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US 7,405,210 B2Granted
Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
AssigneeOSI Pharmaceuticals, Inc.
InventorsStuart Edward Bradley, Thomas Martin Krulle, Peter John Murray, Martin James Procter, Robert John Rowley, Colin Peter Sambrook Smith, Gerard Hugh Thomas
Life of this patent
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Abstract
Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
Claims20
A compound of Formula (I):
- or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- X3 is N;
- and X1, X2, and X4 are each C;
- R1 and R1′ are each independently, halogen, hydroxy, cyano, C0-4alkyl, C1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
- R2 is C0-4alkyl, COOR6, COR6, C1-4alkoxyC1-4alkyl-, hydroxyC1-4alkyl-, arylC0-4alkyl-, hetarylC0-4alkyl-, wherein any of the aryl or hetaryl rings are optionally substituted with 1–2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
- Y is C0-2alkyl or —CH(OH)—;
- Z is CH2, —C(O)—, —O—, >N(C0-4alkyl), >N(C3-6cycloalkyl), or absent;
- but when Y is —CH(OH)—, Z or R3 must be bonded to Y through a carbon-carbon bond;
- R3 is hydrogen, —COOC0-4alkyl, C1-4alkoxy, C1-4alkyl, arylC1-4alkylthio-, —C0-4alkylaryl, —C0-4alkylhetaryl, —C0-4alkylcycloalkyl or —C0-4alkylheterocyclyl, wherein any of the rings is optionally substituted with 1–3 independent halogen, cyano, C1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, —C0-4alkylNHC(O)O(C1-4alkyl), —C0-4alkylNR7R8, —C(O)R9, C1-4alkoxyC0-4alkyl-, —COOC0-4alkyl, —C0-4alkylNHC(O)R9, —C0-4alkylC(O)N(R10)2, —C1-4alkoxyC1-4alkoxy, hydroxyC0-4alkyl-, —NHSO2R10, —SO2(C1-4alkyl), —SO2NR11R12, 5- to 6-membered heterocyclyl, phenylC0-2alkoxy, or phenylC0-2alkyl substituents, wherein phenyl is optionally substituted with 1–2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl or trifluoromethyl substituents, or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- or R3 is —NR4(—C0-4alkylR5);
- R4 is C0-3alkyl, —C2-3alkyl-NR7R8, C3-6cycloalkyl optionally substituted by hydroxyC0-4alkyl- further optionally substituted by hydroxy, C1-2alkoxyC2-4alkyl-, or C1-2alkyl-S(O)n—C2-3alkyl-;
- n is 0, 1, or 2;
- R5 is hydrogen, hydroxyC2-3alkyl-, C1-2alkoxyC0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
- wherein a heterocyclic nitrogen-containing R5 ring optionally is mono-substituted on the ring nitrogen with C1-4alkyl, benzyl, benzoyl, C1-4alkyl-C(O)—, —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), C1-4alkoxycarbonyl or aryl(C1-4alkoxy) carbonyl;
- and wherein the R5 rings are optionally mono-substituted on a ring carbon with halogen, cyano, C1-4alkyl-C(O)—, C1-4alkyl-SO2—, C1-4alkyl, C1-4alkoxy, hydroxy, —N(C0-4alkyl)(C0-4alkyl), hydroxyC0-4alkyl-, or C0-4alkylcarbamoyl-, provided that no quatemised nitrogen is included;
- or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- R6 is C1-4alkyl, aryl, or hetaryl;
- R7 and R8 are independently C0-4alkyl, C3-6cycloalkyl, or CO(C1-4alkyl);
- R9 is C1-4alkyl, or C3-6cycloalkyl;
- R10 is C0-4alkyl, or C3-6cycloalkyl;
- R11 and R12 are independently C0-4alkyl or together with the nitrogen to which they are attached may form a 4- to 6-membered heterocycle;
- and
- wherein there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds in linking the three components —Y—Z—R3 to each other.
