CS258500B2 - Method of 4-methyl-6-methylsulfinyl-thieno (3,2-b)pyrid-7(4h)-on's production - Google Patents

Abstract

4-Methyl-6-methyl- -sulfinylthieno [3,2-b] pyridin-7 (4H) -one a its pharmaceutically acceptable addition O salts with acids consisting of methylation the compound of formula (II) and, if desired, the conversion by reaction with acid on the farm- (Γ ΥΐΓ “1 (AND) a salt suitable for use. Slou | </s></s> </s></s> the compound of formula I and its salts are therapeutically effective as antihypertensive reagents.

Description

The invention relates to a process for the preparation of novel 4-methyl-6-methylsulfinylthieno [3,2-b] pyrid-7 (4H) -one and its pharmaceutically acceptable acid addition salts. The above novel compound corresponds to formula I

The compound of formula I has been found to exhibit antihypertensive activity. The present compound reduces blood pressure when administered to hypertensive mammals.

The compound of formula I forms addition salts with inorganic or organic acids, for example hydrochloric acid, fumaric acid, tartaric acid and citric acid. It is understood that these salts, if they are pharmaceutically acceptable, may be used in therapy instead of the corresponding free compound of formula I. Said salts are prepared in a conventional manner by reacting a compound of formula I with a suitable acid.

The term active ingredient as used herein refers to the thienopyridone of formula (I) or a pharmaceutically acceptable acid addition salt thereof. For therapeutic purposes, the active ingredient may be administered orally, rectally, parenterally or topically, preferably orally. The therapeutic compositions used may be in any form known for pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the pharmaceutical art.

Oral formulations are preferred, such as known dosage forms such as tablets, capsules, syrups and aqueous or oily suspensions.

The therapeutic activity of the compound of formula I was demonstrated by means of teats in standard laboratory animals. These assays include, for example, oral administration of a test compound to a strain of spontaneously hypertensive rats. The compound of formula I is useful for reducing the blood pressure of hypertensive mammals, including humans. Suitable dosages for enteral administration to mammals, including humans, generally range from 0.1 to 25 mg / kg / day, in particular from 0.5 to 10 mg / kg / day, the total daily dose being administered in a single dose or in multiple doses. sub-doses. For parenteral administration, suitable dosages generally range from 0.01 to 2.5 mg / kg / day, in particular from 0.05 to 1.0 mg / kg / day. Oral administration is preferred.

The present invention provides a process for the preparation of a compound of formula (I) and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula (II) is methylated

OH £ j

The -5OCH ₃ (II) and the resulting product of formula I are optionally converted by treatment with an acid to a pharmaceutically acceptable acid addition salt 8.

Methylation according to the invention can be carried out by reacting a compound of formula II with a methylating agent, for example methyl sulfate or a methyl halide such as methyl iodide, as is usual for this type of reaction.

The compound of formula II is novel and can be prepared by cyclization of a compound of formula III wherein coor ₂ (III) is lower alkyl, preferably methyl or ethyl, and is hydrogen or carboxyl.

to form a compound of formula IV

sch ₃ (IV) which is then oxidized to the desired starting material of formula II.

The aforementioned cyclization can be carried out by heating the compound of formula III to a temperature in the range from 200 to 280 ° C, for example by heating a mixture of this compound with diphenyl ether to reflux.

A suitable oxidizing agent for the oxidation of the compound of formula IV is, for example, an organic peracid such as 3-chloroperbenzoic acid.

The intermediates of formula III are novel and can be prepared by reacting a compound of formula V

S / 1 * 4 (V) ^ _NH2 in which represents hydrogen or a COOM, wherein M is an alkali metal, for example sodium, with an acrylate of Formula VI

COOR ₂

CH3SC-CHOM '(VI) wherein

M 'is an alkali metal, for example sodium.

Acrylates of the formula VI can be prepared, for example, by reacting a compound of the formula VII and ₃ sch ₂ coor ₂ (VII) with sodium methoxide to give the sodium salt of the corresponding anion, which is then reacted with methyl formate.

The 4-methyl-6-methylsulfinylthieno [3,2-13-pyrid-7 (4H) -one of the invention may exist in at least two polymorphic forms referred to as type 1 and type 2 having characteristic IC spectra and different melting points. Type 2 is less stable than type 1 and is converted to type 1 during heating, grinding or storage.

As mentioned above, the therapeutic efficacy of the thienopyridone of the invention is demonstrated by appropriate tests, including oral administration of test compounds to spontaneously hypertensive rats (Test A). The test is carried out as follows.

Test A

A strain of spontaneously hypertensive rats (Aoku-Okamoto), a female weighing 180-240 g, is used for the test. Rats divided into groups of four animals are fasted overnight before administration of the test compound. Animal blood pressure is determined as follows. The rats are placed in chambers in which a temperature of 38 ° C is maintained and which are arranged so that the animal's tail protrudes through the openings in the chamber walls. After 30 minutes, the animal's blood pressure in the chamber is measured using an inflatable cuff placed around the base of the tail and the arterial pulse is monitored using a pneumatic pulse transducer.

The cuff is inflated with a pressure that is higher than the expected blood pressure, and this pressure slowly decreases. The cuff pressure at which the arterial pulse reappears is considered to be blood pressure. The test rats are removed from the chambers and each group of animals is orally administered an appropriate dose of the test compound as a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to pre-administration measurements, blood pressure is measured at 1.5 and 5.0 hours after administration of the test substance. A test compound is considered to be effective if it lowers blood pressure to an extent equal to or greater than what is known to be the minimum significant decrease based on known control data (p <0.01).

In this test, the 4-methyl-6-methylsulfinylthieno [1,2-b] pyrid-7 (4H) -one of the formula I according to the invention shows an efficacy of 30 mg / kg.

The invention is illustrated by the following non-limiting examples. In these examples, all parts and percentages refer to parts and percentages by weight, and the composition of the solvent mixtures is always given by volume. The novel compounds were characterized using one or more of the following spectroscopic techniques:

nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.

Example 1 (a) 6.9 g of sodium are dissolved in 200 ml of dry methanol and the solution is evaporated to dryness. The obtained sodium methoxide is suspended in 300 ml of dry diethyl ether and 36 g of methyl methylthioacetate are added over 15 minutes while maintaining the temperature below 5 ° C. The mixture was stirred at 0 ° C for 1 hour and added thereto while maintaining the temperature below 5 ° C

20.4 ml of methyl formate. The reaction mixture was stirred at room temperature overnight and then extracted twice with 150 ml of water each time. An aqueous solution of methyl 3-hydroxy-2- (methylthio, acrylate) sodium salt is obtained, which compound can also be isolated in solid form by filtration of the above ethereal reaction mixture.

(b) A mixture of 26.2 g of methyl 3-amino-thiophene-2-carboxylate and 260 ml of a 10% aqueous sodium hydroxide solution was heated with stirring on a steam bath overnight to give an aqueous solution of sodium 3-aminothiophene-2-carboxylate . To this solution was added a portion (200 mL) of the above prepared aqueous solution of methyl 3-hydroxy-2- (methylthio) acrylate sodium salt while stirring and maintaining the temperature below 5 ° C. Concentrated hydrochloric acid (30 ml) was added dropwise to the stirred mixture, maintaining the temperature at 0-5 ° C, then allowed to warm to room temperature over 1 hour. The resulting yellow solid was collected, washed with water and dried. New 3- (2-methoxycarbonyl-2-methylthiovinylamino) -thiophene-2-carboxylic acid is obtained. A portion of this product, after crystallization from methanol-denatured industrial alcohol, gave an analytical sample, m.p. 179-180 ° C.

(c) 20.0 g of the above prepared carboxylic acid are added portionwise over 30 minutes to 200 ml of stirred diphenyl ether preheated to 240-250 ° C. The mixture was stirred at the above temperature for 30 minutes while methanol formed was distilled off. The reaction mixture was cooled to room temperature, filtered, the solid product washed with diethyl ether, dried and crystallized from technical alcohol denatured with methanol. New 7-hydroxy-6-methylthiothieno [3,2-b] pyridine is obtained, m.p. 210-212 ° C.

(d) To a stirred solution of 1.97 g of the thieno [3,2-b] pyridine prepared above and 1.68 g of potassium hydroxide in 20 ml of water at 0-5 ° C was added 2 ml of dimethyl sulfate. The mixture was allowed to warm to room temperature and maintained at this temperature for 2 hours. The solid product is filtered off and, after drying, crystallized from ethyl acetate. New 4-methyl-6-methylthiothienoyl] -2-b] pyrid-7 (4H) -one, m.p. 171-174 ° C, is obtained.

(e) A stirred solution of 7-hydroxy-6-methylthiothieno [1,2-b] pyridine (15 g) in dichloromethane (500 ml) was added dropwise at 0-5 ° C over 7 hours with a solution of 13.9 g of 85% 3-chloroperbenzoic acid in 400 ml of dichloromethane. To complete the reaction (according to thin-layer chromatography), the oxidation should be continued further by adding two more portions (1.5 g each) of 3-chloroperbenzoic acid. The remaining peroxide compounds are quenched by the addition of a solution of 6 g of sodium sulfite in 20 ml of water, the mixture is evaporated to dryness and the residue is triturated with diethyl ether. The solid product was recrystallized from water and purified by high pressure liquid chromatography on silica gel, eluting with dichloromethane / methanol (90:10), eluting with methanol. New 7-hydroxy-6-methylsulfinylthleno [1,3,2-b] pyridine, m.p. 271-273 ° C, is obtained.

(f) A solution of 3.0 g of the thienopyridine prepared above and 2.5 g of potassium hydroxide in 31.7 ml of water at 0-5 ° C was added dropwise to 3.85 g of dimethyl sulfate. The mixture was allowed to warm to room temperature and stirred at room temperature for 4 hours. The precipitate formed is filtered off and crystallized from methanol-denatured industrial alcohol to give new 4-methyl-6-methylsulphinylthienol-3,2-b] pyrid-7 (4H) -one, m.p. 199 ° C. The IC spectrum of this product is characteristic of the type 1 polymorph.

Example 2

To a solution of 0.5 g of fumaric acid in 20 ml of absolute ethanol is added a solution of 1 g of 4-methyl-6-methylsulfinylthieno [3,2-b] pyrid-7 (4H) -one in 70 ml of absolute ethanol, and the mixture is left over stand at 0 to 5 ° C overnight. The precipitate formed is filtered off and dried, yielding new 4-methyl-6-methylsulphinylthieno [3,2-1] pyrid-7 (4H) -one-0,45-fumarate, m.p. 205-206 ° C.

Example 3

To a solution of 1 g of 4-methyl-6-methylsulfinylthieno [3,2-b] pyrid-7 (4H) -one in 70 ml of absolute ethanol is added hydrogen chloride gas while maintaining the temperature by ice cooling at about 20 ° C, leaving a white precipitate. . Hydrogen chloride was continued until the precipitate had ceased, and the mixture was allowed to stand overnight at room temperature. The solid product was filtered off and dried to give the new 4-methyl-6-methylsulphinylthieno [3,2-d] pyrid-7 (4H) -one hydrochloride in the crude state. On standing, a second crop of pure product precipitated from the filtrate and was filtered off. After drying, pure hydrochloride is obtained, melting at 147-153 ° C with decomposition.

Claims (1)

A process for the preparation of 4-methyl-6-methylsulfinylthieno [3,2-b] pyridin-7 (4H) -one of formula I and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula II is methylated OH (II) The SOCH ₃ and the resulting product of formula I are optionally converted by treatment with an acid to a pharmaceutically acceptable acid addition salt.