Cytotoxic compounds and conjugates with cleavable substrates

• US 7,714,016 B2
• Filed: 04/06/2006
• Issued: 05/11/2010
• Est. Priority Date: 04/08/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Gangwar, Sanjeev, Sufi, Bilal
• Primary Examiner(s): Saeed; Kamal A
• Application Number:
  US11/398,854
• Publication Number:
  US 20060247295A1
• Time in Patent Office: 1,496 Days
• Field of Search: None
• US Class Current: 514/411
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

The present disclosure provides drug-cleavable substrate conjugates that are potent cytotoxins. The disclosure is also directed to compositions containing the drug-cleavable substrate conjugates, and to methods of treatment using them.

Claims

1. A compound having the following structure:

X²L¹_mD 

 

(2)

wherein L¹ is a self-immolative spacer;

m is an integer of 1, 2, 3, 4, 5, or 6;

X² is a cleavable substrate, wherein the cleavable substrate comprises a cephalosporin derivative; and

D is a drug having the following formula;

2. The compound of claim 1, wherein R²⁴ and R²⁵ are unsubstituted alkyl.

3. The compound of claim 2, wherein at least one of R⁴, R^4′

, R⁵ and R^5′

is O(CH₂)_nNR²⁴R²⁵.

4. The compound of claim 3, wherein R⁴ is O(CH₂)_nNR²⁴R²⁵.

5. The compound of claim 4, wherein R⁴ is O(CH₂)_nN(CH₃)₂.

6. The compound of claim 1, wherein R⁴ is O(CH₂)_nNH₂.

7. The compound of claim 4, wherein R^4′

, R⁵ and R^5′

are H.

8. The compound of claim 1, wherein R⁶ is absent and R⁷ is CH₂—

X¹, wherein X¹ is F, Cl, or Br.

9. The compound of claim 1, wherein R¹, R^1′

, R², and R^2′

are H.

10. The compound of claim 1, wherein X is O and Z is O.

11. The compound of claim 1, wherein D has the following formula:

12. The compound of claim 1, wherein D has the following formula:

13. The compound of claim 1, wherein D has the following formula:

14. The compound of claim 1, wherein D has the following formula:

16. The compound of claim 1, wherein the compound is:

17. The compound of claim 1, wherein the compound has the following formula:

18. The compound of claim 1, wherein the compound has the following formula:

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

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

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

15. A compound having the formula: