WO2003002550A1

WO2003002550A1 - Dioxalane derivatives and a process for their preparation

Info

Publication number: WO2003002550A1
Application number: PCT/IN2001/000127
Authority: WO
Inventors: Venkateswarlu Akella; Om Reddy Gaddam; Mahender Rao Siripragada; Madhusudhan Gutta; Nageshwar Dussa; Ramabhadra Sarma Mamillapalli
Original assignee: Dr. Reddy's Research Foundation
Priority date: 2001-06-28
Filing date: 2001-06-28
Publication date: 2003-01-09

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 dioxalane of the 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, (C¿1-6?) alkyl or unsubstituted or substituted phenyl or R?1 and R2¿ together may form a 5 or 6 membered cyclic structure.

Description

DIOXALANE DERIVATIVES AND A PROCESS FOR THEIR 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 dioxalane of the general formula (I), their derivatives, their analogs, their polymorphs and pharmaceutically acceptable compositions containing them.

1 -y wherein R and R may be same^' or different and represent hydrogen, (C

C₆)alkyl or unsubstituted or substituted phenyl or R and R together may form a 5 or 6 membered cyclic structure.

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

The present invention also relates to novel intermediate of formula (Ilg) and its 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 compound of formula (I) 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 (Ha) 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. The dioxalane compounds in racemic form have been described in WO

00/59889 as an intermediate having the formula (lie)

wherein W represents alkylene and B represents O or S for preparing the compounds of formula (lib)

The process for preparing compounds of formula (lie) comprises reacting compound of formula (He) with acetone is shown in scheme 1 below:

Scheme-1 This patent did not disclose the existence of compounds of formula

(He) in chiral form and also a process for their preparation.

The chiral compounds of the formula (Ha) and (lib) are used in the treatment of diabetes and other related disorders, and with the aim of developing an improved process for "the preparation of these compounds we have developed the novel compound of formula (I) and a process for its preparation. 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 dioxalane compounds of the formula (I) their derivatives, their analogs, their polymorphs

wherein R¹ and R² may be same or different and represent hydrogen, ( - C₆)alkyl or unsubstituted or substituted phenyl or R¹ and R² together may form a 5 or 6 membered cyclic structure.

The substituents on the phenyl group may be selected from alkyl or alkoxy group such as methoxy, ethoxy, propoxy and the like.

__ 1 9

The cyclic structure formed by R and R together may be selected from cyclopentane or cyclohexane.

The term (C_rC₆)alkyl represents methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl and the like. Particularly useful compounds of the formula (I) according to the present invention, include :

(S)-3-(4-Hydroxyphenyl)-5,5-dimethyl-l,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5,5-diethyl- 1 ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5-phenyl-l,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)- 1 ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5-methyl- 1 ,4-dioxala-2-one ; (S)-3 -(4-Hydroxyphenyl)-5-ethyl- 1 ,4-dioxala-2-one ;

According to another embodiment of the present invention there is provided a process for the preparation of novel dioxalane derivatives of the formula (I) wherein R and R may be same or different and represent

1 j hydrogen, (C C₆)alkyl or phenyl or R and R together may form a 5 or 6 membered cyclic structure, which comprises : (i). cyclizing the compound of the formula (Ilf) where R³ represents benzyl to a compound of formula (Ilg) where R¹, R² and R³ are as defined above and _, (ii). debenzylating the compound of formula (Ilg) where R³ represents benzyl in the presence of metal catalysts to yield pure compound of formula

(I) where R¹ and R² are as defined above. The process explained above is shown in scheme-2 below :

Scheme-2

The cyclization of compound of formula (llf) may be carried out using benzaldehyde or its derivatives such as p-nitro benzaldehyde, anisaldehyde and the like; dimethoxyethane, dimethoxypropane, diethoxypropane, paraformaldehyde, trioxane, paraldehyde, methylethyl ketone, MIBK, acetone, acetaldehyde, trimethyltrioxane, cyclohexanone, cyclopentanone and the like or mixtures thereof. The reaction may be carried out in the presence of catalytic amount of pyridinium para toluene sulphonate, p-TSA, methane sulfonic acid and the like. The reaction may be also 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 (Ilg) to produce compound of formula (I) may be carried out using THF, ethyl acetate, aqueous ( - ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C. According to another embodiment of the present invention there is provided a novel intermediate of formula (Ilg)

1 7 wherein R and R may be same or different and represent hydrogen, (C C₆)alkyl or unsubstituted or substituted phenyl or R¹ and R² together may form a 5 or 6 membered cyclic structure.

The compounds of formula (I) are useful in the preparation of pharmaceutically important compounds such as

The process for preparing the compounds of formula (lib) starting from compound of formula (I) is as shown in scheme -3 :

(lib) (Hj)

Scheme - 3 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 polymoφhs 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 nrnr 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-l Step (i)

Preparation of (S)-3-(4-benzyloxyphenyl)-5,5-dimethyl-l,4-dioxala-2-one

To a solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxyproparioic acid (5 g, 0.018 M), in 2,2-dimethoxypropane (19.14 g, 0.18 M) and chloroform (15 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 a solution of sodium bicarbonate and water. The organic phase was concentrated to yield the title compound as a semi solid (yield 5.5 g, 96.5 %, purity: 96 % by HPLC).

1H NMR (200 MHz, CDC1₃) δ : 7.4 (m, 5H), 7.1 (d, 2H), 6.9 (d, 2H), 5.05 (s, 2H), 4.6 (t, 1H), 3.3 (dd, 1H), 3.1 (dd, 1H), 1.5 (s, 3H), 1.35 (s, 3H). Mass m/z : 312, 197, 91.

Step (ii)

Preparation of (S)-3-(4-hydroxyphenyl)-5,5-dimethyl-l,4-dioxala-2-one

A solution of (S)-3-(4-benzyloxyphenyl)-5,5-dimethyl-l,4-dioxala-2-one (5.0 g, 0.016 M) in isopropanol (25 ml) was hydrogenated over 5 % Pd-C (1 g) at 60 psi of hydrogen pressure for 14 h at room temperature. The reaction mass was filtered and concentrated to yield the title compound as a thick syrup

(yield 2.6 g, 73 %, purity 98 % by HPLC).

1H NMR (200 MHz, CDC1₃) δ : 7.1 (d, 2H), 6.7 (d, 2H), 4.6 (t, 1H), 3.3 (dd,

1H), 3.0 (dd, 1H), 1.5 (s, 3H), 1.35 (s, 3H). ^"Mass m/z : 222, 165.

ExampIe-2

Step (i)

Preparation of (S)-3-(4-benzyIoxyphenyl)-5-phenyl-l,4-dioxala-2-one To a solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (1 g, 3.6 mmol), in benzaldehyde (4.6 g, 4.4 mmol) and toluene (20 ml), catalytic amount of para toluene sulphonic acid was added and heated under reflux with Dean Stark apparatus for 6 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT and washed with water. The organic phase was concentrated to yield the title compound as a semi solid (yield 5.5 g, 77 %, purity 97 % by HPLC). 1H NMR (200 MHz, CDC1₃) δ : 7.6-6.9 (m, 14H), 6.3 and 6.1 (s, together 1H), 5.0 (s, 2H), 3.3-3.0 (m, 2H). ^• 5 Mass m/z : 360, 197, 91.

Step (ii)

Preparation of (S)-3-(4-hydroxyphenyι)-5-phenyl-l,4-dioxala-2-one

A solution of (S)-3-(4-benzyloxyphenyl)-5-phenyl-l,4-dioxala-2-one (1.0 g, 0 2.7 mmol) in isopropanol (20 ml) was hydrogenated over 5 % Pd-C (200 mg) at 60 psi of hydrogen pressure for 14 h at room temperature. The reaction mass was filtered and concentrated to -yield the title compound as a thick syrup

(yield 650 mg, 86.6 %).

1H NMR (200 MHz, CDC1₃) δ : 7.6-6.9 (m, 14H), 6.3 and 6.1 (s, together 1H), 5 5.0 (s, 2H), 4.8-4.6 (m, 1H) 3.3-3.0 (m, 2H).

Mass m z : 270, 195, 107.

Example-3 Step (i) 0 Preparation of (S)-3-(4-benzyloxyphenyl)-l,4-dioxala-2-one

To a solution of (S)-3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (1 g, 3.6 mmol), in toluene (20 ml) and para farmaldehyde (0.6 g), catalytic amount of para toluene sulphonic acid was added and heated under reflux with Dean Stark apparatus for 24 h. The reaction was monitored by TLC. After 5 completion of the reaction, the reaction mixture was cooled to RT and washed with water. The organic phase was concentrated to yield the title compound as a pale brown coloured solid (yield 1.0 g, 96 %, purity 98 % by HPLC). 1H NMR (200 MHz, CDC1₃) δ : 7.5-7.1 (m, 7H), 6.9 (d, 2H), 5.3 (d, 2H), 5.0 (s, 2H), 4.4 (t, 1H), 3.3 (dd, 1H), 3.0 (dd, 1H). Mass m/z : 284, 197, 91.

Step (ii)

Preparation of (S)-3-(4-hydroxyphenyl)-l,4-dioxala-2-one A solution of (S)-3-(4-benzyloxyphenyl)-l,4-dioxala-2-one (1.0 g, 3.5 mmol) in isopropanol (20 ml) was hydrogenated over 5 % Pd-C (200 mg) at 60 psi of hydrogen pressure for 14 h at room temperature. The reaction mass was filtered and concentrated to yield the title compound as a thick syrup, yield (540 mg, 80.0 %, purity 97.5 % by HPLC). 1H NMR (200 MHz, CDC1₃) δ : 7.15 (d, 2H), 6.8 (d, 2H), 5.3 (d, 2H), 4.45 (t, 1H), 3.3 (dd, 1H), 3.0 (dd, 1H). Mass m/z (CI method) : 195, 149.

Example 4 Step (i)

Preparation of (S)-3-(4-benzyloxyphenyl)-5-methyl-l,4-dioxala-2-one

To a solution of (S)-3-(4-benzyloxy)phenyl)-2-hydroxypropanoic acid (10 g 0.036 M) in acetaldehyde, diethoxypropane (43.4 g, 0.36 M) and cyclohexane (100 ml), catalytic amount of pyridinium para toluene sulphonate was added and heated under reflux with Dean Stark apparatus for 30 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 thick syrup (yield 10.0 g, 91.3 %). 1H NMR (200 MHz, CDC1₃) δ : 7.4 m, (5H), 7.2 (d, 2H), 6.9 (d, 2H), 5.6 (q, 1H), 5.0 (s, 2H), 4.5 (m, 1H), 3.3 (dd, 1H), 3.0 (dd, 1H), 1.4 (d, 3H). Mass m/z (CI method) : 299, 255, 91. Step (ii)

Preparation of 3-(4-hydroxyphenyl)-5-methyl-l,4-dioxala-2-one

A solution of 3-(4-benzyloxyphenyl)-5-dimethyl-l,4-dioxala-2-one (5.0 g, 0.016 M) in isopropanol (25 ml) was hydrogenated over 5 % Pd-C (1 g) at 60 psi of hydrogen pressure for 14 h at room temperature. The reaction mass was filtered and concentrated to yield thick syrup (yield 2.6 g, 74.7 %). 1H NMR (200 MHz, CDC1₃) δ : 7.2 (d, 2H), 6.8 (d, 2H), 5.6 (q, 1H), 4.5 (m, 1H), 3.3 (dd, 1H), 3.0 (dd, 1H), 1.4 (d, 3H). Mass m/z (CI method) : 209, 107.

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-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 will be calculated according to the formula.

Formulae for calculation :

Percent reduction in Blood sugar can be calculated according to the formula Percent reduction (%) ^; X 100

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. Novel compound of formula (I)

their derivatives, their analogs, their polymorphs wherein R¹ and R^ may be same or different and represent hydrogen, (C C₆)alkyl or unsubstituted or substituted phenyl or R and R together may form a 5 or 6 membered cyclic structure.

2. A compound as claimed in claim 1, wherein the substituents on the phenyl group may be selected from alkyl or alkoxy group.

3. A compound as claimed in claim 1, wherein the cyclic structure formed by R¹ and R² are selected from cyclopentane or cyclohexane.

4. A compound according to claim 1 which is selected from : (S)-3-(4-Hydroxyphenyl)-5,5-dimethyl- 1 ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5,5-diethyl- 1 ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5-phenyl-l,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-l ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5-methyl- 1 ,4-dioxala-2-one ; (S)-3-(4-Hydroxyphenyl)-5-ethyl- 1 ,4-^'dioxala-2-one ;

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

wherein R¹ and R² may be same or different and represent hydrogen,

C₆)alkyl or unsubstituted or substituted phenyl or R¹ and R² together may form a 5 or 6 membered cyclic structure, which comprises : (i). cyclizing the compound of the formula (llf)

where R represents benzyl to a compound of formula (Ilg) w

here R , R and R are as defined above and (ii). debenzylating the compound . of formula (Ilg) where R³ represents benzyl using aqueous alcohol in the presence of metal catalysts to yield pure

1 _j compound of formula (I) where R and R are as defined above.

6. The process as claimed in claim 4 wherein the cyclization in step (i) is carried out using benzaldehyde or its derivatives such as p-nitro benzaldehyde or anisaldehyde; dimethoxyethane, dimethoxypropane, paraformaldehyde, trioxane, paraldehyde, methylethyl ketone, MIBK, acetone, acetaldehyde, trimethyltrioxane, cyclohexanone or cyclopentanone or mixtures thereof.

7. The process as claimed in claims 5 and 6, wherein the cyclization in step (i) is carried out in the presence of catalytic amount of pyridinium para toluene sulphonate, p-TSA or methane sulfonic acid.

8. The process as claimed in claims 5 to 7, wherein the cyclization in step (i) is carried out in the presence of solvents such as toluene, pentane, chloroform or cyclohexane.

9. The process as claimed in claims 5 to 8, wherein the cyclization in step (i) is 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.

10. The process as claimed in claims 5 to 9, wherein the debenzylation in step (ii) is carried out using THF, aqueous acetic acid, ethyl acetate, aqueous ( -C₆) alcohols such as aqueous methanol, ethanol, propanol or isopropanol

11. The process as claimed in claims 5 to 10, wherein the debenzylation in step (ii) is carried out in the presence of metal catalysts such as Pd/C.

12. An intermediate of formula (Ilg)

I 7 wherein R and R may be same or different and represent hydrogen, ( - C₆)alkyl or unsubstituted or substituted phenyl or R¹ and R² together may form a 5 or 6 membered cyclic structure, R represents benzyl.

13. A compound of formula (Ilg) • according to claim 12 which is selected from : (S)-3-(4-Benzyloxyphenyl)-5-methyl-l,4-dioxala-2-one ; (S)-3-(4-Benzyloxyphenyl)- 1 ,4-dioxala-2-one ; (S)-3-(4-Benzyloxyphenyl)-5-phenyl-l ,4-dioxala-2-one ; (S)-3-(4-Benzyloxyphenyl)-5,5-dimethyl-l,4-dioxala-2-one.

14. Use of a compound of formula (I) as defined in claim 1 or a compound as claimed in claim 4 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.

15. Use of a compound of formula (I) as defined in claim 1 or a compound claimed in claim 4 for reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDL and free fatty acids.