Biaryl amides with modified sugar groups for treatment of diseases associated with heat shock protein pathway
Inventors
Jiang, Xin • Visnick, Melean • Bender, Christopher F. • Bolton, Gary • Caprathe, Bradley • Lee, Chitase
Assignees
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Publication Number
US-11827664-B2
Publication Date
2023-11-28
Expiration Date
Abstract
Provided are biaryl amides and coumarin-based compounds with modified sugar groups for treatment of diseases associated with heat shock protein pathway. The compounds having the following formulas, wherein variables are as defined herein. Formulae (I), (II), (III), (IV), and (V), Pharmaceutical compositions of the compounds are also provided. These biaryl amides and coumarin-based derivatives with modified sugar groups are useful for treatment and prevention of diseases and disorders, including neurological disorders, such as neurodegenerative diseases and nerve damaging disorders, for example, diabetic peripheral neuropathy.
Core Innovation
The invention relates to compounds defined by a specific chemical formula in which n is 1, Y1 is -alkanediyl (C6), -C(O)-alkanediyl (C6), or a substituted version of these groups, and Y2 is O. The compound class further specifies R3 as -NR11R11' or -C(O)NR12R12', with defined substituent ranges for R11, R11', R12, and R12'.
Additional substituent constraints define R7 as alkyl (C6) or substituted alkyl (C6), R8 as hydroxy, alkoxy (C6), or substituted alkoxy (C6), and R9 and R10 as each hydroxy. The scope includes pharmaceutically acceptable salts of the formula.
The disclosure also includes stereochemically defined and deuterated compound embodiments, including essentially stereoisomer-free deuterated variants, and pharmaceutical compositions comprising a compound and a pharmaceutically acceptable excipient. It further refers to fluorinated aryl-containing compounds, modified sugar groups, T-series compounds, and related target compounds and intermediates.
Claims Coverage
The consolidated claim coverage centers on one independent claim defining a compound class by a chemical formula with n=1 and constrained substituent positions, with coverage extending to pharmaceutically acceptable salts. Dependent claims further narrow substituent definitions and add a pharmaceutical composition including an excipient.
Defined compound scaffold with n=1 and Y1/Y2 selection
A compound of the formula wherein n is 1; Y1 is -alkanediyl (C6), -C(O)-alkanediyl (C6), or a substituted version of any of these groups; and Y2 is O.
R3 functionality selected as amine or amide with constrained substituents
R3 is -NR11R11' or -C(O)NR12R12', wherein R11 and R11' are each independently hydrogen, alkyl (C6), substituted alkyl (C6), acyl (C6), or substituted acyl (C6), and R12 and R12' are each independently hydrogen, alkyl (C6), or substituted alkyl (C6).
Side-group constraints including R7/R8/R9/R10
R7 is alkyl (C6) or substituted alkyl (C6); R8 is hydroxy, alkoxy (C6), or substituted alkoxy (C6); and R9 and R10 are each hydroxy.
Pharmaceutically acceptable salt coverage
A pharmaceutically acceptable salt of the formula.
Deuterated stereochemically defined variants
The disclosure includes deuterated stereochemically defined compound structures, including essentially stereoisomer-free deuterated variants.
Pharmaceutical composition including an excipient
A pharmaceutical composition comprising a compound of the formula and an excipient.
Overall, the claim coverage focuses on a defined n=1 compound scaffold with specified Y1 and Y2 positions, an R3 amine or amide motif with constrained substituent sets, and additional R7, R8, R9, and R10 limitations, together with pharmaceutically acceptable salts. Dependent coverage also includes deuterated stereochemically defined variants and a pharmaceutical composition comprising a compound and an excipient.
Stated Advantages
The compounds are described as biaryl Hsp90 inhibitors with altered sugar group features compared with prior noviose-based biphenyl analogs.
The disclosure reports acidic stability testing of KU-596 and selected test compounds in acidic medium.
Documented Applications
Treating or preventing diseases associated with the heat-shock protein pathway, including neurodegenerative and nerve-damaging disorders such as diabetic peripheral neuropathy.
Biological evaluation of KU-596 and related compounds in a streptozotocin-induced rat model of painful diabetic neuropathy using Von Frey testing.
Acidic stability testing of KU-596 and selected test compounds by HPLC over time.
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