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WO2000078758A1 - Nouveaux derives d'imidazole - Google Patents

Nouveaux derives d'imidazole Download PDF

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Publication number
WO2000078758A1
WO2000078758A1 PCT/JP2000/004009 JP0004009W WO0078758A1 WO 2000078758 A1 WO2000078758 A1 WO 2000078758A1 JP 0004009 W JP0004009 W JP 0004009W WO 0078758 A1 WO0078758 A1 WO 0078758A1
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group
phenyl
raw material
synthesis example
material synthesis
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PCT/JP2000/004009
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English (en)
Japanese (ja)
Inventor
Syuji Ehara
Katsuya Yamamoto
Kunio Sugahara
Kei Sakata
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Mitsubishi Pharma Corporation
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Priority to AU52512/00A priority Critical patent/AU5251200A/en
Publication of WO2000078758A1 publication Critical patent/WO2000078758A1/fr

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    • 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
    • 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

Definitions

  • the present invention has an inhibitory effect on the production of interleukin-4 (hereinafter, IL-4) and interleukin 5 (hereinafter, IL-5) from evening eve 2 helper T cells (hereinafter abbreviated as Th2 cells).
  • IL-4 interleukin-4
  • IL-5 interleukin 5
  • Th2 cells evening eve 2 helper T cells
  • Th1 cells produce cytokins such as inulin-leukin 2 (hereinafter, IL_2) and interferon-I (hereafter, IFN- ⁇ ) and mainly regulate cell-mediated immunity.
  • Th2 cells produce cytokines such as IL-14, IL-5, and IL-1 leukin 10 (hereinafter IL-10), and mainly regulate humoral immunity.
  • the immune response is regulated by the balance between Th1 and Th2 cells, and IFN-y produced by Th1 cells promotes differentiation into Th1 cells and inhibits differentiation into Th2 cells .
  • IL-4 produced by Th2 cells promotes differentiation into Th2 cells and inhibits differentiation into Th1 cells.
  • Th2 cells are predominant in allergic diseases and systemic autoimmune diseases
  • Th 1 cells are predominant in organ-specific immunological diseases.
  • IL-4 acts on immunoglobulin E (IgE) such as class switching and differentiation into Th2 cells
  • IgE immunoglobulin E
  • IL-5 acts on eosinophils. It has been suggested that it is deeply involved in the pathogenesis of allergies in particular. In fact, high levels of IL-4 and IL-15 were shown in bronchoalveolar lavage fluid of asthmatic patients, and mRNAs of IL-4 and IL-5 were found in the rash of patients with arthritis dermatitis. Are reported to exist (Am. J. Respir. Cell MoI. Biol., Vol. 12, pp. 477-487, 1995, J. Immunol., Vol. 158, p. p. 3539-3544 and J. Exp. Med., Vol. 173, p. 775-778, 1991).
  • IL-14 or IL-5 is involved in the development of allergic disease in animal models of allergic disease.
  • 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 may be a useful antiallergic drug .
  • Japanese Patent Publication No. 7-537 16 describes a certain imidazole derivative having anti-inflammatory and analgesic effects, but inhibits the production of IL-4 and IL-5 from Th2 cells. No effect is described.
  • IPD-115T A recently developed subratose tosylate (IPD-115T) has an inhibitory effect on the specific production of IL-14 and IL-5 from Th2 cells, Clinical results have been reported to be effective against inflammation (Clinical Medicine, Vol. 8, No. 7, 19992). However, the inhibitory effect of IFD-1 11 1 on 11 ⁇ -4 and 11 ⁇ -5 is not so strong, and it shows the inhibitory effect of IL-14 and IL-5 production in clinical fi It is not clear if they do.
  • steroids are widely used as therapeutic agents for allergic diseases and have shown high clinical effects.
  • Steroids produce IL-5 in a wide range of actions It has Pfl harmful effects, and its inhibitory effect on IL-15 production is considered to be a mechanism of eosinophilic inflammation suppression.
  • Compounds that have a specific inhibitory effect on the production of IL-14 and IL-5 can improve the bias toward Th2 cells in allergic patients and suppress eosinophilic inflammation, and It is expected to be a useful drug for the prevention and treatment of allergic diseases such as atherosclerotic dermatitis, bronchial asthma, and allergic flare, which have relatively few side effects.
  • the purpose 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 allergic diseases, among the cytokines produced from Th2 cells. is there.
  • the present inventors have conducted intensive studies in view of the above-mentioned pathological conditions.
  • the novel imidazole compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof have excellent IL-4 and IL
  • the present inventors have found that they have a production inhibitory activity of 5, and are useful as preventive and therapeutic agents for allergic diseases, and have completed the present invention.
  • the present invention is as follows.
  • R 1 represents an optionally substituted phenyl group or an optionally substituted heteroaryl group
  • R 2 is a cyano group, a substituted alkyl group, a substituted or unsubstituted oxygen atom or a saturated 6 or 7 ring heterocycle containing 1 or 2 nitrogen atoms, which may contain a sulfur atom;
  • a monocyclic group, which may be substituted or may contain an oxygen atom or may contain a sulfur atom, may be the same or different and may contain 1 to 3 nitrogen atoms, and two saturated 6 or 7 members Subiro ring group consisting of a ring heteromonocycle, and formula (II)
  • R 1 is an optionally substituted phenyl or an optionally substituted heteroaryl group
  • R 2 is a cyano group, a substituted alkyl group, a saturated 6 or 7 H ring heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom, And formula (II)
  • n is an integer of 0 to 3
  • the alkyl chain part may be substituted.
  • the same or different groups selected from the group consisting of The imidazole derivative according to the above (1), which is a phenyl group substituted by one or two groups, or a pharmaceutically acceptable salt thereof.
  • R 1 is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group
  • R 2 is an ft-substituted alkyl group
  • n is an integer of 0 to 3
  • the alkyl chain portion may be substituted.
  • R 1 is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group
  • R 2 is a trifluoromethyl group, a morpholino group, and a morpholinomethyl group.
  • 41- (dimethylaminomethyl) bipyridine-1-yl group and formula (III)
  • n is an integer of 0 to 3.
  • the above-mentioned (1) is a phenyl group substituted by one group selected from the group consisting of groups represented by d) The imidazole 'derivative described in d or a pharmaceutically acceptable salt thereof.
  • R 1 is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group
  • R 2 may be a masked oxygen atom or
  • An antiallergic agent comprising the imidazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (7).
  • Figure 1 shows the auricular region of the compound in Examples 1 and 16 in the late phase (24 hours after antigen challenge) in the ovalbumin (OA) -induced mouse biphasic ear edema model of Experimental Example 2. It is the figure which showed the effect
  • FIG. 2 shows the effect of Example 1 on the number of eosinophils in BALF in the mouse OA-induced airway inflammation model of Experimental Example 3. Each value represents the mean ⁇ standard error. (The number of cases is 9-10). The significance test was performed using a t-test. * Indicates that a significant difference from the control was observed at P ⁇ 0.5.
  • FIG. 3 shows I ⁇ I showing the effect on the swelling of the pinna in the late phase (24 hours after antigen challenge) of the 0A-induced mouse biphasic ear edema model of Surprising Example 5.
  • ⁇ indicates the hydrocortisone butyrate-applied group
  • Hata indicates the combination group of hydrocortisone butyrate (applied) and the compound of Example 16 (10 mg / kg, oral administration), and indicates the group applied betamethasone valerate.
  • Each value represents the mean soil standard error. (The number of cases is 6-12).
  • the significant difference test was performed using a two-way analysis of variance (vs. each group).
  • the substituent of the “phenyl group which may be substituted” of R 1 includes a halogen atom (fluorine, chlorine, bromine, iodine); a lower alkyl group (methyl group, ethyl group, propyl group, Represents an IS chain or a branched alkyl group having 1 to 6 carbon atoms such as an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a hexyl group; a haloalkyl group ( Halogen (fluorine, chlorine, bromine, iodine) such as chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, dichloroethyl group, dibromoethyl group, pentafluor
  • haloalkyl group which is H-substituted into a branched alkyl group having 1 to 6 carbon atoms); a hydroxyalkyl group (a hydroxymethyl group, a hydroxyxethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxybutyl group) , Hydroxyisobutyl, hydroxypentyl, etc.
  • a halogen atom- a fluorine atom, a chlorine atom-, a santan atom atom, Iodine atom
  • the “optionally substituted phenyl group” may be substituted by one or two substituents, which may be the same or different.
  • the substituent of the "optionally substituted heteroaryl group" for R 1 has the same meaning as the substituent of the "optionally substituted phenyl group", and is substituted by one or two substituents. And the substituents may be the same or different.
  • Preferred substitutions include a lower alkyl group, a halogen atom (a fluorine atom, a chlorine atom, a nitrogen atom, an iodine atom) and the like.
  • heteroaryl of the "optionally substituted heteroaryl group” means pyridine or thiophene.
  • a substituent of the phenyl group in R 2 ⁇ a saturated 6- or 7-membered heterocyclic ring containing 1 or 2 nitrogen atoms which may be substituted and which may contain an oxygen atom or a sulfur atom
  • the substituent of the “unit group” may be a lower alkyl group (such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a hexyl group).
  • haloalkyl group chloromethyl group, Halogen (fluorine, chlorine, bromine, iodine) such as lomomethyl group, fluoromethyl group, trifluoromethyl group, dichloroethyl group, dibromoethyl group, penfluorofluorethyl group, chlorobutyl building group, dichlorobutyl group, etc.
  • a hydroxyalkyl group (a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxybutyl group, a hydroxyalkyl group).
  • a monoalkylamino group (methylamino group, ethylamino group, propylamino group
  • a alkyl group such as a butylamino group represents a linear or branched monoalkylamino group having 1 to 6 carbon atoms, which is a monoalkylamino group; a dialkylamino group (a dimethylamino group, a cetylamino grave, a dibutyl amino group, a diis
  • An aminoalkyl group an aminoalkyl group in which the alkyl portion such as an aminomethyl group, an aminoethyl group, an aminobutyl group, or an aminobutyl group is a linear or branched alkyl group having 1 to 6 carbon atoms
  • Monoalkylaminoalkyl tomb alkyl group on nitrogen such as methylaminomethyl group, methylaminoethyl group, methylaminopropyl group, methylaminoethyl group, etc.
  • a saturated 6- or 7-membered heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom is one or four substituents. And the substituents may be the same or different.
  • Preferred substituents include a lower alkyl group, a hydroxyalkyl group, a saturated alkyl group containing one or two nitrogen atoms which may be substituted or may contain an oxygen atom or a sulfur atom. And a 6- or 7-membered heterocyclic monocyclic group, a dialkylaminoalkyl group, an acyloxyalkyl group and the like.
  • Contains an oxygen or sulfur atom in the ⁇ saturated 6- or 7-membered heterocyclic monocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom '' Saturated 6- or 7-membered double-stranded monocyclic ring containing 1 to 2 nitrogen atoms may be morpholine, bipyridine, biperazine, homobiberazine, homobiperidine, thiomorpholine, etc. Is shown. Preferred are morpholine and viridine.
  • the alkyl group of the “g-substituted alkyl group” as a substituent of the phenyl group in R 2 is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group And isopropyl, butyl, isobutyl, tert-butyl, ventil, isopentyl, hexyl, isohexyl and the like, preferably an alkyl group having 1 to 3 carbon atoms.
  • substituent of the “substituted alkyl group” examples include a halogen atom (fluorine, chlorine, bromine, and iodine); a hydroxyl group; and a straight-chain or branched carbon atom such as an acyloxy group (acetyloxy group, propionyloxy group).
  • Lower alkoxy group (linear or branched carbon number such as methoxy group, ethoxy, propyloxy group, isopropyloxy group, butoxy group, etc.), which represents 2 to 6 aliphatic acyloxy and benzoyloxy groups; 1 to 6 alkoxy groups); haloalkoxy groups (chloromethoxy group, bromomethoxy group, fluoromethoxy group, trifluoromethoxy group, dichloroethoxy group, dibromoethoxy group, penoxyfluorethoxy group, chloropropyloxy group, dichloromethoxy group)
  • Straight-chain or branched lower alcohol having 1 to 6 carbon atoms such as butoxy group
  • Xyl group represents a haloalkoxy group in which a halogen atom (fluorine, chlorine, bromine, iodine) is substituted; alkylthio group (methylthio group, ethylthio group, propylthio group, iso
  • a dialkylamino group which is a alkyl group); a saturated 6- or 7-ring heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom (Substituents are as defined above, and represent morpholino group, 4-methylpiperidino group, 4-dimethylaminobiperidine-11-yl, etc.); acylamino group (acetylamino group, propionylamino group, etc.) A straight-chain or branched-chain aliphatic acylamino group having 2 to 6 carbon atoms and a benzoylamino group; a carboxyl group; an alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, a proviroxycarbonyl group, Alkoxycarbonyl wherein the alkoxy moiety such as a butoxycarbonyl group is a linear or branched alkoxy group having 1 to 6 carbon
  • a halogen atom, a hydroxyl group, a lower alkoxy group, an acyloxy group, an amino group, a dialkylamino group, and 1 to 2 which may be substituted and may contain an oxygen atom or a sulfur atom And a saturated 6- or 7-membered heterocyclic monocyclic group containing a nitrogen atom, a fluorinated ethyl group and the like, and more preferably a halogen atom, a hydroxyl group and a lower alkoxy group.
  • a “substituted alkyl group” may be substituted with one to three substituents, which may be different or different.
  • substituted alkyl groups include trifluoromethyl, morpholinomethyl, aminomethyl, dimethylaminomethyl, dimethylaminoethyl, hydroxymethyl, hydroxyethyl and the like.
  • the substituent of the alkyl chain portion of the group represented by the formula (II) or the formula (III) includes a substituent of “substituted alkyl group” and a lower alkyl group (methyl group).
  • Straight- or branched-chain alkyl groups having 1 to 6 carbon atoms such as, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, isopentyl, hexyl, etc. Is shown).
  • the alkyl chain portion may be substituted by one or two substituents, and the substituents may be the same or different.
  • the carbon number of the alkoxy moiety of the group represented by the formulas (II) and (II I) is an integer of 1 to 4, and the group represented by the formulas (II) and (III) is 2-methoxy. Ethoxy groups,
  • a 2-methoxyethoxy group preferably, a 2-methoxyethoxy group, a 2-ethoxyethoxy group, a 2-isopropoxyethoxy group, a 4-methoxybutoxy group, a 3-methoxybutoxy group
  • Examples include a methoxypropoxy group, a 2- (2-methoxyethoxy) ethoxy group, and a 2- (2- (2-methoxyethoxy) ethoxydiethoxy) ethoxy group, and more preferably a 2-methoxyethoxy group.
  • the spiro ring of the “saturated 6- or 7-membered heterocyclic monocyclic spiro ring group” includes 4,8- (or 4,9-1) diazasbiro [5,5] indene, 1,4,9-1 (or 1,4,8-) Triazaspiro [5,5] indecan, 1- (2—, 3—, or 5—) Oxa-1,4,8 diazaspiro [5,5] indecan, 1— (2—, 3 —, Or 5—) Oxa-1,4,9-Diazaspiro [5,5] indecane, 1-1 (2—, 3—, or 41) Thia 5,9, Diazaspiro [5,5] indecan, 1-11 (2—, 3—, or 5—) Chia 4,9—Diazabiro [
  • the spiro ring group may be substituted by one or two substituents, and the substituents may be the same or different.
  • substituents examples include lower alkyl (methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, A linear or branched alkyl group having 1 to 6 carbon atoms such as a pentyl group and a hexyl group), oxo and the like, and preferably methyl and oxo.
  • Preferred examples of the "ring” include 4-methyl-1-oxa-1,4,9-diazsubiro [5,5] indecan, 1-oxa-4,9-diazsubiro [5,5] indecan, 1-oxa-3-oxo 1,4,9 diazaspiro [5,5] indecan, 2,3-dioxo-1,4,9-triazaspiro [5,5] indecan, 1,4-dimethyl-1,4,9-triazaspiro [5,5] indecan 1,4,9-triazaspiro [5,5] pandecane, 4-methyl-1-oxa-1,4,8-diazaspone [5,5] pandecane, 4-oxo-1-chia-5,9-diazaspir
  • the pharmaceutically acceptable salts of compound (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, propionic acid, Salts with organic acids such as 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 Can be Also, salts with dehydrates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, and salts with organic bases such as triethylamine and pyridine may be mentioned. I can do it.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof contains an asymmetric carbon cable, it can be obtained in the form of a racemic mixture or an optically active substance. Can be separated into each optically active substance.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof further has an additional asymmetric carbon atom, the compound may be used as a diastereomer mixture or as a single substance. — Can also exist as diastereomers, and these can also be separated from each other by the ⁇ -method known per se.
