CS236449B1 - Aminoalcohol 2-chlorodibenzo (b, e) thiepine series and its salts - Google Patents

Abstract

The invention is an aminoalcohol of the 2-chlorodibenzo(b, e)thiepine series of formula I, i.e. (E)-1-/3-(2-chloro-S,ll-dihydrodibenzo/b,e)thiepin-ll-ylidene)propyl/-4-(2- -hydroxyethyl) piperazine and its salts with pharmaceutically acceptable acids. The substance of formula I and its salts have the properties of a non-cataleptic tranquilizer, which results in their utility in | neurology and psychopharmacotherapy. They also have antimicrobial properties, which provide utility in the chemotherapy of infectious diseases.

Description

The invention relates to the amino alcohol 2-chlorodibenzo (b, e) of the thiepine series of formula I,

i.e. (E) -1- [3- (2-chloro-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propyl] -4- (2-hydroxyethyl) piperazine, and its salts with pharmaceutically acceptable salts thereof; harmless acids.

The literature (Dutch Pat. Appl. 64 / 11,861; Gallant DM et al .; Curr.Ther.Res., Clin.Exp. 8, 241, 1966) discloses for Z1- / 3- (2-chloro-6-ol), 11-dihydrodibenz (b, e (oxepin-11-ylidene) propyl) -4- (2-hydroxyethyl) piperazine, referred to as pinoxepine, properties of a cataleptic neuroleptic. It has now been found that the analogous aminoalcohol dibenzo (b, e) of the thiepine series, but with the double bond transconfiguration, i.e., " substance I, " It is therefore a tranquilizer without the risk of extrapyramidal side effects. As such, it is suitable for soothing agitated neurotifs and psychotics, generally as a sedative and potentiator of hypnotic effects. In addition, it has a fairly broad spectrum of antimicrobial effects in in vitro assays, so that it is also considered as a chemotherapeutic for infectious diseases. ·

The pharmacodynamic effects of Compound I were investigated in mice and rats. It was administered orally in the form of maleate; featured

236 449 doses are calculated based on · The substance is very toxic in the acute toxicity test in mice; up to 800 mg / kg does not act lethal at all. In a Dew vest, in which the spontaneous motility of mice is determined by the beam method, the dose of 100 mg / kg reduces motility to 50%. Suppressive efficacy is significant at a dose of 50 mg / kg. · Ataxia occurs at similar doses in the rotating rod test in mice; mean effective dose of E & gQ ^with 103 mg / kg · At the same dose, it is completely free of cataleptic activity in rats. In vitro inhibitory activity against microorganisms is demonstrated at the following concentrations · (Values in µg / ml): Streptococcus-haemolyticus, 25; Streptococcus faecalis, 50; Staphylococcus pyogenes aureus, 50; Escherichia coli 50; Mycobacterium tuberculosis, 100; Trichophyton mentagrophytes, 51 ·

The compound of the formula I according to the invention can be prepared by a three-step process starting from the known 2-chlorodibenzo (b, e) thiepin-11 (6H) -one (Rajšner M. et al., Czech Pharm. 11,

451 (1962). In a first step, this ketone is treated with cyclopropylmagnesium bromide (Rajsner M. et al., Collect.Czech. Chem.Commun. 44, 2536, 1979) in tetrahydrofuran and the usual work-up gives new 2-chloro-11-cyclopropyl-6,11. -dihydroj.

dibenzo (b, e) thiepine-11-ol. In the second step, this alcohol is treated with a solution of hydrogen bromide in acetic acid at room temperature to give a mixture of the geometric isomers of 11- (3-bromopropyl) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine, in which E-isomer (trans), which is readily obtained by crystallization of the crude product. In the third step, this homogeneous bromo derivative is subjected to a substitution reaction with 1- (2-hydroxyethyl) piperazine in boiling chloroform. The desired product of formula (I) is obtained, which is isolated and purified in the form of crystalline bis (hydrogen maleate). The decomposition of this salt, which is also the subject of the invention, by alkalization with aqueous ammonia yields pure crystalline base I. The identity of the end product I as well as the said novel intermediates was ensured by analyzes and by means of spectra. The double bond configuration was attributed to the analysis of infrared spectra in the area of extra-plane vibrations (700-900 cm ^-1 ) (Rajšner M. et al., Collect. Czech.Chem. Commun. 34, 1963, 1969). The details of the preparation of the substance I are given in the example below, which is merely illustrative of the possibilities for the preparation of the substance I and foams its purpose in a comprehensive manner to describe all these possibilities.

Step 1: Reaction of 4.7 g of magnesium with 25.0 g of cyclopropyl bromide (Meek JS, Osuga DT, Ogr. Syn., Coll. Vol. 5, 126, 1973) in 100 ml of tetrahydrofuran gives a solution of Grignard reagent (cited above). ). The reagent solution was cooled to room temperature and a warm solution of 25.0 g of 2-chlorodibenzo (b, e) thiepin-11 (6H) -one (lit. quoted) in 100 ml of tetrahydrofuran was added dropwise over 1 hour with stirring. . The mixture was refluxed for 1 h, cooled in an ice bath, and quenched with slow addition of 135 mL of saturated ammonium chloride solution with stirring. The mixture was extracted with ether, the extract was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Upon standing the residue crystallized overnight to give 26.7 g (92%) of crystalline 2-chloro-11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepine-11-ol melting at 124-127 ° C. Recrystallization of the sample from a mixture of benzene and petroleum ether gave an analytically pure material, melting at 129-131 ° C.

Step 2: To a stirred solution of 10.0 g of the preceding alcohol in 170 ml of acetic acid is added dropwise over 30 min at 10-15 ° C 85 ml of a 15% solution of hydrogen bromide in acetic acid. The mixture is left at room temperature for 24 h, filtered with charcoal, the filtrate is diluted with 200 ml of water and extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. The residue crystallizes upon dilution with cyclohexane. 9.0 g (75%) of crude (E) -1- (3-bromopropyl) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine are obtained, which is recrystallized from cyclohexane / hexane to give then in the pure state as a substance melting at 109-111 ° C.

*

In I

Step 3: A mixture of 5.0 g of the previous bromo derivative, 6.0 g

Of 1- (2-hydroxyethyl) piperazine and 10 ml of chloroform were stirred and refluxed for 3 h. The mixture is then diluted with 50 ml of chloroform, filtered with charcoal, the filtrate is washed with water and then extracted with a solution of 10 ml of hydrochloric acid in 60 ml of water. The aqueous layer was filtered with charcoal, the filtrate was made alkaline with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue is dissolved in 50 ml of ethanol and neutralized with a solution of a calculated amount of maleic acid in ethanol. Standing and cooling leads to the crystallization of which

236 449

4 'yielding 5.2 g of bis (hydrogen maleate) (E) -1- [3- (2-chloro-6, casting hydrodibenzo [b, e] thiepin-11-ylidene) propyl] -4- (2- m.p. 163-165 [deg.] C. Crystallization from ethanol / ether yields a pure salt melting at 165-166 [deg.] C. Decomposition of this salt with aqueous ammonia and extraction with chloroform yields a crystalline base I melting at 121 DEG-122 DEG C. (benzene-petroleum ether) · Neutralization of the pure methanesulfonic acid flask with ethanol yields a crystalline dimethanesulfonate melting at 206 DEG-208 DEG C. (ethanol-ether).

Claims (1)

OBJECT OF THE INVENTION OF A Ajino-alcohol 2-chlorodibenzo (b, e) of the thiepine series of formula I, C4I ₂ (I), i.e. (E) -1- / 3- (2-chloro-6, ll-dihydro-dibenzo / b, e / thiepin-l l-ylidene) propyl / -4- (2-hydroxyethyl) piperazine, and salts thereof with pharmaceutically acceptable acids.