Claims
- 1. A compound of the formula
- wherein
- R.sup.1 is hydrogen, C.sub.1-2 alkyl, --CH.sub.2 OH, --CH.sub.2 NH.sub.2, ##STR687## A is an unsubstituted or hydroxy-substituted straight or branched C.sub.1-10 alkylene group or a straight or branched C.sub.1-10 alkylene group having an intervening heteroatom selected from oxygen, sulfur and nitrogen;
- R.sup.2 is hydroxy, halogen, C.sub.1-4 alkoxy, nitrile, azido, a quaternary ammonio group, --NR.sup.5 R.sup.6, ##STR688## azetidinyl, or a 5- or 6-membered heterocyclic group selected from heteroaromatic and heteroalicyclic joined through a carbon atom thereof;
- B is a straight or branched C.sub.1-6 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is a residue of an organic group;
- R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, hydroxyethyl, azidoethyl, aminoethyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl, R.sup.6 is hydroxy, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)-alkylamino, substituted C.sub.1-4 alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is an unsubstituted or substituted heterocyclic group having 1 to 2 ring members and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, nitrile, carboxy, formimidoyl, carbamido, carbamoyl, C.sub.1-4 alkylamino and amino(C.sub.1-4)alkyl;
- W is a direct bond, oxygen, sulfur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, --NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sub.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy or alkanoyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1 having the formula ##STR689## wherein R.sup.1 is hydrogen, C.sub.1-2 alkyl, --CH.sub.2 OH, --CH.sub.2 NH.sub.2, ##STR690## A is an unsubstituted or hydroxy-substituted straight or branched C.sub.1-10 alkylene group or a straight or branched C.sub.1-10 alkylene group having an intervening heteroatom selected from oxygen, sulfur and nitrogen;
- R.sup.2 is hydroxy, halogen, C.sub.1-4 alkoxy, nitrile, azido, a quaternary ammonio group, --NR.sup.5 R.sup.6, ##STR691## azetidinyl, or a 5- or 6-membered heterocyclic group selected from heteroaromatic and heteroalicyclic joined through a carbon atom thereof;
- B is a straight or branched C.sub.1-6 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is hydrogen, C.sub.3-6 cycloalkyl or substituted C.sub.3-6 cycloalkyl, C.sub.5-6 cycloalkenyl or substituted C.sub.5-6 cycloalkenyl, phenyl or substituted phenyl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, phenylthio or substituted phenylthio, halogen, nitrile,
- nitro, --NR.sup.7 R.sup.8, --.sym.R.sup.9 R.sup.9 R.sup.9, ##STR692## or an unsubstituted or substituted heterocyclic group selected from heteroaromatic, heteroalicyclic, ##STR693## having from one to two rings with 4 to 7 ring members in each ring and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, in which said heterocyclic group may be joined through a sulfur atom attached to a carbon atom of said heterocyclic group, wherein said C.sub.3-6 cycloalkyl, C.sub.5-6 cycloalkenyl, phenyl and heterocyclic substituent is selected from the group consisting of one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, nitrile, carboxy, formimidoyl, carbamido, carbamoyl, amino(C.sub.1-4)alkyl, C.sub.1-4 alkylamino(C.sub.1-4)alkyl, di(C.sub.1-4)alkylamino(C.sub.1-4)alkyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxycarbonyl(C.sub.1-4)alkyl, amino(C.sub.1-4)alkylamino(C.sub.1-4) alkyl and C.sub.1-4 alkylcarbonyloxy, and said heterocyclic group may also be substituted with ##STR694## R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, hydroxyethyl, azidoethyl, aminoethyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl, R.sup.6 is hydroxy, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, substituted (C.sub.1-4)alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is an unsubstituted or substituted azetidino, or an unsubstituted or substituted 5- or 6-membered heterocyclic group having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, nitrile, carboxy, formimidoyl, carbamido, carbamoyl, C.sub.1-4 alkylamino and amino(C.sub.1-4)alkyl;
- n is an integer of from 0 to 2; inclusive;
- W is a direct bond, oxygen, sulfur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, --NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sub.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy, or alkanoyl;
- R.sup.9 is a C.sub.1-4 alkyl or C.sub.2-4 alkenyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 3. A compound of claim 1 having the formula ##STR695## wherein R.sup.1 is ##STR696## A is an unsubstituted or hydroxy-substituted straight or branched C.sub.1-10 alkylene group or a straight or branched C.sub.1-10 alkylene group having an intervening heteroatom selected from oxygen, sulfur and nitrogen;
