WO2006035760A1 - Médicament pour le traitement de maladies de peau - Google Patents

Médicament pour le traitement de maladies de peau Download PDF

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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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group
alkyl
alkyl group
hydrogen atom
cycloalkyl
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PCT/JP2005/017720
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English (en)
Japanese (ja)
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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/fr

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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.

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Abstract

La présente invention décrit un dérivé d’urée dont la structure est donnée par la formule générale [1] ci-dessous, et qui présente un nouvel effet pharmacologique. Ledit dérivé d’urée, dont la structure est donnée par la formule générale [1] ci-dessous, ou un sel dérivé de ce composé, présente un excellent effet curatif vis-à-vis des maladies de peau. Dans la formule ci-dessous, A représente -(NR4)-, -(CR5R6)- ou -O- ; B représente un groupement alkylène ou alcénylène ; R1, R2, R4, R5 et R6 représentent chacun un atome d’hydrogène, un groupement alkyle, un groupement alcényle, un groupement adamantylakyle, ou un groupement similaire ; R3 représente un groupement aryle ou un hétérocycle insaturé ; et X représente un atome d'oxygène ou de soufre.
PCT/JP2005/017720 2004-09-27 2005-09-27 Médicament pour le traitement de maladies de peau WO2006035760A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-279395 2004-09-27
JP2004279395 2004-09-27

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US8686006B2 (en) 2008-10-22 2014-04-01 Santen Pharmaceutical Co., Ltd. Pharmaceutical composition for improving intestinal absorption

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JPH07165555A (ja) * 1993-12-09 1995-06-27 Shiseido Co Ltd 皮膚外用剤
JP2002053555A (ja) * 2000-05-31 2002-02-19 Santen Pharmaceut Co Ltd ＴＮＦ−α産生阻害物質
WO2002098869A2 (fr) * 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. Composes de cycloalkyl uree condense avec un 1,4-disubstitue benzo
JP2003192659A (ja) * 2001-12-26 2003-07-09 Bayer Ag フェニル尿素誘導体
WO2003077847A2 (fr) * 2002-03-12 2003-09-25 Merck & Co., Inc. Amides substitues
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JP2002053555A (ja) * 2000-05-31 2002-02-19 Santen Pharmaceut Co Ltd ＴＮＦ−α産生阻害物質
WO2002098869A2 (fr) * 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. Composes de cycloalkyl uree condense avec un 1,4-disubstitue benzo
JP2003192659A (ja) * 2001-12-26 2003-07-09 Bayer Ag フェニル尿素誘導体
WO2003077847A2 (fr) * 2002-03-12 2003-09-25 Merck & Co., Inc. Amides substitues
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8686006B2 (en) 2008-10-22 2014-04-01 Santen Pharmaceutical Co., Ltd. Pharmaceutical composition for improving intestinal absorption

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