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Laulimalide Analogues as Therapeutic Agents

  • US 20080280973A1
  • Filed: 06/28/2005
  • Published: 11/13/2008
  • Est. Priority Date: 06/28/2004
  • Status: Abandoned Application
First Claim
Patent Images

1. A compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, wherein:

  • R1a, R1b, and R5 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C2-C10 alkenoxy, C2-C10 alkynyl, C2-C10 alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, COR8, nitro, cyano, OH, CF3, OCF3, or halogen;

    R2 is absent (when “

    a”

    is a triple bond or when “

    a”

    is a single bond and “

    b”

    is a double bond) or is selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C2-C10 alkenoxy, C2-C10 alkynyl, C2-C10 alkynoxy, aryl, nitro, cyano, halogen, acyl, alkacyl, CHO, CO2H, CO2

    C1-10 alkyl, CF3, OH, OR8′

    , OCF3, SH, SR8′

    , NH2, NHR8′

    , NHR8′

    R8′

    , CON(R8′

    )2, and CONHR8′

    ;



    a”

    can be a single or double bond of either (E)- or (Z)-orientation, or “

    a”

    can be a triple bond when R2, Y, “

    b” and



    c”

    are absent;



    b”

    can be absent or a single bond (when R1 is absent);



    c”

    can be absent, a single, or double bond of either (E)- or (Z)-orientation;

    such that only one of “

    a”

    , “

    b”

    , and “

    c”

    can be a double bond, when “

    b” and



    c”

    are absent, then Y is absent; and

    when “

    a”

    is a single or double bond, one of “

    b” and



    c”

    is a single bond and one is absent, then Y is H, a straight or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl, CH3, CH2R8, CHR8R8, CR8R8R8, CH2F, CH2Cl, CH2Br, CHF2, CHCl2, CHBr2, CF3, CCl3, CBr3, OH, OR8′

    , SH, SR8′

    , NH2, NHR8′

    , or NR8′

    R8′

    ;

    when “

    a”

    , “

    b”

    , and “

    c”

    are single bonds or when “

    a”

    is a single bond, one of “

    b” and



    c”

    is a double bond and one is absent, then Y is CH2, CHR8, CR8R8, CHF, CHCl, CHBr, CF2, CCl2, CBr2, O, S, NH, or NR8′

    ;

    R3 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C2-C10 alkenoxy, C2-C10 alkynyl, C2-C10 alkynoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, cyano, CF3, OH, O-alkyl, hydroxylalkyl, O-acyl, OCF3, SH, S-alkyl, thioalkyl, S-acyl, amine, alkylamine, NH2, NHR8, NR8R8, and halogen;

    R4 is selected from the group consisting of C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, C3-C10 heterocycloalkyl, adamantyl, and C3-C10 heterocycloalkenyl;

    X is CH2, CHR8, CR8R8, NH, NR8′

    , O, or S; and

    when “

    d”

    is a single bond, V is independently selected from the group consisting of CH2, CHR8, CR8R8, NH, NR8′

    , O, S, C═

    O, or C═

    Y2, and W is independently selected from the group consisting of CH2, CHR8, CR8R8, NH, NR8′

    , O, or S;

    such that V and W are not both NH, NR8′

    , O, S, C═

    O, or C═

    Y2;

    W is not NH, NR8′

    , O, or S, when X is N, NR5, O, or S; and

    V is not C═

    O or C═

    Y2, when W is N, NR5, O, or S;

    when “

    d”

    is a double bond of either (E)- or (Z)-orientation, V and W are independently selected from the group consisting of CH, CR8, or N such that V and W are not both N, and X and W are not both N;

    or when “

    d”

    is a triple bond, V and W are both carbon;

    or alternatively, V and W are taken together to form an optionally substituted or unsubstituted carbocyclic ring, such as a 3-6 membered cycloalkyl ring, or an optionally substituted or unsubstituted heterocyclic ring, such as a 3-6 membered heterocyclic ring, such that only 2 adjacent ring members joined via a single or double bond (i.e., “

    d”

    is a single bond or a double bond) are part of the macrocyclic ring system; and

    the ring member directly adjacent to the —

    (C═

    Y1)—

    moiety of the macrocycle is not a heteroatom when X is N, NR5, O, or S;

    when “

    e”

    , “

    f”

    , “

    g”

    , “

    h”

    , or “

    i”

    is a single bond (i.e., the bond between M and P, P and Q, T and U, or U and V, is a single bond), then the respective M, P, T, U, or Q is independently CH2, CHR8, CR8R8, NH, NR8′

    , O, S, C═

    O, or C═

    Y2;

    such that if one of M, P, T, U, V, or W is NH, NR8′

    , O, or S, then its directly adjacent moieties cannot be NH, NR8′

    , O, or S; and

    if one of M, P, T, U, V, or W is NH, NR8′

    , O, or S, then its directly adjacent moieties both cannot be C═

    O or C═

    Y2; and

    , if one of M, P, T, U, or V is C═

    O or C═

    Y2, then its directly adjacent moieties cannot be C═

    O or C═

    Y 2; and

    if one of M, P, T, U, or V is C═

    O or C═

    Y2, then its directly adjacent moieties both cannot be NH, NR8′

    , O, or S;

    or alternatively,when “

    e”

    , “

    f”

    , “

    g”

    , “

    h”

    , or “

    i”

    is a double bond of either (E)- or (Z)-orientation, then the respective M, P, T, U, or Q is independently CH, CR8, or N, such that, if one of M, P, T, U, V, or W is N, then its directly adjacent moieties cannot be N, NH, NR8′

    , O, or S; and

    when “

    e”

    , “

    f”

    , “

    g”

    , “

    h”

    , or “

    i”

    is a triple bond, then the respective M, P, T, U, or Q is a carbon;

    whereinwhen “

    h” and



    i”

    are single bonds, P is CHR*, CR8R*, or NR*;

    when one of “

    h” and



    i”

    is a double bond”

    , P is CR*; and

    when “

    g” and



    f”

    are single bonds, T is CHR*′

    , CR8R*′

    , or NR*′

    ;

    when one of “

    g” and



    f”

    is a double bond”

    , T is CR*′

    ;

    wherein R* and R*′

    are taken together with Q to form an optionally substituted or unsubstituted carbocyclic ring, such as a 3-6 membered cycloalkyl ring, or an optionally substituted or unsubstituted heterocyclic ring, such as a 3-6 membered heterocyclic ring, such that the ring member directly adjacent to M is not a heteroatom when M is N, NR5, O, or S;

    with the proviso that when —

    V—

    W—

    is —

    CH═

    CH—

    or —

    C≡

    C—

    , then —

    P-Q-T- is not each Y1 and Y2 is independently O, S, NH, or NR8′

    ;

    each R8 is independently —

    H;

    an optionally substituted or unsubstituted straight or branched alkyl, such as a —

    C1-8 straight or branched chain alkyl;

    an optionally substituted or unsubstituted straight or branched —

    C2-8 alkenyl;

    an optionally substituted or unsubstituted straight or branched —

    C2-8 alkynyl;



    C3-6 cycloalkyl;

    3-7 membered heterocycle;

    -aryl;

    -aralkyl;

    -heteroaryl, -heteroarylalkyl, -halo (F, Cl, Br, I);

    -haloalkyl;



    CF3;



    CN;



    NO2;

    -acyl (including but not limited to aldehydes, ketones, esters, carboxylic acids, amides, imides, thioesters), —

    (C═

    Y1)-alkyl, —

    O(C═

    Y1)-alkyl, —

    (C═

    Y1)—

    OH, —

    (C═

    Y1)—

    O-alkyl, —

    S—

    (C═

    Y1)-alkyl, —

    (C═

    Y1)—

    SH, —

    (C═

    Y1)—

    S-alkyl, —

    NH(C═

    Y1)-alkyl, —

    NR8 (C═

    Y1)-alkyl, —

    (C═

    Y1)—

    NH2, —

    (C═

    Y1)—

    NH(alkyl), —

    (C═

    Y1)—

    N(alkyl)2, —

    COOH;



    COOC1-8 alkyl;



    CONH2;



    CONH—

    C1-8 alkyl;



    CON(C1-8 alkyl)2;

    alkacyl, -alkyl-(C═

    Y1)-alkyl, -alkyl-O(C═

    Y1)-alkyl, -alkyl-(C═

    Y1)—

    OH, -alkyl-(C═

    Y1)—

    O-alkyl, -alkyl-S—

    (C═

    Y1)-alkyl, -alkyl-(C═

    Y1)—

    SH, -alkyl-(C═

    Y1)—

    S-alkyl, -alkyl-NH(C═

    Y1)-alkyl, -alkyl-NR8′

    (C═

    Y1)-alkyl, -alkyl-(C═

    Y1)—

    NH2, -alkyl-(C═

    Y1)—

    NH(alkyl), -alkyl-(C═

    Y1)—

    N(alkyl)2, -alkyl-COOH;

    -alkyl-COOC1-8 alkyl;

    -alkyl-CONH2;

    -alkyl-CONH—

    C1-8 alkyl;

    -alkyl-CON(C1-8 alkyl)2;

    amino, —

    NH2;



    NH—

    C1-8 alkyl;



    N(C1-8 alkyl)2;



    NHC(O)—

    C1-8 alkyl;

    alkylamino;

    hydroxyl, alkylhydroxyl, alkoxy, thio;

    alkylthio;

    thioalkyl; and

    each R8′

    is independently an optionally substituted or unsubstituted straight or branched alkyl, such as a —

    C1-8 straight or branched chain alkyl;

    an optionally substituted or unsubstituted straight or branched alkenyl, such as a —

    C2-8 alkenyl;

    an optionally substituted or unsubstituted straight or branched alkynyl, such as a —

    C2-8 alkynyl;

    a saturated or unsaturated carbocycle, such as a saturated or unsaturated —

    C3-6 cycloalkyl;

    a heterocycle, such as a 3-7 membered heterocycle;

    aryl;

    or heteroaryl;

    such that there is not a double or triple bond directly adjacent to a double or triple bond.

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