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ARYL-SUBSTITUTED POLYCYCLIC AMINES, METHOD FOR THE PRODUCTION THEREOF, AND USE THEREOF AS A MEDICAMENT

  • US 20090258881A1
  • Filed: 06/23/2009
  • Published: 10/15/2009
  • Est. Priority Date: 08/16/2004
  • Status: Active Grant
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Assignment
First Claim
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1. A compound of formula (I):

  • wherein;

    A, B, D, and G are, independently of one another, N or C(R3);

    or, alternatively,groups A and B or groups D and G are, in each case, C(R3) and together form a 5- or 6-membered carbocyclic or heterocyclic radical to result overall in a bicyclic system;

    wherein R3 is H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—

    (C1-C6)-alkyl, O—

    (C1-C4)-alkoxy-(C1-C4)-alkyl, S—

    (C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—

    (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—

    (C0-C8)-alkylene-aryl, S-aryl, N(R4)(R5), SO2—

    CH3, COOH, COO—

    (C1-C6)-alkyl, CON(R6)(R7), N(R8)CO(R9), N(R10)SO2(R11), CO(R12), or (CR13R14)x—

    O(R15);

    wherein R4, R5, R6, R7, R8, R10 are, independently of one another, H or (C1-C8)-alkyl;

    or, alternatively, R4 and R5, R6 and R7, independently of one another, taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    R9, R11, and R12 are, independently of one another, H, (C1-C8)-alkyl or aryl;

    R13 and R14 are, independently of one another, H or (C1-C8)-alkyl;

    R15 is H, (C1-C6)-alkyl or aryl;

    x is 0, 1, 2, 3, 4, 5 or 6;

    R1 is H, (C1-C8)-alkyl, (C3-C6)-alkenyl, or (C3-C6)-alkynyl;

    X is N(R16), O, a bond, (R17)C═

    C(R18), C≡

    C, or a group of the formula (CR19R20)y, in which one or two (CR19R20) groups may be replaced by Y;

    Y is O, S, N(R21), or C═

    O;

    R16, R17, and R18 are, independently of one another, H or (C1-C8)-alkyl;

    R19 and R20 are, independently of one another, H or (C1-C4)-alkyl;

    y is 1, 2, 3, 4, 5 or 6;

    R21 is H or (C1-C8)-alkyl;

    E is a 3-14 membered bivalent carbo- or heterocyclic ring structure having 0-4 heteroatoms selected from the group consisting of N, O and S, which ring structure may optionally have substituents selected from the group consisting of H, F, Cl, Br, I, OH, CF3, CN, OCF3, oxo, O—

    (C1-C6)-alkyl, O—

    (C1-C4)-alkoxy-(C1-C4)-alkyl, S—

    (C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—

    (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—

    (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—

    (C0-C8)-alkylene-aryl, S-aryl, N(R22)(R23), SO2—

    CH3, CON(R24)(R25), N(R26)CO(R27), N(R28)SO2(R29), and CO(R30) and may be mono- or bicyclic, wherein E is not a tetrazol-5-yl group;

    R22, R23, R24, R25, R26, and R28 are, independently of one another, H, (C1-C8)-alkyl or aryl;

    or, alternatively, R22 and R23, R24 and R25, independently of one another, taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    R27, R29 and R30 are, independently of one another, H, (C1-C8)-alkyl or aryl;

    K is a bond, C≡

    C, (R31)C═

    C(R32), or a group of the formula (CR33R34)z in which one or more (CR33R34) groups may be replaced by Z;

    R31, R32, R35, R36, R37, R38, and R39 are, independently of one another, H or (C1-C8)-alkyl;

    Z is O, S, N(R40), CO, SO, or SO2;

    R33 and R34 are, independently of one another, H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, hydroxy, or (C1-C4)-alkoxy-(C1-C4)-alkyl;

    z is 1, 2, 3, 4, 5 or 6;

    R40 is H or (C1-C8)-alkyl;

    R2 is H, (C1-C8)-alkyl, (C1-C8)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may include 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system may additionally be substituted with one or more of the following substituents;

    F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—

    (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R41), CON(R42)(R43), hydroxy, COO(R44), N(R45)CO(C1-C6)-alkyl, N(R46)(R47), SO2CH3, SCF3 and S—

    (C1-C6)-alkyl, and wherein R2 is not a tetrazol-5-yl group;

    R41, R42, R43, R44, R45, R46, and R47 are, independently of one another, H or (C1-C8)-alkyl;

    or, alternatively, R42 and R43, R46 and R47, independently of one another, taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    E, K and R2 together form a tricyclic system wherein the rings may be, independently of one another, saturated, partially saturated or unsaturated and, in each case, comprise 3-8 ring atoms;

    L is a (CR48R49)m group in which one or more (CR48R49) groups may be replaced by M, provided that L is M if Q is wherein R91 is as defined below;

    M is O;

    m is 1, 2, 3, 4, 5, or 6, R48 and R49 are, independently of one another, H, (C1-C6)-alkyl, or aryl;

    Q is selected from the following structures;

    R91 is H, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, CO(R92), (CR93R94)O′

    -R95, or CO(CR93R94)p′

    -R96;

    R92 is H or (C1-C8)-alkyl;

    R93 and R94 are, independently of one another, H, (C1-C8)-alkyl, OH, (C3-C8)-cycloalkyl, or (C1-C4)-alkoxy-(C1-C4)-alkyl;

    o′ and

    p′

    are, independently of one another, 0, 1, 2, 3, 4, 5 or 6;

    R95 and R96 are, independently of one another, OH, O—

    (C1-C8)-alkyl, CON(R97)(R98), N(R99)CO(R100), N(R101)(R102), CO2(R103), SO2Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, and which may be substituted with one or more of the following substituents;

    F, Cl, Br, CF3, (C1-C8)-alkyl, O—

    (C1-C8)-alkyl, CO(R104), oxo, and OH;

    R97, R98, R99, R100, R103, and R104 are, independently of one another, H or (C1-C8)-alkyl;

    or, alternatively, R97 and R98 taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    R101 and R102 are, independently of one another, H, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, CO(R105), (CR106R107)q′

    -R108, or CO(CR109R110)r′

    -R111;

    or, alternatively, R101 and R102 form, together with the nitrogen atom to which they are bonded, a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, comprises 0 to 3 additional heteroatoms selected from the group consisting of N, O and S and which ring may additionally be substituted with one or more of the following substituents;

    F, Cl, Br, CF3, O—

    (C1-C8)-alkyl, (C1-C6)-alkyl, CO(R112), oxo, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, CON(R113)(R114), N(R115)CO(R116), N(R117)(R118), CO2(R119), and SO2Me;

    R105, R106, R107, R108, R109, R10, R112, R113, R114, R115, R116, R117, R118, and R119 are, independently of one another, H or (C1-C8)-alkyl;

    or, alternatively, R117 and R118 taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    q′ and

    r′

    are, independently of one another, 0, 1, 2, 3, 4, 5 or 6;

    R108 and R111 are, independently of one another, OH, O—

    (C1-C8)-alkyl, CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO2(R126), SO2Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, which ring system may be substituted with one or more of the following substituents;

    F, Cl, Br, CF3, (C1-C8)-alkyl, O—

    (C1-C8)-alkyl, CO(R127), oxo, and OH;

    R120, R121, R122, R123, R124, R125, R126, and R127 are, independently of one another, H or (C1-C8)-alkyl;

    or, alternatively, R120 and R121, R124 and R125, independently of one another, taken together with the nitrogen atom to which they are attached form a 5-6 membered ring which optionally may contain an additional heteroatom selected from the group consisting of NH, N—

    (C1-C6)-alkyl, oxygen and sulfur;

    or an N-oxide thereof or a physiologically tolerated salt thereof.

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