Compounds which are used in the preparation of the compound of formula (II)
Inventors
Sunose, Mihiro • COLLEY, Thomas Christopher • Ito, Kazuhiro • RAPEPORT, Garth • Strong, Peter
Assignees
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Publication Number
US-10800762-B2
Publication Date
2020-10-13
Expiration Date
Abstract
This invention relates to compounds which are used in the preparation of the compound of formula (II).
Core Innovation
The invention relates to a therapeutic compound for mycoses, in particular Aspergillus. The core chemical entity is Compound (I), described as a substituted piperazine benzamide bearing difluoro groups and a triazole-functionalized tetrahydrofuran moiety. Compound (I) exhibits potent in vitro inhibition of Aspergillus fumigatus and inhibition in immunosuppressed mice, supporting therapeutic use for the mycosis context.
The document describes a process for preparing a compound of formula (II) or a salt thereof. The process comprises reacting a compound of formula (XIII) or a salt thereof with a compound of formula (X), where R_a represents C1-5 alkyl, or a salt thereof, to give a compound of formula (IV), where R_a represents C1-5 alkyl, or a salt thereof, followed by hydrolysis of the compound of formula (IV) to give said compound of formula (II).
The description presents a multi-step route to a target compound (I), including synthesis and scale-up, with formation of intermediates and subsequent conversion steps. A coupling reaction is supported using RuPhos/RuPhos G3 mediated conditions to form intermediate (IVb) from ethyl benzoate (X) and intermediate (XIII), and the sequence proceeds through functional-group transformations to reach the benzoic acid intermediate (II).
The disclosure also addresses formulation and administration, including topical pulmonary and intranasal administration, and includes coverage of pharmaceutically acceptable salts, polymorphs, tautomers, solvates, and isotopes. The document further includes a subsequent amide coupling in which benzoic acid (II) is reacted with 4-fluoroaniline (III) to form compound (I), and it also supports analytical characterization of intermediates and compound (I), including LCMS/HPLC retention times and 1H NMR data.
Claims Coverage
The partial claim set includes two independent claims that cover a compound of formula (XIII), including salts, and a preparation process to obtain a compound of formula (II), including salts, via reaction of formula (XIII) with a specified compound of formula (X) followed by hydrolysis of an intermediate of formula (IV).
Compound of formula (XIII) or salt
A compound defined by formula (XIII), or a salt thereof.
Reaction of formula (XIII) with formula (X) to form formula (IV)
Reacting a compound of formula (XIII) or a salt thereof with a compound of formula (X), where R_a represents C1-C5 alkyl or a salt thereof, to give a compound of formula (IV), where R_a represents C1-C5 alkyl or a salt thereof.
Hydrolysis of formula (IV) to form compound of formula (II)
Following the reaction, hydrolyzing the compound of formula (IV) to give said compound of formula (II) or a salt thereof.
Across the independent claims, the coverage centers on a compound of formula (XIII), including salts, and on a synthetic sequence that transforms formula (XIII) to formula (II) by formation of formula (IV) followed by hydrolysis, with Ra limited to C1-C5 alkyl.
Stated Advantages
Potent in vitro inhibition of Aspergillus fumigatus.
Inhibition in immunosuppressed mice.
Documented Applications
Therapeutic treatment of mycoses, notably Aspergillus.
Topical pulmonary and intranasal administration.
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