  • the compound (I) of the present invention or a salt thereof which is refreshingly acceptable can exhibit polymorphism, and can exist as more than one tautomer.
  • the present invention includes any of the above-mentioned isomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof.
  • 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; azide group; N-hydroxybenzotriazolyl group; p-ditrophenyl Ethoxy group; p-chloro phenyloxy group; alkoxy group such as methoxy group, ethoxy group; acetyl group such as acetyloxy group, bivaloyloxy group; isobutyloxycarbonyloxy group; methoxycarbonyloxy group; ethoxycarponyl And a hydroxy group.
  • the compound represented by the general formula (IV) is reacted with thionyl chloride, isobutyl carbonate, methyl carbonate, ethyl carbonate, or the like in an inert solvent according to a conventional method, thereby obtaining a reaction during the reaction.
  • the compound (I) is produced by reacting with 2-aminothiazole in the presence or absence of a salt tomb, preferably in the presence of a base, in an inert organic solvent after conversion into the compound (V). (Steps 1 and 2).
  • the compound represented by the general formula (IV) can be converted into a reactive derivative thereof without using a suitable condensing agent or the like in the presence or absence of 2-aminothiazole and a base.
  • the compound (I) can also be produced by reacting in an inert solvent, preferably in the presence of a base (step 3).
  • the base used in the method of the present invention includes pyridine, picoline, lutidin, collidine, N-methylbiveridine, N-methylbiopenidine, N-methylmorpholine, N, N-dimethylaminoviridine, triethylamine And diisoprovirethylamine, potassium carbonate, sodium carbonate and the like, and preferred are viridin, 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 react, and is preferably ether, benzene, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, Examples 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 ranging from ⁇ 30 ° C. to a temperature corresponding to the reflux of the solvent used, preferably from room temperature to a temperature corresponding to the reflux of the solvent used, particularly preferably at a temperature corresponding to the reflux of the solvent used. Is advantageous.
  • the reaction is carried out for 1 to 30 hours, preferably for 1 to 3 hours.
  • condensing agent examples include N, N'-dicyclohexylcarpoimide, 2-chloro-1,3-dimethylimidazolinium chloride, 1,1-carbonyldiimidazole, and 1-hydroxyl.
  • Benzotriazole 1-hydroxy-7-azabenzotriazole, 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride, benzotriazoyl-1-yloxytris (dimethylamino) phosphonium It is preferable to use hexafluorophosphate, 4,4, dichloro-1-methylbenzhydrol or the like.
  • a compound having a lower alkoxy group or an aralkyloxy group as a substituent may be a compound having a hydroxy group corresponding to the lower alkyl alcohol or phenylene compound corresponding to the general formula (I).
  • it can be produced by reacting a lower alkyl alcohol in the presence of triphenylphosphine and acetyl dicarboxylate.
  • the corresponding substituent of the general formula (I) may be an acyloxy group or an acyloxyalkyl group.
  • a compound which is 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 penzyloxy group, a benzyloxyalkyl group,
  • a compound that is a benzylamino group or a benzylaminoalkyl group is hydrogenated in the presence of a catalyst such as palladium. It can also be prepared by adding, reacting with hydrobromic acid in a solvent such as acetic acid, or treating in thiodisole and trifluoroacetic acid.
  • a compound having an amino group or an aminoalkyl group as a substituent may be a compound in which the corresponding substituent of the general formula (I) is a nitro group or a nitroalkyl group.
  • Reduction with an acid such as 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 (II) chloride hexahydrate Can be manufactured. It can also be produced by reducing a compound of the general formula (I) in which the corresponding substituent is a cyano group or an amide group using a reducing agent such as lithium aluminum hydride.
  • a compound having a dialkylamino group or a monoalkylamino group as a substituent can be obtained by alkylating a compound in which the corresponding substituent of the general formula (I) is an amino group. Can also be obtained.
  • the alkylation is carried out by using an alkyl halide, an alkyl paratoluenesulfonate or the like and, if necessary, a base such as triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate or the like.
  • the method includes, for example, so-called reductive alkylation or the like, in which formalin or an alkyl aldehyde is allowed to react with a metal hydride complex compound such as sodium borohydride or sodium borohydride, or is subjected to catalytic reduction.
  • a metal hydride complex compound such as sodium borohydride or sodium borohydride
  • the compound of the general formula (IV) used as a starting material in the present invention is obtained, for example, by converting the compound of the general formula (VIII) obtained by the following methods 1 to 3 under alkaline or acidic conditions. It can be produced by hydrolysis.
  • the compound represented by the general formula (VI) By reacting the compound represented by the general formula (VI) with the compound represented by the general formula (VII), the compound of the general formula (VIII) can be produced (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 ranging from ⁇ 30 ° 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 reaction is carried out for 1 to 30 hours, preferably for 10 to 15 hours.
  • R i and R 2 have the same meanings as described above, and R 3 represents a lower alkyl group.
  • the compound represented by the general formula (IX) is an ammonium salt of a lower alkane carboxylic acid ammonium salt such as ammonium acetate or ammonium formate or an ammonium salt of an inorganic acid such as ammonium carbonate.
  • the compound represented by the general formula (VIII) is produced by reacting the compound represented by the general formula (X) with an acidic solution of lower carboxylic acid of formic acid, acetic acid, and propionic acid II. (Step 5).
  • reaction solvent for example, toluene, benzene, xylene, pyridine, vicolin, dioxane, hexane, petroleum ether, acetic acid and the like can be used.
  • the reaction may be performed without a solvent.
  • Reaction of 'interest carried out at the reflux temperature of a solvent used from 0 ° C is from 1 to 30 hours, preferably for 12 to 15 hours.
  • R 1 R 2 has the same meaning as described above, and R 3 is 7 J; a lower alkyl group.
  • reaction solvent for example, acetic acid, toluene, pyridine, ethyl acetate and the like can be used.
  • the reaction is o. It is preferable to carry out at a temperature equivalent to the reflux of the solvent used from c. However, it is particularly preferable to carry out the reaction at a temperature corresponding to the reflux of the solvent used.
  • the reaction is carried out for 1 to 30 hours, preferably for 12 to 15 hours.
  • the pharmaceutically acceptable salts of compound (I) of the present invention include inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, etc.).
  • 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.
  • 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 can be treated with an organic base by treating with triethylamine, pyridine, etc. Can also be used as a salt. Further, when the obtained crystals of the compound of the present invention are anhydrous, the compound of the present invention can be converted into a hydrate or a solvate by treating the compound with water, a hydrated 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 and a column chromatography method.
  • a conventional method such as a recrystallization method and a column chromatography method.
  • the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column packed with an optically active carrier. Can be done.
  • 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 a recrystallization method, a column chromatography method, or the like.
  • the novel imidazole derivative of the present invention and a pharmaceutically acceptable salt thereof are used as a medicament
  • the compound of the present invention is converted into a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, Pharmaceutical compositions or preparations obtained by mixing with emulsifiers, diluents, solubilizing agents, etc.
  • tablettes pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, Solutions, injections, drops, ointments, tablets Starches, liniments, lotions, blasters, cataplasms, eye drops, ointments, suppositories, compresses, inhalants, sprays, aerosols, liniments, nasal drops, creams , Tapes, patches, etc.
  • the pharmaceutical composition can be formulated according to a usual method.
  • excipients lactose, D-mannitol, starch, crystalline cellulose, etc.
  • binders hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylidolidone, etc.
  • disintegrants carboxymethyl Lubricants (magnesium stearate, talc, etc.)
  • coating agents hydroxylpropyl methylcellulose, sucrose, etc.
  • bases polyethylene glycol, hard fat, etc.
  • a solubilizer or solubilizing agent that can constitute an aqueous or ready-to-use injection (such as swallow water for injection, saline, propylene glycol, etc.), and pH adjustment
  • Pharmaceutical ingredients such as agents (inorganic acids, organic acids or inorganic bases) and stabilizers are used.
  • the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof inhibit the production of IL-14 and IL-15 produced from Th2 cells, and It is effective in preventing and / or treating allergic diseases such as bronchial asthma and allergic rhinitis.
  • the dose of Compound (I) to the treated patient may vary depending on the type and degree of the disease, the compound to be administered, the administration route, the age, sex, and weight of the patient, etc., but in general, the daily dose for adults is The dose is about 1.0 to 100 mg for perro-dose and about 1.0 to 500 mg for parenteral administration.
  • the compound (I) or a pharmaceutically acceptable salt thereof according to the present invention can be used in a preparation containing a conventionally used steroid (hydrocortisone butyrate, dexamethasone acetate, methylprednisolone acetate, etc.) (preferably, for external use)
  • a conventionally used steroid hydrocortisone butyrate, dexamethasone acetate, methylprednisolone acetate, etc.
  • an anti-allergic agent When used together with an anti-allergic agent, a stronger anti-allergic effect can be brought about, and the effect of preventing or treating allergies or exerting a therapeutic effect can be more effectively exerted.
  • a steroid agent hydrocortisone butyrate, dexamethasone acetate, methylprednisolone acetate, etc.
  • Raw material synthesis example 14 Raw material synthesis example In the same manner as in Example 10, 4- (4-methylbiperidine-11-yl) pen V nitrile 15 g of the desired 4- (4-methylbiperidine-11-yl) benzaldehyde was converted into an oily substance from 15 g. 3.8 g was obtained and used for the next raw material synthesis example 15 without purification.
  • Raw material synthesis example 1 In the same manner as in Raw Material Synthesis Example 9, the desired 4- (4,4-dimethylbiperidin-11-yl) benzoate was obtained from 23 g of 4-fluorobenzobenzonitrile and 28.5 g of 4,4-dimethylbiveridine hydrochloride. 34 ⁇ 7 g of nitrile were obtained. Melting point 1 15—117 ° C.
  • Raw material synthesis example 18 Raw material synthesis example In the same manner as in 1 °, the desired 4- (4,4-dimethylbiperidine-1-yl) was obtained from 18 g of 4- (4,4-dimethylbiperidine-11-yl) benzonitrile. 13.1 lg of benzaldehyde was obtained as an oil. Melting point 48 ° C.
  • Raw material synthesis example 21 In the same manner as in Raw Material Synthesis Example 9, 27 g of 4-fluorobenzonitrile and 41 g of 4- (dimethylaminomethyl) biveridine are obtained from 32 g of 4- (dimethylaminomethyl) piperidine. 35.5 g of benzonitrile. Melting point 841-86. C.
  • Raw material synthesis example 29 In the same manner as in Raw Material Synthesis Example 9, 39 g of 4-fluorene benzonitrile and 41- [41- (dimethylamino) biberidin-1-yl] benzonitrile as an oily substance were obtained from 41-dimethylaminobiperidine 41 as an oil. 14 g were obtained.
  • Raw material synthesis example 4 1 In the same manner as in Raw Material Synthesis Example 2, 3- (4-fluorophenyl) -1-hydroxyminoh 3-oxopropionic acid ethyl ester 15.0 g, 4-cyanobenzaldehyde 12.3 g and ammonium acetate 48.4 From 5-g, 5- (4-fluorophenyl) 1-2- (4-cyanophenyl) imidazole-14-ethyl ribonate 3.lg was obtained. Melting point 208—2 11 ° C.
  • Example of raw material synthesis 65 In the same manner as in Raw Material Synthesis Example 9, 50 g of 4-fluorobenzonitrile and 39.6 g of hexamethylenimine were used to obtain 24.5 g of the target 4- (homobiberidine-11-yl) benzonitrile. . Melting point 62. C.
  • Raw material synthesis example 66 In the same manner as in Raw Material Synthesis Example 10, 45 g of target 4- (homopiperidine-11-yl) benzaldehyde was obtained as an oil from 54 g of 4- (homobiberidine-11-yl) benzonitrile as an oil. This was used in the next raw material synthesis example 67 without purification.
  • Raw material synthesis example 8 9 3- (4-fluorophenyl) -1-hydroxyimino-3-oxopropionic acid ethyl ester 15.0 g in the same manner as in Raw Material Synthesis Example 2; 4- (2-methoxhetoxy) obtained in Raw Material Synthesis Example 47 Penzaldehyde 16.9 g and ammonium acetate acetate 48.3 g from 5- (4-fluorophenyl) _2- [4- (2-methoxyethoxy) phenyl] imidazole-1-ethyl carboxylate 7. I got 2. 183-184 ° C.
  • Lithium aluminum hydride 5 To a suspension of 70 mg of THF in 80 ml of THF 4-acetamide methyl benzoate 3.1: A 20 ml solution was added under ice cooling. After stirring the reaction solution at room temperature for 1.5 hours, 7 ml of a saturated aqueous sodium sulfate solution was added at 10 ° C, and the mixture was stirred at room temperature for 1 hour. The precipitate was separated by filtration and the solvent was distilled off to obtain 2.8 g of the target N- (4-hydroxymethylphenylmethyl) acetamide as a color solid.
  • Raw material synthesis example 104 In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimino-3-oxoethyl ester, 4- [4- (4-methylbiperazin-1-yl) piperidine-1 1 5- (4-phenylphenyl) 1-2- ⁇ 4-(4- (4-methylbiperazine-111) bibenzyl-1- (1-yl) phenyl) from benzaldehyde and ammonium acetate Imidazo 1-fluoroethyl ester is obtained.
  • N— (4-chloromethylphenylmethyl) acetamide 20 Og and 9.9 g of dimethylamine hydrochloride are dissolved in 19 ml of acetonitrile, and 28 g of potassium carbonate is further added. Heated to reflux. After filtering off the insoluble solid, the solvent was distilled off to obtain 28.4 g of the desired N- [4- (dimethylaminomethyl) phenylmethyl] acetamide as an oily substance.
  • N- [4-1 (dimethylaminomethyl) phenylmethyl] acetamide 22 g was dissolved in 100 ml of 4N hydrochloric acid, and the mixture was heated under reflux for 3 hours and 40 minutes. The solvent was distilled off, and the crystals were collected by filtration from ethyl acetate. The obtained crystals were dissolved in 4 Oml of water, potassium carbonate was added until saturation, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain 11.7 g of the desired 4- (dimethylaminomethyl) phenylmethylamine. Mp 38-39. C
  • Raw material synthesis example 124 Ingredients ⁇ In the same manner as in Example 9, 4-fluorene benzonitrile 10 g, 4-methyl-11-oxa-4,9,1 diazasbylo [5,5-dedecane 15.7 g to 4 4-Methyl-1-oxer 4,9-dazaspiro [5,5] indecan-9-yl) benzonitrile 9.7 g was obtained. 105-109 ° C.
  • Lithium aluminum hydride (2 g) is suspended in THF (40 ml), and cooled under ice-cooling. A solution of 100 ml of 2 11 was added dropwise. After stirring at room temperature for 2 hours and 40 minutes, a saturated aqueous sodium sulfate solution was added little by little under ice-cooling, and the precipitated solid was separated by filtration and washed with a black hole form.
  • monohydrochloride was obtained by adding hydrochloric acid. 233-238 (decomposition).
  • Raw material synthesis example 5 (4-Fluorophenyl) -12- (4-trifluoromethylphenyl) imidazole-1-4 rubonic acid 3.0 g in 6 mL of methylene chloride Suspended. 0.9 g of 2-aminothiazole and 2.4 ml of triethylamine were added to the suspension solution. A solution of 2.lg of 1,2-dimethylimidazolinium chloride in 20 ml of methylene chloride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, saturated aqueous sodium hydrogen carbonate was added, and the organic layer was extracted with ethyl acetate.
  • monohydrochloride was obtained by adding hydrochloric acid. Melting point 75-80 ° C;
  • dihydrochloride was obtained by adding hydrochloric acid. Melting point 260 or less.
  • Raw material synthesis example 105 (4-chlorophenyl) obtained in 05—2— ⁇ 4- [4- (4-methylbiverazine-1-yl) piberidine-1-1-yl] phenyl ⁇ imida
  • sol-4-carboxylic acid 2N hydrogen chloride-ether solution, DMF, thionyl chloride, and 2-aminothiazole in the same manner as in Example 1, 5- (4-chlorophenol) was obtained.
  • Example 3 2- (4-Acetoxymethylphenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from Example 9 4-Carboxamide was hydrolyzed with an aqueous sodium hydroxide solution. By decomposition, the desired 5- (4-chlorophenyl) -12- (4-hydroxymethylphenyl) -1-N- (2-thiazolyl) Midazolu-41-carboxamide is obtained,
  • Example 41 2- [4-1- (2-acetoxyl) phenyl] -15- (4-chlorophenyl) 1N- (2-thiazolyl) obtained in Example 41 in the same manner as in Example 40 From the imidazole 4-carboxamide, the desired 5- (4-chlorophenyl) 1-2 [4- (2-Hydroxityl) phenyl] 1-N- (2-thiazolyl) imidazo 1-ru 41-carboxamide is obtained.
  • test substance was dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) at 1 Ommo 1 / Dissolved so that L, and to a final concentration of 10-5 one 10- 7 MO L Bruno L and diluted with RPMI 1640 medium (Nacalai Tesque Inc.).
  • D 10. G4.1 (from ATCC) was used as the Th2 cell line.
  • D 10.G 4.1 recognizes cona 1 bum in as an antigen in I ⁇ ⁇ restriction.
  • Inactivated fetal bovine serum (Gibco BRL) was added to RPMI 1640 medium at 10%, and 2-mercaptophenol (Wako Pure Chemical Industries, Ltd.) was added to 50 ⁇ mol ZL. .
  • a 6-12 week old male C3H / HeN mouse (Nippon Charls River Co., Ltd.) was bled to death and the spleen was aseptically removed to prepare a spleen cell suspension.
  • Mitomycin C (Sigma) was added to a final concentration of 40 g / mL and incubated at 37 ° C for 30 minutes. Thereafter, the spleen cells were washed twice with the medium and used as antigen-presenting cells.
  • the concentrations of IL-14 and IL-15 in the supernatant were determined by sandwich ELISA (anti-mouse IL-14 antibody, anti-mouse IL-4 antibody, anti-mouse IL-4 antibody, biotin-labeled anti-mouse IL-5 antibody, anti-mouse IL-5 antibody, biotin-labeled anti-mouse IL-5 antibody).
  • sandwich ELISA anti-mouse IL-14 antibody, anti-mouse IL-4 antibody, anti-mouse IL-4 antibody, biotin-labeled anti-mouse IL-5 antibody, anti-mouse IL-5 antibody, biotin-labeled anti-mouse IL-5 antibody.
  • POD-labeled streptavidin were purchased from Pharmingen, and Peroxidase Coloring Kit 0 was purchased from Sumitomo Beicrypt Co., Ltd.).
  • test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 mL per 10 g of body weight.
  • HPMC hydroxypropylmethylcellulose
  • OA ova lbumi n, Sigma, Lot 37 H70 10
  • L-S'L Lot 74502 22
  • lmg physiological saline (( (Otsuka Pharmaceutical Factory) 0.5 mL was intraperitoneally administered to a 7-week-old male BALB mouse (l-Challus Riva Co., Ltd.) for active sensitization.
  • OA5 was intradermally administered to the auricle area to perform antigen challenge.
  • the thickness of the pinna at 1 and 24 hours before and after antigen challenge is measured with a dial thickness gauge (Peacock, G-1A).
  • the change in the thickness of the pinna was calculated by the following equation.
  • FIG. 1 shows the effects of the compounds of Examples 1 and 16 on swelling of the pinna in the late phase (24 hours after antigen challenge). Each value represents the average soil standard error (the number of examples is 12 to 16). The significance test was performed using the multiple comparison of the dangling.
  • Example 1 at a dose of 1 mgZkg or more, and in Example 16 at a dose of 3 mg / kg, late-phase edema mainly involving T cells and eosinophils was significantly suppressed.
  • test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution to a concentration of 0.1 mL per 10 g of rest.
  • HPMC hydroxypropylmethylcellulose
  • mice Seven-week-old male B ALBZc mice were actively sensitized on the 1st and 15th days by intraperitoneal administration of 0.5 mL of saline containing 10 ⁇ g of OA and 1 mg of aluminum hydroxide gel. On days 25, 29, and 33, 5 ⁇ L of a physiological saline solution containing OA l ⁇ g was administered into the respiratory tract. 24 hours after the last intratracheal administration, bronchoalveolar lavage was performed, and bronchoalveolar lavage fluid (BALF) was collected. The total white blood cell count in BALF was measured with an automatic blood cell counter (Nihon Kohden Kogyo Co., Ltd.).
  • BALF cytosbin (Shandon, Cytospin3) specimens were prepared, stained with Diff-Quick (International Reagents Co., Ltd.), and the eosinophil ratio was calculated by microscopy. .
  • Total white blood cell count The number of eosinophils in BALF was calculated from the ratio of eosinophils and eosinophils.
  • test substance was orally administered every day for 10 EI from day 24 to day 33.
  • Example 1 The effect of Example 1 on the number of eosinophils in BALF is shown in FIG. Each value represents the standard error of the mean. (The number of cases is 9-10). The significance test was performed using the t-test.
  • Example 1 Indicates that a significant difference from the control was observed at P ⁇ 0.5.
  • Example 1 at 3 mg / k, the number of eosinophils having a B ALF width was significantly inhibited.
  • test substance was used in a 0.5% hydroxypropyl methylcellulose (HPMC) solution in a turbid state so as to be 0.1 mL per 10 g body weight.
  • HPMC hydroxypropyl methylcellulose
  • mice Seven-week-old male B ALBZc mice were actively sensitized on day 1 and day 15 by intraperitoneal administration of 0.5 mL of saline containing 5 g of OA and 1 mg of aluminum hydroxide gel. From 22, mice were instilled with 20 mL of 2 mg ZmL OA solution every other day for a total of eight times. After the last nasal drip on day 36, the number of sneezes for 10 minutes was measured.
  • the airway of the mouse was incised under deep anesthesia, a catheter was inserted into the subcutaneous space side, and 0.5% BSA (bovi ne se rum al bumi n, Wako Pure Chemical Industries, Ltd.)
  • the nasal cavity was washed with 3 mL of a phosphate buffer solution.
  • the total leukocyte count in the lavage fluid was measured with an automatic hemocytometer.
  • a site spin specimen of the nasal washing was prepared, and after Diff-Quick staining, the ratio of eosinophils was determined by microscopy. From the total ⁇ blood cell count and the ratio of eosinophils, the number of eosinophils in the nasal washings was calculated.
  • the test substance was orally administered for 8 consecutive days from the 29th to the 36th day.
  • 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
  • Hydrate Butyrate Oral cortisone medium class steroid topical drug, Sigma, Lot 40H0863
  • betamethasone valerate strong class steroid topical drug, Sigma, L ot 9 3 H 0330
  • ethanol Woodo Pure Chemical Co., Ltd.
  • An A-induced mouse biphasic ear edema model was prepared in the same manner as in Experimental Example 2 and R1.
  • the test substance was administered orally (dose 10 mg / kg) once a day for 3 times from the day before the antigen challenge to the day of the antigen challenge.
  • the topical steroid preparation was applied to the auricle area 1 bl at a time, once a day for 3 days.
  • the group to which only the solvent of each test substance was administered was set as a positive control group, and the group to which only a physiological saline solution was challenged instead of the antigen solution containing OA was set as a negative control group.
  • Fig. 3 shows the effect of ffl on the auricular swelling in the late phase (24 hours after antigen challenge). Each value represents the standard error of the mean. (The number of cases is 6 to 12). The significance test was performed using a two-way analysis of variance.
  • the imidazole derivative 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, allergic rhinitis and the like. It is effective for prevention and treatment of allergic diseases.
  • the present invention is based on Japanese Patent Application No. 1-74074 and Japanese Patent Application No. 2000-045165 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

L'invention concerne de nouveaux dérivés d'imidazole représentés par la formule générale (I). L'invention concerne également des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des compositions médicamenteuses contenant ces dérivés ou leurs sels [dans cette formule, R1 représente phényle ou hétéroaryle éventuellement substitué; et R2 désigne phényle substitué par un ou deux éléments pouvant être identiques ou différents, choisis dans le groupe composé de cyano, alkyle substitué, des groupes hétéromonocycliques saturés à six ou sept chaînons éventuellement substitués qui contiennent chacun un ou deux atomes d'azote et éventuellement O ou S, des groupes à cycle spiro composés chacun de deux hétéromonocycles saturés à six ou sept chaînons éventuellement substitués qui contiennent chacun un à trois atomes d'azote, ces groupes à cycle spiro étant identiques ou différents et pouvant également renfermer O ou S, et des groupes représentés par la formule générale (II): -(O-(CH2)1)m-O-(CH2)nCH3) (dans laquelle 1 et m symbolisent chacun un nombre entier allant de 1 à 4; n est un nombre entier variant entre 1 et 3; et le fragment de chaîne alkyle peut être substitué)]. Ces composés, qui présentent une action d'inhibition de la production de IL-4 et de IL-5 par les cellules Th2, sont utilisés comme médicaments permettant de prévenir et/ou de traiter les maladies allergiques.
PCT/JP2000/004009 1999-06-21 2000-06-20 Nouveaux derives d'imidazole WO2000078758A1 (fr)

Priority Applications (1)

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JP17407499 1999-06-21
JP11/174074 1999-06-21
JP2000045165 2000-02-17
JP2000/45165 2000-02-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066137A1 (fr) * 2003-12-19 2005-07-21 Neurogen Corporation 2,5-diaryl-1h-imidazole-4-carboxamides utilises en tant que modulateurs des recepteurs de la neurokinine-3 pour le traitement de maladies du systeme nerveux central et peripherique
WO2005070925A1 (fr) * 2004-01-25 2005-08-04 Sanofi-Aventis Deutschland Gmbh Heterocycles aryl-substitues, procede pour leur production et leur utilisation comme medicaments
US8299104B2 (en) 2004-01-25 2012-10-30 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments

Citations (2)

* 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
WO1999033827A1 (fr) * 1997-12-26 1999-07-08 Yoshitomi Pharmaceutical Industries, Ltd. Nouveaux derives d'imidazole

Patent Citations (2)

* 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
WO1999033827A1 (fr) * 1997-12-26 1999-07-08 Yoshitomi Pharmaceutical Industries, Ltd. Nouveaux derives d'imidazole

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066137A1 (fr) * 2003-12-19 2005-07-21 Neurogen Corporation 2,5-diaryl-1h-imidazole-4-carboxamides utilises en tant que modulateurs des recepteurs de la neurokinine-3 pour le traitement de maladies du systeme nerveux central et peripherique
WO2005070925A1 (fr) * 2004-01-25 2005-08-04 Sanofi-Aventis Deutschland Gmbh Heterocycles aryl-substitues, procede pour leur production et leur utilisation comme medicaments
US8299104B2 (en) 2004-01-25 2012-10-30 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments

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