CN110885318B - 苯并恶唑衍生物及其制备方法和应用 - Google Patents
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Abstract
本发明提供了苯并恶唑衍生物及其制备方法和应用,本发明提供的苯并恶唑衍生物作为P2Y14抑制剂具有较好的抑制活性和抗炎活性,进而通过研究发现,其对P2Y14受体相关的高尿酸血症以及急性痛风性关节炎也有很好的活性,可以作为治疗高尿酸血症以及急性痛风性关节炎的药物。
Description
技术领域
本发明涉及药物化学领域,尤其涉及一种苯并恶唑衍生物及其制备方法和应用。
背景技术
P2Y14受体属于视紫红质样G蛋白偶联受体(GPCR)的δ-分支。它通过Gi蛋白抑制3′,5′-环腺苷一磷酸(cAMP)的产生,并被尿苷-5′-二磷酸葡萄糖(UDPG)和其他内源性UDP-糖激活。P2Y14受体主要存在于心脏、胎盘、脂肪组织、胃肠道以及外周免疫细胞中,参与促炎作用和细胞焦亡过程,其活化增强中性粒细胞趋化性和促进肥大细胞释放介质。最近的研究表明,在P2Y14受体基因敲除的小鼠中,P2Y14受体的拮抗作用具有潜在的治疗糖尿病的作用。另有报道称UDP和UDPG作为配体激活P2Y14受体与炎症、哮喘等疾病有很大关系。然而,关于P2Y14受体与痛风的研究尚未见报道,痛风是一组由先天免疫紊乱引起的特征性炎症反应。急性痛风性关节炎通常是痛风的首发症状,其由关节中尿酸单钠结晶(MSU)的沉积引发。急性痛风性关节炎的治疗仍然缺乏理想的药物,并且与急性痛风性关节炎的发病机制相结合的痛风治疗药物即将开启新的治疗靶点。
目前对P2Y14受体抑制剂的研究仅仅报道了3种结构类型的化合物(嘧啶并哌啶类、2-萘酸类和3-取代苯甲酸类),都在临床前研究阶段。其中活性和选择性最高的为2-萘酸类,然而目前报道的2-萘酸类结构的抑制剂存在溶解性差、口服生物利用度低、合成纯化难度大等缺陷,给进一步讨论构效关系及生物学评价带来了较大的困难。因此寻找新结构类型的P2Y14受体拮抗剂,改善2-萘酸类抑制剂存在的成药性差等问题,成为发现活性强、选择性好的P2Y14受体抑制剂的新策略。
发明内容
有鉴于此,本发明所要解决的技术问题在于提供一种苯并恶唑衍生物及其制备方法和应用,本发明提供的苯并恶唑衍生物作为P2Y14受体抑制剂具有很好的活性,且成药性好。
与现有技术相比,本发明提供了苯并恶唑衍生物及其制备方法和应用,通过实验发现,本发明提供的苯并恶唑衍生物作为P2Y14抑制剂具有较好的抑制活性和抗炎活性,进而通过研究发现,其对P2Y14受体相关的高尿酸血症以及急性痛风性关节炎也有很好的活性,可以作为治疗高尿酸血症以及急性痛风性关节炎的药物。
具体实施方式
本发明提供了一种苯并恶唑衍生物,具有式(I)所示结构,
其中,所述R为氢、C1~C10的烷基或卤素;
按照本发明,所述R优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、氟、氯、溴或碘,本发明对苯并恶唑环上R的位置没有特殊要求,可以在环上的任意一个碳上,优选的,所述R在苯并恶唑的5位或6位。
按照本发明,所述优选为取代的或未取代的C5~C8杂环烷基、取代的或未取代的C5~C8杂环芳基、取代的或未取代的C8~C15的芳基,其中,所述取代的杂环烷基、取代的杂环芳基和取代的的芳基中的取代基优选为卤素、C1~C6的烷基、卤代的C1~C6的烷基、C1~C6的烷氧基、C1~C6的烷巯基、卤素取代的C1~C6的烷氧基或卤素取代的C1~C6的烷巯基,更优选为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、正己氧基、甲巯基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、正戊硫基、异戊硫基、正己硫基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基或三氟甲氧基;所述杂环烷基、杂环芳基中的杂原子为氧、氮或硫;更具体的,所述为噻吩基、四氢吡喃基、苯基、4-丁氧基苯基、4-叔丁基苯基、3,4-(亚甲基二氧)基苯基、4-溴代苯基、3-溴代苯基、2-溴代苯基、4-氯代苯基、3-氯代苯基、2-氯代苯基、4-甲基苯基、4-甲硫基苯基、3-甲基苯基、2-甲基苯基、4-甲氧基苯基、3-甲氧基苯基、2-甲氧基苯基、4-三氟甲基苯基、3-三氟甲基苯基、2-三氟甲基苯基、4-三氟甲氧基苯基或3-三氟甲氧基苯基。
具体的,所述苯并恶唑衍生物为式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-6)、式(I-7)、式(I-8)、式(I-9)、式(I-10)、式(I-11)、式(I-12)、式(I-13)、式(I-14)、式(I-15)、式(I-16)、式(I-17)、式(I-18)、式(I-19)、式(I-20)、式(I-21)、式(I-22)、式(I-23)、式(I-24)、式(I-25)、式(I-26)、式(I-27)、式(I-28)、式(I-29)、式(I-30)、式(I-31)、式(I-32)、式(I-33)、式(I-34)、式(I-35)、式(I-36)、式(I-37)、式(I-38)、式(I-39)、式(I-40)、式(I-41)、式(I-42)、式(I-43)、式(I-44)、式(I-45)、式(I-46)、式(I-47)、式(I-48)、式(I-49)、式(I-50)、式(I-51)、式(I-52)、式(I-53)、式(I-54)、式(I-55)、式(I-56)、式(I-57)、式(I-58)、式(I-59)、式(I-60)、式(I-61)、式(I-62)、式(I-63)。
本发明还提供了一种具有式(I)所示结构的苯并恶唑衍生物的制备方法,包括:
将式(II)结构的化合物和式(III)结构的化合物反应,得到式(I)结构的化合物;
其中,所述R为氢、C1~C10的烷基或卤素;
按照本发明,本发明将将式(II)结构的化合物和式(III)结构的化合物反应,得到式(I)结构的化合物;其中,本发明对反应的方法的条件没有特殊要求,本领域技术人员可以根据反应原料结合现有技术选择合适的制备工艺;本发明对式(II)结构的化合物以及式(III)结构的化合物的来源没有特殊要求,本领域技术人员可以根据实际需要自制或者购买得到。
更具体的,所述N-(3-(苯并[d]恶唑-2-基)苯基)-2-苯基乙酰胺及其衍生物合成反应的反应式如下:
本发明还提供了一种本发明所述的苯并恶唑衍生物在制备P2Y14受体抑制剂中的应用。
本发明还提供了一种本发明所述的苯并恶唑衍生物在制备治疗高尿酸血症药物以及急性痛风性关节炎的药物中的应用。
本发明提供了苯并恶唑衍生物具有较好的P2Y14抑制活性和抗炎活性,可以作为制备P2Y14受体相关炎症性疾病治疗药物,如治疗高尿酸血症的药物以及急性痛风性关节炎的药物。
下面将结合本发明实施例的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例0
3-(苯并[d]恶唑-2-基)苯胺的合成:
将邻氨基苯酚(1g),间氨基苯甲酸(1.256g),10mL多聚磷酸(PPA)加入到50mL圆底烧瓶中,185℃加热,回流6h,反应结束后,冷却至室温,用冷的6N的NaOH中和,过滤沉淀,烘干。用乙酸乙酯溶解沉淀,多次过滤,收集滤液,旋干。对该产物用石油醚:乙酸乙酯(PE:EA)=4:1过柱,得到红色固体即为产物。
1H NMR(600MHz,cdcl3)δ7.76-7.74(m,1H),7.63(d,J=7.7Hz,1H),7.58-7.54(m,2H),7.34-7.31(m,2H),7.28(t,J=7.8Hz,1H),6.82(dd,J=8.0,2.1Hz,1H).
实施例1
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-氯苯基)乙酰胺的合成:
将3-(苯并[d]恶唑-2-基)苯胺,4-氯苯乙酸,EDCI,HOBt,DIPEA,以摩尔比1∶1∶1.5∶1.5∶3的量投到10mL DMF中,TLC监测反应,反应结束后,加水淬灭,萃取,干燥,旋干。加少量乙酸乙酯,使产物析出,过滤,烘干。
1H NMR(600MHz,DMSO)δ8.58(s,1H),7.86(d,J=7.6Hz,1H),7.79-7.72(m,3H),7.52(t,J=7.9Hz,1H),7.43-7.34(m,6H),3.68(s,2H).
13C NMR(151MHz,DMSO)δ169.20,162.12,150.20,141.44,139.91,134.73,131.37,131.09,129.90,128.27,126.85,125.62,124.94,122.25,122.06,119.86,117.63,110.94,42.48,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例2
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-溴苯基)乙酰胺的合成:
以4-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.57(s,1H),7.86(d,J=7.8Hz,1H),7.79-7.72(m,3H),7.52(dd,J=12.2,5.4Hz,3H),7.43-7.38(m,2H),7.30(d,J=8.3Hz,2H),3.66(s,2H).
13C NMR(151MHz,DMSO)δ169.07,162.09,150.17,141.42,139.88,135.13,131.45,131.16,129.85,126.83,125.57,124.89,122.21,122.02,119.83,119.82,117.60,110.91,42.53,39.52.
实施例3
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(对甲苯基)乙酰胺的合成:
以4-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.57(s,1H),7.85(d,J=7.7Hz,1H),7.78(t,J=7.1Hz,2H),7.74(d,J=7.8Hz,1H),7.51(t,J=7.9Hz,1H),7.40(dt,J=14.4,7.1Hz,2H),7.22(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),3.61(s,2H),2.25(s,3H).
13C NMR(101MHz,DMSO)δ169.72,162.14,150.19,141.45,140.03,135.63,132.68,129.85,128.97,128.90,126.81,125.58,124.91,122.20,121.93,119.85,117.58,110.93,43.00,39.52,20.65.
实施例4
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(噻吩-2-基)乙酰胺的合成:
以2-噻吩乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.59(s,1H),7.87(d,J=7.8Hz,1H),7.78(t,J=7.1Hz,2H),7.73-7.71(m,1H),7.53(t,J=7.9Hz,1H),7.43-7.37(m,3H),7.01-6.96(m,2H),3.90(s,2H).
13C NMR(101MHz,DMSO)δ168.47,162.11,150.20,141.44,139.85,136.81,129.91,126.87,126.70,126.47,125.60,125.17,124.92,122.25,122.12,119.86,117.59,110.94,39.52,37.58.
实施例5
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-甲氧基苯基)乙酰胺的合成:
以4-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.88(d,J=7.5Hz,1H),7.84-7.75(m,3H),7.55(t,J=7.8Hz,1H),7.45(d,J=12.4Hz,2H),7.29(d,J=8.2Hz,2H),6.91(d,J=8.2Hz,2H),3.74(s,3H),3.62(s,2H).
13C NMR(101MHz,DMSO)δ169.91,162.14,158.09,150.19,141.45,140.05,130.12,129.84,127.65,126.81,125.58,124.90,122.19,121.91,119.84,117.57,113.78,110.92,55.03,42.51,39.52.
实施例6
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(2-溴苯基)乙酰胺的合成:
以2-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.90(d,J=7.8Hz,1H),7.83-7.79(m,2H),7.78-7.75(m,1H),7.64(dd,J=8.0,0.9Hz,1H),7.56(t,J=7.9Hz,1H),7.48-7.45(m,1H),7.43(dd,J=5.0,2.6Hz,1H),7.42-7.40(m,1H),7.38(dd,J=7.5,1.0Hz,1H),7.25(td,J=7.7,1.7Hz,1H),3.92(s,2H).
13C NMR(151MHz,DMSO)δ168.31,162.14,150.19,141.44,139.98,135.49,132.30,132.27,129.87,128.86,127.62,126.85,125.58,124.90,124.60,122.16,121.95,119.84,117.56,110.92,43.29,39.52.
实施例7
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(四氢-2H-吡喃-4-基)乙酰胺的合成:
以四氢吡喃4-乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(s,1H),7.88(d,J=7.8Hz,1H),7.84-7.81(m,2H),7.75(d,J=9.3Hz,1H),7.54(t,J=7.9Hz,1H),7.48-7.41(m,2H),3.87-3.82(m,2H),2.31(d,J=7.2Hz,2H),1.63(d,J=11.3Hz,2H),1.33-1.22(m,5H).
13C NMR(151MHz,DMSO)δ170.44,162.19,150.20,141.45,139.97,129.78,126.79,125.57,124.91,122.19,121.84,119.84,117.54,110.93,66.88,43.66,39.94,39.80,39.66,39.52,39.38,39.24,39.10,32.39,32.13.
实施例8
N-(3-(苯并[d]恶唑-2-基)苯基)-2-苯基乙酰胺的合成:
以苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.89(d,J=7.7Hz,1H),7.83-7.76(m,3H),7.55(t,J=7.9Hz,1H),7.48-7.40(m,2H),7.36(q,J=8.1Hz,4H),7.29-7.24(m,1H),3.70(s,2H).
13C NMR(101MHz,DMSO)δ169.55,162.13,150.19,141.44,140.00,135.76,129.86,129.13,128.34,126.83,126.61,125.58,124.91,122.21,121.97,119.85,117.58,110.93,43.37,39.52.
实施例9
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(邻甲苯基)乙酰胺的合成:
以2-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(t,J=1.8Hz,1H),7.91-7.88(m,1H),7.82-7.76(m,3H),7.56(t,J=8.0Hz,1H),7.43(ddd,J=12.4,5.9,3.8Hz,2H),7.29(dd,J=4.9,3.9Hz,1H),7.18(ddd,J=11.4,5.9,3.3Hz,3H),3.75(s,2H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.49,162.14,150.19,141.44,140.01,136.68,134.42,129.99,129.90,129.85,126.83,126.75,125.78,125.57,124.90,122.21,121.93,119.83,117.60,110.92,40.99,39.52,19.40.
实施例10
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(2-氯苯基)乙酰胺的合成:
以2-氯苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.90(d,J=7.8Hz,1H),7.83-7.79(m,2H),7.76(d,J=9.3Hz,1H),7.56(t,J=7.9Hz,1H),7.49-7.46(m,2H),7.45-7.42(m,2H),7.35-7.32(m,2H),3.91(s,2H).
13C NMR(151MHz,DMSO)δ168.37,162.13,150.19,141.44,139.96,133.73,133.70,132.24,129.87,129.01,128.66,127.08,126.85,125.58,124.90,122.16,121.96,119.84,117.57,110.91,40.84,39.52.
实施例11
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-(叔丁基)苯基)乙酰胺的合成:
以4-叔丁基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.89(d,J=7.8Hz,1H),7.83-7.76(m,3H),7.55(t,J=7.9Hz,1H),7.47-7.40(m,2H),7.37(d,J=8.3Hz,2H),7.30(d,J=8.3Hz,2H),3.65(s,2H),1.28(s,9H).
13C NMR(101MHz,DMSO)δ169.67,162.12,150.17,148.91,141.43,140.00,132.69,129.79,128.73,126.79,125.53,125.05,124.86,122.17,121.90,119.80,117.58,110.87,42.92,39.52,34.08,31.11.
实施例12
N-(3-(苯并[d]恶唑-2-基)苯基)2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺的合成:
以3,4-(亚甲基二氧)苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(t,J=1.8Hz,1H),7.89-7.86(m,1H),7.81(ddd,J=5.6,3.2,1.0Hz,3H),7.54(t,J=8.0Hz,1H),7.45-7.41(m,2H),6.98(d,J=1.3Hz,1H),6.89-6.83(m,2H),5.99(s,2H),3.63(s,2H).
13C NMR(101MHz,DMSO)δ169.80,162.19,150.18,147.09,145.90,141.44,140.19,129.68,129.57,126.72,125.54,124.87,122.30,122.19,121.86,119.81,117.59,110.89,109.62,108.03,100.75,42.80,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例13
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲基)苯基)乙酰胺的合成:
以4-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.7Hz,1H),7.92-7.88(m,1H),7.83-7.79(m,2H),7.77(ddd,J=8.2,2.1,0.9Hz,1H),7.72(d,J=8.1Hz,2H),7.62-7.58(m,2H),7.55(d,J=7.9Hz,1H),7.43(ddd,J=12.6,6.0,3.8Hz,2H),3.84(s,2H).
13C NMR(151MHz,DMSO)δ168.81,162.09,150.19,141.43,140.54,139.84,130.10,129.88,127.49,127.28,126.86,125.58,125.14,124.90,122.24,122.09,119.84,117.63,110.91,42.91,39.52.
实施例14
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺的合成:
以2-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(s,1H),7.90(d,J=7.8Hz,1H),7.82-7.78(m,2H),7.74(d,J=8.0Hz,2H),7.68(t,J=7.5Hz,1H),7.57(d,J=7.9Hz,2H),7.55-7.50(m,1H),7.45-7.41(m,2H),3.99(s,2H).
13C NMR(101MHz,DMSO)δ168.44,162.12,150.19,141.44,139.90,133.66,133.46,132.22,129.85,127.73,127.44,127.36,126.86,125.65,125.59,125.55,124.88,122.17,121.97,119.81,117.59,110.88,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例15
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲氧基)苯基)乙酰胺的合成:
以4-三氟甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(s,1H),7.90(d,J=7.8Hz,1H),7.83-7.76(m,3H),7.56(t,J=8.0Hz,1H),7.50(d,J=8.6Hz,2H),7.46-7.42(m,2H),7.35(d,J=8.0Hz,2H),3.77(s,2H).
13C NMR(101MHz,DMSO)δ169.14,162.11,150.19,147.17,141.43,139.88,135.22,131.07,129.85,126.85,125.57,124.89,122.23,122.05,121.37,120.89,119.83,117.63,110.90,42.37,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例16
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(4-丁氧基苯基)乙酰胺的合成:
以4-丁氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(t,J=1.7Hz,1H),7.90-7.87(m,1H),7.79(dddd,J=11.4,7.3,2.4,1.1Hz,3H),7.55(t,J=8.0Hz,1H),7.45-7.41(m,2H),7.27(d,J=8.6Hz,2H),6.91-6.88(m,2H),3.94(t,J=6.5Hz,2H),3.61(s,2H),1.70-1.64(m,2H),1.42(dd,J=15.0,7.4Hz,2H),0.92(t,J=7.4Hz,3H).
13C NMR(101MHz,DMSO)δ169.88,162.13,157.50,150.17,141.43,140.03,130.06,129.78,127.49,126.79,125.53,124.86,122.17,121.88,119.80,117.58,114.30,110.87,67.06,42.50,39.52,30.72,18.69,13.63.
实施例17
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(3-甲氧基苯基)乙酰胺的合成:
以3-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.8Hz,1H),7.90-7.87(m,1H),7.83-7.80(m,1H),7.80-7.76(m,2H),7.55(t,J=8.0Hz,1H),7.47-7.40(m,2H),7.26(dd,J=11.6,4.6Hz,1H),6.95(t,J=4.1Hz,2H),6.86-6.82(m,1H),3.76(s,3H),3.67(s,2H).
13C NMR(101MHz,DMSO)δ169.38,162.12,159.23,150.18,141.43,139.97,137.14,129.82,129.32,126.82,125.55,124.88,122.22,121.97,121.32,119.82,117.61,114.95,111.98,110.89,54.98,43.41,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例18
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(3-(三氟甲氧基)苯基)乙酰胺的合成:
以3-三氟甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(t,J=1.7Hz,1H),7.92-7.88(m,1H),7.83-7.79(m,2H),7.77(ddd,J=8.1,2.0,0.9Hz,1H),7.56(t,J=8.0Hz,1H),7.49(t,J=7.9Hz,1H),7.45-7.43(m,1H),7.42-7.37(m,3H),7.28(dd,J=8.2,1.1Hz,1H),3.80(s,2H).
13C NMR(151MHz,DMSO)δ168.95,162.13,150.22,148.34,141.45,139.88,138.36,130.19,129.93,128.47,126.89,125.64,124.96,122.29,122.14,121.76,120.98,119.88,119.17,117.64,110.96,42.66,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例19
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(间甲苯基)乙酰胺的合成:
以3-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(t,J=1.7Hz,1H),7.91-7.88(m,1H),7.83-7.76(m,3H),7.56(t,J=8.0Hz,1H),7.43(ddd,J=12.5,5.9,3.9Hz,2H),7.29(dd,J=4.9,3.9Hz,1H),7.18(ddd,J=11.4,5.8,3.3Hz,3H),3.75(s,2H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.50,162.15,150.19,141.45,140.02,136.69,134.42,130.00,129.91,129.85,126.84,126.76,125.78,125.58,124.91,122.22,121.94,119.84,117.60,110.92,41.00,39.94,39.80,39.66,39.52,39.38,39.24,39.10,19.40.
实施例20
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(3-溴苯基)乙酰胺的合成:
以3-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.7Hz,1H),7.91-7.88(m,1H),7.83-7.79(m,2H),7.78-7.75(m,1H),7.59(d,J=1.6Hz,1H),7.56(t,J=8.0Hz,1H),7.50-7.47(m,1H),7.45-7.42(m,2H),7.39(dd,J=8.5,4.7Hz,1H),7.32(t,J=7.7Hz,1H),3.73(s,2H).
13C NMR(151MHz,DMSO)δ168.99,162.10,150.19,141.44,139.87,138.39,132.00,130.45,129.89,129.51,128.36,126.85,125.59,124.91,122.23,122.07,121.48,119.85,117.61,110.93,42.64,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例21
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(2-甲氧基苯基)乙酰胺的合成:
以2-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.88(d,J=7.8Hz,1H),7.83-7.76(m,3H),7.55(t,J=7.9Hz,1H),7.46-7.40(m,2H),7.27(t,J=7.3Hz,2H),7.00(d,J=8.2Hz,1H),6.93(t,J=7.4Hz,1H),3.79(s,3H),3.70(s,2H).
13C NMR(151MHz,DMSO)δ169.58,162.20,157.27,150.19,141.46,140.18,130.88,129.81,128.12,126.81,125.57,124.90,123.96,122.14,121.78,120.17,119.83,117.51,110.91,110.70,55.45,39.94,39.80,39.66,39.52,39.38,39.24,39.10,37.79.
实施例22
N-(3-(苯并[d]恶唑-2-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺的合成:
以3-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(s,1H),7.90(d,J=7.8Hz,1H),7.83-7.79(m,2H),7.79-7.74(m,2H),7.67(dd,J=13.0,7.7Hz,2H),7.62-7.54(m,2H),7.43(ddd,J=12.5,5.9,3.9Hz,2H),3.86(s,2H).
13C NMR(101MHz,DMSO)δ168.93,162.09,150.18,141.42,139.84,137.03,133.47,129.85,129.29,129.13,128.82,126.85,125.89,125.85,125.56,124.88,122.22,122.06,119.82,117.61,110.89,42.61,39.52.
实施例00
3-(5-甲基苯并[d]恶唑-2-基)苯胺的合成:
将邻氨基对甲苯酚(2.46g),间氨基苯甲酸(2.74g),10mL多聚磷酸(PPA)加入到50mL圆底烧瓶中,185℃加热,回流6h,反应结束后,冷却至室温,用冷的6N的NaOH中和,过滤沉淀,烘干。用乙酸乙酯溶解沉淀,多次过滤,收集滤液,旋干。对该产物用石油醚∶乙酸乙酯(PE∶EA)=4∶1过柱,得到淡粉色固体即为产物。
实施例23
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(2-溴苯基)乙酰胺的合成:
以2-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(s,1H),7.87(d,J=7.8Hz,1H),7.77-7.73(m,1H),7.65(t,J=7.9Hz,2H),7.60(s,1H),7.55(t,J=7.9Hz,1H),7.46(dd,J=7.6,1.5Hz,1H),7.39(dd,J=10.7,4.2Hz,1H),7.27-7.22(m,2H),3.92(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ168.31,162.21,148.44,141.66,139.97,135.51,134.31,132.30,132.27,129.84,128.86,127.63,126.98,126.56,124.60,122.05,121.86,119.62,117.49,110.30,43.29,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例24
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(邻甲苯基)乙酰胺的合成:
以2-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(t,J=1.7Hz,1H),7.88-7.85(m,1H),7.79-7.75(m,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.28(dd,J=4.8,3.9Hz,1H),7.25(dd,J=8.3,1.1Hz,1H),7.20-7.15(m,3H),3.74(s,2H),2.45(s,3H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.48,162.21,148.44,141.66,139.99,136.69,134.42,134.31,130.00,129.91,129.82,126.96,126.76,126.56,125.79,122.10,121.85,119.62,117.52,110.30,41.00,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00,19.40.
实施例25
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(对甲苯基)乙酰胺的合成:
以4-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.54(s,1H),7.82(d,J=7.7Hz,1H),7.73(d,J=8.2Hz,1H),7.63(d,J=8.4Hz,1H),7.57(s,1H),7.50(t,J=8.0Hz,1H),7.22(d,J=8.0Hz,3H),7.12(d,J=7.7Hz,2H),3.60(s,2H),2.42(s,3H),2.25(s,3H).
13C NMR(151MHz,DMSO)δ169.75,162.22,148.46,141.67,140.01,135.67,134.35,132.70,129.84,128.99,128.92,126.95,126.59,122.13,121.88,119.64,117.53,110.34,43.02,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.02,20.68.
实施例26
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(噻吩-2-基)乙酰胺的合成:
以2-噻吩乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.60(s,1H),7.88(d,J=7.6Hz,1H),7.75(d,J=7.9Hz,1H),7.68(d,J=8.3Hz,1H),7.61(s,1H),7.55(t,J=7.9Hz,1H),7.42(d,J=4.2Hz,1H),7.26(d,J=8.4Hz,1H),7.01(dd,J=9.1,4.2Hz,2H),3.93(s,2H),2.45(s,3H).
13C NMR(101MHz,DMSO)δ168.45,162.16,148.45,141.66,139.82,136.81,134.31,129.87,126.99,126.70,126.57,126.47,125.16,122.13,122.02,119.63,117.52,110.32,39.52,37.58,20.99.
实施例27
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(4-甲氧基苯基)乙酰胺的合成:
以4-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.58(d,J=1.6Hz,1H),7.85(d,J=7.8Hz,1H),7.76(dd,J=8.2,1.1Hz,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.53(t,J=8.0Hz,1H),7.31-7.23(m,3H),6.94-6.88(m,2H),3.74(s,3H),3.61(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ169.16,162.18,148.45,147.18,141.66,139.87,135.25,134.34,131.10,129.86,126.98,126.59,122.13,121.98,120.94,119.63,117.55,110.32,42.40,40.06,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例28
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(2-氯苯基)乙酰胺的合成:
以2-氯苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.87(d,J=7.8Hz,1H),7.75(d,J=9.2Hz,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.55(t,J=8.0Hz,1H),7.49-7.45(m,2H),7.35-7.32(m,2H),7.25(d,J=8.3Hz,1H),3.90(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ168.36,162.20,148.44,141.66,139.94,134.31,133.73,133.71,132.25,129.84,129.02,128.67,127.08,126.98,126.56,122.05,121.88,119.62,117.50,110.30,40.85,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例29
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(四氢-2H-吡喃-4-基)乙酰胺的合成:
以四氢吡喃4-乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.58(s,1H),7.82(d,J=7.8Hz,1H),7.71(d,J=9.2Hz,1H),7.64(d,J=8.3Hz,1H),7.58(s,1H),7.49(t,J=7.9Hz,1H),7.22(d,J=7.3Hz,1H),3.81(dd,J=11.6,2.4Hz,2H),2.42(s,3H),2.27(d,J=7.2Hz,2H),1.59(d,J=12.9Hz,2H),1.30-1.16(m,5H).
13C NMR(101MHz,DMSO)δ170.40,162.21,148.48,141.66,139.93,134.28,129.72,126.90,126.52,122.06,121.72,119.60,117.46,110.29,66.85,43.63,40.15,39.94,39.73,39.52,39.31,39.10,38.89,32.37,32.09,20.97.
实施例30
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-苯基乙酰胺的合成:
以苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(s,1H),7.86(d,J=7.8Hz,1H),7.77(d,J=7.8Hz,1H),7.67(d,J=8.2Hz,1H),7.60(s,1H),7.59-7.59(m,1H),7.54(t,J=7.9Hz,1H),7.40-7.32(m,4H),7.25(d,J=8.2Hz,2H),3.70(s,2H),2.45(s,3H).
13C NMR(101MHz,DMSO)δ169.52,162.19,148.44,141.66,139.97,135.76,134.29,129.81,129.13,128.33,126.94,126.60,126.54,122.08,121.87,119.62,117.50,110.29,43.38,39.52,20.98.
实施例31
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺的合成:
以2-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.87(d,J=7.8Hz,1H),7.74(d,J=8.0Hz,2H),7.66(t,J=7.5Hz,2H),7.60-7.56(m,2H),7.55-7.49(m,2H),7.24(d,J=8.3Hz,1H),3.99(s,2H),2.44(s,3H).
13C NMR(151MHz,DMSO)δ168.45,162.19,148.44,141.66,139.90,134.31,133.67,133.51,132.26,129.86,127.69,127.50,127.39,127.00,126.56,125.66,125.62,122.05,121.89,119.62,117.50,110.30,39.94,39.80,39.66,39.52,39.38,39.24,39.10,20.99.
实施例32
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(3-甲氧基苯基)乙酰胺的合成:
以3-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(t,J=1.7Hz,1H),7.88-7.85(m,1H),7.79-7.76(m,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.25(dd,J=13.5,5.3Hz,2H),6.95(t,J=4.1Hz,2H),6.86-6.82(m,1H),3.76(s,3H),3.67(s,2H),2.45(s,3H).
13C NMR(101MHz,DMSO)δ169.37,162.18,159.23,148.43,141.65,139.95,137.15,134.28,129.79,129.33,126.93,126.53,122.09,121.87,121.32,119.60,117.51,114.95,111.98,110.28,54.97,43.41,40.15,39.94,39.73,39.52,39.31,39.10,38.89,20.96.
实施例33
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(4-(叔丁基)苯基)乙酰胺的合成:
以4-叔丁基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(s,1H),7.86(d,J=7.9Hz,1H),7.77(d,J=9.3Hz,1H),7.67(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.37(d,J=8.3Hz,2H),7.27(dd,J=16.1,8.4Hz,3H),3.64(s,2H),2.45(s,3H),1.28(s,9H).
13C NMR(101MHz,DMSO)δ169.70,162.20,148.93,148.44,141.66,140.01,134.30,132.73,129.80,128.76,126.93,126.55,125.09,122.05,121.83,119.62,117.48,110.30,42.95,39.52,34.12,31.14,20.99.
实施例34
N-(3-(5-甲基苯并[d]恶唑-2-基)-2-(苯并[d][1,3]二氧杂环戊烯-5-基)-苯基)乙酰胺的合成:
以3,4-(亚甲基二氧)苯乙酸为原料,合成方法参见实施例。
1H NMR(600MHz,DMSO)δ8.54(s,1H),7.83(d,J=7.8Hz,1H),7.73(d,J=9.0Hz,1H),7.63(d,J=8.3Hz,1H),7.57(s,1H),7.50(t,J=7.9Hz,1H),7.22(d,J=8.3Hz,1H),6.91(s,1H),6.84(d,J=7.9Hz,1H),6.79(d,J=7.9Hz,1H),5.96(s,2H),3.56(s,2H),2.42(s,3H).
13C NMR(151MHz,DMSO)δ169.65,162.20,148.44,147.17,145.98,141.66,139.97,134.31,129.82,129.33,126.94,126.56,122.17,122.10,121.87,119.62,117.53,110.31,109.57,108.11,100.82,42.95,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例35
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲基)苯基)乙酰胺的合成:
以4-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(t,J=1.8Hz,1H),7.89-7.86(m,1H),7.76(ddd,J=8.2,2.1,1.0Hz,1H),7.72(d,J=8.1Hz,2H),7.66(d,J=8.3Hz,1H),7.62-7.58(m,3H),7.55(t,J=8.0Hz,1H),7.25(dd,J=8.3,1.1Hz,1H),3.84(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ168.80,162.15,148.43,141.65,140.54,139.81,134.30,130.10,129.84,127.49,127.28,126.97,126.55,125.14,122.11,121.99,119.62,117.55,110.29,42.91,39.94,39.80,39.66,39.52,39.38,39.24,39.10,20.98.
实施例36
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(3-氯苯基)乙酰胺的合成:
以3-氯苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(s,1H),7.87(d,J=7.8Hz,1H),7.78-7.74(m,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.45(s,1H),7.38(dd,J=9.4,5.7Hz,1H),7.36-7.32(m,2H),7.25(d,J=7.5Hz,1H),3.74(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ168.97,162.17,148.44,141.65,139.85,138.11,134.32,132.84,130.15,129.86,129.13,127.98,126.97,126.63,126.58,122.12,121.98,119.63,117.54,110.32,42.69,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例37
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲氧基)苯基)乙酰胺的合成:
以4-三氟甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.60(t,J=1.8Hz,1H),7.89-7.85(m,1H),7.76(ddd,J=8.1,2.0,0.9Hz,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.51-7.48(m,2H),7.35(d,J=7.9Hz,2H),7.25(dd,J=8.3,1.1Hz,1H),3.76(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ169.16,162.18,148.45,147.18,141.66,139.87,135.25,134.34,131.10,129.86,126.98,126.59,122.13,121.98,120.94,119.63,117.55,110.32,42.40,40.06,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00.
实施例38
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(4-丁氧基苯基)乙酰胺的合成:
以4-丁氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.54(s,1H),7.82(d,J=7.8Hz,1H),7.73(d,J=8.2Hz,1H),7.62(d,J=8.3Hz,1H),7.56(s,1H),7.50(t,J=7.9Hz,1H),7.22(t,J=9.9Hz,3H),6.86(d,J=8.6Hz,2H),3.91(t,J=6.5Hz,2H),3.57(s,2H),2.41(s,3H),1.67-1.62(m,2H),1.43-1.36(m,2H),0.89(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ169.89,162.19,157.50,148.43,141.65,140.02,134.30,130.09,129.79,127.50,126.92,126.54,122.06,121.81,119.61,117.48,114.31,110.30,67.06,42.52,39.52,30.75,20.99,18.73,13.68.
实施例39
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(间甲苯基)乙酰胺的合成:
以3-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(t,J=1.7Hz,1H),7.88-7.85(m,1H),7.77(ddd,J=8.1,2.0,0.9Hz,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.54(t,J=8.0Hz,1H),7.28(dd,J=4.8,3.9Hz,1H),7.25(dd,J=8.3,1.1Hz,1H),7.21-7.15(m,3H),3.74(s,2H),2.45(s,3H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.50,162.22,148.45,141.67,140.00,136.70,134.43,134.32,130.01,129.92,129.82,126.96,126.77,126.56,125.79,122.12,121.86,119.62,117.54,110.30,41.01,39.94,39.80,39.66,39.52,39.38,39.24,39.10,21.00,19.41.
实施例40
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(3-溴苯基)乙酰胺的合成:
以3-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.59(t,J=1.7Hz,1H),7.89-7.86(m,1H),7.78-7.74(m,1H),7.67(d,J=8.3Hz,1H),7.61-7.59(m,2H),7.54(t,J=8.0Hz,1H),7.50-7.46(m,1H),7.38(d,J=7.7Hz,1H),7.32(t,J=7.7Hz,1H),7.25(dd,J=8.3,1.1Hz,1H),3.73(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ168.95,162.14,148.42,141.64,139.83,138.38,134.28,131.98,130.42,129.82,129.49,128.34,126.96,126.54,122.08,121.95,121.46,119.60,117.51,110.28,42.63,39.94,39.80,39.66,39.52,39.38,39.24,39.10,20.98.
实施例41
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(2-甲氧基苯基)乙酰胺的合成:
以2-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.86(d,J=7.8Hz,1H),7.76(d,J=8.2Hz,1H),7.66(d,J=8.3Hz,1H),7.60(s,1H),7.53(t,J=7.9Hz,1H),7.29-7.23(m,3H),7.00(d,J=8.0Hz,1H),6.93(t,J=7.4Hz,1H),3.78(s,3H),3.69(s,2H),2.45(s,3H).
13C NMR(151MHz,DMSO)δ169.53,162.24,157.26,148.42,141.66,140.14,134.27,130.86,129.74,128.09,126.92,126.51,123.95,121.99,121.66,120.15,119.59,117.42,110.68,110.27,55.43,39.94,39.80,39.66,39.52,39.38,39.24,39.10,37.77,20.98.
实施例42
N-(3-(5-甲基苯并[d]恶唑-2-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺的合成:
以3-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.60(s,1H),7.87(d,J=7.8Hz,1H),7.78-7.73(m,2H),7.69-7.64(m,3H),7.61(d,J=7.0Hz,2H),7.55(t,J=8.0Hz,1H),7.25(d,J=8.4Hz,1H),3.85(s,2H),2.45(s,3H).
13C NMR(101MHz,DMSO)δ168.91,162.14,148.43,141.64,139.81,137.03,134.28,133.46,129.81,129.29,129.12,128.81,126.96,126.53,125.84,123.35,122.10,121.96,119.59,117.53,110.27,42.61,39.52,20.95.
实施例000
3-(5-氯苯并[d]恶唑-2-基)苯胺的合成:
将邻氨基对氯苯酚(1.44g),间氨基苯甲酸(1.37g),10mL多聚磷酸(PPA)加入到50mL圆底烧瓶中,185℃加热,回流6h,反应结束后,冷却至室温,用冷的6N的NaOH中和,过滤沉淀,烘干。用乙酸乙酯溶解沉淀,多次过滤,收集滤液,旋干。对该产物用石油醚∶乙酸乙酯(PE∶EA)=4∶1过柱,得到红色固体即为产物。
实施例43
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(2-溴苯基)乙酰胺的合成:
以2-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.66(t,J=1.7Hz,1H),7.93(d,J=1.9Hz,1H),7.90-7.88(m,1H),7.85(d,J=8.7Hz,1H),7.77(ddd,J=8.2,2.1,0.9Hz,1H),7.64(dd,J=8.0,1.1Hz,1H),7.57(dd,J=10.3,5.6Hz,1H),7.50-7.45(m,2H),7.39(td,J=7.5,1.2Hz,1H),7.25(td,J=7.8,1.8Hz,1H),3.92(s,2H).
13C NMR(151MHz,DMSO)δ168.32,163.64,149.02,142.74,140.01,135.46,132.28,132.25,129.92,129.06,128.85,127.61,126.40,125.55,124.58,122.50,122.09,119.51,117.69,112.29,43.27,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例44
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(对甲硫基苯基)乙酰胺的合成:
以4-甲硫基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.54(s,1H),7.85(d,J=1.7Hz,1H),7.78(dd,J=13.1,8.3Hz,2H),7.71(d,J=8.0Hz,1H),7.48(t,J=7.9Hz,1H),7.41(dd,J=8.7,1.8Hz,1H),7.25(d,J=8.1Hz,2H),7.18(d,J=8.2Hz,2H),3.59(s,2H),2.39(s,3H).
13C NMR(101MHz,DMSO)δ169.53,163.64,149.03,142.74,140.01,136.21,132.40,129.90,129.73,129.08,126.37,126.17,125.56,122.57,122.13,119.53,117.74,112.30,42.75,40.15,39.94,39.73,39.52,39.31,39.10,38.89,14.93.
实施例45
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(对甲苯基)乙酰胺的合成:
以4-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.59(s,1H),7.90(d,J=2.1Hz,1H),7.83(dd,J=14.8,8.2Hz,2H),7.75(d,J=8.2Hz,1H),7.53(t,J=7.9Hz,1H),7.46(dd,J=8.6,2.1Hz,1H),7.22(d,J=7.9Hz,2H),7.12(d,J=7.8Hz,2H),3.61(s,2H),2.26(s,3H).
13C NMR(151MHz,DMSO)δ169.69,163.61,149.05,142.76,140.07,135.66,132.66,129.94,129.10,128.98,128.91,126.38,125.60,122.60,122.13,119.56,117.74,112.35,43.00,39.94,39.80,39.66,39.52,39.38,39.24,39.10,20.67.
实施例46
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(邻甲苯基)乙酰胺的合成:
以2-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(t,J=1.8Hz,1H),7.92(d,J=1.9Hz,1H),7.89-7.86(m,1H),7.84(d,J=8.7Hz,1H),7.78(ddd,J=8.2,2.1,1.0Hz,1H),7.56(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.28(dd,J=4.8,3.9Hz,1H),7.20-7.15(m,3H),3.74(s,2H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.49,163.64,149.01,142.73,140.03,136.66,134.38,129.97,129.88,129.06,126.74,126.37,125.76,125.54,122.55,122.07,119.50,117.72,112.27,40.97,40.06,39.94,39.80,39.66,39.52,39.38,39.24,39.10,19.38.
实施例47
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(4-甲氧基苯基)乙酰胺的合成:
以4-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.58(s,1H),7.89(d,J=2.1Hz,1H),7.82(dd,J=15.7,8.2Hz,2H),7.74(dd,J=8.2,1.1Hz,1H),7.52(t,J=7.9Hz,1H),7.45(dd,J=8.7,2.1Hz,1H),7.25(d,J=8.6Hz,2H),6.89-6.86(m,2H),3.70(s,3H),3.58(s,2H).
13C NMR(151MHz,DMSO)δ169.92,163.65,158.08,149.03,142.74,140.07,130.11,129.90,129.07,127.61,126.36,125.57,122.55,122.07,119.53,117.71,113.77,112.31,55.03,42.49,39.52.
实施例48
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(2-氯苯基)乙酰胺的合成:
以2-氯苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.92(d,J=2.0Hz,1H),7.89(d,J=7.9Hz,1H),7.84(d,J=8.7Hz,1H),7.78-7.75(m,1H),7.57(t,J=8.0Hz,1H),7.47(ddd,J=8.0,5.2,2.5Hz,3H),7.35-7.32(m,2H),3.90(s,2H).
13C NMR(151MHz,DMSO)δ168.37,163.64,149.02,142.73,139.99,133.69,132.22,129.91,129.06,128.99,128.65,127.06,126.40,125.55,122.50,122.11,119.51,117.70,112.28,40.83,40.06,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例49
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(四氢-2H-吡喃-4-基)乙酰胺的合成:
以四氢吡喃4-乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.66(s,1H),7.93(d,J=2.0Hz,1H),7.88-7.84(m,2H),7.78(d,J=8.9Hz,1H),7.54(t,J=8.0Hz,1H),7.49(dd,J=8.7,2.1Hz,1H),3.84(dd,J=11.3,2.6Hz,2H),2.51(d,J=1.5Hz,2H),2.32(d,J=7.1Hz,2H),2.03(ddd,J=17.3,8.6,5.0Hz,1H),1.62(d,J=11.4Hz,2H),1.28(ddd,J=24.8,12.2,4.3Hz,2H).
13C NMR(151MHz,DMSO)δ170.52,163.72,149.02,142.76,140.08,129.76,129.05,126.29,125.53,122.57,121.94,119.51,117.66,112.30,66.87,43.58,39.52,32.37,32.13.
实施例50
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-苯基乙酰胺的合成:
以苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(t,J=1.7Hz,1H),7.92(d,J=2.0Hz,1H),7.87(dd,J=7.9,1.2Hz,1H),7.84(d,J=8.7Hz,1H),7.80-7.77(m,1H),7.56(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.36(qd,J=6.3,2.0Hz,4H),7.29-7.25(m,1H),3.70(s,2H).
13C NMR(151MHz,DMSO)δ169.54,163.63,149.01,142.73,140.01,135.71,129.89,129.11,129.06,128.32,126.60,126.36,125.54,122.55,122.11,119.51,117.71,112.29,43.36,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例51
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺的合成:
以2-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(t,J=1.7Hz,1H),7.92(d,J=2.0Hz,1H),7.89(dd,J=6.6,1.3Hz,1H),7.84(d,J=8.7Hz,1H),7.76-7.72(m,2H),7.68(t,J=7.5Hz,1H),7.57(dd,J=7.7,3.6Hz,2H),7.55-7.51(m,1H),7.48(dd,J=8.7,2.1Hz,1H),3.99(s,2H).
13C NMR(151MHz,DMSO)δ168.47,163.63,149.03,142.74,139.94,133.62,133.49,132.24,129.94,129.06,127.47,127.38,126.42,125.64,125.60,125.56,125.41,122.51,122.13,119.52,117.70,112.30,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例52
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(3-甲氧基苯基)乙酰胺的合成:
以3-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.7Hz,1H),7.92(d,J=2.0Hz,1H),7.89-7.86(m,1H),7.84(d,J=8.7Hz,1H),7.80-7.77(m,1H),7.55(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.26(t,J=8.1Hz,1H),6.95(t,J=4.1Hz,2H),6.86-6.82(m,1H),3.76(s,3H),3.66(s,2H).
13C NMR(101MHz,DMSO)δ169.40,163.64,159.22,149.02,142.74,140.01,137.12,129.90,129.33,129.07,126.37,125.55,122.57,122.12,121.31,119.52,117.73,114.94,112.29,111.98,54.97,43.40,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例53
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(4-(叔丁基)苯基)乙酰胺的合成:
以4-叔丁基苯乙酸为原料,合成方法参见实施例1。
1H NMR(600MHz,DMSO)δ8.59(s,1H),7.89(d,J=2.0Hz,1H),7.84(d,J=7.8Hz,1H),7.81(d,J=8.7Hz,1H),7.75(dd,J=8.2,1.0Hz,1H),7.52(t,J=8.0Hz,1H),7.45(dd,J=8.7,2.1Hz,1H),7.33(d,J=8.3Hz,2H),7.26(d,J=8.2Hz,2H),3.61(s,2H),1.24(s,9H).
13C NMR(151MHz,DMSO)δ169.72,163.64,149.01,148.93,142.74,140.05,132.68,129.88,129.07,128.75,126.35,125.55,125.08,122.53,122.08,119.52,117.70,112.29,42.94,39.52,34.12,31.14.
实施例54
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺的合成:
以3,4-(亚甲基二氧)苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.93(d,J=2.0Hz,1H),7.86(dd,J=10.7,8.4Hz,2H),7.78(dd,J=8.2,1.1Hz,1H),7.55(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),6.94(d,J=1.4Hz,1H),6.88(d,J=7.9Hz,1H),6.82(dd,J=8.0,1.5Hz,1H),5.99(s,2H),3.60(s,2H).
13C NMR(101MHz,DMSO)δ169.69,163.66,149.04,147.17,145.99,142.75,140.04,129.91,129.31,129.08,126.38,125.58,122.57,122.17,122.12,119.54,117.74,112.32,109.57,108.11,100.82,42.94,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例55
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲基)苯基)乙酰胺的合成:
以4-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(t,J=1.7Hz,1H),7.93(d,J=2.0Hz,1H),7.90-7.87(m,1H),7.84(d,J=8.7Hz,1H),7.78(dd,J=8.2,1.1Hz,1H),7.72(d,J=8.1Hz,2H),7.60(d,J=8.9Hz,2H),7.56(d,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),3.84(s,2H).
13C NMR(151MHz,DMSO)δ168.83,163.60,149.02,142.73,140.51,139.87,130.10,129.93,129.08,127.50,126.40,125.57,125.14,125.11,122.59,122.25,119.53,117.76,112.29,42.90,39.52.
实施例56
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(3-(三氟甲氧基)苯基)乙酰胺的合成:
以3-三氟甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.63(t,J=1.8Hz,1H),7.92(d,J=1.9Hz,1H),7.90-7.87(m,1H),7.84(d,J=8.7Hz,1H),7.77(ddd,J=8.2,2.1,0.9Hz,1H),7.56(t,J=8.0Hz,1H),7.50(dd,J=4.9,4.2Hz,1H),7.47(d,J=2.1Hz,1H),7.39(dd,J=6.8,5.7Hz,2H),7.30-7.26(m,1H),3.80(s,2H).
13C NMR(101MHz,DMSO)δ168.89,163.61,149.02,148.29,142.72,139.88,138.30,130.12,129.91,129.06,128.40,126.39,125.55,122.58,122.22,121.70,121.35,119.51,119.09,117.74,112.28,42.60,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例57
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(4-(三氟甲氧基)苯基)乙酰胺的合成:
以4-三氟甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.68(s,1H),7.93(d,J=2.0Hz,1H),7.89-7.83(m,3H),7.54(dd,J=15.1,8.3Hz,3H),7.48(dd,J=8.7,2.1Hz,1H),7.34(d,J=7.9Hz,2H),3.81(s,2H).
13C NMR(101MHz,DMSO)δ169.27,163.67,149.01,147.12,142.74,140.07,135.38,131.07,129.79,129.04,126.32,125.53,122.64,122.13,121.35,120.83,119.50,117.73,112.28,42.28,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例58
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(4-丁氧基苯基)乙酰胺的合成:
以4-丁氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.7Hz,1H),7.93(d,J=2.1Hz,1H),7.86(t,J=8.8Hz,2H),7.77(dd,J=8.2,1.1Hz,1H),7.55(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.26(d,J=8.6Hz,2H),6.89(d,J=8.7Hz,2H),3.94(t,J=6.5Hz,2H),3.60(s,2H),1.71-1.64(m,2H),1.42(dd,J=15.0,7.4Hz,2H),0.92(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ169.94,163.66,157.51,149.03,142.75,140.08,130.09,129.91,129.08,127.47,126.36,125.58,122.55,122.08,119.54,117.71,114.31,112.32,67.07,42.51,39.94,39.80,39.66,39.52,39.38,39.24,39.10,30.75,18.73,13.68.
实施例59
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(3-氯苯基)乙酰胺的合成:
以3-氯苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(t,J=1.6Hz,1H),7.92(d,J=2.0Hz,1H),7.88(d,J=7.9Hz,1H),7.84(d,J=8.7Hz,1H),7.77(dd,J=8.2,1.1Hz,1H),7.56(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.45(s,1H),7.38(dd,J=9.6,5.4Hz,1H),7.35-7.32(m,2H),3.74(s,2H).
13C NMR(101MHz,DMSO)δ168.96,163.60,149.02,142.72,139.88,138.06,132.81,130.10,129.90,129.10,129.06,127.94,126.59,126.38,125.55,122.57,122.20,119.51,117.75,112.28,42.64,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例60
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(间甲苯基)乙酰胺的合成:
以3-甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(s,1H),7.92(d,J=2.0Hz,1H),7.88(d,J=7.8Hz,1H),7.84(d,J=8.7Hz,1H),7.78(d,J=8.2Hz,1H),7.56(t,J=8.0Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.30-7.26(m,1H),7.17(dt,J=6.6,4.7Hz,3H),3.74(s,2H),2.33(s,3H).
13C NMR(151MHz,DMSO)δ169.50,163.65,149.02,142.74,140.05,136.67,134.39,129.98,129.89,129.06,126.74,126.37,125.77,125.55,122.56,122.08,119.51,117.73,112.29,40.97,39.94,39.80,39.66,39.52,39.38,39.24,39.10,19.39.
实施例61
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(3-溴苯基)乙酰胺的合成:
以3-溴苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.93(d,J=1.7Hz,1H),7.88(d,J=7.7Hz,1H),7.84(d,J=8.7Hz,1H),7.77(d,J=7.6Hz,1H),7.60-7.54(m,2H),7.50-7.46(m,2H),7.37(d,J=7.6Hz,1H),7.32(t,J=7.7Hz,1H),3.73(s,2H).
13C NMR(151MHz,DMSO)δ168.99,163.60,149.02,142.72,139.89,138.35,131.99,130.43,129.92,129.50,129.07,128.34,126.39,125.56,122.56,122.21,121.46,119.52,117.73,112.30,42.62,39.94,39.80,39.66,39.52,39.38,39.24,39.10.
实施例62
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(2-甲氧基苯基)乙酰胺的合成:
以2-甲氧基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.92(d,J=1.9Hz,1H),7.85(dd,J=12.5,8.2Hz,2H),7.78(d,J=8.1Hz,1H),7.55(t,J=7.9Hz,1H),7.48(dd,J=8.7,1.9Hz,1H),7.27(t,J=7.5Hz,2H),7.00(d,J=8.1Hz,1H),6.93(t,J=7.4Hz,1H),3.79(s,3H),3.69(s,2H).
13C NMR(101MHz,DMSO)δ169.61,163.72,157.27,149.04,142.77,140.23,130.88,129.88,129.07,128.13,126.37,125.56,123.93,122.49,121.94,120.17,119.53,117.64,112.31,110.70,55.44,40.15,39.94,39.73,39.52,39.31,39.10,38.89,37.78.
实施例63
N-(3-(5-氯苯并[d]恶唑-2-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺的合成:
以3-三氟甲基苯乙酸为原料,合成方法参见实施例1。
1H NMR(400MHz,DMSO)δ8.64(s,1H),7.92(d,J=2.0Hz,1H),7.88(d,J=7.8Hz,1H),7.84(d,J=8.7Hz,1H),7.78(dd,J=8.2,1.1Hz,1H),7.75(s,1H),7.68(d,J=7.5Hz,1H),7.64(s,1H),7.61(d,J=7.5Hz,1H),7.57(t,J=7.9Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),3.86(s,2H).
13C NMR(101MHz,DMSO)δ168.95,163.61,149.02,142.72,139.87,137.00,133.46,129.91,129.29,129.06,126.40,125.89,125.85,125.55,123.40,123.36,122.58,122.22,119.51,117.75,112.28,42.60,39.52.
实施例64
式I化合物作为P2Y14受体抑制剂的抑制活性评价实验方法:
稳转P2Y14受体的HEK293细胞株培养于DMEM培养基中(含10%胎牛血清、100U/ml青霉素和100μg/ml链霉素),实验前接种至培养板,改用无血清培养基,接种密度为1×105个细胞/孔,细胞于37℃、95%O2、5%CO2湿度条件下培养。加入IBMX抑制PDEs活性,以保证cAMP在一个较高的水平上。采用AC激动剂Forskolin(30μM)刺激细胞cAMP的产生,预先加入不同浓度的受试化合物(0.01、0.1、1、10、100nm),以PPTN作为阳性对照。随后加入1μM的P2Y14受体激动剂UDPG,4h后cAMP GloTM Assay试剂盒(PROMEGA Co.Ltd,美国)检测细胞内cAMP的含量。根据对cAMP含量的抑制率计算IC50值,结果见表1,表1为本发明实施例1~63得到的部分化合物对cAMP的抑制率及IC50。
表1
从以上结果可以看出,大部分化合物显示出较好的P2Y14抑制活性,尤其是当苯并恶唑环上R基为对位Cl原子取代时,化合物的P2Y14抑制活性较好,如化合物55,57,58等,其中化合物55的抑制活性为4.1nM;而苯并恶唑环上为甲基取代的化合物,普遍表现出较差的P2Y14抑制活性,如化合物23,27,28等。
实施例65化合物对急性痛风关节炎大鼠踝关节肿胀度的影响(单位:cm)
为了进一步研究评价化合物对急性痛风性关节炎的治疗效果,选取了降尿酸活性筛选中活性较好的化合物I55和I5进行急性痛风关节炎大鼠踝关节肿胀度的影响活性实验。
选用雄性清洁级SD大鼠,体重200±20g,自由水食,每天12h照明,环境温度为25±2℃。采用一次性关节腔注射MSU诱导痛风性关节炎模型,正常对照组采用等量的生理盐水注射入关节腔,造模动物分为4组,每组8只,模型对照组(MSU 0.2mL+生理盐水)、化合物I9和I23低剂量组(MSU 0.2mL+化合物10mg/kg)、中剂量组(MSU 0.2mL+化合物20mg/kg)、高剂量组(MSU 0.2mL+先导化合物40mg/kg)、阳性药对照组(MSU 0.2mL+地塞米松5mg/kg)给药5天,观察造模前及治疗期各组受试大鼠步态及关节容积的变化,检测关节炎症指数,结果见表2。
组别 | 2h | 4h | 8h | 12h | 24h | 48h |
正常对照组 | 4.2±0.7 | 4.6±1.0 | 4.1±0.8 | 2.5±0.6 | 1.9±0.6 | 1.1±0.3 |
模型对照组 | 7.5±1.6<sup>###</sup> | 8.8±1.7<sup>###</sup> | 7.8±1.6<sup>###</sup> | 6.6±1.5<sup>###</sup> | 5.6±1.8<sup>###</sup> | 3.4±0.5<sup>###</sup> |
I5高剂量组 | 4.5±1.1*** | 4.0±1.6*** | 3.2±1.5*** | 2.9±1.2*** | 2.0±0.8*** | 1.6±0.6*** |
I5中剂量组 | 6.5±1.5* | 6.1±1.9** | 5.8±1.5** | 4.7±1.4** | 3.9±1.9** | 2.8±0.5** |
I55高剂量组 | 3.9±0.7* | 3.7±0.8* | 3.3±1.5** | 2.7±1.2** | 1.6±0.7*** | 1.4±0.8*** |
I55中剂量组 | 5.2±0.8* | 4.5±0.6** | 3.5±1.1** | 2.9±1.1** | 2.8±0.8** | 2.6±0.8** |
地塞米松组 | 4.9±1.4*** | 4.3±0.8*** | 4.0±0.9*** | 3.5±0.9*** | 2.8±0.7*** | 2.0±0.7** |
注:###P<0.001与正常对照组比较;*P<0.05,**P<0.01,***P<0.001与模型对照组比较
如表2所示,MSU注射之后,大鼠踝关节肿胀度显著增加,在2~24h达到高峰,化合物I5和I55的干预可以使肿胀度出现不同程度下降,其中中高剂量的化合物对于肿胀度的降低作用均达到了显著性差异,表明本发明受试化合物具有很好的治疗急性痛风性关节炎作用。
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。
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