CN110615774B - 具有抗炎活性的苄基哌嗪类化合物、制法及医药用途 - Google Patents

具有抗炎活性的苄基哌嗪类化合物、制法及医药用途 Download PDF

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CN110615774B
CN110615774B CN201910884803.0A CN201910884803A CN110615774B CN 110615774 B CN110615774 B CN 110615774B CN 201910884803 A CN201910884803 A CN 201910884803A CN 110615774 B CN110615774 B CN 110615774B
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piperazine
inflammation
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李家明
何广卫
马晓东
刘万冬
刘为中
储昭兴
侯彩云
许勤龙
黄元政
金帆
莫佳佳
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Hefei Amvite Pharmaceutical Co ltd
Hefei Industrial Pharmaceutical Institute Co ltd
Anhui University of Traditional Chinese Medicine AHUTCM
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Hefei Industrial Pharmaceutical Institute Co ltd
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Abstract

本发明涉及药物化学领域，具体涉及一类具有抗炎活性的苄基哌嗪类化合物(I)及其制备方法，药效学试验证明，本发明的化合物具有COX‑2、NF‑κB以及p38 MAPK多靶点抑制功效，可用于预防和治疗炎症相关疾病。

Description

具有抗炎活性的苄基哌嗪类化合物、制法及医药用途
技术领域
本发明涉及药物化学领域，具体涉及一类具有抗炎活性的苄基哌嗪类化合物、制备方法及医药用途。
背景技术
炎症是机体受到外界刺激或细胞损伤所发生的适应性反应，通过清除炎症因子和修复受损组织维持机体的内环境稳定。虽然炎症反应对于保持机体健康至关重要，但是不可控制的炎症反应却能参与诸多慢性疾病的发生，例如哮喘、动脉粥样硬化、类风湿性关节炎以及癌症等[Sun S,Ji Y,Kersten S,et al.Mechanisms of inflammatory responsesin obese adipose tissue[J].Annual Review of Nutrition,2012(1):261-286]。因此，临床应用极为广泛的抗炎药成为使用最多的药物种类之一。
目前，大多数抗炎药物的研发策略主要集中于以下两个方面，其一直接通过相关介质或其靶点抑制某些促炎症介质的生成，如使用非甾体抗炎药直接抑制COX酶的活性，阻断花生四烯酸转化成强效的促炎介质***素2[Carlo Patrono,BiancaRocca.Nonsteroidal antiinflammatory drugs:Past,present and future[J].Pharmacological Research,2009,59(5): 285-289]；其二通过调控炎症的上游靶点，阻断相关酶的转录与表达，从而间接抑制促炎症介质的生成，如MAPK p38抑制剂阻断COX-2、iNOS基因的转录与表达，间接抑制***素2以及一氧化氮的生成[Chian-Jiun Liou,Wen-BinLen,Shu-JuWu,et al.Casticin inhibits COX-2 and iNOS expression viasuppression of NF-κB and MAPK signaling in lipopolysaccharide-stimulatedmouse macrophages[J].Journal of Ethnopharmacology,2014,158: 310-316]。然而，非甾体抗炎药由于胃肠道副作用和潜在的心血管不良反应，严重限制了其临床应用；MAPKp38以及相关靶点的抑制剂也因存在不可避免的副作用，难以进入临床应用。炎症是一个由多种介质组成的网络体系，能否根据单一的靶点开发出治疗效果好、副作用小的抗炎药尚存疑问。因此，寻找研发新策略，设计出高效低毒的候选药成为抗炎药物研发的重要方向。
基于炎症的消退涉及诸多的细胞因子和调节机制，多靶点药物对多个炎症靶点进行适度调控，可通过协同作用提高治疗效果，也避免某些靶点的受到过度抑制所介导的不良反应。临床上也常采用低剂量的药物组合治疗炎性疼痛，以达到治疗效果最大化的同时又能避免副作用的目的。一直以来，多靶点药物都是治疗由多通路、多靶点介导的慢性疾病的重要手段。现有的抗炎药由于对单一靶点过度抑制引起的副作用，严重威胁患者的生命安全。因此，基于多靶点研发出新型抗炎药物对治疗炎症尤其是慢性炎症性疾病具有开创性意义。
发明内容
本发明公开了一类苄基哌嗪类化合物，结构式如下：
Figure BDA0002206979960000021
其中R1代表任意取代的C1～C6的烷基或卤素；
A代表：
Figure BDA0002206979960000022
其中R2代表任意取代的 C1～C6的烷基、卤素、羟基、三氟甲基、氰基、甲氧基、氨基或硝基。
所述卤素优选F、Cl或Br。
本发明优选下列任一结构的化合物(化合物编号同实施例)：
Figure BDA0002206979960000023
Figure BDA0002206979960000031
更优选如下结构化合物：
Figure BDA0002206979960000032
本发明所述化合物药学上可接受的盐，是化合物与药学上可接受的无机酸或者有机酸形成的盐，所述无机酸或有机酸优选盐酸、硫酸、磷酸、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、三氟乙酸、酒石酸或醋酸。
本发明所述化合物或其药用盐的药物组合物具有COX-2、NF-κB以及p38 MAPK多靶点抑制功效。本发明所述化合物或其药用盐可用于预防和炎症相关疾病。
本发明所述的炎症相关疾病包括：类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎、全身性红斑狼疮、牛皮癣、湿疹、皮下炎和产后炎症、肠病、胃炎、头痛、动脉外膜炎、中风、缺血、精神创伤、变应性鼻炎、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症、胃溃疡中的一种。
本发明还公开了一种药物组合物，其中含有治疗有效量的式(I)化合物或其药学上可接受的盐或任意一种和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、口服液、糖浆剂、栓剂、透皮制剂、注射剂等制剂学上常规的制剂形式。
本发明所述化合物的制备方法，优选如下方法：
Figure BDA0002206979960000041
步骤1：起始原料1在加入碱和反应溶剂条件下进行，所用的碱优选自正丁基锂、苯基锂、氨基钠、醇钠、叔丁醇钾或叔丁醇钠；反应溶剂优选自N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、***；反应温度优选自65℃～95℃；
步骤2：化合物2经卤内酯化反应制备化合物3，所用的卤素优选自氯、溴、碘；溶剂优选自四氢呋喃、二氧六环、乙腈；反应温度优选自25℃～45℃；
步骤3：化合物3经酰化反应制备化合物3，所用的碱优选自碳酸钾、碳酸钠、磷酸钾、乙酸钠；反应溶剂优选自N,N-二甲基甲酰胺、四氢呋喃、二氧六环、乙腈、二氯甲烷；反应温度优选自20℃～60℃。
本发明所述化合物的制备方法，还优选如下方法：
Figure BDA0002206979960000042
其中R1、A定义同前。
具体步骤：起始原料是在加入缩合剂、碱和反应溶剂条件下进行，其中缩合剂选自1-羟基苯并***、二环己基碳二亚胺、N,N'-羰基二咪唑或草酰氯；碱选自三乙胺或N,N-二异丙基乙胺；反应溶剂选自N,N-二甲基甲酰胺、四氢呋喃、二氧六环、乙腈或二氯甲烷；反应温度为20℃～60℃。
药效学试验证明，本发明的化合物具有COX-2、NF-κB以及p38 MAPK多靶点抑制功效。下面是本发明部分化合物的药效学试验及结果：
一、本发明化合物对2,4-二硝基氟苯诱导(DNFB)的小鼠接触性皮炎模型的抗炎作用
(1)实验方法
取雄性ICR小鼠18-22g，适应性饲养7天后，按体重随机分为25组，每组8只，分别为正常组、模型组、***组、本发明化合物(22个)组。实验第1天除空白组外，各组小鼠均在脱毛部位均匀涂50μL 1％DNFB丙酮橄榄油溶液致敏，实验第2天继续涂1％DNFB丙酮橄榄油溶液强化一次。在致敏当天开始给药，正常组及模型组给予等剂量的溶媒，阳性组给予***(DEX)0.5mg/kg，化合物组分别给予5mg/kg，均灌胃给药，实验过程中每天给药1次，持续给药6天。实验第6天，小鼠右耳两侧均匀涂10μL 1％DNFB丙酮橄榄油溶液激发炎症反应，左耳涂等量丙酮橄榄油溶液做对照。激发24h后处死动物，立即沿双耳耳基线剪下双耳，用直径8mm打孔器分别在两耳同一部位打下圆耳片，称重，计算肿胀度及抑制率，计算公式如下：
耳肿胀度＝右耳片平均重量-左耳片平均重量
抑制率＝(模型组平均肿胀度-给药组平均肿胀度)/模型组平均肿胀度*100％
(2)实验结果
表1.化合物对2,4-二硝基氟苯致小鼠耳廓肿胀度及肿胀抑制率的影响(Mean±SD，n＝8)
Figure BDA0002206979960000051
Figure BDA0002206979960000061
注：△P<0.05，△△P<0.01vs空白▲P<0.05，▲▲P<0.01vs模型
实验结果如表1所示，与空白组相比模型组在涂抹DNFB造模后肿胀度达到16.4±3.6mg，表明造模效果明显。与模型组相比，阳性药***以及大部分本发明化合物均能显著降低耳肿胀度(P<0.05)，其中化合物4f、4j、4n、4p能极显著降低DNFB诱导的小鼠耳肿胀度 (P<0.01)。
二、本发明部分化合物对COX-1、COX-2酶的抑制作用
(1)实验方法
在阴性对照孔加入160μl assay buffer和10μl Heme；在全活孔及样品孔中分别加入 150μl assay buffer，10μl Heme和10μl COX-2(或者COX-1)；阴性对照孔和全活孔中加入 10μl溶剂(4.5％DMSO)，向样品孔中加入10μl待测样品，保证加入的样品所有孔中的DMSO浓度为4.5％，样品浓度为10μM。震荡混匀，室温放置10min，使化合物与酶充分作用。每孔中加入20μl显色底物。每孔中加入花生四烯酸。震荡混匀后立即放置于酶标仪中，读OD590光吸收值，2分钟内完成读值，计算抑制率[抑制率(％)＝(RFU100％酶活性对照 -RFU样品)/(RFU100％酶活性对照-RFU空白对照)×100％]。通过倍比稀释，测定化合物和化合物的IC50值。
(2)实验结果
见表2所示：
表2.化合物对COX-1、COX-2酶的抑制活性
Figure BDA0002206979960000062
注：aSI:IC50(COX-1)/IC50(COX-2)，SI值代表化合物对COX-1、COX-2抑制的选择度，值越高表示对 COX-2的选择性越高。
实验结果如表2所示，根据体内实验结果挑选出具有较强抗炎活性的化合物4f、4j、4n，这些化合物对环氧合酶具有良好的体外抑制活性，其中化合物4j、4n表现出突出的COX-2 酶抑制活性，且对COX-2酶具有一定的选择性。
三、本发明部分化合物对MAPK p38α酶的抑制作用
(1)实验方法
化合物在DMSO溶解后，用水稀释到待测浓度。酶试剂与待测样品混合后，加入含有200 μM生物素-肽底物和600μM ATP引发反应。在30℃下孵育60分钟后，加入10μL1.5％的磷酸溶液终止反应。将部分反应液转移到涂有链霉抗生物素蛋白的Flash板的孔中。用含0.01％吐温的磷酸缓冲溶液洗涤3次后密封。用闪烁计数器对每一孔进行计数。将每个孔的计数结果中减去背景计数值，并将结果计数与空白组的计数值进行比较，便可得到待测样品在每个浓度下的酶相对抑制活性。与空白组相比，使得反应中生物素-肽底物减少一半的浓度，即为待测样品对MAPK p38α酶的IC50值。
(2)实验结果
见表3所示：
表3.化合物对MAPK p38α酶的抑制活性
Figure BDA0002206979960000071
SB203580为特异性p38α MAPK抑制剂
结果如表3所示，化合物4n表现出较强的p38α MAPK抑制活性。
四、化合物4n对MAPK-NF-κB-iNOS/COX-2的调控作用研究
(1)实验方法
小鼠巨噬细胞RAW264.7在含有10％牛胎血清、100U/mL青霉素以及100mg/mL的链霉素的DMEM为培养基，置于37℃、5％CO2的培养箱中孵育。将细胞接种到96板中，分别加入DMSO 和4n(5μM、10μM、20μM)孵育两小时后，加入200ng/mL的脂多糖孵育24小时。收集细胞后用含有1％PMSF的RIPA高效细胞裂解液提取细胞蛋白，BCA法进行蛋白定量测定。通过SDS-PAGE凝胶对蛋白进行分离和转膜，在含5％脱脂奶粉的TBST溶液中摇动封闭一个小时，加入一抗于4℃孵育一夜后，加入二抗孵育一小时，用Tanon 6600发光成像工作站进行检测。
实验结果如附图1至附图11所示，本发明化合物4n能够剂量依赖性的减少p38MAPK以及 NFκ-B的磷酸化水平，进而显著抑制iNOS、COX-2的活性。
综上所述，本发明化合物对COX-2、NFκ-B、p38 MAPK多个炎症靶点都具有抑制活性，尤其是化合物4n最为突出，显示出良好的研究价值和药用前景，可用于预防和治疗炎症性疾病。
附图说明
图1是本发明化合物4n对脂多糖诱导的RAW264.7中iNOS与COX-2蛋白的WesternBlot图。
图2是本发明化合物4n对脂多糖诱导的RAW264.7中iNOS蛋白表达的柱状图。
图3是本发明化合物4n对脂多糖诱导的RAW264.7中COX-2蛋白表达的柱状图。
图4是本发明化合物4n对脂多糖诱导的RAW264.7中IκB与p65蛋白的Western Blot图。
图5是本发明化合物4n对脂多糖诱导的RAW264.7中IκB蛋白表达的柱状图。
图6是本发明化合物4n对脂多糖诱导的RAW264.7中IκB含量的柱状图。
图7是本发明化合物4n对脂多糖诱导的RAW264.7中p65蛋白表达的柱状图
图8是本发明化合物4n对脂多糖诱导的RAW264.7中p38、JNK以及ERK1/2蛋白的Western Blot 图。
图9是本发明化合物4n对脂多糖诱导的RAW264.7中p38蛋白表达的柱状图。
图10是本发明化合物4n对脂多糖诱导的RAW264.7中JNK蛋白表达的柱状图。
图11是本发明化合物4n对脂多糖诱导的RAW264.7中ERK1/2蛋白表达的柱状图。
(图中**代表模型组与空白组相比，P<0.01；#代表化合物组与模型组相比P<0.05；##代表化合物组与模型组相比P<0.01)
具体实施方式
实施例1
1-(2-(4-(4-氯苄基)哌嗪-1-羰基)苯基)乙酮(4a)的合成
步骤1：2-乙烯基苯甲酸(2)的合成
在干燥的100mL圆底烧瓶中，依次加入甲基三苯磷溴化铵(7.15g,20.0mmol)、叔丁醇钾 (3.37g,30.0mmol)，加无水四氢呋喃(100.0mL)溶解，反应液在氮气保护下室温搅拌1小时。将2-甲酰苯甲酸(1.5g,10.0mmol)无水四氢呋喃溶液缓慢滴加至反应液中，反应液回流搅拌 12小时。TLC[V(石油醚):V(乙酸乙酯)＝2:1为展开剂]显示反应基本完全。向反应液中加入饱和氯化铵溶液100mL。将反应液转移至分液漏斗，分离有机层，水层加二氯甲烷(30mL×3) 萃取，收集合并有机层用无水硫酸钠干燥，减压浓缩至干。硅胶柱分离所得白色固体化合物 2.67g,收率90.2％。
步骤2：3-(碘甲基)-3H-异苯并呋喃-1-酮(3)的合成
在干燥的50mL圆底烧瓶中，依次加入化合物2(2.67g,18mmol)、碘(9.07g，36mmol)、无水乙腈(30mL)，反应液在氮气保护下室温搅拌1小时。TLC[V(石油醚):V(乙酸乙酯)＝2:1 为展开剂]显示反应基本完全。向反应液中加入饱和硫代硫酸钠溶液15mL。反应液转移至分液漏斗，分离有机层，水层加乙酸乙酯(30mL×3)萃取，收集合并有机相用100mL水，饱和碳酸氢钠溶液和饱和硫代硫酸钠溶液洗涤一次。有机层用无水硫酸钠干燥，减压浓缩至干，得到黄色固体。通过从热乙醇中重结晶纯化粗产物，得到无色针状晶体2.10g，收率43.3％。
步骤3：1-(2-(4-(4-氯苄基)哌嗪-1-羰基)苯基)乙酮(4a)的合成
在干燥的50mL圆底烧瓶中，依次加入化合物3(0.82g,3mmol)、碳酸钾(0.70g,5mmol)、二氯甲烷20mL搅拌溶解，将1-(4-氯苄基)哌嗪(0.84g，4mmol)加入反应液中，室温搅拌2 小时。TLC[V(石油醚):V(乙酸乙酯)＝1:1为展开剂]显示反应基本完全。向反应液中加入水20 mL。反应液转移至分液漏斗，分离有机层，水层加二氯甲烷(30mL×3)萃取，收集合并有机层用无水硫酸钠干燥，减压浓缩至干。柱层析纯化得白色固体0.37g，收率34.6％。m.p. 97.5～98.4℃.1H NMR(400MHz,DMSO-d6)δ:7.63(dd,J＝7.5,1.3Hz,1H Ar-H),7.55(dd,J＝ 7.6,1.4Hz,1H Ar-H),7.41-7.36(m,2H,Ar-H),7.36-7.31(m,2H,Ar-H),7.30-7.26(m,1H,Ar-H), 3.59(t,J＝5.1Hz,2H,piperazine-H),3.42(s,2H,CH2),3.04(t,J＝5.0Hz,2H,piperazine-H), 2.55(s,3H,CH3),2.44(t,J＝5.1Hz,2H,piperazine-H),2.28(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,CDCl3)δ:198.57,170.28,137.19,136.46,135.31,132.86,132.62,130.31, 129.66,128.85,128.45,127.24,62.04,52.50,52.34,46.83,41.62,27.67.ESI-MS m/z:357.229 [M+H]+.
实施例2
1-(2-(4-(4-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4b)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-甲氧基苄基)哌嗪(0.84g,4 mmol)为原料，柱层析纯化得到白色固体0.38g，收率35.9％。m.p.88.4～89.6℃.1H NMR(400 MHz,DMSO-d6)δ:7.98(dd,J＝7.7,1.2Hz,1H,Ar-H),7.63(d,J＝7.5,1.3Hz,1H,Ar-H),7.55 (d,J＝7.6,1.4Hz,1H,Ar-H),7.32-7.25(m,1H,Ar-H),7.25-7.18(m,2H,Ar-H),6.94–6.84(m, 2H,Ar-H),3.73(s,3H,CH3),3.57(d,J＝5.1Hz,2H,piperazine-H),3.42(s,2H,CH2),3.04(t,J＝ 5.0Hz,2H,piperazine-H),2.55(s,3H,CH3),2.41(t,J＝5.1Hz,2H,piperazine-H),2.26(t,J＝5.0 Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.22,169.35,158.78,137.12,135.80, 132.92,130.54,130.25,130.12,129.28,127.41,114.04,61.78,55.45,52.47,52.16,46.75,41.54, 28.33.ESI-MS m/z:353.232[M+H]+.
实施例3
1-(2-(4-(4-氰基苄基)哌嗪-1-羰基)苯基)乙酮(4c)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-氰基苄基)哌嗪(0.80g,4 mmol)为原料，柱层析纯化得到白色固体0.48g，收率46.1％。m.p.143.6～145.6℃.1H NMR(400 MHz,DMSO-d6)δ:7.98(dd,J＝7.8,1.2Hz,1H,Ar-H),7.80(d,J＝8.2Hz,2H,Ar-H),7.64(dd,J ＝7.5,1.3Hz,1H,Ar-H),7.59-7.49(m,3H,Ar-H),7.29(dd,J＝7.8,1.2Hz,1H,Ar-H),3.60(d,J ＝4.4Hz,4H,piperazine-H,CH2),3.06(t,J＝5.0Hz,2H,piperazine-H),2.56(s,3H,CH3),2.46(t, J＝5.1Hz,2H,piperazine-H),2.30(t,J＝5.0Hz,2H,piperazine-H)；13C NMR(101MHz, DMSO-d6)δ:199.22,169.41,144.61,137.07,135.70,132.98,132.65,130.33,130.01,129.32, 127.40,110.23,61.60,52.53,52.29,46.70,41.50,28.31.ESI-MS m/z:348.237[M+H]+.
实施例4
1-(2-(4-(4-三氟甲基苄基)哌嗪-1-羰基)苯基)乙酮(4d)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-三氟甲基苄基)哌嗪(0.98g, 4mmol)为原料，柱层析纯化得到白色固体0.24g，收率20.9％。m.p.63.1～64.5℃.1H NMR(400 MHz,DMSO-d6)δ:7.99(dd,J＝7.7,1.3Hz,1H,Ar-H),7.69(d,J＝8.1Hz,2H,Ar-H),7.64(dd,J ＝7.5,1.3Hz,1H,Ar-H),7.60-7.51(m,3H,Ar-H),7.29(dd,J＝7.7,1.3Hz,1H,Ar-H),3.61(d,J ＝7.4Hz,4H,piperazine-H,CH2),3.07(dd,J＝5.0,4.1Hz,2H,piperazine-H),2.56(s,3H,CH3), 2.46(d,J＝5.0Hz,2H,piperazine-H),2.31(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz, DMSO-d6)δ:199.20,169.41,143.51,137.09,135.71,132.96,130.31,129.84,129.30,127.40, 125.53(q,JC-F＝3.8Hz),61.58,52.55,52.28,46.70,41.51,28.29.ESI-MS m/z:391.251[M+H]+.
实施例5
1-(2-(4-(4-硝基苄基)哌嗪-1-羰基)苯基)乙酮(4e)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-硝基苄基)哌嗪(0.88g,4 mmol)为原料，柱层析纯化得到白色固体0.46g，收率42.1％。m.p.190.8～192.4℃.1H NMR(400 MHz,DMSO-d6)δ:8.29-8.15(m,2H,Ar-H),7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.69-7.59(m, 3H,Ar-H),7.55(dd,J＝7.5,1.3Hz,1H,Ar-H),7.29(dd,J＝7.8,1.3Hz,1H,Ar-H),3.65(s,2H, CH2),3.64-3.56(m,2H,piperazine-H),3.07(dd,J＝5.0,4.0Hz,2H,piperazine-H),2.55(s,3H, CH3),2.48(t,J＝5.0Hz,2H,piperazine-H),2.32(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101 MHz,DMSO-d6)δ:199.24,174.88,169.42,147.05,146.91,137.06,135.70,132.99,130.33,130.18, 129.33,127.40,123.86,61.28,52.55,52.31,46.70,41.50,28.32,25.97.ESI-MS m/z:368.240 [M+H]+.
实施例6
1-(2-(4-(3-硝基苄基)哌嗪-1-羰基)苯基)乙酮(4f)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(3-硝基苄基)哌嗪(0.88g,4 mmol)为原料，柱层析纯化得到白色固体0.33g，收率30.2％。m.p.180.1～181.8℃.1H NMR(400 MHz,DMSO-d6)δ:8.18(t,J＝1.9Hz,1H,Ar-H),8.13(m,1H,Ar-H),7.98(dd,J＝7.7,1.3Hz, 1H,Ar-H),7.79(dd,J＝7.6,1.3Hz,1H,Ar-H),7.64(m,2H,Ar-H),7.55(dd,J＝7.5,1.3Hz,1H, Ar-H),7.29(dd,J＝7.7,1.3Hz,1H,Ar-H),3.65(s,2H,CH2),3.61(d,J＝5.0Hz,2H, piperazine-H),3.07(dd,J＝5.0,4.0Hz,2H,piperazine-H),2.56(s,3H,CH3),2.48(d,J＝5.0Hz, 2H,piperazine-H),2.38-2.28(m,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.25, 169.40,148.29,137.06,135.95,135.70,132.98,130.33,130.24,129.32,127.40,123.60,122.55, 61.02,52.42,52.19,46.70,41.48,28.32.ESI-MS m/z:368.253[M+H]+.
实施例7
1-(2-(4-(2,4-二氯苄基)哌嗪-1-羰基)苯基)乙酮(4g)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(2,4-二氯苄基)哌嗪(0.98g,4 mmol)为原料，柱层析纯化得到白色固体0.43g，收率36.5％。m.p.74.9～76.4℃.1H NMR(400 MHz,DMSO-d6)δ:7.99(dd,J＝7.8,1.3Hz,1H,Ar-H),7.64(m,1H,Ar-H),7.60(d,J＝2.2Hz, 1H,Ar-H),7.58-7.50(m,2H,Ar-H),7.42(dd,J＝8.3,2.2Hz,1H,Ar-H),7.29(dd,J＝7.8,1.3Hz, 1H,Ar-H),3.60(t,J＝5.0Hz,2H,piperazine-H),3.58(s,2H,CH2),3.10-3.02(m,2H, piperazine-H),2.56(s,3H,CH3),2.49(d,J＝5.0Hz,2H,piperazine-H),2.34(t,J＝5.0Hz,2H, piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.24,169.40,137.07,135.73,135.06,134.63, 132.98,132.72,132.56,130.32,129.32,129.16,127.70,127.41,58.33,52.54,52.34,46.72,41.52, 28.33.ESI-MS m/z:391.183[M+H]+.
实施例8
1-(2-(4-(2-氯苄基)哌嗪-1-羰基)苯基)乙酮(4h)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(2-氯苄基)哌嗪(0.84g,4mmol) 为原料，柱层析纯化得到白色固体0.47g，收率43.7％。m.p.133.5～134.6℃.1HNMR(400MHz, DMSO-d6)δ:7.99(dd,J＝7.8,1.3Hz,1H,Ar-H),7.64(m,1H,Ar-H),7.59-7.48(m,2H,Ar-H), 7.43(dd,J＝7.7,1.6Hz,1H,Ar-H),7.37-7.26(m,3H,Ar-H),3.60(d,J＝5.6Hz,4H, piperazine-H,CH2),3.06(dd,J＝5.0,4.0Hz,2H,piperazine-H),2.56(s,3H,CH3),2.49(d,J＝5.0 Hz,2H,piperazine-H),2.35(t,J＝5.0Hz,2H,piperazine-H).13CNMR(101MHz,DMSO-d6)δ: 199.25,169.39,137.09,135.76,133.77,132.98,131.33,130.32,129.74,129.31,129.17,127.52, 127.42,58.96,52.63,52.40,46.73,41.54,28.33.ESI-MS m/z:357.229[M+H]+.
实施例9
1-(2-(4-(3-氯苄基)哌嗪-1-羰基)苯基)乙酮(4i)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(3-氯苄基)哌嗪(0.84g,4mmol) 为原料，柱层析纯化得到白色固体0.52g，收率48.2％。m.p.105.8～107.5℃.1HNMR(400MHz, DMSO-d6)δ:7.99(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(m,1H,Ar-H),7.55(dd,J＝7.5,1.3Hz, 1H,Ar-H),7.41-7.25(m,5H,Ar-H),3.60(t,J＝5.0Hz,2H,piperazine-H),3.51(s,2H,CH2), 3.13-2.99(m,2H,piperazine-H),2.55(s,3H,CH3),2.45(t,J＝5.0Hz,2H,piperazine-H),2.29(t, J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.20,169.38,141.15,137.10, 135.72,133.42,132.96,130.55,130.30,129.29,128.88,127.87,127.42,61.48,52.47,52.24,46.71, 41.50,28.32.ESI-MS m/z:357.212[M+H]+.
实施例10
1-(2-(4-(4-氟苄基)哌嗪-1-羰基)苯基)乙酮(4j)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-氟苄基)哌嗪(0.77g,4mmol) 为原料，柱层析纯化得到白色固体0.39g，收率38.4％。m.p.107.6～108.8℃.1HNMR(400MHz, DMSO-d6)δ:7.99(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝7.6,1.3Hz,1H,Ar-H),7.55(dd,J ＝7.6,1.3Hz,1H,Ar-H),7.40-7.31(m,2H,Ar-H),7.28(dd,J＝7.8,1.3Hz,1H,Ar-H),7.20-7.10 (m,2H,Ar-H),3.59(t,J＝5.0Hz,2H,piperazine-H),3.48(s,2H,CH2),3.04(t,J＝5.0Hz,2H, piperazine-H),2.55(s,3H,CH3),2.43(t,J＝5.0Hz,2H,piperazine-H),2.27(t,J＝5.0Hz,2H, piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.23,169.37,137.09,135.74,134.51(d,J C-F＝3.0Hz),132.96(d,J C-F＝3.0Hz),132.57,130.30(d,J C-F＝3.0Hz),129.22,127.55, 115.49,115.28,61.40,58.32,52.38,46.72,41.51,28.32.ESI-MS m/z:341.199[M+H]+.
实施例11
1-(2-(4-(4-苄基)哌嗪-1-羰基)苯基)乙酮(4k)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-苄基)哌嗪(0.70g,4mmol) 为原料，柱层析纯化得到白色固体0.36g，收率37.8％。m.p.69.7～70.9℃.1H NMR(400MHz, DMSO-d6)δ:7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝7.6,1.3Hz,1H,Ar-H),7.55(dd,J ＝7.6,1.3Hz,1H,Ar-H),7.36-7.22(m,6H,Ar-H),3.59(t,J＝5.0Hz,2H,piperazine-H),3.50(s, 2H,CH2),3.05(dd,J＝5.0,4.1Hz,2H,piperazine-H),2.55(s,3H,CH3),2.44(t,J＝5.0Hz,2H, piperazine-H),2.29(t,J＝5.0Hz,2H,piperazine-H).13CNMR(101MHz,DMSO-d6)δ:199.21, 169.36,138.36,137.12,135.76,132.94,130.28,129.29,128.67,127.47,127.41,62.38,52.58, 52.29,46.74,41.53,28.34.ESI-MS m/z:323.231[M+H]+.
实施例12
1-(2-(4-(4-甲基苄基)哌嗪-1-羰基)苯基)乙酮(4l)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(4-甲基苄基)哌嗪(0.76g,4 mmol)为原料，柱层析纯化得到白色固体0.47g，收率46.3％。m.p.116.7～118.3℃.1H NMR(400 MHz,DMSO-d6)δ:7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝7.6,1.3Hz,1H,Ar-H),7.55 (dd,J＝7.6,1.3Hz,1H,Ar-H),7.28(dd,J＝7.8,1.3Hz,1H,Ar-H),7.19(d,J＝8.0Hz,2H, Ar-H),7.13(d,J＝8.0Hz,2H,Ar-H),3.58(t,J＝5.0Hz,2H,piperazine-H),3.44(s,2H,CH2), 3.04(t,J＝5.0Hz,2H,piperazine-H),2.55(s,3H,CH3),2.42(t,J＝5.0Hz,2H,piperazine-H), 2.28(s,5H,piperazine-H,CH3).13C NMR(101MHz,DMSO-d6)δ:199.20,169.37,137.13, 136.49,135.75,135.22,132.94,130.29,129.26,127.40,62.14,52.52,52.24,46.73,41.53,28.32, 21.17.ESI-MS m/z:337.255[M+H]+.
实施例13
1-(2-(4-(2,4-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4m)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(2,4-甲氧基苄基)哌嗪(0.94g, 4mmol)为原料，柱层析纯化得到白色固体0.53g，收率46.2％。m.p.113.9～115.4℃.1H NMR (400MHz,DMSO-d6)δ:7.97(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝7.6,1.3Hz,1H,Ar-H), 7.54(dd,J＝7.6,1.3Hz,1H,Ar-H),7.27(dd,J＝7.8,1.3Hz,1H,Ar-H),7.17(d,J＝8.3Hz,1H, Ar-H),6.53(d,J＝2.4Hz,1H,Ar-H),6.49(dd,J＝8.2,2.4Hz,1H,Ar-H),3.75(d,J＝3.0Hz,6H, OCH3×2),3.57(t,J＝5.0Hz,2H,piperazine-H),3.41(s,2H,CH2),3.03(t,J＝5.0Hz,2H, piperazine-H),2.55(s,3H,CH3),2.43(t,J＝5.0Hz,2H,piperazine-H),2.27(t,J＝5.0Hz,2H, piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.22,169.32,160.06,158.85,137.14,135.76, 132.94,131.37,130.27,129.27,127.41,117.86,104.88,98.67,55.83,55.55,55.48,52.54,52.23, 46.76,41.56,28.34.ESI-MS m/z:383.300[M+H]+.
实施例14
1-(2-(4-(2-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4n)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(2-甲氧基苄基)哌嗪(0.83g,4 mmol)为原料，柱层析纯化得到白色固体0.42g，收率39.8％。m.p.117.9～119.7℃.1H NMR (400MHz,DMSO-d6)δ:7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝7.6,1.3Hz,1H,Ar-H), 7.55(dd,J＝7.6,1.3Hz,1H,Ar-H),7.27(m,3H,Ar-H),6.97(dd,J＝8.3,1.1Hz,1H,Ar-H),6.92 (dd,J＝7.5,1.2Hz,1H,Ar-H),3.77(s,3H,OCH3),3.59(s,2H,piperazine-H),3.49(s,2H,CH2), 3.05(t,J＝5.0Hz,2H,piperazine-H),2.55(s,3H,CH3),2.47(t,J＝5.0Hz,2H,piperazine-H), 2.31(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.23,169.36,157.79, 137.12,135.76,132.95,130.29,129.28,128.58,127.42,125.82,120.57,111.22,55.76,52.69, 52.42,46.77,41.57,28.33.ESI-MS m/z:353.251[M+H]+.
实施例15
1-(2-(4-(3-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4o)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(3-甲氧基苄基)哌嗪(0.83g,4 mmol)为原料，柱层析纯化得到白色固体0.48g，收率45.3％。m.p.119.3～120.7℃.1H NMR(400 MHz,DMSO-d6)δ:7.98(dd,J＝7.6,1.2Hz,1H,Ar-H),7.63(dd,J＝7.5,1.3Hz,1H,Ar-H),7.55 (dd,J＝7.6,1.2Hz,1H,Ar-H),7.32-7.19(m,2H,Ar-H),6.92–6.85(m,2H,Ar-H),6.85-6.78(m, 1H,Ar-H),3.74(s,3H,OCH3),3.58(t,J＝5.0Hz,2H,CH2),3.47(s,2H,CH2),3.05(t,J＝5.0Hz, 2H,piperazine-H),2.55(s,3H,CH3),2.42(t,J＝5.0Hz,2H,piperazine-H),2.28(t,J＝5.0Hz,2H, piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.22,169.35,158.78,137.12,135.80,132.92, 130.54,130.25,130.12,129.28,127.41,114.04,61.78,55.45,52.47,52.16,46.75,41.54,28.33. ESI-MS m/z:353.240[M+H]+.
实施例16
1-(2-(4-(苯并[d][1,3]二氧杂环戊烯-5-基甲基)哌嗪-1-羰基)苯基)乙酮(4p)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(苯并[d][1,3]二氧杂环戊烯-5- 基甲基)哌嗪(0.88g,4mmol)为原料，柱层析纯化得到白色固体0.40g，收率36.3％。m.p. 103.4～104.5℃.1H NMR(400MHz,DMSO-d6)δ:7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd, J＝7.6,1.3Hz,1H,Ar-H),7.55(dd,J＝7.6,1.3Hz,1H,Ar-H),7.28(dd,J＝7.8,1.3Hz,1H, Ar-H),6.92-6.80(m,2H,Ar-H),6.75(dd,J＝7.9,1.7Hz,1H,Ar-H),5.99(s,2H,OCH3),3.58(t, J＝5.0Hz,2H,,piperazine-H),3.40(s,2H,CH2),3.04(t,J＝5.0Hz,2H,piperazine-H),2.55(s, 3H,CH3),2.42(t,J＝5.0Hz,2H,piperazine-H),2.26(t,J＝5.0Hz,2H,piperazine-H).13C NMR (101MHz,DMSO-d6)δ:199.21,169.35,147.68,146.65,137.12,135.74,132.94,132.17,130.28, 129.28,127.40,122.44,109.50,108.31,101.24,62.03,52.42,52.12,46.74,41.52,28.32.ESI-MS m/z:367.239[M+H]+.
实施例17
1-(2-(4-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲基)哌嗪-1-羰基)苯基)乙酮(4q)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲基)哌嗪(0.94g,4mmol)为原料，柱层析纯化得到白色固体0.45g，收率39.7％。 m.p.124.9～126.4℃.1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63 (dd,J＝7.6,1.3Hz,1H,Ar-H),7.55(dd,J＝7.6,1.3Hz,1H,Ar-H),7.28(dd,J＝7.8,1.3Hz,1H, Ar-H),6.84–6.71(m,3H,Ar-H),4.21(s,4H,OCH2×2),3.58(t,J＝5.0Hz,2H,piperazine-H), 3.37(s,2H,CH2),3.04(t,J＝5.0Hz,2H,piperazine-H),2.55(s,3H,CH3),2.41(t,J＝5.0Hz,2H, piperazine-H),2.26(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ199.22, 169.35,143.50,142.82,135.74,132.95,131.31,130.28,129.29,127.40,122.07,117.80,117.13, 64.44(d,J＝4.7Hz),61.76,52.50,52.15,46.74,41.53,28.33.ESI-MS m/z:381.248[M+H]+.
实施例18
1-(2-(4-((3,5,6-三甲基吡嗪-2-基)甲基)哌嗪-1-羰基)苯基)乙酮(4r)的合成
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和2,3,5-三甲基-6-(哌嗪-1-基甲基)吡嗪(0.88g,4mmol)为原料，柱层析纯化得到白色固体0.52g，收率47.4％。m.p.119.0～120.1℃.1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.64(dd,J＝7.5,1.3Hz,1H,Ar-H),7.55(dd,J＝7.5,1.3Hz,1H,Ar-H),7.29(dd,J＝7.8,1.3Hz,1H,Ar-H), 3.58(s,2H,CH2),3.55(t,J＝5.0Hz,2H,piperazine-H),3.01(t,J＝5.0Hz,2H,piperazine-H), 2.55(s,3H,CH3),2.50(s,3H,CH3),2.47(t,J＝5.0Hz,2H,piperazine-H),2.40(d,J＝4.3Hz,6H, CH3×2),2.30(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ199.22,169.36, 149.99,149.88,147.94,147.61,137.08,135.73,132.95,130.28,129.29,127.41,61.78,52.71, 52.51,46.71,41.53,28.32,21.54,21.44,20.93.ESI-MS m/z:367.306[M+H]+.
实施例19
1-(2-(4-(吡啶-4-基甲基)哌嗪-1-羰基)苯基)乙酮(4s)
参考实施例1的合成方法，以化合物3(0.82g,3mmol)和1-(吡啶-4-基甲基)哌嗪(0.71g,4 mmol)为原料，柱层析纯化得到白色固体0.42g，收率43.8％。m.p.129.0～131.2℃.1H NMR(400 MHz,DMSO-d6)δ:8.55-8.47(m,2H,Py-H),7.98(dd,J＝7.8,1.3Hz,1H,Ar-H),7.63(dd,J＝ 7.5,1.3Hz,1H,Ar-H),7.55(dd,J＝7.8,1.3Hz,1H,Ar-H),7.38-7.32(m,2H,Py-H),7.29(dd,J＝ 7.8,1.3Hz,1H,Ar-H),3.62(t,J＝5.0Hz,2H,piperazine-H),3.54(s,2H,CH2),3.07(t,J＝5.0Hz, 2H,piperazine-H),2.56(s,3H,CH3),2.47(t,J＝5.0Hz,2H,piperazine-H),2.30(t,J＝5.0Hz,2H, piperazine-H).13C NMR(101MHz,DMSO-d6)δ:199.23,169.41,150.02,147.59,137.08,135.72, 132.97,130.32,129.31,127.41,124.19,60.90,52.57,52.35,46.70,41.49,28.32.ESI-MS m/z: 324.257[M+H]+.
实施例20
1-(2-(4-(4-氯苄基)哌嗪-1-羰基)-5-甲基苯基)乙酮(7a)的合成
在干燥的50mL圆底烧瓶中，加入2-乙酰基-4-甲基苯甲酸(0.44g,2.5mmol)溶解于20mL 的无水二氯甲烷中，在0℃时缓慢滴加草酰氯(0.48g,3.8mmol)，滴加一滴DMF后升至室温反应3小时。TLC[V(石油醚):V(乙酸乙酯)＝3:1为展开剂]显示反应基本完全。反应液减压浓缩，再溶于10mL的无水二氯甲烷中，缓慢滴加至1-(4-氯苄基)哌嗪二氯甲烷溶液中，室温搅拌3 小时。TLC[V(石油醚):V(乙酸乙酯)＝1:1为展开剂]显示反应基本完全。向反应液中加入水20 mL。反应液转移至分液漏斗，分离有机层，水层加二氯甲烷(30mL×3)萃取，收集合并有机层用无水硫酸钠干燥，减压浓缩至干。硅胶柱分离所得白色固体0.48g,收率51.8％。m.p. 107.9～110.8℃.1H NMR(400MHz,DMSO-d6)δ:7.92-7.75(m,1H,Ar-H),7.46-7.31(m,5H, Ar-H),7.16(d,J＝7.7Hz,1H,Ar-H),3.58(t,J＝5.0Hz,2H,piperazine-H),3.48(s,2H,CH2),3.03 (m,2H,piperazine-H),2.53(d,J＝4.6Hz,3H,CH3),2.42(t,J＝5.0Hz,2H,piperazine-H),2.38(d, J＝8.5Hz,3H,CH3),2.27(t,J＝5.0Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ: 199.34,169.52,138.92,137.48,135.96,133.26,132.80,131.96,131.05,129.66,128.63,127.89, 127.34,61.40,52.47,52.22,46.67,41.49,28.35,21.36.ESI-MS m/z:371.228[M+H]+.
实施例21
1-(5-氯-2-(4-(4-氯苄基)哌嗪-1-羰基)苯基)乙酮(7b)的合成
参考实施例20的合成方法，以2-乙酰基-4-氯苯甲酸(0.59g,3mmol)和1-(4-氯苄基)哌嗪(0.84g,4mmol)为原料，柱层析纯化得到白色固体0.62g，收率52.6％。m.p.108.1～110.7℃. 1H NMR(400MHz,DMSO-d6)δ:8.06-7.99(m,1H,Ar-H),7.67(m,1H,Ar-H),7.43-7.30(m,5H, Ar-H),3.58(t,J＝5.0Hz,2H,piperazine-H),3.49(s,2H,CH2),3.06(q,J＝4.4Hz,2H, piperazine-H),2.56(d,J＝7.3Hz,3H,CH3),2.44(q,J＝5.0Hz,2H,piperazine-H),2.29(q,J＝4.4 Hz,2H,piperazine-H).13C NMR(101MHz,DMSO-d6)δ:198.44,168.31,137.72,137.45,135.70, 133.86,132.62,132.41,131.98,131.05,130.01,129.26,128.64,127.28,61.37,52.41,52.12,46.72, 41.59,28.50,28.29.ESI-MSm/z:391.197[M+H]+。

Claims (9)

1.通式(I)的苄基哌嗪类化合物或其药学上可接受的盐：
Figure FDA0003848484100000011
其中R1代表C1～C6的烷基或卤素；
A代表：
Figure FDA0003848484100000012
其中R2代表C1～C6的烷基、卤素、羟基、三氟甲基、氰基、甲氧基、氨基或硝基。
2.下列任一结构的苄基哌嗪类化合物或其药学上可接受的盐：
Figure FDA0003848484100000013
Figure FDA0003848484100000021
3.权利要求2的化合物或其药学上可接受的盐，为下列结构化合物或其药学上可接受的盐
Figure FDA0003848484100000022
4.权利要求1或2的化合物或其药学上可接受的盐，其中所述的药学上可接受的盐是通式(I)或权利要求2中任一化合物的盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、三氟乙酸盐、酒石酸盐或醋酸盐。
5.权利要求1的化合物的制备方法，包括：
Figure FDA0003848484100000023
其中R1、A的定义同权利要求1。
6.一种药物组合物，其中含有权利要求1或2的化合物或其药学上可接受的盐及药学上可接受的载体。
7.权利要求1或2的化合物或其药学上可接受的盐用于制备COX-2、NF-κB、p38 MAPK多靶点抑制剂的用途。
8.权利要求1或2的化合物或其药学上可接受的盐用于制备预防和炎症相关疾病的药物的用途。
9.权利要求8的用途，其中和炎症相关疾病为类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎、全身性红斑狼疮、牛皮癣、湿疹、皮下炎、产后炎症、肠病、胃炎、头痛、动脉外膜炎、中风、缺血、精神创伤、变应性鼻炎、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症或胃溃疡。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1520409A (zh) * 2001-07-09 2004-08-11 ������ҩ�����޹�˾ 具有nk-1受体拮抗活性的哌嗪肟衍生物
CN1730476A (zh) * 2004-08-06 2006-02-08 中国医学科学院药物研究所 芳胺酮类化合物、其合成方法、含有其的药物组合物及用途
CN1913898A (zh) * 2003-12-09 2007-02-14 凯莫森特里克斯股份有限公司 取代的哌嗪
CN101538254A (zh) * 2003-12-23 2009-09-23 赛诺菲-安万特 1-哌嗪-和1-高哌嗪-羧酸酯衍生物、制备和其治疗用途
CN102216282A (zh) * 2008-11-20 2011-10-12 奥赖恩公司 芳基哌嗪及其作为α2C 拮抗剂的用途
CN102627631A (zh) * 2012-03-31 2012-08-08 中国药科大学 苯并杂环类化合物、其制备方法及其医药用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1520409A (zh) * 2001-07-09 2004-08-11 ������ҩ�����޹�˾ 具有nk-1受体拮抗活性的哌嗪肟衍生物
CN1913898A (zh) * 2003-12-09 2007-02-14 凯莫森特里克斯股份有限公司 取代的哌嗪
CN101538254A (zh) * 2003-12-23 2009-09-23 赛诺菲-安万特 1-哌嗪-和1-高哌嗪-羧酸酯衍生物、制备和其治疗用途
CN1730476A (zh) * 2004-08-06 2006-02-08 中国医学科学院药物研究所 芳胺酮类化合物、其合成方法、含有其的药物组合物及用途
CN102216282A (zh) * 2008-11-20 2011-10-12 奥赖恩公司 芳基哌嗪及其作为α2C 拮抗剂的用途
CN102627631A (zh) * 2012-03-31 2012-08-08 中国药科大学 苯并杂环类化合物、其制备方法及其医药用途

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