CS267046B1 - 2- (2-Chloro-10,11-dihydrodibenzo / b, f / thiepin-10-ylthio) ethylamines and their hydrochlorides - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is 2-(.2-chloro-10,11-dihydrodibenzo/b,f/thiepin10-ylthio)ethylamines and their hydrochlorides, which show antireserpine activity in animal tests and are therefore potential antidepressants, and also show significant antimicrobial activity in in vitro tests, which indicates their applicability in the chemotherapy of infectious diseases. The substances according to the solution are accessible by chain synthesis, which starts from 2-chloro-10,11-dihydrodibenzo/b,f/thiepin-10-thiol, which in the form of the sodium salt is alkylated with 2-chloroethylamine hydrochloride in the presence of potassium carbonate in boiling ethanol. 2-(2-chloro-10,11-dihydrodibenzo/b,f/thiepin-10-ylthio)ethylamine (one substance according to the solution) is obtained, which is converted into an N-(ethoxycarbonyl) derivative by the action of ethyl chloroformate. Reduction of this substance with aluminum hydride gives N-methyl-2-(2-chloro10,11-dihydrodibenzo/b,f/thiepin-10-ylthio)ethylamine, i.e. the second substance according to the solution. Both bases are converted into hydrochlorides, which are included in the subject of the solution.

Description

The invention relates to novel ethylamines of the general formula S

2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio I

Cl

CH 2 CH 2 NHR (Ϊ) in which R represents a hydrogen atom or methyl, and their hydrochlorides.

The compounds of the formula I according to the invention show antireserpine activity in pharmacological tests in animals, which predicts their applicability in the treatment of mental depressive conditions. The compounds of the formula I furthermore show considerable antimicrobial activity in in vitro tests, which suggests their utility in the chemotherapy of infectious diseases. The following are the specific results of biological tests:

N-Methyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-1C-ylthio] ethylamine (1, R = CH 2) was tested as the hydrochloride for its acute toxicity in mice when administered orally, LD $ q = 523 mg / kg At a dose of 25 mg / kg po statistically significantly antagonizes hypothermia in mice induced by a standard dose of reserpine At a dose of ICO mg / kg po significantly antagonizes the formation of gastric ulcers in rats also induced by reserpine. mg / kg shows a statistically significant antagonism in the reserpine ptosis test in mice, while its central damping activity is very low, in the rotating rod test in mice it induces ataxia only at a mean effective dose ED $ q = 66.8 mg / kg. mg / kg po does not affect the toxicity of adrenaline in mice, indicating a minimal adrenolytic and cardiotoxic effect.At concentrations of 25 / Ug / ml, it acts antimicrobially in the in vitro test against Streptococcus / 3-haemolyticus, Streptococcus faecalis, Staphylococcus pyogenes aureus co Trichesichentaophy cotya coliusli, Escherich V Proteus vulgaris even acts at a concentration of 6.2 .mu.g / ml.

2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) -ethylamine (1, R = H) was tested as the hydrochloride hemihydrate. In a mouse test for reserpine hypothermia, this substance has a significant antireserpine effect at a dose of 100 mg / kg after the substance potentiates the toxicity of yohimbine in mice; ΕΏ ^ θ ⁼ 123 mg / -kg po Has only a slight discoordinating effect in the rotating rod test in mice; ΕΏ ^ θ = 210 mg / kg po Up to a high dose of 250 mgAg po antagonizes adrenaline toxicity in 40% of mice, again indicating very low adrenolytic and cardiotoxic activity. At concentrations of 12.5 .mu.g / ml, it has an antimicrobial effect on Streptococcus (3-haemolyticus, Streptococcus faecalis, Escherichia coli, Proteus vulgaris, Saccharomyces pasterianus). At concentrations of 6.25 .mu.g / ml, it acts against Trichophyton mentagrophytes and Candida albicans. It has an inhibitory effect on Staphylococcus pyogenes aureus even at a concentration of 3.125 .mu.g / ml.

The compounds of the invention are accessible by chain synthesis starting from the novel 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol (the preparation of which is described in the example), which in the first step is in the form of the sodium salt. alkylates with 2-chloroethylamine, which can preferably be used in the form of the hydrochloride (Seitz 0., Ber. Dtsch. Chem. Ges. 24, 2626, 1891). The reaction is preferably carried out in boiling ethanol in the presence of anhydrous potassium carbonate. Compound I (R = H) is obtained in a yield of 82%. It gives a crystalline hydrochloride which crystallizes from a mixture of 95% ethanol and ether as a hemihydrate. The pure base liberated from this salt is then treated with ethyl chloroformate in boiling chloroform in the presence of sodium carbonate. Crystalline (ethyl) -N- (2) is obtained in high yield

CS 267 046 Bl

- (2-chloro-10,11-dihydrodibenzo [b, f] -thiepin-10-ylthio) ethyl) carbamate, which is reduced in a final step with lithium aluminum hydride in ether to give the compound of formula I (R = CH 2). Further details of the preparation of the compounds of the formula I follow from the examples, which, however, are merely illustrative of the possibilities for the preparation of these compounds. The compounds of formula 1 are basic in nature and neutralization with hydrochloric acid or hydrogen chloride affords the corresponding hydrochlorides, which are also the subject of the invention. Described substances and intermediates. they are new and their identity has been ensured by analytical and spectral methods.

