CS223430B1 - 3- [6,11-Dihydrodibenzo (b, e) thiepin-3-yl] -propyl-diol derivative and its salts - Google Patents

Abstract

The invention relates to a new 11-phenyl-3-(3-dimethylaminopropyl)-6,11-dihydrodibenzo-[b,e]thiepine and its salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention are antimicrobially active, reduce blood pressure in normotensive rats and are spasmolytics acting against both acetylcholine and barium chloride contractions of smooth muscles. The listed effects provide a basis for the use of the substances according to the invention as drugs.

Description

The present invention relates to novel 11-phenyl-3- (3-dimethylaroinopropyl) -6,11-dihydrodibenzo [b, e] thiepine and its salts with pharmaceutically acceptable inorganic or organic acids. The compounds of the invention are antimicrobially active, lower the blood pressure of normotensive rats and are spasmolytics acting against both acetylcholine and barium chloride smooth muscle contractions. These effects provide a basis for the use of the compounds of the invention as medicaments.

This invention relates to a novel 3- [6,11-dihydrodibenzo (b, e) thiepin-3-yl] propylamine derivative of the formula I

and salts thereof with pharmaceutically acceptable inorganic and organic acids.

The compound of formula I and its salts exhibit antimicrobial and pharmacodynamic activity, which makes them useful in therapy. Thus, hydrobromaleinate of compound I showed inhibitory activity in in vitro tests against the following microorganisms and at the indicated concentrations (in _[ mu] g / ml): Streptococcus / 3-haemolyticus, 12.5; Streptococcus faecalis, 12.5; Staphylococcus pyogenes aureus, 12.5 ; Escherichia coli, 12.5; Proteus vulgaris, 100; Trichophyton mentagrophytes, 50; Candida albicans, 50. A mean lethal dose of LD50 = 40 mg / kg was found at an intravenous dose of 8 mg in the indicative acute toxicity study in mice by intravenous administration. / kg induces short and deep reductions in blood pressure at normotensive rats at concentrations of 1 to 10 µg / ml, significantly attenuating the contraction of isolated rat duodenum induced by standard doses of acetylcholine and barium chloride, respectively, with antimicrobial, hypotensive and spasmolytic effects.

Compound I is prepared by reacting 11-phenyl-11-chloro-6,11-dihydrodibenzo (b, e) thiepine (M. Hori et al., Yakugaku Zasshi 98, 1195, 1978) with 3-dimethylaminopropylmagnesium chloride in boiling ether / benzene . This reaction yields a mixture of the two isomers which is separated by chromatography on alumina. The desired base I is more polar in the mixture and therefore elutes with a mixture of benzene and petroleum ether only after washing out the less polar isomer. It is the oily material, the resolution of a less polar isomer, the ^X H-NMR the typical signal at 5.20 5 (a), corresponding to the proton on the carbon backbone 11. The presence of this proton indicates that the substitution reaction did not occur on the carbon carrying the eliminated chlorine atom. Thus, substitution had to occur on one of the carbons of the aromatic nuclei. Structure I was assigned on the basis of the above-mentioned 1 H-NMR spectrum and analogy to the substitution reactions of 11-phenyl-11-chloro-6,11-dihydrodibene, z (b, ejthiepine with other nucleophilic agents.) The resulting positively charged carbonate cation at position 11 isomerized to a carbonated cation at position 3 of the skeleton by shifting the double bonds and the charge at position 3. Identification of the substance I was also ensured by analysis of the crystalline hydrogen maleate formed by neutralization of base I with maleic acid. These salts are more suitable than the free base for carrying out biological assays and for preparing dosage forms, and in this respect the hydrogen maleate is particularly suitable. »

Example 11-phenyl-3- (3-dime, thylaminopropyl) -6,11-dihydrodibenzo (h, e) thiepine (I)

To 3.6 g of magnesium under 36 ml of ether was added a small portion of a solution of 19.5 g of 3-dimethylaminopropyl chloride in 18 ml of ether, and the reaction was started by adding an iodine bead and 0.5 ml of 1,2-dibromoethane. When the reaction was started, the remainder of the 3-dimethylaminopropyl chloride solution was added dropwise at such a rate that the mixture was kept under gentle reflux. A solution of 19.5 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo (b, e) thiepine in 100 ml of benzene is then added dropwise with stirring over 25 minutes, and the mixture is refluxed for 3.5 hours. After cooling, it is diluted with 30 ml of benzene and 100 ml of a 10% ammonium chloride solution is added dropwise with stirring. The resulting mixture was extracted with ether. The organic phase was separated, washed with water, and the basic product was converted to an aqueous phase by shaking three times with 60 ml of 1 M HCl. The acidic aqueous solution was basified with excess 2.5 M NaOH and the liberated base was isolated by extraction with benzene. The extract was dried over potassium carbonate and evaporated under reduced pressure. The residual oil (21.1 g] was dissolved in a small volume mixture of benzene and petroleum ether 9: 1 and the solution is chromatographed on a column of 1.2 kg of neutral alumina (activity II). Elution with a solvent mixture, and said constant R _£ Monitoring the eluted material was it elutes first the less polar isomer and then elutes with 6.9 g of the desired base I. This provides neutralization with maleic acid in ethanol and ether addition of crystalline hydrogen maleate, which after recrystallization from ethanol / ether is obtained in a pure state and melts at 169.5 - 172 [deg.] C.

Claims (1)

SUBJECT INVENTION The novel 3- [6,11-dihydrodibenzo (b, e) thiepin-3-yl] propylamine derivative of formula I and its inorganic salts thereof. pharmaceutically safe or organic acids-