PSMA binding ligand-linker conjugates and methods for using

• US 9,951,324 B2
• Filed: 02/08/2016
• Issued: 04/24/2018
• Est. Priority Date: 02/25/2010
• Status: Active Grant

• Current Assignee: Purdue Research Foundation (The Trustees of Purdue University (d/b/a Purdue University))
• Original Assignee: Purdue Research Foundation (The Trustees of Purdue University (d/b/a Purdue University))
• Inventors: Low, Philip Stewart, Chelvam, Venkatesh, Kim, Youngsoon, Kularatne, Sumith A.
• Primary Examiner(s): Cordero Garcia, Marcela M
• Application Number:
  US15/018,068
• Publication Number:
  US 20160151508A1
• Time in Patent Office: 806 Days
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: C12N 9/485 Exopeptidases (3.4.11-3.4.19)
• CPC Class Codes: C12N 9/96 Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
• CPC Class Codes: C12Y 304/17021 Glutamate carboxypeptidase II (3.4.17.21)

Abstract

Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical compositions containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.

Claims

1. A conjugate or a pharmaceutically acceptable salt thereof, the conjugate or the pharmaceutically acceptable salt thereof comprising a ligand of PSMA (B), a linker (L), and a drug (D), wherein the ligand comprises a carbon-sulfur double bond, a phosphorus-sulfur double bond, a phosphorus-sulfur single bond, a thioester, or a combination thereof wherein the linker is covalently bound to the drug via a hydrazide linkage, wherein the linker is covalently bound to the ligand wherein the linker comprises a chain of at least seven atoms, and wherein the linker comprises a disulfide linkage.

2. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein B is a compound having a formula

3. The conjugate or the pharmaceutically acceptable salt thereof of claim 2, wherein B is a compound of the formula

4. The conjugate or the pharmaceutically acceptable salt thereof of claim 2, wherein q is 1.

5. The conjugate or the pharmaceutically acceptable salt thereof of claim 2, wherein Y is independently selected in each instance from —

CR₁R₂—

, and —

NR₃—

.

6. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises a chain of at least 14 atoms.

7. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises a peptide.

8. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises one or more phenylalanine residues, each of which is independently optionally substituted.

9. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises phenylalanyl-phenylalanyl, each of which is independently optionally substituted.

10. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the ligand is a compound selected from the group consisting of

11. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the ligand is a fragment having a formula

12. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the drug is selected from the group consisting of vinca alkaloids, taxanes, tubulysins, mitomycins, and camptothecins.

13. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the drug is an imaging agent selected from the group consisting of Oregon Greens, AlexaFluors, fluoresceins, BODIPY fluorescent agents, rhodamines, and DyLight fluorescent agents.

14. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the drug is a compound having a formula

15. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the drug is a PET imaging agent.

16. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate or the pharmaceutically acceptable salt thereof of claim 1, and a component selected from the group consisting of carriers, diluents, and excipients, and combinations thereof.

17. A method for treating a disease involving a pathogenic cell population expressing PSMA, the method comprising administering to a patient in need of relief from the disease a therapeutically effective amount of the conjugate or the pharmaceutically acceptable salt thereof of claim 1, optionally with a component selected from the group consisting of carriers, diluents, and excipients, and combinations thereof.

18. The conjugate or the pharmaceutically acceptable salt thereof of claim 3, wherein q is 1 and Y is independently selected in each instance from —

CR₁R₂—

, and —

NR₃—

.

19. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the conjugate or the pharmaceutically acceptable salt thereof comprises a fragment having a formula selected from the group consisting of

20. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the conjugate or the pharmaceutically acceptable salt thereof comprises a fragment having a formula

21. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the conjugate or the pharmaceutically acceptable salt thereof comprises a fragment having a formula

22. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the conjugate or the pharmaceutically acceptable salt thereof comprises a fragment having a formula

23. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises an amino acid selected from the group consisting of Glu, Asp, Phe, Cys, beta-amino Ala, Gly, amino valeric acid, and amino caproic acid.

24. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises Cys and at least one additional amino acid.

25. The conjugate or the pharmaceutically acceptable salt thereof of claim 1, wherein the linker comprises a fragment having the formula