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WO2004026841A1 - Nouveau derive d'uracile 6-substitue et agent therapeutique pour maladies allergiques - Google Patents

Nouveau derive d'uracile 6-substitue et agent therapeutique pour maladies allergiques Download PDF

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WO2004026841A1
WO2004026841A1 PCT/JP2003/011787 JP0311787W WO2004026841A1 WO 2004026841 A1 WO2004026841 A1 WO 2004026841A1 JP 0311787 W JP0311787 W JP 0311787W WO 2004026841 A1 WO2004026841 A1 WO 2004026841A1
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group
phch
substituted
methyl
atom
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PCT/JP2003/011787
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Japanese (ja)
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Yoshiaki Isobe
Fumihiro Obara
Yoshifumi Inoue
Masanori Tobe
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to AU2003264448A priority Critical patent/AU2003264448A1/en
Publication of WO2004026841A1 publication Critical patent/WO2004026841A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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 excellent antiallergic action, antihistamine action, antiinflammatory action, etc., and is useful as a preventive / therapeutic agent for atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic jujube, etc.
  • the present invention relates to a novel peracil derivative and its pharmaceutical use. Background art
  • Allergic diseases such as allergic conjunctivitis, allergic rhinitis, chronic juvenile rash, atopic dermatitis, etc. are mainly caused by type I allergies, but after chronic progress, inflammatory mainly eosinophils The cells invade the affected area and become inflammatory.
  • Antihistamines are widely used as symptomatic treatments for these diseases.
  • antihistamines are ineffective against inflammation itself and cannot be used as a curative.
  • treatments using steroids which are anti-inflammatory agents, in addition to antihistamines are being performed.
  • steroids have side effects such as infections, adrenal atrophy, osteoporosis, diabetes, and impaired child growth.
  • the present invention includes the following inventions.
  • R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms
  • R 2 represents a hydrogen atom or a carbon atom having 1 to 6 carbon atoms.
  • Ar 6 represents an alkyl group
  • Ar 1 represents a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • Ar 2 and Ar 3 are the same or different
  • an unsubstituted phenyl group or a substituted or unsubstituted monocyclic aromatic heterocyclic group, or Ar 2 and Ar 3 are tricyclic together with a divalent group bonded to both Ar 2 and Ar 3
  • X may represent a methine group (CH) or a nitrogen atom
  • Y represents a single bond or an oxygen atom when X is a methine group
  • Z represents a hydrogen atom or a hydroxyl group when X is a methine group and Y is a single bond, and X is a methine group.
  • Y is an oxygen atom and X is a nitrogen atom (Y is a single bond), it represents a hydrogen atom, and m represents 2 to 6.
  • Ar 2 and Ar 3 are the same or different, and Or the unsubstituted phenyl group according to the above (1) or (2), or a pharmaceutically acceptable salt thereof.
  • Ar 2 and Ar 3 are the same or different, respectively, and (i) a phenyl group which may be substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms, or (ii) A) a 5- to 8-membered monocyclic aromatic heterocyclic group containing 1 to 4 hetero P atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; ), Or a pharmaceutically acceptable salt thereof.
  • An antiallergic agent comprising, as an active ingredient, the peracil derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (6).
  • an alkyl group having 1 to 6 carbon atoms represents a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group (1-propane group). Butyl group), isopropyl group (2-propyl group), butyl group (1-butyl group), sec-butyl group (2-butyl group), isobutyl group (2_methyl-1-propyl group), t-butyl Group (2-methyl-1-propyl group) and the like.
  • an alkoxy group having 1 to 6 carbon atoms represents a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
  • (2-propoxy group) butoxy group, sec-butoxy group (2-butoxy group) Xy group
  • isobutyloxy group (2-methyl-1-propoxy group)
  • t-butoxy group (2-methyl-21-propoxy group) and the like.
  • the C 2-6 oxy group represents a linear or branched C 2-6 oxy group, specifically, an acetoxy group, a propanoyloxy group, a butanoyloxy group. , 2-methyl-propanoyloxy group) and the like.
  • an alkoxycarbonyl group having 2 to 6 carbon atoms represents a group in which a carbonyl is bonded to an oxygen atom of the alkoxy group, and specifically, a methoxycarbonyl group, an ethoxycarbel group, a propoxycarbol group, Isopropoxycarbonyl group (2-propoxycarbonyl group), butoxycarbonyl group, sec-butoxycarbol group (2-butoxycarbonyl group), isobutyloxycarbonyl group (2-methyl-1-propoxycarbol group), t -Butoxycarbyl group (2-methyl-2-propoxycarbonyl group) and the like.
