CN1994998A - 4-methyl cyclopentadecanone and its uses - Google Patents
4-methyl cyclopentadecanone and its uses Download PDFInfo
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Abstract
The invention discloses an application of 4-methyl cyclopentadecanone in the drug of ischemic cerebrovascular disease, which also treats antirheumatic, rheumatoid disease as well as prevent tumour.
Description
Technical field
The present invention relates to a kind of have treatment cerebral ischemia cerebro-vascular diseases, rheumatism, rheumatism, antitumor, 4-methyl exaltone and the application for the treatment of and improve the dementia effect.
Background technology
Moschus is that musk deer section musk deer belongs to the secretory product in the male musk deer abdomen sachet, is world's rare medicinal herbs, also is one of four big rare medicinal herbss of China, in China medicine and pharmacology field long medicinal history is arranged, and " legendary god of farming's book on Chinese herbal medicine " classified Moschus as top grade.In 2621 kinds of prescriptions that existing national Chinese medicine prescription collection is loaded with, what contain Moschus just reaches 295 kinds more than.The Moschus inducing resuscitation of having one's ideas straightened out, promoting blood circulation and stopping pain are mainly used in cardiovascular and cerebrovascular, stroke hemiplegia, lose consciousness, wound, rheumatosis, gynecopathy, cancer etc.Country belonged to all kinds in 2003 with musk deer section musk deer and is adjusted into wildlife under first class protection by national wildlife under second class protection, strengthened the protection of musk deer resource comprehensively, and gathering of Moschus is subjected to strict restriction.The research of this scarce resource substitute of Moschus has become the vital task of modernization of Chinese medicine development outline.
From the domestic research that just begins the muskone seventies in 20th century, muskone's main raw material---muskone is researched and developed as the emphasis problem.Through several generations' painstaking effort, finished from the laboratory lab scale to suitability for industrialized production.Hongjitang Pharmacy Co., Ltd., Jinan obtains the New Drug Certificate of the Ministry of Health on February 25th, 1994.The muskone obtains the first class national new drug certificate the same year.Muskone is one of important component of a national class new Chinese medicine muskone.The market requirement in nearly 3 years of the muskone is annual just up to 3000 kilograms, and is annual to 3831.62 ten thousand yuan of national taxs revenue turned over to the state, creates 3574.6 ten thousand yuan of net profits.Main raw material muskone among the muskone, it is 3-methyl exaltone, in itself and the 4-methyl exaltone deposited then as muskone's synthetic by product, past is not owing to carry out perfect fundamental research, in becoming the product process, go out of use, show that through pharmacological research 4-methyl exaltone has identical effect with muskone (3-methyl exaltone) now, fully can be with the surrogate of muskone as the muskone.
Summary of the invention
The purpose of this invention is to provide 4-methyl exaltone and be used for as preparation treatment cerebral ischemia cerebro-vascular diseases, rheumatism, rheumatism, antitumor, the application for the treatment of and improve the medicine of dementia.With 4-methyl exaltone preparation treatment cerebral ischemia cerebro-vascular diseases, rheumatism, rheumatism, antitumor, treat and to improve the effect of drugs of dementia definite, few side effects.
4-methyl exaltone of the present invention, structural formula is as follows:
4-methyl exaltone preparation technology of the present invention is:
1, electrolysis
Raw material: dodecanedioic acid mono-methyl β-first class monomethyl glutarate is weighed and is mixed the back and add in the electrolyzer that sodium methylate is a medium and carry out the kolbe electrolysis, work in-process 1 mixture; Liquid material after electrolytic reaction is finished is transferred in the cooling jar lowers the temperature; Treat to carry out centrifugation after temperature drops in the scope of processing requirement, liquid material extracts in extractor with sherwood oil, distilled water, alkali lye and salt solution; The oil reservoir liquid that contains work in-process 1 after the extraction through concentrating, work in-process 1 after the fractionation;
2, cyclization
Dimethylbenzene, sodium Metal 99.5, work in-process 1 adds the cyclization jar, drips methyl alcohol, sulfuric acid then and carry out that the stoll alcohol ketone contracts and cyclisation gets work in-process 2 mixtures, logical nitrogen protection in the cyclization process through the metering back.After cyclization is finished liquid is transferred in the extractor and extracts with dimethylbenzene, distilled water, alkali lye and salt solution; After containing the oil reservoir liquid dried of work in-process 2 after the extraction, through the work in-process 2 of distillation, rectifying;
3, reduction
Ethanol, zinc powder, work in-process 2 processes are measured the back and are added the reduction jar, and dripping hydrochloric acid is reduced, and gets the mixture of synthetic musk ketone and isomers thereof, and the liquid material after the reduction reaction is transferred in the extractor and extracts with sherwood oil alkali lye and saturated aqueous common salt; Drying is carried out to oil reservoir liquid in extraction back, then through the work in-process 3 of distillation, rectifying;
4, column chromatography
In chromatography column, add activated silica gel and ether, sherwood oil, utilize the difference of silica gel to muskone and isomers 4-methyl exaltone adsorptive power thereof, muskone is separated with 4-methyl exaltone, after concentrated, distillation, rectifying, obtain pure product 4-methyl exaltone again.
4-methyl exaltone of the present invention has treatment cerebral ischemia cerebro-vascular diseases, rheumatism, rheumatism, antitumor, the effect for the treatment of and improve dementia.
4-methyl exaltone of the present invention is used for the application as the medicine of preparation treatment cerebral ischemia cerebro-vascular diseases; Be used for application as preparation treatment rheumatism, rheumatism medicine; Be used for application as preparation treatment antitumor drug; Be used for treating and improving the application of the medicine of dementia as preparation.
The advantage that the present invention has is:
1, meets the requirement of the modernization of Chinese medicine development outline of department's propositions such as the Ministry of Science and Technology fully;
2, help strengthening improvement of the ecological environment, protection animals on the brink of extinction and medicine resource improve human life's quality and health level;
3, the market requirement is wide; remarkable in economical benefits; after particularly country rises to first class of protection with musk deer class animal by second class protection; natural musk is with disabled, and the muskone's consumption that replaces will increase rapidly, and existing national natural musk supply is only about 10 kilograms; the continuous release of the development of the modernization of Chinese medicine and novel form in addition; the market requirement in nearly 3 years of the muskone is annual just up to 3000 kilograms, and is annual to 3831.62 ten thousand yuan of national taxs revenue turned over to the state, creates 3574.6 ten thousand yuan of net profits.
4,4-methyl exaltone is as muskone's synthetic by product, its yield is the 30%-50% of muskone (3-methyl exaltone), past is not owing to carry out perfect fundamental research, and in becoming the product process, go out of use, cause great waste, show to have identical effect through pharmacological research now with muskone (3-methyl exaltone), fully can be with the surrogate of muskone (3-methyl exaltone) as the muskone.
Muskone is existing to be studies have shown that has pharmacologically active to aspects such as central nervous system, anticancer, anti-inflammatory, analgesia and enhancing immunity, anti-allergic, antiearly pregnancy:
1, be used for the treatment of cancer, the tumor model mouse had better therapeutic effect:
Find that by test muskone has the effect that prolongs tumor model mouse storaging current, reduction knurl/body ratio, improves the immunology detection index.1. lifetime: average every the mouse of administration group prolongs 6.9 days than control group, and when control group was all dead, the administration group still had 11 survivals, and wherein Moschus has 9 with hyte, illustrates with hyte more effective; 2. knurl is heavy: the control group knurl heavily is (1.61 ± 0.51) g, administration group average out to (1.14 ± 0.42) g (P＜0.05); 3. immunology detection: NK cytoactive control group is 20%, administration group average out to 28.3%, Moschus group average out to 21.5%; IR-2R: control group average out to 29.3%, administration group average out to 41.6%, the Moschus group is 32.4%; T-TR: control group is 37.4%, administration group average out to 58.3%, and the Moschus group is 34.5%.Administration group and other two groups compare, and the effect that all is significantly improved (P＜0.01) illustrates that Moschus is used for the treatment of tumour and the life of prolongation is not only arranged, dwindle the effect of tumour, but also can improve body's immunological function.
2, be used for the treatment of rheumatism, similar rheumatism has good therapeutic action:
Found through experiments and the rheumatism model mice had effects such as the symptom of improvement, anti-inflammatory, adjusting immunity, swelling and pain relieving.
3, be used to improve brain injury aspect disease:
Studies show that this product has provide protection to several low, anaerobic brain injurys and ischemia cerebral disorders tissue.Mainly show: 1. Moschus can obviously shorten the animal lethargic sleep time that KCN brings out, and is dose-dependence; Can obviously shorten righting reflex time of recovery.2. KCN brings out the influence of survival time, and control group is dead behind (47.0 ± 3.9) s, and the Moschus group is all not dead.3. Moschus can prolong the breathing time after animal breaks end, but dose-effect relationship is not remarkable.4. can obviously prolong the survival time behind the ligation of carotid, and be dose-dependence.5. can obviously prolong the survival time of animal under the normal pressure anaerobic loading condiction.6. can obviously prolong the survival time of animal under the decompression property anaerobic loading condiction.Thus, think that Moschus has provide protection to the brain injury that cerebral ischemia causes, its consciousness regaining effect may be with to improve the cerebral blood flow effect relevant.
4, mouse is intended Model of Dementia and has good improvement effect:
Observe muskone to intending the dementia mice ability of learning and memory due to the D-semi-lactosi and serum superoxide dismutases (SOD) is active, the influence of cerebral tissue mda (MDA) content and monoamine oxidase (MAO) vigor.Found that muskone obviously the learning and memory function of antagonism dementia mice go down (water maze method), and its serum activity of SOD that can raise reduces the MDA content that raises in the cerebral tissue, suppresses the MAO vigor, thereby shows the dementia resisting effect that it is certain.
5, observe muskone Transdermal absorption effect:
Adopt the Franze diffusion cell to carry out the relatively transdermal diffusion characteristic of muskone of mouse isolated skin infiltration diffusion test.The result shows transdermal penetration speed behind muskone HP-beta-cyclodextrin molecular clathrate and the liposome obviously greater than muskone, and the muskone Benexate Hydrochloride is then lower.Conclusion: the transdermal penetration that can promote muskone after muskone HP-beta-cyclodextrin inclusion compound or the liposomeization.
Embodiment
Embodiment 1
4-methyl exaltone of the present invention, structural formula is as follows:
4-methyl exaltone preparation technology of the present invention is:
(1) electrolysis
Raw material: dodecanedioic acid mono-methyl 900g β-first class monomethyl glutarate 900g weighs and mixes the back and add in the electrolyzer that sodium methylate is a medium and carry out the kolbe electrolysis, work in-process 1 mixture; Liquid material after electrolytic reaction is finished is transferred in the cooling jar lowers the temperature; Treat to carry out centrifugation after temperature drops in the scope of processing requirement, liquid material extracts in extractor with sherwood oil, distilled water, alkali lye and salt solution; The oil reservoir liquid that contains work in-process 1 after the extraction through concentrating, work in-process 1 after the fractionation;
(2) cyclization
Dimethylbenzene, sodium Metal 99.5, work in-process 1 adds the cyclization jar, drips methyl alcohol, sulfuric acid then and carry out that the stoll alcohol ketone contracts and cyclisation gets work in-process 2 mixtures, logical nitrogen protection in the cyclization process through the metering back.After cyclization is finished liquid is transferred in the extractor and extracts with dimethylbenzene, distilled water, alkali lye and salt solution; After containing the oil reservoir liquid dried of work in-process 2 after the extraction, through the work in-process 2 of distillation, rectifying;
(3) reduction
Ethanol, zinc powder, work in-process 2 processes are measured the back and are added the reduction jar, and dripping hydrochloric acid is reduced, and gets the mixture of synthetic musk ketone and isomers thereof, and the liquid material after the reduction reaction is transferred in the extractor and extracts with sherwood oil alkali lye and saturated aqueous common salt; Drying is carried out to oil reservoir liquid in extraction back, then through the work in-process 3 of distillation, rectifying;
(4) column chromatography
In chromatography column, add activated silica gel and ether, sherwood oil, utilize the difference of silica gel to muskone and isomers 4-methyl exaltone adsorptive power thereof, muskone is separated with 4-methyl exaltone, after concentrated, distillation, rectifying, obtain pure product 4-methyl exaltone again.
Obtain pure product 4-methyl exaltone 36g, yield is 2%.
Embodiment 2 (Application Example)
The present invention further specifies the activity of 4-methyl exaltone anti-cerebral ischemia by following examples.
The focal cerebral ischemia in rats model neuroethology that 4-methyl exaltone causes the fishing line method, whole brain tissue's weight, right side brain weight, full brain/body ratio, right brain/body ratio all have improvement effect in various degree, to infarct area TTC chromoscopy, 4-methyl exaltone high and low dose group all can be improved the ischemic and the anoxia-induced apoptosis degree of rat cerebral tissue, the high dose group action intensity is suitable with the nimodipine group, but not as good as sham operated rats.After being prompted to rat oral gavage 4-methyl exaltone, can alleviate the effect of focal cerebral ischemia model oedema, focal cerebral ischemic model is had significant protective effect.4-methyl exaltone is not obvious to rat clotting time influence, but there is significant prolongation effect in the clotting time of the focal cerebral ischemia in rats model that 4-methyl exaltone high dosage causes the fishing line method.The mouse global brain ischemia model whole brain tissue weight that 4-methyl exaltone causes the total A ligation method of bilateral neck, full brain/body ratio all have improvement effect in various degree, to infarct area TTC chromoscopy, the high, medium and low dosage group of 4-methyl exaltone all can be improved the ischemic and the anoxia-induced apoptosis degree of mouse whole brain tissue, the high dose group action intensity is suitable with the nimodipine group, but not as good as sham operated rats.After being prompted to mouse stomach 4-methyl exaltone, can alleviate the effect of global brain ischemia model oedema, the total A ligation method of bilateral neck global brain ischemia model is had significant protective effect.
Test objective: observe 4-methyl exaltone different brains and function are cured mainly relevant main pharmacodynamics index.
Be subjected to the reagent thing:
The name of an article and producer's lot number: 4-methyl exaltone is provided by Hongjitang Pharmacy Co., Ltd., Jinan.
Usage and dosage: muskone pharmacopeia specified volume 5-10mg generally is no more than 30mg.
Positive drug: nimodipine tablet, 20mg/ sheet, people's daily dosage portion 30-120mg.
