CS210369B1 - New derivatives of the 6,11-dihydlodibenzo/b,e/thiepin-5,5-dioxide,the salts thereof and method of preparation thereof - Google Patents

Abstract

The present invention is antiarrhythmic active 11-secaminoacetamido-6,11-dihydrodibenzo (b, e) thiepine 5,5-dioxides and their preparation by reaction of 1-haloalketamido-6,1-dihydrodibenzo (b, e) thiepine-5,5-dioxide with sek.aminy.

Description

The invention relates to novel 6,11-dihydrodibenzo (b, e) thiepine-5,5-dioxide derivatives of the general formula I,

(I) nhcoch ₂ nr ₂ in which R represents ethyl or the whole NRg group denotes morpholino-, piperidino- or 4- (2-hydroxyethyl) piperazino, their salts with pharmacologically acceptable inorganic or organic acids, and a process for their preparation,

The compounds of formula I exhibit valuable antiarrhythmic effects at low negative inotropic activity and low toxicity in pharmacological evaluation (LD 50 = 700 mg to more than 1 g / kg when administered p.o. in mice). These effects were demonstrated in vitro on isolated, electrically stimulated rabbit atria, with the antiarrhythmic effect manifested by prolonging the functional refractory period and the negative inotropic effect was determined by measuring the amplitude reduction of individual contractions at a constant frequency of electrical pulses.

In vivo antiarrhythmic activity has been demonstrated by both intravenous and oral administration in rabbits under pentobarbitel anesthesia in which arrhythmias were induced by intravenous administration of barium chloride at a dose of 2 mg / kg.

The compounds of the formula I can be prepared according to the invention by a three-step procedure starting from the known (Valenta V. et al., Collection Czech. Chem. Commun. 45, 517 (1980)) 11-amino-6,11-dihydrodibenzo (b, e) thiepine, which in the first step is acylated with a haloacetyl halide, preferably chloroacetyl chloride, in an inert organic solvent, e.g., dry chloroform, in the presence of a reagent capable of binding hydrogen halide formed in the reaction, e.g., alkali carbonates. The N-haloacetyl derivative of the formula II thus obtained,

NHCOCH ₂ X wherein X is chlorine or bromine, are further oxidized by known methods for the oxidation of sulphide to sulphone, preferably with hydrogen peroxide in hot acetic acid VE, to a sulfone of the formula III,

NHCOCH ₂ X wherein X is chlorine or bromine. Compounds of formula I are then obtained by reacting sulfone III with an excess of a base of formula HNR 8 in which R or NR 6 has the same meaning as in formula I in a suitable solvent, e.g. acetone or dimethylformamide, optionally in the presence of an alkaline iodide. Base I, isolated by evaporation of the reaction mixture, stirring the residue with water and a water-immiscible organic solvent, e.g. e.g., ethanol, to salts.

Further details of the preparation of the compounds of the present invention are described in the Examples, which, however, are merely illustrative of the possibilities of the invention, but are not intended to fully describe these possibilities.

Example 1

11-Chloroacetamido-6,11-dihydrodibenzo (b, e) thiepine (II, X = C1)

To a solution of 11.5 g of 1-1-amino-6,11-dihydrodibenzoib, e) thiepine in 80 ml of dry chloroform heated to about 40 ° C was added 21 g of anhydrous sodium carbonate and stirred vigorously to 40-50 ° C. A solution of 17 g of chloroacetyl chloride in 25 ml of dry chloroform is added dropwise to the mixture at 50 DEG C. over a period of about 1.5 hours. After stirring for another three hours at 40-50 ° C, the reaction mixture was not diluted with chloroform (100 mL), shaken twice with 100 mL of water, twice with 50 mL of 2056 hydrochloric acid, and finally washed with water until neutral.

The organic layer was separated and dried over anhydrous magnesium sulfate. Evaporation of chloroform gave 15.2 g (98.5%) of product, melting at 187-191 ° C. An analytically pure material recrystallized from benzene / ethanol melted at 191.5-192.5 ° C.

Example 2>

11-Chloroacetamido-6,11-dihydrodibenzotb, e) thiepine-5,5-dioxide (III, X = C1)

To a solution of 107.5 g of 11-chloroacetamido-6,11-dihydrodibeflzo (b, e) thiepine in 500 ml of glacial acetic acid was added 176 ml of a 30% aqueous hydrogen peroxide solution with stirring. The mixture is heated to boiling. After the exothermic reaction has subsided, resulting in continued boiling of the mixture without external heat (about 10 minutes), the mixture is heated to boiling for one hour. After cooling and standing at room temperature overnight, the crystallized product is filtered off with suction and washed with 50 ml of 75% acetic acid. After drying, 95.9 g (80.7%) of sulfone III are obtained, m.p. 205-207 ° C. An analytically pure material, recrystallized from benzene / acetic acid, melts at 206-208 ° C. ’

Example3

(Diethylaminoacetamido) -6,11-dihydrodibenzo [b, e] thiepine-5,5-dioxide

A mixture of 6 g of 1,1-chloroacetamido-6,11-dihydrodibenzoib, e) thiepine, 6.5 g of diethylamine and

3.3. Heat potassium iodide in 150 ml of dry acetone to boiling with stirring for 7 hours. After standing at room temperature overnight, acetone was distilled off and the residue was partitioned between water and chloroform. The chloroform solution was separated, dried over anhydrous potassium carbonate, filtered with charcoal and the chloroform evaporated under reduced pressure. The residue is recrystallized from 120 ml of ethanol. 5.7 g (85.1%) of the title compound are obtained, m.p. 191.5-193 ° C. The analytically pure material had a melting point of 192.5-193.5 ° C. Hydrogen fumarate prepared by neutralizing the base with fumaric acid in 80% ethanol in a yield of 81% at mp 218-220.5 ° C.

Example 1 a d 4

1l-Piperidinoacetamido-6,11-dihydrodibenzo (b, e) thiepine-5,5-dioxide

In analogy to Example 3, from 5 g of 11-chloroacetamide derivative II (X = Cl)

6.3 g of piperidine and 2.7 g of potassium iodide in 120 ml of dry acetone gave 4.6 g (80.4%) of the base of the title compound, m.p. 180-184 ° C. An analytical sample recrystallized from ethanol had a melting point of 183 to 185 ^Q C Hydrogen fumarate melts at 248-257 ° C dec chloride.

Example 5

11-Morpholinoacetamido-6,11-dihydrodibenzo (b, e) thiepine-5,5-dioxide

From 5 g of the 11-chloroacetamide derivative II (X = C1),

8.3 g of morpholine and 2.7 g of potassium iodide in 120 ml of dry acetone prepared an oily base which was converted to fumarate in 70% ethanol to hydrogen fumarate, m.p. 225-236 ° C. The yield of the crude product is almost quantitative.

Example 6

11- (4- / 2-Hydroxyethyl / piperazinoacetamido) -6,11-dihydrodibenzo (b, e) thiepine-5,5-dioxide

In analogy to Example 3, 6.7 g of crude are obtained from 5 g of 11-chloroacetamide derivative II (X = C1), 9.6 g of 2- (2-hydroxyethyl) piperazine and 2.7 g of potassium iodide in 120 ml of dry acetone. base, which is converted to a crystalline fumarate in ethanol. Yield 7.5 g (92.3%), mp 2.1-212.5 ° C. The analytically pure material melts at 213.5-215.5 ° C.

Claims (3)

Novel 6,11-dihydrodibenzo (b, e) thiepine-5,5-dioxide derivatives of the general formula I, wherein _{2 is 2} in which R represents ethyl or the whole of NR 1 denotes piperidino, morpholino or 4- (2- hydroxyethyl) piperazino, and their addition salts with pharmacologically acceptable inorganic or organic acids. 2. A process sloučein according to claim 1, characterized by reacting a derivative haloacetamide of the formula III (III) NHCOCH ₂ X wherein X is chlorine or bromine, with an excess of amine of formula HNRj wherein R or a group NR ₂ is the same as in formula I, in an inert organic solvent, optionally in the presence of an alkaline iodide, and the isolated base I is optionally converted into salts by neutral pharmacologically acceptable inorganic or organic acids. 3. A process according to claim 2, wherein the reaction is carried out using a chloroacetamide derivative of the formula III in which X is chlorine and the reaction is carried out for several hours by heating the mixture in boiling acetone in the presence of potassium iodide.