WO2024050389A1 - Polythérapies comprenant des activateurs des canaux métalliques et des antagonistes des récepteurs nmda - Google Patents

Polythérapies comprenant des activateurs des canaux métalliques et des antagonistes des récepteurs nmda Download PDF

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WO2024050389A1
WO2024050389A1 PCT/US2023/073125 US2023073125W WO2024050389A1 WO 2024050389 A1 WO2024050389 A1 WO 2024050389A1 US 2023073125 W US2023073125 W US 2023073125W WO 2024050389 A1 WO2024050389 A1 WO 2024050389A1
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alk
cycloalk
phenyl
methyl
amino
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PCT/US2023/073125
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Vladimir Coric
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Biohaven Therapeutics Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to combination therapies for treatment of various medical conditions. Specifically, the present invention relates to a combination of a metal channer activator and N-methyl-D-aspartate (NMDA) receptor antagonists for treatment of neurological and neurodegenerative disorders.
  • NMDA N-methyl-D-aspartate
  • Metal channel activators are associated with a wide range of physiological functions including the regulation of the electrical properties of excitable cells. Metal channels control the follow of metal ions such as Potassium (K + ) and Sodium (Na + ) across a cell membrane. A primary function of these channels in the brain is to regulate the neuronal action potential. Several neurologic disorders are potentially due to dysregulation of metal channels. [0004] Potassium (K + ) channels, present on the plasma membranes of most cell types, are the most diverse class of all ion channels.
  • Potassium channels of the Kv7 family of voltage-gated potassium (K + ) channels are of particular therapeutic interest due to their importance in neurological conditions such as excitability disorders including Amyotrophic lateral sclerosis (ALS).
  • ALS Amyotrophic lateral sclerosis
  • Kv7 voltage-gated potassium
  • K + voltage-gated potassium
  • Metal channel activators have been reported to be useful for treatment of various neurological and neurodegenerative disorders. Thus far, only one metal channel activator, Retigabine, has been FDA approved. Retigabine is used as anticonvulsant for the treatment of epilepsy.
  • Kv7 channel activators have been proposed for the treatment of many conditions including substance abuse and mood disorders (Vigil FA, Carver CM, Shapiro MS. Pharmacological Manipulation of K v 7 Channels as a New Therapeutic Tool for Multiple Brain Disorders. Front Physiol.2020 Jun 19;11:688. doi: 10.3389/fphys.2020.00688). There remains a need, however, for new therapies utilizing Kv7.
  • One solution is combining metal channel activators with other therapeutic agents to significantly improve treatment outcomes.
  • NDMA receptor antagonists target the NDMA receptor, a receptor which allows calcium efflux in the presence of glutamate or glycine when neurons are depolarized.
  • NDMA receptor antagonists prevent calcium efflux and have been used as anesthetics. Recent research, primarily focused on Ketamine, has revealed an unexpected antidepressant effect. Lanicemine has been developed as an alternative antidepressant to Ketamine with reduced side effects but has not successfully treated depression as a single agent in randomized controlled trials. [0007] Described herein are compositions and methods for combination therapies of Kv7 openers with NMDA receptor antagonists.
  • the combination therapies have treatment capabilities greater than Kv7 openers or NMDA receptor antagonists alone, and may be particularly useful for depressive disorders. Pharmaceutical compositions combining these agents may also be useful for treatment of a pain and neurological or neurodegenerative diseases.
  • the present invention is directed to combination therapies including a metal channel activator and an NMDA receptor antagonist.
  • a pharmaceutical composition including a metal channel activator and an NMDA receptor antagonist.
  • a method of treating a depressive disorder including administering the pharmaceutical composition.
  • a method of treating a pain disorder including administering the pharmaceutical composition.
  • DETAILED DESCRIPTION [0013] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.
  • the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the present description.
  • the term “and/or” includes any and all combinations of one or more of the associated listed items.
  • the term “or” means “and/or.” Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list. [0015] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers, and/or sections, these elements, components, regions, layers, and/or sections should not be limited by these terms.
  • substituted refers to a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH 2 ), a carboxyl group (-CO 2 H), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO 2 ), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a C1 to C10 trifluoroalkyl group such as a trifluoromethyl group (-CF 3 ) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound.
  • modulator when describing compounds, describe compounds that may enact their effect through a number of mechanisms of action including but not limited to: binding to the active site of a protein, binding to a region of the protein away from the active site, causing relocalization of a protein, inducing degradation of a protein, inducing stabilization of a protein, causing a conformational change in a protein, decreasing the activation threshold for a protein, increasing the activation threshold for a protein, altering posttranslational modifications for a protein, reducing the transcription of a gene, increasing the transcription of a gene, reducing the translation of an mRNA transcript, increasing the translation of an mRNA transcript, disrupting an interaction between two proteins, and stabilizing an interaction between two proteins; wherein the protein may be the target of modulation or an intermediary protein which is associated with modulation
  • Modulators of the targets described herein may each or both be small molecule compounds, proteins, antibody fragments or antibodies, or any other construct effecting modulation. It should be appreciated that an NMDA receptor antagonist is a type of modulator of the NMDA receptor. [0023] As used herein, “NMDA receptor antagonist” or alternatively “NMDA modulator” means any compound (small molecule, peptide, etc.) effecting modulation or desired change in biological activity of the NMDA receptor.
  • NMDA receptor antagonists may target particular portions of an NMDA receptor, such as GluN1 (alternatively NR1) or GluN2 (alternatively NR2) subunits, or additionally or alternatively GluN3 subunits.
  • NMDA receptor antagonist target GluN1 subunits, in some cases selectively.
  • NMDA receptor antagonists target one or more GluN2 subtypes GluN2A, GluN2B, GluN2C, and/or GluN2D, in some cases selectively.
  • NMDA receptor antagonists may target one or more GluN3 subtypes GluN3A, GluN3B, and/or GluN3C, in some cases selectively. In some embodiments, NMDA receptor antagonists may target an allosteric site. In some embodiments, NMDA receptor antagonists may include partial agonists which exert dual (agonist/antagonist) effects on NMDA receptors. In certain embodiments, NMDA receptor antagonists may include agents which have a target other than the NMDA receptor which result in an NMDA receptor antagonist-like physiologic effect. [0024] As used herein, “neurological disease” refers to a disease or disorder which affects the brain and/or nerves found elsewhere in the body.
  • Such neurologic diseases may include: Absence of the Septum Pellucidum, Acid Lipase Disease, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Aicardi-Goutieres Syndrome, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Anencephaly, Angelman Syndrome, Antiphospholipid Syndrome, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arteriovenous Malformation, Asperger Syndrome, Ataxia Telangiectasia, Ataxias and Cerebellar or Spinocerebellar Degeneration, Atrial Fibrillation and Stroke, Attention Deficit-Hyperactivity Disorder, Autism Spectrum Disorder, Back Pain, Barth Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Bin
  • the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof.
  • NMDA receptor antagonist or “NMDA modulator” is construed to include both NMDA receptor antagonist and pharmaceutically acceptable salt thereof.
  • AUC is the definite integral of the concentration of a drug in blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given as a function of time. AUC in this context is used to measure the total exposure to the drug across time.
  • AUC can be evaluated over a definite time interval or estimated based on the integral drug concentrations measured over a time interval extrapolated to infinite time.
  • Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given.
  • Tmax is the time taken after administration for a drug to reach its highest concentration in the blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given.
  • proteinopathies refers to diseases characterized by an accumulation or aggregation of a single protein, or multiple proteins.
  • Proteinopathies include but are not limited to: Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, Amyotrophic lateral sclerosis (ALS), Frontotemporal Lobar Degeneration, and Lewy Body Dementia.
  • ALS Amyotrophic lateral sclerosis
  • ALS Frontotemporal Lobar Degeneration
  • Lewy Body Dementia Proteinopathies include but are not limited to: Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, Amyotrophic lateral sclerosis (ALS), Frontotemporal Lobar Degeneration, and Lewy Body Dementia.
  • Kv7 channel activator may be selected from one of the following compounds according to Formula 1. Such compounds are described in US Patent No 9,481,653, issued November 1, 2016, and corresponding to US Application No.
  • the Kv7 channel activator is a compound according to formula 1: Formula 1 , wherein D is optionally substituted C 3-6 carbocyclyl, optionally substituted C 2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-1,2-diyl; A is C 1-8 alkyl; X is F; and Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl.
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl, wherein each substituent of D and Y, if present, independently has a molecular weight of 15 Da to 200 Da and consists of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
  • the Kv7 channel activator is a compound according to formula 1 wherein, D is optionally substituted C 3-6 carbocyclyl, optionally substituted C 2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-1,2-diyl; A is C 1-8 alkyl; X is H, F, CF 3 , optionally substituted phenyl, or optionally substituted pyridinyl; and Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl.
  • each substituent of D, X, and Y independently has a molecular weight of 15 Da to 200 Da and consists of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is optionally substituted pyridinyl.
  • X is H.
  • Y is H.
  • Y is OH.
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 2.
  • Such compounds are described in US Patent No.9,481,653 issued November 1, 2016 and corresponding to US Application No. US14/853,815 filed September 14, 2015; US Patent No.9,914,708, issued March 13, 2018 and corresponding to US Application No.15/339,590 filed October, 31; US patent No 10,385,025, issued August 20, 2019 and corresponding to US Application No.15/879,792 filed January 25, 2018; US Patent No.10,906,877 issued on February 2, 2021 and corresponding to US Application No.16/460,449 filed July 2, 2019; US Patent No. 10,851,067 issued on December 1, 2020 and corresponding to US Application No.
  • the Kv7 channel activator is a compound according to formula 2: Formula 2 , wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; A is C 2-8 alkyl; X is H, F, CF 3 optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; R 1 is F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 —CO 2 -alkyl, C 1-4 alkyl, —CH 2 CO 2 H, — CH 2 CO 2 CH
  • Y is H, F, CF 3 , OH, C 1-5 O-alkyl, C 0-6 alkylamino, optionally substituted tetrahydropyranyl, or C 0-6 fluoroalkylamino.
  • R 1 is Cl, Br, —OCH 3 , —CN, —CF 3 , —CH 2 OH, — COOCH 2 CH 3 , —C(CH 3 ) 2 OH, —CHOHCH 2 CH 3 , —CHOHCH 3 , —CHF 2 , —CH(CH 3 ) 2 , — C(CH 2 CH 3 ) 2 OH, —CH 2 COOCH 2 CH 3 , —CH 2 C(CH 3 ) 2 OH, —CH 2 COOH, or — CH 2 CON(CH 3 ) 2 .
  • R 2 is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH.
  • R 3 is H.
  • R 4 is H, —CH 3 , or —CF 3 .
  • R 1 is Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is optionally substituted pyridinyl.
  • X is H.
  • Y is H.
  • Y is OH.
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound according to formula 2 wherein, D is optionally substituted cyclobutyl, or t-butyl; A is C 2-8 alkyl; X is H, CF 3 , or optionally substituted phenyl; Y is H or OH; R 1 is CN or C 1-4 hydroxyalkyl; and R 2 , R 3 , and R 4 are independently H, or F. [0065] In further embodiments, R 1 is CN, —C(CH 3 ) 2 OH, or —CH 2 C(CH 3 ) 2 OH. [0066] In further embodiments, R 2 is F. [0067] In further embodiments, R 3 is H.
  • R 4 is H.
  • R 1 is CN.
  • R 1 is C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is H.
  • Y is H. [0075] In further embodiments, Y is OH.
  • the Kv7 channel activator is a compound according to formula 2 wherein, D is cyclobutyl; A is C 1-8 alkyl; X is CF 3 ; Y is H; R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl; R 2 is H, F, —CH 2 OH, — CO 2 Me, or —C(CH 3 ) 2 OH; R 3 is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R 4 is H, —CH 3 , or —CF 3 ; or D is optionally substituted cyclobutyl; A is C 1-8 alkyl; X is CF 3 ;
  • R 1 , R 2 , R 3 , and R 4 are independently H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
  • Y is H, F, CF 3 , OH, C 1-5 O-alkyl, C 0-6 alkylamino, optionally substituted tetrahydropyranyl, or C 0-6 fluoroalkylamino.
  • R 1 is H, Cl, Br, —OCH 3 , —CN, —CF 3 , —CH 2 OH, — COOCH 2 CH 3 , —C(CH 3 ) 2 OH, —CHOHCH 2 CH 3 , —CHOHCH 3 , —CHF 2 , —CH(CH 3 ) 2 , — C(CH 2 CH 3 )OH, —CH 2 COOCH 2 CH 3 , —CH 2 C(CH 3 ) 2 OH, —CH 2 COOH, or — CH 2 CON(CH 3 ) 2 .
  • R 2 is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH.
  • R 3 is H.
  • R 4 is H, —CH 3 , or —CF 3 .
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof. [0093] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0094] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0095] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0096] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0097] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is:
  • D is optionally substituted cyclobutyl, or t-butyl; A is C 2-8 alkyl, X is H, CF 3 , or optionally substituted phenyl, Y is H or OH, R 1 is CN or C 1-4 hydroxyalkyl; and R 2 , R 3 , and R 4 are independently H, or F.
  • R 1 is CN, -C(CH 3 ) 2 OH, or -CH 2 C(CH 3 ) 2 OH.
  • R 2 is F.
  • R 3 is H.
  • R 4 is H.
  • R 1 is CN.
  • R 1 is C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is H.
  • Y is H. In a further embodiment, Y is OH.
  • D is cyclobutyl;
  • A is C 1-8 alkyl, X is CF 3 , Y is H,
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, - CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH;
  • R 3 is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or B; and
  • R 4 is H, -CH 3 , or -CF 3 .
  • D is optionally substituted cyclobutyl
  • A is C 1-8 alkyl
  • X is CH 3
  • Y is H
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl
  • R 2 is H, F, -CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH
  • R 3 is H
  • R 4 is H, -CH 3 , or - CF 3 .
  • D is t-butyl;
  • A is C 1-8 alkyl;
  • X is H;
  • Y is H;
  • R 1 is Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, -CH 2 OH, - CO 2 Me, or -C(CH 3 ) 2 OH;
  • R 3 is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and
  • R 4 is H, -CH 3 , or -CF 3 .
  • D is t-butyl;
  • A is C 1-8 alkyl;
  • X is CF 3 ;
  • Y is H;
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, - CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH;
  • R 3 is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and
  • R 4 is H, CH 3 , or CF 3 .
  • D is cyclobutyl; A is C 1-8 alkyl; X is H; Y is methyl(2,2,2-trifluoroethyl)amino; R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl; R 2 is H, F, -CH 2 OH, -CO 2 Me, or -CH(CH 3 ) 2 OH; R 3 is H; and R 4 is H, - CH 3 , or -CF 3 .
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, or optionally substituted C 2-5 alkyl, wherein the optional substituents are selected from -CH 3 and F;
  • A is C 1 alkyl, X is substituted cyclobutyl, wherein the substituent is F;
  • Y is H;
  • R 1 is selected from H, C 3 hydroxyalkyl, CN, F, or Cl;
  • R 2 is selected from H, CN, F, Br, or -OCF 3 ;
  • R 3 is selected from H, F, or -OCH 3 ;
  • R 4 is H or F; and wherein when X is substituted with 2 fluorine atoms, the fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 3. Such compounds are described in US Patent No. 8,293,911 issued on October 23, 2012 and corresponding to US Application No.11/894,877 filed August 22, 2007; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 3, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 3: Formula 3 , wherein, R 1 and R 2 , vary independently, and are selected from the group consisting of H, CN, halogen, CH 2 CN, OH, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl; NH—C 1 - C 6 alkyl; N(C 1 -C 6 alkyl)-C 1 -C 6 alkyl, NHC( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)N(CH 3 ) 2 , C( ⁇ O)N(Et) 2 , C( ⁇ O)NH 2 , C( ⁇ O)NH—C 1 -C 6 alkyl, SO 2 NH 2 , NHSO 2 —C 1 -C 6 alkyl; C( ⁇ O)OC 1 -C 6 alkyl
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)OC 1 -C 6 alkyl, OC( ⁇ O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, and (CH 2 ) m pyridyl; wherein said cycloalkyl groups optionally contain one or two heteroatoms selected independently from the group consisting of O, N, and S; wherein said alkyl, cycloalkyl groups optionally contain one or two heteroatoms
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)OC 1 -C 6 alkyl, OC( ⁇ O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , (CH 2 ) m cyclopropyl, (CH 2 ) m cyclobutyl, (CH 2 ) m cyclopentyl, (CH 2 ) m cyclohexyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , OC 1 -C 3 alkyl, C 1 -C 6 alkyl, C( ⁇ O)OC 1 -C 3 alkyl, OC( ⁇ O)C 1 -C 3 alkyl, and C( ⁇ O)C 1 -C 3 alkyl;
  • R′ is selected from the group consisting of H, F, CH 3 , and ethyl;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl; and
  • R 5 is C 1 -C 6 alkyl, (CHR 6 ) w C 3 - C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w
  • R 2 is H or F;
  • R′ is H;
  • R 3 is selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl;
  • R 4 is selected from the group consisting of CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl;
  • R 5 is C 3 -C 6 alkyl or (CH 2 ) w C 3 -C 6 cycloalkyl.
  • R 1 is halogen or CF 3 ;
  • R 2 is H or F;
  • R′ is H;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , or Cl;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alken
  • R 1 is halogen or CF 3 ;
  • R 2 is H or F;
  • R′ is H;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , or Cl;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alken
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 4. Such compounds are described in US Patent No.8,293,911 issued on October 23, 2012 and corresponding to US Application No. 11/894,877; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 4, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 4: Formula 4 , wherein, R 1 is selected from the group consisting of H, halogen, CN, CH 2 CN, CF 3 , C 1 - C 6 alkyl, OCH 3 , (C ⁇ O)OCH 3 , O(C ⁇ O)CH 3 , OCF 3 , (CH 2 ) m C 3 -C 6 cycloalkyl, phenyl, and pyridyl; R 2 is selected from the group consisting of H, F, OCH 3 , CH 3 , and CF 3 ; R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl; and R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cyclo
  • R 1 is selected from the group consisting of H, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , and OCH 2 CH 3 ;
  • R′ is selected from the group consisting of H, CH 3 , CH 2 CH 3 , or halogen;
  • R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OCH 3 , and CH 3 ;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 C 3 -C 6 cycloalkyl, CH 2 CH 2 C 3 - C 6 cycloalkyl, CH ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CH—C 5 -C 6 cycloalkenyl, CH 2 C 5 - C 6 cycloalkenyl, CH 2 C 5
  • R 1 is selected from the group consisting of H, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , and OCH 2 CH 3 ;
  • R′ is selected from the group consisting of H, CH 3 , CH 2 CH 3 , or halogen;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OCH 3 , and CH 3 ;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 C 3 -C 6 cycloalkyl, CH 2 CH 2 C 3 - C 6 cycloalkyl, CH ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CH—C 5 -C 6 cycloalkenyl, CH 2 C 5 - C 6 cycloalkenyl, CH 2 C 5
  • R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH 3 , CH 2 OCH 3 , CH 2 OCH 2 CH 3 , OCF 3 , phenyl, thienyl, and H;
  • R 2 is selected from the group consisting of H, F, Cl, and OCH 3 ;
  • R′ is selected from the group consisting of H, F, CH 2 CH 3 , and CH 3 ;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ;
  • R 5 is selected from the group consisting of C 4 -C 6 alkyl, (CH 2 ) w Ar, and (CH 2 ) w C 5 -C 6 cycloalkyl; wherein w is 1, 2, or 3.
  • R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , OCH 3 , CH 2 OCH 3 , and H;
  • R 2 is selected from the group consisting of H, F, CH 3 , and Cl;
  • R′ is H;
  • R 3 is selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ;
  • R 4 is selected from the group consisting of Cl, OCH 3 , and CH 3 ; and
  • R 5 is C 4 -C 6 alkyl or 2- cyclopentyl ethyl.
  • R 3 and R 4 are both CH 3 or both OCH 3 ; and R 5 is C 5 -C 6 alkyl.
  • R′ and R 2 are H; R 3 and R 4 are both methyl; and R 5 is C 5 - C 6 alkyl or (CH 2 ) w C 5 -C 6 cycloalkyl; wherein w is 1, 2, or 3.
  • the compound is selected from the group consisting of: N-(2- chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3- dimethylbutanamide; N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide; N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6- (trifluoromethyl)phenyl)-3-cyclopentylpropanamide; N-(2-chloro-4-(6-fluoro-3,4- dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethylphenyl)-3,3-dimethylbutanamide; N-[2- chloro-4-(3,4-dihydro-1H-isoquinolin-2(1H
  • the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in US Patent No.8,993,593 issued on March 31, 2015 and corresponding to US Application No.12/698,070 filed February 1, 2010; US Publication No. US20220265634A1, published August 25, 2022 and corresponding to US Application No.17/668,340 filed February 9, 2022;which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 5, these references incorporated by reference herein control. [0134]
  • the Kv7 channel activator is a compound according to formula 5: Formula 5 , optionally wherein the compound is substituted at any position.
  • the Kv7 channel activator may be the following compound (ezogabine, also known as retigabine) or a pharmaceutically acceptable salt thereof.
  • Ezogabine is a compound according to formula 6: In the case of any conflict of terminology in the context of Formula 6, these references incorporated by reference herein control.
  • Formula 6 or, optionally, wherein the compound is substituted at any position.
  • Formula 7 In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 7. Such compounds are described in US Patent No.
  • the Kv7 channel activator is a compound according to formula 7: Formula 7 , wherein, L is CH 2 ; R 1 is optionally substituted cyclic C 3 H 5 , wherein the optional substituent of R 1 is CF 3 ; R 2 is optionally substituted cyclobutyl; R 3 is optionally substituted C 3 alkyl, wherein the optional substituent of R 3 is OH; R 4 is H; and R 5 is H; or wherein, L is CH 2 ; R 1 is optionally substituted C 2 alkyl, wherein the optional substituents of R 1 are independently CF 3 or CH 3 ; R 2 is optionally substituted cyclobutyl; R 3 is optionally substituted C 3 alkyl, wherein the optional substituent of R 3 is OH; R 4 is H; and R 5 is H; or wherein, wherein L is CH 2 , CF 2 , CHCH 3 , CH 2 CH 2 , C 3 H 6 , CH 2 O, C 2 H 4
  • R 2 is optionally substituted C 4 H 9 , optionally substituted cyclobutyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heterocyclyl. [0138] In further embodiments, R 2 is optionally substituted C 4 H 9 , or optionally substituted cyclobutyl. [0139] In further embodiments, R 2 is optionally substituted phenyl, or optionally substituted C 2-9 heterocyclyl. [0140] In further embodiments, R 1 is optionally substituted phenyl. [0141] In further embodiments, R 1 is optionally substituted phenyl.
  • R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. [0143] In further embodiments, R 1 is C 2-4 —O-alkyl. [0144] In further embodiments, R 1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl. [0145] In further embodiments, R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: [0147] In further embodiments, R 3 is CF 3 , Cl, CN, OCH 3 , or H. [0148] In further embodiments, R 1 is selected from the group consisting of:
  • R 4 is CH 3 , CF 3 , Cl, or H.
  • R 2 is selected from the group consisting of:
  • the Kv7 channel activator is selected from the group consisting of:
  • the Kv7 channel activator is selected from the group consisting of: Formula 8
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 8. Such compounds are described in US Patent No. 9,650,376, published on February 4, 2014 and corresponding to US Application No. 14/776,271 filed March 17, 2014; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 8, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 8: Formula 8 , wherein, L is CH 2 , CF 2 , CHCH 3 , CH 2 CH 2 , C 3 H 6 , CH 2 O, C 2 H 4 O, or C 3 H 6 O with the O of CH 2 O, C 2 H 4 O, or C 3 H 6 O bonded with R 1 ; wherein R 1 is optionally substituted C 1-2 alkyl, optionally substituted C 5-10 cycloalkyl, optionally substituted C 1-12 —O-alkyl, optionally substituted C 6-10 aryl, optionally substituted C 6-10 —O-aryl, or optionally substituted C 2- 9 heterocyclyl, wherein the optional substituents of R 1 are independently R A , F, Cl, CN, OR A , CF 3 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B ,
  • R 2 is optionally substituted C 4 H 9 , optionally substituted cyclobutyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heterocyclyl. [0155] In further embodiments, R 2 is optionally substituted C 4 H 9 , or optionally substituted cyclobutyl. [0156] In further embodiments, R 2 is optionally substituted phenyl, or optionally substituted C 2-9 heterocyclyl. [0157] In further embodiments, R 1 is optionally substituted phenyl. [0158] In further embodiments, R 1 is optionally substituted phenyl.
  • R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.
  • R 1 is C 2-4 —O-alkyl.
  • R 1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl.
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: [0164] In further embodiments, R 3 is CF 3 , Cl, CN, OCH 3 , or H. [0165] In further embodiments, R 1 is selected from the group consisting of:
  • R 4 is CH 3 , CF 3 , Cl, or H.
  • R 2 is selected from the group consisting of: Formula 9
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 9. Such compounds are described in International Publication No. WO2021023616A1, published February 11, 2021 and corresponding to International Application No. PCT/EP2020/071514 filed July 30, 2020; International Publication No. WO2019161877A1, published August 29, 2019 and corresponding to International Application No. PCT/EP2018/054057 filed February 20, 2018; US Publication No.
  • the Kv7 channel activator is a compound according to formula 9: Formula 9 wherein, R1 is selected from the group consisting of C 1 -C 6 alkyl, CF 3 , CH 2 CF 3 , CF 2 CHF 2 , C 3 -C 8 cycloalkyl, wherein said C 3 -C 8 cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of C 1 -C 3 alkyl, F, CHF 2 and CF 3 ; and R2 is H, C 1 -C 6 alkyl or CF 3 ; or R1 and R2 combine to form C 3 -C 5 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 ; and R3 is C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl, said C 1 -C 3 alkyl or CH 2 O—C 1 -C 3 is alkyl substituted with C ⁇ N, 3
  • R3 is selected from the group consisting of CH 2 —O—CF 3 , CH 2 —O— cyclopropyl, CH 2 —C ⁇ N.
  • R1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 C 1 - C 3 alkyl, F, CHF 2 or CF 3 .
  • R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF 3 or OCHF 2 .
  • the Kv7 channel activator is selected from the group consisting of: (S)—N—((R)-2-cyclopropoxy-1-(3-(difluoromethoxy) phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2- (trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3- (trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((S)—N—((S)
  • the Kv7 channel activator is selected from the group consisting of (R)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4- dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) pentanamide; (R)-3-hydroxy-4,4- dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy) phenyl)ethyl)pentanamide; (R)—N—((R)-2-(difluorometh
  • the Kv7 channel activator is a compound according to formula 8 wherein R 1 is selected from the group consisting of C 1 -C 6 alkyl, CF 3 , CH 2 CF 3 , CF 2 CHF 2 , C 3 -C 8 cycloalkyl, wherein said C 3 -C 8 cycloalkyl may be substituted with 1 or 2 F, CHF 2 or CF 3 , and R 2 is H, C 1 -C 6 alkyl or CF 3 ; or R 1 and R 2 combine to form C 3 -C 5 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 ; R 3 is C1-C3 alkyl or CH 2 O—C1-3 alkyl, said C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl may optionally be substituted with 1 or 2 F; and R 4 is selected from the group consisting of OCF 3 , OCH 2 CF 3 or OCHF
  • R 4 is OCF 3 or OCHF 2 .
  • R 2 is H or CH 3 .
  • R 3 is CH 2 O—C 1-3 alkyl.
  • R 1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 .
  • R 1 is t-butyl and R 2 is H and R 4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .
  • R 1 and R 2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R 4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .
  • the Kv7 channel activator is selected from the group consisting of: (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3- (2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3- (2,2,2- trifluoroethoxy)phen
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 10.
  • Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, published July 15, 2004 and corresponding to International Application No. PCT/DK2003/000906 filed December 18, 2003; US patent No.7,368,472 issued May 6, 2008 and corresponding to US Application No.10/540,075 filed December 18, 2003; US Publication No.
  • the Kv7 channel activator is a compound according to formula 10: wherein R 1 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl and hydroxy-C 3-8 -Cycloalk(en)yl; R 2 and R 2′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1-6 - alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C
  • the Kv7 channel activator is selected from the group consisting of: ⁇ 2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phenyl ⁇ - carbamic acid ethyl ester; ⁇ 2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl ⁇ - carbamic acid ethyl ester; ⁇ 2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-methyl-amino]- phenyl ⁇ -carbamic acid ethyl ester; ⁇ 2-Amino-4-[(5-bromo-thiophen-2-ylmethyl)-amino]- phenyl ⁇ -carbamic acid ethyl ester; ⁇ 2-Amino-4-[(6-chloro-3-methoxy-benzo[b]thiophen-2- yl
  • the Kv7 channel activator is a compound according to the formula: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is selected from the group consisting of: 2-Cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide; N-(2,6- Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide; N-(4,6-Dimethyl-2- morpholin-4-yl-pyrimidin-5-yl)-2-(4-fluoro-phenyl)-acetamide; Hexanoic acid (2,6-difluoro- 4-morpholin-4-yl-phenyl)-amide; 2-Cyclopentyl-N-(4,6-dimethyl-2-morpholin-4-yl- pyrimidin-5-yl)-acetamide; N-(2-Bromo-4-
  • the Kv7 channel activator is a compound according to formula 10 wherein: R 1 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; R 2 and R 2′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1-6 - alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6
  • R 1 is selected from the group consisting of hydrogen and C 1- 6 -alk(en/yn)yl.
  • at least one of the substituents R 2 and R 2′ is a hydrogen atom.
  • both R 2 and R 2′ are hydrogen atoms.
  • X is CO.
  • q is 0.
  • q is 1 and Z is an oxygen atom.
  • R 3 is selected from the group consisting of C 1-6 -alk(en/yn)yl and aryl-C 1-6 -alk(en/yn)yl.
  • R 3 is C 1-6 -alk(en/yn)yl. [0198] In further embodiments, R 3 is aryl-C 1-6 -alk(en/yn)yl. [0199] In further embodiments, W is a sulfur atom.
  • Y is of formula: , wherein: W is S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R 5 is independently selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, —CO—NR 6 R 6′ , cyano, nitro, —NR 7 R 7′ , —S—R 8 , —SO 2 R 8 , and SO 2 OR 8 , wherein: R 6 and R 6′
  • Y is of formula: , wherein: W is S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R 5 is independently selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, —CO—NR 6 R 6′ , cyano, nitro, —NR 7 R 7′ , —S—R 8 , —SO 2 R 8 , and SO 2 OR 8 , wherein: R 6 and R 6′
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 11.
  • Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, published July 15, 2004 and corresponding to International Application No. PCT/DK2003/000906 filed December 18, 2003; US patent No. 7,368,472 issued May 6, 2008 and corresponding to US Application No.10/540,075 filed December 18, 2003; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No.12/671,505 filed July 31, 2008; International Publication No.
  • the Kv7 channel activator is a compound according to formula 11: Formula 11 wherein: s is 0 or 1; U is O, S, SO 2 , SO 2 NR 11 , CO—O or CONR 11 ; wherein: R 11 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, and C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R 2 and R 11 together with the nitrogen atom to which R 11 is attached form a 5-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; q is 0 or 1; X is CO or SO 2 ; with the proviso when X is SO 2 , then q is 0; Z is O or S; R 1 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn
  • the Kv7 channel activator is selected from the group consisting of: ⁇ 4-[(Benzofuran-2-ylmethyl)-amino]-2-methylphenyl ⁇ -carbamic acid propyl ester; ⁇ 4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl ⁇ -carbamic acid ethyl ester; ⁇ 4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl ⁇ -carbamic acid ethyl ester; ⁇ 2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl ⁇ -carbamic acid ethyl ester; [4- (4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester; [4-(4-Fluoro-
  • the Kv7 channel activator is a compound according to formula 11, wherein: s is 0 or 1; U is O, S, SO 2 , SONR 11 , or CONR 11 ; wherein: R 11 is hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, or C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R 2 and R 11 taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms; q is 0 or 1; X is CO or SO 2 ; with the proviso that q is 0 when X is SO 2 ; Z is O or S; R 1 is hydrogen, C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cyclo
  • R 1 is C 1-6 -alk(en/yn)yl or a hydrogen atom.
  • s is 0.
  • s is 1.
  • U is an oxygen atom.
  • R 2 is hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -alk(en/yn)yl or cyano; with the provisos that when R 2 is halogen or cyano, then s is 0; and when s is 1 and R 2 is a hydrogen atom, then U is O or S.
  • Z is an oxygen atom.
  • Z is a sulfur atom.
  • q is 0.
  • R 3 is C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, heterocycloalk (en)yl-C 1 -6 -alk(en/yn)yl, heterocycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, Ar-oxy-C 1-6 -alk (en/yn)yl, Ar—C 1-6 - alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hal
  • R 12 and R 12′ are each independently hydrogen, C 1-6 - alk(en/yn)yl or Ar.
  • V is CH.
  • each R 5 is independently C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl- heterocycloalk(en)yl, Ar, C 1-6 -alk(en/yn)yloxy, Ar-oxy, C 1-6 -alk(en/yn)yloxy-carbonyl, halogen, halo-C 1-6 -alk(en/yn)yl, NR 7 R 7′ , S—R 8 or SO 2 R 8 ; or two adjacent R 5 groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms.
  • both R 7 and R 7′ are C 1-6 -alk(en/yn)yl.
  • R 8 is C 1-6 -alk(en/yn)yl or Ar.
  • the Kv7 channel activator is selected from the group consisting of: 2-(4-Fluorophenyl)-N- ⁇ 2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]- phenyl ⁇ -acetamide; 2-(4-Fluorophenyl)-N- ⁇ 2-methyl-4-[(6-trifluoromethylpyridin-3- ylmethyl)-amino]-phenyl ⁇ -acetamide; 3,3-Dimethyl-N- ⁇ 2-methyl-4-[(6-p-tolyloxypyridin-3- ylmethyl)-amino]-phenyl ⁇ -butyramide; 3,3-Di
  • the Kv7 channel activator is a compound according to formula 11 wherein: U is O, S or NR 2′ ; s is 0 or 1; X is CO or SO 2 ; Z is O, S or NR 4 ; wherein R 4 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl and hydroxy-C 3-8 - cycloalk(en)yl; q is 0 or 1; R 1 and R 1′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6
  • R 1 and R 1 ' are independently selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl. [0224] In further embodiments, at least one of R 1 and R 1 ' is a hydrogen atom. In further embodiments, s is 1. [0225] In further embodiments, s is 0. [0226] In further embodiments, R 2 is selected from the group consisting of hydrogen, C 1-6 - alk(en/yn)yl, Ar and halogen, provided that when R is halogen, then s is 0. [0227] In further embodiments, U is NR 2 ' and at least one of R and R 2 ' is a hydrogen atom.
  • both R 2 and R 2 are hydrogen atoms.
  • X is CO.
  • q is 0.
  • q is 1.
  • Z is an oxygen atom.
  • R 3 is C 1-6 - alk(en/yn)yl.
  • each R 5 is independently selected from the group consisting of a C 1-6 -alk(en yn)yl, C 3-8 - cycloalk(en)yl, Ar, cyano, halogen, halo-C ⁇ -6 -alk(en/yn)yl and C 1- 6 - alk(an/en/yn)yloxy or two adjacent substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms.
  • the Kv7 channel activator is selected from the group consisting of: ⁇ 2-Amino-4-[(4-tert-butyl phenylamino)-methyl]-phenyl ⁇ -carbamic acid ethyl ester; (2-Amino-4-phenylaminomethyl-phenyl)-carbamic acid ethyl ester; [2-Amino-4- (aphthalene-2-ylaminomethyl)-phenyl]carbamic acid ethyl ester; [2-Amino-4-(p-tolylamino- methyl)-phenyl]carbamic acid ethyl ester; ⁇ 2-Amino-4-[(4-trifluoromethylphenylamino)- methyl]-phenyl ⁇ -carbamic acid ethyl ester; ⁇ 2-Amino-4-[(4-chlorophenylamino)-methyl]- phenyl ⁇ -carbamic acid
  • the Kv7 channel activator is a compound according to formula 11 wherein: U is O, S or C s is O or 1; X is CO or SO 2 ; Z is O, S or NR. , wherein R 4 is selected from the group consisting of hydrogen, C ⁇ -6-alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en yn)yl and hydroxy-C 3-8 - cycloalk(en)yl; q is O or 1; R 1 and R 1 ' are independently selected from the group consisting of hydrogen, C ⁇ .
  • R is selected from the group consisting of hydrogen, halogen, C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -6 -alk(en/yn)yl, Ar, Ar-C 1-6 - alk(en/yn)yl, Ar-C 3-8 -cycloalk(en)yl-
  • R 3 is selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -6 -alk(en/yn)yl, Ar, Ar-C 1-6 - alk(en/yn)yl, Ar-C 3-8 - cycloalk(en)yl, hydroxy-C ⁇ -6 -alk(en/yn)yl, hydroxy-C 3-8 - cycloalk(en)yl,
  • Y is selected from groups according to a formula selected from the group consisting of: wherein: the line represents a bond attaching the group represented by Y to the nitrogen atom; W is O or S; a is 0, 1, 2 or 3; b is O, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is O, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; and each R 5 is independently selected from the group consisting of a C 1-6 - alk(en yn)yl, C 3-8 -cycloalk(en)yl, Ar, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en yn)yl, Ar- C ⁇ -6 -alk(en/yn)y
  • R 7 and R 7 ' are independently selected from the group consisting of hydrogen, C ⁇ .
  • R 8 is selected from the group consisting of hydrogen, C 1-6 - alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -6 -alk(en/yn)yl, Ar and -NR 9 R 9 ; wherein R 9 and R 9 ' are independently selected from the group consisting of hydrogen, C 6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; with the provisos that when R 5 is SO 2 OR 8 then R 8 is not
  • the Kv7 channel activator is a compound according to formula 11 wherein: wherein U is O, S or NR 2 s is O or 1; X is CO or SO 2 ; Z is O, S or NR , wherein R is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3 -s-cycloaUc(en)yl-C ⁇ -6 -alk(en/yn)yl, hydroxy-C ⁇ -6 -alk(en/yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; q is O or 1; 11 ' R and R are independently selected from the group consisting of hydrogen, C ⁇ _ 6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl- C 1;
  • R is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -6 -alk(en yn)yl, Ar, Ar-C ⁇ -6 - alk(en yn)yl, Ar-C 3-8 -cycloalk(en)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy- C 3-8 -cycloalk(en)yl, halo-C ⁇ -6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl and cyano; provided that when R 2 is halogen or cyano then s is 0; when s is 1 and U is NR 2 then R 2' is selected from the group consisting of hydrogen, halogen or cyano then
  • R and R together form a 5-8 membered saturated or unsaturated ring which optionally contains one further heteroatom;
  • R 3 is selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en yn)yl, Ar, Ar-C 1-6 -alk(en/yn)yl, Ar-C 3 . 8 -cycloalk(en)yl, acyl, hydroxy-C ⁇ 6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl and halo-C 3- 8 - cycloalk(en)yl; or R and R together form a 5-8 membered saturated or unsaturated ring which optionally contains one further heteroatom;
  • the line represents a bond attaching the group represented by Y to the nitrogen atom;
  • W is O or S;
  • a is 0, 1, 2 or 3;
  • h is 0, 1, 2, 3 or 4;
  • c is 0 or 1;
  • d is 0, 1, 2 or 3;
  • e is 0, 1 or 2;
  • f is O, 1, 2, 3, 4 or 5; is 0, 1, 2, 3 or 4;
  • h is 0, 1, 2 or 3; and each R 5 is independently selected from the group consisting of a C ⁇ -6 - alk(en/yn)yl, C 3 .
  • R 7 and R 7 ' are independently selected from the group consisting of hydrogen, Cj.
  • R 8 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Ar and -NR 9 R 9 ; wherein R 9 and R 9 ' are independently selected from the group consisting of hydrogen, Q.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 12. Such compounds are described in International Publication No.
  • the Kv7 channel activator is a compound according to formula 12: Formula 12 wherein, the dotted line represents an optional bond; R 1 and R 1′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 - cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk
  • the compound of formula I is not: N-[1-(phenylmethyl)-1H- indol-5-yl]-Methanesulfonamide; N-[1-[(4-fluorophenyl)methyl]-1H-indol-5-yl]- Methanesulfonamide; N-[2,3-dihydro-1-(phenylmethyl)-1H-indol-5-yl]- Methanesulfonamide; N-[1-(phenylmethyl)-1H-indol-5-yl]-N′-4-quinolinyl-Urea; N-[1- (phenylmethyl)-1H-indol-5-yl]-N′-4-quinolinyl-Urea; or 1-(1-benzyl-5-indolinyl)-3-phenyl- Urea; or salts thereof.
  • R 1 or R 1′ is a hydrogen atom.
  • R 1 and R 1′ are hydrogen atoms.
  • s is 0.
  • s is 1.
  • R 2 is a hydrogen atom.
  • R 2 is NO 2 or a halogen atom.
  • U is NR 11 .
  • R 11 is a hydrogen atom.
  • X is CO.
  • X is SO 2 .
  • q is 0.
  • R 3 is selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, Ar-oxy-C 1-6 -alk(en/yn)yl, Ar—C 1-6 - alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl and —NR 12 R 12′ ; with the proviso that when R 3 is NR 12 R 12′ then q is 0.
  • R 3 is NR 12 R 12′ , q is 0 and R 12 and R 12′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, Ar and Ar—C 1-6 - alk(en/yn)yl, or R 12 and R 12′ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms.
  • each R 5 is independently selected from the group consisting of C 1-6 -alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen and halo-C 1-6 -alk(en/yn)yl or two adjacent R 5 together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.
  • the Kv7 channel activator is selected from the group consisting of: N-[4-Chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3- dimethylbutyramide; N-[4-Chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5- yl]-3,3-dimethylbutyramide; [1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid propyl ester; N-[1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl- methanesulfonamide; 4-Fluoro-N-[1-(4-fluorobenzyl)
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 13. Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No.12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 13, these references incorporated by reference herein control. [0259] In an embodiment, the Kv7 channel activator is a compound according to formula 13.
  • R1 is selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; R2 is selected from the group consisting of halogen, cyan
  • the Kv7 channel activator is selected from the group consisting of: N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(4-fluoro-phenyl)- acetamide; 2-Cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)- acetamide; N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclopentyl- propionamide; N-(2-Chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl-propionamide; 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide; 2-Cyclopentyl-N- [2,6-dimethyl-4-(2-phenyl-morpholin
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 14.
  • Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2008 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006029623A1, published March 23, 2006 and corresponding to International Application No. PCT/DK2005/000560 filed September 2, 2005; US Patent No.7,601,870, issued October 13, 2009 and corresponding to US Application No.11/312,664 filed December 20, 2005; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No.
  • the Kv7 channel activator is a compound according to formula 14: Formula 14 wherein, Z is O or S; q is 0 or 1; each of R 1 and R 2 is independently selected from the group consisting of halogen, cyano, amino, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Aryl, Heteroaryl, halo-C 1-6 - alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycl
  • the Kv7 channel activator is selected from the group consisting of: Hexanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide; N-(4-Bromo-2,6- dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide; N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4- fluoro-phenyl)-acetamide; N-(2-Bromo-4,6-dimethyl-phenyl)-3,3-dimethyl-butyramide; N- (2-Bromo-4,6-dimethyl-phenyl)-2-cyclopentyl-acetamide; N-(2-Bromo-4,6-dichloro-phenyl)- 3,3-dimethyl-butyramide; N-(2-Bromo-4,6-dichloro-phenyl)-2-(4-fluoro-phenyl)-
  • Z is O or S; q is 0; R 1 and R 2 are each independently selected from the group consisting of halogen, cyano, amino, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; R 3 is selected
  • R 1 and R 2 are each independently selected from the group consisting of halogen, amino, C 1-6 -alk(en/yn)yl, Aryl, and halo-C 1-6 -alk(en/yn)yl.
  • R 3 is selected from the group consisting of C 1-8 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 - cycloalk(en)yl, and amino-C 1-6 -alk(en/yn)yl.
  • R 4 is selected from the group consisting of halogen, C 1-6 - alk(en/yn)yl, NR 5 R 6 and R 7 NH—C 1-6 -alk(en/yn)yl, wherein R 5 , R 6 and R 7 are as previously defined.
  • R 4 is NR 5 R 6 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, Aryl-C 1-6 -alk(en/yn)yl, and C 1-6 -alk(en/yn)yl, with the proviso that R 5 and R 6 cannot both be hydrogen.
  • R 4 is R 7 NH—C 1-6 -alk(en/yn)yl, wherein R 7 is Aryl.
  • any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, C 1-6 - alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, hydroxy, C 1-6 -alk(en/yn)yloxy, halo-C 1-6 - alk(en/yn)yloxy, di-(C 1-6 -alk(en/yn)yl)amino, C 1-6 -alk(en/yn)yl-CO—NH— and C 1-6 - alk(en/yn)yl-sulfonamide; or two adjacent substituents may together with the Aryl group to which they are attached form a 4-8 membered ring,
  • the Kv7 channel activator is a compound according to formula 14, wherein: Z is O or S; q is 0; R 1 and R 2 are each independently selected from the group consisting of halogen, cyano, amino, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo- C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, and C 3-8 - cycloalk(en)yl-C
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 15.
  • Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006092143A1, published September 8, 2006 and corresponding to International Application No. PCT/DK2006/000123 filed March 2, 2006; US Patent No.7,812,020, issued October 12, 2010 and corresponding to US Application No. 11/817,340 filed March 2, 2006; US Publication No.
  • the Kv7 channel activator is a compound according to formula 15: Formula 15 wherein, q is 0 or 1; each of R 1 and R 2 is independently selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/
  • the Kv7 channel activator is selected from the group consisting of: (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-carbamic acid benzyl ester; (2,4- Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-carbamic acid 2-chloro-benzyl ester; 2-(4-Chloro- phenyl)-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; 2-Phenyl- cyclopropanecarboxylic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4- Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-thiophen-2-yl-acetamide; 3-Cyclohexyl-N-(2,4- dimethyl-6-morpholin-4-yl-pyridin
  • R 1 and R 2 each is independently selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; and R 3 is selected from the group consisting of
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 16.
  • Such compounds are described in International Publication No. WO2009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No.12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 16, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 16: Formula 16 wherein: q is 0 or 1; R 1 and R 2 are independently selected from the group consisting of hydrogen and optionally substituted aryl-C 1-6 -alk(en/yn)yl, provided that R 1 and R 2 are not both hydrogen; or R 1 and R 2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom; R 2 and R 4 are independently selected from hydrogen, halogen, cyano, amino, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, halo- C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, C 3- 8 -cycl
  • the Kv7 channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5- yl]-3,3-dimethylbutyramide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)- pyrimidin-5-yl]-2-(4-fluorophenyl)-acetamide; Hexanoic acid [4-amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]-amide; N-[4-Amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]-2
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 17.
  • Such compounds are described in International Publication No. WO2007065449A1, published June 14, 2007 and corresponding to International Application No. PCT/DK2006/050039 filed September 7, 2006; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 17, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 17: Formula 17 , wherein: q is 0 or 1; R 1 and R 2 are independently selected from the group consisting of hydrogen and optionally substituted aryl-C 1-6 -alk(en/yn)yl, provided that R 1 and R 2 are not both hydrogen, or R 1 and R 2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom;R 3 and R 4 are independently selected from hydrogen, halogen, cyano, amino, C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, halo- C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, C 3- 8 -cycloalk(en
  • q is 0. [0281] In further embodiments, q is 1. [0282] In further embodiments, R 1 and R 2 are independently selected from hydrogen and optionally substituted aryl-C 1-6 -alk(en/yn)yl, provided that R 1 and R 2 are not both hydrogen. [0283] In further embodiments, R 1 and R 2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further hetero atom. [0284] In further embodiments, said further hetero atom is oxygen. [0285] In further embodiments, said ring is a 6 membered ring. [0286] In further embodiments, said ring is a morpholine ring.
  • R 3 and R 4 are independently selected from amino and C 1-6 - alk(en/yn)yl, preferably methyl.
  • R 5 is selected from the group consisting of C 1-10 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, optionally substituted aryl-C 1-6 -alk(en/yn)yl and optionally substituted aryl.
  • the Kv7 Channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5- yl]-3,3- dimethylbutyramide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)- pyrimidin-5-yl]-2-(4- fluorophenyl)-acetamide, Hexanoic acid [4-amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]- amide, N-[4-Amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]-2, N-[4-Amin
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 18.
  • Such compounds are described in International Publication No. WO2004096767A1, published November 11, 2004 and corresponding to International Application No. PCT/DK2004/000283 filed April 23, 2004; US Publication No. US20060264496A1, published November 23, 2006 and corresponding to US Application No. 10/551,783 filed April 23, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 18, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 18: Formula 18 , wherein, the dotted line represents an optional bond; R 1 and R 1′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 - cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -C -cycloalk
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 19. Such compounds are described in US Patent No. 9,248,122, issued February 2, 2016 and corresponding to US Application No.14/091,395 filed November 27, 2013; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 19, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 19: Formula 19 wherein, A 1 , A 2 and A 3 independently of each other represent CR 4 , N, O, S or N(CH 3 ), A 4 represents CR 4 or N, and n denotes 0 or 1, with the proviso, that at least one of A 1 , A 2 , A 3 and A 4 does not represent CR 4 , and with the proviso, that if n denotes 0, then precisely one of A 1 , A 2 and A 3 represents O, S or N(CH 3 ), or if n denotes 1, then A 1 , A 2 and A 3 independently of each other represent CR 4 or N, R 1 represents C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted;
  • a 1 , A 2 and A 3 independently of each other represent CR 4 , N, O, S or N(CH 3 ), A 4 represents CR 4 or N, and n denotes 0 or 1, with the proviso, that at least one of A 1 , A 2 , A 3 and A 4 does not represent CR 4 , and with the proviso, that if n denotes 0, then precisely one of A 1 , A 2 and A 3 represents O, S or N(CH 3 ), or if n denotes 1, then A 1 , A 2 and A 3 independently of each other represent CR 4 or N, R 1 denotes C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , NH(C 1-4 -aliphatic residue), N(C 1-4 -aliphatic residue) 2 , OH, ⁇
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents CR 4 and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents N
  • a 3 represents CR 4 and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • N or n denotes 1 and A 1 represents N
  • a 2 represents N
  • a 3 represents CR 4 and A 4 represents CR 4
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; C 1-4 - aliphatic residue, S—C 1-4 -aliphatic residue or O—C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH and O—C 1-4 - aliphatic residue.
  • R 2 represents C 1-4 -aliphatic residue.
  • each R 4 independently represents H; F; Cl; Br; CN; CF 3 ; OCF 3 ; CH 3 , OCH 3 or S( ⁇ O) 2 CH 3 .
  • R 1 represents the partial structure: wherein, m denotes 0, 1, or 2, R 1a and R 1b each independently of one another represent H, F, Cl, Br, I, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl,
  • m denotes 1 or 2
  • R 1a and R 1b represent H
  • R 1c denotes C 1-4 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 - aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • m denotes 0 and R 1c denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the
  • R 3 denotes a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , S—C 1-4 -aliphatic residue, CF 3 , CN and C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3 and O—C 1-4 -aliphatic residue, or denotes C 3-6 -cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • R 3 denotes C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , SCF 3 , CF 3 and C 1-4 -aliphatic residue, or denotes C 3-6 - cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , SCF 3 , CF 3 and C 1-4 - aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O—C 1-4 -
  • a 1 , A 2 and A 3 independently of each other represent CR 4 , N, O, S or N(CH 3 ), A 4 represents CR 4 or N, and n denotes 0 or 1, with the proviso, that at least one of A 1 , A 2 , A 3 and A 4 does not represent CR 4 , and with the proviso, that if n denotes 0, then precisely one of A 1 , A 2 and A 3 represents O, S or N(CH 3 ), or if n denotes 1, then A 1 , A 2 and A 3 independently of each other represent CR 4 or N, R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 1a and R 1b each independently of one another represent H, F, Cl, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at
  • the Kv7 channel activator is selected from the group consisting of:12-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[1,5]naphthyridine-3- carboxylic acid amide; 22-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl- [1,5]naphthyridine-3-carboxylic acid amide; 3-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-[1,6]naphthyridine-3-carboxylic acid amide; 42-Ethylsulfanyl-N-[(4-fluorophenyl)- methyl]-4-methyl-[1,6]naphthyridine-3-carboxylic acid amide; 52-Ethylsulfanyl-N-[(3-fluorophen
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 20.
  • Such compounds are described in US Patent No. 9,284,286 issued March 15, 2016 and corresponding to US Application No.14/091.373 filed November 27, 2013; International Publication No. WO2014082737A1, published June 5, 2014 and corresponding to International Application No. PCT/EP2013/003572 filed November 27, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 20, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 20: Formula 20 wherein: A 1 represents CR 10 R 11 or S; A 2 represents CR 12 R 13 , C( ⁇ O), O, S, S( ⁇ O) or S( ⁇ O) 2 ; A 3 , A 4 and A 5 independently of each other represent CR 7 , N, O, S or NR 8 , A 6 represents CR 7 or N, and n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A 3 , A 4 and A 5 represents O, S or NR 8 , or if n denotes 1, then A 3 , A 4 and A 5 independently of each other represent CR 7 or N; and with the proviso, that if n denotes 1 and A 3 , A 4 and A 5 each represent CR 7 , then A 6 does not represent N; R 1 represents C 1-10 -aliphatic residue, unsubstituted or mono- or poly
  • a 1 represents CR 10 R 11 or S
  • a 2 represents CR 12 R 13 , C( ⁇ O), O, S, S( ⁇ O) or S( ⁇ O) 2
  • a 3 , A 4 and A 5 independently of each other represent CR 7 , N, O, S or NR 8
  • a 6 represents CR 7 or N
  • n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A 3 , A 4 and A 5 represents O, S or NR 8 , or if n denotes 1, then A 3 , A 4 and A 5 independently of each other represent CR 7 or N; and with the proviso, that if n denotes 1 and A 3 , A 4 and A 5 each represent CR 7 , then A 6 does not represent N;
  • R 1 denotes a C 1-10 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • R 8 represents H or C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and O—C 1-4 -aliphatic residue.
  • a 1 represents S; and
  • a 2 represents S, S( ⁇ O) 2 or CR 12 R 13 , wherein R 12 and R 13 both represent H or both represent F.
