Penicillanic acid 1,1-dioxides as β-lactamase inhibitors

Claim 1

A compound of the formula ##STR14## and the pharmaceutically-acceptable base salts thereof, wherein R 1 is selected from the group consisting of hydrogen, alkanoyloxymethyl having from 3 to 8 carbon atoms, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-[alkoxycarbonyl]-amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton -4-yl, tetrahydropyranyl, benzyl, 4-nitrobenzyl, benzyhdryl, 2,2,2-trichloroethyl, t-butyl and phenacyl.

Claim 20

A method of treating a bacterial infection in a mammal subject which comprises administering to said subject (A) a β-lactam antibiotic and (B) a compound of the formula ##STR16## or a pharmaceutically acceptable base salt thereof, the weight ratio of (A) to (B) administered being in the range of from 1:3 to 3:1, the combined amounts of (A) and (B) administered constituting an antibacterially effective dosage, R 1 being selected from the group consisting of hydrogen, alkanoyloxymethyl having from 3 to 8 carbon atoms, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1-(alkoxycarbonyloxy)-ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-[alkoxycarbonyl]amino)ethyl having from: 4to 10 carbon atoms, 3-phthalidyl,4-crotonolactonyl and γ-butyrolacton-4-yl and said β-lactam antibiotic being selected from the group consisting of: 6-(2-phenylacetamido)penicillanic acid, 6(2-phenoxyacetamido)penicillanic acid, 6(2-phenylpropionamido)penicillanic acid, 6-(D-2-amino-2-phenylacetamido)penicillanic acid, 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid, 6-(D-2-amino-2-[1,4-cyclohexadienyl]acetamido)penicillanic acid, 6-(1-aminocyclohexanecarboxamido)penicillanic acid, 6-(2-carboxy-2-phenylacetamido)penicillanic acid, 6-(2-carboxy-2-[3-thienyl]acetamido)penicillanic acid, 6-(D-2-[4-ethylpiperazin-2,3-dione-1-carboxamido]-2-phenylacetamido)penicillanic acid, 6-(D-2-[4-hydroxy-1,5-naphthyridine-3-carboxamido]-2-phenylacetamido)-penicillanicacid, 6-(D-2-sulfo-2-phenylacetamido)penicillanic acid, 6-(D-sulfoamino-2-phenylacetamido)penicillanic acid, 6-(D-2-[imidazolidin-2-one-1-carboxamido]-2-phenylacetamido)penicillanic acid, 6-(D-[3-methylsulfonylimidazolidin-2-one-1-carboxamido]-2-phenylacetamido)-penicillanic acid, 6-(hexahydro-1H-azepin-1-yl]methyleneamino)penicillanic acid, acetoxymethyl 6-(2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, pivaloyloxymethyl 6-(2-phenylacetamido)penicillanate, pivaloyloxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, pivaloyloxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(2-phenylacetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 3-phthalidyl 6-(2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 6-(2-phenoxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)penicillanic acid, 6-(2-phenoxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-[3-thienyl]acetamido)penicillanic acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)penicillanic acid, 7-(2-[2-thienyl]acetamido)cephalosporanic acid, 7-(2-[1-tetrazolyl]acetamido-3-(2-[5-methyl-1,3,4-thiadiazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)desacetoxycephalosporanic acid, 7-α-methoxy-7-(2-[2-thienyl]acetamido)-3-carbamoyloxymethyl-3-desacetoxymethyl-cephalosporanic acid, 7-(2-cyanoacetamido)cephalosporanic acid, 7-(D-2-hydroxy-2-phenylacetamido)-3-(5-[1-methyltetrazolyl]thiomethyl)-3-des-acetoxymethylcephalosporanic acid, 7-(2-[4-pyridylthio]acetamido)cephalosporanic acid, 7-(D-2-amino-2-[1,4-cyclohexadienyl]acetamido)cephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)cephalosporanic acid, and the pharmaceutically-acceptable salts thereof.

Claim 21

A method of treating a bacterial infection in a mammal subject which comprises administering to said subject (A) a β-lactam antibiotic and (B) a compound of the formula ##STR16## or a pharmaceutically acceptable base salt thereof, the weight ratio of (A) to (B) administered being in the range of from 1:3 to 3:1, the combined amounts of (A) and (B) administered constituting an antibacterially effective dosage, R 1 being selected from the group consisting of hydrogen, alkanoyloxymethyl having from 3 to 8 carbon atoms, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1-(alkoxycarbonyloxy)-ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-[alkoxycarbonyl]amino)ethyl having from: 4to 10 carbon atoms, 3-phthalidyl,4-crotonolactonyl and γ-butyrolacton-4-yl and said β-lactam antibiotic being selected from the group consisting of: 6-(2-phenylacetamido)penicillanic acid, 6(2-phenoxyacetamido)penicillanic acid, 6(2-phenylpropionamido)penicillanic acid, 6-(D-2-amino-2-phenylacetamido)penicillanic acid, 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid, 6-(D-2-amino-2-[1,4-cyclohexadienyl]acetamido)penicillanic acid, 6-(1-aminocyclohexanecarboxamido)penicillanic acid, 6-(2-carboxy-2-phenylacetamido)penicillanic acid, 6-(2-carboxy-2-[3-thienyl]acetamido)penicillanic acid, 6-(D-2-[4-ethylpiperazin-2,3-dione-1-carboxamido]-2-phenylacetamido)penicillanic acid, 6-(D-2-[4-hydroxy-1,5-naphthyridine-3-carboxamido]-2-phenylacetamido)-penicillanicacid, 6-(D-2-sulfo-2-phenylacetamido)penicillanic acid, 6-(D-sulfoamino-2-phenylacetamido)penicillanic acid, 6-(D-2-[imidazolidin-2-one-1-carboxamido]-2-phenylacetamido)penicillanic acid, 6-(D-[3-methylsulfonylimidazolidin-2-one-1-carboxamido]-2-phenylacetamido)-penicillanic acid, 6-(hexahydro-1H-azepin-1-yl]methyleneamino)penicillanic acid, acetoxymethyl 6-(2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, acetoxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, pivaloyloxymethyl 6-(2-phenylacetamido)penicillanate, pivaloyloxymethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, pivaloyloxymethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(2-phenylacetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 1-(ethoxycarbonyloxy)ethyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 3-phthalidyl 6-(2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-phenylacetamido)penicillanate, 3-phthalidyl 6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)penicillanate, 6-(2-phenoxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)penicillanic acid, 6-(2-phenoxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-tolyloxycarbonyl-2-[3-thienyl]acetamido)penicillanic acid, 6-(2-[5-indanyloxycarbonyl]-2-[3-thienyl]acetamido)penicillanic acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)penicillanic acid, 7-(2-[2-thienyl]acetamido)cephalosporanic acid, 7-(2-[1-tetrazolyl]acetamido-3-(2-[5-methyl-1,3,4-thiadiazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)desacetoxycephalosporanic acid, 7-α-methoxy-7-(2-[2-thienyl]acetamido)-3-carbamoyloxymethyl-3-desacetoxymethyl-cephalosporanic acid, 7-(2-cyanoacetamido)cephalosporanic acid, 7-(D-2-hydroxy-2-phenylacetamido)-3-(5-[1-methyltetrazolyl]thiomethyl)-3-des-acetoxymethylcephalosporanic acid, 7-(2-[4-pyridylthio]acetamido)cephalosporanic acid, 7-(D-2-amino-2-[1,4-cyclohexadienyl]acetamido)cephalosporanic acid, 7-(D-2-amino-2-phenylacetamido)cephalosporanic acid, and the pharmaceutically-acceptable salts thereof.