WO2011145669A1 - アミド誘導体 - Google Patents

アミド誘導体 Download PDF

Info

Publication number
WO2011145669A1
WO2011145669A1 PCT/JP2011/061473 JP2011061473W WO2011145669A1 WO 2011145669 A1 WO2011145669 A1 WO 2011145669A1 JP 2011061473 W JP2011061473 W JP 2011061473W WO 2011145669 A1 WO2011145669 A1 WO 2011145669A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
alkyl
alk
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/JP2011/061473
Other languages
English (en)
French (fr)
Inventor
聖司 岩間
知行 田中
奈々 後藤
Original Assignee
大日本住友製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大日本住友製薬株式会社 filed Critical 大日本住友製薬株式会社
Publication of WO2011145669A1 publication Critical patent/WO2011145669A1/ja

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
    • C07C233/91—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/50—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/34—Ethylene-urea
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D263/44—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a novel amide derivative useful as a therapeutic agent for epilepsy.
  • Epilepsy is a chronic disease in which paroxysmal movement, consciousness, sensory abnormalities, and behavioral abnormalities resulting from excessive excitation of cranial nerve cells are repeated. And one in three cases of this disease is refractory epilepsy that shows resistance to existing drug treatments.
  • Epilepsy seizures can be broadly classified into partial seizures and generalized seizures. Partial seizures indicate behavioral abnormalities and electroencephalographic abnormalities that start in a limited area of the unilateral cerebral hemisphere. Partial seizures are further classified into simple partial seizures, complex partial seizures, and secondary generalized tonic-clonic seizures. On the other hand, generalized seizures are seizures that do not show a localized seizure origin and manifest symptoms in bilateral hemispheric synchronization.
  • the usual clinical symptoms of generalized seizures are characteristic systemic motor symptoms with loss of consciousness.
  • the electroencephalogram at the time of seizure is bilaterally synchronized. Absence seizure (Absence seizure), atypical absence (Atypical absence seizure), myoclonic seizure (Myoclonic seizure), tonic seizure (Clonic seizure), clonic seizure (Tonic-clonic seizure) ), Atonic seizure, West ⁇ syndrome, and Lennox-Gastaut syndrome are classified as generalized seizures.
  • antiepileptic drugs have no specific mechanism of action, and various mechanisms are considered to act in a complex manner. Therefore, some of the drugs that have been developed as antiepileptic drugs so far have been widely used in multiple neurological and mental disorders (Pawel, DZ et al., Non-epilepsy use of antiepileptic drugs, Pharmacological Reports, 2006, 58, 1-12).
  • bipolar disorder manic-depressive disorder
  • mood modulation has few specific treatments (lithium only)
  • some antiepileptic drugs have a mood-stable effect (mood stabilizer) is recognized and used.
  • Valproic acid has been used.
  • valproic acid has been used in clinical practice as well as lithium (Angel, I and Horovitz, T., Bipolar disorder and valproic acid) as a first-line drug for bipolar depression.
  • lithium Angel, I and Horovitz, T., Bipolar disorder and valproic acid
  • Patent Document 1 describes a phenylsulfonamide represented by the following general formula having an endothelin antagonistic action.
  • One of X and Y is N and the other is O;
  • R 1 , R 2 and R 3 are each independently (a) hydrogen, where R 1 is not hydrogen;
  • R 1 is not hydrogen;
  • R 1 is not hydrogen;
  • R 1 alkyl, alkenyl and the like;
  • C halo;
  • D hydroxy and the like;
  • R 4 and R 5 are each independently (a) hydrogen; (B) alkyl, alkenyl and the like; (C) halo;
  • D is hydroxy or the like].
  • the compound is completely different in use and structure from the compound of the present invention which is a therapeutic agent for epilepsy.
  • An object of the present invention is to provide a novel compound useful as an antiepileptic drug.
  • an amide derivative represented by the following formula (I) (hereinafter also referred to as “the compound of the present invention”) is provided.
  • a ring and B ring each independently represent an aryl ring, heteroaryl ring, 3- to 8-membered saturated carbocyclic ring, 3- to 8-membered partially unsaturated carbocyclic ring or 4- to 10-membered saturated heterocyclic ring;
  • L represents a bond, an optionally substituted linear C 1-6 alkylene, an optionally substituted C 2-6 alkenylene, -L 1 -OL 2- , -L 1 -NR 6 -L 2- , -L 1 -CONR 6 -L 2- , -L 1 -NR 6 CO-L 2 -or -L 1 -S (O) n -L 2-
  • L 1 and L 2 each independently represents a linear or optionally substituted linear C 1-6 alkylene
  • Alk represents a bond, an optionally substituted linear C 1-6 alkylene or an optionally substituted C 2-6 alkenylene
  • X represents —CONR 7 R 8 ,
  • R 4 and R 5 are bonded to any substitutable atom on the B ring to which they are bonded, and are each independently a hydrogen atom, halogen, nitro, —CONR 12 R 13 , C 1-6 alkyl, C Represents 1-6 alkoxy, C 1-6 alkyl-S (O) m —, or cyano, wherein the alkyl, alkoxy or alkyl-S (O) m — is substituted with 1 to 5 fluorine atoms
  • R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, C 1-6 alkyl, hydroxymethyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 3-7
  • the alkyl, cycloalkyl-alkyl and cycloalkyl may be substituted with 1 to 5 fluorine atoms; n and m each independently represents an integer of 0 to 2, Provided that when L is a bond, A and B are both benzene rings, and X is —CONR 7 R 8 , The substitution position on the B ring of L and -Alk-X is 1,3- or 1,4-substitution, or When the substitution position on the B ring of L and -Alk-X is 1,2-substitution, Alk may be substituted linear C 2-6 alkylene or optionally substituted C 2- 6 alkenylene, or methylene substituted with amino or C 1-6 acylamino, or Alk and R 7 , Alk and R 8 , Alk and R 9 , R 7 and R 8 , R 7 and R 9 and R 8 And any combination of R 9 forms a 4- to 10-membered saturated heterocyclic ring which may be substituted as described above] Or
  • the optionally substituted linear alkylene and the optionally substituted alkenylene are each independently C 1-6 alkyl, oxo, hydroxyl group, amino, C 1-6 acylamino, C 1-1 A group which may be substituted with 1 to 5 substituents selected from the group consisting of 6 alkoxy or fluorine, Item 2.
  • a ring and B ring are each independently a benzene ring, thiazole ring, pyridine ring, pyrimidine ring or thiophene ring. Salt.
  • ITEM 7 Alk is the methylene which may be substituted by 1 substituent selected from the group which consists of a bond, C1-4 alkyl, a hydroxyl group, C1-4 alkoxy, and a fluorine atom. Or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 and R 3 are the same or different and each represents a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms. 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or C 1-6 alkyl.
  • Item 12 The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.
  • Both the A ring and the B ring are benzene rings, L is a bond, the substitution position on the B ring of L and -Alk-X is 1,2-substitution, and Alk is a bond.
  • X is —SO 2 NR 7 R 8 , where R 1 to R 5 and R 7 are all hydrogen atoms, R 8 is C 3-6 alkyl, Item 13.
  • a ring is a pyridine ring
  • B ring is a benzene ring
  • L is a bond
  • Alk is methylene which may be unsubstituted or substituted with a hydroxyl group
  • X is —CONR 7 R 8 .
  • substitution position on the B ring of L and -Alk-X is 1,2-substitution, Item 13.
  • a ring and B ring are both aryl rings, L is a bond, and Alk-X is Wherein a saturated heterocyclic ring to be formed is (iii) and R 8 is a hydrogen atom, and any one of R 1 to R 5 is a group other than a hydrogen atom.
  • Is, Item 13 The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • the compound or a pharmaceutically acceptable salt thereof, wherein Alk-X is a group represented by any one of (i) to (vi) above.
  • Alk-X is (i), (ii) or (iii) of item 15; The compound according to any one of claims 1 to 13.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • An antiepileptic drug comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a mood stabilizer for bipolar disorder comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compounds of the present invention exhibit equally strong anticonvulsant activity in any of the model animals used for the evaluation of antiepileptic drugs, antiepileptic drugs exhibiting a broad therapeutic spectrum (eg, simple partial seizures, complex partial seizures) Prophylaxis against generalized seizures such as seizures and secondary seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, weakness seizures, West syndrome and Lennox-Gastaut syndrome (Or therapeutic agent).
  • the group of compounds of the present invention is also expected as a prophylactic and / or therapeutic agent for intractable epileptic seizures where conventional drug treatment is not successful.
  • the compound of the present invention can be expected as a mood stabilizer for bipolar disorder.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • the compound of the present invention may have one or more asymmetric carbon atoms, and may cause geometric isomerism and axial chirality, so that it exists as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
  • the substituents on the A ring and the B ring in the compound of the formula (I) of the present invention can be substituted with a substituent which can be substituted on any atom on these rings.
  • substituents on the B ring are defined as R 4 and R 5 .
  • the substitution positions of R 1 , R 2 and R 3 are bonded one by one to any three of the substitutable carbon atoms or nitrogen atoms on the A ring to which they are bonded, and R The substitution positions of 4 and R 5 mean that they are bonded one by one to any two of the substitutable carbon atoms or nitrogen atoms on the B ring to which they are bonded.
  • the ring B is bonded to L at the 1-position thereof, as indicated by “1” at the bond to L on the ring B, and the ring B is a benzene ring. That the substitution position on the B ring of L, -Alk-X is 1,2-substitution is the relationship between the substitution positions of L and -Alk-X as represented by the following formula (I ') Means ortho substitution. Further, 1,3- or 1,4-substitution means meta substitution and para substitution, respectively.
  • Alkyl means a linear or branched saturated hydrocarbon.
  • C 1-3 alkyl or “C 1-6 alkyl” has 1 to 3 or 1 carbon atoms. Each group represents 6 to 6. Specific examples thereof include methyl, ethyl, propyl, isopropyl and the like in the case of “C 1-3 alkyl”, and in the case of “C 1-6 alkyl”, in addition to the above, butyl, isobutyl, s— Examples include butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • C 3-7 cycloalkyl means a monocyclic saturated hydrocarbon having from 3 to 7 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-7 cycloalkyl-C 1-3 alkyl means a monocyclic saturated hydrocarbon having 3 to 7 carbon atoms, a straight-chain or branched saturated hydrocarbon having 1 to 3 carbon atoms
  • An alkyl group bonded to any carbon atom of Specific examples thereof include cyclopropylmethyl, cyclobutylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylpropyl, 2-cyclopropylpropyl, 1-cyclobutylethyl, 2-cyclobutylethyl, Examples include cyclopentylmethyl and cyclohexylmethyl.
  • C 1-6 alkoxy means linear or branched alkoxy having 1 to 6 carbon atoms. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy and the like.
  • C 1-6 alkyl-S (O) m — means a —S (O) m — group to which a linear or branched alkyl having 1 to 6 carbon atoms is bonded.
  • alkylthio eg, methylthio, ethylthio, etc.
  • alkylsulfinyl eg, methylsulfinyl, ethylsulfinyl, etc.
  • alkylsulfonyl eg, methane
  • Aryl ring includes 6-12 membered monocyclic or bicyclic aryl. Specific examples include benzene and naphthalene. Preferably, benzene is used.
  • heteroaryl ring is a 5- to 7-membered monocyclic aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or 9 to 11 Membered bicyclic aromatic heterocycles.
  • thiazole pyridine, oxadiazole, pyrimidine, oxazole, imidazole, triazole, thiophene, furan, pyrrole, benzothiazole, pyridazine, quinoline, benzothiophene, pyrazine, benzimidazole, benzotriazole, benzofuran, benzoxazole,
  • Examples include imidazole, indole, isoquinoline, quinazoline, pyrazole, tetrazole, and isothiazole.
  • a 5-membered or 6-membered monocyclic aromatic heterocycle is mentioned, and specifically, thiazole, pyridine, oxadiazole, pyrimidine, oxazole, imidazole, triazole, thiophene, furan, pyrrole, pyridazine, pyrazine Is mentioned.
  • “Saturated carbocycle” and “partially unsaturated carbocycle” mean a cyclic saturated or partially unsaturated hydrocarbon ring, for example, “3- to 8-membered saturated carbocycle” means 3- to 8-membered cyclic Of the saturated hydrocarbon ring. Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Preferably, a 5- to 7-membered saturated carbocycle is used. “3- to 8-membered partially unsaturated carbocycle” means a 3- to 8-membered cyclic partially unsaturated hydrocarbon ring. Specific examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene and the like. Preferably, a 5- to 7-membered partially unsaturated carbocycle is used.
  • the “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Means a composed saturated ring. Specific examples include 2-pyrrolidone, azetidine, pyrroline, piperine, morpholine, homopiperine, piperazine, homopiperazine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran and the like.
  • a 4- to 7-membered saturated heterocyclic ring is preferable, and specific examples include 2-pyrrolidone, tetrahydrofuran, and tetrahydropyran.
  • “Straight alkylene” means a straight hydrocarbon chain (the group may form a cyclic hydrocarbon group).
  • linear C 2-6 alkylene” or “linear C 1-6 alkylene” means a hydrocarbon chain having 2 to 6 or 1 to 6 carbon atoms.
  • linear C 2-6 alkylene ethylene, propylene, butylene, isobutylene, pentamethylene and the like can be mentioned, and in the case of “linear C 1-6 alkylene” In addition to the above, methylene is mentioned.
  • “linear C 1-3 alkylene” is preferable.
  • Alkenylene means a straight or branched hydrocarbon chain having one or two double bonds.
  • C 2-6 alkenylene means alkenylene having 2 to 6 carbon atoms. Specific examples include vinylene, propenylene, butenylene, isobutenylene, cyclobutenylene and the like.
  • Halogen means each atom of fluorine, chlorine, bromine or iodine. Preferably, each atom of fluorine, chlorine or bromine is used.
  • C 1-6 acylamino means C 0-5 alkyl-CONH—, and specific examples include acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino and the like. It is done. Acetylamino is preferable.
  • Alkyl, alkyl-S (O) m- , alkoxy, cycloalkyl and cycloalkyl-alkyl optionally substituted with 1 to 5 fluorine atoms are the alkyl, alkoxy, cycloalkyl and cycloalkyl-alkyl.
  • the carbon number of the alkyl part is 1, the number of fluorine atoms that may be substituted is 3 or less.
  • substituent of the hydrocarbon moiety of “optionally substituted linear alkylene” and “optionally substituted alkenylene” (1) a halogen atom, (2) C 1-6 alkyl (3) hydroxyl group, (4) cyano, (5) Oxo, (6) C 3-8 cycloalkyl, (7) C 1-6 alkoxy, (8) C 3-8 cycloalkoxy, (9) C 1-5 alkoxycarbonyl, (10) -NR 14 R 15 , (11) -CONR 14 R 15 , (12) C 1-6 acylamino, and (13) C 1-5 alkylcarbonyl (R 14 and R 15 represent a hydrogen atom or C 1-6 alkyl). More preferred is oxo, hydroxyl group or fluorine.
  • the alkylene and alkenylene may be substituted with 1 to 5 substituents selected from the group consisting of the above (1) to (11).
  • Examples of the pharmaceutically acceptable salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citric acid, and the like. Acid addition salts such as acid salts, fumarate salts, gluconate salts, lactate salts, maleate salts, malate salts, oxalate salts, methanesulfonate salts, tartrate salts, sodium salts, potassium salts, etc.
  • inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citric acid, and the like.
  • Acid addition salts such as acid salts, fumarate salts, gluconate salts, lactate salts, maleate salts, malate salts, oxalate salts, methanesulfonate salt
  • Alkali metal salts such as alkali metal salts, magnesium salts and calcium salts, metal salts such as aluminum salts and zinc salts, ammonium salts such as ammonium and tetramethylammonium, organic amine additions such as morpholine addition salts and piperidine addition salts
  • amino acid addition salts such as glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, glutamic acid addition salts, and the like.
  • Examples of the A ring and the B ring include an aryl ring, a heteroaryl ring, a saturated carbocyclic ring, a partially unsaturated carbocyclic ring, and a saturated heterocyclic ring.
  • an aryl ring or a heteroaryl ring is mentioned, More preferably, a benzene ring, a thiazole ring, a pyridine ring, a pyrimidine ring, or a thiophene ring is mentioned, Especially preferably, a benzene ring is mentioned.
  • L represents a bond, an optionally substituted linear C 1-6 alkylene, an optionally substituted C 2-6 alkenylene, -L 1 -OL 2- , -L 1 -NR 6-.
  • L 2- , -L 1 -CONR 6 -L 2- , -L 1 -NR 6 CO-L 2 -or -L 1 -S (O) n -L 2- (wherein L 1 and L 2 are Each independently represents a linear or optionally substituted linear C 1-6 alkylene), preferably a linear or optionally substituted linear C 1-6 alkylene or an optionally substituted C 2-6 alkenylene may be mentioned, and a bond is more preferable.
  • Alk examples include straight-chain C 1-6 alkylene which may be bonded or substituted, or C 2-6 alkenylene which may be substituted.
  • Preferable examples include linear or optionally substituted C 1-3 alkylene or optionally substituted vinylene, and more preferable examples include a bond.
  • X is —CONR 7 R 8 , —SO 2 NR 7 R 8 , —NR 7 COR 8 , —SO 2 R 7 , —CONR 7 COR 8 , —CONR 7 CONR 8 R 9 , —NR 7 CONR 8 COR 9 , —NR 7 CONR 8 R 9 , —NR 7 COOR 8 , —CONR 7 COOR 8, or —CONR 7 CONR 8 COR 9 .
  • —CONR 7 R 8 , —SO 2 NR 7 R 8 , —NR 7 COR 8 or —SO 2 R 7 is used. More preferred is —CONR 7 R 8 or —SO 2 NR 7 R 8 , and still more preferred is —SO 2 NR 7 R 8 .
  • Alk and X are, when R 7 , R 8 and R 9 are a hydrogen atom or C 1-6 alkyl, Alk and R 7 , Alk and R 8 , Alk and R 9 , R 7 and R 8 , R 7 and In R 9 and any one combination of R 8 and R 9 , each group may be bonded to each other to form an optionally substituted 4- to 10-membered saturated heterocyclic ring.
  • any one of the substituents of Alk, R 7 , R 8 or R 9 is bonded, when each substituent is a hydrocarbon, it is replaced with a hydrogen atom bonded to any carbon atom of each substituent. It means that mutual substituents are bonded.
  • R 7 , R 8 or R 9 is a hydrogen atom
  • the nitrogen atom, carbon atom, oxygen atom or sulfur atom bonded to R 7 , R 8 or R 9 and other substituents (replaces hydrogen atoms) Means to combine.
  • R 7 , R 8 or R 9 is hydroxymethyl, it means that a hydrogen atom bonded to an oxygen atom or a carbon atom is bonded to another substituent.
  • Any carbon atom of the heterocyclic ring thus constructed may be replaced with one to two units selected from the group consisting of carbonyl and nitrogen atoms.
  • Preferred examples of the heterocyclic ring thus constructed include the following saturated heterocyclic rings.
  • R 1 to R 3 are each independently a hydrogen atom, halogen, nitro, —CONR 10 R 11 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S (O) m — Or cyano (wherein the alkyl, alkoxy or alkyl-S (O) m — may be substituted with 1 to 5 fluorine atoms), preferably a hydrogen atom, a fluorine atom, a chlorine atom, A bromine atom, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methylthio, methanesulfonyl or cyano is exemplified.
  • a hydrogen atom, a fluorine atom, a chlorine atom, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy or cyano is mentioned, and still more preferably a hydrogen atom, a fluorine atom, chlorine atom or trifluoromethyl is mentioned.
  • Particularly preferred is a hydrogen atom, a fluorine atom, a chlorine atom or trifluoromethyl, and most preferred is a hydrogen atom, a fluorine atom or a chlorine atom.
  • R 4 and R 5 are each independently a hydrogen atom, halogen, nitro, —CONR 12 R 13 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S (O) m —.
  • cyano wherein the alkyl, alkoxy or alkyl-S (O) m — may be substituted with 1 to 5 fluorine atoms, and m represents an integer of 0 to 2, preferably , Hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methylthio, methanesulfonyl or cyano.
  • a hydrogen atom, a fluorine atom, a chlorine atom, methyl, ethyl, trifluoromethyl, trifluoromethoxy or cyano is mentioned, and still more preferably a hydrogen atom, a fluorine atom, a chlorine atom, trifluoromethyl or trifluoromethoxy. And particularly preferably a hydrogen atom, a fluorine atom or a chlorine atom.
  • R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, C 1-6 alkyl, hydroxymethyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 3-7 cycloalkyl Or aryl (the alkyl, alkoxy, cycloalkyl-alkyl and cycloalkyl may be substituted with 1 to 5 fluorine atoms), preferably a hydrogen atom, methyl or ethyl (the Methyl and ethyl may be substituted with 1 to 5 fluorine atoms). More preferably, a hydrogen atom, methyl, or ethyl is mentioned. Particularly preferred is a hydrogen atom or methyl.
  • R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom, halogen, C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, C 3-7 cycloalkyl-C 1-3 alkyl , C 3-7 cycloalkyl or aryl (wherein the alkyl, alkoxy, cycloalkyl-alkyl and cycloalkyl may be substituted with 1 to 5 fluorine atoms), preferably a hydrogen atom, fluorine An atom, methyl, ethyl, hydroxyl group or C 1-6 alkoxy is mentioned (the methyl, ethyl and alkoxy may be substituted with 1 to 5 fluorine atoms). More preferably, a hydrogen atom, methyl, ethyl, a hydroxyl group, methoxy, or ethoxy is mentioned. Especially preferably, a hydrogen atom, methyl, or a hydroxyl group is mentioned.
  • N and m are each independently an integer of 0 to 2, preferably 0 or 2. Particularly preferably, 2 is mentioned.
  • Epilepsy in the present invention is intended for chronic diseases in which cranial movements, consciousness, sensory abnormalities and behavioral abnormalities derived from excessive excitement of cranial nerve cells are intended, and simple partial seizures, complex partial seizures and secondary generalization Includes generalized seizures such as seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures, weakness seizures, West syndrome and Lennox-Gastaut syndrome.
  • the antiepileptic drug is intended to be a prophylactic and / or therapeutic drug for the above diseases
  • the epilepsy treatment method is intended to be a preventive and / or therapeutic method for the above diseases.
  • the bipolar disorder in the present invention means a disease that repeats a manic state and a depressive state to cause mood modulation
  • the mood stabilizer for bipolar disorder in the present invention is a preventive and / or therapeutic agent for the above-mentioned diseases.
  • a method for treating bipolar disorder intends a method for preventing and / or treating the above-mentioned diseases.
  • the compound of the present invention represented by the formula (I) can be produced by the following production methods 1 to 5.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is a novel compound and can be produced, for example, by the method described below, the examples described later and a method analogous thereto.
  • the compound used in the following production method may form a salt as long as the reaction is not hindered.
  • a compound of the formula (I) wherein X is a group of —CONR 7 R 8 , —SO 2 NR 7 R 8 [compound of the following formula (Ia)] can be produced by the following production method.
  • a ring, B ring, L, Alk, X, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in item 1.
  • Y is —COOH, —COOW, — COCl, —SO 3 H and —SO 2 Cl.
  • W represents C 1-6 alkyl.
  • Compound (Ia) is obtained by amidating compound (II).
  • the raw material compound (II) is commercially available or known in the art such as WO 2004/788, WO 2006/76644, US2005 / 59668, WO 2008/100343, Bioorganic Medicinal Chemistry, 2008, vol.16, p.8607-8618. It can be synthesized by a method according to the method.
  • the amidation reaction of compound (II) can be performed according to a conventional method.
  • this reaction can be achieved by converting compound (II) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting with various amines and ammonia.
  • a reactive derivative eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.
  • the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like.
  • Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.
  • Compound (Ia) can also be produced by reacting Compound (II) with various amines or ammonia in the presence of a condensing agent.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl -Oxytris (pyrrolidino) phosphonium-hexafluorophosphate, Boc 2 O and the like.
  • These condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.
  • the reaction of compound (II) with various amines or ammonia is carried out in a solvent or without a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO, etc. Alternatively, it can be used as a mixed solvent.
  • Various amines or ammonia may be used in the form of an acid addition salt such as hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the target compound (Ia) can also be obtained by deprotecting a compound obtained by condensation using a protected amine.
  • a compound of the formula (I) [a compound of the following formula (Ib)] in which L is a linear or optionally substituted linear C 1-6 alkylene or an optionally substituted C 2-6 alkenylene, It can be produced by the following production method.
  • L is a linear or optionally substituted linear C 1-6 alkylene or an optionally substituted C 2-6 alkenylene
  • a ring, B ring, Alk, X, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in item 1.
  • L 3 may be bonded or substituted.
  • a good linear C 1-6 alkylene, an optionally substituted C 2-6 alkenylene, and Z is chlorine, bromine, iodine, boron, magnesium halide and lithium.
  • Compound (Ib) is obtained by coupling compound (III) with the following reagents.
  • the starting compound (III) is commercially available or conforms to known methods such as Journal of Organic Chemistry, 1968, vol.33, p.900-903, Canadian Journal of Chemistry, 1969, vol.47, p.1543 Can be synthesized by the methods described above.
  • Compound (Ib) is compound (III) and a boron reagent such as various substituted phenylboronic acids, various substituted phenylzinc halides, organometallic reagents such as various substituted organotin reagents, aryl halides, aryl aldehydes, and the like in an appropriate solvent.
  • a boron reagent such as various substituted phenylboronic acids, various substituted phenylzinc halides, organometallic reagents such as various substituted organotin reagents, aryl halides, aryl aldehydes, and the like in an appropriate solvent.
  • a boron reagent such as various substituted phenylboronic acids, various substituted phenylzinc halides, organometallic reagents such as various substituted organotin reagents, aryl halides, aryl aldehydes, and the like in an appropriate
  • inorganic bases such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.) and potassium phosphate
  • organic bases such as triethylamine, diisopropylethylamine, lithium chloride
  • an inorganic salt such as cesium fluoride
  • boron reagents or organometallic reagents are commercially available or are prepared from commercially available reagents according to known methods.
  • Specific examples of the solvent should be selected according to the type of raw material compound and the type of reagent used. For example, toluene, THF, dioxane, DME, ethyl acetate, acetone, acetonitrile, DMF or methanol, ethanol, isopropanol, t -Alcohols such as butanol and water can be mentioned, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally 0 to 200 ° C, preferably 60 to 150 ° C.
  • a compound of formula (Ic) or formula (Ic ′) in which L is —L 1 —CONR 6 —L 2 — or —L 1 —NR 6 CO—L 2 — can be produced by the following production method .
  • a ring, B ring, L 1 , L 2 , Alk, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined in item 1).
  • Compound (Ic) or (Ic ') is obtained by performing a condensation reaction of compound (IV) or (IV') with various carboxylic acids or amines.
  • This reaction can be performed according to a conventional method. For example, this reaction is accomplished by reacting compound (IV) or (IV ′) in the presence of various carboxylic acids or various amines and a condensing agent in a suitable solvent or without solvent. .
  • Various carboxylic acids and the like or various amines are commercially available or are prepared from commercially available reagents according to known methods.
  • the condensing agent examples include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, O- (1H-7-aza-1-benzotriazolyl) -N, N, N ', N'-tetramethyluronium-hexafluorophosphate and the like.
  • condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.
  • Specific examples of the solvent should be selected according to the type of raw material compound, etc., and include, for example, dichloromethane, chloroform, dichloroethane, THF, dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, etc. It can be used as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (Ic) is converted into a reactive derivative (for example, an active ester, an acid anhydride, an acid halide, a lower alkyl ester, etc.) and reacted in a suitable solvent. It can also be obtained by reacting.
  • a reactive derivative for example, an active ester, an acid anhydride, an acid halide, a lower alkyl ester, etc.
  • the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester 2-pyridylthiol ester, N-methylimidazole ester and the like.
  • the acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
  • the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like.
  • Specific examples of the solvent should be selected according to the type of raw material compound, etc., and include, for example, dichloromethane, chloroform, dichloroethane, THF, dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, etc. It can be used as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (Ic ′) can also be obtained by reacting compound (IV ′) with a reactive derivative (eg, active ester, acid anhydride, acid halide, lower alkyl ester, etc.) in a suitable solvent.
  • a reactive derivative eg, active ester, acid anhydride, acid halide, lower alkyl ester, etc.
  • a suitable solvent e.g., benzyl ether, benzyl ether, ether ether, etc.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, dichloromethane, chloroform, dichloroethane, THF, dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, etc. It can be used as a mixed solvent.
  • This reaction may be performed in the presence of a base, and specific examples thereof include sodium carbonate, potassium carbonate, pyridine, triethylamine, diisopropylethylamine and the like. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • L is, -L 1 -O-L 2 - , - L 1 -NR 6 -L 2 - , compound of formula (I) [compound of formula (Id) or (Id ')], the following production methods Can be manufactured.
  • a ring, B ring, L 1 , L 2 , Alk, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined in item 1.
  • V is , Fluorine, chlorine, bromine or iodine.
  • Compound (Id) or (Id ′) can be obtained by performing a coupling reaction between compound (V) and various amines or alcohols.
  • this reaction can be achieved by reacting compound (V) in the presence of various amines or alcohols in the presence of a base in a suitable solvent or in the absence of a solvent.
  • Various amines or alcohols are commercially available or are prepared from commercially available reagents according to known methods.
  • Specific examples of the solvent should be selected according to the type of raw material compound, etc., and include, for example, dichloromethane, chloroform, dichloroethane, THF, dioxane, DME, acetonitrile, DMF, DMA, NMP, pyridine, etc.
  • the base should be selected according to the type of the raw material compound.
  • an inorganic base of alkali metal carbonate for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • the reaction may be carried out in the presence of an organic base or sodium hydride. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 50 to 150 ° C.
  • R 6 , R 7 , R 8 and R 9 are a hydrogen atom or C 1-6 alkyl
  • a compound of the formula (I) in which each group is bonded to form an optionally substituted 4- to 10-membered saturated heterocyclic ring in any combination of R 8 and R 9 [the following formula (Ie) Can be produced by the following production method.
  • Alk ′ is a linear chain which may be substituted.
  • X 1 is —NH 2 , —OH
  • Y 1 is a hydrogen atom, —CONH 2 , —COOH, —COOR, —CH 2 NH 2 , and Cy is substituted It may be a 4 to 10 membered saturated heterocyclic ring.
  • Compound (Ie) is obtained by cyclizing compound (II ′) that can be produced in the same manner as compound (II).
  • the cyclization reaction of compound (II ′) can be performed according to a conventional method.
  • this reaction can be achieved by reacting compound (II ') with a carbonylating agent such as carbonyldiimidazole (CDI), triphosgene, di (2-pyridyl) carbonate, p-nitrophenyl chlorocarbonate and the like.
  • a carbonylating agent such as carbonyldiimidazole (CDI), triphosgene, di (2-pyridyl) carbonate, p-nitrophenyl chlorocarbonate and the like.
  • the reaction between the compound (II ′) and the carbonylating agent is performed in a solvent or without a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO, etc. Alternatively, it can be used as a mixed solvent. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • Compound (Ie) can also be produced by reacting compound (II ′) with an acylating agent such as haloalkyl chlorocarbonate, haloalkyl isocyanate, or haloalkyl acid chloride, and then reacting with a base.
  • an acylating agent such as haloalkyl chlorocarbonate, haloalkyl isocyanate, or haloalkyl acid chloride
  • the reaction between the compound (II ′) and the acylating agent is performed in a solvent or without a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO, etc. Alternatively, it can be used as a mixed solvent. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the reaction between the acylated compound (II ′) and the base is carried out in a solvent or without a solvent.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazide and the like, or triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine And organic bases such as 4-dimethylaminopyridine.
  • the solvent should be selected according to the type of the raw material compound, and include, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. These can be used alone or as a mixed solvent.
  • This reaction is usually carried out in the presence of a base, and the reaction temperature varies depending on the kind of raw material compound used and the like, but is usually about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the compound of formula (I) produced by each of the above production methods can be isolated and purified by conventional methods such as chromatography, recrystallization and reprecipitation.
  • chromatography recrystallization and reprecipitation.
  • the compound of formula (I) is a racemate, according to a conventional method such as an optical resolution method by chromatography using an optically active column, a preferential crystallization method, a diastereomer method, etc. And can be separated and purified.
  • the novel amide derivative of the present invention is useful as an antiepileptic drug as described later.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, and aluminum metasilicate
  • Magnesium sulfate, synthetic aluminum silicate crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate Light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • m is a multiple line
  • br is gentle.
  • Example 1 N-methyl-2- (1,3-thiazol-2-yl) benzamide 2- (1,3-thiazol-2-yl) benzoic acid (196 mg) was dissolved in dichloromethane (5 ml), DMF (1 drop), 1M oxalyl chloride in dichloromethane (1.9 ml) were added, and then at room temperature. Stir for 1 hour. After concentration, the residue was suspended in toluene and azeotroped. The obtained brown crystals were dissolved in THF (10 ml), 40% methylamine methanol solution (1 ml) was added, and the mixture was stirred overnight at room temperature.
  • Example 2-87 The corresponding starting materials were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in Table 1.
  • Example 88 N, N-dimethyl-2- (1,3-oxazol-2-yl) benzenesulfonamide 2-Bromophenyldimethylsulfonamide (400 mg), 2- (tri-n-butylstannyl) oxazole (0.54 ml), bis (triphenylphosphine) palladium (II) dichloride (106 mg), copper (II) oxide (120 mg) was added to DMF (15 ml), and the atmosphere was replaced with nitrogen. After cooling to room temperature, potassium fluoride, water and ethyl acetate were added and stirred for a while.
  • Examples 89-137 The corresponding starting materials were used and reacted and treated in the same manner as in Example 88 to obtain the compounds shown in Table 2.
  • Example 138 2- [Hydroxy (thiophen-2-yl) methyl] -N, N-dimethylbenzenesulfonamide
  • a solution of 2-bromo-N, N-dimethylbenzenesulfonamide (0.301 g) in THF (5.0 ml) is cooled to ⁇ 78 ° C., and 2.5 M n-butyllithium hexane solution (0.55 ml) is added dropwise. And stirred for 60 minutes.
  • Thiophene-2-carbaldehyde (0.12 ml) was added dropwise to the reaction solution, and the mixture was stirred at -78 ° C. for 3 hours.
  • Examples 139-150 The corresponding starting materials were used and reacted and treated in the same manner as in Example 138 to obtain the compounds shown in Table 3.
  • Example 151 N, N-dimethyl-2- [2- (1,3-thiazol-2-yl) ethenyl] benzenesulfonamide
  • a toluene (15 ml) solution of triphenyl (thiazol-2-ylmethyl) phosphonium chloride (0.62 g) was added potassium tert-butoxide (0.200 g), and the mixture was stirred at room temperature for 3 hours.
  • 2-formyl-N, N-dimethylbenzenesulfonamide (0.497 g) in toluene (9 ml) was added dropwise and stirred at room temperature.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated.
  • the residue was purified by silica gel column chromatography to obtain the title compound (0.459 g).
  • MS (m / z) 295 (MH +), Rt 3.17, 3.65 min.
  • Example 153 N, N-dimethyl-2- [2- (1,3-thiazol-2-yl) ethyl] benzenesulfonamide Palladium / carbon (50 mg) was added to a solution of N, N-dimethyl-2- (2-thiazol-2-yl) vinylbenzenesulfonamide (0.103 g) in ethyl acetate (1.5 ml) for 10 hours under a hydrogen atmosphere. Stir. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.092 g).
  • Example 155 N, N-dimethyl-2- (1,3-thiazol-2-ylmethoxy) benzenesulfonamide
  • DMF dimethyl methyl sulfoxide
  • 1,3-thiazol-2-ylmethanol 0.337 g
  • a solution of fluoro-N, N-dimethylbenzenesulfonamide (0.496 g) in DMF (2.0 ml) was added dropwise and stirred overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml).
  • Examples 156-163 The corresponding starting materials were used and reacted and treated in the same manner as in Example 155 to obtain the compounds shown in Table 4.
  • Example 164 2-[(Cyclohexylmethyl) amino] -N, N-dimethylbenzenesulfonamide Cyclohexylmethylamine (0.32 ml) and potassium carbonate (0.337 g) were added to a solution of 2-fluoro-N, N-dimethylbenzenesulfonamide (0.413 g) in NMP (5.0 ml) at 130 ° C. For 7.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated.
  • Examples 165-174 The corresponding starting materials were used and reacted and treated in the same manner as in Example 164 to obtain the compounds shown in Table 5.
  • Example 175 N- [2- (Dimethylsulfamoyl) phenyl] benzamide To a solution of 2-amino-N, N-dimethylbenzenesulfonamide (0.405 g) in methylene chloride (5.0 ml), triethylamine (0.67 ml) and 4-dimethylaminopyridine (5.1 mg) were added and cooled. Benzoyl chloride (0.28 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml).
  • Examples 176-177 The corresponding starting materials were used for the reaction and treatment according to the method according to Example 175, and the compounds shown in Table 6 were obtained.
  • Example 178 (2E) -3- (Biphenyl-2-yl) -N-methylprop-2-enamide (2E) -3- (biphenyl-2-yl) prop-2-enoic acid (300 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide) hydrochloride (411 mg), 1-hydroxybenzotriazole A solution of monohydrate (290 mg), methylamine hydrochloride (181 mg), N, N-diisopropylethylamine (0.93 ml) in DMF (10 ml) was stirred at room temperature overnight.
  • Examples 179-199 The corresponding starting materials were used and reacted and treated in the same manner as in Example 178 to obtain the compounds shown in Table 7.
  • Example 192 1 H-NMR (CDCl 3 ) ⁇ of Example 192: 3.02 (s, 3H), 3.11 (s, 3H), 6.75 (d, 1H), 7.17-7.21 (m, 1H), 7.32-7.41 (m, 6H), 7.59 (d, 1H), 7.65-7.68 (m, 1H).
  • Example 200 (2E) -3 (biphenyl-2-yl) prop-2-enamide (2E) -3- (biphenyl-2-yl) prop-2-enoic acid (300 mg), ammonium bicarbonate (169 mg), di-t-butyl dicarbonate (409 mg) in pyridine (0.17 ml) and dioxane (10 ml) was dissolved in the mixture and stirred at room temperature overnight. After concentration, the residue was purified by silica gel column chromatography to obtain the title compound (187 mg) as white crystals.
  • Examples 201-212 The corresponding starting materials were used and reacted and treated in a manner similar to Example 200 to give the compounds shown in Table 8.
  • Example 213 (E) -2- (Biphenyl-2-yl) -N, N-dimethylethenesulfonamide 2-Bromobiphenyl (1.20 g), N, N-dimethylvinylsulfonamide (0.84 g), palladium (II) acetate (116 mg), triphenylphosphine (270 mg) triethylamine (1.8 ml) in DMF (60 ml) In addition to nitrogen substitution, the mixture was stirred for 18 hours while heating at 140 ° C. Unnecessary substances were removed by Celite filtration. Subsequently, the solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
  • Example 215 2'-Chlorobiphenyl-2-sulfonamide N-tert-butyl-2′-chlorobiphenyl-2-sulfonamide (453 mg) was dissolved in trifluoroacetic acid (8 ml) and stirred at room temperature for 6 hours. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (319 mg) as white crystals.
  • 1 H-NMR (DMSO-d 6 ) ⁇ : 7.24-7.42 (m, 6H), 7.49 (d, 1H), 7.59-7.66 (m, 2H), 8.01-8.04 (m, 1H).
  • MS (m / z) 268 (MH +), Rt 3.47 min.
  • Examples 216-221 The corresponding starting materials were used and reacted and treated in the same manner as in Example 215 to obtain the compounds shown in Table 9.
  • Example 222 Biphenyl-2-ylpropan-2-ylsulfone Under a nitrogen atmosphere, biphenyl-2-sulfonyl fluoride (300 mg) was dissolved in THF (20 ml), 0.7 M isopropyl lithium pentane solution (5.4 ml) was added at ⁇ 78 ° C., and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Examples 223-224 The corresponding starting materials were used for the reaction and treatment according to the method according to Example 222, and the compounds shown in Table 10 were obtained.
  • Examples 225-228 Using the corresponding starting material compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds shown in Table 11.
  • Example 229-232 The corresponding starting materials were used for the reaction and treatment according to the method according to Example 88, and the compounds shown in Table 12 were obtained.
  • Examples 233-236 The corresponding starting materials were used for the reaction and treatment according to the method according to Example 178, and the compounds shown in Table 13 were obtained.
  • Example 237 1- (3′-Chlorobiphenyl-2-yl) pyrrolidin-2-one 3′-Chlorobiphenyl-2-amine (1.00 g) and triethylamine (0.753 ml) were dissolved in THF (20 ml), and 4-chlorobutanoyl chloride (0.549 ml) in THF (20 ml) was cooled with ice. The solution was added dropwise. After stirring at room temperature for 1 hour, the precipitated solid was filtered off and washed with THF. To the filtrate was added sodium hydride (0.216 g) little by little under ice-cooling, and the mixture was stirred overnight at room temperature.
  • Example 238-252 Using the corresponding starting material compounds, the reaction and treatment were carried out in the same manner as in Example 237, and the compounds shown in Table 14 were obtained.
  • Examples 253-257 The corresponding raw material compounds were used for the reaction and treatment by the method according to Example 1, and the compounds shown in Table 15 were obtained.
  • Example 256 1.14 (s, 3H), 3.60 (s, 2H), 7.14-7.18 (m, 1H), 7.22-7.28 (m, 2H), 7.30-7.32 ( m, 1H), 7.36-7.45 (m, 4H), 7.49 (br, 1H), 8.03 (br, 1H).
  • Example cs The corresponding starting materials were used and reacted and treated in the same manner as in Example 200 to obtain the compounds shown in Table 17.
  • Example u Reaction and treatment were carried out using the corresponding starting materials in the same manner as in Example t to obtain the compounds shown in Table 18.
  • the compound shown below can be produced by reacting and treating the corresponding starting material compound by the method according to the above production methods 1 to 5.
  • MES maximum electric shock convulsion model
  • scPTZ minimum convulsion model
  • rat amygdala kindling model evaluation which are typically highly clinically predictable.
  • Compounds that exhibit anticonvulsant activity in these models are expected as antiepileptic drugs in the clinic.
  • compounds exhibiting anticonvulsant activity in both MES evaluation and scPTZ evaluation are expected to show wide efficacy against valproic acid-like broad spectrum, that is, partial seizures and general seizures, and are clinically useful therapeutic agents Can be.
  • Test Example 1 Maximum Electric Shock Convulsion Model (MES) Evaluation This test is a test for evaluating the anticonvulsant action of a drug.
  • the animal model used in this study is an expression system for generalized tonic clonic seizures and secondary generalized partial seizures.
  • Slc ddY male mice (3 mice per group, body weight 20-30 g) were orally administered 50 mg / kg or 100 mg / kg of the test compound, and after 1 hour, electrical stimulation (60 Hz, 25 mA, 0.2 seconds) was given from the cornea Suppression of the expression of induced hindlimb tonic extension convulsions was observed.
  • 0.5% tragacanth solution, 0.5% methylcellulose solution or olive oil was administered.
  • the number of animals showing suppression of convulsions was represented by “A” when 3 animals were represented by “B” when 2 animals were represented, and “C” when less than 1 animal was represented. The results are shown in Table 19 below.
  • Test Example 2 Subcutaneous Pentetrazole Model (scPTZ) Evaluation This test is a test for evaluating the anticonvulsant action of a drug in the same manner as in Test Example 1. Unlike the expression system of Test Example 1, the animal model used in this test is an expression system for generalized absence seizures and myoclonic attacks. Slc: ddY male mice (3 mice per group, body weight 20-30 g) were orally administered 50 mg / kg or 100 mg / kg of the test compound, and 1 hour later, 85 mg / kg of pentetrazole was subcutaneously administered. Thereafter, the presence or absence of onset of clonic convulsions in 30 minutes was observed.
  • scPTZ Subcutaneous Pentetrazole Model
  • the compound of the present invention exhibited an anticonvulsant effect in the maximum electric shock convulsion model (MES) evaluation and / or the subcutaneous injection pentetrazole model (minimum convulsion model, scPTZ) evaluation by oral administration.
  • MES maximum electric shock convulsion model
  • scPTZ subcutaneous injection pentetrazole model
  • the compounds of Examples 36, 117, 181, 192, 208, 215, 241, 244, f, h, k, and r showed strong anticonvulsant effects in both evaluations.
  • Test Example 3 Rat Amygdala Kindling Model Evaluation This test is a test for evaluating the anticonvulsant action of drugs in rats in addition to mice.
  • the animal model (kindling model) used in this study is a model similar to the clinical findings of focal simple partial attacks, complex partial attacks, and secondary generalized partial attacks, and is known to have extremely high clinical predictability.
  • Slc A chronic electrode was placed in the cerebral cortex (front and back) and amygdala of Wistar male rats (body weight 250-300 g), and electrical stimulation was performed once a day for 2 weeks from the 1st week after surgery. (50 Hz, 400 ⁇ A, 1 second). Stimulation conditions followed the method of Loscher et al.
  • the compound of Example 117 significantly increased the seizure induction threshold of the rat amygdala kindling model by oral administration of 100 mg / kg, and decreased the severity of the induced seizure.
  • the compound of Example 117 showed high effectiveness against the rat amygdala kindling model.
  • the amide derivative of the present invention is a representative model for evaluating antiepileptic drugs, such as a maximum electric shock convulsion model (MES) evaluation, a subcutaneous injection pentetrazole model (scPTZ) evaluation, and / or a rat amygdala kindling model. Strong anticonvulsant effect in evaluation.
  • MES maximum electric shock convulsion model
  • scPTZ subcutaneous injection pentetrazole model
  • / or a rat amygdala kindling model strong anticonvulsant effect in evaluation.
  • the compounds of the present invention are antiepileptic drugs (e.g., partial seizures including simple partial seizures, complex partial seizures and persistent secondary generalized seizures with loss of consciousness, absence seizures, myoclonic seizures, clonic seizures, It is useful as a prophylactic and / or therapeutic drug for generalized seizures such as tonic seizures, tonic-clonic seizures, weakness seizures, West syndrome and Lennox-Gastaut syndrome.
  • antiepileptic drugs e.g., partial seizures including simple partial seizures, complex partial seizures and persistent secondary generalized seizures with loss of consciousness, absence seizures, myoclonic seizures, clonic seizures. It is useful as a prophylactic and / or therapeutic drug for generalized seizures such as tonic seizures, tonic-clonic seizures, weakness seizures, West syndrome and Lennox-Gastaut syndrome.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

　本発明は、部分発作及び／又は全般発作の種々てんかん発作に対する治療薬若しくは予防薬として有用な式（Ｉ）の化合物又はその塩［式中、Ａ環及びＢ環は、それぞれ独立して、アリール環等を表し、Ｌは、結合、Ｃ１－６アルキレン等を表し、Ａｌｋは、結合、Ｃ１－６アルキレン等を表し、Ｘは、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８等を表し、Ｒ１、Ｒ２及びＲ３は、同一又は異なって、水素原子、ハロゲン等を表し、Ｒ４及びＲ５は、それぞれ独立して、水素原子、ハロゲン等を表し、Ｒ７、Ｒ８等は、それぞれ独立して、水素原子、Ｃ１－６アルキル等を表す］を提供する。

Description

アミド誘導体
　本発明は、てんかんの治療薬として有用な新規アミド誘導体に関する。
　てんかんは、脳神経細胞の過剰興奮に由来する発作性の運動、意識、知覚の異常及び行動異常が反復する慢性疾患である。そして、この疾患の３例に１例が既存薬治療に抵抗を示す難治性てんかんである。てんかん発作は、部分発作（Partial seizure）及び全般発作（Generalized seizure）に大きく分類される。部分発作は、片側大脳半球の限局した部位を発作起始とする行動異常と脳波像の異常を示す。部分発作は、さらに単純部分発作（Simple partial seizure）、複雑部分発作（Complex partial seizure）ならびに二次性全般化強直・間代発作（Secondarily generalized tonic－clonic seizure）に分類される。一方、全般発作は、限局した発作起始部を示さず、症状が両側大脳半球同期性に現れる発作である。全般発作の通常の臨床症状は、意識消失を伴う特徴的な全身の運動症状である。また、発作時の脳波は両側同期性である。欠神発作（Absence seizure）、非定型欠神発作（Atypical absence seizure）、ミオクロニー発作（Myoclonic seizure）、強直発作（Tonic seizure）、間代発作（Clonic seizure）、強直間代発作（Tonic－clonic seizure）、脱力発作（Atonic seizure）、ウェスト症候群（West syndrome）及びレノックス－ガストー症候群（Lennox－Gastaut syndrome）などが全般発作に分類される。
　これら種々てんかん発作の治療は薬物治療が中心であり、古くから種々の抗てんかん薬が処方されているにも拘らず未だ、部分発作及び全般発作（特に欠神発作やミオクロニー発作）に対し広範囲に有効性を示す抗てんかん薬はバルプロ酸のみである。しかしながら、バルプロ酸は効果及び副作用の面で十分に満足できる薬剤ではなく、更に未だ既存治療薬で効果が期待できない難治患者が存在する。したがって、部分発作及び／又は全般発作に広範に高い有効性、治療抵抗性への効果を示し、また安全性面においても優れた治療薬の開発が望まれている。
　抗てんかん薬の多くは明確な作用機序が特定されておらず、多彩なメカニズムが複合的に作用して効果を発揮しているものと考えられている。従って、これまで抗てんかん薬として開発されてきた薬剤の幾つかは、複数の神経疾患、精神疾患に汎用されている現実がある（Pawel,D.Z ら、Non-epilepsy use of antiepileptic drugs, Pharmacological Reports, 2006, 58, 1-12）。例えば、躁状態とうつ状態を繰り返し、気分変調を来たす双極性障害（躁うつ病）は特異な治療薬が殆どないが（リチウムのみ）、幾つかの抗てんかん薬で気分安定的な効果（mood stabilizer）が認められており、流用されている。最初にカルバマゼピンが使用され（Brambilla, P., Barrale, F., Soares, J.C., Perspectives on the use of anticonvulsants in the treatment of bipolar disorder, International Journal of Neuropsychopharmacology, 2001, 4, 421-446）、続いて、バルプロ酸が使用されるに至っている。特にバルプロ酸は、双極性躁状態への第一選択薬としてリチウムと同様に臨床において多く用いられている（Angel, I and Horovitz, T., Bipolar disorder and valproic acid）。しかしながら、一方の双極性うつ状態に対する治療薬は未だ十分な薬剤がなく、躁・うつ共に高い有用性を発揮する新たな薬剤は待望されている。
　特許文献１には、エンドセリンアンタゴニスト作用を有する下記一般式で表されるフェニルスルホンアミドが記載されている。
Figure JPOXMLDOC01-appb-C000003
 [ＸおよびＹの一方はＮであり他方はＯである；Ｒ１、Ｒ２およびＲ３はそれぞれ独立に（ａ）水素、ただしＲ１は水素ではない；
（ｂ）アルキル、アルケニル等；
（ｃ）ハロ；
（ｄ）ヒドロキシ等；
Ｒ４およびＲ５はそれぞれ独立に（ａ）水素；
（ｂ）アルキル、アルケニル等；
（ｃ）ハロ；
（ｄ）ヒドロキシ等である]で示される化合物。
　該化合物は、てんかんの治療薬である本願発明の化合物とは用途が全く異なり、構造も異なる。
欧州特許第５６９，１９３号明細書
　本発明の課題は、抗てんかん薬として有用な新規化合物を提供することにある。
　本発明者らは、鋭意研究を行った結果、下記式（Ｉ）で表される新規化合物が強い抗痙攣作用を示すことを見出し、本発明を完成した。本発明によれば、下記式（Ｉ）で表されるアミド誘導体（以下、「本発明の化合物」と称することもある。）が提供される。
　［項１］下記式（I）：
Figure JPOXMLDOC01-appb-C000004
 ［式中、
　Ａ環及びＢ環は、それぞれ独立して、アリール環、ヘテロアリール環、３～８員の飽和炭素環、３～８員の部分不飽和炭素環又は４～１０員の飽和複素環を表し、
　Ｌは、結合、置換されていてもよい直鎖のＣ１－６アルキレン、置換されていてもよいＣ２－６アルケニレン、－Ｌ１－Ｏ－Ｌ２－、－Ｌ１－ＮＲ６－Ｌ２－、－Ｌ１－ＣＯＮＲ６－Ｌ２－、－Ｌ１－ＮＲ６ＣＯ－Ｌ２－又は－Ｌ１－Ｓ（Ｏ）ｎ－Ｌ２－を表し、
　Ｌ１及びＬ２は、それぞれ独立して、結合又は置換されていてもよい直鎖のＣ１－６アルキレンを表し、
　Ａｌｋは、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンを表し、
　Ｘは、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８、－ＮＲ７ＣＯＲ８、－ＳＯ２Ｒ７、－ＣＯＮＲ７ＣＯＲ８、－ＣＯＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＮＲ８ＣＯＲ９、－ＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＯＲ８、－ＣＯＮＲ７ＣＯＯＲ８又は－ＣＯＮＲ７ＣＯＮＲ８ＣＯＲ９を表し、
　Ｒ１、Ｒ２及びＲ３は、それらが結合するＡ環上の置換可能な任意の原子に結合し、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１０Ｒ１１、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－又はシアノを表し、該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよく、
　Ｒ４及びＲ５は、それらが結合するＢ環上の置換可能な任意の原子に結合し、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１２Ｒ１３、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－、又はシアノを表し、該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよく、
　Ｒ６、Ｒ７、Ｒ８及びＲ９は、それぞれ独立して、水素原子、Ｃ１－６アルキル、ヒドロキシメチル、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリールを表し、該アルキル、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよく、
　ここにおいて、Ｒ７、Ｒ８及びＲ９が、水素原子、Ｃ１－６アルキル又はヒドロキシメチルのとき、ＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれか１つの組み合わせにおいて、それぞれの基が結合して、置換されていてもよい４～１０員の飽和複素環を形成していてもよく、
　Ｒ１０、Ｒ１１、Ｒ１２及びＲ１３は、それぞれ独立して、水素原子、Ｃ１－６アルキル、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリールを表し、該アルキル、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよく、
　ｎ及びｍは、それぞれ独立して、０～２の整数を表すが、
　但し、Ｌが結合であり、Ａ及びＢが共にベンゼン環であり、Ｘが－ＣＯＮＲ７Ｒ８であるとき、
　Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置は、１，３－若しくは１，４－置換であるか、又は、
　Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が１，２－置換である場合は、Ａｌｋが置換されていてもよい直鎖のＣ２－６アルキレンもしくは置換されていてもよいＣ２－６アルケニレン、またはアミノもしくはＣ１－６アシルアミノで置換されたメチレンであるか、あるいはＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれか１つの組み合わせにおいて、上記のように置換されていてもよい４～１０員の飽和複素環が形成される］
で表される化合物又はそれらの製薬学的に許容される塩。
　［項２］置換されていてもよい直鎖のアルキレン及び置換されていてもよいアルケニレンが、それぞれ独立して、Ｃ１－６アルキル、オキソ、水酸基、アミノ、Ｃ１－６アシルアミノ、Ｃ１－６アルコキシ又はフッ素からなる群から選択される１～５個の置換基で置換されていてもよい基である、
項１に記載の化合物又はそれらの製薬学的に許容される塩。
　［項３］Ａ環及びＢ環が、それぞれ独立して、アリール環又はヘテロアリール環である、項１又は２に記載の化合物又はそれらの製薬学的に許容される塩。
　［項４］Ａ環及びＢ環が、それぞれ独立して、ベンゼン環、チアゾール環、ピリジン環、ピリミジン環又はチオフェン環である、項１又は２に記載の化合物又はそれらの製薬学的に許容される塩。
　［項５］Ｌが、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンである、項１～４のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項６］Ａｌｋが、結合又は置換されていてもよい直鎖のＣ１－４アルキレンである、項１～５のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項７］Ａｌｋが、結合、Ｃ１－４アルキル、水酸基、Ｃ１－４アルコキシ及びフッ素原子からなる群から選択される１個の置換基で置換されていてもよいメチレンである、項６に記載の化合物又はそれらの製薬学的に許容される塩。
　［項８］Ａｌｋが、結合、メチル、水酸基、メトキシ及びフッ素原子からなる群から選択される１個の置換基で置換されていてもよいメチレンである、項６に記載の化合物又はそれらの製薬学的に許容される塩。
　［項９］Ｘが、－ＣＯＮＲ７Ｒ８又は－ＳＯ２ＮＲ７Ｒ８である、項１～８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１０］Ｒ１、Ｒ２及びＲ３が、同一又は異なって、水素原子、ハロゲン、１～５個のフッ素原子で置換されていてよいＣ１－６アルキル又はＣ１－６アルコキシである、項１～９のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１１］Ｒ４及びＲ５が、それぞれ独立して、水素原子、ハロゲン又はＣ１－６アルコキシである、項１～１０のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１２］Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２及びＲ１３が、それぞれ独立して、水素原子又はＣ１－６アルキルである、
項１～１１のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１３］Ａ環及びＢ環が、共にベンゼン環であり、Ｌが結合であり、Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が、１，２－置換であり、Ａｌｋが、結合であり、Ｘが、－ＳＯ２ＮＲ７Ｒ８であり、ここにおいて、Ｒ１～Ｒ５及びＲ７が、すべて水素原子であるとき、Ｒ８がＣ３－６アルキルである、
項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１４］Ａ環がピリジン環、Ｂ環がベンゼン環、Ｌが結合であり、Ａｌｋが、無置換或いは、水酸基で置換されていてもよいメチレンであり、Ｘが、－ＣＯＮＲ７Ｒ８であり、Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が、１，２－置換である、
項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　［項１５］Ａ環及びＢ環が、共にアリール環であり、Ｌが結合であり、Ａｌｋ－Ｘが、
Figure JPOXMLDOC01-appb-C000005
 のいずれかで表される基であり、ここにおいて、形成する飽和複素環が（ｉｉｉ）であり、Ｒ８が水素原子であるとき、Ｒ１～Ｒ５のいずれか１つが水素原子以外の基である、
項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
　好ましくは、Ａｌｋ－Ｘが、上記（ｉ）～（ｖｉ）のいずれかで表される基である上記の化合物又はそれらの製薬学的に許容される塩。
　［項１６］Ａｌｋ－Ｘが、項１５の（ｉ）、（ｉｉ）又は（ｉｉｉ）である、
請求項１～１３のいずれか一項に記載の化合物。
　［項１７］以下の化合物から選択される、項１に記載の化合物又はそれらの製薬学的に許容される塩：
３’－クロロビフェニル－２－スルホンアミド（実施例３６の化合物）、
２’－フルオロ－Ｎ－メチルビフェニル－２－スルホンアミド（実施例１１７の化合物）、
（２Ｅ）－Ｎ，Ｎ－ジメチル－３－［２－（１，３－チアゾール－２－イル）フェニル］プロプ－２－エナミド（実施例１８１の化合物）、
（２Ｅ）－３－（３’－クロロビフェニル－２－イル）－Ｎ，Ｎ－ジメチルプロプ－２－エナミド（実施例１９２の化合物）、
５－クロロ－２－（１，３－チアゾール－２－イル）ベンズアミド（実施例２０８の化合物）、
２’－クロロビフェニル－２－スルホンアミド（実施例２１５の化合物）、
１－（３’－フルオロビフェニル－２－イル）イミダゾリジン－２－オン（実施例２４１の化合物）、
１－（４，４’－ジフルオロビフェニル－２－イル）イミダゾリジン－２－オン（実施例２４４の化合物）、
２－[２－（５－クロロピリジン－３－イル）フェニル]アセトアミド（実施例ｆの化合物）、
２－｛２－[５－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトアミド（実施例ｈの化合物）、
２－｛２－フルオロ－６－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトアミド（実施例ｋの化合物）、
２－[２－（５－クロロピリジン－３－イル）－６－フルオロフェニル]アセトアミド（実施例qの化合物）、及び
２－[２－フルオロ－６－（５－フルオロピリジン－３－イル）フェニル]アセトアミド（実施例ｒの化合物）。
　［項１８］項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩、及び医薬的に許容される担体を含有する医薬組成物。
　［項１９］項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とする抗てんかん薬。
　［項２０］項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とする双極性障害に対する気分安定化薬。
　［項２１］抗てんかん薬を製造するための請求項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩の使用。
　本発明の化合物は、抗てんかん薬の評価に用いられる複数のモデル動物においていずれにも均等に強く抗痙攣活性を示すので、広範な治療スペクトルを示す抗てんかん薬（例えば、単純部分発作、複雑部分発作及び二次性全般化発作等の部分発作、欠神発作、ミオクロニー発作、間代発作、強直発作、強直間代発作、脱力発作、West症候群及びLennox－Gastaut症候群等の全般発作に対する予防薬及び／又は治療薬）として有用である。そして、これら本発明の一群の化合物は従来の薬物治療が奏功しない難治性てんかん発作に対する予防薬及び／又は治療薬としても期待される。また、本発明の化合物は、双極性障害に対する気分安定化薬として期待できる。
　本発明の化合物は、水和物及び／又は溶媒和物の形で存在することもあるので、これらの水和物及び／又は溶媒和物もまた本発明の化合物に包含される。
　また、本発明の化合物は、１個又は場合によりそれ以上の不斉炭素原子を有する場合があり、また幾何異性や軸性キラリティを生じることがあるので、数種の立体異性体として存在することがある。本発明においては、これらの立体異性体、それらの混合物及びラセミ体は本発明の式（Ｉ）で表される化合物に包含される。
　本発明の式（Ｉ）の化合物におけるＡ環及びＢ環上における置換基は、これら環上の任意の原子に置換可能な置換基を置換することができるが、本発明では便宜上、Ａ環上の置換基をＲ１、Ｒ２及びＲ３と定義し、Ｂ環上の置換基をＲ４及びＲ５と定義する。Ｒ１、Ｒ２及びＲ３の置換位置は、それらが結合するＡ環上の置換可能な炭素原子又は窒素原子のうち、いずれかの任意の原子３つに１つずつ結合し、また、Ｒ４及びＲ５の置換位置は、それらが結合するＢ環上の置換可能な炭素原子又は窒素原子のうち、いずれかの任意の原子２つに１つずつ結合することを意味する。
　本発明の式（Ｉ）の化合物において、Ｂ環上のＬとの結合部分に「１」と示すように、Ｂ環はＬとその１位で結合することとし、Ｂ環がベンゼン環であり、Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が、１，２－置換であるとは、下記の式（Ｉ’）で表されるようにＬ及び－Ａｌｋ－Ｘの置換位置の関係がオルト置換であることを意味する。また、１，３－又は１，４－置換であるとは、それぞれメタ置換、パラ置換であることを意味する。
Figure JPOXMLDOC01-appb-C000006
　つぎに、本明細書における用語について以下に説明する。
　「アルキル」とは、直鎖状又は分枝鎖状の飽和炭化水素を意味し、例えば、「Ｃ１－３アルキル」又は「Ｃ１－６アルキル」とは炭素原子数が１～３又は１～６の基をそれぞれ意味する。その具体例として、「Ｃ１－３アルキル」の場合には、メチル、エチル、プロピル、イソプロピル等が、「Ｃ１－６アルキル」の場合には、前記に加えて、ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル等が挙げられる。
　「Ｃ３－７シクロアルキル」とは、炭素原子数が３～７の単環式飽和炭化水素を意味する。その具体例として、シクロプロピル、シクロブチル、シクロペンチル、シクロへキシル等が挙げられる。
　「Ｃ３－７シクロアルキル－Ｃ１－３アルキル」とは、炭素数が３～７の単環式飽和炭化水素が、炭素数１～３の直鎖状又は分枝鎖状の飽和炭化水素の任意の炭素原子上に結合するアルキル基を意味する。その具体例としては、シクロプロピルメチル、シクロブチルメチル、１－シクロプロピルエチル、２－シクロプロピルエチル、１－シクロプロピルプロピル、２－シクロプロピルプロピル、１－シクロブチルエチル、２－シクロブチルエチル、シクロペンチルメチル、シクロヘキシルメチル等が挙げられる。
　「Ｃ１－６アルコキシ」とは、直鎖状又は分枝鎖状の炭素原子数が１～６のアルコキシを意味する。その具体例としては、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等が挙げられる。
　「Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－」とは、直鎖状又は分枝鎖状の炭素原子数が１～６のアルキルが結合した－Ｓ（Ｏ）ｍ－基を意味する。ここで、ｍが０のときはアルキルチオ（例えば、メチルチオ、エチルチオ等）、ｍが１のときはアルキルスルフィニル（例えば、メチルスルフィニル、エチルスルフィニル等）、ｍが２のときはアルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル等）をそれぞれ意味する。
　「アリール環」としては、６～１２員の単環性又は２環性のアリールが挙げられる。具体的には、ベンゼン、ナフタレン等が挙げられる。好ましくは、ベンゼンが挙げられる。
　「ヘテロアリール環」としては、窒素原子、酸素原子および硫黄原子からなる群から独立して選ばれる１から４個の原子を含む、５～７員の単環性芳香族複素環又は９～１１員の２環性芳香族複素環が挙げられる。具体的には、チアゾール、ピリジン、オキサジアゾール、ピリミジン、オキサゾール、イミダゾール、トリアゾール、チオフェン、フラン、ピロール、ベンゾチアゾール、ピリダジン、キノリン、ベンゾチオフェン、ピラジン、ベンゾイミダゾール、ベンゾトリアゾール、ベンゾフラン、ベンゾオキサゾール、イミダゾール、インドール、イソキノリン、キナゾリン、ピラゾール、テトラゾール、イソチアゾール等が挙げられる。好ましくは、５員もしくは６員の単環性芳香族複素環が挙げられ、具体的には、チアゾール、ピリジン、オキサジアゾール、ピリミジン、オキサゾール、イミダゾール、トリアゾール、チオフェン、フラン、ピロール、ピリダジン、ピラジンが挙げられる。
　「飽和炭素環」及び「部分不飽和炭素環」とは、環状の飽和又は部分不飽和炭化水素環を意味し、例えば、「３～８員の飽和炭素環」とは３～８員の環状の飽和炭化水素環を意味する。具体的には、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン等が挙げられる。好ましくは、５～７員の飽和炭素環が挙げられる。「３～８員の部分不飽和炭素環」とは３～８員の環状の部分不飽和炭化水素環を意味する。具体的には、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン等が挙げられる。好ましくは、５～７員の部分不飽和炭素環が挙げられる。
　「４～１０員の飽和複素環」とは、炭素原子以外に窒素原子、酸素原子および硫黄原子からなる群から独立して選ばれる１～３個のヘテロ原子を含む４～１０個の原子で構成される飽和環を意味する。具体例としては、２－ピロリドン、アゼチジン、ピロリン、ピペリン、モルホリン、ホモピペリン、ピペラジン、ホモピペラジン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチオフェン、テトラヒドロチオピラン等が挙げられる。好ましくは、４～７員の飽和複素環であり、具体的には、２－ピロリドン、テトラヒドロフラン、テトラヒドロピランが挙げられる。
　「直鎖のアルキレン」とは、直鎖の炭化水素鎖を意味する（該基は、環状の炭化水素基を形成してもよい）。例えば、「直鎖のＣ２－６アルキレン」または「直鎖のＣ１－６アルキレン」とは、炭素原子数が２～６または１～６の炭化水素鎖を意味する。具体的には、「直鎖のＣ２－６アルキレン」の場合には、エチレン、プロピレン、ブチレン、イソブチレン、ペンタメチレン等が挙げられ、「直鎖のＣ１－６アルキレン」の場合には、前記に加えて、メチレンが挙げられる。中でも好ましくは、「直鎖のＣ１－３アルキレン」が挙げられる。
　「アルケニレン」とは、１つ又は２つの二重結合を有する直鎖又は分枝鎖の炭化水素鎖を意味する。例えば、「Ｃ２－６アルケニレン」とは、炭素原子数が２～６のアルケニレンを意味する。具体的には、ビニレン、プロペニレン、ブテニレン、イソブテニレン、シクロブテニレン等が挙げられる。
　「ハロゲン」とは、フッ素、塩素、臭素またはヨウ素の各原子を意味する。好ましくは、フッ素、塩素または臭素の各原子が挙げられる。
　「Ｃ１－６アシルアミノ」とは、Ｃ０－５アルキル－ＣＯＮＨ－を意味し、具体的にはアセチルアミノ、プロピオニルアミノ、ブチリルアミノ、イソブチリルアミノ、バレリルアミノ、イソバレリルアミノ、ピバロイルアミノ等が挙げられる。好ましくはアセチルアミノが挙げられる。
　１～５個のフッ素原子で置換されていてもよいアルキル、アルキル－Ｓ（Ｏ）ｍ－、アルコキシ、シクロアルキル及びシクロアルキル－アルキルとは、該アルキル、アルコキシ、シクロアルキルおよびシクロアルキル－アルキルの任意の炭素上の１個ないし５個の置換可能な任意の水素原子がフッ素原子で置換されたものを意味し、その具体例としては、トリフルオロメチル、フルオロエチル、トリフルオロエチル、トリフルオロメタンスルホニル、トリフルオロメトキシ、２－フルオロシクロプロピル、（２－フルオロシクロプロピル）メチル等が挙げられる。なお、アルキル部分の炭素数が１のときは、置換されてもよいフッ素原子の数は、３以下である。
　「置換されていてもよい直鎖のアルキレン」及び「置換されていてもよいアルケニレン」の炭化水素部分の置換基としては、
　（１）ハロゲン原子、
　（２）Ｃ１－６アルキル
　（３）水酸基、
　（４）シアノ、
　（５）オキソ、
　（６）Ｃ３－８シクロアルキル、
　（７）Ｃ１－６アルコキシ、
　（８）Ｃ３－８シクロアルコキシ、
　（９）Ｃ１－５アルコキシカルボニル、
　（１０）－ＮＲ１４Ｒ１５、
　（１１）－ＣＯＮＲ１４Ｒ１５、
　（１２）Ｃ１－６アシルアミノ、及び
　（１３）Ｃ１－５アルキルカルボニル
が挙げられる（Ｒ１４及びＲ１５は、水素原子又はＣ１－６アルキルを表す）。より好ましくは、オキソ、水酸基又はフッ素が挙げられる。該アルキレン及びアルケニレンは、上記（１）～（１１）からなる群から選ばれる１～５個の置換基で置換されていてもよい。
　化合物（Ｉ）の製薬学的に許容される塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、ベンゼンスルホン酸塩、安息香酸塩、クエン酸塩、フマル酸塩、グルコン酸塩、乳酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、メタンスルホン酸塩、酒石酸塩等の有機酸塩等の酸付加塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等の金属塩、アンモニウム、テトラメチルアンモニウム等のアンモニウム塩、モルホリン付加塩、ピペリジン付加塩等の有機アミン付加塩、またはグリシン付加塩、フェニルアラニン付加塩、リジン付加塩、アスパラギン酸付加塩、グルタミン酸付加塩等のアミノ酸付加塩等が挙げられる。
　Ａ環及びＢ環としては、アリール環、ヘテロアリール環、飽和炭素環、部分不飽和炭素環、又は飽和複素環が挙げられる。好ましくは、アリール環又はヘテロアリール環が挙げられ、さらに好ましくは、ベンゼン環、チアゾール環、ピリジン環、ピリミジン環又はチオフェン環が挙げられ、特に好ましくは、ベンゼン環が挙げられる。
　Ｌとしては、結合、置換されていてもよい直鎖のＣ１－６アルキレン、置換されていてもよいＣ２－６アルケニレン、－Ｌ１－Ｏ－Ｌ２－、－Ｌ１－ＮＲ６－Ｌ２－、－Ｌ１－ＣＯＮＲ６－Ｌ２－、－Ｌ１－ＮＲ６ＣＯ－Ｌ２－又は－Ｌ１－Ｓ（Ｏ）ｎ－Ｌ２－（該Ｌ１及び該Ｌ２は、それぞれ独立して、結合又は置換されていてもよい直鎖のＣ１－６アルキレンを表す）を表し、好ましくは、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンが挙げられ、さらに好ましくは、結合が挙げられる。
　Ａｌｋとしては、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンが挙げられる。好ましくは、結合又は置換されていてもよい直鎖のＣ１－３アルキレン又は置換されていてもよいビニレンが挙げられ、さらに好ましくは、結合が挙げられる。
　Ｘとしては、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８、－ＮＲ７ＣＯＲ８、－ＳＯ２Ｒ７、－ＣＯＮＲ７ＣＯＲ８、－ＣＯＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＮＲ８ＣＯＲ９、－ＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＯＲ８、－ＣＯＮＲ７ＣＯＯＲ８又は－ＣＯＮＲ７ＣＯＮＲ８ＣＯＲ９が挙げられる。好ましくは、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８、－ＮＲ７ＣＯＲ８又は－ＳＯ２Ｒ７が挙げられる。より好ましくは、－ＣＯＮＲ７Ｒ８又は－ＳＯ２ＮＲ７Ｒ８が挙げられ、さらに好ましくは、－ＳＯ２ＮＲ７Ｒ８が挙げられる。
　Ａｌｋ及びＸは、Ｒ７、Ｒ８及びＲ９が、水素原子又はＣ１－６アルキルのとき、ＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれか１つの組み合わせにおいて、それぞれの基が結合して、置換されていてもよい４～１０員の飽和複素環を形成していてもよい。Ａｌｋ、Ｒ７、Ｒ８又はＲ９の各置換基の任意の１組が結合するとは、各置換基が炭化水素のときは、各置換基の任意の炭素原子に結合する水素原子と置き換えて互いの置換基が結合することを意味する。また、Ｒ７、Ｒ８又はＲ９が水素原子のときは、Ｒ７、Ｒ８又はＲ９に結合する窒素原子、炭素原子、酸素原子又は硫黄原子と他の置換基（水素原子と置き換わる）が結合することを意味する。また、Ｒ７、Ｒ８又はＲ９がヒドロキシメチルのときは、酸素原子または炭素原子に結合する水素原子と他の置換基が結合することを意味する。このように構築される複素環の任意の炭素原子は、カルボニル及び窒素原子からなる群から選択される１～２個のユニットと置き換わってもよい。このように構築される複素環として好ましくは、下記の飽和複素環が挙げられる。
Figure JPOXMLDOC01-appb-C000007
　中でも好ましくは、上記（ｉ）～（ｖｉ）が挙げられ、特に（ｉ）、（ｉｉ）及び（ｉｉｉ）が挙げられる。
　Ｒ１～Ｒ３としては、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１０Ｒ１１、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－又はシアノ（該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよい）が挙げられるが、好ましくは、水素原子、フッ素原子、塩素原子、臭素原子、ジフルオロメチル、ジフルオロメトキシ、トリフルオロメチル、トリフルオロメトキシ、メチルチオ、メタンスルホニル又はシアノが挙げられる。より好ましくは、水素原子、フッ素原子、塩素原子、ジフルオロメチル、ジフルオロメトキシ、トリフルオロメチル、トリフルオロメトキシ又はシアノが挙げられ、さらに好ましくは、水素原子、フッ素原子、塩素原子又はトリフルオロメチルが挙げられ、特に好ましくは、水素原子、フッ素原子、塩素原子又はトリフルオロメチル、もっとも好ましくは、水素原子、フッ素原子又は塩素原子が挙げられる。
　Ｒ４及びＲ５としては、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１２Ｒ１３、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－、又はシアノを表し、（該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよく、ｍは０～２の整数を表す）、好ましくは、水素原子、フッ素原子、塩素原子、メチル、エチル、トリフルオロメチル、トリフルオロメトキシ、メチルチオ、メタンスルホニル又はシアノが挙げられる。より好ましくは、水素原子、フッ素原子、塩素原子、メチル、エチル、トリフルオロメチル、トリフルオロメトキシ又はシアノが挙げられ、さらに好ましくは、水素原子、フッ素原子、塩素原子、トリフルオロメチル又はトリフルオロメトキシが挙げられ、特に好ましくは、水素原子、フッ素原子又は塩素原子が挙げられる。
　Ｒ６、Ｒ７、Ｒ８及びＲ９としては、それぞれ独立して、水素原子、Ｃ１－６アルキル、ヒドロキシメチル、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリール（該アルキル、アルコキシ、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよい）が挙げられ、好ましくは、水素原子、メチル若しくはエチルが挙げられる（該メチル及びエチルは、１～５個のフッ素原子で置換されていてもよい）。より好ましくは、水素原子、メチル又はエチルが挙げられる。特に好ましくは、水素原子又はメチルが挙げられる。
　Ｒ１０、Ｒ１１、Ｒ１２及びＲ１３としては、それぞれ独立して、水素原子、ハロゲン、Ｃ１－６アルキル、水酸基、Ｃ１－６アルコキシ、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリール（該アルキル、アルコキシ、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよい）が挙げられ、好ましくは、水素原子、フッ素原子、メチル、エチル、水酸基若しくはＣ１－６アルコキシが挙げられる（該メチル、エチル及びアルコキシは、１～５個のフッ素原子で置換されていてもよい）。より好ましくは、水素原子、メチル、エチル、水酸基、メトキシ又はエトキシが挙げられる。特に好ましくは、水素原子、メチル又は水酸基が挙げられる。
　ｎ及びｍとしては、それぞれ独立して、０～２の整数が挙げられるが、好ましくは、０又は２が挙げられる。特に好ましくは、２が挙げられる。
　本発明におけるてんかんとは、脳神経細胞の過剰興奮に由来する発作性の運動、意識、知覚の異常及び行動異常が反復する慢性疾患を意図し、単純部分発作、複雑部分発作及び二次性全般化発作等の部分発作、欠神発作、ミオクロニー発作、間代発作、強直発作、強直間代発作、脱力発作、West症候群及びLennox－Gastaut症候群等の全般発作が含まれる。また本発明における抗てんかん薬とは上記疾患の予防薬及び／又は治療薬を意図し、てんかんの治療方法とは上記疾患の予防及び／又は治療方法を意図する。
　本発明における双極性障害とは、躁状態とうつ状態を繰り返し、気分変調を来たす疾患を意味し、本発明における双極性障害に対する気分安定化薬とは上記疾患の予防薬及び／又は治療薬を意図し、双極性障害の治療方法とは上記疾患の予防及び／又は治療方法を意図する。
　なお、本明細書において記載の簡略化のために、次に挙げる略号を用いることもある。ｐ－：ｐａｒａ－、ｔ－：ｔｅｒｔ－、ｓ－：ｓｅｃ－、ＴＨＦ：テトラヒドロフラン、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＤＭＥ：エチレングリコールジメチルエーテル、ＤＭＳＯ：ジメチルスルホキシド、ＣＤＣｌ３：重クロロホルム、ＤＭＳＯ－ｄ６：重ジメチルスルホキシド、ＤＭＡ：ジメチルアセトアミド、ＮＭＰ：Ｎ－メチル－２－ピロリドン
　式（Ｉ）で表される本発明の化合物は、下記に示す製造法１～５により製造することができる。式（Ｉ）で表される化合物又はその製薬学的に許容される塩は、新規化合物であり、例えば、以下に述べる方法、後述する実施例及びそれに準じた方法によって製造することができる。下記の製造法で用いられる化合物は、反応に支障を来たさない範囲において、塩を形成していてもよい。
［製造法１］
　Ｘが、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８の基である式（Ｉ）の化合物［下記式（Ｉａ）の化合物］は、下記製造法により製造することができる。
Figure JPOXMLDOC01-appb-C000008
 （式中、Ａ環、Ｂ環、Ｌ、Ａｌｋ、Ｘ、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、項１の定義に同じである。Ｙは－ＣＯＯＨ、－ＣＯＯＷ、－ＣＯＣｌ、－ＳＯ３Ｈ及び－ＳＯ２Ｃｌである。Ｗは、Ｃ１－６アルキルを表す。）
　化合物（ＩＩ）をアミド化すると、化合物（Ｉａ）が得られる。原料化合物（ＩＩ）は、市販されているか又はＷＯ ２００４／７８８、ＷＯ ２００６／７６６４４、ＵＳ２００５／５９６６８、ＷＯ ２００８／１００４２３、Bioorganic and Medicinal Chemistry, 2008, vol.16, p.8607 - 8618等の公知の方法に準じた方法により合成できる。
　化合物（ＩＩ）のアミド化反応は、常法に従って行うことができる。例えば、この反応は化合物（ＩＩ）を反応性誘導体（例えば、低級アルキルエステル、活性エステル、酸無水物、酸ハライド等）に変換し、各種アミン及びアンモニアと反応させることによって達成される。活性エステルの具体例としては、ｐ－ニトロフェニルエステル、Ｎ－ヒドロキシコハク酸イミドエステル、ペンタフルオロフェニルエステル等が挙げられる。酸無水物の具体例としては、クロロ炭酸エチル、クロロ炭酸イソブチル、イソ吉草酸、ピバリン酸等との混合酸無水物が挙げられる。
　また、化合物（Ｉａ）は、化合物（ＩＩ）と各種アミン又はアンモニアとを縮合剤の存在下で反応させることによっても製造される。縮合剤の具体例としては、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド・１塩酸塩、Ｎ，Ｎ’－カルボニルジイミダゾール、ベンゾトリアゾール－１－イル－オキシトリス（ピロリジノ）ホスホニウム－ヘキサフルオロホスファート、Ｂｏｃ２Ｏ等が挙げられる。これらの縮合剤は単独で、又は、これら縮合剤と、Ｎ－ヒドロキシコハク酸イミド、Ｎ－ヒドロキシベンゾトリアゾール等のペプチド合成試薬とを組み合わせて用いることができる。
　化合物（ＩＩ）と各種アミン又はアンモニアとの反応は、溶媒中又は無溶媒下に行われる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばトルエン、ＴＨＦ、ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、酢酸エチル、アセトン、アセトニトリル、ＤＭＦ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。なお、各種アミン又はアンモニアは、塩酸塩等の酸付加塩の形で使用され、反応系中で遊離塩基を生成させてもよい。本反応は通常塩基の存在下で行われることもあり、使用される塩基の具体例としては、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、又は、トリエチルアミン、エチルジイソプロピルアミン、Ｎ－メチルモルホリン、ピリジン、４－ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は、用いられる原料化合物の種類等により異なるが、通常、約－３０℃～約１５０℃、好ましくは約－１０℃～約７０℃である。
　また、保護されたアミンを用い縮合し得られる化合物を脱保護することでも目的とする化合物（Ｉａ）を得ることが出来る。
［製造法２］
　Ｌが、結合、置換されていてもよい直鎖のＣ１－６アルキレン、置換されていてもよいＣ２－６アルケニレンである式（Ｉ）の化合物［下記式（Ｉｂ）の化合物］は、下記製造法により製造することができる。
Figure JPOXMLDOC01-appb-C000009
 （式中、Ａ環、Ｂ環、Ａｌｋ、Ｘ、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、項１の定義に同じである。Ｌ３は、結合、置換されていてもよい直鎖のＣ１－６アルキレン、置換されていてもよいＣ２－６アルケニレンであり、Ｚは、塩素、臭素、ヨウ素、ホウ素、マグネシウムハライド及びリチウムである。）
化合物（ＩＩＩ）を下記の試薬とカップリング化することで、化合物（Ｉｂ）が得られる。
原料化合物（ＩＩＩ）は、市販されているか又はJournal of Organic Chemistry, 1968, vol.33, p.900-903、Canadian Journal of Chemistry, 1969, vol.47, p.1543等の公知の方法に準じた方法により合成できる。
　化合物（Ｉｂ）は、適当な溶媒中で、化合物（ＩＩＩ）と各種置換フェニルボロン酸等のホウ素試薬、各種置換フェニルジンクハライド、各種置換有機スズ試薬等の有機金属試薬、アリールハライド等、アリールアルデヒド等を、無触媒又はテトラキストリフェニルホスフィンパラジウムに代表されるパラジウム触媒等の遷移金属触媒下、クロスカップリング反応を行うことで得られる。これら反応においては、上記試薬の他に炭酸アルカリ金属（例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等）やリン酸カリウム等の無機塩基、あるいはトリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、さらには塩化リチウム、フッ化セシウム等の無機塩共存下で行う場合もある。
　各種ホウ素試薬、あるいは有機金属試薬は、市販されているか、あるいは市販試薬から公知の方法に従って調整される。溶媒の具体例としては、原料化合物の種類や用いる試薬の種類に従って選択されるべきであるが、例えばトルエン、ＴＨＦ、ジオキサン、ＤＭＥ、酢酸エチル、アセトン、アセトニトリル、ＤＭＦ又はメタノール、エタノール、イソプロパノール、ｔ－ブタノール等のアルコール類及び水等が挙げられ、単独あるいは混合溶媒として使用することが出来る。反応温度は、用いられる原料化合物及び試薬の種類等によって異なるが、通常０～２００℃、好ましくは６０～１５０℃である。
［製造法３］
　Ｌが、－Ｌ１－ＣＯＮＲ６－Ｌ２－又は－Ｌ１－ＮＲ６ＣＯ－Ｌ２－である式（Ｉｃ）又は式（Ｉｃ’）の化合物は、下記製造法により製造することができる。
Figure JPOXMLDOC01-appb-C000010
 （式中、Ａ環、Ｂ環、Ｌ１、Ｌ２、Ａｌｋ、Ｘ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、項１の定義に同じである。）
　化合物（ＩＶ）又は（ＩＶ’）と各種カルボン酸又はアミンとの縮合反応を行うことで、化合物（Ｉｃ）又は（Ｉｃ’）が得られる。本反応は常法に従って行うことができる。例えば、この反応は適当な溶媒中又は無溶媒下で、化合物（ＩＶ）又は（ＩＶ’）を各種カルボン酸等又は各種アミン等と、縮合剤等を共存させて反応を行うことで達成される。各種カルボン酸等又は各種アミンは、市販されているか、あるいは市販試薬から公知の方法に従って調整される。縮合剤の具体例としては、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド・１塩酸塩、Ｎ，Ｎ’－カルボニルジイミダゾール、ジメチルアミノスルホン酸クロリド、１－エトキシカルボニル－２－エトキシ－１，２－ジヒドロキノリン、ベンゾトリアゾール－１－イル－オキシトリス（ピロリジノ）ホスホニウム－ヘキサフルオロホスファート、Ｏ－（１Ｈ―７－アザ－１－ベンゾトリアゾリル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム ヘキサフルオロホスフェート等が挙げられる。これらの縮合剤は単独で、又はこれら縮合剤とＮ－ヒドロキシコハク酸イミド、Ｎ－ヒドロキシベンゾトリアゾール等のペプチド合成試薬とを組み合わせて用いることができる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばジクロロメタン、クロロホルム、ジクロロエタン、ＴＨＦ、ジオキサン、ＤＭＥ、アセトニトリル、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。反応温度は、用いられる原料化合物及び試薬の種類等によって異なるが、通常－２０～２００℃、好ましくは０～１００℃である。
　また、化合物（Ｉｃ）は、適当な溶媒中で、化合物（ＩＶ）を反応性誘導体（例えば、活性エステル、酸無水物、酸ハライド、低級アルキルエステル等）に変換し反応させ、その後各種アミンと反応させることによっても得られる。活性エステルの具体例としては、ｐ－ニトロフェニルエステル、２、４、５－トリクロロフェニルエステル、Ｎ－ヒドロキシコハク酸イミドエステル、Ｎ－ヒドロキシフタルイミドエステル、１－ヒドロキシベンゾトリアゾールエステル、Ｎ－ヒドロキシピペリジンエステル、２－ピリジルチオールエステル、Ｎ－メチルイミダゾールエステル等が挙げられる。酸無水物としては、対称酸無水物又は混合酸無水物が用いられる。混合酸無水物の具体例としては、クロロ炭酸エチル、イソ吉草酸等との混合酸無水物が挙げられる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばジクロロメタン、クロロホルム、ジクロロエタン、ＴＨＦ、ジオキサン、ＤＭＥ、アセトニトリル、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。反応温度は、用いられる原料化合物及び試薬の種類等によって異なるが、通常－２０～２００℃、好ましくは０～１００℃である。
　また、化合物（Ｉｃ’）は、適当な溶媒中で、化合物（ＩＶ’）を反応性誘導体（例えば、活性エステル、酸無水物、酸ハライド、低級アルキルエステル等）と反応させることによっても得られる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばジクロロメタン、クロロホルム、ジクロロエタン、ＴＨＦ、ジオキサン、ＤＭＥ、アセトニトリル、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。本反応は塩基存在下で行われることもあり、その具体例としては、例えば、炭酸ナトリウム、炭酸カリウム、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が挙げられる。反応温度は、用いられる原料化合物及び試薬の種類等によって異なるが、通常－２０～２００℃、好ましくは０～１００℃である。
［製造法４］
　Ｌが、－Ｌ１－Ｏ－Ｌ２－、－Ｌ１－ＮＲ６－Ｌ２－である式（Ｉ）の化合物［下記式（Ｉｄ）又は（Ｉｄ’）の化合物］は、下記製造法により製造することができる。
Figure JPOXMLDOC01-appb-C000011
 （式中、Ａ環、Ｂ環、Ｌ１、Ｌ２、Ａｌｋ、Ｘ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、項１の定義に同じである。Ｖは、フッ素、塩素、臭素又はヨウ素である。）
　化合物（Ｉｄ）又は（Ｉｄ’）は、化合物（Ｖ）と各種アミン又はアルコール等とのカップリング反応を行うことで得られる。例えば、この反応は、適当な溶媒中又は無溶媒下で、化合物（Ｖ）を各種アミン又はアルコール等を塩基共存下で反応を行うことで達成される。各種アミン又はアルコール等は、市販されているか、あるいは市販試薬から公知の方法に従って調整される。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばジクロロメタン、クロロホルム、ジクロロエタン、ＴＨＦ、ジオキサン、ＤＭＥ、アセトニトリル、ＤＭＦ、ＤＭＡ、ＮＭＰ、ピリジン等が挙げられ、単独あるいは混合溶媒として使用することができる。塩基の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えば、炭酸アルカリ金属（例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等）の無機塩基、あるいはトリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、さらには水素化ナトリウム等の共存下で行う場合もある。反応温度は、用いられる原料化合物及び試薬の種類等によって異なるが、通常－２０～２００℃、好ましくは５０～１５０℃である。