  • n denotes 1 and A 3 represents CR 7 , A 4 represents CR 7 , A 5 represents CR 7 and A 6 represents CR 7 ; or n denotes 1 and A 3 represents N, A 4 represents CR 7 , A 5 represents CR 7 and A 6 represents CR 7 ; or n denotes 1 and A 3 represents CR 7 , A 4 represents N, A 5 represents CR 7 and A 6 represents CR 7 ; or n denotes 1 and A 3 represents CR 7 , A 4 represents CR 7 , A 5 represents N and A 6 represents CR 7 ; or n denotes 1 and A 3 represents N, A 4 represents N, A 5 represents CR 7 and A 6 represents CR 7 ; or n denotes 1 and A 3 represents N, A 4 represents N, A 5 represents CR 7 and A 6 represents CR 7 ; or n denotes 1 and A 3 represents N, A 4 represents CR 7 , A 5 represents N and A 6 represents CR 7 ; or n denotes 1
  • R 1 represents the partial structure: wherein: R 14a and R 14b each independently of the other represent H; F; Cl; Br; CF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 -aliphatic residue, O—C 1-4 -aliphatic residue, NH(C 1-4 -aliphatic residue), N(C 1-4 -aliphatic residue) 2 , in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, OH and OCF 3 ; or independently represent C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each
  • R 14a and R 14b each independently of the other represents H; F; Cl; CH 3 ; CH 2 CH 3 ; (CH 2 ) 2 CH 3 ; CH(CH 3 ) 2 ; (CH 2 ) 3 CH 3 ; CH(CH) 3 CH 2 CH 3 ; C(CH 3 ) 3 ; OH; OCH 3 ; OCH 2 CH 3 ; O(CH 2 ) 2 OCH 3 or O(CH 2 ) 2 OH; m represents 0, 1 or 2 and represents 0 and B represents CH 3 ; CH 2 CH 3 ; (CH 2 ) 2 CH 3 ; CH(CH 3 ) 2 ; (CH 2 ) 3 CH 3 ; CH(CH 3 )CH 2 CH 3 ; C(CH 3 ) 3 ; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; adamantyl; bicyclo[2.2.1]heptyl; bicycl
  • R 2 ; R 3 ; R 4 ; R 5 ; R 10 , R 11 , R 12 and R 13 each independently of the others represents H; F; Cl; CF 3 ; CN; OH; OCF 3 ; SCF 3 ; CH 3 ; CH 2 CH 3 ; (CH 2 ) 2 CH 3 ; CH(CH 3 ) 2 ; (CH 2 ) 3 CH 3 ; CH(CH) 3 CH 2 CH 3 ; C(CH 3 ) 3 ; OCH 3 ; OCH 2 CH 3 ; O(CH 2 ) 2 OCH 3 ; O(CH 2 ) 2 OH; SCH 3 ; SCH 2 CH 3 ; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or R 2 and R 3 or R 4 and R 5 or R 10 and R 11 or R 12 and R 13 or R 2 and R 11 or R 2 and R 4 or R 2 and R 13 or R 4 and R 13 or R
  • each R 7 represents H, F; Cl; CN; CF 3 ; CHF 2 ; CH 2 F; OCF 3 ; OCHF 2 ; OCH 2 F; SCF 3 ; CH 3 ; CH 2 CH 3 ; CH 2 CH 2 CH 3 ; CH(CH 3 ) 2 ; OH 2 CH 2 CH 2 CH 3 ; CH(CH) 3 CH 2 CH 3 ; CH 2 CH(CH 3 ) 2 ; O(CH 3 ) 3 ; OCH 3 ; OCH 2 CH 3 ; O(CH 2 ) 2 OCH 3 ; O(CH 2 ) 2 OH; S( ⁇ O) 2 CH 3 S( ⁇ O) 2 CH 2 CH 3 S( ⁇ O) 2 CH(CH 3 ) 2 or S( ⁇ O) 2 CH 2 CH 2 CH 3 ; and R 8 represents H or CH 3 or CH 2 CH 3 or CH(CH 3 ) 2 .
  • R 6 represents a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , C 1-4 -aliphatic residue, CF 3 , SH, S—C 1-4 -aliphatic residue and SCF 3 ; or an aryl or a heteroaryl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, O—C 1-4 -aliphatic residue, OCF 3 , C 1-4 -aliphatic residue
  • R 6 represents phenyl, pyridyl or thienyl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, CN, OH, O—C 1-4 - aliphatic residue, OCF 3 , C 1-4 -aliphatic residue, CF 3 and SCF 3 .
  • the Kv7 channel activator is selected from the group consisting of: 12-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)- benzamide; 2 N-(3,3-Dimethyl-butyl)-2-[3-(4-fluorophenyl)-propylsulfanyl]-benzamide; 33- [[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide; 43-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-2- carboxylic acid amide; 54-[[3,3-Difluoro-3-(4-fluorophenyl
  • the Kv7 channel activator may be selected from one of the following compounds.
  • Such compounds are described in US Publication No. US20140148454A1, published May 29, 2014 and corresponding to US Application No. 14/091,378 filed November 27, 2013; International Publication No. WO2014082739A1, published June 5, 2014 and corresponding to International Application No. PCT/EP2013/003574 filed November 27, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 21, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 21: Formula 21 wherein, A 1 represents CR 5 or N; A 2 represents CR 6 , N, O, S or NR 7 ; A 3 represents CR 8 or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A 2 represents O, S or NR 7 , or if n denotes 1, then A 2 represents CR 6 or N, wherein R 5 is selected from F, Cl, Br, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, OCH 3 , C 2 H 5 , SCH 3 , OCF 3 , OCHF 2 or OCH 2 F; R 6 is selected from H, F, Cl, Br, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, OCH 3 , C 2 H 5 , SCH 3 , OCF 3 , OCHF 2 or OCH 2 F; R 7 represents C
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 , N, O, S or NR 7
  • a 3 represents CR 8 or N
  • n denotes 0 or 1, on the condition, that if n denotes 0, then A 2 represents O, S or NR 7 , or if n denotes 1, then A 2 represents CR 6 or N
  • R 5 is selected from F, Cl, Br, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, OCH 3 , C 2 H 5 , SCH 3 , OCF 3 , OCHF 2 or OCH 2 F
  • R 6 is selected from H, F, Cl, Br, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, OCH 3 , C 2 H 5 , SCH 3 , OCF 3 , OCHF 2 or OCH 2 F
  • R 7 represents C 1-4 -aliphatic residue or C 3-5 -cycloaliphatic residue
  • a 2 represents O and A 3 represents CR 8 ; or A 2 represents S and A 3 represents CR 8 ; or A 2 represents NR 7 and A 3 represents CR 8 ; or A 2 represents O and A 3 represents N; or A 2 represents S and A 3 represents N; or A 2 represents NR 7 and A 3 represents N.
  • the compound is according to formula 21 wherein n denotes 1 and is according to the formula: wherein: A 1 represents N and A 2 represents CR 6 and A 3 represents CR 8 ; or A 1 represents CR 5 and A 2 represents N and A 3 represents CR 8 ; or A 1 represents N and A 2 represents N and A 3 represents CR 8 ; or A 1 represents N and A 2 represents CR 6 and A 3 represents N; or A 1 represents CR 5 and A 2 represents N and A 3 represents N; or A 1 represents N and A 2 represents N and A 3 represents N.
  • R 5 denotes F, Cl, CH 3 , OCH 3 or CH 2 CH 3 ; and/or R 6 denotes H; and/or R 7 denotes CH 3 , CH 2 CH 3 or cyclopropyl; and/or R 8 denotes H.
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 1a and R 1b each independently of one another represent H, F, Cl, Br, I, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and O—C 1-4 -aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstit
  • m denotes 1 or 2
  • R 1a and R 1b represent H
  • R 1c denotes C 1-4 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 - aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • m denotes 0 and R 1c denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the
  • R 2 is selected from the group consisting of CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 -cyclopropyl, OCH 3 , OC 2 H 5 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , O-cyclopropyl, SCH 3 , SC 2 H 5 , SCH 2 CH 2 CH 3 , SCH(CH 3 ) 2 , S-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH(CH 3 ) 2 , N
  • R 3 represents the partial structure: wherein: o denotes 0, 1, 2 or 3, R 3a and R 3b each independently of one another represent H, F, Cl, Br, I, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue or together denote ⁇ O, and R 3c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and O—C 1-4 -aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycl
  • R 3 represents the partial structure: Wherein, o denotes 0, 1, 2 or 3, R 3a and R 3b each independently of one another represent H, F, CH 3 or OCH 3 , or together denote ⁇ O, R 3c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, O—C 1-4 -aliphatic residue, and CF 3 , or denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -alipha
  • a 1 represents CR 5 , N;
  • a 2 represents CR 6 , N, O, S or NR 7 ;
  • a 3 represents CR 8 or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A 2 represents O, S or NR 7 , or if n denotes 1, then A 2 represents CR 6 or N, wherein R 5 denotes F, Cl, CH 3 , OCH 3 or CH 2 CH 3 ; and/or R 6 denotes H; and/or R 7 denotes CH 3 , CH 2 CH 3 or cyclopropyl; and/or R 8 denotes H; with the proviso, that, if n denotes 1, then at least one of A 1 , A 2 and A 3 denotes N, with the proviso, that if n denotes 1 and A 3 denotes N, then A 1 and/or A 2 denotes N, and with the proviso, that if n denotes if
  • the Kv7 channel activator is selected from the group consisting of: N-[(4-Chlorophenyl)-methyl]-4-ethylsulfanyl-6-methyl-2-morpholin-4-yl- pyrimidine-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4,6-dimethoxy-2- morpholin-4-yl-pyrimidine-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4- ethylsulfanyl-2-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-methyl-6-morpholin-4-yl-4-propyl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-ethoxy-2-methyl-6-morpholin-4-yl-pyr
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 22.
  • Such compounds are described in Patent No. 9,278,103 issued March 8, 2016 and corresponding to US Application No.14/230,572 filed March 31, 2014; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 22, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 22: Formula 22 , wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3
  • R 1 represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R 12a and R 12b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1- 4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1- 4 aliphatic residue)
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2 or 3, R 12a and R 12b each independently of one another represent H, F, Cl, Br, I, OH, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O—C 1- 4 aliphatic residue, CN, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubsti
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1- 4 -aliphatic residue, a S—C 1-4 -aliphatic residue, or a O—C 1-4 -aliphatic residue, wherein the C 1- 4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted O—C 1-4 -aliphatic residue, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, or piperidinyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from
  • R 3 represents H; F; Cl; Br; I; CN; CF 3 ; SCF 3 ; NO 2 ; OCF 3 ; a C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, or a S—C 1-4 -aliphatic residue, wherein the C 1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted O—C 1-4 aliphatic residue.
  • R 6 denotes a C 2-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycl
  • R 6 denotes a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case is unsubstituted, or denotes a C 3-10 -cycloaliphatic residue, or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 alipha
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2, and R 12a and R 12b each independently of one another represent H, F, OH, CH 3 or OCH 3 , or together denote ⁇ O, R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, CN, OH, S( ⁇ O) 2 —CH 3 , an unsubstituted O—C 1-4 aliphatic residue, and CF 3 , or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3
  • the Kv7 channel activator is selected from the group consisting of: N-[(3,5-Difluoro-phenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; 9 N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-2-[(E)-prop-1-enyl]-pyridine-3-carboxylic acid amide; 10 N-[(3-Fluorophenyl)-methyl]-4- methyl-6-morpholin-4-yl-2-propyl-pyridine-3-carboxylic acid amide; 19 N-[(3- Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[3-Fluorophenyl)-methyl]-2-(2-methoxy-eth
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 23.
  • Such compounds are described in US Patent No.9,168,259 issued March 8, 2016 and corresponding to US Application No.13/449,472 filed April 18, 2012; US Patent No.8,552,200 issued December 12, 2013 and corresponding to US Application No.13/276,464 filed October 19, 2011; International Publication No. WO2012052167A1, published April 26, 2012 and corresponding to International Application No. PCT/EP2011/005265 filed April 26, 2012; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 23, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 23: Formula 23 wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3
  • R 1 represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R 12a and R 12b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1- 4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1- 4 aliphatic residue)
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2 or 3, R 12a and R 12b each independently of one another represent H, F, Cl, Br, I, OH, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O—C 1- 4 aliphatic residue, CN, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubsti
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1- 4 -aliphatic residue, a S—C 1-4 -aliphatic residue, or a O—C 1-4 -aliphatic residue, wherein the C 1- 4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted aliphatic residue, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, or piperidinyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F
  • R 3 represents H; F; Cl; Br; I; CN; CF 3 ; SCF 3 ; NO 2 ; OCF 3 ; a C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, or a S—C 1-4 -aliphatic residue, wherein the C 1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted O—C 1-4 -aliphatic residue.
  • R 4 represents the partial structure: wherein: n denotes 0, 1, 2, or 3, R 13a and R 13b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O— C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 13c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2
  • R 4 represents the partial structure: wherein: n denotes 0, 1, 2 or 3, R 13a and R 13b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 13c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -
  • R 6 denotes a C 2-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycl
  • R 6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R 6 denotes S—R 7 or O—R 8 wherein R 7 and R 8 in each case denote a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, an NH(C 1-4 aliphatic residue), an N(C 1- 4 aliphatic residue) 2 , CF 3 , a C( ⁇ O)—O—C 1-4 -aliphatic residue, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be un
  • R 6 denotes a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case is unsubstituted, or denotes a C 3-10 -cycloaliphatic residue, or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C
  • C 3-10 -cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted C 1-4 aliphatic group, on the condition that if R 6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R 6 denotes S—R 7 or O—R 8 wherein R 7 and R 8 in each case denote a C 1-8 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, an NH(C 1-4 aliphatic residue), an N(C 1- 4 aliphatic residue) 2
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2, and R 12a and R 12b each independently of one another represent H, F, OH, CH 3 or OCH 3 , or together denote ⁇ O, R 12c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, CN, OH, S( ⁇ O) 2 —CH 3 , an unsubstituted O—C 1-4 aliphatic residue, and CF 3 , or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3
  • the Kv7 channel activator is selected from the group consisting of: N-[(3,5-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2- methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 24.
  • Such compounds are described in US Patent No.9,168,259 issued March 8, 2016 and corresponding to US Application No.13/449,472 filed April 18, 2012; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 24, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 24: Formula 24 wherein, X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and in each case optionally bridged via a C 1- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OX 6 , wherein X 6 represents a C 1-6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3-6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted; X 2 and X 3 independently of one another represent H; F; Cl; Br; I; CN; CH
  • X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCH 2 F, OCHF 2 , OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting
  • X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCH 2 F, OCHF 2 , OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting
  • X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCH 2 F, OCHF 2 , OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue is in each case unsubstituted, or represents a C 3-6 - cycloaliphatic residue, unsubstitute
  • X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O—C 1-4 -aliphatic residue, or represents a C 3-6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O—C 1-4 -aliphatic residue, or represents OX 6 , wherein X 6 represents a C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O—C 1-4 -aliphatic residue.
  • X 1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 —CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), ethenyl or propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )— CH 3 ), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX 6 , wherein X 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-
  • X 2 and X 3 independently of one another represent H; F; Cl; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; a C 1-4 -aliphatic residue, or an O—C 1- 4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O—C 1-4 -aliphatic residue, or represent a C 3-6 - cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O—C 1-4 -aliphatic residue,
  • X 2 and X 3 independently of one another represent H; F; Cl; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; a C 1-4 -aliphatic residue, or an O—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue is in each case unsubstituted, or represent a C 3-6 - cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of X 2 and X 3 denotes H or is linked via a carbon atom, X 4 and X 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a C 1-4 - aliphatic residue, wherein the C 1-4 -aliphatic residue is unsubstituted, or represent a C 3-6 - cycloaliphatic residue or a 3 to 6 membere
  • X 2 and X 3 independently of one another represent H; OH; an unsubstituted C 1-4 -aliphatic residue, or an unsubstituted O—C 1-4 aliphatic residue, with the proviso that at least one of X 2 and X 3 denotes H or is linked via a carbon atom, X 4 and X 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; an unsubstituted C 1-4 - aliphatic residue, or X 2 and X 3 or X 4 and X 5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3-10 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CH 2 F, CHF 2 , CF 3 , an unsubstituted O—C
  • X 2 and X 3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 —CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), OCH 3 or OCH 2 CH 3 , with the proviso that at least one of X 2 and X 3 denotes H or is linked via a carbon atom, X 4 and X 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl,
  • X 1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX 6 , wherein X 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, or tert.- butyl, X 2 and X 3 in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, or tert.-butyl, X 4 and X 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl
  • the Kv7 cannel activator is selected from the group consisting of: 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[[(1S,2R)-2-hydroxy-cyclohexyl]- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N- [[(1R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; N-(3-Hydroxy-4
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 25. Such compounds are described in US Patent No.8,653,101 issued February 18, 2014 and corresponding to US Application No. 10/992,118 filed November 18, 2005; International Publication No. WO2012025236A1, published March 1, 2012 and corresponding to International Application No. PCT/EP2011/004277 filed August 26, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 25, these references incorporated by reference herein control. [0364] In an embodiment, the Kv7 channel activator is a compound according to formula 25.
  • R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 - aliphatic residue, a C
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted aliphatic residue, a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, a C 1-4 - aliphatic residue and a O—C
  • R 3 , R 4 , R 5 and R 6 each independently of one another represent H; F; Cl; Br; I; CN; CF 3 ; OCF 3 ; SCF 3 ; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; S( ⁇ O) 2 —OH; NO 2 ; a C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)—O— C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S— C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 3 , R 4 , R 5 and R 6 each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; OCF 3 ; SCF 3 ; a (C ⁇ O)— C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O—CH 3 .
  • R 1 represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O— C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 ,
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2 and R 8a and R 8b each independently of one another represent H, F, a O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator is selected from the group consisting of: N-(3,3-dimethyl-butyl)-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3- carboxylic acid amide; 2-ethoxy-4-methyl-N-(thiophene-2-yl-methyl)-7-(trifluoromethyl)- quinoline-3-carboxylic acid amide; 2-ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2- methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4- fluorophenyl)-methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethoxy
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 26.
  • Such compounds are described in International Publication No. WO2012025236A1, published March 1, 2012 and corresponding to International Application No. PCT/EP2011/004277 filed August 26, 2011; US Patent No.9,073,862 issued July 7, 2015 and corresponding to US Application No. 14/098,842 filed November 26, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 26, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 26: Formula 26 wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted O—C 1-4 -aliphatic residue, a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, a C 1-4 - aliphatic residue and
  • R 3 , R 4 , R 5 and R 6 each independently of one another represent H; F; Cl; Br; I; CN; CF 3 ; OCF 3 ; SCF 3 ; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; S( ⁇ O) 2 —OH; NO 2 ; a C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)—O— C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S— C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 3 , R 4 , R 5 and R 6 each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; OCF 3 ; SCF 3 ; a (C ⁇ O)— C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O—CH 3 .
  • R 1 represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O— C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 ,
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocyclo
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2 and R 8a and R 8b each independently of one another represent H, F, a O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator may be selected from the group consisting of: [0389] N-[(3-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-7-(trifluoromethyl)- quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4- methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]- 2-(2-hydroxy-ethoxy)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N- [(3-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 27.
  • Such compounds are described in International Publication No. WO2012025238A1, published March 1, 2012 and corresponding to International Application No. PCT/EP2011/004279 filed August 26, 2011; US Patent No.8,445,512 issued May 21, 2013 and corresponding to US Application No. 13/218,556 filed August 26, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 27, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 27: Formula 27 wherein: R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O— C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted aliphatic residue, a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, a C 1-4 - aliphatic residue and a O—C
  • R 2 is ⁇ H.
  • R 3 , R 4 , R 5 and R 6 each independently of one another represent H; F; Cl; Br; I; CN; CF 3 ; OCF 3 ; SCF 3 ; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; S( ⁇ O) 2 —OH; NO 2 ; a C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)—O— C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S— C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or poly
  • R 3 , R 4 , R 5 and R 6 each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; OCF 3 ; SCF 3 ; a (C ⁇ O)— C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O—CH 3 , on the condition that at least one of R 3 , R 4 , R 5 and R 6 is ⁇ H.
  • R 1 represents the partial structure: [0398] Wherein, m denotes 0, 1, 2, 3 or 4, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1- 4 alipha
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a C 2-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue
  • R 7 denotes a C 2-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH,
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2 and R 8a and R 8b each independently of one another represent H, F, a O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator is selected from the group consisting of: 4-methyl-2-propyl-N-(thiophene-2-yl-methyl)-7-(trifluoromethyl)-quinoline-3- carboxylic acid amide; N-(cycloheptyl-methyl)-4-methyl-2-propyl-7-(trifluoromethyl)- quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-4-methyl-2-propyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-4-methyl- 2-propyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethyl-N-[(4-fluorophenyl)- methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethyl-N-[(4-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 28.
  • Such compounds are described in International Publication No. WO2012028300A1, published March 8,2012 and corresponding to International Application No. PCT/EP2011/004369 filed August 31, 2011; US Patent No.8,618,129 issued December 31, 2013 and corresponding to US Application No.13/222,023 filed August 31, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 28, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 28: Formula 28 wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted and optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 - aliphatic residue, a C
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O— C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue, unsubstituted or mono- or poly
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1- 4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, and an unsubstituted O—C 1-4 -aliphatic residue, a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, a C 1-4 - aliphatic residue and
  • R 3 , R 4 , R 5 and R 6 each independently of one another represent H; F; Cl; Br; I; CN; CF 3 ; OCF 3 ; SCF 3 ; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; S( ⁇ O) 2 —OH; NO 2 ; a C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)—O— C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S— C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 3 , R 4 , R 5 and R 6 each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; OCF 3 ; SCF 3 ; a (C ⁇ O)— C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O—CH 3 .
  • R 1 represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, NO 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , ⁇ O, OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S
  • R 1 represents the partial structure wherein, m denotes 0, 1, or 2, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue, unsubstituted or
  • R 7 denotes a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , ⁇ O, OH, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloali
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3 and an un
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2 and R 8a and R 8b each independently of one another represent H, F, a O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue;
  • the Kv7 channel activator is selected from the group consisting of: N-(3-fluorobenzyl)-2,4-dimethyl-1-oxo-7-(trifluoromethyl)-1,2- dihydroisoquinoline-3-carboxamide; N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7- (trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; 2-ethyl-N-(3-fluorobenzyl)-4- methyl-1-oxo-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; N-(3- fluorobenzyl)-2-isopropyl-4-methyl-1-oxo-7-(trifluoromethyl)-1,2 dihydroisoquinoline-3- carboxamide; andN-(3-fluorobenzyl)-2-(2-methoxyethyl)
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 29.
  • Such compounds are described in US Patent No.8,653,102 issued February 18, 2014and corresponding to US Application No.13/218,579 filed August 26, 2011; International Publication No. PCT/EP2011/004280, published March 1, 2012, and corresponding to International Application No. WO2012025239A1filed August 25, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 29, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 29: wherein: X denotes O or S, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO
  • R 1 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), OH, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 - cycloali
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1- 4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted aliphatic residue, a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, OH, a C 1-4 -aliphatic residue and a O— C 1-4 -aliphatic
  • R 3 , R 4 , R 5 and R 6 each independently of one another represent H; F; Cl; Br; I; CN; CF 3 ; OCF 3 ; SCF 3 ; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; S( ⁇ O) 2 —OH; NO 2 ; a C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)—O— C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S— C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 3 , R 4 , R 5 and R 6 each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; OCF 3 ; SCF 3 ; a (C ⁇ O)— C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O—CH 3 .
  • R 1 represents the partial structure: wherein, m denotes 0, 1, 2, 3 or 4, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , NH 2 , an NH(C 1- 4 aliphatic residue), OH, an O
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 8a and R 8b each independently of one another represent H, F, Cl, Br, I, an O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , OH, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, COOH, CF 3 , CN, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O—C 1-4 -aliphatic residue, COOH, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF 3
  • R 1 represents the partial structure: wherein: m is 0, 1 or 2 and R 8a and R 8b each independently of one another represent H, F, a O—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator is selected from the group consisting of: N-[(3-Fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Butyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1,4- dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Ethyl-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 30.
  • Such compounds are described in International Publication No. WO2010075973A1, published July 8, 2010, and corresponding to International Application No. PCT/EP2009/009040 filed December 16, 2009; US Patent No.8,367,700 issued February 5, 2013 and corresponding to US Application No.12/635,800 filed December 11, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 30, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 30: Formula 30 , wherein, R 0 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C 1-8 alkyl-bridged aryl or heteroary
  • R 1 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3- 7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; C 1-8 alkyl-bridged heteroaryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono-
  • R 3 , R 4 , R 5 and R 6 each mutually independently denote H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; —O—(C 1-8 alkyl)-O—; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O) 2 O(R 0 or H); S( ⁇ O) 2 —N(R 0 or H
  • R 7 , R 8 , R 9 , R 10 mutually independently stand for H; or C 1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
  • R 11 stands for H; F; Cl; Br; CN; C 1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted; or C 1-4 alkyl-bridged phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; R 13 stands for H; F; Cl; Br; CN; C 1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted; or C 2-4 alky
  • R 12 and R 14 each mutually independently stand for H; or C 1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
  • R 15 stands for C 3-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3- 7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 31.
  • Such compounds are described in International Publication No. WO2010075973A1, published July 8, 2010, and corresponding to International Application No. PCT/EP2009/009040 filed December 16, 2009; US Patent No.8,367,700 issued February 5, 2013, and corresponding to US Application No.12/635,800 filed December 11, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 31, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 31: wherein, R 1 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl or thienyl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted; or C 1-8 alkyl-bridged thi
  • the Kv7 channel activator is selected from the group consisting of: 4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3- (trifluoromethyl)benzyl)butyric acid amide; 4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-thien-2-yl-3,4- dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide; 4-Oxo-4-[1- (4-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-N-[[3-(trifluoro
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 32.
  • Such compounds are described in International Publication No. WO2010037863A1, published April 8, 2010, and corresponding to International Application No. PCT/EP2009/062859 filed October 2, 2009; US Publication No. US20120238547A1, published September 20, 2012 and corresponding to US Application No.13/394,345 filed September 2, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 32, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 32: Formula 32 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-pyrrol- 1-yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo and trifluoromethyl; R 3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo.
  • R 3 represents furanyl which is optionally substituted with C 1- 6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents morpholinyl.
  • the compound is 3-Methyl-furan-2-carboxylic acid [2-((R)-3- fluoro-pyrrolidin-1-yl)-4-methyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl]-amide. [0449] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid [2-((R)-3- fluoro-pyrrolidin-1-yl)-4-methyl-6-morpholin-4-yl-pyridin-3-yl]-amide; Formula 33 [0450] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 33. Such compounds are described in US Publication No.
  • the Kv7 channel activator is a compound according to formula 33: Formula 33 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents C 1-6 -alkyl; R 3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from C 1-6 -alkyl, C 1 -6 -alkoxy, halo and trifluoromethyl; R 4 represents C 1-6 -alkyl; and R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4- oxazepanyl.
  • R 1 represents metyl or iso-propyl.
  • R 3 represents furanyl which is optionally substituted with C 1- 6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents 1,4-oxazepanyl.
  • the compound is 3-Methyl-furan-2-carboxylic acid(2- isopropyl-4-methyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide; or 3-Methyl-furan-2- carboxylic acid(2,4-dimethyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 34. Such compounds are described in International Publication No.
  • the Kv7 channel activator is a compound according to formula 34: a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-pyrrol- 1-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo, hydroxy, amino, C 1-6 -alkyl, trifluoromethyl, C 1-6 - alkoxy, hydroxy-C 1-6 -alkyl and C 1-6 -alkoxy-C 1 -C 6 -alkyl; L
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl or piperidinyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with halo.
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halo.
  • L represents —CH 2 —.
  • R 3 represents C 1-6 -alkyl.
  • R 3 represents phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or C 3-6 -cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from C 1-6 -alkyl and halo.
  • R 4 represents C 1-6 -alkyl.
  • R 5 represents hydrogen.
  • the Kv7 channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-4- methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide N-[6-(7,8-Dihydro-5H-[1,6]naphthyridin-6- yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3,3-dimethyl-butyramide; N-[6-(7,8-Dihydro- 5H-[1,6]naphthyridin-6-yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3-fluoro-benzamide; N- [6-(7,8-dihydro-5H-1
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 35.
  • Such compounds are described in US Publication No. US20120059037A1, published March 8, 2012, and corresponding to US Application No.13/256,893 filed March 11, 2010; International Publication No. WO2010105960A1, published September 23, 2010 and corresponding to International Application No. PCT/EP2010/053072 filed March 11, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 35, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 35: Formula 35 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent hydrogen, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl or C 1-6 -alkoxy-C 1-6 -alkyl; or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-pyrrol-1-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, C
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen.
  • L represents —CH 2 —, and n is 1.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • R 3 represents C 1-6 -alkyl.
  • R 4 represents halogen.
  • R 4 represents hydrogen.
  • the Kv7 Channel activator is selected from the group consisting of: N- ⁇ 6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin-3-yl ⁇ - 2-(3,5-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 6-[(pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1-yl-pyridin-3-yl ⁇ -acetamide; N- ⁇ 6-[(6-Chloro-pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1yl-pyridin-3-yl ⁇ -3,3-dimethyl-butyramide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N- oxide thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 36.
  • Such compounds are described in Patent Cooperation Treaty application No. EP2010/052257 published September 2, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 36, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to formula 36: Formula 36 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent hydrogen, Ci -6 -alkyl, hydroxy- C- ⁇ - 6 -alkyl or Ci- 6 -alkoxy-Ci- 6 -alkyl; or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 H-pyrrol-1-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen,
  • R 1 and R 2 independently of each other, represent Ci- 6 -alkyl. [0479] In further embodiments, R 1 and R 2 together with the nitrogen to which they are attached, is morpholinyl. [0480] In further embodiments, L represents -CH 2 -. [0481] In further embodiments, R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen. [0482] In further embodiments, R 4 represents methyl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N- ⁇ 4-methyl-6-morpholin-4-yl-2-[(tetrahydro-pyran- 4- ylmethyl)-amino]-pyrimidin-5-yl ⁇ -acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 4- dimethylamino-6-methyl-2-[(tetrahydro-pyran-4- ylmethyl)-amino]-pyrimidin-5-yl ⁇ - acetamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an /V-oxide thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 37.
  • Such compounds are described in International Publication No. WO2010094644A1, published August 26, 2010, and corresponding to International Application No. PCT/EP2010/051839 filed February 15, 2010; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 37, the reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to formula 37: a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent Ci -6 -alkyl; or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 H-pyrrol-1 -yl, piperidinyl and morpholinyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, C 1-6 -alkyl, trifluoromethyl, Ci- 6 -alkoxy, hydroxy-d- 6 -alkyl and Ci- 6 -alkoxy-Ci- 6 -alkyl; L represents a link
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen.
  • R' and R independently of each other, represents hydrogen or methyl.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • R 3 represents d-e-alkyl.
  • R 4 represents methyl.
  • the Kv7 Channel activator is selected from the group consisting of: 3,3-Dimethyl-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl-pyridin-3-yl)- butyramide; 2-(3,5-Difluoro-phenyl)-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl- pyridin-3-yl)-acetamide; N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6-morpholin-4-yl- pyridin-3-yl]-3,3-dimethylbutyramide; (S)-N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6- morpholin-4-yl-pyridin-3-yl]-2-phenylpropionamide;[2-((R)-3-Fluor
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 38.
  • Such compounds are described in International Publication No. WO2010094645A1, published August 26, 2010, and corresponding to International Application No. PCT/EP2010/051840 filed February 15, 2010; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 38, the reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 38: Formula 38 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent d-e-alkyl; or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 H-pyrrol-1-yl, piperidinyl, mor- pholinyl and 1 ,4-oxazepanyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, d -6 -alkyl, trifluoromethyl, d- 6 -alkoxy, hydroxy-Ci -6 -alkyl and Ci-
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen.
  • R 1 and R 2 together with the nitrogen to which they are attached is 1 ,4-oxazepanyl.
  • L is -CH 2 - and n is 1.
  • n is 0.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,4-Difluoro-phenyl)-N-[2-((R)-3-fluoro-pyrrolidin-1-yl)-5-methyl-6- [1 ,4]oxazepan-4-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-/V-(5-methyl-2,6-bis-[1 ,4]oxazepan-4-yl-pyridin-3-yl)- acetamide; 3-Fluoro-/V-(5-methyl-6-[1 ,4]oxazepan-4-yl-2- pyrrolidin-1-yl-pyridin-3-yl)- benzamide; 3-methyl-N-[5-methyl-6-(1 ,4-oxazepan-4-yl)-2- pyrrolidin-1-yl-3-pyri
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 1.
  • Such compounds are described in International Publication No. WO2008142140A2, published November 27, 2008, and corresponding to International Application No. PCT/EP2008/056322 filed May 22, 2008; US Patent No.8,178,544 published May 15, 2012 and corresponding to US Application No. 12/601,124 filed May 22, 2008; which are incorporated by reference in their entirety herein.
  • the reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 39: , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents hydrogen, alkyl or halo; and R 2 represents hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenyl-alkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl (spiro) group; or R 1 represents hydrogen; and R 2 together with one of R 3 , R 4 and R 5 , attached in ortho-position on the aromatic ring, form a —(CH 2 ) n — bridge, wherein n is 1, 2 or 3; R 3 , R 4 and
  • R 1 represents hydrogen or alkyl
  • R 2 represents hydrogen or alkyl
  • R 3 , R 4 and R 5 independently of each other, represent hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, alkyl-sulfanyl, alkyl-sulfonyl, phenyl or phenoxy.
  • R 6 and R 7 independently of each other, represent hydrogen, halo, haloalkyl, hydroxy, alkoxy, or amino.
  • R′ and R′′ independently of each other, represent alkyl, hydroxy-alkyl, cycloalkyl, or phenyl-alkyl.
  • R′ and R′′ together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, homopiperazinyl and morpholinyl, which piperazinyl is optionally substituted one or more times with alkyl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-(2-dimethylamino-4-oxo-4H-quinazolin-3-yl)- acetamide; 2-(4-Chloro-phenyl)-N-(2-diethylamino-4-oxo-4H-quinazolin-3-yl)-acetamide; 2- (3,5-Difluoro-phenyl)-N-[2-(ethyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-acetamide; 2- (3,5-Difluoro-phenyl)-N-(2-dimethylamino
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3-Fluoro-4-trifluoromethyl-phenyl)-N-(4-oxo-2-pyrrolidin-1-yl-4H- quinazolin-3-yl)-acetamide; 2-(3,5-Bis-trifluoromethyl-phenyl)-N- ⁇ 2-[(2-methoxy-ethyl)- methyl-amino]-4-oxo-4H-quinazolin-3-yl ⁇ -acetamide; N-[2-(Benzyl-methyl-amino)-4-oxo- 4H-quinazolin-3-yl]-2-(3,4-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(2- morpholin-4-yl-4-oxo-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluor
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 40. Such compounds are described in International Publication No. WO2010060955A1, published June 3, 2010 and corresponding to International Application No. PCT/EP2009/065890 filed November 26, 2009; US Publication No.
  • the Kv7 channel activator is a compound according to Formula 40: Formula 40 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein Y represents —(CH 2 ) n —, —(CH 2 ) n —O— or — (CH 2 ) n —S— wherein n is 0 or 1;
  • R 1 represents C 1-6 -alkyl, benzo[1,3]dioxolyl, phenyl or pyridyl, which phenyl and pyridyl are optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy and trifluoromethoxy;
  • R 2 and R 3 independently of each other, represent hydrogen or C 1-6 -alkyl; and
  • R 4 and R 5 independently of each
  • Y represents —(CH 2 ) n —, wherein n is 0 or 1;
  • R 1 represents C 1-6 -alkyl, benzo[1,3]dioxolyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy and trifluoromethoxy;
  • R 2 and R 3 independently of each other, represent hydrogen or C 1-6 -alkyl;
  • R 4 and R 5 independently of each other, represent hydrogen, C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy or trifluoromethoxy.
  • n is 1.
  • R 1 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl and C 1-6 -alkoxy.
  • R 2 and R 3 represent hydrogen.
  • R 2 and R 3 represent C 1-6 -alkyl.
  • R 4 and R 5 independently of each other, represent hydrogen or halogen.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)-2-morpholin-4-yl- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 6-[1-(4-fluoro-phenyl)-1-methyl- ethylamino]-2-morpholin-4-yl-pyridin-3-yl ⁇ -acetamide; N-[6-(4-Fluoro-benzylamino)-2- morpholin-4-yl-pyridin-3-yl]-2-methyl-benzamide; 2-Benzo[1,3]dioxol-5-yl-N-[6-(4-fluoro- benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-acetamide;
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 41.
  • Such compounds are described in US Publication No. US20110269783A1, published November 3, 2011, and corresponding to US Application No.13/128,015 filed November 6, 2009; International Publication No. WO2010051819A1, published May 14, 2010, and corresponding to International Application No. PCT/DK2009/050293 filed November 6, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 41, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 41: Formula 41 , A stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein L represents a linker selected from —(CR′R′′) 2 —, —CR′R′′—S—, —CR′R′′—O— or wherein R′ and R′′, independently of each other, represent hydrogen, C 1-6 -alkyl or halogen; R 1 and R 2 , independently of each other, represent C 1-6 -alkyl, hydroxy-C 1-6 -alkyl-, C 1-6 -alkoxy-C 1-6 -alkyl-, phenyl, phenyl-C 1-6 -alkyl-, which phenyl is optionally substituted with one or two times with a substituent selected from the group consisting of C 1-6 -alkoxy, halogen and cyano; or R 1 and
  • R 1 and R 2 independently of each other, represent C 1-6 -alkyl, alkoxy-C 1-6 -alkyl- or phenyl-C 1-6 -alkyl-.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a pyrrolidinyl ring.
  • R 3 , R 4 and R 5 independently of each other, represent hydrogen, C 1-6 -alkyl or halogen.
  • R 6 and R 7 independently of each other, represent hydrogen or halogen.
  • the Kv7 Channel activator is selected from the group consisting of: N-(7-Fluoro-4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-3-(3-fluoro-phenyl)- propionamide; 3-(3-Fluoro-phenyl)-N- ⁇ 2-[(2-methoxy-ethyl)-methyl-amino]-4-oxo-4H- quinazolin-3-yl ⁇ -propionamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-3- (3-fluoro-phenyl)-propionamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-3- (3,5-difluoro-phenyl)-propionamide; 3-(3-Fluoro
  • the compound is of formula: wherein: X represents —CR′R′′—, —S—, or —O—, wherein R′ and R′′, independently of each other, represent hydrogen, C 1-6 -alkyl or halogen, and R′, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above. [0527] In further embodiments, the compound is of formula: wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No.
  • the Kv7 channel activator is a compound according to Formula 42: Formula 42 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-pyrrol- 1-yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo and trifluoromethyl; R 3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one
  • R 1 and R 2 together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo.
  • R 3 represents furanyl which is optionally substituted with C 1- 6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents morpholinyl.
  • the Kv7 Channel activator is selected from the group consisting of: 3-Methyl-furan-2-carboxylic acid [2-((R)-3-fluoro-pyrrolidin-1-yl)-4-methyl-6- [1,4]oxazepan-4-yl-pyridin-3-yl]-amide; 3-Methyl-furan-2-carboxylic acid [2-((R)-3-fluoro- pyrrolidin-1-yl)-4-methyl-6-morpholin-4-yl-pyridin-3-yl]-amide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N- oxide thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 43.
  • Such compounds are described in International Publication No. WO2010026104A1, published March 11, 2010, and corresponding to International Application No. PCT/EP2009/061125 filed August 28, 2009; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 43, the reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 43: a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent Ci -6 -alkyl, hydroxy-d-e-alkyl or Ci -6 - alkoxy-Ci- 6 -alkyl; or R 1 and R 2 , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5- dihydro-1 H-pyrrol-1 -yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the
  • R 1 and R 2 independently of each other, represent Ci -6 -alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo, d- e-alkyl and trifluoromethyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclic ring which is pyrrolidinyl optionally substituted one or more times with a substituent selected from the group consisting of halo, d-e-alkyl and trifluoromethyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclic ring which is piperidinyl optionally substituted one or more times with a substituent selected from the group consisting of halo, d-e-alkyl and trifluoromethyl.
  • R 3 represents te/t-butyl.
  • R 3 represents phenyl, which is optionally substituted one or more times with substituents selected from Ci -6 -alkyl, Ci -6 -alkoxy, halo and trifluoromethyl.
  • L represents -CH 2 -.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluorophenyl)-N- ⁇ 2-pyrrolidin-1-yl-6-[(tetrahydro-pyran-4-ylmethyl)- amino]- pyridin-3-yll-acetamide; 3,3-Dimethyl-N- ⁇ 2-pyrrolidin-1-yl-6-[(tetrahydro-pyran-4- ylmethyl)-amino]-pyridin-3-yllbutyramide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 2-morpholin-4-yl-6- [(tetrahydro-pyran-4-ylmethyl)-amino]- pyridin-3-yll-acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 2-dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- pyridin-3-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 44.
  • Such compounds are described in International Publication No. WO2010105960A1, published September 23, 2010, and corresponding to International Application No. PCT/EP2010/053072 filed March 11, 2010; US Publication No. US20110003865A1, published January 6, 2011, and corresponding to US Application No.12/747,394 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 44, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 44: Formula 44 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R 2 represents hydrogen; R 3 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from —CR′R′′—, —CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally
  • R 1 represents alkyl.
  • R 1 represents phenyl optionally substituted one or more times with substituents selected from alkyl and halo.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • R 3 represents alkyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen or alkyl.
  • the Kv7 Channel activator is selected from the group consisting of: N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,5-difluoro- phenyl)-acetamide; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,4- difluoro-phenyl)-acetamide; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3-fluoro-4-trifluoromethyl-phenyl)-acetamide; (S)—N-[2-Diethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-2-phenyl-propionamide; N-[2-Diethylamino-6-(
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 45.
  • Such compounds are described in US Publication No. US20110039896A1, published February 17, 2011, and corresponding to US Application No.12/747,346 filed December 10, 2008; International Publication No. WO2009074593A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067164 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 45, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 45: Formula 45 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents alkyl, phenyl, benzo[1,3]dioxolyl or benzo[1,4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy; R 2 represents hydrogen; R 3 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from —CR′R′′—, —CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloal
  • R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl
  • R 2 represents hydrogen
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl
  • L represents a linker selected from —CR′R′′—, —CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl.
  • R 1 represents phenyl, benzo[1,3]dioxolyl or benzo[1,4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy.
  • R 3 represents alkyl.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen or alkyl.
  • the Kv7 Channel activator is selected from the group consisting of: N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3-fluoro-4- trifluoromethyl-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)-2- pyrrolidin-1-yl-pyridin-3-yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-[6-(4-fluoro- benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide; (S)-N-[6-(4-Fluoro-benzylamino)- 2-pyrrolidin-1-yl-pyridin-3-yl]-2-phenyl
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 46.
  • Such compounds are described in International Publication No. WO2009074591A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067161 filed December 10, 2008; US Publication No. US20110003866A1, published December 10, 2008, and corresponding to US Application No.12/747,414 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 46, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 46: a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R 2 represents hydrogen; R 3 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl,
  • R 1 represents alkyl.
  • R 1 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl.
  • R 3 represents alkyl.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • L represents a linker selected from —CR′R′′—, —CR′R′′— CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • the Kv7 Channel activator is selected from the group consisting of: N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,4-difluoro- phenyl)-acetamide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,5- difluoro-phenyl)-acetamide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3-fluoro-4-trifluoromethyl-phenyl)-acetamide; (S)—N-[2-Dimethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-2-phenyl-propionamide; N-[2-Dimethylamino-6-(2-Dimethylamino-6
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 47.
  • Such compounds are described in US Publication No. US20110003867A1, published January 6, 2011, and corresponding to US Application No.12/747,422 filed December 10, 2008; International Publication No. WO2009074594A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067165 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 47, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 47: Formula 47 , a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R 2 represents hydrogen; R 3 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from —CR′R′′—, —CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally
  • R 1 represents alkyl.
  • R 1 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • R 3 represents alkyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • the Kv7 Channel activator is selected from the group consisting of: N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,5-difluoro- phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,4- difluoro-phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3- yl]-2-(3-fluoro-4-trifluoromethyl-phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionamide; (
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 48.
  • Such compounds are described in International Publication No. WO2007104717A1, published September 20, 2007, and corresponding to International Application No. PCT/EP2007/052239 filed March 9, 2007; US Publication No. US20090036473A1, published February 5, 2009, and corresponding to US Application No.12/278,091 filed March 9, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 48, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 48:
  • Formula 48 including any of its stereoisomers, or any mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 and R 2 , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, baloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, cyano or nitro; R 3 represents alkyl, cycloalkyl or alkoxy; and R 4 and R 5 , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, nitro or cyano.
  • R 1 and R 2 independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, cyano or nitro.
  • R 3 represents alkyl, cycloalkyl or alkoxy.
  • R 4 and R 5 independently of each other, represent hydrogen, alkyd, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl- amino, nitro or cyano.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H- quinazolin-3-yl)-amide; 2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4- oxo-4H-quinazolin-3-yl)-amide; 2-(3-Fluoro-4-methyl-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)- amide; 2-Phenyl-cyclopropanecarboxylic acid (2- isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 49.
  • Such compounds are described in International Publication No. WO2007057447A1, published May 24, 2007, and corresponding to International Application No. PCT/EP2006/068627 filed November 17, 2006; US Publication No. US20090291973A1, published November 26, 2009, and corresponding to US Application No.12/085,188 filed November 17, 2006; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 49, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 49: Formula 49 , including any of its stereoenantiomers or any mixture of its stereoenantiomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R 1 represents hydrogen or alkyl; and R 2 represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl group; or R 1 represents hydrogen; and R 2 together with R 3 attached in ortho-position on the aromatic ring form a —(CH 2 ) n — bridge, wherein n is 1, 2 or 3; R 3 and R 4 , independently of each other, represent hydrogen, alkyl, cycloalkyl,
  • R 1 represents hydrogen or alkyl.
  • R 2 represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro.
  • R 1 represents hydrogen or methyl; and R 2 represents methyl, ethyl, isopropyl, cyclohexyl, fluoro or benzyl.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl group.
  • R 1 represents hydrogen; and R 2 together with R 3 attached in ortho-position on the aromatic ring form a —(CH 2 ) n — bridge, wherein n is 1, 2 or 3.
  • R 3 and R 4 independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, phenyl, benzoyl, cyano or nitro; or R 3 and R 4 together form a methylenedioxy group.
  • R 3 attached in ortho-position on the aromatic ring and together with R 2 form a —(CH 2 )n— bridge, wherein n is 1, 2 or 3; and R 4 is as defined in claim 7.
  • R 5 represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl.
  • R 6 and R 7 independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl- amino(acetamido), nitro, cyano or phenyl.
  • the Kv7 Channel activator is selected from the group consisting of: N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-3-methyl-2-phenyl-butyramide; 2- (4-Chloro-phenyl)-N-(2-isopropylsulfanyl-4-oxo-4H-quinazolin-3-yl)-butyramide; 2-(3,5- Difluoro-phenyl)-N-(2-isopropylsulfanyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)- propionamide; N-(2-Ethyl-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S)- N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S)-
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 50.
  • Such compounds are described in US Patent No.7,741,352, issued June 22, 2010, and corresponding to US Application No.10/546,533 filed March 11, 2004; International Publication No. WO2004080377A2, published September 23, 2004, and corresponding to International Application No. PCT/EP2004/050290 filed March 11, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 50, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 50: Formula 50 , any of its enantiomers or any mixture of its enantiomers, or a prodrug, or a pharmaceutically- acceptable addition salt thereof, wherein R 1 represents —CN; R 2 represents halo, haloalkyl, hydroxyl or alkoxy; X represents, NR′′ or NR′′CH 2 (read in the stated direction); wherein R′′ represents hydrogen; R 4 represents aryl-alkyl, which is substituted one or more times with substituents selected from the group consisting of halo, or methylenedioxy; or R 4 represents a group of formula -Z′-L′′-Z′′; wherein Z′ and Z′′, independently of one another, represent an aryl group, which aryl may be optionally substituted one or more times with halo; and L′′ represents a single (covalent) bond, or a linker selected from O or OCH 2 , with the proviso
  • R 4 represents benzyl which is substituted one or two times with halo or one time with methylenedioxy. [0599] In further embodiments, R 4 represents 4-fluoro-benzyl, 3,4-dichloro-benzyl or benzo[1,3]dioxol-5-ylmethyl.
  • the Kv7 Channel activator is selected from the group consisting of: 4-(4-Fluoro-benzylamino)-2-hydroxy-benzonitrile 4-(3,4-Dichloro- benzylamino)-2-hydroxy-benzonitrile or 4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2- hydroxy-benzonitrile; or a pharmaceutically-acceptable addition salt thereof.
  • R 4 represents a group of formula -Z′-L′′-Z′′; wherein Z′ represents phenyl, or phen-4-yl; which phenyl may optionally be substituted one or two times with halo; and Z′′ represent phenyl; which may optionally be substituted one or two times with halo; and L′′ represents a single (covalent) bond, or a linker selected from alkyl, O, or OCH 2 .
  • R 4 represents 3-phenoxy-phenyl, 3-benzyloxy-phenyl, or biphenyl-4-yl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-Hydroxy-4-(3-phenoxy-benzylamino)-benzonitrile; 4-(3-Benzyloxy- benzylamino)-2-hydroxy-benzonitrile; or 4-[(Biphenyl-4-ylmethyl)-amino]-2-hydroxy- benzonitrile; or a pharmaceutically-acceptable addition salt thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 51. Such compounds are described in US Patent No.7,741,352, issued June 22, 2010, and corresponding to US Application No.10/546,533 filed March 11, 2004; International Publication No.
  • the Kv7 channel activator is a compound according to Formula 51: Formula 51 , wherein, R represents hydrogen, halogen or hydroxy.
  • R 1 , R 2 , R 3 and R 4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p- trihalogenmethyl-phenyl, or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 are joined together to form a benzo fused ring, R 5 represents hydrogen or alkyl, and R 6 represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof.
  • R represents hydrogen, halogen or hydroxy
  • R 1 , R 2 , R 3 and R 4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, and when R 1 and R 4 are hydrogen, then R 2 or R 3 is phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl; or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 are joined together to form a benzo fused ring, R 5 represents hydrogen or alkyl, and R 6 represents halogen or trihalogenmethyl.
  • R 1 , R 3 and R 4 represent hydrogen, and R 2 represents halogen, trihalogenmethyl or phenyl.
  • R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 are joined together to form a benzo fused ring.
  • R 5 is hydrogen or methyl.
  • R 6 is chlorine.
  • the Kv7 Channel activator is selected from the group consisting of: (+)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2- one; ( ⁇ )-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; ( ⁇ )- 3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6(4-methylphenyl)-2H-indol-2-one; ( ⁇ )-3-(5- chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-one; ( ⁇ )-3-(5-chloro-2-hydroxyphenyl)-4,6- dichloro-1,3-dihydro-2H-indol-one; ( ⁇ )-3-(5-chloro-2-methoxyphen
  • R represents hydrogen, halogen or hydroxy
  • R 1 , R 2 , R 3 and R 4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 are joined together to form a bezo fused ring
  • R 5 represents hydrogen or alkyl
  • R 6 represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 52.
  • Such compounds are described in International Publication No. CN114380731A, published April 22, 2022, and corresponding to International Application No. CN202210226122.7A filed March 9, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 52, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 52: Formula 52 , wherein, R 1 is selected from H, halogen, substituted or unsubstituted phenyl, or a substituted or unsubstituted phenylalkyl group, the substituents of said phenyl and phenylalkyl groups each being independently selected from halogen or haloalkyl; X is selected from S or C; R 2 is optionally selected from H, alkyl, alkenyl or alkynyl; R3 and R4 each independently selected from H or alkyl; y is selected from O or S; R 5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy or furyl, the substituent of the alkyl is selected from alkoxy, dialkylamino or alkoxycarbonyl, and the substituent of the cycloalkyl is selected from hal
  • R 2 is selected from H, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkenyl or C 1 -C 3 Alkynyl.
  • R 3 and R 4 are each independently selected from H or C 1 - C 6 An alkyl group.
  • R 5 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy or furyl, the substituents of the alkyl or the alkoxy being selected from C 1 -C 6 Alkoxy, di (C) 1 -C 4 Alkyl) amino or C 1 - C 6 Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen.
  • the formula is one of formulas II – IV: wherein, n is more than or equal to 0;R 11 and R 12 each independently selected from H, halogen or halomethyl; R 2 is selected from H, C 1 -C 3 Alkyl radical, C 2 -C 3 Alkenyl or C 2 -C 3 An alkynyl group; R 3 and R 4 are independently selected from H or C 1 -C 6 alkyl group; y is selected from O or S; R 5 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy or furyl, the substituents of the alkyl being selected from C 1 -C 6 Alkoxy, di (C) 1 -C 4 Alkyl) amino or C 1 -C 6 Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen
  • n is 0 to 3
  • R 11 is selected from H, F or trifluoromethyl
  • R 12 is selected from H, F, Cl or methyl.
  • R 3 is one of H or methyl
  • R 4 is other of H or methyl.
  • R 5 is selected from methyl, ethyl, isopropyl, isobutyl, neopentyl, cyclobutyl, ethoxy, isopropoxy, tert-butoxy or tetrahydrofuranyl.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 53.
  • the Kv7 channel activator is a compound according to Formula 53: Formula 53 , wherein, X 1 represents nitrogen or CR X1 ; wherein R X1 represents hydrogen, halogen, (C 1- 4 )alkyl, or (C 1-4 )alkoxy; X 2 represents nitrogen or CR X2 ; wherein R X2 represents hydrogen, halogen, (C 1-4 )alkyl, or (C 1-4 )alkoxy; X 3 represents nitrogen or CR X3 ; wherein R X3 represents hydrogen, halogen, (C 1-4 )alkyl, (C1- 4)alkoxy, or hydroxy; R 1 represents hydrogen or methyl; R X4 represents hydrogen, halogen, or (C 1-4 )alkyl; • R 2A represents hydrogen; (C 1-4 )alkyl; (C 2- 4 )alkenyl; (C 2-4 )alkynyl; (C 3-6 )cycloalky
  • X 1 represents CR X1 ; wherein R X1 represents hydrogen or halogen; X 2 represents nitrogen or CH; X 3 represents nitrogen or CH; R 1 represents hydrogen; R X4 represents hydrogen, halogen, or (C 1-4 )alkyl; R 2A represents hydrogen; (C 1- 4 )alkyl; (C 1-4 )fluoroalkyl; (C 1-4 )hydroxyalkyl; or (C 1-4 )alkoxy-(C 1- 2 )alkyl; R 2B represents hydrogen; L represents a direct bond, -CH 2 -O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; R 3 represents hydrogen or fluoro; • R 4 represents hydrogen or (C 1-4 )alkyl; R 5 represents hydrogen, fluoro, or hydroxy; and R 6 represents fluoro or (C 1 )fluoroalkyl; or • R 4 and R 5 together represent a bridge selected
  • R 2A represents hydrogen, (C 1-4 )alkyl, (C 1-4 )fluoroalkyl, (C 1- 4 )hydroxyalkyl, or methoxymethyl; and R 2B represents hydrogen; or a salt thereof.
  • L represents a direct bond; or a salt thereof.
  • R 3 represents fluoro; or a salt thereof.
  • R X4 represents hydrogen; or a salt thereof.
  • each of X 1 , X 2 , and X 3 represents CH; or a salt thereof.
  • the fragment represents: wherein R X4 represents hydrogen or halogen; R 3 represents hydrogen or fluoro; and L represents a direct bond, -CH 2 -O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; or • ; wherein X 3 represents nitrogen or CH; R X4 represents hydrogen or (C 1-4 )alkyl; R 3 represents hydrogen or fluoro; and L represents - CH 2 -O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; or a salt thereof.
  • R 4 represents hydrogen; R 5 represents hydrogen or fluoro; and R 6 represents fluoro, difluoromethyl or trifluoromethyl; or a salt thereof.
  • R 4 and R 5 together represent a -CH 2 - bridge; and R 6 represents hydrogen, fluoro, difluoromethyl, or trifluoromethyl; or a salt thereof.
  • the Kv7 Channel activator is selected from the group consisting of: 1-(3,3-Difluoro-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-urea; 1- Bicyclo[1.1.1]pent-1-yl-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl- cyclobutyl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Diflu
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 54.
  • Such compounds are described in International Publication No. WO2021219594A1, published November 4, 2021 and corresponding to International Application No. PCT/EP2021/060918 filed April 27, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 54, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 54: Formula 54 , wherein, X 1 represents nitrogen or CR x1 ; wherein R X1 represents hydrogen, halogen, (C 1- 4 )alkyl, or (C 1- 4 )alkoxy;X 2 represents nitrogen or CR X2 ; wherein R X2 represents hydrogen, halogen, (C 1-4 )alkyl, or (C 1- 4 )alkoxy; X 3 represents nitrogen or CR X3 ; wherein R X3 represents hydrogen, halogen, (C 1-4 )alkyl, (C 1- 4 )alkoxy, or hydroxy;• R 1 represents hydrogen, or methyl; or• R 1 and R X1 together represent a -CH 2 CH 2 - bridge; Y represents -C(R Y1 )(R Y2 )-, or *-CH 2 -C(R Y3 )(R Y4 )-, wherein
  • R 1 represents hydrogen; or a salt thereof (meaning a salt of compound of Formula 54).
  • R Y1 , R Y2 , R Y3 and R Y4 all represent hydrogen; or a salt thereof.
  • R 2A represents hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C1- 4 )fluoroalkyl, (C 1-4 )hydroxyalkyl, (C 1-4 )alkoxy-(C 1-2 )alkyl, (C 1-2 )alkyl-S-(C 1-2 )alkyl, (C 1- 2 )alkyl-(SO 2 )-(C 1-2 )alkyl, cyano, (C 1- 2 )cyanoalkyl, H 2 N-C(O)-(C 1-2 )alkyl, (R N1 ) 2 N-(C 1- 2 )alkyl, or (R N1 ) 2 N-C(O)-, wherein R N1 independently represents hydrogen or (C 1-2 )alkyl; and R 2B represents hydrogen; or R 2A and R 2B form, together with the carbon atom to which they are attached, a ring of 3- to
  • R 2A represents hydrogen, methyl, or hydroxymethyl; and R 2B represents hydrogen; or a salt thereof.
  • R 3 represents a fragment , where 31 inR represents hydrogen, or fluoro; and L represents a direct bond, -CHR L -O- * , -O-CH 2 - * , -CH 2 -NH- * , -CH 2 - N(CH 3 )- * , or -O-; wherein R L represents hydrogen, methyl, CH 3 -O-CH 2 -, or (CH 3 ) 2 NCH 2 -; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or a salt thereof.
  • R 4 represents hydrogen; or a salt thereof.
  • the fragment represents: wherein X 3 represents nitrogen and X 1 represents CR X1 ; X 1 represents nitrogen and X 3 represents CR X3 ; or X 1 represents CR X1 and X 3 represents CR X3 ; or a salt thereof.
  • the fragment represents wherein R X1 represents hydrogen, fluoro, chloro, methyl, or methoxy; R X2 represents hydrogen; R X3 represents hydrogen, fluoro, or chloro; R 4 represents hydrogen, fluoro, chloro, or methyl; R 31 represents hydrogen, or fluoro; and L represents a direct bond, -CHR L -O- * , - CH 2 -NH- * , -CH 2 -N(CH 3 )- * , -O-, or ; wherein R L represents hydrogen, or methyl; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or wherein X 3 represents nitrogen and X 1 represents CR X1 ; X 1 represents nitrogen and X 3 represents CR X3 ; or X 1 represents CR X1 and X 3 represents CR X3 ; wherein R X1 represents hydrogen, or methoxy; R X3 represents hydrogen; R 4 represents hydrogen,
  • X 1 represents CR X1 ; wherein R X1 represents hydrogen; X 2 represents nitrogen or CR X2 ; wherein R X2 represents hydrogen; X 3 represents nitrogen or CR X3 ; wherein R X3 represents hydrogen; R 1 represents hydrogen; Y represents -CH 2 -, or - CH 2 -CH 2 -; R 2A represents hydrogen, or hydroxymethyl;R 2B represents hydrogen; R 3 represents trifluoromethyl or 2,2,2-trifluoroethoxy; and R 4 represents hydrogen; or a salt thereof.
  • the Kv7 Channel activator is selected from the group consisting of: 1-Spiro[3.3]hept-2-yl-3-(3-trifluoromethyl-benzyl)-urea;1-Spiro[2.3]hex-5-yl- 3-(3-trifluoromethyl-benzyl)-urea;1 -(1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3r,5r)-1,1-Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3s,5s)-1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-(6,6-Difluoro-spir
  • the Kv7 channel activator may be selected from one of the following compounds of Formula 55.
  • Such compounds are described in International Publication No. WO2020157126A1, published August 6, 2020, and corresponding to International Application No. PCT/EP2020/052156 filed January 29, 2020; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 55, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 55: Formula 55 , or a tautomer, salt, solvate, stereoisomer or isotope thereof, wherein: Y is selected from: C1- C10 alkylamino, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, Cl- C10 alkylcarbonyl, Cl -CIO alkylaminocarbonyl, Cl -CIO alkylthio, aryl, heterocycle, Cl -CIO carbonyl, C1-C10 amide and C1-C10 carboxyl and it is optionally mono-substituted or bi- substituted with a first substituent independently selected from: hydroxyl, amino, thiol, carboxylic acid, amide, carbonyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbon
  • b is 1.
  • Y is Cl -CIO alkylamino, Cl -CIO alkyl or Cl -CIO alkoxy.
  • R2 is an aromatic ring optionally substituted with one or more substituents independently selected from the group consisting of: OH, NO2, halogen, NH2, C1-C3 haloalkyl, acetamidyl, C1-C6 alkyloxy, C1-C3 haloalkoxy, and C1-C6 alkylcarbonyl.
  • Ri, R3, R4 and R5 are each independently: H, C1-C6 alkyl, C3- C6 cycloalkyl, NH 2 , NH(C1-C6 alkyl), N(C1-C6 alkyl)2 , azepane, pirrolidine, piperidine, aziridine or halogen.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 56.
  • Such compounds are described in International Publication No. WO2020016297A1, published January 23, 2020, and corresponding to International Application No. PCT/EP2019/069240 filed July 17, 2019; Patent Cooperation Treaty application No. PCT/EP2019/069240 published January 23, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 56, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 56: Formula 56 , wherein, R 1 is selected from a branched or unbranched C1 to C5 alkyl group and – NR 1a R 1b group, where R 1a and R 1b are selected independently of one another from hydrogen atom and branched or unbranched C1 to C5 alkyl group or with one another and with the nitrogen atom the NR 1a R 1b group form a C3 to C9 heterocycloalkyl group, the C3 to C9 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR 1a R 1b - Group has at least one further heteroatom in the cycle; R 2 is selected from the group consisting of branched or unbranched C1 to C10 alkyl group, C3 to C10 cycloalkyl group, C3 to C10 heterocycloalky
  • R 1 is selected from the group consisting of branched or unbranched C1- to C3-alkyl group and - NR 1a R 1b group, wherein R 1a and R 1b are independently selected from hydrogen atom and branched or unbranched C1- to C3-alkyl group or with one another and form a C4 to C6 heterocycloalkyl group with the nitrogen atom of the NR 1a R 1b group, the C4 to C6 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR 1a R 1b group has at least one further oxygen atom in the cycle; and or R 2 is selected from the group consisting of mono- or difluorophenyl group; CF 3 phenyl group;
  • the Kv7 channel activator is selected from the group consisting of: Formulas 57 – 139
  • the Kv7 channel activator may be selected from one of the following compounds of formulas 57 - 139. Such compounds are described in International Publication No. WO2018204765A1, published November 8, 2018, and corresponding to International Application No. PCT/US2018/031057 filed May 4, 2018; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any of Formulas 57 - 139, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to any one of formulas 57 – 139:
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 140.
  • Such compounds are described in International Publication No. WO2016077724A1, published May 19, 2016, and corresponding to International Application No. PCT/US2015/060627 filed November 13, 2015; US Patent No.10,526,280, issued January 7, 2020 and corresponding to US Application No. US10526280B2 filed November 11, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 140, this reference incorporated by reference herein controls.
  • the Kv7 channel activator is a compound according to Formula 140: Formula 140 , wherein, R 1 is H or optionally-substituted alkyl;R 2 is optionally-substituted alkyl;R 3 and R 4 are each independently H or optionally-substituted alkyl;R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;R 6 and R 7 are each independently H, deuterium, optionally- substituted alkyl, or R 6 and R 7 together form a carbocycle;R 8 is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R 8 is 4- halophenyl, then R 2 is substituted alkyl or branched alkyl or at least one of R 6 or R 7 is not H; andR 30 , R 31 and R 32 are each independently H, deuterium,
  • R 1 is H.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is carbocyclic-substituted alkyl or heterocyclic-substituted alkyl.
  • R 3 and R 4 are each H.
  • R 5 is H.
  • R 6 and R 7 are both H; R 6 and R 7 are both deuterium; R 6 and R 7 together form a cycloalkyl; or at least one of R 6 or R 7 is a substituted alkyl.
  • R 8 is selected from: wherein R 9 25 -R are each independently H, halogen, optionally-substituted sulfanyl, or optionally-substituted alkyl. [0671] In further embodiments, R 8 is: wherein at least one of R 9 or R 10 is halogen. [0672] In further embodiments, R 8 is: wherein at least one of R 19 or R 20 is halogen. [0673] In further embodiments, R 8 is: wherein at least one of R 14 -R 18 is substituted sulfanyl or haloalkyl; or wherein R 16 is F.
  • R 14 -R 18 is —SF 5 or CF 3 .
  • R 8 is wherein at least one of R 11 -R 13 or R 23 -R 25 is substituted sulfanyl.
  • R 8 is: wherein at least one of R 14 -R 18 is halo- substituted sulfanyl, haloalkyl or halogen.
  • at least one of R 14 -R 18 is —SF 5 or —CF 3 .
  • R 15 , R 16 , or R 17 is —SF 5 or —CF 3 .
  • R 32 is —F
  • R 30 and R 31 are each H.
  • the Kv7 Channel activator is selected from the group consisting of: [0681]
  • the compound is according to formula 141 wherein: R 1 is H or optionally-substituted alkyl; R 2 is substituted alkyl having one or more hydrogen atoms substituted with a substituent selected from halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl; R 3 and R 4 are each independently H or optionally-substituted alkyl; R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R 6 and R 7 are each independently H, deuterium, optionally-substituted alkyl, or R 6 and R 7 together form a carbocycle; R 8 is optionally-substituted thiazolyl
  • the compound is according to formula 141 wherein: R 1 is H or optionally-substituted alkyl; R 2 is optionally-substituted alkyl; R 3 and R 4 are each independently H or optionally-substituted alkyl; R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R 6 and R 7 are each independently H, deuterium, optionally-substituted alkyl, or R 6 and R 7 together form a carbocycle, provided at least one R 6 or R 7 is not H; R 8 is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R 8 is 4-halophenyl, then R 2 is substituted alkyl or branched alkyl or at least one of R 6 or R 7 is not H; andR 30 , R 31 and R 32 are each independently H,
  • the compound is according to formula 141 wherein: R 1 is H or optionally-substituted alkyl;R 2 is optionally-substituted alkyl;R 3 and R 4 are each independently H or optionally-substituted alkyl;R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;R 6 and R 7 are each independently H, deuterium, optionally-substituted alkyl, or R 6 and R 7 together form a carbocycle;R 8 is 14 wherein at least one of R - R 18 is substituted sulfanyl or haloalkyl; andR 3 and R 31 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy; andR 32 is deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.
  • R 32 is halogen. [0685] In further embodiments, R 32 is —F. [0686] In further embodiments, at least one of R 14 -R 18 is halo-substituted sulfanyl. [0687] In further embodiments, at least one of R 14 -R 18 is haloalkyl. [0688] In further embodiments, at least one of R 14 -R 18 is —SF 5 . [0689] In further embodiments, at least one of R 14 -R 18 is —CF 3 . [0690] In further embodiments, R 16 is —SF 5 . [0691] In further embodiments, R 16 is —CF 3 .
  • R 2 is alkyl.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is ethyl.
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each H.
  • R 32 is —F and R 16 is —CF 3 .
  • R 2 is alkyl.
  • R 3 and R 31 are each H.
  • R 15 , R 16 , or R 17 is —SF 5 or —CF 3 .
  • R 1 , R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 are each H; R 2 is alkyl; and R 32 is —F.
  • Formula 141 the Kv7 channel activator may be selected from one of the following compounds according to Formula 141. Such compounds are described in International Publication No. WO2016077724A1, published May 19, 2016, and corresponding to International Application No. PCT/US2015/060627 filed November 13, 2015; US Patent No.10,526,280, issued January 7, 2020, and corresponding to US Application No. US10526280B2 filed November 11, 2015; which are incorporated by reference in their entirety herein.
  • the Kv7 channel activator is a compound according to Formula 141: wherein, R 1 is H or optionally-substituted alkyl; R 2 is optionally-substituted alkyl; R 3 and R 4 are each independently H or optionally-substituted alkyl; R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R 6 and R 7 are each independently H, deuterium, optionally- substituted alkyl, or R 6 and R 7 together form a carbocycle; andR 8 is optionally-substituted thiazolyl.
  • the compound is according to formula 142 wherein: R 1 is H or optionally-substituted alkyl; R 2 is optionally-substituted alkyl; R 3 and R 4 are each independently H or optionally-substituted alkyl; R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R 6 and R 7 are each independently H, deuterium, optionally-substituted alkyl, or R 6 and R 7 together form a carbocycle; and R 8 is substituted thiophenyl, wherein at least one substituent on the thiophenyl is halo-substituted sulfanyl.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 142.
  • Such compounds are described in US Patent No.10,077,245, issued September 18, 2018, and corresponding to US Application No. 15/306,971 filed April 22, 2015; US Patent No.10,316,008, issued June 11, 2019 and corresponding to US Application No.15/870,276 filed January 12, 2018; international Publication No. WO2015165352A1, published November 5, 2015 and corresponding to International Application No. PCT/CN2015/077216 filed April 22, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 142, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 142: wherein, X is selected from a group consisting of oxygen and sulfur; n is 1, 2 or 3;R 1 is H or halogen;R 2 and R 3 are each independently selected from a group consisting of H, D and C 1 - C 3 alkyl; or R 2 and R 3 together with the carbon atom to which they attached form C 3 - C 6 saturated ring;R 4 and R 5 are each independently selected from a group consisting of H; halogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; cyano; alkoxyl; C 1 -C 6 alkyl substituted by hydroxy, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, or halogen; C 1 -C 4 alkoxy substituted by halogen; C 1 -C 6 alkylcarbonyl; C 1 -C 6 alkoxycarbon
  • R 1 is H or fluorine
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 together with the carbon atom to which they attached form cyclopropyl
  • one of R 4 and R 5 is C 1 -C 4 alkyl, and the other is H or C 1 -C 4 alkyl.
  • one of R4 and R5 is methyl, and the other is H or methyl.
  • Formula 143 [0708]
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 143. Such compounds are described in US Patent No.10,077,245, issued September 18, 2018, and corresponding to US Application No.
  • the Kv7 channel activator is a compound according to Formula 143: Formula 143 , wherein, X: is selected from a group consisting of oxygen and sulfur;R 1 is H or halogen;R 2 and R 3 are each independently selected from a group consisting of H, D and C 1 - C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- C 6 saturated ring;R 4 and R 5 are each independently selected from a group consisting of H; halogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; cyano; C 1 -C 4 alkoxyl; C 1 -C 6 alkyl substituted by hydroxy, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, or halogen; C 1 -C 4 alkoxy substituted by halogen; C 1 -C 6 alkylcarbonyl; C 1 -C 6 alkylcarbonyl; C
  • R 1 is H or fluorine
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 together with the carbon atom to which they attached form cyclopropyl
  • one of R 4 and R 5 is C 1 -C 4 alkyl, and the other is H or C 1 -C 4 alkyl.
  • Formula 144 - 146 [0711]
  • the Kv7 channel activator may be selected from one of the following compounds according to any one of Formulas 144 - 146.
  • the Kv7 channel activator is a compound according to a formula from the group consisting of 144, 145, and 146:
  • R 2 and R 3 are each independently selected from a group consisting of H, D and C 1 - C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- C 6 saturated ring;
  • R 4 and R 5 are each independently selected from a group consisting of H; C 1 - C 6 alkyl; C 1 -C 4 alkoxyl; C 1 -C 6 alkyl substituted by halogen; C 1 -C 4 alkoxy substituted by halogen; provided that R 4 and R 5 are not simultaneously hydrogen;
  • R 9 is selected from a group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
  • R 10 is selected from a group consisting of C 1 - C 6 alkyl; C 1 -C 6 alkyl substituted by halogen, cyano, hydroxy, C 1 -C 6 alkoxyl, di(C 1 - C 4 alkyl)amino, C 1 -
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 together with the carbon atom to which they attached form cyclopropyl; one of R 4 and R 5 is C 1 -C 1 alkyl, and the other is H or C 1 -C 4 alkyl;R 9 is selected from a group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;R 10 is selected from a group consisting of C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by halogen, cyano, hydroxy, C1- C 6 alkoxyl, di(C 1 -C 4 alkyl)amino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylamido, or C 1 - C 6 alkoxycarbonyl; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl; C 3 -C 6
  • R 9 is selected from a group consisting of methyl, ethyl and propyl
  • R 10 is selected from a group consisting of C 1 -C 3 alkyl; C 1 -C 3 alkyl substituted by halogen, cyano, hydroxy, C 1 -C 3 alkoxyl, di(C 1 -C 3 alkyl)amino, C 1 -C 3 alkylcarbonyl, C 1 - C 3 alkylamido, or C 1 -C 3 alkoxycarbonyl; C 3 -C 6 cycloakyl; C 3 -C 6 cycloakyl substituted by halogen; tetrahydrofuranyl; and wherein, R 7 and R 8 are each independently selected from a group consisting of C 1 -C 3 alkyl.
  • the Kv7 Channel activator is selected from the group consisting of: Formula 147
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 147. Such compounds are described in International Publication No. WO2013165575A1, published November 7, 2013, and corresponding to International Application No. PCT/US2013/030984 filed March 13, 2013; US Patent No.9,556,114 issued January 31, 2017, and corresponding to US Application No. 14/566,167 filed December 10, 2014; US Publication No. US20170096390A1, published April 6, 2017, and corresponding to US Application No.15/380,216 filed December 15, 2016; which are incorporated by reference in their entirety herein.
  • the Kv7 channel activator is a compound according to Formula 147: Formula 147 or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from hydrogen, deuterium, and F; X 9 and X 10 are each independently selected from hydrogen and deuterium; and n is 1, 2, or 3, wherein at least one of X 1 , X 2 , and X 3 is F.
  • the Kv7 channel activator is: wherein, A is N or C—X 3 ; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from hydrogen, 19F and 18F; and n is 2 or 3, provided that one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is 18F. [0719] In further embodiments, two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are F.
  • the Kv7 channel activator is: wherein, X 1 , X 2 , X 3 , and X 6 are each independently selected from hydrogen, 18F, and 19F, provided that one of X 1 , X 2 , X 3 , and X 6 is 18F.
  • X 6 is fluorine and one of X 1 , X 2 , and X 3 is fluorine.
  • one of X1, X2, X3, and X6 is 18F.
  • at least one of X 1 , X 2 , and X 3 is 19F.
  • X 6 is 19F or 18F.
  • the compound is selected from the group consisting of: Formula 148
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 148. Such compounds are described in US Publication No. US20130184294A1, published July 18, 2013, and corresponding to US Application No.13/822,669 filed September 7, 2011; International Publication No.
  • the Kv7 channel activator is a compound according to Formula 148: Formula 148 , wherein, R 1 is alkyl, cycloalkyl, wherein alkyl or cycloalkyl may be substituted with one or more halogen, alkoxy, aryl, or aryloxy; R 2 is cycloalkyl or NR 4 R 5 ; R 3 is H, halogen, alkyl, or alkoxy, wherein any alkyl may be substituted with one or more halogen atoms; R 4 and R 5 are independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, or —C 1-6 alkyl-C 3-6 cycloalkyl, wherein each alkyl or each cycloalkyl may be substituted with one or more halogen, provided that both R 4 and R 5 are not H simultaneously; or R 4 and R 5 , together with the N atom to which they are attached, form a heterocycloal
  • R 1 is C 5-6 alkyl
  • R 2 is NR 4 R 5 , wherein one of R 4 or R 5 is H and the other is C 3-6 alkyl, C 3-6 cycloalkyl, or —C 1-3 alkyl-C 3-6 cycloalkyl
  • R 3 is halogen, alkyl, or alkoxy, wherein any alkyl may be substituted with one or more halogen atoms
  • —X—Y— is ⁇ CH—CH ⁇ or —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is —CH 2 C(CH 3 ) 3 ;
  • R 3 is chloro, methyl, trifluoromethyl or 1,1-difluoroethoxy;
  • R 4 is H and
  • R 5 is isopropyl, isobutyl, 1-cyclopropylethyl, cyclobutyl or cyclopentyl;
  • —X—Y— is ⁇ CH—CH ⁇ or —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is C 5-6 alkyl
  • R 2 is C 3-6 cycloalkyl
  • R 3 is halogen, or alkyl, wherein alkyl may be substituted with one or more halogen atoms
  • —X—Y— is ⁇ CH— CH ⁇ or —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is —CH 2 C(CH 3 ) 3 ;
  • R 2 is cyclopropyl;
  • R 3 is chloro, methyl, trifluoromethyl or 1,1-difluoroethoxy;
  • —X—Y— is ⁇ CH—CH ⁇ or —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • Formula 149 [0733]
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 149. Such compounds are described in US Patent No.8,466,201, issued June 18, 2013, and corresponding to US Application No.
  • the Kv7 channel activator is a compound according to Formula 149: Formula 149 , wherein, Ar 1 and Ar 2 are each phenyl; are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5;R 1 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substitu
  • R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different.
  • b is an integer of from 0 to 4.
  • R 2 is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.
  • R 4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.
  • V is selected from the group consisting of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of from 0 to 2, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO—[(CR (CR 6a R 6b ) c1 — O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of 0 or 1, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO—[(CR 6a R 6b ) c1 —O— (CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R 6a , R 6b , R 6c , R 6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atom
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of 0 or 1, each of R 3a and R 3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO—- [CR 6a R 6b ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R 6a , R 6b , R 6c and R 6d is a hydrogen atom.
  • Ar 1 and Ar 2 are each phenyl; a is an integer of from 0 to 3;R 1 is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphony
  • Ar 1 and Ar 2 are each phenyl; a is 0 or 1;R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is an integer of from 0 to 3;R 2 is
  • Ar 1 and Ar 2 are each phenyl; a is 0 or 1;R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is 0 to 3;R 2 is selected from the group
  • Ar 1 and Ar 2 are each phenyl; a is an integer of from 0 to 3;R 1 is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphony
  • the Kv7 Channel activator is selected from the group consisting of: 1-[2-(2,6-Dichlorophenylamino)phenyl]-N-[2-(2-hydroxyethoxy)ethyl]- methanesulfonamide,N-[2-(2-hydroxyethoxy)ethyl]-C-[2-(2,4,6- trichlorophenylamino)phenyl]-methanesulfonamide,1-[2-(2,6-dichloro-4- trifluoromethylphenylamino)phenyl]-N- ⁇ 2-(2-hydroxyethoxy)ethyl]methanesulfonamide,1- [2-(2,6-dichloro-3-methylphenylamino)phenyl]-N- ⁇ 2-(2-hydroxyethoxy)- ethyl]methanesulfonamide,N-(2-hydroxyethyl)-1-[3-(2,4,6- trich
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R 1 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is an integer of from 0 to 5;R 2 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, haloalkoxy groups,
  • Ar 1 and Ar 2 are the same or different and each is an aryl group having from 5 to 14 carbon atoms or a 5- to 7-membered aromatic heterocyclic group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
  • Ar 1 and Ar 2 are the same or different and each is an aryl group having from 6 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 sulfur atoms, oxygen atoms and/or nitrogen atoms.
  • Ar 1 and Ar 2 are each phenyl.
  • R 2 is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, haloalkoxy groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.
  • W is a group of formula NR 4a , wherein R 4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.
  • Y and Z are each a group of formula (CR 5a R 5b ) n1 wherein each n1 is 0.
  • V is selected from the group consisting of (CR 3a R 3b ) p CON(R 3b )X and (CR 3a R 3b ) p N(R 3b CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of from 0 to 2, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7- membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the
  • V is selected from the group consisting of (CR 3a R 3b ) p CON(R 3b )X and (CR 3a R 3b ) p N(R 3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms, polyalkylene glycol residues of general formula HO—[(CR 6a R 6b ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10
  • V is selected from the group consisting of (CR 3a R 3b ) p CON(R 3b )X and (CR 3a R 3b ) p N(R 3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R 3a and R 3b is a hydrogen atom, and X is selected from the group consisting of alkyl groups having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is 0 or 1;R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, nitro groups, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, wherein: Ar 1 and Ar 2 are each
  • the Kv7 Channel activator is selected from the group consisting of: N-(2-hydroxyethyl)-2-[3-(2,4,6-trichlorophenylamino)phenyl]acetamide; ⁇ 2-[5- (3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino ⁇ acetic acid; 2-[4-(2,6-dichloro-4- trifluoromethyl-phenylamino)-phenyl]-N-(2-hydroxyethyl)-acetamide; ⁇ 2-[4-(3,5- dichlorophenylamino)-phenyl]-acetylamino ⁇ acetic acid;N-(2-hydroxy-ethyl)-2-[4-(2,4,6- trichloro-phenylamino)-phenyl]acetamide; 3-(2,6-dichloro-4-trifluoromethyl-phenylamino)- N-(
  • the compound is according to formula 150 wherein: Ar 1 and Ar 2 are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R 1 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is an integer of from 0 to 5; R 2 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, haloalkoxy groups, alkoxycarbonyl groups, carb
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is 1; R 1 is halogen; b is an integer of from 0 to 3; R 2 is selected from the group consisting of alkyl having from 1 to 3 carbon atoms, halogen, haloalkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, haloalkoxy having from 1 to 3 carbon atoms, carboxyl, amino, hydroxyl and cyano, and where b is greater than 1, each substituent R 2 may be the same or different; V is (CR 3a R 3b ) p CON(R 3b )X, wherein said group is in the 3-(meta) or 4-(para) position with respect to the substituent Z;W is NR 4a , wherein R 4a is selected from the group consisting of hydrogen, alkyl having from 1 to 3 carbon atoms and phenyl; X is
  • V is (CR 3a R 3b ) p CON(R 3b )X, wherein said groups is in the 3- (meta) or 4-(para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R 3a and R 3b is hydrogen, and X is selected from the group consisting of alkyl having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.
  • the Kv7 Channel activator is selected from the group consisting of: ⁇ 2-[5-(3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino ⁇ acetic acid; 2- [5-(2,6-dichloro-4-trifluoromethoxy-phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy- ethyl)acetamide; 5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-N-(2-hydroxy- ethyl)-benzamide; 2-[5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-phenyl]-N-(2- hydroxy-2-methyl-propyl)acetamide; and 2-[4-(2,6-dichloro-4-trifluoromethoxy- phenylamino)-2-fluoro-
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R 1 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is an integer of from 0 to 5; R 2 is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups,
  • R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different.
  • b is an integer of from 0 to 4.
  • R 2 is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.
  • R 4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.
  • V is selected from the group consisting of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of from 0 to 2, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO—[(CR (CR 6a R 6b ) c1 — O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of 0 or 1, R 3a and R 3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO—[(CR 6a R 6b ) c1 —O— (CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R 6a , R 6b , R 6c , R 6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atom
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(R 3b )X, wherein p is an integer of 0 or 1, each of R 3a and R 3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO—- [CR 6a R 6b ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R 6a , R 6b , R 6c and R 6d is a hydrogen atom.
