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Labeled macrophage scavenger receptor antagonists for imaging atherosclerosis and vulnerable plaque

  • US 20040057900A1
  • Filed: 08/14/2003
  • Published: 03/25/2004
  • Est. Priority Date: 02/23/2001
  • Status: Active Grant
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First Claim
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1. A compound of formula (I):

  • M-Ch-Ln-(BM)n 

     

    (I) wherein M is a radionuclide selected from;

    99mTc, 117mSn, 111In, 97Ru, 67Ga, 68Ga, 89Zr, 177Lu, 47Sc, 105Rh, 188Re, 60Cu, 62Cu, 64Cu and 67Cu, or a paramagnetic metal ion of atomic number 21-29, 42-44, or 58-70, or a heavy metal ion of atomic number 21-31, 39-49, 50, 56-80, 82, 83, 90;

    Ch is a metal chelator having a formula selected from the group;

    wherein A1, A2, A3, A4, A5, A6, A7, and A8 are independently selected at each occurrence from the group;

    NR19, NR19R20, S, SH, O, OH, PR19, PR19R20, P(O)R21R22, and a direct bond to Ln;

    E is a direct bond, CH, or a spacer group independently selected at each occurrence from the group;

    (C1-C10)alkyl substituted with 0-3 R23, aryl substituted with 0-3 R23, (C3-C10)cycloalkyl substituted with 0-3 R23, heterocyclo-(C1-C10)alkyl substituted with 0-3 R23, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, (C6-C10)aryl-(C1-C10)alkyl substituted with 0-3 R23, (C1-C10)alkyl-(C6-C10)aryl-substituted with 0-3 R23, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R23;

    R19 and R20 are each independently selected from the group;

    a direct bond to Ln, hydrogen, (C1-C10)alkyl substituted with 0-3 R23, aryl substituted with 0-3 R23, (C3-C10)cycloalkyl substituted with 0-3 R23, heterocyclo-(C1-C10)alkyl substituted with 0-3 R23, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, (C6-C10)aryl-(C1-C10)alkyl substituted with 0-3 R23, (C1-C10)alkyl-(C6-C10)aryl-substituted with 0-3 R23, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R23, and an electron, provided that when one of R19 or R20 is an electron, then the other is also an electron;

    R21 and R22 are each independently selected from the group;

    a direct bond to Ln, —

    OH, (C1-C10)alkyl substituted with 0-3 R23, (C1-C10)alkyl substituted with 0-3 R23, aryl substituted with 0-3 R23, (C3-C10)cycloalkyl substituted with 0-3 R23, heterocyclo-(C1-C10)alkyl substituted with 0-3 R23, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, (C6-C10)aryl-(C1-C10)alkyl substituted with 0-3 R23, (C1-C10)alkyl-(C6-C10)aryl-substituted with 0-3 R23, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R23;

    R23 is independently selected at each occurrence from the group;

    a direct bond to Ln, ═

    O, F, Cl, Br, I, —

    CF3, —

    CN, —

    CO2R24, —

    C(═

    O)R24, —

    C(═

    O)N(R24)2, —

    CHO, —

    CH2OR24, —

    OC(═

    O)R24, —

    OC(═

    O)OR24a, —

    OR24, —

    OC(═

    O)N(R24)2, —

    NR25C(═

    O)R24, —

    NR25C(═

    O)OR24a, —

    NR25C(═

    O)N(R24)2, —

    NR25SO2N(R24)2, —

    NR25SO2R24a, —

    SO3H, —

    SO2R24a, —

    SR24, —

    S(═

    O)R24a, —

    SO2N(R24)2, —

    N(R24)2, —

    NHC(═

    S)NHR24, ═

    NOR24, NO2, —

    C(═

    O)NHOR24, —

    C(═

    O)NHNR24R24a, —

    OCH2CO2H, 2-(1-morpholino)ethoxy, (C1-C5)alkyl, (C2-C4)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkylmethyl, (C2-C6)alkoxyalkyl, aryl substituted with 0-2 R24, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;

    R24, R24a, and R25 are independently selected at each occurrence from the group;

    a direct bond to Ln, H, (C1-C6)alkyl, phenyl, benzyl, (C1-C6)alkoxy, halide, nitro, cyano, and trifluoromethyl;

    Ln is a linking group having the formula;

    ((W)h-(CR13R14)g)x-(Z)k-((CR13aR14a)g′

    —

    (W)h′

    )x′

    wherein, W is independently selected at each occurrence from the group;

    O, S, NH, NHC(═

    O), C(═

    O)NH, NR15C(═

    O), C(═

    O)N R15, C(═

    O), C(═

    O)O, OC(═

    O), NHC(═

    S)NH, NHC(═

    O)NH, SO2, SO2NH, (OCH2CH2)s, (CH2CH2O)s′

    , (OCH2CH2CH2)s″

    , (CH    2CH2CH2O)t, and (aa)t′

    ;

    aa is independently at each occurrence an amino acid;

    Z is selected from the group;

    aryl substituted with 0-3 R16, (C3-C10)cycloalkyl substituted with 0-3 R16, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R16;

    R13, R13a, R14, R14a, and R15 are independently selected at each occurrence from the group;

    H, ═

    O, COOH, SO3H, PO3H, (C1-C5)alkyl substituted with 0-3 R16, aryl substituted with 0-3 R16, benzyl substituted with 0-3 R16, and (C1-C5)alkoxy substituted with 0-3 R16, NHC(═

    O)R17, C(═

    O)NHR17, NHC(═

    O)NHR17, NHR17, R17, and a direct bond to Ch;

    R16 is independently selected at each occurrence from the group;

    a direct bond to Ch, COOR17, C(═

    O)NHR17, NHC(═

    O)R17, OH, NHR17, SO3H, PO3H, —

    OPO3H2, —

    OSO3H, aryl substituted with 0-3 R17, (C1-C5)alkyl substituted with 0-1 R18, (C1-C5)alkoxy substituted with 0-1 R18, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17;

    R17 is independently selected at each occurrence from the group;

    H, alkyl substituted with 0-1 R18, aryl substituted with 0-1 R18, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R18, (C3-C10)cycloalkyl substituted with 0-1 R18, polyalkylene glycol substituted with 0-1 R18, carbohydrate substituted with 0-1 R18, cyclodextrin substituted with 0-1 R18, amino acid substituted with 0-1 R18, polycarboxyalkyl substituted with 0-1 R18, polyazaalkyl substituted with 0-1 R18, peptide substituted with 0-1 R18, wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a direct bond to Ch;

    R18 is a direct bond to Ch;

    k is selected from 0, 1, and 2;

    h is selected from 0, 1, and 2;

    h′

    is selected from 0, 1, and 2;

    g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    g′

    is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    s′

    is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    s″

    is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    t′

    is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

    x is selected from 0, 1, 2, 3, 4, and 5;

    x′

    is selected from 0, 1, 2, 3, 4, and 5;

    n is an integer from 1 to 10;

    BM is an SR-A antagonist of formula;

    wherein R1 is independently selected from;

    H, R1-benzamido, R1-benzylether, R1-benzylamino, amino, fluoralkyl, halo, cyano, nitro, aryloxyl, haloaryl, aryl, alkoxy, and 1,2-benzo;

    or R1 represents a fused ring forming naphthalene moiety with the six membered aryl ring it substitutes;

    R2 is a direct bond to Ln; and

    m is an integer from 1 to 4;

    or a pharmaceutically acceptable salt thereof.

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