CS261337B1 - Piperazine derivative of 4,9-dihydrothieno/2,3-c/-2/benzothiepine and its hydrochloride - Google Patents

Abstract

The solution is in the synthetic field drugs. It is 1- (3- (4- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) -1- piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one and its hydrochloride. appointed the substance and its hydrochloride have antihistamine and antianaphylactic effects suitable for the treatment of allergic diseases including asthma. A substitution reaction is obtained 1- (4,9-dihydro-thieno / 2,3-c / 2-benzothiepine-4-yl) piperazine with 1- (3-chloropropyl) - -1,3-dihydro-2H-benzimidazol-2-one.

Description

The invention relates to a piperazine derivative

4,9-dihydrothieno [2,3-c] -2-benzothiepitole of formula I

and its hydrochloride.

The compound of formula I and its hydrochloride show antihistamine and antianaphylactic activity in animal tests. They are therefore suitable for practical use in the treatment of allergic diseases including asthma.

The compound of formula I, i. l- (3- (4- (4,9-dihydro-thieno / 2,3-c / 2-benzothiepine-4-yl) piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2 it has been pharmacologically tested in the form of the hydrochloride (solvate with ethanol). It appears to be minimally toxic in the mouse acute toxicity test; the mean lethal dose of LD ₅₀ is greater than 1.0 g / kg. In oral dose *. 3 mg / kg shows a significant protective effect in the guinea pig histamine aerosol test (antihistamine effect). It significantly prolongs the duration of the preconvulsive interval and protects 50% of the animals. At an oral dose of 10 mg / kg it shows a mild protective effect in the passive skin anaphylaxis test in rats.

The compound of formula I is accessible by a substitution reaction of 1- (4,9-dihydrothieno / 2,3-c) -2-benzothiepin-4-yl) piperazine of formula II

(II) with 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one of formula III, ClCH ₂ CH ₂ CH ₂ N

And '(III).

While the compound of formula III is known (US Pat. 4,200,641; Belg. Pat. 852,405; NSR Publication 2,714,437), the compound of formula II has not yet been described in the literature and its preparation and characterization is therefore exemplified. The reaction of the compounds II and III can be carried out under various conditions, but it is advantageous to carry out the reaction in boiling toluene in the presence of triethylamine and a small amount of potassium iodide. The crude product of formula I crystallizes from ethanol and is thus obtained in the form of a crystalline base. This was then converted by treatment with hydrogen chloride to the hydrochloride, which crystallized from 98% ethanol as a solvate with ethanol (1: 1).

The following example is intended to illustrate the preparation possibilities of the compound of formula (I) but not to exhaustively describe these possibilities. All substances described in the example are new and their identity was assured by conventional analytical and spectral methods.

Example

1- (3- (4- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazole-2- he (I)

To 70 ml of toluene was added sequentially 4.7 g of 1- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) piperazine (II), 4.9 g of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one (III), 2.4 g of triethylamine and 0.15 g of potassium iodide, and the mixture is heated under reflux for 20 hours with stirring. After cooling, 60 ml of water are added, after shaking, the aqueous phase is separated, extracted with 25 ml of toluene and the toluene phases are combined, washed with water, dried over anhydrous potassium carbonate and, after filtration, evaporated in vacuo. The residue (7.5 g) was dissolved in 10 ml of ethanol while warm. On standing, 3.7 g (50%) of the desired base of formula I crystallized, m.p. Mp 195-198 ° C. The pure material is obtained by recrystallization from acetone, m.p. 205 DEG-206 DEG. Neutralization of the base with hydrochloric acid in ethanol gave the monohydrochloride, which crystallized from 98% ethanol as a 1: 1 solvate with ethanol, m.p. Mp 187-188 ° C.

starting 1- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) pipreazine (II), the preparation of which has not yet been described in the literature, is prepared according to the following procedure starting from known 4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol (Rajsner M. et al., Collect. Czech. Chem. Commun. 32, 2854, 1967):

To a stirred solution of 16.2 g of 4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol in 32 ml of pyridine was added dropwise 7.9 g of methanesulfonyl chloride at an external cooling rate of ice and water at such a rate that the temperature the mixture was maintained at 25-28 ° C. The mixture is then allowed to stand at room temperature for 24 hours. 38 g of 1- (ethoxycarbonyl) piperazine are then added, the solution is stirred for 8 h and left to stand at room temperature for a further 16 h. The mixture was then partitioned by shaking between 300 ml of benzene and 250 ml of water, the organic phase was washed with water, dried and evaporated. The glassy residue was dissolved in benzene and chromatographed on a column of 500 g of neutral alumina (activity II). After eluting the small, less polar fraction, 16.0 g (62%) of homogeneous oily 1- (ethoxycarbonyl) -4- (4,9-dihydrothieno / 2,3-c / -2-benzothiepin-4-yl) piperazine are eluted with benzene. which crystallizes after trituration with water and has been identified as the monohydrate, m Mp 55-58 ° C.

To a solution of 20.4 g of the above compound in 20 ml of ethanol was added 10.2 g of potassium hydroxide and the mixture was heated under reflux (bath 105-110 ° C) for 5 hours with stirring. After cooling, it is diluted with 200 ml of water and the product is extracted with benzene. The benzene extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. Crystallization of the residue from a mixture of 20 ml of ether and 5 ml of petroleum ether gave 11.7 g (71%) of the pure desired 1, (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) piperazine (II). ), tt 132-135 ° C.

Claims (1)

Example 1- (3- (4- (4,9-Dihydrothieno [2,3-c] -2-benzothiepin-4-yl) -1-piperazinyl) propyl) -1,3-dihydroxy- 2H-benzimidazol-2-one (I) To 70 ml of toluene was added sequentially 4.7 g of 1- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) piperazine (II) 4.9 g of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one (III), 2.4 g of triethylamine and 0.15 g of potassium iodide, and the mixture is boiled under stirring for 20 hours After cooling, 60 ml of water are added, after shaking the aqueous phase is separated off, extracted with 25 ml of toluene and the toluene phases are combined, washed with water, dried over anhydrous potassium carbonate and filtered after filtration under vacuum. The residue (7.5 g) was dissolved in 10 ml of ethanol while hot. On standing, 3.7 g (50%) of the desired base of the formula I, m.p. Mp 195-198 ° C. The pure product was obtained by recrystallization from acetone, m.p. Mp 205-206 ° C. Neutralization of the base with hydrochloric acid in ethanol gave the monohydrochloride which crystallized from 98% ethanol as a 1: 1 solvate with ethanol, m.p. 187-188 ° C. the starting 1- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) piperazine (II), the preparation of which has so far been described in the literature, is prepared by the following procedure 4, 9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol (Rajshner M. et al., Collect. Czech Chem. Commun. 32, 2854, -1967): To a stirred solution of 16.2 g Of 4.9 g of dihydrothieno [2,3-c] -2-benzothiepin-4-ol in 32 ml of pyridine, 7.9 g of methanesulfonyl chloride are added dropwise under external cooling with water to maintain the temperature of the mixture at 25-28. ° C. The mixture is then left at room temperature for 24 hours. 38 g of 1- (ethoxycarbonyl) piperazine are then added, the resulting solution is stirred for 8 hours and left at room temperature for a further 16 hours. Then the mixture was partitioned between 300 ml of benzene and 250 ml of water, the organic phase was washed with water, dried and evaporated. The glass residue was dissolved in benzene and chromatographed on a column of 500 g of neutral aluminum oxide (activity II). After washing a small, less polar fraction with benzene, 16.0 g (62%) of a homogeneous oily 1- (ethoxycarbonyl) -4- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) is eluted piperazine which crystallizes after trituration with water and has been identified as a monohydrate, m.p. 55-58 ° C. To a solution of 20.4 g of the previous material in 20 ml of ethanol is added 10.2 g of potassium hydroxide and the mixture is refluxed for 5 hours (bath 105 to 110 ° C). After cooling, it is diluted with 200 ml of water and the product is extracted with benzene. The benzene extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. Crystallization of the residue from a mixture of 20 ml and 5 ml of petroleum ether yields 11.7 g (71%) of the pure desired 1 (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) piperazine (II) , tt 132-135 ° C. OBJECT OF THE INVENTION The piperazine derivative of 4,9-dihydrothieno [2,3-c] -2-benzothiepine of formula (I) s. (I) and its hydrochloride.