SU621686A1 - Derivatives of polyvinyloxycarboxyacetalimidazole possessing m-cholinomimetic effect - Google Patents

Description

medium or in dimethylformamide at room temperature. The following 1,5-imidazole derivatives are used in the reaction; 1, d-dimethylimidazole; 1-methyl-5-ethylimidazole; 1-methyl-5 (5-OXO-4 - methyltetrahydrofuryl - (3) - methyl) -imidazole; 1-methyl-b- (e-oxo-4-ethyltetrahydrofuryl- (3) -methyl) -imidazole and 1methyl-y- (e-oxo-tetrahydrofuryl- (3-methyl) imidazole. The starting polymer compound is water-soluble carboxyacetal polyvinyl alcohol with a degree of substitution from 10 to 23 mol.% and a degree of polymerization from 100 to 350. The condensation reaction is carried out at room temperature and constantly moving the reaction mass. The progress of the reaction is controlled by changing the pH of the medium from 8.5 to b, 2-b, 8. From the reaction solution, high molecular weight derivatives 1,; e-imidazole precipitate is precipitated by addition of a precipitant displaced with water or dimethylformamide with the addition of lyophilization after removal by dialysis of unreacted 1,5-imidazole derivatives. The structure of the obtained high molecular compounds is confirmed by qualitative and quantitative analyzes of the composition (content of elements: nitrogen, hydrogen, oxygen ), determination of free hydroxyl groups, potentiometric titration, IR and UV absorption spectra. Example 1. K1g carboxyacetal of polyvinyl alcohol (with a degree of substitution of 10.0 mol.% Acetal) dissolved in 24 ml of water, 0, ib g of 1,5-dimethylimidazole is added. The reaction mixture is stirred for 1 h at room temperature. The high molecular weight product is precipitated from acetone, washed, extracted with ether for H hours and it is reduced to the weight. The content of 1,5-dimethylimidazole in the polymer is determined by analysis of nitrogen. Found,%: N 2.36, which corresponds to 8.11 weight. % 1,5-dimethylimidazole in the polymer. Mol mass 8800. Calculated,%: N 2.98 (corresponding to 10.24 wt.% 1,5-dimethylimidazole). Example 2. K1g carboxyacetal of polyvinyl alcohol (containing 23.0 mol% of acetal units), which was previously dissolved in 25 ml of dimethylformamide, was added at room temperature 0.30 g of 1-methyl-5-ethylimidazole. The reaction is carried out for 1 hour. The high molecular weight product is precipitated, washed and extracted with acetone and it is present in a vacuum dryer at a constant weight. The resulting product is analyzed for nitrogen content. Paydeno,%: N 6.28, which corresponds to 24.74 weight. % 1-methyl-5-ethylimidazole in the polymer. Calculated:%; N 6.39 (corresponding to 25.17 wt.% 1-methyl-5-ethylimidazole). Example 3. To 2.0 g of polyvinyl alcohol carboxyacetal (with a degree of substitution of 20.0 mol% for acetal) was added 50 ml of distilled water. After the polymer is completely dissolved, 1.0 g of 1-methyl-o- (5-oxo-4-ethyltetrahydrofuryl - (3) -methyl) - imidazole is added to the solution. The mixture is stirred for 5 hours at room temperature. The reaction solution is dialyzed for 40 hours, filtered and lyophilized. 2.72 g (95.7% of theory) of a high molecular weight product are obtained. Paidno,%: IN 5, Ы, which corresponds to 42.01 wt. % 1-methyl-5- (5-oxo-4-ethyl-tetrahydrofuryl- (3) -methyl) - imidazole. Mol mass 18200. Calculated,%: N 5.64 (corresponding to 42.13 weight. 7o 1-methyl-5 (5-oxo-4-ethyl - (, 3) methyl) -imidazole). Example 4. To iOO ml of a 5% aqueous solution of carboxyacetal of polyvinyl alcohol (degree of substitution i5 mol. 7o) An equimolar amount of 1-methyl 5- (5-oxo-4-methyltetrahydrofuryl - (3) methyl) -imidazole is added. (i, 5l g). The reaction mass is stirred for 0.5 h at room temperature, filtered, dialyzed for 48 h and subjected to lyophilization. 6.43 g (yA) of the desired product are obtained. Paydeno,%: N 4.23, which corresponds to 29.01 wt. % 1-methyl-5- (5-oxo-4-methyltetrahydrofuryl- (3) -methyl) -imidazole. Calculated,%: N 4, 3L (corresponding to 29.90 wt.% 1-methyl-b- (5-oxo-4-methyl-methylhydrofuryl- (3) -methyl) -imidazole). Example 5. To 100 ml of a L7O3 aqueous solution of polyvinyl alcohol carboxyacetal (with a degree of acetal substitution of 10.0 mol. 7 and a degree of polymerization 110), 2.5 g of 1-methyl-5- (5-oxotetrahydrofuryl - (3 ) - methyl) - imidazole. The mixture is stirred at room temperature for 0.5 h, dialyzed for 4U h, filtered and lyophilized. 6.9 g of a high-molecular derivative of 1-methyl-5- (5-oxotetrahydrofuryl- (3) -methyl) -imidazole are obtained. Found,%: N 3,62, which corresponds to 21.12 weight. % 1-methyl-5- (5-oxotetrahydrofuryl- (3) -methyl) - imidazole. Mol mass 6200. Calculated,%: N 3.71 (corresponds to 2.0 weight. 7o 1-methyl-5- (5-oxotetrahydrofuryl- (3) -methyl) -imidazole). Example 6: To 5 g of carboxyacetal of poly (alcohol) (substitution degree 3 mol. 7y, degree of polymerization 350), 100 ml of distilled water are added and, after dissolving the polymer, 5.2 g of 1-methyl-5- (5- oxotetrahydrofuryl- (3) -methyl) imidazole. The reaction mass is stirred for 0.5 h at room temperature. The high molecular weight product is precipitated from acetone, washed and extracted with acetone for 6 hours. After drying, 9.1 g of a high molecular weight imidazole derivative is obtained, which is analyzed for nitrogen content.

Found,%: N 5.93, which corresponds to 43.7 wt. % 1-methyl-5- (5-oxotetrahydrofuryl- (H) -methyl) -imidazole. Mol weight 29100.

Calculated,%: N 5.77 (corresponding to 42.9% by weight of 1-methyl-5- (5-oxotetrahydrofuryl- (3) -methyl) -imidazole).

The resulting high molecular weight derivatives of 1,5-imidazole were studied in animal experiments.

The high molecular weight derivatives of 1-methyl-5- (5-oxo-4-ethyltetrahydrofuryl- (3) -methyl) -imidazole (high molecular weight pilocarpine derivative) have been found to be 2-6 times more active during the second hour. Monomeric analogue - pilocarping hydrochloride. The compound of the prototype exceeds the strength of the miotic effect of pnocarping hydrochloride during the third hour by 3 times, and the proposed compound exceeds it 40 times. In terms of the duration of the miotic effect, the high molecular weight derivative exceeds pilocarpne hydrochloride by a factor of 2-2.5.

During prolonged storage of the solutions, it was found that the miotic activity of the high molecular weight derivative of pilocarpine at the end of the first year of storage is 4-6 times greater than pilocarping hydrochloride.

The miotic activity of the proposed

compounds when exposed to a living organism decreases in time much slower than the miotic activity of pilocarping hydrochloride.

In this compound, the amount of drug attached can be increased to 23 mol. %, while in a known compound, you can enter no more than And mol.%.

The proposed compound allows a greater degree of substitution, remaining water-soluble, while the known compound already with a degree of substitution above And mol. % becomes water insoluble.

This method makes it possible to obtain high molecular weight derivatives on conventional apparatus used in the chemical industry using available raw materials.

Claims (1)

Invention Formula Polyvinyloxycarboxyacetalimidazole derivatives of the general formula where R is methyl, ethyl, oxotetrahydrofuryl (3) -methyl, 4-methyloxotetrahydrofuryl- (3) -methyl, 4-ethyloxotetrahydrofuryl- (3) -methyl; .x- -77-90 mol. %; y 10-23 mol. % with a mass of macromolecules from 6000 to 30,000, with M-cholinomimetic action.