Chemical linkers and conjugates thereof

• US 7,691,962 B2
• Filed: 05/19/2005
• Issued: 04/06/2010
• Est. Priority Date: 05/19/2004
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Chen, Liang, Guerlavais, Vincent, Horgan, Killian, Boyd, Sharon E., Gangwar, Sanjeev, Sufi, Bilal, Li, Zhi-Hong
• Primary Examiner(s): Kosar; Andrew D
• Application Number:
  US11/134,826
• Publication Number:
  US 20060024317A1
• Time in Patent Office: 1,783 Days
• Field of Search: None
• US Class Current: 530/300
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present disclosure provides drug-ligand conjugates that are potent cytotoxins, wherein the drug is linked to the ligand through either a peptidyl, hydrazine, or disulfide linker. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.

Claims

1. A compound of the formula

2. The compound of claim 1, wherein L³ comprises an aromatic group.

3. The compound of claim 2, wherein L³ comprises a benzoic acid group, an aniline group, or an indole group.

4. The compound of claim 2, wherein -L³—

NH—

comprises a group having a structure selected from the group consisting of;

5. The compound of claim 1, wherein L⁴ comprises a non-cyclic moiety.

6. The compound of claim 1, wherein L⁴ increases solubility of the compound as compared to the compound lacking L⁴.

7. The compound of claim 1, wherein L⁴ decreases aggregation of the compound as compared to the compound lacking L⁴.

8. The compound of claim 1, wherein L⁴ comprises a polyethylene glycol moiety.

9. The compound of claim 8, wherein the polyethylene glycol moiety contains 3-12 repeat units.

10. The compound of claim 9, wherein the polyethylene glycol moiety contains 2-6 repeat units.

11. The compound of claim 10, wherein the polyethylene glycol moiety contains 4 repeat units.

12. The compound of claim 1, wherein (AA¹)_c is a peptide sequence cleavable by a protease expressed in tumor tissue.

13. The compound of claim 12, wherein the protease is a lysosomal protease.

14. The compound of claim 1, wherein c is an integer from 2 to 6.

15. The compound of claim 14, wherein c is 2, 3 or 4.

16. The compound of claim 1, wherein the amino acid in (AA¹)_c located closest to the drug moiety is selected from the group consisting of:

Ala, Asn, Asp, Cit, Cys, Gin, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

17. The compound of claim 1, wherein (AA¹)_c is a peptide sequence selected from the group consisting of Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp, Cit, Phe-Ala, Phe-N⁹-tosyl-Arg, Phe-N⁹-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu (SEQ ID NO:

1), β

-Ala-Leu-Ala-Leu (SEQ ID NO;

     2) and Gly-Phe-Leu-Gly (SEQ ID NO;

     3).

18. The compound of claim 1, wherein (AA¹)_c is Val-Cit or Val-Lys.

19. The compound of claim 1, wherein D comprises a chemically reactive functional group selected from the group consisting of a primary and secondary amines, hydroxyl, sulfhydryl and carboxyl.

20. The compound of claim 1, wherein D is selected from the group consisting of:

duocarmycins, CC-1065, CBI-based duocarmycin analogues, MCBI-based duocarmycin analogues, and CCBI-based duocarmycin analogues.

21. The compound of claim 1, wherein D has the structure:

22. The compound of claim 21, wherein R² is an unsubstituted lower alkyl.

23. The compound of claim 1, wherein NH₂—

(L³)-D has a structure selected from the group consisting of;

24. The compound of claim 1, wherein D has the structure:

25. The compound of claim 1 comprising the structure:

26. The compound of claim 25, having the structure:

27. The compound of claim 1 which is selected from the group consisting of:

28. The compound of claim 1 selected from the group consisting of:

29. The compound of claim 1 having the structure:

30. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

31. A method of killing a cell, said method comprising administering to said cell an amount of a compound according to claim 1 sufficient to kill said cell.

32. The method of claim 31, wherein the cell is a tumor cell.

33. A method of retarding or stopping the growth of a tumor in a mammalian subject, comprising administering to said subject an amount of a compound according to claim 1, sufficient to retard or stop the growth.

34. A compound of the formula

35. The compound of claim 34, wherein R¹⁵ or R¹⁶ links the drug to F.

36. The compound of claim 35, wherein m is 0.

37. The compound of claim 36, wherein c is an integer from 2 to 6.

38. The compound of claim 37, wherein L⁴ is a substituted or unsubstituted heteroalkyl.

39. The compound of claim 38, wherein X⁴ is R²⁹, COOR²⁹, C(O)NR²⁹, and C(O)NNR²⁹, wherein R²⁹ is a member selected from OH;

NHNH₂;

40. The compound of claim 39, wherein R⁶ is absent and X¹ is halogen.

41. The compound of claim 40, wherein L⁴ comprises at least two amide groups (—

NHC(O)—

).

42. The compound of claim 41, wherein -(AA¹)_c is -Val-Cit-.

43. The compound of claim 42, wherein A is substituted or unsubstituted phenyl.

44. The compound of claim 42, where the -L³—

NH—

moiety of F is selected from

45. The compound of claim 42, wherein L⁴ comprises a polyethylene glycol moiety.

46. The compound of claim 45, wherein L⁴ is —

(CH₂)₂—

NH—

C(O)—

(PEG)₄—

(CH₂)₂—

NH—

C(O)—

(CH₂)₂—

.

47. The compound of claim 46, which is selected from the group consisting of: