CN113264928B - 一种二氢吡唑噻唑类衍生物及其制备方法和用途 - Google Patents
一种二氢吡唑噻唑类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种二氢吡唑噻唑类衍生物及其制备方法和用途,其中二氢吡唑噻唑类衍生物具有如下通式:其中,R1选自4‑Br、4‑F、4‑CH3、3‑CH3、2‑CH3或3,4,5‑3OCH3;R2选自OCH3、CH3、F或Br。本发明二氢吡唑噻唑类衍生物对LPS诱导炎症的RAW264.7细胞具有良好的抗炎活性。
Description
技术领域
本发明涉及一种二氢吡唑噻唑类衍生物,具体涉及一种二氢吡唑噻唑类衍生物及其制备方法和用途。本发明二氢吡唑噻唑类衍生物对LPS诱导炎症的RAW264.7细胞具有良好的抗炎活性。
背景技术
二氢吡唑是一种极为重要的含氮的五元杂环化合物,是在许多药物活性化合物中发现的重要结构基序,它具有多种重要的生物学活性例如抗癌、抗真菌、抗病毒、抗结核、抗炎等活性。自然界中,天然存在的生物活性类黄酮和异黄酮以及适当取代的α,β-不饱和酮可作为获得二氢吡唑的理想来源。因为二氢吡唑多为手性环,这一特点非常重要,将会导致环上的取代及分子的构象具有更丰富的多变性,具有更好的生物活性潜质。
噻唑核是许多生物活性化合物中非常重要的杂环,使其成为广泛研究的杂环之一。噻唑在许多药物结构中起着至关重要的作用,例如抗肿瘤、抗病毒、抗真菌、抗寄生虫、抗炎、抗溃疡以及杀虫作用。许多报道都已宣布噻唑核心结构在药物设计和新型治疗剂开发中的应用。噻唑环作为多种五元杂环的一部分,在先导化合物的识别和优化中已发挥了各种作用,包括作为药效团和生物等位线元素以及作为间隔基。同样,噻唑环作为药物结构的一部分的存在可以影响其物理化学和药代动力学性质。
本发明采用“组合药效团”的设计策略,将活性药效团—噻唑环引入到具有良好活性的3,5-二芳基-4,5-二氢吡唑骨架上,筛选并合成高效低毒的新型结构作为抗炎药物的候选化合物。
发明内容
本发明的目的在于提供一种二氢吡唑噻唑类衍生物及其制备方法和用途。本发明二氢吡唑噻唑类化合物对LPS诱导炎症的RAW264.7细胞具有良好的抗炎活性。
所述RAW264.7细胞是小鼠单核巨噬细胞,常常用于细胞炎症实验,用以检测化合物的抗炎活性。
本发明二氢吡唑噻唑类衍生物,具有如下结构通式:
其中,R1选自4-Br、4-F、4-CH3、3-CH3、2-CH3或3,4,5-OCH3;R2选自OCH3、CH3、F或Br。
进一步地,所述二氢吡唑噻唑类衍生物的结构式优选如下:
本发明二氢吡唑噻唑类衍生物的制备方法,包括如下步骤:
步骤1:将苯甲醛衍生物A(10mmol)溶于40mL无水乙醇中,然后缓慢滴加5mL浓度为10%的NaOH溶液,再加入苯乙酮衍生物B(10mmol),常温下搅拌反应,并用TLC监测反应进度,反应约3h后,产物以固体的形式析出;反应完成后,静置,抽滤,用乙醇重结晶,获得查尔酮衍生物C;
所述苯甲醛衍生物A的结构式为:
所述苯乙酮衍生物B的结构式为:
所述查尔酮衍生物C的结构式为:
其中,R1选自4-Br、4-F、4-CH3、3-CH3、2-CH3或3,4,5-OCH3;R2选自OCH3、CH3、F或Br。
步骤2:取干燥后的查尔酮衍生物C(10mmol)溶于40mL的乙醇中,若溶解性不好也可加入3-4mL的N,N-二甲基甲酰胺(DMF)助溶,然后再加入12mmol的氨基硫脲和1g左右的KOH固体,加热到75℃回流,TLC监测反应进度,反应12h后,将反应液倒入大约150mL的冰水中,产物自动析出,静置,抽滤并用石油醚和少量的水洗涤,得化合物D——3,5-二芳基-4,5-二氢-1H-吡唑-碳硫酰胺衍生物。
其中,R1选自4-Br、4-F、4-CH3、3-CH3、2-CH3或3,4,5-OCH3;R2选自OCH3、CH3、F或Br。
步骤3:将化合物D(4mmol)溶于30mL乙醇中,若溶解性不好也可加入3-4mL的N,N-二甲基甲酰胺(DMF)助溶,然后再加入6mmol氯丙酮,室温下搅拌4h并用TLC不断检测反应,反应完成后,将反应液真空浓缩,并采用柱层析(乙酸乙酯:石油醚=1:4,v/v)分离纯化得到目标化合物。
步骤1中,苯甲醛衍生物A与苯乙酮衍生物B的物质的量之比为1:1。
步骤2中,每1毫摩尔查尔酮衍生物C加入1.2毫摩尔氨基硫脲。
步骤3中,化合物D和氯丙酮的物质的量比为1:1.5。
本发明二氢吡唑噻唑类衍生物的用途,是在制备抗炎药物中的应用。所述抗炎药物对LPS诱导炎症的RAW264.7细胞具有良好的抗炎活性。
附图说明
图1是化合物1-21(1μM)对LPS诱导的RAW264.7炎症细胞的NO释放的抑制率。
图2是毒性较大的化合物(1μM)以及对照药物对LPS诱导的RAW264.7炎症细胞的NO释放的抑制率。
图3是毒性较小的化合物(10μM)以及对照药物对LPS诱导的RAW264.7炎症细胞的NO释放的抑制率。
具体实施方式
通过以下具体的实施例对本发明技术方案作进一步详细说明,但应注意本发明的范围并不受这些实施例的任何限制。
实施例1:2-(5-(4-溴苯基)-3-(4-氟苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物1)的制备
1、取一个150mL圆底烧瓶,将4-溴苯甲醛A(1.850g,10mmol)溶于40mL无水乙醇,然后缓慢滴加5mL浓度为10%的NaOH,再加入4-氟苯乙酮B(1.381g,10mmol)。常温下搅拌反应约3h,并用TLC监测反应进度,产物以固体的形式析出。反应完成后,静置,抽滤,用乙醇重结晶,得查尔酮衍生物C。
2、取一个150mL圆底烧瓶,将干燥后的查尔酮衍生物C(3.051g,10mmol)溶于40mL的乙醇,然后可加入3-4mL的N,N-二甲基甲酰胺(DMF)助溶,再加入12mmol的氨基硫脲和1g左右的KOH固体,加热到75℃回流,TLC监测反应进度,反应12h后,将反应液倒入大约150mL的冰水中,产物自动析出,静置,抽滤并用石油醚和少量的水洗涤,得到3,5-二芳基-4,5-二氢-1H-吡唑-碳硫酰胺衍生物D。
3、取一个150mL圆底烧瓶中,将化合物D(1.513g,4mmol)溶于30mL乙醇,加入3-4mL的N,N-二甲基甲酰胺(DMF)助溶,然后再加入氯丙酮(555mg,6mmol),室温下搅拌4h并用TLC不断检测反应,反应完成后,将反应液真空浓缩,并采用柱层析(乙酸乙酯:石油醚=1:4,v/v)分离纯化得到目标化合物1。产物1为黄绿色固体,产率为21.5%,熔点132-135℃。1H NMR(400MHz,CDCl3)δ(ppm)7.80–7.68(m,2H),7.53–7.42(m,2H),7.25–7.19(m,2H),7.15–7.08(m,2H),6.20(q,J=1.1Hz,1H),5.63(dd,J=12.0,5.9Hz,1H),3.87(dd,J=17.3,12.0Hz,1H),3.20(dd,J=17.4,5.9Hz,1H),2.19(d,J=1.1Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.81,162.39,150.07,149.44,140.63,131.89,128.30,128.22,127.99,127.66,121.51,115.96,115.74,103.70,63.70,43.50,17.61.HR-MS(ESI):calcd for C19H15BrFN3S,[M+H]+,416.0232;found 416.0231.
实施例2:2-(5-(4-溴苯基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物2)的制备
制备方法同实施例1。以4-甲氧基苯乙酮代替4-氟苯乙酮,得到棕色固体,产率为24.3%,熔点142-147℃。1H NMR(400MHz,CDCl3)δ(ppm)7.76–7.66(m,2H),7.56–7.41(m,2H),7.28–7.23(m,2H),7.01–6.91(m,2H),6.17(t,J=1.1Hz,1H),5.78(s,1H),3.87(s,4H),3.23(dd,J=17.3,5.3Hz,1H),2.27–2.16(m,3H).13C NMR(101MHz,CDCl3)δ(ppm)165.08,160.97,151.08,149.32,140.86,131.83,128.03,127.95,124.02,121.39,114.11,103.37,63.48,55.40,43.64,17.61.HR-MS(ESI):calcd for C20H18BrN3OS,[M+H]+,428.0432;found 428.0429.
实施例3:2-(5-(4-溴苯基)-3-(4-甲基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物3)的制备
制备方法同实施例1。以4-甲基苯乙酮代替4-氟苯乙酮,得到黄绿色固体,产率为26.8%,熔点192-197℃。1H NMR(400MHz,CDCl3)δ(ppm)7.68–7.63(m,2H),7.48–7.44(m,2H),7.26(t,J=7.8Hz,5H),6.18(q,J=1.1Hz,1H),5.80(s,1H),3.91(dd,J=17.4,11.8Hz,1H),3.25(dd,J=17.4,5.3Hz,1H),2.42(s,3H),2.23(s,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.97,151.29,149.35,140.84,140.10,131.83,129.39,128.04,126.33,121.40,103.50,63.50,43.53,21.51,17.61.ESI MS(m/z):412.0479(C20H18BrN3S,[M+H]).HR-MS(ESI):calcd for C20H18BrN3S,[M+H]+,412.0483;found 412.0479.
实施例4:2-(5-(4-溴苯基)-3-(4-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物4)的制备
制备方法同实施例1。以4-溴苯乙酮代替4-氟苯乙酮,得到黄绿色固体,产率为27.5%,熔点165-170℃。1H NMR(400MHz,CDCl3)δ(ppm)7.65–7.55(m,4H),7.50–7.45(m,2H),7.27(d,J=9.1Hz,2H),6.21(d,J=1.2Hz,1H),5.93(s,1H),3.91(dd,J=17.5,11.6Hz,1H),3.25(dd,J=17.4,4.8Hz,1H),2.24(s,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.57,149.95,149.45,140.51,131.89,130.29,127.98,127.74,123.98,121.56,103.86,63.77,43.22,17.59.HR-MS(ESI):calcd for C19H15Br2N3S,[M+H]+,475.9432;found475.9433.
实施例5:2-(5-(4-溴苯基)-3-(3-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物5)的制备
制备方法同实施例1。以3-甲氧基苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为27.4%,熔点164-169℃。1H NMR(400MHz,CDCl3)δ(ppm)7.52–7.44(m,2H),7.39–7.31(m,2H),7.32–7.22(m,6H),7.05–6.90(m,1H),6.20(q,J=1.1Hz,1H),5.86(s,1H),3.89(s,5H),3.26(dd,J=17.4,5.2Hz,1H),2.24(s,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.79,159.74,151.01,149.39,140.71,132.65,131.86,129.71,128.02,119.03,115.82,111.24,103.69,63.64,55.40,43.51,17.60.HR-MS(ESI):calcd for C20H18BrN3OS,[M+H]+,428.0432;found 428.0424.
实施例6:2-(5-(4-溴苯基)-3-(3-甲基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物6)的制备
制备方法同实施例1。以3-甲基苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为30.2%,熔点192-197℃。1H NMR(400MHz,CDCl3)δ(ppm)7.60(s,1H),7.55(d,J=7.6Hz,1H),7.49–7.45(m,2H),7.34(t,J=7.6Hz,1H),7.29(s,4H),7.27(s,1H),6.20(t,J=1.2Hz,1H),5.96(s,1H),3.94(dd,J=17.6,11.7Hz,1H),3.29(dd,J=18.0,4.5Hz,1H),2.42(s,3H),2.26(s,3H).13CNMR(101MHz,CDCl3)δ(ppm)164.87,151.33,149.37,140.77,138.39,131.85,131.22,130.67,128.58,128.01,126.90,123.58,121.43,103.58,63.52,43.52,21.42,17.60.HR-MS(ESI):calcd for C20H18BrN3S,[M+H]+,412.0483;found 412.0521.
实施例7:2-(5-(4-溴苯基)-3-(3-氟苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物7)的制备
制备方法同实施例1。以3-氟苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为28.7%,熔点165-169℃。1H NMR(400MHz,CDCl3)δ(ppm)7.49(m,J=11.2,9.1,2.1Hz,4H),7.40(td,J=7.9,5.6Hz,1H),7.27–7.22(m,2H),7.12(m,J=8.3,2.7,1.0Hz,1H),6.22(q,J=1.1Hz,1H),5.80(s,1H),3.89(dd,J=17.4,12.0Hz,1H),3.23(dd,J=17.4,5.6Hz,1H),2.26–2.16(m,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.57,161.66,149.84,149.44,140.50,133.58,131.92,130.32,127.97,122.07,121.57,116.77,116.55,113.12,112.89,103.95,63.77,43.30,17.58.HR-MS(ESI):calcd for C19H15BrFN3S,[M+H]+,416.0232;found416.0234.
实施例8:2-(5-(4-溴苯基)-3-(3-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物8)的制备
制备方法同实施例1。以3-溴苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为23.5%,熔点169-174℃。1H NMR(400MHz,CDCl3)δ(ppm)7.91(q,J=3.0,2.4Hz,1H),7.65(m,J=8.5,3.8,2.4Hz,1H),7.58–7.51(m,1H),7.47(m,J=8.6,2.5Hz,2H),7.34–7.26(m,2H),7.26–7.20(m,2H),6.23–6.20(m,1H),5.81(s,1H),3.94–3.81(m,1H),3.22(dd,J=17.4,5.4Hz,1H),2.31–2.18(m,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.49,149.44,140.43,133.40,132.53,131.92,130.19,129.14,127.94,124.81,122.89,121.59,103.97,63.75,43.18,17.57.HR-MS(ESI):calcd for C19H15Br2N3S,[M+H]+,475.9432;found 475.9429.
实施例9:2-(5-(4-溴苯基)-3-(2-甲基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物9)的制备
制备方法同实施例1。以2-甲基苯乙酮代替4-氟苯乙酮,得黄色固体,产率为24.3%,熔点143-148℃。1H NMR(400MHz,CDCl3)δ(ppm)7.49–7.45(m,2H),7.33(m,J=10.0,7.0,1.5Hz,3H),7.28–7.21(m,3H),6.20(q,J=1.1Hz,1H),5.65(dd,J=12.1,5.5Hz,1H),3.97(dd,J=17.2,11.9Hz,1H),3.32(dd,J=17.2,5.6Hz,1H),2.72(s,3H),2.20(d,J=1.1Hz,3H).13CNMR(101MHz,CDCl3)δ(ppm)165.27,151.84,149.48,140.83,138.28,131.84,129.91,129.04,128.53,128.02,125.85,121.39,103.67,62.66,45.67,23.71,17.65.HR-MS(ESI):calcd for C20H18BrN3S,[M+H]+,412.0483;found 412.0478.
实施例10:2-(5-(4-溴苯基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物10)的制备
制备方法同实施例1。以2-甲氧基苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为22.6%,熔点123-128℃。1H NMR(400MHz,CDCl3)δ(ppm)8.01(dd,J=7.8,1.8Hz,1H),7.49–7.44(m,2H),7.41–7.35(m,1H),7.27–7.21(m,2H),7.03(td,J=7.6,1.0Hz,1H),6.93(dd,J=8.4,0.9Hz,1H),6.18(t,J=1.0Hz,1H),5.57(dd,J=11.9,5.8Hz,1H),4.03(dd,J=18.3,12.0Hz,1H),3.84(s,3H),3.40(dd,J=18.3,5.9Hz,1H),2.19(d,J=1.0Hz,3H).13CNMR(101MHz,CDCl3)δ(ppm)165.24,157.82,151.31,149.34,141.14,131.73,131.11,129.18,128.09,121.22,120.93,120.55,111.48,103.40,63.68,55.41,46.73,17.64.HR-MS(ESI):calcd for C20H18BrN3OS,[M+H]+,428.0432;found 428.0434.
实施例11:2-(5-(4-溴苯基)-3-(2-氟苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物11)的制备
制备方法同实施例1。以2-氟苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为24.6%,熔点150-155℃。1H NMR(400MHz,CDCl3)δ(ppm)8.05(td,J=7.7,1.8Hz,1H),7.52–7.34(m,3H),7.28–7.21(m,4H),7.12(m,J=11.6,8.3,1.2Hz,1H),6.21(q,J=1.1Hz,1H),5.79(s,1H),4.02(m,J=18.2,11.9,2.7Hz,1H),3.39(m,J=18.1,5.6,3.0Hz,1H),2.23(s,3H).13CNMR(101MHz,CDCl3)δ(ppm)164.76,161.99,159.48,149.43,147.85,140.65,131.85,131.38,128.77,128.00,124.47,121.45,119.50,119.39,116.53,116.31,103.82,63.69,63.66,45.64,17.60.HR-MS(ESI):calcd for C19H15BrFN3S,[M+H]+,416.0232;found416.0203.
实施例12:2-(5-(4-溴苯基)-3-(2-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物12)的制备
制备方法同实施例1。以2-溴苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为27.5%,熔点124-126℃。1H NMR(400MHz,CDCl3)δ(ppm)7.67(m,J=16.8,7.9,1.5Hz,2H),7.50–7.45(m,2H),7.39(td,J=7.6,1.3Hz,1H),7.28–7.23(m,2H),6.24–6.16(m,1H),5.71(s,1H),4.10(dd,J=17.7,11.9Hz,1H),3.44(dd,J=17.7,5.7Hz,1H),2.20(d,J=1.1Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)164.88,151.59,149.38,140.35,134.18,132.57,131.86,130.84,130.61,129.83,128.69,128.06,127.49,126.36,121.60,103.94,64.11,50.88,46.08,17.56.HR-MS(ESI):calcd for C19H15Br2N3S,[M+H]+,475.9432;found475.9437.
实施例13:2-(5-(4-氟苯基)-3-(2-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物13)的制备
制备方法同实施例1。以4-氟苯甲醛代替4-溴苯甲醛,2-溴苯乙酮代替4-氟苯乙酮,得到棕色固体,产率为26.3%,熔点88-93℃。1H NMR(600MHz,CDCl3)δ(ppm)7.69(dd,J=7.8,1.7Hz,1H),7.62(dd,J=8.1,1.2Hz,1H),7.34(td,J=7.6,1.3Hz,1H),7.27–7.19(m,3H),7.14(d,J=7.8Hz,2H),6.16(d,J=1.4Hz,1H),5.63(dd,J=11.9,5.7Hz,1H),4.07(dd,J=17.6,11.9Hz,1H),3.42(dd,J=17.6,5.7Hz,1H),2.32(s,3H),2.18(d,J=1.2Hz,3H).13CNMR(101MHz,CDCl3)δ(ppm)164.93,163.43,160.98,151.57,149.38,137.03,134.17,132.66,130.85,130.56,128.05,127.47,121.60,115.71,115.50,103.86,64.04,50.87,46.21,17.58.HR-MS(ESI):calcd for C19H15BrFN3S,[M+H]+,416.0232;found416.0218.
实施例14:2-(5-(4-氟苯基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物14)的制备
制备方法同实施例1。以4-氟苯甲醛代替4-溴苯甲醛,2-甲氧基苯乙酮代替4-氟苯乙酮,得到深绿色固体,产率为29.6%,熔点99-104℃。1H NMR(600MHz,CDCl3)δ(ppm)7.98(dd,J=7.8,1.8Hz,1H),7.35(m,J=8.4,7.3,1.8Hz,1H),7.32–7.29(m,2H),7.03–6.97(m,3H),6.91(dd,J=8.4,1.1Hz,1H),6.14(q,J=1.1Hz,1H),5.56(dd,J=11.8,5.7Hz,1H),4.00(dd,J=18.2,11.9Hz,1H),3.82(s,3H),3.38(dd,J=18.2,5.8Hz,1H),2.16(d,J=1.1Hz,3H).13CNMR(101MHz,CDCl3)δ(ppm)170.33,168.34,165.91,163.09,156.55,154.24,143.39,136.27,134.06,133.30,125.90,125.72,120.48,120.27,116.84,108.46,108.44,68.81,60.45,51.90,22.44.HR-MS(ESI):calcd for C20H18FN3OS,[M+H]+,368.1233;found368.1238.
实施例15:2-(5-(4-甲基苯基)-3-(2-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物15)的制备
制备方法同实施例1。以4-甲基苯甲醛代替4-溴苯甲醛,2-溴苯乙酮代替4-氟苯乙酮,得到黄绿色固体,产率为25.7%,熔点82-86℃。1H NMR(600MHz,CDCl3)δ(ppm)7.69(dd,J=7.8,1.7Hz,1H),7.62(dd,J=8.1,1.2Hz,1H),7.34(td,J=7.6,1.3Hz,1H),7.27–7.19(m,3H),7.14(d,J=7.8Hz,2H),6.16(d,J=1.4Hz,1H),5.63(dd,J=11.9,5.7Hz,1H),4.07(dd,J=17.6,11.9Hz,1H),3.42(dd,J=17.6,5.7Hz,1H),2.32(s,3H),2.18(d,J=1.2Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)170.11,156.66,154.28,144.47,142.07,139.42,138.00,136.11,135.86,134.36,132.91,131.41,126.16,108.91,69.57,51.28,25.41,21.94.HR-MS(ESI):calcd for C20H18BrN3S,[M+H]+,412.0483;found 412.0470.
实施例16:2-(5-(4-甲基苯基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物16)的制备
制备方法同实施例1。以4-甲基苯甲醛代替4-溴苯甲醛,2-甲氧基苯乙酮代替4-氟苯乙酮,得到淡黄色固体,产率为28.5%,熔点140-143℃。1H NMR(400MHz,CDCl3)δ(ppm)7.98(dd,J=7.8,1.8Hz),7.33(m,J=8.3,7.3,1.8Hz),7.24–7.19(m),7.14–7.08(m),7.02–6.97(m),6.89(dd,J=8.4,1.1Hz),6.11(q,J=1.1Hz),5.53(dd,J=11.9,5.7Hz),3.99(dd,J=18.2,11.9Hz),3.80,3.38(dd,J=18.2,5.8Hz),2.31,2.16(d,J=1.1Hz).13CNMR(101MHz,CDCl3)δ(ppm)165.36,157.84,151.34,149.37,139.12,137.01,130.90,129.31,126.21,120.87,120.86,111.45,103.06,64.03,55.40,46.96,21.16,17.70.HR-MS(ESI):calcd for C21H21N3OS,[M+H]+,364.1484;found 364.1495.
实施例17:2-(5-(3,4,5-三甲氧基苯基)-3-(2-溴苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物17)的制备
制备方法同实施例1。以3,4,5-甲氧基苯甲醛代替4-溴苯甲醛,2-溴苯乙酮代替4-氟苯乙酮,得到淡黄色固体,产率为30.5%,熔点126-131℃。1H NMR(600MHz,CDCl3)δ(ppm)7.64(m,J=14.2,7.9,1.5Hz,2H),7.36(td,J=7.6,1.2Hz,1H),7.24(td,J=7.7,1.7Hz,1H),6.57(s,2H),6.18(q,J=1.0Hz,1H),5.59(dd,J=11.8,5.4Hz,1H),4.02(dd,J=17.7,11.8Hz,1H),3.82(d,J=1.2Hz,9H),3.48(dd,J=17.6,5.4Hz,1H),2.20(d,J=1.2Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)165.13,153.40,151.77,149.46,137.24,136.85,134.15,132.78,130.79,130.56,127.50,121.64,103.87,103.12,64.90,60.82,56.12,46.15,17.67.HR-MS(ESI):calcd for C22H22BrN3O3S,[M+H]+,488.0643;found 488.0644.
实施例18:2-(5-(3,4,5-三甲氧基苯基)-3-(4-氟苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物18)的制备
制备方法同实施例1。以3,4,5-甲氧基苯甲醛代替4-溴苯甲醛,4-氟苯乙酮代替4-氟苯乙酮,得到淡黄色固体,产率为29.6%,熔点187-190℃。1H NMR(600MHz,CDCl3)δ(ppm)7.82–7.59(m,2H),7.14–7.01(m,2H),6.52(s,2H),6.18(t,J=1.2Hz,1H),5.55(dd,J=11.9,6.0Hz,1H),3.81(d,J=5.1Hz,10H),3.24(dd,J=17.3,6.0Hz,1H),2.20(d,J=1.2Hz,3H).13CNMR(101MHz,CDCl3)δ(ppm)165.18,164.88,162.39,153.48,150.43,149.42,137.28,128.34,127.77,115.94,115.72,103.68,103.01,64.58,60.81,56.13,43.74,17.65.HR-MS(ESI):calcd for C22H22FN3O3S,[M+H]+,428.1444;found 428.1464.
实施例19:2-(5-(3-甲基苯基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物19)的制备
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制备方法同实施例1。以3-甲基苯甲醛代替4-溴苯甲醛,2-甲氧基苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为30.5%,熔点98-100℃。1H NMR(600MHz,CDCl3)δ(ppm)8.01(dd,J=7.8,1.8Hz,1H),7.34(m,J=8.9,7.4,1.8Hz,1H),7.20(t,J=7.6Hz,1H),7.16–7.12(m,2H),7.06(d,J=7.5Hz,1H),7.01(td,J=7.6,1.0Hz,1H),6.91(dd,J=8.4,1.0Hz,1H),6.13(d,J=1.2Hz,1H),5.53(dd,J=12.0,5.8Hz,1H),4.01(dd,J=18.2,12.0Hz,1H),3.81(s,3H),3.39(dd,J=18.2,5.9Hz,1H),2.33(s,3H),2.18(d,J=1.1Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)165.39,157.84,151.36,149.39,142.06,138.27,130.93,129.22,128.50,128.19,126.88,123.27,120.87,111.46,103.09,64.20,55.40,47.02,21.53,17.71.HR-MS(ESI):calcd for C21H21N3OS,[M+H]+,364.1484;found 364.1482.
实施例20:2-(5-(2-甲基苯基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物20)的制备
制备方法同实施例1。以2-甲基苯甲醛代替4-溴苯甲醛,2-甲氧基苯乙酮代替4-氟苯乙酮,得到黄色固体,产率为31.6%,熔点110-112℃。1H NMR(600MHz,CDCl3)δ(ppm)8.00(dt,J=7.8,1.5Hz,1H),7.34(m,J=8.6,7.3,1.5Hz,1H),7.21–7.11(m,4H),7.00(m,J=7.5,1.2Hz,1H),6.90(dd,J=8.4,1.2Hz,1H),6.14(t,J=1.2Hz,1H),5.71(m,J=12.1,6.3,1.2Hz,1H),4.04(m,J=18.1,12.1,1.2Hz,1H),3.81(d,J=1.2Hz,3H),3.27(m,J=18.1,6.3,1.2Hz,1H),2.50(s,2H),2.16(t,J=1.2Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)165.24,157.81,151.27,149.43,140.18,134.68,130.93,130.56,129.24,127.16,126.43,125.46,120.88,111.45,103.10,61.61,55.42,45.97,19.68,17.67.HR-MS(ESI):calcdfor C21H21N3OS,[M+H]+,364.1484;found 364.1483.
实施例21:2-(5-(3-甲基苯基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-4-甲基噻唑(化合物21)的制备
制备方法同实施例1。以3-甲基苯甲醛代替4-溴苯甲醛,4-甲氧基苯乙酮代替4-氟苯乙酮,得到淡黄色固体,产率为31.8%,熔点130-132℃。1H NMR(600MHz,CDCl3)δ(ppm)7.70–7.66(m,2H),7.20(t,J=7.5Hz,1H),7.14–7.10(m,2H),7.08–7.04(m,1H),6.94–6.89(m,2H),6.13(q,J=1.0Hz,1H),5.57(dd,J=11.9,5.7Hz,1H),3.84(s,4H),3.21(dd,J=17.2,5.7Hz,1H),2.32(s,3H),2.17(d,J=1.1Hz,3H).13C NMR(101MHz,CDCl3)δ(ppm)165.21,160.85,151.17,149.36,141.78,138.42,128.60,128.35,127.97,126.77,124.28,123.22,114.05,103.04,63.98,55.39,43.91,21.51,17.68.HR-MS(ESI):calcd forC21H21N3OS,[M+H]+,364.1484;found 364.1475.
实施例22:对RAW264.7细胞的培养
我们选取小鼠单核巨噬细胞RAW264.7细胞进行培养。将RAW264.7细胞在含10%的新生小牛血清及100U/mL青霉素、链霉素的DMEM高糖培养液中进行培养,培养箱培养条件设定为5%CO2,37℃,隔天换液,每日观察细胞的生长状况。待RAW264.7细胞生长至70~80%融合度时,弃去旧的细胞培养液,并用PBS洗涤细胞2次,加入0.25%的胰蛋白酶,于倒置显微镜下观察细胞形态变化,当细胞出现胞质回缩,胞体变圆,细胞间隙变大时,弃去消化液,立即加入含10%血清的细胞培养液终止消化,用吸管吸取培养液,反复轻柔吹打贴壁的细胞使之脱落并悬浮,调整细胞至合适密度后接种于新的培养皿中,置于5%CO2,37℃培养箱中培养。
实施例23:二氢吡唑噻唑类衍生物(化合物1-21)对小鼠单核巨噬细胞RAW264.7的抗炎活性评价
我们使用MTT法测定了化合物1-21对于LPS诱导的小鼠单核巨噬细胞RAW264.7的细胞毒性。将处于对数生长期的RAW264.7细胞,种入96孔板,每孔约10000个细胞。在培养箱中培养16h后,加入LPS预处理1小时,随后加入化合物1-21,且每个化合物设置6个复孔。培养24h后,吸出培养基,并加入MTT溶液,继续培养3h。随后加入二甲亚砜,在摇床上震荡10min。最后,利用酶标仪在550nm处,检测溶液吸光度(OD值),并计算各个药物对细胞活性的影响。
根据MTT的结果,筛选出化合物1-21的合适作用浓度。将处于对数生长期的RAW264.7细胞,种入48孔板。在培养箱中培养16h后,加入LPS预处理1小时,随后加入化合物1-28,且每个化合物都设置3个复孔。培养24小时后,吸取培养基上清溶液,移入96孔板中,并依次加入NO检测试剂,反应5min后,使用酶标仪在550nm处检测溶液吸光度(OD值),并根据标准曲线,计算出各孔NO浓度。测得的化合物1-21以及对照药物吲哚美辛和塞来昔布对于RAW264.7的NO释放的抑制率见图1、图2和图3所示。从图1、图2和图3中可以看出,化合物1-21对LPS诱导的RAW264.7炎症细胞的NO释放有着不同程度的抑制效果。在1μM的作用浓度下,化合物2、10、12、15、16、20都有着不错的抑制效果,在10μM的作用浓度下,化合物14、20、21有着很好的抑制效果。综合看来,化合物20不论是在1μM和10μM的作用浓度下都有很好的抑制效果,甚至超过了阳性对照药物,因此在消除炎症的方向上是一种很有前途的潜在化合物。
Claims (1)
1.一种二氢吡唑噻唑类衍生物在制备抗炎药物中的应用,其特征在于:所述二氢吡唑噻唑类化合物选自如下结构的化合物:
所述抗炎药物对LPS诱导炎症的RAW264.7细胞具有良好的抗炎活性。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH10152437A (ja) * | 1996-09-30 | 1998-06-09 | Otsuka Pharmaceut Co Ltd | サイトカイン産生抑制剤及び接着抑制剤 |
CN101759695A (zh) * | 2009-12-30 | 2010-06-30 | 南京大学 | 一类含有吡唑环的噻唑类衍生物及其制法和用途 |
CN103664926A (zh) * | 2013-11-04 | 2014-03-26 | 南京大学 | 一类二氢吡唑噻唑衍生物的合成及在抗癌药物中的应用 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10152437A (ja) * | 1996-09-30 | 1998-06-09 | Otsuka Pharmaceut Co Ltd | サイトカイン産生抑制剤及び接着抑制剤 |
CN101759695A (zh) * | 2009-12-30 | 2010-06-30 | 南京大学 | 一类含有吡唑环的噻唑类衍生物及其制法和用途 |
CN103664926A (zh) * | 2013-11-04 | 2014-03-26 | 南京大学 | 一类二氢吡唑噻唑衍生物的合成及在抗癌药物中的应用 |
WO2015075051A1 (en) * | 2013-11-19 | 2015-05-28 | Universitaet Des Saarlandes | Allosteric inhibitors of atypical protein kinases c |
Non-Patent Citations (2)
Title |
---|
STN检索报告;Columbus, Ohio, US Registry[Online];《STN Registry》;第1-11页 * |
Zhen Zhang,et al..Design, synthesis, and SAR study of novel 4,5-dihydropyrazole- Thiazole derivatives with anti-inflammatory activities for the treatment of sepsis.《European Journal of Medicinal Chemistry》.2021,第225卷第113743页. * |
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