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-10407392-B2
Publication Date
2019-09-10
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 present invention relates to a process for preparing compound 1, which is useful as an antifungal agent. The invention particularly provides new methodology for preparing compound 1 and its substituted derivatives. It includes methods for synthesis of compounds of formula 1 or 1a, along with pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof. The compounds are designed to attain affinity for metalloenzymes by forming one or more types of chemical interactions or bonds to a metal, including sigma, covalent, coordinate-covalent, ionic, pi, delta bonds, or backbonding interactions.
The problem addressed by the invention stems from the need for improved metal-binding groups for metalloenzyme inhibitors that balance potency and selectivity. Existing metal-binding groups, such as the 1-(1,2,4-triazole) in known azole antifungal agents, have suboptimal selectivity, leading to unintended inhibition of off-target metalloenzymes and associated clinical toxicities. There is also a need for improved efficiency and selectivity in synthetic methodologies for such therapeutic agents applicable in laboratory and commercial scales.
The invention provides various chemical processes to prepare intermediate and final compounds, including morpholine amides, ketones, amino alcohols, epoxides, and further conversions transforming these intermediates into compound 1 or 1a. It also discloses processes for enantiomeric enrichment by crystallization with chiral acids and detailed synthetic schemes involving aryl substitution, olefination, dihydroxylation, activation of primary alcohols, ring closure, and tetrazole formation. The detailed description contemplates various substituents and process conditions to optimize synthesis and stereochemical purity.
Claims Coverage
The patent includes multiple independent claims covering novel compounds and processes for preparing compound 1 and its intermediates. Four main inventive features are identified from the independent claims.
compound of formula XI
An inventive compound of formula XI with defined substituents R4, R5, R6, R11, and R12, where the compound has stereochemical configurations and specific functional groups as described.
process to prepare compound 2-5
A process for preparing compound 2-5 involving specific reaction conditions and reagents such as morpholine amide 2b with Grignard reagents or other nucleophiles, and subsequent transformations through olefination, dihydroxylation, activation, ring closure, epoxide opening, and tetrazole formation steps to produce compound 1 or 1a.
process of enriching enantiomeric purity
Processes for enantiomeric enrichment of compounds using crystallization with chiral acids like tartaric acid derivatives in suitable solvents, followed by isolation, reslurrying, and free-basing to provide enantio-enriched compounds.
processes involving asymmetric dihydroxylation and functional group transformations
Processes employing asymmetric dihydroxylation with AD-mix alpha/beta or catalytic OsO4-based conditions in the presence of chiral ligands and oxidants, followed by activation, ring closure and arylation steps leading to intermediates or final compounds such as 1 or 1a.
The claims cover novel compounds useful as metalloenzyme inhibitors and detailed, efficient synthetic processes for preparing these compounds and their enantiomeric forms, including intermediate transformations, asymmetric synthesis, and crystallization techniques to achieve high purity and yield.
Stated Advantages
Provides improved methodology for preparing antifungal compound 1 and substituted derivatives with enhanced efficiency and selectivity.
Achieves better balance of potency and selectivity in metal-binding groups for metalloenzyme inhibitors, reducing off-target toxicity.
Enables preparation of compounds with high enantiomeric purity through crystallization and resolution methods.
Facilitates scalable synthesis processes applicable in laboratory and commercial manufacturing settings.
Documented Applications
Use of compound 1 and derivatives as antifungal agents by inhibition of metalloenzymes such as lanosterol demethylase (CYP51).
Methods of modulating metalloenzyme activity in subjects to treat metalloenzyme-related disorders or diseases.
Therapeutic methods for treating subjects suffering from or susceptible to metalloenzyme-mediated diseases including cancer, solid tumors, cardiovascular, inflammatory, metabolic, ophthalmologic, CNS, urologic, gastrointestinal, and infectious diseases.
Use in pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers for administration to subjects.
Agricultural applications including treatment or prevention of metalloenzyme-mediated disorders or diseases in plants and agricultural settings, such as herbicides, pesticides, and growth regulators.
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