CN105102427B - 含有环状酰亚胺的肽产物的合成 - Google Patents

含有环状酰亚胺的肽产物的合成 Download PDF

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CN105102427B
CN105102427B CN201480016799.1A CN201480016799A CN105102427B CN 105102427 B CN105102427 B CN 105102427B CN 201480016799 A CN201480016799 A CN 201480016799A CN 105102427 B CN105102427 B CN 105102427B
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B·亨克尔
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Abstract

本发明涉及合成包含至少一个环状酰亚胺基团的肽产物的方法。此外，本发明涉及基本上不含降解产物的包含至少一个环状酰亚胺基团的肽产物。该肽产物可以用作用于质量控制药物肽的参比物质，具体地为用于质量控制GLP‑1激动剂如毒蜥外泌肽的参比物质。

Description

含有环状酰亚胺的肽产物的合成
本发明涉及合成包含至少一个环状酰亚胺基团的肽产物的方法。此外，本发明涉及基本上不含降解产物的包含至少一个环状酰亚胺基团的肽产物。该肽产物可以用作用于质量控制药物肽的参比物质，具体地为用于质量控制GLP-1激动剂如毒蜥外泌肽(exendinpeptide)的参比物质。
使用熟知的重组DNA和化学固相合成方法，已经合成了用于制药的若干蛋白和肽。然而这些蛋白和肽的生产通常导致大量不期望的合成副产物。这在它们通过固相合成而产生时尤其如此。随着肽/蛋白长度的增加，导致了合成步骤的增加，这些副产物可占粗产物的50至70％。
副产物可能包括含有环状酰亚胺基团如天冬酰亚胺或戊二酰亚胺的肽产物。这样的环状酰亚胺基团生成于固相合成期间或之后，例如，当从固相载体除去肽时或当配制或存储肽组合物时(Geiger&Clarke,J.Biol.Chem.262(1987),785-794；Hekman et al.,JPharm.Biomed.Anal.20(1999),763-772；Lindner&Helliger,Exp.Gerontol.36(2001),1551-1563；Aswad et al.,J.Pharm.Biomed.Anal.21(2000),1129-1136；Ritz-Timme&Collins,Ageing Res.Rev.1(2002),43-59；Mergler et al.,J.Pept.Sci.9(2003),36-46；Mergler et al.,J.Pept.Sci.9(2003),518-526:Mergler et al.,J.Pept.Sci.1(2005),650-657；Cebrian et al.,J.Pept.Res.62(2003),238-244；De Boni et al.,J.Chrom.A.1022(2004),95-102；和Houchin et al.,J.Contr.Release 112(2006),111-119)。
含有环状酰亚胺基团的肽产物的靶向合成是未知的。过去，天冬酰亚胺或戊二酰亚胺已经通过“强制降解”方法产生，其中含有氨基酸Asp或Asn的肽经历降解条件，例如在pH 4或pH 8条件下和任选在约40至约50℃的升高的温度下搅拌1-2天。但是，这些方法具有以下缺点：除了所需产物之外，得到了大量的其他降解产物。具体地，环状酰亚胺基团会经历进一步的反应，例如外消旋化，形成异天冬氨酸肽，从Asn转化成Asp，亲核试剂打开天冬酰亚胺，肽键断开，等。因此，在实施强制降解之后，常常难以将所需的环状酰亚胺产物从含肽化合物的复杂混合物中纯化出来。
为了克服这些在制造和纯化环状酰亚胺肽产物中的困难，本发明人研发了用于含环状酰亚胺的肽的靶向合成。
该方法以肽利西拉来(AVE0010)，即一种具有44个氨基酸长度的GLP-1激动剂，作为示例进行显示。利西拉来的氨基酸序列示于SEQ ID NO:1中：
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-
G-A-P-P-s-K-K-K-K-K-K-NH3
利西拉来通过化学固相合成方法来制备。
天冬酰亚胺可以从肽序列-Asn-X-或-Asp-X-(其中X表示C-末端邻接的氨基酸残基)形成。在前一种情况中，环化涉及除去氨(NH3)，在后一种情况中，涉及除去水(H2O)。在图1中，显示了在AVE0010中即在位置-Asn(28)-Gly(29)-和Asp(9)-Leu(10)上形成天冬酰亚胺。所得产物分别标记为[Asp(9)-H2O]-AVE0010和[Asn(28)-NH3]-AVE0010。原则上，相同的反应导致形成从氨基酸Gln或Glu形成戊二酰亚胺。
本发明人现在发现，在合成肽期间在偶联步骤中当在需要形成环状酰亚胺基团的预定位置上使用具有不受保护的COOH或CONH2侧链的氨基酸构造块(building blocks)例如Asp、Asn或Glu、Gln时，靶向合成环状酰亚胺基团是可行的。在不需要形成环状酰亚胺基团的其他位置上，，可以在合成中使用具有受保护的COOH或CONH2侧链的氨基酸构造块。通过增加偶联时间和重复添加偶联试剂，环状酰亚胺基团可以几乎定量的产率得到。因此，本发明允许在肽序列的预定位置选择性形成环状酰亚胺基团，，而不影响可能易于形成环状酰亚胺基团的肽序列的其他位置。
在图2中显示了形成天冬酰亚胺基团。将具有未经保护的羧基侧链的受氨基保护(例如Fmoc)的Asp构造块在偶联试剂的存在下添加至具有游离氨基的载体树脂连接的肽衍生物。天冬酰亚胺基团的形成通过将偶联时间增加至≥1天并重复添加偶联试剂而得到促进。肽合成的其他步骤，即，在先和/或后续步骤，可以在标准条件下进行。但是，应当避免使用用于断开Fmoc保护基的哌啶，因此这会导致天冬酰亚胺环的开环。
本发明的方法实现了以高产率和纯度靶向合成环状酰亚胺肽产物。这些肽产物可以例如用作质量控制药物肽产物如利西拉来的参比物质。
本发明的一个主题是包含至少一个式(I)的环状酰亚胺基团的肽产物或其盐或溶剂化物的合成方法，
其中
R1为1或2个原子长度的桥(或二价自由基)，
R2为氨基酸侧链，
*表示不对称C原子，优选为L-构型，以及
(*)表示任选不对称的C原子，优选为L-构型，
所述方法包括以下步骤：
(a)在其中形成式(I)的环状酰亚胺基团的条件下将式(II)的合成构造块偶联至式(III)的肽产物，
所述式(II)为
其中
X为氨基保护基，
Y为未经保护的羧基或甲酰氨基，
Z为羧基，以及
*表示不对称的C原子，优选为L-构型，
所述式(III)为
其中
R2'为任选保护的氨基酸侧链，
R3为含肽残基，优选结合至固相载体，和
(*)表示任选不对称的C原子，优选为L-构型，
(b)断开氨基保护基X，
(c)任选持续肽合成，以及
(d)任选纯化肽产物(I)。
本发明的另一主题为包含至少一个式(I)的环状酰亚胺基团的肽产物或其盐或溶剂化物：
其中
R1为1或2个原子长度的桥(或二价自由基)，
R2为氨基酸侧链，
*表示不对称的C原子，和
(*)表示任选不对称的C原子。
特别地，肽产物为GLP-激动剂，如毒蜥外泌肽，更具体为利西拉来(AVE0010)。
本发明的进一步的主题为如上所述的式(I)的肽产物或其盐或溶剂化物作为用于质量控制药物肽、特别是GLP-1激动剂肽如毒蜥外泌肽如利西拉来的参比物质的用途。
本发明的再一个主题为用于确定利西拉来(AVE0010)产物组合物中的杂质的量的试剂盒，其包含：
(i)至少一种[Asp(9)-H2O]-AVE0010的贮备制剂(stock preparation)，和/或
(ii)至少一种[Asn(28)-NH3]-AVE0010的贮备制剂。
本发明的再一个主题为用于质量控制组合物的方法，所述组合物包含药物肽产物，具体为GLP-1激动剂肽产物例如毒蜥外泌肽产物，更具体是利西拉来(AVE0010)产物，所述方法包括定量确定具有式(I)的环状酰亚胺基团的肽产物或其盐或溶剂化物在所述组合物中的量。
本发明涉及合成肽产物的方法。术语"肽产物"涵盖具有至少5个或至少10个氨基酸以及至多50个或至多100个氨基酸或甚至更长的长度的肽和蛋白。肽产物可由基因编码的氨基酸构造块组成，或可包含非基因编码的氨基酸构造块，例如非天然存在的氨基酸、D-氨基酸或化学修饰的氨基酸，或可由例如通过二硫桥连接的若干肽链组成。肽产物可进一步含有在N-和/或C-末端和/或在侧链的修饰，例如酰化、酰胺化或添加非肽侧链基团诸如亲脂基团。肽产物可为线性的或环状的。优选地，肽产物具有5-100个氨基酸的长度。
本发明的肽产物可为盐例如药用盐，或溶剂化物例如水合物的形式。药用盐的实例描述于Remington:The Science and Practice of Pharmacy,(20th ed.)ed.A.R.Gennaro A.R.,2000,Lippencott Williams&Wilkins or in Handbook ofPharmaceutical Salts,Properties,Selection and Use,e.d.P.H.Stahl,C.G.Wermuth,2002,jointly published by Verlag Helvetica Chimic Acta,Zurich,Switzerland,andWiley-VCH,Weinheim,Germany。优选地，所述盐为三氟乙酸盐或乙酸盐。
肽产物包含至少一种能够形成式(I)的环状酰亚胺基团的氨基酸残基，特别是具有带有羧基或羧酰胺基团的侧链的氨基酸残基如Asp、Asn、Glu或Gln，在N-末端连接至在肽链中具有可用于环化的N-原子的氨基酸残基。位于C-末端的氨基酸残基可以例如选自D构型或L构型的Gly、Leu、His、Asp、Arg、Phe、Ala、Cys、Gln、Glu、Lys、Met、Asn、Ser、Tyr、Thr、Ile、Trp以及非天然的(例如非基因编码的)氨基酸，它们例如列于供应商的目录中。
优选地，根据本发明方法合成的肽产物包括至少一种式(I)的环状酰亚胺基团和至少一种不呈现为环状酰亚胺基团的具有侧链带有羧基或甲酰氨基的氨基酸残基，如Asp、Asn、Glu或Gln。
肽产物的合成通过如下进行：化学合成方法，具体地本领域熟知的固相合成方法，例如涉及将合成构造块分步偶联至结合于载体(例如合成树脂)的肽链的方法。在本发明优选的实施方案中，肽产物为GLP激动剂肽，具体为毒蜥外泌肽，例如毒蜥外泌肽-4、利拉鲁肽或利西拉来(AVE0010)，或者GLP-1受体激动剂，如GLP-1或-2、胃泌酸调节素(oxyntomodulin)、胰高血糖素(glucagon)，或者同时结合并活化胰高血糖素和GLP-1受体(Hjort et al.,Journal of Biological Chemistry,269,30121-30124,1994；Day JW etal.,Nature Chem.Biol.5:749-757,2009)并抑制体重增加且减少食物摄取的肽(其描述于专利申请WO 2008/071972、WO 2008/101017、WO 2009/155258、WO 2010/096052、WO 2010/096142、WO 2011/075393、WO 2008/152403、WO 2010/070251、WO 2010/070252、WO 2010/070253、WO 2010/070255、WO 2011/160630、WO 2011/006497、WO 2011/117415、WO 2011/117416中，将其内容通过引用的方式并入本申请)，或GIP以及结合并活化GIP和GLP-1受体以及任选高血糖素受体并改善血糖控制、抑制体重增加且减少食物摄取的肽(其描述于专利申请WO 2011/119657、WO 2012/138941、WO 2010/011439、WO 2010/148089、WO 2011/094337和WO 2012/088116中，将其内容通过引用的方式并入本申请)。肽产物的其他实例为胰岛素和胰岛素类似物或DPP-4抑制剂。更具体地，肽产物为毒蜥外泌肽，更优选为利西拉来(AVE0010)。
本发明方法的步骤(a)包括将式(II)的合成酸构造块偶联至式(III)的肽产物。构造块(II)包含基团Z，其中Z为能够在偶联条件下(即在有机溶剂中在偶联试剂的存在下)偶联至氨基的羧基。进一步地，氨基酸构造块(II)包括侧链R1Y，其中R1为具有1至2个原子长度的二价自由基或桥，优选C1-C2基团，更优选-CH2-或-CH2-CH2-基团。Y为未经保护的羧基或甲酰氨基。构造块(II)还具有受保护的氨基NHX，其中X为氨基保护基，例如芴基甲氧基羰基(Fmoc)或其他碱不稳定的保护基，或酸不稳定的保护基如丁氧基羰基(Boc)、三苯甲基(Trt)，或选自羧基苄基(Cbz)或烯丙基氧基羰基(Alloc)的保护基，或在以下中提到的氨基的保护基：Green's Protective Groups in Organic Synthesis,John Wiley&Sons,4thed.2006,chapter 7,Protection for the Amino Group；Protecting Groups,P.J.Kocierski,Thieme,3rd ed.2005,chapter 8,Amino Protecting Groups；或者Houben-Weyl,Methods in Organic Chemistry,Synthesis of Peptides and Peptidomimetics,4lh ed.2001,chapter 2,Protection of Functional groups，将其内容通过引用的方式并入本申请。构造块(II)进一步具有不对称的碳原子，以*标记。优选地，不对称碳原子为L-构型。
肽产物(III)，可以为肽合成的中间体产物，具有能够与合成构造块(II)在偶联条件下(即在有机溶剂中在偶联试剂的存在下)反应的游离氨基。中间体肽产物包含N-末端氨基酸构造块，其具有任选受保护的氨基酸侧链R2'和由一个或多个氨基酸构成的含肽残基R3。含肽残基优选地结合至固相载体，例如示于肽合成的树脂。当R2’不同于H时，肽产物(III)还可以含有不对称的碳原子，以(*)标记。优选地，不对称碳原子为L构型。
步骤(a)中的偶联条件优选包括至少4h、8h、12h、16h或24h和至多48h、72h或96h的反应时间。进一步地，偶联条件优选包括0至50℃、优选15至40℃的反应温度。偶联反应在偶联试剂(诸如TBTU(O-(苯并三唑-1-基)-N,N,N’,N'-四甲基脲鎓四氟硼酸盐)、HBTU(2-(1H-苯并三唑-1-基),1,1,3,3-四甲基脲鎓六氟磷酸盐)或HOBT(1-羟基苯并三唑)/DIC(二异丙基碳二亚胺)或其他偶联试剂)和有机碱(诸如DIPEA(二异丙基乙基胺))的存在下在适当有机溶剂(诸如DMF(二甲基甲酰胺))中进行。例如，可以使用在A.El-Faham,F.Albericio,Chem.Rev.2011,111,6557-6602中提到的偶联试剂，将其内容通过引用的方式并入本申请。
优选地，偶联步骤在其中环状酰亚胺的产率为≥50％、≥60％、≥70％、≥80％或≥90％(基于在偶联步骤(a)中的总产率的量，即，偶联至肽中间体产物(III)的氨基酸构造块(II)的量)的条件下进行。
本发明方法的步骤(b)包括在脱保护试剂如DBU(1,8-二氮杂二环[5.4.0]十一碳-7-烯)的存在下的偶联步骤后断开氨基酸保护基X。进一步适当的脱保护试剂在以下提及：Green's Protective Groups in Organic Synthesis,John Wiley&Sons,4lh ed.2006,chapter 7,Protection for the Amino Group；Protecting Groups,P.J.Kocierski,Thieme,3rd ed.2005,chapter 8,Amino Protecting Groups；或Houben-Weyl,Methods inOrganic Chemistry,Synthesis of Peptides and Peptidomimetics,4lh ed.2001,chapter 2,Protection of Functional groups，将其内容通过引用的方式并入本申请。使用哌啶作为脱保护试剂不是推荐的，因为这会导致环状酰亚胺基团的开环。
任选的步骤(c)包括在形成环状酰亚胺基团后继续合成肽产物。合成可以在标准条件下继续，除了避免使用哌啶作为脱保护试剂之外。步骤(c)还可以包括对侧链保护的氨基酸基团进行脱保护并且将肽从固相载体上断开。这些操作可以在本领域已知的标准条件下进行。
任选的步骤(d)包括将肽产物(I)从肽合成操作中获得的其他肽中纯化。优选地，纯化涉及色谱操作。术语"色谱操作"涉及适于纯化肽产物的色谱操作，包括例如离子交换色谱、疏水作用色谱、亲和色谱、分子排阻色谱，且具体为高效液相色谱(HPLC)，且更具体为反相HPLC，或若干操作的组合。更优选地，色谱操作涉及至少一个反相HPLC色谱步骤。
作为本发明合成方法的结果，可获得分离和纯化的包含式(I)的环状酰亚胺基团的肽产物。优选地，该肽产物基本不含降解产物，例如脱酰胺产物、消旋产物和/或含异天冬酰胺的产物。优选地，降解产物的量小于1％、0.5％或0.1％，基于总产物的量，如经色谱法例如HPLC测量。
肽产物包含至少一个环状酰亚胺基团，例如1、2或3个环状酰亚胺基团。优选地，肽产物包含1或2个环状酰亚胺基团。更优选地，肽产物包含一个或多个未成环的环状酰亚胺基团。
肽产物优选为治疗性肽，例如具有至少一个环状酰亚胺基团的毒蜥外泌肽，特别为利西拉来(AVE0010)。优选的肽产物的实例为[Asp(9)-H2O]-AVE0010、[Asn(28)-NH3]-AVE0010、[Asp(9)-H2O]-毒蜥外泌肽-4、[Asn(28)-NH3]-毒蜥外泌肽-4、[Asp(9)-H20]-利拉鲁肽、[Asp(16)-H20]-GLP-1(7-36)、[Asp(9)-H20]-胰高血糖素、[Asp(15)-H20]-胰高血糖素、[Asp(21)-H2O]-胰高血糖素、[Asn(28)-NH3]-胰高血糖素、[Asp(9)-H2O]-胃泌酸调节素、[Asp(15)-H20]-胃泌酸调节素、[Asp(21)-H20]-胃泌酸调节素、[Asn(28)-NH3]-胃泌酸调节素、[Asn(32)-NH3]-胃泌酸调节素、[Asn(34)-NH3]-胃泌酸调节素、[Asn(35)-NH3]-胃泌酸调节素，以及具有基序-Asn-X-和-Asp-X-的且同时结合并活化胰高血糖素和GLP-1受体的(Hjort et al.,Journal of Biological Chemistry,269,30121-30124,1994；Day JWet al.,Nature Chem Biol,5:749-757,2009)和抑制体重增加且减少食物摄取的(其描述于专利申请WO 2008/071972、WO 2008/101017、WO 2009/155258、WO 2010/096052、WO2010/096142、WO 2011/075393、WO 2008/152403、WO 2010/070251、WO 2010/070252、WO2010/070253、WO 2010/070255、WO 2011/160630、WO 2011/006497、WO 2011/117415、WO2011/117416中，将其内容通过引用的方式并入本申请)所有肽，或GIP以及结合并活化GIP和GLP-1受体以及任选高血糖素受体并改善血糖控制、抑制体重增加且减少食物摄取的肽(其描述于专利申请WO 2011/19657、WO 2012/138941、WO 2010/011439、WO 2010/148089、WO 2011/094337和WO 2012/088116中，将其内容通过引用的方式并入本申请)。
本发明的肽产物可用作例如用于质量控制药物肽的参比物质，具体地用于质量控制方法中的参比物质，在所述方法中定量地确定肽产物制剂中含有环状酰亚胺基团的不期望的副产物的量。
肽产物样品中副产物的定量确定优选包括质谱法。除了质谱法之外，该确定还可涉及先前的色谱操作，例如以将其他杂质与肽产物或与组合物的其他成分分离。优选地，将质谱法与HPLC组合。
质谱法是基于带电粒子的质荷比的测量。在典型的质谱操作中，将样品加载至质谱仪器上并挥发。将样品成分电离并将所得的离子在质量分析器中经电磁场分离。检测所得的离子并将信号加工为质谱。对于肽产物的电离，可使用电喷雾电离(ESI)和基质辅助激光解吸/电离(MALDI)。所得的离子可通过高灵敏度方法检测，诸如轨道阱或傅里叶变换(FT)-离子回旋共振(ICR)检测系统。
借助于质谱法，可以鉴定由含有环状酰亚胺基团的副产物获得的峰，其与非环状产物的质量差18(H2O的质量)或17(NH3的质量)。
此外，本发明应通过下述实施例来进行更详细地阐述，，该实施例描述了含有环状酰亚胺基团的肽[Asp(9)-H2O]-AVE0010的合成、色谱纯化和分析表征。
实施例
1.合成Asp(9)-H2O]-AVE0010
[Asp(9)-H2O]-AVE0010为合成药物肽产物AVE0010的副产物。其如下产生：氨基酸Asp(9)的侧链在除去水的条件下形成具有邻接氨基酸Leu(10)的N-原子的天冬酰亚胺。
[Asp(9)-H2O]-AVE0010的氨基酸序列如下：
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-X-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lIe-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2
肽合成以肽合成器Bio536(CS Bio)进行。作为原料，使用N-末端的Fmoc保护的(20-44)-AVE0010树脂。原料通过在标准条件下的肽合成制备。
将25.56g Fmoc-(20-44)-AVE0010树脂与250ml DMF混合，搅拌5分钟，并且然后溶胀2小时。然后通过剥离漏斗抽吸DMF。溶胀后，Fmoc断开以25％哌啶/DMF进行。
然后，在标准条件下使用具有Fmoc保护的氨基和受保护的侧链如O-叔丁基(OtBu)保护的Glu侧链、三苯甲基(Trt)-保护的Gln侧链、丁基氧基羰基(Boc)-保护的Lys侧链和叔丁基(tBu)-保护的Ser侧链的氨基酸衍生物将氨基酸Val(19)至Leu(10)偶联至原料。
然后，Fmoc-Asp-OH构造块(没有侧链保护基)在有利于形成天冬酰亚胺基团的条件下偶联。
将4.26g Fmoc-Asp-OH、1.9g HOBT水合物和2mL DIC在250mL DMF中与树脂混合。将反应混合物搅拌过夜。然后将偶联溶液泵出，并且将树脂以DMF洗涤两次。然后，将3当量的HOBT和3当量的DIC在DMF中与树脂混合。将树脂搅拌过周末。
为了确定天冬酰亚胺形成的程度，将树脂样品以称为King’s混合物的断开混合物处理(D.S.King,C.G.Fields,G.B.Fields,Int.J.Peptide Protein Res.36,1990,255-266)，从而将含天冬酰亚胺的肽从树脂释放出来。通过质谱方法测量，发现偶联产物主要以环状天冬酰亚胺的形式存在。
接着，使用2％的DBU在DMF中的溶液用于Fmoc断开。
最后，氨基酸Ser(8)至Gly(1)在标准条件下(除了Emoc保护基不是被哌啶而是被DBU断开)偶联，从而防止环状天冬酰亚胺基团的打开。结果是在树脂上得到了30.5g[Asp(9)-H2O]-AVE0010。
将肽与树脂以及侧链保护基的断开以King’s混合物进行。在固相合成后，从30.5gFmoc保护的树脂得到9.25g原产物(纯度为23.4％，由UV在215nm测量)。
肽与树脂的断开在标准条件(King et al.,1990,Supra)下进行。总计而言，在真空干燥后得到9.25g的粗[Asp(9)-H20]-AVE0010。
2.色谱纯化[Asp(9)-H2O]-AVE0010
纯化通过两个RP-HPLC步骤以及随后的冷冻干燥来进行。RP-HPLC步骤使用VarianPrepStar装置进行。填充有C18反相材料(例如用于第一步的Daisogel C18或用于第二步的Hydrospher C18)的不锈钢柱用作为固定相。H2O+0.1％三氟乙酸用作流动相A且乙腈用作流动相B。梯度分别在0-80％流动相B(Daisogel)和0-35％流动相B(Hydrospher)下进行。
结果为获得540mg[Asp(9)-H2O]-AVE0010，纯度为91.50％(面积％，由HPLC测量)。纯化产物的分析色谱图示于图3中。
3.分析表征
纯化产物使用质谱表征。纯化的AVE0010用作参比标准物。
该分析表征显示了正确产物[Asp(9)-H20]-AVE0010，其具有的分子量(M+H)+＝4838.460，并且AVE0010标准为显示分子量4856.544。[Asp(9)-H2O]-AVE0010与AVE0010的质量差为18.084，相当于H2O分子。[Asp(9)-H2O]-AVE0010的理论单一同位素分子量为4837.534。

Claims (9)

1.合成包含至少一个式(I)的环状酰亚胺基团的肽产物或其盐的方法：
其中
R1为-CH2-或-CH2-CH2-，
R2为氨基酸侧链,
*表示不对称C原子，和
(*)表示任选不对称的C原子，
所述方法包括以下步骤：
(a)在其中形成式(I)的环状酰亚胺基团的条件下将式(II)的合成构造块偶联至式(III)的肽产物，
所述式(II)为
其中
R1为-CH2-或-CH2-CH2-，
X为Fmoc氨基保护基，
Y为未经保护的羧基或甲酰氨基，
*表示不对称的C原子，以及
Z为羧基，
所述式(III)为
其中
R2'为任选保护的氨基酸侧链，
R3为含肽残基，其由一个或多个氨基酸构成，以及
(*)表示任选不对称的C原子，
且其中偶联条件包括：(i)至少12h的反应时间；(ii)15至40℃的温度；(iii)重复的添加偶联试剂(a)TBTU或(b)HBTU与DIPEA或(c)HOBt和DIC；和(iv)二甲基甲酰胺作为有机溶剂，
(b)断开氨基保护基X，其中所述步骤(b)不用哌啶作为脱保护试剂进行，
(c)任选持续所述肽合成，以及
(d)任选纯化所述包含至少一个式(I)的环状酰亚胺基团的肽产物。
2.权利要求1的方法，其中R1为-CH2-。
3.权利要求1的方法，其中R1为-CH2-CH2-。
4.权利要求1-3中任一项的方法，其中Y为未经保护的羧基。
5.权利要求1的方法，其中Y为甲酰氨基。
6.权利要求1的方法，其中偶联步骤(a)在树脂上进行。
7.权利要求1的方法，其中在偶联步骤(a)中的环状酰亚胺产物的产率为≥50％、≥60％、≥70％、≥80％或≥90％，基于在偶联步骤(a)中偶联至肽产物(III)的氨基酸构造块(II)的总量。
8.权利要求1的方法，其中断开步骤(b)用脱保护试剂1,8-二氮杂双环[5.4.0]十一碳-7-烯来进行。
9.权利要求1的方法，其中在所述肽产物的至少一个预定位置上选择性地引入式(I)的环状酰亚胺基团。
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