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-10392365-B2
Publication Date
2019-08-27
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. The invention specifically provides new methodology for preparing compound 1 and substituted derivatives thereof through various synthetic processes.
The problem being addressed arises from the need to develop metalloenzyme inhibitors that balance potency and selectivity in targeting active site metal ions without causing off-target toxicities. Existing antifungal agents such as fluconazole and voriconazole utilize 1-(1,2,4-triazole) groups that indiscriminately bind to iron in off-target enzymes like CYP2C9, CYP2C19, and CYP3A4, leading to clinical toxicities. Similarly, previous matrix metalloproteinase inhibitors have toxicity attributed to nonselective inhibition due to hydroxamic acid group binding off-target zinc ions. Therefore, there remains a significant need for metal-binding groups and synthetic methodologies that provide improved efficiency, selectivity, and safety in preparing therapeutically useful metalloenzyme inhibitors.
The invention discloses multiple synthetic methods to prepare compound 1 and its derivatives, including processes involving epoxide opening, arylation of substituted pyridines, enantiomeric enrichment using chiral acids in defined solvent systems, amidation, and tetrazole formation. The processes employ reagents such as morpholine amide intermediates, transition metal catalysts for cross-coupling, and specific salts for chiral resolution and crystallization. The multiple-step methods aim to provide improved efficiencies and enantiomeric purities suitable for therapeutic applications.
Claims Coverage
The patent includes multiple independent claims directed to various processes for preparing enantio-enriched amino-alcohol intermediates and compound 1 or 1a, focusing on synthetic methodologies involving specific reagents, reaction conditions, and intermediates.
Process for preparing enantio-enriched amino-alcohols
Processes comprising steps such as epoxide opening, crystallizing racemic amino-alcohol mixtures with chiral acids in selected solvents (acetonitrile, isopropanol, ethanol, water, methanol or their combinations), isolating enantio-enriched mixtures, reslurrying in selected solvents, and free-basing to yield enantiomerically enriched amino-alcohol 1-6* or 1-7*.
Conversion of morpholine amide intermediates to target compounds
Processes for converting morpholine amide 2b to compound 1 or 1a or mixtures thereof, including reacting morpholine amides with metal-based nucleophiles (Mg, Li, AlX2, etc.) in the presence of halogenated reagents to provide final compounds with various R1 substituents.
Arylation and tetrazole formation steps
Processes involving arylation of substituted pyridine intermediates using boronate reagents and transition metal catalysts, followed by formation of tetrazole moieties via reaction with trimethylsilyl azide and trimethyl orthoformate in acidic conditions to afford compound 1 or 1a.
Methods for enantiomeric enrichment and salt formation
Processes including crystallization of amino-alcohol salts using selected sulfonic acids forming salts of formula IX or IXa, involving specific crystallization solvents, co-solvents and non-aqueous solvents for maximizing purity and yield.
The patent claims comprehensively cover innovative synthetic processes for preparing compound 1 and its enantiomeric forms, employing epoxide opening, chiral resolution, metal-mediated transformations, arylation, tetrazole formation, and salt crystallizations using defined reagents and conditions to produce pharmaceutically relevant enantiomerically enriched antifungal compounds.
Stated Advantages
Provides improved methodology for preparing compound 1 and substituted derivatives with enhanced efficiency and selectivity.
Achieves a better balance of potency and selectivity in metalloenzyme inhibition to reduce off-target toxicities compared to existing antifungal agents.
Enables enantiomeric enrichment to obtain high-purity enantiomers suitable for pharmaceutical use.
Facilitates scalable synthesis of compounds useful as antifungal agents and metalloenzyme inhibitors.
Documented Applications
Use of compound 1 and derivatives as antifungal agents by inhibiting lanosterol demethylase (CYP51).
Methods of modulating metalloenzyme activity in subjects to treat metalloenzyme-mediated disorders, including cancer and infectious diseases.
Pharmaceutical compositions comprising compound 1 for therapeutic administration via various routes including intravenous, oral, topical, and others.
Agricultural uses for treating plants or fields by modulating metalloenzyme activity, including use as herbicides, pesticides, or growth regulators.
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