CS263986B1 - 2 (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -4,5-dihydroimidazoles and their maleates - Google Patents

Abstract

The solution falls into the field of synthetic drugs, its subject is 2-(6,11-dihydrodibenzo/b,e/thiepin-11-yl)-4,5-dihydroimidazoles, optionally substituted in position 2 of the tricyclic skeleton with a halogen atom or a methyl group, and their maleates. The substances according to the solution show thymolytic properties in pharmacological tests and are therefore considered as drugs against mental depression. This is particularly well documented for 2-(2-ctilor-6,11-dihydrodibenzo- /b.e/thiepin-11-yl) -4,5-dihydroimidazole hydrogen maleate, which is similar in intensity of its effects to tricyclic antidepressants used in practice. The substances according to the solution are accessible by heating 6,11-dihydrodibenzo/b.e/thiepine-11-carbonitrile and its 2-substituted derivatives with ethylenediamine-mono-4-toluenesulfonate to 200 °C. The crystalline bases obtained by processing the melts also provide crystalline hydrogen maleates upon neutralization with maleic acid.

Description

The invention relates to 2- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -4,5-dihydroimidazoles of the formula I

in which

R is hydrogen, halogen or methyl, and their maleate.

The compounds of the formula I and their salts with malelic acid show the properties of thymoleptics, ie potential antidepressants, in pharmacological tests. They are therefore suitable as medicines against mental depression.

In this respect, a typical compound of the invention is 2- (2-chloro-6,11-dihydrodibenzo [b, e] thiepin-11-yl) -4,5-dihydro-imidazole, which has been tested in the form of hydrogen maleate. In the in vivo tests, it was administered orally and the doses indicated are recalculated on a basis of basis. Its acute toxicity in white mice, LD 50 = 162 mg / kg.

In the rotating rod test, it has only a weak discoordinating effect in mice; the median effective dose of the ED50 is about 50 mg / kg. This is advantageous because this effect usually correlates with a central depressant effect which is not desirable for antidepressants. The compound is effective in potentiating the yohimbine toxicity potentiation test in mice; the median effective dose ED50 is 41.1 mg per kilogram. The agent further has an antireserpine effect in the eyelid ptosis test in mice; at 30 mg / kg significantly inhibits reserpine-induced ptosis.

In the last two tests, the intensity of action of the compound of the invention is similar to that of the tricyclic antidepressants used (imlpramine, prothiaden). In an in vitro assay, the agent inhibits the binding of 4 nM [ ⁵ H] imipramine and the binding of 4 nM [ ³ H] desipramine to the respective binding sites in the rat brain hypothalamus, indicating that the substance has an affinity for these binding sites of tricyclic antidepressants. Mean inhibitory concentrations of IC 50 in nM are 4,408 against imipramine and 1,381 against desipramine.

The compounds of the formula I according to the invention are novel. No antidepressant activity has yet been reported in any tricyclic dihydroimidazoles of similar type.

The compounds of formula (I) according to the invention are accessible by heating 6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile and its corresponding 2-substituted derivatives with ethylenediamine mono-4-toluenesulfomate to 200 degrees Celsius. Treatment of the resulting melt, as described in the examples, yields crystalline bases of formula I whose identity can be confirmed by analyzes and spectral methods. Neutralization of these bases with maleic acid in ethanol and addition of ether yields crystalline hydrogen maleate compounds which are also subject of the invention, which are more advantageous than bases for pharmacological testing and preparation of dosage forms.

The following examples are merely illustrative of the amount of preparation of the compounds of the invention, but are not intended to fully describe all of these possibilities. The starting 6,11-dihydrodibenzo [b, e] thiepine-11-carbonitriles used are partially known (then the literature cited where the substance is described), but they are mostly new and their preparation is therefore also described in the examples. known substances whose origin is cited.

Example 1

2- (6,11-dihydrodibenzo [b, e] thiep-11-yl) -4,5-dihydroimidazole (I, R = 1 H)

A mixture of 6.0 g of 6,11-dihydrodibenzo [b, e] thlepin-11-carbonitrile (Sindelar K. et al .: Collect. Czech. Chem. Commun. 52, 2 281, 1987) and 12.8 g of ethylenediamine- of mono-4-toluenesulfonate (Oxley P., Short WF: J. Chem. Soc. 1947, 497) was heated to 200 ^{° C} with stirring for 2 hours. After cooling, the melt is diluted with 10% sodium hydroxide solution and the product is extracted with benzene. Upon partial concentration, the benzene solution precipitated on standing 2.57 g (36%) of the desired crude base, mp 191.5-195 ° C. The pure base was obtained by crystallization from benzene, mp 193-195.5 ° C. Neutralization with maleic acid gives the hydrogen maleate which crystallizes from a mixture of 96% ethanol and ether as the hemihydrate and melts at 163.5-167 ° C.

Example 2

2- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) -4,5-dihydroimidazole (I, R = CH 3) • A mixture of 2-methyl-6,11 is heated similarly to Example 1. dihydrodibenzo [b, e] thiepine-11-carbonitrile and 22.0 g of ethylenediamine mono-4-toluenesulfonate at 200 DEG C. for 2 hours, and after cooling, the melt is partitioned by shaking between 100 ml of 10% sodium hydroxide solution and 200 ml of chloroform. . Treatment of the chloroform solution (drying over magnesium sulfate, filtration and evaporation under reduced pressure) gave a non-homogeneous product which was chromatographed on a column of 500 g of neutral alumina (activity II). Elution with chloroform gave 11.0 g (85 percent) of pure crystalline base which crystallized from benzene and melted at 224-226.5 ° C. Neutralization with maleic acid gives a crystalline hydrogen maleate that rats

283986 tallow from ethanol-ether and melts at 188.5-192.5 ° C.

