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Monomethylvaline compounds capable of conjugation to ligands

  • US 20050238649A1
  • Filed: 11/05/2004
  • Published: 10/27/2005
  • Est. Priority Date: 11/06/2003
  • Status: Active Grant
First Claim
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1. A compound having the formula:


  • L-(D)p or a pharmaceutically acceptable salt or solvate thereof wherein, L- is a Ligand unit;

    p ranges from I to about 20; and

    - D is a drug moiety selected from Formulas DE and DF;

    embedded imagewherein, independently at each location;

    R2 is selected from H and C1-C8 alkyl;

    R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);

    R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);

    R5 is selected from H and methyl;

    or R4 and R5 jointly form a carbocyclic ring and have the formula —

    (CRaRb)n

    wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;

    R6 is selected from H and C1-C8 alkyl;

    R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);

    each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—

    (C1-C8 alkyl);

    R9 is selected from H and C1-C8 alkyl;

    R10 is selected from aryl or C3-C8 heterocycle;

    Z is O, S, NH, or NR12, wherein R12 is C1-C8 alkyl;

    R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —

    (R13O)m

    R14, or —

    (R13O)m

    CH(R15)2;

    m is an integer ranging from 1-1000;

    R13 is C2-C8 alkyl;

    R14 is H or C1-C8 alkyl;

    each occurrence of R15 is independently H, COOH, —

    (CH2)n

    N(R16)2, —

    (CH2)n

    SO3H, or —

    (CH2)n

    SO3

    C1-C8 alkyl;

    each occurrence of R16 is independently H, C1-C8 alkyl, or —

    (CH2)n

    COOH;

    R18 is selected from —

    C(R8)2

    (R8)2-aryl, —

    C(R8)2

    C(R8)2

    (C3-C8 heterocycle), and —

    C(R8)2

    C(R8)2

    (C3-C8 carbocycle); and

    n is an integer ranging from 0 to 6.

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