HDAC6 inhibitors and imaging agents

Patent metadata

Field	Value
Publication number	US-11890356-B2
Application number	US-202117455170-A
Country	US
Kind code	B2
Filing date	Nov 16, 2021
Priority date	Apr 11, 2017
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

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 composition comprising a radiolabeled compound of the formula

or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

2. The imaging composition of claim 1 , further comprising a mixture of the radiolabeled compound and a compound of the formula

or a pharmaceutically acceptable salt thereof.

3. The composition of claim 2 , wherein the composition is a formulated as a liquid.

4. The composition of claim 1 , wherein the composition is formulated as a sterile injectable solution.

5. The composition of claim 1 , wherein the composition is formulated for intravenous administration.

6. The composition of claim 1 , wherein the radiolabeled compound is obtained by a process comprising a step of contacting a phenol precursor compound with an air-stable Ruthenium-complex.

7. The composition of claim 6 , wherein
a. the phenol precursor compound is a compound of formula

 and
b. the air-stable Ruthenium-complex is Ru(cp)(cod)Cl.

8. The composition of claim 7 , wherein the reaction of the phenol precursor and the air-stable ruthenium complex forms an η 6 -ruthenium complex of the formula:

9. The composition of claim 8 , wherein the radiolabeled compound is obtained by a process further comprising the step of using the η 6 -ruthenium complex as an eluent to elute 18 F from an anion exchange column or cartridge to obtain an 18 F phenol precursor of the formula

10. The composition of claim 9 , wherein the radiolabeled compound is obtained by a process further comprising the subsequent transacylation of the 18 F phenol precursor to obtain the radiolabeled compound of the formula

11. The composition of claim 1 , wherein the radiolabeled compound is obtained by a process comprising the steps of contacting a precursor compound of the formula

or a pharmaceutically salt thereof,
with an air-stable Ruthenium-complex, transacylation and elution of 18 F from an anion exchange column or cartridge to obtain the radiolabeled compound of claim 1 .

12. The composition of claim 1 , wherein the radiolabeled compound is obtained by a process comprising the step of contacting a precursor compound of the formula

or a pharmaceutically salt thereof,
with Ru(cp)(cod)Cl, N,N-bis-(2,6-diisopropyl)phenyl-2-chloroimidazolium chloride and 18 F radioisotope, in one or more steps under conditions effective to form the radiolabeled compound.

13. The composition of claim 5 , the radiolabeled compound is obtained by a process comprising the steps of
a. contacting a phenol precursor compound of formula

with Ru(cp)(cod)Cl;
b. using the compound resulting from step (a) in an eluent to elute 18 F from an anion exchange column or cartridge; and
c. using the compound resulting from step (b) in a transacylation reaction to obtain the radiolabeled compound.

14. The composition of claim 1 , wherein the radiolabeled compound is obtained by a process comprising the steps of
a. contacting a precursor compound of the formula

or a salt thereof,
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. 1 transacetylating the product of step (b) to obtain the radiolabeled compound of claim 1 .

15. A method comprising the steps of
a. administering the composition of claim 1 a subject; and
b. obtaining an image of the brain of the subject with an imaging technique to detect the radiolabeled imaging composition in the brain of the subject.

16. The method of claim 15 , wherein the composition of claim 1 is detected using positron emission tomography (PET) imaging technique.

17. The composition of claim 1 , wherein the composition provides PET-detectable level of

in the brain of a subject.

Assignees

• Massachusetts Gen Hospital

Inventors

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

Classifications

• A61K51/04 Primary

  Organic compounds · CPC title

• 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

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07C2603/74

  Adamantanes · CPC title