WO2004089945A1

WO2004089945A1 - Rosiglitazone derivatives as antidiabetic agents

Info

Publication number: WO2004089945A1
Application number: PCT/IB2004/001108
Authority: WO
Inventors: Yatendra Kumar; Radhakrishnan Gowrishankar; Ram Chander Aryan; Kumar Hari Bhushan; Manoj Kumar Mishra
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-04-09
Filing date: 2004-04-08
Publication date: 2004-10-21
Anticipated expiration: 2005-10-09

Abstract

The present invention relates to rosiglitazone derivatives of Formula VI and their pharmaceutically acceptable salts. The invention concerns methods for the preparation of such derivatives, pharmaceutical compositions comprising the same and methods of treatment comprising administration of such compositions. These derivatives are putative metabolites of rosiglitazone.

Description

ROSIGLITAZONE DERIVATIVES AS ANTIDIABETIC AGENTS

Field of the Invention

The field of the invention relates to rosiglitazone derivatives of Formula VI and their pharmaceutically acceptable salts. The invention concerns methods for the preparation of such derivatives, pharmaceutical compositions comprising the same and methods of treatment comprising administration of such compositions. These derivatives are putative metabolites of rosiglitazone.

FORMULA VI

Background of the invention

Diabetes is a seminal cause of several chronic and progressive diseases, which adversely affect a number of organs, including the nervous and vascular systems. More than 90% of diabetic patients are non-insulin dependent i.e., type II diabetes (non-insulin dependent diabetes mellitus NIDDM). Type II diabetes is a metabolic disorder characterized by hyperglycemia and insulin resistance and lead to several secondary complications such as neuropathy, nephropathy, retinopathy, atherosclerosis and other coronary artery diseases. In type II diabetes although the pancreatic B cells are capable of producing insulin, insulin is unable to act in all the target tissues due to a metabolic disorder. This abnormality, which leads to hyperinsulinemia, is referred to insulin resistance. Several thiazolidinedione derivatives have been developed which act as insulin sensitizers. A specific advantage of thiazolidinedione derivatives as insulin sensitizers is that they may be able to prevent the progression of diabetes and related complications without the risk of hypoglycemia. Over the past decades and after the discovery of ciglitazones by a group of scientists by Takeda several thiazolidinedione derivatives of diverse structures have been developed. Encouraging clinical reports on troglitazone have generated interest among the people to develop newer thiazolidinedione analogues. The US FDA has approved one of the thiazolidinedione derivatives, commonly termed as rosiglitazone.

Chemically, rosiglitazone is (±)-5- [[4(methypyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and has structural Formula VII.

FOMULA VII The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type II diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia. Rosiglitazone also prevents the development of overt diabetes.

The metabolic changes produced by rosiglitazone result in increased responsiveness of insulin-dependent tissues, and so the metabolites of rosiglitazone are more effective in the treatment of diabetes and as insulin sensitizing agents.

Xenobioteca, 26 (6), (1996) describes various derivatives shown in Figure 1, which are metabolites of rosiglitazone such as phenoxyacetic acid derivatives, N-desmethyl- glucuronide derivatives, 5-0-glucoronide derivatives, N-desmethyl-3-0-sulρhate derivatives, 3-0-glucuronide derivatives, N-desmethyl-3 -sulphate derivatives, N- desmethyl-3-hydroxy derivatives, 5-0 sulphate derivatives, N-desmethyl-5-hydroxy derivatives, 3-0-sulphate, 5-hydroxy derivatives, N-desmethyl, 3-hydroxy derivatives.

FIGURE I

^■ S0₄ » suKate conjugate - GLUC « glucuronkte conjugate

The American society for Pharmacology and Experimental Therapeutics, Vol. 28, No. 7 describes that phase I metabolites, N-desmethyl rosiglitazone (M 12) and unconjugated para hydroxy rosiglitazone (M 13) were 20-fold less potent than and equipotent with rosiglitazone, respectively.

The major routes of metabolism were N-demethylation and hydroxylation, with subsequent conjugation, of which neither was affected by the route of drug administration.

