CN116731005B - 一种pcsk9小分子蛋白降解剂及其制备方法和应用 - Google Patents
一种pcsk9小分子蛋白降解剂及其制备方法和应用 Download PDFInfo
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- CN116731005B CN116731005B CN202210203352.1A CN202210203352A CN116731005B CN 116731005 B CN116731005 B CN 116731005B CN 202210203352 A CN202210203352 A CN 202210203352A CN 116731005 B CN116731005 B CN 116731005B
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明提供一种PCSK9小分子蛋白降解剂及其制备方法,所述PCSK9小分子抑制剂为如下式化学结构通式I的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物:这类化合物具有降解PCSK9或降解LC3的作用,可用于制备预防或治疗与抑制PCSK9或LC3活性相关的疾病的药物。
Description
技术领域
本发明属于药物化学领域,具体涉及一种PCSK9小分子蛋白降解剂及其制备方法,这类化合物具有降解PCSK9或降解LC3的作用,有望于制备预防或治疗与抑制PCSK9或LC3活性相关的疾病的药物。
背景技术
前蛋白转化酶枯草溶菌素9(PCSK9)是2003年Nabil Seidah等人发现的一种主要在肝脏表达的丝氨酸蛋白酶。正常生理情况下,血液中的低密度脂蛋白胆固醇(LDL-C)主要是通过与细胞表面的低密度脂蛋白受体(LDLRs)结合形成复合物进入细胞,核内体的低pH条件导致LDL与其受体分离,LDL在溶酶体中降解,而LDLR则循环到细胞表面,参与下一轮的LDL-C清除工作。而PCSK9通过与LDLRs结合,使得LDLRs与LDL-C在胞内同时发生降解,进而抑制了LDLR循环清除血中低密度脂蛋白胆固醇(LDL-C)的能力。一般来说,抑制PCSK9的生成或分泌可以降低血中胆固醇水平,PCSK的抑制剂可用于治疗高胆固醇血症。
一般而言,PCSK9的抑制剂显示出良好的降脂活性,alirocumab和evolocumab两种单克隆抗体和小干扰RNA Inclisiran是已经在临床上使用的三个PCSK9抑制剂实例,用于治疗心脑血管疾病。已经公开了各种PCSK9抑制剂用于治疗或预防心脑血管疾病、脱发性疾病、白癜风、角化异常性疾病、疤痕以及肺纤维化疾病、代谢综合征、肥胖、糖尿病、阿尔茨海默症、抗排斥反应、非酒精性肝炎以及恶性肿瘤。例如CN113876955A、WO2022002160 A1、WO2021052472 A1、CN113332423A、CN113663075A、WO2021243002 A1、WO2021207712 A1、WO2021154947 A1、WO2021143762 A1、CN112083163A、WO2020229718 A1、CN113412258A、CN111154760A、WO2020252383 A1、WO2018057409 A1。
目前获批临床的三种药物均为生物药,治疗成本较大,给药途径不方便,对于患者而言,依从性较差。目前尚无小分子的PCSK9抑制剂应用于临床,因此开发PCSK9的小分子抑制剂并将其用于治疗或预防心脑血管疾病、脱发性疾病、白癜风、角化异常性疾病、疤痕以及肺纤维化疾病、代谢综合征、肥胖、糖尿病、阿尔茨海默症、抗排斥反应、非酒精性肝炎以及恶性肿瘤具有重要意义。
自噬长期以来一直与调节免疫反应的多个方面有关,包括病原体捕获,代谢调节和细胞稳态等。目前多项研究表明细胞自噬与代谢性疾病、恶性肿瘤、免疫失调以及神经退行性疾病等的发生发展有关。LC3蛋白作为细胞自噬过程中的标志物蛋白,不仅介导了自噬过程,还与自噬小体的形成和融合等过程有关。但是,LC3蛋白与自噬相关蛋白的作用主要通过蛋白-蛋白Protein-protein interaction)相互作用发挥功能,界面比较平整,缺乏小分子药物的结合口袋。因此,目前很少报道LC3的小分子抑制剂。2021年,中科院上海药物研究所研究员罗成等研究员首次报道了与LC3共价结合的小分子抑制剂。因此开发LC3抑制剂具有重要意义。
发明内容
发明要解决的问题:
本发明的目的在于提供一种四氢异喹啉类化合物作为新颖的PCSK9小分子蛋白降解剂或LC3小分子蛋白降解剂,用于降低PCSK9或LC3水平,可用于制备预防或治疗与抑制PCSK9或LC3活性相关的疾病的药物。
解决问题的手段:
为了解决上述技术问题,第一个方面,本发明提供一种PCSK9小分子蛋白降解剂,为如下式化学结构通式I的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物:
其中,
连接基团A为:C1-C20的烷基链、醚链、氧杂链、硫杂链、氮杂链、C1-C20烯基链、C1-C20炔基链、-C(=O)NH(C1-C19的烷基链、醚链、氧杂链、硫杂链、氮杂链、C1-C19烯基、C1-C19炔基);
R1、R2、R3以及R4独立地选自氢、卤素、羟基、硝基、甲氧基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3、C1-6烷基、C2-6烯基、C2-6炔基,其中所述烷基、烯基或炔基任选地被一个或多个选自-O(C1-6烷基)、-O(C3-6环烃基)、-O(C1-4亚烷基-C3-6环烃基)、-O(三元至七元杂环基)、-O(C1-4亚烷基-三元至七元杂环基)、-SH、-S(C1-6烷基)、-S(C3-6环烃基)、-S(C1-4亚烷基-C3-6环烃基)、-S(三元至七元杂环基)、-S(C1-4亚烷基-三元至七元杂环基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烃基)、-N(C3-6环烃基)2、-NH(C1-4亚烷基-C3-6环烃基)、-N(C1-4亚烷基-C3-6环烃基)2、-NH(三元至七元杂环基)、-N(三元至七元杂环基)2、-NH(C1-4亚烷基-三元至七元杂环基)、-N(C1-4亚烷基-三元至七元杂环基)2所取代;
R5独立地选自氢、甲氧基、甲基、卤素、羟基、硝基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3、C1-6烷基、C2-6烯基、C2-6炔基;
R6独立地选自甲基;
R7独立地选自以下结构:
或者/>
基团B为:
其中R8、R9以及R10独立地选自氢、卤素、羟基、硝基、甲氧基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3;X为NH、S、O。
优选地,所述R7为
优选地,所述基团B为R8、R9和R10独立地选自卤素、羟基、甲氧基。
优选地,所述化合物选自下述化合物:
第二个方面,本发明提供一种如上所述的PCSK9小分子蛋白降解剂的制备方法,包括如下步骤:
其中,
R2、R5、R8、R10如前述所定义的。
第三个方面,本发明提供一种药物组合物,包括如上所述的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物,以及药物上可接受的载体。
第四个方面,本发明提供一种如上所述的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物在制备用于预防或治疗与抑制PCSK9活性相关的疾病的药物中的应用。
