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WO2006011669A1 - Nouveaux composés apparentés à l'acide cinnamique - Google Patents

Nouveaux composés apparentés à l'acide cinnamique Download PDF

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WO2006011669A1
WO2006011669A1 PCT/JP2005/014262 JP2005014262W WO2006011669A1 WO 2006011669 A1 WO2006011669 A1 WO 2006011669A1 JP 2005014262 W JP2005014262 W JP 2005014262W WO 2006011669 A1 WO2006011669 A1 WO 2006011669A1
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group
ring
substituted
unsubstituted
compound
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PCT/JP2005/014262
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English (en)
Japanese (ja)
Inventor
Hisashi Tajima
Toshiyuki Mori
Kenichiro Matsubayashi
Hiroshi Suhara
Tomoko Kirihara
Atsushi Shimazaki
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2006011669A1 publication Critical patent/WO2006011669A1/fr

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    • 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
    • C07D211/18—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon 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
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
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    • 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
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
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    • 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
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    • 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
    • C07C323/51—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
    • 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
    • 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
    • C07D295/10—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 doubly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

  • the present invention relates to a novel cinnamic acid-related compound or a salt thereof useful as a medicine.
  • the related compounds have an intraocular aqueous humor circulation improving action and an intraocular pressure lowering action, and are useful as a therapeutic agent for diseases associated with intraocular pressure, such as glaucoma and ocular hypertension.
  • the aqueous humor circulation in the eye is closely related to the intraocular pressure, and if the aqueous humor circulation is inhibited, a large change in intraocular pressure is brought about. In particular, when aqueous humor outflow is hindered, intraocular pressure increases, causing diseases involving intraocular pressure such as glaucoma and ocular hypertension.
  • Aqueous humor is usually produced by the filtration and active transport of plasma components, most of which flows out of the eye via the trabecular drainage pathway. That is, by reducing the aqueous humor outflow resistance in the trabecular meshwork with drugs, the aqueous humor outflow is enhanced, and it becomes possible to treat diseases involving intraocular pressure such as glaucoma and ocular hypertension. .
  • drugs that enhance aqueous humor outflow from the trabecular meshwork include actin polymerization inhibitors such as latrunculin A and MLCK such as ML-7 (myos in 1 i ght cha in k inas e) Inhibitors and Rho kinase inhibitors such as Y-39 98 3 are known (Patent Document 1, Patent Document 2).
  • Patent Document 3 Patent Document 4, Patent Document 5 and Patent Document 6 disclose an intraocular pressure-lowering agent comprising a compound having a chemical structure derived from cinnamic acid as an active ingredient.
  • Patent Document 1 International Publication No. W097 / 30701 Pan Fret
  • Patent Document 2 International Publication WO00 / 09162
  • Patent Document 3 International Publication No. W086 / 07259
  • Patent Document 4 International publication W099 / 61403 pamphlet
  • Patent Document 5 International publication WOO0 / 41993 pamphlet
  • Patent Document 6 Japanese Patent Laid-Open No. 2 0 0 1-2 6 2 2 Disclosure of Invention
  • the present inventors have conducted synthetic studies on cinnamic acid-related compounds having a new chemical structure.
  • the related compound has an effect of improving aqueous circulatory circulation and lowering intraocular pressure, and is used as a therapeutic agent for diseases involving intraocular pressure, such as glaucoma and ocular hypertension. And the present invention was completed.
  • the present invention provides a compound represented by the following general formulas [I] to [VI] or a salt thereof, a pharmaceutical composition containing them, and a compound represented by the following general formulas [VE] to [X]
  • the present invention relates to a pharmaceutical composition containing the salt (hereinafter, unless otherwise specified, “a compound represented by the following general formulas [I] to [X] or a salt thereof” is referred to as “the compound of the present invention”).
  • a preferred invention for its pharmaceutical use is an invention relating to an aqueous humor circulation improving agent, and a particularly preferred invention is an invention relating to an intraocular pressure lowering agent.
  • the present invention has the following features.
  • ring A represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R al represents one or two groups selected from a hydrogen atom, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted alkyl group
  • R a2 represents a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, and 2 or 3 groups selected from a substituted or unsubstituted alkyl group
  • R a3 represents a hydrogen atom, a halogen atom, a hydroxy One or more groups selected from a group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group;
  • R a4 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • R a5 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl carbo yl.
  • R aS and R a7 are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkyl group, a carboxy group or an ester thereof. Or show the amide;
  • R a6 and R a7 may be joined together to form a cyclohexane ring
  • R a8 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • Y a represents an alkylene group, 1 O-alkylene group or alkenylene group; the broken line represents a single bond or a double bond. same as below. ]
  • the number of R al is 2 when the broken line is a single bond and 1 when the broken line is a double bond.
  • the number of R a2 is 3 when the broken line is a single bond and the broken line is a double bond. 2 if there is.
  • the number of R a3 is 1 to 10.
  • a compound having a chemical structure relatively similar to that of the compound of the present invention represented by the general formula [I] is disclosed in International Publication No. W099 / 61403 pamphlet.
  • R a7 —, —S 0 2 — There is no disclosure of compounds having various special chemical structures such as R a7 —, —S 0 2 — and the like.
  • the compound of the present invention represented by the general formula [II] has a chemical structural characteristic in that it is a chemical structure in which a ring containing Xb and exo-olefin is condensed with a B ring.
  • ring B represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R bl and R b2 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl 'group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;
  • R b3 and R b4 are selected from a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group 1 Or multiple groups;
  • R b5 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • R b6 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylcarbonyl Group, substituted or absent A substituted arylcarbonyl group, a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted amino group;
  • R b7 and R b8 are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted lower alkyl group, a carboxy group, an ester thereof or an amide thereof. Indicates;
  • R b7 and R b8 may join together to form a hexane ring
  • R b9 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • Y b represents an alkylene group, 1-alkylene group or alkenylene group; n represents 0 or 1; same as below. ]
  • ring C represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R cl and R c2 are selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group 1 Or multiple groups;
  • R c3 is a carboxy group or an ester thereof or an amide thereof, substituted or unsubstituted A substituted amino group or a substituted or unsubstituted heterocyclic group;
  • R c4 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted arylyl group, a substituted or unsubstituted alkylcarbonyl group, substituted or An unsubstituted allylcarbonyl group, a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted amino group;
  • R c5 and R e6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted lower alkyl group, a carboxy group, an ester thereof or an amide thereof. Indicates;
  • R c5 and R c6 may together form a sucral hexane ring
  • R c7 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • Y c represents an alkylene group, 1 O-alkylene group or an alkene group. same as below. ]
  • the number of R cl is 3, and the number of R ° 2 is 1 to 10.
  • the compound of the present invention represented by the general formula [IV] has chemical structural characteristics when an R dl —carbonyl group is introduced into the terminal benzene ring.
  • ring D represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R dl represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted aryl group;
  • R d2 and R d5 are the same or different and are selected from a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group. Indicate one or more selected groups;
  • R d3 and R are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;
  • R d6 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • Y d represents an alkylene group, 1 O-alkylene group or alkenylene group. same as below. ]
  • the number of R d2 is 4, and the number of R d6 is 1 to 10.
  • the compound of the present invention represented by the general formula [V] has a chemical structural feature in which a hetero 6-membered ring E and an ⁇ , ⁇ -unsaturated carbocycle structure are present simultaneously.
  • ring E represents a hetero 6-membered ring
  • R el represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • R e2 and R e3 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;
  • R e4 is one or more groups selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group Indicates;
  • R e5 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • Y e represents an alkylene group, —O-alkylene group or alkylene group. same as below. ]
  • the number of R e4 is either 1-9.
  • the compound of the present invention represented by the general formula [VI] has chemical structural characteristics in that R f5 which is a heterocyclic group and an ⁇ , ⁇ -unsaturated carbocycle structure are present simultaneously.
  • ring F represents a hydrocarbon six-membered ring
  • R fl is a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyl group. Indicates a reel group
  • R f2 and R f3 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;
  • R i4 represents a plurality of groups selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group. ;
  • Y f represents an alkylene group, 1 O-alkylene group or alkenylene group. same as below. ]
  • the number of R f4 is 4, 6, 8, or 10
  • ring G represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R 1 and R g2 are the same or different and are selected from a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group Indicates one or more groups
  • R s3 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • R s4 is a hydrogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylcarbonyl group, a substituted young Or an unsubstituted aryl carbonate group, a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted amino group;
  • R s5 and R g6 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy tomb, a substituted or unsubstituted lower alkyl group, a carboxy group, an ester thereof or an amide thereof. ;
  • R gS and 'R s6 may be joined together to form a hex ring
  • R g7 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group.
  • Y g represents an alkylene group, 1 O-alkylene group or alkene group
  • Z s represents 1 S— or 1 O—
  • a broken line shows a single bond or a double bond. same as below. ]
  • the number of R gl is either 4 to 6 when the broken line is a single bond, or 2 to 4 when the broken line is a double bond.
  • the number of R g2 is any one of 1-9.
  • ring H represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R hl and R h2 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group;
  • R h3 is one or more selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group
  • R h4 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • R h5 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy grave, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl carbocycle.
  • R h6 and R h7 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted lower alkyl group, a carboxy group, an ester thereof or a amide thereof. Show;
  • R he and R h7 may be joined together to form a hexane ring
  • Y h represents an alkylene group, an alkylene group or an alkenylene group. same as below. ]
  • the number of R h3 is either from 1 to 1 0.
  • a compound having a chemical structure relatively close to that of the compound of the present invention represented by the general formula [] is disclosed in European Patent Publication EP560080. However, the disclosure relates to a toner electrification control agent, and the pharmaceutical use, the aqueous humor circulation improving action, and the intraocular pressure lowering action are not disclosed at all.
  • a feature of the present invention is that the compound of the present invention represented by the general formula [K] bonded to a benzene ring via X 1 is useful as a medicine.
  • ring I represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R "and R i2 are selected from a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group 1 Or multiple groups;
  • R i3 represents a carboxy group or an ester thereof or an amide thereof, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group;
  • R represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted arylyl group, a substituted or unsubstituted alkylcarbonyl group, substituted or An unsubstituted arylcarbonyl group, a carboxy group or an ester or amide thereof, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted amino group;
  • R i5 and R i6 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkyl group, a carboxy group, or The beauty salon Or its amide;
  • R i 5 and R i6 may be joined together to form a hexane ring
  • R i7 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • the number of R " is 5.
  • the number of R i2 is any one of 1 to 10.
  • a compound having a chemical structure that is relatively close to that of the compound of the present invention represented by the general formula [K] is disclosed in Japanese Patent Application Laid-Open No. 20 0 1-2 7 8 8 86.
  • the disclosure is disclosed as a synthetic intermediate for synthesizing a benzoxazine derivative, and its pharmaceutical use, aqueous humor circulation improving action, and intraocular pressure lowering action are not disclosed at all.
  • ring J represents a hydrocarbon 6-membered ring or a hetero 6-membered ring
  • R jl represents a hydrogen atom, a substituted or unsubstituted alkyl group, and 1 or 2 groups selected from substituted or unsubstituted Ari Le group;
  • R j2 is the same or different and represents 2 or 3 groups selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, and a substituted or unsubstituted alkyl group;
  • R j3 is one or more groups selected from a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aryl group Indicates;
  • R J ′ 4 represents a carboxy group or an ester thereof or an amide thereof
  • R j5 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl carbo yl.
  • R j6 and R j7 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl grave, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted lower alkyl group, or a carboxy group or an ester thereof or an amide thereof;
  • R j6 and R may be joined together to form a hexane ring
  • R j8 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group;
  • a broken line shows a single bond or a double bond. same as below. ]
  • the number of R jl is 2 when the broken line is a single bond and when the broken line is a double bond
  • the number of R " is 3 when the broken line is a single bond, and is 2 when the broken line is a double bond.
  • the number of R j3 is any one of 1 to 3.
  • the present invention provides a cinnamic acid-related compound useful as a medicine.
  • the compound according to the present invention has an excellent aqueous humor circulation improvement action and intraocular pressure lowering action, and is useful as a therapeutic agent for diseases involving intraocular pressure, such as glaucoma and ocular hypertension.
  • the hydrocarbon 6-membered ring refers to a monocyclic aromatic hydrocarbon 6-membered ring and a monocyclic non-aromatic hydrocarbon 6-membered ring.
  • monocyclic aromatic hydrocarbon 6-membered rings include benzene rings
  • monocyclic non-aromatic hydrocarbon 6-membered rings include cyclohexagen rings, cyclohexene rings, and cyclohexanes.
  • a xanthan ring etc. are mentioned.
  • a hetero 6-membered ring is a monocyclic aromatic hetero 6-membered ring or monocyclic non-aromatic complex 6 having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring. Indicates a member ring.
  • the monocyclic aromatic hetero 6-membered ring examples include a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring having a nitrogen atom in the ring, and a monocyclic non-aromatic ring.
  • the hetero 6-membered ring examples include a piperidine ring having a nitrogen atom in the ring, a piperazine ring, a pyran ring having an oxygen atom in the ring, a tetrahydropyran ring, etc.
  • Examples thereof include a thiopyran ring having a ring and a tetrahydrothiopyran ring having a nitrogen atom and an oxygen atom in the ring, and a thiomorpholine ring having a nitrogen atom and a sulfur atom in the ring.
  • Alkyl represents straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methinole, ethinole, n-propyl, n-butyl, n-pentinole, n-hexyl, isopropyl, isobutyl, sec-ptyl, tert-ptyl, and isopentyl.
  • Aaryl represents a monocyclic, bicyclic or tricyclic fused polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms.
  • monocyclic aromatic hydrocarbons include phenyl
  • condensed polycyclic aromatic hydrocarbons include naphthyl, anthryl, phenanthryl and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Alkoxy is a straight or branched alkoxy having 1 to 6 carbon atoms. . Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n xyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy and the like.
  • Ryloxy is a monocyclic, bicyclic or tricyclic fused polycyclic aromatic hydrocarbon oxy having 6 14 carbon atoms.
  • monocyclic aromatic hydrocarbons include phenoxy
  • condensed polycyclic aromatic hydrocarbons include naphthyloxy, anthryloxy, phenanthryloxy and the like.
  • Heterocycle is a saturated or unsaturated monocyclic or bicyclic or tricyclic fused polycyclic heterocycle having 14 heteroatoms selected from nitrogen, oxygen and sulfur atoms in the ring. Indicates a ring.
  • saturated monocyclic heterocycles include pyrrolidine, piperidine, homopiperidine, piperazine, imidazolidine, etc., which have a nitrogen atom in the ring, and tetrahydro, which has an oxygen atom in the ring.
  • Drofuran, Tetrahydropyran, etc., Tetrahydrothiophene, which has a sulfur atom in the ring, Tetrahidrothiopyran, etc. have a nitrogen atom and an oxygen atom in the ring
  • Oxazolidine, Morpholine, etc. have a nitrogen atom and a sulfur atom in the ring Examples thereof include thiazolidine and thiomorpholine.
  • saturated monocyclic heterocycles are condensed with a benzene ring or the like to form a bicyclic or tricyclic fused polycyclic complex ring such as tetrahydroquinoline or tetrahydroisoquinoline. May be.
  • unsaturated monocyclic heterocycles include pyridine, pyrimidine, pyrrole, imidazole, pyrazole, triazine, etc. having a nitrogen atom in the ring, and furan having an oxygen atom in the ring.
  • Thiophene having a sulfur atom in the ring
  • oxazole having a nitrogen atom and an oxygen atom in the ring
  • thiazole having a nitrogen atom and a sulfur atom in the ring.
  • these unsaturated monocyclic heterocycles are condensed with benzene rings, etc. to form indole, indazole, quinoline, isoquinoline, phenanthridine, benzoimidazole, benzotriazole, benzoxazole.
  • Benzisoxazole A bicyclic or tricyclic fused polycyclic heterocycle such as benzothiazol may be formed.
  • Al'xylene refers to a straight-chain or branched alkylene having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, propylene, 2-methyltrimethylene and the like.
  • Alkenylene refers to a straight or branched alkenylene having 2 to 6 carbon atoms. Specific examples include those containing one or two double bonds in ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methinolemethylene, propylene, 2-methylenotrimethylene, and the like.
  • the ester of carboxy group refers to an ester formed from carboxy and alkyl alcohol, aryl alcohol or the like.
  • alkyl alcohols include methanol, ethanol, propanol, butanol, benzyl alcohol, and phenethyl alcohol.
  • aryl alcohol include phenol, naphthol, anthrol, cresol, and xylenol. Etc.
  • the carboxy group amide refers to an amide formed from carboxy and alkylamine, arylamine and the like.
  • alkylamines include methylamine, ethylamine, ethylmethylamine, dimethylamine, jetylamine, benzylamine, and the like. Toluidine and the like.
  • the substituted alkyl refers to an alkyl having one or more groups selected from a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a sucrose alkyl group, and an aryl group as a substituent.
  • Substituted aryl refers to one or more groups selected from a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, an alkyl group, and an aryl group.
  • Substituted alkoxy refers to alkoxy having one or more groups selected from a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group and an aryl group as a substituent.
  • the substituted aryloxy is an aryloxy having one or more groups selected from a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, an alkyl group and an aryl group as a substituent.
  • the substituted heterocycle refers to a heterocycle having one or more groups selected from a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, and an aryl group as a substituent.
  • Substituted amino represents amino having one or more groups selected from an alkyl group and an aryl group as a substituent.
  • the compound of the present invention has a free hydroxyl group, amino group, alkylamino group or arylamino group as a substituent, these substituents may be protected with a protecting group.
  • the heterocyclic group has a nitrogen atom, the nitrogen atom may be protected with a protecting group.
  • the protecting group for the hydroxyl group is a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, or a benzyl group; an unsubstituted alkenyl group such as allyl; a 3-protetrahydrodropirael group, a tetrahydrodropirael group, a tetrahydro group A substituted or unsubstituted heterocyclic group such as a drofuranyl group; an acyl group such as an acetyl group or a benzoyl group; a methoxycarbonyl group, an ethoxycarbonyl group, an isobutoxycarbonyl group, a tert-ptoxycarbonyl group, a buroxycarbo- Substituted, unsubstituted alkyl, alkenyl or alkenyl groups such as alkyl group, aryloxy-carbonyl group,
  • Reyloxycarbonyl group Trimethylsilyl group, Triethylyl Such as; group, triisopropoxide building silyl group, t e r t - - Buchirujime Chirushiriru group, t e r t heptyl diphenyl substituted silyl groups such as enyl silyl group
  • the protecting group for the nitrogen atom is an unsubstituted alkenyl group such as an aryl group; a formyl group, an acetyl group, a benzoyl group, Acyl groups such as picolinol group, trichloroacetyl group, trifluoroacetyl group; methoxycarbol group, isobutoxycarbol group, tert-butoxycarbonyl group, 2, 2, 2-trichloro port Ethoxycarbonyl grave, benzyloxycarbonyl group, diphenyl-methoxycarbonyl group, phenoxycarbonyl group, m-di-phenoxycarbonyl group, substituted or unsubstituted alkyl or aryloxycarbonyl group Group: methinolesulfonyl group, benzylsulfoninole group, phenyl
  • the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.
  • Salts of organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, succinic acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid , Quaternary ammonium salts with methyl iodide, etc., salts with alkaline metals such as lithium, sodium, and potassium, salts with alkaline earth metals such as calcium and magnesium ⁇ , salts with ammonia, triethylenedia And salts with amines such as min.
  • organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, succinic acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid , Quaternary ammonium salts with methyl
  • the compound of the present invention has protone tautomerism, the compound is also included in the present invention.
  • Preferred examples of the compound of the present invention represented by the general formula [I] include compounds that satisfy the following a (i) or a (ii).
  • a compound in which ring A is a benzene ring is more preferable.
  • ring A is a pyridine ring, pyridazine ring, pyrimidine ring
  • (A 2) As a more preferred example of the compound of the present invention represented by the general formula [I], the above-mentioned a (i) or a (ii) is satisfied, and the following a (iii), a ( and compounds satisfying the requirements of iv) or a (v).
  • a (iii): —A compound in which X a is one of C ( NR aS ) in the general formula [I].
  • R a6 and R a7 in one CR a6 R a7 are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group.
  • a compound is more preferable, and a compound in which R a6 and R a7 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, or an unsubstituted alkoxy group is particularly preferable.
  • R al is one selected from a hydrogen atom, an unsubstituted alkyl group, or an unsubstituted aryl group, or the same or different two groups;
  • R a2 is the same or different 2 or 3 groups selected from a hydrogen atom and a hydroxyl group
  • R a3 is one or more groups selected from a hydrogen atom and a halogen atom;
  • R a4 is a carboxy group or an ester thereof, or a substituted amino group
  • Y a is one O-alkylene group or alkenylene group.
  • Preferable examples of the compound of the present invention represented by the general formula [II] include compounds satisfying the following requirements of b (i) to b (ii).
  • ring B is a benzene ring is more preferable.
  • ring B is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine ring.
  • a thiopyran ring, a tetrahydrodrothopyran ring or a thiomorpholine ring is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine ring.
  • Preferred examples of the compound of the present invention represented by the general formula [III] include compounds that satisfy the following c (i) to c (ii).
  • c (i) A compound in which the ring C in the general formula [III] is a benzene ring, a cyclohexagen ring, a cyclohexene ring or a cyclohexane ring.
  • a compound in which ring C is a benzene ring is more preferable.
  • ring C is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine ring.
  • c (vii) a compound in which R c3 is a carboxy group.
  • Preferred examples of the compound of the present invention represented by the general formula [IV] include compounds that satisfy the following d (i) to d (ii).
  • a compound in which Ring D is a benzene ring is more preferable.
  • ring D is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydropyran ring, morpholine ring, A compound which is a thiopyran ring, a tetrahydrobrotirane ring or a thiomorpholine ring.
  • R dl is a hydroxyl group or an unsubstituted aryl group.
  • R A R d3 , R d4 and R d5 are hydrogen atoms.
  • Preferred examples of the compound of the present invention represented by the general formula [V] include compounds that satisfy the following e (i).
  • ring E is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydropyran
  • a compound in which ring E is a piperidine ring is more preferable.
  • More preferable examples of the compound of the present invention represented by the general formula [V] include compounds satisfying the following definitions of d (ii) to d (v).
  • e (iii) a compound in which R e2 , R e3 and R ′′ are hydrogen atoms.
  • Compound Y e is Aruke two alkylene groups.
  • ring F is a benzene ring, a cyclohexagen ring, a cyclohexane ring or a cyclohexane ring.
  • a compound in which Ring F is a benzene ring is more preferable.
  • More preferable examples of the compound of the present invention represented by the general formula [VI] include compounds satisfying the following definitions of f (ii) to f (v).
  • f (ii) A compound in which .R fl is an unsubstituted aryl group.
  • R f (iii) A compound in which R f2 , R f3 and R f4 are hydrogen atoms.
  • R f5 is a morpholine ring or a piperazine ring.
  • Y f is a alk-lene group.
  • ring G is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine ring A compound which is a thiobilan ring, a tetrahydrobrotirane ring or a thiomorpholine ring.
  • R gl and R g2 are the same or different and are one or more groups selected from a hydrogen atom and an unsubstituted aryl group.
  • R g3 is a carboxy group or an ester thereof.
  • a compound in which Ring H is a benzene ring is more preferable.
  • ring H is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine ring , A thiopyran ring, a tetrahydrodrothopyran ring or a thiomorpholine ring.
  • R hl and R h2 are the same or different and each is a hydrogen atom, a substituted or unsubstituted alkyl group, an unsubstituted aryl grave or an unsubstituted heterocyclic group.
  • Y h is —O-alkylene group or alkenylene group.
  • Preferable examples of the compound of the present invention represented by the general formula [K] include compounds satisfying the following rules i (i) to i (ii).
  • ring I is a benzene ring, a cyclohexagen ring, a cyclohexane ring, or a cyclohexane ring. More preferred are compounds in which Ring I is a benzene ring.
  • ring I is a pyridine ring, pyridazine ring, pyrimidine ring, virazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydrobilan ring, morpholine A compound which is a ring, a thiopyran ring, a tetrahydrobrotirane ring or a thiomorpholine ring.
  • R ′′ and R i2 are the same or different and are one or more groups selected from a hydrogen atom and a halogen atom.
  • ring J is a benzene ring, a cyclohexagen ring, a cyclohexane ring or a cyclohexane ring.
  • a compound in which ring J is a benzene ring is more preferable.
  • ring J is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperidine ring, piperazine ring, pyran ring, tetrahydropyran ring, morpholine ring, thiopyran A compound which is a ring, a tetrahydrodrothipran ring or a thiomorpholine ring.
  • More preferable examples of the compound of the present invention represented by the general formula [X] include compounds satisfying the following definitions of j (vi) to j (ix).
  • H a 1 represents a halogen atom
  • O T f represents a trimethyl sulfonyloxy group
  • the present compound [a 2 -I] (X a : — CR a6 R a7 —) can be synthesized according to synthesis route 2. That is, the compound [a 2 -I] of the present invention can be obtained by reacting ketone [a 2 -II] (C a II)) with sodium borohydride or the like.
  • the compound [a 3 -1] of the present invention By condensing the sulfone [a 3 -V] with a carbonyl compound (eg, formaldehyde) such as aldehyde in the presence of a base such as potassium carbonate, the compound [a 3 -1] of the present invention can be obtained. .
  • a carbonyl compound eg, formaldehyde
  • a base such as potassium carbonate
  • the compound of the present invention [ci 1 I] (X 1 CO—R cl : ⁇ position of X e ) can be synthesized according to synthesis route 5. That is, hydrogen peroxide Orefin [C l one II]
  • the present compound [ ⁇ -I] can be obtained by oxidation with an oxidizing agent such as. Synthesis route 5
  • [ci- ⁇ ] [c ⁇ I] The compound of the present invention [c 2 — I] (X c : — CR. 5 R c6 —, R cl : ⁇ position of X c ) can be synthesized according to synthesis route 6. it can. That is, ⁇ , —unsaturated ketone [c 2 — II] ([c! -II]) is converted to olefin [c 2 — III] by a method such as reduction with sodium borohydride in the presence of cerium chloride.
  • the compound [c 2 -I] of the present invention can be obtained by oxidizing this olefin [c 2 -III] with an oxidizing agent such as hydrogen peroxide.
  • the compound [d-I] of the present invention can be synthesized according to synthesis route 7.
  • benzil halide [d—II] is reacted with acid chloride [d— ⁇ ] in the presence of zinc and palladium to form ketone [d—IV].
  • This ketone [d-IV] The compound [d_I] of the present invention can be obtained by condensing the compound with a carbonyl compound such as aldehyde (for example, formaldehyde) in the presence of a base such as dimethylamine.
  • the compound of the present invention [e-I] (ring E: bound to carbocycle via a nitrogen atom) can be synthesized according to Synthesis Route 8. That is, the ester [e-II] is condensed with a carboxylic compound such as aldehyde in the presence of a base such as lithium carbonate (eg, formaldehyde). Then, this a, j3-unsaturated ester [e_III] is hydrolyzed with an aqueous solution of sodium hydroxide or the like (p alkaline aqueous solution to obtain carboxylic acid [e-IV].
  • a carboxylic compound such as aldehyde
  • a base such as lithium carbonate
  • j3-unsaturated ester [e_III] is hydrolyzed with an aqueous solution of sodium hydroxide or the like (p alkaline aqueous solution to obtain carboxylic acid [e-IV].
  • This carboxylic acid [e-IV] ] And amine [e-V] can be condensed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carpositimide to give compound [e 1 I] of the present invention.
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carpositimide
  • This alcohol [f 1 V] is converted into a ketone [f_VI] by a method such as oxidation with dimethyl sulfoxide in the presence of an electrophile such as sulfur trioxide, and this ketone [f-VI] is converted into the presence of a base such as dimethylamine.
  • the compound [fI] of the present invention can be obtained by condensation with a carbonyl compound such as aldehyde (for example, formaldehyde).
  • the carboxylic acid V] is converted to an acid halide [ gl — VI] with a halogenating agent such as thionyl chloride, and then a Lewis acid such as aluminum chloride is added and cyclized to obtain the compound I of the present invention. be able to.
  • a halogenating agent such as thionyl chloride
  • the compound of the present invention [g 2 —I] (X g : —CO—, Z g : —S—, broken line: double bond) can be synthesized according to Synthesis Route 11 That is, the compound of the present invention is obtained by oxidizing the compound of the present invention [g 2 -II] ([g "I]) with an oxidant such as 2,3-dichloro-1,5,6-dicyanose 1,4 monobenzoquinone [ g 2 — I] can be obtained.
  • the compound of the present invention [g 3 — I] (Y g : — CH ⁇ CH—) can be synthesized according to Synthesis Route 12. That is, the compound of the present invention [g 3 -I] is obtained by reacting a halide or trifluoromethane sulfonate [g 3 — ⁇ ] with olefin [g 3 — III] in the presence of a catalyst such as palladium. You can. ⁇ Synthesis route 1 2
  • the compound [h—I] (X h : —CO—) of the present invention can be synthesized according to synthesis route 13. That is, the present compound [h-II] and carboxylic acid [h-III] are condensed by a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carpositimide. I] can be obtained.
  • the compound [i 1 I] (Y 1 : — CH ⁇ CH—) of the present invention can be synthesized according to the synthesis route 14. That is, the compound [i-I] of the present invention can be obtained by reacting a halide or trifluoromethanesulfonate [i 1 II] with olefin [i-III] in the presence of a catalyst such as palladium. Synthesis route 1 4
  • the compound of the present invention [j 1 I] (Y J : -co-, zj: — ⁇ ⁇ ,) can be synthesized according to synthesis route 15. That is, a hydroxy compound [j-II] is reacted with an acylating agent such as an acid halide to form an ester [j-III], and a Lewis acid such as aluminum chloride is allowed to act on the ester [j-1III]. In The ketone group is rearranged to give the ketone [j — IV].
  • This ketone [j-IV] is reacted with an ester [j-V] in the presence of a base such as sodium to form a bicyclic compound [j-VI], and this bicyclic compound [j-VI] is converted to hydrochloric acid, etc.
  • the present invention compound [j-I] can be obtained by dehydration with acid.
  • the compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form by using a widely used technique.
  • the compound of the present invention is very useful as a therapeutic agent for diseases involving intraocular pressure, such as glaucoma and ocular hypertension.
  • Diseases involving intraocular pressure include primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous production glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, mixed glaucoma, and steroid glaucoma.
  • Amyloid glaucoma neovascular glaucoma, malignant glaucoma, capsular lens. Glaucoma such as plateau-like iris syndrome, ocular hypertension, etc.
  • the compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, and they can be formulated using a widely used technique.
  • oral preparations such as tablets, capsules, granules, powders, etc. are excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous key acid, calcium carbonate, calcium phosphate phosphate, stearin Lubricants such as acid, magnesium stearate, talc, starch, hydroxypropylcellulose, hydroxy: ° Binders such as methylmethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, low-substituted hydroxy Disintegrants such as propylmethylcellulose and quinoleic citrate, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, stabilizers such as ethyl oxybenzoate and benzyl alcohol, sweeteners, acidulants and fragrances If necessary, use a flavoring agent It is possible to control.
  • excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous key acid, calcium
  • parenterals such as injections and eye drops are made of isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, and phosphoric acid.
  • isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, and phosphoric acid.
  • Buffering agents such as sodium, sodium hydrogen phosphate, sodium acetate, citrate, glacial acetic acid, trometamol, polyoxyethylene sorbitan monolate, polyoxy stearate 40, polyoxyethylene hydrogenated castor oil
  • Surfactants such as sodium citrate, sodium edetate, etc., benzalkonium chloride, paraben, benzotonium chloride, Preservatives such as paraoxybenzoic acid ester, sodium benzoate, chlorobutanol, hydrochloric acid, citrate, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate p
  • a soothing agent such as an H-adjusting agent or benzyl alcohol as necessary.
  • the dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like.
  • oral dosages are usually from 0.0 1 to 100 mg per day, preferably.;! ⁇ L O O mg can be administered in one or several divided doses.
  • eye drops usually have a concentration of 0.0 0 0 1% to 10% (w / v), preferably 0.0 1% to 5% (w / V), divided into one or several times. Can be administered.
  • the organic layer was washed with a saturated aqueous sodium chloride solution (200 ml) and dehydrated with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was collected by filtration with a mixture of hexane and ethyl acetate to obtain the target compound (4.75 g, 94%) as a pale yellow solid.
  • Lithium chloride (17 mg, 0.39 mmol), N, V-diisopropizoleethylamine (0.070 ml, 0.39 mmol), phosphonoacetate trichinole (0.080 ml, 0.39 mmol) was added to the reaction solution, and then further Stir overnight.
  • Water (20 ml) and 1 M hydrochloric acid (10 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 ml).
  • the organic layer was washed successively with a saturated charcoal-aqueous sodium hydrogencarbonate solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml) and dehydrated over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was collected by filtration with a mixed solution of hexane and ethyl acetate to obtain the target compound (0.359 g, 83%) as a pale yellow solid.
  • Reference compound 5-2 was obtained by a production method according to the production method of reference compound 5-1 using Reference compound 4 and a commercially available compound.
  • 6-Hydroxy-1-tetralone (5.02 g, 31.0) was added to a solution of trifluoromethanesulfonic anhydride (6.01 ml, 35.7 mmol) in dichloromethane (100 ml) at 50 ° C under a nitrogen atmosphere. mmol) and triethylamine (5.18 ml, 37.2 mmol) in dichloromethane (50 ml). The reaction solution was stirred at room temperature for 2 hours, and water (300 ml) was added.
  • N-tert-ptoxycarbolysonethyl nipecotate (reference compound 9) Under ice cooling, di-ieri-ptyl dicarbonate (12.2 g, 56.0 mmol) in anhydrous dichloromethane (35 ml) in dichloromethanone (8.00 g, 50.9 mmol) in anhydrous dichloromethane. (25 ml) solution was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, and 10% aqueous citrate solution (60 ml) was added to separate the layers.
  • the organic layer was washed with saturated aqueous sodium chloride solution (100 ml) and dehydrated with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the target compound (12.45 g, 95%) as a colorless oil.
  • the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (30 ml) and a saturated aqueous sodium chloride solution (30 ml), respectively, and dehydrated with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the target compound (2.44 g, 82%) as a colorless oil. .
  • the extract was washed successively with saturated aqueous sodium hydrogen carbonate (130 ml), water, (100 ml) 3 times, saturated aqueous sodium chloride (100 ml) and dehydrated over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, ethyl acetate was added to the residue and filtered to obtain the target compound (465 mg, 52%) as a pale yellow solid.
  • Reference Compound 16-2 was obtained by a production method according to the production method of Reference Compound 16-1, using 4-phenylacetyl cinnamate and a commercially available compound.
  • Reference Compound 1 7-2 was obtained by a production method according to the production method of Reference Compound 17-1, using Reference Compound 16-2 and a commercially available compound.
  • the reaction solution was stirred at room temperature for 5 hours, and then ice-cooled again, and black mouth form (5 ml) and 2 M aqueous sodium hydroxide solution (10 ml) were added. After stirring at room temperature for 15 minutes, black mouth form (50 ml) was added. The organic layer was washed successively with water (50 ml) twice and saturated aqueous sodium chloride solution (50 ml), and dehydrated with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (black mouth form / methanol) to obtain the target compound (117 mg, 57%) as a yellow-orange oil.
  • Reference Compound 1 8-2 was obtained by a production method according to the production method of Reference Compound 1 8-1, using Reference Compound 1 7-2 and a commercially available compound.
  • the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml), then dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Benzene (150 ml) was added to the residue, aluminum chloride (5.20 g, 39.0 mmol) was further added, and the mixture was heated to reflux for 3 hours.
  • the reaction mixture was poured into ice water (150 ml) and extracted twice with ethyl acetate (100 ml).
  • the organic layer was washed with saturated aqueous sodium chloride (100 ml) and dehydrated with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from a mixed solution of ethyl acetate and hexane to obtain the target compound (2.84 g, 74%) as pale yellow crystals.
  • Acetyl chloride (2.00 ml, 28.1 mmol) was added dropwise to a suspension of aluminum chloride (3.91 g, 29.3 mmol) in 1,2-dichloroethane (150 ml) at 0 ° C. After stirring for 18 minutes, a solution of 1,2-dichloroethane (50 ml) in 4 butylylphenol (4.00 g, 24.4 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into ice water (300 ml).
  • the organic layer was washed 6 times with saturated aqueous sodium chloride (80 ml) and dehydrated over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel force chromatography (chromium form / methanol). The obtained solid was washed with a mixed solution of isopropyl ether and hexane to obtain the target compound (2.20 g, 38%) as a colorless solid.
  • Triethylamine (0.19 ml, 1.4 mmol) and methanesulfonyl chloride (0.055 ml, 0.71 mmol) were added, and the mixture was further heated to reflux for 4 hours.
  • the reaction mixture was poured into 1 M hydrochloric acid (20 ml) and extracted with black mouth form (20 ml).
  • the organic layer was 1 M hydrochloric acid (20 ml), 'saturated aqueous sodium bicarbonate solution (20 ml).
  • the extract was washed successively with a saturated aqueous sodium chloride solution (20 ml) and dehydrated with anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the target compound (0.31 g, 98%) as a brown oily substance with an isomer ratio of about 2: 1.
  • the extract was washed successively with 1 M hydrochloric acid (15 m 1), saturated aqueous sodium hydrogen carbonate solution (15 ml) and saturated aqueous sodium chloride solution (15 ml), and dehydrated over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the target compound (542 mg, 86%) as a colorless oil.
  • the organic layer was washed with a saturated aqueous solution of sodium chloride (1-0 ml) and dehydrated with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the target compound (0.33 g, 77%) as a colorless oil.
  • 3-phenyl-1-7-trinoleolomethylsulphononioleoxy 4-monochromene 4-one (1.16 g, 3.13 mmol, reference compound 8-2), paradium acetate (70.2 mg, 0.313 mmol) , Tri (O-tolyl) phosphine (191 mg, 0.626 mmol), acetonitrile, (11 ml), N, V-diisopropylpropylamine (1.25 ml, 7.20 mmol), acrylic acid Methyl (1.41 ml, 15.7 mmo 1) was added and stirred at 80 ° C.
  • Compound 24-2 was obtained by the production method according to the production method of Compound 24-1 using Reference Compound 8-3 and a commercially available compound.
  • a tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, or silicone resin) to obtain the desired coated tablet.
  • a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, or silicone resin
  • a desired tablet can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.
  • a desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
  • Desired eye drops can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.
  • Fluorescein isothiocyanate-d extran (hereinafter referred to as FITC-dextran) intercellular permeability test using urushi trabecular meshwork cells 2.
  • Intraocular pressure reduction test by intraocular administration using normal intraocular monkey 3.
  • Intraocular pressure decrease effect test by short-term frequent instillation using normal intraocular pressure monkey 4.
  • Normal intraocular pressure anesthetized cat The intraocular pressure lowering effect test by intra-anterior administration was used, and the aqueous humor circulation improving action and the intraocular pressure lowering action of the compound of the present invention were examined.
  • the FITC-dextran permeability-enhancing effect of the cultured rabbit trabecular cord cell when treated with the compound of the present invention was examined. .
  • D-MEM Dulbecco's Modified Eagle Medium, Gibco Co., Ltd., hereinafter referred to as Medium A
  • B 2.5 ⁇ g / m 1
  • gentamicin 50 ⁇ g / m 1 added to
  • the FITC-dextran permeability enhancing action by the test compound was expressed as a test compound concentration (EC 5 value) showing 50% of the maximum FITC fluorescence intensity in each test compound.
  • test compound Al After dissolving the test compound Al force Li aqueous solution such as hydroxide Na Application Benefits ⁇ anhydrous solution, by adding physiological saline and diluted to a predetermined concentration (1 0- 3 M or 1 0_ 4 M), test compound A product solution was obtained.
  • aqueous solution such as hydroxide Na Application Benefits ⁇ anhydrous solution
  • Ketamine hydrochloride (5 to 10 mg / kg) was intramuscularly administered to experimental animals (strength cynomolgus: male) and general anesthesia was performed. .
  • test compound solution 100 was administered into one eye of the test animal in the anterior chamber using microsyringe and 30 G needle. The other eye was not treated.
  • the intraocular pressure in both eyes of the experimental animal was measured using an applanation tonometer immediately before administration of the test compound solution and at a predetermined time after administration of the test compound solution. Immediately before each intraocular pressure measurement, 0.4% of oxybupro hydrochloride in-ophthalmic solution (trade name: Benokiseal 0.4% solution) was instilled into each eye, and local anesthesia was performed. The intraocular pressure immediately before administration of the test compound solution was defined as the initial intraocular pressure.
  • Intraocular pressure drop (mmH g) I I O P (D— t) — I O P (D-0)
  • I O P (D-t) Intraocular pressure of the test compound-administered eye t time after administration of the test compound solution
  • I O P (D-0) Initial intraocular pressure of the test compound-administered eye
  • the maximum decrease in intraocular pressure is the average of 2 cases in the 10 group. Moreover, the test compound administration concentration when using Compound 8 2 Contact Yopi Compound 2 1- 3 was 1 0- 4 M. 3. Intraocular pressure lowering effect test by short-term frequent instillation using normal intraocular monkeys
  • test compound was dissolved in an aqueous alkaline solution such as an aqueous sodium hydroxide solution and then diluted with saline to a predetermined concentration (3%) to obtain a test compound solution.
  • an aqueous alkaline solution such as an aqueous sodium hydroxide solution
  • test compound solution 20 1 was administered to one eye of an experimental animal three times at 5-minute intervals. The other eye was not treated.
  • the intraocular pressure in both eyes of the experimental animal was measured using an applanation tonometer at a predetermined time.
  • 0.4% Pro-in eye drops (trade name: Benokiseal 0.4% solution) were instilled into each eye with 1 drop each and subjected to local anesthesia.
  • Intraocular pressure drop (mmH g) I I O P (D—t) — I ⁇ P (D— ⁇ )
  • Table 3 shows the test results [maximum intraocular pressure drop (mmHg)] when using Compound 1-11 as the test compound. As is apparent from Table 3, the compound of the present invention showed an excellent intraocular pressure lowering effect. That is, it is recognized that the compound of the present invention is useful as an intraocular pressure lowering agent.
  • the maximum intraocular pressure drop is the average of 4 patients per group.
  • test compound solution 20 ⁇ 1 was administered into one eye of a test animal in the anterior chamber using microsyringe and 30 G needle. The other eye was not treated.
  • the intraocular pressure of both eyes of the experimental animal was measured using an applanation tonometer at a predetermined time.
  • 0.1% oxybpro hydrochloride Ishi ophthalmic solution (trade name: Benokiseal 0.4% (Dilute the solution) and instill one drop into each of the eyes to give local anesthesia.
  • the intraocular pressure immediately before administration of the test compound solution was taken as the initial intraocular pressure.
  • Intraocular pressure drop (mmH g)
  • I O P (D-t) Intraocular pressure of the test compound administered eye t time after administration of the test compound solution
  • I O P (.N-t) Intraocular pressure of the untreated eye t time after administration of the test compound solution
  • I O P (D—0) Initial intraocular pressure of the test compound-administered eye immediately before administration of the test compound solution
  • I O P (N—0) Intraocular pressure of the untreated eye immediately before administration of the test compound solution
  • Table 4 shows the test results [maximum intraocular pressure drop (mmH g)] when using 23.
  • the compound of the present invention showed an excellent intraocular pressure lowering action. That is, it is recognized that the compound of the present invention is useful as an intraocular pressure lowering agent.
  • the maximum intraocular pressure drop is the average of 3 to 5 cases in the 10 group.
  • the present invention provides a cinnamon husk-related compound useful as a medicine.
  • the compound has an excellent aqueous humor circulation improvement effect and an intraocular pressure lowering effect, and is useful as a therapeutic agent for diseases involving intraocular pressure, such as glaucoma and ocular hypertension.

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Abstract

L'invention concerne de nouveaux composés apparentés à l'acide cinnamique et des sels de ceux-ci lesquels sont utiles comme médicaments, plus précisément des composés représentés par la formule générale [1] et des sels de ceux-ci : [1] dans laquelle A est un cycle hydrocarboné à six éléments ou un hétérocycle à six éléments ; Ra1 est H, un alkyle ou un aryle ; Ra2 est H, un halogéno, OH ou similaire ; Ra3 est H, un halogéno, OH, un alcoxy ou similaire ; Ra4 est un carboxy, un amino ou similaire ; Xa est -C(=N-Ra5)-, -CRa6Ra7-, -NRa8-ou similaire ; Ra5 est H, OH un alcoxy ou similaire ; Ra6 et Ra7 sont chacun H, un halogéno ou similaire ; Ra6 et Ra7 peuvent former un cycle cyclohexane ; Ra8 est H, OH, un alcoxy ou similaire ; Ya est un alkylène, un -O-alkylène ou similaire et la ligne brisée représente une liaison simple ou une double liaison.
PCT/JP2005/014262 2004-07-28 2005-07-28 Nouveaux composés apparentés à l'acide cinnamique WO2006011669A1 (fr)

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WO2008035359A3 (fr) * 2006-06-12 2008-05-15 Cadila Healthcare Ltd Acide oxyminophénoxyalcanoïque et dérivés de l'acide phenylalcanoïque
WO2013033377A1 (fr) * 2011-08-30 2013-03-07 Gilead Sciences, Inc. Inhibiteurs d'aldh-2 dans le traitement de la dépendance à des produits
CN103012349A (zh) * 2008-05-28 2013-04-03 中国医学科学院药物研究所 7-羟基异黄酮的晶c型、其制法和其药物组合物与用途
CN103121986A (zh) * 2008-05-28 2013-05-29 中国医学科学院药物研究所 7-羟基异黄酮的晶e型、其制法和其药物组合物与用途
CN103145674A (zh) * 2008-05-28 2013-06-12 中国医学科学院药物研究所 一种7-羟基异黄酮的晶型、其制法和其药物组合物与用途
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8703759B2 (en) 2010-07-02 2014-04-22 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer

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EP3639855A4 (fr) 2017-06-16 2021-03-17 The Doshisha Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
WO2018230711A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Médicament contenant un inhibiteur de mtor destiné au traitement ou à la prévention de symptômes, de troubles ou de maladies ophtalmiques, et son application

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3501503A (en) * 1967-09-12 1970-03-17 Merck & Co Inc (4-(2,3-epoxyalkanoyl)phenoxy)acetic acids
US4342782A (en) * 1978-11-16 1982-08-03 Merck & Co., Inc. 1-(Substituted-aminoalkoxyphenyl)-2-methylene-1-alkanones, compositions and use thereof
JPH07258074A (ja) * 1994-03-15 1995-10-09 Sanwa Shiyouyaku Kk 新規な血行促進のために使用する医薬
US5506226A (en) * 1993-04-19 1996-04-09 Alcon Laboratories, Inc. Ethacrynic acid-like compounds and use thereof to treat glaucoma
JPH10509987A (ja) * 1996-03-14 1998-09-29 センタ インタナショナル ドゥ リシェルシェ デルマトロジーク ガルデルマ （セ イ エール デ ガルデルマ） 二環式芳香族化合物
JPH11514015A (ja) * 1996-07-25 1999-11-30 ドン ア ファーマシューティカル カンパニー リミテッド 胃腸管保護作用により炎症性腸疾病で治癒効果を有するフラボン及びフラバノン化合物
JP2000063340A (ja) * 1998-03-30 2000-02-29 F Hoffmann La Roche Ag 抗腫瘍活性を有するフェノキシ酢酸及びフェノキシメチルテトラゾ―ルの誘導体
JP2000256259A (ja) * 1999-03-11 2000-09-19 Nippon Zoki Pharmaceut Co Ltd メイラード反応阻害剤
JP2000336063A (ja) * 1998-11-05 2000-12-05 Shuichi Hirono 新規化合物およびその医薬用途
JP2001139550A (ja) * 1999-11-17 2001-05-22 Shionogi & Co Ltd アミド化合物の新規用途

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3501503A (en) * 1967-09-12 1970-03-17 Merck & Co Inc (4-(2,3-epoxyalkanoyl)phenoxy)acetic acids
US4342782A (en) * 1978-11-16 1982-08-03 Merck & Co., Inc. 1-(Substituted-aminoalkoxyphenyl)-2-methylene-1-alkanones, compositions and use thereof
US5506226A (en) * 1993-04-19 1996-04-09 Alcon Laboratories, Inc. Ethacrynic acid-like compounds and use thereof to treat glaucoma
JPH07258074A (ja) * 1994-03-15 1995-10-09 Sanwa Shiyouyaku Kk 新規な血行促進のために使用する医薬
JPH10509987A (ja) * 1996-03-14 1998-09-29 センタ インタナショナル ドゥ リシェルシェ デルマトロジーク ガルデルマ （セ イ エール デ ガルデルマ） 二環式芳香族化合物
JPH11514015A (ja) * 1996-07-25 1999-11-30 ドン ア ファーマシューティカル カンパニー リミテッド 胃腸管保護作用により炎症性腸疾病で治癒効果を有するフラボン及びフラバノン化合物
JP2000063340A (ja) * 1998-03-30 2000-02-29 F Hoffmann La Roche Ag 抗腫瘍活性を有するフェノキシ酢酸及びフェノキシメチルテトラゾ―ルの誘導体
JP2000336063A (ja) * 1998-11-05 2000-12-05 Shuichi Hirono 新規化合物およびその医薬用途
JP2000256259A (ja) * 1999-03-11 2000-09-19 Nippon Zoki Pharmaceut Co Ltd メイラード反応阻害剤
JP2001139550A (ja) * 1999-11-17 2001-05-22 Shionogi & Co Ltd アミド化合物の新規用途

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035359A3 (fr) * 2006-06-12 2008-05-15 Cadila Healthcare Ltd Acide oxyminophénoxyalcanoïque et dérivés de l'acide phenylalcanoïque
CN103145674A (zh) * 2008-05-28 2013-06-12 中国医学科学院药物研究所 一种7-羟基异黄酮的晶型、其制法和其药物组合物与用途
CN103012349A (zh) * 2008-05-28 2013-04-03 中国医学科学院药物研究所 7-羟基异黄酮的晶c型、其制法和其药物组合物与用途
CN103121986A (zh) * 2008-05-28 2013-05-29 中国医学科学院药物研究所 7-羟基异黄酮的晶e型、其制法和其药物组合物与用途
US9371329B2 (en) 2009-07-27 2016-06-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8703759B2 (en) 2010-07-02 2014-04-22 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8697863B2 (en) 2011-07-01 2014-04-15 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN103764640A (zh) * 2011-08-30 2014-04-30 吉利德科学股份有限公司 成瘾治疗中的aldh-2抑制剂
WO2013033377A1 (fr) * 2011-08-30 2013-03-07 Gilead Sciences, Inc. Inhibiteurs d'aldh-2 dans le traitement de la dépendance à des produits
US8673966B2 (en) 2011-08-30 2014-03-18 Gilead Sciences, Inc. ALDH-2 inhibitors in the treatment of addiction
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer

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