Antifungal compound process
Inventors
Hoekstra, William J. • Yates, Christopher M. • Behnke, Mark • Alimardanov, Asaf • David, Scott A. • Fry, Douglas Franklin
Assignees
Mycovia Pharmaceuticals Inc • US Department of Health and Human Services
Publication Number
US-10077250-B2
Publication Date
2018-09-18
Expiration Date
2035-03-19
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Abstract
The present invention relates to a process for preparing compound 1 that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compound 1 and substituted derivatives thereof.
Core Innovation
The invention relates to a process for preparing compound 1, which is useful as an antifungal agent. Specifically, it seeks to provide new methodology for preparing compound 1 and substituted derivatives thereof through improved synthetic processes. These processes encompass preparing morpholine amides, ketones, epoxides, amino alcohols, and tetrazole derivatives, and methods for enriching enantiomeric purity using chiral acids.
The problem being addressed is the need for improved methods of synthesizing metalloenzyme inhibitors, such as antifungal agents, with better potency and selectivity. Existing antifungal agents (e.g., fluconazole, voriconazole) bind indiscriminately to metal ions in metalloenzymes, causing off-target inhibition and resulting clinical toxicity. The invention addresses the need for metal-binding groups that balance potency with selectivity and provides efficient laboratory and commercial scale synthetic methods to prepare such compounds.
Claims Coverage
The patent contains several independent claims focusing on processes for preparing compounds and their salts, particularly compounds of formula IX or IXa.
Process for preparing a compound of formula IX or IXa
A process comprising combining compound 1 or 1a, a sulfonic acid, and a crystallization solvent or solvent mixture; diluting the mixture with a crystallization co-solvent or co-solvent mixture; and isolating a compound of formula IX or IXa, or mixtures thereof, where each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.
Selection of specific substituents for crystallization and salts
Use of Z as phenyl, p-tolyl, methyl or ethyl; selection of crystallization solvents such as ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile and combinations thereof; and use of crystallization co-solvents such as pentane, methyl tert-butylether, hexane, heptane, toluene, or combinations thereof to optimize crystallization and isolation of the salts.
The independent claims cover inventive processes utilizing combinations of compound 1 or 1a with sulfonic acids and defined solvent systems to isolate stable crystalline salts of compounds of formula IX or IXa, with specific choices of substituents and solvents enhancing yield and purity.
Stated Advantages
Improved methodology for preparing compound 1 and substituted derivatives with better efficiency and selectivity.
Processes enabling enantiomeric enrichment of compounds leading to high purity forms suitable for pharmaceutical use.
Facilitation of scalable synthesis of antifungal agents with balanced metal-binding properties to reduce off-target toxicity.
Documented Applications
Use of compounds as antifungal agents by inhibiting metalloenzymes such as lanosterol demethylase (CYP51).
Pharmaceutical compositions comprising the compounds for treating metalloenzyme-mediated disorders or diseases including cancer, solid tumors, cardiovascular, inflammatory, infectious, metabolic, ophthalmologic, CNS, urologic, and gastrointestinal diseases.
Use in agricultural compositions to treat or prevent metalloenzyme-mediated disorders or diseases in plants or agricultural settings.
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