Pentapeptide compounds and uses related thereto
View Patent ↗Pentapeptide compounds are disclosed. The compounds have biological activity, e.g., cytotoxicity. Prodrugs having targeting groups and pentapeptide moieties, as well as precursors thereof are also disclosed. For example, precursors having a reactive linker that can serve as a reaction site for joining to a targeting agent, e.g., an antibody, as disclosed.
1. A compound of the formula
2. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen;
R 2 is selected from hydrogen and lower alkyl;
R 3 is lower alkyl;
R 4 is selected from lower alkyl, aryl, and —CH 2 —C 5-7 carbocycle when R 5 is selected from H and methyl, or R 4 and R 5 together form a carbocycle of the partial formula —(CR a R b ) n — wherein R a and R b are independently selected from hydrogen and lower alkyl and n is selected from 2, 3, 4, 5 and 6;
R 6 is selected from hydrogen and lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is selected from hydrogen and lower alkyl;
R 11 is selected from hydrogen and lower alkyl; and
R 18 is selected from a hydroxyl protecting group and a direct bond such that OR 18 represents=O.
3. A compound of claim 2 wherein R 3 is isopropyl.
4. A compound of claim 2 wherein R 4 is selected from lower alkyl, aryl, and —CH 2 —C 5-7 carbocycle and R 5 is selected from H and methyl.
5. A compound of claim 2 wherein R 4 is selected from lower alkyl, and R 5 is selected from H and methyl.
6. A compound of claim 2 wherein R 4 and R 5 together form a carbocycle of the partial formula —(CR a R b ) n — wherein R a and R b are independently selected from hydrogen and lower alkyl and n is selected from 2, 3, 4, 5 and 6.
7. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 2 wherein R 6 is lower alkyl.
8. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 2 wherein R 8 is hydrogen.
9. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 2 wherein R 11 is hydrogen.
10. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 2 wherein —OR 18 is=O.
11. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof
wherein, independently at each location:
R 1 is selected from hydrogen and lower alkyl;
R 2 is selected from hydrogen and lower alkyl;
R 3 is lower alkyl;
R 4 is selected from lower alkyl, aryl, and —CH 2 —C 5-7 carbocycle when R 5 is selected from H and methyl, or R 4 and R 5 together form a carbocycle of the partial formula —(CR a R b ) n — wherein R a and R b are independently selected from hydrogen and lower alkyl and n is selected from 2, 3, 4, 5 and 6;
R 6 is selected from hydrogen and lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is selected from hydrogen and lower alkyl; and
R 19 is selected from hydroxyl- and oxo-substituted lower alkyl.
12. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 1 is hydrogen.
13. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 1 and R 2 are methyl.
14. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 3 is isopropyl.
15. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 4 is selected from lower alkyl, aryl, and —CH 2 —C 5-7 carbocycle and R 5 is selected from H and methyl.
16. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 4 is selected from lower alkyl, and R 5 is selected from H and methyl.
17. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 4 and R 5 together form a carbocycle of the partial formula —(CR a R b ) n — wherein R a and R b are independently selected from hydrogen and lower alkyl and n is selected from 2, 3, 4, 5 and 6.
18. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 6 is lower alkyl.
19. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 8 is hydrogen.
20. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 11 wherein R 19 is oxo-substituted lower alkyl.
21. A compound of claim 11 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
22. A composition comprising a compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1 , 10 or 20 and a pharmaceutically acceptable carrier, diluent or excipient.
23. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is selected from hydrogen and lower alkyl;
R 2 is selected from hydrogen and lower alkyl;
R 3 is lower alkyl;
R 4 is selected from lower alkyl, aryl, and —CH 2 —C 5-7 carbocycle when R 5 is selected from H and methyl, or R 4 and R 5 together form a carbocycle of the partial formula —(CR a R b ) n — wherein R a and R b are independently selected from hydrogen and lower alkyl and n is selected from 2, 3, 4, 5 and 6;
R 6 is selected from hydrogen and lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is selected from hydrogen and lower alkyl; and
R 11 is selected from hydrogen and lower alkyl.
24. A compound of claim 23 , wherein R 1 is hydrogen.