WO2005035501A1 - Nouveau derive d'olefine - Google Patents

Nouveau derive d'olefine Download PDF

Info

Publication number
WO2005035501A1
WO2005035501A1 PCT/JP2004/015648 JP2004015648W WO2005035501A1 WO 2005035501 A1 WO2005035501 A1 WO 2005035501A1 JP 2004015648 W JP2004015648 W JP 2004015648W WO 2005035501 A1 WO2005035501 A1 WO 2005035501A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
compound
amino
Prior art date
Application number
PCT/JP2004/015648
Other languages
English (en)
Japanese (ja)
Inventor
Masahiko Hagihara
Naoyuki Izumi
Yasunori Tsuzaki
Takeshi Matsugi
Tadashi Nakajima
Masakazu Hatano
Hideaki Hara
Original Assignee
Ube Industries, Ltd.
Santen Pharmaceutical Co., Ltd.
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 Ube Industries, Ltd., Santen Pharmaceutical Co., Ltd. filed Critical Ube Industries, Ltd.
Publication of WO2005035501A1 publication Critical patent/WO2005035501A1/fr

Links

Classifications

    • 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
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a novel olefin derivative or a salt thereof useful as a medicament.
  • the orefin derivative according to the present invention has Rho kinase inhibitory activity and is useful as a therapeutic agent for diseases involving Rho kinase, for example, eye diseases such as glaucoma.
  • Rh a small GTP-binding protein, is activated by signals from various cell membrane receptors. Activated Rho, via Rh-kinase and actomyosin signaling, undergoes smooth muscle contraction, cell morphology changes, cell motility, cell division, cell-cell adhesion, platelet aggregation, leukocyte aggregation, It functions as a molecular switch for various cellular phenomena such as invasion and enhancement of cancer cells.
  • Rh o enables prevention and / or treatment of the above-mentioned diseases involving Rh o.
  • Rhokinase existing downstream of the Rho-mediated signal transduction system.
  • compounds that inhibit Rho kinase include the aforementioned diseases involving Rho, such as hypertension, angina, asthma, peripheral circulatory disorders, premature birth, arteriosclerosis, cancer, inflammatory diseases, and autoimmune diseases. , AIDS, fertilization and implantation of fertilized eggs, osteoporosis, cerebral dysfunction, bacterial gastrointestinal tract disorders, glaucoma, retinopathy, etc. (International Publication WO 98Z06433 pamphlet).
  • Rho kinase inhibitors are generally defined as serine Z threonine kinase inhibitors that are activated upon activation of Rho.
  • the Rh kinase inhibitors include ROKo! (ROCK-II), ROK) 3 (ROCK-I, 160 ROC), and other compounds that inhibit proteins having serine nothreonine kinase activity.
  • Rho kinase inhibitors include amide derivatives disclosed in International Publication WO 98/0643, Pan Fret, International Publication WO 97/23222, Panture, Nature, 389, 990—994 (1 9997) and International Publication W 09 9/640 11 Itkinoline sulfonyl derivative disclosed in Panfret, International Publication WO 01/56988 Heterocycleamino derivative disclosed in Panfret, International Publication WO 02 / And the quinazoline derivative disclosed in International Publication WO 02/076 976 Pan fret and International Publication WO 02/076 977 pamphlet.
  • Rh kinase inhibitor is useful as a therapeutic agent for glaucoma.
  • the present inventors have conducted synthesis studies of novel olefin derivatives to solve the above problems, and have succeeded in creating many new compounds.
  • the usefulness of the orefin derivative according to the present invention as a medicament was examined in various ways, and it has been found that the orefin derivative has an inhibitory effect on Rho kinase and is useful as a therapeutic agent for diseases associated with Rho kinase. I found that.
  • the present invention relates to a compound represented by the following general formula [I] or a salt thereof (hereinafter, referred to as “the compound of the present invention” unless otherwise specified), and a pharmaceutical composition containing the compound of the present invention.
  • the present invention relates to an Rho kinase inhibitor containing the compound of the present invention as an active ingredient, and more specifically to a therapeutic agent for an eye disease such as glaucoma.
  • the compound of the present invention has the following chemical structural characteristics as shown in 1-3):
  • Ring X and ring Y are directly bonded to the ethylene group.
  • Ring X has an alkyl group or a cycloalkyl group substituted with an amino group.
  • Each of the chemical structural characteristics 1) to 3) and / or a combination thereof is important for the Rho kinase inhibitory action of the compound of the present invention.
  • the compound of the present invention in which ring Y is a pyridine ring or a -pyro [2,3-wa] pyridine ring has particularly excellent Rho kinase inhibitory activity.
  • ring X represents a benzene ring, a cycloalkane ring, or a monocyclic aromatic heterocycle having one or more nitrogen atoms in the ring
  • Ring Y represents a pyridine ring or an Iff-pyrro [2,3- 3] pyridine ring;
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a substituted or unsubstituted alkyl group; R 1 and R 2 may combine to form a substituted or unsubstituted cycloalkane ring;
  • a halogen atom 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, an amino group
  • R 5 and R 6 are the same or different and each is a halogen atom, a hydrogen atom, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted cycloalkyl Oxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl Group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aryl group, carboxy group or its ester or amide thereof, hydrocarbonyl group, substituted or unsubstit
  • R 3 and R 5 may combine to form a substituted or unsubstituted cycloalkene ring.
  • the present invention provides a useful novel Orefin derivative or a salt thereof as _ medicament.
  • the compound of the present invention has an excellent Rho kinase inhibitory activity, and is useful as an agent for treating diseases associated with Rho kinase, for example, eye diseases such as glaucoma.
  • FIG. 1 is a graph showing the change over time in intraocular pressure of each administration group.
  • the intraocular pressure is shown as a change from the initial intraocular pressure.
  • ⁇ indicates the test compound 1 administration group
  • ⁇ indicates the control group.
  • FIG. 2 is a graph showing the change over time in intraocular pressure of each administration group.
  • the intraocular pressure is shown as a change from the initial intraocular pressure.
  • the mouth indicates the group to which test compound 2 was administered, and the open square indicates the control group.
  • “Cycloalkane ring” refers to a cycloalkane ring having 3 to 8 carbon atoms. Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopeptane, cyclooctane and the like.
  • a monocyclic aromatic heterocyclic ring having one or more nitrogen atoms in the ring means that it contains one or two nitrogen atoms in the ring and contains an oxygen atom and / or a sulfur atom. And a monocyclic aromatic heterocycle. Specific examples include pyrrol, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine and the like having a nitrogen atom in the ring, and oxazole and isooxazole having a nitrogen atom and an oxygen atom in the ring. Thiazole and isothiazole having a nitrogen atom and a sulfur atom in the ring are exemplified.
  • Cycloalkene ring refers to a cycloalkene ring having 3 to 8 carbon atoms. Specific examples include cyclopropene, cycloptene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, and the like.
  • the “monocyclic heterocycle” refers to a saturated or unsaturated monocyclic heterocycle having one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring.
  • saturated monocyclic heterocycle examples include pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopyridine, homopyridine having a nitrogen atom in the ring. Perazine, etc., tetrahydrofuran, tetrahydropyran, etc.
  • unsaturated monocyclic heterocycles include dihydropyrrol, pyrrole, dihydropyrazole, pyrazol, dihydroimidazole, imidazole, dihydrotriazol, triazole, tetrahydropyridine, which have a nitrogen atom in the ring.
  • Halogen atom refers to fluorine, chlorine, bromine or iodine.
  • Alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, —propyl, —butyl, ⁇ -pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, And sopentyl.
  • Alkoxy refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, 1-propoxy, 1-butoxy, 1-pentoxy, ⁇ -hexyloxy, isopropoxy, isobutoxy, sec-butoxy, ferr-butoxy, isopentoxy and the like.
  • Aryloxy refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbonoxy having 6 to 14 carbon atoms. Specific examples include phenoxy, naphthyloxy, anthroxy, phenanthroxy and the like.
  • Aryl refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • Alkylamino refers to mono or dialkylamino. Specific examples include methylamino, ethylamino, ethylmethylamino, dimethylamino, getylamino, dihexylamino and the like.
  • arylamino refers to an object or a library. Specific examples include phenylamino, naphthylamino, methylphenylamino, ethylphenylamino, diphenylamino and the like.
  • alkenyloxy refers to a straight-chain or branched alkenyloxy having 2 to 8 carbon atoms. Specific examples include vinyloxy, aryloxy, 1-propenyloxy, 3-butenyloxy, 3-pentenyloxy, 4-hexenyloxy, 5-heptenyloxy, 7-octenyloxy, 1-methylvinyloxy, and the like.
  • alkynyloxy refers to a straight-chain or branched alkynyloxy having 2 to 8 carbon atoms. Specific examples include ethynyloxy, 2-propynyloxy, 2-butynyloxy, 3-pentynyloxy, 4-hexynyloxy, 5-heptinyloxy, 7-butynyloxy, 2-methylbutynyloxy, and the like. “Cycloalkyloxy” refers to cycloalkyloxy having 3 to 8 carbon atoms. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.
  • Cycloalkenyloxy refers to cycloalkenyloxy having 3 to 8 carbon atoms. Specific examples include cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy, and the like.
  • Alkenyl refers to straight-chain or branched alkenyl having 2 to 8 carbon atoms. Specific examples include vinyl, aryl, 1-probenyl, 3-butenyl, 3-pentenyl, 4-hexenyl, 5-heptenyl, 71-octenyl, 1-methylvinyl group and the like.
  • Alkynyl refers to straight-chain or branched alkynyl having 2 to 8 carbon atoms. Specific examples include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 4-hexynyl, 5-heptynyl, 71-butynyl, 2-methylbutynyl, and the like.
  • Cycloalkyl refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Cycloalkenyl refers to cycloalkenyl having 3 to 8 carbon atoms. Specific examples include cycloprobenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
  • esters of a carboxy group refers to an ester comprising a carboxy group and an alkyl alcohol, aryl alcohol, or the like.
  • alkyl alcohol include methanol, ethanol, propanol and butanol
  • aryl alcohol include phenol and naphthol.
  • amide of a carboxy group refers to an amide comprising a carboxy group and ammonia, primary or secondary amine, and the like.
  • the amine may be an alkylamine or arylamine.
  • Specific examples of the alkylamine include methylamine, ethylamine, ethylmethylamine, dimethylamine, getylamine, dihexylamine, and the like.
  • Specific examples of the arylamine include aniline, Examples include naphthylamine, methylphenylamine, ethylphenylamine, diphenylamine and the like.
  • Alkyl propyl refers to a linear or branched alkyl carbonyl having 2 to 7 carbon atoms. Specific examples include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, butyl carbonyl, one-pentyl carbonyl, n-hexyl carbonyl, isopropyl carbonyl, isopropyl carbonyl, sec-butyl carbonyl, ter-butyl carbonyl, And sopentyl carbonyl.
  • arylcarbonyl refers to monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon power luponyl having 7 to 15 carbon atoms. Specific examples include fluorcarbonyl, naphthylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl and the like.
  • Alkylthio refers to straight-chain or branched alkylthio having 1 to 6 carbon atoms. Specific examples include methylthio, ethylthio, ' ⁇ -propylthio, ⁇ -butylthio, ⁇ -pentylthio, 1-hexylthio, isopropylthio, isobutylthio, sec-butylthio, erf-butylthio, isopentylthio, and the like.
  • Arylthio refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon thio having 6 to 14 carbon atoms. Specific examples include phenylthio, naphthylthio, anthrylthio, phenanthrylthio and the like.
  • “Sulfinic acid group ester” refers to an ester comprising a sulfinic acid group and an alkyl alcohol, aryl alcohol, or the like.
  • alkyl alcohol include methanol, ethanol, propanol, butanol and the like.
  • alcohol include phenol and naphthol.
  • “Sulfinic acid group amide” refers to an amide comprising a sulfinic acid group and ammonia, primary or secondary amine, and the like.
  • the amine may be an alkylamine or an arylamine. Specific examples of the alkylamine include methylamine, ethylamine, ethylmethylamine, dimethylamine, getylamine, dihexylamine, and the like. Specific examples of the arylamine include aniline, naphthylamine, methylphenylamine, and the like. Tilphenylamine, diphenylamine and the like.
  • Alkylsulfinyl refers to straight-chain or branched alkylsulfinyl having 1 to 6 carbon atoms. Specific examples include methylsulfiel, ethylsulfinyl, ⁇ -propylsulfinyl, ⁇ -butylsulfinyl, —pentylsulfinyl, 1-hexylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butyl. Sulfinyl, isobentylsulfiel, and the like.
  • arylsulfinyl refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon sulfinyl having 6 to 14 carbon atoms. Specific examples include phenylsulfinyl, naphthylsulfinyl, anthrylsulfinyl, phenanthrylsulfinyl and the like.
  • ester of a sulfonic acid group refers to an ester comprising a sulfonic acid group and an alkyl alcohol, aryl alcohol, or the like.
  • alkyl alcohol include methanol, ethanol, propanol and butanol
  • aryl alcohol include phenol and naphthol.
  • the “amide of a sulfonic acid group” refers to an amide comprising a sulfonic acid group and ammonia, a primary or secondary amine, or the like.
  • the amine may be an alkylamine or an arylamine. Specific examples of the alkylamine include methylamine, ethylamine, ethylmethylamine, dimethylamine, dimethylamine, dihexylamine, and the like. Specific examples of the arylamine include aniline, naphthylamine, and methylphenylamine.
  • Alkylsulfonyl refers to straight-chain or branched alkylsulfonyl having 1 to 6 carbon atoms. Specific examples include methylsulfonyl, ethylsulfonyl, _n-propylsulfonyl, —butylsulfonyl, —pentylsulfonyl, 1-hexylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, fer-butylsulfonyl, And isopentylsulfonyl.
  • arylsulfonyl refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon sulfonyl having 6 to 14 carbon atoms. Specific examples include phenylsulfonyl, naphthylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl and the like. '
  • Alkoxyimino refers to a straight-chain or branched alkoxyimino having 1 to 6 carbon atoms. Specific examples include: methoxyimino, ethoxyimino, —propoxymino, ⁇ -butoxyimino, _ ⁇ —pentoxyimino, il-1-hexyloximino, isopropoxyimino, isobutoxyimino, sec-butoxyimino, t6r ⁇ butoxyimino, Isopentoxyimino and the like.
  • Aryl oximino refers to a monocyclic or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon oximino having 6 to 14 carbon atoms. Specific examples include phenoximino, naphthyloximino, anthryloximino, phenanthroxymino, and the like.
  • substituted cycloalkane ring refers to a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or its ester or its amide, amino group, alkylamino group, And a cycloalkane ring having, as a substituent, one or more groups selected from arylamino groups, nitro groups, and cyano groups.
  • “Substituted cycloargen ring” refers to a halogen atom, a hydroxy group, an alkoxy group, One or more groups selected from a lyloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carboxy group or its ester or an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group; It shows a cycloalkene ring as a substituent.
  • “Substituted monocyclic heterocycle” means that the carbon atom part is a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carboxyl group or its ester or its amide, amino 1 or selected from the group consisting of an alkylamino group, an arylamino group, a mercapto group, an alkylthio group, an arylthio group, a formyl group, an alkylcarbonyl group, an arylcarbonyl group, a nitro group, and a cyano group.
  • a monocyclic heterocyclic group having a plurality of groups as substituents is shown.
  • “Substituted alkyl” refers to a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, One or more selected from a lipoxy group or an ester or amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, a cyano group, a hydroxyimino group, an alkoxyimino group, and an aryloxyimino group; It represents an alkyl group having a group as a substituent.
  • “Substituted alkoxy group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, or a propyloxy group.
  • an alkoxy group having, as a substituent, one or more groups selected from an ester or an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted aryloxy group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carboxy group or an ester thereof or an amide, amino group, alkylamino group, arylamino group.
  • Substituted aryl group means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester or an amide, an amino group, an alkylamino group, or an amide thereof.
  • Substituted alkylamino group means an alkyl group whose alkyl moiety is substituted with a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, or an alkoxy group.
  • An alkylamino group having, as a substituent, one or a plurality of groups selected from the group consisting of a propyloxy group or an ester thereof, an amidoamino group thereof, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted arylamino group” means that the aryl moiety is a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group, an ester thereof, an amide thereof, or an amino group.
  • “Substituted alkenyloxy group” refers to a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, or a propyloxy group.
  • an alkenyloxy group having, as a substituent, one or more groups selected from an ester thereof, an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted alkynyloxy group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, or a propyloxy group.
  • an alkynyloxy group having, as a substituent, one or more groups selected from an ester thereof, an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted cycloalkyloxy group” refers to a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a propyloxy group or
  • a cycloalkyloxy group having, as a substituent, one or more groups selected from an ester or an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted cycloalkenyloxy group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof, an amide thereof, an amino group, an alkylamino group.
  • “Substituted alkenyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, A alkenyl group having, as a substituent, one or more groups selected from a carbonyl group or an ester thereof, an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted alkynyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, or a propyloxy group.
  • “Substituted cycloalkyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or a ester thereof, an amide thereof, an amino group, an alkylamino group.
  • a cycloalkyl group having, as a substituent, one or more groups selected from a group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted cycloalkenyl group” ′ refers to a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof or an amide, amino group, alkylamino group, or amino group thereof. Lilamino group, nitro And a cycloalkenyl group having one or more groups selected from a group and a cyano group as substituents. -
  • “Substituted alkylcarbonyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, a propyloxy group or It represents an alkyl group having one or more groups selected from the ester or its amide, amino group, alkylamino group, arylamino group, nitro group, and cyano group as a substituent.
  • “Substituted arylcarbonyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof, an amide thereof, an amino group, an alkylamino group. And shows an aryl group having one or more groups selected from a group, an arylamino group, a nitro group, and a cyano group as a substituent.
  • Substituted alkylthio group means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, It represents an alkylthio group having as a substituent one or more groups selected from a ropoxy group or its ester or its amide, amino group, alkylamino group, arylamino group, nitro group, and cyano group.
  • Substituted arylthio group means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof, an amide thereof, an amino group, It represents an arylthio group having as a substituent one or more groups selected from an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • “Substituted alkylsulfinyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, carboxy group.
  • an alkylsulfinyl group having, as a substituent, one or more groups selected from a group or an ester thereof, an amide thereof, an amino group, an alkylamino group, an arylamino group, a nitro group, and a cyano group.
  • Substituted arylsulfinyl group means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof, or an amide, amino group, alkylamino group, arylamino group.
  • an arylsulfenyl group having, as a substituent, one or more groups selected from a group consisting of a group, a nitro group, and a cyano group.
  • “Substituted alkylsulfonyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with an alkoxy group, a propyloxy group or It represents an alkylsulfonyl group having one or more groups selected from the ester or its amide, amino group, alkylamino group, arylamino group, nitro group, and cyano group as a substituent.
  • “Substituted arylsulfonyl group” means a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, a cycloalkyl group, an aryl group, a carbonyl group or an ester thereof, an amide thereof, an amino group, an alkylamino group.
  • an arylsulfonyl group having, as a substituent, one or more groups selected from a group, an arylamino group, a nitro group, and a cyano group.
  • the compound of the present invention has a free hydroxy group, amino group, alkylamino group or arylamino group as a substituent, those groups may be protected by a protecting group.
  • the protecting group for a free hydroxy group refers to a substituted or unsubstituted alkyl group such as a methoxymethyl group, a benzyl group, a trityl group, a 4-methoxyphenylmethyl group, a benzyloxymethyl group, a methyl group, a aryl group, or an unsubstituted group.
  • a free amino-, alkylamino- or arylamino-protecting group is a substituted alkyl group such as benzyl, trityl, diphenylmethyl, '(4-methoxyphenyl) diphenylmethyl, or aryl.
  • an unsubstituted alkenyl group a hydrocarbonyl group, that is, a formyl group; a substituted or unsubstituted alkylcarbonyl group, such as a trichloroacetyl group, a trifluoroacetyl group, an acetyl group, a benzoyl group, a benzoyl group, a benzoyl group, or a picolinol group; Unsubstituted arylcarbonyl or unsubstituted heterocyclic carbonyl group; 2,2,2-trichloromouth ethoxycarbonyl group, benzyloxycarbonyl group, diphenylmethoxycarbonyl group, methoxycarbonyl group, isobutoxycarbonyl group, er er ⁇ —Butoxycarponyl group, 31 Substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted aryloxycarbonyl group
  • ⁇ ring of the compound of the present invention represented by the general formula I is a ⁇ -pyroport [2,3-b pyridine ring]
  • An atom may be protected with a protecting group.
  • the protecting group for the nitrogen atom of the pyridine ring is benzyl, trityl, diphenylmethyl, (4-methoxyphenyl) diphenylmethyl, aryl, 2- (Trimethylsilyl) a substituted alkyl group such as an ethoxymethyl group or an unsubstituted alkenyl group; a hydrocarbonyl group, that is, a formyl group; a trichloroacetyl group, a trifluoroacetyl group, an acetyl group, a .4-chlorobenzoyl group, a benzoyl group, Substituted or unsubstituted alkyl carbonyl group such as picolinoyl group, substituted or unsubstituted aryl carbonyl group or unsubstituted heterocyclic carbonyl group; 2,2,2-trichloromouth ethoxycarbonyl group,
  • the “plural groups” in the present invention may be the same or different. Further, a halogen atom, a hydrogen atom, and a monocyclic heterocycle are also included in the “group”.
  • the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Salts, organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, _ —toluenesulfonic acid, trifluoroacetic acid, etc., Lithium, sodium, potassium, etc. And salts with alkaline earth metals such as calcium and magnesium, and quaternary salts with ammonia and methyl iodide.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the compound of the present invention has a geometric isomer, for example, a syn-anti isomer or an optical isomer, those isomers are also included in the scope of the present invention.
  • ring X represents a benzene ring
  • ring Y represents a pyridine ring or an Iff-pyrro [2,3-b] pyridine ring;
  • R 1 and R 2 represent a hydrogen atom or an unsubstituted alkyl group
  • R 3 represents hydrogen
  • R 4 represents a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or an unsubstituted alkyl group
  • R 6 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a carbonyl group, an ester thereof, an amide thereof, or a cyano group.
  • ring X represents a benzene ring
  • ring Y represents a pyridine ring or a 1H-pyro [2,3-b] pyridine ring;
  • R 1 and R 2 represent a hydrogen atom or an unsubstituted alkyl group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or an unsubstituted alkyl group
  • R 6 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a carbonyl group, an ester thereof, an amide thereof, or a cyano group
  • substituted alkyl group is an alkyl group substituted with one or more groups selected from the group consisting of a hydroxy group, an unsubstituted aryloxy group, and a hydroxyimino group:
  • ring X represents a benzene ring
  • Ring Y is a pyridine ring or a 1H-pyro [2,3-bl pyridine ring;
  • R ′ and R 2 represent a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or a methyl group
  • R 6 is hydrogen atom, methyl group, ethyl group, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-11-methylethyl group, phenoxymethyl group, hydroxyiminomethyl group, carboxy group, methoxycarbonyl group , An aminocarbonyl group, or a cyano group.
  • ring X represents a benzene ring
  • Ring Y represents a pyridine ring or an Iff-pyro [2,3-wa] pyridine ring;
  • R> and R 2 represent a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or a methyl group
  • R 6 is a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-11-methylethyl group, a phenoxymethyl group, a hydroxyiminomethyl group, a carboxy group, a methoxycarbonyl group, or an aminoaminocarbonyl Or a cyano group
  • the compound of the present invention has the chemical structural characteristics shown in the following 1 to 3), and each of the chemical structural characteristics of 1 to 3) and Z or a combination thereof have an R ho It is very important for the expression of kinase inhibitory action.
  • Ring X and ring Y are directly bonded to the ethylene group.
  • Ring X has an alkyl group or a cycloalkyl group substituted with an amino group.
  • Ring X has an alkyl group or a cycloalkyl group substituted with an amino group.
  • Ring Y is a pyridine ring or a —pyro-opened [2,3-wa] pyridine ring, the compound of the present invention exhibits excellent Rho kinase inhibitory activity, and the compounds of the present invention having these rings are more preferable.
  • the compound of the present invention in which ring X and ring Y are located at the trans position relative to the ethylene group, exhibits even more excellent Rho kinase inhibitory activity, and the compound in which ring X and ring Y are substituted at this position.
  • Invention compounds are more preferred.
  • Compound I Compound F Compound of the present invention Synthesis route 1: Compound of the present invention obtained by subjecting compound A and compound B to an Horner-Eranoms type reaction in an organic solvent in the presence of a base There is a monkey.
  • Synthesis Route 2 Nucleophilic reaction between compound A and compound C in an organic solvent in the presence of a base This gives compound D.
  • the compound of the present invention can also be obtained by introducing a leaving group into this compound D in an organic solvent in the presence of a base, then adding a further base and subjecting it to a elimination reaction.
  • Synthesis route 3 The compound of the present invention can also be obtained by performing a coupling reaction between compound E and compound F in an organic solvent in the presence of a metal catalyst and / or a base.
  • the protecting group when a protecting group is used for convenience of production, the protecting group can be removed by a generally used method.
  • desired substituents may be introduced into the starting material from the beginning. , Reduction, alkylation, amidation, oximation, dehydration reaction, hydrolysis reaction, deprotection reaction and / or a general-purpose synthesis method combining these reactions, and the desired substituent on the basic skeleton is used. May be introduced.
  • Rho kinase inhibitory activity of the compound of the present invention was evaluated and examined. The details thereof will be described in the following example [Pharmacological test (Rho kinase inhibitory activity evaluation test)], which is described in Journal of Biological Chemistry, Vol. 274, Vol. The method of Kaibuchi et al. Described in 1992 [J. Biol. Chem., 274, 32418 (1999)] and a commercially available activated ROCKII [Upstates Biotechnology, Catalog No. 1413-338 , (5 units / 50 microliters) ups t at ebio techno logy, Cat alog No.
  • Rho kinase inhibitory activity of the compound of the present invention was evaluated and examined. As a result, they have found that the compound of the present invention has an excellent Rho kinase inhibitory activity and is very useful as a therapeutic agent for diseases associated with Rho kinase. Furthermore, in order to verify the application of the compound of the present invention to specific diseases involving Rho kinase, the intraocular pressure lowering effect of the compound of the present invention was also examined.
  • Rho kinase is used for hypertension, angina, asthma, peripheral circulatory disorders, premature birth, arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases, AIDS, implantation of fertilized and fertilized eggs, osteoporosis, It is known to be closely related to diseases such as brain dysfunction, bacterial digestive tract disorders, glaucoma, and retinopathy. Therefore, the compound of the present invention is very useful as a therapeutic agent for those diseases in which Rho kinase is involved.
  • Rho kinase inhibitor in the present invention means a compound that inhibits serine nothreonine kinase activated upon activation of Rho.
  • glaucoma includes primary open-angle glaucoma, normal tension glaucoma, excessive glaucoma with aqueous humor production, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, mixed-type glaucoma, and steroid.
  • Examples include glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, and plateau iris syndrom.
  • the compound of the present invention can be administered orally or parenterally.
  • Dosage forms include tablets, capsules, granules, powders, injections, eye drops and the like, and these can be formulated by using commonly used techniques in combination.
  • oral preparations such as tablets, capsules, granules, and powders include excipients such as lactose, mannitol, starch, microcrystalline cellulose, light gay anhydride, calcium carbonate, calcium hydrogen phosphate, and stearic acid.
  • Lubricants such as magnesium stearate and talc; binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone; carboxymethylcellulose; low-substituted hydroxypropylmethylcellulose; calcium citrate Disintegrant, hydroxypropyl methylcellulose, macrogol, silicone resin Etc., a stabilizer such as para-ethyl benzoate, benzyl alcohol, etc., and a flavoring agent such as a sweetener, an acidifier, a flavor, etc., may be combined with the compound of the present invention as necessary. Can be.
  • Parenteral preparations such as injections and eye drops include isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol and mannitol, phosphoric acid, phosphates, citric acid, glacial acetic acid, ⁇ -Buffering agents such as aminocaproic acid and trometamol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, ⁇ regulators such as sodium bicarbonate, polysorbate 80, polyoxyethylene curing Castor oil 60, Macrogol 4000, Refined soybean lecithin, Polyoxyethylene (160) Polyoxypropylene (30) Solubilizing or dispersing agent such as glycol, Cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose , Polyvinyl alcohol, polypinyl pyrrolidone, etc.
  • isotonic agents such as gly
  • Preservatives such as thickeners, stabilizers such as edetic acid and sodium edetate, general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, methyl parabenzoate, propyl paraoxybenzoate, and chlorobutanol.
  • a soothing agent such as a preservative, chlorobutanol, benzyl alcohol, lidocaine and the like can be prepared in combination with the compound of the present invention, if necessary.
  • ⁇ ⁇ ⁇ is preferably set to 4.0-8.0, and the osmotic pressure ratio is preferably set to around 1.0.
  • the dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form, and the like.
  • it can be administered in an amount of usually 0.01 to 1000 mg, preferably 1 to 10 mg per day, in one or several divided doses.
  • the concentration is usually 0.001% to 10% (w / v), preferably 0.01% to 5% (w / v), divided into one or several portions. Can be administered.
  • R f values in the physical properties of the examples represent values measured using thin-layer chromatography (manufactured by Merck, TLC plate silica gel 60 F 2 54 (trade name)). Unless otherwise specified, the chemical structure In the formula, Me is a methyl group, Ac is an acetyl group, Boc ⁇ iier is a butoxycarbonyl group, TBDMS is ter ⁇ : a butyldimethylsilyl group, and SEM is 2- (trimethylsilyl) ethoxymethyl. And TF represents trifluoroacetic acid. .
  • reaction solution was gently poured into 900 g of a saturated aqueous solution of ammonium chloride, 500 ml of water was added, and the mixture was extracted with 2000 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 110 g of the title compound as a brown oil. (96% yield)
  • Reference Compound 112 was produced according to the production method of Reference Compound 111.
  • Reference Compounds 2-2 to 3 were produced according to the method for producing Reference Compound 3-1.
  • Reference Compound 4-2 was produced according to the production method of Reference Compound 411.
  • reaction suspension was filtered, and 15 ml of ethyl acetate and 15 ml of 10% aqueous sodium carbonate were added to the obtained residue 'for extraction.
  • organic layer was washed successively with a 10% aqueous sodium hydrogen sulfite solution, water, and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Rf value 0.58 (ethyl acetate).
  • Reference Compounds 7-2 to 4 were produced according to the method for producing Reference Compound 7-1.
  • reaction solution was added to 100 ml of water, and extracted with 100 ml of ethyl acetate.
  • the organic layer was washed sequentially with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the resulting residue is purified by silica gel column chromatography (solvent). 9
  • reaction solution was added to 100 ml of water, and extracted with 100 ml of ethyl acetate.
  • the organic layer was washed successively with water and then a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate), and the fraction containing the desired compound was concentrated under reduced pressure to obtain the title compound (0.65 g) as a white powder. (80% yield)
  • a tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethyl cellulose, macrogol, or silicone resin) to obtain a target coated tablet (see below).
  • a coating agent for example, a normal coating agent such as hydroxypropylmethyl cellulose, macrogol, or silicone resin
  • Prescription tablets are the same).
  • a desired tablet can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.
  • Rho kinase inhibitory activity of the compound of the present invention was evaluated and examined according to the method described in the attached instruction manual.
  • the test compounds were compound 3-1, compound 3-4, compound 3-5, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 16, compound 17 and compound 1. 9 was used.
  • Buffer solution at 1 Omm ATP solution and commercially available [ ⁇ - 32 P] ATP solution was diluted with a mixture of [NEN Inc. Code No. NEG-002A], 3 0 0 i M ATP [ ⁇ - 32 ⁇ ] AT P A solution was prepared. '
  • S6 Kinase Substrate Peptide [Upstate Biotechnology, Catalog No. 12-124, (2 mg) upstate biotechnology, Catalog No. 12-124, (2 mg)] in distilled water After dissolution, a 1 mM substrate solution was prepared. .
  • DMSO dimethyl sulfoxide
  • the filter paper was transferred to a 7 5 mM beaker one containing the phosphoric acid solution, wash the ⁇ one 32 P] ATP unreacted with shaking child 5 minutes. This washing operation is performed four times.
  • IC 50 values were calculated by XL-fit (I DBS). (Calculation of Ki value)
  • test compound 1 compound 3-5 (hereinafter referred to as test compound 1) and compound 3-8 (hereinafter referred to as test compound 2) were used.
  • test compound solution After dissolving test compound 1 or 2 in physiological saline containing 5% Tween 80 (trade name), the pH is adjusted by adding sodium hydroxide (pH 4.0 to 5.0), and the test compound at a concentration of 1% is added. One or two solutions were prepared.
  • test compound solution was instilled into one eye of the experimental animal (the contralateral eye was untreated).
  • test compound solution As a control, instead of the test compound solution, only the base (physiological saline containing 5% Tween 80) was administered, and the other tests were performed in the same manner as in the above 1 to 4).
  • FIG. 1 shows the results when test compound 1 was used as the test compound
  • FIG. 2 shows the results when test compound 2 was used.
  • the intraocular pressure indicates a change value from the initial intraocular pressure.
  • the compounds of the present invention all exhibited excellent intraocular pressure lowering effects. From the above, it was found that the compound of the present invention is particularly useful as a therapeutic agent for glaucoma. Industrial applicability
  • the present invention provides a novel olefin derivative or a salt thereof which has Rho kinase inhibitory activity and is useful as an agent for treating diseases to which Rho kinase is implicated, for example, eye diseases such as glaucoma.

Abstract

Aux fins de préparer un nouveau dérivé d'oléfines qui convient comme médicament et de découvrir une nouvelle activité pharmacologique de ce dérivé. Ce composé est représenté par la formule générale (II) et possède une excellente activité inhibitrice de rho-kinase. Dans cette formule, X est un cycle benzène, un cycle cycloalkane ou un hétérocycle aromatique monocyclique, Y est un cycle pyridine ou un cycle 1h-pyrrolo(2,3-b)pyridine, R1 et R4 sont chacun halogéno, hydrogène, OH, alcoxy, aryloxy, alkyle, aryle, amino. Alkylamino ou arylamino et, R5 et R6sont chacun halogéno, hydrogène, OH, alcoxy, alkényloxy, alkynyloxy, cycloalkyloxy, cycloalkényloxy, aryloxy, alkyle, alkényle, alkynyle, cycloalkyle, cycloalkényle, aryle, carboxy, formyle, alkylcarbonyle, etc.. ces groupes peuvent être substitués. (I)
PCT/JP2004/015648 2003-10-15 2004-10-15 Nouveau derive d'olefine WO2005035501A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003354946A JP2007015928A (ja) 2003-10-15 2003-10-15 新規オレフィン誘導体
JP2003-354946 2003-10-15

Publications (1)

Publication Number Publication Date
WO2005035501A1 true WO2005035501A1 (fr) 2005-04-21

Family

ID=34431198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/015648 WO2005035501A1 (fr) 2003-10-15 2004-10-15 Nouveau derive d'olefine

Country Status (2)

Country Link
JP (1) JP2007015928A (fr)
WO (1) WO2005035501A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009028631A1 (fr) 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent pour favoriser l'adhérence cellulaire endothéliale cornéenne
US7618984B2 (en) 2005-08-30 2009-11-17 Asahi Kasei Pharma Corporation Sulfonamide compound
US7964613B2 (en) 2007-02-28 2011-06-21 Asahi Kasei Pharma Corporation Sulfonamide compound
US8193193B2 (en) 2005-07-12 2012-06-05 Kowa Co., Ltd. Agent for prevention or treatment of glaucoma
US8211919B2 (en) 2005-09-02 2012-07-03 Astellas Pharma Inc. Amide derivatives as rock inhibitors
US8232292B2 (en) 2007-07-02 2012-07-31 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
US8415372B2 (en) 2007-02-27 2013-04-09 Asahi Kasei Pharma Corporation Sulfonamide compound
WO2013086236A2 (fr) 2011-12-06 2013-06-13 Advanced Cell Technology, Inc. Procédé de différenciation dirigée produisant des cellules endothéliales cornéennes, leurs compositions et leurs utilisations
WO2013100208A1 (fr) 2011-12-28 2013-07-04 京都府公立大学法人 Normalisation d'une culture de cellules endothéliales de la cornée
US8629161B2 (en) 2005-06-21 2014-01-14 Kowa Co., Ltd. Preventive or remedy for glaucoma
WO2015016371A1 (fr) 2013-07-30 2015-02-05 京都府公立大学法人 Marqueur de cellules endothéliales cornéennes
WO2015064768A1 (fr) 2013-10-31 2015-05-07 京都府公立大学法人 Médicament thérapeutique pour des maladies associées à la mort cellulaire du réticulum endoplasmique dans l'endothélium de la cornée
WO2015080297A1 (fr) 2013-11-27 2015-06-04 Kyoto Prefectural Public University Corporation Application de laminine à une culture de cellules endothéliales de la cornée
WO2017064119A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
WO2017141926A1 (fr) 2016-02-15 2017-08-24 Kyoto Prefectural Public University Corporation Cellule endothéliale cornéenne fonctionnelle humaine et application associée
WO2020045642A1 (fr) 2018-08-31 2020-03-05 学校法人同志社 Composition et procédé pour la conservation ou la culture de cellules oculaires
WO2020071438A1 (fr) 2018-10-02 2020-04-09 学校法人同志社 Procédé et récipient pour la conservation de cellules endothéliales cornéennes
WO2021172554A1 (fr) 2020-02-27 2021-09-02 京都府公立大学法人 Cellule endothéliale cornéenne fonctionnelle humaine, et application associée
WO2022235586A1 (fr) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Procédés de génération de cellules endothéliales cornéennes matures
EP4088719A1 (fr) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 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
EP3639854A4 (fr) 2017-06-16 2021-03-03 The Doshisha 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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003073357A (ja) * 2001-09-03 2003-03-12 Mitsubishi Pharma Corp アミド化合物を含有するＲｈｏキナーゼ阻害剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003073357A (ja) * 2001-09-03 2003-03-12 Mitsubishi Pharma Corp アミド化合物を含有するＲｈｏキナーゼ阻害剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WEHRENS, S. ET AL.: "Synthesis of a new photocrosslinkable prepolymer, based on poly(styrene-co-maleic anhydride)", REACTIVE & FUNCTIONAL POLYMERS, vol. 29, no. 1, March 1996 (1996-03-01), pages 21 - 27, XP004052544 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8629161B2 (en) 2005-06-21 2014-01-14 Kowa Co., Ltd. Preventive or remedy for glaucoma
US8193193B2 (en) 2005-07-12 2012-06-05 Kowa Co., Ltd. Agent for prevention or treatment of glaucoma
US7618984B2 (en) 2005-08-30 2009-11-17 Asahi Kasei Pharma Corporation Sulfonamide compound
US8211919B2 (en) 2005-09-02 2012-07-03 Astellas Pharma Inc. Amide derivatives as rock inhibitors
US8415372B2 (en) 2007-02-27 2013-04-09 Asahi Kasei Pharma Corporation Sulfonamide compound
US7964613B2 (en) 2007-02-28 2011-06-21 Asahi Kasei Pharma Corporation Sulfonamide compound
US8232292B2 (en) 2007-07-02 2012-07-31 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
US8664243B2 (en) 2007-07-02 2014-03-04 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
US11839618B2 (en) 2007-08-29 2023-12-12 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
US11633404B2 (en) 2007-08-29 2023-04-25 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
WO2009028631A1 (fr) 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent pour favoriser l'adhérence cellulaire endothéliale cornéenne
WO2013086236A2 (fr) 2011-12-06 2013-06-13 Advanced Cell Technology, Inc. Procédé de différenciation dirigée produisant des cellules endothéliales cornéennes, leurs compositions et leurs utilisations
EP3517604A1 (fr) 2011-12-06 2019-07-31 Astellas Institute for Regenerative Medicine Procédé de différenciation dirigée produisant des cellules endothéliales cornéennes
WO2013100208A1 (fr) 2011-12-28 2013-07-04 京都府公立大学法人 Normalisation d'une culture de cellules endothéliales de la cornée
EP3553169A1 (fr) 2011-12-28 2019-10-16 Kyoto Prefectural Public University Corporation Normalisation de culture de cellules endothéliales cornéennes
WO2015016371A1 (fr) 2013-07-30 2015-02-05 京都府公立大学法人 Marqueur de cellules endothéliales cornéennes
US10908161B2 (en) 2013-07-30 2021-02-02 Kyoto Prefectural Public University Corporation Corneal endothelial cell marker
EP3804760A1 (fr) 2013-10-31 2021-04-14 Kyoto Prefectural Public University Corporation Médicament thérapeutique pour des maladies liées à la mort cellulaire du réticulum endoplasmique dans l'endothélium cornéen
WO2015064768A1 (fr) 2013-10-31 2015-05-07 京都府公立大学法人 Médicament thérapeutique pour des maladies associées à la mort cellulaire du réticulum endoplasmique dans l'endothélium de la cornée
WO2015080297A1 (fr) 2013-11-27 2015-06-04 Kyoto Prefectural Public University Corporation Application de laminine à une culture de cellules endothéliales de la cornée
WO2017064119A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
EP4088719A1 (fr) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne
WO2017141926A1 (fr) 2016-02-15 2017-08-24 Kyoto Prefectural Public University Corporation Cellule endothéliale cornéenne fonctionnelle humaine et application associée
EP4218773A1 (fr) 2016-02-15 2023-08-02 Kyoto Prefectural Public University Corporation Cellule endothéliale cornéenne fonctionnelle humaine et son application
WO2020045642A1 (fr) 2018-08-31 2020-03-05 学校法人同志社 Composition et procédé pour la conservation ou la culture de cellules oculaires
WO2020071438A1 (fr) 2018-10-02 2020-04-09 学校法人同志社 Procédé et récipient pour la conservation de cellules endothéliales cornéennes
WO2021172554A1 (fr) 2020-02-27 2021-09-02 京都府公立大学法人 Cellule endothéliale cornéenne fonctionnelle humaine, et application associée
WO2022235586A1 (fr) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Procédés de génération de cellules endothéliales cornéennes matures

Also Published As

Publication number Publication date
JP2007015928A (ja) 2007-01-25

Similar Documents

Publication Publication Date Title
WO2005035501A1 (fr) Nouveau derive d'olefine
EP2565191B1 (fr) Dérivés d'acide 4-(indol-7-ylcarbonylaminométhyl)cyclohexanecarboxylique comme antagonistes du récepteur EP4 utilisables pour le traitement de l'insuffisance rénale chronique ou de la néphropathie diabétique
JP6466171B2 (ja) 新規アミン誘導体またはその塩
JP4110324B2 (ja) 新規インダゾール誘導体
EP1856045B1 (fr) Derives d'indol-1-yl acide acetique ayant une activite antagoniste de pgd2
US20070232681A1 (en) Compounds Having Crth2 Antagonist Activity
WO2005035503A1 (fr) Nouveau derive isoquinoline
JPWO2007142323A1 (ja) 側鎖にスピロ環構造を有する新規インダゾール誘導体
EP3831383A1 (fr) Inhibiteurs de bromodomaine
AU2014267974B2 (en) Cycloalkyl acid derivative, preparation method thereof, and pharmaceutical application thereof
JP2000502724A (ja) インダゾール誘導体、およびホスホジエステラーゼ（ｐｄｅ）タイプ▲ｉｖ▼と腫瘍壊死因子（ｔｎｆ）産生の阻害剤としてのインダゾール誘導体の使用
JPH07165708A (ja) 二環式ヘテロ環含有スルホンアミドおよびスルホン酸エステル誘導体
SG182187A1 (en) 5-heteroaryl substituted indazoles as kinase inhibitors
JP2009029808A (ja) 炎症の治療のための置換ピラゾリル化合物
KR20140002709A (ko) Ｆａａｈ 저해제
JP2009545540A (ja) ６−１ｈ−イミダゾ−キナゾリンおよびキノリン誘導体、新規有効鎮痛剤および抗炎症剤
JP2009506127A (ja) 糖尿病の処置に有用なアニリノピラゾール誘導体
CA3047002A1 (fr) Nouveaux composes utiles en tant qu'inhibteurs de l'indoleamine 2,3-dioxygenase et/ou du tryptophane dioxygenase
TW201018682A (en) Heterocyclic biaryl derivative, and pde inhibitor comprising same as active ingredient
US8258168B2 (en) 2H or 3H-benzo[E]indazol-1-YL carbamate derivatives, the preparation and therapeutic use thereof
WO2014181788A1 (fr) Dérivé de glycineamide substitué
CN104945411A (zh) 噻吩并[3,2-c]吡啶类化合物、其制备方法及应用
TWI720269B (zh) 用於調節刺蝟途徑之雜芳基胺化合物及其製法及用途
WO2021110574A1 (fr) Inhibiteurs d'alcynyle- (hétéroaryl)-carboxamide hcn1

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP