CS202102B1 - 1-substituted derivatives of 2-/2,4-dinitrophenylthio/benzimidazole and process for preparing them - Google Patents

Description

( ⁵⁴ ) 1-substituted 2- (2,4-dinitrophenylthio) benzimidazole derivatives and processes for their preparation

The present invention relates to novel antimycobacterially active 1-substituted 2- (2,4-dinitrophenylthio) benzimidazole derivatives of the general formula:

Wherein R is CH8-; C ₂ H _g -; nC ₄ H _fl -; ^ O ^> - C-; <CH ₂ -> CH ₂ -; and how they are prepared. 2- (2,4-dinitrophenylthio) benzimidazole is known to exhibit antimicrobial activity. At work: Pianka M. Studies in Fungitoxicity, J. Sci. Fd. Agric. 19, pp. 507-512 (1968), describes its antifungal activity. Antifungal activity against dermatophytes and tuberculostatic activity is the subject of the Czechoslovak AO no. 190856, by Lácová M., Volná F., Odlerová Ž ..

We have now found that the efficacy of the novel compounds synthesized by us, the preparations of which are given in Examples 1 to 5, can be compared with those of known antituberculotics, such as isonicotinic hydrazide and ethylthioisonicotinic acid amide, especially on atypical mycobacterial strains.

At the same time, a process for the preparation of active substances consisting of the reaction of 2- (2,4-di 2 O 2 102 nitrophenylthio) benzimidazole with an alkyl halide or acyl halide in the presence of a base in benzene, ether or tetrahydrofuran has been found.

The active compounds according to the invention can be used in mixtures with other known active compounds.

The following examples illustrate but do not limit the preparation and properties of the compounds of the invention in any way.

Preparation of 2- (2,4-dinitrophenylthio) benzimidazole

To 0.1 mol of 2-mercaptobenzimidazole sodium salt in 50 ml of ethanol with stirring at 40-50 ° C was added 0.1 mol of 2,4-dinitrochlorobenzene in 50 ml of ethanol. Allow to react for 2 hours. Cool. The precipitate formed is filtered off with suction, washed several times with steam (3 to 4 times). Yield 90%.

w

Product suitable for further use. It can be recrystallized from ethanol, from chlorobenzene (mp 233-234 ° C).

Example 1

Preparation of 1-methyl-2- (2,4-dinitrophenylthio) benzimidazole.

A mixture of 0.05 mole of 2- (2,4-dinitrophenylthio, benzimidazole and 0.04 mole of KgCO 3 in benzene (ether, tetrahydrofuran) was stirred at 30-60 ° C for 30 min. 30 minutes of methyl bromide (0.07 mol) dissolved in 40 ml of benzene (or ether or tera hydrofuran) is left to react for 30 minutes and the precipitate is filtered off with suction, washed several times with cold water and recrystallized from ethanol, chloroform. mp 196-198 ° C, yield 80%.

Analysis for ^C 14 ^H 10 ^N 4 ® / 11 = 330.25 / calculated: 50.91% C found: 50.68% C 3.02% H 2.75% H N, 16.96 N, 16.89 9.71% N 9.46% N

Example 2

Preparation of 1-ethyl-2- (2,4-dinitrophenylthio) benzimidazole.

Procedure as in Example 1. Melting point 162-163.5 ° C. Yield 82%.

Analysis for ^c 15 ^H 12 ° 4 ^N 4® / 11 = 344.27 / calculated: 52.33% C found: 52.15% C 3.48% H H, 3.26 N, 16.27 16.15% N 9.31% N 9,01% N

Example 3

Preparation of 1-butyl-2- (2,4-dinitrophenylthio) benzimidazole.

Working procedure as in Example 1. Mp 136-138 ° C. Yield 78%.

Analysis for ^c 17 ^H 16 ^N 4 ° 4 ^S / M = 372.29 / found: 54.52% C calculated: 54.84% C 4.29% H 4.16% H 15.05% N 14.98% N 8.61% N 8.30% N

Example 4

Preparation of 1-benzoyl-2- (2,4-dinitrophenylthio) benzimidazole.

