CN107814798B - 3-取代丙烯酸类化合物及其制备方法和用途 - Google Patents
3-取代丙烯酸类化合物及其制备方法和用途 Download PDFInfo
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- CN107814798B CN107814798B CN201710794564.0A CN201710794564A CN107814798B CN 107814798 B CN107814798 B CN 107814798B CN 201710794564 A CN201710794564 A CN 201710794564A CN 107814798 B CN107814798 B CN 107814798B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请提供3‑取代丙烯酸类化合物及其制备方法和用途,具体地,本申请涉及所述3‑取代丙烯酸类化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯、及其药物组合物、制备方法和用途。本申请的化合物能够抑制雌激素受体活性、下调雌激素受体的表达水平或诱导雌激素受体降解,可用于预防或治疗与雌激素受体过度活性相关的疾病,尤其是雌激素受体阳性(ER+)耐药性疾病(例如对抗雌激素疗法产生耐药性的乳腺癌等)。
Description
技术领域
本申请涉及医药领域,具体地,本申请涉及3-取代丙烯酸类化合物及其制备方法和用途;更具体地,本申请涉及如式I所示化合物在抑制雌激素受体活性、下调雌激素受体表达水平或诱导雌激素受体降解中的用途;本申请还涉及如式I所示化合物在制备预防或治疗与雌激素受体过度活性相关的疾病的药物中的用途,尤其是雌激素受体阳性(ER+)耐药性疾病(例如对抗雌激素疗法产生耐药性的乳腺癌等)。
背景技术
雌激素受体α(ERα)和雌激素受体β(ERβ)是类固醇激素受体,也是核受体大家族的成员。两种受体都参与女性生殖系统的调节和发育,此外也在中枢神经系统,心血管系统和骨代谢中发挥作用(Dahlman-Wright,et al.,Pharmacol.Rev.,2006,58:773-781)。
大约80%的乳腺癌是ERα阳性,其它癌症如卵巢癌和子宫内膜也被认为是依赖于ERα信号来增殖。
选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)是一类在不同组织中对雌激素受体有不同作用的药物,可以根据细胞和转录启动子的不同以及雌激素受体亚型来充当受体激动剂或者拮抗剂。例如他莫昔芬在乳房是雌激素受体拮抗剂,但在骨、心血管系统和子宫系统是部分激动剂(Jordan,V.C.Nat.Rev.DrugDiscovery 2003,2,205-213)。
虽然患者对最初的抗雌激素疗法,如他莫昔芬和芳香化酶抑制剂应答良好,然而在治疗过程中经常会出现抗药现象,这在很大程度上影响了治疗的效果。
有证据表明,在许多情况下雌激素受体对抗药性的产生起着核心的作用,包括突变导致非配体依赖的ER激活(Ali,S.;Coombes,R.C.Nat Rev Cancer 2002;2:101-12)。所以下调雌激素受体的表达水平,或完全抑制雌激素受体活性甚至是除去雌激素受体是治疗乳腺癌等与雌激素受体过度活性相关的疾病,尤其是对抗雌激素疗法产生耐药性的疾病的最佳方式。
选择性雌激素受体下调剂(selective estrogen receptor down-regulators,SERDs)是一类能够通过抑制雌激素受体两个转录激活域AF1和AF2的功能而阻断雌激素的活性的药物,是一类经典的“纯”抗雌激素药物(完全拮抗剂)。以氟维司群(Fulvestrant)为例,其被认为是一个全拮抗剂,可诱导ERα在核基质的固定和通过泛素-蛋白酶体途径的ERα的迅速降解(Nephew,K.P.;Long,X.J.Biol.Chem.2006,14,9607-9615)。该药物同时具有拮抗ERα和降解ERα的两个功能,对已产生抗激素药物抗药现象的乳腺癌患者有一定疗效(Johnston,S.J.;Cheung,K.L.Curr.Med.Chem.2010,17,902-914)。
氟维司群是目前被批准用于临床使用的唯一SERDs类药物,但是其成药物特性差,必须通过肌内注射,且药效低,500mg/月的剂量在患者中只能达到小于50%的雌激素受体的降解(Wardell,et al.,Biochem.Pharm.,2011,82:122-130)。
临床上对能够抑制雌激素受体活性、下调雌激素受体表达水平或诱导雌激素受体降解的药物有很大的需求,以改善针对早期的、转移性的、或耐药性的乳腺癌或其它与雌激素受体过度活性相关的疾病的治疗效果。
发明内容
在本申请中,发明人通过大量研究发现,如式I所示的化合物能够抑制雌激素受体活性、下调雌激素受体表达水平或诱导雌激素受体降解,可用于预防或治疗与雌激素受体过度活性相关的疾病,尤其是雌激素受体阳性(ER+)耐药性疾病(例如对抗雌激素疗法产生耐药性的乳腺癌等),本申请即是基于以上发现而完成。
因此,本申请第一方面涉及式I所示化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯,
其中,
X为-C(R1)-或-N-;
R1和R2各自独立地为氢、氰基、C2-C4烯基、C2-C4炔基或卤素;
R3为氢、C1-C6烷基或卤代C1-C6烷基;
R4为C1-C6烷基或卤代C1-C6烷基;
R5为氢、卤素、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、C1-C6烷氨基、二C1-C6烷基取代的氨基、C1-C6烷酰基氨基、C1-C6烷基磺酰基、6-14元芳基、6-14元芳基甲酰基、5-14元杂芳基或5-14元杂芳基甲酰基;其中,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、C1-C6烷氨基、二C1-C6烷基取代的氨基、C1-C6烷酰基氨基、C1-C6烷基磺酰基、6-14元芳基、6-14元芳基甲酰基、5-14元杂芳基和5-14元杂芳基甲酰基未被取代或被一个或多个(例如1、2、3或4个)选自下述的取代基取代:卤素、羟基、氨基、氰基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷氨基、二C1-C6烷基取代的氨基、C1-C6烷硫基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、3-8元环烷基和3-8元杂环烷基;或者,
R5与环A中编号为1和2的碳原子一起形成3-5元碳环或3-5元杂环,其中所述杂环中含有至少一个至多三个选自N、O和S的杂原子;
R6为氢、卤素、C1-C6烷基或卤代C1-C6烷基;
m为1、2、3或4;
n为1、2或3。
在某些优选实施方案中,当X为-C(R1)-,R1为氟,R2为氟,R3为氢,R4为甲基,R6为氢,m为1,且n为1或3时,R5不为氢和氟。
在某些优选实施方案中,所述化合物具有如式Ia所示结构,
各原子或取代基的定义如本申请第一方面所述。
在某些优选实施方案中,X为-C(R1)-。
在某些优选实施方案中,R1为氰基或卤素。
在某些优选实施方案中,R1为卤素。
在某些优选实施方案中,R1为氟。
在某些优选实施方案中,X为-N-。
在某些优选实施方案中,R2为氢或卤素。
在某些优选实施方案中,R2为氢或氟。
在某些优选实施方案中,R3为氢、C1-C4烷基或卤代C1-C4烷基。
在某些优选实施方案中,R3为氢或C1-C4烷基。
在某些优选实施方案中,R3为氢。
在某些优选实施方案中,R4为C1-C4烷基。
在某些优选实施方案中,R4为C1-C2烷基。
在某些优选实施方案中,R4为甲基。
在某些优选实施方案中,R5为氢、卤素、氨基、氰基、C1-C4烷基、C2-C4烯基、C2-C4炔基、3-6元环烷基、3-6元杂环烷基、C1-C4烷氨基或二C1-C4烷基取代的氨基;其中,所述C1-C4烷基、C2-C4烯基、C2-C4炔基、3-6元环烷基、3-6元杂环烷基、C1-C4烷氨基和二C1-C4烷基取代的氨基未被取代或被一个或多个(例如1、2、3或4个)选自下述的取代基取代:卤素(例如氟)、羟基、氨基、氰基、C2-C4烯基、C2-C6炔基、C1-C4烷氧基、C1-C4烷氨基、二C1-C4烷基取代的氨基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、3-6元环烷基和3-6元杂环烷基;或者,
R5与环A中编号为1和2的碳原子形成3-5元碳环或5元杂环,其中所述杂环中含有1个或2个选自N和O的杂原子。
在某些优选实施方案中,R5为氢、氟、氨基、氰基、C1-C4烷基、乙烯基、乙炔基、3-5元环烷基、3-5元杂环烷基、C1-C2烷氨基或二C1-C2烷基取代的氨基;其中,所述C1-C4烷基未被取代或被一个或多个(例如1、2、3或4个)选自下述的取代基取代:氟、羟基、氨基、氰基、乙烯基、乙炔基、C1-C2烷氧基、C1-C2烷氨基、二C1-C2烷基取代的氨基、C1-C2烷硫基、C1-C2烷基亚磺酰基、C1-C2烷基磺酰基、3-5元环烷基和3-5元杂环烷基;或者,
R5与环A中编号为1和2的碳原子形成3-5元碳环。
在某些优选实施方案中,R5为C1-C4烷基、乙炔基或3-5元环烷基;其中,所述C1-C4烷基未被取代或被一个或多个(例如1、2、3或4个)选自下述的取代基取代:氟、羟基、氨基、氰基、乙烯基、乙炔基、C1-C2烷氧基、C1-C2烷氨基、二C1-C2烷基取代的氨基、C1-C2烷硫基、C1-C2烷基亚磺酰基、C1-C2烷基磺酰基、3-5元环烷基和3-5元杂环烷基。
在某些优选实施方案中,R5为氢、氟、氨基、氰基、甲基、乙基、丙基、异丙基、乙炔基、环丙基、卤代甲基(例如二氟甲基或三氟甲基)、羟基甲基、甲氧基甲基、二甲氨基甲基、氰基甲基、甲硫基甲基、甲磺酰基甲基或二甲氨基;或者,
R5与环A中编号为1和2的碳原子形成三元碳环、四元碳环或五元碳环;优选三元碳环。
在某些优选实施方案中,R5为甲基、乙基、异丙基、乙炔基、环丙基、卤代甲基(例如二氟甲基或三氟甲基)、羟基甲基或甲氧基甲基。
在某些优选实施方案中,R6为氢或卤素。
在某些优选实施方案中,R6为氢或氟。
在某些优选实施方案中,m为1或2。
在某些优选实施方案中,n为1或2。
在某些优选实施方案中,n为1。
在某些优选实施方案中,X为-C(R1)-,R1为氟;
R2为氢或氟;
R3为氢;
R4为甲基;
n为1;
其余原子或取代基定义如本申请第一方面所述。
在本申请的实施方案中,所述式I化合物选自:
本申请的第二方面涉及所述式I化合物的制备方法,其选自以下方法:
方法一:
步骤1:化合物SM-1与化合物SM-2经还原胺化反应得到化合物IN-1,或者化合物SM-1与化合物SM-3经取代反应得到化合物IN-1;
步骤2:化合物IN-1与化合物IN-2合环得到化合物IN-3;
步骤3:化合物IN-3酯水解后得到所述式I化合物;
其中,Y表示离去基团,例如卤素(如氯、溴或碘)、酯基或-OTs,其余各原子或取代基定义如本申请第一方面所述;
方法二:
步骤1:化合物IN-1与化合物IN-4合环得到化合物IN-5;
步骤2:化合物IN-5与丙烯酸酯通过Heck偶联反应得到化合物IN-3;
步骤3:化合物IN-3酯水解后得到所述式I化合物;
其中,Z代表卤素(例如溴、氯),其余各原子或取代基定义如本申请第一方面所述。
本申请的另一方面涉及药物组合物,其含有本申请第一方面所述的化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯,以及任选地一种或多种药学上可接受的载体或赋形剂。
在某些优选实施方案中,所述药物组合物还含有一种或多种抗癌药物,例如palbociclib。
在某些优选实施方案中,所述的载体包括但不限于:氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定,与主药无配伍禁忌,不产生副作用,不影响疗效,在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用,不与主药产生化学或物理作用,不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂;中药丸剂中的酒、醋、药汁等;半固体制剂软膏剂、霜剂中的基质部分;液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
所述药物组合物可以通过以下途径给药:胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
所述药物组合物可根据给药途径制成各种适宜的剂型。例如片剂、胶囊剂、颗粒剂、口服溶液剂、口服混悬剂、口服乳剂、散剂、酊剂、糖浆剂、注射剂、栓剂、软膏剂、乳膏剂、糊剂、眼用制剂、丸剂、植入剂、气雾剂、粉雾剂、喷雾剂等。其中,所述的药物组合物或适宜的剂型可以含有0.01mg至1000mg的本申请化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯、或所述药物组合物,适宜含有0.1mg至800mg,优选含有0.5-500mg,更优选含有0.5至350mg,特别优选1-250mg。
当口服用药时,所述药物组合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时,所述药物组合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
所述药物组合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
本申请还涉及所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或所述药物组合物在制备抑制雌激素受体活性的药物中的用途。
在某些优选实施方案中,所述雌激素受体为雌激素受体α亚型(ERα)。
本申请还涉及所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或所述药物组合物在制备下调雌激素受体表达水平的药物中的用途。
在某些优选实施方案中,所述雌激素受体为雌激素受体α亚型(ERα)。
本申请还涉及所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或所述药物组合物在制备诱导雌激素受体降解的药物中的用途。
在某些优选实施方案中,所述雌激素受体为雌激素受体α亚型(ERα)。
本申请还涉及所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或所述药物组合物在制备治疗与雌激素受体(例如ERα)过度活性相关的疾病的药物中的用途。
本申请还涉及一种预防或治疗与雌激素受体(例如ERα)过度活性相关的疾病的方法,其包括给有此需要的受试者施用有效量的本申请所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或本申请所述药物组合物的步骤。
本申请所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或本申请所述药物组合物,其用于预防或治疗与与雌激素受体(例如ERα)过度活性相关的疾病。
本申请还涉及一种抑制细胞中雌激素受体(例如ERα)活性的方法,其包括向细胞施用有效量的本申请所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或本申请所述药物组合物的步骤。
在某些优选实施方案中,所述细胞为实验室培养或来自受试者。
本申请还涉及一种抑制细胞中雌激素受体(例如ERα)表达的方法,其包括向细胞施用有效量的本申请所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或本申请所述药物组合物的步骤。
在某些优选实施方案中,所述细胞为实验室培养或来自受试者。
本申请还涉及一种诱导细胞中雌激素受体(例如ERα)降解的方法,其包括向细胞施用有效量的本申请所述化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯或本申请所述药物组合物的步骤。
在某些优选实施方案中,所述细胞为实验室培养或来自受试者。
在本申请的实施方案中,所述与雌激素受体(尤其是ERα)过度活性相关的疾病选自:癌症(例如乳腺癌、骨癌、肺癌、结直肠癌、子宫内膜癌、前列腺癌、卵巢癌和子宫癌)、与中枢神经系统(CNS)相关的疾病或病症(例如酒精中毒、偏头痛、痴呆症(如阿尔茨海默病)、帕金森病)、与心血管系统相关的疾病或病症(例如主动脉瘤、心肌梗死、主动脉硬化、冠状动脉硬化、高血压)、深静脉血栓、免疫及炎症疾病(格雷夫斯病、关节炎、多发性硬化、硬化症)、慢性肝病(例如慢性肝炎,如慢性乙型肝炎)、胆汁淤积、尿道下裂、肥胖症、骨关节炎、精神障碍(神经性厌食、注意力缺陷多动障碍(ADHD)、重性抑郁障碍、精神病)、子宫疾病(如子宫平滑肌瘤、子宫内膜增生、子宫内膜异位症)或生殖缺陷(不育症);优选地,所述疾病为癌症(例如乳腺癌、骨癌、肺癌、结直肠癌、子宫内膜癌、前列腺癌、卵巢癌和子宫癌);优选地,所述癌症为耐药性癌症,例如对抗雌激素疗法耐药的乳腺癌。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
本申请中所用术语“立体异构体”包括构象异构体和构型异构体,其中所述构型异构体主要包括顺反异构体和旋光异构体。本申请所述化合物可以以立体异构体的形式存在,并因此涵盖所有可能的立体异构体形式,及其任何组合或任何混合物。例如单一对映异构体,单一非对映异构体或以上的混合物。当本申请所述的化合物含有烯烃双键时,除非特别说明,否则其包括顺式异构体和反式异构体,以及其任何组合。
本申请中所用术语“药学上可接受的盐”是指,(1)本申请化合物中存在的酸性官能团(例如-COOH、-OH、-SO3H等)与适当的无机或者有机阳离子(碱)形成的盐,例如本申请化合物与碱金属或碱土金属形成的盐、本申请化合物的铵盐,和本申请化合物与含氮有机碱形成的盐;以及(2)本申请化合物中存在的碱性官能团(例如-NH2等)与适当的无机或者有机阴离子(酸)形成的盐,例如本申请化合物与无机酸或有机羧酸形成的盐。
因此,本申请化合物的“药学上可接受的盐”包括但不限于,碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等;无机碱盐,如铵盐;有机碱盐,如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐;氢卤酸盐,如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等;无机酸盐,如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对苯磺酸盐等;有机酸盐,如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等;氨基酸盐,如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
本申请中所用术语“药学上可接受的酯”是指,当本申请化合物存在羧基时,其与醇发生酯化反应而形成的酯;当本申请化合物存在羟基时,其与有机酸、无机酸、有机酸盐等发生酯化反应而形成的酯。酯在酸或者碱存在的条件下,可以发生水解反应生成相应的酸或醇。
本申请中所用术语“氢”及所述的各基团中的氢,是指氕(H),氘(D)或氚(T)。在某些优选实施方案中,所述氢为H。在某些优选实施方案中,所述氢为D。
本申请中所用术语“卤素”是指氟、氯、溴或碘。
本申请中所用术语“C1-C6烷基”是指具有1-6个碳原子的直链或支链烷基,例如C1-C4烷基、C1-C2烷基、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基或C6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本申请中所用术语“C2-C6烯基”是指含有2-6个碳原子以及一个、两个或三个碳碳双键的直链或支链烃基,优选含有一个碳碳双键的C2-C6烯基。例如C2-C4烯基、C2烯基、C3烯基、C4烯基、C5烯基或C6烯基。具体的实例包括但不限于乙烯基、丙烯基、2-丙烯基、丁烯基、2-丁烯基、2-甲基-丙烯基、丁二烯基、戊烯基、2-甲基-丁烯基、3-甲基-丁烯基、1,3-戊二烯基、1,4-戊二烯基、己烯基、2-乙基-丁烯基、3-甲基-戊烯基、4-甲基-戊烯基、1,3-己二烯基、1,4-己二烯基、1,5-己二烯基等。
本申请中所用术语“C2-C6炔基”是指含有2-6个碳原子以及一个、两个或三个碳碳三键的直链或支链烃基,优选含有一个碳碳三键的C2-C6炔基。例如C2-C4炔基、C2炔基、C3炔基、C4炔基、C5炔基或C6炔基。具体的实例包括但不限于乙炔基、丙炔基、2-丙炔基、丁炔基、2-丁炔基、2-甲基-丙炔基、丁二炔基、戊炔基、2-甲基-丁炔基、3-甲基-丁炔基、1,3-戊二炔基、1,4-戊二炔基、己炔基、2-乙基-丁炔基、3-甲基-戊炔基、4-甲基-戊炔基、1,3-己二炔基、1,4-己二炔基、1,5-己二炔基等。
本申请中所用术语“C1-C6烷氧基”是指以C1-C6烷基-O-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“C1-C6烷氨基”是指以C1-C6烷基-NH-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“二C1-C6烷基取代的氨基”是指具有结构的基团,其中C1-C6烷基的定义如前文所述,连接在N原子上的两个C1-C6烷基可以相同也可以不同。例如二C1-C4烷基取代的氨基或二C1-C2烷基取代的氨基。具体的实例包括但不限于二甲氨基、二乙胺基、甲基乙基氨基、甲基异丙基氨基、乙基异丙基氨基、甲基叔丁基氨基、乙基叔丁基氨基等。
本申请中所用术语“C1-C6烷硫基”是指以C1-C6烷基-S-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“C1-C6烷酰基氨基”是指以C1-C6烷基-C(O)-NH-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“C1-C6烷基亚磺酰基”是指以C1-C6烷基-S(O)-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“C1-C6烷基磺酰基”是指以C1-C6烷基-S(O)2-方式形成的基团,其中“C1-C6烷基”的定义如前文所述。
本申请中所用术语“3-8元环烷基”是指含有3-8个环成员的单环饱和烷基,例如3-6元环烷基、3-5元环烷基、3元、4元、5元、6元、7元或8元环烷基。具体的实例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
本申请中所用术语“3-5元碳环”是指含有3-5个环成员的单环饱和烷基,例如3元碳环、4元碳环或5元碳环。
本申请中所用术语“3-5元杂环”是指含有3-5个环成员的单环饱和烷基或芳基,其中所述环成员中至少1个至多3个(例如1个、2个或3个)为选自N、O和S的杂原子,例如3元杂环、4元杂环或5元杂环。具体的实例包括但不限于环氧乙烷、氧代环丁烷、吡咯烷、四氢呋喃环、呋喃、噻吩、吡咯、噻唑、异噻唑、噻二唑、噁唑、异噁唑、咪唑、吡唑、1,2,3-三唑、1,2,3-噁二唑等。
本申请中所用术语“3-8元杂环烷基”是指含有3-8个环成员的环烷基,且所述环成员中至少1个至多4个(例如1、2、3或4个)为选自N、O和S的杂原子,例如3-6元杂环烷基、3-5元杂环烷基、3元、4元、5元、6元、7元或8元杂环烷基。具体的实例包括但不限于:环氧乙基、氧代环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫吗啉基等。
本申请中所用术语“6-14元芳基”是指含有6-14个环成员的单环、双环或多环芳香族基团,例如6-10元芳基、10-14元芳基等。具体的实例包括但不限于苯、萘、蒽、菲等。
本申请中所用术语“6-14元芳基甲酰基”是指以6-14元芳基-C(O)-方式形成的基团,其中“6-14元芳基”的定义如前文所述。
本申请中所用术语“5-14元杂芳基”是指含有5-14个环成员的单环、双环或多环芳香族基团,且所述环成员中至少1个至多4个(例如1、2、3或4个)为选自N、O和S的杂原子,例如5-6元杂芳基、6-10元杂芳基、10-14元杂芳基、9元杂芳基等。具体的实例包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。
本申请中所用术语“5-14元杂芳基甲酰基”是指以5-14元杂芳基-C(O)-方式形成的基团,其中“5-14元杂芳基”的定义如前文所述。
本申请中所用术语“受试者”是指动物,特别是哺乳动物,优选人。
本申请中所用术语“有效量”是指,足以获得或至少部分获得期望的效果的量。例如,预防有效量是指,足以预防,阻止,或延迟疾病的发生的量;治疗有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度,患者自己的免疫系统的总体状态,患者的一般情况例如年龄、体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
发明的有益效果
本申请提供一类如式I所示的化合物、其立体异构体、前药、水合物或药学上可接受的盐或酯。本申请的化合物能够抑制雌激素受体活性、下调雌激素受体表达水平或诱导雌激素受体降解,可用于预防或治疗与雌激素受体过度活性相关的疾病,尤其是雌激素受体阳性(ER+)耐药性疾病(例如对抗雌激素疗法产生耐药性的乳腺癌等)。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例中如无特殊说明,反应的温度为室温(20℃-30℃)。
以下对本申请中各缩写的意思解释如下:
Cs2CO3:碳酸铯;DMSO:二甲基亚砜;DIPEA:N,N-二异丙基乙胺;THF:四氢呋喃;Boc:叔丁氧基羰基;m-CPBA:间氯过氧苯甲酸;MeOH:甲醇;TFA:三氟醋酸;TLC:薄层色谱;HPLC:高效液相色谱;DCM:二氯甲烷;DMF:二甲基甲酰胺;EA:乙酸乙酯;PE:石油醚;MTBE:甲基叔丁基醚;LCMS:液相质谱联用仪;NaHCO3:碳酸氢钠;NaBH3CN:氰基硼氢化钠;Et3N:三乙胺;Raney-Ni:雷尼镍;HCl:盐酸;Solutol:聚乙二醇-15羟基硬脂酸酯。
实施例1:
(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物1)
反应路线:
第一步:(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯(化合物1-2)
在氮气氛围中,向2-氟-4-溴苯甲醛(2.019g,10mmol)和碳酸钾(2.76g,20mmol)的DMF(50mL)溶液中加入醋酸钯(224mg,1mmol)、三苯基膦(1.048g,4mmol)和丙烯酸甲酯(1.6g,20mmol),并于80℃下搅拌反应12h。后处理粗品经硅胶柱层析(EA:PE=5:1)得化合物1-2(2g,产率96%)。
MS m/z(ESI):209[M+H]+。
第二步:(1-甲基环丙基)甲醛(化合物1-4)
向(1-甲基环丙基)甲醇(500mg,5.8mmol)和硅胶(500mg)的DCM(20mL)的悬浊液中加入氯铬酸吡啶盐(1.249g,5.8mmol),然后室温搅拌2h,后处理得化合物1-4(400mg,产率82%)。
第三步:(R)-1-(1H-吲哚-3-基)-N-((1-甲基环丙基)甲基)-丙-2-胺(化合物1-6)
向(R)-1-(1H-吲哚-3-基)-丙-2-胺(250mg,1.4mmol)的四氢呋喃(7mL)溶液中加入(1-甲基环丙基)甲醛(241mg,2.8mmol),室温搅拌30min,加入醋酸硼氢化钠(594mg,2.8mmol),并室温搅拌12h。后处理得化合物1-6(288mg,产率85%)。
MS m/z(ESI):243[M+H]+。
第四步:(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-7)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-((1-甲基环丙基)甲基)丙-2-胺(288mg,1.2mmol)和(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯(250mg,1.2mmol)的甲苯(12mL)溶液中加入冰乙酸(3mL),然后加热至100℃,搅拌反应12h。后处理得化合物1-7(415mg,产率80%)。
MS m/z(ESI):433[M+H]+。
第五步:(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物1)
向(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(415mg,0.96mmol)的乙醇(9.6mL)溶液中加入氢氧化钠水溶液(0.96mL,9.6mmol),然后室温搅拌4h。后处理得化合物1(200mg,产率50%)。
MS m/z(ESI):419[M+H]+。
1HNMR:(400MHz,CD3OD)δ:7.56(d,J=16.0Hz,1H),7.48-7.45(m,2H),7.31–7.22(m,2H),7.09–7.01(m,3H),6.53(d,J=16.0Hz,1H),5.73(s,1H),3.81(dd,J=12.1,6.8Hz,1H),3.08(dd,J=15.8,4.7Hz,1H),2.91(d,J=12.5Hz,1H),2.72(dd,J=15.9,7.4Hz,2H),2.37(d,J=13.1Hz,1H),1.23(d,J=6.6Hz,2H),1.18(s,3H),0.47–0.45(m,1H),0.39–0.33(m,3H).
实施例2:
(E)-3-(4-((1R,3R)-2-(环丙基甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-氟苯基)丙烯酸(化合物2)
反应路线:
采用类似于实施例1的方法,用环丙甲醇代替实施例1中的(1-甲基环丙基)甲醇,得到化合物2。
MS m/z(ESI):405[M+H]+。
1HNMR:(400MHz,CD3OD)δ:7.58(d,J=16.0Hz,1H),7.51-7.47(m,2H),7.36–7.24(m,2H),7.14–7.01(m,3H),6.55(d,J=16.0Hz,1H),5.75(s,1H),3.83(dd,J=12.1,6.8Hz,1H),3.15-3.08(m,1H),2.91(d,J=12.5Hz,1H),2.74(dd,J=15.9,7.4Hz,1H),2.39(d,J=13.1Hz,1H),1.10-1.15(m,4H),0.54–0.44(m,2H),0.45–0.31(m,2H).
实施例3:
(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物3)
采用基本类似于实施例1的方法,用2,6-二氟-4-溴苯甲醛代替实施例1中的2-氟-4-溴苯甲醛,得到化合物3。
MS m/z(ESI):437[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.42(dd,J=6.9,1.1Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.55(d,J=16.0Hz,1H),5.37(s,1H),3.87(dd,J=11.1,4.8Hz,1H),3.08(dd,J=15.1,3.6Hz,1H),2.68(dd,J=15.0,3.2Hz,1H),2.48(dd,J=27.8,12.9Hz,2H),1.31–1.29(m,1H),1.11(d,J=6.5Hz,2H),1.00(s,3H),0.42–0.33(m,2H),0.27-0.16(m,2H).
实施例4:
(E)-3-(4-((1R,3R)-2-((1-乙基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物4)
合成路线:
第一步:1-乙基环丙基甲醛(化合物1-9)
向1-乙基环丙基甲醇(580mg,5.8mmol)和硅胶(500mg)的DCM(20mL)的悬浊液中分批次加入氯铬酸吡啶盐(1.249g,5.8mmol),然后室温搅拌2h。抽滤,滤液低温浓缩(浓缩温度小于30℃)得化合物1-9(455mg,产率80%)。
第二步:(R)-1-(1H-吲哚-3-基)-N-((1-乙基环丙基)甲基)丙-2-胺(化合物1-10)
向(R)-1-(1H-吲哚-3-基)丙-2-胺(250mg,1.4mmol)的四氢呋喃(7mL)溶液中加入(1-乙基环丙基)甲醛(274mg,2.8mmol),室温搅拌30min,然后加入醋酸硼氢化钠(594mg,2.8mmol),室温搅拌12h。后处理得化合物1-10(297mg,产率83%)。
MS m/z(ESI):257[M+H]+。
第三步:(1R,3R)-1-(4-溴-2,6-二氟苯基)-2-((1-乙基环丙基)甲基)-3甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(化合物1-12)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-((1-乙基环丙基)甲基)丙-2-胺(290mg,1.1mmol)和2,6-二氟-4-溴苯甲醛(243mg,1.1mmol)的甲苯(12mL)溶液中加入冰乙酸(3mL),然后加热至100℃,搅拌反应12h。后处理得化合物1-12(404mg,产率80%)。
MS m/z(ESI):459[M+H]+。
第四步:(E)-3-(4-((1R,3R)-2-((1-乙基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(化合物1-13)
氮气氛围下,向(1R,3R)-1-(4-溴-2,6-二氟苯基)-2-((1-乙基环丙基)甲基)-3甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(400mg,0.87mmol)的DMF(8mL)溶液中,依次加入醋酸钯(195mg,0.87mmol)、三(邻甲基苯基)膦(1.058g,3.48mmol)、N,N-二异丙基乙胺(226mg,1.74mmol)和丙烯酸甲酯(150mg,1.74mmol),反应混合物于100℃下,微波反应10h。后处理得化合物1-13(283mg,产率70%)。
MS m/z(ESI):465[M+H]+。
第五步:(E)-3-(4-((1R,3R)-2-((1-乙基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物4)
向(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(283mg,0.61mmol)的乙醇(9mL)溶液中加入氢氧化钠水溶液(0.6mL,6.1mmol),然后室温搅拌4h。后处理得化合物4(138mg,产率50%)。
MS m/z(ESI):451[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.41(s,1H),3.07–2.97(m,2H),2.59–2.49(m,1H),2.22(s,2H),1.32–1.25(m,3H),1.19(q,J=8.0Hz,2H),0.84(t,J=7.9Hz,3H),0.51–0.42(m,2H),0.24–0.16(m,2H).
实施例5:
(E)-3-(4-((1R,3R)-2-((1-氰基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-yl)-3,5-二氟苯基)丙烯酸(化合物5)
合成路线:
第一步:(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯(化合物1-15)
在氮气氛围中,向2,6-二氟-4-溴苯甲醛(2.19g,10mmol)和碳酸钾(2.76g,20mmol)的DMF(50mL)溶液中加入醋酸钯(224mg,1mmol)、三苯基膦(1.048g,4mmol)和丙烯酸甲酯(1.6g,20mmol),并于80℃下搅拌反应12h。后处理,粗品经硅胶柱层析(EA:PE=5:1)得化合物1-15(2.16g,产率96%)。
MS m/z(ESI):227[M+H]+。
第二步:(1-氰基环丙基)甲醛(化合物1-17)
向(1-氰基环丙基)甲醇(570mg,5.8mmol)和硅胶(500mg)的DCM(20mL)的悬浊液中加入氯铬酸吡啶盐(1.249g,5.8mmol),然后室温搅拌2h。后处理得化合物1-17(410mg,产率75%)。
第三步:(R)-1-(1H-吲哚-3-基)-N-((1-氰基环丙基)甲基)-丙-2-胺(化合物1-18)
向(R)-1-(1H-吲哚-3-基)-丙-2-胺(250mg,1.4mmol)的四氢呋喃(7mL)溶液中加入(1-氰基环丙基)甲醛(268mg,2.8mmol),室温搅拌30min,加入醋酸硼氢化钠(594mg,2.8mmol),并室温搅拌12h。后处理得化合物1-18(284mg,产率80%)。
MS m/z(ESI):254[M+H]+。
第四步:(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-氰基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-19)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-((1-氰基环丙基)甲基)-丙-2-胺(284mg,1.1mmol)和(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯(248mg,1.1mmol)的甲苯(12mL)溶液中加入冰乙酸(3mL),然后加热至100℃,搅拌反应12h。减压旋干得化合物1-19(450mg,产率90%)。
MS m/z(ESI):462[M+H]+。
第五步:(E)-3-(4-((1R,3R)-2-((1-氰基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物5)
向(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-氰基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(450mg,0.98mmol)的乙醇(9.6mL)溶液中加入氢氧化钠水溶液(0.96mL,9.6mmol),然后室温搅拌4h。后处理得化合物5(250mg,产率57%)。
MS m/z(ESI):448[M+H]+。
1H NMR(400MHz,CD3OD)δ7.58(d,J=15.9Hz,1H),7.43(d,J=7.2Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.61(s,1H),5.33(s,1H),3.70(dd,J=11.6,5.2Hz,1H),3.04(dd,J=15.2,3.6Hz,1H),2.96(d,J=13.9Hz,1H),2.66(dd,J=14.8,4.7Hz,1H),2.45(d,J=13.9Hz,1H),1.24–1.16(m,5H),0.89–0.78(m,2H).
实施例6
(E)-3-(3-氟-4-((1R,3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物6)
合成路线:
第一步:(1-氟环丙基)甲酸(化合物1-21)
冰浴下,向(1-氟环丙基)甲醇(0.9g,10mmol)的丙酮溶液中,缓慢滴加Jone′s试剂(5mL)缓慢升温至室温反应1h过滤,减压除去溶剂,所得化合物1-21(0.8g,产率77%)直接用于下一步。
第二步:(R)-N-(1-(1H-吲哚-3-基)-2-丙基)-1-氟环丙基-甲酰胺(化合物1-22)
向(1-氟环丙基)甲酸(520mg,5mmol)的二氯甲烷溶液(25mL)中,一次加入DIPEA(1.29g,10mmol)和HATU(1.9g,5mmol),室温搅拌0.5h后,加入(R)-1-(1H-吲哚-3-基)-丙-2-胺(870mg,5mmol),继续搅拌5h。后处理得粗品经柱层析纯化得化合物1-22(1.2g产率90%)。
MS m/z(ESI):261[M+H]+。
第三步:(R)-1-(1H-吲哚-3-基)-N-((1-氟环丙基)甲基)-丙-2-胺(化合物1-23)
冰浴条件下,向(R)-N-(1-(1H-吲哚-3-基)-2-丙基)-1-氟环丙基-甲酰胺(1.2g,4.6mmol)的四氢呋喃(23mL)溶液中,分批次加入氢化铝锂(874mg,23mmol),加热至65℃反应5h。反应完全后,降温至0℃,加入十水硫酸钠(1.0g),搅拌1h。抽滤,大量THF洗涤滤饼,所得滤液减压旋干,得化合物1-23(1.07g,产率95%)。
MS m/z(ESI):247[M+H]+。
第四步:(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-氟环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-24)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-((1-氟环丙基)甲基)-丙-2-胺(246mg,1.0mmol)和(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯(208mg,1.0mmol)的甲苯(10mL)溶液中加入冰乙酸(1mL),然后加热至100℃,搅拌反应12h。减压旋干得化合物1-24(395mg,产率90%)。
MS m/z(ESI):437[M+H]+。
第五步:(E)-3-(3-氟-4-((1R,3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物6)
向(E)-3-(3-氟-4-((1R,3R)-3-甲基-2-((1-氟环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(390mg,0.89mmol)的乙醇(9.6mL)溶液中加入氢氧化钠水溶液(0.9mL,8.9mmol),然后室温搅拌4h。后处理得化合物6(263mg,产率70%)。
MS m/z(ESI):423[M+H]+。
1H NMR(400MHz,CD3OD)δ7.48(d,J=16.0Hz,1H),7.38(dd,J=6.9,1.0Hz,1H),7.14(t,J=8.4Hz,3H),6.95(tdd,J=14.5,7.1,1.2Hz,3H),6.49(d,J=15.9Hz,1H),5.32(s,1H),3.81(dd,J=10.9,4.7Hz,1H),3.08–2.99(m,1H),2.77(d,J=13.5Hz,1H),2.60(dd,J=15.2,3.3Hz,1H),2.42(d,J=13.5Hz,1H),1.07(d,J=6.5Hz,3H),0.79-0.76(m,2H),0.60–0.51(m,2H).
实施例7:
(E)-3-(4-((1R,3R)-2-(环丁基甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物7)
采用基本类似于实施例5的方法,用环丁基甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物7.
MS m/z(ESI):437[M+H]+。
1H NMR(400MHz,CD3OD)δ7.72–7.56(m,3H),7.48-7.45(m,1H),7.34-7.28(m,1H),7.24–-7.04(m,1H),6.62(d,J=16.0Hz,1H),6.15(s,1H),4.06(s,1H),3.52(dd,J=13.5,6.5Hz,2H),3.17(dd,J=13.4,7.0Hz,1H),3.02(dd,J=17.0,10.1Hz,2H),2.32(dd,J=19.3,11.0Hz,2H),2.09(q,J=8.0,7.3Hz,2H),1.90(dd,J=15.5,7.2Hz,3H),1.56(t,J=6.3Hz,3H).
实施例8:
E)-3-(3,5-二氟-4-((1R,3R)-2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物8)
采用基本类似于实施例6的方法,用(1-氟环丁基)甲醇代替实施例6第一步中的(1-氟环丙基)甲醇;用(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯代替实施例6第四步中的(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯实施,得到化合物8.
MS m/z(ESI):455[M+H]+。
1H NMR(400MHz,CD3OD)δ7.72–7.56(m,3H),7.48-7.45(m,1H),7.34-7.28(m,1H),7.24–-7.04(m,1H),6.62(d,J=16.0Hz,1H),6.15(s,1H),4.06(s,1H),3.52(dd,J=13.5,6.5Hz,2H),3.17(dd,J=13.4,7.0Hz,1H),3.02(dd,J=17.0,10.1Hz,2H),2.32(dd,J=19.3,11.0Hz,2H),2.09(q,J=8.0,7.3Hz,2H),1.90(dd,J=15.5,7.2Hz,2H),1.56(t,J=6.3Hz,3H).
实施例9
(E)-3-(4-((1R,3R)-2-(环丁基甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-氟苯基)丙烯酸(化合物9)
采用基本类似于实施例1的方法,用环丁基甲醇代替实施例1第二步中的(1-甲基环丙基)甲醇实施,得到化合物9.
MS m/z(ESI):419[M+H]+。
1H NMR(400MHz,CD3OD)δ7.72–7.56(m,4H),7.48-7.45(m,1H),7.34-7.28(m,1H),7.24-7.04(m,1H),6.62(d,J=16.0Hz,1H),6.15(s,1H),4.06(s,1H),3.52(dd,J=13.5,6.5Hz,2H),3.17(dd,J=13.4,7.0Hz,1H),3.02(dd,J=17.0,10.1Hz,2H),2.32(dd,J=19.3,11.0Hz,2H),2.09(q,J=8.0,7.3Hz,2H),1.90(dd,J=15.5,7.2Hz,3H),1.56(t,J=6.3Hz,3H)。
实施例10
(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-(甲氧基甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物10)
采用基本类似于实施例5的方法,用(1-(甲氧基甲基)环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物10.
MS m/z(ESI):467[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.45(d,J=8Hz,1H),7.30(d,J=8Hz,1H),7.21(d,J=8Hz,1H),7.10–6.94(m,2H),6.59(d,J=16.0Hz,1H),5.30(s,1H),4.11(s,1H),3.94(t,J=9.8Hz,1H),3.62(d,J=10.6Hz,1H),3.52(s,3H)3.21–3.04(m,2H),2.91(d,J=13.2Hz,1H),2.73(m,3H),1.18(d,J=6.5Hz,2H),0.73-0.68(m,1H),0.61–0.56(m,1H),0.36–0.31(m,1H),0.27-0.23(m,1H).
实施例11
(E)-3-(4-((1R,3R)-2-((1-(二氟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物11)
合成路线:
第一步:(1-(叔丁基二苯基硅氧基甲基)环丙基)甲醇(化合物1-26)
向(1-羟甲基环丙基)甲醇(1.02g,10mmol)的DMF(20mL)溶液中,加入咪唑(1.36g,20mmol),冷却至0℃,加入TBDPSCl(2.75g,10mmol),反应12h后处理后粗品经柱层析纯化得化合物1-26(2.046g,产率60%)。
第二步:(1-(叔丁基二苯基硅氧基甲基)环丙基)甲醛(化合物1-27)。
向(1-(叔丁基二苯基硅氧基甲基)环丙基)甲醇(2.04g,6mmol)的DCM(20mL)溶液中,依次加入硅胶(2.0g)和PCC(2.6g,12mmol),室温反应4h。抽滤所得滤液旋干,得化合物1-27(2.03g,产率99%)。
第三步:(R)-N-((1-(叔丁基二苯基硅氧基甲基)环丙基)甲基)-1-(1H-吲哚-3-基)-丙-2-胺(化合物1-28)
向(1-(叔丁基二苯基硅氧基甲基)环丙基)甲醛(2.03g,6mmol)的THF(20mL)溶液中,加入(R)-1-(1H-吲哚-3-基)-丙-2-胺(1.044g,6mmol),室温搅拌10min后,加入NaBH(OAc)3(2.5g,12mmol),搅拌过夜,后处理得化合物1-28(2.9g,产率95%)。
MS m/z(ESI):497[M+H]+。
第四步:(E)-3-(4-((1R,3R)-2-((1-(叔丁基二苯基硅氧基甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(化合物1-29)
在氮气氛围中,向(R)-N-((1-(叔丁基二苯基硅氧基甲基)环丙基)甲基)-1-(1H-吲哚-3-基)-丙-2-胺(2.9g,5.8mmol)和(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯(1.32g,5.8mmol)的甲苯(30mL)溶液中加入冰乙酸(3mL),然后加热至100℃,搅拌反应12h。减压旋干得化合物1-29(3.68g,产率90%)。
MS m/z(ESI):705[M+H]+。
第五步:(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-(羟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-30)
向(E)-3-(4-((1R,3R)-2-((1-(叔丁基二苯基硅氧基甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(3.5g,5.0mmol)的四氢呋喃(20mL)溶液中加入1M TBAF的四氢呋喃溶液(5mL),温搅拌5h。后处理所得粗品经柱层析纯化,得化合物1-30(2.1g,产率90%)。
MS m/z(ESI):467[M+H]+。
第六步:(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-甲酰基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-31)
向(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-(羟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(2.0g,4.2mmol)的二氯甲烷溶液(20mL)中,加入硅胶(2.0g)和氯铬酸吡啶盐(9.1g,4.2mmol),室温搅拌反应4h。过滤,所得滤液减压旋干,得化合物1-31(1.9g,产率97%)。
MS m/z(ESI):465[M+H]+。
第七步:(E)-3-(4-((1R,3R)-2-((1-(二氟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(化合物1-32)
冰浴下,向(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-甲酰基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(1.0g,2.15mmol)的DCM(20mL)中,缓慢滴加DAST(1.73g,10.7mmol),缓慢升至室温反应5h。向反应混合物中缓慢滴加饱和碳酸氢钠水溶液,调节体系pH值至7-8,后处理所得粗品经柱层析纯化,得化合物1-32(838mg,产率80%)。
MS m/z(ESI):487[M+H]+。
第八步:(E)-3-(4-((1R,3R)-2-((1-(二氟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物11)
向(E)-3-(4-((1R,3R)-2-((1-(二氟甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(838mg,1.72mmol)的四氢呋喃(25mL)溶液中加入氢氧化锂水溶液(2.5mL,5.16mmol),然后室温搅拌12h。减压蒸除溶剂,加入1N稀盐酸,调节体系pH值至5-6,后处理,所得粗品经柱层析纯化,得化合物11(731mg,产率90%)。
MS m/z(ESI):473[M+H]+。
1H NMR(400MHz,CD3OD)δ7.58(d,J=15.9Hz,1H),7.43(d,J=7.2Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.61(s,1H),5.42-5.19(m,2H),3.70(dd,J=11.6,5.2Hz,1H),3.04(dd,J=15.2,3.6Hz,1H),2.96(d,J=13.9Hz,1H),2.66(dd,J=14.8,4.7Hz,1H),2.45(d,J=13.9Hz,1H),1.24–1.16(m,5H),0.89–0.78(m,2H).
实施例12
(E)-3-(4-((1R,3R)-2-((1-氨基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物12)
采用基本类似于实施例6的方法,用(1-氨基环丙基)甲酸代替实施例6第二步中的(1-氟环丙基)甲酸;用(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯代替实施例6第四步中的(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯实施,得到化合物12。
MS m/z(ESI):438[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.43(s,1H),3.63(d,J=5.0Hz,1H),3.27(d,J=4.7Hz,1H),3.19–2.94(m,2H),2.70–2.59(m,1H),2.42(d,J=3.6Hz,3H),1.22(d,J=6.6Hz,1H),1.04-0.88(m,1H),0.86–0.68(m,2H).
实施例13
(E)-3-(4-((1R,3R)-2-((2,2-二氟-1-甲基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物13)
采用基本类似于实施例6的方法,用(2,2-二氟-1-甲基环丙基)甲酸代替实施例6第二步中的(1-氟环丙基)甲酸;用(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯代替实施例6第四步中的(E)-3-(3氟)-4-甲酰基苯基)丙烯酸甲酯实施,得到化合物13。
MS m/z(ESI):473[M+H]+。
1H NMR(400MHz,CD3OD)δ7.48(d,J=16.0Hz,1H),7.38(dd,J=6.9,1.0Hz,1H),7.14(t,J=8.4Hz,3H),6.95(tdd,J=14.5,7.1,1.2Hz,2H),6.49(d,J=15.9Hz,1H),5.32(s,1H),3.81(dd,J=10.9,4.7Hz,1H),3.08–2.99(m,1H),2.77(d,J=13.5Hz,1H),2.60(dd,J=15.2,3.3Hz,1H),2.42(d,J=13.5Hz,1H),1.5(s,3H),1.07-0.92(m,5H).
实施例14
(E)-3-(4-((1R,3R)-2-((1,1'-双环丙基)-1-甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物14)
采用基本类似于实施例5的方法,用(1,1'-双环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物14。
MS m/z(ESI):463[M+H]+。
1H NMR(400MHz,CD3OD)δ7.58(d,J=15.9Hz,1H),7.43(d,J=7.2Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.61(s,1H),5.33(s,1H),3.70(dd,J=11.6,5.2Hz,1H),3.04(dd,J=15.2,3.6Hz,1H),2.96(d,J=13.9Hz,1H),2.66(dd,J=14.8,4.7Hz,1H),2.45(d,J=13.9Hz,1H),1.89-1.84(m,1H),1.24–1.16(m,5H),0.89–0.78(m,2H),0.42-0.36(m,2H),0.18-0.12(m,2H).
实施例15
(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-异丙基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(实施例15)
采用基本类似于实施例5的方法,用(1-异丙基环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物15。
MS m/z(ESI):465[M+H]+。
1H NMR(400MHz,CD3OD)δ7.58(d,J=15.9Hz,1H),7.43(d,J=7.2Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.61(s,1H),5.32(s,1H),3.08–2.95(m,2H),2.53(dd,J=15.5,6.5Hz,1H),2.22(s,2H),1.95-1.89(m,1H),1.24(d,J=6.7Hz,3H),0.87(d,J=6.8Hz,6H),0.43–0.36(m,2H),0.09–0.02(m,2H).
实施例16
(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-(三氟甲基)环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(实施例16)
采用基本类似于实施例6的方法,用(1-三氟甲基环丙基)甲醇代替实施例6第一步中的(1-氟环丙基)甲醇;用(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯代替实施例6第四步中的(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯实施,得到化合物16。
MS m/z(ESI):491[M+H]+。
1H NMR(400MHz,CD3OD)δ7.48(d,J=16.0Hz,1H),7.38(dd,J=6.9,1.0Hz,1H),7.14(t,J=8.4Hz,3H),6.95(tdd,J=14.5,7.1,1.2Hz,2H),6.49(d,J=15.9Hz,1H),5.32(s,1H),3.81(dd,J=10.9,4.7Hz,1H),3.08–2.99(m,1H),2.77(d,J=13.5Hz,1H),2.60(dd,J=15.2,3.3Hz,1H),2.42(d,J=13.5Hz,1H),1.07-0.90(m,5H),0.76-0.51(m,2H).
实施例17
(E)-3-(4-((1R,3R)-2-((1-乙炔基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物17)
采用基本类似于实施例5的方法,用(1-乙炔基环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物17。
MS m/z(ESI):447[M+H]+。
1H NMR(400MHz,CD3OD)δ7.48(d,J=16.0Hz,1H),7.38(dd,J=6.9,1.0Hz,1H),7.14(t,J=8.4Hz,3H),6.95(tdd,J=14.5,7.1,1.2Hz,2H),6.49(d,J=15.9Hz,1H),5.32(s,1H),3.81(dd,J=10.9,4.7Hz,1H),3.08–2.99(m,1H),2.77(d,J=13.5Hz,1H),2.60(dd,J=15.2,3.3Hz,1H),2.42(d,J=13.5Hz,1H),2.03(s,1H),1.07(d,J=6.5Hz,3H),0.78(td,J=4.7,2.4Hz,2H),0.60–0.51(m,2H).
实施例18
(E)-3-(4-((1R,3R)-2-(二环[1.1.0]-丁-1-基甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物18)
采用基本类似于实施例5的方法,用(1-二环[1.1.0]丁基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物18.
MS m/z(ESI):435[M+H]+。
1H NMR(400MHz,CD3OD)δ7.58(d,J=15.9Hz,1H),7.43(d,J=7.2Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.61(s,1H),5.33(s,1H),3.70(dd,J=11.6,5.2Hz,1H),3.04(dd,J=15.2,3.6Hz,1H),2.96(d,J=13.9Hz,1H),2.66(dd,J=14.8,4.7Hz,1H),2.45(d,J=13.9Hz,1H),1.24–1.16(m,5H),0.95-0.90(m,1H),0.89–0.78(m,2H).
实施例19
(E)-3-(4-((1R,3R)-2-((1-(二甲基氨基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物19)
采用基本类似于实施例5的方法,用(1-(二甲基氨基)环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物19.
MS m/z(ESI):466[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.43(s,1H),3.63(d,J=5.0Hz,1H),3.27(d,J=4.7Hz,1H),3.19–2.94(m,2H),2.70–2.59(m,1H),2.42(d,J=3.6Hz,3H),2.36(s,3H),2.33(s,3H)1.22(d,J=6.6Hz,1H),1.04-0.88(m,1H),0.86–0.68(m,2H).
实施例20
(E)-3-(4-((1R,3R)-2-((1-((二甲基氨基)甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物20)
合成路线:
第一步:(E)-3-(4-((1R,3R)-2-((1-((二甲基氨基)甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(化合物1-32)
将实施例11中,第六步得到的(E)-3-(3,5-二氟-4-((1R,3R)-2-((1-甲酰基环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(465mg,1mmol)溶解在1,2-二氯乙烷(10mL)中,加入二甲胺,室温搅拌10min后,加入氰基硼氢化钠(158mg,2.5mmol),室温反应8h。后处理所得粗品经柱层析纯化得化合物1-32(370mg,产率75%)。
MS m/z(ESI):494[M+H]+。
第二步:(E)-3-(4-((1R,3R)-2-((1-((二甲基氨基)甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物20)
向(E)-3-(4-((1R,3R)-2-((1-((二甲基氨基)甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸甲酯(370mg,0.74mmol)的四氢呋喃(10mL)溶液中加入氢氧化锂水溶液(3mL,2.3mmol),室温搅拌12h。减压蒸除溶剂,加入1N稀盐酸,调节体系pH值至5-6,后处理所得粗品经柱层析纯化得化合物20(300mg,产率84%)。
MS m/z(ESI):480[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.43(s,1H),3.63(d,J=5.0Hz,1H),3.27(d,J=4.7Hz,1H),3.19–2.94(m,2H),2.70–2.59(m,1H),2.42(d,J=3.6Hz,3H),2.36(s,3H),2.33(m,5H)1.22(d,J=6.6Hz,1H),1.04-0.88(m,1H),0.86–0.68(m,2H).
实施例21
(E)-3-(4-((1R,3R)-2-((1-(氰基甲基)环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)丙烯酸(化合物21)
采用基本类似于实施例5的方法,用(1-(氰基甲基)环丙基)甲醇代替实施例5第二步中的(1-氰基环丙基)甲醇实施,得到化合物21。
MS m/z(ESI):462[M+H]+。
1H NMR(400MHz,CD3OD)δ7.49(d,J=16.0Hz,1H),7.42(d,J=7.4Hz,1H),7.23–7.16(m,3H),7.00(dd,J=17.5,7.3Hz,2H),6.53(d,J=15.9Hz,1H),5.28(s,1H),3.74(d,J=6.1Hz,1H),3.07(dd,J=14.7,4.1Hz,1H),2.71–2.43(m,5H),1.11(d,J=6.5Hz,3H),0.66(dd,J=10.4,6.7Hz,1H),0.61–0.48(m,2H),0.40(t,J=8.5Hz,1H).
实施例22
(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-(甲硫基甲基)环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物22)
合成路线:
第一步:(R)-(1-((1-(1H-吲哚-3-基)-丙-2-氨基)甲基)环丙基)甲醇(化合物1-33)
向(R)-N-((1-((叔丁基二苯基硅氧基)甲基)环丙基)甲基)-1-(1H-吲哚-3-基)-丙-2-胺(化合物1-28)(2.49g,5mmol)的四氢呋喃溶液中滴加1M TBAF的四氢呋喃溶液(5mL),室温搅拌5h。后处理所得粗品经柱层析纯化,得化合物1-33(1.26g,产率97%)。
MS m/z(ESI):259[M+H]+。
第二步:(R)-4-甲基苯磺酸-(1-(1-(1-对甲苯磺酰基-1H-吲哚-3-基)-丙-2-氨基)甲基环丙基)甲酯(化合物1-34)
冰浴下,向(R)-(1-((1-(1H-吲哚-3-基)-丙-2-氨基)甲基)环丙基)甲醇(1.26g,4.86mmol)的二氯甲烷(25mL)溶液中,分批次加入4-甲苯磺酰氯(2.79g,14.6mmol),缓慢升至室温搅拌12h。后处理所得粗品经柱层析纯化,得化合物1-34(2.07g,产率75%)
MS m/z(ESI):567[M+H]+。
第三步:(R)-N-((1-(甲硫基甲基)环丙基)甲基)-1-(1-对甲苯磺酰基-1H-吲哚-3-基)丙基-2-胺(化合物1-35)
向(R)-4-甲基苯磺酸-(1-(1-(1-对甲苯磺酰基-1H-吲哚-3-基)-丙-2-氨基)甲基环丙基)甲酯(2.0g,3.5mmol)的DMF溶液(17mL)中,加入碳酸铯(1.72g,5.25mmol),室温搅拌10min后,加入甲硫醇钠(294mg,4.2mmol),搅拌12h。后处理,所得粗品经柱层析纯化,得化合物1-35(1.08g,产率70%)。
MS m/z(ESI):443[M+H]+。
第四步:(R)-1-(1H-吲哚-3-基)-N-((1-(甲硫基甲基)环丙基)甲基)丙-2-胺(化合物1-36)
向(R)-N-((1-(甲硫基甲基)环丙基)甲基)-1-(1-对甲苯磺酰基-1H-吲哚-3-基)丙基-2-胺(1.0g,2.25mmol)的乙醇溶液中(10mL),加入氢氧化钠(120mg,3mmol),室温搅拌4h,减压蒸除溶剂,加入10mL水和10mL乙酸乙酯,1N稀盐酸调节体系pH6-7之间,后处理得化合物1-36(550mg,产率85%)。
MS m/z(ESI):289[M+H]+。
第五步:(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-(甲基硫基甲基)环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-37)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-((1-(甲硫基甲基)环丙基)甲基)丙-2-胺(500mg,1.7mmol)和(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯(385mg,1.7mmol)的甲苯(5mL)溶液中加入冰乙酸(0.5mL),加热至100℃,搅拌反应12h。减压旋干得化合物1-37(760mg,产率90%)。
MS m/z(ESI):497[M+H]+。
第六步:(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-(甲硫基甲基)环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物22)
向(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-((1-(甲基硫基甲基)环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(500mg,1mmol)的乙醇(20mL)溶液中加入氢氧化钠水溶液(10mL,10mmol),室温搅拌4h。后处理得化合物22(339mg,产率70%)。
MS m/z(ESI):483[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.45(d,J=8Hz,1H),7.30(d,J=8Hz,1H),7.21(d,J=8Hz,1H),7.10–6.94(m,2H),6.59(d,J=16.0Hz,1H),5.30(s,1H),4.11(s,1H),3.94(t,J=9.8Hz,1H),3.62(d,J=10.6Hz,1H),2.91(d,J=13.2Hz,1H),2.73(m,3H),2.52(s,3H),2.21–2.04(m,2H),1.18(d,J=6.5Hz,2H),0.73-0.68(m,1H),0.63–0.53(m,1H),0.38–0.29(m,1H),0.25-0.21(m,1H).
实施例23
(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-(1-(甲基磺酰基甲基)环丙基)甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物23)
合成路线
第一步:(R)-1-(1H-吲哚-3-基)-N-(1-(甲基磺酰基甲基)环丙基)甲基-丙-2-胺(化合物1-38)
冰浴下,向(R)-1-(1H-吲哚-3-基)-N-(1-(甲硫基甲基)环丙基)甲基-丙-2-胺(600mg,2.08mmol)的二氯甲烷溶液(20mL)中,分批次加入间氯过氧苯甲酸(1.79g,10.4mmol),室温搅拌8h。后处理,所得粗品经柱层析纯化,得化合物1-38(400mg,产率60%)。
MS m/z(ESI):321[M+H]+。
第二步:(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-(1-(甲基磺酰基甲基)环丙基)甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-39)
在氮气氛围中,向(R)-1-(1H-吲哚-3-基)-N-(1-(甲基磺酰基甲基)环丙基)甲基-丙-2-胺(320mg,1.0mmol)和(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯(227mg,1.0mmol)的甲苯(5mL)溶液中加入冰乙酸(0.5mL),然后加热至100℃,搅拌反应12h。减压旋干得化合物1-39(476mg,产率90%)。
MS m/z(ESI):529[M+H]+。
第六步:(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-(1-(甲基磺酰基甲基)环丙基)甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物23)
向(E)-3-(3,5-二氟-4-((1R,3R)-3-甲基-2-(1-(甲基磺酰基甲基)环丙基)甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(300mg,0.57mmol)的乙醇(10mL)溶液中加入氢氧化钠水溶液(5.7mL,5.7mmol),室温搅拌4h。后处理得化合物23(206mg,产率70%)。
MS m/z(ESI):515[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.45(d,J=8Hz,1H),7.30(d,J=8Hz,1H),7.21(d,J=8Hz,1H),7.10–6.94(m,2H),6.59(d,J=16.0Hz,1H),5.30(s,1H),4.11(s,1H),3.94(t,J=9.8Hz,1H),3.62(d,J=10.6Hz,1H),3.2–3.04(m,2H),2.91(d,J=13.2Hz,1H),2.80(s,3H),2.73(m,3H),1.18(d,J=6.5Hz,2H),0.73-0.68(m,1H),0.63–0.53(m,1H),0.38–0.29(m,1H),0.25-0.21(m,1H).
实施例24
(E)-3-(5-氟-6-((1S,3R)-3-甲基-2-((1-甲基环丙基)甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)吡啶-3-基)丙烯酸(化合物24)
用基本类似于实施例1的方法,用5-溴-3-氟吡啶-2-甲醛代替实施例1第一步中的2-氟-4-溴苯甲醛实施,得到化合物24.
MS m/z(ESI):420[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.42(dd,J=6.9,1.1Hz,1H),7.24–7.18(m,3H),7.04-6.95(m,2H),6.55(d,J=16.0Hz,1H),5.37(s,1H),3.87(dd,J=11.1,4.8Hz,1H),3.08(dd,J=15.1,3.6Hz,1H),2.68(dd,J=15.0,3.2Hz,1H),2.48(dd,J=27.8,12.9Hz,2H),1.31–1.29(m,1H),1.11(d,J=6.5Hz,2H),1.00(s,3H),0.42–0.33(m,2H),0.27-0.16(m,2H).
实施例25
(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(氟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物25)
合成路线
第一步:(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(氟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(化合物1-40)
冰浴下,向(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(羟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(467mg,1mmol)的二氯甲烷溶液中(10mL),分批次滴加DAST(322mg,2mmol),缓慢升温至室温,反应8h,缓慢滴加饱和碳酸氢钠水溶液,调节体系pH值至7-8,后处理所得粗品经柱层析纯化得化合物1-40(352mg,产率75%)。
MS m/z(ESI):469[M+H]+。
第二步:(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(氟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物25)
向(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(氟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(300mg,0.64mmol)的四氢呋喃(7mL)溶液中加入氢氧化锂水溶液(0.7mL,1.92mmol),室温搅拌12h。减压蒸除溶剂,加入1N稀盐酸,调节体系pH至5-6之间,后处理,所得粗品经柱层析纯化,得化合物25(203mg,产率70%)。
MS m/z(ESI):455[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.41(s,1H),4.00(s,1H),3.90(s,1H),3.11-3.08(m,1H),2.99(dd,J=15.9,7.0Hz,1H),2.55(dd,J=15.9,7.0Hz,1H),2.22(s,2H),1.28(d,J=6.8Hz,3H),0.61–0.52(m,2H),0.27–0.18(m,2H).
实施例26
(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(2-氟乙基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物26)
采用基本类似于实施例6的方法,用(1-(2-氟乙基)环丙基)甲醇代替实施例6第一步中的(1-氟环丙基)甲醇;用(E)-3-(3,5-二氟)-4-甲酰基苯基)丙烯酸甲酯代替实施例6第四步中的(E)-3-(3-氟-4-甲酰基苯基)丙烯酸甲酯实施,得到化合物26.
MS m/z(ESI):469[M+H]+。
1H NMR(400MHz,CD3OD)δ7.43(d,J=7.6Hz,1H),7.30(d,J=15.9Hz,1H),7.22–7.16(m,3H),7.06-6.96(m,2H),6.53(d,J=15.9Hz,1H),5.49(s,1H),4.12(t,J=7.4Hz,1H),4.02(t,J=7.4Hz,1H),3.11(h,J=6.8Hz,1H),3.00(dd,J=15.7,7.0Hz,1H),2.55(dd,J=15.7,6.9Hz,1H),2.22(s,2H),1.41–1.25(m,5H),0.54–0.46(m,2H),0.29–0.21(m,2H).
实施例27
(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(羟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物27)
合成路线
第一步:(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(羟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物27)
向(E)-3-(3,5-二氟-4-((1R,3R)-2-(1-(羟甲基)环丙基)甲基-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(467mg,1mmol)的四氢呋喃(10mL)溶液中加入氢氧化锂水溶液(1mL,3mmol),然后室温搅拌12h。减压蒸除溶剂,加入1N稀盐酸,调节体系pH值至5-6,后处理,所得粗品经柱层析纯化,得化合物27(317mg,产率70%)。
MS m/z(ESI):453[M+H]+。
1H NMR(400MHz,CD3OD)δ7.57(d,J=16.0Hz,1H),7.45(d,J=8Hz,1H),7.30(d,J=8Hz,1H),7.21(d,J=8Hz,1H),7.10–6.94(m,2H),6.59(d,J=16.0Hz,1H),5.30(s,1H),4.11(s,1H),3.94(t,J=9.8Hz,1H),3.62(d,J=10.6Hz,1H),3.21–3.04(m,2H),2.91(d,J=13.2Hz,1H),2.73(m,3H),1.18(d,J=6.5Hz,2H),0.73-0.68(m,1H),0.63–0.53(m,1H),0.38–0.29(m,1H),0.25-0.21(m,1H).
药效筛选方法及数据
试验例1.乳腺癌MCF-7细胞存活试验
试验方法:
将MCF-7细胞(美国康诺泰)培养在含有10%胎牛血清的DMEM/F12培养基中,放置在37℃,5%CO2培养条件下进行培养。向96孔板中铺入适量细胞,培养箱中过夜培养后,移除培养基,加入含有本申请化合物的完全培养基,37℃孵育3天。第四天向每孔中加入检测试剂CellTiter-GLo(Promega),化学发光检测各孔的相对发光单位(RLU)。
%存活率=(样品RLU-背景RLU)/(未处理细胞的RLU-背景RLU)x100%。
用GraphPad软件计算得到本申请化合物对乳腺癌MCF-7细胞的IC50值,结果见下表1。
表1本申请化合物抑制乳腺癌MCF-7的作用
化合物编号 | IC50(nM) |
化合物1 | 0.64 |
化合物3 | 0.84 |
化合物10 | 1.76 |
化合物11 | 2.41 |
化合物13 | 1.76 |
化合物14 | 7.81 |
化合物15 | 6.58 |
化合物16 | 5.98 |
化合物17 | 7.78 |
化合物25 | 1.02 |
化合物27 | 7.57 |
试验结果显示:本申请化合物对乳腺癌MCF-7细胞具有明显的抑制活性。
试验例2.本申请化合物抑制乳腺癌MCF-7细胞内ERα表达的Western Blot试验
试验方法:
将MCF-7细胞在含有10%经碳吸附的胎牛血清的DMEM/F12培养基中调整适量的细胞浓度,向聚-D-赖氨酸96孔板中铺入细胞,37℃,5%CO2培养条件下培养3天后移除培养基,加入含有本申请化合物的完全培养基,孵育24小时后,移除培养基,用LICOR封闭缓冲液封闭1小时。移除封闭液,加入适量的SP1兔单克隆抗体(Thermo Scientific),室温孵育4小时。移除SP1兔单克隆抗体溶液,用含有0.1%吐温-20的PBS洗涤各孔。加入含有DRAQ5DNA染料的IRDye800CW标记的山羊抗兔二抗(LICOR),室温避光孵育1小时,再次用含有0.1%吐温-20的PBS洗涤各孔。在LICOR Odyssey红外成像系统上对96孔板进行扫描。
数据处理:
测量在800nm波道和700nm波道的累积强度,从而分别确定ER和DNA的水平。如下确定ER百分比水平:
%ER水平=(800nm样品累积强度/700nm样品累积强度)/(800nm未处理细胞的累积强度/700nm未处理细胞的累积强度)x100%。用GraphPad软件计算得到本申请化合物抑制乳腺癌MCF-7细胞中ERα表达的EC50值。试验结果显示,化合物1的EC50值为1.31nM,化合物3的EC50值为0.60nM,化合物13的EC50值为0.66nM,化合物25的EC50值为0.60nM,提示本申请化合物能显著抑制乳腺癌MCF-7细胞中ERα的表达。
试验例3.本申请化合物对炔雌醇诱导的子宫增重的抑制作用试验
试验方法:
雌性SD大鼠,检疫3天后,按体重分组,每组9只,连续给药3天。给药组每天灌胃给予1mg/kg的本申请待测化合物,每日给药后15min,灌胃给予0.1mg/kg的炔雌醇;模型组灌胃给予溶媒和0.1mg/kg的炔雌醇;溶媒组灌胃只给溶媒(5%DMSO+5%Solutol+90%纯化水)。待测化合物的浓度为0.1mg/ml,炔雌醇的浓度为0.01mg/ml。
于末次给药后约24h解剖动物,称量子宫重量,计算本申请化合物对子宫重量抑制率。
子宫重量抑制率=100*(模型组子宫重量-给药组子宫重量)/(模型组子宫重量-溶媒组子宫重量)。
本申请化合物1的抑制率达到94.10%,提示本申请化合物对炔雌醇诱导的子宫增重具有明显的抑制作用。
试验例4.本申请化合物对MCF-7乳腺癌小鼠移植瘤的抑制作用试验。
试验方法:
在免疫缺陷(nu/nu)雌性小鼠中预先手术植入0.36mg的雌激素片(美国Innovative Research公司),第三天,将含有基质胶(美国BD公司)的MCF-7细胞(细胞接种量为5ⅹ106/只,接种体积为0.1ml)皮下接种在小鼠的后胁腹中。待细胞植入的14天,开始随机分组,给药28天。给药组每天灌胃给予30mg/kg的本申请化合物3;溶媒组灌胃只给溶媒(5%DMSO+5%Solutol+90%纯化水)。
每周两次通过游标卡尺确定肿瘤体积的变化。肿瘤体积(Tumor Volume,TV)的计算公式为:V=1/2*a*b2,其中a和b分别表示瘤子的长和宽。根据测量的结果计算出相对肿瘤体积(Relative Tumor Volume,RTV),RTV=Vt/V0,其中V0为分组给药时测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。移植瘤模型的抗肿瘤活性指标为相对肿瘤增殖率T/C%,公式为T/C%=TRTV/CRTV*100%,其中TRTV为给药组RTV,CRTV为溶媒组RTV。当移植瘤模型的相对肿瘤增殖率T/C%<40%时,认为测试化合物具有抗肿瘤活性。
表2本申请化合物对MCF-7乳腺癌小鼠移植瘤相对肿瘤增殖率(T/C%)
由表2可知,在30mg/kg剂量下,本申请化合物3的T/C%<40%,同时P<0.01,表示本申请化合物对MCF-7乳腺癌小鼠移植瘤模型具有明显的抑制作用。
试验例5.本申请化合物与CDK4/6抑制剂(Palbociclib)组合的对MCF-7乳腺癌小鼠移植瘤的抑制作用试验。
试验方法:
在免疫缺陷(nu/nu)雌性小鼠中预先手术植入0.36mg的雌激素片(美国Innovative Research公司),第三天,将含有基质胶(美国BD公司)的MCF-7细胞(细胞接种量为5*106/只,接种体积为0.1ml)皮下接种在小鼠的后胁腹中。待细胞植入的14天,开始随机分组,给药28天。单一给药组每天灌胃给予50mg/kg的Palbociclib;与CDK4/6抑制剂Palbociclib联用组每天灌胃给予50mg/kg的Palbociclib和10mg/kg的本申请化合物3;溶媒组灌胃只给溶媒(5%DMSO+5%Solutol+90%纯化水)。
每周两次通过游标卡尺确定肿瘤体积的变化。肿瘤体积(Tumor Volume,TV)的计算公式为:V=1/2*a*b2,其中a和b分别表示瘤子的长和宽。根据测量的结果计算出相对肿瘤体积(Relative Tumor Volume,RTV),RTV=Vt/V0,其中V0为分组给药时测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。移植瘤模型的抗肿瘤活性指标为相对肿瘤增殖率T/C%,公式为T/C%=TRTV/CRTV*100%,其中TRTV为给药组RTV,CRTV为溶媒组RTV。
表3本申请化合物与palbociclib联用对MCF-7乳腺癌小鼠移植瘤相对肿瘤增殖率(T/C%)
由表3可知,本申请化合物3与已上市CDK4/6抑制剂Palbociclib联用,T/C%<40%,同时P<0.01,提示本申请化合物与Palbociclib联用,对MCF-7乳腺癌小鼠移植瘤模型具有明显的抑制作用。
试验例6.生化hERG实验
试验方法
本实验使用基于荧光偏振技术的生化hERG测定试剂盒(赛默飞世尔,货号:PV5366)对化合物诱导心脏QT间期延长的潜力进行了评估。待测化合物加入到含有hERG细胞膜的微孔板中,再加入具有高hERG亲和性示踪剂Tracer,将微孔板在25℃孵育2小时后,使用BMG PHAREStar多功能酶标仪检测荧光偏振值的变化,最后计算本申请化合物在不同浓度下对hERG百分比抑制率(%),判断化合物的半数最大抑制浓度(IC50)的范围。
测试结果表明,化合物1对于hERG的50%抑制浓度(IC50)值大于30μM,本申请的其余化合物与化合物1具有类似的安全性,抑制hERG的IC50均大于30μM,表明本申请的化合物无明显的hERG毒性。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公开的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (25)
1.式I所示化合物、其立体异构体或其药学上可接受的盐,
其中,
X为-C(R1)-或-N-;
R1和R2各自独立地为氢或卤素;
R3为氢;
R4为C1-C2烷基;
R5为氨基、氰基、C1-C6烷基、含有一个碳碳三键的C2-C6炔基或3-8元环烷基;其中,所述C1-C6烷基、含有一个碳碳三键的C2-C6炔基或3-8元环烷基未被取代或被1或2个选自下述的取代基取代:卤素、羟基、氰基、C1-C6烷氧基、C1-C6烷硫基和C1-C6烷基磺酰基;或者,
R5与环A中编号为1和2的碳原子一起形成3-5元碳环;
R6为氢或卤素;
m为1或2;
n为1、2或3;
其中,当X为-C(R1)-,R1为氟,R2为氟,R3为氢,R4为甲基,R6为氢,m为1,且n为1或3时,R5不为甲基和三氟甲基。
3.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中,
X为-C(R1)-或-N-;
R1为氟。
4.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中,R2为氢或氟。
5.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中,R4为甲基。
6.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中,
R5为氨基、氰基、C1-C4烷基、C2-C4炔基或3-6元环烷基;其中,所述C1-C4烷基、C2-C4炔基或3-6元环烷基未被取代或被1或2个选自下述的取代基取代:卤素、羟基、氰基、C1-C4烷氧基、C1-C4烷硫基和C1-C4烷基磺酰基;或者,
R5与环A中编号为1和2的碳原子形成3-5元碳环。
7.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中R5为氨基、氰基、C1-C4烷基、乙炔基或环丙基;其中,所述C1-C4烷基未被取代或被1或2个选自下述的取代基取代:氟、羟基、氰基、C1-C2烷氧基、C1-C2烷硫基和C1-C2烷基磺酰基;或者,
R5与环A中编号为1和2的碳原子形成3元碳环。
8.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中R5为氰基、甲基、乙基、丙基、异丙基、乙炔基、环丙基、卤代甲基、羟基甲基或甲氧基甲基。
9.权利要求6-8任一项所述的化合物、其立体异构体或其药学上可接受的盐,其中,
R6为氢或氟;
m为2。
10.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中n为1。
11.权利要求1或2的化合物、其立体异构体或其药学上可接受的盐,其中,
X为-C(R1)-,R1为氟;
R2为氢或氟;
R3为氢;
R4为甲基;
n为1;
其余原子或取代基定义如权利要求1所述。
14.权利要求1的化合物的制备方法,其选自以下方法:
方法一:
步骤1:化合物SM-1与化合物SM-2经还原胺化反应得到化合物IN-1,或者化合物SM-1与化合物SM-3经取代反应得到化合物IN-1;
步骤2:化合物IN-1与化合物IN-2合环得到化合物IN-3;
步骤3:化合物IN-3酯水解后得到所述式I化合物;
其中,Y表示离去基团,其余各原子或取代基定义如权利要求1中所述;
方法二:
步骤1:化合物IN-1与化合物IN-4合环得到化合物IN-5;
步骤2:化合物IN-5与丙烯酸酯通过Heck偶联反应得到化合物IN-3;
步骤3:化合物IN-3酯水解后得到所述式I化合物;
其中,Z代表溴或氯,其余各原子或取代基定义如权利要求1所述。
15.权利要求14的制备方法,其中方法一中所述离去基团为氯、溴、碘、酯基或-OTs。
16.药物组合物,其含有权利要求1-13任一项的化合物、其立体异构体或其药学上可接受的盐,以及任选地一种或多种药学上可接受的载体或赋形剂。
17.权利要求16的药物组合物,其中,所述化合物、其立体异构体或其药学上可接受的盐的含量为0.1mg至800mg。
18.权利要求16的药物组合物,其中,所述化合物或其药学上可接受的盐的含量为0.5-500mg。
19.权利要求16的药物组合物,其中,所述化合物或其药学上可接受的盐的含量为0.5至350mg。
20.权利要求16的药物组合物,其中,所述化合物或其药学上可接受的盐的含量为1-250mg。
21.权利要求16-20任一项的药物组合物,其为片剂、胶囊剂、颗粒剂、口服溶液剂、口服混悬剂、口服乳剂、散剂、酊剂、糖浆剂、注射剂或栓剂。
22.权利要求1-13任一项的化合物、其立体异构体或其药学上可接受的盐或权利要求16的药物组合物在制备治疗与雌激素受体过度活性相关的疾病的药物中的用途。
23.权利要求22的用途,其中所述雌激素受体为ERα。
24.权利要求22的用途,其中所述疾病选自:乳腺癌、骨癌、肺癌、结直肠癌、前列腺癌、卵巢癌、子宫癌、酒精中毒、偏头痛、痴呆症、帕金森病、主动脉瘤、心肌梗死、主动脉硬化、冠状动脉硬化、高血压、深静脉血栓、格雷夫斯病、关节炎、硬化症、慢性肝炎、胆汁淤积、尿道下裂、肥胖症、神经性厌食、注意力缺陷多动障碍(ADHD)、精神病和不育症。
25.权利要求22的用途,其中所述疾病选自子宫内膜癌、多发性硬化、骨关节炎、重性抑郁障碍、子宫平滑肌瘤、子宫内膜增生、子宫内膜异位症、阿尔茨海默病和慢性乙型肝炎。
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