CN101234106B - Use of imidazolone compounds for treating cardiovascular and cerebrovascular diseases - Google Patents
Use of imidazolone compounds for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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- CN101234106B CN101234106B CN2008100204179A CN200810020417A CN101234106B CN 101234106 B CN101234106 B CN 101234106B CN 2008100204179 A CN2008100204179 A CN 2008100204179A CN 200810020417 A CN200810020417 A CN 200810020417A CN 101234106 B CN101234106 B CN 101234106B
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Abstract
The invention relates to a medicine field, in particular relates to application of (Z)-1-methyl-1, 5-dihydro-2-amido-5-(4-(mesyl) benzal)-4H-imidazole-4-ketone and pharmaceutically acceptable salt thereof in the treatment of cardiovascular and cerebrovascular diseases of mammals; the compound and the salt of the compound can effectively prohibit formation of thrombus and are used for preventing or curing diseases such as coronary heart disease, atherosclerosis, artery and vein thrombosis, angina, myocardial infarction, coronary heart disease, myocarditis, ischemic cardiomyopathy, myocardial infarction, cardiovascular complications of diabetes, cerebral haemorrhage, cerebral thrombosis, cerebral embolism, cerebral infarction, brain stroke, lacunar infarction, transient ischemic attack, cerebral arteriosclerosis and peripheral vascular diseases such as obstructive vasculitis, aortoarteritis, hypercholesterolemia, or high blood lipids, etc.
Description
Technical field
The present invention relates to drug world, be specifically related to (Z)-1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one or the application of its pharmaceutically acceptable salt in the mammiferous cardiovascular and cerebrovascular disease of treatment.
Background technology
In inventor's early-stage Study, prepared the chemical compound of structural formula I, chemical name: (Z)-the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-the 4H-imidazol-4-one.
(I)
Formula I chemical compound is open in CN1389458A and CN1597673A, and discloses it and have Cycloxygenase (COX) and suppress active, can be used for treating inflammation disease.
Thrombotic disease mainly is meant arterial thrombotic disease and phlebothrombosis, relates to the multiple disease of blood and blood circulation, and common has coronary artery disease formation thrombosis and cause myocardial infarction (AMI) or angina pectoris; Cerebrovascular disease forms thrombosis, i.e. cerebral thrombosis apoplexy; Pulmonary embolism causes lung infraction or acute pulmonary heart disease; Limbs artery thrombosis and thromboembolism cause acrodynia or necrosis; The limbs venous thrombosis causes local edema and pain; The diffusivity thrombosis takes place in the whole body blood capillary, form unique disease and be disseminated inravascular coagulation (Chen Haozhu. the progress of thrombolytic treatment. domestic medical science internal medicine fascicle, 1991).WHO in 2002 statistics, have approximately every year 1800 ten thousand people die from various cardiovascular and cerebrovascular diseases (CardiovascularDiseases.World Health Organization Web site.Available at:http: //www.Who.Int/ncd/cvd/index.htm).Data is estimated according to incompletely statistics, and China has 1.1 hundred million hyperpietics, the person of dyslipidemia more than 100,000,000,3,000 ten thousand diabeticss now.Have people over half to have a kind of cardiovascular risk factors at least among the crowd, about 1,300,000 examples of annual New Development coronary event (comprising acute myocardial infarction, sudden coronary death and chronic coronary heart disease death) are inferior, and about 4,000,000 examples of apoplexy are inferior.From the nineties in last century, the cardiovascular diseases becomes first cause of the death of China urban and rural residents gradually, has accounted for nearly 40% of total death toll at present.(Wu Yangfeng payes attention to cardiovascular diseases's epidemiological study work, Chinese epidemiology magazine, 2003).
The medicine that is used to clinically to prevent and treats thrombosis mainly contains anti-platelet drug, anticoagulation medicine and thrombolytic agent.In recent years, many novel antithrombotic reagents based on anticoagulation medicine and thrombolytic medicine come out, though these medicines have better antithrombotic acitivity and less side reaction, mostly are biological product, are subjected to great limitation in clinical use.Aspirin still is a present clinical practice antiplatelet drug the most widely, has been confirmed to be the classical medication of treatment acute myocardial infarction (AMI), unstable angina and the prevention of myocardial infarction (MI) second phase.Its antithrombotic main mechanism is that the active part of irreversibly acetylation epoxidase-1 (COX-1) is the 529th a serine, causes this enzyme permanent deactivation, blocking-up TXA
2Generate, thus anticoagulant (Vane JR.Inhibition of prostaglandin synthesis as a mechanism of action foraspirin-like drugs.Nat New Biol., 1971,231:232-235).Yet aspirin can also directly suppress prostaglandin synthetase in the blood vessel wall, reduces the synthetic of prostacyclin (PGs), and the interior arachidonic acid metabolic balance of body is tilted to 5-LOX and COX-2 direction, produces a large amount of inflammatory mediators such as LTs and PGE
2Deng, LTs and PGE
2Has multiple biological activity Deng inflammatory mediator, as vasoconstriction, leukocyte adhesion with bring out TNFs and (the Stefano Fiorucci.Dual inhibitorsof cyclooxygenase and 5-lipoxygenase.A new avenue in anti-inflammatory therapy such as generation of ILs? .BiochemicalPharmacology.2001,62 (11): 1433-1438); Simultaneously because aspirin suppresses PGI
2Generation, be unfavorable for the antagonism and balance TXA
2Effect, thereby tangible gastrointestinal untoward reaction takes place, destroy gastric mucosa, cause gastrorrhagia; Even cause side effect such as headache, tinnitus, dizzy, visual deterioration.Therefore, the active novel antithrombotic reagent strong, that toxic and side effects is little of research and development has important practical significance.
Summary of the invention
The invention discloses the new medical use of formula I chemical compound or its pharmaceutically-acceptable salts; i.e. (Z)-1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one and salt thereof can be used for preparing the purposes of the medicine for the treatment of cardiovascular and cerebrovascular disease.The preferred thrombus disease of described cardiovascular and cerebrovascular disease.Formula I chemical compound and salt thereof can effectively suppress the formation of arterial thrombus, are used for preventing the formation of coronary heart disease, atherosclerosis, arteriovenous thrombosis, angina pectoris, myocardial infarction, coronary heart disease, myocarditis, ischemic cardiomyopathy, myocardial infarction, diabetes cardiovascular complication, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, cerebral infarction, apoplexy, lacunar infarction, transient ischemic attack, cerebral arteriosclerosis, peripheral angiopathy such as disease thrombosis such as obstructive angiitis, Takayasu arteritis.Simultaneously, formula I chemical compound and salt thereof also can effectively suppress venothrombotic formation, can be used for preventing the formation of the thrombosis that phlebothrombosis and vein blood vessel inflammation cause.In addition, disease tools such as formula I chemical compound and salt pair atherosclerosis thereof, hypercholesterolemia, hyperlipidemia have some improvement, and can be used for the prevention and the auxiliary treatment of above-mentioned disease.
Above-mentioned described pharmaceutically-acceptable salts preferred salt hydrochlorate, hydrobromate, sulfate, nitrate, oxalates, maleate, tosilate or mesylate.More preferably mesylate.
Formula I chemical compound can be according to the synthetic method preparation of describing among Chinese patent 1389458A and the 1597673A or mentioning.
The synthetic method of formula I chemical compound associated salts, usually, can be by preparing with corresponding acid reaction.When salt is monobasic hydrochlorate (for example hydrochlorate, hydrobromate, tosilate, acetate or mesylate), when the hydrogen salt form of binary acid such as dihydric phosphate, adopt the acid of at least 1 molar equivalent, adopt the excessive acid of mole usually.Yet, when the salt of needs is dicarboxylate such as sulfate, should adopt suitable usually and the acid certainty equivalence data.
Concrete preparation method is as follows: formula I chemical compound is dissolved in (commonly used is oxolane, methanol) in the suitable organic solvent, adds at least 1 normal acid, stirred 24 hours, be evaporated to 30% of about original volume, filter, an amount of oxolane washing, recrystallization, drying, promptly.
In order to prove that The compounds of this invention has cardiovascular and cerebrovascular disease protection activity; we choose formula I chemical compound mesylate promptly: (Z)-the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one mesylate (code name: ZLJ-6) carry out the pharmacological testing of following examples.Enumerated the embodiment of compound when in addition, as follows.
The specific embodiment
Embodiment 1
External antiplatelet aggregation test
Male SD rat, anesthesia separates common carotid artery down, gets blood, with anticoagulant heparin.(third edition 2001:1281) prepares platelet rich plasma (PRP) and platelet poor plasma (PPP) for Xu Shuyun, pharmacological experimental methodology, and with the centrifugal 10min of 150 * g, the sucking-off upper plasma promptly is PRP with anticoagulation according to document; Residue blood is got supernatant and is PPP again with the centrifugal 15min of 3000 * g.The platelet count of adjusting among the PRP with PPP is 5 * 10
8/ ml.Adopt different derivant ADP (50 μ M), arachidonic acid (300 μ gml respectively
-1) and collagen protein (6 μ gml
-1) the induced platelet gathering, measure hematoblastic maximum agglutination rate with the NBY-6 platelet aggregation instrument, by formula calculate suppression ratio: suppression ratio=(A
Model-A
Test)/A
Model* 100%, the result shows that chemical compound ZLJ-6 can suppress the platelet aggregation effect that three kinds of derivants cause, and the inhibitory action of ZLJ-6 and dosage are dependence preferably.The results are shown in Table 1.
From experimental result as can be known, chemical compound ZLJ-6 has platelet aggregation inhibitory activity, and the platelet aggregation that multiple derivant is caused has inhibitory action, illustrates that this chemical compound is a wide spectrum antithrombotic compound.
The influence of the external rat platelet aggregation effect that different derivants are caused of table 1ZLJ-6 (mean+SD, n=5)
Compare with model group,
*P＜0.05,
*P＜0.01
Embodiment 2
Antiplatelet aggregation test in the body
Male SD rat is divided into model control group, aspirin group (30mgkg at random
-1), CI-1004 (Pfizer research and development medicine Darbufelone) group (5mgkg
-1) and ZLJ-6 high and low dose group (10mgkg
-1, 3mgkg
-1), 8 every group.Gastric infusion is 7 days continuously.Behind the last administration 2h, get blood, with anticoagulant heparin, whole blood leaves standstill 50-60min.Blood sampling slowly injects the test tube after the special-purpose silication, adds the Tai Shi buffer, hatches 10min for 37 ℃, sample cell is inserted measure in the hole, puts into stirrer and stirs, and electrode inserts test tube, behind the digital display value stabilization, and zeroing.Add aggregation inducing agent ADP solution (50 μ M), arachidonic acid (300 μ gml more respectively
-1) or collagen protein (6 μ gml
-1), timing.Maximum resistance value, i.e. Zui Da cluster set in the record 5min.By formula calculate suppression ratio: suppression ratio=(Ω
Model-Ω
The administration group)/Ω
Model* 100%, the result shows, test-compound ZLJ-6 and positive control drug aspirin group, CI-1004 can suppress the platelet aggregation effect that three kinds of derivants cause, have compared significant difference (P＜0.01) with model group, and the inhibitory action of ZLJ-6 and dosage are dependence preferably.The results are shown in Table 2.
The influence of platelet aggregation effect in the rat body that table 2ZLJ-6 causes different derivants (mean+SD, n=8)
Compare with model group,
*P＜0.05,
*P＜0.01
Embodiment 3
Rat arteriovenous shut thrombotest
Male SD rat is divided into model control group, aspirin group (30mgkg at random
-1), CI-1004 organizes (5mgkg
-1) and ZLJ-6 high and low dose group (10mgkg
-1, 3mgkg
-1), 8 every group.Gastric infusion is 7 days continuously.After the last administration 2 hours, anesthesia separates right carotid and left side external jugular vein down, put into the silk thread that a long 6cm has weighed in the stage casing of polyethylene tube, be full of tube chamber with heparin-saline, insert in the isolated blood vessel, taking out silk thread behind the open blood flow 15min weighs, gross weight deducts silk thread and heavily is wet weight of thrombus, the result shows, behind the successive administration 7 days, the thrombosed weight in wet base of chemical compound ZLJ-6 group rat arteriovenous shut obviously alleviates, and comparing difference with model group has significance meaning (p＜0.01), and the thrombosis suppression ratio is suitable with positive control aspirin group.The results are shown in Table 3.
The table 3ZLJ-6 to the thrombotic influence of rat arteriovenous shut (mean+SD, n=8)
Compare with model group,
*P＜0.05,
*P＜0.01
Can draw to draw a conclusion from testing 2 and 3: chemical compound ZLJ-6 has antithrombotic acitivity in the body, can effectively suppress the formation of arterial thrombus, be used for preventing the formation of coronary heart disease, atherosclerosis, arteriovenous thrombosis, angina pectoris, myocardial infarction, coronary heart disease, myocarditis, ischemic cardiomyopathy, myocardial infarction, diabetes cardiovascular complication, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, cerebral infarction, apoplexy, lacunar infarction, transient ischemic attack, cerebral arteriosclerosis, peripheral angiopathy such as disease thrombosis such as obstructive angiitis, Takayasu arteritis.
Embodiment 4
The rat vein thrombotest
Male SD rat is divided into model control group, aspirin group (30mgkg at random
-1), CI-1004 organizes (5mgkg
-1) and ZLJ-6 high and low dose group (10mgkg
-1, 3mgkg
-1), 8 every group.Gastric infusion is 7 days continuously.After the last administration 2 hours, anesthesia is cut the about 3cm of skin in ventrimeson down, opens the abdominal cavity and separates postcava, in left renal vein below ligation postcava, sews up stomach wall.Reopen the abdominal cavity behind the 2h, clamp blood vessel at the following 2cm of distance ligation place with mosquito forceps this section tube chamber inner blood is exhausted, tube chamber is cut off in stringer then, observes to have or not thrombosis, weighs if any taking-up.With the thrombus weight is index, measures the influence of each administration group to venous thrombosis.The result shows that successive administration is after 7 days, and the thrombosed weight in wet base of test-compound ZLJ-6 group rat obviously alleviates, and comparing difference with model group has significance meaning (p＜0.01), and the thrombosis suppression ratio is higher than positive control aspirin group.The results are shown in Table 4.
The influence that table 4ZLJ-6 forms the rat dvt (mean ± SD, n=8)
Compare with model group,
*P＜0.05,
*P＜0.01
From The above results as can be known, chemical compound ZLJ-6 can effectively suppress venothrombotic formation, can be used for preventing the formation of the thrombosis that phlebothrombosis and vein blood vessel inflammation cause.
Embodiment 5
The test of mouse lung thromboembolism
Male mice in kunming is divided into model control group, aspirin group (60mgkg at random
-1), CI-1004 organizes (10mgkg
-1) and ZLJ-6 high and low dose group (20mgkg
-1, 6mgkg
-1), 10 every group.Behind the gastric infusion 2h, tail vein injection contains collagen protein and the adrenergic derivant that mixes, timing.Dead mouse number of elements in the 5min is investigated the protective effect of test-compound ZLJ-6 to the mouse lung thrombosis behind the counting injection derivant, and data are carried out χ
2Check, the result shows that ZLJ-6 has the certain protection effect to the lung thrombosis that is caused by collagen protein and epinephrine, can improve the survival rate of mouse lung thromboembolism, wherein high dose group can obviously suppress the death of mice.The results are shown in Table 5.
The influence of the mouse lung thromboembolism that table 5ZLJ-6 causes collagen protein-epinephrine (mean+SD, n=10)
Compare with model group,
*P＜0.05,
*P＜0.01;
The number of mice of death toll=death is tried the number of mice of number=tried
Embodiment 6
The arachidonic acid metabolic test of external whole blood
Male SD rat, anesthesia separates common carotid artery down, gets blood, with anticoagulant heparin, the static 30min of blood sample.Improve slightly according to methods such as ArgentieriDC.The ZLJ-6 that gets the contrast of whole blood and solvent liquid or variable concentrations is mixed, behind 37 ℃ of water-bath 5min, adds A23187 solution, continues 37 ℃ of water-bath 20min, places 4 ℃ of ice-water bath 10min cessation reactions rapidly, and is centrifugal, and it is standby to get supernatant-70 ℃ preservation.Measured by radioimmunoassay TXB
2Content, with reflection ZLJ-6 to the inhibition degree of COX-1.The result shows that comparing ZLJ-6 has obvious suppression effect (p＜0.01) with model group to the arachidonic acid metabolic that is caused by the calcium channel opener, can reduce arachidonic acid metabolite TXB
2Generation.The results are shown in Table 6.
The influence of the external whole blood arachidonic acid metabolic that table 6ZLJ-6 causes the calcium channel opener (mean ± SD, n=6)
Compare with model group,
*P＜0.05,
*P＜0.01; Compare ##p＜0.01 with matched group
Can infer from above result: the mechanism of ZLJ-6 antithrombotic acitivity may be by suppressing the COX-1 enzyme, reducing Ca in the platelet
2+Concentration, thus TXA reduced
2(TXB
2) generate.
Embodiment 7
The test of rabbit experiment atherosclerosis
Male rabbit is divided into matched group, model group, aspirin group and ZLJ-6 high and low dose group (6mgkg at random
-1And 2mgkg
-1), 6 every group.Adopt high lipid food in conjunction with common carotid artery inner membrance air drying art, set up the rabbit Atherosclerosis Model.Get blood at successive administration after 21 days, measure the variation of blood fat in the serum, to investigate ZLJ-6 atherosclerotic protective effect.The result shows, the ZLJ-6 that compares high dose with model group has some improvement to the blood fat tool of atherosclerotic rabbit, can reduce TCH, LDL-C, rising HDL-C (p＜0.01).The results are shown in Table 7.
Table 7ZLJ-6 to the influence of rabbit experiment Atherosclerosis Model blood lipid level (mean+SD, n=6)
Compare with model group,
*P＜0.05,
*P＜0.01; Compare ##p＜0.01 with matched group
Can infer from above result: ZLJ-6 has some improvement to disease tools such as atherosclerosis, hypercholesterolemia, hyperlipidemia, can be used for the prevention and the auxiliary treatment of above-mentioned disease.
Embodiment 8
The cerebral ischemic reperfusion in rats test
Male SD rat is divided into matched group (sham operated rats), model group, aspirin group and ZLJ-6 high and low dose group (20mgkg at random
-1And 10mgkg
-1), 6 every group.Adopt line bolt legal system to make intraluminal middle cerebral artery occlusion in rats obturation (MCAO) model.In the experiment first three day, every day gastric infusion once, with the administration of variable concentrations isometric(al).Modeling in the 4th day is irritated the while intraperitoneal administration once again.Carry out function of nervous system's scoring and broken end behind the 24h and get the mensuration that brain carries out biochemical indexes, to investigate the protective effect of ZLJ-6 cerebral ischemia.
Learn from table 8 and table 9, compare with sham operated rats, the model group rat shows tangible neuromotor dysfunction behind the ischemia-reperfusion, and the ZLJ-6 of high dose improves significantly to the rat neurologic impairment, muscular strength obviously increases, and comparing difference with model group has significance (P＜0.05).Compare with sham operated rats, MPO, NOS, the active obviously rising of iNOS are compared with model in the model group rat cerebral tissue, and ZLJ-6 has the obvious suppression effect to the increase of above-mentioned enzymatic activity.
Table 8ZLJ-6 to the influence of cerebral ischemia reperfusion injury rat model neuromotor function (mean ± SD, n=6)
Compare with model group,
*P＜0.05; Compare ##p＜0.01 with matched group
Table 9ZLJ-6 is to MPO in the cerebral ischemia reperfusion injury rat model cerebral tissue, the active influence of NOS and iNOS (mean+SD)
Compare with model group,
*P＜0.05,
*P＜0.01; Compare #p＜0.05, ##p＜0.01 with matched group
Can infer from above result: ZLJ-6 has the certain protection effect to cerebral ischemia, can be used for the prevention and the auxiliary treatment of this disease.
Embodiment 9
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-the 4H-imidazol-4-one
32.4g (0.176mol) is added in the 400ml glacial acetic acid mesyl benzaldehyde and 20g (0.177mol) creatinine, stir, add 44g fusion sodium acetate; reflux, process are separated out a large amount of yellow solids, finish reaction when TLC detects unmatchful mesyl benzaldehyde; be cooled to room temperature, filter, an amount of washing with alcohol; drain; the frozen water washing is to neutral, and drying gets the 36g yellow solid; yield 73.3%, 262～264 ℃ of mp.
Embodiment 10
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one mesylate
With 20g (Z)-1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-the 4H-imidazol-4-one adds in the 4000mL oxolane, stirs; add the 5.3mL methanesulfonic acid; vigorous stirring is 48 hours under the room temperature, and concentrating under reduced pressure filters; an amount of THF washing; drying, the oxolane recrystallization gets yellow solid 21.5g; yield 80%, 254 ℃ of mp.
Embodiment 11
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one hydrochlorate
With reference to the preparation method of embodiment 9,, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene by (Z)-1-methyl isophthalic acid]-4H-imidazol-4-one and hcl reaction make yellow solid, yield 72.7%, 345 ℃ of mp.
Embodiment 12
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one sulfate
With reference to the preparation method of embodiment 9,, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene by (Z)-1-methyl isophthalic acid]-4H-imidazol-4-one and sulfuric acid reaction make yellow solid, yield 78.6%, 250～254 ℃ of mp.
Embodiment 13
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one oxalates
With reference to the preparation method of embodiment 9,, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene by (Z)-1-methyl isophthalic acid]-4H-imidazol-4-one and oxalic acid reaction make yellow solid, yield 83.5%, 258～260 ℃ of mp.
Embodiment 14
(Z)-and the 1-methyl isophthalic acid, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene]-4H-imidazol-4-one maleate
With reference to the preparation method of embodiment 9,, 5-dihydro-2-amino-5-[4-(mesyl) benzylidene by (Z)-1-methyl isophthalic acid]-4H-imidazol-4-one and maleic acid reaction make yellow solid, yield 85.7%, 220～222 ℃ of mp.
Claims (3)
1. chemical compound (I) or its pharmaceutically acceptable salt are used to prepare the purposes of the medicine for the treatment of cardiovascular and cerebrovascular disease, and wherein said cardiovascular and cerebrovascular disease is thrombotic disease, atherosclerosis, hypercholesterolemia or hyperlipidemia.
2. the purposes of claim 1, wherein pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulfate, nitrate, oxalates, maleate, tosilate or mesylate.
3. the purposes of claim 2, wherein pharmaceutically acceptable salt is a mesylate.
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|---|---|---|---|---|
| CN1194964C (en) * | 2002-07-09 | 2005-03-30 | 中国药科大学 | P-methylsulfonyl phenylacrylate derivative and its prepn process and anti-inflammatory effect |
| CN1286824C (en) * | 2002-07-09 | 2006-11-29 | 中国药科大学 | Paro methylsulfonyl phongl acrylic acid derivative and its preparation method and antiinflammation action |
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| CN1194964C (en) * | 2002-07-09 | 2005-03-30 | 中国药科大学 | P-methylsulfonyl phenylacrylate derivative and its prepn process and anti-inflammatory effect |
| CN1286824C (en) * | 2002-07-09 | 2006-11-29 | 中国药科大学 | Paro methylsulfonyl phongl acrylic acid derivative and its preparation method and antiinflammation action |
Non-Patent Citations (4)
| Title |
|---|
| 敖桂珍等.对甲磺酰基苯乙烯环酮类衍生物的合成及抗炎活性.药学学报39 10.2004,39(10),803-807. |
| 敖桂珍等.对甲磺酰基苯乙烯环酮类衍生物的合成及抗炎活性.药学学报39 10.2004,39(10),803-807. * |
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| 陈颖等.咪唑酮类化合物ZLJ-6对大鼠脑缺血再灌注损伤的保护作用及其机制研究.药学进展33 2.2009,33(2),79-83. * |
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