Hydroxamic acids and uses thereof

Inventors

Johnson, Alan Thomas • Kim, Seong Jin • O'Malley, Sean • Jackson, Henry Lee

Assignees

Hawaii Biotech Inc

Abstract

Compounds of formula I are provided: R1 is an alkoxy or O(CH2)pX, p is an integer from 2 to 3 and X is OH, NH2, or CO2H, m is an integer from 0 to 5, n is an integer from 0 to 5, each R2 is independently selected from hydrogen, alkenyl, hydroxyalkyl, alkoxymethyl, heterocyclyl, hetereocyclylmethyl, amino, amido, hydroxamido, any of which may be optionally substituted with one or more of acyl, alkyl, alkoxy, hydroxyalkyl, or halogen, each R3 is independently selected from hydrogen, halogen, alkyl, alkenyl, carboxy, hydroxymethyl, amido, and at least one of R2 and R3 is not hydrogen.

Core Innovation

The patent describes hydroxamic acid inhibitor compounds for botulinum neurotoxin, including BoNT/A light chain inhibitor compounds, and stereospecifically defined N-hydroxy pentanamide derivatives with (3R,4R) and (3S,4R) configurations. The compounds are defined by Formula I-III or Formula I with variable substituents including R1, R2, and R3, and include specific aryl, heteroaryl, heterocyclic, fluoro-substituted, bromo-, chloro-, morpholinyl-, pyrimidinyl-, or pyridinyl-containing groups, as well as substituted pentanamides with 4-chlorophenyl and 2,4-difluorophenyl groups.

The disclosure addresses the need for inhibitors of botulinum neurotoxin activity, specifically inhibition of BoNT/A LC, and use in treating subjects exposed to botulinum toxin and thereby botulinum toxicity. The compounds include an N-hydroxypentanamide scaffold with hydroxyamino functionality and varied C-3 ether side chains such as butoxy, propoxy, cyclopropylmethoxy, hydroxyethoxy, hydroxypropoxy, and methoxy-related substituents.

The document also describes pharmaceutical compositions comprising the disclosed compounds together with pharmaceutically acceptable carriers, and use for treating a subject for botulinum toxicity by administering such pharmaceutical compositions. Some members are provided as sodium or potassium salts, and the examples include full IUPAC names and analytical characterization such as API-ES mass spectrometry and IR spectral peaks.

Claims Coverage

The claim coverage centers on Formula I compounds defined by specific R1, R2, and R3 substituent assignments, including free-base and salt forms. The independent and related claims combine selected compound members with pharmaceutical composition and treatment language, and the inventive features repeatedly focus on the particular substituent patterns and, in one instance, sodium or potassium salt forms.

Overall, the claim coverage focuses on Formula I members defined by specific R1, R2, and R3 substituent patterns, including at least one explicit sodium or potassium salt embodiment. The scope also extends to pharmaceutical compositions with pharmaceutically acceptable carriers and to a therapeutic method of treating botulinum toxicity by administering the composition.

Stated Advantages

Documented Applications