WO2006035760A1 - Drug for treating skin disease - Google Patents

Drug for treating skin disease Download PDF

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Publication number
WO2006035760A1
WO2006035760A1 PCT/JP2005/017720 JP2005017720W WO2006035760A1 WO 2006035760 A1 WO2006035760 A1 WO 2006035760A1 JP 2005017720 W JP2005017720 W JP 2005017720W WO 2006035760 A1 WO2006035760 A1 WO 2006035760A1
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Prior art keywords
group
alkyl
alkyl group
hydrogen atom
cycloalkyl
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PCT/JP2005/017720
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French (fr)
Japanese (ja)
Inventor
Hiroyuki Aono
Masato Horiuchi
Fumio Tsuji
Masaaki Murai
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2006035760A1 publication Critical patent/WO2006035760A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to urea derivatives, acid amides and the like (hereinafter these are collectively referred to as “urea derivatives”)
  • Skin diseases are diseases that cause inflammatory or proliferative changes in the skin! Skin diseases are painful and painful, and cosmetic problems such as skin rashes, scales, pustules, blisters, scab formation, and pigment abnormalities also occur on exposed parts of the hands, arms, and faces. The development of effective treatments that often adversely affect the so-called quality of life (QOL) such as the family's mental, social and economic aspects is desired. An example of such a skin disease is psoriasis.
  • Psoriasis is a chronic skin disease in which the skin is thickened and papules and erythema with dry scales occur throughout the body. It is not a disease that affects life prognosis, but it is a recurrent disease and is difficult to cure. The cause of psoriasis is unknown, but involvement of genetic elements has been pointed out.
  • steroids that are not clearly effective against antibiotics for aseptic skin diseases are generally considered to have a withdrawal reaction, that is, there is a risk of relapse of symptoms at the time of discontinuation. It is also difficult to do.
  • urea derivatives that are active ingredients in the present invention are known compounds, and are disclosed in Patent Document 1 together with their production methods.
  • Patent Document 1 describes that this urea derivative has a tumor necrosis factor a (TNF- ⁇ ) production inhibitory action and is useful as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis (RA).
  • Patent Document 2 describes that this is useful as an angiogenesis inhibitor.
  • Patent Document 1 Japanese Patent Laid-Open No. 2002-53555
  • Patent Document 2 Japanese Patent Laid-Open No. 2003-226686 Disclosure of the invention
  • these urea derivatives have an action of suppressing neutrophil infiltration and an action of suppressing skin inflammation, which cause exacerbation of inflammation, in skin inflammation models.
  • the present invention has been found to be particularly useful as a therapeutic agent for psoriasis, and has led to the completion of the present invention.
  • Psoriasis is a disease that causes abnormal proliferation of epidermal cells such as keratinocytes in combination with leukocyte infiltration into the epidermis or dermis, such as steroids, retinoids, vitamin D group, or light. Irradiation is used. There is also a report that skin keratinocytes in patients with psoriasis have changed properties compared to normal ones (Jackson M et al. FASE B J 13: 495-502 1999). Psoriasis is said to be associated with autoimmunity. Psoriasis is a disease having properties different from those of general autoimmune diseases, and the development of drugs useful for the treatment is desired.
  • the urea derivative represented by the general formula [I] has a neutrophil infiltration-inhibiting action, and is associated with neutrophils such as psoriasis.
  • the present invention relates to a skin disease therapeutic agent comprising a compound represented by the following general formula [1] or a salt thereof (hereinafter referred to as “the present compound” unless otherwise specified) as an active ingredient.
  • A represents — (NR 4 ) —, — (CR 5 R 6 ) — or —O—; B represents a chain,
  • [0012] represents an alkylene group or a alkylene group which may contain, the alkylene group and the alkylene group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated group.
  • R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom, an alkyl A group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group, an acyl group or an amino group, and the alkyl group, alkenyl group, alkyl group, cycloalkyl group or cycloalkenyl group.
  • Group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an adamantyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxy group.
  • R 1 and R 2, R 2 and R 4, R 2 tR 5 and R 2 and R 6 May form a saturated or unsaturated heterocyclic ring;
  • R 3 represents an aryl group or an unsaturated heterocyclic ring;
  • R 7 represents a hydrogen atom or an alkyl group;
  • n represents an integer of 1 to 5; the hydrogen atom of each of the above-mentioned amino groups, hydroxy groups and aminocarbonyl groups is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an aryl group alkyl.
  • acyl group alkoxyalkyl group, alkoxycarbonyl group, alkylaminocarbol group, cycloalkyloxycarboro group, arylalkylalkoxycarboro group, alkylsulfol group, aryl Substituted with an alkyl group substituted with a rusulfonyl group, a halogenoalkyloxycarbonyl group, an imidazolylcarbol group, a pyridylcarbon group, a saturated or unsaturated heterocycle, or a saturated or unsaturated heterocycle It may be. same as below. ]
  • This compound exhibits an excellent neutrophil infiltration-inhibiting action on skin inflammatory sites, and is a skin disease, especially dry.
  • the alkylene group is a methylene group, ethylene group, trimethylene group, propylene group, tetramethylene group, pentamethylene group, hexamethylene group, otatamethylene group, decamethylene group, dodecamethylene group, methylmethylene group, ethethyleneethylene group, dimethylethylene.
  • a linear or branched alkylene group having 1 to 12 carbon atoms such as a group, a propylethylene group, an isopropylethylene group, a methyltrimethylene group and the like;
  • the alkylene group is a beylene group, a probelene group, a butylene group, a pentylene group, a hexylene group, an otaterene group, a butanediylidene group, or a methylpropylene group.
  • a linear or branched alkylene group having one or more double bonds such as a group and having 2 to 12 carbon atoms.
  • the alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group, a decyl group, a dodecyl group, an isopropyl group, an isobutyl group, an isopentyl group, an isohexyl group, an isooctyl group, A linear or branched alkyl group having 1 to 12 carbon atoms, such as t-butyl group and 3,3-dimethylbutyl group.
  • the alkoxy group is a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexyloxy group, an octyloxy group, a decyloxy group, a dodecyloxy group, an isopropoxy group, a t-butoxy group, or the like.
  • the alkenyl group refers to a linear or branched alkenyl group having 2 to 12 carbon atoms, such as a vinyl group, an aryl group, a 3-butenyl group, a 5-hexenyl group, and an isopropyl group.
  • the alkynyl group refers to a straight-chain or branched alkenyl group having 2 to 12 carbon atoms such as an ethul group, a propynyl group, and a butynyl group.
  • the cycloalkyl group is a cycloalkyl having 3 to 20 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and a cyclododecyl group. Indicates a group.
  • the cycloalkenyl group refers to a cycloalkenyl group having 5 to 20 carbon atoms such as a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • the aryl group represents an aromatic hydrocarbon ring such as a phenyl group or a naphthyl group
  • the substituents which may have one or more substituents include, for example, an alkyl group, a cycloalkyl group, Examples thereof include a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, a hydroxyalkyl group, a nitro group, a cyano group, a halogen atom, and an alkyloxy group.
  • the siloxy group represents a silicon-containing organic group such as a trialkylsilyloxy group, a dialkyl (aryl) silyloxy group, an alkyl (diaryl) oxy group, or a triarylsilyloxy group.
  • the halogen atom represents fluorine, chlorine, bromine or iodine.
  • the heterocycle refers to, for example, a 5- to 20-membered saturated or unsaturated monocyclic heterocycle or bicyclic heterocycle containing 1 to 4 nitrogen, oxygen and sulfur atoms.
  • the heterocyclic ring may have one or more substituents. Examples of the substituent include an alkyl group, a cycloalkyl group, a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, and a hydroxyalkyl group. , A nitro group, a cyano group, a halogen atom, an alkyloxy group, an aryl group, an arylalkyl group, a saturated or unsaturated heterocyclic ring, and the like. Also, when the above heterocycle has a nitrogen atom or sulfur atom in the ring, these atoms are oxidized to form N-oxide, S-oxide, etc.!
  • saturated heterocyclic ring examples include pyrrolidine, piperidine, homopiperidine, piperazine having a nitrogen atom in the ring, morpholine having a nitrogen atom and an oxygen atom in the ring, a nitrogen atom and sulfur.
  • Examples include monocyclic heterocycles such as thiomorpholine having atoms in the ring, and they may be condensed with benzene rings to form bicyclic heterocycles such as tetrahydroquinoline and tetrahydroisoquinoline.
  • the unsaturated heterocycle include monocyclic heterocycles such as pyrrole, pyridine, pyrazole, imidazole, pyrazine, pyridazine, and pyrimidine having a nitrogen atom in the ring, or indole, quinoline, isoquinoline, and benzimidazole.
  • monocyclic heterocycles such as pyrrole, pyridine, pyrazole, imidazole, pyrazine, pyridazine, and pyrimidine having a nitrogen atom in the ring, or indole, quinoline, isoquinoline, and benzimidazole.
  • Bicyclic heterocycles such as naphthyridine, pyrophine pyridine, and imidazopyridine, monocyclic heterocycles such as furan having an oxygen atom in the ring or bicyclic heterocycles such as benzofuran, and sulfur atoms in the ring
  • monocyclic heterocycles such as thiophene or bicyclic heterocycles such as benzothiophene
  • monocyclic heterocycles such as oxazole, isoxazole, thiazole and isothiazole having nitrogen and oxygen or sulfur atoms in the ring, or benzoxazole , Benzothiazole, chenoviridine, oxazolopyridine, thi Examples include bicyclic complex rings such as azolopyridine and furopyridine. Further, the unsaturated heterocyclic ring may partially include a saturated bond.
  • the salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, liquor. Examples thereof include salts with organic acids such as succinic acid, and salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium.
  • the quaternary ammonium salt of the present compound is also included in the salts in the present invention.
  • geometric isomers or optical isomers in the compound these isomers are also included in the scope of the present invention.
  • the compound may be in the form of a hydrate or a solvate.
  • Preferable examples of the present compound include the following (1) to (3).
  • R 3 A pyridine ring.
  • R J , R 2 , R 4 , R 5 and R 6 At least one of R J , R 2 , R 4 , R 5 and R 6 : an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylamino carbo -Rualkyl group.
  • Ri and R 2 ⁇ Daman chill alkyl group, Adamanchiruoki Shiarukiru group, ⁇ Damman chill ⁇ amino alkyl group or ⁇ Dammann chill ⁇ amino carbo - Rua Norekinore group.
  • Ri and R 2 ⁇ Daman chill alkyl group.
  • A (NR 4 ), one (CR 5 R 6 ) or O—;
  • An alkylene group or an alkene group which may contain, wherein the alkylene group is substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group or a saturated or unsaturated heterocyclic ring. It may be combined with A to form a saturated heterocycle,
  • R 1 a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, the alkyl group, an alkyl group, an alkyl group Group, cycloalkyl group or cycloalkenyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group group, an alkylaminocarbo group group, an adamantyl group, an aryl group.
  • each amino group, hydroxy group and aminocarbonyl group in R 1 which may be substituted with an oxycarbonyl group, a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, Aryl group, aryl alkyl group, acyl group, alkoxy carbo group, cycloalkyl oxy group, aryl alkoxy group - group, Harogenoaruki Ruokishikarubo - group, imidazolylmethyl carbo - group, substituted by an alkyl group substituted with an unsaturated heterocyclic ring or unsaturated heterocyclic ring, even if I ,
  • R 2 an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarboalkyl group,
  • R 3 unsaturated heterocycle
  • R 4 a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarboalkyl group, an amino group, an alkylamino group, An acylamino group or an alkoxycarboamino group,
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group, an amino group or an alkoxy carboamino group,
  • R 7 hydrogen atom or alkyl group
  • n An integer from 1 to 5.
  • R 2 is an adamantylalkyl group and R 3 is a pyridine ring.
  • A — (NR 4 ) —, one (CR 5 R 6 ) — or O—;
  • [0039] may contain an alkylene group or an alkylene group
  • R 1 is an alkyl group or an alkyl group, and the alkyl group may be substituted with a halogen atom or an amino group, and the amino group is an alkyl group, an acyl group, an aryl alkyloxycarbon group May be substituted with a cycloalkyloxycarbonyl group or an alkoxycarbol group,
  • R 2 adamantylalkyl group
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 a hydrogen atom
  • n An integer from 1 to 5.
  • An alkylene group or an alkylene group which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocycle, and is bonded to A To form a saturated heterocycle,
  • R 1 a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, the alkyl group, an alkyl group, an alkyl group Group, cycloalkyl group, or cycloalkenyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group group, an aryloxycarbonyl group, an aminocarbonyl group,
  • the hydrogen atom of each amino group, hydroxy group and aminocarbo group of R 1 which may be substituted with a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, an aryl group, Aryl alkyl group, acyl group, alkoxy carbo yl group,
  • R 2 an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group or an arylalkyl group,
  • R 3 pyridine ring
  • R 4 a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarboalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarboamino group,
  • R 5 and R 6 are the same or different and are a hydrogen atom or an alkyl group
  • R 7 hydrogen atom or alkyl group
  • n An integer from 1 to 5.
  • R 1 is an alkyl group or a alkenyl group, and the alkyl group may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring. May be substituted with an alkyl group, an acyl group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group or an arylalkylcarbonyl group;
  • R 2 an alkyl group, an alkyl group or an aryl alkyl group,
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 hydrogen atom
  • R 1 is an alkyl group having 3 or more carbon atoms and R 2 is an alkyl group or an arylalkyl group or salts thereof are particularly preferable.
  • A : — (NR 4 ) —or one (CR 5 R 6 ) —,
  • R 1 an alkyl group, an alkenyl group or a cycloalkyl group
  • the alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group, an aryl group. It may be substituted with an oxycarbol group, an aminocarbol group, a pyridine ring or a thiophene ring, and the hydrogen atom in each R 1 in R 1 is an alkyl group, an aryl group.
  • Base Aryl Archi Substituted with an alkyl group, an acyl group, an alkoxy carbo yl group, a cycloalkyloxy carboxy group, an aryl alkoxy carbo ol group,
  • R 2 a cycloalkyl group, a phenylalkyl group or a cycloalkylalkyl group,
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 a hydrogen atom
  • This compound can be produced, for example, by the method described in JP-A-2002-53555.
  • a pharmacological test on inflammation of the skin of the skin was conducted to examine the usefulness of this compound. For details, it has been found that the power compound shown in the pharmacological test section described later suppresses MPO activity, which is an indicator of neutrophil infiltration, and suppresses skin inflammation in a mouse skin inflammation model. It was.
  • the skin disease referred to in the present invention is a disease in which inflammation occurs in skin tissues such as epidermis and dermis due to various causes, and leukocytes, particularly neutrophils, infiltrate and exacerbate inflammation. It may be accompanied by abnormal cell proliferation of connective tissues such as keratinocytes and fibroblasts, thickening of skin tissue or edema.
  • skin diseases include psoriasis, pyoderma gangrenosuma, Sweet syndrome, palmoplantar pustulosis, pemphigus, bullous pemphigoid, herpes zoster, polymorphic exudative erythema, nodules Erythema and granulomatous vasculitis.
  • leukocytes particularly neutrophils
  • Infiltrated leukocytes are typified by reactive oxygen, low molecular weight inflammatory mediators such as nitrous oxide, GM-CSF, IFN- ⁇ , IL-1, IL-2, and IL-6.
  • chemokines such as, but not limited to, IP-10
  • Substrate-degrading enzymes such as matrix metaprotein, histamine, prostaglandins
  • growth factors such as, but not limited to, vascular permeability enhancing factors such as leukotrienes and PAF, IG Fl, TGF, and KGF are produced.
  • these leukocyte-secreting factors may also cause secretion of various factors involved in peripheral tissue strength and inflammation. These factors have a complex effect and exacerbate inflammation, causing skin diseases such as skin rash, scales, pustules, blisters, crust formation, and pigmentation.
  • drugs that suppress infiltration of leukocytes can suppress exacerbation of skin inflammation.
  • Psoriasis pyoderma gangrenosum, Sweet syndrome, palmoplantar pustulosis
  • It is suitable as a therapeutic agent for skin diseases such as pemphigoid, bullous pemphigoid, herpes zoster, polymorphic exudative erythema, erythema nodosum, granulomatous vasculitis.
  • neutrophils are considered to be involved in the process of exacerbation of inflammation.
  • psoriasis infiltration of leukocytes such as neutrophils into the keratin and epidermis is observed, and neutrophils are considered to be involved in the process of exacerbation of inflammation.
  • active neutrophils are detected not only in the skin but also in peripheral blood.
  • adsorptive removal of neutrophils from peripheral blood is useful for the treatment of psoriasis (Kanekura T et al: J Am Acad Dermatol 49: 329-332, 2003). From these points, the present compound which has an action of suppressing infiltration of leukocytes into the skin, particularly neutrophils and suppresses skin inflammation, is particularly suitable as a therapeutic agent for psoriasis.
  • the compound can be administered parenterally or orally.
  • the dosage form include tablets, capsules, granules, powders, injections, patches, ointments, lotions, suspensions, and aerosols.
  • preparations of this compound are the forces described in Japanese Patent Application Laid-Open No. 2002-53555 and Japanese Patent Application Laid-Open No. 2003-2 26686. be able to.
  • oral preparations such as tablets, capsules, granules, powders, etc.
  • fillers such as lactose, crystalline cellulose, starch, vegetable oil, stearin Lubricants such as magnesium acid and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, coatings such as hydroxypropylmethylcellulose, macrogol, and silicone resin If necessary, add a coating agent such as a coating agent or gelatin coating.
  • a coating agent such as a coating agent or gelatin coating.
  • the present invention also relates to a method for treating skin diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by the general formula [1] or a salt thereof.
  • the dose of this compound can be selected appropriately according to symptoms, age, dosage form, etc., but for oral preparations, it is usually 0.1 to 5000 mg per day, preferably 1 to 1000 mg divided into 1 or several doses. do it.
  • Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, has a neutrophil infiltration and keratinocyte proliferation promoting action
  • PMA-induced skin inflammation model is a skin disease involving neutrophils, It is especially used as a model for psoriasis (Alford JG et al: Agents and Actions, 37: 260-267, Sato H et al: The Journ of Dermatology, 30: 51-524, 2003).
  • MPO myelin peroxidase
  • the above compound 1 is suspended in a 1% methylcellulose aqueous solution to prepare a test compound-containing solution. Prepared at the time of use.
  • a liquid containing betamethasone 21-phosphate sodium salt as a control drug was prepared in the same manner as described above.
  • CD-l mice male, 20-28 g were used. These were subjected to the experiment in 4 to 8 animals in each group after acclimatization for 6 days.
  • a test compound-containing solution at the specified dose was orally administered, and after 30 minutes, an ethanol solution of PMA was applied to the right auricle surface of each individual except for the normal control group.
  • the normal control group and the disease state control group were similarly administered with 1% methylcellulose aqueous solution as a vehicle.
  • Betamethasone 21-phosphate sodium salt was administered at a designated dose in terms of betamethasone.
  • the thickness of the right and left pinna was measured using a micrometer gauge, and the difference was taken as the pinna thickness.
  • the weights of the extracted right and left auricles were measured, and the difference was taken as the weight of the auricle. After weighing, homogenize the right auricular tissue and use the method of Desser et al.
  • MPO activity in the supernatant was measured using the guaiacol method according to Archives of Biochemistry and Biophysics 148; 452-465, 1972). In addition, the amount of protein in the same sample was measured and used to correct MPO activity.
  • the MPO activity of each pinna sample was corrected by the following formula.
  • MPO activity (U / g protein) MPO activity (U) / protein amount (g)
  • Inhibition rate (%) ⁇ 1- (mean value of drug administration group ⁇ mean value of normal control group) / (mean value of disease state control group ⁇ mean value of normal control group) ⁇ X 100
  • Table 1 shows the pinna thickness and pinna weight
  • Table 2 shows the MPO activity. All the results are shown as average standard error and inhibition rate.
  • Compound 1 has an inhibitory effect on skin inflammation by suppressing an increase in auricle thickness and an increase in auricle weight due to acupuncture stimulation.
  • the inhibitory action was equivalent to that of betamethasone as a control agent.
  • the tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone rosin) to obtain the desired coated tablet (the following formulation)
  • a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone rosin
  • desired tablets can be obtained by appropriately changing the amounts of the present compound and additives.
  • a desired capsule can be obtained by appropriately changing the mixing ratio of the present compound and lactose.
  • a desired injection can be obtained by appropriately changing the mixing ratio of the compound and the additive.

Abstract

Disclosed is an urea compound having a structure represented by the general formula [1] below which has a new pharmacological effect. The urea compound having the structure represented by the general formula [1] below or a salt thereof has an excellent curative effect on skin diseases. In the formula below, A represents -(NR4)-, -(CR5R6)- or -O-; B represents an alkylene or alkenylene group; R1, R2, R4, R5 and R6 respectively represent a hydrogen atom, an alkyl group, an alkenyl group, an adamantylalkyl group or the like; R3 represents an aryl group or an unsaturated heterocyclic ring; and X represents an oxygen atom or a sulfur atom.

Description

明 細 書  Specification
皮膚疾患治療剤  Skin disease treatment
技術分野  Technical field
[0001] 本発明は、ゥレア誘導体、酸アミド等 (以下、これらをまとめて「ゥレア誘導体」と呼ぶ The present invention relates to urea derivatives, acid amides and the like (hereinafter these are collectively referred to as “urea derivatives”)
)を有効成分として含む皮膚疾患の治療剤に関するものである。 ) As an active ingredient.
背景技術  Background art
[0002] 皮膚疾患とは、皮膚にお!、て炎症性あるいは増殖性の変化等を生ずる疾患である 。皮膚疾患は痒みや痛みを伴う点、また、手、腕、顔面等の露出部に皮疹、鱗屑、膿 疱、水疱、痂皮形成、色素異常等の美容上の問題も生ずる点から、患者とその家族 の精神面、社会生活面、経済面等の、いわゆる生活の質（QOL)に悪影響を及ぼす ことが多ぐ有効な治療法の開発が望まれている。このような皮膚疾患の例として乾 癬が挙げられる。  [0002] Skin diseases are diseases that cause inflammatory or proliferative changes in the skin! Skin diseases are painful and painful, and cosmetic problems such as skin rashes, scales, pustules, blisters, scab formation, and pigment abnormalities also occur on exposed parts of the hands, arms, and faces. The development of effective treatments that often adversely affect the so-called quality of life (QOL) such as the family's mental, social and economic aspects is desired. An example of such a skin disease is psoriasis.
[0003] 乾癬は、皮膚の肥厚と、乾燥した鱗屑を伴った丘疹や紅斑が全身に発生する慢性 の皮膚疾患である。生命予後に影響を及ぼす疾患ではないが、再発性の疾患であり 、治癒することは困難である。乾癬の原因は不明であるが、遺伝的な要素の関与が 指摘されている。  [0003] Psoriasis is a chronic skin disease in which the skin is thickened and papules and erythema with dry scales occur throughout the body. It is not a disease that affects life prognosis, but it is a recurrent disease and is difficult to cure. The cause of psoriasis is unknown, but involvement of genetic elements has been pointed out.
[0004] このような皮膚疾患の治療に当たり、ステロイド薬あるいは抗生物質の外用 ·内服等 が行われていた。し力しながら、無菌性皮膚疾患に対しては抗生物質の効果は明確 でなぐステロイド薬は一般に離脱反応、すなわち、連用中止時の症状の再燃を生じ る恐れがあるとされており、長期連用しにくいという面もある。  [0004] In the treatment of such skin diseases, steroid drugs or antibiotics have been used externally or internally. However, steroids that are not clearly effective against antibiotics for aseptic skin diseases are generally considered to have a withdrawal reaction, that is, there is a risk of relapse of symptoms at the time of discontinuation. It is also difficult to do.
[0005] 一方、本発明における有効成分であるゥレア誘導体は公知化合物であり、その製 造方法と共に特許文献 1に開示されている。特許文献 1にはこのゥレア誘導体が腫 瘍壊死因子 a (TNF— α )産生阻害作用を有し、関節リウマチ (RA)等の自己免疫 疾患治療薬として有用であることが記載されて 、る。また特許文献 2にはこれが血管 新生抑制薬として有用であることが記載されている。  On the other hand, urea derivatives that are active ingredients in the present invention are known compounds, and are disclosed in Patent Document 1 together with their production methods. Patent Document 1 describes that this urea derivative has a tumor necrosis factor a (TNF-α) production inhibitory action and is useful as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis (RA). Patent Document 2 describes that this is useful as an angiogenesis inhibitor.
特許文献 1：特開 2002— 53555号公報  Patent Document 1: Japanese Patent Laid-Open No. 2002-53555
特許文献 2：特開 2003 - 226686号公報 発明の開示 Patent Document 2: Japanese Patent Laid-Open No. 2003-226686 Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] このような皮膚疾患、特に乾癬の治療薬として好適な化合物を探索すると共に、公 知のウレァ誘導体の新たな医薬用途を見出すことは意義深い。  [0006] It is significant to search for compounds suitable as therapeutic agents for such skin diseases, particularly psoriasis, and to find new pharmaceutical uses of known urea derivatives.
課題を解決するための手段  Means for solving the problem
[0007] そこで、医薬として有用であることが報告されている下記一般式 [1]で示される公知 のゥレア誘導体 (特開 2002— 53555)に着目し、皮膚疾患の治療薬の探索研究を 行った。 [0007] Therefore, focusing on a known urea derivative (Japanese Patent Laid-Open No. 2002-53555) represented by the following general formula [1], which has been reported to be useful as a pharmaceutical, a search research for a therapeutic agent for skin diseases was conducted. It was.
[0008] その結果、これらのゥレア誘導体は、皮膚炎症モデルにぉ 、て、炎症の増悪の原 因となる好中球の浸潤を抑制する作用および皮膚炎症を抑制する作用を有し、皮膚 疾患、特に乾癬の治療剤として有用であることを見出し、本発明を完成するに至った  [0008] As a result, these urea derivatives have an action of suppressing neutrophil infiltration and an action of suppressing skin inflammation, which cause exacerbation of inflammation, in skin inflammation models. The present invention has been found to be particularly useful as a therapeutic agent for psoriasis, and has led to the completion of the present invention.
[0009] 乾癬は表皮あるいは真皮への好中球等の白血球浸潤とともにケラチノサイト等の上 皮性細胞の異常増殖を生じる疾患であり、その治療には、ステロイド剤ゃレチノイド、 ビタミン D群、あるいは光線照射が用いられている。また、乾癬患者の皮膚ケラチノサ イトは正常のものと比べて性質が変化しているとの報告もある (Jackson M et al. FASE B J 13:495-502 1999)。乾癬には自己免疫が関与するとも言われている力 乾癬は 一般的な自己免疫疾患とは異なる性質を有する疾患であり、その治療に有用な薬物 の開発が望まれている。 [0009] Psoriasis is a disease that causes abnormal proliferation of epidermal cells such as keratinocytes in combination with leukocyte infiltration into the epidermis or dermis, such as steroids, retinoids, vitamin D group, or light. Irradiation is used. There is also a report that skin keratinocytes in patients with psoriasis have changed properties compared to normal ones (Jackson M et al. FASE B J 13: 495-502 1999). Psoriasis is said to be associated with autoimmunity. Psoriasis is a disease having properties different from those of general autoimmune diseases, and the development of drugs useful for the treatment is desired.
一般式 [I]で示されるゥレア誘導体は好中球の浸潤抑制作用を有し、乾癬等の好中 球が関  The urea derivative represented by the general formula [I] has a neutrophil infiltration-inhibiting action, and is associated with neutrophils such as psoriasis.
与する皮膚疾患の治療剤として有用である。  It is useful as a therapeutic agent for given skin diseases.
[0010] 本発明は、下記一般式 [1]で示される化合物またはその塩類 (以下特記なき限り「 本化合物」とする）を有効成分として含む皮膚疾患治療剤に関するものである。 The present invention relates to a skin disease therapeutic agent comprising a compound represented by the following general formula [1] or a salt thereof (hereinafter referred to as “the present compound” unless otherwise specified) as an active ingredient.
[化 1] NV [Chemical 1] N V
[0011] [式中、 Aは、―（NR4 )―、 - (CR5 R6 )—または— O—を示し; Bは鎖中に、 [0011] [wherein A represents — (NR 4 ) —, — (CR 5 R 6 ) — or —O—; B represents a chain,
、 一 S—、 一 （NR7 ) 一、 一 CO—、 一 N =若しくは , 1 S—, 1 (NR 7 ) 1, 1 CO—, 1 N = or
[化 2]  [Chemical 2]
CH-CH—
Figure imgf000004_0001
CH-CH—
Figure imgf000004_0001
[0012] を含有してもよいアルキレン基またはァルケ-レン基を示し、該アルキレン基およびァ ルケ-レン基はヒドロキシ基、アルコキシ基、シクロアルキル基、ァリール基、シロキシ 基または飽和若しくは不飽和の複素環で置換されて 、てもよく、 Aと結合して飽和の 複素環を形成してもよく； R1 、 R2 、 R4 、 R5および R6は同一または異なって水素原子 、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル基 、ヒドロキシ基、ァシル基またはアミノ基を示し、該アルキル基、アルケニル基、アルキ -ル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ基、 アミノ基、シクロアルキル基、ァダマンチル基、ァリール基、カルボキシル基、アルコキ シカルボニル基、ァリールォキシカルボ-ル基、ァミノカルボ-ル基、シァノ基または 飽和若しくは不飽和の複素環で置換されていてもよく； R1 と R2 、 R2と R4 , R2tR5 および R2と R6は飽和若しくは不飽和の複素環を形成していてもよく； R3はァリール 基または不飽和の複素環を示し; R7は水素原子またはアルキル基を示し; Xは = O または = Sを示し； nは 1〜5の整数を示し；上記された各ァミノ基、ヒドロキシ基および ァミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァダマンチル基、 ァダマンチルアルキル基、ァリール基、ァリールアルキル基、ァシル基、アルコキシァ ルキル基、アルコキシカルボ-ル基、アルキルアミノカルボ-ル基、シクロアルキルォ キシカルボ-ル基、ァリールアルコキシカルボ-ル基、アルキルスルホ-ル基、ァリー ルスルホニル基、ハロゲノアルキルォキシカルボ-ル基、イミダゾリルカルボ-ル基、 ピリジルカルボ-ル基、飽和若しくは不飽和の複素環、または飽和若しくは不飽和の 複素環で置換されたアルキル基で置換されていてもよい。以下同じ。 ] [0012] represents an alkylene group or a alkylene group which may contain, the alkylene group and the alkylene group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated group. May be substituted with a heterocycle and may combine with A to form a saturated heterocycle; R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom, an alkyl A group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group, an acyl group or an amino group, and the alkyl group, alkenyl group, alkyl group, cycloalkyl group or cycloalkenyl group. Group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an adamantyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxy group. - group, Aminokarubo - group, may be substituted by Shiano group or a saturated or unsaturated heterocyclic ring; R 1 and R 2, R 2 and R 4, R 2 tR 5 and R 2 and R 6 May form a saturated or unsaturated heterocyclic ring; R 3 represents an aryl group or an unsaturated heterocyclic ring; R 7 represents a hydrogen atom or an alkyl group; X represents = O or = S; n represents an integer of 1 to 5; the hydrogen atom of each of the above-mentioned amino groups, hydroxy groups and aminocarbonyl groups is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an aryl group alkyl. Group, acyl group, alkoxyalkyl group, alkoxycarbonyl group, alkylaminocarbol group, cycloalkyloxycarboro group, arylalkylalkoxycarboro group, alkylsulfol group, aryl Substituted with an alkyl group substituted with a rusulfonyl group, a halogenoalkyloxycarbonyl group, an imidazolylcarbol group, a pyridylcarbon group, a saturated or unsaturated heterocycle, or a saturated or unsaturated heterocycle It may be. same as below. ]
本化合物は、優れた皮膚炎症部位への好中球の浸潤抑制作用を示し、皮膚疾患 、特に乾  This compound exhibits an excellent neutrophil infiltration-inhibiting action on skin inflammatory sites, and is a skin disease, especially dry.
癬の治療薬として有用である。 発明を実施するための最良の形態  It is useful as a remedy for scabies. BEST MODE FOR CARRYING OUT THE INVENTION
[0013] 一般式 [1]で規定された各基について詳しく説明する。  [0013] Each group defined by the general formula [1] will be described in detail.
