Caspase inhibitors and methods of use thereof
Inventors
Spada, Alfred P. • Temansky, Robert J. • Mueller, Michael
Assignees
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Publication Number
US-12071412-B2
Publication Date
2024-08-27
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 caspase inhibitor compounds and caspase-modulating agents that target inflammatory caspases, including caspase-1 (ICE), caspase-4, and caspase-5. The disclosed compounds include Formula I compounds and further formulae II–VII, and selected stereochemically defined oxalamide and amide-like compounds with a (2,6-difluorophenyl)amino oxalamide core and a (2,3,5,6-tetrafluorophenoxy) group in the named structures. The disclosure includes multiple stereochemically defined embodiments within the scope of the formulae and named compound structures.
The variable definitions further include enantiomers, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, and polymorph forms of the defined agents. The disclosed chemical scope is controlled by substituent selection rules and linkage constraints expressed through the variable definitions, including X/Y linkages, substituents R1–R10, Z1–Z2, and Q3/Q5, together with ring-A formation and halo/substitution limits. The compound set includes variants with benzyloxy, hydroxy, methoxy, and other aryl and heteroaryl amino substituents, as explicitly recited.
The disclosure further includes pharmaceutical compositions comprising the compounds and therapeutic methods for treatment and prevention. The therapeutic methods are directed to diseases modulated by caspase-1, caspase-4 and/or caspase-5, including inflammatory diseases, autoimmune diseases, infectious diseases, degenerative diseases including CNS disorders, cancers with an inflammatory basis, and other listed disease categories. The document also references pharmaceutical composition, drug-dosage, regimen, and routes of administration concepts, together with administration in therapeutically effective amounts.
Claims Coverage
The consolidated claim coverage includes independent coverage for selected stereochemically defined compounds, with inventive features centered on a shared oxalamide/amide-like or caspase-inhibitor core plus defined stereochemical substituent patterns. Dependent coverage adds pharmaceutical composition context and therapeutic use with specified disease categories.
Selected stereochemically defined caspase inhibitor compounds
A compound selected from a set of stereochemically defined structures, including oxalamide/amide-like embodiments and related Formula I to VII embodiments, with defined substituent patterns and stereochemical linkages.
(2,6-Difluorophenyl)amino oxalamide core with defined stereochemistry
Selected compounds include an N2-(2,6-difluorophenyl)oxalamide element and corresponding oxalamide members together with the stereochemically specified backbone atoms as written in the listed structures.
(2,3,5,6-Tetrafluorophenoxy) substituted side-chain
Selected compounds include a (2,3,5,6-tetrafluorophenoxy) group incorporated into the named side-chain frameworks as written in the recited scaffolds.
Enumerated substituent variants on the phenoxy-linked and amino-linked portions
Selected compounds further include benzyloxy, hydroxy, methoxy, and other named aryl and heteroaryl amino substituents, as recited in the listed compounds and variable definitions.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the selected compound and a pharmaceutically acceptable carrier.
Disease treatment with therapeutically effective amount for enumerated categories
A method of treating a disease by administering a therapeutically effective amount of the compound, where the disease is selected from the enumerated categories including gastrointestinal, respiratory, cardiovascular, dermatological, rheumatological, kidney, autoimmune, CNS, inflammatory, liver, cancer, and ophthalmological diseases.
Overall claim coverage is for a defined family of specific stereochemically specified compounds with shared oxalamide/amide-like or caspase-inhibitor features and enumerated substituent variants, with dependent claims to pharmaceutical composition and therapeutic administration for listed disease categories.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment or prevention of diseases modulated by caspase-1, caspase-4 and/or caspase-5, including inflammatory diseases, autoimmune diseases, infectious diseases, degenerative diseases including CNS disorders, and cancers with an inflammatory basis.
Use of the Formula I compounds for treating diseases associated with modulation of caspase-1/4/5, including CAPS, FMF, SJIA, HIDS, TRAPS, ulcerative colitis, NASH, NAFLD, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, among other listed disease categories.
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