CS235172B1 - Aminoalcohol of dibenzo-(b,e)-thiepin series and its hydrochloride - Google Patents

Abstract

The present invention relates to a dibenzo- (b, e) the thiepine series of Formula I, (AND) i.e., 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene ] -6,11-dihydrodibenzo (b, e) thiepine, a its hydrochloride. The compound of formula I and its hydrochloride have the properties of tranquilizers and antitussives, which is a prerequisite for their practical use in therapy of some nervous and psychological and cough therapy. Pharmacodynamic and the toxicological properties of the hydrochloride the compounds of formula I can be verified in experiments on animals. The substance was tested in hydrochloride form when administered orally; said doses are converted to b2 zi. Acute toxicity in mice, LD 50 = 413 mg / kg; toxic doses induce tremor and repeat seizures. In doses of 10 to 25 mg / kg potentiates thiopental effect in mice (prolongs sleep to 200% against control). It shows at 50 mg / kg antiamphetamine effect in mouse (protects) 100% of the animals before the standard lethal effect amphetamine doses). Tests have shown that the substance is not a neuroleptic: at 50 mg / kg does not cataleptically affect rats, does not affect apomorphine stereotypes in rats and does not affect probenecid-induced increases homovanilic acid levels in the striatum rat brain. It also has no potential properties antidepressants because of the dose 25 mg / kg does not affect reserpine-induced ptos in mice. In contrast, at a dose of 100 mg / / kg has an antitussive effect in guinea pigs in the test, which uses an acid aerosol to induce cough citrónové; said dose decreases the number 61% of cough attacks compared to control group. The compound of formula I according to the invention can be prepared three-step synthesis from the known 2- dihydrodibenzo (b, ejthiepine of formula II (F. Gadient et al., Helv. Chim. Acta 45, 1860, 19B2). This substance was in the first step, R = CH3 III, R = COOC 2 H 5 IV, R = H it is reacted with ethyl chloroformate in boiling, benzene, thereby achieving N-demethylation and carbamate result of formula III, i.e., a neutral nature. Crude the product is purified by chromatography on oxide aluminum and the desired carbamate is obtained in high yield. In the second step, the carbamate is added Formula III is hydrolyzed with ethanolic boiling potassium hydroxide solution a to obtain a crystalline secondary amine of the formula IV. In the last step, IV is alkylated With 2-bromoethanol in boiling acetone in the presence of potassium carbonate. Obtained the oily base of formula I is converted by neutralization with hydrogen chloride or acid hydrochloric acid to crystalline hydrochloride, which is also the subject of the invention. The final product of Formula I as well as the intermediates formulas III and IV are new, whose identity was ensured through analysis i spekter. Details just described the process for the preparation of the compound of formula I are given in the following example is to illustrate the possibilities of the invention, but in in no way does it describe all of these options exhaustively To a stirred solution of 2.5 kg chloroformate of ethyl acetate in 6 ml of benzene at room temperature 70 ° C, a warm solution of 5.6 g of 2-chloro-14 is added dropwise - (1-methyl-4-piperidylidene-6,11-dihydrodibenzo (b, e thiepine (II) (literature cited) in 12 ml of benzene and boil 2.5 hours under reflux. Then take it cooled, quenched with water and extracted chloroform. The extract is washed with dilute hydrochloric acid and water, dried with magnesium sulfate and evaporated. The rest is chromatographed on a 200 g column of neutral · alumina (activity II). Elution with chloroform 5.7 g (87%) of 2-chloro-11- are obtained. - (1-ethoxycarbonyl-4-piperidylidene) -6,11- crystallizes from cyclohexane and melts at 125 ° C 126 ° C. A mixture of 25.0 g of carbamate III, 30 g of hydroxide potassium and 100 ml of ethanol are stirred and stirred under reflux for 1 hour in a bath heated to 140 ° C. Because the mixture solidifies, it is necessary to interrupt the mixing after 30 minutes. After completion of the reaction, the mixture was dissolved in 1 L water and solids are excluded after cooling • suctioning off, washing the product with water and drying it in vacuum. A yield of 19.0 g (93%) is obtained almost pure 2-chloro-11- (4-piperidylidene- -6,11-dihydrodibenzo (b, e) thiepine (IV) melting at 175-180 ° C. Crystallization from benzene and cyclohexane gave a completely pure substance mp 180-182 ° C. A mixture of 12.1 g of amine IV, 6.75 g of 2-bromoethanol, 6.75 g of potassium carbonate and 140 ml The acetone was stirred and refluxed for 5 hours cooler. It was excluded after cooling the salts are filtered off, washed with acetone and the filtrate is filtered evaporates. The residue was dissolved in ether, undissolved a small amount is filtered off again and a slight excess of hydrogen chloride is added to the filtrate as a solution in ether. Excluded 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzoic acid hydrochloride (b, e Jthiepine (I) is isolated by filtration, washed with ether and dried. It is obtained in yield 11.7 g (76%). The only crystallization pure methanol is obtained from aqueous methanol melting at 265-267 ° C.

Description

The present invention relates to the dibenzo (b, e) thiepine series amimoalcohol,

(I) i.e. 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzo (b, e) thiepine, and its hydrochloride.

The compound of formula I and its hydrochloride have the properties of tranquilizers and antitussives, which is a prerequisite for their practical use in the treatment of certain nervous and mental disorders and also in the treatment of cough. The pharmacodynamic and toxicological properties of the hydrochloride of the compound of formula I can be verified in animal experiments. The compound was tested in the form of the hydrochloride when administered orally, the dosages being recalculated to base 2. Acute toxicity in mice, LD 50 = 413 mg / kg; toxic doses induce tremor and repeated seizures. At doses of 10 to 25 mg / kg, the compound potentiates the effect of thiopental in mice (extending sleep duration to 200% over control). At a dose of 50 mg / kg, it shows an antiamphetamine effect in the mouse (protecting 100% of the animals from the lethal effect of the standard amphetamine dose). Tests have shown that the substance is not a neuroleptic: at 50 mg / kg it does not act cataleptically in rats, does not affect apomorphine stereotypes in rats, and does not affect probenecid-induced increase in homovanilic acid levels in rat brain striatum. It also has no potential antidepressant properties as it does not affect reserpine-induced ptosis in mice at 25 mg / kg. In contrast, at a dose of 100 mg / kg, it has an antitussive effect in guinea pigs in a test that uses citric acid aerosol to cause a cough; said dose reduces the number of coughing attacks by 61% compared to the control group.

The compound of formula I according to the invention can be prepared by a three-step synthesis from the known 2-dihydrodibenzo (b, ejthiepine of formula II (F. Gadient et al., Helv. Chim. Acta 45, 1860, 19B2).

II, R = CH 3

III, R = COOC 2 H 5

IV, R = H is reacted with ethyl chloroformate in boiling benzene to give N-demethylation and the carbamate of formula III, i.e. a neutral substance, is obtained. The crude product is purified by alumina chromatography and the desired carbamate is obtained in high yield. In a second step, the carbamate of formula III is hydrolyzed by boiling with an ethanolic potassium hydroxide solution to give a crystalline secondary amine of formula IV. In the final step, compound IV is alkylated with 2-bromoethanol in boiling acetone in the presence of potassium carbonate. The resulting oily base of formula (I) is converted into a crystalline hydrochloride salt by neutralization with hydrochloric acid or hydrochloric acid.

The end product of formula I as well as the intermediates of formulas III and IV are novel substances whose identity has been assured by both analysis and spectra. The details of the method of preparation of the compound of formula I just described are given in the following example, which is intended to illustrate the possibilities of the invention, but in no way discloses all of these possibilities in an exhaustive manner,

A warm solution of 5.6 g of 2-chloro-11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo (b, e) is added dropwise at 70 ° C to a stirred solution of 2.5 kg of ethyl chloroformate in 6 ml of benzene. The reaction mixture was cooled, quenched with water and extracted with chloroform. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is chromatographed on a column of 200 g of neutral alumina (activity II), eluting with chloroform to give 5.7 g (87%) of 2-chloro-11- (1-ethoxycarbonyl-4-piperidylidene) -6,11 crystallized from cyclohexane and melts at 125-126 ° C.

A mixture of 25.0 g of carbamate III, 30 g of potassium hydroxide and 100 ml of ethanol is stirred and refluxed for 1 hour in a bath heated to 140 ° C. As the mixture solidifies, stirring should be stopped for 30 minutes. After completion of the reaction, the mixture was dissolved in 1 L of water and, after cooling, the precipitated solid product was filtered off with suction, washed with water and dried in vacuo. In a yield of 19.0 g (93%), almost pure 2-chloro-11- (4-piperidylidene) -6,11-dihydrodibenzo (b, e) thiepine (IV) melting at 175-180 ° C was obtained. from a mixture of benzene and cyclohexane a completely pure substance is obtained with mp 180-182 ° C.

A mixture of amine IV (12.1 g), 2-bromoethanol (6.75 g), potassium carbonate (6.75 g) and acetone (140 ml) was stirred and refluxed for 5 hours. After cooling, the precipitated salts are filtered off, washed with acetone and the filtrate is evaporated. The residue was dissolved in ether, the insoluble small amount was filtered again and a slight excess of hydrogen chloride was added to the filtrate as a solution in ether. The precipitated 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzo (b, e-thiepine (I) hydrochloride) was collected by filtration, washed with ether and dried to give a yield of 11. 7 g (76%) A single crystallization from aqueous methanol gave a pure material, melting at 265-267 ° C.

Claims (2)

SUBJECT The amino alcohol dibenzo (b, e) of the thiepine series of the invention, i. 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,17-dihydrodibenzo (b, ejthiepine, and its hydrochloride).