CN103396368A - Application of free radical of nitroxide to treatment of ischemia reperfusion injury - Google Patents
Application of free radical of nitroxide to treatment of ischemia reperfusion injury Download PDFInfo
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- CN103396368A CN103396368A CN2013103224457A CN201310322445A CN103396368A CN 103396368 A CN103396368 A CN 103396368A CN 2013103224457 A CN2013103224457 A CN 2013103224457A CN 201310322445 A CN201310322445 A CN 201310322445A CN 103396368 A CN103396368 A CN 103396368A
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- compound
- reperfusion injury
- free radical
- treatment
- ischemia reperfusion
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Abstract
The invention discloses a compound as shown in the structural general formula (I), wherein R is a substituent or double substituents and is independently selected from NO2, OH, OCH3, halogen and H. The compound is used for treating ischemia reperfusion injury. The compound is simple and convenient in synthesis method; and a molecule of the compound contains a structural unit of the free radical of nitroxide to ensure that free radical can be removed efficiently and circularly, and the compound has a remarkable inhibiting effect on ischemia reperfusion injury, so that the compound has important practical values.
Description
Technical field
The present invention relates to the application of the novel nitroxyl free radical of a class in the treatment ischemical reperfusion injury, belong to medical technical field.
Background technology
The caused tissue injury of ischemic is the major cause of fatal disease, such as the myocardial infarction that causes of hat arteriosclerosis, cerebral apoplexy, liver renal ischaemia etc., characteristics with high incidence, high mortality and high disability rate, the serious threat human health, brought huge burden for society, government and family.
The multiple organ injury that organizes who causes for ischemic there is no effective medicine at present, and clinical breach is very large.Therefore, research and development effectively prevent and treat or the new drug that alleviates ischemical reperfusion injury becomes China and even countries in the world pharmacy worker's vital task, are also one of current medical circle major issues urgently to be resolved hurrily.
The experimental results shows at present, and the oxidative stress damage is the major reason of ischemical reperfusion injury, and plays an important role in the ischemical reperfusion injury links of acute phase.The capillary blood vessel that ischemic tissue causes while pouring into again and organa parenchymatosum's damage are mainly caused by active oxygen radical, this has obtained in multiple organ proof.In ischemic tissue, have the antioxidant reductase synthesis capability generation obstacle of removing free radical, thereby aggravated the damage of radical pair postischemic reperfusion tissue.Therefore, the antioxidant that can remove harmful free radical becomes the research emphasis of ischemical reperfusion injury control medicine, and for example, the chemicals Edaravone, can reduce the cerebral infarction volume after local cerebral ischemia, is that first is by the effective free-radical scavengers of clinical proof.
Summary of the invention
One of purpose of the present invention is to provide a class both can be efficiently, the loop cleaning free radical, again ischemical reperfusion injury had to significantly inhibiting novel nitroxyl free radical medicines structure.
Another object of the present invention is to provide the preparation method of above-mentioned novel nitroxyl free radical medicines structure.
A further object of the invention is to provide the application of above-mentioned novel nitroxyl free radical medicine in preparation treatment ischemical reperfusion injury medicine.
Implementation procedure of the present invention is as follows:
Compound shown in general structure (I),
Wherein R is single replacement or disubstituted, is independently selected from NO
2, OH, OCH
3, halogen, H.
The synthetic method of compound shown in general structure (I), its synthetic route is as follows:
The application of compound shown in general structure (I) in preparation treatment ischemical reperfusion injury medicine, described ischemical reperfusion injury comprises: cardiac muscle, brain, lung, kidney, liver, intestinal ischemia reperfusion injury; Described medicine is tablet, capsule, powder, pill, granule, emulsion or injection.
By pharmacodynamics test in body, prove: medicine of the present invention all has significant protective effect to cerebral ischemia/reperfusion injury of rats and myocardial ischemia-reperfusion injury, and resistance is better.
Embodiment
Embodiment 1: the synthetic method of compound 1
(1) 4-hydroxy-cinnamic acid acyl chlorides is synthetic
By 1.64 g(10.0 mmol) p-Coumaric Acid is dissolved in 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 10.0 mL SOCl
2The CH of (1.18 g)
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure is directly used in the next step.
