CS252587B1 - Cis-1- [2- (2,4-dichlorophenyl, -4- (2-alkylthio-5-pyrimidinyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoles and their salts - Google Patents

Abstract

The solution relates to cis-1-/2-(2,4-dichlorophenyl)- -4-(2-alkylthio-5-pyrimidinyloxymethyl)-1,3- -dioxolan-2-ylmethyl/-1H-imidazoles and their salts of the general formula I where R is a methyl group or isobutyl group, Y is a nitric acid molecule, n is 0 or 1. These new, previously undescribed substances show antifungal activity in in vitro testing against strains of Saccharomyces pastorianus, Candida albicans, Trichophyton mentagrophytes and Aspergilus niger.

Description

The present invention relates to cis-1- [2- (2,4-dichlorophenyl) -4- (2-alkylthio-5-pyrimidinyloxymethyl) -1,3-dioxolan-2-ylmethyl) -1H-imidazoles and their salts of formula (I)

Cl

where R is methyl or isobutyl, Y is nitric acid molecule, n is ₍ 0 or 1.

These novel substances, which have not been described yet, exhibit antimycotic activity useful for the prevention and therapy of mycotic infection.

The compounds of the formula I according to the invention can be prepared by the reaction of the known cis-1- [2- (2,4-dihlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole (Heeres LJ et al. (J. Med. Chem. 22, 1005, 1979) with 2-methylthio-5-hydroxypyrimidine or 2-isobutylthio-5-hydroxypyrimidine in the presence of anhydrous potassium carbonate in an aprotic solvent at elevated temperature, preferably dimethylsulfoxide at 100 ° C to 120 ° C.

Salts of compounds of formula I are prepared by reacting compounds of formula I with nitric acid, preferably in a mixture of acetone and diethyl ether.

Evaluation of antifungal efficacy:

Evaluation of antifungal activity was performed by in vitro testing on 4 collection strains of VÚFB, compared to the efficacy of clotrimazole, micronazole and ketoconazole. The determination of the minimum inhibitory concentration in mg / l was tested by the dilution method in liquid medium on strains: Saccharomyces pastorianus (SP), Candida albicans (CA), Triohophyton mentagrophytes (TM), Aspergilus niger (AN). The inoculum size was 10 ® CFU / ml for fungi, CA and SP strain 10 ® and 10 ⁴ CFU / ml for the compounds of Examples 1 and 2 for 10 ⁴ CFU / ml standards. (CFU = International Inoculum Size Unit.) Evaluation results are shown in Table 1.

Table 1

Substances SP ^a Minimum inhibitory concentration in mg / l SP ^b CA ^a CA ^b TM ^b AN ^b EXAMPLE 1 0.15 > 50 0.15 > 50 0.07 0.7 Example 2 fabric 6.2 25 0,7 50 0.15 12.5 clotrimazole 3.1 0.7 - 0.03 3.1 micronazole 6.2 0.7 - 0.03 1.5 ketoconazole 50 0.03 - 0.7 12.5

a = 10 ⁴ CFU / ml b = 10 CFU / ml

As can be seen from the above evaluation results, the compounds of formula I and their salts are comparable and even better compared to selected strains with a minimum inhibitory concentration of 0.07 to 0.7 mg / ml and 0.15 to 6.2 mg / ml, respectively. with the standards used. The process for preparing the substances is simple and provides the desired products in satisfactory yields.

Further details are given in the following examples. These examples are merely illustrative and not limiting.

and

He did

Cis-1- / 2- (2,4-dichlorophenyl) -4- (2-methylthio-5-pyrimidinyloxymethyl) -1,3-dioxolan-2-ylmethyl / -ΙΗ-imidazole (C ₁₉ H _g Cl ₂ N ₄ O ₃ S)

To a solution of 1.01 g (2.5 mmol) of cis-1- [2- (2,4-dichlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole in 16 mL of dimethyl sulfoxide was added 0.45 g (3.1 mmol) of 2-methylthio-5-hydroxypyrimidine and 0.5 g (3.6 mmol) of anhydrous potassium carbonate are added dropwise. The mixture was heated to 100 ° C with stirring for 16 h. After cooling to 30 ° C, the reaction mixture was poured into 35 ml of water, the oily substance separated and stirred with 6 ml of acetone, from which after stirring for 10 minutes 0.5 g (45% yield) of crude product was obtained by recrystallization. 80% water acetone had. mp 113 DEG-114.8 DEG C. and the composition analysis was consistent with _Ig C H ₁₈ Cl ₂ N ₄ O ₃ S.

EXAMPLE 2 cis-1- [2- (2,4-dichlorophenyl) -4- (2-isobutylthio-5-hydroxypyrimidinyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazole nitrate 2 ^ 403 · · ^Η 2θ ^

To a solution of 1.01 g (2.5 mmol) of cis-1- [2- (2,4-dichlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolan-2-ylmethyl] -1H-imidazole in 16 mL of dimethyl sulfoxide was added 0.57 g (3.1 mmol) of 2-isobutylthio-5-hydroxypyrimidine and 0.5 g (3.6 mmol) of anhydrous potassium carbonate are added. The mixture was heated to 110-120 ° C with stirring for 12 h. The cooled mixture was poured into 60 ml of water and the product was extracted into chloroform (3 x 30 ml). The chloroform fraction was freed from the solvent by distillation under reduced pressure and the residual oily product dissolved in 10 ml of acetone.

After addition of 1 ml of concentrated nitric acid, the solution was diluted with 90 ml of diethyl ether and the precipitated nitrate, 0.13 g (30%) was aspirated. Its tt was 118 to 120 ° C and the analysis was consistent with the composition of ^C 22 ^H 24 ^Cl 2 ^N 4 ° 3 ' ^HNO 3' ^H 2 ° -

Claims (1)

SUBJECT OF THE INVENTION Cis-1- [2- (2,4-dichlorophenyl) -4- (2-alkylthio-5-pyrimidynyloxymethyl) -1,3-dioxolan-2-ylmethyl] -1H-imidazoles and salts thereof of formula I wherein R is methyl or isobutyl, Y is a nitric acid molecule, n is 0 or 1.