WO2009096526A1 - Carboxylic acid compound or salt thereof - Google Patents

Carboxylic acid compound or salt thereof Download PDF

Info

Publication number
WO2009096526A1
WO2009096526A1 PCT/JP2009/051587 JP2009051587W WO2009096526A1 WO 2009096526 A1 WO2009096526 A1 WO 2009096526A1 JP 2009051587 W JP2009051587 W JP 2009051587W WO 2009096526 A1 WO2009096526 A1 WO 2009096526A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
salt
amino
compound
Prior art date
Application number
PCT/JP2009/051587
Other languages
French (fr)
Japanese (ja)
Inventor
Tadashi Terasaka
Hiroshi Matsuda
Shinji Ito
Mamoru Tasaki
Original Assignee
Astellas Pharma Inc.
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 Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Publication of WO2009096526A1 publication Critical patent/WO2009096526A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
    • 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
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—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 a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • 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
    • C07D215/16—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 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
    • C07D215/48—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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—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
    • 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
    • C07D233/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • 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
    • C07D239/28—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring 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
    • 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
    • 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
    • C07D277/68—Benzothiazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • 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
    • 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
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a carboxylic acid compound or a salt thereof useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating inflammatory diseases or multiple sclerosis.
  • Mast cells known as conductor cells for allergic inflammation are bound to antigen-specific IgE via Fc epsilon RI on the cell surface. Mast cells are activated when antigens that have entered the body bind to specific IgE on the cell surface, producing various inflammatory mediators and inducing allergic inflammation (Current Opinion in Immunology, 2002, 14 (6), p.688-693).
  • Prostaglandin D 2 is the major prostanoid produced by activated mast cells. In the airways of asthmatic patients, a significant increase in PGD2 production has been observed within a few minutes due to antigen exposure (New England Journal of Medicine, 1986, 315 (13), p. 800-804, American Review of Respiratory). Disesease, 1983, 128 (4), p. 597-602) and reports that PGD2 production in the inflamed area is enhanced when an antigen is exposed to the nasal mucosa of allergic rhinitis patients or the skin of atopic dermatitis patients (Journal of Immunology, 1991, 146 (2), p. 671-676).
  • DP D type prostanoid receptor
  • GPCR G protein coupled receptors
  • CRTH2 chemotractant receptor-homologoous molecular expressed on Th2 cells
  • CRTH2 is a Gs-coupled GPCR that increases cAMP and DP is a Gi-coupled GPCR that inhibits cAMP increase
  • the intracellular signal transduction system is different and has different functions.
  • CRTH2 functions include cell migration activation (Th2 cells, eosinophils, basophils), adhesion molecule expression promotion (Th2 cells, eosinophils) Sphere), Th2 cytokine production promotion (Th2 cells) and the like have been reported.
  • DP platelet aggregation suppression, vasodilation, smooth muscle relaxation, cell migration suppression (DP-expressing cells, eosinophils, dendritic cells), eosinophil apoptosis induction, sleep induction and the like have been reported.
  • PGD2 is thought to promote local allergic inflammation by inducing inflammatory cell infiltration and activation by the action of CRTH2, while inducing local vasodilation and enhancing vascular permeability by the action of DP.
  • PGD2 which is the main prostanoid produced by mast cells activated by antigen stimulation, activates inflammatory cells such as Th2 cells and eosinophils via CRTH2 and promotes migration to the inflammatory site. Furthermore, it is considered that the TH2 cytokine production from Th2 cells is promoted to play a central role in allergic inflammation, and CRTH2 antagonists are eagerly developed as therapeutic agents for allergic inflammation.
  • Patent Document 2 W in (B) is O, S (O) n (n is 0, 1, 2), NR 13 , CR 1 OR 2 , CR 1 R 2 ,
  • L in (C) is CR 6 R 7 , CO, CNR 6 , CS,
  • Patent Document 4 it is indicated that A in (D) is a 5- to 14-membered heterocyclic ring condensed or bonded to B, respectively.
  • Patent document 5 was published after the priority date of this application.
  • the inventors have developed inflammatory diseases based on CRTH2 antagonism (eg, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis, Studies have been conducted for the purpose of providing a pharmaceutical composition useful for the prevention and / or treatment of chronic obstructive pulmonary disease and the like, or multiple sclerosis, and further providing a medicament containing them.
  • CRTH2 antagonism eg, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis.
  • this invention relates to the pharmaceutical composition containing the compound or its salt of a formula (I), or its salt, and an excipient
  • R 1 is — (C 1-6 alkylene) —COOH or —H; 1) When R 1 is — (C 1-6 alkylene) —COOH, R 2 is halogen or —H, R 3 is halogen, C 1-6 alkyl, —O— (C 1-6 alkyl), or —H, 2) When R 1 is -H, R 2 and R 3 together form a benzene ring to which they are bonded together with formula (II)
  • R 4 is halogen or —H, Provided that when R 3 is —H, R 4 is halogen, R 5 is —H, halogen, or C 1-6 alkyl, R 6 is aryl, heteroaryl, heterocycloalkyl, or —N (R 6a ) (R 6b ), each optionally substituted with the same or different groups represented by R XA ; R XA represents
  • the present invention also provides a pharmaceutical composition for the treatment of inflammatory diseases or multiple sclerosis comprising a compound of formula (I) or a salt thereof, ie, an inflammatory disease comprising a compound of formula (I) or a salt thereof. Or it relates to a therapeutic agent for multiple sclerosis.
  • the present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of inflammatory diseases or multiple sclerosis, and an effective amount of a compound of formula (I) or a salt thereof.
  • the present invention relates to a method for treating inflammatory diseases or multiple sclerosis comprising administering to a patient.
  • the compound of formula (I) or a salt thereof has CRTH2 antagonism and has an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like) or multiple sclerosis and the like.
  • an inflammatory disease for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like
  • multiple sclerosis for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like
  • Halogen is F, Cl, Br, or I. In another embodiment, F or Cl.
  • C 1-6 alkyl is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C 1-4 alkyl. Yet another embodiment is methyl or ethyl.
  • Halo C 1-6 alkyl substituted with one or more halogen, C 1-6 alkyl. Another embodiment is C 1-6 alkyl substituted with 1 to 5 halogens, and another embodiment is —CF 3 , —CF 2 H, —CFH 2 or —CH 2 CH 2 F. is there.
  • C 1-6 alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene or the like. Another embodiment is C 1-4 alkylene. Yet another embodiment is methylene or ethylene.
  • C 2-6 alkenylene is a linear or branched alkenylene having 2 to 6 carbon atoms, and examples thereof include vinylene, propylene, butenylene, pentenylene, hexenylene and the like. Another embodiment is C 2-4 alkenylene.
  • Aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, for example, phenyl or naphthyl, and in another embodiment, phenyl.
  • Heteroaryl means a 5- or 6-membered aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which includes a cyclopentane ring or It may be condensed with a benzene ring.
  • Another embodiment is a 5- or 6-membered aromatic heterocycle optionally condensed with a benzene ring, and other embodiments include thienyl, triazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl. , Benzothiazolyl, benzimidazolyl, imidazopyridinyl, isoquinolyl, quinolyl and the like. Another embodiment is indolyl.
  • Heterocycloalkyl means a 5- to 7-membered non-aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are partially May have an unsaturated bond and may be condensed with a benzene ring.
  • Other embodiments include piperidinyl, isoindanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 2,3,4,5-tetrahydro-1H-3-benzoazepinyl and the like.
  • Another embodiment is a 5- to 7-membered non-aromatic hetero ring optionally condensed with a benzene ring, and yet another embodiment is tetrahydroisoquinolyl.
  • Cyclic amino means “heterocycloalkyl” which is monocyclic to tricyclic having at least one nitrogen atom among the above “heterocycloalkyl”. It may have a partially unsaturated bond.
  • Another embodiment is a ring having 4 to 9 ring members, and another embodiment includes pyrrolidinyl, piperidyl, morpholinyl, or homopiperidyl.
  • optionally substituted means unsubstituted or having 1 to 6 substituents, and in another aspect, having 1 to 5 substituents. Means that. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
  • substituted means having 1 to 6 substituents, and in another aspect, having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
  • R XA is R XB
  • R XC is R XB
  • R XB is halogen, C 1-6 alkyl, halo C 1-6 alkyl, —O— (C 1-6 alkyl), —O— (halo C 1-6 alkyl), —S— (C 1-6 Alkyl), —N (C 1-6 alkyl) 2 , aryl, aryl substituted with —O— (C 1-6 alkyl), or aryl substituted with —N (C 1-6 alkyl) 2
  • Indicate R XC is Cl, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —SCH 3 , —N (CH 3 ) 2 , phenyl, phenyl substituted with —OCH 3 , or —N ( CH 3) a phenyl which is substituted by two.
  • a compound of formula (I) wherein R 1 is — (C 1-6 alkylene) —COOH.
  • compounds of formula (I) wherein R 1 is —CH 2 —COOH.
  • the compound of formula (I), wherein R 1 is —H.
  • R 2 is —H.
  • R 3 is halogen, C 1-6 alkyl, or —O— (C 1-6 alkyl).
  • compounds of formula (I), wherein R 3 is halogen.
  • the compound of formula (I), wherein R 3 is F, Br, or Cl.
  • compounds of formula (I), wherein R 6 is phenyl optionally substituted with the same or different R XA In another embodiment, compounds of formula (I), wherein R 6 is phenyl optionally substituted with the same or different R XB .
  • R 6 are identical or different from each other R XB aryl which may be substituted, respectively, a group represented by heteroaryl, heterocycloalkyl or -N, (R 6a) (R 6b), wherein A compound of [I] or a salt thereof.
  • R 3 is halogen, C 1-6 alkyl, or —O—C 1-6 alkyl, The compound or a salt thereof according to [2], wherein R 4 is —H.
  • E is a bond.
  • R 6 is phenyl optionally substituted with the same or different groups represented by R XB .
  • R 6 is phenyl optionally substituted with the same or different groups represented by R XC .
  • R XC is halogen.
  • R 6 is phenyl optionally substituted with the same or different groups represented by R XC .
  • Y is —CH ⁇ or —CF ⁇ .
  • R 1 is —H.
  • Examples of specific compounds included in the present invention include the following compounds or salts thereof. (3-chloro-4- ⁇ 4-[(3,4-dichlorobenzoyl) amino] phenoxy ⁇ phenyl) acetic acid, (4- ⁇ 4-[(1-benzofuran-2-ylcarbonyl) amino] foxy ⁇ -3-chlorophenyl) acetic acid, [3-chloro-4-( ⁇ 4-[(3,4-dichlorobenzoyl) amino] phenyl ⁇ sulfanyl) phenyl] acetic acid, (3-chloro-4- ⁇ 4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy ⁇ phenyl) acetic acid, [4- (4- ⁇ [(2E) -3- (3,4-dichlorophenyl) prop-2-enoyl] amino ⁇ phenoxy) -2-methyl-1H-benzimi
  • tautomers and geometric isomers may exist depending on the type of substituent.
  • the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
  • the compound of the formula (I) may have an asymmetric carbon atom, and optical isomers based on this may exist.
  • the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med. , 5, p. 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the kind of the substituent. is there.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium
  • the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case.
  • protecting groups include, for example, “Green's Protective Groups in Organic Synthesis (4th edition, 2006)” by P. G. M. Wuts and Green (TW Green). The protecting groups described can be mentioned, and may be appropriately selected and used according to these reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
  • the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of formula (I).
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • Compounds of formula (I) can be prepared by deprotecting the protected carboxylic acid.
  • the deprotection can be produced by hydrolysis, hydrogenolysis or catalytic deprotection.
  • an inorganic base NaOH, KOH, NaHCO 3 , Cs 2 CO 3 or the like
  • hydrochloric acid or the like can be used.
  • the reaction can be carried out under conditions where the reaction temperature is from ice-cooling to reflux conditions and the substrate is not decomposed.
  • an organic solvent such as alcohol (MeOH, EtOH, etc.), DMF or DMSO, water, or a mixed solvent thereof can be used.
  • the reaction can usually be carried out in a hydrogen atmosphere in the presence of a palladium catalyst. It can be produced at a reaction temperature from room temperature to reflux in a solvent such as DMF or MeOH. In the case of catalytic deprotection, it can be produced under basic conditions using a catalyst such as palladium.
  • R 1 ′, R 2 ′ and R 3 ′ each represent a group in which a carboxy group in any of R 1 , R 2 and R 3 is protected.
  • Compound (2a) can be produced by reacting the amino group of compound (1) with the corresponding carboxylic acid (R 6 -E-COOH).
  • Carboxylic acid (R 6 -E-COOH) is (i) directly reacted with compound (1) in the presence of a condensing agent in the reaction system, and (ii) after being derivatized into a reactive derivative, There is a method of reacting with compound (1) (Step 1-1).
  • the compound (1) and the corresponding carboxylic acid are used in an equivalent amount or in excess, and the mixture is inactive in the presence of a condensing agent.
  • the mixture is stirred for 0.1 hour to 5 days under cooling to heating, preferably at -20 ° C to 60 ° C.
  • Examples of the solvent include, but are not limited to, aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (DCM, 1,2-dichloroethane, chloroform, etc.), ethers (diethyl ether, THF, dioxane and the like), DMF, DMSO, EtOAc, MeCN or water, and a mixed solvent thereof.
  • Examples of condensing agents include, but are not limited to, WSC, DCC, DPPA, phosphorus oxychloride. It may be preferable for the reaction to use an additive (eg, HOBt). It may be advantageous to carry out the reaction in the presence of an organic base (such as TEA, DIPEA or NMM) or an inorganic base (such as K 2 CO 3 or KOH) in order to facilitate the reaction.
  • an organic base such as TEA, DIPEA or NMM
  • an inorganic base such as K 2 CO 3 or KOH
  • a halogenating agent for example, oxychloride
  • Phosphoric acid, thionyl chloride, etc. acid halides obtained by reacting with them, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, etc., active esters obtained by condensation with HOBt, etc.
  • the reaction of the compound (1) with the reactive derivative is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., from cooling to heating, preferably from ⁇ 20 ° C.
  • Compound (2b) can be produced with the aid of the conditions of Step 1-1. That is, instead of using the carboxylic acid free acid or its reactive derivative as a reagent, the compound (2b) can be produced by using the free acid of sulfonic acid or its reactive derivative (Step 1-2).
  • Compound (2c) can be produced by reacting compound (1) with triphosgene or the like and HN (R 6a ) (R 6b ).
  • the reaction is usually performed in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.).
  • a base for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.
  • halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, MeCN, DMF, DMSO and other organic solvents inert to the reaction, or a mixed solvent thereof are used.
  • the reaction is carried out under cooling, from cooling to room temperature, or from room temperature to heating.
  • Compound (5) can be produced by coupling alcohol or thiol compound (3) and compound (4) (Step 2-1).
  • an inorganic base for example, NaOH, KOH, K 2 CO 3 , NaHCO 3 , Cs 2 CO 3, etc.
  • the reaction solvent is a halogenated hydrocarbon, aromatic hydrocarbon, ether, EtOAc, etc.
  • an organic solvent inert to the reaction such as MeCN, DMF or DMSO, or a mixed solvent thereof. The reaction is carried out from room temperature under heating.
  • Compound (1) can be produced by reducing the nitro group of compound (4) (Step 2-2).
  • a method for reducing an aromatic nitro group is used.
  • iron powder can be produced by reaction or catalytic reduction under hydrochloric acid conditions.
  • Example compounds and intermediates other than those described in the above-described production methods and intermediate production methods the production examples in this specification, the methods described in the Examples, or methods according thereto are used. Further, it can be produced by a known method or a method obvious to those skilled in the art.
  • some compounds represented by the formula (I) can be obtained from the compounds of the present invention produced as described above by known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection and the like. Can be produced by arbitrarily combining the processes that can normally be employed.
  • the compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances.
  • the salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • Test Example 1-2 CRTH2 Binding Experiment Membrane specimen (50 ⁇ g of protein used per assay), test compound and tritium-labeled PGD2 (final concentration: 2 nM) in 0.2 mL of assay buffer at 4 ° C. After 2 hours of incubation, the reaction solution was suction filtered onto a filter on a GF / B plate (PerkinElmer), washed 3 times with a washing buffer (10 mM BES, 0.01% BSA), and then the radiation adsorbed on the filter. Activity was measured with TopCount (PerkinElmer). CRTH2-specific binding was determined as a radioactive moiety that was inhibited when 10 ⁇ M DK-PGD2 was added.
  • Example compounds (Ex) which are the compounds of the present invention exhibited the following activity values (IC 50 values).
  • Ex1 9.1 nM
  • Ex6 11 nM
  • Ex18 14 nM
  • Ex30 2.9 nM
  • Ex34 10 nM
  • Ex35 5.6 nM
  • Ex37 4.8 nM
  • Ex43 9.9 nM
  • Ex55 4.1 nM
  • Ex56 8.7 nM
  • Ex94 4.8 nM
  • Ex109 Ex149: 4.9 nM
  • Ex140 0.53 nM
  • Ex151 1.0 nM
  • Ex152 20 nM.
  • Test Example 2 Guinea Pig Antigen-Induced Airway Reactivity Model
  • the anti-asthmatic action of the compound of the present invention is a slight modification to the method of Burgess et al. (Agents Actions, 1992, 37 (3-4), p. 162-164).
  • the guinea pig antigen-induced airway hyperresponsiveness model was evaluated. That is, 20 mg / mL ovalbumin (hereinafter referred to as OVA) physiological saline is intraperitoneally administered to male Hartley guinea pigs (first sensitization, referred to as Day 0), and further, 1 mg / mL in Day 2 Antigen sensitization was performed by intraperitoneally administering 1 mL of OVA physiological saline.
  • OVA ovalbumin
  • mice were inhaled by exposure to 0.5% OVA physiological saline once a day for 10 minutes (in the physiological saline control group, physiological saline was inhaled).
  • the test compound was orally administered 1 hour or 4 hours before the start of antigen inhalation exposure.
  • pyriramine was intraperitoneally administered at 10 mg / kg 30 minutes before the start of inhalation exposure.
  • a cannula connected to a ventilator (Model 683, Harvard) was inserted into the trachea of an animal under urethane (1.5 g / kg, intraperitoneal) anesthesia, and galamine (6 mg / kg, abdominal cavity). Self-breathing is stopped by methacolin (0, 2, 4, 6, 8, 10, 12, under mechanical ventilation (ventilation rate: 60 strokes per minute, ventilation: 1 mL per 100 g body weight)). 14 ⁇ g / kg) were sequentially administered intravenously at intervals of 3 minutes. The increase in airway pressure was measured with a pressure transducer, and the area under the concentration curve (AUC) when the mesacholine dose and the increase in airway pressure were plotted was calculated. As a result, among the compounds of the present invention, for example, the example compounds shown in the following table were found to exhibit effective activity.
  • the compound of the formula (I) has antagonist activity against CRTH2. Therefore, inflammatory diseases (eg asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis, chronic obstructive pulmonary disease etc.) or multiple It can be used to treat sclerosis.
  • inflammatory diseases eg asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis, chronic obstructive pulmonary disease etc.
  • multiple It can be used to treat sclerosis.
  • the production example compound in which the carboxylic acid of the example compound became an ester did not show activity.
  • the acidic proton of the carboxylic acid of the example compound in the present invention was found to be important for the expression of antagonist activity against CRTH2.
  • compositions containing one or more of the compounds of formula (I) or salts thereof as active ingredients are excipients commonly used in the art, that is, pharmaceutical excipients and drug-soluble carriers.
  • Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. .
  • tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • a transmucosal agent such as an inhalant or a nasal agent
  • a solid, liquid or semi-solid agent is used and can be produced according to a conventionally known method.
  • known excipients and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple administrations, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Yes, this is administered once or divided into 2 to 4 times.
  • the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once a day or in multiple doses.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once a day in a plurality of divided doses. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • the manufacturing method of the compound of Formula (I) is demonstrated in detail.
  • this invention is not limited to the compound as described in the following Example.
  • the manufacturing method of a raw material compound is shown in a manufacture example, respectively.
  • the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
  • the compound of Production Example 11-1 shown in the table below was produced in the same manner as in Production Example 11 using the corresponding raw materials.
  • Table 2 to Table 34 show the structures and physicochemical data of the production example compounds.
  • Example 1 To a solution of ethyl (3-chloro-4- ⁇ 4-[(3,4-dichlorobenzoyl) amino] phenoxy ⁇ phenyl) acetate (210 mg) in EtOH (4.2 mL) was added 2M NaOH aqueous solution (439 ⁇ L). And stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 3 to 4 by adding 1M hydrochloric acid, diluted with water, and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was triturated with IPE and dried to give (3-chloro-4- ⁇ 4-[(3,4-dichlorobenzoyl) amino] phenoxy ⁇ phenyl) acetic acid (182 mg) as a white powder.
  • Example 2 to 153 shown in Tables 35 to 74 below were produced in the same manner as in Example 1 using the corresponding raw materials.
  • the structures of the example compounds are shown in Tables 35 to 60, and the physicochemical data are shown in Tables 61 to 74, respectively.
  • the compound of formula (I) or a salt thereof has CRTH2 antagonism and has an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like) or multiple sclerosis and the like.
  • an inflammatory disease for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like
  • multiple sclerosis for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like

