Method of synthesizing thyroid hormone analogs and polymorphs thereof

Inventors

Kelly, Martha J. • Taub, Rebecca • Chiang, Edward Hung Yang

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 patent describes multi-stage synthetic routes to thyroid hormone analog pyridazinone compounds and thyroid-hormone-receptor targeting heteroaryl compounds, including intermediates such as Int.1, Int.3, Int.7, and Int.8, with conversion among structural formulas and final cyclization to Compound A. The schemes include Grignard addition/isomerization with R1MgX or R1Li, where R1 is isopropenyl or isopropyl, as well as benzamide/amide protection-deprotection chemistry, diazotization/cyanacetylation, and optional further conversion to Formula (IV).

The disclosure also describes compositional and quality improvements for Compound A, including high purity and low impurities, reduced regioisomer levels, improved HPLC purity, low heavy-metal use, and improved yield compared with cited prior art. It further reports easier processing and filtration characteristics, preparation of a DMAC solvate, conversion to crystalline Form I using ethanol/MIBK, and XRPD-based characterization with peak positions around 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.

The document links Compound A and related derivatives to therapeutic use, including treatment of resistance to thyroid hormone (RTH) in subjects with TRβ mutations and methods for determining responsiveness by detecting TR mutations. It also provides pharmaceutical composition and treatment indications, including treatment of fatty liver disease using the specified tetrahydro-1,2,4-triazine-6-carbonitrile compound or a pharmaceutically acceptable salt thereof at a daily dosage range.

Claims Coverage

The consolidated claim coverage includes two independent claims. Both claims cover treatment of fatty liver disease in a subject using the specified tetrahydro-1,2,4-triazine-6-carbonitrile compound, or a pharmaceutically acceptable salt, at a dosage of about 20 mg to about 100 mg per day; one claim additionally requires a pharmaceutical composition with excipients or carriers.

The claim set focuses on therapeutic administration of the specified Compound A derivative, or a pharmaceutically acceptable salt, for treating fatty liver disease at about 20 mg to about 100 mg per day, either directly or through a pharmaceutical composition containing excipients or carriers.

Stated Advantages

Documented Applications