CN114456136A - 双靶点非甾体抗炎化合物及其制备方法与用途 - Google Patents

双靶点非甾体抗炎化合物及其制备方法与用途 Download PDF

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CN114456136A
CN114456136A CN202210101670.7A CN202210101670A CN114456136A CN 114456136 A CN114456136 A CN 114456136A CN 202210101670 A CN202210101670 A CN 202210101670A CN 114456136 A CN114456136 A CN 114456136A
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高红伟
霍丽妮
苑仁祎坤
杨世林
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Abstract

本发明公开了一种双靶点非甾体抗炎化合物，具有以下通式：
Figure DDA0003492468010000011
其中，n＝3或6。本发明具有活性好、不良反应少的优点，本发明的方法将能与受体结合且结合位点不同的两个或者两个以上片段连接并发挥“片段与受体结合力”的加和效应，制备得到安全有效的双靶点新型非甾体抗炎化合物，应用各种免疫技术进行体内外毒性抗炎活性及机制研究。

Description

双靶点非甾体抗炎化合物及其制备方法与用途
技术领域
本发明涉及药物技术领域。更具体地说，本发明涉及一种双靶点非甾体抗炎化合物及其制备方法与用途。
背景技术
炎症(inflammation)，是生物组织受到某种刺激如外伤、感染等损伤因子的刺激所发生的一种以防御反应为主的基本病理过程。炎症反应过度时会对生物体产生重要伤害，如心血管疾病、癌症等多种疾病均与其具有密切联系。非甾体抗炎药在治疗急慢性炎症方面有疗效，但长期服用会产生诸多不良反应，如骨组织损伤、胃肠道损伤、肝脏损伤、中毒性肾损伤等。因此，制备减少此类不良反应是一直非甾体抗炎药的研发宗旨。
发明内容
本发明提供一种双靶点非甾体抗炎化合物及其制备方法与用途，其具有活性好、不良反应少的优点，本发明的方法将能与受体结合且结合位点不同的两个或者两个以上片段连接并发挥“片段与受体结合力”的加和效应，制备得到安全有效的双靶点新型非甾体抗炎化合物，应用各种免疫技术进行体内外毒性抗炎活性及机制研究。
本发明提供一种双靶点非甾体抗炎化合物，具有以下通式：
Figure BDA0003492460990000011
其中，
当化合物(I)为哌嗪类化合物时，X为
Figure BDA0003492460990000012
n＝3时，R6为CH3，CH(CH3)2，C(CH3)3，Ph，COCH3，COPh，Ph-4-CF3或COC4H4O；
n＝6时，R6为CH3，CH(CH3)2，C(CH3)3，Ph，COCH3，COPh，Ph-4-CF3或COC4H4O；
当化合物(I)为咪唑类化合物时，X为
Figure BDA0003492460990000021
n＝3时，R1为CH3、R2为H，R1为Ph、R2为H，R1为NO2、R2为H，R1为H、R2为CH3，R1为H、R2为Ph，或R1为H、R2为NO2；
n＝6时，R1为Ph、R2为H，或R1为NO2、R2为H；
当化合物(I)为四唑类化合物时，X为
Figure BDA0003492460990000022
n＝3时，R3为CH2CH3或CH2Ph，R4为CH3或Ph；
n＝6时，R3为CH2CH3或CH2Ph，R4为CH3或Ph；
当化合物(I)为巯基唑类化合物时，X为
Figure BDA0003492460990000023
n＝3时，R5为S、O；
n＝6时，R5为S、O。
药物，其含有治疗有效量的所述的双靶点非甾体抗炎化合物或其药学上可接受的盐和药学上可接受的载体。
优选的是，药学上可接受的载体包括稀释剂、增溶剂、潜溶剂、崩解剂、分散剂、润滑剂、矫味剂、抗氧剂、粘合剂、吸收剂、湿润剂、缓冲剂、交联剂。
优选的是，所述药物被制成药学上允许的剂型。
优选的是，所述剂型包括丸剂、片剂、粉剂、胶囊剂、颗粒剂、散剂、滴丸、滴剂、喷雾剂、注射剂、混悬液、膏剂、凝胶剂、栓剂。
双靶点非甾体抗炎化合物的制备方法，选定苯并呋喃作母核结构，以含氮杂环化合物作活性基团取代得到，其中含氮杂环化合物包括哌嗪、咪唑、四唑、巯基唑。
优选的是，苯并呋喃作母核结构的合成方法为：
称取对苯醌10.0mmol于N2保护下加入15mL甲苯溶解，称取苯甲酰乙酸乙酯13mmol和5mol％Cu(OTf)2加入25mL甲苯溶解，混合，在110℃下磁搅回流反应8-12h，TLC监测反应，石油醚:乙酸乙酯＝9:1，反应结束后，冷却至室温，用饱和NH4Cl溶液猝灭反应体系，乙酸乙酯萃取，收集有机层，用盐水洗涤，收集有机层用无水硫酸钠过夜干燥，过滤，滤液减压除去溶剂，残留物经柱层析纯化得到结构式为(II)的产物，二氯甲烷:甲醇:石油醚＝50:1:50；
Figure BDA0003492460990000031
称取1.0mmol结构式为(II)的产物，加入30mL乙腈和6.0mmol无水碳酸钾溶解，加入3.0mmol 1,3-二溴丙烷或1,6-二溴丙烷混匀，于60℃下磁搅回流反应6-10h，TLC监测反应，反应结束后，冷却至室温，加入30mL水，乙酸乙酯萃取，收集有机层，用无水硫酸钠过夜干燥，过滤，滤液减压回收溶剂，残留物经柱层析纯化得到结构式为(III)的产物，石油醚:乙酸乙酯＝9:1；
Figure BDA0003492460990000032
其中，n＝3或6。
优选的是，以含氮杂环化合物作活性基团取代反应为：
称取结构式为(III)的产物1.0mmol，加入20mL乙腈溶解，加入4.0mmol无水碳酸钾、5％KI，加入1.2mmol哌嗪化合物、咪唑化合物、四唑化合物或巯基唑类化合物，于45-75℃下磁搅回流反应4-8h至原料点消失，TLC监测反应，反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得结构式为(I)的化合物，石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝1:0.25-3，或二氯甲烷:甲醇:乙酸乙酯＝4:1:5。
所述的双靶点非甾体抗炎化合物在制备治疗急慢性炎症的药物中的应用。
本发明至少包括以下有益效果：
本发明制备的双靶点非甾体抗炎化合物具有活性好、不良反应少的优点，本发明的方法将能与受体结合且结合位点不同的两个或者两个以上片段连接并发挥“片段与受体结合力”的加和效应，制备得到安全有效的双靶点新型非甾体抗炎化合物，应用各种免疫技术进行体内外毒性抗炎活性及机制研究。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为采用MTT法评价部分化合物对小鼠巨噬细胞(RAW264.7)的毒性；
图2为采用MTT法评价部分化合物对小鼠巨噬细胞(RAW264.7)的毒性；
图3为采用MTT法评价部分化合物对小鼠巨噬细胞(RAW264.7)的毒性；
图4为采用MTT法评价部分化合物对小鼠巨噬细胞(RAW264.7)的毒性；
图5为化合物4-XM、1-JS、C1-BP对小鼠巨噬细胞(RAW264.7)的毒性以及对LPS诱导RAW264.7巨噬细胞亚硝酸盐生成的影响；
图6为浓度为80μM的化合物4-XM、1-JS、C1-BP对lps诱导RAW264.7细胞COX-2蛋白表达的影响；
图7为不同浓度的化合物4-XM对lps诱导RAW264.7细胞iNOS和COX-2蛋白表达的影响用不同浓度的4-XM处理细胞。
具体实施方式
下面结合附图对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
需要说明的是，下述实施方案中所述实验方法，如无特殊说明，均为常规方法，所述试剂和材料，如无特殊说明，均可从商业途径获得。
<实例1>
双靶点非甾体抗炎化合物及其制备方法，包括：
步骤一：
先称取对苯醌10.0mmol于N2保护下置于100mL三颈烧瓶中，加入15mL甲苯溶解，另称取苯甲酰乙酸乙酯13mmol和5mol％Cu(OTf)2于50mL单颈烧瓶中，加入25mL甲苯，完全溶解后于N2保护下转移至100mL三颈烧瓶中，在110℃下磁搅回流反应8-12h，TLC监测反应(石油醚:乙酸乙酯＝9:1)。
待反应结束后，冷却至室温，用饱和NH4Cl溶液猝灭反应体系，用乙酸乙酯(50mL×3)萃取，结合有机层，用盐水(30mL×3)洗涤。收集有机层用无水硫酸钠过夜干燥，过滤，滤液减压除去溶剂，残留物经柱层析纯化得到产物①(二氯甲烷:甲醇:石油醚
＝50:1:50)。
Figure BDA0003492460990000051
步骤二：
称取1.0mmol产物①置于50mL三颈烧瓶中，加入30mL乙腈和6.0mmol无水碳酸钾溶解，加入3.0mmol 1,3-二溴丙烷混匀，于60℃下磁搅回流反应6-10h，TLC监测反应。待反应结束后，冷却至室温，加入30mL水，乙酸乙酯萃取(30mL×3)，收集有机层，用无水硫酸钠过夜干燥，过滤，滤液减压回收溶剂，残留物经柱层析纯化的产物②。(石油醚:乙酸乙酯＝9:1)
Figure BDA0003492460990000052
或，
称取1.0mmol产物①置于50mL三颈烧瓶中，加入30mL乙腈和6.0mmol无水碳酸钾溶解，加入3.0mmol)1,6-二溴丙烷混匀，于60℃下磁搅回流反应6-10h，TLC监测反应。待反应结束后，冷却至室温，加入30mL水，乙酸乙酯萃取(30mL×3)，收集有机层，用无水硫酸钠过夜干燥，过滤，滤液减压回收溶剂，残留物经柱层析纯化的产物③。(石油醚:乙酸乙酯＝9:1)
Figure BDA0003492460990000061
步骤三：
称取产物②或③1.0mmol置于50mL三颈烧瓶中，加入20mL乙腈，待完全溶解后，加入4.0mmol无水碳酸钾、5％KI和1.2mmol哌嗪化合物，于60℃下磁搅回流反应至原料点消失(6h左右)，TLC监测反应。反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取三次(20mL×3)，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得产物(石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝1:3；或者二氯甲烷:甲醇:乙酸乙酯＝4:1:5)。
Figure BDA0003492460990000062
或，
称取溴代物1.0mmol置于50mL三颈烧瓶中，加入20mL乙腈，待完全溶解后，加入4.0mmol无水碳酸钾、5％KI和1.2mmol咪唑化合物，于75℃下磁搅回流反应至原料点消失(8h左右)，TLC监测反应。反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取三次(20mL×3)，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得产物(石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝1:2；或者二氯甲烷:甲醇:乙酸乙酯＝4:1:5)。
Figure BDA0003492460990000071
或，
称取溴代物1.0mmol置于50mL三颈烧瓶中，加入20mL乙腈，待完全溶解后，加入4.0mmol无水碳酸钾、5％KI和1.2mmol四唑化合物，于75℃下磁搅回流反应至原料点消失(4h左右)，TLC监测反应。反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取三次(20mL×3)，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得产物(石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝2:1)。
Figure BDA0003492460990000072
或，
称取溴代物1.0mmol置于50mL三颈烧瓶中，加入20mL乙腈，待完全溶解后，加入4.0mmol无水碳酸钾、5％KI和1.2mmol巯基唑化合物，于75℃下磁搅回流反应至原料点消失(4h左右)，TLC监测反应。反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取三次(20mL×3)，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得产物(石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝4:1)。
Figure BDA0003492460990000081
实施例1制备的化合物如下所示，含量均≥50mg，
1 1-YBP：(IC50＝10.66μMol/mL)
Figure BDA0003492460990000082
1H NMR(500MHz,DMSO)δ7.94(s,2H),7.54(t,J＝37.8Hz,5H),7.03(d,J＝7.1Hz,1H),4.32(s,2H),4.08(s,2H),3.34(s,6H),2.95(s,4H),1.94(s,2H),1.26(d,J＝39.0Hz,10H).
13C NMR(151MHz,CDCl3)δ164.05,161.31,156.20,148.82,130.15,129.80,129.48,128.00,127.90,114.65,111.59,108.98,105.75,67.14,60.57,55.36,54.46,53.60,48.70,26.91,18.68,14.26.
2 1-JP：(IC50＝7.837μMol/mL)
Figure BDA0003492460990000083
1H NMR(600MHz,CDCl3)δ7.98(dd,J＝6.6,3.2Hz,2H),7.55(d,J＝2.6Hz,1H),7.51–7.45(m,3H),7.40(d,J＝8.9Hz,1H),6.95(dd,J＝8.9,2.6Hz,1H),4.40(q,J＝7.1Hz,2H),4.10(t,J＝6.3Hz,2H),2.55(dd,J＝30.7,23.1Hz,10H),2.30(s,3H),2.05–1.99(m,2H),1.39(t,J＝7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ164.06,161.33,156.20,148.83,130.16,129.81,129.49,128.01,127.91,114.65,111.61,108.98,105.74,67.09,60.57,55.27,55.16,53.26,46.07,26.91,14.26.
3 1-BP：(IC50>80μMol/mL)
Figure BDA0003492460990000091
1H NMR(500 MHz,DMSO)δ7.94(s,2H),7.57(dd,J＝55.6,20.8 Hz,5H),7.20(t,J＝7.4 Hz,2H),7.04(d,J＝8.9 Hz,1H),6.93(d,J＝7.8 Hz,2H),6.76(t,J＝6.9 Hz,1H),4.32(dd,J＝13.6,6.7 Hz,2H),4.10(s,2H),3.34(s,5H),3.13(s,4H),2.54(s,3H),1.97(s,2H),1.30(t,J＝6.8 Hz,3H).
13C NMR(151 MHz,CDCl3)δ164.06,161.34,156.20,151.35,148.84,130.17,129.81,129.50,129.11,128.01,127.95,127.07,119.67,116.04,114.64,111.63,108.98,105.76,67.03,60.58,55.31,53.34,49.18,26.92,14.27.
4 1-SDP：(IC50＝7.687μMol/mL)
Figure BDA0003492460990000092
1H NMR(500 MHz,CDCl3)δ7.98(dd,J＝6.0,2.4 Hz,2H),7.55(d,J＝1.9 Hz,1H),7.48(d,J＝5.1 Hz,3H),7.41(d,J＝8.9 Hz,1H),6.95(dd,J＝8.9,2.1 Hz,1H),4.40(q,J＝7.1 Hz,2H),4.09(t,J＝6.2 Hz,2H),2.58(dd,J＝25.2,18.0 Hz,10H),2.06–2.00(m,2H),1.39(t,J＝7.1 Hz,3H),1.09(s,9H).
13C NMR(126 MHz,CDCl3)δ164.26,161.50,156.36,148.98,130.35,129.96,129.67,128.19,128.06,114.82,111.79,109.13,105.87,67.31,60.76,55.51,54.18,53.91,45.78,27.09,26.04,14.44.
5 1-YXP：(IC50＝15.98μMol/mL)
Figure BDA0003492460990000093
1H NMR(500 MHz,CDCl3)δ7.98,7.97,7.97,7.96,7.56,7.55,7.48,7.48,7.47,7.42,7.40,6.96,6.96,6.94,6.94,4.41,4.40,4.39,4.37,4.12,4.11,4.10,3.65,3.64,3.63,3.49,3.48,3.47,2.60,2.59,2.58,2.50,2.49,2.48,2.47,2.46,2.45,2.10,2.05,2.04,2.02,2.01,2.00,1.40,1.38,1.37.
13C NMR(126 MHz,CDCl3)δ169.19,164.26,161.55,156.29,149.01,130.40,129.94,129.69,128.21,128.14,114.77,111.86,109.10,105.79,66.90,60.79,55.26,53.57,52.99,46.46,41.59,26.92,21.55,14.42.
6 1-BXP：(IC50>80μMol/mL)
Figure BDA0003492460990000101
1H NMR(500 MHz,CDCl3)δ7.97(dd,J＝6.7,2.9 Hz,2H),7.55(d,J＝2.5 Hz,1H),7.50–7.46(m,3H),7.42–7.39(m,6H),6.95(dd,J＝8.9,2.6 Hz,1H),4.39(q,J＝7.1 Hz,2H),4.11(t,J＝6.3 Hz,2H),3.83(s,2H),3.46(s,2H),2.66–2.54(m,5H),2.44(s,2H),2.05–2.00(m,2H),1.38(t,J＝7.1 Hz,3H).
13C NMR(126 MHz,CDCl3)δ170.57,164.31,161.60,156.36,149.08,136.03,130.46,130.01,129.96,129.76,128.76,128.27,128.21,127.31,114.84,111.92,109.17,105.86,66.94,60.86,55.34,53.87,53.15,47.96,42.36,26.96,14.50.
7 1-SFBP：(IC50>80μMol/mL)
Figure BDA0003492460990000102
1H NMR(500 MHz,CDCl3)δ7.98,7.98,7.97,7.97,7.57,7.57,7.49,7.48,7.47,7.42,7.41,6.98,6.97,6.96,6.95,6.94,6.92,4.41,4.40,4.38,4.37,4.15,4.14,4.12,3.32,3.31,3.30,2.66,2.65,2.64,2.09,2.08,2.06,2.05,2.04,1.40,1.38,1.37.
13C NMR(126 MHz,CDCl3)δ164.06,161.36,156.19,153.32,148.86,130.19,129.81,129.51,128.02,127.99,127.09,126.40,126.37,114.63,114.46,111.65,108.97,105.73,66.92,60.58,55.21,53.02,48.00,26.89,14.24.
8 1-FNXP：(IC50>80μMol/mL)
Figure BDA0003492460990000103
1H NMR(600 MHz,CDCl3)δ7.98,7.98,7.97,7.56,7.48,7.48,7.42,7.41,7.00,7.00,6.96,6.95,6.95,6.48,6.48,4.41,4.40,4.39,4.38,4.13,4.12,4.11,3.85,2.63,2.62,2.61,2.56,2.07,2.06,2.05,2.04,2.02,1.40,1.39,1.37.
13C NMR(151 MHz,CDCl3)δ164.05,161.35,159.06,156.11,148.84,147.93,143.64,130.18,129.77,129.50,128.00,127.96,116.34,114.59,111.65,111.25,108.93,105.64,66.73,60.58,55.08,26.71,14.23.
9 4-BM：(IC50>80μMol/mL)
Figure BDA0003492460990000111
1H NMR(600 MHz,CDCl3)δ7.99,7.99,7.98,7.98,7.75,7.74,7.54,7.49,7.48,7.48,7.44,7.42,7.37,7.36,7.34,7.23,7.23,6.97,6.97,6.95,6.95,4.39,4.38,4.37,4.35,4.25,4.24,4.23,4.05,4.04,4.03,2.32,2.31,2.30,2.29,2.28,1.37,1.36,1.34.
13C NMR(151 MHz,CDCl3)δ163.93,161.53,155.60,149.02,142.36,137.54,134.04,130.24,129.67,129.51,128.58,128.05,128.02,126.77,124.72,114.82,114.34,111.82,108.93,105.88,64.49,60.61,43.80,30.83,14.22.
10 4-XM：(IC50>80μMol/mL)
Figure BDA0003492460990000112
1H NMR(500 MHz,DMSO)δ8.52,7.96,7.95,7.94,7.93,7.64,7.63,7.55,7.54,7.43,7.43,7.01,7.00,6.99,6.99,4.35,4.33,4.32,4.31,4.30,4.06,4.05,4.04,2.34,2.33,2.32,2.31,2.29,1.32,1.30,1.29.
13C NMR(151 MHz,CDCl3)δ164.06,161.31,156.20,148.82,130.15,129.80,129.48,128.00,127.90,114.65,111.59,108.98,105.75,67.14,60.57,55.36,54.46,53.60,48.70,26.91,18.68,14.26.
11 4-JM：(IC50>80μMol/mL)
Figure BDA0003492460990000121
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.98,7.97,7.53,7.48,7.48,7.48,7.47,7.43,7.42,6.96,6.96,6.95,6.95,6.94,6.94,6.66,4.41,4.40,4.39,4.37,4.16,4.15,4.14,4.13,4.12,4.01,4.00,3.99,2.26,2.25,2.24,2.23,2.22,1.39,1.38,1.37.
13C NMR(151 MHz,CDCl3)δ163.95,161.51,155.65,149.00,138.42,136.86,136.37,130.24,129.51,128.02,115.47,114.35,111.79,108.93,105.79,64.55,60.61,43.49,41.12,30.84,14.24,13.62.
12 2-JM：(IC50>80μMol/mL)
Figure BDA0003492460990000122
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.97,7.97,7.53,7.53,7.49,7.48,7.48,7.44,7.43,6.96,6.96,6.94,6.93,6.85,4.41,4.40,4.39,4.37,4.15,4.14,4.12,4.01,4.00,3.99,2.40,2.25,2.24,2.23,2.22,2.21,1.39,1.38,1.36.
13C NMR(126 MHz,CDCl3)δ164.29,161.89,155.85,149.33,144.98,130.60,130.00,129.85,128.37,127.28,119.52,114.62,112.18,109.25,105.98,77.61,77.36,77.11,64.51,60.97,42.83,30.68,14.58,13.08.
13 2-BM：(IC50>80μMol/mL)
Figure BDA0003492460990000123
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.97,7.60,7.59,7.49,7.48,7.48,7.47,7.43,7.42,7.41,7.40,7.39,7.16,7.07,6.84,6.84,6.83,6.83,4.41,4.40,4.39,4.37,4.34,4.33,4.31,3.99,3.98,3.97,2.26,2.25,2.24,2.23,2.22,1.39,1.37,1.36.
13C NMR(151 MHz,CDCl3)δ163.96,161.48,155.48,148.96,147.84,130.25,129.70,129.51,128.87,128.60,128.03,120.70,114.31,111.74,108.92,105.52,64.42,60.61,43.58,30.75,14.26.
14 2-XM：(IC50＝25.78μMol/mL)
Figure BDA0003492460990000131
1H NMR(600 MHz,CDCl3)δ7.98,7.98,7.98,7.97,7.97,7.53,7.52,7.49,7.49,7.48,7.48,7.44,7.43,7.13,7.10,7.10,6.94,6.93,6.92,6.92,4.72,4.71,4.70,4.41,4.40,4.39,4.37,4.05,4.04,4.03,2.41,2.40,2.39,2.38,2.37,1.39,1.38,1.37,-3.86.
13C NMR(151 MHz,CDCl3)δ164.06,161.31,156.20,148.82,130.15,129.80,129.48,128.00,127.90,114.65,111.59,108.98,105.75,67.14,60.57,55.36,54.46,53.60,48.70,26.91,18.68,14.26.
15 1-JS：(IC50>80μMol/mL)
Figure BDA0003492460990000132
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.98,7.97,7.56,7.55,7.49,7.48,7.48,7.48,7.47,7.43,7.41,6.96,6.96,6.95,6.95,4.42,4.41,4.39,4.38,4.20,4.19,4.18,3.93,3.61,3.60,3.59,2.40,2.39,2.38,2.37,2.36,1.40,1.39,1.38,-3.86.
13C NMR(151 MHz,CDCl3)δ163.99,161.47,155.80,154.15,148.96,130.23,129.72,129.50,128.03,127.99,114.53,111.76,108.97,105.72,66.30,60.63,33.38,30.11,29.06,14.29.
16 1-BS：(IC50>80μMol/mL)
Figure BDA0003492460990000133
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.98,7.98,7.98,7.97,7.60,7.60,7.60,7.59,7.59,7.58,7.58,7.57,7.57,7.57,7.56,7.56,7.55,7.55,7.54,7.54,7.49,7.48,7.48,7.47,7.47,7.46,7.42,7.40,6.95,6.95,6.94,6.93,4.41,4.40,4.39,4.37,4.20,4.19,4.18,3.66,3.64,3.63,2.43,2.42,2.42,2.41,2.40,2.39,1.39,1.38,1.37,-3.86.
13C NMR(151 MHz,CDCl3)δ163.99,161.45,155.80,154.18,148.95,133.67,130.22,130.15,129.82,129.73,129.50,128.03,127.96,123.83,114.55,111.74,108.97,105.72,66.36,60.62,30.14,28.93,14.28.
17 5-BSS：(IC50>80μMol/mL)
Figure BDA0003492460990000141
1H NMR(600 MHz,CDCl3)δ7.98,7.98,7.97,7.97,7.52,7.48,7.47,7.42,7.40,7.38,7.37,7.29,7.27,7.26,7.24,7.23,7.22,6.93,6.92,6.91,6.91,4.84,4.83,4.82,4.40,4.39,4.38,4.37,4.08,4.07,4.06,2.52,2.51,2.50,2.49,2.48,1.39,1.38,1.37.
13C NMR(151 MHz,CDCl3)δ163.95,163.74,161.48,155.58,149.01,136.51,130.23,129.68,129.50,129.02,128.57,128.01,127.95,127.62,114.52,111.76,108.94,105.84,64.81,60.62,50.41,36.47,29.11,14.25.
18 5-YSS：(IC50>80μMol/mL)
Figure BDA0003492460990000142
1H NMR(600 MHz,CDCl3)δ7.99,7.99,7.98,7.53,7.49,7.48,7.43,7.41,6.95,6.93,4.86,4.85,4.84,4.42,4.41,4.39,4.38,4.13,4.12,4.11,3.22,3.21,3.20,3.18,2.56,2.55,2.54,2.52,2.51,1.43,1.42,1.40,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ164.28,163.98,161.51,155.62,149.04,130.25,129.71,129.52,128.04,127.97,114.56,111.78,108.97,105.85,64.89,60.64,50.43,29.18,26.48,14.96,14.28.
19 2-QS：(IC50>80μMol/mL)
Figure BDA0003492460990000143
1H NMR(600 MHz,CDCl3)δ7.99,7.99,7.98,7.98,7.68,7.67,7.55,7.55,7.48,7.47,7.42,7.41,7.22,7.21,6.96,6.96,6.95,6.95,4.42,4.41,4.39,4.38,4.20,4.19,4.18,3.47,3.46,3.45,2.32,2.31,2.30,2.29,2.28,1.41,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ164.60,164.01,161.40,155.92,148.89,142.76,130.18,129.74,129.48,128.01,127.91,118.92,114.57,111.66,108.97,105.78,66.58,60.59,31.20,29.12,14.27.
20 2-QBS：(IC50>80μMol/mL)
Figure BDA0003492460990000151
1H NMR(600 MHz,CDCl3)δ8.00,7.99,7.98,7.86,7.85,7.76,7.74,7.56,7.49,7.48,7.42,7.41,7.39,7.30,7.29,7.28,6.98,6.97,4.41,4.40,4.39,4.38,4.24,4.23,4.22,3.61,3.60,3.59,2.41,2.40,2.39,2.38,2.37,1.40,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ166.64,164.02,161.41,155.91,153.27,148.91,135.23,130.19,129.75,129.49,128.02,127.91,126.02,124.22,121.51,120.95,114.58,111.68,108.98,105.79,66.59,60.60,30.30,29.19,14.27,-0.01.
21 2-QBE：(IC50>80μMol/mL)
Figure BDA0003492460990000152
1H NMR(600 MHz,CDCl3)δ8.00,7.99,7.99,7.61,7.59,7.56,7.56,7.49,7.48,7.44,7.43,7.41,7.31,7.29,7.28,7.25,7.24,7.23,4.42,4.40,4.39,4.38,4.24,4.23,4.22,3.57,3.56,3.55,2.43,2.42,2.41,2.40,2.39,1.40,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ164.74,164.01,161.44,155.88,151.84,148.93,141.92,130.20,129.49,128.02,124.28,123.87,118.39,114.56,111.70,109.87,105.77,66.43,60.60,29.13,29.02,14.27,-0.01.
22 C4-BM：(IC50>80μMol/mL)
Figure BDA0003492460990000153
1H NMR(600 MHz,CDCl3)δ7.98,7.98,7.97,7.79,7.77,7.62,7.54,7.48,7.47,7.41,7.39,7.39,7.38,7.36,7.25,7.23,7.22,6.95,6.94,6.93,6.93,4.40,4.39,4.38,4.37,4.05,4.04,4.03,4.02,4.01,4.00,1.92,1.91,1.89,1.88,1.87,1.86,1.85,1.84,1.82,1.81,1.60,1.59,1.57,1.56,1.55,1.47,1.46,1.44,1.43,1.42,1.39,1.38,1.36.
13C NMR(151 MHz,CDCl3)δ164.07,161.35,156.16,148.81,137.01,130.18,129.50,128.66,128.01,126.99,124.80,114.62,111.67,108.94,105.55,68.32,60.57,47.43,30.95,29.12,26.34,25.71,14.23.
23 C4-XM：(IC50>80μMol/mL)
Figure BDA0003492460990000161
1H NMR(500 MHz,CDCl3)δ7.98,7.97,7.96,7.96,7.77,7.55,7.54,7.49,7.48,7.48,7.44,7.43,7.41,6.95,6.94,6.93,6.92,4.41,4.40,4.38,4.37,4.06,4.05,4.03,4.03,1.94,1.93,1.91,1.90,1.89,1.87,1.86,1.84,1.83,1.81,1.59,1.57,1.56,1.47,1.46,1.44,1.43,1.41,1.39,1.38,1.36.
13C NMR(126 MHz,CDCl3)δ164.15,161.46,156.16,148.90,135.94,130.29,129.83,129.59,128.10,128.06,119.07,114.66,111.79,108.97,105.55,68.24,60.67,48.44,30.76,29.11,26.27,25.71,14.30.
24 C1-JP(IC50＝9.505μMol/mL)
Figure BDA0003492460990000162
1H NMR(500 MHz,CDCl3)δ7.98,7.97,7.97,7.54,7.48,7.47,7.47,7.41,7.39,6.96,6.95,6.94,6.93,4.41,4.40,4.39,4.37,4.05,4.03,4.02,2.46,2.37,2.35,2.34,2.28,1.40,1.39,1.37.
13C NMR(126 MHz,CDCl3)δ163.98,161.20,156.14,148.64,130.04,129.66,129.36,127.89,127.75,114.55,111.50,108.82,105.44,68.48,60.46,58.56,54.94,53.08,45.89,29.17,27.30,26.72,25.96,14.12.
25 C1-BP：(IC50>80μMol/mL)
Figure BDA0003492460990000163
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.97,7.55,7.48,7.47,7.42,7.40,7.28,7.25,6.97,6.95,6.93,6.87,6.85,6.84,4.42,4.40,4.39,4.38,4.06,4.05,4.04,3.22,3.21,2.62,2.43,2.42,2.40,1.87,1.85,1.84,1.61,1.60,1.58,1.56,1.55,1.53,1.46,1.44,1.43,1.41,1.39,1.38.
13C NMR(126 MHz,CDCl3)δ164.02,161.25,156.21,151.27,148.70,130.10,129.72,129.42,129.03,127.94,127.82,119.58,115.95,114.60,111.56,108.88,105.50,68.53,60.50,58.66,53.26,49.06,29.23,27.34,26.80,26.02,14.18.
26 C1-SDP：(IC50＝7.673μMol/mL)
Figure BDA0003492460990000171
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.54,7.48,7.48,7.47,7.42,7.41,7.40,7.40,6.96,6.94,4.41,4.40,4.39,4.39,4.05,4.04,4.03,2.63,2.52,2.36,2.35,2.33,1.80,1.54,1.41,1.40,1.39,1.39,1.38,1.38,1.08.
13C NMR(126 MHz,CDCl3)δ163.77,160.98,155.93,148.42,129.82,129.45,129.15,127.67,127.53,114.34,111.28,108.61,105.24,68.28,60.24,58.36,53.57,53.42,45.18,28.96,27.12,26.51,25.75,25.48,13.91.
27 C1-YBP：(IC50＝11.2μMol/mL)
Figure BDA0003492460990000172
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.98,7.97,7.54,7.54,7.48,7.47,7.47,7.41,7.40,6.96,6.96,6.94,6.94,4.42,4.40,4.39,4.38,4.05,4.04,4.02,2.68,2.66,2.65,2.64,2.62,2.37,2.35,2.34,1.86,1.85,1.83,1.82,1.81,1.58,1.56,1.55,1.53,1.52,1.51,1.49,1.41,1.39,1.38,1.06,1.05.
13C NMR(126 MHz,CDCl3)δ164.08,161.31,156.31,148.79,130.14,129.83,129.49,128.01,127.90,114.70,111.60,108.99,105.65,68.66,60.56,58.76,54.46,53.55,48.65,29.31,27.45,26.86,26.09,18.65,14.25.
28 C1-YXP：(IC50＝23.15μMol/mL)
1H NMR(500 MHz,CDCl3)δ7.97,7.96,7.54,7.48,7.47,7.41,7.40,6.95,6.93,4.41,4.40,4.38,4.37,4.05,4.04,4.02,3.62,3.47,3.46,3.46,2.43,2.42,2.41,2.40,2.38,2.36,2.35,2.08,1.85,1.83,1.82,1.81,1.57,1.55,1.54,1.53,1.51,1.49,1.40,1.38,1.37.
13C NMR(126 MHz,CDCl3)δ169.12,164.28,161.52,156.44,148.96,130.37,129.97,129.68,128.20,128.10,114.84,111.82,109.12,105.72,68.75,60.76,58.69,53.55,53.00,46.44,41.55,29.48,27.47,26.92,26.24,21.55,14.43.
29 C1-BXP：(IC50>80μMol/mL)
Figure BDA0003492460990000173
1H NMR(500 MHz,CDCl3)δ7.98,7.98,7.97,7.97,7.96,7.54,7.54,7.48,7.47,7.47,7.41,7.40,6.95,6.95,6.94,6.94,6.93,4.41,4.39,4.39,4.38,4.37,4.37,4.36,4.05,4.04,4.03,4.02,3.80,3.43,2.53,2.40,2.38,2.37,1.85,1.83,1.82,1.54,1.53,1.52,1.42,1.40,1.39,1.39,1.38,1.37,1.37,1.36.
13C NMR(126 MHz,CDCl3)δ170.15,163.97,161.20,156.13,148.64,135.66,130.06,129.66,129.56,129.37,128.36,127.89,127.78,126.92,115.23,114.53,111.51,108.81,105.41,68.43,60.46,58.37,53.45,52.74,47.54,41.94,29.59,29.17,27.14,26.54,25.92,14.12.
30 C1-SFBP：(IC50>80μMol/mL)
Figure BDA0003492460990000181
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.97,7.97,7.56,7.55,7.48,7.47,7.46,7.42,7.40,6.97,6.96,6.95,6.94,6.92,6.91,4.42,4.40,4.39,4.37,4.07,4.05,4.04,3.30,3.29,3.28,2.60,2.59,2.58,2.43,2.41,2.40,1.88,1.87,1.85,1.84,1.82,1.57,1.55,1.53,1.52,1.46,1.45,1.43,1.42,1.40,1.39,1.37.
13C NMR(126 MHz,CDCl3)δ164.08,161.33,156.30,153.34,148.81,130.18,129.82,129.50,128.02,127.95,126.38,126.35,114.69,114.43,111.63,108.98,105.64,68.63,60.56,58.63,53.02,47.97,29.31,27.34,26.85,26.07,14.24.
31 C1-FNXP：(IC50>80μMol/mL)
Figure BDA0003492460990000182
1H NMR(500 MHz,CDCl3)δ7.98,7.98,7.97,7.97,7.55,7.55,7.48,7.42,7.40,6.99,6.98,6.96,6.96,6.95,6.94,6.48,6.48,6.47,6.47,4.42,4.40,4.39,4.37,4.06,4.05,4.03,3.82,2.52,2.51,2.50,2.41,2.40,2.38,1.87,1.86,1.84,1.83,1.82,1.73,1.60,1.58,1.57,1.55,1.54,1.52,1.51,1.40,1.39,1.37.
13C NMR(126 MHz,CDCl3)δ164.09,161.32,159.06,156.28,148.80,147.93,143.64,130.16,129.81,129.49,128.01,127.92,116.31,114.67,111.62,111.25,108.96,105.62,68.61,60.57,58.48,29.30,27.28,26.68,26.05,14.23.
32 C1-JS：(IC50>80μMol/mL)
Figure BDA0003492460990000191
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.98,7.54,7.54,7.48,7.48,7.47,7.42,7.40,6.96,6.95,6.94,6.94,4.42,4.40,4.39,4.38,4.06,4.04,4.03,3.91,3.39,3.38,3.36,1.87,1.86,1.85,1.57,1.56,1.40,1.39,1.38.
13C NMR(126 MHz,CDCl3)δ164.13,161.38,156.26,154.48,148.84,130.24,129.83,129.55,128.07,127.96,114.68,111.71,109.00,105.60,68.45,60.65,33.39,33.25,29.32,29.22,28.40,25.67,14.32.
33 C1-BS：(IC50>80μMol/mL)
Figure BDA0003492460990000192
1H NMR(500 MHz,CDCl3)δ7.98(d,J＝4.7 Hz,2H),7.58(t,J＝6.4 Hz,4H),7.54(d,J＝7.1 Hz,2H),7.48(d,J＝4.8 Hz,3H),7.41(d,J＝8.9 Hz,1H),6.94(d,J＝8.8 Hz,1H),4.39(q,J＝7.1 Hz,2H),4.04(t,J＝6.2 Hz,2H),3.43(t,J＝7.2 Hz,2H),1.94–1.79(m,5H),1.56(s,3H),1.39(t,J＝7.1 Hz,3H).
13C NMR(126 MHz,CDCl3)δ163.99,161.24,156.12,154.37,148.69,133.63,130.09,130.01,129.71,129.41,127.93,127.81,123.76,114.55,111.56,108.87,105.46,68.32,60.50,33.15,29.08,28.97,28.33,25.55,14.18.
34 C1-BSS：(IC50>80μMol/mL)
Figure BDA0003492460990000193
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.97,7.54,7.48,7.47,7.42,7.40,7.40,7.38,7.31,7.30,7.29,7.25,7.24,7.23,6.95,6.95,6.94,6.94,4.59,4.58,4.57,4.41,4.40,4.39,4.38,4.04,4.03,4.02,2.06,2.05,2.03,2.02,2.01,1.84,1.83,1.82,1.81,1.80,1.57,1.40,1.39,1.37.
13C NMR(151 MHz,CDCl3)δ164.06,163.49,161.35,156.18,148.81,136.58,130.17,129.49,129.03,128.57,128.01,127.62,114.62,111.66,108.96,105.57,68.33,60.57,53.28,36.53,29.14,29.07,26.11,25.53,14.25,-0.01.
35 C1-YSS：(IC50>80μMol/mL)
Figure BDA0003492460990000201
1H NMR(600 MHz,CDCl3)δ7.99,7.98,7.98,7.54,7.53,7.48,7.48,7.47,7.42,7.40,6.95,6.95,6.94,6.93,4.60,4.59,4.58,4.42,4.40,4.39,4.38,4.05,4.03,4.02,3.23,3.21,3.20,3.19,2.08,2.07,2.06,2.05,2.03,1.85,1.84,1.83,1.82,1.81,1.60,1.58,1.56,1.55,1.43,1.42,1.41,1.40,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ164.06,164.00,161.34,156.17,148.80,130.16,129.78,129.49,128.00,127.90,114.63,111.65,108.96,105.58,68.33,60.57,53.23,29.18,29.08,26.50,26.15,25.53,14.95,14.25.
36 C1-QS：(IC50>80μMol/mL)
Figure BDA0003492460990000202
1H NMR(500 MHz,CDCl3)δ7.99,7.98,7.98,7.97,7.67,7.66,7.54,7.54,7.48,7.47,7.47,7.42,7.40,7.21,7.20,6.96,6.95,6.94,6.94,4.42,4.40,4.39,4.37,4.05,4.04,4.03,3.26,3.24,3.23,1.84,1.84,1.83,1.82,1.81,1.57,1.56,1.55,1.54,1.54,1.40,1.39,1.38.
13C NMR(126 MHz,CDCl3)δ165.15,163.97,161.22,156.12,148.66,142.60,130.06,129.68,129.38,127.90,127.77,118.55,114.54,111.52,108.85,105.46,68.38,60.47,34.34,29.07,28.40,25.56,14.15.
37 C1-QBS：(IC50>80μMol/mL)
Figure BDA0003492460990000203
1H NMR(600 MHz,CDCl3)δ7.99,7.99,7.98,7.87,7.86,7.76,7.75,7.54,7.48,7.47,7.42,7.41,7.41,7.40,7.30,7.29,7.28,6.96,6.96,6.94,6.94,4.41,4.40,4.39,4.38,4.06,4.05,4.04,3.39,3.38,3.37,1.90,1.89,1.88,1.87,1.86,1.85,1.59,1.59,1.58,1.40,1.39,1.38.
13C NMR(151 MHz,CDCl3)δ167.25,164.07,161.32,156.24,153.33,148.78,135.15,130.15,129.80,129.48,128.00,127.89,126.00,124.12,121.45,120.92,114.66,111.62,108.97,105.60,68.50,60.56,33.47,29.18,29.16,28.52,25.65,14.24,-0.01.
38C1-QBE：(IC50>80μMol/mL)
Figure BDA0003492460990000211
1H NMR(600MHz,CDCl3)δ7.97,7.97,7.96,7.59,7.58,7.53,7.53,7.47,7.46,7.43,7.41,7.40,7.38,7.29,7.27,7.26,7.23,7.22,7.21,6.94,6.94,6.93,6.92,4.40,4.38,4.37,4.36,4.05,4.04,4.03,3.34,3.33,3.32,1.90,1.89,1.87,1.86,1.84,1.83,1.58,1.57,1.57,1.38,1.37,1.36.
13C NMR(151MHz,CDCl3)δ165.16,164.08,161.33,156.23,151.80,148.79,141.99,130.15,129.49,128.01,124.23,123.78,118.34,114.66,111.63,109.83,108.97,105.59,77.22,77.01,76.80,68.49,60.57,32.17,29.19,28.43,25.66,14.25,-0.01.
所有化合物用不同梯度浓度(苯并呋喃并哌嗪类化合物：5、10、20、40、80μM；苯并呋喃并氮唑类化合物：20、40、80μM)处理小鼠巨噬细胞(RAW264.7)24h，MTT法检测细胞活力，结果如图1-4所示：化合物浓度高达80μΜ时，绝大部分苯并呋喃并哌嗪类化合物毒性较大，可杀死80～99％的RAW264.7细胞，绝大部分苯并呋喃并氮唑类化合物对RAW264.7细胞的毒性较小，且2位取代相对4位取代的化合物毒性较大。MTT法筛选共得到16个毒性较小化合物：C1-BP、C1-BXP、1-JS、1-BS、C1-JS、C1-BS、4-XM、C4-XM、4-BM、C4-BM、2-QBS、C2-QBS、5-YSS、5-BSS、C5-YSS、C5-B。对筛选得到的毒性较小的16个化合物用不同梯度浓度(20、40、80μM)处理小鼠巨噬细胞(RAW264.7)18h，Griess法测定LPS诱导RAW264.7细胞中亚硝酸盐的含量，结果如图5所示：化合物4-XM,1-JS，C1-BP(20/40/80μΜ)抗炎活性较好。WesternBlotting结果表明LPS刺激显著增加了COX-2蛋白的表达，三个化合物均可降低COX-2的表达，相较于另外两个化合物，化合物4-XM对COX-2蛋白的表达下调更为明显(图6)，具有较好的抗炎活性。此外，进一步研究发现化合物4-XM对iNOs和COX-2的表达浓度依赖性下调，如图7所示。
申请人课题组从中药丹参中分离了一种新的苯并呋喃衍生物，活性研究发现其可极大地抑制脂多糖(LPS)刺激的RAW 264.7巨噬细胞中NO、(TNF)-α和(IL)-6等炎症因子分泌，能显著破坏LPS诱导的RAW264.7巨噬细胞的TLR4二聚，从而抑制MAPK信号通路转导，是一种活性较好的抗炎剂先导物，由于提取产率较低及对天然中草药的保护观念，本研究以DB作优势先导物，结合基于片段的药物设计研究策略，我们将具有5-LOX抑制作用的亲水活性片段与具有COX-2抑制作用的苯并呋喃母核拼合，目的是合成并筛选出毒性小溶解度好活性好的COX-2/5-LOX双靶点非甾体抗炎化合物。根据设计原理我们所合成的38个化合物相较于原先导物DB，具有毒性小，溶解度好及双靶点抑制的优势作用。当然，由于所合成的化合物篇幅过大，课题组对部分化合物毒性以及活性进行探讨，制备得到安全有效的双靶点新型非甾体抗炎化合物，应用各种免疫技术进行体内外毒性抗炎活性及机制研究。
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用，它完全可以被适用于各种适合本发明的领域，对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节和这里示出与描述的图例。

Claims (9)

1.双靶点非甾体抗炎化合物，其特征在于，具有以下通式：
Figure FDA0003492460980000011
其中，
当化合物(I)为哌嗪类化合物时，X为
Figure FDA0003492460980000012
n＝3时，R6为CH3，CH(CH3)2，C(CH3)3，Ph，COCH3，COPh，Ph-4-CF3或COC4H4O；
n＝6时，R6为CH3，CH(CH3)2，C(CH3)3，Ph，COCH3，COPh，Ph-4-CF3或COC4H4O；
当化合物(I)为咪唑类化合物时，X为
Figure FDA0003492460980000013
n＝3时，R1为CH3、R2为H，R1为Ph、R2为H，R1为NO2、R2为H，R1为H、R2为CH3，R1为H、R2为Ph，或R1为H、R2为NO2；
n＝6时，R1为Ph、R2为H，或R1为NO2、R2为H；
当化合物(I)为四唑类化合物时，X为
Figure FDA0003492460980000014
n＝3时，R3为CH2CH3或CH2Ph，R4为CH3或Ph；
n＝6时，R3为CH2CH3或CH2Ph，R4为CH3或Ph；
当化合物(I)为巯基唑类化合物时，X为
Figure FDA0003492460980000021
n＝3时，R5为S、O；
n＝6时，R5为S、O。
2.药物，其特征在于，其含有治疗有效量的权利要求1所述的双靶点非甾体抗炎化合物或其药学上可接受的盐和药学上可接受的载体。
3.如权利要求2所述的药物，其特征在于，药学上可接受的载体包括稀释剂、增溶剂、潜溶剂、崩解剂、分散剂、润滑剂、矫味剂、抗氧剂、粘合剂、吸收剂、湿润剂、缓冲剂、交联剂。
4.如权利要求2所述的药物，其特征在于，所述药物被制成药学上允许的剂型。
5.如权利要求4所述的药物，其特征在于，所述剂型包括丸剂、片剂、粉剂、胶囊剂、颗粒剂、散剂、滴丸、滴剂、喷雾剂、注射剂、混悬液、膏剂、凝胶剂、栓剂。
6.双靶点非甾体抗炎化合物的制备方法，其特征在于，选定苯并呋喃作母核结构，以含氮杂环化合物作活性基团取代得到，其中含氮杂环化合物包括哌嗪、咪唑、四唑、巯基唑。
7.如权利要求6所述的双靶点非甾体抗炎化合物的制备方法，其特征在于，苯并呋喃作母核结构的合成方法为：
称取对苯醌10.0mmol于N2保护下加入15mL甲苯溶解，称取苯甲酰乙酸乙酯13mmol和5mol％Cu(OTf)2加入25mL甲苯溶解，混合，在110℃下磁搅回流反应8-12h，TLC监测反应，石油醚:乙酸乙酯＝9:1，反应结束后，冷却至室温，用饱和NH4Cl溶液猝灭反应体系，乙酸乙酯萃取，收集有机层，用盐水洗涤，收集有机层用无水硫酸钠过夜干燥，过滤，滤液减压除去溶剂，残留物经柱层析纯化得到结构式为(II)的产物，二氯甲烷:甲醇:石油醚＝50:1:50；
Figure FDA0003492460980000022
称取1.0mmol结构式为(II)的产物，加入30mL乙腈和6.0mmol无水碳酸钾溶解，加入3.0mmol 1,3-二溴丙烷或1,6-二溴丙烷混匀，于60℃下磁搅回流反应6-10h，TLC监测反应，反应结束后，冷却至室温，加入30mL水，乙酸乙酯萃取，收集有机层，用无水硫酸钠过夜干燥，过滤，滤液减压回收溶剂，残留物经柱层析纯化得到结构式为(III)的产物，石油醚:乙酸乙酯＝9:1；
Figure FDA0003492460980000031
其中，n＝3或6。
8.如权利要求7所述的双靶点非甾体抗炎化合物的制备方法，其特征在于，以含氮杂环化合物作活性基团取代反应为：
称取结构式为(III)的产物1.0mmol，加入20mL乙腈溶解，加入4.0mmol无水碳酸钾、5％KI，加入1.2mmol哌嗪化合物、咪唑化合物、四唑化合物或巯基唑类化合物，于45-75℃下磁搅回流反应4-8h至原料点消失，TLC监测反应，反应结束后，静置冷却至室温，倒入20mL纯水中，用乙酸乙酯60mL萃取，收集有机层，无水硫酸钠干燥过夜，过滤，滤液减压回收溶剂，残留物经柱层析梯度洗脱纯化可得结构式为(I)的化合物，石油醚:乙酸乙酯＝6:1，石油醚:乙酸乙酯＝1:0.25-3，或二氯甲烷:甲醇:乙酸乙酯＝4:1:5。
9.权利要求1所述的双靶点非甾体抗炎化合物在制备治疗急慢性炎症的药物中的应用。
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