TWI535440B - 包括吲哚化合物之醫藥組成物 - Google Patents
包括吲哚化合物之醫藥組成物 Download PDFInfo
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- TWI535440B TWI535440B TW102147720A TW102147720A TWI535440B TW I535440 B TWI535440 B TW I535440B TW 102147720 A TW102147720 A TW 102147720A TW 102147720 A TW102147720 A TW 102147720A TW I535440 B TWI535440 B TW I535440B
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Description
本發明係有關一種包含吲哚化合物之醫藥組成物,其用於預防或治療與氧化性壓力、粒線體功能障礙、低氧傷害、壞死及/或絕血性再灌流傷害有關之疾病,並有關一種包含吲哚化合物之具有抗氧化效應之美容組成物。
包括人體之生物體係透過呼吸過程得到能量,所吸入的氧氣中約2%轉化成反應性氧物質(ROS),稱為“氧毒素”。該反應性氧物質係指包含游離自由基(指具有未配對電子之原子或分子之一般術語)之氧,通常包括脂質過氧化物、脂質過氧自由基、過氧亞硝酸根,等等。已知此等反應性氧物質不安定,因此極易與周邊物質反應,而對細胞中帶有遺傳訊息之DNA及蛋白質或脂質分子造成氧化性傷害,最後對細胞產生致命性傷害。另一方面,在免疫系統之細胞(如:巨噬細胞或嗜中性白血球)中,所誘發產生之反應性氧物質在殺死自外面入侵之病原菌方面扮演有利的角色。不同於上述例子和最近發現反應性氧物質在細胞內之訊號轉導中扮演重要角色之例子,反應性氧物質通常被認為係會造成細胞傷害之物質,因此對生物體有害。因此,為了保護細胞
免於氧毒素傷害,細胞本身即含有抗氧化劑(例如:維生素C、維生素E、小分子肽如:穀胱甘肽)與抗氧化劑酵素(例如:催化酶、超氧化物岐化酶[SOD]、依賴穀胱甘肽之過氧化酶[GPX],等等)。
與反應性氧物質(ROS)或抗氧化劑酵素有關之疾病或新陳代謝實例如下:
1.胰島素依賴型糖尿病係由ROS之異常表現以致胰臟β-細胞受損所發展出來之疾病。
2.唐氏症候群,係目前之臨床焦點,已知係第21對染色體異常所致。此例中,SOD(一種抗氧化劑酵素)之表現異常。
3.所分析之早衰患者細胞中之抗氧化劑酵素(催化酶、依賴穀胱甘肽之過氧化酶)顯示低度酵素活性。
4.甚至在正常細胞轉變成癌細胞之過程中,當投予數種致癌物質及輻射時,細胞中會積極產生ROS。
5.除了上述以外,已知ROS涉及動脈粥樣硬化、阿茲海默氏症、絕血性疾病,等等。
有些游離自由基、反應性氧物質與過氧化物甚至在正常細胞之代謝過程中產生。然而,細胞本身會使用抗氧化劑酵素(如:SOD、催化酶、過氧化酶,等等)作為防禦機制,併用抗氧化劑(如:維生素E、維生素C、穀胱甘肽、泛素、尿酸,等等)保護自己對抗此等有害物質。然而,當此防禦系統異常或所產生之反應性氧物質因各種不同物理或化學因素而超出防禦系統之能力時,即誘發出氧化壓力。若一個人之疾病與體內氧化壓力與抗氧化性防禦系統之間失去平衡有關時,理論上可藉由添加抗氧化物質來降低氧化性傷害或進一步壓制疾病發展。因此,抗氧化功
能性物質(如:游離自由基清除劑或抑制產生過氧化物之物質)現在已廣泛用於聚合物、食品、美容用品,等等領域中。依據最近發現反應性氧物質涉及與各種不同疾病相關之生理現象,其亦可用為此等氧化物所造成之老化及各種不同疾病之抑制劑或醫療劑。利用該等物質發展醫療劑之興趣已日漸提高,且該等製劑已在美國以健康補充品上市,且持續受到歡迎。
已證實氧化性壓力為誘發各種不同疾病(包括老化)之重要肇因。因此,極重視有能力排除反應性氧物質之抗氧化性功能物質作為防止老化及治療疾病之製劑之可能性。因此需要發展一種可能具有治療由氧化性壓力所引起之老化及各種不同疾病之功能之新穎抗氧化性功能物質。
有許多種抗氧化劑,但大多無法有效傳遞至粒線體,因此展現弱效力或極低效力。這就是傳遞抗氧化劑進入粒線體對治療上述疾病非常重要的原因。以化合物Mito Q為例,可以組合使用共軛輔酶Q10與靶向粒線體之肽作為醫療劑。
另一方面,據報導,此等氧化性壓力為絕血性再灌流傷害之主要機轉。絕血性疾病包括切除、器官移植、栓塞、心肌梗塞、中風,等等。
因此,本發明目的之一在於提供一種包含吲哚化合物之醫藥組成物,其適用於預防或治療與氧化性壓力、粒線體功能障礙、低氧傷害、壞死及/或絕血性再灌流傷害有關之疾病,及包含吲哚化合物之具有抗氧化效應之美容組成物。
本發明提供一種用於預防或治療與氧化性壓力相關疾病之醫藥組成物,其包含醫療有效量之下式(1)、(2)或(3)化合物,其醫藥上可接受之鹽或異構物作為活性成份;及醫藥上可接受之載劑。
上式(1),各取代基明確定義於國際專利申請案公告案號WO 2009/025477中,如下:式(1)中,na表示數字0至3,Aa代表5員雜芳基或雜環,其各具有1至3個選自N、O與S之雜原子,R1a代表R5a-Xa-Ba-X’a-,Ba代表一個直接鍵,或代表3至10員雜環或雜芳基,其各具有1至4個選自N、O與S之雜原子,Xa與X’a獨立代表一個直接鍵,或選自下列各者所組成群中:-NR6a-、-CO-、-CONR6a-、-CO2-、-OC(O)-、-S(O)ma-、-O-(CH2)ma-、-(CH2)ma-O-、-(CH2)ma-、-NR6aCO-、-(R6aO)2P(O)-與-NHCO2-,其中ma表示數字0至3,與R6a代表氫、烷基或環烷基,R5a代表氫、腈、羥基、烷基、烷氧基、環烷基或芳基,或
代表3至10員單環狀或稠合環狀雜環或雜芳基,其各具有1至3個選自N、O與S之雜原子,且可視需要經側氧基或烷基取代,或R5a與R6a可共同形成4至8員環,R2a代表-(CR8aR9a)pa-Ya-R7a,pa表示數字0至2,R8a與R9a獨立代表氫或烷基,或可共同形成4至8員環,Ya代表一個直接鍵,或係選自下列各者所組成群中:-O-、-S-、-NR6a-、-NR6aC(O)-、-CO2-、-C(O)-、-C(O)NR6a-、-S(O)qa-與-S(O)qaNR6a-,其中qa表示數字0至2,R7a代表氫、鹵素、氰基、羥基、硝基、烷基、環烷基或芳基,或代表3至10員雜環或雜芳基,其各具有1至3個選自N、S與O之雜原子,且其可視需要包含側氧基,R3a代表氫、烷基、-(CH2)qa-環烷基或-(CH2)qa-雜環,R4a代表-(CH2)pa-Da-R10a,Da代表一個直接鍵,代表可視需要包含側氧基之環烷基,代表芳基,或代表3至10員雜環或雜芳基,其各具有1至3個選自N、S與O之雜原子,R10a代表氫、鹵素、胺基、氰基、硝基、羥基、烷基、烷基羰基、烷基磺醯基或-(CH2)pa-NR8aR9a,其中烷基、烷氧基、芳基、環烷基、雜環與雜芳基可視需要經取代,且取代基為一個或多個選自下列各者所組成群中之取代基:羥基、鹵素、腈、胺基、烷基胺基、二烷基胺基、烷基、鹵烷基、烷基磺醯基、羧基烷基、烷基羰基氧基、烷硫基、烷基氧
基羰基、烷基胺基羰基、芳基烷氧基與側氧基。
上式(2)中,各取代基明確定義於國際專利申請案公告案號WO 2009/025478中,如下:式(2)中,nb表示數字1至3,mb代表0或1,Ab代表一個直接鍵,代表苯基,或代表具有1至2個氮原子之6員雜芳基,Xb代表C或N,但其限制條件為當Xb為N時,mb為0,及當Xb為C時,mb為1,R1b代表氫、烷基、-(CH2)rbNR7bR8b或-(CH2)rbCO2H,其中rb表示數字1至5,與R7b與R8b獨立代表氫、烷基或烷基羰基,或可共同形成可視需要經烷基取代之伸烷基鏈,其中一個亞甲基可視需要被N原子置換,R2b代表氫、鹵素、氰基、硝基、羥基、烷基、烷氧基或三烷基矽烷基,代表-(CH2)pbCO2R7b、-(CH2)pbOR7b、-(CH2)pbNR7bR8b、-NHR10b、-N(H)S(O)2R7b、-NHC(O)R10b、-(CH2)pbS(O)2R7b或(CH2)pb-雜環-R10b,其中pb表示數字0至3,R7b與R8b如上述定義,R10b代表
氫、側氧基、烷基磺醯基、烷基羰基、烷基氧羰基、烷基胺基羰基、烷氧基、烷基或雜環,R3b代表氫、氰基、鹵素、烷基或苯基,或代表-(CH2)nb-雜環或-(CH2)nb-芳基,其中nb表示數字0至3,R4b代表-YbR11b,其中Yb代表一個直接鍵,或-(CR7bR8b)pbY’b-,其中pb表示數字0至3,R7b與R8b如上述定義,Y’b係選自下列各者所組成群中:-O-、-S-、-NR12b-、-NR12bC(O)-、-C(O)-、-C(O)O-、-C(O)NR12b-、-S(O)qb-與-S(O)qbNR12b-,其中R12b代表氫、烷基、芳基或雜芳基,qb表示數字0至2,R11b係選自下列各者所組成群中:氫、氰基、鹵素、羥基、硫醇基、羧基、烷基與-(CH2)tbBb-R13b,其中tb代表數字0至3,Bb表示雜環、雜芳基或芳基,R13b代表氫、氰基、鹵素、羥基、側氧基、硫醇基、羧基、羧基烷基、烷基羰基氧基、烷基、烷氧基、烷硫基、烷基羰基或烷基磺醯基,R5b代表氫、烷基、環烷基、雜環或雜環基烷基,R6b代表-(CR7bR8b)pb-Zb-Db-Wb-R14b,其中Zb代表一個直接鍵,或係選自下列各者所組成群中:-C(O)-、-C(O)O-、-C(O)NR12b-與-S(O)yb-,yb表示數字1或2,Db代表一個直接鍵,或代表環烷基、雜芳基或雜環,Wb代表一個直接鍵,或代表-NR7b-、-C(O)-、-C(O)O-、-C(O)NR12b-、-S(O)yb-、-S(O)ybNR12b-或-NR12bS(O)yb-,其中R14b代表氫、羥基、烷基、烷氧基、雜環、雜芳基、芳基或芳烷基,R5b與R6b共同代表伸烷基鏈,其中烷基、烷氧基、芳基、環烷基、雜環與雜芳基可視需要經取代,且取代基為一個或多個選自下列各者所組成群中之取代
基:羥基、鹵素、腈、胺基、烷基胺基、二烷基胺基、羧基、烷基、烷氧基、羧基烷基、烷基羰基氧基、烷硫基、烷基氧基羰基、烷基胺基羰基、芳基烷氧基與側氧基。
式(3)中,Bc代表芳基,或代表4至8員雜環或雜芳基,其各具有1至2個選自N、O與S之雜原子,R7c代表氫、鹵素、羥基、腈、硝基或烷氧基,R8c代表C1-C6-烷基、C3-C8-環烷基、雜環基、芳基、芳基烷基、環烷基-烷基或雜環基-烷基,R9c代表氫、鹵素、羥基、腈、硝基、烷氧基、烯丙基氧基、烷基胺基或芳基胺基,其中烷基、烷氧基、芳基、環烷基、雜環與雜芳基可視需要經取代,且取代基為一個或多個選自下列各者所組成群中之取代基:羥基、鹵素、腈、胺基、C1-C6-烷基胺基、二(C1-C6-烷基)胺基、羧基、C1-C6-烷基、鹵素-C1-C6-烷基、C1-C6-烷氧基、芳基-C1-C6-烷氧基與側氧基。
上述式(1)、(2)與(3)化合物之定義中,術語‘烷基’係指脂族烴自由基。烷基可為不包括烯基或炔基部份(moiety)之飽和烷基,或包括至少一個烯基或炔基部份之不飽和烷基。“烯基”係指包含至少一個碳-碳雙鍵之基團,及“炔基”係指包含至少一
個碳-碳參鍵之基團。當烷基單獨使用或呈組合使用,如:烷氧基,其可為分支或直鏈。
烷基可具有1至20個碳原子,除非另有其他定義。烷基可為具有1至10個碳原子之中等鏈長烷基。否則烷基可為具有1至6個碳原子之低碳數烷基。其典型實例包括(但不限於):甲基、乙基、丙基、異丙基、正丁基、異丁基、第三丁基、戊基、己基、乙烯基、丙烯基、丁烯基,等等。例如:C1-C4-烷基在烷基鏈中具有1至4個碳原子,且係選自下列各者所組成群中:甲基、乙基、丙基、異丙基、正丁基、異-丁基、第二丁基與第三丁基。
術語‘烷氧基’係指具有1至10個碳原子之烷基氧基,除非另有其他定義。
術語‘環烷基’係指飽和脂族3至10員環,除非另有其他定義。其典型實例包括(但不限於):環丙基、環丁基、環戊基、環己基,等等。
術語‘芳基’包括至少一個具有共價π電子系統之環,例如:單環狀或稠合多環狀(亦即,共用相鄰碳原子對之環)基團。本說明書中,芳基係指芳香族4至10員(較佳為6至10員)單環狀或多環狀環,包括苯基、萘基,等等,除非另有其他定義。
術語‘雜芳基’係指具有1至4個選自N、O與S之雜原子且可與苯環或C3-C8環烷基稠合之芳香族3至10員(較佳為4至8員,更佳為5至6員)環,除非另有其他定義。單環狀雜芳基包括(但不限於):噻唑、唑、噻吩、呋喃、吡咯、咪唑、異唑、異噻唑、吡唑、三唑、三、噻二唑、四唑、二唑、吡啶、嗒、嘧啶、吡,等等。雙環狀雜芳基包括(但不限於):
吲哚、吲哚啉、苯并噻吩、苯并呋喃、苯并咪唑、苯并唑、苯并異唑、苯并噻唑、苯并噻二唑、苯并三唑、喹啉、異喹啉、嘌呤、嘌呤并吡啶,等等。
術語‘雜環’係指3至10員,較佳為4至8員,更佳為5至6員環,其可具有1至4個選自N、O與S之雜原子,可與苯環或C3-C8環烷基稠合,且係飽和或包含1或2個雙鍵,除非另有其他定義。雜環包括(但不限於):吡咯啉、吡咯啶、咪唑啉、咪唑啶、吡唑啉、吡唑啶、哌喃、哌啶、嗎啉、硫嗎啉、哌、氫呋喃,等等。
咸了解,本說明書中其他術語與縮寫具有熟知此相關技藝之人士常用之定義,除非另有其他定義。
式(1)或(2)化合物之較佳實例如下列:
化合物1:[(S)-2-(7-環戊基胺基-5-甲基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物2:{(S)-2-[5-甲基-7-(四氫哌喃-4-基胺基)-1H-吲哚-2-基]-4,5-二氫-噻唑-4-基}-乙酸
化合物3:[(S)-2-(7-環戊基胺基-5-甲基-1H-吲哚-2-基)-4,5-二氫-唑-4-基]-乙酸
化合物4:[(S)-2-(7-環戊基胺基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物5:[(S)-2-(7-環戊基胺基-5-苯氧基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物6:4-{2-[(S)-2-(7-環戊基胺基-5-苯氧基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙基}-哌-2-酮
化合物7:環戊基-(2-{(S)-4-[2-(3-甲基-5,6-二氫-8H-[1,2,4]三唑并[4,3-a]吡-7-基)-乙基]-4,5-二氫-噻唑-4-基}-5-苯氧基-1H-吲哚-7-基)-胺
化合物8:((S)-2-{7-[(四氫哌喃-4-基甲基)-胺基]-1H-吲哚-2-基}-4,5-二氫-噻唑-4-基)-乙酸
化合物9:(四氫哌喃-4-基)-[2-苯基-5-(1,1-二側氧基-硫嗎啉-4-基)甲基-1H-吲哚-7-基]-胺
化合物10:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-(四氫哌喃-4-基)甲基-胺
化合物11:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-雙-[(四氫哌喃-4-基)甲基]-胺
化合物12:{4-[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基胺基]-哌啶-1-基}-(四氫哌喃-3-基)甲酮
化合物13:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-(1-甲基磺醯基-哌啶-4-基)-胺
化合物14:((S)-2-{5-甲基-7-[(四氫哌喃-4-基甲基)-胺基]-1H-吲哚-2-基}-4,5-二氫-噻唑-4-基)-乙酸
上式(3)化合物中較佳化合物為彼等其中Bc代表芳基,或代表5至6員雜環或雜芳基,其各具有1至2個選自N、O與S之雜原子,R7c代表氫、鹵素、腈或烷氧基,R8c代表C1-C6-烷基、C3-C8-環烷基、雜環基、芳基烷基、環烷基-烷基或雜環基-烷基,R9c代表氫、鹵素、腈、烷氧基、烯丙基氧基、烷基
胺基或芳基胺基。
更佳為式(3)中,Bc代表苯基或吡啶。
更佳為式(3)中,R7c代表氫、鹵素或烷氧基,最佳為氫。
更佳為式(3)中,R8c代表C1-C6-烷基、雜環基、環烷基-烷基、雜環基-烷基或芳基烷基,及最佳為環戊基或四氫哌喃。
更佳為式(3)中,R9c代表氫、鹵素或烷氧基,及最佳為氫。
代表性式(3)化合物包括下列:環戊基-(2-苯基-3H-苯并咪唑-4-基)-胺
(2-苯基-3H-苯并咪唑-4-基)-(四氫-哌喃-4-基)-胺
環戊基-(2-吡啶-2-基-3H-苯并咪唑-4-基)-胺
本發明醫藥組成物可有效用於預防與治療由氧化性壓力引起之疾病。
本發明醫藥組成物可有效用於預防與治療由反應性氧物質(ROS)或反應性氮物質(RNS)所媒介之氧化性壓力引起之疾病。
本發明醫藥組成物可壓制絕血性再灌流傷害。
本發明醫藥組成物可有效用於預防與治療由低氧傷害引起之疾病。
本發明醫藥組成物可有效用於預防與治療由壞死細胞死亡引起之疾病。
本發明醫藥組成物可壓制粒線體功能障礙。
本發明醫藥組成物可有效用於預防與治療由粒線體
功能障礙引起之MELAS(粒線體肌病、腦病變、乳酸中毒與似中風發作症)、MERRF症候群(出現如破布般紅色肌肉纖維之肌陣攣性癲癇發作)或Kearns-Sayre症候群,其均由粒線體功能障礙所引起。
本發明醫藥組成物可壓制分泌HMGB1(高遷移率族蛋白1)之細胞壞死。
此外,本發明醫藥組成物可預防及/或治療由HMGB1媒介之疾病,特定言之,由發炎所媒介或相關之疾病。此等疾病包括敗血病、風濕性關節炎、骨關節炎、肝硬化、出血性疾病、各種不同壞死性疾病、病毒或細菌感染,等等。
本發明可預防及/或治療之疾病包括肝臟疾病、心臟病、血管疾病、退化性腦疾病、由絕血性再灌流傷害引起之疾病及由病毒或細菌引起之傳染性疾病;肝臟移植、肝臟切除、肝臟栓塞、肝臟纖維化、肝臟硬化、酒精性/非酒精性脂肪肝與由病毒或藥物(例如:抗癌劑、乙醯胺酚(acetaminophen),等等)引起之肝炎;心臟或心血管疾病,如:心律不整、心臟麻痺、心肌梗塞,等等;退化性腦部疾病,如:葛雷克氏症(Lou Gehrig’s disease)、中風、癡呆、帕金森氏症、亨丁頓氏症,等等;各由絕血性再灌流傷害引起之糖尿病併發症、動脈粥樣硬化、心肌梗塞或中風;由病毒(如:流感病毒、HBV、HCV、HIV,等等)或細菌感染引起之疾病。
本發明中,肝臟疾病可為一種或多種選自下列各者所組成群者:肝臟移植、肝臟切除、肝臟栓塞、肝臟纖維化、肝臟硬化、酒精性/非酒精性脂肪肝、及由病毒或藥物(例如:抗癌
劑、乙醯胺酚,等等)引起之肝炎。
本發明,心臟或心血管疾病可為選自下列各者所組成群中之一種或多種疾病:心律不整、心臟麻痺、心肌梗塞、心臟衰竭與心絞痛。
本發明醫藥組成物可有效用於預防與治療分別由絕血性再灌流傷害引起之肝臟疾病、心臟或心血管疾病,其中絕血性再灌流傷害可肇因於粒線體功能障礙、低氧傷害及/或壞死性細胞死亡。
本發明醫藥組成物可有效用於預防與治療分別由絕血性再灌流傷害引起之選自下列各者所組成群中一種或多種疾病:糖尿病併發症、動脈粥樣硬化與中風。
合成本發明式(1)或(2)化合物之具體實施例分別揭示於WO 2009/025477與WO 2009/025478。
本發明亦提供一種式(3)化合物與其製備方法。下文中,將依據例舉之反應圖說明製備式(3)化合物之方法,以協助了解本發明。然而,應了解,熟知此相關技藝之人士可依據式(3)結構,利用各種不同方法製備式(3)化合物,且所有此等方法均落入本發明之範疇內。換言之,咸了解,可透過本文所說明或先前技藝曾揭示之各種不同合成法之任何組合來製備式(3)化合物,且所有此等組合均在本發明之範疇內。製備式(3)化合物之方法不限於下文說明者。
首先,式(3)化合物可依據下列反應圖1所示之方法合成,由式(4)化合物之硝基還原,產生式(5)胺化合物,並於所形成之胺基上,與式(6)化合物進行還原性胺化反應(RA)。
其中Bc、R7c、R8c與R9c如式(3)之定義;R10c代表烷基、環烷基、雜環基、雜芳基或芳基;R11c代表氫或烷基;或R10c與R11c可環化形成環烷基或雜環。
式(5)化合物可由式(4)化合物還原製得。還原反應可使用酸觸媒與金屬或使用金屬觸媒,於氫氣之存在下進行。
可用於涉及使用酸觸媒及金屬之還原反應之酸實例包括無機酸,如:鹽酸、硫酸、硝酸與磷酸;有機碳酸,如:乙酸與三氟乙酸;及胺酸之鹽,如:氯化銨。較佳酸類為鹽酸、乙酸、氯化銨,等等。酸之用量通常為1當量式(4)化合物使用0.01至10當量,較佳為0.1至5當量。可使用之金屬實例包括鐵、鋅、鋰、鈉與錫(通常為氯化錫)。較佳金屬為鐵、鋅、氯化錫,等等。金屬之用量通常為1當量式(4)化合物使用1至20當量,較佳為1至10當量。於酸觸媒存在下進行之金屬反應可在惰性溶劑中進行。惰性溶劑實例包括烷基醇,如:甲醇與乙醇;醚類,如:四氫呋喃與二乙醚;及烷基酯,如:乙酸乙酯。較佳溶劑為甲醇、乙醇、四氫呋喃與乙酸乙酯,等等。反應溫度通常在-10至200℃之間,較佳為25至120℃。反應時間通常在10分鐘至60小時,
較佳為10分鐘至12小時。
可用於涉及在氫氣存在下使用金屬觸媒之還原反應之金屬觸媒實例包括鈀、鎳、鉑、釕、銠,等等。較佳金屬觸媒為鈀、鎳,等等。金屬觸媒之用量通常為1當量式(2)化合物使用0.001至2當量,較佳為0.01至1當量。氫氣壓力通常為1至10atm,較佳為1至3atm。該反應可在惰性溶劑中進行,例如:烷基醇,如:甲醇與乙醇;醚類,如:四氫呋喃與二乙醚;及乙酸烷基酯,如:乙酸甲酯與乙酸乙酯。較佳溶劑為甲醇、乙醇、乙酸乙酯,等等。在涉及使用金屬觸媒之還原反應中,反應溫度通常為-10至200℃之間,較佳為25至50℃。反應時間通常為10分鐘至60小時,較佳為10分鐘至12小時。
式(6)化合物係自商品取得,且可經由式(5)化合物之胺基進行還原性胺化反應製得。
進行還原性胺化反應時,可由醛或酮與還原劑與若需要時使用之酸觸媒反應。醛或酮之用量通常為1當量式(5)化合物使用1至10當量,較佳為1至3當量。可使用之還原劑實例包括氫硼化鈉、氰基氫硼化鈉(NaBH3CN)與三乙醯氧基氫硼化鈉{NaBH(OAc)3}。還原劑之用量通常為1當量式(5)化合物使用1至10當量,較佳為1至3當量。可使用之酸觸媒實例包括無機酸,如:鹽酸、硫酸、硝酸與磷酸;有機碳酸,如:乙酸與三氟乙酸;及胺酸之鹽,如:氯化銨。較佳酸類為鹽酸、乙酸,等等。酸之用量通常為1當量式(5)化合物使用0.1至10當量,較佳為1至5當量。該反應可在惰性溶劑中進行,例如,如:四氫呋喃與二乙醚;及氯烷,如:二氯甲烷、氯仿與二氯乙烷,較佳為二氯乙烷、
氯仿,等等。反應溫度通常為-10至100℃,較佳為-10至50℃。反應時間通常為10分鐘至60小時,較佳為10分鐘至12小時。
式(4)化合物可由式(7)醛化合物與式(8)化合物進行連結反應(linking reaction)及環化反應製得,如下列反應圖2所示。
其中Bc、R7c與R9c如式(3)之定義。
首先,由自商品取得之醛(如:式(7)化合物)與自商品取得之二胺化合物(如:式(8)化合物)攪拌加熱,形成環化。然後在酸觸媒之存在下加熱,產生式(4)化合物。可使用之酸觸媒實例包括無機酸,如:鹽酸、硫酸、硝酸與磷酸;有機碳酸,如:乙酸與三氟乙酸;及胺酸之鹽,如:氯化銨。較佳酸觸媒為鹽酸、乙酸,等等。酸之用量通常為1當量式(5)化合物使用0.1至10當量,較佳為1至5當量。依各例而定,該反應可在作為溶劑之有機酸(如:乙酸)中進行。
本說明書中,“醫藥上可接受之鹽”包括含有醫藥上可接受之陰離子之無毒性酸加成鹽,例如:與無機酸(如:硫酸、鹽酸、硝酸、磷酸、氫溴酸、氫碘酸,等等)形成之鹽;與有機羧酸(如:酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富馬酸、馬來酸、水楊酸,等等)形成之鹽;或與磺酸類(如:甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、萘磺酸,
等等)形成之鹽。式(I)化合物亦可形成醫藥上可接受之鹼加成鹽,例如:與鹼金屬或鹼土金屬(如:鋰、鈉、鉀、鈣、鎂,等等)形成之鹽;及與胺基酸(如:離胺酸、精胺酸、胍,等等)形成之鹽;或與二環己基胺、N-甲基-D-葡糖胺、參(羥基甲基)甲基胺、二乙醇胺、膽鹼、三乙基胺,等等)形成之有機鹽。本發明式(1)、(2)與(3)化合物可根據任何習知方法轉化成其鹽類,該鹽形成法很容易由熟知此相關技藝之人士依據結構式(1)、(2)與(3)進行,不需另外解釋。
本說明書之術語“異構物”意指彼等具有與式(I)化合物或其鹽類相同之化學式或分子式,但光學上或立體上不同之化合物。本發明式(1)、(2)與(3)化合物之結構式可能具有不對稱碳中心,因此可能呈光學異構物(R或S異構物)、消旋物、非對映異構性混合物或個別之非對映異構物,等等。當化合物具有雙鍵,其可能呈幾何異構物(反式或順式異構物)形式。本發明亦涵蓋所有異構物與其混合物。
下文中,式(1)、(2)與(3)化合物包括其醫藥上可接受之鹽類與異構物,除非本文中另有說明。應解釋為本發明涵蓋其鹽與異構物。為了方便,本說明書簡稱該等鹽類與異構物為式(1)化合物。
上述“醫藥組成物”可包含醫藥上可接受之載劑、稀釋劑、賦形劑或其組合,若需要時,與本發明化合物共同使用。醫藥組成物有利於投予化合物至活生物體。有許多種技術用於投予化合物,其包括(但不限於):經口、注射、氣霧劑、非經腸式與局部投藥。
本文所採用“載劑”係指促進化合物進入細胞或組織之物質。例如:二甲亞碸(DMSO)為典型載劑,其用於促進各種不同有機化合物進入活生物體之細胞或組織。
本文所採用“稀釋劑”之定義為可於水中稀釋而溶解化合物並安定目標化合物之生物活性型之物質。溶於緩衝溶液中之鹽即可作為相關技藝之稀釋劑。典型使用之緩衝溶液為模擬人體溶液之鹽型之磷酸鹽緩衝生理食鹽水。緩衝稀釋劑幾乎不會改變化合物之生物活性,因為緩衝鹽類可在低濃度下控制溶液之pH。
本文所採用“醫藥上可接受”係指不會破壞化合物之生物活性與物理性質之性質。
本發明化合物可根據所需目的調配成各種不同醫藥劑型。製備本發明醫藥組成物時,由本發明活性成份(明確言之,式(1)、(2)或(3)化合物)、其醫藥上可接受之鹽類或異構物與依據欲製備之調配物而選用之各種不同醫藥上可接受之載劑混合。例如:本發明醫藥組成物可依據所需目的調配成注射製劑、口服製劑,等等。
本發明化合物可依相關技藝已知方法,利用相關技藝已知之醫藥載劑與賦形劑調配,並填入單位劑量型式或多劑量型式之容器中。製劑型式可為含於油性或水性媒劑中之溶液、懸浮液或乳液,且包含典型之勻散劑、懸浮劑或安定劑。此外,例如:其可呈乾粉型式,意圖用於在臨用前先溶解在無菌無熱源水中而重現。本發明化合物亦可利用典型栓劑基質(如:可可奶油或其他甘油酯)調配成栓劑型。口服用固體劑型可製成膠囊、錠劑、
丸劑、粉劑與粒劑,以膠囊與錠劑特別適用。較佳為錠劑與丸劑係製成腸溶性包衣型。固體劑型製法為混合本發明化合物與載劑如:一種或多種惰性稀釋劑,如:蔗糖、乳糖、澱粉,等等,潤滑劑,如:硬脂酸鎂、崩解劑、結合劑,等等。
本發明亦提供一種具有抗氧化效應之美容組成物,其包含上述式(1)、(2)或(3)化合物、其醫藥上可接受之鹽或異構物作為活性成份;及可接受之載劑。
本發明醫藥組成物具有優越之抗氧化劑活性,因此可有效用於預防或治療各種與氧化性壓力有關之疾病。
此外,本發明醫藥組成物可壓制心肌細胞之粒線體功能障礙、低氧傷害、壞死與絕血性再灌流傷害,而有效用於預防或治療心臟或心血管疾病。此外,其可在再灌流治療(如:手術療法,包括冠狀動脈繞道移植或經皮冠狀動脈血管成型術及使用溶血栓劑之藥物療法,等等)中用作心臟保護劑。
第1圖為利用DHR123探針顯示(四氫哌喃-4-基)-[2-苯基-5-(1,1-二側氧基-硫嗎啉-4-基)甲基-1H-吲哚-7-基]-胺(化合物9)在細胞中之抗氧化效應之照片。
第2圖為利用MitoSOX紅色探針在細胞中顯示化合物9之抗氧化效應之照片。
第3圖為比較化合物9處理組與未處理組之左邊肝臟葉片之照片。
第4圖為表示化合物9處理與未處理時在絕血性再灌流傷害後之ALT(麩胺酸丙酮酸轉胺脢;左)與AST(麩胺酸單醯酸轉胺脢;右)數值之圖形。
第5圖為顯示投予13mg/kg化合物9之群組與未投予化合物9之群組之間組織染色之照片(IR:絕血性再灌流傷害)。
第6圖為顯示依據顯微鏡觀察之化合物9處理組與未非處理組之間比較結果之圖形(肝細胞退化(左)、血管竇充血(中)與發炎細胞浸潤(右),(*P<0.05 vs.Normal;**P<0.05 vs.IR))。
第7圖為顯示投予13mg/kg化合物9之群組與絕血性再灌流傷害對照組之間MGB1濃度之比較之圖形。
第8圖為顯示化合物9處理組與未處理組之間在絕血性再灌流傷害後之粒線體複合物I活性之比較之圖形。
第9圖為表示化合物9處理後之HMGB1隨時間釋放之圖形。
第10圖為表示化合物9處理後由化合物9所造成ATP含量變化之圖形。
第11圖為經過FDA(螢光素二乙酸鹽-綠色,活細胞)與PI(碘化丙啶-紅色,壞死細胞)雙重染色之H9C2細胞之螢光顯微鏡照片,以顯示化合物9對抗壞死性細胞死亡之保護效應。
第12圖為表示直接細胞計數以顯示化合物9對抗壞死性細胞死亡之保護效應之圖形。
第13圖為表示FACS分析結果以顯示化合物9對抗壞死性細胞死亡之保護效應之圖形。
第14圖為顯示化合物9對粒線體膨脹之抑制效應之圖形。
第15圖為顯示化合物9之粒線體保護效應之螢光顯微鏡照
片。
第16圖為顯示化合物9在絕血性再灌流傷害模式中對左心室膨脹之抑制效應之圖形。
第17圖為顯示化合物9在絕血性再灌流傷害後對左心室短縮分率之抑制效應之圖形(比較IR傷害前及第14天之間短縮分率之減少%)。
第18圖為顯示心臟纖維化利用MT(梅森三色(Masson-Trichrome))染色法以比較化合物9與環孢素A之影像。
第19圖為顯示實驗例2中肝臟手術過程之照片。
下文中,將參考下列實施例更詳細說明本發明,但不應以任何方式構成本發明之限制範疇。
步驟A:4-硝基-2-苯基-2,3-二氫-1H-苯并咪唑
在含3-硝基-苯-1,2-二胺1.0g(6.5mmol)之甲醇(10mL)溶液中添加苯甲醛0.69g(6.7mmol),於80℃下攪拌2天。反應完成後,真空排除溶劑,殘質經管柱層析法純化,產生標題化合物1.1g(產率:70%)。
1H-NMR(500HMz,DMSO);δ 8.68(s,1H),7.43至7.31(m,5H),7.18(s,1H),6.95(d,1H),6.44(s,1H),6.36(t,1H),6.29(d,1H)
步驟B:7-硝基-2-苯基-1H-苯并咪唑
取步驟A所得4-硝基-2-苯基-2,3-二氫-1H-苯并咪唑1.1g(4.6mmol)溶於乙酸(10mL),於80℃下攪拌3小時。反應完成後,加水,以乙酸乙酯萃取,以1N氫氧化鈉洗滌。經無水硫酸鎂脫
水後,將濾液真空蒸餾,殘質經管柱層析法純化,產生標題化合物0.91g(產率:83%)。
1H-NMR(400HMz,DMSO);δ 13.3(br s,1H),8.37(d,2),8.15(d,2H),7.65至7.56(m,3H),7.46(t,1H)
步驟C:2-苯基-3H-苯并咪唑-4-基胺
取步驟B所得7-硝基-2-苯基-1H-苯并咪唑0.137g(0.57mmol)溶於四氫呋喃(5mL)、甲醇(5mL)與水(5mL)。在溶液中添加鐵粉0.40g(7.2mmol)與氯化銨0.39g(7.2mmol),於60℃下攪拌1小時。反應完成後,添加水,以乙酸乙酯萃取。經無水硫酸鎂脫水後,將濾液真空蒸餾,殘質經管柱層析法純化,產生標題化合物0.12g(產率:79%)。
1H-NMR(500HMz,DMSO);δ 12.5(s,1H),8.10(d,2H),7.55至7.45(m,3H),6.87(t,1H),6.67(d,1H),6.32(d,1H),5.21(s,2H)
步驟D:環戊基-(2-苯基-3H-苯并咪唑-4-基)-胺
取步驟C所得2-苯基-3H-苯并咪唑-4-基胺0.040g(0.19mmol)溶於二氯乙烷(5mL)。在溶液中添加乙酸0.012mg(0.19mmol)、環戊酮0.048g(0.57mmol)與三乙醯氧基-氫硼化鈉0.049mg(0.23mmol),於室溫下攪拌18小時。反應完成後,加水,以二氯甲烷萃取,以飽和氯化鈉溶液洗滌。經無水硫酸鎂脫水後,將濾液真空蒸餾,殘質經管柱層析法純化,產生標題化合物0.026mg(產率:49%)。
1H-NMR(40HMz,CDCl3);δ 9.36(br s,1H),8.02(m,2H),7.56至7.45(m,3H),7.17(t,1H),6.83(d,1H),6.47(d,1H)5.06(br s,1H),4.02(m,1H),2.13(m,2H),1.82(m,2H),1.69(m,4H)
使用實施例1步驟C所得之2-苯基-3H-苯并咪唑-4-基胺0.040g(0.19mmol)與四氫呋喃-4-甲醛0.026g(0.23mmol),依據實施例1步驟D說明之相同方法製備標題化合物0.030mg(產率:51%)。
1H-NMR(40HMz,CDCl3);δ 8.02(m,2H),7.56至7.45(m,3H),7.17(t,1H),6.85(d,1H),6.44(d,1H)4.05(dd,1H),3.45(td,2H),3.27(d,2H),2.02(m,1H),1.85(m,2H),1.45(m,2H)
使用2-羧基醛、3-硝基-苯-1,2-二胺與環戊酮,依據實施例1說明之相同方法製備標題化合物。
1H-NMR(40HMz,CDCl3);δ 1.64(m,6H),2.10(m,2H),4.14(s,1H),6.38至6.34(d,1H),6.69至6.71(d,1H),7.09至7.13(t,1H),7.25至7.26(m,1H),7.75至7.79(m,1H),8.40至8.41(d,1H),8.54至8.55(m,1H).
本發明之效果將由下文實驗例具體說明。實驗例所採用之化合物如下。
化合物1:[(S)-2-(7-環戊基胺基-5-甲基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物2:{(S)-2-[5-甲基-7-(四氫哌喃-4-基胺基)-1H-吲哚-2-基]-4,5-二氫-噻唑-4-基}-乙酸
化合物3:[(S)-2-(7-環戊基胺基-5-甲基-1H-吲哚-2-基)-4,5-二氫-唑-4-基]-乙酸
化合物4:[(S)-2-(7-環戊基胺基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物5:[(S)-2-(7-環戊基胺基-5-苯氧基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙酸
化合物6:4-{2-[(S)-2-(7-環戊基胺基-5-苯氧基-1H-吲哚-2-基)-4,5-二氫-噻唑-4-基]-乙基}-哌-2-酮
化合物7:環戊基-(2-{(S)-4-[2-(3-甲基-5,6-二氫-8H-[1,2,4]三唑并[4,3-a]吡-7-基)-乙基]-4,5-二氫-噻唑-4-基}-5-苯氧基-1H-吲哚-7-基)-胺
化合物8:((S)-2-{7-[(四氫哌喃-4-基甲基)-胺基]-1H-吲哚-2-基}-4,5-二氫-噻唑-4-基)-乙酸
化合物9:(四氫哌喃-4-基)-[2-苯基-5-(1,1-二側氧基-硫嗎啉-4-基)甲基-1H-吲哚-7-基]-胺
化合物10:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-(四氫哌喃-4-基)甲基-胺
化合物11:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-雙-[(四氫哌喃-4-基)甲基]-胺
化合物12:{4-[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基胺基]-哌啶-1-基}-(四氫哌喃-3-基)甲酮
化合物13:[5-(1,1-二側氧基-硫嗎啉-4-基)甲基-2-苯基-1H-吲哚-7-基]-(1-甲基磺醯基-哌啶-4-基)-胺
化合物14:((S)-2-{5-甲基-7-[(四氫哌喃-4-基甲基)-胺基]-1H-吲哚-2-基}-4,5-二氫-噻唑-4-基)-乙酸
實施例1:環戊基-(2-苯基-3H-苯并咪唑-4-基)-胺
實施例2:(2-苯基-3H-苯并咪唑-4-基)-(四氫-哌喃-4-基)-胺
進行下列實驗,測定各化合物之抗氧化效應:測定總抗氧化效應之DPPH方法、利用二氫若丹明123測定抗氧化效應之方法、利用tBOOH對細胞造成氧化壓力來測定壞死抑制作用之方法、測定清除ONOO-(過氧亞硝酸根)能力之方法與測定對H2O2(過氧化氫)與tBOOH之抗氧化效應之直接方法。
DPPH(1,1-二苯基-2-苦基肼基)為安定之自由基且呈紫色。測定化合物之抗氧化效應係利用化合物還原DPPH時,DPPH會轉呈黃色之原理。DPPH在517nm顯示強烈吸光度,且當DPPH還原時,顏色會轉呈黃色,517nm之吸光度即下降。本文中,術語“IC50”係指使517nm之吸光度下降至原數值之50%時之化合物濃度。
取180μl DPPH溶液(200μM DMSO溶液)分配至96孔板之各孔中,在其中添加20μl自2,000μM連續稀釋2倍之化合物。然後將其混合均勻,於室溫下維持30分鐘。30分鐘後,採用spectraMAX ELISA讀數器測定517nm之O.D.值。結果示於下表1。
二氫若丹明123本身無螢光,但當被ROS(反應性氧物質)或RNS(反應性氮物質)氧化時,即轉化成為螢光若丹明123。利用此等性質,於細胞中或於活體外測定化合物之抗氧化效應。取H9C2細胞分配至96孔板(1.5×104個細胞/100μl/孔)之各孔中。次日,以自最高濃度連續稀釋3倍之各化合物前處理細胞1小時,然後以10μl DHR123 12.5μM母液(終濃度:1.25μM),於37℃培養箱中處理30分鐘。然後立即以400μM tBOOH處理細胞,培養2小時。然後採用spectraMAX Gemini微板讀數器,在480nm激發光及538nm發射光下測定螢光。本文中,術語“IC25”係指tBOOH處理後2小時之螢光定為100%時,值受到25%抑制之化合物濃度,該螢光因氧化壓力提高而造成DHR123氧化所發
射。其結果示於表2。此外,為了檢視化合物是否對細胞真正具有抗氧化效應,經過上述分析法後,以4%甲醛固定96孔板中之細胞,以PBS洗滌3次。然後添加100μl PBS至96孔板之各孔中,採用免疫螢光顯微鏡(螢光顯微鏡:Olympus)測定各細胞中之螢光(由於細胞中之DHR123,所發射螢光與氧化作用呈比例)。其結果示於第1圖。此外,採用MitoSOX紅色探針(終濃度:5μM),依相同方法測定之超氧化物產生之抑制。
已知第三-丁基過氧化氫(tBOOH)會在各種不同細胞中造成氧化壓力,而誘發細胞壞死。因此,以tBOOH處理H9C2細胞,測定抗氧化效應對細胞壞死之抑制。取H9C2細胞分配至96孔板之各孔中(1.5×104個細胞/100μl/孔)。次日,以各化合物前處理細胞,然後以tBOOH(終濃度:400μM)處理2小時。在各孔中添加50μl甲醛,固定細胞。固定細胞30分鐘,以蒸餾水洗滌3次。然後在50℃烘箱中完全乾燥板,在其中添加SRB溶液,使殘餘蛋白質染色。以1%乙酸洗滌板及乾燥。然後添加100μl Tris溶液(10mM)至板以再度溶解染料,採用spectraMAX ELISA讀數器,測定590nm與650nm之O.D.而計算IC50。本文中,術語“IC50”係指可以保護50%細胞免於因tBOOH處理所誘發之壞死時之化合
物濃度。其結果示於下表3。
已知ONOO-(過氧亞硝酸根)為一種RNS,在氧化壓力中扮演極重要角色。因此評估壞死抑制劑清除ONOO-之能力非常重要。周知DHR123探針會被ONOO-氧化。因此,利用此等性質測定各化合物之能力。
化合物各取10μl(其已自50μM連續稀釋3倍)加至96孔板之各孔中,然後添加170μl分析混合物(10μM DHR123,1×PBS,100μM不含ONOO-之DPTA)至各孔中。最後,添加20μl ONOO-溶液(終濃度:1μM)以起始反應。本文中,術語“IC50”係指使ONOO-對DHR123之氧化作用受到50%抑制時之化合物濃度。
化合物之ONOO-清除能力之結構-活性關係(SAR)結果示於表4。
為了得知具有吲哚結構式之壞死抑制劑之抗氧化效應,評估對特異性ROS、H2O2(過氧化氫)與tBOOHh之直接抗氧化效應。
添加10μl DHR123探針(終濃度:1.25μM)至10μl各化合物(其已經過100μl DMEM完全培養基稀釋)。依下表5所示之濃度添加H2O2與tBOOH,2小時後,採用spectraMax Gemini,在波長(480nm(ex)/538nm(em))下測定螢光。本文中,術語“IC25”係指當以H2O2或tBOOH所造成之DHR123氧化程度定為100%時,化合物使螢光發射量下降25%時之濃度。
試驗設計:選出27隻健康小獵犬(體重:8.5至11.5kg)進行試驗。本試驗係經過艾山醫院倫理委員會(Asan Hospital Ethics Commission)同意進行。為了將肝中之肝醣累積降至最低,手術前,讓小獵犬禁食24小時,並剃毛。將小獵犬隨機分成對照組(n=9)、B組(n=6)、C組(n=6)與D組(n=6)。進行氣管內插管,使用舒太(zoletil)與2.5%安氟醚(enflurane)麻醉小獵犬。依據委員會之核准程序,分別使用西華樂林(Cefazolin)與克妥洛(ketorolac)作為抗生素與止痛劑。
手術過程:讓小獵犬躺在手術台上,任一側置有保溫毯與溫水瓶。利用一個開口,將21號IV導管插入左邊外頸靜脈與右邊大隱靜脈。切開右邊內頸動脈並插管,以便在手術期間監測血液動力學。完成靜脈內注射準備後,吸入2.5%安氟醚(enflurane)維持麻醉。依15mL/kg/hr之輸液速率投予晶質溶液。
分別經由IV對B、C與D組投予13mg/kg、4.5mg/kg與1.5mg/kg之藥物20分鐘後,封閉左邊肝臟入口。同時提供劑量與輸液,使Cmax 12.5mg/mL(20分鐘時)為Css 5mg/mL。手術期間,每15分鐘監測所有獵犬之血壓、心跳速率、呼吸速率與動脈氧飽和度。以倒T型切割法進行手術。分開小網膜後,單離出肝十二指腸韌帶。固定膽囊與第4葉肝臟,沿著肺門結構小心搜尋上方結構。第19a圖顯示沿著坎特利線(Cantlie’s line)分割之左邊與右邊肝臟葉。第19b圖顯示典型之肺門結構。人體中,右蒂占肝臟總體積之60至70%。封閉肝臟入口90分鐘,以誘發絕血傷害,並拿開鉗子,以誘發再灌流傷害60分鐘(第19圖c)。因此,此模式係一種採用90分鐘絕血傷害與60分鐘再灌流傷害之系
統。手術後,縫合腹腔與皮膚。
取血樣與活組織檢查:依預指定間隔取血樣及進行活組織檢查,包括全血計數(FBE;Hb、WCC、HCT、Plt、MCR、MCH與MCHC)、肝臟功能試驗(LFT;AST、ALT、LDH與總膽紅素)、尿素與電解質(U&E;BUN與肌酸)、肝臟活組織檢查(組織病理學與H&E染色)及HMGB1測定。採用光學顯微照片與電子顯微照片探討肝細胞形狀。手術後之小獵犬保持在保溫且乾淨環境下,且持續投予止痛劑及流質高蛋白質飲食。48小時後,依據程序殺死。結果示於第3、4與5圖。
IR傷害後之組織學分析:取肝臟活組織檢查樣本固定與脫水,然後包埋在石蠟中。取石蠟塊切成4μm厚度,以Mayers蘇木素-伊紅染色法染色,並以光學顯微鏡觀察。每一個樣本均隨機分配,並在不知情下分析。探討肝細胞退化與壞死、血管竇與門靜脈充血與發炎細胞浸潤。依據已報導之方法(HafezT等人.,Journal of Surgical Research 2007;138:88-99),分級定量組織學分析結果:(0(0%,無)、1(1至25%,輕度)、2(26至50%,中度)或3(51至100%,顯著)。其結果示於第6圖。
HMGB1測定:依據製造商之程序,使用HMGB1ELISA分析套組測定HMGB1。其結果示於第7圖。
粒線體複合物I活性測定法:以冰冷緩衝液A(320mM蔗糖、1mMEDTA、10mM Tris(pH 7.5))洗滌肝臟組織2次。切成小片,於玻璃-鐵弗龍均質器中,每1克碎片使用4mL AT緩衝液(75mM蔗糖、225mM甘露糖醇、1mM EGTA與0.01% BSA,pH 7.4)均質化。均質液於4℃以1000g離心5分鐘,所得上清液
於13,000g離心2次。取富含粒線體之塊狀物(mass)用於測定粒線體複合物I活性。複合物I活性(NADH:CoQ氧化還原酶)測定法係於癸基泛醌之存在下,在340nm下監測NADH對魚藤酮敏感之還原作用而測得。其結果示於第8圖。
周知當細胞發生壞死時會釋放HMGB1。因此,以會造成氧化壓力之400μM tBOOH處理後,測試化合物9預防HMGB1釋放之效應。
取H9C2細胞分配在1.5×104個細胞/100μl/孔。次日,以濃度10μM之化合物9處理30分鐘。經過tBOOH(終濃度:400μM)處理後,由50μl上清液進行HMGB1 ELISA,隨時間測定HMGB1濃度。其結果示於第9圖。
壞死過程中,細胞之ATP含量會下降。ATP含量之維持對細胞存活非常重要。因此,在以tBOOH處理後,觀察ATP含量之變化。
取H9C2細胞分配在1.5×104個細胞/100μl/孔。次日,以10μM濃度之化合物9處理30分鐘。以tBOOH(終濃度:400μM)處理後,採用ATP監視套組(PerkinElmer Life Sciences)測定細胞中殘留之ATP量。其結果-示於第10圖。
進行下列實驗,測定化合物9在絕血性再灌流傷害後對H9C2細胞壞死之保護效應:FDA與PI雙重染色、細胞計數、
FACS分析法與粒線體膨脹測定法。
細胞培養與低氧傷害條件:取H9C2細胞於含FBS與抗生素之DMEM培養基中培養。當80至90%細胞匯合時,開始進行實驗。實驗前24小時,先接種H9C2細胞至35mm燒瓶與150mm燒瓶中。當約80%細胞匯合時,培養基換成含0.5%FBS與抗生素之DMEM培養基。細胞在低氧箱中培養24小時。23.5小時後,在低氧箱中,以各種不同化學物質(0.01% DMSO、化合物9(20μM)、維生素C(10μM)與z-VAD-fmk(20μM))處理細胞。細胞轉移至37℃培養箱中,然後在即將再培養之前再以H2O2(400μM)處理。進行再供氧1.5小時。
由H9C2細胞在35mm燒瓶中培養,供利用FDA(螢光素二乙酸鹽,Sigma)與PI(碘化丙啶(propidium iodide))進行雙重染色以產生螢光。製備FDA與PI母液。以PBS洗滌細胞,添加4.5μl FDA溶液(5mg/ml)與4μl PI溶液(2mg/ml)至1.5ml細胞培養基中。利用螢光顯微鏡得到經過FDA/PI染色之影像。其結果示於第11圖。
於實驗例5-1中利用螢光顯微鏡取得FDA/PI染色影像後,使用Image Pron計算活細胞數與死細胞數。其結果示於第12圖。
使用FITC與膜聯蛋白V細胞凋亡檢測套組染色凋亡或壞死性細胞,然後利用流式細胞計分析。取在35mm燒瓶中培養之細胞,根據PI與膜聯蛋白V-FITC之染色法,分成三(3)組:未處理組、單一染色組與雙重染色組。經過再供氧後,所收集之細胞在2,000rpm及4℃離心10分鐘。排除培養基上清液後,細胞再懸浮於與膜聯蛋白V-結合之緩衝液中,於黑暗中,以5μl PI及5μl膜聯蛋白V-FITC染色15分鐘,然後進行FACS分析。其結果示於第13圖。
取於150mm燒瓶中培養之H9C2細胞用於測定粒線體膨脹。以0.05%胰蛋白酶收集細胞,於2,000rpm與4℃離心10分鐘。排除上清液後,以PBS洗滌細胞。細胞再度於2,000rpm與4℃離心10分鐘,然後棄置上清液。取所得細胞塊加至500μl濾過之單離緩衝液(300mM甘露糖醇、0.2mM EDTA、5mM Tris-HCl(pH 7.4)、1%牛血清白蛋白)中,用於隨後之實驗。使用針筒打破細胞,以錐藍質(trypan blue)染色溶液測試。當打破大部份細胞時,細胞溶液立即在2,000rpm離心4分鐘。收集含粒線體之上清液,於13,000rpm與4℃離心10分鐘。棄置上清液後,所得粒線體塊再度懸浮於100μl培養緩衝液(150mM KCl、20mM Tris-HCl(pH 7.4))中。採用蛋白質定量套組測定蛋白質濃度。取一些單離之粒線體蛋白質分配至96孔板,然後以分光光度計,在513nm測定。其結果示於第14圖。
粒線體可視化與3D影像:為了檢視於35mm燒瓶培養之H9C2細胞之粒線體,製備1mM MitoTracker Green FM之DMSO溶液。以細胞培養基洗滌細胞後,使用0.5mM MitoTracker Green FM與4μl PI溶液進行雙重染色。1小時後,以螢光顯微鏡分析細胞,及使用Imaris程式得到之3D影像細胞。
電子顯微鏡:採用已於底部具有蓋玻片之24孔板中培養之H9C2細胞。以含2%戊二醛之0.1M磷酸鈉緩衝液(pH 7.4)固定細胞。細胞經PBS緩衝液洗滌後,以1% OsO4與1.5%鉀進行後固定(postfix)1小時。細胞依序經PBS緩衝液與蒸餾水洗滌2次,然後以濾過之0.5%醋酸鈾,於4℃處理過夜。細胞經蒸餾水洗滌2次,使用乙醇脫水,包埋在Epon中2次,每次1小時。細胞於Epon中,在60℃聚合2天,然後利用電子顯微鏡分析。
螢光免疫染色法:取OCT包埋之組織切片經冰冷之0.05% TBST洗滌10分鐘3次。於室溫,以含1% BSA之阻斷溶液處理組織切片1小時。對重鏈心肌蛋白進行免疫螢光染色時,以抗重鏈心肌蛋白(1:100,Abcam)作為第一抗體處理組織切片。以PBS-Tween 20洗滌組織切片2次後,以第二抗體:驢抗小鼠633 IgM(Invitrogen)染色,以PBS-Tween 20洗滌2次。進行小麥胚芽凝聚素染色時,以Alexa Fluor 555小麥胚芽凝聚素(Invitrogen)於37℃處理組織切片10分鐘。對α-肌節肌動蛋白進行免疫螢光染色時,以第一抗體:抗-α-肌節肌動蛋白於4℃處理組織切片24小時。以0.05% TBST洗滌組織切片2次後,以第二抗體:Alexa Fluor
555驢抗小鼠IgG(Invitrogen)染色。以蘇木素對組織切片染色5秒,使核染色。安置組織切片定位後,由螢光顯微鏡取得影像。其結果示於第15圖。
動物安排:雄性SD大鼠(270至360g)係購自首爾國立大學動物中心(Seoul National University Animal Center)。大鼠飼養在半特異性無病原菌條件(semi-specific pathogen free condition)下,其中開燈與關燈為12小時循環,溫度與濕度分別維持在22℃與55%。提供標準固態囓齒類飼料和自來水,以供自由飲用。每隻均經過1週適應期後才進行實驗,其均經過首爾國立大學IACUC之許可後進行。
手術準備:經過1週適應期後,以氯胺酮(ketamine)(100mg/kg,韓國首爾Yuhan Corp.)與甲苯噻(xylazine)(10mg/kg,Bayer,Shawnee Mission,Kansas,USA)經由腹膜內輸液麻醉大鼠。經過適當麻醉後,進行基本心臟超音波分析,然後提供100%氧氣給所有大鼠。
藉由暫時結紮LAD 45分鐘,誘發絕血再灌流。以具有10號聚乙烯管之8-0 Ethilon縫合線(Ethicon)結紮LAD 45分鐘。以裸視觀察心肌去色及心室心跳過快來辨認絕血。
大鼠分成3組:對照組(5mL 0.9%生理食鹽水)、環孢素處理組(25mg/kg,含於5mL 0.9%生理食鹽水)與化合物9處理組(30mg/kg,含於5mL 5%右旋糖)。利用動物輸液幫浦,經由尾靜脈輸液藥物20分鐘。
打開結紮及10號聚乙烯管後,開始再灌流,且由受傷之心肌在第一段數分鐘期間內之典型充血變化特徵定義為再灌流。保留鬆開之紮線以界定終止時之絕血面積。
手術後,針對化合物9處理組,一天一次經口投予相同劑量之化合物9共3天。其餘各組依相同劑量投藥。
利用心臟超音波探討梗塞之大鼠心臟功能:在麻醉狀態下,剃除左半側胸腔上的毛。在即將進行冠狀動物結紮之前先進行胸前心臟超音波,並使用附裝線性排列轉換器之杜普勒心臟超音波系統(Doppler echocardiographic system)收集數據。採用胸骨縱軸切面與橫軸切面之二維模式取得心臟影像。採用包括乳頭肌之橫軸切面定位與室間隔及LV後壁垂直之M-型游標位置。在訓練期間取得之影像不納入記錄。根據美國心臟超音波學會(American Society of Echocardiography)之前緣技術(leading-edge technology),測量左心室舒張末期(LVEDD)與收縮末期(LVESD)之大小。由公式100×(LVEDD-LVESD)/LVEDD計算LV短縮分率百分比(%)。
梗塞大鼠心臟之組織分析:在心肌絕血事件後3天,麻醉大鼠。為了分析梗塞面積,以石蠟包埋代表性之LV切片,切成厚度4μm之切片。以蘇木素與伊紅對嗜中性白血球染色,然後使用光學顯微鏡觀察。在每片切片之1mm2面積下計算發炎細胞數。採用影像分析系統(Image Pro 4.5版;MediaCybernetics,Bethesda,Maryand,USA),觀察被梅森三色染色法(Masson’s trichrome)染色之纖維化面積。在2片個別切片上測定纖維化面積,並取平均值進行數值分析。
進行免疫組織學染色與研究時,取大鼠心臟置入含有8μm切片之OCT-化合物(Tissue-Teck,Sakura,Torrance,California,USA)中,迅速冷凍與保存。由每隻動物(n=3)在10 HPF中染色之陽性細胞數定量測定染色度。評估細胞凋亡時,進行TUNEL分析法(Chemicon S7100套組,Chemicon,Temecula,California,USA)及針對半胱天冬酶(caspase)-3之免疫組織染色法。每隻動物取至少3個不同切片,在10個不同顯微鏡面積下觀察TUNEL分析法或半胱天冬酶-3之陽性細胞。
使用抗心臟鈣蛋白I(Santa Cruz Biotechnology)進行免疫螢光染色法。採用綠色FITC共軛山羊抗兔子IgG抗體(Molecular Probes)進行檢測。進行紅色PI染色法來代表核,及利用Fluro 350進行藍色Alexa HMGB1染色法來代表核。以螢光顯微鏡(LSM 510 META,Carl Zeiss,Peabody,Massachusetts,USA)探討標記紅色Dil之MSC與綠色連接蛋白-43之共定位(colocalization)或心臟鈣蛋白I表現之共定位。
梗塞面積測定:在心肌受到I/R傷害後72小時,決定心肌梗塞面積,以AAR(風險面積)百分比表示。AAR與LV(左心室)之比例代表心肌組織受到I/R影響之程度。IS/AAR比例為測定受傷之心肌中IS之準確指數,亦為評估藥物治療效力之主要終點。測定AAR時,再度結紮左邊冠狀動脈,經由逆行性方法,自胸主動脈輸入4%伊凡藍氏染劑(Evans Blue dye)。快速取出心臟,於0.9%生理食鹽水中洗滌後,保存在冷凍庫中(-20℃)。將心臟切成5片各1mm橫切片。心臟切片保存在37℃之1%氯化三苯基四銼溶液中15分鐘,然後置入甲醛溶液中。正常組織會染成紅色,
梗塞組織則染成白色。於顯微鏡(Canon EOS 400D)下以數位模式攝影心臟切片之相片,並利用ImagePro軟體(1.34版)測定IS、AAR與總LV面積。
數據分析:所有數據均以平均值表示(SE)。由史登式(Student)-t試驗比較連續變數,採用變方分析進行多重比較,以彭菲尼事後試驗(Bonferroni post hoc)校正。若p值低於0.05,則該數值視為統計上顯著,所有分析均採用SPSS 17.0版(SPSS,Chicago,Illinois,USA)進行。
化合物9對抗左心室質量(LV)增加之壓制效應示於第16圖,且化合物9對抗I/R傷害後之LV短縮分率之壓制效應示於第17圖,及化合物9與CsA對心肌纖維化之比較分析結果示於第18圖。
Claims (7)
- 一種使用下式(1)或(2)化合物、其醫藥上可接受之鹽或R或S異構物於製造用於預防或治療與氧化性壓力有關之疾病之藥物之用途,
- 如申請專利範圍第1項所述之用途,其中該藥物係用於預防與治療由反應性氧物質(ROS)或反應性氮物質(RNS)所媒介之氧化壓力所引起之疾病。
- 如申請專利範圍第1項所述之用途,其中,該藥物壓制因粒線體功能障礙、低氧傷害或HMGB1釋放所引起之絕血性再灌流傷害。
- 如申請專利範圍第1項所述之用途,其中,該藥物壓制粒線體功能障礙。
- 如申請專利範圍第4項所述之用途,其係用於預防與治療MELAS(粒線體肌病、腦病變、乳酸中毒與似中風發作症)、MERRF症候群(出現如破布般紅色肌肉纖維之肌陣攣性癲癇發作)或Kearns-Sayre症候群。
- 如申請專利範圍第1項所述之用途,其中,該藥物壓制低氧傷害。
- 如申請專利範圍第3項所述之用途,其係用於預防與治療心律不整、心臟麻痺或心肌梗塞。
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CN107434819B (zh) * | 2017-02-15 | 2020-03-17 | 河北医科大学第二医院 | 吲哚-tempo缀合物及其在保护远隔器官对抗缺血再灌注损伤中的用途 |
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