CN114276338A - 2-吡唑-3-苯并咪唑衍生物及其制备方法和应用 - Google Patents
2-吡唑-3-苯并咪唑衍生物及其制备方法和应用 Download PDFInfo
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- CN114276338A CN114276338A CN202210012999.6A CN202210012999A CN114276338A CN 114276338 A CN114276338 A CN 114276338A CN 202210012999 A CN202210012999 A CN 202210012999A CN 114276338 A CN114276338 A CN 114276338A
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- 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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Abstract
本发明提供的2‑吡唑‑3‑苯并咪唑衍生物及其制备方法和应用,2‑吡唑‑3‑苯并咪唑衍生物具有式Ⅰ所示结构。实验结果表明,本发明提供的2‑吡唑‑3‑苯并咪唑衍生物具有较好的P2Y6受体拮抗活性和体外抗炎活性,可以作为制备P2Y6受体相关炎症性疾病治疗药物的应用。
Description
技术领域
本发明属于药物化学技术领域,尤其涉及2-吡唑-3-苯并咪唑衍生物及其制备方法和应用。
背景技术
P2Y6R是P2Y受体家族八个亚型(P2Y1R,P2Y2R,P2Y4R,P2Y6R,P2Y11R,P2Y12R,P2Y13R和P2Y14R)中的一员,在免疫器官、心血管系统、神经组织等多种器官和组织中表达,P2Y6受体的内源性配体是胞外核苷酸分子,通过其选择性激动剂UDP特异性激活磷脂酶C(PLC),上调细胞内Ca2+浓度,达到传递细胞间信号、调节细胞各种生理功能的目的。目前研究表明,当P2Y6受体受到激动时,可促进中性粒细胞和巨噬细胞的募集和趋化,并释放多种炎症细胞因子、趋化因子和肥大细胞介质。对P2Y6受体的基因敲除的小鼠模型的研究表明,P2Y6受体参与心血管疾病、呼吸道炎症及胃肠道炎症等疾病的发生发展。
P2Y6受体拮抗剂在炎症性肠病,动脉粥样硬化等相关炎症疾病药物开发领域有很好的创新性和应用前景。有文献指出,在葡聚糖硫酸钠DSS诱导的结肠炎模型中,单独阻断P2Y6受体,可以保护肠道免受炎症的影响。肠上皮细胞表面的细胞外核苷酸信号在肠道炎症的发展以及可能在炎症性肠病IBD中起着重要作用。调控P2Y6信号可能是治疗IBD的一个新的潜在目标。在drug discovery today上发表的一篇论文,阐明了P2Y6受体广泛分布于各种组织和免疫细胞中,通过调节细胞因子和促炎分子的表达和分泌参与炎症反应。它会引起一系列人类疾病,因此,已成为治疗许多疾病(包括动脉粥样硬化和其他心血管疾病)的治疗靶点。
发明内容
有鉴于此,本发明的目的在于提供2-吡唑-3-苯并咪唑衍生物及其制备方法和应用,该2-吡唑-3-苯并咪唑衍生物具有较好的拮抗P2Y6受体活性,对相关炎症反应具有明显的抑制作用,可以作为制备P2Y6受体相关炎症性疾病治疗药物的应用。
本发明提供的2-吡唑-3-苯并咪唑衍生物具有式Ⅰ结构:
所述R1选自取代或非取代苯基、或5~6元杂环基团;
所述R2选自取代或非取代的C1~C6的烷基、烷氧基、氢、杂环基、烯基、氰基、羟基、或卤素。
在本发明中,所述R1选自呋喃基、吡咯基、苯基、或取代苯基;
所述R2选自甲基、乙基、异丙基、异丁基、甲氧基、氢、酚羟基、氰基、三氟甲基、硝基或卤素。
在本发明中,苯并咪唑类化合物具有广泛的生物活性。研究表明,苯并咪唑类杂环化合物具有很好的抗炎抗菌、治疗动脉粥样硬化、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苯并咪唑基团后,其活性得到很大的提高。正是由于苯并咪唑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。
在本发明中,所述苯并咪唑衍生物具有以下任一结构:
本发明提供了一种上述技术方案所述2-吡唑-3-苯并咪唑衍生物的制备方法,包括以下步骤:
将具有式Ⅱ结构的化合物和具有式Ⅲ结构的化合物反应,得到具有式Ⅰ结构的2-吡唑-3-苯并咪唑衍生物:
在本发明具体实施例中,所述式Ⅰ结构的化合物具体按照以下路线制得:
本发明提供了一种上述技术方案所述2-吡唑-3-苯并咪唑衍生物或上述技术方案所述的制备方法制备的2-吡唑-3-苯并咪唑衍生物在制备P2Y6受体相关炎症性疾病治疗药物中的应用。
在本发明中,所述P2Y6受体相关炎症性疾病包括动脉粥样硬化,炎症性肠病等。
本发明提供了一种P2Y6受体相关炎症性疾病治疗药物,其特征在于,包括上述技术方案所述2-吡唑-3-苯并咪唑衍生物或上述技术方案所述制备方法制备的2-吡唑-3-苯并咪唑衍生物以及药学上可接受的辅料。
本发明提供的上述治疗动脉粥样硬化,炎症性肠病等炎症性疾病药物还可以与其他治疗炎症性疾病药物联合使用。
本发明提供的2-吡唑-3-苯并咪唑衍生物,具有式(Ⅰ)所示结构。实验结果表明,本发明提供的2-吡唑-3-苯并咪唑衍生物具有较好的P2Y6受体拮抗活性和体外抗炎活性,可以作为制备P2Y6受体相关炎症性疾病治疗药物的应用。
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2-吡唑-3-苯并咪唑衍生物及其制备方法和应用进行详细地描述,但不能将它们理解为对本发明保护范围的限定。
实施例1
2-(1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-基)-苯并[d]咪唑的合成:
将2.8g叔丁醇钾置于在11mLTHF中形成悬浮液,在0℃的冰浴中冷却;将1.1g乙酰呋喃和2.7ml草酸二乙酯溶解在11ml乙二醇二甲醚中,将此溶液逐滴加入0℃叔丁醇钾的悬浮液中;将混合物在室温下搅拌1小时。通过TLC监测所有乙酰基呋喃已消耗完后,添加7.5mL的1MHCl溶液。粗产物用乙酸乙酯萃取,有机相经无水硫酸钠干燥,减压旋干,通过硅胶柱色谱法纯化,石油醚:乙酸乙酯(4:1)洗脱,得到4-(呋喃-2-基)-2,4-二氧代丁酸乙酯。
将1.4g 4-(呋喃-2-基)-2,4-二氧代丁酸乙酯溶于乙醇中,加入0.9g叔丁基肼盐酸盐,并将混合物在室温搅拌过夜。当反应完成时,用水和乙酸乙酯萃取粗产物。有机相用无水硫酸钠干燥并在减压下旋干。产物通过硅胶柱色谱法纯化,用石油醚:乙酸乙酯(50:1~20:1)洗脱,得到1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-羧酸乙酯。
将200mg 1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-羧酸乙酯溶解在3mL四氢呋喃中,然后在0℃下将其滴加到氢化锂铝(50mg)在10mL四氢呋喃中的浆液中。在此温度下保持30分钟后,将反应加热至回流2小时。将反应冷却至室温,并向反应中加入10mL乙酸乙酯。向反应液中加入5N氢氧化钠,直到出现白色沉淀为止。过滤,滤液用乙酸乙酯和水萃取。用硫酸镁干燥有机层,过滤,减压旋干,得到粗制的(1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-基)甲醇。
将188mg(1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-基)甲醇溶于DCM中,冰浴下加入434mg Dess-Martin试剂,室温下搅拌1h,用饱和碳酸钠淬灭,硅藻土过滤,乙酸乙酯萃取滤液,无水硫酸钠干燥,减压旋干得到粗制的1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-甲醛。
将80mg1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-甲醛,60mg邻苯二胺,80mg亚硫酸氢钠溶于乙醇:水=2:1的溶液中,回流1h。乙酸乙酯萃取,无水硫酸钠干燥,减压旋干,通过薄层色谱法纯化,石油醚:乙酸乙酯(3:1),得到纯净目标产物。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.92(s,1H),7.57(d,J=35.0Hz,2H),7.18(d,J=6.4Hz,2H),7.01(s,1H),6.77(d,J=3.3Hz,1H),6.68(t,J=2.5Hz,1H),1.56(s,9H).
13C NMR(101MHz,DMSO-d6)δ152.42,152.17,142.66,142.19,137.03,135.49,129.92,123.10,123.04,119.30,112.40,112.13,111.52,104.50,60.49,28.94.
实施例2
2-(1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-基)-5-甲基-1H-苯并[d]咪唑的合成:
以3,4-二氨基甲苯为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),7.92(d,J=1.7Hz,1H),7.45(d,J=8.1Hz,1H),7.36(s,1H),7.00(s,2H),6.77(d,J=3.2Hz,1H),6.68(dd,J=3.3,1.9Hz,1H),2.43(s,3H),1.56(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,152.16,142.66,137.16,137.03,135.12,129.92,129.80,127.10,113.83,113.30,112.40,111.52,104.50,60.49,28.94,20.92.
实施例3
2-(1-(叔丁基)-5-(呋喃-2-基)-1H-吡唑-3-基)-5-氯-1H-苯并[d]咪唑的合成:
以4-氯-1,2-苯二胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.80(d,J=25.1Hz,1H),7.91(d,J=1.8Hz,1H),7.70–7.61(m,1H),7.52(s,1H),7.21(s,1H),7.03(s,1H),6.77(d,J=3.2Hz,1H),6.67(dd,J=3.3,1.9Hz,1H),1.55(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,152.16,142.66,137.03,135.15,135.06,129.92,128.37,125.20,115.61,113.93,112.40,111.52,104.50,60.49,28.94.
实施例4
2-(1-(叔丁基)-5-(1H-吡咯-2-基)-1H-吡唑-3-基)-1H-苯并[d]咪唑的合成:
以2-乙酰基吡咯为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ11.27–11.24(m,1H),7.58(dd,J=5.9,3.3Hz,2H),7.18(dd,J=6.0,3.2Hz,2H),6.91(q,J=2.4Hz,1H),6.86(s,1H),6.25(dt,J=3.7,2.2Hz,1H),6.16(q,J=2.8Hz,1H),1.50(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,152.16,142.66,137.03,135.15,135.06,129.92,128.37,125.20,115.61,113.93,112.40,111.52,104.50,60.49,28.94.
实施例5
2-(1-(叔丁基)-5-(1H-吡咯-2-基)-1H-吡唑-3-基)-5-甲基-1H-苯并[d]咪唑的合成:
以2-乙酰基吡咯和3,4-二氨基甲苯为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),11.25–11.19(m,1H),7.44(d,J=8.2Hz,1H),7.34(s,1H),6.99(d,J=8.1Hz,1H),6.90(q,J=2.4Hz,1H),6.80(s,1H),6.23(q,J=2.6,1.9Hz,1H),6.15(q,J=2.8Hz,1H),2.42(s,3H),1.49(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,152.16,142.66,137.03,135.15,135.06,129.92,128.37,125.20,115.61,113.93,112.40,111.52,104.50,60.49,28.94.
实施例6
2-(1-(叔丁基)-5-(1H-吡咯-2-基)-1H-吡唑-3-基)-5-氯-1H-苯并[d]咪唑的合成:
以2-乙酰基吡咯和4-氯-1,2-苯二胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),11.23(d,J=2.9Hz,1H),7.63–7.51(m,2H),7.20(dd,J=8.5,2.1Hz,1H),6.90(q,J=2.4Hz,1H),6.84(s,1H),6.23(dt,J=3.9,1.8Hz,1H),6.15(q,J=2.7Hz,1H),1.49(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,152.16,142.66,137.03,135.15,135.06,129.92,128.37,125.20,115.61,113.93,112.40,111.52,104.50,60.49,28.94.
实施例7
2-(1-(叔丁基)-5-苯基-1H-吡唑-3-基)-1H-苯并[d]咪唑的合成:
以苯乙酮为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),7.48(s,7H),7.17(d,J=6.5Hz,2H),6.74(s,1H),1.49(s,9H).
13C NMR(101MHz,DMSO-d6)δ152.42,144.60,142.19,137.14,135.49,131.16,128.86,128.52,127.10,123.10,123.04,119.30,112.13,105.02,60.32,28.94.
实施例8
2-(1-(叔丁基)-5-苯基-1H-吡唑-3-基)-5-甲基-1H-苯并[d]咪唑的合成:
以苯乙酮和3,4-二氨基甲苯为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.44(d,J=10.7Hz,1H),7.48(s,6H),7.42–7.36(m,1H),6.99(dd,J=15.6,8.1Hz,1H),6.71(s,1H),2.41(d,J=7.2Hz,3H),1.48(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,144.60,137.15,135.12,131.16,129.80,128.86,128.52,127.10,113.83,113.30,105.02,60.32,28.94,20.92.
实施例9
2-(1-(叔丁基)-5-苯基-1H-吡唑-3-基)-5-氯-1H-苯并[d]咪唑的合成:
以苯乙酮和4-氯-1,2-苯二胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.76(d,J=25.0Hz,1H),7.69–7.60(m,1H),7.48(d,J=2.2Hz,6H),7.20(dd,J=14.0,8.3Hz,1H),6.75(s,1H),1.48(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,144.60,137.14,135.15,135.06,131.16,128.86,128.52,128.37,127.10,125.20,115.61,113.93,105.02,60.32,28.94.
实施例10
2-(1-(叔丁基)-5-(对甲苯基)-1H-吡唑-3-基)-5-氯-1H-苯并[d]咪唑的合成:
以对甲基苯乙酮和4-氯-1,2-苯二胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ12.76(d,J=25.0Hz,1H),7.69–7.60(m,1H),7.48(d,J=2.2Hz,6H),7.20(dd,J=14.0,8.3Hz,1H),6.75(s,1H),1.48(s,9H).
13C NMR(101MHz,DMSO-d6)δ153.16,144.60,137.74,137.14,135.15,135.06,131.02,129.03,128.37,127.15,125.20,115.61,113.93,105.02,60.32,28.94,21.42.
实施例11化合物对P2Y6受体体外拮抗活性测试方法
将前期构建的人P2Y6R稳转HEK293细胞培养于DMEM培养基中(含10%胎牛血清、100U/ml青霉素和100μg/ml链霉素),实验前接种至6孔培养板,接种密度为5×105cells/ml,细胞于37℃、95%O2、5%CO2湿度条件下培养。实验前换无血清培养基饥饿12h,每孔加入1μM化合物,反应30min后加入10μM UDP孵育12h后收集样品检测胞内3磷酸肌醇(IP3)含量。
3磷酸肌醇(IP3)酶联免疫吸附测定试剂盒采用竞争ELISA法。用IP3抗原包被于酶标板上,实验时样品或标准品中的IP3与包被的IP3竞争生物素标记的抗IP3单抗上的结合位点,游离的成分被洗去。加入辣根过氧化物酶标记的亲和素,生物素与亲和素特异性结合而形成免疫复合物,游离的成分被洗去。加入显色底物(TMB),TMB在辣根过氧化物酶的催化下呈现蓝色,加终止液后变成黄色。用酶标仪在450nm波长处测OD值,IP3浓度与OD450值之间呈反比,通过绘制标准曲线计算出样品中IP3的浓度。
最后计算每组复孔的平均OD值。以浓度为横坐标,OD值为纵坐标,在双对数坐标纸上绘出四参数逻辑函数的标准曲线;通过标准曲线计算出样品中IP3的浓度。实验重复三次,取平均值并计算化合物对P2Y6R的IC50。
实验结果如表1所示:
表1 化合物对P2Y6R体外拮抗活性测试结果
化合物 | %inhibition at 10μM | hP2Y<sub>6</sub>R IC<sub>50</sub>(nM) |
Ⅰ-1 | 69.12 | 878.54 |
Ⅰ-2 | 67.45 | 765.32 |
Ⅰ-3 | 132.71 | 5.75 |
Ⅰ-4 | 78.76 | 920.35 |
Ⅰ-5 | 69.56 | 278.56 |
Ⅰ-6 | 100.62 | 132.54 |
Ⅰ-7 | 73.92 | 335.09 |
Ⅰ-8 | 86.39 | 97.27 |
Ⅰ-9 | 106.39 | 18.30 |
Ⅰ-10 | 112.58 | 54.23 |
实施例12优选化合物体外抗炎活性测试方法
采用质粒构建P2Y6R过表达的THP-1细胞模型,用正常细胞作为平行对照组,培养于RPMI-1640培养基中(含10%胎牛血清、100U/ml青霉素和100μg/ml链霉素),实验前接种至细胞培养板,接种密度为1×106cells/ml,细胞于37℃、95%O2、5%CO2湿度条件下培养。实验前预先向培养基中分别加入U73122(PLCβ抑制剂)和BAPTA-AM(Ca2+螯合剂),1h后向细胞中加入终浓度为50μg/ml的ox-LDL,24h后显微镜下观察细胞形态,检测细胞培养上清液中NLRP3炎症小体,IL-1β、TNF-α等炎症因子的表达含量,计算IC50。
实验结果如表2所示:
表2 化合物对体外抗炎活性测试结果
由上述实施例可知,本发明制备的2-吡唑-3-苯并咪唑衍生物具有较好的拮抗P2Y6受体抑制活性及P2Y6诱导的体外炎症反应,可以用于制备P2Y6受体相关炎症性疾病治疗药物。
由以上实施例可知,本发明提供的2-吡唑-3-苯并咪唑衍生物,具有式(Ⅰ)所示结构。实验结果表明,本发明提供的2-吡唑-3-苯并咪唑衍生物具有较好的P2Y6受体拮抗活性和体外抗炎活性,可以作为制备P2Y6受体相关炎症性疾病治疗药物的应用。
以上所述仅是本发明的优选实施方式,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,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (6)
2.根据权利要求1所述的2-吡唑-3-苯并咪唑衍生物,其特征在于,所述R1选自呋喃基、吡咯基、苯基、或取代苯基;
所述R2选自甲基、乙基、异丙基、异丁基、甲氧基、氢、酚羟基、氰基、三氟甲基、硝基或卤素。
5.一种权利要求1~3任一项所述2-吡唑-3-苯并咪唑衍生物或权利要求4所述的制备方法制备的2-吡唑-3-苯并咪唑衍生物在制备P2Y6受体相关炎症性疾病治疗药物中的应用。
6.一种P2Y6受体相关炎症性疾病治疗药物,其特征在于,包括权利要求1~3任一项所述2-吡唑-3-苯并咪唑衍生物或权利要求4所述制备方法制备的2-吡唑-3-苯并咪唑衍生物以及药学上可接受的辅料。
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