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WO1999033827A1 - Nouveaux derives d'imidazole - Google Patents

Nouveaux derives d'imidazole Download PDF

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Publication number
WO1999033827A1
WO1999033827A1 PCT/JP1998/005930 JP9805930W WO9933827A1 WO 1999033827 A1 WO1999033827 A1 WO 1999033827A1 JP 9805930 W JP9805930 W JP 9805930W WO 9933827 A1 WO9933827 A1 WO 9933827A1
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WIPO (PCT)
Prior art keywords
group
thiazolyl
carboxamide
imidazo
imidazole
Prior art date
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Ceased
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PCT/JP1998/005930
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English (en)
Japanese (ja)
Inventor
Hiroyuki Sueoka
Jouji Yasuoka
Akira Nishiyama
Masatoshi Kiuchi
Katsuya Yamamoto
Kunio Sugahara
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Tanabe Pharma Corp
Original Assignee
Yoshitomi Pharmaceutical Industries Ltd
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Priority to AU16901/99A priority Critical patent/AU1690199A/en
Publication of WO1999033827A1 publication Critical patent/WO1999033827A1/fr
Priority to US09/598,216 priority patent/US6288061B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention has an inhibitory effect on the production of interleukin 4 (hereinafter, IL-4) and interleukin 5 (hereinafter, IL-15) from type 2 helper T cells (hereinafter, abbreviated as Th2 cells).
  • IL-4 interleukin 4
  • IL-15 interleukin 5
  • Th2 cells type 2 helper T cells
  • Th1 cells produce cytokines such as interleukin 2 (hereinafter, IL-2) and interferon-7 (hereinafter, IFN-7), and mainly regulate cellular immunity.
  • Th2 cells produce cytokines such as IL-4, IL-5, and interleukin 10 (hereinafter, IL-10), and mainly regulate humoral immunity.
  • Immune response is regulated by the balance between Th1 and Th2 cells, and IFN-7 produced by Th1 cells promotes differentiation into Th1 cells and inhibits differentiation into Th2 cells .
  • IL-4 produced by Th 2 cells promotes differentiation into Th 2 cells and inhibits differentiation into Th 1 cells.
  • ThlZTh2 cells are predominant in allergic diseases and systemic autoimmune diseases
  • Th 1 cells are predominant in organ-specific autoimmune diseases.
  • IL-14 has the effect of class switching to immunoglobulin E (IgE) and inducing differentiation into Th2 cells, and IL-5 activates eosinophils. It has effects such as infiltration induction, and it has been suggested that it is particularly deeply involved in the pathogenesis of allergy. In fact, in the alveolar lavage fluid of asthmatics I
  • IL-4 or IL-15 is involved in the development of allergic diseases in animal models of allergic diseases.
  • a drug that inhibits the production of IL-4 and IL-5 in allergic patients improves the bias toward Th2 cells, and suppresses eosinophilic inflammation can be a useful antiallergic drug.
  • Japanese Patent Publication No. 7-537 16 describes a certain imidazole derivative having anti-inflammatory and analgesic effects, but it inhibits the production of IL_4 and IL-5 from Th2 cells. None is described.
  • IPD-1151T sublatast tosilate
  • steroids are widely used as therapeutic agents for allergic diseases and have shown high clinical effects.
  • Steroids produce IL-5 due to their wide-ranging effects. It has an inhibitory effect on biosynthesis, and its inhibitory effect on IL-15 production is considered to be a mechanism for suppressing eosinophilic inflammation.
  • Steroids have a wide range of effects, and their side effects are problematic.
  • immunosuppressants such as cyclosporin A and tacrolimus also inhibit IL-5 production and are effective against eosinophilic inflammation.
  • these drugs have side effects on the kidneys and side effects such as immunosuppression and induction of infection by widely inhibiting the production of cytokines such as IL-2 as well as IL-5.
  • a compound that has a specific inhibitory effect on IL-14 and IL-15 production can be compared to conventional drugs by improving the bias toward Th2 cells in allergic patients and suppressing eosinophilic inflammation.
  • Atopic dermatitis, bronchial asthma, and allergic drugs with fewer side effects compared to other drugs are expected to be useful for the prevention and treatment of allergic diseases such as rhinitis o
  • An object of the present invention is to provide a drug that specifically inhibits the production of IL-14 and IL-5, which are deeply involved in the pathogenesis of allergies, among the cytokines produced from Th2 cells. is there.
  • the present inventors have conducted intensive studies in view of the above circumstances, and as a result, have found that a novel imidazole compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof are excellent in IL-4 and IL.
  • the present inventors have found that they have an inhibitory effect on the production of 5, and are useful as preventive and therapeutic agents for allergic diseases, thereby completing the present invention.
  • the present invention is as follows.
  • R 1 represents hydrogen, an optionally substituted alkyl group, an optionally substituted aralkyl group or a morpholinoalkyl group
  • R 2 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted quinolyl group Represents an optionally substituted isoquinolyl group, an optionally substituted pyridyl group or an optionally substituted aralkyl group.
  • R 3 represents an optionally substituted heteroaryl group
  • R represents an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group.
  • R 1 is hydrogen
  • R 2 is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 4 is a phenyl group or a halogen atom
  • R 3 is a benzothiazolyl group or a thiazolyl group substituted with a phenyl group.
  • R 1 is hydrogen, an optionally substituted alkyl group, or an optionally substituted Represents an aralkyl group or a morpholinoalkyl group,
  • R 2 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted quinolyl group Represents an optionally substituted isoquinolyl group, an optionally substituted pyridyl group or an optionally substituted aralkyl group.
  • R 3 represents an optionally substituted heteroaryl group
  • R 4 represents a cycloalkyl group which may be substituted, a phenyl group which may be substituted, a naphthyl group which may be substituted, or a heteroaryl group which may be substituted.
  • R 1 is hydrogen and R 2 is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 4 is a phenyl group or a halogen atom. And represents a group other than a phenyl group substituted with a lower alkyl group or a lower alkoxy group.
  • R 1 in the general formula (I) represents hydrogen
  • R 2 is a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, an acylamino group, a dialkylaminoalkylamino group, an acyloxyalkylcarbonylamino group, a dialkylaminoalkoxy group, an acyloxyalkoxy group, It may be substituted with a hydroxyalkoxy group or a lower alkyl group having 1 to 6 carbon atoms, and may contain an oxygen atom.Saturated 5- or 6-membered heteromonocyclic ring containing 1 to 2 nitrogen atoms. A phenyl group substituted by any one of the groups; R 3 represents an optionally substituted heteroaryl group;
  • R 1 in the general formula (I) represents hydrogen
  • R 2 represents a naphthyl group which may be substituted
  • R 3 represents a heteroaryl group which may be substituted
  • a pharmaceutical composition comprising a therapeutically effective amount of the imidazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5) and a pharmaceutically acceptable additive.
  • a selective production inhibitor of interleukin-4 and interleukin-5 comprising the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • FIG. 1 is a graph showing the effect of the compound of Example 1 on an ovalbumin-induced mouse biphasic edema model in Experimental Example 2. Each value represents the mean soil standard error. (The number of cases is 23 to 28). The significance test was performed using Dunnet's multiple comparison. ** indicates that a significant difference from the control was observed at P ⁇ 0.01.
  • FIG. 2 shows the effects of the compounds of Examples 79 and 99 on the increase in Eosinophi 1 peroxidase (EPO) activity in the ovalbumin-induced mouse biphasic edema model in Experimental Example 3. It is a graph. Each value represents the standard error of the mean. (The number of cases is 13 to 16). The significance test was performed using Dunnett's multiple comparison. ** indicates that a significant difference from the control was observed at p ⁇ 0.01.
  • the alkyl group of the ⁇ optionally substituted alkyl group '' of R 1 and R 2 is a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, Propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, o Octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl
  • Octadecyl group, icosyl group and the like preferably alkyl having 1 to 6 carbon atoms.
  • substituent of the “optionally substituted alkyl group” examples include an aralkyloxy group (a benzyl group such as a benzyloxy group, a phenylethoxy group, a phenylpropyloxy group, and a phenylbutoxy group).
  • an alkylthioalkoxy group an acyloxyalkoxy group (acetyloxyethoxy group, propionyloxyethoxy group, isoptyryloxypropyloxy group, acetyloxypropyloxy group, 1 to 6 carbon atoms such as xypropyloxy group A lower alkoxy group having 2 to 6 carbon atoms substituted with an aliphatic alkoxy group, which represents an acyloxy alkoxy group); a cyanoalkoxy group (cyanoethoxy group, cyanopropyloxy group, cyanoisopropyloxy group, A cyanoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a cyanobutoxy group and a cyanoisobutoxy group is substituted with a cyano group; and a ditroalkoxy group (a ditroethoxy group, a nitropropyloxy group, a nitrobutoxy group,
  • Dial group in which the alkyl moiety such as an amino group is an alkyl group having 1 to 6 carbon atoms
  • a dialkylaminoalkylamino group an alkyl group such as a dimethylaminoethylamino group or a dimethylaminopropylamino group.
  • Part represents a dialkylaminoalkylamino group having 1 to 6 carbon atoms); a carbamoyl group; a monoalkyl carbamoyl group (a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a butylcarbamoyl group)
  • a monoalkyl group having an alkyl moiety of 1 to 6 carbon atoms such as a monoalkyl group having an alkyl group of 1 to 6; a dialkyl group having a carbamoyl group (dimethylcarbamoyl group, getylcarbamoyl group, dipropylcarbamoyl group, dibutylcarbamoyl group, etc.);
  • the alkyl part is an alkyl group having 1 to 6 carbon atoms
  • An acylamino group (indicating an aliphatic acylamino group having 2 to 6 carbon
  • An alkoxy group such as a xycarbonyl group or a butoxycarbonyl group represents an alkoxycarbonyl group having 1 to 6 carbon atoms; an acyl group (a carbon atom such as a formyl group, an acetyl group or a propionyl group); Represents an aliphatic acetyl group and a benzoyl group of from 6 to 6); Xy group (indicating an aliphatic acyloxy group having 1 to 6 carbon atoms such as a formyloxy group, an acetyloxy group, a propionyloxy group and a benzoyloxy group), and the like, preferably a hydroxyl group, an amino group, a monoalkylamino group, a dialkylamino group A lower alkoxy group, a halogen atom, an aralkyloxy group and the like.
  • the “optionally substituted alkyl group” may be substituted by 1 to 3 substituents, which may be the same or different.
  • the aralkyl group in the “optionally substituted aralkyl group” of R 1 and R 2 is a phenyl group substituted with an alkyl group having 1 to 6 carbon atoms, and is a benzyl group, a phenylethyl group, a phenylpropyl group. And a phenylbutyl group.
  • Examples of the substituent on the phenyl ring of the “optionally substituted aralkyl group” include lower alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl) An alkyl group having 1 to 6 carbon atoms, such as an isopentyl group, a hexyl group, etc.); a hydroxyalkyl group (a hydroxymethyl group, a hydroxyethyl group, a hydroxylpropyl group, a hydroxyisopropyl group, a hydroxypropyl group) A hydroxyalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a hydroxy group, a hydroxylisobutyl group, or a hydroxypentyl group is substituted with a hydroxyl group); an alkoxyalkyl group (a methoxyxyl group, a methoxy
  • a mercaptoalkyl group (indicating a mincapalkyl group); a mercaptoalkyl group (indicating a mercaptoalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a mercaptomethyl group, a mercaptoethyl group, and a mercaptoisopropyl group is substituted with a mercapto group); Alkylthioalkyl groups (1 to 6 carbon atoms such as methylthiomethyl group, methylthioethyl group, ethylthioethyl group, ethylthiopropyl group, peroxypropylthioisopropyl group, isopropylthiobutyl group, etc.) Represents an alkylthioalkyl group substituted with an alkylthio group of ⁇ 6) Acyloxyalkyl group (carbon such as acetyloxymethyl group, acetyloxyethy
  • An alkoxycarbonylalkyl group (a methoxycarbonylmethyl group, an ethoxy group).
  • a lower alkyl group having 1 to 6 carbon atoms such as a cicarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, a methoxycarbonylethyl group, or a methoxycarbonylpropyl group;
  • Halogens fluorine, chlorine, bromine, iodine
  • alkyl groups having 1 to 6 carbon atoms.
  • An aralkyloxy group which may be substituted with chlorine, bromine or iodine); a hydroxyl group; a lower alkoxy group (having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group).
  • An alkoxy group a hydroxyalkoxy group (a hydroxyethoxy group, a hydroxypropyloxy group, A hydroxyalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a droxyisopropyloxy group, a hydroxybutoxy group, a hydroxyisobutoxy group, or a hydroxypentyloxy group is substituted with a hydroxyl group); Alkoxy groups (lower alkoxy having 1 to 6 carbon atoms such as methoxy methoxy, methoxy ethoxy, methoxy propyl oxy, ethoxy propyl oxy, propyl oxy ethoxy, isopropyl oxy butoxy, butoxy isopropyl oxy, etc.
  • a monoalkylaminoalkoxy group methylaminoethoxy group, ethylaminoethoxy group, ethylaminoisobutoxy group, propylaminoethoxy group, isopropylaminobutoxy group
  • An alkyl group such as an amino group represents a monoalkylamino group having 1 to 6 carbon atoms); a dialkylamino group (a dimethylamino group, a di
  • a dialkylamino group ); a dialkylaminoalkylamino group (a dialkylaminoalkylamino group in which the alkyl moiety such as a dimethylaminoethylamino group or a dimethylaminopropylamino group is an alkyl group having 1 to 6 carbon atoms)
  • a monoalkyl carbamoyl group (a monoalkyl carbamoyl group, a methyl carbamoyl group, an ethyl carbamoyl group, a propyl carbamoyl group, a butyl carbamoyl group, etc.) wherein the alkyl portion is an alkyl group having 1 to 6 carbon atoms.
  • a dialkyl carbamoyl group (indicating a dialkyl carbamoyl group in which the alkyl moiety such as a dimethylcarbamoyl group, a getylcarbamoyl group, a dipropyl carbamoyl group, a dibutylcarbamoyl group is an alkyl group having 1 to 6 carbon atoms)
  • An acetylamino group (acetylyl) Amino group, propionylamino group, etc., represent an acylamino group and a benzoylamino group in which the acyl moiety is an aliphatic acryl group having 1 to 6 carbon atoms); nitro group; cyano group; alkylsulfonyl group (methylsulfonyl group, ethylsulfonyl) Where the alkyl part of the group is an alkylsulfonyl group having 1 to 6 carbon atoms)
  • alkylsulfinyl group an alkylsulfinyl group in which the alkyl portion is an alkyl group having 1 to 6 carbon atoms, such as a methylsulfinyl group or an ethylsulfinyl group
  • alkylsulfinyloxyalkyl group (methylsulfinyloxymethyl group, methylsulfinyloxyshethyl group, methylsulfinyloxypropyl group, An alkylsulfinyloxyalkyl group in which the alkyl portion is an alkyl group having 1 to 6 carbon atoms, such as an ethylsulfinyloxymethyl group, an ethylsulfinyloxyxethyl group, and an ethylsulfinyloxypropyl group.
  • Monoalkylsulfamoyl group monoalkylsulfamoyl group in which the alkyl part such as methylsulfamoyl group and ethylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms; Sulfamoyl group (dialkylsulfamoyl group in which the alkyl part such as dimethylsulfamoyl group and acetylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms); cycloalkyl group (cyclopropyl group, cyclobutyl group) Group, cyclopentyl group, cyclohexyl group, etc.
  • a cycloalkylalkyl group (a cycloalkyl in which a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group is substituted with an alkyl group having 1 to 6 carbon atoms)
  • a halogen atom (indicating fluorine, chlorine, bromine, or iodine); a carboxyl group; an alkoxycarbonyl group (such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, or a butoxycarbonyl group)
  • a moiety represents an alkoxycarbonyl group having 1 to 6 carbon atoms); an acyl group (an aliphatic acyl group having 1 to 6 carbon atoms such as a formyl group, an acetyl group, a pro
  • a saturated 5- or 6-membered heterocyclic monocyclic group containing 1 to 2 nitrogen atoms e.g., represents lipidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl, morpholino, etc.
  • To 6 lower alkyl groups for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group Or a tert-butyl group, a pentyl group, an isopentyl group, or a hexyl group, etc.
  • a nitrogen-containing heteromonocyclic alkyl group the nitrogen-containing heterocyclic ring contains an oxygen atom.
  • a saturated 5- or 6-membered heterocyclic monocyclic group containing 1 to 2 nitrogen atoms for example, pyrrolidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl, morpholino, etc.
  • a saturated 5- or 6-membered heterocyclic monocyclic group containing one nitrogen atom a nitrogen-containing heteromonocyclic alkyl group which may be substituted with a lower alkyl group having 1 to 6 carbon atoms, and the like.
  • the phenyl ring of the "optionally substituted aralkyl group” may be substituted by 1 to 3 substituents, which may be the same or different.
  • substituent of the alkyl portion of the “optionally substituted aralkyl group” include a phenyl group, an aralkyloxy group (a phenyl group such as a benzyloxy group, a phenylethoxy group, a phenylpropyloxy group, a phenylbutoxy group, etc.).
  • a dialkyl rubamoyl group an acylamino group (acetyl An aliphatic acylamino group having 2 to 6 carbon atoms and a benzoylamino group such as an amino group and a propionylamino group; a nitro group; a cyano group; an alkylsulfonyl group (an alkyl moiety such as a methylsulfonyl group and an ethylsulfonyl group); An alkylsulfonyl group which is an alkyl group having 1 to 6 carbon atoms); an alkylsulfinyl group (where the alkyl portion such as a methylsulfinyl group or an ethylsulfinyl group is an alkyl group having 1 to 6 carbon atoms) Sulfamoyl group; monoalkylsulfamoyl group (indicating a monoalkylsulfamoyl group in which the al
  • Asiloxy group (formyloxy group, acetyloxy group, propionyloxy group, etc.) Preferably represents a hydroxyl group, an amino group, a monoalkylamino group, a dialkylamino group, a nitro group, a lower alkyl group, a lower alkoxy group, a haloalkyl group, or the like. Examples include a halogen atom, an aralkyl group, and an aralkyloxy group.
  • the substituents on the alkyl portion of the “optionally substituted aralkyl group” may be substituted by 1 to 3 substituents, and the substituents may be the same or different.
  • the “morpholinoalkyl group” of R 1 is a morpholino group substituted by an alkyl group having 1 to 6 carbon atoms, and is a morpholinomethyl group, a morpholinoethyl group, It represents a linopropyl group, a morpholinobutyl group and the like.
  • the cycloalkyl group of the “optionally substituted cycloalkyl group” of R 2 and R 4 represents a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. .
  • substituent of the “optionally substituted cycloalkyl group” has the same meaning as the substituent that can be substituted on the fuunyl ring of the “optionally substituted aralkyl group”.
  • the cycloalkyl group of the “optionally substituted cycloalkyl group” may be substituted with 1 to 3 substituents, and the substituents may be the same or different.
  • the heteroaryl group of the "optionally substituted heteroaryl group" for R 3 and R 4 includes thiazolyl, thiazolinyl, oxazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzozoxazolyl, and benzozimiyl. Dazolyl, quinolyl, isoquinolyl, etc. Further, the substituent of the “optionally substituted heteroaryl group” has the same meaning as the substituent that can be substituted on the fuunyl ring of the “optionally substituted aralkyl group”.
  • heteroaryl group in the “optionally substituted heteroaryl group” may be substituted with one to three substituents, and the substituents may be the same or different.
  • R 2 , R 4 "optionally substituted phenyl group”, “optionally substituted naphthyl group”, R 2 "optionally substituted quinolyl group”, “optionally substituted isoquinolyl”
  • the substituents of the “group” and the “optionally substituted pyridyl group” are the same as the substituents that can be substituted on the phenyl ring of the “optionally substituted aralkyl group”.
  • Optionally substituted phenyl group may be substituted by 1 to 3 substituents, and the substituents may be the same or the same. It may be different.
  • halogen atom “lower alkyl group” and “lower alkoxy group” of R 2 and R 4 are the “halogen atom which can be substituted on the phenyl ring of the“ optionally substituted aralkyl group ”. ",” Lower alkyl group “and” lower alkoxy group ".
  • Preferred examples of the "optionally substituted heteroaryl group" for R 3 include thiazolyl, thiazolinyl, thiadiazolyl, benzothiazolyl, pyrimidinyl, and imidazolyl.
  • Preferred examples of the substituent that can be substituted on the heteroaryl group include: Examples include lower alkyl groups, alkoxycarbonylalkyl groups, and phenyl groups.
  • Preferred examples of the "optionally substituted heteroaryl group" for R 4 include pyridyl and pyrimidinyl.
  • Preferred examples of the substituent that can be substituted on the heteroaryl group include a lower alkyl group and a lower alkoxyl group Is mentioned.
  • Preferred examples of the substituent of the “optionally substituted phenyl group” for R 2 include a lower alkyl group, an aralkyloxy group optionally substituted with halogen, a hydroxyl group, a lower alkoxy group, an amino group, and a mono group.
  • substituent of the “naphthyl group which may be substituted” in R 2 include a monoalkylamino group, a dialkylamino group, a nitro group, a lower alkyl group and a lower alkoxy group.
  • Preferred examples of the substituent of the “optionally substituted phenyl group” for R 4 include a lower alkyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an acyloxyalkyl group, a haloalkyl group, a hydroxyl group and a lower alkoxy group.
  • Pharmaceutically acceptable salts of the compound of the general formula (I) of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and acetic acid. Salts with organic acids such as pionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Is mentioned.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and acetic acid.
  • Salts with organic acids such as pionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid,
  • salts with metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and salts with organic bases such as triethylamine and pyridine can be given. Since the compound of the general formula (I) and the pharmaceutically acceptable salt thereof of the present invention may exist in the form of a hydrate or a solvate, these hydrates or solvates are also included in the present invention. Is included.
  • the present compound when it contains an asymmetric carbon, it can be obtained in the form of a racemic mixture or an optically active substance. When the compound further has at least two asymmetric carbons, it can be obtained as an individual diastereomer or a mixture thereof. can get.
  • the present invention includes these mixtures and individual isomers as well as stereoisomers.
  • novel imidazole compound represented by the general formula (I) of the present invention can be produced, for example, by the following method. However, the method for producing the compound of the present invention is not limited to these.
  • Z is a halogen atom such as chlorine or bromine; an azide group; an N-hydroxybenzotriazolyl group; (Ii) trophenyloxy group; p-chlorophenyloxy group; alkoxy group such as methoxy group and ethoxy group; and acyloxy group such as acetyloxy group and bivaloyloxy group.
  • the compound represented by the general formula (II) is reacted with thionyl chloride, isobutyl carbonate, methyl carbonate, ethyl carbonate, or the like in an inert solvent according to a conventional method to form a reactive intermediate. (III) and then reacting with a compound represented by the general formula (IV) in an inert organic solvent in the presence or absence of a base, preferably in the presence of a base. Can be made (process
  • the compound represented by the general formula (II) may be converted to a compound represented by the general formula (IV) in the presence of a base or by using a suitable condensing agent without converting the compound represented by the general formula (II) into a reactive derivative. Reaction in an inert organic solvent in the absence, preferably in the presence of a base It can also be manufactured by performing the process (Step 3).
  • the base used in the method of the present invention includes pyridine, picoline, lutidin, collidine, N-methylbiperidine, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaminopyridine, triethylamine, diisopropyl
  • Examples include ethylamine, potassium carbonate, sodium carbonate and the like, with preference given to pyridin, N, N-dimethylaminopyridine, triethylamine, diisopropylethylamine and potassium carbonate.
  • the inert organic solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, and is preferably ether, benzene, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, Examples thereof include methylene chloride, dimethyl sulfoxide, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like. Particularly preferred are toluene, tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like.
  • the reaction is carried out at a temperature equivalent to the reflux temperature of the solvent used from _30 ° C, preferably from room temperature to a temperature equivalent to the reflux temperature of the solvent used, particularly preferably at a temperature equivalent to the reflux temperature of the solvent used. It is advantageous to carry out.
  • condensing agent examples include N, N'-dicyclohexylcarbodiimide, 1,1-carbonyldimidazole, 1-hydroxybenzotriazol, and 1-hydroxy-17-azabe Benzotriazole, 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4,4,1-dichloro It is preferable to use ⁇ -methylbenzhydrol or the like.
  • the compound having a lower alkoxy group or an aralkyloxy group as a substituent is a compound in which the corresponding substituent of the general formula (I) is a hydroxy group and a corresponding lower alkyl alcohol or phenyl lower group. Reaction of alkyl alcohol in the presence of triphenylphosphine and acetyldicarboxylate Therefore, it can be manufactured.
  • a compound having a hydroxyl group, a hydroxyalkyl group, an amino group or an aminoalkyl group as a substituent is a compound in which the corresponding substituent of the general formula (I) is an acyloxy group, an acyloxyalkyl group,
  • a compound having an acylamino group or an acylaminoalkyl group can be produced by performing a hydrolysis reaction under basic or acidic conditions.
  • a compound having a hydroxyl group, a hydroxyalkyl group, an amino group, or an aminoalkyl group as a substituent is a compound in which the corresponding substituent of the general formula (I) is a benzyloxy group, a benzyloxyalkyl group, Hydrogenation of a compound that is a benzylamino group or a benzylaminoalkyl group in the presence of a catalyst such as palladium, or reaction with hydrobromic acid in a solvent such as acetic acid, or treatment in thioanisole or trifluoroacetic acid Can also be manufactured.
  • a compound having an amino group or an aminoalkyl group as a substituent is a compound in which the corresponding substituent in the general formula (I) is a nitro group or a nitroalkyl group, and iron powder.
  • Reduction with an acid such as hydrochloric acid, acetic acid or sulfuric acid, hydrogenation in the presence of a catalyst such as palladium, or heating to reflux in a 6 molar hydrochloric acid solution of tin chloride (II) hexahydrate Can be manufactured.
  • the compound having a dialkylamino group or a monoalkylamino group as a substituent can be obtained by alkylating a compound of the general formula (I) in which the corresponding substituent is an amino group.
  • Alkylation methods include alkylation using alkyl halide, alkyl paratoluenesulfonate and the like and, if necessary, bases such as triethylamine, pyridine, carbonated sodium carbonate, sodium carbonate and sodium hydrogencarbonate.
  • bases such as triethylamine, pyridine, carbonated sodium carbonate, sodium carbonate and sodium hydrogencarbonate.
  • the compound of the general formula (II) used as a starting material in the present invention is obtained, for example, by hydrolyzing a compound of the general formula (VII and XI) obtained by the following methods 1 to 4 under alkaline or acidic conditions. It can be manufactured by decomposing. Method 1
  • R 2 and R 4 have the same meanings as described above, and R 5 represents a lower alkyl group.
  • the compound represented by the general formula (VII) can be produced by reacting the compound represented by the general formula (V) with the compound represented by the general formula (VI) (Step 4).
  • the reaction solvent for example, toluene, benzene, xylene, pyridine, picolin, dioxane, hexane, petroleum ether, acetonitrile, acetic acid, tetrahydrofuran and the like can be used.
  • the reaction is carried out at a temperature equivalent to the reflux temperature of the solvent to be used, preferably from room temperature to a temperature equivalent to the reflux temperature of the solvent used, particularly preferably at a temperature equivalent to the reflux temperature of the solvent used. It is.
  • R 2 and R 4 have the same meanings as described above, and R 5 represents a lower alkyl group.
  • reaction solvent for example, toluene, benzene, xylene, pyridine, picolin, dioxane, hexane, petroleum ether, acetic acid and the like can be used.
  • the reaction may be performed without a solvent.
  • reaction is advantageously carried out from 0 ° C. under the reflux temperature of the solvent used. 4 — CO
  • R 2 and R 4 have the same meanings as described above, and R 5 represents a lower alkyl group.
  • the compound represented by the general formula (V) is represented by the general formula (IX) in the presence of an ammonium salt of a lower alkanecarboxylic acid ammonium salt such as ammonium acetate or ammonium formate, or an inorganic acid ammonium salt such as ammonium carbonate.
  • the compound represented by the general formula (VII) can be produced by reacting with the compound (Step 6) o
  • reaction solvent for example, acetic acid, toluene, pyridine, ethyl acetate and the like can be used.
  • the reaction is preferably carried out at a temperature equivalent to the reflux of the solvent used from 0, but it is particularly preferred to carry out the reaction at a temperature equivalent to the reflux of the solvent used.
  • the compound represented by the general formula (XI) can be obtained by converting the compound represented by the general formula (VII) in the presence or absence of a base such as sodium hydroxide, potassium hydroxide, sodium hydride, and the like. Can be produced by reacting the compound represented by the formula with an inert organic solvent (step 7).
  • the inert organic solvent examples include toluene, tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylformamide and the like.
  • the reaction is carried out at a temperature ranging from 130 ° C. to a temperature equivalent to the reflux of the solvent used, preferably from room temperature to a temperature equivalent to the reflux of the solvent used, particularly preferably at a temperature equivalent to the reflux of the solvent used. It is advantageous.
  • the pharmaceutically acceptable salts of the compounds of the general formula (I) of the present invention include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (acetic acid, Treated with pionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and conventional methods By doing so, the above-mentioned acid addition salt can be obtained. Oxalate can also be used for the purpose of crystallization of the compound.
  • the corresponding metal salt can be obtained by treating with lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc., and the salt with an organic base by treating with triethylamine, pyridine, etc. You can do it.
  • the compound of the present invention can be converted into a hydrate or a solvate by treating the compound with water, an aqueous solvent or another solvent.
  • the compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method or a column chromatography method.
  • a recrystallization method or a column chromatography method.
  • the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid, or By passing through a column filled with a suitable carrier, the desired optically active substance can be separated.
  • Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like.
  • Stereoisomers can be isolated by recrystallization, column chromatography, or the like.
  • the compound of the present invention is pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, odorant).
  • pharmaceutical compositions or preparations tablettes, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions obtained by mixing with pharmaceuticals, emulsifiers, diluents, solubilizers, etc.
  • the pharmaceutical compositions can be formulated according to the usual methods.
  • excipients lactose, D-mannitol, starch, crystalline cellulose, etc.
  • binders hydroxypropylcellulose, hydroxylpropylmethylcellulose, polyvinylpyrrolidone, etc.
  • disintegrants carboxymethylcellulose potassium
  • lubricants magnesium stearate, talc, etc.
  • coating agents hydroxylpropyl methylcellulose, sucrose, etc.
  • base materials polyethylene glycol, hard fat, etc.
  • Solubilizers or solubilizers that can constitute aqueous or time-adjustable injections
  • PH regulators inorganic acids, organic acids or inorganic bases
  • stabilizers are used.
  • the compound of general formula (I) of the present invention and a pharmaceutically acceptable salt thereof inhibit the production of IL-4 and IL-5 produced from Th2 cells, It is effective as a preventive and therapeutic agent for allergic diseases such as asthma and allergic rhinitis.
  • the dosage of this drug to treated patients can vary depending on the type and extent of the disease, the compound administered, the route of administration, the age, sex, and weight of the patient, but in general, for adults, the daily dose is oral. About 1.0 to 100 Omg for parenteral administration, and about 1.0 to 500 Omg for parenteral administration.
  • reaction solution was subjected to a reaction treatment in the same manner as in Raw Material Synthesis Example 2, to obtain 4.1 g of 5- (4-chlorophenyl) -2- (1-naphthyl) imidazo-1-lu-4-carboxylic acid. Melting point 210 ° C (decomposition)
  • Raw material synthesis example 19 5- (4-methylphenyl) -2- (4-pyridyl) imidazole-4-carboxylic acid obtained by reacting the compound obtained in 9 in the same manner as in Raw material synthesis example 2 1.0 g, 1 mol hydrochloric acid-ether solution (1.3 ml), thionyl chloride (3 ml), and 2-aminothiazol (0.36 g), the reaction was carried out in the same manner as in Example 1 to give 5- (4 1-methylphenyl) 1 2— (4 pyridyl) 1 N—
  • Raw material synthesis example 24 5- (4-methylphenyl) -2-nonylimidazole-1-4 cal obtained by reacting the compound obtained in 4 in the same manner as in raw material synthesis example 2 The reaction was carried out in the same manner as in Example 1 using 80 Omg of boric acid, 1.Oml of thionyl chloride, 20 mg of N, N-dimethylaminopyridine and 230 mg of 2-aminothiazol, to give 5- (4 ⁇ Methylphenyl) -1-nonyl-N- (2-thiazolyl) imidazo-41-carboxamide 40 Omg was obtained. This was used as a hydrochloride to obtain amorphous 5- (4-methylphenyl) -2-nonyl-N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride (24 Omg). Melting point
  • 2-tert-butyl-5- (4-methylphenyl) imidazole-4 obtained by reacting the compound obtained in the raw material synthesis example 25 in the same manner as in the raw material synthesis example 2, 500 mg of rubutyric acid, thionyl chloride 0 3 ml, N, N-dimethylaminoviridine 2 Omg, 2-aminothiazole 250 mg, and the reaction treatment in the same manner as in Example 1 to give 2-tert-butyl-5- (4-methylphenyl) One N- (2-thiazolyl) imidazo-l-41-carboxamide 2 10 mg was obtained. Melting point 218, lH -NMR 400 MHz (CDC I s, ppm) ⁇
  • Raw material synthesis example 26 5- (4-methylphenyl)-2- (2-phenylethyl) imidazol-4 obtained by reacting the compound obtained in 6 in the same manner as in raw material synthesis example 2 The reaction was carried out in the same manner as in Example 1 using 80 Omg of acid, 2.60 ml of thionyl chloride, 20 mg of N, N-dimethylaminopyridine, and 260 mg of 2-aminothiazole to give 5- (4 —Methylphenyl) — 2— (2-phenylethyl) — N— (2-thiazolyl) imidazole—4-carboxamide
  • Example 22 2- (4-benzyloxyphenyl) -5- (4-methylphenyl) -1- (2-thiazolyl) imidazole-4-1-carboxamide obtained in (3) 5.10 g, 6.4 ml of thioanisol was dissolved in 100 ml of trifluoroacetic acid and stirred for 6 hours. The reaction solution was made alkaline with a 2 molar aqueous sodium hydroxide solution, acidified with aqueous citric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried, and the solvent was distilled off.
  • Example 27 1.22 g of 1-methyl-5- (4-methylphenyl) -2- (1-naphthyl) imidazole-4-carboxylic acid ethyl ester obtained in (1) was hydrolyzed in the same manner as in Raw Material Synthesis Example 2. The obtained residue was subjected to a reaction treatment in the same manner as in Example 1 to give 1-methyl-15- (4-methylphenyl) -12- (1-naphthyl) -N- (2-thiazolyl) imidazole-4- 0.45 g of carboxamide was obtained. With a melting point of 251-252, Hydrochloride: - NMR 40 0 MHz (DMSO - D 6, p pm) ⁇ : 2. 4 1
  • Example 29 0.71 g of 5- (4-methylphenyl) -1- (2-morpholinoethyl) -1-2- (1-naphthyl) imidazo-1-ru 4-carboxylate obtained in Example (1) was synthesized as a raw material. The residue obtained by the reaction treatment in the same manner as in Example 2 was subjected to the reaction treatment in the same manner as in Example 1 to give 5- (4-methylphenyl) — 1— (2- ⁇ ulfolinoethyl) —2— (1-naphthyl) 0.40 g of 1 N- (2-thiazolyl) imidazole 4-carboxamide was obtained.
  • the solvent was distilled off under reduced pressure. To the obtained residue, 40 ml of pyridine and 0.333 g of 2-aminothiazole were added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. After the organic layer was washed with water and dried, the solvent was distilled off. The obtained residue was dissolved in ethyl acetate, 3 ml of a 1M hydrochloric acid / ether solution was added, and the precipitated crystals were collected by filtration.
  • Example 3 9 Raw material synthesis example 13 2- (3-Methoxyphenyl) -1- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in 1.3 1.4 g, trifluoroacetic acid 30 m 1 Using 0.5 m 1 of thionyl chloride and 0.34 g of 2-aminothiazole, the reaction treatment was carried out in the same manner as in Example 31 to give 2- (3-methoxyphenyl) — 5 -— (4-pyridyl) 0.27 g of 1 N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride was obtained.
  • Example 4 7 Raw material synthesis example 3 5- (4-Methoxyphenyl) 1-2- (412-Trophenyl) imidazole-4 obtained from Example 7 4.9 g of rubonic acid, 1 M hydrochloric acid-ether solution 30 m 1, 50 ml of thionyl chloride and 1.5 g of 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-methoxyphenyl) 1-2- (4-1 There was obtained 0.93 g of ditrophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide.
  • Example 4 2- (4-nitrophenyl) -5- (4-trifluoromethylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 9 Hydrogenate 0.42 g in methanol using palladium. Then, the catalyst is removed by filtration, and the mixture is concentrated to give 2- (4-aminophenyl) 1.51- (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazole-4-1. 0.25 g of carboxamide was obtained. With a melting point of 1 7 5—1 7 7
  • Example 51 2- (4-212-tropinyl) -1-5-N- (2-thiazolyl) imidazo-1-41-carboxamide obtained in 1-0.52 g, tin (II) 6 water
  • the same reaction treatment as in Example 59 was carried out using 1.2 g of the hydrate to give 2- (4-aminophenyl) -15-phenyl-2-N- (2-thiazolyl) imidazole—4-force 0.17 g of lipoxamide was obtained.
  • Example of raw material synthesis Example 2 using 2,5-bis (4-nitrophenyl) imidazole obtained in 40--4 rubonic acid, 1M hydrochloric acid-ether solution, thionyl chloride, and 2-aminothiazole. By performing the reaction treatment in the same manner as in 1, 2,5-bis (412-tropinyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained.
  • Example 53 The 2,5-bis (412-trophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in Example 53 is suspended in methanol and cooled with ice. To the suspension was added a 6 molar hydrochloric acid solution of ⁇ ( ⁇ ) chloride, and the reaction was carried out in the same manner as in Example 48. ) Imidazole-4-carboxamide is obtained.
  • Example 55 5- (4-chlorophenyl) -12- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 5 is suspended in methanol and cooled with ice. A 6 molar hydrochloric acid solution of tin (II) chloride hexahydrate was added to the suspension solution, and the reaction was carried out in the same manner as in Example 48 to give 2- (4-aminophenyl) -15- (4-chloro (Phenyl) -N- (2-thiazolyl) imidazole-4-potassium lipoxamide is obtained.
  • Example 5 5- (4-Fluorophenyl) 1-2- (412-trifluoro) -lN- (2-thiazolyl) imidazole-41-carboxamide obtained in 7 was converted to methanol. And cool on ice. A 6 molar hydrochloric acid solution of tin chloride (II) hexahydrate was added to the suspension, and the reaction was carried out in the same manner as in Example 48 to give 2- (4-aminophenyl) -5- (4-fluorophenyl) — N- (2-thiazolyl) imidazole-4-carboxamide is obtained.
  • Example 18 1.22 g of 2- (1-naphthyl) -5- (4-nitrophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in Example 8 was suspended in methanol and iced. Cooled down. To the suspension was added 3 Om 1 of a solution of 3.O g of chloride (II) hexahydrate in 6 mol of hydrochloric acid, and the mixture was heated under reflux for 1.5 hours, and the precipitated white crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium hydrogen carbonate solution and water, and then dried.
  • II chloride
  • Example 6 5- (4-Acetoxymethylphenyl) 1-2- (1-naphthyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in (2) 2. 98 g of acetone was dissolved in 250 ml of acetone, and 56 ml of a 0.25 M aqueous sodium hydroxide solution was added under ice cooling, followed by stirring at room temperature for 2 hours. Acetone was distilled off under reduced pressure, acidified with aqueous citric acid solution, and extracted with ethyl sulphate.
  • Example 21 2- (4-aminophenyl) -5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide 0.1 g obtained in 1 and sodium borohydride 1.5 g of tetrahydrofuran suspension in 3N sulfuric acid 3 m
  • Example 5 5- (4-aminophenyl) -2- (1-naphthyl) -N- (thiazolyl) imidazole obtained in Example 9-41-lipoxamide 0.42 g, sodium borohydride 1.5 g, 3N sulfuric acid 3 ml, 37% formaldehyde 3 ml 1
  • 5- (4-dimethylaminophenyl) 1-2- (1-naphthyl) —N— (2-thiazolyl) imidazo-1-ru 4-carboxamide 0.1 6 g were obtained. Melting point 2 4 2-2 4 3 (decomposition)
  • Example 21 2- (4-Aminophenyl) -1-5- (4-methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 0.3 g, sodium borohydride 0.5 g, 3 ml of 3N sulfuric acid and 0.3 ml of acetoaldehyde were treated in the same manner as in Example 62 to give 2- (4-ethylpyraminophenyl) 1 5— (4— 0.117 g of methylphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide was obtained. Melting point 9 8-9 9 (decomposition)
  • Example 48 2- (4-aminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 8 0.5 g, sodium borohydride 1.5 g g, 3N sulfuric acid (3 ml) and 37% formaldehyde (3 ml) were treated in the same manner as in Example 62 to give 2- (4-dimethylaminophenyl) -15- (4-methoxyphenyl) -1-N — (2-thiazolyl) imidazole—4-carboxamide 0.27 g was obtained. By converting this to the hydrochloride,
  • Example 48 2- (4-aminophenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in 8 1.5 g, sodium borohydride 3.0 g, 6 ml of 3N sulfuric acid and 2 ml of acetoaldehyde were treated in the same manner as in Example 62 to give 2- (4-getylaminophenyl) -5- (4-methoxyphenyl). 0.85 g of 1 N- (2-thiazolyl) imidazole-4 -carboxamide was obtained.
  • Example 48 2- (4-Aminophenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from Example 8 1.0 g of tetrahydrofuran, methanol It was dissolved in a mixed solvent and added to a tetrahydrofuran solution of 0.2 ml of 4N sulfuric acid and 0.2 ml of acetoaldehyde. 0.13 g of sodium borohydride was added to the solution, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate phase was washed with saturated saline and dried. After concentration, purification was carried out by chromatography on a silylation gel using a chromate form / ethyl ester mixture in a ratio of 100: 1 as a fluid phase. Then, 1.2 g of 2- (4-ethylaminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was obtained.
  • Example 48 2- (4-aminophenyl) -5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 8 1.0 g, sodium borohydride By treating 0.13 g, 0.2 ml of 4N sulfuric acid and 0.2 ml of propyl aldehyde in the same manner as in Example 72, 5- (4-methoxyphenyl) -2- (4-propylamino (Phenyl) —N— (2-thiazolyl) imidazole-41-carboxamide 1. lg was obtained.
  • Example 4 2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 8 1.0 g, sodium borohydride 0.13 g, 0.2 ml of 4N sulfuric acid and 0.3 ml of butyraldehyde were treated in the same manner as in Example 72 to give 2- (4-butylaminophenyl) -1-5- (4-methoxyphenyl).
  • Le) -N- (2-thiazolyl) imidazo-lu-41-carboxamide 1. lg was obtained. By converting this to the hydrochloride,
  • Example 48 2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 8-0.8 g, sodium borohydride 0.1 3 g, 2.5 N sulfuric acid (0.4 ml) and isopentyl aldehyde (0.3 ml) were treated in the same manner as in Example 72 to obtain 2- (4-sopentylaminophenyl) 1-5- ( 0.3 g of 4- (methoxyphenyl) -N- (2-thiazolyl) imidazo-l-l-loxaxamide was obtained. Melting point 2 3 5— 2 3 9T;
  • Example 7 2.0 g of 5- (4-aminophenyl) 1-2- (4-tert-butylphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 7 was dissolved in methanol, and Add 3.6 ml of 7% formaldehyde and ice Under cooling, sodium boron cyanide (3.0 g) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated, and purified by silica gel chromatography using a mixture of ethyl formnoacetate having a ratio of 100: 1 as a fluid phase.
  • Example 7 0.5- (4-aminophenyl) 1-2- (4-tert-butylphenyl) -N_ (2-thiazolyl) imidazole-41-carboxamide obtained in 7-0.5 g in triethyl orthoformate was added. ⁇ After refluxing, the mixture was concentrated. Ethanol and tetrahydrofuran were added thereto, 0.4 g of sodium borohydride was added, and the mixture was heated under reflux for 2 hours. After the reflux, water was added, extraction was performed with ethyl acetate, and the ethyl acetate phase was washed with saturated saline and dried.
  • Example 8 5- (4-Methoxyphenyl) 1-2- (3-methyl-4-12-trophenyl) obtained in 4: 1-N- (2-thiazolyl) imidazole-4-carboxamide 1.5 was dissolved in 60 ml of 50% aqueous ethanol solution and 50 ml of dioxane, 6 g of iron powder was added, and 0.06 ml of concentrated hydrochloric acid was added under reflux, followed by refluxing for 1 hour. The filtrate was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure.
  • 1-N- (2-thiazolyl) imidazole-4-carboxamide 1.5 was dissolved in 60 ml of 50% aqueous ethanol solution and 50 ml of dioxane, 6 g of iron powder was added, and 0.06 ml of concentrated hydrochloric acid was added under reflux, followed by refluxing for 1 hour. The filtrate was concentrated under
  • Example 85 In a solution of 7 ml of tetrahydrofuran, 8.3 ml of 2.5 N sulfuric acid and 7 ml of 37% formalin, stirred under ice-cooling, the 2- (4-amino-3-methylphenyl) -1-5- obtained in Example 85 was obtained. (4 main Tokishifuweniru) Single N-(2-thiazolyl) to give a Imi Dazo one route 4 one Karubokisami de 1. 2 g and tetrahydrofuran 4 5 m 1 pressure and stirred 5 min _. After adding 3.5 g of sodium borohydride little by little, the mixture was stirred at room temperature for 2.5 hours.
  • Raw material synthesis example 5 (4-Isopropoxyphenyl) —2— (4-nitrophenyl) imidazo-4,4-hydroxyethyl ether ester 1.4 g obtained from 50 was synthesized as raw material synthesis example 2.
  • 5- (4-isopropane) 55-Omg of 2- (4-ditrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained.
  • Example 8 9 with a melting point of 26 7 to 27 0
  • Example 6 5- (4-Hydroxymethylphenyl) -1-2- (1-naphthyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 1 30 Omg of pyridine was added to 5 m of pyridine. 1 and 5 ml of propionic anhydride were dissolved and left for 12 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The residue obtained by washing, drying and concentrating the ethyl acetate layer with water is recrystallized from ethyl acetate to obtain 2- (1-naphthyl). One 5-O-mg of 5- (4-propionyloxymethylphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide was obtained.
  • Example 9 1 with a melting point of 281-283
  • Example 6 5- (4-Hydroxymethylphenyl) -1-2- (1-naphthyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 1.0 g of tetrahydrofuran 2 It was dissolved in Om1 and 1.24 g of triphenylphosphine and 63 mg of N-chlorosuccinimide were added. After stirring for 15 minutes, 1.24 g of triphenylphosphine and 63 mg of N-chlorosuccinimide were further added, followed by stirring for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate.
  • Example 9 4.9 g of 5- (4-acetoxymethylphenyl) -12- (4-ditropenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 2 was carried out.
  • Example 6 5- (4-Hydroxymethylphenyl) -12- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-caproloxamate 4. 45 g were obtained.
  • Example 9 5- (4-Hydroxymethylphenyl) -2- (4--2-trophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide 2.67 g obtained in 3 was added to tetrahydrofuran 30 It was dissolved in Om1, and 3.33 g of triphenylphosphine and 1.70 g of N-chlorosuccinimide were added. After stirring for 15 minutes, 3.33 g of triphenylphosphine and 1.70 g of N-chlorosuccinimide were further added, followed by stirring for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate.
  • Example 9 5- (4-Chloromethylphenyl) —2- (4-ditrophenyl) —N— (2-thiazolyl) imidazole-4-carboxamide obtained in 4 700 mg and sodium methanesulfinate (325 mg) were dissolved in dimethylformamide (30 ml), and the mixture was stirred at 80 ° C for 1 hour. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the solvent was distilled off. The obtained residue was suspended in acetone (3 Oml), a 1 M hydrochloric acid ether solution (3 ml) was added, and the solvent was distilled off.
  • Example 9 5- (4-Chloromethylphenyl) —2- (4-nitrophenyl) -1-N— (2-thiazolyl) imidazole—41-carboxamide obtained in 4 900 mg and 1 By reacting 30.9 mg of 1-methylbiperazine in the same manner as in Example 95, 5- (4- (4-methylbiperazine-11-ylmethyl) phenyl) 1-2- (4-nitrophenyl) —N— ( 2-thiazolyl) imidazole-4-carboxamide trihydrochloride 742 2 mg was obtained. Melting point 2 48 to 25 2 (decomposition)
  • Example 9 5- (4-Chloromethylphenyl) —2- (412-Trophenyl) —N— (2-Thiazolyl) imidazo-l-uyl 4-carboxamide 900 mg and dimethylamine obtained in 4 By reacting 5 ml of a 50% aqueous solution in the same manner as in Example 95, 5- (4-dimethylaminomethylphenyl) 1-2- (4-nitrophenyl) —N— (2-thiazolyl ) 645 mg of imidazole-4-carboxamide dihydrochloride were obtained. Melting point 2 7 3 to 2 7 QV (decomposition)
  • Example 4 2- (4-aminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-u 4- 4-potassium propyloxamide obtained in 8 to 1.35 g of ethyl ethyl orthoformate 4 Om 1 and 0.5 ml of trifluoroacetic acid were added, and the mixture was heated and refluxed overnight. The reaction solution was concentrated, and 40 ml of tetrahydrofuran and 25 ml of ethyl alcohol were added to the residue, and sodium borohydride was added with stirring. 2 g was added. After stirring at room temperature for 1 hour, the mixture was heated and refluxed for 2 hours.
  • Example 1 Using 5- (4-Methoxyphenyl) -1-2- (412-trophenyl) imidazole-4-carboxylic acid, 1M hydrochloric acid-ether solution, thionyl chloride, 2-amino-1,3,4-thiadiazole 5- (4-Methoxyphenyl) -1- (4-nitrophenyl) -1-N— (1,3,4-thiadiazol-2-yl) imidazo-1-ru-4 carboxamide Get.
  • Example 1 0 4
  • Example 81 5- (4-Ethoxyphenyl) -1-2- (4-nitrophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 was treated in the same manner as in Example 85.
  • the desired 2- (4-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru 4-carboxamide is obtained.
  • Example 1 2- (4-aminophenyl) -1-5- (4-ethoxyphenyl) -1-N- (2 thiazolyl) imidazo-1-ru 4-carboxamide obtained in Example 25 was treated in the same manner as in Example 102. Thus, the desired 2- (4-dimethylaminophenyl) -5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide is obtained.
  • Example 1 2- (4-Aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide obtained in 25 was treated in the same manner as in Example 99. This gives the desired 5- (4-ethoxyphenyl) -2- (4-methylaminophenyl) -N- (2-thiazolyl) imidazole-41-carboxamide.
  • Example 1 2- (4-Aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazoyl-4 __________________________________________________ Oxide obtained by Example 25 can be converted into By treatment, the desired 2- (4-butylaminophenyl) -1-5- (4-ethoxyphenyl) _N- (2-thiazolyl) imidazole-4-carboxamide is obtained.
  • Example 12 5- (4-ethoxyphenyl) —2- (3-nitrophenyl) —N— (2-thiazolyl) imidazole-41-carboxamide obtained in Example 9 was prepared in the same manner as in Example 85.
  • the desired 2- (3-aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained by the treatment.
  • Example 13
  • Example 13 2- (3-Aminophenyl) -5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 30 was treated in the same manner as in Example 102. This gives the desired 2- (3-dimethylaminophenyl) -5- (4-ethoxyphenyl) —N— (2-thiazolyl) imidazole—41-carboxamide.
  • Example 13 2- (3-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from 30 is treated with 4-carboxamide in the same manner as in Example 99. This gives the desired 5- (4-ethoxyethoxy)-2- (3-methylaminophenyl) -N- (2-thiazolyl) imidazole- 4-carboxamide.
  • Example 13 2- (3-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazoyl-4 4-carboxamide obtained in 30 is treated in the same manner as in Example 74. This gives the desired 2- (3-butylaminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide.
  • Example 13 The treatment of 5- (3-methoxyphenyl) 1-2- (3-ditrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 34 in the same manner as in Example 85 This gives the desired 2- (3-aminophenyl) -1-5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-1-yl 4-carboxamide.
  • Example 13 2- (3-Aminophenyl) -15- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 35 was treated in the same manner as in Example 102. This gives the desired 2- (3-dimethylaminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide.
  • Example 13 2 (3-Aminophenyl) -1-5 -— (3-methoxyphenyl) -1-N— (2-thiazolyl) imidazolyl-4_carboxamide obtained in 35 was prepared in the same manner as in Example 99. By treatment, the desired 5- (3-methoxyphenyl) -2- (3-methylaminophenyl) -1-N- (2-thiazolyl) imidazo-1-lu-4-carboxamide is obtained.
  • Example 13 By treating 2— (3-aminophenyl) -1-5- (3-methoxyphenyl) —N— (2-thiazolyl) imidazole-4—carboxamide obtained in 35 in the same manner as in Example 74, The desired 2- (3-butylaminophenyl) — 5- (3-methoxyphenyl) — N— (2-thiazolyl) imidazole—4-carboxamide is obtained.
  • Example 80 1.8 g of 5- (3-methoxyphenyl) —2- (4-nitrophenyl) —N— (2-thiazolyl) imidazole—4-carboxamide obtained in Example 80 was obtained in the same manner as in Example 85. Thus, 1.3 g of the desired 2- (4-aminofuunyl) -5- (3-methoxyphenyl) -1-N- (2-thiazolyl) imidazoyl-41-carboxamide was obtained. Melting point 2 6 2— 2 6 3
  • Example 15 0.4-g of 2- (4-aminophenyl) -1-5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-1-ru 4-carboxamide obtained in 55 was used as in Example 99. In the same manner, 0.32 g of the desired 5- (3-methoxyphenyl) -2- (4-methylaminophenyl) -1-N- (2-thiazolyl) imidazole-1-carboxamide is obtained. Obtained. Melting point 2 4 8—2 5 1 (hydrochloride) Example 1 5 7
  • Example 1 0.8 g of 2- (4-aminophenyl) -15- (3-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in 55 was added to Example 74.
  • the desired 2- (4-butylaminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide can be obtained by treating in the same manner as described above. 8 g were obtained. Melting point 2 28—2 3 IX) (Hydrochloride) Example 15 8
  • Example 15 2- (4-Aminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in Example 5 was obtained in the same manner as in Example 102. By treatment, the desired 2- (4-dimethylaminophenyl) -1- (3-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained.
  • 5- (4-Methoxyphenyl) 1-2- (4- (1-pyrrolidinyl) phenyl) imidazo-1-yl 4-carboxylic acid was treated in the same manner as in Example 1 to give 5- (4-methoxyphenyl).
  • 2- (4- (1-pyrrolidinyl) phenyl) 1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide is obtained.
  • test substance at dimethylsulfoxide id dissolved so as to 1 Omm, final concentration 10-5 and diluted with culture land - was 10 7 M.
  • D 10. G4.1 was used as the Th2 cell line.
  • D 10. G 4. 1 recognizes the antigen cona 1 b urn in the restricted I- Alpha kappa.
  • Inactivated fetal bovine serum was added to RPMI 1640 medium at 10%, and 2-mercaptoethanol was added to 50 M for use.
  • 6- to 12-week-old male C 3H / HeN mice are bled to death and the spleen is aseptically removed. Then, a spleen cell suspension was prepared. Mitomycin C was added to a final concentration of 40 // g / ml and incubated at 37T; for 30 minutes. Thereafter, the spleen cells were washed twice with the medium and used as antigen-presenting cells.
  • test substance was suspended in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per 10 g body weight.
  • HPMC hydroxypropylmethylcellulose
  • a physiological saline solution containing 10 ig of 0A and 1 mg of aluminum hydroxide gel was intraperitoneally administered to 7-week-old male BALBZc mice to actively sensitize.
  • 5 ⁇ g of OA was intradermally administered to the auricle to perform antigen challenge.
  • the thickness of the auricle before and after the antigen challenge and at 1 and 24 hours after the antigen challenge was measured with a dial thickness gauge, and the change in the thickness of the auricle was calculated by the following equation.
  • Thickness of the auricle after intradermal administration of antigen -Thickness of auricle before intradermal administration of antigen The test substance was orally administered daily for 3 days from 2 days before the antigen challenge to the day of the antigen challenge.
  • the effect of the compound of Example 1 on swelling of the pinna during the late phase is shown in FIG.
  • the compound of Example 1 significantly suppressed the late-stage edema mainly involving T cells and eosinophils at a dose of 1 Omg / kg.
  • test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution to a concentration of 0.1 ml per 10 g body weight.
  • HPMC hydroxypropylmethylcellulose
  • OA egg A albumin
  • aluminum hydroxide gel 0.5 ml of physiological saline was intraperitoneally administered to 7-week-old male B ALB-noc mice for active sensitization.
  • 5 g of OA was intradermally administered to the pinna, and antigen challenge was performed.
  • the test substance was orally administered every day for three days from the day before the antigen challenge to the day of the antigen challenge.
  • the mice were bled to death 12 hours after the antigen challenge, and the pinna was removed.
  • FIG. 2 shows the effects of the compounds of Example 79 and Example 99 on increasing the auricular EP0 activity.
  • the compound of Example 79 was 1 OmgZkg, and the compound of Example 99 significantly inhibited the increase in EP0 activity in the auricle from 3 mg kg.
  • test substance was suspended in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per body weight and used.
  • HPMC hydroxypropylmethylcellulose
  • test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per 10 g body weight.
  • HPMC hydroxypropylmethylcellulose
  • the total leukocyte count in the lavage fluid was measured with an automatic hemocytometer.
  • a site spin specimen of nasal washings was prepared, and after Diff-Quick staining, the ratio of eosinophils was calculated by microscopy.
  • the eosinophil count in BALF was calculated from the total leukocyte count and the ratio of eosinophils.
  • test substance was orally administered every day for 8 days from the 29th to 36th days.
  • the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof inhibit the production of IL-4 and IL-5 produced from Th2 cells, and produce atopic dermatitis, bronchial asthma, Effective as a preventive and remedy for allergic diseases such as rhinitis rhinitis

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Abstract

Cette invention a trait à de nouveaux dérivés d'imidazole correspondant à la formule générale (I) ou à leurs sels acceptables du point de vue pharmaceutique. Dans cette formule, R1 représente un hydrogène, un alkyle à substitution optique ou analogue, R2 représente un hydrogène un alkyle à substitution optique ou analogue, R3 représente un hétéroaryle à substitution optique et R4 un cycloalkyle à substitution optique, un phényle à substitution optique ou analogue, à condition que, lorsque R1 représente un hydrogène et R2 un phényle ou un phényle à substitution halogéno, alkyle ou alcoxy de faibles poids moléculaires, R3 représente un benzothiazolyle ou un benzothiazolyle à substitution phényle. Ces dérivés et leurs sels, qui font preuve d'une action inhibitrice à l'encontre de la production de cellules Th2 de forme IL-4 et IL-5, sont, par le fait, utilisés en tant qu'agents prophylactiques et thérapeutiques s'agissant de maladies allergiques, notamment l'eczéma atopique, l'asthme bronchique et la rhinite allergique.
PCT/JP1998/005930 1997-12-26 1998-12-24 Nouveaux derives d'imidazole Ceased WO1999033827A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078758A1 (fr) * 1999-06-21 2000-12-28 Mitsubishi Pharma Corporation Nouveaux derives d'imidazole
WO2012007500A2 (fr) 2010-07-15 2012-01-19 Bayer Cropscience Ag Nouveaux composés hétérocycliques servant d'agents de lutte contre les nuisibles
US8618125B2 (en) 2011-01-14 2013-12-31 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
US9334242B2 (en) 2008-06-16 2016-05-10 Gtx, Inc. Compounds for treatment of cancer
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
US10865196B2 (en) 2008-06-16 2020-12-15 University Of Tennessee Research Foundation Compounds for treatment of cancer

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829198B2 (en) * 2007-10-31 2014-09-09 Proteotech Inc Compounds, compositions and methods for the treatment of beta-amyloid diseases and synucleinopathies
KR20080104147A (ko) * 2006-03-15 2008-12-01 4에스체 악티엔게젤샤프트 신규의 헤테로환 ＮＦ-κＢ 억제제

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6310767A (ja) * 1986-07-02 1988-01-18 Yoshitomi Pharmaceut Ind Ltd イミダゾ−ルカルボキサミド誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6310767A (ja) * 1986-07-02 1988-01-18 Yoshitomi Pharmaceut Ind Ltd イミダゾ−ルカルボキサミド誘導体

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078758A1 (fr) * 1999-06-21 2000-12-28 Mitsubishi Pharma Corporation Nouveaux derives d'imidazole
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
US9334242B2 (en) 2008-06-16 2016-05-10 Gtx, Inc. Compounds for treatment of cancer
US10301285B2 (en) 2008-06-16 2019-05-28 Gtx, Inc. Compounds for treatment of cancer
US10865196B2 (en) 2008-06-16 2020-12-15 University Of Tennessee Research Foundation Compounds for treatment of cancer
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
US11465987B2 (en) 2010-03-01 2022-10-11 Oncternal Therapeutics, Inc. Compounds for treatment of cancer
WO2012007500A2 (fr) 2010-07-15 2012-01-19 Bayer Cropscience Ag Nouveaux composés hétérocycliques servant d'agents de lutte contre les nuisibles
US8618125B2 (en) 2011-01-14 2013-12-31 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
US9408841B2 (en) 2011-01-14 2016-08-09 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
US9498473B2 (en) 2011-01-14 2016-11-22 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance

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