CN112778316A - N-(吲哚-5-基)双环芳酰胺类化合物及其制备方法和用途 - Google Patents
N-(吲哚-5-基)双环芳酰胺类化合物及其制备方法和用途 Download PDFInfo
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- CN112778316A CN112778316A CN202110127031.3A CN202110127031A CN112778316A CN 112778316 A CN112778316 A CN 112778316A CN 202110127031 A CN202110127031 A CN 202110127031A CN 112778316 A CN112778316 A CN 112778316A
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- indol
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- carboxamide
- indole
- bicyclic aromatic
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- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 7
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- C07D403/02—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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明属于医药领域，涉及一种N‑(吲哚‑5‑基)双环芳酰胺类化合物及其制备方法和应用。所述的N‑(吲哚‑5‑基)双环芳酰胺类化合物的结构通式如下：
Description
技术领域
本发明属于医药领域，涉及一种N-(吲哚-5-基)双环芳酰胺类化合物、含有该化合物的组合物及其制备方法和在治疗痛风疾病中的用途。
背景技术
痛风(Gout)是由于长期高尿酸血症(Hyperuricemia)导致尿酸盐沉积于关节和软组织而形成的一组异质性、代谢类疾病。其临床特点为：高尿酸血症，急、慢性关节炎，关节畸形，慢性间质性肾炎和肾结等，严重者还会并发肾衰竭和心脑血管病而危及生命。并且，高尿酸血症还与合作共赢慢性疾病相关。据统计，痛风已成为仅次于糖尿病的第二大代谢性疾病。近年来随着人民生活水平的提高和饮食结构的改变，我国的痛风发病率呈逐年上升的趋势，给社会带来了巨大的压力和沉重的经济负担。
痛风的发病机制为：当体内尿酸生成增多或排泄减少时，可导致体内尿酸水平升高，当超过其溶解限度时，尿酸会沉积于关节和软组织，引起炎症反应。尿酸是人体嘌呤代谢的最终产物。黄嘌呤氧化酶是嘌呤代谢中的一个关键酶。在嘌呤代谢的最后阶段，催化黄嘌呤和次黄嘌呤氧化生成尿酸，因此抑制黄嘌呤氧化酶的活性可以有效的减少尿酸的生成，在高尿酸血症和痛风的治疗中，黄嘌呤氧化酶抑制剂占有非常重要的地位。
目前已上市的黄嘌呤氧化酶抑制剂有别嘌醇(Allopurinol)，非布司他(Febuxostat)和托匹司他(Topiroxostat)，种类十分有限且有一定的毒副作用，因此，研制高效低毒的黄嘌呤氧化酶抑制剂具有良好的市场前景。
在前期研究中，申请人发现了一系列的N-(3-取代-1-取代-1H-吲哚-5-基)酰胺类是由申请人公开或报道XO抑制剂(CN111072634A)。由于异烟酰胺结构片段方向扭转，无法与活性口袋的氨基酸残基稳定结合，故活性虽然优于别嘌醇，但是比托吡司他低了很多。
发明内容
本发明的目的在于提供一种N-(吲哚-5-基)双环芳酰胺类化合物及其制备方法和应用，所制备的化合物在体外黄嘌呤氧化酶抑制活性测试中显现出了良好的效果。本发明所提供的化合物的制备方法简单可行，收率较高，易于大规模生产。
为实现上述目的，本发明采用以下技术方案。
一种N-(吲哚-5-基)双环芳酰胺类化合物，该化合物为如通式I-II所示的化合物或其在药学上可接受的盐、水合物或溶剂化物，
其中：
X,Y,Z为N,NH或CH；各R1独立为2-8个碳的烷基、3-8个碳原子环烷基、烯丙基、苄基或取代苄基；取代苄基为卤代苄基、氰基苄基、烷氧基苄基、烷基苄基或烷氨基苄基。
所述的N-(吲哚-5-基)双环芳酰胺类化合物，所述通式I-II或其药学上可接受的盐、水合物或溶剂化物，选自下述任意一种：
N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA1)；
N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA)；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA3)；
N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB1)；
N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB2)；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB3)；
N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC1)；
N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC2)；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC3)；
N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD1)；
N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD2)；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD3)。
但不仅限于以上化合物，只要化合物结构式满足通式，均为本发明的限定范围。
所述的N-(吲哚-5-基)双环芳酰胺类化合物的制备方法，具体包括以下步骤。
步骤1、以5-硝基吲哚为起始原料，经醛基化，制得中间体5-硝基-1H-吲哚-3-甲醛。
步骤2、5-硝基-1H-吲哚-3-甲醛与羟胺反应，再经脱水，烃化后，制得重要中间体5-硝基-1-烷基-1H-吲哚-3-腈。
步骤3、5-硝基-1-烷基-1H-吲哚-3-腈经还原后与各类型酰氯反应，得到终产物。
一种药物组合物包括所述的N-(吲哚-5-基)双环芳酰胺类化合物、其药学上可接受的盐、水合物或溶剂化物和药学上可接受的载体。
所述的N-(吲哚-5-基)双环芳酰胺类化合物或其药学上可接受的盐、水合物或溶剂化物或所述的药物组合物在制备抗高尿酸血症和抗痛风药物中的应用。
进一步地，所述药物的剂型为药物治疗学上可接受的剂型。
进一步地，所述药物的剂量为药物治疗学上可接受的剂量。
与现有技术相比，本发明的有益效果如下。
本发明所提供的N-(吲哚-5-基)双环芳酰胺类化合物通过引入双环芳香杂环，以增强与Glu 1261残基的氢键作用，同时提供更多的潜在氢键受体，使其能与XO活性口袋稳定结合，与申请人已经公开的现有技术(CN111072634A)相比，分子结构创新性更强，活性大幅提升。且本发明所提供的通式I-II的化合物的制备方法简单可行，收率较高，易于大规模生产。
具体实施方式
下面结合实施例对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但这些实施例仅为了对本发明加以说明，本发明并不限于这些内容。
一种N-(吲哚-5-基)双环芳酰胺类化合物，该化合物为如通式I-II化合物或其在药学上可接受的盐、水合物或溶剂化物，
其中：
X,Y,Z为N、NH或CH；各R1独立为2-8个碳的烷基、3-8个碳原子环烷基、烯丙基、苄基或取代苄基；取代苄基为卤代苄基、氰基苄基、烷氧基苄基、烷基苄基或烷氨基苄基。
通式I-II所示化合物，在药学上可接受的盐包括钠盐、钾盐、钙盐、乙二胺盐等；在药学上可接受的水合物包括一水合物，二水合物、五水合物等；在药学上可接受的溶剂化物包括乙醇合物、双乙醇合物等。
通式I-II所示化合物还可以与淀粉、微晶纤维素、硬质酸镁、甘油等药学上可接受的辅料制成组合物制剂。
下面通过实施例进一步说明N-(吲哚-5-基)双环芳酰胺类化合物的制备方法。
实施例1 5-硝基-1H-吲哚-3-甲醛的制备。
于500mL反应瓶中加入5-硝基吲哚(5.00g，30.84mmol)，在0℃搅拌下缓慢加入三氯氧磷(14.18g，92.51mmol)，维护温度反应1h后，室温反应完过夜。反应完毕后，加入冰水，调节pH至8-9，105℃下回流1h，冷却后倒入大量冰水，抽滤，滤饼用大量水洗，得滤饼，放入烘箱干燥，得黄棕色固体11.7g，收率：94.2％。
实施例25-硝基-1H-吲哚-3-腈的制备。
于150mL反应瓶中加入5-硝基-1H-吲哚-3-甲醛(2.0g，10.52mmol)，盐酸羟胺(3.65g，52.59mmol)，甲酸钠(5.72g，57.92mmol)和甲酸(40mL)，110℃下回流反应2h，反应完全，冷却后倒入大量冰水中，搅拌析出沉淀，抽滤，滤饼用大量水洗，得滤饼，放入烘箱干燥，得淡黄色固体1.72g，收率87.8％。实施例35-硝基-1-烷基-1H-吲哚-3-腈的制备。
于150mL反应瓶中加入5-硝基-1H-吲哚-3-腈(1.0g，5.34mmol)，以DMF(30mL)为溶剂，在-10℃条件下缓慢加入氢化钠(60％，1.7g，8.01mmol)反应2h，然后加入各种溴代或氯代烷烃(8.01mmol)和碘化钾(0.1g，0.53mmol)在60℃条件下反应15h。反应完全后抽滤得滤液，滤液真空干燥得淡黄色固体，收率36.8％-88.7％。
实施例45-氨基-1-烷基-1H-吲哚-3-腈的制备。
于150mL反应瓶中加入5-硝基-1-烷基-1H-吲哚-3-腈(1.0g)，钯碳(0.1g)和乙醇(50mL)，在氢气加压下室温搅拌4h后，抽滤，得滤液，减压浓缩至干得粗产品0.64g，收率：76.7-78.4％。
实施例5N-(1-烷基-3-氰基-1H-吲哚-5-基)芳杂环酰胺的制备。
于100mL反应瓶中加入各类羧酸芳杂环(10.00mmol)，以氯仿(50mL)为溶剂，加入二氯亚砜(3.57g，30.00mmol)和两滴DMF，在50℃搅拌下反应5h，反应完毕后真空干燥除去溶剂制得酰氯备用。
在150mL反应瓶中加入5-氨基-1-烷基-1H-吲哚-3-腈(4.07mmol)，三乙胺(1.24g，12.22mmol)和四氢呋喃(80mL)，-10℃搅拌下缓慢加入制备好的酰氯(6.11mmol)，维持反应温度30min后，室温反应过夜。反应完毕后，抽滤，滤饼用大量四氢呋喃洗，得滤液，减压浓缩除去大部分溶剂，加入大量水溶液(pH＝11-12)，析出沉淀，抽滤，滤饼用大量水洗，得滤饼，过快速硅胶柱，乙醇-水体系重结晶得到精产品，产率为36.8-83.7％。
(1)N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA1)。
白色固体粉末，收率83.7％。1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),9.28(s,1H),8.29(s,1H),8.20(s,1H),8.11(s,1H),7.79(d,J＝8.9Hz,1H),7.70(s,4H),4.21(s,2H),1.82(d,J＝6.6Hz,2H),0.84(s,3H).13C NMR(125MHz,DMSO-d6)δ163.17,144.50,136.96,134.41,133.67,131.99,128.62,127.19,123.05,120.11,117.42,116.02,115.92,114.18,111.54,109.70,83.15,47.85,22.63,10.75。
(2)N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA2)。
白色固体粉末，收率74.8％。1H NMR(500MHz,DMSO-d6)δ10.42(s,1H),9.28(s,1H),8.47(s,1H),8.22(s,1H),8.12(s,1H),7.78(d,J＝9.3Hz,1H),7.72–7.63(m,4H),7.34(d,J＝6.9Hz,2H),7.29(d,J＝7.0Hz,3H),5.52(s,2H).13C NMR(125MHz,DMSO-d6)δ163.20,144.50,137.34,136.51,134.42,133.85,131.87,128.63,128.58(2C),127.67,127.36,127.09(2C),123.03,120.08,117.64,116.02,115.72,114.18,111.84,109.78,83.85,49.84。
(3)N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺(WA3)。
白色固体粉末，收率72.6％。1H NMR(500MHz,DMSO-d6)δ10.44(s,1H),9.30(s,1H),8.37(s,1H),8.21(s,1H),8.12(s,1H),7.80(d,J＝9.0Hz,1H),7.70(d,J＝5.6Hz,4H),4.92(d,J＝6.6Hz,1H),2.18(d,J＝7.1Hz,2H),1.89–1.81(m,4H),1.70(s,2H).13C NMR(125MHz,DMSO-d6)δ163.17,144.50,136.85,134.23,133.76,132.06,128.63,127.34,123.08,120.10,117.34,116.01,115.89,114.23,111.80,109.64,83.50,57.34,31.84(2C),23.28(2C)。
(4)N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB1)。
黄色固体粉末，收率55.6％。1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),12.31(s,1H),8.64(s,1H),8.34(s,1H),8.30(s,1H),8.03(d,J＝5.7Hz,1H),7.84(d,J＝6.1Hz,1H),7.73(d,J＝7.3Hz,1H),7.56(d,J＝6.9Hz,1H),7.45(s,1H),4.22(s,2H),1.81(d,J＝5.6Hz,2H),0.85(s,3H).13C NMR(125MHz,DMSO-d6)δ162.71,142.92,139.90,137.03,133.70,133.35,131.85,127.51,122.56,122.41,122.12,116.55,115.94,115.92,112.03,108.52,83.17,47.85,22.64,10.75。
(5)N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB2)。
黄色固体粉末，收率38.5％。1H NMR(500MHz,DMSO-d6)δ13.15(s,1H),12.29(s,1H),8.63(s,1H),8.47(s,1H),8.36(s,1H),8.02(d,J＝7.0Hz,1H),7.84(d,J＝7.3Hz,1H),7.68(d,J＝8.5Hz,1H),7.54(d,J＝8.1Hz,1H),7.45(d,J＝6.9Hz,1H),7.33(d,J＝6.8Hz,2H),7.29(d,J＝6.7Hz,3H),5.53(s,2H).13C NMR(125MHz,DMSO-d6)δ162.75,142.90,139.89,137.42,136.52,133.87,133.35,131.75,128.58(2C),127.67,127.50,127.06(2C),122.57,122.42,122.08,116.82,115.92,115.75,112.33,108.64,83.87,49.82。
(6)N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺(WB3)。
黄色固体粉末，收率44.7％。1H NMR(500MHz,DMSO-d6)δ13.15(s,1H),12.31(s,1H),8.64(s,1H),8.39(s,1H),8.34(s,1H),8.03(d,J＝7.5Hz,1H),7.85(d,J＝7.0Hz,1H),7.75(d,J＝8.8Hz,1H),7.58(s,1H),7.44(s,1H),4.94(dd,J＝13.7,6.7Hz,1H),2.19(d,J＝7.7Hz,2H),1.91–1.82(m,4H),1.71(s,2H).13C NMR(125MHz,DMSO-d6)δ162.70,142.95,139.88,134.30,133.80,133.35,131.97,127.62,122.54,122.42,122.10,116.49,116.04,115.91,112.27,108.44,83.54,57.31,31.88(2C),23.26(2C)。
(7)N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC1)。
黄色固体粉末，收率42.7％。1H NMR(500MHz,DMSO-d6)δ10.61(s,1H),9.23(s,1H),8.71(d,J＝7.3Hz,2H),8.37(s,1H),8.29(s,1H),8.02(d,J＝4.2Hz,1H),7.78(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,1H),4.21(t,J＝6.7Hz,2H),1.80(dd,J＝14.1,7.0Hz,2H),0.83(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ159.91,143.60,141.16,139.01,136.95,133.27,131.96,129.19,127.07,120.81,117.54,116.42,115.96,111.49,109.59,83.18,47.80,22.64,10.74。
(8)N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC2)。
黄色固体粉末，收率36.8％。1H NMR(500MHz,DMSO-d6)δ10.60(s,1H),9.20(s,1H),8.68(s,1H),8.66(s,1H),8.45(s,1H),8.40(s,1H),8.00(d,J＝3.5Hz,1H),7.73(d,J＝8.7Hz,1H),7.62(d,J＝8.8Hz,1H),7.33(d,J＝6.9Hz,2H),7.30(d,J＝5.7Hz,3H),5.50(s,2H).13C NMR(125MHz,DMSO-d6)δ160.00,143.83,140.96,139.08,137.30,136.53,133.46,131.79,129.56,128.57(2C),127.67,127.26,127.13(2C),120.60,117.75,116.26,115.77,111.79,109.64,83.86,49.82。
(9)N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺(WC3)。
黄色固体粉末，收率40.2％。1H NMR(500MHz,DMSO-d6)δ10.60(s,1H),9.21(s,1H),8.69(s,1H),8.67(d,J＝4.6Hz,1H),8.38(s,2H),8.01(d,J＝4.4Hz,1H),7.78(d,J＝8.9Hz,1H),7.70(d,J＝8.9Hz,1H),4.94(dd,J＝13.7,6.7Hz,1H),2.20(d,J＝7.9Hz,2H),1.91–1.82(m,4H),1.71(s,2H).13C NMR(125MHz,DMSO-d6)δ159.99,143.84,141.02,139.10,134.23,133.39,132.03,129.57,127.25,120.61,117.44,116.25,116.04,111.77,109.52,83.54,57.30,31.84(2C),23.31(2C)。
(10)N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD1)。
白色固体粉末，收率45.2％。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),10.34(s,1H),8.66(d,J＝14.8Hz,1H),8.52(s,1H),8.28(s,3H),8.00(d,J＝6.7Hz,1H),7.74–7.64(m,2H),4.21(s,2H),1.81(s,2H),0.84(s,3H).13C NMR(125MHz,DMSO-d6)δ165.53,140.85,136.79,134.77,134.22,131.78,128.78,127.19,125.49,122.22,120.94,117.46,116.02,111.39,109.75,109.49,83.08,47.82,22.64,10.75。
(11)N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD2)。
白色固体粉末，收率66.5％。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),10.33(s,1H),8.73(s,1H),8.63(s,1H),8.58–8.49(m,1H),8.45(d,J＝8.3Hz,1H),8.32(d,J＝12.8Hz,1H),8.28(s,1H),7.98(d,J＝7.6Hz,1H),7.69(s,1H),7.66(s,1H),7.34(s,1H),7.30(s,3H),5.52(s,2H).13C NMR(125MHz,DMSO-d6)δ165.55,140.94,137.30,136.54,134.77,134.39,131.81,128.77,128.58(2C),127.67,127.36,127.09(2C),125.48,121.56,120.95,117.69,115.78,111.71,109.75,109.55,83.83,49.82。
(12)N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺(WD3)。
白色固体粉末，收率57.8％。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),10.33(s,1H),8.73(s,1H),8.63(s,1H),8.58–8.49(m,1H),8.45(d,J＝8.3Hz,1H),8.32(d,J＝12.8Hz,1H),8.28(s,1H),7.98(d,J＝7.6Hz,1H),7.69(s,1H),7.66(s,1H),7.34(s,1H),7.30(s,3H),5.52(s,2H).13C NMR(125MHz,DMSO-d6)δ165.55,140.94,137.30,136.54,134.77,134.39,131.81,128.77,128.58(2C),127.67,127.36,127.09(2C),125.48,121.56,120.95,117.69,115.78,111.71,109.75,109.55,83.83,49.82。
实施实例6N-(吲哚-5-基)双环芳酰胺类化合物的黄嘌呤氧化酶抑制活性研究。
1、试验材料。
试剂：黄嘌呤氧化酶(from bovin,Sigma)、黄嘌呤、磷酸二氢钾、氢氧化钠。
仪器：电子分析天平(AR1140型)、电热恒温水浴锅(DK-98-1型)、UV2100型紫外可见分光光度仪。
2、实验方法。
反应稀释液：50mM的磷酸钾缓冲液，pH值7.4。
样品配制：准确称取10μmmol的样品，加100μL的DMSO溶解，然后加900ml的PBS得10mM的母液。
黄嘌呤底物的配制：准确称取9.127mg黄嘌呤，加少量NaOH溶液溶解，再加PBS溶液稀释至100mL定容(每天现配)。
实验步骤：反应体系中依次加入黄嘌呤氧化酶(反应浓度1.4U/L)、受试药物(阳性药物采用托匹司他)，25℃孵育15min后加入黄嘌呤底物(反应浓度86μM)，反应60min后测294nm吸光度值。每个样品平行操作3次，分别记录反应速率，取平均值计算样品的抑制率。
空白对照组不加黄嘌呤氧化酶，加与样品同样体积的PBS，记录吸光度的变化作为空白对照。
根据下列公式计算样品对XOD的抑制率：
式中A样、A阴、A样空、A阴空：分别表示样品、空白对照、XOD对照品和酶对照品的吸收峰值。测试结果见表1。
表1样品在1.04μM浓度下对XO的抑制率。
实施例7N-(吲哚-5-基)双环芳酰胺类化合物与N-(3-取代-1-取代-1H-吲哚-5-基)酰胺类化合物A9的活性对比研究。
N-(3-取代-1-取代-1H-吲哚-5-基)酰胺类化合物是由申请人公开或报道XO抑制剂(CN111072634A)，其中活性最好的化合物为A9，它的分子结构如下：
实验步骤：反应体系中依次加入黄嘌呤氧化酶(反应浓度1.4U/L)、受试药物(终浓度分别为2.08μM，1.04μM，0.52μM,0.26μM,0.13μM)，25℃孵育15min后加入黄嘌呤底物(反应浓度86μM)，反应60min后测294nm吸光度值。每个样品平行操作3次，分别记录反应速率，取平均值计算样品的抑制率。活性对比研究结果见表2。
由表2可以发现该发明中部分化合物如WC3、WD1的XO抑制活性较A9提高了1位数量级。该发明中化合物无论分子结构方面还是药理活性方面均有显著的优势。
表2.不同化合物在2.08μM,1.04μM，0.52μM浓度下的XO抑制活性。
Claims (7)
1.一种N-(吲哚-5-基)双环芳酰胺类化合物，其特征在于，所述化合物为如通式I-II所示的化合物或其在药学上可接受的盐、水合物或溶剂化物，
其中：X,Y,Z为N、NH或CH；各R1独立为2-8个碳的烷基、3-8个碳原子环烷基、烯丙基、苄基或取代苄基；取代苄基为卤代苄基、氰基苄基、烷氧基苄基、烷基苄基或烷氨基苄基。
2.如权利要求1所述的N-(吲哚-5-基)双环芳酰胺类化合物，其特征在于，所述通式为I-II的化合物或其药学上可接受的盐、水合物或溶剂化物，结构选自下述任意一种：
N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺；
N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-6-甲酰胺；
N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺；
N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H苯并[d]咪唑-4-甲酰胺；
N-(1-丙基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺；
N-(1-苄基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)咪唑并[1,2-a]吡嗪-2-甲酰胺；
N-(1-丙基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺；
N-(1-苄基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺；
N-(1-环戊基-3-氰基-1H-吲哚-5-基)-1H-吲唑-5-甲酰胺。
3.如权利要求1所述的N-(吲哚-5-基)双环芳酰胺类化合物的制备方法，其特征在于，具体包括以下步骤：
步骤1、以5-硝基吲哚为起始原料，经醛基化，制得中间体5-硝基-1H-吲哚-3-甲醛；
步骤2、5-硝基-1H-吲哚-3-甲醛与羟胺反应，再经脱水，烃化后，制得重要中间体5-硝基-1-烷基-1H-吲哚-3-腈；
步骤3、5-硝基-1-烷基-1H-吲哚-3-腈经还原后与各类型酰氯反应，得到终产物。
4.一种药物组合物，其特征在于，包括所述的N-(吲哚-5-基)双环芳酰胺类化合物、其药学上可接受的盐、水合物或溶剂化物和药学上可接受的载体。
5.如权利要求1所述的N-(吲哚-5-基)双环芳酰胺类化合物或其药学上可接受的盐、水合物或溶剂化物或权利要求4所述的药物组合物在制备抗高尿酸血症和抗痛风药物中的应用。
6.如权利要求5所述的应用，其特征在于，所述药物的剂型为药物治疗学上可接受的剂型。
7.如权利要求5所述的应用，其特征在于，所述药物的剂量为药物治疗学上可接受的剂量。
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| CN111072634A (zh) * | 2020-01-03 | 2020-04-28 | 中国医科大学 | 1-取代-3-取代-5-取代酰胺-1h-吲哚类化合物及其制备方法和应用 |
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