- R.sup.2 is hydroxy, fluoro, C.sub.1-4 alkoxy, nitrile, azido, a quaternary ammonio group, --NR.sup.5 R.sup.6, ##STR697## azetidinyl, or a 5- or 6-membered heterocyclic group selected from heteroaromatic and heteroalicyclic joined through a carbon atom thereof;
- B is a straight or branched C.sub.1-6 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is hydrogen, C.sub.3-6 cycloalkyl or substituted C.sub.3-6 cycloalkyl, C.sub.5-6 cycloalkenyl or substituted C.sub.5-6 cycloalkenyl, phenyl or substituted phenyl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, phenylthio or substituted phenylthio, halogen, nitrile, --NR.sup.7 R.sup.8, ##STR698## or an unsubstituted or substituted heterocyclic group selected from heteroaromatic, heteroalicyclic, ##STR699## having from one to two rings with 5 to 6 ring members in each ring and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, in which said heterocyclic group may be joined through a sulfur atom attached to a carbon atom of said heterocyclic group, wherein said C.sub.3-6 cycloalkyl, C.sub.5-6 cycloalkenyl, phenyl and heterocyclic substituent is selected from the group consisting of one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, nitrile, carboxy, formimidoyl, carbamido, carbamoyl, amino(C.sub.1-4)alkyl, C.sub.1-4 alkylamino(C.sub.1-4)alkyl, di(C.sub.1-4)alkylamino(C.sub.1-4)alkyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxycarbonyl(C.sub.1-4)alkyl, amino(C.sub.1-4)alkylamino(C.sub.4)alkyl and C.sub.1-4 alkylcarbonyloxy, and said heterocyclic group may also be substituted with ##STR700## R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen and C.sub.1-6 alkyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl, R.sup.6 is hydroxy, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, substituted (C.sub.1-4)alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is an unsubstituted or substituted azetidino, or an unsubstituted or substituted 5- or 6-membered heterocyclic group having up to two heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from the group consisting of C.sub.1-4 alkyl, hydroxy, amino, nitrile, formimidoyl, C.sub.1-4 alkylamino and amino(C.sub.1-4)alkyl;
- n is an integer of from 0 to 2; inclusive;
- W is a direct bond, oxygen, sulfur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sup.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy or alkanoyl;
- R.sup.9 is a C.sub.1-4 alkyl or C.sub.2-4 alkenyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 4. A compound of claim 1 having the formula ##STR701## wherein R.sup.1 is ##STR702## A is a straight or branched C.sub.1-10 alkylene group; R.sup.2 is hydroxy, nitrile, azido, --NR.sup.5 R.sup.6 or ##STR703## B is a straight or branched C.sub.1-6 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is hydrogen, C.sub.3-6 cycloalkyl or substituted C.sub.3-6 cycloalkyl, phenyl or substituted phenyl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, phenylthio or substituted phenylthio, halogen, nitrile, --NR.sup.7 R.sup.8, ##STR704## or an unsubstituted or substituted heterocyclic group selected from heteroaromatic and heteroalicyclic, having from one to two rings with 5 to 6 ring members in each ring and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, in which said heterocyclic group may be joined through a sulfur atom attached to a carbon atom of said heterocyclic group, wherein said C.sub.3-6 cycloalkyl, phenyl and heterocyclic substituent is selected from the group consisting of one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, nitrile, carboxy, formimidoyl, carbamido, carbamoyl, amino(C.sub.1-4)alkyl, C.sub.1-4 alkylamino(C.sub.1-4)alkyl, di(C.sub.1-4)alkylamino(C.sub.1-4)alkyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxycarbonyl(C.sub.1-4)alkyl, amino(C.sub.1-4)alkylamino(C.sub.4)alkyl and C.sub.1-4 alkylcarbonyloxy, and said heterocyclic group may also be substituted with ##STR705## R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen and C.sub.1-6 alkyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl R.sup.6 is substituted (C.sub.1-4)alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is an unsubstituted or substituted azetidino, or an unsubstituted or substituted 5- or 6-membered heterocyclic group having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, in which said heterocyclic group may be joined through a sulfur atom attached to a carbon atom of said heterocyclic group, wherein said substituent is selected from the group consisting of C.sub.1-4 alkyl, amino, formimidoyl, C.sub.1-4 alkylamino and amino(C.sub.1-4)alkyl;
