Propenyl cephalosporin derivatives and process for the manufacture thereof

A compound of the formula

• in which R1 is hydrogen, lower alkyl, or phenyl;
• Hal is halogen;
• A+ is a quaternary nitrogen residue substituted by an organic residue with a molecular weight not exceeding 400 of the formula
• wherein R2, R3 and R4 may be the same or different and each are taken from the group consisting of alkyl, substituted alkyl, cycloalkyl, alkenylalkyl, saturated heterocyclyl and saturated heterocyclyl substituted by one or more substituents;
• or
• R2 and R3 together with the N atom represent a ring taken from the group consisting of saturated 5 to 8 membered heterocyclic rings, partly unsaturated 5 to 8 membered heterocyclic rings, saturated fused 10 to 14 membered heterocyclic rings, partly unsaturated fused 10 to 14 membered heterocyclic rings and said heterocyclic rings substituted by one or more substituents R8, said ring having one or more hetero atoms, R4 being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or vinylene bridge to the heterocyclic ring represented by R2 and R3;
• or
• R2, R3 and R4 together with the N atom represent a ring taken from the group consisting of aromatic 5 and 6 membered heterocyclic rings, aromatic 10 to 12 membered fused heterocyclic rings and said heterocyclic rings substituted by one or more substituents R8, said ring having one or more hetero atoms;
• and
• A is a secondary or tertiary nitrogen residue substituted by an organic residue with a molecular weight not exceeding 400 of the general formula
• wherein R5 and R6 may be the same or different and each are taken from the group consisting of unsubstituted alkyl, hydroxy-, lower alkoxy-, cyano-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, or one to three halogen-substituted alkyl, cycloalkyl, alkenylalkyl, heterocyclyl, and heterocyclyl substituted by one or more substituents R8, or R5 is hydrogen;
• or R5 and R6 together with the N atom represent a ring taken from the group consisting of 5 and 6 membered heterocyclic rings, 10 to 12 membered fused heterocyclic rings and any of said heterocyclic rings substituted by one, or more substituents R8, said ring having one or more hetero atoms, and wherein, where R2, R3, R4, R5 or R6 represent substituted alkyl, the substituent of the alkyl group is carbamoyloxy or one or more substituents R7;
• and esters and salts thereof;
• wherein R7 is taken from the group consisting of halogen, lower cycloalkyl, naphthyl, phenyl or heterocyclyl, lower alkoxy- cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen,- lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alky amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl-, or one to three halogen-substituted, hydroxy, acylated hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-, carbamoyl-, or one to three halogen-substituted, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy, the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, methoxy, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, cyano, amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino;
• and
• wherein R8 is taken from the group consisting of halogen, the subgroup of lower alkyl and lower alkenyl and lower cycloalkyl any one of which is unsubstituted or is hydroxy-, lower alkoxy-, cyano-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyl-oxy-, or one to three halogen-substituted, unsubstituted phenyl or heterocyclyl, lower alkoxy- cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen-, lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl- or one to three halogen-substituted, hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-, carbamoyl-, or one to three halogen-substituted, acylated hydroxy, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy or the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, methoxy, carboxy-, carbamoyl-, carbamoyloxy, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, sulfonyl, lower alkylsulfonyl, phenylsulfonyl, and cyano.

A compound of the formula

• in which R1 is hydrogen, lower alkyl, or phenyl;
• Rh represents a negative charge when Am has a net positive charge or a carboxy protecting group when Am has no net positive charge;
• Rk is an organic residue with a molecular weight not exceeding 400 and is taken from the group consisting of lower alkyl, lower alkenyl, lower alkyl substituted by one or more substituent(s) R7 and lower alkenyl substituted by one or more substituent(s) R7, wherein R7 is taken from the group consisting of halogen, lower cycloalkyl, naphthyl, phenyl or heterocyclyl, lower alkoxy- cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen,- lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alky amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl-, or one to three halogen-substituted, hydroxy, acylated hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-,carbamoyl-, or one to three halogen-substituted, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy, the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, cyano, amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino;
• or
• is taken from the group consisting of phenyl, naphthyl, heterocyclyl, phenyl substituted by one or more substituents R8, naphthyl substituted by one or more substituents R8, and heterocyclyl substituted by one or more substituents R8,
• wherein R8 is taken from the group consisting of halogen, the subgroup of lower alkyl and lower alkenyl and lower cycloalkyl any one of which is unsubstituted or is hydroxy-, lower alkoxy-, cyano-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyl-oxy-, or one to three halogen-substituted, unsubstituted phenyl or heterocyclyl, lower alkoxy- cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen-, lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl- or one to three halogen-substituted, hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-, carbamoyl-, or one to three halogen-substituted, acylated hydroxy, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy or the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, sulfonyl, lower alkylsulfonyl, phenylsulfonyl, and cyano;
• Am is a quaternary nitrogen residue substituted by an organic residue with a molecular weight not exceeding 400 of the formula
• wherein R2, R3 and R4 may be the same or different and each are taken from the group consisting of unsubstituted alkyl, hydroxy-, lower alkoxy-, cyano-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, or one to three halogen-substituted alkyl, cycloalkyl, alkenylalkyl, saturated heterocyclyl and saturated heterocyclyl substituted by one or more substituents R8;
• or
• R2 and R3 together with the N atom represent a ring taken from the group consisting of saturated 5 to 8 membered heterocyclic rings, partly unsaturated 5 to 8 membered heterocyclic rings, saturated fused 10 to 14 membered heterocyclic rings, partly unsaturated fused 10 to 14 membered heterocyclic rings and said heterocyclic rings substituted by one or more substituents R8, said ring having one or more hetero atoms,
• R4 being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or vinylene bridge to the heterocyclic ring represented by R2 and R3;
• or
• R2, R3 and R4 together with the N atom represent a ring taken from the group consisting of aromatic 5 and 6 membered heterocyclic rings, aromatic 10 to 12 membered fused heterocyclic rings and said heterocyclic rings substituted by one or more substituents R8, said ring having one or more hetero atoms;
• or
• Am is s secondary or tertiary nitrogen residue substituted by an organic residue with a molecular weight not exceeding 400 of the general formula
• wherein R5 and R6 may be the same or different and each are taken from the group consisting of unsubstituted alkyl, hydroxy-, lower alkoxy-, cyano-, carboxy-, amino, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, or one to three halogen-substituted alkyl, cycloalkyl, alkenylalkyl, heterocyclyl, and heterocyclyl substituted by one or more substituents R8, or R5 is hydrogen;
• or R5 and R6 together with the N atom represent a ring taken from the group consisting of 5 and 6 membered heterocyclic rings, 10 to 12 membered fused heterocyclic rings and any of said heterocyclic rings substituted by one or more substituents R8, said ring having one or more hetero atoms, and wherein, where R2, R3, R4, R5 or R6 represent substituted alkyl, the substituent of the alkyl group is carbamoyloxy or one or more substituents R7;
• and in addition with the proviso that at least one of the following provisions is fulfilled:
• (i) Rh is a carboxylic acid protecting group,
• (ii) Rk includes therein, at least one of a protected amino group, a protected hydroxy group and a protected carboxylic group,
• (iii) Am includes therein, at least one of a protected amino group, a protected hydroxy group and a protected carboxylic group.

A compound of the formula

• in which R is an organic residue with a molecular weight not exceeding 400 and is taken from the group consisting of lower alkyl, lower alkenyl, lower alkyl substituted by one or more substituent(s) R7 and lower alkenyl substituted by one or more substituent(s) R7, wherein R7 is taken from the group consisting of halogen, lower cycloalkyl, naphthyl, phenyl or heterocyclyl, lower alkoxy- cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen-, lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alky amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl-, or one to three halogen-substituted, hydroxy, acylated hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-, carbamoyl-, or one to three halogen-substituted, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy, the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, cyano, amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino;
• or
• is taken from the group consisting of phenyl, naphthyl, heterocyclyl, phenyl substituted by one or more substituents R8, naphthyl substituted by one or more substituents R8, and heterocyclyl substituted by one or more substituents R8,
• wherein R8 is taken from the group consisting of halogen, the subgroup of lower alkyl and lower alkenyl and lower cycloalkyl any one of which is unsubstituted or is hydroxy-, lower alkoxy-, cyano-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyl-, oxy-, or one to three halogen-substituted, unsubstituted phenyl or heterocyclyl, lower alkoxy-, cyano-, hydroxy-, carbamoyl-, or one to three halogen-substituted phenyl or hydroxy-, halogen-, lower alkoxy-, carboxy-, amino-, lower alkyl amino-, di lower alkyl amino-, cyano-, or oxo-substituted heterocycyl, the subgroup of lower alkanoyl and lower cycloalkanoyl and benzoyl, any one of which is unsubstituted or hydroxy-, lower alkoxy-, amino-, lower alkyl amino-, di lower alkyl amino-, carbamoyl-, carbamoyloxy-, cyano-, phenyl- or one to three halogen-substituted, hydroxy, the subgroup of lower alkoxy and phenoxy and lower cycloalkoxy any one of which is unsubstituted or amino-, hydroxy-, methoxy-, carbamoyloxy-, carboxy-, carbamoyl-, or one to three halogen-substituted, acylated hydroxy, amino, acylated amino, (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino, carboxy, esterified carboxy or the subgroup of carbamoyl and lower alkyl carbamoyl and di lower alkyl carbamoyl and lower cycloalkyl carbamoyl each of which is unsubstituted or amino-, lower alkyl amino-, di lower alkyl amino-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, the subgroup of lower alkylthio and lower cycloalkylthio and phenylthio and lower alkyl amino sulfonyl and cycloalkyl amino sulfonyl any one of which is unsubstituted or amino-, lower alkyl amino-, dilower alkyl amino-, hydroxy-, methoxy-, carboxy-, carbamoyl-, carbamoyloxy-, or one to three halogen-substituted, lower alkylsulfinyl, phenylsulfinyl, sulfonyl, lower alkylsulfonyl, phenylsulfonyl, and cyano;
• R1 is hydrogen, lower alkyl, or phenyl;
• and Re is a carboxy protecting group.