Abstract

Provided is a compound having a CRTH2 antagonism and being useful as a preventive and/or remedy for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, angiitis, chronic obstructive pulmonary disease, etc.) or multiple sclerosis. As the results of studies on compounds having a CRTH2 antagonism, it has been confirmed that a carboxylic acid compound or a salt thereof has a CRTH2 antagonism. The above-described carboxylic acid compound or a salt thereof has a CRTH2 antagonism and is usable as a preventive and/or remedy for inflammatory diseases (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, angiitis, chronic obstructive pulmonary disease, etc.) or multiple sclerosis.

Description

カルボン酸化合物又はその塩Carboxylic acid compound or salt thereof
　本発明は医薬組成物、殊に炎症性疾患または多発性硬化症治療用医薬組成物の有効成分として有用なカルボン酸化合物又はその塩に関する。 The present invention relates to a carboxylic acid compound or a salt thereof useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating inflammatory diseases or multiple sclerosis.
　アレルギー炎症のコンダクター細胞として知られる肥満細胞は、その細胞表面のＦｃ　ｅｐｓｉｌｏｎ　ＲＩを介して抗原特異的ＩｇＥと結合している。生体内に侵入した抗原がこの細胞表面上の特異的ＩｇＥに結合することにより肥満細胞は活性化され、様々な炎症性メディエーターを産生し、アレルギー炎症を誘発する（Ｃｕｒｒｅｎｔ　Ｏｐｉｎｉｏｎ　ｉｎ　Ｉｍｍｕｎｏｌｏｇｙ、２００２年、１４（６）巻、ｐ．６８８－６９３）。 Mast cells known as conductor cells for allergic inflammation are bound to antigen-specific IgE via Fc epsilon RI on the cell surface. Mast cells are activated when antigens that have entered the body bind to specific IgE on the cell surface, producing various inflammatory mediators and inducing allergic inflammation (Current Opinion in Immunology, 2002, 14 (6), p.688-693).
　プロスタグランジンＤ2（ＰＧＤ２）は活性化された肥満細胞が産生する主要なプロスタノイドである。これまでに喘息患者気道では抗原暴露によりＰＧＤ２の顕著な産生亢進が数分以内に認められること（Ｎｅｗ　Ｅｎｇｌａｎｄ　Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎｅ、１９８６年、３１５（１３）巻、ｐ．８００－８０４、Ａｍｅｒｉｃａｎ　Ｒｅｖｉｅｗ　ｏｆ　Ｒｅｓｐｉｒａｔｏｒｙ　Ｄｉｓｅａｓｅ、１９８３年、１２８（４）巻、ｐ．５９７－６０２）や、アレルギー性鼻炎患者の鼻粘膜やアトピー皮膚炎患者の皮膚に抗原を暴露すると炎症局所でのＰＧＤ２産生が亢進することが報告されている（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、１９９１年、１４６（２）巻、ｐ．６７１－６７６）。また、ＰＧＤ２をヒトに皮内投与すると紅斑が発症し、ラットにおいては血管透過性が亢進し浮腫が形成され（Ｂｒｉｔｉｓｈ　Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、１９７６年、５６（２）巻、ｐ．２２９－２３３）、イヌ気管においてもＰＧＤ２が好酸球の蓄積を誘発すること（Ｊｏｕｒｎａｌ　ｏｆ　Ａｐｐｌｉｅｄ　Ｐｈｙｓｉｏｌｏｇｙ、１９８９年、６７（３）巻、ｐ．９５９－９６２）が以前から報告されていた。Ｆｕｊｉｔａｎｉらは抗原誘発喘息モデルを用い、正常マウスに比べＰＧＤ２産生が増加したＰＧＤ２合成酵素トランスジェニックマウスでは気道における好酸球浸潤及びＴｈ２サイトカイン産生が亢進していることを報告し（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、２００２年、１６８（１）巻、ｐ．４４３－４４９）、ＰＧＤ２がアレルギー炎症を促進することを示した。このようにＰＧＤ２はアレルギー炎症部位での産生が亢進し、アレルギー反応を促進しうることから、アレルギー疾患の発症及び増悪に密接に関与していると考えられてきた。 Prostaglandin D 2 (PGD2) is the major prostanoid produced by activated mast cells. In the airways of asthmatic patients, a significant increase in PGD2 production has been observed within a few minutes due to antigen exposure (New England Journal of Medicine, 1986, 315 (13), p. 800-804, American Review of Respiratory). Disesease, 1983, 128 (4), p. 597-602) and reports that PGD2 production in the inflamed area is enhanced when an antigen is exposed to the nasal mucosa of allergic rhinitis patients or the skin of atopic dermatitis patients (Journal of Immunology, 1991, 146 (2), p. 671-676). Moreover, when PGD2 is intradermally administered to humans, erythema develops, and vascular permeability is increased and edema is formed in rats (British Journal of Immunology, 1976, 56 (2), p.229-233), It has been previously reported that PGD2 also induces eosinophil accumulation in the canine trachea (Journal of Applied Physiology, 1989, 67 (3), p. 959-962). Fujitani et al. Reported that eosinophil infiltration and Th2 cytokine production in the airway were increased in PGD2 synthase transgenic mice with increased PGD2 production compared to normal mice (Journal of Immunology, 2002, 168 (1), p.443-449), showed that PGD2 promotes allergic inflammation. Thus, PGD2 has been considered to be closely involved in the onset and exacerbation of allergic diseases because production at allergic inflammation sites is enhanced and allergic reactions can be promoted.
　当初、ＰＧＤ２受容体としてはＧ蛋白共役型受容体（ＧＰＣＲ）の一つであるＤＰ（Ｄ　ｔｙｐｅ　ｐｒｏｓｔａｎｏｉｄ　ｒｅｃｅｐｔｏｒ）が知られていた。しかしながら、モルモットにおいてＰＧＤ２は眼圧低下作用及び結膜における炎症誘発作用（特に好酸球浸潤）を示すが、ＤＰ選択的作動薬であるＢＷ２４５Ｃは眼圧低下作用を示すものの結膜への好酸球浸潤を誘発せず、ＰＧＤ２の好酸球浸潤誘発作用はＤＰを介していないことが示唆された（Ｉｎｖｅｓｔｉｇａｔｅ　Ｏｐｔｈｌｍｏｌｏｇｙ　＆　Ｖｉｓｕａｌ　Ｓｃｉｅｎｃｅ、１９９０年、１巻、ｐ．１３８－１４６）。さらに、２００１年にＭｏｎｎｅｒｅｔらは、ヒト血液から単離した好酸球を用い、ＰＧＤ２は好酸球を活性化するがＤＰ選択的作動薬であるＢＷ２４５Ｃは好酸球を活性化しないこと及びＤＰ拮抗薬であるＢＷＡ８６８ＣはＰＧＤ２による好酸球活性化を阻害しないことからＰＧＤ２の好酸球活性化作用は新規のＰＧＤ２受容体を介していることを提唱した（Ｂｌｏｏｄ、２００１年、９８（６）巻、ｐ．１９４２－１９４８）。同時期にＨｉｒａｉらはＰＧＤ２が、ＣＲＴＨ２（ｃｈｅｍｏａｔｔｒａｃｔａｎｔ　ｒｅｃｅｐｔｏｒ－ｈｏｍｏｌｏｇｏｕｓ　ｍｏｌｅｃｕｌｅ　ｅｘｐｒｅｓｓｅｄ　ｏｎ　Ｔｈ２　ｃｅｌｌｓ）のリガンドとして作用することにより、Ｔｈ２細胞、好酸球、好塩基球の遊走を誘発することを報告した（Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｍｅｄｉｃｉｎｅ、２００１年、１９３（２）巻、ｐ．２５５－２６１）。もともと、ＣＲＴＨ２はＴｈ１細胞には発現が認められず、Ｔｈ２細胞選択的に発現しているケモアトラクタント様受容体としてクローニングされたＧ蛋白共役型のオーファン受容体であり、活性化した肥満細胞の培養上清中にそのリガンド活性が存在すること及びＴｈ２細胞以外にも好酸球、好塩基球といったアレルギー反応に関与する炎症性細胞に発現していることが報告されていた（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、１９９９年、１６２（３）巻、ｐ．１２７８－１２８６、ＦＥＢＳ　Ｌｅｔｔｅｒ、１９９９年、８巻、４５９（２）、ｐ．１９５－１９９）。このようなことから現在、ＰＧＤ２はＣＲＴＨ２とＤＰの２種類の受容体を介してその生物活性を発揮していると考えられている。 Initially, DP (D type prostanoid receptor), which is one of G protein coupled receptors (GPCR), was known as a PGD2 receptor. However, in guinea pigs, PGD2 exhibits an intraocular pressure-lowering effect and inflammation-inducing action in the conjunctiva (particularly eosinophil infiltration), whereas DP selective agonist BW245C exhibits an intraocular pressure-lowering action, but eosinophil infiltration into the conjunctiva It was suggested that the eosinophil infiltration-inducing action of PGD2 was not mediated by DP (Investigate Opthmology & Visual Science, 1990, Vol. 1, p.138-146). Furthermore, Monneret et al. In 2001 used eosinophils isolated from human blood, where PGD2 activates eosinophils but the DP selective agonist BW245C does not activate eosinophils and DP Since the antagonist BWA868C does not inhibit eosinophil activation by PGD2, it was proposed that the eosinophil activation action of PGD2 is mediated by a novel PGD2 receptor (Blood, 2001, 98 (6) Vol., P.1942-1948). At the same time, Hirai et al. Reported that PGD2 induces the migration of Th2 cells, eosinophils, and basophils by acting as a ligand for CRTH2 (chemotractant receptor-homologoous molecular expressed on Th2 cells) (Th). Journal of Experimental Medicine, 2001, 193 (2), pages 255-261). Originally, CRTH2 is a G protein-coupled orphan receptor which is not expressed in Th1 cells but is cloned as a chemotractant-like receptor that is selectively expressed in Th2 cells. It has been reported that its ligand activity is present in the culture supernatant and that it is expressed in inflammatory cells involved in allergic reactions such as eosinophils and basophils in addition to Th2 cells (Journal of Immunology). 1999, 162 (3), p. 1278-1286, FEBS Letter, 1999, 8, 459 (2), p. 195-199). For this reason, PGD2 is currently considered to exert its biological activity via two types of receptors, CRTH2 and DP.
　ＣＲＴＨ２はｃＡＭＰを上昇させるＧｓカップル型ＧＰＣＲであり、ＤＰはｃＡＭＰ上昇を阻害するＧｉカップル型ＧＰＣＲであることから、細胞内シグナル伝達系が異なり、違った機能を有する。これまでのＣＲＴＨ２及びＤＰに対する作動薬、拮抗薬を用いた検討から、ＣＲＴＨ２の機能としては細胞遊走活性化（Ｔｈ２細胞、好酸球、好塩基球）、接着分子発現促進（Ｔｈ２細胞、好酸球）、Ｔｈ２サイトカイン産生促進（Ｔｈ２細胞）などが報告されている。一方、ＤＰの機能としては血小板凝集抑制、血管拡張、平滑筋弛緩、細胞遊走抑制（ＤＰ発現細胞、好酸球、樹状細胞）、好酸球アポトーシス誘導、睡眠誘導などが報告されている。ＰＧＤ２は、ＤＰの作用により局所での血管拡張を誘発し血管透過性を亢進させる一方、ＣＲＴＨ２の作用により炎症性細胞浸潤及び活性化を惹起することでアレルギー炎症を促進すると考えられる。これらの点についてはＮａｇａｔａら及びＰｅｔｔｉｐｈｅｒらの総説に詳細に述べられている（Ｐｒｏｓｔａｇｌａｎｄｉｎｓ　Ｌｅｕｋｏｔｒｉｅｎｅｓ　＆　Ｅｓｓｅｎｔｉａｌ　Ｆａｔｔｙ　Ａｃｉｄｓ、２００３年、６９（２－３）巻、ｐ．１６９－１７７；Ｎａｔｕｒａｌ　Ｒｅｖｉｅｗ　Ｄｒｕｇ　Ｄｉｓｃｏｖｅｒｙ、２００７年、６（４）巻、ｐ．３１３－３２５）。 Since CRTH2 is a Gs-coupled GPCR that increases cAMP and DP is a Gi-coupled GPCR that inhibits cAMP increase, the intracellular signal transduction system is different and has different functions. Based on previous studies using agonists and antagonists for CRTH2 and DP, CRTH2 functions include cell migration activation (Th2 cells, eosinophils, basophils), adhesion molecule expression promotion (Th2 cells, eosinophils) Sphere), Th2 cytokine production promotion (Th2 cells) and the like have been reported. On the other hand, as functions of DP, platelet aggregation suppression, vasodilation, smooth muscle relaxation, cell migration suppression (DP-expressing cells, eosinophils, dendritic cells), eosinophil apoptosis induction, sleep induction and the like have been reported. PGD2 is thought to promote local allergic inflammation by inducing inflammatory cell infiltration and activation by the action of CRTH2, while inducing local vasodilation and enhancing vascular permeability by the action of DP. These points are described in detail in a review by Nagata et al. And Pettipher et al. (Prostaglandins Leukotrienes & Essential Fatty Acids, 2003, 69 (2-3), p.169-177; Natural ReviewDr. 6 (4), pp. 313-325).
　以上から、抗原刺激により活性化された肥満細胞が産生する主要なプロスタノイドであるＰＧＤ２はＣＲＴＨ２を介してＴｈ２細胞や好酸球などの炎症性細胞を活性化し、炎症部位への遊走を促進し、さらにＴｈ２細胞からのＴｈ２サイトカイン産生を促進させることによりアレルギー炎症における中心的な役割を担っていると考えられ、ＣＲＴＨ２拮抗薬はアレルギー炎症に対する治療薬としてその開発が切望される。 From the above, PGD2, which is the main prostanoid produced by mast cells activated by antigen stimulation, activates inflammatory cells such as Th2 cells and eosinophils via CRTH2 and promotes migration to the inflammatory site. Furthermore, it is considered that the TH2 cytokine production from Th2 cells is promoted to play a central role in allergic inflammation, and CRTH2 antagonists are eagerly developed as therapeutic agents for allergic inflammation.
　例えば、ＣＲＴＨ２拮抗作用を有し、抗喘息作用を有する化合物として、下記式（Ａ）、（Ｂ）、（Ｃ）、（Ｄ）、（Ｅ）で示される化合物が知られている（それぞれ特許文献１、２、３、４、５）。 For example, compounds represented by the following formulas (A), (B), (C), (D), and (E) are known as compounds having CRTH2 antagonistic activity and anti-asthma activity (each patented) Literature 1, 2, 3, 4, 5).
Figure JPOXMLDOC01-appb-C000003
［式中の記号は、それぞれ当該公報を参照のこと。
　ただし、特許文献２において、（Ｂ）のＷは、Ｏ、Ｓ（Ｏ）ｎ（ｎは０，１，２）、ＮＲ13、ＣＲ1ＯＲ2、ＣＲ1Ｒ2、
特許文献３において、（Ｃ）のＬは、ＣＲ6Ｒ7、ＣＯ、ＣＮＲ6、ＣＳ、
特許文献４において、（Ｄ）のＡは、Ｂと縮合又は結合する５から１４員環ヘテロ環、であることがそれぞれ示されている。］
　特許文献５は、本出願の優先日後に公開された。
Figure JPOXMLDOC01-appb-C000003
[Refer to the official gazette for the symbols in the formula.
However, in Patent Document 2, W in (B) is O, S (O) n (n is 0, 1, 2), NR 13 , CR 1 OR 2 , CR 1 R 2 ,
In Patent Document 3, L in (C) is CR 6 R 7 , CO, CNR 6 , CS,
In Patent Document 4, it is indicated that A in (D) is a 5- to 14-membered heterocyclic ring condensed or bonded to B, respectively. ]
Patent document 5 was published after the priority date of this application.
　また例えば、特許文献６、７、および８には、（Ｆ）に示す化合物が製造中間体として開示されている。 Further, for example, in Patent Documents 6, 7, and 8, the compound shown in (F) is disclosed as a production intermediate.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
国際公開第ＷＯ２００４／０５８１６４パンフレットInternational Publication No. WO2004 / 058164 Pamphlet 国際公開第ＷＯ２００６／００５９０９パンフレットInternational Publication No. WO2006 / 005909 Pamphlet 国際公開第ＷＯ２００７／１４３７４５パンフレットInternational Publication No. WO2007 / 143745 Pamphlet 国際公開第ＷＯ２００７／１４６８３８パンフレットInternational Publication No. WO2007 / 146838 Pamphlet 国際公開第ＷＯ２００８／０２４７４６パンフレットInternational Publication No. WO2008 / 024746 Pamphlet 国際公開第ＷＯ２００６／０１４０１２パンフレットInternational Publication No. WO2006 / 014012 Pamphlet 国際公開第ＷＯ２００７／０６６７８４パンフレットInternational Publication No. WO2007 / 066784 Pamphlet 特開２００７－２３１００５号JP 2007-231005
　本発明者らは、ＣＲＴＨ２拮抗作用に基づく、炎症性疾患（例えば、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、血管炎、慢性閉塞性肺疾患等）または多発性硬化症等の予防及び／または治療に有用な医薬組成物を提供すること、さらには、これらを含有する医薬を提供することを目的として研究を行った。 The inventors have developed inflammatory diseases based on CRTH2 antagonism (eg, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis, Studies have been conducted for the purpose of providing a pharmaceutical composition useful for the prevention and / or treatment of chronic obstructive pulmonary disease and the like, or multiple sclerosis, and further providing a medicament containing them.
　本発明者らは、ＣＲＴＨ２拮抗作用を有する化合物につき鋭意検討した結果、式（Ｉ）の化合物が、ＣＲＴＨ２拮抗作用として有用であることを見出し、本発明を完成した。
　即ち、本発明は、式（Ｉ）の化合物またはその塩、並びに、式（Ｉ）の化合物またはその塩、及び賦形剤を含有する医薬組成物に関する。 As a result of intensive studies on compounds having CRTH2 antagonism, the present inventors have found that the compound of formula (I) is useful as CRTH2 antagonism, and completed the present invention.
