TWI394572B - Application of Cynanchum aurantii Cyclohexenone Compounds in the Preparation of Drugs for the Treatment of Autoimmune Diseases - Google Patents
Application of Cynanchum aurantii Cyclohexenone Compounds in the Preparation of Drugs for the Treatment of Autoimmune Diseases Download PDFInfo
- Publication number
- TWI394572B TWI394572B TW096121138A TW96121138A TWI394572B TW I394572 B TWI394572 B TW I394572B TW 096121138 A TW096121138 A TW 096121138A TW 96121138 A TW96121138 A TW 96121138A TW I394572 B TWI394572 B TW I394572B
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- Prior art keywords
- compound
- lupus erythematosus
- systemic lupus
- application
- autoimmune diseases
- Prior art date
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- C07C403/02—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains containing only carbon and hydrogen atoms
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Description
本發明係關於一種用於治療免疫相關疾病之化合物，尤其係關於一種自牛樟芝(Antrodia camphorata
)萃取物中分離純化而得且可用於治療系統性紅斑性狼瘡等自體免疫性疾病之環己烯酮化合物。
因免疫系統的反應異常而對於自體組織造成破壞之自體免疫疾病(autoimmune diseases)的種類繁多，例如系統性紅斑性狼瘡(systemic lupus erythematosus,SLE)、類風濕性關節炎(Rheumatoid arthritis)、硬皮病(Scleroderma)、多發性肌炎(Polymyositis)與皮肌炎(dermatomyositis)、類過敏性紫斑(Anaphylactoid purpura)、休格蘭症候群(Sjogren syndrome)等，其它如原發性膽道系統肝硬化，慢性活動性肝炎，橋本氏甲狀腺炎等病亦均與自體免疫有關；其中，系統性紅斑性狼瘡(SLE)或稱全身性紅斑性狼瘡是自體免疫疾病中最嚴重的一種，其係好發於育齡期婦女，患者體內會產生對抗細胞核內自體抗原(autoantigens)之自體抗體(autoantibodies)，又稱抗核抗體(antinuclear antibodies,ANA)，而造成多種組織與器官例如：皮膚、關節、骨骼、腎臟、心血管系統、凝血系統、腸胃道、漿膜(心包膜、胸膜、腹膜)及腦神經系統等之傷害，且其中有些自體抗體會和抗原結合並形成免疫複合體(immune complex,IC)，再隨著血液沈積在不同的組織細胞中而造成傷害，其臨床上會呈現蝴蝶斑、溶血性貧血、關節炎、血管炎和腎炎等病徵。自體免疫疾病多以類固醇或其他化學藥物治療之，然長期服用該些治療劑多會引發患者產生不適之併發症或副作用，因此，若能以天然且無副作用之中草藥物質治療該些自體免疫疾病，將可造福自體免疫病患並舒緩其病痛程度。
牛樟芝(Antrodia camphorata
)，又稱樟芝、牛樟菇或紅樟芝等，屬於非褶菌目(Aphyllophorales
)、多孔菌科(Polyporaceae
)之多年生蕈菌類，為台灣特有種真菌，僅生長於台灣保育類樹種－牛樟樹(Cinnamoum kanehirai
Hay)之中空腐朽心材內壁上。由於牛樟樹分布數量極為稀少，加上人為的盜伐，使得寄生於其中方能生長之野生牛樟芝數量更形稀少，且由於其子實體生長相當緩慢，生長期亦僅在六月至十月之間，因此價格非常昂貴。
牛樟芝之子實體為多年生，無柄，呈木栓質至木質，其具強烈之樟樹香氣，且形態多變化，有板狀、鐘狀、馬蹄狀或塔狀。初生時為扁平型並呈鮮紅色，之後其週邊會呈現放射反捲狀，並向四週擴展生長，顏色亦轉變為淡紅褐色或淡黃褐色，並有許多細孔，且其係為牛樟芝之藥用價值最豐富的部位。
在台灣民俗醫學上，牛樟芝具有解毒、減輕腹瀉症狀、消炎、治療肝臟相關疾病及抗癌等功用。牛樟芝如同一般食藥用之蕈菇類，具有許多複雜的成分，已知的生理活性成分中，包括：三萜類化合物(triterpenoids)、多醣體(polysaccharides，如β－D－葡聚醣)、腺苷(adenosine)、維生素(如維生素B、菸鹼酸)、蛋白質(含免疫球蛋白)、超氧歧化酵素(superoxide dismutase,SOD)、微量元素(如：鈣、磷、鍺)、核酸、固醇類以及血壓穩定物質(如antodia acid)等，此些生理活性成分被認為具有抗腫瘤、增加免疫能力、抗過敏、抗病菌、抗高血壓、降血糖及降膽固醇等多種功效。
牛樟芝眾多成分中以三萜類化合物被研究的最多，三萜類化合物是由三十個碳元素結合成六角形或五角形天然化合物之總稱，牛樟芝所具之苦味即主要來自三萜類此成分。1995年時，Cherng等人發現牛樟芝子實體萃取物中含有三種新的以麥角甾烷(ergostane)為骨架的三萜類化合物：antcin A、antcin B與antcin C(Cherng,I.H.,and Chiang,H.C.1995.Three new triterpenoids fromAntrodia cinnamomea
.J.Nat.Prod.58：365－371)。Chen等人以乙醇萃取樟芝子實體後發現zhankuic acid A、zhankuic acid B及zhankuic acid C等三種三萜類化合物(Chen,C.H.,and Yang,S.W.1995.New steroid acids fromAntrodia cinnamomea
,－a fungus parasitic on Cinnamomum micranthum.J.Nat.Prod.58：1655－1661)。此外，Chiang等人於1995年也由子實體萃取物中發現另外三種分別為倍半萜內酯(sesquiterpene lactone)與兩種雙酚類衍生物的新三萜類化合物，此即antrocin,4,7－二甲氧基－5－甲基－1,3－苯並二氧環(4,7－dimethoxy－5－methy－1,3－benzodioxole)與2,2',5,5'－四甲氧基－3,4,3',4'－雙－亞甲二氧基－6,6'－二甲基聯苯(2,2',5,5'－teramethoxy－3,4,3',4'－bi－methylenedioxy－6,6'－dimethylbiphenyl)(Chiang,H.C.,Wu,D.P.,Cherng,I.W.,and Ueng,C.H.1995.A sesquiterpene lactone,phenyl and biphenyl compounds fromAntrodia cinnamomea.
Phytochemistry.39：613－6l6)。到了1996年，Cherng等人以同樣分析方法再度發現四種新的三萜類化合物：antcin E、antcin F、methyl antcinate G、methyl antcinate H(Cherng,I.H.,Wu,D.P.,and Chiang,H.C.1996.Triteroenoids fromAntrodia cinnamomea
.Phytochemistry.41：263－267)；而Yang等人則發現了二種以麥角甾烷為骨架的新化合物zhankuic acid D、zhankuic acid E，和三種以羊毛甾烷(lanostane)為骨架的新化合物：15 α－乙醯－去氫硫色多孔菌酸(15 α－acetyl－dehydrosulphurenic acid)、去氫齒孔酸(dehydroeburicoic acid)與去水硫色多孔菌酸(dehydrasulphurenic acid)(Yang,s.W.,Shen,Y.C.,and Chen,C.H.1996.Steroids and triterpenoids ofAntrodia cinnamomea
－a fungus parasitic on Cinnamomum micranthum.Phytochemistry.41：1389－1392)。
雖然由目前諸多之實驗可得知牛樟芝萃取物具有前述功效，且其所含成分亦陸續被分析出，但卻未見有將牛樟芝萃取物用於治療自體免疫性疾病上，且究竟牛樟芝萃取物之何種有效成分可有效改善自體免疫性疾病之病症，亦有待進一步實驗研究來釐清，故若能找出該萃取物中所含真正可有效成分，並將此天然成分用於預防或治療系統性紅斑性狼瘡等自體免疫性疾病上，將有助於減輕以化學藥物例如類固醇治療自體免疫性疾病所致之副作用或併發症。
為明瞭牛樟芝萃取物中究竟為何成分具有預防或治療系統性紅斑性狼瘡等自體免疫性疾病之效果，本發明由牛樟芝萃取物中分離純化出具式(1)結構式之化合物；
其中，X係氧(O)或硫(S)，Y係氧或硫；R1係氫基(H)、甲基(CH3
)或(CH2
)m-CH3
，R2係氫基、甲基或(CH2
)m-CH3
，R3係氫基、甲基或(CH2
)m-CH3
，m=1~12；n=1~12。
如式(1)結構式之化合物中，較佳者為如下所示式(2)之化合物：
式(2)之化合物，其化學名為4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮(4－hydroxy－2,3－dimethoxy－6－methy－5(3,7,11－trimethyl－dodeca－2,6,10－trienyl)－cyclohex－2－enone)，分子式為C24
H38
O4
，外觀為淡黃色粉末狀，分子量為390。
本發明中式(1)、式(2)之化合物係分離純化自牛樟芝水萃取物或有機溶劑萃取物，有機溶劑可包括醇類(例如甲醇、乙醇或丙醇)、酯類(例如乙酸乙酯)、烷類(例如己烷)或鹵烷(例如氯甲烷、氯乙烷)，但並不以此為限，其中較佳者為醇類，更佳者為乙醇。
藉由前述化合物，本發明係將其應用於預防或治療紅斑性狼瘡等自體免疫性疾病，當以牛樟芝環己烯酮化合物餵食可表現系統性紅斑性狼瘡之哺乳動物時，其尿蛋白含量係可能因腎臟發炎與病變的現象之減緩而降低，且血液中所含抗核抗體濃度亦可有效減少，進而減緩抗核抗體對人類等哺乳動物自體組織的傷害，而達到治療系統性紅斑性狼瘡等自體免疫性疾病之效果，亦可藉此萃取自牛樟芝之天然物質來減少例如類固醇等化學藥物治療所致之副作用及併發症，並舒解病患之不適症狀。
另一方面，本發明中亦可將式(1)或/與式(2)之化合物利用於治療系統性紅斑性狼瘡等自體免疫性疾病之醫藥組成物的成分中，藉以改善人類等哺乳動物因自體免疫性疾病引發之症狀。前述醫藥組成物除包括有效劑量之式(1)或/與式(2)之化合物外，尚可包括藥學上可接受的載體。載體可為賦形劑(如水)、填充劑(如蔗糖或澱粉)、黏合劑(如纖維素衍生物)、稀釋劑、崩解劑、吸收促進劑或甜味劑，但並未僅限於此。本發明醫藥組成物可依一般習知藥學之製備方法生產製造，將式(1)或/與式(2)有效成分劑量與一種以上之載體相混合，製備出所需之劑型，此劑型可包括錠劑、粉劑、粒劑、膠囊或其他液體製劑，但未以此為限。
以下將配合圖式進一步說明本創作的實施方式，下述所列舉的實施例係用以闡明本創作，並非用以限定本創作之範圍，任何熟習此技藝者，在不脫離本創作之精神和範圍內，當可做些許更動與潤飾，因此本創作之保護範圍當視後附之申請專利範圍所界定者為準。
首先取牛樟芝(Antrodia camphorata
)菌絲體、子實體或二者之混合物，利用習知萃取方式，以水或有機溶劑進行萃取，藉以取得牛樟芝水萃取物或有機溶劑萃取物。其中，有機溶劑可包括醇類(例如甲醇、乙醇或丙醇)、酯類(例如乙酸乙酯)、烷類(例如己烷)或鹵烷(例如氯甲烷、氯乙烷)，但並不以此為限。其中較佳者為醇類，更佳者為乙醇。
經萃取過後之牛樟芝水萃取物或有機溶劑萃取物，可進一步藉由高效液相層析加以分離純化，之後再對每一分液(fraction)進行與治療系統性紅斑性狼瘡等自體免疫疾病相關之生化測試，例如檢測尿液中尿蛋白含量以及血液中抗核抗體濃度等。最後，則針對具效果之分液進行成分分析，將可能產生抑制系統性紅斑性狼瘡等自體免疫疾病病症效果的成分，再進一步分別做相關之生化測試。最終即發現本發明中如式(1)/式(2)之化合物係具有降低尿蛋白含量以及抗核抗體濃度而可達治療系統性紅斑性狼瘡等自體免疫疾病以及腎臟相關疾病之功效。此外，亦可將式(1)或/與式(2)之化合物利用於治療系統性紅斑性狼瘡等自體免疫性疾病之醫藥組成物之成分中，藉此天然成分改善病情，於不引起副作用及併發症之情況下，有效舒緩病患不適症狀。
為方便說明本發明，以下將以式(2)之4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮化合物進行說明。此外，為證實4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮化合物係具治療系統性紅斑性狼瘡等自體免疫疾病之效果，本發明中係藉由餵食可表現系統性紅斑性狼瘡之NZB/WF1雌鼠前述牛樟芝環己烯酮化合物後，並檢測其尿蛋白濃度及血液中抗核抗體含量，以評估牛樟芝環己烯酮化合物於治療系統性紅斑性狼瘡之效用。由該些尿蛋白濃度及抗核抗體含量之結果證實4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮化合物係可藉由減緩腎臟發炎及病變進而降低尿液中之尿蛋白濃度，且具有效抑制或延緩患有系統性紅斑性狼瘡之人類等哺乳動物體內抗核抗體的生成之功效，藉以減緩抗核抗體對哺乳動物自體組織的傷害，而達到治療系統性紅斑性狼瘡病症之效果。茲對前述實施方式詳盡說明如下：
4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮的分離將100克左右之牛樟芝菌絲體、子實體或二者之混合物，置入三角錐形瓶中，加入適當比例的水與醇類(例如70%以上之醇類水溶液)，於20~25℃下攪拌萃取至少1小時以上，之後以濾紙及0.45 m濾膜過濾，收集萃取液。
將前述收集之牛樟芝萃取液，利用高效能液相層析儀(High Performance Liquid chromatography)，以RP18的層析管(column)進行分析，並以甲醇(A)及0.1%~0.5%醋酸水溶液(B)做為移動相(mobile phase)(其溶液比例係：0~10分鐘，B比例為95%~20%；10~20分鐘，B比例為20%~10%；20~35分鐘，B比例為10%~10%；35~40分鐘，B比例為10%~95%)，在每分鐘1 ml之速度下沖提，同時以紫外－可見光全波長偵測器分析。
將25分鐘至30分鐘之沖提液收集濃縮即可得淡黃色粉末狀之固體產物，此即4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮。經分析，其分子式為C24
H38
O4
，分子量390，熔點(m.p.)為48℃~52℃。核磁共振(NMR)分析值則如下所示：1H－NMR(CDCl3)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與5.14。13C－NMR(CDCl3)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與197.12。
牛樟芝環己烯酮化合物於預防或治療系統性紅斑性狼瘡等自體免疫性疾病之藥效評估臨床診斷自體免疫性疾病患者時往往發現，病人體內自體抗體和免疫複合體之含量明顯增加，且這些抗體對抗的抗原往往廣佈於體內之細胞核、細胞質或細胞膜上的正常體蛋白。因此，一般臨床實驗室常利用抗核抗體(antinuclear antibodies,ANA)的出現及變化作為篩選自體免疫性疾病病患之依據。與系統性紅斑性狼瘡相關之抗核抗體的作用對象包括雙股去氧核糖核酸(dsDNA)、與RNA相關之核醣核蛋白例如Sm、Ro、La、RNP、磷脂質(phospholipid)以及核醣體磷蛋白(ribosomal P)等，其中，又以抗dsDNA、抗Sm和aPL之抗體最具有病理意義，且抗dsDNA之抗體是系統性紅斑性狼瘡的特異性抗體，而且與腎臟損害有關，因此本發明係藉由建立可表現系統性紅斑性狼瘡病症之動物模式，並偵測實驗動物血液中抗dsDNA之抗核抗體的濃度，以及實驗動物尿液中尿蛋白含量，來評估用於預防或治療系統性紅斑性狼瘡之牛樟芝環己烯酮化合物的療效。其測試步驟係詳述如下：(1)系統性紅斑性狼瘡動物模式之建立實驗動物係為NZB/WF1雌鼠，該種品系之實驗鼠可自發產生類似人類系統性紅斑性狼瘡之症狀，例如抗核抗體之生成、尿蛋白的產生以及引發腎毒性而致死等各種病症，該些症狀皆與人類紅斑狼瘡患者之病兆極為相似，且NZB/WF1雌鼠之發病率係高於雄鼠，且呈現之病徵亦較為嚴重，因此，本試驗係利用NZB/WF1雌鼠作為篩選治療系統性紅斑性狼瘡藥物之動物模式。
將30隻NZB/WF1雌鼠(購自Jackson Lab,USA)於週齡為12~24週期間內，每雙週檢驗該些雌鼠尿液中尿蛋白含量，且每個月檢測該些雌鼠血清中抗核抗體之濃度，當所測得之抗核抗體數值提升，並呈陽性反應時，表示NZB/WF1雌鼠已開始表現系統性紅斑性狼瘡之病症，此時即可進行動物分組；本發明實施例中該些NZB/WF1雌鼠約於第22週齡出現上述病理現象，並於此時進行分組，且本發明中係將此分組時間定義為第0週。分組時係依據餵食物質之不同而將其區分為3組，別為無投予藥物治療之負對照組、投予類固醇藥物之正對照組及投予牛樟芝環己烯酮化合物之實驗組，每組各有10隻NZB/WF1雌鼠；同時以10隻無罹患系統性紅斑性狼瘡之B6品系實驗鼠(購自中華民國之國家實驗動物中心)為完全正常之控制組，其所分組別係如下列表一所示。
表一中之控制組，其係以不帶有系統性紅斑性狼瘡病症之B6品系實驗鼠進行試驗，且不對其做任何處理，使其進食正常飼料並自然生長；負對照組、正對照組以及實驗組皆係採可表現系統性紅斑性狼瘡病症之NZB/WF1雌鼠進行試驗，唯負對照組僅予以口服不含治療物質之水，正對照組係依雌鼠體重口服以1.25 mg/kg對系統性紅斑性狼瘡具療效之類固醇藥物(prednisolone)，而實驗組則依雌鼠體重予以口服50 mg/kg由實施例一所製備之牛樟芝環己烯酮化合物，並於NZB/WF1雌鼠第23週齡時進行餵食，每週每天一次依各組別投予前述物質，且本發明中係將此開始餵食並進行試驗之時間定義為第1週，整個試驗持續進行至第48週為止，實驗期間需定時進行各對照組及實驗組之採血並收集其尿液，以檢測服用牛樟芝環己烯酮化合物對系統性紅斑性狼瘡實驗鼠病情之影響。
(3)牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WF1雌鼠尿蛋白(protein uria)含量之影響由於系統性紅斑性狼瘡會引發腎臟發炎及病變，造成腎臟無法吸收蛋白質，導致過多蛋白質隨尿液排出，而產生尿蛋白濃度增加之症狀，因此藉由檢測尿液中尿蛋白含量，可了解牛樟芝環己烯酮化合物對系統性紅斑性狼瘡之發病程度的影響。其測量方式係於前述實驗期間，每隔兩週汲取實驗鼠尿液，將10 μl之尿液以蛋白分析組(Bio－Rad Protein Assay Dye Reagent Concentrate,Bio－Rad Laboratories,USA)分析，並以ELISA分析儀於450 nm波長下讀出讀值，再利用標準蛋白曲線定量出蛋白濃度，其結果如第一圖所示。
第一圖係為牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WF1雌鼠尿液所含尿蛋白濃度之影響結果。由圖中可知，於實驗後第6週(亦即NZB/WF1雌鼠第28週齡時)，未罹患系統性紅斑性狼瘡之控制組，其尿液中之尿蛋白濃度係近似於實驗前之濃度數值，表示此段期間完全正常控制組之尿蛋白濃度皆可穩定地維持在65 mg/dL－75 mg/dL之固定範圍內；而相較於控制組，負對照組所呈現之尿蛋白濃度係由最初之89.16 mg/dL急遽上升至六週後之246 mg/dL，尿蛋白含量激增至2.76倍，顯示紅斑性狼瘡已引起實驗鼠腎臟病變，而使尿蛋白含量遽增；餵食類固醇藥物(prednisolone)之正對照組，相較於負對照組，其所顯現之尿蛋白濃度便可低至32.6 mg/dL；而口服50 mg/kg劑量牛樟芝環己烯酮化合物之實驗組，其尿蛋白濃度係為118.2 mg/dL，較負對照組為低，且與給予牛樟芝環己烯酮化合物前實驗鼠尿液中所含尿蛋白濃度相比較後，其僅增加1.3倍，此結果顯示，患有紅斑性狼瘡之實驗鼠經六週餵食牛樟芝環己烯酮化合物之處理後，可有效抑制紅斑性狼瘡所致腎臟病變及發炎現象，進而延緩蛋白尿症狀的發生。此外，由於前述實驗證實牛樟芝環己烯酮化合物可改善並緩和腎臟病變及發炎現象以減低尿蛋白症狀，因此，牛樟芝環己烯酮化合物亦可應用於會引起過多蛋白尿之相關腎臟疾病上，並不以此為限。
(3)牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WF1雌鼠所生成抗核抗體之影響本試驗係藉由檢測實驗鼠血液中所含特異性dsDNA之抗核抗體的濃度，以觀測牛樟芝環己烯酮化合物對系統性紅斑性狼瘡病症之影響。其檢測方式係於前述實驗期間，每隔四週於實驗鼠之眼窩採血，將採集之血液以離心方式將血球及血漿分離，取10 μl血漿以商業化試劑套組(Mouse Anti－dsDNA IgG ELISA kit,adi Alpha Diagnostic,USA)進行dsDNA之抗核抗體的濃度分析，其結果如第二圖所示。
第二圖係為牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WF1雌鼠所生成抗dsDNA抗體之影響結果。由圖中可知，於第0週(亦即NZB/WF1雌鼠第22週齡時)至第8週(亦即NZB/WF1雌鼠第30週齡時)，未罹患系統性紅斑性狼瘡之控制組，其血液中之皆無偵測到dsDNA抗核抗體之存在；此外，相對於控制組，表現紅斑性狼瘡病症之負對照組之NZB/WF1雌鼠血清中所含dsDNA抗核抗體之含量會隨著系統性紅斑性狼瘡發病週期之增長而逐漸增加，於八週內由小於10 mg/dL之濃度攀升至第八週時超過150 mg/dL的量；在正對照組部份，相較於負對照組，類固醇藥物(prednisolone)的服用則可以降低實驗鼠血清內dsDNA抗核抗體的含量，且於第八週時，其抗核抗體含量相較於負對照組，可降低至約50%；而餵食牛樟芝環己烯酮化合物之實驗組，於八週之實驗期間內，其所呈現之抗dsDNA抗體濃度明顯低於負對照組，且於第八週時，實驗鼠血液中之dsDNA抗核抗體含量可降至約34%，此結果顯示牛樟芝環己烯酮化合物可有效抑制或延緩患有系統性紅斑性狼瘡之哺乳動物體內抗核抗體的生成，進而減緩抗核抗體對自體組織的傷害，達到治療系統性紅斑性狼瘡病症之效果。
另一方面，由於樟芝環己烯酮化合物可抑制或延緩患系統性紅斑性狼瘡等自體免疫性疾病所致抗核抗體的大量生成以及腎臟受損引起尿蛋白濃度增加之病症，因此，牛樟芝環己烯酮化合物亦可應用於會形成抗核抗體以及引起腎臟損傷之硬皮症(Scleroderma)、休格蘭症候群(Sjogren syndrome)、類過敏性紫斑(Anaphylactoid purpura)、風濕性腎炎或會造成多種組織與器官例如：皮膚、關節、骨骼、腎臟、心血管系統、凝血系統、腸胃道、漿膜(心包膜、胸膜、腹膜)及腦神經系統等傷害之其他自體免疫性疾病上，並不以此為限。此外，因抗dsDNA之抗核抗體之產生亦與腎臟損害有關，而牛樟芝環己烯酮化合物係可降低抗dsDNA抗體之生成，此顯示牛樟芝環己烯酮化合物係可藉由降低抗dsDNA抗體量而有效減緩腎臟受損程度。因此樟芝環己烯酮化合物可經由減少尿蛋白濃度及抗dsDNA抗體量而可應用於降低腎臟損傷並保護腎臟方面。
綜上所述，本發明分離自牛樟芝之4－羥基－2,3－二甲氧基－6－甲基－5(3,7,11－三甲基－2,6,10－十二碳三烯)－2－環己烯酮化合物，係可有效降低自體免疫疾病所致之尿蛋白濃度以及抗核抗體含量升高等症狀，進而減緩該些病症對人類等哺乳動物所造成之組織器官傷害，且亦可利用其護腎與對降低腎臟損傷之效果，以減輕腎臟疾病對體內造成之傷害。另一方面，因牛樟芝環己烯酮化合物係為天然萃取之物質，故其應用於治療紅斑性狼瘡等自體免疫疾病與腎臟相關疾病時，並不會引起患者不適或產生毒性、併發症等其他副作用，且其亦可與化學藥劑並用，以減少類固醇等化學藥物使用劑量並降低該些化學藥劑所引發之副作用；此外，亦可將其製備成醫藥組成物，其中，該醫藥組成物除包含有效劑量之牛樟芝環己烯酮化合物外，尚可包括藥學上可接受的載體。載體可為賦形劑(如水)、填充劑(如蔗糖或澱粉)、黏合劑(如纖維素衍生物)、稀釋劑、崩解劑、吸收促進劑或甜味劑，但並未僅限於此。本發明醫藥組成物可依一般習知藥學之製備方法生產製造，將有效成分劑量之牛樟芝環己烯酮化合物與一種以上之載體相混合，製備出所需之劑型，此劑型可包括錠劑、粉劑、粒劑、膠囊或其他液體製劑，但未以此為限。藉以達到預防並治療人類等哺乳動物之系統性紅斑性狼瘡等自體免疫疾病與腎臟疾病之目的。
第一圖係本發明實施例牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WF1雌鼠尿液所含尿蛋白濃度之影響結果。
第二圖係本發明實施例牛樟芝環己烯酮化合物對系統性紅斑性狼瘡NZB/WFl雌鼠所生成抗dsDNA抗核抗體之影響結果。圖(A)係為第0週時，牛樟芝環己烯酮化合物對抗dsDNA抗核抗體生成濃度之影響；圖(B)係為第4週時，牛樟芝環己烯酮化合物對抗dsDNA抗核抗體生成濃度之影響；圖(C)係為第8週時，牛樟芝環己烯酮化合物對抗dsDNA抗核抗體生成濃度之影響。
Claims (9)
- 一種具有下列結構式之化合物在製備治療自體免疫疾病之藥物的應用，
- 如申請專利範圍第1項所述之應用，其中該化合物係為4-羥基-2,3-二甲氧基-6-甲基-5(3,7,11-三甲基-2,6,10-十二碳三烯)-2-環己烯酮(4-hydroxy-2,3-dimethoxy-6-methy-5(3,7,11-trimethyl-dodeca-2,6,10-trienyl)-cyclohex-2-enone)。
- 如申請專利範圍第2項所述之應用，其中該化合物係由牛樟芝之乙醇萃取物中所分離製得。
- 如申請專利範圍第1或2項所述之應用，其中該化合物係可減緩自體免疫疾病對哺乳動物造成之腎臟損傷及自體免疫疾病所生成抗核抗體對器官組織之傷害。
- 如申請專利範圍第4項所述之應用，其中該哺乳動物係為 人類。
- 如申請專利範圍第4項所述之應用，其中該自體免疫疾病係為系統性紅斑性狼瘡(systemic lupus erythematosus,SLE)。
- 如申請專利範圍第6項所述之應用，其中該化合物係藉由降低哺乳動物尿蛋白含量，而可減緩系統性紅斑性狼瘡所致腎臟損傷。
- 如申請專利範圍第6項所述之應用，其中該化合物係藉由降低哺乳動物血液中之抗核抗體(antinuclear antibodies,ANA)含量，而可減緩系統性紅斑性狼瘡所致自體組織器官之損傷。
- 如申請專利範圍第8項所述之應用，其中該抗核抗體係為抗雙股脫氧核糖核酸(dsDNA)之抗核抗體。
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| TW096121138A TWI394572B (zh) | 2007-06-12 | 2007-06-12 | Application of Cynanchum aurantii Cyclohexenone Compounds in the Preparation of Drugs for the Treatment of Autoimmune Diseases |
| US11/882,196 US7501454B2 (en) | 2007-06-12 | 2007-07-31 | Cyclohexenone compounds from Antrodia camphorata to treat autoimmune diseases |
| KR1020070086412A KR101150046B1 (ko) | 2007-06-12 | 2007-08-28 | 자가면역 질병을 치료하기 위한 안트로디아 캄포라타로부터얻은 시클로헥세논 화합물 |
| DE102007043186A DE102007043186A1 (de) | 2007-06-12 | 2007-09-11 | Cyclohexenonverbidungen aus Antrodia camphorata zur Behandlung von Autoimmunerkrankungen |
| BRPI0704904-8A BRPI0704904A2 (pt) | 2007-06-12 | 2007-09-24 | compostos de ciclohexenona obtidos de antrodia camphorata para o tratamento de doenÇas auto-imunes |
| GB0724750.5A GB2450190B (en) | 2007-06-12 | 2007-12-19 | Cyclohexenone compounds from antrodia camphorata to treat autoimmune diseases |
| FR0802139A FR2917408A1 (fr) | 2007-06-12 | 2008-04-17 | Cyclohexenones d'antrodia camphorata pour le traitement de maladies auto-immunes et compositions pharmaceutiques les contenant |
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| TWI394575B (zh) * | 2007-07-09 | 2013-05-01 | Golden Biotechnology Corp | Application of Cynanchum auranthone Cyclohexenone Compounds in the Preparation of Drugs for the Suppression of Hepatitis B Virus |
| CN101357883B (zh) * | 2007-07-30 | 2012-09-26 | 国鼎生物科技股份有限公司 | 治疗自体免疫疾病的牛樟芝环己烯酮化合物及医药组成物 |
| TWI448294B (zh) * | 2009-03-04 | 2014-08-11 | Univ Kaohsiung Medical | 增強免疫活性之樟芝子實體水萃取物及其製備方法 |
| US8697086B2 (en) * | 2010-01-19 | 2014-04-15 | Chieh-Chou Yu | Use of Antrodia camphorata for treating diseases |
| TWI452032B (zh) * | 2011-01-21 | 2014-09-11 | Golden Biotechnology Corp | 治療腎病之醫藥組成物 |
| TWI425948B (zh) * | 2012-01-20 | 2014-02-11 | Compositions for the inhibition or killing of Porphyromonas gingivalis and their use for the alleviation or treatment of periodontal disease and other diseases | |
| US9603882B2 (en) | 2013-08-13 | 2017-03-28 | Industrial Technology Research Institute | Method for modulating Th17 cells and method for treating a disease related to modulation of Th17 cells |
| US9789153B2 (en) | 2014-07-02 | 2017-10-17 | Hsiu-Hsien Tsai | Composition for preventing cancer and treating cancer and intensifying the effects of other anticancer drugs |
| CN104873626A (zh) * | 2015-06-01 | 2015-09-02 | 陈爱华 | 一种治疗过敏性紫癜的片剂 |
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| WO2021218974A1 (en) * | 2020-04-28 | 2021-11-04 | Alps Biotech Co., Ltd. | Uses of antrodia cinnamomea extract in manufacturing products for reducing expression and treating associated diseases of angiotensin converting enzyme 2 |
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| US6740517B2 (en) * | 2001-12-14 | 2004-05-25 | Ming-Huang Lan | Incubation method for obtaining solid culture of Zang Zhi, solid culture obtained therefrom, processed products and use thereof |
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| TW200829234A (en) * | 2007-01-08 | 2008-07-16 | Golden Biotechnology Corp | Antrodia camphorata isophorone extract |
| CN101357883B (zh) * | 2007-07-30 | 2012-09-26 | 国鼎生物科技股份有限公司 | 治疗自体免疫疾病的牛樟芝环己烯酮化合物及医药组成物 |
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| US7501454B2 (en) * | 2007-06-12 | 2009-03-10 | Golden Biotechnology Corporation | Cyclohexenone compounds from Antrodia camphorata to treat autoimmune diseases |
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| US7501454B2 (en) | 2009-03-10 |
| KR20080109583A (ko) | 2008-12-17 |
| GB0724750D0 (en) | 2008-01-30 |
| KR101150046B1 (ko) | 2012-06-01 |
| TW200848065A (en) | 2008-12-16 |
| GB2450190B (en) | 2012-03-21 |
| GB2450190A (en) | 2008-12-17 |
| FR2917408A1 (fr) | 2008-12-19 |
| US20080312334A1 (en) | 2008-12-18 |
| DE102007043186A1 (de) | 2008-12-18 |
| BRPI0704904A2 (pt) | 2009-01-27 |
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