Indian Patents
Title of Invention

NOVEL TRICYCLIC COMPOUNDS AND THEIR USE IN MEDICINE: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Abstract The present invention relates to novel hypolipidemic, antihyperglycemic componds, 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 formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
Full Text

Field of the Invention
The present invention relates lo novel hypolipidemic, anlihypcrglyccmic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmacculically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly" the present invention relates lo novel p-aryl-a-oxysubstilutcd alkylcarboxylic acids of the gepcrat formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmacculically 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 derivatives, their analogs, their tautomeric forms, their slcrcojsomcrs, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
The compounds of general formula (I) arc useful for the treatment and / or prophylaxis of insulin resistance (type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hypcrlipidemia, coronary artery disease and other cardiovascular disorders. The compounds of the present invention are also useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis. These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and osteoporosis.

Background of Invention
Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance / insulin resistance in addition to hyperlipidemia 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.
Diabetes is a disease, which severely affects the quality of life of a large population. 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 resulting in frank diabetes. Among developed countries, diabetes mcllitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med. (1987) 317 : 350 - 357 ; J. Clin. Endocrinol. Metab., (1988) 66 : 580 - 583; J. Clin. Invest., (1975) 68 : 957 - 969) and renal complications (Sec Patent Application No, WO 95/21608). It is increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mcllitus. 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.
Thus, therapeutic agents which improve insulin resistance, lower plasma trigyceride, total cholesterol, LDL and VLDL and increase HDL will have great significance in preventing cardiovascular morbidity and improving quality of life.
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

there exists synergism for the molecules, which are agonists for both PPARa and PPARy and suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar 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).
A few P-aryl-oc-hydroxy propionic acids and their derivatives, their analogs have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia. Some of such compounds described in the prior art are outliped below :
i) U.S. Pat. 5,306,726; WO91/19702 disclose several 3-aryl-2-hydroxypppionic acid
derivatives of general formula (Ha) and (lib) as hypolipidemic and hypoglycemic agents.


wherein Ra represents 2- benzoxazolyl or 2-pyridyI and Rb represent CF3 or CH2OCH3 or CH3.
A typical example is (iS)-3-[4-[2-[N-(2-bcnzoxazolyI]N-methylamino]cthoxy]phenyl]-2-(2,2,2-trifIuoroethoxy)propanoic acid (II f).

iii) International Patent Application Nos. WO 94/13650, WO 94/01420 and WO 95/17394 disclose the compounds of general formula (II g)
A1—X (CH2)n— O—A2-A3—Y. R2 (» 6)
wherein A* represent aromatic hcterocydc, A 2 represents substituted benzene ring and A 3 represents moiety of formula (CH2)m-CH-(ORl), wherein R1 represents alkyl groups, m is an
integer; X represent substituted or unsubstitutcd N; Y represents C=0 or C=S. R2 represents OR where R may be alkyl, aralkyl, aryl group. An example of these compounds is shown in formula (II h)

Summary of the Invention
With an objective to develop novel compounds for the treatment and / or prophylaxis of diseases related to increased levels of lipids, especially to treat hypertriglyceridemia and to lower free fatty acids, for the treatment and / or prophylaxis of diseases described as Syndrome-X which include hypcrlipidemia, hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism, for the treatment of hypertension,, atherosclerosis and coronary artery diseases with better efficacy, potency and lower toxicity, we focussed our research to develop new compounds effective in the treatment of above mentioned diseases. Effort in this direction has led to compounds having general formula
(D-

The main objective of the present invention is therefore, to provide novel p-aryl-a-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, ihcir phannaccutically acceptable salts, their phannaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
Another objective of the present invention is to provide novel fl-aryl-ct-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric fonns, their stereoisomers, their polymorphs, their phannaccutically acceptable salts, their phannaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPARa and / or PPARy, and optionally inhibit HMG CoA reductase, in addition to agonist activity against PPARa and / or PPARy.
Another objective of the present invention is to provide novel p-aryl-oc-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their phannaceutically acceptable salts, their phannaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having . enhanced activities, without toxic effect or with reduced toxic effect.
Yet another objective of the present invention is to produce a process for t^e preparation of novel p-aryl-a-oxysubstituted alkylcarboxylic acids and their derivatives of the formula (I) as defined above, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their phannaceutically acceptable salts and their phannaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical 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.
Detailed Description of the Invention
Thppresent invention is related to compounds having the general formula (I)

I 1 T jf
where R , R , R , R may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, hetcroaryl, heteroaralkyl, hctcroaryloxy, hctcroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylaminq, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, araljcoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring containing X and N represents a 5-6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together.with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R6 forms a bond together with R5; R7 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, hetcroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, hetcroaryl, heteroaralkyl groups; Y represents oxygen or NR10, where R10 represents hydrogen, alkyl, aryl, hydroxyalkyl or aralkyl groups; R and R together may form a 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer 0 or 1.
Suitable groups represented by Rl - R4 include hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, formyl; substituted or unsubstitutcd (Q-

C12)alkyl group, especially, linear or branched (C1-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, Nbutyl, n-pentyl, isopentyl, hexyl and the like; cyclo(Cr C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohcxyl and the like, the cycloalkyl group may be substituted; cyclo(C3-C6)alkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohcxyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl or naphlhyl, the aryl group may be substituted; aralkyl such as benzyl or phenethyl, C6H5CH2CH2C] I2, naphthylmethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as CH3C6FI4CH2, Hal-C6H4CH2, CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like; hcteroaryl group such as pyridyl, thicnyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tctrazolyl, benzopyranyl, benzofuranyl and the like, the hcteroaryl group may be substituted; hcterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclyl group may be substituted; aralkoxy group such as benzyloxy, phencthyloxy, naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; hclcroaralkyl group such as furanmcthyl, pyridincmethyl, oxazolcmclhyl, oxazolcthyl and the like, the hcteroaralkyl group may be substituted; aralkylamino group such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like, which may be substituted; aralkoxycarbonyl group such as bcnzyloxycarbonyl, phcncthyloxycarbonyl, naphthylmclhoxycarbonyl and the like, which may be substituted; (Cr C6)alkylamino group such as NHCH3, N(CH3)2, NCH3(C2H5), NHC2H5, NHC3H7, NHC6H13 and the like; alkoxyalkyl group such as mcthoxymcthyl, ethoxymclhyl, methoxyethyl, ethoxyethyl and the like; aryloxyalkyl group such as C6H5OCH2, C6H5OCH2CH2, naphlhyloxymethyl 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 moiety is as defined earlier and may be substituted; aryloxy group such as phenoxy, naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl such as methoxycarbonyl or clhoxycarbonyl; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl, naphlhyloxycarbonyl and the like; arylamino group such as HNCaHs, NCH3(C6Hs), NHC6H4CH3, NHC6H4-Hal and the like; amino group; amino(Ci-C6)alkyl; hydroxy(CrC6)alkyl; * (Q-C6)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like; lhio(CVC6)alkyl; (C|-C6)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5; aralkoxycarbonylamino group such as NHCOOCH2C6H5, NHCOOCH2CH2C6H5, NCH3COOCH2C6H5, NC2H5COOCH2CGH5,i NHCOOCH2C6H4CH3> NlICOOCH2C6H4OCH3 and the like; aryloxycarbonylamino group such as NHCOOC^Hs, NHCOOC6H5, NCH3COOC6H5, NC2H5COOC6H5, NIICOOC6H4CH3, NHCOOC6H4OCH3 and the like;

alkoxycarbonylamino group such as NHCOOC2H5, NHCOOCHj and the like; carboxylic acid or its derivatives such as amides, Ijkc CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, the carboxylic acid derivatives may be substituted; acyloxy group such as OOCMe, OOCEt, OOCPh and the like which may optionally be substituted; sulfonic acid or its derivatives such as S02NH2, S02NHMe, S02NMe2, S02NHCF3 and the like, the sulfonic acid derivatives may be substituted.
When the groups represented by R1 - R4 are substituted, the substituents may be selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, hcterparalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aj)coxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its cjerivatives, or sulfonic acid or its derivatives .
Suitable ring A includes phenyl, naphthyl, cyclohcxyl, cyclohcxcnyl, thicnyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyridyl, pyranyl, dihydropyranyl, pyridazyl, pyrimidinyl and the like; which may be optionally substituted and substituents are selected from the same group as that ofR'-R4 and are defined as they are for R -R4, Preferred substituents are halogen, hydroxy, amino, formyl, optionally halogenated (C|-CrOalkyl, (C1-C6alkoxy, cyclo(C3-C6)alkyl, cycIo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, acylamino, aralkoxycarbonylamino, aminocarbonyl and the like.
It is preferred that cyclic structure represented by ring A is a phenyl or a pyridyl ring.
It is still more preferred that the cyclic structure represented by ring A is a phenyl ring.
Suitable X includes oxygen, sulfur or a group NR9, preferably oxygen and sulfur. Suitably, R9 represent hydrogen, (Ci-Cftjalkyl, (C3-C6)cycloalkyI, aralkyl group such as benzyl, phencthyl; acyl group such as acetyl, propanoyl, butanoyl, benzoyl and the like; (C|-Cejalkoxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl, CH3OC6H4OCO, Hai-Cel^OCC), CH3C6H4OCO, naphthyloxycarbonyl and the like; aralkoxycarbonyl such as benzyloxycarbonyl, phenelhyloxycarbonyl and the like; the groups represented by R9 may be substituted or unsubstituted. When the groups represented by R9 are substituted, the substituents may be selected from halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated (Cr C3)alkoxy groups.
The group represented by Ar includes divalent phenylcne, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl and the like. The substituents on the group represented by Ar includetlinear or branched optionally

halogenated (Ci-C6)alkyl, optionally halogenatcd (C|-C3)alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic and sulfonic acids and their derivatives. The substituents are defined as they are for R'-R4.
It is more preferred that Ar represents a substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, bcnzothiazolyl or benzoxazolyl groups.
It is still more preferred that Ar represents divalent phcnylene or benzofuranyl, which m^y be optionally substituted by methyl, halomclhyl, methoxy or halomelhoxy groups.
Suitable R includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (Q-C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; aralkyl such as benzyl, phcncthyl, which may be optionally subslilutcd or R5 togclhcr with K* represent a bond.
Suitable R6 may be hydrogen, lower alkyl groups such as methyl, ethyl or propyl;
hydroxy, (Q-Cjjalkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; acyl group
such as linear or branched (Ci-Cg)acyl group such as acetyl, propanoyl, bulanoyl, pentanoyl,
benzoyl and the like; aralkyl such as benzyl, phenethyl, which may be optionally substituted or
together with R5 forms a bond. ,
It is preferred that R5 and R6 represent hydrogen atom or R5 and Rf) together represent a bond.
Suitable groups represented by R may be selected from hydrogen, linear jor branched (CrCiG)alkyl, preferably (Cj-Ci2)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (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 substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; aralkyl group wherein the alkyl moiety may contain CpC6 atoms such as benzyl and phenethyl etc, wherein the aryl moiety may be substituted; hetcrocyclyl group such * as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; (Ci-C6)alkoxy(Ci-C6)alkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, cthoxypropyl "and the like, the alkoxyalkyl group may be substituted; acyl group such as acetyl, propanoyl, butanoyl, benzoyl and the like; (C|-C6)alkoxycarbonyl, the alkyl group may be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl, the aryl group may be substituted; (Ci-C6)alkylaminocarbonyl, the alkyl group may be substituted;

