JP2009019020A - Cyclohexaneketone compound extracted from antrodia camphorata useful for treating autoimmune disease - Google Patents
Cyclohexaneketone compound extracted from antrodia camphorata useful for treating autoimmune disease Download PDFInfo
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- JP2009019020A JP2009019020A JP2007184470A JP2007184470A JP2009019020A JP 2009019020 A JP2009019020 A JP 2009019020A JP 2007184470 A JP2007184470 A JP 2007184470A JP 2007184470 A JP2007184470 A JP 2007184470A JP 2009019020 A JP2009019020 A JP 2009019020A
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- Prior art keywords
- treatment
- compound
- autoimmune disease
- lupus erythematosus
- systemic lupus
- Prior art date
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Images
Abstract
Description
本発明は一種の免疫関連疾病の治療に用いる化合物に関する。特に一種のベニクスノキタケ（Antrodia camphorata）抽出物中から分離純化し、システム性エリテマトーデスなどの自己免疫性疾病の治療に用いるベニクスノキタケシクロヘキサンケトン化合物に係る。 The present invention relates to compounds for use in the treatment of a class of immune related diseases. In particular, the present invention relates to a Benix nochtake cyclohexane ketone compound that is separated and purified from a kind of Antrodia camphorata extract and used for the treatment of autoimmune diseases such as systemic lupus erythematosus.
免疫システムの反応異常が自己組織に対して破壊をもたらす自己免疫疾病（autoimmune diseases）にはシステム性エリテマトーデス（systemic lupus erythematosus, SLE）、関節リューマチ（Rheumatoid arthritis）、硬皮症（Scleroderma）、多発性筋炎（Polymyositis）、皮膚筋炎（dermatomyositis）、アナフィラキトイド紫斑（Anaphylactoid purpura）、ショーグレン症候群（Sjogren syndrome）などがあり、非常に種類が多い。他の原発性胆道システム肝硬変、慢性活動性肝炎、橋本氏甲状腺炎なども、自己免疫と関連がある。内、システム性エリテマトーデス（SLE）或いは全身性エリテマトーデスと呼ばれる自己免疫疾病は最も重大な疾病の一つである。それは、出産可能年齢の女性に起こり易く、患者の体内には細胞核内自己抗原（autoantigens）に対抗する自己抗体（autoantibodies）が生じる。自己抗体（autoantibodies）は抗核抗体（antinuclear antibodies,ANA）とも呼ばれ、皮膚、関節、骨格、腎臓、心血管システム、凝血システム、胃腸、漿膜（心包膜、胸膜、腹膜）、脳神経システムなど多種の組織と器官に傷害を与える。しかもある自己抗体と抗原は結合し、免疫複合体（immune complex,IC）を形成し、さらに血液が異なる組織細胞中に沈殿するに従い傷害を引き起こす。これにより臨床上は胡蝶班、溶血性貧血、関節炎、血管炎、腎炎などの病変が現れる。自己免疫疾病の多くはステロイド或いは他の化学薬物により治療されるが、該各治療剤の長期間の服用は患者に不快な合併症或いは副作用をもたらす。よって、もし天然かつ副作用のない漢方生薬物質により、該各自己免疫疾病を治療することができれば、自己免疫疾病の患者にとって大きな利益となり、その病苦を和らげることになる。 Systemic lupus erythematosus (SLE), Rheumatoid arthritis, scleroderma (Scleroderma), multiple occurrences of autoimmune diseases that cause abnormal immune system reactions There are myositis (Polymyositis), dermatomyositis, Anaphylactoid purpura, Sjogren syndrome, and so on. Other primary biliary system cirrhosis, chronic active hepatitis, and Hashimoto's thyroiditis are also associated with autoimmunity. Autoimmune disease called systemic lupus erythematosus (SLE) or systemic lupus erythematosus is one of the most serious diseases. It is likely to occur in women of childbearing age, and autoantibodies against the nuclear autoantigens are produced in the patient's body. Autoantibodies are also called antinuclear antibodies (ANA), such as skin, joints, skeleton, kidney, cardiovascular system, blood clot system, gastrointestinal, serosa (pericardium, pleura, peritoneum), cranial nerve system, etc. Causes damage to various tissues and organs. In addition, certain autoantibodies and antigens combine to form immune complexes (ICs) and cause injury as blood precipitates in different tissue cells. This causes clinical lesions such as phalaenopsis, hemolytic anemia, arthritis, vasculitis, and nephritis. Many autoimmune diseases are treated with steroids or other chemical drugs, but long-term use of each therapeutic agent results in uncomfortable complications or side effects for the patient. Therefore, if each of the autoimmune diseases can be treated with natural herbal medicine having no side effects, it will be a great benefit for patients with autoimmune diseases, and the disease will be alleviated.
ベニクスノキタケ（Antrodia camphorata）は台湾では牛樟芝、樟芝、牛樟キノコ、紅樟芝などと呼称され、ヒダナシタケ目（Aphyllophorales）、多孔菌科（Polyporaceae）の多年生菌類で、台湾固有の真菌である。ベニクスノキタケは台湾の保護樹木である牛樟樹（Cinnamoum kanehirai Hay）の中空の腐敗心材内壁にのみ生長する。牛樟樹は台湾でも極めて希少な保護樹であり、不法伐採の問題もあるため、牛樟樹中に寄生する野生ベニクスノキタケはさらに希少である。しかもその子実体の生長は非常に緩慢で、生長期は六月から十月の間に限られるため、非常に高価である。 Antrodia camphorata is called Taiwanese beetle turf, turfgrass, burdock mushroom, red turf, etc., and is a perennial fungus of Aphyllophorales, Polyporaceae, and is a Taiwan-specific fungus . Benix-no-Makitake grows only on the hollow rotted inner wall of Taiwanese protected tree, Cinnamoum kanehirai Hay. Beef tree is one of the rarest protected trees in Taiwan, and there are problems of illegal logging. Moreover, the growth of the fruiting bodies is very slow and the growth period is limited to between June and October, so it is very expensive.
ベニクスノキタケの子実体は多年生、無柄で、木栓質（スベリン）から木質を呈し、強烈な樟樹香気を備える。その形態は板状、鐘状、馬蹄形、塔状等様々である。初期は扁平型で鮮紅色を呈し、後にその周辺が放射状に巻き上がり、四週へと拡大し生長する。色も淡褐色或いは淡黄褐色へと変化し、多くの細孔を備える。それはベニクスノキタケの薬用価値が最も豊富な部位である。 The fruit body of Benix nokitake is a perennial, unpatterned, woody from submerged wood, and has a strong fragrance of coconut tree. There are various forms such as a plate shape, a bell shape, a horseshoe shape, and a tower shape. Initially, it is flat and bright red, and then its surroundings radiate and radiate and expand to four weeks. The color also changes to light brown or light tan, and has many pores. It is the most abundant medicinal value of Benix nokitake.
台湾の民間療法ではベニクスノキタケは解毒、下痢の症状軽減、消炎、肝臓関連疾病治療、抗癌薬として用いられる。ベニクスノキタケは一般の生薬とされるキノコ類同様に、多くの複雑な成分を含む。既に知られている生理活性成分中には、トリテルペノイド（triterpenoids）、多糖体（polysaccharides，β−グルコースなど）、アデノシン（adenosine）、ビタミン（ビタミンB、ナイアシン等）、タンパク質（免疫グロブリンを含む）、スーパーオキサイドディスムターゼ（superoxide dismutase, SOD）、微量元素（カルシウム、リン、ゲルマニウム等）、核酸、ステロール類、及び血圧安定物質（antodia acid等）等がある。これら生理活性成分は抗腫瘍、免疫能力強化、抗過敏、抗ウィルス、抗高血圧、血糖値低下、コレステロール低下等の多種の機能と効果を備えると考えられている。 In Taiwanese folk remedies, Benix nokitake is used as a detoxifier, diarrhea symptom relief, anti-inflammation, liver related disease treatment, and anticancer drug. Benix-no-Makitake contains many complex components, like mushrooms, which are considered to be common crude drugs. Among the already known physiologically active ingredients, triterpenoids, polysaccharides (polysaccharides, β-glucose, etc.), adenosine, vitamins (vitamin B, niacin, etc.), proteins (including immunoglobulins), Examples include superoxide dismutase (SOD), trace elements (calcium, phosphorus, germanium, etc.), nucleic acids, sterols, and blood pressure stabilizing substances (antodia acid, etc.). These physiologically active ingredients are considered to have various functions and effects such as antitumor, immune capacity enhancement, antihypersensitivity, antiviral, antihypertensive, blood glucose level lowering, cholesterol lowering and the like.
