CN103301099A - Composition of 2,4-disulfonylalpha-phenyl-tert-butyl-nitrone and 2-camphenol - Google Patents
Composition of 2,4-disulfonylalpha-phenyl-tert-butyl-nitrone and 2-camphenol Download PDFInfo
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- CN103301099A CN103301099A CN2012100559399A CN201210055939A CN103301099A CN 103301099 A CN103301099 A CN 103301099A CN 2012100559399 A CN2012100559399 A CN 2012100559399A CN 201210055939 A CN201210055939 A CN 201210055939A CN 103301099 A CN103301099 A CN 103301099A
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- baras camphor
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Abstract
The invention relates to a medicine composition of 2,4-disulfonylalpha-phenyl-tert-butyl-nitrone or pharmaceutically acceptable salt thereof and 2-camphenol, and an application thereof in preparing medicines for treating cerebrovascular diseases.
Description
Technical field
The present invention relates to pharmaceutical composition and the application in preparation treatment cerebrovascular medicine thereof of 2,4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt and 2-baras camphor.
Background technology
Cerebrovascular is a kind of disease of serious harm human health, has become at present that the mankind are disabled and one of dead major reason.Cerebrovascular (cerebrovascular disease is called for short CVD) refers to because the brain lesions that cerebrovascular causes unusually.Apoplexy (stroke) refers generally to acute cerebrovascular disease.
Cerebrovascular can simply be divided into two classes, and a class is owing to the minimizing of blood flow or the ischemic cerebrovascular that cutout causes, and another kind of is because angiorrhexis causes hemorrhagic apoplexy.Ischemic cerebrovascular mainly is cerebral infarction (comprising cerebral thrombosis and cerebral embolism), except cerebral infarction, also have and a kind ofly in 24 hours, can recover fully, do not stay the ischemic cerebrovascular of any sequela, be called as transient ischemic attack or transient cerebral ischemic attack, doctor's custom also is called transient apoplexy referred to as TIA.Hemorrhagic apoplexy also is divided into two classes, and a class is angiorrhexis, and blood flows in the brain essence, is called cerebral hemorrhage or cerebral hemorrhage.Another kind of is angiorrhexis, and the blood person who lives in exile holds the subarachnoid space around the brain, is called subarachnoid hemorrhage, and the doctor is referred to as SAH.
It is useful analytical reagent that α-phenyl tert-butylnitrone (PBN) was identified in the seventies.At the mid-80 in last century, when as if serious traumatic ischemia animal experiment shows that animal that PBN processed is higher than control sample survival rate, hinted that PBN may have therapeutical effect for the first time.2,4-disulfonyl α-phenyl tert-butylnitrone is the PBN derivant, and the structure of 2,4-disulfonyl α-phenyl tert-butylnitrone is suc as formula shown in (II).Disclose 2,4-disulfonyl α-phenyl tert-butylnitrone and salt thereof among the CN1156447A, and be used for the treatment of the purposes such as apoplexy.
The molecular formula of 2-baras camphor is C
10H
18O, molecular weight 154.25.The 2-baras camphor comprises (+)-2-baras camphor and (-)-2-baras camphor.The structural formula of (+)-2-baras camphor and (-)-2-baras camphor is as follows.
Summary of the invention
The purpose of this invention is to provide a kind of formula 2, the application in preparation treatment cerebrovascular medicine of 4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt and 2-baras camphor pharmaceutical composition, 2,4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt and 2-baras camphor have enhancing or synergistic effect when being used in conjunction with, can improve result of use.
The present invention is specifically related to a kind of pharmaceutical composition, comprises formula (I) chemical compound and 2-baras camphor; X in the formula (I)
+Be H
+Or pharmaceutically acceptable cation.
Preferably, acceptable cation is selected from Na on formula (I) Chinese materia medica
+, K
+, NH
4 +, 1/2Ca
2+, 1/2Mg
2+, 1/2Zn
2+, CaY
+, MgY
+Or ZnY
+Y is pharmaceutically acceptable univalent anion, includes but not limited to chloride ion, bromide ion, iodide ion, hydroxyl, nitrate anion, sulfonate radical, acetate.
