Title of Invention

NOVEL HETEROCYCLIC COMPOUNDS AND THEIR USE IN MEDICINE: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract A two-Stage method is proposed for producing a highly transparent anode emitter (2) in a GTO (1) . In a first step, an anode emitter (2) is indiffused whose thickness is greater than 0.5 μm and whose doping concentration is greater than 1017- cm-3. In a second step, the emitter efficiency of the anode emitter (2) is subsequently reduced to a desired degree by local carrier life setting. (Figure 1)
Full Text

Field of Invention the present invention relates (o 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 the general fonnula (I), their derivatives, their analogs, their tautomeric forms, their stereo-somcrs, 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 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, very low density lipoprotein (VLDL) 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, retinopathy, and nephropathy The compounds of general formula (I) are also useful for the treatment/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/concomittant with one or more HMG CoA reductase inhibitors or hypolipidcmic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol. Background of Invention
Atherosclerosis and other peripheral vascular diseases are the major causes effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hypcrlipidemia and the 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 lipoprotein (LDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and partially as very low density lipoprotcin (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and atherosclerosis with serum HDL-choleslerol 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 humans, 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
the 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 which 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 has 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, osteoarthritis, reduced fertility and many other psychological and social problems.
Diabetes and insulin resistence is yet another disease which severely effects the quality of life of a large population in the world. In 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. Chn. Endocrinol. Mctab., (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 of 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 hyperlipidemia having glucose intolerance/insuh'n resistance in addition to hyperiipidemia 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 (y) isoform of PPAR (PPARy) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (a) isoform of PPAR (PPARa) 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). PPARa agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that the hypolipidacmic effect is enhanced when the molecule has both PPARa and PPARy agonist activity and are suggested to be useful for the treatment of syndrome X (WO 97/25042). Synergism between the insulin sensitizer (PPARy 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 PPARy 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. PPARy is consistently expressed in certain cells and activation of this nuclear receptor with PPARy 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 cancer expression of prostate cancer tissue (Cancer Research (1998) 58, 3344-3352). This would be useful in the treatment of certain types of cancer, which expresses PPARy and could leading 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, cardiovascular 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 their PPAR agonist expression and therefore lower plasm 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 β aryl-α-hydroxy propionic acids, their derivatives, and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of such compounds described in the prior art are outlined below :
i) U,S. Pat. 5,306,726; and WO 91/19702 disclose several 3-arykyl-2-hydroxy-
propionic acid derivatives of general formula (II a) and (II b) as hypolipidemic and hypoglycemic agents.

wherein Ra represents 2- benzoxazolyl or 2-pyridyl and Rb represents CF3, CH2OCH3 or CH3. A typical example is (5)-3-[4-[2-[N-(2-benzoxazolyl)-N'methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (II f).


wherein A1 represent aromatic hetcrocycle, A2 represents substituted benzene ring and A3
represents moiety of formula (CH2)m-CH-(OR1), wherein R1 represents alkyl groups, m is an
integer of the range of 1-5; X represents substituted or unsubstituted N; and Y represents C=O or C=S. R2 represents OR3 where R'3 may be hydrogen, alkyl, aralkyl, or aryl group; and n represents an integer in the range of 2-6. An example of these compounds is shown in formula (II h)

Summary 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, atherosclerosis, coronary artery diseases, Syndromc-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetic complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism, for the treatment and/or prophylaxis of leptin resistance and complications thereof, 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 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 β-aryl-α-oxysubstitulcd alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their

pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
Another objective of the present invention is to provide novel β-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their phannaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPARa and/or PPARy, and or unsubstitutcd or substitutcdinhibit HMG CoA reductase, in addition to agonist activity against PPARa and/or PPARy.
Another objective of the present invention is to provide novel β-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaccutically acceptable salts, and their pharmaceutically acceptable solvates and phannaceutical 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 to produce a process for the preparation of novel β-aryl-α-oxysubstitutcd alkylcarboxylic acids of the formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaccutically acceptable salts and their pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide phannaceutical compositions containing compounds of the general formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, 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 intennediates, a process for their preparation and use of the intennediates in processes for preparation of β-aryl-α-oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates.

Detailed Description of the Invention
α~Oxysubstituted propionic aeids, their derivatives, and their analogs of the present invention have the general fonnula (I)

where X represents O or S; the groups R1, R2, R3, R4 and the group's.R5, and R6 when attached to carbon atom may be the same or different and represenl hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubslituted or substituted groups selected from alkyl, cycloalky!, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterpcyclyl, hcteroaryl, hctcroaryloxy, hctcroaralkyl, hetcroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxy-carbonyl, aralkoxycarbonyl, ammo, alkylamtno which may be mono or dialkylamino group, arylamino, acyhunino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxy-carbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5, and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, hctcroaralkyl, hetcroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an or unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group or forms a bond with R8 ; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group, or unsubstituted or substituted aralkyl, or R forms a bond together with R7; R9 may be hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl,

alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 may be hydrogen or unsubstituted or substituted groups selected from alky!, cycloalkyi, aryl, aralkyl, hetcrocyclyl, hcteroaryl, heteroaralkyl groups; Y- represents oxygen or NR , where R12 represents hydrogen, or unsubstituted or substituted alkyl, aryl, hydroxy-alkyl, aralkyl, heterocyclyl, hcteroaryl, or heteroaralkyl groups; R10 and R12 together may fonii a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may be unsubstituted or substituted contain one or more heteroatoms selected from oxygea, sulfur or nitrogen; the linking group represented by -(CH2)n-0- may be attached either through nitrogen atom or carbon atom.
Suitable groups represented by R1, R2, R3, R4 and the groups, R5, 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-C12)alkyl group, especially, linear or branched (C1-C6)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl and the like; cyclo(C3-C6)alkyl group such as cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl and the like, the cycloalkyi 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, 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, benzopyranyl, benzofuryl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclyl group may be substituted; aralkoxy group such as benzyloxy, phenethyloxy, naphthyl-mcthyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; heteroaralkyl group such as furanmcthyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkylamino group such as C6H5CH2NH, Crai5CH2CH2NH, C6H5CH2NCH3 and the like, which may be substituted; alkoxycarbonyl such as mclhoxycarbonyl or ethoxycarbonyl which may be substituted; aryloxycarbonyl group such as or unsubstituted or substituted phenoxycarbonyl, naphthyloxycarbonyl and the

like; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthyl-
methoxycarbonyl and the like, which may be substituted; monoalkylamino group such as
NHCII3, NHC2H5, NHC3H7, NHCcHiaand the like, which may be substituted, dialkylamino
group such as N(CH3)2, NCH3(C2H5), and the like, which may be substituted; alkoxyalkyl
group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like which
may be substituted; aryloxyalky! group such as C6H5OCH2, C6H5OCH2CH2,
naphthyloxymethyl and the like, which may be substituted; aralkoxyalkyl group such as
C6H5CH2OCH2, G6H5CH2OCH2CH2 and the like, which may be substituted; heteroaryloxy
and heteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are as defined earlier and
may be substituted; aryloxy group such as phenoxy, naphthyloxy, the aryloxy group may be
substituted; arylamino group such as HNC6H5, NCHaCCeHs), NHC6H4CH3, NHC6H4-Hal and
the like, which may be substituted; amino group which may be substituted; amino(C1-C6)
alkyl which mfy be substituted; hydroxy(C1-C6)aIkyl which may be substituted; (C1-Ce)
alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like which may
be substituted; thio(C1-C6)alkyl which may be substituted; (C1-C6)alkylthio which may be
substituted; acyl group such as acetyl, propanoyl or benzoyl, the acyl group may be
substituted; acylalihino groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOCfiHs
which may be substituted; aralkoxycarbonyl amino group such as NHCOOCH2C6H5,
NHCOOCHaCHiCrfls, N(CH3)COOCH2C6H5, N(C2H5)COOCH2C6H5,
NHCOOCH2Cf,H4CH3, NHCOOCH2C6H4OCH3 and the like, which may be substituted; aiyloxycarbonylamino group such as NFICOOC6H5, NCH3COOC6H5, NC2H5COOC6H5, NllCOOC6H4CH3, NIICOOCf,H40CH3 and the like, which may be substituted; alkoxy-carbonylamino group such as NHCOOC2II5, NHCOOCH3 and the like, which may be substituted; carboxylic acid or its derivatives such as amides, like CONH2, CONHMe, CONMC2, CONHBt, CONEt2, CONJ IPh and the like, the carboxylic kcid derivatives may be substituted; acyloxy group such as OCOMe, OCOEt, OCOPh and the like, which may be substituted; or sulfonic acid or its derivatives such as SO2NH2, S02NHMe, S02NMe2, SO2NHCF3 and the like, the sulfonic acid derivatives maybe substituted.
When the groups represented by R1, R2, R3 R4, R5 and R6 are substituted, the substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,

heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. The substituents are defined as above.
It is preferred that the substituents on R1-R6 represent halogen atom such as fluorine, chlorine, or bromine, hydroxy; or unsubstitulcd or substituted halogenatcd alkyl groups, the alkyl group is selected from a group such as methyl, ethyl, isopropyl, n-propyl, or n-butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; araikyl group such as benzyl; (CJ-CB) alkoxy; benzyloxy, acyl or acyloxy groups.
Suitable R11 and the groups R5, R6 when attached to nitrogen atom are selected from hydrogen, hydroxy, fomiyl; substituted or unsubstituted (C1-C12)alkyl group, especially, linear or branched (C1-C6)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, is O-butyl, t-butyl, n-pentyl, iso-pentyl, hcxyl and the like; cyclo(C3-C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohcxyl and the like, the cycloalkyl group may be substituted; cycIo(C3-C6)alkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclo-pcntyloxy, cyclohexyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; araikyl such as benzyl or phcncthyl, C6H5CTI2CH2CH2, naphthylmcthyl and the like, the araikyl group may be substituted and the substituted araikyl is a group such as CH3C6H4CH2, Hal-C6H4CH2, CHJOC6H4CH2, CH3OC6H4CH2CH2 and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, Ictrazolyl, benzopyranyl, bcnzofuryl and the like, the heteroaryl group may be substituted; heteroeyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heteroeyclyl group may be substituted; aralkoxy group such as benzyloxy, phenethyloxy, naphthyl-methyloxy, phcnylpropyloxy 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 or ethoxyearbony which may be substituted; aryloxycarbonyl group such as or unsubstituted or substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthyl-

mctnoxycaffionyi and the iike, which may be substituted; monoalkylamino group such as NHCH3, IWC2H5, NHC3H7, NHCfiHiaand the h'ke, which may be substituted; dialkylamino group such as N(CH3)2, NCH3(C2H5), and (he like, which may be substituted; alkoxyalkyl group such as methoxymethyl, elhoxymethyl, methoxyethyl, ethoxyethyl and the hke, which may be substituted; aryloxyalkyl group such as C6H5OCH2, C6H5OCH2CH2, naphthyl-oxymcthyl and the Hkc, which may bo substituted; aralkoxyalkyl group such as C6(l5CM20CH2, C6H5CH20CH2CH2 and the Hke, which may be substituted; hetcroaryloxy and lictcroaralkoxy, wherein heteroaryl and hetcroaralkyl moieties arc as defined cariier and may be substituted; aryloxy group such as phcnoxy, naphthyloxy, the aryloxy group may be substituted; arylamino group such as NUCrdf.s NCH3(C6H5), NHCr,H4CFl3, NHC6H4-Hal and the Hke, which may be substituted; amino group which may be substituted; amino(C|-C6) alkyl which may be substituted; hydroxy(C'rC6)alkyl which may be substituted; (C1-C6) alkoxy such as mcthoxy, cthoxy, propyloxy, butyloxy, iso-propyloxy and the hke which may be substituted; thio(CrC6) When the groups represented by R`` and the groups R5, R6 attached to nitrogen are substituted, preferred substituents may be selected from halogen such as fluorine, chlorine; hydroxy, acyl, acyloxy, or amino groups.
When the groups represented by R11 and the groups R5, R6 are attached to nitrogen atom, R5-R6 are same as defined earlier.
The group represented by Ar includes substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, benzoxazolyl, benzo-thiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzo-

pyranyl, dihydrobcnzopyranyl, pyrazolyl and the like. The substituents on the group represented by Ar include linear or branched or unsubstituted or substituted halogcnated (C1-C6)alkyl, or unsubstituted or substituted halogcnated (C1-C3)alkoxy, halogen, acyl, amino, acyhiniino, thio, carboxylic and sulfonic acids and their derivatives. The substituents arc defined as they are for R1-R4.
It is more preferred that Ar represents a substituted or unsubstituted divalent, phcnylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
It is still more preferred that Ar is represented by divalent phenylene or naphthylene, which may be unsubstituted or substituted by methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R7 includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C1-C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, or iodine; aralkyl such as benzyl, or phenethyl, which may be unsubstituted or substituted with halogen, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, benzyloxy, acetyl, acetyloxy groups, preferably with hydroxy, halogen, (C1-C3)alkyl or alkoxy (C1-C3), or R7 together with R8 represent a bond.
Suitable R8 may be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (CrC3)alkoxy; halogen atom such as fluorine, chlorine, bromine, or iodine; acyl group such as linear or branched (C2-C10)acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl, which may be unsubstituted or substituted with halogen, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, benzyloxy, acetyl, acetyloxy groups, preferably with hydroxy, halogen, (C1-C3)alkyl or (C1-C3) alkoxy, or R8 together with R7 forms a bond.
It is preferred that R7 and R8 represent hydrogen atom or R7 and R8 together represent a bond.
Suitable groups represented by R^ may be selected from hydrogen, linear or branched (CrCuOalkyl, preferably (CrCi2)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-buiyi, pcntyl, hcxyl, octyl and the like, which may be substituted; {C3-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 subslitulcd; hctoroaryl group such as pyridyl, thicnyl, furyl and the like, the hetcroaryl

