CN107325058B - Diaryl methylene disulfide compound and preparation method and application thereof - Google Patents
Diaryl methylene disulfide compound and preparation method and application thereof Download PDFInfo
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- C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
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Abstract
The invention relates to the technical field of medicines, in particular to diaryl methylene disulfide compounds and a preparation method and application thereof. The experimental result shows that the diaryl methylene disulfide compound provided by the invention has the effects of inhibiting neurotoxicity caused by excessive glutamic acid and inhibiting neurotoxicity caused by hydrogen peroxide on a cell model; also has platelet aggregation inhibiting effect, and can reduce cerebral infarction area in mouse MCAO model. These results indicate that the diaryl methylene disulfide compound provided by the invention can have a preventive and/or therapeutic effect on cerebral apoplexy.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to diaryl methylene disulfide compounds and a preparation method and application thereof.
Background
"cerebral apoplexy" (or "stroke") also known as "stroke" or "cerebrovascular accident" (CVA). Is an acute cerebrovascular disease, which is a group of diseases causing brain tissue damage due to sudden rupture of cerebral vessels or blood failure to flow into the brain caused by vessel occlusion.
Worldwide, cerebral stroke is the third leading cause of death worldwide and also the leading cause of disability in adults. According to statistics, 50-75 million people are attacked in the United states every year. In China, the number of attack people and death people of cerebral apoplexy reaches 250 ten thousand per year and 160 ten thousand per year. Stroke has surpassed myocardial infarction and becomes the leading cause of death of people in China. The cerebral apoplexy has high lethality rate, and the survived patients can also leave sequelae such as neurobehavioral function damage, cognitive disorder and the like, thereby causing heavy social and family economic burden and having the characteristics of high morbidity, high mortality and high disability rate.
Cerebral stroke is largely divided into two types. More than 70% of the cerebral ischemic stroke refers to the ischemic brain injury caused by the blockage of cerebral vessels in different brain areas caused by various thrombi, wherein the blockage of middle cerebral artery is the most common. Occlusion and stenosis of internal carotid and vertebral arteries can cause ischemic stroke, which is more than 40 years old, more female than male, and death in severe cases. In addition, less than 30% of the cerebral hemorrhage is caused by cerebral vessel rupture, and finally, cerebral blood supply insufficiency and ischemic brain injury are caused. Cerebral ischemia is also one of the consequences of cardiac arrest.
Current therapeutic drugs for stroke are also very limited compared to the severity and extent of the risk of stroke. The current clinical drug therapies mainly comprise thrombolytic drugs, vasodilating drugs, anti-platelet aggregation drugs and neuroprotective agents. For example, for ischemic stroke, the only drug therapy accepted internationally is acute phase thrombolysis with tissue plasminogen activator. However, due to the short therapeutic window and significant side effects of tissue plasminogen activator (e.g., cerebral hemorrhage and excitotoxicity), less than 5% of the total number of patients with cerebral ischemia can currently be treated with tissue plasminogen activator. Current research also indicates that stroke can cause a series of cellular and molecular response mechanisms in the brain that are interwoven to ultimately cause brain damage. For example, the mechanism of neuronal death or damage caused by ischemic stroke is mainly neurotoxicity due to excessive active oxygen radicals, the mechanism of neuronal damage caused by release of excessive excitatory amino acids such as glutamic acid, neuronal death caused by excessive activation of poly ADP-ribose polymerase, and the mechanism of neuroinflammatory injury caused by excessive inflammatory response in the brain due to cerebral ischemia. The pathological damage mechanisms have great significance for the research and development of cerebral apoplexy treatment drugs, and the search of corresponding drugs aiming at multiple pathological damage mechanisms at the same time becomes an important strategy for developing novel cerebral apoplexy treatment drugs.
In conclusion, in view of the great harm of stroke and the limited current treatment means, the development of novel stroke prevention and/or treatment drugs is always the focus of wide attention of leading scholars in the field and has great significance.
Disclosure of Invention
In view of the above, the present invention provides diaryl methylene disulfide compounds, and a preparation method and applications thereof. The compound provided by the invention not only can better inhibit neurotoxicity caused by excessive glutamic acid and remove excessive free radicals in a nerve cell model, but also has the effect of inhibiting platelet aggregation, and has a good protection effect on the mouse brain with cerebral ischemia reperfusion injury, so that the compound has a prevention or treatment effect on cerebral apoplexy.
The present invention provides compounds of the structure shown in formula I:
wherein Ar is 3,5, 6-trimetylpyrazinyl or 4-COOCH3-Ph。
The compound provided by the invention is 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide or 4,4' -disulfanediylbis (methylene) methyl dibenzoate. The structures of the two compounds are not disclosed before, and the invention prepares the two compounds and verifies that the two compounds can realize the prevention or treatment effect on cerebral apoplexy through various ways.
The invention relates to the application of a compound with a structure shown in formula I in the preparation of a preparation for protecting neuron cells;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
The protective effect on neuronal cells includes a protective effect on glutamate-induced neurotoxicity or a protective effect on hydrogen peroxide-induced neurotoxicity. The neuron cell is a mouse hippocampal neuron HT-22 cell. The protection specifically refers to: protection against glutamate-induced injury to HT22 cells, or protection against H2O2Inducing damage to HT22 cells, and showing that the compound of formula I has the functions of reducing excitatory amino acid toxicity and eliminating H2O2The generated free radicals act. Wherein, 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl]Disulfide has the best effect against glutamate toxicity, and the cell survival rate is remarkably increased compared with that of the glutamate group.
The application of the compound with the structure shown in the formula I in the preparation of a preparation for inhibiting platelet aggregation;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
Experiments of the invention show that the compound provided by the invention can obviously reduce the maximum aggregation rate of platelets, specifically, 0.1, 0.5 and 1mM of 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide is added, the maximum aggregation rate of platelets is obviously reduced (P <0.05 and P <0.01), and the 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide is prompted to have good platelet aggregation resisting activity.
The application of the compound with the structure shown in the formula I in preparing a preparation for preventing and treating brain injury after cerebral ischemia reperfusion;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
The method for preventing and treating cerebral injury after cerebral ischemia reperfusion specifically comprises reducing infarct volume of cortex, striatum and cerebral hemisphere. Experiments show that after the middle cerebral artery is blocked for 24 hours, compared with a solvent group mouse, 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide injected for 3 hours by reperfusion can obviously reduce the infarct volume of cortex, striatum and cerebral hemisphere, and the 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide has obvious protective effect on ischemic brain injury caused by the middle cerebral artery blockage.
In addition to 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide or methyl 4,4' -disulfanediylbis (methylene) dibenzoate, the invention also finds that other diarylmethylidene disulfide compounds also have the effect of preventing and treating cerebral apoplexy. The action mechanism is to inhibit the neurotoxicity caused by excessive glutamic acid.
The application of the compound with the structure shown in the formula I in preparing a preparation for preventing and treating cerebral apoplexy;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
In the present invention, stroke is stroke caused by cerebral embolism and/or stroke caused by cerebral hemorrhage.
Preferably, the cerebral apoplexy comprises cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack, cerebral ischemia caused by cardiac arrest, cerebral hemorrhage and cerebral arteriosclerosis caused by one or more of cerebral ischemia.
In the invention, the dosage of the compound shown in the formula I is 0.05 mg/kg-90 mg/kg.
Preferably, the compound of formula I is 1, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl ] disulfide.
A medicament comprising a compound of formula I and a pharmaceutically acceptable excipient;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
Preferably, the preparation is in the form of oral preparation, injection, suppository, inhalant or preparation capable of being directly applied to cerebral ischemia parts.
Preferably, the preparation is in the form of capsules, microcapsules, tablets, granules, pills, dispersion powder, liquid preparations, soft extracts, suspensions, syrups, gels, aerosols, patches, liposomes, oral liquids, intravenous injections or intramuscular injections.
The preparation method of the compound with the structure shown in the formula I comprises the following steps: reacting the compound A with thiourea in the presence of manganese dioxide and PEG to obtain a compound shown in a formula I;
wherein Ar is 3,5, 6-trimetylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh;
the compound A is 1-bromo-ligustrazine, benzyl bromide, 4- (bromomethyl) methyl benzoate, 2-bromobenzyl bromide, 3-bromobenzyl bromide, 4-bromobenzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 2-nitrobenzyl bromide, 3-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methylbenzyl bromide or 4-cyanobenzyl bromide.
The reaction is carried out under basic conditions. The invention adopts sodium carbonate condition to obtain alkaline environment.
The molar ratio of the compound A to the thiourea is 0.97: 1.45.
The molar ratio of the sodium carbonate to the thiourea is 1: 1.
The molar ratio of the manganese dioxide to the compound A is 1: 1.
The PEG is PEG 200; preferably wet-PEG 200; specifically, in the wet-PEG200, PEG200 and H2The volume ratio of O is 10: 1.
The reaction temperature is 40 ℃, and the stirring reaction is carried out for 3 hours.
After the compound of formula I is prepared, a purification step is also included. Specifically, the purification comprises: the reaction product is extracted with ethyl acetate, the extract is washed with water, dried, filtered and chromatographed (eluent [ petroleum ether: ethyl acetate (v: v) ═ 10:1]) to obtain the compound of formula I.
The invention provides diaryl methylene disulfide compounds, and researches show that the compounds can play a role in preventing cerebral apoplexy through multiple ways. The experimental result shows that the diaryl methylene disulfide compound provided by the invention has the effect of inhibiting neurotoxicity caused by excessive glutamic acid on a cell model; also has effects in inhibiting neurotoxicity caused by hydrogen peroxide; anti-platelet aggregation; and can reduce cerebral infarction area in mouse MCAO model. The results show that the diaryl methylene disulfide compound provided by the invention can be used for preventing and/or treating various pathological mechanisms of cerebral apoplexy.
Drawings
FIG. 1-a shows L YY-I1Influence on survival of mouse hippocampal neuronal cells induced by glutamate damage; FIG. 1-b shows the effect of ligustrazine on survival of hippocampal neurons in mice with glutamate-induced damage; wherein, P represents a very significant difference compared with glutamic acid group<0.01；
FIG. 2-a shows L YY-I1Effect on survival of mouse hippocampal neuronal cells damaged by hydrogen peroxide induction; FIG. 2-b shows the effect of ligustrazine on the survival rate of hippocampal neurons in mice damaged by hydrogen peroxide induction; wherein there is a very significant difference from the hydrogen peroxide group, P<0.01；
FIG. 3 shows L YY-I1The effect on platelet aggregation rate; wherein: marked significant differences from the ADP group, P<0.05; marked by a very significant difference from the ADP group, P<0.01；
FIG. 4 shows abdominal cavity administration of 0.22mmol/kg L YY-I after 3h of reperfusion in mouse MCAO model1Percent volume of cerebral infarction (c), whereinThere is a significant difference, P<0.05; marked by a very significant difference from the solvent group, P<0.01。
Detailed Description
The invention provides diaryl methylene disulfide compounds, and a preparation method and application thereof, and a person skilled in the art can use the contents for reference and appropriately improve process parameters to realize the diaryl methylene disulfide compounds. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention is further illustrated by the following examples:
example 11, 2-bis [ (3,5, 6-trimethylpyrazin-2-yl) methyl]Disulfide (L YY-I)1)
1-Bromoligustrazine (0.210g, 0.97mmol), thiourea (0.111g,1.45mmol), sodium carbonate (0.154g, 1.45mmol), manganese dioxide (0.084g, 0.97mmol) were added to a 100m L reaction flask, and wet-PEG200(20m L) (PEG 200: H)2Heating to 40 ℃, stirring for reaction for 3h, cooling to room temperature, adding water (20m L), extracting with ethyl acetate (20m L) for three times, washing with water (50m L) for three times, drying with anhydrous magnesium sulfate, filtering, and performing column chromatography (eluent petroleum ether: ethyl acetate (v: v) ═ 10:1)]To obtain yellow solid. The yield was 45%. Mp is 73-75 ℃.
1H NMR(400MHz,CDCl3),(ppm):3.99(s,4H,CH2),2.54(s,6H,CH3),2.49(s,12H,CH3).
13C-NMR(600MHz,CDCl3),(ppm):150.17,148.94,148.64,146.61,42.67,21.62,21.40,21.09.
HR-MS:[M+H]+,Calcd:335.1364,Found:335.1360.
Example 21, 2-dibenzyldisulfide (L YY-I)2)
Reference compound L YY-I1The synthesis method of (A) is that benzyl bromide and sulfur are mixedUrea was prepared to give a white solid. The yield was 57%. Mp is 64-68 ℃.
1H NMR(400MHz,CDCl3,(ppm):7.35-7.32(m,2H,ArH),7.32-7.28(m,4H,ArH),7.24(dd,J＝5.8,4.3Hz,4H,ArH),3.60(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):137.60,129.65,128.72,127.66,43.03.
HR-MS:[M+H]+,Calcd:247.0615,Found:247.0611.
Example 34, 4' -Disulfanyldiylbis (methylene) dibenzoate methyl ester (L YY-I3)
Reference compound L YY-I1The synthesis method of (1) is prepared from methyl 4- (bromomethyl) benzoate and thiourea to obtain a white solid. The yield was 51%. Mp is 81-85 ℃.
1H NMR(400MHz,CDCl3),(ppm):8.01–7.97(m,4H,ArH),7.28(d,J＝8.3Hz,4H,ArH),3.92(s,6H,OCH3),3.62(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):166.80,142.61,129.86,129.41,129.35,52.21,42.91.
HR-MS:[M+H]+,Calcd:363.0725,Found:363.0724.
Example 41, 2-bis (2-bromobenzyl) disulfide (L YY-I)4)
Reference compound L YY-I1The synthesis method of (1) is prepared from 2-bromobenzyl bromide and thiourea to obtain a white solid. The yield was 36%. Mp is 93-96 ℃.
1H NMR(400MHz,CDCl3),(ppm):7.56(d,J＝7.8Hz,2H,ArH),7.29-7.26(m,4H,ArH),7.16-7.11(m,2H,ArH),3.80(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):136.66,133.06,131.63,129.11,127.35,124.56,43.74.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8819.
Example 51, 2-bis (3-bromobenzyl) disulfide (L YY-I)5)
Reference compound L YY-I1The synthesis method is to prepare the light yellow solid from the 3-bromobenzyl bromide and the thiourea. The yield was 41%. Mp:57～60℃。
1H NMR(400MHz,CDCl3),(ppm):7.44-7.39(m,2H,ArH),7.38(dd,J＝7.7,1.8Hz,2H,ArH),7.23-7.17(m,2H,ArH),7.17-7.13(m,2H,ArH),3.55(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):139.53,132.32,130.57,130.07,127.98,122.43,42.54.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8811.
Example 61, 2-bis (4-bromobenzyl) disulfide (L YY-I)6)
Reference compound L YY-I1The synthesis method of (1) is prepared from 4-bromobenzyl bromide and thiourea to obtain a white solid. The yield was 33%. Mp 91-95 ℃.
1H NMR(600MHz,CDCl3),(ppm):7.45(d,J＝8.2Hz,4H,ArH),7.09(d,J＝8.3Hz,4H,ArH),3.56(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):136.30,131.62,130.99,121.47,42.53.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8817.
Example 71, 2-bis (3-fluorobenzyl) disulfide (L YY-I)7)
Reference compound L YY-I1The synthesis method of (1) is to prepare yellow liquid from 3-fluorobenzyl bromide and thiourea. The yield was 37%.
1H NMR(400MHz,CDCl3),(ppm):7.32-7.26(m,2H,ArH),7.01(d,J＝7.7Hz,2H,ArH),6.95(ddd,J＝9.2,4.8,2.1Hz,4H,ArH),3.59(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):163.53,139.80,129.99,125.01,116.13,114.50,42.72.
HR-MS:[M+H]+,Calcd:283.0427,Found:283.0435.
Example 81, 2-bis (4-fluorobenzyl) disulfide (L YY-I)8)
Reference compound L YY-I1The synthesis method of (1) is to prepare white solid from 4-fluorobenzyl bromide and thiourea. The yield was 28%. Mp is 67-71 ℃.
1H NMR(400Hz,CDCl3),(ppm):7.22-7.20(m,2H,ArH),7.19(d,J＝5.5Hz,2H,ArH),7.02(d,J＝8.2Hz,2H,ArH),7.01(d,J＝8.6Hz,2H,ArH),3.59(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):163.02,133.09,130.86,115.30,42.40.
HR-MS:[M+H]+,Calcd:283.0427,Found:283.0432.
Example 91, 2-bis (2-nitrobenzyl) disulfide (L YY-I)9)
Reference compound L YY-I1The synthesis method of (1) is to prepare white solid from 2-nitrobenzyl bromide and thiourea. The yield was 21%. Mp is 108-111 ℃.
1H NMR(400MHz,CDCl3),(ppm):8.20-8.02(m,4H,ArH),7.59-7.50(m,4H,ArH),3.72(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):148.25,139.27,135.25,129.58,124.08,122.60,42.08.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0323.
Example 101, 2-bis (3-nitrobenzyl) disulfide (L YY-I)10)
Reference compound L YY-I1The synthesis method of (1) is to prepare white solid from 3-nitrobenzyl bromide and thiourea. The yield was 47%. Mp is 97-101 ℃.
1H NMR(400MHz,CDCl3),(ppm):8.15(dd,J＝7.8,1.4Hz,2H,ArH),8.07(s,2H,ArH),7.58(d,J＝7.6Hz,2H,ArH),7.53(t,J＝7.7Hz,2H,ArH),3.72(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):148.24,139.27,135.26,129.58,124.08,122.60,42.08.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0312.
Example 111, 2-bis (4-nitrobenzyl) disulfide (L YY-I)11)
Reference compound L YY-I1The synthesis method of (1) is to prepare white solid from 4-nitrobenzyl bromide and thiourea. The yield was 24%. Mp is 141-145 ℃.
1H NMR(600MHz,CDCl3),(ppm):8.19(d,J＝8.6Hz,4H,ArH),7.43(dd,J＝12.9,6.3Hz,4H,ArH),3.68(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):129.71,129.63,123.85,123.74,35.18.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0309.
Example 121, 2-bis (4-chlorobenzyl) disulfide (L YY-I)12)
Reference compound L YY-I1The synthesis method of (1) is prepared from 4-chlorobenzyl bromide and thiourea to obtain a white solid. The yield was 29%. Mp is 33-40 ℃.
1H NMR(600MHz,CDCl3),(ppm):7.27(t,J＝7.9Hz,4H,ArH),7.19(d,J＝8.3Hz,4H,ArH),3.54(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):136.34,130.63,130.25,128.62,34.84.
HR-MS:[M+H]+,Calcd:314.9836,Found:314.9828.
Example 131, 2-bis (4-methylbenzyl) disulfide (L YY-I)13)
Reference compound L YY-I1The synthesis method of (1) is prepared from 4-methylbenzyl bromide and thiourea to obtain a white solid. The yield was 34%. Mp is 52-55 ℃.
1H NMR(400MHz,CDCl3),(ppm):7.14-7.12(m,4H,ArH),7.12-7.10(m,4H,ArH),3.60(s,4H,CH2),2.33(s,6H,CH3).
13C-NMR(600MHz,CDCl3),(ppm):137.11,134.28,129.28,129.15,43.04,21.16.
HR-MS:[M+H]+,Calcd:275.0928,Found:275.0924.
Example 141, 2-bis (4-cyanobenzyl) disulfide (L YY-I)14)
Reference compound L YY-I1The synthesis of (1) was prepared from 4-cyanobenzyl bromide and thiourea to give a yellow solid. The yield was 34%. Mp is 136-139 ℃.
1H NMR(400MHz,CDCl3),(ppm):7.63(d,J＝8.2Hz,4H,ArH),7.33(d,J＝8.2Hz,4H,ArH),3.64(s,4H,CH2).
13C-NMR(600MHz,CDCl3),(ppm):142.65,132.31,129.96,118.51,111.45,42.58.
HR-MS:[M+H]+,Calcd:297.0520,Found:297.0513.
Example 152, 2- [ (3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl) -methyl]Disulfide (L YY-I)15)
Pyrithioxine hydrochloride (0.200g, 0.5mmol) was dissolved in water and saturated aqueous sodium carbonate solution was added dropwise to precipitate a white solid with a yield of 70%.
1H NMR(400MHz,CDCl3),(ppm):8.35(s,2H,OH),7.70(s,2H,ArH),4.76(s,4H,OCH2),3.83(s,4H,CH2),2.34(s,6H,CH3).
13C-NMR(600MHz,CDCl3),(ppm):151.05,147.12,140.97,132.05,128.86,56.98,36.83,19.84.
HR-MS:[M+H]+,Calcd.:369.0938,Found:369.0940.
EXAMPLE 16 protective Effect of 16L YY-I Compounds on glutamate induced injury of the mouse hippocampal HT-22 cell line
The test methods are described in the literature [ Cheng J, et al. neurochemistry International,2013,62(8): 1072-1078 ].
The test is divided into blank control group, glutamic acid group and sample group, wherein 5mM glutamic acid is added into the glutamic acid group, 5mM glutamic acid and L YY-I with final concentration of 1, 5, 10, 50 and 100 mu M respectively are simultaneously added into the sample group1-15Or ligustrazine; the blank control group was added with the same volume of DMSO. After 24 hours of dosing, viable cells were detected by the MTT method. Three replicates of each group were run and the results are shown in table 1.
TABLE 1 Effect of 1L YY-I Compounds on survival of glutamate induced injury HT22 cells
Significant differences compared to the glutamic acid group, P <0.01
HT22 cell injury and survival rate induced by 5mM glutamic acid<30 percent. As can be seen from the results in Table 1, the compounds synthesized in examples 1 to 15 at a final concentration of 1 to 100. mu.M can significantly improve the survival rate (P) of HT22 cells caused by glutamic acid<0.05,P<0.01) and reducing nerve cell injury, wherein the effective protection concentration range is 10-100 mu M, and the lowest effective protection concentration is 10 mu M, wherein L YY-I1The protective effect on the glutamic acid induced damage HT22 cells is strongest, the cell survival rate reaches 91.77-95.40% at 10-100 mu M, and the obvious difference (P) exists compared with other compounds<0.01); but at the same concentration ligustrazine had no effect against glutamate toxicity, see figure 1.
Example 17L YY-I1Protection effect on mouse hippocampal neuron HT-22 cell line damaged by hydrogen peroxide induction
The test methods are described in ChenZ, et al cancer L etters,2013,336(2): 281-289).
The test was divided into a blank control group, a hydrogen peroxide group treated with 100. mu.M hydrogen peroxide, and a sample group treated with 100. mu.M hydrogen peroxide and L YY-I at final concentrations of 1, 5, 10, 50 and 100. mu.M, respectively1Or ligustrazine; the control group was added with the same volume of DMSO. After 24 hours of dosing, viable cells were detected by the MTT method. Each group was replicated three times and the results are shown in figure 2.
Shown by FIG. 2 at H2O2Group, survival of HT-22 cells 15.23%, indicating 100. mu. M H2O2Causing damage to HT-22 cells, L YY-I at 50, 100. mu.M1Treatment, the survival of HT-22 cells decreased significantly (P)<0.01), Explanation L YY-I1With removal of H2O2The generated free radicals act on H2O2The damaged HT-22 cells have good protective effect. However, the same concentration of ligustrazine does not clear H2O2The free radicals act.
Example 18L YY-I1Antagonism against ADP-induced platelet aggregation in rats
Experimental methods are described in the literature [ Paul Jurasz, et al. P L oS One, 2013; 8(3): e59281 ].
The tests were divided into the ADP (adenosine diphosphate) group, L YY-I1Group (plus ADP and 0.1, 0.5, 1mM L YY-I1) And ligustrazine group (containing ADP and 0.1, 0.5, and 1mM ligustrazine), each group has 3 parallel tubes. Platelets were taken from SD rats. The maximum aggregation rate (PAGm) of each group was determined on a platelet aggregation meter.
As shown in FIG. 3, the maximum aggregation rate of the ADP group platelets was 78.77%, when 0.1, 0.5, 1mM L YY-I was added1The maximal platelet aggregation rate decreased significantly upon treatment (P)<0.05，P<0.01), prompt L YY-I1Has excellent platelet aggregation inhibiting activity. However, ligustrazine has no platelet aggregation inhibiting effect under the same concentration.
Example 19L YY-I1Brain protection in mouse model of middle cerebral artery occlusion
ICR mice, male, body weight 30 + -2.0 g, purchased from Shanghai laboratory animal center of Chinese academy of sciences. 2,3, 5-Triphenyltetrazolium chloride (TTC) (Sigma).
The experiment was performed in a mouse Middle Cerebral Artery Occlusion (MCAO) model, classified as L YY-I1Group and solvent control group, 8 mice per group, solvent group injected corn oil containing 25% DMSO L YY-I1After 3 hours of ischemia reperfusion, 0.22mmol/kg L YY-I prepared by the invention is administrated to the abdominal cavity1Mice were sacrificed 24h after ischemia reperfusion and cerebral infarct zone size was determined by TTC staining, FIG. 4 is the percent cerebral infarct volume of mice 24h after reperfusion in MCAO, it can be seen from the results of FIG. 4 that mice were injected with L YY-I after 3h of ischemia reperfusion, compared to solvent group mice, 24h after 24h of occlusion of the middle cerebral artery1Obviously reduces the infarct volume of cortex, striatum and cerebral hemisphere, and shows L YY-I1Has obvious protective effect on ischemic brain injury caused by middle cerebral artery blockage.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (10)
1. A compound of the structure of formula I:
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
2. The application of the compound with the structure shown in the formula I in preparing a preparation for protecting neuron cells;
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
3. The application of the compound with the structure shown in the formula I in the preparation of a preparation for inhibiting platelet aggregation;
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
4. The application of the compound with the structure shown in the formula I in preparing a preparation for preventing and treating brain injury after cerebral ischemia reperfusion;
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
5. The application of the compound with the structure shown in the formula I in preparing a preparation for preventing and treating cerebral apoplexy;
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
6. Use according to claim 5, characterized in that the stroke is a stroke caused by cerebral embolism and/or a stroke caused by cerebral hemorrhage.
7. The use according to any one of claims 2 to 6, wherein the compound of formula I is administered in an amount of 0.05mg/kg to 90 mg/kg.
8. Use according to any one of claims 2 to 6, wherein Ar is 3,5, 6-trimethylpyrazin-2-yl.
9. A medicament comprising a compound of formula I and a pharmaceutically acceptable excipient;
wherein Ar is 3,5,6-trimethyl pyrazine-2-radical.
10. The preparation method of the compound with the structure shown in the formula I is characterized in that the compound A reacts with thiourea in the presence of manganese dioxide and PEG to prepare the compound shown in the formula I;
wherein Ar is 3,5, 6-trimethylpyrazin-2-yl; the compound A is 2-bromomethyl-3, 5,6-trimethyl pyrazine.
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