CN116283752A - N-杂芳基-5-氯水杨酰胺类化合物及其制备方法与抗结核菌应用 - Google Patents
N-杂芳基-5-氯水杨酰胺类化合物及其制备方法与抗结核菌应用 Download PDFInfo
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- CN116283752A CN116283752A CN202310311746.3A CN202310311746A CN116283752A CN 116283752 A CN116283752 A CN 116283752A CN 202310311746 A CN202310311746 A CN 202310311746A CN 116283752 A CN116283752 A CN 116283752A
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供了一类通式为(Ⅰ)的N‑杂芳基‑5‑氯水杨酰胺类化合物、其制备方法与应用。所述的N‑杂芳基‑5‑氯水杨酰胺类化合物具有新的抗结核菌药母核结构和优秀的抗结核菌活性,对耐药的变异结核菌株也具有良好的抑制活性。本发明还提供了所述的N‑杂芳基‑5‑氯水杨酰胺类化合物的制备方法,该制备方法的原料廉价易得,无需使用高毒性和高污染试剂,反应步骤简单,可实现工业化生产。
Description
技术领域
本发明属于药物化学领域,特别涉及一类N-杂芳基-5-氯水杨酰胺化合物及其制备方法与抗结核菌应用。
背景技术
结核病是由结核分枝杆菌引起的一种慢性致死性疾病,每年全球有超过1000万人感染结核病且致死人数已超过150万,为全球性致死性顽疾之一。对现有结核病药物库的耐药性上升以及耐药变异菌的出现被认为是现今结核病流行的主要原因,与HIV共同感染的结核病人的出现,大大增加了治疗肺结核的难度。临床上对一线抗结核药物异烟肼、利福平、吡嗪酰胺和链霉素产生耐药的病人比例已经接近15%,而二线药物由于副作用较大,并不适合长期用药。
因此,发现新结构、高选择性、与现有一线药物不产生交叉耐药性的抗结核新药物有着非常迫切的需要。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一类N-杂芳基-5-氯水杨酰胺化合物,所述的N-杂芳基-5-氯水杨酰胺类化合物具有抗结核菌活性。
本发明的第二目的在于提供一种药物组合物,包括所述的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物,以及任选的药学可接受的辅料、载体或赋形剂。
本发明的第三目的在于提供所述的N-杂芳基-5-氯水杨酰胺类化合物的制备方法。
本发明的第四目的在于提供所述的N-杂芳基-5-氯水杨酰胺类化合物在制备预防和/或治疗结核病的药物中的应用。
本发明的第五目的在于提供所述的N-杂芳基-5-氯水杨酰胺类化合物在制备预防和/或治疗分枝杆菌感染,特别是结核分枝杆菌感染,引起的疾病的药物中的应用。
本发明的目的通过下述技术方案实现:
通式(Ⅰ)所示的化合物,或其药学可接受的盐、立体异构体或溶剂化物,
其中,R为无取代、单取代或多取代的吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噻二唑基、苯并噻唑基、喹啉基,取代基可以是氯、三氟甲基、三氟甲氧基;
进一步优选为以下化合物:
5-氯-2-羟基-N-(5-三氟甲基-2-吡啶基)-苯甲酰胺;
5-氯-2-羟基-N-(2-三氟甲基-4-吡啶基)-苯甲酰胺;
5-氯-N-(2,6-二氯-4-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(5,6-二氯-3-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(2,6-二氯-3-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(6-氯-2-吡嗪基)-2-羟基苯甲酰胺;
5-氯-2-羟基-N-(5-三氟甲基-2-吡嗪基)-苯甲酰胺;
5-氯-N-(6-氯-4-嘧啶基)-2-羟基苯甲酰胺;
5-氯-2-羟基-N-(6-三氟甲基-4-嘧啶基)-苯甲酰胺。
一种药物组合物,包括所述的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物,以及任选的药学可接受的辅料、载体或赋形剂。
所述的N-杂芳基-5-氯水杨酰胺类化合物的制备方法,包括如下步骤:
当R为吡啶基或吡嗪基时,以5-氯水杨酸为原料,经过羧酸酰氯化、酰氯胺解反应制备得到所述的N-杂芳基-5-氯水杨酰胺类化合物;
合成路线如下:
所述的合成路线中的反应试剂和条件优选如下:
a.NH2R、PCl3、吡啶、无水PhMe。
当R为嘧啶基、哒嗪基、噻唑基、噻二唑基或苯并噻唑基时,采用5-氯水杨酸为原料,经过羟基乙酰化、羧酸酰氯化、酰氯胺解、去乙酰化反应制备得到所述的N-杂芳基-5-氯水杨酰胺类化合物;
具体地,包括如下步骤:
(1)5-氯水杨酸经过乙酰化得到2-(乙酰氧基)-5-氯苯甲酸;
(2)2-(乙酰氧基)-5-氯苯甲酸经过酰氯化得到2-(乙酰氧基)-5-氯苯甲酰氯;
(3)2-(乙酰氧基)-5-氯苯甲酰氯与RNH2发生胺解反应,得到2-(乙酰氧基)-5-氯苯甲酰胺;
(4)2-(乙酰氧基)-5-氯苯甲酰胺发生去乙酰化反应,即得到所述的N-杂芳基-5-氯水杨酰胺类化合物。
合成路线如下:
所述的合成路线中的反应试剂和条件优选如下:
a.(CH3CO)2O、H2SO4;
b.(COCl)2、DMF、CH2Cl2;
c.NH2R、Et3N、CH2Cl2;
d.36%HCl。
所述的N-杂芳基-5-氯水杨酰胺类化合物或所述的药物组合物在制备预防和/或治疗结核病的药物中的应用。
所述的结核病包括肺结核或肺外结核。
所述的结核病包括活动性结核病、单耐药结核病、多耐药结核病或广泛耐多药结核病。
所述的N-杂芳基-5-氯水杨酰胺类化合物或所述的药物组合物在制备预防和/或治疗分枝杆菌感染引起的疾病的药物中的应用。
所述的分枝杆菌为结核分枝杆菌,特别是临床分离的耐药结核分枝杆菌。
本发明相对于现有技术具有如下的优点及效果:
1.本发明提供了一类N-杂芳基-5-氯水杨酰胺化合物,具有新的抗结核菌药母核结构和优秀的抗结核菌活性。
2.本发明提供了上述的N-杂芳基-5-氯水杨酰胺类化合物的制备方法,采用5-氯水杨酸为原料,经过羧酸酰氯化、酰氯胺解反应制备得到所述的N-杂芳基-5-氯水杨酰胺类化合物;或者采用5-氯水杨酸为原料,经过羟基乙酰化、羧酸酰氯化、酰氯胺解、去乙酰化反应制备得到。上述的合成路线原料廉价易得,不使用高毒性和高污染试剂,反应步骤简单,可实现工业化生产。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例中反应所用的原料可以由本领域技术人员根据已有知识制备得到,或可以通过商业途径购得。
实施例1合成5-氯-N-(5-氯-2-吡啶基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(2.1g,12mmol)和重蒸的甲苯(35mL),缓慢逐滴加入三氯化磷(1.5g,11mmol),再加入吡啶(39.6mg,0.5mmol)和2-氨基-5-氯吡啶(1.3g,10mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(30mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(5-氯-2-吡啶基)-2-羟基苯甲酰胺1.75g,产率62%。
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.98(s,1H),8.41(d,J=2.6Hz,1H),8.28(d,J=8.9Hz,1H),7.98(dd,J=8.9,2.7Hz,1H),7.96(d,J=2.8Hz,1H),7.50(dd,J=8.7,2.9Hz,1H),7.08(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.25,155.80,150.41,147.07,138.65,133.95,130.19,126.19,123.96,120.19,119.57,115.54.高分辨质谱(ESI)C12H8Cl2N2O2[M-H]+:理论值:280.9890,实测值:280.9892.熔点:243–244℃。
实施例2合成5-氯-2-羟基-N-(5-三氟甲基-2-吡啶基)-苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(2.1g,12mmol)和重蒸的甲苯(35mL),缓慢逐滴加入三氯化磷(1.5g,11mmol),再加入吡啶(39.6mg,0.5mmol)和2-氨基-5-三氟甲基吡啶(1.6g,10mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(30mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(5-氯-2-吡啶基)-2-羟基苯甲酰胺1.81g,产率57%。
1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.17(s,1H),8.74(dd,J=2.4,1.3Hz,1H),8.44(d,J=8.8Hz,1H),8.25(dd,J=8.9,2.5Hz,1H),7.95(d,J=2.8Hz,1H),7.51(dd,J=8.8,2.8Hz,1H),7.09(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.54,155.79,154.75,145.99(q,3J=4.3Hz),136.65(q,3J=3.3Hz),134.13,130.28,124.23(q,1J=272.7Hz),124.03,121.35(q,2J=32.5Hz),120.11,119.59,113.95.高分辨质谱(ESI)C13H8ClF3N2O2[M-H]+:理论值:315.0514,实测值:315.0512.熔点:225–226℃。
实施例3合成5-氯-2-羟基-N-(6-三氟甲基-3-吡啶基)-苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(2.1g,12mmol)和重蒸的甲苯(35mL),缓慢逐滴加入三氯化磷(1.5g,11mmol),再加入吡啶(39.6mg,0.5mmol)和3-氨基-6-三氟甲基吡啶(1.6g,10mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(30mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(5-氯-2-吡啶基)-2-羟基苯甲酰胺2.11g,产率68%。
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.83(s,1H),9.03(d,J=2.4Hz,1H),8.46(dd,J=8.7,2.4Hz,1H),7.93(d,J=8.6Hz,1H),7.88(d,J=2.8Hz,1H),7.50(dd,J=8.8,2.8Hz,1H),7.06(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.77,156.57,142.40,141.55(q,2J=34.2Hz),138.43,133.70,129.21,128.44,123.31,122.18(q,1J=273.1Hz),121.65(d,3J=3.1Hz),120.69,119.46.高分辨质谱(ESI)C13H8ClF3N2O2[M-H]+:理论值:315.0514,实测值:315.0515.熔点:258–259℃。
实施例4合成5-氯-2-羟基-N-(2-三氟甲基-4-吡啶基)-苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(1.2g,7.2mmol)和重蒸的甲苯(21mL),缓慢逐滴加入三氯化磷(0.9g,6.6mmol),再加入吡啶(23.7mg,0.3mmol)和4-氨基-2-三氟甲基吡啶(973mg,6mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-2-羟基-N-(5-三氟甲基-3-吡啶基)-苯甲酰胺1.21g,产率63%。
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.91(s,1H),8.68(d,J=5.5Hz,1H),8.28(d,J=2.0Hz,1H),7.96(dd,J=5.6,2.0Hz,1H),7.81(d,J=2.7Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ166.06,156.28,151.59,147.86(q,2J=33.6Hz),147.25,133.71,129.28,123.34,122.05(q,1J=274.1Hz),121.12,119.41,117.12,111.24(d,3J=3.2Hz).高分辨质谱(ESI)C13H8ClF3N2O2[M-H]+:理论值:315.0154,实测值:315.0151.熔点:226–227℃。
实施例5合成5-氯-2-羟基-N-(5-三氟甲基-3-吡啶基)-苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(1.2g,7.2mmol)和重蒸的甲苯(21mL),缓慢逐滴加入三氯化磷(0.9g,6.6mmol),再加入吡啶(23.7mg,0.3mmol)和3-氨基-5-三氟甲基吡啶(973mg,6mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-2-羟基-N-(5-三氟甲基-3-吡啶基)-苯甲酰胺1.19g,产率68%。
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.80(s,1H),9.12(d,J=2.3Hz,1H),8.77–8.69(m,1H),8.62(d,J=2.3Hz,1H),7.88(d,J=2.7Hz,1H),7.50(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.90,156.72,146.08,141.42(q,3J=4.2Hz),135.64,133.76,129.13,125.49(q,2J=32.3Hz),124.21(q,3J=3.8Hz),123.95(q,1J=272.7Hz),123.30,120.36,119.50.高分辨质谱(ESI)C13H8ClF3N2O2[M-H]+:理论值:315.0154,实测值:315.0150.熔点:203–204℃。
实施例6合成5-氯-N-(2,6-二氯-4-吡啶基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(1.2g,7.2mmol)和重蒸的甲苯(21mL),缓慢逐滴加入三氯化磷(0.9g,6.6mmol),再加入吡啶(23.7mg,0.3mmol)和4-氨基-2,6-二氯吡啶(978mg,6mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(2,6-二氯-4-吡啶基)-2-羟基苯甲酰胺1.14g,产率57%。
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.89(s,1H),7.86(s,2H),7.75(d,J=2.8Hz,1H),7.48(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.75,156.06,150.18,133.81,129.40,123.38,121.18,119.39,113.22.高分辨质谱(ESI)C12H7Cl3N2O2[M-H]+:理论值:314.9500,实测值:314.9497.熔点:222–223℃。
实施例7合成5-氯-N-(5,6-二氯-3-吡啶基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(1.2g,7.2mmol)和重蒸的甲苯(21mL),缓慢逐滴加入三氯化磷(0.9g,6.6mmol),再加入吡啶(23.7mg,0.3mmol)和3-氨基-5,6-二氯吡啶(978mg,6mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(5,6-二氯-3-吡啶基)-2-羟基苯甲酰胺1.52g,产率81%。
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.72(d,J=5.0Hz,1H),8.71(d,J=2.5Hz,1H),8.53(d,J=2.5Hz,1H),7.84(d,J=2.8Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),7.04(d,J=8.8Hz,1H).13CNMR(101MHz,DMSO-d6)δ165.56,156.65,141.85,140.19,135.92,133.79,130.55,129.14,129.07,123.32,120.27,119.49.高分辨质谱(ESI)C12H7Cl3N2O2[M-H]+:理论值:314.9500,实测值:314.9503.熔点:237–238℃。
实施例8合成5-氯-N-(2,6-二氯-3-吡啶基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(1.2g,7.2mmol)和重蒸的甲苯(21mL),缓慢逐滴加入三氯化磷(0.9g,6.6mmol),再加入吡啶(23.7mg,0.3mmol)和3-氨基-2,6-二氯吡啶(978mg,6mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即5-氯-N-(2,6-二氯-3-吡啶基)-2-羟基苯甲酰胺1.49g,产率79%。
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.99(s,1H),8.84(d,J=8.5Hz,1H),7.94(d,J=2.8Hz,1H),7.62(d,J=8.6Hz,1H),7.52(dd,J=8.8,2.9Hz,1H),7.09(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.11,155.71,142.56,139.16,134.22,133.20,132.35,130.28,124.55,124.10,119.67,119.53.高分辨质谱(ESI)C12H7Cl3N2O2[M-H]+:理论值:314.9500,实测值:314.9498.熔点:246–247℃。
实施例9合成5-氯-N-(5-氯-2-吡嗪基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(2.1g,12mmol)和重蒸的甲苯(35mL),缓慢逐滴加入三氯化磷(1.5g,11mmol),再加入吡啶(39.6mg,0.5mmol)和2-氨基-5-氯吡嗪(1.3g,10mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(30mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即5-氯-N-(5-氯-2-吡嗪基)-2-羟基苯甲酰胺1.78g,产率65%。
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),11.09(s,1H),9.29(s,1H),8.58(s,1H),7.92(d,J=2.9Hz,1H),7.51(dd,J=8.7,3.0Hz,1H),7.08(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.50,155.94,147.53,142.85,142.54,135.89,134.24,130.13,123.96,119.78,119.60.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9838.熔点:214–215℃。
实施例10合成5-氯-N-(6-氯-2-吡嗪基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(2.1g,12mmol)和重蒸的甲苯(35mL),缓慢逐滴加入三氯化磷(1.5g,11mmol),再加入吡啶(39.6mg,0.5mmol)和2-氨基-6-氯吡嗪(1.3g,10mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(30mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到淡黄色固体即5-氯-N-(6-氯-2-吡嗪基)-2-羟基苯甲酰胺2.25g,产率80%。
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.09(s,1H),9.43(s,1H),8.56(s,1H),7.92(d,J=2.7Hz,1H),7.51(dd,J=8.8,2.8Hz,1H),7.08(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.70,156.02,147.79,145.99,139.40,134.83,134.30,130.08,123.94,119.63,119.57.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9847.熔点:225–226℃。
实施例11合成5-氯-2-羟基-N-(5-三氟甲基-2-吡嗪基)-苯甲酰胺
在25mL圆底烧瓶中,加入5-氯水杨酸(311mg,1.8mmol)和重蒸的甲苯(8mL),缓慢逐滴加入三氯化磷(226mg,1.65mmol),再加入吡啶(6mg,0.075mmol)和2-氨基-5-氯吡嗪(245mg,1.5mmol)。在氩气下,反应于120℃条件下回流12h。将反应液冷却至室温,并向其滴入碳酸氢钠水溶液,使pH值达到6-7,所得混合物用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到淡黄色固体即5-氯-2-羟基-N-(5-三氟甲基-2-吡嗪基)-苯甲酰胺420mg,产率87%。
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),11.32(s,1H),9.59(d,J=1.4Hz,1H),9.00–8.88(m,1H),7.92(d,J=2.8Hz,1H),7.52(dd,J=8.8,2.8Hz,1H),7.09(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.78,155.98,151.08,140.83(d,3J=3.3Hz),137.45(q,2J=35.0Hz),136.50,134.46,130.23,124.02,121.92(q,1J=273.1Hz),119.71,119.64.高分辨质谱(ESI)C12H7ClF3N3O2[M-H]+:理论值:316.0106,实测值:316.0102.熔点:198–199℃。
实施例12合成5-氯-N-(5-氯-2-嘧啶基)-2-羟基苯甲酰胺
在100mL圆底烧瓶中,加入5-氯水杨酸(4.0g,23mmol)和乙酸酐(21mL),常温下搅拌,然后加入浓硫酸(40μL)。反应约20分钟后,反应物凝固,加入冷水,并用乙酸乙酯(40mL)提取,并用适量盐水洗涤,用无水硫酸钠干燥后,减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即2-(乙酰氧基)-5-氯苯甲酸4.4g,产率86%,直接用于下一步反应。
在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入2-氨基-5-氯嘧啶(130mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色油状液体即4-氯-2-[(5-氯-2-嘧啶基)氨基甲氨基]-乙酸苯酯290mg,产率89%。
在25mL圆底烧瓶中,加入4-氯-2-[(5-氯-2-嘧啶基)氨基甲氨基]-乙酸苯酯(196mg,0.6mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(5-氯-2-嘧啶基)-2-羟基苯甲酰胺156mg,产率92%。
1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),11.15(s,1H),8.82(s,2H),7.89(d,J=2.8Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ162.91,157.22,156.00,155.94,133.88,130.08,125.61,123.79,120.74,119.52.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9845.熔点:237–238℃。
实施例13合成5-氯-N-(2-氯-5-嘧啶基)-2-羟基苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(429mg,2mmol)和二氯甲烷(20mL)。在0℃下缓慢滴加草酰氯(508mg,4mmol),加入催化量的N,N-二甲基甲酰胺(8mg,0.11mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(20mL)溶解残留物,缓慢滴加三乙胺(0.68mL,4.8mmol)并加入5-氨基-2-氯嘧啶(259mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(30mL)猝灭,并用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即4-氯-2-[(2-氯-5-嘧啶基)氨基甲氨基]-乙酸苯酯574mg,产率88%。
在25mL圆底烧瓶中,加入4-氯-2-[(2-氯-5-嘧啶基)氨基甲氨基]-乙酸苯酯(326mg,1mmol),并加入36%浓盐酸(5mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(2-氯-5-嘧啶基)-2-羟基苯甲酰胺269mg,产率95%。
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.74(s,1H),9.11(s,2H),7.87(d,J=2.7Hz,1H),7.50(dd,J=8.8,2.7Hz,1H),7.06(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.50,156.68,154.29,151.92,133.94,133.52,129.24,123.37,119.95,119.52.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9846.熔点:201–202℃。
实施例14合成5-氯-N-(6-氯-4-嘧啶基)-2-羟基苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入4-氨基-6-氯嘧啶(130mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即4-氯-2-[(6-氯-4-嘧啶基)氨基甲氨基]-乙酸苯酯304mg,产率94%。
在25mL圆底烧瓶中,加入4-氯-2-[(6-氯-4-嘧啶基)氨基甲氨基]-乙酸苯酯(163mg,0.5mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(6-氯-4-嘧啶基)-2-羟基苯甲酰胺139mg,产率97%。
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),11.24(s,1H),8.78(s,1H),8.23(s,1H),7.86(s,1H),7.51(d,J=8.8Hz,1H),7.07(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.39,161.39,159.10,158.85,155.93,134.55,130.21,124.03,119.79,119.67,109.81.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9845.熔点:180–181℃。
实施例15合成5-氯-2-羟基-N-(4-三氟甲基-2-嘧啶基)-苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入2-氨基-4-三氟甲基嘧啶(163mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色油状液体即4-氯-2-[(4-三氟甲基-2-嘧啶基)氨基甲氨基]-乙酸苯酯325mg,产率91%。
在25mL圆底烧瓶中,加入4-氯-2-[(4-三氟甲基-2-嘧啶基)氨基甲氨基]-乙酸苯酯(126mg,0.35mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到黄色固体即5-氯-N-(4-三氟甲基-2-嘧啶基)-2-羟基苯甲酰胺110mg,产率98%。
1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),11.34(s,1H),9.07(d,J=4.9Hz,1H),7.88(d,J=2.8Hz,1H),7.74(d,J=4.9Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ163.26,162.68,158.13,155.87,155.26(q,2J=35.8Hz),133.92,130.09,123.77,120.88,120.77(q,1J=274.9Hz),119.47,113.21(d,3J=3.0Hz).高分辨质谱(ESI)C12H7ClF3N3O2[M-H]+:理论值:316.0106,实测值:316.0109.熔点:246–247℃。
实施例16合成5-氯-2-羟基-N-(6-三氟甲基-4-嘧啶基)-苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入4-氨基-6-三氟甲基嘧啶(163mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即4-氯-2-[(6-三氟甲基-4-嘧啶基)氨基甲氨基]-乙酸苯酯304mg,产率86%。
在25mL圆底烧瓶中,加入4-氯-2-[(6-三氟甲基-4-嘧啶基)氨基甲氨基]-乙酸苯酯(126mg,0.35mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(6-三氟甲基-4-嘧啶基)-2-羟基苯甲酰胺107mg,产率96%。
1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),11.44(s,1H),9.15(d,J=1.2Hz,1H),8.58(d,J=1.3Hz,1H),7.89(d,J=2.8Hz,1H),7.54(dd,J=8.8,2.8Hz,1H),7.09(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.74,159.72,159.58,155.95,155.39(q,2J=34.9Hz),134.65,130.22,124.07,121.07(q,1J=275.7Hz),119.84,119.69,106.67(q,3J=3.5Hz).高分辨质谱(ESI)C12H7ClF3N3O2[M-H]+:理论值:316.0106,实测值:316.0105.熔点:204–205℃。
实施例17合成5-氯-2-羟基-N-(6-三氟甲氧基-2-苯并噻唑基)-苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入2-氨基-6-三氟甲氧基苯并噻唑(234mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即4-氯-2-[(6-三氟甲氧基-2-苯并噻唑基)氨基甲氨基]-乙酸苯酯396mg,产率92%。
在25mL圆底烧瓶中,加入4-氯-2-[(6-三氟甲氧基-2-苯并噻唑基)氨基甲氨基]-乙酸苯酯(150mg,0.35mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-2-羟基-N-(6-三氟甲氧基-2-苯并噻唑基)-苯甲酰胺130mg,产率95%。
1H NMR(400MHz,DMSO-d6)δ12.32(s,2H),8.14(d,J=1.2Hz,0H),7.93(d,J=2.8Hz,1H),7.81(d,J=8.8Hz,1H),7.51(dd,J=8.8,2.8Hz,1H),7.45(dd,J=8.9,1.5Hz,0H),7.07(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.00,144.74,144.72,134.50,129.84,123.67,120.64(q,1J=256.1Hz),120.62,119.64,119.07,115.72.高分辨质谱(ESI)C15H8ClF3N2O3S[M-H]+:理论值:386.9823,实测值:386.9822.熔点:291–292℃。
实施例18合成5-氯-2-羟基-N-(6-三氟甲基-2-苯并噻唑基)-苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(429mg,2mmol)和二氯甲烷(20mL)。在0℃下缓慢滴加草酰氯(508mg,4mmol),加入催化量的N,N-二甲基甲酰胺(8mg,0.11mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(20mL)溶解残留物,缓慢滴加三乙胺(0.68mL,4.8mmol)并加入2-氨基-6-三氟甲氧基苯并噻唑(436mg,2mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(30mL)猝灭,并用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即4-氯-2-[(6-三氟甲基-2-苯并噻唑基)氨基甲氨基]-乙酸苯酯604mg,产率73%。
在25mL圆底烧瓶中,加入4-氯-2-[(6-三氟甲氧基-2-苯并噻唑基)氨基甲氨基]-乙酸苯酯(207mg,0.5mmol),并加入36%浓盐酸(5mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-2-羟基-N-(6-三氟甲基-2-苯并噻唑基)-苯甲酰胺170mg,产率91%。
1H NMR(400MHz,DMSO-d6)δ12.38(s,2H),8.50(d,J=1.8Hz,1H),7.91(d,J=2.8Hz,1H),7.88(d,J=8.5Hz,1H),7.76(dd,J=8.5,1.9Hz,1H),7.51(dd,J=8.8,2.8Hz,1H),7.07(d,J=8.7Hz,1H).13CNMR(101MHz,DMSO-d6)δ156.90,134.57,129.85,124.92(q,1J=270.0Hz),124.51(q,2J=32.2Hz),123.71,123.67,120.62,120.59,119.67,119.12.高分辨质谱(ESI)C15H8ClF3N2O2S[M-H]+:理论值:370.9874,实测值:370.9871.熔点:316–317℃。
实施例19合成5-氯-N-(6-氯-3-哒嗪基)-2-羟基苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(215mg,1mmol)和二氯甲烷(10mL)。在0℃下缓慢滴加草酰氯(254mg,2mmol),加入催化量的N,N-二甲基甲酰胺(4mg,0.055mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(10mL)溶解残留物,缓慢滴加三乙胺(0.34mL,2.4mmol)并加入3-氨基-6-氯哒嗪(130mg,1mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(20mL)猝灭,并用乙酸乙酯(10mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即4-氯-2-[(6-氯-3-哒嗪基)氨基甲氨基]-乙酸苯酯261mg,产率79%。
在25mL圆底烧瓶中,加入4-氯-2-[(6-氯-3-哒嗪基)氨基甲氨基]-乙酸苯酯(98mg,0.3mmol),并加入36%浓盐酸(3mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(6-氯-3-哒嗪基)-2-羟基苯甲酰胺79mg,产率92%。
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),11.43(s,1H),8.54(dd,J=9.4,1.4Hz,1H),7.96(d,J=9.4Hz,2H),7.94(d,J=2.7Hz,1H),7.53(dd,J=8.8,2.8Hz,1H),7.09(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.09,156.00,155.17,152.00,134.32,130.86,130.14,123.96,122.41,119.89,119.63.高分辨质谱(ESI)C11H7Cl2N3O2[M-H]+:理论值:281.9843,实测值:281.9844.熔点:233–234℃。
实施例20合成5-氯-2-羟基-N-[5-三氟甲基-2-(1,3,4-噻二唑基)]-苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(429mg,2mmol)和二氯甲烷(20mL)。在0℃下缓慢滴加草酰氯(508mg,4mmol),加入催化量的N,N-二甲基甲酰胺(8mg,0.11mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(20mL)溶解残留物,缓慢滴加三乙胺(0.68mL,4.8mmol)并加入2-氨基-5-三氟甲基-1,3,4-噻二唑(338mg,2mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(30mL)猝灭,并用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即4-氯-2-[(5-三氟甲基-2-(1,3,4-噻二唑基))氨基甲氨基]-乙酸苯酯658mg,产率90%。
在25mL圆底烧瓶中,加入4-氯-2-[(5-三氟甲基-2-(1,3,4-噻二唑基))氨基甲氨基]-乙酸苯酯(292mg,0.8mmol),并加入36%浓盐酸(5mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-2-羟基-N-[5-三氟甲基-2-(1,3,4-噻二唑基)]-苯甲酰胺254mg,产率98%。
1H NMR(400MHz,DMSO-d6)δ7.85(d,J=2.7Hz,1H),7.53(dd,J=8.8,2.8Hz,1H),7.07(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.83,162.06,156.68,151.22(q,2J=37.6Hz),134.65,129.83,123.56,120.43(q,1J=272.0Hz),119.56,118.98.高分辨质谱(ESI)C10H5ClF3N3O2S[M-H]+:理论值:321.9670,实测值:321.9668.熔点:257–258℃。
实施例21合成5-氯-N-(5-氯-2-噻唑基)-2-羟基苯甲酰胺
2-(乙酰氧基)-5-氯苯甲酸的合成参见实施例12。在100mL圆底烧瓶中,加入2-(乙酰氧基)-5-氯苯甲酸(429mg,2mmol)和二氯甲烷(20mL)。在0℃下缓慢滴加草酰氯(508mg,4mmol),加入催化量的N,N-二甲基甲酰胺(8mg,0.11mmol),恢复室温,反应约5小时。反应完成后,减压下除去溶剂和草酰氯,并用二氯甲烷(20mL)溶解残留物,缓慢滴加三乙胺(0.68mL,4.8mmol)并加入2-氨基-5-氯噻唑盐酸盐(342mg,2mmol),常温下反应,用薄层色谱检测反应情况,反应完成后向反应液中加入饱和氯化铵溶液(30mL)猝灭,并用乙酸乙酯(20mL×3)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即4-氯-2-[(5-氯-2-噻唑基)氨基甲氨基]-乙酸苯酯524mg,产率78%。
在25mL圆底烧瓶中,加入4-氯-2-[(5-氯-2-噻唑基)氨基甲氨基]-乙酸苯酯(166mg,0.5mmol),并加入36%浓盐酸(5mL),在50℃的条件下反应12小时。反应完成后,将反应沉淀物过滤,并用水和少量乙酸乙酯洗涤滤渣,并将滤渣放置真空干燥箱内干燥得到白色固体即5-氯-N-(5-氯-2-噻唑基)-2-羟基苯甲酰胺131mg,产率90%。
1H NMR(400MHz,DMSO-d6)δ12.11(s,2H),7.88(d,J=2.7Hz,1H),7.64(s,1H),7.51(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.65(s),134.35(s),129.70(s),123.67(s),119.58(s),118.95(s),99.98(s).高分辨质谱(ESI)C10H6Cl2N2O2S[M-H]+:理论值:286.9454,实测值:286.9451.熔点:231–232℃。
上述实施例制得的N-杂芳基-5-氯水杨酰胺类化合物的结构式和编号整理如表1:
表1实施例制得的代表性N-杂芳基-5-氯水杨酰胺类化合物
效果实施例实施例化合物的抗结核活性测定
1.测定实施例化合物抗结核分枝杆菌的最低抑菌浓度(Minimum InhibitoryConcentration,简称MIC)
采用无抗性标记的自主发光Mtb H37Ra(Autoluminescent Mtb H37Ra,简称AlRa)进行抗结核活性测试。AlRa的生长趋势以及对各种临床药物的敏感性与不发光的野生型结核分枝杆菌一致。
(1)将AlRa转接到15mL 7H9(+吐温80)培养基中,放置在37℃恒温摇床中培养至200μL菌液的相对光单位(Relative LightUnits,简称RLUs)达到106时,用7H9(无吐温80)培养基将其稀释成待测菌液(RLUs/200μL为3000-5000之间)。
(2)利用DMSO把待测化合物母液(10mg/mL)稀释至0.8、0.4、0.2、0.1和0.05mg/mL或0.5、0.25、0.125、0.0625和0.003125mg/mL。将4μL药液和196μL稀释好的AlRa加入到同一个灭过菌的1.5mL EP管中,使待测化合物的终浓度为16、8、4、2、1μg/mL或10、5、2.5、1.25、0.625μg/mL,同时设置阳性对照(利福平终浓度设置为1μg/mL)和阴性对照组(DMSO),每个浓度做3个平行。
(3)将EP管放置在37℃恒温箱中,在第0、1、3和5天利用发光检测仪检测发光值。分析数据,得出各化合物抗结核分枝杆菌H37Ra的MIC,结果如下表2。
表2实施例化合物抗结核分枝杆菌H37Ra的MIC
化合物 | MIC(μg/mL) |
1 | 5 |
2 | 1.25 |
3 | 4 |
4 | 1.25 |
5 | 5 |
6 | 1.25 |
7 | 2.5 |
8 | 2.5 |
9 | 4 |
10 | 2.5 |
11 | 1.25 |
12 | 5 |
13 | 5 |
14 | 2.5 |
15 | 5 |
16 | 2.5 |
17 | 10 |
18 | 5 |
19 | 10 |
20 | 10 |
21 | 5 |
由表2结果可知,实施例化合物对结核菌H37Ra的生长具有很强的抑制作用,其中化合物2、4、6、11的MIC值均达到1.25μg/mL。
2.测定实施例化合物在细胞色素bc1抑制剂5-甲氧基-2-甲基-N-(4-(4-(4-(三氟甲氧基)苯基)哌啶-I-取代)苄基)吡唑[1,5-a]吡啶-3-甲酰胺(CAS编号:1799682-71-5,以下简称TB47)的协同作用下抗结核分枝杆菌的MIC
细胞色素bc1抑制剂TB47已被证实存在体内外抗结核菌的活性,且与已知的抗结核药物(如氯法齐明)存在协同抗菌作用。本实验用于判断TB47和实施例化合物是否具有组合抗结核菌活性。
(1)将AlRa转接到15mL 7H9(+吐温80)培养基中,放置在37℃恒温摇床中培养至200μL菌液的RLUs达到106时,用7H9(无吐温80)培养基将其稀释成待测菌液(RLUs/200μL为3000-5000之间)。
(2)利用DMSO把待测化合物母液(10mg/mL)稀释至0.8、0.4、0.2、0.1、0.05、0.025和0.0125mg/mL或0.5、0.25、0.125、0.0625、0.003125mg/mL,把TB47溶液(0.6mg/mL)稀释至0.6μg/mL。将4μL药液、1μL TB47溶液和195μL稀释好的AlRa加入到同一个灭过菌的1.5mLEP管中,使待测化合物的终浓度为16、8、4、2、1、0.5和0.25μg/mL或10、5、2.5、1.25、0.625μg/mL,TB47的终浓度为0.003μg/mL,同时设置阳性对照(利福平终浓度设置为1μg/mL)和阴性对照组(DMSO),每个浓度做3个平行。
(3)将EP管放置在37℃恒温箱中,在第0、1、3和5天利用发光检测仪检测发光值。分析数据,得出各化合物在TB47的协同作用下抗结核分枝杆菌H37Ra的MIC,结果如下表3。
表3实施例化合物在低浓度TB47(0.003μg/mL)的协同作用下抗结核分枝杆菌H37Ra的MIC
由表3结果可知,大多数实施例化合物在TB47的协同作用下对结核菌H37Ra的抗菌活性增强,其中化合物3的MIC值下降到0.25μg/mL(化合物3单用时MIC为4μg/mL),化合物4、6、8、11、16、18的MIC值均降低到0.625μg/mL(化合物4、6和11单用时MIC为1.25μg/mL;化合物8和16单用时MIC为2.5μg/mL;化合物18单用时MIC为5μg/mL)。
3.Alamar Blue法测定实施例化合物对野生型结核分枝杆菌(H37Rv)和K1426552等10株临床分离耐药结核菌株的MIC
(1)将野生型H37Rv和K1426552等10株临床菌株接种到10mL 7H9液体培养基中,放置在37℃摇床中培养至OD600为0.8左右时,将其稀释1000倍制备成待测菌液;
(2)利用DMSO溶液将所选择的6种化合物由母液(10mg/mL)稀释至相应的浓度:化合物3-1.6~0.05mg/mL;化合物4-0.4~0.0125mg/mL;化合物7-0.8~0.025mg/mL;化合物8-0.8~0.025mg/mL;化合物10-0.8~0.025mg/mL;化合物11-0.4~0.0125mg/mL。
(3)将196μL待测菌液和4μL稀释好的化合物加到同一个96孔板的孔中,每个浓度做3个平行。因为野生型H37Rv也检测了和TB47联用的活性,所以也将196μL野生型H37Rv待测菌液、2μL稀释好的化合物和2μLTB47(0.3μg/mL)加到同一个孔中,每个浓度做3个平行。同时设置阴性对照组(DMSO)。
(4)将96孔板放置在37℃恒温箱中培养10天后,向每个孔中加入20μL AlamarBlue和12.5μL20%吐温80(现用现配,并且过滤除菌),然后再将96孔板放置在37℃恒温箱中培养1天后,观察颜色变化。
表4实施例化合物对结核分枝杆菌H37Rv的最低抑制浓度(MIC)
化合物 | MIC(μg/mL) | MIC(μg/mL)+TB47(0.003μg/mL) |
3 | 4 | 0.5 |
4 | 2 | <0.125 |
7 | 4 | 0.25 |
8 | 4 | 0.25 |
10 | 4 | 0.25 |
11 | 2 | <0.125 |
阴性对照DMSO | / | / |
由表4结果可知,实施例化合物对结核菌H37Rv的生长具有良好的抑制作用,其中化合物4和11的MIC值均达到2μg/mL,且所选实施例化合物在TB47的协同作用下对结核菌H37Rv的生长的抑制作用均有明显加强。
K1426552、K1518700、K1603504、181CAZ150、Z106、Z123、5999、5733、6859、2614为从广州市胸科医院临床分离的耐药结核分枝杆菌株。
表5实施例化合物对多药耐药结核菌株的最低抑制浓度MIC
由表5可知,所选化合物对于上述多药耐药结核菌株的生长也具良好的抑制作用,其中化合物11对所选的多药耐药结核菌株的MIC值均达到2μg/mL。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
2.根据权利要求1所述的通式为(Ⅰ)的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物,其特征在于,所述的N-杂芳基-5-氯水杨酰胺类化合物选自如下化合物之一:
5-氯-2-羟基-N-(5-三氟甲基-2-吡啶基)-苯甲酰胺;
5-氯-2-羟基-N-(2-三氟甲基-4-吡啶基)-苯甲酰胺;
5-氯-N-(2,6-二氯-4-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(5,6-二氯-3-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(2,6-二氯-3-吡啶基)-2-羟基苯甲酰胺;
5-氯-N-(6-氯-2-吡嗪基)-2-羟基苯甲酰胺;
5-氯-2-羟基-N-(5-三氟甲基-2-吡嗪基)-苯甲酰胺;
5-氯-N-(6-氯-4-嘧啶基)-2-羟基苯甲酰胺;
5-氯-2-羟基-N-(6-三氟甲基-4-嘧啶基)-苯甲酰胺。
3.一种药物组合物,其特征在于:
包括权利要求1~2任一项所述的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物,以及任选的药学可接受的辅料、载体或赋形剂。
4.权利要求1~2任一项所述的N-杂芳基-5-氯水杨酰胺类化合物的制备方法,其特征在于,
当R为单取代或多取代的吡啶基、吡嗪基时,包括如下步骤:采用5-氯水杨酸为原料,经过羧酸酰氯化、酰氯胺解反应制备得到所述的N-杂芳基-5-氯水杨酰胺类化合物;
或者,
当R为嘧啶基、哒嗪基、噻唑基、噻二唑基或苯并噻唑基时,包括如下步骤:采用5-氯水杨酸为原料,经过羟基乙酰化、羧酸酰氯化、酰氯胺解、去乙酰化反应制备得到所述的N-杂芳基-5-氯水杨酰胺类化合物。
5.权利要求1~2任一项所述的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物或权利要求4所述的药物组合物的应用,其特征在于:
在制备预防和/或治疗结核病的药物中的应用。
6.权利要求1~2任一项所述的N-杂芳基-5-氯水杨酰胺类化合物或其药学可接受的盐、立体异构体或溶剂化物或权利要求4所述的药物组合物的应用,其特征在于:
所述的应用为在制备预防和/或治疗分枝杆菌感染引起的疾病的药物中的应用。
7.根据权利要求6所述的应用,其特征在于:
所述的分枝杆菌为结核分枝杆菌。
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