Method for the production of sulphonylpyrroles as HDAC inhibitors
Inventors
Müller, Matthias • Müller, Bernd • Maier, Thomas
Assignees
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Publication Number
US-8785659-B2
Publication Date
2014-07-22
Expiration Date
Abstract
Process for the preparation of a compound of formula (I) wherein R1, R2, R3, R4, R5 and R6 have the meanings as defined in the specification, comprising the step of reacting an acrylic acid chloride compound of formula (II′): wherein R1, R2, R3, R4, R5 and R6 have the meanings as defined in the specification, with aqueous hydroxylamine and optionally converting the resulting compound into an acid addition salt thereof.
Core Innovation
The patent describes preparing N-sulphonylpyrrole N-hydroxy-acrylamide compounds of formula I as histone deacetylase inhibitors by reacting an acrylic acid chloride compound of formula II with aqueous hydroxylamine. This transformation yields the desired compound of formula I and enables an optional conversion of the resulting product into an acid addition salt thereof.
The core route is centered on direct formation from an acrylic acid chloride (formula II) rather than using protected hydroxylamine and a coupling process. The document contrasts with prior art approaches involving O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and coupling reagents such as EDCb7HCl and HOBt, and positions the described process as a broader reaction scheme for obtaining the N-hydroxy-acrylamide structural motif.
The preparation includes preparing acrylic acid precursors of formula II and enabling in-situ acid chloride formation of formula II using thionyl chloride or oxalyl chloride. The resulting compounds can be provided as a free base or as an acid addition salt, including hydrochloride and other acid addition salts such as methanesulfonate. The document further links the chemistry to downstream use as HDAC inhibitors that induce hyperacetylation and apoptosis/differentiation in neoplasia and other HDAC-inhibitor-responsive diseases.
Claims Coverage
The independent claim covers a process for preparing a compound of formula I by reacting an acrylic acid chloride (formula II) with aqueous hydroxylamine, optionally converting the product into an acid addition salt. Across the dependent claims, multiple inventive features narrow or refine the process by defining additional intermediate conversion to the acid chloride, specifying acid-chloride forming reagents, and specifying particular salt forms and pharmaceutical composition use.
Acrylic acid chloride conversion with aqueous hydroxylamine to formula I
Comprising reacting an acrylic acid chloride compound of formula II with aqueous hydroxylamine, and optionally converting the resulting compound into an acid addition salt thereof.
Acid chloride preparation of the acrylic acid precursor
Providing a compound of formula II and converting that compound into its acid chloride of formula II.
Using thionyl chloride or oxalyl chloride for acid chloride formation
Carrying out the acid chloride formation using thionyl chloride or oxalyl chloride.
Multistep synthesis to the acrylic acid chloride via temporary carboxyl protection
Synthesizing a compound of formula II by converting a compound of formula V to a compound of formula IV, reacting the compound of formula IV with R6-SO2X to give a compound of formula III, and finally removing the carboxyl protective group PG1 to obtain the compound of formula II.
Direct formation of formula I hydrochloride salt
Obtaining the compound of formula I directly as its hydrochloride salt by reacting the compound of formula II with aqueous hydroxylamine.
Methanesulfonate as an acid addition salt other than hydrochloride
Specifying that, for compounds of formula I, the acid addition salt other than hydrochloride is methanesulfonate.
Overall, the claims coverage focuses on forming N-hydroxy-acrylamide HDAC inhibitor compounds (formula I) by reacting acrylic acid chloride (formula II) with aqueous hydroxylamine, with dependent features directed to acid chloride preparation (including specific reagents and intermediate steps using carboxyl protection) and to selecting particular salt forms such as hydrochloride and methanesulfonate.
Stated Advantages
Enables direct formation without relying on protected hydroxylamine and prior art coupling approaches using O-(tetrahydro-2H-pyran-2-yl)hydroxylamine with EDCb7HCl and HOBt.
Provides preparation as a free base or as acid addition salts including hydrochloride and methanesulfonate.
Supports use of the resulting compounds as HDAC inhibitors that induce hyperacetylation and apoptosis/differentiation in neoplasia and other HDAC-inhibitor-responsive diseases.
Documented Applications
HDAC inhibitor use in neoplasia (cancer), described as inducing hyperacetylation and apoptosis/differentiation.
Use in other HDAC-inhibitor-responsive diseases, described in connection with inducing hyperacetylation and apoptosis/differentiation.
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