Methods of synthesizing thyroid hormone analogs and polymorphs thereof

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

Assignees

Hoffmann La Roche Inc • Madrigal Pharmaceuticals Inc

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.

Core Innovation

The disclosed subject matter concerns morphic forms and solvate forms 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 (Compound A / Formula (IV)). One morphic form is characterized by an onset melting temperature of about 321° C. and a differential scanning calorimetry (DSC) endothermic peak at about 329° C. The document also discloses a morphic Form I supported by XRPD and DSC, together with DMAC solvate and MIBK solvate as specific solvates of the same defined compound.

The disclosure relates the compound of Formula (IV) to treating resistance to thyroid hormone (RTH) syndrome in subjects having TRβ mutations. It describes performing an assay to determine the 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. The disclosed approach links targeted therapeutic responsiveness to the presence of specific TRβ mutations and to the use of the defined Compound A solid form characterized by the stated melting and DSC parameters.

Claims Coverage

The independent claims focus on solid-state definitions of a defined Compound A (Formula (IV)) and on a biomarker-guided method of treating RTH syndrome in which TRβ mutation presence determines administration. Across the independent claims, the inventive coverage includes thermal and DSC-defined morphic identity, specific solvent solvate identity, and an assay-conditioned therapeutic method for TRβ mutation-positive subjects.

Overall, the claim coverage combines identification of a specific morphic form of Compound A by onset melting temperature and DSC endothermic peak, identification of DMAC and MIBK solvates of the same compound, and a TRβ mutation-assay guided treatment method in which Compound A (Formula IV) is administered only when a TRβ mutation is detected.

Stated Advantages

Documented Applications