula NHR 10 R 12 , where R I ⁇ and R 12 are as defined earlier.
  • mixed anhydrides may be prepared from compound of formula (I) where
  • YR 10 represents OH and all other symbols are as defined earlier by treating with acid halides such acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like.
  • acid halides such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like.
  • the reaction may be carried out in the presence of suitable base such as pyridine, triethylamine, diisopropyl ethyl amine and the like.
  • Solvents such as halogenated hydrocarbons like CHC1 3 , or CH 2 C1 2; hydrocarbons such as benzene, toluene, xylene and the like may be used.
  • the reaction may be carried out at a temperature in the range of -40 °C to 40 °C, preferably at a temperature in the range of 0 °C to 20 °C.
  • the acid halide or mixed anhydride thus prepared may further be treated with appropriate amines.
  • groups R 1 , R 2 , R 3 , R 4 , and the groups R 5 and R 6 when attached to a carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl.
  • R 5 and R 6 when attached to nitrogen atom represents hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl
  • alkoxyalkyl alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups;
  • the linking group represented by - (CH 2 ) n -(O) m - may be attached either through nitrogen atom or carbon atom;
  • n is an integer ranging from 1-4 and
  • m is an integer 0 or 1 and a process for its preparation and its use in the preparation of ⁇ -aryl- ⁇ -substituted hydroxyalkanoic acids is provided.
  • the compound of (IVi) where all symbols are as defined earlier may be converted to a compound of formula (IVj) where R 7 and R 8 represent hydrogen atoms and all other symbols are as defined earlier, by treating with an alcohol under anhydrous conditions in the presence of a strong anhydrous acid such as p-toluenesulfonic acid.
  • a strong anhydrous acid such as p-toluenesulfonic acid.
  • the compound of formula (IVj) defined above upon treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of formula (IVf) where R 7 and R represent hydrogen atoms and all other symbols are as defined earlier.
  • groups R 1 , R 2 , R 3 , R 4 , and the groups R 5 and R 6 when attached to a carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl.
  • R 5 and R 6 may also represent an oxo group when they are attached to a carbon atom;
  • R 5 and R 6 when attached to a nitrogen atom represents hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroary
  • R 10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups
  • Y represents oxygen
  • the linking group represented by -(CH2) ist-(O) m - may be attached either through nitrogen atom or carbon atom
  • n is an integer ranging from 1-4 and m is an integer 0 or 1 and a process for its preparation and its use in the preparation of ⁇ -aryl- ⁇ -substituted hydroxyalkanoic acids is provided.
  • R 8 is a hydrogen atom and all other symbols are as defined earlier, with an appropriate diazotizing agent.
  • the diazotization reaction may be under conventional conditions.
  • a suitable diazotizing agent is an alkyl nitrile, such as iso-amyl nitrile.
  • the reaction may be carried out in presence of solvents such as THF, dioxane, ether, benzene and the like or a combination thereof. Temperature in the range of -50 °C to 80 may be used.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar or He.
  • the duration of the reaction may range from 1 to 24 h, preferably, 1 to 12 h.
  • the compound of formula (IVk) may also be prepared by a reaction between
  • R 8 is a hydrogen atom and all other symbols are as defined earlier.
  • reaction of compound of formula (Illh) where all symbols are as defined earlier and a compound of formula (IVl) where all symbols are as defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof.
  • Acetone may be used as a solvent when K2CO3 or Na2CO3 is used as a base.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 80 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixtures of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, as
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • polymo ⁇ hs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymo ⁇ hs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the compounds of general formula (I) are useful in the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyshpidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis and for the treatment of cancer.
  • the compounds of the present inventions are useful in the treatment and/or prophylaxis of arteriosclerosis and/or xanthoma in combination with one or more HMG CoA reductase inhibitors, hyupolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol or probucol.
  • HMG CoA reductase inhibitors such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol or probucol.
  • the compounds of the present invention in combination with HMG CoA reductase inhibitors and/or hypolipidemic/hypolipoprotein agents can be administered together or within such a period to act synergistically.
  • the HMG CoA reductase inhibitors may be selected from those used for the treatment or prevention of hyperlipidemia such as lovastatin, provastatin, simvastatin, fluvastatin, atorvastatin. cerivastatin and their analogs thereof.