The starting 2-methyl-6,11-dihydrodibenzo [b, e] thiepine-1-carbonitrile has not been described in the literature yet. It can be prepared from the known 2-methyl-6,11-dihydrodibenzobenzo [b, e] thiepin-11-ol (Rajsner M., et al .: Collect. Czech. Chem. Commun. 34, 1 015, 1969) in two stages as described below:

A suspension of 36.3 g of 2-methyl-6,11-dihydrodibenzo [b, e] thiepine-11-ol and 20 g of anhydrous calcium chloride in 450 ml of benzene is saturated with anhydrous hydrogen chloride for 2.5 hours and then left overnight at room temperature. calm. It is filtered with charcoal, the filtrate is evaporated under reduced pressure and the residue is crystallized from 65 ml of cyclohexane. 37.4 g of 11-chloro-2-methyl-6,11-dihydrodibenzo [b, e] thiepine (96%) are obtained, which melts at 117-118 ° C in the pure state.

To a solution of 13.5 g of this 11-chloro derivative in 80 ml of dichloromethane is added 6.35 g of trimethylsilyl cyanide (Reetz, T. and Chatziiosifidis I .: Synthesis 1932, 330), and then, with stirring, a total of 1.5 ml of tin tetrachloride. . After the first few drops of this substance have been added, a violent reaction occurs, the addition should be stopped and only after the reaction has calmed down. The mixture is then stirred

5.5 hours at room temperature, allowed to stand overnight, poured into 100 ml of water and extracted with dichloromethane. The extract was washed with 100 ml of 5% sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The inhomogeneous residue is chromatographed on 150 g of silica gel (Merck 40). The benzene was eluted with 11.8 g (93%) of 2-methyl-6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, which crystallized from ethanol and melted at 180-180.5 ° C.

Example 3

2- (2-chloro-6,11-dihydrodibenzo [b, e] thien-11-yl) -4,5-dihydroimidazole (I, R = Cl)

As in the previous examples, a mixture of 9.4 g of 2-chloro-6,11-dihydrodibenzo [b, e] thiamine-11-carbonitrile and 20.0 g of ethylenediamine mono-4-toluenesulfonate was heated at 200 degrees Celsius for 2 hours. The cooled mixture was partitioned by shaking between dilute sodium hydroxide solution and chloroform and the chloroform solution was evaporated. The residue was crystallized from benzene to give 5.5 g (51%) of the desired base, m.p. Due to the fact that repeated crystallization leads to decomposition of the substance, it is necessary to be satisfied with such a non-fading base. This provides by crystallization with maleic acid a crystalline hydrogen maleate, m.p. 202-205 ° C (ethanol-ether).

The starting 2-chloro-6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile used is a novel substance which is prepared from the known 2,11-dichloro-6,11-dihydrodibenzo [b, e] thiepine. No. 2,065,636 (Chem. Abstr. 83, 9333, 1975) by the following procedure:

As described in the previous example, a reaction of 10.0 g of 2,1-dichloro-6,11-dlhydrodi, benzo / b, e / thiepine with 4.4 g of trimethylsilyl cyanide in 70 ml of dichloromethane is carried out in the presence of 1.02 ml. tin (II) chloride. 9.6 g (99%) of homogeneous 2-chloro-6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile are obtained, which crystallizes from benzene and melts at 191-192 ° C.

Example 4

2- (2-bromo-6,11-dihydrodibenzo [b, e] thiidin-11-yl) -4,5-dihydroimidazole (I, R = Br)

As in the previous examples, 8.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile was heated with 14.0 g of ethylenediamine mono-4-toluenesulfonate at 200 ° C for 2 hours. . The cooled melt was partitioned by shaking between dilute sodium hydroxide solution and chloroform and the chloroform solution was evaporated. The inhomogeneous residue is chromatographed on a column of 500 g of neutral alumina (activity II). Chloroform elutes 5.06 g (56%) of a practically homogeneous desired base, which crystallizes from chloroform and melts at 210-215.5 ^° C with decomposition. Neutralization with maleic acid affords hydrogen maleate, which crystallizes from a mixture of ethanol and ether and melts at 199-202 ° C.

The starting 2-bromo-6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile used is a novel substance which is prepared from the just described 2-bromo-11-chloro-6,11-dihydrodibenzo [b, e] tliiepine (Sindelar K. et al .: Collect. Czech. Chem. Commun. 53, 340, 1988) as follows:

As in the previous examples, 16.1 g of 2-bromo-11-chloro-6,11-dihydrodibenzo [b, e] thiepine was reacted with 6.45 g of trimethylsilyl cyanide in 100 ml of dichloromethane in the presence of 1.5 ml of tin (II) chloride. The crude product obtained is purified by crystallization from a mixture of 200 ml of benzene and 150 ml of ethanol. 15.2 g (97%) of 2-bromo-6, ll-dihydro rodibenzo / b, e / thiepin-ll-carbonitrile melting at · 195 to 196 ^Q C

Claims (1)

SUBJECT OF THE INVENTION 2-(6,11-dihydrodibenzo/b,e/thiepin-11-yl)- in which -4,5-dihydroimidazoles general formula I R represents a hydrogen atom, halogen or methyl group, and their alkylated forms. if 1 II R (1) Severografia, n.p., plant 7, Most