Heterocyclic compounds as inhibitors of beta-lactamases

A pharmaceutical composition comprising a bacterial β-lactamase inhibitory amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I):

• wherein R1 is hydrogen, COOH, CN, COOR, CONR6R7, (CH2)n′R5 or C(═NR6)NHR7;
• R is selected from the group consisting of alkyl containing 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, —CH2-alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms, wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH2, NO2, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms;
• R6 and R7 are identical or different and are independently selected from the group consisting of hydrogen, alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms optionally substituted by a carbamoyl, ureido or dimethylamino radical, and alkyl containing 1 to 6 carbon atoms substituted by a pyridyl radical;
• n′ is 1 or 2;
• R5 is selected from the group consisting of COOH, CN, OH, NH2, CO-NR6R7, COOR, OR, OCHO, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOH, NHCOR, NHSO2R, NH—COOR, NH—CO—NHR and NHCONH2 wherein R, R6 and R7 are as defined above;
• R2 is hydrogen or (CH2)n′1R5 wherein n′1 is 0, 1 or 2, and R5 is as defined above;
• R3 is hydrogen or alkyl containing 1 to 6 carbon atoms;
• A is a
• group wherein R4 is hydrogen or (CH2)n′1R5 and n′1 and R5 are as defined above, and the dotted line is an optional bond with one of the two carbons which carry R1 and R2;
• n is 1;
• X is a divalent —C(O)—B— group linked to the nitrogen atom by the carbon atom wherein B is a divalent —O—(CH2)n″— group linked to the carbonyl by the oxygen atom, a divalent —NR8—(CH2)n″— or —NR8—O— group linked to the carbonyl by the nitrogen atom, n″ is 0, and wherein B is —NR8—(CH2)n″—, R8 is selected from the group consisting of hydrogen, OH, R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2SOmR, OSiRaRbRc and SiRaRbRc and wherein B is —NR8—O—, R8 is selected from the group consisting of hydrogen, R, Y, Y1, Y2, Y3 and SiRaRbRc, wherein Ra, Rb and Rc is each independently a linear or branched alkyl containing 1 to 6 carbon atoms or aryl containing 6 to 10 carbon atoms, R is as defined above and m is 0, 1 or 2;
• Y is selected from the group consisting of COH, COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN, CH2tetrazole, protected CH2tetrazole, CH2SO3H, CH2SO2R, CH2PO(OR)2, CH2PO(OR)(OH), CH2PO(R)(OH) and CH2PO(OH)2;
• Y1 is selected from the group consisting of SO2R, SO2NHCOH, SO2NHCOR, SO2NHCOOR, SO2NHCONHR, SO2NHCONH2 and SO3H;
• Y2 is selected from the group consisting of PO(OH)2, PO(OR)2, PO(OH)(OR) and PO(OH)(R);
• Y3 is selected from the group consisting of tetrazole, tetrazole substituted by R, squarate, NH or NR-tetrazole, NH or NR-tetrazole substituted by R, NHSO2R and NRSO2R wherein R is as defined above;
• and
• R1, R2 and R3 are not simultaneously hydrogen when n is 1,
• R4 is hydrogen and
• X is —C(O)—O—(CH2)n″ wherein n″ is 0, or
• , or
• X is —CO—NR8—(CH2)n″ wherein n″ is 0 and R8 is hydrogen or phenyl;
• and a therapeutically effective amount of a β-lactamine antibiotic.