  • Suitable fibric acid derivative may gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate and their anologs.
  • the present invention also provides pharmaceutical compositions, containing the compounds of the general formula (I), as defined above, their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %. preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • the compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.01 to about 50 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutical ly-acceptable acid addition salts or salts with base of the compounds.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
  • the reaction mixture was acidified with 10 % sulphuric acid and extracted with ethyl acetate (2 x 75 mL). The combined ethyl acetate layer was washed with water (2 x 50 mL), brine (50 mL), dried (Na 2 SO 4 ). filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over l Q silica gel using a mixture of ethyl acetate and pet. ether (10 : 90) to afford the title compound (4.5 g, 56 %) as a pale yellow solid, mp : 100 - 102 °C.
  • the title compound was prepared as a 38 : 62 ratio of geometric isomers (as measured by ⁇ NMR) (3.2 g, 71 %) as a gum, from 4-[2-(2,3-dihydro-l ,4-benzothiazin- 4-yl)ethoxy]benzaldehyde (3.3 g, 11.03 mmol) prepared according to the process described in Preparation 2 disclosed in Patent Application 08/982,910 by a method analogous to that described in example 1.
  • the title compound (0.14 g, 32 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (1.9 g, 17 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g, 30.0 mmol).
  • potassium carbonate (20.7 g, 150 mmol)
  • ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.4 g, 52 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g. 1.78 mmol). potassium carbonate (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3-(4-h ⁇ diOxyphenyl)piOpanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.31 g, 50 %) was prepared as a colorless syrup from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.35 g, 1.3 mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl 2-hexyloxy-3-(4-hydroxyphenyl) propanoate (0.4 g, 1.3 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.92 g, 58 %) was prepared as a mixture of E : Z isomers (40 : 60) as a syrupy liquid from 4-[2-(2,3-dihydro-1.4-benzoxazin-4-yl)ethoxy]benzaldehyde (1.0 g, 3.0 mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz. et. al. J. Org. Chem., 1983. 48, 3408) (1.3 g, 4.0 mmol) by an analogous procedure to that described in example 1.
  • the title compound (3.7 g, 60 %) was prepared as a mixture of E : Z isomers (35 : 65) as a gummy material from 4-[2-(2,3-dihydro-l ,4-benzothiazin-4- yl)ethoxy]benzaldehyde (4.0 g, 13.0 mmol) and triethy l 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. J. Org. Chem. 1983, 48, 3408). (5.07 g. 16.0 mmol) by an analogous procedure to that described in example 1.
  • the title compound (0.2 g, 80 %) was prepared as a white solid from 3-[4-[2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4 mL) by an analogous procedure to that described in example 31. mp : 107 - 109 °C.
  • the title compound (0.1 g, 73 %) was prepared as a cream colored hygroscopic solid from 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy- propanoic acid (0.13 g, 0.30 mmol) obtained in example 47 by a procedure analogous to that described in example 27.
  • the title compound (0.12 g, 57 %) was prepared as a hygroscopic cream colored solid from 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoic acid (0.2 g, 0.5 mmol) obtained in example 49 by an analogous procedure to that described in example 27.
  • the title compound (0.05 g, 48 %) was prepared as a hygroscopic solid from 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid (0.1 g, 0.24 mmol) obtained in example 53 by a procedure analogous to that described in example 27.
  • the title compound (0.055 g, 46 %) was prepared as a hygroscopic pale yellow powder from 2-methyl-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl] -2- phenoxypropanoic acid (0.13 g, 0.28 mmol) obtained in example 57 by a procedure analogous to that described in example 27.
  • the title compound (0.6 g, 100 %) was prepared as a dark brown liquid from 3-[4 -(4-benzyl-3 ,4-dihydro-2H- 1 ,4-benzoxazin-2-yl)methoxypheny 1] -2-ethoxypropanoic acid (0.5 g, 1.34 mmol) obtained in example 62 and 4-nitro phenol by a procedure analogous to that described in example 32.
  • the compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, VLDL and increased HDL. This was demonstrated by in vitro as well as in vivo animal experiments. Demonstration of Efficacy of Compounds A) In vitro : a) Determination of hPPAR ⁇ activity
  • Ligand binding domain of hPPAR ⁇ was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using superfect (Qiagen, Germany) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at different concentrations after 42 firs of transfection and incubated overnight. Luciferase activity as a function of compound binding/activation capacity of PPAR ⁇ was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992.
  • hPPAR ⁇ activity Ligand binding domain of hPPAR ⁇ l was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at 1 ⁇ M concentration after 48 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of drug binding/activation capacity of PPAR ⁇ l was measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 1 18 : 137 — 141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).
  • c) Determination of HMG CoA reductase inhibition activity Liver microsome bound reductase was prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays were carried out in 100 mM KH 2 PO .
  • mice C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic.
  • db/db model mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled.
  • pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
  • mice of 8 to 14 weeks age having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment.
  • the mice were provided with standard feed (National Institute of Nutrition (NIN), India) and acidified water, ad libitum.
  • the animals having more than 350 mg / dl blood sugar were used for testing.
  • the number of animals in each group was 4.
  • Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
  • the random blood sugar and triglyceride levels were measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-PO oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
  • mice were obtained at 5 weeks of age from Bomholtgard, Demark and were used at 8 weeks of age.
  • Zucker fa/fa fatty rats were obtained from IffaCredo, France at 10 weeks of age and were used at 13 weeks of age.
  • the animals were maintained under 12 hour light and dark cycle at 25 + 1 °C.
  • Animals were given standard laboratory chow (NIN, India) and water, ad libitum (Fujiwara. T., Yoshioka, S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988. 37 : 1549 - 1558).
  • the test compounds were administered at 0.1 to 30 mg/kg/day dose for 9 days.
  • the control animals received the vehicle (0.25 % carboxymethylcellulose, dose 10 ml/kg) through oral gavage.
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 9 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations. Measurement of plasma triglyceride, glucose, total cholesterol were done using commercial kits (Dr. Reddy's Laboratory. Diagnostic Division, India).
  • the plasma free fatty acid was measured using a commercial kit from Boehringer Mannheim, Germany.
  • the plasma insulin was measured using a RIA kit (BARC, India). The reduction of various parameters examined are calculated according to the formula given below.
  • mice oral glucose tolerance test was performed after 9 days treatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg of glucose orally. The blood samples were collected at 0, 15, 30, 60 and 120 min for estimation of plasma glucose levels.
  • Zucker fa/fa rats suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidaemia and other diseases; as it is known from the literature that such diseases are interrelated to each other.
  • Plasma triglyceride and Cholesterol lowering activity in hypercholesterolemic rat models are also lowered at doses greater than 10 mg/kg. Normally, the quantum of reduction is dose dependent and plateaus at certain dose. b) Plasma triglyceride and Cholesterol lowering activity in hypercholesterolemic rat models
  • mice Male Sprague Dawley rats (NIN stock) were bred in DRF animal house. Animals were maintained under 12 hour light and dark cycle at 25 ⁇ 1 °C. Rats of 180 - 200 gram body weight range were used for the experiment. Animals were made hypercholesterolemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow [National Institute of Nutrition (NIN), India] for 6 days. Throughout the experimental period the animals were maintained on the same diet (Petit, D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats. Atherosclerosis. 1988. 74 : 215 - 225). The test compounds were administered orally at a dose 0.1 to 30 mg/kg/day for 3 days. Control group was treated with vehicle alone (0.25 % Carboxymethylcellulose; dose 10 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 3 day of compound treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction of various parameters examined are calculated according to the formula.
  • SAM Swiss albino mice and Guinea pigs
  • Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NIN and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 + 1 C. Animals were given standard laboratory chow (NIN. India) and water, ad libitum. SAM of 20 - 25 g body weight range and Guinea pigs of 500 - 700 g body weight range were used (Oliver, P.. Plancke, M. O., Marzin, D., Clavey, V., Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis. 1988. 70 : 107 - 114).
  • test compounds were administered orally to Swiss albino mice at 0.3 to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds were administered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days. Control animals were treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 6 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27).
  • Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, India).
  • test compounds were administered orally at 1 to 30 mg/kg/day dose for 15 days.
  • Control group animals were treated with vehicle (Mill Q water, dose 10 ml/kg/day).
  • Body weights were measured on every 3 r day.
  • LDL cholesterol in mg/dl Total cholesterol - HDL cholesterol - Triglvceride
  • VLDL cholesterol in mg/dl Total cholesterol - HDL cholesterol - LDL cholesterol

