WO2003008362A1

WO2003008362A1 - Novel 3-aryl-2-hydroxy propanol derivatives and a process for their preparation

Info

Publication number: WO2003008362A1
Application number: PCT/IN2001/000128
Authority: WO
Inventors: Mahender Rao Siripragada; Suresh Thatipally; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam
Original assignee: Dr. Reddy's Laboratories Ltd
Priority date: 2001-06-28
Filing date: 2001-06-28
Publication date: 2003-01-30

Abstract

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-2-hydroxy propanol of general formula (I), their derivatives, their analogs, their polymorphs and pharmaceutically acceptable compositions containing them, wherein R?1 and R2¿ may be same or different and represent hydrogen or (C¿1?-C6)alkyl or OR?1 and OR2¿ together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms.

Description

NOVEL 3-ARYL-2-HYDROXY PROPANOL DERIVATIVES AND A

PROCESS FOR THELR 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-2-hydroxy propanol of the general formula (I), their derivatives, their analogs, their polymorphs and pharmaceutically acceptable compositions containing them.

wherein R¹ and R² may be same or different and represent hydrogen or ( - C₆)alkyl or OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms.

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

The present invention also relates to novel intermediates of formula (IN) and (N) and their use in the preparation of compounds of formula (I).

The compounds of formula (I) are useful in lowering the plasma glucose, triglycerides, 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 compounds of formula (I) are also useful as intermediates 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 (Ila) 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.

Gu, Wenxin et. al., (J. Chem. Res., Synop., (8), 397-399, 2000) describes stereoselective synthesis of (2R,3R)- and (2S,3S)-2-(4- hydroxyphenyl)-3-hydroxymethyl- 1 ,4-benzodioxan-6-carbaldehyde using, ( 1R,2R)- 1 -[4-(phenylmethoxy)phenyl]-l ,2,3-propanerriol.

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 relates to novel 3-aryl-2-hydroxy propanol derivatives of the formula (I)

wherein R and Rι2 may be same or different and represent hydrogen or (C_r C₆)alkyl or OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms. The term (C C₆)alkyl represents methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl and the like.

The substituents on the cyclic structure formed by OR¹ and OR² may be selected from hydroxy, alkyl group such as methyl, ethyl, propyl or isopropyl and the like; alkoxy group such as methoxy, ethoxy, propoxy and the like.

Particularly useful compounds according to the present invention include :

(-) 4-(2-Ethoxy-3-methoxypropyl)phenol ; (-) 4-(2,3-Diethoxypropyl)phenol (-) 4-(2-Ethoxy-3-isopropyloxypropyl)phenol ; (-) 4-(2,3-Dimethoxypropyl)phenol ; (-) 4-(2-Ethoxy-3-hydroxypropyl)phenol; (-) 4-(2-Methoxy-3~hydroxypropyl)phenol ; (-) 3-(4-Hydroxyphenyl)-5,5-dimethyl-l,4-dioxalane;

According to another embodiment of the present invention there is provided a process for the preparation of novel 3-aryl-2-hydroxy propanol and their derivatives of the formula (I)

wherein R^! and R² may be same or different and represent hydrogen or ( -

C₆)alkyl, which comprises : i). reducing the compound of formula (III) where R represents hydrogen or alkyl group, R³ represents benzyl to a compound of formula (IN) where R³ represents benzyl, ii). etherifying the compound of formula (IN) using alkylating agent to a compound of formula (V) where R¹, R² and R³ are as defined above and iii). debenzylating the compound of formula (N) in the presence of metal catalysts to yield pure compound of formula (I).

The reduction of the compound of formula (III) to a compound of formula (IN) may be carried out using reagents such as sodium borohydride/ iodine, lithium aluminum hydride and the like. The reaction may be carried out in the presence of solvents such as THF, dioxane, dialkyl ether such as diisopropyl ether, diethyl ether and the like, at a temperature in the range of 0 °C to reflux temperature, for a period in the range of 1 h to 20 h.

The etherification of the compound of formula (IN) to a compound of formula (N) may be carried out using alkylating agents like alkyl sulphates such as diethyl sulphate, dimethyl sulphate or alkyl halides such as methyl iodide, ethyl iodide and the like in the presence of a base such as sodium bicarbonate, potassium bicarbonate, ΝaH and the like. The reaction may be carried out at a temperature in the range of 0 to 110 °C and the duration of the reaction may range from 2-24 h. The debenzylation of the compound of formula (N) using THF, aqueous acetic acid, ethyl acetate, aqueous

alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C produces pure compound of formula (1).

wherein OR and OR together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, which comprises : i). reducing the compound of formula (ffl) where R represents hydrogen or alkyl group, R³ represents benzyl to a compound of formula (IN) where R³ represents benzyl, ii). cyclizing the compound of formula (IN) to a compound of formula (N) where OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms and R³ represents benzyl and iii). debenzylating the compound of formula (N) in the presence of metal catalysts to yield pure compound of formula (I).

The reduction of the compound of formula (III) to a compound of formula (IN) may be carried out using reagents such as sodium borohydride/ iodine, lithium aluminum hydride and the like. The reaction may be carried out in the presence of solvents such as THF, dioxane, dialkyl ether such as dimethyl ether, diethyl ether and the like, at a temperature in the range of 0 °C to reflux temperature, for a period in the range of 1 h to 20 h.

The cyclization of compound of formula (IN) may be carried out using dimethoxyethane, dimethoxypropane, acetone, acetaldehyde, benzaldehyde, trimethyltrioxane and the like or mixtures thereof. The reaction may be carried out in the presence of catalytic amount of pyridinium para toluene sulphoπate, p-TSA, methane sulfonic acid and the like. The reaction may also be carried out in the presence of solvents such as toluene, pentane, chloroform, cyclohexane and the like. The reaction may be carried out at a temperature in the range of 25 °C to reflux temperature and the duration of the reaction may range from 4 to 36 h.

The debenzylation of the compound of formula (V) using THF, ethyl acetate, aqueous (Cι-C₆) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C produces pure compound of formula (1).

According to another embodiment of the present invention there is provided a novel intermediate of formula (IN)

wherein R represents benzyl.

According to another embodiment of the present invention there is provided a novel intermediate of formula (N)

wherein R¹ and R² may be same or different and represent hydrogen or (C C₆)alkyl or OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, R represents benzyl.

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, trimethyl silyl chloride, acyl, 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 Step (i) Preparation of (S)-3-(4-benzyloxyphenyl)-l,2-propanediol

To a stirred suspension of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (10 g, 0.036 M) in THF (100 ml), sodium borohydride (4.16 g, 0.1 M) was added at room temperature. Iodine (4.55 g, 0.018 M) was added to the reaction mass portion wise in about 1 h and maintained the reaction for 12 h. Water was added to the reaction mass and extracted with ethyl acetate. The organic layer was washed sequentially with sodium thio sulfate, water and concentrated to yield the title compound as a thick syrup, yield 5.12 g, 54 %. 1H NMR (200 MHz, CDC1₃) δ : 7.4 (m, 5H), 7.1 (d, 2H), 6.9 (d, 2H), 5.0 (s, 2H), 3.9 (m, 1H), 3.6 (dd, 1H), 3.5 (dd, 1H), 2.7 (d, 2H). Mass m/z : 258, 241, 197, 91.

Step (ii)

Preparation of (S)-3-(4-benzyloxyphenyI)-l,2-diethoxy propane

A solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanol (2.5 g, 9.6 mmol) in acetone (30 ml) was heated under reflux^' with diethyl sulphate (6.0 g, 38 mmol) and potassium carbonate (606 g, 48 mmol) for 12 h. The reaction mass was cooled, water was added and extracted with ethylacetate. The organic layer was washed with water and concentrated to yield the title compound as a thick syrup, yield 6.0 g, 82 %.

1H NMR (200 MHz, CDC1₃) δ : δ 7.5-7.2 (bm, 5H), 7.1 (d, 2H), 6.9 (d, 2H), 5.1 (s, 2H), 4.3 (q, 2H), 3.6-3.3 (m, 3H), 2.7 (d, 2H), 1.4 (t, 3H), 1.2 (t, 3H). Mass m z : 314, 197, 91.

Step (iii)

Preparation of (S)-4-(2,3-diethoxypropyl)phenol

A solution of (S)-3-(4-benzyloxyphenyl)-l,2-diethoxy propane (4 g) in methanol (40 ml) was hydrogenated over 5 % Pd-C (800 mg) at 60 psi of pressure for 6 h at room temperature. The catalyst was filtered and the solvent was concentrated to yield the title compound as syrup, yield 2.0 g, 70 %.

Η NMR (200 MHz, CDC1₃) δ : 7.1 (d, 2H), 6.8 (d, 2H), 3.7-3.3 (bm, 7H), 2.7

(d, 2H), 1.2 (m, 6H). Mass m/z : 224, 178, 107, 91.

Example-2

Step (i)

Preparation of (S)-3-(4-benzyloxyphenyl)-l,2-propanedioI A solution of (S)-methyl-3-(4-benzyloxyphenyl)-2-hydroxy propanoate (16 g, 0.05 M) in THF (50 ml), was added to a stirred suspension of lithium aluminum hydride (2.028 g, 0.06 M) at 0 C in 20 min. After complete addition, the reaction was maintained for 1 h. The excess reagent was quenched with saturated ammonium chloride solution. Water was added to the reaction mass and extracted with ethylacetate. The organic layer was washed with water and concentrated to yield the title compound as thick syrup, yield 12 g, 83 %.

1H NMR (200 MHz, CDC1₃) δ : 7.4 (m,^'5H), 7.1 (d, 2H), 6.9 (d, 2H), 5.0 (s, 2H), 3.9 (m, 1H), 3.6 (dd, 1H), 3.5 (dd, 1H), 2.7 (d, 2H). Mass m/z : 258, 241, 197, 91.

Step (ii)

Preparation of (S)-3-(4-benzyloxyphenyl)-l,2-diethoxy propane A solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanol (2.5 g, 9.6 mmol) in acetone (30 ml) was heated under reflux with diethyl sulphate (6.0 g, 38 mmol) and potassium carbonate (606 g, 48 mmol) for 12 h. The reaction mass was cooled, water was added and extracted with ethylacetate. The organic layer was washed with water and concentrated to yield the title compound as a thick syrup, yield 6.0 g, 82 %.

1H NMR (200 MHz, CDC1₃) δ : δ 7.5-7.2 (bm, 5H), 7.1 (d, 2H), 6.9 (d, 2H), 5.1 (s, 2H), 4.3 (q, 2H), 3.6-3.3 (m, 3H), 2.7 (d, 2H), 1.4 (t, 3H), 1.2 (t, 3H). Mass /z : 314, 197, 91.

Step (iii)

Preparation of (S)-4-(2,3-diethoxypropyl)phenol

A solution of (S)-3-(4-benzyloxyphenyl)-l,2-diethoxy propane (4 g) in methanol (40 ml) was hydrogenated over 5 % Pd-C (800 mg) at 60 psi of pressure for 6 h at room temperature. The catalyst was filtered and the solvent was concentrated to yield the title compound as syrup, yield 2.0 g, 70 %. 1H NMR (200 MHz, CDC1₃) δ : 7.1 (d, 2H), 6.8 (d, 2H), 3.7-3.3 (bm, 7H), 2.7 (d, 2H), 1.2 (m, 6H). Mass m/z : 22457, 178, 107, 91.

ExampIe-3

Step (i)

Preparation of (S)-3-(4-benzyIoxyphenyI)-l,2-propanediol To a stirred suspension of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (10 g, 0.036 M) in THF (100 ml), sodium borohydride (4.16 g, 0.1 M) was added at room temperature. Iodine (4.55 g, 0.018 M) was added to the reaction mass portion wise in about 1 h and maintained the reaction for 12 h. Water was added to the reaction mass and extracted with ethyl acetate. The organic layer was washed sequentially with sodium thio sulfate, water and concentrated to yield the title compound as a thick syrup, yield 5.12 g, 54 %.

