CS264934B1 - 1- (10,11-Dihydrodibenzo / b, f / thiepin10-yl) piperazine Derivatives, their Hydrochlorides and their Preparation Process - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is 1-(3-(4-(10,11- -dihydrodibenzo/b,f/thiepin-10-yl)-1- -piperazinyl)propyl)-1,3-dihydro-2H-benzimidazol-2-one, its 2- and 8-chloro- and methylthio-derivatives, their hydrochlorides and a method of their preparation. The substances according to the solution show antihistamine and antianaphylactic effects in animal tests and are considered for practical use in the therapy of allergic diseases. Their method of preparation consists in the substitution reaction of 1-(10,11-dihydrodibenzo/b,f/thiepin-10- -yl)piperazines with 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one. The hydrochlorides are obtained by neutralizing the prepared bases with hydrogen chloride or hydrochloric acid.

Description

The present invention relates to 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine derivatives of the general formula I

2 wherein R, R is a combination of H, H, H, Cl, Cl, H and H / SCH 2, their hydrochlorides and a process for their preparation.

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

For hydrochlorides of the individual compounds of the formula I, the following pharmacological and toxicological data obtained in animal tests when administered orally:

1- (3- (4- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H1 2

-benzimidazol-2-one (I, R = R = H). In the acute toxicity test in mice, the mean lethal dose LD 150 is equal to 180 mg / kg. At a dose of 3.0 mg / kg, the compound exhibits a significant protective effect in the guinea pig histamine aerosol test; '4.6 mg / kg. The substance significantly prolongs the duration of the preconvulsive interval. It also shows a mild antihistamine effect in the guinea pig histamine detoxification test; a dose of 10 mg / kg protects 25% of the animals. At the same dose, it has a very pronounced protective effect in the passive skin anaphylaxis test in rats (protects 80% of animals) (Martin U., Romer D., Arzneim.-Forsch, 29, 770, 1978); The ED50 was 1/9 mg / kg. In this test, the substance is approximately three times more potent than the antiallergic preparation oxatomide (Richards D. M. et al., Drugs 27, 210,

1984), which has proven itself particularly in the treatment of chronic urticaria and allergic rhinitis.

1- (3- (4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-di12

-hydro-2H-benzimidazol-2-one (I, R = Cl, R-H). Acute toxicity in mice, LD _5Q = 800 mg / kg.

At a dose of 3.0 mg / kg, the compound has a pronounced antihistamine effect in the guinea pig histamine aerosol test; = 3.3 mg / kg. The substance significantly prolongs the duration of the preconvulsive interval.

It also shows a mild antihistamine effect in the guinea pig histamine detoxification test; a dose of 10 mg / kg protects 25% of the animals from the lethal effect of histamine. At the same dose, it shows statistically significant anti-anaphylactic efficacy in a passive cutaneous anaphylaxis test in rats (anaphylactic reaction blockade 42%).

1- (3- (4- (8-chloro-10,11-dihydro-dibenzo / b, f / thiepin-10-yl) -1-piperazinyl) propyl) ^-1,3-9 DI1 dihydro-2H-benzimidazol-2 -on- (I, R = H, R '= Cl). In the acute toxicity test in mice, the substance is very toxic; at a dose of 500 mg / kg, it does not induce dying and only central depression is a toxic sign. In the guinea pig histamine aerosol test, its antihistamine action is very mild; at a dose of 3.0 mg / kg, only 1/8 of the animals protect against histamine bronchospasm.

At a dose of 10 mg / kg, it has a statistically significant anti-anaphylactic effect in the passive cutaneous anaphylaxis test in rats (15-42% blockade of response).

1- (3- (4-) 8- (methylthio) -10,11-dihydrodibenzo [b, f (thiepin-10-yl) -1-piperazinyl) propyl) 1 2

-1,3-dihydro-2H-benzimidazol-2-one (I, R = H, R = SCH 2). It is very toxic in acute toxicity in mice; the 500 mg / kg dose is lethal for 10% and the 1000 mg / kg dose for 20% of the animals. Toxic symptoms of the highest dose mentioned are intense central depression and loss of righting reflex. At a dose of 3.0 mg / kg, the compound exhibits antihistamine activity in a guinea pig histamine aerosol test; at this dose, virtually 50% of the animals protect against histamine bronchospasm. At a dose of 10 mg / kg, it has a statistically significant anti-anaphylactic effect in the passive cutaneous anaphylaxis test in rats (reaction blocking from 15 to 42 S compared to control).

CS 264 934 Bl

The process for the preparation of the compounds of the formula I, which is also part of this invention, consists in the substitution reaction of piperazine derivatives of the formula II

2 wherein R and R are the same as in Formula I, with 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 4,200,641; Belg. Pat. 852,405) NSR Publication No. 2,714,437). Piperazine derivatives of formula II, i.e. 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Jílek JO et al., Collect. Czech. Chem. Commun. 32, 3 186, 1967) 1- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Valenta V. et al., Collect. Czech. Chem. Commun. 44, 3 008, 1979), 1- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Jílek JO et al., Collect. Czech. Chem. Commun. 36, 2226, 1971) and 1- ( 8- (methylthio) -10,11-dihydrodibenzo [b, f, thiepin-10-yl] piperazine (previous reference) are generally known. The substitution reaction can be carried out under various conditions, but it is preferred to carry out the reaction in boiling toluene in the presence of triethylamine and a small amount of potassium iodide. The crude products of formula I can either be directly purified by crystallization to obtain a homogeneous base of formula I, or the crude products need to be purified by chromatography, which is well suited for neutral alumina (activity II). By treatment with hydrochloric or hydrochloric acid, bases are neutralized to the hydrochlorides, which are also part of the invention. These usually crystallize as solvates with water.

The following examples are intended to illustrate the preparation possibilities of the compounds of formula (I) of the present invention, but are not intended to be exhaustive. All substances described in the examples are new and their identity has been assured by conventional analytical and spectral methods.

Example 1

1- (3- (4- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H1 2

-benzimidazol-2-one (I, R = R = H)

4.5 g of 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine, 4.8 g of 1- (3-chloropropyl) -1,3-dihydro- 2H-benzimidazol-2-one, 2.3 g of triethylamine and 0.15 g of potassium iodide, and the mixture is heated under reflux (bath 125-135 ° C) for 20 h. After dilution with 30 ml of toluene, it is washed while still warm with 60 ml of water, which is repeated once more. The toluene solution was dried over anhydrous potassium carbonate and evaporated under reduced pressure. The inhomogeneous residue (8.6 g) is chromatographed on a column of 230 g of alumina. Elution with benzene removes a small amount of low polar contaminants and then elutes with benzene from 3% ethanol 4.6 g (65%) of the desired base, which crystallizes from a mixture of ethanol and di (2-propyl) ether and melts at 146-147 ° C. . Neutralization with hydrogen chloride in ethanol / ether and crystallization of the crude product from 95% ethanol gave the dihydrochloride monohydrate, m.p. Mp 181-382 ° C.

Example 2

1- (3- (4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl-1,3-di3 2 hydro-2H-benzimidazole-2 -on (I, R = Cl, R = H)

As in the previous example, 6.2 g of 1- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 5.95 g of 1- (3-chloropropyl) -1 3-dihydro-2H-benzimidazol-2-one in the presence of 2.84 g of triethylamine and 0.15 g of potassium iodide in 70 ml of toluene. Analogous work-up gives a crude product which is chromatographed on 220 g of aluminum oxide. The desired homogeneous base is obtained in a yield of 73%, m.p. 113 DEG-114 DEG C. (acetone). Neutralization of the base with hydrogen chloride in a mixture of ethanol, benzene and ether and crystallization of the crude product from 85% aqueous ethanol gives the dihydrochloride sesquihydrate, m.p. Mp 167-168 ° C.

Example 3

1- (3- (4- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, r3-H, = Cl)

As in the previous examples, 6.6 g of 1- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 6.3 g of 1- (3-chloropropyl) -1 3-dihydro-2H-benzimidazol-2-one in the presence of 3.1 g of triethylamine and 0.15 g of potassium iodide in 100 ml of boiling toluene (18 h). The inhomogeneous product obtained (11.0 g) is purified by crystallization from 20 ml of ethanol? 7.65 g (76%) of the desired base melting at 177-178 ° C is obtained. By neutralizing the base with hydrogen chloride in a mixture of ethanol, benzene and ether and crystallizing the crude product from 95% ethanol, dihydrochloride monohydrate is obtained, m.p. 178-179 ° C.

Example 4

1- (3- (4- (8- (methylthio) -10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl-1,31 2

-dihydro-2h-benzimidazol-2-one (I, R = H, R = SCH)

As in the previous examples, 6.8 g of 1- (8- (methylthio) -10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 6.3 g of 1- (3-chloropropyl) - 1,3-dihydro-2H-benzimidazol-2-one in the presence of 3.1 g of triethylamine and 0.15 g of potassium iodide in 100 ml of boiling toluene (20 h). The crude product obtained (10.5 g) is chromatographed on 300 g of alumina. Elution with benzene with 3% ethanol gave 6.9 g (67%) of a homogeneous base, which crystallized from a mixture of di (2-propyl) ether and acetone and melted at 109-111 ° C. Neutralization with hydrogen chloride in acetone / ether and crystallization of the product from 85% ethanol gave the dihydrochloride monohydrate, m.p. Mp 198 ° C.

Claims (3)

SUBJECT OF THE INVENTION 1. 1- (10,11-Dihydrodibenzo [b, f] thiepin-10-yl) piperazine derivatives of the general formula I Wherein R, R is a combination of H, H, H, Cl, Cl, H and H, SCH 2, and their hydrochlorides. 2. A process for the preparation of compounds of the formula I according to claim 1, characterized in that the piperazine derivatives of the formula II in which R is the same as in the formula I are subjected to a substitution reaction with 1- (3-chloroC 264 934 B1 propyl) -1,3. dihydro-2H-benzimidazol-2-one and the bases of the formula I obtained are converted into hydrochlorides by neutralization with hydrochloric acid or hydrochloric acid. 3. The process of claim 2 wherein the substitution reaction is carried out in boiling toluene in the presence of triethylamine and a small amount of potassium iodide.