More preferably acceptable cation is selected from Na on formula (I) Chinese materia medica
+, K
+Or NH
4 +
Most preferably acceptable cation is Na on formula (I) Chinese materia medica
+
2-baras camphor described in the present invention can for the mixture of (+)-2-baras camphor with (-)-2-baras camphor arbitrary proportion, also can be (+)-2-baras camphor or (-)-2-baras camphor; Be preferably (+)-2-baras camphor or (-)-2-baras camphor; It more preferably is (+)-2-baras camphor.
The mass ratio of formula of the present invention (I) chemical compound and 2-baras camphor is 1:1 ~ 9:1, and preferred mass ratio is 1:1 ~ 6:1, and further preferred mass ratio is 2:1 ~ 4:1, further preferred 2:1 or 3:1 or 4:1.
Pharmaceutical composition method of application among the present invention includes but not limited to intradermal injection, subcutaneous injection, intramuscular injection, intravenous injection, vertebra intracavitary administration, intra-arterial injection preferably with the injection form administration; Preferred intravenous injection.
Injection is comprised of pharmaceutical composition, solvent, additives and the container for the treatment of effective dose.Described additives are in order to guarantee the safe, effective and stable of injection." treatment effective dose " is to realize that the treatment benefit for example stops disease or preventative prevention or prevents the amount of chemical compound of the outbreak of disease in suffering from the object of disease.The treatment effective dose can be one or more symptoms of alleviating to a certain extent disease in the object or disease, it is relevant with disease or disease to make or one or more physiology of its cause of disease or biochemical parameters are partially or completely recovered the amount of the outbreak probability of normal and/or reduction disease or disease.
Pharmaceutical composition is dissolved in solvent, can be so that 2,4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt mix better with the 2-baras camphor.Described solvent can be selected the mixture of water, water-miscible organic solvent or water-miscible organic solvent and water.The mixture of preferred water, water-miscible organic solvent and water among the present invention.Water-miscible organic solvent commonly used mainly contains alcohols solvent, ether solvent, ketones solvent etc.
The injection that contains Chinese medicine compositions of the present invention also can be made in instant mode of joining.That is, can use like this: make the solid that contains pharmaceutical composition, additives (alternatively), be dissolved in before use in the aseptic solvent.
Another object of the present invention provide a kind of with aforementioned pharmaceutical compositions for the preparation of the application in the treatment cerebrovascular medicine.
Preferably, with aforementioned pharmaceutical compositions for the preparation of the application in treatment ischemic cerebrovascular or the cerebral infarction medicine.
The invention provides the compound medicine combination of 2,4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt and 2-baras camphor, both make up the protection effect that has improved ischemic brain injury.Because 2, the minimizing of 4-disulfonyl α-phenyl tert-butylnitrone or its pharmaceutically acceptable salt administration concentration has reduced the risk that untoward reaction occurs.
Description of drawings
Among Fig. 1 embodiment 32,4-disulfonyl α-phenyl tert-butylnitrone disodium salt/baras camphor compound recipe is on the impact of rat cerebral infarction area
The specific embodiment
The medicine preparation
2,4-disulfonyl α-phenyl tert-butylnitrone disodium salt solution: accurately take by weighing 0.2g 2,4-disulfonyl α-phenyl tert-butylnitrone disodium salt behind physiological saline solution, is settled to 100mL; Obtaining final concentration is 2 of 2mg/mL, 4-disulfonyl α-phenyl tert-butylnitrone disodium salt solution.X in formula (I)
+Be Na
+The time, be 2,4-disulfonyl α-phenyl tert-butylnitrone disodium salt.In following examples with 2,4-disulfonyl α-phenyl tert-butylnitrone disodium salt referred to as sodium salt.
Baras camphor solution: accurately take by weighing 0.0625g (+)-2-baras camphor, add the 8mL propylene glycol, behind physiological saline solution, be settled to 1000mL; Obtaining final concentration is the baras camphor solution of 0.0625mg/mL.
Sodium salt/baras camphor compound recipe solution (1.0mg/mL): accurately take by weighing the 0.75g sodium salt, use physiological saline solution; Accurately take by weighing 0.25g (+)-2-baras camphor, add the 8mL propylene glycol, use physiological saline solution; After two parts of solution mixing, be settled to 1000mL; Obtain final concentration and be the sodium salt of 1.0mg/mL/baras camphor compound recipe solution.
