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-8129427-B2
Publication Date
2012-03-06
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
The invention provides compounds of formula I in which J is hydrogen and W is a group A-[(CH2)n—O]r—, wherein n is zero, 1 or 2 and r is zero or 1. A is defined as (C1-C4)alkyl, trifluoromethyl, cyclopropyl, cyclopentyl, phenyl optionally substituted with selected groups, thienyl optionally substituted with chloro, furanyl, isoxazolyl optionally substituted with methyl groups, piperidinyl, morpholinyl, pyridinyl or pyrimidinyl with optional methoxy substitution, and R is hydrogen or fluoro.
The structural definitions further specify R0, R1, R2, R3 and R4, including R4 as hydrogen or (C1-C4)alkyl optionally substituted with selected groups, or heterocyclyl selected from isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and 1,3,4 thiadiazolyl, optionally substituted with a (C1-C2)alkyl group. The invention also includes the option that R3 and R4 together with the adjacent nitrogen atom form a pyrrolidine ring.
The compounds are described as 2-phenylethylamino carboxamide derivatives and as substituted amide and carbamate compounds built on a fluorinated benzyloxy/methoxy phenethyl scaffold. The disclosure includes single optical isomers or mixtures thereof and pharmaceutically acceptable salts, including hydrochloride forms.
Claims Coverage
The consolidated claim coverage identifies multiple inventive features across the independent claims, centered on a formula I chemical genus with extensive substituent definitions and a proviso restricting r for certain A groups.
Formula I compounds with defined substituents
A compound of formula I wherein J is hydrogen and W is a group A-[(CH2)n—O]r—, with n zero, 1 or 2 and r zero or 1; A, R, R0, R1, R2, R3 and R4 are defined by extensive substituent options, including the possibility that R3 and R4 together with the adjacent nitrogen atom form a pyrrolidine ring.
Proviso limiting r for selected A groups
When A is (C1-C4)alkyl, trifluoromethyl, cyclopropyl or cyclopentyl, then r is 1; the claim coverage also includes the compound as a single optical isomer or mixtures thereof, and pharmaceutically acceptable salts.
Pharmaceutical composition with a second active agent
A pharmaceutical composition further comprising a second active agent.
Hydrochloric acid salt form
A pharmaceutically acceptable hydrochloric acid salt form for the claimed compound.
Independent claim coverage is directed to Formula I compounds with broad substituent definitions and stereochemical and salt coverage, together with a proviso that constrains r for certain A groups. The claim set also covers pharmaceutical compositions that include a second active agent and hydrochloride salt forms.
Stated Advantages
Compounds are substantially free of, or significantly reduced in, monoamine oxidase inhibitory activity to reduce side effects.
Documented Applications
Voltage-dependent sodium channel and/or calcium channel modulation for therapeutic use, with broad therapeutic indications stated across neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urogenital, and gastrointestinal areas.
Pharmacology testing and in vivo models described include patch clamp/fluorescence assays and in vivo evaluations such as anti-nociceptive and anticonvulsant models, maximal electroshock test, and other CNS behavioral and disease-model style tests listed in the document summary.
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