Substitutions in the basic structure are believed to be responsible for differences in disposition, metabolism and antidiabetic efficacy among thiazolidinediones. We hypothesize that the conversion of the methylene functional group adjacent to the nitrogen atom in the chain to the carbonyl functionality would improve the pharmacological profile of the compound and possibly increase its potency.

Summary of the Invention

In one general aspect there are provided novel derivatives of rosiglitazone of Formula VI and pharmaceutically acceptable salts thereof. These derivatives are putative metabolites of rosiglitazone and belong to the class of phenoxy acetic acid derivatives.

FORMULA VI The term compounds of Formula VI or pharmaceutically acceptable salts thereof, wherein R is hydrogen or a lower alkyl group having from one to four carbon atoms includes solvates, hydrates and polymorphic forms of compounds of Formula VI .

In another general aspect there are provided processes for preparing the compounds of Formula VI, and pharmaceutically acceptable salts thereof.

In another aspect there are provided pharmaceutical compositions that include a therapeutically effective amount of compounds of Formula VI or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another aspect there are provided methods of treating and/or prophylaxis of hyperglycemia or Type II diabetes wherein said method comprises of administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula VI or a pharmaceutically acceptable salt thereof.

In another aspect there are provided methods of treating and/or prophylaxis of hyperlipidaemia and hypertension wherein said method comprises of administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula VI or a pharmaceutically acceptable salt thereof.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

The inventors have developed processes for the preparation of compounds of Formula VI and salts thereof, wherein R is hydrogen or a lower alkyl group, which are putative metabolites of rosiglitazone.

FORMULA VI

The process involves a) treating 4-hydroxybenzaldehyde of Formula I

FORMULA I

with bromoacetic acid in the presence of an organic solvent and a base to get a compound of Formula II,

FORMULA II

b) reacting the compound of Formula II with 2-amino pyridine derivatives of Formula III,

FORMULA III

wherein R is as defined above, in an organic solvent in the presence of a condensing agent to get a compound of Formula IV,

FORMULA IV

c) reacting the compound of Formula IV with 2,4-thiazolidinedione, to get a compound of Formula V, and

FORMULA V

d) reducing the compound of Formula V with a reducing agent in the presence of cobalt chloride hexahydrate and dimethyl glyoxime, to get the compound of Formula VI, wherein R is as defined above.

FORMULA VI

4-Hydroxybenzaldehyde of Formula I is reacted with bromoacetic acid in the presence of an organic solvent and abase. After the completion of reaction, water is added to the reaction mass and extracted with ethyl acetate to obtain 4-formylphenoxyacetic acid of Formula II.

The organic solvent may be one or more of ketones and mixtures thereof. The ketone may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone.

The base may be one or more of hydroxides, or carbonates of an alkali metal. Potassium carbonate in anhydrous form is a particular example. In step b), the compound of Formula II is reacted with 2-amino pyridine derivatives of Formula III, wherein R is same as above, in an organic solvent in the presence of a condensing agent to get a compound of Formula IV.

The condensing agent may be one or more of N'-ethylcarbodiimide, N-(3- dimethylaminopropyl)-! -hydroxy-7-azabenzotriazole, chlorodimethoxytriazine, benzotriazole-l-yloxy-tris(dimethyl amino)phosphonium hexaflourophosphate (BOP reagent), triethylamine, and N-methyl morpholine.

The organic solvent may be one or more of chlorinated hydrocarbons and mixtures thereof. The chlorinated hydrocarbon may include one or more of chloroform, dichloromethane, and 1,2-dichloroethane.

The compound of Formula IV is further condensed with 2,4-thiazolidinedione, to obtain compound of Formula V. The reaction can be carried out in the presence of an organic solvent.

The organic solvent may be one or more of lower alkanols and mixtures thereof. The lower alkanol may include one or more of a primary, secondary and tertiary alcohol having from one to six carbon atoms. In particular, lower alkanol may include one or more of a primary, secondary and tertiary alcohol having from one to four carbon atoms. Examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n- butanol, and t-butanol. In the last step, the compound of Formula V is reduced with a reducing agent, in the presence of cobalt chloride hexahydrate and dimethyl glyoxime, to form the compound of Formula VI, which can then be converted into its pharmaceutically acceptable salt by any conventional method.