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention porte sur de nouveaux composés anti-obésité et hypocholestérolémiants, leurs dérivés, leurs analogues, leurs tautomères, leurs stéréo-isomères, leurs polymorphes, leurs sels acceptables sur le plan pharmaceutique, leurs solvants acceptables sur le plan pharmaceutique ainsi que les compositions les contenant qui sont acceptables sur le plan pharmaceutique. Elle porte plus particulièrement sur de nouveaux acides alkylcarboxyliques β-aryl-α-oxysubstitués de la formule générale (I), leurs dérivés, leurs analogues, leurs tautomères, leurs stéréo-isomères, leurs polymorphes, leurs sels acceptables sur le plan pharmaceutique, leus solvants acceptables sur le plan pharmaceutique et les compositions les contenant qui sont acceptables sur le plan pharmaceutique.
PCT/US1998/022570 1997-10-27 1998-10-26 Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant WO1999020614A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
NZ504106A NZ504106A (en) 1998-05-27 1998-10-26 Fused Oxazine, Thiazine and pipyridine compounds, process for their preparation and pharmaceutical compositions containing them
EP98953970A EP1082313A1 (fr) 1998-05-27 1998-10-26 Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant
JP2000516956A JP2002507543A (ja) 1998-05-27 1998-10-26 二環系化合物、その製造方法およびそれらを含有する薬学的組成物
AU11206/99A AU752059B2 (en) 1997-10-27 1998-10-26 Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
UA2000052997A UA72883C2 (uk) 1997-10-27 1998-10-26 Біциклічна сполука, способи її одержання, фармацевтичні композиції, що її містять,способи лікування та попередження різних захворювань, проміжні сполуки та способи їх одержання
PL98341795A PL341795A1 (en) 1998-05-27 1998-10-26 Bicycle compounds, process for obtaining them and pharmacological compositions containing such compounds
BR9812770-5A BR9812770A (pt) 1997-10-27 1998-10-26 Compostos bicìclicos, processo para seu preparo e composições farmacêuticas contendo os mesmos
IL13583998A IL135839A (en) 1998-10-26 1998-10-26 Bicyclic compounds, processes or the preparation thereof and pharmaceutical compositions containing the same
CA002307068A CA2307068C (fr) 1997-10-27 1998-10-26 Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant
HU0101110A HUP0101110A3 (en) 1997-10-27 1998-10-26 Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
NO20002114A NO319208B1 (no) 1997-10-27 2000-04-26 Bisykliske forbindelser, intermediater, fremgangsmate for deres fremstilling, farmasoytiske sammensetninger inneholdende dem, og anvendelse av dem for fremstilling av et farmasoytisk preparat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/085,292 1998-05-27
US09/085,292 US6265401B1 (en) 1997-10-27 1998-05-27 Bicyclic compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
WO1999020614A1 true WO1999020614A1 (fr) 1999-04-29

Family

ID=22190649

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/022570 WO1999020614A1 (fr) 1997-10-27 1998-10-26 Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant

Country Status (6)

Country Link
EP (1) EP1082313A1 (fr)
JP (1) JP2002507543A (fr)
CN (1) CN100357281C (fr)
NZ (1) NZ504106A (fr)
PL (1) PL341795A1 (fr)
WO (1) WO1999020614A1 (fr)

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035437A2 (fr) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Utilisation accrue de glucose par le cerveau
WO2000063153A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation de ces derniers
WO2000063209A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation associees
WO2000063193A1 (fr) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Nouvelles formes polymorphes d'un agent antidiabetique: leur procede de preparation et composition pharmaceutique contenant lesdites formes
WO2000063190A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, leur preparation et utilisation
WO2000063192A1 (fr) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant
WO2000066572A1 (fr) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques
WO2001055085A1 (fr) * 2000-01-28 2001-08-02 Novo Nordisk A/S Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite
WO2001087862A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. 4h-benzo[1,4]oxazine-3-ones biologiquement actives
WO2001087861A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Methodes de traitement mettant en oeuvre des benzoxazinones comme modulateurs du recepteur gamma active par le proliferateur du peroxisome
WO2001087860A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Nouveaux benzoxazinones utilises comme modulateurs du recepteur gamma active de la proliferation des peroxysomes, et methode de traitement associee
WO2002020499A1 (fr) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Procede de preparation de 2-[3,4-dihydro-1,4-benzothiazin-4-yl]ethylmethane sulphonate
US6369055B1 (en) 1999-04-20 2002-04-09 Novo Nordisk A/S Compounds, their preparation and use
WO2002030914A1 (fr) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Sels de derives de benzothiazine et de benzoxazine et compositions pharmaceutiques a base de ces sels
WO2001053257A3 (fr) * 2000-01-19 2002-06-27 Cadila Healthcare Ltd Nouveaux composes hypolipidemiques et hypocholesterolemiques, leur procede de preparation, et compositions pharmaceutiques les contenant
WO2002100397A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un agent hypolipemiant
WO2003006022A1 (fr) * 2001-07-09 2003-01-23 Dr. Reddy's Laboratories Ltd. Derives de tetrahydroquinoline et leur utilisation en medecine, procede de preparation associe et compositions pharmaceutiques contenant lesdits composes
WO2003009841A1 (fr) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Nouveaux pyrroles possedant des activites hypolipidemiantes et hypocholesterolemiantes, procede de preparation de ceux-ci, compositions pharmaceutiques les contenant et leur utilisation en medecine
US6528507B1 (en) 1999-04-16 2003-03-04 Dr. Reddy's Laboratories Limited Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
WO2003033481A1 (fr) * 2001-10-16 2003-04-24 Dr. Reddy's Laboratories Ltd. Derives de benzoxazine et de benzothiazine, et compositions pharmaceutiques contenant ces derives
US6555577B1 (en) 2000-01-28 2003-04-29 Novo Nordisk A/S Compounds, their preparation and use
US6569901B2 (en) 2000-01-28 2003-05-27 Novo Nordisk A/S Alkynyl-substituted propionic acid derivatives, their preparation and use
EP1314729A1 (fr) * 2001-11-21 2003-05-28 Ortho-McNeil Pharmaceutical, Inc. Dérivés de 4H-Benzo(1,4)oxazin-3-one biologiquement actifs
WO2003099800A1 (fr) * 2002-05-23 2003-12-04 Dr. Reddy's Laboratories Limited Procede ameliore pour la preparation d'agents antidiabetiques bicycliques
US6939853B2 (en) 2001-12-29 2005-09-06 Novo Nordisk A/S Combined use of a GLP-1 compound and another drug for treating dyslipidemia
US6972294B1 (en) 1999-04-20 2005-12-06 Novo Nordisk, A/S Compounds, their preparation and use
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
US7790745B2 (en) 2005-10-21 2010-09-07 Bristol-Myers Squibb Company Tetrahydroisoquinoline LXR Modulators
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012104869A1 (fr) 2011-01-31 2012-08-09 Cadila Healthcare Limited Traitement de la lipodystrophie
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013082106A1 (fr) 2011-12-02 2013-06-06 The General Hospital Corporation Différenciation en adipocytes bruns
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015001573A1 (fr) 2013-07-05 2015-01-08 Cadila Healthcare Limited Compositions synergiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US9814697B2 (en) 2013-04-22 2017-11-14 Cadila Healthcare Limited Composition for nonalcoholic fatty liver disease (NAFLD)
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10098868B2 (en) 2013-07-25 2018-10-16 Cadila Healthcare Limited Formula comprising a hypolipidemic agent
US10112898B2 (en) 2013-09-06 2018-10-30 Cadila Healthcare Limited Process for the preparation of saroglitazar pharmaceutical salts
US10385017B2 (en) 2015-10-14 2019-08-20 Cadila Healthcare Limited Pyrrole compound, compositions and process for preparation thereof
US10435363B2 (en) 2013-05-30 2019-10-08 Cadila Healthcare Limited Process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
US11433050B2 (en) 2016-12-09 2022-09-06 Cadila Healthcare Ltd. Treatment for primary biliary cholangitis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110092774B (zh) * 2018-01-29 2022-04-08 中国科学院上海药物研究所 芳香丙酸类衍生物、及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0441539A2 (fr) * 1990-02-08 1991-08-14 Tanabe Seiyaku Co., Ltd. Dérivés de thiazine (ou oxazine) et leur préparation
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
US5104888A (en) * 1985-02-26 1992-04-14 Sankyo Company, Limited Thiazolidine derivatives, their preparation and use
JPH05194236A (ja) * 1991-07-25 1993-08-03 Tanabe Seiyaku Co Ltd 中枢性カルシウム拮抗剤
WO1996004260A1 (fr) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii
US5496815A (en) * 1990-02-08 1996-03-05 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
JPH0912575A (ja) * 1995-06-28 1997-01-14 Sankyo Co Ltd ベンゾオキサジンおよびベンゾチアジン誘導体

