CS235172B1 - Amino alcohol dibenzo (b, e) thiepine series and its hydrochloride - Google Patents

Abstract

The invention relates to an aminoalcohol of the dibenzo-(b,e)thiepine series of formula I, (I) i.e. 2-chloro-ll-[1-(2-hydroxyethyl)-4-piperidylidene]-6,11-dihydrodibenzo(b,e)thiepine, and its hydrochloride. The substance of formula I and its hydrochloride have properties of tranquilizers and antitussives, which is a prerequisite for their practical use in the therapy of some nervous and mental diseases and further in the therapy of cough. The pharmacodynamic and toxicological properties of the hydrochloride of the substance of formula I can be verified in animal experiments. The substance was tested in the form of hydrochloride during oral administration, the doses given being converted to a base. Acute toxicity in mice, LD50 = 413 mg/kg; toxic doses cause tremor and repeated convulsive attacks. At doses of 10 to 25 mg/kg, the substance potentiates the effect of thiopental in mice (extending sleep duration to 200% compared to control). At a dose of 50 mg/kg, it exhibits an antiamphetamine effect in mice (protecting 100% of animals from the lethal effect of a standard dose of amphetamine). Tests have shown that the substance is not a neuroleptic: at a dose of 50 mg/kg, it does not act cataleptically in rats, does not affect apomorphine stereotypies in rats, and does not affect probenecid-induced increases in homovanillic acid levels in the striatum of the rat brain. It also does not have the properties of a potential antidepressant, since at a dose of 25 mg/kg, it does not affect reserpine-induced ptosis in mice. On the other hand, at a dose of 100 mg/kg, it has an antitussive effect in guinea pigs in a test that uses citric acid aerosol to induce cough; this 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). In the first step, this compound is subjected to a reaction with ethyl chloroformate in boiling benzene, whereby N-demethylation is achieved and the carbamate of formula III results, i.e. a neutral compound. The crude product is purified by chromatography on alumina and the desired carbamate is obtained in high yield. In the second step, the carbamate of formula III is hydrolyzed by boiling with an ethanolic solution of potassium hydroxide and a crystalline secondary amine of formula IV is obtained. In the last step, compound IV is alkylated with 2-bromoethanol in boiling acetone in the presence of potassium carbonate. The oily base of formula I obtained is converted by neutralization with hydrogen chloride or hydrochloric acid to give the crystalline hydrochloride, which is also the subject of the invention. The final product of formula I, as well as the intermediates of formulas III and IV, are new substances, the identity of which has been ensured by analyses and spectra. Details of the method of preparation of the substance of formula I just described are given in the following example, the purpose of which is to illustrate the possibilities of the invention, but in no way describes all these possibilities in an exhaustive manner. To a stirred solution of 2.5 kg of ethyl chloroformate in 6 ml of benzene at 70 “C is added dropwise a warm solution of 5.6 g of 2-chloro-114 - (1-methyl-4-piperidylidene j -6,11-dihydrodibenzo[b,e jthiepine (II) (literature cited] in 12 ml of benzene and the mixture is boiled under reflux for 2.5 hours. It is then cooled, decomposed with water and extracted with chloroform. The extract is washed with dilute hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue is chromatographed on a column of 200 g of neutral alumina (activity II). Elution with chloroform yields 5.7 g (87%) of 2-chloro-11- -(1-ethoxycarbonyl-4-piperidylidene)-6,11- which crystallizes from cyclohexane and melts at 125 to 126 °C. A mixture of 25.0 g of carbamate III, 30 g of potassium hydroxide and 100 ml of ethanol is stirred and heated for 1 hour under reflux in a bath heated to 140 °C. Since the mixture solidifies, it is necessary to interrupt the stirring after 30 minutes. After the reaction is complete, the mixture is dissolved in 1 l of water and, after cooling, the separated solid product is filtered off with suction, washed with water and dried in vacuo. An almost pure product is obtained in a yield of 19.0 g (93 %/o). 2-chloro-11-(4-piperidylidene)-6,11-dihydrodibenzo(b,e)thiepine (IV) melting at 175 to 180 °C. Crystallization from a mixture of benzene and cyclohexane gives a completely pure substance with a m.p. of 180 to 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 of acetone is stirred and refluxed for 5 hours. After cooling, the precipitated salts are filtered off, washed with acetone and the filtrate is evaporated. The residue is dissolved in ether, the undissolved small amount is filtered off again and a slight excess of hydrogen chloride is added to the filtrate in the form of a solution in ether. The precipitated hydrochloride 2-chloro-11-[1- (2-hydroxyethyl)-4-piperidylidene]-6,11-dihydrodibenzo[b,e jthiepine (I) was isolated by filtration, washed with ether and dried. It was obtained in a yield of 11.7 g (76%). A single crystallization from aqueous methanol gave a pure substance 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).