The reducing agent may include one or more of conventional reducing agents such as sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride. Sodium borohydride is a particular example.

The resulting compounds of Formula VI or pharmaceutically acceptable salts thereof may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutically acceptable excipients, diluents and carriers.

The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral including subcutaneous, intramuscular, and ophthalmic administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like. The present invention is further illustrated by the following examples which are provided merely to be exemplary and are not intended to limit the scope of the invention.

Example 1

Step (A): Preparation of (4-Formyl Phenoxy) Acetic Acid To 4-hydroxybenzaldehyde (10 g, 0.082 moles) in acetone (150 ml), anhydrous potassium carbonate (24.92 g, 0.18 moles) was added and was stirred at 40-45°C for 15 minutes. This was followed by the addition of bromoacetic acid (11.96 g, 0.86 moles) in portions. The reaction mixture was refluxed overnight, and was cooled to room temperature, followed by the addition of water (300 ml) to dissolve the solid. The resulting solution was washed with ethyl acetate (200ml x 2) and pH of the aqueous layer was adjusted to about 2.0 with 6N hydrochloric acid. The product was extracted with ethyl acetate (400ml x 2). The combined organic layer was washed with water (200ml x 2) and was concentrated to oily mass. The oily mass was triturated with hexane (20 ml) to obtain (4-formyl phenoxy) acetic acid (11.2 g). Mass (M⁺ l): 181

1H NMR, DMSO-D₆ (δ, ppm): 4.86 (s, 2H), 7.14 (d, 2H), 7.90 (d, 2H) 9.9 (s, 1H). IR B^ cm^"1: 2921, 2851, 1754, 1718, 1648, 1592, 1510, 1425.

Step (B): Preparation of 2-(4-Formylphenoxy)-N-Pyridin-2-Yl-Acetamide Dicyclohexyl carbodiimide (DCC) (5.072 g, 0.0246 moles) was added to (4- formylphenoxy)-acetic acid (4.024 g, 0.0224 moles) obtained from step (a), in dichloromethane (25 ml) at 0-5°C and the reaction mixture was stirred for 30 minutes. 2- aminopyridine (2.0 g, 0.0213 moles) was added and stirred for 30 minutes. Then, the temperature was raised to 24-25°C and the reaction mixture was stirred at room temperature overnight. Additional quantities of (4-formyl phenoxy) acetic acid (2.012 g, 0.0112 moles) and dicyclohexyl carbodiimide (2.536 g, 0.0123 moles) were added and the reaction mixture was again stirred at room temperature overnight. The reaction mass was filtered, and was washed with dichloromethane. The filtrate was washed with 5% hydrochloric acid (100 ml), followed by the addition of water (100ml x 2).

The organic layer was concentrated and chromatographed over silica gel (60-120 mesh) while using 20% ethyl acetate in hexane as eluent to obtain 2-(4-formylphenoxy)- N-pyridin-2-yl-acetamide (1.28g).

Mass (M?l): 257

¹HMR in DMSO D₆ (δ, ppm): 4.96 (s, 2H). 7.15 - 7.18 (m, 3H), 7.78-7.90 (m, 3H),

8.04 (d, 1H), 8.35 (bs, 1H), 9.88 (s, 1H) 10.65 (s, 1H).

FR (K Br) cm-¹: 3387, 1696, 1604, 1575, 1525, 1506, 1435, 1302.