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5104888A (en) * 1985-02-26 1992-04-14 Sankyo Company, Limited Thiazolidine derivatives, their preparation and use
EP0441539A2 (fr) * 1990-02-08 1991-08-14 Tanabe Seiyaku Co., Ltd. Dérivés de thiazine (ou oxazine) et leur préparation
US5496815A (en) * 1990-02-08 1996-03-05 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
US5306726A (en) * 1990-06-14 1994-04-26 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
JPH05194236A (ja) * 1991-07-25 1993-08-03 Tanabe Seiyaku Co Ltd 中枢性カルシウム拮抗剤
WO1996004260A1 (fr) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii
JPH0912575A (ja) * 1995-06-28 1997-01-14 Sankyo Co Ltd ベンゾオキサジンおよびベンゾチアジン誘導体

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 17, no. 627 (C - 1131) 19 November 1993 (1993-11-19) *
PATENT ABSTRACTS OF JAPAN vol. 97, no. 5 30 May 1997 (1997-05-30) *

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035437A2 (fr) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Utilisation accrue de glucose par le cerveau
WO2000035437A3 (fr) * 1998-12-17 2000-11-09 Mindset Biopharmaceuticals Usa Utilisation accrue de glucose par le cerveau
WO2000063192A1 (fr) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant
US6528507B1 (en) 1999-04-16 2003-03-04 Dr. Reddy's Laboratories Limited Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
WO2000063193A1 (fr) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Nouvelles formes polymorphes d'un agent antidiabetique: leur procede de preparation et composition pharmaceutique contenant lesdites formes
US6369055B1 (en) 1999-04-20 2002-04-09 Novo Nordisk A/S Compounds, their preparation and use
WO2000063190A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, leur preparation et utilisation
US6534517B2 (en) 1999-04-20 2003-03-18 Novo Nordisk A/S Compounds, their preparation and use
US6972294B1 (en) 1999-04-20 2005-12-06 Novo Nordisk, A/S Compounds, their preparation and use
WO2000063153A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation de ces derniers
WO2000063209A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation associees
WO2000066572A1 (fr) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques
US7348426B1 (en) 1999-04-28 2008-03-25 Dr. Reddy's Laboraties Limited Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
EA007959B1 (ru) * 2000-01-19 2007-02-27 Кадила Хелзкэр Лтд. Новые соединения, обладающие гиполипидемической, гипохолестеринемической активностью, способ их получения и содержащие их композиции
HRP20020643B1 (hr) * 2000-01-19 2015-04-24 Cadila Healthcare Ltd Zydus Tower, Satellite Cross Roads, Rrd Center Novi spojevi koji imaju hipolipedemiäśne, hipokolesteremiäśne aktivnosti, postupak njihove priprave i farmaceutski pripravci koji ih sadržavaju
CZ304346B6 (cs) * 2000-01-19 2014-03-19 Cadila Healthcare Ltd. Substituovaný pyrrolový derivát s hypolipidemickou hypocholesteremickou aktivitou, způsob jeho přípravy a farmaceutický přípravek obsahující tyto sloučeniny
WO2001053257A3 (fr) * 2000-01-19 2002-06-27 Cadila Healthcare Ltd Nouveaux composes hypolipidemiques et hypocholesterolemiques, leur procede de preparation, et compositions pharmaceutiques les contenant
US7202213B2 (en) 2000-01-28 2007-04-10 Novo Nordisk A/S Combination therapy using a dual PPAR-α/PPAR-γ activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders
US6867218B2 (en) 2000-01-28 2005-03-15 Novo Nordisk A/S Compounds, their preparation and use
US6569901B2 (en) 2000-01-28 2003-05-27 Novo Nordisk A/S Alkynyl-substituted propionic acid derivatives, their preparation and use
US6555577B1 (en) 2000-01-28 2003-04-29 Novo Nordisk A/S Compounds, their preparation and use
WO2001055085A1 (fr) * 2000-01-28 2001-08-02 Novo Nordisk A/S Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite
WO2001087860A3 (fr) * 2000-05-12 2002-03-28 Ortho Mcneil Pharm Inc Nouveaux benzoxazinones utilises comme modulateurs du recepteur gamma active de la proliferation des peroxysomes, et methode de traitement associee
WO2001087862A3 (fr) * 2000-05-12 2002-05-30 Ortho Mcneil Pharm Inc 4h-benzo[1,4]oxazine-3-ones biologiquement actives
WO2001087861A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Methodes de traitement mettant en oeuvre des benzoxazinones comme modulateurs du recepteur gamma active par le proliferateur du peroxisome
WO2001087862A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. 4h-benzo[1,4]oxazine-3-ones biologiquement actives
US6555536B2 (en) 2000-05-12 2003-04-29 Ortho-Mcneil Pharmaceutical, Inc. Biologically active 4H-benzo [1,4]oxazin-3-ones
WO2001087860A2 (fr) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Nouveaux benzoxazinones utilises comme modulateurs du recepteur gamma active de la proliferation des peroxysomes, et methode de traitement associee
WO2001087861A3 (fr) * 2000-05-12 2002-03-28 Ortho Mcneil Pharm Inc Methodes de traitement mettant en oeuvre des benzoxazinones comme modulateurs du recepteur gamma active par le proliferateur du peroxisome
US6599899B2 (en) 2000-05-12 2003-07-29 Ortho-Mcneil Pharmaceutical, Inc. Benzoxazinones as peroxisome proliferator activated receptor gamma modulators and method of treatment
US6908908B2 (en) 2000-05-12 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Biologically active 4H-benzo [1,4] oxazin-3-ones
WO2002020499A1 (fr) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Procede de preparation de 2-[3,4-dihydro-1,4-benzothiazin-4-yl]ethylmethane sulphonate
WO2002030914A1 (fr) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Sels de derives de benzothiazine et de benzoxazine et compositions pharmaceutiques a base de ces sels
WO2002100397A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un agent hypolipemiant
WO2003006022A1 (fr) * 2001-07-09 2003-01-23 Dr. Reddy's Laboratories Ltd. Derives de tetrahydroquinoline et leur utilisation en medecine, procede de preparation associe et compositions pharmaceutiques contenant lesdits composes
HRP20040138B1 (hr) * 2001-07-26 2016-12-02 Cadila Healthcare Limited Novi piroli s hipolipidemičnom hipokolesteremičnom aktivnošću, postupak za njihovu pripravu i farmaceutski pripravci koji ih sadržavaju i njihova uporaba u medicini
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
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
US7323491B2 (en) 2001-07-26 2008-01-29 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
AU2002355205B2 (en) * 2001-07-26 2004-11-18 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
WO2003009841A1 (fr) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Nouveaux pyrroles possedant des activites hypolipidemiantes et hypocholesterolemiantes, procede de preparation de ceux-ci, compositions pharmaceutiques les contenant et leur utilisation en medecine
US8110598B2 (en) 2001-07-26 2012-02-07 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US7365064B2 (en) 2001-10-16 2008-04-29 Dr. Reddy's Laboratories Limited Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them
WO2003033481A1 (fr) * 2001-10-16 2003-04-24 Dr. Reddy's Laboratories Ltd. Derives de benzoxazine et de benzothiazine, et compositions pharmaceutiques contenant ces derives
EP1314729A1 (fr) * 2001-11-21 2003-05-28 Ortho-McNeil Pharmaceutical, Inc. Dérivés de 4H-Benzo(1,4)oxazin-3-one biologiquement actifs
EP1852427A1 (fr) * 2001-11-21 2007-11-07 Ortho-McNeil Pharmaceutical, Inc. 4H-benzo [1,4] oxazin-3-ones biologiquement actives
US6939853B2 (en) 2001-12-29 2005-09-06 Novo Nordisk A/S Combined use of a GLP-1 compound and another drug for treating dyslipidemia
WO2003099800A1 (fr) * 2002-05-23 2003-12-04 Dr. Reddy's Laboratories Limited Procede ameliore pour la preparation d'agents antidiabetiques bicycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7790745B2 (en) 2005-10-21 2010-09-07 Bristol-Myers Squibb Company Tetrahydroisoquinoline LXR Modulators
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US9783495B2 (en) 2011-01-31 2017-10-10 Cadila Healthcare Limited Treatment for lipodystrophy
US10017470B2 (en) 2011-01-31 2018-07-10 Cadila Healthcare Limited Treatment for lipodystrophy
WO2012104869A1 (fr) 2011-01-31 2012-08-09 Cadila Healthcare Limited Traitement de la lipodystrophie
EP3009136A1 (fr) 2011-01-31 2016-04-20 Cadila Healthcare Limited Traitement de la lipodystrophie
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013082106A1 (fr) 2011-12-02 2013-06-06 The General Hospital Corporation Différenciation en adipocytes bruns
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
US9814697B2 (en) 2013-04-22 2017-11-14 Cadila Healthcare Limited Composition for nonalcoholic fatty liver disease (NAFLD)
US10435363B2 (en) 2013-05-30 2019-10-08 Cadila Healthcare Limited Process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
US9656954B2 (en) 2013-07-05 2017-05-23 Cadila Healthcare Limited Synergistic compositions
US10315993B2 (en) 2013-07-05 2019-06-11 Cadila Healthcare Limited Synergistic compositions
US9957230B2 (en) 2013-07-05 2018-05-01 Cadila Healthcare Limited Synergistic compositions
EP3120845A1 (fr) 2013-07-05 2017-01-25 Cadila Healthcare Limited Compositions synergiques
WO2015001573A1 (fr) 2013-07-05 2015-01-08 Cadila Healthcare Limited Compositions synergiques
US10098868B2 (en) 2013-07-25 2018-10-16 Cadila Healthcare Limited Formula comprising a hypolipidemic agent
US10112898B2 (en) 2013-09-06 2018-10-30 Cadila Healthcare Limited Process for the preparation of saroglitazar pharmaceutical salts
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US10385017B2 (en) 2015-10-14 2019-08-20 Cadila Healthcare Limited Pyrrole compound, compositions and process for preparation thereof
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
US11433050B2 (en) 2016-12-09 2022-09-06 Cadila Healthcare Ltd. Treatment for primary biliary cholangitis
US11872209B2 (en) 2016-12-09 2024-01-16 Zydus Lifesciences Limited Treatment for primary biliary cholangitis
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

