WO1999020614A1 - Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them - Google Patents

Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them Download PDF

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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
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Prior art keywords
ethoxy
dihydro
phenyl
benzoxazin
formula
Prior art date
Application number
PCT/US1998/022570
Other languages
French (fr)
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 CA002307068A priority Critical patent/CA2307068C/en
Priority to EP98953970A priority patent/EP1082313A1/en
Priority to AU11206/99A priority patent/AU752059B2/en
Priority to BR9812770-5A priority patent/BR9812770A/en
Priority to JP2000516956A priority patent/JP2002507543A/en
Application filed by Dr. Reddy's Research Foundation, Reddy-Cheminor, Inc. filed Critical Dr. Reddy's Research Foundation
Priority to UA2000052997A priority patent/UA72883C2/en
Priority to NZ504106A priority patent/NZ504106A/en
Priority to PL98341795A priority patent/PL341795A1/en
Priority to IL13583998A priority patent/IL135839A/en
Priority to HU0101110A priority patent/HUP0101110A3/en
Publication of WO1999020614A1 publication Critical patent/WO1999020614A1/en
Priority to NO20002114A priority patent/NO319208B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—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

Abstract

The present invention relates to novel antiobesity and hypocholesterolemic compounds, 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. More particularly, the present invention relates to novel β-aryl-α-oxysubstituted alkylcarboxylic acids of 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.

Description

BICYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUΗCAL COMPOSIΗONS CONTAINING THEM
Field of Invention 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 β-aryl-α-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.
Figure imgf000003_0001
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. Background of Invention
Atherosclerosis and other peripheral vascular diseases are the major causes effecting the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyper- lipidemia and development of effective therapeutic strategies. 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. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as Low density lipo-protein (LDL), intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and athero-sclerosis with serum HDL-cholesterol concentrations. ( Stampfer et al, N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increases with increasing levels of LDL and VLDL. In CAD, generally "fatty streaks" in carotid, coronary and cerebral arteries, are found which are primarily free and esterified cholesterol. Miller et al, (Br. Med. J., 282 (1981), 1741 - 1744) have shown that increase in 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).
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. Among the developed countries, 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. Invest, (1975) 68 : 957 - 969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link- Syndrome-X.
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. 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 (PPAR) are members of the nuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) 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 (α) isoform of PPAR (PPARα) 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). PPARα 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 PPARα and PPARγ and suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar synergism between the insulin sensitizer (PPARγ agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma. (EP 0 753 298).
It is known that PPARγ 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. PPARγ is consistently expressed in certain cells and activation of this nuclear receptor with PPARγ 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. Sci., (1997) 94, 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research (1998) 58:3344-3352) This would be useful in the treatment of certain types of cancer, which express PPARγ and could lead to a quite nontoxic chemotherapy.
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. However, it has been recently disclosed that 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).
A few -aryl- -hydroxy propionic acids their derivatives and their analogs have been reported to be useful in the treatment of hyperglycemia and hyperchole-sterolemia. Some of such compounds described in the prior art are outlined below: i) U.S. Pat. 5,306,726 WO 91/19702 disclose several 3-aryl-2- hydroxypropionic acid derivatives of general formulas (Ha) and (lib) as hypolipidemic and hypoglycemic agents.
Figure imgf000007_0001
(li b)
Examples of these compounds are shown in formulas (II c) and (II d)
Figure imgf000007_0002
Figure imgf000007_0003
ii) International Patent Applications, WO 95/03038 and WO 96/04260 disclose compounds of formula (II e)
Figure imgf000008_0001
wherein Ra represents 2- benzoxazolyl or 2-pyridyl and 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).
Figure imgf000008_0002
iii) International Patent Application Nos. WO 94/13650, WO 94/01420 and WO 95/17394 disclose the compounds of general formula (II g)
A J1 -X v— ( /CrMH_ι2)n- ■ ^O— A Λ22_-AΛ 33 — v Y. D R22 (Il g)
wherein A* represents aromatic heterocycle, A^ represents substituted benzene ring and
A^ represents a moiety of formula (CH2)m-CH-(OR'), wherein Ri represents alkyl groups, m is an integer; X represents substituted or unsubstituted N; Y represents C=O or C=S; R2 represents OR3 where R3 may be alkyl, aralkyl, or aryl group; n represents an integer in the range of 2-6. An example of these compounds is shown in formula (Ilh).
Figure imgf000008_0003
ummarv of the Invention
With an objective to develop novel compounds for lowering cholesterol and reducing body weight with beneficial effects in the treatment and/or prophylaxis of diseases related to increased levels of lipids, athero-sclerosis, coronary artery diseases, Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism, for the treatment of hypertension, atherosclerosis and coronary artery diseases with better efficacy, potency and lower toxicity, we focussed our research to develop new compounds effective in the treatment of the above mentioned diseases. Effort in this direction has led to compounds having general formula (I).
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 polymoφhs, 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 PPARα and/or PPARγ, and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPARα and/or PPARγ.
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-moφhs, 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 β-aryl-α-oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereo-isomers, their polymoφhs, their salts and their pharmaceutically acceptable solvates.
Detailed Description of the Invention
-Oxysubstituted propionic acids, their derivatives and their analogs of the present invention have the general formula (I)
Figure imgf000010_0001
where the groups R1, R2, R3, R4, 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. carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R~ and R may also represent an oxo group when they are attached to a carbon atom; R~ and R6 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 NR1 1 where R11 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; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl. optionally substituted aralkyl group or forms a bond together with the adjacent group R8; R8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl or R forms a bond together with R7; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl. alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, aryl-aminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl. aryl, aralkyl, heterocyclyl. heteroaryl, or heteroaralkyl groups; Y represents oxygen or NR , where R represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl. or heteroaralkyl groups; R10 and R12 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 -(CH2)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 R1 - R4 and the groups R^ and R6 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 ( - C1 )alkyl group, especially, linear or branched (C|-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl and the like; cyclo(C3-C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl and the like, the cycloalkyl group may be substituted; cyclo(C3-C6)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. CόHsCHaC^CH^ naphthylmethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like: heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl. oxazolyl, thiazolyl. imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, moφholinyl, 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 C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like, which may be substituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl group such as benzyloxycarbonyl. phenethyl-oxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; (CrC6)alkylamino group such as NHCH3, NHC2H5, NHC3H7. NHC6Hπ, and the like, which may be substituted; (Cι-C6)dialkylamino group such as N(CH3)2, NCH3(C2H5). N(C2H5)2 and the like, which may be substituted; alkoxyalkyl group such as methoxy-methyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group such as C6H5OCH2, C6H5OCH2CH2, naphthyloxymethyl and the like, which may be substituted; aralkoxyalkyl group such as C6H5CH2OCH2, C6H CH2OCH2CH2 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 HNC6H5, NCH3(C H5), NHC6H4CH3, NHC6H4-Hal and the like, which may be substituted; amino group which may be substituted; amino(Cι- C )alkyl which may be substituted; hydroxy(Cι-C6)alkyl which may be substituted; ( - C6)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; thio(Cι-C6)alkyl which may be substituted; (C|-C6)alkylthio which may be substituted; acyl group such as acetyl, propionyl or benzoyl and the like, the acyl group may be substituted; acylamino groups such as NHCOCH , NHCOC2H5, NHCOC H7, NHCOC6H5 and the like, which may be substituted; aralkoxycarbonylamino group such as NHCOOCH2C6H5, NHCOOCH2CH2C6H5, N(CH3)COOCH2C6H5, N(C2H5)COOCH2C6H5, NHCOOCH2C6H4CH3, NHCOOCH2C6H4OCH3 and the like, which may be substituted; aryloxycarbonylamino group such as NHCOOC6H5, NHCOOC6H5, NCH3COOC6H5, NC2H5COOC6H5, NHCOOC6H4CH3,
NHCOOC6H OCH3 and the like, which may be substituted; alkoxycarbonyl-amino group such as NHCOOC2H5, NHCOOCH3 and the like, which may be substituted; carboxylic acid or its derivatives such as amides, like CONH2, CONHMe, CONMe2, CONHEt, CONEt2, 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 SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3 and the like, the sulfonic acid derivatives may be substituted. One or both of R5 and R6 may also represent an oxo group.
When the groups represented by R1 - R4 and the groups R5 and R6 when attached to carbon atom are substituted, 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 .
It is preferred that the substituents on R1 - R6 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; (Cι-C3)alkoxy, benzyloxy, hydroxy group, acyl or acyloxy groups.
Suitable R5 and R6 when attached to nitrogen atom is selected from hydrogen, hydroxy, formyl; substituted or unsubstituted (C|-C|2)alkyl group, especially, linear or branched (Cι-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; cyclo(C3-C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; cyclo(C3-C6)alkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl or phenethyl, C6H5CH2CH2CH2, naphthylmethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzo-pyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, moφholinyl, 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 C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like, which may be substituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthyl- methoxycarbonyl and the like, which may be substituted; (C|-C6)alkylamino group such as NHCH3, N(CH3)2, NCH3(C2H5), NHC2H5, NHC3H7, NHC6Hι3 and the like, which may be substituted; alkoxyalkyl group such as methoxy-methyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group such as C6H5OCH2, C6H5OCH2CH2, naphthyloxymethyl and the like, which may be substituted; aralkoxyalkyl group such as C6H5CH2OCH2, C6H5CH2OCH2CH2 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 HNC6H5, NCH3(C6H5), NHC6H4CH3, NH HL-Hal and the like, which may be substituted; amino group which may be substituted; amino(Cι-C6)alkyl which may be substituted; hydroxy(Cι-C6)alkyl which may be substituted; ( -C )alkoxy such as methoxy. ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; thio(Cι-C6)alkyl which may be substituted; (C|-C6)alkylthio which may be substituted; acyl group such as acetyl, propionyl, benzoyl and the like, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H3, NHCOC3H7, NHCOC6H5 and the like, which may be substituted; carboxylic acid derivatives such as amides, like CONH2, CONHMe,
CONMe2, CONHEt, CONEt2, 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 derivatives such as SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3 and the like, the sulfonic acid derivatives may be substituted. When the groups represented by R5 and R6 attached to nitrogen are 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 NR1 ' as defined above, preferably oxygen and sulfur. Suitably R11 represent hydrogen, (Cι-C )alkyl, (C3-C6)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; (Cι-C6)alkoxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl, CH3OC6H OCO, Hal-C6H OCO,
CH3C6H4OCO, naphthyloxycarbonyl and the like; aralkoxycarbonyl such as benzyl- oxycarbonyl, phenethyloxycarbonyl and the like; the groups represented by R1 ' may be substituted or unsubstituted. When the groups represented by R1 ' are substituted, the substituents may be selected from halogen, optionally halogenated lower alkyl, hydroxy, and optionally halogenated (Cι-C3)alkoxy groups.
It is preferred that 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|-C6)alkyl, optionally halogenated (0-C3)alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives.
It is more preferred that Ar represents a substituted or unsubstituted divalent, phenylene, naphthylene, benzofuranyl, indolyl, indolinyl. quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
It is still more preferred that Ar is represented by divalent phenylene or benzofuranyl, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R7 includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, ( -C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; aralkyl such as benzyl, phenethyl, which may be optionally substituted or R7 together with R8 represents a bond.
Suitable R may be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, ( -C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; acyl group such as linear or branched (C2-Cιo)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 R7 forms a bond. Suitable groups represented by R9 may be selected from hydrogen, linear or branched (Cι-CJ6)alkyl, preferably (Cι-Ci2)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C -C7)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-emethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkyl group such as benzyl and phenethyl and the like, wherein the alkyl moiety may contain Cι-C6 atoms, wherein the aryl moiety may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; (Cι-C6)alkoxy(Cι-C6)alkyl group such as methoxy methyl, ethoxymethyl, methoxyethyl, ethoxypropyl and the like, the alkoxyalkyl group may be substituted; linear or branched (C2-Cι )acyl group such as acetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl and the like, which may be substituted; (CjO alkoxycarbonyl, the alkyl group may be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxy- carbonyl and the like, the aryl group may be substituted; (Cι-C6)alkylaminocarbonyl, the alkyl group may be substituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl and the like, the aryl moiety may be substituted. 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 R10 may be selected from hydrogen, linear or branched (C]-Ci6)alkyl, preferably (Cι-Cι2)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C3-C7)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, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkyl group such as benzyl and phenethyl and the like, the aralkyl group may be substituted; and heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted. The substituents on R10 may be selected from the same group of R'-R6. Suitable groups represented by R12 may be selected from hydrogen, linear or branched (C]-C16)alkyl, preferably (C]-Cι2)alkyl; hydroxy
(Cι-C6)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 R10 and R12 together may be selected from pyrrolidinyl, piperidinyl, moφholinyl, piperazinyl and the like.
Suitable m is an integer ranging from 0-1. It is preferred that when m = 0, Ar represents a divalent benzofuranyl, benzoxazolyl. benzothiazolyl, indolyl. indolinyl, dihydrobenzofuryl, or dihydrobenzopyranyl group and when m = 1 , Ar represents a be substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl. benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl. benzothiazolyl, benzoxazolyl and the like.
Suitable n is an integer ranging from 1 to 4, preferably n represents an integer 1 or 2.
It is preferred that when m = 1 , n represents 2. It is also preferred that when m = 0, n represents 1. Pharmaceutically acceptable 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. 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 :
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropenoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate; (-) Methyl 3-[4-[2-(2,3-dihydro-1.4-benzoxazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate;
Ethyl (E/Z)-3-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]
-2-ethoxypropenoate;
Ethyl (E/Z)-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzothiazin-4-y 1 )ethoxy jpheny 1] -2-ethoxypropenoate;
(+) Methyl 3-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropanoate;
(+) Methyl 3 -[2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)mefhylbenzofuran-5-yl]-2- ethoxypropanoate ; (-) Methyl 3-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropanoate ;
(+) Methyl-3-[4-[2-(2,3-dihydro-1.4-benzothiazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate;
(+) Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxypropanoate;
(-) Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate;
(±) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate ; (+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate;
(-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl] -2-ethoxypropanoate;
(+) Methyl 2-(2-fluorobenzyl)-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy] phenyl] -2-ethoxypropanoate ;
(+) Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy] phenyl]-2-ethoxypropanoate;
(-) Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy] phenyl] -2-ethoxypropanoate ;
Ethyl (E/Z)-3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]- 2-ethoxypropenoate; (+) Methyl 3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate;
(+) Methyl 3-[4-[2-(3-oxo-2H-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;
(-) Methyl 3-[4-[2-(3-oxo-2H-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypt opanoate;
Ethyl (E/Z)-3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropenoate ; (±) Methyl 3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate;
(+) Methyl 3-[6-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate ;
(-) Methyl 3-[6-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]- 2-hydroxypropanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoate; Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- benzyloxy-propanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxy propanoate;
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propenoate; (+) Methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxy- propanoate; (+) Methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate;
(-) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate; Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propenoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate;
(-) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate;
Ethyl (E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]- 2-ethoxypropenoate; (+) Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-
2-ethoxypropanoate;
(+) Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]- 2-ethoxypropanoate;
(-) Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
Ethyl (E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropenoate;
(+) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate ; (+) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
(-) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate ;
(+) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzoxazin-4-y l)ethoxy]pheny 1] -2-ethoxypropanoic acid and its salts; •
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts; (-) 3-[4-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy-propanoic acid and its salts;
(+) 3-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid and its salts; (+) 3-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
(-) 3-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
(+) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy-propanoic acid and its salts;
(+) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy-propanoic acid and its salts;
(-) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy-propanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;
(+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(-) N-Methy 1-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzothiazin-4-y l)ethoxy]phenyl] -2-ethoxy- propanamide; (+) 3-[4-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;
(-) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzoxazin-4-y l)ethoxy ]pheny 1] -2-ethoxypropanamide; (+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide; (-) N-Methyl-3- [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(-) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide; (+) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(-) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
2-Methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethox} -propanoic acid and its salts;
2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and its salts;
(±) 3-[4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts; (+) 3-[4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(-) 3 - [4- [2-(3 -Oxo-2H- 1 ,4-benzoxazin-4-y l)ethoxy]pheny 1] -2-ethoxypropanoic acid and its salts;
(±) 3-[4-[2-(3-Oxo-2H-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(3-Oxo-2H-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts; (-) 3-[4-[2-(3-Oxo-2H-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[6-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts; (+) 3-[6-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts;
(-) 3-[6-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts;
(-) 3-[6-[2-(2,3-Dihydro-1.4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-1.4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts; (-) 3-[4-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;
(±) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic acid and its salts; (±) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic acid and its salts; (-) 3-[4-[2-(2,3-Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid and its salts;
(+) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]pheny 1] -2-hexyloxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts;
(±) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts; (±) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) 2-Methy 1-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]pheny 1] -2- phenoxypropanoic acid and its salts; (+) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoic acid and its salts;
(-) 2-Methy 1-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]pheny 1] -2- phenoxypropanoic acid and its salts; (+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) Methyl 2-methyl-3- [4- [2-(2,3 -dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate ;
(-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts;
(+) 2-Methyl-3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts; (-) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts;
(+) 4-Nitrophenyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxy propanoate;
(+) 4-Nitrophenyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxy propanoate;
(-) 4-Nitrophenyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxy propanoate;
(+) 3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl] -2-ethoxypropanoic acid and its salts; (+) 3-[4-(4-Benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoic acid and its salts;
(-) 3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoic acid and its salts;
(+) 4-Nitrophenyl-3 - [4-(4-benzyl-3 ,4-dihy dro-2H- 1 ,4-benzoxazin-2-yl) methoxy phenyl]-2-ethoxypropanoate;
(+) 4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl) methoxy phenyl]-2-ethoxypropanoate; and (-) 4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxy phenyl]-2-ethoxypropanoate.
According to a feature of the present invention, the compound of general formula (I) where R7 and R8 together represent a bond, Y represents oxygen atom, R1, R2, R3, R4, R5, R6, R9, R10, X, n, m and Ar are as defined earlier, can be prepared by any of the following routes shown in Scheme I.
Figure imgf000026_0001
Scheme - 1
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 (Cι-C6)alkyl, to yield compound of general formula (I) where R7, R8 together represent a bond and Y represents an oxygen atom may be carried out neat in the presence of a base such as alkali metal hydrides like NaH, or KH or organolithiums like CH3Li, 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 R7, R8 together represent a bond and all symbols are as defined earlier and L1 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. 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.
Route (3): The reaction of a compound of formula (Hie) where all symbols are as defined earlier with a compound of formula (Illf) where R9 = R10 and are as defined earlier, to produce a compound of the formula (I) where R and R together represent a bond may be carried out neat in the presence of a base such as alkali metal hydrides like NaH, KH or organolithiums like CH3Li, BuLi and the like or alkoxides such as NaOMe, NaOEt, K+BuO" and the like or mixtures thereof. 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. Route (4): The reaction of a compound of the general formula (Ilia) where all other symbols are as defined earlier, with a compound of formula (Illg) where R8 represents hydrogen atom, R and R are as defined earlier may be carried out in the presence of a base. 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 LiNH2, or LiN(ipr)2 may be used. 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 β- hydroxy product initially produced may be dehydrated under conventional dehydration conditions such as treating with PTSA in 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 L1 represents a leaving group such as as halogen atom, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like with a compound of formula (Hli) where R7 and R8 together represent a bond and R9. R10 and Ar are as defined earlier to produce a compound of the formula (I) where m = 1 and all other symbols are as defined above may be carried out in the presence of aprotic 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 K2CO3, Na2CO3 or NaH or mixtures thereof. Acetone may be used as solvent when Na2CO3 or
K2CO3 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. Route (6): The reaction of compound of general formula (IIIj) where all symbols are as defined earlier with a compound of general formula (Illi) where R7 and R8 together represent a bond and R9, R10 and Ar are as defined earlier to produce a compound of the formula (I) where m = 1 and all other symbols are as defined above may be carried out using suitable coupling agents such as dicyclohexyl urea, triaryl- phosphine/dialkylazadicarboxylate such as PPh3 / DEAD and the like. The reaction may be carried out in the presence of solvents such as THF, DME, CH2C12, 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.
In yet another embodiment of the present invention, the compound of the general formula (I) where R1, R2, R3, R4, R5, R6, R9, R10, X, n, m, R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group, R8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl or optionally substituted aralkyl and Ar are as defined earlier and Y represents oxygen can be prepared by one or more of the processes shown in Scheme - II:
Figure imgf000029_0001
Scheme - II Route 7: The reduction of compound of the formula (IVa) which represents a compound of formula (I) where R7 and R8 together represent a bond and Y represents an oxygen atom and all other symbols are as defined earlier, obtained as described earlier
(Scheme-I), to yield a compound of the general formula (I) where R7 and R8 each represent a hydrogen atom and all symbols are as defined earlier, may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like.
Mixtures of catalysts may be used. 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 L2 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. 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.
Route 9: The reaction of compound of formula (Illh) defined earlier with compound of formula (Illi) where all symbols are as defined earlier to produce a compound of the formula (I) where m = 1 and all other symbols are as defined above, may be carried out in the presence of 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? 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 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.
Route 10: The reaction of compound of general formula (IIIj) defined earlier with a compound of general formula (Illi) where all symbols are as defined earlier to produce a compound of the formula (I) where m = 1 and all other symbols are as defined above may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as PPh3 / DEAD and the like. The reaction may be carried out in the presence of solvents such as THF, DME, CH2CI2, CHC13, toluene, acetonitrile, carbon tetrachloride 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 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 R9 represents hydrogen atom and all other symbols are as defined earlier with a compound of formula (IV e) where R9 is as defined earlier and L2 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. 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, KlBuO", or NaOEt; metal amides such as L1NH2, 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 β-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 CH2CI2 may be used. Favorably, 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 L1 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. 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.
Route 14: 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 R9 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 R9OH 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 N2, 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 R10 is as defined earlier may be converted to compound of formula (I), where Y represents NR12 by reaction with appropriate amines of the formula NHR10R12, where RIϋ and R12 are as defined earlier. Suitably the compound of formula (I) where YR10 represents OH may be converted to acid halide, preferably YR10 = Cl, by reacting with appropriate reagents such as oxalyl chloride, thionyl chloride and the like, followed by treatment with amines. Alternatively, mixed anhydrides may be prepared from compound of formula (I) where
YR10 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. 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 CHC13, or CH2C12; 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.
In another embodiment of the present invention the novel intermediate of formula (IVf)
Figure imgf000034_0001
where the groups R1, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R5 and R6 when attached to 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, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; one or both of R and R6 may also represent an oxo group when they are attached to carbon atom; X represents a heteroatom selected from oxygen, sulfur or NR1 ' where R 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 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group; R8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl group; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl. alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; the linking group represented by - (CH2)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 β-aryl-α-substituted hydroxyalkanoic acids is provided.
7 o
The compound of formula (IVf) where R and R each represent hydrogen atoms and all other symbols are as defined earlier is prepared by a process outlined in Scheme- Ill.
Figure imgf000035_0001
(IVj)
Scheme III The reaction of a compound of formula (Ilia) where all symbols are as defined earlier with a compound of formula (IVh) where R is as defined earlier and Hal represents a halogen atom such as Cl, Br, or I may be carried out under conventional conditions in the presence of a base. The base is not critical. Any base normally employed for Wittig reaction may be employed, metal hydride such as NaH, or KH; metal alkoxides such as NaOMe, KlBuO", or NaOEt; or metal amides such as LiNH2, or LiN(ipr)2. Aprotic solvent such as THF, DMSO, dioxane, DME and the like may be used. Mixture of solvents may be used. HMPA may be used as a cosolvent. 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 100 °C may be used.
The compound of (IVi) where all symbols are as defined earlier may be converted to a compound of formula (IVj) where R7 and R8 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. The compound of formula (IVj) defined above upon treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of formula (IVf) where R7 and R represent hydrogen atoms and all other symbols are as defined earlier.
In still another embodiment of the present invention the novel intermediate of formula (IVg)
Figure imgf000036_0001
where the groups R1, R2, R3, R4, and the groups R5 and R6 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. alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R5 and R6 may also represent an oxo group when they are attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' 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; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl. or optionally substituted aralkyl group; R10 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)„-(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 β-aryl-α-substituted hydroxyalkanoic acids is provided.
The compound of formula (IVg) where all other symbols are as defined earlier may be prepared by reacting a compound of formula (I Vk)
Figure imgf000037_0001
where R8 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 N2, 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
(Illh) where all symbols are as defined earlier and a compound of formula (IV1)
Figure imgf000038_0001
where R8 is a hydrogen atom and all other symbols are as defined earlier.
The 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. 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.
As used in this application the term neat means the reaction is carried out without the use of solvent. 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. Alternatively, 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.
The 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. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula (I) where YR10 represents OH may be converted to a 1 : 1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
Various polymoφhs 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 polymoφhs 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. 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 polymoφhs, 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 absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, 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. However, 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. Thus, for oral administration, 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. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, 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.
Preparation 1 4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]benzaldehyde
Figure imgf000041_0001
A mixture of 2H-l,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol), 4-(2- bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) was stirred at 80 °C for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL). dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) to afford the title compound (2.9 g, 91 %) as a colorless solid, mp : 75 - 78 °C.
1H NMR (CDC13, 200 MHz): 4.37 (s, 4H), 4.62 (s, 2H), 6.96 - 7.26 (complex, 6H), 7.82 (d, J = 8.4 Hz, 2H), 9.89 (s, 1H).
Preparation 2 6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene
Figure imgf000042_0001
A mixture of 2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethyl methanesulfonate (0.49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene (0.28 , 1.65 mmol) and potassium carbonate (1.15 g, 8.28 mmol) in dry dimethyl formamide (15 mL) was stirred at 80 °C for 12 h. Water (50 mL) was added and extracted with ethyl acetate (2 x 25 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (20 mL), dried (Na2SO ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether to afford the title compound (0.41 g, 72 %) as a pale yellow solid, mp : 94 - 96 °C.
'H NMR (CDCI3, 200 MHz): 3.05 (t, J = 5.21 Hz, 2H), 3.79 - 3.85 (complex, 4H), 4.31 (t, J = 5.82 Hz, 2H), 6.64 - 6.78 (complex, 2H), 6.97 - 7.25 (complex, 4H), 7.53 - 7.80 (complex, 3H), 8.13 (s, 1H).
Preparation 3 6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthaldehyde
Figure imgf000042_0002
To a solution of 6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]cyano- naphthalene (8 g, 22.9 mmol) obtained in preparation 2 in dry tetrahydrofuran (15 mL) was added diisobutyl aluminum hydride (93 mL, 20 % in toluene) at - 70 °C over a period of lh. After the addition reaction mixture was stirred at 25 °C for 16 h. At the end of this time, ethyl formate (20 mL) was added and stirred for 1 h at 25 °C. Saturated ammonium chloride solution (15 mL) was added. 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 (Na2SO4). 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.
1H NMR (CDC13, 200 MHz) : 3.06 (t, J = 5.2 Hz. 2H), 3.72 - 3.86 (complex. 4H), 4.33 (t, J = 5.67 Hz. 2H), 6.60 - 6.79 (complex, 2H). 6.97 - 7.25 (complex, 4H). 7.74 - 7.93 (complex, 3H), 8.25 (s, 1H), 10.09 (s, 1H).
15 Preparation 4
4-[4-Methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl]methoxybenzaldehyde
Figure imgf000043_0001
To a solution of 4-methyl-3,4-dihydro-2H-l ,4-benzoxazin-2-methanol (6.0 g. 33.51 mmol) in dichloromethane (20 mL) was added triethylamine (10.15 g, 100.5 mmol)
20 under nitrogen atmosphere at 25 °C. Methanesulfonyl chloride (5.75 g. 50.25 mmol) was added to the above reaction mixture at 0 °C and stirring was continued for further 10 h at 25 °C. Water (50 mL) was added and extracted with chloroform (2 x 25 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed
25 over silica gel using a mixture of ethyl acetate and hexane (2 : 8) to yield (4-methyl-3,4- dihydro-2H-l,4-benzoxazin-2-yl)methyl methanesulfonate (3.7 g, 43 %) as a syrup. Η NMR (CDC13, 200 MHz): 2.88 (s, 3H), 3.07 (s, 3H), 3.13 - 3.31 (complex, 2H), 4.41 (d, J = 5.2 Hz, 2H), 4.53 - 4.55 (complex, IH), 6.81 - 6.89 (complex, 4H). A mixture of (4-methyl-3,4-dihydro-2H-l,4-benzoxazin-4-yl)methyl methanesulfonate (3.7 g, 14.39 mmol), 4-hydroxy benzaldehyde (2.6 g, 21.29 mmol) and potassium carbonate (5.9 g, 42.7 mmol) in dry dimethyl formamide (30 mL) was stirred at 80 °C for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with water (50 mL), brine (50 mL) and dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) to afford the title compound (1.3 g, 32 %) as a thick liquid.
1H NMR (CDC13, 200 MHz): 2.93 (s, 3H), 3.24 - 3.46 (complex. 2H). 4.14 - 4.37 (complex, 2H). 4.68 - 4.71 (complex, IH), 6.72 - 7.10 (complex, 6H). 7.86 (d, J = 8.8 Hz, 2H). 9.92 (s. IH).
Preparation 5
4-[4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl]methoxybenzaldehyde
Figure imgf000044_0001
The title compound (3.2 g, 80 %) was prepared as a pale yellow solid from 4- benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-methanol (4.0 g, 15.68 mmol) by a procedure similar to that described for preparation 4. mp : 92 - 94 °C.
1H NMR (CDC13, 200 MHz) : 3.38 - 3.43 (complex, 2H), 4.14 - 4.32 (complex, 2H), 4.46 (d. J = 7.8 Hz, 2H), 4.60 - 4.65 (complex, IH), 6.65 - 6.89 (complex, 4H), 7.00 (d, J = 8.8 Hz. 2H). 7.32 (s, 5H), 7.83 (d, J = 8.8 Hz, 2H), 9.90 (s, IH).
Example 1 Ethyl (E/Z)-3- [4- [2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy] phenyl] -2- ethoxypropenoate
Figure imgf000045_0001
A solution of triethyl 2-ethoxyphosphonoacetate (W. Grell and H. Machleidt, Annalen Chemie, 1960, 699, 53). (7.8 g, 29.1 mmol) in dry tetrahydrofuran (15 mL) was added slowly to a stirred, ice-cooled suspension of sodium hydride (60 % dispersion in oil) (1.39 g, 29.1 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture was stirred at 0 °C for 30 minutes followed by the addition of a solution of 4-[2- (2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]benzaldehyde (7.5 g, 26.5 mmol) which is prepared according to the process described in Preparation 1 disclosed in U.S. Patent Application No. 08/982,910, in dry tetrahydrofuran (20 mL). The mixture was allowed to warm to 25 °C and stirred further for 20 h. The solvent was evaporated and the residue was suspended in water (100 mL) and extracted with ethyl acetate (2 x 75 mL). The combined ethyl acetate layers were washed with water (75 mL), brine (50 mL), dried (Na2SO ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and petroleum ether (2 : 8) as eluent to afford the title compound (8.0 g, 75 %) a gum as a 65:35 Z:E mixture of geometric isomers (R. A. Aitken and G. L. Thom, Synthesis. 1989, 958).
Η NMR (CDC13, 200 MHz) : 1.18 and 1.36 (combined 6H, isomeric OEt, triplet signals), 3.51 (t, J = 4.48 Hz, 2H), 3.71 (t, J = 5.39 Hz, 2H), 3.89 - 4.03 (complex, 2H), 4.10 - 4.34 (complex, 6H), 6.07 (s, 0.35H, E olefinic proton), 6.63 - 7.14 (complex, 6.65H), 7.73 (d, J = 8.72 Hz, 2H).
Example 2 Methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoate
Figure imgf000045_0002
A mixture of ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy] phenyl]-2-ethoxypropenoate (8.0 g, 20.0 mmol) obtained in example 1 and magnesium turnings (9.64 g, 396.7 mmol) in dry methanol (50 mL) was stirred at 25 °C for 20 h. At the end of this time water (50 mL) was added and pH was adjusted to ca 7.0 using 10 % aqueous hydrochloric acid and the solution was extracted with ethyl acetate (2 x 10 mL). The combined organic extract was washed with water (75 mL), brine (75 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as an eluent to get the title compound (5.0 g, 64 %) as a gummy liquid.
!H NMR (CDC13, 200 MHz) : 1.15 (t, J = 7.0 Hz, 3H). 2.93 (d, J = 6.64 Hz, 2H), 3.23 - 3.38 (complex, IH), 3.43 - 3.72 (complex, 8H), 3.97 (t, J = 6.9 Hz, IH), 4.14 (t, J = 5.81 Hz, 2H). 4.19 (t, J = 4.2 Hz, 2H), 6.55 - 6.83 (complex, 6H), 7.13 (d, J = 8.39 Hz, 2H).
Example 3 Ethyl (E/Z)-3-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)methyIbenzofuran-5-yl]-2- ethoxypropenoate
Figure imgf000046_0001
The title compound (0.8 g, 58 %) was prepared as a gummy material from 5- formyl-2-(2,3-dihydro-l,4-benzoxazin-4-yl)methyl benzofuran (1.0 g, 3.41 mmol) by a procedure analogous to that described in example 1.
Η NMR (CDCI3, 200 MHz) : 1.06 and 1.38 ( 6H, OCH2CH3 and OCH2CH3, triplet signals), 3.48 (t, J = 4.98 Hz, 2H), 3.89 - 4.18 (complex, 2H), 4.28 - 4.40 (complex, 4H), 4.54 and 4.56 (combined, 2H, -NCH2-signals), 6.20 (0.5 H, E isomer of olefinic proton), 6.52 and 6.59 (combined, IH), 6.65 - 6.83 (complex, 2.5 H), 7.08 - 7.11 (complex, IH), 7.32 - 7.44 (complex, 2H), 7.69 (d, J = 8.3 Hz, IH), 7.99 (s, IH). Example 4
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropenoate
Figure imgf000047_0001
The title compound was prepared as a 38 : 62 ratio of geometric isomers (as measured by Η 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.
!H NMR (CDC13. 200 MHz) : 1.14 and 1.35 (combined, 6H. isomeric - OCH2CH3 triplet signals). 3.02 (t, J = 4.9 Hz, 2H), 3.69 - 3.88 (complex, 4H), 3.92 - 4.03 (complex, 2H), 4.12 - 4.33 (complex, 4H), 6.06 (s, 0.38 H, E olefinic proton), 6.61 - 7.14 (complex, 6.62 H), 7.73 (d, J = 8.81 Hz, 2H).
Example 5 Methyl 3-[2-(2,3-dihydro-l,4-benzoxazin-4-yI)methylbenzofuran-5-yl]-2- ethoxypropanoate
Figure imgf000047_0002
The title compound (0.6 g, 78 %) was prepared as a gum from Ethyl (E/Z)-3-[2- (2,3-dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate (0.8 g, 1.96 mmol) obtained in example 3 by a procedure analogous to that described for example 2.
Η NMR (CDCI3. 200 MHz) : 1.15 (t, J = 7.0 Hz, 3H), 3.07 (d, J = 5.8 Hz, 2H), 3.28 - 3.67 (complex, 4H), 3.70 (s, 3H), 4.03 (t, J = 6.0 Hz, IH), 4.28 (t, J = 4.47 Hz, 2H), 4.54 (s, 2H), 6.52 (s, IH), 6.62 - 6.89 (complex, 4H), 7.10 (d, J = 7.05 Hz. IH), 7.35 (complex, 2H).
Example 6 Methyl-3- [4- [2-(2,3-dihydro-l ,4-benzothiazin-4-y l)ethoxy ] phenyl] -2- ethoxypropanoate
Figure imgf000048_0001
The title compound (2.3 g, 76 %) was prepared as a gummy liquid from ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate (3.1 g, 7.50 mmol) obtained in example 4 by an analogous procedure to that described in example 2.
Η NMR (CDCl3, 200 MHz) : 1.15 (t, J = 7.01 Hz. 3H), 2.93 (d. J = 6.65 Hz, 2H), 3.03 (t, J = 5.21 Hz, 2H), 3.23 - 3.41 (complex, IH), 3.52 - 3.80 (complex. 8H), 3.97 (t, J = 7.01 Hz, IH), 4.14 (t, J = 5.81 Hz, 2H), 6.61 - 6.82 (complex, 4H), 6.92 - 7.05 (complex, 2H), 7.13 (d, J = 8.53 Hz, 2H).
Example 7 Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate
Figure imgf000048_0002
To a solution of methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]- 2-ethoxypropanoate (0.6 g, 1.5 mmol) obtained in example 2 in dry tetrahydrofuran (5 mL) was added lithium diisopropyl amide (5.25 L , 0.5 mL solution in THF / hexane) at -78 °C. After stirring for lh at -78 °C, methyl iodide (0.75 mL) was added and the reaction mixture was allowed to warm to room temperature (ca 25 °C) and stirred for further 20 h at the same temperature. Water (20 mL) was added, acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2 x 25 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (25 mL), dried (Na SO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (0.5 g, 80 %) as an oil.
ΪH NMR CCDC^OO MHz) : 1 .21 (t, J = 6.97 Hz, 3H), 1.31 (s. 3H), 2.95 (s,
2H), 3.32 - 3.58 (complex, 4H), 3.62 - 3.84 (complex, 5H), 4.14 (t, J = 5.81 Hz, 2H), 4.22 (t, J = 4.25 Hz, 2H), 6.55 - 6.88 (complex, 6H), 7.08 (d, J = 8.63 Hz, 2H).
Example 8 Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI]-
2-ethoxypropanoate
Figure imgf000049_0001
The title compound (0.6 g, 78 %) was prepared as a brown liquid from methyl 3- [4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (0.6 g, 1.5 mmol) obtained in example 2 by an analogous procedure to that described in example 7. Η NMR (CDC13, 200 MHz) : 1.22 (t, J = 6.96 Hz, 3H). 3.03 - 3.18 (complex, 4H), 3.51 (t. J = 4.2 Hz, 2H), 3.59 - 3.71 (complex, 7H), 4.14 (t, J = 5.81 Hz. 2H), 4.22 (t, J = 4.24 Hz, 2H), 6.42 - 6.85 (complex, 6H), 6.90 - 7.32 (complex 6H).
Example 9 Ethyl (E/Z)-3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropenoate
Figure imgf000049_0002
The title compound (3.9 g, 97 %) was obtained in 32 : 68 ratio of E:Z isomers as a white solid from 4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]benzaldehyde (2.9 g, 9.7 mmol) obtained in preparation 1 by an analogous procedure to that described in example 1. mp : 92 - 95 °C. 1H NMR (CDCI3, 200 MHz) : 1.13 - 1.43 (complex, 6H), 3.88 - 4.02 (complex, 2H), 4.07 - 4.40 (complex, 6H), 4.60 (s, 2H), 6.05 (s, 0.32 H, E olefinic proton), 6.76 - 7.32 (complex, 6.68 H), 7.71 (d, J = 8.72 Hz, 2H).
Example 10 Methyl 3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yI)ethoxy]phenyl]-2-ethoxypropanoate
Figure imgf000050_0001
The title compound (1.0 g, 51 %) was prepared as a colorless syrup from ethyl (E/Z)-3-[4-[2-(3-oxo-2H-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate (2.0 g, 4.8 mmol) obtained in example 9 by a procedure analogous to that described in example 2.
Η NMR (CDCI3, 200 MHz) : 1 .14 (t, J = 7.0 Hz. 3H), 2.92 (d. J = 6.6 Hz, 2H), 3.25 - 3.41 (complex, IH), 3.53 - 3.61 (complex, IH), 3.68 (s, 3H), 3.96 (t, J = 7.0 Hz, IH), 4.21 - 4.32 (complex, 4H), 4.68 (s, 2H), 6.77 (d, J = 8.63 Hz, 2H), 6.98 - 7.33 (complex, 6H).
Example 11 Ethyl (E/Z)-3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropenoate
Figure imgf000050_0002
The title compound as a 1 : 1 mixture of E/Z isomers (1.74 g, 87 %) was prepared as a brown syrup from 6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy] naphthaldehyde (1.5 g, 4.29 mmol) obtained in preparation 3 by a procedure analogous to that described in example 1.
'H NMR (CDCI3, 200 MHz) : 0.99 - 1.47 (complex, 6H), 3.06 (t, J = 4.98 Hz, 2H), 3.79 - 3.95 (complex, 4H), 3.99 - 4.18 (complex, 2H), 4.25 - 4.37 (complex, 4H), 6.23 (s, 0.5 H, E olefinic proton), 6.59 - 6.79 (complex, 2H), 6.97 - 7.29 (complex, 4.5H). 7.57 - 7.95 (complex, 3H), 8.14 (s, IH).
Example 12 Methyl 3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate
Figure imgf000051_0001
The title compound (1.25 g, 75 %) was prepared as a colorless syrup from eth\l (E/Z)-3-[6-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate (1.7 g, 3.67 mmol) obtained in example 11 by an analogous procedure to that described in example 2.
]H NMR (CDC13, 200 MHz): 1 .14 (t, J - 7.06 Hz. 3H), 3.06 (t J = 5.21 Hz, 2H), 3.13 (d, J = 7.15 Hz, 2H), 3.29 - 3.37 (complex, I H), 3.57 - 3.64 (complex, IH), 3.70 (s, 3H), 3.77 - 3.83 (complex, 4H), 4.09 (t, J = 7.2 Hz, I H), 4.25 (f J = 5.81 Hz, 2H), 6.62 - 6.79 (complex. 2H), 6.96 - 7.36 (complex, 5H). 7.60 - 7.70 (complex. 3H).
Example 13 Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI]-2-hydroxypropanoate
Figure imgf000051_0002
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.
Η NMR (CDCI3, 200 MHz) : 1 .24 (t, J = 7.15 Hz, 3H), 2.71 (d, J = 6.23 Hz, IH, D2O exchangeable), 2.84-3.10 (complex, 2H), 3.50 (t, J = 4.47 Hz. 2H), 3.67 (t, J = 5.48 Hz, 2H), 4.11 - 4.26 (complex, 6H), 4.37 - 4.39 (complex, IH), 6.61 - 6.86 (complex, 6H), 7.11 (d, J = 8.62 Hz, 2H). Example 14
Ethyl 3- [4- [2-(2,3-dihy dro-1 ,4-benzothiazin-4-yl)ethoxy ] phenyl] -2- hydroxypropanoate
Figure imgf000052_0001
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) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) using conditions analogous to that described in preparation 2.
ΪH NMR CDCl^OO MHz) : 1 .29 (f J = 7.1 1 Hz. 3H). 2.70 - 2.80 (bs. IH.
D2O exchangeable). 2.82 - 3.15 (complex, 4H), 3.65 - 3.82 (complex. 4H). 4.10 - 4.30 (complex, 4H), 4.28 - 4.40 (complex, IH), 6.62 - 6.89 (complex, 4H). 6.92 - 7.18 (complex, 4H).
Example 15 Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yI)ethoxy]phenyl]-2- benzyloxypropanoate
Figure imgf000052_0002
A solution of ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- hydroxypropanoate (0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5 mL) was added to a stirred ice cooled suspension of sodium hydride (60 % dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25 °C and stirring was continued for further 18 h. Water (25 mL) was added and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as eluent to afford the title compound (0.3 g) along with benzyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate. This mixture (1 : 1) is used in example 47 without any separation.
Η NMR (CDC13, 200 MHz) : 1.23 (t, J = 7.05 Hz, 1.5H), 2.99 (d. J = 7.06 Hz, 4H), 3.0 - 3.72 (complex, 8H), 4.05 - 4.30 (complex, 12H), 4.32 - 4.71 (complex, 4H), 5.13 (s, 2H), 6.55 - 6.89 (complex, 12H), 7.05 - 7.36 (complex, 19H).
Example 16 Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate
Figure imgf000053_0001
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-hγdiOxyphenyl)piOpanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
'H NMR (CDC13, 200 MHz) : 0.84 (t. J = 7.53 Hz. 3H), 1.19 - 1.34 (complex, 5H), 1.43 - 1.55 (complex, 2H), 2.92 (d, J = 6.32 Hz. 2H), 3.22 - 3.36 (complex, IH), 3.48 - 3.59 (complex, 3H), 3.68 (t, J = 5.82 Hz, 2H). 3.93 (t. J = 6.2 Hz, IH). 4.11 - 4.24 (complex, 6H), 6.61 - 6.86 (complex, 6H), 7.13 (d. J = 8.3 Hz, 2H).
Example 17 Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yI)ethoxy]phenyl]-2- hexyloxypropanoate
Figure imgf000053_0002
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.
1H NMR (CDC13, 200 MHz) : 0.85 (t, J = 5.72 Hz, 3H), 1.20 - 1.34 (complex, 7H), 1.40 - 1.66 (complex, 4H), 2.93 (d, J = 6.0 Hz, 2H), 3.21 - 3.31 (complex, IH), 3.49 - 3.60 (complex, 3H), 3.68 (t, J = 5.72 Hz, 2H), 3.93 (t, J = 5.81 Hz, IH). 4.11 - 4.24 (complex, 6H), 6.62 - 6.81 (complex, 5 H), 7.09 - 7.16 (complex, 3H).
Example 18
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropenoate
Figure imgf000054_0001
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.
Η NMR (CDCI3. 200 MHz) : 1.06 and 1.18 (combined 3H. isomeric OCH2CH3, triplet singals), 3.43 - 3.57 (complex, 2H), 3.64 - 3.75 (complex, 2H), 4.06 - 4.28 (complex, 6H), 6.60 - 6.90 (complex, 8H), 6.94 - 7.12 (complex, 2H), 7.22 - 7.45 (complex, 3H), 7.64 (d, J = 8.72 Hz, IH).
Example 19 Methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate
Figure imgf000054_0002
The title compound (0.49 g, 57 %) was prepared as a gummy material from ethyl (E/Z)-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]pheny 1] -2-phenoxypropenoate (0.9 g, 2.0 mmol) obtained in example 18 by an analogous procedure to that described for example 2.
'H NMR (CDC13, 200 MHz) : 3.17 (d, J = 6.2 Hz, 2H), 3.50 (t, J = 4.3 Hz, 2H). 3.65 - 3.70 (complex, 5H), 4.14 (t, J = 5.76 Hz, 2H), 4.21 (t, J = 4.15 Hz, 2H), 4.75 (t, J = 6.4 Hz, IH), 6.61 - 6.98 (complex, 9H), 7.17 - 7.27 (complex, 4H).
Example 20 Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropenoate
Figure imgf000055_0001
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.
'H NMR (CDCI3, 200 MHz) : 1.05 - 1.36 (complex, 3H). 3.00 - 3.1 1 (complex. 2H), 3.64 - 3.85 (complex, 4H), 4.09 - 4.30 (complex, 4H). 6.58 - 7.13 (complex, 8H), 7.20 - 7.46 (complex. 4H). 7.65 (d, J = 8.7 Hz, 2H).
Example 21 Methyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate
Figure imgf000055_0002
The title compound (2.3 g, 64 %) was prepared as a gummy material from ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate (3.7 g, 8.0 mmol) obtained in example 20 by an analogous procedure to that described for example 2.
1H NMR (CDC13, 200 MHz) : 2.99 (t, J = 5.439 Hz, 2H), 3.15 (d, J = 5.99 Hz, 2H), 3.60 - 3.78 (complex, 7H), 4.13 (t, J = 5.4 Hz, 2H), 4.74 (t, J = 6.23 Hz. IH). 6.58 - 6.89 (complex, 6H), 6.90 - 7.06 (complex, 2H), 7.11 - 7.30 (complex, 5H).
Example 22 Ethyl (E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropenoate
Figure imgf000056_0001
The title compound (0.4 g, 25 %) was prepared as a mixture of E : Z isomers (1 : 1) as a brown liquid from 4-(4-methyl-3,4-dihydro-2H-l ,4-benzoxazin-2- yl)methoxybenzaldehyde (1.2 g, 4.24 mmol) obtained in preparation 4 by an analogous procedure to that described in example 1.
Η NMR (CDCI3, 200 MHz) : 1.36 (t, J = 7.1 Hz. 6H). 2.90 (s, 3H). 3.26 - 3.45 (complex, 2H). 3.99 (q, J = 7.2 Hz, 2H), 4.10 - 4.38 (complex. 4H), 4.50 - 4.60 (complex, IH), 6.70 (d. J = 7.47 Hz, 2H), 6.81 - 6.90 (complex. 5H). 7.75(d, J - 8.8 Hz, 2H).
Example 23 Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate
Figure imgf000056_0002
The title compound (0.25 g, 65 %) was prepared as a thick liquid from ethyl (E/Z)-3 - [4-(4-methyl-3 ,4-dihydro- 1 ,4-benzoxazin-2 -yl)methoxyphenyl] -2- ethoxypropenoate (0.4 g, 1.0 mmol) obtained in example 22 by an analogous procedure to that described in example 2.
!H NMR (CDC13, 200 MHz) : 1.16 (t, J = 7.0 Hz, 3H), 2.89 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 3.19 - 3.41 (complex, 3H), 3.55 - 3.66 (complex, IH). 3.70 (s, 3H), 3.95 - 4.24 (complex, 3H), 4.60 - 4.64 (complex, IH), 6.64 - 7.08 (complex. 6H), 7.15 (d, J = 8.4 Hz, 2H).
Example 24 Ethyl (E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropenoate
Figure imgf000057_0001
The title compound (3.0 g, 76 %) was prepared as E:Z isomers (1 : 1), as a syrupy liquid from 4-[4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxybenzaldehyde (3.0 g, 8.35 mmol) obtained in preparation 5 by a procedure analogous to that described for example 1.
!H NMR (CDCI3, 200 MHz) : 1.33 - 1.40 (complex. 6H). 3.39 - 3.44 (complex, 2H), 3.99 (q, J = 7.0 Hz, 2H), 4.1 1 - 4.38 (complex. 4H), 4.46 (d, J = 5.0 Hz, 2H), 4.52 - 4.66 (complex. IH), 6.60 - 6.97 (complex, 7H), 7.28 (s, 5H), 7.75 (d. J = 8.8 Hz, 2H).
Example 25 Methyl 3-[4-(4-benzyI-3,4-dihydro-2H-l,4-benzoxazin-2-yI)methoxyphenyl]-2- ethoxypropanoate
Figure imgf000057_0002
The title compound (1.5 g, 100 %) was prepared from ethyl (E/Z)-3-[4-(4-benzyl- 3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate (1.5 g, 3.17 mmol) obtained in example 24 by an analogous procedure to that described in example 2. 1H NMR (CDC13, 200 MHz) : 1.17 (t, J = 7.0 Hz, 3H), 2.96 (d, J = 6.6 Hz, 2H). 3.31 - 3.57 (complex, 3H), 3.60 - 3.70 (complex, IH), 3.71 (s, 3H), 3.97 - 4.26 (complex. 3H), 4.47 (d, J = 4.0 Hz, 2H), 4.56 - 4.61 (complex, IH), 6.68 - 6.90 (complex, 6H), 7.15 (d, J = 8.5 Hz, 2H), 7.29 (s, 5H).
Example 26 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI]-2-ethoxypropanoic acid
Figure imgf000058_0001
To a solution of methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]- 2-ethoxy propanoate (4.7 g, 12.2 mmol) obtained in example 2 in methanol (50 mL) was added aqueous 10 % sodium hydroxide (28 mL). The mixture was stirred at 25 °C for 3h. The solvent was removed under reduced pressure and the residue was acidified with 2N hydrochloric acid extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layers were washed with water (75 mL), brine (50 mL), dried (Na2S04), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using ethyl acetate to give the title compound (3.0 g, 66 %) as a syrupy liquid. ]H NMR (CDCI3, 200 MHz) : 1 .17 (t, J = 6.96 Hz, 3H), 2.85 - 3.12 (complex, 2H), 3.40 - 3.61 (complex, 4H), 3.69 (t, J = 5.72 Hz, 2H), 4.04 (dd, J = 7.38 and 4.27 Hz, IH), 4.10 - 4.28 (complex, 4H), 6.52 - 6.85 (complex, 6H), 7.14 (d, J = 8.6 Hz, 2H), COOH proton is too broad to observe.
Example 27 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, sodium salt
Figure imgf000059_0001
A mixture of 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid (0.15 g, 0.4 mmol) obtained in example 26 and sodium methoxide (23.4 mg) in methanol (5 mL) was stirred at 25 °C for 2h. The solvent was removed and the residue was triturated with dry ether (3 x 10 mL). The precipitated solids were filtered, washed with dry ether (2 x 5 mL) and dried over P2O5 under vacuum to afford the title compound (0.12 g, 75 %) as a colorless hygroscopic solid.
Η NMR (DMSO-d6, 200 MHz) : δ 0.98 (t J = 6.83 Hz, 3H), 2.60-2.69 (complex, IH), 2.78 - 2.92 (complex, IH), 3.05 - 3.21 (complex, 2H). 3.41 - 3.75 (complex, 5H), 4.08 - 4.21 (complex, 4H), 6.49 - 6.85 (complex, 6H). 7.12 (d. J = 8.3 Hz, 2H).
Example 28 3-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)methyIbenzofuran-5-yl]-2- ethoxy-propanoic acid
Figure imgf000059_0002
The title compound (0.5 g, 87 %) was prepared as a gummy material from methyl 3-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)methyl benzofuran-5-yl]-2-ethoxy- propanoate (0.6 g, 1.51 mmol) obtained in example 5 by a procedure analogous to that described for example 26.
Η NMR (CDC13, 200 MHz) δ : 1.26 (t, J = 7.06 Hz, 3H), 3.05 - 3.28 (complex, 2H), 3.40 - 3.68 (complex, 4H), 4.09 (dd, J = 7.47 and 4.24 Hz, IH), 4.28 (t, J = 4.15 Hz, 2H), 4.53 (s, 2H), 6.52 (s, IH), 6.60 - 6.90 (complex, 4H), 7.13 (d, J = 8.7 Hz, IH), 7.32 - 7.36 (complex, 2H), COOH proton is too broad to observe.
Example 29 3- [4- [2-(2,3-Dihydro-l ,4-benzothiazin-4-yI)ethoxy] phenyl] -2-ethoxypropanoic acid
Figure imgf000060_0001
The title compound (1.4 g, 63 %) was prepared as a gummy material from methyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (2.3 g, 5.73 mmol) obtained in example 6 by a procedure analogous to that described for example 26.
'H NMR (CDC13. 200 MHz) δ : 1.18 (t, J = 7.0 Hz, 3H), 2.82 - 3.15 (complex, 4H), 3.40 - 3.68 (complex, 2H), 3.70 - 3.81 (complex, 4H), 4.05 (dd, J = 7.29, 4.33 Hz. IH), 4.16 (t, J = 5.72 Hz, 2H), 6.68 - 6.74 (complex, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.94 - 7.06 (complex, 2H), 7.14 (d, J = 8.5 Hz, 2H). COOH proton is too broad to observe.
Example 30
3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yI)ethoxy]phenyl]-2-ethoxypropanoic acid,sodium salt
Figure imgf000060_0002
The title compound (0.42 g, 81 %) was prepared as a colorless solid from 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.5 g, 1.30 mmol) obtained in example 29 by an analogous procedure to that described for example 27.
Η NMR (CDCI3. 200 MHz) : δ 0.98 (t, J = 7.0 Hz, 3H), 2.72 - 3.25 (complex, 5H), 3.30 - 3.51 (complex, IH), 3.61 - 3.73 (complex, 4H), 3.82 - 3.91 (complex, IH), 4.04 (t, J = 5.72 Hz, 2H), 6.52 - 6.79 (complex, 4H), 6.91 - 7.03 (complex, 2H), 7.10 (d, J = 8.4 Hz, 2H). Example 31 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide
Figure imgf000061_0001
A solution of oxalyl chloride (0.28 mL, 3.1 mmol) and 3-[4-[2-(2,3-dihydro-l ,
4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.6 g, 1.55 mmol) obtained in example 29 in dry dichloromethane (10 mL) was refluxed for 2 h. The solvent and excess oxalyl chloride were removed under reduced pressure. The residue was dissolved in dichloromethane and stirred with aqueous ammonia (5 mL) for 30 min. The reaction mixture was extracted with chloroform (2 x 25 mL).
The combined chloroform layer was washed with water (25 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. Ether (7 : 3) as an eluent to afford the title compound (0.32 g. 54 %) as a white solid. mp : 120 - 122 °C. iH NMR (CDC13, 200 MHz) : δ 1.15 (t, J = 6.96 Hz. 3H), 2.81 - 3.20 (complex,
4H), 3.38 - 3.58 (complex, 2H), 3.71 - 3.90 (complex, 4H). 3.91 (dd, J = 7.38 and 3.73 Hz, IH), 4.16 (t, J = 5.58 Hz, 2H), 5.54 (bs, D2O exchangeable, IH), 6.44 (bs, D2O exchangeable, IH), 6.59 - 6.84 (complex, 4H), 6.92 - 7.19 (complex, 4H). Example 32
N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxy-propanamide
Figure imgf000061_0002
To an ice cooled solution of 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy] phenyl]-2-ethoxypropanoic acid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162 g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride (0.10 g, 0.86 mmol) and stirring was continued for 30 min at
0 °C. To the above reaction mixture, methyl amine (40 % solution) (0.124 mL) was added at 25 °C and stirring was continued for 1 h at 25 °C. Water (20 mL) was added and extracted with ethyl acetate (2 x 20 mL). The combined organic extract was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (1 : 1) to afford the title compound as a colorless solid, mp : 80 - 82 °C.
ΪH NMR (CDCI3, 200 MHz) : δ 1.11 (t, J = 7.0 Hz, 3H), 2.76 (d. J = 4.89 Hz,
3H), 2.81 - 2.88 (complex, IH), 3.01 - 3.12 (complex, 3H), 3.39 - 3.52 (complex, 2H), 3.70 - 3.81 (complex, 4H), 3.86 - 3.91 (complex, IH), 4.14 (t. J = 5.81 Hz, 2H), 6.48 (bs, IH), 6.61 - 6.81 (complex, 4H), 6.94 - 7.14 (complex, 4H). Example 33
3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide
Figure imgf000062_0001
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.
'H NMR (CDCI3, 200 MHz) : δ 1.13 (t, J = 6.96 Hz 3H), 2.81 - 2.93 (complex, IH), 3.03 - 3.19 (complex, IH), 3.34 - 3.59 (complex, 4H), 3.69 (t, J = 5.53 Hz, 2H), 3.88 (dd, J = 7.43 and 3.7 Hz, IH), 4.15 (t, J = 5.58 Hz, 2H), 4.28 (t, J
= 4.24 Hz, 2H), 5.49 (bs, IH, D2O exchangeable), 6.43 (bs, IH, D2O exchangeable), 6.68 - 6.87 (complex, 6H), 7.15 (d, J = 8.49 Hz, 2H). Example 34
N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxy-propanamide
Figure imgf000063_0001
The title compound (0.23 g, 74 %) was prepared as a white solid from 3 -[4- [2- (2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40 % solution) ( 2 mL) by an analogous procedure to that described in example 32. mp : 97 - 99 °C.
Η NMR (CDC13, 200 MHz) : δ 1.14 (t. J = 7.0 Hz. 3H), 2.76 (d, J = 4.98 Hz, 3H), 4.80 - 4.90 (complex, IH), 3.02 - 3.14 (complex, IH), 3.35 - 3.45 (complex, 2H), 3.52 (t, J = 4.57 Hz, 2H), 3.68 (t, J = 5.81 Hz. 2H). 7.88 (dd, J = 7.06 and 3.74 Hz, IH), 4.14 (t, J = 5.72 Hz, 2H), 4.22 (t J = 4.15 Hz, 2H). 6.50 (bs, IH), 6.55 - 6.89 (complex, 6H), 7.11 (d, J = 8.3 Hz, 2H).
Example 35
N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-ethoxy-propanamide
Figure imgf000063_0002
The title compound (0.25 g, 67 %) was prepared as a white solid from 3-[4-[2- (2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and benzyl amine (0.095 g, 0.88 mmol) by a procedure analogous to that described in example 32. mp : 94 - 96 °C.
Η NMR (CDC13, 200 MHz) : δ 1.11 (t, J = 7.0 Hz, 3H), 2.82 - 3.18 (complex, 2H), 3.40 - 3.55 (complex, 4H), 3.70 (t, J = 5.49 Hz, 2H), 3.94 - 3.98 (complex, IH), 4.14 (t, J = 5.72 Hz, 2H), 4.23 (t, J = 4.24 Hz, 2H), 4.28 - 4.52 (complex, 2H), 6.60 - 6.87 (complex, 6H), 7.06 - 7.32 (complex, 7H). CONH proton is too broad to observe.
Example 36 N-BenzyI-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyI]-2-ethoxy- propanamide
Figure imgf000064_0001
The title compound (0.22 g, 74 %) was prepared as a white solid from 3-[4-[2- (2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076 g, 0.71 mmol) by an analogous procedure to that described in example 32. mp : 92 - 93 °C.
Η NMR (CDC13, 200 MHz) : δ 1.15 (t, J = 7.0 Hz, 3H). 2.88 - 3.20 (complex. 4H). 3.42 - 3.60 (complex, 2H), 3.73 - 3.87 (complex, 4H), 3.98 - 4.06 (complex, IH), 4.18 (t, J = 5.72 Hz, 2H), 4.30 - 4.56 (complex, 2H), 6.61 - 6.90 (complex. 4H). 7.00 - 7.43 (complex, 9H), CONH proton is too broad to observe.
Example 37
2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI]-2-ethoxy- propanoic acid
Figure imgf000064_0002
The title compound (0.3 g, 62 %) was prepared as a gummy liquid from methyl 2- methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (0.5 g, 1.2 mmol) obtained in example 7 by an analogous procedure to that described in example 26.
'H NMR (CDCI3, 200 MHz) δ : 1.24 (complex, 6H), 2.98, 3.04 (IH each, 2d. J = 14.1 Hz each), 3.51 (t, J = 4.25 Hz, 2H), 3.49 - 3.71 (complex, 4H), 4.15 (t, J = 5.63 Hz, 2H), 4.22 (t, J = 4.48 Hz, 2H), 6.60 - 6.87 (complex, 6H), 7.07 (d, J = 8.67 Hz, 2H), COOH proton is too broad to observe. Example 38
2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid, sodium salt
Figure imgf000065_0001
The title compound (0.12 g, 51 %) was prepared as a white solid from 2-methyl-3- [4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.22 g, 0.57 mmol) obtained in example 37 by an analogous procedure to that described in example 27.
Η NMR (DMSO-d6, 200 MHz) δ : 0.96 - 1.08 (complex, 6H). 2.79 (s. 2H), 3.28 - 3.52 (complex, 4H), 3.64 (t, J = 5.3 Hz, 2H), 4.05 - 4.19 (complex, 4H), 6.48 - 6.59 (complex, IH), 6.62 - 6.86 (complex, 4H), 7.03 - 7.28 (complex, 3H).
Example 39
2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl) ethoxy] phenyl]-2-ethoxypropanoic acid
Figure imgf000065_0002
The title compound (0.25 g, 42 %) was prepared as a gummy liquid from methyl 2-(2-fluorobenzyl)-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-y l)ethoxy]phenyl] -2- ethoxy -propanoate (0.6 g, 1.2 mmol) obtained in example 8 by an analogous procedure to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 1.12 (t, J = 6.82 Hz, 3H), 1.65 (bs, IH, D2O exchangeable), 3.11 - 3.42 (complex, 4H), 3.50 (t, J = 4.34 Hz, 2H), 3.68 (t, J = 5.67 Hz, 2H), 3.70 - 3.89 (complex, 2H), 4.14 (t, J = 5.67 Hz, 2H), 4.21 (t, J= 4.15 Hz, 2H), 6.62 - 6.86 (complex, 6H), 7.03 - 7.12 (complex, 4H), 7.18 - 7.30 (complex, 2H). Example 40
2-(2-Fluorobenzyl)-3- [4- [2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy] phenyl] -2- ethoxypropanoic acid, sodium salt
Figure imgf000066_0001
The title compound (0.11 g, 48 %) was prepared as a white solid from 2-(2- fluorobenzyl)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid (0.22 g, 0.45 mmol) obtained in example 39 by an analogous procedure to that described in example 27.
Η NMR (CDC13, 200 MHz) : δ 1.02 (t, J = 6.65 Hz. 3H), 2.75 - 2.92 (complex, 4H), 3.39 - 3.58 (complex, 4H), 3.62 (bs, 2H), 4.04 - 4.20 (complex, 4H), 6.49 - 6.82 (complex, 5H), 6.90 - 7.28 (complex, 6H), 7.49 - 7.13 (complex, IH).
Example 41 3-[4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid:
Figure imgf000066_0002
The title compound (0.75 g, 77 %) was prepared as a white solid from methyl 3-[4-
[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (1.0 g, 2.5 mmol) obtained in example 10 by a procedure analogous to that described in example 26. mp : 90 - 03 °C. 'H NMR (CDCI3, 200 MHz) : δ 1.18 (t, J = 6.96 Hz, 3H), 2.88 - 3.13 (complex, 2H),
3.41 - 3.63 (complex, 2H), 4.06 (dd, J = 7.43 and 4.33 Hz, IH), 4.25 - 4.52
(complex, 4H), 4.61 (s, 2H), 6.80 (d, J = 8.62 Hz, 2H), 7.00 - 7.34 (complex, 6H).
COOH proton is too broad to observe. Example 42 3-[4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, sodium salt
Figure imgf000067_0001
The title compound (0.12 g, 56 %) was prepared as a white solid from 3-[4-[2-(3- oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.2 g, 0.51 mmol) obtained in example 41 by an analogous procedure to that described in example 27.
1H NMR (CDC13, 200 MHz) : δ 0.99 (t, J = 6.97 Hz. 3H), 2.61 - 2.80 (complex, 2H), 3.32 - 3.57 (complex, IH), 3.60 - 3.72 (complex, IH), 3.65 - 3.70 (complex, IH), 4.18 (bs, 2H), 4.30 (bs, 2H), 4.68 (s, 2H), 6.78 (d, J = 8.4 Hz, 2H). 7.03 - 7.14 (complex, 5H), 7.42 (d, J = 7.06 Hz, IH).
Example 43 3-[6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid
Figure imgf000067_0002
The title compound (0.8 g, 69 %) was prepared as a white solid from methyl 3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate (1.2 g, 2.66 mmol) obtained in example 12 by an analogous procedure to that described in example 26. mp : 102 - 104 °C.
Η NMR (CDCI3, 200 MHz) : δ 1.15 (t, J = 7.01 Hz, 3H), 3.06 (t, J = 4.98 Hz, 2H), 3.08 - 3.63 (complex, 4H), 3.77 - 3.83 (complex, 4H), 4.15 (dd, J = 4.15 and 4.18 Hz, IH), 4.28 (t, J = 5.95 Hz, 2H), 6.59 - 6.79 (complex, 2H). 6.96 - 7.36 (complex, 5H), 7.61 - 7.79 (complex, 3H). COOH proton is too broad to observe. Example 44
3-[6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid, sodium salt
Figure imgf000068_0001
The title compound (0.16 g, 76 %) was prepared as a white solid from 3-[6-[2- (2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid (0.2 g, 0.457 mmol) obtained in example 43 by an analogous procedure to that described in example 27. mp: 138 - 140 °C.
! H NMR (DMSO-d6, 200 MHz) : δ 0.98 (t, J = 7.06 Hz. 3H), 2.72 - 2.90 (complex.
IH), 2.92 - 3.21 (complex, 3H), 3.32 - 3.54 (complex, 2H). 3.61 - 3.91 (complex, 5H), 4.28 (bs, 2H), 6.56 (t, J = 7.00 Hz, IH), 6.73 - 7.00 (complex, 3H), 7.05 - 7.30 (complex, 2H). 7.38 (d, J = 8.3 Hz, IH), 7.60 - 7.82 (complex, 3H).
Example 45 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI]-2-hydroxy- propanoic acid
Figure imgf000068_0002
The title compound (0.06 g, 43 %) was prepared as a brown syrupy liquid from ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.15 g, 0.40 mmol) obtained in example 13 by an analogous procedure to that described in example 26.
!H NMR (CDC13. 200 MHz) : δ 2.85 - 3.19 (complex, 2H), 3.43 (t, J = 4.15 Hz, 2H), 3.61 (t, J = 5.49 Hz, 2H), 4.07 (t, J = 5.40 Hz, 2H), 4.16 (t, J = 4.48 Hz, 2H), 4.45 (bs, IH), 6.50 - 6.82 (complex, 6H), 7.08 (d, J = 7.88 Hz, 2H). COOH and OH protons are too broad to observe. Example 46 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid
Figure imgf000069_0001
The title compound (0.7 g, 46 %) was prepared as a white solid from ethyl 3-[4- [2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (1.7 g, 4.39 mmol) obtained in example 14 by a procedure analogous to that described in example 26. mp : 74 - 76 °C.
!H NMR (CDC13, 200 MHz) : δ 2.88 - 3.18 (complex, 4H), 3.69 - 3.79 (complex,
4H), 4.15 (t, J = 5.72 Hz, 2H), 4.45 (dd, J = 6.73 and 4.79 Hz, IH), 4.51 - 4.97 (bs, D2O exchangeable, IH), 6.65 - 6.89 (complex, 4H). 6.94 - 7.17 (complex, 4H), COOH proton is too broad to observe.
Example 47 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy] phenyl] -2-benzyloxy- propanoic acid
Figure imgf000069_0002
The title compound (0.15 g, 67 %) was prepared as a thick liquid from ethyl 3- [4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate (0.24 g, 0.52 mmol) obtained in example 15 by a procedure analogous to that described in example 26.
Η NMR (CDCI3, 200 MHz) : δ 1.40 - 2.80 (br, IH, D2O exchangeable), 2.99 3.18 (complex, 2H), 3.51 (t, J = 4.34 Hz, 2H), 3.70 (t, J = 5.82 Hz, 2H), 4.13 - 4.24 (complex, 5H), 4.51 (d, J = 17.0 Hz, 2H), 6.60 - 6.89 (complex, 6H), 7.10 - 7.37 (complex, 7H). Example 48 3- [4- [2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy] phenyl] -2-benzyloxy- propanoic acid, sodium salt
Figure imgf000070_0001
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.
Η NMR (DMSO-d6, 200 MHz) : δ 2.62 - 2.74 (complex. IH), 2.89 - 2.98 (complex, IH), 3.48 (t, J = 4.2 Hz, 2H), 3.67 (t, J = 5.48 Hz, 2H), 4.12 - 4.26 (complex, 5H), 4.65 (d, J = 12.45 Hz, 2H), 6.45 - 6.84 (complex, 6H), 7.12 - 7.25 (complex, 7H).
Example 49 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoic acid
Figure imgf000070_0002
The title compound (0.25 g, 67 %) was prepared as a syrupy liquid from ethyl 3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate (0.4 g, 0.93 mmol), obtained in example 16 by an analogous procedure to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 0.87 (t, J = 7.15 Hz, 3H), 1.25 - 1.40 (complex, 2H), 1.49 - 1.66 (complex, 2H), 2.95 - 3.15 (complex, 2H), 3.43 - 3.53 (complex, 4H), 3.68 (t, J = 5.49 Hz, 2H), 4.00 - 4.12 (complex, IH), 4.14 (t, J = 5.65 Hz, 2H), 4.22 (t, J = 4.25 Hz, 2H), 6.60 - 6.89 (complex, 6H), 7.12 (d, J = 8.39 Hz, 2H). COOH proton is too broad to observe. Example 50 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic acid, sodium salt
Figure imgf000071_0001
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.
Η NMR (DMSO-d6, 200 MHz) : δ 0.78 (t, J = 7.06 Hz, 3H). 1.16 - 1.56 (complex, 4H), 2.52 - 2.64 (complex, IH), 2.79 - 2.87 (complex, IH). 2.99 - 3.18 (complex, 2H), 3.40 (bs, 2H), 3.66 (t, J = 5.31 Hz, 2H), 4.10 - 4.25 (complex, 5H), 6.52 - 6.90 (complex, 6H), 7.12 (d, J = 8.3 Hz, 2H).
Example 51 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxy- propanoic acid
Figure imgf000071_0002
The title compound (0.17 g, 60 %) was prepared as a greenish liquid from ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate (0.3 g, 0.65 mmol) obtained in example 17 by a procedure analogous to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 0.86 (t, J = 5.72 Hz, 3H), 1.25 - 1.33 (complex, 4H), 1.41 - 1.75 (complex, 4H), 2.94 - 3.06 (complex, 2H), 3.36 - 3.58 (complex, 4H), 3.68 (t, J = 5.49 Hz, 2H), 4.01 - 4.06 (complex, IH), 4.14 (t, J = 5.7 Hz, 2H), 4.22 (t, J = 4.15 Hz, 2H), 6.71 - 7.08 (complex, 6H), 7.12 (d, J = 8.4 Hz, 2H). COOH proton is too broad to observe. Example 52 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid, sodium salt
Figure imgf000072_0001
The title compound (0.1 g, 52 %) was prepared as a white hygroscopic solid from 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid (0.18 g, 0.42 mmol) obtained in example 51 by an analogous procedure to that described in example 27.
Η NMR (DMSO-d6, 200 MHz) : δ 0.82 (t J = 5.72 Hz, 3 H), 1.10 - 1.45 (complex, 8H), 2.75 - 2.96 (complex, 2H), 3.35 - 3.56 (complex, 4H), 3.67 (t, J = 5.3 Hz, 2H), 4.08 - 4.21 (complex, 5H), 6.50 - 6.82 (complex, 6H). 7.12 (d, J = 8.0 Hz, 2H).
Example 53 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid
Figure imgf000072_0002
The title compound (0.1 g, 53 %) was prepared as a colorless liquid from methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate (0.2 g, 0.461 mmol) obtained in example 19 by an analogous procedure to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 2.40 - 2.80 (bs, IH, D2O exchangeable), 3.22 (d, J = 5.8 Hz, 2H), 3.49 (t, J = 4.25 Hz, 2H), 3.67 (t, J - 5.81 Hz, 2H). 4.14 (t, J = 5.81 Hz, 2H), 4.21 (t, J = 4.16 Hz, 2H), 4.82 (t, J = 5.9 Hz, IH), 6.61 - 7.02 (complex, 8H). 7.17 - 7.30 (complex, 5H). Example 54 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid
Figure imgf000073_0001
The title compound (0.2 g, 51 %) was prepared as a gummy solid from methyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate (0.4 g, 0.9 mmol) obtained in example 21 by a procedure analogous to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 3.02 (t, J = 5.0 Hz, 2H), 3.22 (d. J = 6.25 Hz, 2H), 3.68 - 3.78 (complex, 4H), 4.14 (t, J = 5.81 Hz, 2H). 4.50 (t. J = 6.19 Hz. IH), 4.90 - 5.40 (b, IH. D2O exchangeable), 6.58 - 6.86 (complex, 7H), 6.94 - 7.07 (complex, 2H), 7.18 - 7.29 (complex, 4H).
Example 55
3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid, sodium salt
Figure imgf000073_0002
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.
Η NMR (DMSO-d6, 200 MHz) : δ 2.81 - 3.09 (complex, 2H), 3.42 (bs, 2H), 3.65 (t, J = 4.5 Hz. 2H), 4.12 (bs, 4H), 4.22 - 4.32 (complex, IH), 6.50 - 6.92 (complex, 8H), 7.10 - 7.33 (complex, 5H). Example 56
Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-phenoxypropanoate
The title compound (0.27 g, 87 %) was prepared as a syrupy liquid from methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate (0.3 g, 0.69 mmol) obtained in example 19 by an analogous procedure to that described in example 7.
'H NMR (CDCI3, 200 MHz) : δ 1.39 (s, 3H), 3.09, 3.26 (IH each. 2d. J = 13.7 Hz each), 3.51 (t, J = 4.3 Hz, 2H), 3.66 - 3.73 (complex, 5H), 4.15 (f J = 5.5 Hz. 2H), 4.22 (t, J = 4.24 Hz, 2H), 6.61 - 7.01 (complex, 9 H), 7.12 - 7.22 (complex, 4H).
Example 57
2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yI)ethoxy]phenyI]-2-phenoxy- propanoic acid
Figure imgf000074_0002
The title compound (0.13 g, 50 %) was prepared as a pale yellow hygroscopic solid from methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy] phenyl]-2-phenoxypropanoate (0.27 g, 0.60 mmol) obtained in example 56 by a procedure analogous to that described in example 26.
'H NMR (CDCl3, 200 MHz) : δ 1.42 (s, 3H), 3.12, 3.29 (IH each, 2d, J = 14.1 Hz each), 3.50 (t, J = 4.5 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 4.16 (t, J = 5.81 Hz, 2H), 4.22 (t, J = 4.5 Hz, 2H), 6.62 - 7.17 (complex, 9H), 7.21 - 7.30 (complex, 4H). COOH proton is too broad to observe. Example 58
2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid, sodium salt
Figure imgf000075_0001
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.
'H NMR (CDC13, 200 MHz) : δ 1.15 (s, 3H). 2.99 - 3.21 (complex, 2H). 3.47 (bs, 2H), 3.67 (bs, 2H), 4.14 (bs, 4H), 6.53 - 6.9 (complex. 9H). 7.08 - 7.30 (complex, 4H).
Example 59 Methyl 2-methyI-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2 phenoxypropanoate
Figure imgf000075_0002
The title compound (0.96 g, 93 %) was prepared as a pale yellow liquid from methyl 3-[4-[2-(2,3-dihydo-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate (1.0 g, 2.22 mmol) obtained in example 21 by an analogous procedure to that described in example 7. 'H NMR (CDC13, 200 MHz) : δ 1.40 (s, 3H), 3.03 (t, J = 4.9 Hz, 2H), 3.09, 3.27
(IH each, 2d, J = 13.7 Hz each), 3.70 - 3.85 (complex, 7H), 4.16 (t, J = 5.81 Hz, 2H), 6.60 - 6.89 (complex, 6H), 6.96 - 7.30 (complex, 7H).
Example 60 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid
Figure imgf000076_0001
The title compound (0.6 g, 65 %) was prepared as a syrupy liquid from methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoate (0.96 g, 2.00 mmol) obtained in example 59 by an analogous procedure to that described in example 26.
Η NMR (CDC13, 200 MHz) : δ 1.42 (s, 3H), 3.03 (t, J = 5.0 Hz, 2H), 3.12, 3.30 (IH each, 2d, J = 13.8 Hz each), 3.70 - 3.80 (complex, 4H), 4.15 (t, J = 5.5 Hz, 2H), 6.58 - 7.08 (complex, 8H). 7.18 - 7.30 (complex, 5H), COOH proton is too broad to observe. Example 61
4-Nitrophenyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]
-2-ethoxypropanoate:
Figure imgf000076_0002
The title compound (0.15 g, 38 %) was prepared as a yellow liquid from 3-[4-[2- (2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by an analogous procedure to that described in example 32.
'H NMR (CDCI3, 200 MHz) : δ 1.24 (t, J = 6.92 Hz, 3H), 3.04 (t, J = 5.16 Hz, 2H), 3.12 (d, J = 6.63 Hz, 2H), 3.46 - 3.65 (complex, IH), 3.70 - 3.86 (complex, 5H), 4.16 (t, J = 5.23 Hz, 2H), 4.26 (t, J = 5.5 Hz, IH), 6.62 - 6.74 (complex,
2H), 6.84 (d, J = 8.62 Hz, 2H), 6.94 - 7.22 (complex, 6H), 8.23 (d, J = 9.0 Hz, 2H).
Example 62 3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy- propanoic acid
Figure imgf000077_0001
The title compound (0.4 g, 57 %) was prepared as a syrupy liquid from methyl 3- [4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate (0.8 g, 2.16 mmol) obtained in example 25 by an analogous procedure to that described in example 26 .
'H NMR (CDC13, 200 MHZ) : δ 1.17 (f J = 7.0 Hz, 3H), 2.99 - 3.13 (complex, 2H), 3.31 - 3.65 (complex, 4H), 4.01 - 4.24 (complex, 3H), 4.45 (d, J = 3.4 Hz, 2H), 4.52 - 4.59 (complex, IH), 6.62 - 6.68 (complex, 6H), 7.14 (d. J = 8.6 Hz, 2H), 7.27 (s, 5H). COOH proton is too broad to observe. Example 63
3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyI]-2-ethoxy- propanoic acid, sodium salt
Figure imgf000077_0002
The title compound (0.15 g, 75 %) was prepared as a colorless hygroscopic solid from 3-[4-(4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy- propanoic acid (0.2 g, 0.44 mmol) obtained in example 62 by an analogous procedure to that described in example 27.
Η NMR (DMSO-d6, 200 MHz) : δ 0.99 (t, J = 6.97 Hz, 3H), 2.60 - 2.90 (complex, 2H), 3.30 - 3.65 (complex, 5H), 4.16 (d, J = 5.0 Hz, 2H), 4.40 - 4.65 (complex, 3H), 6.55 - 6.89 (complex, 6H), 7.14 (d, J = 8.5 Hz, 2H), 7.32 (s, 5H).
Example 64 4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxy- phenyl]-2-ethoxypropanoate
Figure imgf000078_0001
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.
'H NMR (CDC13, 200 MHz) : δ 1.25 (t, J = 7.0 Hz, 3H). 3.14 (d. J = 6.6 Hz, 2H), 3.33 - 3.55 (complex, 3H), 3.69 - 3.77 (complex. IH), 4.05 - 4.31 (complex, 3H), 4.46 (d, J = 3.4 Hz, 2H), 4.55 - 4.61 (complex, IH), 6.63 - 6.68 (complex, 6H), 7.11 - 7.28 (complex, 7H), 7.52 (d, J = 7.6 Hz, 2H), 8.23 (d, J = 9.0 Hz, 2H). 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 hPPARα activity
Ligand binding domain of hPPARα 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 PPARα was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 1 18 : 137 -141; Superfect Transfection Reagent Handbook. February, 1997. Qiagen, Germany). b) Determination of hPPARγ activity Ligand binding domain of hPPARγl 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 μM concentration after 48 hrs of transfection and incubated overnight. Luciferase activity as a function of drug binding/activation capacity of PPARγl 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 KH2PO . 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg of liver microsomal enzyme. Total reaction mixture volume was kept as 1 ml. Reaction was started by addition of HMG CoA. Reaction mixture was incubated at 37 °C for 30 min and decrease in absorbance at 340 nm was recorded. Reaction mixture without substrate was used as blank (Goldstein, J. L and Brown, M. S. Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res. 1984, 25: 1450 - 1461). The test compounds inhibited the HMG CoA reductase enzyme.
B) In vivo a) Efficacy in genetic models Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non-insulin dependent diabetes and hyperlipidemia associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (Diabetes, (1982) 31 (1) : 1- 6) mice and zucker fa/fa rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838 ; Annu. Rep. Sankyo Res. Lab. (1994). 46 : 1-57). The homozygous animals, 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. In 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.
The state of 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.
Male C57BL/KsJ-db/db 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), Hyderabad, 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). On 6th day 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 μl) 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, Hyderabad, India) methods respectively.
The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
No adverse effects were observed for any of the mentioned compounds of invention in the above test.
Figure imgf000081_0001
The ob/ob 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, Hyderabad, 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.
In ob/ob 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. The experimental results from the db/db mice, ob/ob mice. 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.
Blood glucose level and triglycerides 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
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), Hyderabad. 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.
Figure imgf000083_0001
I reduction ; t increase c) Plasma triglyceride and total cholesterol lowering activity in
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. Hyderabad, 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).
The 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, Hyderabad, India).
Figure imgf000084_0001
c) Body weight reducing effect in cholesterol fed hamsters :
Male Syrian Hamsters were procured from NIN, Hyderabad, India. Animals were housed at DRF animal house under 12 hour light and dark cycle at 25 ± 1 °C with free access to food and water. Animals were maintained with 1 % cholesterol containing standard laboratory chow (NIN) from the day of treatment.
The 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 3r day.
Figure imgf000084_0002
Formulae for calculation :
1. Percent reduction in Blood sugar / triglycerides / total cholesterol / body weight were calculated according to the formula:
Percent reduction (%) = 1 - TT/OT X 100
TC/OC OC = Zero day control group value
OT = Zero day treated group value
TC = Test day control group value
TT = Test day treated group value 2. LDL and VLDL cholesterol levels were calculated according to the formula :
LDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - Triglvceride
5 VLDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - LDL cholesterol

Claims

C L A I M S
1. A compound of formula (I)
Figure imgf000086_0001
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymoφhs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein the groups R1, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R and R may represent an oxo group when attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with adjacent group R8; R8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl or R8 forms a bond together with R7; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygen or NR12, where R12 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 and R12 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 -(CH2)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.
2. A compound according to claim 1, wherein when the groups represented by R1 - R4 and the groups Ra and R6 when attached to a carbon atom are substituted, the substituents are selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy. aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl. alkylthio, thioalkyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives .
3. A compound according to claim 1, wherein when the groups R? and R6 attached to nitrogen are substituted, the substituents are selected from halogen atoms, hydroxy, acyl, acyloxy, or amino groups.
4. A compound according to claim 1 , wherein Ar represents optionally substituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, or benzoxazolyl groups.
5. A compound according to claim 1, wherein the substituents on the group represented by R are selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, 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 .
6. A process for the preparation of compound of formula (I)
Figure imgf000088_0001
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymoφhs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. wherein the groups R1, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl. alkoxycarbonylamino. aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R^ and R6 may represent an oxo group when attached to a carbon atom; R5 and R6 when attached to 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, 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 NR1 ' where Rπ is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 and R8 together represent a bond; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl. alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl. arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; Y represents oxygen; the linking group represented by -(CH2)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 , which comprises : a) reacting a compound of formula (Ilia)
Figure imgf000089_0001
where all symbols are as defined above with a compound of formula (Illb)
O (R,4O)2-P-CH-(COOR10) (Illb)
OR9 where R9 and R10 are as defined above and R14 represents (Cι-C6)alkyl. to yield compound of formula (I) defined above; b) reacting a compound of formula (IIIc)
Figure imgf000089_0002
where all symbols are as defined above with a compound of formula (Hid)
Figure imgf000089_0003
where R7 and R together represent a bond and all symbols are as defined above and L1 is a leaving group to produce a compound of formula (I) defined above;
c) reacting a compound of formula (Hie)
Figure imgf000090_0001
where all symbols are as defined above with a compound of formula (Illf)
Figure imgf000090_0002
where R > _ = r R. 10 and are as defined above to produce a compound of the formula (I); d) reacting a compound of formula (Ilia)
Figure imgf000090_0003
where all other symbols are as defined above with a compound of formula (Illg)
Figure imgf000090_0004
where R , R . and R , 10 are as defined above to yield a compound of formula (I) as defined above after dehydration;
e) reacting a compound of formula (Illh)
Figure imgf000090_0005
where all symbols are as defined earlier and L! represents a leaving group, with compound of formula (Illi)
Figure imgf000091_0001
where R7 and R8 together represent a bond and R9, R10 and Ar are as defined earlier to produce a compound of the formula (I) where m represents an integer 1 and all other symbols are as defined above; f) reacting a compound of formula (IIIj)
Figure imgf000091_0002
where all symbols are as defined above with a compound of formula (Illi)
Figure imgf000091_0003
where R7 and R8 together represent a bond and R9. Rl () and Ar are as defined above to produce a compound of formula (I) where m represents an integer 1 and all other symbols are as defined above; and optionally,
g) converting the compounds of formula (I) obtained in any of the processes described above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates. 7. A process for the preparation of compound of formula (I)
Figure imgf000091_0004
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs. its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. wherein the groups R , R , R , R , and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R3 and R may represent an oxo group when attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group; R represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl: R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl. alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 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 -(CH )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 , which comprises : a) reducing a compound of formula (IVa)
Figure imgf000093_0001
which represents a compound of formula (I) where R7 and R8 together represent a bond and Y represents an oxygen atom and all other symbols are as defined above, prepared according to any of the processes claimed in claim 6, to yield a compound of the formula
7 8
(I) where R and R each represent hydrogen atom and all symbols are as defined above; a) reacting a compound of formula (I Vb)
Figure imgf000093_0002
where all symbols are as defined above and L2 is a leaving group with an alcohol of formula (IVc),
R9-OH <IVc) where R9 represents optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups produce a compound of the formula (I) defined above; b) reacting a compound of formula (Illh)
Figure imgf000093_0003
where all symbols are as defined above and L is a leaving group with a compound of formula (Illi)
Figure imgf000093_0004
where all symbols are as defined above to produce a compound of the formula (I) where m represents an integer 1 and all other symbols are as defined above;
c) reacting a compound of formula (IIIj)
Figure imgf000094_0001
where all symbols are as defined above with a compound of formula (Illi)
Figure imgf000094_0002
where all symbols are as defined above to produce a compound of formula (I) where m represents an integer 1 and all other symbols are as defined above; d) reacting a compound of formula (I Vd)
Figure imgf000094_0003
which represents a compound of formula (I) where R9 represents a hydrogen atom and all other symbols are as defined above with a compound of formula (IVe)
R9— L2 (IVe) where R represents optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups and L2 is a halogen atom to produce a compound of formula (I) defined above; f) reacting a compound of the formula (Ilia)
Figure imgf000094_0004
where all symbols are as defined above with a compound of formula (Illg)
Figure imgf000095_0001
where R , R , R are as defined above to produce a compound of formula (I) after dehydroxylation; g) reacting a compound of formula (IIIc)
Figure imgf000095_0002
where all symbols are as defined above with a compound of formula (Hid)
Figure imgf000095_0003
where L! is a leaving group and all other symbols are as defined above to produce a compound of formula (I) defined above;
h) converting a compound of formula (IVf)
Figure imgf000095_0004
where all symbols are as defined above to a compound of formula (I) defined above; i) reacting a compound of formula (IVg)
Figure imgf000095_0005
where all symbols are as defined above with a compound of formula (IVe)
R9-OH <IVc) where R9 represents optionally substituted groups selected from alkyl, cycloalkyl, aryl. aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl. arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups to produce a compound of formula (I), optionally; j). resolving the compound of formula (I) obtained in any of the processes described above into its stereoisomers, and optionally;
k) converting the compounds of formula (I) or its stereoisomers obtained in any of the processes described above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates. 8. A process for the preparation of compound of formula (I)
Figure imgf000096_0001
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. wherein the groups R1, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; or one or both of R3 and R6 may represent an oxo group when attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group or forms a bond together with the adjacent group R ; R represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl or R forms a bond
7 0 together with R ; R represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl. or heteroaralkyl groups; R10 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl. or heteroaralkyl groups: Y represents NR12, where R12 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl. heterocyclyl, heteroaryl. or heteroaralkyl group; R10 and R12 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 - (CH2)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 , which comprises: a) reacting a compound of formula (I)
Figure imgf000097_0001
where all symbols are as defined above and Y represents oxygen, YR10 represents a halogen atom, or COYR10 represents a mixed anhydride group with appropriate amines of the formula NHR10R12, where R10 and R12 are as defined earlier and, optionally; b) resolving the compound of formula (I) obtained above into stereoisomers, optionally;
c) converting the compounds of formula (I) obtained above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates. A compound of formula (I)
Figure imgf000098_0001
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein the groups R1, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R5 and R may represent an oxo group when attached to a carbon atom; R and R when attached to 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 and R8 together represent a bond; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl. arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 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)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, prepared according to the process of claim 6.
10. A compound of formula (I)
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs. its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein the groups R!, R2, R3, R4, and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R^ and R6 may represent an oxo group when attached to a carbon atom; R and R 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, 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 where R is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group; R8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 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)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
I, prepared according to the process of claim 7.
I I . A compound of formula (I)
Figure imgf000100_0001
its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein the groups R1, R2, R3, R4. and the groups R5 and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R5 and R6 may represent an oxo group when attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group or forms a bond together with the adjacent group R ; R represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionally substituted aralkyl or R8 forms a bond
7 Q together with R ; R represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl. or heteroaralkyl group; R1 represents hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl. aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups: Y represents NR12, where R12 represents hydrogen, alkyl, aryl. hydroxyalkyl, aralkyl. heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 and R12 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 - (CH2)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 , prepared according to the process of claim 8. 12. An intermediate of formula (IVf)
Figure imgf000101_0001
where the groups R1, R2, R3, R4, and the groups R^ and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R5 and R1 may represent an oxo group when attached to a carbon atom; R3 and R6 when attached to 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, 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 NR1 ' where R1 ! is selected from hydrogen, or optionally substituted alkyl. cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group; R8 represents hydrogen, hydroxy. alkoxy. halogen, lower alkyl group, acyl, or optionally substituted aralkyl; R9 represents hydrogen, or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl. alkoxyalkyl, alkoxycarbonyl. aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; the linking group represented by - (CH2)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.
13. A process for the preparation of compound of formula (IVf) described in claim 12 where R7 and R8 represent hydrogen atoms and all other symbols are as defined in claim 12 which comprises : a) reacting a compound of formula (Ilia)
Figure imgf000103_0001
where all symbols are as defined above with a compound of formula (IVh)
R9OCH2P+PPh3 "Hal (IVh) where R9 represents optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups and Hal represents a halogen atom, to yield a compound of formula (IVi)
Figure imgf000103_0002
where all symbols are as defined above, b) reacting a compound of formula (IVi) with an alcohol of the formula
R9OH where R9 is as defined above to yield a compound of formula (IVj),
Figure imgf000103_0003
where are all symbols are as defined above, c) reacting a compound of formula (IVj) obtained above where all symbols are as defined above with trialkylsilyl cyanide to produce a compound of formula (IVf) where all symbols are as defined above. 14. An intermediate of formula (IVg)
0
Figure imgf000103_0004
where the groups R1, R2, R3, R4, and the groups R~ and R6 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, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R" and R6 may represent an oxo group when attached to a carbon atom; R5 and R6 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, 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 NR1 ' where R1 ' is selected from hydrogen, or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl. alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group: R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group; R! 0 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)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.
15. A process for the preparation of compound of formula (IVg) described in claim 14, which comprises: a) reacting a compound of formula (Illh)
Figure imgf000105_0001
where L is a leaving group and all other symbols are as defined in claim 14 with a compound of formula (IVI)
Figure imgf000105_0002
where R is a hydrogen atom and all other symbols are as defined in claim 14, to yield a compound of formula (IVk)
Figure imgf000105_0003
where R is a hydrogen atom and all other symbols are as defined above, b) reacting a compound of formula (IVk) obtained above with a diazotizing agent.
16. A compound according to claim 1 which is selected from:
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropenoate ;
(±) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate ;
(-) Methyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate ; Ethyl (E/Z)-3-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropenoate;
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropenoate ; (+) Methyl 3-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropanoate ;
(+) Methyl 3-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropanoate ; (-) Methyl 3-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2- ethoxypropanoate;
(+) Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate ;
(+) Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate;
(-) Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate;
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate; (+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate;
(-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoate ;
(±) Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-l .4-benzoxazin-4-yl)ethoxy] phenyl]-2-ethoxypropanoate;
(+) Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-l .4-benzoxazin-4-yl)ethoxy] phenyl]-2-ethoxypropanoate;
(-) Methyl 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy] phenyl] -2-ethoxypropanoate ; Ethyl (E/Z)-3-[4-[2-(3-oxo-2H-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propenoate;
(+) Methyl 3 - [4- [2-(3 -oxo-2H- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl] -2-ethoxypropanoate;
(+) Methyl 3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoate;
(-) Methyl 3-[4-[2-(3-oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoate; Ethyl (E/Z)-3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropenoate ;
(+) Methyl 3-[6-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate; (+) Methyl 3-[6-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2- ethoxypropanoate;
(-) Methyl 3 - [6- [2-(2,3 -dihydro- 1 ,4-benzothiazin-4-y l)ethoxy]naphthyl]-2 - ethoxypropanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy- propanoate; Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoate;
Ethyl 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxy propanoate;
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropenoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate ; (-) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropenoate ;
(±) Methyl 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate; (-) Methyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate ;
Ethyl (E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropenoate ; (±) Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
(+) Methyl 3-[4-(4-methyl-3,4-dihydro-2H- 1 ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
(-) Methyl 3-[4-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
Ethyl (E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropenoate;
(±) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H-l .4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate; (+) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H- 1 ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
(-) Methyl 3-[4-(4-benzyl-3,4-dihydro-2H-l ,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoate;
(±) 3-[4-[2-(2.3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(2.3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts:
(-) 3-[4-[2-(2.3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts: (+) 3-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
(+) 3-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy- propanoic acid and its salts;
(-) 3-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy- propanoic acid and its salts;
(+) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy- propanoic acid and its salts; (+) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy- propanoic acid and its salts;
(-) 3-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxy- propanoic acid and its salts; (±) 3-[4-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid and its salts;
(±) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxy- propanamide;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide; (-) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(±) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide ;
(+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(-) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide; (+) 3-[4-[2-(2,3-Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(-) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy- propanamide;
(+) N-Methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(+) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide ; (-) N-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide ; (+) N-Benzyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(-) N-Benzyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide;
(+) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide ;
(-) N-Benzyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanamide ; 2-Methyl-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl] -2-ethoxy- propanoic acid and its salts;
2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(3-Oxo-2H-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3 - [4- [2-(3 -Oxo-2H- 1 ,4-benzoxazin-4-y l)ethoxy ]pheny 1] -2-ethoxypropanoic acid and its salts;
(-) 3- [4- [2-(3 -Oxo-2H- 1 ,4-benzoxazin-4-y l)ethoxy]pheny 1] -2-ethoxypropanoic acid and its salts; (+) 3-[4-[2-(3-Oxo-2H-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3 - [4- [2-(3 -Oxo-2H- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(-) 3-[4-[2-(3-Oxo-2H- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[6-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts; (+) 3-[6-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts;
(-) 3-[6-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts; (±) 3-[6-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts;
(+) 3-[6-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts;
(-) 3-[6-[2-(2,3-Dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxy- propanoic acid and its salts;
(±) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts; (-) 3-[4-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts;
(-) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzothiazin-4-y l)ethoxy]phenyl]-2-hydroxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy- propanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy- propanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy- propanoic acid and its salts;
(±) 3-[4-[2-(2,3-Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoic acid and its salts; (-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxy- propanoic acid and its salts;
(±) 3-[4-[2-(2,3-Dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- hexyloxypropanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- hexyloxypropanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxy- propanoic acid and its salts;
(±) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl] -2-phenoxy- propanoic acid and its salts;
(+) 3 - [4- [2 -(2,3 -Dihydro- 1 ,4-benzoxazin-4-y l)ethoxy]phenyl] -2-phenoxy- propanoic acid and its salts;
(-) 3-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid and its salts; (+) 3-[4-[2-(2,3-Dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid and its salts;
(+) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy- propanoic acid and its salts;
(-) 3 - [4- [2-(2,3 -Dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]pheny 1] -2-phenoxy- propanoic acid and its salts;
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl] -2-phenoxypropanoate;
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl] -2-phenoxypropanoate; (-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzoxazin-4-yl)ethoxy]phenyl]
-2-phenoxypropanoate;
(±) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoic acid and its salts;
(+) 2-Methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoic acid and its salts;
(-) 2-Methyl-3 - [4- [2-(2,3 -dihydro- 1 ,4-benzoxazin-4-y l)ethoxy]phenyl]-2- phenoxypropanoic acid and its salts; - I l l -
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate; (-) Methyl 2-methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoate;
(+) 2-Methyl-3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts;
(+) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts;
(-) 2-Methyl-3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy propanoic acid and its salts;
(+) 4-Nitrophenyl 3-[4-[2-(2,3-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl] -2-ethoxy propanoate; (+) 4-Nitrophenyl 3-[4-[2-(2,3-dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxy propanoate;
(-) 4-Nitrophenyl 3-[4- [2-(2,3 -dihydro- 1 ,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxy propanoate;
(+) 3 - [4-(4-Benzyl-3 ,4-dihydro-2H- 1 ,4-benzoxazin-2-y l)methoxyphenyl] -2- ethoxypropanoic acid and its salts;
(+) 3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoic acid and its salts;
(-) 3-[4-(4-Benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxyphenyl]-2- ethoxypropanoic acid and its salts; (+) 4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxy phenyl]-2-ethoxypropanoate;
(+) 4-Nitrophenyl-3 - [4-(4-benzyl-3 ,4-dihydro-2H- 1 ,4-benzoxazin-2-yl)methoxy phenyl]-2-ethoxypropanoate; and
(-) 4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-l,4-benzoxazin-2-yl)methoxy phenyl]-2-ethoxypropanoate.
17. A pharmaceutical composition which comprises a compound of formula (I)
Figure imgf000114_0001
as defined in claim 1 or 16, and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
18. A pharmaceutical composition as claimed in claim 19, in the form of a tablet, capsule, powder, syrup, solution or suspension.
19. A method of preventing or treating hypercholesteremia, obesity with beneficial effects on hyperlipemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a compound of formula (I) as defined in any one of claims 1-5, 9-11 or 16 or a pharmaceutical composition according to claim 17 or 18 and a pharmaceutically acceptable carrier, diluent, solvate or excipient to a patient in need thereof.
20. A method according to claim 19, wherein the disease is type II diabetes, impaired glucose tolerance, dyshpidemia, disorders related to Syndrome X including hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders; renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, or hypertensive nephrosclerosis; psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabetic complications and osteoporosis.
21. A method of reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDL and free fatty acids in the plasma comprising administering a compound of formula (1), as defined in any one of claims 1-5, 9-1 1 or 16 or a pharmaceutical composition according to claim 17 or 18 to a patient in need thereof.
22. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a compound of formula (I) as defined in any one of claims 1-5, 9-11 or 16, or a pharmaceutical composition according to claim 17 or 18 in combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol which may be administered together or within such a period as to act synergestically together to a patient in need thereof.
23. A method according to claim 22, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atheosclerosis, hypperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
24. A method according to claim 23, for the treatment or prophylaxis of disorders related to Syndrome X, which comprises administering a compound of formula (I) in combination with HMG CoA reductase inhibitors, fibrates, nicotinic acid, chloestyramine, colestipol, or probucol which may be administered together or within such a period as to act synergestically together.
25. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma, which comprises administering a compound of formula (I) claimed in any one of claims 1-5, 9-11 or 16 or a pharmaceutical composition according to claim 17 or 18, combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol which may be administered together or within such a period as to act synergestically together to a patient in need thereof.
PCT/US1998/022570 1997-10-27 1998-10-26 Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them WO1999020614A1 (en)

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Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035437A2 (en) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Improving mental performance by increasing brain insulin sensitivity
WO2000063209A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000063192A1 (en) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
WO2000063193A1 (en) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
WO2000063190A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000063153A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000066572A1 (en) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
WO2001055085A1 (en) * 2000-01-28 2001-08-02 Novo Nordisk A/S Propionic acid derivatives and their use in the treatment of diabetes and obesity
WO2001087860A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Novel benzoxazinones as peroxisome proliferator activated receptor gamma modulators and method of treatment
WO2001087861A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Methods of treatment using benzoxazinones as peroxisome proliferator activated receptor gamma modulators
WO2001087862A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Biologically active 4h-benzo[1,4]oxazin-3-ones
WO2002020499A1 (en) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Process for the preparation of 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 (en) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them
WO2001053257A3 (en) * 2000-01-19 2002-06-27 Cadila Healthcare Ltd Compounds having hypolipedemic and hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them
WO2002100397A1 (en) * 2001-06-07 2002-12-19 Wyeth COMBINATION OF A PTPase INHIBITOR AND AN ANTILIPEMIC AGENT
WO2003006022A1 (en) * 2001-07-09 2003-01-23 Dr. Reddy's Laboratories Ltd. Tetrahydroquinoline derivatives and their use in medicine, process for their preparation and pharmaceutical compositions containing them
WO2003009841A1 (en) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
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 (en) * 2001-10-16 2003-04-24 Dr. Reddy's Laboratories Ltd. Benzoxazine and benzothiazine derivatives and parmaceutical compositions containing them
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 (en) * 2001-11-21 2003-05-28 Ortho-McNeil Pharmaceutical, Inc. Biologically active 4H-benzo(1,4)oxazin-3-ones
WO2003099800A1 (en) * 2002-05-23 2003-12-04 Dr. Reddy's Laboratories Limited An improved process for the preparation of bicyclic antidiabetic agents
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 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US7790745B2 (en) 2005-10-21 2010-09-07 Bristol-Myers Squibb Company Tetrahydroisoquinoline LXR Modulators
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
WO2012104869A1 (en) 2011-01-31 2012-08-09 Cadila Healthcare Limited Treatment for lipodystrophy
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015001573A1 (en) 2013-07-05 2015-01-08 Cadila Healthcare Limited Synergistic compositions
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US9814697B2 (en) 2013-04-22 2017-11-14 Cadila Healthcare Limited Composition for nonalcoholic fatty liver disease (NAFLD)
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
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US10112898B2 (en) 2013-09-06 2018-10-30 Cadila Healthcare Limited Process for the preparation of saroglitazar pharmaceutical salts
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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 (en) * 2018-01-29 2022-04-08 中国科学院上海药物研究所 Aromatic propionic acid derivative, preparation method and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0441539A2 (en) * 1990-02-08 1991-08-14 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
WO1991019702A1 (en) * 1990-06-14 1991-12-26 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
US5104888A (en) * 1985-02-26 1992-04-14 Sankyo Company, Limited Thiazolidine derivatives, their preparation and use
JPH05194236A (en) * 1991-07-25 1993-08-03 Tanabe Seiyaku Co Ltd Central calcium antagonistic agent
WO1996004260A1 (en) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Benzoxazoles and pyridine derivatives useful in the treatment of the type ii diabetes
US5496815A (en) * 1990-02-08 1996-03-05 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
JPH0912575A (en) * 1995-06-28 1997-01-14 Sankyo Co Ltd Benzoxazine and benzothiazine derivative

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 (en) * 1990-02-08 1991-08-14 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
US5496815A (en) * 1990-02-08 1996-03-05 Tanabe Seiyaku Co., Ltd. Thiazine (or oxazine) derivatives and preparation thereof
WO1991019702A1 (en) * 1990-06-14 1991-12-26 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
US5306726A (en) * 1990-06-14 1994-04-26 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
JPH05194236A (en) * 1991-07-25 1993-08-03 Tanabe Seiyaku Co Ltd Central calcium antagonistic agent
WO1996004260A1 (en) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Benzoxazoles and pyridine derivatives useful in the treatment of the type ii diabetes
JPH0912575A (en) * 1995-06-28 1997-01-14 Sankyo Co Ltd Benzoxazine and benzothiazine derivative

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 (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035437A3 (en) * 1998-12-17 2000-11-09 Mindset Biopharmaceuticals Usa Improving mental performance by increasing brain insulin sensitivity
WO2000035437A2 (en) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Improving mental performance by increasing brain insulin sensitivity
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
WO2000063192A1 (en) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
WO2000063193A1 (en) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
US6369055B1 (en) 1999-04-20 2002-04-09 Novo Nordisk A/S Compounds, their preparation and use
WO2000063153A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
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
WO2000063209A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000063190A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
WO2000066572A1 (en) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
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 (en) * 2000-01-19 2007-02-27 Кадила Хелзкэр Лтд. Compounds having hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them
HRP20020643B1 (en) * 2000-01-19 2015-04-24 Cadila Healthcare Ltd Zydus Tower, Satellite Cross Roads, Rrd Center Novel compounds having hypolipedemic, hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them
CZ304346B6 (en) * 2000-01-19 2014-03-19 Cadila Healthcare Ltd. Substituted pyrrole derivative exhibiting hypolipidemic and hypocholesteremic activity , process for its preparation and pharmaceutical composition containing thereof
WO2001053257A3 (en) * 2000-01-19 2002-06-27 Cadila Healthcare Ltd Compounds having hypolipedemic and hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them
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 (en) * 2000-01-28 2001-08-02 Novo Nordisk A/S Propionic acid derivatives and their use in the treatment of diabetes and obesity
WO2001087861A3 (en) * 2000-05-12 2002-03-28 Ortho Mcneil Pharm Inc Methods of treatment using benzoxazinones as peroxisome proliferator activated receptor gamma modulators
WO2001087862A3 (en) * 2000-05-12 2002-05-30 Ortho Mcneil Pharm Inc Biologically active 4h-benzo[1,4]oxazin-3-ones
WO2001087861A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Methods of treatment using benzoxazinones as peroxisome proliferator activated receptor gamma modulators
US6555536B2 (en) 2000-05-12 2003-04-29 Ortho-Mcneil Pharmaceutical, Inc. Biologically active 4H-benzo [1,4]oxazin-3-ones
WO2001087860A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Novel benzoxazinones as peroxisome proliferator activated receptor gamma modulators and method of treatment
WO2001087862A2 (en) * 2000-05-12 2001-11-22 Ortho-Mcneil Pharmaceutical, Inc. Biologically active 4h-benzo[1,4]oxazin-3-ones
WO2001087860A3 (en) * 2000-05-12 2002-03-28 Ortho Mcneil Pharm Inc Novel benzoxazinones as peroxisome proliferator activated receptor gamma modulators and method of treatment
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 (en) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Process for the preparation of 2-[3,4-dihydro-1,4-benzothiazin-4-yl]ethylmethane sulphonate
WO2002030914A1 (en) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them
WO2002100397A1 (en) * 2001-06-07 2002-12-19 Wyeth COMBINATION OF A PTPase INHIBITOR AND AN ANTILIPEMIC AGENT
WO2003006022A1 (en) * 2001-07-09 2003-01-23 Dr. Reddy's Laboratories Ltd. Tetrahydroquinoline derivatives and their use in medicine, process for their preparation and pharmaceutical compositions containing them
HRP20040138B1 (en) * 2001-07-26 2016-12-02 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hipocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
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 (en) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
US8110598B2 (en) 2001-07-26 2012-02-07 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US7365064B2 (en) 2001-10-16 2008-04-29 Dr. Reddy's Laboratories Limited Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them
WO2003033481A1 (en) * 2001-10-16 2003-04-24 Dr. Reddy's Laboratories Ltd. Benzoxazine and benzothiazine derivatives and parmaceutical compositions containing them
EP1314729A1 (en) * 2001-11-21 2003-05-28 Ortho-McNeil Pharmaceutical, Inc. Biologically active 4H-benzo(1,4)oxazin-3-ones
EP1852427A1 (en) * 2001-11-21 2007-11-07 Ortho-McNeil Pharmaceutical, Inc. Biologically active 4H-Benzo [1,4] oxazin-3-ones
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 (en) * 2002-05-23 2003-12-04 Dr. Reddy's Laboratories Limited An improved process for the preparation of bicyclic antidiabetic agents
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
US7790745B2 (en) 2005-10-21 2010-09-07 Bristol-Myers Squibb Company Tetrahydroisoquinoline LXR Modulators
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
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WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US9783495B2 (en) 2011-01-31 2017-10-10 Cadila Healthcare Limited Treatment for lipodystrophy
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WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
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WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
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WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
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