WO2002036592A1 - Remedies for arachidonic acid-induced skin diseases - Google Patents

Remedies for arachidonic acid-induced skin diseases Download PDF

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WO2002036592A1
WO2002036592A1 PCT/JP2001/009575 JP0109575W WO0236592A1 WO 2002036592 A1 WO2002036592 A1 WO 2002036592A1 JP 0109575 W JP0109575 W JP 0109575W WO 0236592 A1 WO0236592 A1 WO 0236592A1
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arachidonic acid
acid
skin diseases
cell carcinoma
skin
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PCT/JP2001/009575
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French (fr)
Japanese (ja)
Inventor
Takamasa Watanabe
Masako Uchida
Masazumi Terashima
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Sumitomo Pharmaceuticals Company, Limited
Japan Energy Corporation
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Priority to AU2002212695A priority Critical patent/AU2002212695A1/en
Publication of WO2002036592A1 publication Critical patent/WO2002036592A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for skin diseases. More specifically, the present invention relates to a preventive or therapeutic agent for a skin disease caused by an increase in arachidonic acid metabolism, such as psoriasis, ultraviolet dermatitis, hypertrophy, basal cell carcinoma or stabular cell carcinoma.
  • arachidonic acid metabolism such as psoriasis, ultraviolet dermatitis, hypertrophy, basal cell carcinoma or stabular cell carcinoma.
  • Prostaglandins (PGs) and leucos (LTs) produced by acid metabolic pathways are involved in the regulation of physiological functions such as gastric acid secretion, platelet aggregation, and various smooth muscle contractions, and are fatty acids that cause tissue inflammation.
  • Communicator (mediator) PG and LT are important for the maintenance of homeostasis in the body, but overproduction of some dermatological diseases is considered to be the main cause of the disease.
  • Psoriasis is a chronic disease that shows benign abnormal proliferation of epidermal cells and infiltration of polymorphonuclear leukocytes into the epidermis, and is closely related to abnormalities of arachidonic acid metabolites for the following reasons (1) to (4). It is considered a disease.
  • (1) PG, arachidonic acid and 12-HETE increase in psoriatic rash
  • LTB 4 Leukotriene 5,12-dihydroxy form
  • Representative examples of skin diseases caused by abnormal arachidonic acid metabolism include the following diseases.
  • Mastocytosis This is a condition in which histamine and other substances are released from mast cells grown on the skin, causing flushing of the skin and junctional measles. Although these symptoms are considered to be mainly due to histamine, antihistamines are used.However, histamine-resistant cases in which PG synthesis inhibitors are significantly improved are seen (Main, RA et al. Br. . J.
  • Sunlight dermatitis It is thought that inflammatory mediators such as PG cause vasodilation by medium wavelength ultraviolet light.
  • Basal cell carcinoma or stab cell carcinoma (all skin cancers): PG is increased, and it has been suggested that PG is involved in the growth of the tumor (Vanderveen, ⁇ ., . ⁇ ⁇ et al.
  • Antiviral activity Antiviral activity in a herpesvirus (Tomai. MA. Et al. Antiviral Res. 28, 253-264 (1995)) infection system has been reported.
  • Cytokine 9883-845 (1997)), which is not found in imiquimod but found only in R848, is due to the skin inflammation-inducing action of TNF_a; (Kondo, S et al. Eur Combined with J. Immunol. 27, 1713-8 (1997), it suggests that R848 may induce skin inflammation.
  • An object of the present invention is to provide a novel skin disease therapeutic agent for treating and Z or preventing a skin disease caused by enhanced arachidonic acid metabolism, that is, a skin disease caused by increased production of PG, LT and the like. .
  • the present inventors have already found the inhibitory effect of imiquimod on arachidonic acid-induced mouse ear edema, and have filed a patent application for the invention of a therapeutic agent for skin diseases such as psoriasis (Japanese Patent Application Laid-Open No. 2000-247884, supra).
  • Rimi848 an analog of imiquimod, exhibits an extremely strong and persistent inhibitory action on arachidonic acid-induced mouse ear edema, and thus completed the present invention. That is, the gist of the present invention is represented by the following [1] to [6].
  • R848 (4-amino-2-ethoxymethyl- ⁇ , ⁇ -dimethyl-1 ⁇ -imidazo [4,5-c] quinolin-1-ethanol, hereinafter abbreviated as R848) or an acid addition salt or solvate thereof
  • R848 4-amino-2-ethoxymethyl- ⁇ , ⁇ -dimethyl-1 ⁇ -imidazo [4,5-c] quinolin-1-ethanol, hereinafter abbreviated as R848) or an acid addition salt or solvate thereof
  • skin disease caused by an increase in arachidonic acid metabolism means a skin disease caused by an abnormal increase in arachidonic acid and its metabolites constituting an arachidonic acid metabolic pathway (arachidonic acid cascade).
  • Typical disease names include psoriasis, UV dermatitis, mastocytosis, basal cell carcinoma or barbed cell carcinoma.
  • Arachidonic acid metabolites are: (1) Prostaglandins produced by cyclooxygenase enzymes: PGE (prostaglandin E), PGF, PGI, TXA (thrompoxane A), etc., (2) lipoxygenase enzymes Leukotrienes produced by: LTB4, LTC, LTD, LTE, etc., and (3) 12-HETE etc., and inflammatory skin diseases resulting from abnormal increase of these mediators are described in the present invention. Applicable.
  • the skin disease according to the present invention is caused by a virus or bacterial infection, skin inflammation due to burn injury or trauma, skin disease associated with collagen disease (autoimmune disease such as systemic lupus erythematosus, scleroderma), or a heterogeneous immune reaction. Does not include allergic skin diseases (junction, contact dermatitis, atopic dermatitis, etc.).
  • autoimmune disease such as systemic lupus erythematosus, scleroderma
  • a heterogeneous immune reaction Does not include allergic skin diseases (junction, contact dermatitis, atopic dermatitis, etc.).
  • the active ingredient of the present invention can be easily synthesized according to a known method.
  • a method described in W098 / 17279 may be used.
  • the acid of the acid addition salt of R848 is not particularly limited as long as it is a pharmacologically acceptable acid, and may be a solvate such as a hydrate.
  • Acid addition salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid), acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid It is formed with organic acids such as arginic acid, polydalminic acid, naphthylene sulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid. Hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, ascorbic acid and the like are suitable acid addition salts.
  • R848 and its salts can take various formulation forms (eg, liquids, solids, capsules, etc.).
  • Dosage forms for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, suspensions, and the like.
  • Dosage forms for parenteral administration include, for example, injections Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned.
  • the active ingredient can be incorporated with excipients and used in solutions, powders, powders, tablets, troches or capsules.
