CN114262306A - 3-(3-芳基-4-噻唑啉酮基)-n-芳基苯甲酰胺类化合物及其制备和应用 - Google Patents
3-(3-芳基-4-噻唑啉酮基)-n-芳基苯甲酰胺类化合物及其制备和应用 Download PDFInfo
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- CN114262306A CN114262306A CN202010971435.6A CN202010971435A CN114262306A CN 114262306 A CN114262306 A CN 114262306A CN 202010971435 A CN202010971435 A CN 202010971435A CN 114262306 A CN114262306 A CN 114262306A
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- benzamide
- thiazolinonyl
- phenylbutyl
- aryl
- methoxyphenyl
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Abstract
本发明公开了一种3‑(3‑芳基‑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制备方法,本发明还公开了该类化合物或者其药物组合物可用于治疗骨肉瘤,结直肠癌,胰腺癌以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
本发明涉及合成医药化工领域,主要涉及一种3-(3-芳基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物及其制备方法和应用。
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(V)所示的化合物具有抗炎症活性以及式(VI)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。
本发明提出了一种如式(I)、(II)、(Ⅲ)和(Ⅳ)所示的3-(3-芳基-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,所述化合物为全新化合物,未有相关报道:
其中,
V为N或者CH;
W为O、NR3、S或者CH2;其中,R3为烷基,芳基,烷氧基,苯基;
X为O、NR4、S或者CH2;其中,R4为烷基,芳基,烷氧基,苯基;
Z为O、NR5、S或者CH2;其中,R5为烷基,芳基,烷氧基,苯基;
本发明中,所述芳基包括苯环、含氮,含氧,含硫杂芳环;
Y为O、NR6、S或者CH2;其中,R6为烷基,芳基,烷氧基,苯基;
R1为卤素,烷氧基,烷基,硝基,氰基,三氟甲基,氢等;
R2为烷基,芳基,烷氧基,苯基;
n=1,2;
优选地,
V为N或者CH;
W为O、NR3或者CH2;其中,R3为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
X为O、NR4或者CH2;其中,R4为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
Z为O、NR5或者CH2;其中,R5为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
Y为O、NR6或者CH2;其中,R6为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
R1为卤素,C1-C10烷氧基,C1-C10烷基,硝基,氰基,三氟甲基,氢等;
R2为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
n=1,2;
进一步优选地,
V为N或者CH;
W为O、NR3或者CH2,其中,R3为C1-C5烷基,C1-C5烷氧基;
X为O、NR4或者CH2,其中,R4为C1-C5烷基,C1-C5烷氧基;
Z为O、NR5或者CH2,其中,R5为C1-C5烷基,C1-C5烷氧基;
Y为O、NR6或者CH2;其中,R6为C1-C5烷基,C1-C5烷氧基;
R1为卤素,C1-C5烷氧基,甲基,乙基,异丙基,硝基,氰基,三氟甲基,氢等;
R2为C1-C5烷基,萘基,C1-C5烷氧基,苯基;
n=1,2;
进一步地,本发明所述3-(3-芳基-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包括式(Ⅶ)、式(Ⅷ)所示的结构:
其中,式(Ⅶ)、式(Ⅷ)中R2、W、Z、X、V、n的定义同式(I)、式(II)、式(Ⅲ)、式(Ⅳ)。
本发明所述3-(3-芳基-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,包括但不限于以下:
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
4-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(4-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯(4-氟)基丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺;
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-苯并三氮唑基丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
(E)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰;
(E)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(苯基)丁-3-烯-1-基)苯甲酰;
(E)-3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰胺;
(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰;
(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(苯基)丁-3-烯-1-基)苯甲酰;
(Z)-3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺。
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺
3-(3-(3-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,5-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,3-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2,4-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(5-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺。
在一个具体的实施方式中,所述如式(I)、(II)、(III)所示化合物中所用到的原料的合成方法,具体包括步骤如下四种方法:
方法一:
在干燥的三颈烧瓶中加入S1、氢化钠,进行氮气保护,随后加入干燥的DMSO或者DMF,于110℃下搅拌10min,然后将N-(6-溴己基)邻苯二甲酰亚胺和催化量的KI溶于干燥的DMSO或DMF溶液中加入到反应液中,于110℃下继续搅拌,薄层色谱法监测反应。反应完全后加入饱和氯化钠,用二氯甲烷萃取三次,收集有机相,无水硫酸钠干燥,浓缩后通过柱层分析法分离纯化(石油醚/乙酸乙酯=9:1)。
向上述分离纯化得到的产物加入甲醇、肼,65℃下反应15h,薄层色谱法监测反应,反应完全后加入1M氢氧化钠溶液,用二氯甲烷萃取三次,收集有机相,无水硫酸钠干燥,浓缩后无需纯化直接用于反应。
方法二:
在干燥的三颈烧瓶中加入S1、碳酸钾,N-(6-溴己基)邻苯二甲酰亚胺和催化量的KI,随后加入干燥的乙腈,于回流条件反应,薄层色谱法监测反应。反应完全后加入饱和氯化钠,用二氯甲烷萃取三次,收集有机相,无水硫酸钠干燥,浓缩后通过柱层分析法分离纯化(石油醚/乙酸乙酯=10:1~1:1)。
向上述分离纯化得到的产物加入甲醇、肼,65℃下反应15h,薄层色谱法监测反应,反应完全后加入1M氢氧化钠溶液,用二氯甲烷萃取三次,收集有机相,无水硫酸钠干燥,浓缩后无需纯化直接用于反应。
方法三:
在干燥的三颈烧瓶中加入N-(3-溴丙基)苯二胺和S1以及THF。氮气保护后降温到-55℃,加入叔丁醇钾。加完后将反应混合物升至10℃,反应4小时后,倒入水中。用乙酸乙酯萃取,合并有机相,用水洗涤,硫酸镁干燥。减压浓缩,得到油状粗产物,柱层析纯化,用于下一步;
将上述产物溶解在乙醇中,加入水合肼,回流过夜,滤出白色不溶物,减压除去溶剂。将所得油状物溶解在乙酸乙酯中,用2M NaOH洗涤;再将水相用乙酸乙酯萃取,合并有机相后用硫酸镁干燥。减压除去溶剂,无需纯化直接用于反应。
方法四:
在干燥的三颈烧瓶中加入N-(3-溴丙基)苯二胺和S1以及THF。氮气保护后降温到-55℃,加入叔丁醇钾。加完后将反应混合物升至10℃,反应4小时后,倒入水中。用乙酸乙酯萃取,合并有机相,用水洗涤,硫酸镁干燥。减压浓缩,得到油状粗产物,柱层析纯化,用于下一步;
将上述产物溶解在乙醇中,加入水合肼,回流过夜,滤出白色不溶物,减压除去溶剂。将所得油状物溶解在乙酸乙酯中,用2M NaOH洗涤;再将水相用乙酸乙酯萃取,合并有机相后用硫酸镁干燥。减压除去溶剂,无需纯化直接用于反应。
将上步所得粗产品放置于三口瓶中,加入含量10%的钯碳,氮气保护之后加入甲醇,再用氢气置换氮气,整个反应体系在氢气氛围和室温下反应16h之后,反应液用硅藻土抽滤,收集滤液,旋干溶剂,直接用于下步反应。
本发明还提出了一种如式(I)或式(II)或式(III)或式(IV)所示的3-(3-芳基-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(A)、(B)、(C)所示:(本发明中所设计化合物合成路线均与下述方法一致,下述方法仅描述式(I)的合成方法,式(II)、式(III)、式(IV)的合成方法均参见式(I))
第一步,用邻甲氧基苯胺(10mmol,1.0eq)与3-甲醛苯甲酸甲酯(10mmo,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酸(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。
第二步,将第一步所得酯类化合物(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3NHCl酸化,有大量白色固体析出,用pH试纸监测直至pH=1。用布氏漏斗将白色固体抽滤出来,用乙酸乙酯溶解白色固体,无水硫酸钠干燥之后,旋蒸得羧酸类产物。
第三步,将第二步所得羧酸类产物(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,3.0eq),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。
