Patent GB-1308370-A (GB)
Title: 1-hydroxy-3-oxo-benzimidazoles quinoxaline-di-n-oxides and  benzimidazole-mono-and di-n-oxides
IPC: C07D235/02
Filed: 1970-10-05
Abstract: 1308370 Quinoxaline-di-N-oxides and benzimidazole-N-oxides RESEARCH CORP 5 Oct 1970 [9 Dec 1969] 47202/70 Addition to 1215815 Heading C2C Novel process for preparing quinoxaline-di- N-oxides and benzimidazole mono- and di- N-oxides which comprises reacting a compound having a methylene group activated by two electron-withdrawing groups, or a compound containing a methylene group which is activated by one electron-withdrawing group selected from nitro, carbonyl of a ketone or aldehyde, with an iosbenzofuroxan in the presence of a base, the activated methylene containing compound and bases being (a) a malonic acid diester in the presence of an alkali metal hydroxide or an alkali metal hydride; (b) a malonamate in 'the presence of alkali metal hydroxide, alkali 'metal alkoxide or alkali metal hydride; (c) a malonic acid diamide in the presence of a base; (d) #-keto ester in the presence of ammonia, a primary or secondary amine or an alkali metal hydride; (e) #-diketone in the presence of ammonia, a primary or secondary amine or alkali metal hydride; (f) #-keto amide in the presence of a tertiary amine, an alkali metal hydroxide, and alkali metal alkoxide, or an alkali metal hydride; (g) a primary or secondary nitro compound in the presence of an alkali metal hydroxide, an alkali metal alkoxide or an alkali metal hydride; (h) malononitrile, cyanoacetamide or a cyano acetate with an alkali metal hydride; (i) a pyruvaldehyde acetal other than the dimethyl acetal in the presence of ammonia or a primary, secondary or tertiary amine; (j) an alicyclic ketone in the presence of alkali metal hydroxide, alkoxide or hydride; (k) a heterocyclic ketone in the presence of ammonia, primary, secondary or tertiary amine or an alkali metal hydroxide, alkoxide or hydride; (1) a ketosulphonyl compound or ketosulphonamide in the presence of a base ; or (m) a C 1-7  alkyl-γ-γ-di-(C 1-7  alkoxy)-acetoacetate other than ethyl-γ,γ-diethoxy acetoacetate in the presence of ammonia, a primary, secondary or tertiary amine or an alkali metal hydroxide, alkoxide or hydride. Novel compounds produced by the process are wherein X is fluoro, trifluoromethyl, sulphonamido, N-methyl sulphonamido or N,N-dimethylsulphonamido substituted on one or more positions of the benzene ring of the quinoxaline and each of R<SP>1</SP> and R<SP>11</SP> is hydrogen or C 1-7  alkyl; wherein R 6  is C 1-7  alkoxy, aryloxy, benzyloxy or NR 8 R 9  where R 8  and R 9  are hydrogen, C 1-7  alkyl, or phenyl; and X is hydrogen, chloro, fluoro, methyl, methoxy, trifluoromethyl, sulphonamido, N-methylsulphonamido or N, N-dimethylsulphonamido substituted on one or more positions of the benzene ring of the quinoxaline, excluding the compounds 2-carbomethoxy-3- hydroxy quinoxaline-di-N-oxide and 2-carboethoxy-3-hydroxy quinoline-di-N-oxide; where X is as in Formula XI where X and R 6  are as in Formula XII wherein X is as in Formula XII, R is C 1-7  alkyl and Y<SP>1</SP> is hydrogen, carbo-C 1-7  alkoxy, excluding 2-formyldimethyl-acetal quinoxaline di-N- oxide and 2-carboethoxy-3-formyl-diethyl acetalquinoxaline di-N-oxide; where X is as in Formula XII, R 4  is C 1-7  alkyl or phenyl and m is zero or 1; where X is as in Formula XII, Z is oxygen, sulphur imino or N-methylimino, m is zero or 1 and n is 2 or 3; where X is as in Formula XII, R 7  is C 1-7  alkyl and Z<SP>1</SP> is halogen, C 1-7  alkoxy, C 1-7  alkanoyloxy, cyano, phenoxy, amino, mercapto or C 1-7  alkylmercapto ; where X is as in Formula XII, R 11  and R 12  are each methyl or ethyl optionally substituted'with chloro, bromo, hydroxy or diethylamino or, taken with the carbon to which they are attached, are cyclohexyl, excluding 2,2-dimethyl- 2H-benzimidazole-1,3-dioxide and 2-methyl-2- ethyl-2H-benzimidazole-1,3-dioxide ; where X is as defined in XII and R 10  is hydrogen, optionally substituted alkyl or aryl, carbalkoxy, or carboxamido, excluding 1-hydroxy-2-benzimidazole propionamide-3-oxide and 1-hydroxy- 2-carbethoxy benzimidazole-3-oxide; where X is as defined in Formula XII, m is 2 to 16, R 3  is halogen, hydroxyl, alkoxy, acetoxy, alkyl, aryl, acetyl, amino, alkylamino, arylamino, acylamino, aroylamino, carboxy, carbalkoxy, nitrile or amido. Other known compounds may also be prepared by the process. Methyl γ,γ-diethoxyacetoacetate may be prepared by reaction of ethyl diethoxyacetate and methyl acetate in the presence of sodium, the former reactant being prepared by reaction of sodium ethoxide and dichloroacetic acid. Pharmaceutical compositions of the compounds of the process show antimicrobial activity when administered topically with the usual excipients and many of the compounds described show growth promotion activity in animals, control chronic respiratory disease in pultry, infectious sinusitis in turkeys, urinary-tract and systemic and non-systemic infections in animals. The compounds are also useful as industrial antimicrobials.