CN106496213B - Lcl161前药及其制备方法和应用 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract
本发明公开了一种LCL161前药及其制备方法和应用。本发明提供了通式Ⅰ所示的LCL161前药及其药学上可接受的盐、水合物或溶剂化物。所述制备方法包括:化合物LCL161与R1COR6、R3PhCnCOR6或(OR4)(OR5)POR6发生取代反应得到;或者化合物LCL161与R2OCOR6发生缩合反应得到;其中,n,R1,R2,R3,R4和R5与通式I中的限定相同;R6为卤素,所述卤素可以选择氯或溴。本发明还公开了所述化合物在作为IAPs抑制剂、制备预防或治疗IAPs相关疾病的药物中的应用。本发明提供了一类IAPs拮抗剂LCL161的前药,可以在胃液、肠液或血液中转化为LCL161。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,尤其涉及LCL161前药的设计合成及其制备方法和用途。
背景技术
细胞凋亡,即程序性细胞死亡,在调节细胞数量和从正常组织中清除应激或受损细胞方面起关键作用。实际上,大部分细胞类型中所固有的凋亡信号传导网络机制提供了抗人类癌症发展和恶化的主要屏障。由于通常所用的放射治疗和化学治疗依赖于活化凋亡途径以杀死癌细胞,所以能逃避程序性细胞死亡的肿瘤细胞通常对治疗有抵抗力。
凋亡信号传导网络分为由死亡受体-配体相互作用介导的外在网络或由细胞应激和线粒体透化作用介导的内在网络。两条途径最终均集中在半胱氨酸蛋白酶(caspase)上。一旦被活化,caspase裂解许多细胞死亡相关底物,实现对细胞的破坏。长期以来,人们仅仅意识到肿瘤是异常细胞过度增生疾病,以杀死肿瘤细胞为着眼点的放化疗成为治疗的主要手段。但肿瘤放化疗选择性不高,毒副作用大。不断的研究阐明肿瘤的发生是细胞增殖与细胞凋亡失衡所致,受体内外多因素调控,靶向治疗是提高治疗效果的一条重要的途径。
凋亡抑制蛋白(inhibitor of apoptosis proteins,IAPs)是一类内源性细胞抑制因子,在很多物种起抑制凋亡的作用,其过度表达引起凋亡不足与肿瘤发生密切相关。因此以IAPs为靶点,寻找有效的IAPs拮抗剂有广泛的应用前景。IAPs家族首先是由CROOK等在杆状病毒CpGV中发现的,是一类新的抗凋亡蛋白。目前在哺乳动物体内已经发现了8种IAPs:cIAP1(cellular IAP-1),cIAP2(cellular IAP-2),XIAP(X-chromosome linkedIAP),NAIP(neuronal apoptosis inhibitory protein),ILP-2(IAP like protein 2),survivin,bruce及livin(melanoma IAP,MLIAP)。IAPs家族的结构具有很大相似性,有三个结构域:(1)N末端IAPs重复序列域BIR,IAPs一般含有1~3个BIR结构域;(2)大多数IAPs在羧基末端存在锌指(Zine-finger Ring)结构,该区域含有泛素化连接酶E3,具有泛素化作用(ubiquination),能够促进与IAPs相接触的蛋白的降解;(3)cIAP1和cIAP2有caspases募集结构域CARD(caspase recruitment domain),CARD功能目前还不清楚,可能与IAPs的功能特异性及多样性有关。
目前针对IAPs的拮抗剂取得了很大的进展,以IAPs为靶点的反义寡核苷酸、核酶以及免疫治疗大量应用于实验研究,获得了一定的效果。但是这些基因产物往往缺乏合适的载体系统,转染率低,不能在体内稳定高效表达,容易降解,不能口服,限制了其广泛应用。针对IAPs与肿瘤发生发展的密切关系,筛选有较好抑制肿瘤活性和选择性的化合物,研制调控有基因特异性的拮抗剂成为基因组时代药物开发的新趋势。Smac(second-mitochondria derived activator of caspases)又称作DIABLO,是一种新发现的凋亡促进剂,能够直接与cIAP-1、cIAP-2、XIAP、survivin、livin相互作用。
2000年7月Du等的实验小组首次报道从HeLa细胞中分离出的一种新型线粒体蛋白质,后来通过免疫分析确定是Smac。Smac前体存在于正常细胞线粒体,在凋亡信号刺激下,释放到细胞质。结构及生物学研究发现,Smac以其N末端四肽AVPI(Ala-Val-Pro-Ile)与IAPs的BIR域结合,从而使与IAPs结合的caspases得以释放,达到促凋亡的目的。AVPI通过IBM(IAP binding motif)与IAPs结合,而此结合位点也是IAPs与caspases结合位点。因此,Samc与IAPs结合能使与IAPs结合的caspases释放出来,阻止IAPs对caspases活性的抑制,以达到促凋亡的目的。
Smac类似物(Smac-mimics)是一类具有与smac有效作用部位功能相似的小分子化合物,此类化合物的促凋亡活性具有很多明显的优势,如易透过细胞膜抑制抗凋亡蛋白,药效活性强以及对正常细胞无毒性等。目前针对Smac类似物的研究主要是基于化学合成肽类或非肽类小分子化合物。Smac类似物有两种类型:一种是基于单体的研究,其与IAPs只有一个结合位点;另一种是基于二聚体的研究,其与IAPs有两个结合位点。最初的Smac类似物都是单体,能与XIAP、cIAP1、cIAP2的BIR3域结合,也能与其他几个IAPs的单个的BIR域结合。实验证明二聚体具有更高的亲和力,活性更高,但是单体口服具有更高的生物利用度,因此主要合成单体。Smac类似物作为一类有前景的抗癌小分子药正在进行临床前研究和临床研究。
其中,Novartis公司开发的LCL161,为可口服的小分子IAP抑制剂,主要用来治疗乳腺癌,复发或难治性多发性骨髓瘤,原发性骨髓纤维化,真性红细胞增多性骨髓纤维化以及后原发性血小板增多性骨髓纤维化,同时也用于治疗晚期实体瘤。目前并未有LCL161前药结构设计的报道。
发明内容
发明目的:针对现有技术中存在的问题,本发明的一个目的是提供一类结构新颖的IAPs拮抗剂LCL161的前药,本发明的另一个目的是提供所述前药的制备方法和用途。
技术方案:一种由下述通式Ⅰ所示的LCL161前药及其药学上可接受的盐、水合物或溶剂化物:
其中:
R为-C(=O)R1、-C(=O)OR2、-C(=O)CnPhR3或-P(=O)(OR4)(OR5);
R1选自取代或未被取代的C1-C8烷基;优选的,R1选自未被取代或被选自下组的取代基取代的C1-C8烷基:卤素、羧基或氰基;优选的,R1选自取代或未被取代的C1-C5烷基;进一步优选的,R1选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、二甲基丙烷基、溴乙基、溴丙基、氯乙基、氯丙基、甲酸基、乙酸基、丙酸基或氰基甲烷基;
R2选自取代或未被取代的C1-C8烷基;优选的,R2选自未被取代或被选自下组的取代基取代的C1-C8烷基:卤素、羧基或氰基;优选的,R2选自取代或未被取代的C1-C5烷基;进一步优选的,R1选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、二甲基丙烷基、溴乙基、溴丙基、氯乙基、氯丙基、甲酸基、乙酸基、丙酸基或氰基甲烷基;
R3选自H、卤素、取代或未被取代的C1-C8烷基,R3处于苯环上的邻位、对位或间位;优选的,R3选自H、卤素、取代或未被取代的C1-C6烷基;进一步优选的,R3选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、氢、氟、氯、溴或碘;
R4、R5选自相同或不同的基团,各自独立的为取代或未被取代的C1-C4烷基、芳环或杂芳环,环上的取代基可选自卤素、硝基、氰基、羟基、氨基、C1-C6烷基、C1-C6烷氧基;进一步优选自相同或不同的基团,各自独立的为未被取代的C1-C2烷基、芳环或杂芳环,环上的取代基可选自卤素、C1-C6烷基;最后优选自相同基团,各自独立地是乙基、苯环;
n为0或1。
通式Ⅰ所示化合物的药学上可接受的盐可以但并不限制的包括:无机酸盐,如盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、亚硫酸盐、磷酸盐、偏磷酸盐、高氯酸盐等;有机酸盐,如甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、羟基苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等;烷基磺酸盐,如甲基磺酸盐、乙基磺酸盐等;芳基磺酸盐,如苯磺酸盐、对甲苯磺酸盐等。
通式Ⅰ所示化合物的药学上可接受的溶剂化物包括通式Ⅰ所示化合物与水、乙醇、异丙醇、乙醚、丙酮、二氯甲烷、甲苯等的溶剂合物。
优选地,通式Ⅰ所示化合物包括以下通式所示的化合物:
其中,n,R1,R2,R3,R4和R5与通式Ⅰ中的限定相同。
在本发明的优选实施方案中,所述通式Ⅰ的化合物具体结构如下:
本发明还提供了通式Ⅰ所示化合物的制备方法,包括:
化合物LCL161与R1COR6、R3PhCnCOR6或(OR4)(OR5)POR6发生取代反应得到;或者化合物LCL161与R2OCOR6发生缩合反应得到;
其中,n,R1,R2,R3,R4和R5与通式I中的限定相同;R6为卤素,所述卤素可以选择氯或溴。
反应式如下:
化合物LCL161(即化合物1)可采用常规的方法制备得到;化合物1与不同取代的酰卤(R1COR6、R3PhCnCOR6)发生取代反应,获得通式A或通式C化合物,化合物1与不同取代的卤甲酸酯(R2OCOR6)发生缩合反应,获得通式B化合物,化合物1与不同取代的膦酰卤((OR4)(OR5)POR6)发生取代反应,获得通式D化合物;其中,n,R1,R2,R3,R4和R5与通式I中的限定相同;R6为卤素,所述卤素可以选择氯或溴。。
上述的取代反应或缩合反应为本领域的常规反应条件,通常在碱性条件下进行,碱可以为碳酸铯、碳酸纳、碳酸氢纳、碳酸钾、吡啶、哌啶或三乙胺,优选为碳酸钾或三乙胺。通常反应在有机溶剂中进行反应,有机溶剂一般选择二氯甲烷、乙醇、甲苯或几种溶剂的混合溶剂。
本发明还提供了所述通式Ⅰ所示LCL161前药及其药学上可接受的盐、水合物或溶剂化物在预防或治疗IAPs相关疾病中的应用。
本发明还提供了通式Ⅰ所示LCL161前药及其药学上可接受的盐、水合物或溶剂化物在作为IAPs抑制剂中的应用。
本发明还提供了通式Ⅰ所示LCL161前药及其药学上可接受的盐、水合物或溶剂化物在制备预防或治疗IAPs相关疾病的药物中的应用。
本发明还提供了一种药物组合物,包含有效量的通式Ⅰ所示LCL161前药及其药学上可接受的盐、水合物或溶剂化物中的任意一种或几种化合物。所述的药物组合物还可以包含药学上可接受的载体、佐剂或辅料。
本发明还提供了所述的药物组合物在预防或治疗IAPs相关疾病中的应用。
本发明还提供了一种预防或治疗IAPs相关疾病的方法,包括向患者给药治疗有效量的本发明的通式Ⅰ所示LCL161前药及其药学上可接受的盐、水合物或溶剂化物。
上述应用中涉及的IAPs相关疾病为与生物体内的IAPs相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病。
上述应用中涉及的IAPs相关疾病为肿瘤。
与现有技术相比,本发明的有益效果包括:本发明提供了一类IAPs拮抗剂LCL161的前药,可以在胃液、肠液或血液中转化为LCL161。
本发明化合物中的一些如A-1、B-4、B-5、C-3和D-1的转化率都很高,其中化合物A-1和B-4的各药代动力学参数均与LCL161类似或优于LCL161,它们的半衰期和最大血药浓度时间均有所延长。
附图说明
图1为人工胃液稳定性试验结果图;
图2为人工肠液稳定性试验结果图。
具体实施方式
下面结合具体实施例,进一步阐明本发明,应理解这些实施例仅用于说明本发明而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
化合物1的制备可参考US8552003B2,WO2011018474A1,WO2005097791A1。
lH-NMR用Bruker DPX 300/500MHz NMR谱仪测定,所用试剂均通过商业途径购买,所使用的无水溶剂均是按标准方法干燥处理获得;除说明外所有反应均在二氯甲烷溶剂中室温反应并用TLC跟踪;产品的纯化除说明外均使用硅胶(200-300目)柱色谱法;其中硅胶(200-300目)是由青岛海洋化工厂生产,薄层硅胶板由烟台江友硅胶开发有限公司生产。
实施例1化合物A-1的制备
将150mg(0.30mmol)的化合物1溶于10mL二氯甲烷中,加入0.208ml(1.50mmol)的TEA后,在冰浴条件下缓慢滴加0.064ml(0.90mmol)的乙酰氯,室温反应2h。TLC检测反应完全,浓缩至干,柱层析分离(硅胶:100目-200目,V乙酸乙酯:V石油醚=1:1),得到148mg目标化合物A-1。
1H NMR(500MHz,CDCl3)δ:8.47–8.24(m,2H),8.16(d,J=1.1Hz,1H),7.15(dd,J=12.3,5.0Hz,2H),6.73(s,1H),5.55(m,J=7.8Hz,1H),5.27–5.17(m,1H),4.60(m,J=6.8Hz,1H),4.00–3.63(m,2H),2.94(s,3H),2.49–2.04(m,7H),1.85–1.51(m,5H),1.29–0.80(m,9H).
13C NMR(125MHz,CDCl3)δ184.2,174.0,171.1,170.6,170.1,167.5,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,39.8,30.6,29.0,28.7,27.1,25.1,24.9,24.8,23.6,21.0,12.5.
HRMS(ESI)m/z:calcd for C28H35FN4O4S[M+H]+543.23630;found:543.24512.
实施例2化合物A-2的制备
除了用丙酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-2(125mg)。
1H NMR(500MHz,CDCl3)δ:8.47–8.24(m,2H),8.16(d,J=1.1Hz,1H),7.15(dd,J=12.3,5.0Hz,2H),6.73(s,1H),5.55(m,J=7.8Hz,1H),5.27–5.17(m,1H),4.60(m,J=6.8Hz,1H),4.00–3.63(m,2H),2.94(s,3H),2.53–1.95(m,7H),1.82–1.48(m,6H),1.41–0.74(m,10H).
13C NMR(125MHz,CDCl3)δ184.2,173.8,171.1,170.9,170.2,167.5,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.8,46.6,39.8,30.6,29.6,29.0,28.7,27.1,26.1,25.1,24.9,24.7,23.6,21.0,12.4.
HRMS(ESI)m/z:calcd for C29H37FN4O4S[M+H]+557.25195;found:557.26349.
实施例3化合物A-3的制备
除了用正丁酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-3(154mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.92(s,3H),2.41–2.01(m,7H),1.86–1.58(m,6H),1.39–1.15(m,4H),1.15–0.84(m,8H).
13C NMR(125MHz,CDCl3)δ184.2,173.0,171.1,170.2,170.1,165.7,163.6,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,39.9,34.8,30.6,29.7,29.0,28.7,27.1,25.1,24.7,24.7,23.6,17.5,13.0,12.4
HRMS(ESI)m/z:calcd for C30H39FN4O4S[M+H]+571.26760;found:571.27638.
实施例4化合物A-4的制备
除了用异丁酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-4(148mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.92(s,3H),2.88–2.70(m,1H),2.49–2.36(m,1H),2.35–2.22(m,1H),2.14(m,J=13.4,11.0,7.8Hz,2H),2.01(m,J=21.9,9.4Hz,1H),1.80–1.48(m,4H),1.36–0.74(m,15H).
13C NMR(125MHz,CDCl3)δ184.2,177.0,171.2,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,39.8,30.5,29.8,29.5,29.2,28.7,27.1,25.1,24.9,24.7,23.6,18.2,18.2,12.4.
HRMS(ESI)m/z:calcd for C30H39FN4O4S[M+H]+571.26760;found:571.27638.
实施例5化合物A-5的制备
除了用戊酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-5(156mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.93(s,3H),2.50–2.05(m,7H),1.78–1.55(m,4H),1.44–1.21(m,6H),1.20–0.83(m,10H).
13C NMR(125MHz,CDCl3)δ184.2,173.2,171.1,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,39.8,32.6,30.5,29.8,29.0,28.7,27.1,26.2,25.1,24.9,24.7,23.6,21.6,12.9,12.4.
HRMS(ESI)m/z:calcd for C31H41FN4O4S[M+H]+585.28325;found:585.29275.
实施例6化合物A-6的制备
除了用异戊酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-6(152mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.93(s,3H),2.46–2.36(m,1H),2.35–2.19(m,3H),2.19–2.05(m,4H),1.79–1.55(m,4H),1.44–0.79(m,15H).
13C NMR(125MHz,CDCl3)δ184.2,172.5,171.1,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,41.6,39.8,30.5,29.9,29.0,28.7,27.2,25.1,24.9,24.7,24.6,23.6,21.8,21.7 12.4.
HRMS(ESI)m/z:calcd for C31H41FN4O4S[M+H]+585.28325;found:585.31769.
实施例7化合物A-7的制备
除了用三甲基乙酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-7(146mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.99(s,3H),2.49–2.36(m,1H),2.35–2.22(m,1H),2.14(m,J=13.4,11.0,7.8Hz,2H),2.01(m,J=21.9,9.4Hz,1H),1.80–1.48(m,4H),1.43–0.64(m,18H).
13C NMR(125MHz,CDCl3)δ184.2,177.8,171.1,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,53.1,46.6,39.8,38.2,31.3,31.0,30.6,30.5,29.2,29.1,28.7,27.2,25.1,24.9,24.7,23.6,12.4.
HRMS(ESI)m/z:calcd for C31H41FN4O4S[M+H]+585.28325;found:585.31777.
实施例8化合物A-8的制备
除了用己酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-8(145mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.93(s,3H),2.50–2.05(m,7H),1.78–1.55(m,4H),1.44–1.21(m,6H),1.20–0.83(m,12H).
13C NMR(125MHz,CDCl3)δ184.2,173.2,171.1,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,39.8,32.9,30.6,29.8,29.2,29.0,28.7,27.2,25.1,24.9,24.7,23.8,23.6,21.7,13.1,12.4.
HRMS(ESI)m/z:calcd for C32H43FN4O4S[M+Na]+621.29890;found:621.29273.
实施例9化合物A-9的制备
除了用3,3-二甲基丁酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物A-9(142mg)。
1H NMR(500MHz,CDCl3)δ:8.42–8.23(m,2H),8.16(s,1H),7.15(dd,J=8.6Hz,2H),6.75(d,J=8.5Hz,1H),5.54(m,J=6.4Hz,1H),5.23(d,J=7.1Hz,1H),4.67–4.46(m,1H),4.00–3.63(m,2H),2.99(s,3H),2.50–2.37(m,1H),2.34–2.24(m,3H),2.20–2.05(m,3H),1.80–1.48(m,4H),1.43–0.64(m,18H).
13C NMR(125MHz,CDCl3)δ184.2,171.9,171.1,170.2,170.1,165.7,163.7,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,50.7,46.6,44.3,39.8,31.0,30.6,29.8,29.2,29.0,28.7,27.2,27.1,25.1,24.9,24.7,23.6,21.7,13.1,12.4.
HRMS(ESI)m/z:calcd for C32H43FN4O4S[M+Na]+621.29890;found:621.29226.
实施例10化合物B-1的制备
除了用氯甲酸甲酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-1(132mg)。
1H NMR(500MHz,CDCl3)δ:8.38–8.25(m,2H),8.17(d,J=1.2Hz,1H),7.15(dd,J=8.3Hz,2H),6.68(s,1H),5.54(m,J=7.8Hz,1H),4.64(m,J=7.3Hz,1H),4.00–3.63(m,2H),3.73(s,3H),2.84(s,3H),2.42(m,1H),2.31(m,1H),2.16(m,2H),1.81–1.54(m,5H),1.44–0.83(m,10H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,57.7,54.1,55.2,46.6,40.0,30.6,29.1,28.7,27.1,25.1,24.9,24.8,23.6,12.8.
HRMS(ESI)m/z:calcd for C28H35FN4O5S[M+Na]+581.23122;found:581.22531.
实施例11化合物B-2的制备
除了用氯甲酸丙酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-2(130mg)。
1H NMR(500MHz,CDCl3)δ:8.36–8.25(m,2H),8.17(d,J=1.3Hz,1H),7.21–7.10(m,2H),6.69(s,1H),5.54(m,J=7.8Hz,1H),4.72–4.58(m,1H),4.08(m,J=6.4,4.7Hz,2H),4.00–3.63(m,2H),2.84(s,3H),2.42(m,1H),2.37–2.23(m,1H),2.23–2.07(m,2H),1.68(m,J=21.1,9.9,5.3Hz,7H),1.47–0.76(m,13H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,66.7,57.7,54.1,46.6,40.0,30.6,29.1,28.7,27.1,25.1,24.9,24.8,23.6,21.3,12.8,9.4.
HRMS(ESI)m/z:calcd for C30H39FN4O5S[M+Na]+609.26252;found:609.25597.
实施例12化合物B-3的制备
除了用氯甲酸异丙酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-3(128mg)。
1H NMR(500MHz,CDCl3)δ:8.34–8.25(m,2H),8.17(d,J=1.3Hz,1H),7.21–7.10(m,2H),6.72(s,1H),5.58–5.52(m,1H),4.94(m,J=11.9,5.8Hz,1H),4.66–4.58(m,1H),4.00–3.63(m,2H),2.82(s,3H),2.42(m,J=7.8,4.8Hz,1H),2.30(m,J=15.3,7.5Hz,1H),2.24–2.07(m,2H),1.89–1.52(m,6H),1.40–0.79(m,15H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,68.6,57.7,54.1,46.6,40.0,30.6,29.1,28.7,27.1,25.1,24.9,24.8,23.6,21.3,12.8.
HRMS(ESI)m/z:calcd for C30H39FN4O5S[M+Na]+609.26252;found:609.25378.
实施例13化合物B-4的制备
除了用氯甲酸丁酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-4(126mg)。
1H NMR(500MHz,CDCl3)δ:8.36–8.25(m,2H),8.17(d,J=1.3Hz,1H),7.21–7.10(m,2H),6.69(s,1H),5.54(m,J=7.8Hz,1H),4.72–4.58(m,1H),4.08(m,J=6.4,4.7Hz,2H),4.00–3.63(m,2H),2.84(s,3H),2.42(m,1H),2.37–2.23(m,1H),2.23–2.07(m,2H),1.68(m,J=21.1,9.9,5.3Hz,7H),1.47–0.76(m,15H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,65.0,57.7,54.1,46.6,40.0,30.6,30.1,29.1,28.7,27.1,25.1,24.9,24.8,23.6,18.2,13.1,12.8.
HRMS(ESI)m/z:calcd for C31H41FN4O5S[M+Na]+623.27817;found:623.26914.
实施例14化合物B-5的制备
除了用氯甲酸异丁酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-5(124mg)。
1H NMR(500MHz,CDCl3)δ:8.55–8.22(m,2H),8.17–8.07(m,1H),7.16(m,2H),6.83(s,1H),5.52(m,J=7.8Hz,1H),5.10(m,1H),4.61(m,1H),4.00–3.63(m,2H),2.94(s,3H),2.56–1.46(m,9H),1.48–0.71(m,18H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,71.2,57.7,54.1,46.6,40.0,30.6,29.1,28.7,27.1,27.0,25.1,24.9,24.8,23.6,18.2,12.8.
HRMS(ESI)m/z:calcd for C31H41FN4O5S[M+Na]+623.27817;found:623.26916.
实施例15化合物B-6的制备
除了用氯甲酸戊酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物B-6(116mg)。
1H NMR(500MHz,CDCl3)δ:8.36–8.25(m,2H),8.17(d,J=1.3Hz,1H),7.21–7.10(m,2H),6.69(s,1H),5.54(m,J=7.8Hz,1H),4.72–4.58(m,1H),4.08(m,J=6.4,4.7Hz,2H),4.00–3.63(m,2H),2.84(s,3H),2.42(m,1H),2.37–2.23(m,1H),2.23–2.07(m,2H),1.68(m,J=21.1,9.9,5.3Hz,7H),1.47–0.76(m,17H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.2,170.1,165.7,163.7,156.3,152.9,132.4,132.4,127.4,114.4,114.2,65.3,57.7,54.1,46.6,40.0,30.6,29.1,28.7,27.7,27.1,25.1,24.9,24.8,23.6,21.3,13.0,12.8.
HRMS(ESI)m/z:calcd for C32H43FN4O5S[M+Na]+637.29382;found:637.28507.
实施例16化合物C-1的制备
除了用苯甲酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物C-1(150mg)。
1H NMR(500MHz,CDCl3)δ:8.31(m,2H),8.17(d,J=1.3Hz,1H),7.42(m,J=6.7Hz,5H),7.16(m,2H),5.57(m,J=6.4Hz,1H),5.29(m,1H),4.65(m,J=8.5,6.7Hz,1H),4.13–3.71(m,2H),2.93(s,3H),2.53–2.39(m,1H),2.38–2.25(m,1H),2.26–2.07(m,2H),1.71(m,J=39.0,29.0Hz,6H),1.52 0.74(m,9H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.9,170.1,169.7,163.7,152.9,132.4,132.4,127.9,127.8,127.4,114.4,114.2,57.7,54.1,46.6,40.0,30.6,30.5,29.1,28.7,27.2,25.1,24.9,24.8,23.6,13.2,12.3.
HRMS(ESI)m/z:calcd for C33H37FN4O4S[M+Na]+627.25195;found:627.24627.
实施例17化合物C-2的制备
除了用苯乙酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物C-2(140mg)。
1H NMR(500MHz,CDCl3)δ:8.44–8.24(m,2H),8.17(d,J=1.3Hz,1H),7.37–7.29(m,2H),7.29–7.22(m,3H),7.19–7.10(m,2H),6.66(s,1H),5.75–5.43(m,1H),5.40–5.14(m,1H),4.70–4.45(m,1H),3.98–3.65(m,4H),2.93(s,3H),2.53–2.39(m,1H),2.38–2.25(m,1H),2.26–2.07(m,2H),1.71(m,J=39.0,29.0Hz,5H),1.52 0.74(m,9H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.9,170.1,169.7,163.7,152.9,132.4,132.4,127.9,127.8,127.4,114.4,114.2,57.7,54.1,46.6,40.4,40.0,30.6,30.5,29.1,28.7,27.2,25.1,24.9,24.8,23.6,13.2,12.3.
HRMS(ESI)m/z:calcd for C34H39FN4O4S[M+Na]+641.26760;found:641.26158.
实施例18化合物C-3的制备
除了用4-甲基苯甲酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物C-3(146mg)。
1H NMR(300MHz,CDCl3)δ:8.41–8.22(m,2H),8.17(d,J=1.3Hz,1H),7.34(d,J=8.1Hz,2H),7.18(m,4H),5.57(m,J=5.5Hz,1H),4.72–4.56(m,1H),3.84(m,2H),2.94(s,3H),2.55–2.31(m,5H),2.26–2.02(m,3H),1.71(m,J=39.0,29.0Hz,6H),1.52 0.74(m,9H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.9,170.1,169.7,163.7,152.9,132.4,132.4,127.9,127.8,127.4,114.4,114.2,57.7,54.1,46.6,40.0,30.6,30.5,29.1,28.7,27.2,25.1,24.9,24.8,23.6,21.3,13.2,12.3.
HRMS(ESI)m/z:calcd for C34H39FN4O4S[M+Na]+641.26760;found:641.26122.
实施例19化合物C-4的制备
除了用氯苯甲酰氯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物C-4(137mg)。
1H NMR(300MHz,CDCl3)δ:8.44–8.17(m,2H),8.11(d,J=13.8Hz,1H),7.35(m,4H),7.16(m,J=8.6Hz,2H),5.47(m,J=19.2Hz,1H),4.59(m,1H),4.10(dd,J=8.0Hz,1H),3.83–3.52(m,2H),2.93(s,3H),2.53–2.39(m,1H),2.38–2.25(m,1H),2.26–2.07(m,2H),1.71(m,J=39.0,29.0Hz,6H),1.52–0.74(m,9H).
13C NMR(125MHz,CDCl3)δ184.2,171.1,170.9,170.1,169.7,163.7,152.9,135.3,132.4,132.4,127.9,127.8,114.4,114.2,57.7,54.1,46.6,40.0,30.6,30.5,29.1,28.7,27.2,25.1,24.9,24.8,23.6,13.2,12.3.
HRMS(ESI)m/z:calcd for C33H36ClFN4O4S[M+Na]+661.21298;found:661.20238.
实施例20化合物D-1的制备
除了用氯磷酸二乙酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物D-1(149mg)。
1H NMR(500MHz,DMSO-d6)δ:8.56(d,1H),8.28(m,2H),7.66(m,1H),7.43(m,2H),5.43(m,1H),4.50(m,1H),4.18(dd,1H),3.90(m,6H),2.53(s,3H),2.37–1.93(m,4H),1.71–1.62(m,6H),1.52–0.74(m,14H).
13C NMR(125MHz,DMSO-d6)δ184.2,171.1,170.6,170.1,167.5,163.7,152.9,132.4,132.4,127.4,114.4,114.2,62.1,57.7,54.4,53.9,46.6,39.8,30.6,29.0,28.7,28.1,27.4,25.1,24.9,24.8,23.5,15.2,13.1.
HRMS(ESI)m/z:calcd for C30H42FN4O6PS[M+H]+637.25467;found:637.26733.
实施例21化合物D-2的制备
除了用氯磷酸二苯酯代替乙酰氯以外,采用与实施例1的合成化合物A-1相同的方法合成化合物D-2(151mg)。
1H NMR(500MHz,DMSO-d6)δ:8.56(d,1H),8.34–8.20(m,2H),7.87(m,J=8.3Hz,1H),7.50–7.37(m,6H),7.37–7.10(m,6H),5.42(m,1H),4.45(m,2H),3.81(m,2H),2.86(s,3H),2.29(m,1H),2.24–2.15(m,1H),2.14–1.99(m,2H),1.58(m,J=49.4,15.6,8.4Hz,6H),1.32(dd,J=37.2,16.0Hz,4H),1.18–0.77(m,5H).
13C NMR(125MHz,DMSO-d6)δ184.2,172.5,170.9,170.1,169.8,163.3,152.0,149.9,149.8,132.9,132.6,132.6,129.3,128.7,124.5,124.4,122.6,119.6,119.4,115.0,114.8,57.7,54.1,50.7,52.3,46.6,31.0,28.7,27.1,25.1,24.9,24.8,23.6,14.8.
HRMS(ESI)m/z:calcd for C38H42FN4O6PS[M+Na]+755.25467;found:755.24852.
实施例22药理活性研究:人工胃肠液稳定性试验
各化合物溶解在配制好的人工胃液和人工肠液中,在37℃下,分别在1,2,3和4小时进行取样分析。用C18分析柱进行HPLC检测,流动相以水和乙腈(体积比为50:50),流速为1.0mL·min-1,检测波长为266nm。
LCL161的释放情况如图1和图2所示,在人工胃液和肠液中的稳定性试验结果表明,大部分化合物在37℃条件下温孵,4小时以内均稳定存在,而化合物A-1、B-4、B-5在人工胃液和人工肠液中均有释放出LCL161,化合物D-1在人工肠液中也有部分转化。
实施例23药理活性研究:血浆稳定性试验
各化合物溶解在大鼠血浆中,在37℃下,分别在3,6,12和24小时进行取样分析。用C18分析柱进行HPLC检测,流动相以水和乙腈(体积比为50:50),流速为1.0mL·min-1,检测波长为266nm。
LCL161的释放情况如表1所示。
表1
由上表中的结果可知,所有化合物在血浆中均有转化为LCL161,尤其是化合物A-1、B-4、B-5、C-3和D-1的转化率都较为理想。
实施例24药理活性研究:药代动力学试验
根据人工胃肠液稳定性试验和血浆稳定性试验的结果,我们进一步对化合物A-1和B-4进行前药性质的验证,我们进行了体内药代动力学性质的研究(实验方法及参数测定均为常规技术),其结果如表2所示。
表2
参数 | LCL161 | A-1 | B-4 |
C<sub>max</sub>(ng/ml) | 1170±398 | 1064±356 | 1108±379 |
T<sub>max</sub>(h) | 2.00 | 3.65±0.23 | 2.78±0.21 |
t<sub>1/2</sub>(h) | 5.78±0.90 | 5.89±0.73 | 5.82±0.85 |
AUC<sub>0-t</sub>(ng*h/ml) | 11388±3282 | 11401±3367 | 11275±3108 |
AUC<sub>0-∞</sub>(ng*h/ml) | 11400±3283 | 11487±3259 | 11354±3295 |
CL/F(L/h) | 57.1±16.9 | 59.3±15.7 | 58.2±12.3 |
由上表可知,A-1和B-4的各药代动力学参数均与LCL161类似或优于LCL161,它们的半衰期和最大血药浓度时间均有所延长,是比较理想的LCL161前药。
Claims (5)
1.一种由下述通式Ⅰ所示的LCL161前药:
其中:
R为-C(=O)R1或-C(=O)OR2;
R1选自甲基;R2选自丁基。
2.根据权利要求1所述化合物的制备方法,其特征在于,包括:化合物LCL161与R1COR6发生取代反应得到;或者化合物LCL161与R2OCOR6发生缩合反应得到;
其中,R1,R2与通式I中的限定相同;R6为卤素,所述卤素为氯或溴;化合物LCL161的结构如下式:
3.根据权利要求1所述的化合物在制备IAPs抑制剂中的应用。
4.根据权利要求1所述的化合物在制备预防或治疗IAPs相关疾病的药物中的应用。
5.一种药物组合物,包含有效量的根据权利要求1所述的化合物中的一种或几种化合物。
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