Methods of treating amyloid disease using analogs of 1-(4-nitrophenyl) piperazine
Inventors
Barden, Christopher J. • Carter, Michael D. • Reed, Mark A. • Weaver, Donald F. • Yadav, Arun • Sun, Shengguo
Assignees
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Publication Number
US-8420640-B2
Publication Date
2013-04-16
Expiration Date
Abstract
The present invention is directed to compounds that inhibit amyloid aggregation and methods of treatment therewith.
Core Innovation
The invention relates to compounds of Formula Ic and pharmaceutically acceptable salts thereof, wherein the structural variability is defined by substituent selections for R1, R2, R3, and R4. The substitutions are selected from explicitly listed groups, with additional optional substitution patterns for aryl, benzyl, and phenonyl moieties, and the permitted structures are refined by additional constraints and explicit exception rules.
The disclosed compound framework includes functional-group options such as nitro, carboxylic acid, alkylcarboxylic acid, acetamide connected in either direction, N-(2-ethanol)amine, N-(2-morpholinethyl)amine, amine optionally substituted with one or more alkyl groups, and amide optionally substituted with one or more alkyl groups, together with alkoxy options. For R2, R3, and R4, the definition includes carboxylic acid, alkyl, alkanoyl, alkanesulfonyl, benzenesulfonyl, and aryl/benzyl/phenonyl substituent patterns with alkoxy, halogen, and alkyl.
The invention is directed to amyloidogenic protein aggregation inhibition and treatment of amyloid diseases using a compound of Formula Ic or a pharmaceutically acceptable salt thereof. The described compounds are used for treating amyloid diseases by administering a compound of Formula Ic to a human in a pharmaceutically effective dosage form, and the document also includes pharmaceutical compositions containing a therapeutically effective amount of such a compound.
Claims Coverage
The independent claims cover three inventive features: Formula Ic compounds, a method of treating amyloid diseases by administering those compounds, and pharmaceutical compositions containing therapeutically effective amounts of those compounds. Across the independent claims, the inventive scope is anchored by the Formula Ic structural definition using substituent selections for R1, R2, R3, and R4, and is coupled to amyloid-disease treatment and pharmaceutical compositions.
Formula Ic compound defined by R1-R4 substituent selections
A compound of Formula Ic or a pharmaceutically acceptable salt thereof, wherein R1 is selected from nitro, carboxylic acid, alkylcarboxylic acid, acetamide connected in either direction, N-(2-ethanol)amine, N-(2-morpholinethyl)amine, amine optionally substituted with one or more alkyl groups, amide optionally substituted with one or more alkyl groups, and alkoxy; R2 is selected from carboxylic acid, alkyl, alkanoyl, alkanesulfonyl, benzenesulfonyl, phenonyl optionally substituted with any one or more of alkoxy, halogen, or alkyl groups, benzyl optionally substituted with any one or more of alkoxy, halogen, or alkyl groups, and amide optionally substituted with any one or more of alkyl or aryl groups; R3 is selected from H, alkyl, furanoalkyl, thiophenealkyl, alkanoyl, phenyl optionally substituted with any one or more halogen, alkyl, or alkoxy groups, benzyl optionally substituted with any one or more of halogen, alkyl, or alkoxy groups, and phenonyl optionally substituted with any one or more of halogen, alkyl, or alkoxy groups; and R4 is selected from H, alkyl, or phenyl optionally substituted with any one or more of halogen, alkyl, or alkoxy groups.
Treatment of amyloid diseases by administering Formula Ic compounds
A method of treating amyloid diseases, comprising administering to a human a compound of Formula Ic or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are selected from the specified groups, and wherein the method is performed in the manufacture of a dosage form for the treatment of amyloid diseases.
Pharmaceutical composition with therapeutically effective Formula Ic amount
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ic or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are selected from the specified groups for Formula Ic.
Overall, the claims cover Formula Ic compounds and pharmaceutically acceptable salts defined by R1-R4 substituent selection sets, and extend to administration for treatment of amyloid diseases and to pharmaceutical compositions containing a therapeutically effective amount of the same compounds. Dependent refinements further constrain substituent selections and introduce explicit exceptions and dosage-form routes.
Stated Advantages
Inhibits the aggregation of an amyloidogenic protein.
Potent inhibition of beta-amyloid aggregation.
Some compounds are also potent inhibitors of alpha-synuclein aggregation.
Treats amyloid diseases.
Documented Applications
Inhibiting amyloidogenic protein aggregation.
Inhibition of beta-amyloid aggregation by potent inhibitor compounds within the described amyloid-aggregation inhibitor scaffold.
Inhibition of alpha-synuclein aggregation by some inhibitor scaffold members.
Treating amyloid diseases by administering to a human a compound of Formula Ic or a pharmaceutically acceptable salt thereof, including manufacture of a dosage form for such treatment.
Pharmaceutical compositions for oral dosage form.
Pharmaceutical compositions for parenteral dosage form.
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