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-10000465-B2
Publication Date
2018-06-19
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 that is useful as an antifungal agent, specifically focusing on new methodology for synthesizing compound 1 and its substituted derivatives. The invention provides multiple synthetic routes, including steps such as amidation, arylation, formation of trimethylsilyl-cyanohydrin intermediates, nitrile reduction to amino-alcohol intermediates, enantiomeric enrichment via crystallization with chiral acids, and formation of tetrazole groups, culminating in the production of compound 1 or its enantiomer 1a.
The background identifies the challenge in designing clinically safe and effective metalloenzyme inhibitors, which must balance metal-binding potency and selectivity to avoid off-target toxicities. Existing antifungal agents like fluconazole and voriconazole use a 1-(1,2,4-triazole) group that binds heme iron but have limitations such as off-target inhibition leading to clinical toxicities. The invention seeks to develop alternative metal-binding groups and synthetic methods to overcome these issues, including improved efficiency and selectivity in the preparation of therapeutic metalloenzyme inhibitors.
Claims Coverage
The patent contains independent claims focused on processes for preparing amino-alcohol intermediates and their enantiomeric enrichment to produce antifungal compounds.
Process for preparing amino-alcohol intermediates
A process to prepare amino-alcohol compounds 1-6 or 1-7 as intermediates in the synthesis of antifungal agents.
Enantiomeric enrichment of amino-alcohol intermediates
A process for enriching the enantiomeric purity of amino-alcohol 1-6 or 1-7 comprising: (i) crystallizing the amino-alcohol with a chiral acid in selected solvents (acetonitrile, isopropanol, ethanol, water, methanol, or their combinations); (ii) isolating the enantio-enriched compound; and (iii) free-basing the enantio-enriched chiral salt mixture to obtain enantio-enriched amino-alcohol 1-6* or 1-7*.
The claims focus on novel processes for synthesizing key amino-alcohol intermediates and methods for improving their enantiomeric purity, which form important steps in producing the antifungal compound 1 and its derivatives.
Stated Advantages
The invention provides new methodology for the efficient and selective synthesis of compound 1 and its substituted derivatives.
Improved balance of potency and selectivity in metal-binding groups used in metalloenzyme inhibitors to reduce clinical toxicity associated with off-target enzyme inhibition.
Processes include enantiomeric enrichment steps that allow isolation of compounds with high enantiomeric purity.
Documented Applications
Use of compound 1 and derivatives as antifungal agents to inhibit metalloenzymes such as lanosterol demethylase (CYP51).
Pharmaceutical compositions containing the compounds for treating metalloenzyme-mediated disorders and diseases, including fungal infections.
Methods of modulating metalloenzyme activity in subjects, including treatment of metalloenzyme-related diseases such as cancer, cardiovascular disease, inflammatory diseases, infectious diseases, metabolic, ophthalmologic, central nervous system, urologic, and gastrointestinal diseases.
Use of the compounds and compositions as agricultural agents for controlling metalloenzyme-mediated disorders in plants, including herbicide, pesticide, and growth regulation applications.
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