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Antifungal Compound Process

a compound process and antifungal technology, applied in the field of antifungal compound process, can solve the problem of dramatic decrease of the activity of the enzym

Inactive Publication Date: 2019-06-13
MYCOVIA PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These methods enable the creation of compounds with improved affinity and specificity for target metalloenzymes, reducing the risk of off-target inhibition and enhancing therapeutic efficacy while minimizing toxicity, thus addressing the limitations of existing antifungal agents.

Problems solved by technology

It is well recognized that agents which bind to and inactivate the active site metal ion dramatically decrease the activity of the enzyme.
The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes.

Method used

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  • Antifungal Compound Process
  • Antifungal Compound Process
  • Antifungal Compound Process

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)ethanone (1-4)

1a. ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (2)

Process Development

[0449]

[0450]Table 1 illustrates the effects of the relative proportions of each of the reagents and reactants, the effect of temperature, and the effect of varying the solvent had on the overall performance of the transformation as measured by the overall yield and purity of the reaction.

TABLE 1Process Development for the Preparation of compound 2-BrBr-esterCuSolventTempTime2-Br1Br-esterOtherEntry(eq1)(size / eq1)(vol)2(° C.)(h)(%)(%)(%)(%)11.043 μm / 2.5DMF (4)51847631121.043 μm / 2.5NMP (4)51841966631.04Cu bronzeDMF (4)5172078341.04Cu bronzeNMP (4)51721283351.043 μm / 2.5DMF (4)5148804761.023 μm / 2.4DMF (4)7520741.5971.023 μm / 1.0DMF (4)7517759481.023 μm / 1.5DMF (4)75178463691.023 μm / 2.0DMF (4)7517856100.9 3 μm / 2.16DMF (4)7517801116110.79 3 μm / 1.98DMF (4)751788416120.67 3 μm / 1.67DMF (4)75178675130.83 μm / 0.8DMF (4)751...

example 4

on of 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (1 or 1a)

[0478]

[0479]The procedure used to generate compound 1 or 1a is as described in U.S. Pat. No. 4,426,531. Table 13 illustrates the efficient and quantitative nature of this procedure as performed on amino-alcohol 1-6* or 1-7* produced from both the TMS-cyanohydrin method and the TMSI-epoxidation method.

TABLE 13Formation of Compound 1 or 1a1-6* or 1-7*Cmpd 1 or 1a1-6* or 1-7*1-6* or 1-7*PurityPurityYieldEntryOriginAmt (g)(HPLC %)(HPLC %)(%)1TMSI-199.097.496.5epoxidationMethod2TMS-198.097.999.2cyanohydrinMethod

example 5

fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol benzenesulfonate (1 or 1a-BSA)

[0480]

Typical Procedure for Converting 1 or 1a to 1 or 1a-BSA

[0481]46.6 g of compound 1 or 1a was dissolved in ethylacetate (360 ml). The solution was filtered through a glass microfiber filter and placed in a 2 L reaction flask equipped with an overhead stirrer, condenser, and a J-Kem thermocouple. Pharma-grade benzenesulfonic acid (BSA, 14.39 g, 1 eq) was dissolved in ethyl acetate (100 ml). The BSA solution was filtered through a glass microfiber filter and added to the stirred 1 or 1a solution in one portion. The mixture was warmed to 60-65° C.; precipitation of the 1 or 1a / BSA salt occurred during the warm up period. The slurry was held for 60 minutes at 60-65° C. The suspension was allowed to slowly cool to 22° C. and was stirred at 20-25° C. for 16 hours. n-Heptane (920 ml) was charged in one portion and the suspension was stirred at 22° C. f...

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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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. patent application Ser. No. 15 / 126,359 filed Sep. 15, 2016, which is the U.S. National Stage, pursuant to 35 U.S.C § 371, of International Application No. PCT / US2015 / 21464 filed Mar. 19, 2015, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61 / 955,532 filed Mar. 19, 2014, the entire disclosures of which are incorporated by reference herein.[0002]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 a new methodology for preparing compound 1 and substituted derivatives thereof.STATEMENT OF GOVERNMENT SUPPORT[0003]This invention was created in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in thi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/06C07D213/56C07D405/06C07D213/38C07D213/50
CPCC07D213/56C07D213/50C07D401/06C07D405/06C07D213/38A61P31/04A61K31/435A61K31/5377C07D413/06
Inventor HOEKSTRA, WILLIAM J.YATES, CHRISTOPHER M.BEHNKE, MARKALIMARDANOV, ASAFDAVID, SCOTT A.FRY, DOUGLAS FRANKLIN
Owner MYCOVIA PHARMA INC
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