Methods of synthesizing thyroid hormone analogs and polymorphs thereof

Patent metadata

Field	Value
Publication number	US-2021161904-A1
Application number	US-202017118706-A
Country	US
Kind code	A1
Filing date	Dec 11, 2020
Priority date	Sep 17, 2012
Publication date	Jun 3, 2021
Grant date	—

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

1 .- 4 . (canceled)

5 . A morphic form of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, characterized by an onset melting temperature of about 321° C. and a differential scanning calorimetry (DSC) diagram that includes an endothermic peak at about 329° C.

6 . The morphic form of claim 5 , wherein the DSC diagram is substantially the same as that shown in FIG. 2 .

7 . The morphic form of claim 5 , having a purity of greater than 85%.

8 . The morphic form of claim 5 , having a purity of greater than 90%.

9 . The morphic form of claim 5 , having a purity of greater than 95%.

10 . A pharmaceutical composition comprising the morphic form of claim 5 and a pharmaceutically acceptable carrier.

11 . A method for treating nonalcoholic steatohepatitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the morphic form of claim 5 .

12 . The method of claim 11 , wherein the morphic form is administered orally.

13 . A method for treating hypercholesterolemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the morphic form of claim 5 .

14 . The method of claim 13 , wherein the morphic form is administered orally.

15 . A method for treating fatty liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the morphic form of claim 5 .

16 . The method of claim 15 , wherein the morphic form is administered orally.

17 . A method for treating a resistance to thyroid hormone (RTH) syndrome in a subject having at least one TRβ mutation, the method comprising administering to the subject a therapeutically effective amount of the morphic form of claim 5 .

18 . The method of claim 17 , wherein the morphic form is administered orally.

19 . A dimethylacetamide (DMAC) solvate of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

20 . A methyl isobutyl ketone (MIBK) solvate of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

21 . A method of treating a subject having a resistance to thyroid hormone (RTH) syndrome, the method comprising:
performing an assay to determine a presence of a TRβ mutation in a sample obtained from the subject; and administering a therapeutically effective amount of a compound of Formula (IV), if the TRβ mutation is present in the sample, wherein the compound of Formula (IV) has the following structure:

wherein
R 3 is H or CH 2 R a , in which R a is hydroxyl, O-linked amino acid, —OP(O)(OH) 2 or —OC(O)—R b , R b being lower alkyl, alkoxy, alkyl acid, or cycloalkyl; and
R 4 and R 5 together are —N═C(R c )—C(O)—NH—C(O)—, in which R c is H or cyano.

22 . The method of claim 21 , wherein the TRβ mutation is selected from the group consisting of a substitution of threonine (T) for the wild type residue alanine (A) at amino acid position 234 of SEQ ID NO: 1 (A234T); a substitution of glutamine (Q) for the wild type residue arginine (R) at amino acid position 243 of SEQ ID NO: 1 (R243Q); a substitution of histidine (H) for the wild type residue arginine (R) at amino acid position 316 of SEQ ID NO: 1 (R316H); and a substitution of threonine (T) for the wild type residue alanine (A) at amino acid position 317 of SEQ ID NO: 1 (A317T).

23 . The method of claim 21 , wherein the TRβ mutation is a gene mutation or a mutation in the ligand-binding domain of a TRβ polypeptide.

24 . The method of claim 23 , wherein the TRβ polypeptide has a sequence of SEQ ID NO.: 1.

25 . The method of claim 21 , wherein the assay comprises:
amplifying a nucleic acid in the sample with a primer that is complementary to a mutant TRβ polynucleotide; and determining the presence of the amplified nucleic acid.

26 . The method of claim 25 , wherein the mutant TRβ polynucleotide has a sequence of SEQ ID NO.: 2.

27 . The method of claim 21 , wherein the compound of Formula (IV) is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”).

28 . The method of claim 27 , wherein Compound A is in a morphic form characterized by an onset melting temperature of about 321° C. and a differential scanning calorimetry (DSC) diagram that includes an endothermic peak at about 329° C.

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