Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Inventors
Beaton, Graham • Chen, Mi • Coon, Timothy Richard • Ewing, Todd • Jiang, Wanlong • Moree, Willy • Rowbottom, Martin • Wade, Warren • Zhao, Liren • Lowe, Richard • Smith, Nicole • Ashweek, Neil • Zhu, Yun-Fei
Assignees
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Publication Number
US-11713324-B2
Publication Date
2023-08-01
Expiration Date
Abstract
GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
Core Innovation
The disclosed subject matter provides processes for preparing substituted phenoxy propionic acid and substituted phenoxy butyric acid compounds. In particular, a benzamide-containing solution of 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide is contacted with sodium periodate followed by ruthenium (III) chloride, and the target 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid is isolated.
Another process prepares a substituted phenoxy butyric acid by contacting a methyl ester of 4-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyric acid with lithium hydroxide in tetrahydrofuran, and then isolating the corresponding 4-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyric acid.
The document further supports a chemical series through examples that include target scaffold members built from benzamide/phenoxyalkyl/butyric or propionic acid motifs, including methyl or ethyl ester variants. Analytical characterization is described using MS and HPLC retention times for the synthesized members.
Claims Coverage
The provided content includes two independent process claims. Each claim is centered on a distinct contacting sequence followed by isolation, and each defines one inventive feature directed to conversion of a specified precursor into a specific substituted carboxylic acid.
Oxidative conversion to propionic acid via sodium periodate and ruthenium (III) chloride
Contacting a solution of 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide with a solution of sodium periodate, followed by ruthenium (III) chloride, and isolating 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid.
Ester-to-acid conversion via lithium hydroxide in tetrahydrofuran and isolation
Contacting a solution of 4-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyric acid methyl ester in tetrahydrofuran with an aqueous solution of lithium hydroxide, and isolating 4-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyric acid.
Across the two independent claims, the coverage is directed to making specific substituted propionic and butyric acids by contacting defined intermediates with sodium periodate followed by ruthenium (III) chloride, or with lithium hydroxide in tetrahydrofuran, and then isolating the corresponding acids.
Stated Advantages
Documented Applications
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