arylaminocarbonyl such as PhNI ICO, naphthylaminocarbonyl, the ary 1 moiety may be substituted. The substiluents on R7 may be selected from the same group of R'-R4.
Suitable groups represented by R8 may be selected from hydrogen, linear or branched (Ci-Ci6)alkyl, preferably (Ci-C|2)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C3-C7)cycloalkyl such as cyclopropyl/cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, the aryl group may be substituted; hcleroaryl group such as pyridyl, thienyl, furyl and the like, the helerbaryl group may be substituted; hctcroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemclhyl, oxazolcthyl and the like, the hctcroaralkyl group may be substituted; aralkyl group such as benzyl and phenethyl, the aralkyl group may |>e substituted; hctcrocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted. The substituents on R may be selected from the same group ofR'-R4.
Suitable groups represented by R10 may be selected from hydrogen, linear or branched
(C|-Ci6)alkyl, preferably (Ci-Ci2)alkyl; hydroxy(CpC6)alkyl; aryl group such as phenyl,
naphthyl; aralkyl group such as benzyl and phenethyl. I
Suitable ring structures formed by RR and R10 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.
Suitable m is an integer ranging from 0-1. It is preferred that when m = 0, Ar represents a divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihyejrobenzofuryl, dihydrobenzopyranyl groups, preferably benzofuranyl group and when m = 1, Ar represents divalent phenylenc, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl groups.
It is preferred that when m = 0, Ar represents a divalent a benzofuranyl group, more preferably benzofuran-2,5-diyl group, and when m = 1, Ar represents a phenylcne group.
Suitable n is an integer ranging from 1 to 4, preferably n represents an integer 1 or 2.
It is preferred that when m = 1, n represents 2.
It is also preferred that when m - 0, n represents 1.
Pharmaceutically acceptable salts forming part of this invention include salts of the carboxylic acid moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine,
dicthanolamine, choline and the like, ammonium or substituted ammonium salts, aluminum salts.
P Salts may include acid addition'salts where appropriate which are, sulphates, nitrates,
phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates,
palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoatcs, benzcncsulfonates,

ascorbates, glycerophosphates, kctoglutarales and the like. pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compounds according to the present invention include :
Ethyl (E/Z)-3-[4-[2-(Phenothiazin-10-yl)cthoxyjphenyI]-2-elhoxy propenoate and its salts ; Ethyl (E)-3-[4-[2-(Phenothiazin-10'yl)ethoxy]phenyI]-2-ethoxy propenoate and its salts ; Ethyl (Z)-3-f4-[2-(Phenothiazin-10-yl)elhoxy]phcnyl]-2-ethoxy propenoate and its salts ; EthylE/Z)-3-[4-[2-[phenothiazin-l 0-yl)methylbcnzofuran-5-yI)-2-cthoxypropcnoatc and its salts; Ethyl(E)O-[442-fphenothiazin*10-yl)rriethyIbenzofuran-5-yl)-2-ethoxypropcnoate and its salts ; Ethyl(Z)-3-[4-[2-[phenothiazin-10-yl)melhylbcnzofuran-5-yl)-2-cthoxypropcnoate and its salts ; Ethyl (E/Z)-3-t4-[2-(phenoxazin-10"yl)cthoxy]phenyl]-2-ethoxypropenoate and its salts ; Ethyl (E)"3-[4-[2«(phenoxazin-10'yl)ethoxy]phcnylJ"2-clhoxypropenoate and its salts ; Ethyl (Z)-3*[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate and its salts ; (+) Methyl 3-[4-[2-(phenothiazin-10-yl)elhoxy]phenyl]-2-ethoxypropanoate and its salts ; (+) Methyl 3-[4-[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoate and its salts ; (-) Methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate and its salts ; (+) Methyl 3-[2-(phenolhiazin»10-yl)methylbcnzofuran-5-yl]-2-ethoxypropanoate and its salts; (+) Methyl 3-[2-(phcnothiazin-10-yl)mcthylbcnzofuran™5-yl]-2-cthoxypropanoate and its salts; (-) Methyl 3-[2-(phcnothiazin-10-yl)methylbcnzofuran-5-yl]-2"Cthoxypropanoate and its salts; (+) Methyl 3-[4-[2-(phenoxazin-10-yl)cthoxy]phcnyl]-2-ethoxypropanoate and its salts ; (4-) Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-ethoxypropanoate and its salts ; (-) Methyl 3-[4-t2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-ethoxypropanoate and its salts ; (4) Ethyl 3-[4-(2-(phcnoxazin-10-yl)cthoxy]phcnyl-2-cthoxypropanoate and its salts ; (+) Ethyl 3-[4-(2-(phenoxazin-10-yl)ethoxy]phcnyl-2-cthoxypropanoate and its salts ;
(~) Ethyl 3-f4-(2-(phcnoxazin-10-yl)ethoxy]phcnyl-2-clhoxypropanoatc and its salts ; (+) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-hydroxypropanoate and its salts ; (+) Ethyl 3-[4-[2-(phcnoxazin-10-yl)ethoxy]phenyI]-2-hydroxypropanoate and its salts ; (-) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-hydroxypropanoate and its salts ; (+) Ethyl 3-[4*[2-(phenoxazin-10-yl)elhoxy]phcnyl]-2-butoxypropanoate and its salts ; (+) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyI]-2-butoxypropanoate and its salts ;

{-) Ethyl 3-[4-[2-(phcnoxazin-10«yl)c(lioxy]phenyl]-2-butoxypropanoatc and its salts ; [+) Ethyl 3-[4-[2-(phcnoxazin-10-yI)clhoxy]phcnyI]-2-hcxyIoxypropanoa(e and its salts ; '+) Ethyl 3-f4-[2-(phenoxazin-10-yl)cthoxy]phcnyl]-2-hexyloxypropanoate and its salts ; » Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyI]-2-hcxyloxypropanoatc and its salts ; '+) 3-[4-[2-(PhenothiaziivlO-yl)cthoxy]phcnyI]-2-ethoxypropanoic acid and its salts ; '+) 3-[4-[2^(Phcnothiazin-10-yl)cthoxy]phenyIJ-2-ethoxypropanoic acid and its salts ; ) 3«[4-f2-(Phenothiazin-10-yl)ethoxy]phcnyI]-2-ethoxypropanoic acid and its salts ;
'+) 3-[4«[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2^cthoxy-2-methylpropanoic acid aryd its salts ;
+) 3-[4-[2-(Phenothiazin-10-yl)clhoxy]phenyI]-2-ethoxy-2-methyIpropanoic acid and its salts ;
-) 3-[442-(Phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoic acid and its salts ;
+) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phcnyl]-2-phcnoxypropanoic acid and its salts ;
+) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts ;
-) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phcnyl]-2-phcnoxypropanoic acid and its salts ;
'+) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phcnyl]-2^phenoxy-2-methylpropanoic acid and its salts ;
'+) 3-[4-f2-(Phenothiazin-10-yl)clhoxy]phcnyl]-2-phenoxy-2-mcthylpropanoic acid and its salts ;
■) 3-[4*f2-(Phenothiazin-10-yl)ethoxy]phenyI]-2-phcnoxy-2-mclhyIprcipanoic acid and its salts ;
+) 3-[2-(Phenothiazin-10-yl)melhyl benzofuran-5-yl]-2-ethoxypropanoic acid and itt> salts;
+) 3-[2-(Phenothiazin-10-yl)methyl benzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
-) 3-[2-(Phenothiazin-10-yI)methyI bcnzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
'+) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phcnyl]-2-cthoxypropanoic acid and its salts;
+) 3-[4-[2-(Phcnoxazin-10-yl)ethoxy]phcnyI]-2-elhoxypropanoic acid and its salts ;
■) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2-ethoxypropanoic acid and its salts ;
."+) 3-t4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2«ethoxy-2-methylpropanoic acid and its salts;
'+) 3-[4-[2-(Phcnoxazin-10-yl)cthoxy]phcnyl]-2-cthoxy-2-methyIpropanoic acid and its salts-;
-) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phcnyI]-2-ethoxy-2'methylpropanoic acid and its salts ;
i) 3-[4-[2-(Phcnoxazin-10-yl)cthoxy]phcnyl]-2-phcnoxypropanoic acid and its salts;
.'+) 3-[4-[2-(Phenoxazin-10^yl)ethoxy]phcnyl]-2-phenoxypropanoic acid and its salts ;
» 3-[4-t2-(Phenoxazin-10-yl)elhoxy]phcnyl]-2-phcnoxypropanoic acid and its salts ;
+) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phcnyl]-2"phenoxy-2«methylpropanoic acid and its salts;
'+) 3-[4-[2-(Phenoxazin-10-yl)clhoxy]plicnyl]-2-phcnoxy-2-mclhylpropanoic acid and its salts ;

(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxyjphenyl]-2-phenoxy-2«methylpropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts ; (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2-butoxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin"10-yl)ethoxy]phenyl]-2-butoxypropanoic acid and its salts ; (■) 3-[4-[2-(Phenoxazin-10-yl)elhoxy]phcnyl]-2-butoxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxypropanoic acid and its s^lts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2-hexyloxypropanoic acid and its sa)ts ; (-) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phenyl]-2-hcxyloxypropanoic acid and its salts ; t(2R)-N(iS)]-3-[4>t2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy"N-(2-hydroxy-l"phenyl ethyl)propanamide and its salts ; [(2S)-N(lS)]044-[2-(Phcnoxazin'10-yl)cthoxy]phcnyl]-2-cthoxy^N-(2-hydroxy^l-phenyl
cthyl)propanamide and its salts ;
[(2S)-N(lS)]-3-[442-(phenothiazin-10-yI)cthoxy]phenyl]-2-ethoxy-N-(2-hydro cthyOpropanamide and its salts ;
[(2R)-N(lS)]-3-[442-(phenothiazin-10-yI)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-j^ cthyl)propanamide and its salts ;
*
According to a feature of the present invention, the compound of general formula (III) where R1, R2, R3, R4, R7, R8, X, A, n, m, Ar are as defined earlier and R5 and R6 together represent a bond, can be prepared by any of the following routes shown in Scheme I. The compound of general formula (III) represent a compound of general formula (I), wherein all the symbols are as defined earlier and R5 and R6 together represent a bond and Y represents oxygen atom.


Scheme-1
Route (1) : The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier with a compound of formula (Illb), where Rn may be a lower alkyl group and R7, R are as defined earlier, to yield a compound of general formula (III) may be carried out in the . presence of a base such as alkali metal hydrides like NaH, KH or organolithiums like CH3U, BuLi and the like or alkoxides such as NaOMe, NaOEt, K+BuO" or mixtures thereof. The reaction may be carried out in presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof. HMPA may be used as cosolvent. The reaction temperature may range from -78 °C to 50 °C» preferably at a temperature in the range of-10 °C to 30 °C, The compound of general formula (III b) may be prepared according to the procedure described in the literature (Annalen. Chemie, (1996) 53, 699).
1 1

Route (2) : The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier with a compound of formula (IIIc) where R represents a hydrogen atom and R , R8 are as defined earlier may be carried out under conventional conditions. The base is not critical. Any base normally employed for aldol condensation reaction may be employed; bases like metal hydride such as NaH, KH, metal alkoxides such as NaOMe, K+BuO\ NaOEt, metal amides such as L1NH2, LiN(ipr)2 may be used. Aprotic solvent such as THF, ether, 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 undpr anhydrous
conditions. Temperature in the range of -80 °C to 35 °C may be used. The p-hyejfoxy product may be dehydrated under conventional dehydration conditions such as treating \yilh PTSA in solvents such as benzene or toluene. The nature of solvent and dehydrating agent jp 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 continous removal of water using a Dean Stark water separator.
Route (3) : The reaction of compound of formula (Hie) where L1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifiuoromethanesulfonate and the like and all symbols are as defined earlier with a compound of formula (Hid) where R , R and Ar are as defined earlier to produce a compound of the formula (III) 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. Acetone may be used as solvent when Na2CC>3 or K2CO3 is used as a base. The reaction temperature may range from 0 °C - 120 °C, preferably at a temperature in the
range of 30 °C - 100 °C The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (Hid) can be prepared according to known procedure by a Witlig Homer reaction between the hydroxy protected aryl aldehyde such as benzyloxyaryl aldehyde and compound of formula (Illb), followed by deprotcction.
Route (4) : The reaction of a compound of general formula (Illg) where all symbols are as defined earlier with a compound of general formula (IHf) where all symbols are as defined earlier and L1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifiuoromethanesulfonate and the like, preferably a halogen atom to produce a compound of

general formula (III) 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, potassium hydroxide, alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium, alkali metal amides like sodamidc or mixtures thereof The amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (Ilia), preferably the amount of base ranges from 1 to 3 equivalents. Phase transfer catalysts such as tctraalkylammonium halide or hydroxide may be added* The reaction may be carried out at a
temperature in the range of 0 °C to 150 °C, preferably at a temperature in the nmge of 15 °C
to 100 °C. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.25 to 12 hours.
Route (5): The reaction of compound of general formula (Illh) where all symbols are as defined earlier with*a compound of general formula (Hid) may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as PPlr*/ DEAD and the like. The reaction may be carried out in the presence of solvents such as THF, DME, CH2CI2, CHClj, toluene, acctonitrile, carbontctrachloride and the like. The inert atmosphere may be maintained by using inert gases such as N2,~Ar, He. The reaction may be Qffected in the presence of DMAP, HOBT and they may be used in the range of 0.05 to ^ equivalents, preferably 0.25 to 1 equivalents. The reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C. The duration of the reaction may
range from 0.5 to 24 hours, preferably from 6 to 12 hours.
1
According to another embodiment of the present invention, the compound of the general formula (I) where R1, R2, R3, R4, R5, R6, R7, R8, X, A, n, m, Ar as defined earlier and Y represents oxygen atom can be prepared by one or more of the processes shown in Scheme - II:


