Title of Invention	NOVEL AZOLIDINEDIONE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Abstract	Novel Azolidinedione compounds, process for their preparation and pharmaceutical compositions containing them Novel antidiabetic compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them; methods for preparing the antidiabetic compounds and their uses.

Title of Invention

NOVEL AZOLIDINEDIONE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

Novel Azolidinedione compounds, process for their preparation and pharmaceutical compositions containing them Novel antidiabetic compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them; methods for preparing the antidiabetic compounds and their uses.

Full Text	Field of the Invention The present invention relates to novel antidiabetic compounds, their tautomeric forms, their dervatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione of the general formula (I), their derivativesj their analogues, their tautomeric fprms, .their stereoisomers, their polymorphs and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process for the preparation of the above said novel azolidinedione compounds, their analogues, their d«ivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and pharmaceutical compositions containing them. _ This invention also relate to novel intermediates, processes for preparing the intehnediates and processes for using the intermediates. The azolidinediones of the general fonnula (I) defined above of the present invention are useful for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes^ impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis. The azolidinediones of the fonnula (I) are useful for the treatoient of insulin resistance associated with obesity and psoriasis. The Azolidinediones of the fonnula (I) can also be used to treat diabetic complications and can be used for treatment and/or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), cwtain renal diseases, including diabetic n^hropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage raial diseases and microalbuminuria as well as certain eating disorders, as aldose reductase Inhibitors and for improving cognitive functions in dementia. Background of the Invention 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 whichj the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnonnalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl J. Med. (1987) 317: 350 - 357 ; J. Clin. Endocrinol. Metab., (1988) 66 :580 - 583; J. Clin. Invest, (1975) 68 : 957 - 969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being reco^iized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclCTOsis and type 2 diabetes mellitus. The association of insulin resistance wifli obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108), draientia (Behavioral Brain Research (1996) 75 : 1 - 1 1) etc. may also have insulin resistance as a central pathogenic feature. Recently, it has also been reported that thia2oHdinediones improve the bone mineral density and thus may be useful for the treatment of osteoporosis (EP-783888). A number of molecular defects have been associated with insulin resistarifee. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis. Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related implications, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compound^ which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref Chem. Pharm. Bull 1982, Jf?, 3580-3600). In the formula (II), V rq)resents substituted or unsubstituted divalent aromatic group, B represents a sulfur or an groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R" and R^ may also together represent, along with carbon atoms to which they are attached an aromatic pyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR" where R" is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like wherein these groups are defined as for R"-R; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group, R" represents hydrogen atom, hydroxy, alkoxy, halogen or lower alkyl such as (d - Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted aralkyl group or forms a bond together with the adjacent group R"; R represents hydrogen, hydroxy, alkoxy, halogen or lower alkyl group such as (Ci-Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted suralkyl or R* forms a bond together with R"; B represents an oxygen atom or a sulfiir atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one. . Suitable groups represented by R" - R^ include hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro; substituted or unsubstituted (Q-Ci2)alkyl group, especially, linear or branched group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; aryloxyalkyl group such as CgHjOCHa, C6H5OCH2CH2, naphthyloxymethyl and the like; Jbieteroaiyloxy 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 ethoxycarbonyl; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aiylamino group such as HNCgHs; NCH3(C6H5)-hfHC6H4CH3; -NHC6H4-Hal and the like; amino group; amino(C\|-C6)alkyl; hydroxy(C\|-C6)alkyl; (Ci-C6)alkoxy; thio(Ci-C6)alkyl; (Ci- C6)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acylamitio groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOCeHs, aralkoxycarbonylamino group such as NHCOOCH2C6H5, -NHCOOCH2CH2C6H5, - NCH3COOCH2C6H5, -NC2H5COOCH2C6H5, -NHCOOCH2C6H4CH3, NHCOOCH2C6H4OGH3 and the like; alkoxycarbonylamino group such as NHCOOC2H5, NHCOOGH3 and the like; carboxylic acid or its derivatives such as amides, like CONH2, CONHMe, CONMea, CONHEt, C0NEt2, 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 SO2NH2, S02NHMe, S02NMe2, SO2NHCF3 and the like; the sulfonic acid derivatives may be substituted. Ail the groups represented by R"-R^ may be substituted and the substituents may be selected from the same groups represented by R"-R^ and are defined in the same way. Suitable cyclic structure formed by R", R^ together with carbon atoms to which they are attached contain 5 to 6 ring atoms, preferably, optionally substituted phenyl, pyridyl, furanyl, thienyl, pyrrolyl, and the like; substituents may be selected from the same groups rqpresraited by R"- R^ and are defused in the same way. Preferred substituents are halogen, (Ci-C6)alkoxy, cyclo(C3-C6) alkyl, cyclo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxy, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, aminocarbonyl and the like. Suitable X includes oxygen, sulfur or a group NR" as defined above. X is preferably oxygen or sulfur. The group represented by Ar includes substituted or unsubstituted divalent phenylene, 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 include linear or branched optionally halogenated (Ci-C6)alkyl, optionally halogenated (C\|-C3)alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic and sulfonic acids and their derivatives. The substituents are defined as they are for R"-R^ It is more preferred that Ar represents a substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl group. It is still more preferred that Ar represents a divalent phenylene or benzofuranyl, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups. Suitable R" includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy; (Ci-C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, or iodine; aralkyl such as C6H5GH2, C6H5CH2CH2, C6H5CH2CH2CH2, naphthylmethyl and the like, substituted aralkyl such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like, or R together with R represents a bond. Suitable R may be a hydrogen atom, hydroxy, (Ci-C3)alkoxy; halogen selected from fluorine, bromine, iodine and chlorine, lower alkyl group such as (C1-C12) alkyl, aralkyl such as G6H5CH2, C6H5CH2CH2, C6H5CH2CH2CH2, naphthyhnethyl and the like, substituted aralkyl such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2. CH3OC6H4CH2CH2 and the like, or together with R forms a bond. It is preferred that R" and R^ represent hydrogen atoms or R" and R* together represent a bond. Suitable B group includes a hetero atom selected from O or S, preferably sulfur atom. Suitabte ring structure comprising B and Y include 2,4-dioxooxazolidin-5-yl, 2,4-dioxothiazolidin-5-yl, 4-oxazolidone-2-thione-5-yl groups. Preferred ring structures comprising B include 2,4rdioxooxazolidin-5-yl and 2,4-dioxothiazolidin-5-yl groups. It is more preferred that the ring structure comprising B is a 2,4-dioxothiazolidin-5-yl group. Suitable Y group is a heteroatom selected from O or S. Suitable m is an integer ranging from 0-1. It is preferred that when m = 0, the linker group (CH2)n- is attached to the carbon atom adjacent to the heteroatom of the group Ar which represents an optionally substituted divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, or dihydrobenzopyranyl group and when m = 1, Ar represents substituted or unsubstituted divalent phenylene, naphthylene* pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, ^azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl. 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. It is also preferred that when n represents 2 and m represents 1, that Ax represents phenyl or naphthyl groups. Pharmaceutically acceptable salts forming part of this invention include salts of the azolidinedione moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, chohne and the like, ammonium or substituted ammonium salts, salts of carboxy group wherever appropriate, such as aluminum, alkali metal salts, alkaline earth metal salts, ammonium or substituted ammonium salts. Salts may include acid addition salts which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. Particularly useful compoimds according to the invention include : 5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yI)ethoxy]phenyl methylene]thiazolidine-2,4-dione; 5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione; 5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl methyl]thiazoIidine-2,4-dione, sodium salt; 5-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl methylene]thiazolidine-2,4-dione; 5-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl]ethoxy]phenyl methylJthiazolidine-2,4-dione; 5-[4-\|;2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyI methyI]thiazolidine-2,4-dione, sodium salt; 5-[4-[2-(Phenoxazin-10-yl)ethoxy]pheny 1 methylene]thiazoUdine-2,4-dione; 5-[4-[2-(Phenoxazin-10-y l)ethoxy]phenyl methyl3thiazolidine-2,4-dione; 5-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt; 5-[2-[(2,3-Dihydro-l,4-benzoxazin-4-ylmethyl)benzofuran-5-yl]methylene]thiazolidine-2,4-dione; = arall^Iamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, aralkoxycarbonylamino, alkoxycarbonylamino, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, mercaptoaikyi groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; or R" and R^ together may represent, along with carbon atoms to which they are " attached an aromatic cyclic structure containing 5 - 6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR" where R" 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; n is an integer ranging from 1 to 4 and m is zero or 1. CHjCN, EtOH, acetone or mixtures thereof. 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 base such as K2CG3, NaaCOj, KOH, NaOH, NaH and the like or mixtures thereof. The amount of base may range firom 1 to 20 equivalents, preferably 1 to 10 equivalents. The reaction may be carried out at a temperature in the range 20 "C to 180 °C, preferably at a temperature in the range 50 °C to 150 °C. Duration of the reaction may range from V to 48 hours, preferably fix)m 1 to 12 hours. The amounts of the compound of general formula (VIII) and (IX) may range from 1 to 20 equivalents, preferably from 1 to 5 equivalents. The reaction may be carried out in the presence of phase transfer catalysts such as quatemay ammonium halides or hydroxides such as tetrabutyl ammonium bromide, tetrabutylammonium hydroxide, benzyl trimethylammonium bromide, aliquat and the like. The present invention provides a process for the preparation of novel azolidinediones of general formula (I), their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polyniorphs, their pharmaceutically acceptable salts and their phannaceuticaUy acceptable solvates wherein R" and R^ together represent a bond and B represents a sulfur or oxygen atom and all symbols are as defined earlier which comprises: reacting the compound of general formula (III), where G is a CHO group with 2,4-thiazolidinedione, 2,4- oxazolidinedione or oxazolidone-4-oxo-2-thione to yield a compound of genwal fonnula (X) where R" - R^ X, Ar, n, m, B, and Y are as defined earlier, R" and R* together represent a bond and removing the water formed during the reaction by conventional methods. The reaction of the compound of the general formula (III) where G is a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound of general formula (X) may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof. The reaction temperature may range from 80 "C to 140 "C depending upon the solvents employed and in the range from 80 "C to 180 ^C when the reaction is carried out neat in the presence of sodium acetate. Suitable catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts may also be employed. Sodium acetate can be used in the presence of solvent, but it is preferred that sodium acetate is used neat. The water produced in the reaction may be removed, for example, by using Dean Stark water separator or by using water absorbing agents like molecular selves. When oxazolidine-4-oxo-2-thione is used to produce a compound of formula (X), wherein B represents oxygen atom and Y represents sulfur atom, the thio group may be converted to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPB A. The compound of the general formula (X) obtained in the manner described above is reduced by known method to obtain the compound of general formula (XI) where R" - R^ X, Ar, n, m, B and Y are as defined earlier. The compound of general formula (XI) represents the compound of general formula (I), wherein R" and R* represent hydrogen atom and all other symbols are as defined earlier. The reduction of compound of the formula (X) to yield a compound of the general formula (XI) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/G, Pt/C, Raney Nickel, and the like. Mixtures of catalysts may be used. The reaction may be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. Mixtures of solvents may be used. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol. The reaction may also be carried out with alkali metal borohydrides such as LiBHU, NaBH4, ICBH4 and the like in the presence of cobalt salt such as C0CI2 and ligands, preferably bidentated ligands such as 2, 2"-bipyridyl, 1, 10-phenanthroline, bisoximes and the like. * The compounds of general formula (X) and general formula (XI) obtained above may be converted into pharmaceuticaily acceptable salts, or pharmaceutically acceptable solvates by conventional methods. In yet another embodiment of the present invention, the compound of the general formula (I) where m represents I and all other symbols are as defined earlier, can also be prepared by reacting a compound of the general formula (IV) defined above with a compound of general formula (XII) HO-Ar (XII) whwe R", R", B, Y and Ar are as defined earlier and R"® is hydrog^ or a nitrogen protecting group which is removed after the reaction. The reaction of compound of general formula (IV) with a compoimd of general formula (XII) to produce a compound of general formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like ©r mixtures thereof. The reaction may be carried put in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide, or mixtures thereof Multiple solvents and bases can be used. The amount of base may range fi-om 1 to 5 equivalents, preferably 1 to 3 equivalents. The reaction temperature may be in the range of 0 "C to 120 "C, preferably at a temperature in the range of 20 °C to 100 °C. The duration of the reaction may range fi-om 0.5 to 24 hours, preferably fiom 0.5 to 6 hours. The removal of protecting groups may be carried out by conventional methods which include treatment with acid such as, hydrochloric acid, trifluoroacetic acid or bases such as, KOH, NaOH, NajCOa, NaHCOa, K2CO3 and the like or mixtures thereof These reagents may be used as aqueous solution or as solutions in alcohols like methanol, ethanol etc. Deprotection can also be effected by gaseous hydrogen in the presence of catalyst such as , NaOAc, KOAc, NaOJsle, NaOEt etc. can be used. The reaction is nonnally followed by treatment witti a mineral acid such as hydrochloric acid at 20 "C to 100 °C. The compound of general formula (XIII) where J is a halogen atom can be prepared by the diazotization of the amino compound of the general formula (XIV) where all symbols are as defined earlier, using alkali metal nitrites followed by treatment with actylic acid esters in the presence of hydrohalo acids and catalytic amount of copper oxide or copper halide. The compound of general formula (XIV) can in turn be prepared by the conventional reduction of the novel intermediate (III) where G is NO2 group and other symbols are as defined earlier. The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts are prepared by treatinent with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzene sulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used. As used in this application, the term neat means the reaction is carried out without the use of solvent. The stereoisomers of the compounds fomiing 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 or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Various polymorphs of the compounds of general formula (I) forming part of this invention may be prepared by crystallization of a 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 heatmg or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential iscanning calorimetry, powder X-ray diffraction or such other techniques. The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their tautomeric forms, their derivatives, their analogues, 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 arid/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglyc^nia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases in which msulin resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dysltpidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis; insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia. The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, s)"rups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active compound, the remainder of the composition being, pharmaeeutically acceptable carriers, diluents, excipients or solyents. A typical tablet production method is exemplified below: Tablet Production Example: a) 1) Active ingredient 30g 2) Lactose 95 g 3) Com starch 30g 4) Carboxymethyl cellulose 44 g 5) Magnesium stearate , Ig 200 g for 1000 tablets The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredients 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient. ) 1) Active ingredient 30g 2) Calcium phosphate 90 g 3) Lactose 40 g 4) Com starch 35 g 5) Polyvinyl pyrrolidone 3.5 g 6) Magnesium stearate 1.5 g 200 g for 1000 tablets The ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure. Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1. The compound of the formula (I) as defined above are clinically administered to mammals, including man, via eittier 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 either route, the dosage is in the range of about 0. 10 mg to about 200 mg / kg body weight of the subject per day or preferably about 0. 