TW201936179A - Hsp90-靶定之共軛物及其調配物 - Google Patents
Hsp90-靶定之共軛物及其調配物 Download PDFInfo
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- TW201936179A TW201936179A TW107145198A TW107145198A TW201936179A TW 201936179 A TW201936179 A TW 201936179A TW 107145198 A TW107145198 A TW 107145198A TW 107145198 A TW107145198 A TW 107145198A TW 201936179 A TW201936179 A TW 201936179A
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Abstract
設計經由鍵聯子附著至靶定之部分(諸如HSP90結合之部分)的活性劑之共軛物及包含此等共軛物之粒子。此等共軛物及粒子可提供改進之活性劑時空遞送(temporospatial delivery)、改進之腫瘤中的生物分布和穿透性及/或降低之毒性。提供製造該共軛物、該粒子及其調配物之方法。提供對有其需要之個體投予該調配物之方法,以例如治療或預防癌症。
Description
本發明概括關於靶定之配體、其共軛物及用於藥物遞送之粒子的領域。本發明更特別地關於靶定熱休克蛋白(包括熱休克蛋白90(HSP90))之分子的用途,例如用於治療癌症。
熱休克蛋白90(HSP90)為細胞內伴隨蛋白,其有助於蛋白質摺疊、穩定蛋白質對抗熱逆境且幫助蛋白質降解。其於許多類型的癌中被調升。許多Hsp90客戶蛋白常以突變形式過度表現癌中且成為無限制的癌細胞增生及存活的原因。HSP90於癌組織中活化及潛伏在正常組織中。源自腫瘤細胞之HSP90對HSP90抑制劑具有比正常細胞中的潛伏形式更高的結合親和性,容許HSP90抑制劑特異性靶定腫瘤細胞,在正常細胞中具有較低的HSP90功能抑制作用。再者,HSP90最近亦被鑑定為腫瘤入侵之重要的細胞外調介體。因此,HSP90被認為是抗癌藥物開發的主要治療靶標。
奈米微粒藥物遞送系統對全身性藥物遞送具有吸引力,因為彼等能夠延長藥物在循環中的半衰期、減少藥物的非特異性攝取及改進藥物在腫瘤處的累積,例如通過增強的滲透及滯留(EPR)效應。有經調配作為奈米粒子遞送之治療劑的非限制性實例,其包括DOXIL®(經脂質體囊封之多柔比星(doxyrubicin))及ABRAXANE®(經白蛋白結合之紫杉醇(paclitaxel)奈米粒子)。
以時空調控方式有效遞送藥物或候選藥物至特定的生病細胞及組織(例如在特定器官或組織中的癌細胞)之奈米技術的開發可能可克服或改善治療挑戰,諸如全身性毒性。然而,雖然遞送系統之靶定可優先遞送藥物至需要治療的位點,但是自奈米粒子釋放之藥物無法例如以有效量維持在靶定之細胞區域內,或不可能以相對無毒的狀態於循環內維持充分的時間量以降低治療頻率或允許投予較低的藥物量,同時仍達到治療效應。因此,本技術仍對改進之藥物靶定及遞送有需求,包括可併入粒子中且其存在不實質地干擾藥物功效的靶定之分子的鑑定。
本發明提供包含以鍵聯子與HSP90靶定之部分偶合的活性劑之共軛物及包含此共軛物之醫藥組成物。
亦提供製造及使用此等共軛物之方法。
相關的說明
申請人已設計包含活性劑的HSP90靶定之共軛物及包含此等共軛物之新穎粒子。此靶定可例如改進在位點上的活性劑量及降低對個體的活性劑毒性。本發明的HSP90靶定之共軛物具有深入及快速的腫瘤穿透性且不需要受體內化作用。HSP90靶定之共軛物的高累積及長滯留時間使得能夠使用細胞毒性及非細胞毒性酬載,諸如化學治療劑、激酶抑制劑或免疫腫瘤學調節劑。
如本文所使用的「毒性」係指物質或組成物對細胞、組織有機體或細胞環境有害或有毒的能力。低毒性係指物質或組成物對細胞、組織有機體或細胞環境有害或有毒的能力降低。此降低的毒性或低毒性可相對於標準量測、相對於治療或相對於未治療。
毒性可另外相對於個體的體重減輕來測量,其中超過體重的15%、超過20%或超過30%之體重減輕為毒性的指標。亦可測量毒性的其他測度,諸如患者表現的測度,包括嗜睡及一般不適。嗜中性球減少症或血小板減少症亦可為毒性的測度。
毒性的藥理指標包括上升的AST/ALT含量、神經毒性、腎臟受損、GI受損及類似者。
共軛物係在投予粒子後釋放。經靶定之藥物共軛物係利用活性分子靶定與增強的滲透及滯留效應(EPR)和改進的粒子整體生物分布之組合以提供與投予經靶定之粒子或經囊封的未靶定之藥物相比而更大的功效及耐藥性。
另外,與單獨的活性劑之毒性相比,預期含有與活性劑鍵聯的HSP90靶定之部分的共軛物對不過度表現HSP90之細胞的毒性降低。不承諾於任何特定的理論,申請人相信此特點是因為使經共軛之活性劑保留在正常細胞內比保留在腫瘤細胞內的能力降低。
本發明之目的係提供用於時空藥物遞送的經改進之化合物、組成物及調配物。
本發明之另一目的係提供製造用於時空藥物遞送的經改進之化合物、組成物及調配物之方法。
本發明之又一目的係提供對有其需要的個體投予經改進之化合物、組成物及調配物之方法。
I. 共軛物
I. 共軛物
共軛物包括以鍵聯子附著至靶定之部分(例如可結合至HSP90之分子)的活性劑或其前藥。共軛物可為在單一活性劑與單一靶定之部分之間的共軛物,例如具有結構X-Y-Z之共軛物,其中X為靶定之部分,Y為鍵聯子,及Z為活性劑。
在一些實施態樣中,共軛物含有超過一個靶定之部分、超過一個鍵聯子、超過一個活性劑或彼之任何組合。共軛物可具有任何數目的靶定之部分、鍵聯子及活性劑。共軛物可具有結構X-Y-Z-Y-X,(X-Y)n
-Z、X-(Y-Z)n
、Xn
-Y-Z,X-Y-Zn
、(X-Y-Z)n
、(X-Y-Z-Y)n
-Z,其中X為靶定之部分,Y為鍵聯子,Z為活性劑,及n為介於1與50之間、介於2與20之間的整數,例如介於1與5之間。每次出現的X、Y和Z可相同或不同,例如共軛物可含有超過一種類型的靶定之部分、超過一種類型的鍵聯子及/或超過一種類型的活性劑。
共軛物可含有超過一個附著至單一活性劑的靶定之部分。例如,共軛物可包括具有多個分別經由不同的鍵聯子附著的靶定之部分的活性劑。共軛物可具有結構X-Y-Z-Y-X,其中各X為可相同或不同的靶定之部分,各Y為可相同或不同的鍵聯子,及Z為活性劑。
共軛物可含有超過一個附著至單一靶定之部分的活性劑。例如,共軛物可包括具有多個分別經由不同的鍵聯子附著之活性劑的靶定之部分。共軛物可具有結構Z-Y-X-Y-Z,其中X為靶定之部分,各Y為可相同或不同的鍵聯子,及各Z為可相同或不同的活性劑。
A. 活性劑
A. 活性劑
如本文所述之共軛物含有至少一種活性劑(第一活性劑)。共軛物可含有超過一個可相同或不同於第一活性劑的活性劑。活性劑可為治療劑、預防劑、診斷劑或營養劑。各種活性劑為本技術已知且可用於本文所述之共軛物中。活性劑可為蛋白質或肽、小分子、核酸或核酸分子、脂質、糖、醣脂、醣蛋白、脂蛋白或彼之組合。在一些實施態樣中,活性劑為抗原、佐劑、放射活性物、成像劑(例如螢光部分)或多核苷酸。在一些實施態樣中,活性劑為有機金屬化合物。
在特定的實施態樣中,共軛物之活性劑包含約1%至約10%、或約10%至約20%、或約20%至約30%、或約30%至約40%、或約40%至約50%、或約50%至約60%、或約60%至約70%、或約70%至約80%、或約80%至約90%、或約90%至約99%之預定的莫耳重量百分比,使得共軛物之組分的莫耳重量百分比總合為100%。共軛物之活性劑的量亦可以相對於靶定之配體的比例方式表示。例如,本發明之指導提供約10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4;1:5、1:6、1:7、1:8、1:9或1:10之活性劑對配體之比。
在一些實施態樣中,活性劑可為癌治療劑。癌治療劑包括例如死亡受體促效劑,諸如TNF相關之細胞凋亡誘發配體(TRAIL)、或Fas配體、或結合或活化死亡受體或以其他方式誘發細胞凋亡的任何配體或抗體。適合的死亡受體包括但不限於TNFR1、Fas、DR3、DR4、DR5、DR6、LTβR及彼之組合。
癌治療劑(諸如化學治療劑、細胞激素、趨化激素和放射治療劑)可用作為活性劑。化學治療劑包括例如烷基化劑、抗代謝物、蒽環素、植物鹼、拓樸異構酶抑制劑和其他的抗腫瘤劑。此等藥劑通常影響細胞分裂或DNA合成及功能。可用作活性劑之治療劑的額外實例包括單株抗體和酪胺酸激酶抑制劑,例如伊馬替尼(imatinib)甲磺酸鹽,其直接靶定特定類型的癌中之分子異常(例如慢性骨髓性白血病、胃腸道基質瘤)。
化學治療劑包括但不限於順鉑(cisplatin)、卡鉑(卡鉑)、奧沙利鉑(oxaliplatin)、甲基二(氯乙基)胺(mechlorethamine)、環磷醯胺、氯芥苯丁酸、長春新鹼、長春鹼、溫諾平(vinorelbine)、長春地辛(vindesine)、紫杉醇(taxol)與其衍生物、艾來諾康(irinotecan)、拓普康(topotecan)、安沙吖啶(amsacrine)、依托泊苷(etoposide)、依托泊苷磷酸鹽、替尼泊苷(teniposide)、表鬼臼毒素(epipodophyllotoxin)、曲妥珠單抗(trastuzumab)、西妥昔單抗(cetuximab)和利妥昔單抗(rituximab)、貝伐單抗(bevacizumab)及彼之組合。該等中之任一者可用作為共軛物中的活性劑。
在本發明中使用之小分子活性劑(例如抗增生劑(細胞毒性劑和細胞生長抑制劑))包括細胞毒性化合物(例如廣效性)、血管生成抑制劑、細胞週期進展抑制劑、PBK/m-TOR/AKT路徑抑制劑、MAPK傳訊路徑抑制劑、激酶抑制劑、蛋白伴隨抑制劑、HDAC抑制劑、PARP抑制劑、Wnt/刺蝟傳訊路徑抑制劑、RNA聚合酶抑制劑和蛋白酶體抑制劑。在一些實施態樣中,活性劑為小分子活性劑,其類似物、衍生物、前藥或其醫藥上可接受之鹽。
廣效性細胞毒素包括但不限於DNA-結合或烷基化藥物、微管穩定和去穩定劑、鉑化合物及拓樸異構酶I或II抑制劑。
例示性DNA-結合或烷基化藥物包括CC-1065與其類似物、蒽環素(多柔比星(doxorubicin)、泛艾黴素(epirubicin)、艾達黴素(idarubicin)、道諾黴素(daunorubicin))與其類似物、烷基化劑(諸如加利奇黴素(calicheamicin)、更生黴素(dactinomycine)、絲裂黴素(mitromycine)、吡咯并苯并二氮呯)及類似者。
例示性多柔比星類似物包括在Cohen等人之US 20140227299中所揭示之紐莫柔比星(nemorubicin)代謝物或類似的藥物部分,將其內容以彼之全文併入本文以供參考。
例示性CC-1065類似物包括杜卡黴素(duocarmycin)SA、杜卡黴素CI、杜卡黴素C2、杜卡黴素B2、DU-86、KW-2189、比哲來新(bizelesin)、seco-阿朵來新(adozelesin)及那些在美國專利案號5,475,092、5,595,499、5,846,545、6,534,660、6,586,618、6,756,397和7,049,316中所述者。多柔比星與其類似物包括PNU-159682及那些在美國專利案號6,630,579中所述者,及在Cohen等人之US 20140227299所揭示之紐莫柔比星代謝物或類似藥物,將該等內容以彼之全文併入本文以供參考。
加利奇黴素包括那些在美國專利案號5,714,586和5,739,116中所述者。杜卡黴素包括那些在美國專利案號5,070,092、5,101,038、5,187,186、6,548,530、6,660,742和7,553,816 B2及Li等人之Tet Letts., 50:2932-2935(2009)中所述者。吡咯并苯并二氮呯包括SG2057及那些在Denny, Exp. Opin. Ther. Patents., 10(4):459-474(2000), Anti-Cancer Agents in Medicinal Chemistry, 2009, 9, 1-31、WO 2011/130613 A1、EP 2 789 622 A1、Blood 2013, 122, 1455、J. Antimicrob. Chemother. 2012, 67, 1683-1696、Cancer Res. 2004, 64, 6693-6699、WO 2013041606、US 8481042、WO 2013177481、WO 2011130613、WO2011130598中所述者。
例示性微管穩定和去穩定劑包括紫杉烷(taxane)化合物(諸如紫杉醇、歐洲紫杉醇(docetaxel)、卡巴他賽(cabazitaxel))、類美登新(maytansinoid)、奧瑞他汀(auristatin)與其類似物、微管溶素(tubulysin)A和B 衍生物、長春花生物鹼(vinca alkaloid)衍生物、埃坡黴素(epothilone)、PM060184及念珠藻素(cryptophycin)。
例示性類美登新或類美登新類似物包括美登醇(maytansinol)與美登醇類似物、美登新(maytansine)或DM-1和DM-4及那些在美國專利案號5,208,020、5,416,064、6,333.410、6,441,163、6,716,821、RE39,151和7,276,497中所述者。在特定的實施態樣中,細胞毒性劑為類美登新、另一族群的抗微管蛋白劑(ImmunoGen, Inc.;亦參見Chari等人之1992, Cancer Res. 52:127-131)、類美登新或類美登新類似物。適合的類美登新的實例包括美登醇與美登醇類似物。適合的類美登新係揭示於美國專利案號4,424,219、4,256,746、4,294,757、4,307,016、4,313,946、4,315,929、4,331,598、4,361,650、4,362,663、4,364,866、4,450,254、4,322,348、4,371,533、6,333,410、5,475,092、5,585,499和5,846,545中。
例示性奧瑞他汀包括奧瑞他汀E(亦稱為尾海兔素(dolastatin)-10之衍生物)、奧瑞他汀EB(AEB)、奧瑞他汀EFP(AEFP)、單甲基奧瑞他汀E(MMAE)、單甲基奧瑞他汀F(MMAF)、奧瑞他汀F和尾海兔素。適合的奧瑞他汀亦說明於美國公開案2003/0083263, 2011/0020343和2011/0070248;PCT申請公開案WO 09/117531、WO 2005/081711、WO 04/010957、WO02/088172和WO01/24763;及美國專利案號7,498,298、6,884,869、6,323,315、6,239,104、6,124,431、6,034,065、5,780,588、5,767,237、5,665,860、5,663,149、5,635,483、5,599,902;5,554,725、5,530,097、5,521,284、5,504,191、5,410,024、5,138,036、5,076,973、4,986,988、4,978,744、4,879,278、4,816,444和4,486,414中,將該等揭示內容以彼之全文併入本文以供參考。
例示性微管溶素化合物包括在美國專利案號7,816,377、7,776,814、7,754,885;美國公開案2011/0021568、2010/004784、2010/0048490、2010/00240701、2008/0176958;及PCT 申請案號WO 98/13375、WO 2004/005269;WO 2008/138561、WO 2009/002993、WO 2009/055562、WO 2009/012958、WO 2009/026177、WO 2009/134279、WO 2010/033733、WO 2010/034724、WO 2011/017249、WO 2011/057805中所述之化合物,將該等揭示內容以彼之全文併入本文以供參考。
例示性長春花生物鹼包括長春新鹼、長春鹼、長春地辛和溫諾平(navelbine)(溫諾平(vinorelbine))。可在本發明中使用之適合的長春花生物鹼亦揭示於美國公開案2002/0103136和2010/0305149及美國專利案號7,303,749 Bl中,將該等揭示內容以彼之全文併入本文以供參考。
例示性埃坡黴素化合物包括埃坡黴素 A、B、C、D、E和F與其衍生物。適合的埃坡黴素化合物與其衍生物說明於例如美國專利案號6,956,036、6,989,450、6,121,029、6,117,659、6,096,757、6,043,372、5,969,145和5,886,026;及WO 97/19086、WO 98/08849、WO 98/22461、WO 98/25929、WO 98/38192、WO 99/01124、WO 99/02514、WO 99/03848、WO 99/07692、WO 99/27890和WO 99/28324中;將該等揭示內容以彼之全文併入本文以供參考。
例示性念珠藻素化合物說明於美國專利案號6,680,311和6,747,021中,將該等揭示內容以彼之全文併入本文以供參考。
例示性鉑化合物包括順鉑(PLATINOL®)、卡鉑(PARAPLATIN®)、奧沙利鉑(ELOX ATINE®)、異丙鉑(iproplatin)、奧馬鉑(ormaplatin)和四鉑(tetraplatin)。
例示性拓樸異構酶I抑制劑包括喜樹鹼、喜樹鹼衍生物、喜樹鹼類似物和非天然喜樹鹼,諸如CPT-11(艾來諾康)、SN-38、拓普康、9-胺基喜樹鹼、盧比替康(rubitecan)、吉馬替康(gimatecan)、卡瑞尼特辛(karenitecin)、席拉特康(silatecan)、勒托替康(lurtotecan)、依喜替康(exatecan)、第弗羅替康(diflomotecan)、貝羅替康(belotecan)、勒托替康(lurtotecan)和S39625。可在本發明中使用之其他的喜樹鹼化合物包括那些在例如J. Med. Chem., 29:2358-2363 (1986)、J. Med. Chem., 23:554(1980)、J. Med. Chem., 30:1774(1987)中所述者。
例示性拓樸異構酶II抑制劑包括阿柔萘非特(azonafide)和依托泊苷。
在DNA上起作用之額外的藥劑包括如在WO 200107711、WO 2003014127中所述之盧必奈克定(Lurbinectedin)(PM01183)、曲貝替定(Trabectedin)(亦稱為海鞘素(ecteinascidin)743或ET-743)及類似物。
血管生成抑制劑包括但不限於MetAP2抑制劑。
例示性MetAP2抑制劑包括煙曲黴素醇(fumagillol)類似物,意指任何包括煙曲黴素(fumagillin)核心結構之化合物,包括抑制MetAP-2自蛋白質移除NH2
端蛋胺酸之能力的煙曲黴胺(fumagillamine),如在Rodeschini等人之Org. Chem., 69, 357-373, 2004及Liu,等人之Science 282, 1324-1327, 1998中所述。「煙曲黴素醇類似物」的非限制性實例揭示於Org. Chem., 69, 357, 2004;J.Org. Chem., 70, 6870, 2005;歐洲專利申請案0 354 787;Med. Chem., 49, 5645, 2006;Bioorg. Med. Chem., 11, 5051, 2003;Bioorg. Med. Chem., 14, 91, 2004;Tet. Lett. 40, 4797, 1999;W099/61432;美國專利案號6,603,812、5,789,405、5,767,293、6,566,541和6,207,704中。
例示性細胞週期進展抑制劑包括CDK抑制劑,諸如BMS-387032和PD0332991;Rho-激酶抑制劑,諸如GSK429286;檢查點激酶抑制劑,諸如AZD7762;極光激酶抑制劑,諸如AZD1152、MLN8054和MLN8237;PLK抑制劑,諸如BI 2536、BI6727(瓦拉司替(Volasertib))、GSK461364、ON-01910(埃斯特邦(Estybon));及KSP抑制劑,諸如SB 743921、SB 715992(依斯平希(ispinesib))、MK-0731、AZD8477、AZ3146和ARRY-520。
例示性PI3K/m-TOR/AKT傳訊路徑抑制劑包括肌醇磷脂3-激酶(PI3K)抑制劑、GSK-3抑制劑、ATM抑制劑、DNA-PK抑制劑和PDK-1抑制劑。
例示性PI3激酶抑制劑係揭示於美國專利案號6,608,053中,且包括BEZ235、BGT226、BKM120、CAL101、CAL263、去甲氧基綠膠黴素(demethoxyviridin)、GDC-0941、GSK615、IC87114、LY294002、Palomid 529、哌立福新、PF-04691502、PX-866、SAR245408、SAR245409、SF1126、渥曼青黴素(Wortmannin)、XL147、XL765、GSK2126458(歐米帕利希布)、GDC-0326、GDC-0032(泰利斯布(Taselisib)、RG7604)、PF-05212384(捷達特利斯(Gedatolisib)、PKI-587)、BAY 80-6946(柯潘利希布)、PF-04691502、PF-04989216、PI-103、PKI-402 VS-5584(SB2343)、GDC-0941、NVP-BEZ235(Dactoslisib)、BGT226、NVP-BKM120(布帕利希布)、NVP-BYL719(阿哌利希布)、GSK2636771、AMG-319、GSK2269557、PQR309、PWT143、TGR-1202 (RP5264)、PX-866、GDC-0980(阿匹托利希布)、AZD8835、MLN1117、DS-7423、ZSTK474、CUDC-907、IPI-145(INK-1197、杜維利希布)、AZD8186、XL147(SAR245408)、XL765(SAR245409)、CAL-101(艾德拉利希布、GS-1101)、GS-9820(阿卡利希布)和KA2237。
例示性AKT抑制劑包括但不限於AT7867、MK-2206、哌立福新、GSK690693、依帕他昔替(Ipatasertib)、AZD5363、TIC10、阿福替布(Afuresertib)、SC79、AT13148、PHT-427、A-674563和CCT128930。
例示性MAPK傳訊路徑抑制劑包括MEK、Ras、JNK、B-Raf和p38 MAPK抑制劑。
例示性MEK抑制劑係揭示於美國專利案號7,517,994中,且包括GDC-0973、GSK1120212、MSC1936369B、AS703026、R05126766和R04987655、PD0325901、AZD6244、AZD 8330及GDC-0973。
例示性B-raf抑制劑包括CDC-0879、PLX-4032和SB590885。
例示性B p38 MAPK抑制劑包括BIRB 796、LY2228820和SB202190。
受體酪胺酸激酶(RTK)為細胞表面受體,其常與刺激癌細胞失控增生及新血管生成之傳訊路徑相關聯。已鑑定許多過度表現或具有導致受體之組成性活化的突變之RTK,包括但不限於VEGFR、EGFR、FGFR、PDGFR、EphR和RET受體家族受體。例示性RTK特異性標靶包括ErbB2、FLT-3、c-Kit、c-Met和HIF。
ErbB2受體(EGFR家族)之例示性抑制劑包括但不限於AEE788(NVP-AEE 788)、BIBW2992(阿法替尼(Afatinib))、拉帕替尼(Lapatinib)、埃羅替尼(Erlotinib)(塔西瓦(Tarceva))和吉非替尼(Gefitinib)(易瑞沙(Iressa))。
靶定超過一種傳訊路徑之例示性RTK抑制劑(經多重靶定之激酶抑制劑)包括靶定FGFR、FLT-3、VEGFR-PDGFR和Bcr-Abl受體之AP24534(朋那替尼(Ponatinib));靶定FLT-3和VEGFR- PDGFR受體之ABT-869(里尼凡尼(Linifanib));靶定VEGFR-PDGFR、Flt-1和VEGF受體之AZD2171;靶定VEGFR-PDGFR、FGFR、Flt-3和c-Kit受體之CHR-258(多韋替尼(Dovitinib))。
例示性激酶抑制劑包括激酶ATM、ATR、CHK1、CHK2、WEE1和RSK之抑制劑。
例示性蛋白伴隨抑制劑包括HSP90抑制劑。例示性HSP90抑制劑包括17AAG衍生物、BIIB021、BIIB028、SNX-5422、NVP-AUY-922和KW-2478。
例示性HDAC抑制劑包括貝利諾司他(Belinostat)(PXD101)、CUDC-101、多希諾司他(Doxinostat)、ITF2357(吉威諾司他(Givinostat)、佳威諾司他(Gavinostat))、JNJ-26481585、LAQ824(NVP-LAQ824、達希諾司他(Dacinostat))、LBH-589(潘諾畢諾司他(Panobinostat))、MC1568、MGCD0103(墨瑟提諾司他(Mocetinostat))、MS-275(英提諾司他(Entinostat))、PCI-24781、派若沙米德(Pyroxamide)(NSC 696085)、SB939、翠丘司他(Trichostatin)A和佛瑞諾泰(Vorinostat)(SAHA)。
例示性PARP抑制劑包括依尼帕瑞(iniparib)(BSI 201)、奧拉帕瑞(olaparib)(AZD-2281)、ABT-888(凡尼帕瑞(Veliparib))、AG014699、CEP 9722、MK 4827、KU-0059436(AZD2281)、LT-673、3-胺基苯甲醯胺、A-966492和AZD2461。
例示性Wnt/刺蝟傳訊路徑抑制劑包括韋斯莫德吉(vismodegib)(RG3616/GDC-0449)、環帕胺(cyclopamine)(11-去氧芥芬鹼(deoxojervine))(刺蝟路徑抑制劑)和XAV-939(Wnt路徑抑制劑)。
例示性RNA聚合酶抑制劑包括鵝膏蕈毒素(amatoxin)。例示性鵝膏蕈毒素包括a-瓢菌素、β-瓢菌素、γ-瓢菌素、ε-瓢菌素、鵝膏無毒環肽(amanullin)、二羥鵝膏毒肽羧酸(amanullic acid)、阿瑪米德(鵝膏素amide)、鵝膏素(amanin)和鵝膏無毒環肽原(proamanullin)。
例示性蛋白酶體抑制劑包括硼替佐米(bortezomib)、卡非唑米(carfilzomib)、ONX 0912, CEP-18770和MLN9708。
在一個實施態樣中,本發明之藥物為非天然喜樹鹼化合物、長春花生物鹼、激酶抑制劑(例如PI3激酶抑制劑(GDC-0941和PI-103))、MEK抑制劑、KSP抑制劑、RNA聚合酶抑制劑、PARP抑制劑、歐洲紫杉醇、紫杉醇、多柔比星、杜卡黴素、微管溶素、奧瑞他汀或鉑化合物。在特定的實施態樣中,藥物為SN-38之衍生物、長春地辛、長春鹼、PI-103、AZD 8330、奧瑞他汀E、奧瑞他汀F、杜卡黴素化合物、微管溶素化合物或ARRY-520。
在另一實施態樣中,在本發明中使用之藥物為二或更多種藥物之組合,諸如PI3激酶與MEK抑制劑、廣效性細胞毒性化合物與鉑化合物、PARP抑制劑與鉑化合物、廣效性細胞毒性化合物與PARP抑制劑。
活性劑可為癌治療劑。癌治療劑可包括死亡受體促效劑,諸如TNF相關之細胞凋亡誘發配體(TRAIL)、或Fas配體、或結合或活化死亡受體或以其他方式誘發細胞凋亡的任何配體或抗體。適合的死亡受體包括但不限於TNFR1、Fas、DR3、DR4、DR5、DR6、LTβR及彼之組合。
活性劑可為DNA小溝結合劑,諸如盧貝替丁(lurbectidin)和推貝替丁(trabectidin)。
活性劑可為E3泛素接合酶抑制劑、去泛素化酶(adeubiquitinase)抑制劑或NFkB路徑抑制劑。
活性劑可為可為磷酸酶抑制劑,包括PTP1B、SHP2、LYP、FAP-1、CD45、STEP、MKP-1、PRL、LMWPTP或CDC25之抑制劑。
活性劑可為腫瘤代謝抑制劑,諸如GAPDH、GLUT1、HK II、PFK、GAPDH、PK、LDH或MCT之抑制劑。
活性劑可靶定表觀遺傳標靶,包括EZH2、MLL、DOT1樣蛋白(DOT1L)、含溴結構域蛋白4(BRD4)、BRD2、BRD3、NUT、ATAD2或SMYD2。
活性劑可靶定身體的免疫系統以助於抗癌,包括靶定IDO1、IDO2、TDO、CD39、CD73、A2A拮抗劑、STING活化劑、TLR 促效劑(TLR 1-13)、ALK5、CBP/EP300溴結構域、ARG1、ARG2、iNOS、PDE5、P2X7、P2Y11、COX2、EP2受體或EP4受體之分子。
活性劑可靶定Bcl-2、IAP或脂肪酸合成酶。
