HDAC6 inhibitors and imaging agents

Patent metadata

Field	Value
Publication number	US-12472271-B2
Application number	US-202318390906-A
Country	US
Kind code	B2
Filing date	Dec 20, 2023
Priority date	Apr 11, 2017
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

Provided herein are compounds useful for binding to one or more histone deacetylase enzymes (HDACs). The present application further provides radiolabeled compounds useful as a radiotracer for position emission tomography imaging of HDAC. Methods for prepared unlabeled and labeled compounds, diagnostic methods, and methods of treating diseases associated HDAC are also provided.

First claim

What is claimed is:

1 . A compound which is methyl 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl)-3-hydroxybenzoate, having the structure:

2 . A method of preparing the compound of claim 1 or salt thereof, the method comprising:
a. contacting dimethyl hydroxyterephthalate with a first reducing agent

 (Dimethyl hydroxyterephthalate);
to provide methyl 3-hydroxy-4-(hydroxymethyl)benzoate

 (Methyl 3-hydroxy-4-(hydroxymethyl)benzoate);
b. contacting the methyl 3-hydroxy-4-(hydroxymethyl)benzoate with an oxidizing agent to provide methyl 4-formyl-3-hydroxybenzoate

 (Methyl 4-formyl-3-hydroxybenzoate); and
c. contacting the methyl 4-formyl-3-hydroxybenzoate with adamantanemethylamine and a second reducing agent to provide methyl 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl)-3-hydroxybenzoate, or a salt thereof.

3 . The method of claim 2 , wherein the first reducing agent comprises sodium borohydride.

4 . The method of claim 3 , wherein the first reducing agent is sodium borohydride.

5 . The method of claim 2 , wherein the oxidizing agent comprises Pd/C, potassium carbonate, sodium borohydride, and oxygen.

6 . The method of claim 5 , wherein the oxidizing agent consists essentially of Pd/C, potassium carbonate, sodium borohydride, and oxygen.

7 . The method of claim 2 , wherein the second reducing agent comprises sodium borohydride.

8 . The method of claim 7 , wherein the second reducing agent is sodium borohydride.

9 . The method of claim 2 , wherein
the first reducing agent comprises sodium borohydride; the oxidizing agent comprises Pd/C, potassium carbonate, sodium borohydride, and oxygen; and the second reducing agent comprises sodium borohydride.

10 . The method of claim 2 , wherein
the first reducing agent is sodium borohydride; the oxidizing agent is Pd/C, potassium carbonate, sodium borohydride, and oxygen; and the second reducing agent is sodium borohydride.

11 . The method of claim 2 further comprising
a. contacting the methyl 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl)-3-hydroxybenzoate with Ru(cp)(cod)Cl;
b. contacting the product of step (a) with N,N-bis-(2,6-diisopropyl)phenyl-2-chloroimidazolium chloride and 18 F radioisotope; and
c. contacting the product of step (b) with a transacylation agent to obtain 4-((((adamantan-1-yl)methyl)(methyl)amino)methyl)-3-[ 18 F]fluoro-N-hydroxybenzamide, having the structure:

12 . The method of claim 8 , wherein the transacylation agent comprises NH 2 OH and NaOH.

Assignees

• Massachusetts Gen Hospital

Inventors

• Hooker Jacob
• Wang Changning
• Strebl-Bantillo Martin Georg
• Rokka Johanna Kaarina

Classifications

• C07C259/10 Primary

  having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07C2603/74

  Adamantanes · CPC title

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07D213/79

  Acids; Esters · CPC title