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-10017494-B2
Publication Date
2018-07-10
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 invention relates to a process for preparing compound 1, which is useful as an antifungal agent, specifically providing new methodology for preparing compound 1 and substituted derivatives thereof. The invention encompasses methods of synthesis including epoxide opening, arylation, olefination, dihydroxylation, activation of alcohol, ring closure, formation of tetrazole, crystallization, and enantiomeric enrichment steps as detailed within the specification.
The background addresses the problem of designing metalloenzyme inhibitors that selectively bind metal ions in enzyme active sites to achieve therapeutic efficacy without off-target toxicity. Existing antifungal agents use triazole groups binding to heme iron, but this leads to clinical toxicity through indiscriminate inhibition of human drug metabolizing enzymes. There is a need for improved metal-binding groups that balance potency and selectivity, and for efficient synthetic methods to produce such compounds, exemplified by compound 1 and its derivatives.
The invention provides processes for preparing compounds with affinity for metalloenzymes via various types of chemical interactions with metal ions, and includes methods for enantioenrichment to obtain compounds with high enantiomeric purity. The methodology encompasses specific reaction sequences involving different intermediates and reagents, enabling scalable synthesis of compound 1 or 1a and salts thereof, along with methods of crystallization and purification. The combination of these synthetic steps addresses the challenge of access to compounds with desired activity and selectivity profiles.
Claims Coverage
The patent contains one independent claim directed to a process for preparing compound 1 or 1a, or their salts or mixtures thereof with multiple inventive features related to specific reaction steps and conditions described in dependent claims.
Process for preparing compound 1 or 1a
A process to prepare compound 1 or 1a, or a mixture thereof, including salts of such compounds.
Use of dihydroxylation conditions
Reacting a compound of formula IVa under asymmetric dihydroxylation conditions comprising a catalytic oxidant (OsO4 or K2OsO2(OH)4), stoichiometric oxidant (K3Fe(CN)6 or N-methylmorpholine-N-oxide), a base (Cs2CO3, Na2CO3, K2CO3 or NaHCO3), and a chiral ligand selected from specified ligands such as (DHQ)2PHAL, (DHQD)2PHAL, (DHQD)2AQN, (DHQ)2AQN, (DHQD)2PYR, and (DHQ)2PYR.
Selection of chiral ligand
The chiral ligand for the dihydroxylation is specifically selected from (DHQ)2PHAL, (DHQD)2PHAL, (DHQD)2AQN, and (DHQD)2PYR.
Use of methanesulfonamide (MeSO2NH2) additive
The process further comprises the addition of methanesulfonamide during the reaction sequence.
Activation and ring-closing steps
Processes comprising activating the primary alcohol of certain intermediates (2-6a, 2-6c, 2-6b or 2-6d) to form mesylate or tosylate derivatives, followed by ring-closing to form epoxides or other intermediates.
Crystallization and salt formation
Combining compound 1 or 1a with a sulfonic acid and specific crystallization solvents (e.g., ethyl acetate, isopropyl acetate, ethanol, methanol, acetonitrile) and co-solvents (e.g., pentane, methyl tert-butylether, hexane, heptane, toluene) to prepare sulfonic acid salts of formula IX or IXa, with optional use of substituents Z being phenyl, p-tolyl, methyl, or ethyl.
The claims cover a comprehensive process for synthesizing compound 1 or 1a, including oxidation, activation, ring closure, epoxide opening, tetrazole formation, crystallization, and use of specific reagents and conditions, demonstrating inventive methods to achieve selective and efficient preparation of the antifungal compounds and their salts.
Stated Advantages
Improved balance of potency and selectivity for metalloenzyme inhibition.
Methods for efficient and scalable synthesis of compound 1 and derivatives.
Enantiomeric enrichment processes to obtain high purity compounds.
Reduction of clinical toxicity through selective metal-binding groups compared to existing azole antifungal agents.
Documented Applications
Use of compound 1 and derivatives as antifungal agents by modulation of metalloenzyme activity.
Pharmaceutical compositions comprising compound 1 for treating metalloenzyme-mediated disorders or diseases.
Methods of treating subjects suffering from or susceptible to metalloenzyme-mediated disorders, including cancers, cardiovascular, inflammatory, infectious, metabolic, ophthalmologic, CNS, urologic, and gastrointestinal diseases.
Agricultural applications such as herbicides, pesticides, and growth regulators to modulate metalloenzyme activity in plants or microorganisms on plants.
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