JP2002145777A - Therapeutic agent for arachidonic acid-induced dermatosis - Google Patents

Therapeutic agent for arachidonic acid-induced dermatosis

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Publication number
JP2002145777A
JP2002145777A JP2000337359A JP2000337359A JP2002145777A JP 2002145777 A JP2002145777 A JP 2002145777A JP 2000337359 A JP2000337359 A JP 2000337359A JP 2000337359 A JP2000337359 A JP 2000337359A JP 2002145777 A JP2002145777 A JP 2002145777A
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Prior art keywords
acid
r848
arachidonic acid
skin
caused
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JP2000337359A
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Japanese (ja)
Inventor
Masazumi Terajima
Masako Uchida
Kosei Watanabe
昌子 内田
寺島  正純
孝正 渡辺
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Japan Energy Corp
Sumitomo Pharmaceut Co Ltd
住友製薬株式会社
株式会社ジャパンエナジー
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Application filed by Japan Energy Corp, Sumitomo Pharmaceut Co Ltd, 住友製薬株式会社, 株式会社ジャパンエナジー filed Critical Japan Energy Corp
Priority to JP2000337359A priority Critical patent/JP2002145777A/en
Publication of JP2002145777A publication Critical patent/JP2002145777A/en
Application status is Pending legal-status Critical

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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 TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, 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

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine capable of safely and effectively treating various dermatoses (psoriasis, ultraviolet dematisis, mastocytosis and basal cell tumor, squamous cell carcinoma, etc.), caused by arachidonic acid hypermetabolism.
SOLUTION: This agent for prophylaxis and/or treatment of the dermatoses caused by the arachidonic acid hypermetabolism comprises a compound represented by the following formula (4-amino-2-ethoxymethyl-α,α-dimethyl-1H- imidazo [4,5-c]quinoline-1-ethanol: R848) or its acid addition salt or a solvate thereof as an active ingredient.
COPYRIGHT: (C)2002,JPO

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【発明の属する技術分野】本発明は、皮膚疾患治療剤に関する。 The present invention relates to relates to the treatment of skin diseases agents. 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ア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。 More particularly, psoriasis, UV dermatitis, mastocytosis, relates to a preventive or therapeutic agent for a skin disease caused by arachidonic acid hypermetabolism, such as basal cell carcinoma or barbed cell carcinoma.

【0002】 [0002]

【従来の技術】アラキドン酸代謝経路により生成されるプロスタグランジン(PG)類やロイコトリエン類(L Prostaglandins generated by the Related Art Arachidonic acid metabolism pathway (PG) compound and leukotrienes (L
T)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(メディエーター)である。 T) is a gastric acid secretion and platelet aggregation, various smooth muscle contraction, such as fatty acid of messenger which cause inflammation of the tissue together with related physiological functions regulated (mediator). P
G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。 G and LT are important in homeostasis of a living body, in some skin diseases, its overproduction is considered as a major etiology of the disease.

【0003】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。 [0003] Representative examples of such skin diseases, is first psoriasis. 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、ア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。 Psoriasis is a chronic disease that shows the abnormal growth of benign epidermal cells, polymorphonuclear leukocytes penetrate into the epidermis, for the following reasons (1) to (4), closely related to arachidonic acid metabolites abnormalities It is believed that disease. (1)乾癬皮疹部ではPG、アラキドン酸、12−HETEが増加する(Ham (1) In the psoriasis skin 疹部 PG, arachidonic acid, 12-HETE is increased (Ham
merstrom, S. et al. Proc. Nat. Acad. Sci. USA. 72, merstrom, S. et al. Proc. Nat. Acad. Sci. USA. 72,
5130-5134 (1975))、(2)LTB4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, 202-20 5130-5134 (1975)), (if 2) LTB4 the to patch to human skin, small abscesses in the skin seen in psoriasis skin 疹部 is formed (Camp, S. et al. J. Invest. Dermatol. 82 , 202-20
4 (1984))、(3)PGの血管拡張作用とロイコトリエン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)ロイコトリエン5,12−ジヒドロキシ体(LTB4)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。 4 (1984)), (3) vasodilating activity and leukotriene C of PG, D and E (LTC, LTD, redness swelling response of the skin is caused by vascular hyperpermeability LTE), (4) a leukotriene 5 , 12-dihydroxy form characteristic subcorneal polynuclear leukocyte migration is enhanced psoriasis by (LTB4), is better angular layer pus is formed. 現在、トレチナート(ビタミンA誘導体)、活性型ビタミンD3、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−' Currently, Torechinato (vitamin A derivatives), active vitamin D3, but such as cyclosporin are used, side effects surface more useful therapeutic agent for psoriasis is desired (latest skin disease treatment in such '97 - '
98、p4−7、106−107)。 98, p4-7,106-107).

【0004】ア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。 [0004] Representative examples of arachidonic acid metabolism caused by abnormal skin diseases, diseases of the following may be mentioned other. 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、皮膚の潮紅と蕁麻疹を呈する症状である。 Mastocytosis: such as histamine from mast cells grown in the skin is released, which is a condition that exhibits a flushing and hives of skin. 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, RA et al. Br. J.Dermatol.107(S Although antihistamines because these symptoms are primarily believed to be due to histamine is used, histamine resistant cases marked improvement is seen when administering PG synthesis inhibitors (Main, RA et al. Br. J.Dermatol.107 (S
uppl. 22), 53 (1982))やPGD2の過剰産生が知られている(Roberts, LJ et al. N. Engl. J. Med.303, 14 uppl. 22), 53 (1982)) and overproduction of PGD2 is known (Roberts, LJ et al. N. Engl. J. Med.303, 14
00-1404 (1980))。 00-1404 (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ターが血管拡張を惹起すると考えられている。 Sunburn: inflammatory mediators such as PG by UVB is believed to induce vasodilation. 基底細胞癌あるいは有刺細胞癌(いずれも皮膚癌):P Basal cell carcinoma or barbed cell carcinoma (both skin cancer): P
G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, EE et al.Arch.Derm G is increasing, it has been suggested that PG is involved in the growth of the tumor (Vanderveen, EE et al.Arch.Derm
atol. 122, 407-412(1986))。 atol. 122, 407-412 (1986)).

【0005】一方、4-アミノ-2-エトキシメチル-α,α-ジメチル-1H−イミダゾ[4,5−c]キノリン−1−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-.alpha., alpha-dimethyl--1H- imidazo [4,5-c] quinolin-1-ethanol (R848) is a compound pharmacological action following is known it is. 1)抗ウイルス作用:ヘルペスウィルス(Tomai. MA. et 1) anti-viral action:.. Herpes virus (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。 al. Antiviral Res. 28,253-264 (1995)) has been reported anti-viral effect of the infected system. 2)サイトカイン誘導作用: IFN、インターロイキン類(IL−1、IL−6、IL−8)や腫瘍壊死因子α 2) cytokine-inducing activity: IFN, interleukins (IL-1, IL-6, IL-8) and tumor necrosis factor α
(TNF−α)の産生を誘導することが報告されている(W To induce the production of (TNF-α) has been reported (W
agner et al. Cytokine 9 837-845 (1997))。 agner et al. Cytokine 9 837-845 (1997)).

【0006】R848と 1-(2-メチルプロピル)−1H-イミダゾ[4,5-c]キノリン-4-アミン(イミキモド)について、 [0006] R848 and the 1- (2-methylpropyl)-1H-imidazo [4,5-c] quinolin-4-amine (imiquimod),
Th2型サイトカ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(WO 98/ Are known for pharmaceutical applications to allergic dermatitis using Th2-type cytokine production inhibitory activity (WO 98 /
17279)。 17279). また、イミキモド、については、ア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)。 Further, imiquimod, for application to the skin diseases caused by arachidonic acid metabolism is patent application by the present inventors (JP 2000-247884). しかし、R848がア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。 However, with respect to exhibit any preventive / therapeutic effect on the skin disease R848 is due to arachidonic acid metabolic disorders, prior art document mentioned above does not describe anything. むしろ、イミキモドに無く、R848にのみ認められるTNF−αの産生誘導作用(Wagner et al. Cytokine9 837-845 (199 Rather, without the imiquimod, production-inducing effect of TNF-α, which is found only in R848 (Wagner et al. Cytokine9 837-845 (199
7))は、TNF−αの皮膚炎症惹起作用(Kondo, S et 7)), the skin inflammation inducing action of TNF-α (Kondo, S et
al. Eur. J. Immunol. 27, 1713-8(1997) と相まって、 al. Eur. J. Immunol. 27, coupled with the 1713-8 (1997),
R848の皮膚炎症惹起の可能性を示唆するものである。 It is intended to suggest the possibility of skin inflammation induced in R848.

