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WO2004060367A1 - Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs - Google Patents

Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs Download PDF

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Publication number
WO2004060367A1
WO2004060367A1 PCT/JP2003/015921 JP0315921W WO2004060367A1 WO 2004060367 A1 WO2004060367 A1 WO 2004060367A1 JP 0315921 W JP0315921 W JP 0315921W WO 2004060367 A1 WO2004060367 A1 WO 2004060367A1
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Prior art keywords
compound
esi
methoxyphenyl
triazol
phenoxy
Prior art date
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PCT/JP2003/015921
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English (en)
Inventor
Fumie Takahashi
Toshiya Nakagawa
Yuji Matsushima
Katsuya Nakamura
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Fujisawa Pharmaceutical Co., Ltd.
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Publication date
Priority claimed from AU2002953602A external-priority patent/AU2002953602A0/en
Priority claimed from AU2003901804A external-priority patent/AU2003901804A0/en
Priority claimed from AU2003903928A external-priority patent/AU2003903928A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU2003288746A priority Critical patent/AU2003288746A1/en
Publication of WO2004060367A1 publication Critical patent/WO2004060367A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to new azole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same.
  • WO02/055502 shows some pyridine derivatives having cyclooxygenase inhibiting activity, particularly cyclooxygenase-I inhibiting activity. Further, WO03/040110 shows some triazole derivatives having cyclooxygenase inhibiting activity, particulary cyclooxygenase-I inhibiting activity . And WO99/51580 shows some triazole derivatives having an inhibiting activity of cytokine production.
  • This invention relates to azole compounds, which have pharmacological activity such as cyclooxygenase (hereinafter described as COX) inhibiting activity, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.
  • COX cyclooxygenase
  • one object of this invention is to provide the azole compounds, which have a COX inhibiting activity.
  • Another object of this invention is to provide a process for production of the azole compounds.
  • a further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the azole compounds.
  • Still further object of this invention is to provide a use of the azole compounds for manufacturing a medicament for treating or preventing various diseases.
  • the new azole compounds of this invention can be represented by the following general formula (I) :
  • R 1 is lower alkyl optionally substituted with suitable substituent (s) ; cyclo (lower) alkyl; lower alkynyl; cyano; acyl; heterocyclic group; lower alkenyl; lower alkoxy optionally substituted with lower alkoxy, N,N-di (lower) alkylcarbamoyl, cyclo (lower) alkyl, aroyl or halogen; or cyclo (lower) alkyloxy;
  • R 2 is lower alkyl, lower alkoxy, cyano or lH-pyrrol-1-yl
  • R 3 is lower alkylene or lower alkenylene
  • R 4 is hydroxy, protected hydroxy, amino, protected amino, acylamino, acyl, cyano or heterocyclic group
  • X is 0, S, SO or S0 2 ;
  • Y is CH or N
  • Z is CH or N; is 0, S, SO or S0 2 ; m is 0 or 1; n is 0 or 1; and
  • the object compound (I) of the present invention can be prepared by the following processes.
  • L 1 is a leaving group
  • L 2 is a leaving group
  • L 3 is a leaving group
  • W 1 is 0 or S
  • L 4 is a leaving group
  • L 5 is a leaving group
  • Xa is 0 or S
  • Q is hydroxy or a leaving group.
  • the compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. This invention includes both mixtures and separate individual isomers.
  • the compounds of the formula ( I ) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • the compounds of the formula (I) and its salts can be in a form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate.
  • radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • lower alkenyl lower alkynyl
  • lower alkenylene lower moiety
  • Suitable "lower alkyl”, and lower alkyl moiety in the terms “lower alkylsulofonyl” and halo (lower) alkyl may be a straight or branched C ⁇ -C 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which preferable one is methyl, propyl or isopropyl.
  • Suitable "lower alkoxy” and lower alkoxy moiety in the term “lower alkoxyimino” may be a straight or branched C ⁇ -C 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, or the like, in which preferable one is methoxy, ethoxy or isopropoxy.
  • Suitable “halogen” may be fluoro, chloro, bromo or iodo or the like.
  • Suitable "cyclo (lower) alkyl” , and cyclo (lower) alkyl moiety in the terms “cyclo (lower) alkylcarbonyl” and “cyclo (lower) alkyloxy” may include 3 to 8-membered cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, preferably one having 3 to 6 carbon atoms, and more preferable one is cyclopropyl, cyclopentyl or cyclohexyl.
  • Suitable alkynyl may be a monovalent branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond, for example ethynyl, 2-propynyl, 2-butynyl, and the like.
  • Suitable "lower alkylene” may be a straight or branched Ci-C ⁇ alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethlyene, ethylethylene, or the like, in which preferable one is methylene, ethylene or trimethylene.
  • Suitable "lower alkenyl” may be a straight or branched C 2 -C 6 alkeny such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, butadienyl, pentadienyl, hexadienyl or the like, in which preferable one is isopropenyl.
  • Suitable "lower alkenylene” may be a straight or branched chain aliphatic hydrocarbon divalent group having more than one double bond between two carbon atoms, such as ethenylene, propenylene, methylethenylene, butenylene, methylpropenylene, dimethylpropenylene, pentenylene, hexenylene or the like, and it is preferably (C 2 -C 4 ) alkenylene.
  • Suitable “heterocyclic group” maybe one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclicheterocyclic group, andpreferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.
  • pyrrolidinyl imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.
  • oxazolinyl e.g. 2-oxazolinyl, etc.]
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.]
  • thiazolyl 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl
  • heterocyclic group may be substituted with lower alkyl as exemplified above or oxo, in which preferable one is pieridyl or oxoimidazolidinyl .
  • acyl and acyl moiety in the term “acylamino” may be carboxy; esterified carboxy; carbamoyl; carbamoyl substitutedwith lower alkyl, aryl, ar (lower) alkyl, arylsulfonyl, lower alkylsulfonyl, a heterocyclic group; or halo (lower) alkyl . substituted or unsubstituted arylsulfonyl; substituted or unsubstituted lower alkylsulfonyl; cyclo (lower) alkylcarbonyl; lower alkanoyl; substituted or unsubstituted aroyl; a heterocycliccarbonyl and the like.
  • the esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl,
  • lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl
  • aryloxycarbonyl e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.
  • substituted or unsubstituted ar (lower) alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.
  • preferable one is unsubstituted lower alkoxycarbonyl and more preferable one is ethoxycarbonyl .
  • the carbamoyl substitutedwith lower alkyl may be a carbamoyl group substituted with the same or different above lower alkyl groups onnitrogen atom, suchasmethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, N-methyl-N-ethylcarbamoyl or the like. It is preferably di (C 1 -C 4 ) carbamoyl, more preferably di (C ⁇ -C 2 alkyl) carbamoyl .
  • the carbamoyl substituted with aryl may be phenylcarbamoyl, naphthylcarba oyl, lower alkyl-substituted phenylcarbamoyl
  • the carbamoyl substituted with ar (lower) alkyl may be benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl and the like, in which preferable one is benzylcarbamoyl.
  • the carbamoyl substituted with arylsulfonyl may be phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.
  • the carbamoyl substituted with lower alkylsulfonyl may be methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.
  • the carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above.
  • the carbamoyl substituted with halo (lower) alkyl may be chloromethylcarbamoyl, brommethylcarbamoy, chloroethylcarbamoyl, bromomethylcarbamoyl , chloropropylcarbamoyl, bromopropylcarbamoyl and the like, in which preferable one is chloropyopylcarmamoyl .
  • the lower alkanoyl may be for yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl andthe like, in which preferable one is acetyl, propionyl or isobutyryl.
  • the substituted or unsubstituted aroyl may be benzoyl, naphthoyl, toluoyl, di (tert-butyl) benzoyl, halo (lower) alkoxybenzoyl [e.g.
  • the substituted or unsubstituted arylsulfonyl may be phenylsulfonyl, tolylsulfonyl, halophenylsulfonyl [e.g. fluorophenylsulfonyl, etc.] and the like, in which preferable one is fluorophenylsulfonyl .
  • the substituted or unsubstituted lower alkylsulfonyl may be methylsulfonyl, ethylsulfonyl, halo (lower) alkylsulfonyl
  • the cyclo (lower) alkylcarbonyl may be 3 to 8-membered cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, in which preferable one is cyclopropylcarbonyl or cyclohexylcarbonyl .
  • heterocyclic moiety in the term "a heterocycliccarbonyl" may be one mentioned above as a heterocyclic group, in which preferable one is piperidyl .
  • hydroxy protective group in the term of “protective hydroxy” may include acyl [e.g. lower alkanoyl, lower alkylsulfonyl, halo (lower) alkylsulfonyl (e.g. trifluoromethysulfonyl, etc.), etc.] as mentioned above, phenyl (lower) alkyl which may be one or more suitable substituen (s) (e.g. benzyl, 4-methoxybenzyl, trityl, etc.), tri-substituted silyl [e.g. tri (lower) alkylsilyl (e.g.
  • Suitable "a leaving group” may be halogen (e.g. fluoro, chloro, bro o, iodo) , arenesulfonyloxy (e.g. benzenesulofonyloxy, tosyloxy, etc.), alkanesulofnyloxy (e.g. esyloxy, ethanesulfonyloxy, etc.), and the like, in which preferable one is halogen.
  • halogen e.g. fluoro, chloro, bro o, iodo
  • arenesulfonyloxy e.g. benzenesulofonyloxy, tosyloxy, etc.
  • alkanesulofnyloxy e.g. esyloxy, ethanesulfonyloxy, etc.
  • preferable one is halogen.
  • protected amino may be common N-protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl [e.g.
  • benzenesulfonyl, tosyl, etc.] nitrophenylsulfenyl, aralkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phthaloyl or lower alkoxycarbonyl.
  • Preferred "suitable substituent" as the substituent of lower alkyl for R 1 may be halo (lower) alkoxy, lower alkenyl, lower alkynyl, lower alkylamino, acylamino, acyl, lower alkylsily, lower alkoxy, aryl, acyloxy, hydroxy, nitro, amino, cyano, halogen, aryloxy, lower alkylthio, lower alkoxyimino and the like.
  • Preferred “lower alkyl substituted with suitable substituten (s) " for R 1 may be lower alkyl substituted with one or more halogen atom(s) or lower alkoxyimino.
  • More preferred "lower alkyl substituted with one or more halogen atom(s) " may be lower alkyl substituted with 1 to 5 (more preferably 1 to 3) above halogen atom(s) , such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl , tribromomethyl, fluoroethyl, chloroethyl, 2, 2, 2-trifluoroethyl, 2,2, 2-trichloroethyl, 2,2,3,3, 3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, or the like, in which preferable one is halogen-substituted C ⁇ -C 2 alkyl. More preferable one is fluorine-substituted methyl, and most preferable one is difluoromethyl or trifluoromethyl .
  • lower alkyl substituted with lower alkoxyimino may be methoxyimmoethyl (e.g.1-methoxyiminoethyl, 2-methoxyimmoethyl) , methoxyiminomethylpropyl (e.g. l-methoxyimino-2-methylpropyl, etc.) and the like, in which preferable one is 1-methoxyiminoethyl or l-methoxy-2-methylpropyl .
  • Preferred "acyl" for R 1 may be lower alkanoyl, carbamoyl substituted with lower alkyl, cylo (lower) alkylcarbonyl, aroyl, or heterocycliccarbonyl mentioned above.
  • Preferred "lower alkoxy substituted with lower alkoxy" for R 1 may be methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like, in which preferable one is ethoxyethoxy.
  • Preferred "lower alkoxy substituted with halogen" for R 1 may be lower alkoxy substituted with one or more (more preferably 1 to 5, most preferably 1 to 3) above halogen atom(s), such as fluoromethoxy, chloromethoxy, difluomomethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, " chloroethoxy, 2, 2-difluoroethoxy, 2, 2-dichloroethoxy, 2,2, 2-trifluoroethoxy, 2,2, 2-trichloroethoxy, 2,2,3, 3-pentafluoroethoxy, fluoropropoxy, fluorobutoxy, fluorohexyloxy, or the like, and it is preferably (C 1 -C 4 ) alkoxy substituted with halogen, more preferably (C 1 -C 2 ) alkoxy substituted with halogen, more preferably (C 1 -C 2
  • Preferred "acyl" for R 4 may be carboxy, esterified carboxy, carbamoyl or lower alkylsulfonyl mentioned above.
  • Preferred compound (I) is one having lower alkyl optionally substituted with one or more halogen atom(s) ; cyclo (lower) alkyl; lower alkanoyl; carbamoyl substituted with lower alkyl; cyclo (lower) alkylcarbonyl; aroyl; or heterocycliccarbonyl for Rl; lower alkoxy for R2; lower alkylene or lower alkenylene (more preferably lower alkylene) for R3; hydroxy, protected hydroxy, amino, protected amino, acylamino, acyl or cyano (more preferably hydroxy, amino, carbamoylamino, lower alkylsulfonylamino, lower alkanoylamino, sulfamoylamino or lower alkylslufonyl) for R4; 0 for X; CH or N for Y; CH for Z; 0 for ; 0 or 1 for ; 0 or 1 for n; and
  • Suitable salts of the compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt
  • acetate maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc .
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • the object compound (la) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt in the presence of base to form imidazole ring.
  • Suitable salts of the compounds (II) or (III) may be the same as those exemplified for the compound (I) .
  • the base employable in this process for making basic condition is not particularly limited so long as it accelerate this reaction and may include alkali metal bicarbonate (e.g. lithiumbicarbonate, sodiumbicarbonate, potassiumbicarbonate, etc.), alkali metal carbonate (e.g. lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkalimetal hydroxide (e.g. lithiumhydroxide, sodiumhydroxide, potassium hydroxide, etc.), etc., in which preferable one is alkali metal bicarbonate, especially sodium bicarbonate.
  • alkali metal bicarbonate e.g. lithiumbicarbonate, sodiumbicarbonate, potassiumbicarbonate, etc.
  • alkali metal carbonate e.g. lithium carbonate, sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
  • alkalimetal hydroxide
  • the reaction is carried out in a conventional solvent such as an alcohol (e.g. methanol, ethanol, propanol, isopropanol, etc.), diisopropyl ether, tetrahydrfuran, dioxane, etc, or a mixture of thereof.
  • a conventional solvent such as an alcohol (e.g. methanol, ethanol, propanol, isopropanol, etc.), diisopropyl ether, tetrahydrfuran, dioxane, etc, or a mixture of thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the heterocyclic ring is formed but not to form imidazole ring.
  • the dehydration process is need to form imidazole ring.
  • the dehydration process is carried out in the hot and acidic condition.
  • the solvent employable in this process is not particularly limited, but acid such as acetic acid, sulfuric acid or the like may be used as solvent.
  • the object compound (lb) or its salt can be prepared by reacting a compound (II) or its salt with a compound (IV) or its salt.
  • Suitable salts of the compounds (II), (IV) or (V) may be the same as those exemplified for the compound (I) .
  • Process (2) -1 is carried out under in the presence of Hunig' s base (N, N-diisopropylethylamine) .
  • the reaction is carried out in a conventional solvent such as diisopropyl ether, tetrahydrfuran, dioxane.
  • a conventional solvent such as diisopropyl ether, tetrahydrfuran, dioxane.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Process (2) -2 i-s the oxidation process to form imidazole ring in the presence of catalyst.
  • the oxidative catalyst employable in this process is not particularly limited so long as it can catalyze the reaction from 4, 5-dihydro-imidazole derivative to imidazole derivative and include manganese (IV) oxide (Mn0 2 ) .
  • the solvent in this process is not particularly limited so long as it is inactive in this reaction and may include amides such as N,N-dimethylformamide, dimethylacetamide, hexamethylphosophoric triamide; aromatic hydrocarbon such as benzene, toluene; or the like.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the object compound (Ic) or its salt can be prepared by reacting a compound (VI) or its salt with a compound (VII) or its salt.
  • the reaction is usually carried out in a conventional solvent such tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • This reaction is preferably carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkalimetal hydrogencarbonate, alkalimetal carbonate, alkali metal acetate, tri (lower) alkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N-,N-di (lower) alkylbenzylamine, N-,N-di (lower) alkylaniline or the like.
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkalimetal hydrogencarbonate, alkalimetal carbonate, alkali metal acetate, tri (lower) alkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N-,N-d
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (IX) or its salt can be prepared by converting a compound (VIII) or its salt under basic condition.
  • the reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • alcohols e.g., methanol, ethanol, isopropyl alcohol, etc.
  • tetrahydrofuran e.g., methanol, ethanol, isopropyl alcohol, etc.
  • tetrahydrofuran
  • This reaction is preferably carried out in the presence of an inorganic or an organicbase such as an alkali metal hydroxide, an alkalimetal hydrogencarbonate, alkalimetal carbonate, alkali metal acetate, tri (lower) alkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N-,N-di (lower) alkylbenzylamine, N-,N-di (lower) alkylaniline or the like.
  • an inorganic or an organicbase such as an alkali metal hydroxide, an alkalimetal hydrogencarbonate, alkalimetal carbonate, alkali metal acetate, tri (lower) alkylamine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N-,N-d
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process 3, or any other organic solvent which does not adversely influence the reaction.
  • hydrophilic solvents may be used in a mixture with water.
  • the suitable base may include a tertiary amine [e.g. triethylamine, pyridine, N, N-dimethylaniline, etc.], an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc. ] , an alkalimetal carbonate [e.g. sodiumcarbonate, potassium carbonate, etc.], alkali metal bicarbonate (e.g. sodium bicarbonate, etc.),asaltof anorganic acid [e.g. sodium acetate, etc.] and the like.
  • the base is liquid, the base can be used as a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (XII) or its salt can be prepared by reacting a compound (X) or its salt with a compound (XI) or its salt under basic condition.
  • the reaction is usually carried out in a suitable solvent such as acetates, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not affect the reaction.
  • This reaction is preferably carried out in the presence of an inorganic or an organic base such as an alkali metal hydrogencarbonate, alkalimetal carbonate, alkalimetal acetate, trialkylamine, pyridine (e.g.
  • Incase base, acid and/or starting compound are liquid, they can play a role of solvent.
  • the reaction temperature is not critical to the reaction in the yield or purity and the reaction is allowed to be carried out independent of temperature.
  • the compound (XII) or its salt is reacted with a compound (XIII) or its salt under acidic condition to give a compound (Ie) or its salt.
  • a salt of the compound (XIII) is used in this reaction, a suitable base may be added to neutralize the system.
  • the reaction is usually carried out in a suitable solvent such as water, acetic acid, methanol, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not affect the reaction.
  • a suitable solvent such as water, acetic acid, methanol, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, N, N-dimethylformamide or any other organic solvent which does not affect the reaction.
  • a mixed solvent is allowed to be used.
  • the suitable acid may include an organic carboxylic acid [e.g. formic acid, acetic acid, propionic acid, etc.), anorganic sulfonic acid [e. g. methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.], a mineral acid [e.g. hydrochloric acid, sulfuric acid, etc.].
