Pentapeptide compounds and uses related thereto

• US 7,256,257 B2
• Filed: 04/30/2002
• Issued: 08/14/2007
• Est. Priority Date: 04/30/2001
• Status: Expired due to Term

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Doronina, Svetlana, Senter, Peter D., Toki, Brian E.
• Primary Examiner(s): Lukton; David
• Application Number:
  US10/476,391
• Publication Number:
  US 20040157782A1
• Time in Patent Office: 1,932 Days
• Field of Search: 530/330, 514/17, 514/18, 424/178.1, 424/181.1
• US Class Current: 530/330
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

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.

Claims

1. A compound of the formula

2. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹ is hydrogen.

3. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹ and R² are methyl.

4. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R³ is isopropyl.

5. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁴ is lower alkyl, aryl, or —

CH₂—

C_5-7carbocycle and R⁵ H or methyl.

6. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁴ is lower alkyl, and R⁵ is H or methyl.

7. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁴ and R⁵ together form a carbocycle of the partial formula —

(CR^aR^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 R⁶ is lower alkyl.

9. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁸ is hydrogen.

10. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁹ is

11. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R¹⁰ is

12. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R¹⁰ is

13. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 10 wherein R¹⁴ is arylene or lower alkylene;

R¹⁵ is lower alkyl or aryl; and

R¹⁶ is lower alkylene.

14. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁹ is

15. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R¹⁰ is

16. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R¹⁰ is

17. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 14 wherein R¹⁴ is arylene or lower alkylene;

R¹⁵ is lower alkyl or aryl; and

R¹⁶ is lower alkylene.

18. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁹ is

19. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 18 wherein R¹⁵ is lower alkyl;

and R¹⁶ is lower alkylene.

20. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁹ is

21. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 20 wherein R¹⁶ is lower alkylene or arylene.

22. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R⁹ is

23. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 22 wherein R¹⁶ is lower alkylene or arylene.

24. A compound of claim 1 having the structure

25. A compound of claim 1 having the structure

26. A compound of claim 1 having the structure

27. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹⁷ is

28. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹⁷ is

29. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹⁷ is

30. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹⁷ is

31. A compound of claim 1 having the structure

32. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 wherein R¹³ is

33. A compound of claim 1 having the structure

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.

34. A compound of the formula

35. A compound of claim 34 having the formula

36. A compound of claim 34 having the formula

37. A compound of claim 34 having the formula

38. A compound of claim 34 having the formula

39. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 34 wherein R¹⁷ is isocyanate, isothiocyanate,

40. A compound of the formula

41. A compound of claim 40 having the formula

42. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 40 wherein R¹⁷ is isocyanate, isothiocyanate,

43. A compound of the formula

44. A compound of claim 43 having the formula

45. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 43 wherein R¹⁷ is isocyanate, isothiocyanate,

46. A compound of the formula

47. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 46 wherein R¹⁷ is isocyanate, isothiocyanate,

48. A compound of the formula

49. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 48 wherein R¹⁷ is isocyanate, isothiocyanate,

50. A compound of the formula

51. A compound or a pharmaceutically acceptable salt or solvate thereof of claim 50 wherein R¹⁷ is isocyanate, isothiocyanate,