Dosage is provided with:
Clinical Coming-of-Age Day, dose was 10.0mg.Press the conversion of body surface area ratio, the rat high and low dose is respectively 3.6mg/kg and 0.9mg/kg, is equivalent to 25.2 times and 6.3 times of clinical day for human beings dosing, presses the volume gastric infusion of 1ml/100g body weight.The high, medium and low dosage of mouse is respectively 5.2mg/kg2.6mg/kg, 1.3mg/kg, is equivalent to 37.6,18.3,9.2 times of 70kg day for human beings dosing, presses the volume gastric infusion of 0.2ml/10g body weight.Nimodipine tablet dose of clinical Coming-of-Age Day is 120.0mg.Press the conversion of body surface area ratio, the rat dose,equivalent is 10.8mg/kg, and the mouse dose,equivalent is 15.6mg/kg.Sham-operated control group and model control group are all by irritating stomach with upper volume to distilled water.
Animal subject:
The Wister rat, male and female are regardless of, body weight 140-190g, available from Shandong University's Experimental Animal Center, No. 20030004, conformity certification SCXK (Shandong).
Kunming mouse, male and female are regardless of, body weight 18-22g, available from Shandong University's Experimental Animal Center, No. 20030004, conformity certification SCXK (Shandong).
Test apparatus: Sai Duolisi company limited produces ten thousand grades of electronic balances.
Test method and result
1.4-the methyl exaltone is to the provide protection of focal cerebral ischemia in rats:
90 of extracting male Wistar rats are divided into six groups at random by body weight: Sham-operated control group, model control group, 4-methyl exaltone high and low dose group, nimodipine group.Rat medicine high and low dose is respectively 4-methyl exaltone 3.6mg/kg, 0.9mg/kg, and positive controls is given the nimodipine tablet of 10.8mg/kg, all by 1ml/100g volume gastric infusion, once a day, successive administration 8 days.Fasting in the 5th day of administration be can't help water 12 hours, all rats by intraperitoneal injection Chloral Hydrate 10ml/kg implement anesthesia, it is fixing to face upward the position, neck median incision, expose right carotid and external carotid artery and internal carotid artery, branch's occipital artery of ligation external carotid artery, superior thyroid artery and external carotid artery end eventually prop up, and separate the outer branch of the cranium pterygoid process arteria palatina of internal carotid artery, with silk thread ligation right carotid.The rat of ischemia model control group, medicine high and low dose group, nimodipine group all inserts fishing line (0.3mm) from external carotid artery, behind the careful importing internal carotid artery, fishing line continues to insert its intracranial segment, when feeling obvious resistance is arranged, the long approximately 19mm of fishing line that inserts, operation is local to cover with the warm saline gauze.The rat of Sham-operated control group does not insert fishing line, and all the other operations are identical.Fishing line inserted postoperative 1 hour, and carefully extract fishing line out and irritate again, after the sham-operation exclusion 1 hour, layer-by-layer suture local organization, muscle, subcutaneous fascia and skin, 3 medicines are continued to give in operation back 24-72 hour again.Carry out the neuroethology scoring in 24,48,72 hours respectively at irritating again, carry out following inspection after 72 hours.
1.1 the neuroethology of animal scoring:
After operation end animal is clear-headed fully, carry out the 1st study of behaviour scoring immediately, perform the operation and mark again 1 time after 24,48,72 hours,, see Table 1, carry out the neuroethology evaluation respectively according to the standards of grading of bibliographical information.
| Table 1. neuroethology standards of grading | ||
| Rank | Score value | The neuroethology performance |
| The I level | 0 minute | Behavior is normal fully |
| The II level | 1 minute | The left side fore paw can not launch fully |
| The III level | 2 minutes | Draw circle to the left side when moving ahead |
| The IV level | 3 minutes | Topple over to the left |
| The V level | 4 minutes | Can not normally walk |
Ranked data result carries out Raddit and analyzes, and sees horizontal table 2.
The study of behaviour integral result is organized a t check and is handled, and sees horizontal table 3.
Table 2 is the result show: at once neuroethology classification and Sham-operated control group relatively had utmost point significant difference after focal cerebral ischemia model control group rat was clear-headed fully, illustrated that modeling successfully.4-methyl exaltone high and low dose to focal cerebral ischemic model rat clear-headed fully after at once neuroethology classification and modeling control group significant difference is more all arranged.Nimodipine tablet to focal cerebral ischemic model rat clear-headed fully after at once the influence of neuroethology fractionated and modeling control group there was no significant difference relatively.
Neuroethology classification and Sham-operated control group that model control group is performed the operation back 24 hours to focal cerebral ischemic model rat relatively have utmost point significant difference, further specify the modeling success.Neuroethology classification and modeling control group that 4-methyl exaltone high and low dose is performed the operation back 24 hours to focal cerebral ischemic model rat more all have significant differences.Neuroethology classification and modeling control group that nimodipine tablet is performed the operation back 24 hours to focal cerebral ischemic model rat relatively have significant difference.
Model control group relatively has utmost point significant difference to focal cerebral ischemic model rat operation back 48 and 72 hours neuroethology classification and Sham-operated control group, and the modeling success is described.Neuroethology integration and modeling control group that 4-methyl exaltone high and low dose is performed the operation back 48 hours to focal cerebral ischemic model rat have significant differences and significant difference more respectively.Neuroethology integration and modeling control group that nimodipine tablet is performed the operation back 48 hours to focal cerebral ischemic model rat relatively have significant difference.
Table 3 is the result show: at once neuroethology integration and Sham-operated control group relatively had utmost point significant difference after focal cerebral ischemia model control group rat was clear-headed fully, illustrated that modeling successfully.4-methyl exaltone high and low dose to focal cerebral ischemic model rat clear-headed fully after at once neuroethology integration and modeling control group significant difference is more all arranged.Nimodipine tablet to focal cerebral ischemic model rat clear-headed fully after at once the influence and modeling control group comparison there was no significant difference of neuroethology integration.
Neuroethology integration and Sham-operated control group that model control group is performed the operation back 24 hours to focal cerebral ischemic model rat relatively have utmost point significant difference, further specify the modeling success.Neuroethology integration and modeling control group that 4-methyl exaltone high and low dose is performed the operation back 24 hours to focal cerebral ischemic model rat more all have significant differences.Neuroethology integration and modeling control group that nimodipine tablet is performed the operation back 24 hours to focal cerebral ischemic model rat relatively have significant difference.
Model control group relatively has utmost point significant difference to focal cerebral ischemic model rat operation back 48 and 72 hours neuroethology integration and Sham-operated control group, and the modeling success is described.Neuroethology integration and modeling control group that 4-methyl exaltone high and low dose is performed the operation back 48 hours to focal cerebral ischemic model rat have significant differences and significant difference more respectively.Neuroethology integration and modeling control group that nimodipine tablet is performed the operation back 48 hours to focal cerebral ischemic model rat relatively have significant difference.
Table 4 is the result show: focal cerebral ischemia model control group rat whole brain tissue weight, right brain weight all increase its weight because of brain cell sex change, oedema and stroma inflammatory reaction take place after modeling, with Sham-operated control group utmost point significant difference is arranged more all, the modeling success is described.
4-methyl exaltone high and low dose has significant differences and significant difference more respectively to influence and the modeling control group that focal cerebral ischemic model rat whole brain tissue weight increases.4-methyl exaltone high and low dose has significant differences and significant difference more respectively to influence and the modeling control group that the right brain weight of focal cerebral ischemic model rat increases.
Nimodipine tablet relatively has significant differences to influence and the modeling control group that focal cerebral ischemic model rat whole brain tissue weight increases, and nimodipine tablet relatively has significant differences to the influence and the modeling control group of the right brain weight increase of focal cerebral ischemic model rat.
After being prompted to rat oral gavage 4-methyl exaltone, can alleviate the effect of cerebral ischemic model oedema, cerebral ischemic model is had significant protective effect.
Table 5 is the result show: focal cerebral ischemia model control group rat whole brain/body ratio obviously increases, and with Sham-operated control group significant difference is arranged relatively; The right brain of focal cerebral ischemia model control group rat/body ratio obviously increases, and with Sham-operated control group utmost point significant difference is arranged relatively, and These parameters all illustrates the modeling success.
4-methyl exaltone high and low dose compares there was no significant difference to influence and the modeling control group that focal cerebral ischemic model rat whole brain/body ratio increases, and only presents certain effect trend.4-methyl exaltone high dosage relatively has significant difference to focal cerebral ischemic model rat influence and modeling control group that right brain/body ratio increases, 4-methyl exaltone low dosage compares there was no significant difference to influence that right brain/body ratio increases of focal cerebral ischemic model rat and modeling control group, also only presents certain effect trend.
Nimodipine tablet compares there was no significant difference to the influence and the modeling control group of focal cerebral ischemic model rat whole brain/body ratio and right brain/body ratio increase, only presents certain effect trend.
After being prompted to rat oral gavage 4-methyl exaltone, can alleviate the effect of cerebral ischemic model oedema, cerebral ischemic model is had significant protective effect.
