CN108484511A - A kind of ligustrazine chalcone compounds and its preparation method and application - Google Patents

A kind of ligustrazine chalcone compounds and its preparation method and application Download PDF

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CN108484511A
CN108484511A CN201810412751.2A CN201810412751A CN108484511A CN 108484511 A CN108484511 A CN 108484511A CN 201810412751 A CN201810412751 A CN 201810412751A CN 108484511 A CN108484511 A CN 108484511A
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acetophenones
ligustrazine
hydroxyl
chalcone compounds
methoxyl group
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刘新泳
邹今幂
展鹏
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Shandong University
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Abstract

The present invention relates to a kind of ligustrazine chalcone compounds and its preparation method and application.The ligustrazine chalcone compounds of the present invention are a series of antioxidants of structure novels, and most compounds show relatively good antioxidant activity.Therefore such ligustrazine chalcone compounds has the value of further research and development, can be used as antioxidant lead compound and is used.Application of the composition the present invention also provides such compound and containing one or more such compounds in preparing anti-oxidation medicine.

Description

A kind of ligustrazine chalcone compounds and its preparation method and application
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to a kind of ligustrazine chalcones Compound and its preparation method and application.
Background technology
Cerebral apoplexy is to be only second to cancer to lead to the second largest reason of human death.Headstroke is broadly divided into hemorrhagic cerebral apoplexy (cerebral hemorrhage or subarachnoid hemorrhage) and ischemia apoplexy (cerebral infarction, cerebral thrombosis) two major classes, most of apoplexy are Since blood clotting leads to cerebral artery occlusion or rupture, lead to oxidative stress and the sudden death of certain brain cells.Oxidative stress by The active oxygen (reactive oxygen species, ROS) generated in body mediates, and causes oxidative and anti-oxidative unbalance, to Cause the oxidative damage of tissue, cell.Cerebral injury caused by the free radical that oxidative stress generates is the important of cerebral apoplexy generation One of causes for pathological.Therefore, the research of antioxidant is the important directions for finding novel prevention and treating cerebral apoplexy drug.
Natural products is the important sources of new drug initiative.Main work of the ligustrazine (Ligustrazine) as chuanxiong Property ingredient, have very strong oxidation resistance, internal active oxygen radical can be removed.Ligustrazine is to cerebral ischemia re-pouring institute It causes cerebral injury to have protective effect, and neuron and microvascular endothelial cell injury can be mitigated, have improvement to completeness cerebral ischemia Effect reduces patients with acute ischemic cerebral stroke blood viscosity and platelet aggregation.Chuanxiong-rhizome azine injecta has been used for brain soldier at present In clinical treatment.However ligustrazine metabolism is rapid, half-life period is shorter, and therefore, synthesizing ligustrazine derivant by design improves Its pharmacokinetic property becomes the hot spot of ligustrazine research to obtain efficient anti-cerebral apoplexy activity lead compound.
Invention content
In view of the deficiencies of the prior art, the present invention provides a kind of ligustrazine chalcone compounds and preparation method thereof, The active ingredients result as antioxidant and its application the present invention also provides above compound.
Technical scheme is as follows：
1. ligustrazine chalcone compounds
A kind of ligustrazine chalcone compounds or its pharmaceutically acceptable salt are one of the compound of having structure：
Heretofore described " pharmaceutically acceptable salt " refers to the salt of compound in reliable medicine range of value Class is suitable for being in contact without unsuitable toxicity, stimulation and allergic reaction etc. with people or compared with the tissue of lower animal, has suitable Rational income and risk ratio, typically water or oil are soluble or dispersible, and are effectively used for its expected purposes. Including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts, be herein can do expected purposes and with The chemical property of above compound is compatible.The list of suitable salt referring to S.M.Birge etc., J.Pharm.Sci., 1977, 66,1-19 pages.
2. the preparation method of ligustrazine chalcone compounds
The preparation method of ligustrazine chalcone compounds, step include：Using ligustrazine 1 as starting material, in ice vinegar In acid intermediate 2 is obtained through hydrogen peroxide list nitrogen oxidation；Then intermediate 2 obtains esterification products after rearrangement reaction occurs with acetic anhydride 3, obtain intermediate 4 through basic hydrolysis；Intermediate 4 obtains 3,5,6- front three of key intermediate through manganese dioxide incomplete oxidation Base pyrazine -2- formaldehyde 5；Finally from different substituted acetophenones through Claisen-Schmidt condensation (Claisen-Schmidt Condensation target compound 6) is obtained, specific synthetic route is as follows：
Reagent and condition:(i) hydrogen peroxide, glacial acetic acid, 94 DEG C；(ii) acetic anhydride, 150 DEG C；(iii) sodium hydroxide solution (mass fraction 20%), room temperature；(iv) manganese dioxide, ethyl alcohol, 75 DEG C；(v) sodium hydroxide solution (mass fraction 20%), substitution Acetophenone, ice-water bath.
Ar is：2- hydroxyl -4- chloro-acetophenones, 2- hydroxyl -6- chloro-acetophenones, 2- hydroxyl -5- bromoacetophenones, 3- fluorophenethyls Ketone, 2- hydroxyl -4- bromoacetophenones, 2- hydroxy-5-methyls benzoylformaldoxime, 2- methoxyl group -4- fluoro acetophenones, 2,4- dimethoxy benzene second Ketone, 2,6- dimethoxy-acetophenones, 2- methoxyl group -4- bromoacetophenones, 2- hydroxyl -5- chloro-acetophenones, 2- methoxyl group -5- fluorophenethyls Ketone, 2,5- dimethoxy-acetophenones, 2- methoxyl group -3- fluoro acetophenones, 2- methyl acetophenones, 2- hydroxyl -6- methoxyacetophenones.
Room temperature of the present invention is 20-30 DEG C.
3. ligustrazine chalcone compounds antioxidant activity and application
The present invention has carried out the anti-oxidant of cellular level to the ligustrazine chalcone compounds synthesized according to the method described above Screening active ingredients, using ligustrazine and lipoic acid as positive control.Antioxidant activity data are as shown in table 1.As can be seen from Table 1, originally The ligustrazine chalcone compounds of invention are a series of antioxidants of structure novels, and most compounds show ratio Preferable antioxidant activity.Wherein, especially prominent, the EC of activity of compound Z1150It is 4.54 μM, is antioxidant lipoic acid (EC50=16.52 μM) 3.6 times.At 10 μM, cell proliferation rate 57.50% is higher than lipoic acid (30.21%), remote high In ligustrazine (3.61%).Therefore such ligustrazine chalcone compounds has the value of further research and development, can make It is used for antioxidant lead compound.
The ligustrazine chalcone compounds of the present invention can be used as antioxidant application.Specifically, as antioxidant It is used to prepare the drug of anti-cerebral apoplexy.
A kind of antioxidant drug compositions, including the ligustrazine chalcone compounds of the present invention and one or more pharmacy Upper acceptable carriers or excipient.
The present invention provides the completely new ligustrazine chalcone compounds and preparation method thereof of structure, the present invention also provides Compound with oxidation resistance active ingredients result and its first Application in anti-cerebral apoplexy.Test proves that Rhizoma Chuanxiong of the invention Piperazine chalcone compounds can be used as antioxidant and apply and have very high application value.Specifically, as antioxidant It is used to prepare anti-cerebral apoplexy drug.
Specific implementation mode
Contribute to understand the present invention by following embodiments, but present disclosure cannot be limited.
Involved synthetic route is as follows in embodiment：
Embodiment 1：The preparation of 3,5,6- trimethylpyrazine -2- formaldehyde
Ligustrazine (6.8g, 50mmol) is weighed, is dissolved in 50mL glacial acetic acid, 30% hydrogenperoxide steam generator is added (11.25mL, 100mmol) reacts 2h in 94 DEG C, and 30% hydrogen peroxide (11.25mL, 100mmol) is added in supplement later, continues 2h is reacted, the reaction was complete for TLC monitorings, and reaction solution is cooled to room temperature, and reaction solution pH to 10 is adjusted with 50% sodium hydroxide solution, A large amount of white solid is had at this time to be precipitated, and chloroform 100mL is added and extracts 3 times, the chloroform soln of gained is collected It to together, is dried overnight with anhydrous sodium sulfate, filters chloroform soln, be evaporated with Rotary Evaporators, obtain white solid, i.e., For ligustrazine list nitrogen oxides crude product.It takes the crude product (7.6g, 50mmol) to pour into round-bottomed flask, acetic anhydride is added, is heated to Ligustrazine list nitrogen oxides is completely dissolved, and is heated to reflux 2h, and TLC is monitored to after the reaction was complete, is removed solvent under reduced pressure, is obtained black 20% sodium hydroxide solution (100mL) is added after black slurry object is cooled to room temperature in slurry, adjusts pH to 14, at room temperature It is stirred to react 12h, TLC monitorings are added diatomite and are filtered under diminished pressure pigment and insoluble impurity of the solution except black removal after the reaction was complete, Dichloromethane extraction (50mL × 3) is added, the dichloromethane solution of gained is collected into together, it is dried with anhydrous sodium sulfate Night filters dichloromethane solution, is evaporated with Rotary Evaporators, obtains faint yellow solid, as 2- methylols -3,5,6- trimethyls Pyrazine crude product recrystallizes this crude product with petroleum ether, obtains faint yellow acicular crystal, as 2- methylols -3,5,6- trimethyl pyrroles Piperazine sterling yield 66%, 88-89 DEG C of fusing point.
2- methylols -3,5 are weighed, 6- trimethylpyrazines (3.0g, 25mmol) are dissolved in 50mL absolute ethyl alcohols, under stirring Manganese dioxide powder (4.34g, 50mmol) is added, 6h is reacted under heated reflux condition, diatomite decompression is added in cooling reaction solution Filtering, after filter cake is rinsed with ethyl alcohol, merges with filtrate, and solvent evaporated obtains faint yellow solid, is 3,5,6- trimethylpyrazine -2- first Then aldehyde crude product carries out rapid column chromatography separation, obtain faint yellow solid, as 3, and 5,6- trimethylpyrazine -2- formaldehyde sterlings are received Rate 90%, 84-85 DEG C of fusing point.
Embodiment 2：The preparation of Z1-Z16
3,5,6- trimethylpyrazine -2- formaldehyde (0.15g, 1mmol) are taken, is dissolved in 10mL absolute ethyl alcohols, is added dropwise to substitution Acetophenone (1mmol) ethanol solution 10mL, stir 5min under condition of ice bath, be added dropwise to 20% NaOH solution 2.4mL, ice The reaction was complete for bath reaction 0.3h, TLC detection, is added dropwise to 10% dilute hydrochloric acid and adjusts pH to 5,100mL water is added, is filtered under diminished pressure, soon Fast column chromatography for separation obtains target compound, and then carries out solvent pairs in methanol-water and be recrystallized to give target compound Z1- Z16。
Target chemical combination is made respectively in aforementioned manners with different substituted acetophenones and 3,5,6- trimethylpyrazine -2- formaldehyde Object Z1-Z16, it is as a result as follows：
Operation is same as above, except that using 2- hydroxyl -4- chloro-acetophenones.
Product is yellow solid, yield 35%, 139-143 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:12.10 (s, 1H ,-OH), 8.11 (d, J=14.9Hz, 1H ,-CH=CH-), 7.91 (s, 1H ,-CH=CH-), 7.90-7.83 (m, 1H, Ar-H), 7.08 (d, J=2.1Hz, 1H, Ar-H), 7.03 (dd, J= 8.5,2.1Hz,1H,Ar-H),2.58(s,3H,-CH3), 2.50 (t, J=5.2Hz, 6H ,-CH3).13C NMR(100MHz, DMSO-d6)δ:192.05,161.56,153.65,150.32,150.18,142.38,140.15,138.67,132.63, 127.10,121.81,120.16,117.72,22.20,21.91,20.87.ESI-MS:303.4(M+1),305.3(M+3) .C16H15ClN2O2[302.4]。
Operation is same as above, except that using 2- hydroxyl -6- chloro-acetophenones.
Product is yellow powder, yield 30%, 165-166 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:10.40 (s, 1H ,-OH), 7.50 (d, J=15.4Hz, 1H ,-CH=CH-), 7.31 (d, J=4.6Hz, 1H ,-CH=CH-), 7.28 (d, J=2.7Hz, 1H, Ar-H), 6.99 (d, J=8.0Hz, 1H), 6.93 (d, J=8.2Hz, 1H, Ar-H), 2.51 (s, 3H ,-CH3),2.47(s,3H,-CH3),2.46(s,3H,-CH3).13C NMR(100MHz,DMSO-d6)δ:193.24,156.20,153.76,150.47,149.78,142.04,139.45,131.79, 131.08,130.30,127.19,120.31,115.25,22.18,21.86,20.69.ESI-MS:303.4(M+1),305.3 (M+3).C16H15ClN2O2[302.4]。
Operation is same as above, except that using 2- hydroxyl -5- bromoacetophenones.
Product is pale yellow powder, yield 36%, 132~136 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:11.57 (s, 1H ,-OH), 8.10 (d, J=15.0Hz, 1H ,-CH=CH-), 7.87 (d, J=2.6Hz, 1H, Ar-H), 7.84 (d, J=15.0Hz, 1H ,-CH=CH-), 7.64 (dd, J=8.8,2.6Hz, 1H, Ar-H) 6.99 (d, J=8.8Hz, 1H, Ar-H), 2.59 (s, 3H ,-CH3),2.50(s,3H,-CH3),2.49(s,3H,- CH3).13C NMR(100MHz,DMSO-d6)δ:191.34,159.01,153.55,150.32,150.12,142.51, 138.33,137.87,132.68,128.17,125.75,120.43,110.84,22.20,21.93,20.90.ESI-MS: 348.2(M+1),350.2(M+3).C16H15BrN2O2[347.2]。
Operation is same as above, except that using 3- fluoro acetophenones.
Product is faint yellow crystalline solid, yield 33%, 141~144 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:8.04 (d, J=15.0Hz, 1H ,-CH=CH-), 7.92 (d, J=7.8Hz, 1H, Ar-H), 7.87 (d, J=15.0Hz, 1H ,-CH=CH-), 7.79 (dt, J=9.8,2.1Hz, 1H, Ar-H), 7.64 (dd, J=7.9,5.8Hz, 1H, Ar-H), 7.55 (dt, J=8.4,4.2Hz, 1H), 2.59 (s, 3H ,-CH3), 2.52 (s, 3H ,- CH3), 2.49 (s, 3H ,-CH3).ESI-MS:271.3(M+1).C16H15FN2O[270.3]。
Operation is same as above, except that using 2- hydroxyl -4- bromoacetophenones.
Product is pale yellow powder, yield 41%, 88~93 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:12.94 (s, 1H ,-OH), 8.22 (d, J=14.7Hz, 1H ,-CH =CH-), 8.08 (d, J=14.7Hz, 1H ,-CH=CH-), 7.88 (d, J=8.6Hz, 1H, Ar-H), 7.23 (d, J= 1.9Hz, 1H, Ar-H), 7.10 (dd, J=8.6,1.9Hz, 1H, Ar-H), 2.68 (s, 3H ,-CH3), 2.57 (d, J=6.8Hz, 6H,-CH3).13C NMR(100MHz,Chloroform-d)δ:193.33,164.13,153.52,150.18,142.46, 139.57(2×C),131.11(2×C),124.29,122.48,121.75,118.94,22.23,21.84,20.81.ESI- MS:375.2(M+1),357.2(M+3).C16H15BrN2O2[374.2]。
Operation is same as above, except that using 2- hydroxy-4-methyl benzene second.
Product is yellow crystals, yield 42%, 148~152 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:12.63 (s, 1H ,-OH), 8.28 (d, J=14.8Hz, 1H ,-CH =CH-), 8.06 (d, J=14.8Hz, 1H ,-CH=CH-), 7.85-7.71 (m, 1H, Ar-H), 7.34 (dd, J=8.4, 2.1Hz, 1H, Ar-H), 6.94 (d, J=8.5Hz, 1H, Ar-H), 2.68 (s, 3H ,-CH3),2.60(s,3H,-CH3),2.56 (s,3H,-CH3),2.37(s,3H,-CH3).13C NMR(100MHz,Chloroform-d)δ:193.80,161.65, 153.19,150.07,150.01,142.77,138.79,137.81,129.87,128.04,124.88,119.71,118.27, 22.19,21.87,20.85,20.63.ESI-MS:283.3(M+1).C17H18N2O3[282.3]。
Operation is same as above, except that using 2- methoxyl group -4- fluoro acetophenones.
Product is yellow crystals, yield 40%, 102~106 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:7.99 (d, J=15.1Hz, 1H ,-CH=CH-), 7.86 (d, J= 15.1Hz, 1H ,-CH=CH-), 7.75 (dd, J=8.5,6.9Hz, 1H, Ar-H), 6.85-6.64 (m, 2H, Ar-H), 3.93 (s,3H,O-CH3),2.64(s,3H,-CH3),2.54(s,6H,-CH3).13C NMR(100MHz,Chloroform-d)δ: 190.65,166.08 (d, J=252.8Hz), 160.46,152.40,149.70 (d, J=24.7Hz), 143.42,136.68, (132.81,132.71,130.92,125.31,107.74 d, J=21.8Hz), 99.76 (d, J=25.7Hz), 56.06, 22.07,21.87,20.90.ESI-MS:301.5(M+1),303.4(M+3).C17H17FN2O2[300.3]。
Operation is same as above, except that using 2,4- dimethoxy-acetophenones.
Product is yellow powder, yield 35%, 116~119 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:8.07 (d, J=15.1Hz, 1H ,-CH=CH-), 7.79-7.68 (d, J= 15.1Hz, 1H ,-CH=CH-), 7.67 (s, 1H, Ar-H), 6.71 (d, J=11.4Hz, 1H, Ar-H), 6.67 (s, 1H, Ar- H), 3.93 (s, 3H, O-CH3), 3.88 (s, 3H, O-CH3), 3.34 (s, 9H ,-CH3).ESI-MS:313.3(M+1) .C18H20N2O3[312.3]。
Operation is same as above, except that using 2,6- dimethoxy-acetophenones.
Product is pale yellow powder, yield 31%, 152~156 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6)δ:7.42 (d, J=8.1Hz, 1H ,-CH=CH-), 7.39 (s, 1H, Ar-H), 7.22 (d, J=15.4Hz, 1H ,-CH=CH-), 6.77 (d, J=8.4Hz, 2H, Ar-H), 3.74 (s, 6H, O-CH3),2.45 (d, J=11.8Hz, 9H ,-CH3).13C NMR(100MHz,DMSO-d6)δ:193.77,157.33(2×C),153.44, 150.34,149.56,142.27,138.45,132.10,131.69,118.39,104.90(2×C),56.32(2×C), 22.14,21.86,20.70.ESI-MS:313.3[M+H]+.ESI-MS:313.4(M+1).C18H20N2O3[312.3]。
Operation is same as above, except that using 2- methoxy -4- bromoacetophenones.
Product is pale yellow powder, yield 30%, 100~104 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:7.94 (d, J=15.1Hz, 1H ,-CH=CH-), 7.84 (d, J= 15.1Hz, 1H ,-CH=CH-), 7.56 (d, J=8.2Hz, 1H, Ar-H), 7.19 (d, J=8.2Hz, 1H, Ar-H), 7.16 (s, 1H,Ar-H),3.93(s,3H,O-CH3),2.63(s,3H,-CH3),2.53(s,6H,-CH3).13C NMR(100MHz, Chloroform-d)δ:191.26,158.94,152.55,149.87,149.66,143.30,137.06,131.83, 130.76,127.96,127.40,124.05,115.34,56.11,22.09,21.86,20.90.ESI-MS:362.2(M+1), 364.2(M+3).C17H17BrN2O2[361.2]。
Operation is same as above, except that using 2- hydroxyl -5- chloro-acetophenones.
Product is yellow powder, yield 50%, 171~174 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 11.57 (s, 1H ,-OH), δ 8.10 (d, J=14.9Hz, 1H ,-CH=CH-), 7.84 (d, J=15.0Hz, 1H ,-CH=CH-), 7.77 (d, J=2.7Hz, 1H, Ar-H), 7.53 (dd, J=8.8,2.7Hz, 1H, Ar-H), 7.04 (d, J=8.8Hz, 1H, Ar-H) .2.59 (s, 3H ,-CH3), 2.50 (s, 6H ,-CH3).13C NMR (100MHz,DMSO-d6)δ191.46,158.63,153.57,150.33,150.13,142.51,138.40,135.12, 129.79,128.14,125.12,123.44,120.01,22.20,21.93,20.90.ESI-MS:303.4(M+1),305.4 (M+3).C16H15ClN2O2[302.4]。
Operation is same as above, except that using 2- methoxy -5- fluoro acetophenones.
Product is pale yellow powder, yield 30%, 135~139 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:7.97 (d, J=15.1Hz, 1H ,-CH=CH-), 7.85 (d, J= 15.1Hz, 1H ,-CH=CH-), 7.39 (dd, J=8.6,3.2Hz, 1H, Ar-H), 7.18 (ddd, J=9.2,7.6,3.2Hz, 1H, Ar-H), 6.96 (dd, J=9.1,4.0Hz, 1H, Ar-H), 3.91 (s, 3H, O-CH3),2.63(s,3H,-CH3),2.54 (s,6H,-CH3).13C NMR(100MHz,Chloroform-d)δ:(191.07,156.79 d, J=240.4Hz), 154.68, (152.59,149.88,149.67,143.25,137.26,130.54,119.52 d, J=23.2Hz), 116.84 (d, J= 24.1Hz),113.10,113.02,56.40,22.10,21.86,20.89.ESI-MS:301.3(M+1),302.3(M+3) .C17H17FN2O2[300.3]。
Operation is same as above, except that using 2,5- dimethoxy-acetophenones.
Product is yellow crystals, yield 33%, 80~85 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:8.01 (d, J=15.1Hz, 1H ,-CH=CH-), 7.85 (d, J= 15.1Hz, 1H ,-CH=CH-), 7.23 (d, J=3.2Hz, 1H, Ar-H), 7.05 (dd, J=9.0,3.2Hz, 1H, Ar-H), 6.95 (d, J=9.0Hz, 1H, Ar-H), 3.89 (s, 3H, O-CH3),3.82(s,3H,O-CH3),2.63(s,3H,-CH3), 2.53(s,6H,-CH3).13C NMR(100MHz,Chloroform-d)δ:192.09,153.56,152.98,152.34, 149.81,149.55,143.49,136.71,131.14,129.46,119.65,114.39,113.39,56.45,55.88, 22.07,21.87,20.93.ESI-MS:313.3(M+1).C18H20N2O3[312.3]。
Operation is same as above, except that using 2- methoxyl group -3- fluoro acetophenones.
Product is yellow powder, yield 32%, 111~115 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:7.95-7.77 (m, 2H, Ar-H), 7.40 (dt, J=7.7, 1.4Hz, 1H ,-CH=CH-), 7.28-7.25 (m, 1H, Ar-H), 7.11 (td, J=8.0,4.6Hz, 1H ,-CH=CH-), 4.01 (d, J=2.1Hz, 3H, O-CH3),2.62(s,3H,CH3), 2.53 (d, J=2.2Hz, 6H, CH3).ESI-MS:301.3 (M+1),303.3(M+3).C17H17FN2O2[300.3]。
Operation is same as above, except that using 2- methyl acetophenones.
Product is yellow powder, yield 32%, 102~105 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:7.83 (d, J=15.2Hz, 1H ,-CH=CH-), 7.76 (d, J= 15.2Hz, 1H ,-CH=CH-), 7.65 (d, J=7.3Hz, 1H, Ar-H), 7.40 (td, J=7.4,1.4Hz, 1H, Ar-H), 7.34-7.24(m,2H,Ar-H),2.60(s,3H,-CH3),2.53(s,6H,-CH3),2.50(s,3H,-CH3).ESI-MS: 267.3(M+1).C17H18N2O[266.3]。
Operation is same as above, except that using 2- hydroxyl -6- methoxyacetophenones.
Product is pale yellow powder, yield 31%, 115~118 DEG C of fusing point.
1H NMR(400MHz,Chloroform-d)δ:13.10 (s, 1H ,-OH), 8.41 (d, J=14.9Hz, 1H ,-CH =CH-), 7.94 (d, J=15.0Hz, 1H ,-CH=CH-), 7.38 (t, J=8.3Hz, 1H, Ar-H), 6.62 (d, J= 8.3Hz, 1H, Ar-H), 6.44 (d, J=8.3Hz, 1H, Ar-H), 3.96 (s, 3H, O-CH3),2.66(s,3H,-CH3),2.55 (d, J=2.9Hz, 6H ,-CH3).ESI-MS:299.3(M+1).C17H18N2O3[298.3]。
Embodiment 3：The antioxidant activity test experiments of target compound
Test philosophy：
The screening of Compound ira vitro antioxidant activity uses mtt assay.MTT full name are bromination -3- (4,5- dimethyl -2- thiazoles Base) -2,5- diphenyltetrazoliumbromide nitrogen (trade names：Tetrazolium bromide), it can be used for detecting the survival and growth of cell.Testing principle is：MTT The bluish violet crystallization first a ceremonial jade-ladle, used in libation for being reduced to water-insoluble can be combined to be deposited in cell with intracellular succinate dehydrogenase living, and Dead cell has no this function.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, its extinction at 570nm is detected with microplate reader Degree (A) value can indirectly reflect the quantity of living cells.Within the scope of certain cell number, MTT crystallizes the amount to be formed and cell Number is directly proportional.
This experiment uses pig hip arterial endothelial cell (PIEC cell strains), then uses H2O2Solution (360 μM, 4h) is right PIEC cells carry out oxidative damage, to H2O2The compound solution to be detected of debita spissitudo is added in the PIEC of oxidation, is trained through 12h After supporting, by MTT colorimetric determination cell activity, drug concentration (EC of 50% cell of protection from oxidative death is obtained50) i.e. It can obtain the oxidation resistant activity of target compound.
Test material and method：
(1) pig hip arterial endothelium cells strain purchase is in Shanghai life science cell bank.
(2)MTT：Purchased from Sigma Co., USA.
(3) sample treatment：Sample is dissolved in DMSO and is made into debita spissitudo before use, is diluted with culture medium.
(4) hydrogen peroxide is diluted with culture medium before use.
(5) positive control drug：Ligustrazine, lipoic acid.
Test method：It is added in the PIEC cell suspensions of hydrogen peroxide oxidation after sample dilution, is used after 12h MTT colorimetric method for determining cell viabilities calculate EC with absorbance (A) value being recorded in microplate reader under 570nm50。
(6) MTT colorimetric methods：After sample solution culture for a period of time is added, MTT solution (5mg/mL) 10 μ is added to every hole L after continuing culture 4 hours, abandons dyeing liquor, and 150 μ L DMSO are added to every hole, is sufficiently mixed, is measured in microplate reader Absorbance (A) value under 570nm.
Experimental method：
After PIEC cells cultivate about 24 hours on 96 orifice plates, observe under the microscope, if cell growth to 80% or so, It can carry out oxidative damage experiment.Normal incubation medium is added in normal group, is added in model group and contains a concentration of 400 μM of H2O2's Finally final concentration of 400 μM of H are added in culture medium in protection group2O2Culture solution and final concentration of 2.5 μM, 5 μM, 10 μ are added M, 20 μM of drug, at 37 DEG C, CO2Continue to cultivate 12h in a concentration of 5% incubator, cell state is observed, then in every hole 10 μ L MTT solution are added with sample loading gun, continues to cultivate 4h, sucks culture medium with 1mL sample loading guns, be then added 150 in every hole The dimethyl sulfoxide (DMSO) of μ L places 10min.Absorbance (the A at 570nm is measured in microplate reader570nm).Set blank and drug simultaneously Thus control group and positive drug control group calculate compound and protect 50% cell from aoxidizing concentration (EC50)。
Activity Results are as shown in table 1.
The antioxidant activity of 1. ligustrazine chalcone compounds of table
A=P%:Cell proliferation rate when final compound concentration is 10 μM.
bEC50:Protect 50% cell from the compound concentration of oxidation.
*-indicate there is no accretion to cell.

Claims (4)

1. a kind of ligustrazine chalcone compounds or its pharmaceutically acceptable salt, which is characterized in that be the change of having structure Close one of object：
2. the preparation method of ligustrazine chalcone compounds as described in claim 1, step include：Using ligustrazine 1 as Starting material obtains intermediate 2 through hydrogen peroxide list nitrogen oxidation in glacial acetic acid；Then intermediate 2 is reset with acetic anhydride Esterification products 3 are obtained after reaction, and intermediate 4 is obtained through basic hydrolysis；Intermediate 4 obtains crucial through manganese dioxide incomplete oxidation Intermediate 3,5,6- trimethylpyrazine -2- formaldehyde 5；Finally from different substituted acetophenones through Claisen-Schmidt condensation (Claisen-Schmidt condensation) obtains target compound 6, and specific synthetic route is as follows：
Reagent and condition:(i) hydrogen peroxide, glacial acetic acid, 94 DEG C；(ii) acetic anhydride, 150 DEG C；(iii) sodium hydroxide solution (matter Measure score 20%), room temperature；(iv) manganese dioxide, ethyl alcohol, 75 DEG C；(v) sodium hydroxide solution (mass fraction 20%), substituted benzene Ethyl ketone, ice-water bath；
Ar is：2- hydroxyl -4- chloro-acetophenones, 2- hydroxyl -6- chloro-acetophenones, 2- hydroxyl -5- bromoacetophenones, 3- fluoro acetophenones, 2- Hydroxyl -4- bromoacetophenones, 2- hydroxy-5-methyls benzoylformaldoxime, 2- methoxyl group -4- fluoro acetophenones, 2,4- dimethoxy-acetophenones, 2, 6- dimethoxy-acetophenones, 2- methoxyl group -4- bromoacetophenones, 2- hydroxyl -5- chloro-acetophenones, 2- methoxyl group -5- fluoro acetophenones, 2, 5- dimethoxy-acetophenones, 2- methoxyl group -3- fluoro acetophenones, 2- methyl acetophenones, 2- hydroxyl -6- methoxyacetophenones.
3. application of the ligustrazine chalcone compounds as described in claim 1 in preparing anti-cerebral apoplexy drug.
4. a kind of antioxidant drug compositions, including ligustrazine chalcone compounds described in claim 1 and one kind or more Kind pharmaceutically acceptable carrier or excipient.
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