[0014] アルキレン基とはメチレン基、エチレン基、トリメチレン基、プロピレン基、テトラメチレ ン基、ペンタメチレン基、へキサメチレン基、オタタメチレン基、デカメチレン基、ドデカ メチレン基、メチルメチレン基、ェチルエチレン基、ジメチルエチレン基、プロピルェ チレン基、イソプロピルエチレン基、メチルトリメチレン基等の 1〜12個の炭素原子を 有する直鎖または分枝のアルキレン基を示す。  [0014] The alkylene group is a methylene group, ethylene group, trimethylene group, propylene group, tetramethylene group, pentamethylene group, hexamethylene group, otatamethylene group, decamethylene group, dodecamethylene group, methylmethylene group, ethethyleneethylene group, dimethylethylene. A linear or branched alkylene group having 1 to 12 carbon atoms such as a group, a propylethylene group, an isopropylethylene group, a methyltrimethylene group and the like;
[0015] ァルケ-レン基とは、ビ-レン基、プロべ-レン基、ブテ-レン基、ペンテ-レン基、 へキセ-レン基、オタテ-レン基、ブタンジイリデン基、メチルプロべ-レン基等の 1個 以上の二重結合を有し、 2〜12個の炭素原子を有する直鎖または分枝のァルケ-レ ン基を示す。  [0015] The alkylene group is a beylene group, a probelene group, a butylene group, a pentylene group, a hexylene group, an otaterene group, a butanediylidene group, or a methylpropylene group. A linear or branched alkylene group having one or more double bonds such as a group and having 2 to 12 carbon atoms.
[0016] アルキル基とはメチル基、ェチル基、プロピル基、ブチル基、へキシル基、ォクチル 基、デシル基、ドデシル基、イソプロピル基、イソブチル基、イソペンチル基、イソへキ シル基、イソォクチル基、 t-ブチル基、 3, 3—ジメチルブチル基等の 1〜12個の炭素 原子を有する直鎖または分枝のアルキル基を示す。  [0016] The alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group, a decyl group, a dodecyl group, an isopropyl group, an isobutyl group, an isopentyl group, an isohexyl group, an isooctyl group, A linear or branched alkyl group having 1 to 12 carbon atoms, such as t-butyl group and 3,3-dimethylbutyl group.
[0017] アルコキシ基とはメトキシ基、エトキシ基、プロポキシ基、ブトキシ基、へキシルォキ シ基、ォクチルォキシ基、デシルォキシ基、ドデシルォキシ基、イソプロポキシ基、 t- ブトキシ基等の 1〜12個の炭素原子を有する直鎖または分枝のアルコキシ基を示す  [0017] The alkoxy group is a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexyloxy group, an octyloxy group, a decyloxy group, a dodecyloxy group, an isopropoxy group, a t-butoxy group, or the like. Represents a straight-chain or branched alkoxy group having
[0018] アルケニル基とはビニル基、ァリル基、 3—ブテニル基、 5—へキセニル基、イソプロ ぺ-ル基等の 2〜 12個の炭素原子を有する直鎖または分枝のアルケニル基を示す [0019] アルキニル基とは、ェチュル基、プロピニル基、ブチニル基等の 2〜12個の炭素原 子を有する直鎖または分枝のアルキ-ル基を示す。 [0018] The alkenyl group refers to a linear or branched alkenyl group having 2 to 12 carbon atoms, such as a vinyl group, an aryl group, a 3-butenyl group, a 5-hexenyl group, and an isopropyl group. [0019] The alkynyl group refers to a straight-chain or branched alkenyl group having 2 to 12 carbon atoms such as an ethul group, a propynyl group, and a butynyl group.
[0020] シクロアルキル基とはシクロプロピル基、シクロブチル基、シクロペンチル基、シクロ へキシル基、シクロへプチル基、シクロォクチル基、シクロデシル基、シクロドデシル 基等の 3〜20個の炭素原子を有するシクロアルキル基を示す。  [0020] The cycloalkyl group is a cycloalkyl having 3 to 20 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and a cyclododecyl group. Indicates a group.
[0021] シクロアルケ-ル基とはシクロペンテ-ル基、シクロへキセ-ル基、シクロへプテ- ル基等の 5〜20個の炭素原子を有するシクロアルケ二ル基を示す。  [0021] The cycloalkenyl group refers to a cycloalkenyl group having 5 to 20 carbon atoms such as a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
[0022] ァリール基とはフエニル基、ナフチル基等の芳香族炭化水素環を示し、それらは 1 個以上の置換基を有してもよぐ置換基としては、例えばアルキル基、シクロアルキル 基、カルボキシ基、アミノ基、ヒドロキシ基、アミノアルキル基、ヒドロキシアルキル基、 ニトロ基、シァノ基、ハロゲン原子、アルキルォキシ基などが挙げられる。  [0022] The aryl group represents an aromatic hydrocarbon ring such as a phenyl group or a naphthyl group, and the substituents which may have one or more substituents include, for example, an alkyl group, a cycloalkyl group, Examples thereof include a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, a hydroxyalkyl group, a nitro group, a cyano group, a halogen atom, and an alkyloxy group.
[0023] シロキシ基とは、トリアルキルシリルォキシ基、ジアルキル（ァリール）シリルォキシ基 、アルキル (ジァリール)ォキシ基、トリアリールシリルォキシ基などの珪素含有有機基 を示す。  [0023] The siloxy group represents a silicon-containing organic group such as a trialkylsilyloxy group, a dialkyl (aryl) silyloxy group, an alkyl (diaryl) oxy group, or a triarylsilyloxy group.
[0024] ハロゲン原子とはフッ素、塩素、臭素、ヨウ素を示す。  [0024] The halogen atom represents fluorine, chlorine, bromine or iodine.
[0025] 複素環とは、例えば窒素原子、酸素原子、硫黄原子を 1〜4個を含む 5〜20員環 の飽和若しくは不飽和の単環式複素環または 2環式複素環を示し、これらの複素環 は、 1個以上の置換基を有してもよぐその置換基としては、例えばアルキル基、シク 口アルキル基、カルボキシ基、アミノ基、ヒドロキシ基、アミノアルキル基、ヒドロキシァ ルキル基、ニトロ基、シァノ基、ハロゲン原子、アルキルォキシ基、ァリール基、ァリー ルアルキル基、飽和若しくは不飽和の複素環などが挙げられる。また上記の複素環 が環内に窒素原子または硫黄原子を有するとき、それらの原子が酸化され、 N—才 キシド、 S—ォキシドなどの形になって!/、てもよ!/、。  [0025] The heterocycle refers to, for example, a 5- to 20-membered saturated or unsaturated monocyclic heterocycle or bicyclic heterocycle containing 1 to 4 nitrogen, oxygen and sulfur atoms. The heterocyclic ring may have one or more substituents. Examples of the substituent include an alkyl group, a cycloalkyl group, a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, and a hydroxyalkyl group. , A nitro group, a cyano group, a halogen atom, an alkyloxy group, an aryl group, an arylalkyl group, a saturated or unsaturated heterocyclic ring, and the like. Also, when the above heterocycle has a nitrogen atom or sulfur atom in the ring, these atoms are oxidized to form N-oxide, S-oxide, etc.!
[0026] 飽和の複素環の具体例としては、窒素原子を環内に有するピロリジン、ピぺリジン、 ホモピぺリジン、ピぺラジン、窒素原子と酸素原子を環内に有するモルホリン、窒素 原子と硫黄原子を環内に有するチオモルホリンなどの単環式複素環が挙げられ、そ れらはベンゼン環等と縮合してテトラヒドロキノリン、テトラヒドロイソキノリンなどの 2環 式複素環を形成してもよい。 [0027] 不飽和の複素環の具体例としては、窒素原子を環内に有するピロール、ピリジン、 ピラゾール、イミダゾール、ピラジン、ピリダジン、ピリミジンなどの単環式複素環または インドール、キノリン、イソキノリン、ベンズイミダゾール、ナフチリジン、ピロ口ピリジン、 イミダゾピリジンなどの 2環式複素環、酸素原子を環内に有するフランなどの単環式 複素環またはべンゾフランなどの 2環式複素環、硫黄原子を環内に有するチオフ ン などの単環式複素環またはベンゾチォフェンなどの 2環式複素環、窒素原子と酸素 原子若しくは硫黄原子を環内に有するォキサゾール、イソォキサゾール、チアゾール 、イソチアゾールなどの単環式複素環またはべンゾォキサゾール、ベンゾチアゾール 、チェノビリジン、ォキサゾロピリジン、チアゾロピリジン、フロピリジンなどの 2環式複 素環などが挙げられる。さらに、上記の不飽和複素環は部分的に飽和結合を含む形 であってもよい。 [0026] Specific examples of the saturated heterocyclic ring include pyrrolidine, piperidine, homopiperidine, piperazine having a nitrogen atom in the ring, morpholine having a nitrogen atom and an oxygen atom in the ring, a nitrogen atom and sulfur. Examples include monocyclic heterocycles such as thiomorpholine having atoms in the ring, and they may be condensed with benzene rings to form bicyclic heterocycles such as tetrahydroquinoline and tetrahydroisoquinoline. [0027] Specific examples of the unsaturated heterocycle include monocyclic heterocycles such as pyrrole, pyridine, pyrazole, imidazole, pyrazine, pyridazine, and pyrimidine having a nitrogen atom in the ring, or indole, quinoline, isoquinoline, and benzimidazole. Bicyclic heterocycles such as naphthyridine, pyrophine pyridine, and imidazopyridine, monocyclic heterocycles such as furan having an oxygen atom in the ring or bicyclic heterocycles such as benzofuran, and sulfur atoms in the ring Monocyclic heterocycles such as thiophene or bicyclic heterocycles such as benzothiophene, monocyclic heterocycles such as oxazole, isoxazole, thiazole and isothiazole having nitrogen and oxygen or sulfur atoms in the ring, or benzoxazole , Benzothiazole, chenoviridine, oxazolopyridine, thi Examples include bicyclic complex rings such as azolopyridine and furopyridine. Further, the unsaturated heterocyclic ring may partially include a saturated bond.
[0028] 本発明における塩類とは医薬として許容される塩であれば特に制限はなぐ塩酸、 硝酸、硫酸、リン酸等の無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、酒石 酸等の有機酸との塩、また、ナトリウム、カリウム、カルシウム等のアルカリ金属または アルカリ土類金属との塩などが挙げられる。また、本ィ匕合物の第四級アンモ-ゥム塩 も本発明における塩類に包含される。さらに、本ィ匕合物に幾何異性体または光学異 性体が存在する場合には、それらの異性体も本発明の範囲に含まれる。なお、本ィ匕 合物は水和物および溶媒和物の形態をとつて 、てもよ 、。  [0028] The salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, liquor. Examples thereof include salts with organic acids such as succinic acid, and salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium. The quaternary ammonium salt of the present compound is also included in the salts in the present invention. Furthermore, when there are geometric isomers or optical isomers in the compound, these isomers are also included in the scope of the present invention. The compound may be in the form of a hydrate or a solvate.
[0029] 本ィ匕合物の好ましい例としては、下記（1)〜（3)のものが挙げられる。 [0029] Preferable examples of the present compound include the following (1) to (3).
[0030] (1)一般式 [1]で規定された各基が以下の基から選択され、またはそれらの組み合 わせ力もなる化合物またはその塩類 [0030] (1) A compound or a salt thereof in which each group defined by the general formula [1] is selected from the following groups or has a combination force thereof:
1) R3：ピリジン環。 1) R 3 : A pyridine ring.
[0031] 2)RJ 、 R2、 R4 、 R5 および R6のうちの少なくとも 1つ：ァダマンチルアルキル基、ァ ダマンチルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァ ミノカルボ-ルアルキル基。 [0031] 2) At least one of R J , R 2 , R 4 , R 5 and R 6 : an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylamino carbo -Rualkyl group.
[0032] 3)Riおよび R2のうちの少なくとも 1つ：ァダマンチルアルキル基、ァダマンチルォキ シアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカルボ-ルァ ノレキノレ基。 [0033] 4)Riおよび R2 のうちの少なくとも 1つ：ァダマンチルアルキル基。 [0032] 3) at least one of Ri and R 2: § Daman chill alkyl group, Adamanchiruoki Shiarukiru group, § Damman chill § amino alkyl group or § Dammann chill § amino carbo - Rua Norekinore group. [0033] 4) at least one of Ri and R 2: § Daman chill alkyl group.
[0034] (2)一般式 [1]で規定された各基が以下の基力 なる化合物またはその塩類 [0034] (2) A compound or salt thereof in which each group defined by the general formula [1] has the following basic force
A: (NR4 ) 、 一 (CR5 R6 ) または O—； A: (NR 4 ), one (CR 5 R 6 ) or O—;
B :鎖中に、 O 、 一 S―、 - (NR7 )―、 一 CO 、 一 N =若しくは B: In the chain, O, 1 S-,-(NR 7 )-, 1 CO, 1 N = or
[化 3]  [Chemical 3]
—— CH-CH— (陶2 —— CH-CH— (Ceramic 2
[0035] を含有してもよいアルキレン基またはァルケ-レン基であって、該アルキレン基はヒド ロキシ基、アルコキシ基、ァリール基、シロキシ基または飽和若しくは不飽和の複素 環で置換されて ヽてもよく、 Aと結合して飽和の複素環を形成してもよ 、、  [0035] An alkylene group or an alkene group which may contain, wherein the alkylene group is substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group or a saturated or unsaturated heterocyclic ring. It may be combined with A to form a saturated heterocycle,
R1：水素原子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロ ァルケ-ル基、ヒドロキシ基またはァミノ基であって、該アルキル基、ァルケ-ル基、 アルキ-ル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロ キシ基、アミノ基、シクロアルキル基、ァリール基、カルボキシル基、アルコキシカルボ -ル基、アルキルアミノカルボ-ル基、ァダマンチル基、ァリールォキシカルボ-ル基 、シァノ基または飽和若しくは不飽和の複素環で置換されていてもよぐ R1 中の各 アミノ基、ヒドロキシ基およびアミノカルボニル基の水素原子はアルキル基、シクロア ルキル基、ァリール基、ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シ クロアルキルォキシカルボ-ル基、ァリールアルコキシカルボ-ル基、ハロゲノアルキ ルォキシカルボ-ル基、イミダゾリルカルボ-ル基、不飽和の複素環または不飽和の 複素環で置換されたアルキル基で置換されて 、てもよ 、、 R 1 : a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, the alkyl group, an alkyl group, an alkyl group Group, cycloalkyl group or cycloalkenyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group group, an alkylaminocarbo group group, an adamantyl group, an aryl group. The hydrogen atom of each amino group, hydroxy group and aminocarbonyl group in R 1 which may be substituted with an oxycarbonyl group, a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, Aryl group, aryl alkyl group, acyl group, alkoxy carbo group, cycloalkyl oxy group, aryl alkoxy group - group, Harogenoaruki Ruokishikarubo - group, imidazolylmethyl carbo - group, substituted by an alkyl group substituted with an unsaturated heterocyclic ring or unsaturated heterocyclic ring, even if I ,,
R2：ァダマンチルアルキル基、ァダマンチルォキシアルキル基、ァダマンチルァミノ アルキル基またはァダマンチルァミノカルボ-ルアルキル基、 R 2 : an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarboalkyl group,
R3 :不飽和の複素環、 R 3 : unsaturated heterocycle,
R4：水素原子、アルキル基、ァダマンチルアルキル基、カルボキシアルキル基、アル コキシカルボ-ル基、アルコキシカルボ-ルアルキル基、アミノ基、アルキルアミノ基、 ァシルァミノ基またはアルコキシカルボ-ルァミノ基、 R 4 : a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarboalkyl group, an amino group, an alkylamino group, An acylamino group or an alkoxycarboamino group,
R5および R6：同一または異なって水素原子、アルキル基、アミノ基またはアルコキシ カルボ-ルァミノ基、 R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group, an amino group or an alkoxy carboamino group,
R7：水素原子またはアルキル基、 R 7 : hydrogen atom or alkyl group,
x: =oまたは =s、  x: = o or = s,
n: l〜5の整数。  n: An integer from 1 to 5.
[0036] これらのうち、 R2がァダマンチルアルキル基であって、 R3がピリジン環であるものが より好まし 、。 Of these, it is more preferable that R 2 is an adamantylalkyl group and R 3 is a pyridine ring.
[0037] さらに、一般式 [1]で規定された各基が以下の基力 なる化合物またはその塩類が 特に好ましい。  [0037] Furthermore, a compound or a salt thereof in which each group defined by the general formula [1] has the following basic force is particularly preferable.
