DK2953931T3 - Pyridonamider som natriumkanal-modulatorer - Google Patents

Pyridonamider som natriumkanal-modulatorer Download PDF

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DK2953931T3
DK2953931T3 DK14704053.9T DK14704053T DK2953931T3 DK 2953931 T3 DK2953931 T3 DK 2953931T3 DK 14704053 T DK14704053 T DK 14704053T DK 2953931 T3 DK2953931 T3 DK 2953931T3
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alkyl
benzamide
another embodiment
oxo
dihydropyridin
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DK14704053.9T
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Corey Anderson
Vijayalaksmi Arumugam
Brian Richard Bear
Andreas P Termin
James Philip Johnson
Sara Sabina Hadida-Ruah
Iuliana Luci Asgian
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Vertex Pharma
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    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • 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
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Ink Jet (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)

Claims (15)

1. Forbindelse med formel I eller Γ
eller et farmaceutisk acceptabelt salt deraf, hvor, uafhængigt af hver forekomst: G er
X er en binding eller Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende Chh-enheder af Ci-Ce-alkyl kan erstattes med -O-; Rx er fraværende, H eller cycloalifatisk C3-C8, hvor op til to ikke-tilstødende CH2-enheder af cycloalifatisk C3-C8 kan erstattes med -O- og cycloalifatisk C3-C8 er substitueret med 0-3 substituenter valgt fra halogen og C1-C4-alkyl; R1 er H, halogen, CN eller Ci-C6-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende CFte-enheder af Ci-C6-alkyl kan erstattes med -O-; R2 er H, halogen, CN eller Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende CH2-enheder af Ci-Ce-alkyl kan erstattes med -O-; R3 er H, halogen, CN eller Ci-C6-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende Chb-enheder af Ci-C6-alkyl kan erstattes med -O-; R4 er H, halogen, CN eller Ci-C6-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende CH2-enheder af Ci-Ce-alkyl kan erstattes med -O-; R5 er H, halogen, CN eller -X-Rx; R5’ er H, halogen, CN eller -X-Rx; R6 er H, halogen, CN eller -X-Rx; R6’ er H, halogen, CN eller -X-Rx; R7 er H, halogen, CN eller -X-Rx; R8 er halogen, eller Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende Chh-enheder af Ci-C6-alkyl kan erstattes med -O-; p er et helt tal fra 0 til 3 inklusiv; og R9 er H, eller Ci-C6-alkyl hvor op til to ikke-tilstødende CFte-enheder Ci-Ce-alkyl kan erstattes med -O-.
2. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 1, hvor R3 er Ci-Ce-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen, og/eller hvor R3 er t-butyl, CF3 eller CF2CF3.
3. Forbindelse eller farmaceutisk acceptabelt salt ifølge et hvilket som helst af kravene 1 til 2, hvor G er
hvor: R5 er H, halogen, CN eller -X-Rx; R5' er H, halogen, CN eller -X-Rx; R6 er H, halogen, CN eller -X-Rx; R6' er H, halogen, CN eller -X-Rx; R7 er H, halogen, CN eller -X-Rx; X er en binding eller Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende Chh-enheder af Ci-Ce-alkyl kan erstattes med -O-; og Rx er fraværende, H, eller cycloalifatisk C3-C8, hvor op til to ikke-tilstødende CH2-enheder af cycloalifatisk C3-C8 kan erstattes med -O- og cycloalifatisk C3-C8 er substitueret med 0-3 substituenter valgt fra halogen og Ci-C4-alkyl, fortrinsvis hvor G er valgt fra:
4. Forbindelse eller farmaceutisk acceptabelt salt ifølge et hvilket som helst af kravene 1 til 2, hvor G er:
og G er valgt fra
eller hvor G er -χ-κΛ og -X-Rx er valgt fra:
5. Forbindelse eller farmaceutisk acceptabelt salt ifølge et hvilket som helst af kravene 1 til 4, hvor p er 0, og/eller hvor R9 er H.
6. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 1, hvor forbindelsen eller det farmaceutisk acceptable salt har formel I-F eller I'-F: i
eller et farmaceutisk acceptabelt salt deraf, hvor, uafhængigt af hver forekomst: R3 er halogen, CN eller Ci-C6-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen, hvor op til to ikke-tilstødende CH2 enheder af Ci-Ce alkyl kan erstattes med -O-; R5 er halogen, CN eller -X-Rx; R7 er halogen, CN eller -X-Rx; X er en binding eller Ci-Ce-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende CFh-enheder af Ci-C6-alkyl kan 1 erstattes med -O-; Rx er fraværende, H eller cycloalifatisk C3-C8, hvor op til to ikke-tilstødende CH2-enheder af cycloalifatisk C3-C8 kan erstattes med -O- og cycloalifatisk C3-Ce er substitueret med 0-3 substituenter valgt fra halogen og C1-C4-alkyl; R8 er halogen eller Ci-C6-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende Cl-h-enheder af Ci-C6-alkyl kan erstattes med -O-; p er et helt tal fra 0 til 3 inklusiv; og R9 er H, eller Ci-Ce-alkyl hvor op til to ikke-tilstødende Chh-enheder af Ci-C6-alkyl kan erstattes med -O-.
7. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 6, hvor R3 er Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, og/eller hvor R3 er t-butyl, CF3 eller CF2CF3, og/eller hvor ring A er valgt fra:
og/eller hvor p er 0, og/eller hvor R9 er H.
8. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 1, hvor forbindelsen eller det farmaceutisk acceptable salt har formel I-G eller I'-G:
eller et farmaceutisk acceptabelt salt deraf, hvor, uafhængigt af hver forekomst: R2 er halogen, CN eller Ci-C6-alkyl hvor Ci-C6-alkyl is substituted with 0-6 halogen og hvor op til to ikke-tilstødende CH2-enheder af Ci-C6-alkyl kan erstattes med -O-; R3 er halogen, CN eller Ci-C6-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende CH2-enheder af Ci-Ce-alkyl kan erstattes med -O-; R5 er halogen, CN eller -X-Rx; R7 er halogen, CN eller -X-Rx; X er en binding eller Ci-C6-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende CH2-enheder af Ci-C6-alkyl kan erstattes med -O-; Rx er fraværende, H, eller cycloalifatisk C3-C8, hvor op til to ikke-tilstødende CH2-enheder af cycloalifatisk C3-C8 kan erstattes med -O- og cycloalifatisk C3-C8 er substitueret med 0-3 substituenter valgt fra halogen og Ci-C4-alkyl; R8 er halogen eller Ci-C6-alkyl hvor Ci-C6-alkyl er substitueret med 0-6 halogen og hvor op til to ikke-tilstødende Cl-h-enheder af Ci-Ce-alkyl kan erstattes med -O-; p er et helt tal fra 0 til 3 inklusiv; og R9 er H, eller Ci-C6-alkyl hvor op til to ikke-tilstødende Chh-enheder af Ci-C6-alkyl kan erstattes med -O-.
9. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 8, hvor R2 er F, Cl, CN, CF3 eller OCF3, og/eller hvor R3 er Ci-Ce-alkyl hvor Ci-Ce-alkyl er substitueret med 0-6 halogen, og/eller hvor R3 er t-butyl, CF3 eller CF2CF3, og/eller hvor ring A er valgt fra:
og/eller hvor p er 0, og/eller hvor R9 er H.
10. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 1, hvor forbindelsen eller det farmaceutisk acceptable salt er valgt fra gruppen bestående af:
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(6-oxo-l,6-dihydropyridin-3-yl)benzamid;
2-(4-fluorphenoxy)-N-(6-oxo-l,6-dihydropyridin-3-yl)-5- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(6-oxo-l,6-dihydropyridin-3-yl)-4- (trifluormethyl)benzamid;
2-(2,4-difluorphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-(2-methoxyethoxy)phenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-4- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-phenoxy-4-(trifluormethyl)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-4- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-4-(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-4-(trifluormethyl)benzamid;
4-chlor-2-(2,4-difluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(2-chlor-4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid;
4-chlor-2-(2-fluor-6-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(2-chlor-6-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(2,6-difluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-chlor-2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-cyano-2-(4-fluorphenoxy)-IM-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4-cyano-2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid;
4-cyano-2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid;
2-(2,4-difluorphenoxy)-N-(2-oxo-1,2-dihydropyrid in-4-yl)-5-(trifluormethyl)benzamid;
2-(4-cyanophenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2,6-difluorphenoxy)-N-(2-oxo- 1,2-dihydropyrid in-4-yl)-5-(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluormethyl)benzamid;
2-(2-chlor-4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluormethyl)benzamid;
2-(2,4-difluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethoxy)benzamid;
2-(2,6-difluorphenoxy)-N-(2-oxo- 1,2-dihydropyrid in-4-yl)-5-(trifluormethoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluormethoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluormethoxy)benzamid;
2-(2-chlor-4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethoxy)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethoxy)benzamid;
2-(2-fluor-6-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethoxy)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-5- (trifluormethoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluormethoxy)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethoxy)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-6- (trifluormethyl)benzamid;
2-(4-ethoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-ethoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-methoxy-4-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-fluor-6-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-chlor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid; (
2-(4-chlor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-chlor-2-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(5-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)-5- (trifluormethyl)benzamid;
2-(3-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(5-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(3-fluor-5-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(4-chlorphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(6-chlor-2-oxo-l,2-dihydropyridin-4-yl)-2-(4-fluor-2-methylphenoxy)-5- (trifluormethyl)benzamid
2-(4-fluor-2-methylphenoxy)-N-(6-methyl-2-oxo-l,2-dihydrc>pyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2-propoxyphenoxy)-5- (trifluormethyl)benzamid;
2-(4-methoxy-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-isopropoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-chlorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
5-chlor-2-(2-chlor-4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
5-chlor-2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)benzamid;
5-chlor-2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
5-chlor-2-(2,4-difluorphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)benzamid;
5-chlor-2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4- yl)benzamid;
5-chlor-2-(3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4- yl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(trifluormethoxy)phenoxy)-5- (trifluormethyl)benzamid;
2-(4-(difluormethoxy)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)-2-(4- (trifluormethyl)phenoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2-(trifluormethoxy)phenoxy)-5- (trifluormethyl)benzamid;
2-(2-(difluormethoxy)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-(2-chlor-4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-chlorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(trifluormethoxy)phenoxy)-4- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2-(trifluormethoxy)phenoxy)-4- (trifluormethyl)benzamid;
2-(3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-(difluormethoxy)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(2-(difluormethoxy)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(2-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydrc>pyndin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(l-(2-hydroxyethyl)-2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(5-methyl-2-oxo-l,2-dihydrc>pyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(3-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(perfluorethyl)benzamid;
2-(3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (perfluorethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)-2-(2,3,4- trifluorphenoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)-2-(2,3,5- trimethylphenoxy)benzamid;
2-(2,3-difluor-4-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)-2-(2,4,5- trimethylphenoxy)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2,3,5-trimethylphenoxy)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-phenoxybenzamid;
2-(4-cyclopropylphenoxy)-5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
2-(4-(tert-butoxy)phenoxy)-5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
2-(4-ethoxyphenoxy)-5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
5-fluor-2-(4-isopropylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4- (trifluormethoxy)phenoxy)benzamid;
5-fluor-2-(4-(2-methoxyethyl)phenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4- yl)benzamid;
2-(2-chlor-4-methoxyphenoxy)-5-fluor-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid;
5-fluor-2-(4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2,4,5-trimethylphenoxy)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-5- (trifluormethyl)benzamid;
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(2,2,2- trifluorethoxy)phenoxy)benzamid;
2-(4-(cyclopropylmethoxy)phenoxy)-5-fluor-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid;
4-chlor-2-(2-chlor-4-fluorphenoxy)-5-fluor-N-(2-oxo-l,2-dihydrc>pyridin-4- yl)benzamid;
2-(2-chlor-3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydrc>pyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (perfluorethyl)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydrc>pyndin-4-yl)-4- (perfluorethyl)benzamid;
4,5-dichlor-2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4.5- dichlor-2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
4.5- dichlor-2-(3-fluor-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
2-(isopentyloxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluorrnethyl)benzamid;
2-isobutoxy-N-(2-oxo-l,2-dihydropyndin-4-yl)-4-(trifluormethyl)benzamid;
2-((2R)-bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-((l-methylcyclopropyl)methoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(cyclopentylmethoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-((tetrahydrofuran-3-yl)methoxy)-4- (trifluormethyl)benzamid;
2-cyclobutoxy-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4,4,4-tnfluorbutoxy)-4- (trifluormethyl)benzamid;
2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo- 1,2-d ihydropyridin-4-yl)-4-(trifluormethyl)benzamid;
2-((lR,5S)-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-((2,2-difluorcyclopropyl)methoxy)-N-(2-oxo-l, 2-dihydropyridin-4-yl)-4-(trifluormethyl)benzamid;
2-(bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(cyclohexyloxy)-N-(2-oxo-l,2-dihydropyndin-4-yl)-4-(trifluormethyl)benzamid;
4-chlor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorbutoxy)benzamid;
2-(cyclopentylmethoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-isobutoxy-N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethyl)-2-(3,3,3- trifluorpropoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5- (trifluormethyl)benzamid;
2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo- 1,2-d ihydropyridin-4-yl)-5-(trifluormethyl)benzamid;
2-(( lR,5S)-bicyclo[3.1.0] hexan-3-yloxy)-N-(2-oxo-l, 2-dihydropyridin-4-yl)-5-(trifluormethyl)benzamid;
2-(cyclopentylmethoxy)-N-(2-oxo- 1,2-d ihydropyrid in-4-yl)-5-(trifluormethoxy)benzamid;
2-(cyclohexyloxy)-N-(2-oxo- 1,2-d ihydropyrid in-4-yl)-5-(trifluormethoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluormethoxy)-2-(3,3,3- trifluorpropoxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorbutoxy)-5- (trifluormethoxy)benzamid;
2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo- 1,2-d ihydropyridin-4-yl)-5-(trifluormethoxy)benzamid;
4-(tert-butyl)-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-((6-(trifluormethyl)pyridin-3- yl)oxy)benzamid;
4-(tert-butyl)-N-(6-oxo-l,6-dihydropyridin-3-yl)-2-((6-(trifluormethyl)pyridin-3- yl)oxy)benzamid;
4-chlor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-((6-(trifluormethyl)pyridin-3- yl)oxy)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluormethyl)-2-((6-(trifluormethyl)pyridin- 3-yl)oxy)benzamid;
N-(6-oxo-l,6-dihydropyridin-3-yl)-4-(trifluormethyl)-2-((6-(trifluormethyl)pyridin- 3-yl)oxy)benzamid;
2-((6-methylpyridin-3-yl)oxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
4-(tert-butyl)-N-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-2-((6- (trifluormethyl)pyridin-3-yl)oxy)benzamid;
4-(tert-butyl)-N-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((6- (trifluormethyl)pyridin-3-yl)oxy)benzamid;
2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
2-((2-methylpyridin-3-yl)oxy)-l\l-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethoxy)benzamid;
2-(2,4-difluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4,6- bis(trifluormethyl)benzamid;
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4,6- bis(trifluormethyl)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4,6- bis(trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4,6- bis(trifluormethyl)benzamid;
N-(2-oxo-l,2-dihydropyridin-4-yl)-2-phenoxy-4,6-bis(trifluormethyl)benzamid;
2-(4-fluor-2-(hydroxymethyl)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluormethyl)benzamid;
2-((5-fluor-2-hydroxybenzyl)oxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluormethyl)benzamid; og
5-fluor-N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(4,4,4- trifluorbutoxy)phenoxy)benzamid; eller et farmaceutisk acceptabelt salt deraf.
11. Forbindelse eller farmaceutisk acceptabelt salt ifølge krav 1, hvor forbindelsen eller det farmaceutisk acceptable salt er valgt fra gruppen bestående af:
2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyndin-4-yl)-4- (trifluormethyl)benzamid;
2-(4-fluorphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluormethyl)benzamid;
4-chlor-2-(4-fluor-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamid;
2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(perfluorethyl)benzamid; og
4,5-dichlor-2-(4-fluor-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamid, eller et farmaceutisk acceptabelt salt deraf.
12. Farmaceutisk sammensætning omfattende en terapeutisk effektiv mængde af forbindelsen eller et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 11 og en eller flere farmaceutisk acceptable bærere eller vehikler.
13. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 11 eller en farmaceutisk sammensætning ifølge krav 12 til anvendelse i en fremgangsmåde til at inhibere en spændings-styret natriumkanal hos en patient, fortrinsvis hvor den spændings-styrede natriumkanal er Navl.8.
14. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 11 eller en farmaceutisk sammensætning ifølge krav 12 til anvendelse i en fremgangsmåde til behandling eller mindskelse af sværhedsgraden hos en patient med kronisk smerte, mavesmerte, neuropatisk smerte, muskuloskeletale smerter, akut smerte, inflammatorisk smerte, cancersmerte, idiopatisk smerte, multipel sklerose, Charcot-Marie-Tooths syndrom, inkontinens eller hjertearytmi, fortrinsvis hvor mavesmerte omfatter smerter ved inflammatorisk tarmsygdom, smerter ved Crohns sygdom eller smerter ved interstitiel cystit, eller hvor neuropatisk smerte omfatter postherpetisk neuralgi, diabetisk neuralgi, smertefuld sensorisk neuropati forbundet med HIV, trigeminusneuralgi, mundbrandssyndrom, postamputationssmerte, fantomsmerte, smertefuld neurom; traumatisk neurom; Mortons neurom; skade ved nerve der er i klemme, spinalstenose, karpaltunnelsyndrom, radikulær smerte, iskiassmerte; nerveavulsionsskade, plexus brachialis avulsionsskade; komplekst regionalt smertesyndrom, neuralgi fremkaldt af medicinsk behandling, neuralgi fremkaldt af cancerkemoterapi, neuralgi fremkaldt af anti-retroviral behandling; smerte efter rygmarvsskade, idiopatisk småfiber-neuropati, idiopatisk sensorisk neuropati eller trigeminal autonom cefalalgi, eller hvor muskuloskeletale smerter omfatter osteoarthritissmerte, rygsmerter, smerte forårsaget af kulde, smerte forårsaget af en forbrænding eller tandpine, eller hvor inflammatorisk smerte omfatter rheumatoid arthritissmerte eller vulvodyni, eller hvor idiopatisk smerte omfatter fibromyalgismerte.
15. Forbindelse eller farmaceutisk acceptabelt salt eller farmaceutisk sammensætning til anvendelse ifølge et hvilket som helst af kravene 13 til 14, hvor patienten behandles med et eller flere yderligere terapeutiske midler som indgives samtidigt med, inden, eller efterfølgende til behandling med forbindelsen eller det farmaceutisk acceptable salt eller den farmaceutiske sammensætning.
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