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3-3-Di-Substituted-Oxindoles As Inhibitors of Translation Initiation

  • US 20100249201A1
  • Filed: 06/09/2010
  • Published: 09/30/2010
  • Est. Priority Date: 02/13/2004
  • Status: Active Grant
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1. A method of treating a cellular proliferative disorder in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII or formula XIV whereinthe compound of formula I is:

  • wherein A is selected from the group consisting of carbocyclic aromatic ring, heterocyclic ring and heteroaromatic ring;

    R1 is selected from the group consisting of (halo)alkyl, (un)substituted (alkyl)aryl, halogen, CN, COOH, alkenyl, alkynyl, alkoxy and cycloalkoxy;

    R2 is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

    NHSO2Ar and Ar—

    NHCOAr;

    R3 is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

    NHSO2Ar and Ar—

    NHCOAr;

    R4 is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

    NHSO2Ar and Ar—

    NHCOAr;

    X is selected from the group consisting of unsubstituted or substituted nitrogen, oxygen, sulfur and carbon;

    Y is selected from the group consisting of unsubstituted or substituted nitrogen, oxygen and sulfur and carbon; and

    n=0-4;

    the compound of formula II is;

    wherein R1 is selected from the group consisting of H, 5-bromo, 5-chloro, 7-bromo, 5-iodo, 5-OCF3, 5-sulfonic acid, 5-nitro, 4-bromo, 6-bromo, 5-ethyl, 7-ethyl, 4-ethyl, 6-ethyl, 7-iodo, 5-fluoro, 7-COOH, 7-COOMe and 4-Cl; and

    R2 is selected from the group consisting of 7-formamide-N-[2-(4-amino-phenyl)-ethyl], 7-CO2H, 7-CH2OH, 7-CH2—

    N-imidazole and H with the proviso that R1 and R2 cannot both be H, and with the further proviso that when R2 is H, R1 cannot be 5-chloro, 5-nitro or 5-fluoro;

    the compound of formula III is;

    wherein X is selected from the group consisting of oxygen, NH and CH2; and

    R is selected from the group consisting of 3′

    -CH2CH(CO2Me)NH2, 3′

    -CH2CH(CO2Me)NHFmoc, 3′

    -t-Bu, 3′

    -OH, 3′

    -O(CH2)3CHCH2, 3′

    -O(CH2)4Br, 3′

    -O(CH2)4NMe2, 3′

    -O(CH2)4N3, 3′

    -O(CH2)4NH2, 3′

    -CF3, 3′

    -CH3, 3′

    -n-heptyl, 3′

    -n-nonyl, 3′

    -1-Bu, 3′

    -1-propyl, 3′

    -n-propyl, 3′

    -n-octyl, 3′

    -Et, 3′

    -n-pentyl, 3′

    -n-Bu, 3′

    -n-hexyl, 3′

    -n-cyclopentyl, 3′

    -n-cyclohexyl, 4-NHSO2(4-tBu)Ph and 3′

    —

    NHSO2(4-tBu)Ph;

    the compound of formula IV is;

    wherein R is selected from the group consisting of 4-F, 4-O(CH2)3CHCH2, 3-Cl, 3-F, 3-Me, 2-Me and 2-OMe;

    the compound of formula V is;

    wherein R is selected from the group consisting of —

    SO2-Camphor, —

    CO(CH2)6CO2H, —

    CO(CH2)3CONHOH, —

    CH2CH2NHBoc, —

    CO(CH2)3CO2H, —

    CH2CO2H, —

    CH2CO-Leu-Phe-CH2OH and —

    CH2CO2Me;

    the compound of formula VI is;

    wherein R1 is selected from the group consisting of 7-Br, 4-Cl, 5-Br, 5-NO2, 5-I, 5-OMe, 5-Cl, 7-CF3, 5-NH2, 4-Br, 6-Br, H, 7-OMe, 7-I, 5-Et, 7-Et, 4-Et, 6-Et, 5-F, 5-N3, 7-COOH, 7-CO2H, 4-Cl, 6-Cl and 5-NHSO2-1-napthyl; and

    R2 is H or 7-CO2H;

    the compound of formula VII is;

    wherein R1 is selected from the group consisting of H, 2-OH, 3-O(CH2)4NMe2, 3-O(CH2)4N3, 3-t-Bu, 2-OMe, 3-OMe, 4-OH, 4-OPh, 4-Ph, 4-NMe2, 4-n-propyl, 4-i-Bu, 4-n-Bu, 4-O(CH2)2OH, 4-OMe, 2-CH2CO2H and 4-t-Bu; and

    R2 is selected from the group consisting of 2-OH, 4-OH, 4-t-Bu and H with the proviso that R1 and R2 cannot both be H;

    the compound of formula VIII is;

    wherein R1 is selected from the group consisting of H and 7-CO2H;

    R2 is selected from the group consisting of H, 2-Me, 3′

    -Me, 3-F and 3-CF3; and

    R3 is selected from the group consisting of H, 2-NHFmoc, 2-NHSO2CH2Ph, 2-NHSO2CH3, 2-NHSO2(4-tBu)Ph, 2-NHSO2(4-NHAc)Ph, 2-NHSO2(3-CF3)Ph, 2-NHSO2(4-NO2)Ph, 2-NHSO2(4-OMe)Ph, 2-NHSO2(4-Br)Ph, 2-NHSO2(4-I)Ph, 2-NHSO2(4-Ph)Ph, 2-NHSO2(4-OPh)Ph, 2-NHAc, 2-NHCO(4-tBu)Ph and 3′

    -NHSO2(4-tBu)Ph;

    the compound of formula IX is;

    wherein R is selected from the group consisting of —

    CH2-(4-Cl)Ph, —

    CH2CHCH2, —

    CH2OH, —

    CH2CO2H, —

    CH2OCH2CHCH2, —

    SO2(4-O-n-Bu)Ph, —

    SO2(4-O-Ph)Ph, —

    SO2(4-NHAc)Ph, —

    SO2(4-CH2CH2CO2Me)Ph, —

    SO2(4-OMe)Ph and —

    SO2(4-t-Bu)Ph;

    the compound of formula X is;

    the compound of formula XI is;

    the compound of formula XII is;

    the compound of formula XIII is;

    wherein R is selected from the group consisting of 2-Thiophene, —

    (CH2)11CH3, —

    CH2Ph, —

    CCH, -cyclohexyl and —

    C6F5; and

    the compound of formula XIV is;

    wherein R is selected from the group consisting of H, 3-Cl, 3-F, 3-Me and 3-t-Bu.

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