Table 2.4-methyl exaltone is analyzed the neuroethology classification and the Ridit of cerebral ischemic model rat different time
| Group | Clear-headed study of behaviour classification at once | The study of behaviour classification in back 24 hours of performing the operation | The study of behaviour classification in back 48 hours of performing the operation | The study of behaviour classification in back 72 hours of performing the operation | ||||||||||||||||||||
| The I level | The II level | The III level | The IV level | The V level | Ridit analyzes | The I level | The II level | The III level | The IV level | The V level | Ridit analyzes | The I level | The II level | The III level | The IV level | The V level | Ridit analyzes | The I level | The II level | The III level | The IV level | The V level | Ridit analyzes | |
| Sham-operated control group | 8 | 2 | 0 | 0 | 0 | 8 | 2 | 0 | 0 | 0 | 8 | 2 | 0 | 0 | 0 | 8 | 2 | 0 | 0 | 0 | ||||
| Model control group | 0 | 1 | 2 | 4 | 5 | ### | 0 | 1 | 0 | 7 | 3 | ### | 0 | 2 | 1 | 4 | 5 | ### | 0 | 1 | 2 | 5 | 3 | ### |
| 4-methyl exaltone high dose group | 0 | 1 | 4 | 5 | 0 | ###* | 0 | 3 | 5 | 2 | 0 | ###* * | 0 | 4 | 4 | 2 | 0 | ### * * | 0 | 4 | 6 | 0 | 0 | ##** |
| 4-methyl exaltone low dose group | 0 | 1 | 4 | 4 | 1 | ###* | 0 | 2 | 3 | 5 | 0 | ###* * | 0 | 2 | 4 | 3 | 1 | ### * | 0 | 2 | 6 | 2 | 0 | ###* |
| The nimodipine group | 0 | 0 | 6 | 3 | 4 | ### | 0 | 3 | 4 | 3 | 0 | ###* | 0 | 1 | 4 | 5 | 0 | ### * | 0 | 4 | 4 | 2 | 0 | ###* |
Annotate: with Sham-operated control group than #P＜0.05, ##P＜0.01, ###P＜0.001; With the model control group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001;
The influence that mark to the cerebral ischemic model rat behavior of table 3.4-methyl exaltone (
, n=10)
| Group | The clear-headed scoring of study of behaviour at once | The 24 hours study of behaviour of performing the operation are marked | The 48 hours study of behaviour of performing the operation are marked | The 72 hours study of behaviour of performing the operation are marked |
| Sham-operated control group model control group medicine high dose group medicine low dose group nimodipine tablet group | 0.22±0.44 3.43±0.98### 2.29±0.76###* 2.38±0.92###* 2.67±0.82### | 0.22±0.44 3.43±0.79### 2.00±0.82###** 2.13±0.83###** 2.33±0.82###* | 0.22±0.44 3.57±1.13### 1.86±0.90### **2.38±1.06### *2.33±0.82### * | 0.22±0.44 3.00±1.00### 1.57±0.53###** 2.13±0.64###* 2.00±0.89###* |
Annotate: with Sham-operated control group than #P＜0.05, ##P＜0.01, ###P＜0.001 is with the model control group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001;
Table 4:4-methyl exaltone to the influence of focal cerebral ischemic model rat cerebral tissue weight (
, n=10)
| Group | Dosage (mg/kg) | Body weight (g) | Full brain heavy (g) | Left side brain heavy (g) | Right brain heavy (g) |
| Sham-operated control group model control group medicine high dose group medicine low dose group nimodipine tablet group | - - 3.6 0.9 10.8 | 186.1±20.2 177.9±16.7 169.9±21.2 169.8±22.6 171.3±12.9 | 1.197±0.078 1.377±0.097### 1.246±0.080** 1.287±0.089# *1.259±0.064** | 0.608±0.032 0.611±0.029 0.614±0.034 0.599±0.027 0.603±0.024 | 0.584±0.105 0.788±0.111### 0.619±0.094** 0.678±0.084# * 0.649±0.062** |
Annotate: with Sham-operated control group than #P＜0.05, ##P＜0.01, ###P＜0.001.With the model control group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Table 5:4-methyl exaltone to the influence of focal cerebral ischemic model rat brain/body ratio (
, n=10)
| Group | Dosage (mg/kg) | Full brain/body ratio (g/100g) | Left side brain/body ratio (g/100g) | Right brain/body ratio (g/100g) |
| Sham-operated control group model control group medicine high dose group medicine low dose group nimodipine tablet group | - - 3.6 0.9 10.8 | 0.6484±0.0727 0.7791±0.1090### 0.7425±0.0627# 0.7654±0.1419## 0.7391±0.0789## | 0.3267±0.0411 0.3422±0.0473 0.3645±0.0348 0.3636±0.0617 0.3538±0.0351 | 0.3124±0.0627 0.4402±0.0980### 0.3285±0.0541* 0.4119±0.0908## 0.3812±0.0607# |
Annotate: with Sham-operated control group than #P＜0.05, ##P＜0.01, ###P＜0.001 is with the model control group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001;
1.2. brain weight:
After the off-test, after each experimental group rat opens cranium, careful separation brain, row vertically cut, be divided into left and right brain, with the full brain weight of the smart sweet weighing of electronic balance, left brain weight, right brain weight, calculate full brain body ratio (mg/100g) and the left and right brain body ratio (mg/100g) of each rat, the result organizes a t check and handles, and sees horizontal table 4 and table 5.
1.3. influence to the clotting time
When respectively organizing rat and making the fishing line embolism, measure its clotting time above-mentioned; After irritating 72 hours again, in its clotting time of repetition measurement, all data are organized a t check and are handled, and see Table 6 then.
Table 6.4-methyl exaltone to the influence in focal rats with cerebral ischemia clotting time (
, n=10)
| Group | Dosage (mg/kg) | Clotting time (second) before the embolism | The multiple filling back clotting time (second) |
| Sham-operated control group model control group medicine high dose group medicine low dose group nimodipine tablet group | - - 3.6 0.9 10.8 | 171.40±16.55 168.70±30.71 174.30±18.68 168.00±28.15 167.90±26.89 | 199.80±36.07 147.60±66.20# 202.10±36.50* 193.00±18.88 188.90±44.28 |
Annotate: compare #P＜0.05, ##P＜0.01, ###P＜0.001 with Sham-operated control group;
Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model water control group
Table 6 is the result show: 4-methyl exaltone to embolism before the clotting time influence of rat not obvious, with Sham-operated control group and model control group there was no significant difference relatively.The focal cerebral ischemia in rats model control group rat clotting time obviously shortens due to the fishing line method, with Sham-operated control group significant difference is arranged relatively; 4-methyl exaltone high dosage has significant prolongation effect to the clotting time of the focal cerebral ischemia in rats model that the fishing line method causes, and with model control group significant difference is arranged relatively.4-methyl exaltone low dosage and nimodipine tablet are not obvious to the cruor time extending effect of the focal cerebral ischemia in rats model that the fishing line method causes, and compare there was no significant difference with model control group, only present certain effect trend.
1.4.TTC dyeing and general pathology are observed:
Behind the cerebral ischemia re-pouring, the sacrificed by decapitation animal, get right half brain with brain take out weigh after, do totally 6 of the thick crown sections of 2mm backward in the past, put into the physiological saline of 2%TTC, 37 ℃ of lucifuges are hatched 30min, the TTC stained preparation is observed the infraction situation.
Change substantially: TTC coloration result display model control rats right side cortex of cerebral hemispheres, the large stretch of necrosis region of Basal ganglia.4-methyl exaltone high and low dose group necrosis region has minimizing to some extent.
2.4-the methyl exaltone is to the provide protection of mouse global brain ischemia
Get 94 of Kunming mouses, body weight 18-22g is divided into 6 groups at random after weighing, Sham-operated control group, model control group, the high, medium and low dosage group of 4-methyl exaltone, nimodipine tablet group, irritate stomach, successive administration 5 days, 10% Chloral Hydrate intraperitoneal injection of anesthesia by aforementioned dosage, mouse lies on the back fixing, separate bilateral common carotid arteries, threading is standby, walks and the sympathetic nerve underpass bilateral carotid, external carotid artery, tracheae, fan, behind neck, it is standby to beat slip-knot around one week of neck.Cause global brain ischemia 30min, remove ligation then and recover perfusion 60min.Sham-operated control group mouse bilateral common carotid arteries, not ligation of threading; Separate neck blood vessel, nerve and tracheae, beat slip-knot at its underpass around one week of neck, but 90min is observed in not ligation pressurization.
Observe the performance of respectively organizing mouse, after the execution, cut open and get brain, weigh, calculate full brain/body weight ratio, the part sample is done TTC dyeing and is observed.
The t check was handled between all data were carried out carefully, saw Table 7.
Table 7.4-methyl exaltone to the influence of global brain ischemia mouse brain weight and brain/body ratio (
, n=10)
| Group | Dosage (mg/kg) | Body weight behind the medicine (g) | Full brain weight (g) | Full brain/body weight ratio (mg/g) |
| Dosage group medicine low dose group nimodipine tablet group in the Sham-operated control group model control group medicine high dose group medicine | - - 5.2 2.6 1.3 15.6 | 23.25±2.66 23.33±1.13 23.85±1.48 22.73±0.91 22.65±1.24 22.86±1.28 | 0.272±0.018 0.313±0.020### 0.281±0.025** 0.291±0.020# * 0.292±0.016# * 0.287±0.021* | 11.77±1.03 13.44±1.28## 11.83±1.23* 12.83±1.11# 12.89±0.32##@$ 12.53±0.37# * |
Annotate: compare #P＜0.05, ##P＜0.01, ###P＜0.001 with Sham-operated control group; Compare ， @P＜0.05 with high dose group,
Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model water control group; Compare ， $P＜0.05 with nimodipine tablet.
Table 7 is the result show: brain cell sex change, oedema and stroma inflammatory reaction take place and its weight are increased in global brain ischemia model control group mouse whole brain tissue weight after modeling, with Sham-operated control group utmost point significant difference is arranged more all; The full brain of global brain ischemia model control group mouse/body ratio obviously increases, and with Sham-operated control group utmost point significant difference is arranged relatively, and These parameters all illustrates the modeling success.
The high, medium and low dosage of 4-methyl exaltone has significant differences, significant differences and significant difference more respectively to influence and the modeling control group that global brain ischemia model mice whole brain tissue weight increases.4-methyl exaltone high dosage relatively has significant difference to influence and the modeling control group that the full brain of global brain ischemia model mice/body ratio increases; In the 4-methyl exaltone, low dosage is to influence and modeling control group there was no significant difference that the full brain of global brain ischemia model mice/body ratio increases, only presents certain effect trend.4-methyl exaltone high dosage relatively has significant difference to influence and the 4-methyl exaltone low dosage that the full brain of global brain ischemia model mice/body ratio increases, and presents certain dose-dependence.4-methyl exaltone high dosage compares there was no significant difference to influence and the nimodipine tablet that the full brain of global brain ischemia model mice/body ratio increases, and suggesting effect intensity is suitable.4-methyl exaltone low dosage relatively has significant difference to influence and the nimodipine tablet that the full brain of global brain ischemia model mice/body ratio increases, and illustrates that its action intensity is not as good as nimodipine tablet.
Nimodipine tablet relatively has significant difference to influence and the modeling control group that global brain ischemia model mice whole brain tissue weight increases.Nimodipine tablet relatively has significant difference to influence and the modeling control group that the full brain of global brain ischemia model mice/body ratio increases.
After being prompted to mouse stomach 4-methyl exaltone, can alleviating the total A ligation method of bilateral neck and cause the effect of global brain ischemia model oedema, the global brain ischemia model is had significant protective effect.
The TTC observation of dyeing:
To infarct area TTC chromoscopy, the high, medium and low dosage group of 4-methyl exaltone all can be improved the ischemic and the anoxia-induced apoptosis degree of mouse whole brain tissue.
Conclusion (of pressure testing) and discussion
1,4-methyl exaltone focal cerebral ischemia in rats model neuroethology that the fishing line method is caused, whole brain tissue's weight, right side brain weight, full brain/body ratio, right brain/body ratio all have improvement effect in various degree, to infarct area TTC chromoscopy, 4-methyl exaltone high and low dose group all can be improved the ischemic and the anoxia-induced apoptosis degree of rat cerebral tissue, the high dose group action intensity is suitable with the nimodipine group, but not as good as sham operated rats.After being prompted to rat oral gavage 4-methyl exaltone, can alleviate the effect of focal cerebral ischemia model oedema, focal cerebral ischemic model is had significant protective effect.
2,4-methyl exaltone is not obvious to rat clotting time influence, but there is significant prolongation effect in the clotting time of the focal cerebral ischemia in rats model that 4-methyl exaltone high dosage causes the fishing line method.
3,4-methyl exaltone mouse global brain ischemia model whole brain tissue weight that the total A ligation method of bilateral neck is caused, full brain/body ratio all have improvement effect in various degree, to infarct area TTC chromoscopy, the high, medium and low dosage group of 4-methyl exaltone all can be improved the ischemic and the anoxia-induced apoptosis degree of mouse whole brain tissue, the high dose group action intensity is suitable with the nimodipine group, but not as good as sham operated rats.After being prompted to mouse stomach 4-methyl exaltone, can alleviate the effect of global brain ischemia model oedema, the total A ligation method of bilateral neck global brain ischemia model is had significant protective effect.
Claims (6)
1,4-methyl exaltone is characterized in that structural formula is as follows:
2,4-methyl exaltone according to claim 1 is characterized in that the preparation method is as follows:
(1) electrolysis
Raw material: dodecanedioic acid mono-methyl β-first class monomethyl glutarate is weighed and is mixed the back and add in the electrolyzer that sodium methylate is a medium and carry out the kolbe electrolysis, work in-process 1 mixture; Liquid material after electrolytic reaction is finished is transferred in the cooling jar lowers the temperature; Treat to carry out centrifugation after temperature drops in the scope of processing requirement, liquid material extracts in extractor with sherwood oil, distilled water, alkali lye and salt solution; The oil reservoir liquid that contains work in-process 1 after the extraction through concentrating, work in-process 1 after the fractionation.
(2) cyclization
Dimethylbenzene, sodium Metal 99.5, work in-process 1 adds the cyclization jar, drips methyl alcohol, sulfuric acid then and carry out that the stoll alcohol ketone contracts and cyclisation gets work in-process 2 mixtures, logical nitrogen protection in the cyclization process through the metering back.After cyclization is finished liquid is transferred in the extractor and extracts with dimethylbenzene, distilled water, alkali lye and salt solution; After containing the oil reservoir liquid dried of work in-process 2 after the extraction, through the work in-process 2 of distillation, rectifying.
(3) reduction
Ethanol, zinc powder, work in-process 2 processes are measured the back and are added the reduction jar, and dripping hydrochloric acid is reduced, and gets the mixture of synthetic musk ketone and isomers thereof, and the liquid material after the reduction reaction is transferred in the extractor and extracts with sherwood oil alkali lye and saturated aqueous common salt; Drying is carried out to oil reservoir liquid in extraction back, then through the work in-process 3 of distillation, rectifying.
(4) column chromatography
In chromatography column, add activated silica gel and ether, sherwood oil, utilize the difference of silica gel to muskone and isomers 4-methyl exaltone adsorptive power thereof, muskone is separated with 4-methyl exaltone, after concentrated, distillation, rectifying, obtain pure product 4-methyl exaltone again.
3,4-methyl exaltone is used for the application as the medicine of preparation treatment cerebral ischemia cerebro-vascular diseases.
4,4-methyl exaltone is used for the application as the medicine of preparation treatment rheumatism, rheumatism.
5,4-methyl exaltone is used for the application as preparation treatment anti-tumor drug.
6,4-methyl exaltone is used for treating and improving as preparation the application of the medicine of dementia.
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