  • Pharmaceutically compatible binding agents, and Z or adjuvant materials can be included as part of the composition.
  • Tablets, pills, capsules and troches and the like can contain any of the following ingredients or compounds which are similar in nature: binder such as microcrystalline cellulose, gum tragacanth or gelatin; starch or lactate.
  • Excipients such as glucose; dispersing agents such as alginic acid, rimogel or corn starch; magnesium stearate or Are lubricants such as Sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or, such as peppermint, methyl salicylate or orange flavor. Flavoring agent.
  • the dosage unit form When the dosage unit form is forceps, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac or enteric agents.
  • R848 and a pharmaceutically acceptable salt can be administered as an ingredient such as an elixir, suspension, syrup, wafer, or gum.
  • a syrup may contain, in addition to the active ingredients, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • R8488 can also be prepared as a sustained release formulation including implants and microcapsule administration systems.
  • a biodegradable and biocompatible polymer such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, silicon, polyorthoester and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art, and the materials are also commercially available.
  • a ribosome suspension can be prepared by a method known to those skilled in the art using an appropriate lipid (eg, stearoyl phosphatidylethanolamine, stearate roll) as a carrier.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical applications containing R848 as an active ingredient can include the following ingredients.
  • Sterile diluents such as water for injection, saline solution, fixed oils, fixed oils, polyethylene glycols, glycerin, propylene dalycol or other synthetic solvents; fungicides such as benzyl alcohol or methyl paraben; ascorbic acid or sulfite Antioxidants such as sodium hydrogen; chelating agents such as ethylenediaminetetraacetic acid; acetate, citrate Or buffers such as phosphate and agents for adjusting tonicity such as sodium chloride or dextrose.
  • Parenteral preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Injectables can be prepared in a conventional manner, for example, by dissolving the compound in an appropriate solvent (eg, sterilized water, buffer, physiological saline, etc.), and then sterilizing by filtering through a filter or the like. Then, it can be prepared by filling in a sterile container.
  • the preferred carriers are saline or phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • an external preparation is one of particularly suitable dosage forms.
  • R 848 is imiquimod with approximate chemical structure, 1- (2-methylpropyl)-1H-imidazo [4,5-c] quinoline-4- at least 20 times more water-soluble than quinoline-4-amine (Water solubility at pH 2.5, 5.5, and 7: 1000 ⁇ /] 111 or more). Due to this property, the medicament of the present invention is not only easy to formulate, but also has a low transferability of the active ingredient to the central and other tissues. The effect on the affected area is durable. As described above, the R848-containing preparation of the present invention has particularly excellent properties as an external preparation.
  • the form of the external preparation is not particularly limited, and may be in the form of cream, paste, jelly, gel, emulsion, liquid, etc.
  • any pharmaceutically acceptable base may be used, and conventionally known bases such as ointments, liniments, lotions and the like can be used.
  • polyvinyl alcohol sodium polyacrylate, methoxyethylene-polymers such as maleic anhydride copolymer, poly
  • inorganic fillers such as kaolin, bentonite, zinc oxide, and titanium oxide; viscosity regulators; antioxidants; PH regulators; humectants such as glycerin and propylene glycol may be added. .
  • external bases In the case of external bases (ointments, creams, etc.), generally 1 to 100 mg, preferably 3 to 300 mg, of R8488 or a salt thereof is contained as an active ingredient per 1 g of plaster. Can be.
  • the dosage form and dosage of the medicament of the present invention are not particularly limited, and may be any method that can be used by a person skilled in the art as appropriate.
  • oral administration in the case of oral administration, it can be administered in the form of inhalants or capsules, tablets, granules, etc.
  • inhalants or capsules, tablets, granules, etc. in the range of about 1 to about 100 mg / day for adults for adults It is preferably administered in the range of about 10 to about 50 mg in one or several doses.
  • parenteral administration it can be used in the form of subcutaneous or intravenous injections, drops, or ointments in an aqueous suspension.
  • the dose varies depending on the patient's condition, age, weight, etc., and the dose used will be appropriately large enough to effectively treat the target disease.
  • a range of 100 mg, preferably about 3 to about 100 mg, can be administered in one or several divided doses.
  • topical transdermal preparations solutions, oily ointments, hydrophilic ointments or creams
  • the amount used depends on the type and condition of the disease.
  • the amount of external preparation should be 0.1 to 100 g, more preferably 1 to 10 g per day, applied once or at appropriate times to the affected area. Good. Industrial applicability
  • various skin diseases caused by abnormal arachidonic acid metabolism can be treated safely and effectively.
  • arachidonic acid metabolism such as psoriasis, ultraviolet dermatitis, mastocytosis, basal cell tumor, and barbed cell carcinoma
  • BALB / c mice female, 6 weeks old were purchased from Charles River Japan (Kanagawa, Japan) and preliminarily reared and used until 8 weeks old.
  • R848 (2 mg / mK 20 mg / ml) showed a significant inhibitory effect on arachidonic acid-induced intradermal reaction even after 4 hours from application. This result indicates that the preparation containing R848 is effective as a therapeutic or prophylactic agent for skin diseases caused by increased arachidonic acid metabolism.
  • Table 2 Water solubility of R848 and imiquimod in the acidic to neutral range

Abstract

Drugs for preventing and/or treating arachidonic acid-induced skin diseases which contain as the active ingredient 4-amino-2-ethoxymethyl-α,α dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol:R848 or its acid addition salt or solvate. By using these drugs, various skin diseases caused by the accelerated arachidonic acid metabolism (psoriasis, ultraviolet dermatitis, mastocytoma, basiloma, squamous cell carcinoma, etc.) can be safely and effectively treated.

Description

明細 ^ ァラキドン酸誘発皮膚疾患治療剤 技術分野  Description ^ Drug for treating arachidonic acid-induced skin disease
本発明は、 皮膚疾患治療剤に関する。 さらに詳しくは、 乾癬、 紫外線皮膚炎、 肥 満細胞症、 基底細胞癌または有刺細胞癌などのァラキドン酸代謝亢進に起因する皮 膚疾患の予防または治療剤に関する。 背景技術  The present invention relates to a therapeutic agent for skin diseases. More specifically, the present invention relates to a preventive or therapeutic agent for a skin disease caused by an increase in arachidonic acid metabolism, such as psoriasis, ultraviolet dermatitis, hypertrophy, basal cell carcinoma or stabular cell carcinoma. Background art
酸代謝経路により生成されるプロスタグランジン (PG) 類やロイコ 類(LT)は、 胃酸分泌や血小板凝集、 種々の平滑筋収縮など生理的機能調 節に係わるとともに組織の炎症を惹起する脂肪酸系の情報伝達物質 (メディェ一タ 一) である。 PGや LTは生体の恒常性維持に重要であるが、 一部の皮膚疾患にお いては、 その過剰産生が疾患の主たる病因と考えられている。  Prostaglandins (PGs) and leucos (LTs) produced by acid metabolic pathways are involved in the regulation of physiological functions such as gastric acid secretion, platelet aggregation, and various smooth muscle contractions, and are fatty acids that cause tissue inflammation. Communicator (mediator). PG and LT are important for the maintenance of homeostasis in the body, but overproduction of some dermatological diseases is considered to be the main cause of the disease.
このような皮膚疾患の代表例として、 まず乾癬が挙げられる。 乾癬は表皮細胞の 良性の異常増殖と、 表皮内への多形核白血球の侵入を示す慢性疾患であり、 下記(1) 〜 (4)の理由から、 ァラキドン酸代謝産物異常と密接に関連する疾患と考えられてい る。 (1)乾癬皮疹部では PG、 ァラキドン酸、 12— HETEが増加する  A typical example of such a skin disease is psoriasis. Psoriasis is a chronic disease that shows benign abnormal proliferation of epidermal cells and infiltration of polymorphonuclear leukocytes into the epidermis, and is closely related to abnormalities of arachidonic acid metabolites for the following reasons (1) to (4). It is considered a disease. (1) PG, arachidonic acid and 12-HETE increase in psoriatic rash
(Ha匪 erstrom, S. et al. Proc. Nat. Acad. Sci. USA. 72, 5130-5134 (1975) )、 (2)LTB をヒト皮膚に貼布すると、 乾癬皮疹部にみられる表皮内の微小膿瘍が形 成される(Camp, S. et al. J. Invest. Dermatol. 82, 202-204 (1984) )、 (3) P G の血管拡張作用とロイコトリェン C、 Dおよび E(LTC、 LTD, LTE)の血管 透過性亢進により皮膚の発赤 ·浮腫反応が惹起される、 (4)ロイコトリェン 5, 12 ージヒドロキシ体(LTB 4)により多核白血球遊走が増強され乾癬等に特徴的な角 層下、 角層内膿ほうが形成される。 現在、 トレチナ一ト(ビタミン A誘導体)、 活性 型ビタミン D 3、 シクロスポリンなどが用いられているが、 副作用などの面でより 有用な乾癬治療剤が望まれている(皮膚疾患最新の治療 ' 97—' 98、 p4_7、 106— 107)。 (Hadan erstrom, S. et al. Proc. Nat. Acad. Sci. USA. 72, 5130-5134 (1975)), (2) When LTB is applied to human skin, the epidermis in psoriatic eruption (Camp, S. et al. J. Invest. Dermatol. 82, 202-204 (1984)), and (3) the vasodilator effect of PG and leukotrienes C, D and E (LTC, (LTD, LTE) induces skin redness and edema reaction due to increased vascular permeability. (4) Leukotriene 5,12-dihydroxy form (LTB 4) enhances polynuclear leukocyte migration and is characteristic of the substratum, such as psoriasis. The pustules in the stratum corneum are formed. Currently, Tretinato (vitamin A derivative), active Vitamin D3, cyclosporine, etc. are used, but a more effective treatment for psoriasis in terms of side effects is desired (the latest treatment for skin diseases '97 -'98, p4_7, 106-107).
ァラキドン酸代謝異常に起因する皮膚疾患の代表例として、 他に下記の疾患が挙 げられる。  Representative examples of skin diseases caused by abnormal arachidonic acid metabolism include the following diseases.
肥満細胞症: 皮膚で増殖した肥満細胞からヒスタミンなどが放出され、 皮膚の 潮紅と蓴麻疹を呈する症状である。 これらの症状は主としてヒスタミンによると考 えられているため抗ヒスタミン薬が使用されるが、 PG合成阻害剤を投与すると著 明な改善が見られるヒスタミン抵抗性の症例 (Main, R. A. et al. Br. J.  Mastocytosis: This is a condition in which histamine and other substances are released from mast cells grown on the skin, causing flushing of the skin and junctional measles. Although these symptoms are considered to be mainly due to histamine, antihistamines are used.However, histamine-resistant cases in which PG synthesis inhibitors are significantly improved are seen (Main, RA et al. Br. . J.
Dermatol.107 (Suppl. 22), 53 (1982))や P GD 2の過剰産生が知られている (Roberts, L. J. et al. N. Engl. J. Med.303, 1400-1404 (1980))。 Dermatol. 107 (Suppl. 22), 53 (1982)) and overproduction of PGD2 are known (Roberts, LJ et al. N. Engl. J. Med. 303, 1400-1404 (1980)) .
日光皮膚炎:中波長紫外線により PGなどの炎症性メディエー夕一が血管拡張を 惹起すると考えられている。  Sunlight dermatitis: It is thought that inflammatory mediators such as PG cause vasodilation by medium wavelength ultraviolet light.
基底細胞癌あるいは有刺細胞癌 (いずれも皮膚癌) : PGが増加しており、 その 腫瘍の増殖に PGが関与する事が示唆されている(Vanderveen, Ε.、.Ε· et al.  Basal cell carcinoma or stab cell carcinoma (all skin cancers): PG is increased, and it has been suggested that PG is involved in the growth of the tumor (Vanderveen, Ε., .Ε · et al.
Arch. Dermatol. 122, 407—412(1986))。 Arch. Dermatol. 122, 407-412 (1986)).
一方、 4 -ァミノ- 2-エトキシメチル- a, a-ジメチル- 1 H—イミダゾ [4, 5— c ]キノリン一 1一エタノール (R848) は、 下記の薬理作用が知られている化合 物である。  On the other hand, 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c] quinoline-l-ethanol (R848) is a compound with the following known pharmacological actions. is there.
1)抗ウィルス作用:ヘルぺスウィルス(Tomai. MA. et al. Antiviral Res. 28, 253- 264(1995))感染系での抗ウィルス作用が報告されている。  1) Antiviral activity: Antiviral activity in a herpesvirus (Tomai. MA. Et al. Antiviral Res. 28, 253-264 (1995)) infection system has been reported.
2) サイト力イン誘導作用: I FN、 イン夕一ロイキン類(I L一 1、 I L一 6、 I L一 8 )や腫瘍壊死因子 a (TN F—ひ)の産生を誘導することが報告されている (Wagner et al. Cytokine 9 837-845 (1997))。  2) Induced effect of cytodynamic force: It has been reported that it induces the production of IFN, IL-1 leukins (IL-11, IL-16, IL-18) and tumor necrosis factor a (TN F-H). (Wagner et al. Cytokine 9 837-845 (1997)).
R 848と 卜(2 -メチルプロピル)一 1H -ィミダゾ [4, 5 - c]キノリン- 4-ァミン (ィ ミキモド) について、 Th 2型サイト力イン産生阻害作用を利用したアレルギー性 皮膚炎への医薬適用については公知である (W0 98/17279) 。 また、 ィミキモドにつ いては、 ァラキドン酸代謝異常に起因する皮膚疾患への適用が本発明者らにより特 許出願されている (特開 2000- 247884) 。 しかし、 R 848がァラキドン酸代謝異 常に起因する皮膚疾患に何らかの予防/治療効果を示すことに関して、 上述の先行 技術文献は何も記載していない。 むしろ、 ィミキモドに無く、 R848にのみ認め られる TNF— αの産生誘導作用 (Wagner et al. Cytokine 9 837-845 (1997)) は 、 TNF_ a;の皮膚炎症惹起作用 (Kondo, S et al. Eur. J. Immunol. 27, 1713- 8(1997) と相まって、 R848の皮膚炎症惹起の可能性を示唆するものである。 発明の開示 Allergic effects of R 848 and tri- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine (imimimod) by inhibiting the production of Th2-type cytokin Pharmaceutical applications for dermatitis are known (W098 / 17279). The present inventors have filed a patent application for imiquimod with application to skin diseases caused by abnormal arachidonic acid metabolism (Japanese Patent Application Laid-Open No. 2000-247884). However, none of the above-mentioned prior art documents describes that R848 shows any preventive / therapeutic effect on skin diseases caused by arachidonic acid metabolism disorder. Rather, TNF-α production-inducing action (Wagner et al. Cytokine 9883-845 (1997)), which is not found in imiquimod but found only in R848, is due to the skin inflammation-inducing action of TNF_a; (Kondo, S et al. Eur Combined with J. Immunol. 27, 1713-8 (1997), it suggests that R848 may induce skin inflammation.
本発明の課題は、 ァラキドン酸代謝宂進に起因する皮膚疾患、 即ち、 PG、 LT 等の産生亢進に起因する皮膚疾患を治療および Zまたは予防するための新規な皮膚 疾患治療剤の提供である。  An object of the present invention is to provide a novel skin disease therapeutic agent for treating and Z or preventing a skin disease caused by enhanced arachidonic acid metabolism, that is, a skin disease caused by increased production of PG, LT and the like. .
本発明者らは、 すでにィミキモドのァラキドン酸誘発マウス耳浮腫抑制作用を見 いだし、 乾癬などの皮膚疾患治療剤の発明として特許出願している (特開 2000- 247884、'前出) 。 しかし、 今回、 ィミキモドの類縁化合物 R 848が極めて強く持 続性のあるァラキドン酸誘発マウス耳浮腫抑制作用を示すことを発見し、 本発明を 完成した。 すなわち本発明の要旨は、 以下の [1] 〜 [6] で表される。  The present inventors have already found the inhibitory effect of imiquimod on arachidonic acid-induced mouse ear edema, and have filed a patent application for the invention of a therapeutic agent for skin diseases such as psoriasis (Japanese Patent Application Laid-Open No. 2000-247884, supra). However, the present inventors have now found that Rimi848, an analog of imiquimod, exhibits an extremely strong and persistent inhibitory action on arachidonic acid-induced mouse ear edema, and thus completed the present invention. That is, the gist of the present invention is represented by the following [1] to [6].
[1] 下式で表される化合物  [1] a compound represented by the following formula
(4-ァミノ- 2 _エトキシメチル -α, α-ジメチル- 1 Η—イミダゾ [4, 5— c]キノリ ンー 1一エタノール、 以下、 R 848と略す) またはその酸付加塩または溶媒和物 を有効成分とするァラキドン酸代謝亢進に起因する皮膚疾患の予防および/または 治療のための薬剤。 (4-amino-2-ethoxymethyl-α, α-dimethyl-1Η-imidazo [4,5-c] quinolin-1-ethanol, hereinafter abbreviated as R848) or an acid addition salt or solvate thereof For preventing and / or treating a skin disease caused by an increase in arachidonic acid metabolism, comprising as an active ingredient.
[2] ァラキドン酸代謝亢進に起因する皮膚疾患が乾癬、 紫外線皮膚炎、 肥満細胞 症、 基底細胞癌または有剌細胞癌である [1] 記載の薬剤。  [2] The agent according to [1], wherein the skin disease caused by an increase in arachidonic acid metabolism is psoriasis, ultraviolet dermatitis, mastocytosis, basal cell carcinoma or stimulating cell carcinoma.
[3] 経口投与用剤形である [1] または [2] に記載の薬剤。 [3] The drug according to [1] or [2], which is a dosage form for oral administration.
[4] 約 0. 1〜約 100 Omg/日の投与単位用量の R 848を含有する [3] 記載の薬剤。  [4] The agent according to [3], which contains R 848 at a dosage unit dose of about 0.1 to about 100 Omg / day.
[5] 非経口投与用剤形である [1] または [2] に記載の薬剤。  [5] The drug according to [1] or [2], which is a dosage form for parenteral administration.
[6] 約 0. 1〜約 5 Omg/日の投与単位用量の R 848を含有する外用剤である [6] An external preparation containing R 848 in a dosage unit dose of about 0.1 to about 5 Omg / day
[5] 記載の薬剤。 本発明において、 「ァラキドン酸代謝昂進に起因する皮膚疾患」 とは、 ァラキド ン酸代謝経路 (ァラキドン酸カスケード) を構成するァラキドン酸およびその代謝 物の異常な増加によって生じる皮膚疾患を意味し、 具体的疾患名としては、 乾癬、 紫外線皮膚炎、 肥満細胞症、 基底細胞癌または有刺細胞癌が挙げられる。 ァラキド ン酸代謝物とは、 (1) シクロォキシゲナーゼ酵素により産生されるプロスタグラ ンジン類: PGE (プロスタグランジン E) 、 PGF、 PGI、 TXA (トロンポ キサン A) など、 (2) リポキシゲナーゼ酵素により産生されるロイコトリェン 類: LTB 4、 LTC、 LTD, LTE等、 および (3) 12— HETE等を意 味し、 これらのメディエーターが異常に増加した結果生じる炎症性の皮膚疾患が、 本発明の適用対象である。 [5] The drug according to the above. In the present invention, “skin disease caused by an increase in arachidonic acid metabolism” means a skin disease caused by an abnormal increase in arachidonic acid and its metabolites constituting an arachidonic acid metabolic pathway (arachidonic acid cascade). Typical disease names include psoriasis, UV dermatitis, mastocytosis, basal cell carcinoma or barbed cell carcinoma. Arachidonic acid metabolites are: (1) Prostaglandins produced by cyclooxygenase enzymes: PGE (prostaglandin E), PGF, PGI, TXA (thrompoxane A), etc., (2) lipoxygenase enzymes Leukotrienes produced by: LTB4, LTC, LTD, LTE, etc., and (3) 12-HETE etc., and inflammatory skin diseases resulting from abnormal increase of these mediators are described in the present invention. Applicable.
ただし、 本発明における皮膚疾患には、 ウィルスや細菌感染症、 火傷凍傷、 外傷 による皮膚炎症、 膠原病 (全身性エリテマトーデス、 強皮症などの自己免疫疾患) に伴う皮膚疾患、 異種免疫反応によって生じるアレルギー性皮膚疾患 (蓴麻疹、 接 触皮膚炎、 アトピー性皮膚炎など) は含まれない。 以下に本発明の有効成分とその製造方法について述べる。 However, the skin disease according to the present invention is caused by a virus or bacterial infection, skin inflammation due to burn injury or trauma, skin disease associated with collagen disease (autoimmune disease such as systemic lupus erythematosus, scleroderma), or a heterogeneous immune reaction. Does not include allergic skin diseases (junction, contact dermatitis, atopic dermatitis, etc.). The active ingredient of the present invention and the method for producing the same will be described below.
本発明の有効成分である R 8 4 8およびその酸付加塩は、 公知の方法に準じて容 易に合成することができる。 例えば、 W098/17279 に記載の方法に準じればよい。 R 8 4 8の酸付加塩の酸としては、 薬理学的に許容される酸であれば特に限定されず、 水和物等の溶媒和物であってもよい。 酸付加塩は、 無機酸 (例えば、 塩酸、 臭化水 素酸、 硫酸、 リン酸および硝酸等) や酢酸、 蓚酸、 酒石酸、 コハク酸、 リンゴ酸、 ァスコルビン酸、 安息香酸、 タンニン酸、 パモイン酸、 アルギニン酸、 ポリダル夕 ミン酸、 ナフ夕レンスルホン酸、 ナフタレンジスルホン酸およびポリガラクトウ口 ン酸 (po lygal acturonic aci d)のような有機酸とで形成される。 塩酸、 硫酸、 酢酸、 蓚酸、 ァスコルビン酸などが好適な酸付加塩である。  The active ingredient of the present invention, R848 and its acid addition salt, can be easily synthesized according to a known method. For example, a method described in W098 / 17279 may be used. The acid of the acid addition salt of R848 is not particularly limited as long as it is a pharmacologically acceptable acid, and may be a solvate such as a hydrate. Acid addition salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid), acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid It is formed with organic acids such as arginic acid, polydalminic acid, naphthylene sulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid. Hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, ascorbic acid and the like are suitable acid addition salts.
R 8 4 8およびその塩は、 種々の製剤形態 (例えば、 液剤、 固形剤、 カプセル剤 等) をとりうる。 経口投与のための剤型としては、 例えば、 錠剤、 カプセル剤、 丸 剤、 顆粒剤、 散剤、 液剤、 懸濁剤などが挙げられ、 非経口投与のための剤型として は、 例えば、 注射用水性剤、 もしくは油性剤、 軟膏剤、 クリーム剤、 ローション剤、 エアロゾル剤、 坐剤、 貼付剤などが挙げられる。 R848 and its salts can take various formulation forms (eg, liquids, solids, capsules, etc.). Dosage forms for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, suspensions, and the like. Dosage forms for parenteral administration include, for example, injections Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned.
また、 所望の作用を損なわない他の活性材料、 または抗生物質、 抗真菌剤、 他 の抗炎症剤または抗ウィルス性化合物のような所望の作用を補足する材料と混合し て用いることもできる。  It can also be used in admixture with other active ingredients that do not impair the desired effect, or with materials that supplement the desired effect, such as antibiotics, antifungals, other anti-inflammatory or antiviral compounds.
経口治療投与の目的のために、 活性成分は賦形剤に組み込み、 液剤、 粉剤、 散剤、 錠剤、 トローチまたはカプセルで用いることができる。 薬学的に相溶性のある結合 剤および Zまたはアジュパント材料を組成物の一部として含むことができる。 錠剤、 丸剤、 カプセルおよびトローチ等は、 任意の、 以下の性質が類似している成分また は化合物を含むことができる:微結晶性セルロース、 ガムトラガカントまたはゼラ チンのような結合剤;澱粉またはラク卜一スのような賦形剤;アルギン酸、 リモゲ ル (rimogel) またはコーンスターチのような分散剤;ステアリン酸マグネシムまた はステロ一ッ (Sterotes ) のような潤滑剤; コロイド状二酸化ケイ素のような滑 剤;スクロ一スまたはサッカリンのような甘味料;または、 ペッパーミント、 サリ チル酸メチルまたはォレンジ風味剤のような風味剤。 投与単位形態が力プセルの場 合、 前述の種類の材料に加えて、 脂肪油のような液体キヤリャ一を含むことができ る。 さらに、 投与単位形態は、 投与単位の物理的形態を改良する種々の他の材料、 例えば糖の被膜、 シェラックまたは溶腸性剤を含むことができる。 R 8 4 8および 薬学的に許容できる塩は、 エリキシル、 懸濁液、 シロップ、 ウエハース、 または チュ Γンガム等の成分として投与することができる。 シロップは、 活性成分に加 えて、 甘味料としてのスクロース、 および特定の防腐剤、 染料および着色剤ならび に風味料を含み得る。 また、 R 8 4 8は、 移植およびマイクロカプセル投与系を含む徐放性製剤として 調製されうる。 担体としては、 エチレン酢酸ビニル、 ポリ無水物、 ポリグリコール 酸、 コラーゲン、 シリコン、 ポリオルトエステルおよびポリ乳酸のような生分解性 で生物適合性のポリマーを用いることができる。 そのような製剤を調製する方法は 当業者に明らかであり、 材料も市販品として入手できる。 また、 リボソーム懸濁 液も適当な脂質 (例えばステアロイルホスファチジルエタノールァミン、 ステア口 ロール) を担体に用いて当業者に知られている方法によって調製することができる。 For the purpose of oral therapeutic administration, the active ingredient can be incorporated with excipients and used in solutions, powders, powders, tablets, troches or capsules. Pharmaceutically compatible binding agents, and Z or adjuvant materials can be included as part of the composition. Tablets, pills, capsules and troches and the like can contain any of the following ingredients or compounds which are similar in nature: binder such as microcrystalline cellulose, gum tragacanth or gelatin; starch or lactate. Excipients such as glucose; dispersing agents such as alginic acid, rimogel or corn starch; magnesium stearate or Are lubricants such as Sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or, such as peppermint, methyl salicylate or orange flavor. Flavoring agent. When the dosage unit form is forceps, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac or enteric agents. R848 and a pharmaceutically acceptable salt can be administered as an ingredient such as an elixir, suspension, syrup, wafer, or gum. A syrup may contain, in addition to the active ingredients, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. R8488 can also be prepared as a sustained release formulation including implants and microcapsule administration systems. As the carrier, a biodegradable and biocompatible polymer such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, silicon, polyorthoester and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art, and the materials are also commercially available. Also, a ribosome suspension can be prepared by a method known to those skilled in the art using an appropriate lipid (eg, stearoyl phosphatidylethanolamine, stearate roll) as a carrier.
R 8 4 8を有効成分として含有する非経口、 皮内、 皮下または局所適用のために 用いられる溶液または懸濁液は以下の成分を含むことができる。 注入用水、 塩水溶 液、 固定油(f ixedo i l)、 ポリエチレングリコール、 グリセリン、 プロピレンダリ コールまたは他の合成溶媒のような滅菌希釈剤;ベンジルアルコールまたはメチル パラベンのような殺菌剤;ァスコルビン酸または亜硫酸水素ナトリウムのような酸 化防止剤;エチレンジアミ.ン四酢酸のようなキレート化剤;アセテート、 クェン酸 またはリン酸のような緩衝剤および塩化ナトリウムまたはデキストロースのような 張度を調整するための薬剤など。 非経口製剤は、 アンプル、 使い捨て注射器または ガラスまたはプラスチック製の複投与量パイアル中に封入し得る。 注射剤は、 常法 により調製することができ、 例えば、 当該化合物を適切な溶剤 (例えば、 滅菌され た水、 緩衝液、 生理食塩水等) に溶解した後、 フィルタ一等で濾過して滅菌し、 次 いで無菌的な容器に充填することにより調製することができる。 静脈内に投与する 場合、 好ましいキヤリャ一は生理食塩水またはリン酸緩衝食塩水 (PBS)である。 本発明において、 外用剤は特に好適な剤型の一つである。 R 8 4 8は、 近似の化 学構造を有するィミキモド、 1- (2-メチルプロピル)— 1H -イミダゾ [4, 5-c]キノリン- 4 -ァミンと比較した場合、 少なくとも 2 0倍水溶性が高いという特性を持つ (p H 2. 5、 5. 5,ぉょび7での水溶解度 1000 § /]111以上) 。 この特性により、 本発明の医 薬は製剤化が容易なだけでなく、 中枢や他の組織への有効成分移行性が低い。 また、 患部での効果は持続的である。 このように本発明の R 8 4 8含有製剤は、 外用剤と して特に優れた性質を有する。 外用剤の剤型は、 特に限定されるものではなく、 クリーム状、 ぺ一スト状、 ジェ リー状、 ゲル状、 乳液状、 液状等の形状になされたもの (軟膏剤、 リニメント剤、 ローション剤等) が薬物及び経皮吸収促進剤を溶解または混合分散させたものを支 持体上に展延したもの (パップ剤等) 、 粘着剤中に上記薬物及び経皮吸収促進剤 (本発明 3の場合使用) を溶解または混合分散させたものを支持体上に展延したもの (プラスター剤、 テープ剤等) などが挙げられる。 上記基剤としては、 薬学的に許容 しうるものであればよく、 軟膏剤、 リニメント剤、 ローション等の基剤として従来 公知のものを用いることができ、 例えば、 アルギン酸ナトリウム、 ゼラチン、 コー ンス夕一チ、 トラガントガム、 メチルセルロース、 ヒドロキシェチルセルロース、 カルポキシメチルセルロース、 キサンタンガム、 デキストリン、 カルポキシメチル デンプン、 ポリビニルアルコール、 ポリアクリル酸ナトリウム、 メトキシエチレン —無水マレイン酸共重合体、 ポリビニルエーテル、 ポリビニルピロリドン等のポリ マー;ミツロウ、 オリ一ブ油、 カカオ油、 ゴマ油、 ダイズ油、 ツバキ油、 ラッカセ ィ油、 牛油、 豚油、 ラノリン等の油脂類;白色ワセリン、 黄色ワセリン;パラフィ ン;ハイド口カーボンゲル軟膏 (例えば、 商品名プラスチベース、 大正製薬社 製) ;ステアリン酸等の高級脂肪酸;セチルアルコール、 ステアリルアルコール等 の高級アルコール;ポリエチレングリコール;水などが挙げられる。 さらに必要に 応じて、 カオリン、 ベントナイト、 酸化亜鉛、 酸化チタン等の無機充填剤;粘度調 節剤;老化防止剤; P H調節剤;グリセリン、 プロピレングリコール等の保湿剤な どを添加してもよい。 Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical applications containing R848 as an active ingredient can include the following ingredients. Sterile diluents such as water for injection, saline solution, fixed oils, fixed oils, polyethylene glycols, glycerin, propylene dalycol or other synthetic solvents; fungicides such as benzyl alcohol or methyl paraben; ascorbic acid or sulfite Antioxidants such as sodium hydrogen; chelating agents such as ethylenediaminetetraacetic acid; acetate, citrate Or buffers such as phosphate and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Injectables can be prepared in a conventional manner, for example, by dissolving the compound in an appropriate solvent (eg, sterilized water, buffer, physiological saline, etc.), and then sterilizing by filtering through a filter or the like. Then, it can be prepared by filling in a sterile container. For intravenous administration, the preferred carriers are saline or phosphate buffered saline (PBS). In the present invention, an external preparation is one of particularly suitable dosage forms. R 848 is imiquimod with approximate chemical structure, 1- (2-methylpropyl)-1H-imidazo [4,5-c] quinoline-4- at least 20 times more water-soluble than quinoline-4-amine (Water solubility at pH 2.5, 5.5, and 7: 1000 § /] 111 or more). Due to this property, the medicament of the present invention is not only easy to formulate, but also has a low transferability of the active ingredient to the central and other tissues. The effect on the affected area is durable. As described above, the R848-containing preparation of the present invention has particularly excellent properties as an external preparation. The form of the external preparation is not particularly limited, and may be in the form of cream, paste, jelly, gel, emulsion, liquid, etc. (ointment, liniment, lotion, etc.) And the like, and a solution in which a drug and a transdermal absorption enhancer are dissolved or mixed and dispersed are spread on a support (such as a poultice). ) Is dissolved or mixed and dispersed, and is spread on a support (plaster, tape, etc.). As the base, any pharmaceutically acceptable base may be used, and conventionally known bases such as ointments, liniments, lotions and the like can be used. For example, sodium alginate, gelatin, corn sugar Ichi, Tragant gum, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, xanthan gum, dextrin, carboxymethyl Starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-polymers such as maleic anhydride copolymer, polyvinyl ether, polyvinylpyrrolidone; beeswax, olive oil, cocoa oil, sesame oil, soybean oil, camellia oil, laccase Oils, oils, beef oil, pork oil, lanolin, etc .; white petrolatum, yellow petrolatum; paraffin; hide mouth carbon gel ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical); higher fatty acids such as stearic acid; cetyl alcohol And higher alcohols such as stearyl alcohol; polyethylene glycol; and water. If necessary, inorganic fillers such as kaolin, bentonite, zinc oxide, and titanium oxide; viscosity regulators; antioxidants; PH regulators; humectants such as glycerin and propylene glycol may be added. .
外用基剤 (軟膏、 クリームなど) の場合、 一般に膏体 l gあたり、 1〜 1 0 0 0 m gの、 好ましくは 3〜3 0 0 mgの R 8 4 8あるいはその塩を有効成分として含有 させることができる。 本発明の医薬は、 投与形態や投与量には特に限定は無く、 適宜当業者が用いうる 方法で有れば良いが、 下記の方法が例示される。  In the case of external bases (ointments, creams, etc.), generally 1 to 100 mg, preferably 3 to 300 mg, of R8488 or a salt thereof is contained as an active ingredient per 1 g of plaster. Can be. The dosage form and dosage of the medicament of the present invention are not particularly limited, and may be any method that can be used by a person skilled in the art as appropriate.
すなわち、 経口投与の場合、 吸入剤またはカプセル剤、 錠剤、 顆粒剤などの剤形 で投与することができ、 一般に、 経口投与の場合、 大人では 1日当たり約 1〜約 1 0 0 O m gの範囲、 好ましくは約 1 0〜約 5 0 O m gの範囲を 1 回または数回に分 けて投与する。  That is, in the case of oral administration, it can be administered in the form of inhalants or capsules, tablets, granules, etc. In general, in the case of oral administration, in the range of about 1 to about 100 mg / day for adults for adults It is preferably administered in the range of about 10 to about 50 mg in one or several doses.
非経口投与の場合、 水溶性懸濁液による皮下あるいは静脈注射剤、 点滴剤、 ある いは軟膏などの剤形で用いることができる。 注射剤の場合、 投与量は、 患者の症状、 年齢、 体重等により異なり、 また、 対象疾患を有効に治療するに充分な量を適宜使 用することになるが、 約 0 . 1〜約 5 0 0 m gの範囲、 好ましくは約 3〜約 1 0 0 m gの範囲を 1回または数回に分けて投与することができる。 外用経皮製剤 (液剤、 油性軟膏、 親水性軟膏あるいはクリーム) の場合、 使用量は、 疾患の種類や症状の 程度、 患部の大きさ等によって異なるが、 外用剤の量として、 1日当たり 0. 1〜 100 g、 さらに好ましくは、 1〜10 gを 1回又は適当な回数に分けて患部に適 用すればよい。 産業上の利用可能性 For parenteral administration, it can be used in the form of subcutaneous or intravenous injections, drops, or ointments in an aqueous suspension. In the case of an injection, the dose varies depending on the patient's condition, age, weight, etc., and the dose used will be appropriately large enough to effectively treat the target disease. A range of 100 mg, preferably about 3 to about 100 mg, can be administered in one or several divided doses. For topical transdermal preparations (solutions, oily ointments, hydrophilic ointments or creams), the amount used depends on the type and condition of the disease. Depending on the degree and size of the affected area, etc., the amount of external preparation should be 0.1 to 100 g, more preferably 1 to 10 g per day, applied once or at appropriate times to the affected area. Good. Industrial applicability
本発明により、 ァラキドン酸代謝異常に起因する各種皮膚疾患 (乾癬、 紫外線皮 膚炎、 肥満細胞症、 基底細胞腫、 有刺細胞癌等) が安全かつ効果的に治療できる。 実施例  According to the present invention, various skin diseases caused by abnormal arachidonic acid metabolism (such as psoriasis, ultraviolet dermatitis, mastocytosis, basal cell tumor, and barbed cell carcinoma) can be treated safely and effectively. Example
以下、 実施例を挙げて本発明を更に詳細に説明するが、 本発明はこれらの実施例 になんら限定されるものではない。 製剤例 1 注射用液剤  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Formulation Example 1 Injectable solution
精製水 (2mL) に、 R848 (20 Omg) およびエリスリトール (250 mg) を溶解し、 非経口投与用液剤を調製する。 製剤例 2 経口用液剤  Dissolve R848 (20 mg) and erythritol (250 mg) in purified water (2 mL) to prepare a solution for parenteral administration. Formulation Example 2 Oral solution
精製水 (lmL) に、 R 848 (20 Omg) 、 グリセリン (20 Omg) 、 クェン酸 (6mg) およびクェン酸ナトリウム (2 Omg) を溶解し、 経口投与用 液剤を調製する。 製剤例 3 クリーム  R 848 (20 Omg), glycerin (20 Omg), cunic acid (6 mg) and sodium citrate (2 Omg) are dissolved in purified water (1 mL) to prepare a solution for oral administration. Formulation Example 3 Cream
R 848 (2 g) にクロタミトン 5 g、 ニッコール (TS— 10) 5 g、 流動 パラフィン 3 g、 ミリスチン酸イソプロピル 15 gを加え、 70°Cに加温して溶解 する。 これに力ルポキシビ二ルポリマ一 1 gを水 60 gに膨潤した溶液を加え、 攪 拌して乳化する。 次に、 ジイソプロパノールァミン 0. 5 gを水 9. 75 gに溶か した溶液を加え、 均一になるまで攪拌して R 848を有効成分として含有するク リームを得る。 製剤例 4 油性軟膏 Add 5 g of crotamiton, 5 g of Nikkor (TS-10), 3 g of liquid paraffin, and 15 g of isopropyl myristate to R848 (2 g), and dissolve by heating to 70 ° C. A solution prepared by swelling 1 g of Ripoxyvinyl polymer in 60 g of water is added, and the mixture is stirred and emulsified. Next, 0.5 g of diisopropanolamine was dissolved in 9.75 g of water. The resulting solution is added and stirred until uniform to obtain a cream containing R848 as an active ingredient. Formulation Example 4 Oily ointment
R848 (10 g) を精製水 (30 g) に溶解させ、 へキシレンダリコール (120 g) と混合する。 これを溶融させた白色ワセリン (700 g) 、 白色ヮッ クス (80 g) とプロピレングリコールステアレート (20 g) の混合物に添加し 、 温度を下げながら均質に攪拌して R848を有効成分として含有する軟膏を得る  Dissolve R848 (10 g) in purified water (30 g) and mix with hexylene glycol (120 g). This was added to a mixture of molten white petrolatum (700 g), white powder (80 g) and propylene glycol stearate (20 g), and the mixture was stirred homogeneously while lowering the temperature to contain R848 as an active ingredient. Get an ointment
実施例 1 Example 1
ァラキドン酸誘発皮内反応に対する R 848の抑制作用 Inhibitory effect of R848 on arachidonic acid-induced intradermal response
1) BALB/cマウス(雌、 6週令)を日本チャールズリバ一 (神奈川、 日本)より購 入し、 8週令まで予備飼育し使用した。  1) BALB / c mice (female, 6 weeks old) were purchased from Charles River Japan (Kanagawa, Japan) and preliminarily reared and used until 8 weeks old.
2)試験薬物: R848 (フリー体)  2) Test drug: R848 (free form)
3) R848を抨量後、 アセトンに 2 Omg/m 1と 2mgZm 1の濃度に懸濁した 。 ジェチルェ一テル麻酔下でマウス左耳介の表裏に 10 /X 1ずつ R 848懸濁液を 塗布した(R 848投与群)。 コントロール群としてアセトンだけを左耳介の表裏に 10^ 1ずつ塗布したマウスを用意した。  3) After weighing R848, it was suspended in acetone at a concentration of 2 Omg / m1 and 2 mgZm1. The R848 suspension was applied to the front and back of the left auricle of the mouse at a rate of 10 / X1 each under the anesthesia of Jeti-Ruther (R848-administered group). As a control group, mice to which only acetone was applied to the front and back of the left auricle 10 ^ 1 each were prepared.
4)ァラキドン酸塗布: R848あるいはアセトン塗布 4時間後に 10%ァラキドン 酸 (CAYMAN CHEMICAL. Co.、 ミシガン、 アメリカ)を R 848投与群とコントロール 群の左耳介の表裏に 10 1ずつ塗布した。  4) Application of arachidonic acid: Four hours after the application of R848 or acetone, 10% arachidonic acid (CAYMAN CHEMICAL. Co., Michigan, USA) was applied to the front and back of the left auricle of the R848-administered group and the control group in 10 1 portions.
5)皮内反応の測定: R848あるいはアセトン塗布前 (抗原惹起せず)と 10%ァ ラキドン酸塗布 1時間後 (抗原惹起したもの)にジェチルェ一テル麻酔下で Dial Thic kness Gage(Mitutoyo Co.、 東京、 日本)で左右両耳介の厚さを測定した。 皮内反応 は、 (抗原惹起した左耳介の厚さ)一(抗原惹起しない右耳介の厚さ)で表現した。 6)解析:スチューデント t—テスト(Student's t— test)検定で有意差検定を行 つた。 1%以下の危険率で有意差が認められた場合は、 p<0.01の表示で表した 。 その結果を表 1に示す。 表 1. R848のァラキドン酸誘発皮内反応に対する抑制効果 5) Measurement of intradermal reaction: Dial Thickness Gage (Mitutoyo Co.) before application of R848 or acetone (without antigen induction) and 1 hour after application of 10% arachidonic acid (with antigen induction) under geetyl ether anesthesia. , Tokyo, Japan). The intradermal response was expressed as (thickness of left ear pinna in which antigen was induced) / (thickness of right pinna without inducing antigen). 6) Analysis: A significant difference test was performed using the Student's t-test test. When a significant difference was observed at a risk rate of 1% or less, it was expressed as p <0.01. The results are shown in Table 1. Table 1. Inhibitory effect of R848 on arachidonic acid-induced intradermal reaction
表 1から明らかなように、 R 848 (2mg/mK 20mg/ml) は塗布後 4時間後におい ても有意なァラキドン酸誘発皮内反応抑制効果を示した。 この結果は、 R848含 有製剤がァラキドン酸代謝亢進に起因する皮膚疾患の治療剤または予防剤として有 効である事を示す。 表 2. 酸性〜中性領域での R848およぴィミキモドの水溶解度 As is clear from Table 1, R848 (2 mg / mK 20 mg / ml) showed a significant inhibitory effect on arachidonic acid-induced intradermal reaction even after 4 hours from application. This result indicates that the preparation containing R848 is effective as a therapeutic or prophylactic agent for skin diseases caused by increased arachidonic acid metabolism. Table 2. Water solubility of R848 and imiquimod in the acidic to neutral range
1mlあたりの最大溶解量 g)Maximum dissolution amount per ml g)
H 2. 5 pH 5. 5 pH 7. 4 ィミキモド 32. 4 50. 4 3. 4  H2.5 pH 5.5 pH 7.4 imiquimod 32.4 50.4 3.4
R848 >1000 1000〉 1000>  R848> 1000 1000> 1000>

Claims

請求の範囲 下式で表される化合物  Claims Compound represented by the following formula
(R848 : 4-ァミノ- 2-エトキシメチル- α, α -ジメチル- 1H—イミダゾ [4, 5 一 c]キノリンー 1—エタノール) またはその酸付加塩または溶媒和物を有効成分と して含有するァラキドン酸代謝亢進に起因する皮膚疾患の予防および または治療 のための薬剤。  (R848: 4-amino-2-ethoxymethyl-α, α-dimethyl-1H-imidazo [4,5-1c] quinoline-1-ethanol) or its acid addition salt or solvate as the active ingredient A drug for preventing and / or treating skin diseases caused by increased arachidonic acid metabolism.
2. ァラキドン酸代謝亢進に起因する皮膚疾患が乾癬、 紫外線皮膚炎、 肥満細胞 症、 基底細胞癌または有刺細胞癌である、 1に記載の薬剤。 2. The agent according to 1, wherein the skin disease caused by an increase in arachidonic acid metabolism is psoriasis, ultraviolet dermatitis, mastocytosis, basal cell carcinoma or barbed cell carcinoma.
3. 経口投与用剤形である 1または 2に記載の薬剤。 3. The drug according to 1 or 2, which is a dosage form for oral administration.
4. 約 1〜約 100 OmgZ日の投与単位用量の R848を含有する、 3に記載 の薬剤。 4. The medicament of claim 3, comprising a dosage unit dose of R848 from about 1 to about 100 OmgZ days.
5. 非経口投与用剤形である 1または 2に記載の薬剤。 5. The drug according to 1 or 2, which is a dosage form for parenteral administration.
6. 約 0.1〜約 50 OmgZ日の投与単位用量の R 848を含有する外用剤であ る 5に記載の薬剤。 6. The drug according to 5, which is an external preparation containing R848 in a dosage unit dose of about 0.1 to about 50 OmgZ per day.
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