Process for preparing a compound useful to treat mycoses
Inventors
COLLEY, Thomas Christopher • Ito, Kazuhiro • RAPEPORT, Garth • Strong, Peter • Murray, Peter John • Onions, Stuart Thomas • Sunose, Mihiro
Assignees
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Publication Number
US-10858345-B2
Publication Date
2020-12-08
Expiration Date
Abstract
A process for preparing a compound of formula (II):includes reacting a compound of formula (VIII):with a compound of formula (XIV):
Core Innovation
The invention relates to a process for preparing a compound of formula (II) or a salt thereof. The process uses a two-stage sequence in which a compound of formula (VIII) is reacted with a compound of formula (XIV) to give a compound of formula (IV), followed by hydrolysis of the compound of formula (IV) to give the compound of formula (II) or a salt.
The substituent scope is defined by R2, R3, R4, X, and Ra. R2 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 alkoxy, or C1-4 haloalkoxy; R3 is halo, cyano, C1-4 alkyl, or C1-4 hydroxyalkyl; R4 is hydrogen or C1-4 alkyl; X is CH or N; and Ra is H or C1-5 alkyl.
The document further describes representative compound preparations and analogs within the claimed chemical space, including substituted benzamide piperazine compounds with piperazinylbenzamide scaffold and tetrahydrofuran/1,2,4-triazol-1-yl motifs. It also reports analytical characterization such as LC retention time, m/z (M+H)+, 1H NMR, HPLC retention times, LC-MS values, and X-ray/structure images of certain examples.
Claims Coverage
The document contains one independent claim directed to a multi-step process for preparing a compound of formula (II) or a salt thereof. The main inventive content is the reaction of formula (VIII) with formula (XIV) to form formula (IV), followed by hydrolysis of formula (IV) to obtain formula (II), with defined substituent ranges for R2, R3, R4, X, and Ra.
Two-stage preparation via intermediate formula (IV) and hydrolysis to formula (II)
Reacting a compound of formula (VIII) with a compound of formula (XIV) to give a compound of formula (IV), followed by hydrolysis of the compound of formula (IV) to give the compound of formula (II) or a salt thereof.
Defined substituent scope for R2, R3, R4, X, and Ra
R2 is hydrogen, halo, cyano, C1-4 alkyl, C1-4 alkoxy, or C1-4 haloalkoxy; R3 is halo, cyano, C1-4 alkyl, or C1-4 hydroxyalkyl; R4 is hydrogen or C1-4 alkyl; X is CH or N; and Ra is H or C1-5 alkyl.
Overall, the claim coverage centers on preparing formula (II) or salts by reacting formula (VIII) with formula (XIV) to form formula (IV), then hydrolyzing formula (IV) to obtain formula (II), with explicit substituent definitions across the formulas.
Stated Advantages
The document reports biological testing of the compounds against Aspergillus fumigatus, including screening results relative to reference antifungal agents, as well as additional performance and resistance-strain comparisons.
Example 1 generally outperforms or matches reference antifungals including voriconazole, amphotericin B, and posaconazole.
Combination with posaconazole prolongs inhibition and increases survival time.
Demonstrated in vitro potency against Aspergillus fumigatus.
Demonstrated efficacy in immunosuppressed mice.
Documented Applications
Treatment of mycoses, notably Aspergillus fumigatus, including invasive aspergillosis and azole resistant mycoses.
Use of pharmaceutical compositions with topical pulmonary/intranasal administration concepts.
In vitro planktonic growth inhibition against Aspergillus fumigatus using MIC/MIC75/MIC90 measures with resazurin microtitre assay and broth microdilution assay.
Inhibition of infection in bronchial epithelial cells (BEAS2B) using a resazurin readout.
Invasion and infection assessment using a human alveolar epithelial/endothelial bilayer transwell invasion model, measuring galactomannan (GM), including combination effects versus posaconazole and DFB50 values.
In vivo antifungal efficacy in immunocompromised neutropenic A/J mice, with endpoints including lung CFU fungal load, BALF/serum galactomannan, cytokines, MDA oxidative stress marker, and immune-cell accumulation by FACS.
Biological testing of the disclosed compounds against Aspergillus fumigatus, including in vitro/planktonic growth testing and infection models in bronchial epithelial cells and human alveolar bilayers, as well as in vivo mouse anti-fungal activity.
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