CS224990B1 - The substituted 10-/4-/chloralkyl/piperazine/-10,11-dihydrodibenzo/b,f-thiepines and their salts - Google Patents

Description

The present invention relates to 8-substituted 1H- [4- (chloroalkyl) piperazino] -1H-11-dihydrodibenzo (b, f) thiepines of formula (I): (I) wherein R is chlorine or methylthio and n is 2 or 3, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts are low-cataleptic neuroleptics with considerable central buffering and discoordinating activity. They are antipsychotically active substances with a low incidence of extrapyramidal side reactions. In part, they act intensively adrenolytically and lower blood pressure, so they can be considered as antihypertensives. In in vitro assays, they inhibit many pathogenic microorganisms, so that they also have the character of antimicrobial chemotherapeutics. These effects have been found both in in vivo tests in experimental animals and in in vitro tests, as follows.

A typical compound of the invention is 2-chloro-11- [4- (2-chloroethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I, R = Cl, n = 2), which was tested in the form of raethane sulfonate and the doses are calculated on a basis. Acute toxicity in mice, LD ^ q «

115 mg / kg p.o. Discoordination effect in rotating rod test,

ED 50 (mean effective dose inducing ataxia in 50% of animals at time of maximum effect) is 3.0 mg / kg p.o. Cataleptic effect,

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EDi-θ (mean effective dose inducing catalepsy in 50% of rats) is 26 mg / kg p.o. The acute toxicity by intravenous administration to mice is not much higher than oral toxicity, LD 50 q 75 mg / kg i.v.

At a dose of 15 mg / kg i.v, it induces significant decreases in blood pressure in normotensive rats. It has a marked adrenolytic effect at a dose of 0.5 mg / kg i.v. decreases the adrenaline response to 50% of the control value in rats. At concentrations of 12.5 to 50 µg / ml, it inhibits the growth of the following microorganisms in in vitro assays: Streptococcus β-haemolyticus, Streptococcus faecalis, Staphylococcus pyogenes aureus, Mycobacterium tuberculosis, Saccharomyces pasterianus, Trichophyton mentagrophytes.

Another typical compound of the invention is 2-methylthio-11 / 4- (3-chloropropyl) piperazino / -10,11-dihydrodibenzo (b, f) thiepine (I, R ' SCH '), n ' = 3) , which was tested in the form of dimethanesulfonate. Its acute toxicity in mice, LD ^ q β 190 mg / kg p.o. Discoordination effect in rotating rod test in mice, ED ^ q *

3.9 mg / kg p.o. Cataleptic effect in rats, ED50 and 23.5 mg / kg p.o. At concentrations of 25 to 50 µg / ml, it inhibits the growth of Mycobacterium tuberculosis and Trichophyton mentagrophytes cultures.

The compounds of formula I can be obtained from the corresponding aminoalkcholes in general.

in which Ran denotes the same as in formula I by treatment with thionyl chloride, preferably in benzene or chloroform in the presence of pyridine. The starting materials of the formula II are known compounds (Jílek J.0. Et al., Collect.Czech.Chem.Commun. 6, 2226, 1971). The compounds of the formula I as bases are relatively stable and give the corresponding salts by acid neutralization, of which, in particular, the methanesulphonates are advantageous for their excellent water solubility than bases for carrying out pharmacological tests and for producing pharmaceutical forms.

Example 1

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2-Chloro-11- [4- (2-chloroethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I, R, Cl, n, 2). To a solution of 30.0 g of 2-chloro-11- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine hemihydrate (Jílek JO et al., Cited) in a mixture of 250 ml of benzene and 12.5 g of pyridine are slowly added dropwise with stirring at 10 ° C

16.4 g of thionyl chloride. The mixture was stirred for another 2 h at room temperature, quenched with 250 mL of water and basified with 5% sodium hydroxide. The product was extracted with benzene, the extract was washed with water and then shaken with an excess of 3M-HCl. The precipitated hydrochloride is filtered off with suction, suspended in the aqueous phase of the filtrate, the suspension is made alkaline with 10% sodium hydroxide solution and the product is again extracted with benzene. Evaporation of the extract gave 29.5 g of crude product which was dissolved in 50 ml of benzene and chromatographed on a column

120 g of neutral alumina (activity II). Elution with benzene gave 24.4 g of a homogeneous product which crystallized on standing, m.p. 105-106 ° C (cyclohexane). Heutralization with maleic acid in a mixture of ethanol and acetone affords the maleate melting at 151-153 ° C (ethanol). Heutralization of the base with methanesulfonic acid in a mixture of ethanol and ether gave a crystalline monomethanesulfonate melting at 168-169 ° C (ethanol-ether).

Example 2

2-Methylthio-11- [4- (3-chloropropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I, R ' SCH2, n = 3). To a solution of 20 g of 2-methylthio-11- [4- (3-hydroxypropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (Jílek JO et al., Cited) in 200 ml of chloroform is added 8 ml of pyridine. and then 24 g of thionyl chloride is slowly added dropwise with stirring so that the temperature does not exceed 40-45 ° C. The mixture is left at room temperature overnight, quenched with 200 ml of 10% sodium hydroxide solution and strongly alkalized with 35% sodium hydroxide solution while cooling with ice water. The chloroform phase was separated and evaporated under reduced pressure. The residue is dissolved in 250 ml of benzene, shaken with 200 ml of 3M-HCl, the precipitated hydrochloride is filtered off with suction and suspended in water. The suspension was basified with 15% sodium hydroxide and the base extracted with benzene. The extract is evaporated and the residue is chromatographed on a column of 500 g of neutral alumina (activity II). Elution with benzene yields

13.5 g (65%) of homogeneous oily product which neutralize ^1224990 suction maleic acid in ethanol, the crystalline maleate, mp 162-164 ° C (aqueous ethanol). Neutralizing base acid «? methanesulfonic acid line in ethanol. dimethane sulfonate is obtained which crystallizes from acetone and melts in the pure state at 160-163 ° C.

Claims (1)

8-Sulfated 10- [4- (chloroalkyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepines of the general formula I in which R represents a chlorine atom or a methylthio group and n represents 2 or 3, and their salts with pharmaceutically acceptable inorganic or organic acids.