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is an integer of from 0 to 3;R 1 is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is 0 or 1;R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is an
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is 0 or 1; R 1 is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R 1 may be the same or different; b is
  • the compound is according to Formula 149 wherein: Ar 1 and Ar 2 are each phenyl; a is an integer of from 0 to 3; R 1 is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 150.
  • Such compounds are described in International Publication No. WO2012004698A1, published January 12, 2012, and corresponding to International Application No. PCT/IB2011/052686 filed June 20, 2011; US Patent No.8,883,812, issued November 11, 2014 and corresponding to US Application No. 13/808,355 filed June 20, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 150, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 150: Formula 150 , wherein, n is an integer of 1 or 2; t is 0 or 1; each R 1 is independently selected from C 1- 3 alkoxy, C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl; R 2 and R 3 are independently C 1-3 alkyl, C 1- 3 alkoxy, or C 3-6 cyloalkyl provided that at least one is C 1-3 alkoxy; R 4 is C 1-6 alkyl, C 1-3 alkyl- C 3-6 cyloalkyl, C 3-6 heterocycloalkyl; or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each C 1-3 alkoxy; wherein R 4 is C 4-6 alkyl, and wherein n and t are each 1, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each methoxy; R 4 is —CH 2 -t-butyl, and n and t are each 1, or a pharmaceutically acceptable salt thereof.
  • the compound is N-(4,6-dimethoxy-2-(4-methoxypiperidin- 1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 151.
  • Such compounds are described in US Patent No.9,353,048 issued May 31, 2016, and corresponding to US Application No.14/353,842 filed October 23, 2012; International Publication No. WO2013060097A1, published May 2, 2013, and corresponding to International Application No. PCT/CN2012/001423 filed October 23, 2012; which are incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control are described in US Patent No.9,353,048 issued May 31, 2016, and corresponding to US Application No.14/353,842 filed October 23, 2012; International Publication No. WO2013060097A1, published May 2, 2013, and corresponding to International Application No. PCT/CN2012/001423 filed October 23, 2012; which are incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control are described in US Patent No.9,353,048 issued May 31, 2016, and corresponding to US Application No.14/353,842 filed
  • the Kv7 channel activator is a compound according to Formula 151: Formula 151 , wherein, R 1 is a radical selected from the group consisting of C 2 -C 8 alkenyl, C 5 - C 7 cycloalkenyl and C 2 -C 8 alkynyl; wherein, the C 2 -C 8 alkenyl is unsubstituted or optionally substituted by hydroxyl, amino, halogen atom, phenyl or halogenated phenyl; the C 2 - C 8 alkynyl is unsubstituted or optionally substituted by hydroxyl, amino, halogen atom, phenyl or halogenated phenyl; R 2 is a radical selected from the group consisting of F, Cl and methoxyl;R 3 is a radical selected from the group consisting of H, halogen atom and trifluoromethyl; Y is not present or Y is O;R 4 is a radical selected from
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 152.
  • the Kv7 channel activator may be selected from one of the following compounds.
  • Such compounds are described in International Publication No. US20100057224A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; US Patent No.8,629,143 published January 14, 2014, and corresponding to US Application No.12/949,435 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 152, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 152: Formula 152 , or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein Z is a ring fused with the pyridazine ring, selected from the group consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle, and heteroaryl;R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO 2 , -OR a , -OC(O)R a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , - S(O) 2 R a , -S(O)
  • Z 1 is benzo, heteroaryl, or cycloalkyl.
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a .
  • R 4 is unsubstituted alkyl, haloalkyl, -C(R 4a R 4b ) n -G 4a , or alkyl substituted with a -S(R la ) group.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; and R 4 is unsubstituted alkyl, haloalkyl, -C(R 4a R 4b ) n -G 4a , or alkyl substituted with a -S(R la ) group.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; and R 4 is -C(R 4a R 4b ) n -G 4a .
  • Z 1 is benzo, cycloalkyl, or heteroaryl;
  • R 4 is -C(R 4a R 4b ) n -G 4a ; and
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a .
  • Z 1 is benzo, cycloalkyl, or heteroaryl;
  • R 4 is -C(R 4a R 4b ) n - G 4a ;
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a ; and
  • G 3a is aryl or cycloalkyl.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; andR 4 is unsubstituted alkyl or haloalkyl.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; R 4 is unsubstituted alkyl or haloalkyl; and R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a .
  • Z 1 is benzo, cycloalkyl, or heteroaryl; R 4 is unsubstituted alkyl or haloalkyl; R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a ; and G 3a is aryl or cycloalkyl.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; and R 4 is alkyl substituted with a -S(R la ) group.
  • Z 1 is benzo, cycloalkyl, or heteroaryl;
  • R 4 is alkyl substituted with a -S(R la ) group; and
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a .
  • Z 1 is benzo, cycloalkyl, or heteroaryl;
  • R 4 is alkyl substituted with a -S(R la ) group;
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a ; and
  • G 3a is aryl or cycloalkyl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(4-chlorophenyl)-N-(4-isopropyl-l-oxophthalazin-2(lH)-yl)acetamide; 2-( 1 - adamantyl)-N- [4-(4-bromophenyl)- 1 -oxophthalazin-2( 1 H)-yl]acetamide; N-[4-(4- bromophenyl)-l-oxophthalazin-2(lH)-yl]-2-(4-chlorophenyl)acetamide; 2-(4-chlorophenyl)- N-( 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(3,5-difluorophenyl)-N-(4-isopropyl- l-oxophthalazin-2(lH)-yl)acetamide;
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 153.
  • Such compounds are described in US Patent No.8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 153, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 153: Formula 153 , or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein, R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO 2 , -OR a , -OC(O)R a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b ,- N(R
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 154.
  • Such compounds are described in US Patent No.8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 154, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 154: Formula 154 , or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, whereinR 1 is an optional substituent wherein each occurrence of R 1 is independently G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO 2 , -OR a , -OC(O)R a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b ,- N(R a
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 155.
  • Such compounds are described in US Patent No.8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 155, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 155: Formula 155 , or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO 2 , -OR a , -OC(O)R a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b ,- N(R a
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 156.
  • Such compounds are described in US Patent No.8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 156, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 156: Formula 156 , or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO 2 , -OR a , -OC(O)R a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b ,- N(R a
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 157.
  • Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No.12/223,136 filed January 25, 2007; International Publication No. WO2007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 157, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 157: [0810] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-5,7-Diiodo-8-hydroxyquinoline and zinc-8-Hydroxyquinoline. [0811] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-pyrrolidine dithiocarbamate, zinc-diethyldithiocarbamate, zinc-disulfiram and zinc-dimethyldithiocarbamate. [0812] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-vitamin E and zinc-vitamin A.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 158.
  • Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No.12/223,136 filed January 25, 2007; International Publication No. WO2007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 158, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 158: Formula 158 wherein, A is a bond, CH 2 , CHR b , CH 2 S, CHR b S, CH 2 O, CH 2 NR c , or NH; Rb is alkyl; R c is H or S(O) m -aryl; R 1 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted cycloalkyl, or an optionally substituted heteroaryl; R 2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, an optionally substituted aralkyl, H or alkyl; each R d and R e is independently an optionally substituted alkyl, an optionally substituted aryl, or R d and R e together
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 159.
  • Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No.12/223,136 filed January 25, 2007; International Publication No. WO2007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 159, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 159: Formula 159 wherein, R 4 is H, an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, allyl, or an optionally substituted aryl; R 5 is H, hal, or hydroxyl; R 6 is H, hal, hydroxyl, NH 2 , a mono- or di-substituted amine, or an optionally substituted alkoxy; R 7 is H, hal, hydroxyl, an optionally substituted alkoxy, or nitro; X is S or NR a ; Y is O, S, or NR a ; and each R a is independently H or an optionally substituted aryl.
  • the Kv7 Channel activator is selected from the group consisting of: N-Benzo[g]quinolin-4-yl-N′-(2-diethylamino-ethyl)-benzene-1,4-diamine; 2- [2-(3,4-Dihydroxy-phenyl)-2-oxo-ethylsulfanyl]-4,6-dimethyl-nicotinonitrile; 2-[2-(4- Methoxy-phenyl)-2-oxo-ethylsulfanyl]-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-quinoline- 3-carbonitrile; 6-Methyl-4-(5-methyl-furan-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)- nicotinonitrile; 2-(2-Oxo-2-thiophen-2-yl-ethylsulfanyl)- nico
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 160.
  • Such compounds are described in International Publication No. WO2004060880A1, published July 22, 2004, and corresponding to International Application No. PCT/US2003/039352 filed December 11, 2003; US Patent No.6,933,308, issued August 23, 2005, and corresponding to US Application No.10/730,781 filed December 9, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 160, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 160: Formula 160 , wherein, R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, —(CH 2 ) 1-4 C 3-7 cycloalkyl, —(CH 2 ) 2-4 N(C 1-6 alkyl) 2 , —(CH 2 ) 2-4 OC 1-6 alkyl, R 2 is hydrogen, C 1-6 alkyl, or — (CH 2 ) 2-4 OC 1-6 alkyl; or where R 1 and R 2 taken together are —CH 2 CH 2 XCH 2 CH 2 —, where X is a chemical bond, CH 2 , CHOH, NH, NCH 3 , NCOCH 3 , O, or S; R 3 is hydrogen or hydroxy, provided that where R 3 is hydroxy, m is not 0; R 4 is hydrogen, C 1-6 alkyl, hydroxymethyl, or trifluoromethyl; R 5 is halogen, C 1-6 alkyl, C 3-7
  • R 3 is hydrogen and m is 1.
  • R 4 is methyl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-[2-(4-morpholinyl)ethyl]-N-[1-[3-(3-pyridinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; N-[1-[3-(dimethylamino)phenyl]ethyl]-2-[2-(1- pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methyl
  • the Kv7 Channel activator is selected from the group consisting of: 2-[1-hydroxy-2-(1-piperidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]- 4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]-1-hydroxyethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide
  • the compound has a stereochemical configuration according to the formula: [0827] In further embodiments, the compound is according to the formula: [0828] Wherein, R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, —(CH 2 ) 1-4 C 3-7 cycloalkyl, —(CH 2 ) 2-4 N(C 1- 6 alkyl) 2 , —(CH 2 ) 2-4 OC 1-6 alkyl, R 2 is hydrogen C 1-6 alkyl, or —(CH 2 ) 2-4 OC 1-6 alkyl; or where R 1 and R 2 taken together are —CH 2 CH 2 XCH 2 CH 2 —, where X is a chemical bond, CH 2 , CHOH, NH, NCH 3 , NCOCH 3 , O, or S; R 3 is hydrogen or hydroxy, provided that where R 3 is hydroxy, m is not 0; R 4 is hydrogen, C 1-6 alkyl, hydroxymethyl, or trifluoride
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 161.
  • Such compounds are described in US Patent No.7,144,881 issued December 5, 2006, and corresponding to US Application No. 10/919,184 filed November 21, 2003; International Publication No. WO2004047738A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037305 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 161, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 161: wherein, R is C 1-4 alkyl, CF 3 or hydroxymethyl; R 1 and R 2 are each independently hydrogen, C 1-4 alkyl, halogen or morpholin-4-yl; R 4 is selected from the group consisting of optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent is independently selected from the group consisting of C 1-4 alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R 5 is hydrogen or fluoro; or R 4 and R 5 taken together are —CH ⁇ CH—CH ⁇ CH— or —CH 2 CH 2 O—; and R 3 , R 6 and R 7 are each independently selected from hydrogen or fluoro.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 162.
  • Such compounds are described in US Patent No.7,144,881 issued December 5, 2006, and corresponding to US Application No. 10/919,184 filed November 21, 2003; International Publication No. WO2004047738A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037305 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 162, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 162: Formula 162 , wherein, R is methyl or hydroxymethyl; R 1 and R 2 are each independently hydrogen, C 1- 4 alkyl, halogen or morpholin-4-yl; R 4 is selected from the group consisting of optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent is independently selected from the group consisting of C 1-4 alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R 5 is hydrogen or fluoro; or R 4 and R 5 taken together are —CH ⁇ CH—CH ⁇ CH— or —CH 2 CH 2 O—; and R 3 , R 6 and R 7 are each independently selected from hydrogen or fluoro.
  • R is methyl or hydroxymethyl
  • R 1 and R 2 are each independently hydrogen, C 1- 4 alkyl, halogen or morpholin-4-yl
  • R 4
  • the Kv7 Channel activator is selected from the group consisting of: 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro-benzofuran-5- yl)-ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro- benzofuran-5-yl)-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3- dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid(2- hydroxy-1-naphthalen-2-yl-ethyl)-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-y
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 163.
  • Such compounds are described in International Publication No. WO2004047743A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037348 filed November 21, 2003; US Patent No.7,045,551 issued May 16, 2006, and corresponding to US Application No.10/719,465 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 163, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 163: Formula 163 , wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is —CH ⁇ CH— or —(CH 2 ) n —; R 2 is hydrogen or hydroxymethyl; n is an integer of 0, 1 or 2; R 4 is selected from the group consisting of di(C 1- 4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4- ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substitu
  • R 1 is selected from
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 164.
  • Such compounds are described in International Publication No. WO2004047743A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037348 filed November 21, 2003; US Patent No.7,045,551 issued May 16, 2006, and corresponding to US Application No.10/719,465 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 164, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 164: Formula 164 , wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is —CH ⁇ CH— or —(CH 2 ) n —; R 2 is hydrogen; n is an integer of 0, 1 or 2; R 4 is selected from the group consisting of di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said
  • the Kv7 Channel activator is selected from the group consisting of: (R)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)- 3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)-3- (2,4-difluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)-N- [1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(2-fluor
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 165.
  • Such compounds are described in US Patent No.7,135,472 issued November 14, 2006, and corresponding to US Application No. 10/719,187 filed November 21, 2003; International Publication No. WO2004047744A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037349 filed November 21, 2003; US Patent No.7,135,472 issued November 14, 2006, and Patent Cooperation Treaty application No. US2003/037349 published June 10, 2004, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 165, these references incorporated by reference herein control.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 166.
  • Such compounds are described in US Patent No.7,135,472, issued November 14, 2006, and corresponding to US Application No. 10/719,187 filed November 21, 2003; International Publication No. WO2004047744A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037349 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 166, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 166: Formula 166 , wherein, R 1 is selected from the group consisting of straight or branched chain C 1-6 alkyl optionally substituted with amino, C 1-4 alkylamino or di(C 1-4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy; A is — CH ⁇ CH—, 1,1-cyclopropyl, or —(CH 2 ) n —; R 2 is methyl or hydroxymethyl; R 3 , R 4 , R 5 and R 6 each are independently hydrogen or fluoro; n
  • the Kv7 Channel activator is selected from the group consisting of: (S)-3-(2-fluoro-phenyl)-N-[1-(3-[1,2,4]triazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro- phenyl)-N-[1-(3-pyrazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[1-(3- imidazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-4-phenyl-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]-butyr
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 167.
  • Such compounds are described in International Publication No. WO2002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No.6,831,080, issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 167, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 167: Formula 167 , wherein, R is C 1-4 alkyl or trifluoromethyl; R 1 is selected from the group consisting of pyridinyl, quinolinyl, thienyl, furanyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, chromanyl, indanyl, biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, C 1- 4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and halogen; R 4 is selected from the group consisting of di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 168.
  • Such compounds are described in International Publication No. WO2002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No.6,831,080 issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 168, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 168: Formula 168 , wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-benzodioxol-5-yl, chroman-5-yl, indan-5-yl, 4-biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C -4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 4 is selected from the group consisting of optionally substituted di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one
  • R 1 is substituted phenyl or 1,3-benzodioxol-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, and C 1-4 alkoxy; and R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X and Y are each O, and m is 1.
  • R 1 is selected from the group consisting of substituted phenyl, 1,3-benzodioxol-5-yl, and indan-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy and trifluoromethyl; and R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X is CH 2 , Y is O, and m is 1.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy, trifluoromethyl and nitro;
  • R 4 is optionally substituted morpholin-4-yl with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and
  • R 5 is hydrogen or fluoro.
  • R 1 is phenyl, fluorophenyl or difluorophenyl.
  • R 1 is substituted phenyl or 1,3-benzodioxol-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen or C 1-4 alkyl; and R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X and Y are O, and m is 2.
  • R 1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen or C 1-4 alkyl;
  • R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X is (CH 2 ) n N(R 9 )—; Y is CH 2 , and m and n are 1; and
  • R 9 is CO 2 (C 1-4 alkyl).
  • R 1 is substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen; R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X is (CH 2 ) n N(R 9 )— and Y is O wherein m is 2 and n is 0; and R 9 is hydrogen, cyclopropylmethyl or C 1-4 alkyl.
  • R 1 is 3-quinolinyl or pyridinyl; R 4 is trifluoromethoxy; and R 5 is hydrogen.
  • R 1 is substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen or C 1-4 alkyl;
  • R 4 and R 5 taken together are —X(CH 2 ) m Y—, in which X is CH 2 and Y is (CH 2 ) n N(R 9 )— wherein m is 1 and n is 0; and R 9 is CO 2 (C 1-4 alkyl).
  • R 1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen;
  • R 4 and R 5 taken together are —X(CH 2 ) m Y—, in which X is (CH 2 ) n N(R 9 )— and Y is CH 2 wherein m is 2 and n is 0; and
  • R 9 is hydrogen, C 1-4 alkyl, acetyl, hydroxyethyl or methoxyethyl.
  • R 1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen;
  • R 4 and R 5 taken together are —X(CH 2 ) n Y—, in which X is CH 2 and Y is (CH 2 ) n N(R 9 )— wherein m is 2 and n is 0; and
  • R 9 is hydrogen, C 1-4 alkyl, acetyl, hydroxyethyl or methoxyethyl.
  • R 1 is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R 4 is optionally substituted pyridinyl with one or two substituents each independently selected from C 1-4 alkyl and halogen; and R 5 is hydrogen or fluoro.
  • R 1 is 1,3-benzodioxol-5-yl; R 4 is di(C 1-4 alkyl)amino; and R 5 is hydrogen or fluoro.
  • R 1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R 4 is pyrimidinyl; and R 5 is hydrogen or fluoro.
  • R 1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R 4 is pyrazinyl; and R 5 is hydrogen or fluoro.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C 1-4 alkyl and halogen;
  • R 4 is piperazinyl or 4-methylpiperazinyl; and
  • R 5 is hydrogen or fluoro.
  • the Kv7 Channel activator is selected from the group consisting of: 2-Methyl-3-phenyl-but-2-enoic acid (1-naphthalen-2-ylethyl)-amide; N-(1- Benzo[1,3]dioxol-5-yl-ethyl)-3-(3-methoxy-phenyl)-acrylamide; N-[1-(2,3- Dihydrobenzofuran-5-yl)ethyl]-3-(3-methoxyphenyl)-acrylamide; (S)-3-Phenyl-N-[1-(3- morpholin-4-yl-phenyl)ethyl]acrylamide; 3-(3-Fluorophenyl)-N-[1-(2,3- dihydrobenzo[1,4]dioxin-6-yl)-ethyl]acrylamide; ( ⁇ )-7- ⁇ 1-[3-(4- Fluorophenyl
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 169.
  • Such compounds are described in International Publication No. WO2002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No.6,831,080, issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 169, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 169: Formula 169 , wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-benzodioxol-5-yl, chroman-5-yl, indan-5-yl, 4-biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 4 is selected from the group consisting of optionally substituted di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one
  • R 1 is selected from the group consisting of 2-thienyl, chroman-5-yl, 4-biphenylyl, phenyl and substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy and nitro; and R 4 and R 5 taken together are —CH ⁇ CH—CH ⁇ CH—.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy, trifluoromethyl and nitro;
  • R 4 is optionally substituted morpholin-4-yl with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and
  • R 5 is hydrogen or fluoro.
  • R 1 is phenyl, fluorophenyl or difluorophenyl.
  • R 1 is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R 4 is optionally substituted pyridinyl with one or two substituents each independently selected from C 1-4 alkyl and halogen; and R 5 is hydrogen or fluoro.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C 1-4 alkyl and halogen; R 4 is piperazinyl or 4-methylpiperazinyl; and R 5 is hydrogen or fluoro.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 170.
  • Such compounds are described in US Patent No.6,326,385, issued December 4, 2001, and corresponding to US Application No. 09/361,747 filed August 4, 2000; International Publication No. WO2001010381A2, published February 15, 2001, and corresponding to International Application No. PCT/US2000/021309 filed August 4, 2000; US Patent No.6,326,385 issued December 4, 2001, and Patent Cooperation Treaty application No. US2000/021309 published February 15, 2001, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 170, these references incorporated by reference herein control.
  • the Kv7 channel activator is a compound according to Formula 170: Formula 170 , wherein, Ar 1 and Ar 2 are each members independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and X is a member selected from the group consisting of O, S and N—R 1 , wherein R 1 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C 1 -C 4 )alkyl, substituted aryl(C 1 -C 4 )alkyl, CN, —C(O)R 2 , —OR 3 , —C(O)NR 3 R 4 , and —S(O) 2 NR 3 R 4 ; wherein R 2 is a member selected from the group consisting of (C 1 -C 8 )
  • Ar 1 is a member selected from the group consisting of phenyl, substituted phenyl, indolyl, substituted indolyl, benzofuranyl, substituted benzofuranyl, furanyl, substituted furanyl, thienyl, substituted thienyl, isothiazolyl, substituted isothiazolyl, pyrazolyl and substituted pyrazolyl.
  • Ar 1 is substituted phenyl, substituted or unsubstituted 2- indolyl and substituted or unsubstituted 2-thienyl.
  • X is O.
  • the Ar 1 substituents are selected from the group consisting of halogen, alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, nitro, cyano, — NHC(O)R 7 , —NHR 7 , phenyl and substituted phenyl, wherein R 7 is a member selected from hydrogen, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted hcterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C 1 -C 4 )alkyl and substituted aryl(C 1 -C 4 )alkyl, or R 7 can
  • Ar 2 is selected from the group consisting of heteroaryl and substituted heteroaryl.
  • Ar 1 is substituted aryl;
  • Ar 2 is heteroaryl or substituted heteroaryl; and
  • X is O.
  • Ar 2 is pyridyl or substituted pyridyl.
  • Ar 2 is selected from the group consisting of 6-methyl-3- pyridyl and 2-chloro-5-pyridyl.
  • Ar 1 is substituted phenyl.
  • the compound is according to the formula: , [0884] wherein, Y is a member selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 substituted alkyl, —OCH 3 and —OCF 3 , and R 5 and R 6 are members independently selected from the group consisting of H, halogen, alkyl, halo(C 1 -C 4 )alkyl, nitro, cyano and phenyl, with the proviso that both R 5 and R 6 are not H.
  • R 5 and R 6 are members independently selected from the group consisting of H, F, and Cl, with the optional proviso that both R 5 and R 6 are not H.
  • Further embodiments (Collectively referred to as “Formula 171” for ease of reference in the appended claims. “Formula 171”, as recited in the claims, captures any of the below compounds preceding the NMDA receptor antanogists section.)
  • the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No. WO2021055538A1, published March 25, 2021, and corresponding to International Application No. PCT/US2020/051171 filed September 17, 2020; International Publication No.
  • the compound is selected from the group consisting of N-(l- cyclobutyl-4-fluoro-6-(l- hydroxycyclobutyl)-lH-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3- dimethylbutanamide; N-(l -(tert-butyl)-6-(difluoromethoxy)- 1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N-(6-cyano-l-(l,l,l- trifluoro-2-methylpropan-2-yl)-lH- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N-(l -cyclobutyl -4-fluoro-6-(2- hydroxypropan-2-yl)- 1H- benzo[d]imidazol-2-yl)-2-(l -methyl cyclo
  • the Kv7 channel activator is selected from the group consisting of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.98 (°2 ⁇ ) using CuK ⁇ 1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°2 ⁇ ) using CuK ⁇ 1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°2 ⁇ ) using CuK ⁇ 1 radiation.
  • the Kv7 Channel activator is selected from the group consisting of: Chromanol 293B, MIR-1556, UCL2077, JNJ303, L-735821 (L-7), fenofibrate; and a salt or hydrate thereof.
  • the Kv7 Channel activator is selected from the group consisting of: a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083.
  • the Kv7 Channel activator is selected from the group consisting of: NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof.
  • the Kv7 channel activator is selected from the group consisting of: linopirdine, (1,3-Dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one)
  • XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991)
  • DMP-543 (10,10- bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP-543)
  • ML252 ((S)-2-phenyl-N- (2-(pyrrolidin-1-yl)phenyl)butanamide (ML252)) and UCL2077.
  • the Kv7 channel activator is an analog of flupirtine.
  • the Kv7 channel activator is selected from the group consisting of: N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-3-carboxamide; N- (2,6- dimethylphenyl)bicyclo[2.2.1]heptane-3-carboxamide; N-(2,5- dimethylphenyl)bicyclo[2.2.1]heptane-3-carboxamide; N-(2-chloro-4,6- dimethylphenyl)pentanamide; N-(2-chloro-4,6-dimethylphenyl)-3,3-dimethylbutanamide; 2- (l -adamantyl)-N-(2,6-difluorophenyl)acetamide; N-(2-bromo-4-methylphenyl)-2- cyclopentylacetamide; N-(2,3-dimethylpheny
  • the metal channel activator is QRA-244 as described in Dan Elbaum et al. “TST-20: QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for Motor System Hyperexcitability induced Disease Progression in ALS patients”; 31 st International symposium on ALS/MND; Live Poster Session C, December 11, 2020.
  • NMDA RECEPTOR ANTAGONISTS [0896] NMDA receptor antagonists are a class of pharmaceutically active molecules that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDA R ).
  • NMDA receptor antagonists include ketamine, lanicemine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N 2 O).
  • DXM dextromethorphan
  • PCP phencyclidine
  • MXE methoxetamine
  • N 2 O nitrous oxide
  • NMDA R -antagonists such as pethidine, levorphanol, methadone, dextropropoxyphene, tramadol and ketobemidone.
  • NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open.
  • NMDA receptor antagonists Chemicals that deactivate the NMDA receptor are known as NMDA receptor antagonists (NMDA R ).
  • NMDA R antagonists fall into four categories: competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists, which inhibit NMDA R by binding to allosteric sites; and uncompetitive antagonists, which block the ion channel by binding to a site within it.
  • the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist is (S)-1- phenyl-2-(pyridin-2-yl)ethanamine (lanicemine) or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist may be a prodrug of ketamine or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist may be EVT-101 pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist is rapastinel: , (S)—N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2- yl)-1-((S)-1-((S)-2-amino-3-hydroxypropanoyl)pyrrolidine-2-carbonyl)pyrrolidine-2- carboxamide, (S)—N—((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-1-((2S,3R)-2- amino-3-hydroxybutanoyl) pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide, (S)—N— ((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-1-((S)-2-amino-3-hydroxy-propanoyl)- pyrrolidine-2-carbonyl)-pyrrolidine-2-carboxamide, (S)
  • the NMDA receptor antagonist may be lanicemine.
  • the NMDA receptor antagonist may be a prodrug of lanicemine.
  • the prodrug of lanicemine may have the following chemical structure:
  • the prodrug of lanicemine may have the following structure: , or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist may be selected from ketamine, lanicemine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O).
  • a pharmaceutical composition including the following compound (ezogabine) or a pharmaceutically acceptable salt thereof and an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof:
  • the NMDA receptor antagonist is flupirtine: acceptable salt thereof.
  • the NMDA receptor antagonist may be selected from ketamine, lanicemine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and pharmaceutically acceptable salts and prodrugs thereof, or nitrous oxide (N2O).
  • the NMDA receptor antagonist is one or more of a compound according to Formulas 200 – 260.
  • compositions may include one or more metal channel activators according to Formulas 1 – 171 and one or more NMDA receptor antagonist compounds according to Formulas 200-260 described below.
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 200.
  • Such compounds are described in International Publication No. WO2015/067923, published May 14, 2015, and corresponding to International Application No. PCT/GB2014/053236 filed October 30, 2014, as well as U.S. Patent No.9,822,075 issued on November 21, 2017; U.S. Patent No.10,207,994 issued on February 19, 2019; U.S. Patent No.10,815,199 issued on October 27, 2020, and U.S.
  • the NMDA receptor antagonist is lanicemine, or a prodrug of lanicemine or a pharmaceutically acceptable salt thereof.
  • the prodrug of lanicemine may have the following chemical structure: Formula 200
  • the prodrug of lanicemine may have the following chemical structure: , or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist is one or more of: (S)-(l-Phenyl-2-(pyridin-2-yl)ethylcarbamoyloxy)methyl isobutyrate; 2-Methyl- 1 -((S)- 1 -phenyl-2-(pyridin-2-yl)ethylcarbamoyloxy)propyl isobutyrate; 2-Methyl- 1 -((S)- 1 -phenyl-2-(pyridin-2-yl)ethylcarbamoyloxy)propyl isobutyrate diastereomer 1 ; 2-Methyl- 1 -((S)- 1 -phenyl-2-(pyridin-2-yl)ethylcarbamoyloxy)propyl isobutyrate diastereomer 2; 1 -((S)- 1 -phenyl-2-(pyridin-2-yl)ethylcarbam
  • the NMDA receptor antagonist is (S)- 1 -((S)-2-amino-3 - methylbutanoyl)-N-((S)- 1 -phenyl-2-(pyridin-2- yl)ethyl)pyrrolidine-2-carboxamide or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist is:
  • the NMDA receptor antagonist is: .
  • the NMDA receptor antagonist is a compound according to: , wherein R1 is C1-6 alkylC(O)O(C1-6 alkoxy), or wherein AA is a peptide bond-lined natural amino acid; or a pharmaceutically acceptable salt thereof.
  • the NMDA receptor antagonist is (S)-1-((S)-2-amino-3- methylbutanoyl)-N—((S)-1-phenyl-2-(pyridin-2-yl)ethyl)pyrrolidine-2-carboxamide dihydrochloride salt: [0919] In further embodiments, the NMDA receptor antagonist is (S)-1-((S)-2-amino-3- methylbutanoyl)-N—((S)-1-phenyl-2-(pyridin-2-yl)ethyl)pyrrolidine-2-carboxamide fumarate salt: .
  • the NMDA receptor modulator may be selected from one of the following compounds according to Formula 201.
  • Such compounds are described in International Publication No. WO 2021/228123, published November 18, 2021 and corresponding to PCT/CN2021/093264, filed May 12, 2021, is incorporated by reference in its entirety herein. In the case of any conflict of terminology of Formula 201, these references incorporated by reference herein control.
  • the NMDA receptor modulator is a compound according to Formula 201: [0922] or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein, Ring A is 3- to 8-membered aliphatic heterocycle; R 1 is selected from H, C1- C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R2 is selected from H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R3 is selected from H, cyano, 3- to 8-membered nitrogen-containing aliphatic heterocycle- C1-C4 acyl, C1-C6 alkoxycarbonyl and - CONHR4; R and R' are each independently selected from H and C1-C6 alkyl; R4 is selected from H, C1-C6 alkyl; R4 is
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 202.
  • Such compounds are described in International Publication No. WO 2021/080880, published April 29, 2021 and corresponding to PCT/US2020/056171, filed October 16, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology of Formula 202, these references incorporated by reference herein control.
  • the compound according to Formula 202 is: or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, R7, and X are as defined above.
  • the compound according to Formula 202 is: or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, R7, and X are as defined above.
  • the compound according to Formula 202 is selected from: pharmaceutically acceptable salts thereof.
  • Formula 203 [0929]
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 203.
  • the compound according to Formula 203 is: Formula 203 , and/or wherein ring A is a 6-membered aromatic ring further substituted by 1 to 4 substituents selected from (1) a C1-3 alkyl group, (2) a C1-3 haloalkyl group, (3) an optionally substituted cyclic group, (4) an optionally substituted C1-6 alkoxy group, and (5) a halogen atom; R1 and R2 are each independently a hydrogen atom or a C1-3 alkyl group optionally substituted by fluorine atom(s); R3 is (1) a group represented by wherein R4 is a substituent selected from (1) a C1-3 haloalkyl group, (2) an optionally substituted C3-7 cycloalkyl group, and (3) an optionally substituted C1-6 alkoxy group, Y is a nitrogen atom or CR6, R6 is a hydrogen atom or a halogen atom, and Z is a hydrogen atom or a halogen atom,
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 204.
  • Such compounds are described in WO2019/210130, published October 31, 2019, corresponding to PCT/US2019/029285, filed April 26, 2019, and US2021/0094920, published April 1, 2021, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 204, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is: Formula 204 , wherein X is O or S, specifically O;R1 is H, C1-C6 alkyl, C1-C6 haloalkyl, specifically C1-C3 alkyl, and more specifically methyl; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, specifically H or C1-C3 alkyl, and more specifically H; R3 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —OH, halo, —COOH, —CN, —NO2, amino, mono- or di-alkylamino, C2-C6 alkanoyl, C2-C8 cycloalkyl, or heterocycloalkyl, specifically H, C1-C3 alkyl, or C1-C3 haloalkyl, and more
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 205. Such compounds are described in WO2019/152688, published August 8, 2019 and corresponding to PCT/US2019/016114, filed January 31, 2019, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology of Formula 205, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 205: Formula 205
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 206. Such compounds are described in, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 206, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is selected from:
  • the NMDA receptor antagonist is selected from: pharmaceutically acceptable salts thereof.
  • Formula 207 [0943] In an embodiment, the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 207. Such compounds are described in WO2018/075699, published April 26, 2018 and corresponding to PCT/US2017/057277, filed October 18, 2017, and US 11,149,054, issued October 19, 2021, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 207, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 207: Formula 207 , or a pharmaceutically acceptable salt thereof, wherein: each of R2 and R3 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, or R2 and R3, together with the carbon atom to which they are attached form a substituted or unsubstituted 3-8 membered ring; each of R4 and R5 is independently hydrogen, halo, or -ORc, wherein Rc is hydrogen or substituted or unsubstituted C1-C6 alkyl, or R4 and R5, together with the carbon atom to which they are attached form an oxo group; R6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; when both of are single bonds, then R is hydrogen;
  • the NMDA receptor antagonist is a compound selected from: . [0946] In further embodiments, the NMDA receptor antagonist is a compound selected from: [0947] In further embodiments, the NMDA receptor antagonist is a compound selected from: ⁇
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 208.
  • Such compounds are described in WO 2016/196513, published December 8, 2016, corresponding to PCT/US2016/035098, filed May 31, 2016, and US 10,584,127 issued March 10, 2020, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 208, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 208: Formula 208 , wherein R1 is alkyl, cycloalkyi, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl, wherein each of cycloalkyi, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl and (heteroaryl)alkyl is independently optionally substituted with 1 to 3 groups independently selected from -F, -CI, C1-C4 alkyl, cyclopropyl, -C ⁇ CH, -CFH2, -CF2H, - CF3, -CF2CH3, -CH2CF3, C1-C4 alkoxy, -OCFH2, -OC
  • the NMDA receptor antagonist is a compound selected from: , wherein R5, R6 and R7 independently are -H, -F, -CI, C C alkyl, cyclopropyl, -C ⁇ CH, -CFH2, -CF2H, -CF3, -CF2CH3, -CH2CF3, C1-C4 alkoxy, - OCFH2, -OCF2H, -OCF3, -CN, -N(R2)(R3), -NO2, C C4 alkylthio, C1-C4 alkylsulfonyl or - S(O)2CF3; wherein each instance of R2 and R3 independently is -H or C1-C4 alkyl, or C1- C4 alkyl, or , including pharmaceutically acceptable salts thereof.
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist is selected from:
  • the NMDA receptor antagonist is selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 209.
  • Such compounds are described in International application publication no. WO2010/088414, published August 5, 2010, corresponding to PCT/US2010/022439, filed January 28, 2010, International application publication no. WO 2010/088408, published August 5, 2010, corresponding to PCT/US2010/022432, filed January 28, 2010, and US 8,822,462, issued September 2, 2014, which are each incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control are described in International application publication no. WO2010/088414, published August 5, 2010, corresponding to PCT/US2010/022439, filed January 28, 2010, International application publication no. WO 2010/088408, published August 5, 2010, corresponding to PCT/US2010/022432, filed January 28, 2010, and US 8,822,462, issued September 2, 2014, which are each incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 209a – 209b:
  • Formula 209a , Formula 209b X is, independently, N or C bonded to H or a substituent, J, with the proviso that no more than three of X are N;
  • Y is independently selected from O, S, NR1, CH2, and CR2;
  • R1 and R2 are, independently, selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and hydroxy, and, when R1 is attached to a carbon atom, it can be halo or cyano
  • T is, independently, CHR1, CR2, O, S, or NR1
  • V is, independently, N, or C bonded to H or a substituent J
  • J is a non-hydrogen substituent selected from the group consisting of halo (-F, -Cl, -B
  • the NMDA receptor antagonist is a compound according to Formula 209c: wherein A-B i s a linker moiety selected from: X is, independently, N, or C bonded to H or a substituent, J, with the proviso that no more than three of X are N; Y1 and Y2 are, independently, selected from O, S, NR1, CH2, and CRX 1 2 ; R1 and R2 are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and hydroxy, R1 and R2 can optionally join to form a C3-10 heterocyclic moiety, which heterocyclic moiety can optionally include a second heteroatom selected from O, S, and N, R2 is absent when Q is O or S, Z is, independently, (CH2) n , CHR, CR2, O, S, or NR1, T is,
  • the NMDA receptor antagonist has a structure according to Formula I or J:
  • R7 is selected from the group consisting of H, -Ci_6 alkyl, -Ci_6 substituted alkyl, - C6-io aryl, - Ce io substituted aryl, -Ce io heteroaryl, -Ce io substituted heteroaryl, - C(O)-alkyl, -C(O)-substituted alkyl, -C(O)-aryl, -C(O)-substituted aryl, -C(O)- arylalkyl, C(O)-substituted arylalkyl, -C(O)-alkylaryl, -C(O)-substituted alkylaryl- CN, N3, NO2, -OH, -NH2, -SH, -OR1, -NHR1, -N(R1K -SR1, -OC(O)R1,
  • the NMDA receptor antagonist is a compound according to: , and pharmaceutically acceptable salts, esters, prodrugs, or derivatives therof.
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 210.
  • Such compounds are described in WO 2011/100585, published August 18, 2011, corresponding to PCT/US2011/024583, filed February 11, 2011, and US 9,101,612, issued August 11, 2015, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 210, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 210: Formula 210 and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof; wherein T is, independently for each occurrence, CR4R4 , and n is 0, 1, 2 or 3; A is optionally present and is selected from phenyl or pyridine, wherein A is optionally substituted by one or more substituents selected from Ra; Ri is selected from the group consisting of H, hydroxyl, -S(O)2-C1-4alkyl; -SO2, C1- 4alkyl, C2-C4alkenyl, phenyl, R7, or , wherein C1-4 alkyl, C2-4alkenyl, or phenyl is optionally substituted by one or more substituents selected from Ra; X is CH or N; R3 and R3 are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C1-4alkyl, amido, amine
  • the NMDA receptor antagonist is a compound according to: , wherein R4 is H, R1 is benzyl, R5 is R2 is H or CH3, R3 is H or CH3, and stereoisomers, N-oxides or pharmaceutically acceptable salts thereof.
  • the NMDA receptor antagonist is a compound according to: .
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 211. Such compounds are described in WO 2012/019106, published February 9, 2012, correcponding to PCT/US2011/046756, filed August 5, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology of Formula 211, this references incorporated by reference herein controls.
  • the NMDA receptor antagonist is a compound according to formulas 211 a – c: Formula 211a - c , wherein R1b is iodo, alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, aryl, heteroaryl, alkyleneamino, alkylene-CO2H, alkenylene-CO2alkyl, alkylene-OH, alkylene-cycloalkyl, alkylenearyl, alkenylenearyl, CHO, or thioalkyl; R2b and R5a are each independently R A , alkylene-R A , NH 2 , C(O)NH-alkylenearyl, C(O)NH-alkyleneheteroaryl, C(O)NH-alkylene-R A , alkylene-OH, C(O)alkyl, or NO2; Rla is halo; R2a is C(Odo, alkyl,
  • the NMDA receptor antagonist is a compound selected from: [0979]
  • the NMDA receptor antagonist is a compound according to Formula 212d-e: Formula 212d and 212e , wherein R6b is RA or alkylene-RA; R7b is OH, alkoxy, or CO2H; R8b is H, halo, or C4-C20alkyl; R9b is halo, alkenyl, aryl, or alkyl; R13b is H, C4-C2oalkyl, alkenyl, aryl, heteroaryl, alkeylenearyl, or alkenylenearyl; R13a is C4-C20alkyl, alkenyl, alkenylene-CO2H, alkenylene-CO2alkyl, O-alkylene- CO2alkyl, or alkylenearyl; R6a is RA, alkylene-RA, or alkylene-OH;
  • the NMDA receptor antagonist is a compound according to: Formula 212
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 212. Such compounds are described in US 2011/0206780 published August 25, 2011 corresponding to US 12/984,989 filed January 5, 2011 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology of Formula 212, this reference incorporated by reference herein controls.
  • the NMDA receptor antagonist is dextromethorphan: [0984] In further embodiments, the NMDA receptor antagonist is dextromethorphan or a dextromethorphan analogue having one or more H replaced with deuterium (D).
  • the NMDA receptor antagonist is a compound according to Formula 212: or a salt thereof, wherein: R1 and R2 are independently selected from the group consisting of —CH3, —CH2D, —CD2H, and —CD3; R3-R25 are independently selected from the group consisting of hydrogen and deuterium; at least one of R3-R25 is deuterium; and if R6-R8 and R20-R21 are deuterium and R2 is —CD3, then at least one of R1-R5, R9-R19, and R22-R25 is deuterium or contains deuterium. [0986] In further embodiments, the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 213. Such compounds are described in, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 213, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a derivative of quinazoline, i.e. the following molecule portion, substituted in any manner: .
  • the NMDA receptor antagonist is: , or a pharmaceutically acceptable salt or derivative thereof.
  • the NMDA receptor antagonist is a compound according to: , or a pharmaceutically acceptable salt or derivative thereof.
  • the NMDA receptor antagonist is a compound according to: , wherein Z is N; a is 1 or 2; b is 1, 2or 3; c is 1, 2 or 3; each R1 is independently selected from groups of the formula ⁇ (X)d ⁇ (CH2)e ⁇ R5 wherein d is 0 or 1; e is 0 to 6; X is O, NR or S(O)f where f is 0, 1 or 2; R is hydrogen, halogen, Ci_6 alkyl, C2-6 alkyl, C2-6 alkenyl, C3-12 cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro, trihalomethyl, NR7R8, C5H4NR7R8, C5H4(CH2)NR7R8, C(O)R7, C(O)R7, C(O
  • the compound is l-oxa-8-thia-3-aza- dibenzo[e,h]azulene; l,8-dioxa-3-aza-dibenzo[e,h]azulene; 3-(l-oxa-8-thia-3-aza- dibenzo[e,h]azulen-2-yl)- propionic acid ethyl ester; 3-(l,8-dioxa-3-aza- dibenzo[e,h]azulen-2-yl)-propionic acid ethyl ester; 2-methyl-l-oxa-8-thia-3-aza- dibenzo[e,h]azulene; 2-methyl-l,8-dioxa-3-aza- dibenzo[e,h]azulene; 1 l-chloro-2- methyl-l-oxa-8-thia-3-aza-dibenzo[e,h]azulene; 5-chloro- 2-methyl
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 214.
  • Such compounds are described in US 2010/0130617, published May 27, 2010 and corresponding to US application No. 12/623,948, filed November 23, 2009, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 214, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 214: Formula 214 , or a salt thereof, wherein: R1-R23 are independently selected from the group consisting of hydrogen and deuterium; at least one of R1-R23 is deuterium; and if each of R1-R3 are deuterium, then at least one of R4-R23 is deuterium.
  • R1-R23 are independently selected from the group consisting of hydrogen and deuterium; at least one of R1-R23 is deuterium; and if each of R1-R3 are deuterium, then at least one of R4-R23 is deuterium.
  • the NMDA receptor antagonist is a compound according to:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 215.
  • Such compounds are described in WO 2010/0033757, published March 25, 2010 and corresponding to PCT/US2009/057401, filed September 18, 2009, US 9,512,133, issued December 6, 2016, US 9,802,946, issued October 31, 2017, and US 10,906,913, issued February 2, 2021, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 215, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to: Formula 215 , and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof; wherein T is, independently for each occurrence, CR4R4 , and n is 0, 1, 2 or 3; A is optionally present and is selected from phenyl or pyridine, wherein A is optionally substituted by one or more substituents selected from Ra; R1 is selected from the group consisting of H, hydroxyl, -S(O)2-C1-C4alkyl; -SO2, C1- C4alkyl, C2-C4alkenyl, phenyl, R7, or wherein C1-C4alkyl, C2-C4alkenyl, or phenyl is optionally substituted by one or more substituents selected from Ra; X is CH or N; R3 and R3 are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C1-C
  • the NMDA receptor antagonist is a compound according to: , wherein R1 is C(O)-C2-C4alkyl, wherein C2-C4alkyl is substituted at one carbon with NH2 or -N- carbobenzyloxy and at a different carbon by hydroxyl.
  • the NMDA receptor antagonist is represented by: [1007]
  • the NMDA receptor antagonist is a compound according to: and pharmaceutically acceptable salts, stereoisomers and N-oxides thereof; wherein R1 is selected from the group consisting of H, hydroxyl, -S(O)2-C1-C4alkyl; -SO2, C1- C 4alkyl; R7, or X is CH or N; R3 and R3' are each independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C1-C4alkyl, amido, amine, or C2-C4alkenyl, wherein C1-C4alkyl, C2- C4alkenyl and phenyl are optionally substituted by one or more substituents selected from Ra; R2 is selected from the group consisting of H, R7, -S(O)2, S(O)2-C1-C4alkyl, C1-C4
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 216.
  • Such compounds are described in US 2009/0004112, published January 1, 2009 and corresponding to application no 12/049,782, filed March 17, 2008, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 216, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 216: or a pharmaceutically acceptable base or acid addition salt, hydrate, stereoisomer, or mixture thereof, wherein X is one or more halogen radicals; Q is NH or N; W is CR2, CHR2, NR3, or CH ⁇ COH; Y is C or CH; Z is C ⁇ O, SO2, COH, CHOH, or NHR4; R1 is CO2H or oxo ( ⁇ O); R2 is H, C( ⁇ O)—C1-C6 alkyl, C( ⁇ O)O—C1-C6 alkyl, or C( ⁇ O)—C3-C8 cycloalkyl; R3 is optionally substituted C3-C10 aryl; and R4 is R2 and R1 combine with the carbons to which they are attached to form a 6 membered heterocycle that is optionally substituted at one or more of the heteroatoms with C3-C10 aryl, wherein the
  • the NMDA receptor antagonist is a compound according to: or a pharmaceutically acceptable base or acid addition salt, hydrate, stereoisomer, or mixture thereof, wherein X is one or more halogen radicals; R1 is (CH2)n—CO2H, or CH ⁇ CHC( ⁇ O)NHR2; and R2 is C3-C10 aryl optionally substituted with one or more of C1-C6 alkyl, —O—C1- C6 alkyl, or halogen; and n is 0, 1, 2, 3, 4, 5, or 6. [1012] In an embodiment, the NMDA receptor antagonist is an NMDA receptor glycine site antagonist.
  • the NMDA receptor antagonist is ACEA 1021 (liconstinel), GV150526 (Gavestinal), GV196771, MDL 105,519, L-701324, L-687414, RPR 104632, ACPC (SYM2030), ZD9379, AR-R15896AR, or RPR118723.
  • the NMDA receptor antagonist is selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 217. Such compounds are described in WO2008/134525, published November 6, 2008 and corresponding to PCT/US2008/061598, filed April 25, 2008, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 217, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a deuterium-labeled ketamine analogue.
  • the NMDA receptor antagonist is a compound according to Formula 217: Formula 217 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 are independently selected from the group consisting of hydrogen and deuterium; and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, and R16 is deuterium.
  • the NMDA receptor antagonist is a compound selected from:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 218. Such compounds are described in WO 2008/022285, published February 2008, corresponding to PCT/US2007/076146, filed August 16, 2007 which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 218, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 218: Formula 218
  • any bond represented by a dashed line and a solid line represents a bond selected from the group consisting of a single bond and a double bond, and any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans;
  • R2, R3, R4, R5, R6, R8, R9, R10, R11 and R12 are independently selected from the group consisting of hydrogen, and deuterium;
  • R1 and R7 are independently selected from the group consisting of hydrogen, and deuterium;
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 219. Such compounds are described in WO 2006/017409, published February 16, 2006 and corresponding to PCT/US2005/027160, filed July 29, 2005, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 219, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 219: Formula 219 , wherein W is aryl or heteroaryl, unsubstituted or substituted with 1-5 substituents independently selected from halogen and C1-6 alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, and C1-4 alkoxy, C1 -4 alkoxy, C3-6 cycloalkyl, cyano and N(R4)2; Y is absent or is selected from C 1-3 alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl and C 1-4 alkoxy, cyclopropyl and C(O); Z is N and P and Q are C(R4)2, or Z is CR5 and P and Q are C(R5)2; A, B and D are each independently selected from O, CR6, S and NR6; Rl , R4 and R6 are each independently selected from hydrogen or C 1-4 alkyl optionally substituted with one or
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 220. Such compounds are described in WO 2003/097637, published November 27, 2003 and corresponding to PCT/EP2003/005151, filed May 16, 2003, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 220, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 220a or 220b: , wherein A is an unsubstituted or substituted cyclic group; and R is a hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof.
  • A is the group: , and wherein R1, R2, R3, and R4 are independently hydrogen, halogen, CF3, CHF2, C(CH3)F2, C3-C6 cycloalkyl, lower alkoxy, lower alkyl, OCF3, or phenyl; or A is , and R5, R6, R7, R8, R9, R10 are independently hydrogen, halogen, lower alkyl, lower alkoxy, or CHF2; or A , and R11, R12, R13, R14, R15, and R16 are independently hydrogen, halogen, lower alkoxy, or lower alkyl.
  • A is , wherein R17 is hydrogen or CHF2; or A is , or , wherein R18, R19, and R20 are independently hydrogen, lower alkyl or lower alkoxy.
  • the compound is:
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 221.
  • Such compounds are described in US 2002/0072485, published June 13, 2002, corresponding to Application No.09/969,354, filed October 2, 2001, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 221, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a compound according to Formula 221: Formula 221 , or a pharmaceutically acceptable acid addition salt thereof, wherein: (a) R2 and R5 are taken separately and R1, R2, R3 and R4 are each independently hydrogen, (C1-C6) alkyl, halo, CF3, OH or OR7 and R5 is methyl or ethyl; or (b) R2 and R5 are, taken together, thereby forming a chroman-4-ol ring, and R1, R3 and R4 are each independently hydrogen, (C1-C6) alkyl, halo, CF3, OH or OR7; R6 is R7 is methyl, ethyl, isopropyl or n-propyl; R8 is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C1-C6) alkyl, halo and CF3; X is O, S or (CH2)n; and
  • the NMDA receptor antagonis is selected from: (+)-(1S, 2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; a pharmaceutically acceptable acid addition salt thereof; (1S, 2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; a pharmaceutically acceptable acid addition salt thereof; (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman4,7-diol; a pharmaceutically acceptable acid addition salt thereof; and (1R*, 2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)- propan-1 -ol-mesylate.
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 222. Such compounds are described in US 2002/0077352, published June 20, 2002, corresponding to US application No.09/922,535, filed August 3, 2001, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 222, these references incorporated by reference herein control. [1034] In an embodiment, the NMDA receptor antagonist is selected from: . [1035] In further embodiments, the NMDA receptor antagonist is: , or . Formula 223 [1036] In an embodiment, the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 223.
  • the NMDA receptor antagonist is a bicycle-substituted cyclohexylamine.
  • the NMDA receptor antagonist is a compound of Formula 223: Formula 223 wherein: Ar is substituted 1 to 3 times or unsubstituted aryl or substituted 1 to 3 times or unsubstituted heteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from N, O, and S wherein the substituents are selected from the groups F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2;
  • V is –(CH 2 ) n -, -S(O)-, or -S(O) 2 -;
  • W is –(CH 2 ) n -, —S(SO)—, —S(O)2—, — O—, —S—, —C ⁇ C—, or
  • d is an integer from 0 to 2;
  • n is an integer from 1 to 6;
  • q is an integer from 0 to 6;
  • R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, aralkyl, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl, and thioalkyl;
  • R is hydrogen, alkyl, C(O)R6, C(O)OR6, C
  • the NMDA receptor antagonist is a compound selected from: 6-[trans-4-(3-Phenylpropylamino)cyclohexyl]-3H-benzoxazol-2-one; 6- ⁇ trans-4-[2-(4-Fluorophenoxy)ethylamino]cyclohexyl ⁇ -3H-benzoxazol-2-one; 6-[trans-4-(2-Phenoxyethylamino)cyclohexyl]-3H-benzoxazol-2-one; 6- ⁇ trans-4-[3-(4-Fluorophenyl)propylamino]cyclohexyl ⁇ -3H-benzoxazol-2-one; 6- ⁇ cis-4-[3-(4-Fluorophenyl)propylamino]cyclohexyl ⁇ -3H-benzoxazol-2-one; 6-[trans-4-(2-Phenylsulfanylethylamino)cyclohexyl]-3H-benz
  • the NMDA receptor antagonist may be selected from one of the following compounds according to Formula 224. Such compounds are described in, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 224, these references incorporated by reference herein control. [1041] In an embodiment, the NMDA receptor antagonist is a compound according to Formula 224: Formula 224:
  • B is CH or N
  • R1, R2, and R5 are independently H, A, or halogen
  • R3 and R4 are independently H, A, OH, OA, halogen, CF3, NO2, NH2, NHA, N(A)2 or NHAc
  • R6 is H or halogen
  • X is -CH2-, -CO-, -O-, -NH-, -NA- or -S-
  • A is alkyl having 1-4 carbon atoms
  • Ac is an alkanoyl having 1-6 carbon atoms
  • benzoyl and halogen is F, Cl, Br, or I, and pharmaceutically acceptable salts thereof.
  • the NMDA receptor antagonist is 2-Chloro-3-methyl-4-hydroxy-5- phenyl-6,7-dihydrothieno-2,3-bipyridin-6-one Peptide NMDA Receptor Antagonists
  • the NMDA receptor antagonist is a peptide agent.
  • the peptide NMDA receptor antagonists are classified under Formula numbers, each of which may refer to one or more different peptide sequences. Where a sequence homology percentage is recited, e.g. at least 80% sequence homology, it is contemplated that higher percentages are also contemplated.
  • the peptides may be useful as therapeutic agents.
  • the peptides may be produced in vivo from a therapeutic agent containing a polynucleotide sequence encoding the peptide.
  • a polynucleotide sequence may be a DNA sequence or an RNA sequence.
  • the sequence may be delivered or introduced to the patient by a plasmid or vector. It should be appreciated that any known delivery technique or construct is contemplated.
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 250. Such peptides are described in US 10,689,418, issued June 23, 2020 and corresponding to Application No.16/065,078, filed June 21, 2018, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 250, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a peptide comprising the amino acid sequence GEDDLQDNQDLIRDKSN, or a sequence having at least 80% sequence homology thereto.
  • the NMDA receptor antagonist is a peptide comprising the amino acid sequence GEDDYQDAQDLIRDKSN, or a sequence having at least 80% sequence homology thereto.
  • the NMDA receptor antagonist is a peptide comprising the amino acid sequence KLGMRSELQIDNDQDAD, or a sequence having at least 80% sequence homology thereto.
  • Formula 251 [1049] In an embodiment, the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 251.
  • the NMDA receptor antagonist is a natural or modified conantokin-P peptide.
  • the NDMA receptor antagonist is a peptide comprises one or more amino acid sequences according to: or one or more amino acid sequences having at least 80% sequence homology thereto.
  • the NMDA receptor antagonist comprises one or more amino acid sequences according to: sequences having at least 80% sequence homology thereto.
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 252. Such peptides are described in WO 2019/074858, published April 18, 2019, corresponding to PCT/US2018/054889, filed October 8, 2018, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 252, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a peptide comprising one or more amino acid sequences according to:
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 253. Such peptides are described in CN 109553685, filed September 25, 2017 which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 253, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a polypeptide comprising one or more of an NR2B (NMDA receptor subunit NR2B) sequence, a CTM (chaperone-mediated autophagy targeting motif) sequence, and a cell-penetrating peptide (such as a TAT cell- penetrating peptide or others).
  • NR2B NMDA receptor subunit NR2B
  • CTM chaperone-mediated autophagy targeting motif
  • cell-penetrating peptide such as a TAT cell- penetrating peptide or others.
  • the NMDA receptor antagonist comprises one or more of an TAT cell-penetrating peptide sequence having a polypeptide sequence having at least 80% homology to YGRKKRRQRRR; an NR2B peptide sequence having a polypeptide sequence having at least 80% homology to RRPPRSPDHKRYFRDKE; and a CTM sequence having at least 80% homology to KFERQKILDQRFFE.
  • the NMDA receptor antagonist comprises the sequence YGRKKRRQRRRRRPPRSPDHKRYFRDKEKFERQKILDQRFFE, or a sequence having at least 80% homology thereto.
  • the NMDA expression may be selectively reduced by administration or dosing with a peptide according to Formula 254.
  • a peptide according to Formula 254 Such peptides are described in WO2019/036511, published February 21, 2019 and corresponding to PCT/US2018/046770, filed August 14, 2018, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 254, these references incorporated by reference herein control.
  • the peptide comprises the polypeptide sequence VSGLNPSLWSIFGLQFILLWLVSGSRHYLW or YGRKKRRQRRRVSGLNPSLWSIFGLQFILLWLVSGSRHYLW, or a sequence having at least 80% sequence homology with either of these sequences.
  • the peptide may be a polypeptide having portions (for example, three or more consecutive amino acids) of either of these sequences and having an overall length of 10 – 50 residues.
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 255. Such peptides are described in WO 2010/004003, published January 14, 2010, corresponding to PCT/EP2009/058752, filed July 9, 2009, and US 9,241,967, issued January 26, 2016, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 255, these references incorporated by reference herein control.
  • a compound comprising a first peptide or peptide analogue linked to a second peptide or peptide analogue by a linker, optionally a PEG linker, wherein said linker is associated with a N-terminus of said first and second peptide or peptide analogue, and wherein said first and said second peptide or peptide analogue comprise at least four amide-bonded residues having a sequence Xaa1-Thr-Xaa3-Val or Xaa1-Ser-Xaa3-Val, wherein: a. Xaa1 is selected from among E, Q, and A, or an analogue thereof, and b.
  • Xaa3 is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analogue thereof. [1063] In further embodiments, the compound is selected from:
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 256. Such peptides are described in WO 2014/096402, published June 26, 2014 corresponding to PCT/EP2013/077780, filed December 20, 2013 and US 2015/0337276, published November 26, 2015, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 256, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is an enzyme, optionally a metalloenzyme comprising at least one divalent cation.
  • the divalent cation is Zn2+, Mg2+, Ni2+, Cd2+, Mn2+, Co2+, Fe2+, and Ag2+, preferably is Zn2+.
  • the enzyme is a phosphotriesterase or phosphotriesterase derivative.
  • the enzyme comprises a sequence, or functional portion thereof, having a sequence according to: MQTRRVVLKSAAAAGTLLGGLAGCASVAGSIGTGDRINTVRGPITISEAGFTL THEHICGSSAGFLRAWPEFFGSRKALAEKAVRGLRRARAAGVRTIVDVSTFDI GRDVSLLAEVSRAADVHIVAATGLWFDPPLSMRLRSVEELTQFFLREIQYGIE DTGIRAGIIKVATTGKATPFQELVLKAAARASLATGVPVTTHTAASQRDGEQ QAAIFESEGLSPSRVCIGHSDDTDDLSYLTALAARGYLIGLDHIPHSAIGLEDN ASASALLGIRSWQTRALLIKALIDQGYMKQILVSNDWLFGFSSYVTNIMDVM DRVNPDGMAFIPLRVIPFLREKGVPQETLAGITVTNPARFLSPTLRAS; or SIGTGDRINTVRGPITISEAGFTLTHEHICGSSAGFLRAWPEFFG
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 257.
  • Such peptides are described in WO 2013/185572, published December 19, 2013 and corresponding to PCT/CN2013/076967, filed June 8, 2013, and US 9,718,864, issued August 1, 2017. which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 257, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a polypeptide comprising one or more sequences according to: MKLTCVLIITVLFLTACQLTTAVTYSRGEHKHRALMSTGTNYRLPKTCRSSGR YCRSPYDCRRRYCRRITDACV; or MKLTCVVIITVLFLTACQLTTAVTYSRGEHKHRALMSTGTNYRLPKTCRSSG RYCRSPYDCRRRYCRRITDACV; or TCRSSGRYCRSPYDCRRRYCRRITDACV; or MKLTCVLIITVLFLTACQLTTAVTYSRGEHKHRALMSTGTNYRLPKTCRSSGR YCRSPYDRRRRYCRRITDACV; or MKLTCVVIITVLFLTACQLTTAVTYSRGEHKHRALMSTGTNYRLPKTCRSSG RYCRSPYDRRRRYCRRITDACV; or TCRSSGRYCRSPYDRRRRYCRRITDACV, or a sequence comprising a portion having at least 80% homology with any
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 258. Such peptides are described in WO2008/014917, published February 7, 2008, corresponding to PCT/EP2007/006619, filed July 25, 2007, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 258, these references incorporated by reference herein control.
  • the NMDA receptor antagonist is a polypeptide comprising entirely D-enantiomeric amino acids.
  • the NMDA receptor antagonist is a fusion peptide comprising at least a component (I), wherein component (I) comprises a transporter peptide, and a component (II), selected from a peptide inhibiting interaction of neuronal N-methyl-D-aspartate receptor (NMDAR) with NMDAR interacting proteins, wherein component (II) entirely consists of D- enantiomeric amino acids.
  • component (I) comprises a transporter peptide
  • component (II) selected from a peptide inhibiting interaction of neuronal N-methyl-D-aspartate receptor (NMDAR) with NMDAR interacting proteins, wherein component (II) entirely consists of D- enantiomeric amino acids.
  • component (I) is selected from cell penetrating peptides including: (a) protein transduction domains (PTD) and protein derived CPPs, including sequences derived from Antennapedia, pAntp (43-58), comprising the sequences RQI KIVVFQN RRMKWKK or RQIKIWFQNRRMKWKK-amide, including sequences derived from human immunodeficiency virus 1 (HIV-1 ), TAT, region 37 to 72, region 37 to 60, region 48 to 60 or region 49 to 57 from TAT, sequences GRKKRRQRRR, YGRKKRRQRRR, CGRKKRRQRRRPPQC or CGRKKRRQRRRPPQCC, including hCT(9-32) having the sequence LGTYTQDFNKFHTFPQTAIGVGAP-NH2, pVEC comprising the sequence LLIILRRRIRKQAHAHSK-NH2, plSL comprising the sequence RVIRVWFQNKRCKDKK-
  • (Arg)9-NH2 or (c) designed CPPs including MPG comprising the sequence GALFLGFLGAAGSTMGAWSQPKSKRKV or GALFLGFLGAAGSTMGAWSQPKSKRKV-cysteamide; Transportan comprising the sequence GWTLNSAGYLLGKINLKALAALAKKIL- NH2 (SEQ , Transportan 10 comprising the sequence AGYLLGKINLKALAALAKKIL-NH2, Pep-1 comprising the sequence KETWWETWWTEWSQPKKKRKV or KETWWETWWTEWSQPKKKRKV- cysteamide, or may be selected from the KALA peptide comprising the sequence WEAKLAKALAKALAKHLAKALAKALKACEA or from Bulforin 2 comprising the sequence TRSSRAGLQFPVGRVHRLLRK, or an retro-inverso isomer of any of these sequences composed of D amino acids, or any sequences having at least 80% homology with any of these sequences.
  • Transportan compris
  • component (II) comprises the polypeptide sequence vdseisslk, or a sequence having at least 80% homology thereto. In an embodiment, the component (II) sequence comprises a length of 5 to 40 amino acids.
  • the NMDA receptor antagonist may be selected from one of the following peptides according to Formula 259 Such peptides are described in US 5,854,217, issued December 29, 1998, and US 6,284,731, issued September 4, 2001, which are each incorporated by reference in their entirety herein. In the case of any conflict of terminology of Formula 259, these references incorporated by reference herein control.
  • the NMDA receptor antagonist comprises one or more sequences according to: Asn Gly Glu Gla Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn-NH2; Phe Gly Glu Gla Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn-NH2; t-BuTyr Gly Glu Gla Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn- NH2; Ser Gly Glu Gla Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn-NH2; Gly Glu Ser Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn-NH2, wherein the serine at position 3 is phosphorylated; Gly Glu Ala Gla Leu Gln Gla Asn Gln Gla Leu Ile Arg Gla Lys Ser Asn-NH2; Gly Glu Ala Gla Le
  • the NMDA receptor antagonist has the structure: A1-A2-A3-A4-A5-A6-(A7)x c-[A8-(A9-A10)x d—NH2]n wherein A1 is glycine, alanine, valine, leucine or isoleucine; A2 is glutamic acid, aspartic acid, ⁇ -carboxyglutamate (Gla), 3-carboxyaspartic acid, D-glutamic acid, phosphoserine or phosphothreonine; A3 is glutamic acid, aspartic acid, ⁇ -carboxyglutamate (Gla), 3-carboxyaspartic acid, D-glutamic acid, phosphoserine or phosphothreonine; A4 is Gla; A5 is glycine, alanine, valinc, leucine or isoleucine; A6 is a peptide of 7-9 amino acids; A7 is an amino acid selected
  • the NMDA receptor antagonist is a histogranin or analog thereof, as described in CA 2097533, published December 4, 1993.
  • PHARMACEUTICAL COMPOSITIONS [1079]
  • a pharmaceutical composition comprising a metal channel activator and a NMDA receptor antagonist.
  • the metal channel activator in said pharmaceutical composition is a potassium channel activator.
  • the potassium channel activator in said pharmaceutical composition is a Kv7 channel activator.
  • the Kv7 channel activator in said pharmaceutical composition is selected from the group consisting of a Kv7.1 channel activator, a Kv7.2 channel activator, a Kv7.3 channel activator, a Kv7.4 channel activator, a Kv7.5 channel activator, or any combination thereof.
  • the Kv7 channel activator in said pharmaceutical composition is a Kv7.2/7.3 channel activator.
  • the metal channel activator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.
  • the NMDA receptor antagonist in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 260.
  • the NMDA receptor antagonist in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 260, and the metal channel activator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.
  • the NMDA receptor antagonist or a pharmaceutically acceptable salt thereof in said pharmaceutical composition is in a form of a prodrug.
  • the combination therapies (comprising at least one of any metal channel activator described herein and at least one NMDA receptor antagonist described herein) disclosed herein are useful for treating various depressive disorders.
  • the depressive disorder include major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.
  • disorders include amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer’s disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, Huntington’s disease, or any combination thereof.
  • the combination therapies disclosed herein are useful for treating various pain disorders.
  • the pain disorders include acute pain, chronic pain, neuropathic pain, nociceptive pain, radicular pain.
  • the pain disorders may also include migraine, inflammatory pain, persistent pain, cancer pain, and postoperative pain.
  • the metal channel activator and the NMDA receptor antagonist may be given orally, sublingually, subcutaneously or in any other means of delivery.
  • the agents may be delivered simultaneously or sequentially. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time.
  • kits for treating a patient afflicted with at least one of the aforementioned disorders said kit including: (a) a metal channel activator; and (b) instructions for administering said metal channel activator in combination with an NMDA receptor antagonist by one of the aforementioned methods.
  • a kit for treating a patient afflicted with at least one of the aforementioned disorders said kit including: (a) an NMDA receptor antagonist; and (b) instructions for administering said NMDA receptor antagonist with a metal channel activator by one of the aforementioned methods.
  • the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof.
  • NMDA receptor antagonist is construed to include both NMDA receptor antagonist and pharmaceutically acceptable salt thereof.
  • various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.
  • Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein.
  • Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of any one of Formulas 1 – 180, Formulas 200 – 260, those listed in “Further Embodiments” under the “METAL CHANNEL ACTIVATORS” subsection, or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients.
  • a therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art.
  • Pharmaceutically acceptable carriers are those having acceptable safety profiles which are conventionally known.
  • compositions encompass common solid and liquid forms including but not limited to capsules, tablets, lozenges, liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formulated to timed or sustained release. Compositions are made using common formulation techniques, such as the aforementioned solid and liquid forms, conventional excipients, such as binding and wetting agents, and vehicles, such as water and alcohols. [1099] The NMDA receptor antagonists of the present invention may be given orally, sublingually, intranasally, buccally, subcutaneously or in any other suitable means of delivery in table 1.
  • the NMDA receptor antagonists may be in the form of a prodrug, which releases the agent in the body, a sustained release vehicle, a delayed release vehicle, or any other suitable delivery form.
  • the NMDA receptor antagonists and the metal channel activator may be delivered simultaneously or sequentially. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time.
  • the NMDA receptor antagonist is administered at a time proximate to the administration of the metal channel activator, e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the metal channel activator or simultaneously with the metal channel activator.
  • the metal channel activators of the present invention may be given orally, sublingually, intranasally, buccally, subcutaneously or in any other suitable means of delivery in table 1.
  • Metal channel activators may be given in the form of a prodrug, which will release the active compound in the body, a delayed release formulation, which will release the active compound after a time delay, a sustained release formulation, which will release the active compound slowly over time, or any other suitable formulation to deliver the active ingredient.
  • the metal channel activator may be delivered simultaneously or sequentially with the NMDA receptor antagonist. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time.
  • the metal channel activator will be administered at a time nearing the administration of the NMDA receptor antagonist e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the NMDA receptor antagonist or simultaneously with the metal channel activator.
  • the dose of the NMDA receptor antagonist and metal channel activator for use together may depend on the subject to be treated inclusive of the age, sex, weight, and general health condition thereof. In this regard, precise amounts of the agent(s) for administration will depend on the judgment of the practitioner. In determining the effective amount of the NMDA receptor antagonist and metal channel activator to be administered in the treatment or reducing of the conditions associated with the symptoms and disorders, the physician may evaluate clinical factors including symptoms severity or progression of the disorder.
  • a rapid absorption of the NMDA receptor antagonist or metal channel activator may be desirable.
  • the effective amount of the treatment will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art.
  • Some of the NMDA receptor antagonists and metal channel activators can be administered sublingually.
  • the sublingual formulation may be administered in an effective amount to a subject in need thereof.
  • the subject may be an animal or human.
  • the NMDA receptor antagonist or metal channel activator is prepared as a sublingual formulation, the sublingually administered chemical agent or the drug can diffuse into capillaries through mucous membrane under the tongue, and then enter venous circulation of the subject.
  • a sublingual formulation useful in the present invention comprises an effective amount of an NMDA receptor antagonist, metal channel activator, or pharmaceutically acceptable salts, solvates, anomers, enantiomers, hydrates, or prodrugs thereof.
  • the formulation provides sufficient solubility for a NMDA receptor antagonist and/or metal channel activator to be incorporated into the sublingual formulation at relatively large doses and sublingually delivered.
  • the formulation is preferably a modified oral disintegrating formulation of a NMDA receptor antagonist and/or metal channel activator.
  • the excipients including mannitol and gelatin, are blended, solubilized with water and deaerated before being mixed with the active pharmaceutical ingredient (or “API”), a NMDA receptor antagonist and/or a metal channel activator, which have been milled separately.
  • Particle size of the API (D50) may be less than about 2 microns.
  • the mixture is lyophilized by flash freezing and then freeze-dried.
  • the formulation has good oral palatability.
  • the effective amount of a NMDA receptor antagonist and/or metal channel activator for the sublingual formulation useful in the present invention to achieve a lower therapeutic dose may be less than that of orally administered agent.
  • the NMDA receptor antagonist and/or metal channel activator is provided in a sublingual formulation in a form of an orally dissolving or disintegrating tablet (ODT).
  • ODT as used herein may be prepared by mixing the NMDA receptor antagonist and/or the metal channel activator with water-soluble diluents and compressed in a tablet.
  • a suspension comprising the active product may be prepared with appropriate excipients and the suspension may be dispensed into blister packs and freeze- dried.
  • An exemplary freeze-dried preparation platform that could be used for the ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation.
  • the excipients including water
  • the NMDA receptor antagonist and/or metal channel activator are separately milled to size and mixed with the excipients.
  • the suspension then undergoes lyophilization by flash freezing and freeze drying.
  • the clinical or therapeutic effect of the sublingually formulated NMDA receptor antagonist may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters.
  • the T max , C max and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound.
  • the sublingual formulation of the NMDA receptor antagonist may have a greater C max than the orally administered NMDA receptor antagonist to provide a therapeutically beneficial effect.
  • the sublingual formulation of the NMDA receptor antagonist may have an earlier or lesser T max than the orally administered NMDA receptor antagonist to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect.
  • the sublingual formulation of the NMDA receptor antagonist may have a greater AUC per milligram of the agent than the orally administered NMDA receptor antagonist.
  • the NMDA receptor antagonist may make the metal channel activator more effective, lesser amounts of the metal channel activator may be needed to achieve the same results, lessening the inherent side effects.
  • the clinical or therapeutic effect of the sublingually formulated metal channel activator may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters. When the metal channel activator is administered sublingually, the T max , C max and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound.
  • the sublingual formulation of the metal channel activator may have a greater C max than the orally administered metal channel activator to provide a therapeutically beneficial effect.
  • the sublingual formulation of the metal modulator may have an earlier or lesser T max than the orally administered metal channel activator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect.
  • the sublingual formulation of the metal channel activator may have a greater AUC per milligram of the agent than the orally administered metal channel activator.
  • the metal channel activator may make the NMDA receptor antagonist more effective, lesser amounts of the NMDA receptor antagonist may be needed to achieve the same results, lessening the inherent side effects.
  • the disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods.
  • routes of administration the standard routes of administration described by the FDA are contemplated herein as shown in Table 1 below (FDA Routes of Administration; retrieved from www.fda.gov; content current as of 11/1/2022).
  • Table 1 FDA Routes of Administration
  • the route of administration may be oral, intranasal, inhalation, intravenous, sublingual, topical, injectable and/or transdermal.
  • compositions of the present invention comprising the NMDA receptor antagonist and/or metal channel activator may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof.
  • binders such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof.
  • binders such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical. Excipients may also serve as part of the overall vehicle for delivery. Excipients may also be used to achieve effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating. Excipients herein may also serve an antimicrobial function or improve pharmaceutical composition characteristics such as lubricity, flowability, disintegration and taste. [1111] Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • Pharmaceutically acceptable carriers are biologically acceptable and compatible with the other ingredients in the formulation.
  • compositions herein are not limited to a single active ingredient, and supplementary active ingredients can also be incorporated.
  • Examples of pharmaceutically acceptable carriers may include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose; other carriers such as, polyvinylpyrrolidone (PVP), talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl
  • disintegrating agents may be combined as well, and exemplary disintegrating agents may be, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more chemical agents as described above with the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical compositions of the present invention may be manufactured in conventional methods known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes, and the like.
  • NMDA receptor antagonists, metal channel activator, and/or the pharmaceutically acceptable salts thereof can be formulated using pharmaceutically acceptable carriers well known in the art into dosages suitable for sublingual, intranasal or buccal administration.
  • Such carriers enable the NMDA receptor antagonists and/or metal channel activator to be formulated in dosage forms such as tablets, powders, pills, capsules, liquids, gels, films, syrups, slurries, suspensions, and the like.
  • the NMDA receptor antagonist and/or metal channel activator compounds disclosed can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • Oral formulations containing a compound disclosed can be any conventionally used oral form, including but not limited to tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions, or solutions.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided compound.
  • a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, e
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s).
  • the oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Liquid carriers can be used in preparing solutions for oral, parenteral (such as intravenous, intramuscular, or other injections), or inhalation administration including but not limited to suspensions, emulsions, syrups, and elixirs.
  • An NMDA receptor antagonist and/or metal channel activator compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile injectable solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes, or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, and transdermally.
  • parenterally including intravenous, intraperitoneal, and subcutaneous injections
  • rectally vaginally
  • transdermally transdermally.
  • an effective dosage can vary depending upon the particular compound utilized, the pharmaceutical composition formulated, the mode of administration, physical factors related to the individual being treated, and severity of the condition being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition, stage of said condition, and the characteristics of the patient including their size, age and response pattern to the compound utilized.
  • the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition.
  • the liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser.
  • the solvents can be, for example, isotonic saline or bacteriostatic water.
  • the solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation.
  • the aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device.
  • the propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
  • compositions described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form can be sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues.
  • Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in- oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.
  • a variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature. [1125]
  • Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
  • a method of treating a neurological disease may be characterized by one or more pharmacokinetic parameters such as AUC, C max , T max , and others known and understood to persons of skill in the art.
  • pharmacokinetic as used herein is used in its ordinary sense to mean the pharmacokinetic aspects of drug delivery.
  • pharmacokinetics is the study of how an organism affect a drug, e.g., how, and how fast it metabolizes the drug.
  • the pharmacokinetics typically vary based upon the dosage amount of one or more of the disclosed NMDA receptor antagonists and/or metal channel activators.
  • a method of treating a neurological disease may be characterized by an AUC for a NMDA receptor antagonist and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 260, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof.
  • the AUC 0-t and/or AUC 0-inf may be from about 80 – 125% of a given AUC value.
  • the AUC may be within 80 – 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 hr*ng/mL.
  • a systemic treatment may have a larger AUC than a localized (such as topical or subdermal) treatment.
  • a method of treating a neurological disease may be characterized by a C max for a NMDA receptor antagonist and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 260, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof.
  • the C max may be from about 80 – 125% of a given C max value.
  • the C max may be within 80 – 125 % of about 1, 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL.
  • a systemic treatment may have a larger C max than a localized (such as topical or subdermal) treatment.
  • a ratio C max /AUC may be used to characterize a method of treating a neurological disease wherein one or more of a NMDA receptor antagonist and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 260, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof are administered to a subject.
  • the C max /AUC ratio may be from about 80 – 125 % of a given C max /AUC ratio.
  • the C max /AUC ratio may be from about 80 – 125 % of about 0.01, 0.03, 0.05, 0.08, 0.1, 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9.
  • the T max may range from about 0.1 – 16 hours, or from about 0.3 – 8 hours, or from about 0.5 – 4 hours, or from 0.5 – 2 hours, or from about 1 – 2 hours.
  • the route of administration which may be any route described herein or known to a person of skill in the art, may affect the T max of a compound according to Formulas 1 – 180, Formulas 200 – 260, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof.
  • Excipients or other pharmaceutically acceptable carriers in pharmaceutical compositions of one or more compounds according to Formulas 1 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof may alter the T max value by making it larger or smaller than a pharmaceutical composition having the excipient or carrier excluded.
  • Solid compositions are normally formulated in dosage units providing from about 0.1 to about 1000 mg of the active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg, and 1000 mg. Liquid compositions are generally in a unit dosage range of 0.1-100 mg/mL.
  • liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • a dose is daily.
  • a dose is twice daily.
  • a does is one, two, three, four, or five times daily.
  • a dose is once every other day, once every second day, once every third day, once every fourth day, once every fifth day, once every sixth day, weekly, bi-weekly, or monthly.
  • a dose may be from 0.01-100 mg/kg body weight, or from .05 – 50 mg/kg body weight, or from 0.1 – 10 mg/kg body weight, or from 0.15 – 5 mg/kg body weight, or from 0.2 – 2 mg/kg body weight, or from 0.5 – 1.5 mg/kg body weight, or from 1 – 1.5 mg/kg body weight.
  • the dosing regimen may comprise one or more optional loading doses and a subsequent maintenance dose regimen.
  • a loading dose may be larger than the doses given in a subsequent maintenance dose regimen.
  • the dosage is adjusted based upon neurological disease symptoms observed in the patient.
  • a symptom-dependent regimen may have a larger treatment dose while symptoms are present and a smaller preventative dose while symptoms are lessened, in remission, controlled, etc.
  • a treatment dose may comprise a unit dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg of an NMDA receptor antagonist according to any one of Formulas 1 – 180, and/or a metal channel activator according to any one of Formulas 200 – 260, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof .
  • a preventative dose may comprise a unit dosage of about 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, or 140 mg of a NMDA receptor antagonist according to any one of Formulas 200 – 260, and/or a metal channel activator according to any one of Formulas 1 – 180, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof .
  • the preventative dose is an amount that is about 7/8, 3/4, 5/8, 1/2, 3/8, 1/4, or about 1/8 of the amount of the treatment dose.
  • a treatment dosing regimen may replace the preventative dosing regimen until symptoms have lessened or subsided.
  • Each of the treatment and/or preventative doses may be adjusted during the regimen based upon the severity of neurological disorder symptoms.

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Abstract

L'invention concerne une composition pharmaceutique comprenant un activateur des canaux métalliques et un antagoniste des récepteur NMDA. L'invention concerne également une méthode de traitement d'un trouble dépressif, comprenant l'administration de la composition pharmaceutique. L'invention concerne également une méthode de traitement d'un trouble neurologique ou neurodégénératif, comprenant l'administration de la composition pharmaceutique. L'invention concerne également une méthode de traitement d'un trouble de la douleur, comprenant l'administration de la composition pharmaceutique.
PCT/US2023/073125 2022-08-30 2023-08-30 Polythérapies comprenant des activateurs des canaux métalliques et des antagonistes des récepteurs nmda WO2024050389A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080139610A1 (en) * 2006-08-23 2008-06-12 Valeant Pharmaceuticals North America Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
US20140243350A1 (en) * 2011-07-05 2014-08-28 Contera Pharma Aps Use of serotonin receptor agonists for treatment of movement disorders
US9675567B2 (en) * 2008-07-22 2017-06-13 Ramot At Tel-Aviv University Ltd. Potassium ion channel modulators and uses thereof
US20210130299A1 (en) * 2018-03-19 2021-05-06 Knopp Biosciences Llc Kv7 channel activators compositions and methods of use
WO2022215080A1 (fr) * 2021-04-08 2022-10-13 Yeda Research And Development Co. Ltd. Utilisation combinée de kétamine et de rétigabine (ézogabine) pour le traitement de troubles psychiatriques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080139610A1 (en) * 2006-08-23 2008-06-12 Valeant Pharmaceuticals North America Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
US9675567B2 (en) * 2008-07-22 2017-06-13 Ramot At Tel-Aviv University Ltd. Potassium ion channel modulators and uses thereof
US20140243350A1 (en) * 2011-07-05 2014-08-28 Contera Pharma Aps Use of serotonin receptor agonists for treatment of movement disorders
US20210130299A1 (en) * 2018-03-19 2021-05-06 Knopp Biosciences Llc Kv7 channel activators compositions and methods of use
WO2022215080A1 (fr) * 2021-04-08 2022-10-13 Yeda Research And Development Co. Ltd. Utilisation combinée de kétamine et de rétigabine (ézogabine) pour le traitement de troubles psychiatriques

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