Triazole-containing releasable linkers, conjugates thereof, and methods of preparation

• US 8,158,590 B2
• Filed: 08/03/2006
• Issued: 04/17/2012
• Est. Priority Date: 08/05/2005
• Status: Active Grant

• Current Assignee: Byondis B.V.
• Original Assignee: Syntarga BV (Synthon International Holding BV)
• Inventors: Beusker, Patrick Henry, De Groot, Franciscus Marinus Hendrikus
• Primary Examiner(s): Tsang, Cecilia J
• Assistant Examiner(s): NIEBAUER, RONALD T
• Application Number:
  US11/997,981
• Publication Number:
  US 20080311136A1
• Time in Patent Office: 2,084 Days
• Field of Search: None
• US Class Current: 514/21.9
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Abstract

This invention relates to compounds comprising one or more therapeutic and/or diagnostic moieties and one or more functional moieties linked together via one or more triazole-containing linkers and to their intermediates and methods of their preparation. The triazole-containing linker may optionally contain one or more conditionally-cleavable or conditionally-transformable moieties and one or more spacer systems in between said moiety/moieties and the one or more therapeutic and/or diagnostic moieties.

Claims

1. A method of producing a compound containing a reactive moiety and a cleavable therapeutic or diagnostic moiety, said method comprising reacting a first compound containing an azide-containing or acetylene-containing group, said first compound being of formula (V) or (VI), respectively:

2. The method of claim 1 which further comprises the reaction of said reactive moiety in said third compound of formula (III) or (IV) with a functional moiety to form a fourth compound of formula (I) or (II), respectively:

3. The method of claim 1 wherein Y is a self-elimination spacer system.

4. The method of claim 3 wherein the spacer system Y is selected from

5. The method of claim 1 wherein V₁ contains a substrate that can be cleaved by plasmin, a cathepsin, cathepsin B, β

-glucuronidase, prostate-specific antigen (PSA), urokinase-type plasminogen activator (u-PA), a member of the family of matrix metalloproteinases, or an enzyme localized by means of directed enzyme prodrug therapy, or wherein V₁ contains a nitro(hetero)aromatic moiety that can be cleaved or transformed by reduction under hypoxic conditions or by reduction by a nitroreductase.

6. The method of claim 1 wherein one or more moieties Z are therapeutic agents.

7. The method of claim 1 wherein the moieties Z comprise at least two different therapeutic moieties.

8. The method of claim 1 wherein the moieties Z each are independently an antibiotic, an anti-bacterial agent, an antimicrobial agent, an anti-inflammatory agent, an anti-infectious disease agent, an anti-autoimmune disease agent, an anti-viral agent, or an anticancer agent.

9. The method of claim 1 wherein the moieties Z are each an anticancer agent.

10. The method of claim 1 wherein L₁ is

11. The method of claim 1 wherein L₂ is

12. The method of claim 2 wherein the moiety L₃ is

13. The method of claim 2 wherein the moiety V₂ is a targeting moiety and is selected from the group consisting of a protein or protein fragment, an antibody or an antibody fragment, a receptor-binding or peptide vector moiety, and a polymeric or dendritic moiety, or any combination thereof.

14. The method of claim 2 wherein V₂ is an antibody or antibody fragment.

15. The method of claim 2 wherein V₂ is a receptor-binding moiety.

16. The method of claim 2 wherein V₂ is a polymer.

17. The method of claim 2 wherein V₂ is an oligoethylene glycol or a polyethylene glycol or a derivative thereof.

18. The method of claim 1 wherein L₁ is connected to V₁.

19. The method of claim 2 wherein L₃ is

20. The method of claim 1 wherein Y is a self-elimination spacer system, and one or more moieties Z are therapeutic agents.

21. The method of claim 1 wherein V¹ is a dipeptide, tripeptide, tetrapeptide, or oligopeptide moiety comprised of natural L amino acids, unnatural D amino acids, or synthetic amino acids, or a peptidomimetic, or any combination thereof.

22. The method of claim 1 wherein RM is