CN108276366A - 一种丙烯酰胺类衍生物及其制备方法与应用 - Google Patents
一种丙烯酰胺类衍生物及其制备方法与应用 Download PDFInfo
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- CN108276366A CN108276366A CN201810015576.3A CN201810015576A CN108276366A CN 108276366 A CN108276366 A CN 108276366A CN 201810015576 A CN201810015576 A CN 201810015576A CN 108276366 A CN108276366 A CN 108276366A
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
本发明属于化学医药领域,具体涉及丙烯酰胺类衍生物,其结构同时如下:通过该丙烯酰胺类衍生物的一些实施方案证实,该丙烯酰胺类衍生物对组蛋白乙酰转氨酶p300有较好的抑制作用,同时对肿瘤细胞具有很好的抑制作用,能够作为制备治疗癌症药物进行使用;本发明还公开了该新化合物的制备方法,其制备方法具有操作简便,反应条件温和,便于操作和控制,能耗小,产率高,成本低,可适合产业化生产,制备得到的化合物生物活性较高,对肿瘤细胞的选择性强,类药性显著,具有广阔的市场前景。
Description
技术领域
本发明涉及化学合成药物技术领域,具体是指一种丙烯酰胺类衍生物及其制备方法与应用。
背景技术
由组蛋白乙酰转移酶(HATs)和组蛋白去乙酰化酶(HDACs)催化的蛋白质的动态和可逆的乙酰化是基因转录表观遗传的主要调控机制。研究表明,细胞的许多正常生物过程,均需要这两种酶的积极参与,而且这两种酶与许多疾病息息相关。组蛋白去乙酰化酶抑制剂目前已经在临床上被批准用于治疗某些癌症,但是组蛋白乙酰转移酶抑制剂却未能有进一步发展,到目前为止,还未见有关于组蛋白乙酰转移酶抑制剂被作为可用于临床使用的药物。组蛋白乙酰转移酶旁系同源物p300和CREB-结合蛋白(CBP)是关键的转录共激活因子,其对于多种细胞过程是必不可少的,通过进一步研究,细胞信号通路中的钙离子信号通路、对缺氧的应答信号通路、Notch信号通路、以及NFκB信号通路均有这两种因子参与,且还涉及到多种人类病理状况(包括癌症)。p300/CBP是高等真核生物中的关键酶,其在许多主要的细胞信号传导途径中作为效应物,其响应于各种信号而调节蛋白质功能和基因表达。这些过程通过超过400个蛋白质配体与其各种蛋白质相互作用介导结构域的结合以及个蛋白质底物的乙酰化来实现。目前已经报道的p300和CBP组蛋白乙酰转移酶结构域的抑制剂,包括天然产物、双底物类似物和广泛使用的小分子C646,这些都缺乏活性或选择性,因此开发出高活性、选择性和类药性的P300小分子抑制剂是目前临床上急需要解决的难题。
发明内容
本发明的目的在于提供一种能够在制备治疗癌症药物中进行使用的丙烯酰胺类衍生物。
本发明的另一个目的在于提供一种上述丙烯酰胺类衍生物的制备方法。
本发明还有一个目的在于提供一种活性较高,选择性强,类药性显著的组蛋白乙酰转氨酶P300抑制剂以及相应治疗癌症的药物。
本发明还有一个目的在于提供该组蛋白乙酰转氨酶P300抑制剂的具体应用。
本发明提供一种丙烯酰胺类衍生物,其通式如下:
其中,
X为独立的
Y为独立的
R1为独立的H、C1~C4烷基、三元饱和环、四元饱和环、五元饱和环、六元饱和环、七元饱和环、八元饱和环;
R2为独立的H、芳基、杂芳基、取代芳基、取代杂芳基、五元饱和环或六元饱和环。
其具体制备方法如下:
(1)将0.8~1.2当量的原料A使用DCM溶解,并加入1.5~3.0当量的三乙胺,搅拌30分钟后,加入1~1.5当量的4-溴苯磺酰氯,继续室温搅拌反应过夜,检测反应完全后,浓缩溶剂加入水和DCM萃取3次,合并有机相,使用污水Na2SO4干燥,浓缩后得中间体Ⅰ;
(2)取0.8~1.2当量的中间体Ⅰ、1.2~2.0当量的5-醛基-呋喃-2-硼酸、无1.2~2.0当量的水碳酸钠和0.1~0.5当量的双三苯基膦二氯化钯,用MeCN:H2O=2:1溶解后,置换氩气三次后,升温至80℃反应2h,检测反应完全后,冷却至室温,用硅藻土过滤掉不溶物催化剂,减压浓缩,加水经乙酸乙酯萃取,浓缩,柱层析得到中间体Ⅱ;
(3)使用乙醇溶解0.5~2.0当量的中间体Ⅱ,再加入0.8~1.5当量的氰基乙酰胺或中间体Ⅲ,滴加催化量的哌啶,升温至85℃反应4h,检测反应完全后,冷却至室温,浓缩,柱层析得到该丙烯酰胺类衍生物;所述中间体Ⅲ主要由0.8~1.5当量的氰基乙酸与1.0~1.5当量的原料C缩合而成。
制备得到的该丙烯酰胺类衍生物具有抑制组蛋白乙酰转氨酶p300的效果,而抑制组蛋白乙酰转氨酶p300是高等真核生物中的关键酶,其在许多主要的细胞信号传导途径中作为效应物,其响应于各种信号而调节蛋白质功能和基因表达,在抑制组蛋白乙酰转氨酶p300收到抑制时,真核生物的细胞无法正常分裂,对肿瘤细胞的无限增殖有明显的治疗作用,因此可以以该丙烯酰胺类衍生物为主要活性成分,添加生物药学上能够接受的辅助性成分制成治疗癌症的药物。重点针对的癌症有包括前列腺癌、宫颈癌、肺癌、胰腺癌、淋巴瘤、三阴性乳腺癌、卵巢癌、纤维肉瘤。
为了验证丙烯酰胺类衍生物的抗肿瘤作用,分别自氨水、环丙胺、环丁基胺、环戊胺、环己胺、4-氨基四氢吡喃、4-氨基-1-甲基哌啶、4-氨基环己烷、吗啉、N-甲基哌嗪、4-羟基哌嗪、N-甲基高哌嗪中选取至少一种作为以原料A;自3-甲基-4-硝基苯胺、6-氨基苯并噻唑、3,4-二甲基苯胺、4-氨基-2-三氟甲基苯甲腈、4,5-二甲-2-硝基苯胺、3-甲氧基-4-甲基苯胺、6-氨基-1,4-苯并二氧杂环、3,4,5-三甲氧基苯胺、3-氨甲基吡啶、3-(2-氨基乙基)吡啶、2-噻吩乙胺、N-(2-氨基乙基)吗啉、4-(4-吗啉基)苯胺中选取至少一种作为原料C,合成若干该丙烯酰胺类衍生物的具体结构式,然后进行针对性的实验测试。
本发明与现有技术相比,具有以下优点及有益效果:
本发明合成了一种新的能够抑制组蛋白乙酰转氨酶p300的丙烯酰胺类衍生物,并证实了该丙烯酰胺类衍生物的一些实施方案中,能够对组蛋白乙酰转氨酶p300产生较好的抑制作用,同时对肿瘤细胞具有很好的抑制作用,具有很好的药用潜力,为临床用药提供了一种新的潜在选择;同时,本发明提供的新化合物的制备方法简便,反应条件温和,便于操作和控制,能耗小,产率高,成本低,可适合产业化生产,制备得到的化合物生物活性较高,对肿瘤细胞的选择性强,类药性显著,具有广阔的市场前景。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其他特征、目的和优点将会变得更为明显:
图1为本发明中化合物在肿瘤细胞中对P300乙酰化底物的抑制效果图。
具体实施方式
下面结合实施例对本发明作进一步地详细说明,但本发明的实施方式不限于此,在不脱离本发明上述技术思想情况下,根据本领域普通技术知识和惯用手段,做出各种替换和变更,均应包括在本发明的范围内。
为使本发明的目的、工艺条件及优点作用更加清楚明白,结合以下实施实例,对本发明作进一步详细说明,此处所描述的具体实施实例仅用以解释本发明,并不用于限定本发明。
实施例1:
本实施例以氨水为原料,合成化合物1:(E)-2-氰基-N-(3-甲基-4-硝基苯基)-3-(5-(4-胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
首先,将氨水(1b,1.0当量)于圆底烧瓶中,用DCM溶解,加入三乙胺(2.0当量),搅拌30分钟后,加入4-溴苯磺酰氯(1a,1.2当量)继续室温搅拌反应过夜。经TLC检测反应完全后,浓缩溶剂加入水和DCM萃取3次,合并有机相,无水Na2SO4干燥,浓缩后得化合物1c。
然后,将化合物1c(1.0当量)、5-醛基-呋喃-2-硼酸(1d,1.5当量)、无水碳酸钠(2.0当量)和双三苯基膦二氯化钯(0.1当量)用MeCN:H2O=2:1溶解后,置换氩气三次后,升温至80℃反应2h,经TLC检测反应完全后,冷却至室温,用硅藻土过滤掉不溶物催化剂,减压浓缩,加水经乙酸乙酯萃取,浓缩,柱层析得到中间体1e。
另外,中间体1f通过3-甲基-4-硝基苯胺(1fb,1.0当量)和氰基乙酸(1fa,1.2当量)在五氯化磷作用下缩合得到,合成路线如下:
最后,中间体1f和1e用乙醇溶解,滴加催化量的哌啶,升温至85℃反应4h,经TLC检测反应完全后,冷却至室温,浓缩,柱层析得到化合物1,产率为91%。
化合物1的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.65(s,1H),8.20(s,1H),8.09(s,3H),7.97(d,J=6.8Hz,2H),7.78(s,2H),7.56(s,2H),7.50(s,2H),2.56(s,3H).LC-MS:m/z452.0[M+H]+。
实施例2:
本实施例以环丙胺为原料,合成化合物2:(E)-2-氰基-3-(5-(4-(N-环丙基胺磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物2,产率为88%。
化合物2的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.67(s,1H),8.20(s,1H),8.13(d,J=8.3Hz,2H),8.09(d,J=9.5Hz,1H),8.02(s,1H),7.95(d,J=8.3Hz,2H),7.79(d,J=6.5Hz,2H),7.58(s,2H),2.56(s,3H),2.18(s,1H),0.52(d,J=5.2Hz,2H),0.41(s,2H).LC-MS:m/z 492.1[M+H]+。
实施例3:
本实施例以环丁基胺为原料,合成化合物3:(E)-2-氰基-3-(5-(4-(N-环丁基胺磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物3,产率为82%。
化合物3的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.70(s,1H),8.20(s,1H),8.10(d,J=6.6Hz,4H),7.92(d,J=7.7Hz,2H),7.79(s,2H),7.58(s,2H),3.68(dd,J=15.6,7.7Hz,1H),2.57(s,3H),1.91(s,2H),1.82–1.65(m,2H),1.49(s,2H).LC-MS:m/z506.1[M+H]+。
实施例4:
本实施例以环戊胺为原料,合成化合物4:(E)-2-氰基-3-(5-(4-(N-环戊基胺磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物4,产率为78%。
化合物4的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.67(s,1H),8.20(s,1H),8.10(t,J=8.8Hz,3H),7.95(d,J=8.0Hz,2H),7.77(d,J=11.3Hz,3H),7.57(s,2H),3.48(d,J=6.5Hz,1H),2.56(s,3H),1.60(dd,J=18.8,13.2Hz,4H),1.34(dd,J=20.4,14.2Hz,4H).LC-MS:m/z 520.1[M+H]+。
实施例5:
本实施例以环己胺为原料,合成化合物5:(E)-2-氰基-3-(5-(4-(N-环己基胺磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物5,产率为80%。
化合物5的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.67(s,1H),8.20(s,1H),8.10(d,J=7.8Hz,3H),7.95(d,J=8.3Hz,2H),7.77(d,J=15.8Hz,3H),7.57(s,2H),2.99(s,1H),2.57(s,3H),1.58(d,J=6.6Hz,4H),1.45(d,J=11.0Hz,1H),1.14(s,4H),1.11–0.93(m,2H).LC-MS:m/z 534.1[M+H]+。
实施例6:
本实施例以4-氨基四氢吡喃为原料,合成化合物6:(E)-2-氰基-N-(3-甲基-4-硝基苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物6,产率为88%。
化合物6的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.65(s,1H),8.20(s,1H),8.10(dd,J=8.9,4.4Hz,3H),7.96(d,J=8.4Hz,2H),7.91(d,J=7.0Hz,1H),7.79(d,J=5.0Hz,2H),7.58(s,2H),3.72(d,J=11.6Hz,2H),3.24(t,J=10.6Hz,3H),2.57(s,3H),1.53(d,J=10.9Hz,2H),1.45–1.27(m,2H).LC-MS:m/z 536.1[M+H]+。
实施例7:
本实施例以4-氨基-1-甲基哌啶为原料,合成化合物7:(E)-2-氰基-N-(3-甲基-4-硝基苯基)-3-(5-(4-(N-(1-甲基哌啶-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物7,产率为80%。
化合物7的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.65(s,1H),8.43(d,J=1.9Hz,1H),8.19(s,1H),8.10(d,J=8.4Hz,2H),7.94(d,J=8.6Hz,2H),7.91(d,J=1.9Hz,1H),7.81(s,1H),7.56(s,2H),7.50(d,J=8.5Hz,1H),2.95(s,1H),2.58(d,J=11.5Hz,2H),2.57(s,3H),2.06(s,3H),1.80(t,J=10.9Hz,2H),1.52(d,J=10.1Hz,2H),1.39(dd,J=17.3,6.5Hz,2H).LC-MS:m/z522.1[M+H]+。
实施例8:
本实施例以4-氨基环己烷为原料,合成化合物8:(E)-3-(5-(4-(N-(4-羟基环己基)胺磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物8,产率为85%。
化合物8的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.70(s,1H),8.20(s,1H),8.10(d,J=6.8Hz,3H),7.96(d,J=7.6Hz,2H),7.88–7.70(m,3H),7.57(s,2H),4.35(s,1H),3.59(s,1H),3.05(s,1H),2.57(s,3H),1.52(d,J=9.4Hz,4H),1.36(s,4H).LC-MS:m/z 550.1[M+H]+。
实施例9:
本实施例以吗啉为原料,合成化合物9:(E)-2-氰基-N-(3-甲基-4-硝基苯基)-3-(5-(4-(吗啉基胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物9,产率为90%。
化合物9的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.66(s,1H),8.43(d,J=2.1Hz,1H),8.26–8.07(m,3H),7.91(dd,J=15.4,5.3Hz,3H),7.63(d,J=3.7Hz,1H),7.57(d,J=3.8Hz,1H),7.50(d,J=8.5Hz,1H),3.75–3.56(m,4H),3.03–2.84(m,4H),
2.56(s,3H).LC-MS:m/z 522.1[M+H]+。
实施例10:
本实施例以N-甲基哌嗪为原料,合成化合物10:(E)-2-氰基-N-(3-甲基-4-硝基苯基)-3-(5-(4-((4-甲基哌嗪-1-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物10,产率为79%。
化合物10的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.66(s,1H),8.43(d,J=2.0Hz,1H),8.30–8.08(m,3H),7.90(dd,J=15.6,5.2Hz,3H),7.62(d,J=3.7Hz,1H),7.57(d,J=3.7Hz,1H),7.49(d,J=8.5Hz,1H),2.95(s,4H),2.56(s,3H),2.36(s,4H),2.14(s,3H).LC-MS:m/z 535.1[M+H]+。
实施例11:
本实施例以4-羟基哌嗪为原料,合成化合物11:(E)-2-氰基-3-(5-(4-((4-羟基哌啶-1-基)磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物11,产率为86%。
化合物11的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.66(s,1H),8.43(d,J=1.9Hz,1H),8.19(s,1H),8.15(d,J=8.4Hz,2H),7.96–7.85(m,3H),7.61(d,J=3.7Hz,1H),7.57(d,J=3.7Hz,1H),7.50(d,J=8.5Hz,1H),4.68(s,1H),3.53(s,1H),3.22(s,2H),2.77(t,J=8.6Hz,2H),2.56(s,3H),1.85–1.67(m,2H),1.53–1.35(m,2H).LC-MS:m/z 536.1[M+H]+。
实施例12:
本实施例以N-甲基高哌嗪为原料,合成化合物12:(E)-2-氰基-3-(5-(4-((4-甲基-1,4-高哌嗪-1-基)磺酰基)苯基)呋喃-2-基)-N-(3-甲基-4-硝基苯基)丙烯酰胺,合成路线如下:
合成具体步骤同上述实施例,制备得到化合物12,产率为85%。
化合物12的1H NMR和LC-MS数据如下:
1HNMR(400MHz,DMSO)δ10.66(s,1H),8.43(d,J=1.9Hz,1H),8.19(s,1H),8.15(d,J=8.4Hz,2H),7.96–7.85(m,3H),7.61(d,J=3.7Hz,1H),7.57(d,J=3.7Hz,1H),7.50(d,J=8.5Hz,1H),4.68(s,1H),3.53(s,1H),3.22(s,2H),2.77(t,J=8.6Hz,2H),2.56(s,3H),1.85–1.67(m,2H),1.53–1.35(m,2H).LC-MS:m/z 536.1[M+H]+。
实施例13:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酰胺与中间体6e反应制备得到化合物13:(E)-2-氰基-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物13,产率为80%。
化合物13的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ8.09(s,1H),8.07(s,1H),8.03(s,1H),7.95(d,J=8.5Hz,2H),7.90(d,J=7.3Hz,1H),7.84(s,1H),7.74(s,1H),7.52(d,J=3.7Hz,1H),7.47(d,J=3.8Hz,1H),3.72(dd,J=8.3,3.2Hz,2H),3.30–3.16(m,3H),1.52(d,J=10.4Hz,2H),1.44–1.30(m,2H).LC-MS:m/z 401.1[M+H]+。
实施例14:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和4-甲基-3-硝基苯胺合成化合物14:(E)-2-氰基-N-(4-甲基-3-硝基苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物14,产率为80%。
化合物14的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.65(s,1H),8.20(s,1H),8.10(dd,J=8.9,4.4Hz,3H),7.96(d,J=8.4Hz,2H),7.91(d,J=7.0Hz,1H),7.79(d,J=5.0Hz,2H),7.58(s,2H),3.72(d,J=11.6Hz,2H),3.24(t,J=10.6Hz,3H),2.57(s,3H),1.53(d,J=10.9Hz,2H),1.38(dd,J=11.9,7.9Hz,2H).LC-MS:m/z 536.1[M+H]+。
实施例15:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和6-氨基苯并噻唑合成化合物15:(E)-N-(苯并[d]噻唑-6-基)-2-氰基-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为78%。
化合物15的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.55(s,1H),9.33(s,1H),8.56(d,J=1.6Hz,1H),8.19(s,1H),8.10(dd,J=11.4,8.8Hz,3H),7.96(d,J=8.4Hz,2H),7.76(dd,J=8.8,1.8Hz,1H),7.57(s,2H),3.72(d,J=11.5Hz,2H),3.24(t,J=10.6Hz,3H),1.53(d,J=10.6Hz,2H),1.45–1.28(m,2H).LC-MS:m/z 534.1[M+H]+。
实施例16:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和3,4-二甲基苯胺合成化合物16:(E)-2-氰基-N-(3,4-二甲基苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物16,产率为83%。
化合物16的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),8.11(dd,J=11.4,7.8Hz,3H),7.95(d,J=8.5Hz,2H),7.90(s,1H),7.55(d,J=3.7Hz,1H),7.52(d,J=3.8Hz,1H),7.44(s,1H),7.40(d,J=8.1Hz,1H),7.12(d,J=8.2Hz,1H),3.72(d,J=11.6Hz,2H),3.23(dd,J=11.2,9.8Hz,3H),2.21(d,J=9.4Hz,6H),1.52(d,J=10.5Hz,2H),1.44–1.28(m,2H).LC-MS:m/z505.1[M+H]+。
实施例17:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和4-氨基-2-三氟甲基苯甲腈合成化合物17:(E)-2-氰基-N-(4-氰基-3-(三氟甲基)苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物17,产率为85%。
化合物17的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.96(s,1H),8.35(s,1H),8.23(s,1H),8.17(t,J=8.2Hz,2H),8.11(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.91(d,J=7.3Hz,1H),7.70–7.51(m,2H),3.72(d,J=11.6Hz,2H),3.24(t,J=10.7Hz,3H),1.53(d,J=11.0Hz,2H),1.38(dd,J=17.4,6.6Hz,2H).LC-MS:m/z 570.1[M+H]+。
实施例18:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和4,5-二甲-2-硝基苯胺合成化合物18:(E)-2-氰基-N-(4,5-二甲基-2-硝基苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物18,产率为80%)。
化合物18的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.80(s,1H),8.19(s,1H),8.10(d,J=8.1Hz,2H),7.96(d,J=8.2Hz,2H),7.89(d,J=17.3Hz,3H),7.62(d,J=3.2Hz,1H),7.57(s,1H),3.72(d,J=11.2Hz,2H),3.24(t,J=10.8Hz,3H),2.31(d,J=12.8Hz,6H),1.53(d,J=11.7Hz,2H),1.36(d,J=9.3Hz,2H).LC-MS:m/z 550.1[M+H]+。
实施例19:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和3-甲氧基-4-甲基苯胺合成化合物19:(E)-2-氰基-N-(3-甲氧基-4-甲基苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物19,产率为85%。
化合物19的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),8.22–8.07(m,2H),8.03(d,J=8.3Hz,1H),7.94(dd,J=13.1,8.5Hz,2H),7.66–7.49(m,1H),7.48–7.36(m,1H),7.33(d,J=4.9Hz,1H),7.19(dd,J=12.4,4.6Hz,2H),7.13–7.06(m,1H),3.78(d,J=2.9Hz,3H),3.72(d,J=11.5Hz,2H),3.23(t,J=10.9Hz,3H),2.12(s,3H),1.52(d,J=12.4Hz,2H),1.45–1.28(m,2H).LC-MS:m/z 521.1[M+H]+。
实施例20:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和6-氨基-1,4-苯并二氧杂环合成化合物20:(E)-2-氰基-N-(2,3-二氢苯并[b][1,4]二氧杂-6-基)-3-(5-(4-(N-(四氢-2H-pyran-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为81%。
化合物20的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),8.09(d,J=7.6Hz,3H),7.95(d,J=8.5Hz,2H),7.90(d,J=6.5Hz,1H),7.55(d,J=3.7Hz,1H),7.52(d,J=3.8Hz,1H),7.28(d,J=2.4Hz,1H),7.11(dd,J=8.7,2.4Hz,1H),6.84(d,J=8.7Hz,1H),4.24(q,J=4.9Hz,4H),3.71(dd,J=8.4,3.2Hz,2H),3.23(dd,J=11.3,9.7Hz,3H),1.52(d,J=10.4Hz,2H),1.36(dd,J=12.0,3.3Hz,2H).LC-MS:m/z 535.1[M+H]+。
实施例21:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和3,4,5-三甲氧基苯胺合成化合物21:(E)-2-氰基-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)-N-(3,4,5-三甲氧基苯基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为88%。
化合物21的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),8.14(s,1H),8.10(d,J=8.5Hz,2H),7.96(d,J=8.5Hz,2H),7.90(d,J=7.3Hz,1H),7.56(d,J=3.8Hz,1H),7.53(d,J=3.8Hz,1H),7.12(s,2H),3.78(s,6H),3.72(dd,J=8.2,3.1Hz,2H),3.65(s,3H),3.23(t,J=10.6Hz,3H),1.52(d,J=10.5Hz,2H),1.36(dd,J=12.0,3.2Hz,2H).LC-MS:m/z 567.1[M+H]+。
实施例22:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和3-氨甲基吡啶合成化合物22:(E)-2-氰基-N-(吡啶-3-基甲基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为88%。
化合物22的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ9.01(t,J=5.5Hz,1H),8.56(s,1H),8.48(d,J=4.1Hz,1H),8.08(d,J=9.0Hz,3H),7.95(d,J=8.3Hz,2H),7.86(s,1H),7.74(d,J=7.7Hz,1H),7.51(dd,J=8.7,3.5Hz,2H),7.38(dd,J=7.5,4.9Hz,1H),4.46(d,J=5.5Hz,2H),3.72(d,J=11.4Hz,2H),3.23(t,J=10.6Hz,3H),1.52(d,J=11.1Hz,2H),1.43–1.25(m,2H).LC-MS:m/z 492.1[M+H]+。
实施例23:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和3-(2-氨基乙基)吡啶合成化合物23:(E)-2-氰基-N-(2-(吡啶-3-基)乙基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为80%。
化合物23的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ8.53(dd,J=9.0,4.6Hz,2H),8.07(d,J=8.5Hz,2H),8.01(s,1H),7.95(d,J=8.5Hz,2H),7.90(d,J=6.1Hz,1H),7.73(td,J=7.7,1.7Hz,1H),7.52(d,J=3.7Hz,1H),7.49(d,J=3.8Hz,1H),7.29(d,J=7.8Hz,1H),7.25(dd,J=7.0,5.3Hz,1H),3.71(dd,J=8.4,3.1Hz,2H),3.60(dd,J=13.1,6.9Hz,2H),3.23(dd,J=11.3,9.7Hz,3H),3.00(t,J=7.3Hz,2H),1.52(d,J=10.5Hz,2H),1.44–1.27(m,2H).LC-MS:m/z506.1[M+H]+。
实施例24:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和2-噻吩乙胺合成化合物24:(E)-2-氰基-3-(5-(4-(N-(四氢-2H-吡喃-4-yl)胺磺酰基)苯基)呋喃-2-基)-N-(2-(氨基噻吩-2-基)乙基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为84%。
化合物24的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ8.51(t,J=5.6Hz,1H),8.08(d,J=8.5Hz,2H),8.02(s,1H),7.95(d,J=8.5Hz,2H),7.89(d,J=7.2Hz,1H),7.52(d,J=3.7Hz,1H),7.50(d,J=3.8Hz,1H),7.36(dd,J=5.1,0.9Hz,1H),6.97(dd,J=5.0,3.5Hz,1H),6.92(d,J=2.7Hz,1H),3.78–3.63(m,2H),3.48(dd,J=13.0,7.0Hz,2H),3.23(dd,J=11.3,9.8Hz,3H),3.06(t,J=7.2Hz,2H),1.52(d,J=10.6Hz,2H),1.37(td,J=11.0,3.3Hz,2H).LC-MS:m/z511.1[M+H]+。
实施例25:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和N-(2-氨基乙基)吗啉合成化合物25:(E)-2-氰基-N-(2-吗啉代乙基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)本家)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为88%。
化合物25的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ8.05(s,1H),7.97(s,4H),7.18(d,J=3.7Hz,2H),7.02(d,J=3.7Hz,1H),4.79(d,J=7.7Hz,1H),3.87(dt,J=11.9,3.4Hz,2H),3.76(dd,J=8.7,4.1Hz,4H),3.52(dd,J=11.2,5.8Hz,2H),3.46–3.29(m,3H),2.62(t,J=6.0Hz,2H),2.54(d,J=4.1Hz,4H),1.76(dd,J=12.7,2.2Hz,2H),1.55–1.41(m,2H).LC-MS:m/z 514.1[M+H]+。
实施例26:
本实施例以4-氨基四氢吡喃为原料,合成中间体6e,再以原料氰基乙酸和4-(40吗啉基)苯胺合成化合物26:(E)-2-氰基-N-(4-吗啉代苯基)-3-(5-(4-(N-(四氢-2H-吡喃-4-基)胺磺酰基)苯基)呋喃-2-基)丙烯酰胺,合成路线如下:
其他具体合成步骤同上述实施例,制备得到化合物15,产率为86%。
化合物26的1H NMR和LC-MS数据如下:
1H NMR(400MHz,DMSO-d6):δ8.05(s,1H),7.97(s,4H),7.18(d,J=3.7Hz,2H),7.02(d,J=3.7Hz,1H),4.79(d,J=7.7Hz,1H),3.87(dt,J=11.9,3.4Hz,2H),3.76(dd,J=8.7,4.1Hz,4H),3.52(dd,J=11.2,5.8Hz,2H),3.46–3.29(m,3H),2.62(t,J=6.0Hz,2H),2.54(d,J=4.1Hz,4H),1.76(dd,J=12.7,2.2Hz,2H),1.55–1.41(m,2H).LC-MS:m/z 514.1[M+H]+。
实施例27:
本实施例以上述26个实施例提供的丙烯酰胺类衍生物的具体化学结构为基础,对其分别进行体外P300蛋白活性的抑制效果的测试实验。
测试方法如下:
(1)实验材料:
购买于美国BPS Bioscience公司的P300酶(产品编号:50013);美国Perkin Elmer公司的384孔板(产品编号:6007279);Sigma公司的阳性对照产品Suramin(产品编号:S2671)。
(2)实验方法:
将待测化合物用100%DMSO溶解,并稀释至使检测浓度分别为10μM、1μM。分别吸取2.5μL上述稀释后的待测化合物溶液加入到384孔板中。将P300酶用分析测试缓冲液稀释40倍后取100μL依次加入到384孔板中,随后分别将试剂盒中的底物、辣根过氧化氢酶、H3K4me2以及10-acetyl-3,7-dihydroxyphenoxazine(10-乙酰基-3,7-二羟基吩噻嗪)依次加入384孔板中,调节荧光酶标仪激发波长530nm,发射波长595nm进行检测。
(3)实验结果:
通过以上实验方法,测试了本发明化合物针对P300的抑制活性,具体的化合物在10μM、1μM浓度下的抑制活性及部分化合物对SIRT2的半数抑制有效浓度(IC50)见表一,其中“-”表示未得到稳定数值。
表一 本发明化合物对P300的抑制活性(Inh%)
由表一可知,本发明提供的26种具体的化合物均能对p300有一定的抑制作用,其中,化合物1、6、7、12、13、15、26对p300抑制效果非常显著,无论是10μM、1μM,均明显优于阳性对照组C646的抑制活性,其他组别化合物p300的也有较好的抑制效果,与阳性对照组C646的抑制活性相近,由此可证明本发明提供的丙烯酰胺类衍生物对p300酶具有明显抑制效果,部分化学结构远远优于现有C646的抑制活性,因此本发明中合成的丙烯酰胺类衍生物在p300酶抑制领域具有显著的进步。
实施例28:
本实施例以上述26个实施例提供的丙烯酰胺类衍生物的具体化学结构为基础,对其分别对多种肿瘤细胞株增殖进行抑制实验,验证其对肿瘤细胞的抑制效果。
(1)实验材料:
主要试剂:RPMI-1640、胎牛血清、胰酶等购自Gibco BRL公司(InvitrogenCorporation,USA),IMDM培养基购自ATCC(American Type Culture Collection)。四甲基偶氮唑盐(MTT)、二甲基亚砜(DMSO)为Sigma公司(USA)产品。人前列腺癌细胞系(PC-3),人宫颈癌细胞系(Hela),人肺癌细胞系(H2228),人肺癌细胞系(NCI-H1975),人肺癌细胞系(PC-9),人肺癌细胞系(NCI-H358),人肺癌细胞系(Calu-1),人胰腺癌细胞系(AsPC-1),人胰腺癌细胞系(BxPC-3),淋巴瘤细胞系(Jeko-1),淋巴瘤细胞系(Molt-4),人三阴性乳腺癌细胞系(MDA-MB-231),人三阴性乳腺癌细胞系(MDA-MB-435),人卵巢癌细胞系(SK-OV-3),人卵巢癌细胞系(OVCAR-3),人卵巢癌细胞系(HO8910),人卵巢癌细胞系(A2780S),人卵巢癌细胞系(A2780/T),人纤维肉瘤细胞(HT1080)等均购于美国ATCC(American typeculture collection),由本实验室保存。
(2)实验方法:
用完全细胞培养液调整细胞浓度为1~2×104个/mL的细胞悬液,接种于96孔板,每孔200μl细胞悬液,培养过夜。次日,吸弃上清(悬浮细胞离心后吸取上清),然后分别用梯度浓度的受试化合物处理细胞。同时设不含药物的阴性对照组和等体积的溶剂对照组,DMSO浓度为0.1%,每个剂量组设3个复孔,在37℃,5%CO2条件下培养。72小时后,每孔加入浓度为5mg/mL的MTT试剂20μl,再培养2-4h后,弃上清,每孔再加入DMSO 150μL,振荡混匀15min,用酶标仪(λ=570nm)测定吸光度(A)值(A值与活细胞数成正比),取其平均值。相对细胞增殖抑制率=(阴性对照组A570-实验组A570)/阴性对照组A 570×100%。实验至少重复3次。实验数据用均数表示,数据统计资料采用t检验,P<0.05为差异有统计学意义。以下各化合物对细胞增殖抑制作用均用IC50表示。
(3)实验结果:
采用以上方法,选取对p300酶抑制效果相对显著的化合物6作为测试对象,对其分别进行了人前列腺癌细胞系(PC-3),人宫颈癌细胞系(Hela),人肺癌细胞系(H2228),人肺癌细胞系(NCI-H1975),人肺癌细胞系(PC-9),人肺癌细胞系(NCI-H358),人肺癌细胞系(Calu-1),人胰腺癌细胞系(AsPC-1),人胰腺癌细胞系(BxPC-3),淋巴瘤细胞系(Jeko-1),淋巴瘤细胞系(Molt-4),人三阴性乳腺癌细胞系(MDA-MB-231),人三阴性乳腺癌细胞系(MDA-MB-435),人卵巢癌细胞系(SK-OV-3),人卵巢癌细胞系(OVCAR-3),人卵巢癌细胞系(HO8910),人卵巢癌细胞系(A2780S),人卵巢癌细胞系(A2780/T),人纤维肉瘤细胞(HT1080)等增殖抑制活性测试,具体抑制效果见表二:
表二 本发明化合物对不同肿瘤细胞株的增殖抑制活性(IC50)
由表二内容可知,化合物6对各肿瘤细胞的IC50(μM)数量均小于10,其抑制效果显著,针对的肿瘤细胞较多元,未发生额外异变,具有很好的药用潜力。可以用于制备治疗和/或预防肿瘤的药物。
实施例29:
本实施例以上述26个实施例提供的丙烯酰胺类衍生物的具体化学结构为基础,选取对酶活性抑制效果最好的化合物6,测试其在多种肿瘤细胞株中对P300乙酰化底物的抑制效果。
(1)实验材料:
处于对数生长期的PC-3细胞和HeLA细胞。
(2)实验方法:
分别将处于对数生长期的PC-3细胞和HeLA细胞制成细胞悬液,用血细胞计数板计数后以2x107个细胞/瓶的密度接种于培养瓶中,加入分别加入0.3μM、1μM、3μM、10μM几种浓度的化合物6,并设置相应浓度的C646作为阳性对照组。将培养瓶置于37℃,5%CO2细胞培养孵箱内培养2小时。将细胞按照要求处理后弃掉培养基,用预冷的生理盐水漂洗两次,吸尽瓶中残留的液体,均匀加入适当体积的RIPA裂解液(含有cocktail和PMSF蛋白酶抑制剂)覆盖细胞并置于冰上裂解约10min。随后收集方瓶中的细胞并转入1.5mL EP管中低温保存,再用超声破碎仪超声破碎细胞,离心除去细胞碎片。采用G250蛋白定量试剂按Bradford法定量统一各组蛋白样品的浓度,加入缓冲液,在高温下煮5-10min使蛋白变性。处理好的蛋白样品分装后保存于-20℃冰箱备用。然后采用聚丙烯酰胺凝胶电泳(SDS-PAGE)分离蛋白。电泳分离完毕后凝胶在转膜缓冲液中平衡30分钟,PVDF膜在甲醇中浸泡10秒后,以板(黑色)-纤维棉-滤纸-胶-膜-滤纸-纤维棉-板(红色)的顺序装置,排除各层间的气泡,100V电压电泳60分钟。在室温下将PVDF膜置于水平摇床上TBS/T浸洗3次,5分钟/次。室温下,二抗孵育1小时。室温下,PVDF膜洗3次,5分钟/次。曝光显影试剂盒A液和B液以1:1混合均匀后,滴加在PVDF膜蛋白,暗室曝光后,取出光片,置于自动光片洗片机冲洗照片。
(3)实验结果:
如图1所示,在PC-3细胞中,化合物6对组蛋白底物H3K27组蛋白底物H3K9的乙酰化均有明显的抑制效果,随着化合物6浓度的增加,其抑制效果更为显著,其抑制效果明显优于相同浓度的C646。
在Hela细胞中,化合物6对组蛋白底物H3K27组蛋白底物H3K9的乙酰化的抑制效果也较为显著,且化合物6浓度的增加,其抑制效果也随之提升,优于相同浓度的C646对组蛋白底物H3K27组蛋白底物H3K9的乙酰化的抑制效果。
实验结论,本发明化合物在肿瘤细胞中对P300乙酰化底物的有显著的抑制效果,能够有效遏制肿瘤细胞的分裂增殖,且10μM以下浓度的该化合物均对肿瘤细胞增殖有抑制效果,其类药性显著。
尽管已经示出和描述了本发明的实施例,本领域的普通技术人员可以理解:在不脱离本发明的原理和宗旨下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。
Claims (10)
1.一种丙烯酰胺类衍生物,其通式如下:
其中,
X为独立的
Y为独立的
R1为独立的H、C1~C4烷基、三元饱和环、四元饱和环、五元饱和环、六元饱和环、七元饱和环、八元饱和环;
R2为独立的H、芳基、杂芳基、取代芳基、取代杂芳基、五元饱和环或六元饱和环。
2.根据权利要求1所述的丙烯酰胺类衍生物,其特征在于,包括以下结构式:
3.根据权利要求1或2所述的一种丙烯酰胺类衍生物的制备方法,其特征在于,包括以下步骤:
(1)将0.8~1.2当量的原料A使用DCM溶解,并加入1.5~3.0当量的三乙胺,搅拌30分钟后,加入1~1.5当量的4-溴苯磺酰氯,继续室温搅拌反应过夜,检测反应完全后,浓缩溶剂加入水和DCM萃取3次,合并有机相,使用污水Na2SO4干燥,浓缩后得中间体Ⅰ;
(2)取0.8~1.2当量的中间体Ⅰ、1.2~2.0当量的5-醛基-呋喃-2-硼酸、无1.2~2.0当量的水碳酸钠和0.1~0.5当量的双三苯基膦二氯化钯,用MeCN:H2O=2:1溶解后,置换氩气三次后,升温至80℃反应2h,检测反应完全后,冷却至室温,用硅藻土过滤掉不溶物催化剂,减压浓缩,加水经乙酸乙酯萃取,浓缩,柱层析得到中间体Ⅱ;
(3)使用乙醇溶解0.5~2.0当量的中间体Ⅱ,再加入0.8~1.5当量的氰基乙酰胺或中间体Ⅲ,滴加催化量的哌啶,升温至85℃反应4h,检测反应完全后,冷却至室温,浓缩,柱层析得到该丙烯酰胺类衍生物;所述中间体Ⅲ主要由0.8~1.5当量的氰基乙酸与1.0~1.5当量的原料C缩合而成。
4.根据权利要求3所述的一种丙烯酰胺类衍生物的制备方法,其特征在于,包括以下步骤:
(1)将1.0当量的原料A使用DCM溶解,并加入1.5~3.0当量的三乙胺,搅拌30分钟后,加入1~1.5当量的4-溴苯磺酰氯,继续室温搅拌反应过夜,检测反应完全后,浓缩溶剂加入水和DCM萃取3次,合并有机相,使用污水Na2SO4干燥,浓缩后得中间体Ⅰ;
(2)取1.0当量的中间体Ⅰ、1.5当量的5-醛基-呋喃-2-硼酸、2.0当量的无水碳酸钠和0.1当量的双三苯基膦二氯化钯,用MeCN:H2O=2:1溶解后,置换氩气三次后,升温至80℃反应2h,检测反应完全后,冷却至室温,用硅藻土过滤掉不溶物催化剂,减压浓缩,加水经乙酸乙酯萃取,浓缩,柱层析得到中间体Ⅱ;
(3)使用乙醇溶解1.0当量的中间体Ⅱ,再加入2当量的氰基乙酰胺或中间体Ⅲ,滴加催化量的哌啶,升温至85℃反应4h,检测反应完全后,冷却至室温,浓缩,柱层析得到该丙烯酰胺类衍生物;所述中间体Ⅲ主要由0.8~1.5当量的氰基乙酸与1.0~1.5当量的原料C缩合而成。
5.根据权利要求3或4所述的一种丙烯酰胺类衍生物的制备方法,其特征在于,所述步骤(1)中的原料A主要选自氨水、环丙胺、环丁基胺、环戊胺、环己胺、4-氨基四氢吡喃、4-氨基-1-甲基哌啶、4-氨基环己烷、吗啉、N-甲基哌嗪、4-羟基哌嗪、N-甲基高哌嗪中的至少一种。
6.根据权利要求3或4所述的一种丙烯酰胺类衍生物的制备方法,其特征在于,所述步骤(3)中的原料C主要选自3-甲基-4-硝基苯胺、6-氨基苯并噻唑、3,4-二甲基苯胺、4-氨基-2-三氟甲基苯甲腈、4,5-二甲-2-硝基苯胺、3-甲氧基-4-甲基苯胺、6-氨基-1,4-苯并二氧杂环、3,4,5-三甲氧基苯胺、3-氨甲基吡啶、3-(2-氨基乙基)吡啶、2-噻吩乙胺、N-(2-氨基乙基)吗啉、4-(4-吗啉基)苯胺中的至少一种。
7.根据权利要求3或4所述的一种丙烯酰胺类衍生物的制备方法,其特征在于,所述一种丙烯酰胺类衍生物的制备方法,其特征在于,反应是否完全均使用TLC进行检测。
8.一种组蛋白乙酰转氨酶P300抑制剂,其特征在于,以权利要求1或2所述丙烯酰胺类衍生物为主要活性成分的生物药学上可接受的盐、晶型、溶剂合物。
9.一种治疗癌症的药物,其特征在于,以权利要求9所述的组蛋白乙酰转氨酶P300抑制剂为主要成分,添加生物药学上能够接受的辅助性成分制备而成。
10.根据权利要求9所述治疗癌症的药物,其特征在于,治疗的癌症包括前列腺癌、宫颈癌、肺癌、胰腺癌、淋巴瘤、三阴性乳腺癌、卵巢癌、纤维肉瘤。
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