Methods of synthesizing thyroid hormone analogs and polymorphs thereof

Inventors

Taub, Rebecca • Reynolds, Charles H. • 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 disclosure relates to synthetic schemes for preparing a thyroid-hormone-receptor beta (TRβ) agonist, Compound A, including use of intermediates such as Int.7 and Int.8. The schemes describe forming substituents on a pyridazine core and converting intermediates through N-protecting-group removal and diazotization/cyanoacetyl carbamate formation to reach Compound A.

The disclosure further addresses conversion and characterization of Compound A solid forms, including Compound A DMAC solvate and conversion to morphic Form I and hydrate forms such as dihydrate and related hydrate forms described. X-ray powder diffraction characterization is provided for Form I, including peak-based characterization.

In addition to chemical and solid-form disclosure, the document describes pharmaceutical compositions and therapeutic use of Compound A, with treatment concepts involving TRβ mutation-guided responsiveness and resistance to thyroid hormone (RTH). The document includes therapeutic indications such as obesity, hyperlipidemia/hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), and fatty liver, together with other condition categories described in the disclosure.

Claims Coverage

The partial claim set provided includes one morphic-form independent claim and three independent method-of-treatment claims. The coverage centers on defining Compound A as a hydrate, including morphic Form I characterized by an X-ray powder diffraction (XRPD) pattern with specified peak positions, and on therapeutic methods administering a therapeutically effective amount of that morphic form.

Across the independent claims, the inventive theme is the administration of a morphic hydrate of Compound A, including morphic Form I defined by an XRPD peak pattern at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ, for treating specified conditions.

Stated Advantages

Documented Applications