CN114262307A - 3-(3-环丙烷取代苯基-4-噻唑啉酮基)-n-芳基苯甲酰胺类化合物和应用 - Google Patents
3-(3-环丙烷取代苯基-4-噻唑啉酮基)-n-芳基苯甲酰胺类化合物和应用 Download PDFInfo
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- CN114262307A CN114262307A CN202010972804.3A CN202010972804A CN114262307A CN 114262307 A CN114262307 A CN 114262307A CN 202010972804 A CN202010972804 A CN 202010972804A CN 114262307 A CN114262307 A CN 114262307A
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- thiazolinone
- acid
- benzamide
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Abstract
本发明公开了一种3‑(3‑环丙烷取代苯基‑4‑噻唑啉酮基)‑N‑芳基苯甲酰胺类化合物或药学上可接受的盐及其合成方法,本发明还公开了该类化合物可用于治疗骨肉瘤、结直肠癌及白血病等相关疾病的用途,在肿瘤疾病的研究上具有重要意义。
Description
技术领域
本发明属于合成医药、生物医药领域,主要涉及一种3-(3-环丙烷取代苯基-4-噻唑啉酮基) -N-芳基苯甲酰胺类化合物及其制备和应用。
背景技术
骨肉瘤也叫成骨肉瘤,是较常见的发生在20岁以下的青少年或儿童的一种恶性骨肿瘤(Link MP:Osteosarcoma in adolescents and young adults:new developmentsand controversies. Commentary on the use of presurgical chemotherapy.CancerTreat Res 62:383-385,1993.),根据骨肉瘤流行病学研究显示:在小儿骨恶性肿瘤中最多见,约为小儿肿瘤的5%。骨肉瘤目前仍是儿童和青少年恶性肿瘤死亡率很高的疾病,仅次于淋巴瘤和脑癌,但早期发现和及时治疗已经从很大程度上提高了该病的生存率。
针对不同类型骨肉瘤治疗方法通常采用手术后联合用药,值得注意的是骨肉瘤患者的癌症转移率高达80%,在发生转移的患者中,90%都是肺部转移。其中复发率20-30%,原位或者原位组织都有可能复发,并且复发好后生存率,在过去的几十年,尽管通过调整增加剂量,变更次数以及多种化疗药联用等治疗方法,生存率并没有提高。
目前,针对骨肉瘤治疗靶点的研究主要集中在细胞表面受体酪氨酸激酶家族(PTKs),和细胞内信号靶点。而针对这些靶点,主要的治疗药物分为三类:1)免疫调节剂;2)受体酪氨酸激酶抑制剂;3)细胞内信号通路抑制剂。此外,骨肉瘤的新靶点和治疗方案还有NK-kB 配体、叶酸抑制剂等,但均处于试验研究阶段。
发明内容
本发明人注意到,在以往的文献报道中,噻唑琳酮骨架结构的化合物具有多种药理学活性,如式(II)所示的化合物具有抗炎症活性以及式(III)所示的化合物具有抗艾滋活性:
在本发明之前未有针对该类骨架关于骨肉瘤细胞活性测试评价的相关报道。本发明人研究发现并提出,该骨架化合物可能会产生一系列在结构和活性上有意义的新化合物分子,可能为生物活性筛选提供新的化合物来源。
本发明提出了一种3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其结构如式(I)所示;
其中,
Ar为芳基、芳杂环、烷基取代的芳基、卤素取代的芳基、烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘烷基、呋喃烷基、烯基、炔基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪等;
R1为卤素、烷氧基、烷基、硝基、氰基、三氟甲基、苯基、氢等;
R2为烷基或氢等;
R3为卤素、烷氧基、烷基、环烷基、硝基、氰基、三氟甲基、苯基、氢等。
n=0;1;2;3;4;5;6。
优选地,
Ar为芳基、芳杂环、C1-C10烷基取代的芳基、卤素取代的芳基、C1-C10烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪;
R1为卤素、C1-C10烷氧基、甲基、乙基、异丙基、硝基、氰基、三氟甲基、苯基、氢;
R2为甲基或氢;
R3为卤素、C1-C10烷氧基、甲基、乙基、异丙基、环丙基、硝基、氰基、三氟甲基、苯基、氢。
n=1;2;3;4;5;6。
本发明所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其包括:
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基乙基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丙基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-苯基-4-噻唑啉酮基)-5-环丙烷基-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙基苯基)-4-噻唑琳酮基)-N-(4-(N-吡唑)丁基)-苯甲酰胺;
3-(3-(3-环丙基苯基)-4-噻唑琳酮基)-N-(4-(N-吲哚)丁基)-苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(N-吡唑)丁基)苯甲酰胺;
3-环丙基-5-(3-(2-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺;
3-环丙基-5-(3-(3-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺;
3-环丙基-5-(3-(4-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺。
本发明还提出了所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物与酸形成的酸加成盐;其中,所述酸是盐酸、硫酸、磷酸、氢溴酸、乙酸、水杨酸、酒石酸、乳酸、柠檬酸、甲磺酸、对甲苯磺酸、马来酸、丙酮酸或琥珀酸等。
本发明还提出了一种药物组合物,其包含所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N- 芳基苯甲酰胺类化合物或药学上可接受的盐,以及药学上可接受的载体。
其中,所述的药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂等。
本发明还提出了所述的3-(3-环丙烷基取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,或药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
其中,所述3-(3-环丙烷基取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发,或促进肿瘤细胞凋亡。
其中,所述肿瘤包括骨肉瘤、结直肠癌、白血病、肺癌等。
所述骨肉瘤细胞包括SJSA-1型骨肉瘤细胞、MNNG/HOS型骨肉瘤细胞、U-2-OS型骨肉瘤细胞、MG63型骨肉瘤细胞、HOS型骨肉瘤细胞、143B型骨肉瘤细胞。
所述肺癌细胞包括A549型肺癌细胞。
所述白血病细胞包括Jurkat白血病细胞。
所述结直肠癌细胞包括HCT116结直肠癌细胞。
本发明还提出了一种如式(I)所示的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐的合成方法,当苯环上的环丙烷基在胺基的间位时,所述如式(I)所示的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐的合成方法,具体包括步骤如下,包含如下四个反应式(A)、(B)、(C)、(D):
第一步,用间溴苯胺与环丙硼酸在醋酸钯/环己基磷体系催化下进行偶联,得到间环丙烷基苯胺。
第二步,用对间环丙基苯胺(10mmol,1.0eq)与3-甲醛苯甲酸甲酯(10mmol,1.0eq)在甲苯回流条件下反应30分钟,此时会生成相应的亚胺化合物。随后冷却至室温,再向反应体系中加入硫代乙醇(10mmol,1.0eq)继续回流,反应5h后冷却至室温,点板监测反应结束,再通过柱层析(石油醚:乙酸乙酯=3:1~1:1)分离纯化得到酯类化合物。
第三步,将第二步所得酯类化合物(5mmol,1.0eq)与LiOH(5.25mmol,1.05eq)在甲醇:水(4:1)的溶剂中,室温下条件下反应20小时,点板监测到底物消耗完全,反应结束后,将溶剂中的甲醇旋蒸除去,再将剩下的反应液倒入50mL水中,滴加3N HCl酸化,用pH 试纸监测直至pH=1。用乙酸乙酯萃取出有机相,无水硫酸钠干燥之后,旋蒸得羧酸类产物。
第四步,将第三步所得羧酸类产物(1.5mmol,1.0eq)与1-羟基苯并三唑(即HOBt,3.0mmol, 2.0eq)溶于20mL四氢呋喃中,冰浴条件下,加入N,N-二异丙基乙胺(DIPEA,4.5mmol,3.0 eq),搅拌20分钟后,加入化合物苯丁胺,继续搅拌10分钟。随后,分批加入缩合剂1-乙基 -(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI,3mmol,2.0eq),反应两小时后,点板监测,原料消耗完全。往反应液中依次加入适量饱和碳酸氢钠,用饱和食盐水洗涤,再用乙酸乙酯萃取三次,旋蒸得到的粗产物通过柱层析(石油醚:乙酸乙酯=3:1~1:1)最终得到目标产物。
当苯环上的环丙烷基在胺基对(或邻)位时,所述如式(I)所示的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐的合成方法,具体包括步骤如下,包含如下四个反应式(E)、(F)、(G)、(H):
首先,如反应式(E)所示,将对(或邻)硝基溴苯与环丙硼酸在醋酸钯/环己基磷体系催化下进行偶联,得到4-(或2-)环丙烷基硝基苯。随后用过量铁粉与醋酸将硝基还原为胺基,得到的对(或邻)环丙烷基苯胺类产物,参照反应式(B)、(C)、(D)最终得到目标化合物。
其中,反应式(A)(B)(C)(D)及反应式(E)中,Ar、R1、R2的定义同式(I)。
本发明的有益效果在于:本发明公开了一种3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐对肿瘤细胞有抑制活性的作用,可用于治疗骨肉瘤、结直肠癌、及白血病等相关疾病,在肿瘤疾病的研究上具有重要意义。
附图说明
图1为实施例1所得产物Cyclo-1的1H NMR(图1A)和13C NMR(图1B)示意图。
图2为实施例2所得产物Cyclo-2的1H NMR(图2A)和13C NMR(图2B)示意图。
图3为实施例3所得产物Cyclo-3的1H NMR(图3A)和13C NMR(图3B)示意图。
图4为实施例4所得产物Cyclo-4的1H NMR(图4A)和13C NMR(图4B)示意图。
图5为实施例5所得产物Cyclo-5的1H NMR(图5A)和13C NMR(图5B)示意图。
图6为实施例6所得产物Cyclo-6的1H NMR(图6A)和13C NMR(图6B)示意图。
图7为实施例7所得产物Cyclo-7的1H NMR(图7A)和13C NMR(图7B)示意图。
图8为实施例8所得产物Cyclo-8的1H NMR(图8)。
图9为实施例9所得产物Cyclo-9的1H NMR(图9A)和13C NMR(图9B)示意图。
图10为实施例10所得产物Cyclo-10的1H NMR(图10A)和13C NMR(图10B)示意图。
具体实施方式
结合以下具体实施例和附图,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
本发明以下实施例中关于化合物的制备方法参考上文中提到的式(I)所示化合物的制备。测定方法:低分辨质谱(分子量)以及核磁仪器(氢谱以及碳谱)。
实施例1:
核磁共振1H NMR、13C NMR图谱如图1所示:
1H NMR(400MHz,Chloroform-d)δ7.78(d,J=6.4Hz,1H),7.57(d,J=7.8Hz,1H),7.42(t, J=6.2Hz,1H),7.29–7.05(m,9H),6.71–6.60(m,1H),6.08(s,1H),3.92–3.75(m,3H),3.73– 3.59(m,3H),3.40–3.20(m,2H),2.91(s,1H),2.57(q,J=7.0Hz,2H),1.56(dt,J=24.2Hz,7.6 Hz,4H).
13C NMR(101MHz,CDCl3)δ171.04,169.55,166.73,145.51,141.98,140.35,137.18,135.30, 129.81,129.14,128.41,127.10,124.75,123.28,122.76,65.36,40.02,35.47,33.47,29.17,28.68, 15.29,9.42.
实施例2:
核磁共振1H NMR、13C NMR图谱如图2所示:
1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.62(d,J=7.2Hz,1H),7.43(s,1H),7.39– 7.17(m,5H),7.04(t,J=7.7Hz,1H),6.79(d,J=16.8Hz,4H),6.18(s,1H),6.02(s,1H),4.12(t,J =6.2Hz,3H),3.91(d,J=15.9Hz,1H),3.79(d,J=15.7Hz,1H),3.35(d,J=5.6Hz,3H),1.94– 1.79(m,4H),1.57–1.46(m,4H),0.81(d,J=7.8Hz,3H),0.51–0.43(m,2H).
13C NMR(100MHz,Chloroform-d)δ170.02,165.74,144.46,139.27,138.18,136.18,134.13, 128.79,128.29,128.06,127.99,126.35,124.99,123.70,122.27,121.76,104.55,64.37,50.22,38.58, 32.44,28.68,27.00,24.98,14.26,8.46,8.40.
实施例3:
核磁共振1H NMR、13C NMR图谱如图3所示:
1H NMR(400MHz,Chloroform-d)δ7.70(t,J=1.8Hz,1H),7.59(dt,J=7.6Hz,1.5Hz,1H), 7.40(dt,J=7.8Hz,1.4Hz,1H),7.34–7.24(m,4H),7.18(td,J=7.4Hz,6.8Hz,1.7Hz,4H),6.99 (d,J=8.5Hz,2H),6.91(d,J=8.6Hz,2H),6.31(t,J=5.8Hz,1H),6.06(d,J=1.6Hz,1H),3.95 (dd,J=15.8Hz,1.7Hz,1H),3.83(d,J=15.8Hz,1H),3.48–3.32(m,2H),2.64(t,J=7.4Hz,3H), 1.91(s,1H),0.98–0.80(m,2H),0.58(dd,J=4.8Hz,1.9Hz,2H).
13C NMR(101MHz,CDCl3)δ171.05,166.72,143.41,142.04,140.35,135.33,134.38,129.76, 129.11,128.38,127.21,126.41,125.93,125.88,125.65,65.29,40.00,35.49,33.43,29.15,28.72, 15.04,9.46,9.36.
实施例4:
核磁共振1H NMR、13C NMR图谱如图4所示:
1H NMR(400MHz,Chloroform-d)δ7.64(d,J=3.7Hz,1H),7.49(dd,J=22.7Hz,7.6Hz, 1H),7.32(dd,J=20.4Hz,7.7Hz,2H),7.13(d,J=8.1Hz,3H),6.98(d,J=8.1Hz,4H),6.81(s, 1H),5.99(s,1H),4.11(d,J=6.9Hz,0H),3.99(d,J=6.9Hz,1H),3.27(d,J=6.0Hz,3H),2.49(t, J=6.6Hz,5H),1.62(d,J=6.9Hz,2H),1.17(s,1H),0.77(d,J=7.5Hz,3H).
13C NMR(101MHz,CDCl3)δ173.82,166.74,145.41,140.50,137.64,135.31,135.00,131.47, 130.38,129.77,129.33,128.94,128.41,127.10,124.60,123.36,122.83,122.28,63.29,42.72,41.80, 39.87,34.78,29.06,28.57,19.98,19.22,15.32,9.51.
实施例5:
核磁共振1H NMR、13C NMR图谱如图5所示:
1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.56(dd,J=17.1Hz,7.5Hz,1H),7.42(d,J =23.8Hz,1H),7.17(d,J=7.4Hz,3H),7.04(d,J=8.1Hz,1H),6.99(d,J=8.1Hz,1H),6.92(t,J =9.0Hz,2H),6.13(s,1H),4.20(d,J=6.9Hz,0H),4.10(d,J=6.9Hz,0H),3.42(d,J=6.1Hz, 2H),2.65(t,J=7.0Hz,2H),1.73(d,J=7.1Hz,3H),1.27(d,J=10.3Hz,1H),0.89(s,2H).
13C NMR(101MHz,CDCl3)δ173.78,166.74,143.11,142.01,130.35,129.32,129.17,129.02, 128.41,126.99,126.88,126.56,126.35,125.88,125.71,125.52,125.20,42.68,41.78,39.98,35.48, 29.17,28.70,20.15,19.31,15.02,9.41,9.30.
实施例6:
核磁共振1H NMR、13C NMR图谱如图6所示:
1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.57(d,J=27.7Hz,1H),7.41(dd,J=18.6, 7.7Hz,1H),7.16(d,J=7.0Hz,4H),7.07(d,J=8.1Hz,1H),6.90(s,1H),6.80(d,J=12.1Hz, 2H),6.00(s,0H),4.19(d,J=6.9Hz,0H),4.09(d,J=6.9Hz,0H),3.39(d,J=5.9Hz,2H),2.62(d, J=7.0Hz,3H),1.72(s,1H),1.33(s,1H),0.86(s,2H).
13C NMR(101MHz,CDCl3)δ173.81,166.75,145.42,142.04,140.81,139.56,137.66,135.38, 130.37,129.30,128.96,126.71,125.87,124.62,123.38,122.84,122.28,63.29,41.82,39.98,35.49, 29.72,29.16,28.71,20.00,19.24,15.33,9.48.
实施例7:
核磁共振1H NMR、13C NMR图谱如图7所示:
1H NMR(400MHz,Chloroform-d)δ7.64(d,J=3.7Hz,1H),7.49(dd,J=22.7Hz,7.6Hz, 1H),7.32(dd,J=20.4Hz,7.7Hz,2H),7.13(d,J=8.1Hz,3H),6.98(d,J=8.1Hz,4H),6.81(s, 1H),5.99(s,1H),4.11(d,J=6.9Hz,0H),3.99(d,J=6.9Hz,1H),3.27(d,J=6.0Hz,3H),2.49(t, J=6.6Hz,5H),1.62(d,J=6.9Hz,2H),1.17(s,1H),0.77(d,J=7.5Hz,3H).
13C NMR(101MHz,CDCl3)δ173.82,166.74,145.41,140.50,137.64,135.31,135.00,131.47, 130.38,129.77,129.33,128.94,128.41,127.10,124.60,123.36,122.83,122.28,63.29,42.72,41.80, 39.87,34.78,29.06,28.57,19.98,19.22,15.32,9.51.
实施例8:
核磁共振1H NMR图谱如图8所示:
1H NMR(400MHz,Chloroform-d)δ7.95(dd,J=3.2Hz,1.6Hz,1H),7.94–7.84(m,1H), 7.69(s,1H),7.64–7.53(m,2H),7.50–7.40(m,3H),7.40–7.22(m,6H),7.19(s,1H),7.10–6.98 (m,2H),6.92–6.73(m,3H),6.19(s,0H),6.04(d,J=7.0Hz,1H),5.96(d,J=11.9Hz,0H),4.23– 3.85(m,3H),3.49–3.19(m,1H),2.00–1.76(m,2H),1.79–1.56(m,4H),1.52(dd,J=14.3Hz, 7.5Hz,3H),1.18(s,3H),0.82(dd,J=7.7Hz,4.7Hz,3H),0.60–0.40(m,4H).
实施例9:
核磁共振1H NMR、13C NMR图谱如图9所示:
1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.46(d,J=7.4Hz,1H),7.37(d,J=7.3Hz, 1H),7.22(dd,J=16.0Hz,7.7Hz,6H),7.14(d,J=7.1Hz,3H),7.08(d,J=7.9Hz,1H),6.77(dd, J=12.5Hz,8.7Hz,3H),6.69(t,J=7.4Hz,1H),6.17(s,1H),6.04(s,1H),3.91–3.76(m,2H), 3.71(s,3H),3.59(d,J=6.1Hz,2H),2.83(t,J=6.2Hz,3H).
13C NMR(101MHz,CDCl3)δ170.39,165.75,153.76,138.76,137.81,133.86,129.71,129.09, 128.68,127.78,127.70,126.24,125.61,125.49,124.13,119.86,111.07,63.29,54.69,40.16,34.58, 32.11.
实施例10:
核磁共振1H NMR、13C NMR图谱如图10所示:
1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.42(d,J=7.5Hz,1H),7.37(d,J=7.5Hz, 1H),7.18(d,J=5.0Hz,4H),7.13–7.03(m,5H),6.80(d,J=7.6Hz,1H),6.74(d,J=8.2Hz,1H), 6.66(t,J=7.4Hz,1H),6.32(s,1H),6.03(s,1H),3.81(q,J=15.6Hz,4H),3.70(s,3H),3.32(d,J =6.0Hz,3H),2.59(t,J=7.2Hz,3H),1.89–1.74(m,3H).
13C NMR(101MHz,CDCl3)δ171.52,166.72,154.80,141.47,139.72,134.86,130.60,130.14, 129.74,128.68,128.54,128.39,127.30,126.61,126.07,125.18,120.87,112.09,64.37,55.74,39.87, 33.48,33.16,31.01.
实施例11:
抗肿瘤活性测试实验
1、接种细胞:
1)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个SJSA-1型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
2)用含10%胎牛血清、1%青霉素和链霉素的DMEM培养液配成单个细胞悬液,以每孔 2500个MNNG/HOS型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
3)用含10%胎牛血清、1%青霉素和链霉素的McCoy'5A培养液配成单个细胞悬液,以每孔2500个U-2-OS型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
4)用含10%胎牛血清、1%青霉素和链霉素的DMEM培养液配成单个细胞悬液,以每孔 2500个MG63型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
5)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个HOS型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
6)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个143B型骨肉瘤细胞接种到96孔细胞培养板,每孔体积100μl。
7)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个A549型肺癌细胞接种到96孔细胞培养板,每孔体积100μl。
8)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个Jurkat白血病细胞接种到96孔细胞培养板,每孔体积100μl。
9)用含10%胎牛血清、1%青霉素和链霉素的1640培养液配成单个细胞悬液,以每孔2500 个HCT116结直肠癌细胞接种到96孔细胞培养板,每孔体积100μl。
2、给药:分别将本发明前述实施例中合成的式(I)化合物(表1,表2及表3中所列的10个化合物Cyclo-1~Cyclo-10)用DMSO配制成终浓度为25mM的母液,用完全培养基稀释至1uM,作用于细胞,设置三个复孔。
3、培养:5%CO2,37℃饱和湿度育孵箱培养72小时。
4、呈色:培养72小时吸出培养基,每孔加入100μl完全培养基和10μl CCK8,37℃孵育 4小时。
5、比色:选择620、450nm波长,在酶标仪上测定各孔光密度(OD)值,记录结果。
6、同一孔450nm吸光光度值-620nm吸光光度值(背景吸光光度值)作为最终吸光度,代入以下公式。
7、细胞增殖活力(%)=[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
A(加药):具有肿瘤细胞、CCK溶液(Cell Counting Kit-8,是一种基于WST-8(化学名:2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的细胞增殖和细胞毒性快速高灵敏度检测试剂)和药物溶液(药物溶液即指待测试的化合物样品DMSO溶液) 的孔的吸光度
A(空白):具有培养基和CCK溶液而没有细胞的孔的吸光度
A(0加药):具有细胞、CCK溶液而没有药物溶液的孔的吸光度
8、实验结果表明:在浓度为1μM本发明式(I)化合物的作用下,各化合物(表1中所列的10个化合物Cyclo-1~Cyclo-10)的6种亚型的人骨肉瘤细胞株存活率如下表1。由此表明,在这10个化合物中,4个化合物Cyclo-1、Cyclo-3、Cyclo-5、Cyclo-6对骨肉瘤细胞143B表现出较好的抑制活性;4个化合物Cyclo-1、Cyclo-3、Cyclo-6、Cyclo-7对骨肉瘤细胞SJSA-1 表现出较好的抑制活性;4个化合物Cyclo-1、Cyclo-3、Cyclo-5、Cyclo-6对骨肉瘤细胞HOS 表现出较好的抑制活性;5个化合物Cyclo-1、Cyclo-2、Cyclo-3、Cyclo-5、Cyclo-6对骨肉瘤细胞MNNG/HOS表现出较好的抑制活性;7个化合物Cyclo-1、Cyclo-2、Cyclo-3、Cyclo-5、 Cyclo-6、Cyclo-7、Cyclo-8对骨肉瘤细胞MG63表现出非常好的抑制活性。
表1
9、实验结果表明:在浓度为1μM本发明式(I)化合物的作用下,各化合物(表2中所列的10个化合物Cyclo-1~Cyclo-10)的肺癌细胞株A549存活率如下表2。由此表明,在这10个化合物中,4个化合物Cyclo-1、Cyclo-3、Cyclo-6、Cyclo-7对肺癌细胞A549表现出较好的抑制活性。
表2
10、实验结果表明:在浓度为1μM本发明式(I)化合物的作用下,各化合物(表3中所列的10个化合物Cyclo-1~Cyclo-10)的白血病细胞株Jurkat存活率如下表3。由此表明,在这 10个化合物中,7个化合物Cyclo-1、Cyclo-2、Cyclo-3、Cyclo-5、Cyclo-6、Cyclo-7、Cyclo-8 对白血病细胞Jurkat表现出非常好的抑制活性。
表3
11、实验结果表明:在浓度为1μM本发明式(I)化合物的作用下,各化合物(表4中所列的10个化合物Cyclo-1~Cyclo-10)的结直肠癌细胞HCT116存活率如下表4。由此表明,在这10个化合物中,8个化合物Cyclo-1、Cyclo-2、Cyclo-3、Cyclo-4、Cyclo-5、Cyclo-6、Cyclo-7、 Cyclo-8对结直肠癌细胞HCT116表现出非常好的抑制活性。
表4
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (10)
1.一种3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其特征在于,其结构如式(I)所示:
其中,
Ar为芳基、芳杂环、烷基取代的芳基、卤素取代的芳基、烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘烷基、呋喃烷基、烯基、炔基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪;
R1为卤素、烷氧基、烷基、硝基、氰基、三氟甲基、苯基、氢;
R2为烷基或氢;
R3为卤素、烷氧基、烷基、环烷基、硝基、氰基、三氟甲基、苯基、氢;
n=0;1;2;4;5;6。
2.根据权利要求1所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其特征在于,Ar为芳基、芳杂环、C1-C10烷基取代的芳基、卤素取代的芳基、C1-C10烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪;
R1为卤素、C1-C10烷氧基、甲基、乙基、异丙基、硝基、氰基、三氟甲基、苯基、氢;
R2为甲基或氢;
R3为卤素、C1-C10烷氧基、甲基、乙基、异丙基、环丙基、硝基、氰基、三氟甲基、苯基、氢;
n=1;2;3;4;5;6。
3.根据权利要求1或2所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其特征在于,选自于以下:
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基乙基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丙基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺;
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺;
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(N-吡唑)苯基丁基)苯甲酰胺。
4.根据权利要求1-3之任一项所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,其特征在于,所述化合物与酸形成的酸加成盐;其中,所述酸是盐酸、硫酸、磷酸、氢溴酸、乙酸、水杨酸、酒石酸、乳酸、柠檬酸、甲磺酸、对甲苯磺酸、马来酸、丙酮酸或琥珀酸。
5.一种药物组合物,其特征在于,其包含如权利要求1-3之任一项所述的3-(3-环丙烷取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,以及药学上可接受的载体。
6.根据权利要求5所述的药物组合物,其特征在于,所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂。
7.根据权利要求1-3之任一项所述的3-(3-环丙烷基取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,或如权利要求5所述的药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述3-(3-环丙烷基取代苯基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐,或药物组合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发,或促进肿瘤细胞凋亡。
9.根据权利要求7所述的应用,其特征在于,所述肿瘤包括骨肉瘤、结直肠癌、白血病、肺癌。
10.根据权利要求9所述的应用,其特征在于,所述骨肉瘤细胞包括SJSA-1型骨肉瘤细胞、MNNG/HOS型骨肉瘤细胞、U-2-OS型骨肉瘤细胞、MG63型骨肉瘤细胞、HOS型骨肉瘤细胞、143B型骨肉瘤细胞;所述肺癌细胞包括A549型肺癌细胞;所述白血病包括Jurkat白血病细胞;所述结直肠癌包括HCT116。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102653526A (zh) * | 2012-05-08 | 2012-09-05 | 华东师范大学 | 2,3-二芳香基噻唑啉酮类化合物及其在制备治疗肿瘤药物中的用途 |
CN102786493A (zh) * | 2012-07-30 | 2012-11-21 | 华东师范大学 | 2,3-二芳香基噻唑啉酮类化合物及类似物及其在制备抗血管新生药物中的用途 |
CN104447608A (zh) * | 2014-11-10 | 2015-03-25 | 华东师范大学 | 含有噻唑啉酮结构的异羟肟酸类小分子有机化合物及其衍生物、用途及其制备方法 |
-
2020
- 2020-09-16 CN CN202010972804.3A patent/CN114262307A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102653526A (zh) * | 2012-05-08 | 2012-09-05 | 华东师范大学 | 2,3-二芳香基噻唑啉酮类化合物及其在制备治疗肿瘤药物中的用途 |
CN102786493A (zh) * | 2012-07-30 | 2012-11-21 | 华东师范大学 | 2,3-二芳香基噻唑啉酮类化合物及类似物及其在制备抗血管新生药物中的用途 |
CN104447608A (zh) * | 2014-11-10 | 2015-03-25 | 华东师范大学 | 含有噻唑啉酮结构的异羟肟酸类小分子有机化合物及其衍生物、用途及其制备方法 |
Non-Patent Citations (4)
Title |
---|
FEIFEI YANG, ET AL.: ""A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities"", 《ORG. BIOMOL. CHEM.》, vol. 14, 31 December 2016 (2016-12-31), pages 1727 * |
JING WU,ET AL.: ""Optimization of 2-(3-(arylalkyl amino carbonyl) phenyl)-3-(2- methoxyphenyl)-4-thiazolidinone derivatives as potent antitumor growth and metastasis agents"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 80, 23 April 2014 (2014-04-23), pages 340 - 351, XP055781860, DOI: 10.1016/j.ejmech.2014.04.068 * |
TAO ZHANG, ET AL.: ""A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer"", 《NATURE COMMUNICATIONS》, vol. 9, 31 December 2018 (2018-12-31), pages 3726 * |
郑亚东等: ""3-氨基苯甲酰胺联合顺铂抑制骨肉瘤细胞生长的作用"", 《医药导报》, vol. 30, no. 7, 31 July 2011 (2011-07-31), pages 852 - 855 * |
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