CN117164601A - 一种高喜树碱类小分子及其应用 - Google Patents
一种高喜树碱类小分子及其应用 Download PDFInfo
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- CN117164601A CN117164601A CN202310651279.9A CN202310651279A CN117164601A CN 117164601 A CN117164601 A CN 117164601A CN 202310651279 A CN202310651279 A CN 202310651279A CN 117164601 A CN117164601 A CN 117164601A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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Abstract
本发明公开了一种高喜树碱类小分子及其应用。本发明具体公开了一种如式I所示的高喜树碱类小分子或其药学上可接受的盐,及其抗体药物偶联物,能够抑制肿瘤细胞的增殖。
Description
技术领域
本发明涉及一种高喜树碱类小分子及其应用。
背景技术
喜树碱类化合物是DNA拓扑异构酶I的特异性抑制剂。喜树碱类化合物通过与TopoI-DNA可裂解二元复合物的结合形成稳定的Topo I-DNA-CPT三元复合物,影响了DNA的再连接,加大了Topo I介导的DNA损伤,最终导致细胞死亡。
传统喜树碱化合物是一个五环喹啉类生物碱,结构中包含喹啉环AB、吡咯环C、吡啶酮环D和α-羟基内酯环E,其中20-位为S构型。1998年,Bigg等人发现包含一个七元β-羟基内酯环结构的高喜树碱类化合物,在增加内酯环稳定性的同时保持了抗肿瘤活性(Bailly,C.Crit.Rev.Oncol.Hematol.2003,45,91)。其中Diflomotecan是第一个进入临床研究的高喜树碱类化合物,表现出高的体外细胞毒性和良好的体内抗肿瘤活性;Diflomotecan的Topo I抑制活性要强于喜树碱(Kroep,J.R.;Gelderblom,H.Expert.Opin.Investig.Drugs2009,18,69)。吕伟课题组在高喜树碱的结构基础上,在内酯环羧基α位引入甲氧基制备新型高喜树碱衍生物。甲氧基修饰的高喜树碱衍生物在保持高细胞毒活性,其相关衍生物在某些肿瘤细胞中能达到pM级别的肿瘤抑制活性,并且在体内抗肿瘤实验中表现出优异的抗肿瘤效果和低毒性(DOI:10.1016/j.bmc.2015.03.031),进一步表明以甲氧基修饰的高喜树碱母核结构用于新型喜树碱结构改造的可行性。同时,该类母核衍生物体现的高细胞毒活性也为高喜树碱类衍生物用于抗体药物偶联物提供可能。但目前,高喜树碱衍生物并未有作为ADC效应分子的报道。
发明内容
本发明所要解决的技术问题是为了克服现有技术中高喜树碱类衍生物及其抗体药物偶联物结构单一的缺陷,而提供了一种高喜树碱类小分子、抗体药物偶联物及其应用。本发明提供的高喜树碱类小分子、抗体药物偶联物具有很好的细胞毒活性,能够抑制肿瘤细胞的增值。
本发明提供了一种如式I所示的高喜树碱类小分子或其药学上可接受的盐,
其中,A1为H或-C(=O)-C1-6亚烷基-OH;
R1和R2独立地为C1-6烷基、C1-6烷氧基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
在本发明的某一方案中,所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐中,A1为H或-C(=O)-C1-6亚烷基-OH;
R1和R2独立地为C1-6烷基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
在本发明的某一方案中,所述的药学上可接受的盐可为三氟醋酸盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐或丙二酸盐,例如三氟醋酸盐。
在本发明的某一方案中,A1为-C(=O)-C1-6亚烷基-OH时,所述的C1-6亚烷基优选为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH(CH3)CH2-,例如-CH2-。
在本发明的某一方案中,R1和R2独立地为C1-6烷基时,所述的C1-6烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基。
在本发明的某一方案中,R1和R2独立地为C1-6烷氧基时,所述的C1-6烷氧基为甲氧基、-OCH2CH3、异丙氧基或叔丁氧基,例如甲氧基。
在本发明的某一方案中,R1和R2独立地为卤素时,所述的卤素为氟、氯、溴或碘,例如氟。
在本发明的某一方案中,A1为H或-C(=O)CH2OH。
在本发明的某一方案中,所述的如式I所示的高喜树碱类小分子选自如下任一结构:
在本发明的某一方案中,所述的如式I所示的高喜树碱类小分子其药学上可接受的盐选自如下任一结构:
本发明还提供了一种如式II所示的连接基-药物偶联物,
其中,Q为单个氨基酸残基、二肽残基、三肽残基或四肽残基;
X为-(OCH2CH2)m-、-(CRaRb)m-、-O(CRaRb)m、-NH-(CRaRb)m-CRcRd-或-S(CRaRb)m-CRcRd-;
Y为
Ra和Rb独立地为H、D、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、羟基、氨基、氰基、硝基、3-10元环烷基或3-10元杂环基;
或者,Ra和Rb与其相连接的碳原子一起形成3-10元环烷基或或3-10元杂环基;
Rc和Rd独立地为H、C1-6烷基、卤素、卤代C1-6烷基、氘代C1-6烷基、3-10元环烷基、3-10杂环基、6-14元芳基或5-10元杂芳基;
或者,Rc和Rd与其相连接的碳原子一起形成3-10元环烷基或3-10元杂环基;
m独立地为0-10;
n为1-6;
R1、R2、“*1”和“*2”的定义如前所述。
在本发明的某一方案中,所述3-10元杂环基和5-10元杂芳基中的杂原子选自N、O和S中的一种或多种,杂原子的个数为1-3个。
在本发明的某一方案中,所述的如式II所示的连接基-药物偶联物中,Q为单个氨基酸残基、二肽残基、三肽残基或四肽残基;
X为-(OCH2CH2)m-、-(CRaRb)m-、-O(CRaRb)m、-NH-(CRaRb)m-CRcRd-或-S(CRaRb)m-CRcRd-;
Y为
Ra和Rb独立地为H、D、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、羟基、氨基、氰基、硝基、3-10元环烷基或3-10元杂环基;
或者,Ra和Rb与其相连接的碳原子一起形成3-10元环烷基或或3-10元杂环基;
Rc和Rd独立地为H、C1-6烷基、卤素、卤代C1-6烷基、氘代C1-6烷基、3-10元环烷基、3-10杂环基、6-14元芳基或5-10元杂芳基;
或者,Rc和Rd与其相连接的碳原子一起形成3-10元环烷基或3-10元杂环基;
m独立地为0-10;
n为1-6;
R1和R2独立地为C1-6烷基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
在本发明的某一方案中,所述的单个氨基酸残基为-Phe-、-Lys-、-Val-、-Ala-、-Cit-、-Leu-、-Ile-、-Arg-或-Trp-。
在本发明的某一方案中,所述的二肽残基为C=O-Lys-Phe-NH、C=O-Ala-Val-NH、C=O-Lys-Val-NH、C=O-Lys-Ala-NH、C=O-Cit-Val-NH、C=O Cit-Phe-NH、C=O-Cit-Leu-NH、C=O Cit-Ile-NH、C=O-Arg-Phe-NH、C=O-Cit-Trp-NH或C=O-Val-Gly-NH。
在本发明的某一方案中,所述的三肽残基为C=O-Ala-Val-Glu-NH、C=O-Cit-Val-Glu-NH、C=O-Ala-Val-αGlu-NH或C=O-Cit-Val-αGlu-NH。
在本发明的某一方案中,所述的四肽残基为C=O-Gly-Phe-(Gly)2-NH或C=O-(Gly)2-Phe-Gly-NH。
在本发明的某一方案中,所述的二肽残基、三肽残基或四肽残基中的C=O表示所述的二肽残基、三肽残基或四肽残基的左侧通过羰基与所述的如式III所示的抗体药物偶联物中的氨基连接,所述的二肽残基、三肽残基或四肽残基中的NH表示所述的二肽残基、三肽残基或四肽残基的右侧通过氨基与所述的如式III所示的抗体药物偶联物中的羰基连接。
在本发明的某一方案中,Ra和Rb独立地为H。
在本发明的某一方案中,m独立地为5。
在本发明的某一方案中,n为1。
在本发明的某一方案中,所述的四肽残基为C=O-Gly-Phe-(Gly)2-NH。
在本发明的某一方案中,所述的如式II所示的连接基-药物偶联物可为如下结构:
本发明还提供了一种如式III所示的抗体药物偶联物:
其中,GL为抗体;
p为1-8;
Z为其中b端与X连接,a端与GL连接;
R1、R2、X、Q、n、“*1”和“*2”的定义如前所述。
在本发明的某一方案中,所述的如式III所示的抗体药物偶联物中,GL为抗体;
p为1-8;
Z为其中b端与X连接,a端与GL连接;
Q为单个氨基酸残基、二肽残基、三肽残基或四肽残基;
X为-(OCH2CH2)m-、-(CRaRb)m-、-O(CRaRb)m、-NH-(CRaRb)m-CRcRd-或-S(CRaRb)m-CRcRd-;
Ra和Rb独立地为H、D、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、羟基、氨基、氰基、硝基、3-10元环烷基或3-10元杂环基;
或者,Ra和Rb与其相连接的碳原子一起形成3-10元环烷基或或3-10元杂环基;
Rc和Rd独立地为H、C1-6烷基、卤素、卤代C1-6烷基、氘代C1-6烷基、3-10元环烷基、3-10杂环基、6-14元芳基或5-10元杂芳基;
或者,Rc和Rd与其相连接的碳原子一起形成3-10元环烷基或3-10元杂环基;
m独立地为0-10;
n为1-6;
R1和R2独立地为C1-6烷基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
在本发明的某一方案中,GL为HER2抗体,例如Trastuzumab(曲妥珠单抗)。
在本发明的某一方案中,p可以为整数,也可以为小数,优选为6.7-7.2,例如6.8、6.9或7.1。
在本发明的某一方案中,p可以为整数,也可以为小数,例如6.7。
在本发明的某一方案中,所述Z的a端和所述的GL以硫醚键相连。所述的GL可通过含二硫键的抗体(例如Trastuzumab)在还原剂作用下将二硫键还原为巯基后得到。
在本发明的某一方案中,所述的如式III所示的抗体药物偶联物可为如下结构:
其中HER2抗体为Trastuzumab。
本领域技术人员可以理解的是,Z是与打开二硫键后的抗体自身所含有巯基(例如,通过还原剂还原抗体自身的二硫键可以打开二硫键,生成-SH)进行连接。例如抗体药物偶联物HER2-L-5中,-S-并非另外外接的硫原子,而是打开双硫键后的HER2抗体自身所含有巯基与进行连接后形成的-S-。
本发明还提供了一种药物组合物,其包括如上所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐、或如上所述的如式III所示的抗体药物偶联物,和至少一种药用辅料。
本发明还提供了一种如上所述的如式I所示的高喜树碱类小分子、或其药学上可接受的盐、或如上所述的如式III所示的抗体药物偶联物在制备用于预防或治疗癌症的药物中的用途。所述的癌症优选为乳腺癌、肺癌、肾癌、肝癌、卵巢癌、尿道癌、前列腺癌、多形性成胶质细胞瘤、胰腺癌、大肠癌、胃肠道间质瘤、宫颈癌、鳞状细胞癌、腹膜癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、外阴癌、甲状腺癌、阴茎癌、白血病、恶性淋巴瘤、浆细胞瘤、骨髓瘤、肉瘤、黑色素瘤、膀胱癌、胃癌或食道癌,优选为乳腺癌。
本发明还提供了如下所式的化合物,
术语定义
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数(例如C1~C6)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。
术语“芳基”是指具有指定的碳原子数(例如C6~C10)的、仅由碳原子组成的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。芳基包括但不限于苯基、萘基等。
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。例如,CH3-C(=O)-是指乙酰基。
在本申请中,作为基团或是其它基团的一部分,术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团;即烷基中的一个氢被取代,烷基的定义如上所述。亚烷基基团的实例包括亚甲基(-CH2-),亚乙基{包括-CH2CH2-或-CH(CH3)-},亚异丙基{包括-CH(CH3)CH2-或-C(CH3)2-}等等。
术语“烷氧基”是指-O-烷基,烷基的定义如上所述。
术语“环烷基”是指具有指定的碳原子数(例如C3~C6)的、仅由碳原子组成的、饱和的单环环状基团。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“杂环基”是指具有指定环原子数(例如5~10元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团,其为单环、桥环或螺环,且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基、哌啶基等。
术语“杂芳基”是指具有指定环原子数(例如5~10元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。杂芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基等。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明提供了一类结构新颖的高喜树碱类小分子、其抗体药物偶联物,能够抑制肿瘤细胞的增殖。
附图说明
图1为实验例2中HER2-CZY-8和HER2-L-4对NCl-N87肿瘤细胞增殖能力的影响。
图2为实验例3中抗体药物偶联物对NOG小鼠皮下移植NCI-N87细胞动物模型的抗肿瘤药效检测结果。
图3为实验例3中NOG小鼠皮下移植NCI-N87细胞动物模型的体重变化。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下列实施例中,DCC表示二环己基碳二亚胺;DMAP表示二甲氨基吡啶;DIPEA表示二异丙基乙胺;DMF表示N,N-二甲基甲酰胺;PBS表示磷酸缓冲盐溶液。
实施例1化合物GX-1和化合物GX-2的制备
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步骤1:
氮气保护下,将80mL三氯化硼的二氯甲烷溶液(1mol/L)溶于400mL无水1,2-二氯甲烷中,冰水浴下将体系冷却至0℃。在冰水浴下,将化合物1a(12.5g,99.9mmol)加入反应体系,保持冰水浴反应10min,再依次将氯乙腈(13.5mL,213.3mmol)和无水氯化铝(17.5g,131.2mmol),保持冰水浴反应10分钟,再将体系移至室温反应10分钟,然后将体系升温至回流反应40小时。反应完毕后将体系冷却至室温,缓慢加入200mL冰水,然后加入200mL 5%盐酸水溶液搅拌30分钟,用二氯甲烷(300mL×3)萃取,有机相依次用水、饱和氯化钠水洗涤,无水MgSO4干燥。旋干溶剂后得粗产品,经柱层析(石油醚:乙酸乙酯=20:1)分离纯化得到7.0g化合物1b,收率35%。1H NMR(400MHz,DMSO-d6)δ7.68(d,J=8.7Hz,1H),7.31(s,2H),6.53(d,J=12.5Hz,1H),4.98(s,2H),2.10(s,3H).MS(ESI)m/z=202.5(M+H+)。
步骤2:
将化合物1b(2.7g,13.4mmol)溶于20mL无水二氯甲烷中,依次加入DCC(5.5g,26.8mmol),DMAP(160mg,1.3mmol),在冰水浴下,将丙二酸单乙酯(2.4mL,20.1mmol)缓慢滴入体系,滴加完毕后在室温下反应12小时。反应完毕后,过滤,滤液旋干得到粗产物4.0g,将粗产物溶于20mL乙醇。向体系分批加入乙醇钠(1.4g,20.6mmol),室温下继续反应2小时。反应完毕后将体系中析出的固体滤出,固体用二氯甲烷和乙醚打浆得到2.5g化合物1c,收率63%。1H NMR(400MHz,Chloroform-d)δ7.90(d,J=7.3Hz,1H),7.62(d,J=9.9Hz,1H),4.86(s,2H),4.53(q,J=6.2Hz,2H),2.51(s,3H),1.46(t,J=6.7Hz,3H).13C NMR(101MHz,Chloroform-d)δ165.28,163.44(d,J=255.0Hz),147.94(d,J=13.3Hz),146.31,141.49,129.15(d,J=20.8Hz),126.98–126.82(m),125.81(d,J=6.7Hz),121.19,112.87(d,J=22.3Hz),62.89,37.93,15.78(d,J=3.5Hz),14.09.MS(ESI)m/z=298.6(M+H+)。
步骤3:
将化合物1c(2.0g,6.7mmol)分散于30ml无水乙腈中,向体系加入三溴氧磷(2.8g,10.1mol),加料完毕后升温回流反应12h。反应完毕后将体系倒入100mL冰水中,用乙酸乙酯(100mL×3)萃取,有机相依次用水、饱和氯化钠水溶液洗涤,无水MgSO4干燥。旋干溶剂后得粗产品,经柱层析(石油醚:乙酸乙酯=90:1)分离纯化得到2.0g化合物1d,收率75%。1HNMR(400MHz,Chloroform-d)δ7.89(d,J=7.6Hz,1H),7.68–7.61(m,1H),4.74(d,J=6.2Hz,2H),4.54(q,J=6.7Hz,2H),2.51(s,3H),1.48(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ165.89,165.37,148.58(d,J=13.2Hz),141.12,137.64,129.81–128.45(m),125.80(d,J=6.7Hz),121.15(d,J=10.3Hz),113.32–112.42(m),100.02,62.92(d,J=5.6Hz),23.45(d,J=14.7Hz),15.88(t,J=3.6Hz),14.11.MS(ESI)m/z=406.4(M+H+)。
步骤4:
在冰水浴下,将化合物1d(2.0g,4.9mmol)溶于40mL无水二氯甲烷中,向反应体系逐滴加入1M的二异丁基氢化铝的正己烷溶液(25mL,24.5mmol),滴加完毕后保持冰水浴反应2小时。反应完毕后,将反应液缓慢加入40mL饱和酒石酸钠盐水溶液中,搅拌4小时后,用二氯甲烷(20mL×3)萃取,有机相用饱和氯化钠水溶液洗涤,无水MgSO4干燥。旋干溶剂得粗产品,经柱层析(石油醚:乙酸乙酯=5:1)分离纯化得到1.4g化合物1e,收率80%。1H NMR(400MHz,Chloroform-d)δ7.85(d,J=7.8Hz,1H),7.61(d,J=10.1Hz,1H),5.06(s,2H),4.98(s,2H),2.50(s,3H),2.40(s,1H).13C NMR(101MHz,Chloroform-d)δ163.05(d,J=254.1Hz),148.22(d,J=13.2Hz),145.08,143.96–143.36(m),130.52(d,J=2.6Hz),128.71(d,J=20.9Hz),125.50(d,J=6.6Hz),122.51,112.71(d,J=22.1Hz),61.28,23.75,15.87.MS(ESI)m/z=364.1(M+H+)。
步骤5:
将化合物1e(1.4g,3.9mmol)溶于15ml二甲基亚砜中,加入叠氮化钠(300mg,4.7mmol),室温搅拌反应12小时。反应完毕后加入150ml水,有固体析出,直接过滤得到1.2g化合物1f,不进一步分离,直接进行下一步反应。MS(ESI)m/z=326.2(M+H+)。
步骤6:
将化合物1f(1.2g,3.7mmol)溶于四氢呋喃和水(3:1,40mL)混合溶剂中,在冰水浴下向体系加入1M的三甲基磷的四氢呋喃溶液(6.5mL,5.6mmol),滴加完毕后保持冰水浴反应3小时。反应完毕后将反应体系旋干得到粗产物,经柱层析(二氯甲烷:甲醇=30:1)分离纯化得到1.0g化合物1g,收率90%。1H NMR(400MHz,DMSO-d6)δ8.23(d,J=8.2Hz,1H),7.65(d,J=10.6Hz,1H),4.83(s,2H),4.25(s,2H),2.45(s,3H).13C NMR(101MHz,DMSO-d6)δ163.16,160.67,150.53,147.13(d,J=13.0Hz),145.81,131.64(d,J=2.2Hz),127.36(d,J=6.4Hz),126.71(d,J=20.4Hz),123.52,111.39(d,J=21.6Hz),60.19,15.09.MS(ESI)m/z=300.2(M+H+)。
步骤7:
在冰水浴下,将化合物1g(1.0g,3.3mmol)溶于20mL无水N,N-二甲基甲酰胺中,加入Boc酸酐(1.0g,4.6mmol),将体系逐渐升至室温反应4小时。反应完毕后加入200mL水并用乙酸乙酯(50mL×3)萃取,有机相依次用水、饱和氯化钠水洗涤,无水MgSO4干燥。旋干溶剂后得粗产品,经柱层析(石油醚:乙酸乙酯=5:1)分离纯化得到1.0g化合物1h,收率80%。1HNMR(400MHz,Chloroform-d)δ7.94(d,J=7.8Hz,1H),7.59(d,J=10.2Hz,1H),5.25(s,1H),5.09(d,J=4.0Hz,2H),4.87(d,J=6.1Hz,2H),3.39(s,1H),2.47(s,3H),1.41(s,9H).13CNMR(101MHz,Chloroform-d)δ164.08,161.57,155.79,148.10(d,J=13.0Hz),145.72,144.61,131.51,128.34(d,J=20.6Hz),126.09(d,J=6.5Hz),123.44,112.62(d,J=21.9Hz),80.74,61.42,38.02,28.34,15.75.MS(ESI)m/z=400.3(M+H+)。
步骤8:
化合物1i参考文献(Bioorganic&Medicinal Chemistry,2015,23(9),1950-1962)制备得到。
在氮气保护下,将化合物1h(380mg,0.95mmol)、化合物1i((240mg,0.95mmol)和三苯基磷(300mg,1.14mmol)溶于20mL无水二氯甲烷中,在冰水浴下向体系逐滴加入偶氮二甲酸二乙酯(180μL,1.14mmol),滴加完毕后将体系移至室温反应6小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=80:1)分离纯化得到400mg化合物1j,收率67%。1HNMR(400MHz,Chloroform-d)δ8.15(d,J=8.2Hz,1H),7.58(d,J=10.2Hz,1H),7.43(d,J=7.5Hz,1H),6.50(d,J=7.7Hz,1H),5.88(s,1H),5.61–5.33(m,3H),5.19(d,J=15.2Hz,1H),4.98–4.78(m,2H),4.45(s,1H),3.55(s,3H),3.16(s,1H),2.46(s,3H),2.07(dd,J=14.4,7.4Hz,1H),1.73(dt,J=14.9,7.5Hz,1H),1.45(s,9H),0.85(t,J=7.5Hz,3H).13CNMR(101MHz,Chloroform-d)δ168.88,164.50,160.62,155.54,152.64,148.20,144.47,137.42,128.79(d,J=20.4Hz),127.13,125.69,123.50,112.31(d,J=23.1Hz),105.91,82.54,80.20,76.19,62.35,59.19,50.57,38.25,33.01,28.36,15.67,8.46.MS(ESI)m/z=635.3(M+H+)。
步骤9:
在氮气保护下,将化合物1j(250mg,0.39mmol),醋酸钯(90mg,0.39mmol),醋酸钾(155mg,1.58mmol),三(邻甲基苯基)磷(120mg,0.39mmol)和四丁基氯化铵(110mg,0.39mmol)溶于25mL无水乙腈中,升温至回流反应12小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=80:1)分离纯化得到150mg化合物1k,收率69%。MS(ESI)m/z=554.4(M+H+)。
步骤10:
将含150mg化合物1k溶于15mL含5%三氟醋酸的二氯甲烷中,室温搅拌反应6小时。反应完毕后将溶剂旋干得到粗产物,经乙醚打浆得到110mg化合物GX-1,收率90%。1H NMR(400MHz,DMSO-d6)δ8.54–8.35(m,4H),7.97(d,J=10.5Hz,1H),7.37(s,1H),5.96(s,1H),5.63–5.44(m,4H),4.98(s,1H),4.71(s,2H),3.47(s,3H),2.54(s,3H),2.29(dd,J=14.3,7.5Hz,1H),1.81(dd,J=14.3,7.4Hz,1H),0.74(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ169.80,163.37,160.88,158.83,158.11(d,J=31.2Hz),153.77,152.55,148.64(d,J=12.9Hz),144.11,134.22,130.46,127.96(d,J=20.9Hz),126.70,123.66(d,J=11.4Hz),112.63(d,J=21.5Hz),99.97,99.55,78.75,77.07,60.76,58.11,50.14,35.82,32.50,15.26,8.73.HRMS(ESI)m/z calcd for C24H25N3O5F[M+H+]:454.1778;found454.1768。
步骤11:
将GX-1(50mg,0.09mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水N,N-二甲基甲酰胺中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应12小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到20mg GX-2,收率30%。1H NMR(400MHz,DMSO-d6)δ8.74(d,J=6.3Hz,1H),8.46(d,J=8.2Hz,1H),7.87(d,J=10.7Hz,1H),7.33(d,J=2.1Hz,1H),5.91(d,J=2.0Hz,1H),5.61–5.54(m,2H),5.49(d,J=10.5Hz,3H),4.97(s,1H),4.83(d,J=5.9Hz,2H),3.84(d,J=5.8Hz,2H),3.46(s,3H),2.27(dt,J=14.6,7.3Hz,1H),1.81(dd,J=14.3,7.5Hz,1H),1.36–1.19(m,2H),0.73(t,J=7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.39,169.80,161.82(d,J=249.7Hz),158.82,153.62,152.38,148.62(d,J=13.0Hz),144.39,139.62,128.80,127.34(d,J=20.6Hz),126.84,123.80,123.35,112.41(d,J=22.0Hz),99.59,78.79,77.02,61.44,60.82,58.08,50.33,36.88,32.47,15.29,8.69.HRMS(ESI)m/z calcd for C26H27N3O7F[M+H+]:512.1833;found512.1838。
实施例2:化合物GX-3和化合物GX-4的制备
步骤1:
将化合物2a(2.7g,12.6mmol)溶于20mL无水二氯甲烷中,依次加入DCC(5.2g,25.2mmol),DMAP(160mg,1.3mmol),在冰水浴下,将丙二酸单乙酯(2.3mL,18.9mmol)缓慢滴入体系,滴加完毕后在室温下反应12小时。反应完毕后,过滤,滤液旋干得到粗产物4.0g,将粗产物溶于20mL乙醇。向体系分批加入乙醇钠(1.3g,18.9mmol),室温下继续反应2小时。反应完毕后将体系中析出的固体滤出,固体用二氯甲烷和乙醚打浆得到化合物2b白色固体2.5g,收率64%。1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.40(s,1H),6.86(s,1H),6.16(s,2H),4.82(s,2H),4.32(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.21,158.29,151.14,144.16,142.42,136.41,124.57,110.47,103.06,102.36,95.52,61.43,14.02.MS(ESI)m/z=310.5(M+H+)。
步骤2:
将化合物2b(2.0g,6.5mmol)分散于30ml无水乙腈中,向体系加入三溴氧磷(2.7g,9.8mol),加料完毕后升温回流反应12h。反应完毕后将体系倒入100mL冰水中,用乙酸乙酯(100mL×3)萃取,有机相依次用水、饱和氯化钠水溶液洗涤,无水MgSO4干燥。旋干溶剂后得粗产品,经柱层析(石油醚:乙酸乙酯=90:1)分离纯化得到化合物2c白色固体2.0g,白色固体,收率74%。1H NMR(400MHz,Chloroform-d)δ7.33(d,J=10.7Hz,2H),6.18(s,2H),4.67(d,J=6.4Hz,2H),4.53(q,J=7.1Hz,2H),1.47(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ166.24,152.26,149.45,147.29,140.30,134.92,127.91,121.70,106.13,102.64,99.58,62.80,24.27,14.12.MS(ESI)m/z=418.2(M+H+)。
步骤3:
在冰水浴下,将化合物2c(2.0g,4.8mmol)溶于40mL无水二氯甲烷中,向反应体系逐滴加入1M的二异丁基氢化铝的正己烷溶液(24.5mL,24.0mmol),滴加完毕后保持冰水浴反应2小时。反应完毕后,将反应液缓慢加入40mL饱和酒石酸钠盐水溶液中,搅拌4小时后,用二氯甲烷(20mL×3)萃取,有机相用饱和氯化钠水溶液洗涤,无水MgSO4干燥。旋干溶剂得粗产品,经柱层析(石油醚:乙酸乙酯=5:1)分离纯化得到化合物2d白色固体1.4g,收率78%。1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.34(s,1H),6.27(s,2H),5.47(s,1H),5.20(s,2H),4.80(s,2H).13C NMR(101MHz,DMSO-d6)δ151.42,148.81,145.94,143.55,142.26,130.29,122.60,104.70,102.80,99.91,59.67,26.17.MS(ESI)m/z=376.1(M+H+)。
步骤4:
将化合物2d(1.4g,3.7mmol)溶于15mL二甲基亚砜中,加入叠氮化钠(280mg,4.4mmol),室温搅拌反应12小时。反应完毕后加入150mL水,有固体析出,直接过滤得到化合物2e粗产物1.2g,不进一步分离,直接进行下一步反应。MS(ESI)m/z=338.2(M+H+)。
步骤5:
将化合物2e(1.2g,3.6mmol)溶于四氢呋喃和水(3:1,40mL)混合溶剂中,在冰水浴下向体系加入1M的三甲基磷的四氢呋喃溶液(6.3mL,5.4mmol),滴加完毕后保持冰水浴反应3小时。反应完毕后将反应体系旋干得到粗产物,经柱层析(二氯甲烷:甲醇=30:1)分离纯化得到化合物2f白色固体1.0g,收率90%。1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.29(s,1H),6.24(s,2H),4.80(s,2H),4.16(s,2H).13C NMR(101MHz,DMSO-d6)δ151.29,150.35,148.77,146.22,143.12,130.85,123.84,104.96,102.86,100.93,60.79.MS(ESI)m/z=312.2(M+H+)。
步骤6:
在冰水浴下,将化合物2f(1.0g,3.2mmol)溶于20mL无水DMF中,加入Boc酸酐(1.0g,4.6mmol),将体系逐渐升至室温反应4小时。反应完毕后加入200mL水并用乙酸乙酯(50mL×3)萃取,有机相依次用水、饱和氯化钠水洗涤,无水MgSO4干燥。旋干溶剂后得粗产品,经柱层析(石油醚:乙酸乙酯=5:1)分离纯化得到化合物2g白色固体1.0g,收率75%。1HNMR(400MHz,DMSO-d6)δ7.59(s,1H),7.40(t,J=5.8Hz,1H),7.31(s,1H),6.24(s,2H),5.22(s,1H),4.87(s,2H),4.63(d,J=5.5Hz,2H),1.36(s,9H).13C NMR(101MHz,DMSO-d6)δ155.99,151.37,148.99,146.13,145.50,143.19,131.61,123.91,105.08,103.00,100.81,78.95,60.39,38.04,28.61.MS(ESI)m/z=412.1(M+H+)。
步骤7:
在氮气保护下,将化合物2g(380mg,0.93mmol)、化合物1i(240mg,0.95mmol)和三苯基磷(300mg,1.14mmol)溶于20mL无水二氯甲烷中,在冰水浴下向体系逐滴加入偶氮二甲酸二乙酯(180μL,1.14mmol),滴加完毕后将体系移至室温反应6小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=80:1)分离纯化得到化合物2h油状液体400mg,收率67%。1H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.34(d,J=6.8Hz,1H),7.28(s,1H),6.48(d,J=7.4Hz,1H),6.14(s,2H),5.70–5.56(m,2H),5.52–5.35(m,2H),5.23(d,J=15.2Hz,1H),4.74(tt,J=14.9,8.0Hz,2H),4.46(s,1H),3.57(s,3H),3.12(s,1H),2.07(dd,J=14.4,7.4Hz,1H),1.74(dd,J=14.4,7.4Hz,1H),1.44(s,9H),0.86(t,J=7.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ168.88,160.58,152.42,151.86,149.48,147.06,142.15,136.72,124.72,123.84,123.39,105.88,105.52,102.37,100.47,82.60,80.18,76.15,62.44,59.17,38.54,32.96,32.59,28.35,8.43.MS(ESI)m/z=647.4(M+H+)。
步骤8:
在氮气保护下,将化合物2h(250mg,0.39mmol)、醋酸钯(90mg,0.39mmol)、醋酸钾(155mg,1.58mmol)、三(邻甲基苯基)磷(120mg,0.39mmol)和四丁基氯化铵(110mg,0.39mmol)溶于25mL无水乙腈中,升温至回流反应12小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=80:1)分离纯化得到化合物2i白色固体150mg,不进一步分离,直接进行下一步反应。MS(ESI)m/z=566.4(M+H+)。
步骤9:
将150mg化合物2i溶于5mL含5%三氟醋酸的二氯甲烷中,室温搅拌反应6小时。反应完毕后将溶剂旋干得到粗产物,经乙醚打浆得到化合物GX-3淡黄色固体138mg,收率90%。1H NMR(400MHz,DMSO-d6)δ8.32(s,3H),7.82(s,1H),7.56(s,1H),7.26(s,1H),6.31(s,2H),5.91(s,1H),5.60–5.38(m,4H),4.96(s,1H),4.60(s,2H),3.44(s,3H),2.26(dd,J=14.1,7.4Hz,1H),1.78(dq,J=14.9,7.5Hz,1H),0.70(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ169.86,158.89,158.11,157.81,153.85,151.34,149.70,149.43,147.49,144.69,133.28,129.53,124.26,122.79,105.56,103.00,100.14,99.12,78.66,77.11,60.75,58.10,50.13,36.19,32.51,8.76.HRMS(ESI)m/z calcd for C24H24N3O7[M+H+]:466.1614;found 466.1632。
步骤10:
将化合物GX-3(50mg,0.09mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水DMF中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应12小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到GX-4(淡黄色固体)18mg,收率40%。1H NMR(400MHz,DMSO-d6)δ8.71(t,J=6.0Hz,1H),7.87(s,1H),7.50(s,1H),7.26(s,1H),6.29(d,J=2.5Hz,2H),5.89(s,1H),4.97(s,1H),4.72(d,J=6.1Hz,2H),3.82(d,J=4.9Hz,2H),3.47(s,3H),2.28(dd,J=14.0,7.3Hz,1H),1.80(dt,J=16.3,8.3Hz,1H),1.39–1.21(m,2H),0.73(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.77,170.33,159.34,154.16,151.28,149.95,149.43,147.78,145.45,139.00,128.74,124.56,122.90,105.86,103.09,100.66,99.24,77.52,61.90,61.29,58.53,50.78,37.54,32.95,9.18.HRMS(ESI)m/zcalcd for C26H26N3O9[M+H+]:524.1669;found 524.1665。
实施例3:化合物GX-5和化合物GX-6的制备
参照实施例1合成化合物GX-5,MS(ESI)m/z=458.4(M+H+)。
GX-6的合成,步骤1:将化合物GX-5(50mg,0.087mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水DMF中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应8小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到GX-6(20mg,收率44%)。1HNMR(400MHz,DMSO-d6)δ8.72(d,J=6.2Hz,1H),8.26(d,J=8.3Hz,1H),8.11(d,J=10.6Hz,1H),7.23(d,J=2.2Hz,1H),5.81(d,J=2.0Hz,1H),5.66–5.54(m,3H),4.97(s,1H),4.85(d,J=5.9Hz,2H),3.85(d,J=5.8Hz,2H),3.47(s,3H),2.25(dt,J=14.6,7.3Hz,1H),1.82(dd,J=14.3,7.5Hz,1H),1.35–1.19(m,2H),0.71(t,J=7.6Hz,3H).MS(ESI)m/z=516.5(M+H+)。
实施例4:化合物GX-7和化合物GX-8的制备
参照实施例1合成化合物GX-7,MS(ESI)m/z=480.5(M+H+)。
化合物GX-8的合成,步骤1:
将化合物GX-7(50mg,0.084mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水DMF中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应8小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到GX-8(22mg,收率48%)。1H NMR(400MHz,DMSO-d6)δ8.73(t,J=6.2Hz,1H),7.97(s,1H),7.85(s,1H),7.26(s,1H),5.89(s,1H),5.60-5.43(m,3H),4.92(s,1H),4.76(d,J=6.1Hz,2H),4.35(m,4H)3.81(d,J=4.9Hz,2H),3.46(s,3H),2.27(dd,J=14.0,7.3Hz,1H),1.82(dt,J=16.3,8.3Hz,1H),1.39–1.21(m,2H),0.72(t,J=7.4Hz,3H).MS(ESI)m/z=538.5(M+H+)。
实施例5:化合物GX-9和化合物GX-10的制备
参照实施例1合成化合物GX-9,MS(ESI)m/z=470.9(M+H+)。
化合物GX-10的合成,步骤1:
将化合物GX-9(50mg,0.086mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水DMF中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应8小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到GX-10(18mg,收率39%)。1H NMR(400MHz,DMSO-d6)δ8.76(d,J=6.2Hz,1H),8.18(d,J=8.2Hz,1H),7.67(d,J=10.7Hz,1H),7.36(d,J=2.0Hz,1H),5.92(d,J=2.0Hz,1H),5.63–5.44(m,3H),4.98(s,1H),4.83(d,J=5.9Hz,2H),3.85(d,J=5.9Hz,2H),3.48(s,3H),2.40(s,3H),2.28(dt,J=14.6,7.3Hz,1H),1.81(dd,J=14.3,7.5Hz,1H),1.33–1.14(m,2H),0.73(t,J=7.6Hz,3H).MS(ESI)m/z=528.9(M+H+)。
实施例6:化合物GX-11和化合物GX-12的制备
参照实施例1合成化合物GX-11,MS(ESI)m/z=470.3(M+H+)。
化合物GX-12的合成,步骤1:
将化合物GX-11(50mg,0.088mmol)和乙醇酸(10mg,0.14mmol)溶于2mL无水DMF中,加入DIPEA(32μL,0.27mmol)后室温搅拌反应8小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=15:1)分离纯化得到GX-12(15mg,收率32%)。1H NMR(400MHz,DMSO-d6)δ8.75(t,J=6.1Hz,1H),8.55(d,J=8.5Hz,1H),7.97(d,J=10.8Hz,1H),7.22(s,1H),5.89(s,1H),5.58-5.42(m,3H),4.97(s,1H),4.72(d,J=6.1Hz,2H),4.02(s,3H),3.82(d,J=4.9Hz,2H),3.47(s,3H),2.28(dd,J=14.0,7.3Hz,1H),1.80(dt,J=16.3,8.3Hz,1H),1.39–1.21(m,2H),0.73(t,J=7.4Hz,3H).MS(ESI)m/z=528.6(M+H+)。
实施例7:参照化合物P5的制备
化合物P5参考专利(WO2020219287)制备得到。1H NMR(400MHz,DMSO-d6)δ0.86(t,J=7.2Hz,3H),1.79–1.99(m,3H),2.59(s,0H),3.87(d,J=5.5Hz,3H),4.80(d,J=6.0Hz,2H),5.42(s,3H),5.53(s,2H),5.58(t,J=5.8Hz,1H),6.53(s,1H),7.34(s,1H),7.93(d,J=10.7Hz,1H),8.44(d,J=1.2,8.2Hz,1H),8.77(t,J=6.0Hz,1H).(ESI)m/z=468.2(M+H+)。
实施例8:化合物CZY-8的制备
步骤1:
N-((S)-12-苄基-1-((4S,5S)-5-乙基-9-氟-5-羟基-4-甲氧基-10-甲基-3,15-二氧代-4,5,13,15-四氢-1H,3H-氧杂环[3',4':6,7]吲哚嗪并[1,2-b]喹啉-12-基)-3,8,11,14,17-五氧代-5-氧杂-2,7,10,13,16-五氮杂十八-18-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺CZY-8
将化合物GX-1(30mg,0.05mmol)和化合物3a(购于上海禧耀医药科技有限公司,CAS:1599440-25-1)(50mg,0.08mmol)溶于2mL无水N,N-二甲基甲酰胺中,依次加入DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐,20mg,0.06mmol)和DIPEA(15μL,0.15mmol),室温搅拌反应12小时。反应完毕后将溶剂旋干得到粗产物,经柱层析(二氯甲烷:甲醇=10:1)分离纯化得到30mg化合物CZY-8,收率55%。1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.63(d,J=7.0Hz,1H),8.42(d,J=8.2Hz,1H),8.31(d,J=6.2Hz,1H),8.14(d,J=7.9Hz,1H),8.03(d,J=23.2Hz,2H),7.87(d,J=10.7Hz,1H),7.34(s,1H),7.23(d,J=7.3Hz,3H),7.17(d,J=6.8Hz,1H),6.98(s,2H),5.91(s,1H),5.51(d,J=39.2Hz,3H),4.97(s,1H),4.86(d,J=5.9Hz,2H),4.59(d,J=6.5Hz,2H),4.47(s,1H),3.91(s,2H),3.68(dd,J=21.3,6.3Hz,4H),3.58(dd,J=15.1,4.0Hz,1H),3.46(s,3H),3.04(d,J=13.6Hz,1H),2.80(t,J=11.5Hz,1H),2.32–2.23(m,1H),2.09(t,J=7.6Hz,2H),1.85–1.76(m,1H),1.45(q,J=7.2Hz,4H),1.32(d,J=15.3Hz,1H),1.20(d,J=24.5Hz,6H),0.72(d,J=7.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.61,171.39,171.05,170.12,169.80,169.57,169.46,168.90,163.07,160.59,158.84,153.67,152.41,148.62(d,J=13.0Hz),144.37,139.38,137.80,134.42,129.12,128.74,128.07,127.54,127.33,126.78,126.25,123.73,123.36,99.66,77.02,69.61,66.96,60.83,58.09,54.23,50.33,42.09(d,J=4.4Hz),41.84,37.22,36.96,34.89,32.49,29.00,27.77,25.81,24.56,15.27(d,J=2.8Hz),8.69.HRMS(ESI)m/zcalcd for C52H59N9O14F[M+H+]:1052.4166;found 1052.4146。
实施例9
参照实施例8的合成方法,将GX-1分别替换成GX-3、GX-5、GX-7、GX-9、GX-11后和化合物3a缩合,分别合成化合物L-1~L-5:L-1,淡黄色固体,MS(ESI)m/z=1064.4(M+H+);L-2,淡黄色固体,MS(ESI)m/z=1056.7(M+H+);L-3,淡黄色固体,MS(ESI)m/z=1078.5(M+H+);L-4,淡黄色固体,MS(ESI)m/z=1068.4(M+H+);L-5,淡黄色固体,MS(ESI)m/z=1050.5(M+H+)。
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实施例10:
在37℃条件下,向抗体Trastuzumab(HER2抗体,CAS:180288-69-1)购自杭州皓阳生物技术有限公司)的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;10.0mg/mL,1.0mL,67.6nmol)加入配置好的三(2羧乙基)膦(TCEP)的水溶液(10mM,37.2μL,372nmol),置于水浴振荡器,于37℃下振荡反应3小时后,停止反应。将反应液用水浴降温至25℃。将化合物CZY-8(1.32mg,1014nmol)溶解于50μL DMSO中,加入到上述反应液中,置于水浴振荡器,于25℃下振荡反应3小时后,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(流动相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到偶联物HER2-CZY-8的PBS缓冲液(1.1mg/mL,7.5mL),于4℃储存。SEC-HPLC检测纯度:96.68%,RP-HPLC计算的载药量平均值(DAR)为6.7。
实施例11
参照实施例15的合成方法,将CZY-8分别替换成L-1、L-2、L-3、L-4、L-5后和抗体Trastuzumab偶联,分别得到相应的偶联物:HER2-L-1(DAR=6.8)、HER2-L-2(DAR=7.2)、HER2-L-3(DAR=7.1)、HER2-L-4(DAR=6.8)、HER2-L-5(DAR=6.9)。
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生物学评价
实验例1.化合物对肿瘤细胞的增殖抑制活性测定
使用SRB法测试高喜树碱衍生物GX-1、GX-2、GX-3、GX-4、GX-5、GX-6、GX-7、GX-8、GX-9、GX-10、GX-11、GX-12、喜树碱P5、Exatecan(CAS号为171335-80-1,购自上海禧耀医药科技有限公司)和DXd(CAS号为1599440-33-1,购自上海禧耀医药科技有限公司)对肿瘤细胞增殖能力的影响。处于对数生长期的细胞按相应浓度接种至96孔培养板,每孔100μL完全培养基培养过夜。加入不同浓度的化合物,每个浓度设三复孔,并设置无化合物作用的阳性对照孔及无细胞阴性对照孔。细胞在37℃、5%CO2条件下培养72h。药物作用结束后,用磺酰罗丹明B(Sulforhodamine B,SRB)蛋白染色法检测化合物对细胞增殖的抑制作用,具体操作步骤如下:倾去培养液,用10%三氯乙酸固定细胞,4℃放置1h后用蒸馏水洗涤5次,烘箱中烘干后。加入由1%冰醋酸配制的SRB 4mg/ml溶液100μL/孔,室温中染色15min,去上清液,用1%冰醋酸洗涤5次,烘箱中烘干。最后加入150μL/孔的Tris溶液,振荡混匀,用全波长式微孔板酶标仪SpectraMax 190测定560nm处的OD值。化合物对细胞增殖的抑制率由以下公式计算:
抑制率(%)=[1-(OD给药孔-OD阴性对照孔)/(OD阳性对照孔-OD阴性对照孔)]×100%。
本次筛选所用细胞株见表1,化合物GX-1、GX-2、GX-3、GX-4、GX-5、GX-6、GX-7、GX-8、GX-9、GX-10、GX-11、GX-12、P5、Exatecan和DXd抑制肿瘤细胞增殖结果见表2。
表1.本次筛选所用细胞株概况
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表2.化合物对肿瘤细胞增殖能力的影响
实验例2.抗体药物偶联物对肿瘤细胞的增殖抑制活性测定
(1)HER2-CZY-8对肿瘤细胞增殖能力测试方法:
抗体药物偶联物HER2-GGFG-DXd其CAS号为1826843-81-5,购自杭州皓阳生物技术有限公司。
通过CTG(CELL TITER-GLO)发光法检测抗体对NCI-N87肿瘤细胞体外活性的影响从而研究抗体抑制细胞增殖的作用。共计4块96孔板,双复孔测试,测试药物在NCI-N87细胞上处理6天和7天的活性。
首先进行细胞培养,将肿瘤细胞系在37℃,5% CO2的培养箱中进行培养。定期传代,取处于对数生长期的细胞用于铺板。用台盼兰进行细胞染色并计数活细胞,将细胞浓度调整至合适浓度。在培养板中每孔加入135μL细胞悬液,在空白对照空中加入不含细胞的培养液,将培养板在37℃,5% CO2,及100%相对湿度的培养箱中培养过夜。再制备100X抗体稀释母板:将抗体用PBS从最高浓度梯度稀释至最低浓度。30μg/mL的作用浓度,直接在135μL的细胞中加入10.5μL的培养基,然后加上4.5μL的1mg/mL的抗体。10X抗体工作液的配制:在V形底的96孔板中加入135μL细胞培养液,从100X抗体稀释母板中吸取15μL抗体加入96孔板的细胞培养液中。在溶媒对照和空白对照中加入15μL PBS。加入抗体或PBS后用排枪吹打混匀。
加药:取15μL的10X抗体工作液加入到细胞培养板中。在溶媒对照和空白对照中加入15μLPBS-细胞培养液混合液。将96孔细胞板放回培养箱中培养6天和7天。
随后用CellTiter-Glo发光法检测细胞活性:将CellTiter-Glo缓冲液融化并放置至室温,同时将CellTiter-Glo底物放置至室温。在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物,从而配制CellTiter-Glo工作液。缓慢涡旋震荡使充分溶解。取出细胞培养板放置30分钟使其平衡至室温。在每孔中加入75μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液。用铝箔纸包裹细胞板以避光。将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。培养板在室温放置10分钟以稳定发光信号。在2104EnVision读板器上检测发光信号。最后用下列公式来计算检测抗体的抑制率(Inhibition rate,IR):IR(%)=(1–(RLU抗体–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100%。在Excel中计算不同浓度抗体的抑制率,然后用GraphPad Prism软件作抑制曲线图,计算EC50。HER2-CZY-8对肿瘤细胞增殖结果见表3。
表3.HER2-CZY-8对肿瘤细胞增殖能力的影响
(2)HER2-CZY-8和HER2-L-4对肿瘤细胞增殖能力测试方法:
阳性对照抗体Trastuzumab(HER2抗体,CAS:180288-69-1)购自杭州皓阳生物技术有限公司)。
将NCI-N87细胞消化后重悬细胞计数,离心去除上清液,调整细胞密度。细胞计数仪计数,吸取20uL细胞悬液,与20uL VisStain AOPI Staining Solution混合,取20uL液体,细胞计数。分别铺细胞于96孔细胞培养板中,每孔加180uL,每孔种1000细胞或者每孔种2000细胞。轻轻拍打混匀,将细胞培养板放入37℃细胞培养箱孵育16小时。用RPMI1640medium/10%FBS稀释化合物,每孔加入20uL,使得最大浓度为100nM,3倍稀释,10个点。溶媒对照为DMSO,在空白对照中加入20uL RPMI1640 medium/10%FBS。轻轻拍打混匀,将细胞培养板放入37℃细胞培养箱孵育7days。培养7天后,将细胞板从培养箱中取出,吸去培养液,加入20uL培养液,再每孔加入20uL CTG。振荡器振荡5min,室温静置10min,取30uL反应液到Viewplate-96white白色透明底酶标板,在EnVision读板器进行数据分析。
计算公式:用下列公式来计算检测抗体的抑制率(Inhibition rate,IR):IR(%)=(1–(RLU抗体–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100%。在Excel中计算不同浓度抗体的抑制率,然后用GraphPad Prism软件作抑制曲线图和计算相关参数,包括最小抑制率Emin,最大抑制率Emax及半数有效抑制率IC50。结果如表4和图1所示。
表4HER2-CZY-8和HER2-L-4对NCl-N87肿瘤细胞增殖能力的影响
实施例3:HER2-CZY-8对NOG小鼠皮下移植NCI-N87细胞动物模型的抗肿瘤药效试验:
本试验采用NCI-N87细胞皮下接种NOG小鼠测定HER2-CZY-8的抗肿瘤作用。
NOG小鼠:雌性NOG小鼠(6周)购自浙江维通利华实验动物技术有限公司。小鼠在到达后适应性饲养7天,随后开始研究。
细胞:人源乳腺癌NCI-N87细胞(ATCC来源,货号CRL-5822),按照说明书进行常规传代培养;无血清培养基重悬细胞并调整细胞密度,在第0天将细胞悬液皮下接种至雌性NOG小鼠右腋窝皮下来建立NCI-N87荷瘤小鼠模型。
给药:在细胞接种后第6天,入组动物平均肿瘤体积达到167mm3时开始分组给药(每组6只小鼠),阴性对照抗体(人IgG Control,来源:杭州皓阳生物技术有限公司,货号:HSP067-F1)、阳性对照抗体Trastuzumab(HER2抗体,CAS:180288-69-1)购自杭州皓阳生物技术有限公司)、本发明抗体HER2-CZY-8,给药期间监测各组小鼠瘤体积和体重变化,监测频率均为2次/周,连续监测3周。在每次给药前测定体重和肿瘤体积,接种后第49天计算肿瘤体积抑制率(TGI%),计算公式如下:TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100;其中Ti:给药组肿瘤体积均数,T0:给药组D0天的肿瘤体积均数,Vi:同型对照组肿瘤体积均数,V0:同型对照组D0天的肿瘤体积均数。肿瘤体积测定:采用游标卡尺测定肿瘤的长径(a)和宽径(b),肿瘤体积按如下公式计算:TV=1/2×a×b2。采用电子天平测定体重。表5为给药剂量和方式。
表5给药试验设计
注:QW表示一周一次;BIW表示一周两次。
表6结果表明接种后第49天,本发明抗体HER2-GGFG-DXd肿瘤体积抑制率为75.2%,显著优于阳性抗体Trastuzumab。
表6第49天ADC体内抑制肿瘤生长能力
根据图2和图3可知,HER2-CZY-8显著性抑制NOG小鼠皮下移植NCI-N87细胞动物模型肿瘤的生长,并且对NOG小鼠体重没有明显影响。
Claims (14)
1.一种如式I所示的高喜树碱类小分子或其药学上可接受的盐,
其中,A1为H或-C(=O)-C1-6亚烷基-OH;
R1和R2独立地为C1-6烷基、C1-6烷氧基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
2.如权利要求1所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐,其特征在于,A1为H或-C(=O)-C1-6亚烷基-OH;
R1和R2独立地为C1-6烷基或卤素;
或者R1和R2与相邻的碳原子形成 表示并环的连接位置;
以“*1”和“*2”标记的碳原子独立地表示S构型、R构型或它们的混合物。
3.如权利要求1或2所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐,其特征在于,所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐满足下述条件中的一个或多个:
(1)所述的药学上可接受的盐为三氟醋酸盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐或丙二酸盐;
(2)A1为-C(=O)-C1-6亚烷基-OH时,所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH(CH3)CH2-,例如-CH2-;
(3)R1和R2独立地为C1-6烷基时,所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基;
(4)R1和R2独立地为卤素时,所述的卤素为氟、氯、溴或碘,例如氟;
(5)所述的如式I所示的高喜树碱类小分子选自如下任一结构:
(6)所述的如式I所示的高喜树碱类小分子其药学上可接受的盐选自如下任一结构:
4.如权利要求1所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐,其特征在于,所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐满足下述条件中的一个或多个:
(1)R1和R2独立地为C1-6烷氧基时,所述的C1-6烷氧基为甲氧基、-OCH2CH3、异丙氧基或叔丁氧基;
(2)A1为H或-C(=O)CH2OH;
(3)所述的如式I所示的高喜树碱类小分子选自如下任一结构:
(4)所述的如式I所示的高喜树碱类小分子其药学上可接受的盐选自如下任一结构:
5.一种如式II所示的连接基-药物偶联物,
其中,Q为单个氨基酸残基、二肽残基、三肽残基或四肽残基;
X为-(OCH2CH2)m-、-(CRaRb)m-、-O(CRaRb)m、-NH-(CRaRb)m-CRcRd-或-S(CRaRb)m-CRcRd-;
Y为
Ra和Rb独立地为H、D、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、羟基、氨基、氰基、硝基、3-10元环烷基或3-10元杂环基;
或者,Ra和Rb与其相连接的碳原子一起形成3-10元环烷基或或3-10元杂环基;
Rc和Rd独立地为H、C1-6烷基、卤素、卤代C1-6烷基、氘代C1-6烷基、3-10元环烷基、3-10杂环基、6-14元芳基或5-10元杂芳基;
或者,Rc和Rd与其相连接的碳原子一起形成3-10元环烷基或3-10元杂环基;
m独立地为0-10;
n为1-6;
R1、R2、“*1”和“*2”的定义如权利要求1-4中任一项所述。
6.如权利要求5所述的如式II所示的连接基-药物偶联物,其特征在于,所述的如式II所示的连接基-药物偶联物满足下述条件中的一个或多个:
(1)Ra和Rb独立地为H;
(2)m独立地为5;
(3)n为1;
(4)所述的单个氨基酸残基为-Phe-、-Lys-、-Val-、-Ala-、-Cit-、-Leu-、-Ile-、-Arg-或-Trp-;
(5)所述的二肽残基为C=O-Lys-Phe-NH、C=O-Ala-Val-NH、C=O-Lys-Val-NH、C=O-Lys-Ala-NH、C=O-Cit-Val-NH、C=O Cit-Phe-NH、C=O-Cit-Leu-NH、C=O Cit-Ile-NH、C=O-Arg-Phe-NH、C=O-Cit-Trp-NH或C=O-Val-Gly-NH;
(6)所述的三肽残基为C=O-Ala-Val-Glu-NH、C=O-Cit-Val-Glu-NH、C=O-Ala-Val-αGlu-NH或C=O-Cit-Val-αGlu-NH;
(7)所述的四肽残基为C=O-Gly-Phe-(Gly)2-NH或C=O–(Gly)2-Phe-Gly-NH;
(8)所述3-10元杂环基和5-10元杂芳基中的杂原子选自N、O和S中的一种或多种,杂原子的个数为1-3个。
7.如权利要求5所述的如式II所示的连接基-药物偶联物,其特征在于,所述的如式II所示的连接基-药物偶联物为如下结构:
8.一种如式III所示的抗体药物偶联物:
其中,GL为抗体;
p为1-8;
Z为其中b端与X连接,a端与GL连接;
R1、R2、X、Q、n、“*1”和“*2”的定义如权利要求5或6所述。
9.如权利要求8所述的抗体药物偶联物,其特征在于,所述的抗体药物偶联物满足下述条件中的一个或多个:
(1)p为6.7;
(2)Z的a端和GL以硫醚键的形式相连;
(3)GL为HER2抗体,例如Trastuzumab;
(4)所述的如式III所示的抗体药物偶联物为如下结构:
其中HER2抗体为Trastuzumab。
10.如权利要求8所述的抗体药物偶联物,其特征在于,p为6.7-7.2,例如6.8、6.9或7.1;
和/或,所述的如式III所示的抗体药物偶联物为如下结构:
其中HER2抗体为Trastuzumab。
11.一种药物组合物,其包括如权利要求1-4中任一项所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐、或如权利要求8-10中任一项所述的如式III所示的抗体药物偶联物,和至少一种药用辅料。
12.一种如权利要求1-4中任一项所述的如式I所示的高喜树碱类小分子或其药学上可接受的盐、或如权利要求8-10中任一项所述的如式III所示的抗体药物偶联物在制备用于预防或治疗癌症的药物中的应用。
13.如权利要求12所述的应用,其特征在于,所述的癌症为乳腺癌、肺癌、肾癌、肝癌、卵巢癌、尿道癌、前列腺癌、多形性成胶质细胞瘤、胰腺癌、大肠癌、胃肠道间质瘤、宫颈癌、鳞状细胞癌、腹膜癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、外阴癌、甲状腺癌、阴茎癌、白血病、恶性淋巴瘤、浆细胞瘤、骨髓瘤、肉瘤、黑色素瘤、膀胱癌、胃癌或食道癌。
14.如下所示的化合物,
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FR2757514B1 (fr) * | 1996-12-20 | 1999-02-12 | Sod Conseils Rech Applic | Nouveaux analogues de la camptothecine, des procedes de preparation, leur application comme medicaments et les compositions pharmaceutiques les contenant |
CZ296156B6 (cs) * | 1995-06-21 | 2006-01-11 | Nové analogy kamptothecinu, zpusoby jejich prípravy, jejich aplikace jako léciva, a farmaceutické kompozice, které je obsahují | |
UA57757C2 (uk) * | 1996-12-20 | 2003-07-15 | Сос'Єте Де Консей Де Решерш Е Даплікасьон С'Єнтіфік (С.К.Р.А.С.) | Аналоги камптотецину, спосіб їх отримання (варіанти) і фармацевтична композиція |
CN112138171A (zh) * | 2019-06-28 | 2020-12-29 | 上海复旦张江生物医药股份有限公司 | 抗体偶联药物、其中间体、制备方法及应用 |
CN112125915A (zh) * | 2019-09-18 | 2020-12-25 | 四川百利药业有限责任公司 | 一种喜树碱衍生物及其偶联物 |
CN115103858A (zh) * | 2020-03-25 | 2022-09-23 | 江苏恒瑞医药股份有限公司 | 一种抗体药物偶联物的制备方法 |
EP4227310A1 (en) * | 2020-10-12 | 2023-08-16 | Sichuan Baili Pharmaceutical Co. Ltd. | Camptothecin derivative and ligand-drug conjugate thereof |
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