Mono- and bicyclic DNA gyrase inhibitors

A compound of the formula ##STR86## wherein R.sup.1 is hydrogen, halogen, or optionally substituted lower alkyl, the optional substituent being halogen, R.sup.03 is cyano or optionally substituted esterified carboxy,;

• nitro, COOZ.sup.1, CONH.sub.2, protected amino group, protected hydroxy group, or protected carboxy group;
• R.sup.22 is hydrogen, hydroxy, amino, loweralkylamino, di-loweralkylamino, optionally substituted lower alkoxy, a group -OP, nitro, protected amino group, protected hydroxy group, or protected carboxy group;
• R.sup.31 is hydrogen, hydroxy, lower alkyl, halogen, a group -OP, protected amino group, protected hydroxy group, or protected carboxy group;
• R.sup.41 is halogen, hydroxy, a group -OP, protected amino group, protected hydroxy group, or protected carboxy group;
• R.sup.53 is a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1, COOZ.sup.1, CONH.sub.2, nitro, protected amino group, protected hydroxy group or protected carboxy group;
• R.sup.63 is --NR.sup.7 -A or --N.dbd.B, in which R.sup.7 is hydrogen or lower alkyl, A is optionally substituted imimethyl, optionally substituted (thio)acyl, optionally substituted esterified carboxy, optionally substituted amidated (thio)carboxy or a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1 and B is optionally substituted alkylidene, nitro, --NR.sup.7 Z.sup.2, protected amino group, protected hydroxy group, or protected carboxy group;
• -OP is an easily hydrolyzable group;
• Z.sup.1 is hydrogen or a carboxy protected group;
• and Z.sup.2 is hydroxy or amino protected group, the optionally substituted groups of R.sup.03, R.sup.22, R.sup.53, and R.sup.63 additionally being optionally substituted by nitro and the optionally substituted groups of R.sup.03, R.sup.22, R.sup.31, R.sup.41, R.sup.53, and R.sup.63 being optionally substituted by protected amino group, protected hydroxy group, or protected carboxy group.

A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR87## wherein X.sup.1 is --S-- or --SO--;

• R.sup.1 is hydrogen, halogen or optionally substituted lower alkyl, the optional substituent being halogen;
• R.sup.2 is hydrogen, hydroxy, amino, lower alkylamino, di-lower alkylamino, optionally substituted lower alkoxy or a group -OP;
• OP is an easily hydrolyzable group;
• R.sup.3 is hydrogen, hydroxy, lower alkyl, halogen or a group -OP;
• R.sup.4 is halogen, hydroxy or a group -OP;
• R.sup.5 is a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1;
• R.sup.6 is --NR.sup.7 -A or --N.dbd.B, in which R.sup.7 is hydrogen or lower alkyl, A is optionally substituted iminoyl, optionally substituted (thio)acyl, optionally substituted esterified carboxy, optionally substituted amidated (thio)carboxy or a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1 and B is optionally substituted alkylidene;
• R.sup.0 is cyano or optionally substituted esterified carboxy;
• or the
• pharmaceutically acceptable salts thereof carrying an acidic and/or basic substituent, and a therapeutically inert carrier.

A method of treating bacterial infections in a mammal comprising administering to said mammal in need of such treatment an effective amount of a compound of the formula ##STR88## wherein X.sup.1 is --S-- or --SO--;

• R.sup.1 is hydrogen, halogen or optionally substituted lower alkyl, the optional substituent being halogen;
• R.sup.2 is hydrogen, hydroxy, amino, lower alkylamino, di-lower alkylamino, optionally substituted lower alkoxy or a group -OP;
• OP is an easily hydrolyzable group;
• R.sup.3 is hydrogen, hydroxy, lower alkyl, halogen or a group -OP;
• R.sup.4 is halogen, hydroxy or a group -OP;
• R.sup.5 is a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1;
• R.sup.6 is --NR.sup.7 -A or --N.dbd.B, in which R.sup.7 is hydrogen or lower alkyl, A is optionally substituted iminoyl, optionally substituted (thio)acyl, optionally substituted esterified carboxy, optionally substituted amidated (thio)carboxy or a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more of the following substituents selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy amino, a group -OP, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, heterocycleamino, heterocycleoxy, heterocyclethio, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, quaternary ammonium group, acylamino, amidino optionally mono-, di-, or tri-substituted by lower alkyl, iminoyl optionally mono- or di-substituted by lower alkyl, carbamoyloxy optionally substituted by lower alkyl or lower aryl, lower alkylthio, lower cycloalkyloxy, lower cycloalkylthio, lower alkenylalkoxy, lower alkenylalkylthio, aryloxy, acyloxy, lower alkylsulfinyl or lower alkylsulfonyl, lower alkenylalkylsulfinyl or lower alkenylalkylsulfonyl, lower cycloalkylsulfinyl or lower cycloalkylsulfonyl, arylsulfinyl or arylsulfonyl, or hydroxyimino, or by 1-2 groups of the formula -(E).sub.m -Y, wherein Y is alkyl, alkenyl, alkenylalkyl, alkynylalkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl-lower alkenylalkyl, heterocycle, heterocycle-lower alkyl, heterocycle-lower alkenylalkyl, where heterocycle refers to a 4 to 7 member saturated or unsaturated heterocycle containing 1-4 nitrogen atoms and/or 1-2 sulfur or oxygen atoms which can be optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, lower acyl, halogen, hydroxy, oxo, optionally esterified or amidated carboxy, amino, or a group -OP, and which can be optionally fused to a saturated or unsaturated 5 to 7 membered ring which can contain 1-4 nitrogen atoms and/or a sulfur or oxygen atom, aryl, aryl-lower alkyl, or aryl-lower alkenylalkyl, each of the foregoing Y being optionally substituted by one or more halogen, amino, oxo, thioxo, cyano, nitro, azido, sulfamoyl or aminosulfonyl, lower alkylamino, di-lower-alkylamino, lower cycloalkylamino, di-lower-cycloalkylamino, hydroxy, lower alkoxy, a group -OP, or acylamino and each of the foregoing Y also being optionally substituted by carboxy which is optionally esterified or amidated;
• E is --O--, --S--, --SO.sub.2 --, --COO--, --OCO--, --CONR.sup.7 --, --NR.sup.7 --, --NR.sup.7 --CO--, --NR.sup.7 SO.sub.2 --, --NR.sup.7 COO-- or --NR.sup.7 CONR.sup.7 --, where R.sup.7 is hydrogen or lower alkyl, and m is zero or 1 and B is optionally substituted alkylidene;
• R.sup.0 is cyano or optionally substituted esterified carboxy;
• or the
• pharmaceutically acceptable salts thereof carrying an acidic and/or basic substituent, and a therapeutically inert carrier.