10 mg to about 50 mg / kg body weight per day administered singly or as a diviied 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 combmed 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 orgamc 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 fqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline eaxth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation 1 4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxylben2aldehyde: CHO Step A : Preparation of 2-(2,3-dihydro-l,4-benzoxazine-4-yl)ethyl metbanesuifonate - To a solution of 2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethanoi (17.0 g, 94.9 mmol) in pyridine (200 ml) was added methanesulfbnyl chloride (16.31 g, 142.0 mmol) dropwise at 0 "C. The reaction mixture was stirred for 10 h at 25 °C. Ice water (200 ml) was added and the mixture was extracted witti etltyl acetate ( 2 x 100 ml). The combined organic extracts were washed with 2N HCI (3 X 75 ml), water (75 ml), brine (50 ml) and dried (Na2S04). The sblvent was evaporated under reduced pressure. The residue was triturated with 5% ethyl acetate in pet. ethra-to afford the title cotn^ound (15.0 g, 61 %) as brown solid, mp. 92-95 °C. IH NMR (CDCI3, 200 MHz): 6 2.97 (s, 3H), 3.45 (t, J= 4.43 Hz, 2H), 3.64 (t, J = 5.72 Hz, 2H), 4.23 (t, I=^A2lHz, 21^, 4.4r(t, J = 5.71 Hzj2H)^ 6,66 (m, 2H), 6.83 (m, 2H). Step B : A mixture of 2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (5 g, 19.4 mmol) obtamed above, p-hydroxy benzaldehyde (5.56 g, 29.1 mmol) and potassium carbonate (10.75 g) in dry dimethyl formamide (50 ml) was heated to 70 °C for 7 h. The reaction mixture was cooled to room temperature. WaterflOG mi) was added to the trnxH^me and extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with water (50 n^, brine (50 ml) and dried (Na2S04). The solvent was removed imder reduced pressure to affQixi the title compoimd (4.0 g, 72 %) as a syrupy liquid. IH NIIR (CDCI3, 200 MHz) : 8 3.55 (t, .f = 4.3 Hz, 2H), 3.76 (t, J = 5.5 Hz, 2H), 4.26 (m, 4H), 6.74 (m, 2H), 6.83 (m, 2H), 7.02 (d, J - 8.6 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 9.90 (s, ■■"■ , IH). " ■ ■ To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-l,4-benzothiazin-4-)d)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25 "C. The reaction mixture was stirred for 12 h at 25 °C. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). The organic extracts were dried (Na2S04) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica.gel using a mixture of methanol and chloroform (5 : 95) as an eluent to afford the title compound (1.6 g, 44 %) as an oil. IH NMR (CDCI3, 200 MHz) : 6 3.05 (t, J = S^O Hz, 2H), 3.80 (m, 4H), 4.26 (t, J = 5.5 Hz, 2H), 6.68 (m, 2H), 7.03 (m, 4H), 7.83 (d,.) = 8 6 Hz, 2H), 9.88 (s, IH). To a suspension of sodium hydride (60 % mineral oil, 0.13 g, 3.24 mmol) in dimethyl fonnaldde (3 ml) was added phenoxazine (0.5 g, 2.7 mmol) in dimethyl formamide (5 mL). Tlie reaction mixture was stirred at 25 °C for 0.5 h and a solution of 4-(2-bromoethoxy)benzaldehyde (0.74 g, 3.24 mniol) in dimethyl formamide (3 mL) was added. The reaction mixture was stirred at 25 "C for 6 h. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (50 ml), brine solution (50 ml) and dried (Na2S04). The solvent was evaporated and tfie residue was chromatographed over silica ^el using a mixture of ethyl acetate and pet. ether (3 : 7) as eluent to afford the title compound (0.52 g, 57 %) as a syrupy liquid. IHNMR (CDCI3,200 MHz): 8 3.67 (t, i = 6.2 Hz, IH), 4.05 (t, J = 6.2 Hz, IH), 4.28 (t, J.= 6.3 Hz, IH), 4.38 (t, J = 6.2 Hz, IH), 6.75 (m, 8H), 7.02 (m, 2H), 7.87 (m, 2H), 9.90 (s, IH). Preparation 4 4-[2-(Phenothiazm-10"-yl)ethoxy]benzaIcleliydc: -26- step A : 2-(phenothiazin-10-yl)ethyl nietiinnesulfonate : To a solution of (phenothiazin-IO-yl)ethanoI (20.0 g, 82.0 mmol) in dicliloromethane (150 ml) was added triethyl amine(24.9 g, 24 mmol) at 0 °C. Methanesulfonyl chloride (18.8 g, 160 mmol) in dichloromethane (50 ml) was added diopwise to the above reaction mixture at 0 °C. Tlie reaction mixture was stirred for 3 h at 25 "C. Ice water (250 ml) was added and organic layer was washed with 2 N HCl (2 x 50 ml), water (75 ml) and dried (Na2S04). The solvent was ev^jorated imder reduced pressure. The residue was triturated with pet. ether to afford the title compound (21 g, 80 %) as a brown solid; mp. 96 - 97 °C. »H NMR (CDCI3, 200 MHz) : 8 2.93 (s, 3H), 4.28 (t, J == 5.81 Hz, 2H), 4.52 (t, J = 5.81 Hz, ; 2H), 6,91 (m, 4H), 7.20 (m, 4H). Step B : The title compound (14.0 g, 59 %) was prepared as a white solid from 2-(phenothiazin-lO-yl)ethyl methanesulfonate (22.0 g, 68.8 mmol) obtained above, p-hydroxy benzaldehyde (10.0 g, 82.61 mmol) and potassium carbonate (19.0 g, 187.6 mmol) by an analogous procedure to that described in preparation I. mp : 128-130 C. IH NMR (CDCI3, 200 MHz) : 5 4.39 (s, 4H). 6.98 (m, 6H), 7.16 (m, 4H). 7.82 (d, J = 7.2 Hz, 2H),9.86(s,lH). x^" A mixture of 2,3-dihydro-I,4-benzoxazine (1.07 g, 7.94 mmol), 2-bromomethyl-S-formyl benzofiiran (1.9 g, 7-94 mmol), potassium carbonate (5.5 g, 39.74 mmol) and Aliquat 336 (2 drops) in dimethyl formamide (25 ml) was stirred at 65 °C for 8 h. Water (50 ml) was added to reaction mixture and extracted with ethyl acetate (2 x 50 ml). The. extracts were washed with water (50 ml), brine (50 ml) and dried (Na2S04). The solvent was evaporated to dryness and the residue was chromatographed over siUca gel using a mixture of ethyl acetate : pet. ether (3 : 7) as an eluent to afford the title compoimd (2.1 g, 91 %) as an oil. IH NMR (CDCI3, 200 MHz) : 5 3.39 (t, J = 4.48 Hz, 2H), 4.28 (t, J = 4.57 Hz, 2H), 4.56 (s, 2H), 6.80 (m, 5H), 7.52 (d, J = 8.63 Hz, IH), 7.81 (d, J = 8.62 Hz, IH), 8.01 (s, IH), 10.0 (s, IH). Preparation 6 5-Formyi-2-(phenothia2in-10-ylmethyl)beiizoruran: The title compound (1.14 g, 33 %) was prepared as a syrupy liquid from phenothiazine (2.87 g, 14.0 mmol) and 2-bromomethyl-5-formyl benzofiiran (2.3 g, 9.6 mmol) by a similar procedure to that described in preparation 5. " IH NMR (CDCI3, 200 MHz): 5 5.20 (s, 2H), 6.98 (m, 9H), 7.65 (d. J = 8.6 Hz, IH), 7.89 (d, J = 8.6 Hz, IH), 8.01 (s, IH), 10.09 (s. 1H). Preparation 7 3-Methoxy-4-[2-(pheno\|hiazin-10-yI)ethoxy)bcnzaldehydc: -28 1^ «im««t OMe The title Compound (2.5 g, 71 %) was prepared as a white solid from 2-(phenothiazin-10-yl)ethyl methanesulfonate (3.0 g, 9.3 mmol) and vanillin (1.7 g, n.2 mmol) using a similar procedure to that described in preparation 4. mp:130OC, IHNMR(CDCI3, 200MHz): 8 3.94(s.3H), 4.43 (s, 4H), 6.8 - 7.5 (complex, 1IH), 9.84 (s. IH). I ■ . ■ " " Preparation 8 4-[2-(9-Oxophenothiazin-10-yl)ethoxy]beiizaldehyde: ■ O II CHO The title compound (2.2 g, 67 %) was prepared as a thick liquid from 9-oxophenothiazin (2.0 g, 9.3 mmol) and 2-(4-formylphenoxy)ethyl methanesulfonate (2.7 g, 11 mmol) using a similar procedure to that described in preparation 3. IH NMR (CDCI3,200 MHz) 5 : 4.52 (t, J = 6.4 Hz, 2H), 4.75 (t, J = 6.4 Hz, 2H), 7.0 (d, J = 8.6 Hz, 2H), 7.3 (m, 2H), 7.6 (m, 4H), 7.82 (d, J = 8.6 Hz, 2H), 8.0 (m, 2H), 9.87 (s, IH). Preparation 9 4-[2-(9,9-Dioxophenothiazin-10-yl)ethoxy]benzaIdehyde: -29- CHO To a mixture of 4-[2-(phenothiazin-10-yl)ethoxy]benzaldehyde (0.25 g, 0.7 nimol) obtained in preparation 4 and 4-methyl morpholine N-oxide (0.16 g, 1.4 mmol) in acetone, osmium tetroxide (0.02 g, 0.07 mmol) was added and the mixture was stirred at room temperature for 3 h. At the end of this time, the reaction mixture was diluted with water and extracted with ethylacetate (50 ml). The ethylacetate layer was washed with aq. NaHSOs solution (25 ml), dried and concentrated to get (0.23 g, 65 %) the title compound as a gummy liquid. IH NMR (CDCI3, ?00 MHz) 8 : 4.47 (t, J = 6.4 Hz. 2H), 4.7 (t, J = 6.4 Hz, 2H), 7.0 (d, J = 8.4 Hz, 2H), 7.3 (m, 2H), 7.47 (d, J = 8.8 Hz, 2H). 7.66 (t, J = 7.4 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 7.2 Hz, 2H), 9.89 (s, IH). Preparation 10 4-[2-i2-Trifluoromethylphenothiazin-lG-yl]ethoxylbeBzaldehyde: CHO FaC The title compoimd (1.0 g, 65 %) was prepared as a thick liquid fix)m 2-(trifluoromethyl)phenothiazine (1.0 g, 3.7 mmol) and 4-(2-bromoethoxy)benzaldehyde (1.6 g, 7.49 mmol) by a similar procedure to that described in preparation 3. IH NMR (CDCI3,200 MHz) : 8 4.39 (s, 4H), 7.0 (m, 4H), 7.2 (m, 5H), 7.82 (d, J = 8.8 Hz, 2H), 9.88 (s,lH). Example 1 5-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI dione: methylene] thiazolidine-2,4- -30- A solution of 4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]benzal(iehyde (1.79 g, 6.36 nunol) obtained in preparation 1 and 2,4-thiazoldinedione (0.74 g, 6.36 mmol) in toluene (100 ml) containing piperidine (73 mg, 0.858 mmol) and benzoic acid (90 mg, 0.74 mmol) was heated under reflux for 3 h using Dean-Stark apparatus. The reaction mixture was cooled to room temperature, solid separated was filtered and washed with cold toluene (2 x 10 ml). The solid product was recrystallised from chloroform-methanol to afford the title compound (1.92 g, 79 %) as a yellow solid, mp : 186 -188 "C. »H NMR (DMSO-dg, 200 MHz) : 8 3.47 (bs, 2H), 3.69 (t. J = 4.9 Hz, 2H). 4.13 (bs. 2H), 4.25 (t, J = 4.9 Hz, 2H), 6.52 (m, IH), 6.70 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H). 7.56 (d, J = 8.3 Hz, 2H), 7.75 (s, IH), 12.53 (s, IH). i A mixture of 5-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl]ethoxy]phenyl methylene]thiazolidine-2, 4-diorte (1.2 g, 3 mmol) obtained in example 1 and magnesium turnings (1.25 g, 51 mmol) in methanol (50 ml) was stirred at 25 "C for 20 h. At the end of this time water (50 ml) was added and pH was adjusted to 6.5 - 7.0 using 10 % aqueous hydrochloric acid and the solution was extracted with ethyl acetate (2 x 75 ml). The combined organic extract was washed with water (50 ml), brine (50 ml), dried (Na2S04) and the solvent was removed under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as an eluent to give (0.5 g, 41 %) the title compound as a syrupy liquid. -31- "" :■■:" Tir^^ : ----- .-..— —-- - .- -- -- - ,.,.„^- IH hfMR (CDCI3, 200 MHz) : 5 3.08 (dd, J = 14.11 and 9.2 Hz, IH), 3.47 (m, 3H), 3.66 (t, J = 5.4 Hz, 2H), 4.15 (m, 4H), 4.40 (dd, J = 9.2 and 3.9 Hz, IH), 6.75 (m, 6H), 7.09 (d, J = 8.6 Hz, 2H), 8.12 (bs, IH, D2O exchangeable). A mixture of 5-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl methyljthiazolidine- 2,4-dione (0.25 g, 6,651 mmol) obtained in example 2 and sodium methoxide (0.1 g, 1.95 mmol) in methanol (10 ml) was stirred at 25 °C for 14 h. the resulting solid was filtered, washed with methanpl (2x5 ml), with ether (2 x 10 ml) and dried under vacuum at 70 "C to afford the title compound (0,23 g, 87%) as a wh^ solid, mp: 265-267 °C. . IH NMR (DMSO-dg, 200 MHz): 5 2.53 (m, IH), 3.32 (m, H^, 3.47 (t, J = 4.2 Hz, 2H), 3.67 (t, J = 5,4 Hz, 2H), 4.15 (m, 5H), 6.55 (m, IH), 6.82 (m, 5H), 7.12 (d, J = 8,6 Hz, 2H), The title compound (1.7 g, 85 %) was prepared as a yellow solid from 4-[2-(2,3-dihydro-l,4-ben2othiazin-4-yl)ethoxy]benzaldehyde (1.5 g, 5.01 mmol), obtained in preparation 2 and 2,4-thiazolidinedione (0.65 g, 5.52 mmol), by a similar procedure to that described in example 1. mp : 214 - 217 °C. -32- IH NMR (CDCI3, 200 MHz) : 5 3.04 (t, J = 4.7 Hz, 2H), 3.70 (m, 4H), 4.24 (t, J = 5.3 Hz, 2H), 6.58 (m, IH), 6.90 (m, 3H), 7.12 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.75 (s, IH), 12.53 (s, IH, D2O exchangeable). The title compound (0.5 g, 43 %) was prepared as a syrupy liquid from 5-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yI]ethoxy]phenyl methylene]thiazolidine-2,4-dione obtained in example 4 by an analogous procedure to that described in example 2. IR NMR (GDCI3, 200 MHz) : 8 3.12 (m, 3H), 3.44 (dd, J = 14.2 and 3.7 Hz, IH), 3.73 (m, 4H), 4.16 (t, J = 5.8 Hz, 2H), 4.46 (m, IH), 6.76 (m, 4H). 7.13 (m, 4H). The title compound (0.23 g, 78 %) was prepared as a white solid from 5-[4-[2-(2,3-dihydro- l,4-bettzoxazin-4-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione obtained in example 5 by an analogous procedure to that described in example 3. mp : 261 - 265 *C. IH NMR (DMSO-dfi, 200 MHz) : 5 2.60 (m, IH), 3.02 (t, J = 4.9 Hz, 2H), 3.29 (dd, J = 14.5 and 3.9 Hz, IH), 3.66 (m, 4H), 4.11 (m, 3H), 6.56 (m, IH), 6.89 (m, 5H), 7.09 (d, J = 8.5 Hz, 2H). -33- " - " ■ ^1f»^-^ The title compound (0.06 g, 57 %) was prepared as a white solid from 5-[4-[[2-(phenoxazin-10-yl)ethoxy]phenyl methyI]thiazolidine-2,4-dione (0.1 g, 0.2 mmol) obtained in example 8 by an analogous procedure to that described in example 3. mp : 260 - 262 °C. IH NMR (DMSO-dfi, 200 MHz) : 6 2.59 (m, IH), 3.34 (m, IH), 4.04 (m, 2H), 4.16 (m, 3H), 6.65 (m, 3H), 6.83 (m, 7H), 7.09 (d, J = 8.3 Hz, 2H). The title compound (2.3 g, 83 %) was prepared as a pale yellow solid from 5-formyl-2-(2,3-dihydro-l,4-benzoxazin-4-ylmethyl)benzofiiran (2.1 g, 7.17 mmol) obtained in preparation 5 and 2,4-thiazolidinedione (0.838 g, 7.167 mmol) by an analogous procedure to that described in example 1. mp242-244 0C. IH NMR (DMS0-D6, 200 MHz): 8 3.52 (bs, 2H), 4.24 (bs, 2H), 4.71 (s, 2H), 6.57 (m, IH), 6.76 (m, 2H), 6.93 (m. 2H), 7.56 (d, J = 8.72 Hz, IH), 7.73 (d, J = 8.71 Hz, IH), 7.86 (s, IH), 7.90 (s, IH), 12.60 (bs, IH, D2O exchangeable). Example 11 5-l2-[(2,3-Dihydro-l,4-benzoxazin-4-ylmethyI)benzofuraii-5-yI]methyI]thiazoIidine-2,4-dione: ( . . -35- The title compound (1.1 g, 65 %) was prepared as a syrupy liquid from 5-[2-[(2,3-dihydro-l,4-benzoxazin-4-ylmcthyI)benzofuran-5-yI]methy1ene3thiazoIidinc-2,4-dione (1.7 g, 4.33 mmol) obtained in example 10 by a similar manner to that described in example 2. IH NMR (CDCI3,200 MHz) : 6 3.20 (dd, J = 14.11 and 9.5 Hz, IH), 3.56 (ra, 3H), 4.30 (t, J = 4.25 Hz, 2H), 4.55 (m, 3H), 6.55 (s, IH), 6.70 (m, IH), 6.83 (m, 3H), 7.09 (d, J = 6.7 Hz, IH), 7.41 (m, 2H), 8.35 (bs, IH, D2O exchangeable). The title compound (0.25 g, 79 %) was prepared as a white solid from 5-[2-[(2,3-dihydro-l,4-benzoxazin-4-ylmethyl]benzofuran-5-yi]methyl]thiazolidine-2,4-dione (0.3 g, 0.761 mmol) obtained in example 11 by an analogous procedure to that described in example 3. mp : 299 - 301 ^C. IH NMR (DMS0-d6, 200 MHz) : 8 2.73 (dd, J = 13.7 and 10.7 Hz, IH), 3.44 (m, 3H), 4.16 (m, 3H), 4.62 (s, 2H), 6.57 (m, IH), 6.75 (m, 3H), 6.88 (d, J = 7.47 Hz, IH), 7.08 (d, J = 9.5 Hz, IH), 7.36 (s, IH), 7.40 (s, IH)! Example 13 5-[2-[(Phenothiazin-10-ylmethyI)-benzofuran-5-yIJmethyIene]thiazoIidine-2,4-dione: -36- o The title compound (1.7 g, 89 %) was prepared as a pale yellow solid from 5-formyI-2-[phenothiazin-10-ylmethyl]benzofuran (1.5 g, 4.0 mmol) obtained in preparation 6 by a similar manner to that described in example 1. mp:199 0C. IH NMR (CDCI3, 200 MHz) : 8 5.18 (s, 2H), 6.63 (s, IH), 6.79 (d, J = 8.9 Hz, 2H), 7.14 (m, 6H), 7,42 (d, J = 8.72 Hz, IH), 7.58 (d, J = 9.0 Hz, 2H), 7.93 (s, IH). t Example 14 5-[2-[(Phenothiazin-10-yImethyI)benzofuran-5-yl]methyI]thiazolidine-2,4-dione: O The title compound (0.5 g, 42 %) was prepared as a fluffy solid from 5-[2-[(phenothiazin-l0-yimethyl)benzoftiran-5-yl3methylene]thiazoUdine-2,4-dione (1.2 g, 2.6 mmol) obtained in example 13 by an analogous procedure to that described in example 2. mp : 97 - 99 °C. IH NMR (CDCI3, 200 MHz) : S 3.23 (dd, J = 14.11 and 9.55 Hz, IH), 3.59 (dd, J = 14.12 and 4.0 Hz, IH), 4.56 (dd, J = 9.55 and 3.9 Hz, IH), 5.15 (s, 2H), 6.52 (s, IH). 6.87 (m, 4H), 7.13 (m, 4H), 7.27 (m, 2H), 7.45 (d, J = 8.31 Hz, IH), 7.92 (bs, IH, D2O exchangeable). Example 15 5-[4-[2-(Phenothiazin-l0-yl)ethoxy]phenyl methylene]thiazolidine-2,4-dione: 37- The title compound (2.0 g, 50 %) was prepared as a brown color solid from 5-[4-[2-(phenothiazi IO-yl)ethoxy]phenyl methylene3thiazolidine-2,4-dione, obtained in example 15, by an analogo procedure to that described in example 2. mp : 68 - 70 °C. iH NMR (CDCI3, 200 Mhz) : 5 3.1 (dd, J = 14.2 and 9.6 Hz, IH), 3.45 (dd, J = 14.0 and 3.8 E IH), 4,32 (s, 4H). 4.5 (dd, J = 9.2 and 4.0 Hz, IH), 6.7 - 7.25 (m, 12 H). Example 18 5-[4-I2-(Phenothiazin-10-yI)ethoxyJphenyI methyI]thiazoUdine-2,4-dione, hydrochiortde : .HCI The title compound (0.76 g, 36 %) was prepared as a dark brown color solid from 5-[4-[2 (phenothiazin-10-yl)ethoxy]phenyl raethyl]thiazolidine-2,4-dione (2.0 g) obtained in example 17, b; an analogous procedure to that decribed in example 16. mp : 102 °C. IH NMR (DMSO-dg, 200 MHz) : 5 2.95 - 3.45 (m. 2H), 4.27 (s, 4H), 4.85 (dd, J = 9.0 and 4.4 Hz IH), 6.75 - 7.4 (m, 12H), 12.0 (s, IH, D2O exchangeable). Example 19 5-[4-(2-(Phenothiazin-10-yI)ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt: .0 O The title compound (0.26 g, 71 %) was prepared as a white solid from 5-[4-[2-(phenothiazin-10-yl)ethoxy3phenyl methyl]thiazolidine-2,4-dione (0.35 g), obtained in example 17, by an analogous procedure to that described in example 3. mp : 206-208^0. o The title compound (0.14 g, 56 %) was prepared as a dark brown color solid from 4[2-(S dioxophenothiazin-lO-ylJethoxyjbenzaldehyde (0.2 g, 0.53 mmol), obtained in preparation 9, b similar procedure to that described in example 1. mp : 248 - 250 ^C. IH NMR (DMSO-dg, 200 MHz) 8 : 4.49 (bs, 2H), 4.79 (bs, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.38 ( = 5.8 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.7 (s, IH), 7.79 (s, 4H), 8.01 (d, J = 7.6 Hz, 2H), 12.5 ( IH, D2O exchangeable). Example 25 5-[4-[2-[2-Trifluoromethylphenothiazin-10-yl)]ethoxyJphenylmethyIeneltMazoiidiiie-2,4-dioi; Y NH The title compound (1.7 g, 71 %) was prepared as a pale yellow solid from 4-[2-[2-trifluorometh phenotiuazin-l0-yl3ethoxy]benzaldehyde (1.9 g, 4.7 mmol) obtained in prepjuration 10, by a simil procedure to that described in example 1. mp : 196 -198 ^C. IH NMR (DMSO-d6, 200 MHz) : 8 4.39 (s, 4H), 6.9 - 7.6 (m, 1 IH), 7.72 (s, IH), 12.5 (bs, IH, D2 exchangeable). Example 26 5-[4-[2-[2-Trifluoromethylphenothiazln-10-ylJethoxylphenyImethyl]thiazolidine-2,4-dione: The title compound (0.2 g, 30 %) was prepared as a pale yellow solid from 5-[4-[2-[2 trifluoromethylphenothiazin-10>yl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (0.68 g, 1.: mmol) obtained in example 25 by an analogous procedure to that described in example 2. mp : 6" IH NMR (CDCI3, 200 MHz) : 8 3.1 (dd, J = 14.2 and 9.4 Hz. IH), 3.44 (dd, J = 14.2 and 4.0 Hz IH), 4.31 (s, 4H), 4.5 (dd, J = 9.4 and 4.0 Hz, IH), 6.7 - 7.3 (m, I IH) Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non-insulin dependent diabetes associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (See Diabetes, (1982) 31(1) : 1- 6) in mice and fa/fa and zucker 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 meilitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities. The compounds of the present inventions showed blood sugar and triglycerides lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments. Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, procured from the Jackson Laboratory, USA, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition, Hyderabad, India) and acidified water, ad libitum. The animals having more than 300 mg / dl blood sugar were used for testing. The number of animals in each group was 4. The random blood sugar and triglyceride levels were measured by collecting blood (100 yil) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma. The plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase en2yme (Dr. Redd/s Lab. Diagnostic Division Kits, Hyderabad, hidia) methods respectively. On 6th day the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity. Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 10 mg to 200 mg / kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml / kg). Troglitazone (100 mg / kg, daily those) was used as a standard drug which showed 28 % reduction in random blood sugar level on 6th day. The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula: The experimental results from the db/db /nice suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for 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 30 mg/kg. Normally, the quantum of reduction is dose dependent. its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates, wherein R", are the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro 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, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, aralkoxycarbonylamino, alkoxycarbonylamino, mercaptoalkyl groups, carboxylic acid or its esters or amides, or sulfonic acid or its esters or amides; or R and R together represent along with carbon atoms to which they are attached an aromatic cyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; Ar represents optionally substituted divalent single or fused aromatic or heterocyclic group, R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl group or forms a bond together with R; R* represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl or R forms a bond together with R""; B represents an oxygen atom or a sulfur atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one. 2. The compound as claimed in claim 1, wherein R1 and R2 together with the adjacent carbon atoms to which they are attached represent an optionally substituted 5 to 6 membered aromatic ring structure having 5 to 6 ring atoms wherein the aromatic ring structure is substituted, the substituents are selected from halogen, (Ci-C6)alkoxy, Gyclo(C3-C6)alkyl, cyclo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxyl, acyl, acyioxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, and aminocarbonyl. 7. The pharmaceutical composition which comprises, a compound according to claim 4, as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient. 8. The pharmaceutical composition as claimed in claim 7, in the form of tablet, capsule, powder, syrup, solution or suspension.

Full Text

Field of the Invention
The present invention relates to novel antidiabetic compounds, their tautomeric forms, their dervatives, their analogues, their stereoisomers, their polymorphs, their
pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione of the general formula (I), their derivativesj their analogues, their tautomeric fprms, .their stereoisomers, their polymorphs and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

The present invention also relates to a process for the preparation of the above said novel azolidinedione compounds, their analogues, their d«ivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and pharmaceutical compositions containing them.
_ This invention also relate to novel intermediates, processes for preparing the intehnediates and processes for using the intermediates.
The azolidinediones of the general fonnula (I) defined above of the present invention are useful for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes^ impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis. The azolidinediones of the fonnula (I) are useful for the treatoient of insulin resistance associated with obesity and psoriasis. The Azolidinediones of the fonnula (I) can also be used to treat diabetic complications and can be used for treatment and/or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome

(PCOS), cwtain renal diseases, including diabetic n^hropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage raial diseases and microalbuminuria as well as certain eating disorders, as aldose reductase Inhibitors and for improving cognitive functions in dementia.
Background of the Invention 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 whichj the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnonnalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl J. Med. (1987) 317: 350 - 357 ; J. Clin. Endocrinol. Metab., (1988) 66 :580 - 583; J. Clin. Invest, (1975) 68 : 957 - 969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being reco^iized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclCTOsis and type 2 diabetes mellitus. The association of insulin resistance wifli obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108), draientia (Behavioral Brain Research (1996) 75 : 1 - 1 1) etc. may also have insulin resistance as a central pathogenic feature. Recently, it has also been reported that thia2oHdinediones improve the bone mineral density and thus may be useful for the treatment of osteoporosis (EP-783888).
A number of molecular defects have been associated with insulin resistarifee. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis.
Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related implications, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compound^ which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref Chem. Pharm. Bull 1982, Jf?, 3580-3600). In the formula (II), V rq)resents substituted or unsubstituted divalent aromatic group, B represents a sulfur or an

groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R" and R^ may also together represent, along with carbon atoms to which they are attached an aromatic pyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR" where R" is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like wherein these groups are defined as for R"-R*; Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group, R" represents hydrogen atom, hydroxy, alkoxy, halogen or lower alkyl such as (d - Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted aralkyl group or forms a bond together with the adjacent group R"; R* represents hydrogen, hydroxy, alkoxy, halogen or lower alkyl group such as (Ci-Ce) alkyl such as methyl, ethyl, propyl and the like, optionally substituted suralkyl or R* forms a bond together with R"; B represents an oxygen atom or a sulfiir atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one. .
Suitable groups represented by R" - R^ include hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro; substituted or unsubstituted (Q-Ci2)alkyl group, especially, linear or branched
group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like;
aryloxyalkyl group such as CgHjOCHa, C6H5OCH2CH2, naphthyloxymethyl and the like;
Jbieteroaiyloxy 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 ethoxycarbonyl; aryloxycarbonyl
group such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl and the like;
aiylamino group such as HNCgHs; NCH3(C6H5)-hfHC6H4CH3; -NHC6H4-Hal and the like;
amino group; amino(C|-C6)alkyl; hydroxy(C|-C6)alkyl; (Ci-C6)alkoxy; thio(Ci-C6)alkyl; (Ci-
C6)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the acyl group may be
substituted; acylamitio groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOCeHs,
aralkoxycarbonylamino group such as NHCOOCH2C6H5, -NHCOOCH2CH2C6H5, -
NCH3COOCH2C6H5, -NC2H5COOCH2C6H5, -NHCOOCH2C6H4CH3,
NHCOOCH2C6H4OGH3 and the like; alkoxycarbonylamino group such as NHCOOC2H5, NHCOOGH3 and the like; carboxylic acid or its derivatives such as amides, like CONH2, CONHMe, CONMea, CONHEt, C0NEt2, 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 SO2NH2, S02NHMe, S02NMe2, SO2NHCF3 and the like; the sulfonic acid derivatives may be substituted.
Ail the groups represented by R"-R*^ may be substituted and the substituents may be selected from the same groups represented by R"-R^ and are defined in the same way.
Suitable cyclic structure formed by R", R^ together with carbon atoms to which they are attached contain 5 to 6 ring atoms, preferably, optionally substituted phenyl, pyridyl, furanyl, thienyl, pyrrolyl, and the like; substituents may be selected from the same groups rqpresraited by R"- R^ and are defused in the same way. Preferred substituents are halogen, (Ci-C6)alkoxy, cyclo(C3-C6) alkyl, cyclo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxy, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, aminocarbonyl and the like.
Suitable X includes oxygen, sulfur or a group NR" as defined above. X is preferably oxygen or sulfur.
The group represented by Ar includes substituted or unsubstituted divalent phenylene, 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 include linear or branched optionally halogenated (Ci-C6)alkyl, optionally halogenated (C|-C3)alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic and sulfonic acids and their derivatives. The substituents are defined as they are for R"-R^
It is more preferred that Ar represents a substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl group.
It is still more preferred that Ar represents a divalent phenylene or benzofuranyl, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R" includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy; (Ci-C3)alkoxy; halogen atom such as fluorine, chlorine, bromine, or iodine; aralkyl such as C6H5GH2, C6H5CH2CH2, C6H5CH2CH2CH2, naphthylmethyl and the like, substituted aralkyl such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like, or R together with R represents a bond.
Suitable R* may be a hydrogen atom, hydroxy, (Ci-C3)alkoxy; halogen selected from fluorine, bromine, iodine and chlorine, lower alkyl group such as (C1-C12) alkyl, aralkyl such as G6H5CH2, C6H5CH2CH2, C6H5CH2CH2CH2, naphthyhnethyl and the like, substituted aralkyl such as CH3C6H4CH2, Hal-C6H4CH2, CH3OC6H4CH2. CH3OC6H4CH2CH2 and the like, or together with R forms a bond.
It is preferred that R" and R^ represent hydrogen atoms or R" and R* together represent a bond.
Suitable B group includes a hetero atom selected from O or S, preferably sulfur atom.
Suitabte ring structure comprising B and Y include 2,4-dioxooxazolidin-5-yl, 2,4-dioxothiazolidin-5-yl, 4-oxazolidone-2-thione-5-yl groups. Preferred ring structures comprising B include 2,4rdioxooxazolidin-5-yl and 2,4-dioxothiazolidin-5-yl groups.
It is more preferred that the ring structure comprising B is a 2,4-dioxothiazolidin-5-yl group.
Suitable Y group is a heteroatom selected from O or S.
Suitable m is an integer ranging from 0-1. It is preferred that when m = 0, the linker group (CH2)n- is attached to the carbon atom adjacent to the heteroatom of the group Ar which represents an optionally substituted divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, or dihydrobenzopyranyl group and

when m = 1, Ar represents substituted or unsubstituted divalent phenylene, naphthylene* pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, ^azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl.
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.
It is also preferred that when n represents 2 and m represents 1, that Ax represents phenyl or naphthyl groups.
Pharmaceutically acceptable salts forming part of this invention include salts of the azolidinedione moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, chohne and the like, ammonium or substituted ammonium salts, salts of carboxy group wherever appropriate, such as aluminum, alkali metal salts, alkaline earth metal salts, ammonium or substituted ammonium salts. Salts may include acid addition salts which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compoimds according to the invention include :
5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yI)ethoxy]phenyl methylene]thiazolidine-2,4-dione;
5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione;
5-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl methyl]thiazoIidine-2,4-dione,
sodium salt;
5-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl methylene]thiazolidine-2,4-dione; 5-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl]ethoxy]phenyl methylJthiazolidine-2,4-dione; 5-[4-|;2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyI methyI]thiazolidine-2,4-dione, sodium salt;
5-[4-[2-(Phenoxazin-10-yl)ethoxy]pheny 1 methylene]thiazoUdine-2,4-dione; 5-[4-[2-(Phenoxazin-10-y l)ethoxy]phenyl methyl3thiazolidine-2,4-dione; 5-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt; 5-[2-[(2,3-Dihydro-l,4-benzoxazin-4-ylmethyl)benzofuran-5-yl]methylene]thiazolidine-2,4-dione;

= arall^Iamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, aralkoxycarbonylamino, alkoxycarbonylamino, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, mercaptoaikyi groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; or R" and R^ together may represent, along with carbon atoms to which they are " attached an aromatic cyclic structure containing 5 - 6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR" where R" 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; n is an integer ranging from 1 to 4 and m is zero or 1.

CHjCN, EtOH, acetone or mixtures thereof. 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 base such as K2CG3, NaaCOj, KOH, NaOH, NaH and the like or mixtures thereof. The amount of base may range firom 1 to 20 equivalents, preferably 1 to 10 equivalents. The reaction may be carried out at a temperature in the range 20 "C to 180 °C, preferably at a temperature in the range 50 °C to 150 °C. Duration of the reaction may range from V to 48 hours, preferably fix)m 1 to 12 hours. The amounts of the compound of general formula (VIII) and (IX) may range from 1 to 20 equivalents, preferably from 1 to 5 equivalents. The reaction may be carried out in the presence of phase transfer catalysts such as quatemay ammonium halides or hydroxides such as tetrabutyl ammonium bromide, tetrabutylammonium hydroxide, benzyl trimethylammonium bromide, aliquat and the like.
The present invention provides a process for the preparation of novel azolidinediones of general formula (I), their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polyniorphs, their pharmaceutically acceptable salts and their phannaceuticaUy acceptable solvates wherein R" and R^ together represent a bond and B represents a sulfur or oxygen atom and all symbols are as defined earlier which comprises: reacting the compound of general formula (III), where G is a CHO group with 2,4-thiazolidinedione, 2,4- oxazolidinedione or oxazolidone-4-oxo-2-thione to yield a compound of genwal fonnula (X)

where R" - R^ X, Ar, n, m, B, and Y are as defined earlier, R" and R* together represent a bond and removing the water formed during the reaction by conventional methods.
The reaction of the compound of the general formula (III) where G is a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound of general formula (X) may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof. The reaction temperature may range from 80 "C to 140 "C depending upon the solvents employed and in the range from 80 "C to 180 ^C when the reaction is carried out neat in the presence of sodium acetate. Suitable

catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts may also be employed. Sodium acetate can be used in the presence of solvent, but it is preferred that sodium acetate is used neat. The water produced in the reaction may be removed, for example, by using Dean Stark water separator or by using water absorbing agents like molecular selves. When oxazolidine-4-oxo-2-thione is used to produce a compound of formula (X), wherein B represents oxygen atom and Y represents sulfur atom, the thio group may be converted to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPB A.
The compound of the general formula (X) obtained in the manner described above is reduced by known method to obtain the compound of general formula (XI)

where R" - R^ X, Ar, n, m, B and Y are as defined earlier. The compound of general formula (XI) represents the compound of general formula (I), wherein R" and R* represent hydrogen atom and all other symbols are as defined earlier.
The reduction of compound of the formula (X) to yield a compound of the general formula (XI) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/G, Pt/C, Raney Nickel, and the like. Mixtures of catalysts may be used. The reaction may be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. Mixtures of solvents may be used. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol. The reaction may also be carried out with alkali metal borohydrides such as LiBHU, NaBH4, ICBH4 and the like in the presence of cobalt salt such as C0CI2 and ligands, preferably bidentated ligands such as 2, 2"-bipyridyl, 1, 10-phenanthroline, bisoximes and the like.

