PSMA binding ligand-linker conjugates and methods for using

• US 10,485,878 B2
• Filed: 05/25/2018
• Issued: 11/26/2019
• 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:
  US15/990,111
• Publication Number:
  US 20180289827A1
• Time in Patent Office: 550 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 each amino acid is independently an aminoalkylcarboxylate substituted with alkyl, hydroxyalkyl, sulfhydrylalkyl, aminoalkyl, or carboxyalkyl;

L is a linker comprising a carbonyl and a divalent radical selected from the group consisting of alkane, alkene, alkyne, cycloalkane, arylene, and imide and the linker has a molecular weight of 30 to 300 g/mol; and

D is a radioisotope covalently bound to the linker.

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

3. The compound of claim 1 or a salt thereof, wherein the divalent radical is an arylene.

4. The compound of claim 2 or a salt thereof, wherein the divalent radical is an arylene.

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

6. The compound of claim 1 or a salt thereof, wherein the linker comprises nitrogen atoms.

7. The compound of claim 1 or a salt thereof, wherein the carbonyl of the linker is substituted with one or more substituents X¹ selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R⁴-carbonyl, R⁵-carbonylalkyl, R⁶-acylamino, and R⁷-acylaminoalkyl, wherein R⁴, R⁵, R⁶ and R⁷ are each independently selected from amino acids, amino acid derivatives, and peptides.

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

9. The compound of claim 1 or a salt thereof, wherein the linker is a linear chain at least 5 atoms in length.

10. The compound of claim 1 or a salt thereof, wherein the linker is about 7 atoms in length.

11. The compound of claim 1 or a salt thereof, wherein the linker is about 7 atoms to about 20 atoms in length.

12. A reconstitutable lyophilizate comprising a compound of claim 1 or a salt thereof.

13. The reconstitutable lyophilizate of claim 12, wherein the lyophilizate comprises a dose of the compound of claim 1 or a salt thereof.

14. A kit comprising the reconstitutable lyophilizate of claim 12.

15. 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 each amino acid is independently an aminoalkylcarboxylate substituted with alkyl, hydroxyalkyl, sulfhydrylalkyl, amino alkyl, or carboxyalkyl;

L is a linker comprising a carbonyl and a divalent radical selected from the group consisting of alkane, alkene, alkyne, cycloalkane, arylene, and imide and the linker does not have an arylalkyl sidechain; and

D is a radioisotope covalently bound to the linker.