Sodium salt/baras camphor compound recipe solution (0.125mg/mL), sodium salt/baras camphor compound recipe solution (0.25mg/mL), sodium salt/baras camphor compound recipe solution (0.5mg/mL): got with normal saline dilution by 1.0mg/ml sodium salt/baras camphor compound recipe solution.
2. the preparation of cerebral ischemic model
Sprague-Dawley(SD) rat, male, SPF level, body weight 250g-280g.Source: Shanghai Slac Experimental Animal Co., Ltd., credit number: SCXK(Shanghai) 2007-0005.
Adopt standby middle cerebral artery occlusion (Middle cerebral artery, MCAO) the cerebral ischemia re-pouring model of internal carotid artery line bolt legal system.After animal is anaesthetized with 7% chloral hydrate (6ml/kg), the ventricumbent position is fixed on the operating-table, sterilization skin, cervical region medisection, separate right carotid, external carotid artery, internal carotid artery, peel off gently vagus nerve, ligation is also cut off external carotid artery, follow internal carotid artery forward, the tie wings arteria palatina.Folder closes the common carotid artery proximal part, make a kerf from the far-end of the ligature of external carotid artery, inserting external diameter is the nylon wire of 0.285mm, advances the common carotid artery bifurcated and enters internal carotid artery, then slowly be inserted into slight resistance till (from the about 20mm of crotch), all blood of blocking-up middle cerebral artery supply, behind the right side cerebral ischemia 2.0h, extract gently nylon wire, recover blood for pouring into again, skin suture, sterilization.
3. sodium salt baras camphor compound recipe synergism experiment
Experiment arranges 4 groups altogether, is divided into model group, sodium salt/baras camphor compound recipe group (0.75mg/kg), baras camphor group (0.1875mg/kg), sodium salt group (6mg/kg*3).
The immediately iv administration 1 time after perfusion again of sodium salt group, iv was administered once in then per 2 hours, and administration is 3 times altogether, each 6mg/kg.All the other organize immediately iv administration 1 time after perfusion again, and administration is 1 time altogether.Model group is given normal saline.Administration volume 0.3ml/100g.Put to death animal after 24 hours after the cerebral ischemia, get brain, brain infarction area is calculated in dyeing.
Detect index: as leading indicator, observe simultaneously the animal clinical manifestation with the cerebral infarction degree.
Each prescription on the impact of cerebral infarct size see Table 1, Fig. 1.Behind LSD method one factor analysis of variance, the result shows, exist between each group significant difference (F (3,50)=8.993, p=0.000).Wherein compare with model group, compound recipe, baras camphor and sodium salt can significantly reduce the brain infarction area (F (3,50)=8.993, p=0.000, p=0.001, p=0.001) of animal behind the cerebral ischemia reperfusion.
Table 1 sodium salt/baras camphor prescription is on the impact of rat cerebral infarction area
Annotate: X ± SD, * *, p＜0.01; * *, p＜0.001 is compared with model group
The assay method of cerebral infarction degree:Behind the sacrifice of animal, broken end is got brain, remove olfactory bulb, cerebellum and low brain stem, with normal saline flushing brain surface bloodstain, suck remained on surface water mark, place 20min in-20 ℃, make vertically downward coronal section in the sight line crossing plane immediately after the taking-up, and cut a slice every 2mm backward, place the 2%TTC dye liquor to hatch (37 ℃ of 90min) the brain sheet, normal cerebral tissue dyes peony, ischemic tissue of brain then is pale asphyxia, behind normal saline flushing, rapidly the brain sheet is arranged in a row from front to back in order, blot remained on surface water mark, take pictures.
Photo calculates the corresponding area of left brain and infarct area with Image J software processes according to formula, obtains infarct percentage ratio.
The Infarction volume computing method:
V=t?(A
1+?A
2+?A
3+?………+A
n)
T is slice thickness, and A is infarct size.
%I=100%×(VC-VL)/VC
%I is Infarction volume percentage ratio, and VC is control sides (left brain hemisphere) brain volume, and VL is the non-infarcted region volume of infarction side (right brain hemisphere).
Claims (10)
1. a pharmaceutical composition comprises formula (I) chemical compound and 2-baras camphor,
X in the formula (I)
+Be H
+Or pharmaceutically acceptable cation.
2. the pharmaceutical composition described in according to claim 1 is characterized in that pharmaceutically acceptable cation is selected from Na
+, K
+, NH
4 +, 1/2Ca
2+, 1/2Mg
2+, 1/2Zn
2+, CaY
+, MgY
+Or ZnY
+Y is pharmaceutically acceptable univalent anion, is selected from chloride ion, bromide ion, iodide ion, hydroxyl, nitrate anion, sulfonate radical or acetate.
3. the pharmaceutical composition described in according to claim 1 is characterized in that pharmaceutically acceptable cation is selected from Na
+, K
+Or NH
4 +
4. the pharmaceutical composition described in according to claim 1 is characterized in that described 2-baras camphor is (+)-2-baras camphor or (-)-2-baras camphor.
5. the pharmaceutical composition described in according to claim 1 is characterized in that described formula (I) chemical compound and 2-baras camphor mass ratio are 1:1 ~ 9:1.
6. the pharmaceutical composition described in according to claim 1 is characterized in that described formula (I) chemical compound and 2-baras camphor mass ratio are 2:1 ~ 4:1.
7. the pharmaceutical composition described in according to claim 1 is characterized in that described formula (I) chemical compound and 2-baras camphor mass ratio are 2:1 or 3:1 or 4:1.
8. the application of the described pharmaceutical composition of any one in preparation treatment cerebrovascular medicine among the claim 1-7.
9. the application described in according to claim 8 is characterized in that described cerebrovascular is ischemic cerebrovascular.
10. the application described in according to claim 8 is characterized in that described cerebrovascular is cerebral infarction.
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|---|---|---|---|
| CN201210055939.9A CN103301099B (en) | 2012-03-06 | 2012-03-06 | 2,4 disulfonyl α Phenyl t-butyl Nitrone and the compositionss of 2 baras camphors |
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|---|---|---|---|
| CN201210055939.9A CN103301099B (en) | 2012-03-06 | 2012-03-06 | 2,4 disulfonyl α Phenyl t-butyl Nitrone and the compositionss of 2 baras camphors |
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| CN103301099B CN103301099B (en) | 2016-12-14 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013845A1 (en) * | 2005-07-26 | 2007-02-01 | Astrazeneca Ab | Use of 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate n-oxide against stroke-in-evolution |
| CN102180832A (en) * | 2011-03-18 | 2011-09-14 | 苏州沪云肿瘤研究中心有限公司 | Compound for protecting cerebral ischemia and preparation method thereof |
-
2012
- 2012-03-06 CN CN201210055939.9A patent/CN103301099B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013845A1 (en) * | 2005-07-26 | 2007-02-01 | Astrazeneca Ab | Use of 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate n-oxide against stroke-in-evolution |
| CN102180832A (en) * | 2011-03-18 | 2011-09-14 | 苏州沪云肿瘤研究中心有限公司 | Compound for protecting cerebral ischemia and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 章思规: "《精细有机化学品技术手册》", 31 July 1997, 科学技术出版社 * |
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Effective date of registration: 20160719 Address after: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Applicant after: Jiangsu Simcere Pharmaceutical Co., Ltd. Address before: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Applicant before: Jiangsu Simcere Pharmaceutical Research Company Limited |
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Effective date of registration: 20180524 Address after: 211800 8 Xing Long Road, Pukou Economic Development Zone, Nanjing, Jiangsu. Co-patentee after: Jiangsu Simcere Pharmaceutical Co., Ltd. Patentee after: Nanjing Simcere Dongyuan Pharmaceutical Co., Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Patentee before: Jiangsu Simcere Pharmaceutical Co., Ltd. |
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Address after: No.99, Huakang Road, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Patentee after: SIMCERE PHARMACEUTICAL Group Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 211800 Nanjing, Pukou Economic Development Zone, Jiangsu Road, No. 8 Patentee before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |