TW202216724A - 一種喜樹鹼類藥物及其抗體偶聯物 - Google Patents
一種喜樹鹼類藥物及其抗體偶聯物 Download PDFInfo
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Abstract
本發明揭示一種喜樹堿類藥物及其抗體偶聯物,發明人在對ADC 類藥物綜合理解的基礎上,設計出一系列抗腫瘤依喜替康活性衍生物,通過實驗發現,新設計的抗腫瘤的分子化合物在實驗中表現出很好的抗腫瘤活性。
Description
本發明涉及作為抗腫瘤藥用的喜樹堿類藥物及其抗體藥物偶聯物。
抗體藥物偶聯物(ADC)作為新型的靶向藥物,一般由三部分所組成:抗體或抗體類配體,小分子藥物以及將配體和藥物偶聯起來的連接子。抗體藥物偶聯物利用抗體對抗原的特異性辨識,將藥物分子運輸至靶細胞附近並有效釋放藥物分子,達到治療目的。2011年8月,美國食品藥品監督管理局(FDA)批准西雅圖基因公司研製的用於治療霍奇金淋巴瘤以及復發性變性大細胞淋巴瘤(ALCL)的ADC新藥Adecteis
TM上市,臨床應用已經證明瞭此類藥物的安全性和有效性。
喜樹堿類藥物作為抗腫瘤性的小分子化合物,已知作為抑制DNA拓撲異構酶I而呈現抗腫瘤作用,包括伊立替康,依喜替康,SN38等。許多喜樹堿類藥物已在臨床中廣泛應用,主要適應症為骨癌、前列腺癌、乳腺癌、胰腺癌等。與目前臨床使用的伊立替康不同,依喜替康不需要通過利用酶進行活化。另外,與作為伊立替康的藥效本體的SN-38、同在臨床中使用的拓撲替康相比,拓撲異構酶I抑制活性更強,在體外針對多種癌細胞具有更強的傷細胞活性。尤其是,對於通過P-糖蛋白的表達面對SN-38等顯示耐性的癌細胞也顯示效果。依喜替康作為單獨化療藥物尚未成功上市,推測與其較高的細胞活性相關,導致治療窗口窄。
抗體藥物偶聯物(ADC)類藥物的優勢在於增加水溶性,提高靶向性,特異性抗體與抗原的結合,將藥物攜帶至靶細胞周圍,通過在靶細胞附近釋放藥物,有效殺滅腫瘤細胞,降低毒副作用。喜樹堿類藥物在ADC藥物中具有可觀的應用前景。
本專利所需要解決的技術問題,就是探索發現更優的抗腫瘤喜樹堿化合物,提高對抗腫瘤的小分子化合物在ADC藥物應用中的安全性、有效性,得到具有優異療效的抗腫瘤藥。
本發明人在對ADC類藥物綜合理解的基礎上,設計出一系列抗腫瘤喜樹堿活性衍生物,通過實驗發現,抗腫瘤的小分子化合物在細胞實驗中表現出更高的抗腫瘤活性。
本發明旨在提供一種具有更優異抗腫瘤效果的喜樹堿衍生物及其抗體藥物偶聯物,一種如式I所示的抗腫瘤喜樹堿類化合物或其藥學上可接受的鹽:
式I
其中R
1及R
2分別獨立的選自C
1-C
3烷基或取代烷基、-H、-CF
3、芳基或取代的芳基;或R
1、R
2連同其所連接碳原子構成環丁烷、環戊烷或環己烷;R
1、R
2不同時為氫。
作為優選方式,R
1為氫,R
2為C
1-C
3烷基、-CF
3、芳基、雜芳基、單氟取代的芳基或者雙氟取代的芳基;或R
1及R
2為C
1-C
3烷基、-CF
3、芳基、雜芳基、單氟取代的芳基或者雙氟取代的芳基;或R
1、R
2連同其所連接碳原子構成環丁烷、環戊烷或環己烷:
在結構式(a)中,R
2獨立地為- (CH
2)n
1-CH
3、-CF
3、芳基、雜芳基、單氟取代的芳基或者雙氟取代的芳基,其中n
1=0、1或2;
在結構式(b)中,R
1及R
2獨立地為- (CH
2)n
1-CH
3、-CF
3、芳基、雜芳基、單氟取代的芳基或者雙氟取代的芳基,其中n
1=0、1或2;
在結構式(c)中,R
1、R
2連同其所連接碳原子構成環丁烷、環戊烷、環己烷, m=1、2或3。
更加優選的,R
1為氫, R
2獨立地為- (CH
2)n
1-CH
3、-CF
3、芳基、雜芳基、單氟取代的芳基或者雙氟取代的芳基,其中n
1=0、1或2:
R
2所連接碳有R、S兩種構型,
在結構式(a-1)中,R
2所連接碳為R構型,
在結構式(a-2)中,R
2所連接碳為S構型。
作為優選例,所述的喜樹堿化合物或其藥學上可接受的鹽為抗腫瘤藥,其用於肺癌、腎癌、尿道癌、結腸癌、直腸癌、前列腺癌、多形成膠質細胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、肺癌或食道癌等實體瘤及血液腫瘤。
本發明的另一方面,包括如式II所示的抗體藥物偶聯物,該偶聯物到達靶細胞後通過釋放藥物D發揮藥效。
式II
其中Ab是抗體,抗體片段或蛋白;
L是任選的連接單元;
D選自上述述的任一喜樹堿化合物或其藥學上可接受的鹽,其通過分子中的羥基與L相連。
m選自1-20的整數。
作為優選例,所述的抗體藥物偶聯物,連接單元L包含選自化學鍵-O-,-N(R) n
1-,-CH
2-,-CH(R )n
1-,醯胺,酯鍵,-S-,—(PEG)n
2—,組成的組;n
1選自1-3整數,n
2選自1-20整數。
本發明的另一方面,包括一種治療有此需要的患者的方法,包括向所述患者給予前述請求項中任一項所述的抗體藥物偶聯物,其中所述患者患有腫瘤、自身免疫疾病或感染性疾病,並且所述的藥物-配體偶聯物的抗體特異性結合至所述癌症、自身免疫疾病的靶細胞。
優選的,所述的抗體偶聯藥物或其鹽,為抗腫瘤藥或抗癌藥,其用於肺癌、腎癌、尿道癌、結腸癌、直腸癌、前列腺癌、多形性膠質細胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、食道癌等實體瘤及血液腫瘤。
縮寫和定義
除非另有說明,否則如本文所用的以下術語和短語旨在具有以下含義。當本文中使用商標名稱時,除非上下文中另有指明,否則商標名稱包括所述商標名稱產品的產品配方、通用藥物和活性藥物成分。
術語「亞烷基」是指具有1-20個碳原子的二價直鏈飽和烴基團,包括從1至10碳原子的基團。亞烷基基團的實施例包括但不限於亞甲基(-CH2-),亞乙基(-CH2-CH2-),亞正丙基,亞正丁基,亞正戊基和亞正己基。除非另有說明,術語「芳基」指多不飽和、一般是芳族的羥基團,它可以是單環或者稠合或共價連接的多環(至多三個環)。術語「芳雜基」指含有1-5個選自N、O或S的雜原子的芳基(或環),其中所述氮和硫原子任選被氧化,所述氮原子任選被季銨化。雜芳基團可通過雜原子連接於分子的其餘部分。芳基基團的非限制性例子係包括:苯基、萘基和二苯基,而雜芳基團的非限制性例子係包括:吡啶基、噠嗪基、吡嗪基、嘧啶基(pyrimindinyl)、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基(phthalaziniyl)、苯並三嗪基、嘌呤基、苯並咪唑基、苯並吡唑基、苯並三唑基、苯並異唑基、異苯並呋喃基、異吲哚基、吲嗪基、苯並三嗪基、噻吩並吡啶基、噻吩並嘧啶基、吡啶並嘧啶基、咪唑並吡啶、苯並噻唑基(benzothiaxolyl)、苯並呋喃基、苯並噻吩基、吲哚基、喹啉基、異喹啉基、異噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、異噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、以及噻吩基等。當描述為「取代的」時,上述芳環和雜芳環系統的取代基選自下述可接受的取代基。
除非文中另有說明,烷基的取代基可以是選自下組的多種基團:-鹵素、-OR’、-NR’R’’、-SR’、-SiR’R’’R’’’、-OC(O)R’、-C(O)R’、-CO
2R’、-CONR’R’’、-OC(O)NR’R’’、-NR’’C(O)R’、-NR’-C(O)NR’’R’’’、-NR’’C(O)
2R’、-NH-C(NH
2)=NH、-NR’C(NH
2)=NH、-NH-C(NH
2)=NR’、-S(O)R’、-S(O)
2R’、-S(O)
2NR’R’’、-NR’S(O)
2R’’、-CN和-NO
2,取代基數量為0至(2m’+1),其中m’為該基團中碳原子的總數。R’、 R’’和R’’’各自獨立的指代氫、未取代的C
1-8烷基、未取代的芳基、由1-3個鹵素取代的芳基、未取代的C
1-8烷基、C
1-8烷氧基或C
1-8硫代烷氧基、或未取代的芳基-C
1-4烷基。R’和 R’’連接於同一個氮原子時,它們可與該氮原子一起形成3-,4-,5-,6-或7-元環。例如,-NR’R’’包括1-吡咯烷基和4-嗎啉基。
本文中所用的化合物的「衍生物」是指具有與化合物相似的化學結構但還含有至少一個化合物中不存在的化學基團及/或缺少至少一個化合物中存在的化學基團的物質。衍生物所比較的化合物被稱為「母體」化合物。通常,「衍生物」可在一或多個化學反應步驟中由母體化合物產生。
L-配體
配體單元是與靶標部分特異性結合的靶向劑。所述配體能夠特異性結合至細胞組分或結合至細胞組分或結合至其他感興趣的靶標分子。靶標部分或靶標通常在細胞表面上。在一些方面中,配體單元的作用是將藥物單元遞送至配體單元與之相互作用的特定靶細胞群。配體包括但不限於蛋白質、多肽和肽,以及非蛋白質如糖。合適的配體單元包括,例如,抗體,例如全長(完整)抗體及其抗原結合片段。 在配體單元是非抗體靶向試劑的實施方式中,其可以是肽或多肽,或非蛋白質分子。這類靶向試劑的示例包括干擾素、淋巴因數、激素、生長因數和集落刺激因數、維生素、營養轉運分子、或任何其他細胞結合分子或物質。在一些實施方式中,連接子共價連接至配體的硫原子。在一些方面中,硫原子是半胱氨酸殘基的硫原子,其形成抗體的鏈間二硫鍵。在另一方面中,硫原子是已經導入配體單元的半胱氨酸殘基的硫原子,其形成抗體的鏈間二硫鍵。在另一方面中,硫原子是已經導入配體單元的半胱氨酸殘基的硫原子(例如,通過定點誘變或化學反應)。在其他方面中,連接子結合的硫原子選自形成抗體的鏈間二硫鍵的半胱氨酸殘基或已經引入配體單元的額半胱氨酸殘基(例如,通過定點誘變或化學反應)。在一些實施方式中,按照Kabat(Kabat E.A等,(1991))《免疫學感興趣的蛋白質序列》(Sequences of proteins of Immunological Interest),第五版,NIH出版物91-3242)中的EU索引編號系統。
如本文所用,「抗體」或「抗體單元」在其所屬的範圍內,包括抗體結構的任何部分。這一單元可以結合,反應性關聯,或者絡合一個受體,抗原,或者靶向細胞群體具有的其它受體單元。抗體可以是任何蛋白或蛋白類分子,它可以結合,絡合,或者與待治療或生物改造的細胞群體的一部分發生反應。
本發明中組成抗體藥物偶聯物的抗體最好保持其原有野生狀態時的抗原結合能力。因此,本發明中的抗體能夠,最好專一性的與抗原結合。涉及的抗原包括,例如,腫瘤相關抗原(TAA),細胞表面受體蛋白和其他細胞表面分子,細胞存活調節因數,細胞增殖調節因數,與組織生長與分化相關的分子(如已知或預知的具有功能性的),淋巴因數,細胞因數,參與細胞循環調節的分子,參與血管產生的分子,以及與血管產生有關的分子(如已知或預知的具有功能性的)。腫瘤相關因數可以是簇分化因數(如CD蛋白)。與本發明中所述
應用在抗體藥物偶聯物中的抗體包括,但不局限於,針對細胞表面受體和腫瘤相關抗原的抗體。這樣的腫瘤相關抗原是業內所熟知的,可以通過業內熟知的抗體製備方法和資訊來製備。為了開發可用於癌症診斷與治療的有效的細胞水平目標物,研究人員力圖找尋跨膜或其他腫瘤相關多肽。這些目標物能夠特異性的表達在一或多個癌細胞表面,而在一或多個非癌細胞表面表達很少或不表達。通常,相對於非癌細胞表面而言,這樣的腫瘤相關多肽在癌細胞表面更加過度表達。確認這樣的腫瘤相關因數,可大大提高基於抗體治療癌症的專一靶向特性。
腫瘤相關抗原包括,但不局限於以下列出的腫瘤相關抗原(1)-(36)。為方便起見,為業內所熟知的抗原相關資訊標示如下,包括名稱,其他名稱,基因庫登錄號。與腫瘤相關抗原對應的核酸和蛋白序列可參見公開資料庫,例如Genbank。抗體靶向對應的腫瘤相關抗原包括所有的氨基酸序列變種和同種,與參考文件中確認的序列具有至少70%,80%,85%,90%,或者95%的同源性,或者具備與引用文件中的腫瘤相關抗原序列具有完全一致的生物性質和特徵。
術語「抑制」或「的抑制」指,減少了可檢測的量,或完全阻止。
術語「癌症」指的是以失調的細胞生長為特徵的生理病症或疾病。「腫瘤」包括癌細胞。
術語「自身免疫疾病」是源自針對個體自身的組織或蛋白質的疾病或紊亂。
本文中所用的短語「藥學上可接受的鹽」指的是,化合物(例如,藥物,藥物-接頭或配體-接頭-藥物偶聯物)的藥學上可接收到有機或無機鹽。該化合物可含有至少一個氨基或羧基,並且因此可與相應的酸或堿形成加成鹽。示例性的鹽包括但不限於:硫酸鹽、三氟乙酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸性磷酸鹽、異煙酸鹽、乳酸鹽、水楊酸鹽、酸性檸檬酸鹽、酒石酸鹽、油酸鹽、單寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、水楊酸鹽、甲酸鹽、本甲酸鹽、谷氨酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽,鉀鹽、鈉鹽等 。另外,藥學上可接受的鹽在結構中具有超過一個的帶點原子。其中多個帶電原子是藥學上可接受的鹽的一部分的示例能有多個抗衡例子。例如,藥學上可接受的鹽具有一或多個帶電原子及/或一或多個抗衡原子。
按照在細胞內藥物釋放的機制,如本文所用,「連接子」或「抗體藥物偶聯物的連接子」可被分為兩類:不可斷裂連接子和可斷裂連接子。
對於含有不可斷裂連接子的抗體藥物偶聯物,其藥物釋放機制為:偶聯物與抗原結合並被細胞內吞後,抗體在溶酶體中被酶解,釋放出由小分子藥物,連接子,和抗體氨基酸殘基共同組成的活性分子。由此帶來的藥物分子結構改變並不減弱其細胞毒性,但由於活性分子是帶電荷的(氨基酸殘基),從而導致其不能滲入鄰近細胞。因此,此類活性藥物不能殺死鄰近不表達靶向抗原(抗原陰性細胞)的腫瘤細胞(旁觀者效應,bystander effect)(Ducry等,2010,Bioconjugate Chem.21:5-13)。
可斷裂連接子,顧名思義,可以在目標細胞內斷裂並釋放出活性藥物(小分子藥物本身)。可斷裂連接子可分為兩個主要的類別:化學不穩定連接子和酶不穩定連接子。
化學不穩定連接子可以由於血漿和細胞質性質的不同而選擇性的斷裂。這樣的性質包括pH值,谷胱甘肽濃度等。
對pH值敏感的連接子,通常又稱為酸斷裂連接子。這樣的連接子在血液的中性環境下相對穩定(pH7.3-7.5),但是在弱酸性的內涵體(pH5.0-6.5)和溶酶體(pH4.5-5.0)內將會被水解。第一代的抗體藥物偶聯物大多應用這類連接子,例如腙,碳酸酯,縮醛,縮酮類。由於酸斷裂連接子有限的血漿穩定性,基於此類連接子的抗體藥物偶聯物通常具有較短的半衰期(2-3天)。這種較短的半衰期在一定程度上限制了pH敏感連接子在新一代抗體藥物偶聯物中的應用。
對於谷胱甘肽敏感的連接子,又稱二硫鍵連接子。藥物釋放是基於細胞內谷胱甘肽的高濃度(毫摩爾範圍)與血液中相對較低的谷胱甘肽濃度(微摩爾範圍)差異引起的。對於腫瘤細胞而言尤其如此,其低含氧量導致還原酶的活性增強,因而導致更高的谷胱甘肽濃度。二硫鍵具有熱力學穩定性,因此在血漿中具有較好的穩定性。
酶不穩定連接子,如肽連接子,能夠更好的控制藥物釋放。肽連接子能夠被溶酶體內蛋白酶,如組織蛋白酶(Cathepsin B)或纖溶酶(在一些腫瘤組織中此類酶含量增加),有效的切斷。這種肽連接被認為在血漿循環中非常穩定,這是因為細胞外不合宜的pH值及血清蛋白酶抑制劑導致蛋白酶通常不具備活性。鑒於較高的血漿穩定性和良好的細胞內斷裂選擇性和有效性,酶不穩定連接子被廣泛用做抗體藥物偶聯物的可斷裂連接子。典型的酶不穩定性連接子包括Val-Cit(vc),Phe-Lys等。
自殺式連接子一般嵌合在可斷裂連接子與活性藥物之間,或者本身就是可斷裂連接子的一部分。自殺式連接子的作用機制是:當可斷裂連接子在合宜的條件下斷裂後,自殺式連接子能夠自發的進行結構重排,進而釋放與之連接的活性藥物。常見的自殺式連接子包括對氨基苄醇類(PAB)和β-葡萄糖醛酸苷類(β-Glucuronide)等。
下面結合具體實施例,進一步闡述本發明,應理解,這些實施例只用於說明本發明,而不用於限制本發明的範圍。下列實施例中未註明具體條件的試驗方法,通常按照一般條件或按照製造廠商所建議的條件。除非另外說明,否則所有的百分數、比例、比率、或份數按重量計。
除非另行定義,文中所使用的所有專業和科學用於與本領域熟練人員所熟悉的意義相同。此外,任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。
實施例1 化合物2的合成
將化合物1(依喜替康甲磺酸鹽,外購)(40 mg, 75.3 mmol, 1.0eq)和L-乳酸(10 mg, 113.0 mmol, 1.5eq)溶於乾燥5 mL DMF,再加入PyBop(58.8 mg, 113.0 mmol, 1.5eq)和DIEA(15.7 uL, 113.0 mmol, 1.5eq)。室溫攪拌3小時後,TLC檢測反應完全,加水淬滅,二氯甲烷萃取(10 mL × 3),合併有機相,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物經柱色譜純化,得化合物2(30.9 mg,81.1%)。LC-MS:[M+H]+: 508.2。1H NMR(400 Mz, CDCl3/CD3OD):0.91-0.94 (3H, m), 1.32-1.39 (3H, m), 1.71-1.83 (2H, m), 2.31 (3H, s), 2.78-3.02 (2H, m), 3.16-3.26 (2H, m), 4.27-4.35 (1H, m), 4.81-4.92 (1H, m), 5.15-5.24 (2H, m), 5.49-5.76 (2H, m), 7.52 (1H, d, J=12.0 Hz), 7.58 (1H, s), 7.75 (1H, d, J=12.0 Hz)。
實施例2 化合物4的合成
於500mL單口瓶中加入化合物3:N-芴甲氧羰基-甘氨醯-甘氨酸(10g, 28.2mmol, 1.0eq),四乙酸鉛(17.5g,55.3mmol, 1.4eq),200mL乾燥四氫呋喃和67mL甲苯,攪拌均勻,氮氣保護,加熱至85℃反應2.5h。TLC監控,原料反應完後,冷卻至室溫,過濾,濾液減壓濃縮,殘餘物經柱色譜純化,得化合物4(8.7g,83.7%))。
實施例3 化合物5的合成
於25mL單口瓶中加入化合物3(500mg,1.4mmol,1.0eq), 對甲苯磺酸一水合物(26mg,0.1mmol,0.1eq)及10mLTHF,攪拌均勻後,降至0℃,再緩慢加入L-乳酸苄酯(1.2g,7.0mmol,5eq),加完後升至室溫反應。TLC監控,反應結束後,加入飽和NaHCO3溶液,用乙酸乙酯萃取,無水硫酸鈉乾燥,過濾,濃縮,殘餘物經反相柱純化得化合物5(400mg,60.3%)。1H NMR(400 Mz, CDCl3):1.39 (3H, d, J=6.8 Hz), 3.78 (2H, t, J=4.0 Hz), 4.17-4.27 (2H, m), 4.42 (2H, d, J=4.0 Hz), 4.72-4.85 (2H, m), 5.11-5.58 (2H, m), 5.43 (1H, s), 7.06 (1H, t, J=8.0 Hz), 7.25-7.33 (6H, m), 7.38 (2H, t, J=8.0 Hz), 7.57 (2H, d, J=8.0 Hz), 7.75 (2H, d, J=8.0 Hz)。
實施例4 化合物6的合成
於25mL單口瓶中加入化合物5(400mg,0.8mmol,1.0eq)和10mL DMF,攪拌均勻後,降至0℃,再緩慢加入DBU(137mg,0.9mmol,1.1eq),加完後升至室溫反應。TLC監控,反應結束後,濃縮,得化合物6粗品(550mg),不經純化,直接投下一步。
實施例5 化合物7的合成
於25mL單口瓶中加入Z-Gly-Gly-Phe-OH(372mg,0.9mmol,1.1eq),PyBOP(852mg,1.6mmol,2.0eq)和3mL DMF,室溫攪拌5分鐘,再加入化合物6粗品(550mg),室溫反應,HPLC監測。反應完畢,加入水,乙酸乙酯萃取,無水硫酸鈉乾燥,過濾,濃縮,殘餘物經反相柱柱純化得化合物7(326mg,59.2%)。
實施例6 化合物8的合成
於25mL單口瓶中加入化合物7(50mg,1.0eq,0.08mmol),5%Pd/C(50mg),3mLDMF,室溫氫化反應。HPLC監控,反應結束後加水過濾,濾液濃縮得化合物8粗品(52mg),不經純化,直接投下一步。
實施例7化合物9的合成
於25mL單口瓶中加入化合物8(52mg),SMCC(23mg,0.07mmol,1.0eq),DIEA(22.2mg,0.24mmol, 2.5eq)及3mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物9(9.0mg,18.1%)。MS:[M-H] 655.1。
實施例8 化合物11的合成
於25mL單口瓶中加入化合物9(9.0mg,0.014 mmol,1.0eq),依喜替康甲磺酸鹽(6.6mg,0.014mmol,1.0eq),PyBOP(14.3mg,0.028mmol, 2.0eq),DIEA(6.2mg,0.048mmol, 3.5eq)及0.5mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物11(7.0mg,48.3%)。TOF:[M+Na]+ 1096.42。
實施例9 化合物12、13的合成
將化合物1(依喜替康甲磺酸鹽)(40 mg, 75.3 mmol, 1.0eq)和三氟乳酸(16.3 mg, 113.0 mmol, 1.5eq)溶於乾燥5 mL DMF,再加入PyBop(58.8 mg, 113.0 mmol, 1.5eq)和DIEA(15.7 uL, 113.0 mmol, 1.5eq)。室溫攪拌3小時後,TLC檢測反應完全,加水淬滅,二氯甲烷萃取(10 mL × 3),合併有機相,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物經柱色譜純化,得化合物12(13.5 mg,32%)。LC-MS:[M+H]+: 562.2。1H NMR(400 Mz, CDCl3/CD3OD):0.91-0.95 (3H, m), 1.78-1.84 (2H, m), 2.34 (3H, s), 3.04-3.14 (2H, m), 3.27-3.32 (2H, m), 4.42-4.47 (1H, m), 5.08-5.20 (3H, m), 5.41-5.58 (2H, m), 7.23-7.25 (1H, m),7.52-7.55 (1H, m);化合物13(15.5 mg,36.7%)。LC-MS:[M+H]+: 562.2。1H NMR(400 Mz, CDCl3/CD3OD):0.90-1.00 (3H, m), 1.74-1.89 (2H, m), 2.34 (3H, s), 3.01-3.09 (2H, m), 3.32-3.38 (2H, m), 4.65-4.71 (1H, m), 4.89-4.96 (1H, m), 5.17-5.30 (2H, m), 5.55-5.65 (2H, m), 7.53-7.61 (2H, m)。
實施例10 化合物14的合成
將三氟乳酸(3.5 g, 24.3 mmol, 1.0eq)和K
2CO
3(5.0 g, 36.5 mmol, 1.5eq)溶於乾燥35 mL DMF,冰水浴下滴加溴化苄(5.0 g, 29.2 mmol, 1.2eq),氮氣保護,加完後升至室溫反應5小時,TLC檢測反應完全,加水淬滅,二氯甲烷萃取(100 mL × 3),合併有機相,依次用飽和食鹽水洗,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物經柱色譜純化,得化合物14(3.14 g,55%)。1H NMR(400 Mz, DMSO):4.91-4.94 (1H, m), 5.25 (2H, s), 7.17-7.19 (1H, d),7.39 (5H, s);
實施例11 化合物15的合成
於50mL單口瓶中加入化合物4(1.45g,3.9mmol,1.0eq), 化合物14(1.84g,7.8mmol,2.0eq), Zn(OAc)
2(1.44g,7.86mmol,2.0eq)及25mLTol,氮氣保護,攪拌均勻後,升至100℃反應5.5 h。TLC監控,產品點明顯,過濾,濾液濃縮得黃色油狀物(4.0g),粗品經柱色譜純化,得化合物15(0.99 g,46%)。1H NMR(400 Mz, CDCl3):3.68-3.83 (2H, m), 4.20-4.23 (1H,m), 4.49 (2H, d,J=8.0 Hz), 4.73-4.78 (1H, m), 4.89-5.00 (2H, m), 5.19(1H, s), 5.25 (2H, s), 7.11 (1H, s, ), 7.29-7.35 (7H, m), 7.43 (2H, t,J=8.0 Hz), 7.59 (2H, d,J=8.0 Hz), 7.79 (2H, d,J=8.0 Hz)。
實施例12 化合物16的合成
於25mL單口瓶中加入化合物15(990mg,1.8mmol,1.0eq)和10mL DMF,攪拌均勻後,降至0℃,再緩慢加入DBU(335mg,2.2mmol,1.2eq),氮氣保護,加完後繼續0℃反應30 min。TLC監控,原料反應完,反應液直接下一步反應。
實施例13 化合物17的合成
於50mL單口瓶中加入Z-Gly-Gly-Phe-OH(909mg,2.2mmol,1.2eq),PyBOP(1.4g,2.7mmol,1.5eq)和10mL DMF,冰水浴下滴加DIEA,氮氣保護,繼續反應10 min,將化合物16反應液冰水浴下緩慢滴加至此反應液中,加完後升至室溫反應1.5 h,HPLC監測,反應完畢,製備純化,凍幹得化合物17(0.91 g,71%)。
實施例14 化合物18的合成
於25mL單口瓶中加入化合物17(85mg,1.0eq,0.12mmol),5%Pd/C(85mg),6mLDMF,室溫氫化反應1 h。HPLC監控,原料反應完,反應液過濾,濾液直接投下一步反應。
實施例15化合物19的合成
將化合物18反應液過濾至25mL單口瓶中,冰水浴下依次加入SMCC(80mg,0.24mmol,2.0eq),DIEA(62mg,0.48mmol, 4.0eq),氮氣保護,加完後升至室溫反應1 h,HPLC監控,製備純化,凍幹得化合物19(66 m g,78%),MS:[M-H] 709.2。
實施例16 化合物20、21的合成
將化合物19(10 mg, 14 umol, 1.0eq)、化合物1(9 mg, 21 umol, 1.5eq)和PyBop(14.6 mg, 28 mmol, 2.0eq)溶於乾燥DMF(0.5 mL),冰水浴下加入DIEA(5 uL,28umol, 2.0eq),氮氣保護,加後升至室溫反應1 h,HPLC監控,原料化合物19反應完,反應液直接HPLC純水製備後分別得到化合物20(2.77 mg,17.5%),LC-MS:[M+H]+: 1128.0;化合物21(3.92 mg,24.8%),LC-MS:[M+H]+: 1128.0。
實施例17化合物22的合成
將化合物18反應液(0.15mmol,1.0eq)過濾至25mL單口瓶中,冰水浴下依次加入MC(93mg,0.3mmol,2.0eq),DIEA(78mg,0.6mmol, 4.0eq),氮氣保護,加完後升至室溫反應1 h,HPLC監控,純水製備純化,凍幹得化合物22(90 m g,86%),MS:[M-H] 683.2。
實施例18 化合物23、24的合成
將化合物22(15 mg, 21.9 umol, 1.0eq)、化合物1(14.3 mg, 32.8 umol, 1.5eq)和PyBop(22.8 mg, 43.8 mmol, 2.0eq)溶於乾燥DMF(0.8 mL),冰水浴下加入DIEA(7.3 uL,43.8umol, 2.0eq),氮氣保護,加後升至室溫反應1 h,HPLC監控,原料化合物22反應完,反應液直接HPLC純水製備後分別得到化合物23(6.01 mg,25%),LC-MS:[M+H]+: 1102.0;化合物24(5.57 mg,23.2%),LC-MS:[M+H]+: 1102.0。
實施例18 化合物25的合成
於5mL單口瓶中加入扁桃酸(42mg,0.09mmol,1.1eq),依喜替康(35mg,0.08mmol,1.0eq),PyBOP(84mg,0.16mmol, 2.0eq),DIEA(36.4mg,0.28mmol, 3.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物25(15.0mg,32.6%)。1H NMR(CDCl
3,400Mz) δ7.70(d,1H,J=8.0Hz),7.64(s,1H),5.64-5.75(m,2H),5.48-5.38(m,1H),5.29-5.21(m,1H),5.19-5.11(m,1H),3.37-3.11(m,2H),2.55-2.38(m,4H),2.32-2.15(m,2H),2.08-1.99(m,1H),1.94-1.85(m,4H),1.33-1.24(m,4H),1.05(t,3H,J=7.2Hz);LC-MS:[M+H] 548.4。
實施例19 化合物26的合成
於5mL單口瓶中加入D-乳酸(11.2mg,0.08mmol,1.1eq),依喜替康(30.0mg,0.07mmol,1.0eq),PyBOP(119.5mg,0.14mmol, 2.0eq),DIEA(31.2mg,0.25mmol, 3.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物26(7.2mg,20.6%)。1H NMR(CDCl
3,400Mz) δ7.75(d,1H,J=10.4Hz),7.70(s,1H),5.75-5.63(m,2H),5.46-5.38(m,1H),5.30-5.16(m,2H),4.50-4.40(m,1H),3.34-3.13(m,2H),2.50-2.36(m,3H),2.34-2.21(m,1H),2.05-2.02(s,1H),1.96-1.84(m,2H),1.35-1.23(m,3H),1.06(t,3H,J=4.0Hz);LC-MS:[M+H] 508.3。
實施例20 化合物27的合成
於5mL單口瓶中加入2-甲基乳酸(10.5mg,0.10mmol,1.1eq),依喜替康(40mg,0.09mmol,1.0eq),PyBOP(95.6mg,0.18mmol, 2.0eq),DIEA(41.4mg,0.32mmol, 3.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物27(10.0mg,20.8%)。1H NMR(CDCl
3,400Mz) δ7.68(d,1H,J=24Hz),7.63(s,1H),5.77-5.59(m,2H),5.48-5.39(m,1H),5.30-5.22(m,1H),5.19-5.11(m,1H),3.33-3.10(m,2H),2.24(s,3H),1.71-1.63(m,2H),1.58-1.52(m,2H),1.40-1.20(m,6H),1.05(t,3H,J=7.2Hz);LC-MS:[M+H] 522.2。
實施例4化合物 28的合成
於5mL單口瓶中加入R)-(-)-扁桃酸(15.2mg,0.10mmol,1.1eq),依喜替康(40mg,0.09mmol,1.0eq),PyBOP(95.6mg,0.18mmol, 2.0eq),DIEA(41.4mg,0.32mmol, 3.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物28(12.2mg,23.3%)。1H NMR(CDCl
3,400Mz) δ7.76(d,1H,J=8.0Hz),7.69(s,1H),7.53-7.35(m,5H),5.77-5.70(m,1H),5.65-5.55(m,1H),5.34-5.20(m,4H),3.32-3.31(m,2H),2.47-2.40(m,3H),2.30-2.27(m,1H),2.05-2.02(s,1H),1.93-1.89(m,3H),1.07(t,3H,J=8.0Hz);LC-MS:[M+H] 570.2。
實施例21 化合物29的合成
於5mL單口瓶中加入3,5-二氟扁桃酸(23.7mg,0.13mmol,1.1eq),依喜替康(50mg,0.11mmol,1.0eq),PyBOP(119.5mg,0.23mmol, 2.0eq),DIEA(37.1mg,0.29mmol, 2.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物29(13.5mg,19.4%)。1H NMR(DMSO,400Mz) δ8.76(d,1H,J=8.4Hz),7.81(d,1H,J=10.8Hz),7.31(s,1H),7.27-7.07(m,4H),5.54-5.47(m,1H),5.43(s,2H),5.20-5.03(m,4H),3.20-3.09(m,2H),2.43-2.38(m,3H),2.17-2.09(m,1H),1.96-1.79(m,3H),0.88(t,3H,J=7.2Hz);LC-MS:[M+H] 606.2。
實施例22 化合物30的合成
於5mL單口瓶中加入3,5-二氟扁桃酸(22.5mg,0.13mmol,1.1eq),依喜替康(50mg,0.11mmol,1.0eq),PyBOP(119.5mg,0.23mmol, 2.0eq),DIEA(37.1mg,0.29mmol, 2.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物30(8.2mg,11.7%)。1H NMR(DMSO,400Mz) δ8.60(d,1H,J=8.4Hz),7.79(d,1H,J=11.2Hz),7.31(s,1H),7.02-6.90(m,2H),6.90-6.72(m,1H),6.05-5.93(m,2H),5.52-5.40(m,2H),5.19-5.09(m,1H),5.09-4.92(m,2H),2.98-2.85(m,2H),2.22-2.14(m,3H),1.94-1.83(m,1H),1.75-1.59(m,1H),1.53-1.45(m,2H),0.66(t,3H,J=7.2Hz);LC-MS:[M+H] 614.2。
實施例23 化合物31的合成
於5mL單口瓶中加入S-2-羥基丁酸(16.3mg,0.16mmol,1.1eq),依喜替康(68.0mg,0.16mmol,1.0eq),HATU(59.4mg,0.16mmol, 1.0eq),DIEA(50.5mg,0.39mmol, 2.5eq)及1mLDMF,室溫反應,HPLC監控,製備純化,凍幹得化合物31(16.3mg,20.1%)。1H NMR(DMSO,400Mz) δ8.36(d,1H,J=8.8Hz),7.79(d,1H,J=11.2Hz),7.31(s,1H),6.53(s,1H),5.60-5.52(m,1H),5.46-5.40(m,3H),5.24-5.17(m,2H),3.23-3.09(m,2H),2.45-2.38(m,3H),2.28-2.08(m,2H),1.94-1.80(m,2H),1.79-1.66(m,1H),1.66-1.55(m,1H),1.05-0.84(m,6H);LC-MS:[M+H] 522.3。
實施例24 喜樹堿藥物細胞活性測試
通過下列實驗程序測定喜樹堿藥物細胞毒性活性:將喜樹堿藥物分別加入到A431、Fadu、Bxpc-3(EGFR陽性表達細胞)和U87-MG、SW620(陰性對照細胞)表達的人的腫瘤細胞培養基中,細胞培養72小時後測定細胞存活率。基於細胞的體外實驗用於測定細胞存活率、細胞毒性和本發明喜樹堿藥物誘導的細胞程式性死亡。
通過細胞增殖試驗測定喜樹堿藥物的體外藥效。CellTiter 96®AqueousOne Solution Cell Proliferation Assay為商購的(Promega Corp.,Madison, WI)。CellTiter 96® AQueous One Solution Cell Proliferation Assay(a)是一種用比色法來檢測細胞增殖和細胞毒性實驗中的活細胞數量的檢測試劑。此試劑含有一個新型的四唑化合物[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium, inner salt; MTS]和一種電子偶聯劑(phenazine ethosulfate; PES)。PES具有增強的化學穩定性,這使它可與MTS混合形成穩定的溶液。這種方便的「單溶液」模式,是在第一代CellTiter 96®AQueous Assay的基礎上的改進,CellTiter 96®AQueous Assay中使用的電子偶聯劑PMS與MTS溶液是分開提供的。 MTS (Owen’s reagent) 被細胞生物還原成為一種有色的甲臢產物,可直接溶解於培養基中(圖1)。這種轉化很可能是在代謝活躍的細胞中的脫氫酶產生的NADPH或NADH的作用下完成的。檢測時,只需將少量的CellTiter 96® AQueous One Solution Reagent 直接加入培養板孔的培養基中,孵育1–4小時,然後以酶標儀讀取490nm的吸光度值。
在490nm處檢測到的甲臢產物的量與培養中的活細胞數成正比。由於MTS的甲臢產物在組織培養基中可溶,CellTiter 96® AQueous One Solution Assay與MTT或INT法相比操作步驟更少。
本發明中採用A431、Fadu、Bxpc-3(EGFR陽性表達細胞)和U87-MG、SW620(陰性對照細胞)作為體外藥效檢測的研究體系。在96孔板中,使用適當的細胞密度進行鋪板,24小時後,進行喜樹堿藥物加藥。24小時後用檢測培養基稀釋喜樹堿藥物(1uM起始,5倍稀釋,9個濃度,第十列添加檢測培養基用來作為空白對照),將稀釋好的喜樹堿藥物加入對應的細胞孔中然後用微孔板震盪器(型號:MX100-4A)震盪3min,震速550rpm/min,震盪完放入二氧化碳培養箱孵育3天。3天后每孔加入20ul MTS(Promega,G3581)反應2小時,酶標儀(Molecular Device,型號:SpectraMAX190)490nM讀數。通過檢測線粒體內的脫氫酶的活性,評價喜樹堿藥物對細胞的增殖抑制作用。
化合物編號 | 細胞活性( nm ) | ||||
Fadu | BXPC-3 | A431 | U87-MG | SW620 | |
SN38 | 42.14 | 119.85 | 13.62 | 15.65 | 3.28 |
2 | 11.09 | 38.82 | 40.93 | 7.4 | 10.43 |
12 | 0.002 | 1.6 | 15.47 | 0.06 | 0.06 |
13 | 0.06 | 40.02 | 6.37 | 0.32-1.6 | 1.06 |
25 | 41.03 | 15.79 | 11.67 | 10.41 | 1.50 |
28 | 14.25 | 80.98 | 5.12 | 18.34 | 11.90 |
29 | 41.29 | 90.10 | 19.55 | 23.61 | 2.15 |
30 | 19.23 | 34.21 | 19.88 | 29.90 | 2.25 |
31 | 17.52 | 55.41 | 14.78 | 10.80 | 17.53 |
SN38為經典的高活性喜樹堿藥物,並已經在IMMU-132 ADC中獲得臨床證明。發明人通過細胞活性實驗,證明本發明所述的喜樹堿衍生物在代表性的腫瘤細胞Fadu、BXPC-3、A431、U87-MG、SW620中均表現出了與SN38相當或更高的細胞活性。
實施例25 偶聯製備ADC通法
將通過初步的純化後單體率大於95% 的抗體分子C,使用超濾離心管換液至磷酸鹽緩衝液中,濃度10mg/ml。加入20倍於抗體摩爾分子數的TCEP,室溫下反應4h以打開抗體鏈間二硫鍵。加入20倍於抗體摩爾分子數的payload,室溫下反應2h。反應結束後,使用截留分子量為30KDa的超濾離心管換液至PBS中,並去除未偶聯的payload。換液後的ADC樣品使用0.22微米除菌篩檢程式過濾後備用。將偶聯用化合物11、20、21、23、24採用本實施例25所述偶聯通法,與抗體分子C偶聯。
實施例26 ADC抗腫瘤細胞活性測試
化合物編號 | 偶聯所得 ADC 編號 |
11 | C-11 |
20 | C-20 |
21 | C-21 |
23 | C-23 |
24 | C-24 |
與喜樹堿藥物細胞活性測試方法相似,本發明中採用A431、Fadu、Bxpc-3(抗原陽性表達細胞)、SW620(抗原陰性對照細胞)作為體外藥效檢測的研究體系。在96孔板中,使用適當的細胞密度進行鋪板,24小時後,進行ADC藥物加藥。24小時後用檢測培養基稀釋ADC藥物(1uM起始,5倍稀釋,9個濃度,第十列添加檢測培養基用來作為空白對照),將稀釋好的ADC藥物加入對應的細胞孔中然後用微孔板震盪器(型號:MX100-4A)震盪3min,震速550rpm/min,震盪完放入二氧化碳培養箱孵育3天。3天后每孔加入20ul MTS(Promega,G3581)反應2小時,酶標儀(Molecular Device,型號:SpectraMAX190)490nM讀數。通過檢測線粒體內的脫氫酶的活性,評價ADC藥物對細胞的增殖抑制作用。
化合物編號 | 細胞活性( nm ) | |||
Fadu | BXPC-3 | A431 | SW620 | |
C-11 | 12.44 | 242.09 | 27.86 | 221.24 |
C-20 | 3.98 | 186.98 | 30.74 | 85.16 |
C-21 | 2.49 | 86.97 | 8.15 | 48.17 |
C-23 | 4.74 | 25.18 | 11.16 | 154.40 |
C-24 | 4.09 | 15.79 | 11.67 | 1.50 |
經過以上ADC細胞活性測試,本發明所述的喜樹堿藥物在通過連接單元L與抗體偶聯後,在多個抗原陽性腫瘤細胞系中均表現出良好的抗腫瘤活性,具有極大的臨床應用價值。
實施例27 ADC體內藥效測試
本發明中建立了A431荷瘤小鼠模型,以評價毒素ADC偶聯藥物的體內藥效。即以3×10
6A431細胞通過皮下注射到4~6周鼠齡的BALB/c裸鼠右側,待小鼠腫瘤平均大小生長至140~150mm3,隨機封包,每組5只,在第0, 7, 14,21天分別給與空白對照(緩衝溶液空白)、抗體藥物偶聯物C-11,均以10mg/kg劑量進行靜脈給藥。腫瘤體積測量資料顯示為測量時腫瘤平均體積±SE,同時記錄小鼠體重變化情況,用以觀察ADC藥物的體內初步毒性。
類別 | 小鼠體重 | ||||||
D0 | D3 | D7 | D10 | D13 | D16 | D20 | |
空白對照 | 16.4±0.31 | 17.4±0.32 | 18.3±0.47 | 18.5±0.42 | 18.9±0.45 | 18.9±0.35 | 19.5±0.33 |
C-11 | 17.6±0.16 | 18.2±0.14 | 18.8±0.31 | 19.2±0.29 | 19.6±0.30 | 19.9±0.28 | 20.1±0.39 |
類別 | 腫瘤平均體積( mm3 ) | ||||||
D0 | D3 | D7 | D10 | D13 | D16 | D20 | |
空白對照 | 152.0±16.22 | 296.0±38.14 | 621.6±87.52 | 823.6±71.51 | 1,028.0±94.51 | 1,227.5±98.30 | 1,526.5±97.14 |
C-11 | 147.4±8.04 | 168.8±6.76 | 256.5±26.69 | 316.8±35.44 | 352.8±39.31 | 333.0±79.16 | 347.2±107.67 |
經過以上ADC小鼠體內藥效實驗,證明本發明所述的喜樹堿藥物在通過連接單元L與抗體偶聯後,在荷瘤小鼠中表現出了明確的抗腫瘤活性,平均瘤體明顯低於空白對照。小鼠體重在給藥期間無明顯變化,組內無小鼠死亡,本發明所述的喜樹堿藥物具有良好的安全性。
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Claims (10)
- 如請求項1之喜樹堿類化合物或其藥學上可接受的鹽,其中:R 1為氫,R 2為C 1-C 3烷基、-CF 3、芳基、取代的芳基或雜芳基;或R 1及R 2為C 1-C 3烷基、-CF 3、芳基、雜芳基或取代的芳基;或R 1、R 2連同其所連接碳原子構成環丁烷、環戊烷或環己烷: 在結構式(a)中,R 2獨立地為- (CH 2)n 1-CH 3、-CF 3、芳基、雜芳基、取代的芳基,其中n 1=0、1或2; 在結構式(b)中,R 1及R 2獨立地為- (CH 2)n 1-CH 3、-CF 3、芳基、雜芳基、取代的芳基,其中n 1=0、 1或 2; 在結構式(c)中,R 1、R 2連同其所連接碳原子構成環丁烷、環戊烷、環己烷, n 2=1、 2或3。
- 如請求項1-3任一所述的喜樹堿類化合物或其藥學上可接受的鹽,其中:芳基取代基選自鹵素、烴基、烷氧基、羥基、硝基、氨基、羥基或氰基。
- 包括請求項1~5任一所述的喜樹堿類化合物或其藥學上可接受的鹽的抗腫瘤藥,其中:用於肺癌、腎癌、尿道癌、結腸癌、直腸癌、前列腺癌、多形成膠質細胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、肺癌或食道癌等實體瘤或血液腫瘤。
- 如請求項7之抗體藥物偶聯物,其中:連接單元L結構中包含選自化學鍵-O-,-N(R) n 1-,-CH 2-,-CH(R )n 1-,醯胺,酯鍵,-S-,—(PEG)n 2—,組成的組;n 1選自1-3整數,n 2選自1-20整數。
- 如請求項7或8中所述的抗體藥物偶聯物,其中:所述的藥物-配體偶聯物的抗體特異性結合至癌症、自身免疫疾病的靶細胞。
- 包括請求項7~9中任一所述的抗體偶聯藥物的藥物,其中:用於肺癌、腎癌、尿道癌、結腸癌、直腸癌、前列腺癌、多形性膠質細胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、食道癌等實體瘤或血液腫瘤。
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