其中,反应式(A)、(B)及反应式(C)中,R1、R2、V、X、Z、W的定义同式(I)。
本发明还提出了所述3-(3-芳基-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-芳基-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3-(3-芳基-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-芳基-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,或促进肿瘤细胞的凋亡。
其中,所述肿瘤细胞为骨肉瘤细胞、结直肠癌细胞、白血病细胞、肺癌细胞、胰腺癌细胞等。
所述骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b;
所述胰腺癌细胞包括PANC-1;
所述肺癌细胞包括A549;
所述结直肠癌细胞包括HCT116;
所述白血病细胞包括Jurkat。
本发明的有益效果在于:本发明公开了一种3-(3-芳基-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制备方法,该类化合物或者组合物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,胰腺癌以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为本发明实施例1所得产物1的1HNMR和13CNMR示意图。
图2为本发明实施例2所得产物2的1HNMR、13CNMR和19FNMR示意图。
图3为本发明实施例3所得产物3的1HNMR、13CNMR和19FNMR示意图。
图4为本发明实施例4所得产物4的1HNMR和13CNMR示意图。
图5为本发明实施例5所得产物5的1HNMR、13CNMR和19FNMR示意图。
图6为本发明实施例6所得产物6的1HNMR和13CNMR示意图。
图7为本发明实施例7所得产物7的1HNMR、13CNMR和19FNMR示意图。
图8为本发明实施例8所得产物8的1HNMR、13CNMR和19FNMR示意图。
图9为本发明实施例9所得产物9的1HNMR和13CNMR示意图。
图10为本发明实施例10所得产物10的1HNMR和13CNMR示意图。
图11为本发明实施例11所得产物11的1HNMR和13CNMR示意图。
图12为本发明实施例12所得产物12的1HNMR和13CNMR示意图。
图13为本发明实施例13所得产物13的1HNMR和13CNMR示意图。
图14为本发明实施例14所得产物14的1HNMR和13CNMR示意图。
图15为本发明实施例15所得产物15的1HNMR、13CNMR和19FNMR示意图。
图16为本发明实施例16所得产物16的1HNMR和13CNMR示意图。
图17为本发明实施例17所得产物17的1HNMR和13CNMR示意图。
图18为本发明实施例18所得产物18的1HNMR、13CNMR和19FNMR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、碳谱以及氟谱)。
实施例1:
1H NMR(400MHz,Chloroform-d)δ7.68(d,J=12.4Hz,1H),7.58(d,J=7.6Hz,1H),7.48(d,J=7.4Hz,1H),7.31(dd,J=16.3Hz,8.2Hz,3H),7.18(q,J=6.2Hz,5.7Hz,3H),3.92(t,J=9.1Hz,2H),3.82(s,2H),3.53(s,0H),3.44(q,J=6.3Hz,2H),2.67(t,J=7.0Hz,2H),1.31–1.22(m,5H).
13C NMR(101MHz,CDCl3)δ171.45,166.80,154.81,142.00,139.78,134.97,129.72,128.76,128.41,127.25,126.51,125.88,120.92,112.15,64.35,55.78,39.97,35.47,33.17,29.18,28.70.
实施例2:
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.61(d,J=7.4Hz,1H),7.48(d,J=7.3Hz,1H),7.40–7.25(m,4H),7.18(d,J=6.9Hz,5H),7.08–6.97(m,5H),6.12(s,1H),4.15–3.76(m,2H),3.40(d,J=22.2Hz,2H),2.65(d,J=7.1Hz,3H),1.66(dd,J=19.2Hz,11.2Hz,8H).
13C NMR(101MHz,CDCl3)δ170.99,166.62,142.00,139.12,135.25,130.40,129.90,129.42,128.41,127.65,126.13,125.89,124.71,116.82,116.62,64.61,39.99,35.47,33.11,29.14,28.69.
19F NMR(376MHz,CDCl3)δ-118.96.
实施例3:
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.58(d,J=7.3Hz,1H),7.49(s,1H),7.38(dd,J=17.1Hz,8.6Hz,7H),7.27(d,J=6.8Hz,3H),7.17(d,J=6.9Hz,4H),6.17(s,1H),6.12(s,1H),3.99(d,J=16.0Hz,1H),3.88(d,J=15.9Hz,1H),3.43(d,J=5.6Hz,2H),2.64(d,J=6.8Hz,3H),1.83–1.52(m,8H).
13C NMR(101MHz,CDCl3)δ171.04,166.52,141.98,139.60,137.84,135.58,129.79,129.62,129.34,128.65,128.37,127.21,126.01,125.88,123.71,122.13,64.86,40.03,35.46,33.37,29.13,28.68.
19F NMR(376MHz,CDCl3)δ-62.73.
实施例4:
1H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.59(d,J=6.7Hz,1H),7.47(d,J=6.6Hz,1H),7.25(d,J=6.3Hz,3H),7.16(s,5H),7.05(t,J=8.0Hz,2H),6.52(s,1H),6.42(d,J=8.0Hz,1H),6.30(d,J=8.0Hz,1H),6.16(s,1H),3.94–3.81(m,2H),3.78(s,3H),3.51(s,3H),3.39–3.26(m,4H),2.61(s,3H),1.67–1.48(m,7H).
13C NMR(101MHz,CDCl3)δ170.75,166.98,156.62,156.13,141.99,139.19,134.52,131.09,129.90,128.41,128.11,127.50,126.50,125.89,113.80,105.14,104.23,63.57,56.08,56.00,39.94,35.48,33.16,29.26,28.72.
实施例5:
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H),7.58(d,J=7.6Hz,1H),7.39(dd,J=20.6Hz,7.3Hz,3H),7.31–7.26(m,4H),7.18(t,J=8.1Hz,7H),6.98(dd,J=23.9Hz,9.0Hz,3H),6.85(t,J=8.1Hz,2H),6.15(d,J=12.9Hz,3H),3.97(d,J=16.0Hz,1H),3.85(d,J=16.0Hz,1H),3.43(d,J=6.0Hz,3H),2.65(t,J=6.6Hz,4H),1.78–1.47(m,5H).
13C NMR(101MHz,CDCl3)δ170.97,166.59,142.66,139.94,135.51,130.24,129.44,129.30,128.41,127.11,125.88,125.84,120.64,114.19,113.98,112.85,112.61,64.87,40.03,35.46,33.40,29.14,28.69.
19F NMR(376MHz,CDCl3)δ-110.67.
实施例6:
1H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.59(d,J=7.1Hz,1H),7.39(d,J=6.9Hz,1H),7.30–7.21(m,5H),7.15(t,J=8.9Hz,5H),7.07(t,J=7.5Hz,2H),6.97(s,1H),6.89(dd,J=17.9Hz,7.2Hz,3H),6.56(s,1H),6.07(s,1H),3.92(d,J=15.7Hz,1H),3.78(d,J=15.7Hz,1H),3.39–3.27(m,3H),2.61(s,3H),2.19(s,3H),1.70–1.49(m,7H).
13C NMR(101MHz,CDCl3)δ171.14,166.74,142.19,140.08,137.10,135.26,129.70,128.96,128.44,128.38,126.45,125.86,122.79,65.34,39.98,35.53,33.50,29.08,28.77,21.35.
实施例7:
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.57(d,J=7.8Hz,1H),7.47(d,J=7.8Hz,1H),7.38–7.27(m,3H),7.22–7.15(m,3H),6.83(t,J=7.4Hz,1H),6.58(d,J=10.3Hz,1H),6.48(t,J=8.6Hz,1H),6.04(d,J=10.6Hz,2H),3.90(dd,2H),3.80(s,3H),3.45(q,J=6.7Hz,2H),2.67(t,J=7.4Hz,2H),1.76–1.62(m,4H).
13C NMR(101MHz,CDCl3)δ171.55,166.69,164.28,161.82,141.99,139.64,135.06,131.20,131.10,128.78,128.38,127.22,126.78,125.89,121.18,107.56,107.34,100.63,100.36,64.32,56.07,39.99,35.47,33.03,29.17,28.71.
19F NMR(376MHz,CDCl3)δ-109.07.
实施例8:
1H NMR(400MHz,Chloroform-d)δ7.44(s,1H),7.31–7.25(m,4H),7.23–7.15(m,4H),6.93(d,J=7.9Hz,1H),6.90–6.78(m,2H),6.11(s,1H),5.96(s,1H),3.92(d,J=816.0Hz,2H),3.83(s,3H),3.47–3.37(m,2H),2.66(t,J=7.4Hz,2H),1.74–1.60(m,4H).
13C NMR(101MHz,CDCl3)δ165.49,154.76,142.47,141.96,137.12,129.87,128.40,125.91,125.00,121.96,121.04,117.56,117.33,114.87,114.64,112.25,63.84,55.78,40.05,35.45,33.02,29.06,28.67.
19F NMR(376MHz,CDCl3)δ-110.98.
实施例9:
1H NMR(400MHz,Chloroform-d)δ7.45(s,1H),7.40(s,1H),7.29(d,J=4.7Hz,3H),7.18(t,J=7.3Hz,5H),6.90(d,J=7.8Hz,1H),6.86(d,J=8.3Hz,1H),6.79(t,J=7.8Hz,1H),6.08(s,1H),5.96(d,J=7.7Hz,1H),3.96(d,J=15.7Hz,1H),3.89(d,J=15.6Hz,1H),3.82(s,3H),3.43(q,J=6.7Hz,2H),2.66(t,J=7.5Hz,2H),2.33(s,3H),1.75–1.58(m,4H).
13C NMR(101MHz,CDCl3)δ171.46,167.00,154.84,142.02,139.78,138.79,131.14,129.99,129.70,128.41,128.14,125.88,123.44,120.91,112.17,64.36,55.78,39.92,35.48,33.16,29.20,28.69,21.31.
实施例10:
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.80(d,J=7.3Hz,2H),7.42(t,J=7.4Hz,2H),7.34(t,J=7.3Hz,1H),6.34(d,J=5.0Hz,1H),4.20(dd,J=14.2Hz,7.4Hz,1H),4.05(dd,J=14.0Hz,7.3Hz,1H),2.75–2.64(m,1H),2.42(dd,J=23.9Hz,12.0Hz,2H),2.14–2.03(m,1H).
13C NMR(101MHz,CDCl3)δ148.08,131.29,130.20,128.84,128.52,126.05,92.25,69.59,31.37,24.50.HRMS(ESI)C12H13N3OCalcd.for(M+H)+,216.1137,Found:216.1124
实施例11:
1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.49(dd,J=12.9Hz,7.9Hz,1H),7.41(dd,J=15.8Hz,7.6Hz,1H),7.22–7.17(m,5H),7.09(q,J=10.6Hz,9.4Hz,6H),6.83–6.60(m,4H),6.17(s,0H),5.99(d,J=13.4Hz,1H),4.24–3.91(m,1H),3.71(s,3H),3.31(s,2H),2.56(d,J=5.9Hz,3H),1.63(dt,J=18.3Hz,9.1Hz,7H),1.52(s,3H).
13C NMR(101MHz,CDCl3)δ174.76,174.35,166.82,154.24,142.04,140.08,139.17,134.99,134.85,131.05,130.57,130.44,129.61,129.43,128.77,128.64,128.41,127.18,127.04,126.51,126.02,125.87,125.72,120.70,112.86,64.12,62.51,42.24,39.94,35.49,29.17,28.72,20.59,19.68,14.96.
实施例12:
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H),7.59(d,J=6.8Hz,1H),7.48–7.35(m,2H),7.32(s,1H),7.29–7.17(m,2H),7.13–7.02(m,2H),6.80(dd,J=18.2Hz,6.7Hz,5H),6.71(d,J=6.7Hz,2H),6.18(s,1H),6.05(s,1H),4.11(s,2H),3.84(q,J=15.7Hz,3H),3.73(s,3H),3.32(s,2H),1.86(s,2H),1.50(s,2H).
13C NMR(101MHz,CDCl3)δ170.49,165.87,153.74,138.71,138.18,133.76,129.66,129.12,128.71,128.29,127.68,126.48,125.61,124.17,119.87,111.07,104.52,63.36,54.72,50.24,38.51,32.13,26.96,25.04.
实施例13:
1H NMR(400MHz,Methanol-d4)δ7.79(s,1H),7.60(d,J=7.5Hz,1H),7.46(s,1H),7.26(d,J=14.6Hz,1H),7.12(t,J=7.8Hz,1H),6.87(t,J=7.4Hz,2H),6.69(t,J=7.7Hz,1H),6.15(s,1H),3.93(d,J=15.8Hz,1H),3.83(d,J=15.9Hz,1H),3.73(s,3H),3.42(s,4H),3.30(s,2H),2.62(s,6H),1.55(s,4H),1.36(s,8H).
13C NMR(101MHz,CDCl3)δ176.34,171.96,159.01,158.54,143.67,138.38,134.95,133.53,132.26,131.27,130.61,129.00,124.16,115.77,84.24,68.55,61.15,58.77,56.05,42.93,36.33,31.10,30.63,26.50.
实施例14:
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.58(d,J=7.4Hz,1H),7.48(d,J=7.3Hz,1H),7.33(t,J=7.5Hz,1H),7.25(d,J=11.1Hz,3H),7.18(t,J=7.1Hz,2H),7.10(d,J=7.3Hz,2H),6.88(dd,J=18.3Hz,7.8Hz,2H),6.78(t,J=7.6Hz,1H),4.00–3.86(m,2H),3.82(s,3H),3.43(d,J=5.8Hz,2H),1.66(d,J=8.3Hz,3H).
13C NMR(101MHz,CDCl3)δ171.45,166.79,154.82,140.41,139.84,134.92,131.57,130.70,130.10,129.75,128.76,128.45,127.23,126.50,125.23,120.91,112.14,64.33,55.77,39.87,34.78,33.16,29.12,28.58.
实施例15:
1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.63(d,J=7.4Hz,1H),7.40(d,J=7.4Hz,1H),7.26(t,J=7.4Hz,4H),7.16(t,J=7.6Hz,4H),6.96–6.86(m,1H),6.79(q,J=7.8Hz,2H),6.70(d,J=7.7Hz,1H),6.58(s,1H),6.08(s,1H),3.94(s,3H),3.86(t,J=14.3Hz,2H),3.40–3.35(m,2H),2.62(t,J=6.9Hz,3H),1.72–1.51(m,7H).
13C NMR(101MHz,CDCl3)δ171.47,166.73,156.92,154.45,144.09,143.98,142.06,139.09,135.23,130.73,130.41,128.82,128.36,127.81,126.26,125.85,124.60,123.17,117.35,117.16,64.82,61.48,61.41,39.99,35.49,33.17,29.12,28.72.
19F NMR(376MHz,CDCl3)δ-127.80.
实施例16:
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.56(d,J=7.6Hz,1H),7.39(d,J=7.5Hz,1H),7.23(dd,J=16.6Hz,8.9Hz,1H),7.11(s,1H),6.81(dd,J=16.9Hz,8.0Hz,2H),6.71(t,J=7.6Hz,1H),6.63(s,1H),6.34(s,1H),6.06(s,1H),3.86(q,J=15.6Hz,2H),3.75(s,2H),3.49(t,J=6.8Hz,2H),3.36(q,J=6.4Hz,3H),1.59(q,J=7.2Hz,3H),1.52(q,J=5.7Hz,4.8Hz,2H).
13C NMR(101MHz,CDCl3)δ171.46,170.90,166.82,154.83,139.87,134.81,134.15,130.74,130.13,129.73,128.75,127.36,126.51,125.22,120.92,112.13,64.34,55.77,39.49,37.28,33.16,26.55,26.11.
实施例17:
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.57(d,J=7.2Hz,1H),7.42(d,J=7.0Hz,1H),7.37–7.31(m,2H),7.23(d,J=7.3Hz,3H),7.21–7.09(m,8H),6.19(s,1H),6.13(s,1H),3.97(d,J=15.8Hz,1H),3.86(d,J=15.8Hz,1H),3.48–3.30(m,4H),2.64(d,J=6.8Hz,4H),1.64(dd,J=23.6Hz,6.7Hz,6H).
13C NMR(101MHz,CDCl3)δ171.01,166.68,142.01,140.22,137.22,135.36,129.73,129.23,129.14,128.38,127.28,127.12,125.93,125.88,125.64,65.21,40.00,35.47,33.48,29.15,28.70.
实施例18:
1H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.58(d,J=6.6Hz,1H),7.45(d,J=6.6Hz,1H),7.29–7.23(m,6H),7.16(s,4H),6.84(s,1H),6.78–6.62(m,3H),6.49(s,1H),6.12(s,1H),3.94–3.80(m,3H),3.75(s,3H),3.44–3.27(m,4H),2.62(s,3H),1.69–1.50(m,8H).
13C NMR(101MHz,CDCl3)δ171.41,166.64,157.32,154.93,151.30,142.09,139.24,135.05,130.49,128.78,128.42,128.36,127.48,126.78,125.85,117.36,117.12,116.03,115.80,112.68,64.19,56.23,39.96,35.48,33.10,29.12,28.72.
19F NMR(376MHz,CDCl3)δ-121.95.
实施例19:
抗肿瘤活性测试实验
本发明采用CCK-8法测定了本发明制备的NL-1至NL-30这30个化合物对6种骨肉瘤细胞(SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b),1种胰腺癌细胞(PANC-1),1种肺癌细胞(A549),1种结直肠癌细胞(HCT116)以及1种白血病细胞(Jurkat)的增殖抑制效果。
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。
10)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PANC-1胰腺癌细胞接种到96孔细胞培养板,每孔体积100μl。
2.然后将本发明制备的30个化合物(NL-1至NL-30)用DMSO溶解,分别用对应的细胞培养基配制成终浓度为1μM的药物溶液,分别加入到十种不同细胞(100μL/孔)中,对照组加入1‰DMSO,CO2培养箱中培养72小时;
3.培养72h后倾去培养液,加入100μL1:10稀释的CCK-8溶液,37℃孵育2小时后,使用LabServK3型酶标仪测450nm处吸光度A,参考波长620nm,计算对肿瘤细胞及白血病细胞的存活率(见表1)。
4.细胞增殖活力(%)=[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
表1
由表1的数据可以看出,化合物1、3、4、5等14个化合物作用下,骨肉瘤细胞SJSA-1存活率低于30%,说明这14个化合物对骨肉瘤细胞SJSA-1有非常好的抑制作用;化合物17对骨肉瘤细胞U2OS具有一定的抑制作用;化合物1等12个化合物作用下,骨肉瘤细胞HOS存活率低于50%,说明这12个化合物对HOS细胞具有较好的抑制作用;化合物1等15个化合物对MNNG/HOS细胞具有很好的抑制作用;化合物3等14个化合物对MG63细胞具有很好的抑制作用;化合物1等10个化合物对143b细胞具有很好的抑制作用;化合物1等14个化合物对白血病细胞Jurkat具有很好的抑制作用;化合物4等9个化合物对结直肠癌细胞HCT116具有较好的抑制作用;化合物1等12个化合物对肺癌细胞A549具有很好的抑制作用;化合物1等12个化合物对胰腺癌细胞PANC-1具有一定的抑制作用。(加粗部分为有抑制活性的数据)
上述实施例仅为了说明本发明的技术构思及特点,其目的在于让本领域技术人员能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效变化或修饰,都涵盖在本发明保护范围内。
Claims (10)
2.如权利1所述的3-(3-芳基-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(Ⅶ)、式(Ⅷ)所示:
其中,
V为N或者CH;
W为O、NR3或者CH2;其中,R3为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
X为O、NR4或者CH2;其中,R4为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
Z为O、NR5或者CH2;其中,R5为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
Y为O、NR6或者CH2;其中,R6为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
R1为卤素,C1-C10烷氧基,C1-C10烷基,硝基,氰基,三氟甲基,氢;
R2为C1-C10烷基,萘基,C1-C10烷氧基,苯基;
n=1,2;
3.根据权利要求1或2所述的3-(3-芳基-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-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)丁基)苯甲酰胺;
3-(3-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰;
3-(3-(2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺
3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺
3-(3-(2-甲氧基苯基)-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;
3-(3-(2-氟-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;
3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺。
4.根据权利要求1或2所述的3-(3-芳基-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-芳基-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-芳基-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-芳基-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、白血病、胰腺癌、肺癌、结直肠癌。
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、U2OS、HOS、MNNG/HOS、MG63、143b;所述胰腺癌细胞包括PANC-1;所述肺癌细胞包括A549;所述结直肠癌细胞包括HCT116;所述白血病细胞包括Jurkat。
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