2-phenylethylamino derivatives as calcium and/or sodium channel modulators
Inventors
Thaler, Florian • Napoletano, Mauro • Sabido-David, Cibele • Moriggi, Ermanno • Caccia, Carla • Faravelli, Laura • Restivo, Alessandra • Salvati, Patricia
Assignees
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Publication Number
US-8470877-B2
Publication Date
2013-06-25
Expiration Date
Abstract
2-Phenylethylamino substituted carboxamide derivatives and their use as sodium and/or calcium channel modulators useful in preventing, alleviating and curing a wide range of pathologies are presented.
Core Innovation
Phenylethylamino substituted carboxamide derivatives of formula I are described as calcium and/or sodium channel modulators. The disclosed structural definitions include groups (a) and (b) with variable substituent definitions for J, W, A, R, R0, R1-R4, and the compounds may be used as a single optical isomer or mixtures thereof, and as pharmaceutically acceptable salts.
The document applies the formula I compounds to treat neuropathic pain, chronic pain, acute pain disorder, headache, migraine, mania, cognitive disorder, epilepsy, bipolar disorder, and anxiety, by administering to a patient in need thereof an effective calcium and/or sodium channel modulating amount of the compound. The structural scope is separated into group (a) and group (b), with additional dependent narrowing to hydrochloride salts and specific group (b) embodiments.
The disclosed approach further states that the compounds modulate voltage-dependent sodium and/or calcium channels, including N-type and L-type calcium channels and voltage-gated sodium channels. The compounds are substantially free of MAO-inhibitory activity, specifically distinguishing MAO-B activity from MAO inhibition to reduce adverse effects.
Claims Coverage
The provided material contains one independent claim covering treatment of a defined set of disorders by administering an effective calcium and/or sodium channel modulating amount of a formula I compound, with two broad structural alternatives and allowance for single optical isomers and pharmaceutically acceptable salts. Dependent claims further narrow the structural scope and specify hydrochloride salt form.
Treatment of selected disorders with formula I calcium and/or sodium channel modulators
A method for the treatment of neuropathic pain, chronic pain, acute pain disorder, headache, migraine, mania, cognitive disorder, epilepsy, bipolar disorder, and anxiety by administering to a patient in need thereof an effective calcium and/or sodium channel modulating amount of a compound of formula I.
Formula I group (a) structural scope
In formula I, J is a group A-[(CH2)n—O]r in para position with respect to the ethylamino chain, where n is zero or 1 and r is 1; A is trifluoromethyl or phenyl optionally substituted with a halo group; W is (C1-C4)alkoxy; and R, R0, R1, R2, R3, and R4 are defined with the listed permissible substituents and ring-formation limitations.
Formula I group (b) structural scope
In formula I, J is hydrogen; W is a group A-[(CH2)n—O—]r— where n is zero, 1 or 2 and r is zero or 1; A is selected from the specified (C1-C4)alkyl, trifluoromethyl, cyclopropyl, cyclopentyl, phenyl, and heteroaryl options; and R, R0, R1, R2, R3, and R4 are defined with the listed permissible substituents and heterocyclyl options.
Hydrochloride salts and specific group (b) embodiments
The pharmaceutically acceptable salts are hydrochloride, and the administered compound is a compound of formula I group (b) selected from the listed embodiments, including specified single optical isomers or mixtures thereof.
The claim set centers on a treatment method for a broad disorder list by administering an effective calcium and/or sodium channel modulating amount of a formula I compound. Coverage is refined by restricting formula I to group (a) or group (b) structural definitions, and dependents further restrict pharmaceutically acceptable salts to hydrochloride and enumerate specific group (b) compound embodiments.
Stated Advantages
Compounds are substantially free of MAO-inhibitory activity, specifically distinguishing MAO-B activity from MAO inhibition to reduce adverse effects.
Documented Applications
Treatment of neuropathic pain, chronic pain, acute pain disorder, headache, migraine, mania, cognitive disorder, epilepsy, bipolar disorder, and anxiety.
In vivo efficacy in models for pain and neuropathy, anticonvulsant effects, anti-mania, anti-schizophrenia, addiction-related activity, migraine, and urological disease models.
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