2-Pyridone derivatives as inhibitors of neutrophile elastase
First Claim
Patent Images
1. A compound of formula (I) wherein:
- X represents O or S;
Y1 represents N or CR2; and
when R1 represents OH, Y1 may also, in the tautomeric form, represent NR6;
Y2 represents CR3; and
when Y1 represents CR2, then Y2 may also represent N;
R1 represents H or C1 to 6 alkyl;
said alkyl being optionally substituted by one or more substituents selected independently from halogen, CN, CHO, OR7, NR8R9, S(O)mR10 and SO2NR11R12;
and, when Y represents N, R1 may also represent OH;
R7 represents H, C1 to 6 alkyl or phenyl;
said phenyl being optionally further substituted by halogen, C1 to 6 alkyl and C1 to 6 alkoxy, R2 represents H, halogen or C1 to 6 alkyl;
R3 represents H or F;
G1 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
or G1 represents a five- or six-membered saturated or partially unsaturated cycloalkyl ring;
or G1 represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and NR13 where R13 represents H or C1 to 6 alkyl;
R5 represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO2, NR14R15, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3 alkoxy substituted by one or more F atoms;
R14 and R15 independently represent H or C1 to 3 alkyl;
said alkyl being optionally further substituted by one or more F atoms;
n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R5 group is selected independently;
R4 and R6 independently represent H or C1 to 6 alkyl;
said alkyl being optionally further substituted by OH or C1 to 6 alkoxy;
or R4 and L are joined together such that the group —
NR4L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR16;
L represents a bond, O, NR29 or C1 to 6 alkyl;
said alkyl optionally incorporating a heteroatom selected from O, S and NR16; and
said alkyl being optionally further substituted by OH or OMe;
G2 represents a monocyclic ring system selected from;
i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR17 and optionally further incorporating a carbonyl group;
or G2 represents a bicyclic ring system in which each of the two rings is independently selected from;
i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR17 and optionally further incorporating a carbonyl group;
and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CH2, said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected from CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR18R19, NO2, OSO2R38, CO2R20, C(═
NH)NH2, C(O)NR21R22, C(S)NR23R24, SC(═
NH)NH2, NR31C(═
NH)NH2, S(O)sR25, SO2NR26R27, C1 to 3 alkoxy substituted by one or more P atoms and C1 to 3 alkyl substituted by SO2R39 or by one or more F atoms;
or when L does not represent a bond, G may also represent H;
m, p, q, s and t independently represent an integer 0, 1 or 2;
R8 and R9 independently represent H, C1 to 6 alkyl, formyl or C2 to 6 alkanoyl;
said alkyl being optionally further substituted by phenyl optionally substituted by halogen, C1 to 6 alkyl, C1 to 6 alkoxy or SO2R30;
or the group NR8R9 together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR28;
R18 and R19 independently represent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR32 or SO2NR33R34;
said alkyl group being optionally further substituted by halogen, CN, C1 to 4 alkoxy or CONR41R42;
R25 represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;
said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, CONR35R36, CO2R37, OCOR40, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR43 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N;
said aromatic ring being optionally further substituted by one or more substituents selected independently from halogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CONR44R45, CO2R46, S(O)sR47 and NHCOCH3;
R26 and R27 independently represent H, C1 to 6 alkyl, formyl or C2 to 6 alkanoyl;
R32 represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;
R38 represents H, C1 to 6 alkyl or phenyl;
said phenyl being optionally further substituted by halogen, C1 to 6 alkyl or C1 to 6 alkoxy;
R10, R11, R12, R16, R17, R20, R21, R22, R23, R24, R28, R29, R30, R31, R33, R34, R35, R36, R37, R39, R40, R41, R42, R43, R44, R45, R46 and 47 independently represent H or C1 to 6 alkyl;
and pharmaceutically acceptable salts thereof, with the proviso that the following compounds are disclaimed;
N-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;
N-(2-phenethyl)-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;
N-[2-(dimethylamino)ethyl)-2, dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;
4-[2-[[1,2-dihydro-1-(4-methylcyclohexyl)-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]benzoic acid; and
4-[2-[[(1-cyclohexyl-1,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic acid.
1 Assignment
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Accused Products
Abstract
There are provided novel compounds of formula (I) wherein R1?, R4?. R5?, G1?, G2?, X, L, Y1?, Y2? and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors or neutrophil elastase.
48 Citations
10 Claims
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1. A compound of formula (I)
wherein: -
X represents O or S;
Y1 represents N or CR2; and
when R1 represents OH, Y1 may also, in the tautomeric form, represent NR6;
Y2 represents CR3; and
when Y1 represents CR2, then Y2 may also represent N;
R1 represents H or C1 to 6 alkyl;
said alkyl being optionally substituted by one or more substituents selected independently from halogen, CN, CHO, OR7, NR8R9, S(O)mR10 and SO2NR11R12;
and, when Y represents N, R1 may also represent OH;
R7 represents H, C1 to 6 alkyl or phenyl;
said phenyl being optionally further substituted by halogen, C1 to 6 alkyl and C1 to 6 alkoxy,R2 represents H, halogen or C1 to 6 alkyl;
R3 represents H or F;
G1 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
or G1 represents a five- or six-membered saturated or partially unsaturated cycloalkyl ring;
or G1 represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and NR13 where R13 represents H or C1 to 6 alkyl;
R5 represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO2, NR14R15, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3 alkoxy substituted by one or more F atoms;
R14 and R15 independently represent H or C1 to 3 alkyl;
said alkyl being optionally further substituted by one or more F atoms;
n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R5 group is selected independently;
R4 and R6 independently represent H or C1 to 6 alkyl;
said alkyl being optionally further substituted by OH or C1 to 6 alkoxy;
or R4 and L are joined together such that the group —
NR4L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR16;
L represents a bond, O, NR29 or C1 to 6 alkyl;
said alkyl optionally incorporating a heteroatom selected from O, S and NR16; and
said alkyl being optionally further substituted by OH or OMe;
G2 represents a monocyclic ring system selected from;
i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR17 and optionally further incorporating a carbonyl group;
orG2 represents a bicyclic ring system in which each of the two rings is independently selected from;
i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR17 and optionally further incorporating a carbonyl group;
and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CH2, said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected from CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR18R19, NO2, OSO2R38, CO2R20, C(═
NH)NH2, C(O)NR21R22, C(S)NR23R24, SC(═
NH)NH2, NR31C(═
NH)NH2, S(O)sR25, SO2NR26R27, C1 to 3 alkoxy substituted by one or more P atoms and C1 to 3 alkyl substituted by SO2R39 or by one or more F atoms;
orwhen L does not represent a bond, G may also represent H;
m, p, q, s and t independently represent an integer 0, 1 or 2;
R8 and R9 independently represent H, C1 to 6 alkyl, formyl or C2 to 6 alkanoyl;
said alkyl being optionally further substituted by phenyl optionally substituted by halogen, C1 to 6 alkyl, C1 to 6 alkoxy or SO2R30;
or the group NR8R9 together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR28;
R18 and R19 independently represent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR32 or SO2NR33R34;
said alkyl group being optionally further substituted by halogen, CN, C1 to 4 alkoxy or CONR41R42;
R25 represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;
said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, CONR35R36, CO2R37, OCOR40, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR43 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N;
said aromatic ring being optionally further substituted by one or more substituents selected independently from halogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CONR44R45, CO2R46, S(O)sR47 and NHCOCH3;
R26 and R27 independently represent H, C1 to 6 alkyl, formyl or C2 to 6 alkanoyl;
R32 represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;
R38 represents H, C1 to 6 alkyl or phenyl;
said phenyl being optionally further substituted by halogen, C1 to 6 alkyl or C1 to 6 alkoxy;
R10, R11, R12, R16, R17, R20, R21, R22, R23, R24, R28, R29, R30, R31, R33, R34, R35, R36, R37, R39, R40, R41, R42, R43, R44, R45, R46 and 47 independently represent H or C1 to 6 alkyl;
and pharmaceutically acceptable salts thereof, with the proviso that the following compounds are disclaimed;
N-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;
N-(2-phenethyl)-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;
N-[2-(dimethylamino)ethyl)-2, dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide;
4-[2-[[1,2-dihydro-1-(4-methylcyclohexyl)-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]benzoic acid; and
4-[2-[[(1-cyclohexyl-1,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic acid. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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Specification