Maytansinoid derivatives
Disclosed herein are maytansinoid drug linker derivatives which can be linked to a antigen binding unit (Abu), and maytansinoid drugs linked with an antigen binding unit (Drug-Linker-Antigen binding Unit: D-L-Abu), for targeted delivery to disease tissues. D-L-Abu, D-L-Abu derivatives, and methods relating to the use of such drug conjugates to treat antigen positive cells in cancers and immunological disorders are provided.
1. A compound of Formula Ia:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Z is independently hydrogen or C 1 -C 4 alkyl or two Z with the carbon atom to which they are attached to form a C(═O);
L is selected from the group consisting of C 1 -C 20 alkylene, substituted C 1 -C 20 alkylene, and substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with —O—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, or —NR 8 C(═O)—; wherein said
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 R 23 , wherein each R 23 is independently unsubstituted C 1-6 alkyl; and
Abu is an antigen binding unit and wherein the wavy line ( ) represents linkage of the Abu through a thioether bond.
2. The compound of claim 1 , which is:
or a salt thereof.
3. The compound of claim 1 , which is of Formula IIIa:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
and
Abu is an antigen binding unit.
4. The compound of claim 1 , which is of Formula IVa:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
m is selected from an integer of 1 to 20; and
Abu is an antigen binding unit.
5. The compound of claim 1 , which is of Formula Va:
or a pharmaceutically acceptable salt or solvate thereof.
6. The compound of claim 1 , selected from the group consisting of
or a pharmaceutically acceptable salt thereof; wherein m is selected from an integer of 1 to 20.
7. The compound of claim 1 , wherein Abu is an antigen binding unit with binding specificity to human EGFR.
8. The compound of claim 1 , wherein Abu is an antigen binding unit with binding specificity to human CD20.
9. The compound of claim 7 , wherein Abu is an antibody, antibody fragment, or cell specific ligands.
10. The compound of claim 1 , wherein Abu is an antibody comprising SEQ ID 1 and 2, or SEQ ID 3 and 4, or SEQ ID 5 and 6, or SEQ ID 7 and 8, or SEQ ID 9 and 10, or SEQ ID 13 and 14.
11. The compound of claim 1 , wherein Abu is an antibody comprising Bat0202 (SEQ ID NO: 1) and/or Bat0204 (SEQ ID NO: 2).
12. The compound of claim 1 , wherein Abu is Bat0206.
13. The compound of claim 1 , wherein Abu is selected from C225, EGF-ABX, EGF-ABX, NIMO, Matu, rituxamab, Cetuximab, and Pertuzumab.
14. A pharmaceutical composition comprising a compound of claim 1 .
15. A method of treating a proliferative, inflammatory or immunological disease or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of claim 1 .