TW201309301A - 處置發炎性疾病、過敏性疾病以及自體免疫疾病用之醫藥組成物 - Google Patents
處置發炎性疾病、過敏性疾病以及自體免疫疾病用之醫藥組成物 Download PDFInfo
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Abstract
本發明係關於藉由下述通式(I)所示之脂肪酸衍生物而施行免疫抑制之方法及醫藥組成物。再者本發明係關於藉由前述之脂肪酸衍生物處置發炎性疾病、過敏性疾病及自體免疫疾病用之方法及醫藥組成物。□
Description
本發明係關於藉由具有特定構造之脂肪酸衍生物施行免疫抑制之方法及醫藥組成物。再者,本發明係關於處置發炎性疾病、過敏性疾病及自體免疫疾病用之方法及醫藥組成物。
適應免疫系細胞為特定型之白血球,其被稱為淋巴球。淋巴球被分為B細胞及T細胞二大類,此等雖皆來自骨髓中之造血幹細胞,但是B細胞以與胸腺無關之方式成熟,而T細胞則在胸腺中分化成熟。其任一者皆能識別特定之抗原標的,B細胞參與體液性免疫回應,T細胞則參與細胞性免疫回應。B細胞係由骨髓中之造血幹細胞受到介白素等細胞激素之刺激而分化成前B細胞、成熟B細胞,然後受到抗原刺激而被活化,最終成為具有抗體產生能力之漿細胞(plasma cell)。另一方面,T細胞係骨髓中之造血幹細胞分化成前T細胞後,移動至胸腺,然後重複進行分化,成為成熟T細胞。之後,其藉由抗原刺激而被活化,形成具有增殖能力或細胞傷害能力之活化T細胞。因此,藉由抑制經活化之B細胞及/或T細胞之增殖,可抑制免疫。
發炎係免疫系統對於感染及傷害最初所產生之回應。相對於暫時性發炎能有效保護而免於感染等,不受調控之發炎會造成組織損傷,而成為多種疾病之潛在要因。
發炎,通常係由抗原與T細胞抗原受體結合而引起。
對於細菌或病毒等外來抗原之免疫回應為防禦、排除感染等。但是,不受調控之異常免疫回應則會引起過敏性疾病或自體免疫疾病。過敏性疾病為針對來自外部之抗原,引發過度免疫反應之疾病,其特徵為T細胞之活化及B細胞所引起之IgE產生過剩。另一方面,自體免疫疾病為對於從自體而來之抗原產生免疫反應,且自體抗體帶來各種障礙之疾病,其特徵為T細胞及B細胞之活化以及發炎性細胞激素之過剩產生。
過敏性疾病及自體免疫疾病由於多係由發炎引起,與發炎密切相關,所以過敏性疾病及自體免疫疾病與被視為發炎性疾病之疾病大部分重複。
脂肪酸衍生物含於人類或其他哺乳類之組織或器官中,為顯示廣範圍生理學活性之有機羧酸中之1群。存在於天然之幾種脂肪酸衍生物一般具有式(A)所示之前列腺烷酸骨架。
另一方面,天然前列腺素(PG)類之幾種合成類似物具有經修飾之骨架。天然PG類,依據5員環部分之構造特性,被分成PGA類、PGB類、PGC類、PGD類、PGE類、
PGF類、PGG類、PGH類、PGI類及PGJ類,再者,依據碳鏈部分之不飽和之數目及位置,被分成以下之3型。
(下標1)...13,14-不飽和-15-OH
(下標2)...5,6-及13,14-二不飽和-15-OH
(下標3)...5,6-、13,14-及17,18-三不飽和-15-OH
再者,PGF類依據9位及11位之羥基之配置,分成α(羥基為α配置)及β(羥基為β配置)二類。
在15位之碳具有2個雜原子之特定脂肪酸衍生物於本技術領域中為已知。美國專利第4088775號(專利文獻1)揭示特定之15-伸乙二氧基-脂肪酸衍生物。再者,美國專利第4870104號(專利文獻2)揭示於15位可具有伸乙二氧基亞甲基之11-鹵素-脂肪酸衍生物及其作為胃酸分泌阻礙劑之用途。再者,美國專利第6353014號(專利文獻3)揭示在高眼壓症及青光眼之處置上有用之9位及11位為羥基之特定15-縮酮-脂肪酸衍生物。再者,國際公開WO2005/013928號(專利文獻4)及國際公開WO2006/070942號(專利文獻5)揭示於15位之碳上具有2個雜原子之脂肪酸衍生物在育毛促進上係有用。
此等先前技術未揭示或暗示於15位之碳具有2個雜原子之脂肪酸衍生物在抑制經活化B細胞及/或T細胞之增殖,以及發炎性疾病、過敏性疾病及自體免疫疾病之處置上係有用。
[專利文獻]
[專利文獻1]美國專利第4088775號說明書
[專利文獻2]美國專利第4870104號說明書
[專利文獻3]美國專利第6353014號說明書
[專利文獻4]國際公開WO2005/013928號
[專利文獻5]國際公開WO2006/070942號(上述文獻皆係以引用方式含於本說明書中)
本發明之目的係提供免疫抑制用之方法及醫藥組成物,進一步提供處置發炎性疾病、過敏性疾病及自體免疫疾病用之方法及醫藥組成物。
本發明者發現藉由具有特定構造之脂肪酸衍生物抑制經活化B細胞及/或T細胞之增殖,可抑制免疫,基於此,具有特定構造之脂肪酸衍生物在發炎性疾病、過敏性疾病及自體免疫疾病之處置上有用。
亦即、本發明為如下。
(1)一種免疫抑制用之醫藥組成物,其含有下述通式(I)所示之脂肪酸衍生物作為有效成分:
[式中,L、M及N為氫、羥基、鹵素、低級烷基、羥基(低級)烷基、低級烷醯氧基或側氧基;其中,L及M之至少一者為氫以外之基,5員環可具有至少1個雙鍵;A為-CH3、-CH2OH、-COCH2OH、-COOH或此等之官能性衍生物;B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;Z1及Z2為氧、氮或硫;R2及R3為低級烷基,此等可連接在一起形成低級伸烷基;R1為未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代之飽和或不飽和之二價低級至中級脂肪族烴,脂肪族烴中之至少1個碳原子可用氧、氮或硫置換;及Ra為未經取代或經鹵素、側氧基、羥基、低級烷基、低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷基