Also Published As

Publication number Publication date
CN100357281C (zh) 2007-12-26
JP2002507543A (ja) 2002-03-12
CN1281443A (zh) 2001-01-24
PL341795A1 (en) 2001-05-07
NZ504106A (en) 2003-02-28
EP1082313A1 (fr) 2001-03-14

Similar Documents

Publication Publication Date Title
EP1082313A1 (fr) Composes bicycliques, procede de preparation et compositions pharmaceutiques les contenant
US6608194B1 (en) Tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6130214A (en) Benzothiazin and benzoxazin derivatives; their preparation and uses
US6054453A (en) Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them
EP1051403A1 (fr) Nouveaux acides alcanoiques et leur utilisation en medecine, leur procede de preparation et compositions pharmaceutiques les contenant
WO1999019313A1 (fr) Nouveaux composes tricycliques et leur utilisation en medecine, procede de preparation de ces derniers et compositions pharmaceutiques les contenant
EP1073643A2 (fr) Nouveaux composes heterocycliques, leur utilisation en medecine, leur procede de preparation et compositions pharmaceutiques les contenant
US7348426B1 (en) Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
EP1363914A1 (fr) Acides alkylcarboxyliques substitues par aryle utilises comme agents hypocholesterolemiques
US6265401B1 (en) Bicyclic compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them
US6809095B2 (en) Bicyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US20020103215A1 (en) New monocyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them
IL135839A (en) Bicyclic compounds, processes or the preparation thereof and pharmaceutical compositions containing the same
MXPA00004032A (en) Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
CZ20001540A3 (cs) Bicyklické sloučeniny, způsob jejich přípravy a farmaceutické kompozice s jejich obsahem
AU2006225184A1 (en) Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
WO2003006022A1 (fr) Derives de tetrahydroquinoline et leur utilisation en medecine, procede de preparation associe et compositions pharmaceutiques contenant lesdits composes

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 135839

Country of ref document: IL

Ref document number: 98811661.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 504106

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/004032

Country of ref document: MX

Ref document number: PV2000-1540

Country of ref document: CZ

ENP Entry into the national phase

Ref document number: 2307068

Country of ref document: CA

Ref document number: 2307068

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2000 516956

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 11206/99

Country of ref document: AU

Ref document number: 1020007004573

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1998953970

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV2000-1540

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1998953970

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1020007004573

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 11206/99

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: 1020007004573

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2000-1540

Country of ref document: CZ