Procedure as in Example 1. Melting point 175-176 ° C. Yield 80%. Analysis for ^C 2O ^H 12 ^N 4®5 ^The ZM »42O, 32 /

calculated: 57.15 % C found: 57.14 % C 2.85 % H 2.64 % H 13.33 % N 13.24 % N 7.62 % WITH 7.29 % WITH

Example 5

Preparation of 1-benzyl-2- (2,4-dinitrophenylthio) benzimidazole.

Working procedure as in Example 1. Mp 232-234 ° C. Yield 80%.

Analysis for C ₂ H ₁₄ N ₄ 0 ₄ S / M = 406.32 / calculated: 59.12% C found: 58.74% C 3.44% H 3.16% H 13.87% N 13.51% N 7.89% N 7.48% N

Example 6

Method of antimycobacterial tests.

Efficacy was monitored in a liquid Granite soil by a dilution test. Dimethylsulfoxide (DMSO) was used as solvent. The final concentration of substances in the soil was 1, 5, 10, 25, 50, 100 µg / ml, while maintaining a constant DMSO concentration of 1%. / Odlerová Ž. et al .: Research of New Antituberculotics I. Stud. pneumol. phtyseol. Čechoslov. 36, 8, p .507, (1976) The efficacy was compared with 2-mercaptobenzothiazole (2-MBT) and with antituberculotics (AT): isonicotinic hydrazide, 2-ethylthioisonicotinic acid amide. Standard strains of Mycobacterium / M / tuberculosis H37Rv from the VUEM collection in Bratislava, atypical mycobacteria M.kansasii PKG 8 from the Dr.Runyon collection were used as test microorganisms,

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Salt Lake City, Utah, U.avium from the collection of VUEM in Bratislava, M.fortuitum from the collection of prof. Hauduroy, Lausanne,

The results

The minimal inhibitory concentration Ztab.1 was determined by this method, while the high potency was golden. methyl, otyl, butyl, benzoyl derivatives of 2- (2,4-dinitrophenylthio) benzimidazole versus li.tbc H37Rv, as well as high activity - as compared to AT - versus atypical mycobacteria. The benzoyl derivative showed the highest and most stable activity, whereas 1-benzyl-2- (2,4-dinitrophenylthio) benzimidazole was not effective against the tested mycobacteria even at a concentration of 100 µg / ml.

Example 7

The antimycobacterial activity of the compounds of the invention. Test results.

Tab. I. Minimum Inhibitory Concentration of M1C µg / ml

compound tuberculosis ^H 37 ^Rv llycobacterium fortuitum kansasii avium Example 1 5 25 (10) 50 (24) 25 (10) Example 2 5 10 50 (25) 10 Example 3 5 5 50 (25) 100 (50) Example 4 5 10 10 10 Example 5 * 100 * 100 * 100 * 100 2-MBT 25 (10) 50 50 (25) 50 (25) isonicotinic acid hydrazide 1 50 100 100 acid amide - 50 2-ethylthioisonicotin ¹ 10 10

(partial MIC / Ug / ml) violet test results.

The butyl derivative was found to have acute toxicity in white mice by a single oral administration according to the Wagner method, following a 95% death over 24 hours. It was found that the acute toxicity was 125 mg / kg as in the control isonicotinic hydrazide.

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It is apparent from the table and the results presented herein that they are active against mycobacteria. Efficacy over atypical mycobacteria is equal to that of AT, in some cases exceeds it, but decreases during cultivation, in particular for alkyl derivatives, suggesting their bacteriostatic activity.

Claims (2)

It is clear from both the table and the results that one is a substance that is effective against mycobacteria. The efficacy over atypical mycobacteria is equal to that of AT, in some cases it exceeds it, but during cultivation it decreases, especially in the case of alkyl derivatives, indicating their bacteriostatic activity. Wagner W.H .: Adv. Tuberc. Res. IX. Cargel, Basel, New York, 1958, (104-177). SUBSTITUTE 1. 1-substituted 2- (2,4-dinitrophenylthio) benzimidazole derivatives of the general formula 0 2. A process for the preparation of the compounds according to claim 1, which is carried out on 2- (2,4-di-nitrophenylthio) benzimidazole alkyl halide or acyl halide in benzene, ether, tetrahydrofuran, in the presence of a base at a temperature of 30-60 ° C. ° C.