Antifungal compound process
Inventors
Hoekstra, William J. • Yates, Christopher M. • Behnke, Mark • Alimardanov, Asaf • David, Scott A. • Fry, Douglas Franklin
Assignees
United States Department Of Health And Human Resources • Mycovia Pharmaceuticals Inc • US Department of Health and Human Services
Publication Number
US-10399943-B2
Publication Date
2019-09-03
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 and substituted derivatives thereof, which are useful as antifungal agents. The invention seeks to provide new methodology for preparing compound 1, its substituted versions, and related pharmaceutical forms, including pharmaceutically acceptable salts, hydrates, solvates, complexes, and prodrugs. The compounds achieve affinity for metalloenzymes through various metal-ligand chemical interactions including sigma bonds, covalent bonds, coordinate-covalent bonds, ionic bonds, pi bonds, delta bonds, or backbonding interactions.
The background identifies the problem of designing metalloenzyme inhibitors with an optimal balance of potency and selectivity. Existing antifungal agents like fluconazole and voriconazole bind indiscriminately to metals such as iron or zinc in enzyme active sites, causing off-target effects and toxicity, including inhibition of human drug-metabolizing enzymes and joint pain due to unwanted matrix metalloproteinase inhibition. Thus, there is a need for metal-binding groups that provide better selectivity and potency, as well as efficient synthetic methods to produce such therapeutic agents on laboratory and commercial scales.
The invention provides multiple specific chemical processes for preparing compound 1 and its derivatives. These include amidation of ester intermediates, aryl substitution, olefination, asymmetric dihydroxylation, alcohol activation, epoxide formation and ring opening, amination, tetrazole formation, and enantiomeric enrichment through crystallization with chiral acids. The processes involve selecting appropriate metal reagents (e.g., Mg or Al-based nucleophiles), chiral ligands for asymmetric catalysis (e.g., (DHQ)2PHAL, (DHQD)2PHAL), and use of sulfonate activation groups (mesylates, tosylates). Detailed steps and reagents are delineated, supporting improved efficiency, selectivity, and enantiopurity in the synthesis.
Claims Coverage
The patent contains multiple independent claims centered on processes for preparing compound 1 or 1a and their pharmaceutically acceptable salts or mixtures. The claims encompass various synthetic steps and reaction conditions in the preparation.
process to prepare compound 1 or 1a or their salts
A process comprising steps such as amidation, aryl substitution, olefination, asymmetric dihydroxylation, activation of primary alcohols, ring-closing to epoxides, epoxide ring-opening, amination, and formation of tetrazole moieties, leading to compound 1 or 1a or their salts or mixtures.
asymmetric dihydroxylation with specific chiral ligands
Use of asymmetric dihydroxylation conditions comprising a catalytic osmium oxidant, a stoichiometric iron oxidant, a base, and a chiral ligand selected from (DHQ)2PHAL, (DHQD)2PHAL, (DHQD)2AQN, or (DHQD)2PYR, optionally with methanesulfonamide.
enantio-enrichment of compound mixtures
Crystallizing an enantiomeric compound mixture with a chiral acid in suitable solvents like acetonitrile, isopropanol, ethanol, methanol, or water, isolating enantio-enriched salts, optional slurrying to improve purity, and free-basing to obtain enantio-enriched compounds.
conversion to sulfonic acid salts
Combining compound 1 or 1a with a sulfonic acid in specified crystallization solvents and co-solvents to form isolated sulfonic acid salts of compound 1 or 1a.
The independent claims cover novel multi-step synthetic processes for preparing compound 1 or 1a and their salts, emphasizing asymmetric dihydroxylation with defined chiral ligands, methods for enantiomeric enrichment, and formation of pharmaceutical salt forms. These inventive features enable more efficient and selective preparation of antifungal agents.
Stated Advantages
The invention provides a methodology with improved efficiency and selectivity for preparing compound 1 and its derivatives.
New metal-binding groups in the compounds achieve a better balance of potency and selectivity, potentially reducing off-target toxicity.
Processes described enable preparation of enantiopure compounds through controlled asymmetric syntheses and crystallization techniques.
Documented Applications
Use of compounds as antifungal agents by inhibiting lanosterol demethylase (CYP51).
Pharmaceutical compositions comprising the compounds for treating metalloenzyme-related disorders or diseases.
Methods of modulating metalloenzyme activity in subjects, including treatment of metalloenzyme-mediated disorders.
Selective targeting of cancer cells over nontransformed cells by the described compounds.
Agricultural applications such as herbicides, pesticides, and growth regulators by modulating metalloenzyme activity in plants or microorganisms on plants.
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