Step (C): Preparation of 2-[4-(2,4-Dioxo-Thiazolidin-5-Ylidene Methyl)-Phenoxy]-N- Pyridin-2-Yl-Acetamide

To a solution of 2-(4-formylphenoxy)-N-pyridin-2-yl-acetamide (1.4 g, 0.00546 moles) from step (b) in methanol (20 ml), 2,4-thiazolidinedione (638 mg, 0.00546 moles) was added, followed by the addition of pyrrolidine (426 mg, 0.006 moles). The reaction mixture was heated and refluxed for 2 hours, followed by cooling the reaction mass to 0- 5°C. The solid was filtered and was washed with chilled methanol (10 ml x 2). The solid was dried under reduced pressure at 45°C for 2 hours to obtain 2-[4-(2,4-dioxo-thiazolidin- 5-ylidene methyl)-phenoxy]-N-pyridin-2-yl-acetamide (1.45 g). Mass (M⁺ 1): 356

1H NMR in DMSO D₆ (δ, ppm): 4.9 (s, 2H), 7.13 (m, 3H), 7.58 (d, 2H), 7.75 (s, 1H) 7.80 (t, 1H), 8.04 (d, 1H), 8.34 (d, 1H), 10.61 (s, 1H) IR (K Br) Cm^"1: 3359, 2728, 1688, 1598, 1578, 1508, 1430.

Step (D): Preparation of 2-[4-(2,4-Dioxo-Thiazolidin-5-Yl-Methyl) Phenoxy] -N-Pyridm- 2-Yl-Acetamide

To the solvent mixture of methanol (20 ml) and water (20 ml), cobalt chloride hexahydrate (13.32 mg, 0.056 millimoles) was added, followed by the addition of dimethyl glyoxime (65.24 mg, 0.562 millimoles). To the above reaction mixture, 4-5 drops of 1.0 N sodium hydroxide were added to bring pH of the mixture to ~ 8-9. The mixture was cooled to 0-5° C, then sodium borohydride (637.2 mg, 16.86 millimoles) was added, followed by slow addition at 0-5°C of a solution of 2-[4-(2,4-dioxo-thiazolidin-5- ylidene methyl)-phenoxy]-N-pyridin-2-yl-acetamide from step (c) (1.0 g, 2.8 millimoles) dissolved in methanol (20 ml). Temperature of the reaction mixture was raised to 28-30°C and it was stirred for 2 hours. The reaction mass was filtered to remove the solid. To the filtrate, acetic acid was added to adjust the pH to ~ 6.0, followed by the addition of water (40 ml). The mass was cooled to 0-5°C. The solid was filtered and dried to obtain 2-[4- (2,4-dioxo-thiazolidin-5-ylmethyl)phenoxy-N-ρyridin-2-yl-acetamide(400 mg).

Mass (M⁺ 1): 358

1H NMR in DMSO-D₆, (δ, ppm): 3.01-3.30 (m, 2H), 4.77 (s, 2H), 4.80-4.84 (dd, 1H),

6.91 (d, 2H), 7.11 - 7.19 (m, 3H), 7.78 - 7.83 (t, 1H), 8.06 (d, 1H), 8.34 (d, 1H), 10.48 (s, 1H).

IR (KBr) cm^"1: 3356, 2962, 2736, 1703, 1577, 1510, 1432, 1303.

Example 2 Step (A): (2-(4-Formylphenoxy)-N-Methyl-N-Pyridin-2-Yl-Acetamide

The above compound was prepared analogously as step (b), Example 1 by reacting compound of step (a), Example 1 with N-methyl-2-amino pyridine. Mass (M⁺l): 271

1H NMR in DMSO-d6, (δ, ppm): 3.35 (s, 3H), 5.06(s, 2H), 7.02 (d, 2H), 7.29-7.33 (m, 1H), 7.58 (d, 1H), 7.80-7.94 (m, 3H), 8.46 (d, 1H), 9.86 (s, 1H).

TR (K Br) cm^"1: 1692, 1679, 1605, 1579, 1512, 1476, 1431, 1346.

Step (B): Preparation of 2-[4-(2,4-Dioxo-Thiazolidin-5-Ylidene Methyl)-Phenoxy]-N- Methyl-N-Pyridm-2-Yl-Acetamide The product was analogously prepared as in Step (c), Example 1.

Mass (M⁺l): 370.

1H NMR in DMSO-d6, (δ, ppm): 3.35 (s, 3H), 5.0 (s, 2H), 6.98 (d, 2H), 7.31 (t, 1H), 7.48-7.62 (m, 3H), 7.74 (s, 1H), 7.91 (t, 1H), 8.48 (s, 1H). TR (KBr) cm^"1: 3544, 3050, 1701, 1630, 1588, 1509, 1441, 1429.