- n is an integer of from 0 to 2; inclusive;
- W is a direct bond, oxygen, sulphur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sub.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy or alkanoyl;
- R.sup.9 is a C.sub.1-4 alkyl or C.sub.2-4 alkenyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 5. A compound of claim 1 having the formula ##STR706## wherein A is a straight or branched C.sub.1-10 alkylene group;
- R.sup.2 is hydroxy, nitrile, azido, --NR.sup.5 R.sup.6 or ##STR707## B is a straight or branched C.sub.1-6 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is hydrogen, substituted C.sub.3-6 cycloalkyl, substituted phenyl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, substituted phenylthio, halogen, nitrile, --NR.sup.7 R.sup.8, ##STR708## or an unsubstituted or substituted heterocyclic group selected from heteroaromatic and heteroalicyclic, having a 5- or 6-membered ring and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, in which said heterocyclic group may be joined through a sulfur atom attached to a carbon atom of said heterocyclic group, wherein said C.sub.3-6 cycloalkyl, phenyl and heterocyclic substituent is selected from the group consisting of one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, hydroxy, halogen, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkyl-amino, nitrile, carboxy, formimidoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxycarbonyl(C.sub.1-4)alkyl, amino(C.sub.1-4)alkylamino(C.sub.1-4)alkyl and C.sub.1-4 alkylcarbonyloxy, and said heterocyclic group may also be substituted with ##STR709## R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen and C.sub.1-6 alkyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl, R.sup.6 is substituted (C.sub.1-4)alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is azetidino, pyrrolidino, pyrrolinio, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, imidazoyl;
- n is an integer of from 0 to 2; inclusive;
- W is a direct bond, oxygen, sulphur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sub.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy or alkanoyl;
- R.sup.9 is a C.sub.1-4 alkyl or C.sub.2-4 alkenyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 6. A compound of claim 1 having the formula ##STR710## wherein A is a straight or branched C.sub.1-8 alkylene group;
- R.sup.2 is --NR.sup.5 R.sup.6 or ##STR711## B is a straight or branched C.sub.1-4 alkylene group or a direct bond when R.sup.3 is joined to the sulfur atom through a carbon atom thereof;
- R.sup.3 is hydrogen, substituted C.sub.3-6 cycloalkyl, substituted phenyl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, substituted phenylthio, fluoro, nitrile, --NR.sup.7 R.sup.8, ##STR712## or an unsubstituted or substituted heterocyclic group selected from heteroaromatic and heteroalicyclic, having a 5- or 6-membered ring and having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said C.sub.3-6 cycloalkyl, phenyl and heterocyclic substituent is selected from the group consisting of methyl, methoxy, trifluoromethyl, hydroxy, halogen, amino, C.sub.1-4 alkylamino, di(C.sub.1-4)alkylamino, nitrile, carboxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkoxycarbonyl(C.sub.1-4) alkyl, amino(C.sub.1-4)alkylamino(C.sub.1-4)alkyl and C.sub.1-4 alkylcarbonyloxy, and said heterocyclic group may also be substituted with ##STR713## R.sup.4 is hydrogen, a removable carboxy-protecting group or a physiologically hydrolyzable ester group;
- R.sup.5 and R.sup.6 each are independently hydrogen and C.sub.1-6 alkyl, and when R.sup.5 is hydrogen or C.sub.1-4 alkyl, R.sup.6 is substituted (C.sub.1-4)alkyl wherein said alkyl substituent is selected from hydroxy, azido, amino, guanidino, nitrile, carboxy, formimidoyl and phenyl, or an acyl residue of an amino acid or peptide; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is azetidino, pyrrolidino, pyrrolinio, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, imidazoyl;
- n is an integer of from 0 to 2; inclusive;
- W is a direct bond, oxygen, sulphur or NR.sup.10 ;
- Y is oxygen or NR.sup.10 ;
- Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, NR.sup.7 R.sup.8, amino(C.sub.1-4)alkyl, azido(C.sub.1-4)alkyl or hydroxy(C.sub.1-4)alkyl;
- R.sup.7 and R.sup.8 each are independently hydrogen, C.sub.1-4 alkyl, hydroxy, benzyloxy or alkanoyl;
- R.sup.9 is a C.sub.1-4 alkyl or C.sub.2-4 alkenyl; and
- R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylamino or di(C.sub.1-4)alkylamino;
- or a non-toxic pharmaceutically acceptable salt thereof.
