Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
Inventors
Melloni, Piero • Restivo, Alessandra • Izzo, Emanuela • Francisconi, Simona • Colombo, Elena • Sabido-David, Cibele
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9474739-B2
Publication Date
2016-10-25
Expiration Date
Abstract
Substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives of formula (I)whereinX, Y, Z, R, R1, R2, R3, R′3 R4, R5, R6, R7 have the meanings defined in the specification and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as active ingredient and their use as sodium and/or calcium channel modulators useful in preventing, alleviating and curing a wide range of pathologies, including, but not limited to, neurological, cognitive, psychiatric, inflammatory, urogenital and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.
Core Innovation
The invention relates to substituted 2-[2-(phenyl)ethylamino]alkaneamide compounds of formula (I) and phenylethylamino derivatives of formula I that act as voltage-dependent sodium and/or calcium channel blockers. The compounds are described as substantially free of MAO inhibitory activity or significantly reduced MAO inhibitory activity, with the aim of avoiding MAO-related adverse effects. The stated pharmacology basis includes use- and frequency-dependent sodium channel block and inactivated-state affinity for sodium channel interactions.
The disclosed formula (I) defines structural variables including X as —O—, Y as hydrogen, —OH, or —O(C1-C4)alkyl, and Z as 〜O or 〜S. The substituent definitions cover R as —(C3-C10)alkyl or ω-trifluoro(C3-C10)alkyl, and aryl substituents R1 and R2 such as hydrogen, hydroxy, (C1-C8)alkoxy, (C1-C8)alkylthio, halo, trifluoromethyl, or 2,2,2-trifluoroethyl, together with additional constraints describing the relationship between R1 and R2 on the phenyl ring.
The patent further characterizes pharmacological rationale in terms of low micromolar potency, including voltage-dependent sodium and/or calcium channel blocking profiles versus ralfinamide and safinamide. Pharmacological evaluation includes patch clamp electrophysiology and fluorescence-based sodium influx assays, as well as assays measuring TTXs sodium influx, TTXr sodium influx, and calcium influx in AtT20 cells. The disclosure also provides representative example compound identification, including NW-3509, within the broader formula I scope.
Claims Coverage
The claim coverage centers on administering an effective amount of a formula (I) compound to modulate voltage gated sodium and/or calcium channels for treating a gastrointestinal disorder. The merged independent-claim features include the defined compound formula and the channel-modulating use, with dependent claims refining the gastrointestinal indication, channel-specific dysfunction, MAO-inhibitory activity constraints, and combination administration.
Administration of a formula (I) compound to modulate voltage gated sodium and/or calcium channels
Administering to a patient in need thereof an effective amount of a compound of formula (I), wherein X is —O—; Y is hydrogen, —OH or —O(C1-C4)alkyl; Z is 〜O or 〜S; R is —(C3-C10)alkyl or ω-trifluoro(C3-C10)alkyl; and R1 and R2 are defined substituents, including pharmaceutically acceptable salts and isolated optical isomers or mixtures and their pharmaceutically acceptable salts.
Gastrointestinal disorder indication for the channel modulation method
Wherein a disease treatable by such modulation is a gastrointestinal disorder.
Channel-dysfunction caused gastrointestinal disorder
Practicing the method wherein the gastrointestinal disorder is caused by a malfunction of a voltage-gated sodium channel or caused by dysfunction of a voltage-gated calcium channel.
Gastrointestinal disorder treated as selected disease/condition set
Treating a gastrointestinal disorder selected from a specified group of gastrointestinal diseases and conditions, including disorders caused by Helicobacter pylori, and symptoms such as emesis, diarrhoea, and visceral inflammation.
Zero or reduced MAO-inhibitory activity constraint
Administering an effective amount of a compound to a patient that either shows no MAO-inhibitory activity or reduced MAO-inhibitory activity.
Combination administration with at least one other therapeutic agent
Administering the compound together with at least one other therapeutic agent.
Overall, the claims cover administration of formula (I) substituted 2-[2-(phenyl)ethylamino]alkaneamide compounds to modulate voltage-gated sodium and/or calcium channels for treating gastrointestinal disorders, with dependent claims narrowing the disorder set, identifying sodium- or calcium-channel dysfunction, and adding MAO-inhibitory activity and combination-therapy features.
Stated Advantages
Compounds are substantially free of MAO inhibitory activity or have significantly reduced MAO inhibitory activity.
Avoidance of MAO-related adverse effects.
Prevention, alleviation, and curing of neurological, cognitive, psychiatric, inflammatory, urogenital, and gastrointestinal pathologies.
Low micromolar potency as voltage-dependent sodium and/or calcium channel blockers.
Use- and frequency-dependent sodium channel block and inactivated-state affinity.
MAO-B inhibition is stated as lacking relevant inhibition.
Documented Applications
Treating a gastrointestinal disorder using modulation of voltage-gated sodium and/or calcium channels.
Treating gastrointestinal disorders that include dysfunction of a voltage-gated sodium channel.
Treating gastrointestinal disorders that include dysfunction of a voltage-gated calcium channel.
Treating a gastrointestinal disorder selected from a specified group of GI diseases and conditions, including disorders associated with Helicobacter pylori and symptoms such as emesis, diarrhoea, and visceral inflammation.
Modulating voltage gated sodium and/or calcium channels to treat a gastrointestinal disorder.
Interested in licensing this patent?