  • a carboxyalkyl group having 2 to 6 carbon atoms represents a group in which an arbitrary hydrogen atom of the alkyl group is substituted with a carboxy group, specifically, a carboxymethyl group, a 2-carboxyethyl group , 3-carboxypropyl, 2-carboxypropyl, 1-carboxy-2-propyl and the like.
  • an alkoxycarbonylalkyl group having 3 to 6 carbon atoms represents a group in which a hydrogen atom of the above-mentioned alkyl group is substituted by an alkoxycarbonyl group having 2 to 5 carbon atoms, and specifically, methoxycarbonyl It represents a methyl group, an ethoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 3-methoxycarbonylpropyl group, a 2-ethoxycarbonylethyl group, a 3-ethoxycarbonylpropyl group, or the like.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the halogen atom preferably represents a fluorine atom or a chlorine atom.
  • examples of the haloalkyl group having 1 to 6 carbon atoms include an alkyl group having 1 to 6 carbon atoms and substituted by 1 to 5 identical or different halogen atoms.
  • Preferable examples include haloalkyl groups having 1 to 4 carbon atoms, and specific examples thereof include a trifluorenomethyl group, a 2,2,2-trifluoroethyl group, and a 2,2-difluoroethyl group.
  • examples of the aromatic carbocyclic group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a biphenyl group. And a biphenyl group.
  • an aralkyl group having 7 to 10 carbon atoms refers to an alkyl group having 1 to 6 carbon atoms substituted with a phenyl group, and specifically, a benzyl group, an 11-phenylethyl group, and a 2-phenylethyl group Groups (phenyl group), 1-phenylpropyl group, 2-phenylpropyl group, 2-phenyl-2-propyl group, 3-phenyl pill group and the like.
  • the aromatic heterocyclic group includes 1 to 3 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom. And a monocyclic or bicyclic 5- to 10-membered aromatic heterocyclic group.
  • a furyl group a phenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a tetrazolyl group, a pyridyl group, a pyridazier group, a pyrimidyl group, a pyrazuryl group, and a benzo [b] furyl group Benzo [b] thenyl group, indolyl group, benzoxazolyl group, benzothiazolyl group, benzoimidazolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group and the like.
  • the monocyclic aromatic heterocyclic group represents a 5- or 6-membered monocyclic aromatic heterocyclic ring, specifically, a furyl group, a phenyl group, a pyrrolyl group, an oxazolyl group.
  • a furyl group specifically, a phenyl group, a pyrrolyl group, an oxazolyl group.
  • thiazolyl group pyrazolyl group, imidazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, virazinyl group, etc.
  • an aromatic carbocyclic group, a phenyl group, an aromatic heterocyclic ring When a group or a monocyclic aromatic heterocyclic group is substituted, the substituent includes a halogen atom, a hydroxyl group, a cyano group, a nitro group, a nitro group, a carboxyl group, a tetrazolyl group, an alkyl group having 1 to 6 carbon atoms.
  • an aralkyl group when substituted, it is substituted on the phenyl group.
  • the substituent is the same as the substituent in the aromatic carbocyclic group or the phenyl group.
  • R 1 As the unsubstituted alkyl group having 1 to 6 carbon atoms represented by R 1 , preferably, a methyl group, an ethyl group, a propyl group (1-propyl group), an isopropyl group (2-propyl group), and a butyl group (1- Butyl group), sec-butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), t-butyl group (2-methyl-2-propyl group), the same or different substitution One or more, preferably 1 to 3 groups may be substituted.
  • Substituents allowed on the alkyl group having 1 to 6 carbon atoms represented by R 1 include a fluorine atom, a halogen atom such as a chlorine atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, and a carbon atom having 1 to 5 carbon atoms. And a carboxyl group and an alkoxycarbonyl group having 2 to 6 carbon atoms.
  • Preferred examples of the substituent include a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, an acetooxy group, a carboxyl group, a methoxycarbonyl group, and an ethoxycarboyl group.
  • substituted alkyl group having 1 to 6 carbon atoms represented by R 1 preferably, a trifluoromethyl group, a 2-chloroethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-methoxylethyl group, Examples include a 2-ethoxyethyl group, a 3-methoxypropyl group, a 2-acetoxyl group, a carboxymethyl group, a methoxycarbonylmethyl group, and an ethoxycarbonylmethyl group.
  • aralkyl group having 1 to 10 carbon atoms represented by R 1 preferably, a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group (a phenyl group), an phenylpropyl group, or a 2-phenyl Examples thereof include an enylpropyl group, 2-phenyl-2-propyl group, and 3-phenylpyrrole group.
  • the substituted aralkyl group having 7 to 10 carbon atoms represented by R 1 is preferably a 2-methylbenzyl group, a 3-methylbenzinole group, a 4-methyl / levenzinole group, a 4-methylphenethylenol group, or a 4-funolenobenzoyl group.
  • R 1 includes a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, and a 2-phenylethyl group, and among them, a hydrogen atom, a methyl group, and an ethyl group are preferred. Particularly preferred.
  • the alkyl group having 1 to 6 carbon atoms represented by R 2 preferably includes a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group, and among them, a hydrogen atom, a methyl group, and an ethyl group are particularly preferable. preferable.
  • the substituent is preferably a fluorine atom, a chlorine atom, a hydroxyl group, a propyloxyl group, a cyano group, a tetrazolyl group, a nitro group, a methyl group, or an ethyl group Methoxy group, ethoxy group, acetooxy group, methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, carboxymethyl group, carboxamide group and the like.
  • substituted aromatic carbocyclic group represented by Ar 1 preferably, a 2 fluorinated phenyl group, a 3-funoleolophenylene group, a 4-phenylenophene group, a 2-phenyleneol group, or a 3-phenyleneol group
  • Black phenol group 4-methyl phenol group, 2-methynolephenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenol group, 3-ethylphenol group, 2,3 —Dimethinolepheninole group, 2,4-Dimethinolephenyl group, 2,5-Dimethylphenyl group, 2,6-Dimethylphenyl group, 3,4-Dimethylphenyl group, 3,5-Dimethylphenyl group, 4-methylphenyl, 2-methylnaphthyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-
  • substituent which may be present on the aromatic heterocyclic group represented by Ar 1 preferably, a chlorine atom, a fluorine atom, a hydroxyl group, a methyl group, a methoxy group, or an ethoxy group is mentioned. Can be.
  • the substituted aromatic heterocyclic group represented by Ar 1 is preferably a 3-methyl-2-furinole group, a 4-methyl-12-furyl group, a 5-methyl-2-furyl group, a 2-methyl-1-furyl group , 4-methyl-13-furyl, 5-methyl-13-furyl, 3-methoxy-2-furyl, 4-methoxy2-furyl, 5-methoxy-2-furyl, 2-methyl Toxyl 3-furyl, 4-methoxy 3-furyl, 5-methoxy-3-furyl, 3-chloro-2-furyl, 4-chloro-1--2-furinole, 5-chloro-1-2 -Furinole, 2-chloro-3-furinole, 4-chloro-3-furinole, 5-chloro-3, furyl, 3-fluoro-2-furyl, 4-fluoro-2-furyl, 5-furesole Mouth _ 2-furinole group, 2-furnole mouth 3-furinole group, 4-fluor
  • 4 isotope / repoxyphenole group, 4-methoxycanoleponinolephenine group, 3-cyanophenyl group, 4-cyanophenyl group, 3-tetrazolylphenyl group, and 4-tetrazolylphenyl group are preferred. .
  • the substituent which may be present on the phenyl group represented by Ar 2 or Ar 3 is preferably a halogen atom such as a fluorine atom or a chlorine atom; an alkyl group such as a methyl group or an ethyl group; a hydroxyl methoxy group or an ethoxy group Alkoxy groups such as ethoxy groups; alkoxy groups such as acetyl groups; carboxyl groups; alkoxy forces such as methoxycarbon groups; rubonyl groups; cyano groups; tetrazolyl groups; nitro groups and the like; and more preferably alkyl. Groups, alkoxy groups or halogen atoms.
  • substituted phenyl group represented by Ar 2 or Ar 3 preferably, a 2-fluorophenyl group, a 3-phenyl group, a 4-phenyl group, a 2-phenyl group, 3-chloro phenyl group, 4-methyl phenyl group, 2-methyl phenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2, 3-dimethylphenyl, 2,4-dimethylphenyl, 2,51-dimethylphenyl, 2,6-dimethyl / rephenyl, 3,4-dimethylphenyl, 3,5-dimethylinophenyl 4-, 4-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-
  • the substituent which may be present on the monocyclic aromatic heterocyclic group represented by Ar 2 or Ar 3 is preferably a halogen atom such as a chlorine atom or a fluorine atom; an alkyl group such as a methyl group An alkoxy group such as a methoxy group or an ethoxy group; and a hydroxyl group.
  • Specific examples of the substituted monocyclic aromatic heterocyclic group represented by Ar 2 or Ar 3 include, preferably, 3-methylinole 2-furinole group, 4-methylinole 1-2-furinole group, and 5-methylinole 2-furyl group.
  • 5-methoxy-12-virazyl group 6-methoxy-2-virazyl group, 5-ethoxy-12-viradil group, 6-ethoxy-12-virazyl group, 5-chloro-12-virazyl group,
  • Ar 2 or Ar 3 include phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, and 3-phenyl. And pyridyl and 4-pyridyl groups. Among them, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 3-pyridyl and 4-pyridyl are particularly preferred. preferable.
  • Ar 2 and Ar 3 form a tricyclic carbocycle together with a divalent group bonded to both Ar 2 and Ar 3 , the following formula in the formula (I):
  • X represents a methine group (CH) or a nitrogen atom
  • Y represents a single bond or an oxygen atom when X is a methine group, and represents a single bond when X is a nitrogen atom
  • Z represents a methine group.
  • Y represents a single bond, it represents a hydrogen atom or a hydroxyl group; when X is a methine group and Y is an oxygen atom; and when X is a nitrogen atom (Y is a single bond), it represents a hydrogen atom.
  • n 2 to 6, preferably 3 to 5, and particularly preferably 3 to 4.
  • Tables 1 and 2 specifically show preferred peracyl derivatives of the present invention.
  • Table 1 specifically show preferred peracyl derivatives of the present invention.
  • Urashiru derivative represented by the general formula (I), t which can be synthesized according to the following formula
  • Hal represents a halogen atom
  • R 2 , Ar ⁇ Ar 2 , Ar 3 , X, Y, Z and m have the same meanings as described above.
  • the peracyl derivative represented by the general formula (I) can form salts with various acids.
  • Pharmaceutically acceptable salts include hydrochloride, sulfate, acetate, succinate and the like.
  • the peracyl derivative when it has an acidic substituent, it may form a salt with various bases.
  • the pharmaceutically acceptable salt includes a sodium salt, a potassium salt, a calcium salt, an ammonium salt and the like. These salts can be obtained by a conventional method such as recrystallization after mixing a peracil derivative with an acid or a base.
  • the present invention also includes solvates such as hydrates and ethanol solvates of the peracyl derivative represented by the general formula (I) or a pharmaceutically acceptable salt. Further, in the present invention, All tautomers, all stereoisomers, such as optical isomers, of the peracyl derivative represented by the general formula (I), and crystal forms of all aspects are also included.
  • the therapeutic drug for allergic diseases of the present invention is It can be used in various dosage forms including oral preparations such as tablets, capsules and powders, as well as injections and external preparations.
  • an ointment can be prepared by mixing a peracil derivative or a pharmaceutically acceptable salt of the present invention with an ointment base such as petrolatum.
  • tablets are prepared by mixing the peracil derivative or the pharmaceutically acceptable salt of the present invention with excipients such as lactose and starch, lubricants such as magnesium stearate and talc, and other commonly used additives. You can also.
  • the dose of the remedy for allergic diseases of the present invention is appropriately determined according to the patient's sex, age, weight, type of disease, symptoms, etc., for example, atopic dermatitis, contact dermatitis, psoriasis, etc.
  • the ointment containing 0.01 to 10% of the active ingredient can be applied to the affected area from lsi times to several times.
  • Oral preparations such as tablets, capsules and powders can generally be administered in a single dose or in divided doses in the range of 0.01 to 100 mg / kg per day.
  • the title compound was obtained in the same manner as in Reference Example 1 except for using 11-((4-fluorophenyl) phenylmethyl) piperazine instead of 11- (diphenylmethyl) piperazine.
  • the aqueous layer was adjusted to pH 11 with a 5N aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was washed with a 10% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.
  • Time-of-flight mass spectrometer TOF-Mass: 510 (M + H)
  • Time-of-flight mass spectrometer (TOF-Mass): 496 (M + H)
  • Time-of-flight mass spectrometer 525 (M + H)
  • the title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-ethoxyethoxycarbonylmethyl-1-phenylperacil was used instead of 6-chloro-3-methinolelate.
  • Time-of-flight mass spectrometer (TOF-Mass): 582 (M + H)
  • the title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-methyl-1- (1-naphthyl) peracil was used instead of 6-chloro-3-methinolene.
  • Time-of-flight mass spectrometer 560 (M + H)
  • Example 7 6- [3- [4- (diphenylmethoxy) -11-piperidinyl] propylpyramino] -13-methyl-11- (1-naphthyl) peracyl (compound 734) 6-chloro-3- Use 6-chloro-3-methyl-11- (1-naphthinole) percinole in place of methinolee 1-fue-norperazinole, and use 3 _ (4— (diphene) instead of 3- (4-1- (diphenylmethyl) _1-piperazinyl) propylamine. The title compound was obtained in the same manner as in Example 1 using dimethyl (11-piberidier) propylamine.
  • Time-of-flight mass spectrometer (TOF-Mass): 575 (M + H)
  • the title compound was obtained in the same manner as in Example 1 except for using 6-chloro-1- (4-fluorophenyl) -13-methylperacyl in place of 6-chloro-3-methinolate.
  • Time-of-flight mass spectrometer 529 (M + H)
  • Example 2 The same operation as in Example 1 was carried out using 6-chloro-1- (4-phenylphenyl) -13-methylperacyl instead of 6-chloro-3-methinolay Thus, the title compound was obtained.
  • Time-of-flight mass spectrometer (TOF-Mass): 545 (M + H)
  • Time-of-flight mass spectrometer (TOF-Mass): 589 (M + H)
  • Time-of-flight mass spectrometer (TOF-Mass): 538 (M + H)
  • Time-of-flight mass spectrometer (T0F_Mass): 553 (M + H)
  • Time-of-flight mass spectrometer TOF-Mass: 540 (M + H)
  • TOF-Mass 540 (M + H)
  • Example 15 6- [3- [4-1- (diphenylmethoxy) -11-piperidinyl] propylamino] -11- (2-methoxyphenyl) _3-methylperacyl (Compound 914)
  • Time-of-flight mass spectrometer TOF-Mass: 555 (M + H)
  • Time-of-flight mass spectrometer (TOF-Mass): 541 (M + H)
  • Time-of-flight mass spectrometer (T0F_Mass): 579 (M + H)
  • 6-Chloro-1- (4-ethoxycarbonylmethylphenyl) -3- 3-ethyl-peracyl is used in place of 3-methyl- 1-pheninolecinole, and is labeled in the same manner as in Example 1. The compound was obtained.
  • Time-of-flight mass spectrometer (T0F_Mass): 611 (M + H)
  • Time-of-flight mass spectrometer (TOF-Mass): 583 (M + H) ''
  • 6-Chloro-11- (4-ethoxycarbonylphenyl) -13-methyldiracil was used in place of 6-chloro-1-3-methynole-1-lacinole to obtain the title compound in the same manner as in Example 1. .

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'uracile ou un sel pharmaceutiquement acceptable de celui-ci, ce dérivé d'uracile étant représenté par la formule générale (I), dans laquelle R1 représente hydrogène, alkyle C1-C6 substitué ou non substitué ou aralkyle C7-C10 substitué ou non substitué ; R2 représente hydrogène ou alkyle C1-C6 ; Ar1 représente un groupe aromatique à noyau carboné substitué ou non substitué ou un groupe hétérocyclique aromatique substitué ou non substitué ; Ar2 et Ar3 sont identiques ou différents et représentent chacun phényle substitué ou non substitué ou un groupe hétérocyclique aromatique à noyau unique substitué ou non substitué, ou Ar2 et Ar3 peuvent former un noyau carboné tricyclique en coopération avec un groupe divalent capable de se lier avec Ar2 et Ar3 ; X représente méthine (CH) ou azote ; Y représente une liaison unique ou oxygène lorsque X représente méthine et représente une liaison unique lorsque X représente azote ; Z représente hydrogène ou hydroxyle lorsque X représente méthine et Y représente une liaison unique Y et représente hydrogène lorsque X représente méthine et Y représente oxygène et lorsque X représente azote (Y représentant une liaison unique) ; et m vaut de 2 à 6. L'invention concerne également l'utilisation médicale dudit dérivé ou de son sel pharmaceutiquement acceptable ainsi qu'un nouveau composé produisant non seulement un effet antihistaminique mais également un effet anti-inflammatoire.
PCT/JP2003/011787 2002-09-18 2003-09-16 Nouveau derive d'uracile 6-substitue et agent therapeutique pour maladies allergiques WO2004026841A1 (fr)

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AU2003264448A AU2003264448A1 (en) 2002-09-18 2003-09-16 Novel 6-substituted uracil derivative and therapeutic agent for allergic disease

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JP2002271030A JP2006096662A (ja) 2002-09-18 2002-09-18 新規６−置換ウラシル誘導体及びアレルギー性疾患の治療剤
JP2002-271030 2002-09-18

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