CS268627B1 - 1-Methyl-4- (2-chloro-10,11-dihydrodibenzo / b, f-thiepin-10-ylthio) piperidine and its hydrochloride - Google Patents

Abstract

The solution relates to the field of synthetic drugs. The subject of the invention is 1-methyl-4-(2-chloro-10,11-dihydrodibenzo/b,f/ thiepin-10-yl thio)piperidine (I) and its hydrochloride. Substance I in the form of hydrochloride shows significant antimicrobial activity in in vitro tests and is a potential chemotherapeutic agent. In addition, it potentiates the toxicity of yohimbine and shows ataxic activity in the rotating rod test in mice; it is therefore slightly centrally depressant and exhibits typical antidepressant properties. Substance I is amenable to alkylation of the sodium salt of 2-chloro-10,11-dihydrodibenzo/b,f/ thiepin-10- -thiol with 4-chloro-1-methylpiperidine. The hydrochloride is prepared by neutralizing base I with hydrogen chloride.

Description

The present invention relates to a novel 1-methyl-4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-

and its hydrochloride.

The hydrochloride compound of the formula I has considerable antimicrobial activity in in vitro tests and affects a wide range of microorganisms. This makes him a potential chemotherapeutic. In addition, it potentiates the toxicity of yohimbine in mice, which is a typical property of antidepressants. At high doses, it shows ataxic activity in the rotating rod test in mice, suggesting a mild central damping effect.

The minimum inhibitory concentrations of substance I (as hydrochloride) in in vitro tests (in pg / ml) against individual micro-organisms are as follows: Streptococcus β-haemolyticus 25, Streptococcus faecalis 25, Staphylococcus pyogenes aureus 6.25, Pseudomonas aeruginosa 100, Escherichia coli 50 , Proteus vulgaris 50, Trichophyton mentagrophytes 25, Candida albicans 50, Aspergillus niger 50. Mean effective dose in the rotating rod test = 144 mg / kg po Mean effective dose for potentiating the toxicity of yohimbine in mice ED ₅₀ = 86 mg / kg po

The compound of formula I is accessible, for example, by alkylation of the sodium salt with 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol with 4-chloro-1-methylpiperidine. The starting thiol is a novel substance, the preparation of which is described in the example. The preparation of 4-chloro-1-methylpiperidine has been described, for example, by A. Adlerová et al. (Česk.Farm. 12, 122, 1963). Alkylation can be performed under various conditions. According to the example, the said thiol is previously converted to the sodium salt by dissolving in a solution of sodium ethoxide in ethanol, the solution is evaporated, a solution of 4-chloro-1-methylpiperidine in dimethylformamide is added to the remaining sodium salt and the mixture is heated to 90 °. C. The basic product is isolated by conversion to aqueous phase with dilute hydrochloric acid, the base is liberated with aqueous ammonia and isolated by extraction with an organic solvent. The base of formula I is crystalline and suitable for spectrum characterization. Neutralization with hydrogen chloride in a mixture of ethanol and ether gives the crystalline hydrochloride, which is suitable for carrying out biological tests as well as for the production of dosage forms.

The following example is only an illustration of the possibilities for preparing the compound of formula I according to the invention.

Example

2-Chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol (4.2 g) was dissolved in a solution of sodium ethoxide prepared by dissolving 0.35 g of sodium in 25 ml of ethanol. The ethanol was evaporated under reduced pressure, and a solution of 2.0 g of 4-chloro-1-methylpiperidine in 10 ml of dimethylformamide was added to the residue. The mixture is stirred at 50 DEG C. for 10 minutes and then at 90 DEG C. for 3.5 hours. After cooling, it is diluted with 50 ml of benzene and the dimethylformamide is removed by washing repeatedly with water. The remaining benzene solution was shaken three times with 15 ml of 2.5M-HCl, the combined aqueous solutions were basified with concentrated aqueous ammonia and the base was isolated by benzene extraction. The extract was dried over anhydrous potassium carbonate and evaporated under reduced pressure. 3.1 g (55%) of an almost homogeneous base of the formula I are obtained, which crystallizes from a mixture of cyclohexane, benzene and petroleum ether and melts in the pure state at 174-177 ° C. The hydrochloride, prepared from a base neutralized with hydrogen chloride in a mixture of ethanol and ether, crystallizes in two forms. Partial crystallization from ethanol gave Form A melting at 240-245 ° C. Repeated precipitation from a solution in a mixture of ethanol and acetone with ether gave Form B, which melts at 208-212 ° C.

CS 268618 B1

The starting 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol is prepared from the known 2,10-dichloro-10,11-dihydrodibenzo [b, f] -1-hiepine (Pelz K. et al., Collec t. Czech.C.hem. Commun. 33, 1852 (1968) as follows:

A mixture of 4.2 g of 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 1.3 g of thiourea and 10 ml of dimethylformamide was stirred at 80 DEG C. for 3.5 hours and the solvent was evaporated in vacuo. The residue is crystallized from a mixture of ethanol and acetone and purified by crystallization from 2-propanol. Yield 5.0 g (94%) of S- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) isothiuronium chloride melting at 137-140 ° C. Crystallization from a mixture of ethanol and ether gave Form B melting at 183.5-184 ° C.

A mixture of 4.4 g of the above solid (Form A or Θ) and 6 ml of 5M NaOH was stirred and refluxed for 2 h under nitrogen, diluted with 15 ml of water, acidified with 5M-H2S0 ₄ to pH 2 and the product isolates benzene extraction. Work-up of the extract gave 3.3 g (99%) of crude thiol melting at 90-110 ° C. Crystallization from cyclohexane gave the pure material, mp 100-102 ° C.

Claims (1)

OBJECT OF THE INVENTION 1-Methyl-4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) piperidine of formula I and its hydrochloride.