CN113620887A - 一类sirt5蛋白抑制剂及其用途 - Google Patents
一类sirt5蛋白抑制剂及其用途 Download PDFInfo
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- CN113620887A CN113620887A CN202111071535.4A CN202111071535A CN113620887A CN 113620887 A CN113620887 A CN 113620887A CN 202111071535 A CN202111071535 A CN 202111071535A CN 113620887 A CN113620887 A CN 113620887A
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
Description
技术领域
本发明涉及医药技术领域,尤其涉及一类新型SIRT5蛋白抑制剂及其用途。
背景技术
沉默信息调节因子2(Silent Information Regulator 2,简称SIRT)是一类依赖辅酶NAD+去除组蛋白或非组蛋白赖氨酸ε-N上酰基的非典型组蛋白去乙酰化酶,共包含SIRT1-SIRT7七个成员。SIRT家族蛋白均具有一个Zn2+结合域、一个Rossmann折叠域和一个催化核心结构域(即底物和NAD+结合位点)。与SIRT家族其他成员相比,SIRT5因含有更大的赖氨酸酰基结合口袋且口袋中包含一个特异性酪氨酸(Tyr102)和精氨酸残基(Arg105)的结构特点,使其除有微弱的去乙酰化活性外,还具有显著的去丙二酰化,去琥珀酰化和去谷氨酰化等酸性酰基化活性,且催化效率约为去乙酰化的1000倍。大量研究发现,SIRT5不仅可调控CPS1、UOX和CytC等蛋白的去乙酰化从而发挥促进尿素循环等生理功能;还可调控HMGCS2、ECHA、GLS、SODl和SHMT2等蛋白的去琥珀酰化调控酮体合成、脂肪酸β-氧化,细胞自噬和线粒体自噬,ROS的清除和丝氨酸代谢等;还可调控GAPDH、ALDOB等蛋白的去丙二酰化从而调控葡萄糖的代谢;另外,还可催化G6PD、GLUD1和CPS1蛋白的去谷氨酰化,从而促使细胞免受氧化损伤,和谷胺酰胺的代谢。鉴于SIRT5重要的生理作用,研究表明SIRT5异常表达与肿瘤、心血管疾病和神经系统疾病等的发生发展密切相关,被认为是相应疾病药物开发的一个有效靶点。
随着SIRT5在不同疾病中扮演的角色逐渐被揭示,近年来SIRT5抑制剂陆续被报道,然而这些抑制剂中仅有少数肽类似物表现出较好的体内外活性,少有的非肽类小分子抑制剂对SIRT5抑制活性都不高且为非特异性抑制剂。此外,由于非肽类小分子抑制剂在药代动力学等成药性方面更具优势,因此目前亟需研发一些新型高效特异性SIRT5小分子抑制剂,为靶向SIRT5的相关疾病药物开发提供候选药物分子。
发明内容
针对现有技术的不足,本发明提供了一类新型SIRT5蛋白抑制剂。
为了实现上述目的,本发明采用的技术方案是这样的:
式(Ⅰ)的化合物或其立体异构体、互变异构体、手性异构体或其盐,
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;
优选的,所述R1选自C1~C3烷基、苯基中的一种;所述C1~C3烷基、苯基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基和苯基所取代;所述卤素为氟、氯、溴原子中的一种。
优选的,所述化合物为:
本发明还提供一种制备上述化合物的方法,其特征在于:
①、化合物A与化合物B反应,得到化合物C1或C2;
其中,化合物A与化合物B的摩尔比为1:1-3;
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;
R5为氨基保护基;
②、所述化合物C经过缩合反应得到化合物(Ⅰ)。
本发明还提供一种制备上述化合物的方法,其特征在于:
a、按照上述的方法,首先制备得到化合物C1或C2;
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;
R5为氨基保护基;
b、化合物C经过水解反应,得到化合D;所述化合物D与化合物E反应得到化合物F,反应式如下;
其中,化合物D与化合物E的摩尔比为1:1-3;
c、所述化合物F经过缩合反应得到化合物(Ⅰ)。
本发明还提供了上述化合物或其立体异构体、互变异构体或其盐在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
本发明还提供了上述化合物或其立体异构体、互变异构体或其盐在制备治疗和/或预防肿瘤的药物中的用途。
优选的,所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
本发明还提供一种治疗和/或预防肿瘤的药物组合物,包括上述化合物或其立体异构体、互变异构体或其盐,或其前药分子和医学上可接受的载体本发明具备以下有益效果:
本发明提供了如式(1)所示的新化合物,该类化合物具有显著的SIRT5蛋白抑制活性,为SIRT5小分子抑制剂的开发和应用提供了更多选择可能性。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~Cb烷基表明任何包含“a”至“b”个碳原子的烷基。因此,例如,C1~C4烷基是指包含1~4个碳原子的烷基,换句话说,C1~C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料,是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分,它具有一定生理活性,但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位,而仅仅发挥辅助功效,这些辅助功效仅仅是对该成分已知活性的利用,是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用,仍然属于本发明保护的范围。
附图说明
图1-图31分别为本发明化合物1-17的1H NMR或13C NMR图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。若未特别指明,实施举例中所用的技术手段为本领域技术人员所熟知的常规手段。
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
1.本发明公开了式(Ⅰ)的化合物或其立体异构体、互变异构体或其盐,
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;作为优选的方案,R1选自C1~C3烷基、苯基中的一种;所述C1~C3烷基、苯基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基和苯基所取代;所述卤素为氟、氯、溴原子中的一种。
本发明制备的化合物包括:
2.本发明提供了一种制备权利要求上述化合物的方法,
①、化合物A与化合物B反应,得到化合物C;
其中,化合物A与化合物B的摩尔比为1:1-3;
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;
R5为氨基保护基;
②、所述化合物C经过缩合反应进一步得到化合物(Ⅰ)。
化合物中的1-13和15的结构差别在于嘧啶环上-2位取代基不同,故以化合物1为例进一步阐述合成方法:
其中,步骤I:将1a(2g,9.05mmol)、N-Boc-1,3-丙二胺(1.74g,9.95mmol)以及Cs2CO3(5.90g,18.10mmol)加入梨形瓶中,用乙腈作溶剂室温反应20min即可反应完成。后处理需先加水,并用EA(40ml,3次)萃取,然后柱层析(PE:EA=6:1→4:1)即得白色固体1.63g(50%),即1b(化合物A)。
步骤II:将1b(200mg,0.56mmol)放入封管,再加入适量甲醇溶解(3~5ml),先在常温下加入HCl(15μl)活化1h,再加入4-溴-2-甲基苯胺(207mg,1.11mmol)并将封管放入115℃油锅中反应8h即可反应完毕。然后将反应液旋干进行柱层析(DCM:MeOH=50:1→10:1),旋干得到白色固体106mg(47%),即1c(化合物C)。另外化合物8、10、11、13、15在该步Boc基团不会脱去,但是后处理方法一致,柱层析层析液用PE:EA=4:1→2:1即得,然后用三氟乙酸:二氯甲烷(v/v)=4:1脱去Boc(室温搅拌30min),将反应液pH调至8,萃取即得相应产品。
步骤III:将β-丙氨酸乙酯盐酸盐(48mg,0.31mmol)溶于干燥DCM中,并加入TEA(108μl,0.78mmol)与CS2(24μl,0.39mmol)常温活化40min,再在冰浴下加入BTC(23mg,0.08mmol)的DCM溶液,添加结束后继续室温活化约100min,然后将反应液旋干,并加入1c(106mg,0.26mmol)与TEA(108μl,0.78mmol)的DCM溶液,常温搅拌过夜。反应结束后采用柱层析(DCM:MeOH=150:1)缓慢过柱,旋干后得到白色固体88mg(62%),即1d。
步骤IV:将1d(88mg,0.16mmol)与NaOH(12mg,0.31mmol)溶于EtOH:H2O=2:1的混合溶剂中(6ml),室温反应20min。后处理时应先将反应液pH调至7左右,再将反应液中的EtOH尽量旋干,再将反应液pH调至5~6之间,EA(20ml,3次)萃取,应在每次萃取时注意水层pH值,使其在每次开始萃取时pH都保持在5~6之间,之后将EA层全部旋干后采用薄层色谱进行纯化(DCM:MeOH=8:1),最终收得白色固体60mg(70%),即化合物1。
化合物1的1H NMR和13C NMR数据如下:
3-(3-(3-((2-((4-Bromo-2-methylphenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(1).1H NMR(400MHz,DMSO-d6)δ12.23(s br,1H),8.96(s,1H),8.81(s,1H),8.21(t,J=5.6Hz,1H),7.57(s,1H),7.53(d,J=8.8Hz,1H),7.43-7.35(m,3H),4.24(q,J=7.2Hz,2H),3.26(s,2H),3.37(q,J=6.0Hz,4H),2.48(t,J=6.8Hz,2H),2.23(s,3H),1.72(p,J=6.8Hz,2H),1.29(s,J=6.8Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.70,166.48,161.74,161.73,160.72,137.31,135.15,132.97,128.94,127.59,116.95,97.25,60.33,41.74,37.92,34.21,30.49,29.23,18.22,14.70ppm.
a、按照上述的方法,制备得到化合物C;
R1选自氢原子、烷基、环烷基、芳基和杂芳基中的一种;所述烷基、环烷基、芳基和杂芳基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基、芳基和杂芳基所取代;
R5为氨基保护基;
b、化合物C经过水解反应之后,得到化合D;所述化合物D与化合物E进一步反应得到化合物F;
其中,化合物D与化合物E的摩尔比为1:1-3;
c、化合物F经过缩合反应进一步得到化合物(Ⅰ)。
化合物14、16和17的结构也较为类似,以化合物16为例进一步阐述合成方法:
其中,步骤I与上述步骤I完全一致;
步骤II:将16b(化合物C)(600mg,1.72mmol)放入封管,再加入适量甲醇溶解(5ml),先在常温下加入HCl(40μl)活化1h,再加入2-氯苯胺(349μl,5.02mmol)并将封管放入115℃油锅中反应8h即可反应完毕。然后将反应液旋干进行柱层析(DCM:MeOH=50:1→10:1),旋干得到白色固体355mg(61%),即16c(化合物F)。
步骤III:将16c(355mg,1.02mmol)、二碳酸二叔丁酯(245mg,1.12mmol)、DMAP(25mg,0.20mmol)、TEA(283μl,2.04mmol)溶于干燥DCM,室温反应45min即可反应完毕。柱层析(PE:EA=4:1)纯化得416mg(91%)白色固体,即16d。由于化合物14进行至步骤II时,Boc基团并不会被脱去,故不需进行该步骤。
步骤IV:将16d(416mg,0.93mmol)与NaOH(74mg,1.96mmol)溶于EtOH:H2O=3:1的混合溶剂中(9ml),80℃回流搅拌2h。后处理时应先将反应液pH调至7左右,再将反应液中的EtOH尽量旋干,再将反应液pH调至5~6之间,EA(30ml,3次)萃取,应在每次萃取时注意水层pH值,使其在每次开始萃取时pH都保持在5~6之间,之后将EA层全部旋干即可收得白色固体342mg(88%),即化合物16e(化合物D)。
步骤V:将16e(171mg,0.41mmol)、HOBt(83mg,0.61mmol)、EDCI(117mg,0.61mmol)以及TEA(169μl,1.22mmol)溶于DCM中常温活化4h后,加入苄胺(89μl,0.81mmol)室温反应30min。柱层析(PE:EA=4:1→1:1)纯化,收白色固体151mg(72%),即16f(化合物F)。
步骤VI:将16f(151mg,0.30mmol)溶于DCM中,搅拌下加入三氟乙酸(1ml)室温反应20min。将反应液pH调至8,EA(20ml,3次)萃取,旋干得白色固体132mg,即16g。
步骤VII:将β-丙氨酸乙酯盐酸盐(59mg,0.38mmol)溶于干燥DCM中,并加入TEA(134μl,0.97mmol)与CS2(29μl,0.48mmol)常温活化40min,再在冰浴下加入BTC(28mg,0.10mmol)的DCM溶液,添加结束后继续室温活化约100min,然后将反应液旋干,并加入16g(132mg,0.32mmol)与TEA(134μl,0.97mmol)的DCM溶液,常温搅拌过夜。反应结束后采用柱层析(DCM:MeOH=200:1)缓慢过柱,旋干后得到白色固体121mg(66%),即16h。
步骤IIX:将16h(121mg,0.21mmol)与NaOH(17mg,0.42mmol)溶于EtOH:H2O=2:1的混合溶剂中(6ml),室温反应20min。后处理时应先将反应液pH调至7左右,再将反应液中的EtOH尽量旋干,再将反应液pH调至5~6之间,EA(20ml,3次)萃取,应在每次萃取时注意水层pH值,使其在每次开始萃取时pH都保持在5~6之间,之后将EA层全部旋干后采用薄层色谱进行纯化(DCM:MeOH=8:1),最终收得白色固体75mg(66%),即化合物16。
化合物16的1H NMR和13C NMR数据如下:
3-(3-(3-((5-(Benzylcarbamoyl)-2-((2-chlorophenyl)amino)pyrimidin-4-yl)amin o)propyl)thioureido)propanoic acid(16).1H NMR(400MHz,DMSO-d6)8.98(t,J=5.6Hz,1H),8.86(t,J=6.0Hz,1H),8.55(s,1H),8.48(s,1H),8.00(dd,J=8.4Hz,J=1.2Hz,1H),7.61(t,1H),7.48(dd,J=8Hz,J=1.6Hz,1H),7.74(t,J=4.8Hz,1H),7.32(m,5H),7.25(m,1H),7.48(td,J=7.6Hz,J=1.2Hz,1H),4.44(d,J=6Hz,2H),3.56(s,2H),3.37(q,J=6.0Hz,4H),2.47(t,J=6.8Hz,2H),1.74(p,J=6.8Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ173.73,167.09,161.81,160.54,156.93,140.14,136.68,129.71,128.75,127.75127.65,127.19,126.42,125.49,125.22,101.26,55.37,42.58,41.87,38.03,34.29,30.48,29.14ppm.
3.本发明化合物对体外SIRT2蛋白的抑制活性
测试方法如下:
(1)实验材料:
重组的人SIRT5蛋白(方法见:Eur.J.Med.Chem.(2020)112201);荧光多肽底物P16(Ac-Leu-Gly-Ser-Lys(Su)-AMC,丹港生物科技公司定制);Sigma公司的阳性对照产品Suramin;所有合成的目标化合物。
(2)实验方法:
具体操作方法参见Eur.J.Med.Chem.(2020)112201;其中测试孔板中每孔加入60μL样品,包括SIRT5(0.2μM),P16(5μM),NAD+(200μM),和不同浓度的化合物以及150mM NaCl、25mM Tris(pH 8.0)和10%甘油,且所有测试孔设置3个平行实验。测试获得的量效关系用GraphPad来拟合相应的半数抑制有效浓度(IC50)。
(3)实验结果:
通过以上实验方法,测试了本发明化合物针对SIRT5的抑制活性,具体的化合物对SIRT5的半数抑制有效浓度(IC50)见表1,。
表1.本发明化合物对SIRT5的抑制活性
上述结果表明,本发明化合物对SIRT5具有良好的抑制活性,可以用于制备沉默信息调节因子5相关蛋白的抑制剂。
本发明其他化合物的1H NMR和13C NMR数据如下:
化合物2:
3-(3-(3-((2-((3,5-Dimethoxyphenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)pro pyl)thioureido)propanoic acid(2).1H NMR(400MHz,DMSO-d6)δ12.18(sbr,1H),9.94(s,1H),8.59(s,1H),8.51(m,1H),7.62(s,1H),7.44(m,1H),7.06(d,J=2.0Hz,2H),6.20(d,J=2.4Hz,1H),4.27(q,J=7.2Hz,2H),3.73(s,6H),3.56(q,J=6Hz,4H),3.44(s,2H),2.48(t,J=6.8Hz,2H),1.83(p,J=6.8Hz,2H),1.31(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ13C NMR(101MHz,DMSO-d6)δ173.53,165.80,161.31,160.94,158.27,157.16,141.13,99.99,98.71,97.72,95.53,60.85,55.60,41.54,38.71,36.81,34.13,28.90,14.62ppm.
化合物3:
3-(3-(3-((2-((2-Bromo-3-methylphenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(3).1H NMR(400MHz,DMSO-d6)δ12.00(s br,1H),8.74(s,1H),8.52(s,1H),8.24(t,J=5.6Hz,1H),7.68(d,J=8Hz,1H),7.57(m,1H),7.41(t,J=5.2Hz,1H),7.28(t,J=8Hz,1H),7.14(d,J=7.2Hz,1H),4.25(q,J=7.2Hz,2H),3.56(s,2H),3.38(q,J=6.0Hz,4H),2.48(t,J=6.8Hz,2H),2.40(s,3H),1.73(p,J=6.8Hz,2H),1.29(t,J=7.2Hz,3H)ppm..13C NMR(101MHz,DMSO-d6)δ173.70,166.42,161.71,161.52,160.72,138.64,137.82,127.54,127.20,124.15,121.31,97.63,60.41,46.06,41.67,38.10,34.2,29.17,23.95,14.68,9.79ppm.
化合物4:
3-(3-(3-((5-(Ethoxycarbonyl)-2-((3-fluoro-2-methylphenyl)amino)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(4).1H NMR(400MHz,DMSO-d6)δ12.18(s br,1H),9.10(s,1H),8.52(s,1H),8.20(t,J=5.6Hz,1H),7.55(s,1H),7.39(d,J=7.6Hz,2H),7.20(q,J=6.8Hz,1H),6.96(t,J=8.8Hz,1H),4.24(q,J=6.8Hz,2H),3.57(s,2H),3.37(q,J=6Hz,4H),2.48(t,J=6.8Hz,2H),2.12(s,3H),1.71(p,J=6.8Hz,2H),1.28(t,J=7.2Hz,3H)ppm..13C NMR(101MHz,DMSO-d6)δ173.67,166.49,162.38,161.94,161.76,160.75,159.99,139.73,139.66,126.66,126.56,121.88,120.02,119.85,111.57,111.34,97.29,60.34,41.69,37.91,34.16,29.19,14.68,10.26ppm.
化合物5:
3-(3-(3-((2-((3-Bromo-2-methylphenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(5).1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.51(s,1H),8.19(t,J=5.6Hz,1H),7.58(s,1H),7.44(m,3H),7.13(t,J=8Hz,1H),4.24(q,J=7.2Hz,2H),3.56(s,2H),3.34(q,J=6Hz,4H),2.48(t,J=6.4Hz,2H),2.28(s,3H),1.70(p,J=6.4Hz,2H),1.28(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.73,166.49,162.03,161.74,160.80,139.37,133.19,129.33,127.48,126.25,124.97,97.28,60.33,55.35,41.71,37.87,34.25,29.21,18.91,14.69ppm.
化合物6:
3-(3-(3-((5-(Ethoxycarbonyl)-2-((2-methoxyphenyl)amino)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(6).1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.56(s,1H),8.40(t,1H),8.34(s,1H),8.15(d,J=7.6Hz,1H),7.60(t,1H),7.41(t,J=5.2Hz,1H),7.07(m,2H),6.91(m,1H),4.27(q,J=6.8Hz,2H),3.86(s,3H),3.56(s,2H),3.49(q,J=6Hz,4H),2.49(m,2H),1.80(p,J=6.8Hz,2H),1.31(t,J=6.8Hz,3H)ppm.
化合物7:
3-(3-(3-((2-((2-Chlorophenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propyl)t hioureido)propanoic acid(7).1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.54(s,1H),8.25(t,J=6.0Hz,1H),7.88(dd,J=8.4Hz,J=1.2Hz,1H),7.61(t,1H),7.49(dd,J=8Hz,J=1.2Hz,1H),7.45(t,J=5.2Hz 1H),7.36(td,J=8Hz,J=1.2Hz,1H),7.16(td,J=7.6Hz,J=1.2Hz,1H),4.24(q,J=6.8Hz,2H),3.57(s,2H),3.39(q,J=6Hz,4H),2.48(t,J=6.8Hz,2H),1.73(p,J=6.8Hz,2H),1.29(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.73,166.40,161.69,161.44,160.71,136.33,129.78,127.73,127.52,126.56,126.00,90.77,65.49,60.44,41.69,38.09,34.28,29.15,19.12,14.67ppm.
化合物8:
3-(3-(3-((2-([1,1'-Biphenyl]-2-ylamino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(8).1H NMR(400MHz,DMSO-d6)δ12.23(sbr,1H),8.54(s,1H),8.41(s,1H),8.15(t,J=5.6Hz,1H),7.55(d,J=7.6Hz,1H),7.55(s,1H),7.38(m,8H),7.26(td,J=7.2Hz,J=1.2Hz,1H),4.22(q,J=7.2Hz,2H),3.57(s,2H),3.35(q,J=6Hz,4H),2.49(t,J=6.4Hz,2H),1.70(p,J=6.8Hz,2H),1.29(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.68,166.48,161.86,161.66,160.62,139.62,136.25,130.57,129.27,128.86,128.18,127.62,125.59,96.90,60.26,41.26,37.96,34.18,29.26,22.94,14.69,11.70ppm.
化合物9:
3-(3-(3-((5-(Ethoxycarbonyl)-2-(propylamino)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(9).1HNMR(400MHz,DMSO-d6)δ12.18(s br,1H),9.73(s,1H),8.57(s,1H),8.31(t,J=5.2Hz,1H),7.79(d,J=8Hz,2H),7.61(s,1H),7.41(t,1H),7.31t,J=8Hz,1H),6.98(t,J=7.2Hz,1H),4.25(q,J=7.2Hz,2H),3.53(m,6H),2.49(t,J=6.4Hz,2H),1.83(p,J=6.8Hz,2H),1.30(t,J=7.2Hz,3H)ppm..13C NMR(101MHz,DMSO-d6)δ173.70,166.45,161.77,161.00,160.46,140.40,131.96,128.95,122.51,119.98,97.08,65.49,60.38,41.83,38.43,34.18,30.57,29.18,14.69ppm.
化合物10:
3-(3-(3-((5-(Ethoxycarbonyl)-2-(phenylamino)pyrimidin-4-yl)amino)propyl)thioureido)propanoic acid(10).1H NMR(400MHz,DMSO-d6)12.20(s br,1H),8.39(s,1H),8.14(s,1H),7.57(s,1H),7.50(t,J=5.2Hz,1H),7.37(m,1H),4.20(q,J=7.2Hz,2H),3.57(s,2H),3.45(m,4H),3.24(q,J=5.6Hz,2H),2.48(t,J=6.8Hz,2H),1.79(p,J=6.8Hz,2H),1.53(p,J=7.2Hz,2H),1.29(t,J=6.8Hz,3H),0.88(t,J=7.2Hz,3H)ppm.13CNMR(101MHz,DMSO-d6)δ173.78,166.76,163.07,161.85,160.58,129.12,96.11,94.81,59.93,42.6,37.84,34.20,29.32,22.96,22.63,14.73,11.97ppm.
化合物11:
3-(3-(3-((5-(Ethoxycarbonyl)-2-((3-phenylpropyl)amino)pyrimidin-4-yl)amino)propyl)t hioureido)propanoic acid(11).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.89(s br,1H),7.57(m,2H),7.22(m,5H),4.20(q,J=7.2Hz,2H),3.53(s,2H),3.40(q,J=5.6Hz,4H),3.30(q,J=6.4Hz,4H),2.62(t,J=7.2Hz,2H),2.36(t,J=6Hz,2H),1.82(p,J=6.8Hz,2H),1.75(p,J=6.8Hz,2H),1.27(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ174.69,166.76,163.18,163.07,161.83,160.84,160.62,142.33,128.77,128.71,126.12,94.87,65.49,59.94,41.86,37.81,35.48,33.20,31.24,29.35,19.12,14.73,14.00ppm.
化合物12:
3-(3-(3-((2-((3,5-Difluorophenyl)amino)-5-(ethoxycarbonyl)pyrimidin-4-yl)amino)propy l)thioureido)propanoic acid(12).1H NMR(400MHz,DMSO-d6)12.23(sbr,1H),10.10(s,1H),8.60(s,1H),8.39(s,1H),7.58(m,3H),7.41(s,1H),6.76(tt,J=9.2Hz,J=1.2Hz,1H),4.26(q,J=7.2Hz,2H),3.53(m,6H),2.49(t,J=6.8Hz,2H),1.84(p,J=6.4Hz,2H),1.31(t,J=7.2Hz,3H)ppm.13C NMR(101MHz,DMSO-d6)δ173.59,166.26,164.09,161.61,160.72,160.41,143.16,102.40,102.11,98.14,97.11,60.59,41.59,38.50,34.09,33.73,28.98,14.63ppm.
化合物13:
3-(3-(3-((2-(Ethoxycarbonyl)-5-(phenethylamino)phenyl)amino)propyl)thioureido)prop anoic acid(13).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.07(t,1H),7.55(m,2H),7.31(m,6H),5.04(m,2H),4.48(m,2H),3.56(s,4H),2.47(s,2H),1.68(m,2H),1.27(m,7H)ppm.13C NMR(101MHz,DMSO-d6)δ173.88,166.29,162.98,161.81,160.88,140.60,128.61,127.83,127.02,95.54,67.31,44.73,41.85,37.85,41.86,34.27,29.27,22.20,22.08ppm.
化合物14:
3-(3-(3-((2-(Benzylamino)-5-(cyclopropylcarbamoyl)pyrimidin-4-yl)amino)propyl)thiou reido)propanoic acid(14).1HNMR(400MHz,DMSO-d6)12.17(s br,1H),8.87(m,1H),8.29(s,1H),8.05(s,1H),7.65(m,3H),7.30(m,4H),7.20(m,1H),4.46(s,2H),3.56(s,2H),3.35(m,4H),2.72(m,J=4.0Hz,1H),2.47(t,J=6.8Hz,2H),1.69(s,2H),0.63(m,2H),0.50(m,2H)ppm.
化合物15:
3-(3-(3-((5-(Ethoxycarbonyl)-2-methoxypyrimidin-4-yl)amino)propyl)thioureido)propa noic acid(15).1H NMR(400MHz,DMSO-d6)8.61(s,1H),8.37(t,J=5.6Hz,1H),7.73(m,1H),7.48(s,1H),4.28(q,J=7.8Hz,2H),3.89(s,3H),3.51(m,6H),2.44(t,J=6.8Hz,2H),1.79(p,J=6.8Hz,2H),1.31(t,J=7.2Hz,3H)ppm.
化合物17:
3-(3-(3-((2-((2-Chlorophenyl)amino)-5-(cyclopropylcarbamoyl)pyrimidin-4-yl)amino)pr opyl)thioureido)propanoic acid(17).1H NMR(400MHz,DMSO-d6)8.99(t,J=5.6Hz,1H),8.41(s,2H),8.25(d,J=3.6Hz,1H),8.02(dd,J=8.4Hz,J=1.2Hz,1H),7.63(s,1H),7.45(m,2H),7.34(td,J=7.6Hz,J=1.2Hz,1H),7.10(td,J=7.6Hz,J=1.2Hz,1H),3.57(s,2H),3.38(q,J=6Hz,4H),2.76(m,J=4Hz,1H),2.48(t,J=6.8Hz,2H),1.75(p,J=6.8Hz,2H),0.68(m,2H),0.55(m,2H)ppm.13C NMR(101MHz,DMSO-d6)δ173.76,168.43,161.66,160.41,156.87,136.68,139.68,127.73,126.16,125.23,125.07,101.35,55.36,41.83,38.03,34.30,29.16,23.07,6.20ppm.
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的化合物或其立体异构体、互变异构体或其盐,其特征在于:所述R1选自C1~C3烷基、苯基中的一种;所述C1~C3烷基、苯基分别被一个或多个各自独立的氢原子、烷基、卤素、甲氧基和苯基所取代;所述卤素为氟、氯、溴原子中的一种。
7.权利要求1-4任一项所述化合物或其立体异构体、互变异构体或其盐在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
8.权利要求1-4任一项所述化合物或其立体异构体、互变异构体或其盐在制备治疗和/或预防肿瘤的药物中的用途。
9.根据权利要求8所述的用途,其特征在于:所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
10.一种治疗和/或预防肿瘤的药物组合物,其特征在于:包括权利要求1所述化合物或其立体异构体、互变异构体或其盐,或其前药分子和医学上可接受的载体。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110257174A1 (en) * | 2008-09-29 | 2011-10-20 | Sirtris Pharmaceuticals, Inc. | Chromenone analogs as sirtuin modulators |
CN103097545A (zh) * | 2010-07-07 | 2013-05-08 | 康奈尔大学 | Sirt5调节剂及其筛选方法 |
CN104010651A (zh) * | 2011-09-07 | 2014-08-27 | 康奈尔大学 | 通过靶向Sirt5治疗癌症的方法 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110257174A1 (en) * | 2008-09-29 | 2011-10-20 | Sirtris Pharmaceuticals, Inc. | Chromenone analogs as sirtuin modulators |
CN103097545A (zh) * | 2010-07-07 | 2013-05-08 | 康奈尔大学 | Sirt5调节剂及其筛选方法 |
CN104010651A (zh) * | 2011-09-07 | 2014-08-27 | 康奈尔大学 | 通过靶向Sirt5治疗癌症的方法 |
Non-Patent Citations (1)
Title |
---|
YANG F. ET AL.: "Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryllysine substrates", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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