JP2000247884A - Arachidonic acid-induced skin disease-treating agent - Google Patents

Arachidonic acid-induced skin disease-treating agent

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Publication number
JP2000247884A
JP2000247884A JP11052523A JP5252399A JP2000247884A JP 2000247884 A JP2000247884 A JP 2000247884A JP 11052523 A JP11052523 A JP 11052523A JP 5252399 A JP5252399 A JP 5252399A JP 2000247884 A JP2000247884 A JP 2000247884A
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Prior art keywords
arachidonic acid
induced skin
imiquimod
agent according
induced
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Japanese (ja)
Inventor
Hiroshi Ochi
Masazumi Terajima
Masako Uchida
Kosei Watanabe
昌子 内田
寺島  正純
孝正 渡辺
宏 越智
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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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Priority to JP11052523A priority Critical patent/JP2000247884A/en
Publication of JP2000247884A publication Critical patent/JP2000247884A/en
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Abstract

PROBLEM TO BE SOLVED: To obtain a medicine useful for the treatment of skin diseases induced with arachidonic acid and having less adverse effect. SOLUTION: This treating agent of arachidonic acid-induced skin diseases contains an imiquimod or its acid adducts salt as an active ingredient. Since the agent has an inhibitory effect to the arachidonic acid-induced skin response, it can treat or prevent the various diseases caused by an abnormal enhancement of the production of arachidonic acid metabolites, e.g. psoriasis, ultraviolet ray dermatitis, mastocytosis, basal cell carcinoma, prickle cell carcinoma, etc., well and with less adverse effect.

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、1H−イミダゾ BACKGROUND OF THE INVENTION The present invention, 1H-imidazo
[4,5−C]キノリン−4−アミン構造を有する化合物R837[イミキモド(Imiquimod)]を有効成分とするアラキドン酸誘発皮膚疾患治療剤に関する。 About [4,5-C] quinolin-4 compound having an amine structure R837 [Imiquimod (Imiquimod)] arachidonic acid-induced skin diseases therapeutic agent as an active ingredient. さらに詳しくは、上記化合物がアラキドン酸代謝産物の産生亢進に起因する疾患、すなわち乾癬、紫外線皮膚炎、肥満細胞症、基底細胞癌または有刺細胞癌等のアラキドン酸誘発皮膚疾患を、良好に、かつ少ない副作用で治療または予防することのできる、新規な皮膚疾患治療剤に関する。 More particularly, the diseases which the compound is due to enhanced production of arachidonic acid metabolites, i.e. psoriasis, UV dermatitis, mastocytosis, arachidonic acid-induced skin diseases such as basal cell carcinoma or barbed cell carcinoma, well, and it can be treated or prevented with fewer side effects, novel skin diseases therapeutics.

【0002】 [0002]

【従来の技術】現在では、各種の皮膚炎症性疾患にアラキドン酸代謝産物の関与が考えられている。 BACKGROUND OF THE INVENTION Currently, the involvement of arachidonic acid metabolites in various skin inflammatory diseases are considered. アラキドン酸代謝産物とは、以下に説明するアラキドン酸代謝経路により産生される因子を意味する。 The arachidonic acid metabolites, means factors produced by the arachidonic acid metabolic pathway described below. アラキドン酸代謝経路とは、通常細胞膜のリン脂質に蓄えられているアラキドン酸が炎症反応による種々の刺激により細胞質中に遊離される事から始まる。 The arachidonic acid metabolic pathway, starts with arachidonic acid, which is usually stored in the phospholipids of the cell membrane are released into the cytoplasm by a variety of stimulation with the inflammatory response. アラキドン酸代謝には2つの大きな系があり、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(PG)と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(LT)とヒドロキシエイコサテトラエン酸(12−HETE)に分けられる。 The arachidonic acid metabolism has two major systems, prostaglandins produced by cyclooxygenase enzymes (PG) and leukotrienes produced by lipoxygenase enzyme (LT) and hydroxy eicosatetraenoic acid (12-HETE) It is divided. これらの代謝産物は炎症反応を惹起するメディエーターである。 These metabolites are mediators that cause inflammatory reactions. PGの血管拡張作用とロイコトリエンC、 Vasodilating action and leukotriene C of PG,
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。 D and E (LTC, LTD, LTE) redness swelling response of the skin is caused by vascular hyperpermeability. また、ロイコトリエン5,12−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。 Also, leukotriene 5,12 dihydroxy form characteristic subcorneal to (LTB 4) by polymorphonuclear leukocyte migration is enhanced psoriasis, more corner layer pus is formed. 以上の説明からアラキドン酸代謝産物とは、アラキドン酸、プロスタグランジン類(P The arachidonic acid metabolites from the above description, arachidonic acid, prostaglandins (P
G)、LTB 4 、LTC、LTD、LTE等のロイコトリエン類(LT)、12−HETEを意味する。 G), LTB 4, LTC, LTD, leukotrienes such as LTE (LT), means 12-HETE.

【0003】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る。 [0003] Psoriasis is a chronic disease that shows abnormal growth and benign epidermal cells, polymorphonuclear leukocytes penetration into the epidermis. 乾癬皮疹部ではPG、アラキドン酸、12−HETEの増加が示されている(Hammerstrom, S. et al. Proc. Nat. PG is psoriasis skin 疹部, arachidonic acid, 12-HETE increase in is shown (Hammerstrom, S. et al. Proc. Nat.
Acad. Sci. USA. 72 , 5130-5134 (1975))。 Acad. Sci. USA. 72, 5130-5134 (1975)). また、LT In addition, LT
4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. Inve When patches B 4 to human skin, small abscesses in the skin seen in psoriasis skin疹部is formed (Camp, S. et al. J. Inve
st. Dermatol. 82 , 202-204 (1984))。 st. Dermatol. 82, 202-204 ( 1984)). 以上の事から、 From the above,
乾癬がアラキドン酸代謝産物異常と関連すると考えられている。 Psoriasis is believed to be associated with arachidonic acid metabolites abnormalities. 肥満細胞症は、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 a condition that exhibits a flushing and hives of the skin is released. 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、それのみでは症状が改善されない症例にPG合成阻害剤を投与すると著明な改善が見られる場合がある(Main, R. These symptoms are mainly antihistamines because it is thought to be due to histamine is used, it alone is sometimes significant improvement is seen when administering PG synthesis inhibitor in patients does not resolve the problem (Main , R.
A. et al. Br. J. Dermatol. 107(Suppl. 22) , 53 (198 A. et al. Br. J. Dermatol . 107 (Suppl. 22), 53 (198
2))。 2)). また肥満細胞症にPGD 2が過剰に産生されている事が知られており(Roberts, LJ et al. N. Engl. J. Further it is known that PGD 2 is produced in excess in mastocytosis (Roberts, LJ et al. N. Engl. J.
Med. 303 , 1400-1404 (1980))、上述の症状の発現にアラキドン酸代謝物であるPGの関与も考えられている。 Med. 303, 1400-1404 (1980) ), and PG involvement also considered arachidonic acid metabolite the expression of the above symptoms.
皮膚癌のうち基底細胞癌あるいは有刺細胞癌で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, EE et al. Arch.Dermatol. And PG is increased in basal cell carcinoma or barbed cell carcinoma of skin cancer, it PG is involved in the proliferation of the tumor has been suggested (Vanderveen, EE et al. Arch.Dermatol.
122 , 407-412 (1986))。 122, 407-412 (1986)). 以上のように、これら皮膚疾患にはアラキドン酸代謝異常が関与している事が考えられ、アラキドン酸によって引き起こされる皮膚炎症を抑制する薬剤は、これら皮膚疾患の有効な治療薬となると考えられる。 As described above, these skin disorders are considered that arachidonic acid metabolism is involved, a drug that inhibits skin inflammation caused by arachidonic acid is considered to be an effective treatment for these skin diseases.