20 more elements
A compound selected from the following:
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of Formula (I):
- or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- X3 is N;
- and X1, X2, and X4 are each C;
- R1 and R1′ are each independently, halogen, hydroxy, cyano, C0-4alkyl, C1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
- R2 is C0-4alkyl, COOR6, COR6, C1-4alkoxyC1-4alkyl-, hydroxyC1-4alkyl-, arylC0-4alkyl-, hetarylC0-4alkyl-, wherein any of the aryl or hetaryl rings are optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
- Y is C0-2alkyl or —CH(OH)—;
- Z is CH2, —C(O)—, —O—, >N(C0-4alkyl), >N(C3-6cycloalkyl), or absent;
- but when Y is —CH(OH)—, Z or R3 must be bonded to Y through a carbon-carbon bond;
- R3 is hydrogen, —COOC0-4alkyl, C1-4alkoxy, C1-4alkyl, arylC1-4alkylthio-, —C0-4alkylaryl, —C0-4alkylhetaryl, —C0-4alkylcycloalkyl or —C0-4alkylheterocyclyl, wherein any of the rings is optionally substituted with 1-3 independent halogen, cyano, C1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, —C0-4alkylNHC(O)O(C1-4alkyl), —C0-4alkylNR7R8, —C(O)R9, C1-4alkoxyC0-4alkyl-, —COOC0-4alkyl, —C0-4alkylNHC(O)R9, —C0-4alkylC(O)N(R10)2, —C1-4alkoxyC1-4alkoxy, hydroxyC0-4alkyl-, —NHSO2R10, —SO2(C1-4alkyl), —SO2NR11R12, 5- to 6-membered heterocyclyl, phenylC0-2alkoxy, or phenylC0-2alkyl substituents, wherein phenyl is optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl or trifluoromethyl substituents, or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- or R3 is —NR4(—C0-4alkylR5);
- R4 is C0-3alkyl, —C2-3alkyl-NR7R8, C3-6cycloalkyl optionally substituted by hydroxyC0-4alkyl- further optionally substituted by hydroxy, C1-2alkoxyC2-4alkyl-, or C1-2alkyl-S(O)n—C2-3alkyl-;
- n is 0, 1, or 2;
- R5 is hydrogen, hydroxyC2-3alkyl-, C1-2alkoxyC0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
- wherein a heterocyclic nitrogen-containing R5 ring optionally is mono-substituted on the ring nitrogen with C1-4alkyl, benzyl, benzoyl, C1-4alkyl-C(O)—, —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), C1-4alkoxycarbonyl or aryl(C1-4alkoxy) carbonyl;
- and wherein the R5 rings are optionally mono-substituted on a ring carbon with halogen, cyano, C1-4alkyl-C(O)—, C1-4alkyl-SO2—, C1-4alkyl, C1-4alkoxy, hydroxy, —N(C0-4alkyl)(C0-4alkyl), hydroxyC0-4alkyl-, or C0-4alkylcarbamoyl-, provided that no quatemised nitrogen is included;
- or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- R6 is C1-4alkyl, aryl, or hetaryl;
- R7 and R8 are independently C0-4alkyl, C3-6cycloalkyl, or CO(C1-4alkyl);
- R9 is C1-4alkyl, or C3-6cycloalkyl;
- R10 is C0-4alkyl, or C3-6cycloalkyl;
- R11 and R12 are independently C0-4alkyl or together with the nitrogen to which they are attached may form a 4- to 6-membered heterocycle;
- and
- wherein there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds in linking the three components —Y—Z—R3 to each other;
- and a pharmaceutically acceptable carrier.
21 more elements
A method of therapeutic treatment of hyperglycemia or diabetes comprising a step of administering an effective amount of a compound of Formula (I):
- or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- X3 is N;
- and X1, X2, and X4 are each C;
- R1 and R1′ are each independently, halogen, hydroxy, cyano, C0-4alkyl, C1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
- R2 is C0-4alkyl, COOR6, COR6, C1-4alkoxyC1-4alkyl-, hydroxyC1-4alkyl-, arylC0-4alkyl-, hetarylC0-4alkyl-, wherein any of the aryl or hetaryl rings are optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
- Y is C0-2alkyl or —CH(OH)—;
- Z is CH2, —C(O)—, —O—, >N(C0-4alkyl), >N(C3-6cycloalkyl), or absent;
- but when Y is —CH(OH)—, Z or R3 must be bonded to Y through a carbon-carbon bond;
- R3 is hydrogen, —COOC0-4alkyl, C1-4alkoxy, C1-4alkyl, arylC1-4alkylthio-, —C0-4alkylaryl, —C0-4alkylhetaryl, —C0-4alkylcycloalkyl or —C0-4alkylheterocyclyl, wherein any of the rings is optionally substituted with 1-3 independent halogen, cyano, C1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, —C0-4alkylNHC(O)O(C1-4alkyl), —C0-4alkylNR7R8, —C(O)R9, C1-4alkoxyC0-4alkyl-, —COOC0-4alkyl, —C0-4alkylNHC(O)R9, —C0-4alkylC(O)N(R10)2, —C1-4alkoxyC1-4alkoxy, hydroxyC0-4alkyl-, —NHSO2R10, —SO2(C1-4alkyl), —SO2NR11R12, 5- to 6-membered heterocyclyl, phenylC0-2alkoxy, or phenylC0-2alkyl substituents, wherein phenyl is optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl or trifluoromethyl substituents, or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- or R3 is —NR4(—C0-4alkylR5);
