EP4580679A1 - 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

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Publication number
EP4580679A1
EP4580679A1 EP23861512.4A EP23861512A EP4580679A1 EP 4580679 A1 EP4580679 A1 EP 4580679A1 EP 23861512 A EP23861512 A EP 23861512A EP 4580679 A1 EP4580679 A1 EP 4580679A1
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EP
European Patent Office
Prior art keywords
alk
cycloalk
phenyl
methyl
amino
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Pending
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EP23861512.4A
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German (de)
English (en)
Inventor
Vladimir Coric
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Biohaven Therapeutics Ltd
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Biohaven Therapeutics Ltd
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Publication of EP4580679A1 publication Critical patent/EP4580679A1/fr
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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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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 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 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 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.
  • 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 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.
  • 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:
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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
  • 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 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.
  • 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 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 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 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
  • 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
  • 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 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.
  • 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, 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 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 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 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
  • 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, 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 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
  • 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.
  • 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, 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
  • 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
  • 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 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 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 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.
  • 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 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.
  • 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 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.
  • 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 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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).
  • 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 (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 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 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 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 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:
  • 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 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 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
  • 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 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.
  • 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 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 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 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.
  • 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.
  • 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 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 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
EP23861512.4A 2022-08-30 2023-08-30 Polythérapies comprenant des activateurs des canaux métalliques et des antagonistes des récepteurs nmda Pending EP4580679A1 (fr)

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US202263402416P 2022-08-30 2022-08-30
PCT/US2023/073125 WO2024050389A1 (fr) 2022-08-30 2023-08-30 Polythérapies comprenant des activateurs des canaux métalliques et des antagonistes des récepteurs nmda

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EP2729176A1 (fr) * 2011-07-05 2014-05-14 Contera Pharma APS Utilisation d'agonistes de récepteur de sérotonine pour le traitement de troubles des mouvements
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CA3266454A1 (fr) 2024-03-07
KR20250105362A (ko) 2025-07-08
WO2024050389A1 (fr) 2024-03-07
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