Chemical linkers and conjugates thereof

• US 20060024317A1
• Filed: 05/19/2005
• Published: 02/02/2006
• 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: Gangwar, Sanjeev, Chen, Liang, Sufi, Bilal, Li, Zhi-Hong, Guerlavais, Vincent, Horgan, Killian, Boyd, Sharon E.
• Granted Patent: US 7,691,962 B2
• Time in Patent Office: Days
• US Class Current: 424/178.100
• 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 the compound comprises the formula:

3. The compound of claim 1, wherein the compound comprises the formula:

4. The compound of claim 3, wherein L³ comprises an aromatic group.

5. The compound of claim 4, wherein L³ comprises a benzoic acid group, an aniline group, or an indole group.

6. The compound of claim 4, wherein -L³-NH—

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

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

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

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

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

11. The compound of claim 10, wherein the polyethylene glycol moiety contains 3-12 repeat units.

12. The compound of claim 11, wherein the polyethylene glycol moiety contains 2-6 repeat units.

13. The compound of claim 12, wherein the polyethylene glycol moiety contains 4 repeat units.

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

15. The compound of claim 14, wherein the protease is a lysosomal protease.

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

17. The compound of claim 16, wherein c is 2, 3 or 4.

18. 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, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

19. 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).

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

21. The compound of claim 1, wherein D is a cytotoxic drug.

22. The compound of claim 21, wherein D comprises a chemically reactive functional group selected from the group consisting of a primary or secondary amine, hydroxyl, sulflhydryl and carboxyl.

23. The compound of claim 21, wherein D is selected from the group consisting of:

duocarmycins, CC-1065, CBI-based duocarmycin analogues, MCBI-based duocarmycin analogues, CCBI-based duocarmycin analogues, doxorubicin, doxorubicin conjugates, morpholino-doxorubicin, cyanomorpholino-doxorubicin, dolastatins, dolestatin-10, combretastatin, calicheamicin, maytansine, maytansine analogues, DM-1, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), 5-benzoylvaleric acid-AE ester (AEVB), tubulysins, disorazole, epothilones, Paclitaxel, docetaxel, SN-38, Topotecan, rhizoxin, echinomycin, colchicine, vinblastin, vindesine, estramustine, cemadotin, eleutherobin, methotrexate, methopterin, dichloromethotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, melphalan, leurosine, leurosideine, actinomycin, daunorubicin, daunorubicin conjugates, mitomycin C, mitomycin A, carminomycin, aminopterin, tallysomycin, podophyllotoxin, podophyllotoxin derivatives, etoposide, etoposide phosphate, vincristine, taxol, taxotere retinoic acid, butyric acid, N⁸-acetyl spermidine and camptothecin.

24. The compound of claim 1, wherein D comprises a structure:

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

26. The compound of claim 25, wherein R² is an unsubstituted lower alkyl.

27. The compound of claim 3, wherein NH₂-(L³)-D has a structure selected from the group consisting of:

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

29. The compound of claim 2, wherein F comprises the structure:

30. The compound of claim 29, wherein —

F-(L¹)_m—

comprises the structure;

31. The compound of claim 29, having the structure:

32. The compound of claim 29, which is selected from the group consisting of:

33. The compound of claim 3, comprising the structure:

34. The compound of claim 33, having the structure:

35. The compound of claim 3, which is selected from the group consisting of:

36. The compound of claim 3, selected from the group consisting of:

37. The compound of claim 3, having the structure:

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

39. 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.

40. The method of claim 39, wherein the cell is a tumor cell.

41. 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.

42. A compound having the structure

43. A compound of the formula

44. A compound having the structure

X⁴-(L⁴)_p-H-(L¹)_m-D

wherein

D is a drug moiety having pendant to the backbone thereof a chemically reactive functional group, said function group selected from the group consisting of a primary or secondary amine, hydroxyl, thiol, carboxyl, aldehyde, and a ketone;

L¹ is a self-immolative linker;

m is an integer selected from 0, 1, 2, 3, 4, 5, or 6;

X⁴ is a member selected from the group consisting of protected reactive functional groups, unprotected reactive functional groups, detectable labels, and targeting agents;

L⁴ is a linker member;

p is 0 or 1;

H is a linker comprising the structure;

where q is 0, 1, 2, 3, 4, 5, or 6; and

wherein each R²⁴ is a member independently selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, and unsubstituted heteroalkyl. This hydrazine structure can also form five-, six-, or seven-membered rings and additional components can be added to form multiple rings.

45. A compound of the formula: