TWI722503B - 新穎的autotac嵌合化合物及包含其之用於透過經靶定之蛋白質降解來預防、改善或治療疾病的組成物 - Google Patents
新穎的autotac嵌合化合物及包含其之用於透過經靶定之蛋白質降解來預防、改善或治療疾病的組成物 Download PDFInfo
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- TWI722503B TWI722503B TW108126236A TW108126236A TWI722503B TW I722503 B TWI722503 B TW I722503B TW 108126236 A TW108126236 A TW 108126236A TW 108126236 A TW108126236 A TW 108126236A TW I722503 B TWI722503 B TW I722503B
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Abstract
本發明有關一種其中一新的p62配位體與一標靶結合配位體由一連接子連接之新穎的AUTOTAC嵌合化合物、其立體異構物、水合物、溶劑合物或前驅藥,及一種包含其作為活性成份,用於通過降解標靶蛋白質來預防或治療疾病的藥學或食品組合物。其等可靶定特定蛋白質以調整他們的濃度,亦可將藥物及其它小分子化合物遞送至溶酶體。根據本發明之AUTOTAC嵌合化合物可有效地作為用於通過選擇性消除特定蛋白質來預防、改善或治療各種疾病的藥學組成物。
Description
(a) 發明領域
本發明有關一種新穎的嵌合化合物,更特定地一種嵌合化合物,其中一p62配位體與一標靶結合配位體通過一連接子連接;及一種包含其之用於透過經靶定之蛋白質降解來預防或治療疾病的藥學或食品組成物。
(b)相關技術之說明
N端規則途徑是一種蛋白質水解系統,其中蛋白質之特定N末端殘基作為降解訊息。N末端規則降解訊息之例子為第I型鹼性殘基,包括N端精胺酸(Nt-Arg)、離胺酸(Nt-Lys)及組胺酸(Nt-His);及第II型疏水殘基,包括苯丙胺酸(Nt-Phe)、白胺酸(Nt-Leu)、色胺酸(Nt-Trp)、酪胺酸(Nt-Tyr)及異白胺酸(Nt-Ile)。此等N端殘基會結合特定的N識別蛋白(之後稱作N配位體)。本發明人首先發現或選殖出先前已知的N識別蛋白,即UBR1、UBR2、UBR4及UBR5,且發現其等利用UBR盒作為基質識別結構域(Tasaki, T. et al., Mol Cell Biol 25, 7120-36 (2005))。本發明人亦發現UBR盒會結合第I型N端規則配位體(Nt-Arg、Nt-Lys、Nt-His)如N末端精胺酸殘基,以識別基質且將泛素鏈連接至該基質。進一步發現UBR1與UBR2具有一種N結構域,其在第2型N端規則配位體(Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu及Nt-Ile)的結合上起重要的作用(Sriram, S.M., Kim, B.Y. & Kwon, Y.T., Nat Rev Mol Cell Biol 12, 735-47 (2011))。由N識別蛋白與N端規則配位體之間的結合而產生的泛素化基質會被送到蛋白酶體,其在此被降解成短胜肽。在此過程中,特定N末端殘基(Nt-Arg、Nt-His、Nt-Lys、Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu、Nt-Leu)是結合的基本決定因子,因為N識別蛋白提供靶定N端規則基質所需的大部分氫鍵(Sriram, S.M. & Kwon, Y.T., Nat Struct Mol Biol 17, 1164-5 (2010))。
胞內蛋白質降解主要是通過泛素-蛋白酶體系統(UPS)及自噬-溶酶體系統進行。一般來說,UPS會調節正常折疊的調節子之胞內濃度,或降解錯誤折疊及已失去其等之功能的蛋白質。此時,基質會被估約500至1,000個E3連接酶直接或間接地識別並泛素化,然後被展開成多肽螺旋及蛋白酶體降解(Ji and Kwon, Mol Cells 40, 441-449 (2017))。在正常細胞中,泛素-蛋白酶體系統之過程是平順的,但疾病相關的蛋白質會變成折疊不正確之錯誤折疊蛋白質,或錯誤折疊蛋白質累積產生的聚集體會阻斷蛋白酶體的功能,或蛋白酶體功能於老化過程下降,或與疾病相關的蛋白質之降解由於蛋白質轉錄及轉譯之重新編程而無法順利進行(Ciechanover, A. & Kwon, Y.T., Exp Mol Med 47, e147 (2015))。在代表性範例中,蛋白質病(阿茲海默症、杭丁頓氏症、帕金森氏症、人類狂牛症、路格裡克氏病/肌肉萎縮性脊髓側索硬化症、α-1抗胰蛋白酶缺乏症、角膜病變、第2型糖尿病等等)之各別主要的病理蛋白質是錯誤折疊、泛素化及累積的,且此等多餘的蛋白質廢物被轉換回聚集體(Aguzzi and O’Connor, Nat Rev Drug Discov 9, 237-48 (2010))。此特定突變蛋白質具有被轉形成聚集體之強烈特性,因此不會被降解進入如上所述之蛋白酶體。理由是因為蛋白酶體具有約13Å之窄內徑,所以必須將錯誤折疊蛋白質展開,但當蛋白質聚集時其等無法被展開。在另一代表性範例中,已知癌細胞會藉由重新編程胞內轉錄與轉譯而增加致癌蛋白質之轉錄與轉譯,同時抑制降解(Xiong et al., J Cell Physiol 234, 14031-14039 (2019))。此外,由於泛素-蛋白酶體系統,形成複合物之次單元蛋白及穿膜蛋白之降解亦受到限制。
自噬與UPS (泛素-蛋白酶體系統)一起是主要的胞內蛋白質降解系統。自噬是一種藉由降解老化或受損的胞器或破損或異常折疊的蛋白質及其等之聚集體來維持細胞恆定及基因安定性之必不可少的蛋白質降解過程(Ji and Kwon, Mol Cells 40, 441-449 (2017))。特別是,當病理蛋白質及其等之聚集體累積在細胞質中時,其等會變成細胞毒性物質,因此必須經由自噬接收及降解。自噬之機制大致分成巨自噬、微自噬及伴護蛋白介導自噬,且其分成整體自噬及選擇性自噬,取決於降解胞內基質之目的(Dikic, I. & Elazar, Z., Nat Rev Mol Cell Biol 19, 349-364 (2018))。其中,選擇性自噬及伴護蛋白介導自噬會引起選擇性降解不要的胞內蛋白質及功能異常胞器。通過引發選擇性自噬,針對基於病理錯誤折疊蛋白質及功能異常胞器累積之疾病之新療法目前正建立一個新的典範。p62/SQSTM1/Sequestosome-1蛋白對於起始自噬小體(其是選擇性自噬機制中之介導體)的形成及內容物的遞送很重要。此時,p62蛋白會與病理蛋白質及其等之聚集體結合,其之後被遞送到自噬小體。P62在將病理蛋白質遞送至自噬小體時,經歷自低聚合(self-oligomerization)之關鍵過程(Dikic, I. & Elazar, Z., Nat Rev Mol Cell Biol 19, 349-364 (2018))。此時,病理蛋白質集中在一起縮小體積,因此促進自噬之降解。PB1結構域介導p62的自低聚合反應,但其調節機制並不清楚。當自噬小體與溶酶體結合時,溶酶體酵素會降解遞送至自噬小體之錯誤折疊蛋白質-p62結合體。
通過上述機制,自噬對於通過調節胞內破損的蛋白質與胞器的變化來維持細胞的恆定很重要。當自噬功能減弱時,會引起錯誤折疊蛋白質的累積及聚集,其導致蛋白質病或癌症。在活化整體自噬以治療此等疾病方面的研究持續積極地進行(Ciechanover, A. & Kwon, Y.T., Exp Mol Med 47, e147 (2015))。一般抑制整體自噬之調節物是mTOR。使用mTOR抑制劑活化自噬之方法是最廣為使用的(Jung, C. H., Ro, S. H., Cao, J., Otto, N. M. & Kim, D. H., FEBS Lett 584, 1287-95 (2010))。具體而言,通過使用雷帕黴素(rapamycin)治療,在過度表達APP之AD動物模型中,可消除澱粉樣蛋白β (Ab)及tau蛋白,同時改善認知能力(Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S., J Biol Chem 285, 13107-20 (2010));在過度表達tau蛋白之AD動物模型中,可消除tau蛋白(Rodriguez-Navarro, J.A. et al., Neurobiol Dis 39, 423-38 (2010));及在PD小鼠模型中,可消除過度表達的突變α-突觸核蛋白聚集體(Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C., J Biol Chem 278, 25009-13 (2003))。在HD小鼠中證實,使用CCI-779,一種雷帕黴素類物質,可有效地消除杭丁頓聚集體,亦可改善動物行為及認知能力(Ravikumar, B., Duden, R. & Rubinsztein, D.C., Hum Mol Genet 11, 1107-17 (2002))。然而,mTOR在包括NF-kB在內之各種胞內途徑中起非常重要的作用。因此,雖然其在消除蛋白質病之錯誤折疊蛋白質聚集體方面展現極佳的活性,但在使用此等已知mTOR是藥物標靶之整體自噬活化劑作為治療劑方面,存在著限制。此外,沒有有效的自噬小體靶定的療法及治療劑可以靶定致病蛋白質。
在中心法則中,儲存在DNA中之遺傳資訊被轉錄成RNA及轉譯成蛋白質,以調節細胞功能。對於DNA,可使用DNA編輯技術如CRISPR進行標靶裂解;對於RNA,可使用siRNA進行標靶降解。然而,對於蛋白質,靶定降解技術相對地有限。假如可通過靶定致病蛋白質而將其降解,則其可作為用於藥廠之藥物開發的平台技術。PROTAC (蛋白質水解靶定嵌合體)是一種開發用於產生胞內降解標靶蛋白質的技術。PROTAC使用具有一會識別標靶蛋白質之配位體與一會識別E3泛素酵素之配位體之嵌合化合物(An and Fu, EBioMedicine 36, 553–562 (2018))。當該標靶結合體與致病蛋白質結合且將其帶靠近E3時,E3識別為基質且進行泛素化以引起蛋白酶體降解。因為現存的疾病治療典範是蛋白質酵素抑制,因此開發針對無法被現存治療劑靶定之蛋白質的新療法非常重要。從此觀點視之,對於無法被傳統酵素抑制方法靶定之蛋白質,能夠在泛素-蛋白酶體系統下選擇性降解蛋白質之PROTAC,是一種具有吸引力的新治療開發方法。然而,PROTAC僅利用會識別E3泛素酵素之配位體來引起蛋白酶體降解,因此當標靶蛋白質錯誤折疊而形成聚集體,或形成複合物,或結合至膜結構時,則很難將其降解(Bondeson et al., Cell Chem Biol 25, 78-87.e5 (2019))。此外,PROTAC無法降解諸如內質網及粒線體之胞器,以及諸如病毒及細菌之病原體。因此,需要開發一種可靶定病理蛋白質、胞器及聚集體並將其等遞送至選擇性自噬之方法。
為了調節細胞功能,廣泛地使用通過編輯DNA或降解RNA來間接調節蛋白質活性及濃度之方法。特別是,使用siRNA使得RNA能夠靶定降解,但siRNA具低細胞滲透性,需使用轉染試劑等送進細胞。因此,該方法複雜且昂貴。再者,假如標靶蛋白質很穩定,則即使降解RNA仍很難降低蛋白質之濃度。因此,必須開發一種可通過靶定特定蛋白質而直接降解之方法或物質,即蛋白質降解劑。
發明概要
傳統藥物如小分子合成化合物、抗體、蛋白質、胜肽等等各不相同,但基本原理是結合特定蛋白質之活性位置,抑制致疾蛋白質之活性,從而展現藥物功效。此等傳統藥物開發方法具某些限制。首先,需要高的藥物濃度,此可能引起藥物之副作用。因為藥物-蛋白質結合不是穩定的共價鍵,所以其可能會分開。即,藥物與標靶蛋白質結合時會展現藥物功效,而藥物與標靶蛋白質分開時不會展現藥物功效。因此,為維持藥物功效,必須全身維持在高的藥物濃度下。然而,為了藥物功效增加藥物濃度,容許了藥物結合其它非預期的蛋白質,此情況可能導致藥物副作用。其次,藥物標靶蛋白質有限。迄今,美國食品藥物管理局(FDA)核准大約400種的藥物標靶蛋白質。此等超過90%是酵素、發送蛋白、通道/膜蛋白等等。因為此等藥物標靶蛋白質具有活性位置及結合位置,所以相對容易用相對傳統的藥物開發方法找到。然而,估計有3,000種與疾病相關的蛋白質,目前僅約13%核准的藥物用於此標靶。因此,新藥物開發典範轉移是必要的,且當使用標靶蛋白質降解技術時,具有下列優於現存治療劑之優點。首先,因為其可降解轉錄因子、透過蛋白質結合參與訊息轉導之蛋白質以及聚集與累積的蛋白質如tau蛋白,所以其能調節很難用傳統藥物靶定之無藥可治的蛋白質。其次,其能克服其中標靶蛋白質過度表達及過度活化,或具藥物耐受性或藥物功效因其它訊息轉導系統的活化而降低之現象。第三,因為標靶蛋白質降解材料在降解標靶蛋白質後可重覆使用,所以可以投與低的劑量,且亦可降低與其相關的副作用。第四,因為降解及重新產生標靶蛋白質需要一定的時間,所以可提高投藥周期且經濟效益高。
為了解決上述現存治療劑之問題,本發明之目的是提供一種新穎的AUTOTAC (自噬靶定嵌合體)化合物,其中引發p62蛋白活化及低聚合反應之一新穎的p62配位體化合物與一標靶結合配位體經由一連接子連接(圖1)。
本發明之另一目的是提供一種包含前述AUTOTAC化合物作為一活性成份之用於消除致病蛋白質的藥學或食品組成物。
本發明之又另一目的是提供一種用於影響胞內標靶蛋白質之降解的生化篩選方法及技術。
為了達到以上之目的,本發明之一實施例提供新穎的AUTOTAC嵌合化合物,其中一結合p62之ZZ結構域之配位體與一標靶結合配位體由一連接子連接。
本發明之另一實施例提供(1)引發p62低聚合反應及結構活化之方法;(2)增加p62-LC3結合之方法;(3)將p62及標靶蛋白質遞送至自噬小體之方法(4)活化自噬小體生合成之方法;(5)靶定標靶蛋白質並將其遞送至自噬之方法;(6)靶定標靶蛋白質並使其失去活性之方法;及(7)透過溶酶體降解標靶蛋白質之方法。
在另一實施例中,本發明提供一種用於預防或治療疾病的藥學組成物或保健功能食品,其含有前述的AUTOTAC嵌合化合物作為一活性成份。較佳地,該疾病不僅包括癌症或退化性腦疾病,亦包括靶定降解某些蛋白質時預期具有治療效果之其它疾病,如罕見難治的疾病。
本發明之核心技術是(1)使用AUTOTAC材料連接標靶蛋白質與p62,(2)引發p62之自低聚合反應,(3)使標靶蛋白質與p62形成複合物,從而以生物方法使該標靶蛋白質失去活性,(4)之後將該標靶蛋白質-p62複合物遞送至自噬膜上,諸如吞噬泡,及(5)在溶酶體中降解該標靶蛋白質-p62複合物。
本發明之藥物動力學及核心技術總結在圖1中。
具體而言,如圖1所示,AUTOTAC嵌合化合物具有一結構,其中一標靶結合配位體(TBL)與一p62 ZZ結構域配位體,即自噬靶定配位體(ATL),透過一連接子連接。其透過該標靶配位體與一標靶蛋白質結合,而該自噬靶定配位體在與該p62 ZZ結構域(其為自噬受體)結合後進行低聚合反應。之後,p62透過結合至從自噬小體膜突出的LC3而被自噬靶定,然後該標靶蛋白質在溶酶體中降解。在本發明中,嘗試藉由使用可與p62 ZZ結構域結合之小分子配位體來活化p62,以有效地消除標靶蛋白質。目前為止,有使用泛素蛋白酶體系統(UPS)來靶定蛋白質降解之PROTAC化合物,但還沒有關於使用自噬來降解標靶蛋白質之低分子量化合物的報告。當使用不同於PROTAC之自噬時,不僅能夠降解無法透過PROTAC降解之蛋白質,如錯誤折疊蛋白質聚集體、膜連型蛋白質及複合物之次單元,且亦可降解胞內結構物(發炎體、壓力顆粒(stress granule)等等)、胞器(內質網、粒線體、過氧化物酶體等等)及侵犯細胞的病原體(病毒、細菌等等)。透過此標靶降解,各種疾病的預防和治療作用是可以預期的。
p62蛋白對於起始自噬小體(其是選擇性自噬機制中之介導體)的形成及內容物(即標靶蛋白質)的遞送很重要。已觀察到,根據本發明之新穎的AUTOTAC嵌合化合物透過p62活化來引起p62之自低聚合反應。此外,證實透過此自低聚合反應,該標靶蛋白質被遞送到自噬小體,因此該標靶蛋白質在溶酶體中降解。
因為根據本發明之AUTOTAC嵌合化合物不僅會引起胞內自噬,還會引起自噬小體靶定標靶蛋白質,因此能夠在自噬機制下選擇性降解無法被傳統酵素抑制方法靶定之蛋白質,其可提供新穎的治療劑。
根據本發明之AUTOTAC嵌合化合物具有一結構,其中一標靶結合配位體(TBL)與一結合至p62蛋白ZZ結構域之配位體,即自噬靶定配位體(ATL),透過一連接子連接。透過自噬靶定配位體活化自噬,將該標靶蛋白質帶至自噬小體並在溶酶體中將其降解。
本發明是能夠在將待降解的蛋白質之配位體連接至自噬靶定配位體-連接子時,降解所欲標靶蛋白質之平台技術,因此可用作預防、改善及治療各種疾病之藥物。
較佳實施例之詳細說明
之後,將更詳細地說明本發明。
本發明提供一種嵌合化合物,其包含一p62配位體(自噬靶定配位體,ATL)、一標靶結合配位體(TBL)及一連接子;及一種使用前述化合物,將標靶蛋白質、胞器及聚集體與p62一起遞送至自噬小體(其是巨自噬之介導體),且在溶酶體中降解其等之方法。透過此一方法,本發明提供一種用於通過將致病蛋白質、胞器及聚集體遞送至自噬並將其等降解來預防、改善或治療疾病的方法,及一種包含上述複合物(之後亦稱作"嵌合化合物")之用於與疾病相關的病原蛋白質、胞器及聚集體之自噬活化及用於預防、改善或治療該疾病之組成物。
本發明人發現,通過使用p62配位體,此一p62配位體可活化自噬,有效地將標靶蛋白質、胞器及聚集體遞送至自噬小體並消除它們。發明人亦發現,當將該配位體與能夠結合以上病理蛋白質之配位體組合使用時,其表現出非常優異的病理蛋白質及聚集體消除功效,且不同於習知PROTAC化合物,不需要為形成用於折疊病理蛋白質、E3連接酶選擇性及有效的降解之三元複合物(標靶蛋白質-連接子-E3連接酶配位體)而優化連接子的長度。本發明人開發之其中一p62配位體與結合至標靶蛋白質之一標靶結合配位體透過一連接子連接之新穎的嵌合化合物,命名為AUTOTAC (AUTOphagy Targeting Chimera)。
本發明之特徵是能夠通過將待降解之蛋白質的配位體連接至與p62配位體連接之一連接子來降解所欲的蛋白質之技術。即,其中該p62配位體與該標靶結合配位體由一連接子連接之嵌合化合物,是一種雙功能小分子,且標靶蛋白質(會在與蛋白質的自噬相關之p62附近降解)與靶定其等之配位體結合,從而形成可輕易地降解該標靶蛋白質之結構。本發明之重點在於,期望通過將與需要預防或治療的各種疾病相關的蛋白質與p62連接,並降解所關注的標靶蛋白質達到治療效果。
在一較佳實施例中,根據本發明之包含p62配位體、標靶結合配位體及連接子之嵌合化合物,是其中該p62配位體與該標靶結合配位體透過一連接子連接之嵌合化合物形式,更佳地,其可具有下列化學式1之結構。
[化學式1]
其中,A代表標靶結合配位體,B代表p62配位體。在化學式1中,A與B可分別連接至至少一個連接子。
在本發明中,該標靶結合配位體是會與體內之特定標靶蛋白質(更具體地,待靶定之引起疾病的病理蛋白質)或胞器或聚集體結合之配位體。此標靶蛋白質包括,但不限於,較佳地與癌症相關的蛋白質,及與各種蛋白質疾病相關的蛋白質。此等標靶結合配位體在使用上沒有特定的限制,只要其等是那些可與待預防、改善及治療之疾病相關的蛋白質,較佳地與由病理蛋白質引起的疾病、癌症、蛋白質疾病、頑固性疾病或遺傳疾病相關之標靶蛋白質、胞器或聚集體,結合即可。具體實施例可包括,但不限於,選自於由以下表1所示之化合物所構成之群組中之一或多個,或從此等結構衍生而得之衍生結構。
該"衍生"結構意指其中該標靶結合配位體之一部分結構通過與一連接子結合而改質之結構(如,該標靶結合配位體與該連接子之連接部分,因取代基中之羧基基團與具有胺基基團之連接子結合產生之過醯胺基團而改變)。
[表1]
化學式1中連接A與B之連接子在使用上沒有特別限制,只要其具有其中A與B二者在結構上相連之結構即可。例如,此一連接子可為-Q-(CH2
CH2
O)x
-(CH2
)y
-P-或-Q-(CH2
CH2
CH2
O)x
-(CH2
)y
-P-或-Q-(CH2
CH2
NH)x
-(CH2
)y
-P-或-Q-(CH2
CH2
CONH)x
-(CH2
)y
-P- (其中Q包括-NH-、-0-、= N- -N (CH3
)-,其是通過與該標靶結合配位體結合而改質之部分;P包括-NH-、-0-、-CH2
-、-C(=O)-,其是通過與p62配位體結合而改質之部分;x是0至4之整數;及y是0至3之整數),但不限於此。較佳地,P與p62配位體間之鍵結可為-CONH-、-O-、-NH-、-NHCO-或-COO-,為了形成此一鍵結,可修改該p62配位體之一部分如Rc部分及該標靶結合配位體之一部分之結構,此等改質方法是業界公知的。
在本發明中,該p62配位體意指p62,更具體地,一種與p62之ZZ結構域結合之材料。由於與該p62 ZZ結構域結合,所以此等p62配位體可增加p62之低聚合反應及活化自噬,具體地,巨自噬。在較佳實施例中,該p62配位體可具有以下化學式2之結構。
[化學式2]
其中,
W是C6
-C10
芳基;
L是-(CH2
)n1
-或-O-(CH2
)n2
-CH(OH)-,但條件是-O-(CH2
)n2
-CH(OH)-中之O與苯環鍵結,其中n1是1至4之整數;
n2是1至4之整數;
m是0至2之整數;
Ra是R1
或-OR1
,
其中R1
是氫或-(CH2
)n3
-R'1
,
R'1
是未取代的或經羥基、鹵素、C1-4
烷基、C1-4
烷氧基、硝基、胺基、(C1-4
烷基)胺基或二(C1-4
烷基)胺基取代的苯基,
n3是1至6之整數;
Rb
是-OR2
,
其中R2
是氫或-(CH2
)n4
-R'2
,
R'2
是未取代的或經羥基、鹵素、C1-4
烷基、C1-4
烷氧基、硝基、胺基、(C1-4
烷基)胺基或二(C1-4
烷基)胺基取代的苯基,
n4是1至6之整數;
Rc
是-(CH2
)n5
-OH、-(CH2
)n5
-NH-C(=NH)NH2
、-C(=NH)NH2
、-CH(R3
)-COOH或-CH(COO-R4
)-CH2
CH2
CH2
-NH-C(=NH)NH2
、-(CH2
)n5
-O-(CH2
)n5
-OH、-CONH(CH2
)n5
-OH、-CO(CH2
)n6
-OH、-(CH2
)n6
-CH(NH2
)-COOH、-(CH2
)n6
-CONH2
,
n5是2至4之整數,
n6是1至4之整數,
R3
是氫或C1-4
烷基,
R4
是C1-4
烷基,及
Rd
是氫、鹵素、C1-4
烷氧基或C1-4
烷基。
較佳地,該W可為苯基。
較佳地,該L是-(CH2
)n1
-或-O-(CH2
)n2
-CH(OH)-,但條件是-O-(CH2
)n2
-CH(OH)-中之O與苯環鍵結。
較佳地,該n1可為0至1之整數。
較佳地,該n2可為1至2之整數。
較佳地,該Ra
可為氫或-O-(CH2
)n3
-R'1
。
較佳地,該R'1
可為未取代的或經羥基、氟基 、氯基、溴基、甲基、乙基、甲氧基、乙氧基、硝基、胺基或二甲胺基取代的苯基。
較佳地,該n3可為1至4之整數。
較佳地,該Rb
可為羥基或-O-(CH2
)n4
-R'2
。
較佳地,該R'2
可為未取代的或經羥基、氟基、氯基、溴基、甲基、乙基、甲氧基、乙氧基、硝基、胺基或二甲胺基取代的苯基。
較佳地,該n4可為1至4之整數。
較佳地,該Rc
可為-(CH2
)n5
-OH、-(CH2
)n5
-NH-C(=NH)NH2
、-C(=NH)NH2
、-(CH2
)n5
-O-(CH2
)n5
-OH、-CONH(CH2
)n5
-OH、-CO(CH2
)n6
-OH、-(CH2
)n6
-CH(NH2
)-COOH或-(CH2
)n6
-CONH2
。
較佳地,該n5可為2至3之整數。
較佳地,該n6可為1至2之整數。
較佳地,該Rd
可為氫、鹵素、C1-2
烷氧基或C1-2
烷基。
在與該連接子結合方面,此一p62配位體可以一衍生物之形式(其中一些基團已改質成可促進與該連接子結合之形式)連接至該連接子。此可由熟悉此技藝之人士依據p62配位體之類型、該連接子之類型及其等之結合形式適當地使用已知的技術改變,且此等改質的衍生物形式亦包括在本發明之p62配位體內。
同時,本發明之化合物可以藥學上可接受的鹽之形式存在。可使用由藥學上可接受的游離酸所形成之加成鹽作為該鹽。本文中所使用的術語"藥學上可接受的鹽"意指由化學式1至3表示的化合物之任何的有機或無機加成鹽,其中在對病患表現出相對無毒及無害的有效活性濃度下,由該鹽引起之副作用不會削弱該化合物之有利作用。
該酸加成鹽可以常用的方法製得,例如,藉由將化合物溶於過量的酸水溶液中,然後使用水不可溶混有機溶劑,如甲醇、乙醇、丙酮或乙腈沈澱所產生的鹽。選擇性地,可在水或酒精(如,乙二醇一甲基醚)中加熱莫耳當量的化合物與酸,然後利用蒸發乾燥所產生的混合物,或可在抽吸下過濾沈澱的鹽。
在此情況下,該游離酸可為無機酸或有機酸。該無機酸之例子包括,但不限於,鹽酸、磷酸、硫酸、硝酸及錫酸。該有機酸之例子包括,但不限於,甲磺酸、對甲苯磺酸、乙酸、三氟乙酸、順丁烯二酸、琥珀酸、草酸、苯甲酸、酒石酸、反丁烯二酸、苦杏仁酸、丙酸、檸檬酸、乳酸、乙醇酸、葡萄糖酸、半乳酸醛酸、麩胺酸、戊二酸、葡萄糖醛酸、天門冬胺酸、抗壞血酸、碳酸、香草酸及氫碘酸。
此外,可使用鹼製備藥學上可接受的金屬鹽。鹼金屬或鹼土金屬鹽之獲得,可通過例如將化合物溶於過量的鹼金屬氫氧化物或鹼土金屬氫氧化物溶液中,過濾未溶解的化合物鹽,然後使濾液蒸發直至乾燥。此時,特別是鈉、鉀或鈣鹽是藥學上適合的金屬鹽,但本發明不限於此。另外,可通過使鹼金屬或鹼土金屬鹽與適當的銀鹽(如,硝酸銀)反應而獲得對應的銀鹽。
本發明之化合物之藥學上可接受的鹽,除非本文另有說明,否則包括存在化學式1之化合物中之酸性或鹼性基團的鹽。例如,該藥學上可接受的鹽包括羥基基團之鈉、鈣及鉀鹽及其它藥學上可接受的胺基基團的鹽,包括氫溴酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、乙酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、杏仁酸鹽、甲磺酸鹽(甲磺酸鹽)和對甲苯磺酸鹽(甲苯磺酸鹽)。該鹽可使用業界已知的鹽製備方法製得。
本發明之化學式1之化合物的鹽是藥學上可接受的鹽,且只要其等表現出與化學式1之化合物相當的藥學活性,即可在無特別限制之情況下使用。
此外,根據本發明之化學式1表示之化合物不僅包括,但不限於,其藥學上可接受的鹽,且亦包括從其製得之所有的溶劑合物或水合物以及所有可能的立體異構物。本化合物之所有的立體異構物(如,由於各種取代基上的不對稱碳而可能存在的那些異構物),包括鏡像異構形式及非鏡像異構形式,均落在本發明之考量範疇內。本發明之化合物之個別的立體異構物可,例如,為實質上無其它異構物的(如,具有特定活性之純或實質上純光學異構物),或可混合成例如消旋物,或混合與所有其它或其它選定的立體異構物。本發明之化合物之手性中心可具有按IUPAC 1974 Recommendations所定義的S或R構型。該外消旋形式可用物理方法分析,如非鏡像異構物衍生物之分段結晶、分離或結晶,或利用手性管柱層析法分離。個別的光學異構物可通過任何適合的方法從該外消旋物獲得,方法包括但不限於,與光學活性酸形成鹽,接著結晶。
以化學式1表示之化合物的溶劑合物及立體異構物,可使用業界已知之方法從以化學式1表示之化合物製得。
此外,根據本發明之化學式1表示的化合物可製備成結晶形式或非結晶形式,當該化合物製備成結晶形式時,其可任擇地水合或溶劑合化的。在本發明中,化學式1之化合物不僅可包括化學計量水合物,亦可包括含各種水量之化合物。根據本發明之化學式1之化合物之溶劑合物,包括化學計量溶劑合物及非化學計量溶劑合物二者。
根據本發明之化學式1之化合物可用下列示範性方法製備,其之具體範例與以下範例所述之反應流程圖相同。
在本發明之製備方法中,反應流程中所使用的反應物可為商購的化合物,或可通過進行一或多個本領域已知的反應或經過適當地修改該反應之反應合成。例如,考慮骨架結構中所含的反應官能基和/或雜元素之存在、類型和/或位置,按照順序進行一或多個反應來合成該反應物,但不限於此。
根據本發明之化學式1之化合物作用為一種嵌合配位體,其與p62之ZZ結構域結合且同時與標靶蛋白質、胞器及聚集體結合,從而活化p62之功能,並將侵犯細胞之標靶蛋白質、胞器(內質網、粒線體、過氧化物酶體等)、胞內結構物(發炎體、壓力顆粒等)、病原體(病毒、細菌等)及聚集體遞送至自噬進行降解,與p62相似。
因此,在另一態樣中,本發明提供一種用於自噬活化之藥學組成物,其包含該化學式1之化合物、其藥學上可接受的鹽、立體異構物、水合物、溶劑合物或前驅藥。
根據本發明之化學式1之化合物可通過將標靶蛋白質、胞器及聚集體遞送至自噬並降解其等來消除病理蛋白質相關的疾病之病理蛋白質、胞器及聚集體。此外,該化學式1之化合物是一p62配位體,其與p62 ZZ結構域結合並活化p62蛋白之PB1結構域及LIR結構域,從而p62產生低聚合反應及形成聚集體,同時增加遞送該標靶蛋白質、胞器及聚集體與p62蛋白至自噬小體。通過以上之方法,標靶蛋白質、胞器及聚集體被有效地消除(見圖1)。此標靶蛋白質可為病理蛋白質相關疾病之主要蛋白質,更特別地是選自由下列所構成之群組中之至少一種:普里昂蛋白、澱粉樣蛋白前驅蛋白(APP)、α突觸核蛋白(alpha-synuclein)、超氧化物岐化酶1、Tau蛋白、免疫球蛋白、澱粉樣-A、甲狀腺素運轉蛋白(transthyretin)、β2-微球蛋白、胱蛋白C (cystatin C)、脂蛋白元A1、TDP-43、胰島澱粉樣多肽、ANF、凝溶膠蛋白(gelsolin)、胰島素、溶酶體、纖維蛋白原、杭丁頓氏蛋白、α-1-抗胰蛋白酶Z、晶體蛋白、c9開讀框72 (c9orf72)、膠質原纖維酸性蛋白、囊腫纖化症跨膜傳導調節蛋白、視紫質及共濟失調蛋白(ataxin)及其它具有多麩醯胺酸延伸(poly-Q stretch)之蛋白。
因此,在又另一態樣中,本發明提供一種藥學組成物,其包含化學式1之AUTOTAC嵌合化合物、其藥學上可接受的鹽、立體異構物、水合物、溶劑合物或前驅藥。該藥學組成物係用於預防或治療由標靶結合配位體靶定的疾病。非限制地,此疾病可為一標靶,只要其可與標靶結合配位體結合即可,較佳地,其可為癌症或蛋白質病,更佳地,其包括各種當靶定及降解特定蛋白時,預期具有療效之疾病,如罕見或頑固性疾病或遺傳疾病。根據本發明之藥學組成物之特徵在於直接消除引起上述疾病之致病蛋白。
在另一態樣中,本發明提供一種用於自噬遞送或降解致病病理蛋白質及錯誤折疊蛋白質之藥學組成物,其包括該化學式1之化合物、其藥學上可接受的鹽、立體異構物、水合物、溶劑合物或前驅藥。
本文中使用的術語“蛋白質病”或"與蛋白質聚集有關的疾病"意指具有存在錯誤折疊蛋白質聚集體之特徵的疾病,其之例子包括,但不限於,神經退化性疾病、α-1抗胰蛋白酶缺乏症、角膜病變、色素性視網膜炎、第2型糖尿病、囊性纖維化等等。
根據本發明,術語"聚集"意指通常是一或多種蛋白質之低聚或多聚複合物之形成,其可能伴隨著整合額外的生物分子,像是碳水化合物、核酸及脂質,進入該複合物中。此聚集的蛋白質可能在特定組織中形成沈積物,更偏好在神經組織或腦組織中。聚集的程度取決於特定疾病。
本文之神經退化性疾病較佳地選自由下列所構成之群組:萊姆病(Lyme borreliosis)、致死性家族性失眠症、庫賈氏症(CJD)、多發性硬化症(MS)、癡呆、阿茲海默氏症、癲癇、帕金森氏症、中風、杭丁頓氏舞蹈症、匹克症(Picks disease)、肌肉萎縮性脊髓側索硬化症(ALS)、脊髓小腦性失調症、其它多麩醯胺酸疾病、遺傳性腦澱粉樣血管病變、家族性澱粉樣多發性神經病變、原發性全身性澱粉樣變性(AL澱粉樣變性)、反應性全身性澱粉樣變性(AA澱粉樣變性)、注射局部澱粉樣變性、β-2微球蛋白澱粉樣變性、遺傳性非神經病性澱粉樣變性、亞歷山大氏症及芬蘭型遺傳性全身性澱粉樣變性(Finnish hereditary systemic amyloidosis)。
本發明之藥學組成物的劑量可視病人的體重、年齡、性別或健康狀況、飲食、投藥周期、投藥方法、排泄及疾病嚴重度而廣範圍變化。然而,有效劑量通常為成人(60kg)約1ng至10mg/天,特別是約1ng至1mg/天。因為劑量可視各種情況而變化,因此對本領域技術人員顯而易見的是,劑量可以增加或減少。據此,本發明之範疇不以任何方式受前述劑量之限制。至於投藥的次數,可以在期望的範圍內每天一次或幾次分次投藥,且該投藥周期亦不受特別的限制。
本文中使用的術語"治療",意指所有可通過投與本發明之藥學組成物而改善或有利地改變各種與錯誤折疊蛋白質聚集相關的疾病或透過靶定蛋白質降解之疾病之症狀的動作。
如上文所述,本發明之化合物展現出(1)引起p62低聚合反應及結構活化、(2)增加p62-LC3結合,及(3)增加遞送p62至自噬小體、(4)活化自噬,及最後(5)消除靶定的蛋白質之作用。因此,包含此化合物作為活性成分之藥學組成物可用預防、改善或治療各種期望的疾病,較佳地癌症或蛋白質病。
例如,本發明之組成物可進一步包括藥學上可接受的載劑、稀釋劑或賦形劑。該組成物可以各種型式使用,如散劑、顆粒劑、錠劑、膠囊、懸液劑、乳劑、糖漿之口服劑型,氣霧劑及無菌注射溶液之注射劑,其等根據各預定用途通過習用之方法配製。該組成物可透過各種途徑投與,包括經口投藥或靜脈內、腹腔內、皮下、直腸及局部投藥。可包含在此組成物中之適合的載劑、賦形劑或稀釋劑之例子可包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藻糖醇、麥芽糖醇、澱粉、阿拉伯膠、海藻酸鹽、明膠、磷酸鈣、矽酸鈣、纖維素、甲基纖維素、微晶纖維素、聚乙烯吡咯啶酮、水、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂、礦物油等等。此外,本發明之組成物可進一步包括填料、抗凝血劑、潤滑劑、保濕劑、香料、乳化劑、防腐劑等等。
經口投藥之固體配方包括錠劑、丸劑、散劑、顆粒劑、膠囊等等,此固體劑型是通過混合本發明之組成物與一或多種賦形劑,如澱粉、碳酸鈣、蔗糖、乳糖、明膠等等,配製而成。且,除了簡單的賦形劑外,亦可使用諸如硬脂酸鎂及滑石之潤滑劑。
經口投藥之液體配方之例子為懸液劑、溶液劑、乳劑、糖漿劑等等,且除常用的稀釋劑水和液態石蠟外,亦可包括各種賦形劑如保濕劑、甜味劑、香料、防腐劑等等。
注射投藥之配方包括無菌水溶液、非水溶劑、懸液劑、乳劑、凍晶劑及栓劑。非水溶劑及懸浮劑可包括丙二醇、聚乙二醇、植物油如橄欖油及可注射酯類如油酸乙酯。用於栓劑之物質,可使用Witepsol、聚乙烯二醇(Macrogol)、Tween 61、可可脂、月桂脂、甘油明膠或類似物。另一方面,注射劑可包括習用的添加物,如助溶劑、等張劑、助懸劑、乳化劑、安定劑或防腐劑。
該配方可依照習用的混合、製粒或包衣法製得,且含有效醫療,特別是用於預防、改善或治療與蛋白質聚集相關之疾病之數量的活性成份。
在此情況下,本發明之組成物以藥學有效量投與。本文中所使用之術語"藥學有效量"意指在適用於任何醫療之合理的利益/風險比率下,能充分治療疾病且足以不引起副作用之數量。有效量之位準可依病人的健康狀況、疾病類型、疾病嚴重度、藥物活性、對藥物的敏感性、投藥方法、投藥時間、投藥途徑、排泄率、治療時間、組合、包括同時使用其它藥品之因素及其它在醫療領域中公知的因素決定。本發明之組成物可以單獨療法或合併其它療法之方式投與,且其可與常規療法同時或依序投與,且一次或多次。重要的是,考慮以上所有的因素,以在無副作用之情況下可提供最大功效之最小藥量投與,熟悉此技藝之人士可以很容易地決定此數量。
例如,該劑量可視投藥途徑、疾病嚴重度、性別、體重、年齡等等而增減,且本發明之範疇不以任何方式受上述劑量之限制。
根據本發明之化合物的較佳劑量可按病人之病況及體重、疾病嚴重度、藥物類型及投藥類型與時間而變化,但可由熟悉此技藝之人士適當地選定。
在另一態樣中,本發明提供一種用於預防、改善或治療疾病之方法,該疾病較佳地為癌症、與病理蛋白質相關之疾病及與蛋白質聚集相關之疾病,其包含對有需要的個體投與本發明之藥學組成物。
在另一態樣中,本發明提供(i)增加標靶蛋白質之降解的方法、(ii)增加胞器及結構體之降解的方法;(iii)增加各種侵犯細胞的病毒及細菌之降解的方法、(iv)將藥物或小分子化合物遞送至自噬及溶酶體的方法、(v) p62之自低聚合及自噬活化的方法及(vi)藉由將細胞中的特定蛋白質連接至p62且將其等遞送至自噬來增加透過溶酶體之降解的方法,其包括該化學式1之化合物、其藥學上可接受的鹽、立體異構物、溶劑合物、水合物或前驅藥。
在又另一態樣中,本發明提供一種方法,其使用一藥物且透過內體將此一藥物遞送至溶酶體,其中根據本發明之嵌合化合物連結至一治療抗體,該治療抗體會專一性地結合至曝露在細胞膜上之蛋白質。該治療性抗體之使用上,只要其能展現對抗需要治療的疾病之藥學活性,沒有限制。
本文中所使用之術語"個體"意指所有具有需要預防、改善或治療之標靶疾病之動物,包含人、猴子、牛、馬、羊、豬、雞、火雞、鵪鶉、貓、狗、小鼠、大鼠、兔子或天竺鼠。通過對該個體投與本發明之藥學組成物,可有效地預防、改善或治療該標靶疾病,較佳地癌症、與病理蛋白質相關的疾病或與錯誤折疊蛋白質聚集相關之疾病。此外,因為本發明之藥學組成物作用為p62配位體,用以活化自噬、因自噬活化而消除錯誤折疊蛋白質的聚集體,因此展現出與此等聚集蛋白質相關之疾病的預防或治療功效,通過與現存治療劑結合投藥,可展現出協同作用。
本文中所使用之術語"投藥"意指以某些適當的方法於病人中引入指示量的物質,且只要本發明之組成物可到達標靶組織,其可透過任一常用的途徑投與。例如,可進行腹腔內投藥、靜脈投藥、肌肉投藥、皮下投藥、皮內投藥、口服投藥、局部投藥、鼻內投藥、肺內投藥和直腸內投藥,但本發明不限於此等示範投藥模式。且,本發明之藥學組成物可使用任何能夠將活性成份遞送至標靶細胞之裝置投與。較佳的投藥模式及配方是靜脈注射、皮下注射、皮內注射、肌肉注射、靜脈滴注或類似方式。注射配方可使用食鹽水、水溶液如林格氏溶液及非水溶液如植物油、高脂肪酸酯(如,油酸乙酯等等)、醇類(如,乙醇、苯甲醇、丙二醇、甘油等等)製備。該注射製劑可包括藥學載劑,包括用於防止降解之安定劑(如,抗壞血酸、亞硫酸氫鈉、焦亞硫酸鈉、BHA、生育酚、EDTA等等)、乳化劑、用於pH控制之緩衝劑及用於抑制細菌生長之防腐劑(如,硝酸苯汞、乙汞硫柳酸鈉、氯化苯銨、酚、甲酚、苯甲醇等)。
在其它態樣中,本發明提供一種用於預防或改善蛋白質病之食品組成物,其包含該化學式1之AUTOTAC嵌合化合物、其藥學上可接受的鹽、立體異構物、水合物、溶劑合物或前驅藥。該食品組成物是保健功能食品,其可以其配方本身之形式或包含在其它保建功能食品中作為保健功能食品之添加物之形式使用。該保健功能食品意指具有身體調整功能之食品,如預防或改善疾病、生物防禦、免疫力、恢復療養、抑制衰老等,且其長期服用應對人體無害。活性成份之混合數量可視使用目的(預防、保健或治療)適當地決定。
食品之種類沒有特別限制。以上物質可添加的食品之例子是肉、香腸、麵包、巧克力、糖果、零食、餅乾、批薩、拉麵、其他麵條、口香糖,包括冰淇淋的乳製品,各種湯品、飲料(beverages)、茶、飲料(drinks)、酒精飲料和維生素複合物等,且其包括所有一般常識之保健功能食品。
本發明之食品組成物可包含在食品或食品添加物之製備中常見的成份,具體地為調味劑;天然甜味劑,如葡萄糖、果糖之單糖類;如麥芽糖、蔗糖之雙糖類;和糊精、環糊精之天然碳水化合物,或合成甜味劑,如糖精、阿斯巴甜;營養素;維他命;電解質;著色劑;有機酸;膠體黏度保護劑;pH調節劑;安定劑;防腐劑;甘油;醇;用於碳酸飲料之碳酸飽充劑等。
在本發明之特定實施例中,以化學式1表示之新穎的AUTOTAC嵌合化合物1至13是新合成的。此外,為了評估根據本發明之新穎的AUTOTAC嵌合化合物是否可增加培養細胞中之自噬現象,用根據本發明之AUTOTAC嵌合化合物處理主要表達標靶蛋白質之細胞株(MCF7、NTERA-2、ACHN、U87-MG、LNCaP、HEK293T)或基因重組細胞株(SH-SY5Y-tau、HeLa-HttQ97、PC12-a-synA30P),培養,然後利用免疫墨點法證實在培養細胞中之標靶蛋白質降解活性。結果,不僅逐步證實了以根據本發明之AUTOTAC化合物按濃度處理之自噬介導的各標靶蛋白質之降解作用,還證實了降解功效優於構成該嵌合化合物之p62配位體或標靶蛋白質之作用。因此,證實根據本發明之AUTOTAC化合物活化及低聚合化p62蛋白,從而遞送至自噬小體,同時選擇性及有效地消除與各種標靶疾病(如癌症相關蛋白質或蛋白質病)相關之蛋白質及其等之聚集體。[ 範例]
之後,將參考範例詳述本發明。然而,此等範例僅供示範之目的,本發明並不受此等範例之限制。
在用於合成本發明之化合物之起始材料方面,各種合成方法均為已知的,假如可從市場上購得,則可從提供者那兒購得。試劑供應商之例子包括Sigma-Aldrich、TCI、Wako、Kanto、Fluorchem、Acros、Alfa、Fluka等等,但不限於此。
本發明之化合物可使用下列一般方法及程序,從方便取得之起始材料製得。至於典型或較佳的製程條件(即,反應溫度、時間、反應物之莫耳比、溶劑、壓力)等等,除非另有說明,否則亦可使用其它製程條件。最佳的反應狀態可隨著所使用之特定反應物或溶劑而變。此條件可由熟悉此技藝之人士通過習用最佳化程序決定。
以下,描述範例1至13之製備方法。範例1 :(2E,4E,6E,8E)-N-(2-(2-(2-(((R)-3-(3,4- 雙( 苯甲氧基) 苯氧基)-2- 羥丙基) 胺基) 乙氧基) 乙氧基) 乙基)-3,7- 二甲基-9-(2,6,6- 三甲基環己-1- 烯-1- 基) 壬-2,4,6,8- 四烯醯胺(RTEG-1104) 之製備
步驟1)製備3,4-雙(苯甲氧基)苯甲醛(1101)
在將3,4-二羥基苯甲醛(0.50g,3.62mmol)溶於無水DMF (5ml)後,加入碳酸鉀(K2
CO3
,1.50g,10.86mmol),然後於該反應中慢慢加入溴甲苯(0.92mL,7.96mmol)且在60°C下攪拌4個小時。反應完全時,令反應混合物冷卻至室溫,用純化水稀釋,及用乙醚(50ml)萃取二次。用純化水(50ml)洗滌有機層二次,然後再用飽和氯化鈉水溶液(50ml)洗滌一次。之後,於該有機層中加入無水硫酸鈉並攪拌,接著在減壓下過濾。將濾出溶液濃縮,然後利用管柱層析法純化,獲得3,4-雙(苯甲氧基)苯甲醛(1101,1.04g,產率:90%)。1
H NMR (CDCl3
,300 MHz) δ 9.81 (s, 1H), 7.49-7.31 (m, 12H), 7.04 (d, J = 8.3 Hz, 1H), 5.27 (s, 2 H), 5.22 (s, 2H);ESIMS m/z:319.33 [M+H]+
。
步驟2)製備3,4-雙(苯甲氧基)酚(1102)
將二氯甲烷(15ml)加至並溶於3,4-雙(苯甲氧基)苯甲醛(1101,1.00g,3.0mmol,1eq.)中,然後於該反應中加入mCPBA (0.78g,4.5mmol,1.5eq.)且於室溫下攪拌4個小時。用乙酸乙酯稀釋該反應混合物,用飽和碳酸鈉水溶液洗滌,之後分離有機層。用氯化鈉水溶液洗滌有機層,之後用無水硫酸鈉脫水且於減壓下過濾。將濾出溶液濃縮,然後再溶於甲醇(10ml)中。於其中加入6N NaOH,在室溫下攪拌30分鐘。於該反應中加入4N HCl溶液,進一步攪拌30分鐘。用乙酸乙酯(50ml)稀釋反應混合物,用鹽水洗滌,用無水硫酸鈉脫水及在減壓下過濾。將濾出溶液濃縮,之後利用管柱層析法純化(己烷/乙酸乙酯之比=7/3),獲得3,4-雙(苯甲氧基)酚(1102,0.87g,產率:90%)。1
H-NMR (CDCl3
,300MHz):δ 7.25–7.42 (m, 10H), 6.80 (d, 1H, J =9.0 Hz), 6.48 (d, 1H, J = 3.0 Hz), 6.29 (dd, 1H, J = 3.0及9.0 Hz), 5.08 (d, 4H, J = 15 Hz), 4.55 (s, 1H);ESIMS m/z: 307.25 [M+H]+
。
步驟3)製備R-2-((3,4-雙(苯甲氧基)苯氧基)甲基)環氧乙烷(1103)
用乙醇(10ml)稀釋3,4-二苯甲氧基酚(1102,306mg,1.0mmol),然後依序加入KOH水溶液(KOH 66mg,1.2mmol,1ml)及(R)-2-(氯甲基)環氧乙烷(410ul,5.0mmol)。在室溫下攪拌反應混合物5個小時,然後在減壓下除去有機溶劑。再次用乙酸乙酯稀釋濃縮的反應混合物,用水之後鹽水洗滌。用無水硫酸鈉對萃取的有機層進行脫水,然後在減壓下過濾。濃縮濾出的有機層,及利用管柱層析法純化,獲得純R-2-((3,4-雙(苯甲氧基)苯氧基)甲基)環氧乙烷(1103,297mg,產率:82%)。ESIMS m/z:363.5 [M+H]+
。
步驟4)製備(R)-1-((2-(2-(2-胺乙氧基)乙氧基)乙基)胺基-3-(3,4-雙(苯甲氧基)苯氧基)丙-2-醇(AL-1)
將R-2-((3,4-雙(苯甲氧基)苯氧基)甲基)環氧乙烷(1103,270mg,0.75mmol)溶於無水乙醇(5ml)中,然後加入2,2'-(乙烷-1,2-二基雙(氧基))雙(乙烷-1-胺) (880mg,5.9mmol)且在室溫下攪拌8個小時。通過TLC確認反應後,在減壓下濃縮反應溶劑。於濃縮的反應中加入水,用二氯甲烷萃取(3×5mL)。用無水硫酸鈉對萃取的有機層進行脫水,然後在減壓下過濾。濃縮濾出的有機層,利用管柱層析法純化(二氯甲烷:甲醇=19:1),獲得(R)-1-((2-(2-(2-胺基乙氧基)乙氧基)乙基)胺基-3-(3,4-雙(苯甲氧基)苯氧基)丙-2-醇(AL-1,267mg,產率:70%)。ESIMS m/z:511.5 [M+H]+
。
步驟5)將(R)-1-((2-(2-(2-胺基乙氧基)乙氧基)乙基)胺基-3-(3,4-雙(苯甲氧基)苯氧基)丙-2-醇(AL-1,100mg,0.19mmol)溶於DMF (4ml)中,然後依序加入1-乙基-3-(3-三甲基胺丙基)碳二亞胺(EDCI,44mg,0.285mmol)、羥苯并三唑(HOBt,38.5mg,0.285mmol)及視網酸(60mg,0.2mol)。之後,於其中加入N,N-二異丙基乙胺(DIPEA,0.6 ml),且於室溫下攪拌12個小時。於該反應中加入水,然後用乙酸乙酯萃取二次,之後用鹽水洗滌有機層一次。用無水硫酸鈉對有機層進行脫水,及在減壓下過濾。在減壓下使濾液濃縮,並利用高解析度液相層析法純化,獲得白色固體,(2E,4E,6E,8E)-N-(2-(2-(2-(((R)-3-(3,4-雙(苯甲氧基)苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙基)-3,7-二甲基-9-(2,6,6-三甲基環己-1-烯-1-基)壬-2,4,6,8-四烯醯胺 (RTEG-1104,60mg,產率:41%)。1
H NMR (400 MHz, DMSO-d6) δ (ppm) 1.01(s, 6H), 1.53(m, 2H), 1.74-1.79(m, 5H), 1.96(m, 2H), 2.12(s, 3H), 2.42(s, 3H), 2.56-2.81(m, 4H), 3.04(m, 2H), 3.52-3.54(m, 6H), 3.67(m, 2H), 3.95-4.05(m, 3H), 5.16(s, 4H), 5.37(br s, 1H), 5.91(br s, 1H), 6.22(s, 2H), 6.51(s, 4H), 6.57-6.61(m, 2H), 6.98(d, 1H), 7.32-7.48(m, 10H), 8.51(br s, 1H);ESI-MS Calcd m/z for C49
H64
N2
O7
[M+H]+
794.35 Found 793.06範例2 :(2E,4E,6E,8E)-N-(2-(2-(2-((3,4- 雙( 苯甲氧基) 苯甲基) 胺基) 乙氧基) 乙氧基) 乙基)-3,7- 二甲基-9-(2,6,6- 三甲基環己-1- 烯-1- 基) 壬-2,4,6,8- 四烯醯胺之製備(RTEG-1105)
步驟1)製備2-(2-(2-胺基乙氧基)乙氧基) -N-(3,4-雙(苯甲氧基)苯甲基)乙-1-胺(AL-2)
將3,4-雙(苯甲氧基)苯甲醛(1101,0.5g,1.57mmol)溶於乙腈(ACN,10ml)中,然後於其中加入叔-丁基(2-(2-(2-胺基乙氧基)乙氧基)乙基)胺甲酸酯(468mg,1.88mmol),並在60至70°C下攪拌5個小時。冷卻至室溫後,慢慢地於反應中加入硼氫化鈉(NaBH4
,106mg,2.82mmol),然後在室溫下攪拌約5個小時。於該反應溶液中加入水使反應完全,用乙酸乙酯(50mLx3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,並使用硫酸鈉進行脫水。將濾出溶劑濃縮,然後再次溶於二氯甲烷(6ml)中。於其中加入三氟乙酸(TFA,2ml),在室溫下攪拌2個小時,然後在減壓下將溶劑濃縮。利用管柱層析法(二氯甲烷/甲醇=15:1)純化濃縮物,得到淡黃色液體,2-(2-(2-胺基乙氧基)乙氧基)-N-(3,4-雙(苯甲氧基)苯甲基)乙-1-胺(AL-2,590mg,產率:84%)。1
H NMR (400 MHz, DMSO-d6
) δ (ppm) 2.59(t, 2H), 3.32-3.61(m, 12H), 4.62(br s, 1H), 5.10(s, 4H), 6.82(d, 1H), 6.97(d, 1H, 7.06(s, 1H), 7.30-7.46(m, 10H)。
步驟2)用與範例1之步驟 5相同的方法,合成(2E,4E,6E,8E)-N-(2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙基)-3,7-二甲基-9-(2,6,6-三甲基環己-1-烯-1-基)壬-2,4,6,8-四烯醯胺(RTEG-1105)。1
H NMR (400 MHz, DMSO-d6
) δ (ppm) 1.01(s, 6H), 1.54(m, 2H), 1.75-1.80(m, 5H), 1.98(m, 2H), 2.12(s, 3H), 2.42(s, 3H), 2.72(t, 2H), 3.04(t, 2H), 3.51-3.54(m, 6H), 3.67(t, 2H), 3.76(s, 2H), 5.14(s, 4H), 6.22(m, 2H), 6.37(br s, 1H), 6.51(s, 4H), 6.80(d, 1H), 6.87(d, 1H), 6.99(s, 1H), 7.31-7.46(m, 10H), 8.41(br s, 1H);ESI-MS Calcd m/z for C47
H60
N2
O5
[M+H]+
734.3 Found 733.01範例3 :(R)-N-(15-(3,4- 雙( 苯甲氧基) 苯氧基)-14- 羥基-3,6,9- 三㗁-12- 氮雜十五基)-4- 苯丁醯胺(PBA-1104) 之製備
步驟1)將2,2'-(2,2'-氧雙(乙烷-2,1-二基)雙(氧基))二乙胺(21g,73.1mmol)溶於二氯甲烷(400ml)中,然後依序加入羥苯并三唑(HOBt,12.3g,91.5mmol)與1-乙基-3-(3-二甲基胺丙基)碳二亞胺(EDCI,17.6g,91.5mmol)。於其中加入三乙胺(Et3
N,18.5g,180mmol)並冷卻至0°C。將4-苯丁酸(15g,91.5mmol)溶於二氯甲烷(200ml)中,然後加至該反應,接著在室溫下攪拌12個小時。用水稀釋反應混合物,然後用二氯甲烷萃取(50ml*3次),用無水硫酸鈉對有機層進行脫水並過濾。在減壓下濃縮濾液,然後利用矽膠管柱層析法純化,得到黃色液體,N-(2-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)乙基)-4-苯丁醯胺(TL-1,12g)。ESIMS m/z:339.1 [M+H]+
。
步驟2)將N-(2-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)乙基)-4-苯丁醯胺(TL-1,100mg,0.295mmol)溶於甲醇(6ml)中,然後於其中加入R-2-((3,4-雙(苯甲氧基)苯氧基)甲基)環氧乙烷(1103,128mg,0.354mmol),在50°C下攪拌10個小時。在減壓下濃縮反應混合物,並用矽膠管柱層析法純化,得到白色固體,(R)-N-(15-(3,4-雙(苯甲氧基)苯氧基)-14-羥基-3,6,9-三㗁-12-氮雜十五烷基)-4-苯丁醯胺(PBA-1104,2013mg,產率:50%)。1
H NMR (400 MHz, DMSO-d6
) δ (ppm) 1.25 (s, 1H ), 1.92 ( m, 2H ), 2.31(t, 2H), 2.56-2.81(m, 4H), 3.28(m, 2H), 3.51-3.53(m, 10H), 3.67(t, 2H), 3.95-4.20(m, 3H), 5.14(s, 4H), 5.37(br s, 1H), 5.90(br s, 1H), 6.57(s, 1H), 6.67(d, 1H), 6.96(d, 1H), 7.16(m, 3H), 7.30(mk 8H), 7.45(m, 4H);ESI-MS Calcd m/z for C41
H52
N2
O8
[M+H]+
701.5 Found 700.87範例4 :N-(1-(3,4- 雙( 苯甲氧基) 苯基)-5,8,11- 三㗁-2- 氮雜十三烷-13- 基)-4- 苯丁醯胺(PBA-1105) 之製備
步驟1)製備N-(1-(3,4-雙(苯甲氧基)苯基)-5,8,11-三㗁-2-氮雜十三烷-13-基)-4-苯丁醯胺(PBA-1105)
將N-(2-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)乙基)-4-苯丁醯胺(TL-1) (10g,29.6mmol)溶於甲醇(MeOH,150mL)中,然後於其中加入3,4-二羥基苯甲醛(10.3g,32.3mmol)。之後,在65°C下攪拌該混合物約5個小時。冷卻至室溫後,加入硼氫化鈉(NaBH4
,2.2g,57.9mmol),且在室溫下攪拌約5個小時。於該反應溶液中加入水使反應完全,用乙酸乙酯(50mLx3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,使用硫酸鈉去除水。將濾出溶劑濃縮,然後利用使用矽膠之管柱層析法純化(二氯甲烷/甲醇=15:1)。從而獲得黃色液體,N-(1-(3,4-雙(苯甲氧基)苯基)-5,8,11-三㗁-2-氮雜十三烷-13-基)-4-苯丁醯胺(PBA-1105) (10.3g)。1
H NMR (CDCl3
, 400 MHz) δ (ppm) 7.45-7.42 (m, 4H), 7.36-7.29 (m, 7H), 7.27-7.26 (m, 1H), 7.18-7.15 (m, 3H), 6.99 (d, 1H), 6.83 (d, 1H), 6.41 (brs, 1H), 5.15 (d, 4H), 3.71 (s, 2H), 3.60-3.55 (m, 10H), 3.55-3.49 (m, 2H), 3.42-3.39 (m, 2H), 2.75-2.73 (m, 2H), 2.65-2.61 (m, 2H), 2.18-2.15 (m, 2H), 1.97-1.93 (m, 2H), 1.25 (brs, 1H);ESI-MS Calcd m/z for C39
H48
N2
O6
[M+H]+
641.00 Found 640.82範例5 :3-(3-( 苯并[d][1,3] 二氧雜環戊烯-5- 基)-1H- 吡唑-5- 基)-N-(2-(2-(2-((3-((4- 氟苯甲基) 氧基)) 苯甲基) 胺基) 乙氧基) 乙氧基) 乙基) 苯胺(Anle138b-F105) 之製備
步驟1)製備3-((4-氟苯甲基)氧基)苯甲醛(YT-102)
將碳酸鉀(K2
CO3
,112.5g,0.81mol)及1-(溴甲基)-4-氟苯(95g,0.50mol)加至配製於乙腈(ACN,500mL)中之3-羥苯甲醛(50g,0.41mol)之溶液中。令混合物在60°C下攪拌約10個小時。反應完成後,過濾並濃縮反應溶液。於其中加入石油醚/乙酸乙酯(PE/EA,20:1,20mL),進一步攪拌約1個小時,然後透過濾器濃縮。從而獲得灰白色固體,3-((4-氟苯甲基)氧基)苯甲醛(YT-102,25g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.98 (s, 1H), 7.54-7.50 (m, 5H), 7.36 (m, 1H), 7.23 (m, 2H), 5.18 (s, 2H)
步驟2)製備叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-溴苯基)-1H-吡唑-1-羧酸酯(T-1)
將3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-溴苯基)-1H-吡唑(200mg,0.58mmol)溶於二氯甲烷(DCM,4mL)中,然後加入三乙胺(TEA,88mg,0.87mmol)及二碳酸二叔丁酯(Boc2
O,153mg,0.70mmol)。在室溫下攪拌該混合物約4個小時。反應完成後,濃縮濾出的溶液,利用使用矽膠之管柱層析法純化(乙酸乙酯/石油醚=1:15至1:5)。從而獲得白色固體,叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-溴苯基)-1H-吡唑-1-羧酸酯(T-1,200mg)。1
H NMR (DMSO-d6
,400MHz) δ (ppm) 8.09-7.43 (m, 5H), 7.11-6.94 (m, 3H), 6.08 (s, 2H), 1.34 (d, J=20Hz, 9H)
步驟3)製備叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-((2,2-二甲基-4-側氧-3,8,11-三㗁-5氮雜十三烷-13-基)胺基)苯基)-1H-吡唑-1-羧酸酯(TL-2)
將叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-溴苯基)-1H-吡唑-1-羧酸酯(T-1,200mg,0.45mmol)溶於二甲基亞碸(DMSO,4mL)中,然後於其中加入叔丁基(2-(2-(2-胺基乙氧基)乙氧基)乙基)胺甲酸酯(L-1,168mg,0.68mmol)及叔丁醇鉀(t-BuOK,101mg,0.90mmol)。在120°C下攪拌該混合物約16個小時。將反應化合物過濾並濃縮,然後利用製備型高效液相層析法(Prep-HPLC)純化。從而獲得淡黃色固體,叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-((2,2-二甲基-4-側氧-3,8,11-三㗁-5氮雜十三烷-13-基)胺基)苯基)-1H-吡唑-1-羧酸酯(TL-2,180mg)。
步驟4)製備N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)苯胺(TL-3)
將叔丁基3-(苯并[d][1,3]二氧雜環戊烯-5-基)-5-(3-((2,2-二甲基-4-側氧-3,8,11-三㗁-5氮雜十三烷-13-基)胺基)苯基)-1H-吡唑-1-羧酸酯(TL-2,180mg,0.29mmol)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸/乙酸乙酯(1mL,3N)溶液。在室溫下攪拌該混合物約2個小時。將反應化合物過濾並濃縮。從而獲得白色固體,N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)苯胺(TL-3,100mg)。
步驟5)製備3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)-N-(2-(2-(2-((3-((4-氟苯甲基)氧基))苯甲基)胺基)乙氧基)乙氧基)乙基)丙胺(Anle138b-F105)
將N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)丙胺(TL-3,90mg,0.22mmol)溶於甲醇(MeOH,2mL)中,然後加入3-((4-氟苯甲基)氧基)苯甲醛(YT-102,50mg,0.22mmol),在65°C下攪拌。之後,在5°C下於其中加入硼氫化鈉(NaBH4
,16mg,0.44mmol),然後進一步攪拌約1個小時。將反應化合物濃縮,然後利用製備型高效液相層析法(Prep-HPLC)純化。從而獲得無色液體,3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)-N-(2-(2-(2-((3-((4-氟苯甲基)氧基))苯甲基)胺基)乙氧基)乙氧基)乙基)丙胺(Anle138b-F105,15mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 13.08 (brs, 1H), 7.47 (q, J=6Hz, 2H), 7.37-7.31 (m, 2H), 7.21-7.17 (m, 3H), 7.11 (t, J=8Hz, 1H), 7.00-6.96 (m, 5H), 6.88-6.82 (m, 2H), 6.56 (d, J=8Hz, 1H), 6.04 (s, 2H), 5.59 (brs, 1H), 5.04 (s, 2H), 3.66 (s, 2H), 3.60-3.52 (m, 6H), 3.47 (t, J=6Hz, 2H), 3.26-3.22 (m, 2H), 2.61 (t, J=5.6Hz, 2H); ESI-MS Calcd m/z for C36
H37
FN4
O5
[M+H]+
625.10 Found 624.71範例6 :(3R,4S,5S,6R)-5- 甲氧基-4-((2R,3R)-2- 甲基-3-(3- 甲基丁-2- 烯-1- 基) 環氧乙烷-2- 基)-1- 㗁螺[2.5] 辛烷-6- 基(13E,15E,17E,19E)-1-(3-( 苯甲氧基) 苯基)-12- 側氧-5,8- 二㗁-2,11- 二氮雜二十一-13,15,17,19- 四烯-21- 酸酯( 煙黴素-105) 之製備
步驟1)製備3-(苯甲氧基)苯甲醛(201)
將碳酸鉀(K2
CO3
,112.5g,0.81mol)及溴甲基苯(85g,0.50mol)加至配製於乙腈(ACN,500mL)中之3-羥苯甲醛(50g,0.41mol)溶液中。在60°C下攪拌該混合物約10個小時。反應完成後,將反應溶液過濾,然後濃縮。之後,於其中加入石油醚/乙酸乙酯(PE/EA,20:1,20mL),進一步攪拌約1個小時,接著透過濾器濃縮。從而獲得灰白色固體,3- (苯甲氧基)苯甲醛(201,25g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.97 (s, 1H), 7.54-7.51(m, 3H), 7.47 (d, J=7.2Hz, 2H), 7.42-7.34 (m, 4H), 5.19 (s, 2H)
步驟2)製備2-(2-(2-胺基乙氧基)乙氧基) -N-(3-(苯甲氧基)苯甲基)乙烷-1-胺(AL-3)
將3-(苯甲氧基)苯甲醛(201,50g,235.8mmol)溶於甲醇(MeOH,500mL)中,然後於其中加入2,2'-(乙烷-1,2-二基雙(氧基))二乙胺(L-2,34.9g,235.8mmol)。在65°C下攪拌該混合物約6個小時。冷卻至室溫後,加入硼氫化鈉(NaBH4
,8.95g,235.8mmol),在50°C下攪拌一整夜。加入水使反應完全,用乙酸乙酯(EtOAc,50mLx3)萃取化合物。用鹽水洗滌萃取的有機層,然後通過添加硫酸鈉(Na2
SO4
)除去水。將溶液濃縮,然後利用使用矽膠之管柱層析法純化(二氯甲烷/甲醇=12:1)。從而獲得黃色液體,2-(2-(2-胺基乙氧基)乙氧基)-N-(3-(苯甲氧基)苯甲基)乙烷-1-胺(AL-3,20g)。1
H NMR (DMSO+D2
O,400 MHz) δ (ppm) 7.41-7.29 (m, 5H), 7.18 (t, J=8Hz, 1H), 6.94 (s, 1H), 6.86-6.81 (m, 2H), 5.03 (s, 2H), 3.60 (s, 2H), 3.45-3.42 (m, 6H), 3.33 (t, J=5.6Hz, 2H), 2.57-2.52 (m, 4H); ESI-MS Calcd m/z for C20
H28
N2
O3
[M+H]+
345.10 Found 344.46
步驟3)製備(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)環氧乙烷-2-基)-1-㗁螺[2.5]辛烷-6-基(13E,15E,17E,19E)-1-(3-(苯甲氧基)苯基)-12-側氧-5,8-二㗁-2,11-二氮雜二十一-13,15,17,19-四烯-21-酸酯(煙黴素-105)
將2-(2-(2-胺基乙氧基)乙氧基)-N-(3-(苯甲氧基)苯甲基)乙烷-1-胺(AL-3,70mg,0.22mmol)溶於二氯甲烷(DCM,2mL)中,然後於其中加入煙黴素(100mg,0.22mmol)、羥基苯并三唑(HOBT,34mg,0.25mmol)、1-乙基-3-(3-二甲基胺丙基)碳二亞胺(EDCI,48mg,0.25mmol)及三乙胺(Et3
N,44mg,0.44mmol)。在30°C下攪拌該混合物約10個小時。反應完成後,用二氯甲烷(DCM,50mLx3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,及使用硫酸鈉除去水。將濾出的溶劑濃縮,然後利用製備型高效液相層析法(Prep-HPLC)純化。從而獲得黃色固體,(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)環氧乙烷-2-基)-1-㗁螺[2.5]辛烷-6-基(13E,15E,17E,19E)-1-(3-(苯甲氧基)苯基)-12-側氧-5,8-二㗁-2,11-二氮雜二十一-13,15,17,19-四烯-21-酸酯(煙黴素-105,3mg)。ESI-MS Calcd m/z for C46
H60
N2
O9
[M]+
784.90 Found 784.99範例7 :3-(3,5- 二氯苯基)-5-((R)-15-(3,4- 二苯乙氧基苯氧基)-14- 羥基-6,9- 二㗁-3,12- 二氮雜十五烷基)-5- 甲基㗁唑烷-2,4- 二酮( 乙烯菌核利-2204) 之製備
步驟1)製備3-羥基-4-苯乙氧基苯甲醛(A-1)
將3,4-二羥基苯甲醛(200g,1.4mol)溶於乙腈(ACN,2L)中,然後於其中加入碳酸鉀(K2
CO3
,260g,1.9mol)及1-(2-溴乙基)苯(267g,1.4mol)。在80°C下攪拌該混合物約16個小時。使用鹽酸(1.5L,1N)使反應完全後,用乙酸乙酯(EA,1LX3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,用硫酸鈉除去水,然後過濾。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=20:1至10:1)純化濃縮的溶液。從而獲得白色固體,3-羥基-4-苯乙氧基苯甲醛(A-1,320g)。ESI-MS Calcd m/z for C15
H14
O3
[M+H]+
243.0 Found 242.27
步驟2)製備3,4-二苯乙氧基苯甲醛(2201)
將3-羥基-4-苯乙氧基苯甲醛(A-1,320g,1.32mol)溶於四氫呋喃(THF,5L)中,然後於其中加入2-苯乙醇(193.5g,1.59mol)、三苯膦(PPh3
,520g,1.98mol)及偶氮二羧酸二異丙酯(DIAD,400g,1.98mol)。在65°C下攪拌該混合物約16個小時。於反應溶液中加入水(100mL)使反應完全,用乙酸乙酯(100mLx2)萃取。於萃取的有機溶劑層中加入硫酸鈉,以除去水,過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的化合物。從而獲得白色固體,3,4-二苯乙氧基苯甲醛(2201,160g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.81 (s, 1H), 7.51 (dd, J=8Hz and 1.6Hz, 1H), 7.40-7.17 (m, 12H), 4.27 (t, J=6.8Hz, 2H), 4.22 (t, J=6.8Hz, 2H), 3.06 (q, J=6.4Hz, 4H);ESI-MS Calcd m/z for C23
H22
O3
[M+H]+
346.90 Found 346.43
步驟3)製備3,4-二苯乙氧基酚(2202)
將3,4-二苯乙氧基苯甲醛(2201,160g,0.46mmol)溶於二氯甲烷(DCM,2L)中,然後於其中加入間氯過氧苯甲酸(m-CPBA,119g,069mmol)。在室溫下攪拌該混合物約16個小時。反應完成後,將該溶液過濾,然後濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚= 1:15至1:5)純化濃縮的溶液。從而獲得灰白色固體,3,4-二苯乙氧基酚(2202,100g)。ESI-MS Calcd m/z for C22
H22
O3
[M+H]+
335.00 Found 334.42
步驟4)製備(R)-2-((3,4-二苯乙氧基苯氧基)甲基)環氧乙烷(A-2)
將3,4-二苯乙氧基酚(2202) (5g,15mmol)溶於乙醇(EtOH,50mL)中,然後於其中加入水(2.5mL)及氫氧化鉀(KOH,1.93g,34.5mmol)。之後,加入(R)-2-(氯甲基)環氧乙烷(8g,87mmol)且在室溫下攪拌約16個小時。於該反應溶液中加入水(50mL)使反應完全,用乙酸乙酯(EA,20mLX3)萃取化合物。用鹽水洗滌萃取的有機溶劑,用硫酸鈉除去水,過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)萃取濃縮的溶液。從而獲得白色固體,(R)-2-((3,4-二苯乙氧基苯氧基)甲基)環氧乙烷(A-2,2.5g)。ESI-MS Calcd m/z for C25
H26
O4
[M+H]+
391.00 Found 390.48
步驟5)製備(R)-1-((2-(2-(2-胺基乙氧基)乙氧基)乙基)胺基)-3-(3,4-二苯乙氧基苯氧基)丙-2-醇 (AL-4)
將(R)-2-((3,4-二苯乙氧基苯氧基)甲基)環氧乙烷(A-2,20g,51.2mmol)溶於乙腈(ACN,200mL)中,然後於其中加入2-(2-(2-胺基乙氧基)乙氧基)乙胺(L-2,15.2g,102.5mmol)。在70°C下攪拌該混合物約40個小時。反應完成時,過濾該反應溶液並濃縮。利用使用矽膠之管柱層析法(二氯甲烷/甲醇=100:1至30:1)純化濃縮的溶液。從而獲得黃色液體,(R)-1-((2-(2-(2-胺基乙氧基)乙氧基)乙基)胺基)-3-(3,4-二苯乙氧基苯氧基)丙-2-醇(AL-4,12g)。1
H NMR (CD3
OD,400 MHz) δ (ppm) 8.52 (s, 3H), 7.30-7.20 (m, 10H), 6.85 (d, J=8Hz, 1H), 6.60 (d, J=2.8Hz, 1H), 6.47 (dd, J=8Hz and 2Hz, 1H), 4.16 (t, J=6.8Hz, 3H), 4.08 (t, J=6.8Hz, 2H), 3.96 (q, J=4Hz, 2H), 3.79 (t, J=5.2Hz, 2H), 3.70 (m, 7H), 3.32-3.25 (m, 3H), 3.17-2.98 (m, 8H);ESI-MS Calcd m/z for C31
H42
N2
O6
[M+H]+
539.20 Found 538.69
步驟6)製備液態3-(3,5-二氯苯基)-5-((R)-15-(3,4-二苯乙氧基苯氧基)-14-羥基-6,9-二㗁-3,12-二氮雜十五烷基)-5-甲基㗁唑烷-2,4-二酮(乙烯菌核利-2204)
將(R)-1-((2-(2-(2-胺基乙氧基)乙氧基)乙基)胺基)-3-(3,4-二苯乙氧基苯氧基)丙-2-醇(AL-4,120mg, 0.22mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入乙烯菌核利(117mg,0.33mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,過濾該溶液並濃縮。利用製備型高效液相層析法(Prep-HPLC)純化該濃縮的溶液。從而獲得無色液體,3-(3,5-二氯苯基)-5-((R)-15-(3,4-二苯乙氧基苯氧基)-14-羥基-6,9-二㗁-3,12-二氮雜十五烷基)-5-甲基㗁唑烷-2,4-二酮(乙烯菌核利-2204,15mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 1.65 (m, 3H), 2.65 (m, 4H), 2.97 (m, 4H), 3.17 (m, 2H), 3.42 (m, 8H), 3.57 (d, J=8Hz, 1H), 3.80 (m, 3H), 4.02 (t, J=8Hz, 2H), 4.13 (t, J=8Hz, 2H), 4.90 (b, 1H), 5.33 (m, 2H), 6.20 (m, 1H), 6.38 (d, J=8Hz, 1H), 6.54 (m, 1H), 6.82 (d, J=8Hz, 1H), 7.25 (m, 11H), 7.49 (d, J=1Hz, 1H), 7.76 (s, 1H), 9.70 (s, 1H);ESI-MS Calcd m/z for C43
H51
Cl2
N3
O9
[M+H]+
825.00 Found 824.79範例8 :(R)-1-(4-( 苯甲氧基)-3-(3- 苯丙氧基) 苯氧基)-3-((2-(2-(2-(4-(2- 苯基-5,7- 雙( 三氟甲基) 吡唑并1,5-a] 嘧啶-3- 基) 苯氧基) 乙氧基) 乙氧基) 乙基) 胺基) 丙-2- 醇(PHTPP-1304) 之製備
步驟1)製備4-(苯甲氧基)-3-羥苯甲醛(A-3)
將3,4-二羥苯甲醛(500g,3.62 mol)溶於乙腈(ACN,7L)中,然後於其中加入碳酸氫鈉(NaHCO3
,395g,4.71mol)及苯甲基溴(BnBr,619g,3.62 mol)。在80°C下攪拌該混合物約16個小時。使用鹽酸(3L,1N)使反應完全,用乙酸乙酯(3LX3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,用硫酸鈉除去剩餘的水,過濾除去雜質並濃縮。利用使用矽膠之管柱層析法(EA/PE =20:1至10:1)純化濃縮的溶液。從而獲得白色固體,4-(苯甲氧基)-3-羥苯甲醛(A-3,250g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.76 (s, 1H), 9.65 (s, 1H), 7.49 (d, J=6.8Hz, 2H), 7.42-7.34 (m, 4H), 7.29 (d, J=2Hz, 1H), 7.19 (d, J=8Hz, 1H), 5.23 (s, 2H)
步驟2)製備4-(苯甲氧基)-3-(3-苯丙氧基)苯甲醛(1301)
將4-(苯甲氧基)-3-羥苯甲醛(A-3,120g,526mmol)溶於四氫呋喃(THF,2L)中,然後於其中加入3-苯丙-1-醇(85.9g,631mmol)、三苯膦(PPh3
,206.9g,789mmol)及偶氮二羧酸二異丙酯(DIAD,159.5g,789mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,將反應混合物過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的溶液。從而獲得白色固體,4-(苯甲氧基)-3-(3-苯丙氧基)苯甲醛(1301,100g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.82 (s, 1H), 7.55-7.50 (m, 3H), 7.38 (t, J=7.2Hz, 3H), 7.36-7.34 (m, 1H), 7.29-7.25 (m, 3H), 7.21-7.16 (m, 3H), 5.26 (s, 2H), 4.04 (t, J=6.4Hz, 2H), 2.76 (t, J=8Hz, 2H), 2.04 (t, J=7.2Hz, 2H)
步驟3)製備4-(苯甲氧基)-3-(3-苯丙氧基)酚(1302)
將4-(苯甲氧基)-3-(3-苯丙氧基)苯甲醛(1301,100g,289mmol)溶於二氯甲烷(DCM,900mL)中,然後於其中加入間氯過氧苯甲酸(m-CPBA,74.7g,433mmol)。在室溫下攪拌該混合物約16個小時。反應完成時,過濾該反應混合物,然後濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:5)純化濃縮的溶液。從而獲得灰白色固體,4-(苯甲氧基)-3-(3-苯丙氧基)酚(1302,66g)。1
H NMR (DMSO-d6
, 400 MHz) δ (ppm) 9.00 (s, 1H), 7.44-7.18 (m, 10H), 6.81 (d, J=8Hz, 1H), 6.39 (d, J=2.8Hz, 1H), 6.22 (dd, J=8.8Hz and 2.8Hz, 1H), 4.96 (s, 2H), 3.90 (t, J=6Hz, 2H), 2.74 (t, J=8Hz, 2H), 2.01 (q, J=5.6Hz, 2H)
步驟4)製備(R)-2-((4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)甲基)環氧乙烷(A-4)
將4-(苯甲氧基)-3-(3-苯丙氧基)酚(1302,40g,60mmol)溶於乙醇(EtOH,800mL)中,然後於其中加入水(40mL)及氫氧化鉀(KOH,8.0g,143mmol)。之後,加入(R)-2-(氯甲基)環氧乙烷(33.2g,359mmol),然後在室溫下攪拌約16個小時。反應完成時,於反應溶液中加入水(1600mL)使反應完全,用乙酸乙酯(1600mLX3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,然後用硫酸鈉除去剩餘的水。利用濾器除去雜質,然後濃縮,利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的溶液。從而獲得白色固體,(R)-2-((4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)甲基)環氧乙烷(A-4,30g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 7.46-7.17 (m, 10H), 6.93 (d, J=8.8Hz, 1H), 6.61 (d, J=3.2Hz, 1H), 6.43 (dd, J=8.8Hz and 2.8Hz, 1H), 5.02 (s, 2H), 4.23 (dd, J=7.6Hz and 2.8Hz, 1H), 3.97 (t, J=6.4Hz, 2H), 3.75 (dd, J=7.2Hz and 1.6Hz, 1H), 3.28 (m, 1H), 2.82 (dd, J=5.2Hz and 4Hz, 1H), 2.75 (t, J=7.6Hz, 2H), 2.73-2.67 (m, 1H), 2.01 (m, 2H)
步驟5)製備叔丁基(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(L-4)
將2-(2-(2-胺基乙氧基)乙氧基)乙-1-醇(L-3,5g,33mmol)溶於二氯甲烷(DCM,100mL)中,然後於其中加入三乙胺(TEA,4.1g,40mmol)及二碳酸二叔丁酯(Boc2
O,8.1g,37mmol)。在室溫下攪拌該混合物約16個小時。反應完成時,過濾該反應混合物,然後濃縮。利用使用矽膠之管柱層析法(EA/PE=1:3至1:1)純化濃縮的溶液。從而獲得無色液體,叔丁基(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(L-4,4.2g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 6.74 (m, 1H), 4.56 (t, J=5.6Hz, 1H), 3.51-3.46 (m, 6H), 3.42-3.37 (m, 4H), 3.07-3.03 (m, 2H), 1.37 (s, 9H)
步驟6)製備叔丁基(2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-4)
將叔丁基(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(L-4,300mg,1.2mmol)溶於四氫呋喃(THF,5mL)中,然後於其中加入4-[2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基]酚(PHTPP,509mg,1.2mmol)、三苯膦(PPh3
,377mg,1.44mmol)及偶氮二羧酸二異丙酯(DIAD,291mg,1.44mmol)。在65°C下攪拌該混合物約16個小時。反應完成後,中止反應,過濾該溶液並濃縮。利用使用矽膠之管柱層析法(DCM/MeOH=100:1至50:1)純化濃縮的溶液。從而獲得黃色固體,叔丁基(2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-4,200mg)。
步驟7)製備2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙-1-胺(TL-5)
將叔丁基(2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-4,200mg, 0.31mmol)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物約2個小時。反應完成後,終止反應,過濾該溶液並濃縮。對濃縮的溶液進行純化處理,從而獲得黃色固體,2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙-1-胺(TL-5,120mg)。
步驟8)製備(R)-1-(4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)-3-((2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺基)丙-2-醇(PHTPP-1304)
將2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙-1-胺(TL-5,120mg,0.22mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入(R)-2-((4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)甲基)環氧乙烷(A-4,117mg,0.33mmol)。在65°C下攪拌該混合物約16個小時。反應完成後,終止反應,過濾該溶液並濃縮,利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色固體,(R)-1-(4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)-3-((2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺基)丙-2-醇(PHTPP-1304,15mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 1.99 (m, 2H), 2.73 (m, 6H), 3.55 (m, 8H), 3.80 (m, 5H), 3.94 (t, J=8Hz, 2H ), 4.13 (t, J=4Hz, 2H), 4.99 (s, 2H), 6.40 (d, J=8Hz, 1H), 6.55 (d, J=4Hz, 1H), 6.89 (d, J=8Hz, 1H), 7.04 (d, J=8Hz, 2H), 7.18 (t, J=4Hz, 3H), 7.27 (dd, J=4Hz and 4Hz, 3H), 7.35 (m, 4H), 7.44 (m, 5H), 7.61 (m, 2H), 8.07 (s, 1H), 8.42 (s, 1H);ESI-MS Calcd m/z for C51
H50
F6
N4
O7
[M+H]+
945.10 Found 944.97範例9 :(R,Z)-4-((2-(2-(2-((3-(3,4- 二苯乙氧基苯氧基)-2- 羥丙基) 胺基) 乙氧基) 乙氧基) 乙基) 亞胺基)-2- 苯基-4H- 𠳭 唏-5,6,7- 三醇( 貝加因-2204) 之製備
步驟1)製備叔丁基(2-(2-(2-胺基乙氧基)乙氧基)乙基)胺甲酸酯(L-1)
將2,2'-(乙烷-1,2-二基雙(氧基))二乙胺(L-2,5g,33.7mmol)溶於二氯甲烷(DCM,100mL)中,然後於其中加入二碳酸二叔丁酯(Boc2
O,7.36g,33.7mmol)。在室溫下攪拌該混合物約16個小時。反應完成後,過濾該反應溶液並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:3至1:1)純化濃縮的溶液。從而獲得無色液體,叔丁基(2-(2-(2-胺基乙氧基)乙氧基)乙基)胺甲酸酯(L-2,2.2g)。
步驟2)製備叔丁基(Z)-(2-(2-(2-((5,6,7-三羥基-2-苯基-4H-𠳭唏-4-亞基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-6)
將叔丁基(2-(2-(2-胺基乙氧基)乙氧基)乙基)胺甲酸酯(TL-6,300mg,1.21mmol)溶於甲醇(MeOH,5mL)中,然後於其中加入5,6,7-三羥黃酮(貝加因,326mg, 1.21mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,過濾該反應溶液並濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色固體,叔丁基(Z)-(2-(2-(2-((5,6,7-三羥基-2-苯基-4H-𠳭唏-4-亞基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-6,120mg)。
步驟3)製備(Z)-4-((2-(2-(2-胺基乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-𠳭唏-5,6,7-三醇(TL-7)
將叔丁基(Z)-(2-(2-(2-((5,6,7-三羥基-2-苯基-4H-𠳭唏-4-亞基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-6,120mg,0.24mmol)溶於乙酸乙酯(EA,2mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物約2個小時。反應完成時,用乙酸乙酯萃取反應混合物,過濾並濃縮。從而獲得黃色固體,(Z)-4-((2-(2-(2-胺基乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-𠳭唏-5,6,7-三醇(TL-7,90mg)。
步驟4)製備(R,Z)-4-((2-(2-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-𠳭唏-5,6,7-三醇(貝加因-2204)
將(Z)-4-((2-(2-(2-胺基乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-𠳭唏-5,6,7-三醇(TL-7,90mg,0.22mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入(R)-2-((3,4-二苯乙氧基苯氧基)甲基)環氧乙烷(A-2,87mg,0.22mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,過濾該反應溶液並濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色固體,(R,Z)-4-((2-(2-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-𠳭唏-5,6,7-三醇(貝加因-2204,12mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 2.91 (m, 7H), 3.35 (m, 11H), 3.80 (m, 3H), 3.96 (t, J=8Hz, 2H), 4.08 (t, J=8Hz, 2H), 6.32 ( dd, J=4Hz and 4Hz, 1H), 6.37 (s, 1H), 6.47 (s, 1H), 6.76 (d, J=12Hz, 2H), 7.25 (m, 10H), 7.58 (t, J=4Hz, 3H), 7.99 (d, J=8Hz, 2H), 8.42 (s, 1H); ESI-MS Calcd m/z for C46
H50
N2
O10
[M+H]+
791.20 Found 790.91範例10 :E)-5-(4-(2-(2-(2-((3,4- 雙( 苯甲氧基) 苯甲基) 胺基) 乙氧基) 乙氧基) 乙氧基) 苯乙烯基) 苯-1,3- 二醇( 白藜蘆醇-1105) 之製備
步驟1)製備2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙-1-醇(AL-5)
將3,4-雙(苯甲氧基)苯甲醛(1101,25g,78.6mmol)溶於甲醇(MeOH,250mL)中,然後於其中加入2-(2-(2-胺基乙氧基)乙氧基)乙醇(L-3,11.7g,78.6mmol)。在65°C下攪拌該混合物約6個小時。冷卻至室溫後,進一步加入硼氫化鈉(NaBH4
,3g,78.6mmol),然後在50°C下攪拌一整夜。於該反應溶液中加入水使反應完全,用乙酸乙酯(EtOAc,50mLx3)萃取化合物。用鹽水洗滌萃取的化合物,用硫酸鈉除去剩餘的水。過濾後,將溶液濃縮且利用使用矽膠之管柱層析法(二氯甲烷/甲醇=20:1)純化濃縮的溶液。從而獲得黃色液體,2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙-1-醇(AL-5,13g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 7.46-7.30 (m, 10H), 7.06 (d, J=1.6Hz, 1H), 6.97 (d, J=8Hz, 1H), 6.82 (d, J=1.2Hz, 1H), 5.10 (d, J=4Hz, 4H), 3.61 (s, 2H), 3.50-3.39 (m, 11H), 2.58 (t, J=6Hz, 2H) ESI-MS Calcd m/z for C27
H33
N5
O5
[M+H]+
452.10 Found 451.56
步驟2)製備叔丁基(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(AL-6)
將2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙-1-醇(AL-5,500mg,1.11mmol)溶於二氯甲烷(DCM,6mL)中,然後於其中加入三乙胺(TEA,168mg,1.66mmol)及二碳酸二叔丁酯(Boc2
O,290mg,1.33mmol)。在室溫下攪拌該混合物約4個小時。反應完成時,將反應溶液過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:5至1:1)純化濃縮的溶液。從而獲得無色的叔丁基(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(AL-6,520mg)。
步驟3)製備叔丁基(E)-(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-(4-(3,5-二羥苯乙烯基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(ATL-1)
將叔丁基(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(AL-6,300mg,0.54g)溶於四氫呋喃(THF,5mL)中,然後於其中加入白藜蘆醇(149mg,0.65mmol)、三苯膦 (PPh3
,214mg,0.82mmol)及偶氮二羧酸二異丙酯DIAD (165mg,0.82mmol)。在65°C下攪拌該混合物約16個小時。反應完成後,將反應溶液過濾並濃縮。利用使用矽膠之管柱層析法(二氯甲烷/甲醇=100:1至50:1)純化濃縮的溶液。從而獲得黃色固體,叔丁基(E)-(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-(4-(3,5-二羥苯乙烯基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(ATL-1,200mg)。
步驟4)製備E)-5-(4-(2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙氧基)苯乙烯基)苯-1,3-二醇(白藜蘆醇-1105)
將叔丁基(E)-(3,4-雙(苯甲氧基)苯甲基)(2-(2-(2-(4-(3,5-二羥苯乙烯基)苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(ATL-1,200mg)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物約2個小時。反應完成後,將反應溶液過濾,然後濃縮。利用高解析液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得白色固體,E)-5-(4-(2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙氧基)苯乙烯基)苯-1,3-二醇(白藜蘆醇-1105,15mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 2.58 (t, J=4Hz, 2H), 3.45 (t, J=4Hz, 2H), 3.51 (m, 2H), 3.57 (m, 4H), 3.73 (m, 2H), 4.06 (m, 2H), 5.07 (m, 4H ), 6.12 (m, 1H), 6.40 (m, 2H), 6.90 (m, 7H), 7.39 (m, 12H), 9.20 (s, 2H); ESI-MS Calcd m/z for C41
H43
NO7
[M+H]+
662.10 Found 661.80範例11 :(R)-2-(4-( 苯并[d] 噻唑-2- 基) 苯基)-14-(3,4- 雙( 苯甲氧基) 苯氧基)-5,8- 二㗁-2,11- 二氮雜十四烷-13- 醇(BTA-1-1104) 之製備
步驟1)製備2,2-二甲基-4-側氧-3,8,11-三㗁-5-氮雜十三烷-13-基-甲磺酸酯(L-5)
將叔丁基(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(L-4,1g,4.0mmol)溶於二氯甲烷(DCM,15mL)中,然後於其中加入三乙胺(TEA,0.486g,4.8mmol)及甲磺醯氯(MsCl,0.504g,4.4mmol)。在室溫下攪拌該混合物約4個小時。反應完成時,萃取化合物,過濾,然後濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:5至1:1)純化濃縮的溶液。從而獲得無色液體,2,2-二甲基-4-側氧-3,8,11-三㗁-5氮雜十三烷-13-基-甲磺酸酯(L-5,1g)。
步驟2)製備叔丁基(2-(2-(2-((4-(苯并[d]噻唑-2-基)苯基)(甲基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-8)
將2,2-二甲基-4-側氧-3,8,11-三㗁-5-氮雜十三烷-13-基-甲磺酸酯(L-5,300mg,0.92mmol)溶於二甲基亞碸(DMSO,5mL)中,然後於其中加入2-(4′-甲胺基苯基)苯并噻唑(BTA-1,220mg,0.92mmol)及叔丁醇鉀(t-BuOK,154mg,1.37mmol)。在120°C下攪拌該混合物約16個小時。反應完成時,將反應溶液過濾,然後濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色液體,叔丁基(2-(2-(2-((4-(苯并[d]噻唑-2-基)苯基)(甲基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-8,180mg)。
步驟3)製備N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-4-(苯并[d]噻唑-2-基)-N-甲苯胺(TL-9)
將叔丁基(2-(2-(2-((4-(苯并[d]噻唑-2-基)苯基)(甲基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-8,180mg,0.38mmol)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物2個小時。反應完成時,萃取化合物,過濾,然後濃縮。從而獲得黃色固體,N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-4-(苯并[d]噻唑-2-基)-N-甲苯胺(TL-9,120mg)。
步驟4)製備(R)-2-(4-(苯并[d]噻唑-2-基)苯基)-14-(3,4-雙(苯甲氧基)苯氧基)-5,8-二㗁-2,11-二氮雜十四烷-13-醇(BTA-1-1104)
將N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-4-(苯并[d]噻唑-2-基)-N-甲苯胺(TL-9,120mg,0.33mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入(R)-2-((3,4-雙(苯甲氧基)苯氧基)甲基)環氧乙烷(1103,117mg, 0.33mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,萃取化合物,過濾,然後濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色固體,(R)-2-(4-(苯并[d]噻唑-2-基)苯基)-14-(3,4-雙(苯甲氧基)苯氧基)-5,8-二㗁-2,11-二氮雜十四烷-13-醇(BTA-1-1104,8mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 1.15 (d, J=8Hz, 3H), 1.23 (s, 1H), 2.67 (m, 4H), 3.50 (m, 11H), 3.81 (m, 4H), 5.01 (s, 2H), 5.10 (s, 2H ), 6.27 (d, J=8Hz, 1H), 6.41 (d, J=8Hz, 1H), 6.69 (m, 3H), 6.91 (d, J=12Hz, 1H), 7.38 (m, 12H), 7.79 (d, J=8Hz, 2H), 7.89 (d, J=8Hz, 1H), 7.90 (d, J=8Hz, 1H), 8.40 (s, 1H); ESI-MS Calcd m/z for C43
H47
N3
O6
S [M+H]+
734.10 Found 733.92範例12 :(1E,6E)-1-(4-(2-(2-(2-(((R)-3-(3-( 苯甲氧基)-4- 苯乙氧基苯氧基)-2- 羥丙基) 胺基) 乙氧基) 乙氧基) 乙氧基)-3- 甲氧苯基)-7-(4- 羥基-3- 甲氧苯基) 庚-1,6- 二烯-3,5- 二酮( 薑黃素-1204) 之製備
步驟1)製備4-(苯甲氧基)-3-苯乙氧基苯甲醛(1201)
將4-(苯甲氧基)-3-羥苯甲醛(A-3,50g,219mmol)溶於四氫呋喃(THF,1L)中,然後於其中加入2-苯乙醇(32.1g,263mmol)、三苯膦(PPh3
,86.2g,329mmol)及偶氮二羧酸二異丙酯(DIAD,66.4g,329mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,萃取化合物,過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的溶液。從而獲得白色固體,4-(苯甲氧基)-3-苯乙氧基苯甲醛(1201,25g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.82 (s, 1H), 7.52 (dd, J=8Hz and 2Hz, 1H), 7.43-7.40 (m, 5H), 7.37-7.32 (m, 3H), 7.28-7.21 (m, 4H), 5.21 (s, 2H), 4.26 (t, J=6.4Hz, 2H), 3.05 (t, J=6.4Hz, 2H)
步驟2)製備4-(苯甲氧基)-3-苯乙氧基酚(1202)
將4-(苯甲氧基)-3-苯乙氧基苯甲醛(1201,50g,150mmol)溶於二氯甲烷(DCM,500mL)中,然後於其中加入間氯過氧苯甲酸(m-CPBA,39g,225mmol)。在室溫下攪拌該混合物約16個小時。反應完成時,萃取化合物,過濾並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:5)純化濃縮的溶液。從而獲得白色固體,4-(苯甲氧基)-3-苯乙氧基酚(1202,32mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.00 (s, 1H), 7.36-7.20 (m, 10H), 6.78 (d, J=8Hz, 1H), 6.43 (d, J=2.8Hz, 1H), 6.22 (dd, J=8Hz and 2.8Hz, 1H), 4.86 (s, 2H), 4.13 (t, J=6.8Hz, 2H), 3.02 (t, J=6.4Hz, 2H)
步驟3)製備(R)-2-((4-(苯甲氧基)-3-苯乙氧基苯氧基)甲基)環氧乙烷(1203)
將4-(苯甲氧基)-3-苯乙氧基酚(1203,40g,64mmol)溶於乙醇(EtOH,800mL)中,然後於其中加入水(40mL)及氫氧化鉀(KOH,8.2g,146mmol)。之後,加入(R)-2-(氯甲基)環氧乙烷(34.6g,374mmol),進一步在室溫下攪拌16個小時。於反應溶液中加入水(1600mL)使反應完全,用乙酸乙酯(1600mLX3)萃取。用鹽水洗滌萃取的有機溶劑層及用硫酸鈉除去剩餘的水。過濾所產生的材料除去雜質,並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的溶液。從而獲得白色固體,(R)-2-((4-(苯甲氧基)-3-苯乙氧基苯氧基)甲基)環氧乙烷(1203,34g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 7.38-7.20 (m, 10H), 6.90 (d, J=8.8Hz, 1H), 6.64 (d, J=2Hz, 1H), 6.41 (dd, J=8.8Hz and 2.8Hz, 1H), 4.93 (s, 2H), 4.25-4.17 (m, 3H), 3.75 (dd, J=11.2Hz and 6.4Hz, 1H), 3.28 (m, 1H), 3.03 (t, J=6.8Hz, 2H), 2.81 (t, J=4.4Hz, 1H), 2.67 (dd, J=5.2Hz and 2.8Hz, 1H)
步驟4)製備叔丁基(2-(2-(2-(4-((1E,6E)-7-(4-羥基-3-甲氧苯基)-3,5-二側氧庚-1,6-二烯-1-基)-2-甲氧苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-10)
將叔丁基(2-(2-(2-羥乙氧基)乙氧基)乙基)胺甲酸酯(L-4,300mg,1.2mmol)溶於四氫呋喃(THF,5mL)中,然後於其中加入薑黃素(442mg,1.2mmol)、三苯膦(PPh3
,377mg,1.44mmol)及偶氮二羧酸二異丙酯(DIAD,291mg, 1.44mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,萃取化合物,過濾並濃縮。利用使用矽膠之管柱層析法(二氯甲烷/甲醇=100:1至50:1)純化濃縮的溶液。從而獲得黃色固體,叔丁基(2-(2-(2-(4-((1E,6E)-7-(4-羥基-3-甲氧苯基)-3,5-二側氧庚-1,6-二烯-1-基)-2-甲氧苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-10,200mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 9.87 (brs, 1H), 7.57 (dd, J=16Hz and 4Hz, 2H), 3.34 (dd, J=12Hz and 1.6Hz, 2H), 7.24 (dd, J=8Hz and 1.2Hz, 1H), 7.16 (dd, J=8Hz and 1.2Hz, 1H), 7.02 (d, J=8Hz, 1H), 6.85-6.74 (m, 4H), 6.08 (s, 1H), 4.13 (t, J=4Hz, 2H), 3.83 (m, 6H), 3.75 (t, J=4Hz, 2H), 3.59 (q, J=4Hz, 2H), 3.52 (q, J=4Hz, 2H), 3.40-3.38 (m, 4H), 3.06 (q, J=6Hz, 2H), 1.36 (s, 9H)
步驟5)製備(1E,6E)-1-(4-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮(TL-11)
將叔丁基(2-(2-(2-(4-((1E,6E)-7-(4-羥基-3-甲氧苯基)-3,5-二側氧庚-1,6-二烯-1-基)-2-甲氧苯氧基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-10,200mg,0.33mmol)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物約2個小時。反應完成後,萃取化合物,過濾,然後濃縮。從而獲得黃色固體, (1E,6E)-1-(4-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮(TL-11,120mg)。
步驟6)製備(1E,6E)-1-(4-(2-(2-(2-(((R)-3-(3-(苯甲氧基)-4-苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮(薑黃素-1204)
將(1E,6E)-1-(4-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮(TL-11,120mg,0.24mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入(R)-2-((4-(苯甲氧基)-3-苯乙氧基苯氧基)甲基)環氧乙烷(1203,90mg,0.24mmol)。在65°C下攪拌該混合物約16個小時。反應完成時,萃取化合物,過濾,然後濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得黃色固體,(1E,6E)-1-(4-(2-(2-(2-(((R)-3-(3-(苯甲氧基)-4-苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮(薑黃素-1204,12mg)。1
H NMR (DMSO-d6
+D2
O, 400 MHz) δ (ppm) 2.81 (m, 1H), 2.92 (m, 3H), 3.00 (t, J=6.4Hz, 2H), 3.56 (m, 9H), 3.80 (m, 9H), 3.97 (b, 2H), 4.09 (m, 2H), 4.14 (t, J=6.4Hz, 2H), 4.88 (s, 2H), 6.36 (dd, J=8.8Hz and 2.8Hz, 1H), 6.56 (d, J=2.8Hz, 1H), 6.79 (m, 4H), 6.97 (d, J=8Hz, 1H), 7.23 (m, 14H), 7.53 (d, J=16Hz, 2H), 8.33 (s, 1H); ESI-MS Calcd m/z for C51
H57
NO12
[M]+
876.10 Found 876.01範例13 :(R)-1-(3- 苯乙氧基苯氧基)-3-((2-(2-(2-((6-( 三氟甲氧基)) 苯并[d] 噻唑-2- 基) 胺基) 乙氧基) 乙氧基) 乙基) 胺基) 丙-2- 醇( 利魯唑-204) 之製備
步驟1)製備3-苯乙氧基酚(A-5)
將間苯二酚(50g,0.45mol)溶於乙腈(ACN,500 mL)中,然後於其中加入碳酸鉀(K2
CO3
,112.5g,0.81mol)及(2-溴乙基)苯(83.2g,0.45mol)。在60°C下攪拌該混合物約10個小時。反應完成後,萃取化合物,過濾並濃縮。利用使用矽膠之管柱層析法(石油醚/乙酸乙酯=5:1)純化濃縮的溶液。從而獲得黃色液體,3-苯乙氧基酚(A-5,25g)。1
H NMR (CDCl3
,400 MHz) δ (ppm) 7.31-7.23 (m, 5H), 7.11 (t, J=8Hz, 1H), 6.50-6.39 (m, 3H), 4.74 (s, 1H), 4.14 (m, 2H), 3.08 (t, J=7.2Hz, 2H)
步驟2)製備(R)-2-((3-苯乙氧基苯氧基)甲基)環氧乙烷(A-6)
將3-苯乙氧基酚(A-5,25g,116.8mmol)溶於乙醇(EtOH,500mL)中,然後於其中加入水(25mL)及氫氧化鉀(KOH,11.1g,278.3mmol)。之後,加入(R)-2-(氯甲基)環氧乙烷(64.6g,698.8mmol),然後在室溫下攪拌約16個小時。於反應溶液中加入水(1000mL)使反應完全,用乙酸乙酯(500mLX3)萃取化合物。用鹽水洗滌萃取的有機溶劑層,用硫酸鈉除去剩餘的水。過濾所產生的材料除去雜質並濃縮。利用使用矽膠之管柱層析法(乙酸乙酯/石油醚=1:15至1:10)純化濃縮的溶液。從而獲得黃色液體(R)-2-((3-苯乙氧基苯氧基)甲基)環氧乙烷(A-6,18g)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 7.32-7.28 (m, 4H), 7.24-7.14 (m, 2H), 6.52 (m, 3H), 4.29 (dd, J=11.2Hz and 2Hz, 1H), 4.16 (t, J=6.8Hz, 2H), 3.79 (m, 1H), 3.34 (s, 1H), 3.01 (t, J=6Hz, 2H), 2.82 (t, J=4Hz, 1H), 2.69-2.67 (m, 1H)
步驟3)製備叔丁基(2-(2-(2-((6-(三氟甲氧基)苯并)[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-12)
將2,2-二甲基-4-側氧-3,8,11-三㗁-5氮雜十三烷-13-基-甲磺酸酯(L-5,300mg,0.92mmol)溶於二甲基亞碸(DMSO,5mL)中,然後於其中加入利魯唑(214mg,0.92mmol)及叔丁醇鉀(t-BuOK,154mg,1.37mmol)。在120°C下攪拌該混合物約16個小時。反應完成後,萃取化合物,過濾,然後濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得淡黃色液體,叔丁基(2-(2-(2-((6-(三氟甲氧基)苯并[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-12,180mg)。1
H NMR (DMSO-d6
,400 MHz) δ (ppm) 8.27-8.25 (m, 1H), 7.78 (d, J=1.6Hz, 1H), 7.41 (d, J=8Hz, 1H), 7.18 (dd, J=8Hz and 1.6Hz, 1H), 6.74 (m, 1H), 3.63-3.51 (m, 12H), 3.05 (q, J=6Hz, 2H), 1.36 (s, 11H)
步驟4)製備N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-6-(三氟甲氧基)苯并[d]噻唑-2-胺(TL-13)
將叔丁基(2-(2-(2-((6-(三氟甲氧基)苯并[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺甲酸酯(TL-12,180mg,0.39mmol)溶於乙酸乙酯(EA,4mL)中,然後於其中加入鹽酸(g)/乙酸乙酯(1mL)。在室溫下攪拌該混合物約2個小時。反應完成時,萃取化合物,過濾並濃縮。從而獲得黃色固體,N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-6-(三氟甲氧基)苯并[d]噻唑-2-胺(TL-13,120mg)。
步驟5)製備(R)-1-(3-苯乙氧基苯氧基)-3-((2-(2-(2-((6-(三氟甲氧基))苯并[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺基)丙-2-醇(利魯唑-204)
將N-(2-(2-(2-胺基乙氧基)乙氧基)乙基)-6-(三氟甲氧基)苯并[d]噻唑-2-胺(TL-13,120mg,0.33mmol)溶於甲醇(MeOH,2mL)中,然後於其中加入(R)-2-((3-苯乙氧基苯氧基)甲基)環氧乙烷(A-6,89mg,0.33mmol)。在65°C下攪拌該混合物約16個小時。反應完成後,萃取化合物,過濾並濃縮。利用製備型高效液相層析法(Prep-HPLC)純化濃縮的溶液。從而獲得無色液體,(R)-1-(3-苯乙氧基苯氧基)-3-((2-(2-(2-((6-(三氟甲氧基))苯并[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺基)丙-2-醇(利魯唑-204,15mg)。1
H NMR (400 MHz,DMSO-d6
) δ (ppm) 2.60 (m, 4H), 3.00 (t, J=8Hz, 2H), 3.52 (m, 10H), 3.85 (m, 3H), 4.15 (t, J=8Hz, 2H), 6.48 (dd, J=12Hz and 8Hz, 3H), 7.18 (m, 3H), 7.31 (d, J=4Hz, 4H), 7.43 (d, J=12Hz, 1H), 7.75 (s, 1H ); ESI-MS Calcd m/z for C31
H36
F3
N3
O6
S [M+H]+
636.10 Found 635.70實驗例1 ,利用免疫墨點法評估培養細胞中p62 蛋白之低聚合反應活性
為了評估化合物1至13 (範例1-13)之p62蛋白低聚合反應活性之功效,收集HEK293細胞株,其是人胚胎腎源性細胞。用範例之化合物及p62配位體化合物YTK-1105處理細胞,及用DMSO處理的細胞作為對照組。
為測量以此等化合物處理之細胞中的胞內p62蛋白活化及低聚合反應,將各別的細胞分配至100 pi盤中。在進一步培養24個小時後,收集細胞,如此細胞完全地貼附至盤的表面。於各樣本中注入100ul之胞溶緩衝液(20mM Tris (pH 7.4)、150mM NaCl、1% Triton X-100、2mM NaF、2mM EDTA、2mM β-甘油磷酸鹽、5mM正釩酸鈉、1mM PMSF、亮抑酶肽(leupeptin)、抑肽酶(aprotinin)),將細胞溶解。根據測得的總蛋白濃度,用測試化合物在室溫下處理各樣本2個小時,然後加入樣本緩衝液,使其在95°C下反應10分鐘。反應後,從樣本中取25ul並將其分配於各個丙烯醯胺凝膠孔中,然後進行免疫墨點法。免疫墨點顯示來自三個或更多個獨立實驗之代表性結果。結果示於圖2a至2c中。
如圖2a至2c所示,證實與作為對照組之DMSO處理時的不同,當用根據本發明之AUTOTAC嵌合化合物及p62配位體化合物YTK-1105處理時,導致p62蛋白之單體減少,同時低聚物及高分子聚集體增加。實驗例2 ,利用免疫墨點法評估培養細胞中之標靶蛋白質降解
為了評估化合物(範例1-13)之標靶蛋白質降解功效,將主要表達標靶蛋白質之細胞株(MCF7、NTERA-2、ACHN、U87-MG、LNCaP、HEK293T)或基因重組細胞株(SH-SY5Y-tau、HeLa-HttQ97、PC12-a-synA30P)培養在12孔盤中,且按濃度以相應的AUTOTAC嵌合化合物處理,然後進行如實驗例1中之免疫墨點法。免疫墨點顯示來自三個或更多個獨立實驗之代表性結果。結果示於圖3a、3b及3c中。
如圖3a、3b及3c所示,證實當用根據本發明之AUTOTAC嵌合化合物處理時,標靶蛋白質位準隨著化合物之濃度逐漸增加。實驗例3 ,利用免疫墨點法評估培養細胞中之標靶蛋白質降解機制
為了評估前述化合物(範例1-13)之標靶蛋白質降解機制是否由自噬介導,將主要表達標靶蛋白質之細胞株或基因重組細胞株培養在12孔盤中,且單獨用2.5uM 之對應的AUTOTAC嵌合化合物處理或結合10uM之羥氯喹(hydrxoxychloroquine;HCQ),一種自噬-溶酶體途徑之抑制劑,處理,然後進行如實驗例1之免疫墨點法。免疫墨點顯示來自三個或更多個獨立實驗之代表性結果。結果示於圖4a及4b中。
如圖4a及4b所示,證實當單獨用根據本發明之AUTOTAC嵌合化合物處理時,該標靶蛋白質位準減少,而當結合HCQ (一種自噬-溶酶體途徑之抑制劑)處理時,降低的標靶蛋白質位準再次增加。實驗例4 ,利用免疫墨點法比較評估培養細胞中之標靶蛋白質降解功效
為評估化合物(範例1-13)之標靶蛋白質降解功效是否優於該p62配位體或該標靶蛋白質配位體(其是嵌合組份)之標靶蛋白質降解功效,將主要表達標靶蛋白質之細胞株或基因重組細胞株培養在12孔盤中,且用相應的AUTOTAC嵌合化合物、p62配位體或標靶蛋白質配位體處理,然後進行如實驗例1之免疫墨點法。免疫墨點顯示來自三個或更多個獨立實驗之代表性結果。結果示於圖5a至5c中。
如圖5a至5c所示,證實與用p62配位體或標靶蛋白質配位體處理後的相比,用根據本發明之AUTOTAC嵌合化合物處理後之標靶蛋白質位準顯著地減少。實驗例5 ,利用免疫螢光染色及共軛焦顯微鏡評估培養細胞中P62 介導的遞送靶標蛋白質之活性
為證實用化合物(範例1-13)處理後p62介導遞送標靶蛋白質至自噬的功效,使用p62及各標靶蛋白質作為標記,進行免疫螢光染色。將覆蓋玻璃置於用於免疫螢光染色之24孔盤上,培養主要表達標靶蛋白質之細胞株或基因重組細胞株。分配細胞並培養24個小時,然後用2.5uM根據本發明之新穎的AUTOTAC嵌合配位體處理。將細胞進一步培養24個小時以發揮化合物之作用,除去培養基,在室溫下使用甲醛固定細胞。為了防止非專一性染色,讓細胞與封閉溶液在室溫下反應1個小時,然後使用該封閉溶液處理稀釋成特定比率之p62抗體及標靶蛋白質抗體,然後在室溫下反應1個小時。在用PBS洗滌抗體處理的細胞三次後,使用封閉溶液將山羊來源二級抗體稀釋至特定比例,然後在室溫下反應30分鐘。再次用PBS洗滌細胞三次,並進行對胞內核染色之DAPI染色處理,然後使用共軛焦顯微鏡觀察p62與LC3之表達位準、胞內螢光斑點形成及胞內共存之位準。結果示於圖6a至6c中。免疫螢光染色顯示來自三個或更多個獨立實驗之代表性結果。
如圖6a至6c所示,證實在用根據本發明之AUTOTAC嵌合化合物處理後,胞內p62蛋白之螢光斑點的形成、胞內標靶蛋白質之螢光斑點的形成及其局部共存增加。
圖1顯示一示意圖,其顯示根據本發明之新穎的AUTOTAC嵌合化合物之構型,及顯示該化合物與p62蛋白結合,同時與標靶蛋白質、胞器及聚集體結合,其被遞送至自噬小體(其是透過p62蛋白之巨自噬的介導體),最後被溶酶體降解。
圖2a、2b及2c是顯示AUTOTAC化合物之相應p62蛋白的低聚合反應及高分子量聚集功效之免疫墨點分析結果。此等顯示p62蛋白之低聚合反應及高分子量聚集作用隨著該化合物的處理而增加。免疫墨點顯示來自三或多個獨立實驗之代表性結果。
圖3、3b及3c是顯示相應的標靶蛋白質被根據本發明之AUTOTAC化合物降解之功效的免疫墨點分析結果。此顯示該標靶蛋白質位準隨著該化合物的處理而減少。免疫墨點顯示來自三或多個獨立實驗之代表性結果。
圖4a及4b是顯示相應標靶蛋白質之降解功效機制由根據本發明之AUTOTAC化合物,透過自噬-溶酶體途徑介導之免疫墨點分析結果。此顯示該標靶蛋白質位準經由該化合物的處理而減少,而當用自噬-溶酶體途徑之抑制劑羥氯喹(HCQ)處理時,該標靶蛋白質位準再次增加。免疫墨點顯示來自三或多個獨立實驗之代表性結果。
圖5a、5b及5c是顯示本發明之AUTOTAC嵌合化合物之標靶蛋白質降解功效,分別優於單獨p62配位體或標靶結合配位體之標靶蛋白質降解功效之免疫墨點分析結果。其顯示相較於用該p62配位體或該標靶蛋白質配位體處理後,用AUTOTAC嵌合化合物處理後之標靶蛋白質位準顯著地減少。免疫墨點顯示來自三或多個獨立實驗之代表性結果。
圖6a、6b及6c是顯示由根據本發明之AUTOTAC嵌合化合物將標靶蛋白質與p62蛋白一起遞送至自噬的功效之免疫螢光染色分析結果。其可證實在用該化合物處理後,胞內螢光斑點(puncta)及標靶蛋白質及p62蛋白與該AUTOTAC化合物的共存逐漸增加。
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Claims (21)
- 一種嵌合化合物,其包含一p62配位體、一標靶結合配位體(TBL)及一連接子。
- 如請求項1之嵌合化合物,其中該p62配位體具有以下化學式2之結構或其衍生結構:
- 如請求項1之嵌合化合物,其中該連接子具有-Q-(CH2CH2O)x-(CH2)y-P-或-Q-(CH2CH2CH2O)x-(CH2)y-P-或-Q-(CH2CH2NH)x-(CH2)y-P-或-Q-(CH2CH2CONH)x-(CH2)y-P-之結構,其中Q包括-NH-、-O-、=N--N(CH3)-,其是通過與該標靶結合配位體結合而改質之部分;P包括-NH-、-O-、-CH2-、-C(=O)-,其是通過與p62配位體結合而改質之部分;x是0至4之整數;及y是0至3之整數。
- 如請求項4之嵌合化合物,其中W是苯基;L是-(CH2)n1-或-O-(CH2)n2-CH(OH)-,但條件是-O-(CH2)n2-CH(OH)-中之O與苯環鍵結,其中n1是0至1之整數;n2是1至2之整數;m是0至2之整體;Ra是氫或-O-(CH2)n3-R'1,R'1是未取代的或經羥基、氟基、氯基、溴基、甲基、乙基、甲氧基、乙氧基、硝基、胺基或二甲胺基取代的苯基,n3是1至4之整數;Rb是羥基或-O-(CH2)n4-R'2, R'2是未取代的或經羥基、氟基、氯基、溴基、甲基、乙基、甲氧基、乙氧基、硝基、胺基或二甲胺基取代的苯基,n4是1至4之整數;Rc是-(CH2)n5-OH、-(CH2)n5-NH-C(=NH)NH2、-C(=NH)NH2、-(CH2)n5-O-(CH2)n5-OH、-CONH(CH2)n5-OH、-CO(CH2)n6-OH、-(CH2)n6-CH(NH2)-COOH或-(CH2)n6-CONH2,n5是2至3之整數,n6是1至2之整數,及該Rd是氫、鹵素、C1-2烷氧基或C1-2烷基。
- 如請求項5之嵌合化合物,其中該P與該p62配位體間之鍵結為-CONH-、-O-、-NH-、-NHCO-或-COO-。
- 如請求項1之嵌合化合物,其以選自由下列化合物1至13所構成之群組之化合物表示:1)(2E,4E,6E,8E)-N-(2-(2-(2-(((R)-3-(3,4-雙(苯甲氧基)苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙基)-3,7-二甲基-9-(2,6,6-三甲基環己-1-烯-1-基)壬-2,4,6,8-四烯醯胺;2)(2E,4E,6E,8E)-N-(2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙基)-3,7-二甲基-9-(2,6,6-三甲基環己-1-烯-1-基)壬-2,4,6,8-四烯醯胺;3)(R)-N-(15-(3,4-雙(苯甲氧基)苯氧基)-14-羥基 -3,6,9-三-12-氮雜十五烷基)-4-苯丁醯胺;4)N-(1-(3,4-雙(苯甲氧基)苯基)-5,8,11-三-2-氮雜十三烷-13-基)-4-苯丁醯胺;5)3-(3-(苯并[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑-5-基)-N-(2-(2-(2-((3-((4-氟苯甲基)氧基))苯甲基)胺基)乙氧基)乙氧基)乙基)苯胺;6)(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)環氧乙烷-2-基)-1-螺[2.5]辛烷-6-基(13E,15E,17E,19E)-1-(3-(苯甲氧基)苯基)-12-側氧-5,8-二-2,11-二氮雜二十一-13,15,17,19-四烯-21-酸酯;7)3-(3,5-二氯苯基)-5-((R)-15-(3,4-二苯乙氧基苯氧基)-14-羥基-6,9-二-3,12-二氮雜十五烷基)-5-甲基唑烷-2,4-二酮;8)(R)-1-(4-(苯甲氧基)-3-(3-苯丙氧基)苯氧基)-3-((2-(2-(2-(4-(2-苯基-5,7-雙(三氟甲基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)乙氧基)乙氧基)乙基)胺基)丙-2-醇;9)(R,Z)-4-((2-(2-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙基)亞胺基)-2-苯基-4H-唏-5,6,7-三醇;10)(E)-5-(4-(2-(2-(2-((3,4-雙(苯甲氧基)苯甲基)胺基)乙氧基)乙氧基)乙氧基)苯乙烯基)苯-1,3-二醇;11)(R)-2-(4-(苯并[d]噻唑-2-基)苯基)-14-(3,4-雙 (苯甲氧基)苯氧基)-5,8-二-2,11-二氮雜十四烷-13-醇;12)(1E,6E)-1-(4-(2-(2-(2-(((R)-3-(3-(苯甲氧基)-4-苯乙氧基苯氧基)-2-羥丙基)胺基)乙氧基)乙氧基)乙氧基)-3-甲氧苯基)-7-(4-羥基-3-甲氧苯基)庚-1,6-二烯-3,5-二酮;13)(R)-1-(3-苯乙氧基苯氧基)-3-((2-(2-(2-((6-(三氟甲氧基))苯并[d]噻唑-2-基)胺基)乙氧基)乙氧基)乙基)胺基)丙-2-醇。
- 一種用於預防、改善或治療疾病的藥學組成物,其包含如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物。
- 如請求項9之藥學組成物,其中該疾病是癌症、蛋白質病、罕見或難治的疾病。
- 如請求項9之藥學組成物,其直接消除引起該疾病之致病蛋白質。
- 如請求項10之藥學組成物,其中該蛋白質病是神經退化性疾病、α-1抗胰蛋白酶缺乏症、角膜病變、色素性視網膜炎、第2型糖尿病或囊性纖維化。
- 如請求項12之藥學組成物,其中該神經退化性疾病選自由下列所構成之群組:萊姆病(Lyme borreliosis)、致死性家族性失眠症、庫賈氏症(CJD)、多發性硬化症(MS)、癡呆、阿茲海默氏症、癲癇、帕金森氏症、中風、杭丁頓氏舞蹈症、匹克症(Picks disease)、肌肉萎縮性脊髓側索硬化症(ALS)、脊髓小腦性失調症、其 它多麩醯胺酸(Poly-Q)疾病、遺傳性腦澱粉樣血管病變、家族性澱粉樣多發性神經病變、原發性全身性澱粉樣變性(AL澱粉樣變性)、反應性全身性澱粉樣變性(AA澱粉樣變性)、注射局部澱粉樣變性、β-2微球蛋白澱粉樣變性、遺傳性非神經病性澱粉樣變性、亞歷山大氏症及芬蘭型遺傳性全身性澱粉樣變性(Finnish hereditary systemic amyloidosis)。
- 一種用於自噬遞送或降解致病病理蛋白質及錯誤折疊蛋白質之藥學組成物,其包括如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於增加標靶蛋白質之降解。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於增加胞器及結構體之降解。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於增加侵犯細胞之病毒及細菌之降解。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於將藥物或小分子化合物遞 送至自噬及溶酶體。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於p62之自低聚合(self-oligomerization)及自噬活化。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於藉由將細胞中的特定蛋白質連接至p62且將其等遞送至自噬來增加透過溶酶體之降解。
- 一種如請求項1至8中任一項之嵌合化合物、或其藥學上可接受的鹽、立體異構物、或水合物於製造一製劑之用途,該製劑係用於透過內體將連結至一治療抗體的一藥物遞送至溶酶體,該治療抗體會專一性地結合至曝露在細胞膜上之蛋白質。
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TW108126238A TWI727377B (zh) | 2018-07-24 | 2019-07-24 | 新穎的p62配體化合物及包含其之用於預防、改善或治療蛋白質構象病(proteinopathies)的組成物 |
TW108126236A TWI722503B (zh) | 2018-07-24 | 2019-07-24 | 新穎的autotac嵌合化合物及包含其之用於透過經靶定之蛋白質降解來預防、改善或治療疾病的組成物 |
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JP7313726B2 (ja) * | 2018-07-24 | 2023-07-25 | プロテック・インコーポレイテッド | 新規なp62リガンド化合物、これを含むタンパク質異常疾患の予防、改善または治療用組成物 |
WO2020256444A1 (ko) * | 2019-06-18 | 2020-12-24 | 서울대학교산학협력단 | p62 리간드 화합물 및 이의 ER-파지 촉진 용도 |
WO2023014006A1 (ko) * | 2021-08-02 | 2023-02-09 | 서울대학교산학협력단 | Ras의 표적 분해를 위한 화합물 |
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CN114573570B (zh) * | 2022-02-21 | 2023-05-30 | 中山大学 | 一类α-突触核蛋白靶向化合物及其制备方法和应用 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013022919A1 (en) * | 2011-08-08 | 2013-02-14 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
WO2016200827A1 (en) * | 2015-06-11 | 2016-12-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
WO2017030292A1 (ko) * | 2015-08-18 | 2017-02-23 | 서울대학교 산학협력단 | P62 zz 도메인에 결합하는 리간드 또는 아르기닌화된 bip에 의해 매개되는 오토파지 활성을 통한 신경변성 질환 예방 및 치료 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4167581A (en) * | 1972-12-15 | 1979-09-11 | Imperial Chemical Industries Limited | Alkanolamine derivatives and pharmaceutical compositions and uses thereof |
US4471116A (en) * | 1982-07-28 | 1984-09-11 | Hoffmann-La Roche Inc. | Substituted (10H-phenothiazin-10-L)-propyl-1-piperazines |
US4857522A (en) | 1988-03-21 | 1989-08-15 | E. R. Squibb & Sons, Inc. | Derivatives of pravastatin for inhibiting cholesterol biosynthesis |
US20040009932A1 (en) | 2002-04-26 | 2004-01-15 | Kathleen Phelan | Antibacterial compounds with activity against penicillin-resistant streptococcus pneumoniae |
CN102229602A (zh) | 2011-05-13 | 2011-11-02 | 中山大学 | 他克林杂合物与制备方法及其在治疗神经退行性疾病药物中的应用 |
US8890745B2 (en) * | 2011-10-27 | 2014-11-18 | Raytheon Company | RF gun barrel detection system |
EP3039022A4 (en) | 2013-08-29 | 2017-08-16 | Baylor College Of Medicine | Compositions and methods for the treatment of metabolic and body weight related disorders |
KR101594168B1 (ko) * | 2013-10-02 | 2016-02-15 | 서울대학교산학협력단 | p62의 ZZ 영역에 의해 매개되는 자가포식 조절 방법 및 그 용도 |
CN108366992A (zh) * | 2015-11-02 | 2018-08-03 | 耶鲁大学 | 蛋白水解靶向嵌合体化合物及其制备和应用方法 |
KR20170023045A (ko) * | 2017-02-20 | 2017-03-02 | 서울대학교산학협력단 | p62 ZZ 도메인에 결합하는 리간드 또는 아르기닌화된 BiP에 의해 매개되는 오토파지 활성을 통한 신경변성 질환 예방 및 치료 |
CN112105598B (zh) | 2018-03-26 | 2023-06-27 | 普罗泰克株式会社 | 用于预防或治疗肥胖或代谢综合征的化合物和包含其的药学组合物 |
JP7313726B2 (ja) | 2018-07-24 | 2023-07-25 | プロテック・インコーポレイテッド | 新規なp62リガンド化合物、これを含むタンパク質異常疾患の予防、改善または治療用組成物 |
WO2020256444A1 (ko) * | 2019-06-18 | 2020-12-24 | 서울대학교산학협력단 | p62 리간드 화합물 및 이의 ER-파지 촉진 용도 |
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- 2023-03-22 JP JP2023045691A patent/JP2023076525A/ja active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013022919A1 (en) * | 2011-08-08 | 2013-02-14 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
WO2016200827A1 (en) * | 2015-06-11 | 2016-12-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
WO2017030292A1 (ko) * | 2015-08-18 | 2017-02-23 | 서울대학교 산학협력단 | P62 zz 도메인에 결합하는 리간드 또는 아르기닌화된 bip에 의해 매개되는 오토파지 활성을 통한 신경변성 질환 예방 및 치료 |
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