Route (6) : The reduction of compound of the formula (III) obtained as described earlier in Schcme-I, to yield a compound of the general formula (I) where R5 and Rfi e^ch 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, R!i/C, Pt/C, and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents sucji as dioxane, acetic acid, ethyl acetate, ethanol and the like. The nature of the solvent is not critical. A pressure between atmospheric pressure and 80 psi may be employed* Higher pressures may be used to reduce the reaction time. The catalyst may be preferably 5 - 10 % Pd/C and the amount of catalyst used may range from 1 - 100 % w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in alcohol or sodium amalgam in alcohol. Route (7) : The reaction of compound of formula (la) where all symbols are as defined earlier and L3 is a leaving group such as halogen atom with an alcohol of general formula (lb), where R7 is 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 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 a$ KOH, NaOH,
NaOMe, NaOEt, K+BuO" or NaH or mixtures thereof. Phase transfer catalysts such as tetraalkylammonium halides or hydroxides may be employed. The reaction temperature may
range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 100 °C The duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours. The compound of formula (la) may be prepared according to the process disclosed in our copending application Attorney Docket No. U 011410-0.
Route (8) : The reaction of compound of formula (Hie) defined earlier with; compound of formula (Ic) where all symbols are as defined earlier to produce a compound of ||ie formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME pd the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which is jnaintained 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 (Ic) may be
prepared by Wittig Homer reaction between the protected hydroxyaryl aldehyde and compound
of formula (Illb) followed by reduction of the double bond and dcprolcction. Alternatively, the
compound of formula (Ic) may be prepared by following a procedure disclosed in WO 94/01420.
Route 9 : The reaction of compound of general formula (Illh) defined earlier with a compound of
> .1
general formula (Ic) where all symbols are as defined earlier may be carried out Rising suitable
coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as
PPI13/ DEAD and the like. The reaction may be carried out in the presence of sojvents such as
THF, DME, CH2CI2, CHCI3, toluene, acetonitrile, carbontetrachloride and the like. The inert
atmosphere may be maintained by using inert gases such as N2, Ar, He. The reaction may be
effected in the presence of DMAP, HOBT and they may be used in the range of 0.05 to 2
equivalents, preferably 0.25 to 1 equivalents. The reaction temperature may be in the range of 0
* °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C. The duration of the
reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
Route (10) : The reaction of compound of formula (Id) where all symbols are as defined earlier
with a compound of formula (Ie) where R is as defined earlier and Hal represents CI, Br, or I, to
produce a compound of formula (I) may be earned out in the presence of solvents such as THF,
DMF, DMSO, DME and the like. The inert atmosphere may be maintained by using inert gases
such as N2, Ar or He. The reaction may be effected in the presence of a base such as KOH,

NaOH, NaOMe, K+BuO", NaH and the like. Phase transfer catalyst such as Ictraalkylammonium
halides or hydroxides may be employed. The reaction temperature may range from 20 °C to 150
°C, preferably at a temperature in the range of 30 °C to 100 °C. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (Id) represents compound of formula (I) where R represents H and Y represents oxygen atom. Route (11) : The reaction of a compound of the general formula (Ilia) as defined earlier with a compound of formula (IIIc) where R , R , R are as defined earlier may be carried out under conventional conditions. The base is not critical. Any base normally employed for aldol condensation reaction may be employed, like, metal hydrides such as NaH, KH, metal alkoxides such as NaOMe, KlBuO\ NaOEt, metal amides such as LiNH2, LiN(ipr)2- Aprotic solvent such as THF, ether, 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 25 °C may be used. The P-hydroxy aldol product may be dehydroxylated using conventional methods, conveniently by ionic hydrogenation technique such as by treating with a trialkyl silane in the presence of an acid such as trifluoroacetic acid. Solvent such as CH2CI2 niay be used. Favorably, reaction proceeds at 25 °C. Higher temperature may be employed if the reaction is slow. Route (12) : The reaction of a compound of general formula (IHg) where all symbols are as defined earlier with a compound of general formula (If) where L1 is a leaving group such as halogen atom, p-toluenesulfonate, methancsulfonatc, trifluoromethanesulfonate and the like, preferably a halogen atom and all other symbols are as defined earlier to produce a compound of general formula (I) may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, He. The reaction
may be effected in the presence of a base such as alkalis like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonate, 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 (Illg), preferably the amount of base ranges from 1 to 3 equivalents. The reaction may be carried out in the presence of phase transfer catalysts such as tetraalkylammonium halides or hydroxides. The reaction may
be carried out at a temperature in the range of 0 °C to 150 °C, preferably at a temperature in
the range of 1$ °C to 100 °C. The duration of the reaction may range from 0.25 to 24 hours, preferably from 0.25 to 12 hours.

The compound of general formula (I) where Y represents oxygen and R* is as defined earlier may be converted to compound of formula (I), where Y represents NR10 by reaction with appropriate amines. Suitably the compound of formula (I) where YR8 represents OH may be converted to acid halide, preferably YR8 = CI, by reacting with appropriate reagents such as oxalyl chloride, thionyl chloride and the like, followed by treatment with amines; Alternatively, mixed anhydrides may be prepared from compound of formula (I) where YR8 represents OH and all other symbols are as defined earlier by treating with acid halides such acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobcnzoyl 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 CHCb, CH2CJ2> 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 ^0 °C to 40 °C, preferably 0 °C to 20 °C. The acid h^Hde or mixed anhydride thus prepared may further be treated with appropriate amines.
The processes for the preparation of compounds of general formula (Ilia) have been described in a copending application No. attorney docket number U 011410-0.
In another embodiment of the present invention the novel intermediate of formula (If)

where Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R6 forms a bond together with R ; R may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, hctcrocyclyl, hctcroaryl, hctcroaralkyl groups; R8 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, hctcrocyclyl, hcteroaryl, hctcroaralkyl groups; n is an integer ranging from 1-4; m is an integer 0 or 1 and L1 is" a leaving group such as halogen atom, p-toluenesulfonate, mcthanesulfonate, trifiuoromethanesulfonate and the like, preferably a halogen atom and a process for its preparation and its use in the preparation of p-aryl-a-substitutcd hydroxyalkanoic acids is provided.

The compound of formula (If) where m = 0 and all other symbols arc as defined may be
where R\ R°, R', R*, Ar are as defined earlier, with a compound of formula (IV)
L1-(CH2)n-L2 (IV)
where L1 and L2 may be same or different and represent a leaving group such as CI, Br, I, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and the like or L may also represent a hydroxy or a protected hydroxy group which may be later converted to a leaving group; n represents an integer ranging from 1-4.
The reaction of compound of formula (Ic) with a compound of formula (IV) to produce a compound of formula (If) may be carried out in the presence of solvents such a$ 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 b?ise such as K2CO3, Na2C03 or NaH or mixtures thereof.
Acetone may be used as solvent when Na2COj or K2CO3 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.
Alternatively, intermediate of formula (10 niay be prepared by reacting a compound of formula (V)
L1-(CH2)n-(0)m-Ar-CHO (V)
where where L represent a leaving group such as CI, Br, I, methanesulfonate, ' trifluoromethanesulfonate, p-toluenesulfonate and the like and all other symbols are as defined


where all symbols are as defined earlier, to yield a compound of formula (IIIQ which is further reduced to yield a compound of formula (If). The compound of formula (IIIQ .represents a compound of formula (If) wherein R and R6 together represent a bond and all other symbols are as defined earlier.
The reaction of compound of formula (V) with (Hlb) may be carried out in the presence of a base such as alkali metal hydrides like NaH, KH or organolithiums like CH3U, BuLi and the like or alkoxides such as NaOMe, NaOEt, K+BuO" or mixtures thereof. The reaction may be carried out in presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof. HMPA may be used as cosolvcnt. The reaction temperature may range from -78 °C to 50 °C, preferably at a temperature in the range of -10 °C to 30 °C. The reduction of compound of the formula (III!) 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, ethanol and the like. The nature of the solvent is not critical. A pressure between atmospheric pressure and 80 psi may be employed. Higher pressures may be used to reduce the reaction time, The catalyst may be preferably 5-10 % Pd/C and the amount of catalyst used may range from 1-100 % w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in alcohol or sodium amalgam in alcohol.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium mcthoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, dicthanolaminc, choline, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methancsulfonic 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 reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like

wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods arc compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula (I) where YR8 represents OH may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated cither by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
Various polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations, Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe mnr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I), as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of insulin resistance (type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hypcrlipidemia, coronary heart disease and other cardiovascular disorders. The compounds of the present invention are also useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, for the treatment of psoriasis, and polycystic ovarian syndrome (PCOS). These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications and osteoporosis.


The compound of the formula (I) as defined above are clinically administered to
mammals, including man, via either oral or parenteral routes. Administration by the oral route
is preferred, being more convenient and avoiding the possible pain and irritation of injection.
However, in circumstances where the patient cannot swallow the medication, or absorption
following oral administration is impaired, as by disease or other abnormality, it is essential that
the drug be administered parenterally. By cither 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
determine the most suitable dosage. ;/
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid 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-^cccptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcijtaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

A solution of triethyl-2-ethoxyphosphonoacelate prepared by the method of Grell and Machleidt, Annalen. Chemie, 1996, 699, 53 (3.53 g, 13.2 mmol) in dry tctrahydrofuran (10 mL)

was added slowly to a stirred ice cooled suspension of sodium hydride (60 % dispersion of oil) (0.62 g, 25.94 mmol) in dry tetrahydrofuran (5 mL), under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. prior to the addition of a 4-benzyloxybenzaldchyde (2.5 g, 11.79 mmol) in dry tetrahydrofuran (20 mL). The mixture was allowed to warm up to room temperature and stirred at that temperature for further 20 h, The solvent was evaporated, water (100 mL) was added and extracted with ethyl acetate (2 x 75 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2S04), filtered and the*solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as an clucnt to afford the title compound (3.84 g, quantitative) as an oil. !H NMR of the product suggests a (76:24 = Z\E) mixture of geometric isomers (R. A. Aitkcn and G. L. Thorn, Synthesis, 1989, 958).
Ui NMR (CDCI3, 200 MHz); 5 1.25 -1.50 (complex, 611), 3.85 - 4.03 (complex, 2H), 4.28 (q, J
= 7.0 Hz, 2H), 5.05, 5.09 (2s, 2H, benzyloxy CH2), 6.08 (s, 0.24H, E isomer of olefinic proton), 6.85 - 6.90 (complex, 2H), 6.99 (s, 0.76H, Z isomcr)7.33 - 7.45 (complex, 511), 7.75 (d, J = 8.72
Hz,2H).
Preparation 2
Methyl 3-[4-bcnzyloxyphcnyl]-2-clhoxypropanoate:

A mixture of ethyl (E/Z)-3-[4-bcnzyloxyphcnyl]-2-cthoxypropanoate (3.84 g, 11.79 mmol obtained in the preparation 1) and magnesium turnings (5.09 g, 0.21 mol) in dry methanol (40 mL) was stirred at 25 °C for 1 h. Water (80 mL) was added and pH of the solutioq was adjusted to 6.5 - 7.5 with 2 N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 75 mL). The organic layers were washed with water (50 mL), brine (50 mL) dried (Na2$04) and filtered. The solvent was evaporated under reduced pressure to afford the title compound (3.7 g, quantitative yield) as an oil.
'H NMR (CDCI3, 200 MHz): 5 1.16 (t, J = 6.97 Hz, 3H), 2.95 (d, J = 6.55 Hz, 2H), 3.30 - 3.38
- (complex, 1H), 3.55 - 3.67 (complex, 1H), 3.69 (s, 3H), 3.99 (t, J = 6.64 Hz, 1H), 5.04 (s, 2H), 6,89 (d, J = 8.63 Hz, 2H), 7.15 (d, J = 8.62 Hz, 211), 7.31 - 7.41 (complex, 5H). Preparation 3 Methyl 3-(4-liydroxyphenyl)-2-ethoxypropanoate :