That is, this invention relates to the pharmaceutical composition containing the compound or its salt of a formula (I), or its salt, and an excipient | filler, and an excipient | filler.
Figure JPOXMLDOC01-appb-C000005
［式中、
Ｒ1は、－（Ｃ1-6アルキレン）－ＣＯＯＨ、または－Ｈであり、
１）Ｒ1が、－（Ｃ1-6アルキレン）－ＣＯＯＨの場合、
　　　Ｒ2は、ハロゲン、または－Ｈ、
　　　Ｒ3は、ハロゲン、Ｃ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、または－Ｈ、
２）Ｒ1が、－Ｈの場合、
　　　Ｒ2とＲ3が一体となって、それらが結合するベンゼン環とともに式（ＩＩ）
Figure JPOXMLDOC01-appb-C000006
　　　で示される基を形成し、
　　　Ｖは、＝ＣＨ－、または＝Ｎ－、
　　　ｍは、１から６の整数を示し、
Ｒ4は、ハロゲン、または－Ｈ、
　　　ただし、Ｒ3が－Ｈの場合、Ｒ4はハロゲン、
Ｒ5は、－Ｈ、ハロゲン、またはＣ1-6アルキル、
Ｒ6は、ＲXAで示される同一または異なった基でそれぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキル、または－Ｎ（Ｒ6a）（Ｒ6b）であり、
ＲXAは、ハロゲン、Ｃ1-6アルキル、ハロＣ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、－Ｏ－（ハロＣ1-6アルキル）、－Ｓ－（Ｃ1-6アルキル）、－Ｎ－（Ｃ1-6アルキル）2、アリール、ハロゲンで置換されているアリール、－Ｏ－（Ｃ1-6アルキル）で置換されているアリール、－Ｎ（Ｃ1-6アルキル）2で置換されているアリール、ハロアリール、－ＯＨ、－ＣＮ、－Ｓ（＝Ｏ）2－（Ｃ1-6アルキル）、－ＮＨＳ（＝Ｏ）2－（Ｃ1-6アルキル）、または環状アミノ、
Ｒ6aは、－（Ｃ1-6アルキレン）－アリール、－（Ｃ1-6アルキレン）－ヘテロアリール、または－（Ｃ1-6アルキレン）－ヘテロシクロアルキル、
Ｒ6bは、－Ｈ、またはＣ1-6アルキル、
Ａは、－Ｏ－、または－Ｓ－、
Ｄは、－Ｃ（＝Ｏ）－、または－Ｓ（＝Ｏ）2－、
Ｅは、結合、Ｃ1-6アルキレン、またはＣ2-6アルケニレン、
Ｙは、－Ｃ（Ｒ5a）＝、または－Ｎ＝、
Ｒ5aは、－Ｈ、ハロゲン、またはＣ1-6アルキル、
Ｚは、＝ＣＨ－、または＝Ｎ－、
Ｕは、－Ｃ（Ｒ5b）＝、または－Ｎ＝、
Ｒ5bは、－Ｈ、ハロゲン、またはＣ1-6アルキル。
　　　ただし、以下の化合物は除く。
３－｛３－フルオロ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
３－｛３－エトキシ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
３－｛３－メトキシ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－フルオロフェニル］プロパン酸、
３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－エトキシフェニル］プロパン酸、
３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－メトキシフェニル］プロパン酸、および
（４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝－３－メトキシフェニル）酢酸。］
　なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。
Figure JPOXMLDOC01-appb-C000005
[Where:
R 1 is — (C 1-6 alkylene) —COOH or —H;
1) When R 1 is — (C 1-6 alkylene) —COOH,
R 2 is halogen or —H,
R 3 is halogen, C 1-6 alkyl, —O— (C 1-6 alkyl), or —H,
2) When R 1 is -H,
R 2 and R 3 together form a benzene ring to which they are bonded together with formula (II)
Figure JPOXMLDOC01-appb-C000006
A group represented by
V is = CH-, or = N-,
m represents an integer of 1 to 6,
R 4 is halogen or —H,
Provided that when R 3 is —H, R 4 is halogen,
R 5 is —H, halogen, or C 1-6 alkyl,
R 6 is aryl, heteroaryl, heterocycloalkyl, or —N (R 6a ) (R 6b ), each optionally substituted with the same or different groups represented by R XA ;
R XA represents halogen, C 1-6 alkyl, halo C 1-6 alkyl, —O— (C 1-6 alkyl), —O— (halo C 1-6 alkyl), —S— (C 1-6 Alkyl), —N— (C 1-6 alkyl) 2 , aryl, aryl substituted with halogen, aryl substituted with —O— (C 1-6 alkyl), —N (C 1-6 alkyl) ) Aryl substituted with 2 , aryl, haloaryl, —OH, —CN, —S (═O) 2 — (C 1-6 alkyl), —NHS (═O) 2 — (C 1-6 alkyl), or Cyclic amino,
R 6a is — (C 1-6 alkylene) -aryl, — (C 1-6 alkylene) -heteroaryl, or — (C 1-6 alkylene) -heterocycloalkyl,
R 6b is —H or C 1-6 alkyl;
A is —O— or —S—,
D is —C (═O) —, or —S (═O) 2 —,
E is a bond, C 1-6 alkylene, or C 2-6 alkenylene,
Y is -C (R 5a ) =, or -N =,
R 5a is —H, halogen, or C 1-6 alkyl;
Z is ═CH— or ═N—,
U is -C (R 5b ) =, or -N =,
R 5b is —H, halogen, or C 1-6 alkyl.
However, the following compounds are excluded.
3- {3-fluoro-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
3- {3-ethoxy-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
3- {3-methoxy-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-fluorophenyl] propanoic acid,
3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-ethoxyphenyl] propanoic acid,
3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-methoxyphenyl] propanoic acid, and (4- {4-[(3,4- Dichlorobenzoyl) amino] phenoxy} -3-methoxyphenyl) acetic acid. ]
Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.
　また、本発明は、式（Ｉ）の化合物またはその塩を含有する炎症性疾患または多発性硬化症の治療用医薬組成物、即ち、式（Ｉ）の化合物またはその塩を含有する炎症性疾患または多発性硬化症治療剤に関する。
　また、本発明は、炎症性疾患または多発性硬化症治療用医薬組成物の製造のための式（Ｉ）の化合物またはその塩の使用、並びに、式（Ｉ）の化合物またはその塩の有効量を患者に投与することからなる炎症性疾患または多発性硬化症の治療方法に関する。 The present invention also provides a pharmaceutical composition for the treatment of inflammatory diseases or multiple sclerosis comprising a compound of formula (I) or a salt thereof, ie, an inflammatory disease comprising a compound of formula (I) or a salt thereof. Or it relates to a therapeutic agent for multiple sclerosis.
The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of inflammatory diseases or multiple sclerosis, and an effective amount of a compound of formula (I) or a salt thereof. The present invention relates to a method for treating inflammatory diseases or multiple sclerosis comprising administering to a patient.
　式（Ｉ）の化合物またはその塩は、ＣＲＴＨ２拮抗作用を有し、炎症性疾患（例えば、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、血管炎、慢性閉塞性肺疾患等）または多発性硬化症等の予防及び／または治療剤として使用できる。 The compound of formula (I) or a salt thereof has CRTH2 antagonism and has an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like) or multiple sclerosis and the like.
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　「ハロゲン」は、Ｆ、Ｃｌ、Ｂｒ、またはＩである。別の態様としては、Ｆ、またはＣｌである。 “Halogen” is F, Cl, Br, or I. In another embodiment, F or Cl.
　「Ｃ1-6アルキル」は、直鎖または分枝状の炭素数が１から６であるアルキルであり、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル等である。別の態様としては、Ｃ1-4アルキルである。さらに別の態様としては、メチル、またはエチルである。 “C 1-6 alkyl” is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C 1-4 alkyl. Yet another embodiment is methyl or ethyl.
　「ハロＣ1-6アルキル」は、１個以上のハロゲンで置換された、Ｃ1-6アルキルである。別の態様としては、１から５個のハロゲンで置換されたＣ1-6アルキルであり、別の態様としては、－ＣＦ3、－ＣＦ2Ｈ、－ＣFH2または－ＣＨ2ＣＨ2Ｆである。 "Halo C 1-6 alkyl" substituted with one or more halogen, C 1-6 alkyl. Another embodiment is C 1-6 alkyl substituted with 1 to 5 halogens, and another embodiment is —CF 3 , —CF 2 H, —CFH 2 or —CH 2 CH 2 F. is there.
　「Ｃ1-6アルキレン」は、直鎖または分枝状の炭素数が１から６であるアルキレンであり、例えばメチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレン、またはヘキサメチレン等である。別の態様としては、Ｃ1-4アルキレンである。さらに別の態様としては、メチレン、またはエチレンである。 “C 1-6 alkylene” is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene or the like. Another embodiment is C 1-4 alkylene. Yet another embodiment is methylene or ethylene.
　「Ｃ2-6アルケニレン」は、直鎖または分枝状の炭素数が２から６であるアルケニレンであり、例えば、ビニレン、プロピレン、ブテニレン、ペンテニレン、またはヘキセニレン等である。別の態様としては、Ｃ2-4アルケニレンである。 “C 2-6 alkenylene” is a linear or branched alkenylene having 2 to 6 carbon atoms, and examples thereof include vinylene, propylene, butenylene, pentenylene, hexenylene and the like. Another embodiment is C 2-4 alkenylene.
　「アリール」は、Ｃ6-14の単環から三環式芳香族炭化水素環基であり、例えばフェニル、またはナフチルであり、別の態様としてはフェニルである。 “Aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, for example, phenyl or naphthyl, and in another embodiment, phenyl.
　「ヘテロアリール」は、窒素、酸素、及び硫黄からなる群より選択された同一または異なるヘテロ原子を１個以上有する５または６員環芳香族へテロ環を意味し、これらは、シクロペンタン環またはベンゼン環と縮合していてもよい。別の態様としては、ベンゼン環と縮合していてもよい５または６員環芳香族へテロ環であり、別の態様としては、チエニル、トリアゾリル、ピリジル、インドリル、ベンゾフラニル、ベンゾチエニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、イミダゾピリジニル、イソキノリル、またはキノリルなどである。別の態様としては、インドリルである。 “Heteroaryl” means a 5- or 6-membered aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which includes a cyclopentane ring or It may be condensed with a benzene ring. Another embodiment is a 5- or 6-membered aromatic heterocycle optionally condensed with a benzene ring, and other embodiments include thienyl, triazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl. , Benzothiazolyl, benzimidazolyl, imidazopyridinyl, isoquinolyl, quinolyl and the like. Another embodiment is indolyl.
　「ヘテロシクロアルキル」は、窒素、酸素、及び硫黄からなる群より選択された同一または異なるヘテロ原子を１個以上有する５から７員環の非芳香族へテロ環を意味し、これらは部分的に不飽和結合を有していてもよく、ベンゼン環と縮合していてもよい。別の態様としては、ピペリジニル、イソインダニル、テトラヒドロキノリル、テトラヒドロイソキノリル、２，３，４，５－テトラヒドロ－１Ｈ－３－ベンゾアゼピニルなどである。別の態様としては、ベンゼン環と縮合していてもよい５から７員環の非芳香族へテロ環であり、さらに別の態様としては、テトラヒドロイソキノリルである。 “Heterocycloalkyl” means a 5- to 7-membered non-aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are partially May have an unsaturated bond and may be condensed with a benzene ring. Other embodiments include piperidinyl, isoindanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 2,3,4,5-tetrahydro-1H-3-benzoazepinyl and the like. Another embodiment is a 5- to 7-membered non-aromatic hetero ring optionally condensed with a benzene ring, and yet another embodiment is tetrahydroisoquinolyl.
　「環状アミノ」は、前記「ヘテロシクロアルキル」のうち、少なくとも１個の窒素原子を有する単環～三環式である「ヘテロシクロアルキル」を意味する。部分的に不飽和結合を有していてもよい。別の態様としては、環員数が４～９の環であり、また別の態様としては、ピロリジニル、ピペリジル、モルホリニル、またはホモピペリジルが挙げられる。 “Cyclic amino” means “heterocycloalkyl” which is monocyclic to tricyclic having at least one nitrogen atom among the above “heterocycloalkyl”. It may have a partially unsaturated bond. Another embodiment is a ring having 4 to 9 ring members, and another embodiment includes pyrrolidinyl, piperidyl, morpholinyl, or homopiperidyl.
　本明細書において、「置換されていてもよい」とは、無置換、若しくは置換基を１から６個有していることを意味し、別の態様としては、１から５個有していることを意味する。なお、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 In the present specification, “optionally substituted” means unsubstituted or having 1 to 6 substituents, and in another aspect, having 1 to 5 substituents. Means that. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
　本明細書において、「置換されている」とは、置換基を１から６個有していることを意味し、別の態様としては、１から５個有していることを意味する。なお、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 In this specification, “substituted” means having 1 to 6 substituents, and in another aspect, having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
　「ＲXA」の別の態様としては、ＲXBであり、また別の態様としては、ＲXCである。
　ＲXBは、ハロゲン、Ｃ1-6アルキル、ハロＣ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、－Ｏ－（ハロＣ1-6アルキル）、－Ｓ－（Ｃ1-6アルキル）、－Ｎ（Ｃ1-6アルキル）2、アリール、－Ｏ－（Ｃ1-6アルキル）で置換されているアリール、または－Ｎ（Ｃ1-6アルキル）2で置換されているアリールを示し、
　ＲXCは、Ｃｌ、－ＣＨ3、－ＣＦ3、－ＯＣＨ3、－ＯＣＦ3、－ＳＣＨ3、－Ｎ（ＣＨ3）2、フェニル、－ＯＣＨ3で置換されているフェニル、または－Ｎ（ＣＨ3）2で置換されているフェニルを示す。 Another embodiment of “R XA ” is R XB , and another embodiment is R XC .
R XB is halogen, C 1-6 alkyl, halo C 1-6 alkyl, —O— (C 1-6 alkyl), —O— (halo C 1-6 alkyl), —S— (C 1-6 Alkyl), —N (C 1-6 alkyl) 2 , aryl, aryl substituted with —O— (C 1-6 alkyl), or aryl substituted with —N (C 1-6 alkyl) 2 Indicate
R XC is Cl, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —SCH 3 , —N (CH 3 ) 2 , phenyl, phenyl substituted with —OCH 3 , or —N ( CH 3) a phenyl which is substituted by two.
　本発明のある態様を以下に示す。
（１）Ｒ1が、－（Ｃ1-6アルキレン）－ＣＯＯＨである式（Ｉ）の化合物。
　　　別の態様として、Ｒ1が－ＣＨ2－ＣＯＯＨである式（Ｉ）の化合物。
　　　また別の態様として、Ｒ1が－Ｈである式（Ｉ）の化合物。
（２）Ｒ2が、－Ｈである式（Ｉ）の化合物。
（３）Ｒ3が、ハロゲン、Ｃ1-6アルキル、または－Ｏ－（Ｃ1-6アルキル）である式（Ｉ）の化合物。
　　　別の態様として、Ｒ3が、ハロゲンである式（Ｉ）の化合物。
　　　また別の態様として、Ｒ3が、Ｆ、Ｂｒ、またはＣｌである式（Ｉ）の化合物。
（４）Ｒ4が、－Ｈである式（Ｉ）の化合物。
（５）Ｒ5が、－Ｈである式（Ｉ）の化合物。
（６）Ｒ6が、同一または互いに異なったＲXAでそれぞれ置換されていてもよいヘテロアリールまたはヘテロシクロアルキルである式（Ｉ）の化合物。
　　　別の態様として、Ｒ6が、同一または互いに異なったＲXAで置換されていてもよいフェニルである式（Ｉ）の化合物。
　　　別の態様として、Ｒ6が、同一または互いに異なったＲXBで置換されていてもよいフェニルである式（Ｉ）の化合物。
　　　さらにまた別の態様として、Ｒ6が、同一または互いに異なったＲXCで置換されていてもよいフェニルである式（Ｉ）の化合物。
（７）Ａが、－Ｏ－である式（Ｉ）の化合物。
（８）Ｄが、－Ｃ（＝Ｏ）－である式（Ｉ）の化合物。
（９）Ｅが、結合である式（Ｉ）の化合物。
（１０）Ｙが、－ＣＨ＝、または－ＣＦ＝である式（Ｉ）の化合物であり、
　　　別の態様として、Ｙが、－Ｎ＝である式（Ｉ）の化合物。
（１１）Ｚが、＝ＣＨ－である式（Ｉ）の化合物。
（１２）Ｕが、－ＣＨ＝である式（Ｉ）の化合物。
（１３）ｍが、１である式（Ｉ）の化合物。
（１４）Ｖが、＝Ｎ－である式（Ｉ）の化合物。
（１５）Ｒ6aが、－（Ｃ1-6アルキレン）－アリールであり、Ｒ6bが、－Ｈである式（Ｉ）の化合物。
（１６）上記（１）から（１５）に記載の基のうち、二以上の組み合わせにより、矛盾のない構造である式（Ｉ）の化合物。 Certain embodiments of the present invention are shown below.
(1) A compound of formula (I) wherein R 1 is — (C 1-6 alkylene) —COOH.
In another embodiment, compounds of formula (I) wherein R 1 is —CH 2 —COOH.
In another embodiment, the compound of formula (I), wherein R 1 is —H.
(2) A compound of formula (I) wherein R 2 is —H.
(3) A compound of formula (I) wherein R 3 is halogen, C 1-6 alkyl, or —O— (C 1-6 alkyl).
In another embodiment, compounds of formula (I), wherein R 3 is halogen.
In yet another embodiment, the compound of formula (I), wherein R 3 is F, Br, or Cl.
(4) A compound of formula (I) wherein R 4 is —H.
(5) A compound of formula (I) wherein R 5 is —H.
(6) The compound of formula (I), wherein R 6 is heteroaryl or heterocycloalkyl each optionally substituted with the same or different R XA .
In another embodiment, compounds of formula (I), wherein R 6 is phenyl optionally substituted with the same or different R XA .
In another embodiment, compounds of formula (I), wherein R 6 is phenyl optionally substituted with the same or different R XB .
In yet another embodiment, the compound of formula (I), wherein R 6 is phenyl optionally substituted with the same or different R XC .
(7) A compound of formula (I) wherein A is —O—.
(8) A compound of formula (I) wherein D is —C (═O) —.
(9) A compound of formula (I) wherein E is a bond.
(10) a compound of formula (I) wherein Y is —CH═ or —CF═;
In another embodiment, compounds of formula (I) wherein Y is —N═.
(11) Compounds of formula (I) wherein Z is = CH-.
(12) The compound of formula (I), wherein U is —CH═.
(13) A compound of formula (I) wherein m is 1.
(14) Compounds of formula (I) wherein V is = N-.
(15) The compound of formula (I), wherein R 6a is — (C 1-6 alkylene) -aryl and R 6b is —H.
(16) A compound of formula (I) having a consistent structure by combining two or more of the groups described in (1) to (15) above.
　具体的には、例えば、以下の化合物が挙げられる。
（Ａ）Ｒ1が、－（Ｃ1-6アルキレン）－ＣＯＯＨであり、Ｒ2が、－Ｈであり、Ｒ3が、Ｆ、Ｃｌ、またはＢｒである式（Ｉ）の化合物。
（Ｂ）Ｒ1が、－ＣＨ2－ＣＯＯＨである、上記（Ａ）に記載の化合物。 Specific examples include the following compounds.
(A) A compound of formula (I) wherein R 1 is — (C 1-6 alkylene) —COOH, R 2 is —H, and R 3 is F, Cl, or Br.
(B) The compound according to (A) above, wherein R 1 is —CH 2 —COOH.
　本発明のさらに別の態様を以下に示す。
［１］Ｒ6が、同一または互いに異なったＲXBで示される基でそれぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキル、または－Ｎ（Ｒ6a）（Ｒ6b）である、式［Ｉ］の化合物またはその塩。
[２]Ｒ1が、－ＣＨ2－ＣＯＯＨ、または－Ｈ、
ｍが、１、
Ｒ6aが、－（Ｃ1-6アルキレン）－アリール、
Ｒ6bが、－Ｈ、
　　　ただし、Ｙが－Ｎ＝の場合、Ｕは－ＣＨ＝であり、
　　　Ｙが－ＣＨ＝または－ＣＦ＝の場合、Ｚが＝ＣＨ－である、[１]に記載の化合物またはその塩。
[３]Ｒ3が、ハロゲン、Ｃ1-6アルキル、または－Ｏ－Ｃ1-6アルキル、
Ｒ4が、－Ｈである、[２]に記載の化合物またはその塩。
[４]Ｙが、－Ｎ＝、
Ｚが、＝ＣＨ－である、[３]に記載の化合物またはその塩。
[５]Ｅが、結合である、[４]に記載の化合物またはその塩。
[６]Ｒ6が、同一または互いに異なったＲXBで示される基で置換されていてもよいフェニルである、[５]に記載の化合物またはその塩。
［７］Ａが、－Ｏ－、
Ｄが、－Ｃ（＝Ｏ）－、
Ｒ2が、－Ｈ、
Ｒ3が、ハロゲンである、［６］に記載の化合物またはその塩。
［８］Ｒ6が、同一または互いに異なったＲXCで示される基で置換されていてもよいフェニルである、［７］に記載の化合物またはその塩。
［９］Ｙが、－ＣＨ＝、または－ＣＦ＝である、［２］に記載の化合物またはその塩。
［１０］Ａが、－Ｏ－、
Ｄが、－Ｃ（＝Ｏ）－、
Ｒ6が、同一または互いに異なったＲXBで示される基で置換されていてもよいフェニルである、[９]に記載の化合物またはその塩。
[１１]Ｒ1が、－Ｈである、[２]に記載の化合物またはその塩。
[１２]Ｖが、＝Ｎ－である、[１１]に記載の化合物またはその塩。 Still another embodiment of the present invention will be described below.
[1] R 6 are identical or different from each other R XB aryl which may be substituted, respectively, a group represented by heteroaryl, heterocycloalkyl or -N, (R 6a) (R 6b), wherein A compound of [I] or a salt thereof.
[2] R 1 is —CH 2 —COOH, or —H,
m is 1,
R 6a is — (C 1-6 alkylene) -aryl,
R 6b is —H,
However, when Y is -N =, U is -CH =,
The compound or salt thereof according to [1], wherein when Y is —CH═ or —CF═, Z is ═CH—.
[3] R 3 is halogen, C 1-6 alkyl, or —O—C 1-6 alkyl,
The compound or a salt thereof according to [2], wherein R 4 is —H.
[4] Y is -N =,
The compound or a salt thereof according to [3], wherein Z is = CH-.
[5] The compound or salt thereof according to [4], wherein E is a bond.
[6] The compound or a salt thereof according to [5], wherein R 6 is phenyl optionally substituted with the same or different groups represented by R XB .
[7] A is -O-,
D is -C (= O)-,
R 2 is —H,
The compound or a salt thereof according to [6], wherein R 3 is halogen.
[8] The compound or salt thereof according to [7], wherein R 6 is phenyl optionally substituted with the same or different groups represented by R XC .
[9] The compound or salt thereof according to [2], wherein Y is —CH═ or —CF═.
[10] A is -O-,
D is -C (= O)-,
The compound or a salt thereof according to [9], wherein R 6 is phenyl optionally substituted with the same or different groups represented by R XB .
[11] The compound or salt thereof according to [2], wherein R 1 is —H.
[12] The compound or salt thereof according to [11], wherein V is = N-.
　本発明に包含される具体的化合物の例として、以下の化合物またはその塩が挙げられる。
（３－クロロ－４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝フェニル）酢酸、
（４－｛４－［（１－ベンゾフラン－２－イルカルボニル）アミノ］フェキシ｝－３－クロロフェニル）酢酸、
［３－クロロ－４－（｛４－［（３，４－ジクロロベンゾイル）アミノ］フェニル｝スルファニル）フェニル］酢酸、
（３－クロロ－４－｛４－［（３，４－ジヒドロイソキノリン－２（１Ｈ）－イルカルボニル）アミノ］フェノキシ｝フェニル）酢酸、
［４－（４－｛［（２Ｅ）－３－（３，４－ジクロロフェニル）プロプ－２－エノイル］アミノ｝フェノキシ）－２－メチル－１Ｈ－ベンゾイミダゾール－１－イル］酢酸、
［３－クロロ－４－（４－｛［４－（トリフロオロメチル）ベンゾイル］アミノ｝フェノキシ）フェニル］酢酸、
（３－クロロ－４－｛２－フルオロ－４－［（１Ｈ－インドール－２－イルカルボニル）アミノ］フェノキシ｝フェニル）酢酸、
［３－クロロ－４－（４－｛［（１－メチル－１Ｈ－インドール－２－イル）カルボニル］アミノ｝フェノキシ）フェニル］酢酸、
［３－クロロ－４－（４－｛［（６－クロロ－１Ｈ－ベンゾイミダゾール－２－イル）カルバモイル］アミノ｝フェノキシ）フェニル］酢酸、
｛３－クロロ－４－［（５－｛［（５－フルオロ－１Ｈ－インドール－２－イル）カルボニル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝酢酸、
［３－ブロモ－４－（４－｛［４－（トリフルオロメトキシ）ベンゾイル］アミノ｝フェノキシ）フェニル］酢酸、および
｛３－クロロ－４－［（５－｛［４－（トリフルオロメトキシ）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝酢酸。 Examples of specific compounds included in the present invention include the following compounds or salts thereof.
(3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetic acid,
(4- {4-[(1-benzofuran-2-ylcarbonyl) amino] foxy} -3-chlorophenyl) acetic acid,
[3-chloro-4-({4-[(3,4-dichlorobenzoyl) amino] phenyl} sulfanyl) phenyl] acetic acid,
(3-chloro-4- {4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy} phenyl) acetic acid,
[4- (4-{[(2E) -3- (3,4-dichlorophenyl) prop-2-enoyl] amino} phenoxy) -2-methyl-1H-benzimidazol-1-yl] acetic acid,
[3-chloro-4- (4-{[4- (trifluoromethyl) benzoyl] amino} phenoxy) phenyl] acetic acid,
(3-chloro-4- {2-fluoro-4-[(1H-indol-2-ylcarbonyl) amino] phenoxy} phenyl) acetic acid,
[3-chloro-4- (4-{[(1-methyl-1H-indol-2-yl) carbonyl] amino} phenoxy) phenyl] acetic acid,
[3-chloro-4- (4-{[(6-chloro-1H-benzimidazol-2-yl) carbamoyl] amino} phenoxy) phenyl] acetic acid,
{3-chloro-4-[(5-{[(5-fluoro-1H-indol-2-yl) carbonyl] amino} pyridin-2-yl) oxy] phenyl} acetic acid,
[3-Bromo-4- (4-{[4- (trifluoromethoxy) benzoyl] amino} phenoxy) phenyl] acetic acid, and {3-chloro-4-[(5-{[4- (trifluoromethoxy) Benzoyl] amino} pyridin-2-yl) oxy] phenyl} acetic acid.
　式（Ｉ）の化合物には、置換基の種類によって、互変異性体や幾何異性体が存在しうる。本明細書中、式（Ｉ）の化合物が異性体の一形態のみで記載されることがあるが、本発明は、それ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含する。
　また、式（Ｉ）の化合物には、不斉炭素原子を有する場合があり、これに基づく光学異性体が存在しうる。本発明は、式（Ｉ）の化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。 In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of the formula (I) may have an asymmetric carbon atom, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
　さらに、本発明は、式（Ｉ）で示される化合物の製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、加溶媒分解によりまたは生理学的条件下で、アミノ基、水酸基、カルボキシル基等に変換されうる基を有する化合物である。プロドラッグを形成する基としては、例えば、Ｐｒｏｇ．Ｍｅｄ．，５，ｐ.２１５７－２１６１（１９８５）や、「医薬品の開発」（廣川書店、１９９０年）第７巻、分子設計１６３－１９８に記載の基が挙げられる。 Furthermore, the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med. , 5, p. 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198.
　また、式（Ｉ）の化合物の塩とは、式（Ｉ）の化合物の製薬学的に許容される塩であり、置換基の種類によって、酸付加塩または塩基との塩を形成する場合がある。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。 The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the kind of the substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.
　さらに、本発明は、式（Ｉ）の化合物及びその塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。また、本発明は、種々の放射性または非放射性同位体でラベルされた化合物も包含する。 Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
　本明細書において、以下の略号を用いることがある。
ＡｃＯＥｔまたはＥｔＯＡｃ：酢酸エチル、ｂｒｉｎｅ：飽和食塩水、ＢｕＯＨ：ブタノール、Ｃｓ2ＣＯ3：炭酸セシウム、ＣＨＣｌ3：クロロホルム、ＣｕＣｌ2：塩化銅、ＤＣＭ：ジクロロメタン、ＤＣＣ：ジシクロヘキシルカルボジイミド、ＤＥＡＤ：ジエチルアゾジカルボキシレート、ＤＭＳＯ：ジメチルスルホキシド、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＤＭＡＰ：４－ジメチルアミノピリジン、ＤＩＰＥＡ：ジイソプロピルエチルアミン、ＤＰＰＡ：ジフェニルリン酸アジド、ＥｔＯＨ：エタノール、ＨＯＢｔ：Ｎ－ヒドロキシベンズトリアゾール、ＩＰＥ：ジイソプロピルエーテル、Ｋ2ＣＯ3：炭酸カリウム、ＫＯＨ：水酸化カリウム、ｍＣＰＢＡ：メタクロロ過安息香酸、ＭｅＣＮ：アセトニトリル、ＭｅＯＨ：メタノール、ＭｇＳＯ4：無水硫酸マグネシウム、Ｎａ2ＣＯ3：炭酸ナトリウム、ＮａＨＣＯ3：炭酸水素ナトリウム、ＮａＯＨ：水酸化ナトリウム、ＮＭＭ：Ｎ－メチルモルホリン、ＴＥＡ：トリエチルアミン、ＴＨＦ：テトラヒドロフラン、ＰｄＣｌ2（ＰＰｈ3）2：ジクロロビス（トリフェニルホスフィン）パラジウム、Ｐｄ（ＰＰｈ3）4：テトラキス（トリフェニルホスフィン）パラジウム（０）、ＷＳＣ：Ｎ－エチル－Ｎ’－（３－ジメチルアミノプロピル）－カルボジイミド、ＷＳＣ・ＨＣｌ：Ｎ－エチル－Ｎ’－（３－ジメチルアミノプロピル）－カルボジイミド塩酸塩、Ｚｎ（ＣＮ）2：ジンクシアニド、ＥＳＩ－ＭＳ：ｅｌｅｃｔｒｏｓｐｒａｙ　ｉｏｎｉｚａｔｉｏｎ　ｍａｓｓ　ｓｐｅｃｔｒｏｍｅｔｒｙ（電子スプレーイオン化法質量分析）、ｍｐ：融点。 In the present specification, the following abbreviations may be used.
AcOEt or EtOAc: ethyl acetate, brine: saturated sodium chloride solution, BuOH: butanol, Cs 2 CO 3: Cesium carbonate, CHCl 3: chloroform, CuCl 2: Copper chloride, DCM: dichloromethane, DCC: dicyclohexylcarbodiimide, DEAD: Jiechiruazoji Carboxylate, DMSO: dimethyl sulfoxide, DMF: N, N-dimethylformamide, DMAP: 4-dimethylaminopyridine, DIPEA: diisopropylethylamine, DPPA: diphenylphosphate azide, EtOH: ethanol, HOBt: N-hydroxybenztriazole, IPE : diisopropyl ether, K 2 CO 3: potassium carbonate, KOH: potassium hydroxide, mCPBA: metachloroperbenzoic acid, MeCN: acetonitrile, MeOH: Ethanol, MgSO 4: anhydrous magnesium sulfate, Na 2 CO 3: sodium carbonate, NaHCO 3: sodium bicarbonate, NaOH: sodium hydroxide, NMM: N-methylmorpholine, TEA: triethylamine, THF: tetrahydrofuran, PdCl 2 (PPh 3 ) 2 : dichlorobis (triphenylphosphine) palladium, Pd (PPh 3 ) 4 : tetrakis (triphenylphosphine) palladium (0), WSC: N-ethyl-N ′-(3-dimethylaminopropyl) -carbodiimide, WSC · HCl: N-ethyl-N ′-(3-dimethylaminopropyl) -carbodiimide hydrochloride, Zn (CN) 2 : zinc cyanide, ESI-MS: electrospray ionization mass spectrometry (electronic spray) -Ionization mass spectrometry), mp: melting point.
（製造法）
　式（Ｉ）の化合物及びその塩は、その基本構造あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料から中間体へ至る段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことが製造技術上効果的な場合がある。このような保護基としては、例えば、ウッツ（Ｐ．　Ｇ．Ｍ．Ｗｕｔｓ）及びグリーン（Ｔ．Ｗ．Ｇｒｅｅｎｅ）著、「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（第４版、２００６年）」に記載の保護基等を挙げることができ、これらの反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行なった後、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
　また、式（Ｉ）の化合物のプロドラッグは、上記保護基と同様、原料から中間体へ至る段階で特定の基を導入、あるいは得られた式（Ｉ）の化合物を用いてさらに反応を行なうことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者に公知の方法を適用することにより行うことができる。
　以下、式（Ｉ）の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には限定されない。 (Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include, for example, “Green's Protective Groups in Organic Synthesis (4th edition, 2006)” by P. G. M. Wuts and Green (TW Green). The protecting groups described can be mentioned, and may be appropriately selected and used according to these reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
In addition, the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of formula (I). Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.
（第一製法）
　式（Ｉ）の化合物は、保護されたカルボン酸を脱保護して製造できる。当該脱保護は、加水分解、加水素分解または触媒的脱保護等により製造することができる。アルカリ加水分解の場合、無機塩基（ＮａＯＨ、ＫＯＨ、ＮａＨＣＯ3、Ｃｓ2ＣＯ3等）を用いる事ができる。酸加水分解の場合、塩酸等を用いることができる。いずれも反応温度は氷冷下から還流条件下で、基質が分解しない条件で反応を行うことができる。溶媒としては、アルコール（ＭｅＯＨ、ＥｔＯＨ等）、ＤＭＦまたはＤＭＳＯ等の有機溶媒や、水あるいはそれらの混合溶媒を用いることができる。加水素分解の場合、通常パラジウム触媒の存在下、水素雰囲気下で反応させることができる。ＤＭＦ、ＭｅＯＨ等の溶媒中、室温から還流までの反応温度で製造できる。触媒的脱保護の場合、パラジウム等の触媒を用い、塩基性条件下で製造できる。 (First manufacturing method)
Compounds of formula (I) can be prepared by deprotecting the protected carboxylic acid. The deprotection can be produced by hydrolysis, hydrogenolysis or catalytic deprotection. In the case of alkaline hydrolysis, an inorganic base (NaOH, KOH, NaHCO 3 , Cs 2 CO 3 or the like) can be used. In the case of acid hydrolysis, hydrochloric acid or the like can be used. In either case, the reaction can be carried out under conditions where the reaction temperature is from ice-cooling to reflux conditions and the substrate is not decomposed. As the solvent, an organic solvent such as alcohol (MeOH, EtOH, etc.), DMF or DMSO, water, or a mixed solvent thereof can be used. In the case of hydrogenolysis, the reaction can usually be carried out in a hydrogen atmosphere in the presence of a palladium catalyst. It can be produced at a reaction temperature from room temperature to reflux in a solvent such as DMF or MeOH. In the case of catalytic deprotection, it can be produced under basic conditions using a catalyst such as palladium.
（原料合成）
Figure JPOXMLDOC01-appb-C000007
［Ｒ1’、Ｒ2’及びＲ3’はそれぞれ、Ｒ1、Ｒ2及びＲ3のいずれかに有するカルボキシ基が保護された基を示す。］ (Raw material synthesis)
Figure JPOXMLDOC01-appb-C000007
[R 1 ′, R 2 ′ and R 3 ′ each represent a group in which a carboxy group in any of R 1 , R 2 and R 3 is protected. ]
　化合物（２ａ）は、化合物（１）のアミノ基と、対応するカルボン酸（Ｒ6－Ｅ－ＣＯＯＨ）とを反応させることにより製造できる。カルボン酸（Ｒ6－Ｅ－ＣＯＯＨ）は、（ｉ）そのまま反応系内で、縮合剤の存在下で化合物（１）と反応させる方法と、（ｉｉ）反応性誘導体へと誘導させた後に、化合物（１）と反応させる方法がある（Ｓｔｅｐ１－１）。 Compound (2a) can be produced by reacting the amino group of compound (1) with the corresponding carboxylic acid (R 6 -E-COOH). Carboxylic acid (R 6 -E-COOH) is (i) directly reacted with compound (1) in the presence of a condensing agent in the reaction system, and (ii) after being derivatized into a reactive derivative, There is a method of reacting with compound (1) (Step 1-1).
　（ｉ）のカルボン酸をそのまま系内で反応させる方法では、化合物（１）と対応するカルボン酸とを等量若しくは一方を過剰量用い、これらの混合物を縮合剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは－２０℃から６０℃で、０．１時間から５日間撹拌する。溶媒の例としては、特に限定はされないが、芳香族炭化水素類（ベンゼン、トルエンまたはキシレン等）、ハロゲン化炭化水素類（ＤＣＭ、１，２－ジクロロエタン若しくはクロロホルム等）、エーテル類（ジエチルエーテル、ＴＨＦまたはジオキサン等）、ＤＭＦ、ＤＭＳＯ、ＥｔＯＡｃ、ＭｅＣＮまたは水、及びこれらの混合溶媒が挙げられる。縮合剤の例としては、ＷＳＣ、ＤＣＣ、ＤＰＰＡ、オキシ塩化リンが挙げられるが、これらに限定されるものではない。添加剤（例えばＨＯＢｔ等）を用いることが反応に好ましい場合がある。有機塩基（例えばＴＥＡ、ＤＩＰＥＡまたはＮＭＭ等）、または無機塩基（例えば、Ｋ2ＣＯ3またはＫＯＨ等）の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。 In the method of reacting the carboxylic acid (i) as it is in the system, the compound (1) and the corresponding carboxylic acid are used in an equivalent amount or in excess, and the mixture is inactive in the presence of a condensing agent. In a solvent, the mixture is stirred for 0.1 hour to 5 days under cooling to heating, preferably at -20 ° C to 60 ° C. Examples of the solvent include, but are not limited to, aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (DCM, 1,2-dichloroethane, chloroform, etc.), ethers (diethyl ether, THF, dioxane and the like), DMF, DMSO, EtOAc, MeCN or water, and a mixed solvent thereof. Examples of condensing agents include, but are not limited to, WSC, DCC, DPPA, phosphorus oxychloride. It may be preferable for the reaction to use an additive (eg, HOBt). It may be advantageous to carry out the reaction in the presence of an organic base (such as TEA, DIPEA or NMM) or an inorganic base (such as K 2 CO 3 or KOH) in order to facilitate the reaction.
　（ｉｉ）のカルボン酸の反応性誘導体へ変換した後に、化合物（１）と反応させて化合物（２ａ）を得る方法では、カルボン酸の反応性誘導体の例として、ハロゲン化剤（例えば、オキシ塩化リン、塩化チオニル等）と反応して得られる酸ハロゲン化物、クロロギ酸イソブチル等と反応して得られる混合酸無水物、ＨＯＢｔ等と縮合して得られる活性エステル等が挙げられる。化合物（１）と反応性誘導体との反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類等の反応に不活性な溶媒中、冷却下から加熱下、好ましくは、－２０℃から６０℃で行うことができる。なお、反応に際して塩基（例えば、ＮＭＭ、ＴＥＡ、ＤＩＰＥＡ、ＤＭＡＰ、ピリジン、ピコリン、ルチジン等）の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。また、ピリジンは溶媒と兼ねることもできる。
［文献］Ｓ．Ｒ．Ｓａｎｄｌｅｒ及びＷ．　Ｋａｒｏ著、「Ｏｒｇａｎｉｃ　Ｆｕｎｃｔｉｏｎａｌ　Ｇｒｏｕｐ　Ｐｒｅｐａｒａｔｉｏｎｓ」、第２版、第１巻、Ａｃａｄｅｍｉｃ　Ｐｒｅｓｓ　Ｉｎｃ．、１９９１年
日本化学会編「実験化学講座（第５版）」１６巻（２００５年）（丸善） In the method of obtaining the compound (2a) by reacting with the compound (1) after conversion to the reactive derivative of the carboxylic acid of (ii), a halogenating agent (for example, oxychloride) is used as an example of the reactive derivative of the carboxylic acid. Phosphoric acid, thionyl chloride, etc.), acid halides obtained by reacting with them, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, etc., active esters obtained by condensation with HOBt, etc. The reaction of the compound (1) with the reactive derivative is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., from cooling to heating, preferably from −20 ° C. It can be performed at 60 ° C. In the reaction, it may be advantageous for the reaction to proceed smoothly in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). Pyridine can also serve as a solvent.
[Literature] R. Sandler and W.W. Karo, “Organic Functional Group Preparations”, 2nd edition, Volume 1, Academic Press Inc. 1991, Chemical Society of Japan "Experimental Chemistry Course (5th Edition)", Volume 16 (2005) (Maruzen)
　化合物（２ｂ）は、Ｓｔｅｐ１－１の条件を援用して製造できる。すなわち、試薬のカルボン酸遊離酸またはその反応性誘導体を用いる代わりに、スルホン酸の遊離酸またはその反応性誘導体を用いることにより化合物（２ｂ）が製造できる（Ｓｔｅｐ１－２）。 Compound (2b) can be produced with the aid of the conditions of Step 1-1. That is, instead of using the carboxylic acid free acid or its reactive derivative as a reagent, the compound (2b) can be produced by using the free acid of sulfonic acid or its reactive derivative (Step 1-2).
　化合物（２ｃ）は、化合物（１）にトリホスゲン等とＨＮ（Ｒ6a）（Ｒ6b）とを反応させて製造できる。反応は、通常塩基（例えば、ＮＭＭ、ＴＥＡ、ＤＩＰＥＡ、ＤＭＡＰ、ピリジン、ピコリン、ルチジン等）の存在下で行う。溶媒はハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、エステル類、ＭｅＣＮ、ＤＭＦまたはＤＭＳＯ等の反応に不活性な有機溶媒、またはそれらの混合溶媒が用いられる。また、反応は冷却下、冷却から室温下、あるいは室温から加熱下に行われる。 Compound (2c) can be produced by reacting compound (1) with triphosgene or the like and HN (R 6a ) (R 6b ). The reaction is usually performed in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). As the solvent, halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, MeCN, DMF, DMSO and other organic solvents inert to the reaction, or a mixed solvent thereof are used. The reaction is carried out under cooling, from cooling to room temperature, or from room temperature to heating.
Figure JPOXMLDOC01-appb-C000008
［式中、Ｘはハロゲン等の脱離基を意味する。］
　化合物（５）は、アルコールまたはチオールの化合物（３）と化合物（４）とをカップリングさせて、製造できる（Ｓｔｅｐ２－１）。塩基としては、無機塩基（例えばＮａＯＨ、ＫＯＨ、Ｋ2ＣＯ3、ＮａＨＣＯ3、Ｃｓ2ＣＯ3等）を用い、反応溶媒は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、ＥｔＯＡｃ等のエステル類、ＭｅＣＮ、ＤＭＦまたはＤＭＳＯ等の反応に不活性な有機溶媒、または、それらの混合溶媒が用いられる。また、反応は室温から加熱下に行われる。
Figure JPOXMLDOC01-appb-C000008
[Wherein X means a leaving group such as halogen. ]
Compound (5) can be produced by coupling alcohol or thiol compound (3) and compound (4) (Step 2-1). As the base, an inorganic base (for example, NaOH, KOH, K 2 CO 3 , NaHCO 3 , Cs 2 CO 3, etc.) is used, and the reaction solvent is a halogenated hydrocarbon, aromatic hydrocarbon, ether, EtOAc, etc. Or an organic solvent inert to the reaction, such as MeCN, DMF or DMSO, or a mixed solvent thereof. The reaction is carried out from room temperature under heating.
　化合物（１）は、化合物（４）のニトロ基を還元して製造できる（Ｓｔｅｐ２－２）。反応は、芳香族ニトロ基の還元方法が用いられ、通常、塩酸条件下で鉄粉末を反応、または接触還元等によって製造することができる。
　なお、上述の製造法および中間体製造法に記載した以外の実施例化合物および中間体を製造する場合には、本明細書の製造例、もしくは実施例に記載の方法、またはそれに準じた方法を採用することもでき、さらに、公知の方法、当業者にとって自明である方法により製造することができる。 Compound (1) can be produced by reducing the nitro group of compound (4) (Step 2-2). For the reaction, a method for reducing an aromatic nitro group is used. Usually, iron powder can be produced by reaction or catalytic reduction under hydrochloric acid conditions.
In addition, when producing Example compounds and intermediates other than those described in the above-described production methods and intermediate production methods, the production examples in this specification, the methods described in the Examples, or methods according thereto are used. Further, it can be produced by a known method or a method obvious to those skilled in the art.
　さらに、式（Ｉ）で示されるいくつかの化合物は、以上のように製造された本発明化合物から、公知のアルキル化、アシル化、置換反応、酸化、還元、加水分解、脱保護など当業者が通常採用しうる工程を任意に組み合わせることにより製造することもできる。 Furthermore, some compounds represented by the formula (I) can be obtained from the compounds of the present invention produced as described above by known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection and the like. Can be produced by arbitrarily combining the processes that can normally be employed.
　式（Ｉ）の化合物は、遊離化合物、その塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。式（Ｉ）の化合物の塩は、常法の造塩反応に付すことにより製造することもできる。
　単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等、通常の化学操作を適用して行なわれる。
　各種の異性体は、適当な原料化合物を選択することにより製造でき、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は、ラセミ体の一般的な光学分割法（例えば、光学活性な塩基または酸とのジアステレオマー塩に導く分別結晶化や、キラルカラム等を用いたクロマトグラフィー等）により得られ、また、適当な光学活性な原料化合物から製造することもできる。 The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
　式（Ｉ）の化合物の薬理活性は、以下の試験により確認した。
試験例１－１：膜標本の調製
　ヒトＣＲＴＨ２　ｃＤＮＡを持続的に発現させたＨＥＫ２９３細胞をバッファー（１０　ｍＭ　ＢＥＳ（Ｎ，Ｎ－ｂｉｓ　（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－２－ａｍｉｎｏ－ｅｔｈａｎｅ－ｓｕｌｆｏｎｉｃ　ａｃｉｄ）、１　ｍＭ　ＥＤＴＡ、１０　ｍＭ　ＭｎＣｌ2、ｐＨ＝７．０、以下アッセイバッファーと記す）中で２６ゲージ注射針内をすばやく通過させ破砕することにより調製した細胞膜を含む懸濁液を膜標本として－８０℃で保存した。以後、用時融解して試験を行った。 The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test Example 1-1: Preparation of Membrane Specimen HEK293 cells continuously expressing human CRTH2 cDNA were buffered (10 mM BES (N, N-bis (2-hydroxyethyl) -2-amino-ethane-sulfonic acid), (1 mM EDTA, 10 mM MnCl 2 , pH = 7.0, hereinafter referred to as assay buffer), a suspension containing a cell membrane prepared by quickly passing through a 26 gauge needle and crushing was used as a membrane specimen. Stored at ° C. Thereafter, the test was conducted after melting at the time of use.
試験例１－２：ＣＲＴＨ２結合実験
　膜標本（１アッセイ当たり蛋白量として５０　μｇ使用）、被験化合物及びトリチウムラベルされたＰＧＤ２（最終濃度：２　ｎＭ）を０．２　ｍＬのアッセイバッファー中で４℃にて２時間インキュベートした後、反応液をＧＦ／Ｂプレート（ＰｅｒｋｉｎＥｌｍｅｒ）のフィルター上に吸引濾過し、洗浄用バッファー（１０ｍＭ　ＢＥＳ、０．０１％　ＢＳＡ）で３回洗浄後、フィルターに吸着した放射活性をＴｏｐＣｏｕｎｔ（ＰｅｒｋｉｎＥｌｍｅｒ）で測定した。尚、ＣＲＴＨ２特異的な結合は１０　μＭのＤＫ－ＰＧＤ２を添加した際に阻害される放射活性部分として求めた。 Test Example 1-2: CRTH2 Binding Experiment Membrane specimen (50 μg of protein used per assay), test compound and tritium-labeled PGD2 (final concentration: 2 nM) in 0.2 mL of assay buffer at 4 ° C. After 2 hours of incubation, the reaction solution was suction filtered onto a filter on a GF / B plate (PerkinElmer), washed 3 times with a washing buffer (10 mM BES, 0.01% BSA), and then the radiation adsorbed on the filter. Activity was measured with TopCount (PerkinElmer). CRTH2-specific binding was determined as a radioactive moiety that was inhibited when 10 μM DK-PGD2 was added.
　その結果、例えば本発明化合物である以下の実施例化合物（Ｅｘ）はそれぞれ以下の活性値（ＩＣ50値）を示した。Ｅｘ１：９．１　ｎＭ、Ｅｘ６：１１　ｎＭ、Ｅｘ１８：１４　ｎＭ、Ｅｘ３０：２．９　ｎＭ、Ｅｘ３４：１０　ｎＭ、Ｅｘ３５：５．６　ｎＭ、Ｅｘ３７：４．８　ｎＭ、Ｅｘ４３：９．９　ｎＭ、Ｅｘ５５：４．１　ｎＭ、Ｅｘ５６：８．７　ｎＭ、Ｅｘ９４：４．８　ｎＭ、Ｅｘ１０９：４．９　ｎＭ、Ｅｘ１４０：０．５３　ｎＭ、Ｅｘ１５１：１．０　ｎＭ、Ｅｘ１５２：２０　ｎＭ。 As a result, for example, the following Example compounds (Ex) which are the compounds of the present invention exhibited the following activity values (IC 50 values). Ex1: 9.1 nM, Ex6: 11 nM, Ex18: 14 nM, Ex30: 2.9 nM, Ex34: 10 nM, Ex35: 5.6 nM, Ex37: 4.8 nM, Ex43: 9.9 nM, Ex55: 4.1 nM, Ex56: 8.7 nM, Ex94: 4.8 nM, Ex109: 4.9 nM, Ex140: 0.53 nM, Ex151: 1.0 nM, Ex152: 20 nM.
試験例２：モルモット抗原誘発気道反応性亢進モデル
　本発明化合物の抗喘息作用はＢｕｒｇｅｓｓらの方法（Ａｇｅｎｔｓ　Ａｃｔｉｏｎｓ、１９９２年、３７（３－４）巻、ｐ．１６２－１６４）に若干の変更を加えたモルモット抗原誘発気道反応性亢進モデルにより評価した。
　即ち、雄性Ｈａｒｔｌｅｙ系モルモットに２０　ｍｇ／ｍＬの卵白アルブミン（以下、ＯＶＡと記す）生理食塩液を１　ｍＬ腹腔内投与（初回感作，Ｄａｙ　０とする）し、さらにＤａｙ　２に１　ｍｇ／ｍＬのＯＶＡ生理食塩液を１　ｍＬ腹腔内投与することにより能動的に抗原感作を行った。Ｄａｙ　１４から２１に超音波ネブライザ（オムロン）を用いて、動物に０．５　％　ＯＶＡ生理食塩液を１日１回１０分間吸入曝露（生理食塩液対照群は生理食塩液を吸入曝露）した。被験化合物は抗原吸入曝露開始の１時間前または４時間前に経口投与した。また、アナフィラキシーを防ぐために吸入曝露開始の３０分前にピリラミンを１０　ｍｇ／ｋｇにて腹腔内投与した。
　Ｄａｙ　２２にウレタン（１．５　ｇ／ｋｇ、腹腔内投与）麻酔下で動物の気管に人工呼吸器（Ｍｏｄｅｌ　６８３，Ｈａｒｖａｒｄ社）に接続されたカニューレを挿入し、ガラミン（６　ｍｇ／ｋｇ、腹腔内投与）で自発呼吸を停止させ、機械的換気（換気速度：毎分６０ストローク，換気量：体重１００　ｇ当たり１　ｍＬ）下でメサコリン（０、２、４、６、８、１０、１２、１４　μｇ／ｋｇ）を３分間隔で順次静脈内投与した。圧トランスデューサーにより気道内圧の上昇を測定し、メサコリン投与量と気道内圧上昇をプロットした際の濃度曲線下面積（ＡＵＣ）を算出した。
　その結果、本発明化合物中、例えば以下の表に示す実施例化合物は有効な活性を示すことが判明した。 Test Example 2: Guinea Pig Antigen-Induced Airway Reactivity Model The anti-asthmatic action of the compound of the present invention is a slight modification to the method of Burgess et al. (Agents Actions, 1992, 37 (3-4), p. 162-164). The guinea pig antigen-induced airway hyperresponsiveness model was evaluated.
That is, 20 mg / mL ovalbumin (hereinafter referred to as OVA) physiological saline is intraperitoneally administered to male Hartley guinea pigs (first sensitization, referred to as Day 0), and further, 1 mg / mL in Day 2 Antigen sensitization was performed by intraperitoneally administering 1 mL of OVA physiological saline. Using an ultrasonic nebulizer (OMRON) from Day 14 to 21, animals were inhaled by exposure to 0.5% OVA physiological saline once a day for 10 minutes (in the physiological saline control group, physiological saline was inhaled). The test compound was orally administered 1 hour or 4 hours before the start of antigen inhalation exposure. In order to prevent anaphylaxis, pyriramine was intraperitoneally administered at 10 mg / kg 30 minutes before the start of inhalation exposure.
On Day 22, a cannula connected to a ventilator (Model 683, Harvard) was inserted into the trachea of an animal under urethane (1.5 g / kg, intraperitoneal) anesthesia, and galamine (6 mg / kg, abdominal cavity). Self-breathing is stopped by methacolin (0, 2, 4, 6, 8, 10, 12, under mechanical ventilation (ventilation rate: 60 strokes per minute, ventilation: 1 mL per 100 g body weight)). 14 μg / kg) were sequentially administered intravenously at intervals of 3 minutes. The increase in airway pressure was measured with a pressure transducer, and the area under the concentration curve (AUC) when the mesacholine dose and the increase in airway pressure were plotted was calculated.
As a result, among the compounds of the present invention, for example, the example compounds shown in the following table were found to exhibit effective activity.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　上記試験の結果、式（Ｉ）の化合物はＣＲＴＨ２に対しアンタゴニスト活性を有することが確認された。従って、炎症性疾患（例えば、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、血管炎、慢性閉塞性肺疾患等）または多発性硬化症等の治療等に使用できる。 As a result of the above test, it was confirmed that the compound of the formula (I) has antagonist activity against CRTH2. Therefore, inflammatory diseases (eg asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, vasculitis, chronic obstructive pulmonary disease etc.) or multiple It can be used to treat sclerosis.
　なお、本願のうち、例えば、実施例化合物のカルボン酸がエステルになった製造例化合物は、活性を示さなかった。本発明における実施例化合物のカルボン酸の酸性プロトンが、ＣＲＴＨ２に対するアンタゴニスト活性発現に重要であることが判明した。 In the present application, for example, the production example compound in which the carboxylic acid of the example compound became an ester did not show activity. The acidic proton of the carboxylic acid of the example compound in the present invention was found to be important for the expression of antagonist activity against CRTH2.
　式（Ｉ）の化合物またはその塩の１種または２種以上を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤溶担体等を用いて、通常使用されている方法によって調製することができる。
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、または、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 Pharmaceutical compositions containing one or more of the compounds of formula (I) or salts thereof as active ingredients are excipients commonly used in the art, that is, pharmaceutical excipients and drug-soluble carriers. Can be prepared by a commonly used method.
Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
　経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、１種または２種以上の有効成分を、少なくとも１種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び／またはメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤または丸剤は必要により糖衣または胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤またはエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水またはエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
　非経口投与のための注射剤は、無菌の水性または非水性の溶液剤、懸濁剤または乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水または生理食塩液が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコールまたはオリーブ油のような植物油、エタノールのようなアルコール類、またはポリソルベート８０（局方名）等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、または溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合または照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水または無菌の注射用溶媒に溶解または懸濁して使用することもできる。 The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
　外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性または非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏またはローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。 External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
　吸入剤や経鼻剤等の経粘膜剤は固体、液体または半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、ｐＨ調製剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入または吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独でまたは処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液または懸濁液として投与することができる。乾燥粉末吸入器等は、単回または多数回の投与用のものであってもよく、乾燥粉末または粉末含有カプセルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカンまたは二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。 As a transmucosal agent such as an inhalant or a nasal agent, a solid, liquid or semi-solid agent is used and can be produced according to a conventionally known method. For example, known excipients and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administrations, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
　通常経口投与の場合、１日の投与量は、体重当たり約０．００１から１００　ｍｇ／ｋｇ、好ましくは０．１から３０　ｍｇ／ｋｇ、更に好ましくは０．１から１０　ｍｇ／ｋｇが適当であり、これを１回であるいは２回から４回に分けて投与する。静脈内投与される場合は、１日の投与量は、体重当たり約０．０００１から１０　ｍｇ／ｋｇが適当で、１日１回から複数回に分けて投与する。また、経粘膜剤としては、体重当たり約０．００１から１００　ｍｇ／ｋｇを１日１回から複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 In the case of normal oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Yes, this is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once a day or in multiple doses. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once a day in a plurality of divided doses. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
　式（Ｉ）の化合物は、前述の式（Ｉ）の化合物が有効性を示すと考えられる疾患の種々の治療剤または予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.
　以下、実施例に基づき、式（Ｉ）の化合物の製造法をさらに詳細に説明する。なお、本発明は、下記実施例に記載の化合物に限定されるものではない。また、原料化合物の製法を製造例にそれぞれ示す。また、式（Ｉ）の化合物の製造法は、以下に示される具体的実施例の製造法のみに限定されるものではなく、式（Ｉ）の化合物はこれらの製造法の組み合わせ、あるいは当業者に自明である方法によっても製造されうる。 Hereinafter, based on an Example, the manufacturing method of the compound of Formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown in a manufacture example, respectively. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
　また、実施例、製造例及び後記表中において、以下の略号を用いることがある。Ｐｒ：製造例番号、Ｅｘ：実施例番号、Ｓｔｒｕｃｔｕｒｅ：構造式、Ｄａｔａ：物理化学データ、ＮＭＲ：1Ｈ－ＮＭＲ（ｄ6－ＤＭＳＯ）、ＮＭＲ（ＣＤＣｌ3）：1Ｈ－ＮＭＲ（ＣＤＣｌ3）、ＥＳＩ：ＥＳＩ－ＭＳ Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below. Pr: Production example number, Ex: Example number, Structure: Structural formula, Data: Physicochemical data, NMR: 1 H-NMR (d 6 -DMSO), NMR (CDCl 3 ): 1 H-NMR (CDCl 3 ) , ESI: ESI-MS
製造例１
　３－クロロ－４－ヒドロキシフェニル酢酸エチル（５．６６　ｇ）のＤＭＦ（１００　ｍＬ）溶液に、Ｋ2ＣＯ3（４．７４　ｇ）とジメチルチオカルバモイルクロライド（３．７５　ｇ）を加え、５０℃で５時間撹拌した。反応混合物を水（５００　ｍＬ）に注ぎ、ＥｔＯＡｃ（３００　ｍＬ）で抽出した。有機層を水（２００　ｍＬ）、ｂｒｉｎｅ（２００　ｍＬ）で洗浄後、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮することにより、３－クロロ－４－（ジメチルアミノカルボノチオニルオキシ）フェニル酢酸エチル（７．６９　ｇ）を橙色オイルとして得た。 Production Example 1
To a solution of ethyl 3-chloro-4-hydroxyphenylacetate (5.66 g) in DMF (100 mL) was added K 2 CO 3 (4.74 g) and dimethylthiocarbamoyl chloride (3.75 g). Stir at 5 ° C. for 5 hours. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give ethyl 3-chloro-4- (dimethylaminocarbonothionyloxy) phenylacetate. (7.69 g) was obtained as an orange oil.
製造例２
　｛３－クロロ－４－（ジメチルアミノカルボノチオニルオキシ）フェニル｝酢酸エチル（７．６　ｇ）を、外温２４０℃で３時間撹拌した。反応物を、シリカゲルカラムクロマトグラフィー（ｎ－ｈｅｘａｎｅ／ＥｔＯＡｃ）で精製し、（３－クロロ－４－（（ジメチルカルバモイル）スルファニル）フェニル）酢酸エチル（１．６５　ｇ）を橙色オイルとして得た。 Production Example 2
{3-Chloro-4- (dimethylaminocarbonothionyloxy) phenyl} ethyl acetate (7.6 g) was stirred at an external temperature of 240 ° C. for 3 hours. The reaction was purified by silica gel column chromatography (n-hexane / EtOAc) to give ethyl (3-chloro-4-((dimethylcarbamoyl) sulfanyl) phenyl) acetate (1.65 g) as an orange oil.
製造例３　
　｛３－クロロ－４－（ジメチルカルバモイルスルファニル）フェニル｝酢酸エチル（１．６４　ｇ）をＭｅＯＨ（１６．４　ｍＬ）に溶かし、ＫＯＨ（１．５２　ｇ）の水（８．２　ｍＬ）溶液を加え、５０　℃で２時間撹拌した。反応混合物を減圧濃縮し、残渣を水（１０　ｍＬ）に溶解し、室温撹拌下、１Ｍ　塩酸（４０　ｍＬ）へ滴下した。３０分間以上撹拌後、析出物をろ取した。ろ取物を乾燥させて、（３－クロロ－４－スルファニルフェニル）酢酸（０．９３　ｇ）を淡黄色粉末として得た。 Production Example 3
Dissolve ethyl {3-chloro-4- (dimethylcarbamoylsulfanyl) phenyl} acetate (1.64 g) in MeOH (16.4 mL) and add a solution of KOH (1.52 g) in water (8.2 mL). The mixture was further stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL) and added dropwise to 1M hydrochloric acid (40 mL) with stirring at room temperature. After stirring for 30 minutes or more, the precipitate was collected by filtration. The filtered product was dried to obtain (3-chloro-4-sulfanylphenyl) acetic acid (0.93 g) as a pale yellow powder.
　後記表に示す製造例３－１から３－２の化合物は、実施例１と同様に、対応する原料を用いて製造した。 The compounds of Production Examples 3-1 to 3-2 shown in the table below were produced using the corresponding raw materials in the same manner as in Example 1.
製造例４　
　｛４－（４－アミノフェノキシ）－３－クロロフェニル｝酢酸エチル（１．５０　ｇ）のＤＣＭ（３０　ｍＬ）溶液に３，４－ジクロロ安息香酸（１．１２　ｇ）、ＷＳＣ・ＨＣｌ（１．１３　ｇ）、ＨＯＢｔ（７９５　ｍｇ）を加え室温で６時間攪拌した。反応液を水（１５０　ｍＬ）に注いだ後、ＥｔＯＡｃ（３００　ｍＬ）で抽出した。有機層を水（１５０　ｍＬ）、ｂｒｉｎｅで洗浄後、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、３－クロロ－４－｛４－（３，４－ジクロロベンゾイルアミノ）フェノキシ｝フェニル酢酸エチル（１．９０　ｇ）を淡黄色固体として得た。 Production Example 4
To a solution of ethyl {4- (4-aminophenoxy) -3-chlorophenyl} acetate (1.50 g) in DCM (30 mL), 3,4-dichlorobenzoic acid (1.12 g), WSC · HCl (1. 13 g) and HOBt (795 mg) were added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (150 mL) and brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl 3-chloro-4- {4- (3,4-dichlorobenzoylamino) phenoxy} phenyl acetate (1.90 g) as a pale yellow solid.
　後記表に示す製造例４－１から４－１３６の化合物を、製造例４と同様に、対応する原料を用いて製造した。 In the same manner as in Production Example 4, the compounds of Production Examples 4-1 to 4-136 shown in the table below were produced using the corresponding raw materials.
製造例５
　｛４－（６－アミノピリジン－３－イルオキシ）－３－クロロフェニル｝酢酸エチル（１５０　ｍｇ）のＤＣＭ（３　ｍＬ）溶液　に３，４－ジクロロベンゾイルクロライド（１０８　ｍｇ）、　ＴＥＡ（８２　μＬ）、ＤＭＡＰ（１２　ｍｇ）を加え、室温下、一晩攪拌した。反応混合物を水に注ぎ、ＥｔＯＡｃで抽出した。有機層を、飽和ＮａＨＣＯ3水溶液、水、ｂｒｉｎｅで順次洗浄した後、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ｈｅｘａｎｅ：ＥｔＯＡｃ＝３：１）で精製し、［３－クロロ－４－（｛６－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－３－イル｝オキシ）フェニル］酢酸エチル（２０９．５　ｍｇ）を無色ガム状物として得た。 Production Example 5
To a solution of ethyl {4- (6-aminopyridin-3-yloxy) -3-chlorophenyl} acetate (150 mg) in DCM (3 mL), 3,4-dichlorobenzoyl chloride (108 mg), TEA (82 μL), DMAP (12 mg) was added and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with a saturated aqueous NaHCO 3 solution, water and brine, then dried over MgSO 4 and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 1), and [3-chloro-4-({6-[(3,4-dichlorobenzoyl) amino] pyridine-3- Yl} oxy) phenyl] ethyl acetate (209.5 mg) was obtained as a colorless gum.
製造例６
　［４－（４－アミノフェノキシ）－３－クロロフェニル］酢酸エチル（３００　ｍｇ）のＴＨＦ（６　ｍＬ）溶液に氷冷下、ＴＥＡ（４１０　μＬ）とトリホスゲン（１４６　ｍｇ）を加え１時間攪拌した後、１，２，３，４－テトラヒドロイソキノリン（１３７　μＬ）を加え、室温で終夜攪拌した。反応液をＥｔＯＡｃで希釈した後、１Ｍ　塩酸、ｂｒｉｎｅで順次洗浄し、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、（３－クロロ－４－｛４－［（３，４－ジヒドロイソキノリン－２（１Ｈ）－イルカルボニル）アミノ］フェノキシ｝フェニル）酢酸エチル（２４３　ｍｇ）を淡褐色アモルファスとして得た。 Production Example 6
To a solution of ethyl [4- (4-aminophenoxy) -3-chlorophenyl] acetate (300 mg) in THF (6 mL) was added TEA (410 μL) and triphosgene (146 mg) under ice cooling, and the mixture was stirred for 1 hour. 1,2,3,4-tetrahydroisoquinoline (137 μL) was added and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed successively with 1M hydrochloric acid and brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl (3-chloro-4- {4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy} phenyl) acetate (243 mg ) Was obtained as a light brown amorphous.
　後記表に示す製造例６－１から６－８の化合物を、製造例６と同様に、対応する原料を用いて製造した。 The compounds of Production Examples 6-1 to 6-8 shown in the table below were produced in the same manner as in Production Example 6 using the corresponding raw materials.
製造例７
　［３－クロロ－４－（４－｛（４－ニトロフェノキシカルボニル）アミノ｝フェノキシ）フェニル］酢酸エチル（２５０　ｍｇ）とＴＥＡ（１４８　μＬ）のＴＨＦ（５　ｍＬ）溶液に氷冷下、フェネチルアミン（８０．４　μＬ）を加え、室温で１時間攪拌した。反応液を水に注いだ後、ＥｔＯＡｃで抽出した。有機層を飽和ＮａＨＣＯ3水、水、ｂｒｉｎｅで順次洗浄後、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮した。残渣をＩＰＥを用いて洗浄し、［３－クロロ－４－（４－｛［（２－フェニルエチル）カルバモイル］アミノ｝フェノキシ）フェニル］酢酸エチル（２０３　ｍｇ）を白色粉末として得た。 Production Example 7
[3-Chloro-4- (4-{(4-nitrophenoxycarbonyl) amino} phenoxy) phenyl] ethyl acetate (250 mg) and TEA (148 μL) in THF (5 mL) were added with phenethylamine (5 mL) under ice-cooling. 80.4 μL) was added and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with saturated NaHCO 3 water, water and brine, dried over MgSO 4 and the filtrate was concentrated under reduced pressure. The residue was washed with IPE to give ethyl [3-chloro-4- (4-{[(2-phenylethyl) carbamoyl] amino} phenoxy) phenyl] acetate (203 mg) as a white powder.
　後記表に示す製造例７－１及び７－２の化合物を、製造例７と同様に、対応する原料を用いて製造した。 In the same manner as in Production Example 7, the compounds of Production Examples 7-1 and 7-2 shown in the table below were produced using the corresponding raw materials.
製造例８
　（３－クロロ－４－ヒドロキシフェニル）酢酸（３．００　ｇ）のＥｔＯＨ（３０　ｍＬ）溶液に濃硫酸（８９．３　μＬ）を加え、室温で終夜攪拌した。反応液を水に注いだ後、ＥｔＯＡｃで抽出した。有機層を水、飽和ＮａＨＣＯ3水、水、ｂｒｉｎｅで順次洗浄した後、ＭｇＳＯ4で乾燥後、ろ液を減圧濃縮して（３－クロロ－４－ヒドロキシフェニル）酢酸エチル（３．３０　ｇ）を褐色油状物質として得た。 Production Example 8
Concentrated sulfuric acid (89.3 μL) was added to a solution of (3-chloro-4-hydroxyphenyl) acetic acid (3.00 g) in EtOH (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with water, saturated aqueous NaHCO 3 , water and brine, then dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to obtain ethyl (3-chloro-4-hydroxyphenyl) acetate (3.30 g). Was obtained as a brown oil.
　後記表に示す製造例８－１及び８－５の化合物を、製造例８と同様に、対応する原料を用いて製造した。 In the same manner as in Production Example 8, the compounds of Production Examples 8-1 and 8-5 shown in the table below were produced using the corresponding raw materials.
製造例９
　［４－（４－アミノフェノキシ）－３－クロロフェニル］酢酸エチル（１．５０　ｇ）のＤＣＭ（３０　ｍＬ）溶液に氷冷下ピリジン（１．３１　ｍＬ）を加え１０分間攪拌し、クロロギ酸（４－ニトロフェニル）（１．１９　ｇ）を徐々に加え室温で２時間攪拌した。反応液に水（１００　ｍＬ）を加え１０分間攪拌した後、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄した後、ＭｇＳＯ4で乾燥しろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ｈｅｘａｎｅ：ＥｔＯＡｃ＝３：２－０：１）で精製し、得られた粗結晶を混合溶媒（ＤＣＭ：ＩＰＥ＝１：４）で洗浄して［３－クロロ－４－（４－｛［（４－ニトロフェノキシ）カルボニル］アミノ｝フェノキシ）フェニル］酢酸エチル（２．３６　ｇ）を白色粉末として得た。 Production Example 9
Pyridine (1.31 mL) was added to a solution of ethyl [4- (4-aminophenoxy) -3-chlorophenyl] acetate (1.50 g) in DCM (30 mL) under ice-cooling, and the mixture was stirred for 10 min. 4-Nitrophenyl) (1.19 g) was gradually added and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, stirred for 10 minutes, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 2-0: 1), and the resulting crude crystals were washed with a mixed solvent (DCM: IPE = 1: 4) [3-chloro Ethyl-4- (4-{[(4-nitrophenoxy) carbonyl] amino} phenoxy) phenyl] acetate (2.36 g) was obtained as a white powder.
製造例１０
　［４－（４－｛［（５－ブロモ－１－ベンゾフラン－２－イル）カルボニル］アミノ｝フェノキシ）－３－クロロフェニル］酢酸エチルのＤＭＦ（５　ｍＬ）溶液にＺｎ（ＣＮ）2（１３３　ｍｇ）とＰｄ（ＰＰｈ3）4（１７５　ｍｇ）を加え、マイクロウェーブ照射下で１５０　℃で１時間反応させた。不溶物をろ別し、ろ液に水（５０　ｍＬ）を加え、ＥｔＯＡｃ（４０　ｍＬ）で抽出した。有機層を水、ｂｒｉｎｅで順次洗浄し、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮し、褐色オイル（５７０　ｍｇ）を得た。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ｈｅｘａｎｅ：ＥｔＯＡｃ＝２：１）で精製し、［３－クロロ－４－（４－｛［（５－シアノ－１－ベンゾフラン－２－イル）カルボニル］アミノ｝フェノキシ）フェニル］酢酸エチル（１９９．３　ｍｇ）を白色固体として得た。 Production Example 10
Zn (CN) 2 (133 mg) was added to a solution of ethyl [4- (4-{[(5-bromo-1-benzofuran-2-yl) carbonyl] amino} phenoxy) -3-chlorophenyl] acetate in DMF (5 mL). ) And Pd (PPh 3 ) 4 (175 mg) were added and reacted at 150 ° C. for 1 hour under microwave irradiation. Insoluble material was filtered off, water (50 mL) was added to the filtrate, and the mixture was extracted with EtOAc (40 mL). The organic layer was washed successively with water and brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give a brown oil (570 mg). The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 2: 1), and [3-chloro-4- (4-{[(5-cyano-1-benzofuran-2-yl) carbonyl] amino} Phenoxy) phenyl] ethyl acetate (199.3 mg) was obtained as a white solid.
製造例１１
　［４－（４－アミノフェノキシ）－３－クロロフェニル］酢酸エチル（３００　ｍｇ）のＤＣＭ（６　ｍＬ）溶液にピリジン（９５．２　μＬ）とベンゼンスルホニルクロリド（１３８　μＬ）を加え室温で終夜攪拌した。反応液を水に注いだ後、ＥｔＯＡｃを用いて抽出した。有機層を水、ｂｒｉｎｅで順次洗浄した後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、（３－クロロ－４－｛４－［（フェニルスルホニル）アミノ］フェノキシ｝フェニル）酢酸エチル（４１０　ｍｇ）を白色粉末として得た。 Production Example 11
Pyridine (95.2 μL) and benzenesulfonyl chloride (138 μL) were added to a solution of ethyl [4- (4-aminophenoxy) -3-chlorophenyl] acetate (300 mg) in DCM (6 mL) and stirred at room temperature overnight. . The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (3-chloro-4- {4-[(phenylsulfonyl) amino] phenoxy} phenyl) acetate (410 mg) as a white powder.
　後記表に示す製造例１１－１の化合物を、製造例１１と同様に、対応する原料を用いて製造した。 The compound of Production Example 11-1 shown in the table below was produced in the same manner as in Production Example 11 using the corresponding raw materials.
製造例１２
　ボラン－ＴＨＦ錯体（１．１７　Ｍ、１２．８　ｍＬ）に氷冷下、シクロヘキセン（３．０４　ｍＬ）を加え５分間攪拌した後、｛［２，５－ジクロロ－４－（４－ニトロフェノキシ）フェニル］エチニル｝（トリメチル）シラン（１．６３　ｇ）のＴＨＦ（２５　ｍＬ）溶液を加え同温で２時間攪拌した。反応液に１Ｍ　ＮａＯＨ水溶液（１０．７　ｍＬ）とＭｅＯＨ（１２．５　ｍＬ）を加えた後、過酸化水素水（３０％，　４．８６　ｍＬ）を加え同温で１時間攪拌した。反応液を水に注いだ後、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をＥｔＯＨ（５　ｍＬ）に溶解した後、濃硫酸を１滴加え、４時間加熱還流した。反応液を室温まで冷却した後、水に注ぎ、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、［２，５－ジクロロ－４－（４－ニトロフェノキシ）フェニル］酢酸エチル（５１０　ｍｇ）を茶色油状物質として得た。 Production Example 12
Cyclohexene (3.04 mL) was added to borane-THF complex (1.17 M, 12.8 mL) under ice-cooling, and the mixture was stirred for 5 minutes, and then {[2,5-dichloro-4- (4-nitrophenoxy). ) Phenyl] ethynyl} (trimethyl) silane (1.63 g) in THF (25 mL) was added and stirred at the same temperature for 2 hours. 1M NaOH aqueous solution (10.7 mL) and MeOH (12.5 mL) were added to the reaction solution, hydrogen peroxide solution (30%, 4.86 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (5 mL), 1 drop of concentrated sulfuric acid was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give [2,5-dichloro-4- (4-nitrophenoxy) phenyl] ethyl acetate (510 mg) as a brown oil.
製造例１３
　１－ブロモ－２，５－ジクロロ－４－（４－ニトロフェノキシ）ベンゼン（１．８５　ｇ）とＴＥＡ（１．０７　ｍＬ）のＭｅＣＮ（１０　ｍＬ）溶液にジクロロビス（トリフェニルホスフィン）パラジウム（３５８　ｍｇ）、ヨウ化銅（Ｉ）（１９４　ｍｇ）、（トリメチルシリル）アセチレン（２．１２　ｍＬ）を加え、マイクロウェーブ照射下８０　℃で２時間反応させた。反応液を水に注いだ後、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄した後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、｛［２，５－ジクロロ－４－（４－ニトロフェノキシ）フェニル］エチニル｝（トリメチル）シラン（１．６３　ｇ）を茶色油状物質として得た。 Production Example 13
A solution of 1-bromo-2,5-dichloro-4- (4-nitrophenoxy) benzene (1.85 g) and TEA (1.07 mL) in MeCN (10 mL) was added to dichlorobis (triphenylphosphine) palladium (358). mg), copper (I) iodide (194 mg), (trimethylsilyl) acetylene (2.12 mL) were added, and the mixture was reacted at 80 ° C. for 2 hours under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain {[2,5-dichloro-4- (4-nitrophenoxy) phenyl] ethynyl} (trimethyl) silane (1.63 g) as a brown oily substance.
製造例１４
　｛３－クロロ－４－（４－ニトロフェノキシ）フェニル｝酢酸エチル（２．３０　ｇ）のＥｔＯＨ（４６　ｍＬ）－水（１１．５　ｍＬ）溶液に塩化アンモニウム（３．６６　ｇ）と鉄粉末（３．８３　ｇ）を加え、３時間加熱還流した。反応液をセライトでろ過した後、減圧濃縮し、飽和ＮａＨＣＯ3を加えた後、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄した後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮することにより、｛４－（４－アミノフェノキシ）－３－クロロフェニル｝酢酸エチル（２．３０　ｇ）を褐色油状物質として得た。 Production Example 14
{3-Chloro-4- (4-nitrophenoxy) phenyl} ethyl acetate (2.30 g) in EtOH (46 mL) -water (11.5 mL) in ammonium chloride (3.66 g) and iron powder (3.83 g) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered through celite, concentrated under reduced pressure, saturated NaHCO 3 was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give ethyl {4- (4-aminophenoxy) -3-chlorophenyl} acetate (2.30 g) as a brown oily substance. Got as.
　後記表に示す製造例１４－１から１４－１５の化合物を、製造例１４と同様に、対応する原料を用いて製造した。 In the same manner as in Production Example 14, the compounds of Production Examples 14-1 to 14-15 shown in the table below were produced using the corresponding raw materials.
製造例１５
　氷冷下、（２－ブロモ－４－メトキシフェニル）酢酸エチル（４．４　ｇ）のＤＣＭ（４４　ｍＬ）溶液に１Ｍ　ＢＢｒ3のＤＣＭ溶液（２４．１　ｍＬ）を滴下した。５℃で５時間攪拌した後、反応混合物にＥｔＯＨ（３０　ｍＬ）を氷冷下、滴下して反応を停止し、減圧濃縮し、得られた残渣をＥｔＯＡｃ（１５０　ｍＬ）で抽出した。有機層を水（１００　ｍＬ）、ｂｒｉｎｅ（１００　ｍＬ）で順次洗浄し、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をｎ－ｈｅｘａｎｅ／ＩＰＥで粉末化後ろ取し、減圧乾燥することにより、（２－ブロモ－４－ヒドロキシフェニル）酢酸エチル（２．５６　ｇ）を白色固体として得た。 Production Example 15
Under ice-cooling, 1M BBr 3 in DCM (24.1 mL) was added dropwise to a solution of ethyl (2-bromo-4-methoxyphenyl) acetate (4.4 g) in DCM (44 mL). After stirring at 5 ° C. for 5 hours, EtOH (30 mL) was added dropwise to the reaction mixture under ice cooling to stop the reaction, and the mixture was concentrated under reduced pressure, and the resulting residue was extracted with EtOAc (150 mL). The organic layer was washed successively with water (100 mL) and brine (100 mL), dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was triturated with n-hexane / IPE and dried under reduced pressure to give ethyl (2-bromo-4-hydroxyphenyl) acetate (2.56 g) as a white solid.
製造例１６
　（３－クロロ－４－ヒドロキシフェニル）酢酸エチル（２．００　ｇ）のＤＭＦ（３０　ｍＬ）溶液にＫ2ＣＯ3（２．５８　ｇ）と４－ニトロフルオロベンゼン（１．０３　ｍＬ）を加え、６０　℃で２時間攪拌した。反応液を室温まで冷却した後、水に注ぎ、ＥｔＯＡｃを用いて抽出した。有機層をｂｒｉｎｅで２回洗浄した後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ｈｅｘａｎｅ：ＥｔＯＡｃ＝４：１）を用いて精製し、｛３－クロロ－４－（４－ニトロフェノキシ）フェニル｝酢酸エチル（２．３０　ｇ）を褐色油状物質として得た。 Production Example 16
To a solution of ethyl (3-chloro-4-hydroxyphenyl) acetate (2.00 g) in DMF (30 mL) was added K 2 CO 3 (2.58 g) and 4-nitrofluorobenzene (1.03 mL). , And stirred at 60 ° C. for 2 hours. The reaction was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed twice with brine and then dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane: EtOAc = 4: 1), and ethyl {3-chloro-4- (4-nitrophenoxy) phenyl} acetate (2.30 g) was obtained as a brown oily substance. Got as.
　後記表に示す製造例１６－１から１６－１５の化合物を、製造例１６と同様に、対応する原料を用いて製造した。 The compounds of Production Examples 16-1 to 16-15 shown in the table below were produced in the same manner as in Production Example 16 using the corresponding raw materials.
製造例１７
　４－ベンジルオキシ－１－インドール（２．９８　ｇ）とＫ2ＣＯ3　（１．１２　ｇ）のＤＭＦ（３０　ｍＬ）懸濁液を室温で撹拌下に、エチルブロモアセテート（１．９　ｍＬ）をすこしづつ加え、一夜室温で撹拌した。Ｋ2ＣＯ3（１．１２　ｇ）とエチルブロモアセテート（１．９　ｍＬ）を追加し、室温で更に８時間撹拌した。反応混合物に水を加えＥｔＯＡｃで抽出し、有機層をｂｒｉｎｅで洗浄後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン）で精製し、エチル（４－ベンジルオキシ－１Ｈ－インドール－１－イル）アセテート（１．６６　ｇ）を白色固体として得た。 Production Example 17
A suspension of 4-benzyloxy-1-indole (2.98 g) and K 2 CO 3 (1.12 g) in DMF (30 mL) was stirred at room temperature with ethyl bromoacetate (1.9 mL). Was added little by little and stirred overnight at room temperature. K 2 CO 3 (1.12 g) and ethyl bromoacetate (1.9 mL) were added, and the mixture was further stirred at room temperature for 8 hours. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene) to obtain ethyl (4-benzyloxy-1H-indol-1-yl) acetate (1.66 g) as a white solid.
製造例１８
　インドール－２－カルボン酸エチル（１　ｇ）　の　ＤＭＦ（１０　ｍＬ）　溶液に氷冷下、　６０％　水素化ナトリウム（２４０　ｍｇ）を加え室温で　１０分間撹拌したのち、１－ブロモ－２－フルオロエタン（１　ｇ）を加え、室温で２時間撹拌した。反応液をＥｔＯＡｃで希釈したのち１Ｍ　塩酸、ｂｒｉｎｅで順次洗浄し、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、１－（２－フルオロエチル）インドール－２－カルボン酸エチル（１．１　ｇ）を無色オイルとして得た。 Production Example 18
To a solution of ethyl indole-2-carboxylate (1 g) in DMF (10 mL) was added 60% sodium hydride (240 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes, and then 1-bromo-2-fluoroethane. (1 g) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed successively with 1M hydrochloric acid and brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl 1- (2-fluoroethyl) indole-2-carboxylate (1.1 g) as a colorless oil.
製造例１９
　エチル（４－ベンジルオキシ－１Ｈ－インドール－１－イル）アセテート（１．７５　ｇ）をＥｔＯＨ（１７．５　ｍＬ）とＴＨＦ（１７．５　ｍＬ）の混合溶媒に溶かし、１０％パラジウム炭素（５０　％水含有）（１．２　ｇ）を加え、水素ガス雰囲気下、室温、常圧で４時間接触還元した。反応混合物をセライトを用いてろ過し、ろ液を減圧濃縮した。エチル（４－ヒドロキシ－１Ｈ－インドール－１－イル）アセテート（１．３７　ｇ）を淡茶色オイルとして得た。 Production Example 19
Ethyl (4-benzyloxy-1H-indol-1-yl) acetate (1.75 g) was dissolved in a mixed solvent of EtOH (17.5 mL) and THF (17.5 mL), and 10% palladium carbon (50 % Water content) (1.2 g) was added, and catalytic reduction was carried out under a hydrogen gas atmosphere at room temperature and normal pressure for 4 hours. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. Ethyl (4-hydroxy-1H-indol-1-yl) acetate (1.37 g) was obtained as a light brown oil.
製造例２０
　２－ブロモ－Ｎ，Ｎ－ジメチルアニリン（５００　ｍｇ）と３－エトキシカルボニルフェニルボロン酸（５８２　ｍｇ）の１，４－ジオキサン（１０　ｍＬ）溶液に２Ｍ　Ｎａ2ＣＯ3水溶液（２．７５　ｍＬ）と［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム　（２０４　ｍｇ）を加え、窒素雰囲気下で９０℃で４時間攪拌した。反応混合物を室温まで冷却したのち水に注ぎ、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄した後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、２’－（ジメチルアミノ）ビフェニル－３－カルボン酸エチル（６２０　ｍｇ）を淡黄色油状物質として得た。 Production Example 20
To a solution of 2-bromo-N, N-dimethylaniline (500 mg) and 3-ethoxycarbonylphenylboronic acid (582 mg) in 1,4-dioxane (10 mL) was added 2M Na 2 CO 3 aqueous solution (2.75 mL). And [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (204 mg) were added, and the mixture was stirred at 90 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl 2 ′-(dimethylamino) biphenyl-3-carboxylate (620 mg) as a pale yellow oily substance.
　製造例化合物の構造および物理化学的データを表２から表３４に示す。 Table 2 to Table 34 show the structures and physicochemical data of the production example compounds.
実施例１
　（３－クロロ－４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝フェニル）酢酸エチル（２１０　ｍｇ）のＥｔＯＨ（４．２　ｍＬ）溶液に２Ｍ　ＮａＯＨ水溶液（４３９　μＬ）を加え、室温で４時間攪拌した。反応液に１Ｍ塩酸を加えｐＨを３から４に調整した後、水で希釈し、ＥｔＯＡｃで抽出した。有機層をｂｒｉｎｅで洗浄後、ＭｇＳＯ4で乾燥し、ろ液を減圧濃縮した。残渣をＩＰＥで粉末化したのち乾燥し、（３－クロロ－４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝フェニル）酢酸（１８２　ｍｇ）を白色粉末として得た。 Example 1
To a solution of ethyl (3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetate (210 mg) in EtOH (4.2 mL) was added 2M NaOH aqueous solution (439 μL). And stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 3 to 4 by adding 1M hydrochloric acid, diluted with water, and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was triturated with IPE and dried to give (3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetic acid (182 mg) as a white powder.
　以下の表３５から表７４に示す実施例２から実施例１５３の化合物を、実施例１と同様に、対応する原料を用いて製造した。実施例化合物の構造を表３５から表６０に、物理化学的データを表６１から表７４にそれぞれ示す。 The compounds of Examples 2 to 153 shown in Tables 35 to 74 below were produced in the same manner as in Example 1 using the corresponding raw materials. The structures of the example compounds are shown in Tables 35 to 60, and the physicochemical data are shown in Tables 61 to 74, respectively.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019

Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020

Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021

Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022

Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035

Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040

Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041

Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042

Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044

Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046

Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049

Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050

Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051

Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052

Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053

Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055

Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065

Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066

Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067

Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069

Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070

Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071


Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072

Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073

Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076

Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078

Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080

Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
　式（Ｉ）の化合物またはその塩は、ＣＲＴＨ２拮抗作用を有し、炎症性疾患（例えば、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、血管炎、慢性閉塞性肺疾患等）または多発性硬化症等の予防及び／または治療剤として使用できる。 The compound of formula (I) or a salt thereof has CRTH2 antagonism and has an inflammatory disease (for example, asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, adjunct Rhinitis, vasculitis, chronic obstructive pulmonary disease and the like) or multiple sclerosis and the like.

Claims (19)

  1. 式（Ｉ）の化合物、その塩またはそのプロドラッグ。
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    Ｒ1は、－（Ｃ1-6アルキレン）－ＣＯＯＨ、または－Ｈであり、
    １）Ｒ1が、－（Ｃ1-6アルキレン）－ＣＯＯＨの場合、
    　　　Ｒ2は、ハロゲン、または－Ｈ、
    　　　Ｒ3は、ハロゲン、Ｃ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、または－Ｈ、
    ２）Ｒ1が、－Ｈの場合、
    　　　Ｒ2とＲ3が一体となって、それらが結合するベンゼン環とともに式（ＩＩ）
    Figure JPOXMLDOC01-appb-C000002
    　　　で示される基を形成し、
    　　　Ｖは、＝ＣＨ－、または＝Ｎ－、
    　　　ｍは、１から６の整数を示し、
    Ｒ4は、ハロゲン、または－Ｈ、
    　　　ただし、Ｒ3が－Ｈの場合、Ｒ4はハロゲン、
    Ｒ5は、－Ｈ、ハロゲン、またはＣ1-6アルキル、
    Ｒ6は、ＲXAで示される基より選択される基でそれぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキル、または－Ｎ（Ｒ6a）（Ｒ6b）であり、
    ＲXAは、ハロゲン、Ｃ1-6アルキル、ハロＣ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、－Ｏ－（ハロＣ1-6アルキル）、－Ｓ－（Ｃ1-6アルキル）、－Ｎ－（Ｃ1-6アルキル）2、アリール、ハロゲンで置換されているアリール、－Ｏ－（Ｃ1-6アルキル）で置換されているアリール、－Ｎ（Ｃ1-6アルキル）2で置換されているアリール、ハロアリール、－ＯＨ、－ＣＮ、－Ｓ（＝Ｏ）2－（Ｃ1-6アルキル）、－ＮＨＳ（＝Ｏ）2－（Ｃ1-6アルキル）、または環状アミノ、
    Ｒ6aは、－（Ｃ1-6アルキレン）－アリール、－（Ｃ1-6アルキレン）－ヘテロアリール、－（Ｃ1-6アルキレン）－ヘテロシクロアルキル、
    Ｒ6bは、－Ｈ、またはＣ1-6アルキル、
    Ａは、－Ｏ－、または－Ｓ－、
    Ｄは、－Ｃ（＝Ｏ）－、または－Ｓ（＝Ｏ）2－
    Ｅは、結合、Ｃ1-6アルキレン、またはＣ2-6アルケニレン、
    Ｙは、－Ｃ（Ｒ5a）＝、または－Ｎ＝、
    Ｒ5aは、－Ｈ、ハロゲン、またはＣ1-6アルキル、
    Ｚは、＝ＣＨ－、または＝Ｎ－、
    Ｕは、－Ｃ（Ｒ5b）＝、または－Ｎ＝、
    Ｒ5bは、－Ｈ、ハロゲン、またはＣ1-6アルキル。
    　　　ただし、以下の化合物は除く。
    ３－｛３－フルオロ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
    ３－｛３－エトキシ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
    ３－｛３－メトキシ－４－［（５－｛［４－（トリフルオロメチル）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝プロパン酸、
    ３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－フルオロフェニル］プロパン酸、
    ３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－エトキシフェニル］プロパン酸、
    ３－［４－（｛５－［（３，４－ジクロロベンゾイル）アミノ］ピリジン－２－イル｝オキシ）－３－メトキシフェニル］プロパン酸、および
    （４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝－３－メトキシフェニル）酢酸。］
    A compound of formula (I), a salt thereof or a prodrug thereof.
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    R 1 is — (C 1-6 alkylene) —COOH or —H;
    1) When R 1 is — (C 1-6 alkylene) —COOH,
    R 2 is halogen or —H,
    R 3 is halogen, C 1-6 alkyl, —O— (C 1-6 alkyl), or —H,
    2) When R 1 is -H,
    R 2 and R 3 together form a benzene ring to which they are bonded together with formula (II)
    Figure JPOXMLDOC01-appb-C000002
    A group represented by
    V is = CH-, or = N-,
    m represents an integer of 1 to 6,
    R 4 is halogen or —H,
    Provided that when R 3 is —H, R 4 is halogen,
    R 5 is —H, halogen, or C 1-6 alkyl,
    R 6 is aryl, heteroaryl, heterocycloalkyl, or —N (R 6a ) (R 6b ), each optionally substituted with a group selected from the group represented by R XA ;
    R XA represents halogen, C 1-6 alkyl, halo C 1-6 alkyl, —O— (C 1-6 alkyl), —O— (halo C 1-6 alkyl), —S— (C 1-6 Alkyl), —N— (C 1-6 alkyl) 2 , aryl, aryl substituted with halogen, aryl substituted with —O— (C 1-6 alkyl), —N (C 1-6 alkyl) ) Aryl substituted with 2 , aryl, haloaryl, —OH, —CN, —S (═O) 2 — (C 1-6 alkyl), —NHS (═O) 2 — (C 1-6 alkyl), or Cyclic amino,
    R 6a is — (C 1-6 alkylene) -aryl, — (C 1-6 alkylene) -heteroaryl, — (C 1-6 alkylene) -heterocycloalkyl,
    R 6b is —H or C 1-6 alkyl;
    A is —O— or —S—,
    D is —C (═O) — or —S (═O) 2 —.
    E is a bond, C 1-6 alkylene, or C 2-6 alkenylene,
    Y is -C (R 5a ) =, or -N =,
    R 5a is —H, halogen, or C 1-6 alkyl;
    Z is ═CH— or ═N—,
    U is -C (R 5b ) =, or -N =,
    R 5b is —H, halogen, or C 1-6 alkyl.
    However, the following compounds are excluded.
    3- {3-fluoro-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
    3- {3-ethoxy-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
    3- {3-methoxy-4-[(5-{[4- (trifluoromethyl) benzoyl] amino} pyridin-2-yl) oxy] phenyl} propanoic acid,
    3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-fluorophenyl] propanoic acid,
    3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-ethoxyphenyl] propanoic acid,
    3- [4-({5-[(3,4-dichlorobenzoyl) amino] pyridin-2-yl} oxy) -3-methoxyphenyl] propanoic acid, and (4- {4-[(3,4- Dichlorobenzoyl) amino] phenoxy} -3-methoxyphenyl) acetic acid. ]
  2. Ｒ6が、同一または互いに異なったＲXBで示される基でそれぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキル、または－Ｎ（Ｒ6a）（Ｒ6b）であり、
    ＲXBが、ハロゲン、Ｃ1-6アルキル、ハロＣ1-6アルキル、－Ｏ－（Ｃ1-6アルキル）、－Ｏ－（ハロＣ1-6アルキル）、－Ｓ－（Ｃ1-6アルキル）、－Ｎ（Ｃ1-6アルキル）2、アリール、－Ｏ－（Ｃ1-6アルキル）で置換されているアリール、または－Ｎ（Ｃ1-6アルキル）2で置換されているアリールである、
    請求項１に記載の化合物またはその塩。
    R 6 is aryl, heteroaryl, heterocycloalkyl, or —N (R 6a ) (R 6b ), each optionally substituted with the same or different groups represented by R XB ;
    R XB is halogen, C 1-6 alkyl, halo C 1-6 alkyl, —O— (C 1-6 alkyl), —O— (halo C 1-6 alkyl), —S— (C 1-6 Alkyl), —N (C 1-6 alkyl) 2 , aryl, aryl substituted with —O— (C 1-6 alkyl), or aryl substituted with —N (C 1-6 alkyl) 2 Is,
    The compound according to claim 1 or a salt thereof.
  3. Ｒ1が、－ＣＨ2－ＣＯＯＨ、または－Ｈ、
    ｍが、１、
    Ｒ6aが、－（Ｃ1-6アルキレン）－アリール、
    Ｒ6bが、－Ｈ、
    　　　ただし、Ｙが－Ｎ＝の場合、Ｕは－ＣＨ＝であり、
    　　　Ｙが－ＣＨ＝または－ＣＦ＝の場合、Ｚが＝ＣＨ－である、
    請求項２に記載の化合物またはその塩。
    R 1 is —CH 2 —COOH, or —H,
    m is 1,
    R 6a is — (C 1-6 alkylene) -aryl,
    R 6b is —H,
    However, when Y is -N =, U is -CH =,
    When Y is —CH═ or —CF═, Z is ═CH—,
    The compound according to claim 2 or a salt thereof.
  4. Ｒ3が、ハロゲン、Ｃ1-6アルキル、または－Ｏ－Ｃ1-6アルキル、
    Ｒ4が、－Ｈである、
    請求項３に記載の化合物またはその塩。
    R 3 is halogen, C 1-6 alkyl, or —O—C 1-6 alkyl,
    R 4 is —H,
    The compound according to claim 3 or a salt thereof.
  5. Ｙが、－Ｎ＝、
    Ｚが、＝ＣＨ－である、
    請求項４に記載の化合物またはその塩。
    Y is -N =,
    Z is = CH-
    The compound or its salt of Claim 4.
  6. Ｅが、結合である、
    請求項５に記載の化合物またはその塩。
    E is a bond,
    The compound according to claim 5 or a salt thereof.
  7. Ｒ6が、同一または互いに異なったＲXBで示される基で置換されていてもよいフェニルである、
    請求項６に記載の化合物またはその塩。
    R 6 is phenyl which may be substituted with the same or different groups represented by R XB .
    The compound or its salt of Claim 6.
  8. Ａが、－Ｏ－、
    Ｄが、－Ｃ（＝Ｏ）－、
    Ｒ2が、－Ｈ、
    Ｒ3が、ハロゲンである、
    請求項７に記載の化合物またはその塩。
    A is -O-,
    D is -C (= O)-,
    R 2 is —H,
    R 3 is halogen,
    The compound according to claim 7 or a salt thereof.
  9. Ｒ6が、同一または互いに異なったＲXCで示される基で置換されていてもよいフェニルであり、
    ＲXCが、Ｃｌ、－ＣＨ3、－ＣＦ3、－ＯＣＨ3、－ＯＣＦ3、－ＳＣＨ3、－Ｎ（ＣＨ3）2、フェニル、－ＯＣＨ3で置換されているフェニル、または－Ｎ（ＣＨ3）2で置換されているフェニルである、
    請求項８に記載の化合物またはその塩。
    R 6 is phenyl optionally substituted with the same or different groups represented by R XC ;
    R XC is Cl, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —SCH 3 , —N (CH 3 ) 2 , phenyl, phenyl substituted with —OCH 3 , or —N ( CH 3 ) is phenyl substituted with 2 ;
    The compound or its salt of Claim 8.
  10. Ｙが、－ＣＨ＝または－ＣＦ＝である、
    請求項３に記載の化合物またはその塩。
    Y is —CH═ or —CF═.
    The compound according to claim 3 or a salt thereof.
  11. Ａが、－Ｏ－、
    Ｄが、－Ｃ（＝Ｏ）－、
    Ｒ6が、同一または互いに異なったＲXBで示される基で置換されていてもよいフェニルである、
    請求項１０に記載の化合物またはその塩。
    A is -O-,
    D is -C (= O)-,
    R 6 is phenyl which may be substituted with the same or different groups represented by R XB .
    The compound or its salt of Claim 10.
  12. Ｒ1が、－Ｈである、
    請求項３に記載の化合物またはその塩。
    R 1 is -H;
    The compound according to claim 3 or a salt thereof.
  13. Ｖが、＝Ｎ－である、
    請求項１２に記載の化合物またはその塩。
    V is = N-
    The compound or its salt of Claim 12.
  14. 以下に示す、請求項２に記載の化合物またはその塩、
    （３－クロロ－４－｛４－［（３，４－ジクロロベンゾイル）アミノ］フェノキシ｝フェニル）酢酸、
    （４－｛４－［（１－ベンゾフラン－２－イルカルボニル）アミノ］フェキシ｝－３－クロロフェニル）酢酸、
    ［３－クロロ－４－（｛４－［（３，４－ジクロロベンゾイル）アミノ］フェニル｝スルファニル）フェニル］酢酸、
    （３－クロロ－４－｛４－［（３，４－ジヒドロイソキノリン－２（１Ｈ）－イルカルボニル）アミノ］フェノキシ｝フェニル）酢酸、
    ［４－（４－｛［（２Ｅ）－３－（３，４－ジクロロフェニル）プロプ－２－エノイル］アミノ｝フェノキシ）－２－メチル－１Ｈ－ベンゾイミダゾール－１－イル］酢酸、
    ［３－クロロ－４－（４－｛［４－（トリフロオロメチル）ベンゾイル］アミノ｝フェノキシ）フェニル］酢酸、
    （３－クロロ－４－｛２－フルオロ－４－［（１Ｈ－インドール－２－イルカルボニル）アミノ］フェノキシ｝フェニル）酢酸、
    ［３－クロロ－４－（４－｛［（１－メチル－１Ｈ－インドール－２－イル）カルボニル］アミノ｝フェノキシ）フェニル］酢酸、
    ［３－クロロ－４－（４－｛［（６－クロロ－１Ｈ－ベンゾイミダゾール－２－イル）カルバモイル］アミノ｝フェノキシ）フェニル］酢酸、
    ｛３－クロロ－４－［（５－｛［（５－フルオロ－１Ｈ－インドール－２－イル）カルボニル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝酢酸、
    ［３－ブロモ－４－（４－｛［４－（トリフルオロメトキシ）ベンゾイル］アミノ｝フェノキシ）フェニル］酢酸、および
    ｛３－クロロ－４－［（５－｛［４－（トリフルオロメトキシ）ベンゾイル］アミノ｝ピリジン－２－イル）オキシ］フェニル｝酢酸。
    The compound or its salt of Claim 2 shown below,
    (3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetic acid,
    (4- {4-[(1-benzofuran-2-ylcarbonyl) amino] foxy} -3-chlorophenyl) acetic acid,
    [3-chloro-4-({4-[(3,4-dichlorobenzoyl) amino] phenyl} sulfanyl) phenyl] acetic acid,
    (3-chloro-4- {4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy} phenyl) acetic acid,
    [4- (4-{[(2E) -3- (3,4-dichlorophenyl) prop-2-enoyl] amino} phenoxy) -2-methyl-1H-benzimidazol-1-yl] acetic acid,
    [3-chloro-4- (4-{[4- (trifluoromethyl) benzoyl] amino} phenoxy) phenyl] acetic acid,
    (3-chloro-4- {2-fluoro-4-[(1H-indol-2-ylcarbonyl) amino] phenoxy} phenyl) acetic acid,
    [3-chloro-4- (4-{[(1-methyl-1H-indol-2-yl) carbonyl] amino} phenoxy) phenyl] acetic acid,
    [3-chloro-4- (4-{[(6-chloro-1H-benzimidazol-2-yl) carbamoyl] amino} phenoxy) phenyl] acetic acid,
    {3-chloro-4-[(5-{[(5-fluoro-1H-indol-2-yl) carbonyl] amino} pyridin-2-yl) oxy] phenyl} acetic acid,
    [3-Bromo-4- (4-{[4- (trifluoromethoxy) benzoyl] amino} phenoxy) phenyl] acetic acid, and {3-chloro-4-[(5-{[4- (trifluoromethoxy) Benzoyl] amino} pyridin-2-yl) oxy] phenyl} acetic acid.
  15. 請求項１に記載の化合物またはその塩、及び製薬学的に許容される賦形剤を含有する医薬組成物。
    A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
  16. 請求項１に記載の化合物またはその塩を含有する炎症性疾患または多発性硬化症治療予防用若しくは治療用医薬組成物。
    A pharmaceutical composition for preventing or treating an inflammatory disease or multiple sclerosis comprising the compound according to claim 1 or a salt thereof.
  17. 炎症性疾患または多発性硬化症の予防若しくは治療用医薬組成物の製造のための請求項１に記載の化合物またはその塩の使用。
    Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of inflammatory diseases or multiple sclerosis.
  18. 炎症性疾患または多発性硬化症の予防若しくは治療のための請求項１に記載の化合物またはその塩の使用。
    Use of the compound according to claim 1 or a salt thereof for the prevention or treatment of inflammatory diseases or multiple sclerosis.
  19. 請求項１に記載の化合物またはその塩の有効量を患者に投与することからなる炎症性疾患または多発性硬化症の予防若しくは治療方法。 A method for preventing or treating inflammatory diseases or multiple sclerosis, comprising administering an effective amount of the compound or salt thereof according to claim 1 to a patient.
PCT/JP2009/051587 2008-01-31 2009-01-30 Carboxylic acid compound or salt thereof WO2009096526A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-022136 2008-01-31
JP2008022136A JP2011088826A (en) 2008-01-31 2008-01-31 Aromatic carboxylic acid compound

Publications (1)

Publication Number Publication Date
WO2009096526A1 true WO2009096526A1 (en) 2009-08-06

Family

ID=40912869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/051587 WO2009096526A1 (en) 2008-01-31 2009-01-30 Carboxylic acid compound or salt thereof

Country Status (3)

Country Link
JP (1) JP2011088826A (en)
TW (1) TW200951122A (en)
WO (1) WO2009096526A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2457900A1 (en) 2010-11-25 2012-05-30 Almirall, S.A. New pyrazole derivatives having CRTh2 antagonistic behaviour
EP2640698A1 (en) * 2010-11-15 2013-09-25 AbbVie Inc. Nampt and rock inhibitors
US8697869B2 (en) 2010-03-22 2014-04-15 Actelion Pharmaceuticals Ltd. 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9H-carbazole derivatives and their use as prostaglandin D2 receptor modulators
US9096595B2 (en) 2011-04-14 2015-08-04 Actelion Pharmaceuticals Ltd 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9850241B2 (en) 2014-03-18 2017-12-26 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9879006B2 (en) 2014-03-17 2018-01-30 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8759386B2 (en) * 2011-01-24 2014-06-24 Boehringer Ingelheim International Gmbh Pyrazole compounds as CRTH2 antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501132A (en) * 2000-06-21 2004-01-15 カロ　バイオ　アクチェブラーグ Thyroid receptor ligands, pharmaceutical compositions containing them and their use in treating disorders affected by thyroid hormone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501132A (en) * 2000-06-21 2004-01-15 カロ　バイオ　アクチェブラーグ Thyroid receptor ligands, pharmaceutical compositions containing them and their use in treating disorders affected by thyroid hormone

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697869B2 (en) 2010-03-22 2014-04-15 Actelion Pharmaceuticals Ltd. 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9H-carbazole derivatives and their use as prostaglandin D2 receptor modulators
EP2640698A1 (en) * 2010-11-15 2013-09-25 AbbVie Inc. Nampt and rock inhibitors
EP2457900A1 (en) 2010-11-25 2012-05-30 Almirall, S.A. New pyrazole derivatives having CRTh2 antagonistic behaviour
WO2012069175A1 (en) 2010-11-25 2012-05-31 Almirall, S.A. New pyrazole derivatives having crth2 antagonistic behaviour
US9096595B2 (en) 2011-04-14 2015-08-04 Actelion Pharmaceuticals Ltd 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9879006B2 (en) 2014-03-17 2018-01-30 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US10301309B2 (en) 2014-03-17 2019-05-28 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9850241B2 (en) 2014-03-18 2017-12-26 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms

Also Published As

Publication number Publication date
TW200951122A (en) 2009-12-16
JP2011088826A (en) 2011-05-06

Similar Documents

Publication Publication Date Title
WO2009096526A1 (en) Carboxylic acid compound or salt thereof
JP5408434B2 (en) Amide compounds
JP5375824B2 (en) Amide compounds
EP2696682B1 (en) Mif inhibitors and their uses
US20100179137A1 (en) Pyridone compound
KR101721025B1 (en) Tetrahydrobenzothiophene compound
US9526732B2 (en) Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated pathologies
JP2000256323A (en) 2-oxoquinoline compound and its medicinal use
BRPI0414130B1 (en) PHENYLAMIDE OR PYRIDYLAMIDE COMPOUNDS, THEIR USE AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM
JPWO2010064707A1 (en) 2H-chromene compounds and derivatives thereof
JPWO2008123207A1 (en) Ornithine derivatives
JP2011529031A (en) 1,1'-diadamantylcarboxylic acid, medicament containing such compounds and use thereof
TW200848036A (en) Novel oxycarbonyl compound
JP6692354B2 (en) 1,4-di-substituted imidazole derivative
EP3144303B1 (en) 6-substituted phenoxychroman carboxylic acid derivatives
JP2013107880A (en) N-thienyl benzamide derivative
JPWO2008133155A1 (en) Bicyclic heterocyclic compounds
JP2006514110A (en) Phenyl or heteroarylaminoalkane derivatives as IP receptor antagonists
JP2010513398A (en) Isoquinoline carboxamide derivatives as stearoyl-CoA desaturase (SCD) inhibitors
TW201031652A (en) Carbamic acid ester compound or salt thereof
JP2005255675A (en) Pharmaceutical composition
TW202308986A (en) DP antagonist
WO2021065893A1 (en) Tetralin derivative or pharmaceutically acceptable acid addition salt thereof
JP2004530650A (en) Aminaldione as a potassium channel opener
EP2781508B9 (en) Nitrogen-containing fused ring compounds for use as crth2 antagonists

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: 09705809

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: 09705809

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP