Back to results
US 5,629,306 AGranted
7-alkylidene cephalosporanic acid derivatives and methods of using the same
AssigneeResearch Corporation Technologies, Inc.
InventorsJohn D. Buynak, Brian Bachmann
Life of this patent
Estimating the term…
Abstract
Derivatives of 7-alkylidene cephalosporanic acid sulfone and the pharmaceutically active salts thereof are found to be potent inhibitors of .beta.-lactamase enzymes.
Claims19
A compound of formula (1) ##STR11## wherein n is 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations.
41 more elements
A compound of formula (1) ##STR12## wherein n is 0 or 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations.
41 more elements
A pharmaceutical composition, comprising:
- a compound of formula (1) ##STR13## wherein n is 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations;
- and
- a pharmaceutically acceptable carrier.
44 more elements
A method of inhibiting .beta.-lactamases, comprising:
- administering to a patient in need thereof an effective amount of at least one compound of formula (1) ##STR14## wherein n is 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -acyloxy or carbamoyloxy;
- k) C.sub.2-10 -acyloxy or carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations.
42 more elements
A method of enhancing the biological activity of a .beta.-lactam antibiotic, comprising:
- coadministering to a patient in need thereof an effective amount of a compound of formula (1) ##STR15## wherein n is 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -acyloxy or carbamoyloxy;
- k) C.sub.2-10 -acyloxy or carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations;
- and
- a pharmaceutically acceptable carrier.
44 more elements
A pharmaceutical composition, comprising:
- a compound of formula (1) ##STR16## wherein n is 0 or 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.5-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations;
- and
- a pharmaceutically acceptable carrier.
44 more elements
A method of inhibiting .beta.-lactamases, comprising:
- administering to a patient in need thereof an effective amount of at least one compound of formula (1) ##STR17## wherein n is 0 or 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-10 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations.
42 more elements
A method of enhancing the biological activity of a .beta.-lactam antibiotic, comprising:
- coadministering to a patient in need thereof an effective amount of a compound of formula (1) ##STR18## wherein n is 0 or 1;
- R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of
- a) hydrogen;
- b) linear or branched C.sub.1-10 -alkyl;
- c) halogen;
- d) hydroxy-C.sub.1-10 -alkyl;
- e) C.sub.1-10 -alkoxy;
- f) C.sub.2-10 -alkanoyloxy;
- g) C.sub.2-10 -alkene;
- h) C.sub.2-10 -alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
- i) C.sub.1-10 -alkoxycarbonyl;
- j) C.sub.1-10 -alkoxycarbamido;
- k) N-C.sub.1-10 -alkoxy-N-C.sub.1-0 -alkylaminocarbonyl;
- l) halo-C.sub.1-10 -alkyl;
- m) C.sub.6-10 -aryl;
- n) C.sub.6-10 -aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
- o) a heterocycle selected from the group consisting of triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl;
- and,
- p) --COOH or --COOY, wherein Y is pharmaceutically acceptable cation;
- R.sub.3 is selected from the group consisting of
- 1) --COOH;
- 2) chlorine or fluorine;
- 3) trifluoromethyl;
- 4) --CHO;
- and,
- 5) --CH.sub.2 M where M is selected from the group consisting of
- a) hydrogen;
- b) halogen;
- c) hydroxy;
- d) C.sub.1-10 -alkoxy;
- e) C.sub.6-10 -aryloxy;
- f) C.sub.6-10 -aryl-C.sub.1-10 -alkoxy;
- g) mercapto;
- h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
- i) C.sub.2-10 -acylthio;
- j) C.sub.2-10 -carbamoyloxy;
- k) C.sub.2-10 -carbamoyloxy substituted with one or more groups selected from the group consisting of --COOH, aminophenyl, phenyl, C.sub.1-6 -alkyl, chlorine, bromine or fluorine;
- l) a quaternary ammonium salt;
- m) amino or amido;
- and,
- n) amino or amido substituted with one or more groups selected from the group consisting of C.sub.1-10 -alkyl groups;
- R.sub.4 is selected from the group consisting of
- a) hydrogen;
- and,
- b) pharmaceutically acceptable cations;
- and
- a pharmaceutically acceptable carrier.
44 more elements
Dependencies are inferred from the claim text.