(2) synthesizing the hydroxyl nitroxyl free radical
By 1.22 g(10.0 mmol) p-Hydroxybenzaldehyde and 1.48 g(10.0 mmol) dihydroxylamine is dissolved in 50 mL methyl alcohol, back flow reaction 24 h.There are a large amount of white insolubless to generate, filter a small amount of methanol wash of filter cake.Filter cake is suspended in to 50.0 mL CH
2Cl
2In, ice-water bath is cooling, adds 30.0 mL NaIO
4(1.7 g) aqueous solution, stopped reaction after stirring 15 min.After stratification, water CH
2Cl
2Extracting twice, merge organic phase, and dried overnight is filtered, removal of solvent under reduced pressure, and column chromatography purification obtains product 1.12 g, productive rate 45%.
(3) compound
1Synthetic
By 2.49 g(10.0 mmol) the hydroxyl nitroxyl free radical is dissolved in to 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 1.82 g(10.0 mmol) 20.0 mL CH of p-Coumaric Acid acyl chlorides
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure, column chromatography purification obtain product 3.67 g, productive rate 93%.Mp:197 ~ 198 ℃; R (
ν max/ cm
-1): 3380,1,716 1645,1630,1505,780; EI-MS (
m/
z) 395.24 [M]
+Ultimate analysis: Found:C, 66.82; H, 5.86; N, 7.08; Calc. for C
22H
23N
2O
5, C, 66.89; H, 5.83; N, 7.05%; ESR (DMF): quintet 1:2:3:2:1, a
N=8.30G,
g=2.00990.
Embodiment 2: the synthetic method of compound 2
(1) 3-methoxyl group-4-hydroxy-cinnamic acid acyl chlorides is synthetic
By 1.94 g(10.0 mmol) p-Coumaric Acid is dissolved in 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 10.0 mL SOCl
2The CH of (1.18 g)
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure is for the next step.
(2) compound
2Synthetic
By 2.49 g(10.0 mmol) the hydroxyl nitroxyl free radical is dissolved in to 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 2.12 g(10.0 mmol) 20.0 mL CH of 3-methoxyl group-4-hydroxy-cinnamic acid acyl chlorides
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure, column chromatography purification obtain product 3.91 g, productive rate 92%.Mp:245 ~ 247 ℃. IR (
ν max/ cm
-1): 3485,1720,1650,1509,1632,880,810. EI-MS (
m/
z) 425 [M]
+Ultimate analysis: Found:C, 64.93; H, 5.92; N, 6.58; Calc. for C
22H
23N
2O
5, C, 64.91; H, 5.95; N, 6.52%; ESR (DMF): quintet 1:2:3:2:1, a
N=8.25 G,
g=2.00987.
Embodiment 3: the synthetic method of compound 3
(1) 3-hydroxy-4-hydroxymethyl base cinnamic acid acyl chlorides is synthetic
By 1.64 g(10.0 mmol) p-Coumaric Acid is dissolved in 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 10.0 mL SOCl
2The CH of (1.18 g)
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure is for the next step.
(2) compound
3Synthetic
By 2.49 g(10.0 mmol) the hydroxyl nitroxyl free radical is dissolved in to 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 1.98 g(10.0 mmol) 20.0 mL CH of p-Coumaric Acid acyl chlorides
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure, column chromatography purification obtain product 3.91 g, productive rate 95%.Mp:203 ~ 204 ℃. IR (
ν max/ cm
-1): 3480,1710,1647,1509,1635,880,810; EI-MS (
m/
z) 411 [M]
+Ultimate analysis: Found:C, 64.22; H, 5.63; N, 6.81; Calc. for C
22H
23N
2O
6, C 64.25, and H 5.61, and N 6.84; ESR (DMF): quintet 1:2:3:2:1, a
N=8.27G,
g=2.00992.
Embodiment 4: the synthetic method of compound 4
Take 2.01g(10 mmo1) 4-hydroxyl-3-bromobenzaldehyde is placed in 50 mL three-necked flasks, 1.46 g(0.014 mo1) propanedioic acid, 15 mL benzene, 3 mL pyridines, 0.5 mL piperidines, oil bath, stirring and dissolving, back flow reaction 6 h.React complete, add 15 mL saturated sodium bicarbonate solutions, water layer 6 molL after being cooled to room temperature
-1Hcl acidifying to pH value is about 2, filters, and oven dry, obtain white solid product 1.87 g, yield 77%.
By upper step product 2.41 g(10.0 mmol) be dissolved in 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 10.0 mL SOCl
2The CH of (1.18 g)
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure is for the next step.
By 2.49 g(10.0 mmol) the hydroxyl nitroxyl free radical is dissolved in to 50 mL CH
2Cl
2In, ice-water bath is cooling, drips 2.62 g(10.0 mmol) to 20.0 mL CH of 4-hydroxyl 3-bromobenzene vinylformic acid acyl chlorides
2Cl
2Solution, then be warming up to back flow reaction 2h, stopped reaction.Removal of solvent under reduced pressure, column chromatography purification obtain product 4.01 g, productive rate 83%.Mp:177 ~ 178 ℃. EI-MS (
m/
z) 473.25 [M]
+Ultimate analysis: Found:C, C 55.71, and H 4.68, and N 5.98; Calc. for C
22H
22BrN
2O
5, C 55.43, and H 4.72, and N 6.15; ESR (DMF): quintet 1:2:3:2:1, a
N=8.01G,
g=2.00754.
Embodiment 5: the cerebral ischemia re-pouring injured pharmacodynamic experiment of compound 1 treatment
(1)
1. the foundation of cerebral ischemia re-pouring model:
(i) research object:Healthy male SD rat, at the 3-4 monthly age, 280-350 g, provided by The Fourth Military Medical University's Experimental Animal Center.
The (ii) preparation of Ischemia-Reperfusion Injury Model:The Zea-Longa method of improvement is a little adopted in the preparation of focal cerebral ischemia/reperfusion in rats damage model, sets up SD intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia-reperfusion injury damage model.With 10% Chloral Hydrate intraperitoneal anesthesia rat, in art, keep anus temperature 36.5-37.5 ℃, expose arteria carotis communis and branch thereof, separate external carotid artery ligation, exposure internal carotid artery, and the 40 mm nylon wires (0.26 mm) that induce one, Xu advances 18-20 mm forward, the blocking-up blood flow of middle cerebral artery, carry out right side arteria cerebri media embolism, after the modeling success, 2 h pull out the line bolt, form the focal cerebral ischemia-reperfusion injury model.If postoperative have rats death before putting to death, random benefit is with the same great mouse of batch similar body.
(iii) experiment grouping and processing:20 rats of sham operated rats, only carry out the Cervical Vessels separation and embolism arteria cerebri media not; Rat after ischemia-reperfusion modeling success carries out the scoring of Zea-Longa study of behaviour after clear-headed, 1-3 is divided into group.60 rats of adopting the table of random number method will enter group are divided into sham operated rats, cerebral ischemia re-pouring group (model group) and medication therapy groups at random.After grouping, the medication therapy groups gavage gives the drug target 0.5mmol/kg of synthesized, every day 2 times, and administration 3 d, model group and sham operated rats give physiological saline 3.0 mL gavages.All rats carry out the study of behaviour scoring after pouring into 72 h again again, and then broken end is got brain rapidly.
2. test index:
(i) neuroethology assessment
Postoperative 24 h are checked the ability to act of all rats by the people who does not know the grouping situation, method is as follows:
0 minute: impassivity disappearance symptom;
1 minute: left front pawl can not full extension;
2 minutes: pitch of the laps to the left;
3 minutes: fall to the left;
4 minutes: without spontaneous action or level of consciousness, descend.
The (ii) long-pending assessment of cerebral infarction stove
With its infarct volume of TTC Determination Staining.Rat broken end is fast got brain, discard cerebellum, brain stem, freezing 10 min under-20 ℃, from antinion, start to cut the thick crown cerebral tissue sheet of 2 mm, the brain sheet is dipped in to dyeing 30 min in 37 ℃ of constant temperature, 2% TTC phosphate buffered saline buffer, lucifuge, infarct can not dyeed by TTC, in 4% paraformaldehyde liquid, fix 2 h.Use image analysis software ImageJ1.36b to count the infarct area, and then calculate infarct volume and infarct per-cent.We proofread and correct the impact of oedema effect on the infarct volume with following formula: proofread and correct infarct volume=left side brain hemisphere volume (right side brain hemisphere volume infarct volume)
(iii) get homogenate supernatant mensuration and the closely-related various index S OD of free radical, MDA, GSH that serum and whole brain tissue make:The GSH activity selects chemical colorimetry to measure; The SOD activity is selected the xanthine enzymatic assays; MDA content selects the thiobarbituricacidα-method to measure; Observe the change of respectively organizing different test index content in rat blood serum, estimate the different target compound to cerebral ischemia re-pouring injured result for the treatment of, analyze the relation of protection effect and compound structure, preliminary overall texture effect relationship.
(5) result: with sham operated rats, compare, obvious neurologic impairment symptom (P<0.05) appears in the model group rat, and after cerebral ischemia 2h poured into 24h again, the neurologic impairment symptom was the most obvious, visible obviously cerebral infarction kitchen range.With model group, compare synthetic nitroxyl free radical
1,2,3Can reduce cerebral ischemia/reperfusion injury of rats tissues following MCAO in rats mda (MDA) content, increase simultaneously the activity of super thing dismutase vigor (SOD) GSH, the enhancing body resistance of oxidation.
Embodiment 6: the cerebral ischemia re-pouring injured pharmacodynamic experiment of compound 2 treatment
Experiment grouping and method are the same, after grouping, and medicine
2The treatment group gavage gives the drug target 0.5mmol/kg of synthesized, every day 2 times, and administration 3d, model group and sham operated rats give physiological saline 3.0 mL gavages.
Embodiment 7: the cerebral ischemia re-pouring injured pharmacodynamic experiment of compound 3 treatment
Experiment grouping and method are the same, after grouping, and medicine
3The treatment group gavage gives the drug target 0.5mmol/kg of synthesized, every day 2 times, and administration 3d, model group and sham operated rats give physiological saline 3.0 mL gavages.
Embodiment 8: the pharmacodynamic experiment of compound 2 and 3 treatment myocardial ischemia-reperfusion injuries
50 rats of experiment grouping are divided into 5 groups at random: sham operated rats, model group, administration group (compound
2, compound
3).The medication therapy groups gavage gives the drug target 0.5mmol/kg of synthesized, and model group and sham operated rats give physiological saline 3.0 mL gavages, every day 1 time, continuous 7 d.Each prepares the rat myocardial ischemia and reperfusion model by literature method after organizing rat administration 7 d.
The experimental result demonstration, model group is compared with sham operated rats, and the serum CK vigor obviously raises (P<0.05), compound
2And compound
3All can reduce the vigor of serum CK, have significant difference (P<0.05).With sham operated rats, compare, the SOD in serum content of model group obviously reduces, MDA content obviously raises (P<0.05), and rat gives compound
2And compound
After 3,Can effectively improve the SOD vigor in serum, reduce the MDA content (P<0.05) of serum, reduce the damage that oxyradical causes, point out it to myocardial ischemia-reperfusion injury, to have certain provide protection.
Claims (5)
1. the compound shown in general structure (I),
Wherein R is single replacement or disubstituted, is independently selected from NO
2, OH, OCH
3, halogen, H.
2. the synthetic method of the described compound of claim 1, its synthetic route is as follows:
3. the application of the described compound of claim 1 in preparation treatment ischemical reperfusion injury medicine.
4. application according to claim 3, described ischemical reperfusion injury comprises: cardiac muscle, brain, lung, kidney, liver, intestinal ischemia reperfusion injury.
5. application according to claim 3, it is characterized in that: described medicine is tablet, capsule, powder, pill, granule, emulsion or injection.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402822A (en) * | 2014-12-04 | 2015-03-11 | 马慧萍 | Nitrogen-oxygen free radical compound and preparation and application therefore in preparation of anti-hypoxia injury drugs |
| CN104910219A (en) * | 2014-12-24 | 2015-09-16 | 中国科学院兰州化学物理研究所 | Phenylethanoid glycoside radioprotective compound and preparation method and application thereof |
| WO2017215680A3 (en) * | 2016-06-13 | 2018-02-15 | 赵吉永 | Chlorprothixene pharmaceutical composition and effects thereof for protecting cerebral ischemia reperfusion injuries |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402822A (en) * | 2014-12-04 | 2015-03-11 | 马慧萍 | Nitrogen-oxygen free radical compound and preparation and application therefore in preparation of anti-hypoxia injury drugs |
| CN104910219A (en) * | 2014-12-24 | 2015-09-16 | 中国科学院兰州化学物理研究所 | Phenylethanoid glycoside radioprotective compound and preparation method and application thereof |
| CN104910219B (en) * | 2014-12-24 | 2018-09-21 | 中国科学院兰州化学物理研究所 | A kind of benzyl carbinol glycoside radioprotective compound and its preparation method and application |
| WO2017215680A3 (en) * | 2016-06-13 | 2018-02-15 | 赵吉永 | Chlorprothixene pharmaceutical composition and effects thereof for protecting cerebral ischemia reperfusion injuries |
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