WO2003010157A1

WO2003010157A1 - Dioxane derivatives and a process for their preparation

Info

Publication number: WO2003010157A1
Application number: PCT/IB2001/001314
Authority: WO
Inventors: Rajender Kumar Potlapally; Narasimha Murthy Kotra; Raju Sirisilla; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam; Venkateswarlu Akella
Original assignee: Dr. Reddy's Research Foundation
Priority date: 2001-07-23
Filing date: 2001-07-23
Publication date: 2003-02-06

Abstract

The present invention relates to novel antidiabetic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel dioxane compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them. wherein R1 represents hydrogen or (C1-C6)alkyl group; n is an integer ranging from 1 to 2.

Description

DIOXANE DERIVATIVES AND A PROCESS FOR THEIR PREPARATION

Field of the invention The present invention relates to novel antidiabetic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel dioxane compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them.

wherein R¹ represents hydrogen or ( -C^alkyl group; n is an integer ranging from 1 to 2. 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

(Ilh) and (IIj) and their use in the preparation of compounds of formula (I).

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 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 (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 raises 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 (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)

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

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

(lie) 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 dioxane compounds and their derivatives, their stereoisomers, their polymoφhs having the formula (I)

wherein R¹ represents hydrogen or (C C_ό^lkyl group; n is an integer ranging from 1 to 2.

The term alkyl group represents methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl and the like.

Particularly useful compounds according to the present invention include : (±) 3-(4-Hydroxybenzyl)-l,4-dioxane~2,5-dione ; (+) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ^•; (±) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (+) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ;

(±) 3-(4-Hyc oxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ; (+) 3-(4-Hydroxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ;

According to another embodiment of the present invention there is provided a process for the preparation of novel dioxane compounds, their derivatives having the formula (I) wherein R¹ represents hydrogen or (C C₆)alkyl group; n is an integer ranging from 1 to 2, which comprises : i). reacting the compound of formula (Ilf) wherein R² represents benzyl; R³ represents hydrogen or alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like using compound of formula (Ilg) where X represents halogen atom such as chlorine, fluorine, bromine or iodine; n is an integer of 1 — 2 to produce compound of formula (lTh) in the presence of a base, solvent at a temperature in the range of 30 to 110 °C and the duration of the reaction may range from 2-40 h, ii). cyclizing the compound of formula (Ilh) in the presence of an acid or base, solvent at a temperature in the range of 0 to 110 °C and the duration of the reaction may range from 2-16 h, to obtain compound of formula (Hi), where R¹ and n are as defined above, R² represents benzyl and iii). debenzylating the compound of formula (Hi) where R represents benzyl using aqueous alcohol in the presence of metal catalysts to yield pure compound of formula (I) where R¹ and n are as define above.

The process explained above is shown in scheme-2 below :

Scheme-2

The reaction of compound of the formula (llf) using compound of formula (Ilg) to obtain a compound of formula (Lib.) may be carried out in the presence of dicyclohexyl carbodiimide (DCC) and a base such as sodium carbonate, potassium carbonate, N,N-dimethyl amino pyridine (DMAP) and the like or lewis acid such as boron trifluoro etherate and the like. The reaction may be carried out in the presence of solvents such as toluene, benzene, DMF, DMSO, dichloromethane (DCM), dichloro ethane and the like. The reaction may be carried out at a temperature in the range of 30 to 110 °C and the duration of the reaction may range from 2-40 h.

The cyclization of compound of formula (Ilh) to obtain compound of formula (Iii) may be carried out in the presence of acids such as sulfuric acid, p-TSA and the like or base such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium ethoxide, sodium methoxide, t- BuOK and the like. The reaction may be carried out in the presence of solvents such as DMF, toluene 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 2-16 h. The debenzylation of the compound of formula (Hi) to yield compound of formula (I) may be carried out using THF, aqueous acetic acid, ethyl acetate, aqueous (C C₆) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C.

According to yet another embodiment of the present invention there is provided another process for the preparation .of novel dioxane compounds, their derivatives, having the formula (I) wherein R¹ represents hydrogen or (C₁-C₆)alkyl group; n is an integer ranging from 1 to 2, which comprises, i). cyclizing the compound of formula (llf) where R represents benzyl with a compound of formula (IIj) where X represents halogen atom such as chlorine, fluorine, bromine or iodine; n is an integer of 1 - 2, in the presence of a base, solvent at a temperature in the range of 30 to 110 °C and the duration of the reaction may range from 2-40 h to obtain compound of formula (Hi), where all symbols are as defined above. ii). debenzylation the compound of formula (Hi) where R represents benzyl using aqueous alcohol in the presence of metal catalysts to yield pure compound of formula (I) where R¹ and n are as define above.

The process explained above is shown in scheme-3 below

Scheme-3

The cyclization of compound of formula (Llf) with compound of formula (I j) to obtain compound of formula (Hi) may be carried out in the presence of base such as triethyl amine, DMAP, N,N-diethylaniline, sodium carbonate, potassium carbonate, potassium sec.butoxide, sodium ethoxide, sodium methoxide, t-BuOK and the like. The reaction may be carried out in the presence of solvents such as DMF, DCE, DCM, toluene and the like. The reaction may be carried out at a temperature in the range of 0 to 11.0 °C and the duration of the reaction may range from 2-16 h.

The debenzylation of the compound of formula (Hi) to yield compound of formula (I) may be carried out using THF, aqueous acetic acid, 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.

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

wherein R represents benzyl; R represents hydrogen or alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like; X represents halogen atom, n is an integer of 1 — 2.

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

1 9 wherein R represents hydrogen or (CrC₆)alkyl; R represents benzyl; n is an integer of 1 - 2.

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 -4 :

(lib) (III)

Scheme - 4

1 where R 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.

The stereoisomers of the compounds forming part of this invention may be prepared by using compound of formula (I) in its single enantiomeric form in the process 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 optically pure bases such as brucine, cinchona alkaloids and their derivatives, optically pure 2-alkyl phenethyl amine, phenyl glycinol and the like. The diastereomeric salts may be obtained in pure form by fractional crystallization. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). 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 be considered to limit the scope of the invention.

Example 1

Step (i)

Preparation of 3-(4-benzyloxyphenyl)-2(S)-(2-chloroacetoxy)propionic acid In a 250 ml round bottom flask 2(S)-3-(4-benzyloxyphenyl)-2- hydroxypropanoic acid (2.5 g), dichloroethane (25 ml), chloroacetic acid (1.72 g), dicyclohexyl carbodiimide (5.67 g) dissolved in dichloroethane (50 ml) was taken. To this reaction mixture N,N-dimethyl amino pyridine (DMAP) (1.12 g) was added and the resultant reaction mass was stirred under nitrogen atmosphere over a period of 12 h. The progress of the reaction was monitored by TLC. Filtered the dicyclohexyl urea from the reaction mass and the filtrate was washed with 5 % aqueous sodium bicarbonate solution, followed by 5% aqueous HC1 and water. The organic layer was separated and concentrated under vacuum at 60 -70 °C to yield the title compound as an oily residue (2.2 g)-

Step (ii) Preparation of 2-(S)-(4-benzyloxybenzyl)-l,4-dioxan-2,5-dione.

To a solution of 3-(4-benzyloxyphenyl)-2(S)-(2-chloroacetoxy)propionic acid (2.0 g), obtained in step (i) above dissolved in toluene (50 ml) was added potassium carbonate (0.5 g) and refluxed for 1-2 h. The completion of reaction was monitored by TLC. The reaction mass was washed with 1% aqueous HC1, followed by water and evaporated under reduced pressure to yield the crude compound (1.2 g). The crude product was further purified by column chromatography to yield the pure title compound (0.8 g).

Step (iii) Preparation of 2(S)-(4-hydroxybenzyl)-l,4-dioxan-2,5-dione

In 250 ml parr hydrogenation flask, palladium carbon (5 %, 1 g) slurred in water (1 ml) was taken. The isopropyl 2(S)-2-(4-benzyloxybenzyl)-l,4- dioxan-2,5-dione (3 g) dissolved in isopropanol (100 ml) was added and hydrogenated at 50-60 psi pressure for 10-12 h. The reaction was monitored by TLC. After completion of the reaction, . catalyst was filtered on a hi-flow bed and the solvent was evaporated on a rotavapour under reduced pressure to yield the title compound as a syrupy liquid (2.1 g).

Example 2 Step (i)

Preparation of 2-(S) (4-benzyloxybenzyl)-l,4-dioxan-2,5-dione

In a 100 ml round bottom flask 2(S)-3-(4-benzyloxyphenyl)-2- hydroxypropanoic acid (5 g), dichlorometliane (25 ml), triethyl amine (5.5 ml) were taken. To this reaction mixture chloroacetyl chloride (2.5 g) was added at 0-5 °C. After the complete addition, the reaction temperature was increased to room temperature and stirred for 4-6 h. The completion of reaction was monitored by TLC. After completion of the reaction, the reaction mass was washed with aqueous sodium bicarbonate solution followed by water. The organic layer was separated and concentrated at 60-70 °C under vacuum to yield the title compound (6.2 g).

Step (ii)

Preparation of 2-(S)-(4-hydroxybenzyl)-l,4-dioxane-2,5-dione In 250 ml parr hydrogenation flask, palladium carbon (5 %, 1 g) slurred in water (1 ml) was taken. The isopropyl 2(S)-2-(4-benzyloxybenzyl)-l,4- dioxane-2,5-dione (3 g) dissolved in isopropanol (100 ml) was added and hydrogenated at 50-60 psi pressure for 10-12 h. The reaction was monitored by TLC. After completion of the reaction, catalyst was filtered on a hi-flow bed and the solvent was evaporated on a rotavapour under reduced pressure to yield the title compound as a syrupy liquid (2.1 g).

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 π 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 (NLN), 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 :

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.

Claims

Claims :

1. A compound of formula (I)

their derivatives, their stereoisomers, their polymoφhs wherein R¹ represents hydrogen or (C₁-C₆)alkyl group; n is an integer ranging from 1 to 2.

2. A compound according to claim 1 which is selected from :

(±) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ;

(+) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ;

(-) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ;

(±) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (+) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ;

(±) 3-(4-Hydroxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ; (+) 3-(4-Hydroxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-6-ethyl-l,4-dioxane-2,5-dione ;

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

wherein R¹ represents hydrogen or (C₁-C₆)alkyl group; n is an integer ranging from 1 to 2, which comprises : i). reacting the compound of formula (llf)

wherein R represents benzyl; R represents hydrogen or alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like using compound of formula (Ilg)

O

I I (iig)

X-(CH₂)_n-C-OH where X represents halogen atom, n is an integer of 1 - 2 in the presence of a base, solvent at a temperature in the range of 30 to 110 °C and the duration of the reaction range from 2-40 h, to produce compound of formula (Ilh)

where R , R , n and X are as defined above, ii). cyclizing the compound of foπnula (Ilh) in the presence of an acid or base, solvent at a temperature in the range of 0 to 110 °C and the duration of the reaction range from 2-16 h to obtain compound of formula (Iii),

where R² and n are as defined above, R² represents benzyl and iii). debenzylating the compound of formula (Hi) where R² represents benzyl using aqueous alcohol in the presence of metal catalysts to yield pure compound of formula (I) where R¹ and n are as define above.

4. The process as claimed in claim 3 wherein the reaction in step (i) is carried out in the presence of dicyclohexyl carbodiimide (DCC).

5. The process as claimed in claims 3 and 4 wherein the reaction in step (i) is carried out in the presence of a base selected from sodium carbonate, potassium carbonate or N,N-dimethyl amino pyridine (DMAP) or lewis acid such as boron trifluoro etherate.

6. The process as claimed in claims 3 to 5, wherein the reaction in step (i) is carried out in the presence of solvents such as toluene, benzene, DMF, DMSO, dichloromethane or dichloro ethane.

7. The process as claimed in claims 3 to 6, wherein the cyclization in step (ii) is carried out in the presence of acids such as sulfuric acid, p-TSA and the like or base selected from sodium carbonate, potassium carbonate, sodimn hydride, potassium hydride, sodium ethoxide, sodium methoxide or t-BuOK.

8. The process as claimed in claims 3 to 7, wherein the cyclization in step (ii) is carried out in the presence of solvents such as DMF or toluene and the like.

9. The process as claimed in claims 3 to 8, wherein the debenzylation in step (iii) is carried out using THF, aqueous acetic acid, ethyl acetate or aqueous ( -Ce) alcohols selected from aqueous methanol, ethanol, propanol or isopropanol

10. The process as claimed in claims 3 to 9, wherein the debenzylation in step (iii) is carried out in the presence of metal catalysts such as Pd/C. ^■

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

wherein R¹ represents hydrogen or (C C₆)alkyl group; n is an integer ranging from 1 to 2, which comprises : i). cyclizing the compound of formula (llf)

where R² represents benzyl with a compound of formula (IIj)

O

II

X-(CH₂)_n-C-X ("j) where X represents halogen atom such as chlorine, fluorine, bromine or iodine; n is an integer of 1 - 2, in the presence of a base, solvent at a temperature in the range of 30 to 110 °C and the duration of the reaction range from 2-40 h, to obtain compound of formula (Hi),

where R¹, R² and n are as defined above. iϊ). debenzylating the compound of formula (Hi) where R² represents benzyl using aqueous alcohol in the presence of metal catalysts to yield pure compound of formula (I) where R¹ and n are as define above.

12. The process as claimed in claim 11, wherein the cyclization in step (i) is carried out in the presence of base such as triethyl amine, DMAP, N,N- diethylaniline, sodium carbonate, potassium carbonate, potassium sec.butoxide, sodium ethoxide, sodium methoxide or potassium tertiary butoxide.

13. The process as claimed in claims 11 and 12 wherein the cyclization in step (i) is carried out in the presence of solvents such as DMF, DCE, DCM or toluene.

14. An intermediate of formula (Ilh)

wherein R² represents benzyl; R³ represents hydrogen or alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like; X represents halogen atom, n is an integer of 1 - 2.

15. An intermediate of formula (Hi)

wherein R¹ represents hydrogen or (C C₆)alkyl; R² represents benzyl; n is an integer of 1 - 2.