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COMPOUND HAVING TGFBETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

  • US 20090312313A1
  • Filed: 05/26/2009
  • Published: 12/17/2009
  • Est. Priority Date: 08/23/2002
  • Status: Abandoned Application
First Claim
Patent Images

1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

  • whereinX represents or N,Z represents —

    O—

    , —

    NH—

    , —

    S—

    , or —

    C(═

    O)—

    ,R and R′

    , which may be the same or different, represent1) a hydrogen atom,2) a halogen atom, or3) C1-6 alkyl optionally substituted by hydroxyl, a halogen atom, ora saturated or unsaturated five- or six-membered heterocyclic group,4) C2-6 alkenyl optionally substituted by an oxygen atom or C1-4 alkoxy,5) amino in which one or two hydrogen atoms on the amino group are optionally substituted by C1-6 alkyl, and the C1-6 alkyl group is optionally substituted by hydroxyl or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group,6) —

    C(═

    O)—

    NH2 wherein one or two hydrogen atoms on the aminocarbonyl group are optionally substituted by C1-6 alkyl,7) —

    OR″

    wherein R″

    represents a hydrogen atom, or —

    (CH2)m

    Ra wherein Ra represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C1-4 alkoxy, C1-4 alkoxycarbonyl, or —

    NRbRc wherein Rb and Rc, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, in which the C1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C1-4 alkyl, and Rb and Rc may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, which may further comprise one or more heteroatoms, and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group;

    m is an integer of 1 to 6; and

    the alkyl chain part in this group, —

    (CH2)m

    , is optionally substituted by hydroxyl, an oxygen atom, —

    ORd group, wherein Rd represents C1-4 alkyl or C1-4 alkylcarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, or8) a saturated or unsaturated five- or six-membered heterocyclic group, andA represents any group selected from the group consisting of formulae (a) to (c);

    (a) a group of formula (a);

    whereinR3 to R6, which may be the same or different, representa hydrogen atom,hydroxyl,a halogen atom,C1-6 alkyl,C1-10 alkoxy optionally substituted by a halogen atom or phenyl,C2-6 alkenylcarbonyloxy,C1-4 alkylcarbonyl,C1-4 alkylthio, orphenyl optionally substituted by a halogen atom,R3 and R4, R4 and R5, and R5 and R6 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a hydrogen atom, a halogen atom, hydroxyl, or C1-4 alkyl,G represents—

    C(═

    O)—

    R7,—

    CH2

    N(—

    R11)R12, or—

    C(—

    R13)(═

    NR14),whereinR7 representsa hydrogen atom,C1-8 alkyl optionally substituted by C1-4 alkoxy, an oxygen atom, or a saturated or unsaturated five- or six-membered carbocyclic group,C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,a saturated or unsaturated five- or six-membered carbocyclic group or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and the C1-4 alkoxy group is optionally substituted by a halogen atom or a saturated or unsaturated five- or six-membered heterocyclic group,group —

    O—

    R8, orgroup —

    N(—

    R9)R10 whereinR8 representsC1-10 alkyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,C2-8 alkenyl, ora saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom,R9 and R10, and R11 and R12, which may be the same or different, each representa hydrogen atom,C1-6 alkyl,a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, ornaphthyl optionally substituted by a halogen atom,R9 and R10, or R11 and R12 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group,R13 representsa hydrogen atom orC1-4 alkyl,R14 representsa hydrogen atom,hydroxyl,C1-4 alkoxy optionally substituted by a saturated or unsaturated six-membered carbocyclic group,C2-6 alkenyloxy,phenyloxy, oramino optionally substituted by a saturated or unsaturated six-membered heterocyclic group,(b) a group of formula (b);

    whereinany one of J, L, and M represents a nitrogen atom with the remaining two representing a carbon atom,R15 to R19, which may be the same or different, representa hydrogen atom,a halogen atom,nitro,cyano,C1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl;

    phenyl;

    amino optionally substituted by C1-4 alkyl;

    C1-4 alkylcarbonyloxy;

    or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C1-4 alkyl,C1-8 alkoxy,C1-4 alkylcarbonyl,C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,C2-6 alkynyl optionally substituted by C1-4 alkylsilyl,C1-4 alkylthio,a saturated or unsaturated three- to eight-membered carbocyclic oxy group,a saturated or unsaturated six-membered carbocyclic carbonyl or heterocyclic carbonyl group optionally substituted by C1-4 alkyl, ora saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;

    cyano;

    a halogen atom;

    C1-4 alkoxy;

    phenyloxy;

    C1-4 alkylcarbonyl;

    amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;

    aminocarbonyl optionally substituted by C1-4 alkyl;

    or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom,R15 and R16, R16 and R17, R17 and R18, and R18 and R19 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, and the carbocyclic or heterocyclic group is optionally substituted by C1-4 alkyl,provided that, among R17 to R19, those in which J, L, or M attached thereto is a nitrogen atom are absent, and(c) a group of formula (c);

    whereinR20 to R24, which may be the same or different, representa hydrogen atom,a halogen atom,C1-10 alkyl optionally substituted by hydroxyl, a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group,C1-8 alkoxy,C2-6 alkenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, an oxygen atom or phenyl,phenylcarbonyl optionally substituted by C1-4 alkyl,amino optionally substituted by phenyl,nitro, ora saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl,R20 and R21, or R23 and R24 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, andR21 and R22, or R22 and R23 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom, and the carbocyclic or heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a tricyclic group together with the six-membered carbocyclic ring of formula (c).

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