DERIVATIVES OF PARA-ETHOXY-PHENILLACTIC ACID PREPARATION Field of the invention The present invention relates to novel antidiabetic compounds, their derivatives, their analogs, their polymorphs and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel 3-aryl-a-oxy substituted propanoic acids of the general formula (I), their derivatives, their analogs, their polymorphs and pharmaceutically acceptable compositions containing them where Rl represents hydroxy or a protecting group such as (C-C8) alkoxy- CH2-0-, mesylate, tosylate, triflate or halogen atom, R represents hydrogen or (C-C6) alkyl group, R3 represents hydrogen, (Cl-C6) alkyl, t-butyldimethyl silyl, trimethyl silyl or alkoxymethyl.

The present invention also relates to a process for the preparation of compounds of formula (1).

The compounds of formula (I) are useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL).

The compounds of formula (I) are useful in reducing body weight, glucose intolerance and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).

The compound of formula (1) is useful as an intermediate for the preparation of many pharmaceutically active compounds. Few representative examples of such compounds are

disclosed in WO 99/62870 and disclosed in WO 99/16758. The compounds of formulae (IIa) and (lib) are shown to have potent blood glucose lowering, triglyceride lowering, cholesterol lowering and body weight reducing activities.

Background of invention Diabetes and insulin resistance is yet another disease which severely effects the quality of life of a large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.

Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest. , (1985) 75: 809-817 ; N. Engl. J. Med.

(1987) 317: 350-357; J. Clin. Endocrinol. Metab. , (1988) 66: 580-583; J.

Clin. Invest. , (1975) 68: 957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in

obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X.

In our WO publication No. 99/19313, we have described compounds of formula (IIc) and a process for its preparation where Ar represents an unsubstituted or substituted divalent single or fused aromatic or heterocyclic group; R5 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or unsubstituted or substituted aralkyl group or forms a bond together with the adjacent group R6 ; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl or unsubstituted or substituted aralkyl or R6 forms a bond together with R5 ; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer ranging from 1-4; m is an integer 0 or 1 and L'is a leaving group such. as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like.

WO 00/59889 describes compounds of formula (IId) as an intermediate wherein Wl represents is alkylene, W2 represents single bond or alkylene, and B represents O or S, R represents hydrogen or the like, Y represents oxygen and the like, R3 represents hydrogen and the like, for preparing the compounds of formula (IIe)

The process for preparing compounds of formula (IId) comprises hydrolyzing the compound of formula (IIf) is shown in scheme 1 below: Scheme-1 In our WO publication No. 00/26200, we have described compounds of formula (IIg) and a process for its preparation where R1 represents hydrogen or (CI-C6) alkyl, R represents (C-C6) alkyl group.

WO 99/66870 and WO 99/66872 describes compounds of formula (IIh) where A is chiral auxiliary group, -OH or ORP, wherein RP is a protective group, example ethyl, Q is hydrogen, -CH2-CH2Ph-4-OSO2CH3 or Rq, wherein RI is a protective group, example benzyl.

Objective of present invention The main objective of the present invention is to provide novel compounds of the formula (I) for the treatment and/or prophylaxis of diabetes with high chiral purity, which can be used in the synthesis of pharmaceutically acceptable compounds, which will not have problems of racemization in subsequent steps, when used in the preparation of pharmaceutically acceptable compounds.

Another objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (I).

Detailed description of the invention Accordingly, the present invention provides novel 3-aryl-a-oxy substituted propanoic acid and their derivatives, their polymorphs having the formula (I) where RI represents hydroxy or a protecting group such as (Cl-C8) alkoxy- CH2-O-, mesylate, tosylate, triflate or halogen atom such as fluorine, chlorine, bromine or iodine; R2 represents hydrogen or (C1-C6)alkyl group, R3 represents hydrogen, (Ci-C6) alkyl, t-butyldimethyl silyl, trimethyl silyl or alkoxymethyl.

The term (CI-C6) alkyl group represents groups such as methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl and the like.

The term (CI-C6) alkoxy group represents groups such as methoxy, ethoxy, propoxy, isopropoxy and the like.

The term alkoxymethyl represents methoxymethyl, ethoxymethyl and the like.

Particularly useful compounds of the formula (I) according to the present invention, include: (-) Methyl 2-hydroxy-3- [4- (2-hydroxyethoxy) phenyl] propanoate; (-) Ethyl 2-hydroxy'3- [4- (2-hydroxyethoxy) phenyl] propanoate; (-) Propyl 2-hydroxy-3- [4- (2-hydroxyethoxy) phenyl] propanoate; Isopropyl 2-hydroxy-3- [4- (2-hydroxyethoxy) phenyl] propanoate; (-) Methyl 2-hydroxy-3- [4- (2-chloroethoxy) phenyl] propanoate ; (-) Ethyl 2-hydroxy-3- [4- (2-chloroethoxy) phenyl] propanoate ; Propyl 2-hydroxy-3- [4- (2-chloroethoxy) phenyl] propanoate ; (-) Isopropyl 2-hydroxy-3- [4- (2-chloroethoxy) phenyl] propanoate ; (-) Ethyl 2-hydroxy-3- [4- [2- (4-methylphenyl sulfonyloxy) ethoxy] phenyl] propanoate; (-) Isopropyl 2-hydroxy-3- [4- [2- (4-methylphenyl sulfonyloxy) ethoxy] phenyl] propanoate ; (-) Ethyl 2-hydroxy-3- [4- [2-methoxymethoxyethoxy] phenyl] propanoate ; Isopropyl 2-hydroxy-3- [4- [2- methoxymetlioxyethoxy] phenyl] propanoate ; Ethyl 2-hydroxy-3- [4- [2-ethoxymethoxyethoxy] phenyl] propanoate; (-) Isopropyl 2-hydroxy-3-[4-[2- ethoxymethoxyethoxy] phenyl] propanoate ; (-) Isopropyl 2-hydroxy-3- [4- (2-hydroxyethoxy) phenyl] propanoate ; (-) Isopropyl 2-tertiary butyl dimethyl silyloxy-3- [4- (2- hydroxyethoxy) phenyl] propanoate; According to another embodiment of the present invention there is provided a process for the preparation of novel 3-aryl-a-oxy substituted propanoic acid and their derivatives, having the formula (I)

where Rl represents hydroxy or a protecting group such as (Cl-C8) alkoxy- CH2-O-, mesylate, tosylate, triflate or halogen atom, R represents hydrogen or (Ci-C6) alkyl group, R3 represents hydrogen, (Cl-C6) alkyl, t-butyldimethyl silyl, trimethyl silyl or alkoxymethyl,. which comprises, reacting the compound of formula (III) where RI is as defined above and Ll is a leaving group such as halogen, hydroxy, mesylate, tosylate and the like with compound of formula (IV) to produce compound of formula (I).

The process explained above is shown in scheme-2 below: Scheme-2 The reaction of compound of formula (III) with compound of formula (IV) may be carried out in the presence of bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, NaH, sodium methoxide, potassium tertiary butoxide and the like. The reaction may be carried out in the presence of solvents such as toluene, xylene, DMF, THF and the like. The reaction may be carried out at a temperature in the range of 20 to reflux temperature and the duration may range form 4 to 30 h.

According to yet another embodiment of the present invention there is provided a process for the preparation of novel 3-aryl-a-oxy substituted propanoic acid and their derivatives, having the formula (I)

where R'represents hydroxy or a protecting group such as (C-C8) alkoxy- CH2-0-, mesylate, tosylate, triflate or halogen atom, R represents hydrogen, R3 represents hydrogen, which comprises, diazotizing the compound of formula (V) where Rl and R2 are as defined above in the presence of an acidic reagent and an organic solvent to produce compound of formula (I) where Rl, R and R3 are as defined above.

The process explained above is shown in scheme-3 below: Scheme-3 The diazotization of the compound of the formula (V) using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite, barium nitrite and the like under acidic conditions using acids such as sulfuric acid, HC1, acetic acid and the like. The reaction may be carried out in the presence of an organic solvent such as CHC13, 1,4-dioxane, THF, acetone and the like. The reaction may be carried out at a temperature in the range of 0 - 5 °C and the duration of the reaction may range from 1 to 5 h.

The compounds of formula (I) are useful in the preparation of pharmaceutically important compounds such as The process for preparing the compounds of formula (IIb) starting from compound of formula (I) is as shown in scheme-4: O 0"IOR2 2 ou3 my O NH R I/OR3 O (ttd) (tic) 0 Hydrolysis 0 COOH O,, COQRz O, 0 GOOR (lib) (live)

Scheme-4 where R4 represents hydrogen or alkyl group.

It is appreciated that in any of the above mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl dimethyl silylchloride, methoxymethyl chloride and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.

Various polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures'for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The

presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X- ray diffraction or such other techniques.

The invention is described in the examples given below which are provided by way of illustration only and therefore should not construed to limit the scope of the invention.

Example-1 Preparation of isopropyl 2 (S)-hydroxy-3-14-(2-chloroethoxy) pllenyl propionate Potassium carbonate Powder (193 g) and toluene were (500 ml) added to 1 L four necked round bottom flask, fitted with a mechanical stirrer and reflux condenser. The reaction mixture was heated to 110-120 °C for 3 h and water was removed azeotropically. The reaction mixture was brought to a temperature of 60 °C, isopropyl 2-hydroxy-3- (4-hydroxyphenyl) propionate (44.8 g) was added to the reaction mixture at 60 °C in about 10 minutes under stirring, followed by chloroethylmethane sulfonate (47.52 g) at 60 °C under stirring. Maintaining gentle reflux of the reaction mixture for 8-10 h and monitored the progress of the reaction. The reaction mixture was cooled to 10- 15 °C and water (200 ml) was added. The organic layer was separated and washed with water (100 ml X 2). The toluene layer was evaporated to dryness on rotavapor bath at 60-80 °C under 20-40 mm vacuum to afford the title compound as an oily mass (weighs about 55 g, yield 98 %, purity 99 % by HPLC).

IR (KBr) cm~': 3500 (O-lI stretch), 3120 (C-H aromatic), 2970 (-C-H aliphatic), 1727 (-COO stretch).

'H NMR (200 MHz, DMSO-d6) 8 : 7. 13 (d, J=8. 4 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 5.42 (d, 1H), 4. 8 (m, 1H), 4.42 (m, 1H), 4.2 (m, 2H), 3.9 (m, 2H), 2. 8 (m, 2H), 1.2 (d, 3H), 1.2 (d, 3H), 1.1 (d, 3H).

Mass m/z: 287 (M+ + 1), Anal. Calcd: Cl4Hl9ClO4 ; % C 58.74 ; % H: 6.64 ; Found % C 58. 58 ; % H 6. 45.

Example-2 Preparation of isopropyl 2 (S)-hydroxy-3- [4- (2-bromoethoxy) phenyl] propionate Potassium carbonate powder (193 g), toluene (500 ml) were added to 1 L four necked round bottom flask, fitted with a mechanical stirrer and reflux condenser. The reaction mixture was heated to 110-120 °C for 3 h and water was removed azeotropically. The reaction mixture was brought to a temperature of 60 °C, isopropyl 2-hydroxy-3-(4-hydroxyphenyl)propionate (44.8 g) was added to the reaction mixture at 60 °C in about 10 minutes under stirring, followed by bromoethylmethane sulfonate (60.89 g) at 60 °C under stirring. Maintained the gentle reflux of the reaction mixture for 8-10 h and monitored the progress of the reaction. The reaction mixture was cooled to 10- 15 °C and water (200 ml) added. The organic layer was separated and washed with water (100 ml X 2). The toluene layer was evaporated to dryness on rotavapor bath at 60-80 °C under 20-40 mm vacuum to afford the title compound as an oily mass (weighs about 65 g, yield 98 %, purity 99 % by HPLC).

IR (KBr) cm~1 : 3500 (O-H stretch), 3120 (C-H aromatic), 2970 (-C-H aliphatic), 1727 (-COO stretch).

'H NMR (200 MHz, DMSO-d6) # : 8 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 5.42 (d, 1H), 4.8 (m, 1H), 4.42 (m, 1H), 4.2 (m, 2H), 3.9 (m, 2H), 2. 8 (m, 2H), 1.2. (d, 3H), 1.2 (d, 3H), 1. 1 (d, 3H).

Mass m/z: 332 (M+ + 1), Anal. Calcd: Cl4HIsBrO4 ; % C 58.74 ; % H: 6.64 ; Found % C 58. 58; % H 6. 45.

Example 3 Preparation of isopropyl 2 (S)-hydroxy-3- [4- (2-hydroxyethoxy) phenyl] propanoate In a 50 ml round bottom flask DMF (20 ml), isopropyl 2-hydroxy-3- (4- hydroxyphenyl) propionate (2 g) and potassium carbonate (3 g) were taken. To this mixture 2-chlorethanol (1.43 g) was added at RT and maintained the reaction mixture at 60-70 °C for a period of 24 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and diluted with water (25 ml), extracted with ethyl acetate (3 x 25 ml). The ethyl acetate layer was washed with water (3 X 25 ml) and concentrated to yield the crude compound. The crude compound was purified by column chromatography using ethyl acetate and pet. ether as an eluent to yield the title compound (weighs about 1 g, yield 41. 7 %).

Example 4 Preparation of isopropyl 2 (S) -tertiary butyl dimethyl silyloxy-3- [4- (2- hydroxyethoxy) phenyl] propanoate In a 50 ml round bottom flask DMF (20 ml), isopropyl 2 (S) -tertiary butyl dimethyl. silyloxy-3- (4-hydroxyphenyl) propionate (2 g) and potassium carbonate (2.04 g) were taken. To this mixture 2-chlorethanol (0.94 g) was added at RT and maintained the reaction mixture at 60-70 °C for a period of 20 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and diluted with water (25 ml), extracted with ethyl acetate (3 x 25 ml). The ethyl acetate layer was washed with water (3 X 25 ml) and concentrated to yield the crude compound.

The crude compound was purified by column chromatography using ethyl

acetate and pet. ether as an eluent to yield the title compound (weighs about 0.9 g, yield 40 %).

Demonstration of Efficacy of Compounds Efficacy in genetic models Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non- insulin dependent diabetes and hyperlipidemia associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (Diabetes, (1982) 31 (1) : 1-6) mice and zucker fa/fa rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab. (1994). 46: 1-57). Thehomozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest. , (1990) 85: 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water, ad libitum. The animals having more than 350 mg/dl blood sugar were used for testing. The number of animals in each group was 4.

Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg/kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml/kg).

On 6th day the blood samples were collected one hour after administration of test compounds/vehicle for assessing the biological activity.

The. random blood sugar and triglyceride levels were measured by collecting blood (100 (il) 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-PO4 oxidase/peroxidase enzyme (Dr. Reddy's Lab.

Diagnostic Division Kits, Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.

Formulae for calculation: Percent reduction in Blood sugar can be calculated according to the formula : TT/OT Percent reduction (%) = 1-X 100 TC/OC OC = Zero day control group value OT = Zero day treated group value TC = Test day control group value TT = Test day treated group value.