* The compounds of general formula (X) and general formula (XI) obtained above may be converted into pharmaceuticaily acceptable salts, or pharmaceutically acceptable solvates by conventional methods.
In yet another embodiment of the present invention, the compound of the general formula (I) where m represents I and all other symbols are as defined earlier, can also be prepared by reacting a compound of the general formula (IV) defined above with a compound of general formula (XII)

HO-Ar
(XII)

whwe R", R", B, Y and Ar are as defined earlier and R"® is hydrog^ or a nitrogen protecting group which is removed after the reaction.
The reaction of compound of general formula (IV) with a compoimd of general formula (XII) to produce a compound of general formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like ©r mixtures thereof. The reaction may be carried put in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide, or mixtures thereof Multiple solvents and bases can be used. The amount of base may range fi-om 1 to 5 equivalents, preferably 1 to 3 equivalents. The reaction temperature may be in the range of 0 "C to 120 "C, preferably at a temperature in the range of 20 °C to 100 °C. The duration of the reaction may range fi-om 0.5 to 24 hours, preferably fi*om 0.5 to 6 hours.
The removal of protecting groups may be carried out by conventional methods which include treatment with acid such as, hydrochloric acid, trifluoroacetic acid or bases such as, KOH, NaOH, NajCOa, NaHCOa, K2CO3 and the like or mixtures thereof These reagents may be used as aqueous solution or as solutions in alcohols like methanol, ethanol etc. Deprotection can also be effected by gaseous hydrogen in the presence of catalyst such as

, NaOAc, KOAc, NaOJsle, NaOEt etc. can be used. The reaction is nonnally followed by
treatment witti a mineral acid such as hydrochloric acid at 20 "C to 100 °C.
The compound of general formula (XIII) where J is a halogen atom can be prepared by the diazotization of the amino compound of the general formula (XIV)

where all symbols are as defined earlier, using alkali metal nitrites followed by treatment with actylic acid esters in the presence of hydrohalo acids and catalytic amount of copper oxide or copper halide.
The compound of general formula (XIV) can in turn be prepared by the conventional reduction of the novel intermediate (III) where G is NO2 group and other symbols are as defined earlier.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts are prepared by treatinent with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzene sulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
As used in this application, the term neat means the reaction is carried out without the use of solvent.
The stereoisomers of the compounds fomiing 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 or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
Various polymorphs of the compounds of general formula (I) forming part of this invention may be prepared by crystallization of a 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 heatmg or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential iscanning calorimetry, powder X-ray diffraction or such other techniques.
The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their tautomeric forms, their derivatives, their analogues, 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 arid/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglyc^nia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases in which msulin resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dysltpidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis; insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, s)"rups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from

1 to 25 %, preferably 1 to 15 % by weight of active compound, the remainder of the composition being, pharmaeeutically acceptable carriers, diluents, excipients or solyents.

A typical tablet production method is exemplified below:
Tablet Production Example:
a) 1) Active ingredient 30g
2) Lactose 95 g
3) Com starch 30g
4) Carboxymethyl cellulose 44 g
5) Magnesium stearate , Ig
200 g for 1000 tablets The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredients 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.

) 1) Active ingredient 30g
2) Calcium phosphate 90 g
3) Lactose 40 g
4) Com starch 35 g
5) Polyvinyl pyrrolidone 3.5 g
6) Magnesium stearate 1.5 g
200 g for 1000 tablets
The ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure. Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
The compound of the formula (I) as defined above are clinically administered to mammals, including man, via eittier 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 either route, the dosage is in the range of about 0. 10 mg to about 200 mg / kg body weight of the subject per day or preferably about 0. 10 mg to about 50 mg / kg body weight per day administered singly or as a diviied 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 combmed 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 orgamc 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 fqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline eaxth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Preparation 1 4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxylben2aldehyde:
CHO
Step A : Preparation of 2-(2,3-dihydro-l,4-benzoxazine-4-yl)ethyl metbanesuifonate - To a solution of 2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethanoi (17.0 g, 94.9 mmol) in pyridine

(200 ml) was added methanesulfbnyl chloride (16.31 g, 142.0 mmol) dropwise at 0 "C. The reaction mixture was stirred for 10 h at 25 °C. Ice water (200 ml) was added and the mixture was extracted witti etltyl acetate ( 2 x 100 ml). The combined organic extracts were washed with 2N HCI (3 X 75 ml), water (75 ml), brine (50 ml) and dried (Na2S04). The sblvent was evaporated under reduced pressure. The residue was triturated with 5% ethyl acetate in pet. ethra-to afford the title cotn^ound (15.0 g, 61 %) as brown solid, mp. 92-95 °C.
IH NMR (CDCI3, 200 MHz): 6 2.97 (s, 3H), 3.45 (t, J= 4.43 Hz, 2H), 3.64 (t, J = 5.72 Hz, 2H), 4.23 (t, I=^A2lHz, 21^, 4.4r(t, J = 5.71 Hzj2H)^ 6,66 (m, 2H), 6.83 (m, 2H).
Step B : A mixture of 2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (5 g, 19.4 mmol) obtamed above, p-hydroxy benzaldehyde (5.56 g, 29.1 mmol) and potassium carbonate (10.75 g) in dry dimethyl formamide (50 ml) was heated to 70 °C for 7 h. The reaction mixture was cooled to room temperature. WaterflOG mi) was added to the trnxH^me and extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with water (50 n^, brine (50 ml) and dried (Na2S04). The solvent was removed imder reduced pressure
to affQixi the title compoimd (4.0 g, 72 %) as a syrupy liquid.
IH NIIR (CDCI3, 200 MHz) : 8 3.55 (t, .f = 4.3 Hz, 2H), 3.76 (t, J = 5.5 Hz, 2H), 4.26 (m,
4H), 6.74 (m, 2H), 6.83 (m, 2H), 7.02 (d, J - 8.6 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 9.90 (s, ■■"■ , IH). " ■ ■

To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-l,4-benzothiazin-4-)d)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25 "C. The reaction mixture was stirred for 12 h at 25 °C. Water (100 ml) was

added and the mixture was extracted with ethyl acetate (2 x 100 ml). The organic extracts were dried (Na2S04) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica.gel using a mixture of methanol and chloroform (5 : 95) as an eluent to afford the title compound (1.6 g, 44 %) as an oil.
IH NMR (CDCI3, 200 MHz) : 6 3.05 (t, J = S^O Hz, 2H), 3.80 (m, 4H), 4.26 (t, J = 5.5 Hz, 2H), 6.68 (m, 2H), 7.03 (m, 4H), 7.83 (d,.) = 8 6 Hz, 2H), 9.88 (s, IH).

To a suspension of sodium hydride (60 % mineral oil, 0.13 g, 3.24 mmol) in dimethyl fonnaldde (3 ml) was added phenoxazine (0.5 g, 2.7 mmol) in dimethyl formamide (5 mL). Tlie reaction mixture was stirred at 25 °C for 0.5 h and a solution of 4-(2-bromoethoxy)benzaldehyde (0.74 g, 3.24 mniol) in dimethyl formamide (3 mL) was added. The reaction mixture was stirred at 25 "C for 6 h. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (50 ml), brine solution (50 ml) and dried (Na2S04). The solvent was evaporated and tfie residue was chromatographed over silica ^el using a mixture of ethyl acetate and pet. ether (3 : 7) as eluent to afford the title compound (0.52 g, 57 %) as a syrupy liquid.
IHNMR (CDCI3,200 MHz): 8 3.67 (t, i = 6.2 Hz, IH), 4.05 (t, J = 6.2 Hz, IH), 4.28 (t, J.= 6.3 Hz, IH), 4.38 (t, J = 6.2 Hz, IH), 6.75 (m, 8H), 7.02 (m, 2H), 7.87 (m, 2H), 9.90 (s, IH).
Preparation 4 4-[2-(Phenothiazm-10"-yl)ethoxy]benzaIcleliydc:
-26-

step A : 2-(phenothiazin-10-yl)ethyl nietiinnesulfonate : To a solution of (phenothiazin-IO-yl)ethanoI (20.0 g, 82.0 mmol) in dicliloromethane (150 ml) was added triethyl amine(24.9 g, 24 mmol) at 0 °C. Methanesulfonyl chloride (18.8 g, 160 mmol) in dichloromethane (50 ml) was added diopwise to the above reaction mixture at 0 °C. Tlie reaction mixture was stirred for 3 h at 25 "C. Ice water (250 ml) was added and organic layer was washed with 2 N HCl (2 x 50 ml), water (75 ml) and dried (Na2S04). The solvent was ev^jorated imder reduced pressure. The residue was triturated with pet. ether to afford the title compound (21 g, 80 %) as a brown solid; mp. 96 - 97 °C.
»H NMR (CDCI3, 200 MHz) : 8 2.93 (s, 3H), 4.28 (t, J == 5.81 Hz, 2H), 4.52 (t, J = 5.81 Hz,
; 2H), 6,91 (m, 4H), 7.20 (m, 4H).
Step B : The title compound (14.0 g, 59 %) was prepared as a white solid from 2-(phenothiazin-lO-yl)ethyl methanesulfonate (22.0 g, 68.8 mmol) obtained above, p-hydroxy benzaldehyde (10.0 g, 82.61 mmol) and potassium carbonate (19.0 g, 187.6 mmol) by an analogous procedure to that described in preparation I. mp : 128-130 **C.
IH NMR (CDCI3, 200 MHz) : 5 4.39 (s, 4H). 6.98 (m, 6H), 7.16 (m, 4H). 7.82 (d, J = 7.2 Hz, 2H),9.86(s,lH).

x^"
A mixture of 2,3-dihydro-I,4-benzoxazine (1.07 g, 7.94 mmol), 2-bromomethyl-S-formyl benzofiiran (1.9 g, 7-94 mmol), potassium carbonate (5.5 g, 39.74 mmol) and Aliquat 336 (2 drops) in dimethyl formamide (25 ml) was stirred at 65 °C for 8 h. Water (50 ml) was added to reaction mixture and extracted with ethyl acetate (2 x 50 ml). The. extracts were washed with water (50 ml), brine (50 ml) and dried (Na2S04). The solvent was evaporated to dryness and the residue was chromatographed over siUca gel using a mixture of ethyl acetate : pet. ether (3 : 7) as an eluent to afford the title compoimd (2.1 g, 91 %) as an oil.
IH NMR (CDCI3, 200 MHz) : 5 3.39 (t, J = 4.48 Hz, 2H), 4.28 (t, J = 4.57 Hz, 2H), 4.56 (s,
2H), 6.80 (m, 5H), 7.52 (d, J = 8.63 Hz, IH), 7.81 (d, J = 8.62 Hz, IH), 8.01 (s, IH), 10.0 (s, IH).
Preparation 6 5-Formyi-2-(phenothia2in-10-ylmethyl)beiizoruran:

The title compound (1.14 g, 33 %) was prepared as a syrupy liquid from phenothiazine (2.87
g, 14.0 mmol) and 2-bromomethyl-5-formyl benzofiiran (2.3 g, 9.6 mmol) by a similar
procedure to that described in preparation 5. "
IH NMR (CDCI3, 200 MHz): 5 5.20 (s, 2H), 6.98 (m, 9H), 7.65 (d. J = 8.6 Hz, IH), 7.89 (d, J = 8.6 Hz, IH), 8.01 (s, IH), 10.09 (s. 1H).
Preparation 7 3-Methoxy-4-[2-(pheno|hiazin-10-yI)ethoxy)bcnzaldehydc:
-28

1^ «im««t

OMe

The title Compound (2.5 g, 71 %) was prepared as a white solid from 2-(phenothiazin-10-yl)ethyl methanesulfonate (3.0 g, 9.3 mmol) and vanillin (1.7 g, n.2 mmol) using a similar procedure to that described in preparation 4. mp:130OC,
IHNMR(CDCI3, 200MHz): 8 3.94(s.3H), 4.43 (s, 4H), 6.8 - 7.5 (complex, 1IH), 9.84 (s. IH).
I ■ . ■ " "
Preparation 8 4-[2-(9-Oxophenothiazin-10-yl)ethoxy]beiizaldehyde:
■ O
II
CHO
The title compound (2.2 g, 67 %) was prepared as a thick liquid from 9-oxophenothiazin (2.0 g, 9.3 mmol) and 2-(4-formylphenoxy)ethyl methanesulfonate (2.7 g, 11 mmol) using a similar procedure to that described in preparation 3.
IH NMR (CDCI3,200 MHz) 5 : 4.52 (t, J = 6.4 Hz, 2H), 4.75 (t, J = 6.4 Hz, 2H), 7.0 (d, J = 8.6 Hz, 2H), 7.3 (m, 2H), 7.6 (m, 4H), 7.82 (d, J = 8.6 Hz, 2H), 8.0 (m, 2H), 9.87 (s, IH).
Preparation 9
4-[2-(9,9-Dioxophenothiazin-10-yl)ethoxy]benzaIdehyde:
-29-

CHO

To a mixture of 4-[2-(phenothiazin-10-yl)ethoxy]benzaldehyde (0.25 g, 0.7 nimol) obtained in preparation 4 and 4-methyl morpholine N-oxide (0.16 g, 1.4 mmol) in acetone, osmium tetroxide (0.02 g, 0.07 mmol) was added and the mixture was stirred at room temperature for 3 h. At the end of this time, the reaction mixture was diluted with water and extracted with ethylacetate (50 ml). The ethylacetate layer was washed with aq. NaHSOs solution (25 ml), dried and concentrated to get (0.23 g, 65 %) the title compound as a gummy liquid. IH NMR (CDCI3, ?00 MHz) 8 : 4.47 (t, J = 6.4 Hz. 2H), 4.7 (t, J = 6.4 Hz, 2H), 7.0 (d, J = 8.4 Hz,
2H), 7.3 (m, 2H), 7.47 (d, J = 8.8 Hz, 2H). 7.66 (t, J = 7.4 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 8.15 (d, J *= 7.2 Hz, 2H), 9.89 (s, IH).
Preparation 10 4-[2-i2-Trifluoromethylphenothiazin-lG-yl]ethoxylbeBzaldehyde:

CHO
FaC

The title compoimd (1.0 g, 65 %) was prepared as a thick liquid fix)m 2-(trifluoromethyl)phenothiazine (1.0 g, 3.7 mmol) and 4-(2-bromoethoxy)benzaldehyde (1.6 g, 7.49 mmol) by a similar procedure to that described in preparation 3. IH NMR (CDCI3,200 MHz) : 8 4.39 (s, 4H), 7.0 (m, 4H), 7.2 (m, 5H), 7.82 (d, J = 8.8 Hz, 2H), 9.88
(s,lH).

Example 1
5-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyI dione:

methylene] thiazolidine-2,4-

-30-

A solution of 4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]benzal(iehyde (1.79 g, 6.36 nunol) obtained in preparation 1 and 2,4-thiazoldinedione (0.74 g, 6.36 mmol) in toluene (100 ml) containing piperidine (73 mg, 0.858 mmol) and benzoic acid (90 mg, 0.74 mmol) was heated under reflux for 3 h using Dean-Stark apparatus. The reaction mixture was cooled to room temperature, solid separated was filtered and washed with cold toluene (2 x 10 ml). The solid product was recrystallised from chloroform-methanol to afford the title compound (1.92 g, 79 %) as a yellow solid, mp : 186 -188 "C. »H NMR (DMSO-dg, 200 MHz) : 8 3.47 (bs, 2H), 3.69 (t. J = 4.9 Hz, 2H). 4.13 (bs. 2H),
4.25 (t, J = 4.9 Hz, 2H), 6.52 (m, IH), 6.70 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H). 7.56 (d, J = 8.3 Hz, 2H), 7.75 (s, IH), 12.53 (s, IH).
i
A mixture of 5-[4-[2-(2,3-Dihydro-l,4-benzoxazin-4-yl]ethoxy]phenyl
methylene]thiazolidine-2, 4-diorte (1.2 g, 3 mmol) obtained in example 1 and magnesium turnings (1.25 g, 51 mmol) in methanol (50 ml) was stirred at 25 "C for 20 h. At the end of this time water (50 ml) was added and pH was adjusted to 6.5 - 7.0 using 10 % aqueous hydrochloric acid and the solution was extracted with ethyl acetate (2 x 75 ml). The combined organic extract was washed with water (50 ml), brine (50 ml), dried (Na2S04) and the solvent was removed under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2 : 8) as an eluent to give (0.5 g, 41 %) the title compound as a syrupy liquid.
-31-

"" :■■:" Tir^^ : ----- .-..— —-- - .- -- -- - ,.,.„^-
IH hfMR (CDCI3, 200 MHz) : 5 3.08 (dd, J = 14.11 and 9.2 Hz, IH), 3.47 (m, 3H), 3.66 (t, J = 5.4 Hz, 2H), 4.15 (m, 4H), 4.40 (dd, J = 9.2 and 3.9 Hz, IH), 6.75 (m, 6H), 7.09 (d, J = 8.6 Hz, 2H), 8.12 (bs, IH, D2O exchangeable).

A mixture of 5-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl methyljthiazolidine-
2,4-dione (0.25 g, 6,651 mmol) obtained in example 2 and sodium methoxide (0.1 g, 1.95
mmol) in methanol (10 ml) was stirred at 25 °C for 14 h. the resulting solid was filtered,
washed with methanpl (2x5 ml), with ether (2 x 10 ml) and dried under vacuum at 70 "C to
afford the title compound (0,23 g, 87%) as a wh^ solid, mp: 265-267 °C. .
IH NMR (DMSO-dg, 200 MHz): 5 2.53 (m, IH), 3.32 (m, H^, 3.47 (t, J = 4.2 Hz, 2H), 3.67 (t, J = 5,4 Hz, 2H), 4.15 (m, 5H), 6.55 (m, IH), 6.82 (m, 5H), 7.12 (d, J = 8,6 Hz, 2H),

The title compound (1.7 g, 85 %) was prepared as a yellow solid from 4-[2-(2,3-dihydro-l,4-ben2othiazin-4-yl)ethoxy]benzaldehyde (1.5 g, 5.01 mmol), obtained in preparation 2 and 2,4-thiazolidinedione (0.65 g, 5.52 mmol), by a similar procedure to that described in example 1. mp : 214 - 217 °C.
-32-

IH NMR (CDCI3, 200 MHz) : 5 3.04 (t, J = 4.7 Hz, 2H), 3.70 (m, 4H), 4.24 (t, J = 5.3 Hz, 2H), 6.58 (m, IH), 6.90 (m, 3H), 7.12 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.75 (s, IH), 12.53 (s, IH, D2O exchangeable).

The title compound (0.5 g, 43 %) was prepared as a syrupy liquid from 5-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yI]ethoxy]phenyl methylene]thiazolidine-2,4-dione obtained in example 4 by an analogous procedure to that described in example 2.
IR NMR (GDCI3, 200 MHz) : 8 3.12 (m, 3H), 3.44 (dd, J = 14.2 and 3.7 Hz, IH), 3.73 (m, 4H), 4.16 (t, J = 5.8 Hz, 2H), 4.46 (m, IH), 6.76 (m, 4H). 7.13 (m, 4H).

The title compound (0.23 g, 78 %) was prepared as a white solid from 5-[4-[2-(2,3-dihydro-
l,4-bettzoxazin-4-yl)ethoxy]phenyl methyl]thiazolidine-2,4-dione obtained in example 5 by
an analogous procedure to that described in example 3. mp : 261 - 265 **C.
IH NMR (DMSO-dfi, 200 MHz) : 5 2.60 (m, IH), 3.02 (t, J = 4.9 Hz, 2H), 3.29 (dd, J = 14.5
and 3.9 Hz, IH), 3.66 (m, 4H), 4.11 (m, 3H), 6.56 (m, IH), 6.89 (m, 5H), 7.09 (d, J = 8.5 Hz,
2H).
-33-

*" - " ■ ^1f»^-^

The title compound (0.06 g, 57 %) was prepared as a white solid from 5-[4-[[2-(phenoxazin-10-yl)ethoxy]phenyl methyI]thiazolidine-2,4-dione (0.1 g, 0.2 mmol) obtained in example 8 by an analogous procedure to that described in example 3. mp : 260 - 262 °C. IH NMR (DMSO-dfi, 200 MHz) : 6 2.59 (m, IH), 3.34 (m, IH), 4.04 (m, 2H), 4.16 (m, 3H), 6.65 (m, 3H), 6.83 (m, 7H), 7.09 (d, J = 8.3 Hz, 2H).

The title compound (2.3 g, 83 %) was prepared as a pale yellow solid from 5-formyl-2-(2,3-dihydro-l,4-benzoxazin-4-ylmethyl)benzofiiran (2.1 g, 7.17 mmol) obtained in preparation 5 and 2,4-thiazolidinedione (0.838 g, 7.167 mmol) by an analogous procedure to that described in example 1. mp242-244 0C. IH NMR (DMS0-D6, 200 MHz): 8 3.52 (bs, 2H), 4.24 (bs, 2H), 4.71 (s, 2H), 6.57 (m, IH), 6.76 (m,
2H), 6.93 (m. 2H), 7.56 (d, J = 8.72 Hz, IH), 7.73 (d, J = 8.71 Hz, IH), 7.86 (s, IH), 7.90 (s, IH), 12.60 (bs, IH, D2O exchangeable).
Example 11 5-l2-[(2,3-Dihydro-l,4-benzoxazin-4-ylmethyI)benzofuraii-5-yI]methyI]thiazoIidine-2,4-dione:
( . .
-35-

The title compound (1.1 g, 65 %) was prepared as a syrupy liquid from 5-[2-[(2,3-dihydro-l,4-benzoxazin-4-ylmcthyI)benzofuran-5-yI]methy1ene3thiazoIidinc-2,4-dione (1.7 g, 4.33 mmol) obtained in example 10 by a similar manner to that described in example 2. IH NMR (CDCI3,200 MHz) : 6 3.20 (dd, J = 14.11 and 9.5 Hz, IH), 3.56 (ra, 3H), 4.30 (t, J = 4.25
Hz, 2H), 4.55 (m, 3H), 6.55 (s, IH), 6.70 (m, IH), 6.83 (m, 3H), 7.09 (d, J = 6.7 Hz, IH), 7.41 (m, 2H), 8.35 (bs, IH, D2O exchangeable).

The title compound (0.25 g, 79 %) was prepared as a white solid from 5-[2-[(2,3-dihydro-l,4-benzoxazin-4-ylmethyl]benzofuran-5-yi]methyl]thiazolidine-2,4-dione (0.3 g, 0.761 mmol) obtained
in example 11 by an analogous procedure to that described in example 3. mp : 299 - 301 ^C. IH NMR (DMS0-d6, 200 MHz) : 8 2.73 (dd, J = 13.7 and 10.7 Hz, IH), 3.44 (m, 3H), 4.16 (m, 3H), 4.62 (s, 2H), 6.57 (m, IH), 6.75 (m, 3H), 6.88 (d, J = 7.47 Hz, IH), 7.08 (d, J = 9.5 Hz, IH), 7.36 (s, IH), 7.40 (s, IH)!
Example 13 5-[2-[(Phenothiazin-10-ylmethyI)-benzofuran-5-yIJmethyIene]thiazoIidine-2,4-dione:
-36-

o
The title compound (1.7 g, 89 %) was prepared as a pale yellow solid from 5-formyI-2-[phenothiazin-10-ylmethyl]benzofuran (1.5 g, 4.0 mmol) obtained in preparation 6 by a similar
manner to that described in example 1. mp:199 0C.
IH NMR (CDCI3, 200 MHz) : 8 5.18 (s, 2H), 6.63 (s, IH), 6.79 (d, J = 8.9 Hz, 2H), 7.14 (m, 6H),
7,42 (d, J = 8.72 Hz, IH), 7.58 (d, J = 9.0 Hz, 2H), 7.93 (s, IH).
t
Example 14 5-[2-[(Phenothiazin-10-yImethyI)benzofuran-5-yl]methyI]thiazolidine-2,4-dione:

O
The title compound (0.5 g, 42 %) was prepared as a fluffy solid from 5-[2-[(phenothiazin-l0-yimethyl)benzoftiran-5-yl3methylene]thiazoUdine-2,4-dione (1.2 g, 2.6 mmol) obtained in example
13 by an analogous procedure to that described in example 2. mp : 97 - 99 °C.
IH NMR (CDCI3, 200 MHz) : S 3.23 (dd, J = 14.11 and 9.55 Hz, IH), 3.59 (dd, J = 14.12 and 4.0
Hz, IH), 4.56 (dd, J = 9.55 and 3.9 Hz, IH), 5.15 (s, 2H), 6.52 (s, IH). 6.87 (m, 4H), 7.13 (m, 4H), 7.27 (m, 2H), 7.45 (d, J = 8.31 Hz, IH), 7.92 (bs, IH, D2O exchangeable).
Example 15
5-[4-[2-(Phenothiazin-l0-yl)ethoxy]phenyl methylene]thiazolidine-2,4-dione:
37-

The title compound (2.0 g, 50 %) was prepared as a brown color solid from 5-[4-[2-(phenothiazi IO-yl)ethoxy]phenyl methylene3thiazolidine-2,4-dione, obtained in example 15, by an analogo procedure to that described in example 2. mp : 68 - 70 °C.
iH NMR (CDCI3, 200 Mhz) : 5 3.1 (dd, J = 14.2 and 9.6 Hz, IH), 3.45 (dd, J = 14.0 and 3.8 E IH), 4,32 (s, 4H). 4.5 (dd, J = 9.2 and 4.0 Hz, IH), 6.7 - 7.25 (m, 12 H).
Example 18
5-[4-I2-(Phenothiazin-10-yI)ethoxyJphenyI methyI]thiazoUdine-2,4-dione, hydrochiortde :

.HCI The title compound (0.76 g, 36 %) was prepared as a dark brown color solid from 5-[4-[2 (phenothiazin-10-yl)ethoxy]phenyl raethyl]thiazolidine-2,4-dione (2.0 g) obtained in example 17, b;
an analogous procedure to that decribed in example 16. mp : 102 °C.
IH NMR (DMSO-dg, 200 MHz) : 5 2.95 - 3.45 (m. 2H), 4.27 (s, 4H), 4.85 (dd, J = 9.0 and 4.4 Hz IH), 6.75 - 7.4 (m, 12H), 12.0 (s, IH, D2O exchangeable).
Example 19
5-[4-(2-(Phenothiazin-10-yI)ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt:
.0
O
The title compound (0.26 g, 71 %) was prepared as a white solid from 5-[4-[2-(phenothiazin-10-yl)ethoxy3phenyl methyl]thiazolidine-2,4-dione (0.35 g), obtained in example 17, by an analogous
procedure to that described in example 3. mp : 206-208^0.

o
The title compound (0.14 g, 56 %) was prepared as a dark brown color solid from 4*[2-(S dioxophenothiazin-lO-ylJethoxyjbenzaldehyde (0.2 g, 0.53 mmol), obtained in preparation 9, b similar procedure to that described in example 1. mp : 248 - 250 ^C.
IH NMR (DMSO-dg, 200 MHz) 8 : 4.49 (bs, 2H), 4.79 (bs, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.38 (
= 5.8 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.7 (s, IH), 7.79 (s, 4H), 8.01 (d, J = 7.6 Hz, 2H), 12.5 ( IH, D2O exchangeable).
Example 25 5-[4-[2-[2-Trifluoromethylphenothiazin-10-yl)]ethoxyJphenylmethyIeneltMazoiidiiie-2,4-dioi;

Y
NH
The title compound (1.7 g, 71 %) was prepared as a pale yellow solid from 4-[2-[2-trifluorometh phenotiuazin-l0-yl3ethoxy]benzaldehyde (1.9 g, 4.7 mmol) obtained in prepjuration 10, by a simil
procedure to that described in example 1. mp : 196 -198 ^C.
IH NMR (DMSO-d6, 200 MHz) : 8 4.39 (s, 4H), 6.9 - 7.6 (m, 1 IH), 7.72 (s, IH), 12.5 (bs, IH, D2
exchangeable).
Example 26 5-[4-[2-[2-Trifluoromethylphenothiazln-10-ylJethoxylphenyImethyl]thiazolidine-2,4-dione:

The title compound (0.2 g, 30 %) was prepared as a pale yellow solid from 5-[4-[2-[2 trifluoromethylphenothiazin-10>yl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (0.68 g, 1.: mmol) obtained in example 25 by an analogous procedure to that described in example 2. mp : 6"
IH NMR (CDCI3, 200 MHz) : 8 3.1 (dd, J = 14.2 and 9.4 Hz. IH), 3.44 (dd, J = 14.2 and 4.0 Hz IH), 4.31 (s, 4H), 4.5 (dd, J = 9.4 and 4.0 Hz, IH), 6.7 - 7.3 (m, I IH)
Mutation in colonies of laboratory animals and different sensitivities to dietary
regimens have made the development of animal models with non-insulin dependent diabetes
associated with obesity and insulin resistance possible. Genetic models such as db/db and
ob/ob (See Diabetes, (1982) 31(1) : 1- 6) in mice and fa/fa and zucker 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 meilitus, the compounds of the
present invention were tested for blood sugar and triglycerides lowering activities.
The compounds of the present inventions showed blood sugar and triglycerides lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments.
Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, procured from the Jackson Laboratory, USA, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition, Hyderabad, India) and

acidified water, ad libitum. The animals having more than 300 mg / dl blood sugar were used for testing. The number of animals in each group was 4.
The random blood sugar and triglyceride levels were measured by collecting blood (100 yil) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma. The plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase en2yme (Dr. Redd/s Lab. Diagnostic Division Kits, Hyderabad, hidia) methods respectively. On 6th day the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 10 mg to 200 mg / kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml / kg). Troglitazone (100 mg / kg, daily those) was used as a standard drug which showed 28 % reduction in random blood sugar level on 6th day.
The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula:

The experimental results from the db/db /nice suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for 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 30 mg/kg. Normally, the quantum of reduction is dose dependent.

its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates, wherein R",
are the same or different and represent hydrogen, halogen, hydroxy, cyano, nitro 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, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, aralkoxycarbonylamino, alkoxycarbonylamino, mercaptoalkyl groups, carboxylic acid or its esters or amides, or sulfonic acid or its esters or amides; or R and R together represent along with carbon atoms to which they are attached an aromatic cyclic structure containing 5-6 ring atoms which may optionally be substituted; X represents a heteroatom selected from oxygen, sulfur or NR9 where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; Ar represents optionally substituted divalent single or fused aromatic or heterocyclic group, R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl group or forms a bond together with R*; R* represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl group or optionally substituted aralkyl or R forms a bond together with R""; B represents an oxygen atom or a sulfur atom; Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one.
2. The compound as claimed in claim 1, wherein R1 and R2 together with the

adjacent carbon atoms to which they are attached represent an optionally substituted 5 to 6 membered aromatic ring structure having 5 to 6 ring atoms wherein the aromatic ring structure is substituted, the substituents are selected from halogen, (Ci-C6)alkoxy, Gyclo(C3-C6)alkyl, cyclo(C3-C6)alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxyl, acyl, acyioxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, and aminocarbonyl.

7. The pharmaceutical composition which comprises, a compound according to claim 4, as an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
8. The pharmaceutical composition as claimed in claim 7, in the form of tablet, capsule, powder, syrup, solution or suspension.

Documents:

1153-mas-1997 abstract duplicate.pdf

1153-mas-1997 abstract.pdf

1153-mas-1997 assignemnt.pdf

1153-mas-1997 claims duplicate.pdf

1153-mas-1997 claims.pdf

1153-mas-1997 correspondence others.pdf

1153-mas-1997 correspondence po.pdf

1153-mas-1997 description (complete) duplicate.pdf

1153-mas-1997 description (complete).pdf

1153-mas-1997 description (provisional).pdf

1153-mas-1997 form-1.pdf

1153-mas-1997 form-18.pdf

1153-mas-1997 form-26.pdf

1153-mas-1997 form-3.pdf

1153-mas-1997 form-6.pdf

1153-mas-1997 others.pdf

1153-mas-1997 petition.pdf

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Patent Number

217044

Indian Patent Application Number

1153/MAS/1997

PG Journal Number

21/2008

Publication Date

23-May-2008

Grant Date

24-Mar-2008

Date of Filing

30-May-1997

Name of Patentee

DR. REDDY'S LABORATORIES LTD

Applicant Address

7-1-27 AMEERPET, HYDERABAD 500 016,

Inventors:

#	Inventor's Name	Inventor's Address
1	BRAJ BHUSHAN LOHRAY	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
2	VIDYA BHUSHAN LOHRAY	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
3	ASHOK CHANNAVEERAPPABAJJI	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
4	KALCHAR SHIVARAMAYYA	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
5	ALLA SEKAR REDDY	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
6	RAMANUJAM RAJAGOPALAN	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,
7	REEBA KANNIMEL VIKRAMADITHYAN	DR. REDDY'S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016,

PCT International Classification Number

A61K 31/41

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA