PSMA binding ligand-linker conjugates and methods for using

• US 10,624,971 B2
• Filed: 05/25/2018
• Issued: 04/21/2020
• 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:
  US15/990,144
• Publication Number:
  US 20180289829A1
• Time in Patent Office: 697 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 prostate specific membrane antigen (PSMA) binding ligand;

L comprises at least one polyoxyalkylene portion and at least one Glu, Asp, Cys, beta-amino Ala, Gly, beta Ala, amino valeric acid, or amino caproic acid, wherein the linker is at least 14 atoms in length and has at least one side chain group comprising a hydrophobic alkyl, cycloalkyl, aryl or arylalkyl; and

D is a radioactive isotope of a metal coordinated to a chelating group.

2. 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.

3. The compound of claim 1 or a salt thereof, wherein comprises Glu.

4. The compound of claim 1 or a salt thereof, wherein D is a tripeptide or a tetrapeptide.

5. The compound of claim 1 or a salt thereof, wherein D is a DOTA group.

6. The compound of claim 1, or a salt thereof, wherein B comprises one or more amino acid selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine.

7. The compound of claim 1, or a salt thereof, wherein B comprises one or more aminoalkylcarboxylate substituted with alkyl, hydroxyalkyl, sulfhydrylalkyl, aminoalkyl, or carboxyalkyl.

8. The compound of claim 1, or a salt thereof, wherein B comprises at least three free carboxylic acid groups.

9. The compound of claim 1, or a salt thereof, wherein B comprises a glutamate.

10. The compound of claim 1, or a salt thereof, wherein the side chain group comprises a hydrophobic arylalkyl.

11. The compound of claim 1, or a salt thereof, wherein L comprises an alkane, alkene, alkyne, cycloalkane, arylene, or imide.

12. The compound of claim 1, or a salt thereof, wherein L comprises an arylene.

13. The compound of claim 1, or a salt thereof, wherein L comprises a Gly, beta Ala, amino valeric acid, or amino caproic acid.

14. The compound of claim 1, or a salt thereof, wherein L comprises an amino caproic acid.

15. The compound of claim 1, or a salt thereof, wherein L is covalently bound to B via an amide bond.

16. The compound of claim 1, or a salt thereof, wherein L is covalently, bound to D via an amide bond.

17. The compound of claim 1, or a salt thereof, wherein B has the structure: