Caspase inhibitors and methods of use thereof
Inventors
Spada, Alfred P. • Temansky, Robert J. • Mueller, Michael
Assignees
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Publication Number
US-11597703-B2
Publication Date
2023-03-07
Expiration Date
Abstract
Provided herein are compounds of formula I, compositions comprising the compounds and method of treating various diseases with the compounds and compositions.
Core Innovation
The invention relates to a compound having formula I, including an enantiomer or a mixture of enantiomers, and pharmaceutically acceptable salts, solvates, hydrates, co-crystals, clathrates, or polymorphs. The compounds are defined by selected X and Y structural elements, with detailed substituent options for Y and additional variables such as Q1, Q2, R groups, Z1, and Z2.
Within the formula I framework, Y1 together with R3 can form an optionally substituted saturated or unsaturated bicyclic ring B, with substituents on ring B selected from one to three groups Q1. Additional options define specific relationships among R3, Y1, Y2, and Y3, and further constrict Q1 substituents and their optional Q2 substitution.
The invention relates to caspase inhibitors that inhibit caspase-1, caspase-4, and/or caspase-5, and the compounds are stated for prevention and/or treatment of diseases that include inflammatory and apoptotic components. The document lists disease categories as therapeutic targets, including inflammatory diseases, autoimmune diseases, infectious diseases, degenerative diseases, cancer, gastrointestinal, respiratory, cardiovascular, dermatological, rheumatological, kidney, CNS, liver, and ophthalmological diseases.
Claims Coverage
The provided independent claims cover one broad formula I compound class and one treatment method based on administration of the claimed compound. The inventive features center on a highly specified substituent framework with ring-formation constraints and a caspase-1/4/5 modulation-based therapeutic administration for enumerated disease categories.
Formula I compound class with controlled substituent framework and ring-formation constraints
A compound having formula I, including an enantiomer or a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph, wherein X and Y are selected according to the specified options, including detailed selections for Q1 and optional Q2 substitution, R group selections, and ring B formation conditions via Y1 together with R3, with a constraint that when X is O, Y1 and R3 cannot form ring B.
Formula VIII variants with substituent index constraint
A compound corresponding to formula VIII selected from the compound of formula I, including an enantiomer or mixture of enantiomers, and including pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph, where each Q6 is independently selected from alkyl, halo, or haloalkyl and m is 0 to 4.
Specified aromatic selection for Z2 and functional substituent set for Q3
In the compound of claim 1, Z2 is selected from defined aromatic ring systems, optionally substituted by one or two groups Q3, where each Q3 is independently selected from the defined list of functional substituents.
Formula XVII variants with halo substitution and quantified index constraints
A compound corresponding to formula XVII selected from the compound of formula I, including an enantiomer or mixture of enantiomers, and including pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph, where each Q3 is halo with n=0 to 2, each Q7 is halo, and x=0 to 4.
Disease treatment method via administration of a therapeutically effective amount
A method for treating a disease by administering a therapeutically effective amount of the compound of claim 1, where the disease is selected from gastrointestinal, respiratory, cardiovascular, dermatological, rheumatological, kidney, autoimmune, CNS, inflammatory, liver, cancer, and ophthalmological diseases.
Coverage is centered on a formula I compound scaffold with extensive X/Y substituent and ring-formation constraint logic, including dependent narrowing to formula VIII and formula XVII variants, specified Z2 and Q3 selections, and quantified index ranges. Additional claim coverage includes treating disease by administering a therapeutically effective amount of the claimed compound.
Stated Advantages
Inhibits or affects caspase-1, caspase-4, and/or caspase-5.
Applicable to prevention and/or treatment of diseases with inflammatory and apoptotic components.
Documented Applications
Prevention and/or treatment of diseases with inflammatory and apoptotic components by modulating caspase-1/4/5.
Therapeutic targeting of inflammatory diseases, autoimmune diseases, infectious diseases, degenerative diseases, cancer, gastrointestinal, respiratory, cardiovascular, dermatological, rheumatological, kidney, CNS, liver, and ophthalmological diseases.
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