CS225570B1 - Preparation of steroisomeric 11-/3-dimetylaminepropyl/-10,11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts - Google Patents

Description

CN (CMP) in which the configurations on carbons 10 and 11 are cis or trans, and salts thereof with pharmaceutically acceptable inorganic or organic acids, preferably oxalic acid.

The compounds of formula I are on the one hand intermediates in the synthesis of other pharmacodynamically active substances and, on the other hand, have therapeutically useful antireserpine, moderate central depressant and analgesic activity. Thus, cis-11- (3-dimethylaminopropyl) -10,11-dihydrodibenzo (b, f) thlepin-10-carbonitrile, which has been tested in the form of hydrogen oxalate, is characterized by mild toxicity in mice; the mean lethal LD50 oral dose is 460 mg / kg. At an oral dose of 100 mg / kg, it has a significant antireserpine effect in the gastric ulcer inhibition test in rats. At an oral dose of 250 mg / kg it has a significant antireserpine effect in the ptosis test in mice. The discoordination effect on the rotating rod in mice by oral administration is expressed by the mean effective dose ED50 = 47.5 mg / kg, after which ataxia occurs in 50% of the animals. Analgesic effect in mice in the Haffner oral test, PD ₅₀ = 62 mg / kg.

The process for the preparation of the compounds of the formula I according to the invention consists in reacting the dibenzo (b, f) thiepine-10-carbonitrile of the formula II with 3-dimethoxy-

thylaminopropylmagnesium chloride in tetrahydrofuran and subsequent hydrolysis of the primarily formed 1,4-adduct. In this way a mixture of the cis and trans isomers of compound I is obtained which is separated by chromatography on alumina and then by crystallization of the oxalate. The predominant part of the product is in the cis configuration as demonstrated by the ¹ H NMR spectrum of the free base. The trans-isomer is obtained as a minor product in approximately 5% yield by treating the mother liquors.

Both stereoisomers of Compound (I) are novel, cis- and trans-base are oily, and the oxalate is crystalline, characterized by melting points. Also, the starting nitrile of formula II is a novel material and the process for its preparation is described below.

By reacting 3.1 g of magnesium with 15.5 g of 3-dimethylaminopropyl chloride in 60 ml of tetrahydrofuran (the reaction is started with an iodine bead and a few drops of 1,2-dibromoethane), which is completed by refluxing the mixture for 1 h, a Grignard reagent solution is prepared. . It was added dropwise at room temperature with stirring over 10 min. solution of 15 g of dibenzo (b, f) thiepine-10-carbonitrile II in 60 ml of tetrahydrofuran. The mixture was refluxed for 5 h, then cooled, hydrolyzed by the addition of 90 ml of 10% hydrochloric acid and 100 ml of water, and the resulting aqueous solution was washed with ether. The horse is then made alkaline. aqueous ammonia, the base mixture is extracted with ether, the extract is dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 500 g of neutral alumina (activity II). The benzene and first chloroform eluates were evaporated to give 18.7 g (91%) of an oily base mixture of Formula I. Neutralization with oxalic acid and crystallization of oxalate from a mixture of aqueous ethanol and ether yielded 16.0 g (61%) of cis- base of formula I with mp 184 to 184

186.5 ° C. The completely pure material is obtained by further crystallization from the same solvent mixture and melting at 186-189 ° C. Decomposition of a sample of this oxalate with aqueous ammonia and extraction with ether gave a sample of pure oily cis-base I, whose 1 H NMR spectrum showed the stated configuration.

The mother liquors of the cis-base oxalate are evaporated and the residue is further crystallized from a mixture of ethanol and ether. 1.4 g (5%) of a different hydrogen oxalate melting at 158 DEG-158 DEG C. are obtained

159.5 ° C, which corresponds based on trans-I, as demonstrated by ^X H-NMR spectrum of a sample of pure oily base released from the salt.

The starting dibenzo (b, f) thiepine-10-carbonitrile (II) is a novel substance prepared from the known 10-bromodibenzo (b, f) -thiepine (JO Jílek et al., Collect. Czech. Chem. Commun. 32) (1987, 3186) using the following procedure:

A mixture of 14.8 g of 10-bromodibenzo (b, f) thiepine, 9.0 g of copper (I) cyanide and 75 ml of dimethylformamide is stirred and refluxed for 5 hours. It is then poured into 300 ml of cold conc. aqueous ammonia. The product was extracted with dichloromethane, the extract was washed with 2M-HCl and water, dried over magnesium sulfate and evaporated. The crystalline residue is recrystallized from 25 ml of benzene. Filtration and treatment of the mother liquor afforded 10.0 g (83%) of dibenzo (b, f) thiepine-10-carbonitrile melting at 133-137 ° C, which is sufficiently pure for further processing. and melts at 136-137 ° C.

Claims (1)

SUBJECT A process for the preparation of stereoisomeric 11- (3-dimethylaminopropyl) -10,11-dihydrodibenzo (b, f) thiepine-10-carbonitriles of formula I, CN (CH ₃ \ OF THE INVENTION wherein the configurations on carbons 10 and 11 are cis or trans, and salts thereof with pharmaceutically acceptable inorganic or organic acids, preferably oxalic acid, characterized by reacting dibenzo (b, f) thiepine-10-carbonitrile with 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran, followed by hydrolysis of the primary 1,4-adduct, chromatography of the resulting mixture, neutralization of the resulting mixture with pharmaceutically acceptable inorganic acids, preferably oxalic acid, and separation of stereoisomeric salts by fractional crystallization. T 54 1840-85