Step (C): Preparation of 2-[4-(2,4-Dioxo-Thiazolidin-5-Ylmethyl)-Phenoxy]-N-Methyl-N- Pyridin-2-Yl-Acetamide The above compound was prepared analogously as Step (d), Example 1 and was isolated as its hydrochloride salt. Mass (M⁺l): 372

1H NMR in DMSO-d6, (δ, ppm): 3.00-3.33 (m, 5H), 4.85 (bs, 3H), 6.75 (d, 2H), 7.12 (d, 2H), 7.31 (t, 1H), 7.57 (d, 1H), 7.90 (t, 1H), 8.45 (d, 1H), 12.03 (s, 1H).

IR (K Br) cm^"1: 3034, 2691, 1682, 1598, 1527, 1462, 1336.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim: 1. Compounds of Formula VI,

FORMULA VI

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, or polymorphs, wherein R is hydrogen or a lower alkyl group having from one to four carbon atoms.

2. The compound of claim 1, wherein R is methyl.

3. A process for the preparation of a compound of Formula VI, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, or polymorphs, wherein R is hydrogen or a lower alkyl group having from one to four carbon atoms, the process comprising

a) treating 4-hydroxybenzaldehyde of Formula I

FORMULA I

FORMULA II b) reacting the compound of Formula II with 2-amino pyridine derivatives of Formula III,

FORMULA III

FORMULA IV

FORMULA V

FORMULA VI

4. The process of claim 3, wherein the organic solvent used in step a) comprises one or more of ketones.

5. The process of claim 4, wherein the ketone comprises one or more of acetone, ethyl methyl ketone, and methyl isobutyl ketone.

6. The process of claim 3, wherein the base in step a) comprises one or more of hydroxides and carbonates of an alkali metal.

7. The process of claim 6, wherein the base is potassium carbonate in anhydrous form.

8. The process of claim 3, wherein the condensing agent in step b) comprises one or more of N'-ethylcarbodiimide, N-(3- dimethylaminopropyl)-l-hydroxy-7- azabenzotriazole, chlorodimethoxytriazine, benzotriazole-l-yloxy-tris(dimethyl amino)phosphonium hexaflourophosphate (BOP reagent), triethylamine, and N- methyl morpholine.

9. The process of claim 3, wherein the organic solvent used in step b) comprises one or more of chlorinated hydrocarbons.

10. The process of claim 9, wherein the chlorinated hydrocarbon comprises one or more of chloroform, dichloromethane, and 1,2-dichloroethane.

11. The process of claim 3, wherein step c) is carried out in the presence of an organic solvent.

12. The process of claim 11, wherein the organic solvent comprises one or more of lower alkanols.

13. The process of claim 12, wherein the lower alkanols comprises one or more of primary, secondary and tertiary alcohols having from one to six carbon atoms.

14. The process of claim 13, wherein the lower alkanol comprises one or more of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, and t-butanol.

15. The process of claim 3, wherein the reducing agent in step d) comprises one or more of sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride.

16. The process of claim 15, wherein the reducing agent is sodium borohydride.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula VI,

FORMULA VI

or a pharmaceutically acceptable salt, solvate, hydrate, or a polymorph thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents.

18. A method of treating and /or prophylaxis of hyperglycemia in a mammal comprising administering to said mammal, the pharmaceutical composition according to claim 17.

19. A method of treating and/or prophylaxis of hyperlipidaemia and hypertension in a mammal comprising administering to said mammal, the pharmaceutical composition according to claim 17.

20. A method of treating and/or prophylaxis of hyperglycemia in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound of Formula VI,

FORMULA VI

and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, and/or a hydrate thereof, and/or a polymorph thereof, wherein R is hydrogen or a lower alkyl group having from one to four carbon atoms.

21. A method of treating and /or prophylaxis of hyperlipidaemia and hypertension in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound of Formula VI,

FORMULA VI