Anticancer drug conjugates

Patent metadata

Field	Value
Publication number	US-11007271-B2
Application number	US-201716082942-A
Country	US
Kind code	B2
Filing date	Jun 13, 2017
Priority date	Jun 13, 2016
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

Provided herein is a conjugate comprising two residues of structurally and/or mechanistically different anticancer bioactive agents, coupled to one another by a biocleavable linking moiety, as well as methods of treating cancer using the same and pharmaceutical compositions comprising the same.

First claim

What is claimed is:

1. A conjugate comprising:
(a) a residue of a first anticancer bioactive agent, said first anticancer bioactive agent having a first chemical structure;
(b) a residue of a second anticancer bioactive agent, said second anticancer bioactive agent having a second chemical structure; and
(c) a monomethyl triazene linking moiety covalently bonding said first residue and said second residue to form the conjugate, wherein:
said first bioactive agent is different than said second bioactive agent;
said first bioactive agent and said second bioactive agent have a first functional group and a second functional group, respectively;
each of said first anticancer bioactive agent and said second bioactive agent is selected from the group consisting of amonafide, camptothecin, chlorambucil, colchicine, cytarabine and doxorubicin;
said monomethyl triazene linking moiety is a biocleavable moiety being formed by coupling said first functional group and said second functional group, such that biocleaving said monomethyl triazene linking moiety releases both said first anticancer bioactive agent characterized by said first chemical structure and said second anticancer bioactive agent characterized by said second chemical structure, and further releases a cytotoxic monomethyl triazene.

2. The conjugate of claim 1 , wherein each of said first functional group and said second functional group is selected from the group consisting of amine, hydroxyl, carboxyl and ester.

3. The conjugate of claim 1 , wherein each of said first bioactive agent and said second bioactive agent is independently characterized by a first therapeutic activity and a second therapeutic activity, respectively, and at least one of said first therapeutic activity and said second therapeutic activity is a low or moderate therapeutic activity.

4. The conjugate of claim 1 , wherein each of said first therapeutic activity and said second therapeutic activity is a low or moderate therapeutic activity.

5. The conjugate of claim 3 , wherein the conjugate is characterized by exerting a therapeutic activity greater than each of said first therapeutic activity and said second therapeutic activity alone or in combination.

6. The conjugate of claim 1 , wherein said first bioactive agent is camptothecin, and said second bioactive agent is chlorambucil.

7. The conjugate of claim 1 , wherein said first bioactive agent is camptothecin, and said second bioactive agent is colchicine.

8. The conjugate of claim 1 , wherein said first bioactive agent is amonafide, and said second bioactive agent is chlorambucil.

9. The conjugate of claim 1 , wherein said first bioactive agent is amonafide, and said second bioactive agent is camptothecin.

10. The conjugate of claim 1 , wherein said first bioactive agent is cytarabine, and said second bioactive agent is chlorambucil.

11. The conjugate of claim 1 , wherein said first bioactive agent is doxorubicin, and said second bioactive agent is chlorambucil.

12. The conjugate of claim 1 , wherein said first bioactive agent is doxorubicin, and said second bioactive agent is camptothecin.

13. The conjugate of claim 1 , wherein said first bioactive agent is cytarabine, and said second bioactive agent is camptothecin.

14. A conjugate selected from the group consisting of:

15. A pharmaceutical composition comprising, the conjugate of claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of cancer.

17. A method of treating cancer in a subject, the method comprising, administering to said subject a therapeutically effective amount of the conjugate of claim 1 .

18. A process of preparing the conjugate of claim 1 , the process comprising coupling said first bioactive agent to said second bioactive agent via said first functional group and said second functional group, to thereby form said linking moiety.

19. The process of claim 18 , further comprising, prior to said coupling, modifying at least one of said first bioactive agent or said second bioactive agent so as to exhibit said first functional group or said second functional group, respectively.

Assignees

• Ariel Scient Innovations Ltd

Inventors

• Gellerman Gary
• Gilad Yosi
• Tuchinsky Helena

Classifications

• C07D221/14

  Aza-phenalenes, e.g. 1,8-naphthalimide · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title