PSMA binding ligand-linker conjugates and methods for using

• US 10,517,956 B2
• Filed: 05/25/2018
• Issued: 12/31/2019
• Est. Priority Date: 08/17/2007
• 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 S., Kularatne, Sumith A.
• Primary Examiner(s): Rao, Savitha M
• Assistant Examiner(s): Polansky, Gregg
• Application Number:
  US15/990,083
• Publication Number:
  US 20180271988A1
• Time in Patent Office: 585 Days
• Field of Search: None
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• 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 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/547 Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 49/0041 Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal in vivo G01N
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0489 Phosphates or phosphonates, e.g. bone-seeking phosphonates; phospholipids: A61K51/0408; nucleotides or nucleic acids: A61K51/0491
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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: C07C 323/52 : the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07D 207/416 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07K 5/08 : Tripeptides

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 composition 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 compound of the formula:

B-L-D

or a salt thereof, wherein

B is a ligand of prostate specific membrane antigen (PSMA) comprising a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine and combinations thereof;

L is a linker comprising D-lysine and D-Phe-D-Phe and L is 14 to 24 atoms in length and L does not comprise a cycloalkylene group; and

D is a drug.

2. The compound of claim 1, wherein B is of the formula

3. The compound of claim 1 or a salt thereof, wherein the linker further comprises an optionally substituted tyrosine.

4. The compound of claim 2 or a salt thereof, wherein the linker further comprises an optionally substituted tyrosine.

5. The compound of claim 1 or a salt thereof, wherein the linker further comprises a substituted phenylalanine.

6. The compound of claim 2 or a salt thereof, wherein the linker further comprises a substituted phenylalanine.

7. The compound of claim 1 or a salt thereof, wherein D comprises a chelating group coordinated to a radioactive isotope of a metal.

8. The compound of claim 2 or a salt thereof, wherein D comprises a chelating group coordinated to a radioactive isotope of a metal.

9. A pharmaceutical composition comprising a compound of claim 1 or a salt thereof and at least one pharmaceutically acceptable carrier, excipient, or a combination thereof.

10. The compound of claim 1 or a salt thereof, wherein at least one Phe is about 7 to 11 atoms from B.

11. The compound of claim 1 or a salt thereof, wherein D is a vinca alkaloid, a tubulysin, or a camptothecin.

12. The compound of claim 7 or a salt thereof, wherein the radioactive isotope of a metal comprises ¹¹¹In, ^99mTc, ⁶⁴Cu, ⁶⁷Ga, or ⁶⁸Ga.

13. The compound of claim 7 or a salt thereof, wherein the radioactive isotope of a metal comprises ^99mTc.

14. The compound of claim 7 or a salt thereof, wherein D is of the formula

15. The compound of claim 14 or a salt thereof, wherein the radioactive isotope is coordinated to the chelating group in a syn configuration.

16. The compound of claim 14 or a salt thereof, wherein the radioactive isotope is coordinated to the chelating group in an anti configuration.

17. The compound of claim 1 or a salt thereof, wherein D comprises a chelating group.

18. The compound of claim 2 or a salt thereof, wherein D comprises a chelating group.