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-10173998-B2
Publication Date
2019-01-08
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 aims to provide new methodology for synthesizing compound 1 and its pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs.
The background explains the crucial role of metals such as zinc and iron in biological metalloenzymes, enzymes that depend on metal ions in their active sites to function properly. Agents that bind these metal ions can dramatically reduce enzymatic activity, a principle utilized by nature and the pharmaceutical industry to inhibit target metalloenzymes. However, current metal-binding groups like 1-(1,2,4-triazole) sometimes bind indiscriminately, causing off-target effects and clinical toxicities, such as inhibition of important human drug-metabolizing enzymes or joint pain from matrix metalloproteinase inhibitors.
Therefore, the invention addresses the need to discover metal-binding groups that achieve a better balance between potency and selectivity to provide safe and effective metalloenzyme inhibitors. Along with new compounds, improved synthetic methods to produce these compounds on laboratory and commercial scales are required. The invention provides processes including epoxide opening, arylation, enantio-enrichment via chiral acid crystallization, amidation, and tetrazole formation steps to synthesize compound 1 and its derivatives with controlled stereochemistry and high purity.
Claims Coverage
The patent includes multiple independent claims focusing on processes for preparing compound 1 or 1a and their salts, involving different synthetic steps and reaction conditions. The following are the main inventive features derived from these independent claims.
Process to prepare compound 1 or 1a via morpholine amide reaction
A process comprising reacting morpholine amide 2b with organometallic reagents where M is Mg or MgX and X is halogen, leading to compound 1 or 1a or their mixture.
Amidation reaction of ester to form morpholine amide
A process involving amidation of ester 2 to provide morpholine amide 2b with various R1 substituents, enabling further synthetic transformations.
Displacement of morpholino portion in morpholine amide
A process step comprising displacement of the morpholino portion of morpholine amide 2b to provide ketone 3 as a key intermediate in the synthesis.
Salt formation and crystallization techniques
Processes involving the formation of salts of compound 1 or intermediates thereof using sulfonic acids, crystallization solvents and co-solvents such as ethyl acetate, isopropyl acetate, ethanol, methanol, acetonitrile, pentane, methyl tert-butylether, hexane, heptane, or toluene to isolate compounds of formula IX or IXa.
Enantiomeric enrichment of amino-alcohol intermediates
Processes to enrich enantiomeric purity of amino-alcohol intermediates by crystallization with chiral acids such as tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid, or di-p-toluoyltartaric acid in suitable solvents like acetonitrile, isopropanol, ethanol, methanol, or mixtures thereof.
Process comprising epoxide ring opening and subsequent arylation
A process comprising ring-opening of epoxides of compounds of formula I followed by arylation steps to provide amino aryl-pyridine intermediates that convert to compound 1 or 1a.
The independent claims collectively cover various novel synthetic steps and processes for preparing compound 1 or its enantiomers and derivatives, using morpholine amide transformations, epoxide ring openings, enantiomeric enrichment techniques, salt formation, and arylation reactions. These inventive features provide a comprehensive methodology for producing antifungal compounds with desired purity and enantiomeric excess.
Stated Advantages
The invention achieves improved efficiency and selectivity in the synthesis of antifungal agents compared to prior art methods.
Provides processes capable of producing enantiomerically enriched compounds to reduce clinical toxicity associated with off-target metalloenzyme inhibition.
Enables preparation of pharmaceutically acceptable salts and formulations suitable for therapeutic applications.
Documented Applications
Treatment or prevention of metalloenzyme-related diseases and disorders, including cancer, solid tumors, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmologic disease, central nervous system disease, urologic disease, and gastrointestinal disease.
Use as antifungal agents targeting metalloenzymes such as lanosterol demethylase (CYP51).
Use in pharmaceutical compositions and kits for administering effective amounts of compound 1 or related compounds to subjects in need thereof.
Agricultural applications including treating plants, seeds, seedlings, or fields by modulating metalloenzyme activity for use as herbicides, pesticides, or growth regulators.
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