【0007】 [0007]

【発明が解決しようとする課題】発明の課題は、アラキドン酸代謝亢進に起因する皮膚疾患、即ち、PG、LT Problem of the invention The object of the invention is to solve the above-skin disease caused by arachidonic acid metabolism increased, that is, PG, LT
等の産生亢進に起因する皮膚疾患を治療および/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。 The provision of novel skin diseases therapeutic agents for skin diseases the treatment and / or prophylaxis due to enhanced production and the like.

【0008】 [0008]

【課題を解決するための手段】本発明者らは、すでにイミキモドのア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)。 The present inventors have SUMMARY OF THE INVENTION already found arachidonic acid-induced mouse ear edema inhibition effect of imiquimod, has filed a patent application as the invention of a skin disease therapeutic agent such as psoriasis (Patent Application 2000-247884 , supra). しかし、今回、イミキモドの類縁化合物R848が極めて強く持続性のあるア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。 But this time, discovered that show arachidonic acid-induced mouse ear edema suppressing effect analogous compounds R848 is with very strong persistent imiquimod, and completed the present invention. すなわち本発明の要旨は、下記(1)〜(6)のものである。 Specifically, the subject matter of the present invention are the following (1) to (6). (1)下式で表される化合物 (1) a compound represented by the following formula

【化2】 ## STR2 ## (4-アミノ-2-エトキシメチル-α,α-ジメチル-1H (4-amino-2-ethoxymethyl-.alpha., alpha-dimethyl -1H
−イミダゾ[4,5−c]キノリン−1−エタノール、以下、R848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ア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。 - imidazo [4,5-c] quinoline-1-ethanol, following the prevention and / or treatment of skin diseases caused by arachidonic acid metabolism increased as an active ingredient and abbreviated) or an acid addition salt or solvate thereof R848 drug for. (2)ア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)記載の薬剤。 (2) Skin diseases psoriasis caused by arachidonic acid hypermetabolic, UV dermatitis, mastocytosis, a basal cell carcinoma or barbed cell carcinoma (1), wherein the drug. (3) 経口投与用剤形である(1)、(2)いずれかに記載の薬剤。 (3) a dosage form for oral administration (1), (2) An agent according to any one. (4) 約0.1〜約1000mg/日の投与単位用量のR848を含有する(3)記載の薬剤。 (4) contains R848 from about 0.1 to about 1000 mg / day dosage unit dose of (3), wherein the drug. (5) 非経口投与用剤形である(1)、(2)いずれかに記載の薬剤。 (5) is a parenteral dosage form (1), (2) An agent according to any one. (6)約0.1〜約50mg/日の投与単位用量のR8 (6) of the dosage unit dose of about 0.1 to about 50 mg / day R8
48を含有する外用剤である(5)記載の薬剤。 It is a external preparation containing 48 (5), wherein the drug.

【0009】(1)文言の定義 「アラキドン酸代謝昂進に起因する皮膚疾患」とは、アラキドン酸代謝経路(アラキドン酸カスケード)を構成するア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。 [0009] (1) the definition of the phrase "skin disease caused by arachidonic acid metabolism Koshin" is a skin disease caused by abnormal increase of arachidonic acid and its metabolites constituting the arachidonic acid metabolic pathway (arachidonic acid cascade) refers to, as a specific disease name, psoriasis, UV dermatitis, mastocytosis include basal cell carcinoma or barbed cell carcinoma. アラキドン酸代謝物とは、(1) The arachidonic acid metabolites, (1)
シクロオ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)、PG Prostaglandins produced by cyclooxygenase enzyme: PGE (prostaglandin E), PG
F、PGI、TXA(トロンボキサンA)など、(2) F, PGI, such as TXA (thromboxane A), (2)
リポキシゲナーゼ酵素により産生されるロイコトリエン類:LTB4、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、 Leukotrienes produced by lipoxygenase enzymes: LTB4, LTC, LTD, LTE, etc., and (3) means 12-HETE, etc., inflammatory skin disorders that result in which these mediators are abnormally increased is,
本発明の適用対象である。 It is the application of the present invention. 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(蕁麻疹、接触皮膚炎、アトピー性皮膚炎など)は含まれない。 However, the skin disorder in the present invention, viral or bacterial infections, burns frostbite, skin trauma inflammation, collagen diseases skin disease associated with (systemic lupus erythematosus, autoimmune diseases such as scleroderma), caused by the heterologous immune response allergic skin diseases (urticaria, contact dermatitis, atopic dermatitis, etc.) are not included.

【0010】(2)製造方法 (2−1)有効成分 R848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。 [0010] (2) the production method (2-1) the active ingredient R848 and its acid addition salts can be easily synthesized according to known methods. 例えば、WO98/17279に記載の方法に準じればよい。 For example, it Junjire to the method described in WO98 / 17279. R848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、 The acid of the acid addition salts of the R848, not particularly limited as long as it is pharmacologically acceptable acid,
水和物等の溶媒和物であってもよい。 A solvate such as a hydrate or. 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、アスコルビン酸、安息香酸、タンニン酸、パモイン酸、アルギニン酸、ポリグルタミン酸、ナフタレンスルホン酸、ナフタレンジスルホン酸およびポリガラクトゥロン酸(polygalacturonic acid)のような有機酸とで形成される。 Acid addition salts are formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, etc.) or acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, formed by the organic acids, such as naphthalene disulfonic acid, and polygalacturonic tO Ron acid (polygalacturonic acid). 塩酸、硫酸、酢酸、蓚酸、アスコルビン酸などが好適な酸付加塩である。 Hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, ascorbic acid, and suitable acid addition salts.

【0011】(2−2)製剤化 R848またはその塩は、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。 [0011] (2-2) formulated R848 or a salt thereof, various preparation forms (e.g., liquid, solid, capsule and the like) can take. 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、 The dosage form for oral administration, e.g., tablets, capsules, pills,
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。 Granules, powders, solutions, suspending agents and the like. Examples of the dosage form for parenteral administration, e.g., injection aqueous agent, or oily, ointments, creams, lotions, aerosols, suppository agents, and the like patches. 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イ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 is also possible to use in admixture with materials that supplement the desired action, such as desired other active materials that do not impair the action or antibiotics, antifungals, other anti-inflammatory agents or anti-viral compounds. (経口製剤) 経口治療投与の目的のために、活性化合物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。 For (oral formulation) the purpose of oral therapeutic administration, the active compounds are incorporated with excipients, it can be used solutions, dusts, powders, tablets, in troches, or capsules. 薬学的に相溶性のある結合剤および/またはアジュバント材料を組成物の一部として含むことができる。 It can include a binder and / or adjuvant materials Pharmaceutically compatible as part of the composition. 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;澱粉またはラクトースのような賦形剤、アルギン酸、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Sterotesのような潤滑剤; Tablets, pills, capsules and troches and the like may include a component or compound following properties of any are similar: microcrystalline cellulose, binders such as gum tragacanth or gelatin; starch or vehicles, such as lactose excipients, alginic acid, dispersing agents such as rimogel or corn starch; a lubricant such as stearic acid magnesium or Sterotes;
コロイド状二酸化ケイ素のような滑剤;スクロー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オレンジ風味剤のような風味剤。 Lubricants such as colloidal silicon dioxide; sucrose or sweeteners such as saccharin; or, peppermint, flavoring agents such as methyl salicylate or orange flavoring. 投与単位形態がカプセルの場合、前述の種類の材料に加えて、脂肪油のような液体キャリヤーを含むことができる。 When the dosage unit form is a capsule, in addition to the foregoing types of materials, can include a liquid carrier such as a fatty oil. 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。 In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, sugar coating, shellac or enteric agents. R848または薬学的に許容できる塩は、エリキシル、懸濁液、シロップ、ウエハまたはチューインガム等の成分として投与することができる。 R848 or a pharmaceutically acceptable salt thereof can be administered elixir, suspension, syrup, as a component, such as a wafer or a chewing gum. シロップは、活性成分に加えて、 Syrup may contain, in addition to the active ingredient,
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。 Sucrose as a sweetening agent and certain preservatives, may include dyes and colorings and flavors.

【0012】(持続性製剤)R848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。 [0012] (depot preparation) R848 can be prepared as a sustained release formulation, including implants and microencapsulated delivery systems. 担体としては、エチレン酢酸ビニル、ポリ無水物、 The carrier, ethylene vinyl acetate, polyanhydrides,
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。 Polyglycolic acid, collagen, silicone, biodegradable such as polyorthoesters, and polylactic acid can be used biocompatible polymers. 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。 Methods for preparation of such formulations will be apparent to those skilled in the art, materials can be commercially available. また、リポ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アミン、ステアロイルホスファチジルコリン、アラカドイルホスファチジルコリンおよびコレステロール)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。 Moreover, it can be prepared by methods known liposome suspension also suitable lipids (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) to the one skilled in the art using the carrier.

【0013】(非経口製剤)R848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。 [0013] Parenteral, intradermal containing (parenteral formulations) R848 as an active ingredient, Solutions or suspensions used for subcutaneous or topical application can include the following components. 注入用水、塩水溶液、固定油(fixedoil)、 ポリエチレングリコール、グリセリン、プロピレング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;ア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、クエ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。 Such as ascorbic acid or sodium bisulfite; water for injection, saline solution, fixed oils (fixedoil), polyethylene glycol, glycerine, a sterile diluent such as propylene glycol or other synthetic solvents; fungicides such as benzyl alcohol or methyl paraben chelating agents such as ethylenediaminetetraacetic acid; antioxidants acetate, agents for adjusting the tonicity, such as buffers and sodium chloride or dextrose, such as citric acid or phosphoric acid. 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バイアル中に封入し得る。 The parenteral preparation can be enclosed in ampoules, multi dose vials disposable syringes or glass or plastic. 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、フィルター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。 Injectables can be prepared by a conventional method, for example, the compounds suitable solvent (e.g., sterilized water, buffer solution, physiological saline or the like) was dissolved in sterilized by filtration through a filter or the like , it can then be prepared by filling a sterile container. 静脈内に投与する場合、好ましいキャリヤーは生理食塩水またはリン酸緩衝食塩水(PBS)である。 If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

【0014】(外用剤)本発明において、外用剤は特に好適な剤型の一つである。 [0014] In (external preparation) present invention, the external preparation is one of particularly preferred dosage forms. R848は、近似の化学構造を有するイミキモド、1-(2-メチルプロピル)−1H-イミダゾ R848 is imiquimod having a chemical structure of approximation, 1- (2-methylpropyl)-1H-imidazo
[4,5-c]キノリン-4-アミンと比較した場合、少なくとも20倍水溶性が高いという特性を持つ(pH2.5、5.5, [4,5-c] when compared with quinoline-4-amine, with the characteristics of high least 20 fold soluble (PH2.5,5.5,
および7での水溶解度1000μg/ml以上)。 And water solubility 1000 [mu] g / ml or more at 7). 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。 This property, the drug of the present invention is not only easy to formulate, is low active ingredient migration to the central and other organizations. また、患部での効果は持続的である。 In addition, the effect in the affected area is sustainable. このように本発明のR848含有製剤は、外用剤として特に優れた性質を有する。 R848 containing formulations according to the present invention in this way have a particularly excellent properties as an external preparation.

【0015】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、ペースト状、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。 [0015] The external preparation of the dosage form is not limited in particular, a cream, paste, jelly, gel, milky lotion, which was made in the shape of a liquid such as (ointments, liniments, lotions etc.) that was spread what is dissolved or mixed and dispersed drug and percutaneous absorption enhancer on a support (poultices), in the pressure-sensitive adhesive the drug and percutaneous absorption enhancer (the present invention 3 If used) dissolved or those mixed dispersed those spread on a support (plasters, tapes, etc.) and the like. 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、 As the base, as long as pharmaceutically acceptable, ointments, liniments,
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、コーンスターチ、トラガントガム、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロース、キサンタンガム、デキストリン、カルボ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、 It may be used any of conventionally known materials used as base such as lotions, for example, sodium alginate, gelatin, corn starch, gum tragacanth, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate , methoxy ethylene - maleic anhydride copolymer,
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、オリーブ油、カカオ油、ゴマ油、ダイズ油、ツバキ油、ラッカセイ油、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; Polyvinyl ethers, polymers such as polyvinylpyrrolidone; beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, fats and lanolin; white petrolatum, yellow petrolatum, paraffin;
ハイドロカーボンゲル軟膏(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; Hydrocarbon gel ointments (e.g., trade name Plastibase, manufactured by Taisho Pharmaceutical Co.); higher fatty acids such as stearic acid;
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。 Polyethylene glycol; cetyl alcohol, higher alcohols such as stearyl alcohol and water. 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;pH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。 If necessary, kaolin, bentonite, zinc oxide, inorganic fillers such as titanium oxide; viscosity modifiers; antioxidants; pH adjusting agents; glycerin, and the like may be added humectants, such as propylene glycol. 外用基剤(軟膏、 External base (ointment,
クリームなど)の場合、一般に膏体1gあたり、1〜1 In the case of cream, etc.), generally per plaster 1g, 1~1
000mgの、好ましくは3〜300mgのR848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。 Of 000Mg, preferably may be contained as R848 or a salt thereof as an active ingredient of 3~300Mg.

【0016】(3)使用方法 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。 [0016] (3) The pharmaceutical Using the present invention, not particularly limited to dosage forms and dose, it is sufficient in a manner appropriate person skilled in the art can be used, the following methods are exemplified. (経口投与)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 (Oral) inhalation or capsules, tablets, can be administered in dosage forms such as granules, in general, in the case of oral administration per day about 1 to about 1 in adults
000mgの範囲、好ましくは約10〜約500mgの範囲を1回または数回に分けて投与する。 Range 000Mg, is preferably divided in the range of about 10 to about 500mg once or several doses. (非経口投与)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。 (Parenteral administration) aqueous suspension by subcutaneous or intravenous injection, it is possible to use drops, or in dosage forms, such as ointments. 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500mg For injection, the dose is the condition of the patient, age, depends weight, etc., also, it will be appropriately used an amount sufficient to effectively treat the target disease, about 0.1 to about 500mg
の範囲、好ましくは約3〜約100mg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。 Range, preferably may be administered separately from about 3 to about 100mg once or several times. 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0.1〜100g、さらに好ましくは、1〜10gを1 For transdermal preparation for external use (solutions, oily ointments, hydrophilic ointments or creams), the amount used, the degree of the type and symptoms of the disease varies depending affected part such as the size, as the amount of external preparation, day 0. 1 to 100 g, more preferably, the 1 to 10 g 1
回又は適当な回数に分けて患部に適用すればよい。 It may be applied to the affected area divided into dose or an appropriate number of times.

【0017】製剤例1 注射用液剤 精製水(2mL)に、R848(200mg)およびエリスリトール(250mg)を溶解し、非経口投与用液剤を調製する。 [0017] Formulation Example 1 injectable solution of purified water (2 mL), was dissolved R848 (200 mg) and erythritol (250 mg), preparing parenterally administrable solutions. 製剤例2 経口用液剤 精製水(1mL)に、R848(200mg)、グリセリン(200mg)、クエン酸(6mg)およびクエン酸ナトリウム(20mg)を溶解し、経口投与用液剤を調製する。 To Formulation Example 2 oral solution Purified water (1mL), R848 (200mg), was dissolved glycerin (200 mg), citric acid (6 mg) and sodium citrate (20 mg), to prepare a liquid for oral administration. 製剤例3 クリーム R848(2g)にクロタミトン5g、ニッコール(T To Formulation Example 3 Cream R848 (2 g) crotamiton 5g, Nikkol (T
S−10)5g、流動パラフィン3g、ミリスチン酸イソプロピル15gを加え、70℃に加温して溶解する。 S-10) 5 g, liquid paraffin 3g, isopropyl myristate 15g added and warming dissolved in 70 ° C..
これにカルボキシビニルポリマー1gを水60gに膨潤した溶液を加え、攪拌して乳化する。 This carboxyvinyl polymers 1g The swollen solution was added to water 60 g, emulsified by stirring. 次に、ジイソプロパノールアミン0.5gを水9.75gに溶かした溶液を加え、均一になるまで攪拌してR848を有効成分として含有するクリームを得る。 Next, the diisopropanolamine 0.5g of solution in water 9.75g was added to obtain a cream containing R848 and stirred until homogeneous, as an active ingredient. 製剤例4 油性軟膏 R848(10g)を精製水(30g)に溶解させ、へキシレングリコール(120g)と混合する。 Formulation Example 4 Oily Ointment R848 (10 g) was dissolved in purified water (30 g), mixed with hexylene glycol (120 g) to. これを溶融させた白色ワセリン(700g)、白色ワックス(8 White petrolatum was melted this (700 g), white wax (8
0g)とプロピレングリコールステアレート(20g) 0 g) propylene glycol stearate (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R Was added to a mixture of, R homogeneously stirred while lowering the temperature
848を有効成分として含有する軟膏を得る。 Give an ointment containing as active ingredient 848.

【0018】 [0018]

【実施例】以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例により限定されるものではない。 EXAMPLES The following provides a detailed explanation of the present invention through examples, the present invention is not limited by these examples. 実施例1 アラキドン酸誘発皮内反応に対するR848の抑制作用 1)BALB/cマウス(雌、6週令)を日本チャールズリバー(神奈川、日本)より購入し、8週令まで予備飼育し使用した。 Example 1 inhibition of R848 on arachidonic acid-induced skin reaction 1) BALB / c mice (female, 6 weeks old) Japan Charles River (Kanagawa, were purchased from Japan), was used to preliminarily fed up to 8 weeks of age. 2)試験薬物:R848(フリー体) 3)R848を秤量後、アセトンに20mg/mlと2 2) Test drug: R848 (after weighing the free form) 3) R848, and 20 mg / ml in acetone 2
mg/mlの濃度に懸濁した。 It was suspended in a concentration of mg / ml. ジエチルエーテル麻酔下でマウス左耳介の表裏に10μlずつR848懸濁液を塗布した(R848投与群)。 Each 10μl the front and back of the mouse left auricle under diethyl ether anesthesia was applied R848 suspension (R848 administration group). コントロール群としてアセトンだけを左耳介の表裏に10μlずつ塗布したマウスを用意した。 Only acetone was prepared mice applied by 10μl the front and back of the left auricle as a control group. 4)アラキドン酸塗布:R848あるいはアセトン塗布4時間後に10%アラキドン酸(CAYMAN CHEMICAL. C 4) arachidonic acid application:. R848 or acetone applied after 4 hours 10% arachidonic acid (CAYMAN CHEMICAL C
o.、ミシガン、アメリカ)をR848投与群とコントロール群の左耳介の表裏に10μlずつ塗布した。 o., it was applied by 10μl Michigan, on the front and back of the left ear of R848 administration group and the control group the United States of America).

【0019】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%アラキドン酸塗布1時間後(抗原惹起したもの)にジエチルエーテル麻酔下でDi [0019] 5) Measurement of skin reaction: R848 or acetone before application (Di diethyl ether anesthesia the antigen without inducing) and 10% arachidonic acid applied 1 hour after (as antigen induced)
al Thickness Gage(Mitutoyo Co.、東京、日本)で左右両耳介の厚さを測定した。 al Thickness Gage (Mitutoyo Co., Tokyo, Japan) to measure the thickness of both the right and left ear in. 皮内反応は、(抗原惹起した左耳介の厚さ)−(抗原惹起しない右耳介の厚さ)で表現した。 Intradermal reaction is, (the thickness of the left ear was antigen induced) - it was expressed in (the thickness of the right ear that does not elicit antigen). 6)解析:スチューデントt−テスト(Student's t−tes 6) Analysis: Student's t- test (Student's t-tes
t)検定で有意差検定を行った。 t) and significant difference tests were performed in the assay. 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。 Significant difference of 1% or less risk ratio when observed, was expressed in the display of p <0.01.
その結果を表1に示す。 The results are shown in Table 1.

【0020】表1. [0020] Table 1. R848のアラキドン酸誘発皮内反応に対する抑制効果 Inhibitory effect on arachidonic acid-induced skin reaction of R848

【表1】 [Table 1]

【0021】表1から明らかなように、R848(2mg/ml、 As it is apparent from Table 1, R848 (2mg / ml,
20mg/ml)は塗布後4時間後においても有意なアラキドン酸誘発皮内反応抑制効果を示した。 20 mg / ml) showed a significant arachidonic acid-induced skin reaction suppressing effect even after 4 hours after application. この結果は、R8 This result, R8
48含有製剤がア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。 It indicates that 48 containing formulations are effective as a therapeutic or prophylactic agent for skin diseases caused by arachidonic acid metabolism increased.

【0022】表2. [0022] Table 2. 酸性〜中性領域でのR848およびイミキモドの水溶解度 Water solubility of R848 and imiquimod in an acidic to neutral region

【表2】 [Table 2]

【0023】 [0023]

【発明の効果】本発明により、ア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。 According to the present invention, various skin diseases caused by arachidonic acid metabolism (psoriasis, UV dermatitis, mastocytosis, basal cell tumor, barbed cell cancer, etc.) can be treated safely and effectively.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl. 7識別記号 FI テーマコート゛(参考) A61P 43/00 111 A61P 43/00 111 // C07D 471/04 105 C07D 471/04 105C (72)発明者 内田 昌子 大阪府大阪市此花区春日出中3丁目1番98 号 住友製薬株式会社内 (72)発明者 寺島 正純 大阪府大阪市此花区春日出中3丁目1番98 号 住友製薬株式会社内 Fターム(参考) 4C065 AA05 AA18 BB06 CC01 DD03 EE02 HH01 JJ07 KK04 KK09 PP01 4C076 AA08 AA12 BB01 BB31 CC18 DD34 DD38 DD43 DD45 DD46 DD50 DD60 EE08 EE23 EE55 FF15 FF68 4C086 AA01 AA02 CB05 MA01 MA04 NA10 NA14 ZA89 ZB26 ZC41 ────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. 7 identifications FI theme coat Bu (reference) A61P 43/00 111 A61P 43/00 111 // C07D 471/04 105 C07D 471/04 105C (72) inventor Masako, Osaka-shi, Osaka Konohana Ward Kasugadenaka 3 chome No. 98 Sumitomo Pharmaceuticals Co., Ltd. in the Uchida (72) inventor Masazumi Terashima Osaka, Osaka Prefecture Konohana Ward Kasugadenaka 3 chome No. 98 Sumitomo Pharmaceuticals Co., Ltd. in the F term (reference) 4C065 AA05 AA18 BB06 CC01 DD03 EE02 HH01 JJ07 KK04 KK09 PP01 4C076 AA08 AA12 BB01 BB31 CC18 DD34 DD38 DD43 DD45 DD46 DD50 DD60 EE08 EE23 EE55 FF15 FF68 4C086 AA01 AA02 CB05 MA01 MA04 NA10 NA14 ZA89 ZB26 ZC41

Claims (6)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 下式で表される化合物 【化1】 1. A compound represented by the following formula ## STR1 ## (R848:4-アミノ-2-エトキシメチル-α,α-ジメチル-1H−イミダゾ[4,5−c]キノリン−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ア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-.alpha., alpha-dimethyl--1H- imidazo [4,5-c] quinolin-1-ethanol) Arachidonic containing or acid addition salt or solvate thereof as an active ingredient prevention of skin disease caused by acid hypermetabolic and / or therapeutic agents for.
  2. 【請求項2】 ア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、請求項1に記載の薬剤。 Wherein the skin disease is psoriasis caused by arachidonic acid hypermetabolic, UV dermatitis, mastocytosis, a basal cell carcinoma or barbed cell carcinoma, agent according to claim 1.
  3. 【請求項3】 経口投与用剤形である請求項1〜2のいずれかに記載の薬剤。 3. The agent of any of claims 1-2 which is orally administered dosage form.
  4. 【請求項4】 約1〜約1000mg/日の投与単位用量のR848を含有する請求項3に記載の薬剤。 Wherein from about 1 to about 1000 mg / day agent according to claim 3 containing R848 dosage unit dose.
  5. 【請求項5】 非経口投与用剤形である請求項1〜2のいずれかに記載の薬剤。 5. The agent according to any one of claims 1-2 is parenteral dosage forms.
  6. 【請求項6】 約0.1〜約500mg/日の投与単位用量のR848を含有する外用剤である請求項5に記載の薬剤。 6. About 0.1 to about 500 mg / day drug according to claim 5, which is a preparation for external use containing R848 dosage unit dose.
JP2000337359A 2000-11-06 2000-11-06 Therapeutic agent for arachidonic acid-induced dermatosis Pending JP2002145777A (en)

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AU1269502A AU1269502A (en) 2000-11-06 2001-10-31 Remedies for arachidonic acid-induced skin diseases
PCT/JP2001/009575 WO2002036592A1 (en) 2000-11-06 2001-10-31 Remedies for arachidonic acid-induced skin diseases

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