SU552328A1 - 2,3-Cycloalkano-4-amino-6,7-dihydro5n-1-pyridines, exhibiting neutropic activity, and method for their preparation - Google Patents

Description

 The shoulder is on the main absorption band. Example 1. Зг (0,028 mol) of 1-amino-2-cyancyclopentene - 1, 3.4 g (0.03 mol) of cycloheptanone and 30 g of polyphosphoric acid are stirred for 2 hours at a temperature of 130-140 ° C. After cooling, the reaction mass is diluted with 50 ml of water and stirred until a homogeneous mass is obtained, which is extracted with ether three times in 40 ml. The ether extract is discarded. The aqueous layer is alkalized with potash to pH 7. The precipitated precipitate is filtered, washed on the filter with water. The waters from the washing of the precipitate are attached to the reaction water layer and the hem, the cond. aqueous ammonia to pH 9-10. The precipitated 2,3-pentamethylene - 4 - amino - 6,7 - dihydro - 5H - 1 - pyridine (1c) is washed on the filter with water. Yield 1v 2.02 g (36%). Brilliant w, oh crystals from a mixture of methanol and water (1: 1), so pl. 213-214 ° C. Found,%: C 77.16; H 8.90; N 13.86. Ci3Hi8N2. Calculated,%: C 77.18; H 8.97; N 13.85. Example 2. 4g (0.037 mol) of 1 - amino-2 cyancyclopentene - 1.8 3.8 g (0.039 mol) of cyclohexanone, 40 g of polyphosphoric acid and 40 ml of dry benzene are stirred at the boil for 2 hours. After cooling, the reaction mixture is diluted with 50 ml of water and extracted with ether. The ether extract is discarded. The aqueous layer is neutralized with potash to pH 7. The precipitate is filtered off and washed several times on the filter with water. After the separation of the precipitate, the washings are added to the aqueous layer and the mixture is made alkaline with conc. aqueous ammonia to pH 9-10. The precipitate of 9 - amino - 2,3,5,6,7,8 - hexahydro - W - cyclopenta (c) quinoline (16) is filtered off and washed on the filter with water. Yield 16 2.45 g (35.2%). Brilliant crystals from methanol / water (1: 1); T. Il. 202-203 ° C. Found,%: C, 70.69; H 8.76; N 13.34. CiaHieNa-HzO. Calculated,%: C 70.0; H 8.75; N 13.58. Characteristics of the compounds obtained are presented in table. 1. Biological tests were carried out on mice tetrahybrids weighing 18-22 g of both sexes, isolated rat organs. The following were studied: 1) acute toxicity of the substance by single-dose administration to mice; 2) animal behavior (the behavioral responses of mice were assessed by a 4-point system; 3) the effect on the orienting activity (by the number of movements in the locomotive activity recorder; 4) the effect on the body temperature of the animals; 5) the effect on the duration of sleep caused by hexaial (75 mg / kg); 6) the effect on the character, duration of apomorphy (30 mg / kg) stereotypy; 7) effects on spleen and tremor caused by corazole (150 mg / kg), maximum electroshock (50 mA, 0.2 sec), arecoline (25 mg / kg), nicotine (7 mg / kg); 8) determination of the dose of 1% corazol, causing a technical extension phase when administered intravenously to mice (DTE) (Orloff method, 1949); 9) effects on the reduction of smooth muscle objects (uterus and rat vasdeferens), on the effects of acetylcholine (), adrenaline (), oxytocin (5-10 U / ml), KC1 (25 mm). Toxicity of substances is given in table. 2. Table 2 LD 50, mg / kg, and confidential substances of the boundary (, 05) with a single intraperitoneal injection of substances to the LDzo mice - the average lethal dose, causing the death of 50% of animals with a single intraperitoneal injection.

Subsequently, doses of a substance equal to 20% of the LDB effect on animals were studied.

In small doses (5, 10, 20% of Ldzo), substances have a weak and moderately pronounced sedative effect, reduce the motor activity of animals, weaken their reactions to stimuli. At doses close to toxic, they cause excitement of the parasympathetic division of the autonomic nervous system (salivation), clonic convulsive twitches, passage w, and clonicotonic c-road seizures. The death of animals with the introduction of toxic doses also occurs quickly with the effects of excitement, convulsions, cyanosis, salivation.

The main pharmacological effects of substances are presented in table. 3

Effect on the contractile effects of smooth muscle objects.

Substances 1a, 16, 1b have a stimulating effect on the contractile activity of smooth muscles. They enhance the reactions to adetilcholine (10 myometrium), adrenaline (2-10, the vas deferens), oxytotia (5-10 myometrium). Contractile responses to CS1 (25 mM, vas deferens) remain unchanged. All three substances somewhat (10-15%) increase the amplitude of spontaneous contractions, without affecting their frequency. The frequency of spontaneous contractions is doubled on a hormone-treated preparation (1a). The mechanism of the stimulating effect of the test substances is apparently non-specific and is related to their effect on the smooth muscle membrane. The test results are shown in table 4.

In their ability to induce hyperkinesis, characteristic of Lg cholinomimetics, the synthesized compounds are superior to arecoline and are likened to galanthamine. The results are given in table. five.

The effect of the synthesized substances on the activity of cholinesterase was investigated; in their anticholinesterase activity, they are superior to galanthamine. The results are given in table. 6

Thus, the synthesized compounds were found to be active inhibitors of holiiesterase with higher activity and less toxicity than those widely used in the practice of galantamine. Their effect is also distinguished by a peculiar, more pronounced effect on smooth muscles.

Table

Table 4

Table 6