CS264933B1 - Piperazines,their hydrochlorides and process for preparing them - Google Patents

Abstract

The solution is in the synthetic field drugs. Its subject matter is 1- (3- (4- (10,11- -dihydro-5H-dibenzo [a, d] cyclohepten-5-yl] - - and 1- (3- (4- (6,11-dihydrodibenzo / b, e / -) thiepine-11-yl) -1-piperazinyl) propyl) - -1,3-dihydro-2H-benzimidazol-2-ones, their hydrochlorides and a process for their preparation. The substances according to the solution show in the tests on antihistamine and antianaphylactic animals action use in the treatment of allergic diseases. Their method of preparation lies in substitution reaction of 1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) - and 1- (6,11- dihydrodibenzo [b, e] thiepin-11-yl) piperazines s 1- (3-chloropropyl) -1,3-dihydro-2H- benzimidazol-2-one. The hydrochlorides are obtained by the neutralization reaction prepared base with hydrogen chloride or hydrochloric acid .

Description

The invention relates to piperazine derivatives of the general formula I

wherein X is CH ₂ and R is hydrogen, or X is sulfur and R is hydrogen or methyl, their hydrochlorides and processes 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 the hydrochlorides of the individual compounds of formula I, the following pharmacological and toxicological data obtained from animal tests (all doses related to oral administration) may be given:

1- (3- (4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, X = CH ₂ , ^R " ^{In the} acute toxicity ^test in mice, the substance is not lethal or toxic at doses of 0.5 and 1.0 g / kg? It is very toxic. At 10 mg / kg in guinea pigs, Protective effect in the histamine detoxification test (protects 3 animals of the group of eight) At the same dose it shows a statistically significant effect in the passive skin anaphylaxis test in rats (Martin U., Romer D., Arzneim.-Forsch. 29, 770, 1978).

1- (3- (4- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, X) = S, R = Η). In the acute toxicity test in mice, the substance does not lethal up to a dose of 700 mg / kg; only at the highest doses it has a weak suppressive effect. It is therefore very little toxic. At an oral dose of 3 mg / kg it has a mild protective effect in the guinea pig histamine aerosol test. At a dose of 10 mg / kg, it shows a significant protective effect in guinea pigs in the histamine detoxification test (in repeated trials, 6 animals from the group of seven are protected against toxicity of the histamine, 4 animals from the group of eight). At the same dose, it has a statistically significant protective effect in the passive skin anaphylaxis test in rats; the mean effective dose ΏΏ θ is 4.1 mg / kg In this test, the substance is compared to an antiallergic oxatomide preparation (Richards D.M. et al., Drugs 27, 210, 1984), which has proven particularly useful in the treatment of chronic urticaria and allergic rhinitis.

1- (3- (4- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) -1-piperazinyl) propyl-1,3-dihydro-2H-benzimidazol-2-one ( I, X = S, R = CH3) In the acute toxicity test in mice it is not lethal or toxic at oral doses of 0.5 and 1.0 g / kg, and at a dose of 3 mg / kg it has a mild protective effect in the histamine aerosol test At 10 mg / kg, it shows a statistically significant protective effect in the passive skin anaphylaxis test in rats.

The process for the preparation of the compounds of the formula I, which is also part of this invention, consists in substitution reaction of piperazine derivatives with a secondary amino group of the formula II ^(II).

(II) wherein X and R are the same as in Formula I, with 1- (3-chloropropyl) -1,3-dihydro-1H-benzimidazole CS 264 933 B1.

-2-one (U.S. Pat. No. 4,200,641; Belg. Pat. No. 852,405; U.S. Pat. No. 2,714,437). Z · novel piperazinyl derivatives of formula II for 1- (10.1 l-dihydro-5H-dibenzo / a, d / cycloheptene-5-yl) piperazine (II, X = _CH2, R = H) has been described in the literature (Fr M 2111 (Chem. Abstr. 60, 6856 (1964)).

The piperazine derivatives of formula II (X = S and R = H or CH 2) are novel and the preparation of is described in the Examples. 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 ethanol or water.

The following examples are intended to illustrate the preparation possibilities of compounds of the general formula

According to the present invention, however, they are not intended to fully describe the possibilities. 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-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazole-2- he (I, X = CH3, R = H)

A mixture of 7.2 g of 1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) piperazine, 7.9 g of 1- (3-chloropropyl) -1,3-dihydro-2H- benzimidazol-2-one, 3.8 g triethylamine, 0.3 g potassium iodide and 75 ml anhydrous toluene were stirred and refluxed for 20 h. It is then diluted with 75 ml of benzene, washed at 100C with 100 ml of water, the separated benzene solution is washed again with water at room temperature and dried over potassium carbonate. The crude product obtained by evaporation of benzene is crystallized from 20 ml of ethanol. 7.0 (60%) of an almost homogeneous base melting at 175-182 ° C is obtained. Recrystallization of the sample from acetone gave the pure product with m.p.

Mp 184-185 ° C. Neutralization of the base with hydrochloric acid in ethanol gives the hydrochloride as a 1: 1 solvate with ethanol, m.p. 221 DEG-222 DEG C. (aqueous ethanol).

Example 2

1- (3- (4- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, X) = S, R = H)

A mixture of 7.4 g of 1- (6,11-dihydrobenzo [b, e] thiepin-11-yl) -1-piperazine, 7.9 g of 1- (3-chloropropyl) -1,3

of dihydro-2H-benzimidazol-2-one, 3.8 g of triethylamine, 0.3 g of potassium iodide and 75 ml of anhydrous toluene are stirred and refluxed for 20 hours. It is then diluted with 75 ml and washed at 100C with 100 ml of water. The separated organic layer was dried over potassium carbonate and evaporated under reduced pressure. The residue is chromatographed on a column of 250 g of alumina. Elution with benzene removes a small amount of less polar contaminants and then elutes with benzene with 3% ethanol to wash 9.70 g (83%) of the desired base, which crystallizes from a mixture of ethanol and di (2-propyl) ether.

It melts at 180-181 ° C in pure state. By neutralization with a solution of hydrogen chloride in ethanol / ether, the salt obtained is crystallized from 95% aqueous ethanol. The monohydrochloride hemihydrate is obtained, melting at 250-260 ° C.

The starting 1- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) piperazine used has not been described in the literature; it can be prepared by the following procedure from the known 11-chloro-6,11-dihydrodibenzo [b, e] thiepine (Seidlová V. et al., Monatsh. Chem. 96, 650, 1965).

To a stirred mixture of 32.0 g of 1- (ethoxycarbonyl) piperazine, 11.0 g of anhydrous sodium carbonate and 50 ml of chloroform was added a solution of 24.6 g of 11-chloro-6,11-dihydrodibenzo (b, e) over 30 min. of thiepine in 25 ml of chloroform. The reaction is exothermic and the reaction mixture spontaneously warms up to the reflux temperature of the mixture. It is then boiled under stirring for 7 hours. After cooling, the inorganic salts are filtered off with suction, the filtrate is washed twice with 100 ml of water and

CS 264 933 B1 the solvent is distilled off. The viscous residue is extracted twice with 150 ml of water at 60 ° C to remove 1- (ethoxycarbonyl) piperazine present, the water is removed by decantation, the product is dissolved in 100 ml of benzene, the solution is dried over potassium carbonate and evaporated. The residue slowly crystallizes from 50 ml of cyclohexane after the addition of petroleum ether; 26.2 g (71%) of 1- (ethoxycarbonyl-4- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) piperazine, mp 111-114 ° C.

A mixture of 26.0 g of the carbamate just described, 13.0 g of potassium hydroxide and 13 ml of ethanol is refluxed for 6 hours at a bath temperature of 125-140 ° C. Ethanol (residues under reduced pressure) is distilled off in the same apparatus for a further 2 hours. The residue was partitioned between 300 mL of water and 300 mL of benzene, the benzene solution was dried with potassium carbonate and evaporated. 20.0 g (96%) of crude oily 1- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -piperazine are obtained, which is crystallized from a mixture of 20 ml of benzene and 50 ml of hexane. 16.2 g (78%) of a homogeneous solid are obtained. To characterize it, neutralization with oxalic acid dihydrate in ethanol can produce crystalline oxalate which crystallizes from 2-propanol and melts at 148-151 ° C.

Example 3

1- (3- (4- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, X = S, R = CH 2)

As in the previous example, 6.2 g of 1- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) piperazine are reacted, 6.3 g of 1- (3-chloropropyl) -1, 3-chloropropyl, 3-dihydro-2H-benzimidazol-2-one, 3.05 g of triethylamine and 0.15 g of potassium iodide in 100 ml of toluene to give 11.1 g of crude product which is chromatographed on 320 g of alumina. which contained 3% ethanol, followed by crystallization from a mixture of ethanol, di (2-propyl) ether and petroleum ether to give 6.2 g (65%) of a homogeneous base, melting at 196-198 [deg.] C. Neutralization with hydrochloric acid in ethanol and crystallization from ethanol. 96% ethanol gives the monohydrate monohydrate, mp 202-203 ° C.

The starting 1- (2-methyl-6,11-dihydrodibenzo [b, e (thiepin-11-yl) piperazine] used is a novel compound which can be prepared, for example, from the known 2-methyl-6,11-dihydrodibenzo) as described below. b, e / thiepine-11-ol (Rajsner M. et al., Collect. Czech. Chem. Commun. 34,1015,

1969).

A suspension of 36.3 g of 2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-ol and 20 g of anhydrous calcium chloride in 450 ml of benzene is saturated with hydrogen chloride gas for 2.5 h, left to stand overnight, it is filtered with charcoal, the filtrate is evaporated and the residue is crystallized from 65 ml of cyclohexane; 37.4 g (96%) of 11-chloro-2-methyl-6,11-dihydrodibenzo [b, e] thiepine, m.p.

Mp 117-118 ° C.

As in the previous example, 20.0 g of the chloro derivative just described are reacted with 24.4 g of 1- (ethoxycarbonyl) piperazine and 8.5 g of anhydrous sodium carbonate in 80 ml of chloroform. A similar treatment yields 26.3 g (90%). 1- (ethoxycarbonyl) -4- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) piperazine, which crystallizes from ethanol and melts at 151-152 ° C.

As in the previous example, 24.7 g of the above compound was reacted with 12.5 g of potassium hydroxide in 20 ml of ethanol for 5 hours under reflux in a 125 ° C bath. Similar work-up gave 17.0 g (85%) of 1- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) piperazine, which crystallized from ethanol and melted at 164-166 ° C.

Claims (3)

SUBJECT OF THE INVENTION Piperazine derivatives of the general formula I in which X represents a group C 6 and R is a hydrogen atom, or X is a sulfur atom and R is a hydrogen atom or a methyl, 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 having a secondary amino group of the formula II (II) in which X and R are the same as in formula I are subjected to a substitution reaction with 1- (3-). chloropropyl) -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.