Example 1

2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) -ethylamine (I, R = H)

2-Chloro-10,11-dihydrodibenzo [b, f] thiepine-1C-thiol (4.2 g) was dissolved with stirring in a solution of sodium ethoxide, which was prepared in advance by dissolving 0.35 g of sodium in 25 ml of absolute ethanol. To the sodium thiol solution thus obtained were added 4.0 g of anhydrous potassium carbonate and a solution of 1.86 g of 2-chloroethylamine hydrochloride (cited) in 30 ml of ethanol. The mixture was refluxed with stirring for 4.5 h, the ethanol was evaporated under reduced pressure, the residue was diluted with water and extracted with benzene. The extract is shaken with 15 ml of 3.5M HCl, the precipitated product hydrochloride is filtered off after standing for 30 minutes, washed with a mixture of acetone and ether and dried in vacuo. 4.4 g (82 of the desired hydrochloride of the compound of formula I (R = H)) are obtained, which melts at 154 DEG-157 DEG C. Crystallization from a mixture of 95% ethanol and ether gives the hydrochloride hemihydrate, melting at 158 DEG-162 DEG C.. of this salt with aqueous ammonia and extraction with ether, a homogeneous oily base of formula I (R = H) is obtained, which is suitable for measuring spectra.

The starting 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol used is a substance not yet described, which is obtained from the known 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiepine (Pelz K. et al., Collect. Czech Chem. Commun. 3, 1852 (1968) by the procedure described below:

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 first from a mixture of 30 ml of acetone and 30 ml of ethanol and then from 2-propanol. Yield 5.0 g (94%) of crystalline form A of S- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) isothiuronium chloride, which melts at 137-140 ° C. Crystallization of the crude material from a mixture of ethanol and ether gives crystalline form B of the title compound, which melts at 183.5-184 ° C. The two forms differ from each other in some details of the infrared spectra, which is common in crystal modifications.

A mixture of 4.4 g of Form A above and 6 mL of 5M-NaOH was refluxed under nitrogen for 2 h under nitrogen. The mixture was diluted with 15 ml of water, acidified with 5M-HgSO 4 (to pH 2) and the product was isolated by extraction with benzene. Work-up of the extract gave 3.3 g (99%) of crude desired thiol melting at 90-110 ° C. Crystallization from cyclohexane gave the pure thiol, m.p. 100-102 ° C. The alkaline hydrolysis of Form B of the intermediate described in the previous paragraph proceeds quite similarly to give the same thiol.

Example 2

N-Methyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethylamine (1, R = CH 2) To a solution of 12.9 g of 2- (2-chloro- 10,11-Dihydrodibenzo [b, f-thiepin-10-ylthio) ethylamine (see Example 1) in 70 ml of chloroform, 14.8 g of finely powdered sodium carbonate are added, followed by stirring at 40-45 ° C. 3 g of ethyl chloroformate

CS 267 046 B1 in 30 ml of chloroform. The mixture was refluxed with stirring for 3.5 h, an additional 3.0 g of ethyl chloroformate was added and boiling was continued for 2 h. The mixture was diluted with 60 mL of chloroform, washed with water, then 60 mL of 1M-HCl and again water, dried over magnesium sulphate and evaporated. The residue (17.2 g) was crystallized from a solution in 10 ml of toluene by slow addition of 20 ml of petroleum ether. 13.4 g (85%) of (ethyl) -N- (2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethyl) carbamate are obtained, which melts in the pure state at 71-73 ° C (toluene-petroleum ether).

To a stirred solution of 3.5 g of lithium aluminum hydride in 250 ml of ether was slowly added 5.5 g of the previous carbamate, the mixture was stirred and refluxed for 4.5 h and allowed to stand overnight at room temperature. With stirring, it is then quenched by the slow addition of 3.5 ml of water, 3.5 ml of 20% sodium hydroxide solution and a further 7 ml of water, 3.5 g of potassium carbonate are added and the mixture is stirred for 30 minutes. The solid was filtered off and washed with ether. Evaporation of the filtrate gave 4.1 g (87%) of the crude desired base of formula I (R = CH 2). A saturated solution of hydrogen chloride in 4 ml of ether is added dropwise to a stirred solution of this base in 15 ml of ethanol. After standing for 1 hour in the cold, the precipitated hydrochloride is filtered off with suction, washed with ether and dried in vacuo. It is obtained in a yield of 3.1 g and melts in the pure state at 206-207 ° C (95% ethanol). As in Example 1, the homogeneous oily base of the formula I released (R = CH 2) is again suitable for measuring spectra.

Claims (2)

OBJECT OF THE INVENTION 2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) -ethylamines of formula I Cl sch ₂ ch ₂ nhr in which R represents a hydrogen atom or a methyl, and their hydrochlorides.