Patent GB-1198941-A (GB)
Title: Benzimidazole Derivatives
Inventor: HOFF D R
IPC: A61K31/415
Filed: 1968-02-01
Abstract: 1,198,941. Benzimidazole derivatives. MERCK & CO. Inc. 1 Feb., 1968 [3 Feb., 1967; 9 Jan., 1968], No. 5259/68. Heading C2C. Novel compounds (I) in which X is O or S; R 1  is a five-membered monocyclic heteroaromatic ring containing 1-3 O, S or N atoms; R 2  is H, OH, C 1-8  alkyl, C 1-8  alkoxy, aralkyl, acyl, acyloxy, carboxyalkoxy, carbamoyl, N-alkylcarbamoyl, or alkoxycarbonyl; R 3  is H, or C 1-8  alkyl and R 4  is H, aralkyl, haloaralkyl, cycloalkyl, C 1-8  alkylamino, di - (C 1-8  alkyl)amino, alkylenimino, hetero - interrupted alkylenimino, cycloalkylamino or a radical R-, RO- or RS- in which R is a C 1-8  univalent aliphatic hydrocarbon, C 1-8  univalent aliphatic halohydrocarbon, aryl, haloaryl, alkaryl, aminoaryl or heterocyclic radical and their acid addition salts and metal complexes when R 2  is H are prepared by: (a) reacting an appropriate 5- NH(R 3 )-substituted benzimidazole with R 4 - C(X)Y where Y is a halogen atom; (b) reacting an appropriate 5-RS-CO-N(R 3 )- substituted benzimidazole with a compound ROH to give a compound (I) in which X is O and R 4  is RO (R being radical R from ROH); (c) reacting an appropriate 5-isothiocyanato benzimidazole with a compound ROH or RSH to give a compound (I) in which X is S and R 4  is RO- or RS-; (d) reacting a compound (I) in which X is O with phosphorus pentasulphide to give a compound (I) in which X is S; (e) reacting an appropriate 5-NH(R 3 )- substituted benzimidazole with an alkyl isocyanate or isothiocyanate to give a compound (I) in which R 4  is alkylamino; (f) reacting an appropriate 5-NH(R 3 )- substituted benzimidazole with a dialkylcarbamoyl halide to give a compound (I) in which X is O and R 4  is dialkylamino; (g) reacting a compound (I) in which X is O and R 4  is alkylthio with a dialkylamine, alkylenimine or hetero-interrupted alkylenimine to give a compound (I) in which R 4  is dialkylamino, alkylenimino or hetero-interrupted alkylenimino; (h) reacting an appropriate 5- isothiocyanato-benzimidazole with a dialkylamine, alkylenimine or hetero-interrupted alkylenimine to give a compound (I) in which X is S and R 4  is dialkylamino, alkylenimino or hetero-interrupted alkylenimino; or (i) introducing the group R 2  into an appropriate benzimidazole by reacting an alkali metal salt of a compound (I) in which R 2  is H with an alkyl, aralkyl or acyl halide, or by reacting a compound (I) in which R 2  is H with an alkyl isocyanate to give a compound (I) where R 2  is carbamoyl, or by reacting a compound (I) in which R 2  is H with an alkyl haloformate to give a compound (I) in which R 2  is alkoxycarbonyl; followed in any of (a)-(i) by salt formation, where desired. Intermediates isolated are 5-nitro-2-(4<SP>1</SP>-thiazolyl)-benzimidazole, prepared by nitration of the 5 - unsubstituted compound; 5 - nitro - 2 - (2<SP>1</SP> - furyl) - benzimidazole, 5 - nitro - 2 - (2<SP>1</SP>- pyrryl) - benzimidazole and 5 - nitro - 2 - (2<SP>1</SP>- thienyl) - benzimidazole, prepared by reacting the appropriate furan-, pyrrole- or thiophene- 2 - aldehyde with o - amino - p - nitro - aniline; 5 - amino - 2 - (4<SP>1 </SP>- thiazolyl) - benzimidazole, prepared by reduction of the 5-nitro compound; 5 - isothiocyanato - 2 - (4<SP>1 </SP>- thiazolyl) - benzimidazole, prepared from the 5-phenoxythiocarbonylamino compound by heating in pyridino; 5 - nitro - 1 - methoxy - 2 - (4<SP>1 </SP>- thiazolyl)- benzimidazole, prepared by nitration of the 5- unsubstituted compound and 5-amino-1-methoxy - 2 - (4<SP>1</SP>- thiazolyl) - benzimidazole hydrochloride, prepared by reduction of the previous intermediate. Pharmaceutical compositions comprise a novel compound (I) in conjunction with a suitable carrier or diluent and are suitable for oral or parenteral administration as anthelmintics or antifungal agents.