CS219077B1 - Derivatives of the 6,11-dihydrodibenzo/b,e/thiepin-11-carbonitrile and the salts thereof - Google Patents

Description

R is dimethylamino- or 4-methylpiperazino-a, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts are spasmolytics and exhibit short-term hypotensive effects. Due to their spasmolytic effect, they are suitable as medicaments for the removal of painful conditions resulting from convulsive contractions of smooth muscle, in particular the gastrointestinal system.

The spasmolytic effect of the compounds according to the invention can be demonstrated in an isolated rat duodenum test, whose contractions are induced both by a constant dose of acetylcholine chloride and by barium chloride. The compounds of the present invention are effective against both types of contractions, i.e. their effect is both parashympatholytic and myotropic.

11- (2-Dimethylaminoethyl) -6,11-dihydrodibenzo (b, e) thiepine-11-carbonitrile, which was tested as oxalate, has an intravenous toxicity in mice, LD 50 = 45 mg / kg. At concentrations of 10-1 µg / ml, the isolated duodenum contractions induced by both acetylchloride and barium chloride attenuate n-a 50%. At a dose of 7 mg / / kg it causes a short-term decrease in blood pressure of 20-35% in anesthetized rats.

11- (3-Dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepine-11-carbonitrile was also tested as o-oxalate. Its toxicity in mice, LD50 = 38 mg / kg i.v. The spasmolytic effect is more pronounced with respect to acetylcholine contractions and occurs already at concentrations of 0 - 1 - 1 µg / m -1; with respect to barium chloride contractions, 50% of the contraction loss was achieved with concentrations of 1-10 µg / ml, approximately equivalent to the spasmolytic effect of papaverine. In i.v. dose of 7 mg / kg causes short-term decreases in blood pressure in rats.

11- [3- (4-Methylpiperazino) propyl] -6,11-dihydrodibenzo [b] thipin-11-carbonitrile was tested as hydrogen maleate. Its acute toxicity in mice is 50 mg / kg i.v. (LD 50). The spasmolytic effect on both types of contractions occurs at concentrations of 1-10 µg / ml.

. The compounds of the formula I according to the invention are prepared by the processes described in detail in the examples. The starting material is 6,11-dihydro dibenzo [b, e] thiepline-11-carbonitrile, the preparation of which is described in M. Rajšner et al., Colleet., Czeeh. Chem. Commun., 44, 2536 (1973). This nitrile is converted by treatment with strong bases, preferably sodium hydride or sodium amide, to the corresponding carbanion, which is then alkylated with the aminolyl halides of the formula II,

Hal '(CH 2) _n R (II) wherein

Hal is a chlorine or bromine atom and

R is the same as in formula I. 50% sodium hydroxide can also be used as the strong base, but then it is necessary to work in the presence of a phase transfer catalysis, preferably trisylbenzylammonium chloride. Alkylation can also be carried out with alkylenedihalides, in particular 1,2-dihromethane and 1,3-dibromopropane, and the resulting 11- (haloalkyl) derivatives are then subjected to a substitution reaction with dimethylamine or 1-methylpiperazine without isolation.

The compounds of the invention are basic in nature, which provide neutralization with pharmaceutically non-toxic inorganic or organic acids to provide the appropriate salts, which are more suitable for pharmacological testing and for the preparation of dosage forms than the free bases. Of the salts, acid oxalates and maleatees have proven to be particularly crystalline and slightly water-soluble.

The identity of the substances according to the invention described in the examples was ensured both analytically and by all conventional spectral methods.

Examples

P. 1 and d l.

11- (2-Dimethylamino-ethyl) -6,11-dihydrodibenzo (b, e) thiepine-11-carbonitrile

A mixture of 4.75 g of 6,11-dihydrodibenzo (b, e) thiepine-11-carbonltril (literature cited), 14.8 g of 2-dimethylaminoethyl chloride, 0.3 g of triethylbenzylammonium chloride and 20 g of 50% sodium hydroxide solution is stirred for 6 hours. hours at 4) 0 - 50 ° C. It is then diluted with water and extracted with benzene. The extract is washed with water and the Basque product is transferred from it to the aqueous phase by shaking with excess dilute hydrochloric acid. The aqueous hydrochloride solution together with the salted oily hydrochloride were separated, basified with 20% sodium hydroxide solution and the liberated base was again extracted with benzene. The extract was dried over potassium carbonate and evaporated. The crude oil base was obtained in a yield of 3.6 g. Neutralization with oxalic acid in ether gave the hydrogen oxalate, which crystallized from 05% ethanol as the hemihydrate and melted at 172-176 ° C in pure state.

Example 2

11- (2-Dimethylaminoethyl) -6,11-dihydrodibenzo (b, e] thiepin-11 '

-carbon? trii

To a solution of 13.4 g of 6,11-dihydrodibenzo (b, e) thiepine-1: 1-carbonitrile in 60 ml of dimethylformamide was added, under stirring under nitrogen, 1.8 g of 80% sodium hydride. The mixture was stirred for 10 minutes and then 0.8 g of 2-dimethylaminoethyl chloride was added. The mixture was heated to 90 ° C and stirred at this temperature for 15 minutes. The cooling was diluted with water and extracted with benzene. The basic product is converted from the benzene extract into an aqueous base by shaking with excess dilute hydrochloric acid and alkalizing the acidic layer with aqueous ammonia to release the purified base. It is isolated by extraction with benzene and the benzene is evaporated. Chromatographic homogeneous oily base is obtained in a yield of 13.9 g and yields hydrogen oxalate melting at 172-176 ° C, identical to the product 2 of Example 1.

Example 3

11- (3-Dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepine-11-carbonitrile

Mixture of 20 g of 50% sodium hydroxide solution, 0,4 g of triethylbenzylammonium chloride,

4.75 g of 6,11-dihydrodibenzo (b, e) thiepine-11-carbonitrile and 15.0 g of 3-dimethylaminopropyl chloride were stirred at 40-50 ° C for 8 hours. After dilution with water, it is extracted with benzene and from the benzene phase the basic product is transferred to the aqueous phase by shaking with excess 3 mM HCl. The acidic aqueous solution was made alkaline with 10% sodium hydroxide and the purified base was isolated by extraction with benzene. The extract was dried over potassium carbonate and evaporated. The oily base was obtained in yield

2.76 g. Neutralization with oxalic acid in a mixture of ether and acetone affords the hydrogen oxalate which crystallizes from ethanol and melts in the pure state at 161-183 ° C.

Example 4

11- (3-Dimethylaminopropyl) -6,11-dihydrodibenzoi (b, e) thiepline-11-carbonitrile

A solution of 4.75 g of 6,11-dihydrodibenzo (b, e) thiepine-11-carboitrile in 25 ml of benzene is added dropwise to a suspension of 1.15 g of 70% sodium amide in 10 ml of benzene, while stirring at 5 [deg.] C. was stirred at 90 ° C for 2 hours. It is then recooled to 5 ° C and a solution of 3.65 g is added dropwise with stirring over 5 minutes

Of 3-dimethylaminopropyl chloride in 20 ml of ether. The mixture was then heated at 50 ° C for 5 hours. After cooling, it is quenched with 10 ml of water and extracted with benzene. The benzene crude extract is further processed in a similar manner as described in the previous example. The homogeneous oily base was obtained in a yield of 3.52 g (55 percent). It yields hydrogen oxalate melting at 161-163 ° C (ethanol-ether), identical to the product obtained in the previous example.

Example 5

11- [3- (4-Methylpiperazino) propyl] -6,11-dlhydrodibenzo (b, e) thiepine-11-carbonitrile

To a solution of 4.75 g of 6,1,1-dihydrodibenzo (b, e) thtepine-11-carbonitrile in 20 ml of dimethylformamide was added 0.65 g of an 80% oily sodium hydride slurry under nitrogen atmosphere and the mixture was stirred for 10 minutes. Then

B 7.5 g of 1,3-dibromopropane are added and the mixture is stirred without heating for 30 minutes. It is then diluted with water and extracted with benzene. The benzene solution was washed with dilute hydrochloric acid and water, dried (MgSO4) and evaporated. To the residue was added 10 mL of 1-methylpiperazino and the mixture was heated under reflux in a 140 ° C bath for 7 hours. After cooling, it is diluted with water and extracted with benzene. The extract was washed with water and then shaken with excess dilute hydrochloric acid. The product was then transferred to the aqueous phase and the separated hydrochloride solution was made alkaline with 20% sodium hydroxide. The base was again isolated by extraction with benzene, dried over potassium carbonate and evaporated. 5.2 g of an oily base are obtained, which is neutralized with maleic acid in a mixture of ether and acetone. 7.6 g of pure bis (hydrogen maleate) are obtained, which crystallizes from ethanol and melts at 170-172 ^q C.

Claims (1)

SUBJECT 6,11-Dihydrodibenzo (b, E-thiepine-11-carbonitrile derivatives of formula I, II) YnALEZU in which n denotes 2 or 3 a R is dimethylamino- or 4-methylpiperazino, and salts thereof with pharmaceutically acceptable inorganic or organic acids.