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
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a benzyl piperazine compound (I) with anti-inflammatory activity and a preparation method thereof, and pharmacodynamic tests prove that the compound has COX-2, NF-kB and p38 MAPK multi-target inhibition effects and can be used for preventing and treating inflammation related diseases.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a benzyl piperazine compound with anti-inflammatory activity, a preparation method and a medical application.
Background
Inflammation is an adaptive reaction of the body caused by external stimulation or cell injury, and maintains the homeostasis of the body by removing inflammatory factors and repairing damaged tissues. Although the inflammatory response is critical to maintaining the health of the body, uncontrolled inflammatory responses can be implicated in the development of a number of chronic diseases, such as asthma, atherosclerosis, rheumatoid arthritis and cancer [ Sun S, Ji Y, Kersten S, et al. Therefore, anti-inflammatory drugs, which are widely used clinically, are one of the most used drugs.
Currently, most anti-inflammatory drug development strategies focus mainly on the two aspects of inhibiting the production of certain pro-inflammatory mediators directly through the relevant mediators or their targets, such as directly inhibiting the activity of COX enzymes using non-steroidal anti-inflammatory drugs, blocking the conversion of arachidonic acid to the potent pro-inflammatory mediator prostaglandin 2[ Carlo Patro, Bianca Rocca. Nonsteroidal anti-inflammatory drugs: Patt, present and future [ J ]. Pharmacological Research,2009,59(5): 285-289 ]; it controls upstream targets of inflammation, blocks transcription and expression of related enzymes, and indirectly inhibits the production of proinflammatory mediators, such as MAPK p38 inhibitor blocking transcription and expression of COX-2 and iNOS genes, and indirectly inhibits the production of prostaglandin 2 and nitric oxide [ Chian-Jiun Liou, Wen-BinLen, Shu-JuWu, et al, casein inhibitors COX-2 and iNOS expression vision of NF- κ B and MAPK signaling in lipopolysaccharide-tyrosine kinase, 2014,158: 310-. However, non-steroidal anti-inflammatory drugs severely limit their clinical application due to gastrointestinal side effects and potential cardiovascular side effects; inhibitors of MAPKp38 and related targets are also difficult to access for clinical use due to the presence of unavoidable side effects. Inflammation is a network system consisting of a plurality of mediums, and the question remains whether anti-inflammatory drugs with good treatment effect and small side effect can be developed according to a single target. Therefore, the search for new strategies and the design of highly effective and low-toxicity candidate drugs become important directions for the research and development of anti-inflammatory drugs.
Based on that the inflammation subsides and involves a plurality of cytokines and regulatory mechanisms, the multi-target drug moderately regulates and controls a plurality of inflammation targets, can improve the treatment effect through the synergistic effect, and also avoids the adverse reaction mediated by over inhibition of certain targets. Clinically, low-dose drug combinations are also often adopted to treat inflammatory pain so as to achieve the aim of maximizing the treatment effect and avoiding side effects. Multi-target drugs have long been an important tool for the treatment of chronic diseases mediated by multiple pathways and multiple targets. The existing anti-inflammatory drugs seriously threaten the life safety of patients due to side effects caused by excessive inhibition of a single target. Therefore, the development of novel anti-inflammatory drugs based on multiple targets has pioneering significance for the treatment of inflammation, especially chronic inflammatory diseases.
Disclosure of Invention
The invention discloses a benzyl piperazine compound, which has the following structural formula:
wherein R is1Represents optionally substituted C1~C6Alkyl or halogen of (a);
a represents:
wherein R is2Represents optionally substituted C1~C6Alkyl, halogen, hydroxy, trifluoromethyl, cyano, methoxy, amino or nitro.
The halogen is preferably F, Cl or Br.
Preferred compounds of the invention are of any of the following structures (compound numbers are as in the examples):
more preferred are compounds of the structure:
the pharmaceutically acceptable salt of the compound is formed by the compound and 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.
The pharmaceutical composition of the compound or the pharmaceutical salt thereof has the effect of multi-target inhibition of COX-2, NF-kB and p38 MAPK. The compounds of the present invention or pharmaceutically acceptable salts thereof are useful in the prevention and treatment of inflammation-related disorders.
The inflammation-related diseases described in the present invention include: rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, hypodermitis and postpartum inflammation, enteropathy, gastritis, headache, adventitial inflammation, apoplexy, ischemia, mental trauma, allergic rhinitis, coronary plaque inflammation, inflammation caused by bacteria, inflammation caused by virus, inflammation caused by operation and gastric ulcer.
The invention also discloses a pharmaceutical composition which contains a therapeutically effective amount of the compound shown in the formula (I) or pharmaceutically acceptable salt or any one of the compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, granules, oral liquid, syrup, suppositories, transdermal preparations, injections and other preparations which are conventional in pharmaceutics.
The preparation method of the compound of the invention is preferably as follows:
step 1: the starting material 1 is carried out under the condition of adding alkali and reaction solvent, wherein the alkali is preferably selected from n-butyl lithium, phenyl lithium, sodium amide, sodium alkoxide, potassium tert-butoxide or sodium tert-butoxide; the reaction solvent is preferably selected from N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and diethyl ether; the reaction temperature is preferably 65-95 ℃;
step 2: preparing a compound 3 from the compound 2 through halogen lactonization, wherein the halogen is preferably selected from chlorine, bromine and iodine; the solvent is preferably selected from tetrahydrofuran, dioxane and acetonitrile; the reaction temperature is preferably 25-45 ℃;
and step 3: preparing a compound 3 by acylation reaction of the compound 3, wherein the used base is preferably selected from potassium carbonate, sodium carbonate, potassium phosphate and sodium acetate; the reaction solvent is preferably selected from N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and dichloromethane; the reaction temperature is preferably from 20 ℃ to 60 ℃.
The preparation method of the compound of the invention is also preferably as follows:
wherein R is1And A is as defined above.
The method comprises the following specific steps: the starting material is prepared by adding a condensing agent, a base and a reaction solvent, wherein the condensing agent is selected from 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, N' -carbonyldiimidazole or oxalyl chloride; the base is selected from triethylamine or N, N-diisopropylethylamine; the reaction solvent is selected from N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or dichloromethane; the reaction temperature is 20-60 ℃.
Pharmacodynamic tests prove that the compound has COX-2, NF-kB and p38 MAPK multi-target inhibition effects. The following are the pharmacodynamic tests and results of some of the compounds of the invention:
anti-inflammatory effect of the compound on 2, 4-dinitrofluorobenzene-induced (DNFB) mouse contact dermatitis model
(1) Experimental methods
18-22g of male ICR mice are taken, after adaptive feeding is carried out for 7 days, the mice are randomly divided into 25 groups according to the weight, and each group comprises 8 mice, namely a normal group, a model group, a dexamethasone group and a compound (22) group. On day 1 of the experiment, except for the blank group, each group of mice was sensitized by uniformly applying 50 μ L of 1% DNFB acetone olive oil solution to the depilated area, and on day 2 of the experiment, the mice were further strengthened by applying 1% DNFB acetone olive oil solution once. The administration is started on the sensitization day, the normal group and the model group are administered with equal doses of solvent, the positive group is administered with Dexamethasone (DEX) of 0.5mg/kg, the compound groups are respectively administered with 5mg/kg, the administration is carried out by intragastric administration, and the administration is carried out 1 time per day and is continued for 6 days in the experimental process. On the 6 th day of the experiment, 10 μ L of 1% DNFB acetone olive oil solution was evenly applied to both sides of the right ear of the mouse to stimulate the inflammatory reaction, and the same amount of acetone olive oil solution was applied to the left ear to serve as a control. The animals are killed after being excited for 24 hours, ears are cut off along the base lines of the ears immediately, round ear pieces are respectively punched at the same positions of the ears by a puncher with the diameter of 8mm, the animals are weighed, and swelling degree and inhibition rate are calculated according to the following calculation formula:
swelling degree of ear-right ear-left ear mean weight
Inhibition rate (average degree of swelling in model group-average degree of swelling in administration group)/average degree of swelling in model group%
(2) Results of the experiment
TABLE 1 Effect of Compounds on the degree of swelling and the rate of inhibition of swelling in mouse auricles by 2, 4-dinitrofluorobenzene (Mean. + -. SD, n ═ 8)
Note:△P<0.05,△△P<0.01vs blank▲P<0.05,▲▲P<0.01vs model
The experimental results are shown in table 1, compared with the blank group, the swelling degree of the model group after DNFB molding reaches 16.4 +/-3.6 mg, and the molding effect is obvious. Compared with a model group, the positive drug dexamethasone and most of the compounds of the invention can obviously reduce the ear swelling degree (P <0.05), wherein the compounds 4f, 4j, 4n and 4P can greatly reduce the ear swelling degree (P <0.01) of mice induced by DNFB.
Secondly, the partial compounds of the invention have the inhibition effect on COX-1 and COX-2 enzymes
(1) Experimental methods
Add 160. mu.l of assay buffer and 10. mu.l of Heme to the negative control wells; adding 150 μ l of assay buffer, 10 μ l of Heme and 10 μ l of COX-2 (or COX-1) into the whole-live well and the sample well respectively; mu.l of solvent (4.5% DMSO) was added to the negative control wells and the whole wells, and 10. mu.l of the sample to be tested was added to the sample wells, ensuring that the DMSO concentration in all the wells of the added samples was 4.5% and the sample concentration was 10. mu.M. Shaking and mixing, standing at room temperature for 10min to make the compound and enzyme fully act. Add 20. mu.l of chromogenic substrate to each well. Arachidonic acid was added to each well. Placing in an enzyme-linked immunosorbent assay (ELISA) instrument immediately after shaking and mixing, and reading OD590Light absorption value, reading completed within 2 minutes, and inhibition rate [ inhibition rate (%) ═ RFU sample (RFU 100% enzyme activity control-RFU sample)/(RFU 100% enzyme activity control-RFU blank) × 100%]. Determination of Compounds and IC of Compounds by dilution by multiple ratio50The value is obtained.
(2) Results of the experiment
See table 2 for:
TABLE 2 inhibitory Activity of Compounds on COX-1, COX-2 enzymes
Note:aSI:IC50(COX-1)/IC50(COX-2), the SI value represents the selectivity of the compound for COX-1, COX-2 inhibition, and a higher value indicates a higher selectivity for COX-2.
The experimental results are shown in table 2, and compounds 4f, 4j and 4n with strong anti-inflammatory activity are selected according to in vivo experimental results, and have good in vitro inhibition activity on cyclooxygenase, wherein the compounds 4j and 4n show prominent COX-2 enzyme inhibition activity and have certain selectivity on COX-2 enzyme.
Thirdly, the inhibition effect of the partial compound of the invention on MAPK p38 alpha enzyme
(1) Experimental methods
After the compound was dissolved in DMSO, it was diluted with water to the concentration to be measured. After mixing the enzyme reagent with the sample to be tested, the reaction was initiated by adding a mixture containing 200. mu.M biotin-peptide substrate and 600. mu.M ATP. After incubation at 30 ℃ for 60 minutes, the reaction was stopped by adding 10. mu.L of 1.5% phosphoric acid solution. Part of the reaction solution was transferred to the wells of a Flash plate coated with streptavidin. After washing 3 times with phosphate buffer solution containing 0.01% tween, the cells were sealed. Each well was counted with a scintillation counter. The relative enzyme inhibition activity of the sample to be tested at each concentration can be obtained by subtracting the background count value from the count result of each well and comparing the count result with the count value of the blank group. Compared with the blank group, the concentration of the biotin-peptide substrate in the reaction is reduced by half, namely the IC of the sample to be detected to the MAPK p38 alpha enzyme50The value is obtained.
(2) Results of the experiment
See table 3 for:
TABLE 3 inhibitory Activity of Compounds on MAPK p38 alpha enzyme
SB203580 is a specific p38 alpha MAPK inhibitor
The results are shown in table 3, compound 4n shows stronger p38 α MAPK inhibitory activity.
Fourth, study of the regulatory action of compound 4n on MAPK-NF-kB-iNOS/COX-2
(1) Experimental methods
Mouse macrophage RAW264.7 was cultured in DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin and 100mg/mL streptomycin at 37 deg.C under 5% CO2Is incubated in an incubator. Cells were seeded in 96 plates and incubated for two hours with DMSO and 4n (5. mu.M, 10. mu.M, 20. mu.M), respectively, followed by incubation for 24 hours with 200ng/mL lipopolysaccharide. After collecting cells, extracting cell protein by RIPA high-efficiency cell lysate containing 1% PMSF, and carrying out protein quantitative determination by a BCA method. Proteins were separated and transmembrane-transfected by SDS-PAGE gel, blocked in 5% skimmed milk powder in TBST for one hour with shaking, incubated overnight at 4 ℃ with the addition of primary antibody, incubated for one hour with the addition of secondary antibody and detected using Tanon 6600 luminescence imaging workstation.
The experimental results are shown in the attached fig. 1 to 11, and the compound 4n can reduce the phosphorylation levels of p38 MAPK and NF kappa-B in a dose-dependent manner, so that the activities of iNOS and COX-2 are obviously inhibited.
In conclusion, the compound has inhibitory activity on a plurality of inflammatory targets of COX-2 and NF kappa-B, p38 MAPK, particularly the compound 4n is the most prominent, shows good research value and medicinal prospect, and can be used for preventing and treating inflammatory diseases.
Drawings
FIG. 1 is a Western Blot of compound 4n of the present invention on iNOS and COX-2 proteins in lipopolysaccharide-induced RAW 264.7.
FIG. 2 is a histogram of the expression of iNOS protein in lipopolysaccharide-induced RAW264.7 by Compound 4n of the present invention.
FIG. 3 is a bar graph of the expression of COX-2 protein in lipopolysaccharide-induced RAW264.7 by Compound 4n of the present invention.
FIG. 4 is a Western Blot of compound 4n of the invention against I κ B and p65 proteins in LPS-induced RAW 264.7.
FIG. 5 is a bar graph of lipopolysaccharide-induced expression of I.kappa.B protein in RAW264.7 by Compound 4n of the present invention.
FIG. 6 is a bar graph of the presence of I.kappa.B in lipopolysaccharide-induced RAW264.7 by Compound 4n of the present invention.
FIG. 7 is a bar graph of the lipopolysaccharide-induced expression of p65 protein in RAW264.7 by Compound 4n of the present invention
FIG. 8 is a Western Blot of compound 4n of the present invention on p38, JNK and ERK1/2 proteins in lipopolysaccharide-induced RAW 264.7.
FIG. 9 is a bar graph of the lipopolysaccharide-induced expression of p38 protein in RAW264.7 by Compound 4n of the present invention.
Fig. 10 is a histogram of the expression of JNK protein in lipopolysaccharide-induced RAW264.7 by compound 4n of the present invention.
FIG. 11 is a bar graph of the effect of Compound 4n of the present invention on lipopolysaccharide-induced expression of ERK1/2 protein in RAW 264.7.
(where P <0.01 in the model group compared to the blank group; # represents P <0.05 in the compound group compared to the model group; # represents P <0.01 in the compound group compared to the model group)
Detailed Description
Example 1
Synthesis of 1- (2- (4- (4-chlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4a)
Step 1: synthesis of 2-vinylbenzoic acid (2)
To a dry 100mL round-bottom flask, ammonium methyltriphenylphosphate bromide (7.15g,20.0mmol) and potassium tert-butoxide (3.37g,30.0mmol) were added in this order, and the mixture was dissolved in anhydrous tetrahydrofuran (100.0mL), and the reaction mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. An anhydrous tetrahydrofuran solution of 2-formylbenzoic acid (1.5g,10.0mmol) 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 agent ] showed that the reaction was essentially complete. To the reaction mixture was added 100mL of a saturated ammonium chloride solution. The reaction mixture was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 2.67g of the obtained white solid compound was separated by silica gel column, and the yield was 90.2%.
Step 2: synthesis of 3- (iodomethyl) -3H-isobenzofuran-1-one (3)
In a dry 50mL round-bottom flask, compound 2(2.67g,18mmol), iodine (9.07g, 36mmol), and anhydrous acetonitrile (30mL) were added in this order, and the reaction was stirred at room temperature for 1 hour under nitrogen. TLC [ V (petroleum ether): V (ethyl acetate) ═ 2:1 as developing agent ] showed that the reaction was essentially complete. To the reaction solution was added 15mL of a 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. times.3), and the combined organic phases were collected and washed once with 100mL of water, a saturated sodium bicarbonate solution and a saturated sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give a yellow solid. The crude product was purified by recrystallization from hot ethanol to give 2.10g of colorless needle crystals in 43.3% yield.
And step 3: synthesis of 1- (2- (4- (4-chlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4a)
In a dry 50mL round-bottom flask, compound 3(0.82g,3mmol), potassium carbonate (0.70g,5mmol) and methylene chloride (20 mL) were added in this order and dissolved with stirring, and 1- (4-chlorobenzyl) piperazine (0.84g,4mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. TLC (petroleum ether) V (ethyl acetate) 1:1 as developing agent]Indicating that the reaction was substantially complete. To the reaction mixture was added 20mL of water. The reaction mixture was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The white solid is obtained by column chromatography purification, and the yield is 34.6 percent. 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]+.
Example 2
Synthesis of 1- (2- (4- (4-methoxybenzyl) piperazine-1-carbonyl) phenyl) ethanone (4b)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-methoxybenzyl) piperazine (0.84g,4mmol) as starting materials, column chromatography purification gave 0.38g of white solid in 35.9% yield. 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]+.
Example 3
Synthesis of 1- (2- (4- (4-cyanobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4c)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-cyanobenzyl) piperazine (0.80g, 4mmol) as starting materials, column chromatography purification gave 0.48g of white solid in 46.1% yield. 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]+.
Example 4
Synthesis of 1- (2- (4- (4-trifluoromethylbenzyl) piperazine-1-carbonyl) phenyl) ethanone (4d)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-trifluoromethylbenzyl) piperazine (0.98g, 4mmol) as starting materials, column chromatography purification gave 0.24g of white solid with a yield of 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]+.
Example 5
Synthesis of 1- (2- (4- (4-nitrobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4e)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-nitrobenzyl) piperazine (0.88g,4mmol) as starting materials, column chromatography purification gave 0.46g of white solid in 42.1% yield. 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]+.
Example 6
Synthesis of 1- (2- (4- (3-nitrobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4f)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (3-nitrobenzyl) piperazine (0.88g,4mmol) as starting materials, column chromatography purification gave 0.33g of white solid in 30.2% yield. 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]+.
Example 7
Synthesis of 1- (2- (4- (2, 4-dichlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4g)
Referring to the synthesis method of example 1, column chromatography purification using compound 3(0.82g,3mmol) and 1- (2, 4-dichlorobenzyl) piperazine (0.98g, 4mmol) as starting materials gave 0.43g of a white solid in 36.5% yield. 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]+.
Example 8
Synthesis of 1- (2- (4- (2-chlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4h)
Synthetic method of reference example 1 to combineStarting from 3(0.82g,3mmol) and 1- (2-chlorobenzyl) piperazine (0.84g,4mmol), purification by column chromatography gave 0.47g of a white solid in 43.7% yield. m.p.133.5-134.6 ℃.1H NMR(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).13C NMR(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]+.
Example 9
Synthesis of 1- (2- (4- (3-chlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4i)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (3-chlorobenzyl) piperazine (0.84g,4mmol) as starting materials, column chromatography purification gave 0.52g of white solid with a yield of 48.2%. m.p.105.8-107.5 ℃.1H NMR(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]+.
Example 10
Synthesis of 1- (2- (4- (4-fluorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (4j)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-fluorobenzyl) piperazine (0.77g,4mmol) as starting materials, column chromatography purification gave 0.39g of white solid in 38.4% yield. m.p.107.6-108.8 ℃.1H NMR(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]+.
Example 11
Synthesis of 1- (2- (4- (4-benzyl) piperazine-1-carbonyl) phenyl) ethanone (4k)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-benzyl) piperazine (0.70g,4mmol) as starting materials, column chromatography purification gave 0.36g of white solid in 37.8% yield. 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).13C NMR(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]+.
Example 12
Synthesis of 1- (2- (4- (4-methylbenzyl) piperazine-1-carbonyl) phenyl) ethanone (4l)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (4-methylbenzyl) piperazine (0.76g, 4mmol) as starting materials, column chromatography purification gave 0.47g of white solid in 46.3% yield. 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]+.
Example 13
Synthesis of 1- (2- (4- (2, 4-methoxybenzyl) piperazine-1-carbonyl) phenyl) ethanone (4m)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (2, 4-methoxybenzyl) piperazine (0.94g,4mmol) as starting materials, column chromatography purification gave 0.53g of white solid in 46.2% yield. 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]+.
Example 14
Synthesis of 1- (2- (4- (2-methoxybenzyl) piperazine-1-carbonyl) phenyl) ethanone (4n)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (2-methoxybenzyl) piperazine (0.83g, 4mmol) as starting materials, column chromatography purification gave 0.42g of white solid in 39.8% yield. 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]+.
Example 15
Synthesis of 1- (2- (4- (3-methoxybenzyl) piperazine-1-carbonyl) phenyl) ethanone (4o)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (3-methoxybenzyl) piperazine (0.83g, 4mmol) as starting materials, column chromatography purification gave 0.48g of white solid in 45.3% yield. 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]+.
Example 16
Synthesis of 1- (2- (4- (benzo [ d ] [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl) phenyl) ethanone (4p)
Referring to the synthesis of example 1, starting with compound 3(0.82g,3mmol) and 1- (benzo [ d ]][1,3]Dioxol-5-ylmethyl) piperazine (0.88g,4mmol) was used as a starting material, which was purified by column chromatography to give 0.40g of a white solid in 36.3% yield. 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]+.
Example 17
Synthesis of 1- (2- (4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) methyl) piperazine-1-carbonyl) phenyl) ethanone (4q)
With reference to the synthesis of example 1, starting with compound 3(0.82g,3mmol) and 1- ((2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) methyl) piperazine (0.94g,4mmol) was used as a starting material and purified by column chromatography to give 0.45g of a white solid in 39.7% yield. 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]+.
Example 18
Synthesis of 1- (2- (4- ((3,5, 6-trimethylpyrazin-2-yl) methyl) piperazine-1-carbonyl) phenyl) ethanone (4r)
Referring to the synthesis of example 1, compound 3(0.82g,3mmol) and 2,3, 5-trimethyl-6- (piperazin-1-ylmethyl) are used) Pyrazine (0.88g,4mmol) was used as the starting material and purified by column chromatography to give 0.52g of white solid in 47.4% yield. 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]+.
Example 19
1- (2- (4- (pyridin-4-ylmethyl) piperazine-1-carbonyl) phenyl) ethanone (4s)
Referring to the synthesis method of example 1, using compound 3(0.82g,3mmol) and 1- (pyridin-4-ylmethyl) piperazine (0.71g, 4mmol) as starting materials, column chromatography purification gave 0.42g of a white solid in 43.8% yield. 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]+.
Example 20
Synthesis of 1- (2- (4- (4-chlorobenzyl) piperazine-1-carbonyl) -5-methylphenyl) ethanone (7a)
In a dry 50mL round bottom flask, 2-acetyl-4-methylbenzoic acid (0.44g,2.5mmol) was added dissolved in 20mL of anhydrous dichloromethaneOxalyl chloride (0.48g,3.8mmol) was slowly added dropwise at 0 deg.c, one drop DMF was added dropwise and the reaction was warmed to room temperature for 3 hours. TLC (petroleum ether) V (ethyl acetate) 3:1 as developing agent]Indicating that the reaction was substantially complete. The reaction mixture was concentrated under reduced pressure, dissolved in 10mL of anhydrous dichloromethane, slowly added dropwise to the 1- (4-chlorobenzyl) piperazine dichloromethane solution, and stirred at room temperature for 3 hours. TLC (petroleum ether) V (ethyl acetate) 1:1 as developing agent]Indicating that the reaction was substantially complete. To the reaction mixture was added 20mL of water. The reaction mixture was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The white solid obtained by silica gel column separation was 0.48g, yield 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]+.
Example 21
Synthesis of 1- (5-chloro-2- (4- (4-chlorobenzyl) piperazine-1-carbonyl) phenyl) ethanone (7b)
Referring to the synthesis of example 20, column chromatography purification using 2-acetyl-4-chlorobenzoic acid (0.59g,3mmol) and 1- (4-chlorobenzyl) piperazine (0.84g,4mmol) as starting materials gave 0.62g of white solid in 52.6% yield. 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. Benzylpiperazines of general formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is1Represents optionally substituted C1~C6Alkyl or halogen of (a);
a represents:
wherein R is2Represents optionally substituted C1~C6Alkyl, halogen, hydroxy, trifluoromethyl, cyano, methoxy, amino or nitro.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is optionally a compound of the following structure:
3. the compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the structure
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, sulfate, phosphate, hydrobromide, maleate, fumarate, citrate, mesylate, p-toluenesulfonate, trifluoroacetate, tartrate or acetate salt of compound (I).
5. A process for preparing a compound of claim 1 comprising:
wherein R is1And A is as defined in claim 1.
6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a COX-2, NF- κ B, p38 MAPK multi-target inhibitor.
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and treatment of inflammation-related disorders.
9. The use of claim 8, wherein the inflammation-related disorder is rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, dermatitis, post-partum inflammation, bowel disease, gastritis, headache, adventitial inflammation, stroke, ischemia, mental trauma, allergic rhinitis, coronary plaque inflammation, bacterial-induced inflammation, viral-induced inflammation, surgery-induced inflammation, or gastric ulcer.
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