TWI802627B - 陽離子性脂質 - Google Patents
陽離子性脂質 Download PDFInfo
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- TWI802627B TWI802627B TW107147438A TW107147438A TWI802627B TW I802627 B TWI802627 B TW I802627B TW 107147438 A TW107147438 A TW 107147438A TW 107147438 A TW107147438 A TW 107147438A TW I802627 B TWI802627 B TW I802627B
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- acid
- nucleic acid
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Abstract
本發明之課題,為提供一種能將活性成分,尤其核酸,以優良效率導入細胞的技術及其所用之陽離子性脂質等。
本發明之解決手段為下述式(I)所示之化合物或其鹽。式中,n表示2至5之整數,R表示直鏈狀C1-5烷基、直鏈狀C7-11烯基或直鏈狀C11二烯基,波線各自獨立地表示順型或反型之鍵結。
Description
本發明係關於可將作為活性成分之核酸導入多種細胞、組織或臟器的陽離子性脂質。再者,本發明係關於含有該陽離子性脂質之脂質粒子、及含有該脂質粒子及核酸之組成物。
近年,以核酸作為活性成分之核酸醫藥的研究開發盛行。例如,多個包含siRNA、miRNA、miRNA mimic或反義核酸等核酸而具有標的mRNA之分解作用或功能抑制作用之核酸醫藥的研究正在進行。又,包含編碼目的蛋白質之mRNA等而用於使目的蛋白質於細胞內表現之核酸醫藥的研究亦在進行。與此等研究開發相關,以高效率將核酸導入細胞、組織或臟器用之技術,亦被開發作為藥物送達系統(DDS)技術。
就上述DDS技術而言,先前已知將核酸與脂質混合,形成複合體後,經由上述複合體,使核酸被細胞攝取之技術。就形成上述複合體所用之脂質而言,先前已知陽離子性脂質、親水性聚合物脂質、輔助脂質等。就上述陽離子性脂質而言,已知例如以下先前技術文獻所記載之化合物。
在專利文獻1中,記載下式所示之化合物或其鹽等。
專利文獻2中,記載下式所示之化合物或其鹽等。
式中,W表示式-NR1R2或式-N+R3R4R5(Z-);R1及R2各自獨立地表示C1-4烷基或氫原子;R3、R4及R5各自獨立地表示C1-4烷基;Z-表示陰離子;X表示可經取代之C1-6伸烷基;YA、YB及YC各自獨立地表示可經取
代之次甲基;LA、LB及LC各自獨立地表示可經取代之亞甲基或鍵結鍵;RA1、RA2、RB1、RB2、RC1及RC2各自獨立地表示可經取代之C4-10烷基。
[專利文獻1]WO2003/102150號小冊子
[專利文獻2]WO2016/021683號小冊子
能將核酸以高效率導入細胞的陽離子性脂質,在藥效表現、安全性(低毒性)等方面優良,可期待其在具有優良治療效果之核酸醫藥的創出有所貢獻。又,期待能將核酸導入各種細胞的陽離子性脂質可能創造出針對各種組織中發生之各種疾病的核酸醫藥。然而,於現況,尚未出現能充分滿足此等者。
本發明之目的,為提供可將核酸以優異效率導入細胞之技術及其所使用的陽離子性脂質等。又,從其他觀點而言,本發明之目的為提供可將核酸導入各種細胞之技術及其所使用的化合物等。
本發明人等為解決上述課題而進行專心檢討之結果,發現藉由使用下述式所示的化合物或其鹽,可解決上述課題,於是完成本發明。
亦即,本發明至少關於以下之發明。
[1]
[式(I)中,n表示2至5之整數;R表示直鏈狀C1-5烷基、直鏈狀C7-11烯基或直鏈狀C11二烯基;波線各自獨立地表示順型或反型之鍵結]。
[2]
(9Z)-十四碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
[3]
(9Z)-十四碳-9-烯酸3-((5-(二甲基胺基)戊醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
[4]
(9Z)-十四碳-9-烯酸3-((6-(二甲基胺基)己醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
[5]
一種脂質粒子,其含有第1項記載之化合物或其鹽。
[6]
一種核酸導入用組成物,其含有核酸及第5項記載之脂質粒子。
[7]
如第6項記載之組成物,其中核酸為RNA。
[7a]
如第6項記載之組成物,其中核酸為DNA。
[8]
如第7項記載之組成物,其中RNA為mRNA或siRNA。
再者,在本說明書中,將「式(I)所示之化合物」記載為「化合物(I)」。又,將「式(I)所示之化合物或其鹽」稱為「本發明之化合物」。將含有「式(I)所示之化合物或其鹽(本發明之化合物)之脂質粒子」稱為「本發明之脂質粒子」。將「含有核酸及本發明之脂質粒子的核酸導入用組成物」稱為「本發明之組成物」。
藉由本發明,變成可將核酸以優異之效率對細胞、組織或臟器導入。又,藉由本發明,可將核酸導入多種細胞、組織或臟器(例如,癌細胞)。藉由本發明,可得到核酸導入多種細胞、組織或臟器之醫藥或研究用試藥。再者,藉由本發明,在核酸導入細胞、組織或臟器之情況,該核酸所具有之活性(例如,藥效)的表現效率高。
以下,關於本說明書中所用的各取代基之定義加以詳述。除非特別記載,各取代基具有以下之定義。
在本說明書中,就「直鏈狀C1-5烷基」而言,例如,可列舉甲基、乙基、丙基、丁基、戊基。
在本說明書中,就「直鏈狀C7-11烯基」而言,例如,可列舉1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、5-庚烯基、6-庚烯基、1-辛烯基、2-辛烯基、3-辛烯基、4-辛烯基、5-辛烯基、6-辛烯基、7-辛烯基、1-壬烯基、2-壬烯基、3-壬烯基、4-壬烯基、5-壬烯基、6-壬烯基、7-壬烯基、8-壬烯基、1-癸烯基、2-癸烯基、3-癸烯基、4-癸烯基、5-癸烯基、6-癸烯基、7-癸烯基、8-癸烯基、9-癸烯基、1-十一碳烯基、2-十一碳烯基、3-十一碳烯基、4-十一碳烯基、5-十一碳烯基、6-十一碳烯基、7-十一碳烯基、8-十一碳烯基、9-十一碳烯基、10-十一碳烯基。此等直鏈狀C7-11烯基由於包含1個碳-碳雙鍵,可取得順型及反型之構造,任一種構造均可。
在本說明書中,就「直鏈狀C11二烯基」而言,例如,可列舉1,3-十一碳二烯基、1,4-十一碳二烯基、1,5-十一碳二烯基、1,6-十一碳二烯基、1,7-十一碳二烯基、1,8-十一碳二烯基、1,9-十一碳二烯基、1,10-十一碳二烯基、2,4-十一碳二烯基、2,5-十一碳二烯基、2,6-十一碳二烯基、2,7-十一碳二烯基、2,8-十一碳二烯基、2,9-十一碳二烯基、2,10-十一碳二烯基、3,5-十一碳二烯基、3,6-十一碳二烯基、3,7-十一碳二烯基、3,8-十一碳二烯基、3,9-十一碳二烯基、3,10-十一碳二烯基、4,6-十一碳二烯基、4,7-十一碳二烯基、4,8-十一碳二烯基、4,9-十一碳二烯基、4,10-十一碳二烯基、5,7-十一碳二烯基、5,8-十一碳二烯基、5,9-十一碳二烯基、5,10-十一碳二
烯基、6,8-十一碳二烯基、6,9-十一碳二烯基、6,10-十一碳二烯基、7,9-十一碳二烯基、7,10-十一碳二烯基、8,10-十一碳二烯基。此等直鏈狀C11二烯基由於包含2個碳-碳雙鍵,雖可分別互相獨立取得順型及反型之構造,然而可分別為任一種構造。
式(I)中之n及波線的較佳例如以下所示。
n較佳為3至5之整數,更佳為3。
波線較佳為兩者均為順型之鍵結。
化合物(I)之較佳具體例如以下說明。
化合物(A):n為3至5之整數,R為順型之直鏈狀C7-11烯基,波線為兩者均成為順型之鍵結的化合物。
化合物(B):n為4,R為2個碳-碳雙鍵之兩者為順型之直鏈狀C11二烯基,波線為兩者均成為順型之鍵結的化合物。
化合物(C):n為2或3,R為直鏈狀C1-5烷基,波線為兩者均成為順型之鍵結的化合物。
化合物(I)之更佳具體例如以下說明。
化合物(A1):n為3至5之整數,R為順型之5-庚烯基、7-壬烯基或9-十一碳烯基,波線為兩者均成為順型之鍵結的化合物。
化合物(B1):n為4,R為2個碳-碳雙鍵均為順型之2,5-十一碳二烯基,波線為兩者均成為順型之鍵結的化合物。
化合物(C1):n為2或3,R為甲基、丙基、或戊基,波線為兩者均為順型之鍵結的化合物。
就化合物(I)之鹽而言,以藥理學上可容許之鹽為較佳,例如,可列舉與無機鹼之鹽、與有機鹼之鹽、與無機酸之鹽、與有機酸之鹽、與鹼性或酸性胺基酸之鹽。
就與無機鹼之鹽的較佳例而言,可列舉鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土金屬鹽;鋁鹽、銨鹽。較佳為鈉鹽、鉀鹽、鈣鹽、鎂鹽,更佳為鈉鹽、鉀鹽。
就與有機鹼之鹽的較佳例而言,可列舉與三甲基胺、三乙基胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、胺基丁三醇[參(羥基甲基)甲基胺]、三級丁基胺、環己基胺、苄基胺、二環己基胺、N,N-二苄基伸乙基二胺之鹽。
就與無機酸之鹽的較佳例而言,可列舉與氫氟酸、鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸之鹽。較佳為與鹽酸之鹽、與磷酸之鹽。
就與有機酸之鹽的較佳例而言,可列舉與甲酸、乙酸、三氟乙酸、酞酸、富馬酸、草酸、酒石酸、馬來酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸之鹽。
就與鹼性胺基酸之鹽的較佳例而言,可列舉與精胺酸、離胺酸、鳥胺酸之鹽。
就與酸性胺基酸之鹽的較佳例而言,可列舉與天冬胺酸、麩胺酸之鹽。
在本發明中,本發明之化合物可使用作為陽離子性脂質。陽離子性脂質在溶劑或分散媒中,可與複數個分子一起形成複合體。上述複
合體中,除本發明之化合物外,亦可包含其他成分。就上述其他成分之例而言,可列舉其他脂質成分及核酸。
就上述其他脂質成分而言,可列舉能構成脂質粒子之構造脂質。就此種構造脂質而言,例如,可使用選自:固醇類(例如,膽固醇、膽固醇酯、膽固醇半琥珀酸酯等);磷脂質(例如,磷脂醯基膽鹼(例如,二棕櫚醯基磷脂醯基膽鹼、二硬脂醯基磷脂醯基膽鹼、溶血磷脂醯基膽鹼、二油醯基磷脂醯基膽鹼、棕櫚醯基油醯基磷脂醯基膽鹼、二亞油醯基磷脂醯基膽鹼、MC-1010(NOF CORPORATION)、MC-2020(NOF CORPORATION)、MC-4040(NOF CORPORATION)等)、磷脂醯基絲胺酸(例如,二棕櫚醯基磷脂醯基絲胺酸、二硬脂醯基磷脂醯基絲胺酸、二油醯基磷脂醯基絲胺酸、棕櫚醯基油醯基磷脂醯基絲胺酸等)、磷脂醯基乙醇胺(例如,二棕櫚醯基磷脂醯基乙醇胺、二硬脂醯基磷脂醯基乙醇胺、二油醯基磷脂醯基乙醇胺、棕櫚醯基油醯基磷脂醯基乙醇胺、溶血磷脂醯基乙醇胺等)、磷脂醯基肌醇、磷脂酸等);聚乙二醇脂質(PEG脂質)(例如,PEG-DAA、PEG-DAG、PEG-磷脂接合物(phospholipid conjugate)、PEG-Cer、PEG-膽固醇(cholesterol)、PEG-C-DOMG、2KPEG-CMG、GM-020(NOF CORPORATION)、GS-020(NOF CORPORATION)、GS-050(NOF CORPORATION)等)所構成之群組中的至少1種。在本發明中,就構造脂質而言,以使用固醇類(尤其膽固醇)、磷脂質(尤其磷脂醯基膽鹼)及聚乙二醇脂質全部3種為較佳。
形成本發明之脂質粒子之混合脂質成分中,本發明化合物與構造脂質的比率,可依據目的或用途而適宜調節。例如,相對於本發明之化合物1莫耳,構造脂質通常為0.008至4莫耳之比率,較佳為0.4至1.5莫耳之比率。又,若採取其他規定之方式,則混合脂質成分中,本發明之化合物通常為1至4莫耳,固醇類通常為0至3莫耳、磷脂質通常為0至2莫耳、聚乙二醇脂質通常為0至1莫耳之比率。在將本發明之化合物與其他脂質成分混合使用的情況,更佳態樣為本發明之化合物1至1.5莫耳、固醇類0至1.25莫耳、磷脂質0至0.5莫耳及聚乙二醇脂質0至0.125莫耳之比率。
本發明之化合物可用於製造本發明之脂質粒子。本發明之脂質粒子意指上述複合體中,不含核酸之複合體。本發明之脂質粒子之形狀無特別限定,例如,本發明之化合物等包含以構成球形之方式而集合的複合體、以不構成特定形狀之方式而集合的複合體、溶解於溶劑的複合體、均勻或不均勻地分散在分散媒介中的複合體等。
本發明之脂質粒子(例如,藉由本發明之化合物及其以外之構造脂質所構成的脂質粒子),例如,可用於製造含有該脂質粒子及核酸(尤其係在醫藥用途或研究目的用途有用之物質的核酸)的本發明之組成物。本發明之組成物可使用作為醫藥或試藥。在本發明之組成物中,以核酸以儘量高之比率內封於脂質粒子(亦即內封率高)者為較佳。
「核酸」若為核苷酸及具有與該核苷酸同等之功能之分子聚合而成的分子,任一者均可,例如,可列舉為核糖核苷酸之聚合物的RNA、為去氧核糖核苷酸之聚合物的DNA、核糖核苷酸及去氧核糖核苷酸混合之
聚合物、及包含核苷酸類似物之核苷酸聚合物,再者,亦可為包含核酸衍生物之核苷酸聚合物。又,核酸可為單股核酸或雙股核酸。又,雙股核酸,亦包含一股於嚴苛條件下可雜交於另一股的雙股核酸。
就核苷酸類似物而言,若係與RNA或DNA相較,為了使核酸酶耐性提高或安定化,為了提高與互補鏈核酸之親和性,或為了提高細胞透過性,或為了進行可視化,而對核糖核苷酸、去氧核糖核苷酸、RNA或DNA施行修飾的分子,任何分子均可。就核苷酸類似物而言,可為天然存在之分子,亦可為非天然之分子,例如,可列舉糖部分修飾核苷酸類似物或磷酸二酯鍵修飾核苷酸類似物等。
就糖部修飾核苷酸類似物而言,若為對於核苷酸之糖之化學構造的一部分或全部,以任何化學構造物質附加或取代者,任一者均可,就其具體例而言,可列舉經2’-O-甲基核糖取代之核苷酸類似物、經2’-O-丙基核糖取代之核苷酸類似物、經2’-甲氧基乙氧基核糖取代之核苷酸類似物、經2’-O-甲氧基乙基核糖取代之核苷酸類似物、經2’-O-[2-(胍鎓)乙基]核糖取代之核苷酸類似物、經2’-O-氟核糖取代之核苷酸類似物、藉由將交聯構造導入糖部而具有2個環狀構造的交聯構造型人工核酸(Bridged Nucleic Acid)(BNA),更具體而言,2’位之氧原子及4’位之碳原子經由亞甲基交聯的鎖人工核酸(Locked Nucleic Acid)(LNA)、及伸乙基交聯構造型人工核酸(Ethylene bridged nucleic acid)(ENA)[Nucleic Acid Research,32,e175(2004)],再者,可列舉肽核酸(PNA)[Acc.Chem.Res.,32,624(1999)]、氧肽核酸(OPNA)[J.Am.Chem.Soc.,123,4653(2001)]、及肽核糖核酸(PRNA)[J.Am.Chem.Soc.,122,6900(2000)]等。
就磷酸二酯鍵修飾核苷酸類似物而言,若為對核苷酸之磷酸二酯鍵之化學構造的一部分或全部,以任何化學物質加成或取代者,任一者均可,就其具體例而言,可列舉經硫代磷酸酯鍵取代之核苷酸類似物、經N3’-P5’磷醯胺鍵取代之核苷酸類似物等[細胞工學,16,1463-1473(1997)][RNAi法及反義法,講談社(2005)]。
就核酸衍生物而言,若係與核酸相比,為了使核酸酶耐性提高,為了使其安定化,為了提高與互補鏈核酸之親和性,為了提高細胞透過性,或為了進行可視化,而將其他化學物質加成於該核酸之分子,任一分子均可,就其具體例而言,可列舉5’-多胺加成衍生物、膽固醇加成衍生物、類固醇加成衍生物、膽汁酸加成衍生物、維生素加成衍生物、Cy5加成衍生物、Cy3加成衍生物、6-FAM加成衍生物、及生物素加成衍生物等。
就本發明之核酸而言,無特別限定,例如,可為以疾病、症狀、障礙、或疾病狀態之改善,及疾病、症狀、障礙或病態之減輕或其發病之預防等(在本說明書中,稱為「疾病之治療等」)作為目的之核酸,亦可為用於調節對疾病之治療等無助益但在研究上有用之期望蛋白質表現的核酸。
疾病相關基因或多核苷酸(在本說明書中,稱為「疾病相關基因」),例如,可從McKusick-Nathans Institute of Genetic Medicine,Johns Hopkins University(Baltimore,Md.)及National Center for Biotechnology Information,National Library of Medicine(Bethesda,Md.)等取得。
就本發明之核酸之具體例而言,可列舉如siRNA、shRNA、miRNA、miRNA mimic、反義核酸、核醇、mRNA、誘餌核酸、適體(aptamer)、質體DNA、黏粒(cosmid)DNA、BAC DNA。就核酸而言,以siRNA、mRNA等RNA或對此等經施行人工修飾之類似物或衍生物為較佳。
在本發明中,「siRNA」意指10至30鹼基,較佳為15至25鹼基之雙股RNA或其類似物、含有互補之序列者。siRNA較佳為在3’末端具有1至3鹼基、更佳為2鹼基之突出鹼基。互補之序列部分可完全地互補,或者亦可包含不互補之鹼基,然而較佳為完全互補。
本發明中之siRNA無特別限定,例如,可使用目的為將針對疾病相關基因之基因表現減弱(knockdown)的siRNA。疾病相關基因意指與非疾病對照之組織或細胞比較,在來自患部組織之細胞中,使轉錄或轉譯產物以異常濃度或異常形態產生的任何基因或多核苷酸。又,就本發明之siRNA而言,亦可使用:調節在研究方面有用之期望蛋白質之表現用的siRNA。
在本發明中,「mRNA」意指包含可轉譯成蛋白質之鹼基序列的RNA。就本發明之mRNA而言,若為可使細胞內期望之蛋白質表現的mRNA,將無特別限定。就上述mRNA而言,以在醫藥用途(例如,疾病治療用途)及/或研究目的之用途有用的mRNA為較佳,就此種mRNA而言,例如,可列舉用於使如螢光素酶之標記蛋白質於細胞內表現的mRNA。
就上述之疾病而言,無特別限定,例如,可列舉以下所記載之疾病。「()」內除記載具體之疾病例的情況,顯示疾病相關基因之例。就
本發明之核酸而言,亦可列舉調節此等疾病相關基因(或彼等所編碼之蛋白質)之表現量的核酸。
(1)血液系疾病[貧血(CDAN1、CDA1、RPS19、DBA、PKLR、PK1、NT5C3、UMPH1、PSN1、RHAG、RH50A、NRAMP2、SPTB、ALAS2、ANH1、ASB、ABCB7、ABC7、ASAT)、不全淋巴球症候群(TAPBP、TPSN、TAP2、ABCB3、PSF2、RING11、MHC2TA、C2TA、RFX5)、出血性疾病(TBXA2R、P2RX1、P2X1)、H因子及類H因子1因子缺損症(HF1、CFH、HUS)、V因子及VIII因子缺損症(MCFD2)、VII因子缺損症(F7)、X因子缺損症(F10)、XI因子缺損症(F11)、XII因子缺損症(F12、HAF)、XIIIA因子缺損症(F13A1、F13A)、XIIIB因子缺損症(F13B)、範可尼(Fanconi)貧血(FANCA、FACA、FA1、FA、FAA、FAAP95、FAAP90、FLJ34064、FANCB、FANCC、FACC、BRCA2、FANCD1、FANCD2、FANCD、FACD、FAD、FACE、FACE、FANCF、XRCC9、FANCG、BRIP1、BACH1、FANCJ、PHF9、FANCL、FANCM、KIAA1596)、血球貪食性淋巴組織球症(PRF1、HPLH2、UNC13D、MUNC13-4、HPLH3、HLH3、FHL3)、血友病A(F8、F8C、HEMA)、血友病B(F9、HEMB)、出血性障礙(PI、ATT、F5)、白血球缺損(ITGB2、CD18、LCAMB、LAD、EIF2B1、EIF2BA、EIF2B2、EIF2B3、EIF2B5、LVWM、CACH、CLE、EIF2B4)、鐮刀型紅血球貧血(HBB)、地中海型貧血(HBA2、HBB、HBD、LCRB、HBA1)等];(2)炎症性、免疫性疾病[AIDS(KIR3DL1、NKAT3、NKB1、AMB11、KIR3DS1、IFNG、CXCL12、SDF1)、自體免疫淋巴球增殖性症候群
(TNFRSF6、APT1、FAS、CD95、ALPS1A)、複合型免疫缺陷症(IL2RG、SCIDX1、SCIDX、IMD4)、HIV感染症(CCL5、SCYA5、D17S135E、TCP228、IL10、CSIF、CMKBR2、CCR2、DMKBR5、CCCKR5、CCR5)、免疫缺陷症(CD3E、CD3G、AICDA、AID、HIGM2、TNFRSF5、CD40、UNG、DGU、HIGM4、TNFSF5、CD40LG、HIGM1、IGM、FOXP3、IPEX、AIID、XPID、PIDX、TNFRSF14B、TACI)、炎症(IL10、IL-1、IL-13、IL-17、IL-23、CTLA4)、重症複合型免疫缺陷症(JAK3、JAKL、DCLRE1C、ATREMIS、SCIDA、RAG1、RAG2、ADA、PTPRC、CD45、LCA、IL7R、CD3D、T3D、IL2RG、SCIDX1、SCIDX、IMD4)、關節風濕症、乾癬、炎症性腸疾病(例如,克隆氏病、潰瘍性大腸炎等)、薛格連氏症候群、白塞氏病(Bechet’s disease)、多發性硬化症、全身性紅斑狼瘡、狼瘡性腎炎、圓板狀紅斑性狼瘡、卡斯曼(Castleman)氏病、僵直性脊椎炎、多發性肌炎、皮膚肌炎、結節性多發性動脈炎、混合性結合性組織症、硬皮症、深部紅斑性狼瘡、慢性甲狀腺炎、格雷夫斯病、自體免疫性胃炎、I型及II型糖尿病、自體免疫性溶血性貧血、自體免疫性嗜中性球減少症、血小板減少症、異位性皮膚炎、慢性活動性肝炎、重症肌無力症、移植片對宿主疾病、艾迪生氏病、異常免疫回應、關節炎、皮膚炎、放射線皮膚炎、原發性膽汁性肝硬變等];(3)代謝、肝臟、腎臟疾病[類澱粉神經病變(TTR、PALB)、類澱粉(APOA1、APP、AAA、CVAP、AD1、GSN、FGA、LYZ、TTR、PALB)、非酒精性脂肪肝炎及肝纖維症(COL1A1)、肝硬變(KRT18、KRT8、CIRH1A、NAIC、TEX292、KIAA1988)、囊胞性纖維症(CFTR、ABCC7、
CF、MRP7)、糖原蓄積症(SLC2A2、GLUT2、G6PC、G6PT、G6PT1、GAA、LAMP2、LAMPB、AGL、GDE、GBE1、GYS2、PYGL、PFKM)、肝細胞腺瘤(TCF1、HFN1A、MODY3、)、肝衰竭(SCOD1、SCO1)、肝性脂肪酶缺損症(LIPC)、肝母細胞瘤(CTNNB1、PDFGRL、PDGRL、PRLTS、AXIN1、AXIN、TP53、P53、LFS1、IGF2R、MPRI、MET、CASP8、MCH5)、髓質囊胞腎疾病(UMOD、HNFJ、FJHN、MCKD2、ADMCKD2)、苯基酮尿症(PAH、PKU1、QDPR、DHPR、PTS)、多囊胞性腎及肝疾病(FCYT、PKHD1、APRKD、PDK1、PDK2、PDK4、PDKTS、PRKCSH、G19P1、PCLD、SEC63)等];(4)神經系疾病[ALS(SOD1、ALS2、STEX、FUS、TARDBP、VEGF)、阿茲海默症(APP、AAA、CVAP、AD1、APOE、AD2、PSEN2、AD4、STM2、APBB2、FE65L1、NOS3、PLAU、URK、ACE、DCP1、ACE1、MPO、PACIP1、PAXIP1L、PTIP、A2M、BLMH、BMH、PSEN1、AD3)、自閉症(BZRAP1、MDGA2、GLO1、MECP2、RTT、PPMX、MRX16、MRX79、NLGN3、NLGN4、KIAA1260、AUTSX2)、脆弱性X症候群(FMR2、FXR1、FXR2、mGLUR5)、亨廷頓氏病(HD,IT15、PRNP、PRIP、JPH3、JP3、HDL2、TBP、SCA17)、巴金森病(NR4A2、NURR1、NOT、TINUR、SNCAIP、TBP、SCA17、SNCA、NACP、PARK1、PARK4、DJ1、DBH、NDUFV2)、雷特症候群(MECP2、RTT、PPMX、MRX16、MRX79、CDKL5、STK9)、思覺失調症(GSK3、5-HTT、COMT、DRD、SLC6A3、DAOA、DTNBP1)、分泌酶關連障礙(APH-1)等];
(5)眼疾病[老年黃斑變性症(Abcr、Ccl2、cp、Timp3、細胞自溶酵素D、Vldlr、Ccr2)、白內障(CRYAA、CRYA1、CRYBB2、CRYB2、PITX3、BFSP2、CP49、CP47、PAX6、AN2、MGDA、CRYBA1、CRYB1、CRYGC、CRYG3、CCL、LIM2、MP19、CRYGD、CRYG4、BSFP2、CP49、CP47、HSF4、CTM、MIP、AQP0、CRYAB、CRYA2、CTPP2、CRYBB1、CRYGD、CRYG4、CRYA1、GJA8、CX50、CAE1、GJA3、CX46、CZP3、CAE3、CCM1、CAM、KRIT1)、角膜混濁(APOA1、TGFB1、CSD2、CDGG1、CSD、BIGH3、CDG2、TASTD2、TROP2、M1S1、VSX1、RINX、PPCD、PPD、KTCN、COL8A2、FECD、PPCD2、PIP5K3、CFD)、先天性遺傳性扁平角膜(KERA、CNA2)、青光眼(MYOC、TIGR、GLC1A、JOAG、GPOA、OPTN、GLC1E、FIP2、HYPL、NRP、CYP1B1、GLC3A、OPA1、NTG、NPG、CYP1B1、GLC3A)、萊伯先天性黑矇症(CRB1、RP12、CRX、CORD2、CRD、RPGRIP1、LCA6、CORD9、RPE65、RP20、AIPL1、LCA4、GUCY2D、GUC2D、LCA1、CORD6、RDH12、LCA3)、黃斑萎縮(ELOVL4、ADMD、STGD2、STGD3、RDS、RP7、PRPH2、PRPH、AVMD、AOFMD、VMD2)等];(6)腫瘤性疾病[惡性腫瘤、血管新生青光眼、幼兒性血管瘤、多發性骨髓瘤、慢性肉瘤、轉移黑色瘤、卡波西肉瘤、血管增殖、惡病質、乳癌之轉移等、癌(例如,大腸癌(例如,家族性大腸癌、遺傳性非息肉大腸癌、消化管間質腫瘤等)、肺癌(例如,非小細胞肺癌、小細胞肺癌、惡性間皮瘤等)、間皮瘤、胰臟癌(例如,胰管癌等)、胃癌(例如,乳突腺癌、黏液性腺癌、腺扁平上皮癌等)、乳癌(例如,浸潤性乳管癌、非浸潤性乳管癌、炎症
性乳癌等)、卵巢癌(例如,上皮性卵巢癌、性腺外胚細胞腫瘤、卵巢性胚細胞腫瘤、卵巢低惡性度腫瘤等)、前列腺癌(例如,賀爾蒙依存性前列腺癌、賀爾蒙非依存性前列腺癌等)、肝臟癌(例如,原發性肝癌、肝外膽管癌等)、甲狀腺癌(例如,類甲狀腺髓癌等)、腎臟癌(例如,腎細胞癌、腎盂及尿管之移行上皮癌等)、子宮癌、腦腫瘤(例如,松果體星細胞腫瘤、毛樣細胞性星細胞瘤、瀰漫性星細胞瘤、退形成性星細胞瘤等)、黑色瘤、肉瘤、膀胱癌、包含多發性骨髓瘤之血液癌等、下垂體腺瘤、神經膠瘤、聽神經鞘瘤、網膜肉瘤、咽頭癌、喉頭癌、舌癌、胸腺瘤、食道癌、十二指腸癌、結腸癌、直腸癌、肝細胞癌、胰內分泌腫瘤、膽管癌、膽囊癌、陰莖癌、尿管癌、睪丸腫瘤、外陰癌、子宮頸部癌、子宮體部癌、子宮肉瘤、絨毛性疾病、陰道癌、皮膚癌、菌狀息肉症、基底細胞瘤、軟部肉瘤、惡性淋巴瘤、霍奇金氏病、骨髓異形成症候群、成人T細胞白血病、慢性骨髓增殖性疾病、胰內分泌腫瘤、纖維性組織球瘤、平滑肌肉瘤、橫紋肌肉瘤、原發不明癌等)、白血病(例如,急性白血病(例如,急性淋巴性白血病、急性骨髓性白血病等)、慢性白血病(例如,慢性淋巴性白血病、慢性骨髓性白血病等)、骨髓形成症候群等)、子宮肉瘤(例如,子宮中胚葉性混合腫瘤、子宮平滑肌肉瘤、子宮內膜間質腫瘤等)、骨髓纖維症等]。
作為醫藥之本發明之組成物,可使用藥學上可容許之載劑,藉由製劑技術領域周知之方法製造。就上述醫藥之劑型而言,例如,可列舉經調配緩衝劑及/或安定劑等習用助劑的非經口投與用製劑(例如,注射劑等液劑)、經調配習用之醫藥用載劑的軟膏、乳膏、液劑或膏藥等局部用製劑。
本發明之組成物可用於將活性成分導入多種細胞、組織或臟器之目的。就可適用本發明之組成物的細胞而言,例如,可列舉間葉系幹細胞、神經幹細胞、皮膚幹細胞、脾細胞、神經細胞、膠質細胞、胰臟B細胞、骨髓細胞、系膜細胞、朗格漢斯細胞、表皮細胞、上皮細胞、內皮細胞、纖維母細胞、纖維細胞、肌肉細胞(例如骨骼肌細胞、心肌細胞、肌肉母細胞、肌衛星細胞、平滑肌細胞)、脂肪細胞、血球細胞(例如巨噬細胞、T細胞、B細胞、自然殺手細胞、肥胖細胞、白血球、嗜中性球、嗜鹼性球、嗜酸性球、單核球、巨核球、造血幹細胞)、滑膜細胞、軟骨細胞、骨細胞、骨母細胞、破骨細胞、乳腺細胞、肝細胞或間質細胞、卵細胞、精細胞、或可誘導分化成此等細胞之前驅細胞、幹細胞(例如,包含誘導性多潛能幹細胞(iPS細胞)、胚性幹細胞(ES細胞))、原始生殖細胞、卵母細胞、受精卵。又,就可適用於本發明之組成物的組織或臟器而言,為上述之細胞存在的任何組織或臟器,例如,可列舉腦、腦之各部位(例如嗅球、扁頭核、大腦基底球、海馬迴、視丘、視丘下部、視丘下核、大腦皮質、延髓、小腦、枕葉、額葉、顳葉、殻核、尾狀核、胼胝體、黑質)、脊髓、腦下垂體、胃、胰臟、腎臟、肝臟、生殖腺、甲狀腺、膽囊、骨髓、副腎、皮膚、肺、消化管(例如大腸、小腸)、血管、心臟、胸腺、脾臟、顎下腺、末梢血、末梢血球、前列腺、胎盤、子宮、骨、關節及肌肉(例如骨骼肌、平滑肌、心肌)等。此等細胞、組織或臟器亦可為癌化之癌細胞或癌組織等。
本發明之組成物於將核酸導入癌細胞之效率特別優異。
本發明之化合物、脂質粒子及組成物安定且低毒性,可安全地使用。在將本發明之組成物用於活體內的情況,或作為醫藥用之情況,
將該組成物以可使核酸之有效量送達作為標的之細胞的方式,投與至投與對象(例如,人類或非人類哺乳動物(較佳為人類))即可。
在將本發明之組成物用於活體內的情況,或作為醫藥使用之情況,例如,可藉由形成錠劑(包含糖衣錠、膜包覆錠、舌下錠、口腔內崩散錠)、散劑、顆粒劑、膠囊劑(包含軟膠囊、微膠囊)、液劑、片劑、糖漿劑、乳劑、懸浮劑、注射劑(例如皮下注射劑、靜脈內注射劑、肌內注射劑、腹腔內注射劑等)、外用劑(例如經鼻投與製劑、經皮製劑、軟膏劑)、栓劑(例如直腸栓劑、陰道栓劑)、丸劑、經鼻劑、經肺劑(吸入劑)、點滴劑等醫藥製劑,可以經口方式或非經口方式(例如局部、直腸、靜脈投與等)安全地投與。此等製劑亦可為速釋性製劑或緩釋性製劑等釋出調控製劑(例如緩釋性微膠囊)。
以下,關於本發明之化合物的製造方法加以說明。
以下之製造方法之各步驟中所用的原料或試藥、以及所得到的化合物,可分別形成鹽。就此種鹽而言,例如,可列舉與前述本發明之化合物中的鹽相同者。
在各步驟中所得到之化合物為游離化合物的情況,可藉由周知之方法,轉化成為目的之鹽。相反地在各步驟中所得到之化合物為鹽的情況,可藉由周知之方法,轉化成游離體或為目的之其他種類之鹽。
在各步驟中所得到之化合物,可將反應液原樣,或以粗生成物得到後,使用於接下來的反應,或者將各步驟中所得到之化合物,依照常法,從反應混合物中藉由濃縮、晶析、再結晶、蒸餾、溶劑萃取、分餾、層析等分離手段進行單離及/或精製。
在各步驟之原料或試藥之化合物為市售的情況,可將市售品原樣使用。
在各步驟之反應中,反應時間可隨所用之試藥或溶劑而異,在無特別記載之情況,通常為1分鐘至48小時,較佳為10分鐘至8小時。
在各步驟之反應中,反應溫度雖可隨所用之試藥或而異,然而在無特別記載之情況,通常為-78℃至300℃,較佳為-78℃至150℃。
在各步驟之反應中,壓力雖可隨所用之試藥或溶劑而異,然而在無特別記載之情況,通常為1氣壓至20氣壓,較佳為1氣壓至3氣壓。
在各步驟之反應中,例如,使用Biotage公司製Initiator等微波合成裝置。反應溫度雖可隨所用之試藥或溶劑而異,然而在無特別記載之情況,通常為室溫至300℃,較佳為室溫至250℃,更佳為50℃至250℃。反應時間雖可隨所用之試藥或溶劑而異,然而在無特別記載之情況,通常為1分鐘至48小時,較佳為1分鐘至8小時。
在各步驟之反應中,試藥在無特別記載之情況,相對於基質,使用0.5當量至20當量,較佳使用0.8當量至5當量。在使用試藥作為觸媒之情況,試藥,相對於基質,可使用0.001當量至1當量,較佳使用0.01當量至0.2當量。在試藥兼為反應溶劑之情況,試藥可使用溶劑量。
在各步驟之反應中,於無特別記載之情況,此等反應可於無溶劑、或溶解或懸浮於適當溶劑而進行。就溶劑之具體例而言,可列舉實施例所記載之溶劑、或以下者。
醇類:甲醇、乙醇、異丙醇、異丁醇、三級丁醇、2-甲氧基乙醇等;醚類:二乙基醚、二異丙基醚、二苯基醚、四氫呋喃、1,2-二甲氧基乙烷等;芳香族烴類:氯苯、甲苯、二甲苯等;飽和烴類:環己烷、己烷、庚烷等;醯胺類:N,N-二甲基甲醯胺、N-甲基吡咯啶酮等;鹵化烴類:二氯甲烷、四氯化碳等;腈類:乙腈等;亞碸類:二甲基亞碸等;芳香族有機鹼類:吡啶等;酸酐類:乙酸酐等;有機酸類:甲酸、乙酸、三氟乙酸等;無機酸類:鹽酸、硫酸等;酯類:乙酸乙酯、乙酸異丙酯等;酮類:丙酮、甲基乙基酮等;水。
上述溶劑亦可將二種以上以適宜比率混合使用。
在各步驟之反應中使用鹼的情況,例如,可使用以下所示之鹼、或實施例所記載之鹼。
無機鹼類:氫氧化鈉、氫氧化鉀、氫氧化鎂等;鹼性鹽類:碳酸鈉、碳酸鈣、碳酸氫鈉等;
有機鹼類:三乙基胺、二乙基胺、吡啶、4-二甲基胺基吡啶、N,N-二甲基苯胺、1,4-二氮雜雙環[2.2.2]辛烷、1,8-二氮雜雙環[5.4.0]-7-十一烯、咪唑、哌啶等;金屬烷氧化物類:乙氧化鈉、三級丁氧化鉀、三級丁氧化鈉等;鹼金屬氫化物類:氫化鈉等;金屬胺化物類:胺化鈉、鋰二異丙基胺、六甲基二矽氮烷鋰等;有機鋰類:正丁基鋰、二級丁基鋰等。
在各步驟之反應中使用酸或酸性觸媒的情況,例如,可使用以下所示之酸或酸性觸媒、或實施例所記載之酸或酸性觸媒。
無機酸類:鹽酸、硫酸、硝酸、氫溴酸、磷酸等;有機酸類:乙酸、三氟乙酸、檸檬酸、對甲苯磺酸、10-樟腦磺酸等;路易斯酸:三氟化硼二乙基醚錯合物、碘化鋅、無水氯化鋁、無水氯化鋅、無水氯化鐵等。
各步驟之反應,只要無特別記載,係以周知之方法,例如,第5版實驗化學講座,13卷至19卷(日本化學會編);新實驗化學講座,14卷至15卷(日本化學會編);精密有機化學改定第2版(L.F.Tietze,Th.Eicher,南江堂);改訂有機人名反應-其原理及要點(東鄉秀雄著,講談社);ORGANIC SYNTHESES Collective Volume I至VII(John Wiley & Sons Inc);Modern Organic Synthesis in the Laboratory,A Collection of Standard Experimental Procedures(Jie Jack Li著,OXFORD UNIVERSITY出版);Comprehensive Heterocyclic Chemistry III,Vol.1
至Vol.14(Elsevier Japan股份有限公司);學自人名反應之有機合成戰略(富岡清監譯,化學同人發行);Comprehensive Organic Transformations(VCH Publishers Inc.)1989年刊等所記載之方法、或實施例所記載之方法為基準進行。
在各步驟中,官能基之保護或脫保護反應,係以周知之方法,例如,Wiley-Interscience公司2007年刊「Protective Groups in Organic Synthesis,4thEd.」(Theodora W.Greene,Peter G.M.Wuts著);Thieme公司2004年刊「Protecting Groups 3rdEd.」(P.J.Kocienski著)等所記載之方法、或實施例所記載之方法為基準進行。
就醇等羥基或酚性羥基之保護基而言,例如,可列舉甲氧基甲基醚、苄基醚、對甲氧基苄基醚、三級丁基二甲基矽基醚、三級丁基二苯基矽基醚、四氫哌喃基醚等醚型保護基;乙酸酯等羧酸酯型保護基;甲磺酸酯等磺酸酯型保護基;三級丁基碳酸酯等碳酸酯型保護基等。
就醛之羰基之保護基而言,例如,可列舉二甲基縮醛等縮醛型保護基;環狀1,3-二噁烷等環狀縮醛型保護基等。
就酮之羰基之保護基而言,例如,可列舉二甲基縮酮等縮酮型保護基;環狀1,3-二噁烷等環狀縮酮型保護基;O-甲基肟等肟型保護基;N,N-二甲基腙等腙型保護基等。
就羧基之保護基而言,例如,可列舉甲酯等酯型保護基;N,N-二甲基醯胺等醯胺型保護基等。
就巰基之保護基而言,例如,可列舉苄基硫醚等醚型保護基;硫乙酸酯、硫碳酸酯、硫胺甲酸酯等酯型保護基等。
就胺基及咪唑、吡咯、吲哚等芳香族雜環之保護基而言,例如,可列舉苄基胺甲酸酯等胺甲酸酯型保護基;乙醯胺等醯胺型保護基;N-三苯基甲基胺等烷基胺型保護基、甲磺醯胺等磺醯胺型保護基等。
保護基之除去,可使用周知之方法,例如,使用酸、鹼、紫外光、肼、苯基肼、N-甲基二硫胺甲酸鈉、四丁基銨氟化物、乙酸鈀、三烷基矽基鹵化物(例如,三甲基矽基碘化物、三甲基矽基溴化物)之方法或還原法等進行。
在各步驟中,進行還原反應之情況,就所使用之還原劑而言,可列舉氫化鋁鋰、氫化三乙醯氧基硼鈉、氫化氰基硼鈉、氫化二異丁基鋁(DIBAL-H)、氫化硼鈉、氫化三乙醯氧基硼四甲基銨等金屬氫化物類;硼烷四氫呋喃錯合物等硼烷類;雷氏鎳;雷氏鈷;氫;甲酸等。例如,可在氫或甲酸存在下,使用雷氏鎳或雷氏鈷。在將碳-碳雙鍵或參鍵還原之情況,為使用鈀-碳或Lindlar觸媒等觸媒的方法。
在各步驟中,進行氧化反應之情況,就所使用之氧化劑而言,可列舉間氯過苯甲酸(MCPBA)、過氧化氫、三級丁基氫過氧化物等過氧類;過氯酸四丁基銨等過氯酸鹽類;氯酸鈉等氯酸鹽類;亞氯酸鈉等亞氯酸鹽類;過碘酸鈉等過碘酸類;氧碘基苯等高原子價碘試藥;二氧化錳、過錳酸鉀等有錳之試藥;四乙酸鉛等鉛類;氯鉻酸吡啶鎓(PCC)、二鉻酸吡啶鎓(PDC)、瓊斯試藥等具有鉻之試藥;N-溴琥珀醯亞胺(NBS)等鹵化合物類;氧;臭氧;三氧化硫‧吡啶錯合物;四氧化鋨;二氧化硒;2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)等。
在各步驟中,進行自由基環化反應之情況,就所使用之自由基起始劑而言,可列舉偶氮雙異丁腈(AIBN)等偶氮化合物;4-4’-偶氮雙-4-氰基戊酸(ACPA)等水溶性自由基起始劑;空氣或氧存在下之三乙基硼;過氧化苄醯基等。又,就所使用之自由基反應試劑而言,可列舉三丁基錫烷、參三甲基矽基矽烷、1,1,2,2-四苯基二矽烷、二苯基矽烷、碘化釤等。
在各步驟中,進行Wittig反應之情況,就所使用之Wittig試藥而言,可列舉亞烷基磷烷類等。亞烷基磷烷類可藉由周知之方法,例如,使鏻鹽與強鹼反應而調製。
在各步驟中,進行Horner-Emmons反應之情況,就所使用之試藥而言,可列舉二甲基膦酸基乙酸甲酯、二乙基膦酸基乙酸乙酯等膦酸基乙酸酯類;鹼金屬氫化物類、有機鋰類等鹼。
在各步驟中,進行Friedel-Crafts反應之情況,就所使用之試藥而言,可列舉路易斯酸、醯氯化物或烷基化劑(例如鹵化烷基類、醇、烯烴類等)。或者,亦可使用有機酸或無機酸代替路易斯酸,使用乙酸酐等酸酐代替醯氯化物。
在各步驟中,進行芳香族親核取代反應之情況,就試藥而言,可使用親核劑(例如胺類、咪唑等)及鹼(例如鹼性鹽類、有機鹼類等)。
在各步驟中,進行藉由碳陰離子之親核加成反應、藉由碳陰離子之親核1,4-加成反應(Michael加成反應)、或藉由碳陰離子之親核取代反應的情況,就用於產生碳陰離子所用之鹼而言,可列舉有機鋰類、金屬烷氧化物類、無機鹼類、有機鹼類等。
在各步驟中,進行Grignard反應之情況,就Grignard試藥而言,可列舉苯基鎂溴化物等芳基鎂鹵化物類;甲基鎂溴化物、異丙基鎂溴化物等烷基鎂鹵化物類。Grignard試藥可藉由周知之方法,例如以醚或四氫呋喃作為溶劑,使鹵化烷基或鹵化芳基與金屬鎂反應而調製。
在各步驟中,進行Knoevenagel縮合反應之情況,就試藥而言,可使用二個電子吸引基所挾持之活性亞甲基化合物(例如丙二酸、丙二酸二乙酯、丙二腈等)及鹼(例如有機鹼類、金屬烷氧化物類、無機鹼類)。
在各步驟中,進行Vilsmeier-Haack反應之情況,就試藥而言,可使用磷醯氯及醯胺衍生物(例如N,N-二甲基甲醯胺等)。
在各步驟中,進行醇類、烷基鹵化物類、磺酸酯類之疊氮化反應的情況,就所使用之疊氮化劑而言,可列舉二苯基磷醯基疊氮化物(DPPA)、三甲基矽基疊氮化物、疊氮化鈉等。例如,在將醇類疊氮化之情況,有使用二苯基磷醯基疊氮化物與1,8-二氮雜雙環[5,4,0]十一碳-7-烯(DBU)之方法,或使用三甲基矽基疊氮化物及路易斯酸之方法等。
在各步驟中,進行還原性胺基化反應之情況,就所使用之還原劑而言,可列舉氫化三乙醯氧基硼鈉、氫化氰基硼鈉、氫、甲酸等。在基質為胺化合物之情況,就所使用之羰基化合物而言,除三聚甲醛之外,可列舉乙醛等醛類、環己酮等酮類。在基質為羰基化合物之情況,就所使用之胺類而言,可列舉氨、甲基胺等1級胺;二甲基胺等2級胺等。
在各步驟中,進行光延反應之情況,就試藥而言,可使用偶氮二羧酸酯類(例如偶氮二羧酸二乙酯(DEAD)、偶氮二羧酸二異丙酯(DIAD)等)及三苯基膦。
在各步驟中,進行酯化反應、醯胺化反應、或脲化反應之情況,就所使用之試藥而言,可列舉醯氯化物、醯溴化物等鹵化醯基體;酸酐、活性酯體、硫酸酯體等活性化之羧酸類。就羧酸之活性化劑而言,可列舉1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(WSCD)等碳化二亞胺系縮合劑;4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基嗎啉鎓氯化物-n-水合物(DMT-MM)等三嗪系縮合劑;1,1-羰基二咪唑(CDI)等碳酸酯系縮合劑;二苯基磷醯疊氮化物(DPPA);苯并三唑-1-基氧基-參二甲基胺基鏻鹽(BOP試藥);碘化2-氯-1-甲基-吡啶鎓(向山試藥);氯化硫醇;氯甲酸乙酯等鹵甲酸低級烷酯;O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽(HATU);硫酸;或此等之組合等。在使用碳化二亞胺系縮合劑之情況,亦可進一步將1-羥基苯并三唑(HOBt)、N-羥基琥珀醯亞胺(HOSu)、二甲基胺基吡啶(DMAP)等添加劑加入反應。
在各步驟中,進行偶合反應之情況,就所使用之金屬觸媒而言,可列舉乙酸鈀(II)、肆(三苯基膦)鈀(0)、二氯雙(三苯基膦)鈀(II)、二氯雙(三乙基膦)鈀(II)、參(二亞苄基丙酮)二鈀(0)、氯化1,1’-雙(二苯基膦基)二茂鐵鈀(II)、乙酸鈀(II)等鈀化合物;肆(三苯基膦)鎳(0)等鎳化合物;氯化參(三苯基膦)銠(III)等銠化合物;鈷化合物;氧化銅、碘化銅(I)等銅化合物;鉑化合物等。再者,亦可於反應中加鹼,就此種鹼而言,可列舉無機鹼類、鹼性鹽類等。
在各步驟中,進行硫羰基化反應之情況,就硫羰基化劑而言,可使用五硫化二磷為代表,然而除五硫化二磷之外,亦可使用2,4-雙(4-甲
氧基苯基)-1,3,2,4-二硫雜二磷雜環丁烷-2,4-二硫化物(Lowesson試藥)等具有1,3,2,4-二硫雜二磷雜環丁烷-2,4-二硫化物構造的試藥。
在各步驟中,進行Wohl-Ziegler反應之情況,就所使用之鹵化劑而言,可列舉N-碘琥珀醯亞胺、N-溴琥珀醯亞胺(NBS)、N-氯琥珀醯亞胺(NCS)、溴、氯化硫醯基等。再者,藉由熱、光、或將過氧化苄醯基、偶氮雙異丁腈等自由基起始劑加入反應中,可使反應加速。
在各步驟中,進行羥基之鹵化反應的情況,就所使用之鹵化劑而言,為氫鹵酸及無機酸之醯鹵化物,具體言之,在氯化方面,可列舉鹽酸、亞硫醯氯、氧氯化磷等,在溴化方面,可列舉48%氫溴酸等。又,亦可採用藉由三苯基膦與四氯化碳或四溴化碳等之作用,從醇得到鹵化烷基體之方法。或者亦可採用經由將醇轉化為磺酸酯之後,與溴化鋰、氯化鋰或碘化鈉反應的2階段反應,合成鹵化烷基體之方法。
在各步驟中,進行Arbuzov反應之情況,就所使用之試藥而言,可列舉溴乙酸乙酯等鹵化烷基類;亞磷酸三乙酯或亞磷酸三(異丙酯)等亞磷酸酯類。
在各步驟中,進行磺醯酯化反應之情況,就所使用之磺醯化劑而言,可列舉甲磺醯氯、對甲苯磺醯氯、甲磺酸酐、對甲苯磺酸酐、三氟甲磺酸酐等。
在各步驟中,進行水解反應之情況,就試藥而言,可使用酸或鹼。又,在進行三級丁酯之酸水解反應的情況,添加以還原方式捕捉副產之三級丁基陽離子用的甲酸或三乙基矽烷等。
在各步驟中,進行脫水反應之情況,就所使用之脫水劑而言,可列舉硫酸、五氧化二磷、氧氯化磷、N,N’-二環己基碳化二亞胺、礬土、多磷酸等。
化合物(I),例如,可藉由以下之製法製造。化合物(I)之中,波線之兩者為順型之鍵結的化合物,及波線之一者或兩者為反型之鍵結的化合物之任一種,可藉由與以下所示之製法相同的製法製造。本發明中,尤其酯化時,依據為目的之化合物(I)的構造而使用適當之原料,可合成期望之構造的化合物(I)。又,化合物(I)之鹽可藉由與無機鹼、有機鹼、有機酸、鹼性或酸性胺基酸適當混合而得到。
以下,記載有關含有本發明化合物之脂質粒子及含有該脂質粒子及核酸之核酸導入用組成物的製造方法。
本發明之脂質粒子,可將本發明之化合物(陽離子性脂質),視需要與其他脂質成分混合後,藉由從脂質成分調製脂質粒子所用之周知方法製造。例如,可藉由將上述之(混合)脂質成分溶解於有機溶劑,再將所得到之有機溶劑溶液與水或緩衝液混合(例如,乳化法),製造為脂質粒子分散液。上述混合,可使用微小流體混合系統(例如,NanoAssemblr裝置(Precision NanoSystems公司))進行。所得到之脂質粒子亦可付諸於脫鹽或透析及滅菌過濾。又,視需要亦可進行pH調整、滲透壓調整。
化合物(I)可藉由式(I)之n、R及波線之定義的組合,取得複數種構造。脂質粒子之製造中,就化合物(I)而言,可將具有特定構造之1種化合物單獨使用,亦可使用作為構造相異之複數種化合物之混合物。
就「其它脂質成分」而言,可列舉如前述之構造脂質,例如,固醇類、磷脂質、聚乙二醇脂質。「其它脂質成分」,例如,相對於1莫耳之本發明之化合物,可使用0.008至4莫耳。本發明之化合物,以與其他脂質成分(尤其膽固醇、磷脂醯基膽鹼及聚乙二醇脂質)混合而使用為較佳。將本發明之化合物與其他脂質成分混合使用之情況的較佳態樣,為1至4莫耳之本發明化合物、0至3莫耳之固醇類、0至2莫耳之磷脂質及0至1莫耳之聚乙二醇脂質的混合物。在將本發明之化合物與其他脂質成分混合而使用之情況的更佳態樣,為1至1.5莫耳之本發明化合物、0至1.25莫耳之固醇類、0至0.5莫耳之磷脂質及0至0.125莫耳之聚乙二醇脂質的混合物。
前述之有機溶劑溶液中的本發明之化合物,或本發明之化合物與其他脂質成分之混合物的濃度,較佳為0.5至100mg/mL。
就有機溶劑而言,例如,可列舉甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、三級丁醇、丙酮、乙腈、N,N-二甲基甲醯胺、二甲基亞碸、或此等之混合物。有機溶劑可含有0至20%之水或緩衝液。
就緩衝液而言,可列舉酸性緩衝液(例如,乙酸緩衝液、檸檬酸緩衝液、2-N-嗎啉基乙磺酸(MES)緩衝液、磷酸緩衝液)、中性緩衝液(例如,4-(2-羥基乙基)-1-哌嗪乙磺酸(HEPES)緩衝液、參(羥基甲基)胺基甲烷(Tris)緩衝液、磷酸緩衝液、磷酸緩衝生理食鹽水(PBS))。
在使用微小流體混合系統進行混合之情況,以相對於有機溶劑溶液1容積份,混合1至5容積份之水或緩衝液為較佳。又,在該系統中,混合液(有機溶劑溶液與水或緩衝液之混合液)流速,較佳為0.1至10mL/分鐘,溫度較佳為15至45℃。
本發明之組成物在製造脂質粒子或脂質粒子分散液時,藉由在水或緩衝液中添加作為活性成分之核酸,可製造含有活性成分之脂質粒子分散液。活性成分以使水或緩衝液中之活性成分的濃度成為0.05至2.0mg/mL之方式添加為較佳。
又,本發明之組成物,可藉由將脂質粒子或脂質粒子分散液與活性成分或其水溶液,依照周知之方法混合,製造為含有活性成分之脂質粒子分散液。脂質粒子分散液可藉由使脂質粒子分散於適當之分散媒介中而調製。又,活性成分之水溶液可藉由使活性成分溶解於適當之溶劑中而調製。
除去分散媒介及溶劑之本發明組成物中的本發明化合物的含量,較佳為40至70重量%。
除去分散媒及溶劑的本發明組成物中的活性成分之含量,較佳為1至20重量%。
含有脂質粒子分散液或組成物之分散液的分散媒介,可於透析中用水或緩衝液置換。透析時係使用分劃分子量為10至20K之超過濾膜,於4℃至室溫實施。可重複地進行透析。分散媒介之置換,亦可使用切向流過濾(tangential flow filtration)(TFF)來進行。又,分散媒介之置換後,視需要可進行pH調整、滲透壓調整。
以下,記載關於含有本發明之化合物的脂質粒子,及含有該脂質粒子及作為活性成分之核酸的組成物的分析方法。
(組成物中之)脂質粒子之粒徑,可藉由周知之手段測定。例如,使用基於NIBS(非接觸後方散射)技術的粒徑測定裝置,Zetasizer Nano ZS(Malvern Instruments),藉由自相關函數之累積量解析,可呈Z平均粒徑而算出。(組成物中之)脂質粒子之粒徑(平均粒徑),較佳為10至200nm。
作為本發明之組成物中的活性成分之核酸(例如siRNA、mRNA)之濃度及內封率,可藉由周知之手段測定。例如,使用Quant-iTTM RiboGreen(註冊商標)(Invitrogen),將核酸進行螢光標識,藉由測定其螢光強度,可求得濃度及內封率。組成物中核酸之濃度,可使用從濃度已知之核酸水溶液所作成的標準曲線算出,內封率可根據Triton-X100(用於使脂質粒子崩散之界面活性劑)有無添加所造成的螢光強度之差異而算出。再者,組成物中之核酸濃度,係指脂質粒子所內封之核酸及未內封之核酸之
合計濃度,內封率係指組成物之全部核酸之中,內封於脂質粒子中者的比率。
本發明進一步藉由以下之實施例、試驗例及製劑例詳細地說明,然而本發明不受此等所限,又,在不超出本發明範圍的範圍內可有各種變化。
以下之實施例中的「室溫」表示通常約10℃至約35℃。在混合溶劑中所示之比,只要未特別聲明,係表示容量比。%只要未特別聲明,係表示重量%。
實施例之管柱層析中的溶出,只要未特別聲明,係藉由TLC(Thin Layer Chromatography,薄層層析)之觀察下進行。在TLC觀察中,就TLC板而言,使用默克(Merck)公司製之60 F254,就展開溶劑而言,使用管柱層析中作為溶出溶劑所用的溶劑。又,檢測係採用UV檢測器,視需要使用TLC顯色試藥進行觀察。在矽膠管柱層析中,在記載為NH之情況,係使用胺基丙基矽烷結合矽膠,在記載為Diol之情況,係使用3-(2,3-二羥基丙氧基)丙基矽烷結合矽膠。在分取HPLC(高速液體層析)中,於記載為C18之情況,使用十八碳基結合矽膠。在溶出溶劑中所示之比,只要未特別聲明,表示容量比。
1H NMR係以傅立葉(Fourier)轉化型NMR測定。1H NMR之解析,係使用ACD/SpecManager(商品名)軟體等。羥基或胺基等之質子峰為非常緩和之峰時,有時未記載。
MS係藉由LC/MS及MALDI/TOFMS測定。就離子化法而言,採用ESI法、APCI法或、MALDI法。就基質而言,使用CHCA。數據係記載實測值(found)。通常,觀測分子離子峰係以片段離子來進行觀測。在鹽之情況,通常可觀測游離體之分子離子峰、陽離子物種、陰離子物種或片段離子峰。
在以下之實施例中,使用下述之簡稱。
MS:質譜
M:莫耳濃度
N:當量濃度
CDCl3:重氯仿
DMSO-d6:重二甲基亞碸
1H NMR:質子核磁共振
LC/MS:液體層析質量分析計
ESI:electrospray ionization,電噴霧離子化
APCI:atmospheric pressure chemical ionization,大氣壓化學離子化
MALDI:Matrix-assisted laser desorption/ionization,基質輔助雷射解析/離子化
TOFMS:Time-of-flight mass spectrometry,飛行時間型質量分析
CHCA:α-氰基-4-羥基桂皮酸
DMF:N,N-二甲基甲醯胺
THF:四氫呋喃
DMAP:4-二甲基胺基吡啶
TBAF:氟化四丁基銨
[實施例1](9Z)-十四碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
A)2-(((三級丁基二甲基矽基)氧基)甲基)-2-(羥基甲基)丙-1,3-二醇
在2,2-雙(羥基甲基)丙-1,3-二醇(5.45g)、1H-咪唑(2.72g)及DMF(190mL)之混合物中,於室溫添加三級丁基氯二甲基矽烷(3.01g)之DMF(10mL)溶液。攪拌24小時後,將反應混合物於減壓下濃縮。將殘餘物以乙酸乙酯稀釋,用水洗淨3次,用飽和食鹽水洗淨1次後,以無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(2.25g)。
1H NMR(300MHz,CDCl3)δ ppm 0.08(6H,s),0.90(9H,s),2.53(3H,t,J=5.5Hz),3.66(2H,s),3.73(6H,d,J=5.5Hz)
B)(9Z)-十四碳-9-烯酸3-((三級丁基(二甲基)矽基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
在2-(((三級丁基二甲基矽基)氧基)甲基)-2-(羥基甲基)丙-1,3-二醇(258mg)、(9Z)-十四碳-9-烯酸(769mg)及DMAP(126mg)之DMF(3mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(790mg)。攪拌18小時後,將反應混合物用乙酸乙酯稀釋,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(860mg)。
1H NMR(300MHz,CDCl3)δppm 0.03(6H,s),0.81-0.96(18H,m),1.18-1.41(36H,m),1.53-1.67(6H,m),1.91-2.10(12H,m),2.29(6H,t,J=7.6Hz),3.58(2H,s),4.08(6H,s),5.27-5.43(6H,m)
C)(9Z)-十四碳-9-烯酸3-羥基-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
在(9Z)-十四碳-9-烯酸3-((三級丁基(二甲基)矽基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯(5.91g)之THF(120mL)溶液中,於室溫添加TBAF之THF溶液(1M,14.85mL)與乙酸(4.91mL)之混合物。攪拌3日後、將反應混合物於減壓下濃縮。將殘餘物用乙酸乙酯稀釋,以飽和碳酸氫鈉水溶液洗淨1次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(4.96g)。
1H NMR(300MHz,CDCl3)δppm 0.82-0.97(9H,m),1.16-1.42(36H,m),1.52-1.68(6H,m),1.90-2.12(12H,m),2.32(6H,t,J=7.6Hz),2.52(1H,t,J=7.0Hz),3.49(2H,d,J=7.0Hz),4.11(6H,s),5.26-5.42(6H,m)
D)(9Z)-十四碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
在(9Z)-十四碳-9-烯酸3-羥基-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯(4.96g)、DMAP(796mg)及4-(二甲基胺基)丁酸鹽酸鹽(2.19g)之DMF(20mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(2.50g)。攪拌18小時後,將反應混合物用乙酸乙酯稀釋,以飽
和碳酸氫鈉水溶液洗淨1次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(5.31g)。
1H NMR(300MHz,CDCl3)δppm 0.82-0.94(9H,m),1.20-1.42(36H,m),1.50-1.66(6H,m),1.69-1.83(2H,m),1.90-2.10(12H,m),2.20(6H,s),2.23-2.41(10H,m),4.11(8H,s),5.23-5.44(6H,m)
[實施例4](9Z)-十六碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
A)2-(((三級丁基(二苯基)矽基)氧基)甲基)-2-(羥基甲基)丙-1,3-二醇
在2,2-雙(羥基甲基)丙-1,3-二醇(5.0g)、1H-咪唑(2.5g)及DMF(200mL)之混合物中,於室溫添加三級丁基氯二苯基矽烷(5.1g)之DMF(10mL)溶液。攪拌18小時後,將反應混合物於減壓下濃縮。將殘餘物用乙酸乙酯稀釋,以水洗淨3次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(6.4g)。
1H NMR(500MHz,CDCl3)δppm 1.07(9H,s),2.34(3H,t,J=5.5Hz),3.67(2H,s),3.74(6H,d,J=5.5Hz),7.39-7.48(6 H,m),7.63-7.67(4H,m)
B)(5-(((三級丁基(二苯基)矽基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲醇
在2-(((三級丁基(二苯基)矽基)氧基)甲基)-2-(羥基甲基)丙-1,3-二醇(3.5g)、2,2-二甲氧基丙烷(1.5g)之丙酮(35mL)溶液中,於室溫添加對甲
苯磺酸一水合物(88.9mg)。攪拌2小時後,在反應混合物中添加稀氨水中和後,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(2.7g)。
1H NMR(500MHz,CDCl3)δppm 1.07(9H,s),1.27(3H,s),1.41(3H,s),2.12-2.18(1 H,m),3.69-3.78(8H,m),7.38-7.47(6H,m),7.65-7.69(4H,m)
C)(9Z)-十六碳-9-烯酸(5-(((三級丁基(二苯基)矽基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在(5-(((三級丁基(二苯基)矽基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲醇(910mg)、DMAP(215mg)及(9Z)-十六碳-9-烯酸(838mg)之DMF(10mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(757mg)。攪拌6小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥後,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(1.43g)。
1H NMR(500MHz,CDCl3)δppm 0.84-0.91(3 H,m),1.03-1.07(9 H,m),1.22-1.35(16 H,m),1.40(6 H,d,J=17.0Hz),1.49-1.63(2 H,m),2.01(4 H,q,J=6.5Hz),2.24(2 H,t,J=7.6Hz),3.65(2 H,s),3.73(2 H,d,J=11.7Hz),3.80(2 H,d,J=12.0Hz),4.17(2 H,s),5.29-5.39(2 H,m),7.35-7.46(6 H,m),7.65(4 H,d,J=6.9Hz)
D)(9Z)-十六碳-9-烯酸(5-(羥基甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在(9Z)-十六碳-9-烯酸(5-(((三級丁基(二苯基)矽基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(1.43g)之THF(4mL)溶液中,於室溫添加TBAF之THF溶液(1M,2.64mL)。攪拌3小時後,將反應混合物於減壓下濃縮。將殘餘物用乙酸乙酯稀釋,以飽和碳酸氫鈉水溶液洗淨1次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(0.82g)。
1H NMR(500MHz,CDCl3)δppm 0.85-0.91(3 H,m),1.24-1.36(16 H,m),1.42(6 H,s),1.58-1.66(2 H,m),2.01(4 H,q,J=6.5Hz),2.30(1 H,t,J=6.6Hz),2.35(2 H,t,J=7.6Hz),3.48(2 H,d,J=6.6Hz),3.69-3.75(4 H,m),4.25(2 H,s),5.31-5.38(2 H,m)
E)(9Z)-十六碳-9-烯酸(5-(((4-(二甲基胺基)丁醯基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在(9Z)-十六碳-9-烯酸(5-(羥基甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(410mg)、DMAP(97mg)及4-(二甲基胺基)丁酸鹽酸鹽(250mg)之DMF(4mL)溶液中,於50℃添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(343mg)。攪拌4小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(430mg)。
1H NMR(500MHz,CDCl3)δppm 0.86-0.91(3 H,m),1.24-1.36(16 H,m),1.42(6 H,s),1.53-1.69(2 H,m),1.78(2 H,m),1.98-2.04
(4 H,m),2.21(6 H,s),2.29(4 H,m),2.37(2 H,t,J=7.6Hz),3.74(4 H,s),4.11(4 H,d,J=5.7Hz),5.31-5.38(2 H,m)
F)(9Z)-十六碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯
在(9Z)-十六碳-9-烯酸(5-(((4-(二甲基胺基)丁醯基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(430mg)中,添加乙酸(2mL)、水(1mL),於75℃攪拌2小時後,將溶劑於減壓下餾去。在殘餘物中添加乙酸乙酯、飽和碳酸氫鈉水溶液,攪拌2小時。以水洗淨2次後,用無水硫酸鈉乾燥後,將溶劑於減壓下餾去。在所得到之殘餘物、DMAP(201mg)及(9Z)-十四碳-9-烯酸(466mg)之DMF(4mL)溶液中,於50℃添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(458mg)。攪拌4小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(604mg)。
1H NMR(500MHz,CDCl3)δppm 0.85-0.92(9 H,m),1.24-1.36(40 H,m),1.55-1.64(6 H,m),1.73-1.80(2 H,m),1.98-2.05(12 H,m),2.20(6 H,s),2.24-2.33(8 H,m),2.36(2 H,t,J=7.6Hz),4.09-4.13(8 H,m),5.31-5.38(6 H,m)
[實施例8](9Z,9'Z)雙-十四碳-9-烯酸2-(((N,N-二甲基-β-丙胺醯基)氧基)甲基)-2-((辛醯基氧基)甲基)丙烷-1,3-二基酯
A)(2-(4-甲氧基苯基)-1,3-二噁烷-5,5-二基)二甲醇
將2,2-雙(羥基甲基)丙-1,3-二醇(506g)之水(2.0L)溶液於50℃攪拌。添加濃鹽酸(18mL),將對甲氧基苄醛(474mL)於30℃左右以3小時滴入。然後,將反應液調至25℃,攪拌5小時。添加2N氫氧化鈉水溶液(120mL),攪拌1小時。將結晶過濾,用水洗淨後,以乙酸乙酯/己烷再結晶,得到標題化合物(769g)。
1H NMR(500MHz,DMSO-d6)δppm3.24(2H,d,J=5.0Hz),3.67(2H,d,J=5.4Hz),3.74(3H,s),3.77(2H,d,J=11.3Hz),3.88(2H,t,J=11.3Hz),4.53(1H,t,J=5.4Hz),4.62(1H,t,J=5.0Hz),5.34(1H,s),6.90(2H,d,J=8.9Hz),7.33(2H,d,J=8.9Hz)
B-1)2-(羥基甲基)-2-(((4-甲氧基苄基)氧基)甲基)丙烷-1,3-二醇
在(2-(4-甲氧基苯基)-1,3-二噁烷-5,5-二基)二甲醇(10.0g)之甲苯(100mL)懸浮溶液中,於室溫滴入1.5M DIBAL-H溶液(105mL),並攪拌5小時。添加甲醇(30mL)後,添加2N鹽酸(20mL)及4N氫氧化鈉水溶液(240mL)並攪拌2小時後,除去甲苯層。將水層以鹽酸中和後,用乙酸乙酯萃取,以飽和食鹽水洗淨2次後,用矽藻土過濾。將溶劑於減壓下餾去,將殘餘物於乙酸乙酯/己烷中再結晶,得到標題化合物(6.6g)。
1H NMR(500MHz,DMSO-d6)δppm 3.32(2H,s),3.39(6H,d,J=5.4Hz),3.74(3H,s),4.21(3H,t,J=5.4Hz),4.36(2H,s),6.90(2H,d like,J=7.8Hz),7.23(2H,d like,J=7.8Hz)
C-1)(5-(((4-甲氧基苄基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲醇
在2-(羥基甲基)-2-(((4-甲氧基苄基)氧基)甲基)丙烷-1,3-二醇(1.00g)、2,2-二甲氧基丙烷(1.22g)之DMF(5mL)溶液中,於室溫添加吡啶鎓對甲苯磺酸鹽(10mg)。攪拌2小時後,在反應混合物中添加乙酸乙酯,以飽和碳酸氫鈉水溶液洗淨1次,以5%食鹽水洗淨2次後,用無水硫酸鈉乾燥後,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(426mg)。
1H NMR(500MHz,DMSO-d6)δppm 1.29(3H,s),1.29(3H,s),3.35(2H,s),3.39(2H,d,J=5.1Hz),3.61(4H,s),3.74(3H,s),4.38(2H,s),4.59(1H,t,J=5.1Hz),6.90(2H,d like,J=7.5Hz),7.24(2H,d like,J=7.5Hz)
B-2)9-(4-甲氧基苯基)-3,3-二甲基-2,4,8,10-四氧雜螺[5.5]十一烷
在(2-(4-甲氧基苯基)-1,3-二噁烷-5,5-二基)二甲醇(2.00g)、2,2-二甲氧基丙烷(2.46g)之DMF(8mL)溶液中,於室溫添加吡啶鎓對甲苯磺酸鹽(20mg)。攪拌4小時後,將反應混合物用乙酸乙酯稀釋,以飽和碳酸氫鈉水溶液洗淨2次,以飽和食鹽水洗淨2次後,用無水硫酸鎂乾燥後,將溶劑於減壓下餾去。將殘餘物於乙酸乙酯/己烷中再結晶,得到標題化合物(1.62g)。
1H NMR(500MHz,DMSO-d6)δppm 1.34(6H,s),3.33(2H,s),3.63(2H,d,J=11.7Hz),3.74(3H,s),3.99(2H,s),4.12(2H,d,J=11.7Hz),5.37(1H,s),6.90(2H,d,J=8.8Hz),7.34(2H,d,J=8.8Hz)
C-2)(5-(((4-甲氧基苄基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲醇
在9-(4-甲氧基苯基)-3,3-二甲基-2,4,8,10-四氧雜螺[5.5]十一烷(22.0g)之甲苯(200mL)懸浮溶液中,於5至20℃滴入1.5M DIBAL-H溶液(60mL),並於15℃攪拌3小時。添加甲醇(22mL)後,依序滴入2N氫氧化鈉水溶液(100mL)、4N氫氧化鈉水溶液(200mL)。攪拌1.5小時後,分取甲苯層,並以5%食鹽水洗淨。將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(14.7g)。
1H NMR(500MHz,DMSO-d6)δppm 1.29(3H,s),1.29(3H,s),3.35(2H,s),3.39(2H,d,J=5.1Hz),3.61(4H,s),3.74(3H,s),4.38(2H,s),4.59(1H,t,J=5.1Hz),6.90(2H,d like,J=7.5Hz),7.24(2H,d like,J=7.5Hz)
D)辛酸(5-(((4-甲氧基苄基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在(5-(((4-甲氧基苄基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲醇(2.00g)、DMAP(412mg)及辛酸(1.27g)之DMF(20mL)溶液中,於50℃添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(1.94g)。攪拌4小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(2.78g)。
1H NMR(500MHz,CDCl3)δ0.84-0.91(3 H,m),1.22-1.33(8 H,m),1.40(6 H,s),1.53-1.61(2 H,m),2.26(2 H,t,J=7.6Hz),3.39(2
H,s),3.68-3.74(2 H,m),3.76-3.80(2 H,m),3.80(3 H,s),4.15(2 H,s),4.42(2 H,s),6.87(2 H,d,J=7.8Hz),7.20-7.24(2 H,m)
E)辛酸(5-(羥基甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在辛酸(5-(((4-甲氧基苄基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(2.78g)之乙醇(30mL)溶液中,於室溫添加Pd/碳(840mg),並於氫蒙氣下攪拌5小時。反應後將Pd/碳過濾除去後,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(1.35g)。
1H NMR(500MHz,CDCl3)δ0.85-0.91(3 H,m),1.23-1.34(8 H,m),1.38-1.44(6 H,m),1.63(2 H,m),2.30-2.38(3 H,m),3.48(2 H,d,J=6.6Hz),3.68-3.75(4 H,m),4.25(2 H,s)
F)辛酸(5-(((N,N-二甲基-β-丙胺醯基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯
在辛酸(5-(羥基甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(400mg)、DMAP(129mg)及3-(二甲基胺基)丙酸鹽酸鹽(305mg)之DMF(4mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(456mg)。攪拌4小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥後,將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(320mg)。
1H NMR(500MHz,CDCl3)δ0.84-0.92(3 H,m),1.21-1.33(8 H,m),1.42(6 H,s),1.61(2 H,br),2.23(6 H,s),2.32(2 H,t,J=7.6Hz),2.47-2.51(2 H,m),2.57-2.61(2 H,m),3.75(4 H,s),4.13(4 H,d,J=11.7Hz)
G)(9Z,9'Z)雙-十四碳-9-烯酸2-(((N,N-二甲基-β-丙胺醯基)氧基)甲基)-2-((辛醯基氧基)甲基)丙-1,3-二基酯
在辛酸(5-(((N,N-二甲基-β-丙胺醯基)氧基)甲基)-2,2-二甲基-1,3-二噁烷-5-基)甲酯(320mg)中,添加乙酸(1.6mL)、水(0.8mL),並於65℃攪拌3.5小時後,將溶劑於減壓下餾去。在殘餘物中添加乙酸乙酯、飽和碳酸氫鈉水溶液,並攪拌2小時。以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。在所得到之殘餘物(150mg)、DMAP(101mg)及(9Z)-十四碳-9-烯酸(235mg)之DMF(4.5mL)溶液中,於50℃添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(231mg)。攪拌8小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(230mg)。
1H NMR(500MHz,CDCl3)δ0.84-0.93(9 H,m),1.24-1.36(30 H,m),1.53-1.65(8 H,m),1.98-2.05(8 H,m),2.22(6 H,s),2.30(6 H,t,J=7.6Hz),2.48(2 H,t,J=6.9Hz),2.58(2 H,t,J=6.8Hz),4.06-4.22(8 H,m),5.31-5.38(4 H,m)
[實施例11](9Z,9'Z)雙-十四碳-9-烯酸2-(((4-(二甲基胺基)丁醯基)氧基)甲基)-2-((十二醯基氧基)甲基)丙烷-1,3-二基酯
A)十二酸3-羥基-2,2-雙(羥基甲基)丙酯
在2,2-雙(羥基甲基)丙烷-1,3-二醇(5.00g)、DMAP(2.24g)及月桂酸(3.68g)之DMF(150mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(7.04g)。攪拌20小時後,在反應混合物中添加乙酸
乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(1.79g)。
1H NMR(500MHz,CDCl3)δ0.85-0.91(3 H,m),1.22-1.33(16 H,m),1.59-1.66(3 H,m),2.36(2 H,t,J=7.6Hz),2.51(2 H,t,J=5.8Hz),3.65(6 H,d,J=5.7Hz),4.23(2 H,s)
B)(9Z,9'Z)雙-十四碳-9-烯酸2-((十二醯基氧基)甲基)-2-(羥基甲基)丙烷-1,3-二基酯
在十二酸3-羥基-2,2-雙(羥基甲基)丙酯(400mg)、DMAP(153mg)及(9Z)-十四碳-9-烯酸(569mg)之DMF(4mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(602mg)。攪拌8小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(乙酸乙酯/己烷)精製,得到標題化合物(230mg)。
1H NMR(500MHz,CDCl3)δ0.85-0.93(9 H,m),1.22-1.36(40 H,m),1.58-1.65(6 H,m),1.99-2.05(8 H,m),2.32(6 H,t,J=7.6Hz),2.52(1 H,t,J=7.1Hz),3.48(2 H,d,J=6.9Hz),4.09-4.14(6 H,m),5.31-5.38(4 H,m)
C)(9Z,9'Z)雙-十四碳-9-烯酸2-(((4-(二甲基胺基)丁醯基)氧基)甲基)-2-((十二醯基氧基)甲基)丙烷-1,3-二基酯
在(9Z,9'Z)雙-十四碳-9-烯酸2-((十二醯基氧基)甲基)-2-(羥基甲基)丙烷-1,3-二基酯(230mg)、DMAP(38mg)及4-(二甲基胺基)丁酸鹽酸鹽(105
mg)之DMF(4mL)溶液中,於室溫添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(150mg)。攪拌3小時後,在反應混合物中添加乙酸乙酯,以水洗淨2次,以飽和食鹽水洗淨1次後,用無水硫酸鈉乾燥,然後將溶劑於減壓下餾去。將殘餘物以矽膠管柱層析(NH,乙酸乙酯/己烷)精製,得到標題化合物(100mg)。
1H NMR(500MHz,CDCl3)δ0.85-0.93(9 H,m),1.23-1.35(40 H,m),1.55-1.67(6 H,m),1.77(2 H,m),1.98-2.05(8 H,m),2.20(6 H,s),2.24-2.33(8 H,m),2.36(2 H,t,J=7.6Hz),4.09-4.13(8 H,m),5.31-5.38(4 H,m)
依照上述之各實施例中所示的方法,或以彼等為基準之方法的任一種,可製造以下表中之實施例2至3、5至7及9至10。關於此等實施例,以及實施例1、4、8及11,一起將化合物之名稱、構造式及製造時所實施之質量數(表中,以MS表示)示於表1中。
[含有本發明之脂質粒子及核酸的核酸導入用組成物之製造例及試驗例]
[製造例1]
將脂質混合物(實施例所製造之陽離子性脂質:DPPC:膽固醇:GM-020=60:10.6:28:1.4,莫耳比)溶解於90%EtOH、10%不含RNase之水中,得到8.5mg/mL之脂質溶液。將螢光素酶mRNA(TriLink BioTechnologies)溶解於10mM 2-N-嗎啉基乙磺酸(MES)緩衝液(pH4.0)中,得到0.22mg/mL之核酸溶液。將所得到之脂質溶液及核酸溶液於室溫,藉由NanoAssemblr裝置(Precision Nanosystems),以流速比3mL/分鐘:6mL/分鐘混合,得到含有內封核酸之脂質粒子的分散液。所得到之分散液,使用Slyde-A-Lyzer(20k之分劃分子量,Thermo scientific),於室溫下對水進行透析1小時,於4℃對PBS進行透析48小時。繼而,使用0.2μm之針筒過濾器(Iwaki)進行過濾,調製成核酸導入用組成物後,於4℃保存。脂質粒子之粒徑係使用Zetasizer Nano ZS(Malvern Instruments)測定。又,脂質粒子中之mRNA濃度及內封率係使用Quant-iTTMRiboGreen(註冊商標)(Invitrogen)測定。將分析之結果示於表2。
[試驗例1]對培養細胞之mRNA轉染試驗
將來自人類大腸癌之細胞株HCT116,以6000細胞/孔之細胞密度於96-孔培養盤中培養,24小時後,將10μL之含有10ng螢光素酶(luciferase)mRNA的核酸導入用組成物(將製造例1所製造者稀釋成mRNA之濃度為10ng/10μL的液體)添加於培養基中。從mRNA之添加經24小時後,於HCT116表現之螢光素酶量,使用Picagene LT2.0套組(東洋紡)測定。將測定之結果示於表3及表4。
[含有本發明之脂質粒子及核酸的核酸導入用組成物之製造例及試驗例]
[製造例2]
將脂質混合物(實施例所製造之陽離子性脂質:DPPC:膽固醇:GM-020=60:10.6:28:1.4,莫耳比)溶解於90% EtOH、10%不含RNase之水中,得到約7mg/ml之脂質溶液。針對Col1a1之siRNA及針對因子VII(FVII)之siRNA各以等量混合,溶解於25mM乙酸緩衝液(pH4.0),得到0.2mg/ml之核酸溶液。再者,各siRNA之序列資料示於下表中。將所得到之脂質溶液及核酸溶液,於室溫,藉由NanoAssemblr裝置(Precision Nanosystems),以流速比3ml/分鐘:9ml/分鐘混合,得到含有內封核酸之脂質粒子的分散液。所得到之分散液,使用Slyde-A-Lyzer(20k之分劃分子量,Thermo scientific),於室溫對水進行透析1小時,於4℃對PBS進行透析48小時。繼而,使用0.2μm之針筒過濾器(Iwaki)進行過濾,調製成核酸導入用組成物後,於4℃保存。脂質粒子之粒徑係使用Zetasizer Nano ZS(Malvern Instruments)測定。又,脂質粒子中之mRNA濃度及內封率係使用Quant-iTTM RiboGreen(註冊商標)(Invitrogen)測定。將分析之結果示於表6。
N:RNA
n:DNA
[mN]:2'-OMe RNA
[ns]:硫代磷酸酯(phosphorothioate)
[試驗例2]四氯化碳肝障礙模型小鼠中之對肝星細胞的siRNA運輸試驗
內封Col1a1siRNA及FVII siRNA之脂質粒子之PBS分散液,以使siRNA濃度成為40μg/ml及120μg/ml之方式,用PBS稀釋,並以對Balb/c小鼠之siRNA投與量成為0.2mg/kg及0.6mg/kg之方式,投與至眼窩靜脈叢內。從siRNA之投與算起經3小時後,以使四氯化碳成為0.1ml/kg之方式進行經口投與。從四氯化碳之投與算起經4日後,將小鼠於異氟烷(isoflurane)麻醉下藉由放血使其安樂死,並回收肝臟。藉由RNeasy Mini Kit(QIAGEN公司)從所得到之肝臟萃取全部RNA,依照定量性PCR法,進行Col1a1mRNA、FVII mRNA及GAPDHmRNA量之測定。以siRNA未投與小鼠為基準,算出相對於GAPDH mRNA量進行標準化後之Col1a1mRNA及FVII mRNA之表現降低率,並將其示於下表。
本發明之化合物、脂質粒子或組成物,可將核酸有效率地導入各種細胞、組織或臟器。因此,本發明之化合物、脂質粒子或組成物可被利用作為核酸醫藥中之DDS技術。又,本發明之化合物、脂質粒子或組成物,亦可被用作研究用核酸導入試藥。
<110> 日商武田藥品工業股份有限公司
<120> 陽離子性脂質
<130> PT38-9027WO
<150> JP 2017-254667
<151> 2017-12-28
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 21
<212> DNA
<213> 人工造序列
<220>
<223> Col1a1 siRNA(正義)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 包含RNA及DNA鹼基二者之序列,其中一些為經修飾鹼基
<220>
<221> 經修飾之鹼基
<222> (2)..(2)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (3)..(3)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (4)..(4)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (8)..(8)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (10)..(10)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (12)..(12)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (12)..(12)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (13)..(13)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (14)..(14)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (17)..(17)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (18)..(18)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> misc_feature
<222> (20)..(21)
<223> 核苷酸(t及t)與硫代磷酸酯結合
<210> 2
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> Col1a1 siRNA(反義)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 包含RNA及DNA鹼基二者之序列,其中一些為經修飾鹼基
<220>
<221> 經修飾之鹼基
<222> (9)..(9)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (15)..(15)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> misc_feature
<222> (20)..(21)
<223> 核苷酸(t及t)與硫代磷酸酯結合
<210> 3
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 因子VII siRNA(正義)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 包含RNA及DNA鹼基二者之序列,其中一些為經修飾鹼基
<220>
<221> 經修飾之鹼基
<222> (1)..(1)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (2)..(2)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (4)..(4)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (10)..(10)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (12)..(12)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (13)..(13)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (14)..(14)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (15)..(15)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (16)..(16)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> 經修飾之鹼基
<222> (17)..(17)
<223> 〝c〞代表2'-O-甲基胞核苷(cm)
<220>
<221> 經修飾之鹼基
<222> (19)..(19)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> misc_feature
<222> (20)..(21)
<223> 核苷酸(t及t)與硫代磷酸酯結合
<210> 4
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 因子VII siRNA(反義)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 包含RNA及DNA鹼基二者之序列,其中一些為經修飾鹼基
<220>
<221> 經修飾之鹼基
<222> (17)..(17)
<223> 〝u〞代表2'-O-甲基尿核苷(um)
<220>
<221> misc_feature
<222> (20)..(21)
<223> 核苷酸(t及t)與硫代磷酸酯結合
Claims (8)
- 一種化合物,其係(9Z)-十四碳-9-烯酸3-((4-(二甲基胺基)丁醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
- 一種化合物,其係(9Z)-十四碳-9-烯酸3-((5-(二甲基胺基)戊醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
- 一種化合物,其係(9Z)-十四碳-9-烯酸3-((6-(二甲基胺基)己醯基)氧基)-2,2-雙(((9Z)-十四碳-9-烯醯基氧基)甲基)丙酯或其鹽。
- 一種脂質粒子,其含有如申請專利範圍第1項所述之化合物或其鹽。
- 一種核酸導入用組成物,其含有核酸及如申請專利範圍第5項所述之脂質粒子。
- 如申請專利範圍第6項所述之組成物,其中該核酸為RNA。
- 如申請專利範圍第7項所述之組成物,其中該RNA為mRNA或siRNA。
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