US 6,150,350 AGranted

Antimicrobial compositions

AssigneeHoffman-La Roche Inc.

InventorsPeter Angehrn, Ingrid Heinze-Krauss, Malcolm Page, Hans G. F. Richter

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Abstract

The invention relates to antimicrobial compositions comprising a combination of (1) a therapeutically effective amount of a compound of formula I ##STR1## with (2) a second ingredient selected from carbapenem antibiotics or with .beta.-lactamase inhibitors, to the use of the compositions for producing a medicament for the treatment and prophylaxis of infectious diseases, including MRSA infections, and to pharmaceutical compositions containing the combination.

Claims17

Dependent claims

A pharmaceutical composition comprising an antimicrobially effective amount of a first compound selected from the group consisting of

(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(2,4,5-trichloro-pheny lsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(]-benzothiazol-2-ylsu lfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-3-(1-cyclopropylm ethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oc t-2-ene-2-carboxylic acid;
(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrroidin-3-ylidenemethyl]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)- acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-3-[1-[1-[(3-Fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1 -ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2-(naphthalen-2-ylsul fanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylat e;
(E)-(6R,7R)-3-[1-(3-Hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo -7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4. 2.0]oct-2-ene-2-carboxylic acid;
(E)-(6R,7S)-3-[1-(3-Hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo -7-[2-naphthalen-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylic acid;
(E)-(6R,7R)-3-[(R)- and -[(S)-2-oxo-[1,3']Bipyrrolidinyl-3-ylidene-methyl]-8-oxo-7-[2-(2,4,5-trich loro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid hydrochloride;
(E)-(6R,7R)-3-[1-[1-[(3-Fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1 -ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfany l-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-7-[2-(2,5-Dichloro-phenylsulfanyl)-acetylamino]-3-[1-[(3-fluoro -4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylate;
(E)-(6R,7R)-8-oxo-3-[(R)-2-oxo-[1,3']Bipyrrolidinyl-3-ylidenemethyl]-7-[2-( phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxy lic acid hydrochloride;
(E)-(6R,7R)-3-(1-Cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(naphth alene-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene -2-carboxylic acid;
(E)-(6R,7R)-3-[1-(4-Hydroxy-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2- (naphthalene-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oc t-2-ene-2-carboxylic acid sodium salt (1:1);
and
(E)-(6R,7R)-8-Oxo-3-[2-oxo-1-(4-sulfamoyl-benzyl)-pyrrolidin-3-ylidenemethy l]-7-[2-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2 -carboxylic acid;
as well as readily hydrolyzable esters thereof and their hydrates and pharmaceutically acceptable salts thereof and their hydrates;
and a second compound selected from the group consisting of carbapenem antibiotics and pharmaceutically acceptable salts thereof and .beta.-lactamase inhibitors and phamaceutically acceptable salts thereof;
and a therapeutically inert carrier.

15 more elements

Dependencies are inferred from the claim text.

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Abstract

A pharmaceutical composition comprising an antimicrobially effective amount of a first compound selected from the group consisting of

(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(2,4,5-trichloro-pheny lsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(]-benzothiazol-2-ylsu lfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-3-(1-cyclopropylm ethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oc t-2-ene-2-carboxylic acid;
(E)-(6R,7R)-3-[1-[1-[(4-Hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl methyl]-2-oxo-pyrroidin-3-ylidenemethyl]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)- acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-3-[1-[1-[(3-Fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1 -ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2-(naphthalen-2-ylsul fanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylat e;
(E)-(6R,7R)-3-[1-(3-Hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo -7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4. 2.0]oct-2-ene-2-carboxylic acid;
(E)-(6R,7S)-3-[1-(3-Hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo -7-[2-naphthalen-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylic acid;
(E)-(6R,7R)-3-[(R)- and -[(S)-2-oxo-[1,3']Bipyrrolidinyl-3-ylidene-methyl]-8-oxo-7-[2-(2,4,5-trich loro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid hydrochloride;
(E)-(6R,7R)-3-[1-[1-[(3-Fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1 -ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfany l-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
(E)-(6R,7R)-7-[2-(2,5-Dichloro-phenylsulfanyl)-acetylamino]-3-[1-[(3-fluoro -4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-yl ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylate;
(E)-(6R,7R)-8-oxo-3-[(R)-2-oxo-[1,3']Bipyrrolidinyl-3-ylidenemethyl]-7-[2-( phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxy lic acid hydrochloride;
(E)-(6R,7R)-3-(1-Cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(naphth alene-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene -2-carboxylic acid;
(E)-(6R,7R)-3-[1-(4-Hydroxy-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2- (naphthalene-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oc t-2-ene-2-carboxylic acid sodium salt (1:1);
and
(E)-(6R,7R)-8-Oxo-3-[2-oxo-1-(4-sulfamoyl-benzyl)-pyrrolidin-3-ylidenemethy l]-7-[2-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2 -carboxylic acid;
as well as readily hydrolyzable esters thereof and their hydrates and pharmaceutically acceptable salts thereof and their hydrates;
and a second compound selected from the group consisting of carbapenem antibiotics and pharmaceutically acceptable salts thereof and .beta.-lactamase inhibitors and phamaceutically acceptable salts thereof;
and a therapeutically inert carrier.

15 more elements