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
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Publication Number
US-11008307-B2
Publication Date
2021-05-18
Expiration Date
Abstract
This invention relates to compounds which are used in the preparation of the compound of formula (I).
Core Innovation
The invention relates to a process for preparing a compound of formula (I), or a salt thereof, by reacting a compound of formula (II), or an activated derivative thereof, or a salt thereof, with a compound of formula (III), or a salt thereof. The disclosed work includes preparation of a substituted benzoamide compound (I) and key intermediates used in the process.
The process includes coupling steps to form benzoate derivatives and intermediate (VIIIb), followed by hydrolysis or saponification to form a benzoic acid intermediate (II). It also includes O-alkylation or conversion from intermediate (IVc) using a tosylate (IX), deprotection to obtain a benzoic acid mono-hydrochloride intermediate (II), and final amide coupling of intermediate (II) with 4-fluoroaniline to afford compound (I).
The described sequence further includes RuPhos-catalyzed coupling, benzoyl chloride coupling, RuPhos/LiHMDS arylation, and BBr3 dealkylation to a phenol intermediate (XV), as well as an alternative phenol intermediate route using a tosylate (IX). The document also describes preparation of a tetra-deuterio derivative and a reported >1 kg scale-up route using ethyl versus tert-butyl ester variants and deprotection to benzoic acid (II).
Claims Coverage
The independent claim coverage centers on a process for preparing compound (I) or a salt thereof by reacting formula (II) with formula (III). Dependent claims specify alternative activated derivatives and narrow the product salt to a pharmaceutically acceptable salt, giving five inventive features in total.
Coupling of formula (II) with formula (III) to prepare formula (I)
Reacting a compound of formula (II), or an activated derivative thereof, or a salt thereof, with a compound of formula (III), or a salt thereof, to prepare a compound of formula (I), or a salt thereof.
Using an acid halide activated derivative
The activated derivative is an acid halide.
Using an acid chloride activated derivative
The acid halide used is an acid chloride.
Using an acid anhydride activated derivative
The activated derivative is an acid anhydride.
Using a pharmaceutically acceptable salt of formula (I)
The process uses the pharmaceutically acceptable salt of the compound of formula (I).
The claims collectively define preparation of formula (I) by reaction of formula (II) with formula (III), with activated derivative options limited to acid halide, acid chloride, or acid anhydride, and with the product optionally being a pharmaceutically acceptable salt.
Stated Advantages
Potent Aspergillus fumigatus inhibition in vitro.
Potent Aspergillus fumigatus inhibition in immunosuppressed mice.
Low systemic exposure.
Safety after topical administration.
The document addresses the need for anti-fungal activity, including activity against Aspergillus fumigatus and other fungi.
The document reports comparison or combination performance against established anti-fungal treatments.
The document describes a reported >1 kg scale-up route.
Documented Applications
Topical lung therapy or topical lung/nose therapy using Compound (I).
Intranasal therapy using Compound (I).
Anti-fungal activity evaluation against Aspergillus fumigatus and other fungi.
Resazurin microtitre and broth microdilution assays.
Infection and invasion-related models using BEAS2B cells and human alveoli bilayers (transwells).
A scale-up route to compound (I) reported on >1 kg scale (Route 2).
Preparation of a tetra-deuterio derivative (4-fluoroaniline-2,3,5,6-d4) yielding a tetra-deuterio compound (I)[4-2H].
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