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US 2006/0040988 A1Published application
Cox-2 Inhibiting pyridine derivatives
AssigneeGlaxo Group Limited
InventorsPaul Beswick, Neil Pegg, Martin Swarbrick, John Skidmore, Sandeep Modi
Life of this patent
Estimating the term…
Abstract
Compounds of formula (I) or pharmaceutically acceptable salts thereof are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever and inflammation of a variety of conditions and diseases.
Claims25
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof in which:
- X is selected from the group consisting of oxygen and NR2;
- Y is selected from the group consisting of CH and nitrogen;
- R1 is selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C1-3alkylOC1-3alkyl, C3-6alkenyl, C3-6alkynyl, C3-10cycloalkylC0-6alkyl, C4-7cycloalkyl substituted by C1-3alkyl or C1-3alkoxy, C4-12bridged cycloalkyl, A(CR6R7)n and B(CR6R7)n;
- R2 is selected from the group consisting of H and C1-6alkyl;
- or
- R1 and R2, together with the nitrogen atom to which they are attached form a 4-8 membered saturated heterocyclic ring, or a 5-membered heteroaryl ring which is unsubstituted or substituted by one R3;
- R3 is selected from the group consisting of C1-5alkyl and C1-2alkyl substituted by one to five fluorine atoms;
- R4 is selected from the group consisting of C1-6alkyl, NH2 and R9CONH;
- R5 is selected from the group consisting of hydrogen, C1-3alkyl, C1-2alkyl substituted by one to five fluorine atoms, C1-3alkylO2C, halogen, cyano, (C1-3alkyl)2NCO, C1-3alkylS and C1-3alkylO2S;
- R6 and R7 are independently selected from H and C1-6alkyl;
- A is an unsubstituted 5- or 6-membered heteroaryl or an unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R8;
- R8 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by one or more F, NH2SO2 and C1-6alkylSO2;
- B is selected from the group consisting of
- defines the point of attachment of the ring;
- R9 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6alkylOC1-6alkyl, phenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1-6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl;
- R10 is selected from the group consisting of H and halogen;
- and
- n is 0 to 4.
16 more elements
A compound of formula (IA)
- or a pharmaceutically acceptable salt thereof in which:
- X is selected from the group consisting of oxygen and NR2;
- Y is selected from the group consisting of CH and nitrogen;
- R1 is selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C1-3alkylOC1-3alkyl, C3-6alkenyl, C3-6alkynyl, C3-10cycloalkylC0-6alkyl, C4-12bridged cycloalkyl, A(CR6R7)n and B(CR6R7)n;
- R2 is selected from the group consisting of H and C1-6alkyl;
- or
- R1 and R2, together with the nitrogen atom to which they are attached form a 4-8 membered saturated heterocyclic ring;
- R3 is selected from the group consisting of C1-5alkyl and C1-2alkyl substituted by one to five fluorine atoms;
- R4 is selected from the group consisting of C1-6alkyl, NH2 and R9CONH;
- R5 is selected from the group consisting of hydrogen, C1-3alkyl, C1-2alkyl substituted by one to five fluorine atoms, halogen, cyano, (C1-3alkyl)2NCO, C1-3alkylS and C1-3alkylO2S;
- R6 and R7 are independently selected from H or C1-6alkyl;
- A is an unsubstituted 5- or 6-membered heteroaryl or an unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R8;
- R8 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by one or more F, NH2SO2 and C1-6alkylSO2;
- B is selected from the group consisting of
- defines the point of attachment of the ring;
- R9 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6alkylOC1-6alkyl, phenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1-6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl;
- R10 is selected from the group consisting of H and halogen;
- and
- n is 0 to 4.
16 more elements
A compound of formula (IC)
- or a pharmaceutically acceptable salt thereof in which:
- X is selected from the group consisting of oxygen and NR2;
- Y is selected from the group consisting of CH and nitrogen;
- R1 is selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C1-3alkylOC1-3alkyl, C3-6alkenyl, C3-6alkynyl, C3-10cycloalkylC0-6alkyl, C4-7cycloalkyl substituted by C1-3alkyl or C1-3alkoxy, C4-12bridged cycloalkyl, A(CR6R7)n and B(CR6R7)n;
- R2 is selected from the group consisting of H and C1-6alkyl;
- or
- R1 and R2, together with the nitrogen atom to which they are attached form a 4-8 membered saturated heterocyclic ring, or a 5-membered heteroaryl ring which is unsubstituted or substituted by one R8;
- R3 is selected from the group consisting of C1-5alkyl and C1-2alkyl substituted by one to five fluorine atoms;
- R4 is selected from the group consisting of C1-6alkyl, NH2 and R9CONH;
- R5 is selected from the group consisting of hydrogen, C1-3alkyl, C1-2alkyl substituted by one to five fluorine atoms, C1-3alkylO2C, halogen, cyano, (C1-3alkyl)2NCO, C1-3alkylS and C1-3alkylO2S;
- R6 and R7 are independently selected from H or C1-6alkyl;
- A is an unsubstituted 5- or 6-membered heteroaryl or an unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R8;
- R8 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by one or more F, NH2SO2 and C1-6alkylSO2;
- B is selected from the group consisting of
- defines the point of attachment of the ring;
- R9 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6alkylOC1-6alkyl, phenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1-6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl;
- R10 is selected from the group consisting of H and halogen;
- and
- n is 1 to 4.
16 more elements
(canceled)
A compound selected from the group consisting of:
- 4-ethyl-6-[4-(methylsulfonyl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)-2-pyridinamine;
- 4-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-methyl-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-methyl-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- 4-(6-{[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}-4-ethyl-2-pyridinyl)benzenesulfonamide;
- N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- 4-{4-methyl-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-2-pyridinyl}benzenesulfonamide;
- 4-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- N-(cyclohexylmethyl)-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-cyclohexyl-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- 2-[4-(methylsulfonyl)phenyl]-6-[(2-pyridinylmethyl)oxy]-4-(trifluoromethyl)pyridine;
- 4-methyl-N-[(3-methyl-4-isoxazolyl)methyl]-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- 6-[4-(methylsulfonyl)phenyl]-N-(2-pyridinylmethyl)-4-(trifluoromethyl)-2-pyridinamine;
- N-cycloheptyl-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-(cis-4-methylcyclohexyl)-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-(1-ethylpropyl)-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- 4-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- N-(cyclopentylmethyl)-6-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-2-pyridinamine;
- N-[(1-ethyl-1H-1,2,4-triazol-5-yl)methyl]-4-methyl-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- 4-ethyl-6-[4-(methylsulfonyl)phenyl]-2-[(2-pyridinylmethyl)amino]-3-pyridinecarbonitrile;
- 4-ethyl-2-{[(5-methyl-2-pyridinyl)methyl]amino}-6-[4-(methylsulfonyl)phenyl]-3-pyridinecarbonitrile;
- 4-ethyl-2-([(6-methyl-3-pyridinyl)methyl]amino)-6-[4-(methylsulfonyl)phenyl]-3-pyridinecarbonitrile;
- 4-ethyl-2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}-6-[4-(methylsulfonyl)phenyl]-3-pyridinecarbonitrile;
- 4-ethyl-6-[4-(methylsulfonyl)phenyl]-2-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}-3-pyridinecarbonitrile;
- 4-ethyl-6-[4-(methylsulfonyl)phenyl]-2-[(2-pyridinylmethyl)oxy]-3-pyridinecarbonitrile;
- 4-ethyl-N-[(1-ethyl-1H-1,2,4-triazol-5-yl)methyl]-6-[4-(methylsulfonyl)phenyl]-2-pyridinamine;
- 4-ethyl-2-{[(6-methyl-3-pyridinyl)methyl]oxy}-6-[4-(methylsulfonyl)phenyl]-3-pyridinecarbonitrile;
- and
- 6-[4-(methylsulfonyl)phenyl]-N-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-4-(trifluoromethyl)-2-pyridinamine.
29 more elements
(canceled)
12-13. (canceled)
Dependencies are inferred from the claim text.