Derivatives of 6.beta.-hydroxyalkylpenicillanic acids as .beta.-lactamase inhibitors
AssigneePfizer Inc.
InventorMichael S. Kellogg
Life of this patent
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Abstract
6.beta.-Hydroxyalkylpenicillanic acids and derivatives thereof as useful enhancers of the effectiveness of several .beta.-lactam antibiotics against many .beta.-lactamase producing bacteria, and 6.beta.-substituted penicillanic acid benzyl ester derivatives as useful intermediates leading to said agents which enhance the effectiveness of .beta.-lactam antibiotics.
Claims37
A compound selected from the formulae ##STR21## or pharmaceutically acceptable base salt thereof, wherein R is 1-hydroxy-3-phenylpropyl;
- R.sub.1 is selected from the group consisting of benzyl, hydrogen and ester-forming residues readily hydrolyzable in vivo;
- R.sub.2 is ##STR22## wherein R.sub.3 is selected from the group consisting of sulfo, hydrogen, alkoxycarbonyl having from two to four carbon atoms, alkanoyl having from two to eighteen carbon atoms, benzoyl, substituted benzoyl wherein said substituent is selected from the group consisting of amino, methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl, alkylsulfonyl having from one to four carbon atoms, phenylsulfonyl and substituted phenylsulfonyl wherein said substituent is selected from the group consisting of methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl;
- and R.sub.4 is selected from the group consisting of hydrogen, alkyl having one to four carbon atoms, phenyl, pyridyl, benzyl and .beta.-phenethyl.
A pharmaceutical composition useful for treating bacterial infections in mammals, which comprises a pharmaceutically acceptable carrier, a .beta.-lactam antibiotic and a compound selected from the formulae ##STR23## or a pharmaceutically acceptable base salt thereof, wherein R is selected from the group consisting of alkylsulfonyloxymethyl having from one to four carbon atoms in the alkyl group, phenylsulfonyloxymethyl, substituted phenylsulfonyloxymethyl wherein said substituent is selected from the group consisting of methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl and 1-hydroxy-3-phenylpropyl;
- R.sub.2 is ##STR24## wherein R.sub.3 is selected from the group consisting of sulfo, hydrogen, alkoxycarbonyl having from two to four carbon atoms, alkanoyl having from two to eighteen carbon atoms, benzoyl, substituted benzoyl wherein said substituent is selected from the group consisting of amino, methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl, alkylsulfonyl having from one to four carbon atoms, phenylsulfonyl and substituted phenylsulfonyl wherein said substituent is selected from the group consisting of methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl, and R.sub.4 is selected from the group consisting of hydrogen, alkyl having one to four carbon atoms, phenyl, pyridyl, benzyl and .beta.-phenethyl;
- R.sub.5 is selected from the group consisting of hydrogen and ester-forming residues readily hydrolyzable in vivo.
A method of increasing the effectiveness of a .beta.-lactam antibiotic in a mammalian subject, which comprises co-administering to said subject a .beta.-lactam antibiotic effectiveness increasing amount of a compound of the formulae ##STR25## or a pharmaceutically acceptable base salt thereof, wherein R is selected from the group consisting of alkylsulfonyloxymethyl having from one to four carbon atoms in the alkyl group, phenylsulfonyloxymethyl, substituted phenylsulfonyloxymethyl wherein said substituent is selected from the group consisting of methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl and 1-hydroxy-3-phenylpropyl;
- R.sub.2 is ##STR26## wherein R.sub.3 is selected from the group consisting of sulfo, hydrogen, alkoxycarbonyl having from two to four carbon atoms, alkanoyl having from two to eighteen carbon atoms, benzoyl, substituted benzoyl wherein said substituent is selected from the group consisting of amino, methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl, alkylsulfonyl having from one to four carbon atoms, phenylsulfonyl and substituted phenylsulfonyl wherein said substituent is selected from the group consisting of methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl;
- and R.sub.4 is selected from the group consisting of hydrogen, alkyl having one to four carbon atoms, phenyl, pyridyl, benzyl and .beta.-phenethyl;
- R.sub.5 is selected from the group consisting of hydrogen and ester-forming residues readily hydrolyzable in vivo.
Dependencies are inferred from the claim text.