【0004】アラキドン酸誘発皮膚疾患の中でも、特に乾癬は頑固な皮膚疾患として知られている。 [0004] Among the arachidonic acid-induced skin diseases, especially psoriasis is known as a stubborn skin disease. また、乾癬は一時的な治療に反応しやすいものの、決定的かつ理想的治療剤はいまだ存在せず、効果の確かな薬剤には副作用もある。 Although psoriasis is likely to react to a temporary treatment, definitive and ideal therapeutic agent not yet present, they are also side effects certain drug effect. このような状況下、治療は長期にわたることになるため、種々の治療をうまく組み合わせ、最小の副作用で最大の効果を得る事が乾癬治療の原則といえる。 Under these circumstances, treatment to become in long-term, well combined with various treatment to obtain the maximum effect with minimal side effects can be said that the principle of treating psoriasis.
その意味で、近年登場したエトレチナート(ビタミンA In that sense, in recent years it appeared in etretinate (vitamin A
誘導体)、活性型ビタミンD3、シクロスポリンなどの乾癬治療剤は、従来の治療と異なる作用機序を有し、皮膚科専門医の乾癬治療に対する選択幅を大きく広げた画期的薬剤といえる。 Derivatives), active vitamin D3, antipsoriatic agents, such as cyclosporine, have different mechanisms of action to conventional treatment, it can be said that large unfolded innovative drug selection range for treating psoriasis of the dermatologist. しかしながら、エトレチナートにはビタミンAの様々な副作用があるため薬効発現の必要十分量の投与を制限される。 However, the etretinate is limited to the administration of necessary and sufficient amount of drug efficacy because of the various side effects of vitamin A. また活性型ビタミンD3は、 The active form of vitamin D3 is,
その効果が必ずしも十分でなく、シクロスポリンには腎毒性、血圧上昇作用が有るため使用に際しては様々な注意を必要とする薬剤である。 Its effect is not always sufficient, the cyclosporine is a drug that requires various care in use nephrotoxicity, since the hypertensive effects there. 以上の事から、現在においても、乾癬治療に対して、良好かつ少ない副作用で治療または予防することのできる薬剤の登場が望まれている From the above, in the currently for treating psoriasis, and appearance of the drug is desired which can be treated or prevented with good and less side effects
(皮膚疾患最新の治療 '97−'98、p4−7、106 (Skin disease latest treatments '97 -'98, p4-7,106
−107)。 -107).

【0005】 [0005]

【発明が解決しようとする課題】本発明の課題は、1H The object of the present invention is to provide a, 1H
−イミダゾ[4,5−C]キノリン−4−アミン構造を有する化合物R837(イミキモド)を有効成分として含み、アラキドン酸によって誘発される皮膚疾患、即ち、 - comprise a compound having an imidazo [4,5-C] quinolin-4-amine structures R837 a (Imiquimod) as an active ingredient, skin diseases induced by arachidonic acid, i.e.,
PG等の産生亢進に起因する皮膚疾患を治療または予防することができる、新規な皮膚疾患治療剤を提供することを目的とする。 It can be used to treat or prevent skin diseases caused by enhanced production such as PG, and an object thereof is to provide a novel skin disease therapeutic agent.

【0006】 [0006]

【課題を解決するための手段】本発明者らは、アラキドン酸代謝産物の産生抑制に関与する薬剤の検討を鋭意検討した結果、1H−イミダゾ[4,5−C]キノリン−4 Means for Solving the Problems The present inventors have found, after extensive studies to study drug involved in inhibiting the production of arachidonic acid metabolites, 1H-imidazo [4,5-C] quinoline -4
−アミン構造を有する化合物、特に、イミキモドに顕著な抑制効果のあることを見出し、本発明を完成することが出来た。 - compounds having an amine structure, in particular, found that a remarkable inhibitory effect on imiquimod, was able to complete the present invention. なお、従来から知られているイミキモドの薬理効果に関しては、次のことが報告されている。 Regarding the pharmacological effects of imiquimod conventionally known, it has been reported following.

【0007】1)抗ウイルス作用 モルモットの単純ヘルペスウィルス(herpes simplex vi [0007] 1) anti-virus action guinea pig of the herpes simplex virus (herpes simplex vi
rus)感染系において、該イミキモドが抗ウイルス作用を示すことが報告されている(Harrison, CJ et al. An rus) in infected systems, the imiquimod have been reported to exhibit antiviral activity (Harrison, CJ et al. An
timicrob. Agents Chemother. 38 , 2059-2064 (199 timicrob. Agents Chemother. 38, 2059-2064 (199
4))。 Four)). さらに、モルモットのサイトメガロウィルス(cyto In addition, guinea pigs of cytomegalovirus (cyto
megalovirus)感染系(Chen, M. et al. Antimicrob. Age megalovirus) infection system (Chen, M. et al. Antimicrob. Age
nts Chemother. 32 , 678-683 (1988))およびマウスのアルボウィルス(arbovirus)感染系(Adv. Biosci. (1988) nts Chemother. 32, 678-683 (1988 )) and mouse arboviruses (arbovirus) infection system (Adv. Biosci. (1988)
68 : 51-63)においても抗ウイルス活性を示すことが示されている。 68: 51-63) have been shown to exhibit antiviral activity in. そして、このようなイミキモドの示す抗ウイルス作用は、ウイルスに対する直接的作用ではなく、インターフェロンα(IFN−α)の誘導を介したものであることが報告されている(Antiviral Res. (1988) 10 : 2 The antiviral action indicated by such Imiquimod is not a direct action on virus, interferon α (IFN-α) has been reported that is obtained through the induction of (Antiviral Res. (1988) 10 : 2
09-224)。 09-224). 事実、該イミキモドはマウスの実験において、in vitroあるいはinvivoでIFN−αを誘導することが報告されている(Reiter, MJ et al. J.Leukoc. In fact, the imiquimod in mice experiments, to induce IFN-alpha in in vitro or invivo has been reported (Reiter, MJ et al. J.Leukoc.
Biol. 55 , 234-240 (1994))。 Biol. 55, 234-240 (1994) ).

【0008】2)抗腫瘍作用 イミキモドはまた種々の実験系において、抗腫瘍作用を示すことが報告されている(Sidky, YA. et al. Cancer [0008] 2) Anti-tumor effect imiquimod also in various experimental systems, has been reported to show antitumor activity (Sidky, YA. Et al. Cancer
Res. 52 , 3528-3533 (1992))。 Res. 52, 3528-3533 (1992) ). そして、該イミキモドはマウスの実験系において、in vitroあるいはin vivoでインターロイキン類(IL−1、IL−6、IL−8)や腫瘍壊死因子α(TNF−α)の産生を誘導することも記載されており(Reiter, MJ et al. J. Leukoc. Biol. Then, the imiquimod in mouse experimental systems, to induce the production of interleukins by in vitro or in vivo (IL-1, IL-6, IL-8) and tumor necrosis factor α (TNF-α) as well It has been described (Reiter, MJ et al. J. Leukoc. Biol.
55 , 234-240 (1994))、特にTNF−αの産生を誘導することから、抗腫瘍作用の一部がこの誘導されたTNF 55, 234-240 (1994)), especially to induce the production of TNF-alpha, TNF some antitumor effect was the induction
−αに起因する可能性が示唆されている。 Can be attributed to -α has been suggested.

【0009】このように、イミキモドが抗ウイルス作用および抗腫瘍作用を有すること、およびそのメカニズムとしてIFN−αあるいはTNF−α等を誘導することが報告されているが、該イミキモドがアラキドン酸によって誘発される皮膚疾患、即ち、PG等の産生亢進に起因する皮膚疾患を治療または予防することができることについては、これら文献は何ら教示していない。 [0009] Thus, it has imiquimod antiviral activity and antitumor activity, and it has been reported to induce IFN-alpha or TNF-alpha or the like as the mechanism, induced the imiquimod by arachidonic acid skin diseases, i.e., for being able to treat or prevent skin diseases caused by enhanced production of PG, etc., these documents do not in any way teach.

【0010】本発明は、以上の知見に基づき完成するに至ったのもである。 [0010] The present invention is also of has been completed based on the above findings. すなわち本発明の要旨は、 (1)R837(イミキモド)を有効成分とするアラキドン酸誘発皮膚疾患治療剤 (2)アラキドン酸誘発皮膚疾患が乾癬である、上記(1) Specifically, the subject matter of the present invention, (1) R837 arachidonic acid-induced skin diseases therapeutic agent as an active ingredient (imiquimod) (2) Arachidonic acid-induced skin disorder is psoriasis, the (1)
記載の皮膚疾患治療剤 (3)アラキドン酸誘発皮膚疾患が紫外線皮膚炎である、 Wherein the skin disease therapeutic agent (3) arachidonic acid-induced skin disorder is ultraviolet dermatitis,
上記(1)記載の皮膚疾患治療剤 (4)アラキドン酸誘発皮膚疾患が肥満細胞症である、上記(1)記載の皮膚疾患治療剤 (5)アラキドン酸誘発皮膚疾患が基底細胞癌である、上記(1)記載の皮膚疾患治療剤 (6)アラキドン酸誘発皮膚疾患が有刺細胞癌である、上記(1)記載の皮膚疾患治療剤 に関する。 It is the above (1), wherein the skin diseases therapeutic agent (4) Arachidonic acid-induced skin disorder is mastocytosis, the (1), wherein the skin diseases therapeutic agent (5) Arachidonic acid-induced skin disease is basal cell carcinoma, above (1), wherein the skin diseases therapeutic agent (6) arachidonic acid-induced skin disorder is barbed cell carcinoma, relating to the above (1), wherein the skin disease treatment agents.

【0011】 [0011]

【発明の実施の形態】本発明において「アラキドン酸誘発皮膚疾患治療剤」とは、アラキドン酸によって誘発される皮膚疾患、即ち、アラキドン酸代謝産物の産生亢進に起因する皮膚疾患の治療剤を意味する。 The "arachidonic acid-induced skin diseases Therapeutics" DETAILED DESCRIPTION OF THE INVENTION In the present invention, skin diseases induced by arachidonic acid, i.e., means a therapeutic agent for skin diseases caused by enhanced production of arachidonic acid metabolites to. 本発明の治療剤は、有効成分としてイミキモドあるいはその酸付加塩を含むものである。 The therapeutic agent of the present invention includes imiquimod or an acid addition salt thereof as an active ingredient.

【0012】イミキモドおよびその酸付加塩の合成方法としては、公知の方法に準じて容易に合成することができる。 [0012] As Imiquimod and synthetic methods of the acid addition salts can be easily synthesized according to known methods. 例えば、特公平5−86391に記載の方法に準じて合成することができる。 For example, it can be synthesized according to the method described in KOKOKU 5-86391. 該イミキモド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よく、例えば塩酸、硫酸、酢酸、蓚酸、アスコルビン酸などの無機酸や有機酸を挙げることができる。 The acid of the acid addition salts of the imiquimod may be a pharmaceutically acceptable acid, for example hydrochloric acid, can be exemplified sulfuric acid, acetic acid, oxalic acid, inorganic acids and organic acids such as ascorbic acid.

【0013】本発明のアラキドン酸誘発皮膚疾患治療剤は、イミキモドやその酸付加塩、水和物等の溶媒和物であってもよく、通常許容される賦形剤、結合剤、安定化剤などを該イミキモドと共に配合することにより製造することができる。 [0013] Arachidonic acid-induced skin diseases therapeutic agent of the present invention, imiquimod and its acid addition salts may be a solvate hydrates such as, excipients normally tolerated, binders, stabilizers etc. can be produced by blending together the imiquimod. また、注射剤形で用いる場合は、通常許容される緩衝剤、溶解補助剤、等張剤等を添加することもできる。 In the case of using the form of an injection is usually acceptable buffers, solubilizing agents, it can be added isotonic agents and the like.

【0014】投与法としては、経口および非経口投与のいずれも使用可能である。 [0014] As the administration, both oral and parenteral administration can be used. 経口投与の場合は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、非経口投与の場合は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。 For oral administration, inhalation, or capsules, tablets, can be administered in dosage forms such as granules, subcutaneous or intravenous injections by aqueous suspension in the case of parenteral administration, drops, or ointment, etc. it can be used in the dosage form.

【0015】投与量は、対象疾患を有効に治療するに充分な量を使用することが可能であるが、一般に、患者の症状、年齢、体重等により異なるが、経口投与の場合、 The dosage, it is possible to use an amount sufficient to effectively treat the target disease, general condition of the patient, age, varies depending body weight and the like in the case of oral administration,
大人では1日当たり約1〜約1000mg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ことができる。 In adults range from 1 day to about 1 to about 1000 mg, preferably may be administered separately in the range of about 10 to about 500mg once or several times. 非経口投与(注射剤)の場合、約0.1〜約500mgの範囲、好ましくは約3〜 For parenteral administration (injection), the range of about 0.1 to about 500mg, preferably about 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。 The range of about 100mg may be administered in single or divided doses.

【0016】 [0016]

【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なんら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 intended to be limited by these examples.

【0017】実施例1 アラキドン酸誘発皮内反応に対するイミキモドの抑制作 The inhibition operation of imiquimod for Example 1 arachidonic acid-induced skin reaction
1)試験動物 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、7週令まで予備飼育し使用した。 Use 1) the test animals BALB / c mice (female, 6 weeks old) Charles River Japan (Kanagawa, were purchased from Japan), was pre-breeding use up to 7 weeks of age. 2)試験薬物:R837(イミキモド) 2) test drug: R837 (Imiquimod)

【0018】3)試験薬物投与方法 R837を秤量後、アセトン(関東化学、東京、日本)に20mg/mlの濃度に懸濁した。 [0018] 3) After weighing the test drug administration R837, acetone (Kanto Chemical, Tokyo, was suspended in a concentration of 20 mg / ml in Japan). 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R837懸濁液を塗布した(R837投与群)。 Each 10μl the front and back of the mouse left auricle under diethyl ether anesthesia was applied R837 suspension (R837 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.

【0019】4)アラキドン酸塗布 R837あるいはアセトン塗布2時間後に10%アラキドン酸(CAYMAN CHEMICAL. Co.、ミシガン、アメリカ)をR837投与群とコントロール群の左耳介の表裏に10 [0019] 4) arachidonic acid applied R837 or acetone applied 2 hours after 10% arachidonic acid (CAYMAN CHEMICAL. Co., Michigan, USA) to the front and back of the left auricle of R837 administration group and the control group 10
μlずつ塗布した。 It was applied by μl.

【0020】5)皮内反応の測定 R837あるいはアセトン塗布前(抗原惹起せず)と10 [0020] 5) Measurement of skin reaction R837 or acetone prior to coating (not antigens elicit) 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Dial Thickness Gage(Mitutoyo C % Arachidonic acid applied 1 hour after (as antigen induced) to under diethyl ether anesthesia Dial Thickness Gage (Mitutoyo C
o.、東京、日本)で左右両耳介の厚さを測定した。 o., Tokyo, to measure the thickness of both the right and left ear in Japan).

【0021】皮内反応は、(抗原惹起した左耳介の厚さ) [0021] The intradermal reaction is, (the thickness of the left ear was antigen induced)
−(抗原惹起しない右耳介の厚さ)で表現した。 - expressed in (the thickness of the right ear that does not elicit antigen).

【0022】6)結果 結果は、スチューデントt−テスト(Student's t−tes [0022] 6) Results The results, 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.

【0023】 [0023]

【表1】表1. [Table 1] Table 1. R837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 R837

【0024】表1から明らかなように、R837はアラキドン酸誘発皮内反応に対して有意な抑制効果を示した。 [0024] As apparent from Table 1, R837 showed a significant inhibitory effect on arachidonic acid-induced skin reaction. この結果は、R837が乾癬等のアラキドン酸誘発皮膚疾患治療剤として有効である事を示す。 This result indicates that R837 is effective as arachidonic acid-induced skin diseases therapeutic agent such as psoriasis.

【0025】 [0025]

【発明の効果】本発明により、R837が、アラキドン酸による皮膚刺激で惹起された皮膚炎症反応を阻害することが初めて見い出された。 According to the present invention, R837 has it been for the first time found to inhibit cutaneous inflammatory response elicited by the skin irritation caused by arachidonic acid. この事実はR837がアラキドン酸代謝異常に起因する各種皮膚疾患に対する治療薬剤として有用であることを示している。 This fact indicates that it is useful as a therapeutic agent for various skin disorders R837 is due to arachidonic acid metabolism. かかる治療効果が期待できる疾患としては、乾癬、紫外線皮膚炎、肥満細胞症および基底細胞腫、有刺細胞癌等の皮膚癌を含む皮膚疾患などがあげられる。 Diseases such therapeutic effects can be expected, psoriasis, UV dermatitis, mastocytosis and basal cell carcinoma, and skin disorders, including skin cancer, such as barbed cell cancer.

───────────────────────────────────────────────────── フロントページの続き (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 (72)発明者 越智 宏 東京都千代田区神田駿河台3丁目11番地 住友製薬株式会社内 Fターム(参考) 4C065 AA01 AA05 BB06 CC09 DD03 EE02 HH01 JJ01 KK01 LL07 PP01 4C086 AA01 AA02 CB05 MA01 MA52 MA55 NA14 ZA89 ZB26 ZB33 ────────────────────────────────────────────────── ─── of the front page continued (72) inventor Masako Uchida Osaka, Osaka Prefecture Konohana Ward Kasugadenaka 3 chome No. 98 Sumitomo Pharmaceuticals Co., Ltd. in the (72) inventor Masazumi Terashima Osaka, Osaka Prefecture Konohana Ward Kasugadenaka 3 chome No. 98 Sumitomo Pharmaceuticals Co., Ltd. in the (72) inventor Hiroshi Ochi Chiyoda-ku, tokyo Surugadai, Kanda 3-chome 11 address Sumitomo Pharmaceuticals Co., Ltd. in the F-term (reference) 4C065 AA01 AA05 BB06 CC09 DD03 EE02 HH01 JJ01 KK01 LL07 PP01 4C086 AA01 AA02 CB05 MA01 MA52 MA55 NA14 ZA89 ZB26 ZB33

Claims (10)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 イミキモド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誘発皮膚疾患予防・治療剤。 1. A imiquimod or arachidonic acid-induced skin diseases preventive or therapeutic agent for the acid addition salt thereof or a solvate thereof as an active ingredient.
  2. 【請求項2】 アラキドン酸誘発皮膚疾患が乾癬である、請求項1に記載の薬剤。 Wherein arachidonic acid-induced skin disorder is psoriasis, agent according to claim 1.
  3. 【請求項3】 アラキドン酸誘発皮膚疾患が紫外線皮膚炎である、請求項1に記載の薬剤。 3. Arachidonic acid-induced skin disorder is ultraviolet dermatitis, agent according to claim 1.
  4. 【請求項4】 アラキドン酸誘発皮膚疾患が肥満細胞症である、請求項1に記載の薬剤。 4. arachidonic acid-induced skin disorder is mastocytosis, agent according to claim 1.
  5. 【請求項5】 アラキドン酸誘発皮膚疾患が基底細胞癌である、請求項1に記載の薬剤。 5. Arachidonic acid-induced skin disease is basal cell carcinoma, the agent of claim 1.
  6. 【請求項6】 アラキドン酸誘発皮膚疾患が有刺細胞癌である、請求項1に記載の薬剤。 6. arachidonic acid-induced skin disorder is barbed cell carcinoma, agent according to claim 1.
  7. 【請求項7】 経口投与用剤形である請求項1〜6のいずれかに記載の薬剤。 7. The agent according to claim 1 which is for oral administration dosage forms.
  8. 【請求項8】 約1〜約1000mg/日の投与単位用量のイミキモドを含有する請求項7に記載の薬剤。 8. about 1 to about 1000 mg / day agent according to claim 7 containing imiquimod administration unit dose.
  9. 【請求項9】 非経口投与用剤形である請求項1〜6のいずれかに記載の薬剤。 9. The agent according to claim 1 is a parenteral dosage form.
  10. 【請求項10】 約0.1〜約500mg/日の投与単位用量のイミキモドを含有する請求項9に記載の薬剤。 10. about 0.1 to about 500 mg / day agent according to claim 9 containing imiquimod administration unit dose.
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