CS197190B1 - 2-Methyl-10-piperazino-10,11-dihydrodibenzo (b, f) thiepines - Google Patents

Abstract

The invention relates to 2-methyl-10-piperazino-10,11-dihydrodibenzo(b,f) thiepines of the general formula Ϊ, \ ‘e in which R is methyl or 2-hydroxyethyl, and their pharmaceutically acceptable salts with inorganic or organic acids.

Description

The compounds of the general formula I and their salts are intensely effective tranquilizers and have a pronounced central depressant action, which are almost devoid of neuroleptic effects. Furthermore, they have antimicrobial effects in vitro. They are therefore technically important and useful as pharmaceuticals.

The substance 1, S ³ CHp was tested on animals in the form of methionyl maleate hemihydrate. Its acute toxicity in male mice when administered orally is low; LBjq » = 240 mg/kg. Its inhibitory effect can be determined on the basis of the incoordination effect in the rotating rod test in mice SX; the median effective dose that causes ataxia is BDj ₀ ³ 4.0 mg/kg po In the catalepsy test in mice, 10 mg/kg were administered orally, but only in 30% of the animals. At higher doses, the additive effect interferes with the attenuation of catalepsy, which makes it impossible to determine the median effective dose. The substance has no anticataleptic effect on perphenazine in mice, on the contrary, it slightly potentiates perphenazine catalepsy.

Unlike typical neuroleptics, the substance, administered at an oral dose of 00 mg/kg, does not increase the levels of dopamine metabolites (3,4-dihydroxyphenylacetic acid and hemevanillic acid) in the corpus atriatum and tubercula olfectorium in the rat brain. In vitro tests it has antimicrobial activity against the following microorganisms (minimum effective concentrations in µg/ml are given): Streptococcus β-haemolyticus 3.12; Streptococcus faecalis 50; Staphylococcus pyogenes aureus 25; Escherichia coli 25; Proteus vulgaris 100; Mycobaeterium tuberculosis 12.5; Saccharomyces pasterianus 12.5; Trichophyton mentagrophytes 25.

Substance I, B · CHgCHgOH, was tested in the form of di(hydrogenmaleate) mostly by oral administration. Its ID ₅₀ in mice is 180 mg/kg. In the rotating rod test, the median effective dose inducing ataxia is ^5.2 mg/kg. In rats, it does not have an antiapomorphine effect up to a dose of 50 mg/kg. Catalepsy was observed from a dose of 10 mg/kg in adult rats; at higher doses, a strong additive effect again interferes with the determination of catalepsy. The substance slightly potentiates perphenazine catalepsy in rats. Similarly to the previous one, it does not affect the levels of dopamine metabolites in the corpus atriatum and tubercula olfactorium of the rat brain at an oral dose of 80 mg/kg. The antimicrobial effect of the substance in vitro is similar to that of the previous substance (in the first four species, the minimum effective concentration is approximately twice that of the previous substance).

The method for preparing compounds of general formula 1, which is described in detail in the examples, is based on the known 2-methyl-10-chloro-10,11-dihydrodibenz(b,f)thiepine of formula II

(II),

i (M.Gereeke et al., NSR patent, publication, file 2,336.130; Chem.Abstr. 80. 108 576, 1974). which is treated by a eubetituation reaction with 1-ethylpiperazine or 1-(2-hydroxyethyl)piperazine. The obtained base of the general formula I is oily; however, neutralization with pharmaceutically acceptable acids provides crystalline salts that are suitable for pharmacological tests and for the preparation of pharmaceutical forms. From this point of view, salts with maleic acid are particularly suitable.

Design examples

Example 1 2-Methyl-10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine (I, R = GH^)

A mixture of 11.4 g of 2-methyl-10-chloro-10,11-dihydrodibenzo(b,f)thiepine, 20 g of 1-methylpiperazine and 20 ml of chloroform is refluxed for 5.5 hours. After cooling, it is diluted with 50 ml of chloroform, washed thoroughly with water and the product is transferred to the aqueous phase by shaking with excess 6N-HgSO^. The separated aqueous acidic sulfate solution is filtered through activated carbon, the filtrate is made alkaline with aqueous ammonia and the product is extracted with chloroform. The extract is dried over anhydrous potassium carbonate and evaporated in vacuo. 10.4 g (74 $) of the desired oily base are obtained. The entire quantity is dissolved in 25 ml of ethanol, a solution of 3.74 g of maleic acid in 25 ml of ethanol is added, and 75 ml of ether is added dropwise to the resulting solution of maleate while stirring. Standing overnight separates 11.8 g of monomaleate hemihydrate, the analytical sample of which is obtained by recrystallization from a mixture of 2-propanol and ether, b.p. 146 to 149.5 °C.

The starting material 2-methyl-10-chloro-10,11-dihydrodibenzo(b,f)thiepine is obtained essentially according to the data in the cited literature (U. Gerecke et al., cited). In contrast to the cited literature, which describes this substance as a yellow oil, it has now been found that the substance crystallizes well from a mixture of cyclohexane and petroleum ether and melts at 84 to 85 °C.

Example 2 2-Uethyl-10-[4-(2-hydroxyethyl)piperazino]-10,11*^lihydrodibenzo(b,f)thiepine (I, R CH ₂ CH ₂ 0H)

A mixture of 4.4 g of 2-ethyl-10-chloro-10,11-dihydrodibenzo(b,f)thiepine, 4.4 g of 1(2-hydroxyethyl)piperazine and 5 ml of chloroform is refluxed for 8 hours. By analogous treatment as in the previous case, 4.7 g (78%) of an oily base are obtained. This gives, on neutralization with maloic acid in acetone and the addition of ether according to the amount used, maleic acid, both amenmaleinate β b.p. 136.5 °C (acetone), and di(hydrogenmaleinate) and b.p. 141 to 142 °C (acetone-ether).

SUBJECT OF THE INVENTION

Claims (2)

SUBJECT MATTER 2-Methyl-10-piperazino-10,11-dihydrodibenzo-3 (b, f) thiepines of the general formula I in which R is methyl or 2-hydroxyethyl, and pharmaceutically acceptable salts thereof with inorganic or organic acids.