Compounds which are used in the preparation of the compound of formula (I)
Inventors
Sunose, Mihiro • COLLEY, Thomas Christopher • Ito, Kazuhiro • RAPEPORT, Garth • Strong, Peter
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10487073-B2
Publication Date
2019-11-26
Expiration Date
Abstract
This invention relates to compounds which are used in the preparation of the compound of formula (I).
Core Innovation
The document describes a mycosis-targeting antifungal program centered on Compound (I), a complex substituted benzamide including a triazole/tetrahydrofuran moiety and difluorophenyl groups, together with fluorinated aryl substituents. Compound (I) is described as an antifungal agent directed to mycoses, including invasive aspergillosis, and the problem addressed is the need for antifungal activity against Aspergillus fumigatus, including azole-resistant aspergillosis.
The document further describes topical antifungal use of Compound (I) for lung and nose administration, including inhalation-related formulations. Experimental support is provided through in vitro and immunosuppressed mouse data demonstrating potent inhibition of Aspergillus fumigatus growth/infection, with readouts including CFU in lung and galactomannan in bronchoalveolar lavage fluid (BALF) and serum.
The patent also describes preparing benzoic-acid intermediates and ultimately forming target compound (I) through multi-step conversion of intermediates (II), (IVa), (IVb), and benzamide-forming transformations. A RuPhos-catalyzed C–N coupling is described, and the document further addresses scale-up of key intermediates together with analytical method conditions for characterization and monitoring, including reverse-phase HPLC/LCMS and 1H NMR.
Claims Coverage
The provided independent claims cover specific chemical compounds defined by structural formulas, including formula (II), (IV), (V), (VII), (VIII), and (XV), with pharmaceutically acceptable salts. The claims also include limited substituent constraints, with R as C1–C5 alkyl in formulas (IV) and (VIII), R as C1–C5 alkyl in the other cited claim set, and P as Boc in formula (VII).
Formula (ii) compound and salts
A compound of formula (II) or a salt thereof.
Formula (iv) compound with c1–c5 alkyl and salts
A compound of formula (IV) wherein R represents C1–C5 alkyl, or a salt thereof.
Formula (v) compound and salts
A compound of formula (V) or a salt thereof.
Formula (vii) compound with boc and salts
A compound of formula (VII) wherein P represents Boc, or a salt thereof.
Formula (viii) compound with c1–c5 alkyl and salts
A compound of formula (VIII) wherein R represents C1–C5 alkyl, or a salt thereof.
Formula (xv) compound and salts
A compound of formula (XV) or a salt thereof.
Formula (ii) or formula (iv) compound with c1–c5 alkyl r
A compound of formula (II) or a compound of formula (IV), or a salt thereof, wherein R represents C1–C5 alkyl.
Formula (viii) or formula (xv) compound with c1–c5 alkyl r
A compound of formula (VIII), or a compound of formula (XV), each or a salt thereof, wherein R represents C1–C5 alkyl.
Across the independent claims, the claimed subject matter is limited to formula-defined compound classes, including salt forms, with R restricted to C1–C5 alkyl in the cited claim sets and P restricted to Boc for formula (VII).
Stated Advantages
Potent inhibition of Aspergillus fumigatus growth/infection.
Demonstrated effects indicated by CFU in lung and galactomannan in BALF and serum.
Topical lung/nose administration as described for the antifungal use.
Compound (I) is reported to be more potent than voriconazole/amphotericin B.
Compound (I) is reported to be similar to or better than posaconazole.
Compound (I) is reported to have activity versus azole-resistant strains.
The document reports strong monotherapy benefits.
The document reports combination benefits (including with posaconazole) with sustained/extended DFB50.
Extended prophylaxis is reported, suggesting drug persistence in lung.
Documented Applications
Topical treatment of lung and nose aspergillosis using inhalation formulations for antifungal delivery.
Use against invasive aspergillosis, including azole-resistant aspergillosis as described.
Prophylactic and therapeutic effects are supported by the described experimental readouts (CFU in lung; galactomannan in BALF/serum).
Antifungal activity testing against Aspergillus fumigatus, including planktonic growth and bronchial epithelial infection/viability assays.
Cell and infection-related assessment using human alveoli bilayers/transwell with GM-EIA readout and invasion measurements.
In vivo use in neutropenic mouse infection with prophylactic and therapeutic regimens, measuring CFU, BALF/serum galactomannan, cytokines, inflammatory cell recruitment, oxidative stress markers, and survival.
Broth microdilution across strains/species including comparison against azoles such as voriconazole and posaconazole and evaluation of activity versus azole-resistant strains.
Interested in licensing this patent?