CS262163B1 - Aminoacyl-and aminoalkyl-derivatives of 6,11-dihydrodibenzo-/b,e/thiepin-11-amine and homolege and salts thereof - Google Patents

Abstract

The solution lies in the field of synthetic drugs The subject of the invention is aminoacyl and aminoalkyl derivatives 6,11-dihydrodibenzo / b, e / - thiepine-11-umin, homologous (6,11-dihydrodibenzo / b, e-thiepin-11-yl) methylamine a. Inorganic or organic salts thereof; pharmaceutically acceptable acids. As aminoacyls, dimethylaminoacetyl is used, 2 -> (4-morpholinyl) acetyl, 2- (4- methyl-1-piperazinyl) acetyl and 2- (4- (2-hydroxyethyl) -1-piperazinyl) acetyl and as aminoalkyls, e.g., 2-aminoethyl and 2-dimethylaminoethyl. Preferred salts are the hydrochlorides and maleates. In the form of these salts exhibit substances according to a locally anesthetic solution antiarrhythmic, spasmolytic, anticonvulsant, tranquilizing, a-ntidepressive, antihist, amine, anticholinergic, and antiulcer efficiency. They are therefore potential drugs in the respective indications. Synthetic they are accessible by substitution reactions on the one hand the corresponding chloroacetamides with amines, both 11-chloro-ej-dihydrodiibenz-o / b.e / - thiepine with ethylenediamine and asymmetrically Ν, Ν-disubstituted derivatives.

Description

The present invention relates to aminoacyl and aminoalkyl derivatives of 6,11-dihydrodibenzo [b, e] thiepine-11-amine and its homologue of general formula.

(0 in which X represents dv, and hydrogen or oxygen, R is amino, dimethylaminosulfonyl, 4-morpholinyl, 4-methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl) and n is 0 or 1, as well as their salts with inorganic or organic acids which are pharmaceutically acceptable The compounds of formula I according to the invention and their salts exhibit a variety of therapeutically useful neurotrophic and cardiovascular pharmacodynamic activities which these are potentially useful drugs in their respective indications, such as, in particular, indacellular anesthetics, antiarrhythmic drugs, spasmolytics, antiepileptics, tranquilizers, antidepressants, antihistamines, anticholinergics, and antiulcer drugs, which are useful in areas of minor surgical intervention where local sensitization is required. irregular heart rhythm, in the removal of painful spastic smooth muscle ga of the intestinal intestinal and urogenital system, in the seizure of central origin, ie, in particular, epileptic seizures, in the field of restless and agitated neurologic patients, in the treatment of mental depression, in the symptomatic treatment of allergic diseases, and finally in the treatment of ulcer disease.

More specifically, the properties of the individual compounds of the invention, which have been found by pharmacological testing in experimental animals or isolated organs in vitro. N- (6,11-dihydrodibenzo / b, e / thiepin-11-yl J-dimethylaminoacetamide (I, X = O, R = 'N / CH3 / 2, n = OJ was tested as its hydrochloride. in mice at IV administration, LD50 = 40 mg / kg, at concentrations of 0.1 to 0.5%, exhibit locally anesthetic activity on the cornea of the rabbit eye (corneal anesthesia test) somewhat higher than that of the known trimekaine preparation. µg / ml has spasmolytic activity on isolated rat duodenum, both acetylcholine and barium chloride contractions, N- (6,11-dihydrofibenzo [b, e] thiepin-11-yl) -2- (4-morpholinyl Jacetamil (I, X = O, R = 4-morpholinyl, n = Oj was also tested in the hydrochloride form. Its acute toxicity in mice when administered iv, LD50-40 'mig / kg. Similar to previous the substance acts spasolytically at concentrations of 1 to 10 gg / ml in the contraction of isolated rat duodenum, induced by both acetylcholine and barium chloride. with doses of 10 to 40 mg / kg exhibited anticonvulsant activity in mice, with respect to pentetrazole. N- (6,11-dihydrodibenzo / b, ehiepin-11-yl) -2- (4- (2-hydroxyethyl) -1-piperazinyl) acetamide (I, X = O, R = 4- (2-hydroxyethyl) -1-piperazinyl, n = 0) was tested as bishydrogen maleate, its acute toxicity in mice at iv administration, LD50-100 mg11a kilogram. locally anesthetic effect of infiltration anesthesia in guinea pigs has been demonstrated in rats at 10 to 20 mg / kg iv, and its doses have been significantly prolonged by latentiventricular extrasystoles induced by aconitine (intensity similar to that of quinidine or In an assay using refractory elongation extension of electrically irritated rabbit atria, the efficacy of the substance was 2.3.10 ~ 8 mol / ml N- (6,11-dihydrodibenzo / b, e-thiepin-11-yl-methyl) -2- (4-methyl-1-piperazinyl J acetamide (I, X = O, R = 4-methyl-1-piperazinyl, n = 1J tested as roonohydrate hydrochloride Acute toxicity in mice by oral administration, LD50 - 152 mg / kg. Substance inhibits very effectively the formation of gastric lesions (ulcers) in rats that are experimentally induced by indomethacin, the median effective dose of ED 50 = 21.4 mg / kg after the drug in this test being more effective than the known anti-ulcer preparation of pyrenzepines whose ED 50 is 32.7 mg / kg po Unlike this, the compound of the present invention is poorly anticholinergic, which was a test of mydriatic effect in mice: a dose of 100 mg / kg po was effective in 90% of animals but 50 mg / kg after only 10% of animals, while Pyrenzepine is an anticholinergic highly effective (10 mg / kg po is effective in 100% of the animals), which is probably the cause of some side effects., N- (6,11-dihydrodibenzo) [b, e] thiopicin-11-yl] -2S 2163 ethylenediamine (I, X = H 2, R = NH 2, n = - = 0) was tested as bisphosphate maleate) Oral acute toxicity in mice, LD 50 approximately 1 200 mg / kg, 200 mg oral dose / kg shows significant anti-reserptive effects in mice, both in the eyelid testuptose and in the reserpine-induced hypotbermia test. At the same dose, it increases the spontaneous locomotor activity of the mouse, resulting in a mild stimulatory effect. N- (6,11-dihydrodibenzo / b, e / thiepin-11-yl) - N ', N -dimethylethylenediamine (I, X = H, R - N / CH 3/2, n - = 0) was tested in dihydrochloride hemihydrate. Acute toxicity in mice when administered orally, LD50 = 238 mg / kg. At an oral dose of 10 mg / kg, it significantly inhibits reserpine-induced hypothermia in mice. In two tests, it demonstrated antilnamine activity. In the so-called de-toxification test in guinea pigs, the dose is 2 mg / kg to 10% and the dose of 10 mg / kg ρ.ο.90 ° / o to the animals before the lethal action of the standard dose of bislamine administered intra-jugularly. In the guinea pig histamine aerosol test, an oral dose of 10 mg / kg protects 80% of the animals and a dose of 2 mg / kg of 40% of the animals before histamine bronchospasm. In the rotating rod test in mice, it elicits ataxia in moderate doses, indicating the nature of a mild tranquilizer; ED50 - 43 mg / kg po (maximum effect for 30ruin after administration of j. The substance also has a mild myiatric effect in mice (at doses of 50 to 0 mg / kg po).

Depending on the nature of the substituent X, the compounds of the formula I according to the invention are accessible by two different methods. Aninoacetamides (I, X = O) are accessible by substitution reactions of the corresponding chloroacetamides with amines, i.e. iipipine with diethylamine, morColin, 1-methylpiperazin, and 2- (1-piperazinylmethanol). (6,11-Dihydrodihenzo [b] thiepin-11-yl] chloroacetamide known (MS Authorization No. 210 369) Homogeneous N- (6,11-dihydrodi-benzoic) thicipin-1-ylmethyl] chloroacetamide however, it has not been described in the literature yet because its preparation is given in the example.

The diamines (I, X-Hz) are accessible by alkylation of an asymmetric N, N-disu (substituted e-ethylenediamines, respectively unsubstituted ethylenediamine, known as 11-chloro-6,11-dihydraziben: z / b, e / thiepine (Seidl V. et al., Monatsh. Chem. 518, 650, 15B5).

The possibilities of carrying out these reactions are very varied, and examples only illustrate these varied options. All of the general formula I according to the invention are essential in nature and provide salts by neutralization with acids. Included within the scope of the present invention are those salts of inorganic or organic acids which are pharmaceutically acceptable. The hydrochlorides and maleates mentioned are very preferred in the examples. All of the compounds described herein are novel; their identity was ensured by analytical and spectral methods. Example 1 N- (6,11-dihydrodibenzo / b, e / thiepin-11-yl) -dimethylaminoacetamide

A mixture of 2.0 g of N- (6,11-dihydrodibenzo [b] e-thiepin-11-yl) chloroacetamides, 70 ml of acetone and 1.2 g of potassium iodide is stirred and refluxed for 2 hours. . After cooling to room temperature, 9.6 g of liquid dimethylamine are added with stirring, which is passed through the tube to the bottom of the reaction vessel. The mixture is stirred at 25 to 30 ° C for 6 hours and refluxed for 2 hours. The volatiles were then evaporated under reduced pressure, the residue (3.6 g dissolved in 50 ml of chloroform, washed with water and then shaken with excess 2M-H 2 SO 4. The precipitated solid sulfate was filtered off, added to the aqueous phase of the filtrate, the suspension was stirred). alkaline with aqueous ammonia, and the mixture is extracted with chloroform.

Treatment of the extract yielded 2.07 g (theoretical yield) of the desired base which crystallized from benzene / petroleum ether and melted at 140-141 ° C. Neutralization with dilute hydrochloric acid gives the hydrochloride which crystallizes from water at 170-171 ° C. EXAMPLE 2 N- (6,11-Dihydrodibenzo / b, e-thiepin-11-yl) -2- (4-morpholinyl) acetamide

A mixture of 4.5 g of N- (6,11-dihydrodibenzo / b, N-thiepin-11-yl) chloroacetamide, 30 ml of toluene and 6.5 g of morpholine is stirred and boiled for 2.5 hours with a reflux condenser. The mixture was washed with water and then shaken with an excess of 5M-HCl. The oily hydrochloride was combined with the aqueous phase, basified with aqueous ammonia and the product was isolated by extraction with benzene. The extract was treated with 4.5 g (85%) oily. base which crystallizes from a mixture of benzene and petroleum ether, mp 135-141 ° C. The analytical sample is obtained by further crystallization from the same solvent mixture, mp 137-139 ° C. Neutralization with hydrogen chloride in ethanol and addition of ether gives hydrochloride. m.p. 198 DEG-199 DEG C. (ethanol-ether). EXAMPLE 3 N-tert-dihydrodibenzo [b] thiepin-11-yl) -2- (4- (2-hydroxyethyl) -1- piperazinyl) acetamide

A mixture of 3.03 g of N- (6,11-dihydrodibenzo / b, e-thiepin-11-yl) chloroacetamides, 10 ml of chloroform and 5.3 g of 2- (1-piperazinyl) ethanol

Claims (1)

After cooling, it is diluted with 50 ml of chloroform, washed several times with water and the basic product is extracted into 50 ml of 2M-H2SO4. After warming to 45 ° C, the aqueous solution was separated, basified with aqueous ammonia and extracted with chloroform. Treatment of the extract yielded 3.7 g (93%) of oleate base, which was dissolved in 15 ml of acetone and neutralized with 2.4 g of maleic acid in 5 ml of ethanol to give 5.8 g of crystalline bis. 86 DEG-89 DEG C. (acetone-ethanol-ether) EXAMPLE 4 N- (6,11-Dihydrodibenzo [b, e] thiepin-1'-yl-methyl) -2- (4 -methyl-1-piperazinyl) acetamide A mixture of 14.8 g of N- (6,11-dihydrodibenzo [b], e-thipinpin-11-ylmethyl) chloroacetamide, 30 ml of chloroform and 10.2 g of 1-methylpiperazine is stirred & After cooling, the mixture was diluted with 250 ml of chloroform, washed several times with water, dried over anhydrous potassium carbonate and evaporated to give 16.4 g (92%) of an oily base, which was formed by hydrogenation with ethanol in ethanol. not crystalline dihydrochloride (17.5 g), which crystallizes from aqueous ethanol as a monohydrate melting at 165.5 DEG-170 DEG C. The starting N- (6,11-dihydrofibenzothiazol-2-one) is used. ylmethyl chloroacetate It has not been described in the literature so far: It can be obtained by the following procedure: To a stirred mixture of 11.2 g of (6,11-dihydrodibenzo [b, e] thiepin-11-yl) methylamine (Valenta V. et. al .: Collect. Czech.Chem. Commun. 47, 984 (1982), 6.06 g of N, N-dimethylacetamide and 120 ml of benzene over 30 min. A solution of 7.86 g of chloroacetyl chloride in 30 ml of benzene is added dropwise. The mixture is stirred for 40 min. at 50 ° C, after cooling, the object of the amino-amino and aminoalkyl derivatives of 6,11-dihydrodibenzo [b, e] thiepine-11-amine and its homologue of formula I it is diluted with benzene, the solution is washed with water, dried over anhydrous magnesium sulfate and evaporated. The oil-yellow residue (13.4 g, 91%), which is a crude product, can be used in further work. To characterize it, crystallize it from a mixture of benzene and hexane. It melts at 108 to 111.5 ° C (benzene) in the pure state. Example 5 N- (6,11-dihydrofibenzo [b, e] thiepin-11-yl) ethylenediamine A mixture of 6.15 g of 11-chloro-6,11-dihydrodibenzo- / b, e / thiepine (literature cited), 6 ml of chloroform and 12 g of ethylenediamide are stirred and refluxed for 8 h, diluted with 70 ml of chloroform, washed with water and extracted with 2.5 M HCl (3 x 30 ml). The filtrate was basified with aqueous ammonia and the base was isolated by chloroform extraction to give 5.9 g (87%) of an oily base, neutralizing it with maleic acid in ethanol to give a crystalline bis (hydro-genomale) melting point. Example 6 N- (6,11-dihydrodibenzo [b, e] thiepin-11-yl) -N ', N'-dimethylethylenediamine A mixture of 4.92 g of 11-chloro-6,11- dihydrodibenzo- / b, e / thiepine, 12.5 ml of chloroform and 1.8 g of Ν-dimethylethylenediamine are stirred and refluxed for 14 hours, and a similar treatment as in Example 5 yields a direct reaction. 4.0 g (60%) of a crystalline dihydrochloride which crystallizes from 93% ethanol as the hemihydrate, mp 168.5 to 169.5 T in which X denotes two hydrogen atoms or an oxygen atom, R is aminosuipine, dimethylamino, 4-morpholinyl, 4-methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl, and n is 0 or 1, and salts thereof with inorganic or organic acids which are pharmaceutically acceptable. Severoierafja, n. P. Plant 7, Most Price 2,40 Kffs 0)