Compounds
Inventors
Miller, Neil • Rutter, Richard • KULAGOWSKI, Jan • MORPHY, Richard • Ladduwahetty, Tammy • MacLean, John • MOROGLU, Mustafa • Talbot, Eric • Rowley, Michael
Assignees
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Publication Number
US-12630516-B2
Publication Date
2026-05-19
Expiration Date
Abstract
The invention relates to compounds of formula (I): and related aspects.
Core Innovation
The invention relates to compounds of formula (I) and pharmaceutically acceptable salt and/or solvate forms thereof. The compounds are defined by multiple structural groups, including R1a and R1b substituents, group A selected from (Aa), (Ab), (Ac) or (Ad), and group B selected from (Ba), (Bb) or (Bc), together with parameterized ring and connectivity variables such as m, n, p, q, r and s.
The definitions include extensive options for aryl, cycloalkyl, heterocycloalkyl, alkyl, alkoxy, haloalkyl, halo, CN, OH, NR2aR2b, SO2R2c and NHSO2R2c substituents, and further constraints on R3, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, R15 and R16. For group B, Y is selected from C(R11)(R12), N(R13), O or S, and D, E and F are each independently C(R16) or one of D, E and F is N.
The disclosure also describes specific (E)-acrylamide derivatives corresponding to the compound class, including indazole, indolinone, indane and benzo[d]imidazole-substituted compounds. It identifies mPTP inhibitory compounds for therapeutic and prophylactic use in degenerative, neurodegenerative and mitochondrial diseases, and references mPTP biology associated with Ca2+ loading, oxidative stress, mitochondrial membrane potential, apoptosis and necrosis, together with cyclophilin D (CypD, Ppif).
Claims Coverage
The claim coverage centers on a broad class of compounds of formula (I) with extensive structural variability across groups A and B, together with pharmaceutically acceptable salt and/or solvate forms. Across the items, the inventive coverage is defined by multiple parameterized substituent sets and ring/connectivity variables, and includes therapeutic use claims.
Formula (I) compounds with defined substituent sets
A compound of formula (I) in which R1a is H or methyl and R1b is H or F, with A selected from group (Aa), (Ab), (Ac) or (Ad) and B selected from group (Ba), (Bb) or (Bc), including the defined substituent and parameter options together with pharmaceutically acceptable salt and/or solvate forms.
Substituent-bearing group A
Group A is defined by selectable substituent patterns and ring/connector options, including aryl, cycloalkyl, heterocycloalkyl, alkyl, alkoxy, haloalkyl, halo, CN, OH, NR2aR2b, SO2R2c and NHSO2R2c substituents.
Substituent-bearing group B
Group B is defined by Y selected from C(R11)(R12), N(R13), O or S, with further constraints on R10, R11, R12, R13, R14, R15, R16 and D, E and F.
Specific (E)-acrylamide structures
A compound comprising one of the listed (E)-acrylamide structures, including pharmaceutically acceptable salt and/or solvate forms and the listed racemic or stereochemically specified variants.
Therapeutic treatment by administering an effective amount
A method of treating one of the listed diseases wherein a subject suffering from the disease is administered an effective amount of a compound as defined, including pharmaceutically acceptable salt and/or solvate forms.
The claim coverage is directed to a large structural genus of formula (I) compounds with tightly specified but highly variable substituent definitions across groups A and B, plus explicit coverage of pharmaceutically acceptable salts and/or solvates. The items also indicate dependent claim refinement of specific (E)-acrylamide examples and therapeutic use concepts.
Stated Advantages
Therapeutic and prophylactic use for degenerative, neurodegenerative and mitochondrial diseases is stated.
An mPTP inhibitory rationale is described in relation to Ca2+ loading, oxidative stress, mitochondrial membrane potential, apoptosis and necrosis through cyclophilin D (CypD, Ppif).
An improved profile is described as including low CYP2D6 inhibition and suitable oral properties.
Documented Applications
Degenerative/neurodegenerative and mitochondrial diseases, including TDP-43 proteinopathy, fibrosis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, chronic kidney disease, non-alcoholic steatohepatitis, ischemia-reperfusion injury, Duchenne/congenital muscular dystrophy, dementia with Lewy bodies and obesity.
Treatment of diseases by administering an effective amount of a compound, including its pharmaceutically acceptable salt and/or solvate, to a subject with the disease.
Oral properties and CYP2D6-related drug-drug interaction context, including reference to fasted state simulated intestinal fluid (FaSSIF).
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