CN110615774A - Benzyl piperazine compound with anti-inflammatory activity, preparation method and medical application - Google Patents
Benzyl piperazine compound with anti-inflammatory activity, preparation method and medical application Download PDFInfo
- Publication number
- CN110615774A CN110615774A CN201910884803.0A CN201910884803A CN110615774A CN 110615774 A CN110615774 A CN 110615774A CN 201910884803 A CN201910884803 A CN 201910884803A CN 110615774 A CN110615774 A CN 110615774A
- Authority
- CN
- China
- Prior art keywords
- compound
- piperazine
- pharmaceutically acceptable
- inflammation
- acceptable salt
- Prior art date
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- Granted
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Abstract
Description
技术领域technical field
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。The invention relates to the field of medicinal chemistry, in particular to a class of benzylpiperazine compounds with anti-inflammatory activity, a preparation method and medical use.
背景技术Background technique
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。Inflammation is an adaptive response of the body to external stimuli or cell damage. It maintains the body's internal environment stability by removing inflammatory factors and repairing damaged tissues. Although the inflammatory response is essential to maintain the body's health, uncontrolled inflammatory response can be involved in the occurrence of many chronic diseases, such as asthma, atherosclerosis, rheumatoid arthritis, and cancer [Sun S, Ji Y, Kersten] S, et al. Mechanisms of inflammatory responses in obese adipose tissue[J]. Annual Review of Nutrition, 2012(1):261-286. Therefore, anti-inflammatory drugs, which are widely used in clinical practice, have become one of the most widely used drugs.
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前列腺素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，间接抑制前列腺素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。At present, the research and development strategies of most anti-inflammatory drugs mainly focus on the following two aspects. One is to directly inhibit the production of some pro-inflammatory mediators through related mediators or their targets, such as the use of non-steroidal anti-inflammatory drugs to directly inhibit the production of COX enzymes. activity, blocking the conversion of arachidonic acid into the potent pro-inflammatory mediator prostaglandin 2 [Carlo Patrono, BiancaRocca.Nonsteroidal antiinflammatory drugs:Past,present and future[J].Pharmacological Research,2009,59(5): 285- 289]; Second, by regulating the upstream targets of inflammation, blocking the transcription and expression of related enzymes, thereby indirectly inhibiting the generation of pro-inflammatory mediators, such as MAPK p38 inhibitors blocking the transcription and expression of COX-2 and iNOS genes, indirectly Inhibits the production of prostaglandin 2 and nitric oxide [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]. However, NSAIDs severely limit their clinical application due to gastrointestinal side effects and potential cardiovascular adverse reactions; inhibitors of MAPKp38 and related targets are also difficult to enter into clinical application due to inevitable side effects. Inflammation is a network system composed of multiple mediators. It is still questionable whether anti-inflammatory drugs with good therapeutic effect and few side effects can be developed based on a single target. Therefore, finding new research and development strategies and designing high-efficiency and low-toxic drug candidates has become an important direction for anti-inflammatory drug research and development.
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。Based on the resolution of inflammation involving many cytokines and regulatory mechanisms, multi-target drugs can moderately regulate multiple inflammatory targets, which can improve the therapeutic effect through synergy, and also avoid the adverse effects mediated by excessive inhibition of some targets. reaction. In clinical practice, low-dose drug combinations are often used to treat inflammatory pain in order to maximize the therapeutic effect while avoiding side effects. For a long time, multi-target drugs have been an important means to treat chronic diseases mediated by multiple pathways and multiple targets. The existing anti-inflammatory drugs seriously threaten the life safety of patients due to the side effects caused by excessive inhibition of a single target. Therefore, the development of new anti-inflammatory drugs based on multiple targets is of pioneering significance for the treatment of inflammation, especially chronic inflammatory diseases.
发明内容SUMMARY OF THE INVENTION
本发明公开了一类苄基哌嗪类化合物，结构式如下：The invention discloses a class of benzyl piperazine compounds, the structural formula is as follows:
其中R1代表任意取代的C1～C6的烷基或卤素；wherein R 1 represents optionally substituted C 1 -C 6 alkyl or halogen;
A代表：A stands for:
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。 wherein R 2 represents optionally substituted C 1 -C 6 alkyl, halogen, hydroxy, trifluoromethyl, cyano, methoxy, amino or nitro.
所述卤素优选F、Cl或Br。The halogen is preferably F, Cl or 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)：The present invention is preferably a compound of any of the following structures (the compound number is the same as the embodiment):
更优选如下结构化合物：More preferred are the following structural compounds:
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。The pharmaceutically acceptable salt of the compound of the present invention is the salt formed by the compound and a pharmaceutically acceptable inorganic acid or organic acid, and the inorganic acid or organic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid , fumaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, tartaric acid or acetic acid.
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。The pharmaceutical composition of the compound of the present invention or a pharmaceutically acceptable salt thereof has the multi-target inhibitory effect of COX-2, NF-κB and p38 MAPK. The compounds of the present invention or their pharmaceutically acceptable salts can be used for the prevention and inflammation-related diseases.
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。The inflammation-related diseases described in the present invention include: rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, subcutaneous inflammation and postpartum inflammation, enteropathy, gastritis, headache, Periarteritis, stroke, ischemia, mental trauma, allergic rhinitis, coronary plaque inflammation, inflammation caused by bacteria, inflammation caused by virus, inflammation caused by surgery, gastric ulcer.
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。The present invention also discloses a pharmaceutical composition, which contains a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or any one thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be conventional formulations such as ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, granules, oral liquids, syrups, suppositories, transdermal preparations, and injections. form.
本发明所述化合物的制备方法，优选如下方法：The preparation method of the compound of the present invention, preferably the following method:
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、乙醚；反应温度优选自65℃～95℃；Step 1: The starting material 1 is carried out under the conditions of adding a base and a reaction solvent, and the base used is preferably selected from n-butyllithium, phenyllithium, sodium amide, sodium alkoxide, potassium tert-butoxide or sodium tert-butoxide; the reaction solvent is preferably from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, diethyl ether; the reaction temperature is preferably from 65°C to 95°C;
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℃；Step 2: Compound 2 is prepared by halogen lactonization reaction to prepare compound 3. The halogen used is preferably selected from chlorine, bromine and iodine; the solvent is preferably selected from tetrahydrofuran, dioxane and acetonitrile; the reaction temperature is preferably selected from 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℃。Step 3: Compound 3 is prepared by acylation reaction of compound 3, the base used is preferably selected from potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate; the reaction solvent is preferably selected from N,N-dimethylformamide, tetrahydrofuran, dioxane , acetonitrile, dichloromethane; the reaction temperature is preferably from 20°C to 60°C.
本发明所述化合物的制备方法，还优选如下方法：The preparation method of the compound of the present invention, also preferably the following method:
其中R1、A定义同前。wherein R 1 and A are as defined above.
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-羟基苯并三唑、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℃。Concrete steps: the starting material is carried out under the condition of adding a condensing agent, a base and a reaction solvent, wherein the condensing agent is selected from 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or Oxalyl chloride; base is selected from triethylamine or N,N-diisopropylethylamine; reaction solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or dichloromethane; reaction temperature It is 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：Pharmacodynamic test proves that the compound of the present invention has multi-target inhibitory effect on COX-2, NF-κB and p38 MAPK. The following are the pharmacodynamic tests and results of some compounds of the present invention:
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. The anti-inflammatory effect of the compounds of the present invention on 2,4-dinitrofluorobenzene-induced (DNFB) mouse contact dermatitis model
(1)实验方法(1) Experimental method
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、地塞米松组、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，阳性组给予地塞米松(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：Male ICR mice of 18-22 g were taken and reared adaptively for 7 days, and then randomly divided into 25 groups according to body weight, with 8 mice in each group, namely the normal group, the model group, the dexamethasone group, and the compound (22) group of the present invention. On the first day of the experiment, except for the blank group, the mice in each group were evenly sensitized by applying 50 μL of 1% DNFB acetone olive oil solution on the depilation site, and continued to apply 1% DNFB acetone olive oil solution to strengthen once on the second day of the experiment. The administration started on the day of sensitization. The normal group and the model group were given the same dose of vehicle, the positive group was given dexamethasone (DEX) 0.5 mg/kg, and the compound group was given 5 mg/kg respectively. Administer once a day for 6 days. On the 6th day of the experiment, 10 μL of 1% DNFB acetone olive oil solution was evenly applied on both sides of the right ear of the mice to stimulate the inflammatory response, and the left ear was applied with the same amount of acetone olive oil solution as a control. After 24 hours of stimulation, the animals were sacrificed, and the ears were immediately cut off along the baseline of both ears, and round ear pieces were punched at the same part of the two ears with a hole punch of 8 mm in diameter, weighed, and the swelling degree and inhibition rate were calculated. The calculation formula is as follows:
耳肿胀度＝右耳片平均重量-左耳片平均重量The degree of ear swelling = the average weight of the right ear piece - the average weight of the left ear piece
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％Inhibition rate=(average swelling degree of model group-average swelling degree of administration group)/average swelling degree of model group*100%
(2)实验结果(2) Experimental results
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)Table 1. Effects of compounds on 2,4-dinitrofluorobenzene-induced ear swelling and swelling inhibition rate in mice (Mean±SD, n=8)
注：△P<0.05，△△P<0.01vs空白▲P<0.05，▲▲P<0.01vs模型Note: △ P<0.05, △△ P<0.01vs blank ▲ P<0.05, ▲▲ P<0.01vs model
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，阳性药地塞米松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)。The experimental results are shown in Table 1. Compared with the blank group, the swelling degree of the model group reached 16.4±3.6 mg after applying DNFB for modeling, indicating that the modeling effect is obvious. Compared with the model group, the positive drug dexamethasone and most of the compounds of the present invention can significantly reduce ear swelling (P<0.05), among which compounds 4f, 4j, 4n, 4p can significantly reduce DNFB-induced ear swelling in mice degree (P<0.01).
二、本发明部分化合物对COX-1、COX-2酶的抑制作用2. Inhibitory effect of some compounds of the present invention on COX-1 and COX-2 enzymes
(1)实验方法(1) Experimental method
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。Add 160 μl assay buffer and 10 μl Heme to negative control wells; add 150 μl assay buffer, 10 μl Heme and 10 μl COX-2 (or COX-1) to full live wells and sample wells respectively; add 10 μl to negative control wells and full live wells Solvent (4.5% DMSO), add 10 μl of the sample to be tested to the sample well, ensure that the DMSO concentration in all wells of the added sample is 4.5%, and the sample concentration is 10 μM. The mixture was shaken and mixed, and placed at room temperature for 10 min to allow the compound to fully interact with the enzyme. Add 20 μl of chromogenic substrate to each well. Add arachidonic acid to each well. Immediately after shaking and mixing, place it in a microplate reader, read the OD 590 light absorption value, complete the reading within 2 minutes, and calculate the inhibition rate [inhibition rate (%) = (RFU100% enzyme activity control-RFU sample)/(RFU100% Enzyme activity control-RFU blank control)×100%]. Compounds and compound IC50 values were determined by doubling dilution.
(2)实验结果(2) Experimental results
见表2所示：See Table 2:
表2.化合物对COX-1、COX-2酶的抑制活性Table 2. Inhibitory activity of compounds on COX-1, COX-2 enzymes
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。Note: a SI: IC 50 (COX-1)/IC 50 (COX-2), the SI value represents the selectivity of the compound to COX-1 and COX-2 inhibition, and the higher the value, the more selective the compound is to COX-2. high.
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。The experimental results are shown in Table 2. According to the in vivo experimental results, compounds 4f, 4j, and 4n with strong anti-inflammatory activities were selected. These compounds have good in vitro inhibitory activity against cyclooxygenase, among which compounds 4j and 4n showed outstanding performance. COX-2 enzyme inhibitory activity, and has certain selectivity to COX-2 enzyme.
三、本发明部分化合物对MAPK p38α酶的抑制作用3. Inhibitory effect of some compounds of the present invention on MAPK p38α enzyme
(1)实验方法(1) Experimental method
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。Compounds were dissolved in DMSO and diluted with water to the concentration to be tested. After the enzyme reagent is mixed with the sample to be tested, the reaction is initiated by adding a substrate containing 200 μM biotin-peptide and 600 μM ATP. After 60 min incubation at 30°C, the reaction was stopped by adding 10 μL of 1.5% phosphoric acid solution. Transfer part of the reaction solution to the wells of a Streptavidin-coated Flash plate. After washing 3 times with phosphate buffered solution containing 0.01% Tween, it was sealed. Count each well with a scintillation counter. The background count value is subtracted from the count result of each well, and the result count is compared with the count value of the blank group to obtain the relative inhibitory activity of the enzyme at each concentration of the sample to be tested. Compared with the blank group, the concentration of the biotin-peptide substrate reduced by half in the reaction is the IC 50 value of the test sample for MAPK p38α enzyme.
(2)实验结果(2) Experimental results
见表3所示：See Table 3:
表3.化合物对MAPK p38α酶的抑制活性Table 3. Inhibitory activity of compounds on MAPK p38α enzyme
SB203580为特异性p38α MAPK抑制剂SB203580 is a specific p38α MAPK inhibitor
结果如表3所示，化合物4n表现出较强的p38α MAPK抑制活性。The results are shown in Table 3. Compound 4n showed strong p38α MAPK inhibitory activity.
四、化合物4n对MAPK-NF-κB-iNOS/COX-2的调控作用研究4. Study on the regulatory effect of compound 4n on MAPK-NF-κB-iNOS/COX-2
(1)实验方法(1) Experimental method
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。Mouse macrophage RAW264.7 was cultured in DMEM containing 10% fetal bovine serum, 100 U/mL penicillin and 100 mg/mL streptomycin, and incubated in a 37°C, 5% CO 2 incubator. The cells were seeded into 96 plates, DMSO and 4n (5 μM, 10 μM, 20 μM) were added to incubate for 2 hours, and 200 ng/mL lipopolysaccharide was added to incubate for 24 hours. After the cells were collected, the cell proteins were extracted with RIPA high-efficiency cell lysate containing 1% PMSF, and the protein was quantitatively determined by BCA method. Proteins were separated and transferred by SDS-PAGE gel, blocked by shaking in TBST solution containing 5% nonfat dry milk for one hour, and incubated overnight at 4°C by adding primary antibody, followed by adding secondary antibody and incubating for one hour. imaging workstation for detection.
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。The experimental results are shown in Figures 1 to 11, the compound 4n of the present invention can dose-dependently reduce the phosphorylation levels of p38 MAPK and NFκ-B, thereby significantly inhibiting the activities of iNOS and COX-2.
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。To sum up, the compounds of the present invention have inhibitory activity on multiple inflammatory targets of COX-2, NFκ-B and p38 MAPK, especially compound 4n, which shows good research value and medicinal prospect, and can be used for prevention. and treatment of inflammatory diseases.
附图说明Description of drawings
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。Figure 1 is a Western Blot diagram of the compound 4n of the present invention on iNOS and COX-2 proteins in RAW264.7 induced by lipopolysaccharide.
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。Fig. 2 is a bar graph of the expression of iNOS protein in RAW264.7 induced by lipopolysaccharide induced by compound 4n of the present invention.
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。Figure 3 is a bar graph of the expression of COX-2 protein in RAW264.7 induced by lipopolysaccharide by compound 4n of the present invention.
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。Figure 4 is a Western Blot diagram of the compound 4n of the present invention on IκB and p65 proteins in RAW264.7 induced by lipopolysaccharide.
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。Figure 5 is a bar graph of the compound 4n of the present invention on lipopolysaccharide-induced IκB protein expression in RAW264.7.
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。Figure 6 is a bar graph of the compound 4n of the present invention on lipopolysaccharide-induced IκB content in RAW264.7.
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Figure 7 is a bar graph of the expression of p65 protein in RAW264.7 induced by lipopolysaccharide by compound 4n of the present invention
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。Fig. 8 is a Western Blot diagram of the compound 4n of the present invention on lipopolysaccharide-induced p38, JNK and ERK1/2 proteins in RAW264.7.
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。Figure 9 is a bar graph showing the effect of compound 4n of the present invention on lipopolysaccharide-induced p38 protein expression in RAW264.7.
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。Figure 10 is a bar graph of the compound 4n of the present invention on lipopolysaccharide-induced JNK protein expression in RAW264.7.
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。Figure 11 is a bar graph of the compound 4n of the present invention on lipopolysaccharide-induced ERK1/2 protein expression in RAW264.7.
(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)(** in the figure represents the model group compared with the blank group, P<0.01; # represents the compound group compared with the model group, P<0.05; ## represents the compound group compared with the model group, P<0.01)
具体实施方式Detailed ways
实施例1Example 1
1-(2-(4-(4-氯苄基)哌嗪-1-羰基)苯基)乙酮(4a)的合成Synthesis of 1-(2-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4a)
步骤1：2-乙烯基苯甲酸(2)的合成Step 1: Synthesis of 2-vinylbenzoic acid (2)
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％。In a dry 100 mL round-bottomed flask, add methyltriphenylphosphonium ammonium bromide (7.15 g, 20.0 mmol), potassium tert-butoxide (3.37 g, 30.0 mmol) in turn, add anhydrous tetrahydrofuran (100.0 mL) to dissolve, and react The liquid was stirred at room temperature for 1 hour under nitrogen protection. A solution of 2-formylbenzoic acid (1.5 g, 10.0 mmol) in anhydrous tetrahydrofuran was slowly added dropwise to the reaction solution, and the reaction solution was stirred under reflux for 12 hours. TLC [V(petroleum ether):V(ethyl acetate)=2:1 as developing solvent] showed that the reaction was substantially complete. To the reaction solution was added 100 mL of saturated ammonium chloride solution. The reaction solution was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL×3), the combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained white solid compound 2.67 g was separated by silica gel column, and the yield was 90.2%.
步骤2：3-(碘甲基)-3H-异苯并呋喃-1-酮(3)的合成Step 2: Synthesis of 3-(iodomethyl)-3H-isobenzofuran-1-one (3)
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％。In a dry 50 mL round-bottomed flask, compound 2 (2.67 g, 18 mmol), iodine (9.07 g, 36 mmol) and anhydrous acetonitrile (30 mL) were sequentially added, and the reaction solution was stirred at room temperature for 1 hour under nitrogen protection. TLC [V(petroleum ether):V(ethyl acetate)=2:1 as developing solvent] showed that the reaction was substantially complete. To the reaction solution was added 15 mL of saturated sodium thiosulfate solution. The reaction solution was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (30 mL×3), the collected and combined organic phases were washed once with 100 mL of water, saturated sodium bicarbonate solution and saturated sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a yellow solid. The crude product was purified by recrystallization from hot ethanol to obtain 2.10 g of colorless needle-like crystals in a yield of 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Step 3: Synthesis of 1-(2-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4a)
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]+.In a dry 50 mL round-bottomed flask, compound 3 (0.82 g, 3 mmol), potassium carbonate (0.70 g, 5 mmol), and 20 mL of dichloromethane were sequentially added with stirring to dissolve, and 1-(4-chlorobenzyl)piperazine (0.84 g, 4 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. TLC [V (petroleum ether):V (ethyl acetate)=1:1 as developing solvent] showed that the reaction was substantially complete. 20 mL of water was added to the reaction solution. The reaction solution was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL×3), the collected and combined organic layers were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. After purification by column chromatography, 0.37 g of white solid was obtained, and the yield was 34.6%. mp 97.5～98.4℃. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.63 (dd, J=7.5, 1.3 Hz, 1H Ar-H), 7.55 (dd, J= 7.6, 1.4 Hz, 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, CH 2 ), 3.04(t, J=5.0Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.44(t, J= 5.1Hz, 2H, piperazine-H), 2.28 (t, J=5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, CDCl 3 )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2Example 2
1-(2-(4-(4-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4b)的合成Synthesis of 1-(2-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)ethanone (4b)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-methoxybenzyl) piperazine (0.84 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.38 g , the yield is 35.9%. mp88.4～89.6℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.98 (dd, J=7.7, 1.2 Hz, 1H, Ar-H), 7.63 (d, J=7.5, 1.3 Hz, 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, CH 3 ), 3.57 (d, J=5.1 Hz, 2H, piperazine-H), 3.42 (s, 2H, CH 2 ), 3.04(t, J＝5.0Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.41(t, J＝5.1Hz, 2H, piperazine-H), 2.26(t, J＝5.0 Hz , 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )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, 52.478, 55.04 , 52.16, 46.75, 41.54, 28.33. ESI-MS m/z: 353.232[M+H] + .
实施例3Example 3
1-(2-(4-(4-氰基苄基)哌嗪-1-羰基)苯基)乙酮(4c)的合成Synthesis of 1-(2-(4-(4-cyanobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4c)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-cyanobenzyl) piperazine (0.80 g, 4 mmol) as raw materials, column chromatography was performed to obtain 0.48 g of a white solid, Yield 46.1%. mp 143.6～145.6℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.98 (dd, J=7.8, 1.2 Hz, 1H, Ar-H), 7.80 (d, J=8.2 Hz, 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, CH 2 ), 3.06 (t, J=5.0 Hz, 2H, piperazine-H), 2.56 (s, 3H, CH 3 ), 2.46 (t, J=5.1 Hz, 2H, piperazine-H), 2.30 (t, J=5.0 Hz, 2H, piperazine-H); 13 C NMR (101 MHz, DMSO-d 6 ) 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4Example 4
1-(2-(4-(4-三氟甲基苄基)哌嗪-1-羰基)苯基)乙酮(4d)的合成Synthesis of 1-(2-(4-(4-trifluoromethylbenzyl)piperazine-1-carbonyl)phenyl)ethanone (4d)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82g, 3mmol) and 1-(4-trifluoromethylbenzyl)piperazine (0.98g, 4mmol) as raw materials, column chromatography was used to obtain a white solid 0.24g , the yield is 20.9%. mp63.1～64.5℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.99 (dd, J=7.7, 1.3 Hz, 1H, Ar-H), 7.69 (d, J=8.1 Hz, 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, CH 2 ), 3.07 (dd, J=5.0, 4.1 Hz, 2H, piperazine-H), 2.56 (s, 3H, CH 3 ) , 2.46(d, J＝5.0Hz, 2H, piperazine-H), 2.31(t, J＝5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )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),61.58,52.55,52.28,46.70,41.51,28.225[M/Z:391. +H] + .
实施例5Example 5
1-(2-(4-(4-硝基苄基)哌嗪-1-羰基)苯基)乙酮(4e)的合成Synthesis of 1-(2-(4-(4-nitrobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4e)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-nitrobenzyl) piperazine (0.88 g, 4 mmol) as raw materials, column chromatography was used to obtain 0.46 g of a white solid, Yield 42.1%. mp190.8～192.4℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 8.29-8.15 (m, 2H, Ar-H), 7.98 (dd, J=7.8, 1.3 Hz, 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,CH 2 ),3.64-3.56(m,2H,piperazine-H),3.07(dd,J=5.0,4.0Hz,2H,piperazine-H),2.55(s,3H,CH 3 ), 2.48(t, J=5.0Hz, 2H, piperazine-H), 2.32(t, J=5.0Hz, 2H, piperazine-H). 13 C NMR (101 MHz, DMSO-d 6 )δ: 199.24, 174.88,169.42,147.05,146.91,137.06,135.70,132.99,130.33,130.18, 129.33,127.40,123.86,61.28,52.55,52.31,46.70,41.50,28MS.32,25.9 ] + .
实施例6Example 6
1-(2-(4-(3-硝基苄基)哌嗪-1-羰基)苯基)乙酮(4f)的合成Synthesis of 1-(2-(4-(3-nitrobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4f)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(3-nitrobenzyl) piperazine (0.88 g, 4 mmol) as raw materials, column chromatography was performed to obtain 0.33 g of a white solid, Yield 30.2%. mp180.1～181.8℃. 1 H NMR(400 MHz, DMSO-d 6 )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,CH 2 ),3.61(d,J=5.0Hz, 2H, piperazine-H), 3.07 (dd, J=5.0, 4.0Hz, 2H, piperazine-H), 2.56 (s, 3H, CH 3 ), 2.48 (d, J=5.0Hz, 2H, piperazine-H) , 2.38-2.28 (m, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )δ: 199.25, 169.40, 148.29, 137.06, 135.95, 135.70, 132.98, 130.33, 130.24, 129.32, 127.60, 123. ,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7Example 7
1-(2-(4-(2,4-二氯苄基)哌嗪-1-羰基)苯基)乙酮(4g)的合成Synthesis of 1-(2-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4g)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(2,4-dichlorobenzyl)piperazine (0.98 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.43 g, yield 36.5%. mp74.9～76.4℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.99 (dd, J=7.8, 1.3 Hz, 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, CH 2 ), 3.10-3.02(m, 2H, piperazine -H), 2.56 (s, 3H, CH 3 ), 2.49 (d, J=5.0Hz, 2H, piperazine-H), 2.34 (t, J=5.0Hz, 2H, piperazine-H). 101MHz,DMSO-d 6 )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8Example 8
1-(2-(4-(2-氯苄基)哌嗪-1-羰基)苯基)乙酮(4h)的合成Synthesis of 1-(2-(4-(2-chlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4h)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(2-chlorobenzyl) piperazine (0.84 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.47 g in a yield of 0.47 g. 43.7%. mp133.5～134.6℃. 1 HNMR(400MHz, DMSO-d 6 )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, CH 2 ), 3.06 (dd, J=5.0, 4.0 Hz, 2H, piperazine-H), 2.56 (s, 3H, CH 3 ), 2.49 (d, J=5.0 Hz, 2H, piperazine-H), 2.35 (t, J=5.0Hz, 2H, piperazine-H). 13 CNMR (101MHz, DMSO-d 6 )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9Example 9
1-(2-(4-(3-氯苄基)哌嗪-1-羰基)苯基)乙酮(4i)的合成Synthesis of 1-(2-(4-(3-chlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4i)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(3-chlorobenzyl) piperazine (0.84 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.52 g in a yield of 0.52 g. 48.2%. mp105.8～107.5℃. 1 HNMR(400MHz, DMSO-d 6 )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 , CH 2 ), 3.13-2.99(m, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.45(t, J=5.0Hz, 2H, piperazine-H), 2.29(t, J= 5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )δ: 199.20, 169.38, 141.15, 137.10, 135.72, 133.42, 132.96, 130.55, 130.30, 129.29, 128.88, 1214.87, 127 , 52.47, 52.24, 46.71, 41.50, 28.32. ESI-MS m/z: 357.212[M+H] + .
实施例10Example 10
1-(2-(4-(4-氟苄基)哌嗪-1-羰基)苯基)乙酮(4j)的合成Synthesis of 1-(2-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (4j)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-fluorobenzyl) piperazine (0.77 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.39 g in a yield of 0.39 g. 38.4%. mp107.6～108.8℃. 1 HNMR(400MHz, DMSO-d 6 )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, CH 2 ), 3.04 (t, J=5.0 Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.43(t, J=5.0Hz, 2H, piperazine-H), 2.27(t, J=5.0Hz, 2H, piperazine-H) . 13 C NMR (101 MHz, DMSO-d 6 ) δ: 199.23, 169.37, 137.09, 135.74, 134.51 (d, J CF=3.0 Hz), 132.96 (d, J CF=3.0 Hz), 132.57, 130.30 (d, J CF=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11Example 11
1-(2-(4-(4-苄基)哌嗪-1-羰基)苯基)乙酮(4k)的合成Synthesis of 1-(2-(4-(4-benzyl)piperazine-1-carbonyl)phenyl)ethanone (4k)
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]+.Referring to the synthesis method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-benzyl)piperazine (0.70 g, 4 mmol) as raw materials, column chromatography was used to obtain 0.36 g of a white solid with a yield of 37.8 %. mp69.7～70.9℃. 1 H NMR(400MHz, DMSO-d 6 )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, CH 2 ), 3.05 (dd, J=5.0, 4.1 Hz, 2H, piperazine-H), 2.55 (s, 3H, CH 3 ), 2.44 (t, J=5.0 Hz, 2H, piperazine-H), 2.29 (t, J＝5.0Hz, 2H, piperazine-H). 13 CNMR (101MHz, DMSO-d 6 )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12Example 12
1-(2-(4-(4-甲基苄基)哌嗪-1-羰基)苯基)乙酮(4l)的合成Synthesis of 1-(2-(4-(4-methylbenzyl)piperazine-1-carbonyl)phenyl)ethanone (4l)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(4-methylbenzyl)piperazine (0.76 g, 4 mmol) as raw materials, column chromatography was performed to obtain 0.47 g of a white solid, Yield 46.3%. mp 116.7～118.3℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.98 (dd, J=7.8, 1.3 Hz, 1H, Ar-H), 7.63 (dd, J=7.6, 1.3 Hz, 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=8.0 Hz, 2H, Ar-H), 7.13 (d, J=8.0 Hz, 2H, Ar-H), 3.58 (t, J=5.0 Hz, 2H, piperazine-H), 3.44 (s, 2H, CH 2 ) , 3.04(t, J＝5.0Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.42(t, J＝5.0Hz, 2H, piperazine-H), 2.28(s, 5H, piperazine -H, CH 3 ). 13 C NMR (101MHz, DMSO-d 6 )δ: 199.20, 169.37, 137.13, 136.49, 135.75, 135.22, 132.94, 130.29, 119.26, 127.40, 62.14, 52.52, 52.24, 46.573,4 28.32, 21.17. ESI-MS m/z: 337.255[M+H] + .
实施例13Example 13
1-(2-(4-(2,4-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4m)的合成Synthesis of 1-(2-(4-(2,4-methoxybenzyl)piperazine-1-carbonyl)phenyl)ethanone (4m)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82g, 3mmol) and 1-(2,4-methoxybenzyl)piperazine (0.94g, 4mmol) as raw materials, column chromatography was used to obtain a white solid 0.53 g, yield 46.2%. mp 113.9～115.4℃. 1 H NMR (400MHz, DMSO-d 6 )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, OCH 3 × 2), 3.57(t, J=5.0Hz, 2H, piperazine-H), 3.41(s, 2H, CH 2 ), 3.03(t, J=5.0Hz, 2H, piperazine-H) , 2.55 (s, 3H, CH 3 ), 2.43 (t, J=5.0 Hz, 2H, piperazine-H), 2.27 (t, J=5.0 Hz, 2H, piperazine-H). 13 C NMR (101 MHz, DMSO -d 6 )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14Example 14
1-(2-(4-(2-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4n)的合成Synthesis of 1-(2-(4-(2-methoxybenzyl)piperazine-1-carbonyl)phenyl)ethanone (4n)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(2-methoxybenzyl)piperazine (0.83 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.42 g , the yield is 39.8%. mp 117.9～119.7℃. 1 H NMR (400MHz, DMSO-d 6 )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, 1.2 Hz, 1H, Ar-H), 3.77 (s, 3H, OCH 3 ), 3.59 (s, 2H, piperazine-H), 3.49 (s, 2H, CH 2 ), 3.05(t, J＝5.0Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.47(t, J＝5.0Hz, 2H, piperazine-H), 2.31(t, J＝ 5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )δ: 199.23, 169.36, 157.79, 137.12, 135.76, 132.95, 130.29, 129.28, 128.58, 127.42, 125.82, 557.67, 111. , 52.69, 52.42, 46.77, 41.57, 28.33. ESI-MS m/z: 353.251[M+H] + .
实施例15Example 15
1-(2-(4-(3-甲氧基苄基)哌嗪-1-羰基)苯基)乙酮(4o)的合成Synthesis of 1-(2-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)ethanone (4o)
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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(3-methoxybenzyl) piperazine (0.83 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.48 g , the yield is 45.3%. mp 119.3～120.7℃. 1 H NMR (400 MHz, DMSO-d 6 )δ: 7.98 (dd, J=7.6, 1.2 Hz, 1H, Ar-H), 7.63 (dd, J=7.5, 1.3 Hz, 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, OCH 3 ), 3.58 (t, J=5.0 Hz, 2H, CH 2 ), 3.47 (s, 2H, CH 2 ), 3.05 (t, J=5.0Hz, 2H, piperazine-H), 2.55 (s, 3H, CH 3 ), 2.42 (t, J=5.0 Hz, 2H, piperazine-H), 2.28 (t, J=5.0 Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )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, 55.4. 52.16, 46.75, 41.54, 28.33. ESI-MS m/z: 353.240[M+H] + .
实施例16Example 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Synthesis of 1-(2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbonyl)phenyl)ethanone (4p)
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]+.Referring to the synthetic method of Example 1, with compound 3 (0.82g, 3mmol) and 1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine (0.88g, 4 mmol) as the raw material, and purified by column chromatography to obtain 0.40 g of a white solid with a yield of 36.3%. mp 103.4～104.5℃. 1 H NMR (400MHz, DMSO-d 6 )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, OCH 3 ), 3.58(t, J=5.0Hz, 2H,, piperazine-H), 3.40 (s, 2H, CH 2 ), 3.04 (t, J=5.0 Hz, 2H, piperazine-H), 2.55 (s, 3H, CH 3 ), 2.42 (t, J=5.0 Hz, 2H, piperazine-H) , 2.26 (t, J=5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )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17Example 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1-(2-(4-((2,3-Dihydrobenzo[b][1,4]dioxen-6-yl)methyl)piperazine-1-carbonyl)phenyl) Synthesis of ethyl ketone (4q)
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]+.Referring to the synthesis method of Example 1, with compound 3 (0.82 g, 3 mmol) and 1-((2,3-dihydrobenzo[b][1,4]dioxen-6-yl)methan yl)piperazine (0.94 g, 4 mmol) was used as the raw material, and purified by column chromatography to obtain 0.45 g of a white solid with a yield of 39.7%. mp124.9～126.4℃. 1 H NMR(400MHz, DMSO-d 6 )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, OCH 2 ×2), 3.58(t, J=5.0Hz, 2H, piperazine-H), 3.37(s, 2H, CH 2 ), 3.04(t, J=5.0 Hz, 2H, piperazine-H), 2.55 (s, 3H, CH 3 ), 2.41 (t, J=5.0Hz, 2H, piperazine-H), 2.26 (t, J=5.0Hz, 2H, piperazine-H) . 13 C NMR (101MHz, DMSO-d 6 )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,.47 Hz) 61.76, 52.50, 52.15, 46.74, 41.53, 28.33. ESI-MS m/z: 381.248[M+H] + .
实施例18Example 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Synthesis of 1-(2-(4-((3,5,6-trimethylpyrazin-2-yl)methyl)piperazine-1-carbonyl)phenyl)ethanone (4r)
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]+.Referring to the synthesis method of Example 1, using compound 3 (0.82g, 3mmol) and 2,3,5-trimethyl-6-(piperazin-1-ylmethyl)pyrazine (0.88g, 4mmol) as raw materials , and purified by column chromatography to obtain 0.52 g of white solid with a yield of 47.4%. mp119.0～120.1℃. 1 H NMR(400MHz, DMSO-d 6 )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, CH 2 ), 3.55(t, J＝5.0Hz, 2H, piperazine-H), 3.01(t, J＝5.0Hz, 2H, piperazine-H), 2.55(s, 3H, CH 3 ), 2.50(s, 3H, CH 3 ), 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 ). 13 C NMR(101MHz,DMSO-d 6 )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19Example 19
1-(2-(4-(吡啶-4-基甲基)哌嗪-1-羰基)苯基)乙酮(4s)1-(2-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)ethanone (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]+.Referring to the synthetic method of Example 1, using compound 3 (0.82 g, 3 mmol) and 1-(pyridin-4-ylmethyl)piperazine (0.71 g, 4 mmol) as raw materials, column chromatography was used to obtain a white solid 0.42 g , the yield is 43.8%. mp129.0～131.2℃. 1 H NMR (400 MHz, DMSO-d 6 )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,CH 2 ),3.07(t,J =5.0Hz, 2H, piperazine-H), 2.56(s, 3H, CH 3 ), 2.47(t, J=5.0Hz, 2H, piperazine-H), 2.30(t, J=5.0Hz, 2H, piperazine- H). 13 C NMR (101MHz, DMSO-d 6 )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, 52.3, 5, 8.3. ESI-MS m/z: 324.257[M+H] + .
实施例20Example 20
1-(2-(4-(4-氯苄基)哌嗪-1-羰基)-5-甲基苯基)乙酮(7a)的合成Synthesis of 1-(2-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-5-methylphenyl)ethanone (7a)
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]+.In a dry 50 mL round-bottomed flask, add 2-acetyl-4-methylbenzoic acid (0.44 g, 2.5 mmol) and dissolve it in 20 mL of anhydrous dichloromethane, and slowly add oxalyl chloride (0.48 g) dropwise at 0 °C. g, 3.8 mmol), a drop of DMF was added dropwise, and the mixture was warmed to room temperature and reacted for 3 hours. TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing solvent] showed that the reaction was substantially complete. The reaction solution was concentrated under reduced pressure, redissolved in 10 mL of anhydrous dichloromethane, slowly added dropwise to 1-(4-chlorobenzyl)piperazine dichloromethane solution, and stirred at room temperature for 3 hours. TLC [V (petroleum ether):V (ethyl acetate)=1:1 as developing solvent] showed that the reaction was substantially complete. 20 mL of water was added to the reaction solution. The reaction solution was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL×3), the collected and combined organic layers were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained white solid 0.48g was separated by silica gel column, and the yield was 51.8%. mp 107.9～110.8℃. 1 H NMR(400MHz, DMSO-d 6 )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,CH 2 ),3.03(m,2H,piperazine-H),2.53( d, J=4.6Hz, 3H, CH 3 ), 2.42 (t, J=5.0 Hz, 2H, piperazine-H), 2.38 (d, J=8.5 Hz, 3H, CH 3 ), 2.27 (t, J= 5.0Hz, 2H, piperazine-H). 13 C NMR (101MHz, DMSO-d 6 )δ: 199.34, 169.52, 138.92, 137.48, 135.96, 133.26, 132.80, 131.96, 131.05, 129.66, 128.63, 127.4.89, 12 , 52.47, 52.22, 46.67, 41.49, 28.35, 21.36. ESI-MS m/z: 371.228[M+H] + .
实施例21Example 21
1-(5-氯-2-(4-(4-氯苄基)哌嗪-1-羰基)苯基)乙酮(7b)的合成Synthesis of 1-(5-chloro-2-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)ethanone (7b)
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]+。With reference to the synthesis method of Example 20, 2-acetyl-4-chlorobenzoic acid (0.59g, 3mmol) and 1-(4-chlorobenzyl)piperazine (0.84g, 4mmol) were used as raw materials, and purified by column chromatography 0.62 g of white solid was obtained with a yield of 52.6%. mp108.1～110.7℃. 1 H NMR (400MHz, DMSO-d 6 )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, CH 2 ), 3.06(q, J=4.4Hz, 2H, piperazine-H), 2.56 (d, J=7.3 Hz, 3H, CH 3 ), 2.44 (q, J=5.0 Hz, 2H, piperazine-H), 2.29 (q, J=4.4 Hz, 2H, piperazine-H). 13 C NMR ( 101MHz,DMSO-d 6 )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-MS m/z: 391.197[M+H] + .
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