第五个方面,本发明提供一种如上所述的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物在制备用于预防或治疗与抑制LC3活性相关的疾病的药物中的应用。
优选地,所述疾病选自心脑血管疾病、脱发性疾病、白癜风、角化异常性疾病、疤痕以及肺纤维化疾病、代谢综合征、肥胖、糖尿病、阿尔茨海默症、抗排斥反应、非酒精性肝炎和恶性肿瘤中的至少一种。
优选地,所述心脑血管疾病选自胆固醇相关疾病、高脂血症和动脉粥样硬化中的至少一种;所述恶性肿瘤选自白血病、前列腺癌、甲状腺癌、肝癌、卵巢癌、乳腺癌、食道癌、腺癌、胃癌、肺癌和结直肠癌中的至少一种。
附图说明
图1示出了根据本发明实施例制备的化合物的Western Blot实验结果;
图2示出了根据本发明实施例制备的化合物I-2与I-4的Western Blot实验结果;
图3示出了根据本发明实施例制备的化合物I-3的qPCR实验结果;
图4示出了根据本发明实施例制备的化合物I-3的MTT毒性试验测定结果;
图5示出了根据本发明实施例制备的化合物I-3在高脂模型中的Western Blot实验结果;
图6示出了根据本发明实施例制备化合物I-3与他汀类药物联用时的WesternBlot实验结果。
图7示出了根据本发明实施例制备的化合物I-1~I-15的Western Blot实验结果。
具体实施方式
以下结合附图和下述实施方式进一步说明本发明,应理解,附图及下述实施方式仅用于说明本发明,而非限制本发明。在各图中相同或相应的附图标记表示同一部件,并省略重复说明。
本发明提供一种新颖的PCSK9小分子靶向降解剂,其具有如下结构通式I的四氢异喹啉类化合物或其药学上可接受的盐或溶剂化物:
其中,
连接基团A为:C1-C20的烷基链、醚链、氧杂链、硫杂链、氮杂链、C1-C20烯基链、C1-C20炔基链、-C(=O)NH(C1-C19的烷基链、醚链、氧杂链、硫杂链、氮杂链、C1-C19烯基、C1-C19炔基);
R1、R2、R3以及R4独立地选自氢、卤素、羟基、硝基、甲氧基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3、C1-6烷基、C2-6烯基、C2-6炔基,其中所述烷基、烯基或炔基任选地被一个或多个选自-O(C1-6烷基)、-O(C3-6环烃基)、-O(C1-4亚烷基-C3-6环烃基)、-O(三元至七元杂环基)、-O(C1-4亚烷基-三元至七元杂环基)、-SH、-S(C1-6烷基)、-S(C3-6环烃基)、-S(C1-4亚烷基-C3-6环烃基)、-S(三元至七元杂环基)、-S(C1-4亚烷基-三元至七元杂环基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-6环烃基)、-N(C3-6环烃基)2、-NH(C1-4亚烷基-C3-6环烃基)、-N(C1-4亚烷基-C3-6环烃基)2、-NH(三元至七元杂环基)、-N(三元至七元杂环基)2、-NH(C1-4亚烷基-三元至七元杂环基)、-N(C1-4亚烷基-三元至七元杂环基)2所取代;
R5独立地选自氢、甲氧基、甲基、卤素、羟基、硝基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3、C1-6烷基、C2-6烯基、C2-6炔基;
R6独立地选自甲基;
R7独立地选自以下结构:
或者/>
基团B为:
其中R8、R9以及R10独立地选自氢、卤素、羟基、硝基、甲氧基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3;X为NH、S、O。
在本发明的一个优选实施方式中,所述R7为
在本发明的一个优选实施方式中,所述基团B为R8、R9和R10独立地选自卤素、羟基、甲氧基。
在本发明的一个优选实施方式中,所述化合物选自下述化合物:
本发明提供的化合物可以通过下述合成方案合成:
其中,R2、R5、R8、R10如前述所定义的。
除非另有说明,上述合成方案中所述基团、术语的含义与通式I化合物中的含义相同。
上述合成方案只是列举了本发明中部分化合物的制备方法,参考本领域中常用技术手段及现有技术,本领域技术人员在上述合成方案的基础上,可采用类似的方法合成本发明的化合物。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如,表述“C1-C20”或“C1—20”涵盖1-20个碳原子的范围,并应理解为还涵盖其中的任意亚范围以及每个点值,例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6等,以及C1、C2、C3、C4、C5、C6、C7、C8等。例如,表述“C3-C10”或“C3-10”也应当以类似的方式理解,例如可以涵盖包含于其中的任意亚范围和点值,例如C3-C9、C6-C9、C6-C8、C6-C7、C7-C10、C7-C9、C7-C8、C8-C9等以及C3、4、5、6、7、8、9、10等。本文中其他类似的表述也应当以类似的方式理解。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团,其通过单键与分子的其余部分连接。“烷基”可以具有1-20个碳原子,即“C1-C20烷基”,例如C1-4烷基、C1-3烷基、C1-2烷基、C3烷基、C4烷基、C1-6烷基、C3-6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基,或者它们的异构体。“亚基”是指在含有自由价电子的碳原子上再去掉一个氢原子而得到的,具有两个与分子其他部分连接的连接位点的基团。例如“亚烷基”或“烷基亚基”指饱和的直链或支链的二价烃基。
术语“亚烷基”,在本文中单独或与其他基团组合使用时,指直链或支链的饱和的二价烃基。例如,术语“C1-20亚烷基”指具有1-20个碳原子的亚烷基,例如亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、1-甲基亚乙基、2-甲基亚乙基、甲基亚丙基或乙基亚丙基等。术语“亚环烷基”是指环状的饱和的二价烃基。例如,术语“C3-6亚环烷基”指具有3-6个碳原子的环烷基亚基,例如环丙基亚基、环丁基亚基、环戊基亚基、环己基亚基,等。术语“烷氧基亚基”是指“-O-亚烷基”或“亚烷基-O-”。“C1-8烷氧基亚基”的实例包括但不限于-O-亚甲基、-O-亚乙基、-O-亚丙基、-O-亚丁基、亚甲基-O-、亚乙基-O-、亚丙基-O-、亚丁基-O-,等。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以具有2-20个碳原子,即“C2-20烯基”,例如C2-4烯基、C3-4烯基。烯基的非限制性实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基可以具有2-20个碳原子,即“C2-8炔基”,例如C2-4炔基、C3-4炔基。炔基的非限制性实例包括但不限于乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基等。
术语“环烃基”是指由碳原子和氢原子组成的饱和或不饱和的非芳香性的环状烃基,优选包含1或2个环。所述环烃基可以是单环、稠合多环、桥环或螺环结构。环烃基可以具有3-10个碳原子,即“C3-10环烃基”,例如C3-8环烃基、C3-6环烃基、C5环烃基、C6环烃基、C7环烃基。环烃基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。该术语还涵盖这样的情况,其中的C原子可以被氧代(=O)取代。
术语“环烷基”是指饱和的环烃基。
术语“杂环基”或“杂环烃基”是指具有例如3-10个(适合地具有3-8个,更适合地具有3-7个,特别是4-6个)环原子的单环或双环的环体系(三元至十元、三元至八元、三元至七元、四元至六元),其中至少一个环原子(例如1或3个)是选自N、O、S和P的杂原子,且其余环原子是C。该环体系可以是饱和(也可以理解为相应的“杂环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)。“杂环基”或“杂环烃基”不具备芳香性。该术语还涵盖这样的情况,其中的C原子可以被氧代(=O)取代和/或环上的S原子可以被1个或2个氧代(=O)取代和/或环上的P原子可以被1个或2个氧代(=O)取代。
杂环基可以是例如四元环,如氮杂环丁烷基、氧杂环丁烷基;或者五元环,如四氢呋喃基、二噁烷基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、氧代吡咯烷基、2-氧代咪唑烷-1-基;或者六元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,1-二氧代-1,2-噻嗪烷-2-基或三噻烷基;或者七元环,如二氮杂基环。任选地,杂环基可以是苯并稠和的。
杂环基可以是双环的,不受其限制,例如五元并五元环,如六氢环戊烷[C]吡咯-2(1H)-基)环;或者五元并六元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。
如上文所提到的,杂环可以是不饱和的,即其可以包含一个或多个双键,不受其限制,例如包含氮原子的不饱和的杂环可以是1,6-二氢嘧啶、1,2-二氢嘧啶、1,4-二氢嘧啶、1,6-二氢吡啶、1,2-二氢吡啶、1,4-二氢吡啶、2,3-二氢-IH-吡咯、3,4-二氢-IH-吡咯、2,5-二氢-IH-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基环,包含氧原子的不饱和的杂环可以是2H-吡喃、4H-吡喃、2,3-二氢呋喃,包含硫原子的不饱和的杂环可以是2H-噻喃、4H-噻喃。杂环可以是苯并稠和的,不受其限制,例如二氢异喹啉基环。
术语“烃链”指由碳原子和氢原子构成的链状基团,其可以是直链或支化的。所述烃链可以是饱和的(即亚烷基),也可以是不饱和的,即可以包含一个或多个碳碳双键或三键。亚烷基的非限制性实例包括但不限于亚甲基(-CH2-)、1,1-亚乙基(-CH(CH3)-)、1,2-亚乙基(-CH2CH2-)、1,1_亚丙基(-CH(CH2CH3)-)、1,2-亚丙基(-CH2CH(CH3)-)、1,3-亚丙基(-CH2CH2CH2-)、1,4-亚丁基(-CH2CH2CH2CH2-)、1,7-亚庚基(-CH2CH2CH2CH2CH2CH2CH2-)等。
本发明所述的“化合物”,包括所有的立体异构体、几何异构体、互变异构体和同位素。
本发明所述的“化合物”,可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有异构体都包括,如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物,可以光学活性纯的形式或外消旋形式被分离出来;光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
本发明所述的“化合物”,还包括几何异构体形式;几何异构体形式可以混合物或分离的E或Z结构形式存在。
本发明所述的“化合物”,还包括互变异构体形式;互变异构体形式源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明所述的“化合物”,还包括所有同位素的原子,无论是中间体或最后的化合物;同位素的原子包括具有相同的质子数、但有不同质量数的,例如,氢的同位素包括氘和氚。又,如果需要的话,例如为了特别的治疗或者诊断治疗,本发明的化合物可以引进现有技术已知的同位素或放射性同位素、例如3H、15O、13C或15N同位素。
“药学上可接受的盐”是指药学上可接受的盐,保持其母体化合物的药理活性的同时可改善理化性质或者代谢性质等。这类盐包括由药学上可接受的酸或者碱(包括有机酸、无机酸、有机碱、无机碱)制备的酸加成盐或碱加成盐,或者两者混合物。在本发明中,合适的无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸或类似的酸;合适的有机酸包括富马酸、酒石酸、乳酸、醋酸、柠檬酸、三氟甲磺酸、扁桃酸、水杨酸或其类似物。
根据本发明的化合物还可以以溶剂化物形式存在。例如水合物(半水合物、一水合物、二水合物、三水合物等)。
给药以及药物组合物
一般来说,本发明的化合物可以在有效量下,通过任何可接受的用于其它类似用途的给药方式进行给药。举例来说,本发明的化合物可以口服、非肠道给药、透皮给药、局部给药、直肠给药、腹腔注射或鼻内给药。
当用作药物时,本发明的化合物通常以药物组合物的形式给药。这些组合物可用制药学领域熟知的方法进行制备,这些组合物包含至少一种活性化合物。在配制本发明提供的组合物时,有效成分通常与赋形剂混合,被赋形剂稀释或被以胶囊,小袋,纸或其它形式的容器包裹。当所述赋形剂作为稀释剂时,可以是固体,半固体,或液体物质,可作为有效成分的运载体、载体或媒介。由此,所述组合物可以是药片、药丸、粉末、锭剂、小袋、胶囊、酏剂、混悬剂、乳剂、溶液、糖浆、喷雾(作为固体或在液体介质里),软膏,软和硬的明胶胶囊,栓剂,无菌注射溶液,和无菌包装粉末的形式。
一些典型的赋形剂包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、无菌水、糖浆和甲基纤维素。另外还可以包括润滑剂(如滑石粉、硬脂酸镁和矿物油)、浸润剂、乳化和悬浊剂、防腐剂(如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)、甜味剂和增味剂。本发明的药物组合物可以通过具体赋形方式在对病人进行给药之后达到药物活性成分的快速、持续或延时释放,这也是本领域中广泛应用的方法。
活性成分,即本发明中的化合物,在药物构成和单位剂型中的数量可根据具体应用情况、特定化合物的活性和预期浓度进行改变或有较大调整。
“治疗”意味着对哺乳动物体内疾病的任何治疗,包括:(1)防止疾病,即造成临床疾病的症状不发展;(2)抑制疾病,即阻止临床症状的发展;(3)减轻疾病,即造成临床症状的消退。
以下结合具体实施例进一步详细说明本发明。同样应理解,以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例,即本领域技术人员可以通过本文的说明做合适的范围内选择,而并非要限定于下文示例的具体数值。
实施例一:化合物I-1的制备
2-(7-(2-(2-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
步骤1:2-甲氧基-4-(2-硝基乙烯基)苯酚的合成
室温下,将香豆素溶于硝基甲烷,并加入醋酸胺。溶解完全后将反应液移入100℃条件下,反应2小时后,移至室温。随后有固体析出,反应液完全降至室温时,将析出的固体直接过滤,并使用少量甲醇润洗滤饼,旋干滤饼得黄色固体P1。1H NMR(400MHz,DMSO)δ10.09(s,1H),8.19-8.15(d,J=13.4Hz,1H),8.05-8.02(d,J=13.5Hz,1H),7.48(s,1H),7.31-7.29(d,J=8.1Hz,1H),6.85-6.83(d,J=8.1Hz,1H),3.82(s,3H).ESI-MScalculated for[M+H]+:196.0,found:196.0.
步骤2:2-甲氧基-4-(2-硝基乙基)苯酚的合成
将P1溶于THF,并将硼氢化钠溶于THF和EtOH,冰浴下,将溶于THF的P1缓慢滴加入硼氢化钠中,滴加完毕后,将反应液移入室温下反应过夜。随后使用盐酸稀溶液(1M)淬灭反应,并用二氯甲烷萃取,用无水硫酸钠干燥有机相,旋干得黑色粗产物。使用PE:EA柱层析纯化得淡黄色油状物P2。1H NMR(600MHz,DMSO)δ8.84(s,1H),6.85(d,J=1.6Hz,1H),6.69-6.67(d,J=8.0Hz,1H),6.63-6.62(dd,J=8.0,1.7Hz,1H),4.78-4.76(t,J=7.1Hz,2H),3.74(s,3H),3.12-3.09(t,J=7.1Hz,2H).ESI-MS calculated for[M-H]+:196.0,found:195.9。
步骤3:4-(2-氨基乙基)-2-甲氧基苯酚的合成
将P2溶于无水THF,并置于冰浴下,随后将LiAlH4溶液缓慢地滴加入溶液中。滴加完成后,将反应液移入75℃油浴中回流4小时。随后降至0℃下,并缓慢加入饱和硫酸钠水溶液淬灭反应,滤掉残渣,旋干可得粗产物。将旋干后的粗产物重新溶于二氧六环的盐酸溶液中,并置于-20℃冰箱过夜,可析出灰色固体P3的盐酸盐。1H NMR(600MHz,D2O)δ7.03(s,1H),6.97-6.96(d,J=8.0Hz,1H),6.88-6.87(d,J=8.0Hz,1H),3.94(s,3H),3.34-3.31(t,J=7.1Hz,2H),3.01-2.98(t,J=7.2Hz,2H).ESI-MS calculated for[M+H]+:168.1,found:168.1。
步骤4:(E)-3-((4-羟基-3-甲氧基苯乙基)氨基)丁-2-烯酸乙酯的合成
将粗产物P3与乙酰乙酸乙酯溶于无水THF中,并加入无水硫酸钠,在氮气保护下反应过夜。反应完成后,过滤除去硫酸钠,旋干得到粗产物。随后用PE:EA过柱,纯化得到黄白色油状化合物P4。ESI-MS calculated for[M+H]+:280.2,found:280.0。
步骤5:2-(7-羟基-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)乙酸乙酯的合成
冰浴下,将五氧化二磷溶于85%的磷酸中,降至室温后,将P4溶于该溶液中,随后将反应液升温至100℃,反应1小时后,将反应液降至0℃,并加入25%的醋酸铵水溶液淬灭反应,二氯甲烷萃取,旋干得紫红色油状物,DCM:MeOH过柱纯化得P5。ESI-MS calculatedfor[M+H]+:280.2,found:280.2。
步骤6:1-(2-乙氧基-2-氧乙基)-7-羟基-6-甲氧基-1-甲基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯的合成
将P5溶于DCM,并加入DIPEA以及(Boc)2O,反应过夜后,旋干得粗产物,PE:EA过柱的淡黄色油状物P6。1H NMR(600MHz,CDCl3)δ6.81(s,1H),6.52(s,1H),5.51(s,1H),4.13-4.10(q,J=7.1Hz,1H),3.93-3.89(q,J=7.1Hz,2H),3.85(s,4H),3.57–3.54(m,1H),2.82–2.76(m,2H),2.65-2.61(ddd,J=15.0,6.8,3.1Hz,1H),1.68(s,3H),1.50(s,9H),1.09-1.06(t,J=7.1Hz,3H).ESI-MS calculated for[M+H]+:380.2,found:379.9。
步骤7:2-(2-(叔丁氧基羰基)-7-羟基-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)乙酸的合成
将P6溶于H2O+THF,并加入LiOH,将反应液移至90℃油浴中反应过夜。反应完成后,DCM萃取,无水硫酸钠干燥,旋干得黄色粉末状化合物P7。1H NMR(600MHz,CDCl3)δ6.80(s,1H),6.51(s,1H),4.04-4.01(d,J=15.5Hz,1H),3.85–3.84(m,4H),3.50–3.49(m,1H),2.84-2.81(d,J=15.5Hz,1H),2.79-2.75(ddd,J=14.7,8.3,3.3Hz,1H),2.61-2.58(ddd,J=15.1,6.5,3.1Hz,1H),1.66(s,3H),1.49(s,9H).ESI-MS calculated for[M-H]-:350.2,found:349.8。
步骤8:叔丁基7-羟基-6-甲氧基-1-甲基-1-(2-氧代-2-(噻唑-2-基氨基)乙基)-3,4-二氢异喹啉-2(1H)-羧酸盐的合成
室温下,将HATU、DIPEA溶于NMP中,反应1小时后加入P7,随后将反应液移至80℃过夜。反应完成后,DCM萃取,旋干后的粗产物,经PE:EA过柱后得淡黄色粉末状化合物P8。1HNMR(600MHz,MeOD)δ7.33-7.32(d,J=3.6Hz,1H),6.99(d,J=3.6Hz,1H),6.83(s,1H),6.58(s,1H),4.09-4.07(d,J=14.8Hz,1H),3.92–3.86(m,1H),3.79(s,3H),3.50–3.46(m,1H),3.03-3.00(d,J=14.8Hz,1H),2.79-2.74(ddd,J=15.0,8.5,3.5Hz,1H),2.61-2.57(ddd,J=15.2,6.5,3.2Hz,1H),1.75(s,3H),1.49(s,9H).ESI-MS calculated for[M+H]+:432.2,found:431.7。
步骤9:5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)吲哚-2-酮的合成
室温下,5-溴氧化吲哚与5-溴香兰素溶于乙酸中,并加入醋酸钠,随后将反应液移至117℃油浴中进行反应,反应过夜后,直接将冰块加至反应液中,可析出淡黄色固体,过滤所得滤渣为粗产品。在75℃条件下,将粗产品溶于THF中,直至澄清透明,随后将溶液降至室温,并缓慢滴加石油醚直至有固体析出。待不再有固体析出后,过滤可得纯净的AN-OCH3。1HNMR(600MHz,DMSO)δ10.72(s,2H),10.35(s,2H),8.52(d,J=1.4Hz,1H),8.30(d,J=1.5Hz,1H),7.89(d,J=1.6Hz,1H),7.84(s,1H),7.80(d,J=1.4Hz,1H),7.59(s,1H),7.52(d,J=1.3Hz,1H),7.40(dd,J=8.3,1.8Hz,1H),7.38(d,J=1.4Hz,1H),7.33(dd,J=8.2,1.8Hz,1H),6.85(d,J=8.3Hz,1H),6.79(d,J=8.2Hz,1H),3.90(s,3H),3.88(s,3H)。
步骤11:5-溴-3-(3-溴-4-(2-(2-溴乙氧基)乙氧基)-5-甲氧基亚苄基)吲哚-2-酮合成
氮气保护,室温条件下,将AN-OCH3溶于无水DMF中,反应0.5小时后,加入2,2'-二溴二乙醚,并继续反应2小时。反应完成后,冰水淬灭反应,EA萃取反应液,旋干可得橙红色油状物。随后使用PE:EA纯化可得AN-OCH3-O5。1H NMR(600MHz,DMSO)δ10.47(s,2H),10.33(s,1H),8.53(d,J=1.6Hz,2H),8.35(d,J=1.6Hz,2H),7.95(d,J=1.9Hz,2H),7.91(s,2H),7.84(d,J=1.8Hz,1H),7.68(s,1H),7.54(d,J=1.3Hz,1H),7.48(dd,J=8.4,1.9Hz,1H),7.42(dd,J=8.4,2.0Hz,2H),7.40(s,1H),7.15(d,J=8.5Hz,1H),7.08(d,J=8.4Hz,2H),3.95(dd,J=12.2,6.6Hz,6H),3.91(s,6H),3.88(s,3H),3.76-3.66(m,12H),3.52(dd,J=10.9,5.2Hz,6H)。
步骤12:叔丁基7-(2-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)乙氧基)-6-甲氧基-1-甲基-1-(2-氧代-2-(噻唑-2-基氨基)乙基)-3,4-二氢异喹啉-2(1H)-羧酸酯的合成
氮气保护,室温条件下,将P8溶于无水DMF中,反应0.5小时后,加入AN-OCH3-O5后,移至75℃条件下反应过夜。反应完成后,冰水淬灭反应,EA萃取反应液,旋干可得橙红色油状物。随后使用DCM:MeOH纯化可得AN-OCH3-O5-P8。ESI-MS calculated for[M+H]+:928.1,found:928.4。
步骤13:2-(7-(2-(2-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
将AN-OCH3-O5-P8溶于DCM中,并加入TFA,室温下反应0.5小时。旋干反应液DCM:MeOH纯化可得终产物I-1。1H NMR(600MHz,CDCl3)δ8.76(d,J=1.2Hz,1H),7.88(d,J=1.6Hz,2H),7.75(d,J=1.4Hz,1H),7.73(s,2H),7.56(d,J=1.7Hz,1H),7.42(s,2H),7.40(d,J=3.5Hz,3H),7.32(s,1H),7.23(dd,J=8.4,1.7Hz,2H),7.21(dd,J=8.3,1.7Hz,1H),7.16(d,J=1.2Hz,2H),6.92(d,J=8.4Hz,2H),6.89(s,2H),6.88(s,1H),6.88(s,1H),6.70(s,2H),6.62(s,1H),6.53(s,2H),6.50(s,1H),4.14-4.06(m,4H),4.05(dd,J=9.1,4.6Hz,2H),4.01(s,3H),3.98(dt,J=14.7,5.7Hz,5H),3.93(s,6H),3.85-3.78(m,12H),3.77(s,6H),3.75(s,3H),3.30(dd,J=12.6,6.0Hz,3H),3.23-3.15(m,3H),3.04(d,J=16.0Hz,2H),2.98(d,J=16.1Hz,1H),2.88(td,J=11.0,5.7Hz,3H),2.78-2.72(m,3H),2.70(d,J=17.3Hz,2H),2.62(d,J=16.1Hz,1H),1.55(s,5H),1.50(s,3H).13C NMR(151MHz,CDCl3)δ168.72,168.65,168.17,165.93,158.00,148.52,148.46,147.16,146.85,146.13,145.12,142.87,140.56,137.49,137.40,137.34,131.98,131.88,131.01,130.83,127.21,127.17,127.09,127.01,126.26,125.25,125.08,123.29,122.77,121.42,114.39,114.13,113.45,113.08,112.13,111.77,111.54,111.12,110.74,110.71,108.75,107.73,69.61,69.33,69.18,69.10,68.96,56.62,56.53,55.78,55.75,54.80,54.64,46.54,40.45,40.37,38.33,29.67,29.32,29.29,29.17,29.14.ESI-MS calculated for[M+H]+:829.0727,found:829.0706。
实施例二:化合物I-2的制备
2-(7-(2-(2-(3,5-二溴-4-羟基亚苄基)-5-溴代-2-氧代吲哚-1-基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
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参照实施例一I-1的合成路线。I-2:1H NMR(600MHz,DMSO)δ8.77(s,10H),7.82(s,2H),7.77(d,J=1.8Hz,4H),7.58(s,4H),7.48(s,1H),7.48(s,4H),7.27(dd,J=8.4,1.7Hz,1H),7.24(d,J=3.5Hz,5H),7.15(dd,J=8.3,1.8Hz,4H),7.03(d,J=8.4Hz,1H),6.93(d,J=8.3Hz,4H),6.82(s,1H),6.81(s,4H),6.73(s,1H),6.72(s,4H),4.03(dd,J=10.2,5.2Hz,5H),3.98(dd,J=10.2,5.2Hz,5H),3.93(dd,J=9.6,5.6Hz,8H),3.90(d,J=6.0Hz,2H),3.73(t,J=4.5Hz,10H),3.71–3.66(m,25H),3.50(d,J=2.8Hz,2H),3.41(s,8H),3.19(s,10H),2.95(d,J=5.7Hz,1H),2.92(d,J=6.6Hz,4H),2.85(s,4H),2.82(s,1H),1.64(s,15H).13C NMR(151MHz,DMSO)δ168.54,165.57,157.04,148.39,146.85,139.09,138.08,137.87,134.79,128.39,127.04,124.38,119.74,114.90,114.07,113.00,112.10,110.29,109.90,68.81,68.17,68.08,57.40,55.54,43.83,37.58,29.10,28.78,25.91,22.17,14.04.ESI-MS calculated for[M+H]+:876.9725,found:876.9695。
实施例三:化合物I-3的制备
2-(7-(4-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)丁氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-3:1H NMR(600MHz,CDCl3)δ8.78(s,1H),7.91(d,J=1.6Hz,2H),7.76(s,1H),7.75(s,2H),7.60(d,J=1.6Hz,1H),7.43(s,2H),7.40(d,J=3.5Hz,3H),7.35(dd,J=8.4,1.7Hz,2H),7.34(s,1H),7.33–7.31(m,1H),7.17(d,J=1.2Hz,2H),6.88(t,J=3.4Hz,3H),6.80(d,J=8.3Hz,2H),6.76(d,J=8.3Hz,1H),6.69(s,2H),6.63(s,1H),6.52(s,2H),6.51(s,1H),4.05–3.99(m,9H),3.94(s,6H),3.91–3.83(m,6H),3.78(s,6H),3.77(s,3H),3.32–3.27(m,3H),3.19(dd,J=12.8,5.2Hz,3H),3.02(dd,J=23.2,16.0Hz,3H),2.91–2.85(m,3H),2.78–2.68(m,5H),2.65(d,J=16.0Hz,1H),1.93–1.85(m,12H),1.56(s,6H),1.52(s,3H).13C NMR(151MHz,CDCl3)δ168.66,168.57,167.87,165.63,157.91,148.35,148.26,147.06,146.78,146.05,145.01,142.33,139.97,137.53,137.36,137.24,131.93,131.80,131.75,130.92,130.78,127.12,127.06,126.93,126.73,126.63,126.41,125.47,125.01,123.24,122.90,121.63,114.31,114.06,113.40,112.97,111.94,111.24,110.89,110.61,110.05,109.63,108.66,107.62,68.75,56.55,56.43,55.67,54.72,54.60,46.54,46.45,39.62,38.25,29.57,29.53,29.20,29.06,26.35,26.28,24.13,24.06.ESI-MS calculated for[M+H]+:813.0778,found:813.0775。
实施例四:化合物I-4的制备
2-(7-(4-(3-(3,5-二溴-4-羟基苄叉)-5-溴代-2-氧代吲哚-1-基)丁氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-4:1H NMR(600MHz,DMSO)δ8.80(s,6H),7.86(s,1H),7.83(s,1H),7.80(d,J=1.8Hz,2H),7.60(s,2H),7.48(s,1H),7.48(d,J=3.5Hz,2H),7.36(dd,J=8.3,1.5Hz,1H),7.24(d,J=3.5Hz,3H),7.22(dd,J=8.3,1.8Hz,2H),7.02(d,J=8.4Hz,1H),6.93(d,J=8.3Hz,2H),6.83(s,2H),6.83(s,1H),6.72(s,3H),4.02–3.96(m,4H),3.91(d,J=9.6Hz,4H),3.81(d,J=8.6Hz,7H),3.71(s,6H),3.70(s,3H),3.51(s,2H),3.22(s,1H),3.17(t,J=17.1Hz,6H),2.95–2.89(m,3H),2.84(d,J=16.8Hz,3H),1.72(d,J=4.9Hz,12H),1.63(s,9H).13C NMR(151MHz,DMSO)δ168.51,165.54,157.06,148.54,146.88,139.14,137.94,137.85,137.79,128.54,127.06,124.40,124.34,119.86,114.96,114.03,113.00,112.01,110.64,109.42,69.86,68.39,55.54,43.91,37.58,31.37,31.23,29.90,29.09,28.78,26.19,24.19,22.17,14.04.ESI-MS calculated for[M+H]+:860.9776,found:860.9756。
实施例五:化合物I-5的制备
2-(7-(2-(2-(3,5-二溴-4-羟基亚苄基)-5-碘代-2-氧代吲哚-1-基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-5:1H NMR(600MHz,DMSO)δ8.83(d,J=52.6Hz,2H),8.08(s,1H),7.93(s,1H),7.81(s,2H),7.57(s,1H),7.49(d,J=8.1Hz,1H),7.45(s,3H),7.38(d,J=8.1Hz,1H),7.21(s,2H),6.89(d,J=8.2Hz,1H),6.81(d,J=11.9Hz,3H),6.69(s,1H),6.67(s,1H),3.96(s,2H),3.90(s,2H),3.84–3.74(m,4H),3.73(s,1H),3.69(s,7H),3.25(s,2H),3.17(s,1H),3.13(s,3H),2.89(d,J=16.5Hz,2H),2.80(d,J=15.5Hz,2H),1.69(s,8H),1.59(s,6H).13C NMR(151MHz,DMSO)δ168.63,167.69,165.34,157.12,148.36,148.28,146.73,140.95,139.03,138.94,138.23,137.77,134.90,132.86,128.91,128.65,125.37,124.67,117.38,115.06,114.81,113.85,112.02,110.82,110.76,109.98,83.94,68.39,68.21,56.83,55.51,44.33,37.62,26.51,26.22,26.11,24.19,23.95.ESI-MS calculated for[M+H]+:924.9588,found:924.9581。
实施例六:化合物I-6的制备
2-(7-(4-(3-(3,5-二溴-4-羟基苄叉)-5-碘代-2-氧代吲哚-1-基)丁氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-6:1H NMR(600MHz,DMSO)δ8.83(d,J=52.6Hz,2H),8.08(s,1H),7.93(s,1H),7.81(s,2H),7.57(s,1H),7.49(d,J=8.1Hz,1H),7.45(s,3H),7.38(d,J=8.1Hz,1H),7.21(s,2H),6.89(d,J=8.2Hz,1H),6.81(d,J=11.9Hz,3H),6.69(s,1H),6.67(s,1H),3.96(s,2H),3.90(s,2H),3.84–3.74(m,4H),3.73(s,1H),3.69(s,7H),3.25(s,2H),3.17(s,1H),3.13(s,3H),2.89(d,J=16.5Hz,2H),2.80(d,J=15.5Hz,2H),1.69(s,8H),1.59(s,6H).13C NMR(151MHz,DMSO)δ168.63,167.69,165.34,157.12,148.36,148.28,146.73,140.95,139.03,138.94,138.23,137.77,134.90,132.86,128.91,128.65,125.37,124.67,117.38,115.06,114.81,113.85,112.02,110.82,110.76,109.98,83.94,68.39,68.21,56.83,55.51,44.33,37.62,26.51,26.22,26.11,24.19,23.95.ESI-MS calculated for[M+H]+:908.9639,found:908.9644。
实施例七:化合物I-7的制备
2-(7-((5-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)戊基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-7:ESI-MS calculated for[M+H]+:826.1,found:826.5。
实施例八:化合物I-8的制备
2-(7-((8-(5-溴-3-(3-溴-4-羟基-5-甲氧基亚苄基)-2-氧代吲哚-1-基)辛基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-8:ESI-MS calculated for[M+H]+:869.1405,found:869.1403。
实施例九:化合物I-9的制备
2-(7-(2-(2-(2-(2-(5-溴-3-(3-溴-4-羟基-5-甲氧基苄叉)-2-氧代吲哚-1-基)乙氧基)乙氧基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-9:1H NMR(600MHz,DMSO+CDCl3)δ8.38(dd,J=66.8,15.5Hz,6H),7.94(d,J=15.5Hz,1H),7.75(d,J=11.3Hz,2H),7.60(d,J=10.2Hz,2H),7.52(d,J=11.4Hz,1H),7.39(d,J=2.2Hz,3H),7.19-7.14(m,3H),7.12(d,J=3.2Hz,3H),7.04(d,J=7.5Hz,1H),6.94(d,J=8.3Hz,2H),6.83(s,3H),6.58(s,3H),3.93-3.81(m,12H),3.74(s,9H),3.71-3.63(m,15H),3.63-3.60(m,6H),3.50(d,J=5.1Hz,12H),3.48-3.44(m,12H),3.11-3.05(m,3H),3.02(d,J=6.1Hz,3H),2.96(d,J=15.1Hz,3H),2.78(dd,J=14.7,6.7Hz,3H),2.75-2.67(m,3H),2.67-2.59(m,3H),1.39(s,9H).13C NMR(151MHz,DMSO)δ169.24,165.52,157.35,149.84,147.39,146.18,140.29,137.88,137.61,137.51,132.97,128.75,127.09,126.50,119.32,113.21,112.85,112.18,111.25,109.80,72.26,69.94,69.88,69.78,69.01,68.12,68.01,59.82,55.37,54.76,45.93,37.88,29.03,28.77,26.41,20.83,14.15.ESI-MS calculated for[M+H]+:917.1252,found:917.1261。
实施例十:化合物I-10的制备
2-(7-((5-(5-溴-3-(3,5-二溴-4-羟基亚苄基)-2-氧代吲哚-1-基)戊基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。1H NMR(600MHz,DMSO)δ8.77(s,2H),7.90(s,1H),7.81(s,2H),7.78(s,1H),7.57(s,1H),7.45(s,1H),7.39(s,2H),7.32(d,J=8.3Hz,1H),7.20(d,J=8.1Hz,1H),7.12(s,2H),6.99(d,J=8.2Hz,1H),6.90(d,J=8.1Hz,1H),6.81(s,2H),6.58(s,2H),3.86(dd,J=12.9,5.0Hz,4H),3.80-3.71(m,4H),3.65(s,6H),3.11(d,J=11.8Hz,2H),3.04(d,J=5.8Hz,2H),2.98(s,1H),2.96(s,1H),2.83(s,1H),2.81(s,1H),2.71(s,2H),2.65(d,J=15.2Hz,2H),1.69(s,4H),1.66–1.60(m,4H),1.44(s,6H),1.42-1.36(m,4H).13C NMR(151MHz,DMSO)δ169.16,167.97,166.09,165.52,165.42,157.32,147.54,146.42,140.40,139.52,139.28,137.69,137.61,135.07,132.60,128.84,128.66,126.84,126.61,124.39,122.59,119.64,116.81,115.23,115.13,114.52,113.94,113.25,112.87,112.68,112.20,111.18,111.14,111.02,110.09,109.34,72.34,68.43,60.30,55.42,54.99,48.66,45.79,37.84,31.35,29.09,28.80,28.76,28.70,28.58,27.44,27.19,23.15,22.98,22.16,14.02.I-10:ESI-MS calculated for[M+H]+:874.9933,found:874.9936。
实施例十一:化合物I-11的制备
2-(7-((8-(5-溴-3-(3,5-二溴-4-羟基亚苄基)-2-氧代吲哚-1-基)辛基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-11:ESI-MS calculated for[M+H]+:917.0403,found:917.0406。
实施例十二:化合物I-12的制备
2-(7-(2-(2-(2-(2-(5-溴-3-(3,5-二溴-4-羟基亚苄基)-2-氧吲哚-1-基)乙氧基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-12:1H NMR(600MHz,DMSO)δ8.80(s,2H),8.55(s,1H),7.89(d,J=6.5Hz,2H),7.81(s,1H),7.77(s,2H),7.58(s,2H),7.46(s,1H),7.42(s,3H),7.31(t,J=9.1Hz,2H),7.19(d,J=8.2Hz,1H),7.15(s,2H),7.03(d,J=8.3Hz,1H),6.94(d,J=8.1Hz,1H),6.89(s,1H),6.83(s,2H),6.63(d,J=8.2Hz,3H),6.59(d,J=8.2Hz,1H),4.00(dd,J=14.9,9.5Hz,6H),3.93-3.87(m,6H),3.68(s,3H),3.67(s,6H),3.65-3.60(m,12H),3.52(d,J=8.8Hz,12H),3.45(s,12H),3.23(d,J=4.8Hz,3H),3.13(s,3H),3.06(d,J=15.1Hz,3H),2.99(dd,J=15.0,8.1Hz,3H),2.84-2.75(m,3H),2.70(d,J=16.0Hz,3H),1.53(s,3H),1.52(s,6H).13C NMR(151MHz,DMSO)δ170.44,169.46,168.45,166.39,166.02,165.61,157.71,157.67,149.86,148.08,146.81,141.18,139.79,139.66,138.48,138.37,138.07,135.40,135.02,134.14,131.85,131.65,129.31,128.85,127.33,126.58,126.44,124.58,122.95,120.02,117.60,115.57,115.46,115.42,114.86,113.87,113.35,113.27,113.14,112.49,111.89,111.33,111.21,111.10,110.32,104.80,70.29,70.23,70.17,70.13,69.44,69.39,69.36,68.52,68.46,68.28,68.20,56.19,56.08,56.01,55.80,55.36,49.08,45.63,45.48,42.62,38.16,38.09,28.30,28.23,28.15,28.05.ESI-MS calculated for[M+H]+:965.0250,found:965.0251。
实施例十三:化合物I-13的制备
2-(7-((5-(3,5-二溴-4-羟基亚苄基)-5-碘代-2-氧代吲哚-1-基)戊基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-13:1H NMR(600MHz,DMSO)δ8.78(s,2H),8.12(s,1H),7.92(s,2H),7.82(s,1H),7.81(s,2H),7.57(s,1H),7.56(s,2H),7.48(d,J=8.6Hz,1H),7.44(s,1H),7.39(s,2H),7.37(d,J=8.1Hz,2H),7.11(s,3H),6.88(d,J=8.1Hz,1H),6.80(d,J=11.3Hz,5H),6.58(s,3H),3.86(dd,J=12.9,5.7Hz,6H),3.76(s,6H),3.65(s,9H),3.12-3.08(m,3H),3.04(d,J=5.6Hz,3H),2.97(d,J=15.0Hz,3H),2.80(d,J=14.9Hz,3H),2.73(d,J=15.4Hz,3H),2.65(d,J=15.7Hz,3H),1.69(s,6H),1.66-1.60(m,6H),1.44(s,9H),1.40(d,J=6.9Hz,6H).13C NMR(151MHz,DMSO)δ170.44,169.46,168.45,166.39,166.02,165.61,157.71,157.67,149.86,148.08,146.81,141.18,139.79,139.66,138.48,138.37,138.07,135.40,135.02,134.14,131.85,131.65,129.31,128.85,127.33,126.58,126.44,124.58,122.95,120.02,117.60,115.57,115.46,115.42,114.86,113.87,113.35,113.27,113.14,112.49,111.89,111.33,111.21,111.10,110.32,104.80,70.29,70.23,70.17,70.13,69.44,69.39,69.36,68.52,68.46,68.28,68.20,56.19,56.08,56.01,55.80,55.36,49.08,45.63,45.48,42.62,38.16,38.09,28.30,28.23,28.15,28.05.ESI-MS calculated for[M+H]+:922.9795,found:922.9787。
实施例十四:化合物I-14的制备
2-(7-((8-(3,5-二溴-4-羟基亚苄基)-5-碘代-2-氧代吲哚-1-基)辛基)氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-14:ESI-MS calculated for[M+H]+:965.0265,found:965.0271。
实施例十五:化合物I-15的制备
2-(7-(2-(2-(2-(3-(3,5-二溴-4-羟基亚苄基)-5-碘-2-氧代吲哚-1-基)乙氧基)乙氧基)-6-甲氧基-1-甲基-1,2,3,4-四氢异喹啉-1-基)-N-(噻唑-2-基)乙酰胺的合成
参照实施例一I-1的合成路线。I-15:ESI-MS calculated for[M+H]+:1013.0113,found:1013.0123
实施例十六:细胞水平测定化合物对PCSK9的靶向降解活性试验,对本发明的化合物I-1~I-4采用Western Blot实验即蛋白印迹实验和细胞免疫荧光实验来测定化合物对PCSK9的靶向降解能力。该靶向降解能力主要用PCSK9蛋白最大降解程度以及化合物最佳降解浓度两个指标来表示。同时采用定时定量PCR实验证明本发明化合物对SREBP2-PCSK9-LDLR mRNA表达水平没有明显影响,仅在蛋白水平对PCSK9有降解作用。并对LDLR以及LC3B等蛋白水平的测定来进行佐证。
实验方法:
细胞系和试剂
Huh7细胞(ATCC)在补充有10%胎牛血清(BI)和1%青霉素和链霉素(Sigma)的高糖DMEM培养基(Hyclone)中培养,培养箱环境为37℃,95%的空气和5%二氧化碳。除棕榈酸溶液外,其他药物溶液均以1000倍实际使用浓度储存于DMSO或PBS中。油酸和(Sigma)棕榈酸(Sigma)加热溶解后,溶于含15%FAF-BSA(Yeason)的高糖DMEM中,过滤除菌后,配成含5mM的油酸:棕榈酸=2:1或棕榈酸溶液并储存。
细胞生长到约70%密度时,直接给药或者造模后给药。造模使用500μM棕榈酸和1μg/mL LPS共同处理或500μM油酸:棕榈酸=2:1处理24小时,他汀组则另外再孵育4小时辛伐他汀(Sigma)后,与化合物共孵育。
LDLR抗体购自Abcam,PCSK9、LC3B抗体购自Cell Signaling Technologies,GAPDH抗体购自Bioworld,所有其他试剂均从Sigma Aldrich购得。
实验方法:
细胞经过药物处理后,RIPA(Beyotime)冰上裂解30分钟,高速离心取上清,经BCA法(Beyotime)测定蛋白浓度并平衡至同一浓度后,加入5X Loading Buffer,煮沸5分钟制成蛋白上样液用于蛋白印迹实验。蛋白印迹实验主要包括聚丙烯酰胺凝胶电泳分离蛋白,PVDF膜转印,含5%脱脂奶粉的TBST溶液封闭30分钟,一抗溶液4℃孵育过夜,二抗室温孵育60分钟,显影液(Millipore)显影并使用凝胶成像系统记录。
图1示出了根据本发明实施例制备的化合物的Western Blot实验结果。从图1可以看出,化合物I-1~I-4均能够对Huh7细胞系产生从蛋白水平降低PCSK9的效果,并且具有明显勾状效应,其中I-3药物相对作用效果更好。而Huh7与接头化合物孵育实验证明其接头化合物AN-Br、AN-OCH3以及P8并没有单独降低PCSK9活性。说明本发明化合物对PCSK9蛋白有较好的降解作用。
图2示出了根据本发明实施例制备的化合物I-2与I-4的Western Blot实验结果。从图2可以看出,化合物I-2与I-4均能够对Huh7细胞系产生从蛋白水平降低LC3的效果,并且具有明显的浓度依赖作用,表明本发明化合物的I-2与I-4对LC3蛋白有较好的降解作用。
实验方法:
定时定量PCR实验:
用于实时定量PCR的引物由Sangon Inc合成,TRIZOL购自TAKARA,其余实时定量PCR相关试剂均购自Yeason。实时定量PCR结果根据GAPDH进行均一化处理。引物序列如下:
LDLR:正向5'-GACGTGGCGTGAACATCTG-3';
反向,5'-CTGGCAGGCAATGCTTTGG-3';
PCSK9:正向,5'-AGGGGAGGACATCATTGGTG-3';
反向,5-CAGGTTGGGGGTCAGTACC-3;
SREBP2:正向,5'-CCCTGGGAGACATCGACGA-3';
反向,5'-CGTTGCACTGAAGGGTCCA-3';
GAPDH:正向,5'-ATGGGGAAGGTGAAGGTCG-3';
反向,5'-GGGGTCATTGATGGCAACAATA-3'。
图3示出了根据本发明实施例制备的化合物I-3的qPCR实验结果。从图3可以看出,化合物I-3对SREBP2-PCSK9-LDLR mRNA表达水平没有明显影响,仅在蛋白水平对PCSK9有作用。
图4示出了根据本发明实施例制备的化合物I-3的MTT毒性试验测定结果。从图4可以看出,化合物I-3无明显细胞毒性。
图5示出了根据本发明实施例制备的化合物I-3在高脂模型中的Western Blot实验结果。从图5可以看出,在棕榈酸、LPS模拟的高脂炎症环境下,PCSK9升高,化合物I-3药物能够降低PCSK9含量并提高LDLR,实验结果表明了化合物I-3药物作为高脂血症患者治疗药物的可能性。
图6示出了根据本发明实施例制备的化合物I-3与他汀类药物联用时的WesternBlot实验结果。化合物I-3药物能够与他汀类药物—辛伐他汀产生协同效果,降低由他汀类药物引起的PCSK9升高,并进一步提高LDLR的蛋白含量,实验结果表明了化合物I-3药物和他汀类药物联合使用作为高脂血症患者治疗药物的可能性。
图7示出了根据本发明实施例制备的化合物I-1~I-15的Western Blot实验结果,化合物I-1、I-8、I-15的PCSK9降解效果更优。说明本发明化合物对PCSK9蛋白有较好的降解作用。
以上的具体实施方式对本发明的目的、技术方案和有益效果进行了进一步详细说明,应当理解的是,以上仅为本发明的一种具体实施方式而已,并不限于本发明的保护范围,在不脱离本发明的基本特征的宗旨下,本发明可体现为多种形式,因此本发明中的实施形态是用于说明而非限制,由于本发明的范围由权利要求限定而非由说明书限定,而且落在权利要求界定的范围,或其界定的范围的等价范围内的所有变化都应理解为包括在权利要求书中。凡在本发明的精神和原则之内的,所做出的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种PCSK9小分子蛋白降解剂,其特征在于,为如下式化学结构通式I的四氢异喹啉类化合物或其药学上可接受的盐:
其中,
连接基团A为:C1-C20的烷基链、醚链、氧杂链;
R1、R2、R3以及R4独立地选自氢、卤素;
R5独立地选自氢、甲氧基、卤素、羟基、硝基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-N3、C1-6烷基、C2-6烯基、C2-6炔基;
R6独立地选自甲基;
R7独立地选自以下结构:
或者/>
基团B为:
其中R8、R9以及R10独立地选自氢、卤素、羟基、硝基、甲氧基、氨基、甲氨基、二甲氨基、羧基、氰基、-CO2Me、-CO2Et、-CH3、-Et、-N3;X为NH、S、O。
2.根据权利要求1所述的PCSK9小分子蛋白降解剂,其特征在于,所述R7为
3.根据权利要求1或2所述的PCSK9小分子蛋白降解剂,其特征在于,所述基团B为R8、R9和R10独立地选自卤素、羟基、甲氧基。
4.根据权利要求1-3任一项所述的PCSK9小分子蛋白降解剂,其特征在于,所述化合物选自下述化合物:
5.一种如权利要求1-4任一项所述的PCSK9小分子蛋白降解剂的制备方法,其特征在于,包括如下步骤:
其中,
R2、R5、R8、R10如权利要求1所定义的。
6.一种药物组合物,其特征在于,包括如权利要求1-4任一项所述的PCSK9小分子蛋白降解剂,以及药物上可接受的载体。
7.如权利要求1-4任一项所述的PCSK9小分子蛋白降解剂在制备用于预防或治疗与抑制PCSK9活性相关的疾病的药物中的应用。
8.如权利要求1-4任一项所述的PCSK9小分子蛋白降解剂在制备用于预防或治疗与抑制LC3活性相关的疾病的药物中的应用。
9.根据权利要求7或8所述的应用,其特征在于,所述疾病选自心脑血管疾病、脱发性疾病、白癜风、角化异常性疾病、疤痕以及肺纤维化疾病、代谢综合征、糖尿病、阿尔茨海默症、抗排斥反应、非酒精性肝炎和恶性肿瘤中的至少一种。
10.根据权利要求9所述的应用,其特征在于,所述心脑血管疾病选自胆固醇相关疾病、高脂血症和动脉粥样硬化中的至少一种;所述恶性肿瘤选自白血病、前列腺癌、甲状腺癌、肝癌、卵巢癌、乳腺癌、食道癌、腺癌、胃癌、肺癌和结直肠癌中的至少一种。
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