在一些實施態樣中,活性劑可為20-epi-l,25二羥基維生素D3、4-番薯酮醇(ipomeanol)、5-乙炔基尿嘧啶、9-二氫紫杉醇(9-dihydrotaxol)、阿比特龍(abiraterone)、阿西維星(acivicin)、阿柔比星(aclarubicin)、阿考達唑(acodazole)鹽酸鹽、阿克羅寧(acronine)、醯基富烯(acylfulvene)、阿地培諾(adecypenol)、阿朵來新、阿地白血球殺菌素(aldesleukin)、all-tk拮抗劑、六甲蜜胺(altretamine)、安莫司汀(ambamustine)、安波黴素(ambomycin)、阿美坦宗(ametantrone)乙酸鹽、阿米達(amidox)、阿米弗司汀(amifostine)、胺基格魯米特(aminoglutethimide)、胺基戊酮酸、安如比星(amrubicin)、安沙吖啶、阿那格雷(anagrelide)、阿那曲唑(anastrozole)、穿心蓮內酯(andrographolide)、血管生成抑制劑、拮抗劑D、拮抗劑G、安雷利斯(antarelix)、安曲黴素(anthramycin)、抗背側化形態生成蛋白質-1(anti-dorsalizing morphogenetic protein-1)、抗雌激素(antiestrogen)、抗瘤酮(antineoplaston)、反義寡核苷酸、甘胺酸阿非科林(aphidicolin glycinate)、細胞凋亡基因調節物、細胞凋亡調節劑、無嘌呤核酸、ARA-CDP-DL-PTBA、精胺酸脫胺基酶、天冬醯胺酸酶、曲林菌素(asperlin)、阿蘇拉林(asulacrine)、阿他美坦(atamestane)、阿莫司汀(atrimustine)、阿西那司坦汀1(axinastatin 1)、阿西那司坦汀2、阿西那司坦汀3、阿扎胞苷(azacitidine)、阿扎司壯(azasetron)、阿扎毒素(azatoxin)、氮雜酪胺酸、阿扎替派(azetepa)、阿佐托黴素(azotomycin)、漿果赤黴素III(baccatin III)衍生物、巴拉諾(balanol)、巴馬司他(batimastat)、苯佐克洛林(benzochlorin)、苯佐地帕(benzodepa)、苯甲醯基星形孢菌素(benzoylstaurosporine)、β內醯胺衍生物、β-阿立辛(beta-alethine)、β克林黴素B(betaclamycin B)、樺木酸、BFGF抑制劑、比卡魯胺(bicalutamide)、比生群(bisantrene)、比生群鹽酸鹽、雙氮雜環丙烷基鯨胺(bisaziridinylspermine)、雙奈法德(bisnafide)、雙奈法德二甲磺酸鹽、比挫停A(bistratene A)、比哲來新、博來黴素(bleomycin)、博來黴素硫酸鹽、BRC/ABL拮抗劑、貝伏勒(breflate)、布喹那鈉(brequinar sodium)、溴匹立明(bropirimine)、布度鈦(budotitane)、補舒方(busulfan)、丁硫胺酸磺醯亞胺(buthionine sulfoximine)、卡巴他賽、放線菌素(cactinomycin)、卡泊三醇(calcipotriol)、卡弗汀C(calphostin C)、卡魯固酮(calusterone)、喜樹鹼、喜樹鹼衍生物、金絲雀痘IL-2、卡培他濱(capecitabine)、卡乙醯脲(caracemide)、卡貝替姆(carbetimer)、卡鉑、羧醯胺-胺基-三唑、羥基醯胺基三唑、卡瑞M3(carest M3)、卡莫司汀(carmustine)、earn 700、軟骨衍生之抑制劑、卡柔比星(carubicin)鹽酸鹽、卡哲折來新(carzelesin)、酪蛋白激酶抑制劑、卡斯塔紐鯨胺(castano spermine)、色羅平B(cecropin B)、西地芬哥(cedefingol)、西曲瑞克(cetrorelix)、氯芥苯丁酸、克洛林(chlorin)、氯喹㗁啉磺醯胺(chloroquinoxaline sulfonamide)、西卡前列素(cicaprost)、西羅里黴素(cirolemycin)、順鉑、順紫質、克拉屈濱(cladribine)、可洛米芬(clomifene)類似物、克氯黴唑(clotrimazole)、科里黴素A(collismycin A)、科里黴素B、康瑞特司達汀A4(combretastatin A4)、康瑞特司達汀類似物、科納吉尼(conagenin)、克蘭比西汀816 (crambescidin 816)、克里納托(crisnatol)、克里納托甲磺酸鹽、念珠藻素8、念珠藻素A衍生物、居拉辛A(curacin A)、環戊蒽醌(cyclopentanthraquinone)、環磷醯胺、環普拉壇(cycloplatam)、賽普黴素(cypemycin)、阿糖胞苷(cytarabine)、阿糖胞苷十八烷基磷酸鈉(cytarabine ocfosfate)、細胞溶解因子、喜多司他汀(cytostatin)、達卡巴仁(dacarbazine)、達昔單抗(dacliximab)、更生黴素、道諾黴素(daunorubicin)鹽酸鹽、德西他濱(decitabine)、脫氫戴得寧B(dehydrodidemnin B)、德舍瑞林(deslorelin)、右旋異弗醯胺(dexifosfamide)、右旋奧馬鉑(dexormaplatin)、右旋雷佐生(dexrazoxane)、右旋維拉帕米(dexverapamil)、地扎胍寧(dezaguanine)、地扎胍寧甲磺酸鹽、地吖醌(diaziquone)、代得寧B(didemnin B)、迪朵克斯(didox)、二乙基去甲鯨胺(diethylnorspermine)、二氫-5-阿扎胞苷(dihydro-5-azacytidine)、二㗁黴素(dioxamycin)、二苯基螺莫司汀(diphenyl spiromustine)、歐洲紫杉醇、二十二烷醇、多拉司瓊(dolasetron)、5’-去氧-5-氟尿苷(doxifluridine)、多柔比星、多柔比星鹽酸鹽、屈羅西芬(droloxifene)、屈羅西芬檸檬酸鹽、屈莫斯坦龍(dromostanolone)丙酸鹽、屈大麻酚(dronabinol)、達佐黴素(duazomycin)、杜卡黴素SA、依布硒(ebselen)、依考莫司汀(ecomustine)、依達曲沙(edatrexate)、依地福新(edelfosine)、依決洛單抗(edrecolomab)、依氟鳥胺酸(eflornithine)、依氟鳥胺酸鹽酸鹽、欖烯(elemene)、依沙蘆星(elsamitrucin)、乙嘧替氟(emitefur)、恩洛鉑(enloplatin)、恩普氨酯(enpromate)、依匹哌啶(epipropidine)、泛艾黴素(epirubicin)、泛艾黴素鹽酸鹽、愛普列特(epristeride)、厄布洛唑(erbulozole)、紅血球基因療法向量系統、依索比星(esorubicin)鹽酸鹽、雌莫司汀(estramustine)、雌莫司汀類似物、雌莫司汀磷酸鈉、雌激素促效劑、雌激素拮抗劑、依他硝唑(etanidazole)、依托泊苷、依托泊苷磷酸鹽、艾托卜寧(etoprine)、依西美坦(exemestane)、法屈唑(fadrozole)、法屈唑鹽酸鹽、法扎拉濱(fazarabine)、芬瑞替尼(fenretinide)、非格司亭(filgrastim)、非那斯特萊(finasteride)、夫拉平度(flavopiridol)、弗卓斯汀(flezelastine)、氟尿苷(floxuridine)、弗拉固酮(fluasterone)、福達拉濱(fludarabine)、福達拉濱鹽、氟道諾黴素(fluorodaunorunicin)鹽酸鹽、氟尿嘧啶(fluorouracil)、氟西他濱(flurocitabine)、福酚美克(forfenimex)、福美司坦(formestane)、磷喹酮(fosquidone)、福司曲星(fostriecin)、福司曲星鈉、福莫司汀(fotemustine)、莫特沙芬釓(gadolinium texaphyrin)、硝酸鎵、加洛他濱(galocitabine)、加尼瑞克(ganirelix)、明膠酶抑制劑、吉西他濱(gemcitabine)、吉西他濱鹽酸鹽、麩胱甘肽抑制劑、亥舒凡(hepsulfam)、神經調節素(heregulin)、六亞甲基雙乙醯胺、羥基脲、金絲桃素、伊班膦酸(ibandronic acid)、艾達黴素、艾達黴素鹽酸鹽、艾多昔芬(idoxifene)、伊決孟酮(idramantone)、異弗醯胺(ifosfamide)、伊莫福新(ilmofosine)、伊洛馬司他(ilomastat)、咪唑并吖啶酮(imidazoacridone)、咪喹莫特(imiquimod)、免疫刺激物肽、第1型類胰島素生長因子受體抑制劑、干擾素促效劑、干擾素α-2A、干擾素α-2B、干擾素α-N1、干擾素α-N3、干擾素β-IA、干擾素γ-IB、干擾素、介白素、碘苄胍(iobenguane)、碘多柔比星(iododoxorubicin)、異丙鉑、艾來諾康、艾來諾康鹽酸鹽、伊羅普拉(iroplact)、伊索拉定(irsogladine)、異本加定(isobengazole)、異哈立康定B(isohomohalicondrin B)、伊他司瓊(itasetron)、傑普拉基諾立得(jasplakinolide)、卡哈拉立得F(kahalalide F)、拉梅拉素N(lamellarin-N)三乙酸鹽、蘭瑞肽(lanreotide)、拉洛他西(larotaxel)、蘭瑞肽乙酸鹽、雷拉黴素(leinamycin)、來格司亭(lenograstim)、香菇多醣(lentinan)硫酸鹽、立托斯他汀(leptolstatin)、來曲唑(letrozole)、白血病抑制因子、白血球α干擾素、柳菩林(leuprolide)乙酸鹽、柳菩林/雌激素/助孕酮、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、利阿唑(liarozole)、利阿唑鹽酸鹽、線型多胺類似物、親脂性雙醣肽、親脂性鉑化合物、立索林醯胺7(lissoclinamide 7)、洛鉑(lobaplatin)、龍布利新(lombricine)、洛美曲索(lometrexol)、洛美曲索鈉、洛莫司汀(lomustine)、氯尼達明(lonidamine)、洛索恩沖(losoxantrone)、洛索恩沖鹽酸鹽、洛伐他汀(lovastatin)、洛索立濱(loxoribine)、勒托替康(lurtotecan)、鎦特沙卟啉(lutetium texaphyrin)、萊索飛靈(lysofylline)、細胞溶解肽、美坦新(maitansine)、門諾他汀A(mannostatin A)、馬立馬司他(marimastat)、馬索羅酚(masoprocol)、馬司平(maspin)、馬曲來新(matrilysin)抑制劑、基質金屬蛋白酶抑制劑、美登新、類美登新、莫坦辛(mertansine)(DM1)、甲基二(氯乙基)胺鹽酸鹽、美雌酚(megestrol)乙酸鹽、美侖雌酚(melengestrol)乙酸鹽、黴法蘭(melphalan)、美諾加立(menogaril)、美布龍(merbarone)、巰基嘌呤、美特萊林(meterelin)、甲硫胺酸酶(methioninase)、胺甲喋呤、胺甲喋呤鈉、美托拉麥(metoclopramide)、美托普林(metoprine)、美妥替哌(meturedepa)、微藻蛋白激酶C抑制劑、MIF抑制劑、美服培酮(mifepristone)、米替福新(miltefosine)、米立司亭(mirimostim)、錯配雙股RNA、米丁度胺(mitindomide)、米托卡星(mitocarcin)、米托洛明(mitocromin)、米托潔林(mitogillin)、米托胍腙(mitoguazone)、米托雷托(mitolactol)、米托馬星(mitomalcin)、絲裂黴素、絲裂黴素類似物、米托萘胺(mitonafide)、米托司培(mitosper)、米托坦(mitotane)、米托毒素(mitotoxin)纖維母細胞生長因子-皂草素(saporin)、米托恩沖(mitoxantrone)、米托恩沖鹽酸鹽、莫法羅汀(mofarotene)、莫拉司亭(molgramostim)、單株抗體、人類絨膜促性腺素、單磷醯脂質a(monophosphoryl lipid a)/分枝桿菌細胞壁SK (myobacterium cell wall SK)、莫哌達醇(mopidamol)、多重抗藥性基因抑制劑、基於第1型多重腫瘤抑制劑之療法、芥子抗癌劑、美卡過氧化物B(mycaperoxide B)、分枝桿菌細胞壁萃取物、黴酚酸、米瑞普龍(myriaporone)、正乙醯基地那林(n-acetyldinaline)、那法瑞林(nafarelin)、納瑞斯提(nagrestip)、納洛酮(naloxone)/噴他佐辛(pentazocine)、納帕文(napavin)、納帖平(naphterpin)、那托司亭(nartograstim)、奈達鉑(nedaplatin)、紐莫柔比星、紐立膦酸(neridronic acid)、中性內肽酶、尼魯米特(nilutamide)、尼沙黴素(nisamycin)、一氧化氮調節物、氮氧化物抗氧化劑、奈曲林(nitrullyn)、諾考達唑(nocodazole)、諾加黴素(nogalamycin)、n-取代之苯甲醯胺、06-苯甲基鳥嘌呤、體抑素胜肽(octreotide)、歐基西農(okicenone)、寡核苷酸、奧那司酮(onapristone)、歐丹西挫(ondansetron)、歐拉星(oracin)、口服細胞介素誘導物、奧馬鉑、奧沙特隆(osaterone)、奧沙利鉑、奧沙諾黴素(oxaunomycin)、奧昔舒侖(oxisuran)、紫杉醇、紫杉醇類似物、紫杉醇衍生物、帕勞胺(palauamine)、棕櫚醯基利索新(palmitoylrhizoxin)、帕米膦酸(pamidronic acid)、人參炔三醇(panaxytriol)、帕諾米芬(panomifene)、帕拉巴汀(parabactin)、帕折普汀(pazelliptine)、培加帕酶(pegaspargase)、皮地新(peldesine)、培利黴素(peliomycin)、戊莫司汀(pentamustine)、多戊糖多硫酸鈉(pentosan polysulfate sodium)、噴托他汀(pentostatin)、噴曲唑(pentrozole)、培洛黴素(peplomycin)硫酸鹽、全氟溴烷(perflubron)、培弗醯胺(perfosfamide)、紫蘇醇(perillyl alcohol)、芬納齊諾黴素(phenazinomycin)、苯乙酸酯(phenylacetate)、磷酸酶抑制劑、必醫你舒(picibanil)、毛果芸香鹼鹽酸鹽、哌泊溴烷(pipobroman)、哌泊舒凡(piposulfan)、吡柔比星(pirarubicin)、比曲克辛(piritrexim)、比羅恩沖(piroxantrone)鹽酸鹽、帕斯婷A(placetin A)、帕斯婷B、血漿蛋白原活化因子抑制劑、鉑(IV)錯合物、鉑化合物、鉑-三胺錯合物、普卡黴素(plicamycin)、普洛美坦(plomestane)、泡非美鈉(porfimer sodium)、波弗黴素(porfiromycin)、潑尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)鹽酸鹽、丙基雙吖啶酮、前列腺素J2、前列腺癌抗雄激素、蛋白酶體抑制劑、基於蛋白質A之免疫調節物、蛋白激酶C抑制劑、蛋白酪胺酸磷酸酶抑制劑、嘌呤核苷磷酸化酶抑制劑、嘌黴素、嘌黴素鹽酸鹽、紫色寧、吡唑呋喃菌素(pyrazofurin)、吡唑并吖啶(pyrazoloacridine)、吡哆醛化血紅素聚氧乙烯共軛物(pyridoxylated hemoglobin polyoxy ehylene conjugate)、RAF拮抗劑、雷替曲塞(raltitrexed)、雷莫司瓊(ramosetron)、RAS法尼基(farnesyl)蛋白轉移酶抑制劑、RAS抑制劑、RAS-GAP抑制劑、去甲基瑞替立汀(retelliptine demethylated)、依替膦酸錸RE 186(rhenium RE 186 etidronate)、利索新(rhizoxin)、利波腺苷(riboprine)、核糖酵素、RII視黃醯胺(RII retinamide)、RNAi、羅谷亞胺(rogletimide)、羅希土鹼(rohitukine)、羅莫肽(romurtide)、羅喹美克(roquinimex)、羅比吉農BI(rubiginone BI)、如伯西(ruboxyl)、沙芬戈(safingol)、沙芬戈鹽酸鹽、山托平(saintopin)、沙克努(sarcnu)、肌植醇A(sarcophytol A)、沙格司亭(sargramostim)、SDI 1模擬物、司莫司汀(semustine)、老化衍生之抑制劑第1型、正義股寡核苷酸、siRNA、信號傳導抑制劑、信號傳導調節物、辛曲秦(simtrazene)、單鏈抗原結合蛋白、西佐非蘭(sizofiran)、索布佐生(sobuzoxane)、硼卡鈉(sodium borocaptate)、苯乙酸鈉、索弗羅(solverol)、體介素結合蛋白、索納明(sonermin)、司帕弗酸鈉(sparfosate sodium)、司帕弗酸(sparfosic acid)、司帕黴素(sparsomycin)、史匹卡黴素D(spicamycin D)、螺鍺(spirogermanium)鹽酸鹽、螺莫司汀(spiromustine)、螺鉑(spiroplatin)、脾五肽(splenopentin)、海綿他汀第1型(spongistatin 1)、角鯊胺(squalamine)、幹細胞抑制劑、幹細胞分裂抑制劑、史提皮醯胺(stipiamide)、鏈黴黑素(streptonigrin)、鏈佐黴素(streptozocin)、溶基質素(stromelysin)抑制劑、斯非諾新(sulfinosine)、斯洛非納(sulofenur)、超活性激脈腸肽拮抗劑、蘇拉第達(suradista)、蘇拉明(suramin)、苦馬豆素(swainsonine)、合成醣胺聚醣、他利黴素(talisomycin)、他莫司汀(tallimustine)、泰莫西芬甲基碘化物(tamoxifen methiodide)、牛磺莫司汀(tauromustine)、他扎羅汀(tazarotene)、特寇加藍鈉(tecogalan sodium)、替加弗(tegafur)、碲吡鹽(tellurapyrylium)、端粒酶(telomerase)抑制劑、替洛恩沖(teloxantrone)鹽酸鹽、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替尼泊苷、特拉昔龍(teroxirone)、睪內酯(testolactone)、四氯十氧化物(tetrachlorodecaoxide)、替唑明(tetrazomine)、噻立拉斯汀(thaliblastine)、沙力度胺(thalidomide)、硫咪嘌呤(thiamiprine)、噻考瑞林(thiocoraline)、硫鳥嘌呤(thioguanine)、噻替哌(thiotepa)、促血小板生成素(thrombopoietin)、促血小板生成素模擬物、胸腺法新(thymalfasin)、胸腺生成素(thymopoietin)受體促效劑、胸腺曲南(thymotrinan)、促甲狀腺素、噻唑呋林(tiazofurin)、錫乙基初卟啉(tin ethyl etiopurpurin)、替拉札明(tirapazamine)、二氯環戊二烯鈦(titanocene dichloride)、拓普康鹽酸鹽、托升汀(topsentin)、托瑞米芬(toremifene)、托瑞米芬檸檬酸鹽、全能幹細胞因子、轉譯抑制劑、曲托龍(trestolone)乙酸鹽、視網酸、三乙醯基尿苷(triacetyluridine)、曲西立濱(triciribine)、曲西立濱磷酸鹽、三甲曲沙(trimetrexate)、三甲曲沙葡萄糖醛酸鹽、曲托瑞林(triptorelin)、托匹司瓊(tropisetron)、妥布氯唑(tubulozole)鹽酸鹽、妥羅雄脲(turosteride)、酪胺酸激酶抑制劑、酪胺酸磷酸化抑制劑(tyrphostin)、UBC抑制劑、烏苯美司(ubenimex)、尿嘧啶氮芥(uracil mustard)、烏瑞替派(uredepa)、泌尿生殖竇(urogenital sinus)衍生之生長抑制因子、尿激酶受體拮抗劑、伐普肽(vapreotide)、法端歐林B(variolin B)、法雷鎖(velaresol)、凡拉明(veramine)、凡啶(verdins)、維替泊芬(verteporfin)、長春鹼硫酸鹽、長春新鹼硫酸鹽、長春地辛、長春地辛硫酸鹽、長春匹定(vinepidine)硫酸鹽、長春甘酯(vinglycinate)硫酸鹽、長春羅辛(vinleurosine)硫酸鹽、溫諾平、溫諾平酒石酸鹽、長春羅定(vinrosidine)硫酸鹽、文沙汀(vinxaltine)、硫酸長春利定(vinzolidine)硫酸鹽、文塔新(vitaxin)、伏羅唑(vorozole)、扎諾特隆(zanoterone)、增尼鉑(zeniplatin)、鎖拉寇(zilascorb)、淨諾他汀(zinostatin)、淨諾他汀司替馬拉莫(zinostatin stimalamer)或佐柔比星(zorubicin)鹽酸鹽。
活性劑可為含有一或多個金屬中心之無機或有機金屬化合物。在一些實例中,化合物含有一個金屬中心。活性劑可為例如鉑化合物、釕化合物(例如反式-[RuCl2
(DMSO)4
]或反式-[RuCl4
(咪唑)2
等)、鈷化合物、銅化合物或鐵化合物。
在一些實施態樣中,活性劑為小分子。在一些實施態樣中,活性劑為小分子細胞毒素。在一個實施態樣中,活性劑為卡巴他賽或其類似物、衍生物、前藥或醫藥上可接受之鹽。在另一實施態樣中,活性劑為莫坦辛(DM1)或DM4或其類似物、衍生物、前藥或醫藥上可接受之鹽。DM1或DM4係藉由結合至微管蛋白而抑制微管之組合。DM1之結構顯示如下:
在一些實施態樣中,活性劑Z為單甲基奧瑞他汀E(MMAE)或其類似物、衍生物、前藥或醫藥上可接受之鹽。MMAE之結構顯示如下:
在一些實施態樣中,活性劑Z為序列選擇性DNA小溝結合交聯劑。例如,Z可為吡咯并苯并二氮呯(PBD)、PBD二聚物或其類似物、衍生物、前藥或醫藥上可接受之鹽。PBD及PBD二聚物之結構顯示如下:
在一些實施態樣中,活性劑Z為拓樸異構酶I抑制劑,諸如喜樹鹼、艾來諾康、SN-38或其類似物、衍生物、前藥或醫藥上可接受之鹽。
在WO2013158644、WO2015038649、WO2015066053、WO2015116774、WO2015134464、WO2015143004、WO2015184246(將每一該等揭示內容以彼之全文併入本文以供參考)中所揭示之任何細胞毒性毒性部分可用作為本發明之共軛物中的活性劑,諸如苯達莫斯汀(bendamustine)、VDA、多柔比星、培美曲塞(pemetrexed)、佛瑞諾泰、來那度麥德(lenalidomide)、歐洲紫杉醇、17-AAG、5-FU、阿比特龍、克唑替尼(crizotinib)、KW-2189、BUMB2、DC1、CC-1065、阿朵來新或其衍生物/類似物。
PI3K抑制劑
PI3K抑制劑
PI3K/AKT/mTOR傳訊網絡(PI3K路徑)控制癌的大部分標誌:細胞週期、存活、代謝、移動及基因組穩定性。PI3K路徑為人類癌中最常改變的路徑。PI3K活化係通過PIK3CA突變或擴增及功能性腫瘤抑制因子PTEN的喪失而與癌症直接連結。PIK3CA基因為第二最常突變的致癌基因。PTEN為最常突變的腫瘤抑制基因之一。路徑抑制劑在異種移植模型中展示出抗腫瘤功效,但毒性限制患者的臨床利益。PI3K抑制劑與HSP90靶定之部分共軛提供以降低的毒性於腫瘤中遞送具有充分的PI3K抑制之PI3K抑制劑的方法。
包含PI3K抑制劑之共軛物可用於治療血液系統惡性腫瘤及實體腫瘤。在一些實施態樣中,包含PI3K抑制劑之共軛物係用於治療結腸直腸癌、多發性骨髓瘤、白血病、淋巴瘤、結腸癌、胃癌、腎癌、肺癌或乳癌,包括轉移性乳癌。在一些實施態樣中,包含PI3K抑制劑之共軛物係用於治療經PIK3CA改變之癌或HER2陽性癌。
任何PI3K抑制劑可用作為活性劑。在一些實施態樣中,PI3K抑制劑可為小分子。非限制性實例包括歐米帕利希布(GSK2126458、GSK458)、BAY 80-6946(柯潘利希布)、PF-04691502、PI-103、BGT226(NVP-BGT226)、阿匹托利希布(GDC-0980、RG7422)、杜維利希布(IPI-145、INK1197)、AZD8186、皮拉利希布(XL147)、PIK-93、艾德拉利希布(GS-1101)、MLN1117、VS-5584、SB2343、GDC-0941、BM120、NVP-BKM120、布帕利希布、AZD8835、XL765(SAR245409)、GS-9820阿卡利希布、GSK2636771、AMG-319、IPI-549、哌立福新、阿哌利希布、TGR 1202(RP5264)、PX-866、AMG-319、GDC-0980、GDC-0941、Sanofi XL147、XL499、XL756、XL147、PF-46915032、BKM 120、CAL 263、SF1126、PX-886、KA2237、雙重PI3K抑制劑(例如Novartis BEZ235)、異喹啉酮或其衍生物/類似物。
在一些實施態樣中,PI3K抑制劑可為PI3K的δ及γ同型異構體之抑制劑。在一些實施態樣中,PI3K抑制劑為PI3K的α同型異構體之抑制劑。在其他的實施態樣中,PI3K抑制劑為PI3K的一或多種α、β、δ及γ同型異構體之抑制劑。PI3K抑制劑的非限制性實例包括在US 9,546,180(Infinity Pharmaceuticals)、WO 2009088990 (Intellikine Inc.)、WO 2011008302(Intellikine Inc.)、WO 2010036380(Intellikine Inc.)、WO 2010/006086(Intellikine Inc.)、WO 2005113556(Icos Corp.)、US 2011/0046165 (Intellikine Inc.)或US 20130315865(Pfizer)中所揭示之化合物,將每一該等揭示內容以彼之全文併入本文以供參考。
在一些實施態樣中,PI3K抑制劑係選自下列群組:歐米帕利希布(GSK458)或其衍生物/類似物、BAY 80-6946(柯潘利希布)或其衍生物/類似物、PF-04691502或其衍生物/類似物、PI-103或其衍生物/類似物、BGT226(NVP-BGT226)或其衍生物/類似物、阿匹托利希布(GDC-0980、RG7422)或其衍生物/類似物、杜維利希布(IPI-145、INK1197)或其衍生物/類似物、AZD8186或其衍生物/類似物、皮拉利希布(XL147)或其衍生物/類似物和PIK-93或其衍生物/類似物。
本發明之共軛物特別地可包含連接至歐米帕利希布(GSK458)或其衍生物/類似物、BAY 80-6946(柯潘利希布)或其衍生物/類似物、PF-04691502或其衍生物/類似物或PI-103或其衍生物/類似物的HSP90靶定之部分。
PARP抑制劑
PARP抑制劑
聚(ADP核糖)聚合酶(PARP)為涉及許多細胞過程的酶家族,包括修復單股DNA斷裂及程序性細胞死亡。一些癌細胞(諸如小細胞肺癌(SCLC)細胞或BRCA突變癌細胞)比常規細胞更依賴於PARP,使得彼等對PARP抑制具有獨特的敏感性。大部分的PARP抑制劑具有兩種可能的作用:抑制PARP功能或在單股DNA斷裂上捕獲RAPP。
PARP抑制劑的主要毒性為血液學(血小板減少症),有時觀察到骨髓抑制。經HSP90調介之PARP抑制劑遞送增加的腫瘤內PARP抑制劑濃度且藉由改進腫瘤:血漿比來降低血液學毒性。自共軛物持續釋放PARP抑制劑可提供連續的抑制作用且得到比單獨的PARP抑制劑更大的功效。
包含PARP抑制劑之共軛物可用於治療血液系統惡性腫瘤及實體腫瘤。當雙股斷裂修復機制損傷時,BRCA突變型癌係依賴作為DNA修復的唯一機制之PARP。抑制PARP導致BRCA突變型癌中的雙股DNA斷裂及細胞死亡。具有低的BRCA1/2蛋白質之任何癌細胞可能對PARP抑制具有敏感性。PARP過度表現在SCLC細胞中,使得SCLC細胞對PARP抑制更敏感。在一些實施態樣中,包含PARP抑制劑之共軛物係用於治療SCLC、非小細胞肺癌(NSCLC)、乳癌(包括三陰性乳癌和BRCA突變型乳癌)、卵巢癌、結腸直腸癌、前列腺癌、黑色素瘤或轉移性癌,包括轉移性乳癌、轉移性卵巢癌和轉移性黑色素瘤。
任何PARP抑制劑可用作為活性劑。在一些實施態樣中,PARP抑制劑可為小分子。非限制性實例包括奧拉帕瑞、凡尼帕瑞(ABT-888)、茹卡帕瑞(rucaparib)(AG014699或PF-01367338)、加尼特斯皮、塔拉唑帕布(BMN673)、尼拉帕瑞(niraparib)、依尼帕瑞(BSI 201)、CEP 9722、E7016、BGB-290或其衍生物/類似物。
在一些實施態樣中,PARP抑制劑係選自下列群組:奧拉帕瑞或其衍生物/類似物和塔拉唑帕布或其衍生物/類似物。本發明之共軛物可包含連接至奧拉帕瑞或其衍生物/類似物或塔拉唑帕布或其衍生物/類似物的HSP90靶定之部分。
在一些實施態樣中,包含PARP抑制劑或其衍生物之共軛物不具有作為PARP抑制劑的活性且為了PARP抑制活性而需要鍵聯子釋放。此等共軛物可具有比單獨的PARP抑制劑更大的最大耐受劑量(MTD)。鍵聯子可包含二硫化物鍵,其在呈還原環境的細胞溶質中斷裂以釋放共軛物中的PARP抑制劑。例如,奧拉帕瑞或其衍生物或塔拉唑帕布或其衍生物可連接在雜環上的鍵聯子,使PARP抑制功能失活。包含作為PARP抑制劑的失活之奧拉帕瑞的共軛物及包含作為PARP抑制劑的失活之塔拉唑帕布的共軛物顯示如下。
奧拉帕瑞共軛物:
塔拉唑帕布共軛物:
在PI3K路徑中的一些蛋白質在以PARP抑制劑處理後調升。PI3K抑制劑可增加DNA損傷且使細胞(例如三陰性乳癌細胞和SCLC細胞)對PARP抑制具有敏感性。因此,PI3K抑制劑與PARP抑制劑的組合具有協同效應且提高任一單獨藥劑之效應。在一些實施態樣中,投予包含PI3K抑制劑之共軛物與包含PARP抑制劑之共軛物的組合。在一些實施態樣中,共軛物包含超過一個活性劑,其中共軛物包含至少一種PARP抑制劑及至少一種PI3K抑制劑。
B. HSP90 靶定之部分
B. HSP90 靶定之部分
如本文所述的靶定之配體(亦稱為靶定之部分)包括可結合一或多種HSP90蛋白質的任何分子。此等靶定之配體可為肽、抗體模擬物、核酸(例如適配體)、多肽(例如抗體)、醣蛋白、小分子、碳水化合物或脂質。
靶定之部分X可為任何HSP90結合之部分,諸如但不限於天然化合物(例如格爾德黴素和根赤殼菌素(radicicol))及合成化合物,諸如格爾德黴素類似物17-AAG(亦即17-烯丙基胺基格爾德黴素)、嘌呤支架HSP90抑制劑系列,包括PU24FC1(He H.等人之J. Med. Chem.
, vol.49:381(2006),將其揭示內容以彼之全文併入本文以供參考)、BIIB021(Lundgren K.等人之Mol. Cancer Ther.
, vol.8(4):921(2009),將其揭示內容以彼之全文併入本文以供參考)、4,5-二芳基吡唑(Cheung K.M.等人之Bioorg. Med. Chem. Lett
., vol.15:3338(2005),將其揭示內容以彼之全文併入本文以供參考)、3-芳基,4-甲醯胺吡唑(Brough P.A.等人之Bioorg. Med. Chem. Lett.
, vol.15:5197(2005),將其揭示內容以彼之全文併入本文以供參考)、4,5-二芳基異㗁唑(Brough P.A.等人之J. Med. Chem.
, vol.51:196(2008),將其揭示內容以彼之全文併入本文以供參考)、3,4-二芳基吡唑間苯二酚衍生物(Dymock B.W.等人之J. Med. Chem.
, vol.48:4212(2005),將其揭示內容以彼之全文併入本文以供參考)、噻吩并[2,3-d]嘧啶(VERNALIS等人之WO2005034950,將其揭示內容以彼之全文併入本文以供參考)、Giannini等人之EP2655345中的式I之芳基三唑衍生物(將其揭示內容以彼之全文併入本文以供參考)或HSP90結合之配體或彼之衍生物/類似物的任何其他實例。
在一些實施態樣中,HSP90結合之部分可為含有三個雜原子的雜環衍生物。MATULIS等人之WO2009134110(將其揭示內容以彼之全文併入本文以供參考)揭示4,5-二芳基噻二唑,其展示良好的HSP90結合親和性。儘管彼等具有相當適度的細胞生長抑制作用,但是彼等可用作為本發明之共軛物中的HSP90結合之部分。另一類別的氮雜-雜環加成物(亦即三唑衍生物或彼之類似物)可用作為本發明之共軛物中的HSP90結合之部分。例如,1,2,4-三唑支架經大量地記載為具有HSP90抑制特性。BURLISON等人之WO2009139916(Synta Pharmaceuticals Corp.)(將其揭示內容以彼之全文併入本文以供參考)揭示以高的微莫耳濃度抑制HSP90之三環1,2,4-三唑衍生物。在WO2009139916中揭示之任何三環1,2,4-三唑衍生物或彼之衍生物/類似物可用作為本發明之共軛物中的HSP90結合之部分。在WO 2010017479和WO 2010017545(Synta Pharmaceuticals Corp.)(將該等揭示內容以彼之全文併入本文以供參考)中揭示的任何經三取代之1,2,4-三唑衍生物或彼之衍生物/類似物可用作為本發明之共軛物中的HSP90結合之部分。在另一實例中,在WO2006055760(Synta Pharmaceuticals Corp.)(將其揭示內容以彼之全文併入本文以供參考)中揭示之稱為加尼特斯皮的含三唑酮(triazolone)之HSP90抑制劑(先前被稱為STA-9090或其高可溶性磷酸鹽前藥STA-1474)或其衍生物/類似物可用作為本發明之共軛物中的HSP90結合之部分。
在一些實施態樣中,加尼特斯皮或其衍生物/類似物可用作為靶定之部分。加尼特斯皮衍生物/類似物的非限制性實例顯示如下。
在一些實施態樣中,歐那利斯皮(AT13387)或其衍生物/類似物可用作為本發明之共軛物中的靶定之部分。歐那利斯皮及歐那利斯皮衍生物/類似物的非限制性實例顯示如下。
在WO2013158644、WO2015038649、WO2015066053、WO2015116774、WO2015134464、WO2015143004、WO2015184246(將該等揭示內容以彼之全文併入本文以供參考)中所揭示之任何HSP90配體或HSP90抑制劑或彼之衍生物/類似物可用作為本發明之共軛物中的HSP90結合之部分,諸如:
式I,其中R1可為烷基、芳基、鹵化物、甲醯胺或磺醯胺;R2可為烷基、環烷基、芳基或雜芳基,其中當R2為6員芳基或雜芳基時,則R2係在相對於三唑環上的連接點之3-和4-位置上通過其附著之鍵聯子L取代;及R3可為SH、OH、-CONHR4、芳基或雜芳基,其中當R3為6員芳基或雜芳基時,則R3係在3或4位置上經取代;
式II,其中R1可為烷基、芳基、鹵基、甲醯胺基、磺醯胺基;及R2可為隨意地經取代之烷基、環烷基、芳基或雜芳基。此等化合物的實例包括5-(2,4-二羥基-5-異丙基苯基)-N-(2-嗎啉基乙基)-4-(4-(嗎啉基甲基)苯基)-4H-1,2,4-三唑-3-甲醯胺和5-(2,4-二羥基-5-異丙基苯基)-4-(4-(4-甲基哌𠯤-1-基)苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲醯胺;
式III,其中X、Y和Z可獨立為CH、N、O或S(具有適當的取代且滿足對應之原子的價位及環的芳族性);R1可為烷基、芳基、鹵化物、甲醯胺基或磺醯胺基;R2可為經取代之烷基、環烷基、芳基或雜芳基,其中鍵聯子L可直接連接或連接至該等環上的擴展延伸取代;R3可為可以效應子部分連接之SH、OH、NR4R5和-CONHR6;R4和R5可獨立為H、烷基、芳基或雜芳基;及R6可為具有最少一個可以效應子部分連接之官能基的烷基、芳基或雜芳基;或
式IV,其中R1可為烷基、芳基、鹵基、甲醯胺基或磺醯胺基;R2和R3獨立為隨意地經羥基、鹵素、C1-C2烷氧基、胺基、單-和二-C1-C2烷基胺基中之一或多者取代之C1-C5烴基;5-至12-員芳基或雜芳基;或取R2及R3與彼等附著之氮原子一起形成4-至8-員單環狀雜環基,其中最多5個環員係選自O、N和S。此等化合物的實例包括AT-13387。
HSP90靶定之部分可為加尼特斯皮、露米奈斯皮(AUY-922、NVP-AUY922)、Debio-0932、MPC-3100、歐那利斯皮(AT-13387)、SNX-2112、17-胺基-格爾德黴素氫醌、PU-H71、AT13387或其衍生物/類似物。
HSP90靶定之部分可為SNX5422(PF-04929113)或在US 8080556(Pfizer)、WO2008096218 (Pfizer)、WO2006117669(Pfizer)、WO2008059368 (Pfizer)、WO2008053319(Pfizer)、WO2006117669(Pfizer)、EP1885701 (Novartis)、EP1776110(Novartis)、EP2572709 (Novartis)、WO2012131413(Debiopharm)或WO2012131468(Debiopharm)中揭示之任何其他的HSP90抑制劑,將每一該等揭示內容以彼之全文併入本文以供參考。
HSP90靶定之部分亦可為PU-H71(經124
I放射標記而用於PET成像之HSP90抑制劑)或其衍生物/類似物。
包含SNX-2112、17-胺基-格爾德黴素氫醌、PU-H71或AT13387之共軛物可具有結構:
在一些實施態樣中,HSP90靶定之部分包含山沙維麥德(Sansalvamide)A 衍生物。山沙維麥德A(San A)為自海羊真菌單離且結合至HSP90之環五肽。在Alexander等人之J Med Chem.
, vol.52(24):7927(2009)(將其揭示內容以彼之全文併入本文以供參考)中揭示之任何二-山沙維麥德A衍生物(經二聚合之San A分子)(例如在Alexander之圖1中的二-San A分子)可用作為本發明之共軛物的靶定之部分。
在特定的實施態樣中,共軛物的靶定之部分或部分類係以約0.1%至約10%、或約1%至約10%、或約10%至約20%、或約20%至約30%、或約30%至約40%、或約40%至約50%、或約50%至約60%、或約60%至約70%、或約70%至約80%、或約80%至約90%、或約90%至約99%之預定的莫耳重量百分比存在,使得共軛物之組分的莫耳重量百分總和為100%。共軛物的靶定之部分的量亦可以相對於活性劑之比例方式表示,例如約10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4;1:5、1:6、1:7、1:8、1:9或1:10之配體對活性劑之比。
C. 鍵聯子
C. 鍵聯子
共軛物含有一或多個附著活性劑及靶定之部分的鍵聯子。鍵聯子Y結合至一或多個活性劑及一或多個靶定之配體以形成共軛物。鍵聯子Y係藉由獨立地選自下列的官能基附著至靶定之部分X及活性劑Z:酯鍵、二硫化物、醯胺、醯腙、醚、胺甲酸酯、碳酸酯和脲。另一選擇地,鍵聯子可藉由諸如以硫醇與順丁烯二醯亞胺、疊氮化物及炔之間的共軛物提供之不可切割的基團附著至靶定之配體或活性藥物。鍵聯子係獨立地選自由下列者所組成之群組:烷基、環烷基、雜環基、芳基和雜芳基,其中烷基、烯基、環烷基、雜環基、芳基和雜芳基中之各者隨意地經一或多個基團取代,各基團係獨立地選自鹵素、氰基、硝基、羥基、羧基、胺甲醯基、醚、烷氧基、芳氧基、胺基、醯胺、胺甲酸酯、烷基、烯基、炔基、芳基、芳基烷基、環烷基、雜芳基、雜環基,其中羧基、胺甲醯基、醚、烷氧基、芳氧基、胺基、醯胺、胺甲酸酯、烷基、烯基、炔基、芳基、芳基烷基、環烷基、雜芳基或雜環基中之各者隨意地經一或多個基團取代,各基團係獨立地選自鹵素、氰基、硝基、羥基、羧基、胺甲醯基、醚、烷氧基、芳氧基、胺基、醯胺、胺甲酸酯、烷基、烯基、炔基、芳基、芳基烷基、環烷基、雜芳基、雜環基。
在一些實施態樣中,鍵聯子包含可切割的官能基,其為可切割的。可切割的官能基可於活體內水解或可經設計以例如組織蛋白酶B經酶水解。如本文所使用之「可切割的」鍵聯子係指可經物理或化學切割的任何鍵聯子。物理切割的實例可為以光、放射活性物發射或熱切割,而化學切割的實例包括以還原-氧化反應、水解、pH依賴性切割或以酶切割。例如,可切割的官能基可為二硫化物鍵或胺甲酸酯鍵。
在一些實施態樣中,鍵聯子之烷基鏈可隨意地經一或多個原子或選自-O-, -C(=O)-, -NR, -O-C(=O)-NR-, -S-, -S-S-之基團中斷。鍵聯子可選自丁二酸、戊二酸或二乙醇酸之二羧酸酯衍生物。在一些實施態樣中,鍵聯子Y可為X’-R1
-Y’-R2
-Z’,及共軛物可為根據式Ia之化合物:
其中X為上文定義的靶定之部分;Z為活性劑;X’、R1 、Y’、R2 和Z’係如本文所定義。
其中X為上文定義的靶定之部分;Z為活性劑;X’、R1 、Y’、R2 和Z’係如本文所定義。
X’是不存的在或獨立地選自羰基、醯胺、脲、胺基、酯、芳基、芳基羰基、芳氧基、芳基胺基、一或多種天然或非天然胺基酸、硫基或丁二醯亞胺基;R1
和R2
是不存在的或由烷基、經取代之烷基、芳基、經取代之芳基、聚乙二醇(2個30個單元)所組成;Y’是不存在的、經取代或未經取代之1,2-二胺基乙烷、聚乙二醇(2至30個單元)或醯胺;Z’是不存在的在或獨立地選自羰基、醯胺、脲、胺基、酯、芳基、芳基羰基、芳氧基、芳基胺基、硫基或丁二醯亞胺基。在一些實施態樣中,鍵聯子可容許一個活性劑分子鍵聯至二或更多個配體或一個配體鍵聯至二或更多個活性劑分子。
在一些實施態樣中,鍵聯子Y可為Am
及共軛物可為根據式Ib之化合物:
其中A係如本文所定義,m=0至20。
其中A係如本文所定義,m=0至20。
在式Ia中的A為間隔單元、不存在的或獨立地選自下列的取代基。各取代基的虛線表示具有X、Z或另一獨立選擇的A單元之取代位點,其中X、Z或A可附著在取代基的任一側上:
,其中z=0至40,R為H或隨意地經取代之烷基,及R’為天然或非天然胺基酸中發現的任何側鏈。
,其中z=0至40,R為H或隨意地經取代之烷基,及R’為天然或非天然胺基酸中發現的任何側鏈。
在一些實施態樣中,共軛物可為根據式Ic之化合物:
其中A係如上文所定義,m=0至40,n=0至40,x=1至5,y=1至5,及C為本文定義之支鏈元素。
其中A係如上文所定義,m=0至40,n=0至40,x=1至5,y=1至5,及C為本文定義之支鏈元素。
在式Ic中的C為含有3至6個用於共價附著選自胺、羧酸、硫醇或丁二醯亞胺之間隔單元、配體或活性藥物的官能基之支鏈單元,包括胺基酸,諸如離胺酸、2,3-二胺基丙酸、2,4-二胺基丁酸、麩胺酸、天冬胺酸和半胱胺酸。
共軛物的非限制性實例
作為活性劑的DM1
共軛物的非限制性實例
作為活性劑的DM1
在一些實施態樣中,活性劑Z為DM1及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物,其中活性劑Z及靶定之部分X係以可切割的鍵聯子連接。可切割的鍵聯子可包含二硫化物鍵,其容許活性劑在呈還原環境的細胞溶質中釋放。共軛物的非限制性實例為化合物1、2、3和14。
作為活性劑的MMAE
作為活性劑的MMAE
在一些實施態樣中,活性劑Z為MMAE及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物,其中活性劑Z及靶定之部分X係以可切割的鍵聯子連接。可切割的鍵聯子可包含二硫化物鍵,其容許活性劑在呈還原環境的細胞溶質中釋放。共軛物的非限制性實例為化合物15和16。
作為活性劑的PARP抑制劑
作為活性劑的PARP抑制劑
在一些實施態樣中,活性劑Z為PARP抑制劑及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物,其中活性劑Z及靶定之部分X係以可切割的鍵聯子連接。PARP抑制劑可為奧拉帕瑞或塔拉唑帕布。可切割的鍵聯子可包含二硫化物鍵。
作為活性劑的奧拉帕瑞
作為活性劑的奧拉帕瑞
在一些實施態樣中,活性劑Z為奧拉帕瑞或其衍生物/類似物及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物。共軛物的一般結構顯示如下:
在一些實施態樣中,可切割的鍵聯子可包含二硫化物鍵。在一些實施態樣中,二硫化物鍵聯子包含間隔子及胺甲酸酯基團。共軛物之結構顯示如下:
其中X為氫或非氫取代基,及R為氫或非氫取代基。不想受到任何理論的束縛,與二硫化物相鄰的R基團大大地影響血漿及腫瘤穩定性。當R不為氫時,例如當R為-Me時,則較慢釋放的二硫化物鍵聯子提供緩慢釋放的輪廓。當胺甲酸酯取代基X不為氫時,則改進共軛物之血漿半衰期。間隔子改進共軛物在腫瘤細胞中的之半衰期及質量恢復。間隔子可為但不限於-O-CH2 CH2 -、或
其中X為氫或非氫取代基,及R為氫或非氫取代基。不想受到任何理論的束縛,與二硫化物相鄰的R基團大大地影響血漿及腫瘤穩定性。當R不為氫時,例如當R為-Me時,則較慢釋放的二硫化物鍵聯子提供緩慢釋放的輪廓。當胺甲酸酯取代基X不為氫時,則改進共軛物之血漿半衰期。間隔子改進共軛物在腫瘤細胞中的之半衰期及質量恢復。間隔子可為但不限於-O-CH2 CH2 -、或
在一些實施態樣中,R為甲基,及共軛物的實例可具有以下結構:
其中R’為可經取代的H或任何其他的取代基,諸如烷基。
其中R’為可經取代的H或任何其他的取代基,諸如烷基。
當R’=H時,則共軛物為具有以下結構的化合物4:
在一些實施態樣中,R’不為氫,且此等共軛物可具有比化合物4更大的穩定性。其中R’不為氫之共軛物的一個非限制性實例為具有以下結構的化合物5,其中R’=-CH2
CH2
NMe2
:
在一些實施態樣中,R為H,且共軛物具有以下結構:
其中R’為可經取代的H或任何其他的取代基,諸如烷基。
其中R’為可經取代的H或任何其他的取代基,諸如烷基。
當R’=-CH2
CH2
NMe2
時,則共軛物具有以下結構:
在一些實施態樣中,可切割的鍵聯子可包含二硫化物鍵及間隔子:
當間隔子包含時,則共軛物具有以下結構:
當間隔子包含,則共軛物具有以下結構:
作為活性劑之塔拉唑帕布
作為活性劑之塔拉唑帕布
在一些實施態樣中,活性劑Z為塔拉唑帕布或其衍生物/類似物及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物。共軛物的一般結構顯示如下:
共軛物的一個非限制性實例具有以下結構:
作為活性劑的PI3K抑制劑
作為活性劑的PI3K抑制劑
在一些實施態樣中,活性劑Z為PI3K抑制劑及HSP90靶定之部分X為加尼特斯皮或其衍生物/類似物,其中活性劑Z及靶定之部分X係以鍵聯子連接。PI3K抑制劑可為PI-103或PF-04691502。鍵聯子可為包含二硫化物鍵之可切割的鍵聯子。共軛物可包含可切割的胺甲酸酯基團。共軛物的非限制性實例為化合物10、11、12和13,其中化合物10、12和13包含PI-103及加尼特斯皮之衍生物,及化合物11包含PF-04691502及加尼特斯皮之衍生物。
作為活性劑的柯潘利希布
作為活性劑的柯潘利希布
在一些實施態樣中,共軛物包含作為酬載之柯潘利希布或其片段/衍生物/類似物。柯潘利希布片段/衍生物/類似物可包含之結構。靶定之部分可為加尼特斯皮衍生物,諸如但不限於TM1、TM2、TM3、TM4、TM5和TM8。靶定之部分亦可為歐那利斯皮衍生物,諸如但不限於TM6和TM7。包含柯潘利希布或其衍生物/類似物之共軛的非限制性實例包括:
作為活性劑的歐米帕利希布
作為活性劑的歐米帕利希布
在一些實施態樣中,共軛物包含作為酬載之歐米帕利希布或其片段/其衍生物/類似物。歐米帕利希布片段/衍生物/類似物可包含之結構。靶定之部分可為加尼特斯皮衍生物,諸如但不限於TM1、TM2、TM3、TM4、TM5和TM8。靶定之部分亦可為歐那利斯皮衍生物,諸如但不限於TM6和TM7。包含柯潘利希布或其衍生物/類似物之共軛物的非限制性實例包括:
作為活性劑的PI-103
作為活性劑的PI-103
在一些實施態樣中,共軛物包含作為酬載之PI-103或其片段/其衍生物/類似物。PI-103片段/衍生物/類似物可包含之結構。靶定之部分可為加尼特斯皮衍生物,諸如但不限於TM1、TM2、TM3、TM4、TM5和TM8。靶定之部分亦可為歐那利斯皮衍生物,諸如但不限於TM6和TM7。包含柯潘利希布或其衍生物/類似物之共軛物的非限制性實例包括:
D. 遮蔽之部分
D. 遮蔽之部分
本發明亦提供可活化的組成物,其包括與遮蔽之部分偶合的共軛物,其中共軛物具有結合至HSP90的能力。此等共軛物被稱為經遮蔽之共軛物。結合靶定之部分至HSP90可以遮蔽之部分抑制或阻礙。例如,結合可在遮蔽之部分的存在下受到空間阻礙或可以遮蔽之部分的電荷抑制。
遮蔽之部分的切割、構形改變或化學變換可使共軛物去遮蔽/活化。遮蔽/去遮蔽過程可為可逆的或不可逆的。當經遮蔽之共軛物活化時,則與HSP90結合的能力至少可比得上對應的未經遮蔽之共軛物。
在一些實施態樣中,遮蔽之部分含有肽序列,其包括蛋白酶的受質。蛋白酶可由腫瘤細胞產生。一旦遮蔽之部分經蛋白酶切割,則遮蔽之部分不再干擾共軛物結合至HSP90,從而活化本發明之共軛物。遮蔽之部分阻止本發明之共軛物在非治療位點上結合。此等共軛物可進一步提供改進的生物分布特徵。
在一些實施態樣中,遮蔽之部分包含肽,其可為選自由下列者所組成之酶的受質:MMP1、MMP2、MMP3、MMP8、MMP9、MMP14、胞漿素、PSA、PSMA、組織蛋白酶D、組織蛋白酶K、組織蛋白酶S、ADAM10、ADAM12、ADAMTS、半胱天冬酶-1、半胱天冬酶-2、半胱天冬酶-3、半胱天冬酶-4、半胱天冬酶-5、半胱天冬酶-6、半胱天冬酶-7、半胱天冬酶-8、半胱天冬酶-9、半胱天冬酶-10、半胱天冬酶-11、半胱天冬酶-12、半胱天冬酶-13、半胱天冬酶-14和TACE。例如,遮蔽之部分可包含蛋白酶受質,諸如胞漿素受質、半胱天冬酶受質或基質金屬蛋白酶(MMP)受質(例如MMP-1、MMP-2、MMP-9或MMP-14之受質)。
在一些實施態樣中,遮蔽之部分係藉由在腫瘤的化學環境中(例如在腫瘤的酸性或還原環境中)可切割之可切割的鍵聯子連接至共軛物的任何位置。經遮蔽之共軛物在循環中具有穩定性,在意欲之治療及/或診斷位點上活化,但不在正常組織中活化。例如,可切割的鍵聯子可包含能夠形成可還原的二硫化物鍵之半胱胺酸-半胱胺酸對,其可以還原劑切割。特別關注的還原劑包括細胞還原劑,諸如蛋白質或能夠在生理條件下還原二硫化物鍵的其他劑,例如穀胱甘肽、硫氧還原蛋白(thioredoxin)、NADPH、黃素和抗壞血酸酯。在另一實例中,遮蔽之部分或鍵聯子可為酸可切割的,且共軛物在酸性腫瘤環境中變成未經遮蔽。
E. 藥物動力學調節單元
E. 藥物動力學調節單元
本發明之共軛物可另外包含至少一種連接至與蛋白質或工程化蛋白質或其衍生物/類似物/模擬物上的官能基反應之反應基團的外部鍵聯子,或包含至少一種連接至藥物動力學調節單元的外部鍵聯子。連接共軛物及反應基團或藥物動力學調節單元的外部鍵聯子可為容許共軛物釋放之可切割的鍵聯子。於是,共軛物可在需要時自蛋白質或藥物動力學調節單元分離。
在WO2017/197241(將其揭示內容以彼之全文併入本文以供參考)中揭示之任何反應基團或PMU(諸如包含聚合物之PMU)可附著至本發明之共軛物。
F. 滲透性調節單元
F. 滲透性調節單元
本發明之共軛物可另外包含至少一種滲透性調節單元。在一些實施態樣中,滲透性調節單元係附著至共軛物之酬載,其中滲透性調節單元調控酬載之細胞膜滲透性。在一些實施態樣中,滲透性調節單元降低酬載之滲透性。不想受到任何理論的束縛,一旦酬載自共軛物釋放,則附著至酬載之滲透性調節單元降低酬載之細胞膜滲透性、增加酬載在標靶細胞中的滯留時間、改進酬載之細胞內累積及改進其功效。
在一些實施態樣中,滲透性調節單元不對共軛物之滲透性或靶定之部分的結合能力有不利的衝擊。在一些實施態樣中,滲透性調節單元僅在酬載自共軛物釋放後具有活性,例如在酬載與靶定之部分之間的可切割的鍵聯子切割後。
在一些實施態樣中,滲透性調節單元為經共價附著至共軛物之酬載的官能基。在一些實施態樣中,滲透性調節單元為酬載的主要部分。
在一些實施態樣中,滲透性調節單元係經由外部鍵聯子附著至酬載。外部鍵聯子可為不可切割的鍵聯子。
通過生物細胞膜的酬載之被動滲透係強力取決於分子之物理化學特性。影響細胞膜滲透的重要因素包括分子之酸-鹼特徵(其在特定的pH下影響分子之電荷)、其親脂性(親脂性影響分子在水性與脂質環境之間的分配)及其溶解度。為了使酬載為可滲透的,在疏水性與親水性之間應有適當的平衡。在一些實施態樣中,滲透性調節單元具有親水性。在一些實施態樣中,滲透性調節單元具有疏水性。在一些實施態樣中,滲透性調節單元具有極性。在一些實施態樣中,滲透性調節單元在生理pH下帶電荷。例如,滲透性調節單元可帶正電荷、帶負電荷或多個電荷之組合。
滲透性調節單元的非限制性實例包括具有至少一個氮的官能基,諸如哌𠯤官能基。例如,化合物38包含哌𠯤官能基。不想受到任何理論的束縛,一旦切割鍵聯子之醯胺鍵及釋放酬載,則哌𠯤基團降低柯潘利希布衍生物酬載之滲透性。
II. 粒子
II. 粒子
含有一或多種共軛物的粒子可為聚合物粒子、脂質粒子、固態脂質粒子、無機粒子或彼之組合(例如經脂質穩定之聚合物粒子)。在一些實施態樣中,粒子為聚合物粒子或含有聚合物基質。粒子可含有本文所述之聚合物或其衍生物或共聚物中之任一者。粒子通常含有一或多種生物可相容的聚合物。聚合物可為生物可降解的聚合物。聚合物可為疏水性聚合物、親水性聚合物或兩親性聚合物。在一些實施態樣中,粒子含有一或多種具有附著至其之額外的靶定之部分的聚合物。
粒子的大小可出於意欲的應用而調整。粒子可為奈米粒子或微粒子。粒子可具有約10 nm至約10微米、約10 nm至約1微米、約10 nm至約500 nm、約20 nm至約500 nm或約25 nm至約250 nm之直徑。在一些實施態樣中,粒子為具有約25 nm至約250 nm之直徑的奈米粒子。那些本技術者應理解複數個粒子具有此大小的範圍,且應理解直徑為粒徑分布之中位直徑。
在各種實施態樣中,粒子可為奈米粒子,亦即粒子具有少於約1微米之特徵尺寸,其中粒子之特徵尺寸為具有與粒子相同體積之完美球體的直徑。複數個粒子可以平均直徑(例如複數個粒子之平均直徑)特徵化。在一些實施態樣中,粒子之直徑可具有高斯(Gaussian)型分布。在一些實施態樣中,複數個粒子具有少於約300 nm、少於約250 nm、少於約200 nm、少於約150 nm、少於約100 nm、少於約50 nm、少於約30 nm、少於約10 nm、少於約3 nm或少於約1 nm之平均直徑。在一些實施態樣中,粒子具有至少約5 nm、至少約10 nm、至少約30 nm、至少約50 nm、至少約100 nm、至少約150 nm或更大的平均直徑。在特定的實施態樣中,複數個粒子具有約10 nm、約25 nm、約50 nm、約100 nm、約150 nm、約200 nm、約250 nm、約300 nm、約500 nm或類似的平均直徑。在一些實施態樣中,複數個粒子具有介於約10 nm與約500 nm之間、介於約50 nm與約400 nm之間、介於約100 nm與約300 nm之間、介於約150 nm與約250 nm之間、介於約175 nm與約225 nm之間或類似的平均直徑。在一些實施態樣中,複數個粒子具有介於約10 nm與約500 nm之間、介於約20 nm與約400 nm之間、介於約30 nm與約300 nm之間、介於約40 nm與約200 nm之間、介於約50 nm與約175 nm之間、介於約60 nm與約150 nm之間、介於約70 nm與約130 nm之間或類似的平均直徑。例如,平均直徑可為介於約70 nm與130 nm之間。在一些實施態樣中,複數個粒子具有介於約20 nm與約220 nm之間、介於約30 nm與約200 nm之間、介於約40 nm與約180 nm之間、介於約50 nm與約170 nm之間、介於約60 nm與約150 nm之間或介於約70 nm與約130 nm之間的平均直徑。在一個實施態樣中,粒子具有40至120 nm之大小,在低至零離子強度(1至10 mM)下具有接近0 mV之ζ電位、介於+5至-5 Mv之間的ζ電位值及零/中性或小的-ve表面電荷。
A. 共軛物
A. 共軛物
粒子含有一或多種如上述之共軛物。共軛物可存於粒子的內部上、粒子的外部上或二者上。粒子可包含由一或多種上述之共軛物及相對離子所形成之疏水性離子配對複合物或疏水性離子對。
疏水性離子配對(HIP)為藉由庫侖(Coulombic)引力而保持在一起的一對帶相反電荷的離子之間的相互作用。如本文所使用之HIP係指在本發明之共軛物與其相對離子之間的相互作用,其中相對離子不為H+
或HO-
離子。如本文所使用之疏水性離子配對複合物或疏水性離子對係指由本發明之共軛物及其相對離子所形成之複合物。在一些實施態樣中,相對離子具有疏水性。在一些實施態樣中,相對離子係由疏水性酸或疏水性酸之鹽提供。在一些實施態樣中,相對離子係由膽酸或鹽、脂肪酸或鹽、脂質或胺基酸提供。在一些實施態樣中,相對離子帶負電荷(陰離子性)。帶負電荷之相對離子的非限制性實例包括相對離子磺琥珀酸鈉(AOT)、油酸鈉、十二烷基硫酸鈉(SDS)、人類血清白蛋白(HSA)、硫酸聚葡萄糖、去氧膽酸鈉、膽酸鈉、陰離子性脂質、胺基酸或彼之任何組合。不想受到任何理論的束縛,在一些實施態樣中,HIP可增加本發明之共軛物的疏水性及/或親脂性。在一些實施態樣中,增加本發明之共軛物的疏水性及/或親脂性可對粒子調配物有利,且可提供本發明之共軛物在有機溶劑中更高的溶解度。不想受到任何理論的束縛,咸信包括HIP對之粒子調配物具有改進的調配物特性,諸如載藥量(drug loading)及/或釋放輪廓。不想受到任何理論的束縛,在一些實施態樣中,可能發生本發明之共軛物自粒子緩慢釋放,此係起因於共軛物在水溶液中的溶解度降低。另外,不想受到任何理論的束縛,共軛物與大的疏水性相對離子之複合可減慢共軛物在聚合物基質內擴散。在一些實施態樣中,HIP係在相對離子未共價駁斥至本發明之共軛物而發生。
不想受到任何理論的束縛,HIP的強度可衝擊本發明之粒子的載藥量及釋放速率。在一些實施態樣中,HIP的強度可藉由增加本發明之共軛物的pKa與提供相對離子之藥劑的pKa之間的差異量級而增加。亦不想受到任何理論的束縛,用於離子對形成的條件可衝擊本發明之粒子的載藥量及釋放速率。
在一些實施態樣中,任何適合的疏水性酸或彼之組合可與本發明之共軛物形成HIP對。在一些實施態樣中,疏水性酸可為羧酸(諸如但不限於單羧酸、二羧酸、三羧酸)、亞磺酸、次磺酸或磺酸。在一些實施態樣中,可使用適合的疏水性酸之鹽或彼之組合與本發明之共軛物形成HIP對。疏水性酸、飽和脂肪酸、不飽和脂肪酸、芳族酸、膽酸、聚電解質、彼等在水中的解離常數(pKa)及logP值的實例係揭示於WO2014/043,625,將該等內容以彼之全文併入本文以供參考。疏水性酸的強度、在疏水性酸的pKa與本發明之共軛物的pKa之間的差異、疏水性酸的logP、疏水性酸的相轉變溫度、疏水性酸對本發明之共軛物的莫耳比及疏水性酸的濃度亦揭示於WO2014/043,625,將該等內容以彼之全文併入本文以供參考。
在一些實施態樣中,包含HIP複合物及/或藉由提供相對離子與共軛物形成HIP複合物之方法所製備的本發明之粒子可具有比沒有HIP複合物或藉由不提供任何相對離子與共軛物形成HIP複合物之方法所製備的粒子更高的載藥量。在一些實施態樣中,載藥量可增加50%、100%、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍或10倍。
在一些實施態樣中,當本發明之粒子放入在37℃之磷酸鹽緩衝溶液中時,本發明之粒子可保留共軛物至少約1分鐘、至少約15分鐘、至少約1小時。
在一些實施態樣中,在粒子中的共軛物之重量百分比為至少約0.05%、0.1%、0.5%、1%、5%、10%、15%、20%、25%、30%、35%、40%、45%或50%,使得粒子之組分的重量百分比總和為100%。在一些實施態樣中,在粒子中的共軛物之重量百分比為約0.5%至約10%、或約10%至約20%、或約20%至約30%、或約30%至約40%、或約40%至約50%、或約50%至約60%、或約60%至約70%、或約70%至約80%、或約80%至約90%或約90%至約99%,使得粒子之組分的重量百分比總和為100%。
在一些事例中,共軛物可具有少於約50,000 Da、少於約40,000 Da、少於約30,000 Da、少於約20,000 Da、少於約15,000 Da、少於約10,000 Da、少於約8,000 Da、少於約5,000 Da、少於約3,000 Da、少於2000 Da、少於1500 Da、少於1000 Da或少於500 Da之分子量。在一些例子中,共軛物可具有介於約1,000 Da與約50,000 Da之間、介於約1,000 Da與約40,000 Da之間的分子量,在一些實施態樣中介於約1,000 Da與約30,000 Da之間,在一些實施態樣中介於約1,000 Da與約50,000 Da之間、介於約1,000 Da與約20,000 Da之間,在一些實施態樣中介於約1,000 Da與約15,000 Da之間,在一些實施態樣中介於約1,000 Da與約10,000 Da之間,在一些實施態樣中介於約1,000 Da與約8,000 Da之間,在一些實施態樣中介於約1,000 Da與約5,000 Da之間,及在一些實施態樣中介於約1,000 Da與約3,000 Da之間。共軛物之分子量可以共軛物化學式中的各原子之原子量總和乘以各原子數目來計算。其亦可藉由質譜法、NMR、層析術、光散射、黏度及/或本技術中已知的任何其他方法來測量。在本技術中已知分子量的單位可為g/mol、道耳頓(Dalton)(Da)或原子質量單位(amu),其中1 g/mol=1 Da=1 amu。
B.聚合物
B.聚合物
粒子可含有一或多種聚合物。聚合物可含有下列聚酯中之一或多者:包括下列的均聚物:乙醇酸單元(在本文稱為「PGA」)、及乳酸單元,諸如聚-L-乳酸、聚-D-乳酸、聚-D,L-乳酸、聚-L-乳交酯、聚-D-乳交酯和聚-D,L-乳交酯(本文中統稱為「PLA」)、及己內酯單元,諸如聚(ε-己內酯)(在本文統稱為「PCL」);及包括下列的共聚物:乳酸及乙醇酸單元,諸如以乳酸:乙醇酸之比特徵化的各種形式之聚(乳酸-共-乙醇酸)和聚(乳交酯-共聚-乙交酯)(在本文統稱為「PLGA」);及聚丙烯酸酯與其衍生物。例示性聚合物亦包括聚乙二醇(PEG)與前述之聚酯的共聚物,諸如各種形式之PLGA-PEG或PLA-PEG共聚物(在本文統稱為「PEG化(PEGylated)聚合物」)。在特定的實施態樣中,PEG區可藉由可切割的鍵聯子而與聚合物共價締合,以得到「PEG化聚合物」。
粒子可含有一或多種親水性聚合物。親水性聚合物包括纖維素聚合物(諸如澱粉和多醣)、親水性多肽、聚(胺基酸)(諸如聚-L-麩胺酸(PGS)、γ-聚麩胺酸、聚-L-天冬胺酸、聚-L-絲胺酸或聚-L-離胺酸)、聚烷二醇和聚環氧烷(諸如聚乙二醇(PEG)、聚丙二醇(PPG)和聚(環氧乙烷)(PEO))、聚(氧乙基化多元醇)(poly(oxyethylated polyol))、聚(烯烴醇)、聚乙烯基吡咯啶酮、聚(羥烷基甲基丙烯醯胺)、聚(羥烷基甲基丙烯酸酯)、聚(醣)、聚(羥基酸)、聚(乙烯醇)、聚㗁唑啉及彼之共聚物。
粒子可含有一或多種疏水性聚合物。適合的疏水性聚合物的實例包括聚羥基酸(諸如聚(乳酸)、聚(乙醇酸)和聚(乳酸-共-乙醇酸))、聚羥基烷酸酯(polyhydroxyalkanoate)(諸如聚3-羥基丁酸酯或聚4-羥基丁酸酯)、聚己內酯、聚(原酯)、聚酐、聚(磷腈)、聚(乳交酯-共-己內酯)、聚碳酸酯(諸如酪胺酸聚碳酸酯)、聚醯胺(包括合成和天然聚醯胺)、多肽和聚(胺基酸)、聚酯醯胺、聚酯、聚(二氧環己酮)(poly(dioxanone))、聚(伸烷基烷基化物)、疏水性聚醚、聚胺甲酸酯、聚醚酯、聚縮醛、聚丙烯酸氰酯、聚丙烯酸酯、聚甲基丙烯酸甲酯、聚矽氧烷、聚(氧乙烯)/聚(氧丙烯)共聚物、聚縮酮、聚磷酸酯、聚羥基戊酸酯、聚草酸伸烷酯、聚丁二酸伸烷酯、聚(順丁烯二酸)以及彼之共聚物。
在特定的實施態樣中,疏水性聚合物為脂族聚酯。在一些實施態樣中,疏水性聚合物為聚(乳酸)、聚(乙醇酸)或聚(乳酸-共-乙醇酸)。
粒子可含有一或多種生物可降解的聚合物。生物可降解的聚合物可包括在體內經化學或酶轉化成水溶性材料的不溶或微溶於水之聚合物。生物可降解的聚合物可包括以可水解的交聯基團交聯之可溶性聚合物,使得經交聯之聚合物不溶或微溶於水。
在粒子中的生物可降解的聚合物可包括聚醯胺、聚碳酸酯、聚烯烴、聚烷二醇、聚環氧烷、聚對酞酸烷二酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、聚鹵乙烯、聚乙烯吡咯啶酮、聚乙交酯、聚矽氧烷、聚胺甲酸酯和其共聚物、烷基纖維素(諸如甲基纖維素和乙基纖維素)、羥烷基纖維素(諸如羥丙基纖維素、羥丙基甲基纖維素及羥丁基甲基纖維素)、纖維素醚、纖維素酯、硝化纖維素、乙酸纖維素、丙酸纖維素、乙酸丁酸纖維素、乙酸酞酸纖維素、羧乙基纖維素、三乙酸纖維素、硫酸纖維素鈉鹽、丙烯酸和甲基丙烯酸酯之聚合物(諸如聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸異丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸異癸酯)、聚(甲基丙烯酸月桂酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸異丙酯)、聚(丙烯酸異丁酯)、聚(丙烯酸十八酯))、聚乙烯、聚丙烯、聚(乙二醇)、聚(環氧乙烷)、聚(對酞酸乙二酯)、聚(乙烯醇)、聚(乙酸乙烯酯)、聚氯乙烯、聚苯乙烯和聚乙烯吡咯啶酮、彼之衍生物、彼之直鏈和支鏈共聚物與嵌段共聚物、及彼之摻合物。例示性生物可降解的聚合物包括聚酯、聚(原酯)、聚(伸乙亞胺)、聚(己內酯)、聚(羥基烷酸酯)、聚(羥基戊酸酯)、聚酐、聚(丙烯酸)、聚乙交酯、聚(胺甲酸酯)、聚碳酸酯、聚磷酸酯、聚磷腈、其衍生物、其直鏈和支鏈共聚物與嵌段共聚物、及其摻合物。在一些實施態樣中,粒子含有生物可降解的聚酯或聚酐,諸如聚(乳酸)、聚(乙醇酸)和及聚(乳酸-共-乙醇酸)。
粒子可含有一或多種兩親性聚合物。兩親性聚合物可為含有疏水性聚合物嵌段及親水性聚合物嵌段之聚合物。疏水性聚合物嵌段可含有上述疏水性聚合物或彼之衍生物或共聚物中之一或多者。親水性聚合物嵌段可含有上述親水性聚合物或彼之衍生物或共聚物中之一或多者。在一些實施態樣中,兩親性聚合物為含有自疏水性聚合物所形成的疏水性端及由親水性聚合物所形成的親水性端之二嵌段聚合物。在一些實施態樣中,一部分可附著至疏水性端、親水性端或二者。粒子可含有二或更多種兩親性聚合物。
C. 脂質
C. 脂質
粒子可含有一或多種脂質或兩親性化合物。例如,粒子可為脂質體、脂質微胞、固態脂質粒子或經脂質穩定之聚合物粒子。脂質粒子可自一種脂質或不同脂質之混合物製成。脂質粒子係自一或多種脂質形成,其在生理pH下可為中性、陰離子性或陽離子性。在一些實施態樣中,脂質粒子併入一或多種生物可相容的脂質。脂質粒子可使用超過一種脂質之組合形成。例如,帶電荷之脂質可與在生理pH下為非離子性或不帶電荷之脂質組合。
粒子可為脂質微胞。在本技術中已知用於藥物遞送之脂質微胞。脂質微胞可以脂質界面活性劑形成為例如油包水型乳液。乳液為兩種不溶混相之摻合物,其中添加界面活性劑以穩定分散之液滴。在一些實施態樣中,脂質微胞為微乳液。微乳液為至少由水、油及產生透明且熱力學穩定系統之脂質界面活性劑所組成之熱力學穩定系統,其液滴大小為少於1微米、約10 nm至約500 nm或約10 nm至約250 nm。脂質微胞通常有用於囊封疏水性活性劑,包括疏水性治療劑、疏水性預防劑或疏水性診斷劑。
粒子可為脂質體。脂質體為由排列成球形雙層之脂質環繞的水性介質所組成之小微脂粒。脂質體可被分類成單層小微脂粒、單層大微脂粒或多層微脂粒。多層脂質體含有多個同心脂質雙層。脂質體可藉捕獲親水劑於水性內部或於雙層之間,或藉由捕獲疏水劑於雙層內而用於囊封藥劑。
脂質微胞及脂質體通常具有水性中心。水性中心可含有水或水與醇之混合物。適合的醇包括但不限於甲醇、乙醇、丙醇(諸如異丙醇)、丁醇(諸如正丁醇、異丁醇、二級丁醇、三級丁醇)、戊醇(諸如戊醇、異丁基甲醇)、己醇(諸如1-己醇、2-己醇、3-己醇)、庚醇(諸如1-庚醇、2-庚醇、3-庚醇和4-庚醇)或辛醇(諸如1-辛醇)或彼之組合。
粒子可為固態脂質粒子。固態脂質粒子係以膠態微胞及脂質體的替代物存在。固態脂質粒子通常呈次微米大小,亦即約10 nm至約1微米、10 nm至約500 nm或10 nm至約250 nm。固態脂質粒子係由在室溫下為固體之脂質所形成。彼等係藉由以固態脂質置換液態油而自水包油型乳液衍生而來。
適合的中性及陰離子性脂質包括但不限於固醇和脂質,諸如膽固醇、磷脂、溶血性脂質(lysolipid)、溶血性磷脂(lysophospholipid)、神經鞘脂質或PEG化脂質。中性及陰離子性脂質包括但不限於磷脂醯膽鹼(PC)(諸如蛋PC、大豆PC),包括1,2-二醯基-甘油-3-磷膽鹼;磷脂醯絲胺酸(PS)、磷脂醯甘油、磷脂醯肌醇(PI);醣脂;神經鞘磷脂,諸如神經鞘髓磷脂和神經鞘醣脂(亦稱為1-神經醯胺基糖苷),諸如神經醯胺半乳哌喃糖苷、神經節苷脂和腦苷脂;脂肪酸、固醇(含有羧酸基,例如膽固醇);1,2-二醯基-sn-甘油-3-磷乙醇胺,包括但不限於1,2-二油基磷乙醇胺(DOPE)、1,2-二-十六烷基磷乙醇胺(DHPE)、1,2-二硬脂醯基磷脂醯膽鹼(DSPC)、1,2-二棕櫚醯基磷脂醯膽鹼(DPPC)和1,2-二肉豆蔻醯基磷脂醯膽鹼(DMPC)。脂質亦可包括脂質的各種天然衍生物(例如經組織衍生之L-α-磷脂醯:蛋黃、心臟、腦、肝臟、大豆)及/或合成衍生物(例如飽和與不飽和1,2-二醯基-sn-甘油-3-磷膽鹼、1-醯基-2-醯基-sn-甘油-3-磷膽鹼、1,2-二庚醯基-SN-甘油-3-磷膽鹼)。
適合的陽離子性脂質包括但不限於N-[1-(2,3-二油醯氧基)丙基]-N,N,N-三甲基銨鹽,亦稱為TAP脂質,例如甲基硫酸鹽。適合的TAP脂質包括但不限於DOTAP(二油醯基-)、DMTAP(二肉豆蔻醯基-)、DPTAP(二棕櫚醯基-)和DSTAP(二硬脂醯基-)。適合於脂質體中的陽離子性脂質包括但不限於溴化二甲基雙十八烷基銨(DDAB)、1,2-二醯氧基-3-三甲基銨丙烷、N-[1-(2,3-二油醯氧基(dioloyloxy))丙基]-N,N-二甲基胺(DODAP)、1,2-二醯氧基-3-二甲基銨丙烷、氯化N-[1-(2,3-二油氧基(dioleyloxy))丙基]-N,N,N-三甲銨(DOTMA)、1,2-二烷氧基-3-二甲基銨丙烷、二-十八烷基醯胺基甘胺醯基鯨胺(DOGS)、3-[N-(N’,N’-二甲基胺基乙烷)胺甲醯基]膽固醇(DC-Chol)、三氟乙酸2,3-二油醯氧基-N-(2-(鯨胺甲醯胺基)-乙基)-N,N-二甲基-1-丙胺鎓(DOSPA)、β-丙胺醯基膽固醇、溴化鯨蠟基三甲基銨(CTAB)、二C14
-脒、N-ferf-丁基-N’-十四烷基-3-十四烷基胺基丙脒、氯化N-(α-三甲基銨乙醯基)二-十二烷基-D-麩胺酸鹽(TMAG)、氯化二-十四醯基-N-(三甲基銨乙醯基)二乙醇胺、1,3-二油醯氧基-2-(6-羧基-鯨胺基(spermyl))-丙醯胺(DOSPER)和碘化N,N,N’,N’-四甲基-,N’-雙(2-羥乙基)-2,3-二油醯氧基-1,4-丁二銨。在一個實施態樣中,陽離子性脂質可為氯化1-[2-(醯氧基)乙基]2-烷基(烯基)-3-(2-羥乙基)-咪唑啉鎓衍生物,例如氯化1-[2-(9(Z)-十八烯醯氧基)乙基]-2-(8(Z)-十七烯基-3-(2-羥乙基)咪唑啉鎓(DOTIM)和氯化1-[2-(十六醯氧基)乙基]-2-十五烷基-3-(2-羥乙基)咪唑啉鎓(DPTIM)。在一個實施態樣中,陽離子性脂質可為含有羥烷基部分在四級胺上的2,3-二烷氧基丙基四級銨化合物衍生物,例如溴化1,2-二油醯基-3-二甲基-羥乙基銨(DORI)、溴化1,2-二油氧基丙基-3-二甲基-羥乙基銨(DORIE)、溴化1,2-二油氧基丙基-3-二甲基-羥丙基銨(DORIE-HP)、溴化1,2-二油氧基丙基-3-二甲基-羥丁基銨(DORIE-HB)、溴化1,2-二油氧基丙基-3-二甲基-羥戊基銨(DORIE-Hpe)、溴化1,2-二肉豆蔻氧基丙基-3-二甲基-羥乙基銨(DMRIE)、溴化1,2-二棕櫚氧基丙基-3-二甲基-羥乙基銨(DPRIE)和溴化1,2-二硬脂氧基丙基-3-二甲基-羥乙基銨(DSRIE)。
適合的固態脂質包括但不限於高碳飽和醇、高碳脂肪酸、神經鞘脂質、合成酯及高碳飽和脂肪酸之單甘油酯、二甘油酯和三甘油酯。固態脂質可包括具有10至40,例如12至30個碳原子的脂族醇,諸如鯨蠟硬脂醇。固態脂質可包括10至40,例如12至30個碳原子的高碳脂肪酸,諸如硬脂酸、棕櫚酸、癸酸和蘿酸。固態脂質可包括具有10至40,例如12至30個碳原子的高碳飽和脂肪酸之甘油酯,包括單甘油酯、二甘油酯和三甘油酯,諸如單硬脂酸甘油酯、甘油蘿酸酯、甘油棕櫚硬脂酸酯、甘油三月桂酸酯(glycerol trilaurate)、三癸酸甘油酯、三月桂酸甘油酯(trilaurin)、三肉豆蔻酸甘油酯、三棕櫚酸甘油酯、三硬脂酸甘油酯和氫化蓖麻油。適合的固態脂質可包括棕櫚酸鯨蠟酯、蜂蠟或環糊精。
兩親性化合物包括但不限於磷脂,諸如1,2-二硬脂醯基-sn-甘油-3-磷乙醇胺(DSPE)、二棕櫚醯基磷脂醯膽鹼(DPPC)、二硬脂醯基磷脂醯膽鹼(DSPC)、二花生醯基磷脂醯膽鹼(DAPC)、二蘿醯基磷脂醯膽鹼(DBPC)、二-二十三醯基磷脂醯膽鹼(DTPC)和二-二十四醯基磷脂醯膽鹼(dilignoceroylphatidylcholine)(DLPC),其係以介於0.01至60(脂質重量/聚合物重量),例如介於0.1至30(脂質重量/聚合物重量)之比併入。可使用之磷脂包括但不限於磷脂酸、具有飽和與不飽和脂質二者的磷脂醯膽鹼、磷脂醯基乙醇胺、磷脂醯甘油、磷脂醯絲胺酸、磷脂醯肌醇、溶血性磷脂醯衍生物、心脂和β-醯基-y-烷基磷脂。磷脂的實例包括但不限於磷脂醯膽鹼,諸如二油醯基磷脂醯膽鹼、二肉豆蔻醯基磷脂醯膽鹼、二-十五醯基磷脂醯膽鹼、二月桂醯基磷脂醯膽鹼、二棕櫚醯基磷脂醯膽鹼(DPPC)、二硬脂醯基磷脂醯膽鹼(DSPC)、二花生醯基磷脂醯膽鹼(DAPC)、二蘿醯基磷脂醯膽鹼(DBPC)、二-二十三醯基磷脂醯膽鹼(DTPC)、二-二十四醯基磷脂醯膽鹼(DLPC);及磷脂醯基乙醇胺,諸如二油醯基磷脂醯基乙醇胺或1-十六烷基-2-棕櫚醯基甘油磷乙醇胺。亦可使用具有不對稱醯基鏈(例如一個醯基鏈為6個碳原子及另一醯基鏈為12個碳原子)之合成磷脂。
D. 額外的活性劑
D. 額外的活性劑
除了共軛物中的那些活性劑之外,粒子可含有一或多種額外的活性劑。額外的活性劑可為如上文列示之治療劑、預防劑、診斷劑或營養劑。額外的活性劑可以任何量存在,例如以粒子重量為基礎計約0.5%至約90%、約0.5%至約50%、約0.5%至約25%、約0.5%至約20%、約0.5%至約10%或約5%至約10%(w/w)。在一個實施態樣中,活性劑係以約0.5%至約10% w/w之裝載量併入。
E. 額外的靶定之部分
E. 額外的靶定之部分
除了共軛物的靶定之部分以外,粒子可含有一或多種靶定粒子至特定器官、組織、細胞類型或亞細胞隔室(subcellular compartment)的靶定之部分。額外的靶定之部分可存在於粒子的表面上、粒子的內部上或二者上。額外的靶定之部分可固定在粒子表面上,例如可共價附著至粒子中的聚合物或脂質。在一些實施態樣中,額外的靶定之部分係共價附著至兩親性聚合物或脂質,使得靶定之部分在粒子表面上定向。
F. 製造粒子之方法
F. 製造粒子之方法
在各種實施態樣中,製造粒子之方法包括提供在WO2014/106208及WO2016/004043中揭示之任何方法,將每一該等內容以彼之全文併入本文以供參考。
III. 調配物
III. 調配物
在一些實施態樣中,將組成物投予人類、人類患者或個體。出於本發明之目的,詞組「活性成分」通常係指如本文所述欲遞送之共軛物或包含共軛物之粒子。
儘管本文提供之醫藥組成物的說明主要指向適合投予人類的醫藥組成物,但熟習本技術領域者應理解此等組成物通常適合投予任何其他的動物,例如投予非人類動物,例如非人類哺乳動物。為了使得組成物適合投予各種動物,對適合投予人類之醫藥組成物進行修飾是完全可理解的,且一般熟習本技術的獸醫藥理學家僅以常規實驗(若有的話)即可設計及/或進行此等修飾。預期以醫藥組成物投予的個體包括但不限於人類及/或其他靈長類動物;哺乳動物,包括商業相關的哺乳動物,諸如牛、豬、馬、綿羊、貓、狗、小鼠及/或大鼠;及/或鳥類,包括商業相關的鳥類,諸如家禽、雞、鴨、鵝及/或火雞。
本文所述之醫藥組成物的調配物可以藥理學技術中已知或隨後發展的任何方法製備。此等製備方法通常包括使活性成分與賦形劑及/或一或多種其他的輔助成分締合及接著若必要及/或需要時將產物分隔、成型及/或包裝成所欲單一或多劑量單位。
依照本發明之醫藥組成物可以單一單位劑量及/或以複數個單一單位劑量之散裝形式製備、包裝或銷售。如本文所使用之「單位劑量」為包含預定量的活性成分之醫藥組成物的個別量。活性成分量通常等於可投予個體的活性成分劑量及/或此劑量的合宜部分,例如此劑量的一半或三分之一。
在依照本發明之醫藥組成物中的活性成分、醫藥上可接受之賦形劑及/或任何額外的成分之相對量係取決於受治療之個體的特質、體形及/或病況及另外取決於欲投予組成物之途徑而改變。以實例說明,組成物可包含介於0.1%與100%之間,例如介於.5與50%之間、介於1至30%之間、介於5至80%之間、至少80%(w/w)之間的活性成分。
本發明之共軛物或粒子可使用一或多種賦形劑調配,以:(1)增加穩定性;(2)允許持續或延緩釋放(例如自單順丁烯二醯亞胺之貯庫調配物釋放);(3)改變生物分布(例如使單順丁烯二醯亞胺化合物靶定特定的組織或細胞類型);(4)改變單順丁烯二醯亞胺化合物於活體內的釋放輪廓。賦形劑的非限制性實例包括任何及所有的溶劑、分散介質、稀釋劑或其他的液體媒劑、分散或懸浮助劑、表面活性劑、等滲壓劑、增稠或乳化劑及防腐劑。本發明之賦形劑亦可包括而不限於類脂質(lipidoid)、脂質體、脂質奈米粒子、聚合物、脂質複合物(lipoplex)、核-殼奈米粒子、肽、蛋白質、玻尿酸酶、奈米粒子模擬物及彼之組合。因此,本發明之調配物可包括一或多種賦形劑,各者的量一起增加單順丁烯二醯亞胺化合物的穩定性。
賦形劑
賦形劑
醫藥調配物可另外包含適合於所欲特定劑型的醫藥上可接受之賦形劑,如本文所使用之賦形劑包括任何及所有的溶劑、分散介質、稀釋劑或其他的液體媒劑、分散或懸浮助劑、表面活性劑、等滲壓劑、增稠或乳化劑、防腐劑、固體黏合劑、潤滑劑及類似者。Remington’s The Science and Practice of Pharmacy,第21版,A. R. Gennaro(Lippincott, Williams & Wilkins, Baltimore, MD, 2006;以其全文併入本文以供參考)揭示在調配醫藥組成物所使用之各種賦形劑及用於其製備之已知的技術。除非任何慣例的賦形劑介質與物質或其衍生物不相容,諸如產生任何非所欲生物效應或在其他方面以有害的方式與醫藥組成物的任何其他組分相互作用,否則其用途涵蓋在本發明之範疇內。
在一些實施態樣中,醫藥上可接受之賦形劑具有至少95%、至少96%、至少97%、至少98%、至少99%或100%純度。在一些實施態樣中,賦形劑經批准用於人類及獸醫用途。在一些實施態樣中,賦形劑係經美國食品及藥物管理局(United States Food and Drug Administration)批准。在一些實施態樣中,賦形劑為醫藥級。在一些實施態樣中,賦形劑符合美國藥典(United States Pharmacopoeia(USP))、歐洲藥典(European Pharmacopoeia (EP))、英國藥典(British Pharmacopoeia)及/或國際藥典(International Pharmacopoeia)的標準。
用於製造醫藥組成物的醫藥上可接受之賦形劑包括但不限於惰性稀釋劑、分散及/或造粒劑、表面活性劑及/或乳化劑、崩散劑、黏合劑、防腐劑、緩衝劑、潤滑劑及/或油。此等賦形劑可隨意地包括在醫藥組成物中。
例示性稀釋劑包括但不限於碳酸鈣、碳酸鈉、磷酸鈣、磷酸二鈣、硫酸鈣、磷酸氫鈣、磷酸鈉、乳糖、蔗糖、纖維素、微晶型纖維素、高嶺土、甘露醇、山梨醇、肌醇、氯化鈉、乾燥澱粉、玉米澱粉、糖粉等及/或彼之組合。
例示性造粒及/或分散劑包括但不限於馬鈴薯澱粉、玉米澱粉、樹薯澱粉、乙醇酸澱粉鈉、黏土、藻酸、瓜爾膠、柑橘渣、洋菜、膨土、纖維素和木製品、天然海綿、陽離子交換樹脂、碳酸鈣、矽酸鹽、碳酸鈉、經交聯之聚(乙烯吡咯啶酮)(crospovidone)、羧甲基澱粉鈉(乙醇酸澱粉鈉)、羧甲基纖維素、經交聯之羧甲基纖維素鈉(croscarmellose)、甲基纖維素、預糊化澱粉(澱粉1500)、微晶型澱粉、不溶於水之澱粉、羧甲基纖維素鈣、矽酸鎂鋁(VEEGUM®)、月桂基硫酸鈉、四級銨化合物等及/或彼之組合。
例示性表面活性劑及/或乳化劑包括但不限於天然乳化劑(例如阿拉伯膠、洋菜、藻酸、藻酸鈉、黃蓍樹膠、軟骨泥(chondrux)、膽固醇、黃原膠、果膠、明膠、蛋黃、酪蛋白、羊毛脂、膽固醇、蠟和卵磷脂)、膠態黏土(例如膨土[矽酸鋁]和VEEGUM® [矽酸鎂鋁])、長鏈胺基酸衍生物、高分子量醇(例如硬酯醇、鯨臘醇、油醇、三乙酸甘油單硬脂酸酯、乙二醇二硬脂酸酯、單硬脂酸甘油酯和丙二醇單硬脂酸酯、聚乙烯醇)、卡波姆(carbomer)(例如聚羧乙烯(carboxy polymethylene)、聚丙烯酸、丙烯酸聚合物和羧乙烯基聚合物)、鹿角菜膠、纖維素衍生物(例如羧甲基纖維素鈉、粉末狀纖維素、羥甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素)、山梨醇酐脂肪酸酯(例如聚氧乙烯山梨醇酐單月桂酸酯[TWEEN®20]、聚氧乙烯山梨醇酐[TWEENn®60]、聚氧乙烯山梨醇酐單油酸酯[TWEEN®80]、山梨醇酐單棕櫚酸酯[SPAN®40]、山梨醇酐單硬脂酸酯[SPAN®60]、山梨醇酐三硬脂酸酯[SPAN®65]、單油酸甘油酯、山梨醇酐單油酸酯[SPAN®80])、聚氧乙烯酯(例如聚氧乙烯單硬脂酸酯[MYRJ®45]、聚氧乙烯氫化蓖麻油、聚氧乙基化蓖麻油、聚甲醛硬脂酸酯和SOLUTOL®)、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯(例如CREMOPHOR®)、聚氧乙烯醚(例如聚氧乙烯月桂醚[BRIJ®30])、聚(乙烯吡咯啶酮)、二乙二醇單月桂酸酯、三乙醇胺油酸酯、油酸鈉、油酸鉀、油酸乙酯、油酸、月桂酸乙酯、月桂基硫酸鈉、PLUORINC®F 68、POLOXAMER®188、溴化鯨蠟基三甲銨(cetrimonium bromide)、氯化鯨蠟基吡啶鎓、氯化烷基二甲基苯甲銨(benzalkonium chloride)、多庫酯鈉(docusate sodium)等及/或彼之組合。
例示性黏合劑包括但不限於澱粉(例如玉米澱粉和澱粉糊)、明膠、糖(例如蔗糖、葡萄糖、右旋糖、糊精、糖蜜、乳糖、乳糖醇、甘露醇)、天然和合成膠(例如阿拉伯膠、藻酸鈉、鹿角菜(Irish moss)萃取物、潘瓦膠(panwar gum)、甘地膠(ghatti gum)、洋車前子果殼(isapol husks)膠漿、羧甲基纖維素、甲基纖維素、乙基纖維素、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、微晶型纖維素、乙酸纖維素、聚(乙烯吡咯啶酮)、矽酸鎂鋁(Veegum®)和落葉松阿拉伯半乳聚糖(larch arabogalactan))、藻酸鹽、聚環氧乙烷、聚乙二醇、無機鈣鹽、矽酸、聚甲基丙烯酸酯、蠟、水、醇等及彼之組合。
例示性防腐劑可包括但不限於抗氧化劑、螯合劑、抗微生物防腐劑、抗真菌防腐劑、醇防腐劑、酸性防腐劑及/或其他防腐劑。例示性抗氧化劑包括但不限於α生育酚、抗壞血酸、棕櫚酸抗壞血酯(acorbyl palmitate)、丁基化羥基茴香醚、丁基化羥基甲苯、單硫甘油、偏二亞硫酸鉀、丙酸、五倍子酸丙酯、抗壞血酸鈉、亞硫酸氫鈉、偏二亞硫酸鈉及/或亞硫酸鈉。例示性螯合劑包括乙二胺四乙酸(EDTA)、檸檬酸單水合物、乙二胺四乙酸二鈉、乙二胺四乙酸二鉀、乙二胺四乙酸、反丁烯二酸、蘋果酸、磷酸、乙二胺四乙酸鈉、酒石酸及/或乙二胺四乙酸三鈉。例示性抗微生物防腐劑包括但不限於氯化烷基二甲基苯甲銨、氯化苯銨(benzethonium chloride)、苯甲醇、泊諾帕(bronopol)、溴化十六基三甲銨、氯化鯨蠟基吡啶鎓、氯己定(chlorhexidine)、氯丁醇、氯甲酚、羅薩諾(chloroxylenol)、甲酚、乙醇、甘油、赫西替定(hexetidine)、咪唑啶基脲(imidurea)、酚、苯氧基乙醇、苯乙醇、硝酸苯基汞、丙二醇及/或乙汞硫柳酸鈉。例示性抗真菌防腐劑包括但不限於對羥苯甲酸丁酯、對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯、苯甲酸、羥基苯甲酸、苯甲酸鉀、山梨酸鉀、苯甲酸鈉、丙酸鈉及/或山梨酸。例示性醇防腐劑包括但不限於乙醇、聚乙二醇、酚、酚化合物、雙酚、氯丁醇、羥基苯甲酸酯及/或苯乙醇。例示性酸性防腐劑包括但不限於維生素A、維生素C、維生素E、β-胡蘿蔔素、檸檬酸、乙酸、去氫乙酸、抗壞血酸、山梨酸及/或植酸。其他的防腐劑包括但不現於生育酚、生育酚乙酸酯、甲磺酸迪特肟(deteroxime mesylate)、溴化鯨蠟基三甲銨、丁基化羥基茴香醚(BHA)、丁基化羥基甲苯(BHT)、乙二胺、月桂基硫酸鈉(SLS)、月桂醚硫酸鈉(SLES)、亞硫酸氫鈉、偏二亞硫酸鈉、亞硫酸鉀、偏二亞硫酸鉀、GLYDANT PLUS®、PHENONIP®、對羥苯甲酸甲酯、GERMALL®115、GERMABEN®II、NEOLONE™, KATHON™及/或EUXYL®。
例示性緩衝劑包括但不限於檸檬酸鹽緩衝溶液、乙酸鹽緩衝溶液、磷酸鹽緩衝溶液、氯化銨、碳酸鈣、氯化鈣、檸檬酸鈣、葡乳醛酸鈣(calcium glubionate)、葡庚糖酸鈣(calcium gluceptate)、葡萄糖酸鈣、D-葡萄糖酸、甘油磷酸鈣、乳酸鈣、丙酸、乙醯丙酸鈣、戊酸、磷酸氫二鈣、磷酸、磷酸三鈣、氫氧化磷酸鈣、乙酸鉀、氯化鉀、葡萄糖酸鉀、鉀混合物、磷酸氫二鉀、磷酸二氫鉀、磷酸鉀混合物、乙酸鈉、碳酸氫鈉、氯化鈉、檸檬酸鈉、乳酸鈉、磷酸氫二鈉、磷酸二氫鈉、磷酸鈉混合物、緩血酸胺(tromethamine)、氫氧化鎂、氫氧化鋁、藻酸、無熱原水、等滲壓食鹽水、林格氏液(Ringer’s solution)、乙醇等及/或彼之組合。
例示性潤滑劑包括但不限於硬脂酸鎂、硬脂酸鈣、硬脂酸、二氧化矽、滑石、麥芽、蘿酸甘油酯、氫化植物油、聚乙二醇、苯甲酸鈉、乙酸鈉、氯化鈉、白胺酸、月桂基硫酸鎂、月桂基硫酸鈉等及彼之組合。
例示性油包括但不限於扁桃(almond)油、杏仁(apricot kernel)油、酪梨油、棕櫚仁油(babassu)、佛手柑油、黑加侖籽(black current seed)油、琉璃苣油、杜松油、黃金菊油、芥花油、香菜油、巴西棕櫚油、蓖麻油、肉桂油、可可脂油、椰子油、鱈魚肝油、咖啡油、玉米油、棉籽油、鴯鶓油、桉樹油、月見草油、魚油、亞麻籽油、香葉草醇油、葫蘆油、葡萄籽油、榛果油、牛膝草油、肉豆蔻酸異丙酯油、荷荷芭(jojoba)油、夏威夷果油、醒目薰衣草(lavandin)油、薰衣草(lavender)油、檸檬油、山胡椒油、夏威夷豆(macademia nut)油、錦葵油、芒果籽油、白芒花籽(meadowfoam seed)油、貂油、肉荳蔻油、橄欖油、橙油、大西洋胸棘鯛(orange roughy)油、棕櫚油、棕櫚果仁(palm kernel)油、桃仁油、花生油、罌粟籽油、南瓜籽油、菜籽油、米糠油、迷迭香油、紅花油、檀香木油、山茶(sasquana)油、歐洲薄荷油、沙棘油、芝麻油、牛油樹油脂油、聚矽氧油、大豆油、葵花油、茶樹油、薊油、樁油、香根草油、胡桃和小麥胚芽油。例示性油包括但不限於硬脂酸丁酯、辛酸三甘油酯、癸酸三甘油酯、環甲聚矽氧烷(cyclomethicone)、癸二酸二乙酯、二甲聚矽氧烷(dimethicone)360、肉豆蔻酸異丙酯、礦油、辛基十二醇、油醇、聚矽氧油及/或彼之組合。
根據調配者的判斷,賦形劑(諸如可可脂和栓劑蠟、著色劑、包膜劑、甜味劑、調味劑及/或芳香劑)可存在於組成物中。
投予
投予
本發明之共軛物或粒子可以得到治療有效結果的任何途徑投予。此等途徑包括但不限於經腸、胃腸、硬膜外、經口、經皮、硬膜外(硬膜周圍)、腦內(至大腦內)、腦室內(至腦室內)、皮上(施予皮膚上)、皮內(至皮膚本身內)、皮下(在皮膚下)、鼻腔投予(通過鼻子)、靜脈內(至靜脈內)、動脈內(至動脈內)、肌肉內(至肌肉內)、心內(至心臟內)、骨內輸注(至骨髓內)、鞘內(至脊管內)、腹膜內(輸注或注射至腹膜內)、膀胱輸注、玻璃體內(通過眼睛)、海綿體內注射(至陰莖基部內)、陰道內投予、子宮內、羊膜外(extra-amniotic)投予、經皮(通過完整皮膚擴散而於全身性分布)、經黏膜(通過黏膜擴散)、吸入(鼻吸(snorting))、舌下、唇下、灌腸、眼滴劑(至結膜上)或耳滴劑。在特定的實施態樣中,組成物可容許彼等穿過血腦障壁、血管障壁或其他上皮障壁的方式投予。
本文所述之調配物含有有效量的共軛物或粒子於適合投予有其需要之個體的醫藥載劑中。調配物可以非經腸(例如以注射或輸注)投予。調配物或其變型可以任何方式投予,包括經腸、局部(例如至眼睛)或經由肺部投予。在一些實施態樣中,調配物係局部投予。
A. 非經腸調配物
A. 非經腸調配物
共軛物或粒子可經調配以溶液、懸浮液或乳液形式用於非經腸遞送(諸如注射或輸注)。調配物可經全身性、局部或直接投予欲治療之器官或組織。
非經腸調配物可使用本技術中已知的技術製備成水性組成物。此等組成物通常可製備成可注射調配物,例如溶液或懸浮液;適合在注射前添加重組介質而用於製備溶液或懸浮液之固體形式;乳液,諸如油包水型(w/o)乳液、水包油型(o/w)乳液和其微乳液、脂質體或乳液體(emulsome)。
載劑可為含有例如下列者之溶劑或分散介質:水、乙醇、一或多種多元醇(例如甘油、丙二醇和液態聚乙二醇)、油(諸如植物油,例如花生油、玉米油、芝麻油等)及彼之組合。適當的流動性可藉由例如使用包膜(諸如卵磷脂)、在分散液的例子中藉由維持所需之粒徑及/或藉由使用界面活性劑來維持。在一些例子中,包括等滲壓劑,例如一或多種糖、氯化鈉或本技術中已知的其他適合的劑。
共軛物或粒子的溶液及分散液可在水或其他的溶劑或分散介質中與一或多種醫藥上可接受之賦形劑(包括但不限於界面活性劑、分散劑、乳化劑、pH調整劑及彼之組合)適當地混合而製得。
適合的界面活性劑可為陰離子、陽離子、兩性或非離子表面活性劑。適合的陰離子界面活性劑包括但不限於那些含有羧酸根、磺酸根和硫酸根離子者。陰離子界面活性劑的實例包括長鏈烷基磺酸及烷基芳基磺酸之鈉鹽、鉀鹽、銨鹽,諸如十二烷基苯磺酸鈉;二烷基磺琥珀酸鈉,諸如十二烷基苯磺酸鈉;二烷基磺琥珀酸鈉,諸如雙(2-乙基硫氧基)磺琥珀酸鈉;及烷基硫酸鹽,諸如月桂基硫酸鈉。陽離子界面活性劑包括但不限於四級銨化合物,諸如氯化烷基二甲基苯甲銨、氯化苯銨、溴化鯨蠟基三甲銨、氯化硬脂基二甲基苯甲銨、聚氧乙烯和椰油胺(coconut amine)。非離子界面活性劑的實例包括乙二醇單硬脂酸酯、丙二醇肉豆蔻酸酯、單硬脂酸甘油酯、硬脂酸甘油酯、聚甘油基-4-油酸酯、山梨醇酐丙烯酸酯、蔗糖丙烯酸酯、PEG-150月桂酸酯、PEG-400單月桂酸酯、聚氧乙烯單月桂酸酯、聚山梨醇酯、聚氧乙烯辛基苯醚、PEG-1000鯨蠟醚、聚氧乙烯十三烷醚、聚丙二醇丁醚、Poloxamer® 401、硬脂醯基單異丙醇醯胺和聚氧乙烯氫化牛脂醯胺。兩性界面活性劑的實例包括N-十二烷基-β-丙胺酸鈉、N-月桂基-β-亞胺基二丙酸鈉、肉豆蔻兩性乙酸鹽(myristoamphoacetate)、月桂基甜菜鹼和月桂基磺基甜菜鹼(lauryl sulfobetaine)。
調配物可含有防腐劑以防止微生物生長。適合的防腐劑包括但不限於對羥苯甲酸酯、氯丁醇、酚、山梨酸和乙汞硫柳酸鈉。調配物亦可含有抗氧化劑以防止活性劑或粒子降解。
調配物通常在重組時經緩衝至3至8之pH而用於非經腸投予。適合的緩衝劑包括但不限於磷酸鹽緩衝劑、乙酸鹽緩衝劑和檸檬酸鹽緩衝劑。若使用10%之蔗糖或5%之右旋糖,則可以不需要緩衝劑。
水溶性聚合物經常被用於非經腸投予之調配物中。適合的水溶性聚合物包括但不限於聚乙烯吡咯啶酮、聚葡萄糖、羧甲基纖維素和聚乙二醇。
無菌可注射溶液可藉由將所需量的共軛物或粒子與上文列示之賦形劑中之一或多者在適當的溶劑或分散介質中合併,若需要時接著經過濾滅菌而製得。分散液通常係藉由將各種經滅菌之共軛物或粒子併入含有基礎分散介質及來自那些上文列示之所需的其他成分之滅菌媒劑中而製得。在用於製備無菌可注射溶液之無菌粉末的例子中,製備方法的實例包括真空乾燥及冷凍乾燥技術,該等技術係自先前經滅菌過濾之溶液得到粒子加上任何額外的所欲成分之粉末。粉末可以粒子呈多孔性質的方式製備,其可增加粒子的溶解作用。在本技術中已知製造多孔粒子之方法。
用於非經腸投予之醫藥調配物可呈共軛物或自一或多種聚合物-藥物共軛物所形成之粒子的無菌水溶液或懸浮液的形式。可接受之溶劑包括例如水、林格氏液、磷酸鹽緩衝之食鹽水(PBS)和等滲壓氯化鈉溶液。調配物亦可為非經腸可接受之無毒性稀釋劑或溶劑(諸如1,3-丁二醇)中的無菌溶液、懸浮液或乳液。
在一些事例中,調配物係呈液體形式分配或包裝。另一選擇地,用於非經腸投予之調配物可呈固體包裝,其係例如藉由將適合的液體調配物凍乾而獲得。固體可在投予前以適當載劑或稀釋劑重組。
用於非經腸投予之溶液、懸浮液或乳液可經維持適合於眼部投予之pH所必要的有效量緩衝液緩衝。適合的緩衝液為那些熟習本技術領域者所熟知,且有用的緩衝液的一些實例為乙酸鹽、硼酸鹽、碳酸鹽、檸檬酸鹽和磷酸鹽緩衝劑。
用於非經腸投予之溶液、懸浮液或乳液亦可含有一或多種張力劑以調整調配物之等滲壓範圍。適合的張力劑為那些熟習本技術領域者所熟知,且一些實例包括甘油、蔗糖、右旋糖、甘露醇、山梨醇、氯化鈉和其他的電解質。
用於非經腸投予之溶液、懸浮液或乳液亦可含有一或多種防腐劑以防止眼用製劑的細菌污染。適合的防腐劑為本技術中已知且包括聚六亞甲基雙胍(PHMB)、氯化烷基二甲基苯甲銨(BAK)、經穩定之氧氯複合物(oxychloro complex)(另外亦稱為Purite®)、苯基乙酸汞、氯丁醇、山梨酸、氯己定、苯甲醇、對羥苯甲酸酯、乙汞硫柳酸鈉及彼之混合物。
用於非經腸投予之溶液、懸浮液或乳液亦可含有一或多種本技術已知的賦形劑,諸如分散劑、潤濕劑和及懸浮劑。
B. 黏膜用局部調配物
B. 黏膜用局部調配物
共軛物或粒子可經調配而用於局部投予黏膜表面。適合於局部投予之劑型包括乳霜、軟膏、油膏、噴劑、凝膠、洗劑、乳液、液體和經皮貼片。調配物可經調配而用於經黏膜上皮或內皮投予。組成物含有一或多種化學穿透增強劑、膜滲透性劑、膜輸送劑、軟化劑、界面活性劑、穩定劑及彼之組合。在一些實施態樣中,共軛物或粒子可作為液體調配物(諸如溶液或懸浮液)、半固體調配物(諸如洗劑或軟膏)或固體調配物投予。在一些實施態樣中,共軛物或粒子經調配成液體(包括溶液和懸浮液,諸如眼滴劑)或半固體調配物而用於黏膜,諸如眼睛或陰道或直腸。
「界面活性劑」為降低表面張力且從而增加產物之乳化、發泡、分散、擴展及潤濕性質的表面活性劑。適合非離子界面活性劑包括乳化蠟、單油酸甘油酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚山梨醇酯、山梨醇酐酯、苯甲醇、苯甲酸苯甲酯、環糊精、甘油單硬脂酸酯、泊洛沙姆(poloxamer)、普維酮(povidone)及彼之組合。在一個實施態樣中,非離子界面活性劑為硬酯醇。
「乳化劑」為促進一種液體懸浮於另一液體中且促進油與水形成穩定的混合物或乳液之表面活性物質。常用的乳化劑為:金屬皂、特定的動物和植物油及各種極性化合物。適合的乳化劑包括阿拉伯膠、陰離子乳化蠟、硬脂酸鈣、卡波姆、鯨蠟硬脂醇、鯨臘醇、膽固醇、二乙醇胺、乙二醇棕櫚硬脂酸酯、甘油單硬脂酸酯、單油酸甘油酯、羥丙基纖維素、羥丙基甲基纖維素(hypromellose)、羊毛脂(含水)、羊毛脂醇、卵磷脂、中鏈三甘油酯、甲基纖維素、礦油和羊毛脂醇、磷酸二氫鈉、單乙醇胺、非離子乳化蠟、油酸、泊洛沙姆、泊洛沙姆類、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯硬脂酸酯、丙二醇藻酸酯、自乳化單硬脂酸甘油酯、檸檬酸鈉去水物、月桂基硫酸鈉、山梨醇酐酯、硬脂酸、葵花油、黃蓍樹膠、三乙醇胺、黃原膠及彼之組合。在一個實施態樣中,乳化劑為甘油硬脂酸酯。
適合的穿透增強劑類別為本技術中已知且包括但不限於脂肪醇、脂肪酸酯、脂肪酸、脂肪醇醚、胺基酸、磷脂、卵磷脂、膽酸鹽、酶、胺和醯胺、複合劑(脂質體、環糊精、經修飾之纖維素和二醯亞胺)、巨環(諸如巨環內酯、酮和酐)及環脲、界面活性劑、N-甲基吡咯啶酮與其衍生物、DMSO和相關化合物、離子化合物、氮酮(azone)和相關化合物及溶劑(諸如醇、酮、醯胺、多元醇,例如二醇)。在本技術中已知該等類別的實例。
給藥
給藥
本發明提供包含將共軛物或含有如本文所述之共軛物的粒子投予有其需要的個體之方法。共軛物或含有如本文所述之共軛物的粒子可使用有效預防或治療或成像疾病、病症及/或病況(例如與工作記憶缺損相關之疾病、病症及/或病況)的任何量或任何投予途徑投予個體。所需之精確量係取決於個體的物種、年齡和一般狀態、疾病的嚴重性、特定的組成物、其投予模式、其活性模式及類似者而於個體之間不同。
依照本發明之組成物通常經調配成容易投予及劑量均勻的單位劑型。然而,應理解本發明之組成物的總日使用量可由主治醫師在健全的醫學判斷範圍內決定。用於任何特別的患者之特定的治療有效劑量、預防有效劑量或適當的成像劑量水平係取決各種因素而定,包括正治療之病症和病症的嚴重性;所使用之特定的化合物活性;所使用之特定的組成物;患者的年齡、體重、一般健康、性別和飲食;所使用之特定的化合物之投予時間、投予途徑和排泄速率;治療的持續時間;與所使用之特定的化合物組合或巧合使用之藥物;及在醫療技術中熟知的類似因素。
在一些實施態樣中,依照本發明之組成物可以每日充分遞送下列量的劑量水平投予:約0.0001 mg/kg至約100 mg/kg、約0.001 mg/kg至約0.05 mg/kg、約0.005 mg/kg至約0.05 mg/kg、約0.001 mg/kg至約0.005 mg/kg、約0.05 mg/kg至約0.5 mg/kg、約0.01 mg/kg至約50 mg/kg、約0.1 mg/kg至約40 mg/kg、約0.5 mg/kg至約30 mg/kg、約0.01 mg/kg至約10 mg/kg、約0.1 mg/kg至約10 mg/kg、或約1 mg/kg至約25 mg/kg、約25 mg/kg至約50 mg/kg、約50 mg/kg至約100 mg/kg、約100 mg/kg至約125 mg/kg、約125 mg/kg至約150 mg/kg、約150 mg/至約175 mg/kg、約175 mg/kg至約200 mg/kg、約200 mg/kg至約250 mg/kg個體體重,一天一或多次以獲得所欲治療、診斷、預防或成像效應。所欲劑量可遞送一天三次、一天兩次、一天一次、每隔一天一次、每三天一次、每週一次、每兩週一次、每三週一次或每四週一次。在一些實施態樣中,所欲劑量可使用多次投予(例如二、三、四、五、六、七、八、九、十、十一、十二、十三、十四或更多次投予)遞送。當使用多次投予時,可使用分次給藥方案,諸如那些本文所述者。
在醫藥組成物中的本發明之共軛物或粒子的濃度可介於約0.01 mg/mL至約50 mg/mL、約0.1 mg/mL至約25 mg/mL、約0.5 mg/mL至約10 mg/mL或約1 mg/mL至約5 mg/mL之間。
如本文使用之「分次劑量」為單一單位劑量或總日劑量分成二或更多劑量,例如投予二或更多次的單一單位劑量。如本文所使用之「單一單位劑量」為以一個劑量/一次/單一途徑/單一接觸點投予(亦即單一投予事件)的任何治療劑量。如本文使用之「總日劑量」為在24小時期間給予或處方之量。其可作為單一單位劑量投予。在一個實施態樣中,本發明之單順丁烯二醯亞胺化合物係以分次劑量投予個體。單順丁烯二醯亞胺化合物可僅調配於緩衝液中或調配於本文所述之調配物中。
劑型
劑型
本文所述之醫藥組成物可經調配成本文所述之劑型,諸如局部、鼻腔內、氣管內或可注射劑型(例如靜脈內、眼內、玻璃體內、肌肉內、心內、腹膜內和皮下)。
液體劑型
液體劑型
用於非經腸投予之液體劑型包括但不限於醫藥上可接受之乳液、微乳液、溶液、懸浮液、糖漿及/或酏劑。除了活性成分以外,液體劑型可包含本技術中常用的惰性稀釋劑,包括但不限於水或其他溶劑、增溶劑和乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(特別為棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油和芝麻油)、甘油、四氫糠醇、聚乙二醇和山梨醇酐之脂肪酸酯及彼之混合物。在用於非經腸投予之特定的實施態樣中,組成物可與增溶劑混合,諸如CREMOPHOR®、醇、油、改質油、二醇、聚山梨醇酯、環糊精、聚合物及/或彼之組合。
可注射劑型
可注射劑型
可注射製劑(例如無菌可注射水性或含油懸浮液)可根據已知的技術調配,且可包括適合的分散劑、潤濕劑及/或懸浮劑。滅菌可注射製劑可為在非經腸可接受之無毒性稀釋劑及/或溶劑中的無菌可注射溶液、懸浮液及/或乳液,例如在1,3-丁二醇中的溶液。在可使用的可接受之媒劑及溶劑之中,該等包括但不限於水、林格氏液、U.S.P.和等滲壓氯化鈉溶液。無菌的不揮發油照慣例用作為溶劑或懸浮介質。出於此目的,可使用任何無刺激性的不揮發油,包括合成單甘油酯或二甘油酯。脂肪酸(諸如油酸)可用於可注射劑型之製備。
可將注射調配物滅菌,例如藉由通過保留細菌之過濾器過濾,及/或藉由併入呈無菌固體組成物形式的滅菌劑,其在使用前可溶解或分散於無菌水或其他的無菌可注射介質中。
為了延長活性成分的效應,可能希望減慢自皮下或肌內注射之活性成分的吸收。這可藉由使用具有差的水溶性之結晶或非晶形材料的液體懸浮液而達成。單順丁烯二醯亞胺化合物的吸收速率接著取決於其溶解速率而定,該溶解速率依次可取決於晶體大小和結晶形式而定。另一選擇地,延緩非經腸投予之單順丁烯二醯亞胺化合物的吸收可藉由將單順丁烯二醯亞胺溶解或懸浮於油性媒劑中而達成。可注射的貯庫形式係藉由在生物可降解的聚合物(諸如聚乳交酯-聚乙交酯)中形成單順丁烯二醯亞胺化合物之微膠囊基質而製得。單順丁烯二醯亞胺化合物的釋放速率可取決於單順丁烯二醯亞胺化合物對聚合物之比及所使用之特定的聚合物本性來控制。其他生物可降解的聚合物之實例包括但不限於聚(原酯)和聚(酐)。可注射的貯庫型調配物可藉由將單順丁烯二醯亞胺化合物截留在與體組織可相容的脂質體或微乳液中而製得。
肺部
肺部
用於肺部遞送的本文所述之調配物亦可用於經鼻腔內遞送醫藥組成物。適合於鼻腔內投予之另一調配物可為包含活性成分且具有約0.2 µm至500 µm之平均粒子的粗粉末。此種調配物可採用嗅吸的方式投予,亦即自保持在靠近鼻子的粉末容器通過鼻道快速吸入。
適合於鼻腔投予之調配物可例如包含約少至0.1%(w/w)及多至100%(w/w)之活性成分,且可包含本文所述之額外的成分中之一或多者。可製備、包裝及/或銷售適合於頰內投予之調配物的醫藥組成物。此等調配物可呈例如使用慣例的方法製成之錠劑及/或菱形錠形式,且可例如含有約0.1%至20%(w/w)之活性成分,其中其餘部分可包含經口可溶解及/或可降解的組成物及隨意的本文所述之額外的成分中之一或多者。另一選擇地,適合於頰內投予之調配物可包含粉末及/或氣霧化及/或霧化溶液及/或懸浮液,其包含活性成分。此等粉末化、氣霧化及/或氣霧化調配物在分散時具有在約0.1 nm至約200 nm之範圍內的平均粒子及/或液滴大小,且可另外包含本文所述之任何額外的成分中之一或多者。
調配及/或製造醫藥劑的一般考量可見於例如例如Remington:The Science and Practice of Pharmacy,第21版,Lippincott Williams & Wilkins, 2005(以其全文併入本文以供參考)。
包膜或殼
包膜或殼
錠劑、糖衣錠、膠囊、丸劑及顆粒的固體劑型可以包膜及殼製備,諸如腸衣包膜和醫藥調配技術中熟知的其他包膜。該等劑型可隨意地包含失透劑且可具有使其僅在或優先在腸道的特定部分中隨意地以延遲方式釋放活性成份的組成物。可使用之包埋組成物的實例包括聚合物質和蠟。類似型式的固體組成物可用作為使用賦形劑(諸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇及類似者)的軟及硬填充式明膠膠囊中的填料。
I. 使用共軛物及粒子之方法
I. 使用共軛物及粒子之方法
在適當時,可投予如本文所述之共軛物或粒子以治療任何過度增生疾病、代謝疾病、傳染病或癌症。調配物可藉由注射、經口或局部投予,通常投予黏膜表面(肺、鼻、口、頰內、舌下、陰道、直腸)或投予眼睛(眼內或經眼)。
在各種實施態樣中,提供治療患有癌症的個體之方法,其中方法包含將治療有效量的如本文所述之共軛物、其鹽形式或包含此等共軛物之粒子投予患有癌症、疑似患有癌症或易罹癌之個體。根據本發明,癌症包含以失控的細胞增生(例如過度增生)為特徵的任何疾病或病。癌可以腫瘤為特徵,例如實體腫瘤或任何贅生物。
在一些實施態樣中,癌為實體腫瘤。大型藥物分子在實體腫瘤中的穿透性受到限制。大型藥物分子具有緩慢的穿透性。另一方面,小分子(諸如本發明之共軛物)可迅速且更深入地穿透實體腫瘤。關於藥物的穿透深度,儘管較大的分子具有更耐久的藥物動力學,但穿透得較少。小分子(諸如本發明之共軛物)穿透得較深。Dreher等人(Dreher等人之JNCI,
vol.98(5):335(2006),將其揭示內容以彼之全文併入以供參考)研究具有不同大小的聚葡萄糖至腫瘤異種移植物中的穿透性。如Dreher之圖6(參見本發明申請案之圖1)及表1所彙總,具有3.3 kDa或10 kDa之分子量的聚葡萄糖顯示迅速深入穿透至腫瘤組織中(自腫瘤之血管表面起>35um)。然而,40 kDa、70 kDa或2 mDa大小之聚葡萄糖的穿透遠少於3.3 kDa或10 kDa之聚葡萄糖。70 kDa之聚葡萄糖僅到達自腫瘤之血管表面起約15 um處。本發明之共軛物具有相當於3.3 kDa及10 kDa之聚葡萄糖的分子量,而抗體藥物共軛物具有至少與70 kDa之聚葡萄糖一樣大的分子量。因此,本發明之共軛物可深入且迅速地穿透至實體腫瘤的核心/中心。
在一個實施態樣中,本發明之共軛物係自腫瘤之血管表面起到達實體腫瘤內至少約25 µm、約30 µm、約35 µm、約40 µm、約45 µm、約50 µm、約75 µm、約100 µm、約150 µm、約200 µm、約250 µm、約300 µm、約400 µm、約500 µm、約600 µm、約700 µm、約800 µm、約900 µm、約1000 µm、約1100 µm、約1200 µm、約1300 µm、約1400 µm或約1500 µm。零距離經定義為腫瘤之血管表面,且大於零的每一距離經定義為以三維量測而最接近於血管表面的距離。
在另一實施態樣中,本發明之共軛物穿透至腫瘤的核心。如本文所使用之腫瘤的「核心」係指腫瘤的中心區域。自腫瘤之核心區域的任何部分至腫瘤之血管表面的距離係介於腫瘤之長度或寬度的約30%至約50%之間。自腫瘤之核心區域的任何部分至腫瘤之中心點的距離小於腫瘤之長度或寬度的約20%。腫瘤之核心區域大略為腫瘤的中心1/3。
在另一實施態樣中,本發明之共軛物穿透至實體腫瘤的中間。如本文所使用之腫瘤的「中間」係指腫瘤的中間區域。自腫瘤之中間區域的任何部分至腫瘤之血管表面的距離係介於腫瘤之長度或寬度的約15%與約30%之間。自腫瘤之中間區域的任何部分至腫瘤之中心點的距離係介於腫瘤之長度或寬度的約20%至約35%。腫瘤之中間區域大略介於腫瘤的中心1/3與腫瘤的外側1/3之間。
在一些實施態樣中,個體在其他方面可能沒有以共軛物或粒子治療的適應症。在一些實施態樣中,該方法包括使用癌細胞,包括但不限於哺乳動物癌細胞。在一些事例中,哺乳動物癌細胞為人類癌細胞。
在一些實施態樣中,已發現本發明指導之共軛物或粒子抑制癌及/或腫瘤生長。彼等亦可降低包括細胞增生、入侵及/或轉移,從而使彼等有用於癌症治療。
在一些實施態樣中,本發明指導之共軛物或粒子可用於阻止腫瘤或癌生長,及/或阻止腫瘤或癌轉移。在一些實施態樣中,本發明指導之組成物可用於縮小或破壞癌。
在一些實施態樣中,本文提供之共軛物或粒子有用於抑制癌細胞增生。在一些實施態樣中,本文提供之共軛物或粒子有用於抑制細胞增生,例如抑制細胞增生速率、阻止細胞增生及/或誘發細胞死亡。如本文所述之共軛物或粒子通常可抑制癌細胞增生或同時抑制癌細胞增生及/或誘發癌細胞死亡。在一些實施態樣中,與未治療之細胞相比,細胞增生在以本發明之共軛物或粒子治療後減少至少約25%、約50%、約75%或約90%。在一些實施態樣中,與未治療之細胞相比,細胞週期停止標記磷酸化組蛋白(phospho histone)H3(PH3或PHH3)在以本發明之共軛物治療後增加至少約50%、約75%、約100%、約200%、約400%或約600%。在一些實施態樣中,與未治療之細胞相比,細胞凋亡標記切割之半胱天冬酶-3(CC3)在以本發明之共軛物或粒子治療後增加至少50%、約75%、約100%、約200%、約400%或約600%。
此外,在一些實施態樣中,本發明之共軛物或粒子有效抑制多種類型之腫瘤中的腫瘤生長,不論是否以大小淨值(重量、表面積或體積)或隨著時間的生長速率來測量。
在一些實施態樣中,腫瘤大小在以本發明之共軛物或粒子治療後縮小約60%或更多。在一些實施態樣中,以重量及/或面積及/或體積量測之腫瘤大小縮小至少約20%、至少約30%、至少約40%、至少約50%、至少約60%、至少約70%、至少約80%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%、至少約100%。
以本發明指導之方法可治療的癌症通常發生在哺乳動物中。哺乳動物包括例如人類、非人類靈長類動物、狗、貓、大鼠、小鼠、兔子、雪貂、天竺鼠、馬、豬、綿羊、山羊和牛。在各種實施態樣中,癌包括但不限於聽覺神經瘤、急性白血病、急性淋巴球性白血病、急性骨髓細胞白血病(單核細胞、成髓細胞、腺癌、血管肉瘤、星狀細胞瘤、骨髓單核球和前髓細胞)、急性T細胞白血病、基底細胞癌、膽管癌、膀胱癌、腦癌、乳癌、枝氣管癌、子宮頸癌、軟骨肉瘤、脊索瘤、絨毛膜癌、慢性白血病、慢性淋巴球性白血病、慢性骨髓細胞(粒細胞)白血病、慢性骨髓性白血病、結腸癌、結腸直腸癌、顱咽管瘤、囊腺癌、瀰漫性大型B細胞淋巴瘤、伯基特氏(Burkitt’s)淋巴瘤、異常增生性改變(發育不良和化生)、胚胎癌、子宮內膜癌、內皮肉瘤、室管膜瘤、上皮癌、紅血球性白血病、食道癌、雌激素受體陽性乳腺癌、原發性血小板增多症、尤文氏(Ewing’s)腫瘤、纖維肉瘤、濾泡性淋巴瘤、生殖細胞睾丸癌、膠質瘤、重鏈疾病、血管母細胞瘤、肝癌、肝細胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴結內皮細胞瘤、淋巴管肉瘤、成淋巴細胞白血病、淋巴瘤(霍奇金氏(Hodgkin’s)和非霍奇金氏),膀胱、乳房、結腸、肺、卵巢、胰臟、前列腺、皮膚和子宮的惡性腫瘤和過度增生性疾病,T細胞或B細胞起源的淋巴惡性腫瘤、白血病、淋巴瘤、髓質癌、神經管胚細胞瘤、黑色素瘤、腦膜瘤、中皮瘤、多發性骨髓瘤、骨髓性白血病、骨髓瘤、黏液瘤、神經母細胞瘤、非小細胞肺癌、寡樹突細胞瘤、口腔癌、成骨肉瘤、卵巢癌、胰臟癌、乳頭狀腺癌、乳頭狀癌、松果體瘤、真性紅細胞增多症、前列腺癌、直腸癌、腎細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、肉瘤、皮脂腺癌、精原細胞瘤、皮膚癌、小細胞肺癌、實體腫瘤(癌和肉瘤)、小細胞肺癌、胃癌、鱗狀細胞癌、滑膜瘤、汗腺癌、甲狀腺癌、瓦爾登斯特倫氏(Waldenstrom’s)巨球蛋白血症、睾丸腫瘤、子宮癌和威爾姆斯(Wilms’)瘤。其他的癌包括原發癌、轉移性癌、口咽癌、下咽癌、肝癌、膽囊癌、膽管癌、小腸癌、泌尿道癌、腎癌、尿道上皮癌、女性生殖道癌、子宮癌、妊娠滋養細胞疾病、男性生殖道癌、精囊癌、睾丸癌、生殖細胞腫瘤、內分泌腺腫瘤、甲狀腺癌、腎上腺癌、腦垂體癌、血管瘤、源於骨和軟組織之肉瘤、卡波西氏(Kaposi’s)肉瘤、神經癌、眼癌、腦膜癌、膠質母細胞瘤、神經瘤、神經母細胞瘤、神經鞘瘤、源於造血系統惡性腫瘤之實體腫瘤(諸如白血病)、轉移性黑色素瘤、復發性或持續性卵巢上皮癌、輸卵管癌、原發性腹膜癌、胃腸道基質瘤、結腸直腸癌、胃癌、黑色素瘤、多形性膠質母細胞瘤、非鱗狀非小細胞肺癌、惡性膠質瘤、上皮性卵巢癌、原發性腹膜漿液性癌、非轉移性肝癌、神經內分泌癌、難治性惡性腫瘤、三陰性乳癌、HER2擴增型乳癌、鼻咽癌、口腔癌、膽道癌、肝細胞癌、頭頸部鱗狀細胞癌(SCCHN)、非甲狀腺髓質癌、復發性多形性膠質母細胞瘤、神經纖維瘤第1型、CNS癌、脂肪肉瘤、平滑肌肉瘤、唾液腺癌、黏膜黑色素瘤、肢端/點狀惡性黑色素瘤、副神經節瘤、嗜鉻細胞瘤、晚期轉移性癌、實體腫瘤、三陰性乳癌、結腸直腸癌、肉瘤、黑色素瘤、腎癌、子宮內膜癌、甲狀腺癌、橫紋肌肉瘤、多發性骨髓瘤、卵巢癌、膠質母細胞瘤、胃腸道間質瘤、套細胞淋巴瘤和難治性惡性腫瘤。
在一個實施態樣中,如本文所述之共軛物或粒子或如本文所述之含有共軛物或粒子之調配物係用於治療小細胞肺癌。患有肺癌的患者中約12%至15%患有小細胞肺癌。轉移性小細胞肺癌的存活率低。在診斷後五年存活率低於5%。美國的小細胞肺癌發生率為約26000至30000人。
在一些實施態樣中,如本文所述之共軛物或粒子或如本文所述之含有共軛物或粒子之調配物係用於治療患有表現或過度表現HSP90之腫瘤的患者。
本發明之共軛物或粒子的特點為對有機體相對低的毒性,且保持抑制(例如減慢或停止)腫瘤生長的功效。如本文所使用之「毒性」係指物質或組成物對細胞、組織有機體或細胞環境有害或有毒的能力。低毒性係指物質或組成物對細胞、組織有機體或細胞環境有害或有毒的能力降低。此降低的毒性或低毒性可相對於標準量測、相對於治療或相對於未治療。例如,本發明之共軛物或粒子可具有比單獨投予之活性劑部分Z更低的毒性。包含DM1之共軛物的毒性比單獨投予之DM1更低。
毒性可另外相對於個體的體重減輕來測量,其中超過體重的15%、超過20%或超過30%之體重減輕為毒性的指標。亦可測量毒性的其他測度,諸如患者表現測度,包括嗜睡及一般不適。嗜中性球減少症、血小板減少症、白血球(WBC)數、全血球(CBC)數亦可為毒性的測度。毒性的藥理指標包括上升的轉胺酶(AST/ALT)含量、神經毒性、腎臟受損、GI受損及類似者。在一個實施態樣中,本發明之共軛物或粒子不引起個體體重顯著的變化。在以本發明之共軛物或粒子治療後,個體減少的體重少於約30%、約20%、約15%、約10%或約5%。在另一實施態樣中,本發明之共軛物或粒子不引起個體之AST/ALT含量顯著的增加。在以本發明之共軛物或粒子治療後,個體增加的AST或ALT含量少於約30%、約20%、約15%、約10%或約5%。在又另一實施態樣中,在以本發明之共軛物或粒子治療後,本發明之共軛物或粒子不引起個體之CBC或WBC數顯著的變化。在以本發明之共軛物或粒子治療後,個體減少的CBC或WBC數少於約30%、約20%、約15%、約10%或約5%。
在一些實施態樣中,本發明之共軛物遮蔽其酬載的活性。各共軛物阻斷各個酬載之標靶活性,直到鍵聯子部分在腫瘤中被切割且釋放活性酬載為止。通過HSP90平台,使毒性藉由遮蔽酬載的活性位點而減輕,直到酬載可遞送至腫瘤為止。例如,在一個實施態樣中,酬載抑制PI3K活性。與單獨的酬載相比,包含酬載之共軛物具有較少的PI3K抑制活性。
在一些實施態樣中,本發明之共軛物亦不引起接受治療的個體之血糖含量顯著的增加。如本文所使用之「顯著的增加」意指與治療前的含量相比而增加超過25%。在一些實施態樣中,與治療前的含量相比,接受本發明之共軛物治療的個體增加之血糖含量少於約200%、約150%、約100%、約75%、約50%、約40%、約30%、約20%或約10%。
在一些實施態樣中,本發明之共軛物或粒子係與至少一種額外的活性劑組合。活性劑可為任何適合的藥物。共軛物及至少一種額外的活性劑可同時、依序或以任何順序投予。共軛物及至少一種額外的活性劑可以不同的劑量、以不同的給藥頻率或經由不同的途徑投予,端取哪一種適合。額外的活性劑可選自本文所述之任何活性劑,諸如用於治療癌症的藥物。其亦可為癌症狀緩解藥物。症狀緩解藥物的非限制性實例包括:體抑素胜肽或蘭瑞肽;干擾素、賽庚啶(cypoheptadine)或任何其他的抗組織胺。在一些實施態樣中,本發明之共軛物或粒子與額外的活性劑不具有藥物-藥物干擾。在一個實施態樣中,本發明之共軛物或粒子不抑制細胞色素P450(CYP)同功酶。CYP同功酶可包括CYP3A4咪達唑侖(Midazolam)、CYP3A4睪固酮、CYP2C9、CYP2D6、CYP1A2、CYP2C8、CYP2B6和CYP2C19。額外的活性劑可伴隨本發明之共軛物或粒子投予。
在另一實例中,本發明之共軛物或粒子可與適當劑量的化學治療劑(諸如絲裂黴素C、長春鹼和順鉑)組合(參見Ellis等人之Br J Cancer
, vol.71(2):366-370 (1995),將其揭示內容以彼之全文併入以供參考)。
在又另一實例中,患者可先接受醫藥有效劑量的未經共軛之活性劑,繼而接受醫藥有效劑量的包含相同活性劑之共軛物。
如本文所述之共軛物或粒子或如本文所述之含有共軛物或粒子之調配物可用於選擇性組織遞送治療劑、預防劑或診斷劑至有其需要的患者。例如,本發明之DM1共軛物或粒子係用於遞送DM1至選擇性組織。該等組織可為腫瘤組織。劑量方案可經調整以提供最優化所欲反應(例如治療或預防反應)。例如,可投予單一濃注劑量(bolus),可隨時間投予數個分次劑量,或劑量可根據治療情況的緊急程度之指示而依比例減少或增加。如本文所使用之單位劑型係指適合作為欲治療之哺乳動物個體的單位劑量之物理分離單元;各單位含有經計算以得到所欲治療之預定量的活性化合物。
在各種實施態樣中,在粒子內含有的共軛物係以受控制的方式釋放。釋放可為活體外或活體內。例如,粒子可在特定的條件下(包括那些在美國藥典中所指定者及其變化)接受釋放試驗。
在各種實施態樣中,在粒子內含有的共軛物在粒子暴露於釋放試驗的條件後第1小時內釋放少於約90%、少於約80%、少於約70%、少於約60%、少於約50%、少於約40%、少於約30%、少於約20%。在一些實施態樣中,在粒子內含有的共軛物在粒子暴露於釋放試驗的條件後第1小時內釋放少於約90%、少於約80%、少於約70%、少於約60%或少於約50%。在特定的實施態樣中,在粒子內含有的共軛物在粒子暴露於釋放試驗的條件後第1小時內釋放少於約50%。
關於活體內釋放之共軛物,例如在投予個體之粒子內含有的共軛物可受到保護而免於暴露於個體的體內,且身體亦可與共軛物隔離,直到共軛物自粒子釋放為止。
因此,在一些實施態樣中,共軛物可實質地內含在粒子內,直到粒子被遞送至個體的體內為止。例如,少於約90%、少於約80%、少於約70%、少於約60%、少於約50%、少於約40%、少於約30%、少於約20%、少於約15%、少於約10%、少於約5%或少於約1%之總共軛物係在粒子被遞送至體內(例如治療位點)前自粒子釋放。在一些實施態樣中,共軛物可經擴展的時期釋放或以爆發性釋放(例如共軛物的量係在短時期內釋放,繼而經一段實質上沒有共軛物釋放的時期)。例如,共軛物可經6小時、12小時、24小時或48小時釋放。在特定的實施態樣中,共軛物係經一週或一個月釋放。
V. 套組及裝置
V. 套組及裝置
本發明提供各種用於方便及/或有效地進行本發明之方法的套組及裝置。套組通常包含充分的組分量及/或數目以容許使用者進行多次的個體治療及/或進行多次實驗。
在一個實施態樣中,本發明提供用於試管內或活體內抑制腫瘤細胞生長之套組,其包含本發明之共軛物及/或粒子或本發明之共軛物及/或粒子隨意地與任何其他的活性劑組合之組合。
套組可另外包含包裝及用法說明及/或用於形成調配組成物之遞送劑。遞送劑可包含食鹽水、緩衝溶液或本文所揭示之任何遞送劑。可改變各組分的量以賦予一致、可重現的較高濃度之食鹽水或簡單的緩衝液調配物。亦可改變組分以增加共軛物及/或粒子在緩衝溶液中經一段時期及/或在各種條件下的穩定性。
本發明提供可併入本發明之共軛物及/或粒子的裝置。該等裝置含有能立即遞送至有其需要的個體(諸如人類患者)之穩定的調配物。在一些實施態樣中,個體患有癌症。
裝置的非限制性實例包括泵、導管、針、經皮貼片、加壓嗅吸遞送裝置、離子電泳法裝置、多層微流體裝置。裝置可根據單次、多次或分次給藥方案而用於遞送本發明之共軛物及/或粒子。裝置可穿過生物組織、皮內、皮下或肌內而用於遞送本發明之共軛物及/或粒子。
VI. 定義
VI. 定義
如本文所使用之術語「化合物」意謂著包括所述之結構的所有立體異構物、幾何異構物、互變異構物及同位素。在本發明申請案中,化合物可與共軛物交換使用。因此,如本文所使用之共軛物亦意謂著包括所述之結構的所有立體異構物、幾何異構物、互變異構物及同位素。
本文所述之化合物可為不對稱(例如具有一或多個立構中心)。除非另有其他的指示,否則意欲包括所有的立體異構物,諸如鏡像異構物和非鏡像異構物。含有經不對稱取代之碳原子的本發明之化合物可以光學活性或消旋形式單離。在本技術中已知如何自光學活性起始材料製備光學活性形式之方法,諸如藉由消旋混合物之解析或藉由立體選擇性合成。烯烴(C=N雙鍵)及類似者的許多幾何異構物亦可存在本文所述之化合物中,且所有此等穩定的異構物均涵蓋在本發明中。說明本發明之化合物的順式及反式幾何異構物,且可將彼等分離成異構物之混合物或經單離之異構物形式。
本發明之化合物亦包括互變異構物形式。互變異構物形式係起因於單鍵與相鄰的雙鍵互換及質子的伴隨遷移。互變異構物形式包括質子轉移互變異構物,其為具有相同的實驗式及總電荷之異構物質子化狀態。質子轉移互變異構物的實例包括酮-烯醇對、醯胺-醯亞胺酸對、內醯胺-內醯亞胺對、醯胺-醯亞胺酸對、烯胺-亞胺對及其中質子可佔據雜環系統之二或更多個位置的環狀形式,諸如1H-和3H-咪唑、1H-、2H-和4H-1,2,4-三唑、1H-和2H-異吲哚及1H-和2H-吡唑。互變異構物形式可呈平衡狀態或藉由適當的取代而立體地鎖成一種形式。
本發明之化合物亦包括出現在中間物或最終化合物中的原子之所有的同位素。「同位素」係指具有相同的原子序但由核中不同的中子數所致之不同的質量數之原子。例如,氫之同位素包括氚及氘。
本發明之化合物及鹽可藉由例行的方法與溶劑或水分子組合以形成溶劑合物及水合物而製得。
如本文所使用之術語「個體」或「患者」係指可出於例如實驗、治療、診斷及/或預防目的而投予粒子之任何有機體。典型的個體包括動物(例如哺乳動物,諸如小鼠、大鼠、兔子、天竺鼠、牛、豬、綿羊、馬、狗、貓、倉鼠、駱馬、非人類靈長類動物和人類)。
如本文所使用之術語「治療」或「預防」可包括預防在可能易罹患疾病、病症及/或病況但尚未被確診為患有疾病、病症或病況之動物中發生的疾病、病症或病況;抑制疾病、病症或病況,例如阻礙其進程;及緩解疾病、病症或病況,例如造成疾病、病症及/或病況消退。治療疾病、病症或病況可包括改善特定的疾病、病症或病況中至少一種症狀,即使根本的病理生理未受影響,諸如藉由投予止痛劑治療個體的疼痛,儘管此種藥劑不治療疼痛的原因。
如本文所使用之「靶定」應意指經靶定之構築體結合之位點。標靶可於活體內或試管內。在特定的實施態樣中,標靶可為白血病或腫瘤(例如腦、肺(小細胞和非小細胞)、卵巢、前列腺、乳房及結腸之腫瘤,以及其他的惡性腫瘤及肉瘤)中發現的癌細胞。在又其他的實施態樣中,標靶可指靶定之部分或配體結合之分子結構,諸如不全抗原、抗原決定區、受體、dsDNA片段、碳水化合物或酶。標靶可為組織類型,例如神經元組織、腸組織、胰臟組織、肝、腎、前列腺、卵巢、肺、骨髓或乳房組織。
可用作為方法或共軛物或粒子之標靶的「靶細胞」通常為動物細胞,例如哺乳動物細胞。本發明之方法可用於試管內(亦即在細胞培養物中)或活體內修飾活細胞的細胞功能,其中細胞構成動物組織的一部分或者存在動物組織中。因此,靶細胞可包括例如血液、淋巴組織、消化道內襯細胞(諸如口腔及咽部黏膜)、形成小腸絨毛之細胞、大腸內襯細胞、動物的呼吸系統(鼻道/肺)內襯細胞(其可藉由吸入本發明主題而接觸)、皮膚/表皮細胞、陰道和直腸細胞、內臟器官之細胞(包括胎盤細胞和所謂的血/腦障壁細胞)等。靶細胞通常表現至少一種類型的HSP90。在一些實施態樣中,靶細胞可為表現HSP90之細胞且以本文所述之共軛物靶定,且靠近受到共軛物之活性劑釋放影響的細胞。例如,在腫瘤附近表現HSP90之血管可為標靶,而在位點上釋放之活性劑會影響腫瘤。
術語「治療效應」係經本技術認可且係指由藥理活性物質在動物,特別為哺乳動物,且更特別為人類中引起的局部或全身性效應。術語因此意指意欲用於診斷、治癒、減輕、治療或預防疾病、病症或病況之任何物質,以增進動物(例如人類)之所欲身體或精神發展及狀態。
術語「調節」係經本技術認可且係指調升(亦即活化或刺激)、調降(亦即抑制或制止)反應或此二者之組合或分開。調節通常係與可相對於經治療之實體的內部或外部之基線或參考物相比。
如本文所使用之「非經腸投予」意指藉由除了通過消化道(腸道)或非侵入式局部途徑以外的任何方法投予。例如,非經腸投予可包括經靜脈內、皮內、腹膜內、胸膜內、氣管內、骨內、腦內、鞘內、肌肉內、皮下、結膜下(subjunctivally)、藉由注射及藉由輸注投予患者。
如本文所使用之「局部投予」意指非侵入式投予皮膚、孔口或黏膜。局部投予可經局部遞送,亦即治療劑可在遞送區域提供局部效應,而無需全身性暴露或具有最小的全身性暴露。一些局部用調配物可提供全身性效應,例如經由吸附至個體的血流內。局部投予可包括但不限於皮膚和經皮投予、頰內投予、鼻腔內投予、陰道內投予、膀胱內投予、眼睛投予及直腸投予。
如本文所使用之「腸道投予」意指通過胃腸道而經由吸收投予。腸道投予可包括經口和舌下投予、胃部投予或直腸投予。
如本文所使用之「肺部投予」意指藉由吸入而投予肺或氣管內投予。如本文所使用之術語「吸入」係指攝入空氣至肺泡內。攝入空氣可通過口或鼻發生。
如本文可交換使用之術語「充足」及「有效」係指達成一或多種所欲結果所需要的量(例如質量、體積、劑量、濃度及/或時期)。「治療有效量」為實現可預見的至少一種症狀或特別的病況或病症之改進或預防、實現可預見的提高之壽命預期性或概括改進患者的生活品質所需的至少最低濃度。治療有效量因此取決於特定的生物活性分子及欲治療之特定的病況或病症而定。在本技術中已知許多活性劑(諸如抗體)的治療有效量。本文所述之例如用於治療特定的病症之化合物及組成物的治療有效量可由熟習本技術領域者(諸如醫師)熟知的技術測定。
如本文可交換使用之術語「生物活性劑」及「活性劑」包括而不限於在體內局部或全身性作用的生理或藥理活性物質。生物活性劑為用於治療之物質(例如治療劑)、預防之物質(例如預防劑)、診斷之物質(例如診斷劑)、治癒或減輕疾病或病之物質、影響身體結構或功能之物質或在置於預定的生理環境後變成生物活性或更具活性之前藥。
術語「前藥」係指在試管內及/或活體內轉化成生物活性形式之藥劑,包括小有機分子、肽、核酸或蛋白質。可使用前藥,因為彼等在一些情況下比親體化合物(活性化合物)更容易投予。例如,前藥可藉由經口投予而為生物可利用的,而親體化合物則不然。與親體藥物相比,前藥亦可在醫藥組成物中具有改進的溶解度。前藥亦可具有比親體藥物更低的毒性。前藥可以各種機制轉化成親體藥物,包括酶製程和代謝水解。Harper, N.J.之(1962)Drug Latentiation in Jucker, ed.Progress in Drug Research
,4:221-294;Morozowich等人之(1977) Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed.Design of Biopharmaceutical Properties through Prodrugs and Analogs
, APhA; Acad. Pharm. Sci.;E. B. Roche編輯之(1977)Bioreversible Carriers in Drug in Drug Design, Theory and Application
, APhA;H. Bundgaard編輯之(1985)Design of Prodrugs
, Elsevier;Wang等人之(1999)Prodrug approaches to the improved delivery of peptide drug, Curr. Pharm. Design. 5(4):265-287;Pauletti等人之(1997)Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev.
27:235-256;Mizen等人之(1998)The Use of Esters as Prodrugs for Oral Delivery of β-Lactam antibiotics, Pharm. Biotech. 11:345-365;Gaignault等人之(1996)Designing Prodrugs and Bioprecursors I. Carrier Prodrugs, Pract. Med. Chem.671-696;M. Asgharnejad(2000)Improving Oral Drug Transport Via Prodrugs, in G. L. Amidon, P. I. Lee和E. M. Topp編輯之Transport Processes in Pharmaceutical Systems
, Marcell Dekker, p. 185-218;Balant等人之(1990)Prodrugs for the improvement of drug absorption via different routes of administration,Eur. J. Drug Metab. Pharmacokinet
., 15(2):143-53;Balimane和Sinko(1999)Involvement of multiple transporters in the oral absorption of nucleoside analogues,Adv. Drug Delivery Rev
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. 20(1):1-12;Bundgaard(1979)Bioreversible derivatization of drugs--principle and applicability to improve the therapeutic effects of drugs,Arch. Pharm. Chemi
. 86(1):1-39;H. Bundgaard編輯之(1985)Design of Prodrugs,
New York:Elsevier;Fleisher等人之(1996)Improved oral drug delivery:solubility limitations overcome by the use of prodrugs,Adv. Drug Delivery Rev.
19(2):115-130;Fleisher等人之(1985)Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting,Methods Enzymol
. 112:360-81;Farquhar D.等人之(1983)Biologically Reversible Phosphate-Protective Groups,J. Pharm. Sci
., 72(3):324-325;Han, H.K. 等人之(2000) Targeted prodrug design to optimize drug delivery,AAPS PharmSci
., 2(1):E6;Sadzuka Y.(2000)Effective prodrug liposome and conversion to active metabolite,Curr. Drug Metab.
, 1(1):31-48;D.M. Lambert(2000)Rationale and applications of lipids as prodrug carriers,Eur. J. Pharm. Sci.
, 11 Suppl. 2:S15-27;Wang, W. 等人之(1999)Prodrug approaches to the improved delivery of peptide drugs.Curr. Pharm. Des.,
5(4):265-87。
如本文所使用之術語「生物可相容的」係指對接受者通常為無毒的且不引起接受者任何顯著的副作用之材料連同其任何代謝物或降解產物。一般而言,生物可相容的材料為在投予患者時不誘出顯著的發炎或免疫反應之材料。
如本文所使用之術語「生物可降解的」通常係指在生理條件下降解或侵蝕成能被個體代謝、消除或排出之較小的單元或化學物種之材料。降解時間係隨著組成物及形態起作用。降解時間可自數小時至數週。
如本文所使用之術語「醫藥上可接受之」係指依照諸如美國食品及藥物管理局之機構的指南,在健全的醫學判斷範圍內適合與人類及動物接觸使用而無過度毒性、刺激、過敏反應或與合理的利益/風險比相稱的其他問題或併發症之化合物、材料、組成物及/或劑型。如本文所使用之「醫藥上可接受之載劑」係指促進組成物於活體內遞送之醫藥調配物的所有組分。醫藥上可接受之載劑包括但不限於稀釋劑、防腐劑、黏合劑、潤滑劑、崩散劑、膨脹劑、填充劑、穩定劑及彼之組合。
如本文所使用之術語「分子量」通常係指材料之質量或平均質量。若為聚合物或寡聚物,則分子量可指總體聚合物之相對平均鏈長或相對鏈質量。事實上,聚合物及寡聚物之分子量可以各種方式評估及特徵化,包括凝膠滲透層析術(GPC)或毛細管黏度測定法。GPC分子量係以重量平均分子量(Mw
)而非數量平均分子量(Mn
)記述。毛細管黏度測定法係使用特別設定的濃度、溫度及溶劑條件自稀釋的聚合物溶液所測定之固有黏度提供分子量之估計值。
如本文所使用之術語「小分子」通常係指分子量少於2000 g/mol、少於1500 g/mol、少於1000 g/mol、少於800 g/mol或少於500 g/mol之有機分子。小分子為非聚合物及/或非寡聚物。
如本文所使用之術語「親水性」係指具有與水輕易地相互作用的強極性基團之物質。
如本文所使用之術語「疏水性」係指對水缺乏親和性;具有排斥且不吸收水以及不溶解於水中或不與水混合的傾向之物質。
如本文所使用之術語「親脂性」係指對脂質具有親和性之化合物。
如本文所使用之術語「兩親性」係指結合親水性與親脂性(疏水性)之分子。如本文所使用之「兩親性材料」係指含有疏水性或更疏水性寡聚物或聚合物(例如生物可降解的寡聚物或聚合物)及親水性或更親水性寡聚物或聚合物之材料。
如本文所使用之術語「靶定之部分」係指結合或定位至特定的場域之部分。部分可為例如蛋白質、核酸、核酸類似物、碳水化合物或小分子。場域可為組織、特別的細胞類型或亞細胞區室。在一些實施態樣中,靶定之部分可特異性地結合至經選擇之分子。
如本文所使用之術語「反應性偶合基團」係指能夠與第二官能基反應以形成共價鍵之任何化學官能基。反應性偶合基團之選擇係在那些熟習本技術領域者的能力範圍內。反應性偶合基團的實例可包括包括一級胺 (-NH2
)及胺反應性鍵聯基團,諸如異硫氰酸酯、異氰酸酯、醯基疊氮化物、NHS酯、磺醯氯、醛、乙二醛、環氧化物、環氧乙烷、碳酸酯、芳基鹵化物、醯亞胺酯、碳二醯亞胺、酐和氟苯酯。大部分的該等基團係藉由醯化或烷基化共軛至胺。反應性偶合基團的實例可包括醛(-COH)及醛反應性鍵聯基團,諸如醯肼、烷氧基胺和一級胺。反應性偶合基團的實例可包括巰基(-SH)及氫硫基反應性基團,諸如順丁烯二醯亞胺、鹵乙醯基和吡啶基二硫化物。反應性偶合基團的實例可包括光反應性偶合基團,諸如芳基疊氮化物或二氮雜環丙烷。偶合反應可包括使用觸媒、熱、pH緩衝劑、光或彼之組合。
如本文所使用之術語「保護基」係指可添加至及/或取代另一所欲官能基以保護所欲官能基免於特定的反應條件,且選擇性地移除及/或置換以去保護或暴露所欲官能基之官能基。熟習本技術領域者已知保護基。適合的保護基可包括那些在Greene and Wuts, Protective Groups in Organic Synthesis,(1991)中所述者。酸敏感性保護基包括二甲氧基三苯甲基(DMT)、三級丁基胺甲酸酯(tBoc)和三氟乙醯基(tFA)。鹼敏感性保護基包括9-茀基甲氧基羰基(Fmoc)、異丁基(iBu)、苯甲醯基(Bz)和苯氧基乙醯基(pac)。其他的保護基包括乙醯胺基甲基、乙醯基、三級戊氧基羰基、苯甲基、苯甲氧基羰基、2-(4-聯苯基)-2-丙氧基羰基、2-溴苯甲氧基羰基、三級丁基、三級丁氧基羰基、1-碳苯并草醯胺基-2,2.2-三氟乙基、2,6-二氯苯甲基、2-(3,5-二甲氧基苯基)-2-丙氧基羰基、2,4-二硝苯基、二硫雜丁二醯基、甲醯基、4-甲氧基苯磺醯基、4-甲氧基苯甲基、4-甲基苯甲基、鄰-硝苯基次磺醯基(o-nitrophenylsulfenyl)、2-苯基-2-丙氧基羰基、α-2,4,5-四甲基苯甲氧基羰基、對-甲苯磺醯基、𠮿基、苯甲酯、N-羥基丁二醯亞胺酯、對-硝基苯甲酯、對-硝基苯酯、苯酯、對-硝基碳酸酯、對-硝基苯甲基碳酸酯、三甲基矽基和五氯苯酯。
如本文所使用之術語「活化酯」係指羧酸之烷基酯,其中烷基為使得羰基易遭受攜有胺基之分子親核攻擊之良好的脫離基。活化酯因此易遭受胺解且與胺反應以形成醯胺。活化酯含有羧酸酯基-CO2
R,其中R為脫離基。
術語「烷基」係指飽和脂族基團之基,包括直鏈烷基、支鏈烷基、環烷基(脂環基)、經烷基取代之環烷基和經環烷基取代之烷基。
在一些實施態樣中,直鏈或支鏈烷基具有30個或更少的碳原子於其主鏈中(例如直鏈為C1
-C30
,支鏈為C3
-C30
)、20個或更少、12個或更少或7個或更少的碳原子。同樣地,在一些實施態樣中,環烷基具有3至10個碳原子於其環結構中,例如具有5、6或7個碳原子於環結構中。如整篇說明書、實施例及申請專利範圍中所使用之術語「烷基」(或「低碳烷基」)意欲包括「未經取代之烷基」及「經取代之烷基」二者,後者係指烷基部分具有一或多個置換在烴主鏈的一或多個碳上的氫之取代基。此等取代基包括但不限於鹵素、羥基、羰基(諸如羧基、烷氧基羰基、甲醯基或醯基)、硫羰基(諸如硫酯、硫乙酸酯或硫甲酸酯)、烷氧基、磷醯基、磷酸酯、膦酸酯、次膦酸酯、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、氫硫基、烷硫基、硫酸酯、磺酸酯、胺磺醯基、磺醯胺基、磺醯基、雜環基、芳烷基或芳族或雜芳族部分。
除非另有其他的碳數目指定,否則如本文所使用之「低碳烷基」意指如上文所定義之烷基,但是其具有1至10個碳原子或1至6個碳原子於其主鏈結構中。同樣地,「低碳烯基」及「低碳炔基」具有類似的鏈長度。在一些實施態樣中,烷基為低碳烷基。在一些實施態樣中,本文稱為烷基之取代基為低碳烷基。
那些熟習本技術領域者應理解在烴鏈上經取代之部分若適當時本身可經取代。例如,經取代之烷基的取代基可包括鹵素、羥基、硝基、硫醇、胺基、疊氮基、亞胺基、醯胺基、磷醯基(包括膦酸酯和次膦酸酯)、磺醯基(包括硫酸酯、磺醯胺基、胺磺醯基和磺酸酯)及矽基,以及醚、烷硫基、羰基(包括酮、醛、羧酸酯和酯)、 -CF3
、-CN及類似者。環烷基可以相同的方式經取代。
如本文所使用之術語「雜烷基」係指含有至少一個雜原子的直鏈或支鏈、或環狀含碳基團或彼之組合。適合的雜原子包括但不限於O、N、Si、P、Se、B和S,其中磷及硫原子隨意地經氧化,及氮雜原子隨意地經四級化。雜烷基可經取代,如上文就烷基所定義。
術語「烷硫基」係指具有附著至其之硫基團的如上文所定義之烷基。在一些實施態樣中,「烷硫基」部分係以-S-烷基、-S-烯基及-S-炔基中之一者表示。代表性烷硫基包括甲硫基和乙硫基。術語「烷硫基」亦包含環烷基、烯烴基和環烯烴基和炔烴基。「芳硫基」係指芳基或雜芳基。烷硫基可經取代,如上文就烷基所定義。
術語「烯基」及「炔基」係指具有類似於上述烷基的長度及可能的取代烷基,但是分別含有至少一個雙鍵或三鍵的不飽和脂族基團。
如本文所使用之術語「烷氧基(alkoxyl或alkoxy)」係指具有附著至其之氧基團的如上文所定義之烷基。代表性烷氧基包括甲氧基、乙氧基、丙氧基和三級丁氧基。「醚」為兩個藉由氧共價鍵聯之烴。因此,使得烷基成為醚之烷基的取代基為或類似於烷氧基,諸如可以 -O-烷基、-O-烯基和-O-炔基中之一者表示。芳氧基可以 -O-芳基或O-雜芳基表示,其中芳基及雜芳基係如下文所定義。烷氧基及芳氧基可經取代,如上文就烷基所述。
術語「胺」及「胺基」係經本技術認可且係指未經取代及經取代之胺二者,例如可以下列通式表示之部分:
其中R9 、R10 和R’10 各自獨立地表示氫、烷基、烯基、-(CH2 )m -R8 ,或採R9 和R10 與彼等所附著之N原子一起完成具有4至8個原子於環結構中的雜環;R8 表示芳基、環烷基、環烯基、雜環或多環;且m為0或在1至8之範圍內的整數。在一些實施態樣中,R9 或R10 中僅有一者可為羰基,例如R9 、R10 與氮不一起形成醯亞胺。在又其他的實施態樣中,術語「胺」不包含醯胺,例如其中R9 和R10 中之一者表示羰基。在額外的實施態樣中,R9 和R10( 及隨意的R’10 )各自獨立地表示氫、烷基或環烷基、烯基或環烯基或炔基。如此,如本文所使用之術語「烷基胺」意指具有附著至其之經取代或未經取代之烷基的如上文所定義之胺基團,亦即R9 和R10 中之至少一者為烷基。
其中R9 、R10 和R’10 各自獨立地表示氫、烷基、烯基、-(CH2 )m -R8 ,或採R9 和R10 與彼等所附著之N原子一起完成具有4至8個原子於環結構中的雜環;R8 表示芳基、環烷基、環烯基、雜環或多環;且m為0或在1至8之範圍內的整數。在一些實施態樣中,R9 或R10 中僅有一者可為羰基,例如R9 、R10 與氮不一起形成醯亞胺。在又其他的實施態樣中,術語「胺」不包含醯胺,例如其中R9 和R10 中之一者表示羰基。在額外的實施態樣中,R9 和R10( 及隨意的R’10 )各自獨立地表示氫、烷基或環烷基、烯基或環烯基或炔基。如此,如本文所使用之術語「烷基胺」意指具有附著至其之經取代或未經取代之烷基的如上文所定義之胺基團,亦即R9 和R10 中之至少一者為烷基。
術語「醯胺基」係經本技術認可為經胺基取代之羰基且包括可以下列通式表示的部分:
其中R9 和R10 係如上文所定義。
其中R9 和R10 係如上文所定義。
如本文所使用之「芳基」係指C5
-C10
-員芳族、雜環、稠合芳族、稠合雜環、雙芳族或雙雜環系統。廣義地定義,如本文所使用之「芳基」包括5-、6-、7-、8-、9-和10-員單環芳族基團,其可包括0至4個雜原子,例如苯、吡咯、呋喃、噻吩、咪唑、㗁唑、噻唑、三唑、吡唑、吡啶、吡𠯤、嗒𠯤和嘧啶及類似者。具有雜原子於環結構中的該等芳基亦可稱為「芳基雜環」或「雜芳族」。芳族環可在一或多個環位置經一或多個取代基取代,包括但不限於鹵素、疊氮化物、烷基、芳烷基、烯基、炔基、環烷基、羥基、烷氧基、胺基(或四級胺基)、硝基、氫硫基、亞胺基、醯胺基、膦酸酯、次膦酸酯、羰基、羧基、矽基、醚、烷硫基、磺醯基、磺醯胺基、酮、醛、酯、雜環基、芳族或雜芳族部分-CF3
、-CN及彼之組合。
術語「芳基」亦包括具有二或更多個環狀環的多環狀環系統,其中二或更多個碳為兩個相鄰的環共用(亦即「稠合環」),其中環中之至少一者為芳族,例如其他環狀環或環類可為環烷基、環烯基、環炔基、芳基及/或雜環。雜環的實例包括但不限於苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并苯硫基、苯并㗁唑基、苯并㗁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異㗁唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH咔唑基、咔啉基、苯并二氫哌喃基、苯并哌喃基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻𠯤基、二氫呋喃并[2,3b]四氫呋喃、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基(indolenyl)、吲哚啉基、吲哚𠯤基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯并呋喃基、異苯并二氫哌喃基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異㗁唑基、甲二氧基苯基、嗎啉基、萘啶基、八氫異喹啉基、㗁二唑基、1,2,3-㗁二唑基、1,2,4-㗁二唑基、1,2,5-㗁二唑基、1,3,4-㗁二唑基、㗁唑啶基、㗁唑基、吲哚酮基、嘧啶基、啡啶基、啡啉基、啡𠯤基、啡噻𠯤基、啡㗁噻基、啡㗁𠯤基、酞𠯤基、哌𠯤基、哌啶基、哌啶酮基、4-哌啶酮基、向日葵基、喋啶基、嘌呤基、哌喃基、吡𠯤基、吡唑啶基、吡唑啉基、吡唑基、嗒𠯤基、吡啶并㗁唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯啶基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹𠯤基、喹㗁啉基、啶基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四唑基、6H-1,2,5-噻二𠯤基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻嗯基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并㗁唑基、噻吩并咪唑基、苯硫基和𠮿基。環中之一或多者可經取代,如上文就「芳基」所定義。
如本文所使用之術語「芳烷基」係指經芳基(例如芳族或雜芳族基團)取代之烷基。
如本文所使用之術語「碳環」係指其中環之各原子為碳的芳族或非芳族環。
如本文所使用之「雜環(Heterocycle或Heterocyclic)」係指之環狀基團,其為經由環碳或氮附著之含有3至10個環原子(例如5至6個環原子)的單環狀或雙環狀環,由碳及1至4個各自選自由非過氧化氧、硫和N(Y)(其中Y不存在或為H、O、(C1
-C10
)烷基、苯基或苯甲基)所組成之群組的雜原子所組成、及隨意地含有1至3個雙鍵、及隨意地經一或多個取代基取代。雜環狀環的實例包括但不限於苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并苯硫基、苯并㗁唑基、苯并㗁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異㗁唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氫哌喃基、苯并哌喃基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻𠯤基、二氫呋喃并[2,3-b]四氫呋喃、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、吲哚啉基、吲哚𠯤基、吲哚基、3H-吲哚基、靛紅醯基、異苯并呋喃基、異苯并二氫哌喃基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異㗁唑基、甲二氧基苯基、嗎啉基、萘啶基、八氫異喹啉基、㗁二唑基、1,2,3-㗁二唑基、1,2,4-㗁二唑基、1,2,5-㗁二唑基、1,3,4-㗁二唑基、㗁唑啶基、㗁唑基、氧雜環庚基(oxepanyl)、氧雜環丁基、吲哚酮基、嘧啶基、啡啶基、啡啉基、啡𠯤基、啡噻𠯤基、啡㗁噻基、啡㗁𠯤基、酞𠯤基、哌𠯤基、哌啶基、哌啶酮基、4-哌啶酮基、向日葵基、喋啶基、嘌呤基、哌喃基、吡𠯤基、吡唑啶基、吡唑啉基、吡唑基、嗒𠯤基、吡啶并㗁唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯啶基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹𠯤基、喹㗁啉基、啶基、四氫呋喃基、四氫異喹啉基、四氫哌喃基、四氫喹啉基、四唑基、6H-1,2,5-噻二𠯤基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻嗯基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并㗁唑基、噻吩并咪唑基、苯硫基及𠮿基。雜環基團可在一或多個位置上經一或多個取代基取代,如上文就烷基及芳基所定義,例如經鹵素、烷基、芳烷基、烯基、炔基、環烷基、羥基、胺基、硝基、氫硫基、亞胺基、醯胺基、磷酸酯、膦酸酯、次膦酸酯、羰基、羧基、矽基、醚、烷硫基、磺醯基、酮、醛、酯、雜環基、芳族或雜芳族部分、-CF3
和-CN取代。
術語「羰基」係經本技術認可且包括可以下列通式表示的此等部分:
其中X為鍵或表示氧或硫,且R11 表示氫、烷基、環烷基、烯基、環烯基或炔基,R’11 表示氫、烷基、環烷基、烯基、環烯基或炔基。其中X為氧,且R11 或R’11 不為氫,上式表示「酯」。其中X為氧,且R11 係如上文所定義,此部分在本文被稱為羧基,且特別地當R11 為氫時,則上式表示「羧酸」。其中X為氧,且R’11 為氫,上式表示「甲酸酯」。其中上式之氧原子通常經硫置換,上式表示「硫代羰基」。其中X為硫,且R11 或R’11 不為氫,上式表示「硫酯」。其中X為硫,且R11 為氫,上式表示「硫代羧酸」。其中X為硫,且R’11 為氫,上式表示「硫甲酸酯」。另一方面,其中X為鍵,且R11 不為氫,上式表示「酮」基。其中X為鍵,且R11 為氫,上式表示「醛」基。
其中X為鍵或表示氧或硫,且R11 表示氫、烷基、環烷基、烯基、環烯基或炔基,R’11 表示氫、烷基、環烷基、烯基、環烯基或炔基。其中X為氧,且R11 或R’11 不為氫,上式表示「酯」。其中X為氧,且R11 係如上文所定義,此部分在本文被稱為羧基,且特別地當R11 為氫時,則上式表示「羧酸」。其中X為氧,且R’11 為氫,上式表示「甲酸酯」。其中上式之氧原子通常經硫置換,上式表示「硫代羰基」。其中X為硫,且R11 或R’11 不為氫,上式表示「硫酯」。其中X為硫,且R11 為氫,上式表示「硫代羧酸」。其中X為硫,且R’11 為氫,上式表示「硫甲酸酯」。另一方面,其中X為鍵,且R11 不為氫,上式表示「酮」基。其中X為鍵,且R11 為氫,上式表示「醛」基。
如本文所使用之術語「單酯」係指二羧酸之類似物,其中羧酸之一經官能化為酯及其他羧酸為游離羧酸或羧酸之鹽。單酯的實例包括但不限於丁二酸、戊二酸、己二酸、辛二酸、癸二酸、壬二酸、草酸和順丁烯二酸之單酯。
如本文所使用之術語「雜原子」意指除了碳或氫以外的任何元素之原子。雜原子的實例為硼、氮、氧、磷、硫和硒。其他有用的雜原子包括矽和砷。
如本文所使用之術語「硝基」意指-NO2
;術語「鹵素」指明-F、-Cl、-Br或-I;術語「氫硫基」意指 -SH;術語「羥基」意指-OH;及術語「磺醯基」意指 -SO2
-。
如本文所使用之術語「經取代」係指本文所述化合物之所有可允許的取代基。最廣義而言,可允許的取代基包括有機化合物之非環和環狀、支鏈和非支鏈、碳環和雜環、芳族和非芳族取代基。例示性取代基包括但不限於鹵素、羥基或含有任何數目的碳原子(例如1至14個碳原子)之任何其他的有機群組(grouping),且隨意地包括在直鏈、支鏈或環狀結構格式中的一或多個雜原子,諸如氧、硫或氮群組。代表性取代基包括烷基、經取代之烷基、烯基、經取代之烯基、炔基、經取代之炔基、苯基、經取代之苯基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、鹵基、羥基、烷氧基、經取代之烷氧基、苯氧基、經取代之苯氧基、芳氧基、經取代之芳氧基、烷硫基、經取代之烷硫基、苯硫基、經取代之苯硫基、芳硫基、經取代之芳硫基、氰基、異氰基、經取代之異氰基、羰基、經取代之羰基、羧基、經取代之羧基、胺基、經取代之胺基、醯胺基、經取代之醯胺基、磺醯基、經取代之磺醯基、磺酸、磷醯基、經取代之磷醯基、膦醯基、經取代之膦醯基、聚芳基(polyaryl)、經取代之聚芳基、C3
-C20
環、經取代之C3
-C20
環、雜環、經取代之雜環、胺基酸、肽和多肽基。
雜原子(諸如氮)可具有符合雜原子價位的本文所述之有機化合物的氫取代基及/或任何可允許的取代基。應暸解「取代」或「經取代」包括如下隱含條件:此種取代係依照經取代之原子及取代基的經允許之價位,及取代得到穩定的化合物,亦即不會例如藉由重排、結晶或消除而自發地發生轉變之化合物。
在廣義的態樣中,可允許的取代基包括有機化合物之非環和環狀、支鏈和非支鏈、碳環和雜環、芳族和及非芳族取代基。例示性取代基包括例如那些本文所述者。可允許的取代基對於適當有機化合物而言可為一或多個且相同或不同。雜原子(諸如氮)可具有符合雜原子價位的本文所述之有機化合物的氫取代基及/或任何可允許的取代基。
在各種實施態樣中,取代基係選自烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺甲酸酯、羧基、氰基、環烷基、酯、醚、甲醯基、鹵素、鹵烷基、雜芳基、雜環基、羥基、酮、硝基、磷酸酯、硫化物、亞磺醯基、磺醯基、磺酸、磺醯胺和硫酮,各者隨意地經一或多個適合的取代基取代。在一些實施態樣中,取代基係選自烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺甲酸酯、羧基、環烷基、酯、醚、甲醯基、鹵烷基、雜芳基、雜環基、酮、磷酸酯、硫化物、亞磺醯基、磺醯基、磺酸、磺醯胺和硫酮,其中烷氧基、芳氧基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、胺甲酸酯、羧基、環烷基、酯、醚、甲醯基、鹵烷基、雜芳基、雜環基、酮、磷酸酯、硫化物、亞磺醯基、磺醯基、磺酸、磺醯胺和硫酮之各者可另外經一或多個適合的取代基取代。
取代基的實例包括但不限於鹵素、疊氮化物、烷基、芳烷基、烯基、炔基、環烷基、羥基、烷氧基、胺基、硝基、氫硫基、亞胺基、醯胺基、膦酸酯、次膦酸酯、羰基、羧基、矽基、醚、烷硫基、磺醯基、磺醯胺基、酮、醛、硫酮、酯、雜環基、-CN、芳基、芳氧基、全鹵烷氧基、芳烷氧基、雜芳基、雜芳氧基、雜芳基烷基、雜芳烷氧基、疊氮基、烷硫基、側氧基、醯基烷基、羧基酯、甲醯胺基、醯氧基、胺基烷基、烷基胺基芳基、烷基芳基、烷基胺基烷基、烷氧基芳基、芳基胺基、芳烷基胺基、烷基磺醯基、甲醯胺基烷基芳基、甲醯胺基芳基、羥烷基、鹵烷基、烷基胺基烷基羧基、胺基甲醯胺基烷基、氰基、烷氧基烷基、全鹵烷基、芳基烷氧基烷基及類似者。在一些實施態樣中,取代基係選自氰基、鹵素、羥基和硝基。
如本文所使用之術語「共聚物」通常係指由二或更多種不同的單體組成之單一聚合物材料。共聚物可具有任何形式,例如隨機、嵌段或接枝形式。共聚物可具有任何端基,包括封端或酸端基。
如本文所使用之術語「平均粒徑」通常係指組成物中的粒子之統計平均粒徑(直徑)。本質上為球體粒子的直徑可稱為物理或流體動力直徑。非球體粒子的直徑可稱為流體動力直徑。如本文所使用之非球體粒子的直徑可指在粒子表面上介於兩點之間的最大直線距離。平均粒徑可使用本技術中已知的方法測量,諸如動態光散射。當第一粒子群體之統計平均粒徑係在第二粒子群體之統計平均粒徑的20%之內時,例如在15%之內或在10%之內,則兩個群體可說是具有「實質上等效的平均粒徑」。
如本文交換使用之術語「單分散」及「均勻的粒子分布」描述全部具有相同或幾乎相同大小的粒子、微粒子或奈米粒子之群體。如本文使用之單分散分布係指其中90%之分布係落在平均粒徑的5%之內的粒子分布。
術語「多肽」、「肽」及「蛋白質」通常係指胺基酸殘基之聚合物。如本文所使用之術語亦適用於其中一或多種胺基酸為對應的天然生成胺基酸之化學類似物或經修飾之衍生物或為非天然胺基酸之胺基酸聚合物。如本文概括使用之術語「蛋白質」係指藉由肽鍵而彼此鍵聯的胺基酸之聚合物,以形成鏈長度足以產生三級及/或四級結構之多肽。術語「蛋白質」排除定義上的小型肽,小型肽缺乏被視為蛋白質必要的較高級之必需結構。
術語「核酸」、「多核苷酸」及「寡核苷酸」可交換使用且指呈直線或圓形構形及呈單股或雙股形式的去氧核糖核苷酸或核糖核苷酸聚合物。該等術語不應解釋為限制有關的聚合物長度。術語可包含天然核苷酸之已知的類似物,以及在鹼、糖及/或磷酸酯部分(例如硫代磷酸酯主鏈)中經修飾之核苷酸。一般及除非另有其他指定,否則特定的核苷酸之類似物具有相同的鹼配對特異性,亦即A之類似物係與T鹼配對。術語「核酸」為本技術之術語,其係指至少兩個鹼-糖-磷酸酯單體單元之鏈。核苷酸為核酸聚合物之單體單元。術語包括呈信使RNA、反義、質體DNA、質體DNA的一部分或衍生自病毒的基因物質之形式的去氧核糖核酸(DNA)及核糖核酸(RNA)。反義核酸為干擾DNA及/或RNA序列表現的多核苷酸。術語核酸係指至少兩個鹼-糖-磷酸酯組合之鏈。天然核酸具有磷酸酯主鏈。人工核酸可含有其他類型的主鏈,但含有與天然核酸相同的鹼。術語亦包括PNA(肽核酸)、硫代磷酸酯和天然核酸之磷酸酯主鏈的其他變體。
蛋白質、多肽或核酸之「功能片段」為序列與全長蛋白質、多肽或核酸不相同但保留至少一種如同全長蛋白質、多肽或核酸之功能的蛋白質、多肽或核酸。功能片段可具有比對應的天然分子更多、更少或相同數目的殘基,及/或可含有一或多個胺基酸或核苷酸取代。在本技術中熟知測定核酸功能(例如編碼功能、與另一核酸雜交的能力)之方法。同樣地,亦熟知測定蛋白質功能之方法。例如,多肽之DNA結合功能可例如藉由過濾器結合、電泳移動性位移或免疫沉澱檢定法來測定。DNA切割可以凝膠電泳法檢定。蛋白質與其他蛋白質交互作用的能力可例如藉由共免疫沉澱、雙雜交檢定或互補(例如基因或生化互補)來測定。詳見例如Fields等人之(1989)Nature 340:245-246;美國專利第5,585,245號及PCT WO 98/44350。
如本文所使用之術語「鍵聯子」係指可含有雜原子(例如,氮、氧、硫等)及可為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50個原子長度的碳鏈。鍵聯子可經各種取代基取代,包括但不限於氫原子、烷基、烯基、炔基、胺基、烷基胺基、二烷基胺基、三烷基胺基、羥基、烷氧基、鹵素、芳基、雜環、芳族雜環、氰基、醯胺、胺甲醯基、羧酸、酯、硫醚、烷基硫醚、硫醇和脲基。那些熟習本技術領域者認可該等基團中之各者可依次經取代。鍵聯子的實例包括但不限於pH-敏感性鍵聯子、蛋白酶可切割的肽鍵聯子、核酸酶敏感性核酸鍵聯子、脂酶敏感性脂質鍵聯子、醣苷酶敏感性碳水化合物鍵聯子、缺氧敏感性鍵聯子、光可切割的鍵聯子、熱不穩定性鍵聯子、酶可切割的鍵聯子(例如酯酶可切割的鍵聯子)、超音波敏感性鍵聯子和X射線可切割的鍵聯子。
術語「醫藥上可接受之相對離子」係指醫藥上可接受之陰離子或陽離子。在各種實施態樣中,醫藥上可接受之相對離子為醫藥上可接受之離子。例如,醫藥上可接受之相對離子係選自檸檬酸根、蘋果酸根、乙酸根、草酸根、氯化物、溴化物、碘化物、硝酸根、硫酸根、硫酸氫根、磷酸根、酸式磷酸根、異菸鹼酸根、乙酸根、乳酸根、柳酸根、酒石酸根、油酸根、單寧酸根、泛酸根、酒石酸氫根、抗壞血酸根、丁二酸根、順丁烯二酸根、龍膽酸根、反丁烯二酸根、葡萄糖酸根、葡萄糖醛酸根、葡萄糖二酸根、甲酸根、苯甲酸根、麩胺酸根、甲烷磺酸根、乙烷磺酸根、苯磺酸根、對-甲苯磺酸根和雙羥萘酸根(亦即1,1’-亞甲基-雙-(2-羥基-3-萘酸根)。在一些實施態樣中,醫藥上可接受之相對離子係選自氯化物、溴化物、碘化物、硝酸根、硫酸根、硫酸氫根、磷酸根、酸式磷酸根、檸檬酸根、蘋果酸根、乙酸根、草酸根、乙酸根和乳酸根。在特定的實施態樣中,醫藥上可接受之相對離子係選自氯化物、溴化物、碘化物、硝酸根、硫酸根、硫酸氫根和磷酸根。
術語「醫藥上可接受之鹽」係指可存在於本發明之組成物所使用之化合物中的酸基或鹼基之鹽。呈鹼本性的包括在本發明之組成物中的化合物能夠與各種無機及有機酸形成各種鹽。可用於製備此等鹼性化合物的醫藥上可接受之酸加成鹽的酸為那些形成無毒性酸加成鹽(亦即含有藥理上可接受之陰離子的鹽)之酸,該等鹽包括但不限於硫酸鹽、檸檬酸鹽、蘋果酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸鹼酸鹽、乙酸鹽、乳酸鹽、柳酸鹽、檸檬酸鹽、酒石酸鹽、油酸鹽、單寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、丁二酸鹽、順丁烯二酸鹽、龍膽酸鹽、反丁烯二酸鹽、葡萄糖酸鹽、葡萄糖醛酸鹽、葡萄糖二酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、對-甲苯磺酸鹽和雙羥萘酸鹽(亦即1,1’-亞甲基-雙-(2-羥基-3-萘酸鹽)。除了上述酸以外,包括胺基部分之包括在本發明之組成物中的化合物可與各種胺基酸形成醫藥上可接受之鹽。呈酸本性之包括在本發明之組成物中的化合物能夠與各種藥理上可接受之陽離子形成鹼鹽。此等鹽的實例包括鹼金屬或鹼土金屬鹽,且特別為鈣、鎂、鈉、鋰、鋅、鉀和鐵鹽。
若本文所述之化合物係以酸加成鹽獲得,則游離鹼可藉由鹼化酸鹽溶液而獲得。反之,若產物為游離鹼,則依照自鹼化合物製備酸加成鹽的慣例程序,加成鹽(特別為醫藥上可接受之加成鹽)可藉由將游離鹼溶解在適合的有機溶劑中且以酸處理溶液而製得。那些熟習本技術領域者認可使用各種合成方法製備醫藥上可接受之無毒性加成鹽。
醫藥上可接受之鹽可衍生自選自下列之酸:1-羥基-2-萘甲酸、2,2-二氯乙酸、2-羥基乙烷磺酸、2-側氧戊二酸、4-乙醯胺基苯甲酸、4-胺基柳酸、乙酸、己二酸、抗壞血酸、天冬胺酸、苯磺酸、苯甲酸、樟腦酸、樟腦-10-磺酸、癸酸(capric acid/decanoic acid)、己酸(caproic acid/hexanoic acid)、辛酸(caprylic acid/octanoic acid)、碳酸、肉桂酸、檸檬酸、環己基胺磺酸(cyclamic acid)、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡萄糖甲酸、葡萄糖酸、葡萄醣醛酸、麩胺酸、戊二酸、甘油磷酸、乙醇酸、馬尿酸、氫溴酸、氫氯酸、2-羥乙磺酸、異丁酸、乳酸、乳糖醛酸、月桂酸、順丁烯二酸、蘋果酸、丙二酸、苦杏仁酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、菸鹼酸、硝酸、油酸、草酸、棕櫚酸、雙羥萘酸、泛酸、磷酸、丙酸、焦麩胺酸、柳酸、癸二酸、硬脂酸、丁二酸、硫酸、酒石酸、硫氰酸、甲苯磺酸、三氟乙酸和十一烯酸。
術語「生物可利用的」為本技術認可且係指容許本發明主題之投予量或其一部分被其所投予之個體或患者吸收、併入或以其他方式於生理上可利用的本發明主題之形式。
應理解下列的實施例意欲例證而非限制本發明。在閱讀本發明之後,前述說明及實例的各種不違背本發明之精神及範疇的其他實例及修飾將為熟習本技術領域者所明白,且意欲將所有此等實例或修飾包括在所附之申請專利範圍之範疇內。本文參考之所有公開案及專利特此以彼之全文併入本文以供參考。
實施例
實施例1:共軛物之合成
實施例
實施例1:共軛物之合成
本發明之共軛物可使用任何方便的方法製備。在合理的方法中,共軛物係自彼等個別的組分、靶定之部分、在一些例子中的鍵聯子及活性劑部分構築。組分可通過官能基彼此共價鍵結,如本技術中已知,其中此等官能基可存在於組分上或使用一或多個步驟(例如氧化反應、還原反應、切割反應及類似者)引入組分上。可用於使組分一起共價鍵結以生產醫藥共軛物之官能基包括:羥基、氫硫基、胺基及類似者。選擇經修飾不同組份的特定部分以提供共價鍵聯,不實質地以不利的方式干擾組分的所欲結合活性,例如修飾不影響標靶結合活性的活性劑部分之區域,使得保留足夠量的所欲藥物活性。在必要及/或要求的情況下,可使用阻隔基保護組分上的特定部分,如本技術中已知,參見例如Green & Wuts, Protective Groups in Organic Synthesis(John Wiley & Sons)(1991)。
另一選擇地,共軛物可使用已知的組合方法生產以得到大量庫藏的潛在共軛物,接著可篩選以鑑定具有藥物動力學輪廓的雙功能分子。另一選擇地,共軛物可使用醫藥化學及已知的靶定之部分與活性劑部分之結構-活性關係來生產。此方法特別提供兩個部分於何處連結至鍵聯子之之見解。
化合物3之合成
化合物3之合成
將2-氯乙酸鈉(2.61 g,22.4 mmol)及碳酸鈉(4.45 g,42.0 mmol)添加至DMF(50 mL)中的2,4-二羥基-5-異丙基-苯二硫代羧酸(3.20 g,14.0 mmol)之溶液中,且將溶液以通過溶液的起泡氮脫氣。將混合物在室溫下攪拌3 h,接著添加在DMF(10 mL)中的4-(4-胺基苯甲基)哌𠯤-1-羧酸三級丁酯(4.08 g,14.0 mmol)之溶液。將所得混合物在80℃下攪拌3 h。將反應混合物倒入冰水中且以乙酸乙酯(3×100 ml)萃取。將合併的有機層以食鹽水清洗,經硫酸鈉乾燥且在真空中移除溶劑,以給出3A(5.20 g,10.7 mmol,76%之產率)。
將羰基二咪唑(2.00 g,13.9 mmol)添加至THF(80 mL)中的3A(5.20 g,10.7 mmol)之溶液中。將反應在室溫下攪拌2 h,接著倒入氯化銨飽和溶液(200 ml)中且以乙酸乙酯(3×50 mL)萃取。將合併的有機層以食鹽水(50 mL)清洗,經硫酸鈉乾燥且在真空中移除溶劑,以給出3B(4.30 g,8.37 mmol,78%之產率),其未經純化而用於下一步驟中。LCMS M/Z=512.3(M+1)。
將水合肼(1.26 g,25.1 mmol)添加至乙醇(50 mL)中的3B(4.30 g,8.37 mmol)之溶液中。將混合物在室溫下攪拌16 h且在真空中移除溶劑。將乙醇(20 mL)添加至剩餘的殘餘物中,將所得固體濾出,以乙醇(10 mL)清洗且乾燥,以給出3C(2.86 g,5.61 mmol,67%之產率)。LCMS M/Z=510.2(M+1)。
將MeOH中的4N HCl溶液(5 mL)添加至甲醇(20 mL)中的3C(2.86 g,5.61 mmol)之溶液中。將溶液在室溫下攪拌16 h,在真空下移除溶劑,將所得固體以甲醇(2×5 mL)清洗且乾燥,以給出3D鹽酸鹽(1.90 g,4.26 mmol,75%之產率)。LCMS M/Z=410.1(M+1)。
化合物17之合成
化合物17之合成
將17A(10.0 mg,19.6 umol)裝入小瓶中且溶解在DMF(1 mL)中。添加17B(8.2 mg,23.5 umol)且將溶液在室溫下攪拌30 mins,接著添加DIPEA(10.2 L,3.00當量)且攪拌2 h。
將17C(18.7 mg,23.5 umol)裝入另外的小瓶中,懸浮於1,1,1-三氟乙醇(0.4 mL)中,接著添加四甲基二矽氧烷(50 μL),繼而添加在0.4 mL TFE中的0.015 mL HCl(12 M)。在15 min之後,蒸發溶劑,接著添加0.5 mL DMF。將去保護之17C溶液添加至溶液中。
在1 h之後,將粗製物以製備性HPLC純化(0-95%之MeCN/水,0.1%之乙酸)。匯集、冷凍且凍乾純流份。獲得3.4 mg(14%)凍乾的白色粉末(3.18 min,M+H=1170)。
化合物17D之合成
化合物17D之合成
將4-巰基苯甲酸(10.0 g,64.9 mmol)添加至0℃下在THF(500 ml)中的氫化鋰鋁(3.69 g,97.3 mmol)之溶液中。接著將混合物溫熱至室溫且攪拌16 h,接著以2M HCl淬滅至pH=2。將水溶液以二乙醚(3×500 mL)萃取,將合併的有機層經硫酸鈉乾燥且在真空中移除溶劑,以給出17D,其未經進一步純化而使用(6.70 g,43%之純度,20.6 mmol,31%之產率)。
將2,2’-二硫二吡啶(11.3 g,51.4 mmol)添加至甲醇(80 mL)中的17D(6.00 g,43%之純度,18.4 mmol)之溶液中。將反應在室溫下攪拌3 h,接著在真空中移除溶劑。將所得混合物以矽膠層析術純化(8:1至6:1之石油醚:乙酸乙酯),以給出17E(2.00 g,8.02 mmol,43%之產率)。LCMS M/Z=250(M+1)。
化合物9之合成
化合物9之合成
將17E(1.00 g,4.01 mmol)溶解在二氯甲烷(10 mL)及三乙胺(410 mg,4.00 mmol)中。將此溶液逐滴添加至0℃下在二氯甲烷(5 mL)中的三光氣(476 mg,1.60 mmol)之溶液中。接著將此溶液溫熱至室溫且攪拌3 h。緩慢地添加在二氯甲烷(10 mL)中的HOBt(542 mg,4.01 mmol)之溶液及三乙胺(410 mg,4.00 mmol),且將此混合物在室溫下攪拌16 h。將反應混合物以2N HCl(20 ml)、水(3×20 mL)及食鹽水(20 mL)清洗,將有機層經硫酸鈉乾燥且在真空中濃縮,以給出17B(850 mg,2.07 mmol,51%之產率)。LCMS M/Z=411.0(M+1)。
17C之合成
17C之合成
將氯碳酸(4-硝基苯基)酯(37 mg,183 umol)及二氯甲烷(0.5 mL)裝入小瓶中。將S-三苯甲基-L-半胱胺酸醯胺(53 mg,147 umol)裝入小瓶中且溶解在二氯甲烷(0.5 mL)中。將S-三苯甲基-L-半胱胺酸醯胺溶液添加至氯碳酸(4-硝基苯基)酯溶液中。在20 min之後,蒸發溶劑,接著添加0.5 mL DMF。將T-1817(25 mg,61 umol)裝入小瓶中且懸浮於DMF(1 mL)中。添加胺甲酸酯溶液,繼而添加二異丙基乙胺(24 mg,183 umol,32 uL)。將溶液在室溫下攪拌隔夜。將粗製物以製備性HPLC純化(40-95%之MeCN/水,0.1%之乙酸)。匯集、冷凍且凍乾純流份。獲得21 mg(43%)凍乾的白色粉末(3.86 min,M+H=799)。
化合物18之合成
化合物18之合成
將CDI(9.2 mg,57 umol)裝入小瓶中且溶解在DMF(1 mL)中。添加18A(30.0 mg,57 umol)及DIPEA(7.4 mg,57 umol,10 uL)且將反應攪拌2小時。將BT-1132(26.3 mg,57 umol)以固體添加至小瓶中且將反應在室溫下攪拌隔夜。將反應以乙酸乙酯(30 mL)稀釋,將有機相以水中的1M HCl(2×20 mL)清洗且經無水硫酸鈉乾燥。在真空下移除溶劑,將殘餘物再懸浮於DMF中且裝填至反相管柱(5-60%之乙腈/水-0.2%之AcOH)中。匯集、冷凍且凍乾純流份。分離出成為灰白色固體的18(15.1 mg,24%之產率)。
化合物19之合成
化合物19之合成
將PI-103(20.0 mg,52.0 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(27.2 uL,3.00當量),繼而添加氯碳酸(4-硝基苯基)酯(12.6 mg,62.4 umol)。在30 min之後,添加0.5 mL DMF,接著蒸發DMF。添加在DMF(0.5 mL)及DIPEA(30 uL)中成為溶液的T-1818(29.0 mg,62.4 umol)。在1 h之後,將粗製物以製備性HPLC純化(30-85%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的20 mg(45%)化合物19(3.83 min,M+H=840)。
化合物20之合成
化合物20之合成
將PI-103(50.0 mg,130 umol)及DCM(5 mL)裝入小瓶中,接著添加DIPEA(68 uL,3.00當量),繼而添加氯碳酸(4-硝基苯基)酯(31.4 mg,156 umol)。在30 min之後,添加1.0 mL DMF,接著蒸發DCM。添加在DMF(0.5 mL)及DIPEA(70 uL)中成為溶液的T-1847(61.7 mg,156 umol)。在1 h之後,將粗製物以製備性HPLC純化(30-85%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的42 mg(41%)化合物20(3.87 min,M+H=770)。
化合物21之合成
化合物21之合成
將PI-103(20.0 mg,52.0 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(27.2 uL,3.00當量),繼而添加氯碳酸(4-硝基苯基)酯(12.6 mg,62.4 umol)。在30 min之後,添加0.5 mL DMF,接著蒸發DCM。添加在DMF(0.5 mL)及DIPEA(30 uL)中成為溶液的21A(23.1 mg,62.4 umol)。在1 h之後,將粗製物以製備性HPLC純化(40-95%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的14 mg(36%)化合物21(5.15 min,M+H=745)。
化合物22之合成
化合物22之合成
將22A(30.0 mg,52.1 umol)裝入小瓶中且溶解在DMF(2.0 mL)中。添加HATU(19.8 mg,52.1 umol)及DIPEA(20.2 mg,156 umol,27.2 uL)且將反應攪拌2分鐘,然後添加17A(28 mg,54.7 umol)。將反應在室溫下攪拌10分鐘。將粗製物以製備性HPLC純化(0-95%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的20.6 mg(37%)化合物22(2.95 min,M+H =1069)。
化合物22A之合成
化合物22A之合成
將BT-1132(160.00 mg,346.66 umol)裝入小瓶中且溶解在DMF(2.00 mL)中。添加四氫哌喃-2,6-二酮(39.55 mg,346.66 umol)及DIPEA(134.4 mg,1.04 mmol,182 uL)且將反應在室溫下攪拌2小時。將粗製反應以製備性HPLC純化(5-65%之MeCN/水,0.2%之乙酸)。匯集、冷凍且凍乾純流份。獲得成為灰白色凍乾粉末的148 mg 22A(74%)(2.73m,M+H=576)。
化合物23之合成
化合物23之合成
將23A(15.4 mg,27.4 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(10.4 mg,27.4 umol)及DIPEA(17.7 mg,137 umol,23.9 uL)且將反應攪拌2分鐘,然後添加17A(14.7 mg,28.7 umol)。將反應在室溫下攪拌10分鐘。將粗製物以製備性HPLC純化(0-95%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的8.0 mg(25%)化合物23(2.98 min,M+H=1056)。
化合物23A之合成
化合物23A之合成
將BT-1132(50.00 mg,108.33 umol)裝入小瓶中且溶解在DMF(3.00 mL)中。添加DIPEA(56.00 mg,433.32 umol,75.47 uL),繼而添加DSC(30.53 mg,119.16 umol)且在室溫下攪拌30分鐘。添加DMAP(13.23 mg,108.33 umol)及2-胺基乙酸三級丁酯(36.32 mg,216.66 umol,HCl)。將反應加熱至60℃且攪拌1小時,然而將其冷卻至室溫。將反應以MTBE(40 mL)及在水中的1N HCl(40 mL)稀釋。收集有機相且將水相以MTBE(2×20 mL)萃取。將有機相以飽和碳酸氫鈉(3×20 mL)清洗,以食鹽水(1×20 mL)清洗,經硫酸鈉乾燥且蒸發至乾燥。將粗製材料(3.23m,M+H=619 m/z)直接移到下一步驟。
將粗製物再懸浮於三氟乙酸(2.98 g,26.14 mmol,2.00 mL)中且在室溫下攪拌1小時,然後蒸發至乾燥。將殘餘物再懸浮於甲苯(2×5 mL)中且蒸發至乾燥。將剩餘的殘餘物在DMF中重組且裝填至製備性HPLC(ACN/水w/0.1%之TFA)。收集且蒸發含有純材料的流份,以得到成為灰白色粉末的15.4 mg化合物23A(25%)(2.62m,M+H=563)。
化合物24之合成
化合物24之合成
將PI-103(46.3 mg,120 umol)及DCM(5 mL)裝入小瓶中,接著添加DIPEA(37 uL,3.00當量),繼而添加氯碳酸(4-硝基苯基)酯(28.5 mg,141 umol)。在30 min之後,添加0.5 mL DMF,接著蒸發DCM。添加在DMF(0.5 mL)中成為溶液的24A(33.0 mg,70.7 umol)。在1 h之後,將粗製物以製備性HPLC純化(30-85%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的14 mg(36%)化合物24(3.51 min,M+H=841)。
24A之合成
24A之合成
將T-1817(100 mg,244 umol)及2-(9H-茀-9-基甲氧基羰基胺基)乙酸(145 mg,488 umol)裝入小瓶中且溶解在DMF(5.0 mL)中。添加DIPEA(94.7 mg,733 umol,128 uL),繼而添加HATU(184 mg,488 umol)且將反應在室溫下攪拌3 h。將粗製物以反相層析術純化(10-90%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的168 mg(81%)化合物24B(3.61 min,M+H=689)。
將24B(87 mg,126 umol)裝入小瓶中,接著溶解在2 mL在DMF中的20%之哌啶溶液。將溶液在室溫下攪拌90 min,接著以反相層析術純化(在具有0.1%之三氟乙酸之水中的5-30%之乙腈)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的48 mg(81%)化合物24A。
化合物25之合成
化合物25之合成
將25A(19.0 mg,41.1 umol)及T-1817(25.2 mg,61.6 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加DIPEA(15.9 mg,123 umol,21.5 uL),繼而添加HATU(23.2 mg,61.6 umol,1.50當量)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(30-85%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的7.0 mg(19%)化合物25(3.69 min,M+H=854).
25A之合成
25A之合成
將PI-103(50.0 mg,144 umol)裝入小瓶中且溶解在DMF(5.0 mL)中。添加戊二酸酐(49.1 mg,431 umol),繼而添加NaH(10.0 mg,430 umol,3.00當量)且將反應在室溫下攪拌6 h。添加戊二酸酐(49.1 mg,431 umol),繼而添加NaH(10.0 mg,430 umol,3.00當量)。在2 h之後,將粗製物在反相管柱上純化(5-60%之MeCN/水,2%之乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的38 mg(57%)化合物25A(4.13 min,M+H=463)。
化合物26之合成
化合物26之合成
將26B(15 mg,26.6 umol)溶解在DMF(1 mL)中,接著將溶液添加至DMF(0.5 mL)中的26A(29.7 mg,31.9 umol)中且添加0.2 M NaOAc(0.5 mL)溶液。在30 min之後,將粗製物以製備性HPLC純化(40-95%之MeCN/水,0.1%之乙酸)。匯集、冷凍且凍乾純流份。獲得23.5 mg(64%)白色凍乾粉末。
化合物27之合成
化合物27之合成
將27A(50 mg,70.7 umol)及T-1815(25.1 mg,70.7 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加DIPEA(45.7 mg,353 umol,61.7 uL),繼而添加HATU(26.9 mg,70.7 umol)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(5-30%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的26 mg(39%)化合物27(2.72 min,M+H=818)。
化合物27A之合成
化合物27A之合成
將三苯基膦(1.86 g,7.08 mmol)在氮氛圍下裝入圓底燒瓶中且溶解在無水四氫呋喃(40 mL)中。將溶液經由乙腈/乾冰浴冷卻至-40℃。在冷卻30分鐘之後,經約30分鐘過程逐滴添加DIAD(1.14 g,7.08 mmol,1.11 mL)。溶液變成白色沉澱物漿液且容許在-40℃下攪拌10分鐘,然後添加27B(500 mg,1.42 mmol)及4-(3-羥丙基)哌𠯤-1-羧酸三級丁酯(1.04 g,4.25 mmol)。反應繼續攪拌1小時,然後將反應自冷卻浴取出且容許溫熱至室溫及攪拌3天。以水(150 mL)自反應沉澱出經boc保護之產物且以真空過濾分離。將固體再懸浮於TFA(7.45 g,65.34 mmol,5 mL)及二氯甲烷(5 mL)中且攪拌隔夜。以MTBE(100 mL)沉澱出產物且以過濾分離,以得到211 mg成為灰白色固體的化合物27A(42%)(2.23m,M+H=480)。
化合物28之合成
化合物28之合成
將28A(30 mg,32.9 umol)及T-1815(11.7 mg,32.9 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加DIPEA(4.3 mg,32.9 umol,5.7 uL),繼而添加HATU (12.5 mg,32.9 umol)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(5-30%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的15 mg(37%)化合物28(2.80 min,M+H=1022)。
化合物28A之合成
化合物28A之合成
將化合物27A(200 mg,282.65 umol,2TFA)及化合物28B(125.34 mg,282.65 umol)溶解在DMF(5 mL)中。經1分鐘過程逐滴添加胡尼格氏(Hunig’s)鹼(73.06 mg,565.30 umol,98.46 uL)。將反應在室溫下攪拌15分鐘,然後將其以水(10 mL)淬滅。沉澱出產物且將其過濾,以分離經boc保護之化合物28A。將固體再溶解於三氟乙酸(5.96 g,52.27 mmol,4 mL)中且在室溫下攪拌1小時。將反應以甲苯(2×5 mL)稀釋且蒸發。將剩餘的殘餘物再懸浮於MeOH(2 mL)中且以MTBE(20 mL)沉澱出化合物28A。分離出成為淺棕色固體的230 mg化合物28A(89%)。
化合物28B之合成
化合物28B之合成
將4-(4-羥基苯基)哌𠯤-1-羧酸三級丁酯(5 g,17.96 mmol)及氯碳酸(4-硝基苯基)酯(1.81 g,8.98 mmol)裝入圓底燒瓶中且在室溫下溶解在THF(17.96 mL)中。一旦完全溶解時,逐滴添加胡尼格氏鹼(6.96 g,53.89 mmol,9.39 mL)。保持30分鐘澄清的反應。在1小時之後,開始形成沉澱物。將溶液過濾以移除沉澱物且蒸發溶劑。將產物以矽膠管柱分離(0-35%B,庚烷/乙酸乙酯),以得到成為黃色結晶固體的2.01 g化合物28B(25%) (3.78m,M+H=444)。
化合物29之合成
化合物29之合成
將28A(77 mg,70.2 umol)及T-1816(28.8 mg,70.2 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加DIPEA(45.3 mg,350 umol,61 uL),繼而添加HATU(26.7 mg,70.2 umol)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(15-40%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的47 mg(55%)化合物29(2.89 min,M+H=1077)。
化合物30之合成
化合物30之合成
將30A(80 mg,87.64 umol,TFA)、HATU (36.65 mg,96.40 umol)及T-1818(66.77 mg,96.40 umol,2TFA)裝入小瓶中且溶解在DMF(5 mL)中。在室溫下逐滴添加胡尼格氏鹼(90.61 mg,701.12 umol,122.12 uL)。將反應在室溫下攪拌30分鐘且以製備性HPLC分離(15-30% B,MeCN/水,0.1%之三氟乙酸)。收集、冷凍且凍乾純流份,以得到成為白色凍乾粉末的32.9 mg化合物30(26%) (2.58m,M+H=1091)。
化合物30A之合成
化合物30A之合成
將氯碳酸(4-硝基苯基)酯(43.87 mg,217.64 umol)及4-羥基苯甲酸三級丁酯(48.31 mg,248.74 umol)裝入小瓶中且溶解在無水四氫呋喃(2.00 mL)中。在室溫下,將胡尼格氏鹼(80.37 mg,621.84 umol,108.31 uL)經1分鐘逐滴添加至溶液中。在再攪拌30分鐘之後,添加額外一份胡尼格氏鹼(80.37 mg,621.84 umol,108.31 uL),繼而緩慢添加在DMF(5 mL)中的27A(100 mg,124.37 umol,2TFA)之漿液。將反應攪拌隔夜且隔天以水(20 mL)淬滅。沉澱出經三級丁基保護之產物且傾析上清液。將剩餘的殘餘物溶解在ACN(8 mL)中且以水(12 mL)再沉澱。將固體過濾且留在濾紙上經30分鐘乾燥。接著將固體溶解在三氟乙酸(2.98 g,26.14 mmol,2 mL)中且攪拌2小時。在真空中移除溶劑且將產物以MTBE(10 mL)濕磨,以給出成為灰白色固體的79.9 mg化合物30A(85%)(2.52m,M+H=644)。
化合物31之合成
化合物31之合成
將28A(100 mg,91.13 umol,2TFA)、T-1885(49.58 mg,91.13 umol,HCl)、HATU(34.65 mg,91.13 umol)及HOBT(36.94 mg,273.38 umol)裝入小瓶中且溶解在DMF(4 mL)中,然後逐滴添加胡尼格氏鹼(117.77 mg,911.27 umol,158.73 uL)。將偶合物在室溫下攪拌30分鐘,然後以製備性HPLC純化(15-30% B,MeCN/水,0.1%之三氟乙酸)。收集、冷凍且凍乾純流份,以得到成為白色凍乾粉末的27.3 mg化合物31(24%)(2.69m,M+H=1174)。
化合物32之合成
化合物32之合成
將T-1816(48.15 mg,117.33 umol)、32A (122.01 mg,117.33 umol,3TFA)及HATU(44.61 mg,117.33 umol)裝入小瓶中且溶解在DMF(5 mL)中。經1分鐘逐滴添加胡尼格氏鹼(121.31 mg,938.6 umol,163 uL)且將反應在室溫下攪拌30分鐘,然後將產物以製備性HPLC分離(15-30% B,MeCN/水,0.1%之三氟乙酸)。收集、冷凍且凍乾純流份,以得到成為白色凍乾粉末的17.3 mg化合物32(13%)。
化合物32A之合成
化合物32A之合成
將32B(69.71 mg,211.99 umol,HCl)及DSC (52.50 mg,204.92 umol)裝入小瓶中且溶解在DMF(5 mL)中。經1分鐘逐滴添加胡尼格氏鹼(91.33 mg,706.63 umol,123.08 uL)且將反應在室溫下攪拌隔夜。分開將T-2026(100 mg,141.33 umol,2TFA)溶解在DMF(1mL)中且逐滴添加至預活化之溶液中。將反應繼續在室溫下攪拌隔夜。將反應以DI水(15 mL)稀釋且沉澱出經boc保護之產物。將固體過濾且在真空下乾燥。將殘餘物再懸浮於三氟乙酸(1.99 g,17.42 mmol,1.33 mL)中且在室溫下攪拌2小時。將反應以MTBE稀釋至20 mL且攪拌3天。將沉澱之產物過濾且放置在真空下,以獲得成為黃色油的143.7 mg化合物32A(68%)。
化合物32B之合成
化合物32B之合成
將哌𠯤-1-羧酸三級丁酯(1 g,5.37 mmol)及4-羥基苯甲醛(1.31 g,10.74 mmol)裝入圓底燒瓶中且懸浮於THF(30 mL)及乙酸(6.45 g,107.38 mmol,6.14 mL)中。在室溫下攪拌1小時以形成亞胺,然後添加三乙醯氧基硼氫化鈉(5.69 g,26.85 mmol)。將反應加熱至40℃且攪拌隔夜。將反應以飽和碳酸氫鈉(50 mL)中和且以MTBE(50 mL)萃取。將有機相以食鹽水清洗且經無水硫酸鈉乾燥,然後蒸發。將剩餘的殘餘物溶解在甲醇中且以二乙醚中的2M HCl(5 mL)沉澱。將產物過濾且放置在真空下。將固體再懸浮於具有幾滴MeOH的DCM中且裝填至矽膠管柱(0-8% DCM/MeOH)。匯集且蒸發純流份,以得到成為灰白色固體的1.15 g 32B(65%)。
化合物33之合成
化合物33之合成
將T-1816(39.22 mg,95.56 umol)、33A (111.9 mg,106.18 umol,3TFA)及HATU(40.37 mg,1106.18 umol)裝入小瓶中且將內容物溶解在DMF(5 mL)中。經1分鐘逐滴添加胡尼格氏鹼(109.78 mg,849.43 umol,148 uL)且將反應在室溫下攪拌30分鐘。將產物以製備性HPLC分離(15-30% B,MeCN/水,0.1%之三氟乙酸)。收集、冷凍且凍乾純流份,以得到成為白色凍乾粉末的48.79 mg化合物33(32%)(2.67m,M+H=1105)。
化合物33A之合成
化合物33A之合成
將33B(64.95 mg,211.99 umol,HCl)及DSC(52.50 mg,204.9 umol,TFA)裝入小瓶中且溶解在DMF(5 mL)中。經1分鐘逐滴添加胡尼格氏鹼(91.33 mg,706.63 umol,123.08 uL)且在室溫下攪拌隔夜以進行活化。經1分鐘逐滴添加分開溶解在DMF(1 mL)中的27A(100 mg,141.33 umol,2TFA)且在室溫下經隔夜繼續反應。將反應以水(14 mL)稀釋且沉澱經boc保護之產物。將固體過濾且再懸浮於三氟乙酸(1.99 g,17.42 mmol,1.33 mL)中。繼續2小時去保護,然後以MTBE(20 mL)沉澱出產物。傾析出溶劑且將固體放置在真空下以移除殘餘溶劑。142.4 mg化合物33A為(76%)灰白色固體的(2.26m,M+H=713)。
化合物33B之合成
化合物33B之合成
將哌𠯤-1-羧酸三級丁酯(1.00 g,5.37 mmol)及4-羥基-3-甲基-苯甲醛(1.46 g,10.74 mmol)裝入圓底燒瓶中且懸浮於THF(30 mL)及乙酸(6.45 g,107.40 mmol,6.14 mL)中。在室溫下進行1小時亞胺形成作用,然後添加三乙醯氧基硼氫化鈉(5.69 g,26.85 mmol)。將反應加熱至40℃且攪拌隔夜。將反應以飽和碳酸氫鈉(50 mL)中和且以MTBE(50 mL)萃取。將有機相以食鹽水清洗且經無水硫酸鈉乾燥,然後蒸發。將剩餘的殘餘物溶解在甲醇中且以二乙醚中的2M HCl(5 mL)沉澱。將產物過濾且放置在真空下乾燥。將固體再懸浮於具有幾滴甲醇的DCM中且裝填至矽膠管柱(0-9% MeOH於DCM中)。匯集且蒸發純流份,以得到成為灰白色固體的536 mg化合物33B(29%)(2.82m,M+H=307)。
化合物34之合成
化合物34之合成
將34A(172 mg,172.21 umol,3TFA)、HATU(65.48 mg,172.21 umol)、1-羥基苯并三唑(69.81 mg,516.62 umol)及T-1816(70.68 mg,172.21 umol)裝入小瓶中且溶解在DMF(5 mL)中。經1分鐘逐滴添加胡尼格氏鹼(178.05 mg,1.38 mmol,239.96 uL)且將反應在室溫下攪拌30分鐘。將產物以製備性HPLC分離(15-35% B, MeCN/水,0.1%之三氟乙酸)。收集、冷凍且凍乾純流份,以得到成為白色凍乾粉末的70 mg化合物34(31%)(2.90 m,M+H=1049)。
化合物34A之合成
化合物34A之合成
將N-[(4-羥基-3,5-二甲基-苯基)甲基]胺甲酸三級丁酯(61.01 mg,211.99 umol,HCl)及DSC(52.50 mg,204.92 umol)裝入小瓶中且溶解在DMF(5 mL)中。添加胡尼格氏鹼(91.33 mg,706.63 umol,123.08 uL)且將反應在室溫下攪拌隔夜。經1分鐘逐滴添加分開溶解在DMF(1 mL)中的T-2026(100 mg,141.33 umol,2TFA)且在室溫下經隔夜繼續攪拌反應。將反應以水(14 mL)稀釋且沉澱出產物。將固體過濾且再懸浮於三氟乙酸(1.99 g,17.42 mmol,1.33 mL)中,且在室溫下攪拌2小時。以MTBE(20 mL)沉澱出產物。傾析出溶劑且將固體放置在真空下以移除殘餘溶劑。獲得成為灰白色固體的172.4 mg化合物34A(96%)(2.46m,M+H=657)。
化合物35之合成
化合物35之合成
將35A(58.61 mg,73.74 umol,2TFA)及35B (64 mg,73.74 uL)裝入小瓶中且溶解在DMF(4 mL)及PBS(pH 7.4,2 mL)中。將反應在室溫下攪拌2小時。將產物以製備性HPLC分離(15-55% B,MeCN/水,0.1%之三氟乙酸)。獲得成為白色凍乾粉末的65.9 mg化合物35(57%)(6.99m,M+H=1211)。
化合物35A之合成
化合物35A之合成
將T-1818(250 mg,360.96 umol,2TFA)及4-((4-甲氧基苯甲基)硫代)-4-甲基戊醛(172.06 mg,721.91 umol)裝入小瓶中且懸浮於THF(5 mL)及乙酸(440.17 mg,7.33 mmol,360.80 uL)中。在室溫下攪拌1小時以形成亞胺,然後添加三乙醯氧基硼氫化鈉(382.51 mg,1.80 mmol)。將反應加熱至40℃且攪拌隔夜。將反應以飽和碳酸氫鈉(20 mL)中和且以MTBE(3×20 mL)萃取。將有機相合併,以食鹽水清洗且經無水硫酸鈉乾燥,然後蒸發。將剩餘的殘餘物溶解在甲醇中且以二乙醚中的2M HCl(5 mL)沉澱。將產物過濾且放置在真空下以移除殘餘溶劑。接著將固體溶解在三氟乙酸(5.10 mL)中,繼而添加茴香硫醚(292.23 mg,2.35 mmol,275.69 uL)及三氟甲烷磺酸(407.87 mg,2.72 mmol,241.34 uL)。將反應在室溫下攪拌15分鐘,然後將產物以製備性分離(10-50% B,MeCN/水,0.1%之三氟乙酸)。匯集且蒸發純流份,以給出成為灰白色固體的312.3 mg化合物35A(85%)(2.99m,M+H=567)。
化合物35B之合成
化合物35B之合成
將27A(150 mg,211.99 umol,2TFA)、T-1842(87.02 mg,211.99 umol)、胡尼格氏鹼(82.19 mg,635.97 umol,110.77 uL)及DMAP(25.90 mg,211.99 umol)裝入小瓶中,溶解在DMF(2.12 mL)中且在室溫下攪拌隔夜。將反應以15 mL MTBE稀釋且沉澱出產物。傾析出MTBE,將殘餘物溶解在DMSO(3 mL)中且摻入TFA(100 uL),然後以製備性HPLC純化(15-75% B,MeCN/水,0.1% TFA)。將純流份合併、冷凍且凍乾,以得到成為白色凍乾粉末的64 mg化合物35B(40%)(2.96m,M+H=756)。
化合物36之合成
化合物36之合成
將27A(40 mg,56.5 umol)及T-1885(31.6 mg,62.2 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(32.0 mg,84.8 umol),繼而添加DIPEA(21.9 mg,170 umol,29.5 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(20-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的28 mg(51%)化合物36(2.73 min,M+H=970)。
化合物37之合成
化合物37之合成
將27A(40 mg,56.5 umol)及37A(47.1 mg,62.2 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(32.0 mg,84.8 umol),繼而添加DIPEA(21.9 mg,170 umol,29.5 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(10-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的55 mg(73%)化合物37(2.81 min,M+H=1105)。
37A之合成
37A之合成
將2-(4-羥基苯基)乙酸甲酯(40 mg,240 umol)及DCM(2 mL)裝入小瓶中甲基,接著添加DIPEA(93 mg,722 umol,125 uL),繼而添加氯碳酸(4-硝基苯基)酯(58.2 mg,289 umol)。在30 min之後,添加T-1818(134 mg,289 umol)。在1 h之後,添加氫氧化鈉(29.6 mg,740 umol)。在30 min之後,添加更多氫氧化鈉(29.6 mg,740 umol)。在3 h之後,將粗製物以TFA酸化,接著以製備性HPLC純化(20-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的133 mg(71%)化合物37A(3.17 min,M+H=643)。
化合物38之合成
化合物38之合成
將38A(47 mg,60.9 umol)及T-1818(42.3 mg,73.1 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(34.5 mg,91.4 umol),繼而添加DIPEA(23.6 mg,183 umol,31.8 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(10-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的48 mg(59%)化合物38(2.89 min,M+H=1105)。
38A之合成
38A之合成
將2-(4-羥基苯基)乙酸甲酯(41.6 mg,250 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(80.9 mg,625 umol,108 uL),繼而添加氯碳酸(4-硝基苯基)酯(50.4 mg,250 umol)。在30 min之後,添加在DMF(2 mL)中的27A(100 mg,209 umol)。在1 h之後,添加在水(1 mL)中的氫氧化鈉(75 mg,1.88 mmol)。在3 h之後,將粗製物以TFA酸化,接著以反相層析術純化(10-50%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的356 mg(73%)化合物38A(2.73 min,M+H=659)。
化合物39之合成
化合物39之合成
將38A(40 mg,51.8 umol)及T-1817(32.6 mg,62.2 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(25.4 mg,67.4 umol),繼而添加DIPEA(20.1 mg,155 umol,27 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(10-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的28 mg(42%)化合物39(2.71 min,M+H=1050)。
化合物40之合成
化合物40之合成
將38A(40 mg,51.8 umol)及BT-1132(35.8 mg,62.2 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(25.4 mg,67.4 umol),繼而添加DIPEA(20.1 mg,155 umol,27 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(10-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的18 mg(28%)化合物40(3.14 min,M+H=1102)。
化合物41之合成
化合物41之合成
將41A(33 mg,48 umol)及T-1815(23.6 mg,57.6 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(23.5 mg,62.4 umol),繼而添加DIPEA(18.6 mg,144 umol,25 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(10-70%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的22 mg(42%)化合物41(3.26 min,M+H=967)。
41A之合成
41A之合成
將N-[2-(4-羥基苯基)乙基]胺甲酸三級丁酯(24.4 mg,103 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(33.3 mg,257 umol,45 uL),繼而添加氯碳酸(4-硝基苯基)酯(20.8 mg,103 umol)。在30 min之後,添加41B(45 mg,85.8 umol)。在3 h之後,將粗製物以TFA(5 mL)酸化且在室溫下攪拌2 h。將粗製物以反相層析術純化(10-45%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的33 mg(55%)化合物41A(2.77 min,M+H=574)。
41B之合成
41B之合成
將27B(165 mg,284 umol)裝入 50 mL圓底燒瓶,將燒瓶設定在氮氣下,接著添加25 mL THF。將碳酸鈉(200 mg)添加至懸浮液中,繼而添加N-(3-羥丙基)胺甲酸三級丁酯(149 mg,851 umol)及三苯基膦(298 mg,1.14 mmol)。將溶液經由乙腈/乾冰浴冷卻至-40℃。在冷卻15分鐘之後,經15分鐘過程逐滴添加偶氮二羧酸二異丙酯(172 mg,851 umol,167 uL),直到溶液為乳白色為止。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在90 min之後,添加三苯基膦(297 mg,1.14 mmol),將溶液冷卻至-40℃,接著添加偶氮二羧酸二異丙酯(172 mg,851 umol,167 uL)。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在1 h之後,將反應以水(40 mL)稀釋且形成白色沉澱。以過濾收集固體且溶解在三氟乙酸(1.49 g,13.1 mmol,1.00 mL)中。將溶液在室溫下攪拌15分鐘。將粗製物以水稀釋且以反相層析術純化(10-50%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的142 mg(79%)化合物41A(2.05 min,M+H=411)。
化合物42之合成
化合物42之合成
將42A(13 mg,17.8 umol)及T-1816(8.8 mg,21.4 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(10.1 mg,26.7 umol),繼而添加DIPEA(6.9 mg,53.5 umol,9.3 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(20-75%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的11 mg(55%)化合物27(3.34 min,M+H=1008)。
42A之合成
42A之合成
將N-[2-(4-羥苯基)乙基]胺甲酸三級丁酯(17.6 mg,74.1 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(24.0 mg,185 umol,32 uL),繼而添加氯碳酸(4-硝基苯基)酯(14.9 mg,74.1 umol)。在30 min之後,添加42B(35 mg,61.8 umol)。在2 h之後,添加DIPEA(24.0 mg,185 umol,32 uL)且將溶液在室溫下攪拌2天。添加DMF(1 mL)且將懸浮液溫熱至60℃。在2 h之後,添加TFA(20 uL),得到幾乎完全均勻的溶液。在1 h之後,添加DIPEA(20 ul)且溶液變澄清。添加DIPEA(50微升)且將溶液在60℃下攪拌16 h。添加水,將固體過濾及以TFA(5 mL)溶解且在室溫下攪拌2 h。將粗製物以反相層析術純化(10-45%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的13 mg(28%)化合物42A(2.63 min,M+H=616)。
42B之合成
42B之合成
將27B(165 mg,284 umol)裝入50 mL圓底燒瓶中,將燒瓶設定在氮氣下,接著添加25 mL THF。將碳酸鈉(200 mg)添加至懸浮液中,繼而添加N-(3-羥丙基)-N-異丙基胺甲酸三級丁酯(185 mg,851 umol)及三苯基膦(298 mg,1.14 mmol)。將溶液經由乙腈/乾冰浴冷卻至-40℃。在冷卻15分鐘之後,經15分鐘過程逐滴添加偶氮二羧酸二異丙酯(172 mg,851 umol,167 uL),直到溶液為乳白色為止。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在90 min之後,添加三苯基膦(297 mg,1.14 mmol),將溶液冷卻至-40℃,接著添加偶氮二羧酸二異丙酯(172 mg,851 umol,167 uL)。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在1 h之後,將反應以水(40 mL)稀釋且形成白色沉澱。以過濾收集固體且溶解在三氟乙酸(1.49 g,13.1 mmol,1.00 mL)中。將溶液在室溫下攪拌15分鐘。將粗製物以水稀釋且以反相層析術純化(10-50%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的86 mg(66%)化合物41A(2.39 min,M+H=453)。
化合物43之合成
化合物43之合成
將43A(18 mg,25.1 umol)及T-1818(14 mg,30.1 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU( 14.2 mg,37.7 umol),繼而添加DIPEA(9.7 mg,75.4 umol,13 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(20-75%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的29 mg(86%)化合物43(3.08 min,M+H=1049)。
43A之合成
43A之合成
將2-(4-羥基苯基)乙酸甲酯(13 mg,78 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(25.2 mg,195 umol,34 uL),繼而添加氯碳酸(4-硝基苯基)酯(15.7 mg,78 umol)。在30 min之後,添加43B(35 mg,65 umol)。在1 h之後,添加在水(1 mL)中的氫氧化鈉(26 mg,650 mmol)。在3 h之後,將粗製物以TFA酸化,接著以反相層析術純化(10-45%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的18 mg(38%)化合物43A(2.86 min,M+H=603)。
43B之合成
43B之合成
將27B(800 mg,1.38 mmol)裝入50 mL圓底燒瓶中,將燒瓶設定在氮氣下,接著添加25 mL THF。將碳酸鈉(200 mg)添加至懸浮液中,繼而添加N-(3-羥丙基)-N-甲基胺甲酸酯(781 mg,4.13 umol)及三苯基膦(1.44 g,5.50 mmol)。將溶液經由乙腈/乾冰浴冷卻至-40℃。在冷卻15分鐘之後,經15分鐘過程逐滴添加偶氮二羧酸二異丙酯(835 mg,4.13 mmol,810 uL),直到溶液為乳白色為止。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在90 min之後,添加三苯基膦(1.44 g,5.50 mmol),將溶液冷卻至-40℃,接著添加偶氮二羧酸二異丙酯(835 mg,4.13 mmol,810 uL)。在添加之後,將反應自冷卻浴取出且容許溫熱至室溫,在惰性氛圍下繼續攪拌。在1 h之後,將反應以水(25 mL)稀釋且形成白色沉澱。以過濾收集固體且溶解在三氟乙酸(7.24 g,63.5 mmol,4.86 mL)中。將溶液在室溫下攪拌15分鐘。將粗製物以水稀釋且以反相層析術純化(10-50%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的663 mg(89%)化合物43B(1.77 min,M+H=425)。
化合物44之合成
化合物44之合成
將44A(26 mg,44.3 umol)及T-1816(21.8 mg,53.1 umol)裝入小瓶中且溶解在DMF(1.0 mL)中。添加HATU(21.7 mg,57.5 umol),繼而添加DIPEA(17.2 mg,133 umol,23 uL)且將反應在室溫下攪拌3 h。將粗製物以製備性HPLC純化(20-75%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的7 mg(14%)化合物44(3.22 min,M+H=980)。
44A之合成
44A之合成
將N-[2-(4-羥基苯基)乙基]胺甲酸三級丁酯(18.5 mg,78.0 umol)及DCM(2 mL)裝入小瓶中,接著添加DIPEA(25.2 mg,195 umol,34 uL),繼而添加氯碳酸(4-硝基苯基)酯(15.7 mg,78.0 umol)。在30 min之後,添加43B(35 mg,65 umol)。在2 h之後,添加DMF(1 mL)且將溶液在室溫下攪拌2天。將懸浮液溫熱至60℃。在4 h之後,添加DIPEA(25.2 mg,195 umol,34 uL)且將溶液在60℃下攪拌2 h。添加水,將固體過濾及以TFA(1.5 mL)溶解且在室溫下攪拌2 h。將粗製物以反相層析術純化(10-45%之MeCN/水,0.1%之三氟乙酸)。匯集、冷凍且凍乾純流份。獲得成為白色凍乾粉末的26 mg(57%)化合物44A(2.40 min,M+H=588)。
實施例2:使用共軛物之試管內研究
HER2降解檢定法:
實施例2:使用共軛物之試管內研究
HER2降解檢定法:
將BT474(乳癌)細胞以每一槽孔12,000個細胞平鋪且在37℃及5%之CO2
下培育20至24小時。在細胞培育後,將化合物在DMSO中重組至5 mM之儲備濃度。接著在DMSO中製備含有10點稀釋的化合物盤。接著將2 uL該等稀釋液添加至細胞中而達到5 uM至0.0003 uM之最終操作濃度。將化合物及細胞培育16小時。接著移除培養基,將細胞清洗、溶解且以ELISA分析人類總EbB2/Her2含量。
HSP90結合:
HSP90結合:
共軛物與HSP90之結合係以HSP90α檢定套組研究。設計HSP90α檢定套組,使用螢光偏振鑑定HSP90α抑制劑。檢定法係建基於經螢光標記之格爾德黴素與經純化之重組HSP90α之結合競爭。HSP90α檢定套組的關鍵為經螢光標記之格爾德黴素。將經螢光標記之格爾德黴素與含有HSP90α酶之樣品培育以引起螢光偏振的變化,其接著可使用螢光讀數器測量。
NCI-H460腫瘤細胞毒性檢定法:
NCI-H460腫瘤細胞毒性檢定法:
將NCI-H460細胞(非小細胞肺癌)以每一槽孔500個細胞平鋪且在37℃及5%之CO2
下培育20至24小時。在細胞培育後,將化合物在DMSO中重組至200 uM之儲備濃度。接著在RPMI +10%之FBS + 0.25%之DMSO中製備含有10點稀釋的化合物盤。接著添加5 uL稀釋液而達到10 uM至0.0005 uM之最終操作濃度。接著將化合物及細胞培育48小時。接著以CellTiter-Glo分析細胞的ATP含量及經計算之抑制百分比。
實施例3:使用共軛物之活體內研究
H1975異種移植研究:
實施例3:使用共軛物之活體內研究
H1975異種移植研究:
在雌性無胸腺裸鼠的右後腹側以每隻小鼠植入5×106
個H1975細胞(非小細胞肺癌)。一旦腫瘤達到50mm3
至150mm3
體積,將彼等隨機分成的10隻的兩組以獲得每組114.4mm3
之平均起始腫瘤體積。接著將小鼠以對照媒劑或12.5 mg/kg之共軛物38處理。所有的給藥係以每週兩次經靜脈內進行三週,共投予五個劑量。測量小鼠的腫瘤體積。在第19天取得最後的研究測量,研究在該點終止,因為對照媒劑之腫瘤體積接近IACUC界限。如圖1中所示,在研究結束時,與其對照媒劑相比,以12.5 mg/kg於一週投予兩次的共軛物38能夠達成70.8%之腫瘤生長抑制。
H460小鼠腫瘤PK:
H460小鼠腫瘤PK:
在攜有H460腫瘤之小鼠中於96及144 h的共軛物及未經共軛之酬載累積。共軛物38係以25 mg/kg經靜脈內給藥。
共軛物38累積且保留在異種移植腫瘤組織中。其釋放呈其活性形式的其酬載柯潘利希布,其驅動優於單獨的柯潘利希布或單獨的加尼特斯皮之功效,如圖2中所示。
LS174t結腸癌模式
LS174t結腸癌模式
在使用LS174t結腸腫瘤異種移植模式的另一研究中,以共軛物38觀察到顯著的腫瘤生長抑制。如圖3A中所示,共軛物38顯示優越的功效,與缺乏功效之各個單獨的PI3K抑制劑(柯潘利希布)或HSP90抑制劑(加尼特斯皮)成對比。驚訝的是共軛物38亦比包含柯潘利希布及加尼特斯皮之組合療法作用得更好。
共軛物38之累積及保留係在此腫瘤異種移植模式中測試。共軛物38顯示強且持續的藥效學反應。如圖4中所示,共軛物38維持在腫瘤異種移植中且釋放活性PI3K抑制劑酬載>96小時。柯潘利希布本身具有更短的滯留時間。PI3K之抑制係通過48 h過程建立,如以顯著減少的pAKT(S473)所示(圖5)。
其他的活體內模式
共軛物38之累積及保留係在此腫瘤異種移植模式中測試。共軛物38顯示強且持續的藥效學反應。如圖4中所示,共軛物38維持在腫瘤異種移植中且釋放活性PI3K抑制劑酬載>96小時。柯潘利希布本身具有更短的滯留時間。PI3K之抑制係通過48 h過程建立,如以顯著減少的pAKT(S473)所示(圖5)。
其他的活體內模式
PIK3A突變係發生在約15%之30%之乳癌、子宮內膜癌及結腸癌中。除了LS174t模式以外,亦選擇藏匿共同的PIK3CA突變之其他的異種移植模式進行測試。在一個研究中,將攜有SKOV3(卵巢癌)腫瘤異種移植之小鼠以25 mg/kg之共軛物38及6 mg/kg之柯潘利希布的IV劑量處理。劑量的選擇係建基於最大耐受性劑量。平均腫瘤體積變化顯示於圖3B中。在另一研究中,將攜有BT474(乳癌)腫瘤異種移植之小鼠以25 mg/kg之共軛物38及6 mg/kg之柯潘利希布的IV劑量處理。平均腫瘤體積變化顯示於圖3C中。在所有測試之異種移植模式中,當比較共軛物38與柯潘利希布時,可見統計上顯著增加的腫瘤生長抑制。
實施例4:遮蔽酬載以降低正常組織毒性
實施例4:遮蔽酬載以降低正常組織毒性
在此實施例中,發現衍生自多種酬載的本發明之共軛物在彼等的各個試管內功能測定中具有顯著較低的活性,同時仍保留HSP90靶定。各個酬載的活性被阻斷,直到鍵聯子部分在腫瘤中被切割且釋放活性未阻斷之酬載為止。通過HSP90平台,使毒性藉由遮蔽酬載的活性位點而減輕,直到酬載可遞送至腫瘤為止。
靶定PI3K路徑之抑制劑的已知且潛在的劑量限制副作用為高血糖症。在此研究中,測試共軛物38以測定是否可降低其PI3K抑制劑酬載的副作用。
在無細胞的PI3K酶檢定中,共軛物38具有遠低於其PI3K酶抑制劑酬載的活性,如圖6中所示。因此,使PI3K酶抑制劑酬載與HSP90靶定之配體共軛以遮蔽PI3K酶抑制作用。
在小鼠的活體內研究中,葡萄糖含量係在PI3K抑制劑(柯潘利希布)及共軛物38給藥後監測。如圖7中所示,以共軛物38處理之小鼠具有比PI3K抑制劑酬載處理之小鼠更低葡萄糖濃度。因此,使PI3K酶抑制劑酬載與HSP90靶定之配體共軛降低小鼠中葡萄糖增加的正常組織活性。共軛物38能夠減少以單獨的PI3K抑制劑給藥後觀察到的葡萄糖含量增加,証實與單獨的PI3K抑制劑相比,選擇性遞送能夠增加治療窗口。
該等數據証實藉由發揮HSP90-靶定之配體在腫瘤中的優先積累,可選擇性地遞送PI3K抑制劑以達成深入的路徑抑制,在小鼠中多種腫瘤模型中得到功效,而未誘發高血糖症。
在一些其他的研究中,測試包含HSP90結合之配體及其他酬載的共軛物。共軛物45包含加尼特斯皮衍生物作為靶定之部分及塔拉唑帕布(PARP抑制劑)作為酬載。共軛物46包含加尼特斯皮衍生物作為靶定之部分及尤克替尼布(ERK1/2抑制劑)作為酬載。共軛物47包含加尼特斯皮衍生物作為靶定之部分及TAK-733(MEK抑制劑)作為酬載。
圖8A比較共軛物45與其酬載(塔拉唑帕布)之活性。圖8B比較共軛物46與其酬載(尤克替尼布)之活性。圖8C比較共軛物47與其酬載TAK-733之活性。數據進一步支持使酬載附著至HSP90結合之配體阻斷酬載之標靶活性。HSP90配體之HSP90結合不受影響。共軛物保留對HSP90之高親和性,如下表中所示:
在一個進一步的研究中,比較由共軛物48(包含加尼特斯皮衍生物及SN-38之共軛物)所引起的DNA損傷與由SN-38(共軛物48之酬載)所引起的DNA損傷。SN-38及其前藥艾來諾康(喜樹鹼類似物)為拓樸異構酶-1之抑制劑且有效地引起DNA損傷,其造成DNA中的缺口。如圖9中所示,艾來諾康顯示中等程度的DNA損傷活性及加尼特斯皮如預期般未顯示DNA損傷活性。以高達100 uM的共軛物48顯示可忽略的DNA損傷程度,而SN-38顯示DNA損傷,甚至在1 uM。SN-38與HSP90配體之共軛導致遮蔽SN-38之活性,直到其可選擇性地遞送至發生鍵聯子切割的腫瘤為止。
因此,本發明之共軛物遮蔽廣泛的酬載以降低正常組織毒性,且在鍵聯子切割時釋放有效力的酬載。
實施例5:測定酬載及共軛物之滲透性
實施例5:測定酬載及共軛物之滲透性
為了測試酬載及/或共軛物進入細胞的能力,利用使用Caco-2細胞(人類上皮結腸直腸腺癌細胞株)之細胞單層檢定法。
實驗程序:將組織培養瓶中生長的Caco-2細胞經胰蛋白酶處理、懸浮於培養基中且將懸浮液施予Millipore 96槽孔Caco-2盤之槽孔。容許細胞經三週生長及分化,每隔2天餵食。對頂點至底側(A→B)滲透性,之試驗劑添加至頂點(A)端且測定在底側(B)端上的滲透量;對底側至頂點(B→A)滲透性,試驗劑添加至B端且測定在A端上的滲透量。
化合物27A係在Caco-2 滲透性檢定法中測試且顯示具有非常低的滲透性。發現A至B方向的平均滲透率(Papp)為0.00320×10-6
cm/s,及B至A方向的平均滲透率(Papp)為0.0162×10-6
cm/s。
圖1顯示小鼠在實施例3所述之活體內H1975異種移植研究中以共軛物38治療後的腫瘤體積。
圖2顯示小鼠在活體內H460肺癌異種移植模式中以共軛物38治療後的腫瘤體積。
圖3A顯示小鼠在活體內LS174t結腸癌異種移植模式中以共軛物38治療後的腫瘤體積。圖3B顯示小鼠在活體內SKOV3卵巢癌異種移植模式中以共軛物38治療後的腫瘤體積。圖3C顯示小鼠在活體內BT474 乳癌異種移植模式中以共軛物38治療後的腫瘤體積。
圖4顯示共軛物38之擴展的腫瘤PK及酬載釋放。
圖5顯示共軛物38之持續的腫瘤藥效學反應。
圖6顯示柯潘利希布(Copanlisib)及共軛物38之PI3K IC50值。共軛物38遮蔽PI3K酶抑制作用。
圖7顯示在給藥後的葡萄糖濃度。共軛物38能夠減少在以單獨的PI3K抑制劑給藥後觀察到的葡萄糖含量增加。
圖8A顯示共軛物45之PARP抑制活性比其酬載(塔拉唑帕布(talazoparib))更低。圖8B顯示共軛物46之ERK1/2抑制活性比其酬載(尤克替尼布(ulixertinib))更低。圖8C顯示共軛物47之MEK活性比其酬載TAK-733更低。
圖9比較SN-38及共軛物48之拓樸異構酶活性。
Claims (32)
- 一種共軛物,其包含經由鍵聯子與HSP90靶定之部分偶合的活性劑。
- 根據申請專利範圍第1項之共軛物,其中該活性劑抑制PI3K活性。
- 根據申請專利範圍第2項之共軛物,其中該共軛物比該活性劑更少抑制PI3K活性。
- 根據申請專利範圍第2項之共軛物,其中該活性劑係選自由下列者所組成之群組:BAY 80-6946(柯潘利希布(Copanlisib))、歐米帕利希布(Omipalisib)(GSK2126458、GSK458)、PF-04691502、PI-103、BGT226(NVP-BGT226)、阿匹托利希布(Apitolisib)(GDC-0980、RG7422)、杜維利希布(Duvelisib)(IPI-145、INK1197)、AZD8186、皮拉利希布(Pilaralisib)(XL147)、PIK-93、艾德拉利希布(Idelalisib)(GS-1101)、MLN1117、VS-5584、SB2343、GDC-0941、BM120、NVP-BKM120、布帕利希布(Buparlisib)、AZD8835、XL765(SAR245409)、GS-9820 阿卡利希布(Acalisib)、GSK2636771、AMG-319、IPI-549、哌立福新(Perifosine)、阿哌利希布(Alpelisib)、TGR 1202(RP5264)、PX-866及其衍生物/類似物。
- 根據申請專利範圍第1項之共軛物,其中該HSP90靶定之部分為HSP90抑制劑。
- 根據申請專利範圍第5項之共軛物,其中該HSP90抑制劑為小分子。
- 根據申請專利範圍第6項之共軛物,其中該HSP90抑制劑係選自由下列者所組成之群組:加尼特斯皮(Ganetespib)、露米奈斯皮(Luminespib)(AUY-922、NVP-AUY922)、Debio-0932、MPC-3100、或歐那利斯皮(Onalespib)(AT-13387)、SNX-2112、17-胺基-格爾德黴素(geldanamycin)氫醌、PU-H71、AT13387及其衍生物/類似物。
- 根據申請專利範圍第1項之共軛物,其中該HSP90靶定之部分為加尼特斯皮或其衍生物。
- 根據申請專利範圍第8項之共軛物,其中該HSP90靶定之部分係選自由下列者所組成之群組:TM1、TM2、TM3、TM4、TM5或TM8。
- 根據申請專利範圍第1項之共軛物,其中該HSP90靶定之部分為歐那利斯皮或其衍生物。
- 根據申請專利範圍第10項之共軛物,其中該HSP90靶定之部分係選自由下列者所組成之群組:TM6和TM7。
- 根據申請專利範圍第1項之共軛物,其中該鍵聯子包含酯基團、二硫化物基團、醯胺基團、醯腙基團、醚基團、胺甲酸酯基團、碳酸酯基團或脲基團。
- 根據申請專利範圍第1項之共軛物,其中該鍵聯子為可切割的鍵聯子。
- 根據申請專利範圍第1項之共軛物,其中該共軛物具有少於約50,000 Da、少於約40,000 Da、少於約30,000 Da、少於約20,000 Da、少於約15,000 Da、少於約10,000 Da、少於約8,000 Da、少於約5,000 Da、少於約3,000 Da、少於2000 Da、少於1500 Da、少於1000 Da或少於500 Da之分子量。
- 根據申請專利範圍第1項之共軛物,其中該共軛物包含柯潘利希布或其衍生物及加尼特斯皮或其衍生物。
- 根據申請專利範圍第15項之共軛物,其中該共軛物係選自由下列者所組成之群組:共軛物38、共軛物40、共軛物39、共軛物27、共軛物28、共軛物29、共軛物32、共軛物33、共軛物34、共軛物41、共軛物42、共軛物44、共軛物30、共軛物35、共軛物37、共軛物43、共軛物31及共軛物36或其醫藥上可接受之鹽。
- 根據申請專利範圍第1項之共軛物,其中該共軛物包含歐米帕利希布或其衍生物及加尼特斯皮或其衍生物。
- 根據申請專利範圍第17項之共軛物,其中該共軛物係選自由下列者所組成之群組:共軛物18、共軛物22、共軛物23及共軛物17。
- 根據申請專利範圍第1項之共軛物,其中該共軛物包含PI-103或其衍生物及加尼特斯皮或其衍生物。
- 根據申請專利範圍第19項之共軛物,其中該共軛物係選自由下列者所組成之群組:共軛物24、共軛物25及共軛物19或其醫藥上可接受之鹽。
- 根據申請專利範圍第1項之共軛物,其中該共軛物包含PI-103或其衍生物及歐那利斯皮或其衍生物。
- 根據申請專利範圍第21項之共軛物,其中該共軛物係選自由下列者所組成之群組:共軛物20、共軛物26及共軛物21或其醫藥上可接受之鹽。
- 根據申請專利範圍第1項之共軛物,其另外包含滲透性調節單元。
- 根據申請專利範圍第1項之共軛物,其另外包含藥物動力學調節單元。
- 一種醫藥組成物,其包含申請專利範圍第1至24項中任一項之共軛物及至少一種醫藥上可接受之賦形劑。
- 一種減少細胞增生之方法,其包含對細胞投予治療有效量的至少一種申請專利範圍第1至24項中任一項之共軛物。
- 根據申請專利範圍第26項之方法,其中該細胞為癌細胞。
- 根據申請專利範圍第27項之方法,其中該癌細胞為小細胞肺癌細胞、非小細胞肺癌細胞、肉瘤細胞、胰臟癌細胞、乳癌細胞或結腸癌細胞。
- 一種治療對有其需要之個體的癌症之方法,其包含對該個體投予醫藥有效量的申請專利範圍第25項之醫藥組成物。
- 根據申請專利範圍第29項之方法,其中該癌為小細胞肺癌、非小細胞肺癌、肉瘤、胰臟癌、卵巢癌、乳癌或結腸癌。
- 根據申請專利範圍第29項之方法,其中該個體之該血糖含量未顯示出顯著的增加。
- 根據申請專利範圍第29項之方法,其中該癌具有PIK3CA突變。
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AU2015231413B2 (en) | 2014-03-19 | 2020-04-23 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds for use in the treatment of PI3K-gamma mediated disorders |
NZ740616A (en) | 2015-09-14 | 2023-05-26 | Infinity Pharmaceuticals Inc | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
US20220031853A1 (en) * | 2018-09-14 | 2022-02-03 | Tarveda Therapeutics, Inc. | Hsp90-targeting conjugates and formulations thereof |
CA3168495A1 (en) * | 2020-01-20 | 2021-07-29 | Neophore Limited | Isoindoline derivatives which bind to an atp binding site |
GB202008201D0 (en) * | 2020-06-01 | 2020-07-15 | Neophore Ltd | Inhibitor compounds |
MX2023004373A (es) * | 2020-10-14 | 2023-07-07 | Ranok Therapeutics Hangzhou Co Ltd | Metodos y composiciones para la degradacion dirigida de proteinas. |
CN116354933B (zh) * | 2021-12-27 | 2025-06-20 | 青岛普泰科生物医药科技有限公司 | 作为雄激素受体调节剂的杂环化合物及其应用 |
WO2024197429A1 (zh) * | 2023-03-24 | 2024-10-03 | 青岛普泰科生物医药科技有限公司 | 作为雄激素受体调节剂的杂环化合物及其应用 |
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BR212016030926U2 (pt) * | 2014-06-30 | 2018-05-29 | Tarveda Therapeutics Inc | conjugados de alvo e partículas e formulações dos mesmos |
EP3164420A4 (en) * | 2014-06-30 | 2018-05-23 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
WO2017151425A1 (en) * | 2016-02-29 | 2017-09-08 | Madrigal Pharmaceuticals, Inc. | Hsp90 inhibitor drug conjugates |
CN109071452A (zh) * | 2016-04-13 | 2018-12-21 | 英特塞普特医药品公司 | 治疗癌症的方法 |
WO2017210246A2 (en) * | 2016-05-31 | 2017-12-07 | Tarveda Therapeutics, Inc. | Penicillamine conjugates and particles and formulations thereof |
WO2018112176A1 (en) * | 2016-12-14 | 2018-06-21 | Tarveda Therapeutics, Inc. | Hsp90-targeting conjugates and formulations thereof |
US20180296685A1 (en) * | 2017-04-13 | 2018-10-18 | Tarveda Therapeutics, Inc. | Targeted constructs and formulations thereof |
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