Step (ii)

Preparation of 3-(4-benzyloxyphenyl)-5,5-dimethyl-l,4-dioxaIane. To a solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxy propanol (5 g), in 2,2- dimethoxy propane (20 ml) and chloroform (50 ml), catalytic amount of pyridinium para 'toluene sulphonate was added and heated under reflux for 15 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT and washed with saturated solution, of sodium bicarbonate and water. The Organic phase was concentrated to yield the title compound as a semi solid yield 5.5 g, 96 %.

Step (iii)

Preparation of 3-(4-hydroxyphenyl)-5,5-dimethyl-l,4-dioxalane: A solution of 3-(4-benzyloxyphenyl)-5,5-dimethyl-l,4-dioxalane (3 g) in methanol (40 ml) was hydrogenated over 5 % Pd-C (600 mg) at 60 psi of pressure for 6 h at room temperature. The catalyst was filtered and the solvent was concentrated to yield the title compound as a syrup, yield 1.5 g, 72 %.

Example-4

Step (i)

Preparation of (S)-3-(4-benzyloxyphenyl)- 1,2-propanediol

A solution of (S)-methyl-3-(4~benzyloxyphenyl)-2-hydroxy propanoate (16 g, 0.05 M) in THF (50 ml), was added to a stirred suspension of lithium aluminum hydride (2.028 g, 1.2 M) at 0 C in 20 min. After complete addition, the reaction was maintained for 1 h. The excess reagent was quenched with saturated ammonium chloride solution Water was added to the reaction mass and extracted with ethylacetate. The organic layer was washed with water and concentrated to yield the title compound as thick syrup, yield 12 g, 83 %.

Step (ii)

Preparation of 3-(4-Benzyloxyphenyl)-5,5-dimethyl-l,4-dioxalane.

To a solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxy propanol (5 g), in 2,2- dimethoxy propane (20 ml) and chloroform (50 ml), catalytic amount of pyridinium para toluene sulphonate was added and heated under reflux for 15 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT and washed with saturated solution of sodium bicarbonate and water. The organic phase was concentrated to yield the title compound as a semi solid yield 5.5 g, 96 %.

Step (iii)

The compounds of the present invention lower random blood sugar level. This can be demonstrated by in vitro as well as in vivo animal experiments.

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). The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention can be 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, can be used in the experiment. The mice are provided with standard feed (National Institute of Nutrition (NTN), Hyderabad, India) and acidified water, ad libitum. The animals having more than 350 mg / dl blood sugar can be used for testing. The number of animals in each group is 4.

Test compounds will be suspended on 0.25 % carboxymethyl cellulose and administer to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days. The control group receives vehicle (dose 10 ml / kg). On 6th day the blood samples can be collected one hour after administration of test compounds / vehicle for assessing the biological activity.

The random blood sugar and triglyceride levels can be measured by collecting blood (100 μl) through orbital sinus, using heparinised capillary in tubes containing EDTA which will be centrifuged to obtain plasma. The plasma glucose and triglyceride levels can be measured spectrometrically, by glucose oxidase and glycerol-3-P0₄ 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 will be calculated according to the formula.

Formulae for calculation :

Percent reduction in Blood sugar can be calculated according to the formula :

TT / OT

Percent reduction (%) = 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.

Claims

Claims :

1. A compound of formula (I)

1 wherein R and R may be same or different and represent hydrogen or ( - C₆)alkyl or OR and OR together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms.

2. A compound according to claim 1, where the substituents on the cyclic

1 structure formed by OR and OR are selected from hydroxy, alkyl or alkoxy group. 3. A compound according to claim 1 which is selected from :

4-(2-Ethoxy-3-methoxypropyl)phenol ; 4-(2,3-Diethoxypropyl)phenol 4-(2-Ethoxy-3-isopropyloxypropyl)phenol ; 4-(2,

3-Dimethoxypropyl)phenol ; 2-Ethoxy-3-(4-hydroxyphenyl)- 1 -propanol ; 3-(4-Hydroxyphenyl)-2-methoxy- 1 -propanol ; 3-(4-Hydroxyphenyl)-5,5-dimethyl-l,4-dioxalane;

4. A process for the preparation of compound of formula (I)

wherein R¹ and R² may be same or different and represent hydrogen or (C C₆)alkyl, which comprises : i). reducing the compound of formula (III)

where R represents hydrogen or alkyl group, R³ represents benzyl to a compound of formula (IN)

where R represents benzyl, ii). etherifying the compound of formula (IN) using alkylating agent to a compound of formula (N)

where R , R and R are as defined above. and iii). debenzylating the compound of formula (N) in the presence of metal catalysts to yield pure compound of formula (I).

5. The process as claimed in claim 4 wherein the reducing reagent used in step (i) is selected from sodium borohydride / iodine or lithium aluminum hydride.

6. The process as claimed in claim 4 and 5 wherein the solvent used in step (i) is selected from THF, dioxane or dialkyl ether.

7. The process as claimed in claims 4 to 6, wherein the reduction in step (i) is carried out at a temperature in the range of 0 °C to reflux temperature, for a period in the range of 1 h to 20 h.

8. The process as claimed in claims 5 to 7, wherein the etherification in step (ii) is carried out using alkylating agents selected from alkyl sulphates such as diethyl sulphate, dimethyl sulphate or alkyl halides such as methyl iodide or ethyl iodide

9. The process as claimed in claims 5 to 8, wherein the etherification in step (ii) is carried out in the presence of base selected from sodium bicarbonate, potassium bicarbonate or ΝaH.

10. The process as claimed in claims 4 to 9, wherein the etherification in step (ii) is carried out at a temperature in the range of 0 to 110 °C for a period in the range of 2-24 h.

11. The process as claimed in claims 4 to 10, wherein the debenzylation in step (iii) is carried out using THF, aqueous acetic acid, ethyl acetate, aqueous (C C₆) alcohols such as aqueous methanol, ethanol, propanol or isopropanol.

12. The process as claimed in claims 4 to 11, wherein the debenzylation in step (iii) is carried out using Pd/C.

13. A process for the preparation of compound of formula (I)

wherein OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, which comprises :

i). reducing the compound of formula (III)

where R represents hydrogen or alkyl group, R represents benzyl to a compound of formula (IN)

where R³ represents benzyl, ii). cyclizing the compound of formula (IN) to a compound of formula (N)

where OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms and R³ represents benzyl and iii). debenzylating the compound of formula (N) in the presence of metal catalysts to yield pure compound of formula (I).

14. A process as claimed in claim 13, wherein the cyclization in step (ii) is carried out using dimethoxyethane, dimethoxypropane, acetone, acetaldehyde, benzaldehyde or trimethyltrioxane or mixtures thereof.

15. A process as claimed in claim 14, wherein the cyclization in step (ii) is carried out in the presence of catalytic amount of pyridinium para toluene sulphonate, p-TSA or methane sulfonic acid and the like.

16. A process as claimed in claims 13 to 15, wherein the cyclization in step (ii) is carried out in the presence of solvents such as toluene, pentane, chloroform or cyclohexane.

17. A process as claimed in claims 13 to 16, wherein the cyclization in step (ii) is carried out at a temperature in the range of 25 °C to reflux temperature for a period in the range of 4 to 36 h.

18. An intermediate of formula (IN)

wherein R³ represents benzyl.

19. An intermediate of formula (N)

wherein R¹ and R² may be same or different and represent hydrogen or (C C₆)alkyl or OR¹ and OR² together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, R³ represents benzyl.

20. Use of a compound of formula (I) as defined in claim 1 or a compound as claimed in claim 3 for treating diabetes, obesity, glucose intolerance, insulin resistance and other related disorders such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders."

21. Use of a compound of formula (I) as defined in claim 1 or a compound claimed in claim 3 for reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, NLDL and free fatty acids.