CS211326B1 - 3,4-dichlor-11-piperazinodibenzol/b,f/zhiepins and the salts thereof - Google Patents

Abstract

The invention relates to novel 3,4-dichloro- -1 1-piperazinodibenzo (b, f) thiepine. Includes as 10,11-double bond, ie. enamines, 10,11-dihydro derivatives. Like The N-subtituent in the piperazine residue applies methyl or 2-hydroxyethyl. Invention it also includes pharmaceutically safe salts. The compounds of the invention are both neuroleptics with low central damping efficiency on the one hand, very low tranquilizers cateleptic efficiency; are applicable in the treatment of schizophrenic psychos and neuros. They are prepared by substitution reactions 3,4-11-trichloro-10,11-dihydrodibenzo (b, f) - thiepine with 1-methylpiperazine or 1 - 2 - -hydroxyethylpiperazine, and by reaction 7,8-dichlorodibenzo (b, f) thiepine-10 (11H) - -one with said piperazin derivatives and titanium tetrachloride in boiling benzene.

Description

The present invention relates to novel 3,4-dichloro-11-piperazinodibenzo (b, f) thiepines of formula (I),

Cl

(I) wherein they are methyl or 2-hydroxyethyl and X and Y are either hydrogen atoms or together are another bond, and their pharmaceutically acceptable salts with inorganic or organic acids.

The compounds of the invention are neuroleptics with moderate central depressant activity, which are useful in the treatment of schizophrenic circuit psychos. If they retain only a centrally buffering component, they are tranquilizers useful in the treatment of neuros. states of restlessness and anxiosity.

Animal pharmacological tests have shown the following properties for each substance:

3,4-Dichloro-1- (4-methylpiperazino) -1,10,11-dihydrodibenzo (b, f) thiepine was tested as the maleate. Acute oral toxicity in mice, LD ^ q = 260 mg / kg. In the rotating rod test in mice, the substance induces a movement coordination disorder that leads to ataxia, the mean effective dose of ED ≥ g = 2.0 mg / kg i.v. In the rat catalepsy test, the mean effective dose is greater than 50 mg / kg at oral administration (this dose induces catalepsy in 30% of the animals). Thus, the substance is a tranquilizer with poor cataleptic activity.

3,4-Dichloro-11- (4- (2-hydroxyethyl) piperazino) -10,11-dihydrodibenzo (b, f) thiepine was also tested as the maleate. Its actual toxicity is LD 50 q = 50 mg / kg i.v. In the rotating rod test, the median effective dose inducing ED ataxia is ≥ 5.0 mg / kg

i. v. In the rat catalepsy test, the median effective dose is Εϋ ^ θ = 8.7 mg / kg orally. At a subcutaneous dose of 10 mg / kg, the substance significantly attenuates the spontaneous motility of mice in a known environment.

At doses of 5 to 10 mg / kg i.v., thiopental sleep prolongs the mice to twice the control value

At a dose of 10 mg / kg i.v., it exhibits a significant antiamphetamine effect in mice (this dose protects 100% of the mice from the lethal effect of the standard amphetamine dose). The substance also has an antihistamine action: a dose of 5 mg / kg s. C. Protects 50% of guinea pigs from the lethal effect of 5 mg / kg histamine, administered intra -ugularly. It also has a very significant antiarrhythmic effect: a dose of 0.5 mg / kg i. The substance is a neuroleptic with a mild tranquilizing effect.

3,4-Dichloro-11- (4-methylpiperazino) dibenzo (b, f) thiepine was also tested as a maleate. Acute toxicity, LD ^ ₀ = 228 mg / kg orally. Rotating rod, ED? Q = 3.1 mg / kg iv Catalepsia, ED? Q = 12.5 mg / kg orally. The substance is a neuroleptic with mild tranquilization. efficiency

The compounds of the formula I according to the invention can be prepared according to the methods described in detail in the examples. Essentially, there are two possible ways of preparation:

In the first, 3,4,11-trichloro-10,11-dihydrodibenzo (b, f) thiepine of formula II

Cl

Cl

Cl (IX) undergoes a substitution reaction with 1-methylpiperazine or 1- (2-hydroxyethyl) piperazine at temperatures of 60-100 ° C. It is possible either to heat the mixture of the chloride of formula II with the appropriate amine (1.00% excess) or to work in a suitable inert solvent. Boiled chloroform is a proven environment for this reaction. The starting tri-derivative of formula (II) is a novel, not yet described in the literature; its preparation is described in an exemplary embodiment. In this way, compounds of the formula I are obtained, where Χ = Ϊ = Η.

In the second method, the starting material is 6,7-dichlorodibenzo (b, f) thiepin-10 (11H) -one of formula III

Cl

This ketone is reacted with 1-methylpiperazine or 1- (2-hydroxyethyl) piperazine in boiling benzene in the presence of titanium tetrachloride as a means to remove water from the reaction mixture simultaneously with the formation of enamine. This is because the flights of formula I are accessible, where X and Y taken together represent another bond. These compounds of formula (I) are therefore of enamine character. The ketone of formula III is a novel substance not previously described in the literature. The method of its preparation is described in the exemplary embodiment.

The compounds of the formula I according to the invention are basic in nature; by neutralization with pharmaceutically acceptable inorganic or organic acids, they can be converted to crystalline salts, which are part of the present invention and which are more advantageous than bases for performing pharmacological tests and for preparing dosage forms.

The identity of all compounds described in the invention was assured by analyzes and spectra (UF, IR, 1 H-nmr).

Examples

1. 3,4-Dichloro-11- (4-methylpiperazino) -1,11-dihydrodibenzo (b, f) thiepine

A mixture of 10.0 g of 3,4,11-trichloro-10,11-dihydrodibenzo (b, f) thiepine, 1.2 g of 1-methylpiperazine and 15 ml of chloroform is refluxed for 8 h. The chloroform is evaporated under reduced pressure, the residue is diluted with 170 ml of water and extracted with benzene. The benzene solution is washed with water and then shaken with 75 ml of 3M-HCl. The precipitated solid hydrochloride is filtered off with suction, washed with benzene and quenched with aqueous ammonia. The liberated base is extracted with benzene, the extract is dried and evaporated. 7.3 g (61%) of a base are obtained, which crystallizes slowly from petroleum ether. The analytical sample melted at 126 ° C (90% aqueous ethanol). Neutralization with maleic acid in ethanol gives a crystalline maleate, m.p. 78-179 ° C.

The starting 3,4,11-trichloro-10,11-dihydrodibenzo (b, f) thiepine has not been described in the literature yet. It can be obtained by the following synthesis from known raw materials:

To a solution of 100 g of potassium hydroxide in 1200 ml of water at 55 ° C was added with stirring 98.8 g of 2,3-dichlorothiophenol (C.S., Mahajanshetti et al., J. Karnatek Univ. 6, 9, 1961; Chem., 59, 8636 (1963): Eli Lilly and Co., Fr. 1,481,052). The mixture is stirred for 10 min and then 137 g of 2-iodobenzoic acid (W. Wachter. Ber. Deut. Chem. Ges. 6, 1744 1893) and 5 g of copper catalyst are added; the mixture was then stirred and refluxed for 7 h.

It is filtered while hot and the filtrate is acidified with 100 ml of hydrochloric acid after cooling.

After standing overnight, the precipitated product was collected by filtration, washed with water and dried in vacuo.

165 g (almost theoretical yield) of crude 2- (2,3-dichlorophenylthio) benzoic acid of m.p. 235 DEG-237 DEG C. are obtained. Crystallization from ethanol gave an analytically pure material, m.p. 239-240 ° C.

To a stirred suspension of 22.1 g of lithium aluminum hydride in 300 ml of ether was slowly added dropwise a suspension of 130 g of the preceding acid in 200 ml of tetrahydrofuran and 1900 ml of ether. The mixture is refluxed for 6 h, quenched by slow addition of 500 ml of wet ether, 300 ml of water and finally 900 ml of 1: 3 dilute hydrochloric acid. The organic layer is separated, washed with 900 ml of 10% sodium carbonate with magnesium sulfate and evaporated. On standing, 96.1 g (78%) of 2- (2,3-dichlorophenylthio) benzyl alcohol melting slowly at 54-57 ° C. Crystallization from a mixture of benzene and petroleum ether gave an analytically pure material, m.p. 64 ° C.

A solution of 96 g of the preceding alcohol in 220 ml of benzene is boiled under reflux and 60 g of thionyl chloride are added dropwise over 45 minutes. The mixture was refluxed for a further 30 min and then the volatiles of the reaction mixture were evaporated under reduced pressure. The residue (99.1 g, 97%), which is homogeneous by thin layer chromatography and represents the desired 2- (2,3-dichlorophenylthio) benzyl chloride, was used without further characterization.

A solution of 91 g of the crude chloride just described in 200 ml of dimethylformamide is stirred and 44.5 g of sodium cyanide are added. The mixture was heated at 100-110 ° C for 8 h. The dimethylformamide is evaporated in vacuo, the residue is diluted with 150 ml of water and extracted with benzene. The extract was washed with water, dried with calcium chloride and evaporated. The residue was dissolved in benzene and the solution was filtered through a 1 kg neutral alumina column (Act II). Evaporation of the filtrate gave 78 g (89%) of crystalline (2- / 2,3-dichlorophenylthio / phenyl) acetonitrile, melting at 68-71 ° C. Crystallization from cyclohexane gave an analytically pure sample, m.p. 178 ° C.

To a solution of 70.8 g of the previous nitrile in 375 ml of ethanol was added a solution of 68 g of potassium hydroxide in 300 ml of water, and the mixture was stirred and refluxed for 18 h. The ethanol was evaporated, the residue was diluted with water and the solution was washed with benzene and filtered with charcoal. The filtrate was acidified with 3M-HCl under cooling. The precipitated oily product crystallizes after a short stirring time of the emulsion. After standing overnight, it is filtered, washed with water and dried in vacuo. 60.3 g (80%) of (2- / 2,3-dichlorophenylthio / phenyl) acetic acid, m.p. 137-141 ° C, are obtained. Crystallization from a mixture of benzene and petroleum ether gave an analytically pure material, m.p.

146 ° C.

A mixture of 60.3 g of the previous acid, 400 g of polyphosphoric acid and 180 ml of toluene is heated under reflux (bath temperature 130-135 ° C) for 8 hours under vigorous stirring. After partial cooling, the mixture was quenched with 2.5 L of ice water and extracted with toluene. The organic phase was washed with water, 5% sodium hydroxide solution and again with water, dried over potassium carbonate and evaporated. Upon standing, the residue crystallized to give 56.1 g (99.56) of crude 6,7-dichlorodibenzo (b, f) thiepin-10 (1, H) -one, mp 154-158 ° C. Crystallization from ethanol gave an analytically pure material, mp 160-161 ° C.

A solution of 13.5 g of sodium borohydride in 150 ml of water containing 1 ml of 10% sodium hydroxide solution was slowly added dropwise at 70 ° C to a stirred solution of 35.5 g of the previous ketone in a mixture of 150 ml of benzene and 1000 ml of ethanol. The mixture was refluxed for 4 h, the ethanol was evaporated, the residue was diluted with water and extracted with benzene. The extract was washed with water, dried over sodium sulfate and evaporated. 34 g (95%) of crude 6,7-dichloro-10,11-dihydrodibenzo (b, f) thiepin-10-ol are obtained, m.p. 117-120 ° C. Crystallization from aqueous ethanol gave an analytically pure material, m.p. 127 ° C.

To a solution of 26.5 g of the preceding alcohol in 300 ml of benzene was added 25 g of powdered anhydrous calcium chloride, and the stirred suspension was saturated with anhydrous hydrogen chloride for 30 minutes. After standing for 2 h, the mixture was filtered with carboraffin and the filtrate was evaporated. 27.0 g (96%) of crude 3,4,11-trichloro-10,11-dihydrodibenzo (b, f) thiepine are obtained, m.p. 100-101 ° C. Crystallization from cyclohexane gave an analytically pure product, m.p. 106.5 ° C.

O

2. 3,4-Dichloro-11- (4- (2-hydroxyethyl) piperazino) -10,11-dihydrodibenzo (b, f) thiepine

211326 4

The mixture, 20 g of 3,4,1 1-trichloro-10,11-dihydrodibenzo (b, f) thiepline (described in the previous embodiment), 20 g of 1- (2-hydroxyethyl) piperazine and 40 ml of chloroform are boiled for 8 h. and treated similarly as described in the previous example. 18.8 g (73%) of an oil base is obtained which crystallizes from cyclohexane as a half-molecule solvate of this solvent, m.p. 87-88 ° C. Neutralization with maleic acid gives a crystalline maleate, m.p. 145-146 ° C (acetone).

3. 3,4-Dichloro-11- (4-methylpiperazino) dibenzo (b, f) thiepine

To a stirred solution of 12.4 g of 6,7-dichlorodibenzo (b, f) thiepin-10 (11H) -one (see Example 1) and 2.1 g of 1-methylpiperazine in 100 ml of benzene is added dropwise over 5 min. 4.0 g of titanium tetrachloride in 25 ml of benzene. The mixture was stirred and refluxed for 24 h. It is then cooled and treated dropwise with 125 ml of water. After stirring for 40 min, the precipitated solid was filtered off and washed with benzene. The filtrate was separated, the benzene layer was washed with water, dried over magnesium sulfate and evaporated. The residue crystallized upon mixing with some petroleum ether. 12.0 g (76%) of the crude base are obtained, m.p. 135-139 ° C. Crystallization from ethanol gave an analytically pure material, m.p. 143-144 ° C. Neutralization with maleic acid in ethanol gives crystalline maleate, m.p. 224 ° C (90% aqueous ethanol).

Claims (1)

3,4-Dichloro-11-piperazinodibenzo (b, f) thiepines of formula (I) wherein R is methyl or 2-hydroxyethyl and X and Y are either hydrogen or taken together are another bond, and their pharmaceutically acceptable salts with inorganic or organic acids.