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2-Pyridone derivatives as inhibitors of neutrophile elastase

  • US 20060035938A1
  • Filed: 11/11/2003
  • Published: 02/16/2006
  • Est. Priority Date: 11/12/2002
  • Status: Abandoned Application
First Claim
Patent Images

1. A compound of formula (I) embedded image 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.

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