Hydroxamic acids comprising pyrazole moiety and uses thereof
Inventors
Jiao, Guan-Sheng • Johnson, Alan T. • O'Malley, Sean • Kim, Seong Jin
Assignees
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Publication Number
US-11046652-B2
Publication Date
2021-06-29
Expiration Date
Abstract
Compounds of Formula I are provided: R1 is —OR5, m is an integer from 0 to 5, n is an integer from 0 to 2, each R2 is independently selected from hydrogen, halogen, and alkyl, R3 is selected from hydrogen, alkyl, cycloalkyl, aryl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aralkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkylaminoalkyl, and heterocycloalkyl, R5 is an alkyl, each R4 is independently hydrogen or alkyl, and each of R2, R3, R4, and R5 is independently optionally substituted. Compounds of Formula I are included in pharmaceutical compositions for the treatment of a subject exposed to a botulinum toxin.
Core Innovation
The disclosure describes hydroxamic acid inhibitors that contain a pyrazole moiety for treating and/or neutralizing botulinum neurotoxin, including botulinum neurotoxin type A (BoNT/A). It identifies the botulinum neurotoxin mechanism of action at the level of BoNT/A light chain (LC) activity and its effect on intracellular targets such as SNAP-25 and the SNARE complex, including acetylcholine release.
The disclosure describes that the inhibitors can show an intracellular LC inhibition profile that slows intoxication. The disclosure also describes a second efficacy profile that restores neurotransmission to accelerate recovery.
The disclosure provides chemical scaffolds for hydroxamic acid, pyrazole-containing compounds defined by Formulas I-IV, including substituent variables R1-R5 and integers m and n, along with pharmaceutically acceptable salts. It states use in pharmaceutical compositions administered to a subject exposed to botulinum toxin.
Claims Coverage
The independent claims cover compound frameworks defined by Formula I, Formula II, Formula III, and Formula IV, including pharmaceutically acceptable salts, with specific substituent variables R1-R5 and constrained integers m and n. The claim set also includes a treatment method by administering the compound or a pharmaceutical composition to a subject exposed to botulinum toxin.
Formula I substituted compound framework
A compound of Formula I or pharmaceutically acceptable salt thereof, wherein R1 is —OR5; m is an integer from 0 to 5; n is an integer from 0 to 2; each R2 is independently selected from hydrogen, halogen, and alkyl; R3 is selected from hydrogen, alkyl, cycloalkyl, aryl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aralkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkylaminoalkyl, and heterocycloalkyl; each R4 is independently hydrogen or alkyl; R5 is an alkyl; and each of R2, R3, R4, and R5 being independently optionally substituted.
Formula II substituted compound framework
A compound of Formula II or pharmaceutically acceptable salt thereof, wherein R1 is —OR5; m is an integer from 0 to 5; n is an integer from 0 to 2; each R2 is independently selected from hydrogen, halogen, and alkyl; R3 is selected from hydrogen, alkyl, cycloalkyl aryl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aralkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkylaminoalkyl, and heterocycloalkyl; each R4 is independently hydrogen or alkyl; R5 is an alkyl; and each of R2, R3, R4, and R5 being independently optionally substituted with hydroxy, alkoxy, halogen, or alkyl.
Formula III substituted compound framework
A compound of Formula III or pharmaceutically acceptable salt thereof, wherein R1 is —OR5; m is an integer from 0 to 5; n is an integer from 0 to 2; each R2 is independently selected from hydrogen, halogen, and alkyl; R3 is selected from hydrogen, alkyl, cycloalkyl aryl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aralkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkylaminoalkyl, and heterocycloalkyl; each R4 is independently hydrogen or alkyl; R5 is an alkyl; and each of R2, R3, R4, and R5 being independently optionally substituted with hydroxy, alkoxy, halogen, or alkyl.
Formula IV substituted compound framework
A compound of Formula IV, wherein each R2 is independently selected from hydrogen, halogen, and alkyl; R3 is selected from hydrogen, alkyl, cycloalkyl aryl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aralkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkylaminoalkyl, and heterocycloalkyl; R5 is methyl or ethyl; each of R2, R3, and R5 being independently optionally substituted with hydroxy, alkoxy, halogen, or alkyl; and m is an integer from 0 to 5.
Coverage is centered on compound frameworks defined by Formula I, Formula II, Formula III, and Formula IV, with the stated substituent limits and optional salt forms. The claim set also includes administration for treating a subject exposed to botulinum toxin.
Stated Advantages
Slows intoxication through intracellular LC inhibition.
Accelerates recovery by restoring neurotransmission.
Documented Applications
Treating and/or neutralizing botulinum neurotoxin in a subject exposed to botulinum toxin, using a pharmaceutical composition containing the claimed compound.
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