ベニクスノキタケの多種の成分の内、トリテルペノイドに対する研究が最も多い。トリテルペノイドは三十個の炭元素が六角形或いは五角形に結合した天然化合物の総称である。ベニクスノキタケが具える苦味は、トリテルペノイドが成分である。１９９５年、Cherng氏等はベニクスノキタケ子実体の抽出物中に三種の新しいエルゴスタン（ergostane）を骨格とするトリテルペノイド：antcin A、antcin Bとantcin C（引用文献１）が含まれることを発見した。Chen氏等はエタノールによりベニクスノキタケ子実体を抽出後、zhankuic acid A、zhankuic acid B 及びzhankuic acid C等三種のトリテルペノイドを発見した（引用文献２）。この他、Chiang氏等は１９９５年、子実体抽出物中より別の三種のセスキテルペンラクトン（sesquiterpene lactone）と二種のビスフェノール類派生物である新しいトリテルペノイドを発見した。これがすなわち、antrocin, ４,７−ジメトキシ−５−メチル−１,３−ベンゾジオキソール（４,７−dimethoxy−５−methy−１,３− benzodioxole）と２,２',５,５'−テラメトキシ−３,４,３',４'−ビ−メチルレネジオキシ−６,６'−ジメチルビフィニール（２,２',５,５'−teramethoxy−３,４,３',４'−bi− methylenedioxy−６,６'− dimethylbiphenyl）（引用文献３）である。１９９６年になって、Cherng氏等は同様の分析方法により再度四種の新しいトリテルペノイド：antcin E、antcin F、methyl antcinate G、methyl antcinate H（引用文献４）を発見した。
またYang氏等は二種のエルゴスタンを骨格とする新化合物zhankuic acid D、zhankuic acid Eと三種のラノスタン（lanostane）を骨格とする新化合物：１５ α−アセチル−デハイドロサルファレニック酸（１５ α−acetyl−dehydrosulphurenic acid）、デハイドロエブリコイック酸（dehydroeburicoic acid）とデハイドラサルファレニック酸（dehydrasulphurenic acid）（引用文献５）を発見した。
Among the various components of Benicus mushrooms, the most research has been on triterpenoids. Triterpenoid is a general term for natural compounds in which thirty carbon elements are bound in hexagonal or pentagonal form. Triterpenoid is a component of the bitter taste of Benix nokitake. In 1995, Cherng et al. Discovered that the extracts of the fruit bodies of Benix nokitake contained three new triterpenoids with ergostane skeletons: antcin A, antcin B and antcin C (reference document 1). . Chen et al. Discovered three types of triterpenoids such as zhankuic acid A, zhankuic acid B and zhankuic acid C after extracting the fruit bodies of Benix nokitake with ethanol (Cited document 2). In addition, Chiang et al. Discovered in 1995 a new triterpenoid that is a derivative of three other sesquiterpene lactones and two bisphenol derivatives in fruit body extracts. That is, antrocin, 4,7-dimethoxy-5-methyl-1,3-benzodioxole and 2,2 ', 5,5' -Teramethoxy-3,4,3 ', 4'-bimethyllenezoxy-6,6'-dimethylbifinyl (2,2', 5,5'-teramethoxy-3,4,3 ', 4 '-Bi-methylenedioxy-6,6'-dimethylbiphenyl) (cited document 3). In 1996, Cherng et al. Again discovered four new triterpenoids: antcin E, antcin F, methyl antcinate G, and methyl antcinate H (cited document 4) by the same analysis method.
Yang et al. Also proposed two new compounds zhankuic acid D and zhankuic acid E having two ergostane skeletons and three lanostane skeletons: 15 α-acetyl-dehydrosulfarenic acid (15 α-acetyl-dehydrosulphurenic acid), dehydroeburicoic acid and dehydrasulphurenic acid (Cited document 5) were discovered.
現在では様々な実験により、ベニクスノキタケ抽出物が前記効果を備えることが知られており、しかもそれが含む成分も続々と分析されている。しかしベニクスノキタケ抽出物の自己免疫性疾病治療への使用は未だ見られず、しかもベニクスノキタケ抽出物のどの種の有効成分が自己免疫性疾病症状の改善に有効かは、現在もなお試験段階にある。よって該抽出物中に含まれる真に有効な成分を探し出し、この天然成分をシステム性エリテマトーデスなどの自己免疫性疾病の予防或いは治療に用いることができれば、ステロイドなどの化学薬物による自己免疫性疾病への治療が引き起こす副作用或いは合併症の軽減に役立つ。 At present, it has been known through various experiments that Benix nokitake extract has the above-mentioned effect, and components contained therein are also analyzed one after another. However, the use of Benix nokitake extract for the treatment of autoimmune diseases has not been seen yet, and what kind of active ingredient of Benix nokitake extract is still effective to improve the symptoms of autoimmune disease. In the stage. Therefore, if a truly effective component contained in the extract can be found and this natural component can be used for the prevention or treatment of autoimmune diseases such as systemic lupus erythematosus, it will lead to autoimmune diseases caused by chemical drugs such as steroids. It helps to reduce side effects and complications caused by treatment.
[引用文献１] Cherng, I. H., and Chiang, H. C. １９９５. Three new triterpenoids from Antrodia cinnamomea. J. Nat. Prod. ５８:３６５−３７１
[引用文献２] Chen, C. H., and Yang, S. W. １９９５. New steroid acids from Antrodia cinnamomea, −a fungus parasitic on Cinnamomum micranthum. J. Nat. Prod. ５８:１６５５−１６６１
[引用文献３] Chiang, H. C., Wu, D. P., Cherng, I. W., and Ueng, C. H. １９９５. A sesquiterpene lactone, phenyl and biphenyl compounds from Antrodia cinnamomea. Phytochemistry. ３９:６１３−６１６
[引用文献４] Cherng, I. H., Wu, D. P., and Chiang, H. C. １９９６. Triteroenoids from Antrodia cinnamomea. Phytochemistry. ４１:２６３−２６７
[引用文献５] Yang, S. W., Shen, Y. C., and Chen, C. H. １９９６. Steroids and triterpenoids of Antrodia cinnamomea−a fungus parasitic on Cinnamomum micranthum. Phytochemistry. ４１:１３８９−１３９２
[Cited document 1] Cherng, IH, and Chiang, HC 1995. Three new triterpenoids from Antrodia cinnamomea. J. Nat. Prod. 58: 365-371
[Cited document 2] Chen, CH, and Yang, SW 1995. New steroid acids from Antrodia cinnamomea, −a fungus parasitic on Cinnamomum micranthum. J. Nat. Prod. 58: 1655-1661
[Cited document 3] Chiang, HC, Wu, DP, Cherng, IW, and Ueng, CH 1995. A sesquiterpene lactone, phenyl and biphenyl compounds from Antrodia cinnamomea. Phytochemistry. 39: 613-616
[Cited document 4] Cherng, IH, Wu, DP, and Chiang, HC 1996. Triteroenoids from Antrodia cinnamomea. Phytochemistry. 41: 263-267
[Cited document 5] Yang, SW, Shen, YC, and Chen, CH 1996. Steroids and triterpenoids of Antrodia cinnamomea-a fungus parasitic on Cinnamomum micranthum. Phytochemistry. 41: 1389-1392
上記課題を解決するため、本発明は下記の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物を提供する。ベニクスノキタケ抽出物のどの成分がシステム性エリテマトーデスなどの自己免疫性疾病の予防或いは治療に有効かを明確にするため、本発明はベニクスノキタケ抽出物中から以下の構造式（１）を備える化合物を分離純化する。
式（１）の化合物中において、以下に示す式（２）の化合物が最適である。
本発明中式（１）、式（２）の化合物はベニクスノキタケ水抽出物或いは有機溶剤抽出物より分離純化し、有機溶剤はアルコール類（メタノール、エタノール或いはプロパノール等）、エステル類（アセチジン等）、アルケン類（ヘキサン等）或いはハロセン（クロロメタン、エチルクロライド等）を含むが、これらに限定しない。内、アルコール類が最適で、エタノールがより最適である。 In the present invention, the compounds of the formulas (1) and (2) are separated and purified from Benix nokitake water extract or organic solvent extract, and the organic solvents are alcohols (methanol, ethanol, propanol etc.), esters (acetylidine etc.) Alkenes (hexane, etc.) or halocenes (chloromethane, ethyl chloride, etc.), but are not limited thereto. Of these, alcohols are optimal, and ethanol is more optimal.
本発明は前記化合物をシステム性エリテマトーデスなどの自己免疫性疾病の予防或いは治療に応用する。ベニクスノキタケシクロヘキサンケトン化合物をシステム性エリテマトーデスを発症する哺乳動物に与える時、その尿タンパク含量は腎臓の炎症と病変の減少により緩和され、低下し得る。しかも血液中に含まれる抗核抗体濃度も効果的に減少し、こうして抗核抗体のヒトなど哺乳動物の自己組織に対する傷害を緩和し、システム性エリテマトーデスなどの自己免疫性疾病の治療効果を達成する。また該ベニクスノキタケから抽出した天然物質により、ステロイドなどの化学薬物治療が引き起こす副作用或いは合併症を減少させ、患者の不快な症状を緩和することができる。 The present invention applies the compounds to the prevention or treatment of autoimmune diseases such as systemic lupus erythematosus. When a Benix nocturnus cyclohexane ketone compound is given to a mammal that develops systemic lupus erythematosus, its urinary protein content can be mitigated and reduced by a decrease in kidney inflammation and lesions. Moreover, the concentration of antinuclear antibodies contained in the blood is also effectively reduced, thus alleviating the damage of antinuclear antibodies to the self-organization of mammals such as humans and achieving therapeutic effects for autoimmune diseases such as systemic lupus erythematosus. . In addition, the natural substance extracted from the Benicaria mushroom can reduce side effects or complications caused by chemical drug treatment such as steroids, and can alleviate unpleasant symptoms of patients.
また、本発明中では式（１）或いは／と式（２）の化合物を乳システム性エリテマトーデスなどの自己免疫性疾病を治療する医薬組成物の成分中に利用し、これによりヒトなどの哺乳動物が自己免疫性疾病により発症する症状を改善する。前記医薬組成物は有効剤量の式（１）或いは／と式（２）の化合物を含む他に、薬学上受け入れ可能なキャリアを含むことができる。キャリアは賦形剤（水など）、充填剤（蔗糖或いはでんぷん）、接着剤（セルロース派生物など）、希釈剤、崩解剤、吸收促進剤或いは甘味剤であるが、これに限定するものではない。本発明医薬組成物は一般公知の薬学の製作準備方法により製造することができ、式（１）或いは／と式（２）の有効成分剤量と一種以上のキャリアを相互に混合し、必要な剤型を製作準備する。この剤型は錠剤、粉剤、粒剤、カプセル剤或いはその他液体製剤であるが、これに限定するものではない。 Further, in the present invention, the compound of the formula (1) or / and the formula (2) is used in a component of a pharmaceutical composition for treating an autoimmune disease such as milk system lupus erythematosus, thereby a mammal such as a human being. Improves symptoms caused by autoimmune diseases. In addition to containing an effective amount of the compound of Formula (1) or / and Formula (2), the pharmaceutical composition can include a pharmaceutically acceptable carrier. Carriers are excipients (such as water), fillers (such as sucrose or starch), adhesives (such as cellulose derivatives), diluents, disintegrants, absorption enhancers or sweeteners, but are not limited to this. Absent. The pharmaceutical composition of the present invention can be produced by a generally known preparation method for producing pharmaceutics, and the amount of the active ingredient of formula (1) or / and formula (2) and one or more carriers are mixed with each other, and necessary Prepare the dosage form. The dosage form is a tablet, powder, granule, capsule or other liquid preparation, but is not limited thereto.
請求項１の発明は、自己免疫疾病の治療に用いるベニクスノキタケシクロヘキサンケトン化合物で、以下の構造式を備え、
請求項２の発明は、前記化合物はベニクスノキタケの有機溶剤抽出物中から分離製造することを特徴とする請求項１記載の自己免疫疾病治療に用いるベニクスノキタケのシクロヘキサンケトン抽出物としている。
請求項３の発明は、前記有機溶剤はエステル類、アルコール類、アルケン類或いはハロセンにより組成するグループから選択することを特徴とする請求項２記載の自己免疫疾病治療に用いるベニクスノキタケのシクロヘキサンケトン抽出物としている。
請求項４の発明は、前記アルコール類はエタノールであることを特徴とする請求項３記載の自己免疫疾病治療に用いるベニクスノキタケのシクロヘキサンケトン抽出物としている。
請求項５の発明は、前記化合物はベニクスノキタケの水抽出物中より分離製造することを特徴とする請求項１記載の自己免疫疾病治療に用いるベニクスノキタケのシクロヘキサンケトン抽出物としている。
請求項６の発明は、前記化合物は４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトン（４−hydroxy−２,３−dimethoxy−６−methy−５（３,７,１１− trimethyl−dodeca−２,６,１０−trienyl）−cyclohex−２−enone）であることを特徴とする請求項１記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項７の発明は、前記化合物は自己免疫疾病が哺乳動物に対して引き起こす腎臓損傷及び自己免疫疾病が生成する抗核抗体の器官組織に対する傷害を緩和可能であることを特徴とする請求項１或いは請求項６記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項８の発明は、前記哺乳動物はヒトであることを特徴とする請求項７記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項９の発明は、前記自己免疫疾病はシステム性エリテマトーデスであることを特徴とする請求項８記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項１０の発明は、前記化合物は哺乳動物の尿タンパク含量を低下させることにより、システム性エリテマトーデスが引き起こす腎臓損傷を緩和することができることを特徴とする請求項９記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項１１の発明は、前記化合物は哺乳動物血清中の抗核抗体含量を低下させ、システム性エリテマトーデスが引き起こす自己組織器官への損傷を緩和することができることを特徴とする請求項９記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項１２の発明は、前記抗核抗体はダブルストランドDNAの抗核抗体であることを特徴とする請求項１１記載の自己免疫疾病治療に用いるベニクスノキタケシクロヘキサンケトン化合物としている。
請求項１３の発明は、自己免疫疾病治療に用いる医薬組成物は少なくとも有効剤量の請求項１記載の化合物と医学上受け入れ可能なキャリアを含むことを特徴とする自己免疫疾病治療に用いる医薬組成物としている。
請求項１４の発明は、前記自己免疫疾病はシステム性エリテマトーデスであることを特徴とする請求項１３記載の自己免疫疾病治療に用いる医薬組成物としている。
請求項１５の発明は、自己免疫疾病治療に用いる医薬組成物は少なくとも有効剤量の請求項６記載の化合物と医学上受け入れ可能なキャリアを含むことを特徴とする自己免疫疾病治療に用いる医薬組成物としている。
請求項１６の発明は、前記自己免疫疾病はシステム性エリテマトーデスであることを特徴とする請求項１５記載の自己免疫疾病治療に用いる医薬組成物としている。
The invention of claim 1 is a Benix nokitake cyclohexane ketone compound used for the treatment of autoimmune diseases, comprising the following structural formula:
According to a second aspect of the present invention, there is provided a cyclohexane ketone extract of venix mushroom used for autoimmune disease treatment according to the first aspect, wherein the compound is produced by separation from an organic solvent extract of venix mushroom.
The invention according to claim 3 is characterized in that the organic solvent is selected from the group consisting of esters, alcohols, alkenes or halocenes. It is an extract.
According to a fourth aspect of the present invention, there is provided a cyclohexanone ketone extract of Benicaria communis used for the treatment of autoimmune diseases according to the third aspect, wherein the alcohol is ethanol.
According to a fifth aspect of the present invention, there is provided a cyclohexanone ketone extract of venix mushroom used for the treatment of autoimmune disease according to claim 1, wherein the compound is separated and produced from an aqueous extract of venix mushroom.
The invention of claim 6 is characterized in that the compound is 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexaneketone (4- 2. Hydroxy-2,3-dimethoxy-6-methy-5 (3,7,11-trimethyl-dodeca-2,6,10-trienyl) -cyclohex-2-enone) Benix nokitake cyclohexane ketone compound used for the treatment of autoimmune diseases.
The invention of claim 7 is characterized in that the compound is capable of alleviating kidney damage caused by autoimmune diseases to mammals and damage to organ tissues of antinuclear antibodies produced by autoimmune diseases. Or it is set as the Benix nokitake cyclohexane ketone compound used for the autoimmune disease treatment of Claim 6.
The invention according to claim 8 is the Benix nokitake cyclohexane ketone compound used for autoimmune disease treatment according to claim 7, wherein the mammal is a human.
The invention according to claim 9 is the Benix nocitake cyclohexane ketone compound used for the treatment of autoimmune disease according to claim 8, wherein the autoimmune disease is systemic lupus erythematosus.
The invention according to claim 10 is used for the treatment of autoimmune diseases according to claim 9, characterized in that the compound can alleviate kidney damage caused by systemic lupus erythematosus by reducing the urinary protein content of mammals. Benix nokitake cyclohexane ketone compound.
The invention according to claim 11 is characterized in that the compound reduces the content of antinuclear antibodies in mammalian serum and can alleviate the damage to self-organ organs caused by systemic lupus erythematosus. Benix-no-take mushroom cyclohexane ketone compound used for treatment of immune diseases.
According to a twelfth aspect of the present invention, the antinuclear antibody is a double strand DNA antinuclear antibody, which is a Benix nosytake cyclohexane ketone compound used for autoimmune disease treatment according to the eleventh aspect.
According to a thirteenth aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment of an autoimmune disease, wherein the pharmaceutical composition used for the treatment of an autoimmune disease comprises at least an effective amount of the compound of the first aspect and a medically acceptable carrier. It is a thing.
The invention of claim 14 is the pharmaceutical composition for use in the treatment of autoimmune disease according to claim 13, wherein the autoimmune disease is systemic lupus erythematosus.
According to a fifteenth aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment of an autoimmune disease, wherein the pharmaceutical composition used for the treatment of an autoimmune disease comprises at least an effective amount of the compound of the sixth aspect and a medically acceptable carrier. It is a thing.
The invention according to claim 16 is the pharmaceutical composition used for the treatment of autoimmune disease according to claim 15, wherein the autoimmune disease is systemic lupus erythematosus.
上記のように、本発明は本発明ベニクスノキタケから分離した４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトン化合物は、自己免疫疾病が引き起こす尿タンパク濃度及び抗核抗体含量の上昇などの症状を効果的に緩和することができ、これにより該各疾病がヒトなどの哺乳動物に対して引き起こす組織器官の傷害を緩和することができ、しかもその腎臓に対する保護と腎臓損傷を低下させる効果を利用し、腎臓疾病が体内で引き起こす傷害を軽減することができる。また、ベニクスノキタケシクロヘキサンケトン化合物は天然抽出の物質であるため、それをシステム性エリテマトーデスなどの自己免疫疾病と腎臓関連疾病への治療に応用しても、患者に不快な症状或いは毒性、合併症などの他の副作用を発することがない。しかも、それは化学薬剤と併用することができ、ステロイドなどの化学薬物の使用量を減少させることができ、該各化学薬物が引き起こす副作用を低減することができる。さらに、それは医薬組成物を製造調整することができ、該医薬組成物は有効成分剤量のベニクスノキタケシクロヘキサンケトン化合物を含む他、薬学上受け入れ可能なキャリアを含むことができる。キャリアは賦形剤（水など）、充填剤（蔗糖或いはでんぷん）、接着剤（セルロース派生物など）、希釈剤、崩解剤、吸收促進剤或いは甘味剤であるが、これに限定するものではない。本発明医薬組成物は一般公知の薬学の製作準備方法により製造することができ、有効成分剤量のベニクスノキタケシクロヘキサンケトン化合物と一種以上のキャリアを相互に混合し、必要な剤型を製作準備する。この剤型は錠剤、粉剤、粒剤、カプセル剤或いはその他液体製剤であるが、これに限定するものではない。こうしてヒトなどの哺乳動物のシステム性エリテマトーデスなどの自己免疫疾病と腎臓疾病を予防及び治療する目的を達成する。 As described above, the present invention relates to 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2 isolated from the present Benix nocturnus. -The cyclohexane ketone compound can effectively relieve symptoms such as an increase in urinary protein concentration and antinuclear antibody content caused by autoimmune diseases, thereby causing each disease to cause mammals such as humans Injuries to organs can be alleviated, and the damage caused by kidney disease in the body can be reduced by utilizing the protection of the kidneys and the effect of reducing kidney damage. In addition, Benix nokitake cyclohexaneketone compound is a naturally extracted substance, so even if it is applied to the treatment of autoimmune diseases such as systemic lupus erythematosus and kidney related diseases, it may be unpleasant symptoms or toxicity and complications to the patient. No other side effects occur. In addition, it can be used in combination with a chemical agent, the amount of a chemical drug such as steroid can be reduced, and the side effects caused by each chemical drug can be reduced. In addition, it can be prepared to prepare a pharmaceutical composition, which can contain a pharmaceutically acceptable carrier in addition to containing an active ingredient amount of Benix nocturnal cyclohexane ketone compound. Carriers are excipients (such as water), fillers (such as sucrose or starch), adhesives (such as cellulose derivatives), diluents, disintegrants, absorption enhancers or sweeteners, but are not limited to this. Absent. The pharmaceutical composition of the present invention can be produced by a generally known pharmacy production preparation method. The amount of active ingredient Benix nokitake cyclohexane ketone compound and one or more carriers are mixed with each other to prepare the necessary dosage form. To do. The dosage form is a tablet, powder, granule, capsule or other liquid preparation, but is not limited thereto. Thus, the object of preventing and treating autoimmune diseases and kidney diseases such as systemic lupus erythematosus in mammals such as humans is achieved.
先ず、ベニクスノキタケ（Antrodia camphorata）菌糸体、子実体或いは二者の混合物を取り、公知の抽出方式を利用し、水或いは有機溶剤により抽出し、ベニクスノキタケ水抽出物或いは有機溶剤抽出物を取得する。内、有機溶剤はアルコール類（メタノール、エタノール或いはプロパノール等）、エステル類（アセチジン等）、アルケン類（ヘキサン等）或いはハロセン（クロロメタン、エチルクロライド等）を含むが、これらに限定しない。内、アルコール類が最適で、エタノールがより最適である。 First, take the mycelium, fruit body or mixture of the two of the Antrodia camphorata, extract using water or an organic solvent using a known extraction method, get. Among them, the organic solvent includes alcohols (such as methanol, ethanol or propanol), esters (such as acetylidine), alkenes (such as hexane), or halocene (such as chloromethane and ethyl chloride), but is not limited thereto. Of these, alcohols are optimal, and ethanol is more optimal.
抽出後のベニクスノキタケ水抽出物或いは有機溶剤抽出物は、さらに高速液体クロマトグラフィー（High performance liquid chromatography、HPLC）により分離純化し、各一分液（fraction）に対してシステム性エリテマトーデスなどの自己免疫性疾病治療に関連する尿中の尿タンパク含量及び血液中の抗核抗体濃度などを計測するなどの生物化学テストを行う。最後に、効果を備える分液に対して成分分析を行い、システム性エリテマトーデスなどの自己免疫性疾病の症状効果を生じる可能性のある成分に対してさらにそれぞれ異なる関連の生物化学テストを行う。こうして最終的に、本発明中の式（１）／式（２）の化合物は尿タンパク含量及び抗核抗体濃度を低下させ、システム性エリテマトーデスなどの自己免疫性疾病及び腎臓関連疾病を治療する機能と効果を備えることが発見された。この他、式（１）／式（２）の化合物は、システム性エリテマトーデスなどの自己免疫性疾病及び腎臓関連疾病を治療する医薬組成物の成分中において、天然成分により病状を改善するため、副作用及び合併症を引き起こさない状況で、患者の不快な症状を効果的に緩和することができる。 The extracted Benix nokitake water extract or organic solvent extract is further separated and purified by high performance liquid chromatography (HPLC), and each fraction is self-tested such as systemic lupus erythematosus. Biochemical tests such as measurement of urine protein content in urine and antinuclear antibody concentration in blood related to treatment of immune diseases are conducted. Finally, a component analysis is performed on the effective separation, and further different related biochemical tests are performed on components that may cause symptomatic effects of autoimmune diseases such as systemic lupus erythematosus. Thus, finally, the compound of formula (1) / formula (2) in the present invention reduces urinary protein content and antinuclear antibody concentration, and functions to treat autoimmune diseases such as systemic lupus erythematosus and kidney related diseases. And was found to be effective. In addition, the compound of formula (1) / formula (2) improves the pathology with natural ingredients in the components of pharmaceutical compositions for treating autoimmune diseases such as systemic lupus erythematosus and kidney-related diseases. And in situations that do not cause complications, the patient's unpleasant symptoms can be effectively relieved.
本発明の説明の便のために、以下に式（２）の４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトン化合物について説明する。この他、４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトン化合物がシステム性エリテマトーデスなどの自己免疫性疾病に対して生じる治療効果について、本発明中ではシステム性エリテマトーデスを発症するNZB／WF１雌ネズミに前記ベニクスノキタケシクロヘキサンケトン化合物を与えた後に、その尿タンパク濃度及び血液中の抗核抗体含量を計測し、ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデス治療における効用を評価する。該各尿タンパク濃度及び抗核抗体含量の結果により、４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトンは腎臓の炎症と病変を緩和し、尿中の尿タンパク濃度を低下させ、しかもシステム性エリテマトーデスを発症するヒトなどの哺乳動物体内の抗核抗体の生成を抑制或いは減少させる効果を備えることが証明された。これにより抗核抗体の哺乳動物の自己組織への傷害を緩和し、システム性エリテマトーデスの症状を治療する効果を達成することができる。前記実施方式に対して以下に詳細に説明する。 For convenience of explanation of the present invention, 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl)- The 2-cyclohexane ketone compound will be described. In addition, 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexane ketone compound is an autoimmune agent such as systemic lupus erythematosus. In the present invention, NZB / WF1 female mice that develop systemic lupus erythematosus are given the above-mentioned Benix nokitake cyclohexane ketone compound, and then the urinary protein concentration and the antinuclear antibody content in blood are determined. We measure and evaluate the utility of Benix nokitake cyclohexane ketone compound in the treatment of systemic lupus erythematosus. 4-Hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexane depending on the results of the respective urinary protein concentration and antinuclear antibody content Ketones have the effect of reducing kidney inflammation and lesions, reducing urinary urinary protein levels, and suppressing or reducing the production of antinuclear antibodies in mammals such as humans who develop systemic lupus erythematosus Proven. Thereby, the damage to the self-organization of the mammal by the antinuclear antibody can be alleviated and the effect of treating the symptoms of systemic lupus erythematosus can be achieved. The implementation method will be described in detail below.
実施例１：４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトンの分離。 Example 1: Separation of 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexaneketone.
１００グラム前後のベニクスノキタケ菌糸体、子実体或いは二者の混合物を、フラスコ中に入れ、適当な割合の水とアルコール類（７０％以上のアルコール類水溶液）を加え、２０〜２５℃で少なくとも１時間以上撹拌抽出し、この後、濾紙及び０.４５ mフィルターにより濾過し抽出液を集める。 About 100 grams of Benix nokitake mycelium, fruiting body or a mixture of the two is placed in a flask, and a suitable ratio of water and alcohol (70% or more alcoholic acid aqueous solution) is added, at least at 20-25 ° C. Extract with stirring for 1 hour or longer, and then filter through a filter paper and 0.45 m filter to collect the extract.
前記收集したベニクスノキタケ抽出液を、高速液体クロマトグラフィー （High Performance Liquid chromatography）を利用し、RP１８のコラム（column）により分析を行い、メタノール（A）及び０.１％〜０.５％の酢酸水溶液（B）をモバイルフェーズ（mobile phase）とし（その溶液比率は：０〜１０分間、B比率は９５％ 〜２０％；１０〜２０分間、B比率は２０％〜１０％；２０〜３５分間、B比率は１０％〜１０％; ３５〜４０分間、B比率は１０％〜９５％）、毎分１ mlの速度で溶出し、同時に紫外線−可視光線全波長探知器により分析する。 The collected venix mushroom extract is analyzed by RP18 column using high performance liquid chromatography, methanol (A) and 0.1% to 0.5%. The acetic acid aqueous solution (B) is used as a mobile phase (the solution ratio is: 0 to 10 minutes, the B ratio is 95% to 20%; 10 to 20 minutes, the B ratio is 20% to 10%; 20 to 35 Elution at a rate of 1 ml per minute, and simultaneously analyzed by a UV-visible full wavelength detector, at a B ratio of 10% to 10% for 35 minutes; 35-40 minutes, B ratio of 10% to 95%).
２５分間から３０分間の溶出液收集濃縮により、淡黄色粉末状の固体産物を得ることができる。これが４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトンである。分析により、その分子式はC24H38O4で、分子量は３９０、熔点（m.p.）は４８℃〜５２℃であることが分かる。核磁気共鳴（NMR）分析値は以下に示す。１H−NMR（CDC１３）δ（ppm）：１.５１、１.６７、１.７１、１.７５、１.９４、２.０３、２.０７、２.２２、２.２５、３.６８、４.０５、５.０７と５.１４。１３C−NMR（CDC１３）δ（ppm）：１２.３１、１６.１、１６.１２、１７.６７、２５.６７、２６.４４、２６.７４、２７.００、３９.７１、３９.８１、４.０２７、４３.３４、５９.２２、６０.５９、１２０.９７、１２３.８４、１２４.３０、１３１.３２、１３５.３５、１３５.９２、１３８.０５、１６０.４５と１９７.１２。 A solid product in the form of a pale yellow powder can be obtained by collecting and concentrating the eluate for 25 to 30 minutes. This is 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexaneketone. Analysis shows that the molecular formula is C 24 H 38 O 4 , the molecular weight is 390, and the melting point (mp) is 48 ° C. to 52 ° C. Nuclear magnetic resonance (NMR) analysis values are shown below. 1H-NMR (CDC13) δ (ppm): 1.51, 1.67, 1.71, 1.75, 1.94, 2.03, 2.07, 2.22, 2.25, 3.68 4.05, 5.07 and 5.14. 13C-NMR (CDC13) δ (ppm): 12.31, 16.1, 16.12, 17.67, 25.67, 26.44, 26. 74, 27.00, 39.71, 39.81, 4.027, 43.34, 59.22, 60.59, 120.97, 123.84, 124.30, 131.32, 135.35, 135.92, 138.05, 160.45 and 197.12.
実施例２：ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデスなどの自己免疫性疾病予防或いは治療に対する薬効評価。 Example 2: Efficacy evaluation for prevention or treatment of autoimmune diseases such as systemic lupus erythematosus of Benix nokitake cyclohexane ketone compound.
臨床診断において、自己免疫性疾病の患者の体内には、自己抗体と免疫複合体の含量の明らかな増加がしばしば見られる。しかも、これら抗体が対抗する抗原はしばしば体内の細胞核、細胞質、或いは細胞膜上の正常体タンパクに広く分布している。よって、一般の臨床実験室では抗核抗体（antinuclear antibodies,ANA）の出現と変化を、自己免疫性疾病患者のスクリーニングの根拠として利用している。システム性エリテマトーデスと関連する抗核抗体の作用対象は、ダブルストランドDNA（dsDNA）、RNAと関連するSm、Ro、La、RNP、リン脂質（phospholipid）、リボソームタンパク質（ribosomal P）などのDNAタンパクである。内、抗dsDNA、抗SmとaPLの抗体が最も病理意義が高く、しかもdsDNAの抗体はシステム性エリテマトーデスの特異性抗体で、腎臓損害と関連がある。よって、本発明はシステム性エリテマトーデスを発病する動物モードを確立することにより、実験動物血液中の抗dsDNAの抗核抗体の濃度及び実験動物尿中の尿タンパク含量を計測し、システム性エリテマトーデスの予防或いは治療に用いるベニクスノキタケシクロヘキサンケトン化合物の治療効果について評価する。
そのテストのステップは以下に詳述する。
In clinical diagnosis, there is often a clear increase in the content of autoantibodies and immune complexes in patients with autoimmune diseases. Moreover, the antigens to which these antibodies oppose are often widely distributed in the body nucleus, cytoplasm, or normal protein on the cell membrane. Therefore, general clinical laboratories use the appearance and changes of antinuclear antibodies (ANA) as a basis for screening autoimmune disease patients. Antinuclear antibodies related to systemic lupus erythematosus target DNA proteins such as double-stranded DNA (dsDNA), RNA-related Sm, Ro, La, RNP, phospholipid, and ribosomal protein (ribosomal P). is there. Among them, anti-dsDNA, anti-Sm and aPL antibodies have the highest pathological significance, and dsDNA antibodies are systemic lupus erythematosus specific antibodies and are associated with kidney damage. Therefore, the present invention establishes an animal mode for causing systemic lupus erythematosus, thereby measuring the anti-dsDNA antinuclear antibody concentration in laboratory animal blood and the urine protein content in laboratory animal urine to prevent systemic lupus erythematosus. Alternatively, the therapeutic effect of the Benix nokitake cyclohexane ketone compound used for treatment is evaluated.
The test steps are detailed below.
（１）システム性エリテマトーデス動物モードの確立：実験動物はNZB／WF１雌ネズミで、該品種の実験ネズミは抗核抗体の生成、尿タンパクの発生、及び腎毒性発症による致死などのヒトのシステム性エリテマトーデスに類似の症状を発症する。該品種の実験ネズミが発症する該各症状はヒトのシステム性エリテマトーデス患者の病状と極めて類似しており、しかもNZB／WF１雌ネズミの発病率は雄ネズミより高く、かつ発症した病状はより重篤である。よって、本テストはNZB／WF１雌ネズミをシステム性エリテマトーデス薬物治療のスクリーニングの動物モードとする。 (1) Establishment of systemic lupus erythematosus animal mode: The experimental animal is a NZB / WF1 female mouse, and the experimental mouse of this breed is a human system such as production of antinuclear antibodies, generation of urine protein, and lethality due to development of nephrotoxicity. Symptoms similar to lupus erythematosus develop. Each of the symptoms that the experimental rat of this breed develops is very similar to the pathology of a human systemic lupus erythematosus patient, and the incidence of NZB / WF1 female mice is higher than that of male mice, and the pathology that has developed is more severe. It is. Thus, this test places NZB / WF1 female mice in the animal mode of screening for systemic lupus erythematosus medication.
３０匹のNZB／WF１雌ネズミ（Jackson Lab,USAから購入）を週齢１２〜２４週期間内において、２週間毎に該各雌ネズミの尿中タンパク含量を計測し、かつ該各雌ネズミの血清中の抗核抗体の濃度を毎月計測する。計測された抗核抗体数値が上昇し、陽性反応を示せば、NZB／WF１雌ネズミが既にシステム性エリテマトーデスを発病したことを示している。この時点で動物を組分けする。本発明実施例中では該各NZB／WF１雌ネズミは約２２週齢で上記病理現象を出現し、この時組分けを行い、しかも本発明中ではこの組分け時点を第０週と定義する。組分け時は、飼料物質の差異に応じて３組に区分し、薬物治療を行わないマイナス対照組、ステロイド薬物を与えるプラス対照組、ベニクスノキタケシクロヘキサンケトン化合物を与える実験組とする。各組はそれぞれ１０匹のNZB／WF１雌ネズミを有する。同時に１０匹のシステム性エリテマトーデスを発病していないB６品種の実験ネズミ（中華民国国家実験動物センターから購入）を完全に正常な制御組とする。その組分けは以下の表一に示す。表１は実験動物組別及びその飼料物質と剤量です。
表１中の制御組は、システム性エリテマトーデスを発病していないB６品種の実験ネズミにより試験を行い、しかもそれに対しては一切の処理を行わず、正常な飼料を与え自然に生長させる。マイナス対照組、プラス対照組、実験組には、システム性エリテマトーデスを発病したNZB／WF１雌ネズミを採用し試験を行う。但し、マイナス対象組には治療物資を含まない水を経口摂取させ、プラス対照組には雌ネズミの体重に応じて１.２５mg／kgのシステム性エリテマトーデスに治療効果を備えるステロイド薬物（prednisolone）を経口摂取させる。実験組には雌ネズミの体重に応じて、実施例一で製造調整した５０mg／kgのベニクスノキタケシクロヘキサンケトン化合物を経口摂取させ、さらにNZB／WF１雌ネズミが第２３週齢時に経口摂取を開始し、毎週毎日一回各組別に前記物質を与える。しかも本発明中では経口摂取を開始し、試験を開始した時点を第１週と定義する。試験全体は第４８週までで、実験期間は各対照組及び実験組の採血と尿の採集を定時に行う必要があり、ベニクスノキタケシクロヘキサンケトン化合物の服用のシステム性エリテマトーデス実験ネズミの病状に対する影響を検査測定する。 The control group in Table 1 is tested by an experimental rat of B6 varieties not causing systemic lupus erythematosus, and without any treatment, it is fed with normal feed and grows naturally. For the negative control group, the positive control group, and the experimental group, NZB / WF1 female mice with systemic lupus erythematosus are employed and tested. However, the negative target group is orally ingested with water that does not contain therapeutic materials, and the positive control group is given a steroid drug (prednisolone) that has a therapeutic effect on systemic lupus erythematosus at 1.25 mg / kg depending on the body weight of female mice. Ingested orally. The experimental group was orally ingested 50 mg / kg venix cynomolgus cyclohexane ketone compound prepared in Example 1 according to the weight of female mice, and NZB / WF1 female mice started to ingest at 23 weeks of age. The substance is given to each group once a week every day. Moreover, in the present invention, the time when oral intake is started and the test is started is defined as the first week. The entire study is up to the 48th week, and it is necessary to collect blood and urine collection of each control group and experimental group at regular intervals during the experiment period, and the effect of taking Benix nokitake cyclohexane ketone compound on the pathology of systemic lupus erythematosus experimental rats Inspect and measure.
（２）ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデスNZB／WF１雌ネズミの尿タンパク（protein uria）含量に対する影響：システム性エリテマトーデスは腎臓の炎症と病変を引き起こし、腎臓のタンパク質吸収不能を招き、過多のタンパク質が尿中に排出されるようになり、尿タンパク濃度の増加という症状が現れる。よって、尿中の尿タンパク含量計測により、ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデス発病の程度への影響を理解することができる。測量標識は前記の実験期間において、２週間毎に実験ネズミの尿を抽出し、１０μlの尿をタンパク分析組（Bio−Rad Protein Assay Dye Reagent Concentrate, Bio−Rad Laboratories,USA）により分析し、ELISA分析器により４５０nm波長において読み取る。さらに標準タンパク曲線を利用しタンパク濃度を定量する。その結果は図１に示す。 (2) Effects of Benix nokitake cyclohexane ketone compound on protein uria content of systemic lupus erythematosus NZB / WF1 female mice: Systemic lupus erythematosus causes renal inflammation and lesions, leading to inability of kidney protein absorption Protein is excreted in the urine, and the urine protein concentration increases. Therefore, by measuring the urinary protein content in urine, it is possible to understand the effect of Benix nokitake cyclohexane ketone compound on the degree of systemic lupus erythematosus pathogenesis. Survey labeling was performed by extracting experimental mouse urine every 2 weeks during the above-mentioned experimental period, analyzing 10 μl of urine by a protein analysis group (Bio-Rad Protein Assay Dye Reagent Concentrate, Bio-Rad Laboratories, USA), and ELISA. Read by analyzer at 450 nm wavelength. Furthermore, the protein concentration is quantified using a standard protein curve. The result is shown in FIG.
図１はベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデスNZB／WF１雌ネズミ尿中に含まれる尿タンパク濃度の影響結果である。図が示すように、実験開始第６週（すなわちNZB／WF１雌ネズミ第２８週齢時）にシステム性エリテマトーデスを罹患していない制御組の尿中の尿タンパク濃度は、実験前の数値に近似している。これはこの期間に、正常制御組の尿タンパク濃度は６５mg／dl−７５mg／dlの固定範囲内に安定的に維持されていることを示す。制御組に比較し、マイナス対照組が示す尿タンパク濃度は最初の８９.１６ mg／dlから、第６週の２４６ mg／dlに急激に上昇し、尿タンパク濃度は２.７６倍に激増している。これはシステム性エリテマトーデスが実験ネズミの腎臓の病変を引き起こしたことにより、尿タンパク含量が激増したことを示している。ステロイド薬物（prednisolone）を経口摂取させるプラス対照組では、マイナス対照組に比較し、それが示す尿タンパク濃度は３２.６ mg／dlと低い。５０mg／kgのベニクスノキタケシクロヘキサンケトン化合物を経口摂取させる実験組では、その尿タンパク濃度は１１８.２ mg／dlで、マイナス対照組に比べ低く、しかもベニクスノキタケシクロヘキサンケトン化合物を与える前の実験ネズミの尿中に含まれていた尿タンパク濃度と比較すると、わずかに１.３倍に増加しているだけである。この結果は、システム性エリテマトーデスを罹患する実験ネズミにベニクスノキタケシクロヘキサンケトン化合物を６週間与えた後、システム性エリテマトーデスが引き起こす腎臓の病変と炎症減少を効果的に抑制し、タンパク尿の症状の発生を緩和できたことを示す。この他、前記実験はベニクスノキタケシクロヘキサンケトン化合物が、腎臓の病変と炎症減少を改善、緩和可能で、尿タンパクの症状を低減できることを証明しているため、ベニクスノキタケシクロヘキサンケトン化合物は、過多タンパク尿を引き起こす腎臓関連の疾病に応用することができる。しかもこれに限定しない。 FIG. 1 shows the effect of the urinary protein concentration in the systemic lupus erythematosus NZB / WF1 female mouse urine of Benix nokitake cyclohexane ketone compound. As shown in the figure, the urine protein concentration in the urine of the control group not affected by systemic lupus erythematosus at the 6th week of the experiment (ie, at the age of 28 weeks of NZB / WF1 female mice) approximates the value before the experiment is doing. This indicates that during this period, the urinary protein concentration of the normal control group is stably maintained within a fixed range of 65 mg / dl-75 mg / dl. Compared to the control group, the urine protein concentration of the negative control group increased rapidly from the initial 89.16 mg / dl to 246 mg / dl in the sixth week, and the urine protein concentration increased 2.76 times. ing. This indicates that systemic lupus erythematosus caused urine protein content to increase due to renal lesions in experimental mice. In the positive control group in which a steroid drug (prednisolone) is taken orally, the urinary protein concentration shown by the positive control group is 32.6 mg / dl, which is lower than that in the negative control group. In the experimental group that ingests 50 mg / kg of Benix nokitake cyclohexane ketone compound, the urine protein concentration is 118.2 mg / dl, which is lower than that of the negative control group, and before giving the Benix nokitake cyclohexane ketone compound. Compared to the urine protein concentration contained in the urine of mice, there is only a 1.3-fold increase. This result shows that, after giving experimental mice suffering from systemic lupus erythematosus for 6 weeks, the kidney lesion and inflammation decrease caused by systemic lupus erythematosus are effectively suppressed, and the occurrence of proteinuria symptoms. It was shown that it was able to relax. In addition, the above experiment proves that Benix nokitake cyclohexane ketone compound can improve and alleviate kidney lesions and inflammation reduction, and can reduce urinary protein symptoms. It can be applied to kidney-related diseases that cause proteinuria. And it is not limited to this.
（３）ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデスNZB／WF１雌ネズミが生成する抗核抗体への影響：本テストは実験ネズミの血液中に含まれる特異性dsDNAの抗核抗体の濃度を計測することにより、ベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデス症状に対する影響を観測する。その計測方式は、前記実験期間において、４週間毎に実験ネズミの眼窩から採血し、採集した血液を遠心分離方式により血球と血漿に分離し、１０μlの血漿を取り商業化試薬セット（Mouse Anti−dsDNA IgG ELISA kit, adi Alpha Diagnostic,USA）により抗核抗体の濃度を分析する。その結果は図２に示す。 (3) Effects of Benix nocturnus cyclohexane ketone compounds on antinuclear antibodies produced by systemic lupus erythematosus NZB / WF1 female mice: This test measures the concentration of antinuclear antibodies in specific dsDNA contained in the blood of experimental mice To observe the effects of Benix nokitake cyclohexane ketone compounds on systemic lupus erythematosus symptoms. In the experimental period, blood was collected from the orbits of experimental mice every 4 weeks during the experimental period, and the collected blood was separated into blood cells and plasma by centrifugation, and 10 μl of plasma was collected and a commercial reagent set (Mouse Anti- dsDNA IgG ELISA kit, adi Alpha Diagnostic, USA). The result is shown in FIG.
図２はベニクスノキタケシクロヘキサンケトン化合物のシステム性エリテマトーデスNZB／WF１雌ネズミが生成するdsDNA抗体への影響結果を示す。図に示すように、第０週（NZB／WF１雌ネズミ第２２週齢時）から第８週（NZB／WF１雌ネズミ第３０週齢時）まで、システム性エリテマトーデスを発病していない制御組の血液中にはdsDNA抗体の存在は全く測定されない。制御組に対して、システム性エリテマトーデスの症状を示すマイナス対照組のNZB／WF１雌ネズミ血清中に含まれるdsDNA抗核抗体の含量は、システム性エリテマトーデス発病週期の増加に従い徐々に増加し、８週までは１０mg／dl以下であった濃度は８週時には１５０ mg／dlまで上昇している。プラス対照組では、マイナス対照組に比較し、ステロイド薬物（prednisolone）の服用は実験ネズミの血清内のdsDNA抗核抗体の含量を低下させることができ、しかも第８週時に、その抗核抗体含量はマイナス対照組に比べ、約５０％まで低下させることができる。ベニクスノキタケシクロヘキサンケトン化合物を与える実験組では、８週の実験期間内において、それが示すdsDNA抗体濃度はマイナス対照組より明らかに低く、しかも第８週時には、実験ネズミ血液中のdsDNA抗核抗体含量は約３４％に低下している。この結果はベニクスノキタケシクロヘキサンケトン化合物が、システム性エリテマトーデスを罹患する哺乳動物体内の抗核抗体の生成を効果的に抑制或いは緩和可能で、これにより抗核抗体の自己組織への傷害を低減し、システム性エリテマトーデスの治療効果を達成することを示している。 FIG. 2 shows the results of the effect of the Benix nokitake cyclohexane ketone compound on the dsDNA antibody produced by the systemic lupus erythematosus NZB / WF1 female mouse. As shown in the figure, from the 0th week (NZB / WF1 female mouse at the age of 22 weeks) to the 8th week (NZB / WF1 female mouse at the age of 30 weeks), the control group that did not develop systemic lupus erythematosus The presence of dsDNA antibodies in the blood is not measured at all. In contrast to the control group, the dsDNA antinuclear antibody content in the NZB / WF1 female murine serum of the negative control group showing symptoms of systemic lupus erythematosus gradually increased with the increase in the number of systemic lupus erythematosus onset. The concentration which was 10 mg / dl or less until now increases to 150 mg / dl at 8 weeks. In the positive control group, compared to the negative control group, taking a steroid drug (prednisolone) can reduce the content of dsDNA antinuclear antibody in the serum of experimental mice, and at week 8 its antinuclear antibody content. Can be reduced to about 50% compared to the negative control group. In the experimental group giving the Benix nocturnal cyclohexane ketone compound, the dsDNA antibody concentration it shows is clearly lower than the negative control group within the 8 week experimental period, and at the 8th week the dsDNA antinuclear antibody in the experimental murine blood The content has dropped to about 34%. This result shows that Benix nocturnal cyclohexane ketone compounds can effectively suppress or alleviate the production of antinuclear antibodies in mammals suffering from systemic lupus erythematosus, thereby reducing the damage of antinuclear antibodies to self-organization. It has been shown to achieve the therapeutic effects of systemic lupus erythematosus.
また、ベニクスノキタケシクロヘキサンケトン化合物はシステム性エリテマトーデスなどの自己免疫性疾病が引き起こす抗核抗体の大量生成と腎臓が損傷を受けることにより起こる尿タンパク濃度増加の症状を抑制或いは緩和することができるため、ベニクスノキタケシクロヘキサンケトン化合物は抗核抗体を形成し、腎臓の損傷を引き起こす硬皮症（Scleroderma）、ショーグレン症候群（Sjogren syndrome）アナフィラキトイド紫斑（Anaphylactoid purpura）、関節リューマチ（Rheumatoid arthritis）、或いは皮膚、関節、骨格、腎臓、心血管システム、凝血システム、胃腸、漿膜（心包膜、胸膜、腹膜）、脳神経システムなど多種の組織と器官に損傷を与える他の自己免疫性疾病に応用することができ、またこれに限定しない。この他、抗dsDNAの抗核抗体の発生は腎臓損害と関連があるため、ベニクスノキタケシクロヘキサンケトン化合物は抗dsDNA抗体の生成を低下させることができる。これは、ベニクスノキタケシクロヘキサンケトン化合物が抗dsDNA抗体量を低下させることにより、腎臓の損傷程度を効果的に低減することを示している。よって、ベニクスノキタケシクロヘキサンケトン化合物は尿タンパク濃度と抗dsDNA抗体量を減少させることにより、腎臓損傷を低下させ、腎臓保護の分野に応用することができる。 In addition, Benix nocturnal cyclohexane ketone compound can suppress or alleviate the symptoms of mass production of antinuclear antibodies caused by autoimmune diseases such as systemic lupus erythematosus and increased urine protein concentration caused by kidney damage , Benicus edodes cyclohexane ketone compounds form antinuclear antibodies and cause kidney damage, Scleroderma, Sjogren syndrome, Anaphylactoid purpura, Rheumatoid arthritis, Or apply to other autoimmune diseases that damage various tissues and organs such as skin, joints, skeleton, kidney, cardiovascular system, coagulation system, gastrointestinal tract, serosa (pericardium, pleura, peritoneum), cranial nerve system etc. However, the present invention is not limited to this. In addition, the occurrence of anti-dsDNA antinuclear antibodies is associated with kidney damage, and therefore, Benix nochitake cyclohexane ketone compounds can reduce the production of anti-dsDNA antibodies. This indicates that Benix nocturnal cyclohexane ketone compound effectively reduces the degree of kidney damage by reducing the amount of anti-dsDNA antibody. Therefore, the Benix nocturnal cyclohexane ketone compound can be applied to the field of kidney protection by reducing kidney damage by reducing the urinary protein concentration and the amount of anti-dsDNA antibody.
上記のように、本発明ベニクスノキタケから分離した４−ハイドロキシ−２,３−ジメトキシ−６−メチル−５（３,７,１１−トリメチル−２,６,１０−トリエニル）−２−シクロヘキサンケトン化合物は、自己免疫疾病が引き起こす尿タンパク濃度及び抗核抗体含量の上昇などの症状を効果的に緩和することができ、これにより該各疾病がヒトなどの哺乳動物に対して引き起こす組織器官の傷害を緩和することができ、しかもその腎臓に対する保護と腎臓損傷を低下させる効果を利用し、腎臓疾病が体内で引き起こす傷害を軽減することができる。また、ベニクスノキタケシクロヘキサンケトン化合物は天然抽出の物質であるため、それをシステム性エリテマトーデスなどの自己免疫疾病と腎臓関連疾病への治療に応用しても、患者に不快な症状或いは毒性、合併症などの他の副作用を発することがない。しかも、それは化学薬剤と併用することができ、ステロイドなどの化学薬物の使用量を減少させることができ、該各化学薬物が引き起こす副作用を低減することができる。さらに、それは医薬組成物を製造調整することができ、該医薬組成物は有効成分剤量のベニクスノキタケシクロヘキサンケトン化合物を含む他、薬学上受け入れ可能なキャリアを含むことができる。キャリアは賦形剤（水など）、充填剤（蔗糖或いはでんぷん）、接着剤（セルロース派生物など）、希釈剤、崩解剤、吸收促進剤或いは甘味剤であるが、これに限定するものではない。本発明医薬組成物は一般公知の薬学の製作準備方法により製造することができ、有効成分剤量のベニクスノキタケシクロヘキサンケトン化合物と一種以上のキャリアを相互に混合し、必要な剤型を製作準備する。この剤型は錠剤、粉剤、粒剤、カプセル剤或いはその他液体製剤であるが、これに限定するものではない。こうしてヒトなどの哺乳動物のシステム性エリテマトーデスなどの自己免疫疾病と腎臓疾病を予防及び治療する目的を達成する。 As described above, 4-hydroxy-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-trienyl) -2-cyclohexaneketone isolated from the present Benix nochitake The compound can effectively relieve symptoms such as increased urinary protein concentration and antinuclear antibody content caused by autoimmune diseases, thereby causing tissue organ damage caused by each disease to mammals such as humans In addition, the damage to the kidney caused by kidney disease can be reduced by utilizing the effects of protecting the kidney and reducing kidney damage. In addition, Benix nokitake cyclohexaneketone compound is a naturally extracted substance, so even if it is applied to the treatment of autoimmune diseases such as systemic lupus erythematosus and kidney related diseases, it may be unpleasant symptoms or toxicity and complications to the patient. No other side effects occur. In addition, it can be used in combination with a chemical agent, the amount of a chemical drug such as steroid can be reduced, and the side effects caused by each chemical drug can be reduced. In addition, it can be prepared to prepare a pharmaceutical composition, which can contain a pharmaceutically acceptable carrier in addition to containing an active ingredient amount of Benix nocturnal cyclohexane ketone compound. Carriers are excipients (such as water), fillers (such as sucrose or starch), adhesives (such as cellulose derivatives), diluents, disintegrants, absorption enhancers or sweeteners, but are not limited to this. Absent. The pharmaceutical composition of the present invention can be produced by a generally known pharmacy production preparation method. The amount of active ingredient Benix nokitake cyclohexane ketone compound and one or more carriers are mixed with each other to prepare the necessary dosage form. To do. The dosage form is a tablet, powder, granule, capsule or other liquid preparation, but is not limited thereto. Thus, the object of preventing and treating autoimmune diseases and kidney diseases such as systemic lupus erythematosus in mammals such as humans is achieved.
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| JP2008308479A (en) * | 2007-06-14 | 2008-12-25 | Golden Biotechnology Corp | Cyclohex-2-enone compound from antrodia camphorata used for protecting liver |
| JP2009013152A (en) * | 2007-07-09 | 2009-01-22 | Golden Biotechnology Corp | Cyclohexane ketone compound from antrodia camphorata used for inhibiting hepatitis b virus |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008308479A (en) * | 2007-06-14 | 2008-12-25 | Golden Biotechnology Corp | Cyclohex-2-enone compound from antrodia camphorata used for protecting liver |
| WO2012100228A3 (en) * | 2011-01-21 | 2012-11-22 | Golden Biotechnology Corporation | Methods and compositions for treating kidney disorders |
| US10406120B2 (en) | 2011-01-21 | 2019-09-10 | Golden Biotechnology Corporation | Methods and compositions for treating kidney disorders |
| CN104857029A (en) * | 2015-05-13 | 2015-08-26 | 柳州市耕青科技有限公司 | Antrodia camphorate medicine for allergic dermatitis |
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