METHOD OF SYNTHESIZING THYROID HORMONE ANALOGS AND POLYMORPHS THEREOF
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.
1 . A method for treating a fatty liver disease in a subject, comprising:
administering to the subject 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 at a dosage of from about 20 mg to about 100 mg per day.
2 . The method of claim 1 , wherein the fatty liver disease is nonalcoholic steatohepatitis.
3 . The method of claim 1 , wherein the morphic form is administered at a dosage of about 100 mg per day.
4 . The method of claim 1 , wherein the morphic form is administered orally.
5 . The method of claim 4 , wherein a tablet comprising the morphic form is administered orally.
6 . The method of claim 1 , wherein the morphic form is administered daily as a single dose.
7 . The method of claim 1 , wherein the morphic form is characterized by an X-ray powder diffraction pattern comprising three or more peaks as described in Table 11.
8 . The method of claim 7 , wherein the morphic form is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, about 18.7, and about 22.9 degrees 2θ.
9 . The method of claim 8 , wherein the morphic form is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, about 18.7, about 22.9, and about 23.6 degrees 2θ.
10 . The method of claim 9 , wherein the morphic form is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, about 18.7, about 22.9, about 23.6, and about 24.7 degrees 2θ.
11 . The method of claim 10 , wherein the X-ray powder diffraction pattern further comprises one or more peaks at about 8.2, about 11.2, about 15.7, about 16.4, about 17.7, about 30.0, or about 32.2 degrees 2θ.
12 . The method of claim 11 , wherein the X-ray powder diffraction pattern comprises the peaks as described in Table 11.
13 . The method of claim 12 , wherein the X-ray powder diffraction pattern is substantially similar to that set forth in FIG. 1 .
14 . The method of claim 1 , wherein the morphic form is characterized by a differential scanning calorimetry (DSC) diagram comprising an endothermic peak at about 329° C.
15 . The method of claim 14 , wherein the DSC diagram is substantially similar to that set forth in FIG. 2 .
16 . The method of claim 14 , wherein the morphic form is further characterized by an onset melting temperature of about 321° C.
17 . The method of claim 1 , wherein the morphic form has a purity of 95% or greater.
18 . The method of claim 17 , wherein the morphic form has a purity of 98% or greater.
19 . A method for treating a fatty liver disease in a subject, comprising:
administering to the subject a pharmaceutical composition comprising:
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; and
at least one pharmaceutically acceptable excipient or carrier;
wherein the pharmaceutical composition is suitable for administering the morphic form at a dosage of from about 20 mg to about 100 mg per day.
20 . The method of claim 19 , wherein the fatty liver disease is nonalcoholic steatohepatitis.
21 . The method of claim 19 , wherein the pharmaceutical composition is suitable for administering the morphic form at a dosage of about 100 mg per day.
22 . The method of claim 19 , wherein the pharmaceutical composition is administered orally.
23 . The method of claim 22 , wherein the pharmaceutical composition is a tablet.
24 . The method of claim 19 , wherein the pharmaceutical composition is suitable for administering the morphic form daily as a single dose.
25 . The method of claim 19 , wherein the morphic form is characterized by an X-ray powder diffraction pattern comprising three or more peaks as described in Table 11.
26 . The method of claim 25 , wherein the X-ray powder diffraction pattern is substantially similar to that set forth in FIG. 1 .
27 . The method of claim 19 , wherein the morphic form is characterized by a differential scanning calorimetry (DSC) diagram that includes an endothermic peak at about 329° C.
28 . The method of claim 27 , wherein the morphic form is further characterized by an onset melting temperature of about 321° C.
29 . The method of claim 19 , wherein the morphic form has a purity of 95% or greater.
30 . The method of claim 29 , wherein the morphic form has a purity of 98% or greater.