Claims for Patent: 10,376,517

Summary for Patent: 10,376,517

Title:	Methods of synthesizing thyroid hormone analogs and polymorphs thereof
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.
Inventor(s):	Taub Rebecca, Reynolds Charles H., Shu Lianhe, Wang Ping, Choi Duk Soon
Assignee:
Application Number:	US15949389
Patent Claims:	2. The morphic form of claim 1 , wherein the hydrate is monohydrate.3. The morphic form of claim 1 , wherein the hydrate is a dihydrate.4. A pharmaceutical composition comprising the morphic form of and a pharmaceutically acceptable carrier.5. A method for treating a resistance to thyroid hormone (RTH) syndrome in a subject having at least one TRβ mutation claim 3 , the method comprising administering to the subject a therapeutically effective amount of the morphic form of .6. The method of claim 5 , wherein the subject has a disease or disorder selected from the group consisting of fatty liver disease claim 5 , attention deficit hyperactivity disorder claim 5 , a learning disability claim 5 , thyroid axis alteration claim 5 , atherosclerosis claim 5 , a cardiovascular disorder claim 5 , tachycardia claim 5 , hyperkinetic behavior claim 5 , hypothyroidism claim 5 , goiter claim 5 , hearing loss claim 5 , delayed bone age claim 5 , and thyroid cancer.7. The method of claim 6 , wherein the disease or disorder is selected from the group consisting of fatty liver disease claim 6 , attention deficit hyperactivity disorder claim 6 , a learning disability claim 6 , atherosclerosis claim 6 , and a cardiovascular disorder.8. The method of claim 5 , 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).9. The method of claim 5 , wherein the morphic form has a purity of Compound A of 95% or greater.10. A method for treating nonalcoholic steatohepatitis in a subject in need thereof claim 3 , the method comprising administering to the subject a therapeutically effective amount of the morphic form of .11. The method of claim 10 , wherein the morphic form has a purity of Compound A of 95% or greater.13. The method of claim 12 , wherein the X-ray powder diffraction pattern further includes peaks at about 8.2 claim 12 , 11.2 claim 12 , 15.7 claim 12 , 16.4 claim 12 , 17.7 claim 12 , 30.0 claim 12 , and 32.2 degrees 2θ.14. The method of claim 12 , wherein the morphic form is characterized by an X-ray powder diffraction pattern substantially similar to that set forth in .15. The method of claim 12 , wherein the morphic form has a purity of Compound A of 95% or greater.16. A method for treating hypercholesterolemia in a subject in need thereof claim 3 , the method comprising administering to the subject a therapeutically effective amount of the morphic form of .17. The method of claim 16 , wherein the morphic form has a purity of Compound A of 95% or greater.19. The method of claim 18 , wherein the morphic form has a purity of Compound A of 95% or greater.20. A method for treating fatty liver disease in a subject in need thereof claim 3 , the method comprising administering to the subject a therapeutically effective amount of the morphic form of .21. The method of claim 20 , wherein the morphic form has a purity of Compound A of 95% or greater.23. The method of claim 22 , wherein the morphic form has a purity of Compound A of 95% or greater.24. The method of claim 18 , wherein the X-ray powder diffraction pattern further includes peaks at about 8.2 claim 18 , 11.2 claim 18 , 15.7 claim 18 , 16.4 claim 18 , 17.7 claim 18 , 30.0 claim 18 , and 32.2 degrees 2θ.25. The method of claim 22 , wherein the X-ray powder diffraction pattern further includes peaks at about 8.2 claim 22 , 11.2 claim 22 , 15.7 claim 22 , 16.4 claim 22 , 17.7 claim 22 , 30.0 claim 22 , and 32.2 degrees 2θ.