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US 2014/0227295 A1Published application
Tubulysin compounds, methods of making and use
AssigneeBristol-Myers Squibb Company
InventorsQiang CONG, Heng Cheng, Sanjeev Gangwar
Life of this patent
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Abstract
Tubulysin compounds of the formula (I) where R1, R2, R3a, R3b, R4, R5, W, and n are as defined herein, are anti-mitotic agents that can be used in the treatment of cancer, especially when conjugated to a targeting moiety.
Claims20
A compound having a structure represented by formula (I)
- wherein
- R1 is H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH2)1-2O(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkynyl), (CH2)1-2OC(═O)(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkynyl), unsubstituted or substituted C(═O)(C1-C10 alkyl), unsubstituted or substituted C(═O)(C2-C10 alkenyl), unsubstituted or substituted C(═O)(C2-C10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, or unsubstituted or substituted alkylaryl;
- R2 is H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH2)1-2O(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkynyl), (CH2)1-2OC(═O)(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkynyl), unsubstituted or substituted C(═O)(C1-C10 alkyl), unsubstituted or substituted C(═O)(C2-C10 alkenyl), unsubstituted or substituted C(═O)(C2-C10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, unsubstituted or substituted alkylaryl, or
- wherein each R2a is independently H, NH2, NHMe, Cl, F, Me, Et, or CN;
- R3a and R3b are independently H, C1-C5 alkyl, CH2(C5-C6 cycloalkyl), CH2C6H5, C6H5, or CH2CH2OH;
- R4 is
- wherein R4a is H or C1-C3 alkyl;
- and Y is H, OH, Cl, F, CN, Me, Et, NO2, or NH2;
- R5 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, CO(C1-C5 alkyl), CO(C2-C5 alkenyl), or CO(C2-C5 alkynyl);
- W is O or S;
- and
- n is 0, 1, or 2;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A drug-linker compound having a structure according to formula (III)
- D-(XD)aC(XZ)b—R31 (III)
- wherein
- R31 is a reactive functional group;
- XD is a first spacer moiety;
- XZ is a second spacer moiety;
- C is a cleavable group;
- subscripts a and b are independently 0 or 1;
- subscript m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- and
- D is according to formula (D-a)
- or formula (D-b)
- wherein Y is H or NO2;
- R4a is H, Me, or Et;
- and R3a and R3b are independently H, Me, or Et;
- and R6 is C1-C5 alkyl, CH2OC(═O)C1-C5 alkyl, or (CH2)1-2C6H5;
- or a pharmaceutically acceptable salt thereof.
13 more elements
Dependencies are inferred from the claim text.