- 7. A compound of claim 1 wherein R.sup.2 is amino.
- 8. A compound of claim 1 wherein R.sup.2 is dimethylamino.
- 9. A compound of claim 1 wherein R.sup.2 is N-formimidoylamino.
- 10. A compound of claim 1 wherein R.sup.2 is guanidino.
- 11. A compound of claim 1 wherein R.sup.2 is pyrrolidino.
- 12. A compound of claim 1 wherein R.sup.2 is methylamino.
- 13. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(pyridin-2-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 14. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(pyridin-2-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 15. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(1-methylpyridinium-2-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 16. The compound of claim 1 which is (4R,5S,6S)-4-(4"-aminobutyl)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 17. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-4-�4"-(N-formimidoyl)aminobutyl!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 18. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-4-(4"-N,N-dimethylaminobutyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 19. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(pyridin-3-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 20. The compound of claim 1 which is (4R,5S,6S)-4-(2"-N,N-dimethylaminoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(pyridin-3-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!-hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 21. The compound of claim 1 which is (4R,5S,6S)-4-�2"-(N-cyanomethyl-N-methylamino)ethyl!-6-�(1'R)-1'-hydroxyethyl!-3-�(pyridin-3-yl)methylthio!-7-oxo-1-azabicyclo-�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 22. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(2-hydroxyethyl)thio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 23. The compound of claim 1 which is (4R,5S,6S)-4-�3"-(N-formimidoyl)aminopropyl!-6-�(1'R)-1'-hydroxyethyl!-3-�(2-hydroxyethyl)thio!-7-oxo-1-azabicyclo�3.2.0!hept2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 24. The compound of claim 1 which is (4R,5S,6S)-4-�3"-(N-formimidoyl)aminopropyl!-6-�(1'R)-1'-hydroxyethyl!-3-methylthio-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 25. The compound of claim 1 which is (4R,5S,6S)-4-�3"-(N-guanidinyl)aminopropyl!-6-�(1'R)-1'-hydroxyethyl!-3-methylthio-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 26. The compound of claim 1 which is (4R,5S,6S)-4-�3"-(N-guanidinyl)aminopropyl!-6-�(1'R)-1'-hydroxyethyl!-3-�(2-hydroxyethyl)thio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 27. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxy ethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 28. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(1,2,3-thiadiazol-4-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 29. The compound of claim 1 which is (4R,5S,6S)-4-(2"-guanidinoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(1,2,3-thiadiazol-4-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 30. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 31. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-(3"-hydroxypropyl)-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 32. The compound of claim 1 which is (4R,5S,6S)-4-�3"-(N-formimidoyl)aminopropyl!-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 33. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-�(3-cyanopropyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 34. The compound of claim 1 which is (4R,5S,6S)-6-�(1'R)-1'-hydroxyethyl!-4-(2"-aminoethyl)-3�(pyridin-4-yl)methyl- thio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 35. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-4-(3"-guanidinopropyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 36. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-�2"(1-pyrrolidinyl)ethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 37. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-�(1-methyl-1,2,3-triazol-4-yl)methylthio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 38. The compound of claim 1 which is (4R,5S,6S)-4-(4"-aminobutyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(2-hydroxyethyl)thio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 39. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-4-(4"-guanidinobutyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 40. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-4-(2"-guanidinoethyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 41. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(1-methyl-1,2,3-triazol-4-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 42. The compound of claim 1 which is (4R,5S,6S)-3-�(2-carbamoyloxyethyl)thio!-4-�3"-(N-formimidoyl)aminopropyl!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 43. The compound of claim 1 which is (4R,5S,6S)-4-(4"-aminobutyl)-3-�(2-carbamoyloxy)ethylthio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 44. The compound of claim 1 which is (4R,5S,6S)-4-(3"-guanidinopropyl)-6-�(1'R)-1'-hydroxyethyl!-3-�(1,2,3-thiadiazol-4-yl)methylthio!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 45. The compound of claim 1 which is (4R,5S,6S)-3-�(2-carbamoyloxyethyl)thio!-4-(4"-N,N-dimethylaminobutyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 46. The compound of claim 1 which is (4R,5S,6S)-4-(2"-acetaldehydo)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 47. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-(hydroxycarbonylmethyl)-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylate or a non-toxic pharmaceutically acceptable salt thereof.
- 48. The compound of claim 1 which is (4R,5S,6S)-3-{(4S)-4-�(2S)-2-dimethylaminocarbonyl!pyrrolidinylthio}-6-�(1'R)-1'-hydroxyethyl!-4-(2"-hydroxyethyl)-7-oxo-1-azabicyclo-�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 49. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-{(4S)-4-�(2S)-2-dimethylaminocarbonyl!-pyrrolidinylthio}-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 50. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-{(4S)-4-�(2S)-2-dimethylaminocarbonyl!-pyrrolidinylthio}-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 51. The compound of claim 1 which is (4R,5S,6S)-3-((4S)-4-�(2S)-2-dimethylaminocarbonyl!pyrrolidinylthio)-4-(3"-guanidinopropyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 52. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-�(2-aminoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 53. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(2-aminoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 54. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(2-N-formimidoylaminoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 55. The compound of claim 1 which is (4R,5S,6S)-6-�(1'R)-1'-hydroxyethyl!-3-�(2-hydroxyethyl)thio!-4-(2"-aminoethyl)-7-oxo-1-azabicyclo-�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 56. The compound of claim 1 which is (4R,5S,6S)-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-�2"-(1-N-methylpyrrolidinium)ethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylate or a non-toxic pharmaceutically acceptable salt thereof.
- 57. The compound of claim 1 which is (4R,5S,6S)-3-�(2- cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-�2"-(4-methyl- piperazine-1-yl)ethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 58. The compound of claim 1 which is (4R,5S,6S)-4-(3"-guanidinopropyl)-6-�(1'R)-1'-hydroxyethyl!3-(�2-(1-pyrrolidinyl)ethyl!thio)-7-oxo-1-azabicyclo�3.2.0!-hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 59. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(2-N,N-dimethyl aminoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 60. The compound of claim 1 which is (4R,5S,6S)-3-{(4S)-4-�(2S)-2-dimethylaminocarbonyl!pyrrolidinylthio}-4-(2"-guanidinoethyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid salt or a non-toxic pharmaceutically acceptable salt thereof.
- 61. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(N,N-dimethylamidinomethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 62. The compound of claim 1 which is (4R,5S,6S)-4-(2"-guanidinoethyl)-6-�(1'R)-1'-hydroxyethyl!-3-�2-(1-pyrrolidinyl)ethylthio!-7-oxo-1-azabicyclo�3.2.0!-hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 63. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(3S)-3-pyrrolidinylthio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 64. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(2-guanidinoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 65. The compound of claim 1 which is (4R,5S,6S)-4-(2"-guanidinoethyl)-3-�(2-guanidinoethyl)thio!-6-�(1,R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid salt or a non-toxic pharmaceutically acceptable salt thereof.
- 66. The compound of claim 1 which is (4R,5S,6S)-6-�(1'R)-1'-hydroxyethyl!-3-�(2-cyanoethyl)thio!-4-�2"-(.beta.-chloro-L-alanyl-.beta.-chloro-L-alanyl) aminoethyl!-7-oxo-1-azabicyclo�3.2.!-hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 67. The compound of claim 1 which is (4R,5S,6S)-4-(2"-azidoethyl)-3-�(2-fluoroethyl)thio!-6-�(1'R)-1'- hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylate or a non-toxic pharmaceutically acceptable salt thereof.
- 68. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-3-�(4-piperidinyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 69. The compound of claim 1 which is (4R,5S,6S)-4-(2"-aminoethyl)-3-�(N,N-dimethylamidinomethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 70. The compound of claim 1 which is (4R,5S,6S)-3-�(N,N-dimethylamidinomethyl)thio!-4-(2"-guanidinoethyl)-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 71. The compound of claim 1 which is (4R,5S,6S)-3-�(3R)-(pyrrolidin-3-yl)thio!-4-�2"-N-methylaminoethyl!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 72. The compound of claim 1 which is (4R,5S,6S)-4-(2"-N-formimidoyl-N-methylaminoethyl)-3-{�(3R)-(N-formimidoyl-pyrrolidin-3-yl)!thio}-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 73. The compound of claim 1 which is (4R,5S,6S)-4-(3"-aminopropyl)-6-�(1'R)-1'-hydroxyethyl!-3-{�2-(4-methylpiperazin-1-yl)ethyl!thio}-7-oxo-1-azabicyclo-�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 74. The compound of claim 1 which is (4R,5S,6S) 3-{(4S)-4-�(2S)-2-dimethylaminocarbonylpyrrolidinyl!thio}-6-�(1'R)-1'-hydroxyethyl!-4-(2"-N-methylaminoethyl)-7-oxo-1-azabicyclo-�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 75. The compound of claim 1 which is (4R,5S,6S)-3-�(2-fluoroethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-(2"-N-methylaminoethyl)-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 76. The compound of claim 1 which is (4R,5S,6S)-3-�(2-aminoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-4-�(2"S)-(2"-pyrrolidinyl)methyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
- 77. The compound of claim 1 which is (4R,5S,6S)-4-�3"-amino-(2" R or S)-2"-hydroxypropyl!-3-�(2-cyanoethyl)thio!-6-�(1'R)-1'-hydroxyethyl!-7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid or a non-toxic pharmaceutically acceptable salt thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of Ser. No. 08/196876 filed Feb. 15, 1994 which is a continuation of Ser. No. 08/032818 filed Mar. 15, 1993 which is a continuation of Ser. No. 07/708951 filed May 31, 1991 which is a cip of Ser. No. 07/613921 filed Nov. 20, 1990 which is a cip of Ser. No. 07/466017 Jan. 16, 1990 all now abandoned.
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Foreign Referenced Citations (10)
Number |
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10317 |
Apr 1980 |
EPX |
30032 |
Jun 1981 |
EPX |
45198 |
Feb 1982 |
EPX |
71908 |
Feb 1983 |
EPX |
160391 |
Nov 1985 |
EPX |
160876 |
Nov 1985 |
EPX |
170019 |
Feb 1986 |
EPX |
235823 |
Sep 1987 |
EPX |
336143 |
Mar 1989 |
EPX |
433759 |
Jun 1991 |
EPX |
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Entry |
Vasil'Eva C.A. 72 (121120j) 1970. |
Fedin C.A.72 (116554z) 1970. |
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Continuations (3)
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Number |
Date |
Country |
Parent |
196876 |
Feb 1994 |
|
Parent |
32818 |
Mar 1993 |
|
Parent |
708951 |
May 1991 |
|
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
613921 |
Nov 1990 |
|
Parent |
466017 |
Jan 1990 |
|