Methods of synthesizing thyroid hormone analogs and polymorphs thereof

Patent metadata

Field	Value
Publication number	US-10894050-B2
Application number	US-201916458546-A
Country	US
Kind code	B2
Filing date	Jul 1, 2019
Priority date	Sep 17, 2012
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

The disclosure describes methods of synthesis of pyridazinone compounds as thyroid hormone analogs and their prodrugs. Preferred methods according to the disclosure allow for large-scale preparation of pyridazinone compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of pyridazinone compounds in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of a pyridazinone compound. Further disclosed is a method for treating resistance to thyroid hormone in a subject having at least one TRβ mutation.

First claim

What is claimed is:

1. A compound selected from:

and a salt thereof.

2. The compound of claim 1 , having the following structure:

or a salt thereof.

3. The compound of claim 1 , having the following structure:

or a salt thereof.

4. The compound of claim 1 , having the following structure:

or a salt thereof.

5. The compound of claim 1 , having the following structure:

or a salt thereof.

6. The compound of claim 1 , having the following structure:

or a salt thereof.

7. The compound of claim 1 , having the following structure:

or a salt thereof.

8. The compound of claim 1 , having the following structure:

or a salt thereof.

9. A process comprising:
(a) contacting R 1 MgX or R 1 Li with a compound of Formula (I):

(I) to form a compound of Formula (II):

(II), in which R 1 is isopropyl or isopropenyl, X is halo and R 2 is H or an amine protecting group;
(b) converting the compound of Formula (II) to a compound of Formula (III):

(III) in the presence of a base when R 1 is isopropenyl or in the presence of an oxidizing agent when R 2 is isopropyl;
(c) when present, removing the amine protecting group R 2 of the compound of Formula (III) to form 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one;
(d) converting 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one to 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-di oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”); and
(e) forming a morphic form of Compound A (Form I) characterized by an X-ray powder diffraction pattern that includes peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.

10. The process of claim 9 , wherein the compound of Formula (I) is

11. The process of claim 9 , wherein the compound of Formula (II) is selected from:

12. The process of claim 9 , wherein the compound of Formula (III) is

Assignees

• Madrigal Pharmaceuticals Inc
• Hoffmann La Roche

Inventors

• Hester Ii D Keith
• Duguid Robert J
• Kelly Martha J
• Chasnoff Anna
• Dong Gang
• Crow Edwin L
• Shu Lianhe
• Wang Ping
• Choi Duk Soon

Classifications

• C07D237/14 Primary

  Oxygen atoms · CPC title

• A61K31/501 Primary

  not condensed and containing further heterocyclic rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D237/16

  Two oxygen atoms · CPC title