Functionalized 9-bromo-camptothecin derivatives

摘要

The present disclosure is directed to a compound of formula (I);
wherein L is null or a conditionally-cleavable moiety; W is null or a self-immolative system, 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 that can be attached to one or more of L, W or Z groups, or RM is attached to oxygen when L, W and Z are all null; provided that at least one of L, W, Z and RM is not null; or a pharmaceutically acceptable salt thereof.

主权项

1. A compound of formula (I)wherein:
L is null or a group selected from: wherein:
R1, R2 and R3 are, each independently, null, 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 sulfhydrylalkyl, linear or branched C1-C4 aminoalkyl, linear or branched C1-C4 alkylcarbonyl and linear or branched C1-C4 alkoxycarbonyl;each of n is independently an integer from 0 to 2; andn1 is an integer from 0 to 5; W is null or a group selected from: wherein:
one of R1 and R2 is null and the other is as defined above;R3 is as defined above;R4 and R5 are, each independently, halogen, methyl, ethyl or linear or branched C1-C4 hydroxyalkyl;m is an integer from 0 to 3;A is C1-C3 alkyl, CH2NH, NH or N—R4, wherein R4 is as defined above; andR12 and R13 are, each independently, hydrogen, halogen, methyl, ethyl, linear or branched C1-C4 hydroxyalkyl, linear or branched C1-C4 haloalkyl, or R12 and R13, taken together, form a 3- to 6-membered carbocycle; Z is independently null or
Z1, wherein Z1 is a dipeptide or a tripeptide, linked via its C-terminus to W, or to L when W is null, or to oxygen when W and L are both null, wherein the C-terminal aminoacid residue of the dipeptide or of the tripeptide is selected from glycine, leucine, alanine, arginine and citrulline; and the N-terminal aminoacid residue is selected from any natural or unnatural aminoacid; and, in the case of the tripeptide, the middle aminoacid residue is selected from alanine, valine, leucine, isoleucine, methionine, phenylalanine and proline;Z2, wherein Z2 is a group selected from: wherein
one of R1 and R2 is null and the other is as defined above, andp is an integer from 1 to 20;Z1-Z2, wherein Z1 and Z2 are as defined above; RM is a group selected from: wherein R4 and R5 are as defined above;
R6 is C1-C3 alkyl or an electron-withdrawing group, comprising NO2 and CN group;r is an integer from 0 to 7;or a pharmaceutically acceptable salt thereof.