CN115417877B - 组蛋白去乙酰化酶抑制剂及其制备和在制备抗癌症药物上的应用 - Google Patents
组蛋白去乙酰化酶抑制剂及其制备和在制备抗癌症药物上的应用 Download PDFInfo
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- CN115417877B CN115417877B CN202211144260.7A CN202211144260A CN115417877B CN 115417877 B CN115417877 B CN 115417877B CN 202211144260 A CN202211144260 A CN 202211144260A CN 115417877 B CN115417877 B CN 115417877B
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明公开组蛋白去乙酰化酶抑制剂及其制备和在制备抗癌症药物上的应用。本发明提供了式(I)所示结构的一类结构新颖的组蛋白去乙酰化酶抑制剂、含有式(I)化合物的药物组合物及水合物,以及这些化合物的同位素衍生物、手性异构体、变构体、不同的盐、前药和制剂等。本发明还提供了所述一类结构新颖的组蛋白去乙酰化酶抑制剂的制备方法、用途,以及这些化合物对血液癌细胞株、淋巴瘤细胞株增殖抑制的活性。
Description
技术领域
本发明属于抗肿瘤药物合成技术领域,具体地说,涉及组蛋白去乙酰化酶抑制剂及其制备和在制备抗癌症药物上的应用。
背景技术
在癌细胞中,组蛋白去乙酰化酶(histone deacetylases,HDACs)的过度表达导致乙酰化作用增强,促使组蛋白带正电荷,进而增加DNA与组蛋白之间的引力,使松弛的核小体变得紧密,影响特定基因表达,如抑癌基因。施加HDACs抑制剂可通过提高染色质特定区域的组蛋白乙酰化,调控细胞凋亡及分化。经典的HDACs抑制剂药效团模型包括三个部分:(1)帽子(cap)结构,用于识别HDAC活性;(2)锌离子螯合基团(ZBG),用于螯合HDAC催化口袋底部的锌离子;(3)连接链,用于连接cap与ZBG,并与活性口袋中的疏水性通道相互作用。而根据结构特点,已报道的HDACs抑制剂可大致分为四大类:异羟肟酸类、苯甲酰胺类、环肽类和短链脂肪酸类。其中异羟肟酸类包括曲古抑菌素和伏立诺他(SAHA)及其衍生物等。这一类HDAC抑制剂的研究倍受瞩目,它被证明可在小剂量、低浓度情况下导致肿瘤分化,抑制肿瘤生长。因此,我们设计与合成了一些新型的HDACs抑制剂以扩大其在临床上的应用范围。
发明内容
本发明的第一个目的是针对现有技术的不足,提供一种组蛋白去乙酰化酶抑制剂化合物。
一种组蛋白去乙酰化酶抑制剂化合物,或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体,或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物,其结构如式(I)所示:
其中L1,L2与一起可以组合成稳定的化学结构。
选自以下结构之一:
其中表示/>与L1连接的位点;
L1选自以下结构之一:
其中表示L1与L2连接的位点;
L2选自以下结构之一: 其中n为0-8的自然数。
进一步地,所述组蛋白去乙酰化酶抑制剂化合物的结构式如式1~26中的任一种:
本发明的第二个目的是提供一种组蛋白去乙酰化酶靶点抑制剂的制备方法,可采用如下合成路线:
当选自/>L1选自以下结构之一:/>时,本发明方法采用路线一,具体包括如下步骤:
(1)化合物a-1和化合物a-2经取代反应,得到化合物a-3;
(2)化合物a-3经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物a-4;
(3)化合物a-4和化合物a-5经酰胺缩合反应或取代反应或还原胺化反应得到化合物a-6;
(4)化合物a-6经羟胺取代反应得到化合物a-7;
或,化合物a-6经水解反应,酰胺缩合反应,水解反应得到化合物a-7;
其合成路线如下:
化合物a-2的结构式选自下式之一:
化合物a-5的结构式选自下式之一:
其中n为0-8的自然数;
化合物a-6中L2’选自以下结构之一:
其中n为0-8的自然数;
化合物a-7中L1选自以下结构之一:
L2选自以下结构之一:
其中n为0-8的自然数。
当选自/>L1选自以下结构之一:/>时,本发明方法采用路线二,具体包括如下步骤:
(1)化合物b-1和化合物b-2经Suzuki反应,得到化合物b-3;
(2)化合物b-3经氢气还原,得到化合物b-3’;
(3)化合物b-3和化合物b-3’经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物b-4;
(4)化合物b-4和化合物b-5经酰胺缩合或取代反应得到化合物b-6;
(5)化合物b-6经羟胺取代反应得到化合物b-7;
或,化合物b-6经水解反应,酰胺缩合反应,水解反应得到化合物b-7;
其合成路线如下:
化合物b-5的结构式选自下式之一:
其中n为0-8的自然数;
化合物b-6中L2’选自以下结构之一:
其中n为0-8的自然数;
化合物b-7选自以下结构之一:
L2选自以下结构之一:
其中n为0-8的自然数。
当选自/>L1选自以下结构之一:/>时,本发明方法采用路线三,具体包括如下步骤:
(1)化合物c-1与化合物c-2经Buchwald-Hartwig反应制得化合物c-3;
(2)化合物c-3经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物c-4;
(3)化合物c-4和化合物c-5经酰胺缩合反应或取代反应或还原胺化反应得到化合物c-6;
(4)化合物c-6经羟胺取代反应得到化合物c-7或化合物c-6经水解反应,酰胺缩合反应,水解反应得到化合物c-7;
其合成路线如下:
化合物c-2的结构式选自下式之一:
化合物c-5的结构式选自下式之一:
其中n为0-8的自然数;
化合物c-6中L2’选自以下结构之一:
其中n为0-8的自然数。
化合物c-7中L1选自以下结构之一:
L2选自以下结构之一:
其中n为0-8的自然数。
本发明式(I)所示化合物可通过如上的方法制得,然而该方法的条件,如反应物、溶剂、所用化合物的量、反应温度、反应所需时间等不限于上面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明的第三个目的是提供上述组蛋白去乙酰化酶抑制剂化合物,或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体,或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物在制备抗肿瘤药物中的应用。
本发明的第四个目的是提供了一种抗肿瘤药物,含有安全有效量的所述的一类结构新颖的组蛋白去乙酰化酶抑制剂化合物,或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体,或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物。
作为优选,所述抗肿瘤药物还可以包括药学上可以接受的载体。
作为优选,所述肿瘤为实体瘤,更为优选为结肠癌。
药物组合物和施用方法
由于本发明化合物具有抑制各种肿瘤细胞株增殖的活性,因此,本发明化合物及其各种晶型、药学上可接受的无机或有机盐、水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解各种疾病,包括各种癌症。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
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、瘤内、直肠、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)填料或增溶剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,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,如甘油;(d)崩解剂,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,如石蜡;(f)吸收加速剂,如季胺化合物;(g)润湿剂,如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,如高岭土;(i)润滑剂,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位中释放。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,如乙醇、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,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,或必要时可能需要推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~5000mg,优选5~2000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明与现有技术相比,主要优点包括:提供式(I)所示结构的一种结构新颖的组蛋白去乙酰化酶靶点抑制剂、有式(I)化合物的药物组合物及水合物,及这些化合物的光学异构体、消旋体、单一对映异构体、可能的非对映异构体,或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物。本发明还提供了所述一类结构新颖的组蛋白去乙酰化酶靶点抑制剂的制备方法、对各种肿瘤细胞株增殖抑制的活性并应用于抗肿瘤药物中。本发明中的一类结构新颖的组蛋白去乙酰化酶靶点抑制剂有望成为抗肿瘤候选药物,治疗结肠癌。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实例1:化合物1的制备
将化合物1a(5000mg,32.47mmol)、化合物1b(7247mg,38.96mmol)、置于150mL封管里,加入DMF溶液(50mL),加入DIPEA(8.5mL),加热至110℃反应16小时。停止加热,待反应液冷却至室温,滤液减压条件下浓缩,DCM溶液溶解固体,H2O洗2遍,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(EA/PE体系洗脱),得到白色固体化合物1c(6453mg,收率65.6%)。
将化合物1c(6453mg,21.30mmol)转移置500mL的圆底烧瓶中,加MeOH溶液(22mL)溶解,在搅拌下滴加盐酸二氧六环溶液(4N,106mL),于室温下搅拌过夜。产物析出,抽滤,二氧六环溶液洗涤滤饼。收集滤饼,得到白色固体化合物1d(6000mg)的粗品,直接用于下一步反应。
将化合物1d(200mg,0.83mmol)、1e(130mg,0.69mmol)和DIPEA(0.58mL,3.33mmol)、EDCI(346mg,1.80mmol)、HOBT(122mg,0.90mmol)置于25mL的圆底烧瓶中,加入DMF溶液(4mL),室温搅拌至原料消失。加入EA(40mL),H2O(40mL X 3)洗,饱和食盐水洗,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(EA/PE体系洗脱),得到白色固体化合物1f(140mg,收率54.1%)。
将化合物1f(100mg,0.27mmol)置于25mL的圆底烧瓶中,加入DCM溶液(2.5mL)、MeOH溶液(5mL),冰浴条件下加入NH2OH水溶液(50%,530mg,8.04mmol)、NaOH(107mg,2.68mmol),冰浴条件,搅拌3h。在搅拌状态下,用HCl水溶液(1M)调节PH至7~8,有机溶剂在减压条件下浓缩过程中,产物以固体形式析出,加适量H2O,超声波超声2分钟,过滤,得到白色固体化合物1(50mg,50.0%)。1H NMR(500MHz,DMSO-d6)δ11.73(s,1H),10.33(s,1H),8.67(s,1H),8.16(s,1H),7.21(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),3.89(dt,J=27.3,5.1Hz,4H),3.69–3.53(m,4H),2.34(t,J=7.5Hz,2H),1.94(t,J=7.4Hz,2H),1.59–1.42(m,4H),1.28(tq,J=11.0,6.8,4.5Hz,4H).
实例2:化合物2的制备
将化合物2a(200mg,0.83mmol)、2b(185mg,1.00mmol)和DIPEA(0.50mL,2.50mmol)、置于10mL的圆底烧瓶中,加入DFM(2mL),加热至80℃反应过夜。冷却至室温,加入EA(20mL),H2O(20mL x 3)洗,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(DCM/MeOH体系洗脱),得到白色固体化合物2c(157mg,收率53.8%)。
参照实例1中化合物1的合成步骤,得到白色固体化合物2(62mg,62.0%)。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),11.19(s,1H),9.04(s,1H),8.14(s,1H),7.73(d,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),7.26–7.09(m,1H),6.60(dd,J=3.6,1.8Hz,1H),3.87(t,J=4.9Hz,4H),3.56(s,2H),2.48(d,J=4.9Hz,4H).
实例3:化合物3的制备
参照实例2中化合物2c的合成步骤,得白色固体化合物3c(455mg,收率64.4%)。
参照实例1中化合物1的合成步骤,得白色固体化合物3(30mg,收率30.0%)。1HNMR(500MHz,DMSO-d6)δ11.70(s,1H),9.91(s,2H),8.14(s,1H),7.52(d,J=7.8Hz,2H),7.38(t,J=9.4Hz,3H),7.18(d,J=3.5Hz,1H),6.60(d,J=3.6Hz,1H),6.45(d,J=15.8Hz,1H),3.96–3.83(m,4H),3.54(s,2H),2.50(d,J=4.7Hz,4H).
实例4:化合物4的制备
参照实例1中化合物1c的合成步骤,得白色固体化合物4c(1726mg,收率80.8%)。
参照实例1中化合物1d的合成步骤,得白色固体化合物4d(1520mg)粗品,直接用于下一步反应。
参照实例1中化合物1f的合成步骤,得白色固体化合物4f(190mg,收率55.3%)。
参照实例1中化合物1的合成步骤,得白色固体化合物4(60mg,收率40.0%)。1HNMR(500MHz,DMSO-d6)δ11.59(s,1H),10.33(s,1H),8.67(s,1H),8.08(s,1H),7.11(d,J=3.5Hz,1H),6.58(d,J=3.5Hz,1H),4.06–3.88(m,2H),3.78–3.54(m,4H),3.40(dd,J=10.5,4.8Hz,1H),3.29(dd,J=12.2,4.1Hz,1H),3.14–2.93(m,2H),2.28–2.16(m,2H),1.92(t,J=7.4Hz,2H),1.45(dt,J=14.1,6.9Hz,4H),1.23(tt,J=9.6,4.4Hz,4H).
实例5:化合物5的制备
参照实例2中化合物2c的合成步骤,得白色固体化合物5c(190mg,收率50.4%)。
参照实例1中化合物1的合成步骤,得淡黄色固体化合物5(63mg,收率63.0%)。1HNMR(400MHz,DMSO-d6)δ11.62(s,1H),9.89(s,2H),8.09(s,1H),7.68(d,J=8.2Hz,2H),7.32(d,J=7.9Hz,2H),7.11(d,J=3.6Hz,1H),6.58(d,J=3.6Hz,1H),3.97(t,J=9.2Hz,2H),3.67–3.61(m,2H),3.60(s,2H),2.93(s,2H),2.60(t,J=7.7Hz,2H),2.57–2.52(m,2H).
实例6:化合物6的制备
参照实例2中化合物2c的合成步骤,得白色固体化合物6c(200mg,收率49.6%)。
参照实例1中化合物1的合成步骤,得白色固体化合物6(40mg,收率40.0%)。1HNMR(500MHz,DMSO-d6)δ11.60(s,1H),9.94(s,2H),8.09(s,1H),7.48(d,J=7.8Hz,2H),7.40(d,J=15.8Hz,1H),7.31(d,J=7.9Hz,2H),7.11(d,J=3.5Hz,1H),6.58(d,J=3.5Hz,1H),6.43(d,J=15.8Hz,1H),4.02–3.91(m,2H),3.63(dd,J=11.0,3.1Hz,2H),3.58(s,2H),2.94(dq,J=8.0,3.9Hz,2H),2.59(td,J=6.7,3.1Hz,2H),2.55(dd,J=9.3,2.5Hz,2H).
实例7:化合物7的制备
参照实例1中化合物1c的合成步骤,得白色固体化合物7c(469mg,收率45.6%)。
参照实例1中化合物1d的合成步骤,得白色固体化合物7d(325mg)粗品,直接用于下一步反应。
参照实例1中化合物1f的合成步骤,得白色固体化合物7f(218mg,收率82.0%)。
参照实例1中化合物1的合成步骤,得白色固体化合物7(35mg,收率35.0%)。1HNMR(500MHz,DMSO-d6)δ10.08(s,3H),8.13(s,1H),7.83(d,J=7.8Hz,1H),7.17(d,J=3.6Hz,1H),6.57(d,J=3.6Hz,1H),4.56(d,J=13.3Hz,2H),3.89(dh,J=14.8,4.2Hz,1H),3.24–3.18(m,2H),2.02(t,J=7.4Hz,2H),1.88–1.77(m,4H),1.49–1.34(m,6H),1.21(d,J=6.6Hz,4H).
实例8:化合物8的制备
将化合物8a(1302mg,6.00mmol)、8b(1140mg,6.00mmol)置于200mL的圆底烧瓶中,加入(ClCH2)2溶液(60mL),室温搅拌3h,加入NaBH(OAc)3(1696mg,8.00mmol)室温反应过夜。加入DCM溶液稀释,饱和NH4Cl水溶液洗1遍,饱和NaHCO3水溶液洗1遍,H2O洗1遍,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(EA/PE体系洗脱),得到白色固体化合物8c(1035mg,收率44.1%)。
参照实例1中化合物1的合成步骤,得白色固体化合物8(445mg,收率56.8%)。1HNMR(500MHz,DMSO-d6)δ8.17(s,1H),7.49(d,J=8.0Hz,2H),7.39(d,J=15.8Hz,1H),7.33(d,J=3.7Hz,1H),7.23(d,J=8.1Hz,2H),6.66(d,J=3.7Hz,1H),6.40(d,J=15.8Hz,1H),5.38(s,2H),4.60–4.51(m,2H),3.17(ddd,J=13.7,11.4,2.8Hz,2H),2.88(tt,J=9.9,4.1Hz,1H),1.86–1.78(m,2H),1.23(tdd,J=12.8,10.3,4.0Hz,2H).
实例9:化合物9的制备
将化合物9a(2000mg,12.99mmol)、化合物9b(4013mg,12.99mmol)和Na2CO3(5506mg,51.95mmol)置于150mL的封管中,加入(CH3OCH2)2溶液(51mL)和H2O(17mL),用氮气流将反应液里的空气排除(15min),加入Pd(PPh3)4(751mg,0.649mmol),再通氮气15min,反应液在密闭体系中加至90℃反应过夜。将反应液冷却至室温,加入DCM溶液稀释,过滤,用DCM溶液洗涤滤饼,滤液减压条件下浓缩,DCM溶解,H2O洗1遍,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(EA/PE体系洗脱),得到白色固体化合物9c(2019mg,收率51.8%)。
参照实例1中化合物1d的合成步骤,得黄色固体化合物9d(842mg)粗品,直接用于下一步反应。
参照实例1中化合物1f的合成步骤,得黄色固体化合物19f(120mg,收率50.2%)。
参照实例1中化合物1的合成步骤,得黄色固体化合物9(59mg,收率59.0%)。1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),10.34(s,1H),8.71(s,1H),8.66(s,1H),7.58(t,J=2.8Hz,1H),6.92(d,J=9.0Hz,1H),6.81(d,J=3.6Hz,1H),4.27(dd,J=21.7,3.3Hz,2H),3.69(dt,J=11.9,5.6Hz,2H),2.75(d,J=38.7Hz,2H),2.38(dt,J=15.8,7.4Hz,2H),1.94(t,J=7.3Hz,2H),1.50(dt,J=14.3,7.4Hz,4H),1.28(s,4H).
实例10:化合物10的制备
将Pd/C(400mg)置于50mL的圆底烧瓶中,加入CH3OH溶液(10mL),加入化合物10a(1000mg,3.33mmol),置换3次氢气,室温反应过夜。加入CH3OH溶液稀释,Pd/C经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(EA/PE体系洗脱),得到灰白色固体化合物10b(976mg,收率97.0%)。
参照实例1中化合物1d的合成步骤,得灰白色固体化合物10c(826mg)粗品,直接用于下一步反应。参照实例1中化合物1f的合成步骤,得淡黄色油状化合物10e(170mg,收率63.2%)。
参照实例1中化合物1的合成步骤,得白色固体化合物10(99mg,收率58.2%)。1HNMR(500MHz,DMSO-d6)δ12.05(s,1H),8.66(s,2H),7.50(dd,J=3.6,2.4Hz,1H),6.70(dd,J=3.7,1.3Hz,1H),3.40(tt,J=11.2,4.2Hz,1H),2.34(td,J=7.4,3.8Hz,2H),1.95(t,J=7.4Hz,2H),1.91–1.64(m,4H),1.50(h,J=7.6Hz,4H),1.33–1.22(m,4H).
实例11:化合物11的制备
将化合物11a(200mg,0.72mmol)、11b(160mg,0.87mmol)和DIPEA(0.65mL,3.61mmol)、置于10mL的圆底烧瓶中,加入N,N-二甲基甲酰胺溶液(2mL),加热至80℃反应过夜。冷却至室温,加入乙酸乙酯(20mL),水(20mL x 3)洗,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(DCM/MeOH体系洗脱),得到棕黄色固体化合物11c(144mg,收率56.9%)。
参照实例1中化合物1的合成步骤,得白色固体11(91mg,收率75.0%)。1H NMR(500MHz,DMSO-d6)δ12.00(s,1H),11.16(s,1H),9.01(s,1H),8.66(s,1H),7.73(d,J=8.2Hz,2H),7.47(d,J=3.5Hz,1H),7.42(d,J=8.2Hz,2H),6.67(d,J=3.5Hz,1H),3.57(s,2H),3.10(tt,J=11.6,3.6Hz,1H),2.94(d,J=11.3Hz,2H),2.21–2.09(m,2H),1.97(qd,J=12.5,3.5Hz,2H),1.80(d,J=11.1Hz,2H).
实例12:化合物12的制备
参照实例11中化合物11c的合成步骤,得白色固体化合物12c(154mg,收率58.3%)。
参照实例1中化合物1的合成步骤,得淡黄色固体12(60mg,收率50.0%)。H NMR(500MHz,DMSO-d6)δ10.78(s,3H),8.66(s,1H),7.55–7.41(m,3H),7.32(d,J=8.0Hz,2H),7.19(d,J=15.8Hz,1H),6.67(d,J=3.5Hz,1H),6.42(d,J=15.8Hz,1H),3.52(s,2H),3.09(tt,J=11.6,3.5Hz,1H),2.94(d,J=11.2Hz,2H),2.13(t,J=10.9Hz,2H),1.97(qd,J=12.4,3.3Hz,2H),1.80(d,J=11.2Hz,2H).
实例13:化合物13的制备
将化合物13a(2000mg,10.15mmol)、化合物13b(2455mg,13.20mmol)和RuPhos(95mg,0.20mmol)置于150mL的封管中,加入THF溶液(26mL)用氮气流将反应液里的空气排除(15min),加入RuPhos Pd G2(158mg,0.20mmol),再通氮气15min,加入LiHMDS(1.0Msolution in THF,25.4mL,25.38mmol)反应液在密闭体系中加至60℃反应4h。将反应液冷却至室温,滤液减压条件下浓缩,加入适量饱和NH4Cl水溶液,EA溶液萃取3次,H2O洗1遍,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(乙酸乙酯/石油醚体系洗脱),得到白色固体化合物13c(2455mg,收率80.1%)。
参照实例1中化合物1d的合成步骤,得白色固体化合物13d(2163mg)粗品,直接用于下一步反应。
参照实例1中化合物1f的合成步骤,得白色固体化合物13f(110mg,收率46.2%)。
参照实例1中化合物1的合成步骤,得淡黄色固体化合物13(85mg,收率85.0%)。1HNMR(500MHz,DMSO-d6)δ11.39(s,1H),10.33(s,1H),8.65(s,1H),8.08(d,J=2.6Hz,1H),7.51(d,J=2.5Hz,1H),7.40–7.35(m,1H),6.32(dd,J=3.3,1.9Hz,1H),3.67–3.58(m,4H),3.03(dt,J=28.7,4.7Hz,4H),2.34(t,J=7.5Hz,2H),1.94(t,J=7.4Hz,2H),1.49(h,J=7.8Hz,4H),1.27(tq,J=12.6,7.4,6.2Hz,4H).
实例14:化合物14的制备
将化合物14a(400mg,1.06mmol)、11b(256mg,1.38mmol)和DIPEA(1.10mL,6.38mmol)、置于25mL的圆底烧瓶中,加入N,N-二甲基甲酰胺溶液(4mL),加热至80℃反应过夜。冷却至室温,加入乙酸乙酯(40mL),水(40mL x 3)洗,饱和食盐水洗1遍,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(DCM/MeOH体系洗脱),得到白色固体化合物14c(221mg,收率55.3%)。
参照实例1中化合物1的合成步骤,得白色固体14(17mg,收率17.0%)。1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),11.17(s,1H),9.03(s,1H),8.05(d,J=2.6Hz,1H),7.73(d,J=8.2Hz,2H),7.46(d,J=2.5Hz,1H),7.41(d,J=8.0Hz,2H),7.37–7.32(m,1H),6.30(dd,J=3.3,1.7Hz,1H),3.58(s,2H),3.13–3.05(m,4H),2.60–2.53(m,4H).
实例15:化合物15的制备
参照实例14中化合物14c的合成步骤,得棕黄色固体化合物15c(138mg,收率57.3%)。
参照实例1中化合物1的合成步骤,得淡黄色固体15(15mg,收率15.0%)。1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),8.05(s,1H),7.52(d,J=7.9Hz,2H),7.46(d,J=2.5Hz,1H),7.44–7.33(m,4H),6.45(d,J=15.8Hz,1H),6.30(dd,J=3.1,1.2Hz,1H),3.55(s,2H),3.08(s,4H),2.56(s,4H).
实例16:化合物16的制备
参照实例13中化合物13c的合成步骤,得到白色固体化合物16c(2295mg,收率68.9%)。
参照实例1中化合物1d的合成步骤,得白色固体化合物16d(2365mg)粗品,直接用于下一步反应。
参照实例1中化合物1f的合成步骤,得淡黄色固体化合物16f(146mg,收率68.9%)。
参照实例1中化合物1的合成步骤,得白色固体化合物16(20mg,收率20.0%)。1HNMR(500MHz,DMSO-d6)δ11.18(s,1H),10.35(s,1H),8.64(s,1H),7.76(d,J=2.5Hz,1H),7.38–7.26(m,1H),7.09(d,J=2.5Hz,1H),6.25(dd,J=3.2,1.8Hz,1H),3.67(ddd,J=67.4,11.4,7.9Hz,2H),3.48–3.35(m,3H),3.29(dd,J=12.3,4.6Hz,1H),3.23–3.17(m,2H),3.03(ddtd,J=50.4,12.3,7.8,4.7Hz,2H),2.22(q,J=8.1Hz,2H),1.92(t,J=7.3Hz,2H),1.52–1.40(m,4H),1.23(q,J=8.9,5.5Hz,4H).
实例17:化合物17的制备
参照实例14中化合物14c的合成步骤,得白色固体化合物17c(221mg,收率55.3%)。
参照实例1中化合物1的合成步骤,得棕黄色固体17(63mg,收率63.0%)。1H NMR(500MHz,DMSO-d6)δ11.22(s,2H),9.04(s,1H),7.86(d,J=2.6Hz,1H),7.68(d,J=8.2Hz,2H),7.40–7.29(m,3H),7.20(d,J=2.5Hz,1H),6.26(dd,J=3.2,1.7Hz,1H),3.60(s,2H),3.35(s,1H),3.31(s,1H),3.04(dd,J=9.1,3.1Hz,2H),2.92–2.82(m,2H),2.73–2.61(m,2H),2.39(dd,J=9.0,3.2Hz,2H).
实例18:化合物18的制备
参照实例14中化合物14c的合成步骤,得黄色固体化合物18c(142mg,收率66.7%)。
参照实例1中化合物1的合成步骤,得淡黄色固体18(53mg,收率53.0%)。1H NMR(500MHz,DMSO-d6)δ11.22(s,1H),10.73(s,1H),9.02(s,1H),7.86(d,J=2.6Hz,1H),7.49(d,J=7.9Hz,2H),7.43(d,J=15.8Hz,1H),7.37–7.30(m,3H),7.20(d,J=2.5Hz,1H),6.42(d,J=15.8Hz,1H),6.26(dd,J=3.3,1.9Hz,1H),3.59(s,2H),3.05(d,J=7.9Hz,2H),2.93–2.84(m,2H),2.77–2.60(m,2H),2.36(dt,J=3.6,1.8Hz,2H).
实例19:化合物19的制备
将化合物19a(300mg,0.80mmol)、1e(187mg,1.04mmol)和DIPEA(0.83mL,4.79mmol)、EDCI(398mg,2.08mmol)、HOBT(140mg,1.04mmol)置于25mL的圆底烧瓶中,加入DMF溶液(3mL),室温搅拌至原料消失。加入EA(30mL),H2O(30mL X 3)洗,饱和食盐水洗,无水Na2SO4干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析纯化(DCM/MeOH体系洗脱),得白色固体化合物19c(117mg,收率56.9%)。
参照实例1中化合物1的合成步骤,得白色固体化合物19(42mg,收率52.5%)。1HNMR(500MHz,DMSO-d6)δ11.19(s,1H),9.14(s,2H),7.87–7.72(m,3H),7.56(d,J=8.3Hz,2H),7.36–7.29(m,1H),7.10(d,J=2.5Hz,1H),6.25(dd,J=3.3,1.8Hz,1H),3.86(dd,J=12.3,8.0Hz,1H),3.71(dd,J=10.7,7.5Hz,1H),3.58–3.40(m,2H),3.38–3.35(m,1H),3.30(dd,J=9.4,3.7Hz,1H),3.20–3.12(m,2H),3.11–2.98(m,2H).
实例20:化合物20的制备
参照实例19中化合物19c的合成步骤,得白色固体化合物20c(266mg,收率76.2%)。
参照实例1中化合物1的合成步骤,得白色固体化合物20(33mg,收率33.0%)。1HNMR(500MHz,DMSO-d6)δ11.40(s,1H),9.33(s,2H),8.08(d,J=2.5Hz,1H),7.83(d,J=8.1Hz,2H),7.51(dd,J=15.1,5.1Hz,3H),7.42–7.34(m,1H),6.37–6.29(m,1H),3.93–3.73(m,2H),3.62–3.42(m,2H),3.16–2.91(m,4H).
实例21:部分化合物体外HDAC1和HDAC6酶抑制率活性测试
1.实验材料和仪器
实验材料:HDAC1(BPS,Cat.No.50051);Tris缓冲液(Coolaber,Cat.No.SL3090-100mL);HDAC6(BPS,Cat.No.50006);384-well plate(Perkin Elmer,Cat.No.6007279);DMSO(Coolaber);
仪器:SpectraMax Paradigm多功能微孔板检测仪。
2.实验方法
1)准备1x检测缓冲液:准备1x检测缓冲液(改良的Tris缓冲液);
2)复合系列稀释:通过Echo在100%DMSO中将化合物转移到测定板,DMSO的含量不超过1%;
3)制备酶溶液:在1x检测缓冲液中分别制备HDAC1和HDAC6酶溶液;
4)制备底物溶液:在1x检测缓冲液中加入胰蛋白酶和乙酰化肽底物,制成底物溶液;
5)将15μL酶溶液转移到检测板或用于低对照转移15μL 1x测定缓冲液;
6)在室温下孵育15分钟;
7)向每个孔中加入10μL底物溶液以开始反应;
8)在Paradigm上读取板,激发波长为355nm,发射波长为460nm;
9)曲线拟合:使用等式(1)在Excel中拟合数据以获得抑制值
等式(1):Inh%=(Max-Signal)/(Max-Min)*100
使用等式(2)拟合XL-Fit中的数据以获得IC50值
等式(2):Y=Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope)
Y是抑制百分比,X是化合物浓度。
3.实验结果
按上述实验方法测定了部分目标化合物对HDAC1酶和HDAC6酶的抑制作用。结果如表1和表2所示。
表1 目标化合物对HDAC1酶和HDAC6酶的单浓度抑制率
表2 目标化合物对HDAC1酶和HDAC6酶的半数抑制浓度
注:N/D–没有测定
实例22:部分化合物进行体外抗肿瘤活性评价
1.实验材料和仪器
实验材料:DMEM(浙江森瑞生物科技有限公司);RPMI 1640(浙江森瑞生物科技有限公司);Fatal Bovine Serum(BI);PBS(浙江森瑞生物科技有限公司);Trypsin(浙江森瑞生物科技有限公司);DMSO(Coolaber);CCK8(Coolaber);
实验仪器:生物安全柜(上海百基生物科技有限公司);恒温二氧化碳培养箱(THERMO);酶联免疫分析仪(Spark);倒置显微镜(Nikon);移液枪一套(Eppendorf);离心机(Beckman coulter);
实验细胞株:MV-4-11,K562,WSUDLCL2。
2.实验方法
1)取对数生长期的受试细胞,经胰酶消化、计数后,将肿瘤细胞悬浮液稀释至5×104个/mL的浓度接种于96孔培养板中,除了空白组加100μL不含细胞的培养基外,其余每孔加入含有细胞的培养基100μL(每孔5×103个细胞);
2)在湿润的含5%CO2培养箱中37℃孵育8h后,吸掉96孔板中原有的培养基,除了对照和空白组加100μL不含待测化合物的培养基,其余每孔加入100μL含待测化合物的培养基(使用10%FBS/RPMI 1640完全培养基),每个浓度设置6个复孔,不加细胞不加化合物的孔为空白组,加细胞不加化合物的孔为对照组,加细胞加待测化合物的为实验组。实验选取SAHA作为阳性对照;
3)于37℃、5%CO2湿润的培养箱中继续培养72h;
4)避光条件下,每孔加入CCK-8溶液10μL,于37℃、5%CO2湿润的培养箱中继续培养1-4h,在酶标仪450nm处测定每个孔的吸光度值(OD值);
5)用以下公式计算存活率和抑制率
细胞存活率=[(As-Ab)/(Ac-Ab)]×100%
抑制率=[(Ac-As)/(Ac-Ab)]×100%
应用Excel计算单浓度抑制率;应用GraphPad Prism 7.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
As:实验孔(含有细胞的培养基、CCK-8、待测药物)的吸光度
Ac:对照孔(含有细胞的培养基、CCK-8、溶媒(DMSO))的吸光度
Ab:空白孔(不含细胞的培养基、CCK-8、溶媒(DMSO))的吸光度
3.实验结果
按上述实验方法测定了部分目标化合物对3种细胞株的增殖抑制作用,结果如表3和表4所示。
表3 目标化合物对3种细胞株抗增殖的单浓度抑制率
注:N/D–没有测定
表4 目标化合物对3种细胞株抗增殖的半数抑制浓度
4.结果讨论
在细胞水平上:化合物3,6,8,12,15和18表现出明显强于阳性对照SAHA的抑制细胞增殖的活性。
Claims (10)
1.一种组蛋白去乙酰化酶抑制剂化合物,或其药学上可接受的盐,其特征在于,所述化合物的结构如式(I)所示:
式(I)中的选自如下:
其中表示/>与L1连接的位点;
L1选自以下结构之一:
其中表示L1与L2连接的位点;
L2选自以下结构之一:其中n为0-8的自然数。
2.根据权利要求1所述的组蛋白去乙酰化酶抑制剂化合物,其特征在于,所述化合物选自以下化合物中的任意一种:
3.一种组蛋白去乙酰化酶抑制剂化合物,或其药学上可接受的盐,其特征在于,所述化合物的结构如式(I)所示:
式(I)中的选自如下:
其中表示/>与L1连接的位点;
L1选自以下结构之一:
其中表示L1与L2连接的位点;
L2选自以下结构之一:
4.根据权利要求3所述的组蛋白去乙酰化酶抑制剂化合物,其特征在于,所述化合物选自以下化合物中的任意一种:
5.一种组蛋白去乙酰化酶抑制剂化合物的制备方法,其特征在于所述方法包括以下步骤:
(1)化合物a-1和化合物a-2经取代反应,得到化合物a-3;
(2)化合物a-3经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物a-4;
(3)化合物a-4和化合物a-5经酰胺缩合反应或取代反应或还原胺化反应得到化合物a-6;
(4)化合物a-6经羟胺取代反应得到化合物a-7;
或,化合物a-6经水解反应,酰胺缩合反应,水解反应得到化合物a-7;
其中n为0-8的自然数;
其合成路线如下:
化合物a-2的结构式选自下式之一:
化合物a-5的结构式选自下式之一:
其中n为0-8的自然数;
化合物a-6中L2’选自以下结构之一:
其中n为0-8的自然数;
化合物a-7中L1选自以下结构之一:
L2选自以下结构之一:
或包括以下步骤:
(1)化合物c-1与化合物c-2经Buchwald-Hartwig反应制得化合物c-3;
(2)化合物c-3经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物c-4;
(3)化合物c-4和化合物c-5经酰胺缩合反应或取代反应或还原胺化反应得到化合物c-6;
(4)化合物c-6经羟胺取代反应得到化合物c-7;
或,化合物c-6经水解反应,酰胺缩合反应,水解反应得到化合物c-7;
其合成路线如下:
化合物c-2的结构式选自下式之一:
化合物c-5的结构式选自下式之一:
其中n为0-8的自然数;
化合物c-6中L2’选自以下结构之一:
其中n为0-8的自然数;
化合物c-7中L1选自以下结构之一:
L2选自以下结构之一:
或包括以下步骤:
(1)化合物b-1和化合物b-2经Suzuki反应,得到化合物b-3;
(2)化合物b-3经氢气还原,得到化合物b-3’;
(3)化合物b-3和化合物b-3’经盐酸二氧六环溶液脱去叔丁氧羰基,得到化合物b-4;
(4)化合物b-4和化合物b-5经酰胺缩合或取代反应得到化合物b-6;
(5)化合物b-6经羟胺取代反应得到化合物b-7;
或,化合物b-6经水解反应,酰胺缩合反应,水解反应得到化合物b-7;
其合成路线如下:
化合物b-5的结构式为其中n为0-8的自然数;
化合物b-6中L2’为其中n为0-8的自然数;
化合物b-7选自以下结构之一:
其中L2为/>
6.根据权利要求1-4任一项所述的化合物,或其药学上可接受的盐作为组蛋白去乙酰化酶抑制剂在制备抗肿瘤药物中的应用。
7.根据权利要求6所述应用,其特征在于所述肿瘤为实体瘤。
8.根据权利要求7所述应用,其特征在于所述肿瘤为结肠癌。
9.一种药物组合物,含有安全有效量的权利要求1-4任一项所述的组蛋白去乙酰化酶抑制剂化合物,或其药学上可接受的盐。
10.根据权利要求9所述的药物组合物,其特征在于还包括药学上可以接受的载体。
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