CN111533696A - 苯并咪唑衍生物、苯并噻吩衍生物及其制备方法和应用 - Google Patents
苯并咪唑衍生物、苯并噻吩衍生物及其制备方法和应用 Download PDFInfo
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- HQALDKFFRYFTKP-UHFFFAOYSA-N 2-[4-[4-(2-benzyl-1-benzothiophen-3-yl)phenyl]-2-bromo-6-(3-methoxyphenyl)phenoxy]acetic acid Chemical compound COC1=CC=CC(C=2C(=C(Br)C=C(C=2)C=2C=CC(=CC=2)C=2C3=CC=CC=C3SC=2CC=2C=CC=CC=2)OCC(O)=O)=C1 HQALDKFFRYFTKP-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims description 16
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
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- SPMLMLQATWNZEE-UHFFFAOYSA-N 2-(chloromethyl)-1h-benzimidazole Chemical compound C1=CC=C2NC(CCl)=NC2=C1 SPMLMLQATWNZEE-UHFFFAOYSA-N 0.000 description 2
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- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
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- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- RDSIMGKJEYNNLF-UHFFFAOYSA-N 5-bromo-1-benzothiophene Chemical compound BrC1=CC=C2SC=CC2=C1 RDSIMGKJEYNNLF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
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- RICPDSJTBAXDLV-UHFFFAOYSA-N n-(1h-benzimidazol-2-ylmethyl)aniline Chemical compound N=1C2=CC=CC=C2NC=1CNC1=CC=CC=C1 RICPDSJTBAXDLV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了苯并咪唑衍生物和苯并噻吩衍生物,分别具有式(Ⅰ)和式(Ⅳ)所示结构。实验结果表明,本发明提供的苯并咪唑衍生物和苯并噻吩衍生物具有较好的抗肿瘤活性,可以作为制备相关肿瘤疾病治疗药物。
Description
技术领域
本发明涉及药物化学技术领域,尤其涉及一种苯并咪唑衍生物、苯并噻吩衍生物及其制备方法和应用。
背景技术
癌症的发病原因,目前仍在深入研究之中,大量的临床观察和实验研究资料表明,许多因素与癌症的发病有着密切的关系。依据2019年我国国家癌症中心发布的最新一期的全国癌症统计数据显示,癌症死亡率占居民全部死因的23.91%,近十几年来癌症的发病率和死亡率均呈持续上升态势。
苯并咪唑环是现代药物发现中的重要药效团。许多突出成果表明,苯并咪唑、苯并噻吩类化合物具有广泛的潜在应用作为药用药物和诊断剂。尤其是临床抗癌,抗肿瘤等,大量苯并咪唑、苯并噻吩类化合物已经被成功开发,销售和广泛应用于预防和治疗各种疾病,其具有低毒性,高生物利用度,良好生物相容性和疗效。苯并咪唑、苯并噻吩类化合物具有广泛的生物活性。研究表明,噻吩类杂环化合物具有很好的抗肿瘤、抗炎抗菌、抗病毒等生物活性,由于具有独特的结构、低毒性和优良的生物活性,因此在化学、医学、生物学和材料科学等众多领域得到了广泛应用。利用活性叠加原理,在许多小分子药物中引入噻吩基团后,其活性得到很大的提高正是由于噻吩类衍生物具有众多优良特性,使得它成为药物研发中的一大热点。
发明内容
有鉴于此,本发明要解决的技术问题在于提供一种苯并咪唑衍生物、苯并噻吩衍生物及其制备方法和应用,制备的苯并咪唑衍生物、苯并噻吩衍生物具有较好的抗肿瘤活性。
本发明提供了一种苯并咪唑衍生物,具有式(I)所示结构:
其中,所述R1、R2、R3、R4、R5独立的选自氢、卤素、C1~C4烷基或C1~C4烷氧基。
优选的,所述R1、R2、R3、R4、R5独立的选自氢、卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基或叔丁氧基。
进一步优选的,所述R1、R2、R3、R4、R5独立的选自氢、氟、氯、溴、碘、甲基或甲氧基。
进一步的,所述R1、R2、R3、R4、R5中的任意三个或四个选自氢。即R1、R2、R3、R4、R5所在的苯基为单取代或双取代的苯基。
在本发明的一些具体实施例中,所述苯并咪唑衍生物具有以下任一结构:
本发明提供了上述苯并咪唑衍生物的制备方法,包括以下步骤:
将式(II)结构的化合物和式(III)结构的化合物反应,得到式(I)所示的苯并咪唑衍生物;
其中,所述R1、R2、R3、R4、R5的范围同上,在此不再赘述。
其中,所述式(II)结构的化合物由邻苯二胺和氯乙酸反应制得。
上述制备方法的反应方程式如下:
所述R代表R1、R2、R3、R4、R5。
本发明提供了一种苯并噻吩衍生物,具有式(Ⅳ)所示结构:
其中,所述R6、R7、R8和R9独立的选自氢或溴;
所述R10、R11、R12、R13和R14独立的选自氢、卤素、C1~C4烷基、C1~C4烷氧基、硝基或羟基。
优选的,所述R10、R11、R12、R13和R14独立的选自氢、卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、硝基或羟基。
进一步优选的,所述R10、R11、R12、R13和R14独立的选自氢、氟、氯、溴、碘、甲基、甲氧基、硝基或羟基。
进一步的,所述R10、R11、R12、R13和R14中的任意四个选自氢。即R10、R11、R12、R13和R14所在的苯基为单取代的苯基。
在本发明的一些具体实施例中,所述苯并噻吩衍生物具有以下任一结构:
本发明提供了上述苯并噻吩衍生物的制备方法,包括以下步骤:
将式(Ⅴ)结构的化合物和式(Ⅵ)结构的化合物反应,得到式(Ⅳ)结构的化合物;
其中,所述R6、R7、R8、R9、R10、R11、R12、R13和R14范围同上,在此不再赘述。
其中,所述式(Ⅴ)结构的化合物由苯并噻吩和多聚甲醛反应,得到的中间体再与氨基硫脲进行反应,制备得到。
上述制备方法的反应方程式如下:
其中,R表示R6、R7、R8和R9;R1表示R10、R11、R12、R13和R14。
本发明提供了上述苯并咪唑衍生物或上述制备方法制备的苯并咪唑衍生物,或上述苯并噻吩衍生物或上述制备方法制备的苯并噻吩衍生物在制备抗肿瘤药物中的应用。
本发明提供了一种抗肿瘤药物,包括上述苯并咪唑衍生物或上述制备方法制备的苯并咪唑衍生物,或上述苯并噻吩衍生物或上述制备方法制备的苯并噻吩衍生物以及辅料。
所述辅料可以为药学上可接受的辅料。
本发明提供的上述抗肿瘤药物还可以与其他抗肿瘤药物联合使用。
与现有技术相比,本发明提供了苯并咪唑衍生物和苯并噻吩衍生物,实验结果表明,本发明提供的苯并咪唑衍生物和苯并噻吩衍生物具有较好的抗肿瘤活性,可以作为制备相关肿瘤疾病治疗药物。
具体实施方式
为了进一步说明本发明,下面结合实施例对本发明提供的苯并咪唑衍生物、苯并噻吩衍生物及其制备方法和应用进行详细描述。
实施例1
N-((1H-苯并[d]咪唑-2-基)甲基)苯胺的合成:
将邻苯二胺(1.08g),氯乙酸(0.945g)溶于10ml HCl(4M),回流3h,待体系冷却至室温,用浓氨水调节PH至10-11,固体析出,过滤、干燥,得到白色至淡黄色固体2-氯甲基苯并咪唑。
将2-氯甲基苯并咪唑(500mg),苯胺(0.28ml),碘化钾500mg加入10ml乙醇中,回流6h,将KOH(171mg)溶于5ml水中,再将KOH水溶液加入反应体系,继续回流2h,冷却至室温,倒入冰水中,固体析出,过滤干燥,乙醇重结晶,得到白色至浅黄色产物。
核磁数据如下:
1H NMR(600MHz,DMSO)δ12.25(s,1H),7.55(d,J=7.0Hz,1H),7.41(d,J=7.0Hz,1H),7.15–7.09(m,2H),7.06(dd,J=8.3,7.5Hz,2H),6.64(d,J=7.8Hz,2H),6.56(t,J=7.3Hz,1H),6.26(t,J=5.7Hz,1H),4.46(d,J=5.7Hz,2H).
13C NMR(151MHz,DMSO)δ154.14,148.86,141.09,129.89,129.29,122.00,121.69,118.74,116.89,114.29,113.05,112.87,111.65,42.32,40.35,40.21,40.07,39.93,39.79,39.65,39.51,39.33.
实施例2
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-溴苯胺的合成:
以4-溴苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(600MHz,DMSO)δ12.27(s,1H),7.48(d,J=73.2Hz,2H),7.20(dd,J=9.5,2.5Hz,2H),7.12(t,J=6.0Hz,2H),6.61–6.58(m,2H),6.52(dd,J=9.9,4.2Hz,1H),4.45(d,J=5.7Hz,2H).
13C NMR(151MHz,DMSO)δ157.33,151.41,140.09,131.52,127.33,125.35,119.02,116.33,114.58,109.63,56.47,42.10,40.46,40.34,40.20,40.06,39.92,39.78,39.65,39.51,18.98.
实施例3
N-(((1H-苯并[d]咪唑-2-基)甲基]-3-溴苯胺的合成:
以3-溴苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(600MHz,DMSO)δ7.56(d,J=7.2Hz,1H),7.42(d,J=7.4Hz,1H),7.16–7.10(m,2H),7.00(t,J=8.0Hz,1H),6.82(s,1H),6.69(d,J=7.8Hz,1H),6.61(s,1H),4.47(d,J=5.7Hz,2H).
13C NMR(151MHz,DMSO)δ153.47,150.51,131.15,122.68,121.93,119.13,118.19,116.27,115.03,113.12,111.72,41.87,40.35,40.21,40.07,39.93,39.79,39.65,39.51.
实施例4
N-(((1H-苯并[d]咪唑-2-基)甲基]-2-溴苯胺的合成:
以2-溴苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ7.52(dd,J=21.3,12.6Hz,2H),7.28(dd,J=7.8,1.2Hz,1H),7.13(dd,J=6.0,3.1Hz,2H),7.07(t,J=7.7Hz,1H),6.67(d,J=8.2Hz,1H),6.61(td,J=7.8,1.2Hz,1H),4.60(d,J=5.8Hz,2H).
13C NMR(151MHz,DMSO)δ156.47,153.34,141.15,132.68,121.93,119.13,118.19,116.27,115.03,113.12,111.72,42.87,41.55,40.08,40.07,39.93,33.08,30.65,20.33.
实施例5
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-氯苯胺的合成:
以4-氯苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ7.66(dd,J=5.5,3.1Hz,2H),7.31(dd,J=5.9,3.0Hz,2H),7.26(d,J=8.7Hz,2H),6.82(d,J=8.7Hz,2H),6.68(s,1H),4.63(d,J=3.6Hz,2H).
13C NMR(151MHz,DMSO)δ153.61,148.11,138.89,131.82,122.27,121.93,116.20,115.21,114.81,107.63,56.47,42.10,40.46,40.34,40.20,40.06,39.92,39.78,39.65,39.51,18.98.
实施例6
N-(((1H-苯并[d]咪唑-2-基)甲基]-3-氯苯胺的合成:
以3-氯苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,CDCl3)δ7.56(dd,J=6.3,2.8Hz,1H),7.53(dd,J=6.3,2.9Hz,1H),7.36–7.34(m,2H),7.30(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),4.61(d,J=6.0Hz,2H).
13C NMR(151MHz,CDCl3)δ154.26,151.38,150.28,145.83,141.53,140.87,131.83,127.81,125.39,123.09,119.83,112.37,110.52,40.55,27.37.
实施例7
N-(((1H-苯并[d]咪唑-2-基)甲基]-2-氯苯胺的合成:
以2-氯苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ7.52(dd,J=21.3,12.6Hz,2H),7.28(dd,J=7.8,1.2Hz,1H),7.13(dd,J=6.0,3.1Hz,2H),7.07(t,J=7.7Hz,1H),6.67(d,J=8.2Hz,1H),6.61(td,J=7.8,1.2Hz,1H),4.60(d,J=5.8Hz,2H).
实施例8
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-碘苯胺的合成:
以4-碘苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ7.47(d,J=71.0Hz,2H),7.34(d,J=8.7Hz,2H),7.14–7.10(m,2H),6.53(t,J=5.7Hz,1H),6.50(d,J=8.8Hz,2H),4.44(d,J=5.8Hz,2H).
实施例9
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-甲基苯胺的合成:
以4-甲基苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ7.48(dd,J=5.9,3.2Hz,2H),7.14(dd,J=5.8,3.2Hz,2H),6.87(d,J=8.1Hz,2H),6.54(d,J=8.4Hz,2H),4.44(s,2H),2.11(s,3H).
13C NMR(151MHz,CDCl3)δ157.26,153.61,147.82,145.59,143.53,140.97,129.77,127.91,125.80,124.49,119.98,113.33,110.32,42.35,19.88.
实施例10
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-甲氧基苯胺的合成:
以4-甲氧基苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ12.23(s,1H),7.54(d,J=7.3Hz,1H),7.41(d,J=7.2Hz,1H),7.14–7.09(m,2H),6.70(d,J=8.8Hz,2H),6.59(d,J=8.8Hz,2H),4.40(d,J=5.8Hz,2H),3.60(s,3H).
13C NMR(101MHz,CDCl3)δ166.10,151.92,150.76,140.93,139.91,127.04,125.35,119.96,116.76,114.94,114.68,110.65,77.36,77.25,77.05,76.73,55.72,42.87,29.71.
实施例11
N-(((1H-苯并[d]咪唑-2-基)甲基]-2-甲氧基苯胺的合成:
以2-甲氧基苯胺为原料,合成方法参见实施例1。
1H NMR(600MHz,CDCl3)δ7.52(s,2H),7.23–7.20(m,2H),6.79–6.70(m,3H),6.50(dd,J=7.6,1.0Hz,1H),4.63(s,2H),3.83(d,J=5.3Hz,3H).
13C NMR(151MHz,cdcl3)δ153.51,146.98,145.83,145.80,137.19,122.36,121.42,118.17,110.53,109.55,77.22,77.01,76.80,55.40,43.08.
实施例12
N-(((1H-苯并[d]咪唑-2-基)甲基]-4-溴-3-甲基苯胺的合成:
以4-溴,3-甲基苯胺为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ7.48–7.44(m,1H),7.35–7.32(m,1H),7.12(d,J=8.6Hz,1H),7.06–7.02(m,2H),6.56(d,J=2.7Hz,1H),6.35–6.32(m,2H),4.36(d,J=5.8Hz,2H),2.11(s,3H).
实施例13
N-(((1H-苯并[d]咪唑-2-基)甲基]-3,4-二甲基苯胺的合成:
以3,4-二甲基苯胺为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ7.48(s,2H),7.12(dd,J=6.0,3.2Hz,2H),6.82(d,J=8.1Hz,1H),6.49(d,J=2.2Hz,1H),6.37(dd,J=8.1,2.4Hz,1H),5.95(t,J=5.7Hz,1H),4.42(d,J=5.6Hz,2H),2.08(s,3H),2.04(s,3H).
实施例14
(E)-2-(2-(((5-溴苯并[b]噻吩-2-基)亚甲基]肼基)-4-(4-溴苯基)噻唑的合成:
将5-溴苯并噻吩(2g),多聚甲醛(2.817g),混溶于10ml乙腈,再加入DDQ(4.263g),浓硫酸(1ml),回流5h,TLC监测。待体系冷却至室温,硅藻土过滤,除去不溶物,乙酸乙酯萃取,干燥,旋干,过柱子,得到橙色结晶粉末2-甲醛-5-溴苯并噻吩。
先将氨基硫脲(140mg)溶于10ml无水乙醇中,搅拌,再加2-甲醛-5-溴苯并噻吩(300mg),浓盐酸两滴,室温搅拌,TLC监测。待反应完成后,过滤,用水:乙醇=1:1洗涤滤饼,干燥,得到氨基硫脲中间体。最后将中间体与2,4’-二溴苯乙酮以摩尔比1:1的量溶于无水乙醇,室温搅拌,待反应结束,过滤,得到产物。
1H NMR(400MHz,DMSO)δ8.44(d,J=1.9Hz,1H),7.63–7.59(m,1H),7.56–7.52(m,3H),7.43(d,J=8.9Hz,2H),7.32(d,J=8.6Hz,1H),6.94(s,1H),6.87(dd,J=8.6,2.0Hz,1H).
实施例15
(E)-2-(2-(((5-溴苯并[b]噻吩-2-基)亚甲基]肼基)-4-(4-硝基苯基)噻唑的合成:
以2-溴-4’-硝基苯乙酮为原料,合成方法参见实施例14。
1H NMR(400MHz,DMSO)δ8.98(d,J=1.9Hz,1H),8.38–8.34(m,1H),8.32–8.27(m,3H),8.14(d,J=8.9Hz,2H),8.08(d,J=8.6Hz,1H),7.83(s,1H),7.65(dd,J=8.6,2.0Hz,1H).
实施例16
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-(4-甲氧基苯基)噻唑的合成:
以苯并噻吩,2-溴-4’-甲氧基苯乙酮为原料,合成方法参见实施例14。
1H NMR(400MHz,DMSO)δ8.73(d,J=8.0Hz,1H),8.36(s,1H),8.18–8.06(m,1H),7.83(d,J=8.5Hz,1H),7.63–7.53(m,2H),7.47(dd,J=13.8,5.7Hz,1H),3.32(s,3H).
实施例17
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-(4-硝基苯基)噻唑的合成:
以苯并噻吩,2-溴-4’-硝基苯乙酮为原料,合成方法参见实施例14。
1H NMR(600MHz,DMSO)δ8.70(d,J=8.1Hz,1H),8.35(s,1H),8.26(d,J=8.9Hz,2H),8.16(s,1H),8.11(d,J=8.9Hz,2H),8.05(d,J=8.0Hz,1H),7.74(s,1H),7.53(dd,J=11.2,4.0Hz,1H),7.45(dd,J=11.1,4.0Hz,1H).
实施例18
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-(4-氯苯基)噻唑的合成:
以苯并噻吩,2-溴-4’-氯苯乙酮为原料,合成方法参见实施例14。
1H NMR(600MHz,DMSO)δ8.70(d,J=8.0Hz,1H),8.33(s,1H),8.13(s,1H),8.04(d,J=8.0Hz,1H),7.86(d,J=8.5Hz,2H),7.53(t,J=7.1Hz,1H),7.45(t,J=7.0Hz,3H),7.41(s,1H).
实施例19
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-苯基噻唑的合成:
以苯并噻吩,2-溴苯乙酮为原料,合成方法参见实施例14。
1H NMR(600MHz,DMSO)δ8.71(d,J=8.1Hz,1H),8.33(s,1H),8.13(s,1H),8.04(d,J=8.0Hz,1H),7.85(d,J=7.4Hz,2H),7.55–7.51(m,1H),7.45(t,J=8.1Hz,1H),7.39(t,J=7.7Hz,2H),7.34(s,1H),7.28(t,J=7.3Hz,1H).
实施例20
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-(4-甲基苯基)噻唑的合成:
以苯并噻吩,2-溴-4’-甲基苯乙酮为原料,合成方法参见实施例14。
1H NMR(400MHz,DMSO)δ8.74(d,J=8.1Hz,1H),8.38(d,J=21.3Hz,1H),8.15(s,1H),8.06(t,J=8.8Hz,1H),7.76(d,J=8.0Hz,2H),7.56(t,J=7.6Hz,1H),7.48(t,J=7.5Hz,1H),7.30–7.19(m,3H),2.33(s,3H).
实施例21
(E)-2-(2-(苯并[b]噻吩-2-基亚甲基)肼基)-4-(4-羟基苯基)噻唑的合成:
以苯并噻吩,2-溴-4’-羟基苯乙酮为原料,合成方法参见实施例14。
1H NMR(600MHz,DMSO)δ8.70(d,J=8.0Hz,1H),7.67(s,1H),8.13(s,1H),7.34(d,J=8.0Hz,1H),7.86(d,J=8.5Hz,2H),6.65(t,J=7.1Hz,1H),7.45(t,J=7.0Hz,3H),6.73(s,1H).
实施例22
化合物的抗肿瘤活性测定
取处于对数生长期细胞,消化计数,将细胞状态调整好后,进行铺板操作。按3000/孔细胞密度接种于96孔板,在培养箱中放置过夜。(注:外圈PBS填满。)18-24h后,进行给药操作。吸走细胞培养基,加入含有一定浓度的药物的培养液。实验设置空白组(溶剂对照组)、调零组、实验组。实验组的药物浓度依次为1,5,20,50,100,200μM。每组实验均设置3个副孔。
给药72h后,每孔加入10ulMTT溶液,置于细胞培养箱继续孵育2h。用酶标仪检测每孔在492nm波长处的光吸收值。
根据吸光值计算每孔细胞的存活率,从而算出药物的IC50值。
实验结果如表1所示。
表1本发明抗肿瘤活性测定结果
*无表示没有活性。
由上述实施例可知,本发明制备的苯并咪唑化合物衍生物和苯并噻吩化合物衍生物具有较好的抗肿瘤活性。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
2.根据权利要求1所述的苯并咪唑衍生物,其特征在于,所述R1、R2、R3、R4、R5独立的选自氢、卤素、甲基或甲氧基。
6.根据权利要求5所述的苯并噻吩衍生物,其特征在于,所述R10、R11、R12、R13和R14独立的选自氢、氯、溴、甲基、甲氧基、硝基或羟基。
9.权利要求1~3任一项所述的苯并咪唑衍生物或权利要求4所述的制备方法制备的苯并咪唑衍生物,或权利要求5~7任一项所述的苯并噻吩衍生物或权利要求8所述的制备方法制备的苯并噻吩衍生物在制备抗肿瘤药物中的应用。
10.一种抗肿瘤药物,包括权利要求1~3任一项所述的苯并咪唑衍生物或权利要求4所述的制备方法制备的苯并咪唑衍生物,或权利要求5~7任一项所述的苯并噻吩衍生物或权利要求8所述的制备方法制备的苯并噻吩衍生物以及辅料。
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