Acrylamide derivatives
Inventors
Miller, Neil • Rutter, Richard • KULAGOWSKI, Jan • MORPHY, Richard • Ladduwahetty, Tammy • MacLean, John • Talbot, Eric
Assignees
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Publication Number
US-12497359-B2
Publication Date
2025-12-16
Expiration Date
Abstract
The invention relates to compounds of formula (I) and related aspects.
Core Innovation
The invention relates to compounds of formula (I) defined by substituent variables R1a, R1b, groups A, B and X, and additional substituents R4, R4a, R4b, R4c, R5, each R6, R7, each R8, each R9, R10, n, o, p and q. The compounds comprise an acrylamide scaffold with group A being group (Ab), (Ac) or (Ad), and the scope includes pharmaceutically acceptable salts and/or solvates, including isomers, tautomeric forms and isotopic forms. The formula (I) is expressly defined to exclude (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.
The described scaffold is centered on an (E)-acrylamide linkage bearing indazole-6-yl substitution and related indazolyl acrylamide derivatives. Group (Ab) includes optionally substituted aryl, group (Ac) includes R7 selected from alkyl, alkylene(OH), or alkyleneOC1-4alkyl, and group (Ad) includes X selected from a bond, O or CH2 with further allowed substituent patterns. The disclosed derivatives include fluorinated acrylamide intermediates and stereochemical variants consistent with the formula (I) definition.
The document states that compounds of formula (I) inhibit mitochondrial permeability transition pore (mPTP), and use them for treatment and/or prophylaxis of neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease and ALS, ischemia/reperfusion injury, metabolic, inflammatory and renal diseases, mitochondrial diseases, TDP-43 proteinopathy, and fibrosis. Pharmaceutical compositions are also described, with administration routes including oral, intrathecal and intranasal administration. The stated intent is mPTP inhibitory activity with improved solubility and intrinsic clearance.
Claims Coverage
The independent claim set centers on a broad chemical genus of formula (I) with extensive substitution constraints, an explicit exclusion of one named compound, and coverage of pharmaceutically acceptable salts and/or solvates. Two inventive features are present across the independent claims: the defined compound genus and a therapeutic method tied to mPTP inhibition.
Compound of formula (I) with defined substituents
A compound of formula (I) wherein R1a is H or methyl; R1b is H or fluoro; A is group (Ab), (Ac) or (Ad) with group-specific definitions for R4, R4a, R4b, R4c, R5, each R6, n, R7, o, X, each R8, R8a, R8b, R8c, each R9, p and q; wherein B is defined and wherein D, E and F are each independently C(R10) or one is N with the remaining two being independently C(R10); and wherein the compound is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide, or a pharmaceutically acceptable salt and/or solvate thereof.
mPTP inhibition for preventing or treating disease
A method for preventing or treating a disease or disorder by inhibiting the mitochondria permeability transition pore (mPTP) through administering an effective amount of a specified compound, including its pharmaceutically acceptable salt and/or solvate, to a subject in need.
Overall, the claims cover a substitution-defined acrylamide compound class of formula (I) with an explicit exclusion and salt/solvate coverage, together with a therapeutic method using the compounds to inhibit mPTP.
Stated Advantages
Inhibition of mitochondrial permeability transition pore (mPTP).
Improved solubility.
Improved intrinsic clearance.
Documented Applications
Treatment and/or prophylaxis of neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease and ALS via mPTP inhibition.
Treatment and/or prophylaxis of ischemia/reperfusion injury via mPTP inhibition.
Treatment and/or prophylaxis of metabolic, inflammatory and renal diseases via mPTP inhibition.
Treatment and/or prophylaxis of mitochondrial diseases via mPTP inhibition.
Treatment and/or prophylaxis of TDP-43 proteinopathy via mPTP inhibition.
Treatment and/or prophylaxis of fibrosis via mPTP inhibition.
Pharmaceutical compositions containing the compounds, with administration routes including oral, intrathecal and intranasal administration.
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