- R4 is C0-3alkyl, —C2-3alkyl-NR7R8, C3-6cycloalkyl optionally substituted by hydroxyC0-4alkyl— further optionally substituted by hydroxy, C1-2alkoxyC2-4alkyl—, or C1-2alkyl-S(O)n—C2-3alkyl-;
- n is 0, 1, or 2;
- R5 is hydrogen, hydroxyC2-3alkyl-, C1-2alkoxyC0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
- wherein a heterocyclic nitrogen-containing R5 ring optionally is mono-substituted on the ring nitrogen with C1-4alkyl, benzyl, benzoyl, C1-4alkyl-C(O)—, —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), C1-4alkoxycarbonyl or aryl(C1-4alkoxy) carbonyl;
- and wherein the R5 rings are optionally mono-substituted on a ring carbon with halogen, cyano, C1-4alkyl-C(O)—, C1-4alkyl-SO2—, C1-4alkyl, C1-4alkoxy, hydroxy, —N(C0-4alkyl)(C0-4alkyl), hydroxyC0-4alkyl-, or C0-4alkylcarbamoyl-, provided that no quatemised nitrogen is included;
- or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- R6 is C1-4alkyl, aryl, or hetaryl;
- R7 and R8 are independently C0-4alkyl, C3-6cycloalkyl, or CO(C1-4alkyl);
- R9 is C1-4alkyl, or C3-6cycloalkyl;
- R10 is C0-4alkyl, or C3-6cycloalkyl;
- R11 and R12 are independently C0-4alkyl or together with the nitrogen to which they are attached may form a 4- to 6-membered heterocycle;
- and
- wherein there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds in linking the three components —Y—Z—R3 to each other.
20 more elements
A method of treating diabetes in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance comprising a step of administering an effective amount of a compound of Formula (I):
- or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- X3 is N;
- and X1, X2, and X4 are each C;
- R1 and R1′ are each independently, halogen, hydroxy, cyano, C0-4alkyl, C1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
- R2 is C0-4alkyl, COOR6, COR6, C1-4alkoxyC1-4alkyl-, hydroxyC1-4alkyl-, arylC0-4alkyl-, hetarylC0-4alkyl-, wherein any of the aryl or hetaryl rings are optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
- Y is C0-2alkyl or —CH(OH)—;
- Z is CH2, —C(O)—, —O—, >N(C0-4alkyl), >N(C3-6cycloalkyl), or absent;
- but when Y is —CH(OH)—, Z or R3 must be bonded to Y through a carbon-carbon bond;
- R3 is hydrogen, —COOC0-4alkyl, C1-4alkoxy, C1-4alkyl, arylC1-4alkylthio-, —C0-4alkylaryl, —C0-4alkylhetaryl, —C0-4alkylcycloalkyl or —C0-4alkylheterocyclyl, wherein any of the rings is optionally substituted with 1-3 independent halogen, cyano, C1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, —C0-4alkylNHC(O)O(C1-4alkyl), —C0-4alkylNR7R8, —C(O)R9, C1-4alkoxyC0-4alkyl-, —COOC0-4alkyl, —C0-4alkylNHC(O)R9, —C0-4alkylC(O)N(R10)2, —C1-4alkoxyC1-4alkoxy, hydroxyC0-4alkyl-, —NHSO2R10, —SO2(C1-4alkyl), —SO2NR11R12, 5- to 6-membered heterocyclyl, phenylC0-2alkoxy, or phenylC0-2alkyl substituents, wherein phenyl is optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl or trifluoromethyl substituents, or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- or R3 is —NR4(—C0-4alkylR5);
- R4 is C0-3alkyl, —C2-3alkyl-NR7R8, C3-6cycloalkyl optionally substituted by hydroxyC0-4alkyl- further optionally substituted by hydroxy, C1-2alkoxyC2-4alkyl-, or C1-2alkyl-S(O)n—C2-3alkyl-;
- n is 0, 1, or 2;
- R5 is hydrogen, hydroxyC2-3alkyl-, C1-2alkoxyC0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
- wherein a heterocyclic nitrogen-containing R5 ring optionally is mono-substituted on the ring nitrogen with C1-4alkyl, benzyl, benzoyl, C1-4alkyl-C(O)—, —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), C1-4alkoxycarbonyl or aryl(C1-4alkoxy)carbonyl;
- and wherein the R5 rings are optionally mono-substituted on a ring carbon with halogen, cyano, C1-4alkyl-C(O)—, C1-4alkyl-SO2—, C1-4alkyl, C1-4alkoxy, hydroxy, —N(C0-4alkyl)(C0-4alkyl), hydroxyC0-4alkyl-, or C0-4alkylcarbamoyl-, provided that no quatemised nitrogen is included;
- or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- R6 is C1-4alkyl, aryl, or hetaryl;
- R7 and R8 are independently C0-4alkyl, C3-6cycloalkyl, or CO(C1-4alkyl);
- R9 is C1-4alkyl, or C3-6cycloalkyl;
- R10 is C0-4alkyl, or C3-6cycloalkyl;
- R11 and R12 are independently C0-4alkyl or together with the nitrogen to which they are attached may form a 4- to 6-membered heterocycle;
- and
- wherein there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds in linking the three components —Y—Z—R3 to each other.
20 more elements
A method of therapeutic treatment of hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia comprising a step of administering an effective amount of a compound of Formula (I):
- or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- X3 is N;
- and X1, X2, and X4 are each C;
- R1 and R1′ are each independently, halogen, hydroxy, cyano, C0-4alkyl, C1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
- R2 is C0-4alkyl, COOR6, COR6, C1-4alkoxyC1-4alkyl-, hydroxyC1-4alkyl-, arylC0-4alkyl-, hetarylC0-4alkyl-, wherein any of the aryl or hetaryl rings are optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
- Y is C0-2alkyl or —CH(OH)—;
- Z is CH2, —C(O)—, —O—, >N(C0-4alkyl), >N(C3-6cycloalkyl), or absent;
- but when Y is —CH(OH)—, Z or R3 must be bonded to Y through a carbon-carbon bond;
- R3 is hydrogen, —COOC0-4alkyl, C1-4alkoxy, C1-4alkyl, arylC1-4alkylthio-, —C0-4alkylaryl, —C0-4alkylhetaryl, —C0-4alkylcycloalkyl or —C0-4alkylheterocyclyl, wherein any of the rings is optionally substituted with 1-3 independent halogen, cyano, C1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, —C0-4alkylNHC(O)O(C1-4alkyl), —C0-4alkylNR7R8, —C(O)R9, C1-4alkoxyC0-4alkyl-, —COOC0-4alkyl, —C0-4alkylNHC(O)R9, —C0-4alkylC(O)N(R10)2, —C1-4alkoxyC1-4alkoxy, hydroxyC0-4alkyl-, —NHSO2R10, —SO2(C1-4alkyl), —SO2NR11R12, 5- to 6-membered heterocyclyl, phenylC0-2alkoxy, or phenylC0-2alkyl substituents, wherein phenyl is optionally substituted with 1-2 independent halogen, cyano, C1-4alkyl, C1-4alkoxy, —N(C0-4alkyl)(C0-4alkyl), —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), hydroxy, fluoromethyl, difluoromethyl or trifluoromethyl substituents, or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- or R3 is —NR4(—C0-4alkylR5);
- R4 is C0-3alkyl, —C2-3alkyl-NR7R8, C3-6cycloalkyl optionally substituted by hydroxyC0-4alkyl- further optionally substituted by hydroxy, C1-2alkoxyC2-4alkyl-, or C1-2alkyl-S(O)n—C2-3alkyl-;
- n is 0, 1, or 2;
- R5 is hydrogen, hydroxyC2-3alkyl-, C1-2alkoxyC0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
- wherein a heterocyclic nitrogen-containing R5 ring optionally is mono-substituted on the ring nitrogen with C1-4alkyl, benzyl, benzoyl, C1-4alkyl-C(O)—, —SO2C1-4alkyl, —SO2N(C0-4alkyl)(C0-4alkyl), C1-4alkoxycarbonyl or aryl(C1-4alkoxy)carbonyl;
- and wherein the R5 rings are optionally mono-substituted on a ring carbon with halogen, cyano, C1-4alkyl-C(O)—, C1-4alkyl-SO2—, C1-4alkyl, C1-4alkoxy, hydroxy, —N(C0-4alkyl)(C0-4alkyl), hydroxyC0-4alkyl-, or C0-4alkylcarbamoyl-, provided that no quatemised nitrogen is included;
- or two bonds on a ring carbon of the heterocyclyl group optionally can form an oxo (═O) substituent;
- R6 is C1-4alkyl, aryl, or hetaryl;
- R7 and R8 are independently C0-4alkyl, C3-6cycloalkyl, or CO(C1-4alkyl);
- R9 is C1-4alkyl, or C3-6cycloalkyl;
- R10 is C0-4alkyl, or C3-6cycloalkyl;
- R11 and R12 are independently C0-4alkyl or together with the nitrogen to which they are attached may form a 4- to 6-membered heterocycle;
- and
- wherein there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds in linking the three components —Y—Z—R3 to each other.
20 more elements
Dependencies are inferred from the claim text.