A suspension of methyl 3-[4-(bcnzyloxyphcnyl)-2-cthoxypropanoatc (3.7 g, 11.78 mmol; ■ preparation 2) and 10 % Pd-C (0.37 g) in ethyl acetate (50 mL) was stirred at 25 °C under 60 psi hydrogen pressure for 24 h. The catalyst was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as an eluenl to afford the title compound (2.2 g, 84 %) as an oil.
'if NMR (CDCI3, 200 MHz) : 6 1.21 (t, J = 6.97 Hz, 3H), 2.99 (d, J - 6.37 Hz, 2H), 3.32 - 3.49
(complex, 1H), 3.57 - 3.65 (complex, 1H), 3.76 (s, 3H), 4.05 (t, J = 6.64 Hz, 111), 5.19 - 5.40 (bs,
111, D20 exchangeable), 6.80 (d, J = 8.44 Hz, 211), 7.14 (d, J = 8.39 Hz, 2H). Preparation 4
Ethyl 3-[4-hydroxyphenyl]-2-ethoxypropanoatc:
The title compound (1.73 g, 61 %) was prepared as a colourless oil from ethyl (E/Z)-3-[4-bcnzyloxyphenyl]-2-ethoxypropcnoate (3.85 g, 11.80 mmol) obtained in preparation 1 by hydrogenation procedure described in preparation 3.
'H NMR (CDCI3, 200 MHz) : 6 1.12 - 1.29 (complex, 6H), 2.93 (d, J = 6.55 Hz, 2H), 3.28 -
3.45 (complex, 1H), 3.51 - 3.68 (complex, HI), 3.98 (I, J = 6.55 Hz, 1H), 4.16 (q, J = 7.15 Hz, 211), 5.40 (s, 1H, D20 exchangeable), 6.73 (d, J = 8.39 Hz, 2H), 7.08 (d, J = 8.53 Hz, 2H). Preparation 5 Ethyl 3-[4-benzyloxyphenyl]»2-butoxypropanoate:

A solution of ethyl 3-[4-benzyloxyphcnyl)-2-hydroxypropanoate (5.0 g, 16.6 mmol) (prepared in a similar manner as described in Ref: W095/18125) in dry dimethyl formamide (5 mL) was added to a suspension of sodium hydride (0.1 g, 41.6 mmol) (60 % dispersion in oil) in dry dimethyl formamide (3 mL) at 0 °C and stirring was continued for further 1 h. To the above . reaction mixture /i-butyl bromide (3.4 g, 24.0 mmol) was added at 0 °C and stirring was continued for 10 h at ca. 25 °C. Water (30 mL) was added and extracted with ethyl acetate (2 x
50 mL). The combined ethyl acetate layer wtas washed with water (50 mL), brine (25 mL), dried (Na2S04), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and and pet. ether (1 : 9) as an eluent lo afford the title compound (0.7 g, 20 %) as an oil.

•H NMR (CDCI3, 200 MHz): 8 0.85 (t, J = 7.38 Hz, 3H), 1.18-1.40 (complex, 5JI), 1.49 - 1.58
(complex, 2H), 2.94 (d, J = 6.74 Hz, 2H), 3.20 - 3.33 (complex, 1H), 3.46 - 3.61 (complex, 1H), 3.94 (t, J = 6.37 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 5.04 (s, 2H), 6.89 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.48 Hz, 2H), 7.30 - 7.44 (complex, 5M). Preparation 6
Ethyl 3-[4-hydroxyphenyI]-2-butoxypropanoatc :

The title compound (0.475 g, 75 %) was prepared as an oil from ethyl 3-[4-bezyloxyphenyl)-2-butoxypropanoate (0.85 g, 2.38 mmol) obtained in preparation 8 by an analogous procedure to that described in preparation 3.
>H NMR (CDCI3, 200 MHz): 8 0.85 (t, J = 7.24 Hz, 3H), 1.19-1.38 (complex, 5H), 1.44 - 1.58
(complex, 2H), 2.94 (d, J = 6.55 Hz, 211), 3.21 - 3.32 (complex, 1H), 3.49 - 3.62 (complex, 1H),
3.94 (t, J = 6.88 Hz, 1H), 4.16 (q, J = 7.1 Hz, 211), 4.99 (s, 1H, D20 exchangeable), 6.73 (d, J =
8.53 Hz, 2H), 7.09 (d, J = 8.44 Hz, 211).
Preparation 7
Ethyl 3-[4-benzyloxyphenyl]-2-hcxyloxypropanoatc :

The title compound (1.2 g, 22 %) was prepared as an oil from ethyl 3-(4-benzyloxyphcnyl)-2-hydroxypropanoate (4,2 g, 14,0 mmol) and 1-bromohexane (3.4 g, 21.0 mmol) by an analogous procedure to that described in preparation 5.
>H NMR (CDCI3, 200 MHz): 5 0.86 (t, J - 5.9 Hz, 3H), 1.18 - 1.37 (complex, 7H), 1.45 - 1,66
(complex, 4H), 2.94 (d, J = 6.55 Hz, 2H), 3.22 - 3.33 (complex, 1H), 3.52 - 3.64 (complex, 1H),
3.94 (t, J = 6.9 Hz, 1H), 4.16 (q, J = 7.06 Hz, 2H), 5.03 (s, 2H), 6.89 (d, J = 8.63 Hz, 2H), 7.15
(d, J = 8.63 Hz, 2H), 7,31 - 7.44 (complex, 5H).
Preparation 8
Ethyl 3-[4-hydroxyphenyl]-2-hexyIoxypropanoatc :

The title compound (0.7 g, 76 %) was prepared as an oil from ethyl 3~[4-benzyIoxyphenyI)~2-hcxyloxypropanoate (1.2 g, 3.1 mmol) obtained in preparation 7 by an analogous procedure to that described in preparation 3.

•H NMR (CDCI3, 200 MHz) : 5 0.85 (t, J = 5.81 Hz, 3H), 1.19 - 139 (complex, 7H), 1.48 - 1.68
(complex, 4H), 2.92 (d, J = 6.74 Hz, 211), 3.18 - 3.39 (complex, 1H), 3.48 - 3.62 (complex, 1H),
3.93 (t, J - 7.0 Hz, 1H), 4.16 (q, J - 7.06 Hz, 211), 4.85 (s, 1H, D20 exchangeable), 6.73 (d, J =
8.53 Hz, 2H), 7.10 (d, J = 8.31 Hz, 2H).
Preparation 9
Ethyl (E/Z)-3-[4-(2-bromoethoxy)phenyl|-2-cthoxypropenoate :

The title compound (4.0 g, 66 %) was prepared as an oil in 45 : 55 ratio of E\Z isomers (as
measured by *H NMR) from 4-(2-bromoclhoxy)benzaldehydc (4.0 g, 17.4 mmol) and triethyl-2-ethoxyphosphonoacetate (5.61 g, 20.89 mmol) by an analogous procedure to that described in preparation 1,
•H NMR (CDCI3, 200 MHz) : 5 1.17 and 1.42 ( 6H, E and Z triplets, isomeric -OCH2CH3 and
OCH2-CH3), 3.62 - 3.72 (complex, 2H), 3.90 - 4.28 (complex, 2H), 4.30 - 4.37 (complex, 4H),
6.09 (s, 0.45H, olefinic proton of £ isomers), 6.85 and 6.92 (211, d and d, J = 8.67 Hz and 8.7
Hz), 6.98 (s, 0.55H, Z isomer of olefinic proton ), 7.16 and 7.78 (d and d, combined 2H, J = 8,63
Hz and 8.72 Hz).
Preparation 10
Ethyl 3-[4«(2-bronioethoxy)phenyIJ-2-ethoxypropanoate :

The title compound (4.0 g, 80 %) was prepared as colorless oil from ethyl (E/Z)-3-[4-(2-bromoclhoxy)phenyl]-2-ethoxypropenoatc (5.0 g, 14.5 mmol) obtained in preparation 9 using H2 / 10 % Pd-C (4 g) in dioxane as a solvent by an analogous procedure to that described in preparation 3.
Ml NMR (CDCI3, 200 MHz) : 8 1.12 ■ 1.30 (complex, 6H), 2.95 (d, J - 6.64 Hz, 2H), 3.25 -
3.45 (complex, 1H), 3.56 - 3.68 (complex, 3H), 3.96 (t, J = 6.65 Hz, 1H), 4.16 (q, J - 7.1 Hz, 211), 4.27 (t, J - 6.3 Hz, 2H), 6.81 (d, J - 8.67 Hz, 2H), 7.16 (d, J = 8.63 Hz, 2H). Example 1 ' Ktliyl(E/Z)-3-t4-[2-(Phcnothiaziii-10-yI)etlioxy]phenyl|-2-ethoxypropcnoate :


The title compound was obtained as I : 1 E\7. isomers (1.46 g, quantitative) as a syrupy liquid from 4-[2-(phenothiazm-10-yl)elhoxy]benzaldchydc (1,08 g, 3.11 mmol) and triethyl-2-ethoxyphosphonoacetate (W. Grcll & H. Machlcidt, Annalen chemiet 1966, 699, 53) (1.0 g, 3.73 mmol) by an analogous procedure to that described in preparation 1. 'HNMRCCDCl^ 200 MHZ) : 6 1.15-1.43 (complex, 6H), 3.89 - 4.03 (complex, 2H), 4.11 -
4.17 (complex, 2H), 4.30, 4.33 (combined, 411, -Cl^CITj-singlcls), 6.07 (s, 0.5H, olcfinic proton
of E isomer), 6.80 - 7.10 (complex, 6.5H), 7.14 - 7.20 (complex, 4H), 7.73 (d. J - 8.39 Hz, 2H).
Example 2
Ethyl (E/Z)-3-[4-|2-[plicnotliiaziii-10-yI)mc(liylbenzofuaii-5-yl)-2'Ctlioxyi)ropcnoatc:

The title compound was obtained as E:Z isomers (38 :62) (as measured by ]H NMR) (1.5g, 100%) as a colourless liquid from 5-formyl-2-(phenothiazin-10-yI) methylbcnzofuran (1.14g, 3.2 mmol) by a procedure similar to that described for preparation 1.
UlNMR (CDC13, 200 MHz): 8 1.23 - 1.45 ( complex, 6H), 3.55-3.78 (complex, 1H), 3.88 - 4,19
(complex, 1H), 4.22 - 4.35 (complex, 211), 5.14 (sr, 2H), 6.18 (s, 0.38H, olefinic proton of £
isomer) 6.47 and 6.54 (combined, 1H), 6.78 - 7.12 (complex, 8.62H), 7.37 - 7.48 (complex, 1H),
7.71 (d, J = 7.57 Hz, 1H), 7.95 (s, 1H).
Example 3
Ethyl (E/Z)-3-[4-[2-(pheiioxazi!i-10-yI)cthoxy|phcnyl]-2-cthoxypropcnoatc :

The title compound (14.4 g, 76%) was obtained as E.Z isomers (36 : 64) (as measured by !H * NMR) as a white solid from 4-[2-(phenoxazm-10-yl)elhoxy]benzaldehyde (14.0 g, 42.3 mmol) by an analogous procedure to that described for preparation I. mp : 110 - 112 °C.
'H NMR (CDCI3, 200 MHz) : 5 1.16 and 1.38 (combined, 6H, isomeric -OCH2CH3 triplet
signals), 3.89 - 4.05 (complex, 4H), 4.14-4.31 (complex, 4H), 6.06 (s, 0.3611, olefinic proton of E isomer), 6.66 - 6.95 (complex, 10.64H), 7.75 (d, J - 8.76 Hz, 2H). Example 4
Methyl 3-[4-[2-(phenotliiazin-10-yl)cthoxy|phenyl]-2-ctlioxypropanoate :