  • an organic carboxylic acid e.g. formic acid, acetic acid, propionic acid, etc.
  • anorganic sulfonic acid e. g. methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • a mineral acid e.g. hydrochloric acid, sulfuric acid, etc.
  • the acid is liquid, it can play a role of solvent.
  • reaction temperature is not critical to the reaction in the yield or purity and the reaction is allowed to be carried out independent of temperature.
  • the object compound (If) or its salt can be prepared by reacting a compound (XIV) or its salt with a compound (XV) or its salt.
  • Suitable salts of the compounds (If) , (XIV) and (XV) may be the same as those exemplified for the compound (I) .
  • the reaction is preferably carried out in the presence of a base such as alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc. ), the hydride or hydroxide or carbonate or bicarbonate thereof.
  • a base such as alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc. ), the hydride or hydroxide or carbonate or bicarbonate thereof.
  • the reaction is preferably carried out in the presence of diethyl azodicarboxylate and triphenylphosphine.
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dioxane, a alcohol (e . g. methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, acetic acid, N, N-dimethylformamide, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, dioxane, a alcohol (e . g. methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, acetic acid, N, N-dimethylformamide, or a mixture thereof.
  • the reaction temperature is not critical and the reaction can be carried out under cooling to heating.
  • Arthritis was inducedby inj ection of 0.5 mg of Mycobacterium tuberculosis (Difco Laboratories, Detroit, Mich.) in 50 il l of liquid paraffin into the right hind footpad of Lewis rats aged 7 weeks .
  • the mechanical pain threshold of the left hind paw (uninjected hind paw) was determined by compressing the ankle joint with a balance pressure apparatus
  • the threshold pressure of rats squeaking or struggling was expressed in grams .
  • the threshold pressure of rats treated with drugs was compared with that of non-treated rats.
  • a dose showing the ratio of 1.5 is considered to be the effective dose.
  • the blood was centrifuged at 6000 x g for 5min at 4°C to obtain plasma.
  • a 100 ⁇ l aliquot of plasma was mixed with 400 l methanol for protein precipitation.
  • the supernatant was obtained by centrifuging at 6000 x g for 5min at 4°C and was assayed for PGE2 using a radioimmunoassay kit after conversion of PGE2 to its methyl oximate derivative according to the manufacturer' s procedure.
  • the results were expressed as percent inhibition of PGE2 production relative to control incubations containing DMSO vehicle.
  • the data were analyzed by that a test compound at the indicated concentrations was changed log value and was applied simple linear regression. IC50 value was calculated by least squares method.
  • COX particularly a selective inhibiting activity against COX-I .
  • the compounds (I) of the present invention lack undesired side-effects of non-selective NSAIDs, such as gastrointestinal disorders, bleeding, renal toxicity, cardiovascular affection, etc.
  • the object compound (I) or pharmaceutically acceptable salts thereof of this invention possesses COX inhibiting activity and possesses strong anti-inflammatory, antipyretic, analgesic, antithrombotic, anti-cancer activities, and so on.
  • the object compound (I) and pharmaceutically acceptable salt thereof are useful for treating and/or preventing COX mediated diseases, inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals by using administered systemically or topically.
  • the object compound (I) and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and acute or chronic pain in joint and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis, cervical syndrome, etc.]; lumbago; inflammatory skin condition [e.g. sunburn, burns, eczema, dermatitis, etc.]; inflammatory eye condition [e.g. conjunctivitis, etc.]; lung disorder in which inflammation is involved [e.g.
  • asthma wheezing disease
  • bronchitis pigeon fancier's disease, farmer's lung, etc.
  • condition of the gastrointestinal tract associated with inflammation e.g. aphthous ulcer, Chrohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.
  • gingivitis menorrhalgia
  • inflammation pain and tumescence after operation or injury
  • the object compound (I) or a salt thereof is expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.
  • the object compound (I) and a salt thereof can be used for prophylactic and therapeutic treatment of arterial thrombosis, arterial sclerosis, ischemic heart diseases [e. g. angina pectoris
  • ischemic brain diseases e.g. cerebral infarction (e.g. acute cerebral thrombosis, etc.), cerebral thrombosis (e.g. cerebral embolism, etc.), transient cerebral ischemia (e.g. transient ischemic attack, etc.), cerebrovascular spasm after cerebral hemorrhage (e . g. cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.] pulmonary vascular diseases (e.g.
  • peripheral circulatory disorder e.g. arteriosclerosis obliterans, thromboangiitis obliterans (i . e . Buerger' s disease) , Raynaud's disease, complication of diabetes mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.), phiebothrombosis (e.g. deep vein thrombosis, etc.), etc.], complication of tumors (e.g. compression thrombosis), abortion [e.g. placental thrombosis, etc.], restenosis and reocclusion [e.g.
  • thrombolytic drug e.g. tissue plasminogen activator (TPA) , etc.
  • TPA tissue plasminogen activator
  • thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g. surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis, etc.] or transplantation, disseminated intravascular coagulation (DIC) , thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, atrophic thrombosis, creeping thrombosis, dilation thrombosis, jumping thrombosis, mural thrombosis, etc.
  • DIC disseminated intravascular coagulation
  • thrombotic thrombocytopenia e.g. thrombotic thrombocytopenia
  • inflammation e.g. nephritis, etc.
  • immune diseases
  • the object compound (I) and a salt thereof can be used for the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or anticoagulant (e.g. heparin, etc.). And, the compound (I) is also useful for inhibition of thrombosis during extra corporeal circulation such as dialysis.
  • thrombolytic drug e.g. TPA, etc.
  • anticoagulant e.g. heparin, etc.
  • the compound (I) is also useful for inhibition of thrombosis during extra corporeal circulation such as dialysis.
  • the following diseases are exemplified: pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, juvenile arthritis, etc; lumbago; cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain and tumescence after operation or injury; etc.
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting, or emulsifying agents, buffers and other commonly used additives.
  • the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
  • the analgesic agent of the present invention can be used in a form of pharmaceutical preparation suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like.
  • the analgesic agent of this invention is useful for treating or preventing acute or chronic pains associated with acute or chronic inflammations in human beings or animals by using administered systemically or topically.
  • N 1 - (4-Benzyloxyphenyl) -4-methoxybenzamidine obtained by Preparation 1 (2g) 2-chlorocyanoethylene (0.36ml) and N,N-diisopropylethylamine (0.79ml) in tetrahydrofuran (10ml) was stirred at reflux condition overnight.
  • IR (KBr, cm “1 ) : 3149, 3103, 3037, 2964, 2910, 2829, 2690, 2611, 1649, 1614.
  • reaction mixture was filtered off and the filtrate was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo.
  • Preparation 8 4-Ethoxycarbonyl-l- (4-benzyloxyphenyl) -2- (4-methoxyphenyl) - lH-imidazole (P0008)
  • the residue of Preparation 7 was dissolved in N, N-dimethylformamide (10ml), and manganese (IV) oxide (1.63g) was added to the solution.
  • the reaction mixture was cooledto roomtemperature andpoured intowater and ethyl acetate . After filtration, the mixture was extracted with ethyl acetate, driedovermagnesiumsulfate and evaporated invacuo.
  • the residue was purified by silica gel column chromatography eluting with n-hexane/ethyl acetate (1/1) to give 1.5g of desired compound as an oil (93.1%) .
  • reaction mixture was quenched by sat. ammonium chloride aq. , then IN hydrochloric acid was added and extracted with water . After sodiumhydroxide aq. was added, extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo.
  • the target compound was obtained from N 1 - (4-Benzyloxyphenyl) - 2-methoxy-5-pyridylamidine in the similar manner to that of Preparation 2.
  • the target compound was obtained froml- (4-Benzyloxyphenyl) - 4-cyano-4, 5-dihydro-2- (2-methoxy-5-pyridyl) -IH-imidazole obtained by Preparation 19 in the similar manner to that of Preparation 3.
  • the target compound (1.04g) was obtained from
  • the target compound was obtained froml- (4-benzyloxyphenyl) - 4-isopropylcarbonyl-2- (2-methoxy-5-pyridyl) -lH-imidazole obtained by Preparation 21 in the similar manner to that of Preparation 5.
  • the target compound was obtained froml- (4-benzyloxyphenyl) - 4- ethylcarbonyl-2- (2-methoxy-5-pyridyl) -lH-imidazole obtained by Preparation 23 in the similar manner to that of Preparation 5.
  • the reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo.
  • the resulting precipitates were corrected by filtration and washed with diisopropyl ether to give the target compound (0.44g) .
  • the target compound was obtained from 1- (4-benzyloxyphenyl) -4- (N-ethyl-N-methylcarbamoyl) - 2- (4-methoxyphenyl) -lH-imidazole obtained by Preparation 26 in the similar manner to that of Preparation 5.
  • the target compound was obtained from 1- (4-benzyloxyphenyl) -4-carboxy-2- (4-methoxyphenyl) - lH-imidazole obtained by Preparation 25 and N,N-diethylamine in the similar manner to that of Preparation 26.
  • the target compound was obtained from 1- (4-benzyloxyphenyl) -4- (N,N-diethylcarbamoyl) -2- (4-methoxyphenyl) -lH-imidazole obtained by Preparation 28 in the similar manner to that of Preparation 5.
  • the target compound (0.5g) was obtained from 1- (4-benzyloxyphenyl) -4-carboxy-2- (4-methoxyphenyl) - IH-imidazole obtained by Preparation 25 and piperidine in the similar manner to that of Preparation 26.
  • the target compound (0.41g) was obtained from
  • the target compound was obtained from 4-cyano-l- (4- benzyloxyphenyl) -2- (4-methoxyphenyl) -IH-imidazole obtained by Preparation 3 in the similar manner to that of Preparation 5.
  • the target compound was obtained from 1- (4-Benzyloxyphenyl) -4-cyclopentylcarbonyl-2- (2-methoxy- 5-pyridyl) -IH-imidazole obtainedby Preparation 33 in the similar manner to that of Preparation 5.
  • E0031 was obtained in the similar manner to that of E0030.
  • E0032 To a solution of E0031 (200 mg) was added IN aqueous sodium hydroxide (1.06 ml) in methanol (2 ml) . After stirring at room temperature for 1 hour, the reaction mixture was poured into water and ethyl acetate, and extractedwithwater . Then the water layer was acidified with IN aqueous hydrochloride, extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate (1 ml) and 4N hydrogen chloride/ethyl acetate (97 ⁇ l) was added. Resulting precipitates were collected by filtration and washed with diisopropyl ether to give E0032 (52 mg) .
  • E0033 E0030 (0.33 g) and dry 20% Pd(OH) 2 /C (100 mg) in ethanol (6 ml) and cyclohexene (3 ml) was stirred at reflux condition for 4 hours and cooled to room temperature. After filtration, the reaction mixture was evaporated in vacuo to give E0033 (0.19 g) .
  • N, N-dimethylformamide (15 ml) was stirred at lOO'C for 6 hours. After filtration, the reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. To the solution of the residue in N, N-dimethylformamide (10 ml) phosphorus oxychloride (0.27 ml) was added under stirring at 0°C . After stirring at room temperature for 1 hour, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo to give E0035 (1.0 g) .
  • E0041 A solution of E0040 (0.22 g) and sodium thiomethoxide (128 g) in N,N-dimethylformamide (2 ml) was stirred at 60°C for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washedwith water andbrine, dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in tetrehydrofura (2 ml) and OXONE (Trademark, purchased fromALDRICH) (917 mg) in water (2 ml) was added.
  • P0041 was obtained according to a similarmanner to that of P0040.
  • P0044 was obtained according to a similar manner to that of P0043.
  • P0047 was obtained according to a similar manner to that of P0043.
  • IH MR (CDC13, ppm) d 3.84(3H, s) , 4.03(3H, s) , 6.59-6.74 (2H, m) , 6.83-6.98(2H, ) , 7.16-7.35 (4H, m) , 8.79(1H, bs) , MS (ESI, m/e) 298 (M+l)
  • P0049 was obtained according to a similar manner to that of P0063.
  • P0050 was obtained according to a similar manner to that of P0064 MS (ESI, m/e) 414 (M+Na)
  • P0051 was obtained according to a similar manner to that of P0065. IHNMR (CDC13, ppm) d 3.83(3H, s) , 5.05(2H, s) , 6.80-7.05 (4H, m) , 7.18-7.55(10H, m) , MS (ESI, m/e) 374 (M+l)
  • P0053 was obtained according to a similarmanner to that of P0067. IH NMR (CDC13, ppm) d 3.86(3H, s) , 5.07(2H, s) , 6.85-7.05 (4H, m) , 7.20-7.58 (9H, m) , MS (ESI, m/e) 426 (M+l)
  • TBDMSC1 tert-butyldimethylsilyl chloride
  • P0056 was obtained according to a similar manner to that of P0063. IHNMR (DMSO-d6, ppm) d 3.75(3H, s) , 5.99(2H, bs), 6.68 (IH, d,
  • P0059 was obtained according to a similar manner to that of P0040.
  • P0061 was obtained according to a similar manner to that of P0040 (2.1 g, 89% yield) .
  • P0062 was obtained according to a similar manner to that of P0043 (1.5 g, 94.5% yield) .
  • E0065 was obtained according to a similarmanner to that of Example 125. IH NMR (CDC13, ppm) d 2.99(3H, s) , 3.06(3H, s) , 4.03-4.15 (2H, m) , 4.15-4.28 (2H, m) , 4.99 (2H, s) , 6.70-6.82 (2H, m) , 6.82-6.97 (2H, m) , 7.17-7.30 (2H, m) , 7.30-7.42 (2H, m) , 7.68-7.80 (2H, m) , 7.80-7.9K2H, m) , MS (ESI, m/e) 542 (M+l)
  • E0082 To a solution of E0081 (200 mg, 0.512 mmol) in 1 ml of EtOH and 4 ml of IN-HCl, potassium cyanate (208 mg, 2.56 mmol) was added slowly. The mixture was stirred at 50 ° C for lhr. Furthermore, potassium cyanate (124 mg, 1.54 mmol) was added and stirred at same temperature for lhr. After cooling, water and IN-HCl were added and an insoluble material was isolated by filtration. The residue was purified by recrystallized with EtOH (1 ml) to get the white crystal of E0082 (160mg, 72.1%).
  • Example 84 The following compound (s) was (were) obtained in a similar manner to that of Example 83.
  • Example 84
  • Example 92 l- ⁇ 4- [2- (benzyloxy) ethoxy] phenyl ⁇ -2- (4-methoxyphenyl) -4,5- dihydro-lH-imidazole-4-carbonitrile (2.05 g) and manganese (IV) oxide (2.08 g) in DMF (20 ml) was stirred at lOO'O for overnight. After filtration, the reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. To the solution of the residue in DMF (20ml) phosphorus oxychloride (0.45ml) was addedunder stirring at 0°C .
  • Example 93 IN solution of cyclopentylmagnesium chloride in tetrahydrofuran (2.82 ml) was added to a solution of l- ⁇ 4- [2- (benzyloxy) ethoxy] phenyl ⁇ -2- (4-methoxyphenyl) -1H- imidazole-4-carbonitrile (0.3 g) in tetrahydrofuran (3 ml) under stirring at 0°C . After stirring at room temperature for 2 hours, the reaction mixture was poured into aqueous 10% potassium hydrogen sulfate and stirred at room temperature for 30 minutes.
  • the mixture was alkalinized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate, washed with
  • N, N-dimethylformamide (3 ml) was stirred at 75 for overnight.
  • Example 104 -tBuOK (173 mg) was added to a solution of methyltriphenylphosphonium bromide (551 mg) in THF (1ml) . After stirring at room temperature for 10 minutes, 1- [1- [4- (2- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ ethoxy) phenyl] - 2- (4-methoxyphenyl) -lH-imidazol-4-yl] ethanone (0.24 g) in THF (2 ml) was added dropwise. After stirring at room temperature for 1 hour, the reactionmixture was poured into water and extracted with ethyl acetate, dried over MgS04 and evaporated in vacuo.

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Abstract

La présente invention concerne un composé de formule (I) ou des sels de celui-ci, qui sont utiles pour traiter et/ou prévenir des états pathologiques inflammatoires, différentes types de douleur, des maladies liées au collagène, des maladies auto-immunes, la thrombose, le cancer ou des maladies de neurodégénérescence.
PCT/JP2003/015921 2002-12-30 2003-12-12 Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs WO2004060367A1 (fr)

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WO2004099130A3 (fr) * 2003-05-08 2005-01-27 Fujisawa Pharmaceutical Co Inhibiteur de cox
WO2006043594A1 (fr) * 2004-10-19 2006-04-27 Daiichi Pharmaceutical Co., Ltd. Dérivé de 1h-triazole 1,5-dihétérocyclique
WO2007009146A1 (fr) * 2005-07-22 2007-01-25 Universität Wien 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i
WO2008029912A1 (fr) 2006-09-07 2008-03-13 National University Corporation Okayama University Composé ayant un squelette de benzamide et une activité inhibitrice sélective de la cyclo-oxygénase (cox-1)
JP2008526887A (ja) * 2005-01-10 2008-07-24 ユニバーシティ オブ コネチカット カンナビノイド受容体に作用する新規なヘテロピロール類似体
EP1621537A4 (fr) * 2003-04-21 2008-12-31 Daiichi Seiyaku Co Derive heterocyclique a cinq chainons
US7799804B2 (en) 2004-04-03 2010-09-21 Astrazeneca Ab Therapeutic agents
US8536185B2 (en) 2008-09-22 2013-09-17 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
CN104415172A (zh) * 2013-09-09 2015-03-18 廖国建 一种治疗肩周炎的药物
JP2015524850A (ja) * 2012-08-16 2015-08-27 ヤンセン ファーマシューティカ エヌ．ベー． Ｎ型カルシウムチャネル遮断剤としての置換ピラゾール
US9974775B2 (en) 2013-08-16 2018-05-22 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
US10906885B2 (en) 2015-10-07 2021-02-02 Mitobridge, Inc. PPAR agonists, compounds, pharmaceutical compositions, and methods of use thereof
EA039771B1 (ru) * 2016-06-20 2022-03-11 Митобридж, Инк. Агонисты ppar, соединения, фармацевтические композиции и способы их применения
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WO2024009283A1 (fr) * 2022-07-07 2024-01-11 University Of Southern California Antagonistes at2 pour soulager la douleur non addictive
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EA039833B1 (ru) * 2016-06-20 2022-03-17 Митобридж, Инк. Агонисты ppar, соединения, фармацевтические композиции и способы их применения
US11939325B2 (en) 2020-07-27 2024-03-26 Makscientific, Llc Process for making biologically active compounds and intermediates thereof
US12054480B2 (en) 2020-07-31 2024-08-06 Makscientific, Llc Compounds for treating cannabinoid toxicity and acute cannabinoid overdose
WO2024009283A1 (fr) * 2022-07-07 2024-01-11 University Of Southern California Antagonistes at2 pour soulager la douleur non addictive

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