氧基、芳基、芳氧基、雜環基或雜環氧基取代之飽和或不飽和之低級至中級脂肪族烴殘基;低級烷氧基;低級烷醯氧基;環(低級)烷基;環(低級)烷基氧基;芳基;芳氧基;雜環基;雜環氧基]。
(2)如(1)記載之醫藥組成物,其中L及M為羥基。
(3)如(1)或(2)記載之醫藥組成物,其中A為-COOH或其官能性衍生物。
(4)如(1)至(3)之任一項記載之醫藥組成物,其中B為-CH2-CH2-、-CH=CH-或-C≡C-。
(5)如(1)至(4)之任一項記載之醫藥組成物,其中Z1及Z2為氧。
(6)如(1)至(5)之任一項記載之醫藥組成物,其中R2及R3連接在一起形成低級伸烷基。
(7)如(6)記載之醫藥組成物,其中低級伸烷基為碳數3之伸烷基。
(8)如(1)至(7)之任一項記載之醫藥組成物,其中脂肪酸衍生物為(Z)-7-[(1R,2R,3R,5S)-2-(3,3-伸乙二氧基癸基)-3,5-二羥基環戊基]庚-5-烯酸異丙酯。
(9)如(1)至(8)之任一項記載之醫藥組成物,其係用於處置發炎性疾病者。
(10)如(9)記載之醫藥組成物,其係用於處置皮膚之發炎或伴隨其的脫毛症者。
(11)如(10)記載之醫藥組成物,其係用於處置伴隨皮膚之發炎之脫毛症者。
(12)如(1)至(8)之任一項記載之醫藥組成物,其係用於處置過敏性疾病者。
(13)如(12)記載之醫藥組成物,其係用於處置異位性皮膚炎或伴隨其的脫毛症者。
(14)如(13)記載之醫藥組成物,其係用於處置伴隨異位性皮膚炎之脫毛症者。
(15)如(1)至(8)之任一項記載之醫藥組成物,其係用於處置自體免疫疾病者。
(16)一種在哺乳類對象中施行免疫抑制之方法,其包
含將有效量之如申請專利範圍第1項之通式(I)所示之脂肪
酸衍生物投與至需要之對象。
(17)一種如(1)記載之通式(I)所示之脂肪酸衍生物之用途,其係用於在哺乳類對象中施行免疫抑制。
於命名本發明之脂肪酸衍生物時,係使用前述式(A)所示之前列腺烷酸(prostanoic acid)之編號。
前述式(A)雖為具有C-20之基本骨架者,然而在本發明中碳數並不以此為限。亦即,構成基本骨架之碳之編號,係以羧酸為1,向著5員環將α鏈之碳依序編號為2至7,將5員環之碳編號為8至12,將ω鏈之碳編號為13至20,不過在α鏈上碳數減少之情況,係從第2位依次消去編號,在α鏈上碳數增加之情況,於第2位係以取代在羧基(1位)上之取代基來命名。同樣地,ω鏈上碳數減少之情
況,係從第20位依次減去碳之編號,在ω鏈上碳數增加之情況,第21號以後之碳原子係以於第20位之取代基來命名。又,關於立體配置,只要無特別限定,係依循上述式(A)之基本骨架所具有之立體配置。
又,例如PGD、PGE、PGF,意指於9位及/或11位具有羥基之脂肪酸衍生物,然而在本發明中,亦包含於9位及/或11位具有其他基代替羥基者。命名此等化合物時,係以9-去氧-9-取代基或11-去氧-11-取代基之形式來命名。再者,在以氫代替羥基之情況,簡稱為9或11-去氧化合物。
如前述,在本發明中脂肪酸衍生物之命名係根據前列腺烷酸骨架來進行,然而在化合物具有與天然脂肪酸衍生物類似之部分構造之情況中,為簡略化,可利用「PG」之簡稱。在此種情況,α鏈之骨架碳數延長2個之PG化合物,亦即,α鏈之骨架碳數為9之脂肪酸衍生物,有時亦命名為2-去羧基-2-(2-羧基乙基)-PG化合物。同樣地α鏈之骨架碳數為11之脂肪酸衍生物,有時亦命名為2-去羧基-2-(4-羧基丁基)-PG化合物。又,ω鏈之骨架碳數延長2個之脂肪酸衍生物,亦即ω鏈之骨架碳數為10之脂肪酸衍生物,有時亦命名為20-乙基-PG化合物。再者,命名亦可依據IUPAC命名法等來進行。
在本發明中所使用之脂肪酸衍生物,可包含所有脂肪酸衍生物之取代物或衍生物。因此,可為例如:於13-14位具有雙鍵,於15位具有羥基之脂肪酸衍生物、進一步於
5-6位再具有一個雙鍵之脂肪酸衍生物、進一步於17-18位具有雙鍵之脂肪酸衍生物、於15位具有側氧基代替羥基之脂肪酸衍生物、於15位具有氫代替羥基之脂肪酸衍生物、於15位具有氟代替羥基之脂肪酸衍生物,或者此等之13-14位之雙鍵改成單鍵之脂肪酸衍生物,或13-14位之雙鍵改成參鍵之脂肪酸衍生物之任一種。又,就包含取代物或衍生物之類似物之例子而言,可列舉:上述化合物之α鏈之末端羧基經酯化或醯胺化之化合物、或生理學上可容許之鹽、α鏈或ω鏈之碳數減少或延長之化合物、α鏈或ω鏈上具有側鏈(例如碳數1至3)之化合物、5員環上具有羥基、鹵素、低級烷基、羥基(低級)烷基及側氧基等取代基或雙鍵之化合物、在α鏈上具有鹵素、側氧基、芳基及雜環基等取代基之化合物、在ω鏈上具有鹵素、側氧基、羥基、低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷基氧基、芳基、芳氧基、雜環及雜環-氧基等取代基之化合物、ω鏈比通常之前列腺烷酸短之化合物之ω鏈末端具有低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷基氧基、芳基、芳氧基、雜環基及雜環-氧基等取代基之化合物等。
在本發明中所使用之脂肪酸衍生物係以下述式(I)所示者:
[式中,L、M及N為氫、羥基、鹵素、低級烷基、羥基(低級)烷基、低級烷醯氧基或側氧基;其中,L及M之至少一者為氫以外之基,5員環可具有至少1個雙鍵;A為-CH3、-CH2OH、-COCH2OH、-COOH或此等之官能性衍生物;B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;Z1及Z2為氧、氮或硫;R2及R3為低級烷基,此等可連接在一起形成低級伸烷基;R1為未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代之飽和或不飽和二價低級至中級脂肪族烴,脂肪族烴中之至少1個碳原子可用氧、氮或硫置換;及Ra為未經取代或經鹵素、側氧基、羥基、低級烷基、低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷基氧基、芳基、芳氧基、雜環基或雜環氧基取代之飽和或不
飽和之低級至中級脂肪族烴殘基;低級烷氧基;低級烷醯氧基;環(低級)烷基;環(低級)烷基氧基;芳基;芳氧基;雜環基;雜環氧基]。
本發明所使用之較佳脂肪酸衍生物係以式(II)表示:
[式中,L及M為氫、羥基、鹵素、低級烷基、羥基(低級)烷基、低級烷醯氧基或側氧基,其中,L及M之至少一者為氫以外之基,5員環可具有至少1個雙鍵;A為-CH3、-CH2OH、-COCH2OH、-COOH或此等之官能性衍生物;B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;Z1及Z2為氧、氮或硫;R2及R3為低級烷基,此等可連接在一起形成低級伸烷基;X1及X2為氫、低級烷基或鹵素;R1為未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環取代之二價飽和或不飽和低級至中級之脂肪族烴殘
基,脂肪族烴中之至少1個碳原子可任意地用氧、氮或硫置換;R4為單鍵或低級伸烷基;而且R5為低級烷基、低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷氧基、芳基、芳氧基、雜環或雜環氧基]。
上述式中、R1及Ra之定義中之術語「不飽和」,意指就主鏈及/或側鏈之碳原子間之鍵結而言,獨立、分開或連續地含有1個或以上之雙鍵及/或參鍵。依照通常之命名法,連續2個位置間之不飽和鍵係藉由表示較小之位置編號來顯示,未連續之2個位置間之不飽和鍵係以表示兩者之位置編號來顯示。
術語「低級至中級脂肪族烴」意指具有碳原子數1至14之直鏈或分枝鏈(但是,側鏈以碳原子數1至3者為較佳)之烴基,以碳原子數1至10之烴基為較佳,以1至8之烴基為特佳。
術語「鹵素原子」包含氟、氯、溴及碘。
術語「低級」,若無特殊限定,包含具有碳原子數1至6之基。
術語「低級烷基」意指碳原子數1至6之直鏈或分枝狀飽和烴基,包含,例如:甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基、戊基及己基。
術語「低級伸烷基」意指碳原子數1至6之直鏈或分枝狀二價飽和烴基,包含,例如:亞甲基、伸乙基、伸丙
基、伸異丙基、伸丁基、伸異丁基、伸三級丁基、伸戊基及伸己基。
術語「低級烷氧基」意指低級烷基係與上述同意義之低級烷基-O-基。
術語「羥基(低級)烷基」意指經至少1個羥基取代之如上述之低級烷基,可列舉如:羥基甲基、1-羥基乙基、2-羥基乙基及1-甲基-1-羥基乙基。
術語「低級烷醯氧基」意指式RCO-O-(其中,RCO-為如上述之低級烷基被氧化而生成之醯基,例如乙醯基)所示之基。
術語「環(低級)烷基」意指含有碳原子3個以上之如上述之低級烷基閉環而產生之環狀基,包含例如:環丙基、環丁基、環戊基、環己基。
術語「環(低級)烷氧基」意指環(低級)烷基係與上述同意義之環(低級)烷基-O-基。
術語「芳基」包含未經取代或經取代之芳香族烴環基(較佳為單環式基),例如:苯基、甲苯基、二甲苯基。就取代基而言,包含鹵素原子、鹵代(低級)烷基(其中,鹵素原子及低級烷基如同前述之意義)。
術語「芳氧基」意指式ArO-(其中,Ar如同上述之芳基)所示之基。
就術語「雜環基」而言,包含可經取代之碳原子以及1至4個(較佳1至3個)選自氮原子、氧原子及硫原子之1種或2種雜原子之5至14員環(較佳5至10員環)之單環
式至三環式(較佳單環式)之雜環基。就雜環基而言,可例示:呋喃基、噻吩基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、吡唑基、呋呫基、哌喃基、吡啶基、嗒基、嘧啶基、吡基、2-吡咯啉基、吡咯啶基、2-咪唑啉基、咪唑啶基、2-吡唑啉基、吡唑啶基、N-哌啶基(piperidino)、哌基、N-嗎啉基(morpholino)、吲哚基、苯并噻吩基、喹啉基、異喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、啡啶基(phenanthridinyl)、苯并咪唑基、苯并咪唑啉基、苯并噻唑基、吩噻基等。就取代基而言,可例示:鹵素、經鹵素取代之低級烷基(其中,鹵素及低級烷基如同前述之意義)。
術語「雜環氧基」意指式HcO-所示之基(其中,Hc為如上述之雜環基)。
A之「官能性衍生物」包含鹽(較佳為醫藥上可容許之鹽)類、醚類、酯類及醯胺類。
就適當之「醫藥上可容許之鹽」而言,包含習用之非毒性鹽,可列舉:與無機鹼所形成之鹽,例如:鹼金屬鹽(鈉鹽、鉀鹽等)、鹼土類金屬鹽(鈣鹽、鎂鹽等)、銨鹽;或與有機鹼所形成之鹽,例如:胺鹽(例如甲基胺鹽、二甲基胺鹽、環己基胺鹽、苯甲基胺鹽、哌啶鹽、伸乙基二胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、參(羥基甲基胺基)乙烷鹽、單甲基-單乙醇胺鹽、普魯卡因(procaine)鹽、咖啡因鹽等)、鹼性胺基酸鹽(例如精胺酸鹽、離胺酸鹽等)、四烷基銨鹽等。此等鹽類,可藉由常用之反應或藉由鹽交
換從例如對應之酸及鹼來製造。
就醚類之例子而言,可列舉:烷基醚,例如甲基醚、乙基醚、丙基醚、異丙基醚、丁基醚、異丁基醚、三級丁基醚、戊基醚、1-環丙基乙基醚等低級烷基醚;辛基醚、二乙基己基醚、月桂基醚、鯨蠟基醚等中級或高級烷基醚;油基醚、次亞麻油基醚等不飽和醚;乙烯基醚、烯丙基醚等低級烯基醚;乙炔基醚、丙炔基醚等低級炔基醚;羥基乙基醚、羥基異丙基醚等羥基(低級)烷基醚;甲氧基甲基醚、1-甲氧基乙基醚等低級烷氧基(低級)烷基醚;例如苯基醚、甲苯磺醯基醚、三級丁基苯基醚、水楊基醚、3,4-二甲氧基苯基醚、苯甲醯胺苯基醚等依照期望經取代之芳基醚;及苯甲基醚、三苯甲基(trityl)醚、二苯甲基(benzhydryl)醚等芳基(低級)烷基醚。
就酯類而言,可列舉:甲酯、乙酯、丙酯、異丙酯、丁酯、異丁酯、三級丁酯、戊酯、1-環丙基乙酯等低級烷酯;乙烯酯、烯丙酯等低級烯基酯;乙炔酯、丙炔基酯等低級炔基酯;羥基乙基酯等羥基(低級)烷基酯;甲氧基甲基酯、1-甲氧基乙基酯等低級烷氧基(低級)烷基酯等脂肪族酯;及例如苯基酯、甲苯基酯、三級丁基苯基酯、水楊基酯、3,4-二甲氧基苯基酯、苯甲醯胺苯基酯等依期望經取代之芳基酯;苯甲基酯、三苯甲基酯、二苯甲基酯等芳基(低級)烷基酯。
A之醯胺意指式-CONR’R”(式中,R’及R”分別為氫、低級烷基、芳基、烷基-或芳基-磺醯基、低級烯基及低級
炔基)所示之基,可列舉如:甲基醯胺、乙基醯胺、二甲基醯胺、二乙基醯胺等低級烷基醯胺;N-醯基苯胺(anilide)、N-醯基甲苯胺(toluidide)等芳基醯胺;甲基磺醯胺、乙基磺醯胺、甲苯基磺醯胺等烷基-或芳基-磺醯胺。
L及M之較佳例包含氫、羥基、側氧基,以L係羥基且M係羥基為特佳。
A之較佳例為-COOH、其官能性衍生物。
B之較佳例為-CH2-CH2-、-CH=CH-或-C≡C-。
Z1及z2之較佳例皆為氧。
R2及R3之較佳例為:R2及R3連接在一起形成低級伸烷基者;更佳例,可列舉形成碳數3之伸烷基者。
X1及X2之較佳例為氫或鹵素,更佳例,可列舉兩者皆為氫或氟者。
較佳之R1為碳原子數1至10(特佳為碳原子數6至10)之烴殘基。脂肪族烴中之至少1個碳原子可用氧、氮或硫置換。
就R1之具體例而言,可列舉如下列者:-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-O-CH2-、-CH2-CH=CH-CH2-O-CH2-、-CH2-C≡C-CH2-O-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-、及、-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
較佳之Ra為具有1至10個碳原子,更佳為具有1至8個碳原子之烴。Ra可具有1或2個含有1個碳原子之側鏈。
上述式(I)及(II)中之環以及α-及/或ω-鏈之配置可與天然PG類之配置相同,亦可相異。然而,本發明亦包含具有天然類型之配置之化合物及具有非天然類型之配置之化合物之混合物。
在本發明中,各種互變異構物或其混合物、或者光學異構物或其混合物、消旋體、其他立體異構物等異構物可用於相同之目的。
本發明之脂肪酸衍生物在作為免疫抑制用之醫藥組成物上係有用,再者,在作為處置發炎性疾病、過敏性疾病及自體免疫疾病用之醫藥組成物上係有用。
在本發明中所謂的「處置」及/或「改善」包含對象疾病之預防、治療、症狀之減輕、症狀之減退、進行停止等所有控管。
就在本發明中為處置對象之發炎性疾病而言,可列舉:風濕性關節炎等關節炎、肺炎、包含病毒性之肝炎、伴隨感染症之發炎、發炎性腸疾病、絲球體腎炎等腎炎、胃炎、血管炎、胰臟炎、腹膜炎、支氣管炎、心肌炎、腦炎、乾癬、接觸性皮膚炎等皮膚炎等。又,在本發明中發炎性疾病之處置包含伴隨發炎性疾病之症狀之處置,例如伴隨皮膚炎之脫毛症(粃糠性脫毛症、脂漏性脫毛症、瘢痕性脫毛症等)之處置。
就在本發明中為處置對象之過敏性疾病而言,可列舉:過敏性結膜炎、過敏性鼻炎、支氣管性氣喘、異位性皮膚炎、食物過敏、花粉症等。又,在本發明中過敏性疾病之處置包含伴隨過敏性疾病之症狀之處置,例如伴隨異位性皮膚炎之脫毛症之處置。
就在本發明中為處置對象之自體免疫疾病而言,可列舉全身性紅斑、薛格連氏症候群(Sjogren’s sydrome)、多發性硬化症、慢性風濕性關節炎、類天疱瘡、硬皮病、潰瘍性大腸炎等。又,在本發明中,自體免疫疾病之處置包含伴隨自體免疫疾病之症狀之處置。
在本發明中所使用之脂肪酸衍生物之濃度隨著所使用之化合物、對象之種類、年齢、體重、待處置之症狀、期望之治療效果、投與容量、處置期間等而異,可適當選
擇適切之用量。一般而言,本發明之脂肪酸衍生物,藉由全身或局部投與或者連續投與每日約0.001μg/kg至約500mg/kg之用量,較佳約0.01μg/kg至約50mg/kg之用量,1日用量分1至4次投與,可得到充分之效果。
依照本發明,脂肪酸衍生物可適用於全身或局部。通常,脂肪酸衍生物可藉由局部投與、經口投與、鼻腔內投與、口腔內投與、吸入投與而進行投與。在本發明中,較佳將脂肪酸衍生物製劑化成適合依照先前方法投與之醫藥組成物。該組成物可為適合局部投與、經口投與、鼻腔內投與、口腔內投與、藉由吸入投與、静脈內注射(包含點滴)、皮下注射或灌流者,以及適合直腸內投與、陰道內投與、經皮投與等之外用藥、栓劑或陰道栓劑。
本發明之醫藥組成物亦可進一步包含生理學上可容許之添加劑。在此等添加劑方面,可與本發明之化合物一起使用之成分有,例如,賦形劑、稀釋劑、增量劑、溶劑、潤滑劑、輔助劑、黏合劑、崩散劑、被覆劑、膠囊化劑、軟膏基劑、栓劑用基劑、氣溶膠劑、乳化劑、分散劑、懸浮劑、增黏劑、等張化劑、緩衝劑、無痛化劑、保存劑、抗氧化劑、矯味劑、芳香劑、著色劑、機能性物質(例如:環糊精、身體內分解高分子等)、安定劑等。此等添加劑為本技術人士所熟知,只要為從一般製劑學之參考書中所記載者中選擇即可。
在本發明之醫藥組成物中上文規定之脂肪酸衍生物之量,依組成物之處方而變化即可,一般可為0.001至
10.0w/v%、更佳為0.005至5.0w/v%,最佳為0.01至1.0w/v%。
在用於經口投與之固體組成物之例子方面,有錠劑、喉錠(troche)、舌下錠劑、膠囊劑、丸劑、粉末劑、顆粒劑等。固體組成物亦可將1種以上活性成分與至少1種不活性稀釋劑混合而調製。在該組成物中可進一步包含不活性稀釋劑以外之添加劑,例如潤滑劑、崩散劑及安定劑。錠劑及丸劑,視期望,可藉由腸溶性薄膜或胃腸溶性薄膜被覆。此等可用2層以上被覆。亦可使此等被緩釋性物質吸收、或者微膠囊化。再者,對於本組成物,亦可使用明膠等易分解性物質而予以膠囊化。亦可使此等進一步溶解於脂肪酸或其單、二或三甘油酯等適當溶劑中,製成軟膠囊。在必須立即發揮效果之情況,亦可使用舌下錠。
經口投與用之液體組成物之例子有乳劑、溶液劑、懸浮劑、糖漿劑及酏劑等。此等組成物亦可進一步含有習用之不活性稀釋劑,例如精製水或乙醇。此等組成物亦可含有不活性稀釋劑以外之添加劑,例如稱為濕潤劑或懸浮劑之輔助劑、甜味劑、香味劑、芳香劑及保存劑等。
本發明之醫藥組成物亦可為含有1個以上活性成分之噴霧用組成物之態樣,其可藉由已知之方法來調製。
鼻腔內用製劑之例子可為含有1種以上活性成分之水性或油性溶液劑、懸浮劑或乳劑。在藉由吸入活性成分而投與之情況中,本發明之組成物可為可呈氣溶膠形式提供之懸浮液、溶液或乳液之態樣,或適於乾燥粉末之吸入之
粉末態樣。藉由吸入投與用之組成物可進一步包含習用之推進劑。
非經口投與用之本發明注射用組成物之例子有經滅菌之水性或非水性溶液劑、懸浮劑及乳劑等。水性溶液劑或懸浮劑用之稀釋劑可為,例如,注射用蒸餾水、生理食鹽水及林格氏液(Ringer’s solution)等。
溶液劑及懸浮劑用之非水性稀釋劑可為,例如,丙二醇、聚乙二醇、植物油(橄欖油等)、醇(乙醇等)及聚山梨醇酯(polysorbate)等。該組成物亦可進一步含有保存劑、濕潤劑、乳化劑、分散劑等添加劑。此等亦可藉由例如通過細菌保留過濾器過濾、藉由添加滅菌劑,或者藉由氣體或放射性同位素照射而進行滅菌。注射用組成物亦可呈滅菌粉末組成物之形式提供,而於使用前,使其溶解於注射用滅菌溶劑中。
本發明之外部藥包含皮膚科學及耳鼻科學領域中所使用之所有外用製劑,如軟膏劑、乳膏劑、洗劑及噴霧劑等。
本發明之其他態樣為栓劑或陰道栓劑,其等可藉由將活性成分混合於通常所使用之基劑,例如於體溫軟化之可可脂(cocoa butter)中而調製,為了使吸收性提高,亦可使用具有適當軟化溫度之非離子性界面活性劑。
本發明之組成物,在無損及本發明之目的之範圍內,亦可進一步含有其他成分。
又,在本發明中,亦可與其他藥劑併用投與。併用投
與意指於本發明之脂肪酸衍生物投與前、同時(同一製劑或與不同製劑之組合)、或投與後,投與其他藥劑。就可併用投與之其他藥劑而言,可列舉例如皮質醇(cortisol)、潑尼松龍(prednisolone)、安西諾龍(triamcinolone)、地塞美松(dexamethasone)等類固醇類,環孢靈(cyclosporine)、他克莫司(tacrolimus)、環磷醯胺等免疫抑制劑,阿斯匹靈、吲哚美辛(indomethacin)、雙氯芬酸(diclofenac)等非類固醇系消炎鎮痛劑等。
以下,藉由實施例進一步詳細地說明本發明,然而此等並非為本發明設限。
(5Z)-7-[(1R,2R,3R,5S)-2-[2-(2-庚基-1,3-二烷-2-基)乙基]-3,5-二羥基環戊基]庚-5-烯酸異丙酯(5)
在化合物1(510.0mg,1.273mmol)於甲苯(10.2ml)中之溶液內,添加1,3-丙二醇(0.92ml,12.73mmol)及觸媒量之對-甲苯磺酸,將混合物於回流下加熱17小時。之後,放置反應物,直至冷卻至室溫,用碳酸氫鈉飽和水溶液及氯化鈉飽和水溶液洗淨。將有機相以硫酸鎂乾燥,於減壓下蒸發。將殘餘物藉由矽膠管柱層析精製(Merck 7734,己烷:乙酸乙酯=3:2),得到化合物2(581.3mg)。
將化合物2(580.0mg,1.265mmol)於甲苯中(11.6ml)之溶液冷卻至-78℃,在其中,滴入1.5M DIBAH(甲苯中,2.95ml,4.427mmol),並將混合物攪拌1小時,接著,將甲醇(1.79ml)滴入所得到之混合物中。在其中添加酒石酸鈉鉀(Rochelle salt)飽和水溶液(100ml),將混合物激烈地攪拌30分鐘。將所得到之混合物用乙酸乙酯萃取,將有機層以飽和食鹽水洗淨,用硫酸鎂乾燥,於減壓下蒸發。將殘餘物以矽膠層析精製(Merck 7734,己烷:乙酸乙酯=1:9至0:10),得到化合物3(275.2mg,從1算起之產率61.4%)。
在溴化(4-羧基丁基)三苯基鏻(1.346g,3.038mmol)於THF(6ml)中之分散液內,於0℃添加THF中之1M三級丁醇鉀(6.07ml,6.07mmol)。將反應物於室溫攪拌1小時,並冷卻至-20℃。在其中,滴入THF(7ml)中之化合物3(269.2mg,0.7594mmol),於-20至0℃攪拌2小時。對反應添加冰冷水,於減壓下蒸發除去THF。在經濃縮之殘餘物中,於0℃,滴入冰冷的1N鹽酸水溶液,將溶液調整至pH 4。
將溶液用乙酸乙酯萃取,將有機層以氯化鈉飽和水溶液洗淨,用硫酸鎂乾燥,於減壓下蒸發。在殘餘物中添加醚,在室溫攪拌17小時,並經矽藻土過濾。將濾液於減壓下蒸發,得到粗化合物4。
在乙腈(7.6ml)中之化合物4(0.7594mmol)之內添加DBU(0.45ml,3.038mmol)、碘異丙烷(0.30ml,3.038mmol),並於45℃攪拌4小時。將反應混合物於減壓下蒸發。在殘餘物中添加水,用乙酸乙酯萃取。將有機層以氯化鈉飽和水溶液洗淨,用硫酸鎂乾燥,於減壓下蒸發。將殘餘物藉由矽膠層析精製(Merck 9385,己烷:乙酸乙酯=2:3),得到727.2mg之目的生成物(從3算起之產率:72.1%)。將如此得到之化合物4(羧酸,259.0mg)藉由分取HPLC進一步精製,得到化合物5(異丙酯,240.3mg,HPLC精製產率92.8%)。
化合物5之1H-NMR光譜(200MHz,CDCl3):δ 5.57-5.14(2H,m),5.01(1H,sept,J=6.2Hz),4.17(1H,bs),3.97(1H,bs),4.00-3.78(4H,m),2.76(1H,d,J=6.2Hz),2.29(2H,t,J=7.5Hz),2.44-2.06(5H,m,),1.88(2H,bt,),1.93-1.18(22H,m),1.23(6H,d,J=6.2Hz),0.89(3H,t,J=6.8Hz)
(5Z)-7-[(1R,2R,3R,5S)-2-(3,3-二甲氧基癸基)-3,5-二羥基環戊基]庚-5-烯酸異丙酯(10)
在化合物1(797.8mg,2.002mmol)於甲醇(2.4ml)中之溶液內,添加觸媒量之硫酸對-甲苯酯、三甲氧基甲烷(2.19ml,20.02mmol)及無水硫酸鎂(1.20g,10.01mmol),於回流下加熱4小時。將反應物冷却,添加碳酸氫鈉,並經矽藻土過濾。將濾液於減壓下蒸發,將殘餘物藉由矽膠層析精製(Merck 7734g,己烷:乙酸乙酯=3:2),得到化合物7(884.3mg,產率98.9%)。
將化合物7(767.5mg,1.719mmol)於甲苯(15.4ml)中之溶液冷卻至-78℃,在其中滴入1.5M DIBAH(甲苯中,4.0ml,6.016mmol),並將混合物攪拌1小時。接著,在反應物中滴入甲醇,將反應物加熱至室溫。在其中添加酒石酸鈉鉀飽和水溶液(150ml),並將混合物激烈攪拌30分鐘。所得到之混合物用乙酸乙酯萃取,將有機層用飽和食鹽水洗淨,以硫酸鎂乾燥,並於減壓下蒸發。將殘餘物藉由矽膠層析精製(Merck 9385,己烷:乙酸乙酯=1:9),得到化合物8(415.8mg,產率70.2%)。
在溴化(4-羧基丁基)三苯基鏻(1.250g,2.819mmol)於THF中之分散液內,於0℃添加THF中之1M三級丁醇鉀(5.64ml,5.64mmol)。將反應物在室溫攪拌1小時,並冷卻至-20℃。在其中,滴入THF(4ml)中之化合物8(242.8mg,0.7048mmol),於-20至0℃攪拌2小時。對反應中添加冰冷水,於減壓下蒸發除去THF。在殘餘物中,於0℃,滴入冰冷的1N鹽酸水溶液,將溶液調整至pH 5。將溶液用乙酸乙酯萃取,將有機層以氯化鈉飽和水溶液洗淨,以硫酸鎂乾燥,於減壓下蒸發。在殘餘物中添加醚,在室溫攪拌17小時,並經矽藻土過濾。將濾液於減壓下蒸發,得到粗化合物9(羧酸)。
在化合物9(0.7048mmol)於乙腈(7ml)中之溶液內,添加DBU(0.42ml,2.819 mmol)、碘異丙烷(0.28 ml,2.819 mmol),並將混合物於45℃攪拌16小時。將反應混合物於減壓下蒸發。在殘餘物中添加水,用乙酸乙酯萃取。將有機層以氯化鈉飽和水溶液洗淨,以硫酸鎂乾燥,於減壓下蒸發。將殘餘物以矽膠管柱精製(Merck 9385,己烷:乙酸乙酯=1:2),得到化合物10(268.0mg,從8算起之產率:80.8%)。
將如上述得到之化合物10(合計370 mg)進一步以分取HPLC精製,得到純化合物10(341.9mg,HPLC精製產率92.4%)。
化合物10之1H-NMR光譜(200MHz,CDCl3):δ 5.54-5.13(2H,m),5.00(1H,sept,J=6.2Hz),4.18(1H,
bs),3.95(1H,bs),3.16(6H,s),2.66(1H,d,J=6.4Hz),2.29(2H,t,J=7.3Hz),2.48-2.06(5H,m),1.89(2H,bt),1.79-1.17(20H,m),1.23(6H,d,J=6.2Hz),0.89(3H,t,J=6.8Hz)
(5Z)-7-[(1R,2R,3R,5S)-3,5-二羥基-2-{2-[2-(2-苯基乙基)-1,3-二氧雜環戊-2-基]乙基}環戊基]庚-5-烯酸異丙酯(12)
以與合成例1同樣之方式從化合物11調製化合物12。
化合物11之1H-NMR光譜(200MHz,CDCl3):δ 8.04-7.93(2H,m),7.63-7.38(3H,m),7.35-7.11(5H,m),5.215.03(2H,m),2.98-2.24(11H,m),2.12-1.98(1H,m),1.80-1.50(2H,m)
化合物12之1H-NMR光譜(200MHz,CDCl3):δ 7.35-7.12(5H,m),5.56-5.35(2H,m),5.00(1H,sept,J=6.2Hz),4.15(1H,bs),3.96(4H,s),3.92(1H,bs),3.18(1H,bd),2.86(1H,bd),2.75-2.63(2H,m),2.28(2H,t,J=7.3Hz),2.46-1.15(17H,m),1.22(6H,d,J=6.2Hz)
(Z)-7-[(1R,2R,3R,5S)-2-(3,3-伸乙二氧基癸基)-3,5-二羥基環戊基]庚-5-烯酸乙酯(15)
在化合物13(9.18 g,19.59 mmol)於甲醇(91.8 ml)中之溶液內,於0℃添加8N氫氧化鈉水溶液(24.49 ml)。將反應混合物於室溫攪拌3小時、於0℃用6N鹽酸調成酸性。將混合物用乙酸乙酯(100 ml+50 ml)萃取。將有機層用氯化鈉飽和水溶液(100 ml x 2)洗淨,用無水硫酸鎂乾燥。將萃取物於減壓下蒸發,得到呈油之粗酸14。
在粗酸14及1,8-二氮雜雙環[5.4.0]十一-7-烯(11.72 ml)於乙腈(60 ml)中之溶液內,於0℃滴入碘乙烷(6.27 ml)。將反應混合物於45℃攪拌17小時,冷卻至室溫,並蒸發。在殘餘物中,添加水(100 ml)。將混合物用乙酸乙酯(100 ml x 2)萃取。將有機層以0.1N鹽酸、碳酸氫鈉飽和水溶液(100 ml)及氯化鈉飽和水溶液(100 ml)洗淨。將萃取物以無水硫酸鎂乾燥並蒸發。將殘餘物用矽膠管柱層析精製2次(Merck 7734,220 g,己烷:乙酸乙酯=2:3,→BW-300,210g,己烷:2-丙醇=6:1),得到呈無色油之乙酯15(8.60 g,18.92 mmol,從13算起之產率:96.6%)。
化合物15之1H-NMR(200MHz,CDCl3中,TMS=0ppm):δ 5.58-5.29(2H,m),4.15(1H,brs),4.13(2H,q,J=7.1Hz),3.97(1H,brs),3.94(4H,s),2.80-2.70(1H,br),
2.49-2.36(1H,m),2.32(2H,t,J=7.4Hz),2.36-2.15(4H,m),1.90-1.83(2H,m),1.83-1.12(20H,m),1.26(3H,t,J=7.1Hz),0.88(3H,t,J=6.5Hz)
將從Balb/C小鼠(體重17±1g)之脾臟所單離之B淋巴球細胞2x106個/mL,在含有任意濃度之化合物A及10mg/mL脂多糖(LPS)之AIM-V培養基(pH7.4)中,於37°C培養24小時後,加入120nM 3H-胸苷,並進一步培養16小時。將細胞用過濾器過濾並收集,藉由使用液體閃爍計數器測定胸苷之細胞攝入量來評價細胞增殖抑制作用,並求出IC50。將結果示於表1及第1圖中。
將從Balb/C小鼠(體重17±1g)之胸腺所單離之T淋巴球細胞5x106個/mL,在含有任意濃度之化合物A及3.3mg/mL之伴刀豆球蛋白A(Con A)之AIM-V培養基(pH7.4)中於37℃培養24小時後,加入120nM 3H-胸苷,並進一步培養16小時。將細胞用過濾器過濾並收集,藉由使用液體閃爍計數器測定胸苷之細胞攝入量來評價細胞增殖抑制作用,並求出IC50。將結果示於表1及第2圖中。
將以在轉錄調控區域具有轉錄因子NFAT-1之DNA結合部位的β-半乳糖苷酶基因(lacZ)所轉形之人類T淋巴球Jurkat細胞2.3 x 106個/mL,在RPMI-1640培養基(pH7.4)
中,與任意濃度之化合物A一起於37℃培養20分鐘後,加入0.5 mM A23187(鈣離子載體/Calcium ionophore)及50 ng/mL PMA(佛波(Phorbol)12-肉豆蔻酸酯13-乙酸酯),並進一步培養4小時。β半乳糖苷酶活性係藉由從FDG(螢光色素二-β-D-半乳哌喃糖苷)變換為螢光色素來測定,螢光發光係使用SpectroFluor Plus培養盤讀數器來測定,並求出IC50。將結果示於表1及第3圖中。
將以在轉錄調控區域具有轉錄因子NF-κB之DNA結合部位的β-半乳糖苷酶基因(lacZ)所轉形之人類T淋巴球Jurkat細胞2.3 x 106個/mL,在RPMI-1640培養基(pH7.4)中,與任意濃度之化合物A一起於37℃培養20分鐘後,加入0.5 mM A23187(鈣離子載體)及50 ng/mL PMA(佛波(Phorbol)12-肉豆蔻酸酯13-乙酸酯),並進一步培養4小時。β半乳糖苷酶活性係藉由從FDG(螢光色素二-β-D-半乳哌喃糖苷)變換為螢光色素來測定,螢光發光係使用SpectroFluor Plus培養盤讀數器來測定,並求出IC50。將結果示於表1及第4圖中。
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(上述文獻皆係以引用方式含於本說明書中)
使用小鼠(NC/NgaTndCrlj,雄性)之苦基氯(PiCl)所誘發之異位性皮膚炎模型,評價對於皮膚發炎之效果以及發生皮膚發炎之皮膚上毛之狀態。
試驗群,使用在表2中所示之群。對於PiCl誘發異位性皮膚炎模型小鼠,將PiCl溶液塗布於刮去毛之腹部及腳
掌以施行敏化,敏化5日後,將PiCl溶液塗布在刮去毛之背部及左右耳(內外兩側),每週1次,共計5週,以重複施行誘發而製作。各群,從PiCl敏化18日後每日投與1次,共計28日。化合物A以及0.1%他克莫司(tacrolimus)軟膏係開放式塗布於模型動物之頸背部約3 cm×約5 cm之區域。在第5群,即潑尼松龍(prednisolone)與0.6w/v%化合物A之併用投與群中,經口投與1 mg/kg之潑尼松龍,接著經皮投與0.6w/v%化合物A。在第6群,即0.1%他克莫司軟膏與0.6w/v%之併用投與群中,投與0.6w/v%化合物A3小時30分鐘之後,投予0.1%他克莫司軟膏。
各評價係採用皮膚炎計分以及毛生長計分。各計分係以下述基準來評點化投與1、8、15、22日及29日(最終投與翌日)時之皮膚炎以及毛長出‧毛生長狀態。
(1)搔癢行動:觀察2分鐘之行動,並觀察搔抓誘發部位之行動。
0:無症狀:未見到對於誘發部位有搔癢行動之狀態。
1:輕度:連續的搔癢行動為2次以上,且累積未超過約1分鐘之行動。
2:中度:累積超過約1分鐘,未超過約1.5分鐘之行動。
3:重度:累積超過約1.5分鐘,或持續搔癢2分鐘之行動。
(2)發紅‧出血:觀察誘發部位之發紅及出血症狀。
0:無症狀:在誘發部位未見到發紅及出血症狀之狀態。
1:輕度:在誘發部位見到局部地出現,或未見到伴隨連續擦傷之出血之狀態。
2:中度:在誘發部位見到分散地出現,或見到伴隨局部地連續擦傷之發紅及出血症狀之狀態。
3:重度:在誘發部位全面地見到,連續的擦傷擴及廣範圍,且見到發紅及出血症狀之狀態。
(3)浮腫:定性地觀察為誘發部位之耳廓之浮腫。
0:無症狀:未見到左右耳廓變厚之狀態。
1:輕度:見到左右耳廓之任一者略微增厚之狀態。
2:中度:見到任一耳廓明顯增厚、繃緊之狀態。
3:重度:見到任一耳廓皆明顯增厚、繃緊及彎曲,用手指觸摸時指感到變硬之狀態。
(4)擦傷‧組織缺損:觀察到誘發部位之擦傷及組織缺損症狀。
0:無症狀:在誘發部位未見到擦傷及組織缺損症狀之狀態。
1:輕度:在誘發部位見到局部地出現,見到非連續的擦傷,未見到組織缺損之狀態。
2:中度:在誘發部位見到分散地出現,見到小規模地出現連續的擦傷,且未見到組織缺損之狀態。
3:重度:在誘發部位見到全面地出現,連續的擦傷擴及廣範圍,見到組織缺損之狀態。
(5)痂皮形成‧乾燥:觀察到誘發部位之痂皮形成及乾燥症狀。
0:無症狀:於誘發部位無痂皮形成及乾燥症狀。
1:輕度:於誘發部位見到局部地出現,誘發部位之皮膚略微白化,見到角質略微剝離之狀態。
2:中度:於誘發部位見到分散地出現,見到明顯的角質剝離之狀態。
3:重度:於誘發部位見到全面地出現,見到明顯的
角質剝離之狀態。
0:於觀察部位未觀察到毛長出、毛生長。
1:毛長出、毛生長處為觀察部位之0至<25%。
2:毛長出、毛生長處為觀察部位之25%至≦75%。
3:毛長出、毛生長為觀察部位之75%至≦100%。
於投與8日藉由皮膚炎計分評價對於異位性皮膚炎之效果。將結果示於表3中。
可知化合物A投與群,相對於化合物A基劑群,展現抑制初期皮膚炎惡化之傾向。又,可知在化合物A與他克莫司軟膏之併用群中,相對於化合物A基劑群,可顯著地抑制初期皮膚炎之惡化。
從以上結果可知:本發明之脂肪酸衍生物具有抑制異位性等皮膚炎惡化之可能性,藉由併用免疫抑制劑,可期待對於異位性皮膚炎發揮進一步之效果。
藉由投與15日、22日及29日時之毛生長分數來評價發生皮膚發炎之皮膚中毛之狀態。將結果示於表4中。
( )內為皮膚炎分數
與第22日之投與顯著不同(藉由維克松氏試驗(Wilcoxon’s test),#:P<0.05,##:P<0.01)
與基值顯著不同(藉由維克松氏試驗(Wilcoxon’s test),$:P<0.05,$$:P<0.01)
從上表可知化合物A基劑群,於投與15日以後,於投與22日及投與29日,皮膚炎計分上升(皮膚炎惡化),同時毛生長計分降低(脫毛正進行)。另一方面,藥劑投與群之任一群,儘管於投與22日及投與29日見到皮膚炎計分上升,但毛生長計分,確認於投與29日與投與22日相較為上升(脫毛改善)。此效果,在化合物A投與群中可確認為用量依存性,在與潑尼松龍或與他克莫司軟膏之併用群中亦可見到。
從以上之結果,可知本發明之脂肪酸衍生物可抑制‧改善伴隨皮膚發炎狀態惡化之脫毛之進行,與類固醇或免疫抑制劑之併用亦有可能。尤其對於皮膚炎本身之治療被首先要求之(異位性)皮膚炎所伴隨之脫毛症,已知本發明之脂肪酸衍生物縱使於皮膚發炎狀態之惡化進行下,仍可抑制‧改善脫毛。
第1圖係化合物A之B細胞增殖抑制試驗之結果。
第2圖係化合物A之T細胞增殖抑制試驗之結果。
第3圖係化合物A之NF-AT基因轉錄抑制試驗之結果。
第4圖係化合物A之NF-κB基因轉錄抑制試驗之結果。
由於本案的圖為實驗數據,並非本案的代表圖。故本案無指定代表圖。
Claims (17)
- 一種免疫抑制用之醫藥組成物,其含有通式(I)所示之脂肪酸衍生物作為有效成分
- 如申請專利範圍第1項所述之醫藥組成物,其中L及M為羥基。
- 如申請專利範圍第1或2項所述之醫藥組成物,其中A為-COOH或其官能性衍生物。
- 如申請專利範圍第1至3項中任一項所述之醫藥組成物,其中B為-CH2-CH2-、-CH=CH-或-C≡C-。
- 如申請專利範圍第1至4項中任一項所述之醫藥組成物,其中Z1及Z2為氧。
- 如申請專利範圍第1至5項中任一項所述之醫藥組成物,其中R2及R3連接在一起形成低級伸烷基。
- 如申請專利範圍第6項所述之醫藥組成物,其中低級伸烷基為碳數3之伸烷基。
- 如申請專利範圍第1至7項中任一項所述之醫藥組成物,其中脂肪酸衍生物為(Z)-7-[(1R,2R,3R,5S)-2-(3,3-伸乙二氧基癸基)-3,5-二羥基環戊基]庚-5-烯酸異丙酯。
- 如申請專利範圍第1至8項中任一項所述之醫藥組成物,其係用於處置發炎性疾病者。
- 如申請專利範圍第9項之醫藥組成物,其係用於處置皮膚之發炎或伴隨其之脫毛症者。
- 如申請專利範圍第10項所述之醫藥組成物,其係用於處置伴隨皮膚發炎之脫毛症者。
- 如申請專利範圍第1至8項中任一項所述之醫藥組成物,其係用於處置過敏性疾病者。
- 如申請專利範圍第12項所述之醫藥組成物,其係用於處置異位性皮膚炎或伴隨其之脫毛症者。
- 如申請專利範圍第13項所述之醫藥組成物,其係用於處置伴隨異位性皮膚炎之脫毛症者。
- 如申請專利範圍第1至8項中任一項所述之醫藥組成物,其係用於處置自體免疫疾病者。
- 一種在哺乳類對象中施行免疫抑制之方法,其包含將有效量之如申請專利範圍第1項之通式(I)所示之脂肪酸衍生物投與至需要之對象。
- 一種如申請專利範圍第1項之通式(I)所示之脂肪酸衍生物之用途,其係在哺乳類對象中用於免疫抑制。
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- 2012-06-20 KR KR1020147000312A patent/KR20140048196A/ko not_active Application Discontinuation
- 2012-06-20 WO PCT/JP2012/065706 patent/WO2012176792A1/ja active Application Filing
- 2012-06-20 CN CN201280040800.5A patent/CN103974705A/zh active Pending
- 2012-06-20 TW TW101122004A patent/TW201309301A/zh unknown
- 2012-06-20 JP JP2013521593A patent/JPWO2012176792A1/ja active Pending
Also Published As
Publication number | Publication date |
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EP2730283A4 (en) | 2015-06-03 |
WO2012176792A1 (ja) | 2012-12-27 |
CN103974705A (zh) | 2014-08-06 |
US20140212441A1 (en) | 2014-07-31 |
JPWO2012176792A1 (ja) | 2015-02-23 |
CA2840875A1 (en) | 2012-12-27 |
EP2730283A1 (en) | 2014-05-14 |
KR20140048196A (ko) | 2014-04-23 |
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