CS224246B1 - Method of preparing new 4-/4-piperidylidene/-4,9-dihydrothieno/2,3-c/-2-benzothiepin-10-oxines and salts thereof - Google Patents

Abstract

The present invention relates to a process for the preparation of new 4- (4-piperidylidene) 4,9-dihydrothieno (2,3-c) -2-benzothiepine-10-oxides of the general formula I, O wherein R is methyl or hydrogen, and salts thereof with pharmaceutically acceptable inorganic or organic acids. The sulfoxides of formula (I) are both intermediates for the preparation of neurotrophic and psychotropic active drugs, furthermore, they themselves exhibit therapeutically useful pharmacological effects in the form of salts and, finally, are potentially metabolites of the anti-migraine drug "pipethiadene", i.e. 4- (1-methyl). -4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine (Rajshner M. et al., Collect.Czech.Chem.Commun. 32, 2854, 1967). the pharmacological effects found in tests in experimental animals and in in vitro tests are of particular interest in 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzoic acid. thiepine-10-oxide, which has been tested in the form of hydrogen maleate, has a high oral protective effect in the guinea pig histamine aerosol test;

Description

Process for the preparation of novel 4- (4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepine-10-oxides and their salts

224 246

224 24 (

The present invention relates to a process for the preparation of novel 4- (4-piperidylidene)

4,9-Dihydrothieno (2,3-c) -2-benzothiepine-10-oxides of formula I, O

wherein R represents a methyl group or a hydrogen atom, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The sulphoxides of formula I are both intermediates for the preparation of neurotrophic and psychotropic drugs, they themselves exhibit therapeutically useful pharmacological effects in the form of salts and, finally, they are potential metabolites of the anti-migraine drug pipethiadene, i.e. 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine (Rajsner M. et al., Collect.Czech.Chem.Commun. 32, 2854, 1967). Of particular interest for the pharmacological effects found in animal and in vitro tests is 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2 -benzothiepine-10-oxide, which was tested in the form of hydrogen maleate. This substance has a high oral protective effect in the guinea pig histamine aerosol test; medium protective dose

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PD 50% 2 mg / kg. It is therefore a highly effective antihistarainikeni. At the same time, at an intraperitoneal dose of 1 mg / kg in rats, it has a full protective effect against the lethal action of a histamine liberator known as 48/80 ”(Paton WDM, Brit. J. Pharmacol. 6, 499« 1951). an antiserotonin effect in rat rat edema test; a significantly effective dose of ED is 1 to 10 mg / kg orally. Thus, the substance may be said to be useful in the treatment of allergic diseases.

The process for the preparation of the compounds of the formula I according to the invention consists in the oxidation of the compounds of the formula II,

(II) wherein R is again methyl or hydrogen, hydrogen peroxide in acetic acid at room temperature. The resulting sulfoxide bases of formula I are crystalline substances whose identity has been assured analytically, both by spectra and by the course of the polarographic reduction. Neutralization with pharmaceutically acceptable acids provides the corresponding salts, and this neutralization process is also an object of the present invention. Of the starting materials, substance II (R-methyl) is a known substance (Rajšner M. et al. Cited), while substance II (R-H) is a novel substance, the preparation of which is described in the exemplary embodiment.

Example 1

4- (1-Methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine N-oxide (1, R 2 CH 2). To a stirred solution of 4.5 g of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine in 20 ml of acetic acid is slowly added 2.3 g of 30% peroxide The mixture was diluted with 200 ml of water, basified with aqueous ammonia and the oily product isolated by extraction with chloroform. The extract was dried over potassium carbonate and evaporated under reduced pressure. Residue

224 246 was dissolved in boiling benzene (11 ml), cooled and petroleum ether (5 ml) was added. After standing for several hours, the precipitated crystalline base is filtered and dried under vacuum. 3.4 g (72%) of the desired base melting at 149-154 ° C are obtained. Recrystallization from a mixture of benzene and petroleum ether gave the pure material, melting at 155-158 ° C. Neutralization of the base with maleic acid in ethanol yields crystalline hydrogen maleate which is pure after crystallization from aqueous ethanol and melts at 205-207 ° C with decomposition. Example 2

4- (4-Piperidylidene) -4,9-dihydro thieno (2,3-c) -2-benzothiepine 10-oxide (I, R = H). A solution of 9.0 g of 4- (4-piperidylidene) -4,9-dihydrothieno (2,3-c ') - 2-benzothiepine in 45 ml of acetic acid is cooled to 10 ° C and 4.8 dropwise is added dropwise with stirring. g 30% hydrogen peroxide. The mixture is allowed to stand at room temperature for 20 h, then diluted with 120 ml of water, basified with 80 ml of concentrated aqueous ammonia and the base is isolated by extraction with chloroform. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was crystallized from a mixture of 40 ml of benzene and 30 ml of hexane; 7.6 g (80%) of the desired base melting at 175-179 ° C is obtained. Crystallization from a mixture of benzene, ethanol and hexane gave a pure product, m.p. 182-184 ° C. Neutralization with hydrogen chloride in ethanol / ether yields the hydrochloride which, after crystallization from aqueous ethanol, is pure and melts at 289-292 ° C with decomposition.

The starting 4- (4-piperidylidene) -4,9-dihydrothieno (2,3-c) 2-benzothiepine used is a novel substance not yet described. It can be prepared, for example, by the following procedure:

A solution of 12.5 g of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine (Rajsner M. et al., Cited) in 100 ml of benzene was added in 1 ml h, 8.7 g of ethyl chloroformate in 25 ml of benzene are added dropwise to the stirred and refluxing solution. The mixture was stirred and refluxed for 1.5 h, then cooled and washed with a solution of 10 g of (+) - tartaric acid in 100 ml of water. The benzene layer was dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in 100 ml of benzene and the solution was filtered through a 50 g silica gel column (Silpearl). Elution with benzene and evaporation of the filtrate gave 12.0 g (8.1%) of 4- (1-ethoxycarbonyl-4-piperidylidene) -4,9-dihydrothieno4.

224 248 (2,3-c) -2-benzothiepine, which crystallizes on standing. Recrystallization from a mixture of cyclohexane and hexane gave the pure material, melting at 103-105 ° C.

To a solution of the previous crude carbamate (40.1 g) in ethanol (36 ml) was added potassium hydroxide (30 g) and the mixture was refluxed under stirring for 2 h. After cooling, it is diluted with 200 ml of water and the base is isolated by extraction with benzene. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was crystallized from a mixture of 250 ml of cyclohexane and 100 ml of benzene. 25.4 g (79%) of almost pure 4- (4-piperidylidene) 4,9-dihydrothieno (2,3-c) -2-benzothiepine melting at 154-156 ° C is obtained. This product is suitable for further processing. Recrystallization of the benzene sample yields a pure substance melting at 157-158 ° C. Neutralization with maleic acid in ethanol gives crystalline hydrogen maleate which melts at 198.5-199.5 ° C (aqueous ethanol) in the pure state.

Claims (1)

SUBJECT OF THE INVENTION 224 246 A process for the preparation of the novel 4- (4-piperidylidene) -4,9-dihydrothieno (2,3-c) -2-benzothiepine-10-oxides of the formula I wherein R is methyl or hydrogen and their salts with pharmaceutically acceptable inorganic or organic acids, characterized in that the sulfides of formula II (II) wherein R is the same as in formula I are oxidized with hydrogen peroxide in acetic acid at room temperature and the bases obtained are neutralized with pharmaceutically acceptable inorganic or organic acids converted into the corresponding salts.