CN112272669A - 横交联吡咯并苯二氮杂*二聚体(pbd)衍生物及其偶联物 - Google Patents
横交联吡咯并苯二氮杂*二聚体(pbd)衍生物及其偶联物 Download PDFInfo
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- XMTVPWPWVYPLDO-UHFFFAOYSA-N trityloxysilane Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O[SiH3])C1=CC=CC=C1 XMTVPWPWVYPLDO-UHFFFAOYSA-N 0.000 description 1
- 230000001573 trophoblastic effect Effects 0.000 description 1
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- 150000003672 ureas Chemical class 0.000 description 1
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- 229950000386 vapaliximab Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明申请涉及新型可横交联细胞毒剂,吡咯并苯并二氮杂
Description
发明领域
发明背景
抗体药物偶联物(ADC)作为抗癌药物具有广阔的前景,目前已经有四个ADC药物获得FDA批准,100多个使用几种不同类别的细胞毒性剂的ADC药物被批准用于临床研究,如美登素(mytansine)(Zhao,Robert Y.等,J.Med.Chem.,2011,54,3606;Widdison,W.等,J.Med.Chem.,2006,49,4392-4408);奥瑞他汀(autistatin)及其母体化合物海兔毒素(dolastatin)(Doronina,S.O.等,Nat.Biotechnol.,2003,21(7),778-784;Maderna,A.,J.Med.Chem.,2014,57(24),10527–10543);加利车霉素(calicheamycin)(Ricart,A.D.Clin.Cancer Res.,2011,17,6417-6427;Ricart A.D.等,Nat.Clin.Pract.Oncol.,2007;4,245-255),多卡霉素(duocarmycin)及其类似物CC-1065(Elgersma,R.C.Mol.Pharmaceutics,2015,12(6),1813–1835;Zhao,Robert Y.等,J.Med.Chem.,2012,55,766-782),tubulysin(Li,J.Y.等,Cancer Cell,2016,29(1),117-29;Tumey,L.N.等ACSMed Chem Lett.,2016,7(11),977-982;Huang Y.Y.,Zhao,Robert Y.等,Med Chem.#44,249th ACS National Meeting,Denver,CO,Mar.22~26,2015;WO2014009774);喜树碱(camptothecin)及其类似物SN-38(Cardillo.T.M等,Bioconjug Chem.,2015,26(5),919-31;Cardillo.T.M,等,Clin Cancer Res.,2011,17(10),3157-69;Doi T.等,LancetOncol.,2017,18(11),1512-1522;PCT/JP2013/006069;US20160333112);鹅膏菌素(amanitin)(Moldenhauer G.等,J.Natl.Cancer Inst.,2012,104(8),622-34;Zhao,Robert Y.等,PCT/IB2016/052246);长春碱(vinblastine)(Laguzza,B.C.等,J.Med.Chem.,1989,32,548-555;Starling,J.J.等Bioconj.Chem.,1992,3,315-322);阿霉素(doxorubicin)(Yang,H.M.和Reisfeld,R.A.,Proc.Natl.Acad.Sci.USA,1988,85,1189-93;Sapra,P.等,Clin.Cancer Res.,2005,11,5257-64;Geretti,E.等,Mol.Cancer Ther.,2015,14,2060-71);Cryptophycin(Verma,V.A.等,Bioorg.Med.Chem.Lett.,2015,25(4),864-8);艾日布林(Eribulin)(Furuuchi,K.等,MORAb-202,8th World ADC,Sept.,19,2017;US2017252458);和吡咯并苯二氮杂二聚体(PBD)(Mantaj,J.等,Angew.Chem.Int.Ed.,2016,55,2–29;D.Antonow和D.Thurston,Chem.Rev.,2011,111,2815–2864)。近年来,应用PBD类细胞毒剂作为有效载荷的ADC药物不断增加(Kung Sutherland,M.S.等,Blood,2013,122,1455-63;Jeffrey S.C.,Bioconjug Chem.,2013,1256-63;Saunders,L.R.等,SciTransl Med.,2015,7(302),302ra136;Flynn,M.J.等,Mol Cancer Ther.,2016,15(11),2709-272;.Zhao,Robert Y.,WO2015028850;Donnell,A.F.等Bioorg.Med.Chem.Lett.,2017,27,5267-5271)。PBD对美国国家癌症研究所(NCI)的60种肿瘤细胞系大多数具有极强的杀灭力,并且具有独特的抗肿瘤和抗菌机制(Mantaj J.等,Angew.Chem.Int.Ed.,2016,55,2–29)。
如下结构所示,一般而言,PBD都是通过一个条件限制性的稳定连接子与抗体偶联,因为通常认为ADC在血液中循环时必须稳定,以限制脱靶毒性,而一旦药物进入靶细胞内后又能释放小分子毒素(Alain Beck,2017,Nature Reviews Drug Discovery,doi:10.1038/nrd.2016.268)。不幸的是,临床上进展最快的药物Vadastuximab talirine(以条件限制性的稳定连接子连接的CD33抗体-PBD偶联物)(Stein,E.M.等,Blood,2018,131,387-96)由于肝毒性而遭受挫折,在早期试验中因此导致四名患者死亡(www.xconomy.com/seattle/2017/06/19)。
The SGD-1882偶联物,Seattle Genetics开发。
SG3249偶联物,ADC Therapeutics Ltd和MedImmune/AstraZeneca开发。
D-212偶联物,Cellerant Therapeutics开发。
IGN偶联物,ImmunoGen,Inc.开发。
Tomaymysin二聚体(PBD)偶联物,赛诺菲开发。
PBD二聚体偶联物,杭州多禧生物技术有限公司开发。
PBD二聚体偶联物,杭州多禧生物技术有限公司开发。
SG-3199偶联物,Stemcentrx/Abbvie和ADC Therapeutics Ltd.开发。
SG-3199偶联物,Allozyne,Inc.开发。
SG2057偶联物,Genentech Inc.开发。
含无痕连接子的PBD偶联物,Genentech Inc.开发。
PBD二聚体偶联物,百时美施贵宝(Bristol-Myers Squibb)开发。
在本发明中,我们公开了一种PBD二聚体衍生物的偶联物,其通过一个双重横交联连接子分别在PBD二聚体的N10位置连接,因此其DNA烷基化位点,亚胺以前药形式的存在,只有在连接子被分解后偶联物才具有活性。与含有单一连接子的PBD偶联物相比,应用双横交联方法制得,前药形式的PBD偶联物在体外和体内表现出更宽的治疗窗口。因此,在临床应用中,它可能具有更好的抗肿瘤抗菌活性。
发明内容
或是其药学上可接受的盐、水合物或水合盐;或其多晶型晶体;或其光学异构体、外消旋体、非对映异构体或对映异构体;
其中:
-----代表可选的单键或可以缺省;
V和V’相同或不同,独立地选自H、OH、-NHOH、OR5(醚)、OCOR5(酯)、OCOOR5(碳酸酯)、NR5R5’、NR5COR5’或NR5NR5’NR5”(胺)、OCONR5R5’(氨基甲酸酯)、NR5(C=NH)NR5’R5”(胍)、NR5CONR5’R5”(尿素)、OCSNHR5(硫代氨基甲酸酯)、-SH(巯基)、–SR5(硫化物)、SOR5(亚砜)、SOOR5(砜)、SO3、HSO3、HSO2或HSO3-、SO3 2-或-HSO2-的盐(亚硫酸盐)、OSO3(亚硫酸氢盐)、NR5SOOR5’(磺酰胺)、H2S2O5或S2O5 2-盐(偏亚硫酸氢盐)、PO3SH3、PO2S2H2、POS3H2、PS4H2或PO3S3-、PO2S2 3-、POS3 3-、PS4 3-的盐(单、二、三和四硫代磷酸盐)、(R5O)2POSR5’(硫代磷酸酯)、HS2O3或S2O3 2-的盐(硫代硫酸盐)、HS2O4或S2O4 2-的盐(连二亚硫酸盐)、P(=S)(OR5)(S)(OH)(二硫代磷酸酯)或与阳离子形成的盐、-NR5OR5’(羟胺衍生物)、R5C(=O)NOH(异羟肟酸)或与阳离子形成的盐、HOCH2SO2-或其盐(甲醛合次硫酸氢盐)、NR5COR5’(酰胺)、N3(叠氮基)、CN(氰基)、X(卤素)、C(R5)(R5')(R5”)(三烷基)、OP(O)(OR5)(NHR5')或OP(O)(NHR5)(NHR5')(氨基磷酸酯、磷酰胺酸)、P(R5)(R5')(R5”)三芳基膦、Aa(氨基酸)或NR5CO(Aa)t(肽),其中Aa是一种氨基酸或含t=1100个氨基酸单元的多肽;氨基酸衍生基团,例如α-,β-,γ-或ω-氨基酸或非天然氨基酸;其中R5,R5'和R5”定义如下文所述;
l、m、q、l’、m’和q’独立地为0、1、2、3、4、或5;n是1~30;
X、X’、Y和Y’是相同或不同的,各自独立地为N、O、S、烷基(例如CH2或CHR5)、烯烃(例如=CH-或=CR5-)、醚(例如-C(OR5)H-)。
Z和Z’相同或不同,各自独立地为N、CH、CR5、COH、CNH2、CNHR5或COR5,或Z和Z’与–COR5OC-连接在一起,R5独立地选自C1~C8烷基和芳基;
R1、R2、R3、R4、R1’、R2’、R3’和R4’相同或不同,并且独立地选自-H,可被取代的含有1至10个碳的直链、支链或环状烷基、烯基或炔基、-(OCH2CH2)tR5(聚乙二醇单元)、卤素、NH(C=NH)NH2(胍基)、-OR5、-NR5R5'、-NO2、-NCO、-NR5COR5'、-SR5、–SOR5(亚砜)、-SO2R5(砜)、--SO3 -M+(磺酸盐)或-SO3H、–OSO3 -M+(硫酸盐)或OSO3H、-SO2NR5R5’(磺酰胺)、CN(氰基)、N3(叠氮基)、-COR5、-OCOR5、-OCONR5R5'、CF3、OR5、芳基、杂环或P(O)R5R5’R5”和带有反应性基团或链接至细胞结合剂的连接基团(L”)或没有Q、Q’和T缺省;
R5、R5’和R5”独立地选自H、C1-C8烷基、烯基、炔基、杂烷基、芳基、芳基烷基、羰基或药用盐;
另外,R1和R2可以连接在一起,或R1’和R2’连接在一起,形成=O(酮)、=S、=NR、-C(=O)R或含=CR5R5’基团的双键。R1和R2连接在一起,或R1'和R2'连接在一起,或R3和R4连接在一起,或R3'和R4'连接在一起形成C3-C12芳环、杂环或杂芳基环;
U和U’独立地为C(O)、C(O)O、C(O)NH、C(O)N(R5)、C(=NH)、C(=NH)O、C(=NH)NH、C(=NH)N(R5)、-C=N-、C(=S)、C(O)S、C(S)NH、C(S)N(R5)、S(O)、S(O)O、S(O)NH、S(O)(OR5)、S(O)(N(R5))、S(O2)、S(O2)O、P(O)(OR5)、P(O)(OR5)O、P(O)(NH2)、P(O)(NR5R5’)、P(O)(OR5)NH-、P(O)(OR5)NR5’-、P(O)(N(R5R5’)(N(R5)、P(S)(OR5)、P(S)(OR5)O、P(S)(NH2)、P(S)(NR5R5’)、P(S)(OR5)NH-、P(S)(OR5)NR5’-、P(S)(N(R5R5’)N(R5)、R5、R5O;
E1和E2独立地为S、R5S、C(O)S、C(O)NH、C(O)O、C(O)R5S、C(=NH)NH、C(=NH)N(R5)、C(=NH)S、-C=N-、C(=S)S、C(O)S、C(=S)NH、C(=S)N(R5)、Ar-S、NC(O)CH2S、ArC(O)CH2S、S-S、
其中两个原子中间的化学键表示它可以连接两个相邻的原子;L1,L2独立地为连接子,或包含能够与细胞结合剂(CBA)反应的官能团的连接子,L1和L2独立地优选为可断裂的连接子,具有结构式—Ww—(Aa)r—Tt—或—Ww—(Aa)r—Tt—Q或Q—Ww—(Aa)r—Tt—;其中-W-是延展体单元;w是0或1;-Aa-独立地是氨基酸单元;r独立地是0至100的整数;-T-为间隔体单元,可以为直链烷基或支链烷基或聚乙二醇间隔体;t为0或1100。延展体单元W可独立地包含自毁灭间隔体、肽单元、腙键、二硫键、酯键或硫醚键;w是1或2或3;优选的L1和L2独立地选自O、NH、N、S、P、NNH、NHNH、N(R3)、N(R3)N(R3’)、CH、CO、C(O)NH、C(O)O、NHC(O)NH、NHC(O)O、聚乙二醇单元如(OCH2CH2)pOR3、(OCH2CH-(CH3))pOR3、NH(CH2CH2O)pR3、NH(CH2CH(CH3)O)pR3、N[(CH2CH2O)pR3]-[(CH2CH2O)p’R3’]、(OCH2CH2)pCOOR3或CH2CH2(OCH2CH2)p-COOR3,其中p和p’独立地选自0至1000的整数、或它们的组合;C1-C8烷基、C2-C8杂烷基、烷基环烷基、杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;或(Aa)r、r=1-12(1至12个氨基酸单位)、由天然或非天然氨基酸、或相同或不同序列的二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、十一肽或十二肽单元组成;
Q是细胞结合分子,或者能够与细胞结合剂反应的官能团,或者能够与连接在细胞结合剂上的连接子反应的官能团。所述官能团选自巯基、胺、肼、烷氧基氨基、取代的二硫键、马来酰亚胺基、卤代乙酰基、N-羟基琥珀酰亚胺酯、酮、酯、醛、炔基、烯基或受保护的巯基或二硫键,例如SAc、SSR1或SSAr。Ar是芳香基团或杂芳香基团。Q优选为细胞结合剂/分子,选自抗体、单链抗体、与靶细胞结合的抗体片段、单克隆抗体、单链单克隆抗体、结合靶细胞的单克隆抗体片段、嵌合抗体、结合靶细胞的嵌合抗体片段、结构域抗体、结合靶细胞的结构域抗体片段、adnectin类抗体、DARPins、淋巴因子、激素、维生素、生长因子、集落刺激因子、营养转运分子(转铁蛋白)以及结合在白蛋白、聚合物、树状大分子、脂质体、纳米颗粒、囊泡或(病毒)衣壳上的细胞结合肽、蛋白质或小分子。
在第二个实施方案中,本发明公开了PBDs衍生物与细胞结合分子通过单链连接子偶联产生的偶联物,如式(II),(III)和(IV)所示,用于靶向治疗细胞不受限制的增殖。
其中-----、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、G、Q、E1和E2的定义同式(I)。
在第三个实施方案中,本发明公开了一种治疗组合物,包含:(1)有效量的一种或多种吡咯并[2,1-c][1,4]苯并二氮杂衍生物与细胞结合剂连接而产生的偶联物,结构如式(I),(II),(III)或(IV)所示;和(2)本发明式(I)(IV)的药学上可接受的载体,稀释剂或辅料,以杀死靶细胞或含有靶细胞的组织。
附图的简要说明
图31显示了苯二氮杂卓二聚体偶联物中间体的合成。
图34显示了向ICR小鼠注射偶联物CC-4,CC-29,T-DM1和PBS缓冲液后第5天,小鼠肝脏组织的苏木精和曙红染色情况。
发明内容
定义:
“烷基”是指在烷烃上除去一个或两个氢原子而产生的脂肪烃基团或单价基团。它可以是直链或是支链的,在链中含有C1-C8(1-8个碳原子)。“支链”是指直链烷基上连接有一个或多个低碳数的烷基,如甲基、乙基或丙基。示例性的烷基包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、辛基、壬基、癸基、环戊基、环己基、2,2-二甲基丁基、2,3-二甲基丁基、2,2-二甲基戊基、2,3-二甲基戊基、3,3-二甲基戊基、2,3,4-三甲基戊基、3-甲基-己基、2,2-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,5-二甲基己基、2,4-二甲基戊基、2-甲基庚基、3-甲基庚基、正庚基、异庚基、正辛基和异辛基。C1-C8烷基可以是未被取代的或被一个或多个下列基团取代,包括但不限于C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2,-C(O)NHR'、-C(O)N(R')2、-NHC(O)R'、-SR'、-S(O)2R'、-S(O)R'、-OH、-卤素、-N3、-NH2、-NH(R')、-N(R')2和-CN;其中每个R'独立地选自于C1-C8烷基和芳基。
“卤素”指氟、氯、溴或碘原子;优选氟和氯原子。
“杂烷基”指其中1至4个碳原子独立地被选自O、S和N的杂原子所取代的C2-C8烷基。
“碳环”指含有3到8个碳原子的饱和或不饱和单环,或含有7到13个碳原子的饱和或不饱和双环。单环碳环有3到6个环原子,典型的有5或6个环原子。双环碳环有7到12个环原子,构成[4,5]、[5,5]、[5,6]或[6,6]的双环系统,或有9个或10个环原子,构成[5、6]或[6,6]的双环系统。具有代表性的C3-C8的碳环包括但不限于:-环丙基、-环丁基、-环戊基、-环戊二烯基、-环己基、-环己烯基、-1,3-环己二烯基、-1,4-环己二烯基、-环庚基、-1,3-环庚二烯基、-1,3,5-环庚三烯基、-环辛基和-环辛二烯基。
“C3-C8碳环”可以是未被取代的或被一个或多个下列基团取代,包括但不限于C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2、-NHC(O)R'、-SR'、-S(O)R'、-S(O)2R'、-OH、-卤素、-N3、-NH2、-NH(R')、-N(R')2及-CN;其中每个R'独立地选自C1-C8烷基和芳基。
“烯基”指含有碳-碳双键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的烯基包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、己烯基、庚烯基、辛烯基。
“炔基”指含有碳-碳三键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的炔基包括乙炔基、丙炔基、正丁炔基、2-丁炔基、3-甲基丁炔基、5-戊炔基、正戊炔基、己炔基、庚炔基和辛炔基。
“亚烷基”是指含1-18个碳原子的饱和的、支炼或直链或环状烃基,并带有两个通过从母体烷烃的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚烷基包括但不限于:亚甲基(-CH2-)、1,2-乙基(-CH2CH2-)、1,3-丙基(-CH2CH2CH2-)、1,4-丁基(-CH2CH2CH2CH2-)等。
“亚烯基”指含2-18个碳原子的不饱和的、支链或直链或环状烃基,并带有通过从母体烯烃的相同或两个不同碳原子上除去两个氢原子而产生的两个一价自由基。典型的亚烯基包括但不限于:1,2-亚乙基(-CH=CH-)。
“亚炔基”指含2-18个碳原子的不饱和的、支链或直链或环状烃基,并带有通过从母体炔的相同或两个不同碳原子上除去两个氢原子而产生的两个一价自由基。典型的亚炔基包括但不限于:乙炔、炔丙基和4-戊炔基。
“芳基”或“芳香基”指由一个或多个环组成的芳香或杂芳香基团,包含三至十四个碳原子,优选六至十个碳原子。术语“杂芳香基”是指芳香基上的一个或几个碳,最优是一个、两个、三个或四个碳原子,被氧(O)、氮(N)、硅(Si)、硒(Se)、磷(P)或(S)所取代,优选被氧、硫和氮所取代而产生的基团。术语“芳基”或“芳香基”也指其中一个或几个氢原子独立地被-R’、卤素、-OR’、-SR’、-NR’R”、-N=NR’、-N=R’、-NR’R”、-NO2、-S(O)R’、-S(O)2R’、-S(O)2OR’、-OS(O)2OR’、-PR’R”、-P(O)R’R”、-P(OR’)(OR”)、-P(O)(OR’)(OR”)或-OP(O)(OR’)(OR”)所取代而产生的芳香基团。其中R’和R”独立地为氢、烷基、烯基、炔基、杂烷基、芳基、芳烷基、羰基或其药用盐。
“杂环”指一个环结构,其中一到四个环碳原子独立地被O、N、S、Se、B、Si或P等杂原子所取代。优选的杂原子是O、N和S。在《化学与物理手册》第78版的225-226页(TheHandbook of Chemistry and Physics,78th Edition,CRC Press,Inc.,1997-1998,p.225to 226)上也有杂环化合物的相关描述,在此引作参考。优选的非芳基杂环包括环氧基、氮丙啶基、硫杂丙基、吡咯烷基、吡唑烷基、咪唑烷基、环氧乙烷基、四氢呋喃基、二氧戊环基、四氢吡喃基、二噁烷基、二氧戊环基、呱啶基、呱嗪基、吗啉基、吡喃基、咪唑啉基、吡咯啉基、吡唑啉基、噻唑烷基、四氢噻喃基、二噻烷基、硫代吗啉基、二氢吡喃基、四氢吡喃基、二氢吡喃基、四氢吡啶基、二氢吡啶基、四氢嘧啶基、二氢噻喃基、氮杂环庚烷基,以及上述基团与苯基缩合得到的稠环。
术语“杂芳基”或“芳基杂环”是指含3到14,优选5至10个原子的芳香性杂环、包含单环、双环或多环。示例包括吡咯基、吡啶基、吡唑基、噻吩基、嘧啶基、吡嗪基、四唑基、吲哚基、喹啉基、嘌呤基、咪唑基、噻吩基、噻唑基、苯并噻唑基、呋喃基、苯并呋喃基、1,2,4-噻二唑基、异噻唑基、三唑基、四唑基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、咔唑基、苯并咪唑基、异恶唑基、吡啶基-N-氧化物,以及上述基团与苯基缩合得到的稠环。
“烷基”、“环烷基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“杂环”等也指相应的去除两个氢原子而形成的“亚烷基”、“环亚烷基”、“亚烯基”、“亚炔基”等。
“芳烷基”指烷基上一个与碳原子(通常为末端或sp3碳原子)连接的氢原子被芳基取代而得到的一类非环烷基。典型的芳烷基包括芐基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘基甲基、2-萘基乙-1-基、2-萘基乙-1-基、萘并芐基、2-萘基苯基-1-基等。
“杂芳烷基”指烷基上一个与碳原子(通常为末端或sp3碳原子)连接的氢原子被杂芳基取代而得到的一类非环烷基。杂芳烷基的实例有2-苯并咪唑基甲基、2-呋喃基乙基。
“羟基保护基”的实例包括甲氧基甲基醚、2-甲氧基乙氧基甲基醚、四氢吡喃基醚、芐基醚、对甲氧基芐基醚、三甲基甲硅醚、三乙基硅醚、三异丙基硅醚、叔丁基二甲基硅醚、三苯基甲基硅醚、乙酸酯、取代乙酸酯、特戊酸酯、苯甲酸酯、甲磺酸酯和对甲苯磺酸酯。
“离去基团”指可以被另一个官能团取代的官能团。这些离去基团是本领域公知的,实例包括卤化物(如氯化物、溴化物和碘化物)、甲磺酰基、对甲苯磺酰基和三氟甲磺酰基。优选的离去基团选自硝基苯酚基、N-羟基琥珀酰亚胺基(NHS)、苯酚基、二硝基苯酚基、五氟苯酚基、四氟苯酚基、二氟苯酚基、一氟苯酚基、五氯苯酚基、三氟甲磺酰基、咪唑基、氯酚基、四氯苯酚基、1-羟基苯并三唑基、甲苯磺酰基、甲磺酰基、2-乙基-5-苯基异恶唑-3'-磺酰基,酸酐或与其它酸酐作用形成的酸酐,例如乙酸酐、甲酸酐、或与多肽缩合试剂、Mitsunobu反应试剂作用生成的中间体。
以下缩写为本发明所采用,其定义为:Boc,叔丁氧基羰基、BroP,溴代十四烷基鏻六氟磷酸盐;CDI,1,1'-羰基二咪唑;DCC,二环己基碳二亚胺;DCE,二氯乙烷;DCM,二氯甲烷;DEAD,偶氮二甲酸二乙酯;DIAD,偶氮二甲酸二异丙基酯;DIBAL-H,二异丁基氢化铝;DIPEA或DEA,二异丙基乙胺;DEPC,二乙基氰基磷酸酯;DMA,N,N-二甲基乙酰胺;DMAP,4-(N,N-二甲基氨基)吡啶;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;DTPA,二亚乙基三胺五乙酸;DTT,二硫苏糖醇;EDC,1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;ESI-MS,电喷雾质谱;乙酸乙酯,乙酸乙酯;Fmoc,N-(9-芴基甲氧基羰基);HATU,O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;NHS,N-羟基琥珀酰亚胺;MeCN,乙腈;MeOH,甲醇;MMP,4-甲基吗啉;PAB,对氨基苯甲酸;PBS,磷酸盐缓冲液(pH 7.0-7.5);Ph,苯基;Phe,L-苯丙氨酸;PyBrop,溴-三-吡咯烷-鏻六氟磷酸盐;PEG,聚乙二醇;SEC,尺寸排阻色谱;TCEP,三(2-羧乙基)膦;TFA,三氟乙酸;THF,四氢呋喃;Val,缬氨酸;TLC,薄层色谱;UV紫外线。
“氨基酸”可以是天然或非天然的,优选α-氨基酸。天然氨基酸由基因所编码,包括丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、色氨酸和缬氨酸。非天然氨基酸是蛋白质氨基酸的衍生物,包括羟脯氨酸、羊毛硫氨酸、2-氨基异丁酸、脱氢丙氨酸、γ-氨基丁酸(神经递质)、鸟氨酸、瓜氨酸、β-丙氨酸(3-氨基丙酸)、γ-羧基谷氨酸、硒代半胱氨酸(存在于许多非真核以及大多数真核细胞中、但不是由DNA直接进行编码)、吡咯赖氨酸(仅在一些古细菌和一种细菌中发现)、N-甲酰基甲硫氨酸(通常是细菌、线粒体和叶绿体中蛋白质中最初的氨基酸)、5-羟色氨酸、L-二羟基苯丙氨酸、三碘甲腺原氨酸、L-3,4-二羟基苯丙氨酸(DOPA)和O-磷酸丝氨酸。术语“氨基酸”还包括氨基酸类似物和模拟物。类似物是具有与天然氨基酸相同结构通式H2N(R)CHCO2H的化合物,其中R在天然氨基酸里未能发现。类似物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜和甲硫氨酸甲基锍。更优的是氨基酸模拟物,它是具有与α-氨基酸的化学结构不同、但是功能类似的化合物。天然氨基酸多为“L”立体化学构型,“非天然氨基酸”为“D”构型的氨基酸。在本专利申请中使用1至8个氨基酸时、其序列优选为蛋白水解酶可识别的序列。许多水解酶可识别序列是本领域已知的,可以参见:Matayoshi等,Science 247:954(1990);Dunn等,Meth.Enzymol.241:254(1994);Seidah等,Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等,Meth.Enzymol.244:595(1994);Smith等,Meth.Enzymol.244:412(1994)及Bouvier等,Meth.Enzymol.248:614(1995);此处引作参考。特别是选自以下序列:Val-Cit、Ala-Val、Ala-Ala、Val-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Asp-Lys、Asp-Glu、Glu-Lys、Lys、Cit、Ser及Glu。
“糖苷”是糖通过糖苷键在其异头碳上与另一基团键合得到的分子。糖苷可以通过O-、N-、S-或C-糖苷键连接,分别产生O-糖苷、糖基胺、硫代糖苷和C-糖苷。其结构式为Cm(H2O)n(其中m可以不同于n,m、n<36)。本发明中的糖苷包括葡萄糖(右旋糖)、果糖(左旋糖)、阿洛糖、阿卓糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、半乳糖胺、氨基葡萄糖、唾液酸、N-乙酰氨基葡萄糖、磺基奎诺糖(6-脱氧-6-磺基-D-吡喃葡萄糖)、核糖、阿拉伯糖、木糖、来苏糖、山梨糖醇、甘露醇、蔗糖、乳糖、麦芽糖、海藻糖、麦芽糖糊精、棉子糖、葡萄糖醛酸(葡糖苷酸)和水苏糖。它可以是D或L的构型、5原子环状呋喃糖的形式、6原子环状吡喃糖的形式,或是非环形式、α-异构体(异头碳的-OH在Haworth投影碳原子平面之下)、或β-异构体(异头碳的-OH在Haworth投影碳原子平面之上),包括单糖、二糖、多元醇或含3-6个糖单元的低聚糖。
本发明申请中的“抗体”指全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,如含有抗原结合位点的分子,该结合位点免疫特异性地与靶标抗原或部分靶标抗原结合,靶标包括但不限于,癌细胞或产生与自身免疫疾病相关的自免疫抗体的细胞。本发明中的免疫球蛋白可以是免疫球蛋白的任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或子类。免疫球蛋白可以来自任何物种,但优选的免疫球蛋白来源于人、鼠或兔。本发明的抗体优选是单克隆抗体,包括但不限于多克隆、单克隆、双特异性、人、人源化或嵌合抗体,单链抗体,Fv、Fab片段、F(ab')片段、F(ab')2片段、由Fab表达库产生的片段,抗独特型(抗Id)抗体,CDR和任何能免疫特异性地结合癌细胞抗原、病毒抗原或微生物抗原的上述结构的表位结合片段。
“对映异构体”,也称为“光学异构体”,是两个立体异构体中的一个,它们是彼此的镜像,不可重迭(不等同),就像人的左右手,除非沿着某一平面被翻转,它们是不可重迭的(仅通过改变方向不能让双手重迭)。化合物中的单个手性原子或类似的结构特征使得该化合物具有两种可能的结构,它们不可重迭,是彼此的镜像。在某一化合物中存在的多个手性特征增加了可能存在的构型的数目,其中可能会有一些互为镜像。对映体纯的化合物是指在检测方法的能力范围内,仅具有同一种手性的样品。在对称的环境中,两个对映体可以使平面偏振光(+/-)在相反的方向上等量旋转(偏振光可以被认为是不对称的介质),除此之外,它们具有相同的化学性质和物理性质。由于这个原因,它们有时也被称为光学异构体。光学异构体及其等量的对映体的混合物被称为外消旋体,它对平面偏振光无净旋转,因为每个正旋转(+)都被负旋转(-)完全抵消。通常两个对映异构体与其他的对映异构体物质发生不同的化学反应。由于许多生物分子是对映体,因此有时两种对映体对生物有机体的影响存在显著差异。例如,在药物中,通常只有一种对映体可以发生想要的生理作用,而另一种对映体或是活性较低、或无活性,有时甚至产生不良反应。基于这样的发现,可以开发仅由一种对映体(“对映体纯”)组成的药物以增强药理学效力,有时还可以消除一些副作用。
同位素是特定化学元素的质子数相同,中子数不同的不同核素。同一元素的所有同位素具有相同数量的质子。一个原子序数指定一个特定的元素,但非同位素;特定元素原子可以有不同的中子数。核子(质子和中子)的数量是原子的质量数,特定元素的每个同位素具有不同的质量数。例如、碳-12、碳-13和碳-14是碳元素的三种同位素,质量数分别为12,13和14。碳的原子序数为6,意味着每个碳原子都有6个质子,因此这些同位素的中子数分别为6、7和8。氢原子有三种同位素:氕(1H)、氘(2H)和氚(3H),氘的质量是氕的两倍,氚的质量是氕的三倍。通过动力学同位素效应,同位素替代实验可用于确定化学反应的机理。同位素替代实验还可用于研究外源化合物通过吸收和分布机制进入体内后,身体如何对它产生作用,体内物质的代谢变化(例如通过细胞色素P450或葡萄糖醛酸转移酶等代谢酶的作用),以及药物代谢产物的排泄途径,是为药代动力学(PK)研究。同位素替代实验可用于研究药物的生化和生理作用,包括在动物(包括人类)、微生物或生物组合上所显现出来的作用(例如感染),是为药效学(PD)研究。两者(PK和PD)一起决定药物的剂量、益处及副作用。同位素可以采用一种稳定的(非放射性的)或非稳定的元素。药物的同位素取代物还可能具有与原始药物不同的治疗功效。
“药学上”或“药学上可接受的”是指当分子实体和组合物酌情施用于动物或人时,不会产生不利、过敏或其他不良反应。
“药学上可接受的溶剂化物”或“溶剂化物”是指一种或多种溶剂分子与本发明公开的化合物的结合物。形成药学上可接受的溶剂合物的溶剂的实例,包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
“药学上可接受的辅料”包括任何载体、稀释剂、佐剂或其它介质,例如防腐剂或抗氧化剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。这些介质和药剂与药物活性物质一起使用在本领域内是熟知的。任何传统介质或药剂,除非与活性成分不兼容,也可以考虑将其用于治疗组合物中。补充活性成分也可以加入组合物中,成为合适的治疗组合。
本发明中,“药用盐”是指此处公开化合物的衍生物,是母体化合物的酸盐或碱盐。药学上可接受的盐包括由无毒无机酸或有机酸与母体化合物形成的常规无毒盐或季铵盐。例如,所述常规无毒盐包括衍生自无机酸(例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等)的盐;以及由有机酸,例如乙酸、丙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、葡萄糖醛酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、草酸、富马酸、马来酸及乳酸等制备的盐。另外的盐包括铵盐,如三甲胺、葡甲胺、丙三醇等的盐、金属盐、如钠、钾、钙、锌或镁盐。
本发明中的药用盐可以从包含酸性或碱性片段的母体化合物,用常规的化学方法制成。一般地说,这些盐可以通过在本发明化合物的游离酸或碱的水溶液或有机溶液或两者的混合溶液中,加入其它适当的等当量的碱或酸而形成。非水相的反应介质一般为乙醚,乙酸乙酯,乙醇,异丙醇或者乙腈。可以适用盐的列表可参见《Remington’sPharmaceutical Sciences》,第17版,Mack Publishing Company,Easton,PA,1985,第1418页。
“施用”或“给药”是指以任何方式向受试者转移、递送、引入或运输药物或其他药剂。这些方式包括口服用药、局部接触、静脉内、腹膜内、肌肉内、病灶内、鼻内、皮下或鞘内给药。本发明还考虑使用装置或器械来施用药剂。这种装置可以使用主动或被动型传输,而且可以是缓释或快速释放递送装置。
“治疗有效量”是指有效预防或治疗本文提及的病理状况的,本发明化合物/药物的量。
术语“患者”或“受试者”指受到或可能受到本文所述病理状况影响的动物或人。优选地,患者是人类。
就癌症而言,术语“治疗”包括以下任何一项或全部:阻止肿瘤细胞或癌细胞生长、复制,减轻整体肿瘤量,以及改善与该疾病相关的一个或多个症状。
就自身免疫性疾病而言,术语“治疗”包括以下任一项或全部:阻止与自身免疫性疾病相关的细胞的复制,包括但不限于能够产生自身免疫性抗体的细胞,减轻自身免疫性抗体量和改善自身免疫性疾病的一个或多个症状。
就传染病而言、术语“治疗”包括以下任何一项或全部:阻止引起传染病的病原体的生长、增殖或复制、以及改善传染病的一个或多个症状。
“哺乳动物”或“动物”的实例包括但不限于人、鼠、家鼠、豚鼠、猴、猪、山羊、牛、马、狗、猫、鸟和家禽。
术语“化合物”,“细胞毒剂”,“细胞毒性化合物”,“细胞毒性二聚体”和“细胞毒性二聚体化合物”可互换使用,包括本发明中或参考文献中公开的结构、结构式代表的结构或其衍生物。该术语还包括本发明中公开的化合物的立体异构体、几何异构体、互变异构体、溶剂化物、代谢产物、盐(例如药学上可接受的盐)和前药以及它们的盐。还包括任何上述结构的溶剂化物、水合物和多晶型物。本发明中在某些方面具体列举“立体异构体”、“几何异构体”、“互变异构体”、“溶剂化物”、“代谢物”、“盐”、“前药”、“前药盐”、“偶联物”、“偶联物的盐”、“溶剂化物”、“水合物”或“多晶型物”,不应被理解为在本发明的其他方面仅仅使用术语“化合物”,而未列举这些术语时,是特意省略这些形式。
术语“亚胺反应性试剂”是指能够与亚胺基反应的试剂。亚胺反应性试剂的实例包括但不限于亚硫酸盐(H2SO3,H2SO2或HSO3 -,SO3 2-,HSO2 -与阳离子形成的盐),焦亚硫酸盐(H2S2O5或S2O5 2-与阳离子形成的盐),单,二,三和四硫代磷酸酯(PO3SH3、PO2S2H3、POS3H3、PS4H3或PO3S3-、PO2S2 3-、POS3 3-、PS4 3-与阳离子形成的盐),硫代磷酸酯((R5O)2PS(OR5)、R5SH、R5SOH、R5SO2H、R5SO3H),各种胺(羟胺(NH2OH)、肼(NH2NH2)、NH2OR5、R5NHR5’、NH2R5),NH2-CO-NH2、NH2-C(=S)-NH2、硫代硫酸盐(H2S2O3或S2O3 2-与阳离子形成的盐)、连二亚硫酸盐(H2S2O4或S2O4 2-与阳离子形成的盐)、二硫代磷酸酯(P(=S)(OR5)(SH)(OH)或与阳离子形成的盐)、异羟肟酸(R5C(=O)NHOH或与阳离子形成的盐)、酰肼(R5CONHNH2)、甲醛次硫酸盐(HOCH2SO2H或HOCH2SO2 -与阳离子形成的盐,例如HOCH2SO2 -Na+)、糖化核苷酸(例如GDP-甘露糖)、fludarabine或它们的混合物,其中R5和R5'都独立地为具有1至8个碳原子的直链或支链烷基、并被至少一个选自-–N(R5)(R5’)、-CO2H、-SO3H、和-PO3H的取代基取代;R5和R5'可以进一步可选地被本文所述烷基取代基取代;优选地,阳离子是单价阳离子,例如Na+或K+。优选地,亚胺反应性试剂选自亚硫酸盐、羟胺、尿素和肼。更优选地,亚胺反应性试剂是NaHSO3或KHSO3.
“细胞结合剂”或“细胞结合分子”可以是目前已知的或将成为已知的分子,包括肽和非肽。通常,它们可以是抗体(尤其是单克隆抗体)或包含至少一个结合位点的抗体片段、淋巴因子、激素、生长因子、营养转运分子(例如转铁蛋白),或任何其他细胞结合分子或物质(例如维生素)。
可以使用的细胞结合剂的更具体的例子包括:单克隆抗体、单链抗体、抗体的片段,例如Fab、Fab'、F(ab')2、Fv(Parham,J.Immunol.131,2895-2902(1983);Spring等,J.Immunol.,113,470-478(1974);Nisonoff等,Arch.Biochem.Biophys.,89,230-244(1960))、Fab表达文库产生的片段、抗独特型(anti-Id)抗体、CDR、以上任一项的可以其免疫特异性结合癌细胞抗原、病毒抗原或微生物抗原的表位结合片段、干扰素、肽;淋巴因子如IL-2、IL-3、IL-4、IL-6;激素,例如胰岛素、TRH(促甲状腺激素释放激素)、MSH(促黑素细胞刺激激素)、类固醇激素,例如雄激素和雌激素;生长因子和集落刺激因子,例如EGF、TGFα、胰岛素样生长因子(IGF-I、IGF-II)、G-CSF、M-CSF和GM-CSF(Burgess,ImmunologyToday,5,155-158(1984));维生素,例如叶酸;转铁蛋白(O'Keefe等,J.Biol.Chem.,260,932-937(1985))。
利用单克隆抗体技术可以生产极具选择性的细胞结合剂,特异性的单克隆抗体。在本领域中众所周知的产生单克隆抗体技术是,通过用感兴趣的抗原,例如完整的靶细胞,从靶细胞,全病毒,灭火全病毒,病毒蛋白,如病毒外壳蛋白等分离的抗原,来免疫小鼠,大鼠,仓鼠或任何其他哺乳动物而产生。合适的细胞结合剂的选择是取决于待靶向的特定细胞群,但是通常,如果可以获得合适的单克隆抗体,则优选单克隆抗体。
横交联的PBD及其偶联物
具有如式(I)的横交联PBD二聚体衍生物,与细胞结合分子偶联或可以偶联至细胞结合分子,以用于靶向抑制细胞增殖:
或者其药学上可接受的盐,水合物或者水合盐;或者其多晶型物;或者其光学异构体,外消旋体,非对映异构体或对映异构体;
其中:
-----代表可选的单键或可以缺省;
V和V’,相同或不同,独立地选自H、OH、-NHOH、OR5(乙醚)、OCOR5(酯)、OCOOR5(碳酸盐)、NR5R5’、NR5COR5’或NR5NR5’NR5”(胺)、OCONR5R5’(氨基甲酸酯)、NR5(C=NH)NR5’R5”(胍)、NR5CONR5’R5”(尿素)、OCSNHR5(硫代氨基甲酸酯)、-SH(巯基)、–SR5(硫化物)、SOR5(亚砜)、SOOR5(砜)、SO3、HSO3、HSO2或HSO3-、SO3 2-或-HSO2 -的盐(亚硫酸盐)、OSO3(亚硫酸氢盐)、NR5SOOR5’(磺酰胺)、H2S2O5或S2O5 2-的盐(偏亚硫酸氢盐)、PO3SH3、PO2S2H2、POS3H2、PS4H2或PO3S3-、PO2S2 3-、POS3 3-、PS4 3-的盐(单、二、三和四硫代磷酸酯)、(R5O)2POSR5’(硫代磷酸酯)、HS2O3或S2O3 2-的盐(硫代硫酸盐)、HS2O4或S2O4 2-的盐(连二亚硫酸盐)、P(=S)(OR5)(S)(OH)(二硫代磷酸酯)或与阳离子形成的盐、-NR5OR5’(羟胺衍生物)、R5C(=O)NOH(异羟肟酸)或与阳离子形成的盐、HOCH2SO2 -或其盐(甲醛合次硫酸盐)、NR5COR5’(酰胺)、O-糖苷、N3(叠氮基)、CN(氰基)、X(卤素)、C(R5)(R5’)(R5”)(三烷基)、OP(O)(OR5)(NHR5’)或OP(O)(NHR5)(NHR5’)(氨基磷酸酯、磷酰胺酸)、P(R5)(R5’)(R5”)三芳基膦、Aa(氨基酸)、或NR5CO(Aa)t(肽)、其中Aa是一种氨基酸或含t=1100个氨基酸单元的多肽;氨基酸衍生基团、例如α-、β-、γ-、或ω-氨基酸或非天然氨基酸;其中R5、R5’和R5”的定义同前文所述;
l、m、q、l’、m’和q’独立地为0、1、2、3、4、或5;n是1~30;
X、X’、Y和Y’相同或不同,独立地选自N、O、S、烷基(例如CH2或CHR5)、烯烃(例如=CH-或=CR5-)、醚(例如–C(OR5)H-);
Z和Z’相同或不同,独立地选自N、CH、CR5、COH、CNH2、CNHR5或COR5,或Z和Z’与–COR5OC-连接;其中R5独立地选自C1~C8烷基和芳基;
U和U’独立地是C(O)、C(O)O、C(O)NH、C(O)N(R5)、C(=NH)、C(=NH)O、C(=NH)NH、C(=NH)N(R5)、-C=N-、C(=S)、C(O)S、C(S)NH、C(S)N(R5)、S(O)、S(O)O、S(O)NH、S(O)(OR5)、S(O)(N(R5))、S(O2)、S(O2)O、P(O)(OR5)、P(O)(OR5)O、P(O)(NH2)、P(O)(NR5R5’)、P(O)(OR5)NH-、P(O)(OR5)NR5’-、P(O)(N(R5R5’)(N(R5)、P(S)(OR5)、P(S)(OR5)O、P(S)(NH2)、P(S)(NR5R5’)、P(S)(OR5)NH-、P(S)(OR5)NR5’-、P(S)(N(R5R5’)N(R5)、R5、R5O;
E1和E2独立地是S、R5S、C(O)S、C(O)NH、C(O)O、C(O)R5S、C(=NH)NH、C(=NH)N(R5)、C(=NH)S、-C=N-、C(=S)S、C(O)S、C(=S)NH、C(=S)N(R5)、Ar-S、NC(O)CH2S、ArC(O)CH2S、S-S、其中两个原子中间的化学键表示它可以连接两个相邻的原子;
L1和L2独立地为连接子,或包含能够与细胞结合剂(CBA)反应的官能团的连接子,L1和L2独立地优选为可断裂的连接子,具有结构式—Ww—(Aa)r—Tt—或—Ww—(Aa)r—Tt—Q或Q—Ww—(Aa)r—Tt—;其中-W-是延展体单元;w是0或1;-Aa-独立地是氨基酸单元;r独立地是0至100的整数;-T-为间隔体单元,可以为直链烷基或支链烷基或聚乙二醇间隔体;t为0或1100。延展体单元W可独立地包含自毁灭间隔体,肽单元,腙键,二硫键,酯键或硫醚键;w是1或2或3;优选的L1和L2独立地选自O、NH、N、S、P、NNH、NHNH、N(R3)、N(R3)N(R3’)、CH、CO、C(O)NH、C(O)O、NHC(O)NH、NHC(O)O、聚乙二醇单元如(OCH2CH2)pOR3、(OCH2CH-(CH3))pOR3、NH(CH2CH2O)pR3、NH(CH2CH(CH3)O)pR3、N[(CH2CH2O)pR3]-[(CH2CH2O)p’R3’]、(OCH2CH2)pCOOR3或CH2CH2(OCH2CH2)p-COOR3,其中p和p’独立地选自0至1000的整数、或它们的组合;C1-C8烷基、C2-C8杂烷基、烷基环烷基、杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;或(Aa)r、r=1-12(1至12个氨基酸单位)、由天然或非天然氨基酸、或相同或不同序列的二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、十一肽或十二肽单元组成;
R1、R2、R3、R4、R1’、R2’、R3’和R4’相同或不同,并且独立地选自-H,可被取代的含有1至10的碳的直链、支链或环状烷基、烯基或炔基、-(OCH2CH2)tR5(聚乙二醇单元)、卤素、NH(C=NH)NH2(胍基)、-OR5、-NR5R5'、-NO2、-NCO、-NR5COR5'、-SR5、–SOR5(亚砜)、-SO2R5(砜)、--SO3 -M+(磺酸盐)或-SO3H、–OSO3 -M+(硫酸盐)或OSO3H、-SO2NR5R5’磺酰胺)、CN(氰基)、N3(叠氮基)、-COR5、-OCOR5、-OCONR5R5'、CF3、OR5、芳基、杂环或P(O)R5R5’R5”和带有反应性基团的连接基团(L”)或细胞连接剂当Q、Q’和T缺省;
R5、R5’和R5”独立地选自H、C1-C8烷基、烯基、炔基、杂烷基、芳基、芳基烷基、羰基或药用盐;
另外,R1和R2可以连接在一起、或R1’和R2’连接在一起,形成=O(酮)、=S、=NR、-C(=O)R或含==CR5R5’基团的双键。R1和R2连接在一起,或R1'和R2'连接在一起,或R3和R4连接在一起,或R3'和R4'连接在一起形成C3-C12芳环,杂环或杂芳基环;
Q是细胞结合分子,或者能够与细胞结合剂反应的官能团,或者能够与连接在细胞结合剂上的连接子反应的官能团。所述官能团选自巯基、胺、肼、烷氧基氨基、二硫键取代基、马来酰亚胺基、卤代乙酰基、N-羟基琥珀酰亚胺酯、酮、酯、醛、炔基、烯基或受保护的巯基或二硫基、例如SAc、SSR1或SSAr。Ar是芳香基团或杂芳香基团。Q优选为细胞结合剂/分子、选自抗体、单链抗体、与靶细胞结合的抗体片段、单克隆抗体、单链单克隆抗体、结合靶细胞的单克隆抗体片段、嵌合抗体、结合靶细胞的嵌合抗体片段、结构域抗体、结合靶细胞的结构域抗体片段、adnectin类抗体、DARPins、淋巴因子、激素、维生素、生长因子、集落刺激因子、营养转运分子(转铁蛋白)以及结合在白蛋白、聚合物、树状大分子、脂质体、纳米颗粒、囊泡或(病毒)衣壳上的细胞结合肽、蛋白质或小分子。
术语“可断裂连接子”是指包括至少一个可在生理条件下可断裂键的连接子、例如对pH、酸、碱、氧化作用、代谢、生化或酶作用敏感的键。应当理解,导致键断裂不一定是生物或代谢过程、而可能是一个标准化学反应、例如水解或取代反应,例如在内涵体内,pH值比细胞浆内pH低的环境,和/或细胞内发生二硫键交换反应,例如在恶性细胞内存在的毫摩尔浓度的大量谷胱甘肽的环境。
延展体单元(-W-),如果存在,可以将细胞结合分子单元(CBA)连接到氨基酸单元(--Aa--),或者在不存在Aa的情况下,连接至T。延展体单元W可以独立地包含自毁灭间隔体、肽单元、腙键、二硫键或硫醚键。此时,细胞结合分子(CBA)包含有一个官能团,可以与延展体的官能团成键。结合分子上的官能团可以天然地具备,或通过化学方法生成,它们包括但不限于巯基(-SH)、氨基、羟基、氧氨基、炔基、杂芳基、羰基、糖异头碳上的羟基和羧基。优选的官能团是巯基、羧基和氨基。巯基可通过还原配体(例如蛋白质或抗体)的分子内二硫键而产生,或者可以通过2-亚氨基硫杂环戊烷(Traut's试剂)或硫代内酯,与细胞结合剂赖氨酸残基上的氨基反应而生成,或使用其他巯基生成试剂而生成,例如用含二硫键或硫酯的连接子修饰细胞结合分子,然后还原或水解。
优选的L1和L2是包含C、N、O、S、Si和P原子的链状结构,含0-500个原子。L1和L2中的各个原子以所有可能的化学方式结合,优选的形成C1-C20亚烷基、亚烯基和亚炔基、醚、聚氧化烯、酯、胺、亚胺、多胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、氨基甲酸酯、氨基酸、肽、酰氧基胺、异羟肟酸,或上述组合。更优选地,L1和L2,无论相同或不同,独立地选自O、NH、S、NHNH、N(R3)、N(R3)N(R3’),C1-C8烷基,酰胺,胺,亚胺,肼和腙;C2-C8杂烷基、烷基环烷基、醚、酯、腙、脲、氨基脲、卡巴肼、烷氧基胺、氨基甲酸酯、氨基酸、肽、酰氧基胺、羟肟酸或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、异烷基环烷基、烷基羰基或杂芳基;聚乙二醇单元,如(OCH2CH2)pOR3或(OCH2CH(CH3))pOR3或NH(CH2CH2O)pR3或NH(CH2CH(CH3)O)pR3或N[(CH2CH2O)pR3]-[(CH2CH2O)p’R3’]或(OCH2CH2)pCOOR3或CH2CH2(OCH2CH2)pCOOR3,其中p和p'独立地是选自0至约5000的整数,或上述的组合;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、杂烷基、杂烷基环烷基、烷基羰基或杂芳基;或C2-C8酯、醚或酰胺;或1-8个氨基酸;或结构式为(OCH2CH2)p或(OCH2CH(CH3))p的聚乙二醇单元,其中p是0至约5000的整数,或上述组合;
可选的L1和L2可独立地由一个或多个下列连接子组分构成:6-马来酰亚胺基己酰基(“MC”)、马来酰亚胺丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”或“af”)、对氨基芐氧基羰基(“PAB”)、4-硫代戊酰基(“SPP”)、4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”)、(4-乙酰基)氨基苯酰基(“SIAB”)、4-硫丁酰基(SPDB)、4-硫-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),或含有1-8个天然或非天然氨基酸单元的天然或非天然肽。天然氨基酸优选自天冬氨酸、谷氨酸、精氨酸、组氨酸、赖氨酸、丝氨酸、苏氨酸、天冬酰胺、谷氨酰胺、半胱氨酸、硒代半胱氨酸、酪氨酸、苯丙氨酸、甘氨酸、脯氨酸、色氨酸、丙氨酸。
L1和L2独立地可以含有自我毁灭或非自我毁灭的组分、肽单元、腙键、二硫化物、酯、肟、酰胺或硫醚键。自我毁灭单元包括但不限于,与对氨基芐基氨甲酰基(PAB)的电子结构相似的芳香化合物,例如2-氨基咪唑-5-甲醇的衍生物、杂环PAB类似物、β-葡糖苷酸、以及邻或对氨基芐基缩醛;
优选的自我毁灭型连接子组分具有以下结构之一:
其中(*)是另外的间隔体或可断裂的连接子单元,或细胞毒剂、和/或细胞结合分子(CBA)的连接点;X1、Y1、Z2和Z3独立地为NH、O、或S;Z1独立地为H、OH、NHR1、OR1、SR1、COX1R1,其中X1和R1如前文所定义;v是0或1;U1独立地为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NR5R5’、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)或OCH2PO(OR5)(OR5’),其中R5和R5'独立地选自H、C1-C8烷基;C2-C8烯基、炔基、杂烷基或氨基酸;C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基或糖苷;或药用阳离子盐;
非自我毁灭型连接子组分为以下结构之一:
其中(*)是另外的间隔体或可断裂的连接子单元,或细胞毒性分子和/或细胞结合分子的连接点;X1、Y1、U1、R5、R5’如前文所定义;r是0-100;m和n独立地为0-6;
进一步优选地,L1和L2独立地是可断裂连接子。术语“可断裂”是指连接子上包含至少一个可在生理条件下被破坏的键,例如pH、酸、碱、氧化作用、代谢、生化或酶不稳定的键。应当理解,导致键断裂不一定是生物或代谢过程、而可能是一个标准化学反应、例如水解或取代反应,这种生理条件的例子有pH值比细胞浆内pH低的内涵体,和/或它能够与细胞内巯基发生二硫键交换反应,恶性细胞内存在的毫摩尔浓度的大量谷胱甘肽,;
可断裂连接子L1或L2的实例包括但不限于:
-(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-、(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-、(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-、(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-、-(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-、-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m-(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m-苯基CO(Aa)t(CR7R8)n-、-(CR5R6)m-呋喃CO(Aa)t(CR7R8)n-、-(CR5R6)m-恶唑CO(Aa)t(CR7R8)n-、-(CR5R6)m-噻唑基CO(Aa)t(CCR7R8)n-、-(CR5R6)t-噻吩CO(CR7R8)n-、-(CR5R6)t-咪唑CO-(CR7R8)n-、-(CR5R6)t-吗啉CO(Aa)t-(CR7R8)n-、-(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-、-(CR5R6)t-N甲基CO(Aa)t-(CR7R8)n-、-(CR5R)m-(Aa)t苯基-、-(CR5R6)m-(Aa)t呋喃、-(CR5R6)m-恶唑(Aa)t、-(CR5R6)m-噻唑基(Aa)t、-(CR5R6)m-噻吩-(Aa)t-、-(CR5R6)m-咪唑(Aa)t-、-(CR5R6)m-吗啉(Aa)t-、-(CR5R6)m-哌嗪(Aa)t-、-(CR5R6)m-N甲基哌嗪(Aa)t-、K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-、K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-、K(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-、K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-、K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-、K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、K-(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m-苯基CO(Aa)t(CR7R8)n-、K-(CR5R6)m-呋喃CO(Aa)t-(CR7R8)n-、K(CR5R6)m-恶唑CO(Aa)t(CR7R8)n-、K(CR5R6)m-噻唑基CO(Aa)t-(CR7R8)n-、K(CR5R6)t-噻吩CO(CR7R8)n-、K(CR5R6)t咪唑-CO-(CR7R8)n-、K(CR5R6)t吗啉CO(Aa)t(CR7R8)n-、K(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-、K(CR5R6)t-N甲基CO(Aa)t(CR7R8)n-、K(CR5R)m(Aa)t苯基、K-(CR5R6)m-(Aa)t呋喃-、-K(CR5R6)m-恶唑(Aa)t-、K(CR5R6)m-噻唑基(Aa)t-、K(CR5R6)m-噻吩-(Aa)t-、K(CR5R6)m-咪唑(Aa)t-、K(CR5R6)m-吗啉(Aa)t-、K(CR5R6)m-哌嗪(Aa)t-、K(CR5R6)mN甲基哌嗪(Aa)t-;其中Aa、m和n定义如前文所描述;t和r独立地为0-100;R3、R4、R5、R6、R7、和R8独立地选自H、卤化物、C1-C8烷基、C2-C8芳基、烯基、炔基、醚、酯、胺或酰胺,这些基团均可以被以下基团所取代:一个或多个卤素、CN、NR1R2、CF3、OR1、芳基、杂环、S(O)R1、SO2R1、-CO2H、-SO3H、-OR1、-CO2R1、-CONR1、-PO2R1R2、-PO3H或P(O)R1R2R3;K是NR1、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、Het(具有C3-C8的杂环或杂芳环),或含有1-20个相同或不同氨基酸的肽。
另外,U、U’、E、E’、L1和L2独立地可以含有以下一个或多个亲水结构:
其中是连接位点;X2、X3、X4、X5、或X6、独立地选自NH、NHNH、N(R3)、N(R3)N(R3’)、O、S、C1-C6烷基、C2-C6杂烷基、烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基或杂芳基;或1-8个氨基酸;其中R3和R3'独立地为H、C1-C8烷基、C2-C8杂烷基、烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基或杂芳基;或C2-C8酯、醚或酰胺;或结构式为(OCH2CH2)p或(OCH2CH(CH3))p的聚乙二醇单元,其中p是0至约5000的整数;或上述基团的组合;
更优选地,L1或L2独立地为具有1-6个碳原子的直链烷基,或具有式(OCH2CH2)p,p=1-5000的聚乙二醇单元,或含有1-4个氨基酸单元(L或D形式)的肽,或上述的组合。
另外,U、U’、L1、L2、L’、E1或E2独立地可以由以下一种或多种组分组成:6-马来酰亚胺己酰基(MC),马来酰亚胺丙酰基(MP),硫代马来酰亚胺基,硫代氨基氧代丁酸,硫代氨基氧代丁烯酸,缬氨酸-瓜氨酸(val-cit),丙氨酸-苯丙氨酸(ala-phe),赖氨酸-苯丙氨酸(lys-phe),赖氨酸-丙氨酸(lys-ala),p-对氨基芐氧基酰胺基(PAB),4-硫代戊酰基(SPP),4-硫代丁酰基(SPDB),4-(N-马来酰亚胺基甲基)环己烷-1-酰基(MCC),马来酰亚胺乙氨基(ME),4-硫代-2-羟基磺酰基丁酰基(2-Sulfo-SPDB),芳基巯醚基(PySS),(4-乙酰基)氨基苯酰基(SIAB),氧芐基硫醚基,氨基苄基硫醚基,二氧基苄基硫醚基,二氨基苄基硫醚基,氨基氧基苄基硫醚基,烷氧基氨基(AOA),亚乙基氧基(EO),4-甲基-4-硫代-戊酰基(MPDP),三唑,二硫,烷基磺酰基,烷基磺胺,砜基二磺胺,磷二酰胺,烷基膦酰胺,膦酸,N-甲基烷基膦酰胺,N,N’-二甲基磷二酰胺,N,N’-烷基膦二酰,肼,乙脒;肟,二乙酰肼,氨基乙基胺,氨基乙基-氨基乙基-胺,和L-或D-,或含有1-20个氨基酸的天然或非天然肽;其中原子中间的连接键表示它连接相邻的碳原子;波浪线是另一个键连接的部位;
另外,U、U’、E1或E2,可以各自独立地缺省。
通式(I)中化合物的几何和立体异构体也是本发明申请的一部分。
式(I)中化合物优选的立体异构体如式(Ia),(Ib),(Ic),(Id),(Ie)所示:
其中Z1是OH、NH2、OR1、NHR1、NR1R2、SR1、NHR1COX1R1、OR1COX1R1或N(R2)R1COX1R1;-----、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、E1、E2和Q的定义与式(I)中相同。
其中V、V’、n和q的定义同前文所述;mAb是细胞连接分子,优选为抗体;r、r’和r”独立地为0–200。
在另一个实施方案中,通过单链连接子连接的PBD衍生物与细胞结合分子的偶联物,可用于靶向抑制细胞增殖,其结构如式(II)、(III)和(IV)所示:
其中-----、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、G、Q、E1和E2的定义同式(I)。
根据式(II)、(III)和(IV),在更优选的实施方案里,本发明的PBD衍生物的偶联物具有式(II-01)~(II-11)、(III-01)~(III-06)和(IV-01)~(IV-11)的结构:
在另一个优选的实施例中,式(I)、(II)、(III)、(IV)和(V)的偶联物由细胞结合分子与具有结构如式(V)、(VI)、(VII)和(VIII)的PBD二聚体衍生物偶联而制备:
其中E3和E’3独立地选自:
N-羟基琥珀酰亚胺酯;马来酰亚胺基; 二硫化物;卤代乙酰基;酰卤;乙烯磺酰基;丙烯酰基;2-(甲苯磺酰氧基)乙酰基;2-(甲磺酰氧基)乙酰基;2-(硝基苯酚基)乙酰基;2-(二硝基苯基)乙酰基;2-(氟代苯酚基)-乙酰基;2-(二氟苯酚基)-乙酰基;2-((三氟甲基磺酰基)氧基)乙酰基;酮或醛;2-(五氟苯酚基)乙酰基;甲基砜苯基恶二唑(ODA);酸酐, 羰基咪唑,烷氧基胺;叠氮基,炔基,β-内酰胺,或酰肼,异硫氰酸根;其中X1’和X3’独立地是F、Cl、Br、I或Lv3;X2’是O、NH、N(R1)或CH2;R3和R5独立地是H、R1、芳基或杂芳基,或芳基基团,其中一个或几个氢原子独立地被-R1、-卤素、-OR1、-SR1、-NR1R2、-NO2、-S(O)R1、-S(O)2R1或-COOR1取代;Lv3是离去基团,选自甲磺酰基(mesyl)、甲苯磺酰基(tosyl)、三氟甲基磺酰基(triflate)、三氟甲基磺酸酯基、硝基苯氧基、苯硫基、吡啶基硫基、N-琥珀酰亚胺基氧基(NHS)、苯氧基、二硝基苯氧基、五氟苯氧基、四氟苯氧基、三氟苯氧基、二氟苯氧基、一氟苯氧基、五氯苯氧基、1H-咪唑-1-基、氯苯氧基、二氯苯氧基、三氯苯氧基、四氯苯氧基、N-(苯并三唑基)氧基、2-乙基-5-苯基异恶唑基、苯基恶二唑基(ODA)、恶二唑基、或与Mitsunobu反应缩合剂产生的中间分子,其中R1和R2如前文所定义;
优选的E3和E’3独立地选自-SH、-S-SCH3、-S-SAc、-S-S-吡啶、-S-S-Ar(-NO2)、-S-细胞结合剂、或下列任一结构:
其中D是H、-NO2、SO3H或F;R1、R2、R3、R4、r、m和n的定义同前文所述;w和w’独立地选自0、1或2;
其中R5和R5’独立地选自C1~C6烷基、芳基、环烷基、杂环基、H、或M(其中M是Na、K、Ca、铵或其他药学上可接受的盐);
在一些实施例中,结构式如式(V)、(VI)、(VII)和(VIII)的PBD衍生物由(V-01)~(V-20)、(VI-01)~(VI-05)、(VII-01)~(VII-06)、(VIII-01)~(VIII-06)表示:
其中U,U’,V,V’,n,n’和L的定义同前文所述;R6和R6’独立地选自C1~C6烷基,芳基,环烷基,杂环基,卤素,卤代烷基,烷氧基,卤代烷氧基,烷基氨基,-NO2,-CN或H;X1和X1’独立地是H,F,Cl,Br,I,甲苯磺酸酯(OTs),甲磺酸酯(OMs),硝基苯酚基(OArNO2),二硝基苯酚基(OAr(NO2)2),单氟苯酚基(OArF),五氟苯酚基(OArF5),二氟苯酚基(OArF2),N-羟基琥珀酰亚胺基(NHS),苯酚基,四氟苯酚基,五氯苯酚基,三氟甲磺酸酯,咪唑基,二氯苯酚基,四氯苯酚基,1-羟基苯并三唑或2-乙基-5-苯基异恶唑-3′-磺酸酯。
作为细胞毒剂的、结构式如(V),(VI),(VII)和(VIII)的横交联PBD二聚体衍生物合成
本发明的化合物可以通过本领域技术人员众所周知的各种方法来制备。可以通过应用实施例中描述的方法,或者根据技术人员的理解,做适当修饰而制备。对于本领域技术人员而言,适当的修饰和替代是显而易见,并且众所周知,可以很容易的从科学文献中获得。特别是,这些方法在《Comprehensive Organic Transformations,A Guide toFunctional Group Preparations》(R.C.Larock著,2010,Wiley-VCH出版,第2版)一书中有很多的介绍。
因为本发明的细胞毒剂可以包含一个或多个不对称取代的碳原子,或者在纯化分离时以光学纯或外消旋体形式获得,所以除非特别指出了立体化学或异构体形式,否则所示结构包含的所有手性结构,非对映异构体,外消旋体和几何异构体。制备和分离各种光学异构体的方法,在本领域中是众所周知的。例如,立体异构体的混合物可以通过标准分离技术分离,包括但不限于拆分外消旋体,正相,反相和手性色谱法,优先成盐,重结晶等,或通过使用手性原料或构建手性中心的方法进行手性合成。
本发明的细胞毒剂可以通过多种合成途径制备。试剂和原料或者是市售的,或者是由本领域普通技术人员通过已知的技术合成。除非另有说明,所有取代基的定义同前文所述。
在本发明的细胞毒剂的合成反应中,有时会有必要保护可能参与反应的活性官能团,例如羟基、氨基、亚氨基、巯基和羧基,以避免副反应的发生。常规保护基的使用方法可参考P.G.Wuts和T.W.Greene所著的《Greene's Protective Groups in OrganicSynthesis》(2006年,Wiley-Interscience出版,第4版),Ian T.Harrison和ShuyenHarrison所著的《Compendium of Organic Synthetic Methods》,卷1,2,卷1&2(IanT.Harrison&Shuyen Harrison),卷3~5(Louis S.Hegedus,Leroy Wade),卷6~12(Michael B.Smith),John Wiley and Sons出版,2006~2012。
通常,合成反应在合适的溶剂,温度和时间下进行。合成细胞毒剂时,反应中可以使用对反应或所涉及的试剂没有不利影响的多种溶剂。合适溶剂包括:烃类,可以是芳烃,脂肪族或环脂肪族烃,例如己烷,环己烷,苯,甲苯和二甲苯;含卤素的烃,例如氯仿,二氯甲烷,二氯乙烷;酰胺,例如二甲基乙酰胺或二甲基甲酰胺;醇,例如乙醇和甲醇,以及醚,例如乙醚和四氢呋喃。反应可在-100℃300℃的温度下进行,更优选0℃至150℃。反应所需的时间取决于许多因素,特别是反应温度和试剂的性质,也可以在很大范围内变化,可以为5秒至4周,更优选为10分钟至24小时。另外,制备的细胞毒剂可以通过常规方法从反应混合物中分离或纯化,例如从反应混合物中蒸发或蒸馏出溶剂,或者从反应混合物中蒸馏出溶剂之后,将残余物倒入水中,使用与水不混溶的有机溶剂萃取,然后蒸馏出萃取物中的溶剂。它还可能涉及各种众所周知的技术,例如重结晶,再沉淀或各种色谱技术,特别是柱色谱,制备型薄层色谱或高效液相色谱。
细胞毒剂的合成反应及其与细胞结合剂的偶联,示例如图1-32(包括但是不限于此)和以下说明书中所展示的实施例。
横交联PBD二聚体与细胞结合剂的偶联物
本发明提供了一种偶联物分子,其通过连接子的官能团将至少一个PBD衍生物与细胞结合剂(Q)共价连接。优选地,所述偶联物包含本发明中的一至二十个的横交联的PBD二聚体衍生物分子,通过与PBD二聚体衍生物共价结合的连接子上的官能团,与细胞结合剂(Q)偶联。
如上所述,横交联的PBD二聚体衍生物与细胞表面结合分子偶联物的结构,如式(I),(II),(III)和(IV)所示。
在式(I)至(IV)中,每个抗体荷载1至30个小分子药物(D),优选地,每个抗体连接平均2至8个药物。在通过偶联反应制备ADC时,每个抗体上的药物平均数可以通过常规方法表征,例如质谱法,ELISA测定法和HPLC。还可以确定偶联物上药物的定量分布。在一些情况下,在偶联物上的载药量为一定值时,均相偶联物的分离,纯化和表征可以通过反相HPLC或电泳等方法实现。
细胞结合剂(CBA)可以是任何种类的分子,包括肽和非肽。通常,细胞结合剂包括但不限于,大分子量蛋白质,例如全长抗体(多克隆抗体和单克隆抗体);单链抗体;抗体的片段,例如Fab,Fab',F(ab')2,Fv[Parham,J.Immunol.131,2895-2902(1983)],由Fab表达文库产生的片段,抗独特性(抗-Id)抗体,CDR;上述任何抗体的,能免疫特异性结合癌细胞抗原,病毒抗原,微生物抗原的表位结合片段;抗体模拟物,例如亲和体;结构域抗体(dAb);纳米抗体;单价抗体,DARPin;anticalin;versabody;duocalin;lipocalin;vimer;干扰素(如I,II,III型);多肽;淋巴因子如IL-2,IL-3,IL-4,IL-6,IL-8,IL-10,IL-12,IL-13,GM-CSF,干扰素-γ(IFN-γ);激素,如胰岛素,TRH(促甲状腺素释放激素),MSH(促黑素细胞激素),类固醇激素如雄激素和雌激素;生长因子和集落刺激因子,如表皮生长因子(EGF),粒细胞巨噬细胞集落刺激因子(GM-CSF),转化生长因子(TGF),如TGFα,TGFβ,胰岛素和胰岛素样生长因子(IGF-I,IGF-II),G-CSF,M-CSF和GM-CSF[Burgess,Immunology Today,5,155-158(1984)];牛痘生长因子(VGF);成纤维细胞生长因子(FGF);小分子量蛋白质;多肽;肽和肽激素,如铃蟾肽,胃泌素,胃泌素释放肽;血小板衍生的生长因子;白细胞介素和细胞因子,例如,白细胞介素-2(IL-2),白细胞介素-6(IL-6),白血病抑制因子,粒细胞巨噬细胞集落刺激因子(GM-CSF);维生素,如叶酸;脱辅基蛋白和糖蛋白,如转铁蛋白(O'Keefe等,J.Biol.Chem.1985 260 932-937);糖结合蛋白或脂蛋白,如凝集素;细胞营养传递分子;小分子抑制剂,如前列腺特异性膜抗原(PSMA)抑制剂和小分子酪氨酸激酶抑制剂(TKI),非肽或任何其它细胞结合分子或物质,如生物活性聚合物(Dhar等,Proc.Natl.Acad.Sci.2008,105,17356-61),枝状大分子(Lee等,Nat.Biotechnol.2005,23,1517-26;Almutairi等;Proc.Natl.Acad.Sci.2009,106,685-90),纳米粒子(Liong等,ACS Nano,2008,19,1309-12;Medarova等,Nat.Med.2007,13,372-7;Javier等,Bioconjugate Chem.2008,19,1309-12),脂质体(Medinai等,Curr.Phar.Des.2004,10,2981-9)和病毒外壳(Flenniken等,Viruses Nanotechnol.2009,327,71-93)。一般而言,如果适当的单克隆抗体是可用的,则优选单克隆抗体作为细胞表面结合剂。
用于本发明的连接子包括但不限于二硫键连接子,硫醚连接子,酰胺键连接子,肽酶不稳定连接子,光不稳定连接子,酸不稳定连接子(例如腙键连接子),酯酶不稳定连接子,氧化不稳定连接子,代谢不稳定连接子,生化不稳定连接子。
优选地,连接子通过官能团与细胞结合剂的巯基和氨基,其分别来自还原的二硫键和赖氨酸残基,反应而与细胞结合剂连接。更具体地,所述官能团通过羰基与所述细胞结合剂赖氨酸残基上的氨基官能团连接,从而形成酰胺键。
另外,连接子可以由一个或多个连接子组分组成。示例性连接子组分包括:6-马来酰亚胺基己酰基(“MC”)、马来酰亚胺丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”或“af”)、对氨基芐氧基羰基(“PAB”)、4-硫代戊酰基(“SPP”)、4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”)、(4-乙酰基)氨基苯酰基(“SIAB”)、一个或多个重复单元(“EO”或“PEO”)的乙基氧基(--CH2CH2O--)。连接子可以是“可断裂连接子”,以促进药物在细胞中的释放。更多的连接子组分在本领域是已知的,其中一些如下所示:
其中R7,R8和R9独立地选自–C1~C8亚烷基-、--C1~C7碳环-、-O-(C1~C8烷基)-、-亚芳基-、--C1~C8亚烷基-亚芳基-、-亚芳基、-C1~C8亚烷基-、-C1~C8亚烷基(C1~C8碳环)-、-(C3~C7碳环)-C1~C8亚烷基-、-C3~C8杂环-、-C1~C8亚烷基-(C3~C8杂环)-、-(C3~C8杂环)-C1~C9亚烷基-、-(CH2CH2O)k-、-(CH(CH3)CH2O)k-、和-(CH2CH2O)k-CH2-;k是选自1-30的整数;X”’、Y”’和Z”’独立地选自于NH、O或S;Q、R1和R2的定义同前文所述。
在一个优选的实施方案中,本发明的偶联物是抗体/细胞毒剂、抗体片段/细胞毒剂、双抗体/细胞毒剂、三(单)抗体/细胞毒剂、表皮生长因子(EGF)/细胞毒剂、前列腺特异性膜抗原(PSMA)抑制剂/细胞毒剂、黑素细胞刺激激素(MSH)/细胞毒剂、甲状腺刺激激素(TSH)/细胞毒剂、多克隆抗体/细胞毒剂、生长抑素/细胞毒剂、叶酸/细胞毒剂、蛋白裂解酶抑制剂/细胞毒剂、雌激素/细胞毒剂、雌激素类似物/细胞毒剂、设计的锚蛋白重复蛋白(DARPin)/细胞毒剂、雄激素/细胞毒剂和雄激素类似物/细胞毒剂。
在优选的实施例中,本发明的细胞结合分子是单克隆抗体。用于与本发明的与细胞毒剂偶联的抗体的例子包括,但不限于3F8(抗GD2)、阿巴单抗(抗CA-125)、阿昔单抗(抗CD41(整联蛋白α-IIb)、阿达木单抗(抗TNF-α)、Adecatumumab(抗EpCAM、CD326)、阿非莫单抗(抗TNF-α)、Afutuzumab(抗CD20)、Alacizumab单抗(抗VEGFR2)、ALD518(抗IL-6)、Alemtuzumab(Campath、MabCampath、抗CD52)、Altumomab(抗CEA)、Anatumomab(抗TAG-72)、Anrukinzumab(IMA-638、抗-IL-13)、Apolizumab(抗-HLA-DR)、阿奇单抗(抗-CEA)、阿塞珠单抗(抗-L-选择蛋白CD62L)、Atlizumab(tocilizumab、Actemra、RoActemra、抗-IL-6受体)、Atorolimumab(抗-Rhesus因子)、Bapineuzumab(抗-β淀粉样蛋白)、Basiliximab(Simulect、抗CD25(IL-2受体的α链))、Bavituximab(抗磷脂酰丝氨酸)、Bectumomab(LymphoScan、抗-CD22)、贝利单抗(Benlysta、LymphoStat-B、抗BAFF)、Benralizumab(抗CD125)、Bertilimumab(抗CCL11(eotaxin-1))、Besilesomab(Scintimun、抗CEA相关抗原)、贝伐单抗(Avastin、抗VEGF-A)、Biciromab(FibriScint、抗纤维蛋白IIβ链)、Bivatuzumab(抗-CD44v6)、Blinatumomab(BiTE、抗CD19)、Brentuximab(cAC10、抗-CD30 TNRSF8)、Briakinumab(抗IL-12、IL-23)、Canakinumab(Ilaris、抗IL-1)、Cantuzumab(C242、抗CanAg)、Capromab、Catumaxomab(Removab、抗EpCAM、抗CD3)、CC49(抗TAG-72)、Cedelizumab(抗CD4)、Certolizumab单抗(Cimzia抗TNF-α)、西妥昔单抗(爱必妥、IMC-C225、抗EGFR)、Citatuzumab bogatox(抗EpCAM)、Cixutumumab(抗IGF-1)、Clenoliximab(抗CD4)、Clivatuzu-mab(抗MUC1)、Conatumumab(抗TRAIL-R2)、CR6261(抗流感A血凝素)、Dacetuzumab(抗CD40)、Daclizumab(Zenapax、抗CD25(IL-2受体α链))、Daratumumab(抗CD38(环ADP核糖水解酶)、Denosumab(Prolia、抗RANKL)、Detumomab(抗B淋巴瘤细胞)、Dorlimomab、Dorlixizumab、Ecromeximab(抗GD3神经节苷脂)、Eculizumab(Soliris、抗-C5)、Edobacomab(抗内毒素)、Edrecolomab(Panorex、MAb17-1A、抗-EpCAM)、Efalizumab(Raptiva、抗LFA-1(CD11a))、Efungumab(Mycograb、抗Hsp90)、Elotuzumab(抗SLAMF7)、Elsilimomab(抗IL-6)、Enlimomab单抗(抗ICAM-1(CD54))、Epitumomab(抗episialin)、依他珠单抗(抗-CD22)、Erlizumab(抗-ITGB2(CD18))、Ertumaxomab(Rexomun、抗HER2/neu、CD3)、依他拉单抗(Abegrin、抗整联蛋白αvβ3)、Exbivirumab(抗乙肝表面抗原)、Fanolesomab(NeutroSpec、抗CD15)、Faralimomab(抗干扰素受体)、Farletuzumab(抗叶酸受体1)、Felvizumab(抗呼吸道合胞病毒)、Fezakinumab(抗-IL-22)、Figitumumab(抗-IGF-1受体)、Fontolizumab(抗-IFN-γ)、Foravirumab(抗狂犬病病毒糖蛋白)、Fresolimumab(抗TGF-β)、Galiximab(抗CD80)、Gantenerumab(抗β淀粉样蛋白)、Gavilimomab(抗CD147(basigin))、Gemtuzumab(抗CD33)、Girentuximab(抗碳酸酐酶9)、Glembatumumab(CR011、抗GPNMB)、Golimumab(Simponi、抗-TNF-α)、Gomiliximab(抗-CD23(IgE受体))、Ibalizumab(抗-CD4)、Ibritumomab(抗CD20)、Igovomab(Indimacis-125、抗CA-125)、Imciromab(Myoscint、抗心肌肌凝蛋白)、Infliximab(Remicade、抗TNF-α)、Intetumumab(抗CD51)、Inolimomab(抗CD25(IL-2受体α链)、伊珠单抗(抗-CD22)、Ipilimumab(抗CD152)、Iratumumab(抗CD30(TNFRSF8))、Keliximab(抗-CD4)、Labetuzumab(CEA-Cide、抗CEA)、Lebrikizumab(抗IL-13)、Lemalesomab(抗NCA-90(粒细胞抗原))、Lerdelimumab(抗TGFβ2)、Lexatumumab(抗TRAIL-R2)、Libivirumab(抗乙肝表面抗原)、Lintuzumab(抗CD33)、鲁米木单抗(抗CD40)、鲁米单抗(抗CD23(IgE受体)、Mapatumumab(抗TRAIL-R1)、马西莫单抗(抗T-细胞受体)、马妥珠单抗(抗EGFR)、Mepolizumab(Bosatria、抗IL-5)、Metelimumab(抗TGFβ1)、Milatuzumab(抗CD74)、Minretumomab(抗TAG-72)、Mitumomab(BEC-2、抗GD3神经节苷脂)、Morolimumab(抗恒河猴因子)、Motavizumab(Numax、抗呼吸道合胞病毒)、Muromonab-CD3(Orthoclone OKT3、抗CD3)、Nacolomab(抗C242)、Naptumomab(抗5T4)、那他珠单抗(Tysabri、抗整联蛋白α4)、奈巴单抗(抗内毒素)、Necitumumab(抗EGFR)、Nerelimomab(抗-TNF-α)、Nimotuzumab(Theracim、Theraloc、抗-EGFR)、Nofetumomab、Ocrelizumab(抗CD20)、奥利木单抗(Afolimomab、抗LFA-1(CD11a))、Ofatumumab(Arzerra、抗CD20)、Olaratumab(抗PDGF-Rα)、Omalizumab(Xolair、抗IgE Fc区)Oportuzumab(抗EpCAM)、Oregovomab(OvaRex、抗CA-125)、Otelixizumab(抗CD3)、Pagibaximab(抗脂磷壁酸)、Palivizumab(Synagis、Abbosynagis、抗呼吸道合胞病毒)、帕尼单抗(Vectibix、ABX-EGF、抗EGFR)、Panobacumab(抗铜绿假单胞菌(Pseudomonas aeruginosa))、帕考珠单抗(抗IL-4)、Pemtumomab(Theragyn、抗MUC1)、Pertuzumab(Omnitarg、2C4、抗HER2/neu)、Pexelizumab(抗C5)、Pintumomab(抗腺癌抗原)、Priliximab(抗-CD4)、Pritumumab(抗波形蛋白)、PRO140(抗-CCR5)Racotumomab(1E10、抗-N-羟乙酰神经氨酸(NeuGc、NGNA)-神经节苷脂GM3))、Rafivirumab(抗狂犬病病毒糖蛋白)、Ramucirumab(抗VEGFR2)、Ranibizumab(Lucentis、抗VEGF-A)、Raxibacumab(抗炭疽毒素、保护性抗原)、Regavirumab(抗巨细胞病毒糖蛋白B)、Reslizumab(抗-IL-5)、Rilotumumab(抗-HGF)、Rituximab(MabThera、Rituxanmab、抗-CD20)、Robatumumab(抗-IGF-1受体)、Rontalizumab(抗IFN-α)、Rovelizumab(LeukAr-rest、抗CD11、CD18)、Ruplizumab(Antova、抗CD154(CD40L))、Satumomab(抗TAG-72)、Sevirumab(抗巨细胞病毒)、Sibrotuzumab(抗FAP)、西法木单抗(抗IFN-α)、Siltuximab(抗IL-6)、Siplizumab(抗CD2)、Smart MI95(抗CD33)、Solanezumab(抗β淀粉状蛋白)、Sonepcizumab(抗鞘氨醇-1-磷酸)、Sontuzumab(抗-episialin)、Stamulumab(抗-myostatin)、Sulesomab(LeukoScan、抗NCA-90(粒细胞抗原))、Tacatuzumab(抗α甲胎蛋白)、Tadocizumab(抗整联蛋白αIIbβ3)、Talizumab(抗IgE)、Tanezumab(anti-NGF)、Taplitumomab(抗CD19)、Tefibazumab(Aurexis、(抗凝聚因子A))、Telimomab、Tenatumomab(抗腱生蛋白C)、Teneliximab(抗CD40)、Teplizumab(抗CD3)、TGN1412(抗CD28)、Ticilimumab(Tremelimumab、抗-CTLA-4)、Tigatuzumab(抗TRAIL-R2)、TNX-650(抗IL-13)、Tocilizumab(Atlizumab、Actemra、RoActemra、IL-6受体)、Toralizumab(抗CD154(CD40L))、Tositumomab(抗CD20)、曲妥珠单抗(赫赛汀、抗HER2/neu)、Tremelimumab(抗CTLA-4)、Tucotuzumab celmoleukin(抗EpCAM)、Tuvirumab(抗乙型肝炎病毒)、Urtoxazumab(抗大肠杆菌)、Ustekinumab(Stelara、抗-IL-12、IL-23)、Vapaliximab(抗-AOC3(VAP-1))、维多珠单抗(抗整联蛋白α4β7)、维妥珠单抗(抗CD20)、Vepalimomab(抗AOC3(VAP-1))、Visilizumab(Nuvion、抗CD3)、Vitaxin(抗血管整合素avb3)、Volociximab(抗整联蛋白α5β1)、Votumumab(HumaSPECT、抗肿瘤抗原CTAA16.88)、Zalutumumab(HuMax-EGFR、Zanolimumab(HuMax-CD4、抗-CD4)、Ziralimumab(抗-CD147(basigin))、Zolimomab(抗-CD5)、依那西普AlefaceptAbataceptRilonacept(Arcalyst)、14F7(抗IRP-2(铁调节蛋白2))、14G2a(抗GD2神经节苷脂、源于Nat.Cancer Inst.、治疗黑素瘤和实体瘤)、J591(抗-PSMA、源于WeillCornell医学院、治疗前列腺癌)、225.28S(抗HMW-MAA(高分子量黑素瘤相关抗原)、SorinRadiofarmaci SRL(源于意大利米兰、治疗黑色素瘤)、COL-1(抗CEACAM3、CGM1、源于NatCancer Inst.、治疗结肠直肠癌和胃癌)、CYT-356(治疗前列腺癌)、HNK20(OraVax Inc.治疗呼吸道合胞病毒感染)、ImmuRAIT(源于Immunomedics、治疗NHL)、Lym-1(抗HLA-DR10、Peregrine Pharm)、MAK-195F(抗TNF(肿瘤坏死因子、TNFA、TNF-α、TNFSF2、源于Abbott/Knoll、治疗脓毒症中毒性休克)、MEDI-500(T10B9、抗CD3、TRαβ(T细胞受体α/β)、源于MedImmune Inc、用于移植物抗宿主疾病病)、RING SCAN(抗TAG 72(肿瘤相关糖蛋白72)、源于Neoprobe Corp.、用于乳腺癌、结肠癌和直肠癌)、Avicidin(抗EPCAM(上皮细胞粘附分子))、抗-TACSTD1(肿瘤相关钙信号转导1)、抗GA733-2(胃肠肿瘤相关蛋白2)、抗EGP-2(上皮糖蛋白2)、抗KSA、KS1/4抗原、M4S、肿瘤抗原17-1A、CD326(源于NeoRx公司、治疗结肠癌、卵巢癌、前列腺癌和NHL)、LymphoCide、、Oncolym、Allomune、抗VEGF、CEAcide、IMC-1C11和Cetuximab。
用于结合抗原的其它抗体,包括但不限于抗以下抗原的抗体:氨肽酶N(CD13)、膜联蛋白A1、B7-H3(CD276、各种癌症)、CA125(卵巢癌)、CA15-3(各种癌)、CA19-9(各种癌)、L6(各种癌)、LewisY(各种癌)、LewisX(各种癌)、甲胎蛋白(各种癌)、CA242、胎盘碱性磷酸酶(各种癌)、前列腺特异性抗原(前列腺癌)、前列腺酸性磷酸酶(前列腺癌)、表皮生长因子(各种癌)、CD2(霍奇金病、非霍奇金淋巴瘤的淋巴瘤、多发性骨髓瘤)、CD3的ε(T细胞淋巴瘤、肺癌、乳腺癌、胃癌、卵巢癌、自身免疫性疾病、恶性腹水)、CD19(B细胞恶性肿瘤)、CD20(非霍奇金淋巴瘤)、CD22(白血病、淋巴瘤、多发性骨髓瘤、系统性红斑狼疮)、CD30、CD33、CD37、CD38(多发性骨髓瘤)、CD40(淋巴瘤、多发性骨髓瘤、白血病)、CD51(转移性黑素瘤、肉瘤)、CD52、CD56(小细胞肺癌癌、卵巢癌、Merkel细胞癌、以及液体肿瘤、多发性骨髓瘤)、CD66e(癌症)、CD70(转移性肾细胞癌和非霍奇金淋巴瘤)、CD74(多发性骨髓瘤)、CD80(淋巴瘤)、CD98(癌症),粘蛋白(癌)、CD221(实体瘤)、CD227(乳腺癌、卵巢癌)、CD262(非小细胞肺癌和其他癌)、CD309(卵巢癌)、CD326(实体瘤)、CEACAM3(大肠癌、胃癌)、CEACAM5(癌胚抗原;CEA、CD66e)(乳腺癌、结肠直肠癌和肺癌)、DLL3(Δ状-3)、DLL4(Δ状-4)、EGFR(表皮生长因子受体、各种癌症)、CTLA4(黑色素瘤)、CXCR4(CD184、血红素肿瘤、实体肿瘤)、内皮糖蛋白(CD105、实体瘤)、EPCAM(上皮细胞粘附分子、膀胱癌、头、颈、结肠、前列腺非霍奇金淋巴瘤、和卵巢癌)、ERBB2(表皮生长因子受体2;肺癌、乳腺癌、前列腺癌)、FCGR1(自身免疫性疾病)、FOLR(叶酸受体、卵巢癌)、GD2神经节苷脂(癌症)、G-28(一种细胞表面抗原glyvolipid、黑素瘤)、独特型GD3(癌症)、热休克蛋白(癌症)、HER1(肺、胃癌)、HER2(乳腺癌、肺癌和卵巢癌)、HLA-DR10(NHL)、HLA-DRB(非霍奇金淋巴瘤、B细胞白血病)、人绒毛膜促性腺激素(癌)、IGF1R(胰岛素样生长因子1受体、实体瘤、血液癌症)、IL-2受体(白细胞介素2受体、T-细胞白血病和淋巴瘤)、IL-6R(白细胞介素6受体、多发性骨髓瘤、类风湿性关节炎、Castleman病、IL6依赖性肿瘤)、整合素(素αvβ3、α5β1、α6β4、αllβ3、α5β5、αvβ5细胞附着因子、各种癌症)、MAGE-1(各种癌)、MAGE-2(各种癌)、MAGE-3(各种癌)、MAGE4(各种癌)、抗转铁蛋白受体(各种癌)、P97(黑色素瘤)、MS4A1(跨膜域4亚科A成员1、非霍奇金B细胞淋巴瘤、白血病)、MUC1或MUC1-KLH(乳腺癌、卵巢癌、子宫颈癌、支气管和胃肠道癌症)、MUC16(CA125)(卵巢癌)、CEA(大肠癌)、GP100(黑色素瘤)、MART1(黑色素瘤)、MPG(黑色素瘤)、MS4A1(跨膜域4蛋白A、小细胞肺癌、非霍奇金淋巴瘤)、核仁、神经癌基因产物(癌)、P21(癌)、抗(N-羟乙酰神经氨酸)抗体结合位(乳腺癌、黑色素瘤)、PLAP样睾丸碱性磷酸酶(卵巢癌、睾丸癌)、PSMA(前列腺肿瘤)、PSA(前列腺癌)、ROBO4、TAG72(肿瘤相关糖蛋白72、白血病、胃癌、结肠直肠癌、卵巢癌)、T细胞的跨膜蛋白(各种癌症)、Tie(CD202b)、TNFRSF10B(肿瘤坏死因子受体超家族成员10B、各种癌症)、TNFRSF13B(肿瘤坏死因子受体超家族成员13B、多发性骨髓瘤、非霍奇金淋巴瘤、以及其他癌症、类风湿性关节炎和系统性红斑狼疮)、TPBG(滋养层糖蛋白、肾细胞癌)、TRAIL-R1(肿瘤坏死凋亡诱导配体受体1、淋巴瘤、非霍奇金淋巴瘤、大肠癌、肺癌)、VCAM-1(CD106、黑色素瘤)、血管内皮生长因子、血管内皮生长因子-A、VEGF-2(CD309、各种癌症)。抗体识别的一些其他的肿瘤相关抗原可见于各种综述(Gerber等、mAbs 1:3,247-253(2009);Novellino等,cancer immunol immunother.54(3),187-207(2005)Franke等,cancer biother radiopharm.2000,15,459-76)。抗原的例子还包括:分化抗原(CD2、CD2R、CD3、CD3gd、CD3e、CD4、CD5、CD6、CD7、CD8、CD8a、CD8b、CD9、CD10、CD11a、CD11b、CD11c、CD12、CD12w、CD13、CD14、CD15、CD15s、CD15u、CD16、CD16a、CD16b、CD17、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD42a、CD42b、CD42c、CD42d、CD43、CD44、CD44R、CD45、CD45RA、CD45RB、CD45RO、CD46、CD47、CD47R、CD48、CD49a、CD49b、CD49c、CD49e、CD49f、CD50、CD51、CD52、CD53、CD54、CD55、CD56、CD57、CD58、CD59、CD60、CD60a、CD60b、CD60c、CD61、CD62E、CD62L、CD62P、CD63、CD64、CD65、CD65s、CD66、CD66a、CD66b、CD66c、CD66d、CD66e、CD66f、CD67、CD68、CD69、CD70、CD71、CD72、CD73、CD74、CD74、CD75、CD75s、CD76、CD77、CD78、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CDw84、CD85、CD86、CD87、CD88、CD89、CD90、CD91、CD92、CDw92、CD93、CD94、CD95、CD96、CD97、CD98、CD99、CD99R、CD100、CD101、CD102、CD103、CD104、CD105、CD106、CD107、CD107a、CD107b、CD108、CD109、CD110、CD111、CD112、CD113、CDw113、CD114、CD115、CD116、CD117、CD118、CD119、CDw119、CD120a、CD120b、CD121a、CD121b、CDw121b、CD122、CD123、CDw123、CD124、CD125、CDw125、CD126、CD127、CD128、CDw128、CD129、CD130、CD131、CDw131、CD132、CD133、CD134、CD135、CD136、CDw136、CD137、CDw137、CD138、CD139、CD140a、CD140b、CD141、CD142、CD143、CD144、CD145、CDw145、CD146、CD147、CD148、CD149、CD150、CD151、CD152、CD153、CD154、CD155、CD156a、CD156b、CDw156c、CD157、CD158a、CD158b、CD159a、CD159b、CD159c、CD160、CD161、CD162、CD162R、CD163、CD164、CD165、CD166、CD167、CD167a、CD168、CD169、CD170、CD171、CD172a、CD172b、CD172g、CD173、CD174、CD175、CD175s、CD176、CD177、CD178、CD179、CD180、CD181、CD182、CD183、CD184、CD185、CD186、CDw186、CD187、CD188、CD189、CD190、Cd191、CD192、CD193、CD194、CD195、CD196、CD197、CD198、CDw198、CD199、CDw199、CD200、CD200a、CD200b、CD201、CD202、CD202b、CD203、CD203c、CD204、CD205、CD206、CD207、CD208、CD209、CD210、CDw210、CD212、CD213a1、CD213a2、CDw217、CDw218a、CDw218b、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD231、CD232、CD233、CD234、CD235a、CD235ab、CD235b、CD236、CD236R、CD238、CD239、CD240、CD240CE、CD240D、CD241、CD242、CD243、CD244、CD245、CD246、CD247、CD248、CD249、CD252、CD253、CD254、CD256、CD257、CD258、CD261、CD262、CD263、CD265、CD266、CD267、CD268、CD269、CD271、CD273、CD274、CD275、CD276(B7-H3)、CD277、CD278、CD279、CD280、CD281、CD282、CD283、CD284、CD289、CD292、CDw293、CD294、CD295、CD296、CD297、CD298、CD299、CD300a、CD300c、CD300e、CD301、CD302、CD303、CD304、CD305、CD306、CD309、CD312、CD314、CD315、CD316、CD317、CD318、CD319、CD320、CD321、CD322、CD324、CDw325、CD326、CDw327、CDw328、CDw329、CD331、CD332、CD333、CD334、CD335、CD336、CD337、CDw338、CD339)、AnnexinA1、Nucleolin、Endoglin(CD105)、ROBO4、氨基肽酶N、CTLA-4、Δ-样3(DLL3)、Δ-样4(DLL4)、VEGFR-2(CD309)、CXCR49、CD184)、Tie2、B7-H3、WT1、MUC1、LMP2、HPV E6 E7、EGFRvIII、EGFR、HER-2/neu、独特性抗原、MAGE A3、P53非突变体、NY-ESO-1、GD2、CEA、MelanA/MART1、Ras突变体、gp100、p53突变体、Proteinase3(PR1)、BCR-abl、酪氨酸酶,Survivin,hTERT,肉瘤易位断点,EphA2,PAP,ML-IAP,AFP,EpCAM,ERG(TMPRSS2 ETS融合基因),NA17,PAX3,ALK,雄激素受体,细胞周期蛋白B1,多唾液酸,MYCN,RhoC,TRP-2,GD3,岩藻糖基GM1,间皮素,PSCA,MAGE A1,sLe(a),CYP1B1,PLAC1,GM3,BORIS,Tn,GloboH,ETV6-AML,NY-BR-1,RGS5,SART3,STn,碳酸酐酶IX,PAX5,OY-TES1,精子蛋白17,LCK,HMWMAA,AKAP-4,SSX2,XAGE 1,B7H3,Legumain,Tie2,VEGFR2,MAD-CT-1,FAP,PDGFR-β,MAD-CT-2,Fos相关抗原1。
本发明中使用的抗体可以用体内、体外或者两者组合的方式获得。生产多克隆抗-受体多肽抗体的方法是非常成熟的,在美国专利4,493,795(Nestor等人)都有详细描述。通常,单克隆抗体是应用相应抗原免疫的小鼠脾细胞与骨髓瘤细胞通过杂交瘤技术得到的(G.;Milstein,C.(1975).Nature 256:495-497),详细的操作步骤见“Antibodies--A Laboratory Manual”,Harlow和Lane总编,Cold Spring Harbor Laboratory Press,NewYork(1988),本专利引作参考。特别地,单克隆抗体是通过使小鼠、大鼠、仓鼠或其它哺乳动物免疫需要的抗原,如完整的细胞,从完整细胞中分离得到的抗原,完整病毒,灭活病毒,病毒蛋白等而得到。脾细胞通常在PEG(6000)作用下与骨髓瘤细胞融合,通过它们对HAT(次黄嘌呤-氨基蝶呤-胸腺嘧啶)的敏感性而筛选杂交融合的细胞。实际应用中,本发明所使用的产生单克隆抗体的杂交瘤细胞,是依据它们与靶细胞上的相应受体免疫结合或免疫阻抗的能力而确定。
本发明中所使用的单克隆抗体还可以通过单克隆杂交瘤细胞培养而获得,这样的杂交瘤细胞能分泌抗原特异性的抗体。在培养过程中,通过控制合适的条件使杂交瘤细胞向培养基中分泌抗体。收集包含抗体的培养基,而后通过一些成熟的技术纯化分离抗体,如蛋白A或蛋白G亲和层析,阴离子、阳离子和疏水层析以及分子大小排阻层析(特别是蛋白A、蛋白G亲和层析和分子大小排阻层析),离心,差异溶解或者其他标准的蛋白纯化分离技术。
杂交瘤培养所需有效培养基以及人工合成培养基可以通过技术合成或者商业途径获取。典型的人工合成培养基是向DMEM(Dulbecco等Virol 8:396(1959))中加入4.5mg/L葡萄糖,20mM谷氨酰胺,20%胎牛血清以及消泡剂,如聚乙二醇聚氧丙烯共聚物。
另外,生产抗体的细胞株也可以通过细胞融合之外的方法得到,比如说用癌基因DNA直接转化B淋巴细胞,或者致癌病毒如EB病毒(EBV,也称人疱疹病毒4(HHV-4))或者肉瘤相关疱疹病毒(KSHV)转染B淋巴细胞(可参考美国专利4,341,761;4,399,121;4,427,783;4,444,887;4,451,570;4,466,917;4,472,500;4,491,632;4,493,890)。单克隆抗体也可以通过抗-受体多肽或含末端羧基的多肽而得到。具体可见文献:Niman等,Proc.Natl.Acad.Sci.,1983,80,4949-4953;Geysen等,Proc.Natl.Acad.Sci.,1985,82,178-182;Lei等,Biochemistry,1995,34(20),6675-6688等。通常,抗-受体多肽或多肽类似物可以单独或与免疫原载体连接,作为免疫原生产抗-受体多肽单克隆抗体。
还有其他已知的各种技术,可以用来生产本发明里作为结合分子的单克隆抗体。特别有用的是生产全人源抗体的方法。其中一个方法是噬菌体展示技术,此方法通过亲和富集,从大量的人抗体中筛选出特异性结合抗原的抗体。噬菌体展示技术,包括构建和筛选噬菌体展示库是一种非常成熟的技术,具体可以参考:Dente等,Gene.148(1):7-13(1994);Little等,Biotechnol Adv.12(3):539-55(1994);Clackson等,Nature 352:264-628(1991);Huse等,Science 246:1275-1281(1989);Hoogenboom等,Methods in MolecularBiology 178:1-37(2001),O'Brien等编辑,Human Press,Totowa,N.J.和Lee等.J.Mol.Biol.340:1073-1093(2004)。
通过非人源的如老鼠的杂交瘤技术获得的抗体,可以通过人源化以避免注射入人体时产生抗抗体。最常见的人源化抗体的方法是互补决定区嫁接和表面修饰,这些方法在大量文献中都有描述,如美国专利5,859,205;6,797,492;Liu等,Immunol Rev.,2008,222,9-27;Almagro等,Front Biosci.,2008,1(13),1619-33;Lazar等,Mol Immunol.,2007,44(8),1986-98;Li等,Proc.Natl.Acad.Sci.,2006,103(10),3557-62。全人源抗体也可以通过带有人免疫球蛋白重链、轻链的抗原免疫转基因小鼠、兔子、猴子以及其他转基因哺乳动物而得到。这样的转基因小鼠例子有Xenomouse(Abgenix/Amgen.),HuMAb-Mouse(Medarex/BMS),VelociMouse(Regeneron),参见美国专利6,596,541;6,207,418;6,150,584;6,111,166;6,075,181;5,922,545;5,661,016;5,545,806;5,436,149和5,569,825。在人体治疗中,通过将鼠源的可变区与人的非可变区融合称为“嵌合抗体”,这类抗体比鼠抗在人体中具有更小的免疫原性(Kipriyanov等,MolBiotechnol.,2004,26,39-60;Houdebine,CurrOpin Biotechnol.,2002,13,625-629)。另外,通过可变区的点突变可以使抗体抗原结合的亲和力和特异性提高(Brannigan等,Nat Rev Mol Cell Biol.,2002,3,964-70;Adams等,JImmunol Methods.,1999,231,249-60)。非可变区的替换可以改进抗体介导的结合功能和细胞毒性。
特异免疫癌细胞抗原的抗体可以通过商业购得或者通过任何已知的方法制备,如化学合成和重组表达。表达抗体的DNA序列可以通过商业购买或其他途径,如GenBank数据库或类似的数据库,发表的文献,常规克隆和测序等方法得到。
编码杂交瘤来源的单克隆抗体或噬菌体展示的Fv克隆的DNA,可以使用常规方法方便地分离和测序(例如,使用从杂交瘤或噬菌体DNA模板,特异性扩增目标重链和轻链编码区域的寡核苷酸引物)。一旦得到DNA单元,可以将DNA插入到表达载体中,然后转染进入宿主细胞如大肠杆菌,猴COS细胞,中国仓鼠卵巢(CHO)细胞或者骨髓瘤细胞等不表达免疫球蛋白的细胞中,获得相应的单克隆抗体(Skerra等,Curr.Opinionin Immunol.,1993,5,256;Pluckthun,Immunol.Revs.,1992,130,151)。抗体还可以在这样的一种表达系统中产生,其中表达得到的多肽成分的定量比率可以被控制,以帮助提高抗体产量以及促进抗体正确组装。这种方法至少部分地是由于同时也提高了多肽的翻译效率得以实现。通过常规的发酵得到的抗体蛋白需进一步纯化以获得单一的产物,用于下一步的试验和使用。发酵后采用已知的标准蛋白纯化方法进行纯化。一个示例性的纯化过程包括:免疫亲和分离(如蛋白A柱)或离子交换柱层析,乙醇沉淀,反相高压液相色谱(HPLC)纯化,硅胶柱层析或阳离子交换柱层析(如DEAE),色谱聚焦层析,SDS-PAGE,硫酸铵沉淀以及凝胶过滤(如SephadexG-75)。
除抗体以外,任何通过结合、阻抗、靶向或以其它方式与靶细胞的抗原表位或相应的受体相互作用的多肽或蛋白,可以作为结合分子。这些多肽或蛋白可以是任何一种能够结合相应表位或受体的分子,并不一定要属于免疫球蛋白家族。这些多肽可以应用类似噬菌体抗体展示技术而分离得到(Szardenings,J Recept Signal Transduct Res.,2003,23(4),307-49)。从随机多肽库中筛选到的多肽可以像抗体或抗体片段一样作为结合分子使用。作为结合分子的多肽或蛋白,只要不影响其结合特异性,就可以被偶联或者连接到大分子或材料如,但不限于,白蛋白,高分子,脂质体,纳米微球等。
细胞结合分子或配体,或细胞受体激动剂可以是基于Ig和非基于Ig的蛋白质支架分子。基于Ig的支架可以选自,但不限于,纳米抗体(VHH的衍生物(骆驼科动物Ig))(Muyldermans S.,2013Annu Rev Biochem.82,775–97);结构域抗体(dAb,VH或VL结构域的衍生物)(Holt L.J,等,2003,Trends Biotechnol.21,484–90);双特异性T细胞接头(BiTE、双特异性双抗体)(Baeuerle P.A等,2009,Curr.Opin.Mol.Ther.11,22–30);双重亲和复定位抗体(DART,双特异性双抗体)(Moore PA P等.2011,Blood 117(17),4542–51);四价串联抗体(TandAb,二聚双特异性双抗体)(Cochlovius B等,2000,Cancer Res.60(16):4336–4341)。非Ig支架可以选自,但不限于,Anticalin(Lipocalins的衍生物)(Skerra A.2008,FEBS J.,275(11):2677–83;Beste G等,1999Proc.Nat.Acad.USA.96(5):1898–903;Skerra,A.2000Biochim Biophys Acta,1482(1-2):337–50;Skerra A.2007,Curr OpinBiotechnol.18(4):295–304;Skerra A.2008,FEBS J.275(11):2677–83);Adnectin(第10个FN3(纤连蛋白))(Koide A等,1998J.Mol.Biol.,284(4):1141–51;Batori V,2002,Protein Eng.15(12):1015–20;Tolcher A.W,2011,Clin.Cancer Res.17(2):363–71;Hackel B.J,2010,Protein Eng.Des.Sel.23(4):211–19);设计的锚蛋白重复蛋白(DARPins)(锚蛋白重复(AR)蛋白的衍生物)(Boersma Y L等,2011Curr OpinBiotechnol.22(6):849–57),例如DARPin C9、DARPin Ec4及DARPin E69_LZ3_E01(WinklerJ等,2009Mol Cancer Ther.8(9),2674–83;Patricia M-K.M.等,Clin Cancer Res.2011;17(1):100–10;Boersma Y.L等,2011J.Biol.Chem.286(48),41273–85);高亲和性多聚体(域A/低密度脂蛋白(LDL)受体)(Boersma Y.L,2011J.Biol.Chem.286(48):41273–41285;Silverman J等,2005Nat.Biotechnol.,23(12):1556–61)。
本发明的小分子细胞结合分子/配体或细胞受体激动剂的结构示例如下:LB01(叶酸)、LB02(PMSA配体)、LB03(PMSA配体)、LB04(PMSA配体)、LB05(生长抑制素)、LB06(生长抑制素)、LB07(奥曲肽、生长抑制素类似物)、LB08(兰瑞肽、生长抑制素类似物)、LB09(伐普肽(Sanvar)、生长抑制素类似物)、LB10(CAIX配体)、LB11(CAIX配体)、LB12(胃泌素释放肽受体(GRPr)、MBA)、LB13(促黄体激素释放激素(LH-RH)和GnRH配体)、LB14(促黄体激素释放激素(LH-RH)和GnRH配体)、LB15(GnRH拮抗剂、Abarelix)、LB16(钴胺素、维生素B12类似物)、LB17(钴胺素、维生素B12类似物)、LB18(用于αvβ3整联蛋白受体、环状RGD五肽)、LB19(VEGF受体的异二价肽配体)、LB20(神经髓质素B)、LB21(蛙皮素,作用于G蛋白偶联受体)、LB22(TLR2,作用于类Toll受体)、LB23(作用于雄性激素受体)、LB24(西仑吉肽或环(-RGDfV-)αv整合素受体、LB23(氟可的松)、LB25(利福布汀类似物)、LB26(利福布汀类似物)、LB27(利福布汀类似物)、LB28(氟氢可的松)、LB29(地塞米松)、LB30(丙酸氟替卡松)、LB31(丙酸倍氯米松)、LB32(醋酸曲安奈德)、LB33(泼尼松龙)、LB34(泼尼松龙)、LB35(甲基泼尼松龙)、LB36(倍他米松)、LB37(伊立替康类似物)、LB38(克唑替尼类似物)、LB39(硼替佐米类似物)、LB40(卡菲佐米类似物)、LB41(卡非佐米类似物)、LB42(亮丙瑞林类似物)、LB43(曲普瑞林类似物)、LB44(克林霉素)、LB45(利拉鲁肽类似物)、LB46(半长春新碱类似物)、LB47(瑞他帕林类似物)、LB48(丁布尔类似物)、LB49(长春碱类似物)、LB50(利西森肽类似物)、LB51(奥西丁尼类似物)、LB52(核苷类似物)、LB53(厄洛替尼类似物)和LB54(拉帕替尼类似物),其结构如下所示:
LB12(胃泌素释放肽受体(GRPr),MBA),
LB13(促黄体激素释放激素(LH-RH)和促性腺激素释放激素GnRH配体),
LB14(促黄体激素释放激素(LH-RH)和促性腺激素释放激素GnRH配体),
LB15(GnRH拮抗物、阿巴瑞克),
LB18(环RGD五肽,作用于αvβ3整联蛋白受体),
LB19(异源二价肽配体偶联物,作用于血管内皮生长因子VEGF受体),
LB21(蛙皮素偶联物,作用于G蛋白偶联受体),
LB24(西伦吉肽/环(-RGDfV-)偶联物,作用于αv整合素受体),
其中是连接子的连接位置;X4和Y1独立地是O、NH、NHNH、NR1、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH2、C(O)NHNHC(O)和C(O)NR1;X1是H、CH2、OH、O、C(O)、C(O)NH、C(O)N(R1)、R1、NHR1、NR1、C(O)R1或C(O)O;X5是H、CH3、F或Cl;M1和M2分别是H、Na、K、Ca、Mg、NH4、N(R1R2R3 R4);R1、R2、R3和R4定义同式(I)。
细胞结合分子,优选抗体上的任何一个反应性基团都可以是共轭结合位,如赖氨酸的ε-氨基,糖侧链,羧基,二硫键,巯基等。关于抗体上可用于偶联反应基团的综述,可见于G.T.Hermanson,Bioconjugate Techniques,AcademicPress,2008;Garnett,Adv.DrugDelivery Rev.,2001,53,171-216;Dubowchik,Walker,Pharmacology&Therapeutics,1999,83,67-123等文献,本发明引为参考。
本发明中的细胞毒素横交联PBD二聚体,可以直接或是通过双官能团连接子或交联试剂偶联(连接)到细胞结合分子上。其中双官能团连接子包含两个反应基团:一个可以与细胞结合分子反应,另一个可以与本发明中一个或是多个细胞毒性分子反应。双官能团连接子广泛见于文献(如美国专利5,208,020;Isalm和Dent,Bioconjugation,第5章,218-363页,Groves Dictionaries Inc.,New York,1999)。例如下列双官能团连接子:SPDP(N-琥珀酰亚胺3-(2-吡啶双硫)丙酸酯)、SPDB(N-琥珀酰亚胺4-(2-吡啶双硫)丁酸酯)、SPP(N-琥珀酰亚胺4-(2-吡啶双硫)戊酸酯)、SDPB(N-琥珀酰亚胺3-(2-吡啶双硫)丁酸酯)、2-亚胺基硫烷、N-琥珀酰亚胺4-(5-硝基-2吡啶双硫)丁酸酯(SNPB)、N-琥珀酰亚胺4-(5-硝基-2吡啶双硫)戊酸酯(SNPP)、N-磺酸琥珀酰亚胺4-(5-硝基-2吡啶双硫)丁酸酯(SSNPB)、N-琥珀酰亚胺-4-甲基-4-(5-硝基-2吡啶双硫)戊酸酯(SMNP)、N-磺酸琥珀酰亚胺4-(5-硝基-2吡啶双硫)戊酸酯(SSNPP)、4-琥珀酰亚胺-氧羰基-α-甲基-(2-吡啶双硫)甲苯(SMPT)、N-磺酸琥珀酰亚胺-4-甲基-4-(5-硝基-2吡啶双硫)戊酸酯(SSMNP)、N-琥珀酰亚胺-4-甲基-4-(2吡啶双硫)戊酸酯(SMPDP)、N-琥珀酰亚胺4-(5-N、N-甲基-酰胺-2-吡啶双硫)丁酸酯(SCPB)、N-磺酸琥珀酰亚胺-4-(5-N,N-甲基-酰胺-2-吡啶双硫)丁酸酯(SSCPB)、N-酰亚胺-4、4-二甲基-4-(2-吡啶双硫)戊酸酯(SDMPDP)、琥珀酰亚胺-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、N-琥珀酰亚胺-4-(碘代乙酰基)-胺基苯酸酯(SIAB)、双马来酰亚胺聚乙二醇(BMPEG)、BM(PEG)1-20、N-(β-马来酰亚胺乙氧基)-琥珀酰亚胺酯(BMPS)、2-亚氨基硫烷(IT)、二甲基己二亚酰胺盐酸盐或酰亚胺酯的衍生物、活化的酯(如二琥珀酰亚胺辛二酸酯)、乙醛(如戊二醛)、双叠氮化合物(如双(对位叠氮苯甲酰基)己二胺)、双重氮盐衍生物(如双-(对位重氮苯甲酰基乙二胺)、二异氰酸酯(如甲苯2,6-二异氰酸酯)、以及双活化氟化合物(如1,5-二氟-2,4-二硝基苯)、γ-马来酰亚胺基丁酸琥珀酰亚胺酯(GMBS)、E-马来酰亚胺基己酸琥珀酰亚胺酯(EMCS)、5-马来酰亚胺基戊酸琥珀酰亚胺酯、HBVS、4-马来酰亚胺甲基)-环己烷-1-羰基-6-氨基己酸N-琥珀酰亚胺酯(SMCC的长链类似物(LC-SMCC))、间马来酰亚胺苯甲酰-N-羟基琥珀酰亚胺脂(MBS)、4-(4-N-马来酰亚胺苯基)-丁酸肼或盐酸盐(MPBH)、3-(溴乙酰胺基)丙酸琥珀酰亚胺酯(SBAP)、碘醋酸N-琥珀酰亚胺酯(SIA)、kappa-(马来酰亚胺基)十一烷酸琥珀酰亚胺酯(KMUA)、N-琥珀酰亚胺-4-(对顺丁烯二酰亚胺基苯基)丁酸酯(SMPB)、琥珀酰亚胺基-l-6-(β-马来酰亚胺丙酰胺基)-己酸酯(SMPH)、琥珀酰亚胺基-4-4-乙烯基磺酸苯甲酸酯(SVSB)、二硫基-双马来酰亚胺基乙烷(DTME)、1,4-二马来酰亚胺基丁烷(BMB)、1,4-二马来酰亚胺基-2,3-二羟基丁烷(BMDB)、双马来酰亚胺己烷(BMH)、双马来酰亚胺乙烷(BMOE)、4-(N-马来酰亚胺甲基)环己烷-1-羧酸磺酸基琥珀酰亚胺酯(sulfo-SMCC)、磺酸琥珀酰亚胺基(4-碘代乙酰基)氨基苯甲酯(sulfo-SIAB)、3-马来酰亚胺基苯甲酸-N-羟基磺酸琥珀酰亚胺酯(sulfo-MBS)、N-(gamma-马来酰亚胺丁酸磺基琥珀酰亚胺酯(sulfo-GMBS)、N-(epsilon-马来酰亚胺丙酸磺基琥珀酰亚胺酯(sulfo-EMCS)、N-(kappa-马来酰亚胺基十一酰氧基)磺基琥珀酰亚胺(sulfo-KMUS)、以及磺酸琥珀酰亚胺基4-(p-马来酰亚胺基苯基)丁酸酯(sulfo-SMPB);或市售的连接子(如可购于Thermo Scientific’s Pierce的亚胺酯结合剂:DMA(己二酰亚胺酸二甲酯二盐酸盐)、DMP(庚二酰亚胺酸二甲酯二盐酸盐)、DMS(辛二酰亚胺酸二甲酯二盐酸盐)、DTBP(二甲基3、3-二硫代双丙亚胺酸二甲酯二盐酸盐);NHS-酯胺反应结合剂:BS(PEG)5(双(琥珀酰亚胺)五(乙二醇酯))、BS(PEG)9(双(琥珀酰亚胺)九(乙二醇酯))、BS(双(磺酸琥珀酰亚胺)辛二酸酯)、BSOCOES(双[2-(琥珀酰亚胺氧羰基氧)乙基亚砜)、DSG(二琥珀酰亚胺戊二酸酯)、DSP(3,3'-二硫代双(磺酸琥珀酰亚胺基丙酸酯)、DSS(二琥珀酰亚胺辛二酸酯)、DST(二琥珀酰亚胺酒石酸酯)、DTSSP(3,3'-二硫代双(磺酸琥珀酰亚胺基丙酸酯))、EGS(乙二醇双(丁二酸N-羟基琥珀酰亚胺酯))、Sulfo-EGS(乙二醇双(磺酸丁二酸N-羟基琥珀酰亚胺酯))、TSAT(三-琥珀酰亚胺基氨基三乙酯)、DFDNB(1,5-二氟-2,4-二硝基苯);胺基-巯基结合剂:Sulfo-SIAB(磺酸琥珀酰亚胺(4-碘乙酰基)氨基苯甲酸酯)、SIAB(琥珀酰亚胺(4-碘乙酰基)氨基苯甲酸酯)、SBAP(琥珀酰亚胺基3-(溴代乙酰氨基)丙酸酯)、SIA(琥珀酰亚胺基碘代乙酸酯)、Sulfo-SMCC(4-(N-马来酰亚胺甲基)环己烷-1-羧酸磺酸基琥珀酰亚胺酯);NHS-PEG-马来酰亚胺结合剂:SM(PEG)n(琥珀酰亚胺-(N-马来酰亚胺丙酰胺基)-#乙二醇)酯,#=1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、18、19、20、21、22、23、24)、LC-SMCC琥珀酰亚胺基(4-(N-马来酰亚胺甲基)环己烷-1-羧酸(6-酰胺基己酸酯))、Sulfo-EMCS(N-(epsilon-马来酰亚胺丙酸磺基琥珀酰亚胺酯)、EMCS(N-(epsilon-马来酰亚胺丙酸琥珀酰亚胺酯)、Sulfo-GMBS(N-(gamma-马来酰亚胺丁酸磺基琥珀酰亚胺酯)、GMBS(N-(gamma-马来酰亚胺丁酸琥珀酰亚胺酯)、Sulfo-KMUS(N-(kappa-马来酰亚胺基十一酰氧基)磺基琥珀酰亚胺酯)、Sulfo-MBS(3-马来酰亚胺基苯甲酰基-N-羟基磺酸琥珀酰亚胺酯)、MBS(3-马来酰亚胺基苯甲酰N-羟基琥珀酰亚胺酯)、Sulfo-SMPB((磺酸琥珀酰亚胺基4-(p-马来酰亚胺基苯基)丁酸酯)、SMPB(琥珀酰亚胺基4-(p-马来酰亚胺基苯基)丁酸酯)、AMAS(N-(α马来酰亚胺基乙酰氧基琥珀酰亚胺酯)、BMPS(N-beta-马来酰亚胺基丙氧基琥珀酰亚胺酯)、SMPH(琥珀酰亚胺l-6-(β-马来酰亚胺丙酰胺基)-己酸酯)、PEG12-SPDP(2-吡啶基二硫基-四氧杂三十八烷-N-羟基丁二酰亚胺)、PEG4-SPDP(2-吡啶基二硫基-四氧杂十四烷-N-羟基丁二酰亚胺)、Sulfo-LC-SPDP(磺基琥珀酰亚胺6-[3'-(2-吡啶二硫基)丙酰胺基]己酸酯)、LC-SPDP(琥珀酰亚胺6-[3'-(2-吡啶二巯基)丙酰胺基]己酸酯)、SMPT(4-琥珀酰亚胺-氧羰基-α-甲基-α(2-吡啶二硫)甲苯);羰基-胺基结合剂:DCC(二环己基碳二亚胺)、EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐);光反应结合剂:ANB-NOS(N-5-叠氮基-2-硝基苯甲酰琥珀酰亚胺酯);NHS-重氮甲烷(SDA)结合剂:SDA(NHS-Diazirine)(琥珀酰亚胺基4,4’-叠氮戊酸酯)、LC-SDA(NHS-LC-Diazirine)(琥珀酰亚胺基6-[4,4’-叠氮戊酰胺]己酸酯)、SDAD(NHS-SS-Diazirine)(琥珀酰亚胺基2-([4,4’-叠氮戊酰胺]乙基)1,3’-二硫代丙酸酯)、Sulfo-SDA(Sulfo-NHS-Diazirine)(磺酸基琥珀酰亚胺基4,4’-叠氮戊酸酯)、Sulfo-LC-SDA(Sulfo-NHS-LC-Diazirine)(磺酸基琥珀酰亚胺基6-[4,4’-叠氮戊酰胺基]己酸酯)Sulfo-SDAD(Sulfo-NHS-SS-Diazirine)(磺酸基琥珀酰亚胺基3-([4,4’-叠氮戊酰胺基]乙基)1,3’-二硫代丙酸酯)、Sulfo-SANPAH(磺酸基琥珀酰亚胺基6-(4'-叠氮-2'-硝基苯胺)-己酸酯)、SPB(琥珀酰亚胺基[4-(补骨脂-8-基氧基)]-丁酸酯);巯基-糖类结合剂:BMPH(N-β-马来酰亚胺基丙酸酰肼三氟乙酸盐)、EMCH(N-ε-马来酰亚胺己酰肼三氟乙酸盐)、KMUH(N-kappa-马来酰亚胺基)十一烷酸酰肼三氟乙酸盐)、MPBH(4-(4-N-马来酰亚胺苯基)丁酸酰肼盐酸盐)、PDPH(3-(2-吡啶基二硫)丙酰基酰肼);巯基-羟基结合剂:PMPI(对马来酰亚胺基苯基异氰酸酯);巯基-巯基结合剂:BM(PEG)2(1,8-双马来酰亚胺基二乙二醇)、BM(PEG)3(1,11-双马来酰亚胺基三乙二醇)、BMB(1,4-双马来酰亚胺基丁烷)、BMDB(1,4-二马来酰亚胺基-2,3-二羟基丁烷)、BMH(双马来酰亚胺基己烷)、BMOE(双马来酰亚胺基乙烷)、DTME(二硫基-双马来酰亚胺基乙烷)、TMEA(三(2-马来酰亚胺基乙基)胺)和SVSB(琥珀酰亚胺(4-乙烯基砜)苯甲酸酯)。
双马来酰亚胺或双-2-吡啶二硫代试剂能以连续的或并发的方式把含有巯基的细胞结合分子(如抗体)和含有巯基的药物分子、标记物或是连接子中间体相连接。除马来酰亚胺和吡啶二巯基外,其他官能团如碘代乙酰胺、溴代乙酰胺、乙烯基吡啶、二硫化合物、吡啶二硫化合物、异氰酸酯和异硫氰酸酯也可以与含有巯基的细胞结合分子、药物分子、标记物或是连接子中间体反应。
在另外的实施例中,连接子可以由一种或多个连接子单元构成。典型的连接子单元有:
1.自我毁灭型连接子组分具有以下结构之一:
其中,*标记的是间隔体或可断裂的连接子、或细胞毒剂、和/或结合分子(CBA)的连接点;X1、Y1、Z2和Z3独立地为NH、O或S;Z1为H,NH,O或S;v为0或1;Q1独立地为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR1或SR1、NR1R2、N=NR1、N=R1、NR1R2、NO2、SOR1R2、SO2R1、SO3R1、OSO3R1、PR1R2、POR1R2、PO2R1R2、OPO(OR1)(OR2)或OCH2PO(OR1(OR2),其中R1和R2独立地选自H、C1-C8烷基、C2-C8烯基、炔基、杂烷基、C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基;或药学上的阳离子盐。
2.非自我毁灭的连接子组分示例:
其中,*标记的是间隔体或可断裂的连接子、或细胞毒剂、和/或结合分子(CBA)的连接点;X1、Y1、Q1、R1、R’、R”如前文所定义;r为1-20;m和n为1-6。
3.含有以下单元的连接子:6-马来酰亚胺己酰基(MC)、马来酰亚胺丙酰基(MP)、缬氨酸-瓜氨酸(val-cit或vc)、丙氨酸-苯丙氨酸(ala-phe或af)、对胺基苄氧基-羰基(PAB)、N-琥珀酰亚胺基4-(2-吡啶基硫代)戊酸酯(SPP)、N-琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、N-琥珀酰亚胺基(4-碘代乙酰基)氨基苯甲酸酯(SIAB)、含一个或多个乙基氧(-CH2CH2O-)重复单元的连接子(EO或PEO)。其他的连接子可见于各种文献以及本发明其他各处。
在另外的实施例中,连接子可包含氨基酸残基。示例性的氨基酸连接子组分包括二肽、三肽、四肽或五肽连接子。典型的二肽包括:缬氨酸-瓜氨酸(VC或val-cit)、丙氨酸-苯丙氨酸(af或ala-phe)。典型的三肽包括:甘氨酸-缬氨酸-瓜氨酸(gly-val-cit)和甘氨酸-甘氨酸-甘氨酸(gly-gly-gly)。构成氨基酸连接子单元的氨基酸残基,包括天然存在的以及次要氨基酸和非天然存在的氨基酸类似物,如瓜氨酸。氨基酸连接子组分可以被设计和优化,以利于被特定酶,如肿瘤相关蛋白酶,组织蛋白酶B、C和D,或纤溶酶蛋白酶,选择性酶促水解。
在本发明细胞结合分子-药物分子偶联物中,细胞结合剂(Q)通过一个双功能连接子(L),偶联一个或多个药物分子(药物,或PBD衍生物),比如约1~20个药物分子/细胞结合分子。结构式为(I)、(II)、(III)、和(IV)的偶联物可以应用常规的有机化学反应条件和试剂,通过数种路径来制备,包括:(1)细胞结合分子上的亲核基团和双官能团的连接子反应,形成共价结合的Q-L,之后与药物分子反应;(2)药物分子上的亲核基团和双官能团连接子反应,形成共价结合的Drug-L,之后与细胞结合分子的亲核基团反应。
为了合成通式(I)、(II)、(III)或/和(IV)的偶联物、通常使通式(V)、(VI)、(VII)和(VIII)上的官能团E3和/或E3’与细胞结合分子的一个,两个或多个残基反应,反应在0-60℃,pH 59.5水相介质中进行,可添加或不添加030%的可与水混合(混溶)的有机溶剂,例如DMA、DMF、乙醇、甲醇、丙酮、乙腈、THF、异丙醇、二噁烷、丙二醇或乙二醇,然后通过透析或色谱纯化,形成式(I)、(II)、(III)或/和(IV)中的偶联物。细胞结合分子的一些残基(用于偶联反应的基团)可以通过蛋白质工程产生。
细胞结合分子,如抗体上的巯基或氨基具有亲核性,能够与连接子和药物-连接子中间体上的亲电子基团反应成键,这些亲电基包括:(i)活性酯类,如NHS酯、HOBt酯、卤代甲酸酯、和酰卤;(ii)烷基和苄基卤化物,如卤代乙酰胺;(ⅲ)醛基、酮基、羧基和马来酰亚胺基;(iv)二硫化物,包括吡啶基二硫化物(硫交换反应)。药物分子上的亲核基团包括,但不限于:氨基、巯基、羟基、酰肼、肟、肼、缩氨基硫脲、肼羧酸酯和芳基酰肼基团,这些基团都能够与连接子单元和连接子上的亲电基团反应、形成共价键。
抗体或蛋白质上的亲核基团可以与连接子上的亲电基团反应,之后再与细胞毒性分子反应,或者直接与连接子-细胞毒剂分子反应形成细胞结合分子-细胞毒剂共价偶联物。抗体或蛋白质上的的亲核基团包括,但不限于:(i)N末端氨基;(ii)侧链胺基团,例如赖氨酸;(ⅲ)侧链巯基,例如半胱氨酸,和(iv)糖基化抗体中的糖羟基或氨基。氨基,巯基和羟基具有亲核型,能够与连接子单元和连接子-细胞毒性分子上的亲电基反应、形成共价键。这些亲电子基团包括:(i)活性酯类,如NHS酯、HOBt酯、卤代甲酸酯、和酰卤;(ii)烷基和苄基卤化物,如卤代乙酰胺;(ⅲ)醛基、酮基、羧基和马来酰亚胺基团。某些抗体含有可被还原的链间二硫键,如半胱氨酸桥。它们可以被还原剂如DTT(二硫苏糖醇)、三羰基乙基膦(TCEP)(Getz等,Anal.Biochem.,Vol 273,73-80;SoltecVentures,Beverly,Mass,1999)、二硫赤藓糖醇(DTE)L-谷胱甘肽(GSH)2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)还原而具备反应活性。因此,在理论上每个半胱氨酸桥将生成两个反应性巯基亲核基。或者,巯基可通过对赖氨酸残基的修饰被引入抗体中,例如赖氨酸残基与2-亚氨基硫烷(Traut试剂)反应,从而将氨基转换成巯基。反应活性的巯基可以通过一个、两个、三个、四个或更多个半胱氨酸残基而被引入到抗体(如通过制备包含一个或多个非天然半胱氨酸残基的抗体变体)。在细胞结合分子上游离的巯基可以与细胞毒性分子或者连接子-细胞毒性分子上的巯基反应性基团偶联,如马来酰亚胺、碘乙酰胺、吡啶二硫化物或其它基团。未结合在抗体上的一些游离巯基可再被氧化,形成链间和链内二硫键。
本发明的抗体-药物偶联物也可以通过抗体上的亲电基团,如醛或酮羰基,与连接子或药物上的亲核基团之间的反应产生。连接子上有效的亲核基团包括,但不限于,酰肼、肟、氨基、肼、缩氨基硫脲、肼羧酸酯和芳基酰肼。在一个实施例中,通过引入能够与连接子或药物上的亲核取代基反应的亲电子部分修饰抗体。在另一个实施例中,糖基化抗体的糖可以被氧化剂氧化,如高碘酸盐氧化剂,生成醛或酮,与连接子或药物结构中的氨基反应。所得亚胺Schiff碱基团或者是一个稳定的连接,或可能被还原剂,如硼氢化物试剂还原形成稳定的胺。在一个实施例中,糖基化抗体的糖与半乳糖氧化酶或偏高碘酸钠反应,生成羰基(醛和酮),它们可以与药物上的合适基团反应(Hermanson,Bioconjugate Techniques)。在另一个实施例中,含有N末端丝氨酸或苏氨酸残基的抗体与偏高碘酸钠反应,生成醛来代替第一氨基酸(Geoghegan,Stroh,Bioconjugate Chem.,1992,3,138-146;U.S.Pat.No.5,362,852)。这样的醛可与药物片段或连接子亲核体发生反应。
上述两步法偶联的图示如下:
其中E包括但不限于,羟基琥珀酰亚胺酯(NHS,磺基-NHS等)、4-硝基苯基酯、五氟苯基酯、四氟苯基(包括磺基四氟苯基)酯、酸酐、酰氯、磺酰氯、异氰酸酯和异硫氰酸酯。R'和R”独立地为H或CH3或C2H5;J为F、Cl、Br、I、甲苯磺酸酯(TsO)、甲磺酸酯(MsO)、硝基苯酚基、二硝基苯酚基或五氟苯酚基。
应当说明的是,若细胞结合分子(如抗体)上有不止一个亲核基团,当它与药物-连接子中间体或连接子反应之后,再接着与药物片段反应,所得产物为在抗体上分布有一个或多个药物单元的细胞结合分子-细胞毒剂偶联物的混合物。混合物中每个抗体上的平均药物数目可以通过双重ELISA抗体测定法来测定,该法对于抗体和药物来说具有特异性。混合物中个别偶联物分子可以通过质谱确认,并通过HPLC,如疏水层析色谱分离。在某些实施例中,带有单一载药量的偶联物可以通过电泳或色谱法从混合物中分离出来。
在偶联物中,ADC的载药量(小分子药物/抗体的比例)可以通过不同的方法控制。例如:(i)控制药物-连接子中间体或连接子相对于抗体的摩尔量,(ii)控制偶联反应的时间和温度,(iii)对半胱氨酸巯基部分还原或限制还原条件,(iv)通过工程抗体技术将氨基酸序列与抗体重组,在抗体上修饰赖氨酸或半胱氨酸残基的数量和位置,从而控制药物连接的位置和数量(例如巯基抗体(thioMab)或巯基抗体结合单元(thioFab))。
合成的偶联物可以通过标准的生化方法纯化,如用Sephadex G25或SephacrylS300进行凝胶过滤、吸附层析、离子交换或透析。在某些情形,如小分子细胞结合剂(如叶酸、黑素细胞刺激素、EGF等)与小分子药物偶联后,可以通过HPLC、中压柱层析或离子交换色谱等色谱法纯化。
修饰细胞结合剂的反应一般在pH 4至9,优选6.0至7.5的缓冲液里进行,可以包含该pH范围内的任何没有亲核性的缓冲盐。典型的缓冲液包括磷酸盐、乙酸盐、三乙醇胺盐酸、HEPES和MOPS缓冲液,可以包含其它成分,如环糊精,羟丙基-β-环糊精,聚乙二醇,蔗糖和盐,如氯化钠和氯化钾。将如式(V)、(VI)、(VII)或(VIII)中的药物-连接子溶液加入到被还原的细胞结合剂溶液中,并在4至55℃,优选15℃孵育,可以通过测量在某些UV波长(例如252nm)下的吸收的减少,或在某个UV波长(例如280nm)或其他合适的波长下的吸收的增加来监测反应的进程。反应完成后,可以常规方式分离修饰的细胞结合剂,例如使用凝胶过滤色谱法,离子交换色谱法,吸附色谱法或硅胶或氧化铝柱色谱法,结晶,制备薄层色谱,离子交换色谱或HPLC。
通过测量反应产生的硝基吡啶硫酮、二硝基吡啶二硫酮、吡啶硫酮、甲酰胺吡啶二硫酮和二甲酰胺吡啶二硫酮基团的紫外吸光,可以确定细胞结合剂被修饰的程度。如果偶联物没有发色团,可以用LC-MS或者更优选的HPLC-MS/MS,UPLC-QTOF质谱或毛细管电泳质谱(CE-MS)来分析确定。本发明中的支链连接子上可以含有不同种类的官能团,与各种细胞结合分子反应,尤其是具有合适的取代官能团的细胞结合剂。例如,修饰后含氨基或羟基取代基的细胞结合剂能与含N-羟基琥珀酰亚胺(NHS)酯的药物反应,修饰后含巯基的细胞结合剂能与含马来酰亚胺基或卤素乙酰基的药物反应。此外,通过蛋白工程,酶反应或者化学反应修饰后,含羰基(醛或酮基)的细胞结合剂能与含酰肼或烷氧基胺的药物反应。本领域技术人员可以很容易地根据修饰后细胞结合剂上官能团的反应活性来决定使用怎样的药物-连接子。
在图1-32中记载了更多用于制备ADC的示例性方法,并且在专利说明书中提供了示例。
细胞结合剂和横交联的PBD二聚体偶联物的应用
本发明的细胞结合剂-横交联的PBD二聚体偶联物,优选抗体-横交联的PBD二聚体偶联物物(PBD二聚体ADC)可用于治疗各种疾病或病症,例如过表达的肿瘤抗原的疾病。示例性的疾病或过度增殖性疾病包括良性或恶性肿瘤;白血病和淋巴样恶性肿瘤。其他包括神经元的,神经胶质的,星形细胞的,下丘脑的,腺体的,巨噬细胞的,上皮的,基质的,囊胚的,炎性的,血管生成的和免疫的,包括自身免疫性的疾病。
在具体的实施例中,本专利申请的偶联物、相应的组合物和方法可用于治疗癌症。目标癌症包括但不限于,肾上腺皮质癌、肛门癌、膀胱癌、大脑肿瘤(脑干神经胶质瘤、小脑星形细胞瘤、脑星形细胞瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层和松果体肿瘤、视觉通路和下丘脑胶质瘤)、乳腺癌、类癌肿瘤、胃肠道癌症、未知小细胞癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肝外胆管癌、尤因家族肿瘤(PNET)、颅内生殖细胞肿瘤、眼癌、眼内黑色素瘤、胆囊癌、胃癌(胃癌)、性腺外生殖细胞瘤、孕周滋养细胞瘤、头颈癌、下咽癌、胰岛细胞癌、肾癌(肾细胞癌)、喉癌、白血病(急性淋巴细胞,急性髓系,慢性淋巴细胞,慢性粒细胞,毛细胞)、嘴唇和口腔癌症、肝癌、肺癌(非小细胞,小细胞)、淋巴瘤(艾滋病相关,中枢神经系统的,皮肤T细胞的,霍奇金病,非霍奇金病)、恶性间皮瘤、黑色素瘤、梅克尔细胞癌、转移性鳞状颈癌与隐匿性原发性癌、多发性骨髓瘤和其他浆细胞肿瘤、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢癌(上皮、生殖细胞瘤、低恶性肿瘤)、胰腺癌(外分泌,胰岛细胞癌)、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体肿瘤、浆细胞肿瘤、前列腺癌横纹肌肉瘤、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管(移行细胞)、唾腺癌、赛塞里综合症、皮肤癌(皮肤T细胞淋巴瘤,卡波西氏肉瘤,黑色素瘤)、小肠肿瘤、软组织肉瘤、胃癌、睾丸癌、胸腺瘤(恶性)、甲状腺癌、尿道癌症、子宫癌、不寻常的少年的癌症、阴道肿瘤、外阴肿瘤和维尔姆斯瘤。
在另一个具体的实施例中,本专利申请的偶联物、相应的组合物和方法可以用于治疗或预防自身免疫疾病。自身免疫性疾病包括但不限于,Achlorhydra自身免疫性活动性慢性肝炎、急性播散性脑脊髓炎、急性出血性脑白质炎、艾迪生病、无精症、斑秃、肌萎缩侧索硬化症、强直性脊柱炎、抗GBM/TBM肾炎、抗磷脂综合征、抗异常酶综合征、关节炎、特应性过敏、特应性皮炎、自身免疫性再生障碍性贫血、自身免疫性心肌病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、自身免疫性淋巴组织增生综合征、自身免疫性周围神经病、自身免疫性胰腺炎、自身免疫性多内分泌综合征I、II和III型、自身免疫性黄体酮皮炎、自身免疫性血小板减少性紫癜、自身免疫性葡萄膜炎、Balo病/Balo同心硬化症、Bechets综合征、Berger氏病、Bickerstaff脑炎、Blau综合征、大疱性类天疱疮、Castleman病、Chagas病、慢性疲劳免疫功能障碍综合征、慢性炎性脱髓鞘性多发性神经病、慢性复发性多灶性骨髓炎、慢性莱姆病、慢性阻塞性肺病、Churg-Strauss综合征、瘢痕性类天疱疮、乳糜泄、Cogan综合征、冷凝集素病、补体成分2缺乏症、颅骨动脉炎、CREST综合征、Crohns病(特发性炎症性肠病)、库欣综合征、皮肤白细胞增多性血管炎、德戈氏病、Dercum氏病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤系统性硬化症、Dressler综合征、盘状红斑狼疮、湿疹、子宫内膜异位症、附着点炎相关的关节炎、Eosinophilic筋膜炎、大疱性表皮松解症、结节性红斑、特发性混合性冷球蛋白血症、伊文氏综合征、纤维发育不良性骨化症、纤维肌痛、纤维化性肌炎、纤维性肺泡炎、胃炎、胃肠类天疱疮、巨细胞动脉炎、肾小球肾炎、古德帕斯丘尔综合征、格雷夫斯病、格林-巴利综合征、桥本氏脑炎、桥本氏甲状腺炎、溶血性贫血、过敏性紫癜、妊娠性肝炎、化脓性汗腺炎、休斯综合征(抗磷脂综合征)、低丙球蛋白血症、特发性炎性脱髓鞘疾病、特发性肺纤维化、特发性血小板减少性紫癜(自身免疫性血小板减少性紫癜)、IgA肾病(伯杰氏病)、包涵体肌炎、炎性脱髓鞘性多神经炎、间质性膀胱炎、过敏性肠综合征、少年特发性关节炎、青少年类风湿性关节炎、川崎氏病、朗伯-伊顿重症肌无力综合征、白细胞碎屑性血管炎、扁平苔癣、硬化性硬化症、线状IgA疾病(LAD)、Lou Gehrig病(也称肌萎缩侧索硬化症)、狼疮性肝炎、红斑狼疮、Majeed综合征、美尼尔氏病、显微镜下多动脉炎、米勒-费希尔综合征、混合性结缔组织病、硬斑病、穆罕默德-哈贝曼病、麦考利综合征、多发性骨髓瘤、多发性硬化症、重症肌无力、肌炎、嗜睡症、视神经脊髓炎(Devic病)、神经性肌强直、眼睑瘢痕性类天疱疮、Opsoclonus myoclonus综合征、Ord甲状腺炎、回文风湿病、PANDAS(与链球菌相关的小儿自身免疫性神经精神病)、Paraneoplastic小脑变性、阵发性睡眠性血红蛋白尿症、Parry Romberg综合征、Parsonnage-Turner综合征、睫状体平部炎、天疱疮、寻常型天疱疮、贫血、周围脑脊髓炎、POEMS综合征、结节性多动脉炎、风湿性多肌痛、多发性肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎症性神经病变、牛皮癣、牛皮癣性关节炎、坏疽性皮肤炎、纯红细胞再生障碍、Rasmussen脑炎、雷诺现象、复发性多软骨炎、赖特综合征、不宁腿综合症、后神经纤维化、类风湿性关节炎、类风湿热、结节病、精神分裂症、施密特综合征、Schnitzler综合征、施尼茨勒综合征、巩膜炎、硬皮病、干燥综合征、脊椎关节病、粘稠血症、Still病、僵人综合征、亚急性细菌性心内膜炎、苏萨克综合征、Sweet综合征、小舞蹈病、交感神经性贫血、Takayasu动脉炎、颞动脉炎(巨细胞动脉炎)、Tolosa-Hunt综合征、横贯性脊髓炎、溃疡性结肠炎(特发性炎性肠病)、未分化结缔组织病、未分化脊柱关节病、血管炎、白癜风、韦格纳肉芽肿病、威尔逊氏综合征、威斯科特-奥尔德里奇综合征。
在另一个具体的实施例中,本专利申请中偶联物上的结合分子,可用于治疗或预防自身免疫疾病,包括但不限于,抗弹性蛋白抗体、Abys抗上皮细胞抗体、抗地下室膜IV型胶原蛋白抗体、抗核抗体、抗ds DNA、抗ss DNA、抗心磷脂抗体IgM、IgG、抗乳糜泻抗体、抗磷脂抗体IgK、IgG、抗SM抗体、抗线粒体抗体、甲状腺抗体、微粒体抗体、T细胞抗体、甲状腺球蛋白抗体、抗SCL-70、抗Jo、抗U.sub.1RNP、抗La/SSB、抗SSA、抗SSB、抗壁细胞抗体、抗组蛋白、抗RNP、C-ANCA、P-ANCA、抗着丝粒、抗纤维蛋白原、抗GBM抗体、抗神经节苷脂抗体、抗Desmogein 3抗体、抗p62抗体、抗sp100抗体、抗线粒体(M2)抗体、类风湿因子抗体、抗MCV抗体、抗拓扑异构酶抗体、抗中性粒细胞胞质(cANCA)抗体。
在某些优选的实施例中,本专利申请中偶联物上的结合分子,可以与自身免疫性疾病相关的激活淋巴细胞上表达的受体或受体复合物相结合。受体或受体复合物包含,免疫球蛋白基因超家族成员(例如CD2、CD3、CD4、CD8、CD19、CD20、CD22、CD28、CD30、CD33、CD37、CD38、CD56、CD70、CD79、CD79b、CD90、CD152/CTLA-4、PD-1或ICOS)、TNF受体超家族成员(例如CD27、CD40、CD95/Fas、CD134/OX40、CD137/4-1BB、INF-R1、TNFR-2、RANK、TACI、BCMA、骨保护素、Apo2/TRAIL-R1、TRAIL-R2、TRAIL-R3、TRAIL-R4和APO-3)、整合蛋白、细胞因子受体、趋化因子受体、主要组织相容性蛋白、凝集素(C型、S型或I型)或补体控制蛋白。
在另一个具体实施例中,可用的对病毒或微生物抗原具有免疫特异性的细胞结合配体是人源化或人单克隆抗体。“病毒抗原”包括但不限于,任何能够引发免疫应答的病毒肽,多肽蛋白(例如HIV gp120、HIV nef、RSV F糖蛋白、流感病毒神经氨酸苷酶、流感病毒血凝素、HTLV Tax、疱疹单纯疱疹病毒糖蛋白(例如gB、gC、gD和gE)和乙型肝炎表面抗原)。“微生物抗原”包括但不限于,任何能够引发免疫应答的微生物肽、多肽、蛋白质、糖、多糖或脂质分子(例如细菌、真菌、致病原生动物或酵母多肽、包括如LPS和荚膜多糖5/8)。可用于治疗病毒或微生物感染的抗体的实例,包括但不限于:帕利珠单抗,它是用于治疗RSV感染的,人源化抗呼吸道合胞病毒单克隆抗体;PRO542,是一种CD4融合抗体,用于治疗HIV感染;奥斯他韦,是一种用于治疗乙型肝炎病毒的人抗体;PROTVIR,是一种人源化IgG1抗体,用于治疗巨细胞病毒,和抗LPS抗体。
本专利申请的细胞结合分子-药物偶联物可用于治疗感染性疾病。这些感染性疾病包括但不限于,不动杆菌属感染、放线菌病、非洲昏睡病(非洲锥虫病)、艾滋病(获得性免疫缺陷综合症)、阿米巴病、无形体病、炭疽、溶血性耶尔森菌感染、阿根廷出血热、蛔虫病、曲霉病、星状病毒感染、巴贝斯虫病、蜡状芽孢杆菌感染、细菌性肺炎、细菌性阴道炎、类杆菌感染、小袋虫病、蛔虫感染、BK病毒感染、黑色发结节病、人芽囊原虫感染、芽生菌病、玻利维亚出血热、疏螺旋体感染、肉毒中毒(和婴儿肉毒中毒)、巴西出血热、布鲁氏杆菌病、伯克霍尔德氏菌感染、布鲁里溃疡、杯状病毒感染(诺如病毒和沙波病毒)、弯曲杆菌病、念珠菌病(念珠菌病、鹅口疮)、猫抓病、蜂窝组织炎、Chagas病(美洲锥虫病)、子囊、水痘、衣原体、肺炎衣原体感染、霍乱、色素母细胞瘤、华支睾吸虫、艰难梭状芽孢杆菌感染、球孢子菌病、科罗拉多蜱热病、普通感冒(急性病毒性鼻咽炎、急性鼻炎)、克雅氏病、克里米亚-刚果出血热、隐球菌病、隐孢子虫病、皮肤幼虫迁徙、环孢子虫病、肠杆菌感染、肠道病毒感染、流行性斑疹伤寒、传染性红斑(第五种疾病)、急疹、姜片虫病、肝片吸虫病、致命性家族性失眠、丝虫病、产气荚膜梭菌食物中毒、自由活体阿米巴感染、梭杆菌感染、气性坏疽(梭菌性肌坏死)、地丝菌病、格斯特曼-斯特拉斯勒-谢克尔病综合征、贾第鞭毛虫病、马鼻疽、淋病、肉芽肿性腹泻(第五性病)、A群链球菌感染、B群链球菌感染、流感嗜血杆菌感染、手足口病(HFMD)、汉坦病毒肺综合征、幽门螺杆菌感染、溶血性尿毒综合征、肾综合征出血热、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、戊型肝炎、单纯性疱疹、组织胞浆菌病、钩虫感染、人类博卡病毒感染、人类ewingii埃里希体病、人类粒细胞无形体病、人类偏肺病毒感染、人类单核细胞埃里希体病、人乳头瘤病毒感染、人副流感病毒感染、膜壳绦虫病、艾巴氏病毒传染性单核细胞增多症(单)、流行性感冒、等孢子虫病、川崎病、角膜炎、金格杆菌感染、库鲁病、拉沙热、军团病(退伍军人症)、军团病(庞蒂亚克热)、利什曼病、莱姆病、淋巴丝虫病(象皮病)、淋巴细胞性脉络丛脑膜炎、疟疾、马尔堡出血热、麻疹、类鼻疽病(惠氏病)、脑膜炎、脑膜炎球菌病、后殖吸虫病、微孢子虫病、传染性软疣、腮腺炎、小鼠斑疹伤寒(地方性斑疹伤寒)、支原体肺炎、足菌肿、蝇蛆病、新生儿结膜炎(新生儿眼病)、变异型克雅氏病(vCJD、nvCJD)、诺卡氏菌病、盘尾丝虫病(河盲症)、副球孢子菌病(南美芽生菌病)、肺吸虫病、巴斯德氏菌病、头虱、体虱、阴虱、盆腔炎、百日咳、鼠疫、肺炎球菌感染、肺孢子虫肺炎、肺炎、脊髓灰质炎、普氏菌感染、原发性阿米巴脑膜脑炎、进行性多灶性白质脑病、鹦鹉热、Q热、狂犬病、鼠咬热、呼吸道合胞病毒感染、鼻孢子虫病、鼻病毒感染、立克次体感染、立克次体痘、裂谷热、落基山斑疹热、轮状病毒感染、风疹、沙门氏菌病、SARS(严重急性呼吸综合征)、疥疮、血吸虫病、败血症、志贺氏菌病(Bacillary痢疾)、带状疱疹(带状疱疹)、天花(天花)、孢子丝菌、葡萄球菌食物中毒、感染金黄色葡萄球菌、粪类圆线虫病、梅毒、绦虫病、破伤风、须癣(Barber痒)、头皮癣、体癣、股癣、手癣、掌黑癣、足癣(香港脚)、甲癣(灰指甲)、花斑癣、弓蛔虫病(眼幼虫移行症)、弓蛔虫病(内脏幼虫移行症)、弓形体病、旋毛虫病、滴虫病、鞭虫病(鞭虫感染)、肺结核、兔热病、解脲脲原体感染、委内瑞拉马脑炎、委内瑞拉出血热、病毒性肺炎、西尼罗河热、白毛结节病(白癣)、假结核耶尔森氏菌、耶尔森氏鼠疫杆菌肠道病、黄热病、接合菌病。
本发明的细胞结合剂,更优选为抗体,对抗的病原菌株包括但不限于,鲍氏不动杆菌、以色列放线菌、放线菌和丙酸杆菌、布氏锥虫、HIV(人免疫缺陷病毒病毒)、溶组织内阿米巴、无形体属、炭疽芽孢杆菌、溶血弧菌、胡宁病毒、蛔虫属、曲霉属、星状病毒科、巴贝虫属、蜡状芽孢杆菌、多种细菌、拟杆菌属、大肠杆菌、蛔虫属、BK病毒、结节菌、人芽囊原虫、皮炎芽生菌、马丘波病毒、疏螺旋体属、肉毒梭菌、清风藤属、布鲁氏菌属、通常为洋葱伯克霍尔德菌和其他伯克霍尔德氏菌种、溃疡分枝杆菌、杯状病毒科、弯曲杆菌属、通常为白色假丝酵母和其他假丝酵母属、汉赛巴尔通体、A群链球菌和葡萄球菌、克氏锥虫、杜克雷嗜血杆菌、VZV、沙眼衣原体、科罗拉多蜱热病毒、鼻病毒、冠状病毒、CJD朊病毒、克里米亚-刚果出血热病毒、新型隐球菌、隐孢子虫属、巴西钩虫、多种寄生虫、环孢子虫、带状绦虫、巨细胞病毒、登革热病毒(DEN-1、DEN-2、DEN-3和DEN-4)-黄病毒、脆弱双歧杆菌、白喉棒状杆菌、裂头绦虫、麦地那龙线虫、埃博拉病毒、棘球绦虫属、埃立克体肠球菌属、肠道病毒属、普氏立克次体、细小病毒B19、人疱疹病毒6和人疱疹病毒7、布氏姜片虫、肝片吸虫和巨大片吸虫、FFI朊病毒、丝虫目超家族、产气荚膜梭菌、梭杆菌属、其他梭状芽孢杆菌、白地霉、GSS朊病毒、肠道贾第虫、伯克霍尔德氏菌、刺孢小芽孢杆菌和革兰氏假丝酵母、淋球菌、肉芽肿克雷伯氏菌、化脓性链球菌、无乳链球菌、流感嗜血杆菌、肠道病毒、主要是柯萨奇A病毒和肠道病毒71、无名病毒、幽门螺旋杆菌、大肠杆菌O157:H7、布尼亚病毒科、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒、单纯疱疹病毒1、单纯疱疹病毒2、荚膜组织胞浆菌、十二指肠腺瘤和壶腹癌流感嗜血杆菌、人博卡病毒、埃里希体、嗜吞噬细胞无嗜血杆菌、人偏肺病毒、查菲埃里希体、人乳头瘤病毒、人副流感病毒、微小膜壳绦虫和缩小膜壳绦虫、艾巴氏病毒、正粘病毒科家族、贝氏等孢球虫、金格杆菌、肺炎克雷伯菌、克雷伯氏菌、嗜肺军团菌、嗜肺军团菌、嗜肺军团菌、利什曼原虫属、麻风分枝杆菌和结核分枝杆菌、钩端螺旋体属、单核细胞增多性李斯特氏菌、伯氏疏螺旋体和其他疏螺旋体属物种、班氏旋毛虫和马来丝虫、淋巴细胞脉络丛脑膜炎病毒(LCMV)疟原虫属、马尔堡病毒、麻疹病毒、类鼻疽伯克霍尔德氏菌、脑膜炎奈瑟氏球菌、横川后殖吸虫、小孢子虫目门、传染性软疣病毒(MCV)、腮腺炎病毒、伤寒立克次氏体、肺炎支原体、多种细菌和真菌寄生双翅蝇幼虫、沙眼衣原体和淋病奈瑟菌、vCJD朊病毒、诺卡氏菌和其他诺卡氏菌属、盘尾丝虫属、盘鲍拟亚科、副龙属西马尼和其他副属、巴斯德氏菌属、头虱、人体虱、百日咳博德特氏菌鼠疫耶尔森氏菌、肺炎链球菌、肺炎球菌、脊髓灰质炎病毒、普雷沃氏菌属、奈氏格氏杆菌、JC病毒、鹦鹉热衣原体、伯氏考克斯体、狂犬病病毒、单链球菌和螺旋菌、呼吸道合胞病毒、鼻孢子菌、鼻病毒、立克次体属、由小株立克次体、裂谷热病毒、立克次体立克次体、轮状病毒、风疹、沙门氏菌属、SARS冠状病毒、人疥螨、血吸虫属、体细胞属、志贺菌属、水痘带状疱疹病毒、天花少校或天花小、申克孢子丝菌、金黄色葡萄球菌属、金黄色葡萄球菌、链球菌化脓、圆线虫、梅毒螺旋体、绦虫属、破伤风、癣属癣音铀、癣属、絮状表皮癣菌、红色毛癣菌、须毛癣菌、红色毛癣菌、威尼克外瓶黴、毛癣菌属属、细胞死亡属、弓箭毒或弓箭毒、刚地弓形虫、旋毛虫、阴道毛滴虫、三丘里三种、结核分枝杆菌、弗朗西拉图拉菌、尿素和马脑炎病毒、委内瑞拉马脑炎病毒、霍乱弧菌、瓜纳里托病毒、西尼罗河病毒、beigelii丝孢、假结核耶尔森氏菌、小肠结肠炎耶尔森氏菌、黄热病病毒、毛霉菌目阶(毛霉菌病)和虫霉目阶(虫霉属真菌病)、毛霉菌目绿脓杆菌、弯曲杆菌(弧菌)、气单胞菌、艾氏菌、耶尔森氏菌、志贺痢疾杆菌、志贺氏杆菌、志贺氏菌、沙门氏菌、伤寒沙门氏菌、雅司螺旋体、奋森氏螺旋体、伯氏疏螺旋体、细螺旋体、卡氏肺孢子虫、流产布鲁氏菌、布鲁杆菌、布鲁氏菌、支原体属、普氏立克次体、恙虫病立克次氏体、衣原体属、致病性真菌(烟曲霉、白色念珠菌、荚膜组织胞浆菌)、原生动物(溶组织内阿米巴、Tenas毛滴虫、Hominis毛滴虫、冈比亚锥虫、罗得西亚锥虫、罗氏利什曼原虫、热带利什曼原虫、巴西利什曼原虫、肺孢子虫肺炎、间日疟原虫、恶性疟原虫、疟原虫疟疾)或Helminiths(日本血吸虫、曼氏血吸虫、埃及血吸虫和钩虫)。
其他用作本专利申请的细胞结合剂,治疗病毒性疾病的抗体,包括但不限于,抗下列致病性病毒抗原的抗体:痘病毒、疱疹病毒、腺病毒、小黄病毒、肠病毒、小核糖核酸病毒、细小病毒、呼肠病毒、逆转录病毒、流感病毒、副流感病毒、腮腺炎、麻疹、呼吸道合胞病毒、风疹、虫媒病毒、弹状病毒、沙门氏菌、非a/非b型肝炎病毒、鼻病毒、冠状病毒、罗托病毒、致癌病毒、如HBV(肝细胞癌)、人乳头状瘤病毒(宫颈癌、肛门癌)、卡波济氏肉瘤相关的疱疹病毒(卡波济氏肉瘤肉瘤)、人类疱疹病毒第四型(鼻咽癌、伯基特淋巴瘤、原发性中枢神经系统淋巴瘤)、瘤病毒(默克尔细胞癌)、SV40(猿猴病毒40)、HCV(肝细胞癌)、HTLV-1(成人T细胞白血病/淋巴瘤);免疫紊乱导致病毒,如人类免疫缺陷病毒(艾滋病)、中枢神经系统病毒,如JCV(进行性多灶性脑白质病)、丙型肝炎病毒(亚急性硬化性全脑炎)、LCV(淋巴细胞性脉络丛脑膜炎)、亚博病毒脑炎、正粘病毒(脑炎性脑炎)、RV(狂犬病)、长鼻病毒、疱疹病毒脑膜炎、拉姆齐亨特综合征II型、脊髓灰质炎病毒(脊髓灰质炎病毒、后脊髓灰质炎综合征)、HTLV-1(热带麻痹性麻痹))、巨细胞病毒(巨细胞病毒视网膜炎、HSV(疱疹性角膜炎)、心血管病毒,如CBV(心包炎、心肌炎)、呼吸系统/急性病毒性鼻内炎/病毒性肺炎,如爱泼斯坦-巴尔病毒(EBV感染/传染性单核病)、巨细胞病毒、非典冠状病毒(严重急性呼吸综合征)或正黏液病毒、流感病毒a/b/c(流感/禽流感)、副粘病毒、人类副流感病毒、RSV(人类呼吸道合胞病毒)、hMPV、消化系统病毒(腮腺炎病毒、巨细胞病毒(巨细胞病毒食管炎)、腺病毒(腺病毒感染)、轮状病毒、诺瓦克病毒、星状病毒、冠状病毒、乙型肝炎病毒、CBV、甲型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒、HGV)、泌尿生殖病毒,如BK病毒、MuV(腮腺炎)。
偶联物的制剂及其应用
本专利申请的偶联物被配制成液体,或者适于冻干的形态,冻干后被重新制成液体制剂。液体配方包含0.1g/L300g/L浓度的本专利申请的偶联物作为活性成分,可以在没有高水平抗体聚集的情况下输送给患者,还包括一种或多种多元醇(例如糖),pH值为4.5至7.5的缓冲剂,表面活性剂(如聚山梨酸20或80)、抗氧化剂(例如抗坏血酸和/或蛋氨酸)、强化剂(如甘露醇、山梨醇或氯化钠)、螯合剂,例如EDTA、金属络合物(如锌-蛋白络合物)、可生物降解聚合物,例如聚酯、防腐剂(如苯甲醇)和/或游离氨基酸。
在一个优选的实施方案中,本发明申请的偶联物在体内临床应用中将以溶液或冻干固体(例如粉末)的形式提供,其可以重新溶解在注射用无菌水中。液体配方或配制的冻干粉末中的偶联物,为配方的主要成分,占0.01%-99%的重量。制剂的其余部分为辅料,其由以下一种或多种化合物组成:0.5%25%的缓冲剂,0%20%的多元醇,0%2.0%的表面活性剂,0%5%的防腐剂,0%30%的氨基酸或大体积化合物,0%5%的抗氧化剂,0%0.3%的螯合剂。
用于制剂的合适缓冲试剂包括但不限于,有机酸盐,例如柠檬酸、抗坏血酸、葡糖酸、碳酸、酒石酸、琥珀酸、乙酸或邻苯二甲酸的有机酸盐;三羟甲基氨基甲烷,盐酸三甲胺(三(羟甲基)-氨基甲烷)盐酸盐、或磷酸缓冲液。此外,氨基酸组分也可用作缓冲试剂。这些氨基酸包括但不限于,精氨酸、甘氨酸、甘氨酰甘氨酸和组氨酸。精氨酸缓冲试剂包括精氨酸乙酸盐、精氨酸氯化物、精氨酸磷酸盐、精氨酸硫酸盐,精氨酸琥珀酸盐等。在一个实施例中,精氨酸缓冲试剂是精氨酸乙酸盐。组氨酸缓冲试剂的实例包括组氨酸氯化物-精氨酸氯化物、组氨酸乙酸盐-精氨酸乙酸盐、组氨酸磷酸盐-精氨酸磷酸盐、组氨酸硫酸盐-精氨酸硫酸盐、组氨酸琥珀酸盐-精氨酸琥珀酸盐等。缓冲液的pH是4.5至pH7.5,优选约4.5至约6.5,更优选约5.0至约6.2。在一些实施例中,缓冲液中有机酸盐的浓度为约10mM至约500mM。
在制剂中可选地含有的“多元醇”是具有多个羟基的物质。多元醇可用作液体和冻干制剂中的稳定辅料和/或等渗剂。多元醇可以保护生物药物免受物理和化学降解。最好能被排除的共溶剂增加了蛋白质接口处溶剂的有效表面张力,能量最有利的结构构像是表面积最小的那些溶剂。多元醇包括糖(还原和非还原糖)、糖醇和糖酸。“还原糖”是指含有半缩醛基团的糖,它能够还原金属离子,或与蛋白质中的赖氨酸和其他氨基发生反应,“非还原糖”是指不具有还原糖性质的糖。还原糖的例子有果糖、甘露糖、麦芽糖、乳糖、阿拉伯糖、木糖、核糖、鼠李糖、半乳糖和葡萄糖。非还原糖包括蔗糖、海藻糖、山梨糖、松解糖和棉子糖。糖醇选自甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、苏糖醇、山梨醇和甘油。糖酸包括L-葡萄糖酸盐及其金属盐。在配方中优选浓度约为0.01%到15%的非还原糖,蔗糖或海藻糖,其中由于海藻糖的溶液稳定性,海藻糖更优。
在制剂中可选的表面活性剂可选自聚山梨醇酯(聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯65、聚山梨醇酯80、聚山梨醇酯81、聚山梨醇酯85等)、泊洛沙姆(如泊洛沙姆188、聚(环氧乙烷)-聚(环氧丙烷)、泊洛沙姆407或聚丙二醇-丙二醇等)、Triton、十二烷基硫酸钠(SDS)、月桂基硫酸钠、辛基糖苷钠、十二烷基、肉荳蔻酰基、亚油基或硬脂基磺基甜菜碱、十二烷基、肉荳蔻酰基、亚油基或硬脂基肌氨酸、亚油酸、肉荳蔻基或十六烷基甜菜碱、月桂酰氨基丙基、椰油酰胺丙基、亚油酰胺基丙基、肉荳蔻酰基丙基、棕榈酰基丙基或异硬脂酰氨基丙基-甜菜碱(例如月桂酰胺丙基)、肉荳蔻酰胺丙基、棕榈酰丙基或异硬脂酰氨基丙基-二甲胺、甲基椰油酰基钠或甲基油基牛磺酸二钠、十二烷基甜菜碱、十二烷基二甲基氧化胺、椰油酰胺丙基甜菜碱和可可两性甘氨酸酯、MONAQUATTM系列(如异硬脂基乙基亚胺鎓乙基硫酸盐)、聚乙二醇、聚丙二醇、乙二醇和丙二醇的共聚物(如Pluronic、PF68等)。优选的表面活性剂是聚乙二醇山梨糖醇脂肪酸酯,如聚山梨醇酯20、40、60或80(Tween20、40、60或80)。制剂中表面活性剂的浓度范围,按照重量计,为0.0001%至约1.0%。在某些特定实施例中,表面活性剂浓度为约0.01%至约0.1%。在一个实施例中,表面活性剂浓度为约0.02%。
在制剂中可选的“防腐剂”是可以有效地减小其中细菌的化合物。防腐剂的实例包括十八烷基二甲基芐基氯化铵、六甲基氯化铵、苯扎氯铵(烷基芐基二甲基氯化铵的混合物,其中烷基为长链烷基)和芐索氯铵。其他类型的防腐剂包括芳香醇如苯酚、丁基和芐基醇、对羟基苯甲酸烷基酯,如甲酯或丙酯、儿茶酚、间苯二酚、环己醇、3-戊醇和间甲酚。液体配方或冻干粉末中的防腐剂含量,按照重量计,为0.0%-1.0%。在一个实施例中,所用防腐剂是苯甲醇。
任选用于制剂中的合适的游离氨基酸,但不限于,精氨酸、赖氨酸、组氨酸、鸟氨酸、异亮氨酸、亮氨酸、丙氨酸、甘氨酸谷氨酸或天冬氨酸。优选包含碱性氨基酸、即精氨酸、赖氨酸和/或组氨酸。如果组合物包含组氨酸,则其既可以充当缓冲剂又可以充当游离氨基酸,但是当使用组氨酸缓冲剂时,通常包含非组氨酸游离氨基酸,例如包括组氨酸和赖氨酸。氨基酸可以D和/或L形式存在,但L形式是典型的。氨基酸可以以任何合适的盐,如盐酸盐的形式存在,例如精氨酸盐酸盐。氨基酸的浓度为0.0001%至约15.0%。优选0.01%至5%。
可选地,制剂还包含甲硫氨酸,谷胱甘肽、半胱氨酸、胱氨酸或抗坏血酸作为抗氧化剂,在液体配方中浓度为0.01mg/mL至5mg/mL;可选地,制剂包含金属螯合剂,例如EDTA,EGTA等,在液体配方中浓度为约0.01mM至2mM。
最终的制剂可以用缓冲调节剂(如一种酸,包括HCl、H2SO4、乙酸,H3PO4、柠檬酸等,或是碱,如NaOH、KOH、NH4OH、乙醇胺、二乙醇胺或三乙醇胺、磷酸钠、磷酸钾、柠檬酸三钠、氨基丁三醇等)调节至优选的pH值。制剂还应当被调节至“等渗”,即目标制剂具有与人血基本相同的渗透压。等渗制剂渗透压通常为250至350mOsm。可以使用蒸气压或冰冻型渗透压计测量等渗性。
在液体或冻干制剂中可能有用的其他辅料包括,例如,岩藻糖、纤维二糖、麦芽三糖、褪黑糖、辛酮糖、核糖、木糖醇、精氨酸、组氨酸、甘氨酸、丙氨酸、蛋氨酸、谷氨酸、赖氨酸、咪唑、甘氨酸、甘露糖基甘油酯、Triton X-100、Puloronic F-127、纤维素、环糊精、(2-羟丙基)-β-环糊精、右旋糖酐(10、40和/或70kD)、聚葡萄糖、麦芽糊精、无花果胶、明胶、羟丙基甲基、磷酸钠、磷酸钾、氯化锌、锌、氧化锌、柠檬酸钠、柠檬酸三钠、氨丁三胺、铜、纤维粘连蛋白、肝素、人血清白蛋白、鱼精蛋白、甘油、EDTA、间甲酚、苯甲醇、苯酚、多元醇、被还原的糖、其中一羰基被还原为一级或二级醇。
其它可以在本专利申请的液体制剂中使用的辅料还包括:例如调味剂、抗微生物剂、甜味剂、抗氧化剂、抗静电剂、脂质如磷脂或脂肪酸脂、类固醇如胆固醇、蛋白质辅料如血清白蛋白(人血清白蛋白)、重组人白蛋白、明胶、酪蛋白、成盐反离子如钠等。这些和另外的适用于本发明制剂的,已知的药物辅料和/或添加剂为本领域公知,如在由美国医药协会罗威(Rowe)等人编著的第四版《药用辅料手册》(The Handbook of PharmaceuticalExcipients)中所列;以及由威尔金斯出版公司出版(2005),热纳罗(Gennaro)等人编著的第21版《雷明顿:药学科学与实践》(Remington:the Science and Practice of Pharmacy)中所列。
为了减轻制剂注射期间的患者疼痛,局部镇痛剂可以与制剂注射一起使用或在注射之前使用。常用的镇痛药有:苯甲醇(0.01%-1%)、盐酸普鲁卡因(0.2%2.0%)、盐酸利多卡因(0.2%2.0%)、2-三氯甲基-2-丙醇(0.3%0.5%))、曲马多、吗啡、硫酸吗啡、氢吗啡酮、盐酸羟可待酮、多巴酚丁胺、加巴喷丁、环苯扎林、曲唑酮、可乐定、可待因。
可以将本专利申请的偶联物制剂制备为预填充的注射器溶液,冷冻干燥粉末或高效喷雾干燥粉末。使用药用容器或其他容器容纳偶联物的药物制剂。容器可以是小瓶,瓶子,预填充注射器或预填充自动注射器。
在更进一步的实施例中,本发明提供了制剂的制备方法,包括以下步骤:(a)将包含偶联物,辅料和缓冲体系的制剂冻干至粉末状;(b)在介质中复溶步骤(a)中的冻干混合物,以使得复溶的制剂稳定。步骤(a)中的液体可进一步包含稳定剂和一种或多种辅料,选自前述填充剂、盐、表面活性剂和防腐剂。稀释的有机酸或水,例如无菌水、注射用抑菌水(BWFI)、可以用作复溶介质。复溶介质可选用水,如无菌水、抑菌性注射用水(BWFI)、乙酸、丙酸、琥珀酸、氯化钠、氯化镁溶液、氯化钠的酸性溶液、氯化镁的酸性溶液或精氨酸的酸性溶液,其浓度为约10至约250mM。
本专利申请的偶联物的液体制剂应具有各种设定的特征。需要考虑的主要问题之一是其稳定性,因为蛋白质/抗体在制造和储存期间,常会形成可溶及不溶的聚集体。此外,溶液中会发生各种化学反应(脱酰胺、氧化、剪切、异构化等),导致降解产物水平增加和/或生物活性丧失。液体或冻干制剂中的偶联物最好应在25℃下,具有超过18个月的货架期。更优的液体或冻干制剂中的偶联物应在25℃下具有超过24个月的货架期。最为优选的液体制剂应该在2-8℃下具有约24至36个月的货架期,冻干粉末在2-8℃下,应该具有长达约60个月的货架期。液体制剂和冻干制剂应该具有在-20℃或-70℃下至少两年货架期。
在一些实施例中,该制剂在冷冻(例如-20℃或-70℃)和融化之后是稳定的,例如在1、2或3个冷冻和融化循环之后是稳定的。可以用不同的方式定性和/或定量地评估稳定性,包括评估药物/抗体(蛋白质)的比例和聚集体的形成(例如,使用UV、尺寸排阻色谱法、通过测量浊度和/或通过目测);通过使用阳离子交换色谱、图像毛细管等电聚焦(icIEF)或毛细管区带电泳评估电荷异质性;进行氨基末端或羧基末端序列分析、质谱分析或基质辅助激光解吸电离/飞行时间质谱(MALDI/TOF MS)或HPLC-MS/MS SDS-PAGE分析以比较还原抗体和完整抗体;进行肽图分析(例如胰蛋白酶或LYS-C);评估抗体的生物学活性或抗原结合功能。不稳定可能涉及以下一种或多种:聚集、脱酰胺作用(例如Asn脱酰胺作用)、氧化作用(例如Met氧化作用)、异构化作用(例如Asp异构化作用)、剪切/水解/断裂作用(例如铰链区断裂)、生成琥珀酰亚胺、未成对半胱氨酸、N末端延伸、C末端加工、糖基化差异等。
稳定的偶联物应当在药物制剂中“保持其生物学活性”,例如,如果偶联物的生物活性在给定时间内,例如12个月,按照抗原结合测定和/或体外细胞毒性测定的方法,生物活性可以保持在相差20%以内,优选10%(在测定误差内)。
对于临床体内使用,偶联物给药方式的实例如下:每天一次、每周一次、每两周一次、每三周一次、每次四周一次或每月一次、共854周,静脉推注。注射的剂量是在50至1000mL生理盐水中,可任选地向其中添加人血清白蛋白(例如0.5至1mL人血清白蛋白浓缩溶液,100mg/mL)。每周的剂量约为50μg至20mg/kg体重,静脉推注(每次注射10μg至200mg/kg的范围)。治疗后454周,患者可能会接受第二个疗程。关于给药方式,辅料,稀释剂,剂量,时间等的具体临床方案可以由熟练的临床医生确定。
更进一步,体外用途的实例包括用它处理细胞培养物,以杀死除了不表达靶抗原的变体以外的所有细胞;或者杀死表达不需要的抗原的变体。离体使用的例子包括在进行移植(HSCT)之前对造血干细胞(HSC)进行处理,以杀死患病或恶性肿瘤细胞。例如,在癌症治疗中的自体移植之前或在自身免疫性疾病的治疗中从骨髓中去除肿瘤细胞或淋巴细胞,或在移植之前为了防止移植物抗宿主疾病从同种异体骨髓或组织中除去T细胞和其他淋巴细胞。这样的临床离体治疗可以按如下步骤进行:从患者或其他个体收获骨髓,然后在含有血清的培养基中约37℃下孵育约30分钟至约48小时,在该培养基中加入本发明的偶联物,浓度范围从约1pM至0.1mM。具体的药物浓度和孵育时间应当由专业临床医师决定。孵育后,用含血清的培养基洗涤骨髓细胞,并按照已知的方法通过静脉注射给患者。若患者在骨髓采集和再输注治疗细胞之间,还接受其它治疗(例如消融化疗或全身辐射疗程)的情况下,应使用标准医疗设备将处理后的骨髓细胞在液氮中冷冻储存。
可以根据体内或体外的方法杀死选定的细胞群进行治疗的医学病症,包括任何类型的癌症的恶性肿瘤,自身免疫性疾病,移植排斥和感染(病毒,细菌或寄生虫)。
可以根据体内或体外的方法杀死选定的细胞群进行治疗的医学病症的例子,包括任何类型的恶性肿瘤,包括例如肺癌、乳腺癌、结肠癌、前列腺癌、肾癌、胰腺癌、卵巢癌和淋巴器官黑色素瘤自身免疫性疾病、例如系统性狼疮、类风湿性关节炎和多发性硬化症;移植排斥反应,例如肾移植排斥反应、肝移植排斥反应、肺移植排斥反应、心脏移植排斥反应和骨髓移植排斥反应、移植物抗宿主病;病毒感染,例如巨细胞病毒感染,艾滋病毒感染,艾滋病等;细菌感染,如本领域技术人员所确定的,其还包括寄生虫感染,例如贾第鞭毛虫病,阿米巴病,血吸虫病和其他感染。
对患本文所述的疾病和状况的那些受试者的鉴定,完全在本领域技术人员的能力和知识之内。通过使用临床测试,身体检查,医学/家族病史或生物学和诊断测试,本领域的兽医或医师可以容易地识别那些需要这种治疗的受试者。
如本领域的主治医生可以通过使用常规技术,并通过观察在类似情况下获得的结果来容易地确定治疗有效量。在确定治疗有效量时,主治医生会考虑许多因素,包括但不限于:受试者的种类、治疗的有效剂量、它的体重、年龄和总体健康状况;所涉及的特定疾病、疾病的程度或严重程度、个别受试者的反应、施用的特定化合物、管理方式、所施用制剂的生物利用度特征、选择的剂量方案、伴随药物的使用、和其他相关情况。
获得满意的生物学效应所需的偶联物的量将取决于许多因素,包括偶联物的化学特性,效力和生物利用度,疾病类型,患者的种族,患者的疾病状态,给药途径,这些决定了所需剂量,给药方式和给药方案。
一般而言,可以通过包含本发明的药物为含0.1至30%w/v偶联物的生理缓冲水溶液,用于肠胃外施用。典型剂量范围为1μg/kg至0.1g/kg体重,每天、每周、每两周、每三周或每月一次,优选的剂量范围是人体等效剂量0.01mg/kg至20mg/kg体重,每周,每两周,每三周或每月一次。待给药物的优选剂量可能取决于下列变量,如疾病的类型或病症的进展,患者的总体健康状况,所选化合物的相对生物学功效,药物的制剂,给药方式(静脉内,肌肉内或其他),药物在确定的给药途径的药代动力学特性,给药速度(推注或连续输注)和给药方案(在给定时间内重复次数)。
本发明的偶联物也能够以单位剂量的形式给药,其中术语“单位剂量”是指能够施用于患者并且易于处理和包装的单一剂量,它是保持物理和化学稳定的单位量,包含具有活性的偶联物或者其药学上可接受的组合物。因此,典型的每日总剂量范围是0.01至100mg/kg体重。作为一般原则,人类的单位剂量范围为1至3000mg每天或每周、每两周、每三周一次。优选地,单位剂量范围是1至500mg,每周、每两周或每三周一次至两次,甚至更优选地,10mg至500mg每两周或每三周一次。本发明的偶联物可以与一种或多种药学上可接受的辅料混合,制成药物组合物。这样的单位剂量组合物可以通过静脉注射或口服使用,特别是以粉末、片剂,简单胶囊或软胶囊的形式的药物;或鼻内给药,特别如散剂、滴鼻剂或气雾剂形式的药物;或在皮肤上使用,例如局部使用药膏、乳霜、乳液、凝胶、喷雾剂、或通过透皮贴剂。组合物可以以任何已知的制药方法制得,可以方便地以单位剂量的形式给药,如《Remington:The Science and Practice of Pharmacy,21th ed.》和《LippincottWilliams&Wilkins:Philadelphia》(PA,2005年)中所述。包含本发明的化合物的药物剂型,包括药物组合物首选口服或非肠道给药方式。对于口服给药剂型,如片剂、粉剂、胶囊剂、片剂(锭剂)等可以包含一种或多种以下组分或有类似性质的其它化合物:粘合剂、比如微晶纤维素或黄耆胶;稀释剂,比如淀粉或乳糖;分散剂,比如淀粉和纤维素衍生物;润滑剂,比如硬脂酸镁;助流剂,比如二氧化硅胶体;甜味剂,比如蔗糖或糖精;增味剂,比如薄荷或水杨酸甲酯。胶囊可以是硬胶囊或软胶囊的形式,一般由明胶混合物,或与塑化剂混合制得,淀粉胶囊也是如此。另外,单位剂形可以包含各种其他原料,改变其物理形式,例如包覆糖衣,虫胶或肠溶剂。其它的口服剂型如糖浆或酏剂可以含有甜味剂,防腐剂,颜料,着色剂和调味剂。另外,活性化合物可以通过不同的处理和配方,使其成为可快速溶解的剂型,控释剂型或缓释剂,其中的缓释剂是较好的剂型。片剂首选包含乳糖、玉米淀粉、硅酸镁、横交联羧甲基纤维素钠、聚乙烯吡咯酮、硬脂酸镁、滑石等组合的剂型中。非肠道给药的液体药剂包括无菌的水溶液或非水溶液、悬浮液和乳剂。液体药剂也可以含有粘合剂、缓冲液、防腐剂、螯合剂、甜味剂、调味剂和着色剂等等。非水溶剂包括醇、丙二醇、聚乙二醇、植物油比如橄榄油和有机脂类,比如油酸乙酯。水性溶剂包括了水、醇、缓冲试剂和盐的混合物,特别是,生物相容性的、可降解的丙交酯聚合物、丙交酯/乙交酯聚合物或者聚乙二醇/聚丙三醇共聚物可作为控制活性药物释放的辅料。静脉注射中的赋形剂可以包括液体和营养补充物、电解质补充物、以及基于林格氏葡萄糖的辅料,以及类似的辅料。本发明的活性药物其它可行的非肠道给药系统,包括乙烯-醋酸乙烯酯共聚物微粒,植入式渗透泵和脂质体。
其它可行的给药方式包括吸入剂,包括干粉剂、气雾剂和水滴剂。吸入剂可以是含有如聚乙二醇-9-月桂醚、甘胆酸盐、脱氧胆酸盐或油质的溶液,可以通过滴鼻剂,鼻内胶体的形式给药。口含药剂包括如锭剂、糖果锭剂等,可含有调味剂如蔗糖、阿拉伯胶以及其它辅料如甘胆酸盐等。栓剂适合于单位剂量的形式,以固体如可可油为载体,也可以加入水杨酸。皮肤局部用药剂型、以膏药、乳剂、洗液、贴片、凝胶、喷雾剂、气雾剂或油剂为首选。凡士林、羊毛脂、聚乙二醇、醇类以及它们的混合物可以作为药物载剂。皮肤给药的剂型可以是贴片、乳剂、缓冲溶液、溶解或分散在聚合物或粘合剂中。
特别地,本发明申请的细胞结合剂-细胞毒剂偶联物可以与其它的已知或即将已知的治疗药物,如化疗药物、放射疗法、免疫疗法药物、自身免疫疾病药物、抗感染药物或其它抗体药物偶联物共同作用,达到协同效果。在另一个具体实施例中,协同药物或放射治疗可以在本发明的共轭药物给药之前或之后给药或施行。可以是在本发明的偶联药物给药之前或之后1小时、12小时、一天、一星期、二星期、三星期、一个月、也可以是几个月进行。
协同剂优选选自以下一种或几种药物:
1)化疗药物:a)烷基化剂,[如氮芥:(氯胺苄、环磷酰胺、异环磷酰胺、甲氯苯甲胺、苯丙氨酸氮芥、氨甲酰胺);亚硝基脲(卡莫司汀、洛莫司汀);烷基磺酸盐:(白消安、苏消安);三氮烯(达喀尔巴嗪);含铂化合物(卡铂、顺铂、奥沙利铂);b)植物生物碱:如长春花生物碱(长春新碱、长春碱、长春地辛、长春瑞滨);紫杉醇类(紫杉醇、多西紫杉醇)];c)DNA拓扑异构酶抑制剂,例如[依托泊苷替尼(9-氨基喜树碱、喜树碱、克立那托、依托泊苷、磷酸依托泊苷、伊立替康、替尼泊苷、拓扑替康));丝裂霉素(丝裂霉素C)];d)抗代谢物,例如{[抗叶酸剂:DHFR抑制剂(甲氨蝶呤、三甲蝶呤);IMP脱氢酶抑制剂(麦考酚酸、噻唑呋林、利巴韦林、EICAR);核糖核苷酸还原酶抑制剂(羟基脲、去铁胺);[嘧啶类似物,尿嘧啶类似物:(5-氟尿嘧啶、氟尿苷、ratitrexed(Tomudex);胞嘧啶类似物(阿糖胞苷、胞嘧啶阿拉伯糖苷、氟达拉滨);嘌呤类似物:(硫唑嘌呤、巯嘌呤、硫鸟嘌呤);e)激素疗法剂,例如{受体拮抗剂:[抗雌激素(甲地孕酮、雷洛昔芬、他莫昔芬);LHRH兴奋剂(戈斯他林、醋酸亮丙瑞林);抗雄激素药(比卡鲁胺、氟他胺)];类维生素A/类维生素A:[维生素D3类似物(CB1093、EB1089、KH1060、胆钙化醇、麦角钙化甾醇);光动力疗法剂(维替泊芬、酞菁、光敏剂Pc4、去甲氧基-竹红菌素A);细胞因子(干扰素-α、干扰素-γ、肿瘤坏死因子(TNF)、含TNF的人蛋白)]}};f)激酶抑制剂、例如BIBW 2992(抗-EGFR/Erb2)、伊马替尼、吉非替尼、呱加他尼、索拉非尼、达沙替尼、舒尼替尼、厄洛替尼、尼洛替尼、拉帕替尼、阿西替尼、帕唑帕尼、凡德他尼、E7080(抗VEGFR2)、mubritinib、普纳替尼(AP24534)、bafetinib(INNO-406)、bosutinib(SKI-606)、卡博替尼、维莫德吉、iniparib、鲁索利替尼、CYT387、阿西替尼、tivozanib、索拉非尼、贝伐单抗、西妥昔单抗、曲妥珠单抗、雷珠单抗、帕尼单抗、伊斯平斯;
g)吉西他滨、环氧酶素(如卡菲偌米布)、硼替佐米、沙利度胺、来那度胺、pomalidomide、tosedostat、zybrestat、PLX4032、STA-9090、Stimuvax、allovectin-7、Xegeva、Provenge、Yervoy、异戊二烯化抑制剂、多巴胺能神经毒素(如星形孢菌素)、放线菌素(如放线菌素D、更生霉素)、博莱霉素(如博来霉素A2、博莱霉素B2、培洛霉素)、蒽环类抗生素(如柔红霉素)、鹅膏毒素、阿霉素(亚德里亚霉素)、伊达比星、表柔比星、吡柔比星、佐柔比星、米托蒽醌、MDR抑制剂(如维拉帕米)、Ca2+ATP酶抑制剂(如毒胡萝卜素)、组蛋白去乙酰酶抑制剂(伏立诺他、罗米地辛、帕比司他、丙戊酸、Mocetinostat(MGCD0103)、Belinostat、PCI-24781、恩替诺特、SB939、Resminostat、Givinostat、AR-42、CUDC-101、萝卜硫素、曲古抑菌素A)、塞来昔布、格列酮类、表没食子儿茶素没食子酸酯,双硫仑、Salinosporamide A;可以与本发明申请的化合物和偶联物一起用作联合疗法(协同作用)的已知和即将已知的抗癌药物的更多详细列表,可以在下列网站上查看:美国国家癌症研究所网站(www.cancer.com),美国国家癌症研究所网站(www.cancer.gov;www.cancer.gov/cancertopics/druginfo/alphalist),美国癌症协会(www.cancer.org/treatment/index)和英国癌症研究中心(www.cancerrearchuk.org;(www.cancerresearchuk.org/cancer-help/about-cancer/treatment/cancer-drugs/)。
2)自身免疫疾病药物,包括但不限于,环孢菌素、环孢菌素A、氨基己酸、硫唑嘌呤、溴隐亭、苯丁酸氮芥、氯喹、环磷酰胺、皮质类固醇(例如安西奈德、倍他米松、布地奈德、氢化可的松、氟尼缩松、丙酸氟替卡松、氟可龙达那唑、地塞米松、曲安奈德、二丙酸倍氯米松)、DHEA、依那西普、羟基氯喹、英夫利昔单抗、美洛昔康、甲氨蝶呤、麦考酚酸酯、泼尼松、西罗莫司、他克莫司。
3)抗传染病剂包括,但不限于:a).氨基糖苷类:丁胺卡那霉素、武夷霉素 庆大霉素(奈替米星、西索米星、异帕米星)、潮霉素、卡那霉素(丁胺卡那霉素、阿贝卡星、氨基去氧卡那霉素、地贝卡星、妥布霉素)、新霉素(新霉素B、巴龙霉素、核糖霉素)、奈替米星、大观霉素、链霉素、妥布霉素、甲基姿苏霉素;b).酰胺醇类:叠氮氯霉素、氯霉素、氟甲砜霉素、甲砜霉素;c).安沙霉素类:格尔德霉素、除莠霉素;d).碳青霉烯类:比阿培南、多尼培南、厄他培南、亚胺培南/西司他丁、美罗培南、帕尼培南;e).头孢类:碳头孢烯(氯碳头孢)、头孢乙腈、头孢克洛、头孢拉定、头孢羟氨苄、头孢罗宁、头孢噻啶、头孢噻吩或头孢菌素、头孢氨苄、头孢来星、头孢孟多、头孢匹林、头孢三嗪、头孢氮氟、头孢西酮、头孢唑啉、头孢拉宗、头孢卡品、头孢达肟、头孢吡肟、头孢米诺、头孢西丁、头孢丙烯、头孢沙定、头孢替唑、头孢呋辛、头孢克肟、头孢地尼头孢妥仑、头孢吡肟、头孢他美、头孢甲肟、头孢地嗪、头孢尼西、头孢哌酮、头孢雷特、头孢噻肟、头孢替安、头孢唑兰、头孢氨苄、头孢咪唑、头孢匹胺、头孢匹罗、头孢泊肟、头孢丙烯、头孢喹肟、头孢磺啶、头孢他啶、头孢特仑、头孢布烯、头孢噻林、头孢唑肟、头孢、头孢曲松、头孢呋辛、头孢唑喃、头霉素(头孢西丁、头孢替坦、头孢美唑)氧头孢烯(氟氧头孢、拉氧头孢);f).糖肽:博来霉素、万古霉素(奥利万星、特拉万星)、替考拉宁(达巴万星)雷莫拉宁;g).甘氨酰:如替加环素;h).β-内酰胺酶抑制剂:青霉烷(舒巴坦、他唑巴坦)、克拉维烷(克拉维酸);i).林可酰胺类:克林霉素、林可霉素;j).脂肽:达托霉素、A54145、钙依赖性抗生素(CDA);k).大环内酯类:阿奇霉素、喹红霉素、克拉霉素、地红霉素、红霉素、氟红霉素、交沙霉素、酮内酯类(泰利霉素、喹红霉素)麦迪霉素、美奥卡霉素、竹桃霉素、利福霉素(利福平、利福平、利福布汀、利福喷丁)、罗他霉素、罗红霉素、壮观霉素、螺旋霉素、他克莫司(FK506)、醋竹桃霉素、泰利霉素;l).单环β-内酰胺抗生素:氨曲南、替吉莫南;m).唑烷酮类:利奈唑胺;n).青霉素类:阿莫西林、氨苄西林(匹氨西林、海他西林、巴氨西林、美坦西林、酞氨西林)叠氮西林、阿洛西林、青霉素、苄星青霉素、苯氧基苄星青霉素、氯甲西林、普鲁卡因青霉素、羧苄青霉素(卡茚西林)、邻氯青霉素、双氯青霉素、先锋霉素、氟氯西林、美西林(氮卓脒青霉素双酯)、美洛西林、甲氧西林、萘夫西林、苯唑西林、醋甲西林、青霉素、奈西林、青霉素、哌拉西林、苯丙西林、磺苄西林、替莫西林、替卡西林;o).多肽:杆菌肽、多粘菌素E、多粘菌素B;p).喹诺酮类药物:阿拉沙星、巴洛沙星、环丙沙星、克林沙星、达氟沙星、二氟沙星、依诺沙星、恩诺沙星、Floxin、加雷沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星卡诺、左氧氟沙星、洛美沙星、麻保沙星、莫西沙星、那氟沙星、诺氟沙星、奥比沙星、氧氟沙星、培氟沙星、曲伐沙星、格帕沙星、西他沙星、司帕沙星、替马沙星、妥舒沙星、曲伐沙星;q).菌素:普那霉素、奎奴普丁/达福普汀);r).磺胺类药物:磺胺米隆、百浪多息、磺胺醋酰、磺胺甲、磺胺、柳氮磺胺吡啶、磺胺异恶唑、甲氧苄氨嘧啶、甲氧苄啶-磺胺甲基异恶唑(复方新诺明);s).类固醇抗菌药物:如夫西地酸;t).四环素类:强力霉素、金霉素、氯羟四环素、地美环素、赖甲环素、氯甲烯土霉素、美他环素、米诺环素、土霉素、青哌四环素、罗利环素、四环素、甘氨酰(如替加环素);u).其他类型的抗生素:番荔枝科、胂凡纳明、细菌萜醇抑制剂(杆菌肽)、DADAL/AR抑制剂(环丝氨酸)、dictyostatin、海绵内酯、艾榴塞洛素、埃博霉素、乙胺丁醇、依托泊苷、法罗培南、夫西地酸、痢特灵、异烟肼、laulimalide、甲硝唑、莫匹罗星、mycolactones、NAM合成抑制剂(如磷霉素)、呋喃妥因、紫杉醇、平板霉素、吡嗪酰胺、奎奴普丁/达福普汀、利福平(利福平)、他唑巴坦替硝唑、番荔枝内酯;
4)抗病毒的药物:a)./融合抑制剂:aplaviroc、马拉韦罗、维立韦罗、gp41的(恩夫韦)、PRO140、CD4(Ibalizumab);b).整合酶抑制剂:拉替拉韦、埃替拉韦、globoidnan A;c).成熟抑制剂:贝韦立马、vivecon;d).神经氨酸酶抑制剂:奥司他韦、扎那米韦、帕拉米韦;e).核苷和核苷酸:阿巴卡韦、阿昔洛韦、阿德福韦、氨多索韦、apricitabine、溴夫定、西多福韦克拉夫定、右艾夫他滨、去羟肌苷(DDI)、艾夫他滨、恩曲他滨(FTC)、恩替卡韦、泛昔洛韦、氟脲嘧啶(5-FU)、3'-氟取代的2',3'-二脱氧核苷类似物(例如,3'-氟-2',3'-二脱氧胸苷(FLT)和3'-氟-2',3'-双脱氧(FLG)福米韦生、更昔洛韦、碘苷、拉米夫定(3TC)、L-核苷(如β-L-胸苷、β-L-2'-脱氧胞苷)、喷昔洛韦、Racivir、利巴韦林、stampidine、司他夫定(d4T的)、他利韦林(伟拉咪定)、替比夫定、替诺福韦、伐昔洛韦三氟胸苷、缬更昔洛韦、扎西他滨(DDC)、齐多夫定(AZT);f).非核苷类:金刚烷胺、ateviridine、卡普韦林、二芳基嘧啶(依曲韦林、利匹韦林)、地拉韦啶、二十二烷醇、乙米韦林、依法韦仑、膦甲酸(磷酰基甲酸)、咪喹莫特、干扰素α、洛韦胺、洛德腺苷、他巴唑、奈韦拉平、NOV-205、聚乙二醇干扰素α、鬼臼毒素、利福平、金刚乙胺、瑞喹莫德(R-848)、醋胺金刚烷;g).蛋白酶抑制剂:安普那韦、阿扎那韦、博赛泼维、达芦那韦、福沙那韦、茚地那韦、洛匹那韦、奈非那韦、pleconaril、利托那韦、沙奎那韦、特拉匹韦(VX-950)替拉那韦;h).其他类型的抗病毒的药物:抗体酶、阿比朵尔、calanolides A、浅蓝菌素、蓝藻-N、二芳基嘧啶、表没食子儿茶素没食子酸酯(EGCG)、膦甲酸钠、格瑞弗森、他利韦林(伟拉咪定)、羟基脲、KP-1461、米替福新、普来可那立、合成抑制剂、利巴韦林、seliciclib;
5)其他免疫治疗药物:如咪喹莫特、干扰素(如α、β)、粒细胞集落刺激因子、细胞因子、白细胞介素(IL1~IL35)、抗体(如曲妥珠单抗、帕妥珠单抗、贝伐单抗、西妥昔单抗、帕尼单抗、英夫利昔单抗、阿达木单抗、巴利昔单抗、赛尼哌、奥马珠抗体)、与蛋白结合的药物(例如蛋白结合的紫杉醇)、结合下列药物的抗体偶联物:卡奇霉素衍生物、美登素衍生物(DM1和DM4)、CC-1065和倍癌霉素等小沟结合剂、强效的紫杉醇衍生物、阿霉素、奥瑞斯塔汀和抗有丝分裂的药物,例如曲妥单抗-DM1、Inotuzumab ozogamicin、Brentuximabvedotin、Glembatumumab vedotin、Lorvotuzumab mertansin、AN-152LMB2、TP-38、VB4-845、莫坎妥珠单抗-mertansine、AVE9633、SAR3419、CAT-8015(抗CD22)、30IMGN388、milatuzumab-阿霉素、SGN-75(CD70受体)、抗CD22-MCC-DM1、IMGN853、抗CD22-MMAE、抗CD22-MMAF、抗CD22卡奇霉素。
在更多的实施方案中,协同剂优选自以下药物中的一种或几种:阿巴西普、阿贝西比利、醋酸阿比特龙、阿布拉xane、对乙酰氨基酚/氢可酮、Acalabrutinib、aducanumab、Adalimumab、ADXS31-142、ADXS-HER2、阿法替尼双马来酸酯、aldesleukin alectinib、alemtuzumab、Alitretinoin、ado-trastuzumab emtansine、安非他命/右旋苯丙胺、阿那曲唑、阿立哌唑、蒽环类药物、阿立哌唑、阿扎那韦、阿妥唑单抗、阿托伐他汀、阿韦拉单抗、阿昔布西汀、brentuximab vedotin、brigatinib、Budesonide、Budesonide/福莫特罗、Bupre-norphine、Cabazitaxel、Cabozantinib、capmatinib、Capecitabine、carfilzomib、嵌合抗原受体工程T(CAR-T)细胞、Celecoxib、ceritinib、Cetuxib、Cetuximab、克唑替尼、克比美替尼、科森蒂斯、克唑替尼、CTL019、达比加群、达布拉非尼、达卡巴嗪、达克珠单抗、达科替尼、达托霉素、达拉他珠单抗、达比波锡阿尔法、达鲁那韦、达沙替尼、地尼洛芬、地诺单抗、Depakote、地兰索拉唑、地塞哌甲酯、地塞米松、DigniCap冷却系统、Dinutuximab、强力霉素、Duloxetine、Duvelisib、durvalumab、依洛珠单抗/埃洛珠单抗/艾美洛韦、依诺肝素、恩沙替尼、恩扎鲁胺、依泊汀阿尔法、厄洛替尼、埃索美拉唑、依佐匹克隆、依那西普、依维莫司、依西美坦、依维莫司、艾塞那肽ER、依泽替米贝、依泽替米贝/辛伐他汀、非诺贝特、非格拉斯汀、芬戈利莫德、丙酸氟替卡松、氟替卡松/沙美特罗、fulvestrant、gazyva、吉非替尼、Glatiramer、醋酸高斯瑞林、伊克替尼、伊马替尼、伊布替尼、伊布替尼、依德利西布、异环磷酰胺、英夫利昔单抗、咪喹莫特、ImmuCyst、Immuno BCG、伊尼帕里、阿斯巴肽胰岛素、地塞米尔胰岛素、甘精胰岛素、利斯普洛胰岛素、α-干扰素、α-1b干扰素、α-2a干扰素、α-2b干扰素、β-干扰素、β-1a干扰素、β-1b干扰素、γ-1a干扰素、拉帕蒂尼、伊普利单抗、异丙托品溴铵/沙丁胺醇、异唑MIB、卡努马、醋酸兰诺肽、利奈多明、利奈酰胺、甲磺酸利奈替尼、来曲唑、左旋甲状腺素、左旋甲状腺素、利多卡因、利奈唑胺、利拉鲁肽、利地塞米松、LN-144氯雷替尼、美金刚、甲基哌啶酮、美托洛尔、Mekinist、美西他滨/利吡韦林/替诺福韦、莫达非尼、莫米松、Mycidac-C、尼西妥单抗、neratinib、尼洛替尼、尼拉帕利布、尼古拉单抗、ofatumumab、奥比妥珠单抗、奥拉帕尼、奥美沙坦、奥美沙坦/氢氯噻嗪、奥马珠单抗、Omega-3脂肪酸乙酯、Oncorine、Oseltamivir、Osimertinib、羟考酮、palbociclib、帕利珠单抗、帕尼单抗、panobinostat、帕唑帕尼、pembrolizumab、PD-1抗体、PD-L1抗体、培美曲塞、帕妥珠单抗、肺炎球菌结合疫苗、泊马利度胺、普瑞巴林、ProscaVax、普萘洛尔、喹硫平、雷贝拉唑、普鲁巴新223氯化镭、雷洛昔芬、雷洛昔韦、雷莫昔单抗、雷珠单抗、雷戈非尼、利妥昔单抗、利伐沙班、罗米地辛、瑞舒伐他汀、鲁索替尼磷酸盐、沙丁胺醇、savolitinib、semaglutide、Sevelamer、西地那非、siltuximab、Sipuleucel-T、西他列汀、西他列汀/二甲双胍、Solifenacin、solanezumab、Sonidegib、索拉非尼、舒尼替尼、tacrolimus、tacrimus、塔帕西拉非、tacrimus tataparal、他唑帕尼、替莫唑胺、替西罗莫司、替诺福韦/恩曲他滨、替诺福韦二吡呋酯富马酸酯、睾丸激素凝胶、沙利度胺、TICE BCG、碘托溴铵、替沙吉林、托瑞米芬、曲美替尼、曲妥珠单抗、曲贝汀(ecteinascidin 743)、曲美替尼、曲美单抗、三氟吡啶/替吡西酯、维甲酸Uro-BCG、Ustekinumab、Valsartan、veliparib、vandetanib、vemurafenib、venetoclax、vorinostat、ziv-aflibercept、Zostavax及其类似物、衍生物、药学上可接受的盐、载体、稀释剂或辅料、或其组合。
本发明以下列实施例做进一步说明,但不仅限于以下实施例。
实施例
在以下实施例中进一步描述本发明,这些实施例无意于限制本发明的范围。以下示例中所述的细胞系根据美国典型培养物保藏中心(ATCC)或德国不伦瑞克的德国Deutsche SammLung von Mikroorganismen und Zellkulturen GmbH(DMSZ)或中国科学院上海细胞培养所指定的条件进行培养除非另有说明,否则不适用。除非另有说明,否则细胞培养试剂获自Invitrogen Corp.。所有无水溶剂都可以通过商业途径获得,并在氮气下储存在Sure-Seal瓶中。购买的所有其他试剂和溶剂均为可用的最高等级,无需进一步纯化即可使用。用Varain PreStar HPLC进行制备HPLC分离。NMR光谱在Bruker 500MHz仪器上分析测得。化学位移(δ)以百万分数(ppm)为单位报告,为对四甲基硅烷(0.00ppm)的相对值,偶合常数(J)以Hz为单位报告。质谱数据是在装有Waters Acquity UPLC分离模块和AcquityTUV检测器的Waters Xevo QTOF质谱上获得的。
实施例1. 1,2-双(2-(叔丁氧基)-2-氧乙基)肼-1,2-二羧酸二叔丁基酯的合成
向二叔丁基肼-1,2-二羧酸二叔丁酯(8.01g,34.4mmol)的DMF(150mL)溶液中加入NaH(60%,2.76g,68.8mmol)。在室温搅拌30分钟后,加入2-溴乙酸叔丁酯(14.01g,72.1mmol)。将混合物搅拌过夜,加入甲醇(3mL)淬灭,浓缩,用乙酸乙酯(100mL)和水(100mL)稀释,分离,并将水层用乙酸乙酯(2×50mL)萃取。合并有机层,用MgSO4干燥,过滤,浓缩,并通过SiO2柱色谱法纯化(乙酸乙酯/己烷1∶5至1∶3),得到标题化合物(12.98g,82%收率),为无色油状物。MS ESI m/z C22H41N2O8[M+H]+:计算值461.28,实测值461.40。
实施例2. 2,2'-(肼基-1,2-二基)二乙酸的合成.
向1,2-双(2-(2-(叔丁氧基)-2-氧乙基)肼-1,2-二羧酸二叔丁基酯(6.51g,14.14mmol)的1,4-二噁烷(40mL)中加入HCL(12M,10mL)。将混合物搅拌30分钟,用二噁烷(20mL)和甲苯(40mL)稀释,浓缩并与二噁烷(20mL)和甲苯(40mL)蒸发至干,得到粗品,用于下一步,无需进一步纯化(2.15g,103%产率,93%纯度)。MS ESI m/z C4H9N2O4[M+H]+:计算值149.05,实测值149.40。
实施例3. 2,2'-(1,2-双((苄氧基)羰基)肼-1,2-二基)二乙酸的合成
向2,2'-(肼-1,2-二基)二乙酸(1.10g,7.43mmol)的THF(200mL)和NaH2PO4(0.1M,250mL,pH 8.0)的混合物中分4次在两小时内加入碳酰氯苄酯(5.01g,29.47mmol)。将混合物再搅拌6小时,浓缩并在硅胶柱上纯化,用含有1%甲酸的H2O/CH3CN(1:9)洗脱,得到标题化合物(2.26g,73%收率,95%纯度)。MS ESI m/z C20H21N2O8[M+H]+:计算值417.12,实测值417.40。
实施例4. 1,2-双(2-氯-2-氧乙基)肼-1,2-二羧酸二苄酯的合成
向2,2'-(1,2-双((苄氧基)羰基)肼-1,2-二基)二乙酸(350mg,0.841mmol)的二氯乙烷(30mL)中加入(COCl)2(905mg,7.13mmol),然后加入0.030mL的DMF。在室温搅拌2小时,将混合物用甲苯稀释,浓缩并与二氯乙烷(2×20mL)和甲苯(2×15mL)共同蒸发至干,得到标题粗产物(不稳定)。无需进一步纯化即可用于下一步(365mg,96%产率)。MS ESI m/zC20H19Cl2N2O6[M+H]+:计算值453.05,实测值453.50。
实施例5. 1,2-双(2-(2-(叔丁氧基)-2-氧乙基)肼-1,2-二羧酸二叔丁基酯的合成
在室温下和氮气环境中,在十分钟内向NaH(0.259g,6.48mmol,3.0eq.)的无水DMF(2mL)悬浮液中加入1,2-二羧酸二叔丁酯(0.50g,2.16mmol,1.0eq.)和无水DMF(8mL)中。将混合物在室温搅拌10分钟,然后冷却至0℃。向其中滴加2-溴乙酸叔丁酯(1.4mL,8.61mmol,4.0eq.)。使所得混合物升温至室温,并搅拌过夜。加入饱和氯化铵溶液(100mL)。分离有机层,水层用乙酸乙酯(3×50mL)萃取。用水和盐水洗涤合并的有机溶液,用无水硫酸钠干燥,浓缩并通过硅胶柱色谱法纯化(10∶1正己烷/乙酸乙酯),得到标题化合物,为无色油状物(0.94g,99.6%)。ESI MS m/z[M+Na]+483.4。
实施例6.化合物2,2'-(肼-1,2-二基)二乙酸的合成
在0℃,向1,2-双(2-(叔丁氧基)-2-氧乙基)肼-1,2-二羧酸二叔丁基酯(0.94g,2.04mmol)的二氯甲烷(4mL)溶液中加入TFA(4mL)。搅拌30分钟,然后升温至室温并搅拌过夜。将混合物浓缩,用二氯甲烷稀释,再次浓缩。重复该操作3次,得到白色固体。用二氯甲烷稀释,过滤得到白色固体.232g,76.8%产率)。ESI MS m/z[M+H]+149.2。
实施例7. 2,2'-(1,2-双(2-氯乙酰基)肼-1,2-二基)二乙酸的合成.
在0℃下,在10分钟内向2,2'-(肼-1,2-二基)二乙酸(0.232g,1.57mmol,1.0eq.)的无水四氢呋喃(10mL)溶液中加入2-氯乙酰氯(0.38mL,4.70mmol,3.0eq.)。将反应升温至室温,搅拌过夜并浓缩。将残余物与四氢呋喃共蒸3次,得到白色固体(0.472g,理论产率)。ESI MS m/z[M+H]+301.1。
实施例8. 2,8-二氧代-1,5-恶唑烷-5-羧酸叔丁酯的合成
在4℃下,在1小时内向3,3'-氮杂二基二丙酸(10.00g,62.08mmol)的1.0M NaOH(300mL)溶液中加入二碳酸二叔丁酯(22.10g,101.3mmol)的四氢呋喃(200mL)溶液。加完后,将混合物在4℃下搅拌2小时。将混合物用0.2M H3PO4酸化至pH4,真空浓缩,用二氯甲烷萃取,经硫酸钠干燥,蒸发并用快速硅胶色谱法纯化,用AcOH/甲醇/二氯甲烷(0.01:1:5)洗脱,得到3,3′-((叔丁氧羰基)氮杂二基)二丙酸(13.62g,84%收率)。ESI MS m/zC11H19NO6[M+H]+:计算值262.27,实测值262.40。
实施例9. 3-((苄氧基)氨基)丙酸叔丁酯的合成
向O-苄基羟胺盐酸盐(10.0g,62.7mmol)的四氢呋喃(100mL)中加入三乙胺(15mL)和丙烯酸叔丁酯(12.1g,94.5mmol)。将混合物回流过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/正己烷(1∶4)洗脱,得到标题化合物(13.08g,83%产率)。1H NMR(CDCl3)7.49~7.25(m,5H),4.75(s,2H),3.20(t,J=6.4Hz,2H),2.54(t,J=6.4Hz,2H),1.49(s,9H);ESI MS m/z+C14H21NNaO3(M+Na):计算值274.15,实测值274.20。
实施例10. 3-(羟氨基)丙酸叔丁酯的合成
在氢化容器中,向3-(((苄氧基)氨基)丙酸叔丁酯(13.0g,51.76mmol)的甲醇(100mL)中加入Pd/C(0.85g,10%Pd,50%wet)。在真空下将系统抽真空并置于2atm氢气下后,将反应混合物在室温搅拌过夜。使粗反应物通过硅藻土的短柱,用乙醇冲洗,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1∶10-1∶5)洗脱,得到标题化合物(7.25g,87%收率)。
实施例11. 3-((甲苯磺酰氧基)氨基)丙酸叔丁酯的合成.
在4℃下,向3-(羟基氨基)丙酸叔丁酯(5.10g,31.65mmol)的二氯甲烷(50mL)和吡啶(20mL)的混合物中加入到甲苯磺酸氯(12.05g,63.42)。加完后,将混合物在室温搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶10-1∶6)洗脱,得到标题化合物(8.58g,86%收率)。1H NMR(CDCl3)7.81(s,2H),7.46(s,2H),3.22(t,J=6.4Hz,2H),2.55(t,J=6.4Hz,2H),2.41(s,3H),1.49(s,9H);ESI MS m/z+C14H21NNaO5S(M+Na):计算值338.11,实测值338.30。
实施例12. 3,3'-(肼-1,2-二基)二丙酸二叔丁酯的合成
向3-氨基丙酸叔丁酯(3.05g,21.01mmol)的四氢呋喃(80mL)溶液中加入3-((甲苯磺酰氧基)氨基)丙酸叔丁酯(5.10g,16.18mmol)。将混合物在室温搅拌1小时,然后在45℃下搅拌6小时。将混合物浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷/三乙胺(1:12:0.01~1:8:0.01)洗脱,得到标题化合物(2.89g,62%收率)。ESI MS m/z+C14H28N2NaO4(M+Na):计算值311.20,实测值311.40。
实施例13. 3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰基)丙酰基)肼-1,2-二基)二丙酸二叔丁酯的合成
向3-马来酰丙酸(1.00g,5.91mmol)的二氯甲烷(50mL)中加入草酰氯(2.70g,21.25mmol)和DMF(50μL)。将混合物在室温搅拌2h,蒸发,并与二氯甲烷/甲苯共蒸发,得到粗制的3-马来酰亚胺基丙酰氯。向3,3'-(肼-1,2-二丙基)二丙酸二叔丁酯(0.51g,1.76mmol)的二氯甲烷(35mL)混合物中加入粗制的3-马来酰亚胺丙酰氯。将混合物搅拌过夜,蒸发,浓缩,并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:151:8)洗脱,得到标题化合物(738mg,71%收率)。ESI MS m/z+C28H38N4NaO10(M+Na):计算值613.26,实测值613.40。
实施例14. 3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰基)-肼基-1,2-二基)二丙酸的合成
向化合物14(700mg,1.18mmol)的二噁烷(4mL)中加入盐酸(浓度1mL)。将混合物搅拌30分钟,用EtOH(10mL)和甲苯(10mL)稀释,蒸发并与乙醇(10mL)和甲苯(10mL)共蒸发,得到标题产物(560mg),用于下一步,无需进一步纯化。ESI MS m/z-C20H21N4O10(M-H):计算值477.13,实测值477.20。
实施例15.双(2,5-二氧吡咯烷-1-基)-3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基))丙酰基)肼-1,2-二基)二丙酸酯的合成
向粗制的化合物3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰基)肼-1,2-二基)二丙酸(560mg,1.17mmol)的DMA(8mL)溶液中加入NHS(400mg,3.47mmol)和EDC(1.01g,5.26mmol)。将混合物搅拌过夜,蒸发,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶121∶7)洗脱,得到标题化合物(520mg,2步收率65%)。ESI MS m/z+C28H28N6NaO14(M+Na):计算值695.17,实测值695.40。
实施例16. 3-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成.
一边搅拌一边向350mL的无水四氢呋喃中加入80mg(0.0025mol)的金属钠和三甘醇(150.1g,1.00mol)。在钠完全溶解后,加入丙烯酸叔丁酯(24mL,0.33mol)。将该溶液在室温搅拌20小时,并用8mL的1.0M盐酸中和。真空除去溶剂,并将残余物悬浮在盐水(250mL)中,用乙酸乙酯(3×125mL)萃取。合并的有机层用盐水(100mL)洗涤,然后用水(100mL)洗涤,经硫酸钠干燥,并除去溶剂。真空干燥得到69.78g(76%收率)的无色油,为标题产物。1HNMR:1.41(s,9H),2.49(t,2H,J=6.4Hz),3.59-3.72(m,14H).ESI MS m/z-C13H25O6(M-H):计算值277.17,实测值277.20。
实施例17. 3-(2-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(10.0g,35.95mmol)的乙腈(50.0mL)与吡啶(20.0mL)反应。在30分钟内通过加料漏斗滴加甲苯磺酰氯(7.12g,37.3mmol)的乙腈(50mL)溶液。5小时后,TLC分析表明反应完成。滤出已形成的吡啶盐酸盐,并除去溶剂。残余物在硅胶上纯化,用20%乙酸乙酯/正己烷溶液洗脱,用纯乙酸乙酯洗脱,得到11.2g(76%收率)的标题化合物。1H NMR:1.40(s,9H),2.40(s,3H),2.45(t,2H,J=6.4Hz),3.52-3.68(m,14H),4.11(t,2H,J=4.8Hz),7.30(d,2H,J=8.0Hz),7.75(d,2H,J=8.0Hz);ESI MS m/z+C20H33O8S(M+H):计算值433.18,实测值433.30。
实施例18. 3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成。
向50mL DMF中搅拌加入3-(2-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(4.0g,9.25mmol)和叠氮化钠(0.737g,11.3mmol)。将反应加热至80℃。4小时后,TLC分析表明反应完成。将反应冷却至室温,并用水(25mL)淬灭。分离水层,并萃取到乙酸乙酯(3×35mL)中。合并的有机层经无水硫酸镁干燥,过滤,并真空除去溶剂。叠氮化物粗产物(2.24g,98%收率,HPLC纯度约93%)无需进一步纯化即可用于下一步。1H NMR(CDCl3):1.40(s,9H),2.45(t,2H,J=6.4Hz),3.33(t,2H,J=5.2Hz),3.53-3.66(m,12H).ESI MS m/z+C13H26N3O8(M+H):计算值304.18,实测值304.20。
实施例19. 3-(2-(2-(2-(叠氮基乙氧基)乙氧基)乙氧基)丙酸的合成
向3-(2-(2-(2-(2-(叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(2.20g,7.25mmol)的1,4-二氧六环(40mL)中加入盐酸(12M,10mL)。将混合物搅拌40分钟,用二氧六环(20mL)和甲苯(40mL)稀释,蒸发并与二氧六环(20mL)和甲苯(40mL)共蒸发至干,得到粗制的标题产物,用于下一步。无需进一步纯化(1.88g,105%收率,HPLC纯度约为92%)。MSESI m/z:计算值C9H18N3O5[M+H]+248.12,实测值248.40。
实施例20. 13-氨基-4,7,10-三氧十二烷酸叔丁酯和13-氨基双(4,7,10-三氧十二烷酸叔丁酯)的合成
将叠氮化物粗品3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸(5.0g,14.84mmol)溶于乙醇(80mL)中,然后添加300mg 10%Pd/C。将系统在真空下抽真空,并在剧烈搅拌下于2atm氢气下氢化。将反应物在室温下搅拌过夜,TLC显示原料消失。使粗反应物通过硅藻土短垫,用乙醇冲洗。除去溶剂,在硅胶上纯化,使用甲醇的二氯甲烷溶液(5%至15%)(含1%三乙胺)作为洗脱剂,得到13-氨基-4,7,10-三氧杂十二烷酸叔丁酯(1.83g,44%收率,ESI MS m/z+C13H27NO5(M+H):计算值278.19,实测值278.30)和13-氨基-双(4,7,10-三氧杂十二烷酸叔丁酯)(2.58g,32%收率,ESI MS m/z+C26H52NO10(M+H):计算值538.35,实测值538.40)。
实施例21. 3-(2-(2-(2-(氨基氨基乙氧基)乙氧基)乙氧基)丙酸盐酸盐的合成.
在搅拌下,向13-氨基-4,7,10-三氧十二烷酸叔丁酯(0.80g,2.89mmol)的30mL二氧六环溶液中加入10mL盐酸(36%)。0.5小时后,TLC分析表明反应完成,将反应混合物蒸发,并与乙醇和乙醇/甲苯共蒸发,形成标题化合物的盐酸盐(纯度>90%,0.640g,收率86%),无需进一步纯化。ESI MS m/z+C9H20NO5(M+H):计算值222.12,实测值222.20。
实施例22. 13-氨基双(4,7,10-三氧十二烷酸,盐酸盐)
在搅拌下,向13-氨基双(4,7,10-三氧十二烷酸叔丁酯)(1.00g,1.85mmol)的30mL的二氧六环溶液中加入10mL盐酸(36%)。0.5小时后,TLC分析表明反应完成,将反应混合物蒸发,并与乙醇和乙醇/甲苯共蒸发,形成标题化合物的盐酸盐(纯度>90%,0.71g,收率91%),无需进一步纯化。ESI MS m/z+C18H36NO10(M+H):计算值426.22,实测值426.20。
实施例23. 3-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
向2,2’-(乙烷-1,2-二基双(氧基))二乙醇(55.0mL,410.75mmol,3.0eq.)的无水四氢呋喃(200mL)溶液中加入钠(0.1g)。搅拌混合物直至Na消失,然后滴加丙烯酸叔丁酯(20.0mL,137.79mmol,1.0eq.)。将混合物搅拌过夜,然后在0℃下通过盐酸溶液(20.0mL,1N)淬灭。通过旋转蒸发除去四氢呋喃,加入盐水(300mL),并将所得混合物用乙酸乙酯(3×100mL)萃取。有机层用盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤并浓缩,得到无色油状物(30.20g,79.0%收率),其无需进一步纯化即可使用。MS ESI m/z:计算值C13H27O6[M+H]+278.1729,实测值278.1730。
实施例24. 3-(2-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
在0℃下,向3-(2-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(30.20g,108.5mmol,1.0eq.)和TsCl(41.37g,217.0mmol,2.0eq.)的无水二氯甲烷(220mL)溶液中加入三乙胺(30.0mL,217.0mmol,2.0eq.)。将混合物在室温下搅拌过夜,然后用水(3×300mL)和盐水(300mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(3:1正己烷/乙酸乙酯)得到无色油状物(39.4g,84.0%产率)。MS ESI m/z C20H33O8S[M+H]+:计算值433.1818,实测值433.2838。
实施例25.3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
向3-(2-(2-(2-(2-(甲苯磺酰基氧基)乙氧基)乙氧基)乙氧基)叔丁基丙酸酯(39.4g,91.1mmol,1.0eq.)的无水DMF(100mL)溶液中加入叠氮化钠(20.67g,316.6mmol,3.5eq.)。将混合物在室温搅拌过夜。加入水(500mL),并用乙酸乙酯(3×300mL)萃取。用水(3×900mL)和盐水(900mL)洗涤合并的有机层,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(5:1正己烷/乙酸乙酯),得到浅黄色油状物(23.8g,85.53%的产率)。MS ESIm/z C13H25O3N5Na[M+Na]+:计算值326.2,实测值326.2。
实施例26. 3-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将Raney-镍(7.5g,悬浮于水中)用水(三次)和异丙醇(三次)洗涤,并与3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(5.0g,16.5mmol)的异丙醇溶液混合。将混合物在H2气球下于室温搅拌。保持16小时,然后在硅藻土垫上过滤,用异丙醇洗涤。浓缩滤液,并通过柱色谱法纯化(5-25%甲醇/二氯甲烷),得到浅黄色油状物(2.60g,57%产率)。MS ESI m/z C13H28NO5[M+H]+:计算值279.19;实测值279.19。
实施例27. 2-(2-(二苄氨基)乙氧基)乙醇的合成
向2-(2-氨基乙氧基)乙醇(21.00g,200mmol,1.0eq.)和K2CO3(83.00g,600mmol,3.0eq.)的乙腈(350mL)溶液中加入苄溴(57.0mL,480mmol,2.4eq.)。将混合物回流过夜。加入水(1L),并用乙酸乙酯(3×300mL)萃取。合并的有机层用盐水(1000mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法(4∶1正己烷/乙酸乙酯)纯化,得到无色油状物(50.97g,89.2%收率)。MS ESI m/z C18H23NO2Na[M+Na]+:计算值309.1729,实测值309.1967。
实施例28. 3-(2-(2-(二苄氨基)乙氧基)乙氧基)丙酸叔丁酯的合成
向2-(2-(二(苄基氨基)乙氧基)乙醇(47.17g,165.3mmol,1.0eq.),丙烯酸叔丁酯(72.0mL,495.9mmol,3.0eq.)和n-Bu4NI(6.10g,16.53mmol,0.1eq.)的二氯甲烷(560mL)的混合物中加入氢氧化钠溶液(300mL,50%)。将混合物搅拌过夜。分离有机层,水层用乙酸乙酯(3×100mL)萃取。将有机层用水(3×300mL)和盐水(300mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法(7∶1正己烷/乙酸乙酯)纯化,得到无色油状物(61.08g,产率89.4%)MS ESI m/z C25H36NO4[M+H]+:计算值414.2566,实测值414.2384。
实施例29. 3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯的合成
在氢化瓶中,向3-(2-(2-(2-(二(苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(20.00g,48.36mmol,1.0eq.)的四氢呋喃(30mL)和甲醇(60mL)溶液中添加Pd/C的(2.00g,10wt%,50%wet)。将混合物在1个大气压下H2环境下振摇过夜,通过硅藻土(助滤剂)过滤,并将滤液浓缩,得到无色油状物(10.58g,93.8%收率)。MS ESI m/z C11H24NO4[M+H]+:计算值234.1627,实测值234.1810。
实施例30. 3-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯的合成.
向2,2'-氧二乙醇(19.7mL,206.7mmol,3.0eq.)的无水四氢呋喃(100mL)溶液中加入钠(0.1g)。搅拌混合物直至Na消失,然后滴加丙烯酸叔丁酯(10.0mL,68.9mmol,1.0eq.)。将混合物搅拌过夜,并加入盐水(200mL),用乙酸乙酯(3×100mL)萃取。将有机层用盐水(3×300mL)洗涤,用无水硫酸钠干燥,过滤,浓缩,并通过硅胶柱色谱法(1:1正己烷/乙酸乙酯)纯化,得到无色油状物(8.10g,49.4%产率)。MS ESI m/z C11H23O5[M+H]+:计算值235.1467,实测值235.1667。
实施例31. 3-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯的合成.
在0℃下,向3-(2-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯(6.24g,26.63mmol,1.0eq.)和TsCl(10.15g,53.27mmol,2.0eq.)的无水二氯甲烷(50mL)中加入吡啶(4.3mL,53.27mmol,2.0eq.)。将混合物在室温搅拌过夜,然后用水(100mL)洗涤,水层用二氯甲烷(3×50mL)萃取。合并的有机层用盐水(300mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(5∶1正己烷/乙酸乙酯),得到无色油状物(6.33g,61.3%收率)。MS ESI m/z C18H27O7S[M+H]+:计算值389.1556,实测值389.2809。
实施例32. 3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯的合成
向3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯(5.80g,14.93mmol,1.0eq.)的无水DMF(20mL)液中加入NaN3(5.02g,77.22mmol,5.0eq.)。将混合物在室温搅拌过夜。加入水(120mL),并用乙酸乙酯(3×50mL)萃取。用水(3×150mL)和盐水(150mL)洗涤合并的有机层,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法(5∶1正己烷/乙酸乙酯)纯化,得到无色油状物(3.73g,69.6%的产率)。MS ESI m/z C11H22O3N4Na[M+H]+:计算值260.1532,实测值260.2259。
实施例33. 3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(0.18g,0.69mmol)溶于甲醇(3.0mL,用60μL浓盐酸),加入Pd/C(10wt%,20mg)后在H2气球下搅拌30分钟。通过硅藻土垫过滤催化剂,用甲醇洗涤。浓缩滤液,得到无色油状物(0.15g,93%收率)。MS ESI m/z:计算值C11H24NO4[M+H]+234.16;实测值234.14。
实施例34. 3-(2-(2-叠氮基乙氧基)乙氧基)丙酸的合成
在室温下,将3-(2-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(2.51g,9.68mmol)溶解在1,4-二氧六环(30mL)中与10mL盐酸(浓)混合溶液中。将混合物搅拌35分钟,用乙醇(30mL)和甲苯(30mL)稀释并真空浓缩。将粗品在硅胶上纯化,使用甲醇(5%至10%)和1%甲酸的二氯甲烷溶液作为洗脱液,得到标题化合物(1.63g,收率83%),ESI MS m/zC7H12N3O4[M-H]-:计算值202.06,实测值202.30。
实施例35. 2,5-二氧杂吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯的合成
向3-(2-(2-叠氮基乙氧基)乙氧基)丙酸(1.60g,7.87mmol)的二氯甲烷(30mL)溶液中加入NHS(1.08g,9.39mmol)和EDC(3.60g,18.75mmol)。8小时后TLC分析表明反应完成后,将反应混合物浓缩并在硅胶上纯化,使用乙酸乙酯(5%至10%)和二氯甲烷的混合溶液作为洗脱液,得到标题化合物(1.93g,82%的产率)。ESI MS m/z C11H17N4O6[M+H]+:计算值301.11,实测值301.20。
实施例36.2,5-二氧杂吡咯烷-1-基3-(2-(2-(2-(叠氮基乙氧基)乙氧基)乙氧基)丙酸酯的合成
在搅拌时,向3-(2-(2-(2-(2-(叠氮基乙氧基)乙氧基)乙氧基)乙氧基)丙酸(4.50g,18.21mmol)的二氯甲烷(80mL)溶液中加入NHS(3.0g,26.08mmol)和EDC(7.60g,39.58mmol)。8小时后TLC分析表明反应完成,将反应混合物浓缩并在硅胶上纯化,使用乙酸乙酯(5%至10%)和二氯甲烷的混合溶液作为洗脱液,得到标题化合物(5.38g,86%的产率)。ESI MS m/z C13H20N4O7[M+H]+:计算值345.13,实测值345.30。
实施例37.(14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-((叔丁氧羰基)-氨基)丁基)-12,15-二氧代-3,6,9-三恶唑-13,16-二氮杂十八烷-18-酸的合成
向(S)-2-((S)-2-氨基-6-((叔丁氧基羰基)氨基)六氨基)-4-(叔丁氧基)-4-氧代丁酸(2.81g,6.73mmol)的DMA(70mL)的溶液和0.1M NaH2PO4(50mL,pH 7.5)的混合物中加入2,5-二氧杂吡咯烷-1-基3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)-乙氧基)丙酸酯(3.50g,10.17mmol)。将混合物搅拌4小时,真空浓缩,在硅胶上纯化,使用甲醇(5%至15%)和二氯甲烷混合溶液(含有0.5%乙酸)作为洗脱剂,得到标题化合物(3.35g,77%)。ESI MS m/zC28H51N6O11[M+H]+:计算值647.35,实测值647.80。
实施例38.(14S,17S)-叔丁基1-叠氮基-14-(4-((叔丁氧基羰基)-氨基)丁基)-17-(((4-(羟甲基)苯基)氨基甲酰基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十九烷-19-酯
向(14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-((叔丁氧基羰基)-氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷-18-酸(3.30g,5.10mmol)和(4-氨基苯基)甲醇(0.75g,6.09)的DMA(25mL)溶液中加入EDC(2.30g11.97mmol)。将混合物搅拌过夜,真空浓缩,在硅胶上纯化,使用甲醇(5%至8%)和二氯甲烷的混合溶液作为洗脱剂,得到标题化合物(3.18g,83%收率)。ESI MS m/z C35H58N7O11[M+H]+:计算值752.41,实测值752.85。
实施例39.(14S,17S)-叔丁基1-氨基-14-(4-((叔丁氧基羰基)氨基)-丁基)-17-(((4(羟甲基)苯基)氨基甲酰基)-12,15-二氧杂的合成-3,6,9-三氧杂-13,16-二氮杂十九烷-19-酯
在氢气瓶中向(14S,17S)-叔丁基1-叠氮基-14-(4-((叔丁氧基羰基)氨基)丁基)-17-(((4-(羟甲基)苯基)氨基甲酰基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十九烷-19-酯(1.50g,1.99mmol)的四氢呋喃(35mL)溶液中加入Pd/C(200mg,10%Pd,50%wet)。将混合物在1atm的H2下振摇过夜,通过硅藻土(助滤剂)过滤,并将滤液浓缩,得到标题化合物(1.43g,99%产率),其无需进一步纯化即可直接用于下一步。ESI MS m/z C35H60N5O11[M+H]+:计算值726.42,实测值726.70。
实施例40.(S)-15-叠氮基-5-异丙基-4,7-二氧杂-10,13-二氧杂-3,6-二氮杂十五烷-1-酸的合成
向(S)-2-(2-氨基-3-甲基丁酰胺基)乙酸(Val-Gly)(1.01g,5.80mmol)的DMA(50mL)和0.1M NaH2PO4(50mL,pH 7.5)的溶液中加入3-(2-(2-(2-叠氮基乙氧基)乙氧基)丙酸-2,5-二氧杂吡咯烷-1-基酯(1.90g,6.33)。将混合物搅拌4小时,真空浓缩,在硅胶上使用甲醇(5%至15%)和二氯甲烷的混合溶液(含有0.5%乙酸)作为洗脱液纯化,得到标题化合物(1.52g,73%产率)。ESI MS m/z C14H26N5O6[M+H]+:计算值360.18,实测值360.40。
实施例41.(S)-2,5-二氧杂吡咯烷-1-基15-叠氮基-5-异丙基-4,7-二氧杂-10,13-二氧杂-3,6-二氮杂十五烷-1-酸酯的合成
在搅拌下,向(S)-15-叠氮基-5-异丙基-4,7-二氧杂-10,13-二氧杂-3,6-二氮杂十五烷-1-酸(1.50g,4.17mmol)的二氯甲烷(40mL)溶液中加入NHS(0.88g,7.65mmol)和EDC(2.60g,13.54mmol)。8小时后,TLC分析表明反应完成,将反应混合物浓缩并在硅胶上纯化,使用乙酸乙酯(5%至20%)和二氯甲烷的混合溶液作为洗脱液,得到标题化合物(1.48g,78%的产率)。ESI MS m/z C18H29N6O8[M+H]+:计算值457.20,实测值457.50。
实施例42.4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和NaOH(6g,150mmol)的H2O(40mL)溶液冷却至0℃,并用CbzCl(16.1g,95mmol)的二氯甲烷溶液处理。滴加四氢呋喃(32mL)。1小时后,使反应升温至室温并搅拌3小时。在真空下除去四氢呋喃,通过添加6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MSESI m/z:计算值C12H16NO5[M+H]+238.10,实测值238.08。
实施例43. 4-((((苄氧基)羰基)氨基)丁酸叔丁酯的合成
向4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol))的二氯甲烷(100mL)的溶液中加入DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)。在室温搅拌后过夜,将反应物过滤并将滤液浓缩。将残余物溶解在乙酸乙酯中,并用1N盐酸,盐水洗涤,并经硫酸钠干燥。浓缩并通过柱色谱法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%产率)。MS ESI m/z:计算值C16H23NO4Na[M+Na]+316.16,实测值316.13。
实施例44.4-氨基丁酸叔丁酯的合成
将4-((((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶于甲醇(50mL)中,并与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)3小时。滤出催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%产率)。MS ESI m/z:计算值C8H18NO2[M+H]+160.13,实测值160.13。
实施例45. 3,3'-(苄基氮杂二基)二丙酸二叔丁酯的合成
将苯甲胺(2.0mL,18.29mmol,1.0eq.)和丙烯酸叔丁酯(13.3mL,91.46mmol,5.0eq.)的混合物在80℃回流过夜,然后浓缩。粗产物通过硅胶柱色谱法纯化(20∶1正己烷/乙酸乙酯),得到标题化合物,为无色油状物(5.10g,77%收率)。ESI MS m/z::计算值C21H34NO4[M+H]+364.2,实测值364.2.1H NMR(400MHz,CDCl3)δ7.38–7.21(m,5H),3.58(s,2H),2.76(t,J=7.0Hz,4H),2.38(t,J=7.0Hz,4H),1.43(s,17H)。
实施例46. 3,3'-氮杂二丙二丙酸二叔丁酯的合成
向氢化瓶中加入3,3'-(苄基氮杂二基)二丙酸二叔丁酯(1.37g,3.77mmol,1.0eq.)的甲醇(10mL)溶液和Pd/C(0.20g,10%Pd/C,50%wet)。将混合物在H2下振荡过夜,然后通过硅藻土垫过滤。浓缩滤液,得到标题化合物,为无色油状物(1.22g,89%产率)。ESIMS m/z C14H28NO4[M+H]+:计算值274.19,实测值274.20。
实施例47. 4-(2-((((苄氧基)羰基)氨基)丙烷酰胺基)丁酸叔丁基酯的合成
在0℃下,向4-氨基丁酸叔丁酯(1.00g,6.28mmol,1.0eq.)和Z-L-丙氨酸(2.10g,9.42mmol,1.5eq.)的无水二氯甲烷(50mL)溶液中加入HATU(3.10g,8.164mmol,1.3eq.)和三乙胺(2.6mL,18.8mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌过夜。将混合物用二氯甲烷稀释,并用水和盐水洗涤,用无水硫酸钠干燥,浓缩并通过硅胶柱色谱法纯化(10:3石油醚/乙酸乙酯),得到标题化合物,为无色油状物(1.39g,61%收率)。ESI MS m/z C19H29N2O5Na[M+H]+:计算值387.2,实测值387.2。
实施例48. 4-(2-氨基丙酰胺基)丁酸叔丁酯的合成
向氢化瓶中加入4-(2-((((苄氧基)羰基)氨基)丙酰胺基)丁酸叔丁酯(1.39g,3.808mmol,1.0eq.)的甲醇(12mL)溶液和Pd/C(0.20g,10%(重量),10%wet)。将混合物振荡2小时,然后通过硅藻土(助滤剂)过滤,浓缩,得到标题化合物,为浅黄色油状物(0.838g,95%收率)。ESI MS m/z C11H23N2O3[M+H]+:计算值231.16,实测值231.15。
实施例49. 3-(2-(2-(2-(二苄氨基)乙氧基)乙氧基)丙酸的合成
在室温下,向3-(2-(2-(2-(二(苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(2.3g,5.59mmol,1.0eq)的二氯甲烷(10mL)溶液中加入TFA(5mL)。搅拌90分钟后,将反应混合物用无水甲苯稀释并浓缩,重复此操作3次,得到标题化合物,为浅黄色油状物(2.0g,理论收率),将其直接用于下一步。ESI MS m/z C21H28NO4[M+H]+:计算值358.19,实测值358.19。
实施例50.五氟苯基3-(2-(2-(2-(二苄氨基)乙氧基)乙氧基)-丙酸酯的合成
在0℃下,向3-(2-(2-(2-(二(苄基氨基)乙氧基)乙氧基)乙氧基)丙酸(2.00g,5.59mmol,1.0eq.)的无水二氯甲烷(30mL)溶液中加入DIPEA直至pH为中性,然后加入PFP(1.54g,8.38mmol,1.5eq.)和DIC(1.04mL,6.70mmol,1.2eq.)。10分钟后,将反应升温至室温并搅拌过夜。将混合物过滤,浓缩并通过硅胶柱色谱法纯化(15∶1石油醚/乙酸乙酯),得到标题化合物,为无色油状物(2.10g,72%收率)。ESI MS m/z C27H27F5NO4[M+H]+:计算值524.2,实测值524.2。
实施例51.2-苄基-13-甲基-11,14-二氧杂-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸酯的叔丁基的合成
在0℃下,向4-(2-氨基丙酰胺基)丁酸叔丁酯(0.736g,3.2mmol,1.0eq.)和五氟苯基3-(2-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(2.01g,3.84mmol,1.2eq.)的无水DMA(20mL)的溶液中加入DIPEA(1.7mL,9.6mmol,3.0eq.)。在0℃下搅拌10分钟,将反应升温至室温并搅拌过夜。加入水(100mL),并将混合物用乙酸乙酯(3×100mL)萃取。用水(3×200mL)和盐水(200mL)洗涤合并的有机层,用硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(25:2二氯甲烷/甲醇),得到标题化合物,为无色的油状物(1.46g,80%产率)。ESI MSm/z C32H48N3O6[M+H]+:计算值570.34,实测值570.33。
实施例52. 2-苄基-13-甲基-11,14-二氧-1--1-苯基-5,8-二氧-2,12,15-三氮杂十九烷-19-酸的合成
在室温下,向2-苄基-13-甲基-11,14-二氧杂-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸叔丁基酯(0.057g,0.101mmol,1.0eq)的二氯甲烷(3mL)溶液中加入TFA(1mL)并搅拌40分钟。用无水甲苯稀释反应,然后浓缩。重复该操作3次,得到标题化合物,为无色油状物(0.052g,理论收率),将其直接用于下一步。ESI MS m/z C28H40N3O6[M+H]+:计算值514.28,实测值514.28。
实施例53. 4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和NaOH(6g,150mmol)的水(40mL)溶液冷却至0℃,并与CbzCl(16.1g,95mmol)的四氢呋喃(32mL)溶液搅拌。1小时后,使反应升温至室温,搅拌3小时。在真空下除去四氢呋喃,通过加入6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MS ESI m/z C12H16NO5[M+H]+:计算值238.10,实测值238.08。
实施例54. 4-((((苄氧基)羰基)氨基)丁酸叔丁酯的合成
将DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)加入到4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol)的二氯甲烷(100mL)溶液中。在室温搅拌后过夜,将反应物过滤并将滤液浓缩。将残余物溶解在乙酸乙酯中,并用1N盐酸,盐水洗涤,经硫酸钠干燥。浓缩并通过柱色谱法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%产率)。MS ESI m/z C16H23NO4Na[M+Na]+:计算值316.16,实测值316.13。
实施例55. 4-氨基丁酸叔丁酯的合成
将4-((((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶于甲醇(50mL)中,与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)3小时。滤出催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%收率)。MS ESI m/z C8H18NO2[M+H]+:计算值160.13,实测值160.13。
实施例56. 2-(2-((((苄氧基)羰基)氨基)丙酰胺基)乙酸叔丁酯的合成
将2-(((苯甲氧基)羰基)氨基)丙酸(0.84g,5mmol),2-氨基乙酸叔丁酯(0.66g,5mmol),HOBt(0.68g,5mmol),EDC(1.44g,7.5mmol)溶于二氯甲烷(20mL)中,然后加入DIPEA(1.7mL,10mmol)。将反应混合物在室温搅拌过夜,用水(100mL)洗涤,并将水层用乙酸乙酯萃取。合并有机层,用硫酸镁干燥,过滤,在减压下蒸发,并将残余物在硅胶柱上纯化,得到标题产物1(0.87g,52%)。ESI:m/zC17H25N2O5[M+H]+:计算值337.17,实测值337.17。
实施例57. 2-(2-((((苄氧基)羰基)氨基)丙酰胺基)乙酸的合成
将2-(2-((((苄氧基)羰基)氨基)丙酰胺基)乙酸叔丁酯(0.25g,0.74mmol)溶解在二氯甲烷(30mL)中,然后加入TFA(10mL)。将混合物在室温搅拌过夜,浓缩,得到标题化合物,其无需进一步纯化即可用于下一步骤。ESI:m/z C13H17N2O5[M+H]+:计算值281.11,实测值281.60。
实施例58. 14,17-二氧代-4,7,10,21,24,27-六氧杂-13,18-二氮杂三十烷-15-炔-1,30-二叔丁基酯的合成
将乙炔二羧酸(0.35g,3.09mmol,1.0eq.)溶解在NMP(10mL)中并冷却至0℃,向其中加入3-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基叔丁基)丙酸酯(2.06g,7.43mmol,2.4eq.),然后分批加入DMTMM(2.39g,8.65mmol,2.8eq.)。将反应在0℃下搅拌6h,然后用乙酸乙酯稀释,并用水和盐水洗涤。浓缩有机溶液,并用乙酸乙酯和石油醚的混合溶剂打浆。滤出固体并将滤液浓缩并通过柱色谱法纯化(80-90%乙酸乙酯/石油醚),得到浅黄色油状物(2.26g,>100%收率),其无需进一步纯化即可使用。MS ESI m/z[M+H]+633.30。
实施例59. 14,17-二氧代-4,7,10,21,24,27-六氧杂-13,18-二氮杂三十烷-15-炔-1,30-二酸的合成
将化合物14,17-二氧代-4,7,10,21,24,27-六氧杂-13,18-二氮杂三十烷-15-炔-1,30-二叔丁基酯(2.26g)溶于二氯甲烷(15mL)然后冷却至0℃,然后与TFA(15mL)搅拌。反应升温至室温并搅拌45分钟,然后在旋转蒸发仪上除去溶剂和残留的TFA。通过柱色谱法(0-15%甲醇/二氯甲烷)纯化粗产物,得到浅黄色油状物(1.39g,两步收率86%)。MS ESIm/z[M+H]+521.24。
实施例60. 2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-21-炔-1,42-二酯
向14,17-二氧代-4,7,10,21,24,27-六氧杂-13,18-二氮杂三十烷-15-炔-1,30-二酯(1.38g,2.65mmol),2-(2-氨基丙酰胺基)丙酸叔丁酯(0.75g,3.47mmol)的DMA(40mL)的混合物中加入EDC(2.05g,10.67mmol)。将混合物搅拌过夜,浓缩并在硅胶柱色谱法纯化,用乙酸乙酯/CH 2Cl 2(1∶5至1∶1)洗脱,得到标题化合物(2.01g,82%收率,HPLC纯度约为95%)MS ESI m/z C42H73N6O16[M+H]+:计算值917.50,实测值917.90。
实施例61. 2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-21-炔-1,42-二酸
将二叔丁基-2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19 1,2,37,40-六氮杂四十二烷-21-炔-1,42-二酸酯(1.50g,1.63mmol)溶解在二氯甲烷(10mL)和TFA(10mL)的混合溶液中。将混合物搅拌过夜,用甲苯(20mL)稀释,浓缩,得到标题化合物(1.33g,101%收率,HPLC纯度约为92%),其无需进一步纯化即可用于下一步。MS ESI m/z C34H56N6O16[M+H]+:计算值805.37,实测值805.85。
实施例62.双(2,5-二氧吡咯烷-1-基)2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-21-炔-1,42-二酯的合成
向2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-21-炔-1,42-二酸(1.30g,1.61mmol)和DMA(10mL)的混合物中加入NHS(0.60g,5.21mmol)和EDC(1.95g,10.15mmol)。将混合物搅拌过夜,浓缩并在硅胶柱色谱法纯化,用乙酸乙酯/CH2Cl2(1∶4至2∶1)洗脱,得到标题化合物(1.33g,83%收率,HPLC纯度约为95%)。MS ESI m/z C42H63N8O20[M+H]+:计算值999.40,实测值999.95。
实施例63. 2,3-双(2-溴乙酰氨基)琥珀酰氯的合成
向2,3-二氨基琥珀酸(5.00g,33.77mmol)的四氢呋喃/水/DIPEA(125mL/125mL/8mL)的混合物中加入2-溴乙酰溴(25.0g,125.09mmol)。将混合物搅拌过夜,蒸发并通过硅胶柱色谱法纯化(H 2O/CH3CN 5:95),得到浅黄色油状的2,3-双(2-溴乙酰氨基)琥珀酸(9.95g,76%产率)。MS ESI m/z C8H11Br2N2O6[M+H]+:计算值388.89,实测值388.68。
向2,3-双(2-溴乙酰氨基)琥珀酸(3.50g,9.02mmol)的二氯甲烷(80mL)溶液中,加入草酰氯(5.80g,46.05mmol)和DMF(0.01mL)。将混合物搅拌2.5小时,用甲苯稀释,浓缩并与二氯乙烷(2×20mL)和甲苯(2×15mL)共同蒸发至干,得到2,3-双(2-溴乙酰胺基)琥珀酰氯,为粗产物(不稳定),无需进一步纯化即可用于下一步(3.90g,102%收率)MS ESI m/zC8H9Br2Cl2N2O4[M+H]+:计算值424.82,实测值424.90。
实施例64. 2,3-双(((苄氧基)羰基)氨基)琥珀酸的合成
向2,3-二氨基琥珀酸(4.05g,27.35mmol)的四氢呋喃(250mL)和NaH2PO4(0.1M,250mL,pH 8.0)混合物中,在2小时内,分4份加入碳酸氯苄酯(15.0g,88.23mmol)。将混合物再搅拌6小时,浓缩并在硅胶柱上纯化,用含有1%甲酸的水/乙腈(1∶9)洗脱,得到标题化合物(8.65g,76%收率,95%纯度)。MS ESI m/z C20H21N2O8[M+H]+:计算值417.12,实测值417.60。
实施例65.双(2,5-二氧杂吡咯烷-1-基)2.3-双(((苄氧基)羰基)-氨基)琥珀酸酯的合成
向2,3-双((((苄氧基)羰基)氨基)琥珀酸(4.25g,10.21mmol)的DMA(70mL)混合物中加入NHS(3.60g,31.30mmol)和EDC(7.05)g,36.72mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/CH2 Cl2(1∶6)洗脱,得到标题化合物(5.42g,87%收率,95%纯度)。MS ESI m/z C28H27N4O12[M+H]+:计算值611.15,实测值611.60。
实施例66. 2,3-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)琥珀酸的合成
向2,3-二氨基琥珀酸(5.00g,33.77mmol)的四氢呋喃/水/DIPEA(125mL/125mL/2mL)混合物中加入马来酸酐(6.68g,68.21mmol)。将混合物搅拌过夜,蒸发,得到白色固体状的2,3-双((Z)-3-羧基丙烯酰胺基)琥珀酸(11.05g,99%收率)。MS ESI m/z C12H13N2O10[M+H]+:计算值345.05,实测值345.35。
向2,3-双((Z)-3-羧基丙烯酰胺基)琥珀酸(11.05g,33.43mmol)的HOAc(70mL),DMF(10mL)和甲苯(50mL)的混合溶液中加入到乙酸酐(30mL)。将混合物搅拌2小时,在Dean-Stark蒸馏器下在100℃回流6小时,浓缩,与乙醇(2×40mL)和甲苯(2×40mL)共同蒸发,并在硅胶柱上纯化,用二氯甲烷洗脱。用水/CH3CN(1:10)洗脱得到标题化合物(7.90g,产率76%,纯度约95%)。MS ESI m/z C12H9N2O8[M+H]+:计算值309.03,实测值309.30。
实施例67.双(2,5-二氧杂吡咯烷-1-基)2,3-(双(2,5-二氧杂吡咯烷-1-基)琥珀酸酯的合成
向2,3-双(2,5-二氧杂-2,5-二氢-1H-吡咯-1-基)琥珀酸(4.00g,12.98mmol)的DMF(70mL)的混合物中加入NHS(3.60g,31.30mmol)和EDC(7.05g,36.72mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:6)洗脱,得到标题化合物(5.73g,88%产率,96%HPLC纯)。MS ESI m/z C20H15N4O12[M+H]+:计算值503.06,实测值503.45。
实施例68.(3S,6S,39S,42S)-6,39-双(4-((叔丁氧基羰基)氨基)丁基)-22,23-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3,42-双((4-(羟甲基)苯基)氨基甲酰基)-5,8,21,24,37,40-六氧代-11,14,17,28,31,34-六氧杂-4,7,20,25,38,41-六氮杂四十四烷-1,44-二叔丁基酯的合成
向(14S,17S)-1-氨基-14-(4-((叔丁氧羰基)氨基)丁基)-17-((4-(羟甲基)苯基)氨基甲酰基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十九烷-19-叔丁基酯(1.43g,1.97mmol)和双(2,5-二氧杂吡咯烷-1-基)2,3-(双(2,5-二氧杂吡咯烷-1-基)琥珀酸酯(0.30g,0.97mmol)的DMA(25mL)溶液中加入EDC(1.30g,6.77mmol)。将混合物搅拌过夜,真空浓缩,在硅胶上纯化,使用甲醇(5%至8%)和二氯甲烷的混合溶液作为洗脱剂洗脱,得到标题化合物(1.33g,80%收率)。ESI MS m/z C82H123N12O28[M+H]+:计算值1722.85,实测值1722.98。
实施例69.1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷-18-叔丁基酯的合成
向3-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸(1.55g,6.27mmol),2-(2-氨基丙酰胺基)丙酸叔丁酯(1.35g,6.27mmol)的DMA(60mL)的混合物中加入EDC(3.05g,15.88mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/CH 2Cl2(1∶3)洗脱,得到标题化合物(2.42g,收率86%,HPLC纯度约95%)。MS ESI m/z C19H36N5O7[M+H]+:计算值446.25,实测值446.60。
实施例70.1-叠氮基14,17-二甲基-12,15-二氧-3,6,9-三氧杂-13,16-二氮杂十八烷-18-酸的合成
向1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷-18-叔丁基酯(2.20g,4.94mmol)的1,4-二氧六环(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌40分钟,用二氧六环(20mL)和甲苯(40mL)稀释,蒸发并与二氧六环(20mL)和甲苯(40mL)共同蒸发至干,得到粗制的标题产物,用于下一步,无需进一步纯化(1.92g,100%收率,HPLC纯度约为94%)。MS ESI m/z:计算值C15H28N5O7[M+H]+390.19,实测值390.45。
实施例71. 21,22-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-1,42-二酸的合成
向1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氧杂十八烷-18-酸(1.90g,4.88mmol)的DMA(40mL)溶液中加入Pd/C(0.20g,50%wet)。将系统抽真空,置于2atm氢气下,剧烈搅拌。反应在室温搅拌6小时后,TLC显示起始原料消失。使粗反应物通过硅藻土短垫,用乙醇洗脱。减压浓缩溶剂,得到粗产物1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷-18-酸,直接用于下一步。ESI MS m/z+C15H30N3O7(M+H):计算值364.20,实测值364.30。
向上述氨基化合物的DMA(30mL)溶液中加入0.1M NaH2PO4,pH 7.5(20mL),然后加入双(2,5-二氧杂吡咯烷-1-基)2,3-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)琥珀酸(1.30g,2.59mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用含8%水的乙腈溶液洗脱,得到标题化合物(1.97g,81%收率)。ESI MS m/z+C42H63N8O20(M+H):计算值999.41,实测值999.95。
实施例72.双(2,5-二氧吡咯烷-1-基)21,22-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-2,5,38,41-四甲基-4,7,20,23,36,39-六氧代-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-1,42-二酯的合成
向21,22-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-2,5,38,41-四甲基-4,7,20,23,36,39-六氧杂-10,13,16,27,30,33-六氧杂-3,6,19,24,37,40-六氮杂四十二烷-1,42-二酸(1.50g,1.50mmol)的DMA(10mL)溶液中加入到NHS(0.60g,5.21mmol)和EDC(1.95g,10.15mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶4至2∶1)洗脱,得到标题化合物(1.50g,83%收率,HPLC纯度约为95%)。MS ESI m/z C50H69N10O24[M+H]+:计算值1193.44,实测值1193.95。
实施例73.(2S,4R)-4-羟基吡咯烷-2-羧酸甲酯盐酸盐的合成
在0至4℃下,向反式-4-羟基-L-脯氨酸(15.0g,114.3mmol)的无水甲醇(250mL)溶液中滴加亚硫酰氯(17mL,231mmol)。将得到的混合物在室温搅拌过夜,浓缩,用乙醇/正己烷结晶,得到标题化合物(18.0g,87%收率)ESI MS m/z 168.2([M+Na]+)。
实施例74.(2S,4R)-1-叔丁基-2-甲基4-羟基吡咯烷-1,2-二羧酸酯的合成
向反式-4-羟基-L-脯氨酸甲酯(18.0g,107.0mmol)的甲醇(150mL)和碳酸氢钠溶液(2.0M,350mL)中,在4小时内分三批加入Boc2O(30.0g,137.6mmol)。再搅拌4小时后,将反应浓缩至350mL,并用乙酸乙酯(4×80mL)萃取。合并的有机层用盐水(100mL)洗涤,干燥(MgSO4),过滤,浓缩并通过硅胶柱色谱法(1:1正己烷/乙酸乙酯)纯化,得到标题化合物ESIMS m/z 268.2([M+Na]+)。
实施例75.(S)-1-叔丁基-2-甲基4-氧代吡咯烷-1,2-二羧酸酯的合成
通过Dess-Martin氧化制备的标题化合物的方法记载在Franco Manfre等.J.Org.Chem.1992,57,2060-2065.中。Swern氧化步骤如下:向冷却至-78℃的草酰氯(13.0mL,74.38mmol)在二氯甲烷(350mL)的溶液中加入干燥的DMSO(26.0mL)。将该溶液在-78℃下搅拌15min之后加入(2S,4R)-1-叔丁基-2-甲基4-羟基吡咯烷-1,2-二羧酸酯(8.0g,32.63mmol)的二氯甲烷(100mL)溶液,然后在-78℃搅拌2h,逐滴加入三乙胺(50mL,180.3mmol),并将反应溶液升温至室温。将混合物用NaH2PO4溶液(1.0M,400mL)稀释,分离两相。用二氯甲烷(2×60mL)萃取水层。合并有机层,用硫酸镁干燥,过滤,浓缩并通过硅胶柱色谱法纯化(7:3正己烷/乙酸乙酯),得到标题化合物(6.73g,85%产率)。ESI MS m/z266.2([M+Na]+)。
实施例76.(S)1-叔丁基-2-甲基-4-亚甲基吡咯烷-1,2-二羧酸酯的合成
在0℃下,向甲基三苯基溴化((19.62g,55.11mmol)的四氢呋喃(150mL)的悬浮液中加入叔丁醇钾(6.20g,55.30mmol)的无水四氢呋喃(80mL)溶液。在0℃下搅拌2小时,将所得黄色叶立德加入到(S)-1-叔丁基-2-甲基4-氧代吡咯烷-1,2-二羧酸酯(6.70g,27.55mmol)的四氢呋喃(40毫升)溶液中。在室温搅拌1小时,将反应混合物浓缩,用乙酸乙酯(200mL)稀释,用水(150mL),盐水(150mL)洗涤,用硫酸镁干燥,浓缩并在硅胶柱色谱上纯化(9∶1正己烷/乙酸乙酯),得到标题化合物(5.77g,87%产率)EI MS m/z 264([M+Na]+)。
实施例77.(S)-4-亚甲基吡咯烷-2-羧酸甲酯盐酸盐的合成
在4℃下,向(S)-1-叔丁基-2-甲基-4-亚甲基吡咯烷-1,2-二羧酸酯(5.70g,23.63mmol)的乙酸乙酯(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌1小时,用甲苯(50mL)稀释,浓缩,并用乙醇/正己烷结晶,得到标题化合物,为盐酸盐(3.85g,92%收率)。EI MS m/z 142.2([M+H]+)。
实施例78.(S)叔丁基-2-(羟甲基)-4-亚甲基吡咯烷-1-羧酸酯的合成
在0℃下,向(S)-1-叔丁基-2-甲基4-亚甲基吡咯烷-1,2-二羧酸酯(5.20g,21.56mmol)的无水四氢呋喃(100mL)溶液中加入LiAlH4(15mL,2M的四氢呋喃中)。在0℃下搅拌4小时后,通过加入甲醇(5mL)和水(20mL)将反应淬灭。将反应混合物用1M盐酸中和至pH 7,用乙酸乙酯(80mL)稀释,通过硅藻土过滤,分离,并将水层用乙酸乙酯萃取。合并有机层,经硫酸钠干燥,浓缩并在硅胶柱色谱上纯化(1∶5乙酸乙酯/二氯甲烷),得到标题化合物(3.77g,82%收率)。EI MS m/z 236.40([M+Na]+)。
实施例79.(S)-(4-亚甲基吡咯烷-2-基)甲醇盐酸盐的合成
在4℃下,向(S)2-(羟甲基)-4-亚甲基吡咯烷-1-羧酸叔丁酯(3.70g,17.36mmol)的乙酸乙酯(30mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌1h,用甲苯(50mL)稀释,浓缩,并用乙醇/正己烷结晶,得到标题化合物,为盐酸盐(2.43g,94%收率)。EI MS m/z115.1([M+H]+)。
实施例80. 4-(苄氧基)-3-甲氧基苯甲酸的合成.
向4-羟基-3-甲氧基苯甲酸(50.0g,297.5mmol)的乙醇(350mL)和NaOH溶液(2.0M,350mL)中加入苄溴(140.0g,823.5mmol)。将混合物在65℃下搅拌8小时,浓缩,与水(2×400mL)共蒸发,浓缩至400mL,用6N盐酸酸化至pH 3.0。过滤收集固体,用乙醇结晶,在45℃下真空干燥,得到标题化合物(63.6g,83%产率)。ESI MS m/z 281.2([M+Na]+)。
实施例81. 4-(苄氧基)-5-甲氧基-2-硝基苯甲酸的合成
向4-(苄氧基)-3-甲氧基苯甲酸(63.5g,246.0mmol)的二氯甲烷(400mL)和冰醋酸(100mL)的溶液中加入发烟硝酸(25.0mL,528.5mmol)。将混合物搅拌6小时,浓缩,用乙醇结晶,在40℃下真空干燥,得到标题化合物(63.3g,85%产率)。ESI MS m/z 326.1([M+Na]+)。
实施例82.(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮的合成
将催化量的DMF(30μl)加入到4-(苄氧基)-5-甲氧基-2-硝基苯甲酸(2.70g,8.91mmol)和草酰氯(2.0mL,22.50mmol)的无水二氯甲烷(70mL)溶液中,并将所得混合物在室温搅拌2h。用旋转蒸发仪除去过量的二氯甲烷和草酰氯。在0℃和N2气氛下,将乙酰氯重新悬浮在新鲜的二氯甲烷(70mL)中,并缓慢加入到预先混合好的(S)-(4-亚甲基吡咯烷-2-基)甲醇盐酸盐(1.32g,8.91mmol)和三乙胺(6mL)的二氯甲烷溶液中。使反应混合物升温至室温并继续搅拌8小时。除去二氯甲烷和三乙胺后,将残余物在水和乙酸乙酯(70/70mL)之间分配。将水层进一步用乙酸乙酯(2×60mL)萃取。合并的有机层用盐水(40mL)洗涤,干燥(MgSO4)并浓缩。用快速硅胶柱色谱法(2:8正己烷/乙酸乙酯)纯化残余物,得到标题化合物(2.80g,79%产率)。EI MS m/z421.2([M+Na]+)。
实施例83.(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-亚甲基吡咯烷-1-基)甲酮的合成
向(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮(2.78g,8.52mmol))的二氯甲烷(10mL)和吡啶(10mL)混合物中加入叔丁基氯二甲基硅烷(2.50g,16.66mmol)。将混合物搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶6)洗脱,得到标题化合物(3.62g,83%收率,95%纯度)。MS ESI m/z C27H37N2O6Si[M+H]+:计算值513.23,实测值513.65。
实施例84.(S)-(4-羟基-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮的合成
向(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮(2.80g,7.03mmol))的二氯甲烷(30mL)和CH3SO3H(8mL)的混合物中加入PhSCH3(2.00g,14.06mmol)。将混合物搅拌0.5小时,用二氯甲烷(40mL)稀释,小心加入0.1M Na2CO3溶液中和。分离混合物,并将水溶液用二氯甲烷(2×10mL)萃取。合并有机层,经硫酸钠干燥,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:15至1:6)洗脱,得到标题化合物(1.84g,85%收率,95%纯度)。MS ESI m/z C14H17N2O6[M+H]+:计算值309.10,实测值309.30。
实施例85.(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双(((S)-2-(羟甲基)-4-亚甲基吡咯烷酮-1-基)甲酮)的合成
在丁酮(10mL)中加入(S)-(4-羟基-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮(0.801g,2.60mmol)和Cs2CO3(2.50g,7.67mmol),然后加入1,5-二碘戊烷(415mmol,1.28mmol)。将混合物搅拌26小时,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:15至1:5)洗脱,得到标题化合物(0.675g,77%收率,95%纯度)。MS ESI m/zC33H41N4O12[M+H]+:计算值685.26,实测值685.60。
实施例86.(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基))双(((S)-2-(羟甲基)-4-亚甲基吡咯烷-1-基)甲酮)的合成
向(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双(((S)-2-(羟甲基)-4-亚甲基吡咯烷酮-1-基)甲酮(0.670g,0.98mmol)的甲醇(10mL)溶液中加入Na2S2O4(1.01g,5.80mmol)的水(8mL)溶液。将混合物在室温搅拌30小时。将反应混合物蒸发,并在高真空下与DMA(2×10mL)和乙醇(2×10mL)共蒸发至干,得到含有无机盐的标题化合物(总重量1.63g),将其直接用于下一步反应,无需进一步分离,EIMS m/z 647.32([M+Na]+)。
实施例87.C-1(具有双连接子的PBD二聚体类似物)的合成
在0℃下,向含有吡啶(0.100mL,1.24mmol)和(3S,6S,39S,42S)-二叔丁基6,39-双(4-(((叔丁氧羰基)氨基)丁基)-22,23-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3,42-双((4-(羟甲基)苯基)氨基甲酰基)-5,8,21,24,37,40-六氧代-11,14,17,28,31,34-六氧杂-4,7,20,25,38,41-六氮杂四十四烷-1,44-二酯(0.840g,0.488mmol)的四氢呋喃(8mL)溶液中滴加三光气(0.290mg,0.977mmol)的四氢呋喃(3.0mL)溶液。将反应混合物在0℃下搅拌15分钟,然后直接用于下一步。
在0℃下,向含有无机盐的(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基))双(((S)-2-(羟甲基)-4-亚甲基吡咯烷酮-1-基)甲酮)(0.842mg,0.49mmol)的乙醇(10mL)悬浮液中加入上述四氢呋喃溶液。在0℃下,将混合物搅拌4小时,然后升温至室温1小时,浓缩,并通过反相HPLC纯化(250mm×10mm,C18柱,10-80%乙腈/水,40min,v=8mL/min)得到标题化合物(561.1mg,三步产率48%)。ESI MS m/z:C117H163N16O38[M+H]+:计算值2400.12,实测值2400.90。
实施例88.C-2(具有双连接子的PBD二聚体类似物)的合成
在0℃下,将Dess-Martin高碘烷(138.0mg,0.329mmol)加入到化合物C-1(132.0mg,0.055mmol)的二氯甲烷(5.0mL)溶液中。将反应混合物升温至室温,并搅拌2小时。然后加入NaHCO3/Na2SO3饱和溶液(5.0mL/5.0mL),并将混合物用二氯甲烷(3×25mL)萃取。合并的有机层用NaHCO3/Na2SO3(5.0mL/5.0mL),盐水(10mL)洗涤,经硫酸钠干燥,过滤,浓缩,并通过反相HPLC(250mm×10mm)纯化,C18柱,10-80%乙腈/水,40min,v=8mL/min)得到泡沫状的标题化合物(103.1mg,产率78%)。ESI MS m/z:C117H158N16O38[M+H]+:计算值2396.09,实测值2396.65。
实施例89.C-3(含有有双连接子的PBD二聚体类似物)的合成
在4℃下,将C-2化合物(55.0mg,0.023mmol)溶解在二氯甲烷(3mL)中,加入TFA(3mL)。然后将反应混合物在室温搅拌1h,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-3(48.0mg,100%收率,HPLC纯度为92%),将其进一步通过反相HPLC纯化(250mm×20mm,C18柱,5-60%乙腈/水,40min,v=8mL/min),得到泡沫状纯品C-3(42.1mg,产率88%,纯度96%)。ESI MS m/z C99H126N16O34[M+H]+:计算值2083.86,实测值2084.35。
实施例90.C-4(含有双连接子的PBD二聚体类似物)的合成
将C-3化合物(35.0mg,0.017mmol)溶解在四氢呋喃(3mL)和0.1M NaH2PO4(3mL),pH 7.5的混合溶液中,然后在2小时内分4批加入2,5,8,11,14,17,20,23-八氧杂二十六-26-酸N-琥珀酰亚胺基酯(43.0mg,0.084mmol)。然后将反应混合物在室温继续搅拌4小时,并与DMF(10mL)共同蒸发至干,得到粗产物C-4,将其通过反相HPLC进一步纯化(250mm×20mm,C18色谱柱,20-60%乙腈/水,40min,v=8mL/min洗脱),得到泡沫状纯品C-4(39.4mg,收率81%,纯度96%)。ESI MS m/z:C135H195N16O52[M+H]+:计算值2872.30,实测值2871.65。
实施例91.C-5(含有双连接子的PBD二聚体类似物)的合成
向C-4化合物(35.0mg,0.012mmol)和2,5,8,11,14,17,20,23-八氧杂二十五烷25-胺(15.1mg,0.0394mmol)的无水DMA(2mL)溶液中加入EDC(30.0mg,0.156mmol)。将反应混合物在室温搅拌14h,浓缩,通过反相HPLC纯化(250mm×20mm,C18柱,20-60%乙腈/水)40min,v=8mL/分钟)得到泡沫状纯品C-5(31.2mg,77%产率,HPLC纯度97%)。ESI MS m/z:C161H249N18O62[M+H]+:计算值3426.68,实测值3427.21。
实施例92.(S)1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯的合成
将催化量的DMF(30μL)加入到4-(苄氧基)-5-甲氧基-2-硝基苯甲酸(2.70g,8.91mmol)和草酰氯(2.0mL,22.50mmol)的无水二氯甲烷(70mL)溶液中,所得的混合物在室温搅拌2h。用旋转蒸发仪除去过量的二氯甲烷和草酰氯。在0℃,N2气氛下,将乙酰氯重悬于二氯甲烷(70mL)中,并缓慢加入预制的(S)-4-亚甲基吡咯烷-2-甲酸甲酯(1.58g,8.91mmol)和三乙胺(6mL)的二氯甲烷混合溶液中。使反应混合物升温至室温,继续搅拌8小时。除去二氯甲烷和三乙胺后,将残余物在水和乙酸乙酯(70/70mL)之间分层。将水层进一步用乙酸乙酯(2×60mL)萃取。合并的有机层用盐水(40mL)洗,干燥(MgSO 4),并浓缩。用快速柱色谱(2:8正己烷/乙酸乙酯)纯化残余物,得到标题化合物(2.88g,76%产率)。EI MSm/z 449.1([M+Na]+)。
实施例93.(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛的合成
在-78℃,N2气氛下,在剧烈搅拌下向(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯(2.80g,6.57mmol)的无水二氯甲烷(60mL)中滴加DIBAL-H(1N的二氯甲烷溶液,10mL)。将混合物再搅拌90分钟后,加入2mL甲醇淬灭过量的试剂被,之后再加入5%盐酸(10mL)。使所得混合物升温至0℃。分离各层,并将水层进一步用二氯甲烷(3×50mL)萃取。合并的有机层用盐水洗涤,干燥(MgSO4)并浓缩。用快速柱色谱(硅胶,95:5三氯甲烷/甲醇)纯化残余物,得到标题化合物(2.19g,84%收率)。EIMS m/z419.1([M+Na]+)。
在室温下,将(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛(2.18g,5.50mmol)和Na2S2O4(8.0g,45.97mmol)的混合物在四氢呋喃(60mL)和水(40mL)中搅拌20小时。在高真空下除去溶剂,将残余物重新悬浮于甲醇(60mL)中,并逐滴加入盐酸(6M)直至达到pH2。将得到的混合物在室温搅拌1小时,除去大部分甲醇,然后用乙酸乙酯(100mL)稀释。乙酸乙酯溶液用饱和NaHCO3,盐水洗,干燥(MgSO4)并浓缩。用快速柱色谱法(97:3三氯甲烷/甲醇)纯化残余物,得到标题化合物(1.52g,80%)。EIMS m/z 372.1([M+Na]+)。
在0℃下,向(S)-8-(苄氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂5(11aH)-酮(1.50g,4.32mmol)的二氯甲烷(70mL)溶液中加入CH3SO3H(25mL)。将混合物在0℃下搅拌10分钟,然后在室温下搅拌2小时,用二氯甲烷稀释,用冷的1.0N NaHCO3调节pH至4,并过滤。用二氯甲烷(3×60mL)萃取水层。合并有机层,经硫酸钠干燥,过滤,蒸发,并在硅胶柱(甲醇/二氯甲烷1:15)上纯化,得到811mg(73%收率)的标题产物。EIMS m/z 281.1([M+Na]+)。
向搅拌的Cs2CO3(0.761g,2.33mmol)的丁酮(8mL)中的悬浮溶液中加入(S)-8-羟基-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂-5(11aH)-酮(401mg,1.55mmol)和1,5-二碘戊烷(240mg,0.740mmol)。将混合物在室温搅拌过夜,浓缩,并在硅胶色谱上纯化(乙酸乙酯/二氯甲烷1∶10),得到337mg(78%收率)的标题产物。EIMS m/z607.2([M+Na]+)。
实施例97.(S)-7-甲氧基-8-((5-((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮和(11aS,11a'S)-8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基)-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(10H)-酮)
在0℃下,将(11aS,11a'S)-8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮卓-5(11aH)-酮)(150mg,0.256mmol)的无水二氯甲烷(1mL)和无水乙醇(1.5mL)的溶液中加入硼氢化钠的甲氧乙基醚溶液(85μl,0.5M,0.042mmol)。5分钟后除去冰浴,并将混合物在室温搅拌3小时,然后冷却至0℃,用饱和氯化铵淬灭,用二氯甲烷稀释,并分离两相。有机层用盐水洗涤,用无水硫酸钠干燥,通过硅藻土过滤并浓缩。残余物通过反相HPLC(C18柱,乙腈/水)纯化。相应的组分用二氯甲烷萃取并浓缩,得到半还原化合物,(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(64.7mg,43%),MS m/z 609.2([M+Na]+),625.3([M+K]+)和627.2([M+Na+H2O]+);完全还原的化合物(11aS,11a'S)-8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(10H)-酮)MS m/z 611.2([M+Na]+),627.2([M+K]+),629.2([M+Na+H2O]+);未反应的原料也被回收(10.2mg,7%),MS m/z 607.2([M+Na]+),625.2([M+Na+H2O]+)。
实施例98.(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5-5(11aH)-酮
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧)戊基)氧)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(40.5mg,0.134mmol)的二氯甲烷(5毫升)混合物中加入EDC(100.5mg,0.520mmol)。将混合物在室温搅拌过夜,浓缩并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷,1:6),得到63.1mg(81%收率)标题产物。ESI MS m/zC40H50N7O9[M+H]+:计算值772.36,实测值772.30。
实施例99.(S)-8-((5-(((S)-10-(3-(2-(2-氨基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5-5(11aH)-酮
将(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙基))-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5-5(11aH)-酮(60mg,0.078mmol),四氢呋喃(5mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入PPh3(70mg,0.267mmol)。将混合物在室温搅拌过夜,浓缩并在C18制备HPLC上纯化,用水/CH3CN(在35分钟内从90%的水到35%的水)洗脱,在高真空下干燥后得到45.1mg(79%的收率)标题产物。ESI MS m/z C40H52N5O9[M+H]+:计算值746.37,实测值746.50。
实施例100.(S)-N-(2-((S)-8-((5-((((11S,11aS)-10-((S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氮杂-3,6-二氮杂十五烷-1-基)-11-羟基-7-甲氧基-2-甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)-氧基)-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-3-甲基丁酰胺
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧)戊基)氧)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸(90.2mg,0.25mmol)的DMA(8mL)溶液中的加入BrOP(240.2mg,0.618mmol)。将混合物在60℃搅拌过夜,浓缩,并在硅胶柱色谱上纯化(甲醇/二氯甲烷,1:10至1:5),得到97.1mg(74%收率)标题产物。ESIMS m/z C61H87N14O17[M+H]+:计算值1287.63,实测值1287.95。
实施例101.(S)-N-(2-((S)-8-((5-((((11S,11aS)-10-((S)-15-氨基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-基)-11-羟基-7-甲氧基-2-甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]-吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-2-(3-(2-(2-氨基乙氧基)乙氧基)-丙酰胺基)-3-甲基丁酰胺(C-6)
向(S)-N-(2-((S)-8-((5-((((11S,11aS)-10-((S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酰基)-11-羟基-7-甲氧基-2-亚甲基-5-氧-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)戊基)-氧基)-7-甲氧基-2-亚甲基-5-氧-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧乙基)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-3-甲基丁酰胺(85mg,0.066mmol)的四氢呋喃(5mL)溶液中加入PPh3(100mg,0.381mmol)。将混合物搅拌2小时,然后加入NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL),并将混合物搅拌10分钟。经LC-MS确认形成(S)-N-(2-((S)-8-((5-((((11S,11aS)-10--10-((S)-15-氨基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-基)-11-羟基-7-甲氧基-2--2-甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-2-(3-(2-(2-氨基乙氧基)乙氧基)丙酰胺基)-3-甲基丁酰胺(ESI MS m/z C61H90N10O17[M+Na]+:计算值1257.66,实测值1257.90),然后加入双(2,5-二氧杂吡咯烷-1-基)2,3-双(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)琥珀酸酯(33mg,0.066mmol)。继续搅拌4小时,浓缩并在C18制备型HPLC上纯化,用水/乙腈(35分钟,从90%水至30%水)洗脱,在高真空下浓缩干燥后得到40.1mg(40%收率)的标题产物。ESI MS m/zC73H95N12O23[M+H]+:计算值1507.66,实测值1507.90。
实施例102. 4,4'-(戊烷-1,5-二基双(氧基))双(3-甲氧基苯甲酸)的合成
在4小时内,避光(铝箔包裹),在65℃下将二碘丙烷(19.0g,58.6mmol)的四氢呋喃(75mL)溶液,滴加到剧烈搅拌的香草酸(20.0g,119mmol)的四氢呋喃(150mL)和NaOH(340毫升)溶液中。在暗处加热回流48小时后,将溶液冷却,并通过真空浓缩除去四氢呋喃,残余物用EA萃取。分离水层,并用浓盐酸酸化至pH 2。过滤收集所得沉淀物,洗涤,干燥并用冰醋酸重结晶,得到相应的双羧酸(14.0g,34.7mmol),白色固体,产率(60%)。
实施例103. 4,4'-(戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基苯甲酸)的合成
在室温下,向将4,4'-(戊烷-1,5-二烷基双(氧基))双(3-甲氧基苯甲酸)(18.0g,66.8mmol)的乙酸悬浮液(80mL,1800mmol)中滴加HNO 3(80mL,1778mmol)。搅拌2小时后,将混合物倒入100g冰中,并用乙酸乙酯(2×200mL)萃取,分离有机层,用水(2×100mL)洗涤,然后加入4N NaOH(400mL)。用乙酸乙酯(2×100mL)萃取后,分离碱性水层,并用浓盐酸酸化至pH 2。用乙酸乙酯(2×250mL)萃取混合物。合并的有机萃取物用盐水洗涤,干燥,过滤并浓缩。残余物通过快速色谱法纯化(二氯甲烷/甲醇=4/1),得到4,4'-(戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基苯甲酸)(6.1g,12.3mmol)浅黄色固体,产率18%,TLC Rf 0.3(二氯甲烷/甲醇=3/1)。
实施例104.(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双((((S)-2-(羟甲基)吡咯烷基-1-基)甲酮)
在室温下,向4,4'-(戊烷-1,5-二烷基双(氧基))双(5-甲氧基-2-硝基苯甲酸)(5.0g,10.0mmol)和L-(+)-脯氨醇(2.25g,22.3mmol))的DMF溶液(100mL)中加入TEA(4.0g)。在搅拌10分钟后,加入HATU(10.77g,28.3mmol)。将混合物在室温搅拌过夜。反应完成后,将混合物用水(100mL)稀释,并用乙酸乙酯(2×100mL)和二氯甲烷(2×50mL)萃取,将合并的有机萃取液用盐水洗涤,干燥,过滤并浓缩。残余物通过色谱法纯化(二氯甲烷/甲醇=15/1),得到(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双(((S)-2-(羟甲基)吡咯烷-1-基)甲酮)(6.0g,9.1mmol),为白色泡沫,收率为91%。
实施例105.(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基))双((((S)-2-(羟甲基)吡咯烷基-1-基)甲酮)
向(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))-双((((S)-2-(羟甲基)(吡咯烷-1-基)甲酮)(6.0g,9.1mmol)的甲醇(100mL)溶液中加入10%Pd/C(2.4g),将混合物在氢气下于室温搅拌过夜。搅拌14小时后,通过过滤除去Pd/C,并用甲醇洗涤。将滤液浓缩并将残余物通过色谱法纯化(二氯甲烷/甲醇=10/1),得到(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4),1-亚苯基))双((((S)-2-(羟甲基)吡咯烷-1-基)甲酮)(3.54g,5.9mmol),为白色泡沫,收率65%。
实施例106.双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基)((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(羟甲基)吡咯烷-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯
在5℃下,向烯丙基((S)-1-(((S)-1-((4-(羟甲基)苯基)氨基)-1-氧丙烷-2-基)氨基)-3-甲基-1-氧代丁基-2-基)氨基甲酸酯(8.0g,21.3mmol)的无水四氢呋喃(300mL)溶液中加入DIPEA(5.5g,40.3mmol)和三光气(3.2g,10.8mmol)的干燥四氢呋喃(50mL)溶液。搅拌15分钟后,将溶液重新冷却至5℃,加入(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基)(((S)-2-(羟甲基)-吡咯烷-1-基)甲酮)(3.2g,5.3mmol)和DIPEA(2.75g,21.6mmol)的无水四氢呋喃(150mL)溶液。使所得溶液升温至室温,并搅拌过夜。通过真空浓缩除去四氢呋喃。残余物通过柱色谱法纯化(二氯甲烷/甲醇=20/1),得到双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)-苄基)((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(羟甲基)吡咯烷-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯(7.0g,4.97mmol),为黄色泡沫,产率为94%。
实施例107.(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)-氨基)-3-甲基丁亚氨基)丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸盐)的合成
在室温下氮气中,向双(4-((S)-2-((S)-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基)((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(羟基甲基)吡咯烷-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯(300mg,0.21mmol)的无水二氯甲烷(15mL)溶液中加入DMP(280mg,0.66mmol)。转化完成后,向反应溶液中加入Na2SO3水溶液,然后加入NaHCO3水溶液,将混合物再搅拌15分钟,并用二氯甲烷(3×20mL)萃取。合并的有机萃取物用盐水洗涤,干燥,过滤并浓缩。残余物通过柱色谱法纯化(二氯甲烷/甲醇=20/1),得到(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3甲基丁酰胺基)丙酰胺基)8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(270mg,0.19mmol),为灰白色泡沫,产率为92%。
实施例108.(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)-氨基)-3-甲基丁酰胺基)丙酰胺基)苄基8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂卓-10(5H)-羧酸酯)的合成
向(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基的溶液中8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂卓10(5H)-羧酸酯(774mg,0.55mmol)和吡咯烷(196mg,2.76mmol)的无水二氯甲烷(8mL)溶液中加入Pd(PPh3)4(76mg,0.066mmol)。将反应体系用氩气置换并在室温下搅拌2h,然后将反应物用二氯甲烷稀释,并依次用饱和NH4Cl水溶液和盐水洗涤。有机相经硫酸钠干燥,过滤并浓缩。残余物通过柱色谱法纯化(二氯甲烷/甲醇=6/1),得到(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]-吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)(420mg,0.34mmol),为灰白色固体,产率62%。
实施例109.(S)-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酸的合成
将氯甲酸烯丙酯(24.8g,205mmol)逐滴加入到搅拌的L-缬氨酸(20g,171mmol)和K2CO3(35.4g,257mmol)的水(250mL)和四氢呋喃(250mL)溶液中。将反应混合物在室温搅拌过夜,然后将溶剂减压浓缩并将剩余的溶液用乙醚(100mL)萃取。用浓盐酸将水相酸化至pH2,并用二氯甲烷(3×200mL)萃取。合并的有机相用盐水洗涤,经硫酸钠干燥,过滤并浓缩,得到产物(35g,174mmol),为白色固体,收率100%。
实施例110.(S)-2,5-二氧杂吡咯烷-1-基-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酸酯的合成
在室温下,向(S)-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酸(35g,174mmol)的无水二氯甲烷(500mL)溶液中加入EDC(66.9g,348mmol)和N-羟基琥珀酰亚胺(30g,261mmol)。搅拌14小时后,将反应物用二氯甲烷稀释,并用水和盐水洗涤。有机相经硫酸钠干燥,过滤并浓缩,得到产物(54.5g,产率100%),为粘性无色油,Rf=0.5(石油醚/乙酸乙酯=2/1)。其无需进一步纯化即可用于下一步。
实施例111.(S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)-丙酸的合成
在室温下,向H-Ala-OH(15.7g,176mmol)和NaHCO3(15.5g,185mmol)的四氢呋喃(200mL)和水(200mL)溶液中加入(S)-2,5-二氧代吡咯烷-1--1-基-2-((((烯丙氧基)-羰基)氨基)-3-甲基丁酸酯(50g,168mmol)的四氢呋喃(100mL)溶液。搅拌72小时后,减压蒸馏除去四氢呋喃。用柠檬酸将残余物酸化至pH 3,并用乙酸乙酯(3×350mL)萃取,将合并的萃取物用盐水洗涤,干燥,过滤并浓缩,得到白色固体。用乙醚(过量)打浆,得到纯的产物,为白色粉末(25.2g,93mmol,55%)。
实施例112.烯丙基((S)-1-(((S)-1-((4-(羟甲基)苯基)氨基)-1-氧丙烷-2-基)氨基)-3-甲基-1-氧丁烷-2-基)氨基甲酸酯的合成
在室温下,向(S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺)-丙酸(25.2g,92.6mmol)和对氨基苄醇(12.0g,将97.6mmol)的四氢呋喃(300mL)溶液中加入EEDQ(24.0g,97.2mmol)。搅拌18小时后,减压蒸馏除去溶剂,得到淡褐色固体。将该固体用乙醚打浆,过滤,用过量的乙醚洗涤,得到白色固体产物(40g,106mmol,100%)。
实施例113. 4-(((苄氧基)羰基)氨基)丁酸的合成
在5℃下,将Na2CO3(41.1g,387mmol)加入到4-氨基丁酸(20g,193mmol)的水(300mL)溶液中。搅拌10分钟后,滴加CbzCl(33.2mL,232mmol)的四氢呋喃(100mL)溶液。使反应升温至室温,并搅拌过夜。转化完成后,将混合物用H2O(100mL)稀释并用乙酸乙酯(2×100mL)萃取。用浓盐酸将水层酸化至pH 2。盐酸并用乙酸乙酯(3x100mL)萃取。合并的有机物用盐水洗涤,经硫酸钠干燥,过滤并浓缩,得到白色固体。用石油醚(过量)打浆,得到白色粉末状的纯净产物(31.6g,70%)。
实施例114.4-((((苄氧基)羰基)氨基)丁酸叔丁酯的合成.
在0℃下,向4-((((苄氧基)羰基)氨基)丁酸(5.9g,24.9mmol)和叔丁醇(14.7g,199mmol)的干燥的二氯甲烷(250mL)溶液中加入4-DMAP(0.61g,5mmol)和DIC(4.7g,37.3mmol)。搅拌16小时后,将反应物过滤并用二氯甲烷(2×200mL)萃取。合并的有机萃取物用1N盐酸和盐水洗涤,经硫酸钠干燥,过滤并浓缩。残余物通过柱色谱法纯化(100%二氯甲烷),得到4-((((苄氧基)羰基)氨基)丁酸叔丁酯(4.26g,14.5mmol,58%),为粘性无色油状物。
实施例115. 4-氨基丁酸叔丁酯的合成
向4-((((苄氧基)羰基)氨基)丁酸叔丁酯(1.69g,5.77mmol)的甲醇(40mL)溶液中加入10%Pd/C(400mg),将混合物于室温在氢气下搅拌下过夜。搅拌14小时后,过滤除去Pd/C,并用甲醇洗涤。浓缩滤液,得到产物(897mg,5.64mmol,收率98%),为无色液体。其无需进一步纯化即可用于下一步。
实施例116.(2R,3S)-2,3-双(苄氨基)琥珀酸的合成
向内消旋的2,3-二溴丁二酸(50g,181mmol)的乙醇(400mL)溶液中滴加苄胺(150mL)。加入完成后,将混合物加热至90℃并搅拌过夜。将混合物冷却至室温并用水稀释。加入6N盐酸直至pH为4,得到白色沉淀。过滤沉淀物,用水洗涤并干燥,得到(2R,3S)-2,3-双(苄基氨基)琥珀酸(50g,152mmol,84%)。
实施例117.(2R,3S)-2,3-二氨基琥珀酸的合成
向(2R,3S)-2,3-双(苄氨基)琥珀酸(18g,55mmol)的乙酸(100mL)和盐酸(100mL)溶液中加入10%Pd/C(3g),将混合物在氢气下于50℃搅拌过夜。搅拌48小时后,通过过滤除去Pd/C,并用水洗涤。将滤液浓缩并将残余物溶解在1N NaOH(200mL)中。加入乙酸直至pH为5,得到白色沉淀。过滤沉淀物,用水洗涤并干燥,得到(2R,3S)-2,3-二氨基琥珀酸(8.7g,58.8g,100%)。
实施例118. 2,3-双(((苄氧基)羰基)氨基)琥珀酸的合成
在0℃下,向(2R,3S)-2,3-二氨基琥珀酸(31.74g,214mmol)的四氢呋喃(220mL)和4N NaOH(214mL)溶液中滴加CbzCl(61mL,428mmol)。滴加完成后,将混合物升温至室温并搅拌2h。将反应物用水(1600mL)稀释,并用乙酸乙酯(2×1600mL)萃取。分离水层,并用浓盐酸酸化直至达到pH 2。将所得溶液搅拌1小时并在5℃下静置以产生白色沉淀。过滤沉淀物,用水洗涤并干燥,得到2,3-双(((苄氧基)羰基)氨基)琥珀酸(52.2g,125mmol,59%)。
实施例119.二苄基(3R,4S)-2,5-二氧代四氢呋喃-3,4-二基)二氨基甲酸酯的合成
将2,3-双(((苄氧基)羰基)氨基)琥珀酸(5.0g,12mmol)的乙酸酐(37.5mL)的溶液回流20分钟,冷却并浓缩,得到酸酐。将该非对映异构混合物与氯仿(37mL)与搅拌,过滤不溶的内消旋异构体,并用石油醚洗涤,得到二苄基((3R,4S)-2,5-二氧代四氢呋喃-3,4-二基)二氨基甲酸酯的晶体(2.0g,5mmol,42%)。
实施例120. 4,4'-((((2R,3S)-2,3-双((((苄氧基)羰基)-氨基)琥珀酰基)双(氮杂二基))二丁酸二叔丁基酯的合成
在0℃下,向二苄基(((3R,4S)-2,5-二氧代四氢呋喃-3,4-二基)二氨基甲酸酯)(2.03g,5.1mmol)和4-氨基丁酸叔丁酯(1.79g,11.3mmol)的DMF(45mL)溶液中加入DIPEA(1.98g,15.3mmol)。搅拌5分钟后,加入HATU(4.66g,12.3mmol)。使混合物升温至室温,并搅拌2小时。转化完成后,将混合物用水(90mL)稀释,并用乙酸乙酯(2×200mL)和二氯甲烷(2×90mL)萃取,将合并的有机萃取物用盐水洗涤并经硫酸钠干燥,过滤,减压除去大部分溶剂,沉淀出白色固体,将其收集并干燥,得到二叔丁基4,4'-((((2R,3S)-2,3-双(((苄氧基)羰基)氨基)琥珀酰基)双(氮杂二基))二丁酸酯(2.8g,4.0mmol,产率80%),为白色固体。
实施例121. 4,4'-((((2R,3S)-2,3-二氨基琥珀酰基)双-(氮杂二基))二叔丁酯的合成
向4,4'-((((2R,3S)-2,3-双((((苄氧基)羰基)氨基)琥珀酰基)双-(氮杂二基))二丁酸酯(2.8g,4.0mmol)的甲醇(100mL)溶液中加入10%Pd/C(1.1g),将混合物在氢气下室温搅拌过夜。搅拌18小时后,通过过滤除去Pd/C,并用甲醇洗涤。浓缩滤液,得到产物,为无色液体,其无需进一步纯化即可用于下一步骤(940mg,2.2mmol,收率55%)。
实施例122. 4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)琥珀酰基)双(氮杂二基)二叔丁酯的合成
在0℃下,向4,4'-((((2R,3S)-2,3-二氨基琥珀酸)双(氮杂二基))-二叔丁酯(940mg,2.19mmol)和4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁酸(840mg,4.59mmol)的DMF(25mL)溶液中加入DIPEA(1.13g,8.76mmol)。搅拌5分钟后,加入HATU(1.74g,4.58mmol)。使混合物升温至室温,并搅拌1小时。反应完成后,将混合物用水(50mL)稀释,并用乙酸乙酯(2×100mL)和二氯甲烷(2×50mL)萃取,将合并的有机萃取物用盐水洗涤并用硫酸钠干燥。减压除去大部分溶剂,沉淀出白色固体,将其收集并干燥,得到4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁酰胺基)琥珀酰基)双-(氮杂二基))二叔丁酯(1.36g,1.79mmol)的白色固体,产率为82%。
实施例123. 4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)琥珀酰)氮杂二基))二丁酸的合成
在室温(0℃)下,向4,4'-(((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁酰胺基)琥珀酰基)双(氮杂二烷基))二丁酸酯(1.36g,1.79mmol)的二氯甲烷(15mL)溶液中加入TFA(30mL)。搅拌18小时后,将反应浓缩,并将残余物溶解在无水甲苯中。通过真空浓缩除去溶剂,得到白色固体(1.3mg,2.0mmol,产率100%),其无需进一步纯化即可用于下一步骤。
实施例124.PBD产品C-7的合成
在0℃时,向(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-((((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基8,8'-(戊烷-1,5-二基双(氧基))双(11-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂卓-10(5H)-羧酸酯)(215mg,0.17mmol)和4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧杂-2,5-二氢-1H-吡咯-1-基)丁胺)琥珀基)双(氮杂二基)二丁酸(115mg,0.18mmol)的DMF(18mL)溶液中加入DIPEA(90mg,0.70mmol)。搅拌5分钟后,加入HATU(132mg,0.35mmol)。使混合物升温至室温,并搅拌过夜。反应完成后,将混合物用水(2mL)稀释,并用乙酸乙酯(2×40mL)和二氯甲烷(2×20mL)萃取,将合并的有机萃取液用盐水洗涤,干燥,过滤并浓缩。残余物通过HPLC法纯化,得到PBD产物C-6(10mg),为白色粉末。
实施例125. 4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)琥珀酰基)双(氮杂二基))二丁酸酯
在0℃下,向4,4'-((((2R,3S)-2,3-二氨基琥珀酸)双(氮杂二基))-二叔丁酯(900mg,2.09mmol)和3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酸(840mg,4.97mmol)的DMF(25mL)溶液中加入DIPEA(0.93g,7.21mmol)。搅拌5分钟后,加入EDC(1.74g,9.06mmol)。使混合物升温至室温,并搅拌1小时。反应完成后,将混合物用水(50mL)稀释,并用乙酸乙酯(2×100mL)和二氯甲烷(2×50mL)萃取,将合并的有机萃取物用盐水洗涤并用硫酸钠干燥。减压除去大部分溶剂,将白色固体收集并干燥,得到4,4'-((((2R,3S)-2,3-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)琥珀酰基)双-(氮杂二基))二丁酸酯(1.27g,1.79mmol),产率83%。ESI MS m/z C34H49N6O12:计算值733.33[M+H]+,实测值733.55。
实施例126. 4,4'-((((2R,3S)-2,3-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺)琥珀酰基)双(氮杂二基))二丁酸
在4℃下,向4,4'-((((2R,3S)-2,3-双(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺)琥珀酰)双(氮杂二基))二丁酸二叔丁基酯(502.0mg,0.685mmol)的1,4-二氧六环(8mL)溶液中加入浓盐酸(3毫升)。然后将混合物在室温搅拌30分钟,用1,4-二氧六环(8mL)稀释,浓缩,与二氧六环/甲苯(1:1,2×10mL)共蒸发至干,并用乙醇/正己烷结晶,得到标题化合物(289.0g,68%产率)。ESI MS m/z C26H33N6O12:计算值621.21[M+H]+,实测值621.55。
实施例127.烯丙基((S)-3-甲基-1-(((S)-1-((4-((((4-硝基苯氧基)羰基)-氧)甲基)苯基)氨基)-1-氧丙烷-2-基)氨基)-1-氧丁烷-2-基)氨基甲酸酯
向烯丙基((S)-1-((((S)-1-((4-(羟甲基)苯基)氨基)-1-氧杂丙烷-2-基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸酯(2.21g,5.86mmol),干燥的吡啶(5mL)和二氯甲烷(20mL)的混合物中加入4-硝基苯基碳酰氯(1.82g,9.05mmol)。将混合物在室温搅拌8小时,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:12)洗脱,得到标题化合物(2.63g,83%产率)。MS ESI m/z C26H31N4O9[M+H]+:计算值543.21,实测值543.60。
实施例128.(11aS,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基)双(7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯
向(11aS,11a'S)-8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-5(10H)-酮)(288.2mg,0.490mmol)的干燥的乙腈(5mL)溶液中加入烯丙基((S)-3-甲基-1-(((S)-1-(((4-(((((4-硝基苯氧基)羰基)氧基)-甲基)苯基)氨基)-1-氧杂丙烷-2-基)氨基)-1-氧代丁烷-2-基)氨基甲酸酯(770.2mg,1.420mmol)和DIPEA(2mL)。将混合物在45℃下搅拌8h,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:8)洗脱,得到标题化合物(492.0mg,72%产率)。MS ESI m/zC73H91N10O18[M+H]+:计算值1395.64,实测值1395.95。
实施例129.(11aS,11a'S)-双(4-((S)-2-((S)-2-氨基-3-甲基丁亚氨基)-丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)的合成
向(11aS,11a'S)-双(4-((S)-2-((S)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基))双(7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂10(5H)-羧酸酯)(274.2mg,0.197mmol)和吡咯烷(49mg,6.90mmol)的无水二氯甲烷(5mL)溶液中加入Pd(PPh3)4(152.0mg,0.132mmol)。将反应体系用氩气置换并在室温下搅拌2h,然后将反应物用二氯甲烷稀释,并依次用饱和NH4Cl水溶液和盐水洗涤。有机相经硫酸钠干燥,过滤并浓缩。残余物通过柱色谱法纯化(二氯甲烷/甲醇/Et3N=6/1/0.02),得到标题化合物(166.7mg,69%产率),为灰白色固体。MS ESI m/z C65H83N10O14[M+H]+:计算值1227.60,实测值1227.9。
实施例130.PBD产品C-8的合成
向(11aS,11a'S)-双(4-((S)-2-((S)-2-氨基-3-甲基丁亚氨基)-丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基)))双(7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)(151.1mg,0.123mmol)和4,4'-((((2R,3S)-2,3-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)琥珀酰基)双-(氮杂二基))二丁酸(77.1mg,0.124mmol)的DMA(5mL)溶液中加入EDC(95.2mg,0.496mmol)。将混合物在室温下搅拌8小时,浓缩并在HPLC C18 3μm色谱柱(25×4cm)上纯化,使用(A)乙腈和(B)水/0.1%甲酸的混合物进行梯度洗脱(梯度:15%A/85%B至25%A/75%B,5分钟,至35%A/65%B,15分钟,60%A/40%B至50%A/50%B,15分钟,至15%A/85%B,5分钟),流速为8mL/min。将含有标题化合物的组分合并,蒸发,并在干燥器中用P2O5干燥,得到C-8PBD化合物(149.2mg,67%产率)。MS ESI m/z C91H111N16O24[M+H]+:计算值1811.79,实测值1812.35。
实施例131.(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟乙基)吡咯烷-1-基)甲酮的合成
向4-(苄氧基)-5-甲氧基-2-硝基苯甲酸(10.20g,33.65mmol)和(S)-吡咯烷-2-基甲醇(3.85g,38.09mmol)的无水DMF(150mL)溶液中加入EDC(19.50g,101.56mmol)。将混合物在室温搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶4)洗脱,得到标题化合物(11.56g,89%产率)。MS ESI m/z C20H23N2O6[M+H]+:计算值387.15,实测值387.65。
实施例132.(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)吡咯烷-2-甲醛的合成
在室温下氮气中,向(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟甲基)-吡咯烷-1-基)甲酮(3.80g,9.84mmol)的无水二氯甲烷(15mL)溶液加入Dess-Martin高碘烷(DMP)(5.80g,13.67mmol)。反应完成后,向反应溶液中加入Na2SO3水溶液,然后加入NaHCO3水溶液,将混合物再搅拌15分钟,并用二氯甲烷(3×20mL)萃取。合并的有机萃取物用盐水洗涤,干燥,过滤并浓缩。残余物通过硅胶色谱法纯化(二氯甲烷/乙酸乙酯=4/1),得到标题化合物(3.13g,83%收率),为灰白色泡沫。MS ESI m/z C20H21N2O6[M+H]+:计算值385.13,实测值385.60,404.75[M+水+H]+。
将S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)吡咯烷-2-甲醛(3.00g,7.80mmol)的甲醇(75mL)溶液和Pd/C(10%Pd)50%水,250mg)在氢化反应器中振荡。抽空容器中的空气后,引入氢气(5Psi)。将反应容器振荡过夜,并通过硅藻土过滤。将滤液浓缩并通过硅胶色谱法纯化(二氯甲烷/甲醇/Et3N=4/1/0.05),得到标题化合物(1.66g,86%收率),为灰白色泡沫。MS ESI m/z C13H17N2O3[M+H]+:计算值249.12,实测值249.50。
实施例134. 4-((14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂卓-10(5H)-羧酸酯的合成
在4-8℃下,向(14S,17S)-叔丁基1-叠氮基-14-(4-((叔丁氧基羰基)氨基)丁基)-17-(((4-(羟甲基)苯基)氨基甲酰基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十九烷-19-酯(10.15g,13.50mmol)的干燥四氢呋喃(300mL)中加入DIPEA(3.15g,24.41mmol)和三光气(5.15g,17.36mmol)的干燥的四氢呋喃(50mL)溶液。搅拌15分钟后,将溶液重新冷却至4-8℃,在45分钟内,将其滴加到8-羟基-7-甲氧基-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a]][1,4]二氮杂-5(10H)-1(2.92g,11.76mmol)的四氢呋喃(100mL)混合物中。将所得溶液升温至室温,并搅拌过夜。将混合物用甲苯(50mL)稀释,真空浓缩并通过硅胶色谱纯化(二氯甲烷/甲醇=15/1),得到标题化合物(10.02g,82%产率),为黄色泡沫。MS ESI m/zC50H74N9O15[M+H]+:计算值1040.52,实测值1040.90。
实施例135.(S)-4-((14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧代-13,16-二氮杂十八烷酰胺基)苄基8-(3-碘丙氧基)-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂10(5H)-羧酸酯的合成
向4-((14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-羟基-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂卓10(5H)-羧酸酯(2.02g,1.94mmol)的丁酮(50毫升)溶液中加入Cs2CO3(2.50g,7.67mmol)和1,3-二碘丙烷(2.50g,8.45mmol)。将混合物在暗处于45℃搅拌36h,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:5)洗脱,得到标题化合物(2.08g,90%产率)MS ESI m/z C52H77IN9O15[M+H]+:计算值1194.45,实测值1194.95。
实施例136.(S)-2-((S)-1-叠氮基-14-甲基-12-氧代-3,6,9-三氧杂-13-氮杂十五烷酰胺基)-N-(4-(羟甲基)苯基)丙酰胺的合成
向(14S,17S)-1-叠氮基14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷-18-酸(3.02g,7.75mmol)和(4-氨基苯基)甲醇(1.05g,8.53mmol)的DMA溶液中加入EDC(4.90g,25.52mmol)。将混合物在室温搅拌14小时,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:8至1:3)洗脱,得到标题化合物(3.52g,92%收率)。MS ESI m/z C22H35IN6O7[M+H]+:计算值495.25,实测值495.60。
实施例137.(11R,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8(苄氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的合成
将(S)-(4-(苄氧基)-5-甲氧基-2-硝基苯基)(2-(羟甲基)-4-亚甲基-吡咯烷-1-基)甲酮(3.90g,9.80mmol)和Na2S2O4(在室温下将6.0g,34.47mmol)的四氢呋喃(60mL)和水(40mL)的混合物搅拌20h,用Na2CO3调节pH到10,浓缩,在C-18短柱上纯化,用水/甲醇/三乙胺洗脱(从99.4/0.5/0.2到50/49.8/0.2)。合并含有还原的氨基产物的组分,浓缩,用四氢呋喃(50mL)稀释,然后冷却至4-8℃。在4-8℃下,向2-(1-叠氮基-14-甲基-12-氧代-3,6,9-三氧杂-13-氮杂五烷酰胺基)-N-(4-(羟甲基)苯基)-丙酰胺(6.70g,13.56mmol)的无水四氢呋喃(150mL)溶液中加入DIPEA(3.50g,27.12mmol)和三光气(4.10g,13.80mmol)的无水四氢呋喃(150mL)的溶液。在4-8℃下搅拌15分钟后,在45分钟内将反应溶液滴加到上述氨基溶液中。将混合物升温至室温并继续搅拌2小时,浓缩,用二氯甲烷(3×30mL)萃取,经硫酸钠干燥,蒸发,并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶10至1∶5)洗脱,得到标题化合物(7.23g,两步收率83%)。MS ESI m/z:计算值C45H57IN8O12[M+H]+889.40,实测值889.90。
实施例138.(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8-(苄氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的合成
在室温下氮气中,向(11R,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基溶液8-(苄氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(3.80g,4.27mmol)的干燥二氯甲烷(40mL)溶液中加入Dess-Martin高碘烷(DMP)(2.80g,6.60mmol)。反应完成后,向反应溶液中加入Na2SO3水溶液,然后加入NaHCO3水溶液,将混合物再搅拌15分钟,并用二氯甲烷(3×20mL)萃取。将合并的有机萃取物用盐水洗涤,干燥,过滤并浓缩。残余物通过硅胶色谱法纯化(二氯甲烷/乙酸乙酯=5/1至2∶1),得到标题化合物(2.99g,79%收率),为灰白色泡沫。MS ESI m/z C44H55N8O12[M+H]+:计算值886.39,实测值886.80。
实施例139.(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8,11-二羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的合成
在0℃下,向(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基溶液8-(苄氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(2.90g,3.27mmol)的二氯甲烷(40mL)溶液中的加入CH3SO3H(15mL)。将混合物在0℃下搅拌10分钟,然后在室温下搅拌1小时,用二氯甲烷稀释,用冷的1.0N NaHCO3调节pH至4并过滤。用二氯甲烷(3×60mL)萃取水层。合并有机层,经硫酸钠干燥,过滤,蒸发并在硅胶柱色谱(甲醇/二氯甲烷1∶15至1∶5)上纯化,得到1.95g(75%收率)的标题产物。MS ESI m/zC37H48IN8O12[M+H]+:计算值797.34,实测值797.90。
实施例140.(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8-(3-(((S)-10-(((4-((14S,17S)-1-叠氮基17-(2-(叔丁氧基)-2-氧乙基)-14-(4-((叔丁氧羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基)氧)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的合成
向(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8,11-二羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(402mg,0.504mmol)和(S)-4-((14S,17S)-1-叠氮基17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-(((叔丁氧基羰基)氨基)-丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-(3-碘丙氧基)-7-甲氧基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(650mg,0.544mmol)的丁酮(50mL)溶液中加入Cs2CO3(0.50g,1.53mmol)。将混合物在暗处于45℃搅拌36小时,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1∶8至1∶3)洗脱,得到标题化合物(809mg,86%收率)。MS ESI m/z C89H124N17O27[M+H]+:计算值1862.89,实测值1863.45。
实施例141.(11S,11aS)-4-((14S,17S)-1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8(3-(((S)-10-(((4-((14S,17S)-1-氨基-17-(2-(叔丁氧基)-2-氧乙基)-14-(4-((叔丁氧羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基)氧)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的合成
在0-4℃于N2下,向(11S,11aS)-4-((14S,17S)-1-叠氮基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂十三,16-二氮杂十八烷酰胺基)苄基8-(3-(((S)-10-(((4-((14S,17S)-1-叠氮基-17-(2-(叔丁氧基)-2-氧乙基)-14-(4-((叔-丁氧羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)-苄基)氧基)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5–氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(750mg,0.402mmol)的四氢呋喃(8mL)溶液中加入Me3P(1.0M的甲苯溶液,2.0mL,2.0mmol)。搅拌5分钟后,移去冰浴,并将反应混合物在室温搅拌2小时。然后,加入水(1mL),并将混合物搅拌10分钟。将混合物用1,4-二氧六环(10mL)稀释,浓缩并与二氧六环/甲苯共蒸发至干,得到粗制氨基产物(725mg,99%收率),其无需进一步纯化即可直接用于下一步。MS ESI m/z C89H128N13O27[M+H]+:计算值1810.90,实测值1811.50。
实施例142.不对称横交联的PBD二聚体C-9的合成
向上述所得的粗氨基化合物((11S,11aS)-4-((14S,17S)-1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八烷酰胺基)苄基8-(3-(((S)-10-((((4-((14S,17S)-1-氨基-17-(2-(叔丁氧基)-2-氧代乙基)-14-(4-(((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基)氧基)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5–氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯的干燥的DMA(8mL)溶液中加入4,4'-((((2R,3S)-2,3-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基))琥珀酰基)双(氮杂二基))二丁酸(248.0mg,0.400mmol)和EDC(500.0mg,2.60mmol)。将该混合物搅拌24小时,浓缩并在C18制备型HPLC(17%C18,250mm×50mm)上纯化,用水/乙腈洗脱(从80%水至30%水,45min,9mL/min)。在高真空下浓缩,得到488.1mg(51%收率)的C-9产物。ESI MS m/zC115H156N19O37[M+H]+:计算值2395.08,实测值2395.90。
实施例143.不对称横交联的PBD二聚体C-10的合成
在0-4℃下,将C-9化合物(465.0mg,0.194mmol)溶于二氯甲烷(4mL),然后加入TFA(2mL)。然后将反应混合物在室温搅拌1h,用甲苯(5mL)稀释,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-3(48.0mg,100%收率,92%HPLC纯)。将其通过反相HPLC(250mm×20mm,C18柱,5-60%乙腈/水,40min,v=8mL/min)进一步纯化,得到泡沫状纯产品C-10(373.1mg,产率85%,纯度96%)。ESI MS m/z C106H140N19O35[M+H]+:计算值2238.97,实测值2239.50。
实施例144.不对称横交联的PBD二聚体C-11的合成
将C-10化合物(235.0mg,0.105mmol)溶于四氢呋喃(3mL)和0.1M NaH2PO4(3mL),pH7.5的混合溶液中,在2小时内分4批加入2,5,8,11 1,14,17,20,23-八氧杂二六烷-26-酸N-琥珀酰亚胺酯(43.0mg,0.084mmol)。然后将反应混合物继续在室温搅拌4小时,并与DMF(10mL)共同蒸发至干,得到粗产物C-11,将其通过反相HPLC进一步纯化(250mm×50mm,C18柱,20-60%乙腈/水,40min,v=8mL/min),得到泡沫状纯产物C-11(215.5mg,产率78%,纯度95%)。ESI MS m/z C124H174N19O44[M+H]+:计算值2633.20,实测值2633.85。
实施例145.不对称横交联的PBD二聚体C-12的合成
向C-11化合物(65.0mg,0.0246mmol)和2,5,8,11,14,17,20,23-八氧杂二十五烷25-胺(15.1mg,0.0394mmol)的无水DMA(2mL)溶液中加入EDC(30.0mg,0.156mmol)。将反应混合物在室温搅拌15h,浓缩,通过反相HPLC(250mm×30mm,C18柱,20-60%乙腈/水,40min,v=8mL/分钟)纯化,得到纯产物C-12(60.2mg,81%产率,HPLC纯度95%),为泡沫状固体。ESI MS m/z C141H209N20O51[M+H]+:计算值2998.43,实测值2999.40。
实施例146.不对称横交联的PBD二聚体C-13的合成
向粗制的氨基化合物((11S,11aS)-4-((14S,17S)-1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-(3-((((S)-10-)(((4-((14S,17S)-1-氨基-17-(2-(叔丁氧基)-2-氧乙基)-14-(4-(((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基)氧)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)(120mg,0.0662mmol)的无水四氢呋喃(10mL)溶液中,加入3,4-二溴呋喃-2,5-二酮(16.8mg,0.06611mmol)。将混合物在室温搅拌4h,然后加入EDC(50.2mg,0.261mmol),持续搅拌12小时,浓缩,通过硅胶柱纯化,用甲醇/二氯甲烷(1:12至1:6)洗脱,得到泡沫状纯产物C-13(112.2mg,83%产率)。ESI MS m/z:C93H126Br2N13O29[M+H]+:计算值2046.7073,实测值2046.8260。
实施例147.不对称横交联的PBD二聚体C-14的合成
在0-4℃下,将C-13化合物(100.2mg,0.0489mmol)溶解于二氯甲烷(4mL)中,然后加入TFA(2mL)。然后将反应混合物在室温搅拌1h,用甲苯(5mL)稀释,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-14(94.3mg,102%产率,93%HPLC纯)。将其通过反相HPLC(250mm×20mm,C18柱,5-60%乙腈/水,40min,v=8mL/min)进一步纯化,得到泡沫状纯品C-14(76.6mg,产率83%,纯度96%)。ESI MS m/z C84H109Br2N13O27[M+H]+:计算值1890.5995,实测值1890.6250,1893.6565[M+H+2]+。
实施例148.不对称横交联的PBD二聚体C-15的合成
将C-14化合物(55.0mg,0.0291mmol)溶解于四氢呋喃(3mL)和0.1M NaH2PO4(3mL)的pH 7.5的混合溶液中,然后在2小时内分4批加入2,5,8,11,14,17,20,23,26-九氧杂二十八烷28-酸N-琥珀酰亚胺酯(47.2mg,0.0875mmol)。将反应混合物在室温下继续搅拌4h,并与DMF(10mL)共同蒸发至干,得到粗产物C-15,将其通过反相HPLC进一步纯化(250mm×50mm,C18柱,20-60%乙腈/水,40min,v=8mL/min),得到泡沫状的纯品C-15(215.5mg,产率78%,纯度95%)。ESI MS m/z C103H146Br2N13O37[M+H]+:计算值2314.8309,实测值2314.8575,2316.8705[M+H+2]+,2318.1445[M+H+4]+。
实施例149.不对称横交联的PBD二聚体C-16的合成
向氨基化合物((11S,11aS)-4-((14S,17S)-1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-(3-((((S)-10-)(((4-((14S,17S)-1-氨基-17-(2-(叔丁氧基)-2-氧乙基)-14-(4-(((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基)氧)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)的粗品(120mg,0.0662mmol)的无水四氢呋喃(10mL)溶液中,加入3,4-呋喃-2,5-二酮(6.5mg,0.06611mmol)。将混合物在室温搅拌4h,然后加入EDC(50.2mg,0.261mmol)。将该混合物连续搅拌12小时,浓缩,通过硅胶柱纯化,用甲醇/二氯甲烷(1:12至1:6)洗脱,得到泡沫状纯品C-16(107.3mg,86%产率)。ESI MS m/z C93H128N13O29[M+H]+:计算值1890.8941,实测值1890.8990。
实施例150.不对称横交联的PBD二聚体C-17的合成
在0-4℃下,将C-16化合物(85.5mg,0.0452mmol)溶解于二氯甲烷(4mL)中,然后加入TFA(2mL)。然后将反应混合物在室温搅拌1h,用甲苯(5mL)稀释,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-17(81.3mg,104%收率,92%由HPLC纯化)。将其通过反相HPLC(250mm×20mm,C18柱,5-60%乙腈/水在40分钟内,v=8mL/min)进一步纯化,得到泡沫状纯产品C-17(67.4mg,产率86%,纯度96%)。ESI MS m/z C84H112N13O27[M+H]+:计算值1734.7785,实测值1734.8285。
实施例151.不对称横交联的PBD二聚体C-18的合成
将C-17化合物(53.0mg,0.0305mmol)溶于四氢呋喃(3mL)和0.1M NaH2PO4(3mL)的pH 7.5的混合溶液中,然后在2小时内分4批加入2,5,8,11,14,17,20,23,26-九氧杂二十八烷28-酸N-琥珀酰亚胺酯(47.0mg,0.0874mmol)。然后将反应混合物继续在室温搅拌4小时,并与DMF(10mL)共蒸发至干,得到粗产物C-18,将其通过反相HPLC进一步纯化(250mm×20mmC18柱,20-60%乙腈/水,40min,v=8mL/min),得到泡沫状纯产物C-18(53.25mg,83%收率,95%纯度)。ESI MS m/z C103H148N13O37[M+H]+:计算值2159.0099,实测值2159.0890。
实施例152.不对称横交联的PBD二聚体C-19的合成
向氨基化合物((11S,11aS)-4-((14S,17S)-1-氨基-14,17-二甲基-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基8-(3-((((S)-10-)(((4-((14S,17S)-1-氨基-17-(2-(叔丁氧基)-2-氧乙基)-14-(4-(((叔丁氧基羰基)氨基)丁基)-12,15-二氧代-3,6,9-三氧杂-13,16-二氮杂十八酰胺基)苄基)氧)羰基)-7-甲氧基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂卓-8-基)氧基)丙氧基)-11-羟基-7-甲氧基-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)的粗品(120mg,0.0662mmol)的无水四氢呋喃(10mL)溶液中加入2-炔二酸(7.5mg,0.06611mmol)和EDC(50.2mg,0.261mmol)。将混合物在室温搅拌12小时,浓缩,通过硅胶柱纯化,用甲醇/二氯甲烷(1:12至1:6)洗脱,得到泡沫状纯品C-19(86.3mg,69%产率)。ESI MS m/z C93H126N13O29[M+H]+:计算值1888.8784,实测值1888.8895。
实施例153.不对称横交联的PBD二聚体C-20的合成
在0-4℃下,将C-19化合物(75.5mg,0.0397mmol)溶解于二氯甲烷(4mL)中,然后加入TFA(2mL)。将反应混合物在室温搅拌1h,用甲苯(5mL)稀释,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-17(72.2mg,105%收率,91%HPLC纯)。将其通过反相HPLC(250mm×20mm,C18柱,5-60%乙腈/水,40min,v=8mL/min)进一步纯化,得到泡沫状纯品C-20(55.7mg,产率81%,纯度95%)。ESI MS m/z::计算值C84H110N13O27[M+H]+1732.7629,实测值1732.8025。
实施例154.不对称横交联的PBD二聚体C-21的合成
将C-20化合物(45.0mg,0.026mmol)溶解在四氢呋喃(3mL)和0.1M NaH2PO4(3mL)的pH 7.5的混合溶液中,然后在2小时内分4批分加入2,5,8,1114,17,20,23,26-九氧杂二十八烷-28-酸N-琥珀酰亚胺酯(47.0mg,0.0874mmol)。然后将反应混合物继续在室温搅拌4小时,并与DMF(10mL)共蒸发至干,得到粗产物C-18,将其通过反相HPLC进一步纯化(250mm×20mm,C18柱,20-60%乙腈/水,40min,v=8mL/min),得到泡沫状纯产物C-21(45.3mg,81%收率,95%纯度)。ESI MS m/z C103H146N13O37[M+H]+:计算值2156.9943,实测值2157.1250。
实施例155.横交联PBD二聚体C-22的合成
向(11S,11aS,11'S,11a'S)-双(4-((S)-2-((S)-2-氨基-3-甲基丁亚氨基)丙酰胺基)苄基)8,8'-(戊烷-1,5-二基双(氧基)双(11-((叔丁基二甲基甲硅烷基)氧基)-7-甲氧基-2,5-二氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯)(2.26g,1.51mmol)的二氯乙烷(40mL)溶液中加入1,4-二氧六环-2,6-二酮(176mg,1.51mmol)。将混合物在室温下搅拌4小时,然后加入EDC(1.16g,6.04mmol)和DIPEA(0.40g,3.10mmol)。将混合物在40℃搅拌24h,蒸发并在硅胶柱色谱上纯化(1:15至1:5甲醇/二氯甲烷),得到1.99g(83%收率)C-22化合物。MS ESI m/z C79H109N10O21Si2[M+H]+:计算值1589.7307,实测值1589.9025。
实施例156.横交联PBD二聚体C-23的合成
在氮气中,-45℃下,向化合物C-22(1.98g,1.24mmol)在无水二氯甲烷(30mL)和2,6-二甲基吡啶(2.0mL,17.16mmol)的混合物中加入三氟甲酸酐(2.68mL,15.93mmol)。将混合物在-45℃下搅拌2小时,用二氯甲烷(30mL)稀释,用水(50mL),5%乙酸(2×80mL),饱和NaHCO3(2×80mL),盐水(80毫升)洗,并用硫酸钠干燥。过滤,蒸发溶剂,得到粗产物,将其通过硅胶柱纯化,用乙酸乙酯/二氯甲烷(1∶10至1∶6)洗脱,得到C-23,为白色泡沫状物(1.68g,74%收率)。MS ESI m/z C81H107F6N10O25S2Si2[M+H]+:计算值1583.6293,实测值1583.7055。
实施例157.横交联PBD二聚体C-24的合成
在室温下,向C-23(348.1mg,0.22mmol),甲苯(3mL),乙醇(10mL)和水(1.5mL)的混合物中加入固体Pd(PPh3)4(10mg,8.69mmol),4-甲氧基苯基硼酸(40mg,0.26mmol),Na2CO3(37mg,0.35mmol)。将反应混合物在N2下搅拌24小时,此时通过LC/MS和TLC(乙酸乙酯)判断反应已完成。真空除去溶剂,并将所得残余物在乙酸乙酯(100mL)和水(100mL)之间分配。将水相用乙酸乙酯(3×40mL)萃取,并将合并的有机层用水(40mL),盐水(40mL)洗涤,经硫酸钠干燥,过滤并蒸发,得到粗产物,将其通过硅胶柱纯化(用乙酸乙酯/二氯甲烷,1∶10至1∶6洗脱),得到化合物C-24,为白色泡沫(286mg,72%收率)。MS ESI m/z C87H114F3N10O23SSi2[M+H]+:计算值1811.7270,实测值1811.7965。
实施例158.横交联PBD二聚体C-24的合成
在室温下,向C-24(250.1mg,0.138mmol),甲苯(3mL),乙醇(10mL)和水(1.5mL)的混合物中加入固体Pd(PPh3)4(10mg,8.69mmol),4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(60mg,0.27mmol),Na2CO3(40mg,0.37mmol)。将反应混合物在N2下搅拌24小时,此时通过LC/MS和TLC(乙酸乙酯)判断反应已完成。真空除去溶剂,并将所得残余物在乙酸乙酯(100mL)和水(100mL)之间分配。将水相用乙酸乙酯(3×40mL)萃取,并将合并的有机层用水(40mL),盐水(40mL)洗涤,经硫酸钠干燥,过滤并蒸发,得到粗产物,将其通过硅胶柱纯化(用乙醇/二氯甲烷,1:15至1:8洗脱),得到化合物C-25,为灰色泡沫状物(142mg,59%产率)。MS ESI m/z C92H120N11O20Si2[M+H]+:计算值1754.8250,实测值1754.9830。
实施例159. 2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-叔丁酯
向2,5,8,11,14,17,20,23,26-十氧杂二十八烷-28-醇(42.8g,100mmol)的四氢呋喃(1.0L)溶液中加入NaH(60%,8.0g,200mmol)。在室温,30分钟内,将2-溴乙酸叔丁酯(48.8g,250mmol)加入混合物中,并在室温搅拌1小时。然后将混合物倒入冰水,用二氯甲烷萃取,有机层用盐水洗涤,用无水硫酸钠干燥。通过柱色谱法纯化(0%至5%甲醇/二氯甲烷),得到标题化合物,为黄色油状物(32g,59%产率)。ESI MS 543.35[M+H]+。
实施例160. 2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-酸的合成
将2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-叔丁酯(40.0g,73.8mmol)溶于二氯甲烷(400mL)中,然后加入甲酸(600mL)。将所得溶液在25℃下搅拌过夜。真空除去所有挥发物,得到标题产物,为黄色油状物(36.0g,100%收率)。ESI m/z C21H43O12[M+H]+:计算值487.27,实测值487.24。
实施例161. 1,2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-酰氯合成
将(2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-酸(36.0g,73.8mmol)溶解在二氯甲烷(640mL),加入草酰氯(100mL)和DMF(52g,0.74mmol)。将所得溶液在室温搅拌4小时。真空除去所有挥发物,得到标题产物,为黄色油状物。
实施例162.(S)-37-((((苄氧基)羰基)氨基)-31-氧杂-2,5,8,11,14,17,20,23,26,29-十氧杂-32-氮杂三十八烷-38-酸的合成
将Z-L-Lys-OH(41.4g,147.6mmol),Na2CO3(23.4g,221.4mmol)和NaOH(5.9g,147.6mmol)溶解于水(720mL)中。将该混合物冷却至0℃,向其中加入2,5,8,11,14,17,20,23,26,29-十氧杂三十一烷-31-酰氯(37.2g,73.8mmol)的四氢呋喃(20mL)溶液。将所得混合物在室温搅拌1小时。在真空下除去四氢呋喃,并在冰冷却下加入浓盐酸直至水溶液pH达到3。用二氯甲烷萃取后,有机层用盐水洗涤,经硫酸钠干燥并浓缩,得到标题产物,为黄色油状物(55g,99%收率)。ESI m/z C35H60N2O15[M+H]+7:计算值49.40,实测值749.39。
实施例163.(S)-37-((((苄氧基)羰基)氨基)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸叔丁酯的合成
将4-氨基丁酸叔丁酯(1.03g,6.12mmol)和(S)-37-((((苄氧基)-羰基)氨基)-31-氧杂-2,5,8,11,14,17,20,23,26,29-十氧杂-32-氮杂三十八烷-38-酸(4.16g,5.56mmol)的DMF(18mL)溶液冷却至0℃,然后加入HATU(2.32g,6.12mmol)和TEA(1.2mL,8.34mmol)。将反应搅拌50分钟,然后用水(300mL)稀释,并用乙酸乙酯(3×250mL)萃取。乙酸乙酯溶液用盐水洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(32∶1二氯甲烷/甲醇),得到标题化合物(4.40g,89%产率)。MS ESI m/z C43H75N3O16[M+H]+:计算值890.51,实测值891.09。
实施例164.(S)-37-氨基-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸叔丁基酯的合成
向氢化反应瓶中加入(S)-37-((((苄氧基)羰基)氨基)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧烷-32,39-二氮杂四十三烷-43-酸叔丁基酯(1g,1.13mmol)的甲醇(50mL)溶液,加入Pd/C(10wt%,0.10g)。将混合物振荡2小时,通过硅藻土(助滤剂)过滤,并将滤液浓缩,得到标题化合物(1.0g,1.32mmol,产率>100%),其无需进一步纯化即可直接用于下一步。ESI:m/z C35H70N3O14[M+H]+:计算值756.48,实测值756.47。
实施例165.(S)-37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯l-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸叔丁基酯的合成
在室温下,向(S)-37-氨基-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸叔丁基酯(0.93g,1.23mmol,1.0eq)和4-(马来酰亚胺基)丁酸(0.27g,1.47mmol,1.2eq)的DMA(40mL)溶液中加入EDC(0.90g,4.68mmol)。将混合物搅拌过夜,然后浓缩并用水(50mL)稀释,用二氯甲烷(80mL×3)萃取,有机相经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱色谱法纯化(二氯甲烷/甲醇=25∶1),得到标题化合物,为浅黄色油状物(1.01g,90%)。ESI m/z C43H77N4O17[M+H]+:计算值921.5,实测值:921.5。
实施例166.(S)-37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸的合成
将(S)-37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸叔丁基酯(0.90g,0.98mmol)溶解在HCOOH(50mL)中,并在室温下搅拌1小时。将反应混合物浓缩并与甲苯共蒸发两次,并将残余物置于真空泵上抽干,得到标题化合物(0.85g,0.98mmol,粗产物)。ESI:m/z C39H69N4O17[M+H]+:计算值865.46,实测值865.44。
实施例167.(S)-2,5-二氧吡咯烷-1-基37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯l-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸酯的合成
在室温下,向(S)-37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸(0.80g,0.92mmol,1.0eq.)和1-羟基吡咯烷-2,5-二酮(NHS)(0.20g,1.73mmol,2.0eq)的DMA(20mL)溶液中加入EDC(0.90g,4.68mmol)。将混合物搅拌过夜,然后浓缩并通过硅胶柱色谱法纯化(二氯甲烷/乙酸乙酯=10∶1至5∶1),得到标题化合物,为浅黄色油状物(0.803g,91%)。ESIm/z C43H72N5O19[M+H]+:计算值962.47,实测值:962.55。
实施例168.横交联PBD二聚体C-26的合成
向PBD二聚体C-25(120mg,0.068mmol)和(S)-37-(4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁胺)-31,38-二氧代-2,5,8,11,14,17,20,23,26,29-十氧杂-32,39-二氮杂四十三烷-43-酸(70mg,0.0809mmol)的DMA(3mL)溶液中加入EDC(60mg,0.312mmol)。将混合物搅拌过夜,然后浓缩并通过硅胶柱色谱法纯化(二氯甲烷/乙酸乙酯=10∶1至5∶1),得到标题化合物,为泡沫状物(152mg,86%)。ESI m/z值C131H186N15O36Si2[M+H]+:计算值2601.26,实测值:2601.55。
实施例168.横交联PBD二聚体C-27的合成
在0-4℃下,将C-26化合物(75.5mg,0.0290mmol)溶解在二氯甲烷(2mL)中,然后加入TFA(2mL)。将反应混合物在室温搅拌1h,用甲苯(5mL)稀释,然后浓缩,并与二氯甲烷/甲苯共蒸发至干,得到粗产物C-17(72.2mg,105%收率,91%HPLC纯)。将其通过反相HPLC(250mm×20mm,C18柱,5-60%乙腈/水,40min,v=8mL/min)进一步纯化,得到泡沫状纯品C-27(55.2mg,产率80%,纯度95%)。ESI MS m/z C119H158N15O36[M+H]+:计算值2373.09,实测值2373.90。
实施例169.(S)-叔丁基13-(2-((((苄氧基)羰基)氨基)-5-(叔丁氧基)-5-氧代戊烷酰胺)十三烷酸酯的合成
向(S)-2-((((苄氧基)羰基)氨基)-5-(叔丁氧基)-5-氧戊酸(3.50g,10.38mmol)和13-氨基十三烷酸叔丁酯(3.00g,10.51mmol)的DMF(70mL)溶液中加入EDC(10.00g,52.08mmol)和TEA(1.60mL,11.16mmol)。将反应在室温搅拌8h,真空浓缩,用饱和NaCl(80mL)和乙酸乙酯(100mL)稀释,分离。将水层用乙酸乙酯(50mL×3)萃取,并将合并的有机相用100mL的饱和盐水洗涤一次,然后用无水硫酸钠干燥,过滤并浓缩。残余物通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷,1:15),得到标题化合物(5.45g,87%产率)。ESI:m/zC34H57N2O7[M+H]+:计算值605.41,实测值605.38。
实施例170.(S)-叔丁基13-(2-氨基-5-(叔丁氧基)-5-氧代戊烷酰胺)十三烷酸酯的合成
向S)-叔丁基13-(2-((((苄氧基)羰基)氨基)-5-(叔丁氧基)-5-氧代戊烷酰胺)十三烷酸酯(2.80g,4.63mmol)的DMA(100mL)溶液中加入10%Pd/C(0.41g),将混合物在氢气下室温搅拌18h。然后通过硅藻土过滤除去Pd/C,并用DMA洗涤滤床。浓缩滤液,得到黄色泡沫状固体,其无需进一步纯化即可用于下一步骤(2.19g,101%收率)。ESI:m/z C26H51N2O5[M+H]+:计算值471.37,实测值471.80。
实施例171.2,2-二甲基-4,17-二氧代-3,7,10,13,20,23,26-七氧杂-16-氮杂二十九烷-29-酸的合成
向3-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(6.00g,21.64mmol)和3,3'-((双氧乙烷(乙烷-2,1-二基)双(氧))二丙酸(21.01g,84.00mmol)的DMA(200mL)溶液中加入EDC(18.00g,93.75mmol)和DIPEA(5.00g,38.75mmol)。将混合物搅拌过夜,然后浓缩并通过硅胶柱色谱法纯化(甲醇/二氯甲烷=1:12至1:5),得到标题化合物,为白色油状物(9.15g,86%收率)。ESI m/z C23H44NO11[M+H]+:计算值510.28,实测值:510.55。
实施例172.1-苄基39-叔丁基14,26-二氧代-4,7,10,17,20,23,30,33,36-九氧杂-13,27-二氮杂三十九烷-1,39-二酸酯的合成
向(S)-叔丁基13-(2-氨基-5-(叔丁氧基)-5-氧代戊烷酰胺)十三烷酸酯(5.11g,10.03mmol)和3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙苄基酯(3.21g,10.31mmol)的DMA(100mL)溶液中加入EDC(8.02g,41.77mmol)和DIPEA(3.00g,23.25mmol)。将混合物搅拌过夜,然后浓缩并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷=1∶8至1∶3),得到标题化合物,为白色油状物(7.01g,87%收率)。ESI m/z C39H67N2O15[M+H]+:计算值803.44,实测值:803.80。
实施例173. 3,16,28-三氧代-1-苯基-2,6,9,12,19,22,25,32,35,38-十氧杂-15,29-二氮杂四十一烷-41-酸的合成
在0-4℃下,将1-苄基39-叔丁基14,26-二氧代-4,7,10,17,20,23,30,33,36-九氧杂-13,27-二氮杂三十九烷-1,39-二酸酯(6.90g,8.60mmol)溶解于HCOOH(50mL)中并搅拌1小时。将反应混合物用甲苯(50mL)稀释,浓缩并与甲苯共蒸发两次,并将残余物置于真空泵上,得到标题化合物(6.45g,101%收率,粗产物)。ESI:m/z C35H59N2O15[M+H]+:计算值747.38,实测值747.50。
实施例174. 1-苄基39-(2,5-二氧杂吡咯烷-1-基)14,26-二氧代4,7,10,17,20,23,30,33,36-九氧杂-13,27-二氮杂三十九烷-1,39-二酸酯的合成
向3,16,28-三氧代-1-苄基-2,6,9,12,19,22,25,32,35,38-十氧杂-15,29-二氮杂四十一烷-41-酸(4.01g,5.37mmol)和NHS(N-羟基琥珀酰亚胺)(0.68g,5.91mmol)的DMA(100mL)溶液中加入EDC(1.52g,7.92mmol)和DIPEA(0.50g,3.87mmol)。将混合物搅拌过夜,然后浓缩并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷=1∶8至1∶4),得到标题化合物,为白色泡沫状物(4.17g,92%产率)。ESI m/z C39H62N3O17[M+H]+:计算值844.40,实测值:844.85。
实施例175.(S)-47-((((苄氧基)羰基)氨基)-3,16,28,41-四氧代-1-苯基-2,6,9,12,19,22,25,32,35 38-十氧杂15,29,42-三氮杂四十八烷-48-酸的合成
在2小时内,分4批向(S)-6-氨基-2-((((苄氧基)羰基)氨基)己酸(1.38g,4.92mmol)的DMA(30mL)和100mM NaH2PO4 pH 7.5缓冲液(40mL)混合溶液中加入1-苄基39-(2,5-二氧杂吡咯烷-1-基)14,26-二氧杂-4,7,10,17,20,23,30,33,36-九氧杂-13,27-二氮杂三十九烷-1,39-二酸酯(4.15g,4.92mmol)。将混合物搅拌4小时,然后浓缩并通过硅胶柱色谱法纯化(甲醇/二氯甲烷=1∶7至1∶4),得到标题化合物,为白色泡沫状固体(4.07g,82%收率)。ESI m/z C49H77N4O18[M+H]+:计算值1009.51,实测值:1009.90。
实施例176.(S)-1-苄基51-(2-(三甲基甲硅烷基)乙基)45-((((苄氧基)-羰基)氨基)-14,26,39,46-四氧代-4,7,10,17,20,23,30,33,36-九氧杂13,27,40,47-四氮杂五十一烷-1,51-二酸酯
向(S)-47-((((苄氧基)羰基)氨基)-3,16,28,41-四氧代-1-苯基-2,6,9,12,19,22,25,32,35,38-十氧杂-15,29,42-三氮杂四十八烷-48-酸(4.00g,3.96mmol)和2-(三甲基甲硅烷基)乙基4-氨基丁酯(0.90g,4.43mmol)的DMA(25mL)溶液中加入EDC(2.03g,10.57mmol)。将混合物搅拌6小时,然后浓缩并通过硅胶柱色谱法纯化(甲醇/二氯甲烷=1:15至1:8),得到标题化合物,为白色泡沫状固体(3.97g,84%收率)。ESI m/z C58H96N5O19Si[M+H]+:计算值1194.64,实测值:1194.90。
实施例177. 12-氨基-2,2-二甲基-6,11,18,31,43-五氧代-5,21,24,27,34,37,40,47,50,53-十氧杂,10,17,30,44-四氮杂-2-五十六硅烷-56-酸的合成
在氢化反应瓶中,向(S)-1-苄基51-(2-(三甲基甲硅烷基)乙基)45-((((苄氧基)-羰基)氨基)-14,26,39,46-四氧代-4,7,10,17,20,23,30,33,36-九氧杂-13,27,40,47-四氮杂五十一烷1,51-二酸酯(3.90g,3.33mmol)的甲醇(40mL)溶液中加入Pd/C(10wt%,0.20g)。将混合物在40psi H2下振摇2h,通过硅藻土(助滤剂)过滤,浓缩滤液,得到标题化合物(3.16g,98%产率),其无需进一步纯化即可直接用于下一步ESI:m/z C43H83N5O17Si[M+H]+:计算值970.55,实测值970.70。
实施例178. 2,5-二氧杂吡咯烷-1-基4-(((3aR,7R,7aS)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H))丁酯的合成
将4-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丁酸(10.0g,54.62mmol)和呋喃(5mL,68.74mmol)的乙醚(90mL)溶液在压力容器中170℃下加热6小时。然后将溶液冷却至室温,真空浓缩并在乙醇/正己烷中结晶,得到4-(((3aR,7R,7aS)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁酸(11.24g,44.76mmol,产率82%)。然后将所得产物溶解于二氯甲烷(100mL)中,加入NHS(7.00g,60.86mmol)和EDC(25.00g,130.20mmol)。将混合物搅拌6小时,然后浓缩并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷=1:8至1:5),得到标题化合物,为白色泡沫状固体(13.57g,87%收率)。ESI m/z C16H17N2O7[M+H]+:计算值349.09,实测值:349.55。
实施例179.(12S)-12-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁胺)-2,2-二甲基-6,11,18,31,43-五氧代-5,21,24,27,34,37,40,47,50,53-十氧杂-10,17,30,44-四氮杂-2-五十六硅烷-56-酸的合成
在15℃下,向12-氨基-2,2-二甲基-6,11,18,31,43-五氧代-5,21,24,27,34,37,40,47,50,53-十氧杂-10,17,30,44-四氮杂-2-五十六硅烷-56-酸(3.10g,3.19mmol)的DMA(20mL)和100mM NaH2PO4,pH 7.5(20mL)的混合溶液中,加入2,5-二氧杂吡咯烷酮-1-基4-(((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁酸(1.60g,4.60mmol)的DMA(10mL)溶液。将混合物搅拌6小时,然后浓缩并通过硅胶柱色谱法纯化(甲醇/二氯甲烷=1∶7至1∶4),得到标题化合物,为白色泡沫状固体(3.07g,80%收率)。
实施例180.(7S,53S)-68-叔丁基1-(2-(三甲基甲硅烷基)乙基)53-(3-(叔丁氧基)-3-氧丙基)-7-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁胺)-6,13,26,38,51,54-六氧代-16,19,22,29,32,35,42,45,48-九氧杂-5,12,25,39,52,55-六氮杂六十八烷-1,68-二酸酯
向(12S)-12-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁胺)-2,2-二甲基-6,11,18,31,43-五氧代-5,21,24,27,34,37,40,47,50,53-十氧杂-10,17,30,44-四氮杂-2-五十六硅烷-56-酸(3.00g,2.49mmol)和(S)-叔丁基13-(2-氨基-5-(叔丁氧基)-5-氧戊酰胺基)十三烷酸酯(1.18g,2.49mmol)的DMA(40mL)溶液中加入EDC(2.03g,10.57mmol)。将混合物搅拌6小时,然后浓缩,并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷=1∶10至1∶4),得到标题化合物,为白色泡沫状固体(3.50g,85%产率)。ESI m/z C81H143N8O25Si[M+H]+:计算值1655.98,实测值:1655.90。
实施例181.(19S,65S)-19-(3-(叔丁氧基)-3-氧丙基)-65-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁胺)-2,2-二甲基-4,18,21,34,46,59,66-九氧代-3,24,27,30,37,40,43,50,53,56-十氧杂-17,20,33,47,60,67-六氮杂七十一烷-71-酸
向(7S,53S)-68-叔丁基1-(2-(三甲基甲硅烷基)乙基)53-(3-(叔丁氧基)-3-氧丙基)-7-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁酰胺基)-6,13,26,38,51,54-六氧代-16,19,22,29,32,35,42,45,48-九氧杂-5,12,25,39,52,55-六氮杂七十一烷-1,68-二酸酯(3.40g,2.05mmol)的四氢呋喃(40mL)溶液中加入TBAF(1.53g,5.74mmol)的四氢呋喃(10mL)溶液。将混合物搅拌4小时,然后浓缩,并通过硅胶柱色谱法纯化(甲醇/二氯甲烷=1∶6至1∶3),得到标题化合物,为白色泡沫状固体(2.77g,87%产率)。ESI m/z C76H131N8O25Si[M+H]+:计算值1554.91,实测值:1554.95。
实施例182.横交联PBD二聚体C-28的合成
向(19S,65S)-19-(3-(叔丁氧基)-3-氧丙基)-65-(4-((3aR,4S,7R)-1,3-二氧代-3a,4,7,7a-四氢-1H-4,7-环氧异吲哚-2(3H)-基)丁胺)-2,2-二甲基-4,18,21,34,46,59,66-十氧杂-3,24,27,30,37,40,43,50,53,56-十氧杂-17,20,33,47,60,67-六氮杂七十烷-71-酸(126mg,0.081mmol)和PBD二聚体C-25(140mg,0.080mmol)的DMA(10mL)溶液中加入EDC(45mg,0.234mmol)。将混合物搅拌8小时,然后浓缩并通过硅胶柱色谱法纯化(乙酸乙酯/二氯甲烷=1∶8至1∶3),得到标题化合物,为白色泡沫状固体(195mg,79%收率)。ESI m/z C156H220N19O44[M+H]+:计算值3063.55,实测值:3063.90。
实施例183.横交联PBD二聚体C-29的合成
将横交联PBD二聚体C-28(180mg,0.0587mmol)的DMA(8mL)和甲苯(10mL)的混合溶液在120℃回流6h,LC-MS表明马来酰亚胺脱保护完成。真空浓缩该溶液,并将其重新溶于1,4-二氧六环(6mL)和12M盐酸溶液(2mL)的混合物中。搅拌30分钟后,将混合物浓缩并通过反相HPLC(250mm×30mm,C18柱,5-60%乙腈/水,40min,v=8mL/min)进行纯化。冻干后得到泡沫状纯产物C-29(143.2mg,83%产率,纯度95%)。ESI MS m/z C148H208N19O43[M+H]+:计算值2939.46,实测值2939.90。
实施例184.由PBD二聚体C-3,C-4,C-5,C-6,C-7,C-8,C-10,C-11,C-12,C-14,CC-1,C-17,C-18,C-20,C-21,C-27和C-29制备CC-3,CC-4,CC-5,CC-6,CC-7,CC-8,CC-10,CC-11,CC-12,CC-14,CC-15,CC-17,CC-18,CC-20,CC-21,CC-27和CC-29偶联物的一般方法
在含有2.0mL的10mg/mL赫赛汀的pH 6.08.0PBS缓冲液中,加入0.702.0mL的100mM NaH2PO4 pH 6.58.5缓冲液和TCEP(1445μL,20mM的水溶液),分别加入化合物C-3,C-4,C-5,C-6,C-7,C-8,C-10,C-11,C-12,C-14,CC-1,C-17,C-18,C-20,C-21,C-27或C-29(14-28μL,20mM的DMA溶液)。将混合物在室温下孵育418小时,然后加入DHAA(125160μL,50mM)。在室温下继续孵育过夜后,将混合物在G-25柱上纯化,用100mM NaH2PO4,50mMNaCl,pH6.07.5缓冲液洗脱,制得12.818.1mg的偶联物CC-3,CC-4,CC-5,CC-6,CC-7,CC-8,CC-10,CC-11,C-12,C-14,CC-1,C-17,C-18,C-20,C-21,C-27或C-29(83.6%94%收率)。偶联物的药物/抗体比(DAR)为3.64.1,DAR通过UPLC-QTOF质谱测定。通过SEC HPLC(Tosoh Bioscience,Tskgel G3000SW,7.8mm ID×30cm,0.5mL/min,100min)测得单体含量9599%,SDS-PAGE凝胶测量为单条带。偶联物结构如下所示:
实施例185.偶联物CC-3,CC-4,CC-5,CC-6,CC-7,CC-8,CC-10,CC-11,CC-12,CC-14,CC-15,CC-17,CC-18,CC-20,CC-21,CC-27和CC-29,与T-DM1体外细胞毒性对比:
细胞毒性试验中使用的细胞系是人胃癌细胞系NCI-N87。细胞在含10%FBS的RPMI-1640中生长。为了进行该测定,将细胞(180μL,6000个细胞)加入96孔板各孔中,并在37℃和5%CO 2下孵育24小时。接着,在适当的细胞培养基(总体积0.2mL)中,以各种浓度的试验化合物(20μL)处理细胞。对照孔含有细胞和培养基,但无测试化合物。将孔板在37℃和5%CO2下孵育120小时。然后将MTT(5mg/mL)加入孔(20μL)中,并将板在37℃下温育1.5小时。小心除去培养基,然后加入DMSO(180μL)。振摇15分钟后,用620nm的参考滤光片在490nm和570nm处测量吸光度。根据下式计算抑制百分率:抑制百分率=[1-(测定空白)/(对照空白)]×100。结果列于表1。
IC50的细胞毒性结果:
实施例186.体内抗肿瘤活性(带有NCI-N87异种移植肿瘤的BALB/c裸鼠)。
在人胃癌N-87细胞系肿瘤异种移植模型中评估了偶联物CC-2,CC-3,CC-4,CC-5,CC-6,CC-7,CC-10,CC-11,CC-12,CC-18和CC-29以及T-DM1的抗肿瘤效果。将五周大的雌性BALB/c裸鼠(78只动物)的右肩下方区域皮下接种0.1mL无血清培养基中的N-87癌细胞(5×106细胞/小鼠)。肿瘤生长8天,平均大小为130mm3。然后将动物随机分为13组(每组6只动物)。第一组小鼠作为对照组,并注射磷酸盐缓冲盐水(PBS)。12组分别用偶联物CC-2,CC-3,CC-4,CC-5,CC-6,CC-7,CC-10,CC-11,CC-12,CC-18,CC-29和T-DM1,以3mg/Kg的剂量静脉注射。每4天测量肿瘤体积的三个维度,并使用公式:体积=1/2(长×宽×高)来计算肿瘤体积。还同时测量了动物的体重。满足以下任一条件时处死小鼠:(1)体重比治疗前减轻了20%以上;(2)肿瘤体积大于2000mm3;(3)病重得无法进食和饮水,或(4)皮肤坏死。如果没有可触知的肿瘤,则认为小鼠无肿瘤。
结果显示如图33。在6.0mg/kg的剂量下,所有12种偶联物均未引起动物体重减轻。对照组的动物在第35天因为肿瘤体积大于2000mm3而处死,其中有些小鼠病情严重。与PBS缓冲液相比,所有偶联物均显示出抗肿瘤活性。除CC-6外,其他9个偶联物在体内的抗肿瘤活性均优于T-DM1。所有6/6只动物在第14天至第30天几乎没有可测量的肿瘤。然而,剂量为3mg/kg的T-DM1无法抑制肿瘤。
实施例187.与T-DM1相比,高剂量的偶联物CC-4,CC-29在ICR小鼠中动物肝脏毒性研究
将20只ICR小鼠随机分为4组(每组5只动物),每只动物每次静脉给药75mg/kg(PBS,CC-4,CC-29和T-DM1)。5天后,从每只小鼠的眶后静脉丛(窦)收集150μL血样。血样离心后,使用BioSino Bio-Technology and Science Inc(中国北京)的检测试剂盒,取血清测定AST和ALT水平。下面列出了每组5只动物的AST和ALT的平均值。处死小鼠后,收集其肝组织,固定在10%中性福尔马林溶液中,用一系列乙醇溶液脱水,然后包埋在石蜡中。切片(厚5μm),转移到载玻片上,并用苏木精和曙红(H&E)染色(Kiernan JA(2008)Histologicaland Histochemical Methods:Theory and Practice.4th ed.Bloxham,UK;Scion,Gomori,Sheehan及Hrapchak:Histotechnology A Self-Instructional Text,ASCPPress.American Society of Clinical Pathologists Chicago 1990)。使用光学显微镜检查染色的样品(Nikon Eclipse TE2000-U,Tokyo,Japan),并以200x放大倍数拍照。
如下所示,剂量为75mg/kg的CC-4和T-DM1均使血清AST和ALT升高,且较CC-29组升高得多。
在图34中,CC-4和T-DM1组均表现出肝细胞水解作用,Kupffer细胞增生和局灶性坏死,但CC-29组与对照组PBS组相比没有明显差异。因此,图33和图34都显示CC-29偶联物比T-DM1具有更宽的治疗窗口(体内具有更高的抗肿瘤活性和更低的副作用)。
Claims (20)
或是其药学上可接受的盐、水合物或水合盐;或其多晶型晶体;或其光学异构体、外消旋体、非对映异构体或对映异构体;
其中:
-----代表可选的单键或可以缺省;
V和V’相同或不同,独立地选自H、OH、-NHOH、OR5(醚)、OCOR5(酯)、OCOOR5(碳酸酯)、NR5R5’、NR5COR5’或NR5NR5’NR5”(胺)、OCONR5R5’(氨基甲酸酯)、NR5(C=NH)NR5’R5”(胍)、NR5CONR5’R5”(尿素)、OCSNHR5(硫代氨基甲酸酯)、-SH(巯基)、–SR5(硫化物)、SOR5(亚砜)、SOOR5(砜)、SO3、HSO3、HSO2或HSO3-、SO3 2-或-HSO2-的盐(亚硫酸盐)、OSO3(亚硫酸氢盐)、NR5SOOR5’(磺酰胺)、H2S2O5或S2O5 2-盐(偏亚硫酸氢盐)、PO3SH3、PO2S2H2、POS3H2、PS4H2或PO3S3-、PO2S2 3-、POS3 3-、PS4 3-的盐(单、二、三和四硫代磷酸酯)、(R5O)2POSR5’(硫代磷酸酯)、HS2O3或S2O3 2-的盐(硫代硫酸盐)、HS2O4或S2O4 2-的盐(连二亚硫酸盐)、P(=S)(OR5)(S)(OH)(二硫代磷酸酯)或与阳离子形成的盐、-NR5OR5’(羟胺衍生物)、R5C(=O)NOH(异羟肟酸)或与阳离子形成的盐、HOCH2SO2-或其盐(甲醛合次硫酸氢盐)、NR5COR5’(酰胺)、N3(叠氮基)、CN(氰基)、X(卤素,F,Cl,Br或I)、C(R5)(R5')(R5”)(三烷基)、OP(O)(OR5)(NHR5')或OP(O)(NHR5)(NHR5')(氨基磷酸酯或者磷酰胺酸)、或P(R5)(R5')(R5”)三芳基膦,Aa(氨基酸)或NR5CO(Aa)t(肽),其中Aa是一种氨基酸或含个氨基酸单元的多肽;氨基酸衍生基团,例如α-,β-,γ-或ω-氨基酸或非天然氨基酸;其中R5,R5'和R5”定义如下所述:
l、m、q、l’、m’和q’独立地为0、1、2、3、4、或5;n是1~30;
X、X’、Y和Y’是相同或不同,各自独立地代表N、O、S、烷基(例如CH2或CHR5)、烯烃(例如=CH-或=CR5-)、醚(例如-C(OR5)H-);
Z和Z’相同或不同,各自独立地为N、CH、CR5、COH、CNH2、CNHR5、或COR5、或Z和Z’与–COR5OC-连接,R5独立地选自C1~C8烷基和芳基;
U和U’独立地为C(O)、C(O)O、C(O)NH、C(O)N(R5)、C(=NH)、C(=NH)O、C(=NH)NH、C(=NH)N(R5)、-C=N-、C(=S)、C(O)S、C(S)NH、C(S)N(R5)、S(O)、S(O)O、S(O)NH、S(O)(OR5)、S(O)(N(R5))、S(O2)、S(O2)O、P(O)(OR5)、P(O)(OR5)O、P(O)(NH2)、P(O)(NR5R5’)、P(O)(OR5)NH-、P(O)(OR5)NR5’-、P(O)(N(R5R5’)(N(R5)、P(S)(OR5)、P(S)(OR5)O、P(S)(NH2)、P(S)(NR5R5’)、P(S)(OR5)NH-、P(S)(OR5)NR5’-、P(S)(N(R5R5’)N(R5)、R5、R5O;
E1和E2独立地为S、R5S、C(O)S、C(O)NH、C(O)O、C(O)R5S、C(=NH)NH、C(=NH)N(R5)、C(=NH)S、-C=N-、C(=S)S、C(O)S、C(=S)NH、C(=S)N(R5)、Ar-S、NC(O)CH2S、ArC(O)CH2S、S-S、
其中两个原子中间的化学键表示它可以连接两个相邻原子中的任何一个;波浪线是一个连接位点;
L1和L2独立地为可断裂的连接子,或包含能够与细胞结合剂(CBA)反应的官能团的连接子。L1和L2独立地具有下式结构:—Ww—(Aa)r—Tt—;或—Ww—(Aa)r—Tt—Q;或Q—Ww—(Aa)r—Tt—;其中-W-是延展体单元;w是0或1;-Aa-独立地是氨基酸单元;r独立地是0至100的整数;-T-为间隔体单元,其可以为直链烷基或支链烷基或聚乙二醇间隔体;t为0或延展体单元W可独立地包含自毁灭间隔体、肽单元、腙键、二硫键、酯键或硫醚键;w是1或2或3;延展体单元(--W-),如果存在,可以将目标结合分子单元(CBA)连接到氨基酸单元(--Aa--),或者在不存在Aa的情况下连接至T。延展体单元W可以独立地包含自毁灭间隔体、肽单元、腙键、二硫键或硫醚键。此时,细胞结合分子(CBA)包含有一个官能团,可以与延展体的官能团成键。结合分子上的官能团可以天然地具备,或通过化学方法生成,它们包括但不限于巯基(-SH)、氨基、羟基、氧氨基、炔基、杂芳基、羰基、糖异头碳上的羟基和羧基;
进一步的,L1和L2独立地选自O、NH、N、S、P、NNH、NHNH、N(R3)、N(R3)N(R3’)、CH、CO、C(O)NH、C(O)O、NHC(O)NH、NHC(O)O、结构式如(OCH2CH2)pOR3或(OCH2CH-(CH3))pOR3或NH(CH2CH2O)pR3或NH(CH2CH(CH3)O)pR3或N[(CH2CH2O)pR3]-[(CH2CH2O)p’R3’]或(OCH2CH2)pCOOR3或CH2CH2(OCH2CH2)p-COOR3的聚乙二醇单元,其中p和p’独立地选自0至1000的整数,或其组合;C1-C8烷基、酰胺、胺、亚胺、肼、腙;C2-C8杂烷基、烷基环烷基、醚、酯、腙、脲、氨基脲、卡巴肼、烷氧基胺、氨基甲酸酯、氨基酸、肽、酰氧基胺、羟肟酸或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、异烷基环烷基、烷基羰基或杂芳基;如(OCH2CH2)pOR3或(OCH2CH(CH3))pOR3或NH(CH2CH2O)pR3或NH(CH2CH(CH3)O)pR3或N[(CH2CH2O)pR3]-[(CH2CH2O)p’R3’]或(OCH2CH2)pCOOR3或CH2CH2(OCH2CH2)pCOOR3的聚乙二醇单元,其中p和p'独立地是选自0至约5000的整数,或上述的组合;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、杂烷基、杂烷基环烷基、烷基羰基或杂芳基;或C2-C8酯、醚或酰胺;或1-8个氨基酸;或结构式为(OCH2CH2)p或(OCH2CH(CH3))p的聚乙二醇单元,其中p是0至约5000的整数,或上述组合;或(Aa)r、r=1-12(1至12个氨基酸单位)、由天然或非天然氨基酸、或相同或不同序列的二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、十一肽或十二肽单元组成;术语“可断裂连接子”是指包括至少一个在生理条件下可断裂键的连接子,例如对pH、酸、碱、氧化作用、代谢、生化或酶作用敏感的键。
R1、R2、R3、R4、R1’、R2’、R3’和R4’相同或不同,并且独立地选自-H,可被取代的含有1至10个碳的直链、支链或环状烷基、烯基或炔基、-(OCH2CH2)tR5(聚乙二醇单元)、卤素、NH(C=NH)NH2(胍基)、-OR5、-NR5R5'、-NO2、-NCO、-NR5COR5'、-SR5、–SOR5(亚砜)、-SO2R5(砜)、--SO3 -M+(磺酸盐)或-SO3H、–OSO3 -M+(硫酸盐)或OSO3H、-SO2NR5R5’(磺酰胺)、CN(氰基)、N3(叠氮基)、-COR5、-OCOR5、-OCONR5R5'、CF3、OR5、芳基、杂环或P(O)R5R5’R5”;
R5、R5’和R5”独立地选自H、C1-C8烷基、烯基、炔基、杂烷基、芳基、芳基烷基、羰基或药用盐;
另外,R1和R2可以连接在一起,或R1’和R2’连接在一起,形成=O(酮)、=S、=NR、-C(=O)R或含=CR5R5’基团的双键。R1和R2连接在一起,或R1'和R2'连接在一起,或R3和R4连接在一起,或R3'和R4'连接在一起形成C3-C12芳环、杂环或杂芳基环;
Q是细胞结合分子(CBA),或者能够与细胞结合剂反应的官能团,或者能够与连接在细胞结合剂上的连接子反应的官能团。所述官能团选自巯基、胺、肼、烷氧基氨基、取代的二硫键、马来酰亚胺基、卤代乙酰基、N-羟基琥珀酰亚胺酯、酮、酯、醛、炔基、烯基或受保护的巯基或二硫键,SAc、SSR1或SSAr,其中Ar是芳香基团或杂芳香基团。细胞结合剂/分子优选为,抗体、单链抗体、与靶细胞结合的抗体片段、单克隆抗体、单链单克隆抗体、结合靶细胞的单克隆抗体片段、嵌合抗体、结合靶细胞的嵌合抗体片段、结构域抗体、结合靶细胞的结构域抗体片段、adnectin类抗体、DARPins、淋巴因子、激素、维生素、生长因子、集落刺激因子、营养转运分子(转铁蛋白)以及结合在白蛋白、聚合物、树状大分子、脂质体、纳米颗粒、囊泡或(病毒)衣壳上的细胞结合肽、蛋白质或小分子;
另外,U、U’、L1、L2、L’、E1或E2独立地可以由以下一种或多种组分组成:6-马来酰亚胺己酰基(MC),马来酰亚胺丙酰基(MP),硫代马来酰亚胺基,硫代氨基氧代丁酸,硫代氨基氧代丁烯酸,缬氨酸-瓜氨酸(val-cit),丙氨酸-苯丙氨酸(ala-phe),赖氨酸-苯丙氨酸(lys-phe),赖氨酸-丙氨酸(lys-ala),p-氨基芐氧基酰胺基(PAB),4-硫代戊酰基(SPP),4-硫代丁酰基(SPDB),4-(N-马来酰亚胺基甲基)环己烷-1-酰基(MCC),马来酰亚胺乙氨基(ME),4-硫代-2-羟基磺酰基丁酰基(2-Sulfo-SPDB),芳基巯醚基(PySS),(4-乙酰基)氨基苯酰基(SIAB),氧芐基硫醚基,氨基苄基硫醚基,二氧基苄基硫醚基,二氨基苄基硫醚基,氨基氧基苄基硫醚基,烷氧基氨基(AOA),亚乙基氧基(EO),4-甲基-4-硫代-戊酰基(MPDP),三唑,二硫,烷基磺酰基,烷基磺胺,砜基二磺胺,磷二酰胺,烷基膦酰胺,膦酸,N-甲基烷基膦酰胺,N,N’-二甲基膦酰胺酸,N,N’-二甲基膦二酰胺,肼,乙脒;肟,二乙酰肼,氨基乙基胺,氨基乙基-氨基乙基胺,和L-或D-,或含有1-20个氨基酸的天然或非天然肽;其中原子中间的连接键表示它连接相邻的碳原子;波浪线是另一个键连接的部位;
另外,U、U’、E1或E2,可以独立地缺省。
或是其药学上可接受的盐、水合物或水合盐;或其多晶型晶体;或其光学异构体、外消旋体、非对映异构体或对映异构体;
其中-----、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’L1、L2、E1和E2的定义如权利要求1所述;
其中E3和E3’独立地选自:
N-羟基琥珀酰亚胺酯,马来酰亚胺基, 二硫化物,卤代乙酰基,酰卤,乙烯磺酰基,丙烯酰基,2-(甲苯磺酰氧基)乙酰基,2-(甲磺酰氧基)乙酰基,2-(硝基苯酚基)乙酰基,2-(二硝基苯基)乙酰基,2-(氟代苯酚基)-乙酰基,2-(二氟苯酚基)-乙酰基,2-((三氟甲基磺酰基)氧基)乙酰基,酮或醛,2-(五氟苯酚基)乙酰基,甲基砜苯基恶二唑(ODA),酸酐, 羰基二咪唑,烷氧基胺,叠氮基,炔基,β-内酰胺,或酰肼,异硫氰酸根;其中X1’和X3’独立地是F、Cl、Br、I或Lv3;X2’是O、NH、N(R1)、或CH2;R3和R5独立地是H、R1、芳基或杂芳基,或芳基基团,其中一个或几个氢原子独立地被-R1、-卤素、-OR1、-SR1、-NR1R2、-NO2、-S(O)R1、-S(O)2R1或-COOR1取代;Lv3是离去基团,选自甲磺酰基、甲苯磺酰基、三氟甲基磺酰基、三氟甲基磺酸酯、硝基苯氧基、苯硫基、吡啶基硫基、N-琥珀酰亚胺基氧基(NHS)、苯氧基、二硝基苯氧基、五氟苯氧基、四氟苯氧基、三氟苯氧基、二氟苯氧基、一氟苯氧基、五氯苯氧基、1H-咪唑-1-基、氯苯氧基、二氯苯氧基、三氯苯氧基、四氯苯氧基、N-(苯并三唑基)氧基、2-乙基-5-苯基异恶唑基、苯基恶二唑基(ODA)、恶二唑基、或与Mitsunobu反应缩合剂产生的中间分子,其中R1和R2如前文所定义;
另外,E3和E’3独立地的选自-SH、-S-SCH3、-S-SAc、-S-S-吡啶、-S-S-Ar(-NO2)、-S-细胞结合剂或具有下式的任一结构:
其中D是H、-NO2、SO3H或F;R1、R2、R3、R4、r、m和n的定义同前文所述;w和w’独立地选自0、1或2;
其中R5和R5’独立地选自C1~C6烷基、芳基、环烷基、杂环基、H、或M(其中M是Na、K、Ca、铵或其他药学上可接受的盐)。
10.如权利要求1、2、4或6所述的L1和L2独立地由下列组分构成:
(A):一个或多个下列连接子组分:6-马来酰亚胺基己酰基(“MC”)、马来酰亚胺丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”或“af”)、对氨基芐氧基羰基(“PAB”)、4-硫代戊酰基(“SPP”)、4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”)、(4-乙酰基)氨基苯酰基(“SIAB”)、4-硫丁酰基(SPDB)、4-硫-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),或含有1-12个天然或非天然氨基酸,具有相同或不同序列的天然或非天然多肽;
(B):一个或多个自毁灭组分,肽单元、腙键、二硫化物、酯、肟、酰胺或硫醚键。自毁灭单元包括但不限于,与对氨基芐基氨甲酰基(PAB)的电子结构相似的芳香化合物,2-氨基咪唑-5-甲醇的衍生物、杂环PAB类似物、β-葡糖苷酸、以及邻或对氨基芐基缩醛,或具有以下结构:
其中(*)是另外组分的连接位点;X1、Y1、Z2和Z3独立地为NH、O或S;Z1独立地为H、NHR1、OR1、SR1、COX1R1,其中X1和R1如前文所定义;v是0或1;U1独立地为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NR5R5’、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)或OCH2PO(OR5(OR5’),其中R5和R5’独立地选自H、C1-C8烷基;C2-C8烯基、炔基、杂烷基或氨基酸;C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基或糖苷;或药用阳离子盐;
其中(*)是连接位点。X1、Y1、U1、R5、R5’如前文所定义;r是0-100;m和n独立地为0-20;
(D):一个或多个可断裂的组分,其包含至少一个可在生理条件下被破坏的键,如pH、酸、碱、氧化作用、代谢、生化或酶不稳定的键,具有一种以下结构:-(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-、(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-、(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-、(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-、-(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-、-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(Aa)t(NR11CO)
(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m-(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2)r-、-(CR5R6)m-苯基CO(Aa)t(CR7R8)n-、-(CR5R6)m-呋喃CO(Aa)t(CR7R8)n-、-(CR5R6)m-恶唑CO(Aa)t(CR7R8)n-、-(CR5R6)m-噻唑基CO(Aa)t(CCR7R8)n-、-(CR5R6)t-噻吩CO(CR7R8)n-、-(CR5R6)t-咪唑CO-(CR7R8)n-、-(CR5R6)t-吗啉CO(Aa)t-(CR7R8)n-、-(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-、-(CR5R6)t-N甲基CO(Aa)t-(CR7R8)n-、-(CR5R)m-(Aa)t苯基-、-(CR5R6)m-(Aa)t呋喃、-(CR5R6)m-恶唑(Aa)t、-(CR5R6)m-噻唑基(Aa)t、-(CR5R6)m-噻吩-(Aa)t-、-(CR5R6)m-咪唑(Aa)t-、-(CR5R6)m-吗啉(Aa)t-、-(CR5R6)m-哌嗪(Aa)t-、-(CR5R6)m-N甲基哌嗪(Aa)t-、K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-、K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-、K(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-、K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-、K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-、K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-、K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-、K-(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r-、K(CR5R6)m-苯基CO(Aa)t(CR7R8)n-、K-(CR5R6)m-呋喃CO(Aa)t-(CR7R8)n-、K(CR5R6)m-恶唑CO(Aa)t(CR7R8)n-、K(CR5R6)m-噻唑基CO(Aa)t-(CR7R8)n-、K(CR5R6)t-噻吩CO(CR7R8)n-、K(CR5R6)t咪唑-CO-(CR7R8)n-、K(CR5R6)t吗啉CO(Aa)t(CR7R8)n-、K(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-、K(CR5R6)t-N甲基CO(Aa)t(CR7R8)n-、K(CR5R)m(Aa)t苯基、K-(CR5R6)m-(Aa)t呋喃-、-K(CR5R6)m-恶唑(Aa)t-、K(CR5R6)m-噻唑基(Aa)t-、K(CR5R6)m-噻吩-(Aa)t-、K(CR5R6)m-咪唑(Aa)t-、K(CR5R6)m-吗啉(Aa)t-、K(CR5R6)m-哌嗪(Aa)t-、K(CR5R6)mN甲基哌嗪(Aa)t-;其中Aa、m和n定义如前文所描述;t和r独立地为0-100;R3、R4、R5、R6、R7和R8独立地选自H;卤素;C1-C8烷基;C2-C8芳基、烯基、炔基、醚、酯、胺或酰胺,这些基团均可以被以下基团所取代:一个或多个卤素、CN、NR1R2、CF3、OR1、芳基、杂环、S(O)R1、SO2R1、-CO2H、-SO3H、-OR1、-CO2R1、-CONR1、-PO2R1R2、-PO3H或P(O)R1R2R3;K是NR1、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、Het(具有C3-C8的杂环或杂芳环),或含有1-20个氨基酸的肽;
(E):以下一个或多个亲水结构:
其中是连接位点;X2、X3、X4、X5、或X6、独立地选自NH、NHNH、N(R3)、N(R3)N(R3’)、O、S、C1-C6烷基、C2-C6杂烷基、烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、或杂芳基;或1-8个氨基酸;其中R3和R3'独立地为H、C1-C8烷基、C2-C8杂烷基、烷基环烷基或杂环烷基;C3-C8芳基、芳烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基或杂芳基;或C2-C8酯、醚或酰胺;或结构式为(OCH2CH2)p或(OCH2CH(CH3))p的聚乙二醇单元,其中p是0至约5000的整数,或上述组合;
(F):下面一个或几个结构单元连接至式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(III)或(IV)中E1和/或E2上,或当E1和/或E2独立缺失时,Q直接连接至式(I)、(Ia)、(Ib)、(Ic)、(Id)(Ie)、(II)、(III)或(IV)中,为下列结构的L1和/或L2上:上:
11.如权利要求1、2、3、4、5、6、或8所述的细胞连接剂/分子,选自:
(A):抗体、蛋白质、前药抗体、纳米抗体、维生素(包括叶酸)、肽、高分子胶束、脂质体、基于脂蛋白的药物载体、纳米颗粒药物载体,连接或涂覆有细胞结合配体上的树状聚合物、小分子或颗粒物,或上述的组合;
(B):抗体状蛋白、全长抗体(多克隆抗体、单克隆抗体、抗体二聚体、抗体多聚体)、多特异性抗体(选自双特异性抗体、三特异性抗体或四特异性抗体)、单链抗体、与靶细胞结合的抗体片段、单克隆抗体、单链单克隆抗体、与靶细胞结合的单克隆抗体片段、嵌合抗体、与靶细胞结合的嵌合抗体片段、域抗体、与靶细胞结合的域抗体片段、表面重组抗体、表面重组单链抗体或与靶细胞结合的表面重组抗体片段、人源化抗体或重组抗体、人源化单链抗体、或与靶细胞结合的人源化抗体片段、抗独特型(anti-Id)抗体、CDR's、双抗体、三抗体、四抗体、微型抗体、probody抗体、probody抗体片段、小免疫蛋白(SIP)、淋巴因子、激素、维生素、生长因子、集落刺激因子、营养转运分子、大分子量蛋白、融合蛋白、激酶抑制剂、基因靶向剂、纳米颗粒或被抗体或大分子量蛋白修饰的聚合物;
(C):细胞结合分子或受体激动剂,选自:叶酸衍生物;谷氨酸尿素衍生物;生长抑素及其类似物(选自奥曲肽(Sandostatin)和兰瑞肽(Somatuline));芳族磺酰胺;垂体腺苷酸环化酶激活肽(PACAP)(PAC1);血管活性肠肽(VIP/PACAP)(VPAC1、VPAC2);黑色素细胞刺激激素(α-MSH);胆囊收缩素(CCK)/胃泌素受体激动剂;铃蟾肽(选自由Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2的组合)/胃泌素释放肽(GRP);神经降压素受体配体(NTR1、NTR2、NTR3);P物质(NK1受体)配体;神经肽Y(Y1-Y6);归巢肽包括RGD(Arg-Gly-Asp)、NGR(Asn-Gly-Arg)、二聚和多聚环状RGD肽(选自cRGDfV)、TAASGVRSMH和LTLRWVGLMS(硫酸软骨素蛋白聚糖NG2受体配体)和F3肽;细胞穿透肽(CPPs);肽激素选自促黄体激素释放激素(LHRH)激动剂和拮抗剂、以及促性腺激素释放激素(GnRH)激动剂、其作用是针对促卵泡激素(FSH)和促黄体激素(LH)、以及睾丸激素的生产,选自Buserelin(布舍瑞林)(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt)、Gonadorelin(戈那瑞林)(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2)、Goserelin(戈舍瑞林)(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2)、Histrelin(组氨瑞林)(Pyr-His-Trp-Ser-Tyr-D-His(N-Benzyl)-Leu-Arg-Pro-NHEt)、leuprolide(亮脯利特)(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt)、Nafarelin(那法瑞林)(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2)、Triptorelin(曲普瑞林)(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2)、Deslorelin(地洛瑞林)、Abarelix(阿巴瑞克)(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-IsopropylLys-Pro-DAla-NH2)、Cetrorelix(西曲瑞克)(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2)、Degarelix(地加瑞克)(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carbamoyl)-Leu-IsopropylLys-Pro-D-Ala-NH2)和Ganirelix(加尼瑞克)(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9、N10-diethyl)-homoArg-Leu-(N9、N10-diethyl)-homoArg-Pro-D-Ala-NH2);模式识别受体(PRRs),选自类Toll受体(TLRs)配体、C型凝集素和Nodlike受体(NLRs)配体;降钙素受体激动剂;整联蛋白受体及其受体亚型(选自αVβ1、αVβ3、αVβ5、αVβ6、α6β4、α7β1、αLβ2、αIIbβ3)激动剂,选自GRGDSPK、环(RGDfV)(L1)及其衍生物(环(-N(Me)R-GDfV)、环(R-Sar-DfV)、环(RG-N(Me)D-fV)、环(RGD-N(Me)f-V)、环(RGDf-N(Me)V-)(Cilengitide));纳米抗体(VHH衍生物(骆驼科动物Ig));结构域抗体(dAb,VH或VL结构域的衍生物);双特异性T细胞接头(BiTE,双特异性双抗体);双重亲和复定位抗体(DART,双特异性双抗体);四价串联抗体(TandAb,二聚双特异性双抗体);Anticalin(Lipocalins的衍生物);Adnectins(第10个FN3(纤连蛋白));设计的锚蛋白重复蛋白(DARPins);Avimers;EGF受体或VEGF受体激动剂;
(D):小分子细胞结合分子/配体或细胞受体激动剂的结构示例如下:LB01(叶酸)、LB02(PMSA配体)、LB03(PMSA配体)、LB04(PMSA配体)、LB05(生长抑制素)、LB06(生长抑制素)、LB07(奥曲肽、生长抑制素类似物)、LB08(兰瑞肽、生长抑制素类似物)、LB09(伐普肽(Sanvar)、生长抑制素类似物)、LB10(CAIX配体)、LB11(CAIX配体)、LB12(胃泌素释放肽受体(GRPr)、MBA)、LB13(促黄体激素释放激素(LH-RH)和GnRH配体)、LB14(促黄体激素释放激素(LH-RH)和GnRH配体)、LB15(GnRH拮抗剂、Abarelix)、LB16(钴胺素、维生素B12类似物)、LB17(钴胺素、维生素B12类似物)、LB18(用于αvβ3整联蛋白受体、环状RGD五肽)、LB19(VEGF受体的异二价肽配体)、LB20(神经髓质素B)、LB21(蛙皮素、作用于G蛋白偶联受体)、LB22(TLR2,作用于类Toll受体)、LB23(作用于雄性激素受体)、LB24(西仑吉肽或环(-RGDfV-)αv整合素受体、LB23(氟可的松)、LB25(利福布汀类似物)、LB26(利福布汀类似物)、LB27(利福布汀类似物)、LB28(氟氢可的松)、LB29(地塞米松)、LB30(丙酸氟替卡松)、LB31(丙酸倍氯米松)、LB32(醋酸曲安奈德)、LB33(泼尼松龙)、LB34(泼尼松龙)、LB35(甲基泼尼松龙)、LB36(倍他米松)、LB37(伊立替康类似物)、LB38(克唑替尼类似物)、LB39(硼替佐米类似物)、LB40(卡菲佐米类似物)、LB41(卡非佐米类似物)、LB42(亮丙瑞林类似物)、LB43(曲普瑞林类似物)、LB44(克林霉素)、LB45(利拉鲁肽类似物)、LB46(半长春新碱类似物)、LB47(瑞他帕林类似物)、LB48(丁布尔类似物)、LB49(长春碱类似物)、LB50(利西森肽类似物)、LB51(奥西丁尼类似物)、LB52(核苷类似物)、LB53(厄洛替尼类似物)和LB54(拉帕替尼类似物),其结构如下所示:
LB12(胃泌素释放肽受体(GRPr),MBA),
LB13(促黄体激素释放激素(LH-RH)和促性腺激素释放激素GnRH配体),
LB14(促黄体激素释放激素(LH-RH)和促性腺激素释放激素GnRH配体),
LB15(GnRH拮抗物,阿巴瑞克),
LB18(环RGD五肽,作用于αvβ3整联蛋白受体),
LB19(异源二价肽配体偶联物,作用于血管内皮生长因子VEGF受体),
LB21(蛙皮素偶联物,作用于G蛋白偶联受体),
LB24(西伦吉肽/环(-RGDfV-)偶联物,作用于αv整合素受体),
12.如权利要求1、2、3、4、5、6、8或10所述的细胞结合剂/分子,其能够识别肿瘤细胞、病毒感染细胞、微生物感染细胞、寄生虫感染细胞、自身免疫性疾病细胞、活化的肿瘤细胞、髓样细胞、活化的T细胞、受影响的B细胞或黑素细胞或表达以下任何一种抗原或受体的细胞:CD1、CD1a、CD1b、CD1c、CD1d、CD1e、CD2、CD3、CD3d、CD3e、CD3g、CD4、CD5、CD6、CD7、CD8、CD8a、CD8b、CD9、CD10、CD11a、CD11b、CD11c、CD11d、CD12w、CD14、CD15、CD16、CD16a、CD16b、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD32a、CD32b、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD42a、CD42b、CD42c、CD42d、CD43、CD44、CD45、CD46、CD47、CD48、CD49b、CD49c、CD49c、CD49d、CD49f、CD50、CD51、CD52、CD53、CD54、CD55、CD56、CD57、CD58、CD59、CD60、CD60a、CD60b、CD60c、CD61、CD62E、CD62L、CD62P、CD63、CD64、CD65、CD65s、CD66、CD66a、CD66b、CD66c、CD66d、CD66e、CD66f、CD67、CD68、CD69、CD70、CD71、CD72、CD73、CD74、CD75、CD75s、CD76、CD77、CD78、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD85、CD85a、CD85b、CD85c、CD85d、CD85e、CD85f、CD85g、CD85g、CD85i、CD85j、CD85k、CD85m、CD86、CD87、CD88、CD89、CD90、CD91、CD92、CD93、CD94、CD95、CD96、CD97、CD98、CD99、CD100、CD101、CD102、CD103、CD104、CD105、CD106、CD107、CD107a、CD107b、CD108、CD109、CD110、CD111、CD112、CD113、CD114、CD115、CD116、CD117、CD118、CD119、CD120、CD120a、CD120b、CD121、CD121a、CD121b、CD122、CD123、CD123a、CD124、CD125、CD126、CD127、CD128、CD129、CD130、CD131、CD132、CD133、CD134、CD135、CD136、CD137、CD138、CD139、CD140、CD140a、CD140b、CD141、CD142、CD143、CD144、CD145、CDw145、CD146、CD147、CD148、CD149、CD150、CD151、CD152、CD153、CD154、CD155、CD156、CD156a、CD156b、CD156c、CD156d、CD157、CD158、CD158a、CD158b1、CD158b2、CD158c、CD158d、CD158e1、CD158e2、CD158f2、CD158g、CD158h、CD158i、CD158j、CD158k、CD159、CD159a、CD159b、CD159c、CD160、CD161、CD162、CD163、CD164、CD165、CD166、CD167、CD167a、CD167b、CD168、CD169、CD170、CD171、CD172、CD172a、CD172b、CD172g、CD173、CD174、CD175、CD175s、CD176、CD177、CD178、CD179、CD179a、CD179b、CD180、CD181、CD182、CD183、CD184、CD185、CD186、CDw186、CD187、CD188、CD189、CD190、CD191、CD192、CD193、CD194、CD195、CD196、CD197、CD198、CD199、CDw198、CDw199、CD200、CD201、CD202、CD202(a、b)、CD203、CD203c、CD204、CD205、CD206、CD207、CD208、CD209、CD210、CDw210a、CDw210b、CD211、CD212、CD213、CD213a1、CD213a2、CD214、CD215、CD216、CD217、CD218、CD218a、CD218、CD21b9、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD231、CD232、CD233、CD234、CD235、CD235a、CD235b、CD236、CD237、CD238、CD239、CD240、CD240ce、CD240d、CD241、CD242、CD243、CD244、CD245、CD246、CD247、CD248、CD249、CD250、CD251、CD252、CD253、CD254、CD255、CD256、CD257、CD258、CD259、CD260、CD261、CD262、CD263、CD264、CD265、CD266、CD267、CD268、CD269、CD270、CD271、CD272、CD273、CD274、CD275、CD276、CD277、CD278、CD279、CD281、CD282、CD283、CD284、CD285、CD286、CD287、CD288、CD289、CD290、CD291、CD292、CD293、CD294、CD295、CD296、CD297、CD298、CD299、CD300、CD300a、CD300b、CD300c、CD301、CD302、CD303、CD304、CD305、CD306、CD307、CD307a、CD307b、CD307c、CD307d、CD307e、CD307f、CD308、CD309、CD310、CD311、CD312、CD313、CD314、CD315、CD316、CD317、CD318、CD319、CD320、CD321、CD322、CD323、CD324、CD325、CD326、CD327、CD328、CD329、CD330、CD331、CD332、CD333、CD334、CD335、CD336、CD337、CD338、CD339、CD340、CD341、CD342、CD343、CD344、CD345、CD346、CD347、CD348、CD349、CD350、CD351、CD352、CD353、CD354、CD355、CD356、CD357、CD358、CD359、CD360、CD361、CD362、CD363、CD364、CD365、CD366、CD367、CD368、CD369、CD370、CD371、CD372、CD373、CD374、CD375、CD376、CD377、CD378、CD379、CD381、CD382、CD383、CD384、CD385、CD386、CD387、CD388、CD389、CRIPTO、CRIPTO、CR、CR1、CRGF、CRIPTO、CXCR5、LY64、TDGF1、4-1BB、APO2、ASLG659、BMPR1B、4-1BB、5AC、5T4(滋养层糖蛋白、TPBG、5T4、Wnt激活的抑制因子1或WAIF1)、腺癌抗原、AGS-5、AGS-22M6、激活素受体样激酶1、AFP、AKAP-4、ALK、α整合素、αvβ6、氨基肽酶N、淀粉样蛋白β、雄激素受体、血管生成素2、血管生成素3、膜联蛋白A1、炭疽毒素保护性抗原、抗转铁蛋白受体、AOC3(VAP-1)、B7-H3、炭疽杆菌炭疽、BAFF(B细胞激活因子)、BCMA、B淋巴瘤细胞、bcr-abl、Bombesin、BORIS、C5、C242抗原、CA125(碳水化合物抗原125、MUC16)、CA-IX(或CAIX、碳酸酐酶9)、CALLA、CanAg、犬科狼疮IL31、碳酸酐酶IX、心肌肌球蛋白、CCL11(CC趋化因子11)、CCR4(CC趋化因子受体4型)、CCR5、CD3E(ε)、CEA(癌胚抗原)、CEACAM3、CEACAM5(癌胚)抗原)、CFD(因子D)、Ch4D5、胆囊收缩素2(CCK2R)、CLDN18(Claudin-18)、聚集因子A、cMet、CRIPTO、FCSF1R(集落刺激因子1受体)、CSF 2(集落刺激因子2、粒细胞-巨噬细胞集落刺激因子(GM-CSF))、CSP4、CTLA4(细胞毒性T淋巴细胞相关蛋白4)、CTAA16.88肿瘤抗原、CXCR4、CXC趋化因子受体4、环状ADP核糖水解酶、细胞周期蛋白B1、CYP1B1、巨细胞病毒、巨细胞病毒糖蛋白B、达比加群、DLL3(Δ状-3)、DLL4(Δ状-4)、DPP4(二肽基)肽酶4)、DR5(死亡受体5)、大肠杆菌毒素1型、大肠杆菌毒素2型、ED-B、EGFL7(含EGF状结构域的蛋白7)、EGFR、EGFRII、EGFRvIII、内皮糖蛋白、内皮素B受体、内毒素、EpCAM(上皮细胞粘附分子)、EphA2、上皮唾液酸蛋白、ERBB2(表皮生长因子受体2)、ERBB3、ERG(TMPRSS2 ETS融合基因)、大肠杆菌、ETV6-AML、FAP(成纤维细胞)激活蛋白(α)、FCGR1、α-甲胎蛋白、纤维蛋白II、β链、纤连蛋白额外结构域B、FOLR(叶酸受体)、叶酸受体α、叶酸水解酶、呼吸道合胞病毒的Fos相关抗原1F蛋白、卷曲蛋白受体、岩藻糖基GM1、GD2神经节苷脂、G-28(细胞表面抗原糖脂)、GD3独特型、GloboH、Glypican 3、N-糖基神经氨酸酸、GM3、GMCSF受体α链、生长分化因子8、GP100、GPNMB(跨膜糖蛋白NMB)、GUCY2C(Guanylate环化酶2C、鸟苷酸环化酶C(GC-C)、肠鸟苷酸环化酶、鸟苷酸环化酶C受体、热稳定肠毒素受体(hSTAR)、热休克蛋白、血凝素、乙型肝炎表面抗原、乙型肝炎病毒、HER1(人表皮生长因子受体1)、HER2、HER2/neu、HER3(ERBB-3)、IgG4、HGF/SF(肝细胞生长因子/散射因子)、HHGFR、HIV-1、组蛋白复合物、HLA-DR(人类白细胞抗原)、HLA-DR10、HLA-DRB、HMWMAA、人类绒毛膜促性腺激素、HNGF、人类散射因子受体激酶、HPV E6/E7、Hsp90、hTERT、ICAM-1(细胞间粘附分子1)、独特型、IGF1R(IGF-1、胰岛素样生长因子1受体)、IGHE、IFN-γ、流感血凝素、IgE、IgE Fc区、IGHE、白介素(包括IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-6R、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-17A、IL-18、IL-19、IL-20、IL-21、IL-22、IL-23、IL-27、or IL-28)、IL31RA、ILGF2(胰岛素样生长因子2)、整合素(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5)、干扰素γ诱导蛋白、ITGA2、ITGB2、KIR2D、Kappa Ig、LCK、Le、Legu-main、Lewis-Y抗原、LFA-1(淋巴细胞功能相关抗原1、CD11a)、LHRH、LINGO-1、脂蛋白酸、LIV1A、LMP2、LTA、MAD-CT-1、MAD-CT-2、MAGE-1、MAGE-2、MAGE-3、MAGE A1、MAGE A3、MAGE 4、MART1、MCP-1、MIF(巨噬细胞迁移抑制因子、或糖基化抑制因子(GIF))、MS4A1(跨膜域4亚科A成员1)、MSLN(间皮素)、MUC1(黏蛋白1、细胞表面相关(MUC1)或多态性上皮黏蛋白(PEM))、MUC1-KLH、MUC16(CA125)、MCP1(单核细胞趋化蛋白1)、Me-lanA/MART1、ML-IAP、MPG、MS4A1(跨膜域4亚科A成员A)、MYCN、髓磷脂相关糖蛋白、Myostatin、NA17、NARP-1、NCA-90(粒细胞抗原)、Nectin-4(ASG-22ME)、NGF、神经细胞凋亡调节蛋白酶1、NOGO-A、Notch受体、神经元癌基因产物、NY-BR-1、NY-ESO-1、OX-40、OxLDL(氧化型低密度脂蛋白)、OY-TES1、P21、p53非突变体、P97、Page4、PAP、N-抗-(N-羟乙酸神经氨酸)、PAX3、PAX5、PCSK9、PDCD1(PD-1、PDL-1)、PDGF-Rα(α型血小板衍生的生长因子受体)、PDGFR-β、PDL-1、PLAC1、PLAP-状睾丸碱性磷酸酶、血小板源性生长因子受体β、磷酸钠共转运蛋白、PMEL 17、聚唾液酸、蛋白酶3(PR1)、前列腺癌、PS(磷脂酰丝氨酸)、前列腺癌细胞、铜绿假单胞菌、PSMA、PSA、PSCA、狂犬病病毒糖蛋白、RHD(Rh多肽1(RhPI))、恒河因子、RANKL、RhoC、Ras突变体、RGS5、ROBO4、呼吸道合胞病毒、RON、ROR1、呼吸道合胞病毒、SART3、Sclerostin、SLAMF7(SLAM族7)、Selectin P、SDC1(联合蛋白聚糖1)、sLe(a)、生长激素C、SIP(鞘氨醇-1-磷酸盐)、Somatostatin、Sperm protein 17、SSX2、STEAP1(前列腺六跨膜上皮抗原1)、STEAP2、STn、TAG-72(肿瘤相关糖蛋白72)、Survivin、T-细胞受体、T细胞跨膜蛋白、TEM1(肿瘤内皮标记1)、TENB2、Tenascin C(TN-C)、TGF-α、TGF-β(Transforming growth factor beta)、TGF-β1、TGF-β2(转化生长因子-β2)、Tie(CD202b)、Tie2、TIM-1(CDX-014)、Tn、TNF、TNF-α、TNFRSF8、TNFRSF10B(肿瘤坏死因子受体超家族成员10B)、TNFRSF-13B(肿瘤坏死因子受体超家族成员13B)、TPBG(滋养层糖蛋白)、TRAIL-R1(肿瘤坏死细胞凋亡诱导配体受体1)、TRAILR2(死亡受体5(DR5))、肿瘤相关钙信号转导子2、MUC1的肿瘤特异性糖基化、TWEAK受体、TYRP1(糖蛋白75)、TRP-2、酪氨酸酶、VCAM-1、VEGF、VEGF-A、VEGF-2、VEGFR-1、VEGFR2、或维生素、WT1、XAGE 1,或表达任何胰岛素生长因子受体或任何表皮生长因子受体的细胞。
13.如权利要求12的肿瘤细胞选自淋巴瘤细胞、骨髓瘤细胞、肾细胞、乳腺癌细胞、前列腺癌细胞、卵巢癌细胞、结肠直肠癌细胞、胃癌细胞、鳞状癌细胞、小细胞、肺癌细胞、无小细胞肺癌细胞、睾丸癌细胞、恶性细胞或任何因不受控制快速增长和分裂而引发癌症的细胞。
14.一种药物组合物包含如权利要求1、2、3、4、5或8中任一项所述的具有治疗有效量的偶联物及其药学上可接受的盐、载体、稀释剂或辅料,或偶联物的组合,可用于治疗或预防癌症,自身免疫性疾病或传染性疾病。
15.如权利要求14所述的液体配方或配制的冻干固体形式的药物组合物,包含权利要求1、2、3、4、5或8中任意一种或多种,重量比0.01%-99%的偶联物;0.0%-20.0%的一种或多种多元醇;0.0%-2.0%的一种或多种表面活性剂;0.0%-5.0%的一种或多种防腐剂;0.0%-30%的一种或多种氨基酸;0.0%-5.0%的一种或多种抗氧化剂;0.0%-0.3%的一种或多种金属螯合剂;0.0%-30.0%的一种或多种用于将所述制剂的pH值调节至4.5-8.5的缓冲盐;0.0%-30.0%一种或多种用于在重新配制时将渗透压调节至约250-350mmol/l以施用于患者的等渗剂。
其中多元醇选自:果糖、甘露糖、麦芽糖、乳糖、阿拉伯糖、木糖、核糖、鼠李糖、半乳糖、葡萄糖、蔗糖、海藻糖、山梨糖、松三糖、棉子糖、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、赤藓糖醇山梨糖醇、甘油或L-葡萄糖酸盐及其金属盐;
其中表面活性剂选自:聚山梨酸酯20、聚山梨酸酯40、聚山梨酸酯65、聚山梨酸酯80、聚山梨酸酯81或聚山梨酸酯85、泊洛沙姆、聚(环氧乙烷)-聚(环氧丙烷)、聚乙烯-聚丙烯、Triton、十二烷基硫酸钠(SDS)、月桂硫酸钠辛基糖苷钠、月桂基、肉豆蔻基、亚油基或硬脂基磺基甜菜碱、月桂基、肉豆蔻基、亚油基或硬脂基肌氨酸、亚油基、肉豆蔻基或十六烷基甜菜碱、月桂酰胺基丙基、椰油酰胺基丙基、亚油酰胺基丙基、肉豆蔻酰胺基丙基、棕榈酰胺基丙基或异硬脂酰胺基丙基甜菜碱(月桂酰胺基丙基)、肉豆蔻酰氨基丙基、棕榈酰丙基丙基或异硬脂酰胺基丙基二甲基胺、甲基可可脂酸钠或油酸甲基牛磺酸钠钠、十二烷基甜菜碱、十二烷基二甲基氧化胺、椰油酰胺基丙基甜菜碱和椰油两性甘氨酸盐、或异硬脂基乙基亚胺基乙磺酸盐、聚乙二醇、聚丙二醇以及乙二醇和丙二醇的共聚物;
其中的防腐剂选自:苄醇、十八烷基二甲基苄基氯化铵、六甲基氯化铵、苯扎氯铵、苄索氯铵、苯酚、丁醇和苄醇、对羟基苯甲酸烷基酯、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、邻苯二酚、间苯二酚、环己醇、3-戊醇或间甲酚;
其中氨基酸选自:精氨酸、胱氨酸、甘氨酸、赖氨酸、组氨酸、鸟氨酸、异亮氨酸、亮氨酸、丙氨酸、甘氨酸谷氨酸或天冬氨酸;
其中抗氧化剂选自:抗坏血酸、谷胱甘肽、胱氨酸或甲硫氨酸;
其中螯合剂选自:EDTA或EGTA;
其中缓冲盐选自:柠檬酸、抗坏血酸、葡萄糖酸、碳酸、酒石酸、琥珀酸、乙酸或邻苯二甲酸的钠、钾、铵或三羟基-乙基氨基盐、Tris或氨丁三醇盐酸盐、磷酸盐或硫酸盐;精氨酸、甘氨酸、甘氨酰甘氨酸或组氨酸的乙酸盐、氯化物、磷酸盐、硫酸盐或琥珀酸盐;
其中等渗剂选自:甘露醇、山梨糖醇、乙酸钠、氯化钾、磷酸钠、磷酸钾、柠檬酸三钠或氯化钠。
16.如权利要求14或15所述的药物组合物以液体或冻干粉/固体的形式包装在小瓶、瓶子、预填充注射器或预填充自动注射器中。.
17.如权利要求1、2、3、4、5或8的偶联物或权利要求14或15的药物组合物,其具有体外、体内或离体细胞杀伤活性。
18.如权利要求14或15所述的药物组合物与化疗药物、放疗药物、免疫疗法药物、自身免疫疾病药物、抗感染药物或其他偶联物同时给药、以协同治疗或预防癌症、或自身免疫性疾病或传染性疾病。
19.如权利要求18所述的化学治疗剂,选自:
(1)a)烷基化剂选自:[氮芥类:苯丁酸氮芥、氯苯那嗪、环磷酰胺、达喀尔巴嗪、雌莫司汀、异环磷酰胺、甲氯乙胺、盐酸甲乙胺盐酸盐、甘露司汀、米多巴糖醇、美法仑、美多内醇、哌布溴替尼、新戊比松、苯乙酰胺、苯乙嘌呤、苯丙氨酸芥末;CC-1065和阿多来新、卡折来新、比折来新或其合成类似物;杜卡霉素及其合成类似物KW-2189、CBI-TMI或CBI二聚体;苯二氮卓二聚体或吡咯并苯并二氮杂(PBD)二聚体、托马霉素二聚体、吲哚基苯并二氮杂卓二聚体、咪唑并苯并二氮杂卓二聚体或噁唑烷并苯并二氮杂卓二聚体;亚硝基脲:包括卡莫司汀、洛莫斯汀、氯佐托星、氟莫司汀、尼莫斯汀、雷莫司汀;烷基磺酸盐:包括白消安、曲丁磺酯、英丙舒凡和哌酰硫烷;三氮烯或达喀尔巴嗪;含铂化合物:包括卡铂、顺铂和奥沙利铂、氮丙啶、苯并多巴、羧甲基酮、美多巴或Uredopa;乙炔亚胺和甲基嘧胺、包括六甲蜜胺、三亚乙基三聚氰胺、三苯甲基磷酰胺、三亚乙基硫代磷酰胺和三甲基氟蜜胺;
b)植物生物碱选自:长春花生物碱:长春新碱、长春碱、长春地辛、长春瑞滨和萘韦宾;紫杉醇:紫杉醇、多西紫杉醇及其类似物;美登素生物碱:DM1、DM2、DM3、DM4、DM5、DM6、DM7、美登素、安丝菌素及其类似物、隐藻蛋白(包括隐藻蛋白-1和隐藻蛋白-8);埃博霉素、Eleutherobin、Discodermolide、草苔虫素、多拉霉素、澳瑞他汀、Tubulysin、Cephalostatin;Pancratistatin;Sarcodictyin;Spongistatin;
c)DNA拓扑异构酶抑制剂选自:Epipodophyllin类:9-氨基喜树碱、喜树碱、克立那托、柔红霉素、依托泊苷、磷酸依托泊苷、伊立替康、米托蒽醌、诺万吨酮、维甲酸(或视黄醇)、替尼泊苷、拓扑替康、9-硝基喜树碱或RFS2000、丝裂霉素及其类似物;
d)抗代谢药选自:[抗叶酸剂:DHFR抑制剂,包括甲氨蝶呤、三甲氧苄氨蝶呤、去甲蝶呤、翼龙蝶呤、氨基蝶呤(4-氨基甾体)或叶酸类似物;IMP脱氢酶抑制剂,包括霉酚酸、硫唑嘌呤、利巴韦林、EICAR;核糖核苷酸还原酶抑制剂,包括羟基脲、去铁胺)];[嘧啶类似物:尿嘧啶类似物(包括安西他滨、氮杂胞苷、6-氮杂尿苷、卡培他滨、卡莫氟、阿糖胞苷、双脱氧尿苷、多昔尿苷、依诺他滨、5-氟尿嘧啶、氟尿苷、拉替曲塞);胞嘧啶类似物(包括阿糖胞苷、阿糖胞苷、氟达拉滨);嘌呤类似物(包括硫唑嘌呤、氟达拉滨、巯基嘌呤、硫胺素、硫鸟嘌呤)];叶酸补充剂、亚叶酸;
e)激素疗法剂选自:受体拮抗剂:[抗雌激素(甲地孕酮、雷洛昔芬、他莫昔芬);LHRH兴奋剂(包括戈斯他林、醋酸亮丙瑞林);抗雄激素药(包括比卡鲁胺、氟他胺、卡普睾酮(Calusterone)、Dromostanolone propionate、环硫雄醇(Epitiostanol)、Gose-relin、Leuprolide、Mepitiostane、Nilutamide、Testolactone、曲洛司坦和其他雄激素抑制剂)];类视黄醇/Deltoid:[维生素D3类似物(包括CB1093、EB1089、KH1060、胆钙化醇、麦角钙化醇);光动力疗法剂(包括维替泊芬、酞菁、光敏剂Pc4、去甲氧基-竹红菌素A);细胞因子(干扰素-α、干扰素-γ、肿瘤坏死因子(TNF)、含TNF的人蛋白)];
f)激酶抑制剂选自:BIBW2992(抗EGFR/Erb2)、伊马替尼、吉非替尼、呱加他尼、索拉非尼、达沙替尼、舒尼替尼、厄洛替尼、尼洛替尼、拉帕替尼、阿西替尼、帕唑帕尼、凡德他尼、E7080(抗VEGFR2)、Mubritinib、普纳替尼、Bafetinib、Bosutinib(、卡博替尼、维莫德吉、Iniparib、鲁索利替尼、CYT387、阿西替尼、Tivozanib、索拉非尼、贝伐单抗、西妥昔单抗、曲妥珠单抗、雷珠单抗、帕尼单抗、Ispinesib;
g)聚(ADP-核糖)聚合酶(PARP)抑制剂选自:奥拉帕尼、尼拉帕尼、Iniparib、Talazoparib、维利帕尼、CEP9722(Cephalon公司)、E7016(Eisai公司)、BGB-290(BeiGene公司)或3-氨基苯甲酰胺;
h)抗生素选自:烯二炔类抗生素(选自加利车霉素、加利车霉素γ1,δ1,α1或β1,Dynemicin、包括Dynemicin A和脱氧Dynemicin,Esperamicin、Kedarcidin、C-1027、Maduropeptin,Neocarzinostatin发色团类药物和相关的色蛋白烯二炔抗生素发色团类药物)、阿克拉霉素、放线菌素、蒽霉素、氮杂苦参碱、博来霉素、放线菌素、Carabicin、Carminomycin、Carzinophilin、Chromomycins、放线菌素D、柔红霉素、地托比星、6-叠氮基-5-氧代-L-正亮氨酸、阿霉素、吗啉代阿霉素、氰基吗啉代阿霉素、2-吡咯烷-阿霉素和脱氧阿霉素、表阿霉素、甲磺酸艾日布林、依索比星、伊达比星、Marcellomycin、Nitomycins、麦考酚酸、诺拉霉素、橄榄霉素、匹来霉素、乌苯美司、Potfiromycin、嘌呤霉素、Quelamycin、罗丹霉素,链黑霉素,链脲霉素,结核菌素,Ubenimex,Zinostatin,佐柔比星;
i)聚酮(多聚乙酰)、Bullatacin和Bullatacinone、吉西他滨、环氧霉素和卡非佐米、硼替佐米、沙利度胺、来那度胺、Pomalidomide、Tosedostat、Zybrestat、PLX4032、STA-9090、Stimuvax、Allovectin-7、Xegeva、Provenge、Yervoy、异戊二烯酸化抑制剂和洛伐他汀、多巴胺能神经毒素、1-甲基l-4-苯基吡啶鎓离子、细胞周期抑制剂(包括星孢菌素)、放线菌素(包括放线菌素D、更生霉素)、鹅膏毒素、博莱霉素(包括博来霉素A2、博来霉素B2、匹来霉素)、蒽环类抗生素(包括柔红霉素、阿霉素(Adriamycin)、伊达比星、表阿霉素、吡柔比星、佐柔比星、米托蒽醌、MDR抑制剂或维拉帕米、Ca2+ATPase抑制剂或毒胡萝卜素、组蛋白去乙酰化酶抑制剂(包括伏立诺他、罗米地辛、帕比司他、丙戊酸、莫西他汀(MGCD0103)、恩替诺特、SB939、Resminostat、Givinostat、AR-42、CUDC-101、萝卜硫素、曲古抑菌素A)、毒胡萝卜素、塞来昔布、格列酮、表没食子儿茶素没食子酸酯、双硫仑、Salinosporamide A;抗肾上腺素选自氨鲁米特、米托坦、曲洛司坦、醋葡醛内酯、醛磷酸酰胺糖苷、氨基乙酰丙酸、阿拉伯糖苷、阿莫司汀、比生群、依达曲沙、地磷酰胺、地美可辛、地吖醌、依氟鸟氨酸(DFMO)、Elfomithine、依利醋铵、依托格鲁、硝酸镓、Gacytosine、羟基脲、伊班膦酸盐、香菇多糖、氯尼达明、米托胍腙、米托蒽醌、莫哌达醇、硝化纤维素、喷司他丁、Phenamet、吡柔比星、Podophyllinic acid、2-乙基酰肼、丙卡巴嗪、雷佐生、Rhizoxin、裂裥菌素、锗螺胺、细交链孢菌酮酸、三亚胺醌、2,2’,2”-三氯三乙胺;单端孢菌烯类(包括T-2毒素、疣孢菌素A、Roridin A和Anguidine);氨基甲酸乙酯、siRNA、反义药物;
(2)自身免疫疾病药物,包括但不限于,环孢菌素、环孢菌素A、氨基己酸、硫唑嘌呤、溴隐亭、苯丁酸氮芥、氯喹、环磷酰胺、皮质类固醇(例如安西奈德、倍他米松、布地奈德、氢化可的松、氟尼缩松、丙酸氟替卡松、氟可龙达那唑、地塞米松、曲安奈德、二丙酸倍氯米松)、DHEA、依那西普、羟基氯喹、英夫利昔单抗、美洛昔康、甲氨蝶呤、麦考酚酸酯、泼尼松、西罗莫司、他克莫司。
(3)抗感染性疾病药物包括:
a)氨基糖苷类:丁胺卡那霉素、阿霉素、庆大霉素(奈替米星、西索米星、异帕米星)、潮霉素B、卡那霉素(丁胺卡那霉素、阿贝卡星、氨基去氧卡那霉素、地贝卡星、妥布霉素)、新霉素(新霉素标液、巴龙霉素、核霉素、血霉素)、妥布霉素、verdamicin;
b)酰胺醇类:叠氮氯霉素、氯霉素、氟苯尼考、甲砜霉素;
c)安沙霉素:格尔德霉素、除莠霉素A;
d)碳青霉烯类:比阿培南,多尼培南,厄他培南,亚胺培南,西司他丁,美罗培南,帕尼培南;
e)头孢类:碳头孢烯(氯碳头孢)、头孢乙腈、头孢克洛、头孢拉定、头孢羟氨苄、头孢罗宁、头孢噻啶、头孢噻吩或头孢菌素、头孢氨苄、头孢来星、头孢孟多、头孢匹林、头孢三嗪、头孢氮氟、头孢西酮、头孢唑啉、头孢拉宗、头孢卡品、头孢达肟、头孢吡肟、头孢米诺、头孢西丁、头孢丙烯、头孢沙定、头孢替唑、头孢呋辛、头孢克肟、头孢地尼头孢妥仑、头孢吡肟、头孢他美、头孢甲肟、头孢地嗪、头孢尼西、头孢哌酮、头孢雷特、头孢噻肟、头孢替安、头孢唑兰、头孢氨苄、头孢咪唑、头孢匹胺、头孢匹罗、头孢泊肟、头孢丙烯、头孢喹肟、头孢磺啶、头孢他啶、头孢特仑、头孢布烯、头孢噻林、头孢唑肟、头孢、头孢曲松、头孢呋辛、头孢唑喃、头霉素(头孢西丁、头孢替坦、头孢美唑)氧头孢烯(氟氧头孢、拉氧头孢);
f)糖肽:博来霉素、万古霉素(奥利万星、特拉万星)、替考拉宁(达巴万星)雷莫拉宁;
g)甘氨酰:替加环素;
h)β-内酰胺酶抑制剂:青霉烷(舒巴坦、他唑巴坦)、克拉维烷(克拉维酸);
i)林可酰胺类:克林霉素、林可霉素;
j)脂肽:达托霉素、A54145、钙依赖性抗生素(CDA);
k)大环内酯类:阿奇霉素、喹红霉素、克拉霉素、地红霉素、红霉素、氟红霉素、交沙霉素、酮内酯类(泰利霉素、喹红霉素)麦迪霉素、美奥卡霉素、竹桃霉素、利福霉素(利福平、利福平、利福布汀、利福喷丁)、罗他霉素、罗红霉素、壮观霉素、螺旋霉素、他克莫司(FK506)、醋竹桃霉素、泰利霉素;
l)单环β-内酰胺抗生素:氨曲南、替吉莫南;
m)恶唑烷酮:利奈唑胺;
恶唑烷酮:利奈唑胺;
n)青霉素类:阿莫西林、氨苄西林、哌伐西林、异他西林、巴氨苄西林、美托帕西林、他氨苄西林、阿齐多西林、阿兹洛西林、苄星青霉素、苄星青霉素、苯甲氧基甲基青霉素、氯美西林、普鲁卡因苄青霉素、卡宾西林(卡林达西林)、氯唑西林、双氯西林、美赞林、氟氯西林,美西林(哌美西林)、美洛西林、甲氧西林、萘菲西林、苯唑西林、培那西林、青霉素、菲乃西林、苯氧甲基青霉素、哌拉西林、丙西林、舒本西林、替莫西林、替卡西林;
o)多肽类:杆菌肽、粘菌素、多粘菌素B;
p)喹诺酮类药物:阿拉沙星、巴洛沙星、环丙沙星、克林沙星、达氟沙星、二氟沙星、依诺沙星、恩诺沙星、Floxin、加雷沙星、加替沙星、吉米沙星、格帕沙星、曲伐沙星卡诺、左氧氟沙星、洛美沙星、麻保沙星、莫西沙星、那氟沙星、诺氟沙星、奥比沙星、氧氟沙星、培氟沙星、曲伐沙星、格帕沙星、西他沙星、司帕沙星、替马沙星、妥舒沙星、曲伐沙星;
q)菌素:普那霉素、奎奴普丁/达福普汀;
r)磺胺类药物:磺胺米隆、百浪多息、磺胺醋酰、磺胺甲二唑、磺胺二甲异恶唑、柳氮磺胺吡啶、磺胺异恶唑、甲氧苄氨嘧啶、甲氧苄啶-磺胺甲基异恶唑(复方新诺明);
s)类固醇抗菌剂选自:夫西地酸;
t)四环素:强力霉素、金霉素、氯羟四环素、地美环素、赖甲环素、氯甲烯土霉素、美他环素、米诺环素、土霉素、青哌四环素、罗利环素、四环素、甘氨酰(如替加环素);
u)其他类型的抗生素:番荔枝科、胂凡纳明、细菌萜醇抑制剂(杆菌肽)、DADAL/AR抑制剂(环丝氨酸)、盘基网菌素、海绵内酯、艾榴塞洛素、埃博霉素、乙胺丁醇、依托泊苷、法罗培南、夫西地酸、痢特灵、异烟肼、海米内酯、甲硝唑、莫匹罗星、Mycolactones、NAM合成抑制剂(如磷霉素)、呋喃妥因、紫杉醇、平板霉素、吡嗪酰胺、奎奴普丁/达福普汀、利福平、他唑巴坦替硝唑、番荔枝内酯;
(4)抗病毒药物包括:
a)融合抑制剂:Aplaviroc、马拉韦罗、维立韦罗、gp41(恩夫韦肽)、PRO140、CD4(Ibalizumab);
b)整合酶抑制剂:拉替拉韦、埃替拉韦、Globoidnan A;
c)成熟抑制剂:贝韦立马、Vivecon;
d)神经氨酸酶抑制剂:奥司他韦,扎那米韦,帕拉米韦;
e)核苷和核苷酸:阿巴卡韦、阿昔洛韦、阿德福韦、氨多索韦、Apricitabine、溴夫定、西多福韦克拉夫定、右艾夫他滨、去羟肌苷(DDI)、艾夫他滨、恩曲他滨(FTC)、恩替卡韦、泛昔洛韦、氟脲嘧啶(5-FU)、3'-氟取代的2',3'-二脱氧核苷类似物(例如,3'-氟-2',3'-二脱氧胸苷(FLT)和3'-氟-2',3'-双脱氧(FLG)福米韦生、更昔洛韦、碘苷、拉米夫定(3TC)、L-核苷(如β-L-胸苷、β-L-2'-脱氧胞苷)、喷昔洛韦、Racivir、利巴韦林、Stampidine、司他夫定(d4T的)、他利韦林(伟拉咪定)、替比夫定、替诺福韦、伐昔洛韦三氟胸苷、缬更昔洛韦、扎西他滨(DDC)、齐多夫定(AZT);
f)非核苷类:金刚烷胺、Ateviridine、卡普韦林、二芳基嘧啶(依曲韦林、利匹韦林)、地拉韦啶、二十二烷醇、乙米韦林、依法韦仑、膦甲酸(磷酰基甲酸)、咪喹莫特、干扰素α、洛韦胺、洛德腺苷、他巴唑、奈韦拉平、NOV-205、聚乙二醇干扰素α、鬼臼毒素、利福平、金刚乙胺、瑞喹莫德(R-848)、醋胺金刚烷;
g)蛋白酶抑制剂:安普那韦、阿扎那韦、博赛泼维、达芦那韦、福沙那韦、茚地那韦、洛匹那韦、奈非那韦、Pleconaril、利托那韦、沙奎那韦、特拉匹韦(VX-950)、替拉那韦;
h)其他类型的抗病毒的药物:抗体酶、阿比朵尔、Calanolides A、浅蓝菌素、蓝藻抗病毒蛋白-N、二芳基嘧啶、表没食子儿茶素没食子酸酯(EGCG)、膦甲酸钠、格瑞弗森、他利韦林(伟拉咪定)、羟基脲、KP-1461、米替福新、普来可那立、合成抑制剂、利巴韦林、Seliciclib;
(5)或是其药学上可接受的盐、水合物或水合盐;或其多晶型晶体;或其光学异构体、外消旋体、非对映异构体或对映异构体。
20.如权利要求20的协同剂,选自以下药物中的一种或几种:阿巴西普、阿贝西比利、醋酸阿比特龙、Abraxane、对乙酰氨基酚/氢可酮、Acalabrutinib、Aducanumab、Adalimumab、ADXS31-142、ADXS-HER2、阿法替尼双马来酸酯、Aldesleukin alectinib、Alemtuzumab、Alitretinoin、ado-trastuzumab emtansine、安非他命/右旋苯丙胺、阿那曲唑、阿立哌唑、蒽环类药物、阿立哌唑、阿扎那韦、阿妥唑单抗、阿托伐他汀、阿韦拉单抗、阿昔布西汀、Brentuximab vedotin、Brigatinib、Budesonide、Budesonide/福莫特罗、Bupre-norphine、Cabazitaxel、Cabozantinib、capmatinib、Capecitabine、carfilzomib、嵌合抗原受体工程T细胞(CAR-T)、Celecoxib、Ceritinib、Cetuxib、Cetuximab、克唑替尼、克比美替尼、科森蒂斯、克唑替尼、CTL019、达比加群、达布拉非尼、达卡巴嗪、达克珠单抗、达科替尼、达托霉素、达拉他珠单抗、达比波锡阿尔法、达鲁那韦、达沙替尼、地尼洛芬、地诺单抗、Depakote、地兰索拉唑、地塞哌甲酯、地塞米松、Dinutuximab、多西环素、Duloxetine、Duvelisib、Durvalumab、依洛珠单抗/埃洛珠单抗/艾美洛韦、依诺肝素、恩沙替尼、恩扎鲁胺、依泊汀阿尔法、厄洛替尼、埃索美拉唑、依佐匹克隆、依那西普、依维莫司、依西美坦、依维莫司、exenatide ER、依泽替米贝、依泽替米贝/辛伐他汀、非诺贝特、非格拉斯汀、芬戈利莫德、丙酸氟替卡松、氟替卡松/沙美特罗、Fulvestrant、Gazyva、吉非替尼、Glatiramer、醋酸高斯瑞林、伊克替尼、伊马替尼、替伊莫单抗、伊布替尼、依德利西布、异环磷酰胺、英夫利昔单抗、咪喹莫特、ImmuCyst、Immuno BCG、伊尼帕里、阿斯巴肽胰岛素、地塞米尔胰岛素、甘精胰岛素、利斯普洛胰岛素、α-干扰素、α-1b干扰素、α-2a干扰素、α-2b干扰素、β-干扰素、β-1a干扰素、β-1b干扰素、γ-1a干扰素、拉帕蒂尼、伊普利单抗、异丙托品溴铵/沙丁胺醇、Ixazomib、卡努马、醋酸兰诺肽、利奈多明、利奈酰胺、甲磺酸利奈替尼、来曲唑、左旋甲状腺素、左旋甲状腺素、利多卡因、利奈唑胺、利拉鲁肽、利地塞米松、LN-144氯雷替尼、美金刚、甲基哌啶酮、美托洛尔、Mekinist、美西他滨/利吡韦林/替诺福韦、莫达非尼、莫米松、Mycidac-C、尼西妥单抗、Neratinib、尼洛替尼、尼拉帕利布、尼古拉单抗、Ofatumumab、奥比妥珠单抗、奥拉帕尼、奥美沙坦、奥美沙坦/氢氯噻嗪、奥马珠单抗、Omega-3脂肪酸乙酯、Oncorine、Oseltamivir、Osimertinib、羟考酮、Palbociclib、帕利珠单抗、帕尼单抗、Panobinostat、帕唑帕尼、Pembrolizumab、PD-1抗体、PD-L1抗体、培美曲塞、帕妥珠单抗、肺炎球菌结合疫苗、泊马利度胺、普瑞巴林、ProscaVax、普萘洛尔、喹硫平、雷贝拉唑、普鲁巴新、氯化镭223、雷洛昔芬、雷洛昔韦、雷莫昔单抗、雷珠单抗、雷戈非尼、瑞博西尼、利妥昔单抗、利伐沙班、罗米地辛、瑞舒伐他汀、鲁索替尼磷酸盐、沙丁胺醇、Savolitinib、Semaglutide、Sevelamer、西地那非、Siltuximab、Sipuleucel-T、西他列汀、西他列汀/二甲双胍、Solifenacin、Solanezumab、Sonidegib、索拉非尼、舒尼替尼、Tacrolimus、Tacrimus、塔帕西拉非、Tacrimus tataparal、他唑帕尼、替莫唑胺、替西罗莫司、替诺福韦/恩曲他滨、替诺福韦二吡呋酯富马酸酯、睾丸激素凝胶、沙利度胺、TICE BCG、碘托溴铵、替沙吉林、托瑞米芬、曲美替尼、曲妥珠单抗、曲贝汀(Ecteinascidin 743)、曲美替尼、曲美单抗、三氟吡啶/替吡西酯、Uro-BCG、Ustekinumab、Valsartan、Veliparib、Vandetanib、Vemurafenib、Venetoclax、Vorinostat、Ziv-aflibercept、Zostavax及其类似物、衍生物、药学上可接受的盐、载体、稀释剂或辅料,或其组合。
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CN115737650A (zh) * | 2021-09-03 | 2023-03-07 | 复旦大学 | 一种嘧啶类衍生物或其药学上可接受的盐在制备治疗结核病药物中的应用 |
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AU2020225202B2 (en) | 2019-02-18 | 2023-10-26 | Eli Lilly And Company | Therapeutic antibody formulation |
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