The title compound (1.3 g, 94 %) was prepared as a gummy liquid from ethyl (^/Z)-3-[4-t2-(phenothiazin-10-yl)ethoxy]phenyl]-2-elhoxypropcnoate (1.43 g, 3.10 inmol) obtained in example 1 by an analogous procedure to that described in preparation 2. 'H NMR (CDC13, 200 MHz): 6 1.15 (t, J - 7.0 Hz, 3H), 2,93(d, J = 6.64 Hz, 2H), 3.33 - 3.42
(complex, 1H), 3.52 - 3.63 (complex, 1H), 3.69 (s, 3H), 3.97 (t, J = 6.2 Hz,III), 4.29 (s,4H), 6.81
(d, J - 8.62 Hz, 2H), 6.92 - 6.96 (complex, 4H), 7.12 - 7,22 (complex, 611).
Example 5
Methyl 3-[2-(phenothiazin-10-yI)niethyIbcnzofuran-5-yI]-2-ethoxypropanoate :
1
The title compound (1,0 g, 68 %) was prepared as a gum, from ethyl (E/Z)-3-[2-(phenothiazin-10-yl)mcthylbenzofuran-5-yl]-2-clhoxypropenoatc (1.5 g, 3,0 mmol) obtained in example 2 by an analogous procedure to that described in preparation 2. ■H NMR (CDCI3, 200 MHz) : 5 1.16 (t, J = 7.0 Hz, 3H), 3.07 (d, J = 6.55 Hz, 2H), 3.30 - 3.49
(complex, 1H), 3.56 - 3.68 (complex, HI), 3.70 (s,3H), 4.05 (t, J = 6.3 Hz, 1H), 5.13 (s, 2H),
6.48 (s, 1H), 6.79 - 7.48 (complex, 11H).
Example 6
Methyl 3-[4-[2-(phcnoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate :
Method A
The title compound (0.68 g, 52 %) was prepared as a white solid, from ethyl (£/Z)-3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoale(1.3 g, 2.9 mmol) obtained in example 3
by a procedure similar to that described in preparation 2, mp : 88 - 90 °C.
Method B
A mixture of 2-(phenoxazin-10-yl)ethyl methancsulfonate (1.75 g, 5,0 mmol), methyl 3-(4~
hydroxyphcnyl)-2-ethoxypropanoate (1.5 g, 0 68 mmol) and potassium carbonate (3.16 g) in dry

dimethylformamide (20 mL) was stirred for 12 h at 80 °C. The reaction mixture was cooled to room temperature (ca. 25 °C). Water (30 mL) was added and extracted with ethyl acetate (2 x 50 mL), The combined organic extracts were washed with water (50 mL), dried (Na2SC>4) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and pet. ether (1 : 9) to afford the title compound (1.15 g, 47 %) as a white solid, mp : 89 - 90 °C. lH NMR data matches with the desired product (sec above). !H NMR (CDC13, 200 MHz): 6 1.16 (I, J - 6.92 Hz, 3H), 2.96 (d, J - 6.64 Hz, 2H), 3.22 - 3.40
(complex, 1H), 3,51 - 3.66, (complex, 1H), 3.68 (s, 3H), 4.00 (t, J = 7.0 Hz, 1H), 4.18 (complex,
4H), 6.55 - 6.89 (complex, 10H), 7,12 (d, J - 8.63 Hz, 211).
Example 7
Ethyl 3-[4-[2-(phenoxazin-10-yl)e(hoxy]phenyI-2-ethoxypropanoate :
Method A
To a solution ethyl (E/Z)-3-[4-[2-(phenoxaziii-10-yl)ethoxy]phenyl]-2-ethoxypropenoate (1.0 g,
2.24 mmol) obtained in example 3 in dioxane (50 mL) was added 10 % Pd-C (0.25 g) and stirred
at 25 °C under 60 psi hydrogen pressure for 24 h. At the end of this time reaction mixture was
filtered and solvent was evaporated under reduced pressure. The residue was triturated with pet.
ether to afford the title compound (0.96 g, 96 %) as a white solid, mp : 51 - 53 °C.
Hi NMR (CDCI3, 200 MHz) : 5 1.12 - 1.27 (complex, 6H), 2.94 (d, J - 6.31 Jiz, 2H), 3.26 -
3.41 (complex, 1H), 3.52 - 3.75 (complex, 1H), 3,96 (t, J - 6.64 Hz, 2H), 4.10 - 4.28 (complex,
5H), 6.55 - 6.92 (complex, 10H), 7.16 (d, J - 8.39 Hz, 2H).
Method B
The title compound (0.55 g, 75 %) was prepared as a white solid from 2-(phcnoxazin-10-
yl)ethyl methanesulfonate (0.5 g, 1.63 mmol) and ethyl 3-(4-hydroxyphenyl)-2-
ethoxypropanoate (0.46 g, 1.9 mmol) obtained in preparation 4 by a procedure similar to that
described in example 6 (Method B). mp : 52 - 53 °C. The ]H NMR data matches with the
desired product (see above).
Method C
To a suspension of sodium hydride (60 % dispersion in oil) (0.098 g, 4.0 mmol) in dry dimethyl
formamide (3 mL) was added a solution of phenoxazine (0,3 g, 1.6 mmol) in dry dimethyl
formamide (5 mL) at 0 °C under nitrogen atmosphere and stirring was continued for a further 30
min at ca. 25 °C. To the above reaction mixture a solution of ethyl 3-[4(2-bromoelhoxy)phenyl]-

2-cthoxypropanoate (0.85 g, 2.4 nmml) obtained in preparation 10 in dry dimethyl formamide (5 mL) at 0 °C and stirring was continued for a further 10 h at ca. 25 °C. Water (40 mL) was added and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (N.^SO/j), filtered and evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pel, ether (1 : 9) as an clucnt to afford the title compound (0.3 g, 40 %) as a colourless solid, mp : 52-53°C. The'H NMR data matches with the desired product (see above). Example 8 Ethyl 3-[4-t2-(plieiioxazin-10-yl)cthoxyJplicnyl|-2-hydroxypropaiioatc :

The title compound (LOG g, 43 %) as a pale yellow liquid from 2-(phcnoxazjn-10-yl)ethyl
methanesulfonate (1,8 g, 5.9 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (1.36
i
g, 6.49 mmol) obtained in preparation 6 by an analogous procedure to that described in example 6 (Method B).
•H NMR (CDCI3, 200 MHz): 8 1.29 (t, J = 6.96 Hz, 3H), 2.85 - 3.12 (complex, 2H), 3.92 (bs,
2H), 4.10 - 4.27 (complex, 4H), 4.39 (t, J - 6.1 Hz.-IH), 6.68 - 6.89 (complex, 10 H), 7.13 (d, J
= 8.39 Hz, 2H). OH proton is too broad to observe.
Example 9
Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxylpIicnyl|-2*butoxypropanoalc :

The title compound (0,25 g, 53 %) was prepared as a colourless liquid from 2-(phenoxazin-10-yl)clhyl methanesulfonate (0J g, 0.98 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoale (0.26 g, 0.97 mmol) obtained in preparation 6 by an analogous procedure to that described in example 6 (Method B).
h\ NMR (CDCI3, 200 MHz): 8 0.92 (l, J = 6,4 Hz, 3H), 1.21 - 1.39 (complex, 5H), 1.45 - 1.58
(complex, 2H), 2.94 (d, J = 6.32 Hz, 2H), 3.24 - 3.31 (complex, 1H), 3.50 - 3.57 (complex, 1H), 3.94 (t, J = 6.13 Hz, 1H), 4.13 - 4,23 (complex, 6 H), 6.61 - 6.84'(complex, 10 H), 7.16 (d, J = 8.3 H/.,2H), Example 10

Ethyl 3-[4-{2-(phcnoxazin«10-yl)cthoxy]pheiiylJ-2-liexyloxypropanoatc :

The title compound (0,52 g, 53 %) was prepared as a pale yellow oil from 2-(phenoxazin-10-yl)cthyl methanesulfonate (0.6 g and 1.97 mmol) and clhyl 3-(4-hydroxyphenyl)-2-hcxyloxypropanoatc (0.70 g, 2.4 mmol) obtained in preparation 8 by an analogous procedure to that described in example 6 (Method B).
hi NMR (CDCI3, 200 MHz) : 5 0.85 (t, J = 6.0 Hz, 3H), 1.20 - 1.27 (complex, 7IJ), 1.48 - 1.57
(complex, 411), 2.94 (d, J = 6.0 Hz, 2H), 3.21 - 3.30 (complex, 1H), 3.52 - 3.56 (complex, 1H), 3.90 - 3.99 (complex, 3H), 4.13 - 4.22 (complex, 414), 6.60 - 6.83 (complex, 10 H), 7.15 (d, J = 8,62 Hz, 2H). Example 11 3-|4-|2-(Plienotliiazin-10-yI)ethoxy|phciiyl|-2-c(hoxypropanoic acid :

To a solution of methyl 3-[4-[2-(phenothiazin-10*yl)ethoxy]phenyI]-2-ethoxypropanoate (7.5 g, 16.70 mmol) obtained in example 4 in methanol (50 mL) was added aqueous \0 % sodium hydroxide (20 mL). The reaction mixture was stirred at ca. 25 °C for 3h. Thq solvent was removed under reduced pressure and the residue was acidified with 2 N hydrochloric acid, extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL), dried (Na2SC>4), filtered and solvent was evaporated under
reduced pressure. The residue was chromatographed over silica gel using a mixture of dichloromethane and methanol (9 : 1) as an clucnt to afford the title compound (6.0 g, 83 %) as a white solid, mp : 79 - 82 °C. •H NMR (CDCI3, 200 MHz) : 5 1.18 (t, J = 6.8 Hz, 3H), 2.88 - 3.11 (complex, 2H), 3.39 - 3.64
(complex, 2H), 4.06 (dd, J = 9.2 and 4.3 Hz, 1H), 4.30 (s, 414), 5.30 - 5.98 (bs, 1H, D20
exchangeable), 6.80 - 7.02 (complex, 6H), 7.12-7.21 (complex, 6H).
Example 12
3-[4-[2-(Phcnothiazin-10"yI)cthoxy]phenyI]-2-ctlioxypropanoic acid, sodium salt:


A mixture of 3-[4-[-2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoic acid (03 g, 0.689 mtnol) sodium methoxide (0.041 g, 0.758 mmol) in methanol (5 mL) was stirred at ca. 25 °C for 2h. The solvent was removed under reduced pressure and the residue was triturated with dry ether (3x10 mL). The separated solid was filtered, washed with dry ether (2x5 mL) and dried over P2O5 under reduced pressure to afford the title compound (0.25 g, 89 %) as a white solid.
mp; 188-191 °C.
!
IHNMR (DMSO-d6, 200 MHz): 5 1.04 (t, J = 6.9 Hz, 3H), 2.71 - 2.89 (complex, 1H), 2.90 -
3.06 (complex, 1H), 3.16 - 3.30 (complex, 1H), 3.36 - 3.54 (complex, 1H), 3.88 - 3.91 (complex, 1H), 4.21 (s, 4H), 6.72 (d, J = 8.3 Hz, 2H), 6.89 - 6.99 (complex, 4H), 7,05 - 7.21
(complex, 6H). Example 13 3-[2-(Plienotliiazin-10-yI)metliylbciizofur«in-5-ylJ-2-ethoxypropanoic acid :

The title compound (0.8 g, 83 %) was prepared as a white solid from methyl 3-[2-(phenothiazin-10»yl)methylbenzofuran-5-yl]-2-cthoxypropanoatc (1.0 g, 2.0 mmol) obtained in example 5 by a
procedure analogous to that described in example 10. mp : 120 - 121 °C. COOH proton is too
broad to observe.
Ml NMR (CDCI3, 200 MHz); 5 1.15 (t, J = 6.95 Hz, 3H),3.00 - 3.26 (complex, 2H), 3.40 - 3.68
(complex, 2H), 4.08 (t, J = 4.47 Hz, 1H), 5.11 (s, 2H), 6.46 (s, 1H), 6.77 - 7.40 (complex, 11H).
Example 14
3-|2-(Phenothiazin-10-yl)nietliylbenzofuran-5-yll-2-cthoxypropanoic acid, sodium salt:


The title compound (0.12 g, 67 %) was prepared as a white solid from 3-[2-[(phenothiazin-10-yl)methylbenzofuran-5-yl)-2-ethoxypropanoic acid (0.16 g, 0.38 mmol) obtained in example 13 by a procedure analogous to that described for example 12. mp : 258 - 261 °C. •H NMR (CDC13, 200 MHz) 5 : 0.95 (t, J - 6.97 Hz, 3H), 2,62 - 2.80 (complex, 1H), 2.89 - 3.02
(complex, 1H), 3.06 - 3.18 (complex, 1H), 3.22 - 3.31 (complex, III), 3.50 - 3,61 (complex, 1H), 5.25 (s, 2H), 6.64 (s, 1H),6.90 - 7.39 (complex, 11H). Example 15 3-(4-[2-(Phenoxaziii-10-yl)etlioxy]phcnyl]-2-ctIioxypropanoic acid : !
The title compound (5.4 g, 77 "%) was prepared as a white solid from methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate (7.5 g, 16.8 mmol) obtained in example 6 by a procedure similar to that described in example 11. mp 90 - 92 °C.
Hi NMR (CDC13, 200 MHz) ; 8 1.19 (t, J - 7.0 Hz, 3H), 2.90 - 3.18 (complex, 2H), 3.41 - 3.62
(complex, 2H), 3,90 - 4.10 (complex, 311), 4.18 (t, J = 6.2 Hz, 211), 6.58 - 6.89 (complex, 10H),
7.16 (d, J = 8.4 Hz, 2H), COOH proton is too broad to observe.
Example 16
3"|4-|2-(Plienoxazin-10-yl)etIioxyJplienylJ-2-cllioxypi opanoic acid, sodium salt:

The title compound (0,27 g, 85 %) was prepared as a white solid from 3-[4-[2-(plienoxazin-10-yl)clhoxy]phenyl~2-elhoxypropanoic acid (0.3 g, 0.72 mmol) obtained in example 15 by an analogous procedure to that described in example 12. mp ; 194 - 202 °C. Ml NMR (CDCI3, 200 Mhz): 8 0.92 (I, J - 6.97 Hz, 3H), 2.65 - 2.82 (complex, III), 2.96 - 3.14
(complex, 2H), 3.31 - 3.41 (complex, 1H), 3.70 - 3.90 (complex, 3H), 3.94 - 4.04 (complex, 2H), 6.47 - 6.74 (complex, 10 H), 7.05 (d, J = 8.3 Hz, 2H). Example 17 3-(4-[2-(Phenoxazin-10-yl)etlioxy]phenyI]-2-hydroxypropanoicacid :


The title compound (0.40 g, 72 %) was prepared as a brown liquid from 3-[4-[2-(phenoxazin-10-yl)ethoxy]ph«nyI]-2-hydroxypropanoate (0.6 g, 1.43 mmol) obtained in example 8 by an analogous procedure to that described in example 11.
'H NMR (CDC13, 200 MHz) 5 ; 2.75 (bs, 111, D20 exchangeable), 2.86 - 3.23 (complex, 2H),
3.85 (t, J = 6.0 Hz, 2H), 4.18 (t, J = 5.9 Hz, 211), 4.47 (complex, 1H), 6.58 - 6.89 (complex, 10H), 7,17 (d, J = 8.63 Hz, 2H), COOH proton is too broad to observe. Example 18 3-|4-[2-(Phenoxazin-10-yI)cthoxy]pheiiyIJ-2-butoxypropanoic acid :

The title compound (0.13 g, 69 %) was prepared as a cream coloured solid from ethyl 3[-4-[2-(phcnoxazin-10-yl)ellioxy]phenyl]*2-butoxypropanoatc (0.2 g, 0.42 mmol) obtained in example 9 by an analogous procedure to that described in example 11. mp ; 84 - 88 °C.
> 11 NMR (CDC13, 200 MHz) : 8 0.88 (I, J - 7.5 Hz, 3H), 1.26 - 1.47 (complex, 2H), 1.47 - 1.66
(complex, 2H), 2.87 - 3.16 (complex, 2H), 3.35 - 3.58 (complex, 2H), 3,88 - 4.08 (cpmplcx, 3H),
4.15 (t, J = 6.4 Hz, 2H), 6.65 - 6.86 (complex, 1 OH), 7.15 (d, J = 8.63 Hz, 2H). COjpH proton is
too broad to observe.
Example 19
3-|4-|2-(Pheiioxazin-10-yl)ethoxy]phenylJ-2-butoxypropanoic acid, sodium salt:

The title compound (0.07 g, 83 %) was prepared as a cream coloured hygroscopic solid from 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropanoic acid (0.08 g, 0.178 mmol) obtained in example 18 by a procedure similar to that described in example 12.
!H NMR (DMSO-d6, 200 MHz) : 6 0.78 (t, J = 7.28 Hz, 3H), 1.19 * 1.52 (complex, 4H), 2.72 -
3.02 (complex, 2H), 3.45 - 3.67 (complex, 211), 4.01 (bs, 3H), 4.18 (bs, 2H), 6.61 - 6.89 (complex, 8H), 7.10 - 7.24 (complex, 4H).

Example 20 3-[4-|2-(Phenoxazin-10-yl)etlioxy]plieyl]-2-hcxyloxypropanoic acid :

The title compound (0.10 g, 23 %) was obtained as a syrupy liquid from ethyl 3-[4-[2-(phenoxazin-10-yl)cthoxy]phenyl]"2-hcxyloxypropanoate (0.46 g, 0.96 mmol) obtained in example 10 by an analogous procedure to that described in example 11.
H\ NMR (CDCI3, 200 MHz) : 8 0.86 (t, J = 6.0 Hz, 3H), 1.18 - 1.30 (complex, 4H), 1.42 - 1.80
(complex, 4H), 2.88 - 3.18 (complex, 2H), 3.32 - 3.60 (complex, 2H)» 3.89 - 4.09 (complex, 3H), 4.16 (t, J = 6.0 Hz, 2H), 6.58 - 6.89 (complex, 10H), 7.14 (d, J = 8.63 Hz, 2H). COOH is too broad to observe. Example 21
((2R)-N(lS)]-3-[4-[2-(Phenoxaziii-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l-phenylcthyl)propanamide (21a)

f(2S)-N(lS)l-3-[4-[3-(tticno^ phenylethyl)propalia'mide (21b):

To an ice cooled solution of 3-[442-(phcnoxazin-10-yl)-cthoxy]phenyl]-2-ethoxy propanoic acid (1.2 g, 2.9 mmol) obtained in example 15 and triethylamine (0.48g, 5.8 mmol) in dry dichloromethane (25 mL) was added pivaloyl chloride (0,38 g, 3.19 mmol) and stirring was continued for further 30 min at 0 °C. A mixture of (S)-2-phcnylglycinoI (0.39 g, 2.9 mmol) and triethylamine (0.58 g, 5.8 mmol) in dichloromethane (20 mL) was.added to the above reaction mixture at 0 °C and stirring was continued for 2 h at 25 °C. Water (50 mL) was added and extracted with dichloromethane (2 x 50 mL). The organic extracts were washed with water (2 x

25 mL) and brine (25 mL), dried (Na2SC>4) and evaporated. The residue was chromatographed over silica gel using a gradient of 40 - 60 % ethyl acetate in pet. ether as an eluent to afford firstly a diastereomcr tentatively assigned as [2R, N(liS)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l-phcnylethyl)propanamide (0.55 g, 35 %) (21 a) followed by of [25'-N(lS)]-3-[4-[2-(phenoxazin-l 0-yl)ethoxy]phcnyl]-2-ethoxy-N-(2-hydroxy-l-phcnylethyl) propanamide (0.5 g, 32 %) (21b). 21a : nip: 126-128 °C. [a]D25 = + 24.6 (c = 1.0 %, CHCb).
'H NMR (CDCI3, 200 MHz) : 5 1.16 (I, J = 7.20 Hz, 3H), 2.50 (bs, 1H, D20 exchangeable),
2.92 - 3.20 (complex, 2H), 3.52 (q, J = 7.05 Hz, 2H), 3.72 (bs, 2H), 3.99 (complex, 3H), 4.21 (t,
J = 6.64 Hz, 2H), 4.98 - 5.01 (complex, 1H), 6.64 - 6.70 (complex, 5H), 6.73 - 6.89 (complex,
4H), 7.03 (d, J = 7.15 Hz, 1H), 7.18 - 7.29 (complex, 4H), (J = 7.32 - 7.39 complex, 3H). CONH
is too broad to observe.
21b :mp: 139- 141 °C.
[a]D25 = -13.3 (c, 1.00 %, CHCI3)
lH NMR (CDCI3, 200 MHz) : 5 1.18 (t, J = 6.96 Hz, 3H), 2.05 (bs, 1H, D20 exchangeable),
2.80 - 3.14 (complex, 2H), 3.54 (q, J = 7.0 Hz, 2H), 3.85 (bs, 2H), 3.97 (complex, 3H), 4.14 (t, J = 6.23 Hz, 2H), 4.92 - 5.01 (complex, 1H), 6.62 - 6.85 (complex, 9H), 7.02 - 7.20 (complex, 5H), 7.26 - 7.30 (complex, 3H). CONH is too broad to observe. Example 22 (R)-3-I4-[2-(Phenoxazin-10-yl)ethoxy]phcnyll-2-cthoxypropanoic acid :

A solution of [2R diastereomer, N(lS)]«3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane / water (1 : 1, 39 mL) was heated at 90 °C for 88 h. The pll of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2 x 25 mL) and the organic
extract was washed with water (50 mL), brine (25 mL), dried (Na2S04) and evaporated. The residue was chromatographed over silica gel using a gradient of 50 - 75 % ethyl acetate in pet. ether to afford the title compound (6,2 g, 57 %) as a white solid, mp : 77 - 78 °C. [a]n25 = + 12.1 (c = 1.0 %, CHClj)

]H NMR (CDCI3, 200 MHz) : 6 1.16 (I, J = 7.0 Hz, 3H), 1.43 - 1.85 (bs, 1H, D20
exchangeable), 2.86 - 3.14 (complex, 2H), 3.40 - 3.67 (complex, 2H), 3.90 - 4.08 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.59 - 6.83 (complex, 10 H), 7.13 (d, J = 8.4 Hz, 2FT). Example 23 (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]plicnyl]-2-etIioxypropanoic acid :

The title compound (0.19 g, 54 %) was prepared as a white solid from diaslcreomer [(2S-N(1S)]-
3-[4-[2-(phenoxazin-10-yl)cthoxy]phenyl]-2-cthoxy-N-(2-hydroxy-l-phenyl)propanamide (0.45
g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example
22. mp : 89 - 90 °C. \.
[ot]D25 = -12.6 (c = 1.0 %, CHCI3)
lH NMR (CDCI3, 200 MHz) : 5 1.16 (t, J = 7.02 Hz, 3H), 1.42 - 1.91 (bs, 1H, D20
exchangeable), 2.94 - 3.15 (complex, 2H), 3.40 - 3.65 (complex, 2H), 3.86 - 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 - 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).
1
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.
1
Demonstration of Efficacy of Compounds :
A) In vitro :
a) Determination of hPPARa activity :
Ligand binding domain of hPPARa was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryolic expression vector. Using superfect (Qiagen, Germany) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at different concentrations after 42 hrs of transaction and incubated overnight. Luciferase activity as a function of compound binding/activation capacity of PPARa was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Mollis. Gene. 1992. 118 ; 137 —141; Superfect Transfection Reagent 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 eucaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as
transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid
harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at 1
\xhi 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 Transfcctions with Caiionic Lipid
Reagents. Life Technologies, GIBCO BRL, USA). 'C

c) Determination of HMG CoA reductase inhibition activity : Liver microsome bound
reductase was prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometry
assays were carried out in 100 mM KH2P04, 4 mM DTT, 0.2 mM NADPH, 03 mM HMG CoA
and 125 |ig 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 j-eceptor and
HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol J. Lipid Res.
1984, 25: 1450 - 1461). The test compounds inhibited the HMG CoA reductase enzyme.
B) In vivo :
a) Efficacy in genetic models : ;
Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the, development of animal models with non-insulin dependent diabetes and hypcrlipidemia associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (Diabetes, (1982) 31(1) : 1- 6) mice and zucker fa/fa rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838 ; Annu. Rep. Sankyo

Res. Lab. (1994). 46 : 1-57), The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
■ Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water, ad libitum. The animals having more than 350 mg / dl blood sugar were used for testing. The number of animals in each group was 4.
Test compounds were suspended on 0.25 % carboxymcthyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml / kg). On 6th day the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
The random blood sugar and triglyceride levels were measured by collecting blood (100 j.il) through orbital sinus, using heparinised capillary in tubes containing EDTA which was ccntrifuged to obtain plasma. The plasma glucose and triglyceride levels were measured spcclrometrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase vpnzyme (Dr. Reddy's Lab. Diagnostic Division Kits, Hyderabad, India) methods respectively.
The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
No adverse effects were observed for any of the mentioned compounds of invention in the above test.