[0038] A:— (NR4 )—、一（CR5 R6 )—または O—； [0038] A: — (NR 4 ) —, one (CR 5 R 6 ) — or O—;
B :鎖中に S 若しくは  B: S or in chain
[化 4]  [Chemical 4]
CH-CH—
Figure imgf000009_0001
CH-CH—
Figure imgf000009_0001
[0039] を含有してもよ 、アルキレン基またはァルケ-レン基、 [0039] may contain an alkylene group or an alkylene group,
R1：アルキル基またはァルケ-ル基であって、該アルキル基はハロゲン原子または ァミノ基で置換されていてもよぐさらに該ァミノ基はアルキル基、ァシル基、ァリール アルキルォキシカルボ-ル基、シクロアルキルォキシカルボ-ル基またはアルコキシ カルボ-ル基で置換されて 、てもよ 、、 R 1 is an alkyl group or an alkyl group, and the alkyl group may be substituted with a halogen atom or an amino group, and the amino group is an alkyl group, an acyl group, an aryl alkyloxycarbon group May be substituted with a cycloalkyloxycarbonyl group or an alkoxycarbol group,
R2：ァダマンチルアルキル基、 R 2 : adamantylalkyl group,
R3：ピリジン環、 R 3 : pyridine ring,
R4 :水素原子、 R 4 : hydrogen atom,
R5および R6 ：水素原子、 R 5 and R 6 : a hydrogen atom,
x: =o、  x: = o,
n: l〜5の整数。 (3)—般式 [1]で規定された各基が以下の基力 なる化合物またはその塩類n: An integer from 1 to 5. (3) —Compounds or salts thereof in which each group defined by the general formula [1] has the following basic strength:
A:— (NR 4)—、— (CR5 R6 )—または— O—； A: — (NR 4 ) —, — (CR 5 R 6 ) — or — O—;
B :鎖中に、— O—、— S―、 - (NR7 )―、— N =若しくは B: in the chain — O—, — S—,-(NR 7 ) —, — N = or
[化 5]  [Chemical 5]
Figure imgf000010_0001
を含有してもよいアルキレン基またはァルケ-レン基であって、該アルキレン基はヒド ロキシ基、アルコキシ基、ァリール基または飽和若しくは不飽和の複素環で置換され て 、てもよく、 Aと結合して飽和の複素環を形成してもよ 、、
Figure imgf000010_0001
An alkylene group or an alkylene group, which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocycle, and is bonded to A To form a saturated heterocycle,
R1：水素原子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロ ァルケ-ル基、ヒドロキシ基またはァミノ基であって、該アルキル基、ァルケ-ル基、 アルキ-ル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロ キシ基、アミノ基、シクロアルキル基、ァリール基、カルボキシル基、アルコキシカルボ -ル基、ァリールォキシカルボニル基、ァミノカルボニル基、シァノ基または飽和若し くは不飽和の複素環で置換されていてもよぐ R1の各ァミノ基、ヒドロキシ基およびァ ミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァリール基、ァリール アルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォキシカルボ-ル 基、ァリールアルコキシカルボ-ル基、不飽和の複素環または不飽和の複素環で置 換されたアルキル基で置換されて 、てもよ 、、 R 1 : a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, the alkyl group, an alkyl group, an alkyl group Group, cycloalkyl group, or cycloalkenyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group group, an aryloxycarbonyl group, an aminocarbonyl group, The hydrogen atom of each amino group, hydroxy group and aminocarbo group of R 1 which may be substituted with a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, an aryl group, Aryl alkyl group, acyl group, alkoxy carbo yl group, cycloalkyloxy carbo ol group, aryl alkoxy carbo ol group, unsaturated heterocyclic ring Is substituted with alkyl group substitution unsaturated heterocyclic ring, I even ,,
R2：アルキル基、ァルケ-ル基、シクロアルキル基、シクロアルキルアルキル基また はァリールアルキル基、 R 2 : an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group or an arylalkyl group,
R3：ピリジン環、 R 3 : pyridine ring,
R4：水素原子、アルキル基、ァダマンチルアルキル基、カルボキシアルキル基、アル コキシカルボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはアル コキシカルボ-ルァミノ基、 R 4 : a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarboalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarboamino group,
R5および R6：同一または異なって水素原子またはアルキル基、 R7：水素原子またはアルキル基、 R 5 and R 6 are the same or different and are a hydrogen atom or an alkyl group, R 7 : hydrogen atom or alkyl group,
x: =oまたは =s、  x: = o or = s,
n: l〜5の整数。  n: An integer from 1 to 5.
[0042] これらのうち、一般式 [1]で規定された各基が以下の基力 なる化合物またはその 塩類がより好ましい。  [0042] Of these, compounds in which each group defined by the general formula [1] has the following basic force or salts thereof are more preferable.
[0043] A: - (NR4 )—または一（CR5R6 )—、 [0043] A:-(NR 4 ) —or one (CR 5 R 6 ) —,
B：アルキレン基またはァルケ-レン基、  B: alkylene group or alkylene group,
R1：アルキル基、ァルケ-ル基であって、該アルキル基はハロゲン原子、アミノ基、シ クロアルキル基、ァリール基、イミダゾール基またはピリジン環で置換されていてもよく 、さらに該ァミノ基はアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキ ルォキシカルボ-ル基またはァリールアルコキシカルボ-ル基で置換されていてもよ い、 R 1 is an alkyl group or a alkenyl group, and the alkyl group may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring. May be substituted with an alkyl group, an acyl group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group or an arylalkylcarbonyl group;
R2：アルキル基、ァルケ-ル基またはァリールアルキル基、 R 2 : an alkyl group, an alkyl group or an aryl alkyl group,
R3：ピリジン環、 R 3 : pyridine ring,
R4：水素原子、 R 4 : hydrogen atom,
R5および R6:水素原子、 R 5 and R 6 : hydrogen atom,
x: =o。  x: = o.
[0044] さらに、これらのうち、 R1が炭素数 3以上のアルキル基であって、 R2がアルキル基ま たはァリールアルキル基である化合物またはその塩類が特に好ましい。 [0044] Further, among these, compounds in which R 1 is an alkyl group having 3 or more carbon atoms and R 2 is an alkyl group or an arylalkyl group or salts thereof are particularly preferable.
[0045] また、一般式 [1]で規定された各基が以下の基力 なる化合物またはその塩類がよ り好ましい。  [0045] Further, a compound or a salt thereof in which each group defined by the general formula [1] has the following basic force is more preferable.
[0046] A: :— (NR4 )—または一（CR5R6 )—、 [0046] A:: — (NR 4 ) —or one (CR 5 R 6 ) —,
B：アルキレン基またはァルケ-レン基、  B: alkylene group or alkylene group,
R1：アルキル基、ァルケ-ル基またはシクロアルキル基であって、該アルキル基はハ ロゲン原子、ヒドロキシ基、アミノ基、シクロアルキル基、ァリール基、カルボキシル基、 アルコキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ-ル基、ピリジ ン環またはチォフェン環で置換されていてもよぐさらに R1中の各ァミノ基、ヒドロキシ 基およびアミノカルボ-ル基の水素原子はアルキル基、ァリール基、ァリールアルキ ル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォキシカルボ-ル基、ァリ ールアルコキシカルボ-ル基で置換されて 、てもよ 、、 R 1 : an alkyl group, an alkenyl group or a cycloalkyl group, and the alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group, an aryl group. It may be substituted with an oxycarbol group, an aminocarbol group, a pyridine ring or a thiophene ring, and the hydrogen atom in each R 1 in R 1 is an alkyl group, an aryl group. Base, Aryl Archi Substituted with an alkyl group, an acyl group, an alkoxy carbo yl group, a cycloalkyloxy carboxy group, an aryl alkoxy carbo ol group,
R2：シクロアルキル基、フエ-ルアルキル基またはシクロアルキルアルキル基、R 2 : a cycloalkyl group, a phenylalkyl group or a cycloalkylalkyl group,
R3：ピリジン環、 R 3 : pyridine ring,
R4：水素原子、 R 4 : hydrogen atom,
R5および R6 ：水素原子、 R 5 and R 6 : a hydrogen atom,
x: =o。  x: = o.
[0047] 本ィ匕合物の最も好ましい具体例として、下記化合物およびその塩類が挙げられる。  [0047] The most preferred specific examples of the present compound include the following compounds and salts thereof.
[0048] 〇 1 [2—（ 1 ァダマンチル）ェチル] 1 ペンチルー 3— [3—（4 ピリジル）プ 口ピル]ゥレア（ィ匕合物 1) [0048] 〇 1 [2— (1 Adamantyl) ethyl] 1 Pentyl 3— [3— (4 Pyridyl) pill] urea (Compound 1)
[化 6]  [Chemical 6]
Figure imgf000012_0001
Figure imgf000012_0001
[0049] 本化合物は、例えば特開 2002— 53555記載の方法によって製造できる。 [0049] This compound can be produced, for example, by the method described in JP-A-2002-53555.
[0050] 本化合物の有用性を調べるベぐ皮膚の炎症に関する薬理試験を実施した。詳細 については後述の薬理試験の項で示す力 本ィ匕合物がマウス皮膚炎症モデルにお いて、好中球浸潤の指標である MPO活性を抑制すること、皮膚炎症を抑制すること が見いだされた。 [0050] A pharmacological test on inflammation of the skin of the skin was conducted to examine the usefulness of this compound. For details, it has been found that the power compound shown in the pharmacological test section described later suppresses MPO activity, which is an indicator of neutrophil infiltration, and suppresses skin inflammation in a mouse skin inflammation model. It was.
[0051] 本発明でいう皮膚疾患とは、種々の原因に起因して表皮、真皮等の皮膚組織に炎 症が生じ、白血球、特に好中球が浸潤し炎症を増悪する疾患である。ケラチノサイト や線維芽細胞等の結合組織の細胞の増殖異常、皮膚組織の肥厚または浮腫を伴う こともある。このような皮膚疾患の具体的疾患としては、例えば乾癬、壊疽性膿皮症、 Sweet症候群、掌せき膿疱症、天疱瘡、水疱性類天疱瘡、疱疹状皮膚炎、多型浸出 性紅斑、結節性紅斑、肉芽腫性血管炎が挙げられる。 [0052] 何らかの原因で皮膚に炎症が生じると、炎症局所に白血球、特に好中球が浸潤す る。浸潤した白血球からは活性酸素、一酸ィ匕窒素のような低分子の炎症性メデイエ 一ター、 GM- CSF、 IFN- γ、 IL-1、 IL- 2、 IL-6に代表されるがこれらに限定されない サイト力イン、 IL- 8、 RANTES, GRO a、 MIG、 IP-10に代表されるがこれらに限定さ れないケモカイン、マトリクスメタ口プロティナーゼのような基質分解酵素、ヒスタミン、 プロスタグランジン類、ロイコトリェン類や PAFに代表される血管透過性亢進因子、 IG F-l, TGF、 KGFに代表されるがこれらに限定されない増殖因子等の種々の因子が 産生される。また、これらの白血球力 分泌される因子がさらに周辺組織力 炎症増 悪に関わる種々の因子を分泌させることもある。これらの因子が複雑に影響しあって 炎症を増悪させ、例えば皮疹、鱗屑、膿疱、水疱、痂皮形成、色素異常等の皮膚病 変を生じさせる。 [0051] The skin disease referred to in the present invention is a disease in which inflammation occurs in skin tissues such as epidermis and dermis due to various causes, and leukocytes, particularly neutrophils, infiltrate and exacerbate inflammation. It may be accompanied by abnormal cell proliferation of connective tissues such as keratinocytes and fibroblasts, thickening of skin tissue or edema. Specific examples of such skin diseases include psoriasis, pyoderma gangrenosuma, Sweet syndrome, palmoplantar pustulosis, pemphigus, bullous pemphigoid, herpes zoster, polymorphic exudative erythema, nodules Erythema and granulomatous vasculitis. [0052] When the skin is inflamed for some reason, leukocytes, particularly neutrophils, infiltrate the inflamed area. Infiltrated leukocytes are typified by reactive oxygen, low molecular weight inflammatory mediators such as nitrous oxide, GM-CSF, IFN-γ, IL-1, IL-2, and IL-6. Not limited to Site Power In, IL-8, RANTES, GRO a, MIG, chemokines such as, but not limited to, IP-10 Substrate-degrading enzymes such as matrix metaprotein, histamine, prostaglandins Various factors such as growth factors such as, but not limited to, vascular permeability enhancing factors such as leukotrienes and PAF, IG Fl, TGF, and KGF are produced. In addition, these leukocyte-secreting factors may also cause secretion of various factors involved in peripheral tissue strength and inflammation. These factors have a complex effect and exacerbate inflammation, causing skin diseases such as skin rash, scales, pustules, blisters, crust formation, and pigmentation.
[0053] このため、白血球、特に好中球の浸潤を抑制する薬物は皮膚の炎症の増悪を抑制 することが可能であり、乾癬、壊疽性膿皮症、 Sweet症候群、掌せき膿疱症、天疱瘡、 水疱性類天疱瘡、疱疹状皮膚炎、多型浸出性紅斑、結節性紅斑、肉芽腫性血管炎 のような皮膚疾患の治療薬として好適である。  [0053] For this reason, drugs that suppress infiltration of leukocytes, particularly neutrophils, can suppress exacerbation of skin inflammation. Psoriasis, pyoderma gangrenosum, Sweet syndrome, palmoplantar pustulosis, It is suitable as a therapeutic agent for skin diseases such as pemphigoid, bullous pemphigoid, herpes zoster, polymorphic exudative erythema, erythema nodosum, granulomatous vasculitis.
[0054] 乾癬については、角質および表皮内への好中球等の白血球の浸潤が認められ、 好中球が炎症の増悪過程に関与すると考えられている。重度の乾癬では活性ィ匕好 中球が皮膚のみならず末梢血中でも検出されることも知られている。末梢血から好中 球を吸着除去することが乾癬の治療に有用であるとの報告もなされて 、る (Kanekura T et al: J Am Acad Dermatol 49:329-332, 2003)。これらの点から、皮膚への白血球 、特に好中球の浸潤抑制作用を有し、皮膚炎症を抑制する本化合物は乾癬の治療 薬として特に好適である。  [0054] Regarding psoriasis, infiltration of leukocytes such as neutrophils into the keratin and epidermis is observed, and neutrophils are considered to be involved in the process of exacerbation of inflammation. In severe psoriasis, it is known that active neutrophils are detected not only in the skin but also in peripheral blood. It has also been reported that adsorptive removal of neutrophils from peripheral blood is useful for the treatment of psoriasis (Kanekura T et al: J Am Acad Dermatol 49: 329-332, 2003). From these points, the present compound which has an action of suppressing infiltration of leukocytes into the skin, particularly neutrophils and suppresses skin inflammation, is particularly suitable as a therapeutic agent for psoriasis.
[0055] 本化合物の投与は非経口でも経口でも行うことができる。投与剤型としては、錠剤、 カプセル剤、顆粒剤、散剤、注射剤、貼付剤、軟膏剤、ローション剤、懸濁剤、エアゾ ール剤等が挙げられる。本ィ匕合物の製剤例は特開 2002— 53555、特開 2003— 2 26686に記載されている力 これらの特許文献記載の方法に限らず、汎用されてい る技術を用いて製剤化をすることができる。例えば、錠剤、カプセル剤、顆粒剤、散 剤等の経口剤は、乳糖、結晶セルロース、デンプン、植物油等の増量剤、ステアリン 酸マグネシウム、タルク等の滑沢剤、ヒドロキシプロピルセルロース、ポリビニルピロリ ドン等の結合剤、カルボキシメチルセルロースカルシウム、低置換ヒドロキシプロピル メチルセルロース等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シ リコン榭脂等のコーティング剤、ゼラチン皮膜等の皮膜剤などを必要に応じて加えて[0055] The compound can be administered parenterally or orally. Examples of the dosage form include tablets, capsules, granules, powders, injections, patches, ointments, lotions, suspensions, and aerosols. Examples of preparations of this compound are the forces described in Japanese Patent Application Laid-Open No. 2002-53555 and Japanese Patent Application Laid-Open No. 2003-2 26686. be able to. For example, oral preparations such as tablets, capsules, granules, powders, etc. are fillers such as lactose, crystalline cellulose, starch, vegetable oil, stearin Lubricants such as magnesium acid and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, coatings such as hydroxypropylmethylcellulose, macrogol, and silicone resin If necessary, add a coating agent such as a coating agent or gelatin coating.
、調製することができる。また、必要に応じ汎用されている技術を用いて徐放ィ匕するこ ともできる。また、必要に応じ密閉療法のための組成物とすることもできる。 Can be prepared. In addition, it is possible to perform sustained release using a widely used technique as required. Moreover, it can also be set as the composition for sealing therapy as needed.
[0056] 本発明は、一般式 [1]で表される化合物またはその塩類を患者に治療に有効な量 投与することからなる皮膚疾患の治療方法にも関する。  [0056] The present invention also relates to a method for treating skin diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by the general formula [1] or a salt thereof.
本化合物の投与量は症状、年令、剤型等によって適宜選択できるが、経口剤であ れば通常 1日当り 0. l〜5000mg、好ましくは l〜1000mgを 1回または数回に分け て投与すればよい。  The dose of this compound can be selected appropriately according to symptoms, age, dosage form, etc., but for oral preparations, it is usually 0.1 to 5000 mg per day, preferably 1 to 1000 mg divided into 1 or several doses. do it.
[0057] 以下に本ィ匕合物を用いた薬理試験の結果を例示するが、これらの例は本発明をよ りょく理解するためのものであり、本発明の範囲を限定するものではない。  [0057] The results of pharmacological tests using the present compounds are illustrated below, but these examples are for better understanding of the present invention and are not intended to limit the scope of the present invention. Absent.
[実施例]  [Example]
[0058] 薬理試験  [0058] Pharmacological studies
マウス耳介炎症モデルに対する作用  Action on mouse ear inflammation model
プロテインキナーゼ Cは皮膚において好中球の活性化、ケラチノサイトの増殖促進 に関与するとされている。プロテインキナーゼ Cの活性化剤であるホルボール 12-ミリ ステート 13-アセテート（PMA)は好中球浸潤、ケラチノサイト増殖促進作用を有し、 P MA惹起皮膚炎症モデルは好中球が関与する皮膚疾患、特に乾癬のモデルとして用 いられる (Alford JG et al: Agents and Actions, 37:260-267, Sato H et al: The Journ al of Dermatology, 30:51-524, 2003)。また、ミエ口ペルォキシダーゼ（MPO)は活性 化好中球に発現している酵素であり、組織における活性ィ匕好中球の浸潤の指標とし て用いられる。 Alfordおよび Satoの方法に準じて、 PMA誘発マウス耳介炎症モデル を用い、本化合物の耳介炎症（耳介厚さおよび重量）および MPO活性に対する本ィ匕 合物の作用を検討した。  Protein kinase C has been implicated in neutrophil activation and keratinocyte proliferation in the skin. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, has a neutrophil infiltration and keratinocyte proliferation promoting action, and PMA-induced skin inflammation model is a skin disease involving neutrophils, It is especially used as a model for psoriasis (Alford JG et al: Agents and Actions, 37: 260-267, Sato H et al: The Journ of Dermatology, 30: 51-524, 2003). In addition, myelin peroxidase (MPO) is an enzyme expressed in activated neutrophils and is used as an index of infiltration of activated neutrophils in tissues. According to the method of Alford and Sato, PMA-induced mouse pinna inflammation model was used to examine the effect of this compound on pinna inflammation (auricle thickness and weight) and MPO activity of this compound.
[0059] (被験化合物含有液の調製）  [0059] (Preparation of test compound-containing solution)
上述したィ匕合物 1を 1%メチルセルロース水溶液に懸濁して被験化合物含有液を 用時調製した。 The above compound 1 is suspended in a 1% methylcellulose aqueous solution to prepare a test compound-containing solution. Prepared at the time of use.
[0060] 対照薬としてのベタメタゾン 21-リン酸ナトリウム塩についても上記と同様にしてその 含有液を調製した。  [0060] A liquid containing betamethasone 21-phosphate sodium salt as a control drug was prepared in the same manner as described above.
[0061] (使用動物） [0061] (Animal used)
CD-l(ICR)系マウス（雄性、 20〜28g)を使用した。これらを 6日間の馴化の後、各群 4乃至 8匹で実験に供した。  CD-l (ICR) mice (male, 20-28 g) were used. These were subjected to the experiment in 4 to 8 animals in each group after acclimatization for 6 days.
[0062] (実験方法） [0062] (Experimental method)
指定用量の被験化合物含有液を経口投与し、 30分経過した後、 正常対照群を除 く各群に PMAのエタノール溶液を各個体の右側耳介表面に塗布した。なお、正常対 照群および病態対照群には、媒体である 1%メチルセルロース水溶液を同様に投与 した。また、ベタメタゾン 21-リン酸ナトリウム塩は、ベタメタゾン換算で指定用量となる ように投与した。 6時間後に、右耳介および左耳介の厚さをマイクロメーターゲージを 用いて測定し、その差を耳介厚さとした。また、摘出した右耳介および左耳介それぞ れの重量を測定し、その差を耳介重量とした。重量測定後、右耳介組織をホモジネ ートし、 Desserらの方法 (Desse  A test compound-containing solution at the specified dose was orally administered, and after 30 minutes, an ethanol solution of PMA was applied to the right auricle surface of each individual except for the normal control group. The normal control group and the disease state control group were similarly administered with 1% methylcellulose aqueous solution as a vehicle. Betamethasone 21-phosphate sodium salt was administered at a designated dose in terms of betamethasone. After 6 hours, the thickness of the right and left pinna was measured using a micrometer gauge, and the difference was taken as the pinna thickness. In addition, the weights of the extracted right and left auricles were measured, and the difference was taken as the weight of the auricle. After weighing, homogenize the right auricular tissue and use the method of Desser et al.
r RK他： Archives of Biochemistry and Biophysics 148; 452-465, 1972)に準じグアヤ コール法を用いて上清中の MPO活性を測定した。また、同じサンプルの蛋白量を測 定し、 MPO活性の補正に用いた。  r RK et al .: MPO activity in the supernatant was measured using the guaiacol method according to Archives of Biochemistry and Biophysics 148; 452-465, 1972). In addition, the amount of protein in the same sample was measured and used to correct MPO activity.
[0063] (結果評価） [0063] (Result evaluation)
各耳介サンプルの MPO活性は以下の式で補正した。  The MPO activity of each pinna sample was corrected by the following formula.
[0064] MPO活性 (U/g protein) = MPO活性 (U) /蛋白量（g) [0064] MPO activity (U / g protein) = MPO activity (U) / protein amount (g)
また、耳介厚さ、耳介重量および MPO活性のそれぞれの抑制率は以下の式で求め た。  In addition, the respective inhibition rates of auricle thickness, auricle weight, and MPO activity were determined by the following equations.
[0065] 抑制率（%) = {1- (薬物投与群の平均値-正常対照群の平均値)/ (病態対照群の平均 値-正常対照群の平均値) }X 100  [0065] Inhibition rate (%) = {1- (mean value of drug administration group−mean value of normal control group) / (mean value of disease state control group−mean value of normal control group)} X 100
このように求めた耳介厚さおよび耳介重量を表 1に、 MPO活性を表 2にそれぞれ示 す。結果は全て平均士標準誤差、抑制率で示した。  Table 1 shows the pinna thickness and pinna weight, and Table 2 shows the MPO activity. All the results are shown as average standard error and inhibition rate.
[表 1] 耳介浮腫 耳介重量 群 用量 耳介厚さ 抑制率 耳介重量 抑制率 [table 1] Auricular Edema Auricular Weight Group Dose Auricular Thickness Inhibition Rate Auricular Weight Inhibition Rate
(mg kg) (mm) (%) (mg) (%) 正常対照群 0·03 0.01 - 3.1 1.8 - 病態対照群 0 0.29 土 0.02 - 51.6 ± 2.2 - 化合物 "I 100 0.09 土 0.01 69 17.1 ± 1.8 67 ベタメタゾン 10 0·11 土 0'01 62 12.2 土 1.2 76 (mg kg) (mm) (%) (mg) (%) Normal control group 0 ・ 03 0.01-3.1 1.8-Pathological control group 0 0.29 Sat 0.02-51.6 ± 2.2-Compound `` I 100 0.09 Sat 0.01 69 17.1 ± 1.8 67 betamethasone 10 0 - 11 Sat 0 '01 62 12.2 Sat 1.2 76
[0066] 表 1から明らかなように、化合物 1は ΡΜΑ刺激による耳介厚さの増加および耳介重 量増加を抑制し、皮膚炎症の抑制作用を有することが示された。その抑制作用は対 照薬であるベタメタゾンと同等であった。 [0066] As is clear from Table 1, it was shown that Compound 1 has an inhibitory effect on skin inflammation by suppressing an increase in auricle thickness and an increase in auricle weight due to acupuncture stimulation. The inhibitory action was equivalent to that of betamethasone as a control agent.
[表 2] 用量 ΜΡΟ活性 抑制  [Table 2] Dose ΜΡΟ activity suppression
(mg/kg) (U/g protein) (%) 正常対照群 33 10 - 病態対照群 0 337 ± 56 - 化合物 1 100 42 ± 12 87 ベタメタゾン 10 70 土 27 79  (mg / kg) (U / g protein) (%) Normal control group 33 10-Disease control group 0 337 ± 56-Compound 1 100 42 ± 12 87 Betamethasone 10 70 Sat 27 79
[0067] 表 2から明らかなように、化合物 1は PMA刺激による MPO活性を抑制したことから、 皮膚への好中球浸潤抑制作用を有することが示された。その抑制作用は対照薬で あるベタメタゾンと同等であった。 [0067] As is clear from Table 2, Compound 1 inhibited MPO activity by PMA stimulation, indicating that it has an action to inhibit neutrophil infiltration into the skin. The inhibitory effect was equivalent to that of betamethasone, a control drug.
[0068] 上記の薬理試験の結果から、本化合物は優れた皮膚への好中球浸潤抑制作用お よび皮膚炎症抑制作用を示し、皮膚疾患治療薬として有用であることが認められる。 製剤例 [0068] From the results of the above pharmacological tests, it is recognized that the present compound exhibits an excellent action for suppressing neutrophil infiltration into skin and skin inflammation, and is useful as a therapeutic agent for skin diseases. Formulation example
本ィ匕合物の経口剤および注射剤としての一般的な製剤例を以下に示す。  Examples of general formulations of the present compound as oral preparations and injections are shown below.
1)錠剤  1) Tablet
処方 l (100mg中）  Formula l (in 100mg)
本ィ匕合物 1 mg 乳糖 66. 4mg This compound 1 mg Lactose 66. 4mg
トウモロコシデンプン 20 mg  Corn starch 20 mg
カノレボキシメチノレセノレロースカルシウム 6 mg  Canoleboxoxymethinoresenololose calcium 6 mg
ヒドロキシプロピルセルロース 4 mg  Hydroxypropylcellulose 4 mg
ステアリン酸マグネシウム 0. 6mg  Magnesium stearate 0.6mg
[0069] 上記処方の錠剤に、コーティング剤（例えば、ヒドロキシプロピルメチルセルロース、 マクロゴール、シリコン榭脂等通常のコーティング剤） 2mgを用いてコーティングを施 し、 目的とするコーティング錠を得る（以下の処方の錠剤も同じ)。また、本化合物お よび添加物の量を適宜変更することにより、所望の錠剤を得ることができる。 [0069] The tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone rosin) to obtain the desired coated tablet (the following formulation) The same is true for tablets. In addition, desired tablets can be obtained by appropriately changing the amounts of the present compound and additives.
2)カプセル剤  2) Capsule
処方 l (150mg中）  Formula l (in 150mg)
本化合物 5 mg  This compound 5 mg
乳糖 145 mg  Lactose 145 mg
[0070] 本ィ匕合物および乳糖の混合比を適宜変更することにより、所望のカプセル剤を得る ことができる。  [0070] A desired capsule can be obtained by appropriately changing the mixing ratio of the present compound and lactose.
3)注射剤  3) Injection
処方 1 (10ml中）  Formula 1 (in 10ml)
本化合物 10〜： LOO mg  This compound 10 ~: LOO mg
塩化ナトリウム 90 mg  Sodium chloride 90 mg
水酸化ナトリウム適量  Sodium hydroxide appropriate amount
塩酸適量  Suitable amount of hydrochloric acid
滅菌精製水適量  Appropriate amount of sterile purified water
[0071] 本化合物および添加物の混合比を適宜変更することにより、所望の注射剤を得ること ができる。  [0071] A desired injection can be obtained by appropriately changing the mixing ratio of the compound and the additive.

Claims

請求の範囲  The scope of the claims
[1] 下記一般式 [1]で表される化合物またはその塩類を有効成分として含む皮膚疾患 治療剤。  [1] A skin disease therapeutic agent comprising a compound represented by the following general formula [1] or a salt thereof as an active ingredient.
[化 1]  [Chemical 1]
[1]
Figure imgf000018_0001
[1]
Figure imgf000018_0001
[式中、 Αは、―（NR4 )―、 - (CR5 R6 )—または— O—を示し; Bは鎖中に、 、 一 S—、 一 （NR7 ) 一、 一 CO—、 一 N =若しくは [Wherein Α represents — (NR 4 ) —, — (CR 5 R 6 ) — or —O—; B represents, in the chain, 1 S—, 1 (NR 7 ) 1, 1 CO— , N = or
[化 2]  [Chemical 2]
-CH-CH—
Figure imgf000018_0002
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基およびァ ルケ-レン基はヒドロキシ基、アルコキシ基、シクロアルキル基、ァリール基、シロキシ 基または飽和若しくは不飽和の複素環で置換されて 、てもよく、 Aと結合して飽和の 複素環を形成してもよく； R1 、 R2 、 R4 、 R5および R6は同一または異なって水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基、ァシル基またはアミノ基を示し、該アルキル基、アルケニル基、アル キニル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ 基、アミノ基、シクロアルキル基、ァダマンチル基、ァリール基、カルボキシル基、アル コキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ-ル基、シァノ基ま たは飽和若しくは不飽和の複素環で置換されていてもよく； R1 Rz 、 R2 tR4 、 R2 と および R2と R6は飽和若しくは不飽和の複素環を形成していてもよく； R3はァリ ール基または不飽和の複素環を示し; R7は水素原子またはアルキル基を示し; Xは = Oまたは = Sを示し； nは 1〜5の整数を示し；上記された各ァミノ基、ヒドロキシ基お よびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァダマンチル 基、ァダマンチルアルキル基、ァリール基、ァリールアルキル基、ァシル基、アルコキ シアルキル基、アルコキシカルボ-ル基、アルキルアミノカルボ-ル基、シクロアルキ ルォキシカルボ-ル基、ァリールアルコキシカルボ-ル基、アルキルスルホ-ル基、 ァリールスルホ-ル基、ハロゲノアルキルォキシカルボ-ル基、イミダゾリルカルボ- ル基、ピリジルカルボニル基、飽和若しくは不飽和の複素環、または飽和若しくは不 飽和の複素環で置換されたアルキル基で置換されて 、てもよ 、。 ] -CH-CH—
Figure imgf000018_0002
Which may contain an alkylene group or a alkene group, and the alkylene group and alkylene group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And may be combined with A to form a saturated heterocyclic ring; R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom or an alkyl group. , Alkyl group, alkyl group, cycloalkyl group, cycloalkenyl group, hydroxy group, acyl group or amino group, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group Is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an adamantyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxyball. R 1 R z , R 2 tR 4 , R 2 and R 2 and R 6 may be saturated or unsaturated, which may be substituted with a group, an aminocarbol group, a cyano group or a saturated or unsaturated heterocyclic ring. A saturated heterocyclic ring may be formed; R 3 represents an aryl group or an unsaturated heterocyclic ring; R 7 represents a hydrogen atom or an alkyl group; X represents = O or = S; n represents an integer of 1 to 5; each amino group, hydroxy group and And the hydrogen atom of the aminocarbol group is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an allyl group, an allylalkyl group, an acyl group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkylaminocarboxyl group. Group, cycloalkyl group, cycloalkyl group, arylsulfonyl group, arylsulfol group, halogenoalkyloxycarbonyl group, imidazolyl carbo yl group, pyridyl carbonyl group, saturated or unsaturated Substituted with a saturated heterocycle or an alkyl group substituted with a saturated or unsaturated heterocycle. ]
[2] R3がピリジン環である請求項 1記載の皮膚疾患治療剤。 [2] R 3 is a skin disease therapeutic agent according to claim 1 which is pyridine ring.
[3] R2 、 R4 、 R5および R6の少なくとも 1つ力 ァダマンチルアルキル基、ァダマン チルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカル ボニルアルキル基である請求項 1記載の皮膚疾患治療剤。 [3] At least one of R 2 , R 4 , R 5 and R 6 is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group. The therapeutic agent for skin diseases according to claim 1.
[4] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基、ァダマンチルォキシアル キル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカルボ-ルアルキル 基である請求項 1記載の皮膚疾患治療剤。 [4] At least one of R 1 and R 2 is an adamantylalkyl group, an adamantylalkylalkyl group, an adamantylaminoalkyl group, or an adamantylaminocarboalkyl group. The skin disease therapeutic agent as described.
[5] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基である請求項 1記載の皮 膚疾患治療剤。 [5] skin disease therapeutic agent of claim 1, wherein at least one force § Dammann chill alkyl group of R 1 and R 2.
[6] Aが一（NR4 ) 一、 - (CR5 R6 )—または一 O を示し; Bが鎖中に、 O 、 一 S 一、一（NR7 ) 一、 CO 、 一 N =若しくは [6] A represents one (NR 4 ) one,-(CR 5 R 6 ) — or one O; B represents O, 1 S one, one (NR 7 ) one, CO, one N = in the chain Or
[化 3]  [Chemical 3]
Figure imgf000019_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基、シロキシ基または飽和若しくは不飽和の複素環 で置換されていてもよぐ Aと結合して飽和の複素環を形成してもよく; R1 が水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキニル基、 シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ基、アミノ基 、シクロアルキル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、アルキ ルァミノカルボ-ル基、ァダマンチル基、ァリールォキシカルボ-ル基、シァノ基また は飽和若しくは不飽和の複素環で置換されていてもよぐ上記された各ァミノ基、ヒド ロキシ基およびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァリ ール基、ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォ キシカルボ-ル基、ァリールアルコキシカルボ-ル基、ハロゲノアルキルォキシカル ボ-ル基、イミダゾリルカルボ-ル基、不飽和の複素環または不飽和の複素環で置 換されたアルキル基で置換されていてもよく； R2がァダマンチルアルキル基、ァダマ ンチルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノ力 ルポ-ルアルキル基を示し; R3が不飽和の複素環を示し; R4が水素原子、アルキル 基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカルボ-ル基、ァ ルコキシカルボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはァ ルコキシカルボニルァミノ基を示し; R5および R6が同一または異なって水素原子、ァ ルキル基、アミノ基またはアルコキシカルボニルァミノ基を示し; R7が水素原子または アルキル基を示し; が = Oまたは = Sを示し； nが 1 5の整数を示す請求項 1記載 の皮膚疾患治療剤。
Figure imgf000019_0001
A represents an alkylene group or a alkene group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. To form a saturated heterocyclic ring; R 1 represents a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. The alkyl group, alkenyl group, alkynyl group, A cycloalkyl group or a cycloalkenyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbo group, an alkylaminocarbo group, an adamantyl group, an aryloxycarbo group. The hydrogen atom of each of the above-mentioned amino groups, hydroxy groups, and aminocarbo groups, which may be substituted with a ruthenium group, a cyano group, or a saturated or unsaturated heterocyclic ring, is an alkyl group, a cycloalkyl group, an aryl group. Group, arylalkyl group, acyl group, alkoxycarbonyl group, cycloalkyloxycarboxyl group, aryloxycarboxyl group, halogenoalkyloxycarboxyl group, imidazolylcarbol group, Optionally substituted with an unsaturated heterocycle or an alkyl group substituted with an unsaturated heterocycle; R 2 is adamanti A rualkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylamino force group alkyl group; R 3 represents an unsaturated heterocyclic ring; R 4 represents a hydrogen atom, an alkyl group , An adamantylalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an amino group, an alkylamino group, an acylamino group, or an alkoxycarbonylamino group; R 5 and R 6 are the same Or differently represents a hydrogen atom, an alkyl group, an amino group or an alkoxycarbonylamino group; R 7 represents a hydrogen atom or an alkyl group; represents = O or = S; n represents an integer of 15 Item 1. A skin disease treatment agent according to Item 1.
[7] R2がァダマンチルアルキル基を示し、 R3がピリジン環を示す請求項 6記載の皮膚 疾患治療剤。 7. The skin disease therapeutic agent according to claim 6, wherein R 2 represents an adamantylalkyl group and R 3 represents a pyridine ring.
[8] Aがー（NR4 ) CR5 R6 )—または O を示し; Bが鎖中に S—若しくは[8] A represents-(NR 4 ) CR 5 R 6 ) — or O; B represents S—or in the chain
[化 4] [Chemical 4]
CH-CH—
Figure imgf000020_0001
を含有してもよいアルキレン基またはァルケ-レン基を示し; R1がアルキル基または ァルケ-ル基を示し、該アルキル基はハロゲン原子またはァミノ基で置換されて 、て もよぐさらに該ァミノ基はアルキル基、ァシル基、ァリールアルキルォキシカルボ-ル 基、シクロアルキルォキシカルボ-ル基またはアルコキシカルボ-ル基で置換されて いてもよく； R2がァダマンチルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; が = Oを示し； nが 1〜5の整数を示す請 求項 6記載の皮膚疾患治療剤。 CH-CH—
Figure imgf000020_0001
R 1 represents an alkyl group or a alkenyl group, and the alkyl group is substituted with a halogen atom or an amino group, and the amino group may be further substituted. Groups are alkyl groups, acyl groups, arylalkyloxycarbons R 2 represents an adamantylalkyl group; R 3 represents a pyridine ring; R 4 represents a hydrogen atom; and may be substituted with a group, a cycloalkyloxycarbonyl group or an alkoxycarbonyl group. Wherein R 5 and R 6 represent a hydrogen atom; represents = O; n represents an integer of 1 to 5, The skin disease therapeutic agent according to claim 6.
Aが、一（NR4) —、 - (CR5 R6 )—または一 O を示し; Bが鎖中に、 O 、 一 S 一、一（NR7 ) 一、一 N =若しくは A represents one (NR 4 ) —, — (CR 5 R 6 ) — or one O; B represents O, 1 S one, one (NR 7 ) one, one N = or in the chain
[化 5]  [Chemical 5]
CH—' CH—
Figure imgf000021_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基または飽和若しくは不飽和の複素環で置換されて いてもよぐ Aと結合して飽和の複素環を形成してもよく； R1が水素原子、アルキル基 、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル基、ヒドロキシ基 またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル 基またはシクロアルケニル基は、ハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキ ル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ -ル基、ァミノカルボ-ル基、シァノ基または飽和若しくは不飽和の複素環で置換さ れていてもよぐ上記された各ァミノ基、ヒドロキシ基およびアミノカルボニル基の水素 原子はアルキル基、シクロアルキル基、ァリール基、ァリールアルキル基、ァシル基、 アルコキシカルボ-ル基、シクロアルキルォキシカルボ-ル基、ァリールアルコキシ力 ルボニル基、不飽和の複素環または不飽和の複素環で置換されたアルキル基で置 換されていてもよく； R2がアルキル基、ァルケ-ル基、シクロアルキル基、シクロアルキ ルアルキル基またはァリールアルキル基を示し; R3がピリジン環を示し; R4が水素原 子、アルキル基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカル ボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはアルコキシカル ボニルアミノ基を示し; R5および R6が同一または異なって水素原子またはアルキル 基を示し； R7が水素原子またはアルキル基を示し； が = Oまたは = Sを示し； nが 1〜 5の整数を示す請求項 1記載の皮膚疾患治療剤。 CH— 'CH—
Figure imgf000021_0001
Or an alkylene group or a alkene group, which is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R 1 may be a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. Group, alkyl group, alkyl group, cycloalkyl group or cycloalkenyl group are a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxy group. Each of the above-mentioned amino groups, hydroxy groups and hydroxy groups, which may be substituted with a carbo group, an amino group, a cyano group or a saturated or unsaturated heterocyclic ring. And the hydrogen atom of the aminocarbonyl group is an alkyl group, a cycloalkyl group, an aryl group, an aryl group, an acyl group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an aryloxy alkoxy group, an unsaturated group. Or an alkyl group substituted with an unsaturated heterocyclic ring; R 2 represents an alkyl group, a alkenyl group, a cycloalkyl group, a cycloalkylalkyl group or an arylalkyl group; R 3 represents a pyridine ring; R 4 represents a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an amino group, an alkylamino group, an acylcarbonylamino group, or an alkoxycarbonylamino group. R 5 and R 6 are the same or different and are hydrogen atom or alkyl The skin disease therapeutic agent according to claim 1, wherein R 7 represents a hydrogen atom or an alkyl group; represents = O or = S; and n represents an integer of 1 to 5.
[10] A力 - (NR4 )—または一（CR 6 )—を示し; Bがアルキレン基またはァルケ- レン基を示し; R1がアルキル基、ァルケ-ル基を示し、該アルキル基はハロゲン原子 、アミノ基、シクロアルキル基、ァリール基、イミダゾール基またはピリジン環で置換さ れていてもよぐさらに該ァミノ基はアルキル基、ァシル基、アルコキシカルボ-ル基、 シクロアルキルォキシカルボ-ル基またはァリールアルコキシカルボ-ル基で置換さ れていてもよく； R2がアルキル基、ァルケ-ル基またはァリールアルキル基を示し; R3 がピリジン環を示し; R4 が水素原子を示し; R5および R6が水素原子を示し; Xが =0 を示す請求項 9記載の皮膚疾患治療剤。 [10] A force-(NR 4 ) — or one (CR 6 ) —; B represents an alkylene group or an alkene group; R 1 represents an alkyl group or an alkenyl group, and the alkyl group is It may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring. Further, the amino group may be an alkyl group, an acyl group, an alkoxycarbo group, a cycloalkyloxycarbo- group. R 2 represents an alkyl group, a alkenyl group or an aryl alkyl group; R 3 represents a pyridine ring; R 4 represents a hydrogen atom The therapeutic agent for skin diseases according to claim 9, wherein R 5 and R 6 represent a hydrogen atom; and X represents = 0.
[11] R1がアルキル基を示し、 R2がアルキル基またはァリールアルキル基を示す請求項 1 0記載の皮膚疾患治療剤。 11. The skin disease therapeutic agent according to claim 10, wherein R 1 represents an alkyl group, and R 2 represents an alkyl group or an arylalkyl group.
[12] A力 - (NR4)—または一（CR 6 )—を示し; Bがアルキレン基またはァルケ-レ ン基を示し; R1がアルキル基、ァルケ-ル基またはシクロアルキル基を示し、該アル キル基はハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキル基、ァリール基、カル ボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ- ル基、ピリジン環またはチォフェン環で置換されていてもよぐさらに上記された各アミ ノ基、ヒドロキシ基およびアミノカルボニル基の水素原子はアルキル基、ァリール基、 ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォキシカル ボ-ル基、ァリールアルコキシカルボ-ル基で置換されていてもよく； R2がシクロアル キル基またはシクロアルキルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; Xが =0を示す請求項 9記載の皮膚疾患 治療剤。 [12] A force-(NR 4 ) — or one (CR 6 ) —; B represents an alkylene group or an alkene group; R 1 represents an alkyl group, an alkenyl group, or a cycloalkyl group The alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxy group, an alkoxy carbo group, an aryl carboxy group, an amino carbo ol group, a pyridine ring or a thiophene. The hydrogen atom of each amino group, hydroxy group and aminocarbonyl group which may be substituted with a ring is an alkyl group, aryl group, aryl alkyl group, acyl group, alkoxy carbo group, cycloalkyl group. May be substituted with an oxycarbonyl group or an arylalkoxycarbonyl group; R 2 represents a cycloalkyl group or a cycloalkylalkyl group; R 3 represents a pyridine ring The therapeutic agent for skin disease according to claim 9, wherein R 4 represents a hydrogen atom; R 5 and R 6 represent a hydrogen atom; and X represents = 0.
[13] 1 [ 2—（ 1 ァダマンチル）ェチル] 1 ペンチル 3— [ 3—（4 ピリジル）プロ ピル]ゥレアまたはその塩類を有効成分として含む皮膚疾患治療剤。  [13] 1 [2- (1 adamantyl) ethyl] 1 pentyl 3- [3- (4 pyridyl) propyl] urea or a salt thereof as an active ingredient.
[14] 皮膚疾患が皮膚組織への白血球の浸潤を伴う皮膚疾患である請求項 1〜13の 、ず れかに記載の皮膚疾患治療剤。  14. The skin disease therapeutic agent according to any one of claims 1 to 13, wherein the skin disease is a skin disease accompanied by leukocyte infiltration into the skin tissue.
[15] 白血球が好中球である請求項 14に記載の皮膚疾患治療剤。 [16] 皮膚疾患が乾癬、壊疽性膿皮症、 Sweet症候群、掌せき膿疱症、天疱瘡、水疱性 類天疱瘡、疱疹状皮膚炎、多型浸出性紅斑、結節性紅斑または肉芽腫性血管炎で ある請求項 1〜13のいずれかに記載の皮膚疾患治療剤。 15. The skin disease therapeutic agent according to claim 14, wherein the leukocytes are neutrophils. [16] Skin diseases are psoriasis, pyoderma gangrenosum, Sweet syndrome, palmoplantar pustulosis, pemphigus, bullous pemphigoid, herpes zosteritis, polymorphic exudative erythema, erythema nodosum or granulomatous blood vessels The skin disease therapeutic agent according to any one of claims 1 to 13, which is a flame.
[17] 皮膚疾患が乾癬である請求項 16に記載の皮膚疾患治療剤。 17. The skin disease therapeutic agent according to claim 16, wherein the skin disease is psoriasis.
[18] 剤型が錠剤、カプセル剤、顆粒剤、散剤、注射剤、貼付剤、軟膏剤、ローション剤、 懸濁剤またはエアゾール剤である請求項 1〜13のいずれかに記載の皮膚疾患治療 剤。 [18] The skin disease treatment according to any one of claims 1 to 13, wherein the dosage form is a tablet, capsule, granule, powder, injection, patch, ointment, lotion, suspension, or aerosol. Agent.
[19] 下記一般式 [1]で表される化合物またはその塩類を患者に治療に有効な量投与 することからなる皮膚疾患の治療方法。  [19] A method for treating a skin disease, comprising administering to a patient a therapeutically effective amount of a compound represented by the following general formula [1] or a salt thereof.
[化 6]  [Chemical 6]
NV NV
[式中、 Aは、―（NR4 )―、 - (CR5 R6 )—または— O—を示し; Bは鎖中に、— O— 、 一 S—、 一 （NR7 ) 一、 一 CO—、 一 N =若しくは [In the formula, A represents — (NR 4 ) —, — (CR 5 R 6 ) — or —O—; B represents —O—, 1 S—, 1 (NR 7 ) 1, 1 CO—, 1 N = or
[化 7]  [Chemical 7]
CH-CH—
Figure imgf000023_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基およびァ ルケ-レン基はヒドロキシ基、アルコキシ基、シクロアルキル基、ァリール基、シロキシ 基または飽和若しくは不飽和の複素環で置換されて 、てもよく、 Aと結合して飽和の 複素環を形成してもよく； R1 、 R2 、 R4 、 R5および R6は同一または異なって水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基、ァシル基またはアミノ基を示し、該アルキル基、アルケニル基、アル キニル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ 基、アミノ基、シクロアルキル基、ァダマンチル基、ァリール基、カルボキシル基、アル コキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ-ル基、シァノ基ま たは飽和若しくは不飽和の複素環で置換されていてもよく； R1 R2 、 R2 tR4 、 R2 と および R2と R6は飽和若しくは不飽和の複素環を形成していてもよく； R3はァリ ール基または不飽和の複素環を示し; R7は水素原子またはアルキル基を示し; Xは = Oまたは = Sを示し； nは 1〜5の整数を示し；上記された各ァミノ基、ヒドロキシ基お よびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァダマンチル 基、ァダマンチルアルキル基、ァリール基、ァリールアルキル基、ァシル基、アルコキ シアルキル基、アルコキシカルボ-ル基、アルキルアミノカルボ-ル基、シクロアルキ ルォキシカルボ-ル基、ァリールアルコキシカルボ-ル基、アルキルスルホ-ル基、 ァリールスルホ-ル基、ハロゲノアルキルォキシカルボ-ル基、イミダゾリルカルボ- ル基、ピリジルカルボニル基、飽和若しくは不飽和の複素環、または飽和若しくは不 飽和の複素環で置換されたアルキル基で置換されて 、てもよ 、。 ] CH-CH—
Figure imgf000023_0001
Which may contain an alkylene group or a alkene group, and the alkylene group and alkylene group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And may be combined with A to form a saturated heterocyclic ring; R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom or an alkyl group. , Alkyl group, alkyl group, cycloalkyl group, cycloalkenyl group, hydroxy group, acyl group or amino group, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group Is a halogen atom, hydroxy Group, amino group, cycloalkyl group, adamantyl group, aryl group, carboxyl group, alkoxy carboxylic group, aralkyl carboxylic group, amino carbonyl group, cyano group or saturated or unsaturated heterocyclic ring R 1 R 2 , R 2 tR 4 , R 2 and R 2 and R 6 may form a saturated or unsaturated heterocycle; R 3 may be aryl. shows a heterocyclic group or an unsaturated; R 7 represents a hydrogen atom or an alkyl group; X is = O or = indicates S; n is an integer of 1 to 5; said been the Amino group, hydroxy group And the hydrogen atom of the aminocarbo group is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an aryl group, an acyl group, an alkoxyalkyl group, an alkoxycarbo group group, an alkylaminocarbo group. -Le , Cycloalkyloxycarbonyl group, arylalkoxycarb group, alkylsulfonyl group, arylsulfol group, halogenoalkyloxycarbonyl group, imidazolylcarbon group, pyridylcarbonyl group, saturated or unsaturated Substituted with an alkyl group substituted with a heterocycle, or a saturated or unsaturated heterocycle. ]
[20] R3がピリジン環である請求項 19記載の治療方法。 20. The treatment method according to claim 19, wherein R 3 is a pyridine ring.
[21] R2 、 R4 、 R5および R6の少なくとも 1つ力 ァダマンチルアルキル基、ァダマン チルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカル ボニルアルキル基である請求項 19記載の治療方法。 [21] At least one of R 2 , R 4 , R 5 and R 6 is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group. 20. The treatment method according to claim 19.
[22] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基、ァダマンチルォキシアル キル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカルボ-ルアルキル 基である請求項 19記載の治療方法。 [22] At least one of R 1 and R 2 is an adamantylalkyl group, an adamantylalkylalkyl group, an adamantylaminoalkyl group, or an adamantylaminocarboalkyl group. The method of treatment described.
[23] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基である請求項 19記載の 治療方法。 [23] The method according to [19], wherein at least one of R 1 and R 2 is an adamantylalkyl group.
[24] Aが—（NR4 )―、 - (CR5 R6 )—または— O を示し; Bが鎖中に、 O—、— S 一、一（NR7 ) 一、 CO 、 一 N =若しくは [24] A represents — (NR 4 ) —, — (CR 5 R 6 ) — or — O; B represents O—, — S one, one (NR 7 ) one, CO, one N in the chain = Or
[化 8]  [Chemical 8]
Figure imgf000024_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基、シロキシ基または飽和若しくは不飽和の複素環 で置換されていてもよぐ Aと結合して飽和の複素環を形成してもよく; R1 が水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキニル基、 シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ基、アミノ基 、シクロアルキル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、アルキ ルァミノカルボ-ル基、ァダマンチル基、ァリールォキシカルボ-ル基、シァノ基また は飽和若しくは不飽和の複素環で置換されていてもよぐ上記された各ァミノ基、ヒド ロキシ基およびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァリ ール基、ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォ キシカルボ-ル基、ァリールアルコキシカルボ-ル基、ハロゲノアルキルォキシカル ボ-ル基、イミダゾリルカルボ-ル基、不飽和の複素環または不飽和の複素環で置 換されたアルキル基で置換されていてもよく； R2がァダマンチルアルキル基、ァダマ ンチルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノ力 ルポ-ルアルキル基を示し; R3が不飽和の複素環を示し; R4が水素原子、アルキル 基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカルボ-ル基、ァ ルコキシカルボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはァ ルコキシカルボニルァミノ基を示し; R5および R6が同一または異なって水素原子、ァ ルキル基、アミノ基またはアルコキシカルボニルァミノ基を示し; R7が水素原子または アルキル基を示し； Xが = Oまたは = Sを示し； nが 1 5の整数を示す請求項 19記載 の治療方法。
Figure imgf000024_0001
A represents an alkylene group or a alkene group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. To form a saturated heterocyclic ring; R 1 represents a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxy carbo yl group, an alkyl group; It may be substituted with a ruaminocarbol group, an adamantyl group, an aryloxycarbol group, a cyano group or a saturated or unsaturated heterocyclic ring. The hydrogen atom of each amino group, hydroxy group, and aminocarbo ol group described above is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxy carbo yl group, a cycloalkyl oxy carboxy group. Substituted with an alkyl group substituted by an aryl group, an arylalkoxycarbol group, a halogenoalkyloxycarboxyl group, an imidazolylcarbol group, an unsaturated heterocyclic ring or an unsaturated heterocyclic ring. R 2 represents an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group, or an adamantylamino force group alkyl group; and R 3 represents an unsaturated heterocyclic ring. It is shown; R 4 is a hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, alkoxycarbonyl - group, § Rukokishikarubo - Ruarukiru group, an amino group Alkylamino group, an Ashiruamino group or § alkoxycarbonyl § amino group; R 5 and R 6 are the same or different and each represents a hydrogen atom, § alkyl group, an amino group or an alkoxycarbonyl § amino group; R 7 is a hydrogen atom Or an alkyl group; X represents = O or = S; and n represents an integer of 15.
[25] R2がァダマンチルアルキル基を示し、 R3がピリジン環を示す請求項 24記載の治療 方法。 [25] R 2 represents § Damman chill alkyl group, a method of treatment of claim 24, wherein R 3 represents a pyridine ring.
[26] Aがー（NR4 ) CR5 R6 )—または O を示し; Bが鎖中に S—若しくは [化 9]
Figure imgf000026_0001
を含有してもよいアルキレン基またはァルケ-レン基を示し; R1がアルキル基または ァルケ-ル基を示し、該アルキル基はハロゲン原子またはァミノ基で置換されて 、て もよぐさらに該ァミノ基はアルキル基、ァシル基、ァリールアルキルォキシカルボ-ル 基、シクロアルキルォキシカルボ-ル基またはアルコキシカルボ-ル基で置換されて いてもよく； R2がァダマンチルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; が = Oを示し； nが 1〜5の整数を示す請 求項 24記載の治療方法。 [26] A represents-(NR 4 ) CR 5 R 6 ) — or O; B represents S— or [Chemical 9] in the chain
Figure imgf000026_0001
R 1 represents an alkyl group or a alkenyl group, and the alkyl group is substituted with a halogen atom or an amino group, and the amino group may be further substituted. The group may be substituted with an alkyl group, an acyl group, an arylalkyloxycarbonyl group, a cycloalkyloxycarbonyl group or an alkoxycarbo- col group; R 2 represents an adamantylalkyl group; 25, wherein R 3 represents a pyridine ring; R 4 represents a hydrogen atom; R 5 and R 6 represent a hydrogen atom; represents = O; and n represents an integer of 1 to 5. Method of treatment.
Aが、一（NR4) —、 - (CR5 R6 )—または一 O を示し; Bが鎖中に、 O 、 一 S 一、 一 （NR7 ) 一、 一 N =若しくは A represents one (NR 4 ) —,-(CR 5 R 6 ) — or one O; B represents O, one S one, one (NR 7 ) one, one N = or in the chain
[化 10]  [Chemical 10]
CH—' CH—
Figure imgf000026_0002
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基または飽和若しくは不飽和の複素環で置換されて いてもよぐ Aと結合して飽和の複素環を形成してもよく； R1が水素原子、アルキル基 、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル基、ヒドロキシ基 またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル 基またはシクロアルケニル基は、ハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキ ル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ -ル基、ァミノカルボ-ル基、シァノ基または飽和若しくは不飽和の複素環で置換さ れていてもよぐ上記された各ァミノ基、ヒドロキシ基およびアミノカルボニル基の水素 原子はアルキル基、シクロアルキル基、ァリール基、ァリールアルキル基、ァシル基、 アルコキシカルボ-ル基、シクロアルキルォキシカルボ-ル基、ァリールアルコキシ力 ルボニル基、不飽和の複素環または不飽和の複素環で置換されたアルキル基で置 換されていてもよく； R2がアルキル基、ァルケ-ル基、シクロアルキル基、シクロアルキ ルアルキル基またはァリールアルキル基を示し; R3がピリジン環を示し; R4が水素原 子、アルキル基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカル ボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはアルコキシカル ボニルアミノ基を示し; R5および R6が同一または異なって水素原子またはアルキル 基を示し； R7が水素原子またはアルキル基を示し； が = Oまたは = Sを示し； nが 1〜 5の整数を示す請求項 19記載の治療方法。 CH— 'CH—
Figure imgf000026_0002
Or an alkylene group or a alkene group, which is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R 1 may be a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. Group, alkyl group, alkyl group, cycloalkyl group or cycloalkenyl group are a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxy group. Each of the above-mentioned amino groups, hydroxy groups and hydroxy groups, which may be substituted with a carbo group, an amino group, a cyano group or a saturated or unsaturated heterocyclic ring. Hydrogen atoms of the fine aminocarbonyl group represents an alkyl group, a cycloalkyl group, Ariru group, § reel alkyl group, Ashiru group, alkoxycarbonyl - group, a cycloalkyl O propoxycarbonyl - group, § reel alkoxy force R 2 may be substituted with an alkyl group substituted with a sulfonyl group, an unsaturated heterocyclic ring or an unsaturated heterocyclic ring; R 2 is an alkyl group, a alkenyl group, a cycloalkyl group, a cycloalkylalkyl group or an aryl. R 3 represents a pyridine ring; R 4 represents a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarboalkyl group, an amino group, an alkylamino group, an acylamino group or Represents an alkoxycarbonylamino group; R 5 and R 6 are the same or different and represent a hydrogen atom or an alkyl group; R 7 represents a hydrogen atom or an alkyl group; represents = O or = S; n represents 1 to 5 The treatment method according to claim 19, which represents an integer of.
[28] A力 - (NR4 )—または一（CR 6 )—を示し; Bがアルキレン基またはァルケ- レン基を示し; R1がアルキル基、ァルケ-ル基を示し、該アルキル基はハロゲン原子 、アミノ基、シクロアルキル基、ァリール基、イミダゾール基またはピリジン環で置換さ れていてもよぐさらに該ァミノ基はアルキル基、ァシル基、アルコキシカルボ-ル基、 シクロアルキルォキシカルボ-ル基またはァリールアルコキシカルボ-ル基で置換さ れていてもよく； R2がアルキル基、ァルケ-ル基またはァリールアルキル基を示し; R3 がピリジン環を示し; R4が水素原子を示し; R5および R6が水素原子を示し; Xが =0を 示す請求項 27記載の治療方法。 [28] A force-(NR 4 ) — or one (CR 6 ) —; B represents an alkylene group or an alkene group; R 1 represents an alkyl group or an alkenyl group, and the alkyl group is It may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring. Further, the amino group may be an alkyl group, an acyl group, an alkoxycarbo group, a cycloalkyloxycarbo- group. R 2 represents an alkyl group, a alkenyl group or an aryl alkyl group; R 3 represents a pyridine ring; R 4 represents a hydrogen atom 28. The method according to claim 27, wherein R 5 and R 6 represent a hydrogen atom; and X represents = 0.
[29] R1がアルキル基を示し、 R2がアルキル基またはァリールアルキル基を示す請求項 2 8記載の治療方法。 29. The method according to claim 28, wherein R 1 represents an alkyl group, and R 2 represents an alkyl group or an arylalkyl group.
[30] A力 - (NR4)—または一（CR5R6 )—を示し; Bがアルキレン基またはァルケ-レ ン基を示し; R1がアルキル基、ァルケ-ル基またはシクロアルキル基を示し、該アル キル基はハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキル基、ァリール基、カル ボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ- ル基、ピリジン環またはチォフェン環で置換されていてもよぐさらに上記された各アミ ノ基、ヒドロキシ基およびアミノカルボニル基の水素原子はアルキル基、ァリール基、 ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォキシカル ボ-ル基、ァリールアルコキシカルボ-ル基で置換されていてもよく； R2がシクロアル キル基またはシクロアルキルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; Xが =0を示す請求項 27記載の治療方 [31] 1 [2—（ 1 ァダマンチル）ェチル] 1 ペンチル 3— [3—（4 ピリジル）プロ ピル]ゥレアまたはその塩類を患者に治療に有効な量投与することからなる皮膚疾患 の治療方法。 [30] A force-(NR 4 ) — or one (CR 5 R 6 ) —; B represents an alkylene group or a alkene group; R 1 represents an alkyl group, an alkenyl group, or a cycloalkyl group The alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxy group, an alkoxy carb group, an aryl carboxy group, an amino carbo group, a pyridine ring. Alternatively, the hydrogen atom of each amino group, hydroxy group and aminocarbonyl group which may be substituted with a thiophen ring is an alkyl group, an aryl group, an aryl alkyl group, an acyl group, an alkoxycarbo group group, cycloalkyl O alkoxy Cal ball - group, § reel alkoxycarbonyl - may be substituted with Le group; R 2 represents a cycloalkyl group or a cycloalkyl group; R 3 is pyrid Shows a ring; R 4 represents hydrogen atom; R 5 and R 6 represents a hydrogen atom; treatment side of X claim 27 showing a is = 0 [31] 1 [2- (1-adamantyl) ethyl] 1-pentyl 3- [3- (4-pyridyl) propyl] urea or a salt thereof is administered to a patient in a therapeutically effective amount.
[32] 皮膚疾患が皮膚組織への白血球の浸潤を伴う皮膚疾患である請求項 19〜31の 、 ずれかに記載の治療方法。  [32] The treatment method according to any one of claims 19 to 31, wherein the skin disease is a skin disease accompanied by infiltration of leukocytes into the skin tissue.
[33] 白血球が好中球である請求項 32に記載の治療方法。 [33] The method according to claim 32, wherein the leukocytes are neutrophils.
[34] 皮膚疾患が乾癬、壊疽性膿皮症、 Sweet症候群、掌せき膿疱症、天疱瘡、水疱性 類天疱瘡、疱疹状皮膚炎、多型浸出性紅斑、結節性紅斑または肉芽腫性血管炎で ある請求項 19〜31のいずれかに記載の治療方法。  [34] Skin diseases are psoriasis, pyoderma gangrenosum, Sweet syndrome, palmoplantar pustulosis, pemphigus, bullous pemphigoid, herpes zosteritis, polymorphic exudative erythema, erythema nodosum or granulomatous blood vessels 32. The treatment method according to any one of claims 19 to 31, which is a flame.
[35] 皮膚疾患が乾癬である請求項 34に記載の治療方法。  [35] The method according to claim 34, wherein the skin disease is psoriasis.
[36] 投与を錠剤、カプセル剤、顆粒剤、散剤、注射剤、貼付剤、軟膏剤、ローション剤、 懸濁剤またはエアゾール剤の形態で行う請求項 19〜31のいずれかに記載の治療 方法。  [36] The method according to any one of claims 19 to 31, wherein the administration is performed in the form of a tablet, capsule, granule, powder, injection, patch, ointment, lotion, suspension, or aerosol. .
[37] 皮膚疾患治療剤を製造するための、下記一般式 [1]で表される化合物またはその 塩類の使用。  [37] Use of a compound represented by the following general formula [1] or a salt thereof for the manufacture of a therapeutic agent for skin diseases.
[化 11]  [Chemical 11]
NV NV
[式中、 Aは、―（NR4 )―、 - (CR5 R6 )—または— O を示し; Bは鎖中に、 O— 、 一 S 、 一 （NR7 ) 一、 一 CO 、 一 N =若しくは [In the formula, A represents — (NR 4 ) —, — (CR 5 R 6 ) — or —O; B represents O—, 1 S, 1 (NR 7 ) 1, 1 CO, N = or
[化 12]  [Chemical 12]
CH-CH—
Figure imgf000028_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基およびァ ルケ-レン基はヒドロキシ基、アルコキシ基、シクロアルキル基、ァリール基、シロキシ 基または飽和若しくは不飽和の複素環で置換されて 、てもよく、 Aと結合して飽和の 複素環を形成してもよく； R1、 R2、 R4、 R5および R6は同一または異なって水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基、ァシル基またはアミノ基を示し、該アルキル基、アルケニル基、アル キニル基、シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ 基、アミノ基、シクロアルキル基、ァダマンチル基、ァリール基、カルボキシル基、アル コキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ-ル基、シァノ基ま たは飽和若しくは不飽和の複素環で置換されていてもよく； R1 Rz、 R2 tR4 、 R2 と および R2と R6は飽和若しくは不飽和の複素環を形成していてもよく； R3はァリ ール基または不飽和の複素環を示し; R7は水素原子またはアルキル基を示し; Xは = Oまたは = Sを示し； nは 1〜5の整数を示し；上記された各ァミノ基、ヒドロキシ基お よびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァダマンチル 基、ァダマンチルアルキル基、ァリール基、ァリールアルキル基、ァシル基、アルコキ シアルキル基、アルコキシカルボ-ル基、アルキルアミノカルボ-ル基、シクロアルキ ルォキシカルボ-ル基、ァリールアルコキシカルボ-ル基、アルキルスルホ-ル基、 ァリールスルホ-ル基、ハロゲノアルキルォキシカルボ-ル基、イミダゾリルカルボ- ル基、ピリジルカルボニル基、飽和若しくは不飽和の複素環、または飽和若しくは不 飽和の複素環で置換されたアルキル基で置換されて 、てもよ 、。 ] CH-CH—
Figure imgf000028_0001
Which may contain an alkylene group or a alkene group, and the alkylene group and alkylene group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And may be combined with A to form a saturated heterocyclic ring; R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom or an alkyl group. , Alkyl group, alkyl group, cycloalkyl group, cycloalkenyl group, hydroxy group, acyl group or amino group, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group Is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an adamantyl group, an aryl group, a carboxyl group, an alkoxycarbonyl group, an aryloxyball. R 1 R z , R 2 tR 4 , R 2 and R 2 and R 6 may be saturated or unsaturated, which may be substituted with a group, an aminocarbol group, a cyano group or a saturated or unsaturated heterocyclic ring. A saturated heterocyclic ring may be formed; R 3 represents an aryl group or an unsaturated heterocyclic ring; R 7 represents a hydrogen atom or an alkyl group; X represents = O or = S; n represents an integer of 1 to 5; the hydrogen atom of each of the above amino group, hydroxy group and aminocarbol group is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an aryl group. Alkyl group, acyl group, alkoxyalkyl group, alkoxycarbonyl group, alkylaminocarboxyl group, cycloalkyloxycarbonyl group, aryloxyalkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, halogenoal group Ruokishikarubo - group, imidazolylmethyl carbo - group, pyridylcarbonyl group, saturated or unsaturated heterocycle or a saturated or substituted by an alkyl group substituted with an unsaturated heterocyclic ring, even if,. ]
[38] R3がピリジン環である請求項 37記載の使用。 [38] The use according to claim 37, wherein R 3 is a pyridine ring.
[39] R R2、 R4、 R5および R6の少なくとも 1つ力 ァダマンチルアルキル基、ァダマン チルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカル ボニルアルキル基である請求項 37記載の使用。 [39] At least one of RR 2 , R 4 , R 5 and R 6 is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group. 38. Use according to claim 37.
[40] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基、ァダマンチルォキシアル キル基、ァダマンチルァミノアルキル基またはァダマンチルァミノカルボ-ルアルキル 基である請求項 37記載の使用。 [40] At least one of R 1 and R 2 is an adamantylalkyl group, an adamantylalkylalkyl group, an adamantylaminoalkyl group, or an adamantylaminocarboalkyl group. Use of description.
[41] R1および R2の少なくとも 1つ力 ァダマンチルアルキル基である請求項 37記載の 使用。 [41] according to claim 37, wherein at least one force § Dammann chill alkyl group of R 1 and R 2 use.
[42] Aが—（NR4 )―、 - (CR5 R6 )—または— O を示し; Bが鎖中に、 O—、— S 一、一（NR7 ) 一、 CO 、 一 N =若しくは [42] A represents — (NR 4 ) —, — (CR 5 R 6 ) — or — O; B represents O—, — S one, one (NR 7 ) one, CO, one N in the chain = Or
[化 13]  [Chemical 13]
Figure imgf000030_0001
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基、シロキシ基または飽和若しくは不飽和の複素環 で置換されていてもよぐ Aと結合して飽和の複素環を形成してもよく; R1 が水素原 子、アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル 基、ヒドロキシ基またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキニル基、 シクロアルキル基またはシクロアルケ-ル基は、ハロゲン原子、ヒドロキシ基、アミノ基 、シクロアルキル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、アルキ ルァミノカルボ-ル基、ァダマンチル基、ァリールォキシカルボ-ル基、シァノ基また は飽和若しくは不飽和の複素環で置換されていてもよぐ上記された各ァミノ基、ヒド ロキシ基およびアミノカルボ-ル基の水素原子はアルキル基、シクロアルキル基、ァリ ール基、ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォ キシカルボ-ル基、ァリールアルコキシカルボ-ル基、ハロゲノアルキルォキシカル ボ-ル基、イミダゾリルカルボ-ル基、不飽和の複素環または不飽和の複素環で置 換されたアルキル基で置換されていてもよく； R2がァダマンチルアルキル基、ァダマ ンチルォキシアルキル基、ァダマンチルァミノアルキル基またはァダマンチルァミノ力 ルポ-ルアルキル基を示し; R3が不飽和の複素環を示し; R4が水素原子、アルキル 基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカルボ-ル基、ァ ルコキシカルボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはァ ルコキシカルボニルァミノ基を示し; R5および R6が同一または異なって水素原子、ァ ルキル基、アミノ基またはアルコキシカルボニルァミノ基を示し; R7が水素原子または アルキル基を示し; が = Oまたは = Sを示し； nが 1〜5の整数を示す請求項 37記載 の使用。
Figure imgf000030_0001
A represents an alkylene group or a alkene group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. To form a saturated heterocyclic ring; R 1 represents a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxy carbo yl group, an alkyl group; It may be substituted with a ruaminocarbol group, an adamantyl group, an aryloxycarbol group, a cyano group or a saturated or unsaturated heterocyclic ring. The hydrogen atom of each amino group, hydroxy group, and aminocarbo ol group described above is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxy carbo yl group, a cycloalkyl oxy carboxy group. Substituted with an alkyl group substituted by an aryl group, an arylalkoxycarbol group, a halogenoalkyloxycarboxyl group, an imidazolylcarbol group, an unsaturated heterocyclic ring or an unsaturated heterocyclic ring. R 2 represents an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group, or an adamantylamino force group alkyl group; and R 3 represents an unsaturated heterocyclic ring. It is shown; R 4 is a hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, alkoxycarbonyl - group, § Rukokishikarubo - Ruarukiru group, an amino group Alkylamino group, an Ashiruamino group or § alkoxycarbonyl § amino group; R 5 and R 6 are the same or different and each represents a hydrogen atom, § alkyl group, an amino group or an alkoxycarbonyl § amino group; R 7 is a hydrogen atom Or 38. Use according to claim 37, which represents an alkyl group; represents = O or = S; n represents an integer from 1 to 5.
[43] R2がァダマンチルアルキル基を示し、 R3がピリジン環を示す請求項 42記載の使用 [43] The use according to claim 42, wherein R 2 represents an adamantylalkyl group, and R 3 represents a pyridine ring.
[44] Aが一（NR4 )—、一（CR5 R6 )—または一 O を示し; Bが鎖中に一 S 若しくは [化 14] [44] A represents one (NR 4 ) —, one (CR 5 R 6 ) —, or one O; B represents one S in the chain or
—— CH-CH—
Figure imgf000031_0001
を含有してもよいアルキレン基またはァルケ-レン基を示し; R1がアルキル基または ァルケ-ル基を示し、該アルキル基はハロゲン原子またはァミノ基で置換されて 、て もよぐさらに該ァミノ基はアルキル基、ァシル基、ァリールアルキルォキシカルボ-ル 基、シクロアルキルォキシカルボ-ル基またはアルコキシカルボ-ル基で置換されて いてもよく； R2がァダマンチルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; が = Oを示し； nが 1〜5の整数を示す請 求項 42記載の使用。 —— CH-CH—
Figure imgf000031_0001
R 1 represents an alkyl group or a alkenyl group, and the alkyl group is substituted with a halogen atom or an amino group, and the amino group may be further substituted. The group may be substituted with an alkyl group, an acyl group, an arylalkyloxycarbonyl group, a cycloalkyloxycarbonyl group or an alkoxycarbo- col group; R 2 represents an adamantylalkyl group; 43. The claim according to claim 42, wherein R 3 represents a pyridine ring; R 4 represents a hydrogen atom; R 5 and R 6 represent a hydrogen atom; represents = O; and n represents an integer of 1 to 5 use.
[45] Aが、一（NR4)—、 - (CR5 R6 )—または一 O を示し; Bが鎖中に、 O 、 一 S 一、一（NR7 ) 一、 N=若しくは [45] A represents one (NR 4 ) —, — (CR 5 R 6 ) —, or one O; B represents O, 1 S, 1 (NR 7 ) 1, N = or
[化 15]  [Chemical 15]
—— CH-CH—
Figure imgf000031_0002
を含有してもよ 、アルキレン基またはァルケ-レン基を示し、該アルキレン基はヒドロ キシ基、アルコキシ基、ァリール基または飽和若しくは不飽和の複素環で置換されて いてもよぐ Aと結合して飽和の複素環を形成してもよく； R1が水素原子、アルキル基 、ァルケ-ル基、アルキ-ル基、シクロアルキル基、シクロアルケ-ル基、ヒドロキシ基 またはアミノ基を示し、該アルキル基、ァルケ-ル基、アルキ-ル基、シクロアルキル 基またはシクロアルケニル基は、ハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキ ル基、ァリール基、カルボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ -ル基、ァミノカルボ-ル基、シァノ基または飽和若しくは不飽和の複素環で置換さ れていてもよぐ上記された各ァミノ基、ヒドロキシ基およびアミノカルボニル基の水素 原子はアルキル基、シクロアルキル基、ァリール基、ァリールアルキル基、ァシル基、 アルコキシカルボ-ル基、シクロアルキルォキシカルボ-ル基、ァリールアルコキシ力 ルボニル基、不飽和の複素環または不飽和の複素環で置換されたアルキル基で置 換されていてもよく； R2がアルキル基、ァルケ-ル基、シクロアルキル基、シクロアルキ ルアルキル基またはァリールアルキル基を示し; R3がピリジン環を示し; R4が水素原 子、アルキル基、ァダマンチルアルキル基、カルボキシアルキル基、アルコキシカル ボ-ルアルキル基、アミノ基、アルキルアミノ基、ァシルァミノ基またはアルコキシカル ボニルアミノ基を示し; R5および R6が同一または異なって水素原子またはアルキル 基を示し； R7が水素原子またはアルキル基を示し； が = Oまたは = Sを示し； nが 1〜 5の整数を示す請求項 37記載の使用。 —— CH-CH—
Figure imgf000031_0002
Or an alkylene group or a alkene group, which is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R 1 may be a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxy group or an amino group. Group, alkyl group, alkyl group, cycloalkyl group Group or cycloalkenyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxy carbo yl group, an aryl carboxy group, an amino carbo ol group, a cyano group or a saturated group. Alternatively, the hydrogen atom of each of the above amino groups, hydroxy groups and aminocarbonyl groups which may be substituted with an unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, an aryl group, an aryl group, an acyl group, R 2 may be substituted with an alkoxy group substituted with an alkoxy carbo yl group, a cycloalkyloxy carbo yl group, an aryl alkoxy force carbonyl group, an unsaturated heterocyclic ring or an unsaturated heterocyclic ring; There alkyl group, Aruke - group, a cycloalkyl group, an cycloalkyl Ruarukiru group or § reel alkyl group; R 3 is Shows the lysine ring; R 4 is hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, Arukokishikaru ball - shows Ruarukiru group, an amino group, an alkylamino group, an Ashiruamino group or Arukokishikaru Boniruamino group; R 5 and R 6 represent the same or different hydrogen atom or alkyl group; R 7 represents a hydrogen atom or alkyl group, is = O or = indicates S; n is claim 37, wherein an integer of from 1 to 5 Use of.
[46] A力 - (NR4 )—または一（CR5R6 )—を示し; Bがアルキレン基またはァルケ- レン基を示し; R1がアルキル基、ァルケ-ル基を示し、該アルキル基はハロゲン原子 、アミノ基、シクロアルキル基、ァリール基、イミダゾール基またはピリジン環で置換さ れていてもよぐさらに該ァミノ基はアルキル基、ァシル基、アルコキシカルボ-ル基、 シクロアルキルォキシカルボ-ル基またはァリールアルコキシカルボ-ル基で置換さ れていてもよく； R2がアルキル基、ァルケ-ル基またはァリールアルキル基を示し; R3 がピリジン環を示し; R4が水素原子を示し; R5および R6が水素原子を示し; Xが =0を 示す請求項 45記載の使用。 [46] A force-(NR 4 ) — or one (CR 5 R 6 ) —; B represents an alkylene group or an alkene group; R 1 represents an alkyl group or an alkenyl group; The group may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring. Further, the amino group may be an alkyl group, an acyl group, an alkoxycarbo group, a cycloalkyloxy group. R 2 represents an alkyl group, an alkenyl group or an arylalkyl group; R 3 represents a pyridine ring; and R 4 represents a pyridine ring. 46. Use according to claim 45, wherein R represents hydrogen atom; R 5 and R 6 represent hydrogen atom; and X represents = 0.
[47] R1がアルキル基を示し、 R2がアルキル基またはァリールアルキル基を示す請求項 3 7記載の使用。 [47] The use according to claim 37, wherein R 1 represents an alkyl group, and R 2 represents an alkyl group or an arylalkyl group.
[48] A力 - (NR4)—または一（CR5R6 )—を示し; Bがアルキレン基またはァルケ-レ ン基を示し; R1がアルキル基、ァルケ-ル基またはシクロアルキル基を示し、該アル キル基はハロゲン原子、ヒドロキシ基、アミノ基、シクロアルキル基、ァリール基、カル ボキシル基、アルコキシカルボ-ル基、ァリールォキシカルボ-ル基、ァミノカルボ- ル基、ピリジン環またはチォフェン環で置換されていてもよぐさらに上記された各アミ ノ基、ヒドロキシ基およびアミノカルボニル基の水素原子はアルキル基、ァリール基、 ァリールアルキル基、ァシル基、アルコキシカルボ-ル基、シクロアルキルォキシカル ボ-ル基、ァリールアルコキシカルボ-ル基で置換されていてもよく； R2がシクロアル キル基またはシクロアルキルアルキル基を示し; R3がピリジン環を示し; R4が水素原 子を示し; R5および R6が水素原子を示し; Xが =0を示す請求項 45記載の使用。 [48] A force-(NR 4 ) — or one (CR 5 R 6 ) —; B represents an alkylene group or a alkene group; R 1 represents an alkyl group, an alkenyl group, or a cycloalkyl group The alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxy group, an alkoxy carbo group, an aryl carboxy group, an amino carbo- group. The hydrogen atom of each amino group, hydroxy group and aminocarbonyl group which may be substituted with a benzene group, a pyridine ring or a thiophene ring is an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxy group. R 2 represents a cycloalkyl group or a cycloalkylalkyl group; R 3 represents a pyridine ring; and may be substituted with a carbo yl group, a cycloalkyloxy carbo ol group, or an arylalkoxy carbo ol group; 46. Use according to claim 45, wherein R 4 represents a hydrogen atom; R 5 and R 6 represent a hydrogen atom; and X represents = 0.
[49] 皮膚疾患治療剤を製造するための、 1 [2—（1ーァダマンチル)ェチル] 1ーぺ ンチルー 3— [3—（4 ピリジル）プロピル]ゥレアまたはその塩類の使用。  [49] Use of 1 [2- (1-adamantyl) ethyl] 1-pentyl 3- [3- (4 pyridyl) propyl] urea or a salt thereof for the manufacture of a therapeutic agent for skin diseases.
[50] 皮膚疾患が皮膚組織への白血球の浸潤を伴う皮膚疾患である請求項 37〜49の 、 ずれかに記載の使用。  [50] The use according to any one of claims 37 to 49, wherein the skin disease is a skin disease accompanied by infiltration of leukocytes into the skin tissue.
[51] 白血球が好中球である請求項 50に記載の使用。  51. The use according to claim 50, wherein the leukocytes are neutrophils.
[52] 皮膚疾患が乾癬、壊疽性膿皮症、 Sweet症候群、掌せき膿疱症、天疱瘡、水疱性 類天疱瘡、疱疹状皮膚炎、多型浸出性紅斑、結節性紅斑または肉芽腫性血管炎で ある請求項 37〜49の 、ずれかに記載の使用。  [52] Skin disease is psoriasis, pyoderma gangrenosum, Sweet syndrome, palmoplantar pustulosis, pemphigus, bullous pemphigoid, herpes zosteritis, polymorphic exudative erythema, erythema nodosum or granulomatous blood vessels 50. Use according to any of claims 37 to 49, which is a flame.
[53] 皮膚疾患が乾癬である請求項 52に記載の使用。  [53] The use according to claim 52, wherein the skin disease is psoriasis.
[54] 財形が錠剤、カプセル剤、顆粒剤、散剤、注射剤、貼付剤、軟膏剤、ローション剤、 懸濁剤またはエアゾール剤である請求項 37〜49のいずれかに記載の使用。  [54] The use according to any of claims 37 to 49, wherein the shape is a tablet, capsule, granule, powder, injection, patch, ointment, lotion, suspension or aerosol.
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