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 moieities, 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
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is-hydrogen or lower alkyl; and
R 9 is
R 11 is hydrogen or lower alkyl;
R 12 is lower alkyl, halogen, or methoxy, and m is 0-5 where R 12 is independently selected at each occurrence; and
wherein:
R 14 is a direct bond, lower alkylene, arylene, or arylene(lower alkylene);
R 15 is hydrogen, lower alkyl or aryl;
R 16 is arylene(lower alkylene), lower alkylene, arylene, aryl (lower alkylene), or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
2. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 1 is hydrogen.
3. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 1 and R 2 are methyl.
4. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 3 is isopropyl.
5. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle and R 5 H or methyl.
6. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 4 is lower alkyl, and R 5 is H or methyl.
7. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6.
8. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 6 is lower alkyl.
9. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 8 is hydrogen.
10. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 9 is
11. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R 10 is
12. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R 10 is
13. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R 14 is arylene or lower alkylene; R 15 is lower alkyl or aryl; and R 16 is lower alkylene.
14. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 9 is
15. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R 10 is
16. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R 10 is
17. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R 14 is arylene or lower alkylene; R 15 is lower alkyl or aryl; and R 16 is lower alkylene.
18. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 9 is
and R 13 is
19. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 18 wherein R 15 is lower alkyl; and R 16 is lower alkylene.
20. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 9 is
21. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 20 wherein R 16 is lower alkylene or arylene.
22. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 9 is
23. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 22 wherein R 16 is lower alkylene or arylene.
24. A compound of claim 1 having the structure
or a pharmaceutically acceptable salt or solvate thereof.
25. A compound of claim 1 having the structure
or a pharmaceutically acceptable salt or solvate thereof
wherein R 4 is iso-propyl or sec-butyl.
26. A compound of claim 1 having the structure
or a pharmaceutically acceptable salt or solvate thereof.
27. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 17 is
28. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 17 is
29. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 17 is
30. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 17 is
and Y═O or S.
31. A compound of claim 1 having the structure
or a pharmaceutically acceptable salt or solvate thereof.
32. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R 13 is
33. A compound of claim 1 having the structure
or a pharmaceutically acceptable salt or solvate thereof.
34. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl;
R 11 is hydrogen or lower alkyl;
R 12 is lower alkyl, halogen, or methoxy, and m is 0-5 where R 12 is independently selected at each occurrence; and
R 20 is
wherein:
R 14 is a direct bond, arylene(lower alkylene), lower alkylene or arylene;
R 15 is hydrogen, lower alkyl or aryl;
R 16 is lower alkylene, arylene(lower alkylene), arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
35. A compound of claim 34 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
36. A compound of claim 34 having the formula
or a pharmaceutically acceptable salt or solvate thereof
wherein R 4 is iso-propyl or sec-butyl, and R 5 is hydrogen.
37. A compound of claim 34 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
38. A compound of claim 34 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
39. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 34 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
40. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl;
R 11 is hydrogen or lower alkyl;
R 12 is lower alkyl, halogen, or methoxy, and m is 0-5 where R 12 is independently selected at each occurrence;
R 16 is arylene(lower alkylene), lower alkylene, arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
41. A compound of claim 40 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
42. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 40 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
43. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl;
R 11 is hydrogen or lower alkyl;
R 12 is lower alkyl, halogen, or methoxy, and m is 0-5 where R 12 is independently selected at each occurrence; and
where R 20 is
wherein:
R 14 is a direct bond, arylene(lower alkylene), lower alkylene or arylene;
R 15 is hydrogen, lower alkyl or aryl;
R 16 is arylene(lower alkylene), lower alkylene, arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
44. A compound of claim 43 having the formula
or a pharmaceutically acceptable salt or solvate thereof.
45. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 43 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
46. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl;
R 11 is hydrogen or lower alkyl;
R 12 is lower alkyl, halogen, or methoxy, and m is 0-5 where R12 is independently selected at each occurrence;
R 16 is arylene(lower alkylene), lower alkylene, arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
47. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 46 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
48. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl; and
R 20 is
wherein:
R 14 is a direct bond, arylene(lower alkylene), lower alkylene or arylene;
R 15 is hydrogen, lower alkyl or aryl;
R 16 is arylene(lower alkylene), lower alkylene, arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
49. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 48 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
50. A compound of the formula
or a pharmaceutically acceptable salt or solvate thereof,
wherein, independently at each location:
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen or lower alkyl;
R 3 is lower alkyl;
R 4 is lower alkyl, aryl, or —CH 2 —C 5-7 carbocycle when R 5 is H or 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 hydrogen or lower alkyl and n is 2, 3, 4, 5 or 6;
R 6 is hydrogen or lower alkyl;
R 7 is sec-butyl or iso-butyl;
R 8 is hydrogen or lower alkyl; and R 20 is
wherein, R 15 is hydrogen or lower alkyl, R 16 is arylene(lower alkylene), lower alkylene, arylene, or —(CH 2 OCH 2 ) p CH 2 — where p is 1-5; and
R 17 is an activated ester, an anhydride, an acid chloride, an isocyanate, an isothiocyanate,
wherein X is a leaving group.
51. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 50 wherein R 17 is isocyanate, isothiocyanate,
wherein X is a leaving group.
52. A composition comprising a compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1 - 23 , 24 - 26 , and 27 - 33 and a pharmaceutically acceptable carrier, diluent or excipient.