［製造法５］
　Ｒ６、Ｒ７、Ｒ８及びＲ９が、水素原子又はＣ１－６アルキルのとき、ＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれかの組み合わせにおいて、それぞれの基が結合して、置換されていてもよい４～１０員の飽和複素環を形成する式（Ｉ）の化合物［下記式（Ｉｅ）の化合物］は、下記製造法により製造することができる。
Figure JPOXMLDOC01-appb-C000012
 （式中、Ａ環、Ｂ環、Ｌ、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、項１の定義に同じである。Ａｌｋ’は、置換されていてもよい直鎖のＣ１－６アルキレン又は窒素原子であり、Ｘ１は－ＮＨ２、－ＯＨ、Ｙ１は水素原子、－ＣＯＮＨ２、－ＣＯＯＨ、－ＣＯＯＲ、－ＣＨ２ＮＨ２であり、Ｃｙは置換されていてもよい４～１０員の飽和複素環である。）
　化合物（ＩＩ）と同様にして製造できる化合物（ＩＩ’）を環化すると、化合物（Ｉｅ）が得られる。
　化合物（ＩＩ’）の環化反応は、常法に従って行うことができる。例えば、この反応は化合物（ＩＩ’）とカルボニルジイミダゾール（ＣＤＩ）、トリホスゲン、ジ（２－ピリジル）カーボネート、クロロ炭酸ｐ－ニトロフェニル等のカルボニル化剤と反応させることによって達成される。
　化合物（ＩＩ’）とカルボニル化剤との反応は、溶媒中又は無溶媒下に行われる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばトルエン、ＴＨＦ、ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、酢酸エチル、アセトン、アセトニトリル、ＤＭＦ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。本反応は通常塩基の存在下で行われることもあり、使用される塩基の具体例としては、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、又は、トリエチルアミン、エチルジイソプロピルアミン、Ｎ－メチルモルホリン、ピリジン、４－ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は、用いられる原料化合物の種類等により異なるが、通常、約－３０℃～約１５０℃、好ましくは約－１０℃～約７０℃である。
　また、化合物（Ｉｅ）は、化合物（ＩＩ’）とクロロ炭酸ハロアルキル、ハロアルキルイソシアナート又はハロアルキル酸クロリド等のアシル化剤と反応させた後、塩基を作用させることによっても製造される。
　化合物（ＩＩ’）とアシル化剤との反応は、溶媒中又は無溶媒下に行われる。溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばトルエン、ＴＨＦ、ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、酢酸エチル、アセトン、アセトニトリル、ＤＭＦ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。本反応は通常塩基の存在下で行われることもあり、使用される塩基の具体例としては、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、又は、トリエチルアミン、エチルジイソプロピルアミン、Ｎ－メチルモルホリン、ピリジン、４－ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は、用いられる原料化合物の種類等により異なるが、通常、約－３０℃～約１５０℃、好ましくは約－１０℃～約７０℃である。
　アシル化された化合物（ＩＩ’）と塩基との反応は、溶媒中又は無溶媒下に行われる。使用される塩基の具体例としては、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、水素化ナトリウム、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド等又は、トリエチルアミン、エチルジイソプロピルアミン、Ｎ－メチルモルホリン、ピリジン、４－ジメチルアミノピリジン等の有機塩基が挙げられる。また、溶媒の具体例としては、原料化合物の種類等に従って選択されるべきであるが、例えばトルエン、ＴＨＦ、ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、酢酸エチル、アセトン、アセトニトリル、ＤＭＦ、ＤＭＳＯ等が挙げられ、単独あるいは混合溶媒として使用することができる。本反応は通常塩基の存在下で行われることもあり、反応温度は、用いられる原料化合物の種類等により異なるが、通常、約－３０℃～約１５０℃、好ましくは約－１０℃～約７０℃である。
　前記各製法により生成する式（Ｉ）の化合物は、クロマトグラフィー、再結晶、再沈殿等の常法により単離・精製することができる。また、式（Ｉ）の化合物がラセミ体である場合は、光学活性カラムを用いたクロマトグラフィーによる光学分割方法、優先晶出法、ジアステレオマー法等の常法に従って、それぞれの光学活性体へと分離・精製することができる。
　本発明の新規アミド誘導体は、後述のとおり、抗てんかん薬として有用である。本発明の化合物の投与経路としては、経口投与、非経口投与又は直腸内投与のいずれでもよく、その一日投与量は、化合物の種類、投与方法、患者の症状・年齢等により異なる。例えば、経口投与の場合は、通常、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１～１０００ｍｇ、さらに好ましくは約０．１～５００ｍｇを１～数回に分けて投与することができる。静注等の非経口投与の場合は、通常、例えば、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１ｍｇ～３００ｍｇ、さらに好ましくは約１ｍｇ～１００ｍｇを投与することができる。
　本発明の化合物は、上記のごとき医薬用途に使用する場合、通常、製剤用担体と混合して調製された製剤の形で投与される。製剤用担体としては、製剤分野において常用され、かつ本発明の化合物と反応しない無毒性の物質が用いられる。具体的には、例えばクエン酸、グルタミン酸、グリシン、乳糖、イノシトール、ブドウ糖、マンニトール、デキストラン、ソルビトール、シクロデキストリン、デンプン、部分アルファー化デンプン、白糖、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、結晶セルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルデンプン、カルボキシメチルセルロースカルシウム、イオン交換樹脂、メチルセルロース、ゼラチン、アラビアゴム、プルラン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、アルギン酸、アルギン酸ナトリウム、軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、トラガント、ベントナイト、ビーガム、カルボキシビニルポリマー、酸化チタン、ソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリセリンエステル、精製ラノリン、グリセロゼラチン、ポリソルベート、マクロゴール、植物油、ロウ、プロピレングリコール、エタノール、ベンジルアルコール、塩化ナトリウム、水酸化ナトリウム、塩酸、水等が挙げられる。
　剤型としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、懸濁剤、注射剤、坐剤、点眼剤、軟膏剤、塗布剤、貼付剤、吸入剤等が挙げられる。これらの製剤は常法に従って調製することができる。なお、液体製剤にあっては、用時、水又は他の適当な媒体に溶解又は懸濁する形であってもよい。また、錠剤及び顆粒剤は周知の方法でコーティングしてもよい。さらに、これらの製剤は治療上価値ある他の成分を含有してもよい。
　以下に参考例、実施例及び試験例を挙げて本発明をさらに具体的に説明するが、これらは本発明を限定するものではない。なお、化合物の同定は元素分析値、マス・スペクトル、高速液体クロマト質量分析計；ＬＣＭＳ、ＩＲスペクトル、ＮＭＲスペクトル、高速液体クロマトグラフィー（ＨＰＬＣ）等により行った。
　明細書の記載を簡略化するために実施例及び実施例中の表において以下に示すような略号を用いることもある。ＮＭＲに用いられる記号としては、ｓは一重線、ｄは二重線、ｔは三重線、ｑは四重線、ｍは多重線、及びｂｒはなだらかを意味する。
高速液体クロマト質量分析計;ＬＣＭＳの測定条件は、以下の通りであり、観察された質量分析の値［ＭＳ（ｍ／ｚ）］をＭＨ＋で、保持時間をＲｔ（ｍｉｎ）で示す。
検出機器：ＡＰＩシリーズ用Ａｇｉｌｅｎｔ １１００シリーズ (applied Biosystems社製)
ＨＰＬＣ：ＡＰＩ１５０ＥＸ ＬＣ／ＭＳ ｓｙｓｔｅｍ (applied Biosystems社製)
Ｃｏｌｕｍｎ：ＹＭＣ ＣｏｍｂｉＳｃｒｅｅｎ ＯＤＳ－Ａ (S-5μM, 12 nm, 4.6 x 50 mm)
条件Ａ（以下、実施例表中で特に記載のないものは、本条件での測定である。）
Solvent：Ａ液:0.05% ＴＦＡ／Ｈ２Ｏ、Ｂ液:0.035% ＴＦＡ／ＭｅＯＨ
Gradient Condition：0.0-1.0 min Ａ 60%, 1.0-4.7 min Linear gradient from Ａ 60% to 1%, 4.7-5.7 min Linear gradient from Ａ 1% to 60%
Flow rate：1.8 mL/min
UV：220 nm
条件Ｂ（以下、実施例表中で＊の記載のあるものは、本条件での測定である。）
Solvent：Ａ液: 0.05% ＴＦＡ／Ｈ２Ｏ、Ｂ液: 0.035% ＴＦＡ／ＭｅＯＨ
Gradient Condition: 0.0-1.0 min Ａ 75%, 1.0-4.7 min Linear gradient from Ａ 75% to 1%, 4.7-5.7 min Linear gradient from Ａ 1% to 75%
Flow rate：1.8 mL/min
参考例１：
　エチル ｛２－[５－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセテート
Figure JPOXMLDOC01-appb-C000013
 　ＧＢ２４６６１２１Ａに準じて合成したエチル ２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニルアセテート（７００ｍｇ）、３－ブロモ－５－トリフルオロメチルピリジン（５４５ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（２７９ｍｇ）、リン酸カリウム・３水和物（１．２８ｇ）をジオキサン（２４ｍｌ）に加え、アルゴンで置換した後に、一晩加熱還流した。水を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、アミンシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１９／１）で精製し、標題化合物（５１６ｍｇ）を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.20 (t, 3H), 3.53 (s, 2H), 4.09 (q, 2H), 7.26-7.28 (m, 1H), 7.38-7.45 (m, 3H), 7.96-7.98 (m, 1H), 8.79 (d, 1H), 8.90-8.91 (m, 1H).
参考例２：
｛２－[５－（トリフルオロメチル）ピリジン－３－イル]フェニル｝酢酸
Figure JPOXMLDOC01-appb-C000014
 　エチル ｛２－[５－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセテート（５１６ｍｇ）をＴＨＦ（５ｍｌ）に溶解し、水酸化リチウム・一水和物（２１０ｍｇ）の水（５ｍｌ）溶液に加え、室温で一晩攪拌した。１０％クエン酸水溶液を加えｐＨ ４に調整後、酢酸エチルで抽出、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧留去して標題化合物（４５５ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 3.54 (s, 2H), 7.24‐7.26 (m, 1H), 7.38-7.48 (m, 3H), 7.97-7.98 (m, 1H), 8.86 (s, 1H), 8.87 (s, 1H).
参考例３：
　２－[６－（トリフルオロメチル）ピリジン－３－イル]ベンズアルデヒド
Figure JPOXMLDOC01-appb-C000015
 　２－ホルミルフェニルボロン酸（２．００ｇ）、５－ブロモー２－トリフルオロメチルピリジン（３．３２ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（１．５４ｇ）、フッ化セシウム（４．０５ｇ）をＤＭＥ（５０ｍｌ）に加えアルゴンで置換後、一晩加熱還流した。水を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９／１）で精製し、標題化合物（１．２０ｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 7.41‐7.44 (m, 1H), 7.63-7.67 (m, 1H), 7.72-7.76 (m, 1H), 7.81 (d, 1H), 7.88-7.91 (m, 1H), 8.07-8.10 (m, 1H), 8.77 (d, 1H), 9.98 (s, 1H).
参考例４：
　ヒドロキシ｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトニトリル
Figure JPOXMLDOC01-appb-C000016
 　２－[６－（トリフルオロメチル）ピリジン－３－イル]ベンズアルデヒド（１．２０ｇ）を酢酸エチル（１４ｍｌ）に溶解し、これをシアン化カリウム（０．９３ｇ）、亜硫酸水素ナトリウム（１．４９ｇ）の水（１４ｍｌ）溶液に加え、４０℃加熱下で６０時間攪拌した。酢酸エチルで抽出し飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）で精製し、標題化合物（１．２０ｇ）を無色油状物として得た。
1H-NMR (CDCl3) δ: 3.12 (d, 1H), 5.37 (d, 1H), 7.34-7.36 (m, 1H), 7.56‐7.64 (m, 2H), 7.81 (d, 1H), 7.91 (dd, 1H), 7.97 (dd, 1H), 8.79 (d, 1H).
参考例５：
　メチル ヒドロキシ｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセテート
Figure JPOXMLDOC01-appb-C000017
 ［工程１］
　ヒドロキシ｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトニトリル（１．２０ｇ）を濃硫酸（２０ｍｌ）に溶解し、３０℃加熱下で８時間攪拌後、一晩加熱還流した。水酸化ナトリウムを加えｐＨ ４に調整後、酢酸エチルで抽出し飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去して標題化合物（１．０５ｇ）を白色アモルファスとして得た。
［工程２］
　工程１で得たヒドロキシ｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝酢酸（１．０５ｇ）をトルエン（５ｍｌ）、メタノール（５ｍｌ）に溶解し、２Ｍ トリメチルシリルジアゾメタンのヘキサン溶液を加え、室温で２時間攪拌した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、標題化合物（８６５ｍｇ）を無色油状物として得た。
1H-NMR (CDCl3) δ: 3.47 (d, 1H), 3.73 (s, 3H), 5.08 (d, 1H), 7.29‐7.31 (m, 1H), 7.45-7.51 (m, 3H), 7.78 (dd, 1H), 7.98-8.01 (m, 1H), 8.82 (d, 1H).
実施例１：
　Ｎ－メチル－２－（１，３－チアゾール－２－イル）ベンズアミド
Figure JPOXMLDOC01-appb-C000018
 　２－（１，３－チアゾール－２－イル）安息香酸（１９６ｍｇ）をジクロロメタン（５ｍｌ）に溶解し、ＤＭＦ（１滴）、１Ｍ オキサリルクロリド ジクロロメタン溶液（１．９ｍｌ）を加えた後に、室温で１時間攪拌した。濃縮後、残渣をトルエンに懸濁させて共沸した。得られた褐色結晶をＴＨＦ（１０ｍｌ）に溶解し、４０％メチルアミン メタノール溶液（１ｍｌ）を加え、室温で一晩攪拌した。１０％クエン酸水溶液を加え酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィーで精製し、標題化合物（８８ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 2.91 (d, 3H), 6.45 (br, 1H), 7.43 (d, 1H), 7.48‐7.51 (m, 2H), 7.65-7.73 (m, 2H), 7.89 (d, 1H).
MS (m/z) 219 (MH+), Rt = 1.15 min.
実施例２－８７：
　対応する原料化合物を用いて実施例１に準じた方法で反応・処理し、表１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
実施例３６の1H-NMR (CDCl3) δ: 4.27 (br, 2H), 7.33 (dd, 1H), 7.40-7.46 (m, 4H), 7.51-7.55 (m, 1H), 7.59‐7.63 (m, 1H), 8.17 (dd, 1H).
実施例５１の1H-NMR (CDCl3) δ: 4.89 (br, 2H), 7.38-7.51 (m, 3H), 7.57-7.62 (m, 3H), 7.81 (ddd, 1H), 7.91 (ddd, 1H), 8.16 (dd, 1H).
実施例８８：
　Ｎ，Ｎ－ジメチル－２－（１，３－オキサゾール－２－イル）ベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000024
 　２－ブロモフェニルジメチルスルホンアミド（４００ｍｇ）、２－（トリ－ｎ－ブチルスタニル）オキサゾール（０．５４ｍｌ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（１０６ｍｇ）、酸化銅（ＩＩ）（１２０ｍｇ）をＤＭＦ（１５ｍｌ）に加え窒素置換後、１００℃加熱下で４時間攪拌した。室温まで冷却後、フッ化カリウム、水、酢酸エチルを加えしばらく攪拌した。不溶物をセライトろ過により除去した後に、酢酸エチル層を飽和食塩水で洗浄、続いて無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィーで精製し結晶を得た。これをイソプロピルアルコールで再結晶し、標題化合物（１７９ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 2.77 (s, 6H), 7.29 (d, 1H), 7.64-7.72 (m, 3H), 7.82 (d, 1H), 7.99-8.02 (m, 1H)．
MS (m/z) 253 (MH+), Rt = 1.57 min.
実施例８９－１３７：
　対応する原料化合物を用いて実施例８８に準じた方法で反応・処理し、表２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
実施例１１７の1H-NMR (DMSO-d6) δ: 2.36 (d, 3H), 7.19-7.23 (m, 3H), 7.27-7.45 (m, 3H), 7.60-7.69 (m, 2H), 7.92-7.97 (m, 1H).
実施例１２０の1H-NMR (CDCl3) δ: 2.56 (d, 3H), 3.67 (br, 1H), 7.31-7.66 (m, 7H), 8.16 (dd, 1H).
実施例１３３の1H-NMR (CDCl3) δ: 2.53 (s, 6H), 7.42-7.45 (m, 1H), 7.54-7.67 (m, 3H), 7.71-7.74 (m, 1H), 8.01-8.04 (m, 1H), 8.61 (d, 1H).
実施例１３８：
　２－［ヒドロキシ（チオフェン－２－イル）メチル］－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000028
 　２－ブロモ－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド（０．３０１ｇ）のＴＨＦ（５．０ｍｌ）溶液を－７８℃に冷却し、２．５Ｍ ｎ－ブチルリチウム ヘキサン溶液（０．５５ｍｌ）を滴下し、６０分間攪拌した。反応液にチオフェン－２－カルバルデヒド（０．１２ｍｌ）を滴下後－７８℃で３時間攪拌した。反応混合物に１０％クエン酸水溶液（８０ｍｌ）を加え攪拌後、酢酸エチル（８０ｍｌ）で抽出した。抽出液を飽和食塩水（８０ｍｌ）で洗浄した後、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．１９７ｇ）を得た。
1H-NMR (CDCl3) δ:2.77 (s, 6H), 3.21 (d, 1H), 6.90-6.99 (m, 3H), 7.46 (t, 1H), 7.61 (t, 1H), 7.76 (d, 1H), 7.90 (d, 1H).
MS (m/z) 298 (MH+), Rt = 3.26 min.
実施例１３９－１５０：
　対応する原料化合物を用いて実施例１３８に準じた方法で反応・処理し、表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000029
実施例１５１：
　Ｎ，Ｎ－ジメチル－２－［２－（１，３－チアゾール－２－イル）エテニル］ベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000030
 　トリフェニル（チアゾール－２－イルメチル）ホスホニウムクロリド（０．６２ｇ）のトルエン（１５ｍｌ）溶液にカリウム ｔｅｒｔ－ブトキシド（０．２００ｇ）を加えて室温で３時間攪拌した。反応液に２－ホルミル－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド（０．４９７ｇ）のトルエン（９ｍｌ）液を滴下し、室温で攪拌した。反応混合物をセライト濾過後、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．４５９ｇ）を得た。
MS (m/z) 295 (MH+), Rt = 3.17, 3.65 min. 
実施例１５２：
　対応する原料化合物を用いて実施例１５１に準じた方法で反応・処理し、下記に示す化合物を得た。
Figure JPOXMLDOC01-appb-C000031
 MS(m/z) 288 (MH+), Rt= 4.47 min. 
実施例１５３：
　Ｎ，Ｎ－ジメチル－２－［２－（１，３－チアゾール－２－イル）エチル］ベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000032
 　Ｎ，Ｎ－ジメチル－２－（２－チアゾール－２－イル）ビニルベンゼンスルホンアミド（０．１０３ｇ）の酢酸エチル（１．５ｍｌ）溶液に、パラジウム／炭素（５０ｍｇ）を加え水素雰囲気下１０時間攪拌した。反応混合物をセライト濾過し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．０９２ｇ）を得た。
1H-NMR (CDCl3) δ: 2.81 (s, 6H), 3.35-3.52 (m, 4H), 7.21 (d, 1H), 7.34-7.40 (m, 2H), 7.47-7.52 (m, 1H), 7.71 (d, 1H), 7.90 (d, 1H).
MS (m/z) 297 (MH+), Rt = 3.09 min.
実施例１５４：
　対応する原料化合物を用いて実施例１５３に準じた方法で反応・処理し、下記に示す化合物を得た。
Figure JPOXMLDOC01-appb-C000033
 MS (m/z) 290 (MH+), Rt= 4.59 min.
実施例１５５：
　Ｎ，Ｎ－ジメチル－２－（１，３－チアゾール－２－イルメトキシ）ベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000034
 　水素化ナトリウム（０．１１７ｇ）のＤＭＦ（５．０ｍｌ）懸濁液に、氷冷下１，３－チアゾ－ル－２－イルメタノール（０．３３７ｇ）を加え、３０分間攪拌後、２－フルオロ－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド（０．４９６ｇ）のＤＭＦ（２．０ｍｌ）溶液を滴下し、終夜攪拌した。反応混合物に水（１００ｍｌ）を加え、酢酸エチル（１００ｍｌ）で抽出後、抽出液を飽和食塩水（１００ｍｌ）で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．４８７ｇ）を得た。
1H-NMR (CDCl3) δ: 2.82 (s, 6H), 5.51 (s, 2H), 7.08-7.15 (m, 2H), 7.41 (d, 1H), 7.52.(t, 1H), 7.81 (d, 1H), 7.95 (d, 1H).
MS (m/z) 299 (MH+), Rt = 2.73 min.
実施例１５６－１６３：
　対応する原料化合物を用いて実施例１５５に準じた方法で反応・処理し、表４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000035
実施例１６４：
　２－［（シクロヘキシルメチル）アミノ］－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド
Figure JPOXMLDOC01-appb-C000036
 　２－フルオロ－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド（０．４１３ｇ）のＮＭＰ（５．０ｍｌ）溶液に、シクロへキシルメチルアミン（０．３２ｍｌ）と炭酸カリウム（０．３３７g）を加え、１３０℃で７．５時間攪拌した。反応混合物に水（１００ｍｌ）を加え、酢酸エチル（１００ｍｌ）で抽出後、抽出液を飽和食塩水（１００ｍｌ）で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．２５９ｇ）を得た。
1H-NMR (CDCl3) δ: 0.98-1.02 (m, 2H),1.19-1.28 (m, 5H), 1.73-1.84 (m, 4H), 2.74 (s, 6H), 2.96 (t, 2H), 6.37 (s, 1H), 6.64-6.72 (m, 2H), 7.37 (t, 1H), 7.59 (d, 1H).
MS (m/z) 297 (MH+), Rt = 5.16 min.
実施例１６５－１７４：
　対応する原料化合物を用いて実施例１６４に準じた方法で反応・処理し、表５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000037
実施例１７５：
　Ｎ－［２－（ジメチルスルファモイル）フェニル］ベンズアミド
Figure JPOXMLDOC01-appb-C000038
 　２－アミノ－Ｎ，Ｎ－ジメチルベンゼンスルホンアミド（０．４０５ｇ）の塩化メチレン（５．０ｍｌ）溶液に、トリエチルアミン（０．６７ｍｌ）と４－ジメチルアミノピリジン（５．１ｍｇ）を加え冷却し、氷冷下ベンゾイルクロリド（０．２８ｍｌ）を滴下し、室温で１８時間攪拌した。反応混合物に水（１００ｍｌ）を加え、酢酸エチル（１００ｍｌ）で抽出した。抽出液を飽和食塩水（１００ｍｌ）で洗浄した後、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（０．５１６ｇ）を得た。
1H-NMR (CDCl3) δ:2.72 (s, 6H), 7.24-7.30 (m, 1H), 7.51-7.68 (m, 4H), 7.81 (d, 1H), 8.01-8.04 (m, 2H), 8.73 (d, 1H), 10.54 (s, 1H).
MS (m/z) 305 (MH+),Rt = 4.28 min.
実施例１７６－１７７：
　対応する原料化合物を用いて実施例１７５に準じた方法で反応・処理し、表６に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000039
実施例１７８：
（２Ｅ）－３－（ビフェニル－２－イル）－Ｎ－メチルプロプ－２－エナミド
Figure JPOXMLDOC01-appb-C000040
 　（２Ｅ）－３－（ビフェニル－２－イル）プロプ－２－エノイックアシッド（３００ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピルカルボジイミド）塩酸塩（４１１ｍｇ）、１－ヒドロキシベンゾトリアゾール・１水和物（２９０ｍｇ）、メチルアミン塩酸塩（１８１ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．９３ｍｌ）のＤＭＦ（１０ｍｌ）溶液を室温で終夜攪拌した。反応液に１０％クエン酸水溶液を加え、酢酸エチルで抽出後、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、反応混合物を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（２５０ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 2.90 (d, 3H), 5.53 (br, 1H), 6.30 (d, 1H), 7.30-7.46 (m, 8H), 7.58-7.66 (m, 2H).
MS (m/z) 238 (MH+), Rt = 4.20 min.
実施例１７９－１９９：
　対応する原料化合物を用いて実施例１７８に準じた方法で反応・処理し、表７に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
実施例１８１の1H-NMR (CDCl3) δ: 3.06 (s, 3H), 3.18 (s, 3H), 6.83 (d, 1H), 7.42-7.45 (m, 3H), 7.65-7.67 (m, 1H), 7.75-7.77 (m, 1H), 7.94 (d, 1H), 8.15 (d, 1H).
実施例１９２の1H-NMR (CDCl3) δ: 3.02 (s, 3H), 3.11 (s, 3H), 6.75 (d, 1H), 7.17-7.21 (m, 1H), 7.32-7.41 (m, 6H), 7.59 (d, 1H), 7.65-7.68 (m, 1H).
実施例２００：
（２Ｅ）－３（ビフェニル－２－イル）プロプ－２－エナミド
Figure JPOXMLDOC01-appb-C000043
 　（２Ｅ）－３－（ビフェニル－２－イル）プロプ－２－エノイックアシッド（３００ｍｇ）、炭酸水素アンモニウム（１６９ｍｇ）、二炭酸ジ－ｔ－ブチル（４０９ｍｇ）をピリジン（０．１７ｍｌ）及びジオキサン（１０ｍｌ）の混液に溶解し、室温で終夜攪拌した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（１８７ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 5.60 (br, 2H), 6.37 (d, 1H), 7.30-7.45 (m, 8H), 7.61 (d, 1H), 7.66 (d, 1H).
MS (m/z) 224 (MH+), Rt = 4.03 min.
実施例２０１－２１２：
　対応する原料化合物を用いて実施例２００に準じた方法で反応・処理し、表８に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000044
実施例２０８の1H-NMR (DMSO-d6) δ: 7.51 (d, 1H), 7.59-7.63 (m, 2H), 7.83-7.86 (m, 2H), 7.92 (dd, 1H), 8.04 (br, 1H).
実施例２１３：
　（Ｅ）－２－（ビフェニル－２－イル）－Ｎ，Ｎ－ジメチルエテンスルホンアミド
Figure JPOXMLDOC01-appb-C000045
 　２－ブロモビフェニル（１．２０ｇ）、Ｎ，Ｎ－ジメチルビニルスルホンアミド（０．８４ｇ）、酢酸パラジウム（ＩＩ）（１１６ｍｇ）、トリフェニルホスフィン（２７０ｍｇ）トリエチルアミン（１．８ｍｌ）をＤＭＦ（６０ｍｌ）に加え窒素置換後、１４０℃加熱下で１８時間攪拌した。不要物をセライトろ過により除去、続いて溶媒を減圧留去後、水を加え酢酸エチルで抽出した。飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製、褐色結晶を得た。これをヘキサンで洗浄し、標題化合物（１４９ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 2.78 (s, 6H), 6.57 (d, 1H), 7.29-7.32 (m, 2H), 7.39-7.52 (m, 7H), 7.61 (d, 1H).
MS (m/z) 288 (MH+), Rt = 4.38 min.
実施例２１４：
　対応する原料化合物を用いて実施例２１３に準じた方法で反応・処理し、下記に示す化合物を得た。
Figure JPOXMLDOC01-appb-C000046
 MS (m/z) 274 (MH+), Rt= 4.18 min.
実施例２１５：
　２’－クロロビフェニル－２－スルホンアミド
Figure JPOXMLDOC01-appb-C000047
 　Ｎ－ｔｅｒｔ－ブチル－２’－クロロビフェニル－２－スルホンアミド（４５３ｍｇ）をトリフルオロ酢酸（８ｍｌ）に溶解し、室温で６時間攪拌した。トリフルオロ酢酸を減圧留去後、シリカゲルカラムクロマトグラフィーで精製し標題化合物（３１９ｍｇ）を白色結晶として得た。
1H-NMR (DMSO-d6) δ: 7.24-7.42 (m, 6H), 7.49 (d, 1H), 7.59-7.66 (m, 2H), 8.01-8.04 (m, 1H).
MS (m/z) 268 (MH+), Rt = 3.47 min.
実施例２１６－２２１：
　対応する原料化合物を用いて実施例２１５に準じた方法で反応・処理し、表９に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000048
実施例２２２：
　ビフェニル－２－イルプロパン－２－イルスルホン
Figure JPOXMLDOC01-appb-C000049
 　窒素雰囲気下でビフェニル－２－スルホニルフルオリド（３００ｍｇ）をＴＨＦ（２０ｍｌ）に溶解し、－７８℃で０．７Ｍ イソプロピルリチウム ペンタン溶液（５．４ｍｌ）を加え１時間攪拌した。飽和塩化アンモニウム水溶液を加え反応を終了後、酢酸エチルで抽出した。飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（８４ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 1.07 (d, 6H), 2.50-2.63 (m, 1H), 7.34-7.43 (m, 6H), 7.52-7.66 (m, 2H), 8.20 (dd, 1H).
MS (m/z) 261 (MH+), Rt = 4.03 min.
実施例２２３－２２４：
　対応する原料化合物を用いて実施例２２２に準じた方法で反応・処理し、表１０に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000050
実施例２２５－２２８：
　対応する原料化合物を用いて実施例１に準じた方法で反応・処理し、表１１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000051
実施例２２９－２３２：
　対応する原料化合物を用いて実施例８８に準じた方法で反応・処理し、表１２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000052
実施例２３３－２３６：
　対応する原料化合物を用いて実施例１７８に準じた方法で反応・処理し、表１３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000053
実施例２３７：
　１－（３’－クロロビフェニル－２－イル）ピロリジン－２－オン
Figure JPOXMLDOC01-appb-C000054
 　３’－クロロビフェニル－２－アミン（１．００ｇ）、トリエチルアミン（０．７５３ｍｌ）をＴＨＦ（２０ｍｌ）に溶解し、氷冷下で４－クロロブタノイルクロリド（０．５４９ｍｌ）のＴＨＦ（２０ｍｌ）溶液を滴下した。室温で１時間攪拌後、析出した固体を濾別し、ＴＨＦで洗浄した。濾液に氷冷下で水素化ナトリウム（０．２１６ｇ）を少しずつ加えた後に、室温で終夜攪拌した。飽和塩化アンモニウム水溶液を加え反応を終了させた後に酢酸エチルで抽出した。飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（１．０７ｇ）を黄色油状物として得た。
MS (m/z) 272 (MH+), Rt = 4.26 min.
実施例２３８－２５２：
　対応する原料化合物を用いて実施例２３７に準じた方法で反応・処理し、表１４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000055
実施例２４１の1H-NMR (DMSO-d6) δ: 3.18-3.23 (m, 2H), 3.37-3.42 (m, 2H), 6.58 (br, 1H), 7.19-7.24 (m, 3H), 7.35-7.48 (m, 5H).
実施例２４４の1H-NMR (CDCl3) δ: 3.25-3.36 (m, 4H), 4.96 (br, 1H), 7.01-7.15 (m, 3H), 7.19 (dd, 1H), 7.29-7.32 (m, 1H), 7.36-7.41 (m, 2H).
実施例２５３－２５７：
　対応する原料化合物を用いて実施例１に準じた方法で反応・処理し、表１５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000056
実施例２５６の1H-NMR (CDCl3) δ: 2.14 (s, 3H), 3.60 (s, 2H), 7.14-7.18 (m, 1H), 7.22-7.28 (m, 2H), 7.30-7.32 (m, 1H), 7.36-7.45 (m, 4H), 7.49 (br, 1H), 8.03 (br, 1H).
実施例ａ－ｂ：
　対応する原料化合物を用いて実施例１７８に準じた方法で反応・処理し、表１６に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000057
実施例ｃ－ｓ：
　対応する原料化合物を用いて実施例２００に準じた方法で反応・処理し、表１７に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
実施例ｆの1H-NMR (CDCl3) δ: 3.52 (s, 2H), 5.31 (br, 1H), 5.42 (br, 1H), 7.26-7.28 (m, 1H), 7.39-7.47 (m, 3H), 7.70 (s, 1H), 8.47 (s, 1H), 8.60 (s, 1H).
実施例ｈの1H-NMR (CDCl3) δ: 3.50 (s, 2H), 5.33 (br, 1H), 5.43 (br, 1H), 7.28-7.31 (m, 1H), 7.41-7.50 (m, 3H), 7.95-7.96 (m, 1H), 8.80 (d, 1H), 8.91 (d, 1H).
実施例ｋの1H-NMR (CDCl3) δ: 3.50 (d, 2H), 5.41 (br, 1H), 5.55 (br, 1H), 7.12 (d, 1H), 7.19-7.25 (m, 1H), 7.38-7.43 (m, 1H), 7.77 (d, 1H), 8.05 (dd, 1H), 8.74 (d, 1H).
実施例ｑの1H-NMR (CDCl3) δ: 3.52 (s, 2H), 5.45 (br, 1H), 5.52 (br, 1H), 7.10 (d, 1H), 7.19 (dd, 1H), 7.38 (dd, 1H), 7.82 (s, 1H), 8.51 (s, 1H), 8.62 (s, 1H).
実施例ｒの1H-NMR (CDCl3) δ: 3.52 (d, 2H), 5.51 (br, 2H), 7.11 (d, 1H), 7.19 (dd, 1H), 7.36-7.41 (m, 1H), 7.57-7.61 (m, 1H), 8.44 (s, 1H), 8.52 (d, 1H).
実施例ｔ：
　２－ヒドロキシ－２－｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトアミド
Figure JPOXMLDOC01-appb-C000060
 　メチル ヒドロキシ｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセテート（８６５ｍｇ）を７Ｍ アンモニア メタノール溶液に溶解し、封管中８０℃加熱下で一晩攪拌した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１９）で精製し、２－ヒドロキシ－２－｛２－[６－（トリフルオロメチル）ピリジン－３－イル]フェニル｝アセトアミド（６５４ｍｇ）を白色結晶として得た。
1H-NMR (CDCl3) δ: 3.35 (d, 1H), 5.05 (d, 1H), 5.58 (br, 1H), 6.28 (br, 1H), 7.31 (dd, 1H), 7.46‐7.59 (m, 3H), 7.77 (d, 1H), 8.20 (dd, 1H), 8.78 (s, 1H).
MS (m/z) 297 (MH+), Rt = 3.59 min.＊
実施例ｕ：
　対応する原料化合物を用いて実施例ｔに準じた方法で反応・処理し、表１８に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000061
　さらに、対応する原料化合物を用いて上記製造法１～５に準じた方法で反応・処理し、下記に示す化合物を製造することができる。
Figure JPOXMLDOC01-appb-C000062
試験例
　以下に、本発明の代表的化合物の薬理試験結果を示し、該化合物についての薬理作用を説明するが、本発明はこれらの試験例に限定されるものではない。
　抗てんかん薬の評価には、代表的に臨床予測性の高い最大電撃痙攣モデル（ＭＥＳ）評価、皮下注射ペンテトラゾールモデル（最小痙攣モデル、ｓｃＰＴＺ）評価及びラット扁桃核キンドリングモデル評価が用いられる。これらのモデルにおいて抗痙攣作用を示す化合物は、臨床において抗てんかん薬として期待される。また、ＭＥＳ評価とｓｃＰＴＺ評価いずれにおいても抗痙攣作用を示す化合物は、バルプロ酸様の広域スペクトル、すなわち部分発作及び全般発作に対して幅広く有効性を示すことが期待され、臨床上有用な治療薬となり得る。
試験例１：最大電撃痙攣モデル（ＭＥＳ）評価
　本試験は、薬物の抗痙攣作用を評価する試験である。この試験で用いる動物モデルは、全般性強直間代発作や二次性全般化部分発作の表現系である。Ｓｌｃ：ｄｄＹ系雄性マウス（一群３匹、体重２０～３０ｇ）に被験化合物５０ｍｇ／ｋｇ又は１００ｍｇ／ｋｇを経口投与し、１時間後に角膜より電気刺激（６０Ｈｚ，２５ｍＡ，０．２秒間）を与え、誘発される後肢の強直性伸展痙攣の発現抑制を観察した。なお、コントロールは０．５％トラガント液、０．５％メチルセルロース液又は、オリーブオイルを投与した。３匹中、痙攣の発現抑制を示した匹数が、３匹のときは「Ａ」、２匹のときは「Ｂ」および１匹以下のときは「Ｃ」で表した。結果を以下の表１９に示す。
試験例２：皮下注射ペンテトラゾールモデル（ｓｃＰＴＺ）評価
　本試験は、試験例１と同様に薬物の抗痙攣作用を評価する試験である。この試験で用いる動物モデルは、試験例１の表現系とは異なり、全般性の欠神発作やミオクロニー発作の表現系である。Ｓｌｃ：ｄｄＹ系雄性マウス（一群３匹、体重２０～３０ｇ）に被験化合物５０ｍｇ／ｋｇ又は１００ｍｇ／ｋｇを経口投与し、１時間後にペンテトラゾール８５ｍｇ／ｋｇを皮下投与した。その後、３０分間における間代性痙攣の発現の有無を観察した。なお、コントロールは０．５％トラガント液、０．５％メチルセルロース液又は、オリーブオイルを投与した。３匹中、痙攣の発現抑制を示した匹数が、３匹のときは「Ａ」、２匹のときは「Ｂ」および１匹以下のときは「Ｃ」で表した。１００ｍｇ／ｋｇを経口投与した結果を以下の表１９に示す。
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
　表１９に示すように、本発明の化合物は経口投与で最大電撃痙攣モデル（ＭＥＳ）評価及び／又は皮下注射ペンテトラゾールモデル（最小痙攣モデル、ｓｃＰＴＺ）評価において抗痙攣作用を示した。実施例３６、１１７、１８１，１９２、２０８、２１５、２４１、２４４、ｆ、ｈ、ｋ及びｒの化合物は、両評価において強い抗痙攣作用を示した。
試験例３：ラット扁桃核キンドリングモデル評価
　本試験は、マウスに加え、ラットにおける薬物の抗痙攣作用を評価する試験である。この試験で用いる動物モデル（キンドリングモデル）は、焦点性の単純部分発作、複雑部分発作及び二次性全般化部分発作の臨床所見に類似するモデルであり、極めて臨床予測性が高いことが知られている。Ｓｌｃ：Ｗｉｓｔａｒ系雄性ラット（体重２５０～３００ｇ）の大脳皮質（前、後）ならびに扁桃核に慢性電極を留置し、術後１週間目より扁桃核へ１日１回、２週間前後にわたり電気刺激（５０Ｈｚ，４００μＡ，１秒）を与えた。刺激条件は、Ｌｏｓｃｈｅｒらの方法［Epilepsy Res., 40: 63-77 (2000)］に従った。また、Ｒａｃｉｎｅらの方法［Motor seizure. Electroenceph. Clin. Neurophysiol., 32: 281-294 (1972)］に基づいた発作重症度においてｓｔａｇｅ ５の発作が連続１０回発現するまで刺激を継続し、キンドリングモデルを完成させた。完成したモデルに、試験化合物を各々１００ｍｇ／ｋｇで経口投与し、投与１時間後に、発作が誘発される閾値刺激電流（発作閾値）、脳波上に認められる後発射の持続時間（後発射時間）及び発作重症度（ｓｔａｇｅ ｓｃｏｒｅ １～５）を指標に評価した。発作閾値ならびに後発射時間は試験化合物投与前の各値に対する変化率を平均で表した。なお、コントロールは０．５％トラガント液を投与した。結果を表２０に示す。マイナスは減少あるいは短縮を意味する。
Figure JPOXMLDOC01-appb-T000066
　表２０に示すように、実施例１１７の化合物は１００ｍｇ／ｋｇの経口投与でラット扁桃核キンドリングモデルの発作誘発閾値を著しく上昇させ、誘発された発作の重症度を低下させた。このように実施例１１７の化合物はラット扁桃核キンドリングモデルに対して高い有効性を示した。
　以上で説明したように、本発明のアミド誘導体は、抗てんかん薬の代表的評価モデルである最大電撃痙攣モデル（ＭＥＳ）評価、皮下注射ペンテトラゾールモデル（ｓｃＰＴＺ）評価及び／又はラット扁桃核キンドリングモデル評価において強い抗痙攣作用を示す。したがって、本発明の化合物は抗てんかん薬（例えば、単純部分発作、複雑部分発作及び意識消失を伴う持続的な二次性全般化発作を含む部分発作、欠神発作、ミオクロニー発作、間代発作、強直発作、強直間代発作、脱力発作、ウェスト症候群及びレノックス－ガストー症候群等の全般発作に対する予防薬及び／又は治療薬）として有用である。

Claims (20)

  1. 　下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　Ａ環及びＢ環は、それぞれ独立して、アリール環、ヘテロアリール環、３～８員の飽和炭素環、３～８員の部分不飽和炭素環又は４～１０員の飽和複素環を表し、
    　Ｌは、結合、置換されていてもよい直鎖のＣ１－６アルキレン、置換されていてもよいＣ２－６アルケニレン、－Ｌ１－Ｏ－Ｌ２－、－Ｌ１－ＮＲ６－Ｌ２－、－Ｌ１－ＣＯＮＲ６－Ｌ２－、－Ｌ１－ＮＲ６ＣＯ－Ｌ２－又は－Ｌ１－Ｓ（Ｏ）ｎ－Ｌ２－を表し、
    　Ｌ１及びＬ２は、それぞれ独立して、結合又は置換されていてもよい直鎖のＣ１－６アルキレンを表し、
    　Ａｌｋは、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンを表し、
    　Ｘは、－ＣＯＮＲ７Ｒ８、－ＳＯ２ＮＲ７Ｒ８、－ＮＲ７ＣＯＲ８、－ＳＯ２Ｒ７、－ＣＯＮＲ７ＣＯＲ８、－ＣＯＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＮＲ８ＣＯＲ９、－ＮＲ７ＣＯＮＲ８Ｒ９、－ＮＲ７ＣＯＯＲ８、－ＣＯＮＲ７ＣＯＯＲ８又は－ＣＯＮＲ７ＣＯＮＲ８ＣＯＲ９を表し、
    　Ｒ１、Ｒ２及びＲ３は、それらが結合するＡ環上の置換可能な任意の原子に結合し、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１０Ｒ１１、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－又はシアノを表し、該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよく、
    　Ｒ４及びＲ５は、それらが結合するＢ環上の置換可能な任意の原子に結合し、それぞれ独立して、水素原子、ハロゲン、ニトロ、－ＣＯＮＲ１２Ｒ１３、Ｃ１－６アルキル、Ｃ１－６アルコキシ、Ｃ１－６アルキル－Ｓ（Ｏ）ｍ－、又はシアノを表し、該アルキル、アルコキシ又はアルキル－Ｓ（Ｏ）ｍ－は、１～５個のフッ素原子で置換されていてもよく、
    　Ｒ６、Ｒ７、Ｒ８及びＲ９は、それぞれ独立して、水素原子、Ｃ１－６アルキル、ヒドロキシメチル、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリールを表し、該アルキル、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよく、
    　ここにおいて、Ｒ７、Ｒ８及びＲ９が、水素原子、Ｃ１－６アルキル又はヒドロキシメチルのとき、ＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれか１つの組み合わせにおいて、それぞれの基が結合して、置換されていてもよい４～１０員の飽和複素環を形成していてもよく、
    　Ｒ１０、Ｒ１１、Ｒ１２及びＲ１３は、それぞれ独立して、水素原子、Ｃ１－６アルキル、Ｃ３－７シクロアルキル－Ｃ１－３アルキル、Ｃ３－７シクロアルキル又はアリールを表し、該アルキル、シクロアルキル－アルキル及びシクロアルキルは、１～５個のフッ素原子で置換されていてもよく、
    　ｎ及びｍは、それぞれ独立して、０～２の整数を表すが、
    　但し、Ｌが結合であり、Ａ及びＢが共にベンゼン環であり、Ｘが－ＣＯＮＲ７Ｒ８であるとき、
    　Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置は、１，３－若しくは１，４－置換であるか、又は、
    　Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が１，２－置換である場合は、Ａｌｋが置換されていてもよい直鎖のＣ２－６アルキレンもしくは置換されていてもよいＣ２－６アルケニレン、またはアミノもしくはＣ１－６アシルアミノで置換されたメチレンであるか、あるいはＡｌｋとＲ７、ＡｌｋとＲ８、ＡｌｋとＲ９、Ｒ７とＲ８、Ｒ７とＲ９及びＲ８とＲ９のいずれか１つの組み合わせにおいて、上記のように置換されていてもよい４～１０員の飽和複素環が形成される］
    で表される化合物又はそれらの製薬学的に許容される塩。
  2. 　置換されていてもよい直鎖のアルキレン及び置換されていてもよいアルケニレンが、それぞれ独立して、Ｃ１－６アルキル、オキソ、水酸基、アミノ、Ｃ１－６アシルアミノ、Ｃ１－６アルコキシ又はフッ素からなる群から選択される１～５個の置換基で置換されていてもよい基である、
    請求項１に記載の化合物又はそれらの製薬学的に許容される塩。
  3. 　Ａ環及びＢ環が、それぞれ独立して、アリール環又はヘテロアリール環である、
    請求項１又は２に記載の化合物又はそれらの製薬学的に許容される塩。
  4. 　Ａ環及びＢ環が、それぞれ独立して、ベンゼン環、チアゾール環、ピリジン環、ピリミジン環又はチオフェン環である、
    請求項１又は２に記載の化合物又はそれらの製薬学的に許容される塩。
  5. 　Ｌが、結合、置換されていてもよい直鎖のＣ１－６アルキレン又は置換されていてもよいＣ２－６アルケニレンである、
    請求項１～４のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  6. 　Ａｌｋが、結合又は置換されていてもよい直鎖のＣ１－４アルキレンである、
    請求項１～５のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  7. 　Ａｌｋが、結合、Ｃ１－４アルキル、水酸基、Ｃ１－４アルコキシ及びフッ素原子からなる群から選択される１個の置換基で置換されていてもよいメチレンである、
    請求項６に記載の化合物又はそれらの製薬学的に許容される塩。
  8. 　Ａｌｋが、結合、メチル、水酸基、メトキシ及びフッ素原子からなる群から選択される１個の置換基で置換されていてもよいメチレンである、
    請求項６に記載の化合物又はそれらの製薬学的に許容される塩。
  9. 　Ｘが、－ＣＯＮＲ７Ｒ８又は－ＳＯ２ＮＲ７Ｒ８である、
    請求項１～８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  10. 　Ｒ１、Ｒ２及びＲ３が、同一又は異なって、水素原子、ハロゲン、１～５個のフッ素原子で置換されていてよいＣ１－６アルキル又はＣ１－６アルコキシである、
    請求項１～９のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  11. 　Ｒ４及びＲ５が、それぞれ独立して、水素原子、ハロゲン又はＣ１－６アルコキシである、
    請求項１～１０のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  12. 　Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２及びＲ１３が、それぞれ独立して、水素原子又はＣ１－６アルキルである、
    請求項１～１１のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  13. 　Ａ環及びＢ環が、共にベンゼン環であり、Ｌが結合であり、Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が、１，２－置換であり、Ａｌｋが、結合であり、Ｘが、－ＳＯ２ＮＲ７Ｒ８であり、ここにおいて、Ｒ１～Ｒ５及びＲ７が、すべて水素原子であるとき、Ｒ８がＣ３－６アルキルである、
    請求項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  14. 　Ａ環がピリジン環、Ｂ環がベンゼン環、Ｌが結合であり、Ａｌｋが、無置換或いは、水酸基で置換されていてもよいメチレンであり、Ｘが、－ＣＯＮＲ７Ｒ８であり、Ｌ及び－Ａｌｋ－ＸのＢ環上の置換位置が、１，２－置換である、
    請求項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  15. 　Ａ環及びＢ環が、共にアリール環であり、Ｌが結合であり、Ａｌｋ－Ｘが、
    Figure JPOXMLDOC01-appb-C000002
     のいずれかで表される基であり、ここにおいて、形成する飽和複素環が（ｉｉｉ）であり、Ｒ８が水素原子であるとき、Ｒ１～Ｒ５のいずれか１つが水素原子以外の基である、
    請求項１～１２のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩。
  16. 　Ａｌｋ－Ｘが、請求項１５の（ｉ）、（ｉｉ）又は（ｉｉｉ）である、
    請求項１～１３のいずれか一項に記載の化合物。
  17. 　請求項１～１６のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩、及び医薬的に許容される担体を含有する医薬組成物。
  18. 　請求項１～１６のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とする抗てんかん薬。
  19. 　請求項１～１６のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とする双極性障害に対する気分安定化薬。
  20. 　抗てんかん薬を製造するための請求項１～１６のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩の使用。
PCT/JP2011/061473 2010-05-19 2011-05-19 アミド誘導体 WO2011145669A1 (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010115010 2010-05-19
JP2010-115010 2010-05-19

Publications (1)

Publication Number Publication Date
WO2011145669A1 true WO2011145669A1 (ja) 2011-11-24

Family

ID=44991762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/061473 WO2011145669A1 (ja) 2010-05-19 2011-05-19 アミド誘導体

Country Status (1)

Country Link
WO (1) WO2011145669A1 (ja)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015527345A (ja) * 2012-08-07 2015-09-17 バジリア ファルマスーチカ アーゲーＢａｓｉｌｅａ Ｐｈａｒｍａｃｅｕｔｉｃａ ＡＧ イサブコナゾールまたはラブコナゾールの製造方法
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10604476B2 (en) 2015-10-30 2020-03-31 Trillium Therapeutics Inc. Fluorinated amide derivatives and their uses as therapeutic agents
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11292782B2 (en) 2018-11-30 2022-04-05 Nuvation Bio Inc. Diarylhydantoin compounds and methods of use thereof
US11883381B2 (en) * 2016-05-12 2024-01-30 The Regents Of The University Of Michigan ASH1L inhibitors and methods of treatment therewith
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof
EP4172149A4 (en) * 2020-06-29 2024-09-04 Bacainn Biotherapeutics Ltd PROBENECID COMPOUNDS FOR THE TREATMENT OF INFLAMMASOME-MEDIATED LUNG DISEASE

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000001431A (ja) * 1998-06-15 2000-01-07 Kotobuki Seiyaku Kk 尿酸排泄剤
JP2002520372A (ja) * 1998-07-15 2002-07-09 ジーピーシー バイオテック インコーポレーテッド 真菌の増殖を阻害するための組成物および方法
JP2003231635A (ja) * 2002-02-06 2003-08-19 Tanabe Seiyaku Co Ltd 医薬組成物
JP2004517831A (ja) * 2000-12-01 2004-06-17 ギルフォード ファーマシューティカルズ インコーポレイテッド 化合物およびその使用
JP2004529131A (ja) * 2001-03-22 2004-09-24 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト Δ１ピロリン
JP2008523059A (ja) * 2004-12-13 2008-07-03 シェーリング コーポレイション 複素環式アスパルチルプロテアーゼインヒビター
WO2009055917A1 (en) * 2007-11-02 2009-05-07 Methylgene Inc. Inhibitors of histone deacetylase

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000001431A (ja) * 1998-06-15 2000-01-07 Kotobuki Seiyaku Kk 尿酸排泄剤
JP2002520372A (ja) * 1998-07-15 2002-07-09 ジーピーシー バイオテック インコーポレーテッド 真菌の増殖を阻害するための組成物および方法
JP2004517831A (ja) * 2000-12-01 2004-06-17 ギルフォード ファーマシューティカルズ インコーポレイテッド 化合物およびその使用
JP2004529131A (ja) * 2001-03-22 2004-09-24 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト Δ１ピロリン
JP2003231635A (ja) * 2002-02-06 2003-08-19 Tanabe Seiyaku Co Ltd 医薬組成物
JP2008523059A (ja) * 2004-12-13 2008-07-03 シェーリング コーポレイション 複素環式アスパルチルプロテアーゼインヒビター
WO2009055917A1 (en) * 2007-11-02 2009-05-07 Methylgene Inc. Inhibitors of histone deacetylase

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DIPANNITA KALYANI ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, no. 20, 2005, pages 7330 - 7331 *
IOU-JIUN KANG ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 21, 2009, pages 6063 - 6068 *
NICHOLAS R. DEPREZ ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 31, 2009, pages 11234 - 11241 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
JP2015527345A (ja) * 2012-08-07 2015-09-17 バジリア ファルマスーチカ アーゲーＢａｓｉｌｅａ Ｐｈａｒｍａｃｅｕｔｉｃａ ＡＧ イサブコナゾールまたはラブコナゾールの製造方法
US10590092B2 (en) 2012-08-07 2020-03-17 Basilea Pharmaceutica Ag Process for the manufacture of isavuconazole or ravuconazole
US10604476B2 (en) 2015-10-30 2020-03-31 Trillium Therapeutics Inc. Fluorinated amide derivatives and their uses as therapeutic agents
US11883381B2 (en) * 2016-05-12 2024-01-30 The Regents Of The University Of Michigan ASH1L inhibitors and methods of treatment therewith
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11292782B2 (en) 2018-11-30 2022-04-05 Nuvation Bio Inc. Diarylhydantoin compounds and methods of use thereof
EP4172149A4 (en) * 2020-06-29 2024-09-04 Bacainn Biotherapeutics Ltd PROBENECID COMPOUNDS FOR THE TREATMENT OF INFLAMMASOME-MEDIATED LUNG DISEASE

Similar Documents

Publication Publication Date Title
WO2011145669A1 (ja) アミド誘導体
JP5362565B2 (ja) オピオイド受容体のアンタゴニストまたはインバースアゴニストである新規化合物
CN100369894C (zh) 氧化氮合酶抑制剂磷酸盐
KR100863924B1 (ko) 헤테로아릴설포닐 측쇄를 갖는 안트라닐산 아미드 및 당해 화합물을 함유하는 약제학적 제제
TWI409247B (zh) ４-取代之苯氧基苯基乙酸衍生物
AU725403B2 (en) Thrombin inhibitors
US20040014796A1 (en) Novel compounds and compositions as cathepsin S inhititors
IL145430A (en) N-cyanomethyl-rich, processes for their preparation and pharmaceutical preparations containing them
JP2006518341A (ja) ヒストンデアセチラーゼ（ｈｄａｃ）阻害剤としてのヒドロキサム酸誘導体
CZ183399A3 (cs) Benzamidoaldehydy a jejich použití
WO2005065195A2 (en) Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease
JP2009501236A (ja) ヒストンデアセチラーゼ阻害剤
CN105884767B (zh) 9‑位取代的吡啶并[3,4‑b]吲哚衍生物及其制备方法和作为SIRT蛋白抑制剂的用途
CN110357789B (zh) 作为dhodh抑制剂的n-取代丙烯酰胺衍生物及其制备和用途
NZ260816A (en) N-substituted,2-substituted-2-propen(thio)amide; 4-pyrazolyl-, 4-imidazolyl-propenoic acid intermediates
EA026942B1 (ru) Производные n-проп-2-инилкарбоксамида и их применение в качестве антагонистов trpa1
US20100113512A1 (en) Method of treatment using novel antagonists or inverse agonists at opioid receptors
WO2006042103A2 (en) Reversible inhibitors of cathepsin b
DE60011110T2 (de) Pharmazeutisch wirksame sulfonyl hydrazid-derivate
JPWO2009041559A1 (ja) インダゾールアクリル酸アミド化合物
JP2000063363A (ja) 新規なトリアゾール誘導体
JP6758374B2 (ja) Ｉｄｈ２突然変異を標的とする抗腫瘍化合物及びその使用方法
JPH0662567B2 (ja) ピリジンカルボキシイミダミド誘導体、その製造中間体、製造法および用途
JP2002533338A (ja) 非ペプチドｎｋ１レセプターアンタゴニスト
AU2004276128A1 (en) Amide-type carboxamide derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11783603

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11783603

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP