CS262100B1 - 1-substituted 2-//4-methyl-1-piperazinyl/acetyl/-2,3,4,9-tetrahydro-1h-pyrido/3,4-b/indoles and hydrochlorides them - Google Patents

Abstract

The solution lies in the field of synthetic drugs. Its subject matter is 1-substituted (methyl or phenyl) 2 - [(4-methyl-1-piperazinyl) - acetyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] -, indoles and their hydrochlorides. These substances do they have anti-ulcer activity in oral form administration and at low acute toxicity. Efficiency has been shown in a model of ulcer disease, lesions in the rat stomach wall indomethacin. Substances by solutions can be prepared by substitution reactions similarly 1-substituted 2- (chloroacetyl] -2,3,4,9-tetrahydro-1H-pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido [2,3-d] pyrido] [3,4-b] - of indoles with 1-methylpiperazine. Products are of a basic nature and provide salts of which the Suitable hydrochlorides are included in articles solution.

Description

The invention relates to 1-substituted 2 - ((4-methyl-1-piperazinyl) ethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indoles of formula I

NCOCH ₂ n5 ~ N ^cH 3

H R (I) wherein

R is methyl or phenyl, and their hydrochlorides.

The compounds according to the invention are distinguished by anti-ulcer activity when administered orally and with low acute toxicity. Thus, they are useful in the treatment of ulcer (gastric and duodenal ulcers), and a typical compound of the invention is 1-phenyl-2 - [(4-methyl-1-piperazinyl) acetyl] -2,3,4,9-tetrahydro-1H -pyrido [3,4-b] indole of formula I, R = CeHs, which has been pharmacologically evaluated in the form of dihydrochloride, its acute oral toxicity in mice by oral administration, LD 50 is 906 mg / kg. indomethacin-induced gastric lesions in rats The present invention very effectively inhibits the development of these lesions, with a median effective dose of the ED 50 of 26.3 mg / kg after the known and highly valued anti-ulcer drug pyrenzepine (Kitagawa H. et al .: Arzneim (Forsch. 28, 2122, 1978) in the same assay, the mean effective dose of the ED 50 is 32.7 mlligrams / kg after the substance of the invention exceeds pyrenzepine by its anti-ulcer activity. according to the invention, almost free of anticholinergic activity, which makes it possible to reduce the side effects resulting from this activity. To test this effect, a mydriatic activity test in mice was used primarily. At 100 mg / kg po the substance is ineffective in this test; pyrenzepine, on the other hand, exhibits a significant mydriatic effect at oral doses of 10 and 100 mg / kg, and this effect is dose-dependent. Another criterion of anticholinergic activity is the evaluation of the affinity of substances for muscarinic receptors in rat brain using 0.5 nM ( ³ H) chlorludinyl benzilate as a radioactive ligand. The compound of the invention has only a weak affinity for muscarinic receptors; its mean inhibitory concentration IC 50 is 22 062 nM. For pyrenzepine, this value is 275.5 n'M, so this anti-ulcer is a relatively potent antlcholinergic.

Compounds of formula I are accessible by substitution reactions of 1-substituted 2- (chloroacetyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indoles of formula II

in which

R denotes the same as in formula I, with 1 methylpiperazine.

These reactions can be carried out under different conditions, in different reaction media and in the presence of different basic condensing agents. In the examples, these reactions are described in chloroform in the presence of triethylamine at room temperature. The starting chloroacetyl compounds are either known and then cited in the description of their preparation, or they are new and their preparation is described in the example. The products of said substitution reactions are compounds of formula (I) which are basic in nature and afford the corresponding salts by acid neutralization. The present invention provides well-crystallizing and well-soluble hydrochlorides which can be used both for testing and for the manufacture of dosage forms.

The examples below give further details of the preparation of the compounds of formula (I), but are to be considered merely as illustrative of the possibilities of the invention. The compounds of the invention are novel and their identity has been assured by analytical and spectral methods.

Example 1 1-Methyl-2 - [(4-methyl-1-piperazinyl) ethyl] -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (I, R = CH 3)

A mixture of 1.0 g of 2- (chloroacetyl) -1-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole [Abdusalamov B., Sadykov A. S .: Uzbek. Chlm. Žurn. 8, (1), 48, 1964; Chem. Abstr. 61, 696, 1964] and 7.0 ml of 1-methylpiperazine were stirred at room temperature for 4 hours, diluted with benzene, washed with water, dilute aqueous ammonia and water again, dried and evaporated. The residue was 0.7 g (56%) of the desired material which crystallized from a mixture of chloroform and ether and melted at 203-205 ° C. Example 2

1-Phenyl-2 - [(4-methyl-1-piperazinyl) acetyl] -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (I, R = C 6 H 5)

A mixture of 4,7 gl-phenyl-2- (chloroacetyl) -2,3,4,9-tetrahydro-1H-pyrldo [3,4-b] indole and 20 ml of 1-methylpiperazine was stirred at room temperature for 2 hours, diluted with benzene, the solution is washed with dilute aqueous ammonia and water, dried and evaporated. The residue was crystallized from a mixture of ethanol and ether. The desired product is obtained in a yield of 4.3 g (72%) as a 2: 1 solvate with ethanol, m.p. 148-151.5 ° C. Neutralization with hydrogen chloride gives the dihydrochloride, which crystallizes from a mixture of ethanol and ether as a 1: 1 solvate with ethanol, m.p. 198-202 ° C.

The starting 1-phenyl-2- (chloroacetyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole has not yet been described in the literature and can be obtained from the known 1-phenyl- 2,3,4,9-tetrahydro-1H-pyrido [3,46

-b] indole (Skinner W.A., Parkhurst R.M .: Can. J. Chem. 43, 2251, 1965) as follows:

To a cooled solution of 6.5 g of 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole in 120 ml of chloroform was added 8 ml of triethylamine and added dropwise with stirring at room temperature. 1.0 ml of chloroacetyl chloride. The mixture was stirred for another 2 hours at room temperature, diluted with chloroform, washed with water, 2% hydrochloric acid, again with water and finally with 10% potassium carbonate solution, dried and evaporated. On standing, 4.7 g (55%) of the desired compound melting at 244-245 ° C crystallized.

Claims (1)

SUBJECT VYNALEZU 1-substituted 2 - [(4-methyl-1-piperazinyl) acetyl] -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indoles of the general formula I in which, R is methyl or phenyl, and their hydrochlorides. N ‘ H ŇCCHNN NCUn * · \ ^J fl)