The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Demark and were
used at 8 weeks of age. Zucker fa/fa fatty rats were obtained from IffaCredo, France at 10 weeks
I

of age and were used at 13 weeks of age. The animals were maintained under 1J[ hour light and dark cycle at 25 + 1 °C. Animals were given standard laboratory chow (NIN, Hyderabad, India) and water, ad libitum (Fujiwara, I\, Yoshioka, S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ab 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 % cnrboxymethylcellulose, dose 10 ml/jcg) through oral gavage.
The blood samples were collected in fed state 1 hour after drug administration on 0 and 9 day of treatment. The blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations. Measurement of plasma triglyceride, glucose, total cholesterol were done using commercial kits (Dr. Rcddy's Laboratory, Diagnostic Division, 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, Zucker fa/fa rats suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidaemia and other diseases; as it is known from the literature that such diseases are interrelated to each other.
Blood glucose level and triglycerides are also lowered at doses greater than 10 mg/kg. Normally, the quantum of reduction is dose dependent and plateaus at certain dose.
b) Cholesterol lowering activity in hypcrcholcsterolemic rat models :

Male Sprague Dawley rats (MIN stock) were bred in DRF animal house. Animals were maintained under 12 hour light and dark cycle at 25 ± 1 °C. Rats of 180 - 200 gram body weight range were used for the experiment. Animals were made hypercholesterolcmic by feeding 2% cholesterol and 1% sodium cholalc mixed with standard laboratory chow [National Inslitute of Nutrition (NIN), Hyderabad, India] for 6 days. Throughout the experimental period the animals were maintained on the same diet (Petit* D., Bonncfls, M, T., Rcy, C and Infante, R. Effects of ciprofibralc on liver lipids and lipoprotein synthesis in normo- and hypcrlipidcmic rats. Atherosclerosis. 1988. 74 : 215-225).
The test compounds were administered orally at a dose OJ to 30 mg/kg/d^y for 3 days. Control group was treated with vehicle alone (0.25 % CarboxymclhylcelluIo#c; dosq 10 ml/kg).
The blood samples were collected in fed state 1 hour after drug administration on 0 and 3 day of compound treatment. The blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction of various parameters examined are calculated according to the formula.
c) Plasma triglyceride and total cholesterol lowering activity in Swiss albino mice and
Guinea pigs :
Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NIN and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 ± 1 °C. Animals were given standard laboratory chow (NIN, Hyderabad, India) and water, ad libitum. SAM of 20 - 25 g body weight range and Guinea pigs of 500 - 700 g body weight range were used (Oliver, P., Planckc, M. O., Marzin, D., Clavey, V., Sauzicres, J and Fruchart, J* C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis. 1988. 70 : 107 - 114).
The test compounds were administered orally to Swiss -albino mice at 0.3 to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds were administered orally to
/

Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days. Control animals were treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
The blood samples were collected in fed slate 1 hour after drug administration on 0 and 6 day of treatment. The blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubea. After ccntrifugation, plasma sample was separated for triglyceride and total cholesterol (Wicland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27). Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, Hyderabad, India).
Formulae for calculation :
1. Percent reduction in Blood sugar / triglycerides / total cholesterol were calculated
according to the formula : !
Percent reduction (%) = 1 - TT/OT X 100
TC/OC OC = Zero day control group value
OT = Zero day treated group value
TC - Test day control group value
TT = Test day treated group value
2. LDL and VLDL cholesterol levels were calculated according to the formula :
LDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - Triglyceride
5 VLDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - LDL cholesterol






Claims :

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its
i lit
pharmaceutical^ acceptable salts, its pharmaceutical^ acceptable solvates, wherein R , R, R ,
R4 may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hetcroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyi, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring containing X and N represents a 5-6 membcred cyclic structure containing carbon atoms, which may optionally contain one or more hcteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a hcteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R6 forms a bond together with R's; R7 may be hydrogen or optionally substituted . groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups; Y represents oxygen or NR10, where R10 represents hydrogen, alkyl, aryl, hydroxyalkyL or aralkyl groups; R8 and R10 together may form a 5 or 6 membcred cyclic structure containing carbon atoms, which may

optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer 0 or 1.
2. A compound according to claim 1 wherein the subsitucnts on R1 - R4 are selected from halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxyalkyl, hcterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives .
3. A compound according to claim 1 wherein the cyclic structure A represents phenyl or
pyridyl rings.
i
4. A compound according to claim 1 wherein Ar represents optionally substituted divalent
phcnylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzolhiazolyl,
indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl,
dihydrobenzopyranyl, pyrazolyl groups.
r
5. A compound according to claims 1 and 4 wherein the substitucnts on the group represented by Ar are selected from linear or branched optionally halogenated (Q-Cejalkyl, optionally halogenated (Ci-Cj)alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic acid and sulfonic acids and their derivatives.
6. A compound according to claim 1 wherein when m = 0, Ar represents a divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, dihydrobenzopyranyl groups.
7. A compound according to claim 1 wherein when m = 1, Ar represents divalent
" phcnylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl,
indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl.
8. A process for the preparation of compound of formula (III)'


its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutical^ acceptable salts, its pharmaceutical^ acceptable solvates, wherein R', R\ RJ, R may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, fonnyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxyv aryl, aryloxy, aralkyl, aralkoxy, hcterocyclyl, hctcroaryl, hcteroaralkyl, heteroaryloxy, hetcro||ralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylaminp, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, firalkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, araIkoxy alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, hctcroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted grouPs selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl grpups; n is an integer ranging from 1-4 and m is an integer 0 or 1; which comprises ;





ils derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutical^ acceptable salts, its pharmaceutical^ acceptable solvates, wherein R1, R2, R3, R may be same or different and represent hydrogen, halogen, hydroxy, nilro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, hcterocyclyl, hctcroaryl, hctcroaralkyl, hctcroaryloxy, hetefoaralkoxy, acyl,

acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl* aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring X and N represents a 5-6 membered cyclic structure containing carbon atoms, which may optionally contain one or more hcteroaloms selected from oxygen, sulfur or nitrogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a hcteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alky], aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen, hydroxy, alkoxy, halogep, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R6; R6 . represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R6 forms a bond together with R5; R7 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, hetcrocyclyl, hcteroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, hetcrocyclyl, heteroaryl, heteroaralkyl groups; Y represents oxygen; n is an integer ranging from 1-4 and m is an integer 0 or 1; which comprises :
i







its derivatives, ils analogs, its tautomeric forms, its stereoisomers, its polymorphs, its
pharmacculically acceptable sails, its phnrmnccutically acceptable solvates, wherein R1, R2, RJ,
R may be same or different and represent hydrogen, halogen, hydroxy, nilro, cypno, formyl or
optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy; aryl, aryloxy,
aralkyl, aralkoxy, heterocyclyl, heteroaryl, hclcroaralkyl, hctcroaryloxy, hctcroaralkoxy, acyl,
i acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylaminp, aminoalkyl,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl,
alkyllhio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,
carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring
containing X and N represents a 5-6 membcred cyclic structure containing carbon atoms, which
may optionally contain one or more hetcroatoms selected from oxygen, sulfur or nitrogen atoms,
which may optionally be substituted; the ring A may be saturated or contain one or more double
bonds or may be aromatic; X repreMfcts a heteroatom selected from oxygen, sulfur or NR9
where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused
aromatic or heterocyclic group; R5 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl,
optionally substituted aralkyl group or fonns a bond together with the adjacent group R6; R6
represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted
aralkyl or R forms a bond together with R ; R may be hydrogen or optionally substituted
groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,
aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,
hcteroaralkyl groups; R may be hydrogen or optionally substituted groups selected from alkyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, hcteroaralkyl groups; Y represents NR10,
where R10 represents hydrogen, alkyl, aryl, hydroxyalkyl or aralkyl groups; R8 and R10 together
may form a 5 or 6 membered cyclic structure containing carbon atoms, Which may optionally
contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging
from 1-4 and m is an integer 0 or 1; which comprises

a) reacting a compound of formula (I) where all the symbols are as defined above and Y
represents oxygen with appropriate amines and if needed;
b) converting the compounds of formula (I) obtained above into pharmaceutically
acceptable salts, or pharmaceutically acceptable solvates;

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, hydroxy, nilro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, hclcroaralkyl, heteroaryloxy, hcteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylaraino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aj-alkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fusf;d to the ring containing X and N represents a 5-6 membcred cyclic structure containing carbon tytoms, which may optionally contain one or more hetcroatoms selected from oxygen, sulfur or nijfogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R forms a bond together with R ; R may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted .groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, Heteroaralkyl groups; n is an integer ranging from 1-4 and m is an integer 0 or 1, prepared according to the process of claim 8*

1
Its derivatives, its. analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutical^ acceptable salts, its pharmaceutically acceptable solvates, wherein R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, alkylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring containing X and N represents a 5-6 membcrcd cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a hetcroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen, hydroxy, alkoxy,,halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R ; R represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R6 forms a bond together with R5; R7 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R8 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups; Y represents oxygen; n is an integer ranging from 1-4 and m is an integer 0 or 1, prepared according to the process of claim 9, 13. A compound of formula (I)


its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its
' 12 3
pharmaceutical^ acceptable salts, its pharmaceutical^ acceptable solvates, wherein R , R , R , R4 may be same or different and represent hydrogen, halogen, hydroxy, nilro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, hctcroaralkyl, heteroaryloxy, hctero^ralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, alkylamino, aralkylaminp, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonyiamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the ring A fused to the ring containing X and N represents a 5-6 membcred cyclic structure containing carbon atoms, which may optionally contain one or more hcteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be substituted; the ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a hclcro&tom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl; acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like; Ar represents an optionally substituted divalent ajngle or fused aromatic or heterocyclic group; R represents hydrogen atom, hydroxy, alkoxy, tyilogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R forms a bond together with R'; R may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, hctcroaralkyl groups; R may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heleroaralkyl groups; Y represents NR10, where R10 represents hydrogen, alkyl, aryl, hydroxyalkyl or aralkyl groups; R8 and R10 together may form a 5 or 6 membcred cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer 0 or 1, prepared according to the process of claim 10.
14, A compound according to claim 1 which is selected from :

Ethyl (E/Z)"3-[4-[2-(Phenothiazin-10-yl)c(lioxy]phenyI]-2-ethoxy propenoatc ancj its salts ; Ethyl (E)-3-[4-[2-(Phenothiazin*10-yl)cthoxy]phenyl]-2-ethoxy propenoatc and its salts ; Ethyl (Z)-3-[4-[2-(Phenothiazin-10'yl)cthoxy]phcnyl]-2-cthoxy propenoatc and its salts ;
EthylE/Z)-3-[4-[2-[phenothiazin-10-yI)mclhylbcnzofuran-5-yl)-2-cthoxypropcnoatc and its salts;
i
EthyI(E)-3-[4-[2-[phcnothiazin"10-yI)mcthylbcnzofuran-5-yl)-2-elhoxypropcnoatc and its salts ; Ethyl(Z)-3-[4-[2-[phenothiazin-10-yl)melhyIbcnzofuran-5-yl)-2-cthoxypropcnoatc and its salts ; Ethyl (E/Z)-3-[4-[2-(phenoxazin-10'yl)cthoxy]phenyl]-2-ethoxypropcnoatc and its salts ; Ethyl (E)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2"ethoxypropenoate and its salts ; Ethyl (Z)^3-[4"[2-(phenoxazin-10-yl)cthoxy]phenyI]-2-ethoxypropcnoatc and its s^lts ; (+) Methyl 3-[4-[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoatc and its salts ; (+) Methyl 3-[4-[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoatc and its salts ; (-) Methyl 3-[4«[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoate and its salts ; (+) Methyl 3-[2-(phcnothiazin-10-yl)mclhylbenzofuran-5-yl]-2-cthoxypropanoatc and its salts; (+) Methyl 3-[2-(phenothiazin-10-yl)methylbcnzofuran-5-yl]-2-clhoxypropanoate and its salts; (-) Methyl 3-[2-(phenothiazin-10-yl)niethylbcnzofuran"5-yl]-2-ethoxypropanoate and its salts; (+) Methyl 3«[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate and its salts ;
(+) Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]*2-cthoxypropanoate and its §alts ;
/
!
(-) Methyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate and its s^lts ; (+) Ethyl 3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl-2-ethoxypropanoale and its sal|s ; (+) Ethyl 3«[4-(2-(phenoxazin-10-yl)ethoxy]phcnyl-2-ethoxypropanoatc and its salts ; (-) Ethyl 3-t4-(2-(phenoxazin-10-yl)ethoxy]phenyl-2-ethoxypropanoate and its salts ; (+) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate and its salts ; (+) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate and its salts ; (-) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-hydroxypropanoate and its salts ; (+) Ethyl 3-[4-[2-(phenoxazin-10-yI)cthoxy]phcnyl]-2-butoxypropanoate and its salts ; (+) Ethyl 3"[4-[2-(phenoxazin-10-yl)cthoxyJphcnyl]-2-butoxypropanoatc and its salts ; (-) Ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-butoxypropanoate and its salts ; (+) Elhyl 3"[4-[2-(phenoxazin-10-yl)cthoxy]phcnyl]-2-hexyloxypropanoatc and its salts ; (+) Ethyl 3-[4-t2-(phenoxazin'10-yl)cthoxy]phcnyl]"2»hexyloxypropanoate and its salts ; (-) Ethyl 3-[4-[2-(phenoxazin-10-yl)cthoxy]phcnyl]-2-hexyloxypropanoate and its salts ;

(+) 3-t4-[2-(Phcnothiazin-10-yl)ethoxy]phcnyI]-2-ethoxypropanoic acid and its salts ;
(+) 3-[4-[2-(Phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoic acid and its salts ;
(■) 3-[4-[2-(Phenotliiazin-10-yl)clhoxy]phcnyl]-2-ethoxypropanoic acid and its sails ;
(+) 3-[4-[2-(Phcnothiazin-10'yl)cthoxy]phcnyl]-2-ethoxy-2-methylpropanoic acid and its salts ;
(+) 3-[4-[2-(Phenolhiazin-10-yI)cthoxy]phcnyI]-2-elhoxy-2-methylpropanoic acid and its salts ;
(■) 3-[4-[2-(Phenolhiazin-10-yl)ethoxy]phcnyl]-2-clhoxy-2-melhylpropanoic acid and its salts ;
(jl) 3-[4-[2-(Phcnothiazin-10-yl)clhoxy]phcnyl]-2-phcnoxypropanoic acid and its salts ;
(+) 3-[4-f2*(Phenolhiazin-10-yl)clhoxy]phcnyl]-2-phenoxypropanoic acid and its salts ;
(-) 3-[4-[2-(Phenothiazin-10-yl)ethoxy]phcnyl]-2-phcnoxypropanoic acid and its sqlts ;
(+) 3-[4-[2-(Phenothiazin-10-yl)clhoxy]plicnyl]-2-phcnoxy-2-mcthyIpropanoic acid and its salts ;
(+) 3-[4-[2-(Phenolhiazin-10-yl)clhoxy]phcnyl]-2-phenoxy-2-mclhyIpropanoic acid and its salts ;
(-) 3-[4-[2-(Phcnothiazin-10-yl)cthoxy]phcnyI]-2-phcnoxy-2-mctbyIpropanoic acid and its salts ;
(+) 3-[2-(Phenothiazin-10-yl)mclhyl bcnzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
(+) 3-[2-(Phcnothiazin-10-yI)mcthyl bcnzoryran-5-yl]-2-ethoxypropanoic acid and its salts;
(-) 3-[2-(Phenothiazin-10-yl)metbyl bcnzofuran-5-yl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(Phcnoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts;
(+) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phenyl]-2-ethoxypropanoic acid and its salts ;
(") 3-t4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and its salts '
(±) 3-[4-[2-(Phenoxazin-10-yl)clhoxy]phcnyl]-2-cthoxy-2-melhylpropanoic acid apd its salts;
(+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoic acid and its salts ;
(-) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phenyl]-2-cthoxy-2-methylpropanoic acid and its salts ;
r
(+) 3-[4-[2-(Phenoxazin*10->4)ethoxy]phcnyl]-2-phenoxypropanoic acid and its salts;
(+) 3-[4-[2-(Phenoxazin-10-ypethoxy]phenyl]-2-phenoxypropanoic acid and its salts ;
(-) 3-t4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoic acid and its salts ;
(+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2-phenoxy-2-methylpropanoic acid and its salts;
(+) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phcnyl]-2-phenoxy-2-mcthylpropanoic acid and its salts ;
(-) 3-[4-[2-(Phenoxazin-10*yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)cthoxy]phcnyl]-2-hydroxypropanoic acid and its salts ; (-) 3-[4-[2-(Phenoxazin-10-yl)elhoxy]phcnyl]-2-hydroxypropanoic acid and its salts ;

(+) 3-t4-[2-(Phenoxazin-10-yl)elhoxy]phcnyl]-2-buloxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phcnyl]-2-butoxypropanoic acid and its salts ; (") 3-[4-[2-(Phenoxazin*10-yl)elhoxy]phcnyl]-2-butoxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin-10-yI)ethoxy]phcnyl]-2-hexyloxypropanoic acid and its salts ; (+) 3-[4-[2-(Phenoxazin:10-yl)ethoxy]phcnyI]-2-hexyloxypropanoic acid and its salts ; (-) 3-t4-t2-(Phcnoxazin-10-yl)cthoxy]phcnyI]-2-hexyloxypropanoic acid and its salts ; t(2R)-N(lS)]O-[4-[2-(Phenoxazin-10-yl)clhoxy]phcnyI]-2-ethoxy-N-(2-hydroxy-l-phenyl cthyl)propanamide and its salts ;
[(2S)-N(lS)]-3"[4"[2-(Phenoxazin-10-yl)cthoxy]phenyl]-2-ethoxy-N-(2-hydroxy^j-phenyl cthyl)propanamide and its salts ;
[(2S)-N( 1 S)]-3-[4-[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1 -phenyl ethyl)propanamide and its salts ; [(2R)^N(lS)]-3-[4-[2-(phenothiazin-10-yl)cthoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l-phenyl
ethyl)propanamide and its salts ;
15. A method of preventing or'treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a compound of formula (I) as defined in claim 1 to a patient in need thereof.
16. A method according to claim 15, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic
syndrome, hypertensive nephrosclerosis, psoriasis, and polycystic ovarian syndrome (PCOS),
4
useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating!
diabetic complications and osteoporosis. ,
17. A method according to claim 15 for the treatment and / or prophylaxis of disorders
related to Syndrome X, which comprises administering an agonist of PPARa and / or PPARy of
formula (1).


as defined in claim 1 and a pharmacculically acceptable carrier, diluent, excipient or solvate,
19. A pharmaceutical composition as claimed in claim 18, in the form of a tablet, capsule,
powder, syrup, solution or suspension. /
20. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia,
osteoporosis, obesity, glucose intolerance, insulin resistance, or diseases in which insulin
resistance is the underlying pathophysiological mechanism comprising administering a
compound of formula (I) as defined in claim 1, and a pharmaceutical^ acceptable carrier,
diluent, solvate or excipient to a patient in need thereof
21. A method according to claim 20, wherein the disease is type II diabetes, impaired glucose
tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, insulin

24. A pharmaceutical composition as claimed in claim 18 for the treatment and / or
prophylaxis of type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidcmia,
coronary artery disease and other cardiovascular disorders, certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
psoriasis, and polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for
improving cognitive functions in dementia and treating diabetic complications and osteoporosis.
25. . A pharmaceutical composition which comprises, a compound according to claim 14 as an
active ingredient and a pharmaceutically acceptable carrier, diluent or excipicnt.
26. A pharmaceutical composition as claimed in claim 14, in the form of a tablet, capsule,
powder, syrup, solution or suspension.
27. . A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia,
osteoporosis, obesity, glucose intolerance, insulin resistance, or diseases in which insulin
resistance is the underlying pathophysiological mechanism comprising administering a
compound of as defined in claim 14/ and a pharmaceutical^ acceptable carrier, diluent, solvate
or excipient to a patient in need thereof.
28. A method according to claim 27, wherein the disease is type 2 diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidcmia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis, and polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications and osteoporosis.
29. A method of reducing blood glucose, triglycerides, cholesterol and free fatty acids comprising administering a compound as defined in claim 14 and a phannaceulically acceptable carrier, diluent or solvates or excipient to a patient in need thereof.
*
30. A pharmaceutical composition containing a compound defined in claim 14 for the
treatment and/or prophylaxis of wherein the disease is type II diabetes, impaired glucose
tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, insulin

resistance, atherosclerosis, hyperlipemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis, and polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications and osteoporosis.

where Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group, R5 represents hydrogen, hydroxy, alkoxy, halogen or lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R6; Rfl represents hydrogen, * hydroxy, alkoxy, halogen or lower alkyl group, optionally substituted aralkyl or R6 forms a bond together with R5; R7 may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,
Q
arylaminocarbonyl, acyl, heterocyclyl, hctcroaralkyl groups; R may be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, hctcroaralkyl groups; n is an integer ranging from 1-4 and m represents an integer 1 and L1 is a leaving group, useful in the preparation of pharmaceutical compounds of formula (T).
32, A process for the preparation of compound of formula (If) described in claim 31, which comprises :

where R5, R6, R7, R8 and Ar are as defined in claim 31, with a compound of formula (IV)
L1-(CH2)n-L2 (IV)
where L1 and L2 may be same or different and represent a leaving group or L may also represent a hydroxy or a protected hydroxy group which may be further converted to a leaving group, n represents an integer 1-4.

b) reacting a compound of formula (V)
L1-(CH2)n-(0)m-Ar-CHO (V)
where L1 represent a leaving group and all other symbols are as defined earlier, with a compound of formula (Illb)
11 i &
where R may be a lower alkyl group and R , R are as defined in claim 31, to yield a compound
of formula (Illf)
where all symbols are as defined above and L' is a leaving group, which is further reduced to yield a compound of formula (If).

Documents:

2416-mas-1997-abstract.pdf

2416-mas-1997-assignment.pdf

2416-mas-1997-claims filed.pdf

2416-mas-1997-claims granted.pdf

2416-mas-1997-correspondence others.pdf

2416-mas-1997-correspondence po.pdf

2416-mas-1997-description complete filed.pdf

2416-mas-1997-description complete granted.pdf

2416-mas-1997-description provisional.pdf

2416-mas-1997-form 1.pdf

2416-mas-1997-form 13.pdf

2416-mas-1997-form 18.pdf

2416-mas-1997-form 3.pdf

2416-mas-1997-form 6.pdf

2416-mas-1997-other documents.pdf

2416-mas-1997-pct.pdf

abs-2416-mas-1997.jpg


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Patent Number 211559
Indian Patent Application Number 2416/MAS/1997
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 05-Nov-2007
Date of Filing 27-Oct-1997
Name of Patentee DR. REDDY'S LABORATORIES LTD
Applicant Address 7-1-27 AMEERPET, HYDERABAD 500016,
Inventors:
# Inventor's Name Inventor's Address
1 BRAJ BHUSHAN LOHARY DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
2 VIDYA BHUSHAN LOHARY DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
3 ASHOK CHANNNA VEERAPPA BAJJI DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
4 KANCHAR SHIVARAMAYYA DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
5 RAMANUJAM RAJAGOPALAN DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
6 RANJAN CHAKRAARTI DR. REDDY'S LABORATORIES LTD,7-1-27 AMEERPET, HYDERABAD 500016,
PCT International Classification Number A61K031/54
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA