Patent GB-1153347-A (GB)
Title: Imidazole Derivatives, their preparation and Compositions containing them.
IPC: C07D233/94
Filed: 1966-07-04
Abstract: 1,153,347. Imidazole derivatives. MERCK & CO. Inc. 4 July, 1966 [7 July, 1965; 18 May, 1966], No. 29846/66. Heading C2C. Novel imidazole derivatives of the general formula wherein R 1  is alkyl or substituted alkyl wherein said substituent is aryl, fluorophenyl, nitrophenyl, oxo, alkenyl, hydroxy, halo, alkanoyloxy, aralkanoyloxy, benzoyloxy, alkoxy, aralkoxy, carboxy, carboalkoxy, carboaralkoxy, alkylcarbamoyl, aralkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, carbamoyloxy, carbamoyl, cyano, alkylthio, aralkylthio, arylthio, alkylsulphinyl, aralkylsulphinyl, arylsulphinyl, alkylsulphonyl, aralkylsulphonyl, arylsulphonyl or dialkylamino; Q is C 1-5  alkylene, C 3-5  alkenylene, aralkylidene or C 2-5  alkylidene; W is nitro, cyano, phenyl or hydrogen; and P is hydrogen or nitro; provided that one and only one of W and P is nitro; and T has the structure wherein A is oxygen or sulphur; M is oxygen, sulphur, imino or alkylimino; R 3  and R 4  are each hydrogen, alkyl or substituted alkyl, wherein the substituent(s) is/are halo, hydroxy, alkoxy, oxo, aryl and oxo, carboxy, carboalkoxy, carboaralkoxy, carbamoyloxy, alkanoyloxy, aralkanoyloxy, carbamoyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, dialkylcarbamoyl, sulphamoyl, alkylsulphamoyl, arylsulphamoyl, aralkylsulphamoyl, dialkylsulphamoyl, mercapto, alkylthio, aralkylthio, thioncarbamoyl, dialkylthiocarbamoylthio, diaralkylthiocarbamoylthio, amino, alkylamino, dialkylamino, diaralkylamino or heterocycloalkyl in which the ring contains at least one nitrogen atom, which is bonded to the alkyl group; phenyl, nitrophenyl, chlorophenyl, fluorophenyl, substituted methylene or alkylidene in which the substituent(s) is/are alkoxy, aralkoxy, aryloxy, dialkylamino or diaralkylamino; alkanoyl, aralkanoyl, aroyl, cyanoalkanoyl or C 3-5  alkenoyl; hydroxy, substituted hydroxy wherein said substituent is alkanoyl, aralkanoyl, aroyl, alkyl, aralkyl, aryl, cyanoalkanoyl or C 3-5  alkenoyl; carbamoyl and thiocarbamoyl and N-substituted carbamoyl and thiocarbamoyl wherein said substituent is alkyl, aralkyl or aryl; heterocycloalkylcarbonyl in which the heterocycloalkyl ring contains at least one nitrogen atom, which is bonded to the carbonyl group; nitro, amino and substituted amino, in which the substituent(s) is/are carbamoyl, thiocarbamoyl, C 2-5  alkylidene, aralkylidene, alkanoyl, aralkanoyl, aroyl, cyanoalkanoyl or C 3-6  alkenoyl; alkanoylalkanoyloxy, aralkanoylaralkanoyloxy, sulphamoyl, alkylsulphamoyl, dialkylsulphamoyl, aralkylsulphamoyl, diaminophosphoryl, bis(alkylamino)- phosphoryl, bis(dialkylamino)phosphoryl, bis (phenylamino)phosphoryl and bis(diphenylamino)phosphoryl; or R 3  and R 4  together represent a -(CH 2 ) 2 R 5 (CH 2 ) 2 - group, where R 5  is oxygen, sulphur, methylene, imino, alkylimino or a carbon-to-carbon single bond; the terms " alkyl," " alkanoyl " and " alkoxy " meaning such groups containing from 1 to 5 carbon atoms, are prepared by the following general processes: (i) reaction of an isocyanate or isothiocyanate of the general formula R 3 -N-C=M with an imidazole derivative of the general formula wherein R 1  is not hydroxyalkyl and, where R 1  is alkanoyloxyalkyl, optional hydrolysis with a base to obtain the product wherein R 1  is hydroxyalkyl; (ii) reaction of an alkali metal cyanate or thiocyanate with an imidazole derivative of the general formula wherein X is halo or alkyl- or phenyl-sulphonyloxy, and R 1  is alkyl or substituted alkyl, where the substituent is oxo, alkenyl, hydroxy, phenylalkoxy, alkoxy, carboxy, alkylthio, phenylalkylthio, alkylsulphinyl, phenylalkylsulphinyl, alkylsulphonyl, phenylalkylsulphonyl or phenylsulphonyl, except that R 1  is not hydroxyalkyl in the starting material, followed by treatment of the resulting cyanate or thiocyanate of the general formula with an acid; (iii) reaction of phosgene or thiophosgene with an imidazole derivative of the fourth general formula above, followed by reaction of the resulting halocarbonate or halothioncarbonate of the general formula wherein X is halo, with ammonia or an amine of the general formula R 3 R 4 NH; (iv) reaction of an imidazole derivative of the fourth general formula above with a carbamoyl halide or alkyl carbamate or thion analogue thereof of the general formula wherein B is halo or alkoxy; (v) reaction of an imidazole derivative of the fourth general formula above with a halocarbonate or halothioncarbonate of the general formula wherein X is halo, followed by reaction of the resulting phenyl carbonate or thioncarbonate of the general formula with ammonia or an amine of the general formula R 3 R 4 NH; and (vi) reaction of an imidazole derivative of the fifth general formula above with a thiourea derivative of the general formula wherein M is imino or alkylimino and X is halo, alkylsulphonyloxy or phenylsulphonyloxy. Pharmaceutical compositions, useful against parasitic diseases, amoebiasis, trypanosomiasis and chronic respiratory diseases in fowl and also having antibacterial activity, comprise as active ingredient an imidazole derivative of the first or second general formula above and a pharmaceutical diluent, carrier or coating. 1 - Methyl - 4 - phenyl - 5 - nitroimidazole is prepared by treatment of 4-p-acetylaminophenyl-5-nitroimidazole with sulphuric acid and sodium nitrite and reaction of the resulting 4 - phenyl - 5 - nitroimidazole with dimethyl sulphate. 1 - n - Methyl - 2 - hydroxymethyl - 4- nitroimidazole is produced by reaction of 2- hydroxymethyl-4-nitroimidazole with dimethyl sulphate. 1 - n - Butyl - and 1 - allyl - 5 - nitroimidazoles are prepared by reaction of 4(5)- nitroimidazole with n-butyl or allyl tosylate, respectively. 1 - (2<SP>1 </SP>- Hydroxyethyl) - 5 - nitroimidazole is prepared by reaction of 4(5)-nitroimidazole with ethylene oxide and is converted to 1 - (2<SP>1 </SP>- acetoxyethyl) - 5 - nitroimidazole by reaction with acetic anhydride. 1-(2<SP>1</SP>-Acetoxypropyl) - 5 - nitroimidazole and 1 - (2<SP>1 </SP>- benzoyloxyethyl) - 5 - nitroimidazole are prepared analogously. 1-Ethoxyethyl-5-nitroimidazole is produced by reaction of 4(5)-nitroimidazole with #-ethoxyethyl tosylate; and 1-ethoxypropyl-5- nitroimidazole is produced analogously. 5-Nitroimidazol-1-yl acetic acid is prepared by oxidation of 1 - (2<SP>1</SP> - hydroxyethyl) - 5 - nitroimidazole with chromic acid/sulphuric acid or with trifluoroacetic acid and dicyclohexylcarbodiimide, and then sodium hypochlorite; or by alkaline hydrolysis of the corresponding ethyl ester. 5- Nitroimidazol-1-yl-acetonitrile is prepared by dehydration of 5-nitroimidazol-1-yl-acetamide with thionyl chloride. 5-Nitroimidazol-1-yl-ethyl ethylsulphone is prepared by treatment of 5-nitroimidazol-1-yl-ethyl p-toluenesulphonate with the potassium salt of ethanethiol, oxidation of the resulting 1 - (2<SP>1 </SP>- ethylthioethyl) - 5 - nitroimidazole with perphthalic acid and further oxidation of the obtained 1-(2<SP>1</SP>-ethylsulphinylethyl) - 5 - nitroimidazole with hydrogen peroxide. 1 - (2<SP>1</SP>- N - morpholinylethyl) - 5 - nitroimidazole is prepared by reaction of 1-(2<SP>1</SP>- hydroxyethyl)-5-nitroimidazole with p-toluenesulphonyl chloride and reaction of the resulting 1 - (2<SP>1</SP>- p - toluenesulphonyloxyethyl)- 5 - nitroimidazole with morpholine. 1 - [(2<SP>1</SP> - Tetrahydropyran - 2<SP>11</SP> - yl - oxy)ethyl] - 2 - hydroxymethyl-5-nitroimidazole is prepared by reaction of 1 - (2<SP>1</SP>- hydroxyethyl) - 5 - nitroimidazole with dihydropyran and paraformaldehyde. 1- Methyl - 2 - chloromethyl - 5 - nitroimidazole is produced by treatment of the corresponding 2- hydroxymethyl compound with thionyl chloride and may be converted to 1-methyl-2-mercaptomethyl-5-nitroimidazole with thiourea and sodium hydroxide. 1 - Methyl - 2 - p - toluenesulphonyloxymethyl - 5 - nitroimidazole, 1- methyl - 5 - nitroimidazol - 2 - yl-methyl phenyl carbonate and 1 - methyl - 5 - nitroimidazol - 2- yl-methyl phenyl thionocarbonate are prepared by reaction of 1-methyl-2-hydroxymethyl-5- nitroimidazole with p-toluenesulphonyl chloride, phenyl chloroformate and phenoxythiocarbonyl chloride, respectively.