CS246000B1 - 6-alkyl-10-(4-methylpiperazino)-10,11-dihydrodibenzo (b,f)thiepines and their methanosulphonates - Google Patents

Abstract

The solution is within the scope of the synthetic drugs. Its subject matter is 6-alkyl-10— (4— -methylpiperazino) -10,11-dihydrodibenzo- - (b, f) thiepines of general formula I, R wherein R is methyl or ethyl, and their methanesulfonates. These substances have properties of noncataleptic tranquilizers ■ certain features of neuroleptic resp. antidepressant activities. Possible for use in the therapy of neuros as well as schizophrenic and depressive psychos and they are unlikely to invoke extrapyramidal side reactions. They are accessible from (2-iodophenyl) acetic acid and 2-alkyl (i.e., methyl and ethyl) thiophenols multi-stage synthesis, the last one the degree of substitution reactions 6-alkyl (methyl or ethyl) -10-chloro-10,11- -dihydrodibenzo (b, f) thiepines with excess 1-methyl-piperazine. The base I obtained are converted to methanesulfonates by neutralization methanesulfonic acid.

Description

The invention relates to 6-alkyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepines of formula I,

wherein R is methyl or ethyl, and their methanesulfonates.

The compounds of formula I and their methanesalphonates are neurotrophic and psychotropic active substances which can be described as non-cataleptic tranquillizers with certain features of neuroleptic and / or antidepressant activity. Commun. 33, 1882 (1968) .6-Fluorivative (Red I. et al., Collect.Czech.Chem.Commun. 44, 2139, 1979). The 6-methoxy derivative and the 6-hydroxy derivative (Protiva M. et al., Collect.Czech.Chem.Commun 4Q, 2667, 1975) were also noncataleptic and showed a weaker or stronger incoordination effect in the rotating rod test in mice. In fact, they did not provoke any closer interest. The fourth compound (6-hydroxy derivative) was prepared as a potential metabolite of the neuroleptic parathiepine ”

The compounds of formula I according to the invention are more pharmacologically interesting than the previously prepared analogs. They are suitable for practical use in the therapy of neuros as well as schizophrenic and depressive psychoses.

Compound of formula I, R β CH 2, i.e. 6-methyl-10- (4-methylpipera 2)

246,000 zino) -10,11-dihydrodibenzo (b, f) thiepine, was pharmacologically cross-linked in the form of a water-soluble dimethanesulfonate.

At an oral dose of 10 mg / kg, it significantly reduced the locomotor activity of the mice in the Dews test. Has pronounced affinity for dopaminergic receptors in the rat brain striatum, which shows the inhibition of binding / = H / spiperonuj IC _5Q = 170 nm (in this test is stronger than clozapine but weaker than chlorpromazine) · At an oral dose of 50 mg / kg was ineffective in rats cataleptically and against apomorphine stereotypes. In contrast, at an oral dose of 10 mg / kg, it blocks apomorphine-induced verticalization (climbing) in rats in 60% of animals. Thus, it has the character of a mild neuroleptic that is highly likely to have antischizophrenic effects in psychotic patients without unpleasant extrapyramidal side effects.

The compound of formula I, R = C 8 H 6, 6-ethyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine, was tested in the form of dimethane sulfonate hemihydrate, also excellent in water. Its acute toxicity in mice by intravenous administration,

LD50 = 40 mg / kg. In a rotating rod in mice, the compound has only a weak incoordinating effect, ED ₅₀ = 59.5 mg / kg orally. In contrast, at an oral dose of 30 mg / kg it significantly antagonizes. reserpine ptosis in mice. It also exhibits an antihistamine effect in guinea pigs (1 mg / kg sc protects 50% of the animals from lethal histamine, administered intra -ugularly at 5 mg / kg) and spasmolytic effect in vitro on isolated rat duodenum (1 to 10 µg / ml) ml reduces both acetylcholine and barium chloride contractions to 50%). It can be characterized as a potential antidepressant.

The compounds of formula I according to the invention are accessible from (2-iodophenyl) acetic acid (Shindelar K. et al., Collect. Gechech. Chem, Commun. 37, 1734, 1972). 2-methylthiophenol (commercial product) and 2-ethylthiophenol (Hansch C. et al., J. Org. Chem. 21, 265,

1956) as basic raw materials by multi-stage syntheses, which are described in the following examples. These examples are only intended to illustrate the possibilities of the invention, but are not intended to describe all of these possibilities in an exhaustive manner. The final products of the formula I and all the intermediates described are novel substances not previously described in the literature. Their identity was assured by analyzes and all the usual £

spectral methods. _{24β fl00}

Example 1

6-Methyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine (I, R = Cl);

To a solution of 32.7 g of potassium hydroxide in 350 ml of water was added 21.3 g of 2-methylthiophenol, and after stirring for 10 min, 45.1 g of (2-iodophenyl) acetic acid and 2.0 g of freshly reduced copper were added. The mixture was then stirred and refluxed for 17 h. Filter hot while the solid on the filter was washed with hot water and the filtrate acidified with hydrochloric acid.

After standing overnight at 0 ° C, the precipitated crude product is filtered, dissolved in benzene, and the acidic product is extracted into 60 ml of a 15% sodium carbonate solution, divided into three portions. The combined aqueous solutions were filtered with charcoal, the filtrate was acidified with hydrochloric acid, the precipitated product was filtered after standing overnight at 4 ° C, washed with water and dried in vacuo. 27.2 g (61%) of crude [2- (2-methylphenylthio) phenyl] acetic acid, melting at 77 DEG-83 DEG C., is obtained. Purification is carried out by crystallization from aqueous ethanol.

to 89 ° C.

A mixture of 37.3 g of the previous acid, 160 ml of toluene and 350 g of polyphosphoric acid is stirred vigorously and refluxed for 4.5 hours. After partial cooling, it is poured into 1 kg of ice-water and the product is extracted with benzene. The extract was washed with 5% sodium hydroxide solution and 15.2 g of the starting acid were recovered by acidifying the wash solution with hydrochloric acid. The washed benzene extract was dried over magnesium sulphate and evaporated under reduced pressure. 17.6 g (86% on conversion) of crude 6-methyldibenzo (b, f) thiepin-10 (11H) -one are obtained, which is purified by crystallization from cyclohexane, m.p. Mp 103-106 ° C.

To a stirred solution of 20.9 g of the previous ketone in a mixture of 60 ml of benzene and 300 ml of ethanol is slowly added a solution of 6.6 g of sodium borohydride in 60 ml of water containing 1.5 ml of 10% sodium hydroxide solution. The mixture was then refluxed for 5 h and evaporated in vacuo. The residue was partitioned by shaking between water and benzene, the benzene layer was washed with 3% sodium hydroxide solution and water, dried over magnesium sulfate and filtered to remove from the base. The residue was dissolved in ethanol, the solution was filtered with charcoal and the filtrate was re-evaporated. 19.2 g (91%) of crude 6-methyl-10,11-dihydrodibenzo (b, f) thiepin-10-ol were obtained, which was is purified by crystallization from cyclohexane, m.p. Mp 88-90 ° C.

To a solution of 19.1 g of the preceding alcohol in 250 ml of benzene was added 25 g of anhydrous powdered calcium chloride and the suspension was saturated with anhydrous hydrogen chloride at room temperature for 3 h. After standing overnight, the calcium chloride was filtered off, washed with benzene and the filtrate was evaporated under reduced pressure. The solid residue yielded 15.8 g (77%) of 6-methyl-10-chloro-10,11-dihydrodibenzo (b, f) thiepine, m.p. 75-78 ° C, by crystallization from 25 ml of acetone.

A mixture of 6.9 g of the preceding chloro derivative, 6.6 g of 1-methylpiperazine and 10 ml of chloroform was stirred and refluxed for 7 hours. After standing overnight, the chloroform was evaporated in vacuo, water was added to the residue and extracted with benzene. The benzene extract was washed with water and then shaken with excess 3M-HCl. The precipitated hydrochloride is filtered off with suction, added to the aqueous phase of the filtrate and the suspension is made alkaline with aqueous ammonia. The liberated base is extracted with benzene. The extract was dried over anhydrous potassium carbonate and evaporated under reduced pressure. 6.7 g (78%) of the desired base of 6-methyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine (I, R ' CH3) are obtained, which crystallizes on standing. It recrystallizes from hexane and then melts at 83-85 ° C. Neutralizing methanesulfonic acid in ethanol and addition of ether afforded the dimethanesulfonate, which crystallizes from ethanol and melts in the pure state at 195-197 ° C.

Example 2

6-Ethyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine (I, R = C ^H ^)

34.2 g of 2-ethylthiophenol are dissolved in a stirred solution of 47.5 g of potassium hydroxide in 500 ml of water at 50 DEG C., 64.7 g of (2-iodophenyl) acetic acid and 2.5 g of copper are added and the mixture is boiled. 14 h under reflux. Work up similarly as described in the analogous step in Example 1 to give 65.5 g of an oily product which slowly crystallized from a mixture of benzene and petroleum ether. Filtration gave 44.8 g (67%) of the acid / 2- (2-ethylphenylthio). ) phenyl / acetic acid, melting in the pure state at 56 ° C. A mixture of 13.2 g of the preceding acid and 68 g of polyphosphoric acid is stirred and heated at 100 to 120 ° C (bath temperature) for 5 hours. After cooling, it is quenched with 250 ml of ice-water and the product is extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated under reduced pressure. The crude product obtained was crystallized from 20 ml of ethanol. 9.4 g (76%) of 6-ethyldibenzo (b, f) thiepin-10 (11H) -one, m.p. Mp 76-78 ° C.

A solution of 27.2 g of the preceding ketone is 110 ml of benzene and 220 ml of ethanol is reduced with 2.5 g of sodium borohydride in 20 ml of water containing 0.5 ml of 10% sodium hydroxide solution in a similar manner as described in the corresponding step of the example. 1. Yield: 21.8 g (80%) of 6-ethyl-10,11-dihydrodibenzo (b, f) thiepine-10-ol, which crystallizes from ethanol and melts at 108-110 ° C.

A solution of 18.2 g of the preceding alcohol in 200 ml of benzene was saturated with hydrogen chloride at room temperature in the presence of anhydrous calcium chloride, similarly as described in the appropriate step in Example 1. Similar treatment with sb gave 17.1 g (88%) of 6-ethyl -10-chloro-10,11-dihydrodibenzo (b, f) thiepine, which crystallizes from acetone and melts at 93-95 ° C.

The substitution reaction of 11.0 g of the preceding chloro derivative with 12 g of 1-methylpiperazine in 15 ml of boiling chloroform was carried out similarly as described in Example 1. A similar treatment yielded 10.5 g (78%) of an oily homogeneous base of 6-ethyl- 10- (4-methylpiperazino) -10,11'-dihydrodibenzo (b, f) thiepine (I, R = which is converted to dimethanesulfonate by neutralization with methanesulfonic acid in ethanol. This salt crystallizes from a 95% ethanol / ether mixture as a hemihydrate melting at 175 mp 178 ° C.

Claims (1)

6-Alkyl-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepines of formula I, (I) wherein R is methyl or ethyl, and their methanesulfonates. Printed by Moravian Printing Works,