CN102149708A - 作为hdm2配体的吡咯烷-2-酮 - Google Patents
作为hdm2配体的吡咯烷-2-酮 Download PDFInfo
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- CN102149708A CN102149708A CN200980135970XA CN200980135970A CN102149708A CN 102149708 A CN102149708 A CN 102149708A CN 200980135970X A CN200980135970X A CN 200980135970XA CN 200980135970 A CN200980135970 A CN 200980135970A CN 102149708 A CN102149708 A CN 102149708A
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- alkyl
- cycloalkyl
- assorted alkyl
- hplc
- heteroaryl
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Abstract
本发明提供了式(I)或(Ia)的化合物,其为结合HDM2蛋白,诱导凋亡并抑制增殖,且在癌症治疗和预防中具有治疗用途的配体。式(I)或(Ia)的化合物可用作治疗中风、心肌梗死、缺血、多器官衰竭、脊髓损伤、阿尔茨海默病、源于缺血事件的损伤和心脏瓣膜退行性疾病的治疗剂。而且,式(I)或(Ia)的化合物可用于降低细胞毒性癌症试剂、放射的副作用,并治疗病毒感染。
Description
背景技术
MDM2(也称为HDM2)在调节和影响重要细胞信号转导通路中起重要作用。已知HDM2与控制细胞周期进程、细胞凋亡、增殖和存活的一系列不同蛋白相互作用。
因此,在其它蛋白中,HDM2结合肿瘤抑制蛋白p53并靶向该蛋白以进行泛素化和降解;促进p53从细胞核易位至胞质溶胶并进一步易位至蛋白体。由此,HDM2防止与细胞周期和凋亡调节有关的p53靶基因的反式激活。p53蛋白是强效的细胞周期抑制剂,其通过诱导生长停滞或凋亡来防止永久损伤的细胞克隆的增殖,以此通过保护细胞和基因组的完整性来防止癌症的发展。
p53以及HDM2均与癌症有关:约50%是所有人肿瘤中带有损害正常p53功能的p53基因的突变或缺失。在具有野生型p53的许多癌症中,HDM2过表达,导致正常p53无功能(Momand et al.Nucleic Acids Res.1998,26,3453-3459)。
HDM2基因具有p53应答型启动子元件,并且易位至细胞核的p53水平的升高诱导HDM2的表达。p53对HDM2的诱导形成自调节反馈环,这确保正常增殖的细胞中HDM2和p53均为低水平(Vousden and Lu Nature Reviews Cancer 2002,2,594-604)。然而,在许多癌症中,HDM2与p53的这种正常比例被改变和错误调节。
在具有野生型p53的细胞中抑制HDM2与p53的相互作用应当导致细胞核中p53水平的增加,这促进细胞周期停滞和/或凋亡,并恢复p53的肿瘤抑制作用。这种策略的可行性已通过使用不同的大分子工具(如抗体、反义寡核苷酸、肽)来抑制HDM2-p53相互作用得到了证实。
除了p53外,已发现大量蛋白与HDM2相互作用,行使作用子(affector)(调节HDM2功能)或效应物(被HDM2调节)功能。已描述了共计约20个与HDM2蛋白相互作用的蛋白(Ganguli and Wasylyk,Mol.Cancer Research,2003,v.1,1027-1035),Zhu et al.Mol.Cell,2009,35,316-326)。在它们中,HDM2结合肿瘤抑制子pRB以及E2F-1(Yang et al.Clinical Cancer Research 1999,5,2242-2250)。
E2F-1是调节进入S期的转录因子,并且已证实过表达时在一些细胞类型中引起凋亡。HDM2通过p53的保守结合区结合E2F,激活细胞周期蛋白A的E2F依赖性转录,并且提示HDM2小分子配体或拮抗剂在细胞中也可能具有抗肿瘤效果,而与它们恢复p53功能的作用无关。
HDM2在体外和体内可结合哺乳动物Numb蛋白。这种结合通过HDM2的N端结构域发生,该结构域也是涉及p53结合的区域。Numb蛋白参与细胞命运的调节和多种发育过程,最显著地是神经系统的发育过程。通过与Numb的相互作用,HDM2可影响诸如分化和存活等的过程。这也可有助于过表达HDM2的肿瘤细胞的性质改变(Juven-Gershon et al.Mol.Cell.Biol.1998,18,3974-3982)。
类似地,阻断HDM2与p53相互作用的小分子也阻断HDM2与低氧诱导因子1α(HIF-1α)的相互作用,所述低氧诱导因子1α是在含氧量正常或低氧条件下诱导血管内皮生长因子(VEGF)的蛋白。因为VEGF是促血管生成的,所以小分子对HDM2的抑制也会防止癌症转移和原发肿瘤中的血管形成(G.A.LaRusch et al.Cancer Res.2007,67,450-454)。
这也证明HDM2在调节细胞周期蛋白依赖性激酶抑制剂p21中起直接作用。用抗HDM2反义寡核苷酸或靶向HDM2的小干扰RNA抑制HDM2显著提高无p53的PC3细胞中的p21蛋白水平。相反地,HDM2的过表达通过缩短p21的半衰期来降低p21水平,该效果可被HDM2反义抑制所逆转。HDM2促进与泛素化和HDM2的E3连接酶功能无关的p21降解。取而代之地是,HDM2通过促进p21与蛋白酶体C8亚基的结合来促进p21降解。p21和HDM2通过HDM2蛋白的180至298位氨基酸区结合(Zhang et al.J.Biol.Chem.2004,279,16000-16006)。
这也是除了突变的p53或HDM2过表达以外,功能失常的HDM2调节影响正常p53功能并引起癌症的证据。因此,当E2F发出癌症生长信号时,P14ARF被排出以分解HDM2,释放p53以杀死癌细胞。在某些癌症中缺少P14ARF(Moule et al.Proc.Natl.Acad.Sci.U.S.A.2004,101,14063-6)。P14ARF结合HDM2并促进HDM2的快速降解。ARF介导的HDM2降解与HDM2修饰及同时发生的p53稳定化和积累有关。
小分子HDM2抑制剂也诱导依赖于功能性p53的存在的衰老,然而缺乏p53的细胞则完全不敏感(A.Efeyan,A.Ortega-Molina,S.Velasco-Miguel,D.Herranz,L.T.Vassilev,M.Serrano,Cancer Res.2007,67,7350-7357)。
将抑制HDM2作为治疗概念的有效性首先由反义HDM2抑制剂所证实,所述反义HDM2抑制剂在具有各种p53状态的多种人癌症模型中表现出显著的抗肿瘤活性(Zhang et al.Proc.Natl.Acad Sci.U.S.A.2003,100,11636-11641)。
因此,HDM2蛋白相互作用的小分子拮抗剂可提供可行的癌症治疗方法,作为单独药剂或与多种其它抗肿瘤疗法组合。
还进一步证明HDM2在病毒感染中起重要作用。首先,已知病毒依赖于改变正常p53信号转导(O′shea and Fried M.Cell Cycle 2005;Machida et al.Proc.Natl.Acad.Sci.U.S.A.2004,23,101,4262-7)。
其次,HDM2直接与病毒蛋白相互作用,例如HDM2是细胞转化中和裂解感染期间猿猴病毒40的靶标(Henning et al.J.Virol.1997,71,7609-7618)。而且,在SV40转化的细胞中,类似于p53,HDM2蛋白在代谢上变得稳定。这提示SV40对HDM2的特异性靶定以防止SV40感染和转化的细胞中p53的HDM2介导型蛋白酶体降解,以此使得这些细胞中p53的代谢稳定。在SV40转化的细胞中,三聚LT-p53-HDM2复合物与猿候病毒40大肿瘤抗原(LT)一起形成。
1型人免疫缺陷病毒(HIV-1)编码强效反式激活子Tat。HDM2已被证实与Tat相互作用,并介导其体外和体内泛素化。此外,HDM2是Tat介导的反式激活的正调节子,这表明Tat的转录性质由泛素化所刺激(Bres et al.Nat Cell Biol.2003,5,754-61)。
已报道了HDM2相互作用的小分子抑制剂,且在体外模型中表现出促凋亡效果以及在癌症动物模型中表现出抗肿瘤效果。因此,苯并二氮杂已用作化学骨架来实现HDM2抑制活性(Grasberger et al.J.Med.Chem.2005,48,909-912;Parks et al.Bioorganic & Medicinal Chemistry Letters 2005,15,765-770)。类似地,咪唑啉(Vassilev et al.Science 2004,303,844-848)、异吲哚酮(Hardcastle et al.Bioorganic & Medicinal Chemistry Letters 2005,15,1515-1520)、降莰烷(Zhao et al.Cancer Letters 2002,183,69-77)和磺酰胺(Galatin and Abraham J.Med.Chem.2004,47,4163-4165)已被报道为小分子HDM2抑制剂。
还报道了HDM2配体具有细胞保护效果。因此,HDM2抑制剂可用在诱导细胞保护的方法中,且可用于保护非靶细胞免受化疗剂的有害影响。提供此效果的HDM2抑制剂的量可比诱导凋亡所需的量低约5至约10倍(Koblish et al.WO03095625,METHOD FOR CYTOPROTECTION THROUGH HDM2 AND HDM2 INHIBITION,2003-11-20)。
吡咯烷-2-酮已描述为治疗上有用的化合物,其治疗病毒感染(US 6509359,PYRROLIDIN-2-ONE COMPOUNDS AND THEIR USE AS NEURAMINIDASE INHIBITORS,1999-03-25);抑制因子Xa以治疗心血管病(US 7226929,Pyrrolidin-2-one derivatives as inhibitors of factor Xa,2006-03-17;Watson et al.,Design and Synthesis of Orally Active Pyrrolidin-2-one-Based Factor Xa Inhibitors,Bioorganic & Medicinal Chemistry Letters 2006,16,3784-3788);作为11βHSD1抑制剂以治疗糖尿病(WO/2005/108360,PYRROLIDIN-2-ONE AND PIPERIDIN-2-ONE DERIVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENASE INHIBITORS,2005-04-29)。吡咯烷-2-酮是建立的治疗化合物的骨架,例如咯利普兰、抗抑郁药和奥拉西坦、吡拉西坦或奈拉西坦,其是阿尔茨海默病的促智药。这些化合物具有低毒性、良好的药代动力学性质,且使得吡咯烷-2-酮成为用于新药候选物的令人感兴趣的骨架。
基于与p53物理上相互作用的能力,确定MDMX(也称为MDM4或HDMX)是MDM2的相关物(relative)。越来越多的证据,包括最近的遗传学研究提示MDMX也充当p53的负独立调节子。MDMX的异常表达可促进肿瘤形成,且在如神经胶质瘤、乳腺癌、视网膜母细胞瘤及宫颈癌和卵巢癌细胞系的大亚群中被观察到。在不同起源的原发肿瘤中,表达HDMX的500个人肿瘤的系统分析(Danovi et al,MCB,2004)揭示出广谱的HDMX过表达的人癌症,如乳腺癌、结肠癌、肺癌、前列腺癌、胃癌、睾丸癌、喉癌、子宫癌、黑素瘤和肉瘤。
因此,应当开发特异性MDMX拮抗剂作为药品以确保激活保留野生型p53的细胞中“休眠的”p53活性。
虽然MDMX与MDM2高度同源,但其不具有泛素连接酶能力且其表达水平不依赖于p53。显示MDMX可比MDM2甚至更强地抑制p53转录活性,且两种蛋白在p53的失活中协作。因此,为了实现肿瘤细胞中p53的完全活化,对MDMX和MDM2表现出双特异性的化合物优于单独的MDM2或MDMX特异性结合剂。
Kallen et al.,JBC,2009,284,8812-8821已解决了与优化的p53肽结合的人MDMX蛋白的三维结构。在Popowicz et al.,Cell Cycle 6:19,2386-2392,1October 2007中,结合p53肽的人源化斑马鱼MDMX晶体结构揭示p53与MDM2相互作用的基本特征在p53/MDMX复合物中是保守的,且可开发“杂合”MDM2/MDMX抑制剂。因此,p53/MDMX和p53/MDM2复合物的结构显示MDMX和MDM2均利用相同的p53结合基序和许多相同的残基来结合p53。在疏水结合口袋(pocket)的大体形状和朝向方面,结合位点的大致形状类似,但这些口袋的各自的确切大小和深度略有不同。因此,在MDMX中,p53肽所结合的疏水裂口比MDM2中的疏水裂口看起来更易变形。
发明概述
在本发明的一实施方式中,描述了结合HDM2和/或MDMX的新小分子,其是HDM2和/或MDMX介导的生物学的抑制剂,并且可用作特别是用于治疗癌症和/或病毒感染的新治疗剂。
本发明提供了选自式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的至少一种化合物及其药学可接受的盐和酯。这样的化合物优选为结合HDM2和/或MDMX蛋白,诱导凋亡和抑制增殖,且在癌症治疗和预防中具有治疗用途的配体。该治疗效果可通过单独使用式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物,或与用于治疗或预防癌症的其它试剂联合使用来实现。
式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物还可通过如保护非癌细胞免受细胞毒性癌症治疗药物或放疗的有害作用来治疗或预防癌症。在这样的治疗中,使用抗肿瘤剂或放疗与细胞保护量的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的至少一种化合物,以及优选的一种或多种药学可接受的赋形剂的组合。优选地,式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物(本文也称为HDM2和/或MDMX配体)在抗肿瘤剂给药之前、同时或之后给药。此外,HDM2和/或MDMX抑制剂可连续或以重复的规律间隔给药。
选自式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物可用作治疗中风、心肌梗死、缺血、多器官衰竭、脊髓损伤、阿尔茨海默病、源于缺血事件的损伤、心脏瓣膜退行性疾病;或降低细胞毒性剂副作用如多柔比星或紫杉醇诱发的脱发或心脏中毒的方法中的治疗剂。
选自本发明的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物还可用于治疗病毒感染,特别是用在包括已知抗病毒化合物的药物组合中。
此外,本发明涉及药物组合物,其包含细胞保护量的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物以及一种或多种药学可接受的赋形剂,所述药物组合物在患者接受诸如放疗的细胞毒性癌症治疗或细胞毒性抗肿瘤剂的治疗之前、同时和/或之后施用。
发明详述
本发明提供了式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物,其优选为HDM2和/或MDMX蛋白的小分子配体,且防止或减少其它蛋白与HDM2和/或MDMX的结合。
在基于细胞的体外测定中,本发明的一种或多种化合物抑制HDM2和/或MDMX蛋白与p53蛋白的相互作用。在这样的基于细胞的测定中,这些化合物表现出机械(mechanistic)活性,如诱导凋亡和抑制增殖。用式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物孵育癌细胞导致p53蛋白的积累、p53调节的p21基因的诱导以及细胞周期停滞在G1和G2期,这在体外导致对野生型p53细胞的强效抗增殖活性。相反地,在比较化合物浓度下,在缺少p53的癌细胞中未观察到这些活性。因此,HDM2和/或MDMX拮抗剂的活性可能与其作用机制有关。因此,这些化合物是强效和选择性抗癌剂。
本发明提供了式(I)的一种或多种化合物或其药学可接受的盐、酯、溶剂合物或水合物或者药学可接受的制剂
其中
V为C=O、C=S或CH2(特别地,C=O);
X为硫、氧或式CH2、CR4bR4c、NH、NR4b、SO或SO2的基团,或键;
Y为式CONR6、CH2NR6、CO、COO、CH2O、SO2NR6、NR6CO、NR6SO2、NR5aCONR6、NR6COO、OCONR6、CONR5aNR6、CONR5aOR6、CH2COCH2CONR6、CH2COO、COCR5aR6的基团或键;
n为1、2、3或0;
R1为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R2为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R3为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4b为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4c为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5a为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R6为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
残基R7彼此独立地为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
残基R8彼此独立地为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
或者基团R1、R2、R3、R4、R4b、R4c、R5、R5a、R6、R7和R8的两个一起为任选取代的环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、杂芳基、芳烷基或杂芳基烷基环体系的一部分。
烷基的表述是指包含1至20个碳原子、优选1至12个碳原子、特别是1至6(如1、2、3或4)个碳原子的饱和、直链或支链烃基,如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、2,2-二甲基丁基或正辛基。
烯基和炔基的表述是指包含2至20个碳原子、优选2至12个碳原子、特别是2至6(如2、3或4)个碳原子的至少部分不饱和、直链或支链烃基,如乙烯基(乙烯基(vinyl))、丙烯基(烯丙基)、异丙烯基、丁烯基、乙炔基(ethinyl)、丙炔基、丁炔基、乙炔基(acetylenyl)、炔丙基、异戊二烯基或己-2-烯基。优选地,烯基具有一个或两个(特别优选一个)双键,且炔基具有一个或两个(特别优选一个)三键。
而且,术语烷基、烯基和炔基是指其中一个或多个氢原子由卤原子(优选F或Cl)代替的基团,如2,2,2-三氯乙基或三氟甲基。
杂烷基的表述是指其中一个或多个(优选1、2或3个)碳原子由氧、氮、磷、硼、硒、硅或硫原子(优选由氧、硫或氮原子)代替的烷基、烯基或炔基。而且,杂烷基的表述是指羧酸或衍生自羧酸的基团,如酰基、酰基烷基、烷氧基羰基、酰氧基、酰氧基烷基、羧基烷基酰胺或烷氧基羰氧基。
优选地,杂烷基包含1至12个碳原子和1至4个选自氧、氮和硫(特别是氧和氮)的杂原子。特别优选地,杂烷基包含1至6个(如1、2、3或4个)碳原子和1、2或3个(特别是1或2个)选自氧、氮和硫(特别是氧和氮)的杂原子。术语C1-C6杂烷基是指包含1至6个碳原子和1、2或3个选自O、S和/或N(特别是O和/或N)的杂原子的杂烷基。术语C1-C4杂烷基是指包含1至4个碳原子和1、2或3个选自O、S和/或N(特别是O和/或N)的杂原子的杂烷基。而且,术语杂烷基是指其中一个或多个氢原子由卤原子(优选F或Cl)取代的基团。
杂烷基的实例为下式的基团:Ra-O-Ya-、Ra-S-Ya-、Ra-N(Rb)-Ya-、Ra-CO-Ya-、Ra-O-CO-Ya-、Ra-CO-O-Ya-、Ra-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-Ya-、Ra-O-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-O-Ya-、Ra-N(Rb)-CO-N(Rc)-Ya-、Ra-O-CO-O-Ya-、Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-、Ra-CS-Ya-、Ra-O-CS-Ya-、Ra-CS-O-Ya-、Ra-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-Ya-、Ra-O-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-O-Ya-、Ra-N(Rb)-CS-N(Rc)-Ya-、Ra-O-CS-O-Ya-、Ra-S-CO-Ya-、Ra-CO-S-Ya-、Ra-S-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-S-Ya-、Ra-S-CO-O-Ya-、Ra-O-CO-S-Ya-、Ra-S-CO-S-Ya-、Ra-S-CS-Ya-、Ra-CS-S-Ya-、Ra-S-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-S-Ya-、Ra-S-CS-O-Ya-、Ra-O-CS-S-Ya-,其中Ra为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基;Rb为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基;Rc为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基;Rd为氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基,且Ya为直接的键、C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基,其中每个杂烷基包含至少一个碳原子,且一个或多个氢原子可由氟或氯原子代替。
杂烷基的具体实例为甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、甲氧基甲基、乙氧基甲基、-CH2CH2OH、-CH2OH、甲氧基乙基、1-甲氧基乙基、1-乙氧基乙基、2-甲氧基乙基或2-乙氧基乙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、二甲基氨基、二乙基氨基、异丙基乙基氨基、甲基氨基甲基、乙基氨基甲基、二异丙基氨基乙基、甲硫基、乙硫基、异丙硫基、烯醇醚、二甲基氨基甲基、二甲基氨基乙基、乙酰基、丙酰基、丁酰氧基、乙酰氧基、甲氧基羰基、乙氧基羰基、丙酰氧基、乙酰氨基或丙酰氨基、羧甲基、羧乙基或羧丙基、N-乙基-N-甲基氨基甲酰基或N-甲基氨基甲酰基。杂烷基的其它实例为腈基、异腈基、氰酸基(cyanate)、硫氰酸基、异氰酸基、异硫氰酸基和烷基腈基。
环烷基的表述是指包含一个或多个环(优选1或2个)且包含3至14个环碳原子、优选3至10个(特别是3、4、5、6或7个)环碳原子的饱和或部分饱和(如环烯基)的环基团。而且,环烷基的表述是指其中一个或多个氢原子由氟、氯、溴或碘原子代替,或由OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团,例如环酮,如环己酮、2-环己酮或环戊酮。此外,环烷基的具体实例为环丙基、环丁基、环戊基、螺[4,5]癸基(decanyl)、降冰片基、环己基、环戊烯基、环己二烯基、萘烷基(decalinyl)、双环[4.3.0]壬基、四氢化萘、环戊基环己基、氟代环己基或环己-2-烯基。
杂环烷基的表述是指其中一个或多个(优选1、2或3个)环碳原子由氧、氮、硅、硒、磷或硫原子(优选由氧、硫或氮原子)代替的如上所定义的环烷基。杂环烷基优选具有包含3至10个(特别是3、4、5、6或7个)环原子(优选自C、O、N和S)的1或2个环。而且,杂环烷基的表述是指其中一个或多个氢原子由氟、氯、溴或碘原子代替,或由OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团。实例为哌啶基、脯氨酰基(prolinyl)、咪唑啉基、哌嗪基、吗啉基、六亚甲基四胺基(urotropinyl)、吡咯烷基、四氢苯硫基、四氢吡喃基、四氢呋喃基或2-吡唑啉基以及内酰胺、内酯、环亚胺和环酸酐。
烷基环烷基的表述是指包含如上所定义的环烷基及烷基、烯基或炔基的基团,如烷基环烷基、环烷基烷基、烷基环烯基、烯基环烷基和炔基环烷基。烷基环烷基优选包括含具有3至10个(特别是3、4、5、6或7个)环碳原子的一个或两个环体系的环烷基,以及具有1或2至6个碳原子的一个或两个烷基、烯基或炔基。
杂烷基环烷基的表述是指其中一个或多个(优选1、2或3个)碳原子由氧、氮、硅、硒、磷或硫原子(优选由氧、硫或氮原子)代替的如上所定义的烷基环烷基。杂烷基环烷基优选包含具有3至10个(特别是3、4、5、6或7个)环原子的1或2个环体系,以及具有1或2至6个碳原子的一个或两个烷基、烯基、炔基或杂烷基。这样的基团的实例为烷基杂环烷基、烷基杂环烯基、烯基杂环烷基、炔基杂环烷基、杂烷基环烷基、杂烷基杂环烷基和杂烷基杂环烯基,环基团为饱和的,或者单、二或三不饱和的。
芳基的表述是指包括含6至14个环碳原子、优选6至10个(特别是6个)环碳原子的一个或多个环的芳香族基团。而且,芳基的表述是指其中一个或多个氢原子由氟、氯、溴或碘原子代替,或由OH、SH、NH2、N3或NO2基团代替的基团。实例为苯基、萘基、联苯基、2-氟苯基、苯胺基、3-硝基苯基或4-羟基苯基。
杂芳基的表述是指包括含5至14个环原子、优选5至10个(特别是5或6个)环原子的一个或多个环,并且包括一个或多个(优选1、2、3或4个)氧、氮、磷或硫环原子(优选O、S或N)的芳香族基团。而且,杂芳基的表述是指其中一个或多个氢原子由氟、氯、溴或碘原子代替,或由OH、SH、N3、NH2或NO2基团代替的基团。实例为吡啶基(如4-吡啶基)、咪唑基(如2-咪唑基)、苯基吡咯基(如3-苯基吡咯基)、噻唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、噁二唑基、噻二唑基、吲哚基、吲唑基、四唑基、吡嗪基、嘧啶基、哒嗪基、噁唑基、异噁唑基、三唑基、四唑基、异噁唑基、吲唑基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、哒嗪基、喹啉基、异喹啉基、吡咯基、嘌呤基、咔唑基、吖啶基、嘧啶基、2,3′-二呋喃基、吡唑基(如3-吡唑基)和异喹啉基。
芳烷基的表述是指包含如上所定义的芳基以及烷基、烯基、炔基和/或环烷基的基团,如芳基烷基、芳基烯基、芳基炔基、芳基环烷基、芳基环烯基、烷基芳基环烷基和烷基芳基环烯基。芳烷基的具体实例为甲苯、二甲苯、1,3,5-三甲基苯、苯乙烯、苄基氯、邻氟代甲苯、1H-茚、四氢化萘、二氢萘、二氢茚酮、苯基环戊基、枯烯、环己基苯基、芴和1,2-二氢化茚。芳烷基优选包括含6至10个碳原子的一个或两个芳环体系(1或2个环),和含1或2至6个碳原子的一个或两个烷基、烯基和/或炔基,和/或含5或6个环碳原子的环烷基。
杂芳烷基的表述是指其中一个或多个(优选1、2、3或4个)碳原子由氧、氮、硅、硒、磷、硼或硫原子(优选由氧、硫或氮原子)代替的如上所定义的芳烷基,即,包含如上所定义的各自的芳基或杂芳基以及烷基、烯基、炔基和/或杂烷基和/或环烷基和/或杂环烷基的基团。杂芳烷基优选包括含5或6至10个环碳原子的一个或两个芳环体系(1或2个环),和含1或2至6个碳原子的一个或两个烷基、烯基和/或炔基,和/或含5或6个环碳原子的环烷基,其中这些碳原子中的1、2、3或4个由氧、硫或氮原子代替。
实例为芳基杂烷基、芳基杂环烷基、芳基杂环烯基、芳基烷基杂环烷基、芳基烯基杂环烷基、芳基炔基杂环烷基、芳基烷基杂环烯基、杂芳基烷基、杂芳基烯基、杂芳基炔基、杂芳基杂烷基、杂芳基环烷基、杂芳基环烯基、杂芳基杂环烷基、杂芳基杂环烯基、杂芳基烷基环烷基、杂芳基烷基杂环烯基、杂芳基杂烷基环烷基、杂芳基杂烷基环烯基和杂芳基杂烷基杂环烷基,环基团为饱和或者单、二或三不饱和的。具体实例为四氢异喹啉基、苯甲酰基、2-或3-乙基吲哚基、4-甲基吡啶并、2-、3-或4-甲氧基苯基、4-乙氧基苯基、2-、3-或4-羧基苯基烷基。
如上所述,环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基和杂芳烷基的表述也指这些基团中的一个或多个氢原子由氟、氯、溴或碘原子代替,或由OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团。
“任选取代”的表述特别是指其中一个、两个、三个或更多个氢原子由氟、氯、溴或碘原子代替,或由OH、=O、SH、=S、NH2、=NH、N3或NO2基团代替的基团。而且,此表述是指由一个、两个、三个或更多个未取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C3-C10环烷基、C2-C9杂环烷基、C6-C10芳基、C1-C9杂芳基、C7-C12芳烷基或C2-C11杂芳烷基取代的基团。
优选的取代基为F、Cl、Br、Me、OMe、CN或CF3。
优选地,本文所述的全部烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳烷基和杂芳烷基可以是任选取代的。
优选式(I)的化合物,其中基团R5和R6一起为任选取代的杂环烷基、杂烷基环烷基、杂芳基或杂芳基烷基环体系的一部分,和/或其中R2和R3一起为任选取代的环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基环体系的一部分。
优选式(I)的化合物,其中X为硫、氧、NH、CH2、SO、SO2,特别是硫。
更优选式(I)的化合物,其中Y为式CONR6的基团。
更优选式(I)的化合物,其中n为0或1,特别是1。
更优选式(I)的化合物,其中R7为氢。
更优选式(I)的化合物,其中R8为氢。
特别优选式(Ia)的化合物或其药学可接受的盐、酯、溶剂合物或水合物或者药学可接受的制剂
其中
R1为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R2为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R3为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R6为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
或者基团R5和R6一起为任选取代的杂环烷基、杂烷基环烷基、杂芳基或杂芳基烷基环体系的一部分,和/或R2和R3一起为任选取代的环烷基、烷基环烷基、杂环烷基、杂烷基环烷基、芳烷基或杂芳烷基环体系的一部分。
更优选式(I)或(Ia)的化合物,其中R1为环烷基、烷基环烷基、杂环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基。
更优选式(I)或(Ia)的化合物,其中R1为芳基、杂芳基、芳烷基或杂芳烷基。
更优选式(I)或(Ia)的化合物,其中R1为式-A-Ar或-A-Cy(特别是-A-Ar)的基团,其中A为键、C1-C4烷基(特别是键、CH2或CH(CH3))或C1-C6杂烷基(如CH(CH2N(CH3)2)),或者其中A为式-CHR1a-的基团,其中R1a为C1-C6杂烷基,Cy为任选取代的C3-C7环烷基或包含3至7个环原子的任选取代的杂环烷基,Ar为任选取代的(如由1、2或3个取代基)苯环或包含5或6个环原子(特别是包含1至3个选自O、S和N的杂原子)的任选取代的(如由1、2或3个取代基)杂芳环,特别优选地Ar为任选取代的苯基或任选取代的吡啶残基(如4-溴苄基残基)。优选的取代基为F、Cl、Br、CN、CH3、OCH3和CF3。
更优选式(I)或(Ia)的化合物,其中R1为式-A-Ar的基团,其中A为键或C1-C4烷基(特别是键、CH2或CHCH3),且Ar为任选取代的(如由1、2或3个取代基)苯环或包含5或6个环原子(特别是包含1至3个选自O、S和N的杂原子)的任选取代的(如由1、2或3个取代基)杂芳环,特别优选地Ar为任选取代的苯基或任选取代的吡啶残基(如4-溴苄基残基)。
特别优选地,R1为式-A-苯基(特别是-CH2-苯基)的基团,其是任选取代的,优选由一个或两个选自F、Cl和Br的卤原子取代,且其中A优选为式-CHR1a的基团,其中R1a为C1-C6杂烷基(如COOH、CH2COOH)。
更优选地,R1为环丙基甲基、皮考基、苯基苄基或苯氧基苄基,它们全部可以是任选取代的。
更优选式(I)或(Ia)的化合物,其中R2为氢。
更优选式(I)或(Ia)的化合物,其中R3为C1-C6烷基、芳基(特别是苯基)、杂芳基、芳烷基或杂芳烷基残基,它们全部可以是取代的(如由1、2或3个取代基)。特别优选地,R3为任选取代的苯基、任选取代的苄基或具有1或2个环和5至10个环原子(特别是2个环和总共9个环原子)的任选取代的杂芳基残基,且所述环原子包含1、2、3或4个选自O、S和N(特别是N)的杂原子。优选的取代基为F、Cl、Br、C1-C4烷基(如CH3)和C1-C6杂烷基(如CH2SO3 -、(CH2)5NH2)。
更优选式(I)或(Ia)的化合物,其中R3具有以下结构
其中E为N或CH,R3a为H、C1-C6烷基或C1-C6杂烷基(特别是H或CH3),R3b为H、F、Cl、Br、CH3、OCH3或CF3,且R3c为H、F、Cl、Br、CH3、OCH3或CF3(特别优选地,E为CH,R3a为H,R3b为Cl,且R3c为H)。
更优选式(I)或(Ia)的化合物,其中R3为芳基(特别是苯基)、杂芳基、芳烷基或杂芳烷基残基,它们全部可以是取代的(如由1、2或3个取代基);特别优选地,R3为具有1或2个环和5至10个环原子(特别是2个环和总共9个环原子)的任选取代的杂芳基残基,且所述环原子包含1、2、3或4个选自O、S和N(特别是N)的杂原子。
更优选式(I)或(Ia)的化合物,其中R3具有以下结构
其中E为N或CH,R3a为H或CH3,R3b为F、Cl或Br,且R3c为H、F、Cl或Br(特别优选地,E为CH,R3a为H,R3b为Cl,且R3c为H)。
更优选地,R2和R3一起为任选取代的杂环烷基或杂芳烷基环的一部分。更优选地,R2和R3一起为具有以下结构的基团的一部分:
更优选式(I)或(Ia)的化合物,其中R4为C1-C6烷基、C2-C6烯基、任选取代的C1-C4烷基-C3-C7环烷基、任选取代的苯环、任选取代的苄基或具有5或6个环原子的任选取代的杂芳环,且所述环原子包含1至3个选自O、S和N的杂原子(如吡啶基)。特别优选地,R4为由优选自F、Br、Cl、I、NO2、甲基或氰基(cyanide)的1或2个取代基取代的苯环(如4-甲基苯基),或未取代的苯环。更优选地,R4为苯基或4-甲基苯基。
更优选式(I)或(Ia)的化合物,其中R4为C1-C6烷基或任选取代的苯环或任选取代的杂芳环,其具有5或6个环原子并包含1至3个选自O、S和N的杂原子。特别优选地,R4为由优选自F、Br、Cl、I、甲基或氰基的1或2个取代基取代的苯环(如4-甲基苯基)。
更优选式(I)或(Ia)的化合物,其中R5为烷基、杂烷基、杂环烷基、杂烷基环烷基或杂芳烷基,全部这些基团可以是取代的。
更优选式(I)或(Ia)的化合物,其中R5选自以下基团:C1-C6烷基;杂烷基,其包含1-6个碳原子和1、2或3个选自O、S和N的杂原子;杂烷基环烷基,其包含C1-C4烷基或C1-C4杂烷基以及含有5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂环烷基;杂芳烷基,其包含C1-C4烷基或C1-C4杂烷基以及含有5或6个环原子的任选取代的杂芳基,且所述环原子包含1、2或3个选自O、S和N的杂原子;任选取代的杂芳基,其包含5或6个环原子,且所述环原子包含1、2或3个选自O、S和N的杂原子;以及任选取代的杂环烷基,其包含5或6个环原子和1、2或3个选自O、S和N的杂原子。
更优选式(I)和/或(Ia)的化合物的二聚体,所述二聚体经由杂烷基、杂烷基环烷基或杂芳烷基连接,优选经由R5连接。
更优选式(I)或(Ia)的化合物,其中R5为C1-C6烷基;杂烷基,其包含1-6个碳原子和1、2或3个选自O、S和N的杂原子;杂烷基环烷基,其包含C1-C4烷基以及含有5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂环烷基;杂芳烷基,其包含C1-C4烷基以及含有5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂芳基。
更优选式(I)或(Ia)的化合物,其中R6为氢或C1-C4烷基,特别是氢。
更优选式(I)或(Ia)的化合物,其中R5和R6一起与它们所连接的氮原子形成任选取代(如由1、2或3个取代基)的杂环烷基环,其包含4、5、6或7个环原子和1、2或3个选自O、S和N的杂原子。
更优选地,R5和R6一起与它们所连接的氮原子形成以下基团:
其中,m为0、1或2;o为0、1或2;m与o之和优选为0至3;Q为N-R6x、CR6yR6z、C=O、-CO-NR6x-、-NR6x-CO-NR6y-、-SO2-NR6x-、-SO-NR6x-或-O-CO-NR6x-,其中R6x、R6y和R6z彼此独立地为氢原子、OH、NH2、SH或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基。
优选地,Q为N-CO-R6a、NR6b或CHR6c,其中R6a为C1-C6烷基、C1-C6杂烷基、NH2、任选取代的苯基或氢;R6b为任选取代的苯基或包含5或6个环原子的任选取代的杂芳基,且所述环原子包含1或2个选自O、S或N的杂原子;R6c为C1-C6杂烷基、NH2或OH。
更优选地,Q为N-CO-NHR6d、N-COOR6e、N-SO2R6f、N-SO2NHR6g、N-NHCOR6h、CH-NH2、CH-OH、CH-SH、CH-NH-COR6i、CO、CONH、NHCONH、SO2NH、OCONH、CH-COOH、CH-COOR6j、CH-COR6k或CH-SO2R6l,其中R6d、R6e、R6f、R6g、R6h、R6i、R6j、R6k和R6l彼此独立地为氢原子、OH、NH2、SH或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基,特别是氢或C1-C6烷基或C1-C6杂烷基。
优选地,Q为N-CO-R6a,其中R6a优选为NH2、C1-C6烷基、NH-C1-C6烷基或N(C1-C6烷基)2。
更优选地,基团Q包含氢键受体(特别是具有孤电子对的原子或基团,如电负性原子,如氟、氧或氮)。
更优选地,o为1,且m为1。
特别优选地,m为1,o为1,且Q为N-CO-R6a。因此,R6a优选为C1-C4烷基或NH-C1-C4烷基(如CH3或NHCH2CH3)。
特别优选式(I)或(Ia)的化合物,其中R5和R6一起为任选取代的(如由1、2或3个取代基,如=O)哌嗪环的一部分。
更优选式(I)或(Ia)的化合物,其中R5和R6一起为包含5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代(如由1、2或3个取代基)的杂环烷基环的一部分。
更优选式(Ic)的化合物:
其中,W为任选取代的苯环或具有5或6个环原子的任选取代的杂芳基,且所述环原子包含1或2个选自O、S和N的杂原子;且其中R1、R3a、R4、R5、R7、R8、E、X、Y和n如上所定义。
特别优选式(Ic)的化合物,其中W为任选取代的苯环(优选由1、2或3个选自F、Cl和Br的卤原子取代);R1为任选取代的苄基(优选由1、2或3个选自F、Cl和Br的卤原子取代);X为S;Y为CONR6;n为1;R3a为氢;R4为任选取代的苯基(优选未取代,或由甲基取代,特别是在对位上取代);R7和R8为氢;E为CH;且R5和R6如上所定义;特别优选地,R5和R6一起为任选取代的哌嗪环(特别是如上所定义)的一部分。
更优选式(Id)的化合物:
其中R1、R3a、R3b、R3c、R4、R5、R6、E和X如上所定义。
特别优选式(Id)的化合物,其中R1为任选取代的苄基(优选由1、2或3个选自F、Cl和Br的卤原子取代);X为S;R3a为氢;R3b为Cl;R3c为氢;R4为任选取代的苯基(优选未取代,或由甲基取代,特别是在对位上取代);E为CH;且R5和R6如上所定义;特别优选地,R5和R6一起为任选取代的哌嗪环(特别是如上所定义)的一部分。
更优选式(Ie)的化合物:
其中R1、R3a、R3b、R3c、R4、E、Q、m、o和X如上所定义。
特别优选式(Ie)的化合物,其中R1为任选取代的苄基(优选由1、2或3个选自F、Cl和Br的卤原子取代);X为S;R3a为氢;R3b为Cl;R3c为氢;R4为任选取代的苯基(优选未取代,或由甲基取代,特别是在对位上取代);E为CH;Q为N-CO-R6a,其中R6a优选为C1-C6烷基、NH-C1-C6烷基或N(C1-C6烷基)2;m为0、1或2;o为0、1或2;且m与o之和优选为0至3。特别优选地,m为1,o为1,且Q为N-CO-R6a,其中R6a优选为C1-C46烷基或NH-C1-C4烷基(如CH3或NHCH2CH3)。
更优选式(If)的化合物
其中A、Ar、R3a、R3b、R3c、E、X、R4a和R6a如上所定义。
特别优选式(If)的化合物,其中X为S;R3a为氢;R3b为Cl;R3c为氢;R4a为氢或甲基;E为CH;A为CH2;Ar为由一个或两个选自F、Cl和Br的卤原子取代的苯基;且R6a为C1-C4烷基或NH-C1-C4烷基(如CH3或NHCH2CH3)。
本发明更优选的实施方式涉及式(I)或(Ia)的化合物,其中
R1为芳基、杂芳基、芳基烷基或杂芳基烷基,它们全部可由F、Br、Cl、I、甲基或氰基取代,
R2为氢,
R3为芳基、杂芳基、芳基烷基或杂芳基烷基,它们全部可由F、Br、Cl、I、甲基或氰基取代,
R4为芳基、杂芳基、芳基烷基或杂芳基烷基,
R5和R6独立地选自氢、烷基、杂烷基、芳基、烯基、炔基(akinyl)、环烷基、杂环烷基、芳基、杂芳基、芳基烷基或杂芳基烷基,
或者其中R5和R6可为一个杂芳基、杂环烷基、杂烷基环烷基或杂芳基烷基环体系的一部分,
且其中其它残基和基团如上所定义。
本发明更优选的实施方式涉及式(I)或(Ia)的化合物,其中
R1为芳基、杂芳基、芳基烷基或杂芳基烷基,它们全部可由F、Br、Cl、I、甲基或氰基取代,
R2和R3一起为杂芳基、杂芳烷基、杂环烷基或杂烷基环烷基环体系的一部分,例如但不限于1,3-二氢吲哚、1,3-二氢-吲哚-2-酮、2,3-二氢-1H-吲唑、四氢喹啉、四氢喹啉-2-酮、3,4-二氢-1H-喹啉-2-酮、3,4-二氢-1H-喹唑啉-2-酮,它们全部可由F、Br、Cl、I、甲基或氰基取代,
R4选自芳基、杂芳基、芳基烷基或杂芳基烷基,
R5和R6独立地选自氢、烷基、杂烷基、芳基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、芳基烷基或杂芳基烷基,或者
其中R5和R6也可为一个杂芳基、杂环烷基、杂烷基环烷基或杂芳基烷基环体系的一部分,
且其中其它残基和基团如上所定义。
本发明的另一优选实施方式涉及式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物,其中R3和带有硫烷基(sulfanyl)(即带有X的基团)的R4基团为顺式(特别是当R2为H时)。
特别优选的实施方式为式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的对映异构纯化合物。
更优选以下化合物:
4-[1-(4-溴-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-3-对甲苯基硫烷基-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺
即,以下非对映异构体:
特别是以下非对映异构体:
4-[1-(4-溴-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-3-对甲苯基硫烷基-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺
更优选以下化合物:
4-(4-乙酰基-哌嗪-1-羰基)-1-(4-氯-3-氟-苄基)-5-(6-氯-1H-吲哚-3-基)-4-苯基硫烷基-吡咯烷-2-酮
即,以下非对映异构体:
特别是以下非对映异构体:
更优选以下化合物:
4-[1-(4-氯-3-氟-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-3-苯基硫烷基-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺
即,以下非对映异构体
特别是以下非对映异构体:
优选地,描述于以下文献的化合物排除在本申请和/或专利的范围外:
1.Ng et al.Angew.Chem.Int.Ed.2007,46,5352-5355,和
2.Ng et al.Organic Letters 2006,Vol.8,No.18,3999-4002(及其支持信息)。
更优选地,一种或多种以下化合物排除在本申请和/或专利外:
更优选地,以下化合物也排除在本申请和/或专利外:
其中R3为对-C6H5CH2OH(或与固相结合的其衍生物,如Ng et al.Angew.Chem.Int.Ed.2007,46,5352-5355所述),R1选自以下基团:
R4为对-C6H5CH3,且R5选自以下基团:
全部那些化合物描述于Ng et al.Angew.Chem.Int.Ed.2007,46,5352-5355。
更优选地,排除式(I)或(Ia)的化合物,其中R3为对-C6H5CH2OH(或与固相结合的其衍生物,如Ng et al.Angew.Chem.Int.Ed.2007,46,5352-5355所述)。
更优选地,以下化合物也排除在本申请和/或专利外(X=H,I):
本发明还提供了药物组合物,所述药物组合物包含如本文所定义的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物或其药学可接受的酯、前药、水合物、溶剂合物或盐,任选地与药学可接受的载体组合。
本发明更优选的实施方式涉及药物组合物,所述药物组合物包含如本文所定义的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物或其药学可接受的酯、前药、水合物、溶剂合物或盐,任选地与药学可接受的载体组合,所述药物组合物还包含一种或多种其它抗肿瘤剂,其中所述抗肿瘤药特别地选自16-氮杂-埃博霉素B、阿地白介素、氨磷汀、Aranose、贝伐单抗、博来霉素(Bleocin)、博来霉素(Bleomycin)、BMS-184476、硼替佐米、骨化三醇、卡莫司汀、卡纳替尼、坎磷酰胺、卡培他滨、卡铂、卡莫司汀、头孢克肟、头孢曲松、塞来考昔、西莫白介素、西妥昔单抗、环孢素、顺铂、氯膦酸盐、环磷酰胺、阿糖胞苷、Deoxorubicin、去氧埃博霉素B、己烯雌酚、二氟替康、多西他赛、多柔比星、依达曲沙、乙法昔罗、EKB-569、表柔比星、依帕珠单抗、厄洛替尼、依托泊苷、ET-18-OCH3、依沙替康、氟达拉滨、氟脲嘧啶、亚叶酸、加柔比星、吉非替尼、吉西他滨、吉妥珠单抗、吉马替康、葡磷酰胺、格拉司琼、高三尖杉酯碱、透明质酸、伊班膦酸盐、替伊莫单抗、异环磷酰胺、伊马替尼、干扰素α、干扰素α-2a、干扰素α-2b、伊立替康、异黄酮、异维A酸、伊沙匹隆、酮康唑、拉帕替尼、来氟米特、来格司亭、亚叶酸(Leucovorin)、来昔决南(Lexidronam)、利奈唑胺、洛美曲索、勒托替康、MEN10755、甲氨蝶呤、丝裂霉素、奈立膦酸盐、尼美舒利、硝酸甘油、06-苄基鸟嘌呤、奥美拉唑、奥他赛、奥沙利铂、紫杉醇、帕妥匹龙、培非司亭(Pegfilgrastim)、培非司亭(PEG-filgrastim)、培利替尼、培美曲塞、喷司他丁、哌立福辛、普来曲塞、Polyprenoic acid、奎奴普丁、雷洛昔芬、雷替曲塞、雷莫司琼、维甲酸、利塞膦酸盐、利妥昔单抗、罗非考昔、卢比替康、S-9788、沙柔比星、沙格司亭、沙铂、SN-38、索拉非尼、环庚烷异羟肟酸(Suberanilohydroxamic acid)、马来酸舒尼替尼、他莫昔芬、泰索帝、他扎罗汀、替加氟、替莫唑胺(Temozolamide)、替米利芬、河豚毒素、沙利度胺、替匹法尼、托泊替康、曲贝替定、曲妥珠单克抗、Traszutumab、维A酸、伐他拉尼、长春新碱、长春瑞滨、Vinscristine、ZD-6474、唑来膦酸盐或佐舒喹达。
在优选的实施方式中,本发明的化合物使癌细胞对放疗和/或化疗敏感,然而它们对健康细胞上表现出化疗保护和/或放疗保护的活性。因此,可更好地调节这些疗法的剂量。
本发明更优选的实施方式涉及药物组合物,所述药物组合物包含本文所定义的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的一种或多种化合物或其药学可接受的酯、前药、水合物、溶剂合物或盐,任选地与药学可接受的载体组合。药物组合物任选地包含一种或多种抗病毒剂。优选地,抗病毒剂选自3TC、阿巴卡韦、阿德福韦酯、阿昔洛韦、氨普奈韦、金刚烷胺、Amoxovir、AZT、克来夫定、地位韦啶、d4T、恩曲他滨、恩替卡韦、泛昔洛韦、更昔洛韦、茚地那韦、拉米夫定、奈非那韦、奈韦拉平、奥塞米韦(Oseltamavir)、金刚乙胺、利托那韦、沙奎那韦、Septrin、替比夫定、替诺福韦、伐昔洛韦、伐托他滨、伐洛他滨或扎那米韦。
本发明的另一目的提供了本文所定义的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物或本文所定义的药物组合物,以用于制备用于治疗癌症和/或病毒感染的药物。
选自本发明的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物为例如HDM2和/或MDMX配体,并且表现出的对HDM2和/或MDMX的结合亲合力为约1nM至约100μM,优选约1nM至约10μM,特别是约1nM至约1μM,这防止p53与其它蛋白结合,在基于细胞的测定中,特别是本文所述的测定中抑制增殖且诱导凋亡。
本发明的化合物可用于治疗或控制细胞增殖性病症,特别是肿瘤学病症。这些化合物和包含所述化合物的制剂可用于治疗或控制实体瘤,如乳腺、结肠、肺和前列腺肿瘤,以及骨肉瘤、急性髓细胞白血病、散发性子宫内膜癌、黑素瘤、恶性黑素瘤、软组织肉瘤、B细胞慢性淋巴细胞白血病、胃癌、宫颈癌、肝细胞癌和结肠直肠癌。
本文所述的化合物可特别用于治疗和/或预防与HDM2和/或MDMX过表达有关的癌症。
因此,本发明的化合物可特别用于治疗和/或预防与MDM2和/或MDMX有关的以下癌症:
MDM2在7%的所有人类癌症中扩增。在19种肿瘤中观察到基因扩增,在软组织肿瘤(20%)、骨肉瘤(16%)和食管癌(13%)中观察到的频率最高。显示出MDM2扩增比p53突变更高的发生率的肿瘤是软组织肿瘤、睾丸生殖细胞癌和成神经细胞瘤(Momand et al,NAR,1998)。在MDM2启动子中存在的天然多态性(SNP309)导致MDM2转录和翻译的增加。这些人肿瘤中MDM2扩增的总体频率为7%。这在血液恶性肿瘤中是普通事件。对MDMD2抑制剂敏感的具有野生型p53基因的癌症包括:B细胞CLL(慢性淋巴细胞白血病)(Coll-Muler et al,Blood,2006)、AML(Kojima et al,Blood,2005)、多发性骨髓瘤(Shruhmer et al,Blood,2005)、成神经细胞瘤(Cattelani et al,CCR,2008)、霍奇金淋巴瘤(Drakos et al,CCR,2007)、骨肉瘤和前列腺癌(Vassilev et al,Science,2004)、卡波西肉瘤(Sarek,J.Clinic.Invest.,2007)、横纹肌肉瘤(Miyachi et al,CCR,2009)、RCC(肾细胞癌)(Roberts et al,CR,2009)、鳞状细胞癌和食管癌(Cescon et al,CCR,2009)、皮肤黑素瘤(Firoz et al,CCR,2009)、成视网膜细胞瘤(Laurie et al,Nature,2006)。还有具有野生型p53基因的胰腺癌对MDM2抑制剂敏感的证据(提交公开)。
表1.28种人肿瘤MDM2基因扩增频率的总结(Momand et al,NAR,1998)
所分析的肿瘤样品的总数为3889,且平均MDM2基因扩增频率为7.2%。
a所分析样品的数量。
b未指明软组织来源的肉瘤。
c不属于所列分类的软组织肿瘤。在任何单个分类中,样品的数量小于5。
人MDMX基因位于在人癌症中频繁扩增的染色体区1q32。其在4%的神经胶质瘤(Riemenschneider,CR 1999)和5%的乳腺癌(Danovi et al,MCB,2004)中有记载。最近,已发现约60%的成视网膜细胞瘤(Laurie,Nature 2006)具有HDMX过表达。而且,发现HDMX基因在宫颈和卵巢癌细胞系的许多亚类中过表达(Ramos,CR 2001)。不同来源原发肿瘤中HDMX表达的系统性分析揭示出具有HDMX过表达的大范围的人癌症。
表1.500个人肿瘤的HDMX基因扩增频率的总结(Danovi et al,MCB,2004)
本发明的化合物的治疗有效量是指有效预防、减轻或改善疾病症状或延长治疗个体存活的化合物的量。本领域技术人员可确定治疗有效量。
本发明化合物的治疗有效量或剂量可在宽限度内变化,且可由本领域已知方法确定。在包括给予的具体化合物、给药途径、所治疗的疾病状况以及治疗的患者的各种具体情况中,可根据个体需要调节该剂量。
式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的充分碱性的化合物的药理学可接受的盐的实例为生理可接受的无机酸的盐,如盐酸、氢溴酸、硫酸和磷酸的盐;或有机酸的盐,如甲磺酸、对甲苯磺酸、乳酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸和水杨酸的盐。此外,式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的充分酸性的化合物可形成碱或碱土金属盐,如钠、钾、锂、钙或镁盐;铵盐;或有机碱盐,如甲胺、二甲胺、三甲胺、三乙胺、乙二胺、乙醇胺、氢氧化胆碱、甲基葡胺(meglumin)、哌啶、吗啉、三(2-羟乙基)胺、赖氨酸或精氨酸盐;它们全部是式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的盐的实例。式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物可为溶剂化的,特别是水合的。水化/水合可在制备过程中发生,或由初始无水的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物的吸湿性所产生。溶剂合物和/或水合物可以如固体或液体形式存在。
应当理解,式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的某些化合物可具有互变异构形式,其中可能仅有一种在以下说明书中具体提及或描述;不同的几何异构体(通常称为顺/反异构体,更通常称为(E)和(Z)异构体);或因一个或多个手性碳原子而导致的不同的光学异构体(通常基于Cahn-Ingold-Prelog或R/S体系命名)。全部这些互变异构形式、几何或光学异构体(以及外消旋物和非对映异构体)和多晶型形式包括在本发明中。因为式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物可包含不对称C原子,所以它们可以非手性化合物、非对映异构体的混合物、对映异构体的混合物或光学纯的化合物存在。本发明包括全部纯的对映异构体和全部纯的非对映异构体以及它们的任何混合比例的混合物。
式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物,它们各自的药学可接受的盐、溶剂合物和水合物以及制剂和药物组合物的治疗用途也在本发明的范围内。
本发明的药物组合物包含式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的至少一种化合物作为活性成分,以及任选的载体物质和/或辅助剂。
本发明还涉及前药,其由式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物和在生理条件下裂解的至少一种药学可接受的保护基团组成,如本文所定义的烷氧基-、芳基烷氧基-、酰基-、酰氧基甲基(如新戊酰氧基甲基)、2-烷基-、2-芳基-或2-芳基烷氧基-羰基(arylalkyl-oxycarbonyl)-2-亚烷基乙基或酰氧基,如乙氧基、苄氧基、乙酰基或乙酰氧基,或特别是对于携带羟基(-OH)的式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物:硫酸酯、磷酸酯(-OPO3或-OCH2OPO3)或氨基酸的酯。特别优选式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物的羟基的前药。
如上所述,包含式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物、它们的溶剂合物、盐或制剂的治疗用试剂也包含在本发明的范围内。通常,式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物通过使用本领域已知和可接受的方法单独或与任何其它治疗剂联合给药。
对于口服给药,这样的治疗用试剂可通过以下途径之一进行给药:口服,如片剂、糖衣丸、包衣片、丸剂、半固体、诸如软和硬明胶胶囊的软或硬胶囊、水性或油性溶液、乳液、混悬剂或糖浆;非肠道,包括静脉内、肌肉内和皮下注射,如可注射溶液或混悬剂;直肠,如栓剂;经吸入或吹入,如散剂、微晶或喷雾(如液体气溶胶);透皮,如经由透皮给药系统(TDS),如包含活性成分的膏剂;或鼻内。为了生产这样的片剂、丸剂、半固体、包衣片、糖衣丸和诸如明胶的硬胶囊,可以将治疗用产品可与药学惰性的无机或有机赋形剂混合,如乳糖、蔗糖、葡萄糖、明胶、麦芽、硅胶、淀粉或其衍生物、滑石、硬脂酸或它们的盐、脱脂奶等。为了生产软胶囊,可使用赋形剂,如植物油、石油、动物油或合成油、蜡、脂肪、多元醇。为了生产液体溶液、乳液或混悬剂或糖浆,可使用赋形剂,如水、醇、盐水、水性葡萄糖、多元醇、甘油、脂质、磷脂、环糊精、植物油、石油、动物油或合成油。特别优选脂质,且更优选磷脂(优选天然来源;特别优选粒径为300至350nm),优选磷酸缓冲盐水(pH=7至8,优选7.4)。对于栓剂,可使用赋形剂,如植物油、石油、动物油或合成油、蜡、脂肪和多元醇。对于气溶胶制剂,可使用适用于此目的的压缩气体,如氧气、氮气和二氧化碳。药用试剂也可包含用于保存、稳定的添加剂,如UV稳定剂、乳化剂、甜味剂、芳香剂、改变渗透压的盐、缓冲剂、包衣添加剂和抗氧化剂。
通常,在向体重约80kg的成人口服或非肠道给药的情况下,每天约10mg至约10,000mg、优选约20mg至约1,000mg的剂量应是合适的,尽管在指明时可超过上限。每日剂量可作为单一剂量或以多次剂量给药,或对于非肠道给药,可经连续灌注或皮下注射给药。
本发明的化合物可根据以下步骤制备:
4-硫烷基-吡咯烷-2-酮骨架的合成基于伯胺(II)、醛或酮(III)与马来酸酐(IV)和硫醇(V)之间的四组分反应(4CR)。根据J.Wei,J.T.Shaw Org.Lett.2007,9,4077,反应优选通过化学剂量的起始原料在甲苯中于回流下进行。所得4-硫烷基-吡咯烷-2-酮(VI)以可接受的良好产率作为非对映异构混合物形成。通常,将两种非对映异构体通过制备HPLC色谱分开和分离。式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的最终4-硫烷基-吡咯烷-2-酮酰胺经由氨解获得,其利用根据M.Bodanszky,A.Bodanszky,The practice of Peptide Synthesis 2nd Edition,p 102,Springer-Verlag Berlin Heidelberg New York(1994)合成的式(VII)的对应五氟苯基酯的胺(VIII)。式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的这些化合物可进一步修饰,如从酸转化为酯或盐,从胺转化为盐,或通过使取代基R1至R6中的保护基团裂解。
此外,式(I)的化合物可通过下述步骤制备,其中n为0:
1)M.R.Linder,J.Podlech,Organic Letters 2001,Vol.3,No.12,1849-1851;
2)J.Podlech,M.R.Linder,J.Org.Chem.1997,62,5873-5883;
3)J.Cesar,M.Sollner Dolenc,Tetrahedron Letters 42(2001)7099-7102。
本文所述的反应步骤也可在手性催化剂如脯氨酸衍生的催化剂的存在下进行(如www.organic-chemistry.org/Highlights/2007/25March.shtm所述),以获得对应的对映异构纯的化合物。
实施例
本发明涵盖以下实施例:
实施例1
合成5-氧代-3-硫烷基-吡咯烷-3-甲酰胺(I)的一般步骤:
于密封管中,将马来酸酐(IV,1mmol)、硫醇(V,1mmol)、醛或酮(III,1mmol)和胺(II,1mmol)在甲苯(8mL)中加热至150℃,保持24小时。冷却至室温后,将溶液在真空下浓缩。使用洗脱剂(乙酸乙酯∶甲醇=9∶1至1∶1),在硅胶上纯化,得到式(VI)的化合物的非对映异构混合物。随后,将两种非对映异构体通过制备HPLC色谱分离。制备分离通常用乙腈-水洗脱剂(+0.1%甲酸)在RP Polaris C18柱(长度:250mm,直径:21mm;粒径:5μm)上进行。通常,使用等度体系(70%乙腈:30%水)观察到良好的分离(两种顺/反非对映异构体的保留时间相差1至2分钟)。
在0℃下,向1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(1.5mmol)在8mL乙酸乙酯中的悬浮液加入五氟苯酚(3mmol)。10分钟后,在0℃下加入5-氧代-吡咯烷-3-羧酸VI(1mmol),并将反应混合物在室温下搅拌1小时。将溶剂蒸发后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶己烷=1∶2),以获得无色油状的对应的5-氧代-吡咯烷-3-羧酸五氟苯酯VII。
在室温下,向5-氧代-吡咯烷-3-羧酸五氟苯酯VII(0.5mmol)在2mL无水THF中的悬浮液加入期望的胺VIII(0.5mmol)。将反应混合物在室温下搅拌1小时。随后,加入20mL二氯甲烷。将所得的有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥,并在真空下去除溶剂。最后,将粗产物在硅胶上通过合适的洗脱剂用色谱纯化,以获得期望的白色固体状5-氧代-吡咯烷-3-甲酰胺。
实施例2
根据实施例1的一般步骤,制备以下化合物:
2.1 顺-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C34H30Cl2N4O2S。分子量=629.599。[M+H]+观察值=629.1。分离产率34.08%。
2.2 反-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C34H30Cl2N4O2S。分子量=629.599。[M+H]+观察值=629.1。分离产率3.78%。
2.3 反-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(苯硫-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H29Cl2N3O2S2。分子量=634.638。[M+H]+观察值=656.0。分离产率3.04%。
2.4 顺-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(苯硫-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H29Cl2N3O2S2。分子量=634.638。[M+Na]+观察值=656.0。分离产率27.34%。
2.5 反-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-(4-氯苯基)-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H28Cl2N4O2S。分子量=615.572。[M+H]+观察值=615.1。分离产率2.78%。
2.6 顺-2-(6-氯-1-甲基-1H-吲哚-3-基)-1-(4-氯苯基)-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H28Cl2N4O2S。分子量=615.572。[M+H]+观察值=615.1。分离产率25.06%。
2.7 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H28Cl2N4O2S。分子量=615.572。[M+H]+观察值=615.2。分离产率12.50%。
2.8 反-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代-N-(吡啶-2-基甲基)吡咯烷-3-甲酰胺。分子式=C33H28Cl2N4O2S。分子量=615.572。[M+H]+观察值=615.2。分离产率4.56%。
2.9 反-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34Cl2N4O3S。分子量=637.619。[M+H]+观察值=637.2。分离产率7.30%。
2.10 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34Cl2N4O3S。分子量=637.619。[M+H]+观察值=637.2。分离产率7.18%。
2.11 反-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯-2-甲基苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.2。分离产率5.18%。
2.12 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯-2-甲基苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.2。分离产率7.74%。
2.13 反-2-(6-氯-1H-吲哚-3-基)-1-[(3-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34Cl2N4O3S。分子量=637.619。[M+H]+观察值=637.2。分离产率2.82%。
2.14 顺-2-(6-氯-1H-吲哚-3-基)-1-[(3-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34Cl2N4O3S。分子量=637.619。[M+H]+观察值=637.2。分离产率3.81%。
2.15 反-2-(6-氯-1H-吲哚-3-基)-1-[(1R)-1-(4-氯苯基)乙基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.2。分离产率2.65%。
2.16 顺-2-(6-氯-1H-吲哚-3-基)-1-[(1R)-1-(4-氯苯基)乙基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.2。分离产率1.36%。
2.17 反-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-氯苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H33Cl3N4O3S。分子量=672.064。[M+H]+观察值=671.1。分离产率6.65%。
2.18 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-氯苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H33C13N4O3S。分子量=672.064。[M+H]+观察值=673.1。分离产率19.04%。
2.19 反-1-苄基-2-(6-氯-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H35ClN4O3S。分子量=603.174。[M+H]+观察值=603.0。分离产率4.31%。
2.20 顺-1-苄基-2-(6-氯-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H35ClN4O3S。分子量=603.174。[M+H]+观察值=603.0。分离产率4.59%。
2.21 反-2-(6-氯-1H-吲哚-3-基)-1-[(1S)-1-(4-氯苯基)乙基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=650.9。分离产率4.91%。
2.22 顺-2-(6-氯-1H-吲哚-3-基)-1-[(1S)-1-(4-氯苯基)乙基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.0。分离产率4.86%。
2.23 反-2-(6-溴-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36BrClN4O3S。分子量=696.097。[M+H]+观察值=697.1。分离产率9.27%。
2.24 顺-2-(6-溴-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36BrClN4O3S。分子量=696.097。[M+H]+观察值=697.0。分离产率11.14%。
2.25 反-2-(5-溴-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34BrClN4O3S。分子量=682.07。[M+H]+观察值=682.9。分离产率3.71%。
2.26 顺-2-(5-溴-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34BrClN4O3S。分子量=682.07。[M+H]+观察值=682.8。分离产率4.65%。
2.27 顺-2-(6-氯-1H-吲哚-3-基)-1-[(6-氯吡啶-3-基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C32H33Cl2N5O3S。分子量=638.607。[M+H]+观察值=638.0。分离产率3.76%。
2.28 反-2-(6-氯-1H-吲哚-3-基)-1-[(6-氯吡啶-3-基)甲基]-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C32H33Cl2N5O3S。分子量=638.607。分离产率1.46%。
2.29 反-4-{[2-(6-氯-1H-吲哚-3-基)-1-[(1S)-1-(4-氯苯基)乙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28Cl2N4O3S。分子量=607.55。[M+H]+观察值=607.2。分离产率4.44%。
2.30 顺-4-{[2-(6-氯-1H-吲哚-3-基)-1-[(1S)-1-(4-氯苯基)乙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28Cl2N4O3S。分子量=607.55。[M+H]+观察值=607.2。分离产率4.09%。
2.31 反-4-{[2-(6-氯-1H-吲哚-3-基)-1-[(1R)-1-(4-氯苯基)乙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28Cl2N4O3S。分子量=607.55。[M+H]+观察值=608.8。分离产率2.62%。
2.32 顺-4-{[2-(6-氯-1H-吲哚-3-基)-1-[(1R)-1-(4-氯苯基)乙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28Cl2N4O3S。分子量=607.55。[M+H]+观察值=606.9。分离产率1.89%。
2.33 反-1-[(4-氯苯基)甲基]-2-(6-氟-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34ClFN4O3S。分子量=621.164。[M+H]+观察值=621.0。分离产率2.98%。
2.34 顺-1-[(4-氯苯基)甲基]-2-(6-氟-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-5-氧代-3-(苯基硫烷基)吡咯烷-3-甲酰胺。分子式=C33H34ClFN4O3S。分子量=621.164。[M+H]+观察值=621.0。分离产率4.72%。
2.35 顺-4-{[2-(6-溴-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28BrClN4O3S。分子量=652.001。[M+H]+观察值=651.3。分离产率8.00%。
2.36 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36BrClN4O3S。分子量=696.097。[M+H]+观察值=697.2。分离产率8.39%。
2.37 反-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36BrClN4O3S。分子量=696.097。[M+H]+观察值=697.1。分离产率3.45%。
2.38 顺-2-(6-溴-1H-吲哚-3-基)-1-[(4-溴苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36Br2N4O3S。分子量=740.548。[M+H]+观察值=740.5。分离产率10.00%。
2.39 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯-3-氟苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H35Cl2FN4O3S。分子量=669.636。[M+H]+观察值=669.1。分离产率14.85%。
2.40 反-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯-3-氟苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H35Cl2FN4O3S。分子量=669.636。[M+H]+观察值=669.0。分离产率4.48%。
2.41 顺-2-(6-氯-5-氟-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H35Cl2FN4O3S。分子量=669.636。[M+H]+观察值=669.1。分离产率4.88%。
2.42 反-2-(6-氯-5-氟-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H35Cl2FN4O3S。分子量=669.636。[M+H]+观察值=669.1。分离产率1.08%。
2.43 顺-5-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-4-{[4-(2-羟乙基)哌嗪-1-基]羰基}-4-[(4-甲基苯基)硫烷基]吡咯烷-2-酮。分子式=C33H34Cl2N4O3S。分子量=637.619。[M+H]+观察值=637.0。分离产率7.67%。
2.44 顺-2-(6-氯-1H-吲唑-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H35Cl2N5O3S。分子量=652.634。[M+H]+观察值=652.0。分离产率6.04%。
2.45 顺-2-(6-氯-1H-吲哚-3-基)-1-[(4-氯苯基)甲基]-3-[(4-甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C34H36Cl2N4O3S。分子量=651.646。[M+H]+观察值=651.1。分离产率7.97%。
2.46 顺-1-[(4-溴苯基)甲基]-5-(6-氯-1H-吲哚-3-基)-4-{[4-(2-羟乙基)哌嗪-1-基]羰基}-4-[(4-甲基苯基)硫烷基]吡咯烷-2-酮。分子式=C33H34BrClN4O3S。分子量=682.07。[M+H]+观察值=683.0。分离产率5.35%。
2.47 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-(2,3-二羟丙基)-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C30H29BrClN3O4S。分子量=642.991。[M+Na]+观察值=668.1。分离产率6.92%。
2.48 顺-4-{[1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-基]羰基}哌嗪-2-酮。分子式=C31H28BrClN4O3S。分子量=652.001。[M+H]+观察值=653.1。[M+Na]+观察值=675.3。分离产率3.39%。
2.49 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-N-[2-(吗啉-4-基)乙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H34BrClN4O3S。分子量=682.07。[M+H]+观察值=683.1。分离产率7.30%。
2.50 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-N-[4-(吗啉-4-基)丁基]-5-氧代吡咯烷-3-甲酰胺。分子式=C35H38BrClN4O3S。分子量=710.123。[M+H]+观察值=711.0。分离产率7.08%。
2.50 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-(4-羟丁基)-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C31H31BrClN3O3S。分子量=641.018。[M+Na]+观察值=664.2。分离产率7.32%。
2.51 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-甲基苯基)硫烷基]-N-(1-甲基哌啶-4-基)-5-氧代吡咯烷-3-甲酰胺。分子式=C33H34BrClN4O2S。分子量=666.071。[M+H]+观察值=668.2。分离产率7.51%。
2.52 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(4-乙基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C35H38BrClN4O3S。分子量=710.123。[M+H]+观察值=711.1。分离产率17.16%。
2.53 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(3,4-二甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C35H38BrClN4O3S。分子量=710.123。[M+H]+观察值=711.0。分离产率9.74%。
2.52 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-3-[(2,4-二甲基苯基)硫烷基]-N-[3-(吗啉-4-基)丙基]-5-氧代吡咯烷-3-甲酰胺。分子式=C35H38BrClN4O3S。分子量=710.123。[M+H]+观察值=711.0。分离产率6.38%。
2.53 反-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-3-[(4-硝基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H33BrClN5O5S。分子量=727.068。[M+H]+观察值=726.0。分离产率3.00%。
2.54 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-[3-(吗啉-4-基)丙基]-3-[(4-硝基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C33H33BrClN5O5S。分子量=727.068。[M+H]+观察值=727.9。分离产率0.41%。
2.55 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-[(2R)-1-羟丙-2-基]-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C30H29BrClN3O3S。分子量=626.992。[M+Na]+观察值=650.6。分离产率8.24%。
2.56 顺-1-[(4-溴苯基)甲基]-2-(6-氯-1H-吲哚-3-基)-N-[(2S)-1-羟丙-2-基]-3-[(4-甲基苯基)硫烷基]-5-氧代吡咯烷-3-甲酰胺。分子式=C30H29BrClN3O3S。分子量=626.992。[M+Na]+观察值=650.2。分离产率8.04%。
实施例3
1)4-[5-氧代-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺化合物的合成
(顺)-4-[1-(4-溴-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-3-对甲苯硫烷基-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺[PXN727-d1]的合成
多组分反应(步骤1):
在Dean-Stark条件下,将马来酸酐2(6mmol)、硫醇4(6mmol)、醛3(6mmol)和胺1(6mmol)在甲苯(50mL)中加热至150℃,保持24小时。冷却至室温后,将溶液在真空下浓缩。在硅胶上纯化(乙酸乙酯∶甲醇=9∶1至1∶1),得到非对映异构体混合物5(1.48g,46%)。
文献:J.Wei,J.T.Shaw Org.Lett.2007,9,4077。
非对映异构混合物的分离:
上述反应顺序获得比例为50∶50的两种非对映异构体d1和d2。它们使用以下条件通过制备HPLC色谱分离:
-等度洗脱(70%乙腈∶30%水,0.1%HCOOH),21mL/min,Rt=7.62min。
分离也可用甲醇/水混合物进行。
溶液的真空浓缩获得淡黄色固体状期望的纯非对映异构体6(顺式,d1)(528.9mg,33.6%)。
6的制备总产率:15.47%(顺式异构体d1的MCR和分离)
五氟苯酯的形成:
在0℃下,向1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(267mg,1.4mmol)在8mL乙酸乙酯中的悬浮液加入五氟苯酚(512mg,2.8mmol)。10分钟后,在0℃下加入化合物6(528.9mg,0.9mmol),并将反应混合物在室温下搅拌1小时。将溶剂蒸发后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶己烷=1∶2→1∶1),以获得无色油状的对应的五氟苯酯7(632.0mg,92.5%)。
文献:
M.Bodanszky,A.Bodanszky,The practice of Peptide Synthesis 2nd Edition,p 102,Springer-Verlag Berlin Heidelberg New York(1994)。
酰胺偶联:
在室温下,向五氟苯酯7(1.3g,1.8mmol)在16mL无水THF中的悬浮液加入哌嗪(7.2mmol)。将反应混合物在室温下搅拌20小时。随后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶甲醇=9∶1→1∶1),以获得白色固体状期望的哌嗪酰胺8(977.8mg,84.20%)。
与异氰酸乙酯反应:
在-30℃下,向化合物8(848.3mg,1.3mmol)在15mL无水THF中的溶液加入异氰酸乙酯(283.6mg,4mmol)。在-30℃下搅拌1h后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后将粗产物在硅胶上用色谱纯化,所用体系为乙酸乙酯∶甲醇=19∶1,以获得白色固体状的PXN727-d1(853.4mg,90.5%)。
mp=263.7-267.2℃
1H-NMR(400MHz,DMSO)δ11.57(s,1H),7.57(s,1H),7.50(s,1H),7.44(d,2H,J=6.70Hz),7.25(d,1H,J=7.39Hz),7.09(m,5H),6.90(d,2H,J=7.39Hz),6.53(s,1H),4.93(s,1H),4.74(d,1H,J=15.29Hz),3.84(s,2H),3.60-3.20(m,4H),3.45(d,1H,J=15.29),3.15-2.80(m,4H),3.09-3.06(m,2H),2.25(s,3H),1.03(t,3H,J=7.05Hz).
IR:3397,3174,2923,1674,1625,1535,1487,1401,1361,1241,1174,1118,1002,794.
MS(+ESI):m/z=709.9[M+H],730.2[M+Na].
总产率(四个制备步骤和非对映异构体分离):10.91%
实施例4
2)硫S(基团X)由亚甲基CH
2
代替
(顺)4-[3-苄基-1-(4-氯-3-氟-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺[PXN790-d1]的合成
将商购α-苄基琥珀酸9(1g,4,8mmol)在30mL三氟乙酸酐中回流1h。随后,在真空下去除溶剂。将粗残留物用冷己烷洗涤以获得白色固体状的α-苄基琥珀酸酐10(858.2mg,93.95%)。
多组分反应
于密封管中,将α-苄基琥珀酸酐10(850mg,4.5mmol)、醛3(1mmol)和胺11(1mmol)在甲苯(16mL)中加热至150℃,保持24小时。冷却至室温后,将溶液在真空下浓缩。在硅胶上纯化(乙酸乙酯∶甲醇=9∶1至1∶1),获得非对映异构混合物MCR-产物12(210.3mg,9.20%)。
五氟苯酯的形成
在0℃下,向1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(118.2mg,0.617mmol)在5mL乙酸乙酯中的悬浮液加入五氟苯酚(227.1mg,1.23mmol)。10分钟后,在0℃下加入5-氧代-吡咯烷-3-羧酸12(210.3mg,0.411mmol),并将反应混合物在室温下搅拌1小时。将溶剂蒸发后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶己烷=1∶2→1∶1),以获得无色油状的对应的(顺)-5-氧代-吡咯烷-3-羧酸五氟苯酯13(78.2mg,28.9%)。
酰胺偶联
在室温下,向(顺)-5-氧代-吡咯烷-3-羧酸五氟苯酯13(78.2mg,0.1154mmol)在2mL无水THF中的悬浮液加入哌嗪(39.8mg,0.4616mmol)。将反应混合物在室温下搅拌10小时。随后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶甲醇=9∶1→1∶1),以获得白色固体状期望的(顺)-4-(哌嗪-1-羰基)-吡咯烷-2-酮14(38.5mg,57.55%)。
与异氰酸乙酯反应
在-30℃下,向化合物14(38.5mg,0.066mmol)在3mL无水THF中的溶液加入异氰酸乙酯(14.2mg,0.199mmol)。在-30℃下搅拌1h后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后,将粗产物从乙酸乙酯∶甲醇19∶1中结晶,以获得白色固体状的PXN790-d1(26.9mg,62.24%)。
1H-NMR(400MHz,DMSO)δ11.57(s,1H),7.58-7.43(m,3H),7.28-7.11(m,5H),6.95-6.83(m,4H),6.55(s,1H),4.97-4.91(m,1H),4.71(d,1H,J=15.24Hz),3.63-3.57(m,5H),3.10-3.08(m,3H),2.91-2.85(m,3H),2.69-2.65(m,1H),1.03(t,3H,J=7.02Hz).
IR:3043,3165,3033,2964,2930,1677,1615,1538,1449,1401,1262,1240,1207,1119,796,698.
MS(+ESI):m/z=650.1[M+H],672.1[M+Na].
总产率(四个制备步骤):0.93%
实施例5
硫S(基团X)由氧O代替
(顺)-4-[1-(4-氯-3-氟-苄基)-2-(6-氯-1H-吲哚-3-基)-5-氧代-3-对甲苯氧基-吡咯烷-3-羰基]-哌嗪-1-羧酸乙酰胺[PXN789-d1]的合成
氧取代的酸酐的合成
氧取代的酸酐经由三步合成获得:
将1-苯基-2,5-二氢-1H-吡咯-2,5-二酮19(5.19g,3mmol)、对甲酚20(3.24g,3mmol)和三乙胺(3.03g,3mmol)加入20ml无水甲苯中,并在100℃下加热6h。随后,将混合物冷却至0℃。将沉淀的固体过滤,并用冷甲苯和己烷洗涤,以获得紫色固体状的化合物21(2.895g,34.30%)。
化合物21的分析数据:
1H NMR(DMSO,399.83MHz):2.26(s,3H),2.89-2.94(m,1H),3.31-3.46(m,1H),5.44-5.47(m,1H),6.97(d,2H,J=8,4Hz),7.14(d,2H,J=7.6Hz),7.33(d,2H,J=7,2Hz),7.44-7.53(m,3H).
MS(+ESI):m/z=282[M+H].
将化合物21(610.3mg,2.17mmol)溶于HCl 37%∶HCOOH 1∶1的30ml水性混合物中。将混合物在110℃下加热3h。随后,将混合物冷却至室温,并将水相用DCM洗涤3次,随后蒸发。将所得固体用冷醚洗涤3此,并将所得醚相蒸发,以获得白色固体状的琥珀酸22。最后,将琥珀酸22溶于10ml三氟乙酸酐(TFAA),并在100℃下加热6h。然后,将TFAA蒸发,并将所得固体用冷己烷洗涤,以获得白色固体状的对应琥珀酸酐15(170.4mg,95.56%)。
化合物15的分析数据:
1H NMR(DMSO,399.43MHz):2.25(s,3H),3.21-3.27(m,1H),3.52-3.59(m,1H),5.57-5.61(m,1H),6.92(d,2H,J=8.26Hz),7.14(d,2H,J=8.22Hz).
IR:3001,2920,1865,1781,1608,1508,1396,1213,1178,1086,1021,903,806.
MS(+ESI):m/z=207[M+H].
多组分反应
首先,在室温下,将醛3(646.6mg,3.6mmol)和胺11(478.8mg,3mmol)在3mL原甲酸三甲酯中缩合10小时。随后,在真空下去除溶剂,并将残留物溶于25mL邻二甲苯。随后,加入琥珀酸酐15(850mg,4.5mmol),并在Dean-Stark条件下,将混合物加热至150℃,保持24小时。冷却至室温后,将溶液在真空下浓缩。在硅胶上纯化(乙酸乙酯∶甲醇=9∶1→1∶1),获得非对映异构混合物MCR-产物16(33.9mg,2.11%)。
五氟苯酯的形成
在0℃下,向1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(18.5mg,0.096mmol)在2mL乙酸乙酯中的悬浮液加入五氟苯酚(35.6mg,0.193mmol)。10分钟后,在0℃下加入5-氧代-吡咯烷-3-羧酸16(33.9mg,0.064mmol),并将反应混合物在室温下搅拌1h。将溶剂蒸发后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶己烷=1∶2),以获得无色油状的对应5-氧代-吡咯烷-3-羧酸五氟苯酯17(40.1mg,89.80%)。
酰胺偶联
在室温下,向5-氧代-吡咯烷-3-羧酸五氟苯酯17(40.1mg,0.0578mmol)在2mL无水THF中的悬浮液加入哌嗪(19.9mg,0.231mmol)。将反应混合物在室温下搅拌10小时。随后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后,将粗产物在硅胶上用色谱纯化(乙酸乙酯∶甲醇=9∶1→1∶1),以获得白色固体状期望的4-(哌嗪-1-羰基)-吡咯烷-2-酮18(12.2mg,45.91%)。
与异氰酸乙酯反应
在-30℃下,向化合物18(12.2mg,0.0204mmol)在3mL无水THF中的溶液加入异氰酸乙酯(4.4mg,0.0612mmol)。在-30℃下搅拌1h后,加入20mL二氯甲烷。将所得有机层用20mL饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥并在真空下去除溶剂。最后,将粗产物在硅胶上用色谱纯化(二氯甲烷∶甲醇=95∶5),以获得黄色固体状的PXN789-d1(9.6mg,70.60%)。
MS(+ESI):m/z=666.1[M+H]。
总产率(四个制备步骤):0.61%
其它实施例
根据上述步骤之一制备的其它实施例:获得全部产物并测试为外消旋物。在p53野生型卵巢畸胎瘤细胞(PA-1)上测量细胞活性,且测得的IC50以微摩尔计。CCA是细胞周期停滞的缩写。
PXN610
C28H28Cl2N2O3S;MW:543.52;测定值(HPLC MS):[M+H+]=543.0;产率:47%;IC50=15
PXN611
C29H31Cl2N3O2S;MW:556.56;测定值(HPLC MS):[M+H+]=556.1;产率:28%;IC50=8.3
PXN612
C27H26Cl2N2O3S;MW:529.49;测定值(HPLC MS):[M+H+]=529.0;产率:17%;IC50=10.3
PXN613
C28H29Cl2N3O2S;MW:542.53;测定值(HPLC MS):[M+H+]=542.0;产率:13%;IC50=8
PXN617
C30H29Cl2N3O3S;MW:582.55;测定值(HPLC MS):[M+H+]=582.1;[M+Na+]=604.0;产率:32%;IC50=3.1
PXN618
C31H32Cl2N4O2S;MW:595.60;测定值(HPLC MS):[M+H+]=595.1;产率:35%;IC50=4.2
PXN619
C31H31Cl2N3O3S;MW:596.58;测定值(HPLC MS):[M+Na+]=618.1;产率:40%;IC50=28.7
PXN620
C30H29Cl2N3O3S;MW:582.55;测定值(HPLC MS):[M+H+]=581.9;产率:15%;IC50=15.3
PXN623
C32H36Cl2N4O2S;MW:611.64;测定值(HPLC MS):[M+H+]=611.1;产率:49%;IC50=7.8
PXN624
C31H27Cl2N3O2S;MW:576.55;测定值(HPLC MS):[M+H+]=576.0;产率:41%;IC50=22.4
PXN625
C30H26Cl2N2O2S2;MW:581.59;测定值(HPLC MS):[M+H+]=581.1;产率:37%;IC50>60
PXN626
C31H34Cl2N4O2S;MW:597.61;测定值(HPLC MS):[M+H+]=597.1;产率:21%;IC50=7.4
PXN627
C30H25Cl2N3O2S;MW:562.52;测定值(HPLC MS):[M+H+]=562.0;产率:17%;IC50=10.2
PXN628
C29H24Cl2N2O2S2;MW:567.56;测定值(HPLC MS):[M+H+]=567.0;产率:20%;IC50>60
PXN629
C35H39Cl2N5O2S;MW:664.70;测定值(HPLC MS):[M+H+]=664.2;产率:40%;IC50=7.2
PXN630-d1
C34H30Cl2N4O2S;MW:629.61;测定值(HPLC MS):[M+H+]=629.1;产率:38%;IC50>60
PXN631-d1
C33H29Cl2N3O2S2;MW:634.65;测定值(HPLC MS):[M+Na+]=656.0;产率:30%;IC50>60
PXN632
C34H37Cl2N5O2S;MW:650.68;测定值(HPLC MS):[M+H+]=650.2;产率:36%;IC50=5.2
PXN633-d1
C33H28Cl2N4O2S;MW:615.59;测定值(HPLC MS):[M+H+]=615.1;产率:17%;IC50=23.3
PXN633-d2
C33H28Cl2N4O2S;MW:615.59;测定值(HPLC MS):[M+H+]=615.1;产率:11%;IC50=22.2
PXN634
C32H27Cl2N3O2S2;MW:620.62;测定值(HPLC MS):[M+H+]=620.0;产率:27%;IC50>60
PXN635
C23H26Cl2N2O3S;MW:481.45
PXN636
C27H25Cl3N2O3S;MW:563.93;测定值(HPLC MS):[M+H+]=563.0;产率:26%;IC50>60
PXN637
C30H24Cl3N3O2S;MW:596.97;测定值(HPLC MS):[M+H+]=596.0;产率:24%;IC50>60
PXN638
C30H29Cl2N3O5S;MW:614.55;测定值(HPLC MS):[M+H+]=614.1;产率:11%;IC50=60.4
PXN639
C33H28Cl2N4O4S;MW:647.59;测定值(HPLC MS):[M+H+]=647.1;产率:5%;IC50=65.7
PXN640-d1
C33H28Cl2N4O2S.;MW:615.59;测定值(HPLC MS):[M+H+]=615.2;产率:13%;IC50=18.7
PXN640-d2
C33H28Cl2N4O2S;MW:615.59;测定值(HPLC MS):[M+H+]=615.2;产率:5%;IC50=24.5
PXN641
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.2;产率:9%;IC50=9.4
PXN642
C29H27Cl2N3O2S;MW:552.53;测定值(HPLC MS):[M+H+]=552.1;[M+Na+]=574.1;产率:8%;IC50=5.7
PXN643
C31H28Cl2N4O3S;MW:607.56;测定值(HPLC MS):[M+H+]=607.2;产率:4%;IC50=3.9
PXN644
C28H25Cl2N3O3S;MW:554.50;测定值(HPLC MS):[M+Na+]=576.1;产率:10%;IC50=13.5
PXN645
C27H31Cl2N3O3S;MW:548.54;测定值(HPLC MS):[M+Na+]=570.2;产率:1%
PXN646
C26H24Cl2N2O3S;MW:515.46;测定值(HPLC MS):[M+H+]=515.0;产率:11%;IC50=14.6
PXN647
C25H30Cl2N2O3S;MW:509.50
PXN649
C26H24Cl2N2O3S;MW:515.46
PXN650
C28H25Cl2N3O3S;MW:554.50;测定值(HPLC MS):[M+Na+]=576.1;产率:8%;IC50=17.1
PXN651
C32H32Cl2N4O3S;MW:623.61;测定值(HPLC MS):[M+H+]=623.2;产率:9%;IC50=9.2
PXN652
C30H31Cl2N3O3S;MW:584.57;测定值(HPLC MS):[M+H+]=584.1;产率:29%;IC50=17.4
PXN653
C31H31Cl2N4O4S;MW:625.58;测定值(HPLC MS):[M+H+]=625.1;产率:2%
PXN654
C31H30Cl2N4O4S;MW:625.58;测定值(HPLC MS):[M+H+]=625.1;产率:3%;IC50=29.9
PXN655
C29H34Cl2N4O4S;MW:605.59
PXN656
C31H38Cl2N4O3S;MW:617.64;测定值(HPLC MS):[M+H+]=617.2;产率:1%;IC50=17.8
PXN657
C28H26ClN3O4S;MW:536.05;测定值(HPLC MS):[M+H+]=536.1;产率:11%
PXN658
C32H32Cl2N4O4S;MW:639.61
PXN659-d1
C33H34Cl2N4O3S;MW:637.63;测定值(HPLC MS):[M+H+]=637.2;产率:7%;IC50=6.8
PXN659-d2
C33H34Cl2N4O3S ;MW:637.63;测定值(HPLC MS):[M+H+]=637.2;产率:7%;IC50=12
PXN660-d1
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.2;产率:8%;IC50=13
PXN660-d2
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.2;产率:5%;IC50=8.3
PXN661-d1
C33H34Cl2N4O3S;MW:637.63;测定值(HPLC MS):[M+H+]=637.2;产率:4%;IC50=13.8
PXN661-d2
C33H34Cl2N4O3S;MW:637.63;测定值(HPLC MS):[M+H+]=637.2;产率:3%;IC50=10.2
PXN662-d1
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.2;产率:1%;IC50=17.2
PXN662-d2
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.2;产率:3%;IC50=11.5
PXN663-d1
C33H33Cl3N4O3S;MW:672.08;测定值(HPLC MS):[M+H+]=673.1;产率:19%;IC50=9.2
PXN663-d2
C33H33Cl3N4O3S;MW:672.08;测定值(HPLC MS):[M+H+]=671.1;产率:7%;IC50=11.2
PXN666-d1
C30H29Cl2N3O3S;MW:582.55;PXN617-对映异构体1;IC50=2.9
PXN667-d1
C30H29Cl2N3O3S;MW:582.55;PXN617-对映异构体2;IC50=39
PXN668-d1
C33H35ClN4O3S;MW:603.19;测定值(HPLC MS):[M+H+]=603.0;产率:5%;IC50=18.3
PXN668-d2
C33H35ClN4O3S;MW:603.19;测定值(HPLC MS):[M+H+]=603.0;产率:4%;IC50=26.9
PXN669-d1
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.0;产率:5%;IC50=16.1
PXN669-d2
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=650.9;产率:5%;IC50=10.6
PXN671-d1
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=697.0;产率:11%;IC50=8.7
PXN671-d2
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=697.1;产率:9%;IC50=8.5
PXN672-d1
C33H34BrClN4O3S;MW:682.08;测定值(HPLC MS):[M+H+]=682.8;产率:5%;IC50=29.5
PXN672-d2
C33H34BrClN4O3S;MW:682.08;测定值(HPLC MS):[M+H+]=682.9;产率:4%;IC50=8.8
PXN673-d2
C32H33Cl2N5O3S;MW:638.62;测定值(HPLC MS):[M+H+]=637.9;产率:1%;IC50=163.4
PXN673-d1
C32H33Cl2N5O3S;MW:638.62;测定值(HPLC MS):[M+H+]=638.0;产率:4%;IC50=9.3
PXN674-d1
C31H28Cl2N4O3S;MW:607.56;测定值(HPLC MS):[M+H+]=607.2;产率:4%;IC50=17.5
PXN674-d2
C31H28Cl2N4O3S;MW:607.56;测定值(HPLC MS):[M+H+]=607.2;产率:4%;IC50=28.9
PXN675-d1
C31H28Cl2N4O3S;MW:607.56;测定值(HPLC MS):[M+H+]=606.9;产率:2%;IC50=25.5
PXN675-d2
C31H28Cl2N4O3S;MW:607.56;测定值(HPLC MS):[M+H+]=608.8;产率:3%;IC50=17.8
PXN676-d1
C33H34ClFN4O3S;MW:621.18;测定值(HPLC MS):[M+H+]=621.0;产率:5%;IC50=15.6
PXN676-d2
C33H34ClFN4O3S;MW:621.18;测定值(HPLC MS):[M+H+]=621.0;产率:3%;IC50=18.5
PXN677-d1
C31H28BrClN4O3S;MW:652.01;测定值(HPLC MS):[M+H+]=651.3;产率:8%;IC50=5.45
PXN678-d1
C33H33Cl3N4O5S;MW:704.08;测定值(HPLC MS):[M+H+]=702.9;产率:5%;IC50=49.3
PXN679-d2
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=697.1;产率:3%;IC50=9.3
PXN679-d1
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=697.2;产率:8%;IC50=7.7
PXN680-d1
C34H36Br2N4O3S;MW:740.56;测定值(HPLC MS):[M+H+]=740.5;产率:10%;IC50=8.2
PXN681-d2
C34H35Cl2FN4O3S;MW:669.65;测定值(HPLC MS):[M+H+]=669.0;产率:4%;IC50=11.8
PXN681-d1
C34H35Cl2FN4O3S;MW:669.65;测定值(HPLC MS):[M+H+]=669.1;产率:15%;IC50=9.5
PXN682-d2
C34H35Cl2FN4O3S;MW:669.65;测定值(HPLC MS):[M+H+]=669.1;产率:1%;IC50=16.2
PXN682-d1
C34H35Cl2FN4O3S;MW:669.65;测定值(HPLC MS):[M+H+]=669.1;产率:5%;IC50=8.6
PXN683-d1
C33H34Cl2N4O3S;MW:637.63;测定值(HPLC MS):[M+H+]=637.0;产率:8%;IC50=6.0
PXN684
C30H29Cl2N3O4S;MW:598.55;测定值(HPLC MS):[M+H+]=598.2;产率:7%;IC50=5.7
PXN686-d1
C33H35Cl2N5O3S;MW:652.65;测定值(HPLC MS):[M+H+]=652.0;产率:6%;IC50=6.8
PXN687
C28H24Cl2N2O3S;MW:539.49;测定值(HPLC MS):[M+H+]=539.1
PXN688
C34H36Cl2N4O5S;MW:683.66;测定值(HPLC MS):[M+H+]=683.1;产率:5%;IC50>60
PXN689-d1
C34H36Cl2N4O3S;MW:651.66;测定值(HPLC MS):[M+H+]=651.1;产率:8%;IC50=8.6
PXN690
C33H33Cl2N3O7S;MW:686.62;测定值(HPLC MS):[M+Na+]=710.1;产率:9%;IC50=33.8
PXN691
C34H37Cl2N3O7S;MW:702.66;测定值(HPLC MS):[M+H+]=702.3;[M+Na+]=724.1;产率:4%;IC50=17.6
PXN693-d1
C34H36BrClN4O5S;MW:728.11;测定值(HPLC MS):[M+H+]=729.1;产率:4%
PXN694-d1
C34H35Cl2FN4O5S;MW:701.65;测定值(HPLC MS):[M+H+]=703.1;产率:7%
PXN695-d1
C33H34BrClN4O3S;MW:682.08;测定值(HPLC MS):[M+H+]=683.0;产率:5%;IC50=5.4
PXN696-d1
C30H29BrClN3O4S;MW:643.00;测定值(HPLC MS):[M+H+]=668.1;产率:7%;IC50=4.1
PXN697-d1
C31H28BrClN4O3S;MW:652.01;测定值(HPLC MS):[M+H+]=653.1;[M+Na+]=675.3;产率:3%;IC50=3.6
PXN698-d1
C33H34BrClN4O3S;MW:682.08;测定值(HPLC MS):[M+H+]=683.1;产率:7%;IC50=6.3
PXN699-d1
C35H38BrClN4O3S;MW:710.14;测定值(HPLC MS):[M+H+]=711.0;产率:7%;IC50=4.2
PXN700-d1
C31H31BrClN3O3S;MW:641.03;测定值(HPLC MS):[M+Na+]=664.2;产率:7%;IC50=4.3
PXN701-d1
C33H34BrClN4O2S;MW:666.09;测定值(HPLC MS):[M+H+]=668.2;产率:8%;IC50=4.1
PXN702-d1
C35H38BrClN4O3S;MW:710.14;测定值(HPLC MS):[M+H+]=711.1;产率:17%;IC50=18.6
PXN703-d1
C35H38BrClN4O3S;MW:710.14;测定值(HPLC MS):[M+H+]=711.0;产率:10%;IC50=9.5
PXN704-d1
C35H38BrClN4O3S;MW:710.14;测定值(HPLC MS):[M+H+]=711.0;产率:6%;IC50=11.7
PXN705-d1
C33H33BrClN5O5S;MW:727.08;测定值(HPLC MS):[M+H+]=727.9;产率:1%;IC50=16.4
PXN706-d1
C31H29BrClN3O3S;MW:639.02;测定值(HPLC MS):[M+H+]=640.3;[M+Na+]=662.3;产率:8%;IC50=4.7
PXN707-d1
C31H29BrClN3O3S;MW:639.02;测定值(HPLC MS):[M+H+]=640.3;[M+Na+]=662.3;产率:11%;IC50=5.4
PXN708-d1
C30H29BrClN3O3S;MW:627.00;测定值(HPLC MS):[M+Na+]=650.6;产率:8%;IC50=6.1
PXN709-d1
C30H29BrClN3O3S;MW:627.00;测定值(HPLC MS):[M+Na+]=650.2;产率:8%;IC50=7.4
PXN705-d2
C33H33BrClN5O5S;MW:727.08;测定值(HPLC MS):[M+H+]=726.0;产率:3%;IC50=9.5
PXN710
C35H40BrClN4O2S;MW:696.16;测定值(HPLC MS):[M+H+]=697.3;产率:6%
PXN711-d1
C33H33BrClFN4O3S;MW:700.08;测定值(HPLC MS):[M+H+]=701.2;产率:3%;IC50=7.3
PXN712-d1
C33H34BrClN4O3S;MW:682.08;测定值(HPLC MS):[M+H+]=683.1;产率:6%
PXN713-d1
C32H40BrClN4O3S;MW:676.12;测定值(HPLC MS):[M+H+]=677.2;产率:4%;IC50=8.1
PXN714-d1
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=697.2;产率:2%;IC50=6.8
PXN715-d1
C33H32BrClF2N4O3S;MW:718.07;测定值(HPLC MS):[M+H+]=719.2;产率:4%;IC50=7.9
PXN716-d1
C31H28BrClN4O3S;MW:652.01;测定值(HPLC MS):[M+H+]=653.1;[M+Na+]=675.3;产率:4%
PXN717-d1
C31H29BrClN3O3S;MW:639.02;测定值(HPLC MS):[M+H+]=640.2;[M+Na+]=662.1;产率:10%;IC50=8.9
PXN718-d1
C31H30BrClN4O2S;MW:638.03;测定值(HPLC MS):[M+H+]=639.2;产率:9%;IC50=3.5
PXN719-d1
C33H34BrClN4O2S;MW:666.09;测定值(HPLC MS):[M+H+]=665.4;产率:8%;IC50=8.2
PXN720-d1
C34H36BrClN4O3S;MW:696.11;测定值(HPLC MS):[M+H+]=695.4;产率:5%;IC50=6.6
PXN721-d1
C32H32BrClN4O2S;MW:652.06;测定值(HPLC MS):[M+H+]=651.4;产率:5%;IC50=7.2
PXN722-d1
C33H36BrClN4O2S;MW:668.10;测定值(HPLC MS):[M+H+]=667.3;产率:2%;IC50=13.2
PXN725-d1
C32H32BrClN4O4S2;MW:716.12;测定值(HPLC MS):[M+Na+]=737.2;产率:5%;IC50>60
PXN726-d1
C33H32BrClN4O3S;MW:680.07;测定值(HPLC MS):[M+H+]=681.1;[M+Na+]=703.2;产率:9%;IC50=2.1
PXN727-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.0;[M+Na+]=732.2;产率:11%;IC50=1.4
PXN728-d1
C31H32BrClN4O3S;MW:656.05;测定值(HPLC MS):[M+H+]=657.2;产率:4%
PXN729
C58H52Br2Cl2N6O5S2;MW:1207.94;测定值(HPLC MS):[M+Na+]=1229.5;产率:10%
PXN730-d1
C32H30BrClN4O3S;MW:666.04;测定值(HPLC MS):[M+H+]=666.9;[M+Na+]=689.0;产率:6%;IC50=4.8
PXN731-d1
C34H34BrClN4O4S;MW:710.10;测定值(HPLC MS):[M+H+]=711.5;[M+Na+]=733.5;产率:4%;IC50=118.7
PXN732-d1
C33H32BrClN4O4S;MW:696.07;测定值(HPLC MS):[M+H+]=697.4;[M+Na+]=719.4;产率:4%;IC50=2.1
PXN733-d1
C36H38BrClN4O4S;MW:738.15;测定值(HPLC MS):[M+H+]=739.1;[M+Na+]=759.5;产率:4%
PXN734-d1
C32H30BrClN4O3S;MW:666.04
PXN735-d1
C35H36BrClN4O3S;MW:708.12;测定值(HPLC MS):[M+H+]=711.0;[M+Na+]=731.0;产率:8%;IC50=3.4
PXN736-d1
C36H38BrClN4O3S;MW:722.15;测定值(HPLC MS):[M+H+]=723.4;[M+Na+]=745.4;产率:7%;IC50>60
PXN737-d1
C36H38BrClN4O3S;MW:722.15;测定值(HPLC MS):[M+H+]=721.4;[M+Na+]=743.5;产率:7%;IC50=15.6
PXN738-d1
C33H33BrClN5O3S;MW:695.08
PXN739-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.2;产率:2%;IC50=2.0
PXN740-d1
C35H37BrClN5O3S;MW:723.14
PXN741-d1
C33H33BrClN3O3S;MW:667.07;测定值(HPLC MS):[M+H+]=668.5;[M+Na+]=690.4;产率:5%;IC50=7.0
PXN742-d1
C34H35Cl2N5O3S;MW:664.66;测定值(HPLC MS):[M+H+]=664.2;[M+Na+]=686.1;产率:6%;IC50=1.1
PXN743-d1
C34H34Cl2FN5O3S;MW:682.65;测定值(HPLC MS):[M+H+]=682.7;[M+Na+]=704.2;产率:6%;IC50=1.5
PXN744-d1
C35H38ClN5O3S;MW:644.24;测定值(HPLC MS):[M+H+]=644.4;[M+Na+]=666.3;产率:5%;IC50=107.1
PXN745
C31H32Cl2N4O3S;MW:611.60;测定值(HPLC MS):[M+H+]=611.3;[M+Na+]=633.2;产率:2%
PXN746
C32H34Cl2N4O3S;MW:625.62;测定值(HPLC MS):[M+H+]=625.3;[M+Na+]=649.3;产率:22%;IC50=14.7
PXN747
C30H31Cl2N5O3S;MW:612.58
PXN748-d1
C35H34BrClN4O5S;MW:738.11;测定值(HPLC MS):[M+H+]=739.3;[M+Na+]=762.1;产率:5%;IC50=16.6
PXN749-d1
C35H33BrClN4NaO5S;MW:760.09
PXN750-d1
C34H33BrClN4NaO6S2;MW:796.14
PXN751-d1
C32H31Cl2N5O3S;MW:636.61;测定值(HPLC MS):[M+H+]=636.3;[M+Na+]=658.2;产率:2%;IC50=5.8
PXN752-d1
C32H30Cl2N4O3S;MW:621.59;测定值(HPLC MS):[M+H+]=621.1;产率:6%;IC50=2.0
PXN753-d1
C34H36ClN5O3S;MW:630.21;测定值(HPLC MS):[M+H+]=630.3;[M+Na+]=652.3;产率:5%;IC50=170.6
PXN754-d1
C31H36ClN5O3S;MW:594.18;测定值(HPLC MS):[M+H+]=594.3;产率:12%;IC50=13.6
PXN755-d1
C33H33Cl2N5O3S;MW:650.63;测定值(HPLC MS):[M+H+]=650.1;[M+Na+]=672.3;产率:1%;IC50=3.6
PXN756-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.0;[M+Na+]=732.2;产率:8%;IC50=2.6
PXN757-d1
C35H35BrClN3O4S;MW:709.11;测定值(HPLC MS):[M+Na+]=730.4;产率:12%;IC50=206.1
PXN758-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.0;[M+Na+]=732.2;产率:13%
PXN759-d1
C34H36ClN5O3S;MW:630.21;测定值(HPLC MS):[M+H+]=630.2;[M+Na+]=652.3;产率:6%;IC50=182.6
PXN760-d1
C34H35BrClN5O4S;MW:725.11;测定值(HPLC MS):[M+H+]=726.2;[M+Na+]=748.0;产率:4%;IC50=3.2
PXN761-d1
C34H36BrCl2N5O3S;MW:745.57;测定值(HPLC MS):[M+H+]=708.1;产率:10%;IC50=3.1
PXN762-d1
C33H34Cl3N5O3S;MW:687.09;测定值(HPLC MS):[M+H+]=650.2;产率:4%;IC50=4.5
PXN763-d1
C35H38Cl2N6O3S;MW:693.70;测定值(HPLC MS):[M+H+]=693.2;产率:2%
PXN764-d1
C36H39Cl2N5O4S;MW:708.71;测定值(HPLC MS):[M+H+]=708.2;[M+Na+]=730.2;产率:5%;IC50=3.3
PXN765-d1
C35H37Cl2N5O4S;MW:694.69;测定值(HPLC MS):[M+H+]=694.2;[M+Na+]=716.3;产率:4%;IC50=2.6
PXN766-d1
C33H32BrClN4O4S;MW:696.07;测定值(HPLC MS):[M+Na+]=717.2;产率:6%;IC50=3.8
PXN767-d1
C36H33Cl2N5O2S;MW:670.67;测定值(HPLC MS):[M+H+]=670.2;产率:9%;IC50>60
PXN768-d1
C35H32Cl2N6O2S;MW:671.65;测定值(HPLC MS):[M+H+]=671.4;产率:6%;IC50=118.7
PXN769-d1
C35H32Cl2N6O2S;MW:671.65;测定值(HPLC MS):[M+H+]=671.1;产率:8%;IC50>60
PXN770-d1
C38H35Cl2N5O3S;MW:712.70;测定值(HPLC MS):[M+H+]=712.2;产率:5%;IC50=191.7
PXN771-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.0;[M+Na+]=732.2;产率:10%
PXN775-d1
C35H38BrN5O3S;MW:688.69;测定值(HPLC MS):[M+H+]=690.2;产率:2%;CCA
PXN776-d1
C33H33BrClN5O3S;MW:695.08;测定值(HPLC MS):[M+Na+]=716.1;产率:11%;IC50=2.1
PXN777-d1
C35H37BrClN5O3S;MW:723.14;测定值(HPLC MS):[M+H+]=722.1;产率:10%;IC50=5.5
PXN779-d1
C33H34BrClN6O3S;MW:710.10;测定值(HPLC MS):[M+H+]=711.2;产率:6%;IC50=5.0
PXN780-d1
C35H35ClF3N5O3S;MW:698.21;测定值(HPLC MS):[M+H+]=698.2;[M+Na+]=720.2;产率:6%;IC50=5.3
PXN781-d1
C32H32BrClN6O3S;MW:696.07
PXN782-d1
C36H40BrClN6O4S;MW:768.18;测定值(HPLC MS):[M+H+]=769.2;产率:8%
PXN783-d1
C37H44BrClN6O2S;MW:752.22;测定值(HPLC MS):[M+H+]=753.2;产率:9%
PXN784-d1
C39H46BrClN6O3S;MW:794.26;测定值(HPLC MS):[M+H+]=795.3;产率:5%
PXN785-d1
C39H47BrClN5O3S;MW:781.26;测定值(HPLC MS):[M+H+]=781.6;[M+Na+]=803.8;产率:10%
PXN787-d1
C35H39BrClN5O2S;MW:709.15;测定值(HPLC MS):[M+H+]=709.5;产率:13%;IC50=8.3
PXN791-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=710.2;[M+Na+]=732.0;产率:1%;IC50=6.6
PXN792-d1
C34H35BrClN5O3S;MW:709.11;测定值(HPLC MS):[M+H+]=708.0;[M+Na+]=730.1;产率:8%;IC50=5.3
PXN793-d1
C33H32BrClN4O3S;MW:680.07;测定值(HPLC MS):[M+Na+]=703.1;产率:6%;IC50=4.7
PXN794-d1
C33H32BrClN4O3S;MW:680.07;测定值(HPLC MS):[M+H+]=679.0;[M+Na+]=701.0;产率:4%;IC50=6.0
PXN795-d1
C34H34BrClN4O4S;MW:710.10;测定值(HPLC MS):[M+H+]=711.1;[M+Na+]=733.1;产率:3%;IC50=80.0
PXN796-d1
C34H34BrClN4O4S;MW:710.10
PXN797-d1
C34H35BrFN5O3S;MW:692.66;测定值(HPLC MS):[M+H+]=693.5;[M+Na+]=716.2;产率:11%;CCA
PXN798-d1
C37H42BrClN6O3S;MW:766.21
PXN799-d1
C32H31BrClN3O3S;MW:653.04;测定值(HPLC MS):[M+H+]=651.8;[M+Na+]=675.7;产率:13%;IC50=4.1
PXN800-d1
C34H34BrClN4O4S;MW:710.10;测定值(HPLC MS):[M+H+]=711.3;[M+Na+]=731.2;产率:2%;IC50=11.7
PXN801-d1
C35H37BrClN5O3S;MW:723.14;测定值(HPLC MS):[M+H+]=724.3;[M+Na+]=746.3;产率:5%;IC50>60
PXN802-d1
C34H34BrClN4O3S;MW:694.10;测定值(HPLC MS):[M+H+]=695.3;产率:6%;IC50=4.5
PXN803-d1
C35H36BrClN4O4S;MW:724.12
PXN805-d1
C32H32BrClN4O2S;MW:652.06;测定值(HPLC MS):[M+H+]=653.4;[M+Na+]=675.4;产率:7%;IC50=5.5
PXN806-d1
C33H32BrClN4O4S;MW:696.07
PXN807-d1
C33H32BrClN4O4S;MW:696.07
PXN808-d1
C32H29Cl2FN4O3S;MW:639.58;测定值(HPLC MS):[M+H+]=639.2;[M+Na+]=660.9;产率:16%;IC50=1.3
PXN811-d1
C30H26Cl2FN3O3S;MW:598.53;测定值(HPLC MS):[M+H+]=598.1;[M+Na+]=620.0;产率:7%;IC50=5.6
PXN813-d1
C30H27BrClN3O3S;MW:624.99;测定值(HPLC MS):[M+H+]=624.0;[M+Na+]=646.0;产率:11%;IC50=5.4
PXN814-d1
C28H25BrClN3O3S;MW:598.95
PXN815-d1
C33H32ClF2N5O3S;MW:652.17;测定值(HPLC MS):[M+H+]=652.1;[M+Na+]=674.2;产率:4%;IC50=5.0
PXN816-d1
C33H32Cl2FN5O3S;MW:668.62;测定值(HPLC MS):[M+H+]=668.2;产率:5%;IC50=3.2
PXN817-d2
C34H33ClN6O3S;MW:641.20;测定值(HPLC MS):[M+H+]=641.1;[M+Na+]=663.2;产率:1%;IC50=1.0
PXN820-d1
C31H28Cl2FN3O3S;MW:612.56;测定值(HPLC MS):[M+H+]=612.1;[M+Na+]=634.1;产率:20%;IC50=3.7
PXN821-d1
C32H31Cl2FN4O3S;MW:641.60;测定值(HPLC MS):[M+H+]=641.2;产率:19%;IC50=8.6
PXN822-d1
C33H32Cl2FN5O3S;MW:668.62;测定值(HPLC MS):[M+H+]=668.2;[M+Na+]=690.1;产率:16%;IC50=1.2
PXN825-d1
C31H27Cl2FN4O3S;MW:625.55;测定值(HPLC MS):[M+H+]=627.2;[M+Na+]=647.1;产率:23%;IC50=1.5
PXN826-d1
C32H30Cl2FN3O3S;MW:626.58;测定值(HPLC MS):[M+Na+]=648.1;产率:19%;IC50=3.5
PXN833-d1
C35H37Cl2FN6O4S;MW:727.69;测定值(HPLC MS):[M+H+]=727.2;产率:5%
PXN834-d1
C34H34Cl2FN5O4S;MW:698.65;测定值(HPLC MS):[M+H+]=698.1;产率:23%
PXN835-d1
C34H34Cl2FN5O3S;MW:682.65;测定值(HPLC MS):[M+H+]=684.3;[M+Na+]=703.9;产率:5%;IC50=3.4
PXN836-d2
C33H30ClN5O3S;MW:612.16;测定值(HPLC MS):[M+H+]=612.5;[M+Na+]=634.5;产率:3%
PXN849-d1
C33H31Cl2FN4O3S;MW:653.61;测定值(HPLC MS):[M+H+]=653.4;[M+Na+]=677.4;产率:6%
PXN850-d1
C34H34Cl2FN5O3S;MW:682.65;测定值(HPLC MS):[M+H+]=682.4;产率:11%
PXN670-d1
C33H34Cl2N4O3;MW:605.57;测定值(HPLC MS):[M+H+]=605.0;产率:6%;IC50=12.5
PXN670-d2
C33H34Cl2N4O3;MW:605.57;测定值(HPLC MS):[M+H+]=605.0;产率:7%;IC50=11.2
PXN778-d1
C33H33BrClN5O3;MW:663.02;测定值(HPLC MS):[M+H+]=664.1;产率:11%;IC50=8.1
PXN788-d1
C33H39BrClN5O3;MW:669.07;测定值(HPLC MS):[M+H+]=670.3;[M+Na+]=692.2;产率:1%;IC50=6.6
PXN790-d1
C34H34Cl2FN5O3;MW:650.59;测定值(HPLC MS):[M+H+]=650.1;[M+Na+]=672.1;产率:1%;IC50=3.0
PXN804-d1
C30H33BrClN5O3;MW:626.99;测定值(HPLC MS):[M+H+]=628.2;[M+Na+]=650.2;产率:9%;IC50=9.0
PXN809-d1
C27H26Cl2FN3O3;MW:530.43
PXN810-d1
C28H28Cl2FN3O3;MW:544.46
PXN812-d1
C31H28Cl2FN3O3;MW:580.49;测定值(HPLC MS):[M+H+]=580.1;[M+Na+]=602.1;产率:4%;IC50=11.9
PXN823-d1
C32H30Cl2FN3O3;MW:594.52
PXN824-d1
C33H31Cl2FN4O3;MW:621.54
PXN827-d1
C32H29Cl2FN4O3;MW:607.52
PXN828-d1
C32H35Cl2FN4O3;MW:613.57
PXN829-d1
C33H38Cl2FN5O3;MW:642.61;测定值(HPLC MS):[M+H+]=642.2;[M+Na+]=664.2;产率:1%;IC50=12.5
PXN830-d1
C31H33Cl2FN4O3;MW:599.54;测定值(HPLC MS):[M+H+]=599.2;[M+Na+]=621.2;产率:1%;IC50=10.2
PXN831-d1
C31H34Cl2FN5O3;MW:614.55;测定值(HPLC MS):[M+H+]=614.2;[M+Na+]=636.2;产率:1%;IC50=4.9
PXN832-d1
C31H36Cl2FN5O3;MW:616.57;测定值(HPLC MS):[M+H+]=616.3;产率:1%;IC50=7.9
PXN789-d1
C34H34Cl2FN5O4;MW:666.59;测定值(HPLC MS):[M+H+]=666.1;产率:1%;IC50=11.7
PXN723-d1
C31H31BrClN3O2S;MW:625.03;测定值(HPLC MS):[M+H+]=626.2;产率:2%;IC50=15.1
PXN724-d1
C31H33BrClN3OS;MW:611.05;测定值(HPLC MS):[M+H+]=612.3;产率:1%;IC50=20.6
PXN818-d1
C27H24BrClN2O2S;MW:555.93;测定值(HPLC MS):[M+H+]=556.9;[M+Na+]=577.1;产率:10%;IC50=8.4
PXN819-d1
C34H37BrClN5O2S;MW:695.13
PXN837-d1
C22H24BrNO3S;MW:462.41;测定值(HPLC MS):[M+H+]=464.2;产率:5%
PXN838-d1
C25H22BrNO3S;MW:496.43;测定值(HPLC MS):[M+H+]=496.9;产率:2%
PXN839-d1
C34H30BrClN4O2S;MW:674.06;测定值(HPLC MS):[M+H+]=675.4;[M+Na+]=696.9;产率:10%
PXN840-d1
C34H29BrClN3O3S;MW:675.05;测定值(HPLC MS):[M+H+]=676.7;[M+Na+]=698.3;产率:9%
PXN841-d1
C29H26BrClN2O3S;MW:597.96;测定值(HPLC MS):[M+H+]=599.3;[M+Na+]=620.9;产率:11%
PXN842-d1
C34H35BrClN5O2S2;MW:725.18;测定值(HPLC MS):[M+H+]=726.5;[M+Na+]=749.7;产率:9%
PXN843-d1
C26H22N4O2S;MW:454.55;测定值(HPLC MS):[M+H+]=455.3;[M+Na+]=477.2;产率:22%
PXN844-d1
C27H25N3O4S;MW:487.58;测定值(HPLC MS):[M+H+]=488.2;[M+Na+]=510.3;产率:22%
PXN845-d1
C28H24BrClN2O3S;MW:583.94;测定值(HPLC MS):[M+H+]=585.2;[M+Na+]=607.4;产率:5%
PXN846-d1
C25H21Cl3N2O3;MW:503.82;测定值(HPLC MS):[M+H+]=505.2;产率:4%
PXN847-d1
C29H30BrClN4O3;MW:597.94;测定值(HPLC MS):[M+H+]=597.3;产率:7%
PXN848-d1
C26H21Cl2NO5S;MW:530.43;测定值(HPLC MS):[M+H+]=530.2;[M+Na+]=552.4;产率:13%
PXN 1000
C28H29ClN4O3S;MW:537.1;测定值(HPLC MS):[M+H+]=537.1;产率:9%
PXN 1001
C28H30ClN3O3S;MW:524.1;测定值(HPLC MS):[M+Na+]=546.2;产率:19%
PXN 1002
C28H30N4O3S;MW:502.64;测定值(HPLC MS):[M+H+]=503.2,[M+Na+]=525.2;产率:11%
PXN 1003
C28H31N3O3S;MW:489.64;测定值(HPLC MS):[M+H+]=490.5,[M+Na+]=512.2;产率:12%
PXN 1004
C28H29ClN4O3;MW:505.02;测定值(HPLC MS):[M+H+]=505.2;产率:11%
PXN 1005
C28H30ClN3O3;MW:492.02;测定值(HPLC MS):[M+H+]=492.2;产率:13%
PXN 1006
C29H31ClN4O4;MW:535.05
PXN 1007
C26H28ClN3O3S;MW:498.05;测定值(HPLC MS):[M+H+]=498.3;产率:5%
PXN 1008
C26H29N3O3S;MW:463.60;测定值(HPLC MS):[M+H+]=464.3;产率:31%
PXN 1009
C31H29ClN4O3S;MW:573.12;测定值(HPLC MS):[M+H+]=574.4,[M+Na+]=595.4;产率:1%
PXN 1010
C31H30N4O3S;MW:538.67;测定值(HPLC MS):[M+H+]=539.4;产率:3%
PXN 1011
C29H28ClN3O3S;MW:534.08;测定值(HPLC MS):[M+H+]=534.3;产率:13%
PXN 1012
C29H29N3O3S;MW:499.64;测定值(HPLC MS):[M+H+]=500.3;产率:31%
PXN 1013
C28H27ClN4O3S;MW:535.07;测定值(HPLC MS):[M+H+]=535.3;产率:2%
PXN 1014
C30H34ClN5O3S;MW:580.2;测定值(HPLC MS):[M+Na+]=602.4;产率:14%
PXN 1015
C30H29N5O3S;MW:539.66;测定值(HPLC MS):[M+H+]=540.4;产率:1%
PXN 1016
C28H33ClN4O3S;MW:541.12;测定值(HPLC MS):[M+H+]=541.4;产率:4%
PXN 1017
C37H37ClN4O4S;MW:669.2;测定值(HPLC MS):[M+H+]=671.7,[M+Na+]=691.3;产率:3%
PXN 1018
C30H35N5O3S;MW:545.7;测定值(HPLC MS):[M+H+]=546.3;产率:18%
PXN 1019
C31H35N3O4S;MW:545.7;测定值(HPLC MS):[M+H+]=546.3,[M+Na+]=568.3;产率:27%
PXN 1020
C29H31N3O4S;MW:517.7
PXN 1021
C31H34ClN3O4S;MW:580.15;测定值(HPLC MS):[M+H+]=580.3;产率:20%
PXN 1022
C29H30ClN3O4S;MW:552.1
PXN 1023
C40H40ClN5O4S;MW:722.3;测定值(HPLC MS):[M+H+]=722.6,[M+Na+]=744.3;产率:4%
PXN 1024
C40H40ClN5O3S;MW:706.3;测定值(HPLC MS):[M+H+]=708.2;产率:1%
吡咯烷-2-酮骨架的其它修饰可使用以下步骤:
1)氧化还原变化:
方案1
在NaBH4的存在下,可将MCR-产物的羧酸官能团还原为对应的醇(参见PXN818-d1)。分离的醇可进一步转化为相应的醚(用各种卤素烷基化)或相应的酯(用酰氯酰基化)(方案1)。
而且,可将所得的醇氧化为相应的醛(Swern氧化)。或者,该醛也可通过羧酸的选择性还原来获得。醛可转化为许多其它化合物。
方案2
从方案2可见,胺可经由还原性胺化方法获得。此外,如方案3所示,Knoevenagel缩合也可用于修饰,以获得新的取代的吡咯烷-2-酮。
方案3
2)酰胺变化
利用各种胺,通过五氟苯酯的氨解合成不同的酰胺。如方案4所示,其它亲核化合物也适用于攻击五氟苯酯的活化碳,从而产生新的吡咯烷-2-酮衍生物。
方案4
3)酰胺的还原
将PXN717-d1用BMS(硼烷二甲基硫醚)处理,获得两种化合物PXN723-d1和PXN724-d1的混合物。
4)羧酸的同系化(Arndt-Eistert反应)
在Arndt-Eistert同系化反应的条件下,通过HPLC-MS分析观察到期望产物的形成(参见PXN845-d1)。如上所述,可以将所得羧酸进一步修饰。
在多组分反应中利用取代的琥珀酸酐,可制备式(I)的化合物,其中R7和/或R8不为氢(还参见Org.Lett.2007,9(20),4077-4080)。
5)消除
将PXN736-d1在室温下用1,1eq的氢化钠处理。由此,将消除产物PXN847-d1分离并用HPLC-MS表征。该产物可用于进一步修饰(如迈克尔加成)。
6)X为N的化合物的合成
这些化合物可根据以下方案制备:
此外,式(I)、(Ia)、(Ic)、(Id)、(Ie)和(If)的化合物可通过以下文献中所述的步骤制备,例如:Synlett,(11),1883-1885,2002;Organic Letters,9(20),4077-4080,2007;Organic Letters,8(18),3999-4002,2006;Tetrahedron,50(36),10701-8,1994;Journal of the Chemical Society,Chemical Communications,(5),386-7,1987;Journal of the Chemical Society,Chemical Communications,(5),386-7,1987;Tetrahedron Letters,49(35),5217-5219,2008以及Journal of Organic Chemistry,73(14),5566-5569,2008。
起始原料6-氯-1H-吲哚-3-甲醛的合成:
该Vilsmeyer反应根据H.G.O.Becker,Organikum,pp.364-365,Johann Ambrosius Barth Verlag,Heidelberg-Leipzig(1996)进行。在15℃至20℃的温度范围内,向装有温度计的三颈烧瓶内的5mL DMF中滴加1.8mL POCl3。随后,在20℃至30℃的温度范围内,滴加1g(6.6mMol)6-氯-1H-吲哚在2mL DMF中的溶液。将反应混合物在37℃下搅拌45分钟。随后,将反应混合物倒入15g冰与10mL水的混合物中并搅拌。在20℃至30℃的温度范围内,加入18mL中的3.4g NaOH。随后,将所得的混合物回流5分钟。冷却至室温后,将沉淀滤出,并用10mL冷水洗涤。从乙醇结晶获得白色固体状的6-氯-1H-吲哚-3-甲醛(1.04g,88%)。
增殖测定:
将5000个PA-1或PA-1/E6细胞平板接种于96孔平底板的每个孔中,并在37℃,5%CO2的条件下孵育过夜。向3个对照孔加入7.5微摩尔WST-1试剂(Roche Applied Sciences,Germany),并用SpectraMax250酶标仪(plate reader)测量OD650和OD450吸光值来测量接种的细胞的生长。如果OD650-OD450值大于0.5,则将板的剩余部分用式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物,其它药理试剂或溶剂对照孵育48小时。在此孵育后,如前所述,将WST-1试剂加入板的孔中,并计算OD650-OD450值。每种条件下进行一式三份孔的测定并确定标准偏差:全部实验至少独立进行三次。
凋亡膜联蛋白V和Tunel测定:
根据生产商说明,利用Guava个人细胞分析系统(Guava Personal Cell Analysis System)(PCAS,Guava Technologies,Hayward,CA),用Guava微管连接蛋白(Guava Nexin)和Guava Tunel试剂盒确定膜联蛋白V和BrdU-吸收水平。将1x106PA-1和PA-1/E6细胞在补充了10%FBS和各种浓度的式(I)化合物或DMSO的BME培养基中培养24h。将10μM的外消旋的Nutlin-3(Calbiochem,Roche)用作阳性对照。对于Guava微管连接蛋白测定,将细胞用胰蛋白酶处理,并通过在4℃下以1000rpm离心5min来收集。用冰冷的1×Nexin缓冲液洗涤后,将细胞重悬浮于相同的缓冲液中,用膜联蛋白V-PE和7-氨基放射菌素D在冰上避光标记20min,然后用PCAS分析。根据生产商的Guava Tunel测定方法,将细胞重悬浮于1%低聚甲醛中,在冰上孵育60min,在冰冷的PBS缓冲液中洗涤。随后在-20℃下,将细胞在冰冷的70%乙醇中固定至少16h。孵育后,将细胞在37℃下用BrdU DNA标记混合物标记60min,通过以1000rpm离心5min来收集。将细胞重悬浮于抗BrdU染色混合物中,并在室温下避光孵育45min,随后用PCAS分析。
凋亡测定
将温度敏感型H1299克隆以每孔50,000细胞的密度接种于6孔板上。将Saos2细胞以1x106细胞/100-mm板平板接种。将细胞转移至32℃下,并在温度转换后收获。将对照细胞保持在39℃下。利用生产商(Guava Technologies)提供的方法,通过Guava个人细胞计数器(Guava Technologies)、Guava TUNEL和多胱天蛋白酶检测试剂盒,用式(I)、(Ia)、(Ic)、(Id)、(Ie)或(If)的化合物进行TUNEL和多胱天蛋白酶测定。
Claims (16)
1.式(I)的化合物或其药学可接受的盐、酯、溶剂合物或水合物或者药学可接受的制剂
其中
V为C=O、C=S或CH2;
X为硫、氧或式CH2、CR4bR4c、NH、NR4b、SO、SO2的基团,或键;
Y为式CONR6、CH2NR6、CO、COO、CH2O、SO2NR6、NR6CO、NR6SO2、NR5aCONR6、NR6COO、OCONR6、CONR5aNR6、CONR5aOR6、CH2COCH2CONR6、CH2COO、COCR5aR6的基团或键;
n为1、2、3或0;
R1为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R2为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R3为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4b为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4c为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5a为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R6为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
残基R7彼此独立地为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
残基R8彼此独立地为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
或者基团R1、R2、R3、R4、R4b、R4c、R5、R5a、R6、R7和R8的两个一起为任选取代的环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、杂芳基、芳烷基或杂芳基烷基环体系的一部分。
2.式(Ia)的化合物或其药学可接受的盐、酯、溶剂合物或水合物或者药学可接受的制剂
其中
R1为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R2为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R3为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R4为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R5为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
R6为氢原子,或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
或者基团R5和R6一起为任选取代的杂环烷基、杂烷基环烷基、杂芳基或杂芳基烷基环体系的一部分,和/或R2和R3一起为任选取代的环烷基、烷基环烷基、杂环烷基、杂烷基环烷基、芳烷基或杂芳烷基环体系的一部分。
3.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R1为芳基、杂芳基、芳烷基或杂芳烷基。
4.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R1为式-A-Ar或A-Cy的基团,其中A为键、C1-C4烷基或C1-C6杂烷基,或者其中A为式-CHR1a-的基团,其中R1a为C1-C6杂烷基,Cy为任选取代的C3-C7环烷基或包含3至7个环原子的任选取代的杂环烷基,并且Ar为任选取代的苯环或包含5或6个环原子的任选取代的杂芳环,特别优选地Ar为任选取代的苯基或任选取代的吡啶残基。
5.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R2为氢。
6.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R3为任选取代的苯基、任选取代的苄基或具有1或2个环和5至10个环原子的任选取代的杂芳基残基,且所述环原子包含1、2、3或4个选自O、S和N的杂原子。
8.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R4为C1-C6烷基、C2-C6烯基、任选取代的C1-C4烷基-C3-C7环烷基、任选取代的苯环、任选取代的苄基或具有5或6个环原子的任选取代的杂芳环,且所述环原子包含1至3个选自O、S和N的杂原子。
9.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R5为烷基、杂烷基、杂环烷基、杂烷基环烷基或杂芳烷基,全部这些基团可以是取代的。
10.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R5选自以下基团:C1-C6烷基;杂烷基,其包含1-6个碳原子和1、2或3个选自O、S和N的杂原子;杂烷基环烷基,其包含C1-C4烷基或C1-C4杂烷基以及含有5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂环烷基;杂芳烷基,其包含C1-C4烷基或C1-C4杂烷基以及含有5或6个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂芳基;任选取代的杂芳基,其包含5或6个环原子和1、2或3个选自O、S和N的杂原子;以及任选取代的杂环烷基,其包含5或6个环原子和1、2或3个选自O、S和N的杂原子。
11.根据前述任一项权利要求所述的式(I)或(Ia)的化合物,其中R6为氢或C1-C4烷基。
12.根据权利要求1至8中任一项所述的式(I)或(Ia)的化合物,其中R5和R6一起为包含4、5、6或7个环原子和1、2或3个选自O、S和N的杂原子的任选取代的杂环烷基环的一部分。
13.根据权利要求1至8中任一项所述的式(I)或(Ia)的化合物,其中R5和R6一起为任选取代的哌嗪或哌啶环的一部分。
14.药物组合物,其包含前述任一项权利要求所述的化合物或其药学可接受的酯、前药、水合物、溶剂合物或盐,任选地与药学可接受的载体组合。
15.根据前述任一项权利要求所述的化合物或药物组合物在制备用于治疗癌症和/或病毒感染的药物中的用途。
16.根据权利要求1至14中任一项所述的化合物或药物组合物,其用于治疗癌症和/或病毒感染。
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PCT/EP2009/006670 WO2010028862A1 (en) | 2008-09-15 | 2009-09-15 | Pyrrolidin-2-ones as hdm2 ligands |
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JP (1) | JP5701758B2 (zh) |
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CN (1) | CN102149708A (zh) |
AR (1) | AR073578A1 (zh) |
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CA (1) | CA2736295A1 (zh) |
EA (1) | EA201100483A1 (zh) |
NZ (1) | NZ591073A (zh) |
PE (1) | PE20110931A1 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114558002A (zh) * | 2022-03-15 | 2022-05-31 | 四川轻化工大学 | 化合物在制备治疗肿瘤药物中的应用 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8563573B2 (en) | 2007-11-02 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
AU2009308687A1 (en) * | 2008-11-03 | 2010-05-06 | Chemocentryx, Inc. | Compounds for the treatment of osteoporosis and cancers |
US8293925B2 (en) * | 2009-09-21 | 2012-10-23 | Chemocentryx, Inc. | Pyrrolidinone carboxamide derivatives |
US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
KR20130056244A (ko) | 2010-04-22 | 2013-05-29 | 버텍스 파마슈티칼스 인코포레이티드 | 시클로알킬카르복스아미도-인돌 화합물의 제조 방법 |
JO2998B1 (ar) * | 2010-06-04 | 2016-09-05 | Amgen Inc | مشتقات بيبيريدينون كمثبطات mdm2 لعلاج السرطان |
JP2014502152A (ja) * | 2010-11-12 | 2014-01-30 | ダナ ファーバー キャンサー インスティテュート,インコーポレイテッド | 癌の治療及び診断 |
DK2684880T3 (en) | 2011-03-10 | 2018-05-22 | Daiichi Sankyo Co Ltd | DISPIROPYRROLIDINE DERIVATIVES |
WO2013025939A2 (en) * | 2011-08-16 | 2013-02-21 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
WO2013049250A1 (en) * | 2011-09-27 | 2013-04-04 | Amgen Inc. | Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer |
TWI586668B (zh) | 2012-09-06 | 2017-06-11 | 第一三共股份有限公司 | 二螺吡咯啶衍生物之結晶 |
US9505775B2 (en) | 2012-11-03 | 2016-11-29 | Boehringer Ingelheim International Gmbh | Inhibitors of cytomegalovirus |
CA2895504A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
US11407721B2 (en) | 2013-02-19 | 2022-08-09 | Amgen Inc. | CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer |
AU2014223547B2 (en) | 2013-02-28 | 2017-11-16 | Amgen Inc. | A benzoic acid derivative MDM2 inhibitor for the treatment of cancer |
AU2014236812B2 (en) | 2013-03-14 | 2018-03-01 | Amgen Inc. | Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer |
JOP20200296A1 (ar) | 2013-06-10 | 2017-06-16 | Amgen Inc | عمليات صنع وأشكال بلورية من mdm2 مثبط |
PL3071206T3 (pl) | 2013-11-22 | 2022-01-17 | CL BioSciences LLC | Antagoniści gastryny (eg yf476, netazepid) do leczenia i zapobiegania osteoporozie |
JP6577958B2 (ja) | 2014-04-11 | 2019-09-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | スピロ[3H−インドール−3,2’−ピロリジン]−2(1H)−オン誘導体およびMDM2−p53阻害剤としてのそれらの使用 |
PL3925607T3 (pl) | 2014-04-15 | 2023-10-30 | Vertex Pharmaceuticals Incorporated | Kompozycje farmaceutyczne do leczenia chorób, w których pośredniczy mukowiscydozowy przezbłonowy regulator przewodnictwa |
MY193597A (en) | 2014-05-29 | 2022-10-19 | Mitsubishi Tanabe Pharma Corp | Novel pyrrolidine compound and application as melanocortin receptor agonist |
WO2016001376A1 (en) | 2014-07-03 | 2016-01-07 | Boehringer Ingelheim International Gmbh | New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
DK3183254T3 (da) | 2014-08-21 | 2019-08-19 | Boehringer Ingelheim Int | Nye spiro[3h-indol-3,2 ?-pyrrolidin]-2(1h)-one forbindelser og derivater som mdm2-p53 inhibitorer |
WO2016100940A1 (en) | 2014-12-19 | 2016-06-23 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
EP3233799B1 (en) | 2014-12-19 | 2021-05-19 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
CA2976752C (en) | 2015-02-20 | 2019-12-17 | Daiichi Sankyo Company, Limited | Method for treating cancer by combined use |
JP6823587B2 (ja) | 2015-04-13 | 2021-02-03 | 第一三共株式会社 | Mdm2阻害剤とbtk阻害剤との併用治療法 |
MX2018000202A (es) | 2015-07-02 | 2018-06-27 | Horizon Orphan Llc | Analogos de cisteamina resistentes a la ado y sus usos. |
MX2018004207A (es) | 2015-10-09 | 2018-07-06 | Boehringer Ingelheim Int | Nuevos compuestos de espiro[3h-indol-3,2â´-pirrolidin]-2(1h)-ona y derivados como inhibidores de mdm2-p53. |
JP6837004B2 (ja) * | 2015-11-27 | 2021-03-03 | 田辺三菱製薬株式会社 | 新規イミダゾール化合物およびメラノコルチン受容体作動薬としての用途 |
ES2858151T3 (es) | 2016-05-20 | 2021-09-29 | Hoffmann La Roche | Conjugados de PROTAC-anticuerpo y procedimientos de uso |
KR20190068544A (ko) | 2016-10-17 | 2019-06-18 | 다이이찌 산쿄 가부시키가이샤 | Mdm2 저해제와 dna 메틸트랜스페라아제 저해제의 병용 치료법 |
WO2018185135A1 (en) | 2017-04-05 | 2018-10-11 | Boehringer Ingelheim International Gmbh | Anticancer combination therapy |
WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4219560A (en) * | 1978-04-17 | 1980-08-26 | Sandoz, Inc. | Piperidine and pyrrolidine alcohols |
EP1180513A1 (en) * | 1999-04-28 | 2002-02-20 | Takeda Chemical Industries, Ltd. | Cyclic amide compounds, process for the preparation of the same and uses thereof |
WO2008005268A1 (en) * | 2006-06-30 | 2008-01-10 | Schering Corporation | Substituted piperidines that increase p53 activity and the uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3361759A (en) * | 1963-10-07 | 1968-01-02 | Upjohn Co | 3-(2-pyrrolidinyl)-indoles and method of preparation |
US5574044A (en) * | 1994-10-27 | 1996-11-12 | Merck & Co., Inc. | Muscarine antagonists |
US7977358B2 (en) * | 2007-07-26 | 2011-07-12 | Hoffmann-La Roche Inc. | Pyrazol derivatives |
-
2009
- 2009-09-11 TW TW098130660A patent/TW201011009A/zh unknown
- 2009-09-11 AR ARP090103497A patent/AR073578A1/es not_active Application Discontinuation
- 2009-09-15 EP EP09778533.1A patent/EP2346852B1/en active Active
- 2009-09-15 WO PCT/EP2009/006670 patent/WO2010028862A1/en active Application Filing
- 2009-09-15 CA CA2736295A patent/CA2736295A1/en not_active Abandoned
- 2009-09-15 US US12/560,051 patent/US8119623B2/en active Active
- 2009-09-15 KR KR1020117008667A patent/KR20110063542A/ko not_active Application Discontinuation
- 2009-09-15 BR BRPI0918603A patent/BRPI0918603A2/pt not_active IP Right Cessation
- 2009-09-15 NZ NZ591073A patent/NZ591073A/xx not_active IP Right Cessation
- 2009-09-15 AU AU2009291155A patent/AU2009291155A1/en not_active Abandoned
- 2009-09-15 EA EA201100483A patent/EA201100483A1/ru unknown
- 2009-09-15 PE PE2011000624A patent/PE20110931A1/es not_active Application Discontinuation
- 2009-09-15 JP JP2011526418A patent/JP5701758B2/ja active Active
- 2009-09-15 CN CN200980135970XA patent/CN102149708A/zh active Pending
-
2012
- 2012-01-17 US US13/351,914 patent/US9045414B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4219560A (en) * | 1978-04-17 | 1980-08-26 | Sandoz, Inc. | Piperidine and pyrrolidine alcohols |
EP1180513A1 (en) * | 1999-04-28 | 2002-02-20 | Takeda Chemical Industries, Ltd. | Cyclic amide compounds, process for the preparation of the same and uses thereof |
WO2008005268A1 (en) * | 2006-06-30 | 2008-01-10 | Schering Corporation | Substituted piperidines that increase p53 activity and the uses thereof |
Non-Patent Citations (4)
Title |
---|
JINGQIANG WEI,ET AL.: "Diastereoselective Synthesis of γ-Lactams by a One-Pot,Four-Component Reaction", 《ORGANIC LETTERS》 * |
PUI YEE NG,ET AL.: "Cycloaddition Reactions of Imines with 3-Thiosuccinic Anhydrides: Synthesis of the Tricyclic Core of Martinellic Acid", 《ORGANIC LETTERS》 * |
PUI YEE NG,ET AL.: "Synthesis of Diverse Lactam Carboxamides Leading to the Discovery of a New Transcription-Factor Inhibitor", 《ANGEWANDTE CHEMIE INTATIONAL EDITION》 * |
SHINICHI IMAMURA,ET AL.: "CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives", 《CHEMICAL AND PHARMACEUTICAL BULLETIN》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114558002A (zh) * | 2022-03-15 | 2022-05-31 | 四川轻化工大学 | 化合物在制备治疗肿瘤药物中的应用 |
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TW201011009A (en) | 2010-03-16 |
US20120122839A1 (en) | 2012-05-17 |
EP2346852A1 (en) | 2011-07-27 |
JP5701758B2 (ja) | 2015-04-15 |
JP2012502887A (ja) | 2012-02-02 |
US20100075949A1 (en) | 2010-03-25 |
NZ591073A (en) | 2012-11-30 |
US9045414B2 (en) | 2015-06-02 |
PE20110931A1 (es) | 2012-01-25 |
WO2010028862A1 (en) | 2010-03-18 |
AU2009291155A1 (en) | 2010-03-18 |
KR20110063542A (ko) | 2011-06-10 |
EP2346852B1 (en) | 2015-02-25 |
CA2736295A1 (en) | 2010-03-18 |
EA201100483A1 (ru) | 2011-10-31 |
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