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)
Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence
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. PARASELLI BHEEMA RAO
Dr.Reddy Research Foundation,
7-1-27,Ameerpet,Hyderabad-500 016.
4. RAMANUJAM RAJAGOPALAN
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.
Specification
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)
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