group may be substituted; hctcroaralkyl group such as furanmcthyl, pyridincmcthyl, oxazol-emethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkyl group wherein the aryl group is as defined earlier and the alkyl moiety may contain C1-C6 atoms such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; (C1-C6)alkoxy(C1-C6)alkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and the like, the alkoxyalkyl group may be substituted; aryloxyalkyl group such as C6H5OCH2, C6H5OCH2CH2, naphthyloxymethyl, naphthyl-oxyethyl and the like, which may be substituted; linear or branched (C2-C16)acyl group such as acetyl, propanoyl, isopropanoyl, butanoyl, benzoyl, octanoyl, decanoyl and the like which may be substituted; (C|-C6)alkoxycarbonyI, the alkyl group may be substituted; aryloxy-carbonyl such as phenoxycarbonyl, naphthyloxycarbonyl, the aryl group may be substituted; (C1-C6)alkylaminocarbonyl, the alkyl group may be substituted; and arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl, the aryl moiety may be substituted. The substituents may be selected from halogen, hydroxy, formyl or nitro or unsubstituted or substituted groups selected from alkyl, cycloaikyi, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, aryl-amino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. These groups are as defined above.
Suitable groups represented by R10 may be selected from hydrogen, substituted or unsubstituted linear or branched (C1-C16)a1kyl, preferably (C1-C12)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C1-C7)cycloalkyl such as cyclopropyl, cyclopcntyl, cyclohexyl and the like, the cycloaikyi group may be substituted; aryl group such as phenyl, naphthyl, the aryl group may be substoituted heteroaryl group such as pyridyl, Ihienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmcthyl, pyridincmcthyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkyl group such as benzyl and phenethyl, the aralkyl group may be substituted; heterocyclcyl 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 R1-R4 and are as defined above.
Suitable groups represented by R12 may be selected from hydrogen, substituted or unsubstituted linear or branched (C1-C16)alkyl preferably (CrCi2)alky1; hydroxy (C1-C6) alkyl which may be substituted; aryl group such as phenyl, naphthyl and the like, which may be substituted; aralkyl group such as benzyl and phenethyl and the like, which may be substituted; hcterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl, and the like which may be substituted; hcteroaryl group such as pyridyl, thienyl, furyl and the like, which may be substituted; and heteroaralkyl group such as furanmethyl, pyridincmethyl, oxazolemcthyl, oxazolethyl and the like, which may be substituted.
The cyclic struturc formed by R10 and R12 may be a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms which may be unsubstituted or substituted contain one or two hcteroatoms selected from oxygen, nitrogen on sulfur.
Suitable ring structures formed by R10 and R12 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, pipcrazinyl, oxazolinyl, diazolinyl and the like.
Suitable substituents on the cyclic structure formed by R' and R taken together may be selected from halogen, hydroxy, alkyl, oxo, aralkyl and the like.
Suitable n is an integer ranging from 1 to 4, preferably n represents an integer 1 or 2.
Pharmaccutically acceptable salts forming part of this invention include vsalts 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, tromethamine 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, palmoatcs, methanesulphonates, benzoates, salicylates, hydroxynaphthoatcs, bcnzenesulfonates, ascorbates, glycerophosphates, ketoglutaratcs and the like. Phamiaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compounds according to the present invention include:

Ethyl 2-cthoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-pmpcnoalc;
(d)-Ethyl 2-cthoxy«3-[4-[2-[4-oxo--3,4~dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl] propanoalc;
(- )'-Ethyl 2'Cthoxy-3-[4-[2-[4-oxo-3,4-dihydro-l ,3-benzoxazin-3-yl]cthoxy]phenyl] propanoalc;
(-)-Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl] propanoalc;
(±)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro 1,3 benzoxazin-3-yl]ethoxy]phcnyl] propanoic acid
and its salts;
[2R, N(1S)] 2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]-N-
(2-hydroxy-l-phenylethyl)propanamide;
[2S, N(1S)] 2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]-N-(2-
hydroxy-l-phenylethyl)propanamide;
(4-)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l ,3-benzoxazin-3-yl]ethoxy] phenyl] propanoic
acid and its salts;
(-)-2-Ethoxy-3-[4-[2-[4-oxO-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl] propanoic acid
and its salts;
(±)-Ethyl 2-phenoxy-3-[4-[2-[4-oxo-3,4-dihydro-l ,3-benzoxazin-3-yl]ethoxy]phenyl] -2-
propenoate;
(±)-Ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3:benzoxazin-3-yl]
ethoxy]phenyl]propanoate;
(+)-Ethyl2-elhoxy-3-[4-[2-[2,2-dimcthyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]
cthoxyjphenyljpropanoate;
(-)-Ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]
c(l)oxy]phcnyl]propanoate;
(±)^2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yI]
cthoxy]phenyl]propanoic acid and its salts;
(-f)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3'yl]
cthoxy]phenyl]propanoic acid and salts;

0-2-E(hoxy-3-[4-[2-[2,2-dimcthyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] cthoxy]phenyl]propanoic acid and its salts;
(±)-Mcthyl2-ethoxy-3-[4-[[4-OXo-3,4-dihydro-l',3-benzoxazin-2-yl]methoxyl phenyl]propanoate;
(+)-Methyl 2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy] phenyljpropanoatc;
(-)-Methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]
phenyl]propanoate;
(±)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-13-benzoxazin-2-yl]methoxy] phenyl]pr6panoic acid
and its salts;
(+)--2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy] phenyl] propanoic
acid and its salts;
(-)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy] phenyl] propanoic acid
and its salts;
(±)-Methyl 2~ethoxy-3-[4-[[4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]
propanoate;
(+)-Mcthyl 2-ethoxy-3-[4-[[4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]
propanoate;
(-)-Methyl 2-ethoxy-3-[4-[ [4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phcnyl]propanoate;
(±)-2-E(hoxy-3-[4-[[4-oxo-! ,2,3,4-lctrahydro-2-qufnazolinyl]mcthoxy] phenyl] propanoic
acid;
(+)-2-Ethoxy-3-[4-[[4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl]methoxy] phenyl] propanoic
acid;
(-).2-Elhoxy-3-[4-[[4-oxO'l,2,3,4-tctrahydro-2-quinazolinyl]methoxy]phenyl] propanoic
acid;
(±)-]V1clhyl 2-cthoxy-3-[4-[[()-chloro-4'-oxo-l,2,3,4-tetrahydro-2-quinazo!inyl]
niethoxy]phcnyl] propanoate; (f)-Methyl2-cthoxy-3-[4-[[6-cbloro-4-Oxo-l,2,3,4-tetrahydro-2-quinazolinyli
mcthoxy]phcnyl] propanoate;

(-)-Methyl 2-ethoxy-3-[4-[[6--chloro-4-oxo-l,2,3,4-tctrahydro-2-quinazoliny1] methoxy]phcnyl]propanoate;
{±)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy] phenyljpropanoic acid and its salts;
(f)-2-Ethoxy-3-[4-[[6-chloro-4-OXo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy] phenyljpropanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl] methoxy] phenyljpropanoic acid and its salts;
(±)-Melhyl 2-ethoxy-3-[4-[[3-niethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
mcthoxyjphcnyljpropanoate;
{+)-Mcthyl 2-cthoxy-3-[4-[[3-methyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
mcthoxy]phcnyl]propanoatc;
(-)-Mclhyl 2-ethoxy-3-[4-[[3-mcthyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]
mcthoxy]phcnyl]propanoatc;
(±)-Mcthyl 2-clhoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]
mcthoxy]phcnyi]propanoatc;
(^)-Mcthyl 2-clhoxy-3-[4-([3-niethyl-4-oxo-3,4-dihydro-l,3-bcnzoxazin-2-yl]
mclhoxy]phenyl]propanoale;
(-)-Mcthyl 2-ethoxy-3-[4-[[3-mcthyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]
mcthoxy]pheny1]propanoate;
(±)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]
phenyljpropanoic acid and its salts;
(+)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]
phenyljpropanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]
phenyljpropanoic acid and its salts;
(±)-Methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxy]phenyl]propanoate;
(-*-)-Methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxy]phenyl]propanoate;

(-)-Mcthyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] niethoxy]phcnyl]propanoate;
(±)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy]
phenyljpropanoic acid and its salts;
(f)-2-Ethoxy-3-[4-[[3-c(hyl~4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl]methoxy]
phenyljpropanoic acid and its salts;
(-)-2-Elhoxy-3-[4-[[3-cthyl-4-oxo-l,2,3,4-tctrahydro-2-quinazo!inyl]mcthoxy]
phcnyi)propanoic acid and its salts;
(±)-Mclhyl 2-cthoxy-3-[4-[[K3-dimcthyl-4~oxo-l,2,3i4-tetrahydro-2-quinazolinyl]
mcthoxy]phcnyl]propanoatc;
(f)-Mcthyl 2-cthoxy-3-[4-[[K3-dimcthyl 4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
ineihoxy]phcnyl]propanoatc;
(-)-Mcthyl 2-cthoxy-3-[4-[[l,3-diinethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazoIinyl]
nicthoxy]phenyl]propanoatc;
(±)-2-Ethoxy-3-[4-[[13-dimethyl-4-oxo-l,23,4-tetrahydro-2-quinazolinyl] methoxy]
phenyljpropanoic acid and salts;
(4)-2-Ethoxy-3-[4-{[l,3-dimcthyl-4-oxo-l,2,3,4-'tetrahydro-2-quinazolinyl]methoxy]
phenyljpropanoic acid and salts;
(-)-2-Ethoxy-3-[4-[[l,3-dimethyl-4-oxo-l,2,3,4-telrahydrO-2-quinazolinyl]methoxy]
phenyljpropanoic acid and sails;
(±)-Methyl 2-phenoxy-3-[4-[[4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl]methoxy]
phenyljpropanoate;
{-f)-Methyl 2-phenoxy-3-[4-[[4-oxo-l ,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phenyljpropanoate;
(-)-Methyl2-phenoxy-3-[4-[[4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy]
phenyljpropanoate;
(±)-2-Phenoxy-3-[4-[[4-oxo-l,2,3,4-tetrahydro-2-quinazolinyljmethoxy] phenyljpropanoic
acid and its salts;
(+)-2-Phcnoxy-3-[4-[[4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyljpropanoic acid and its salts;

{-)-2-Phenoxy-3-[4-[[4-oxo-l ,2,3,4-tctrahydro-2-qiiinazolinyl]methoxy] phenyl] propanoic acid and its salts;
(±)-Mcthyi 2-phenoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] mcthoxy] phcnyljpropanoate;
(-l-)-Methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazoIinyl]
methoxylphenyljpropanoate;
(-)- Methyl 2-phcnoxy-3-[4-[l6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]
methoxyjphenyljpropanoate;
(±)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phenyljpropanoic acid and its salts;
(f)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-qiiinazolinylj methoxy]
phenyljpropanoic acid and its salts;
(-)-2-Phcnoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phenyljpropanoic acid and its salts;
(±)-Ethyl 2-ethoxy-3-[4-[2-{6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-ylj ethoxy]
phcnyljpropanoate;
(f)-Ethyl 2-elhoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-[,3-benzoxazin-3-yl]ethoxy]
phcnyljpropanoate;
(-)-Ethyl2-ethoxy-3-[4~[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxyj
phcnyljpropanoate;
(±)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxO'3,4-dihydro-l,3-benzoxazin-3-yljethoxy]phenylj
propanoic acid and its salts;
(^)-2-Ethoxy-3-[4-[2-[6-nilro-4-oxo-3,4-dihydro-l,3-benzoxazih-3-yljethoxyjphcnylj
propanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yljcthoxyjphenylj
propanoic acid tiud its salts;
(J)~Elhyl 2-cthoxy-3-[4'-[2-[6-acctyt-4-oxo-3,4-dihydro-l,3-bcnzoxazin-3-yljefhoxyj
phcnyljpropanoate;
(i)-Elhyl 2-cthoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yljethoxy]
phenylpropanoale;

(-)-Ethyl 2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl] propanoate;
(±)-2-Ethoxy-3-[4-[2-[6-acetyI-4-oxo-3,4'dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]propanoic acid and its salts;
(+)-2-Ethoxy-3-[4T[2-[6-acetyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yI]ethoxy] phenyl]propanoic acid and its salts; and
(-)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl] propanoic acid and its salts;
According to a feature of the present invention, the compound of formula (I) where R7 and R8 together represent a bond, Y represents oxygen atom, R1 R2, R3, R4, R5 R6 X, W, R9 R10, n and Ar are as defined earlier, may be prepared by any of the following routes shown in Scheme-I below


Route (1): The reaction of a compound of the general formula (IIIa) where all other symbols arc as defined earlier, with a compound of fonnula (Illb), where R9, R10 are as defined earlier excluding hydrogen atom and R13 represents (C1-C6)alkyl group, to yield a compound of general formula (T) defined above may be carried out 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, BuO'K4 or mixtures thereof. The reaction may be cnnicd out in the presence of solvents such as THE, dioxane, DMF, DMSO, DME and the like or mixtures thereof. IIMPA may be used as cosolvent. The reaction temperature may range from -78oC to 50'C, preferably at a temperature in the range of-looC to 30oC. The compound of general formula (Illb) may be prepared by Arbuzov reaction.
The intermediate of formula (Ufa) wherein W represents nitrogen atom and the linker group -(CH2)„- is attached through carbon atom and the process for its preparation have been disclosed in the Copending Application Serial No. 08/982,911
Aitcmatively, the compound of fonnula (I) may be prepared by reacting the compound of fonnula (Ilia) where all symbols are as defined earlier with Witlig reagents such as HarPh3P+CH-(OR'9)CO2R10 under similar reaction conditions as described above.
Route (2): The reaction of a compound of the general formula (Ilia) where all other symbols are as defined earlier, with a compound of formula (IIIc) where R8 represents a hydrogen atom and all other symbols are as defined above to produce a compound of formula (1) defined above 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 Nail, 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 35oC 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 (3): The reaction of compound of formula (IIIc) where all symbols are as defined earlier and L represents a leaving group such as halogen atom, β-toluenesulfonate, methancsulfonatc, trifluoromcthanesulfonalc and the like, with a compound of formula (Illd) where R' and R together represent a bond, and all other symbols arc as defined earlier to produce a compound of the formula (I) 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 gajjcs such as N2, Ar, or Me. The reaction may be effected in the presence of a base such as
K2CO3, Na2C03 or NaH or mixtures thereof. Acetone may be used as solvent when
Na2C03 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 compoimd of fonnula (Hid) can be prepared according to known procedure by a Wittig Homer reaction between the hydroxy protected aryl aldehyde such as benzyloxy aryl aldehyde and the compound of formula (Illb), followed by deprotection.
Route (4): The reaction of a compound of general formula (IITf) where all symbols are as defined earlier with a compound of general fomiula (Illg) where R , R together represent a bond, and all symbols are as defined earlier and L' is a leaving group such as halogen atom, β-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom to produce a compound of general fomiula (I) defined above where the linker group -(CH2)n-O- is attached to nitrogen atom 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, 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 (ITlf), preferably the ainount of base ranges from 1 to 3 equivalents. Phase transfer catalysts such as tctraalkylammonium halidc or hydroxide may be added. The reaction may be carried out at a temperature in the range of 0°C to 150oC, preferably at a temperature in the range of 15°C to 100oC. The duration of the reaction may range from 0,25 to 48 hours, preferably from 0.25 to 12 hours.
Route (5): The reaction of compound of general formula (IIIh) where all symbols are as defined carlier, with a compound of general formula (Tiki) where R7 and R8 together represent a bond, and all other symbols are as defined earlier to produce a compound of formula (I) defined above may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphinc/dialkylazadicarboxylate such as PPh3/DEAD and the like. The reaction may be carried out in (he presence of solvents such as TIIF, DME, CH2CI2, CHCI3, toluene, acetonitrile, carbontetrachloride 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 I equivalents. The reaction temperature may be in the range of 0-C to 100-C, preferably at a temperature in the range of 20'oC to 80-C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
Route (6): The reaction of compound of general formula (Illi) where all symbols are as defined earlier, with a compound of formula (lllj) where R14 represents lower alkyl group, R7 and R8 together represent a bond, and all other symbols are as defined earlier to produce a compound of formula (I) wherein the linker group -(CHa),-O- is linked through carbon atom may be carried out in neat or in the presence of solvents such as THF, CHCI3, benzene, toluene, hexane, dioxane and the like or mixture thereof. The reaction may be carried out at a temperature in the range of 0°C to 250°C preferably at a temperature in the range of 10°C to 150°C. The reaction may be carried out in the presence of an acid or a base. The selection of acid or base is not critical. The examples of such acids include H2SO4, HCl, pTsOH, PPE (polyphosphorie ethyl ester) and the like. Examples of bases include pyrrolidine, lutidine, triethyl amine, diisopropylethyl amine, piperidine and the like. 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 0.25 to 24 h preferably, from 1 to 12 h.

Route (7): The reaction of a compound of formula (Illk) where all symbols are as defined earlier with a compound of formula (IIIl) where R9 = R10 and are as defined earlier excluding hydrogen atom to produce a compound of the formula (I) where R7 and R8 together represent a bond 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 NaOMc, 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 lOO^C, preferably at a temperature in the range of-10oC to 50oC.
Route (8): The reaction of compound of general formula (Illm), where R7' and R8 together represent a bond and all other symbols are as defined earlier with a compound of general formula (llln) where R14 represents lower alkyl group and where all symbols are as defined earlier to produce a compound of general formula (I), where -(CH2)n-O- linker group is attached through nitrogen atom and all other symbols are as defined earlier may be carried out in neat or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO 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 earned out at a temperature in the range of 50°C to 200'C, preferably at a temperature in the range of 60- C to 180°C. The reaction may be effected in the presence or in absence of a base or an acid. The nature of the base or the acid is not critical. Examples of such bases include organic bases such as pyridine, lutidine, triethyl amine, diisopropyl-cthyl amine and the like, metal carbonates such as K2CO3, and Na2CO3. Examples of acids include organic acids such as AcOH, C2H5COOH, butyric acid, trifluoroacetic acid, β-
lolucncsulfonic acid, bcnzencsulfonic acid and the like, mineral acids such as HCl, HBr etc. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours.
In yet another embodiment of the present invention, the compound of general formula (I) where all symbols are as defined earlier, R7 represents hydrogen atom, hydroxy,
Q
alkoxy, halogen, lower alkyl, or unsubstitutcd or substituted aralkyl group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstitutcd or

substitutedsubstituted aralkyl, or acyl group; and Y represents an oxygen atom can be prepared by one or more of the processes shown in Scheme-II below:

vScheme-Il
Route (9): The reduction of compound of the formula (IVa) which represents a
compound of formula (I) where R7 and R8 together represent a bond, Y represent oxygen and all other symbols are as defined earlier, obtained as described earlier in Scheme-1, to yield a compound of the general formula (T) where R and R each represent 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 2,3-bis(diphenylphosphino)butane, l,2-bis(diphenyl-phosphino)ethane, l,2-bis(2-methoxy phenylphosphino)ethane, 2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphi?io)butanc, 2,2'-bis(diphenylphosphino)-l ,1 '-binaphthyl and the like. Any suitable chiral catalyst may be employed which would give required optical purity of the product (1) (Rcf : Principles of Asymmetric Synthesis, Tct. Org. Chem. Scries Vol 14, pp311-316, Ed. Baldwin J. E.)-
Route (10): The reaction of compound of formula (IVb) where R10 is as defined carlier excluding hydrogen atom and all other symbols are as defined earlier and L2 is a leaving group such as halogen atom with a compound of general formula (IVc), where R9 is as defined earlier excluding hydrogen atom to produce a compound of the formula (I) 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 tctraalkylammonium halides or hydroxides may be employed. The reaction lemperalure 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) where the linker group -(CH2)n-O- is attached through carbon atom and its preparation has been disclosed in the copending U.S. Application Serial No. 08/982,911.
Route (11): The reaction of compound of formula (Ille) defined earlier with a compound of formula (Illd) where all symbols are as defined earlier to produce a compound of the formula (I) 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, Na2C03 or NaH or mixtures thereof Acetone may be used as a solvent when K2CO3 or Na2C03 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 (Illd) may be prepared by Wittig Homer reaction

between the protected hydroxyaryl aldehyde and compound o? formula (IITb) followed by reduction of the double bond and deprotcction. Altematively, the compound of formula (Illd) may be prepared by following a procedure disclosed in WO 94/01420.
Route (12): The reaction of compound of general formula (Illh) defined earlier with a compound of general formula (IIFd) where all symbols are as defined earlier to produce a compound of the formula (I) where all symbols are as defined above may be carried out using suitable coupling agents such as dicyclohcxyl urea, triarylphosphine/dialkylaza-dicarboxylate such as PPh3/DEAD and the like. The reaction may be cmicd out in the presence of solvents such as THF, DME, CH2CI2, CHCI3, 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 100oC, preferably at a temperature in the range of 20oC to 80°C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
Route (13): The reaction of compound of formula (IVd) where all other symbols are as defined earlier with a compound of formula (IVe) where R9 is as defined earlier excluding hydrogen atom and L is a leaving group such as a halogen atom to produce a compound of formula (I) 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', Nail and the like. Phase transfer catalyst such as tetraalkylanrmonium halidcs 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.
The compound of formula (IVd) represents compound of formula (I) where R9 is hydrogen atom, Y is oxygen atom and all other symbols are as defined earlier.
The compound of general formula (IVd) may also be prepared from compound of formula (IVb), described in copending U.S. Application Serial No. 08/982,911 where L2 is a halogen atom by reacting with formamidc in the presence of water. Alternatively, it can be

prepared from (IVa) by heating with aqueous alkali to 20oC to 100-C followed by recsteri-fication of the hydrolysed acid.
Route (14): The reaction of a compound of the general formula (IIIa) as defined above with a compound of formula (IIIc) where R8 is hydrogen and all other syrribols are as defined earlier to produce a compound of formula (I) 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, KOtBu, or NaOEt; metal amides such as LiNHj, 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 25oC may be used. The β-hydroxyaldol 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 reaction proceeds at 25oC. Higher temperature may be employed if the reaction is slow.
Route (15): The reaction of a compound of general formula (IIIf) where all symbols are as defined earlier with a compound of general formula (Illg) where all symbols are as defined earlier and L1 is a leaving group such as halogen atom, β-toluenesulfonate, methane-sulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom, to produce a compound of general formula (I) defined above where the -(CH2)n-0- is attached through nitrogen atom 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 polassiun) hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organo-mctallic 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 (Illf). preferably the amount of base ranges from 1 to 3 equivalents. The reaction may be carried out at a temperature in the range of 0oC to 150°C, preferably at a

temperature in the range of 15'oC to 100oC. The duration of the reaction may range from 0.25 to 24 hours, preferably from 0,25 to 6 hours.
Route (16): The reaction of compound of general formula (IIIi) where all symbols are as defined earlier, with a compound of formula (IIIj) where R14 represents lower alkyl group and all other symbols are as defined earlier to produce a compound of formula (1) wlierc the linker group -(CH2)n-)O- is attached through carbon atom and all other symbols are as defined earlier, may be carried out in neat or in the presence of solvents such as THF, CHCI3, benzene, toluene, hexane, dioxane and the like or mixture thereof. The reaction may be carried out at a temperature in the range of 0°C to 250'oC preferably at a temperature in the range of 10°C to 150°C. The reaction may be carried out in the presence of an acid or a base. The selection of acid or base is not critical The examples of such acids include H2SO4, HCl, pTsOH, PPE (polyphosphoric ethyl ester) and the like. Examples of bases include pyrrolidine, piperidine and the like. 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 0.25 to 24 h preferably, from 1 to 12 h.
The compound of general formula (lIlj), where all the symbols are as defined earlier may be prepared by a process which comprises, reacting a compound of the general formula (IVh)
(R14O)2CR5CH2),7-L1 (IVh)
where R14 is a lower alkyl group and all other symbols are as defined earlier with a compound of general formula (Illd) where R7, R8, R9 , R10 and Ar are as defined earlier.
The reaction of compound of formula (IVh) with compound of formula (Hid) to produce a compound of the formula (llIj) 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 K2CO3, Na2C03 or NaH or mixtures thereof. The reaction temperature may range from 20oC-120oC, preferably at a temperature in the range of 30°C-80oC. The duration of the reaction may range from 1-12 hours, preferably from 2 to 6 hours.

Route (17): The conversion of compound of formula (IVf) where all symbols are defined above to a compound of fonnula (I) may be carried out either in the presence of a base or an acid and the selection of base or acid is not critical. Any base normally used for hydrolysis of nitrile to acid may be employed; 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 oC to reflux temperature of the solvent used, preferably at a temperature in the range of 25oC to reflux temperature of the solvent used. The duration of the reaction may range from 0.25 to 48 hrs.
Route (18): The reaction of a compound of formula (IVg) where R10 is as defined earlier excluding hydrogen atom and all other symbols are as defined earlier with a compound of formula (IVc) where R9 is as defined earlier excluding hydrogen atom 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.
Route (19): The reaction of compound of general formula (Illm), where R7 and R8 arc as defined earlier, and all other symbols are as defined earlier with a compound of general formula (Illn) where R14 represents lower alkyl group and all other symbols are as defined earlier to produce a compound of general fomiula (I), where -(CH2)n-O- linker group is attached through nitrogen atom and all other symbols are as defined earlier may be carried out in neat or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO 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 carried out at a temperature in the range of 50oC to 200°C, preferably at a temperature in the range of 60oC to 180°C. The reaction may be effected in the presence or in absence of a base or an acid. The nature of the base or the acid is not critical. Examples

of such bases include organic bases such as pyridine, lutidine, triethyl amine, diisopropyl-ethyl amine and the like, metal carbonates such as K2CO3, Na2CO3. Examples of acids include organic acids such as AcOH, C2H5COOH, butyric acid, trifluoroacelic acid, β-
toluenesulfonic acid, benzenesulfonic acid and the like, mineral acids such as HCK HBr etc. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours.
The compound of general formula (I) where R10- represents hydrogen atom may be prepared by hydrolysing a compound of formula (I) where R10 represents all groups defined earlier except hydrogen using conventional methods. The hydrolysis may be carried out in the presence of a base such as Na2CO3 and a suitable solvent such as methanol, ethanol and the like or mixtures thereof The reaction may be carried out at a temperature in the range of 20-40°C, preferably at 25-30°C. The reaction time may range from 2 to 12 h, preferably From 4 to 8 h.
The compound of general formula (I) where Y represents oxygen and R10 represents hydrogen or a lower alkyl group may be converted to compound of formula (I), where Y represents NR12 by reaction with appropriate amines of the formula NHR10R12 where R10 and R12 are as defined earlier. Suitably, the compound of formula (I) where YR10 represents OH may be converted to acid halide, preferably YR10 = CI, by reacting with appropriate reagents such as oxalyl chloride, thionyl chloride and the like, followed by treatment with amines of formula NHR10R12 where R10 and R12 are as defined earlier. 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 CHCl3, or CH2Cl2; 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-40oC to 40'oC, preferably at a temperature in the range of 0oC to 20°C. The acid halide or mixed anhydride thus prepared may further be treated with appropriate amines of fonnula NHR10R2 where R10 and R12 are as defined earlier.


cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, hetero-aryloxy, heleroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxy-alkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonyl-amino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substituted aralkyl group, or forms a bond with R8; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group, unsubstituted or substituted aralkyl, or R8 forms a bond together with R7; R9 may be hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkyl aminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom and

a process for its preparation and its use in the preparation of β-aryl-α-substituted hydroxy-alkanoic acids is provided (Scheme-Ill)

The reaction of a compound of formula (Ilia) where all symbols are as defined earlier with a compound of formula (IVi) where R9 is as defined earlier excluding hydrogen and Hal represent a halogen atom such as CI, 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 or K7BuO- 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 cosolvcnt. Inert atmosphere may be employed such as argon and the reaction is more effective under anhydrous conditions. Temperature in the range of-80T to 100-C may be used.
The compound of formula (IVj) where all symbols arc as defined earlier may be converted to a compound of formula (IVk) where R and R represent hydrogen atoms and all other symbols are as defined earlier, by treating with alcohol under anhydrous conditions in the presence of a strong anhydrous acid such as β-toluenesulfonic acid.
The compound of fonnula (IVk) defined above upon treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of formula (IVf) where R and R8 represent hydrogen atoms and all other symbols are as defined earlier.

In still another embodiment of the present invention there is provided the novel intermediate of formula (IVg)

where X represents O or S; the groups R1, R2, R3, R4 and the groups R5 and R6 when attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, hetero-aryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyi, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxy-alkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonyl-amino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R12 and the groups R5 and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy^ hclcrocyclyl, heteroaryl, hcleroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyi, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group; R^^ may be hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aiyl, aralkyl, hcterocyclyl, heteroaryl, or heteroaralkyl groups; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom and a process for its preparation and its use in the preparation of β-aryl-α-substituted hydroxyalkanoic acids is provided.

The compound of fonnula (IVg) where all other symbols are as defined earlier may be prepared by reacting a compound of formula (IVl)

where R8 is hydrogen atom and all olher 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, dioxanc, ether, benzene and the like or a combination thereof.
Temperature in the range of-50-C to 80-C 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 (IVl) may also be prepared by a reaction between (llle) where all
symbols are as defined earlier and a compound of formula (IVm)

where R is hydrogen atom and all other symbols are as defined earlier.
The reaction of compound of formula (Ille) where all symbols are as defined earlier and a compound of formula (IVm) 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, Na2C03 or NaH or mixtures thereof. Acetone may be used as a solvent when
K2CO3 or Na2C03 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.

In yet another embodiment of the present invention there is provided the novel intermediates of formula (IIIm)

where, X represents O or S; the groups R1, R2, R3 and R4 may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl;or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, hclerocyelyl, hctcroaryl, hetcroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxy-alkyl, alkoxyalkyl, aiyloxyalkyl, aralkoxyalkyl, thioalkyl, alkyllhio, alkoxycarbonylamino, aiyloxycarbonylamino, aralkoxycarbonyhuuino, carlioxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O or S ; n is an integer ranging from 1 - 4; Ar represents an or unsubstituted or substituted divalent aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group or R' foi ms a bond with R ; R represents hydrogen atom, hydroxy, alkoxy, halogen,
Q
lower alkyl, acyl group, unsubstituted or substituted aralkyl, or R forms a bond together with
R7; R9 may be hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, ai-yl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heleroaryl, or heteroaralkyl groups; R10 may be hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom and a process for its preparation and its use in the preparation of β-aryl-α-oxysubstituted alkylcarboxylic acids is provided.
The compound of formula (Illm) where all symbols are as defined above may be prepared by reacting a compound of formula (IVn)


The reaction of compound of formula (IVn) where all symbols are as defined earlier with a compound of formula (IVo) where R1, R2, R3, R4, W and X are as defined earlier to produce a compound of formula (Illm) defined earlier may be carried out neat or in the presence of solvents such as xylene, toluene, dioxane, THF, DMF, DMSO, DME and the like or their mixtures. 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 temperature may range
from 0°C-150°C, preferably at a temperature in the range of 0°C-120°C. The duration of the reaction may range from 0.5 to 12 hours, preferably from 0.5 to 6 hours.
The compound of formula (IVn) and its preparartion has been disclosed in our copending application Attorney Docket No. U 011904-5.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (T) whereever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium mcthoxidc, sodium hydride, potassium t-butoxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-bulanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethaminc, 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, β-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, malcic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, bcnzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may be prepared by using rcaclants in their single enantiomeric fonn 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 inchide use of microbial rcsohilion, resolving the diastereomcric salts fotmed 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 l.i mixture of diastereomcric amides by treating with optically active 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 (1) may be prepared by hydrolyzing the pure diastereomcric amide.
Various polymorphs of compound of general formula (1) 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 polymorphs may be dctermined by solid probe NMR spectroscopy, IR spectroscopy, differentia! scanning calorimetry, powder X-ray diffraction or such other techniques.
The compounds of general formula (1) arc useful in the treatment and/or prophylaxis of insulin resistance (type II diabetes), Icptin resistance, impaired glucose tolerance, dyslipidcmia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary hear! 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, hypolipidemic/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/hypolipoproteinemic 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 hypedipidemia such as lovastatin, provastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and their analogs thereof. Suitable fibric acid derivative may be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, bcnzafibrate and their analogs thereof.
The present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I), as defined above, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual phannaceutically employed carriers, diluents and the like.
The pharmaceutical composition may be in the fonns normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, 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 I 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 irritafion of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnonnality, it is essential that the drug be administered parcnlerally. By either route, the dosage is in the range of about 0.01 to about 100 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 dctermine the most suitable dosage.
Suitable phannaceutically 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 or 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 flavourants, 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 pharmaceutically-acceptablc 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 present invention is explained in detail in the examples given which are provided by way of illustration only and therefore should not to be construed to limit the scope of the invention.

To a stirred suspension of sodium hydride (756 mg, 32 mmol, 95%) in dry THF (60 mL) was added a solution of ethyl(diethylphosphono)ethoxyacetate (6.20 g, 23.1 mmol) in THF (20 mL) at 0-5°C dropwise and stirred for 30 min at 5-25°C. To the reaction mixture was added a solution of 4-[(2,2-diethoxy)ethoxy]benzaldehyde (5.0 g, 21.0 mmol) in THF (10 mL) at 25°C and stirred further for 30 min. After completion of the reaction (TLC monitored), THF was removed and the resultant residue was diluted with water (100 mL) and extracted with

clhyl acclatc (3 x 25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (6.5 g, 88%) as a mixture of E/Z isomers.
11 NMR (CDCl,): δ 7.75 (d, J = 8.77 Hz, 2H), 6.96 (s, IH), 6.92 (d, J = 8.77 Hz, 2H), 4.84 0, .1 - 5.12 Hz, IH), 4,29 (q, J - 7.10 Hz, 211), 4.10 - 3.90 (m, 4H), 3.90 - 3.55 (m, 4H), 1.37 (!, .1 - 7.10 Hz, 6H), 1.25 (t, J - 7.03 Hz, 6H).

A mixture of ethyl 2-ethoxy 3-[4-[(2,2-diethoxy)ethoxy]phenyl]-2-propenoate (500 mg, 1.42 mmol) obtained in preparation 1, and magnesium turnings (340 mg, 14.2 mmpl) in methanol (15 mL) was stirred at 45-50°C until the reaction started (as evidenced by hydrogen evolution). On initiation of the reaction, the mixture was stirred at 25°C for a further 2 h. The reaction mixture was added to ice water (15 mL), the pH adjusted to 7.5-8.0 using 10% aqueous hydrochloric acid, and the solution extracted with ethyl acetate (3 x 50 mL), The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% ethyl acetate in pet ether as eluent to afford the title compound (436 mg, 87%). 'H NMR (CDCI3): δ 7.14 (d, J = 8.50 Hz, 2H), 6,84 (d, J = 8.50 Hz, 2H), 4.82 (t, J - 5.15 Hz, IH), 4.05 - 3.92 (m, IH), 3.97 ( d, J - 5.15 Hz, 2H), 3.85 - 3.50 (m, 5H), 3.70 (s, 3H), 3.45 - 3.25 (m, IH), 2.95 (d, J - 6.64 Hz, 2H), 1.25 (t, J = 7.03 Hz, 6H), 1.16 (t, J - 7.0 Hz, 311).


The title compound (2.25 g, 65%) as a mixture of E/Z isomers was obtained from 4-[(2,2-diethoxy)ethoxy]benzaldehyde (2.05 g, 8.63 mmol), ethyl(diethylphosphono) phenoxy-acctate (3.0 g, 9.49 mmol) and NaH (310 mg, 12.94 mmol, 95%) by a similar procedure to that described in preparation 1.
1H NMR (CDCl3): δ 7.50 - 7.20 (m, 5H), 7.15 - 6.95 (m, 2H), 6.95 - 6.70 (m, 3H), 4.90 -4.70 (m, IH), 4.30 - 4.08 (m, 2H), 4.03 (t, J - 6.80 Hz, 2H), 3.90 - 3.50 (m, 4H), 1.30 - 1.10 (m, 9H).

The title compound (1.36 g, 66%) was obtained as a liquid from ethyl 2-phenoxy-3-[4-[(2,2-
diethoxy)ethoxy]phenyl]-2-propenoate (2.05 g, 5.1 mmol) obtained in preparation 3 and
magnesium turnings (1.23 g, 51 mmol) by a similar procedure to that described in
preparation 2.
1H NMR (CDCl3): δ 7.35 - 7.15 (m, 5H), 7.0 - 6.8 (m, 4H), 4.76 (t, J = 5.20 Hz, IH), 3.98
(d, J - 5.2 Hz, 2H), 3.8 - 3.5 (m, 5H), 3J1 (s, 3H), 3T8 (d, J = 6.96 Hz, 2H), 1.24 (t, J = 7.01
Hz,6H).
Example-I

The title compound (4.7 g, 76%) was obtained as a white solid from 4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]benzaldehydc (4.5 g, 15.15 mmol), ethyl(diethyl-phosphono)cthoxy acetate (4.9 g, 18.18 mmol) and NaH (545 mg, 22.73 mmol) by a similar procedure to that described in preparation 1: mp 81-83°C.

1H NMR (CDCI3): δ 7.95 (cl, J - 6.64 Mz, IH), 7.74 (d, J - 8.72 Hz, 2H), 7.44^:1, J - 6.86 Hz, IH), 7,20 - 7.00 (m, 2H), 7.02 - 6.80 (m, 3H), 5.37 (s, 2H), 4.40 - 4.05 (m, 4H), 4.05 -3.80 (m, 4H), 1.50 - 1.20 (m, 6H). Example-2

A solution of ethyl 2-cthoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] ethoxy]phenyl]-2-propenoate (4.5 g, 10.5 mmol) obtained in Example 1, in 1,4-dioxane (50 ml) was reduced with hydrogen in the presence of 10% palladium charcoal (450 mg) at 50-60 psi for 12 h. The reaction mixture was filtered through a bed of celite and the celite bed was washed with 1,4-dioxane. The filtrate was evaporated to dryness under reduced pressure to yield the title compound (3.5 g, 78%): mp 78-80°C.
1H NMR (CDCI3): δ 7.90 (d, J = 7.56 Hz, IH), 7.44 (t, J - 7.05 Hz, IH), 7.26 - 7.07 (m, 3H), 6.97 (d, J - 8.30 Hz, IH), 6.80 (d, J = 8.62 Hz, 2H), 5.37 (s, 2H), 4.21 - 4.11 (m, 4H), 3.98 -3.92 (m, 3H), 3.63 - 3.55 (m, IH), 3.37 - 3.29 (m, IH), 2.93 (d, J = 6.55 Hz, 2H), 1.23 (t, J = 7.10 Hz, 3H), 1.16 (t, J - 7.05 Hz, 3H).

To a stirred solution of ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yI]cthoxy]phenyl]propanoate (3.5 g, 8.5 mmol), obtained in Example 2, in methanol (25 mL) was added a solution of sodium carbonate (4.5 g, 42.5 mmol) in water (25 mL) and stirred for 5 h at 25-30oC. Methanol was removed under reduced pressure and the aqueous layer was

washed with ethyiacetate. The aqueous layer was acidified to pH 2.0 with 2N HCl. The white solid precipitated was filtered and dried to yield the title compound (3.04 g, 93%): mp 103-105°C.
1H NMR (CDCI3): δ 8.05 (d, J = 6.70 Hz, IH), 7.54 (t, J = 7.30 Hz, IH), 7.25 (d, J = 8.20 Hz, 2H), 7.20 (t, J = 7.30 Hz, IH), 7.06 (d, J = 8.20 Hz, IH), 6.90 (d, J = 8.41 Hz, 2H), 5.46 (s, 2 H), 4.27 (t, J = 4.70 Hz, 2H), 4.11-3.90 (ra, IH), 4.05 (t, J = 4.70 Hz, 2H), 3.80 - 3.60 (m, IH), 3.60 - 3.40 (m, IH), 3.14 (dd, J = 14.10 and 4.27 Hz, IH), 3.04 (dd, J = 14.20 and 7.50 Hz, 1H), 1.26 (t, J = 7.07 Hz, 3H).

To a stirred suspension of (+)-2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-
yl]cthoxy]phcnyl]propanoic acid (100 mg, 0.26 mmol), obtained in Example 3 in methanol
(3 ml,) was added a solution of sodium methoxide (54 mg, 1.0 mmol) in methanol (1 mL)
dropwise at 30°C. The reaction mixture was stirred for further 1 h. Diethylether (5 mL) was
added and the white solid precipitated was filtered and dried to afford the title compound (85
mg, 80%): mp 186-188°C.
1H NMR (CDCI3):δ 7.83 (d, J = 7.56 Hz, IH), 7.56 (t, J = 7.68 Hz, IH), 7.21 - 7.07 (m, 4H),
6.84 (d, .1 - 8.39 Hz, 2H), 5.43 (s, 2 H), 4.13 (t, J = 5.19 Hz, 2H), 3.87 (t, J = 5.02 Hz, 2H),
3.62 - 3.48 (m, 2H), 3.12 (t, J - 4.36 Hz, IH), 2.86 (dd, J = 14.12 and 3.32 Hz, IH), 2.61 (dd,
J = 14.12 and 9.04 Hz, IH), 0.98 (t, J = 7.01 Hz, 3H).
Exainple-5
(+)-Ethyl 2-ethoxy-3-{4-{2-[4-oxo-3,4-dlhydro-l,3-benzoxazin-3-yI]ethoxy]phenyIl
propanoate


To a stirred mixture of 3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-l,3-benzoxazine (325 mg, 1.68 mmol) and triphenylphosphine (660 mg, 2.52 mmol) in toluene (10 mL) was added a solution of (+)-clhyl 2-cthoxy-3-(4-hydroxyphenyl)propanoate (400 mg, 1.68 mmol) at 25°C and stirred for 10 min. To the reaction mixture was added diisopropyldiazodi-carboxylate (0.5 niL, 2.52 mmol) at 25-30°C and stirred for further 40 h. Water was added to the reaction mixture and extracted with ethyl acetate (3x10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographcd on silica gel using a gradient of 5-15% ethyl acetate in pet ether as eluent to afford the title compound (527 mg, 76%): mp 76-78°C.[α]D 12.2 (C-0.5, McOH). ^H NMR (CDCI3): 6 7.94 (d, J - 7.8 Hz, III), 7.44 (t, J - 7.72 Hz, IH), 7.17 - 6.95 (m, 6H), 6.79 (d, J - 8.30 Hz, 2H), 5.38 (s, 2H), 4.22 - 4.11 (m, 3H), 3.95 (t, J = 4.61 Hz, 2H), 3.63 -3.55 (m, IH), 3.37 - 3.29 (m, IH), 2.93 (d, .T - 6.64 Hz, 2H), 1.22 (t, J - 7.06 Hz, 3H), 1.15 (t, .1-7.05 Hz, 3H).

The title compound (500 mg, 64%) was obtained from 3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-l,3-benzoxa2ine (364 mg, 1.89 mmol), (-)-ethyl 2-ethoxy-3-(4-hydroxyphenyl) propanoate (450 mg, 1.89 mmol), triphenylphosphine (745 mg, 2.84 mmol) and diisopropyl-diazodicarboxylate (575 mg, 2.84 mmol) by a similar procedure to that described in Example 5: mp 76-78°C.[α]D 25 = -11.96 (C=0.51, MeOH)
1H NMR (CDCI3): 5 7.95 (d, J = 7.75 Hz, IH), 7.43 (t, J = 7,45 Hz, IH), 7.22 - 7.03 (m, 3H), 6.97 (d, J - 7.75 Hz, IH), 6.79 (d, J - 8.63 Hz, 2 H), 5.37 (s, 2H), 4.22 - 4.05 (m, 4H), 4.05 -

3.86 (m, 3H), 3.70 - 3.50 (m, IH), 3.41 - 3.20 (m, IH), 2.93 (d, J - 6.59 Hz, 2H), 1.22 (t, J -7.05 Hz, 3H), 1.15 (t, J - 7.05 Hz, 3H).

To a stirred solution of 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] ethoxy]phcnyl]propanoic acid (500 mg, 1.30 mmol) obtained in Example 3, in dry dichloro-methane (6 mL) was added triethylamine (0.45 |iL, 3.24 mmol) at 0°C, followed by addition of pivaloyl chloride (180 mg, 1.5 mmol) and stirred for 30 min. at the same temperature. To this reaction mixture was added a solution of (S)(+)-2-phenylglycinol (180 mg, 1.3 mmol) in dichloromethane (2 mL) containing triethylamine (037 mL, 2.6 mmol). After stirring for 1 h, dichloromethane (10 mL) was added and the mixture was washed with water, brine, dried over anhydrous Na2SO4 and evaporated. The residue was chromatographed on siHca gel using a gradient of 10-50% ethyl acetate in pet ether as eluent to afford firstly a diastereomer tentatively assigned as [2R,N(1S)] 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-I,3-benzoxazin-3-yljethoxy] phenyl]-N-(2-hydroxy-l-phenylethyl)propanamide (7a) followed by [2S, N(IS)] 2-cthoxy-3-[4-[2-[4-oxo-3,4-'dihydro-l,3-bcnzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-l-phenylethyl)propanamide (7b). Spectral Data for 7a: [α]D 25 = 43.8 (C-0.5, McOH). mp: 64-68°C

1H NMR (CDCl3): δ 7.94 (d, J = 7.80 Hz, IH), 7.44 (t, J = 7.38 Hz, IH), 7.40 - 7.26 (m, 3H), 7.26 - 7.10 (m, 4H), 7.10 - 6.95 (m, 2H)( 6.82 (d, J - 8.40 Hz, 2H), 5.37 (s, 2HX 5.07 - 4.90 (m, IH), 4.20 (t, J - 4.63 Hz, 2H), 4.06-3.90 (m, 3H), 3.69 - 3.65 (m, 2H), 3.48 (q, J - 7.00 Hz, 2H), 3.11 (dd, J - 14.10 and 3.74 Hz, IH), 2.92 (dd, J = 14.10 and 6.23 Hz, IH), 1.14(t, J - 7.00 Hz, 3H).

A solution of [2R, N(1S)] 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-l-phenylethyl)propanamide (1.60 g, 3.17 mmol) obtained in Example 7a, in a mixture of IM sulphuric acid (40 mL) and dioxane/water (1:1, 144 mL) was heated at 100oC for 16 h. The reaction mixture was cooled to 25oC and dioxane was removed under reduced pressure. The remaining aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (950 mg, 78%). Method B
The title compound (116 mg, 83%) was obtained from (+)-ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate (150 mg, 0.36 mmol) obtained in

Example 5, and sodium carbonate (192 mg, 1.8 mmol) by a similar procedure to that described in Example 3: mp 88-90°C.[α]D -= 18.0 (C=0.5, MeOH).
'H NMR (CDCI3): δ 7.90 (d, J = 7.66 Hz, IH), 7.46 (t, J = 7.60 Hz, 1H), 7.17 (d, J = 8.40
Hz, 2H), 7.12 (t, J = 7.60 Hz, IH), 6.98 (d, J = 7.60 Hz, IH), 6.82 (d, J = 8.40 Hz, 2H), 5.38
(s, 2H), 4.19 (t, .T = 4.70 Hz, 2H), 4.04 (dd, J = 7.35 and 4.35 Hz, IH), 3.97 (t, J = 4.70 Hz,
2H). 3.72 - 3.53 (m, IH), 3.53 - 3.38 (m. IH). 3.12 (dd, J= 14.11 and 4.35 Hz, IH), 2.95 (dd,
.1 - 14.11 and 7.35 Hz, IH), 1.17 (t, J = 7.05 Hz, 3H). >

Method A
The title compound (780 mg, 81%) was obtained from [2S, N(1S)] 2-cthoxy-3-[4-[2-[4-oxo-
3,4-dihydro-l,3-bcnzoxazin-3-yl]cthoxy]phcnyl]-N-(2-hydroxy-l-phcnylethyl) propanamide
(1,03 g, 2.5 mmol) obtained in Example 7b, by a similar procedure described in Example 8
Method A.
Method B
The title compound (130 mg, 94%) was obtained from (-)-ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-
dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate (149 mg, 0.36 mmol) obtained in
Example 6, and sodium carbonate (384 mg, 1.8 mmol) by a similar procedure to that
described in Example 3: mp 91-93°C.[α]D 25 = -19.8 (C=0.5, MeOH).
'H NMR (CDCI3):δ 7.96 (d, J = 7.80 Hz, IH), 7.46 (t, J = 7.80 Hz, IH), 7.16 (d, J = 8.45
Hz, 2H), 7.12 (t, J = 7.40 Hz, IH), 6.98 (d, J = 7.40 Hz, IH), 6.82 (d, J = 8.45 Hz, 2H), 5.38
(s, 2H), 4.19 (t, J = 4.75 Hz, 2H), 4.05 (dd, .T = 7.35 and 4.40 Hz, IH), 3.96 (t, J = 4.75 Hz,
2H), 3.70 - 3.50 (m, IH), 3.50 - 3.33 (m, IH), 3.09 (dd, J = 14.11 and 4.40 Hz, IH), 2.95 (dd,
J = 14.11and7.35Hz, IH), l.l8(t,J = 7.0lHz,3H).


The title compound (520 mg, 56%) as a mixture of E/Z isomer was obtained from 4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]benzaldehyde (594 mg, 2.0 mmol), ethyl(diethyl phosphono)phenoxyacetate (695 mg, 2.2 mmol) (J. Org. Chem., 1983, 48, 3407) and sodium hydride(75 mg, 3.0 mmol, 95%) as a base by a similar procedure to that described in preparation 1: mp 104-106°C.
1H NMR (CDCI3): δ 8.05 - 7.90 (m, IH), 7.67 (d, J - 8.60 Hz, IH), 7.60 - 7.20 (m, 5H), 7.20 - 6.95 (m, 4H), 6.95 - 6M (m, 2H), 6.72 (s, IH), 5.39 and 5.35 (s, 2H), 4.40 - 4.08 (m, 4H), 4.08 - 3.90 (m, 2H), 1.20 and 1.07 (t, J - 7.05 Hz, 3H).

To a stirred solution of 2,2-dimcthyl-4-oxo-3,4-dihydro-l,3-benzoxazine (0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g, 3.39 mmol) and stirred for 30 min. To this reaction mixture was added a solution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70 g, 2.03 mmol) (disclosed in U.S. Patent Application Serial No 09/012, 585) in DMF (I mL) and stirred for 24 h at 60-70°C . The reaction mixture was diluted with water and extracted with ethyl acetate (3x10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent to afford the title compound (0.34 g, 45 %) as a liquid.

1H NMR (CDCI3): δ 7.91 (d. J = 7.50 Hz, IH), 7.43 (t, J = 7.50 Hz, IH), 7.15 (d, J = 8.35 Hz, 2H), 7.06 (t, J = 7.50 Hz, IH), 6.89 (d, J = 7.50 Hz. IH), 6.82 (d, J = 8.35 Hz, 2H), 4.28 -4.05 (m, 4H), 4.05 - 3.80 (m, 3H), 3.70 - 3.50 (m, IH), 3.50 - 3.22 (m, IH), 2.93 (d, J = 6.65 Hz, 2H), 1.74 (s, 6H), 1.22 (t, J = 7.05 Hz, 3H), 1.15 (t, J = 6.95 Hz, 3H).

The title compound (105 r»g, 75%) was obtained from (±)-cthyl 2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate (150 mg, 0.34 mmol) obtained in Example 11 and sodium carbonate (180 mg, 1.7 mmol) by a similar procedure to that described in Example 3. mp: 80-82°C.
1H NMR (CDCI3): δ 7.91 (d, .1 = 7.50 Hz, IH), 7.43 (t, J = 7.50 Hz, IH), 7.16 (d, J = 8.40 Hz, 2H), 7.06 (t, J = 7.50 Hz, IH), 6.88 (d, f = 7.50 Hz, IH), 6.84 (d, J = 8.40 Hz, 2H), 4.20 (t, J = 5.30 Hz, 2H), 4.04 (dd, J = 7.25 and 4.25 Hz, IH), 3.91 (t, J - 5.30 Hz, 2H), 3.70-3.35 (m, 2H), 3.08 (dd, J = 14.11 and 4.25 Hz, IH), 2.93 (dd, J = 14.11 and 7.25 Hz, IH), 1.75 (s, 6H), 1.17 (t, J-6.95 Hz, 3H).

To a stirred solution of polyphosphonate ethyl ester (PPE) (3.46 g, 8.0 mmol) in chloroform (10 mL) was added salicylamide (548 mg, 4.0 mmol) followed by addition of a solution of (+)-Methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.28 g, 4.4 mmol)

obtained in preparation 2, in chloroform (10 mL) dropwise at 25-30°C. The reaction mixture was immersed in a preheated oil bath at 70oC and rcfluxed 12 h. The reaction mixture was cooled to room temperature and CHCI3 was removed under reduced pressure. The resultant residue was neutralised (pH = 7.0) with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was chromatographed on silica gel using a gradient of 5-25% of ethyl acetate in pel ether as cluent to afford the title compound (1.15 g, 72%) as a pale yellow liquid.
1H NMR (CDCI3): δ 7.97 (d, J - 7.75 Hz, IH), 7.50 (t, J - 8.50 Hz, Hi), 7.19 (d, J = 8.62 Hz, 2H), 7.15 (t, J = 7.50 Hz, IH), 7.02 (d, J - 8.50 Hz, IH), 6.87 (d, J = 8.62 Hz, 2H), 5.69 (t, .1 - 4.95 Hz, IH), 4.39 (dd, J = 9.64, 4.19Hz, IH), 4.30 • 3.90 (m, 2H), 3.72 (s, 3H), 3.71 -3.50 (m, IH), 3.45 - 3.21 (m, IH), 2.97 (d, J - 6.96 Hz, 2H), 1.17 (t, J = 7.05 Hz, 3H).

The title compound (300 mg, 75%) was obtained from (±)-methyl 2-ethoxy-3-[4-[[4-oxo-3,4-
dihydro-l,3-benzoxazin-2-yl]ethoxy]phenyl]propanoate (432 mg, 1.08 mmol) obtained in
Example 13, and sodium carbonate (318 mg, 3,0 mmol) by a similar procedure to that
described in Example 3, mp : 126-128°C.
1H NMR (CDCl3): δ 7.96 (d, J - 7.80 Hz, IH), 7.50 (t, J - 7.80 Hz, IH), 7.19 (d, J = 8.50
Hz, 2H), 7.12 (t, J = 7.80 Hz, IH), 7.01 (d, J = 7.80 Hz, IH), 6.84 (d, J - 8.50 Hz, 2H), 5.65
(t, J - 5.35 Hz, IH), 4.35 (dd, J = 9.90 and 4.25 Hz, IH), 4.16 (dd, J - 9.60 and 6.60 Hz, IH),
4.07 (t, J - 5.80 Hz, IH), 3.70 - 3.52 (m, IH), 3.52 - 3.40 (m, IH), 3.20 - 2.90 (m, 2H), 1.20
(t, J - 7.05 Hz, 3H).
Examplc-15
(±)-MethyI 2-ethoxy-3-{4-[ [4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxylphenyll


The title compound (900 mg, 62%) was obtained as a liquid from anthranilamide (500 mg, 3.67 mmol), (+)-methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.43 g, 4.0 mmol) obtained in preparation 2 and polyphosphonatc ethyl ester (3.18 g, 7.35 mmol) by a similar procedure to that described in Example 13 .
1H NMR (CDCI3): δ 7.91 (d, J = 7.50 Hz, IH), 7.36 (t, J = 7.50 Hz, IH), 7.19 (d, J = 8.40 Hz, 2H), 6.90 (t, J = 7.50 Hz, IH), 6.85 (d,.! = 8.40 Hz, 2H), 6.72 (d, J = 7.50 Hz, IH), 6,37 (bs, IH, D2O exchangeable), 5.23 (t, J = 5.00Hz, IH), 4.40 - 4.10 (m, 2H), 4.10 - 3.90 (m, IH), 3.74 (s, 3H), 3.70 - 3.52 (m, IH), 3.48 - 3.22 (m, IH), 2.99 (d, J = 6.22 Hz, 2H), 1.19 (t, J = 6.95 Hz, 3H).

The title compound (360 mg, 69%) was obtained from (±)-mcthyl 2-ethoxy-3-[4-[[4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl]methoxy]phenyl]propanoate (560 mg, 1.4 mmol) obtained in Example 15, and sodium carbonate (750 mg, 7.0 mmol) by a similar procedure to that described in Example 3: mp 173°C.
1H NMR (CDCI3+DMSO): 8 7.79 (d, J = 7.50 Hz, IH), 7.44 (bs, IH, D2O exchangeable), 7.27 (t, J - 7.50 Hz, IH), 7.17 (d, J - 8.30 Hz, 2H), 6.81 - 6.69 (m, 4H), 5.87 (bs, IH, D2O exchangeable ), 5.12 (t, J = 5.10Hz, IH), 4.20 - 3.95 (m, 2H), 3.92 (dd, J = 7.80, 4.89 Hz, rill), 3,72 - 3.50 (m, IH), 3.40 - 3.20 (m, IH), 3.10 - 2.80(m, 2H), 1.14 (t, J = 6.95 Hz, 3H).


The title compound (640 mg, 50%) was obtained as a liquid from 5-chloro anthranilamide (500 mg, 2.93 mmol), (±)-methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy] phenyl]propanoate (1.41 g, 3.22 mmol) obtained in preparation 2 and polyphosphonate ethyl ester (2.53 g, 5.86 mmol) by a similar procedure to that described in Example 13.
^11 NMR (CDCI3): 5 7.83 (d, J - 2.26 Hz, IH), 7.23 (t, J = 8.60 Hz JH), 7.13 (d, J = 8.40 Hz, 2H), 6.78 (d, J - 8.40 Hz, 2H), 6.63 (d, J = 8.60 Hz, IH), 5.17 (t, J - 4.70 Hz, IH), 4.75 (bs, IH, D2O exchangeable), 4.11 (t, J - 6.60, IH), 3.99 (q, J - 4.70 Hz, 2H), 3.70 (s, 3H), 3.70 ^ 3.50 (m, IH), 3.40 - 3.20 (m, IH), 2.95 (d, J - 6.60 Hz, 2H), 1.14 (t, J - 6.95 Hz, 3H).

The title compound (140 mg, 73%) was obtained from (±)-methyl 2-cthoxy-3-[4-[[6-chloro-4-0X0-1,2,3,4-tetrahydro-2-quinazolinyl]mcthoxy]phenyl]propanoate (200 mg, 0.46 mmol) obtained in Example 17 and sodium carbonate (245 mg, 2.31 mmol) by a similar procedure to that described in Example 3: mp: 156-158oC.
HI NMR (CDCl3): δ 8.19 (s, IH), 7.25 - 7,05 (m,lH), 7.13 (d, J - 8.30 Hz, 2H), 7.03 (bs, IH, D2O exchangeable), 6.85 - 6.70 (m, IH), 6.78 (d, J = 8.30 Hz, 2H), 5.02 (t, J - 4.90 Hz,

lU), 4.10 - 3.80 (m, 3H), 3.70 - 3.45 (m, IH), 3.45 - 3.20 (m, IH), 3.0 - 2.70 (m, 2\\), 1.08 (t, .) - 6.95 Hz, 311).

The title compound (870 mg, 41%) was obtained as a liquid from N-methyl anthranilamide (765 mg, 5.1 mmol), (±)-methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy] phenyljpropanoate obtained in preparation 2 (2.0 g, 5.6 mmol) and polyphosphonate ethyl ester (4.40 g, 10.2 mmol) by a similar procedure to that described in Example 13: mp 138-140°C. 1H NMR (CDCI3): δ 7.91 (d, J = 7.60 Hz, IH), 7.27 (t, J = 7.60 Hz ,1H), 7.13 (d, J = 8.50 Hz, 2H), 6.86 (t, J = 7.60 Hz, IH), 6.75 (d, J = 8.50 Hz, 2H), 6.65 (d, J = 7.60 Hz, IH), 4.94 (dd, J = 8.50 and 3.25 Hz, IH), 4.82 (bs, IH, D2O exchangeable), 4.11 (t, J = 8.80 Hz, IH), 4.02 - 3.90 (m, 2H), 3.70 (s, 3H), 3.70 - 3.48 (m, IH), 3.42 - 3.25 (m, IH), 3.20 (s, 3H), 2.94 (d, J = 6.13 Hz, 2H), 1.15 (t, J = 7.01 Hz, 3H).

The title compound (64 mg, 72%) was obtained as a liquid from (+)-methyl 2-cthoxy-3-[4-[(3-mcthyl-4-oxo-l,2,3,4-tetrahydro-2-quina7.olinyl]methoxy]phenyl]propanoatc obtained in

Example 19 (100 mg, 0.23 mmol) and sodium carbonate (124 mg, 1.16 mmol) by a similar procedure to that described in Example 3:
1H NMR (CDCl3): δ 7.90 (d, J = 7.50 Hz, IH), 7.26 (t, J = 7.50 Hz ,1H), 7.14 (d, J = 8.40 Hz, 2H), 6.86 (t, J = 7.50 Hz, IH), 6.75 (d, J = 8.40 Hz, 2H), 6.65 (d, J = 7.50 Hz, IH), 4.95 (dd, J = 8.65 and 3.85 Hz, IH), 4.20 - 3.90 (m, 3H), 3.75 - 3.35 (m, 2H), 3.20 (s, 3H), 3.15 -2.80 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H).

The title compound (735 mg, 60%) was obtained as a gummy mass from N-methyl salicylamide (450 mg, 3.0 mmol), {±)-mcthyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl] propanoate obtained in preparation 2 (1.16 g, 3.3 mmol) and polyphosphonate ethyl ester (2.59 g, 6.0 mmol) by a similar procedure to that described in Example 13. 1H NMR (CDCl3): δ 7.93 (d, J = 7.50 Hz, IH), 7.42 (t, J = 7.50 Hz, IH), 7.12 (d, J = 8.40 Hz, 2H), 7.09 (t, J = 7.50 Hz, IH), 6.94 (d, J = 7.50 Hz, IH), 6.75 (d, J = 8.40 Hz, 2H), 5.62 (t, I = 5.50 Hz, IH), 4.25 (dd, .1 = 10.25 and 6.25 Hz, IH), 4.12 (dd, J = 10.25 and 5.25 Hz, 1H), 3.96 (t, .1 - 6.50 Hz, 1H), 3.70 (s, 3H), 3.70 - 3.50 (m, IH), 3.40 - 3.15 (m, IH), 3.22 (s, 3H), 2.93 (d, .1 - 6.50 Hz, 2H), 1.14 (t, J -= 7.05 Hz, 3H).


The title compound (325 mg, 75%) was obtained as a liquid from (±)-mcthyl 2-etlioxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l ,3-benzoxazin-2-yl]methoxy]phenyl]propanoate (472 mg, 1.18 mmol) obtained in Example 21 and sodium carbonate (362 mg, 3.42 mmol) by a similar procedure to that described in Example 3.
1H NMR (CDCl3): δ 7.90 (d, J = 7.50 Hz, IH), 7.40 (t, J = 7.50 Hz ,1H), 7.10 (d, J = 8.40 Hz, 2H), 7.05 (t, J = 7.50 Hz, IH), 6.90 (d, J = 7.50 Hz, IH), 6.75 (d, J = 8.40 Hz, 2H), 5.30 (t, J = 5.50 Hz, IH), 4.20 (dd, J = 9.75, 5.95 Hz, IH), 4.10 (dd, J = 9!75 and 4.95 Hz, IH), 4.01 (t, J = 6.40 Hz,lH), 3.72 - 3.52 (m, IH), 3.42 - 3.20 (m, IH), 3.20 (s, 3H), 3.05 - 2.80 (m, 2H,), 1.15 (t, J = 6.95 Hz, 3H).

The title compound (1.18 g, 54%) was obtained as a cololess liquid from N-ethyl-anlhranilamide (840 mg, 5.1 mmol), (±)-methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy] phcnyllpropanoatc obtained in preparation 2 (2.0 g, 5.6 mmol) and polyphosphonatc ethyl ester (4.40 g, 10.2 mmol) by a similar procedure to that described in Example 13. 1H NMR (CDCl.): δ 7.89 (d, J - 7.50 Hz, IH), 7.25 (t, J = 7.50 Hz ,1H), 7.11 (d, J - 8.40 Hz, 2H), 6.83 (t, J - 7.50 Hz, IH), 6.73 (d, J - 8.40 Hz, 2H), 6.63 (d, J = 7.50 Hz, IH), 4.95 (dd, J = 8.72 and 3.32 Hz, IH), 4.40 - 3.80 (m, 4H), 3.68 (s, 3H), 3.62 - 3.40 (m, IH), 3.40 -3.22 (m, IH), 3.22 - 3.02 (m, IH,), 2.93 (d, J = 6.22 Hz, 2H), 1.28 (t, J - 7.15 Hz, 3H), 1.14 (t, J - 6.95 Hz, 3H). Exaniplc-24
(±)-2-Ethoxy-3-l4-l[3-ethyl-4-oxo-l,2,3,44etrahydro-2-quinazolinyllmethoxy]pbenyl] propanoic acid


The title compound (324 mg, 81%) was obtained as a liquid from (±)-methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-letrahydro-2-quinazolinyl]methoxy]phenyl]propanoate obtained in Example 23 (520 mg, 1.22 mmol) and sodium carbonate (647 mg, 6.1 mmol) by a similar procedure to that described in Example 3.
1H NMR (CDCI3): δ 7.85 (d, J - 7.50 Hz, 1H), 7.20 (t, J = 7.50 Hz ,1H), 7.10 (d, J - 8.40 Hz, 2H), 6.80 (t, .1 = 7.50 Hz, HI), 6,70 (d, .1 = 8.40 Hz, 2H), 6.60 (d, J = 7.50 Hz, IH), 4.90 (dd, .1 = 8.50 and 3.25 Hz, IH), 4.40 - 3.80 (m, 4H), 3.70 - 3.40 (m, IH), 3.40 -3.20 (m, IH), 3.20 - 3.00 (m, IH), 2.90 (d, .1 = 6.20 Hz, 2H), 1.25 (t, J = 7.10 Hz, 3H). 1.14 (t, J = 7.00 Hz, 3H).

The title compound (400 mg, 54%) was obtained as a liquid from N,N'-dimethyl-anthranilamide (295 mg, 1.79 mmol), (±)-methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy] phenyljpropanoate (700 mg, 1.97 mmol), obtained in preparation 2 and polyphosphonate ethylester (1.54 g, 3,58 mmol) by a similar procedure to that described in Example 13. 1H NMR (CDCl3): δ 7.92 (d, J = 7.50 Hz, IH), 7.35 (t, J = 8.30 Hz ,1H), 7.08 (d, J = 8.40 Hz, 2H), 6.82 (t, J = 7.50 Hz, IH), 6.67 (d, J = 8.40 Hz, 2H), 6.61 (d, J - 8.30 Hz, IH), 4.85 (d, J = 5.80 Hz, IH), 4.29 - 3.90 (m, 3H), 3.70 - 3.50 (m, IH), 3.67 (s, 3H), 3.40 - 3.20 (m, IH), 3.22 (s, 3H), 3.10 (s, 3M), 2.90 (d, J = 6.55 Hz, 2H), 1.12 (t, J = 6.97 Hz, 3H).


The title compound (103 mg, 72%) was obtained as a liquid from (±)-methyl 2-ethoxy-3-[4-[[l,3-dimethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyl] propanoate (150 mg, 0.36 mmol), obtained in Example 25 and sodium carbonate (192 mg, 1.81 mmol) by a similar procedure to that described in Example 3.
1H NMR (CDCI3): δ 7,90 (d, J = 7.50 Hz, IH), 7.30 (t, J = 8.30 Hz , IH), 7.05 (d, J - 8.40 Hz, 2H), 6.80 (t, J = 7.50 Hz, IH), 6.60 (d, J - 8.40 Hz, 2H), 6.60 (d, J = 8.30 Hz, IH), 4.80 (t, J = 5.80 Hz, IH), 4.30 - 3.90 (m, 3H), 3.70 - 3.50 (m, IH), 3.40 - 3.20 (m, IH), 3.20 (s, 3H), 3.10 (s, 3H,), 2.90 (d, J = 6.50 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H).

1.47 mmol), (±)-methyl 2-phenoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (650 mg, 1.61 mmol) obtained in preparation 4 and polyphosphonate ethyl estei- (1.27 g, 2.94 mmol) by a similar procedure to that described in Example 13.
1H NMR (CDCl3): δ 7.90 (d, J = 7.75 Hz, IH), 7.34 (t, J = 7.75 Hz ,1H), 7.35 - 7.15 (m, 3H), 7.23 (d, J = 8.40 Hz, 2H), 6,96 (t, J = 7.80 Hz, IH), 6.90 - 6,80 (m, 2H), 6.83 (d, J - 8.40 Hz, 2H), 6.69 (d, J - 7.80 Hz, IH), 6.55 (bs, IH, D2O exchangeable), 5.20 (t, J = 6.50 Hz, IH),

4.76 (t, J = 6.40 Hz, IH), 4.65 (bs, IH, D2O exchangeable), 4.20 (dd, J = 8.90 and 7.15 Hz, IH), 4.01 (dd, J = 8.90 and 5.15 Hz, IH), 3.72 (s, 3H), 3.19 (d, J = 6.40 Hz, 2H).

The title compound (488 nig, 86%) was obtained as a white solid from (±)-methyl 2-phenoxy-3-[4-[[4-oxo-l ,2,3,4-tctrahydro-2-quinazolinyl]methoxy]phenyl]propanoate (611 mg, 1.14 mmol) obtained in Example 27 and sodium carbonate (726 mg, 6.84 mmol) by a similar procedure to that described in Example 3, m.p: 78-80°C.
1H NMR (CDCl3): δ 7.94 (bs, IH, D2O exchangeable ), 7.83 (d, J = 7.38 Hz ,1H), 7.40 -7.15 (m, 5H), 6.98 (t, J = 7.38 Hz, IH), 6.92 (d, J = 8.30 Hz, 2H), 6.84 (t, J = 8.40 Hz, IH), 6.72 (d, J = 8.30 Hz, 2H), 6.63 (d, J = 8.40 Hz, IH), 4.98 (t, J = 5.10 Hz, IH), 4.89 (t, J= 5.30 Hz, IH), 3.94 (dd, J = 8.90 and 7.15 Hz, IH). 3.70 (dd, J = 8.90 and 4.05 Hz, IH), 3.26 (d, J = 5.30 Hz, 2H).

(368 mg, 2.15 mmol), (±)-methyl 2-phenoxy-3-[4-[(2,2-diethoxy) ethoxy] phenyljpropanoate (954 mg, 2.37 mmol) obtained in preparation 4 and polyphosphonate ethyl ether (1.864 mg, 4.3 mmol) by a similar procedure to that described in Example 13.


u The title compound (300 mg, 65%) was obtained from (±) methyl 2-phenoxy-3-[4-[[6-
chloro-4-oxo-l,2,3,44ctrahydro-2-quinazo1inyl]methoxy]phcnyl]propanoatc (488 nig, 1,01
mmol) obtained in Example 29 and sodium carbonate (530 mg, 5.08 mmo!) by a similar
procedure to that described in Example 3: mp: 54-56°C 1H NMR (CDCb): S 7.80 (s,
1H), 7.31 - 7.18 (m, 5H), 6.99 (d, J - 7.47 H/,, IH), 6.90 (d, J - 8.3 Hz, 2H), 6.73 (d, J - 8.54
H/,, 2H), 6.58 (d, J - 7.88 Hz, IH), 5.02 (bs, IH), 4,89 (t, J - 4.98 Hz, IH), 4.01 - 3.91 (m,
IH), 3.78 - 3.66 (m, IH), 3.25 (d, J - 5.30 Hz, 2H).

nitro-4-oxo-3,4-dihydro-l,3-bcnzoxazine (200 mg, 0.84 mmol), (±)-ethyl 2-ethoxy~3-(4-hydroxyphcnyl)propanoate (200 mg, 0.84 mmol), triphenylphosphine (330 mg, 1.26 mol) and diisopropyldiazodicarboxylate (255 mg, 1.26 mmol) by a similar procedure to that described in Example 5.


T})c title compound (226 mg, 63%) was obtained from (±)-ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate (339 mg, 0.74 mmol) obtained in Example 31 and sodium carbonate (392 mg, 3.70 mmol) by a similar procedure to that described in Example 3: mp: 110oC
1H NMR (CDCl3): δ 8.87 (s, IK), 8.40 - 8.31 (m, 1H), 7,31 - 7.10 (m, 3H), 6.81 (d, J - 8,40 M/, 2H), 5.50 (s, 2H), 4.21 (t, J - 4.56 Hz, 2H), 4.11 - 3.98 (m, 3H), 3.70 ^ 3.39 (m, 2H), 3.16 - 2.90 (m, 2H), 1.19 (t, J - 6.98 Hz, 311).

acetyl-4-oxo-3,4-dihydro-l,3-benzoxazinc (200 mg, 0.85 mmol), (±)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (202 mg, 0.85 mmol), triphenylphosphine (334 mg, 1.27 mmol) and diisopropyldiazodicarboxylate (258 mg, 1,27 mmol) by a similar procedure to that described in Example 5.
1H NMR (CDCl3): δ 8.51 (s, IH), 8.08 (d, J - 6.41 Hz, IH), 7.13 (d, J = 8.63 Hz, 2H), 7.02 (d, J - 8.72 Hz, IH), 6.77 (d, J - 8.63 Hz, 2H), 5.41 (s, 2H), 4.28 - 4.08 (m, 5H), 3.93 (t, J =

4.86 Hz, 2H), 3.65 - 3.49 (m, IH), 3.41 - 3.21 (m, IH), 2.92 (d, J=-6.64 Hz, 2H), 2.59{s, 3H), 1.39-1.10 (m,6H).

The title compound (120 mg, 84%) was obtained as a liquid from (±)-ethyl 2-cthoxy-3-[4-[2-
[6-acetyl-4-oxo-3,4-dihydro-l,3-bcnzoxazin-3-yl]ethoxy]phcnyl]propanoate (152 mg, 0.33 mmol) obtained in Example 33 and sodium carbonate (177 mg, 1.67 mmol) by a similar procedure to that described in Example 3.
1H NMR (CDCl3): δ 8.53 (s, IH), 8.11 (d, J - 6.50 Hz, IH), 7.16 (d, J - 8.40 Hz, 2H), 7.04 (d, J - 8.72 Hz, IH), 6.80 (d, J - 8.40 Hz, 2H), 5.40 (s, 2H), 4.16 (t, J - 4.31 Hz, 2H), 3.91 -4.04 (m, 3H), 3.70 - 3.51 (m, IH), 3.50 - 3.31 (m, IH), 3.12 - 2.88 (m, 2H), 2.61 (s, 3H), 1.16 (t, J - 6.84 Hz, 3H).
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 hPPARa activity
Ligand binding domain of hPPARcx was fused to DNA binding domain of Yeast
transcription factor GAL4 in eucaryotic expression vector. Using superfect (Qiagen,
Germany) as transfeeting 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 hrs of transfcction 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 HoUis. Gene. 1992. 118 : 137 -141; Superfect Transfection Rcagcnt Handbook. February, 1997. Qiagen, Germany).
b) Determination of hPPARY,activity
Ligand binding domain of hPPARyl was fused to DNA binding domain of Yeast transcription factor GAL4 in cncaryofic expression vector. Using lipofectaminc (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 PPARyl was measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118:137-141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL,

Liver microsome bound reductase was prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays were carried out in 100 mM KH2PO4, 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.


such as db/db and ob/ob (Diabetes, (1982) 31(l):l-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 arc 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 0.001 mg to 30 mg/kg through oral gavage daily for 6 days. Tlie 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 (100μl) through orbital sinus, using hcparinised capillary in tubes containing EDTA which was centrifugcd to obtain plasma. The plasma glucose and triglyceride levels were measured spcctromctrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase enzyme (Dr. Rcddy'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 fonnula described below.
No adverse effects were observed for any of the mentioned compounds of invention



The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Dcmark and were used at 8 weeks of age. Zuckcr fa/fa falty 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+l°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 lubes. 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, Hyderabad, India). The plasma free fatty
acid was measured using a commercial kit form 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. ,
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, Zuckcr fa/fa rats suggestthat
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, hypcrlipidaemia 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) Choiesteroi 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±rC. Rats of 180-200 gram body weight range were used for the experiment. Animals were made hypercholesterolcmic 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., Key, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in nonno- 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 hcparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, IfDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Rcddy'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.


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 ± PC. Animals were given standard laboratory chow (NTN, Hyderabad, India) and water, ad libitum. SAM of 20-25 g body weight range and Guinea pigs of 500-700g body weight range were used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V., Sauzicres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in nomial and hypcrlipidcmic 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% Carboxy-mcthylcellulose; 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% Carboxymcthylccllulose; 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 hepariniscd capillary in EDTA containing tubes. After ccntrifugation, plasma sample was separated for triglyceride and total cholesterol (Wicland, O. Methods of Enzymatic analysis. Bergcrmeyer, H. O., Ed., 1963. 211 -• 214; Trinder, P. Ann. Clin. Biochcm. 1969. 6:24-27). Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, Hyderabad, India).

Formulae for calculation :
1. Percent reduction in Blood sugar / triglycerides / total cholesterol were calculated according to the formula:


OC = Zero day control group value OT = Zero day treated group value rC = Test day control group value TT == Test day treated group value

VLDL cholesterol in mg/dl - [Total cholesterol - HDL cholesterol - LDL cholesterol] mg/dl
4




C L A I M S
1. A compound of formula (I)

carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, hetero-aralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkyl amino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or di alkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents or unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or subvStitutcd aralkyl group or forms a bond with R ; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl, or R8 forms a bond together with R7; R9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl.

alkoxyalkyl, aryloxyalkyi, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralky!, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygen or NR12, where R'12 represents hydrogen, or unsubstituted or substituted alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 and R12 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may or unsubstituted or substituted contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom.
2. A compound of the formula (I) according to claim 1, wherein the groups represented by R1-R4 and the groups R7 and R8 when attached to carbon atom are substituted, the substituents are selected from halogen, hydroxy, or nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
3. A compound of the formula (1) according to claims 1 or 2, wherein the groups R^and R6 when attached to nitrogen are substituted, substituents are selected from halogen such as fluorine, chlorine; hydroxy, acyl, acyloxy, or amino groups.
4. A compound of the fonnula (1) according to claim 1, 2 or 3, wherein the group Ar includes substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, a7.aindolinyl, indcnyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, or pyrazolyl.
5. A compound of the formula (I) according to claim 1, 2, 3 or 4, wherein the substituents on the group represented by R9 are selected from halogen, hydroxy, formyl or nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkyl-

amino, alkoxyalkyl, alkyllhio, thioalky! groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives .

carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyi, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy-carbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acyl-amino, aralkylamino, aminoalkyl, hydroxyalkyi, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyi, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyi, amino, acylamino, alkylamino which may be mono or di alkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R together with R forms a bond; R represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyi, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arvlaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents

hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygen; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom, which comprises:


where R8 is hydrogen and all other symbols are as defined above to yield a compound of formula (I) as defined above after dehydration;


where R7 and R8 together represent a bond, 1.' is a leaving group to produce a compound of formula (1) defined above where (he hnkcr group "(CH2)n-O- is attached to nitrogen atom;

where R7 and R8 together represent a bond, R14 represents lower alkyl group and all other symbols are as defined above, to produce a compound of formula (I) defined above, where the linker group -(CH2)n-O- is attached to carbon atom;
h) reacting a compound of formula (IIIk)


where R9 = R10 and arc as defined above excluding hydrogen to produce a compound of the formula (I);
(i) reacting a compound of formula (Illm) where R7, R8 together represent a bond and all other symbols are as defined above

where R14 represents lower alkyl group and all other symbols are as defined above, to produce a compound of formula (I) defined above, where the linker group -(CH2)n-O- is attached to nitrogen atom; and
j) optionally converting the compounds of formula (1) 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)


carbon atom may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, fonnyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be amino or dialkyl group, arylamino, acylamino, aralkylaniino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylaniino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubbstituted or vSubstitutcd divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl; R9 represents hydrogen or or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, aikoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroalkyl groups R10 represents hydrogen or or unsubstituted

or substituted groups selected from alkyl. cycloalkyl, aryl, aralkyl, heterocyclyl, hetcroaryl, or heteroaralkyl groups; Y represents oxygen; the linking group represented by -(CH2)n-O-may be attached either through nitrogen atom or carbon atom, which comprises:

Y represents an oxygen atom and all other symbols are as defined above, to yield a compound of the formula (I) where R and R each represent hydrogen atom and all symbols are as dcffined above;

aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino-carbonyl, arylaminocarbonyi, acyl, heterocyclyl, hetcroaryl, or heteroaralkyl groups defined above;



otlter symbols are as defined above with a compound of formula (IVc)
R9-L2 (IVe)
where R9 represents or unsubstituted or substituted groups selected from alkyl, cycloalkyl,
ary'l, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, acyl, hetcrocyclyl, hctcroaryl, or hetcroaralkyl
groups and L2 is a halogen atom to produce a compound of formula (I) defined above;
f) reacting a compound of the formula (ITIa)


where L1 is a leaving group, and all other symbols are as defined above to produce a compound of formula (I) defined above, where the linker group -(CH2)n-O- is attached to nitrogen atom;


where all symbols are as defined above with a compound of general formula (IIIj)

where R14 represents a lower alkyl group, and all other symbols are as defined above, to produce a compound of formula (I) defined above, where the linker group -(CH2)n-O- is
attached to carbon atom;

i) converting a compound of formula (IV f)

where R9 is as defined above to produce a compound of formula (I), optionally;
(k) reacting a compound of formula (Illm) where all symbols are as defined
above


with a compound of formula (Illn)

where R14 represents lower alky! group and all other symbols are as defined above, to produce a compound of formula (I) defined above, where the linker group -(CH2)n-O- is attached to nitrogen atom;
1) resolving the compound of formula (I) obtained in any of the processes
described above into its stereoisomers, and optionally;
m) converting the compounds of formula (I) or its stereoisomers obtained in any
of the processes described above into pharmaccutically acceptable salts or pharmaceutically
acceptable solvates.
8. A process for the preparation of compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmcetically acceptable salts, or its pharmaceutically acceptable solvates, wherein X represents O or S; the groups R1, R2, R3, R4 and the groups R5 and R6 when attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, hctcroaryl, hctcroaryloxy, hcteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy-carbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxy-alkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxy-

carbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstituted or siibsliluted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, hcteroaryl, heteroaryloxy, hcteroaralkyl, heteroaralkoxy, acyi, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxy alkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubslituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogcn atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group or forms a bond with R8 ; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubslituted or substituted aralkyl, or R forms a bond together with R7 ; R9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkyl-aminocarbonyl, aiylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or hcteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or hcteroaralkyl groups; Y represents NR12, where R12 represents hydrogen or unsubstituted or substituted, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or h2teroaralkyl groups; R10 and R11 together may fonn a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may or unsubstituted or substituted contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; the Unking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom, which comprises :
>

where all symbols arc as defined above and Y represents oxygen, and R10 represents hydrogen or a lower alkyl group or 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 carhcr and, optionally;
b) resolving the compound of formula (J) obtained above into stereoisomers, and optionally;
e) eonvcrting the eompounds of formula (I) obtained above into pharma-ceutically acceptable salts or pharmaccutically acceptable solvates.

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymophs, or its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, where X represents O or S; the groups R1, R2, R3 R4 and the groups R5 and R6 when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, eycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy-carbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acyl-amino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxyearbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5, R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or or unsubstituted or substituted groups selected from alkyl, eycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl.

aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R7 together with R8 forms a bond; R'9 represents hydrogen or or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from atkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygen; the linking group represented by -(CH2),-O- may be attached either through nitrogen atom or carbon atom, prepared according to the process of claim 6.

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaccutically acceptable salts, or its pharmaceutically acceptable solvates, wherein X represents O or S; the groups R1, R2, R3 R4 and the groups R5 and R6 when attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, fonnyl; or unsubstituted or substituted groups selected from atkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11 R11 and the groups R5 and R6 when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino.

acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbony), aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl; R9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino-carbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygen; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom, prepared according to the process of claim 7.

pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein X represents O or S; the groups R1, R2, R3,R4 and the groups R5 and R6 when attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino, arylamino, acylamino, aralkyl-amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11;

R4 and the groups R5 and R6 when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alky!, cycloalkyl, alkoxy, eycloalkoxy, atyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, hctero-aryl, hetcroaryloxy, heteroaralkyl, hc(eroaraIkoxy, acyl, acyloxy, hydroxyalkyl, amino, acyhimino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyi, alkoxycarbonyl, aryloxycarhonyl, aralkoxycarbonyl, aikoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkyUhio, thioalkyl, carboxyUc acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R' represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group or forms a bond with R8; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl, or R5 forms a bond together with R7'; R^9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, eyeloalkyl, aryl, aralkyl, aikoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarhonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, hetcroaryl, or heteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycIoalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents NR'12, where R13 represents hydrogen or unsubstituted or substituted groups selected from, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 and R12 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may or unsubstituted or substituted contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom, prepared according to the process of claim 8.

represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted

groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, araJkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyj, hydroxy-alkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyi, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O or S ; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or
substituted aralkyl group or forms a bond with R8 ; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl, or R forms a bond together with R ; R represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; and the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom.
13. A process for the preparation of compound of formula (Illm) as defined in claim 12, which comprises reacting a compound of formula (IVn)

89


to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy-carbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxy-alkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonyl-amino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents 0, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or di alkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxy alkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group or forms a bond with R8; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substituted aralkyl or R8 forms a bond together with R7; R9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino-carbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; and the linking group represented by -(CH2)n-O- may be attached either tluough nitrogen atom or carbon
atom

15. A process for the preparation of compound of formula (IVf) defined in claim 14,
where R and R represent hydrogen atoms and all other symbols are as defined in claim 14 which comprises:

where R^ represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, hcterocyclyl, heteroaryl, or heteroaralkyi groups and Hal represents a halogen atom, to yield a compound of formula (IVj)

c) reacting a compound of fonnula (IVj) obtained above where all symbols arc as defined above with trialkylsiiyl cyanide to produce a compound of formula (IVf) where all symbols are as defined above.
16. An intermediate of fonnula (IVg)

n
attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, fomiyl; or unsubstitutcd or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, hctcroaryl, hetcroaryloxy, heteroaralkyl, hcteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxy-carbonyl, aralkoxycarbonyl, cimino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarhonylamino, aryloxycarbonylamino, aralkoxy-carbonylamino, carboxyHc acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR*'; R*' and the groups R^ and R^' when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstitutcd or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, ar>'loxy, aralkoxy, heterocyclyl, hetcroaryl, hcteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,.carboxyHc acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstitutcd or substituted divalent aromatic or heterocyclic group; R^ represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstitutcd or substituted aralkyl group; R*^ represents hydrogen or unsubstitutcd or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, hetcroaryl, or heteroaralkyl groups; and the linking group represented by -(CH2)n-0- may be attached either through nitrogen atom or carbon atom. 17. A process for the preparation of compound of formula (IVg)


attached to carbon atom may be the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl; or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, alkoxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heleroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxy-carbonyl, aralkoxycarbonyl, amino, alkylamino which may be mono or dialkylamino group, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyi, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxy-carbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R6 when attached to nitrogen atom may be same or different and represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino which may be mono or dialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyi, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; Ar represents an unsubstituted or substituted divalent aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkyl group; R10 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, atyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; and the linking group represented by -(CH2)n-O- may be attached either through nitrogen atom or carbon atom, which comprises:
a) reacting a compound of formula (IIIe)


b) reacting the compound of formula (IVl) obtained above with an appropriate clia/,otizing agent. 18. A compound according to claim 1 which is selected from :
Ethyl 2-cthoxy-3--[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]cthoxy]phenyl]-2-propcnoatc;
(±)-Ethyl 2-ethoxy"3-|4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl] propanoate;
(+)-Ethyl 2-cthoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl]
propanoate;
(-)-Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl] propanoate;
(±)-2-Elhoxy-3-[4-[2-[4-oxo-3,4-dihydro 1,3 benzoxazin-3-yl]ethoxy]phenyl] propanoic acid and its salts;

[2R, N(1S)] 2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]-N-(2-hydroxy-1 -phenylethyl)propanamide;
[2S, N(1S)] 2-Ethoxy-3-[4-[2-.[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]-N-(2-hydroxy-1 -phenylethyl)propanamide;
(+)'-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]
propanoic acid and its salts;
(-)-2-Ethoxy'3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]
propanoic acid and its salts;
(±)-Ethyl 2-phenoxy-3-[4-[2-[4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl] -2-propenoate;
(±)-Ethy1 2-cthoxy-3-[4-[2-[2,2-dimethyi-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] clhoxy]phcnyl]propanoatc;
(+)-.Ethyi 2-cthoxy-3-[4-[2-[2,2-dimcthyl-4-oxo-3,4-dihydro-l,3-bcnzoxazin-3-yl] cllioxyjphcnyljpropanoate;
(-)-Ethyl 2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] cthoxyjphcnyljpropanoate;
(±)-2-Ethoxy-3-[4-[2'(2,2-'dimethyl-4"Oxo-3,4-dihydro-l,3-benzoxazin-3-yl] ethoxy] phcnyljpropanoic acid and its saltvS;
(+)-2-Efhoxy-3-[4-[2'|2,2'd!nicthyl--4~oxo-3,4-dihydro-l,3-benzoxazin-3-yl]elhoxy] phcnyljpropanoic (-)-2-Ethoxy-3-[4"[2-[2,2-diniethyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]cthoxy]
phcnyljpropanoic acid and its salts;
(±)-Mclhy] 2-cthoxy-3-[4~[[4-oxo-3,4-dihydro-l,3-bcnzoxazin-2-yl]methoxy] phenyl]
propanoalc;
(+)-MethyI 2-clhoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]phenyl]
propanoate;
(-)-Methyl 2-cthoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]phenyl]
propanoalc;
(±)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]phenyl]
propanoic acid and its salts;

1
(+)-2-Elhoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxa2in-2-yl]niethoxy]phenyl] propanoic acid and its salts;
(-)-2"Ethoxy-3-[4-[[4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxy]phenyl] propanoic acid and its salts;
(±)-Metliyl 2-e{hoxy-3-[44[4-oxo-1,23,4-tetrahydro-2-quinazolinyl]methoxy]phenyl] propanoaic;
(+)-Methyl 2-cthoxy-344-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]nicthoxy]phenyl] propanoatc;
(-)-Mclhyl 2-cthoxy-3-[44 [4-0X0-l,2,3,4-tctrahydro-2-quinazoIinyl]mcthoxy] phenyljpropanoalc;
(±)-2-Elhoxy-3-[4-[[4-oxo-l,2,3,4-tclrahydro-2-quinazolinyl]niethoxy]phenyl] propanoic acid;
(+)-2-Ethoxy-3-[4-[[4'-oxo-l,2,3,4-te(rahydro-2-quinazolinyl]niethoxy]phcnyl] propanoic acid;
(-)-2-Ethoxy-3-[4-[[4-oxo-l,2,3,4-tctrahydro-2-quinazolinyl]methoxy]phenyl] propanoic acid;
(±)-Mclhyl 2-ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
mcthoxy]phenyl]propanoatc;
(+)-Methyl 2-cthoxy-3-[4-[[6-chIoro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
nicthoxyjphenyl] propanoatc;
(-)-Methyl 2-ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxyjphenyl] propanoatc;
(±)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phenyl]propanoic acid and its salts;
(+)-2-Ethoxy-3-[4-[[6"Chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy]
phenyljpropanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetraliydro-2-qiunazolinyl] methoxy]
phenyljpropanoic acid and its salts;
(±)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxy]phenyl]propanoate;

(4-).Methyl 2-ethoxy-3"[4-[[3-methyl-4-oxO"l,2,3,4-tetrahydro-2-quinazoHnyl]
methoxyjphenyljpropanoate;
(-)-Methyl 2-ethoxy-3-[4-[[3-methyI-4-oxo^l,2,3,4-tetrahydro-2-quinazolinyl]
methoxyjphenyljpropanoate;
(±)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-ben20xazin-2-yl]
methoxyjphenyljpropanoate;
(4-)-Methyl 2-ethoxy'3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]
methoxyjphenyljpropanoate;
(-)-Methyl 2-ethoxy-'3-[4-[[3-methyl-4-oxo-3,4-dihydro-l,3-ben2oxazin-2-ylJ
methoxyjphenyljpropanoate;
(±)-2-Ethoxy-3-[4-[[3-melhyl-4-oxo-3,4-dihydro-l,3-benzoxazin-2-ylJ methoxyj
phcnyljpropanoic acid and its salts;
(4-)-2-Ethoxy-3-[4-[[3-methyl-4-oxO"3,4-dihydro-l,3-henzoxazin-2-ylJmethoxyJ phenyl] propanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[[3-melhyl~4-oxo-3,4-dihydro-l,3-benzoxazin-2-yl]methoxyJ phenyl] propanoic acid and its salts;
(±)-Mcthyl 2~cthoxy-3-[4-[[3-cthyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxyjphenyljpropanoate;
(+)~-Methyl 2-cthoxy-3-[4-[[3-cthyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl]
methoxyjphenyljpropanoate;
(-)-Methyl 2-cthoxy-3-[4-[[3-ethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinylJ
methoxyjphenyljpropanoate;
(±)-2-Ethoxy-3-[4-[[3-cthyl-4~oxo-l,2,3,4-tetrahydro-2-quinazolinyl]methoxyJ phcnyljpropanoic acid and its salts;
(+)-2-Ethoxy-3-[4-{[3-ethyl-4-oxo-K2,3,4-tetrahydro-2-quinazolinylJmethoxy] phcnyljpropanoic acid and its salts;
(-)-2-Ethoxy-3-[4-[[3-cthyl-4-oxo-l,2,3,4-tetrahydro-2-quinazolinylJmethoxy] phcnyljpropanoic acid and its salts;
(±)-Methyl 2-ethoxy-3-[4-[[l,3-dimethyl-4-oxo-l,2,3,4-tetrahydro-2-quinazo1inylJ methoxyjphenyljpropanoate;



(4-)-2-Phenoxy-3-[4-[I6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy] phenyijpropanoic acid and its salts;
(-)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-l,2,3,4-tetrahydro-2-quinazolinyl] methoxy] phenyl]propanoic acid and its salts; (±)-Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl] ethoxy] phenyljpropanoate;
(-f-)-Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyl]propanoatc;
(-^Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyljpropanoate;
(±)-2-Ethoxy-3-[4-[2-[6-nilro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy] phenyijpropanoic acid and its salts;
(+)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]phenyl] propanoic acid and its sails;
(-)-2-Ethoxy-3-[4-[2-[6-nilro-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yI]ethoxy]phenyl] propanoic acid and its salts;
(±)-Ethyl 2-cthoxy-3--|4-[2-[6-acclyl-4-oxo-3,4-dihydro-K3-bcnzoxazin-3-yl]c(hoxy]
phcnyl]propanoatc;
(4-)-Elhyl 2~ethoxy-3-"[4-t2-[6-acctyl-4-oxo-3,4-dihydro-l,3"henzoxazin-3-yl]ethoxy]
phenyljpropanoate;
(-)-Ethyl 2-ethoxy-3 i4-[2-[6-acelyl-4-oxo-3,4-dihydro-U3-benzoxazin-3-yl]elhoxy]
phenyljpropanoate;
(±)-2-Ethoxy-3-[4-[2-|6-acctyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]elhoxy]
phenyijpropanoic acid and its salts;
(-f)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-l,3-benzoxazin-3-yl]ethoxy]
phenyijpropanoic acid and its salts; and
(-)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-13-benzoxazin-3-yl]ethoxy]
phenyijpropanoic acid and its salts;
19, A pharmaceutical composition which comprises a compound of formula (I)


diluent, excipient or solvate.
20. A pharmaceutical composition as claimed in claim 19, in the form of a tablet, capsule, powder, syrup, solution or suspension.
21. A method of preventing or trcatit\g hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering an effective amount compound of formula (I) as defined in any one of claims 1-5, 9-11 or 18 or a pharmaceutical composition as claimed in claims 19 and , 20 to a patient in need thereof
22. A method according to claim 21, wherein the disease is type II diabetes, impaired
glucose tolerance, dyslipidacmia, disorders related to Syndrome X such as hypertension,
obesity, atherosclerosis, hyperipidcmia, coronary artery disease and other cardiovascular
disorders, certain renal diseases including glomerulonephritis, glomcrulosclerosis, 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 or cancer.
23. A method according to claim 22, for the treatment prophylaxis of disorders related to
Syndrome X, which comprises administering an agonist of PPARa, PPARy or a mixture
thereof of formula (I).
24. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or
free fatty acids in the plasma comprising administering a compound of formula (I) as defined
in any one of claimsl-5, 9-11 or 18 or a pharmaceutical composition as claimed in claims 19
and 20 to a patient in need thereof

25. A method of preventing or treating hyperhpcmia, 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 18 or a pharmaceutical composition as claimed in claims 19 and 20 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 syncrgcstically together to a patient in need thereof.
26. A method according to claim 25, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidacmia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hypcrlipidcmia, 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 or cancer.
27. A method according to claim 26 for the treatment or prevention of disorders related to Syndrome X, which comprises administering a compound of formula (I) in combination 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.
28. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or fi-ee fatty acids in the plasma , which comprises administering a compound of formula (I) claimed in in any one of claims 1-5, 9-11 or 18 or a pharmaceutical composition as claimed in claims 19 and 20 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.
29. Use of a compound according to any one of claim 1-5,9-11 or 18 for 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.
30. Use according to claim 29, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hypcrlipidemia, 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 or cancer.
31. Use of a compound according to any one of claims 1-5, 9-11 or 18 for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma.
32. Use of a compound according to any one of claim 1-5, 9-11 or 18 for preparing a
medicament for 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.
33. Use according to claim 32, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hypcrlipidemia, 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 or cancer.
34. Use of a compound according to any one of claims 1-5, 9-11 or 18 for preparing a medicament for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or
free fatty acids in the plasma.

35. A medicine for 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 an effective amount compound of formula (I) as defined in any one of claims 1-5, 9-11 or 18 to a patient in need thereof
36. A medicine according to claim 35, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, 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 or cancer.
37. A method according to claim 27, for the treatment or prophylaxis of disorders related to Syndrome X, which comprises administering an agonist of PPARa, agonist of PPARy or a mixture thereof of formula (I).
38. A medicine for reducing plasma glucose, triglycerides, totalcholesterol, LDL, VLDL and free fatty acids in the plasma comprising administering a compound of formula (1) as defined in any one of claims 1-5,9-11 or 18 to a patient in need thereof
39. A medicine for 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 fonnula (I) as defined in any one of claims 1-5, 9-11, or 18 in combination/concomiltant 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 synergcstically together to a patient in need thereof
40. A medicine according to claim 39, wherein the disease is type IT diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, afherovsclcrosis, hypcrlipidcrnia, 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 or cancer.

pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein X represents O or S; the groups R1, R2, R3, R4 and the groups R5 and R6 when attached to carbon atom may be the same or differenl and represent hydrogen, halogen, hydroxy, cyano, nitro, forniyl; or unsubstitutcd or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyi, aralkoxy, heterocyclyl, hetcroaryl, heteroaryloxy, hetero-aralkyl, hetcroaralkoxy, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, monoalkylamino, dialkylamino, arylamino, acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aiyloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonyl-amino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; W represents O, S or a group NR11; R11 and the groups R5 and R^ when attached to nitrogen atom may be the same or different and represent hydrogen, hydroxy, fonnyl or unsubstitutcd or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, hetcroaryl, heteroaryloxy, hcleroaralkyl, hetcroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is an integer ranging from 1 - 4; AT represents an unsubstitutcd or substituted divalent aromatic or heterocyclic group; R'7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or unsubstitutcd

or substituted aralkyl group; R8 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alky], acyl or unsubstiuted or substituted aralkyl; R9 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, hctero-cyclyl, heteroaryl, or heteroaralkyl groups; R10 represents hydrogen; Y represents oxygen; the linking group represented by "(CH2)n-O- may be attached either through nitrogen atom or carbon atom, which comprises: hydrolising a compound of fomuila (1) described in any of the claims 6 and 7 where R10 represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups and all other symbols are as defined earlier by conventional methods.
42. Use of a compound of formula (I) as defined in any one of claims 1-5, 9-11, or 18 or a pharmaceutical composition as claimed in claim 19 or 20 in combination with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for 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.
43. Use according to claim 42, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidacmia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidcmia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomcruloncphntis, 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 or cancer,
44. Use of a compound as defined in any one of claims 1-5, 9-11, or 18 or a pharmaceutical composition as claimed in claim 19 or 20 in combination with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.

Documents:

2419-mas-1997- abstract.pdf

2419-mas-1997- assignment.pdf

2419-mas-1997- claims duplicate.pdf

2419-mas-1997- claims original.pdf

2419-mas-1997- correspondence others.pdf

2419-mas-1997- correspondence po.pdf

2419-mas-1997- description complete duplicate.pdf

2419-mas-1997- description complete original.pdf

2419-mas-1997- description provisional.pdf

2419-mas-1997- form 1.pdf

2419-mas-1997- form 26.pdf

2419-mas-1997- form 3.pdf

2419-mas-1997- form 5.pdf

2419-mas-1997- form 6.pdf

2419-mas-1997- pct.pdf

2419.jpg


Patent Number 207617
Indian Patent Application Number 2419/MAS/1997
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 19-Jun-2007
Date of Filing 27-Oct-1997
Name of Patentee Dr.REDDY'S LABORATORIES LTD
Applicant Address 7-1-27,Ameerpet, Hyderabad-500 016.
Inventors:
# Inventor's Name Inventor's Address
1 VIDYA BHUSHAN LOHRAY Dr.Reddy Research Foundation, 7-1-27,Ameerpet,Hyderabad-500 016.
2 BRAJ BHUSHAN LOHRAY Dr.Reddy Research Foundation, 7-1-27,Ameerpet,Hyderabad-500 016.
3 RAMANUJAM RAJAGOPALAN Dr.Reddy Research Foundation, 7-1-27,Ameerpet,Hyderabad-500 016.
4 PARASELLI BHEEMA RAO Dr.Reddy Research Foundation, 7-1-27,Ameerpet,Hyderabad-500 016.
5 RANJAN CHAKRABARTI Dr.Reddy Research Foundation, 7-1-27,Ameerpet,Hyderabad-500 016.
PCT International Classification Number C07D239/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA