Patent GB-1466954-A (GB)
Title: 3-oxyiminomethyl or oxyiminoethyl- cephalasporins their preparation and use
IPC: C07D501/46
Filed: 1974-02-28
Abstract: 1466954 Oximes of 3-(acetyl or formyl)- cephalosporins SHIONOGI & CO Ltd 28 Feb 1974 [28 Feb 1973] 9168/74 Heading C2C Compounds I and salts thereof wherein X is two hydrogens, hydrogen and a monovalent amino-protecting group, two monovalent amino-protecting groups, or a divalent amino-protecting group; Y is hydrogen or methoxy; R is hydrogen or methyl; and R<SP>1</SP> is hydrogen, a group containing up to 12 carbon atoms which is an alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, aralkyl, aralkenyl or aralkynyl group, aryl containing 6 to 12 carbon atoms, or mono- or dicyclic heterocyclic aryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and/or sulphur, R<SP>1</SP> being, where possible, optionally substituted, which process comprises reacting a reactive derivative of a compound II with a compound NH 2 OR<SP>1</SP> or a reactive derivative thereof and optionally converting the product obtained into a salt. Compound I as defined above except for those of Formula IV in which n is 0, R is hydrogen, C 1  to C 8 -alkanoyl, C 2  to C 8 -chloro- or bromoalkanoyl, azidoacetyl, cyanoacetyl, a group Ar-CQQ-CO- (where each Q denotes hydrogen or methyl, and Ar denotes 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, or phenyl substituted with chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxy, C 1  to C 3 -alkyl, C 1  to C 3 -alkyloxy, cyano or nitro, at least one of such substituents being in the meta or para position of the phenyl ring); where X denotes oxygen or sulphur, and G is selected from the same groups Ar defined above; or G is 4-pyridyl where X is sulphur; a group Ar-CH(B)-CO- (where Ar is defined above and B denotes -NH 2 , -NH 3 <SP>(+)</SP>, an amino group protected with a benzyloxycarbonyl, a C 1  to C 4 -alkoxycarbonyl cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, triphenylmethyl, 2,2,2- trichloroethoxycarbonyl), -SO 3 H, phthalimido, the enamine from amino and methyl acetoacetate or acetylacetone, or B is OH, or such -OH group protected by esterification with a C 1  to C 6 -alkanoic acid, -COOH, or such -COOH group protected by esterification with a C 1  to C 6 -alkanol, or B is -N 3 , -CN, -C(O)NH 2 , or R is 2-sydnone-3-C 1  to C 3 -alkanoyl, or a group of Formula V where m is 0, 1 or 2; 5-aminoadipoyl, or 5- aminoadipoyl in which the amino group is protected with a C 1  to C 3 -alkanoyl or C 1  to C 3 - chloroalkanoyl group, and those aminoadipoyl groups in which the carboxy groups are protected with benzhydryl, 2,2,2-trichloroethyl, C 4  to C 6  alkyl or nitrobenzyl; R<SP>1</SP> is hydrogen or R and R<SP>1</SP> taken together with the nitrogen to which they are bonded denote H 3 N-<SP>(+)</SP>, a salt group with an acid having a pKa of less than 4, or a cyclic imide group from a C 3  to C 12 - hydrocarbon dicarboxylic acid; a group of Formula VI where Z is (-CH 2 -)y where y is 1 or 2 or Z is -O-; or R and R<SP>1</SP> taken together with the nitrogen to which they are bonded denotes the group (C 1  to C 2 -alkyl) 2 -N-CH=N-; R<SP>2</SP> is hydrogen; and Y is -H, -C 1  to C 6 -alkyl, C 2  to C 6 -haloalkyl where the halogen is chlorine or bromine, -C 6  to C 12 -aromatic hydrocarbon, -C 4  to C 7 -cycloalkyl, -C 1  to C 3 -alkylene-X-, C 1  to C 3 -alkyl, where X is oxygen or sulphur, -CH 2 COOR<SP>3</SP> where R<SP>3</SP> is hydrogen or a C 1  to C 6 -alkyl, or and the pharmaceutically acceptable salts of such compounds, are novel and are, in addition, prepared by reacting a compound II with NH 2 OR<SP>1</SP> or a reactive derivative thereof. Known methods for preparing compounds I which are used are (i) reduction of the corresponding S-oxide, (ii) acylation of 7-#-amino compounds to prepare amido derivatives, (iii) removal of a protecting diphenylmethyl group at the 4-carboxy position, (iv) deacylation of 7-#- optionally substituted alkanoylamino derivatives to prepare 7-#-amino compounds, (v) acid hydrolysis of the bis-diphenylmethyl ester of 3-(carboxymethoxyiminomethyl)-7-(2- thienylacetamido) - 3 - cephen - 4 - carboxylic acid to given the di-acid and (vi) acid hydrolysis to remove the t-butoxy carbonyl and diphenylmethyl protecting groups from diphenylmethyl 3 - methoxyiminomethyl - 7 - (N - t - butoxycarbonyl - α - phenylglycyl)amino - 3 - cephen- 4-carboxylate.  Compounds I have anti-bacterial activity and form with a carrier or diluent a pharmaceutical composition which may be administered orally, parenterally or topically. The compounds may also be used in compositions for treating plants and perishable goods.