Functionalized thieno-indole derivatives for the treatment of cancer

摘要

The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R1 and R2 taken together form a group (D) or (G): wherein R5 is hydrogen or C1-C4 alkyl; R3 and R4 are independently hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR4—; each of Y is independently —CH═ or —N═; R7 and R8 are independently hydrogen, halogen, hydroxy, C1-C4 alkoxy, cyano, —NHCOOR3, —C(NH)NH2 or —NR3R4; A is —O—, —NH— or —CO—; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R6 is a leaving group; A1 is null or A; L1 is hydrogen or L.;

主权项

1. A compound of formula (II) wherein R1 and R2 taken together form a group (D) or (G): wherein R5 is hydrogen or linear or branched C1-C4 alkyl; R3 and R4 are, each independently, hydrogen, linear or branched C1-C4 alkyl or linear or branched C1-C4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR4—, wherein R4 is as defined above; each of Y is independently —CH═ or —N═; R7 and R8 are independently hydrogen, halogen, hydroxy, linear or branched C1-C4 alkoxy, cyano, —NHCOOR3, —C(NH)NH2 or —NR3R4, wherein R3 and R4 are as defined above; L is null or a group selected from: —NHCOR9 (IIIa); —NHCONHR9 (IIIb); —NHCOOR9 (IIIc); —NHR9 (IIId); wherein: R9 and R10 are, each independently, a point of attachment, hydrogen, hydroxy or an optionally substituted group selected from linear or branched C1-C4 alkyl, linear or branched C1-C4 hydroxyalkyl, linear or branched C1-C4 sulthydrylalkyl and linear or branched C1-C4 aminoalkyl; n1 is an integer from 0 to 4 and n is as defined above; W is null or one or groups independently selected from wherein one of R9 and R10 is null and the other is as defined above; R11 and R12 are, each independently, hydrogen, halogen, methyl, ethyl or linear or branched C1-C4 hydroxymethyl; m is an integer from 0 to 3; and A2 is —CH2, —CH2NR12 or —NR12— wherein R12 is as defined above; Z is null or a linker (Z1), a linker (Z2) or a linker (Z3), wherein Z1 is a single amino acid, a dipeptide, a tripeptide, a tetrapeptide, or an oligopeptide moiety wherein the amino acids are selected from natural L-amino acids, unnatural D-amino acids, synthetic amino acids, or any combination thereof; Z2 is a group selected from: wherein one of R9 and R10 is a point of attachment and the other is as defined above; and p is an integer from 1 to 20; and Z3 has the general formula Z1-Z2 or Z2-Z1 where Z1 and Z2 are as defined above; RM is null or a group selected from wherein R13 is a C1-C3 alkyl or an electron withdrawing group selected from —NO2 and —CN groups; r is an integer from 0 to 7; and R11 and R12 are as defined above; R6 is a leaving group; A1 is null or —O—, —NH— or —CO; L1 is hydrogen or L, wherein L is as defined above; or the pharmaceutically acceptable salts thereof, provided that 1) when L1 is hydrogen, then A1 is —O—, —NH— or —CO—; 2) when A1 is null, then RM is not null.