Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine

Inventors

Becker, Andrew • Radisson, Joel

Assignees

Sanofi SA • Neurocrine Biosciences Inc

Abstract

The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thi-azol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).

Core Innovation

The invention relates to Compound 1, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, and related pharmaceutically acceptable forms, including salts and the free base in anhydrous crystalline Form I. The disclosure requires a defined enantiomeric excess for Compound 1, with the enantiomeric excess being at least 99.7%, and describes the compound as a CRF1 antagonist.

The document describes crystalline Form I and anhydrous crystalline forms of Compound 1 and its tosylate salt, with characterization by X-ray powder diffraction peak positions and differential scanning calorimetry endotherm onset temperature ranges. It further includes pharmaceutical products and pharmaceutical compositions containing Compound 1 or pharmaceutically acceptable salts of Compound 1 having high enantiomeric excess, including oral dosage forms, crystalline anhydrous Form I, and spray-dried dispersion.

The disclosure also provides synthetic process embodiments for forming thiazole-containing target compounds and key intermediates through alkylation, cyclization, deprotection, reduction, condensation, coupling, propargylation, and first-alkylation and second-alkylation steps. It additionally discloses isotopically labeled variants, including deuterium and carbon isotopes such as carbon-12 and carbon-13, and pharmaceutical compositions and method-of-use coverage for treating disorders associated with CRF1 signaling disorder, including congenital adrenal hyperplasia (CAH) and classic CAH.

Claims Coverage

The independent claims cover two core subject matters: Compound 1 itself and a pharmaceutically acceptable salt of Compound 1, each defined by a minimum enantiomeric excess of at least 99.7%. Across the claim families, inventive features also include treatment of congenital adrenal hyperplasia, including classic CAH, with optional glucocorticoid co-administration.

Overall claim coverage focuses on Compound 1 and a pharmaceutically acceptable salt of Compound 1 defined by high enantiomeric excess, together with treatment of congenital adrenal hyperplasia and optional glucocorticoid co-administration.

Stated Advantages

Documented Applications