CS202338B1 - Derivatives of 6,11-dihydrodibenzo/b,e/thiepine-11-thiol - Google Patents

Description

The present invention relates to novel 6,11-dihydrodibenzo (b, e) thiepine-11-thiol derivatives of formula I,

the most typical effect is the anticonvulsant effect that occurs in mice in both the pentetrazole seizure antagonism test and the electroshock test; in both cases the effective oral dose is 100-200 mg / kg. At doses of 50-100 mg / kg, compound II also has an antiarrhythmic effect in rats in the aconitine arrhythmia test. The same dose induces a slight decrease in blood pressure in normotensive rats.

A compound of formula I, R is a residue wherein R is either a residue

-CH ₂ CON

NCH,

or —GH2CO3 / NGH2 * as well as their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts possess pharmacodynamic activity which makes them useful as medicaments. Their effectiveness lies mainly in the area of neurotrophic and circulation effects.

The compound of formula I, R is a residue of _r / NH 1 NH ₂ (hereafter referred to as compound II) was tested for oral hydrochloride hydrochloride. It is a low toxicity substance; its LD ₅₀ in mice is about 1250 mg / kg. Its (hereinafter referred to as substance III) was tested in the form of maleate by parenteral administration, its mean lethal dose in mice at

iv administration of LD ₅₀ is 62.5 mg / kg. Its solutions above 1% act locally anesthetically in the corneal anesthesia test. Most typical is its spasmolytic effect, which manifests itself in an in vitro test on isolated rat intestines; solutions with a concentration of 10 µg / ml suppressed the concentrations of isolated intestine induced by acetylcholine and barium chloride to 50%. Furthermore, the compound exerts an anticoagulant effect in mice, which is manifested at doses above 12 mg / kg

i. v. At the same doses, the substance has a biphasic central effect, manifested first by excitation and then by attenuation. The depressing nature of the effect also suggests the potentiation of thiopental sleep in mice; i. v. dose 5—10

202 338

202 338 mg / kg prolongs thiopental sleep to twice the control value. Thus, the agent is a spasmolytic with mild tranquilizing activity.

The preparation of the compounds of formula I is described in the examples. The starting material is the known 11-chloro-6,11-dihydrodibenzo (b, ejthiepine (V. Seidlová et al., Monatsh. Chem. 96, 650, 1965), which alkylates thiourea, resulting directly in the S- (6, 11-Dihydrodibenzo (b, e) thiepine-11-yl) isothiourea (II) This is cleaved by heating with an aqueous solution of alkaline hydroxide to give the alkali salt of 6,11-dihydrodibenzo (b, e) thiepine-11-thiol. the thiol is obtained in the free state and alkylated without purification with ethyl chloroacetate to give the intermediate of formula IV,

which by heating with excess 1-methylpiperazine gives the desired compound III. It is a basic substance which, by neutralization with acids, provides salts which are more favorable than the free base for pharmacological tests and for the preparation of dosage forms. Examples

1. S- (6,11-Dihydrodibenzo (b, e) thiepin-11-yl) isothiourea hydrochloride (II)

To a solution of 17.0 g of thiourea in 260 ml of ethanol was added 38.5 g of 11-chloro-6,11-dihydrodibenzo (b, ejthiepine) and the mixture was heated under reflux for 8.5 hours with stirring. The precipitated product II, which was washed with a small amount of ether and dried in vacuo, was obtained in a yield of 37.0 g (72%), melting at 169-172 ° C and analytically pure, recrystallization from ethanol / ether to give the melting point of the product. does not increase

2. N-Methyl-S- (6,11-dihydrodibenzo (b, ejthiepin-11-yl) -mercaptoaoetopiperazide (III)

A mixture of 16.2 g of S- [6,11-dihydrodibenzoate hydrochloride (b, e thiepin-11-yl) isothiourea-

Claims (1)

SUBJECT 6,11-Dihydrodibenzo (b, ejthiepin-11-thiol derivatives of formula I) The R (I) and 80 ml of 5M sodium nyaroxide were refluxed under a hydrogen atmosphere for 5 hours. After cooling, the solution was washed with ether, overlaid with benzene and then acidified with 5M hydrochloric acid. After shaking, the benzene layer was separated, dried over magnesium sulfate and evaporated in vacuo. 8.7 g (71%) of a viscous liquid, which is a crude 6,11-dihydrodibenzo (b, e) thiepine-11-thiol, are used in this state for further work. A suitable disulfide, which is formed very easily by oxidation with atmospheric oxygen, is suitable for its characterization; m.p. 198 DEG C. with decomposition (benzenetretroleter). Dissolve in 75 ml of absolute ethanol 1.5 g of sodium and a solution of 15.8 g of crude previous thiol in 40 ml of ether was added. The mixture was stirred at room temperature for 15 minutes and then a solution of 11 g of ethyl bromoacetate in 10 ml of ethanol was added dropwise over 10 minutes. The mixture was then refluxed for 4 hours. The volatiles were evaporated under reduced pressure, the residue was quenched with water and sodium hydrogen carbonate and extracted with benzene. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue (14.4 g, 67%) is crude S- (6,11-dihydrodibenzo (b, ejthiepin-11-yl) mercaptoacetic acid ethyl ester) which crystallizes from a mixture of cyclohexane and hexane and melts in the pure state at 61 to 62 ° C. A mixture of 14.4 g of the preceding ethyl ester and 14.0 g of 1-methylpiperazine was refluxed in a 140 ° C bath for 5 hours. After cooling, it is diluted with 100 ml of chloroform, washed thoroughly with water and the basic product is transferred from the chloroform layer to the aqueous phase by shaking with excess 5M hydrochloric acid. The separated acid solution was basified with 5M sodium hydroxide and the product isolated by extraction with chloroform. The extract was dried over anhydrous potassium carbonate and evaporated. 5.0 g of crude oily base III are obtained, which is dissolved in 15 ml of ethanol and the solution is neutralized by adding a solution of 1.65 g of maleic acid in 5 ml of ethanol. Ether was added to the resulting maleate solution to cause crystallization of the salt. After standing on the second day and suctioning off, 4.4 g of hydrogen maleate are obtained, which crystallizes from a mixture of ethanol and ether and melts in the pure state at 150 to 151.5 ° C. OF THE INVENTION wherein R is a residue -C ^ ^NH or -CHjGON ⁷ \ CH _3, NH ₂ ^ V_ / and salts thereof with pharmaceutically acceptable organic or inorganic acids.