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2-PYRIDINE DERIVATIVES AS INHIBITORS OF NEUTROPHILE ELASTASE

  • US 20090105239A1
  • Filed: 03/14/2006
  • Published: 04/23/2009
  • Est. Priority Date: 03/16/2005
  • Status: Abandoned Application
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Assignment
First Claim
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1. A compound of formula (I) whereinR1 represents hydrogen or C1-C6 alkyl;

  • W represents S(O)m wherein m represents an integer 0, 1 or 2;

    Z represents a single bond, —

    CH2 or —

    NR25—

    ;

    R14 represents a hydrogen atom or OH or a group selected from C1-C6 alkyl and a saturated or unsaturated 3- to 10-membered ring system optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur;

    each group being optionally substituted with at least one substituent selected from phenyl, C1-C6 alkoxycarbonyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, NR12R13, C≡

    CR30, CONR31R32, CHO, C2-C4 alkanoyl, S(O)pR33 and OSO2R34;

    R12 and R13 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl;

    or the group —

    NR12R13 together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR26;

    R30 represents H, C1-C3 alkyl, Si(CH3)3 or phenyl;

    R33 and R34 independently represent H or C1-C3 alkyl;

    said alkyl being optionally substituted by one or more F atoms;

    R6 represents H or F;

    R3 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

    said ring being optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, nitro, methylcarbonyl, NR35R36, C1-C3 alkyl substituted by one or more F atoms or C1-C3 alkoxy substituted by one or more F atoms;

    R35 and R36 independently represent H or C1-C3 alkyl;

    said alkyl being optionally further substituted by one or more F atoms;

    R4 represents hydrogen or C1-C6 alkyl optionally substituted with at least one substituent selected from fluoro, hydroxyl and C1-C6 alkoxy;

    X represents a single bond, O, NR24 or a group —

    C1-C6 alkylene-Y—

    , wherein Y represents a single bond, oxygen atom, NR24 or S(O)w; and

    said alkylene being optionally further substituted by OH, halogen, CN, NR37R38, C1-C3alkoxy, CONR39R40, SO2R41 and SO2NR42R43;

    or R4 and X are joined together such that the group —

    NR4X together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR44;

    said ring being optionally substituted by C1-C6 alkyl or NR45R46;

    said alkyl being optionally further substituted by OH;

    either R5 represents a monocyclic ring system selected fromi) phenoxy,ii) phenyl,iii) a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,iv) a saturated or partially unsaturated C3-C6 hydrocarbyl ring, orv) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising at least one ring heteroatom selected from oxygen, S(O)r and NR20, wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group,or R5 represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or C1-C6 alkylene optionally comprising one or more internal or terminal heteroatoms selected from oxygen, sulphur and NR27 and being optionally substituted by at least one substituent selected from hydroxyl, oxo and C1-C6 alkoxy,the monocyclic or bicyclic ring system being optionally substituted by at least one substituent selected from oxygen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, NR47R48, NO2, OSO2R49, CO2R50, C(═

    NH)NH2, C(O)NR51R52, C(S)NR53R54, SC(═

    NH)NH2, NR55C(═

    NH)NH2, S(O)vR21, SO2NR56R57, C1-C3 alkoxy substituted by one or more F atoms and C1-C3 alkyl substituted by SO2R58 or by one or more F atoms;

    said C1-C6 alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio and —

    C(O)NR22R23;

    or R5 may also represent H;

    R20 represents hydrogen, C1-C6 alkyl, C1-C6 alkylcarbonyl or C1-C6 alkoxycarbonyl;

    R21 represents hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl;

    said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, C1-C3 alkoxy and CONR59R60;

    R37 and R38 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl;

    R47 and R48 independently represent H, C1-C6 alkyl, formyl, C2-C6 alkanoyl, S(O)qR61 or SO2NR62R63;

    said alkyl group being optionally further substituted by halogen, CN, C1-C4 alkoxy or CONR64R65;

    R41 and R61 independently represent H, C1-C6 alkyl or C3-C6 cycloalkyl;

    p is 0, 1 or 2;

    q is 0, 1 or 2;

    r is 0, 1 or 2;

    t is 0, 1 or 2;

    w is 0, 1 or 2;

    v is 0, 1 or 2;

    R22, R23, R24, R25, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64 and R65 each independently represent hydrogen or C1-C6 alkyl;

    or a pharmaceutically acceptable salt thereof.

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