CN101723944A - Compound formed from ferulic acid and matrine compound and purpose thereof - Google Patents
Compound formed from ferulic acid and matrine compound and purpose thereof Download PDFInfo
- Publication number
- CN101723944A CN101723944A CN200810304902A CN200810304902A CN101723944A CN 101723944 A CN101723944 A CN 101723944A CN 200810304902 A CN200810304902 A CN 200810304902A CN 200810304902 A CN200810304902 A CN 200810304902A CN 101723944 A CN101723944 A CN 101723944A
- Authority
- CN
- China
- Prior art keywords
- matrine
- compound
- forulic acid
- ketone
- amides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a salt, ketone, ether, amide or ester compound formed from ferulic acid and a matrine compound. The newly formed compound enhances the biological actions of the matrine compound and/or the ferulic acid, and/ or reduces the toxicity thereof, and/or enhances the dissolubility of a medicament. The compound is used for resisting tumors and arteriosclerosis and treating cardiovascular and cerebrovascular diseases, osteoarthropathy, colds, senile dementia, scytitis, eczema, acne, maculopapule, urticaria, psoriasis, gastrointestinal dynamic deficiency, organ inflammations including hepatitis, nephritis and the like, organ fibrosis and acute and chronic inflammations of a whole body and/or organs.
Description
Technical field
The present invention relates to the formed salt of forulic acid and matrine compound, ketone, ethers, amides or ester compound.The compound of its new formation has the biological action that increases matrine compound and/or forulic acid, and/or reduces its toxicity, and/or increases the solvability of medicine.
The research background
The chemical name of forulic acid is 4-hydroxyl-3-methoxy cinnamic acid, is the ubiquitous a kind of phenolic acid of vegitabilia, is one of Effective Components of Chinese Herb such as Radix Angelicae Sinensis, Ligusticum wallichii, asafoetide, extensively exists in the various plants.Can be by extracting or the acquisition of synthetic method.It has pharmacological action widely, and for example anti-inflammatory, antibiotic, anti-oxidant, enhancing immunity, antitumor, anti-cardiovascular disease, anti-fibrosis, anti-senile dementia etc. all have report.Kuh-seng is one of Chinese medicine of using always.It contains multiple alkaloid, based on matrine (matrine), Oxymatyine (oxyma-trine), next has sophocarpine (1-sophocarpine), sophorine (sophoridine), N-Sophocarpidin (N-oxysophocarpine) and Iosmatrine etc.The medicine of its exploitation has kurarinone, matrine, sophocarpine etc. to be mainly used in the treatment of the treatment of chronic hepatopathy, antiviral, antineoplastic treatment and cardiovascular diseases clinically.Have antiviral, anti-hepatic fibrosis, immunoregulation effect and anti-inflammatory, anti-allergy action etc.We discover, the formed salt of forulic acid and matrine compound, ketone, ethers, amides and ester compound can obviously increase the effect of matrine compound and/or forulic acid, and/or the two has the obvious synergistic effect in vivo.And/or the toxicity of matrine compound, and/or increase the water-soluble and fat-soluble of the two.
Summary of the invention
The present invention relates to the formed compound of forulic acid and matrine compound.
Forulic acid involved in the present invention comprises forulic acid and its isomer.Matrine compound involved in the present invention mainly comprises isomer sophorine, Iosmatrine of matrine, Oxymatyine (kurarinone), sophocarpine, Sophocarpidin, sophoranol, supanine and matrine etc.Its constitutional features is to have tetracyclic quinolizine pyridine, as scheming:
Forulic acid involved in the present invention and matrine compound connecting method can be salt compounds, also can be amides, ketone, ethers or ester compound.React on its forulic acid can phenolic hydroxyl group and/or carboxyl (See Figure R1, R2).Its phenolic hydroxyl group and carboxyl be with after matrine alkaloid is connected, and all the other groups can be by group generation electrophilic substitution reaction or addition reactions (See Figure R3-6) such as pharmacy acceptable salt or hydrogen, hydroxyl, carboxyl, carbonyls.
The esterification that matrine alkaloid took place that the present invention relates to, amidation, salify, one-tenth ether, become reactive ketone can occur on the tetracyclic quinolizine pyridine ring on arbitrary carbon atom.
Salt, amides, ketone, ethers or ester compound that forulic acid can react and form with a kind of matrine alkaloid, also salt, amides, ketone, ethers or the ester compound that can react and form with matrine alkaloid more than 2 kinds or 2 kinds, all the other groups can be by group generation electrophilic substitution reaction or addition reactions such as pharmacy acceptable salt or hydrogen, hydroxyl, carboxyl, carbonyls.
The formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound had not only increased the biological effect of forulic acid but also can increase the biological effect of matrine compound.The effect of for example anti-internal organs fibrosis improves hemorheology, antivirus action, anti-inflammatory action suppresses the effect of Pseudocholinesterase, pain relieving and itching-relieving action, anti thrombotic action, antiplatelet aggregative activity, anti-microbial effect, antitumor action, antioxygenation, reducing blood lipid, arteriosclerosis, rheumatism, increase immunity increase motility of sperm and motion, antihypertensive function etc.
Forulic acid involved in the present invention and matrine compound form the pharmacological action that compound can obviously strengthen forulic acid and matrine compound.Comprise effect to heart and blood vessel, to the effect of central nervous system, the effect of treatment hepatitis, treatment internal organs Fibrotic effect improves hemorheological effect, and anti-inflammatory analgetic and itching-relieving action improve the effect of immunity, antibiotic and antivirus action etc.
The toxic action that salt that forulic acid involved in the present invention and matrine form and ester compound can obviously alleviate forulic acid and/or matrine compound.
The formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound can obviously increase the water-soluble and fat-soluble of forulic acid and matrine alkaloid.
The formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound can adopt the method for pharmaceutics to make oral preparations, injection and the mucocutaneous preparation of using, and its anti-internal organs fibrosis, the hemorheology of improving, antiviral, anti-inflammatory, inhibition Pseudocholinesterase, pain relieving and antipruritic, antithrombotic, platelet aggregation-against, antibiotic, antitumor, anti-oxidant, reducing blood-fat, arteriosclerosis, rheumatism, increase immunity, increase motility of sperm and motion, antihypertensive function etc.It is low to be used for antitumor, arteriosclerosis, the treatment heart, cerebro-vascular diseases, bone and joint diseases, flu, senile dementia, the inflammation of skin, eczema, acne, maculopapule, urticaria, psoriasis, gastrointestinal tract dynamia, the acute and chronic inflammation that the inflammation of internal organs such as hepatitis, ephritis and internal organs fibrosis and whole body and/or internal organs take place.
Specific embodiment:
Embodiment one forulic acid kurarinone compound freeze-dried powder preparation
With a little dissolve with ethanol of forulic acid, add the equimolar kurarinone aqueous solution, make freeze-dried powder according to ordinary method.
Synthesizing of embodiment two forulic acid sophocarpine acid amides
Forulic acid and kurarinone are added in the reactor, add catalyst reaction after, silica gel column chromatography separate compound.
Synthesizing of embodiment three forulic acid matrine esters
Accurately take by weighing a certain amount of forulic acid and place Erlenmeyer flask, add a certain amount of matrine, add catalyst solution, seal, place the constant temperature shaking bath, 80 ℃, reacted 10 hours, after having reacted, silica gel column chromatography separate compound.
The substituted radical of 20 kinds of derivatives of institute's synthetic sees the following form.
Substituting group common on table 1.R1 and the R2 position is represented
| The compound code name | ??R1 | ??R2 |
| ??I | ??H | Kurarinone |
| ??II | Methyl | Matrine |
| ??III | Ethyl | Sophocarpine |
| ??IV | Glycosyl | Sophoranol |
| ??V | Matrine | Sophocarpine |
| ??VI | Kurarinone | Methyl |
| ??VII | Matrine | Magnesium |
| ??VIII | Sophocarpine | Phenyl |
| ??IX | Supanine | Glycosyl |
| ??X | Sophoranol | Methyl |
| The compound code name | ??R1 | ??R2 |
| ??X?I | Sophorine | ??H |
| ??X?II | Sophocarpidin | Glycosyl |
| ??X?III | Iosmatrine | Ethyl |
| ??X?IV | Sodium | Supanine |
| ??X?V | Potassium | Sophoranol |
| ??X?VI | Zinc | Sophorine |
| ??X?VII | Selenium | Sophocarpidin |
| ??X?VIII | Iron | Iosmatrine |
| ??X?IX | Kurarinone | Calcium |
| ??X?X | Carbonyl | Matrine |
Table 2.R4, R5, R6, the substituting group representative that the R7 group is common
| ??H |
| Methyl |
| Ethyl |
| Glycosyl |
| Phenyl |
| Kurarinone |
| Matrine |
| Sophocarpine |
| Supanine |
| Sophoranol |
| ??H |
| Sophorine |
| Sophocarpidin |
| Iosmatrine |
| Sodium |
| Potassium |
| Zinc |
| Selenium |
| Iron |
| Carboxyl |
| Carbonyl |
| Calcium, amino, iodine, magnesium etc. |
The comparison of the anti-inflammatory action of embodiment three several compound anti-inflammatory actions and kurarinone and forulic acid
Choose healthy mice, 10 every group.Gastric infusion 20mg/kg, for three days on end, behind the last administration 30min, abdominal injection 0.6% acetic acid 10ml/kg, the writhing response number of times appears in mouse in the record 15min.Calculate medicine analgesia percentage.
Medicine analgesia percentage (%)=(control group is turned round body number of times treatment group and turned round the body number of times)/control group is turned round body number of times * 100%
Table 3. compound compares the analgesic activity of mouse acetic acid twisting
| Group | ??N | Analgesia percentage (%) |
| The blank group | ??10 | ??-- |
| Kurarinone | ??10 | ??29.98 |
| Forulic acid | ??10 | ??18.30 |
| ??I | ??10 | ??48.86 |
| ??II | ??10 | ??53.29 |
| Group | ??N | Analgesia percentage (%) |
| ??III | ??10 | ??42.42 |
| ??IV | ??10 | ??56.36 |
| ??V | ??10 | ??66.13 |
10 every group of mouse, weigh behind the mark, with the auris dextra of mouse with dimethylbenzene cotton balls contact 5sec, left ear in contrast, after causing scorching 10min, causing on the scorching auricular concha respectively, it is 1% to be subjected to the reagent thing that coating gives drug level, and the blank group is given physiological saline, behind the 30min mouse carotid dislocation is put to death, with diameter 6mm punch tool get an equivalance left side (own control), auris dextra (dimethylbenzene processing) is weighed, and calculates the ear swelling rate.Ear swelling rate (%)=auris dextra weight-left ear weight/left ear weight * 100%. the results are shown in Table 4.
Table 4. compound is to the effect of mice ear
| Group | Swelling rate (%) |
| The blank group | ??173.72 |
| Matrine | ??133.4 |
| Forulic acid | ??164.6 |
| ??I | ??74.9 |
| ??II | ??98.9 |
| ??III | ??136.4 |
| ??IV | ??111.2 |
| ??V | ??96.7 |
Embodiment four several compounds to liver hepatic stellate cell increment and secretor type I collagen protein effect
Material and reagent: rat type i collagen protein ELISA kit, trypsinase, foetal calf serum etc.
Method: (hepatic stellate cell HSC) is seeded in the 100mL plastic culture bottle after the recovery rat liver hepatic stellate cell, cultivates in the CO2 incubator of 5%CO2,95% humidity.After treating that cell grows up to individual layer in the culturing bottle, discard nutrient solution, add 0.25% tryptic Digestive system, collect Digestive system, the centrifugal 7min of 2200rPmin, abandon supernatant liquor, again once with the washing of DMEM medium centrifugal, 20% foetal calf serum DMEM nutrient solution suspends cell mass and counting with containing, with containing DMEM nutrient solution diluting cells suspension, be inoculated in 96 well culture plates, every hole 100 μ l, inhale behind the 48h and go nutrient solution, make cell synchronization stationary phase again with the DMEM nutrient solution synchronization cell that contains 10% calf serum.Experiment grouping (physiological saline), add medicine and make that respectively organizing nutrient solution Chinese traditional medicine concentration is respectively 50 μ mol/L, every group 6 hole repeats to cultivate 3 times, behind the effect 48h, stop cultivating, add 5mg/L tetrazolium bromide (MTT) 20 μ L in every hole respectively, cultivate 4h again, add the 10min that vibrates behind the DMSO, with microplate reader (wavelength 570nm)
Measure the HSC absorbancy.Get the cell behind the drug effect, after cultivating according to the method described above, draw supernatant liquor, measure the type i collagen protein content according to the test kit specification sheets.The results are shown in Table 5
Table 5 compound is to increment of rats'liver hepatic stellate cell and type i collagen protein content
| Group | Mean light absorbency | Type i collagen protein content (μ g/L) |
| The blank group | ??0.45±0.22 | ??73.55±13.28 |
| Matrine | ??0.39±0.17 | ??63.42±9.76 |
| Forulic acid | ??0.42±0.24 | ??64.36±11.22 |
| ??I | ??0.35±0.09 | ??34.57±8.29 |
| ??II | ??0.25±0.07 | ??46.92±11.56 |
| ??III | ??0.32±0.06 | ??36.48±10.07 |
| ??IV | ??0.28±0.13 | ??11.29±8.55 |
| ??V | ??0.22±0.19 | ??44.77±6.99 |
The comparison of the anticholinesterasic effect of embodiment five several compounds
Get blood 5ml from healthy rat, put into the test tube that is added with antithrombotics, with 10 times of physiological saline dilutions, stand-by.
Medicine diluted respectively with physiological saline be 0,5,10,20,40,80,160,320, the solution to be measured of 640mg/L.Get in the different solution to be measured of 0.05ml and to add in the whole blood that 0.5ml diluted, fully behind the mixing, put 37 ℃ of environment and incubate 1h in advance.Measure the activity of whole blood acetylcholinesterase then according to acetylcholinesterase test kit specification sheets.Calculation of half inhibitory concentration (IC
50).The result shows that Compound I-X has the effect that suppresses whole blood vagusstoff ester, and wherein the restraining effect of compound III is the strongest.
Several compounds of table 6 are to the IC of choline esterase inhibition
50
| The compound title | ??IC 50(mg/L) |
| Blank | |
| Kurarinone | ??735.5 |
| Matrine | ??-- |
| Forulic acid | ??-- |
| The compound title | ??IC 50(mg/L) |
| Prostigmin(e) | ??365.7 |
| ??I | ??223.4 |
| ??II | ??86.5 |
| ??III | ??58.8 |
| ??IV | ??433.9 |
| ??V | ??567.1 |
| ??VI | ??588.4 |
| ??VII | ??323.1 |
| ??VIII | ??211.6 |
| ??IX | ??121.8 |
| ??X | ??88.7 |
Embodiment six several compounds are to the comparison of mouse intestinal motive force effect
Medicine and reagent Matrine Injection, Shandong XinHua Pharmacy stock Co., Ltd produces (lot number: 0306003); Methyl-sulfuric acid prostigmin(e) injection liquid, sky, Shandong good fortune pharmaceutical factory produces (lot number: 0404131); Atropine sulfate injection, sky, Shandong good fortune pharmaceutical factory produces (lot number: 0409271); MS Contin, Beijing are sprouted base of a fruit pharmaceutical Co. Ltd and are produced (lot number: 04082312).
The healthy kunming mice of animal and feeding environment, the SPF level, male and female half and half, body weight 18-22g is provided by Shandong Green Leaf Pharmaceutical Co., Ltd experimentation on animals center.Conformity certification number: SYXK (Shandong) 20030020.10 placements of animal per cage.Feed is provided by Shandong Province's Experimental Animal Center.Barrier system is raised, and filters air-supply, room temp 18-22 ℃; Humidity 50-60%; Illumination 12 hours.
The experimental technique mouse stomach is given relative medicine or physiological saline, for three days on end, water 16h is can't help in fasting before the last administration, behind administration 30min, every mouse stomach gives 5% Insta-Char 0.2ml, mouse is put to death in dislocation behind the 20min, opens the abdominal cavity and separates mesentery, and the clip pylorus is to the intestinal tube of ileocecus, place on the pallet, gently small intestine is pulled into straight line, measure intestinal tube length as the small intestine total length, the distance in forward position, end is as charcoal end advance distance in intestines from pylorus to charcoal.Calculate charcoal end propelling rate with following formula.Charcoal end propelling rate (%)=charcoal end advance distance/small intestine total length * 100% in intestines
Several compounds of table 7 are to the influence of small intestine movement of mice charcoal end propelling rate
| Compound | Dosage (mg/kg) | ??N | Charcoal end propelling rate (%) |
| Blank | ??-- | ??10 | ??57.26±9.10 |
| Kurarinone | ??10 | ??10 | ??58.85±13.22 |
| Kurarinone | ??20 | ??10 | ??67.49±11.68* |
| Forulic acid | ??20 | ??10 | ??54.33±10.22 |
| Prostigmin(e) | ??4 | ??10 | ??68.55±4.80** |
| ??I | ??10 | ??10 | ??71.20±8.11** |
| ??II | ??10 | ??10 | ??78.54±12.42* |
| ??III | ??10 | ??10 | ??72.36±8.77** |
| ??IV | ??10 | ??10 | ??75.12±13.35* |
| ??V | ??10 | ??10 | ??79.01±6.88** |
| ??VI | ??10 | ??10 | ??68.52±10.55* |
| ??VII | ??10 | ??10 | ??65.34±11.32* |
| ??VIII | ??10 | ??10 | ??77.58±12.66** |
| ??IX | ??10 | ??10 | ??72.35±10.76** |
| ??X | ??10 | ??10 | ??78.31±11.47** |
Compare with control group: * P＜0.05; * P＜0.01.
The experimental data of embodiment seven several compound acute toxicities
Experimental technique: get mouse, 1 gastric infusion was observed 72 hours, and the record death condition the results are shown in Table 8.
Several compounds of table 8 are to the observation of mouse toxicity
| Compound | Dosage (mg/kg) | ??N | The dead animal number |
| Matrine | ??500 | ??10 | ??10 |
| Forulic acid | ??1000 | ??10 | ??0 |
| Sophocarpine | ??500 | ??10 | ??10 |
| Compound | Dosage (mg/kg) | ??N | The dead animal number |
| ??I | ??1000 | ??10 | ??0 |
| ??II | ??1000 | ??10 | ??0 |
| ??III | ??1000 | ??10 | ??0 |
| ??IV | ??1000 | ??10 | ??0 |
| ??V | ??1000 | ??10 | ??0 |
| ??VI | ??1000 | ??10 | ??0 |
| ??VII | ??1000 | ??10 | ??0 |
| ??VIII | ??1000 | ??10 | ??0 |
| ??IX | ??1000 | ??10 | ??0 |
| ??X | ??1000 | ??10 | ??0 |
The observation of embodiment eight, forulic acid kurarinone ether arteriosclerosis
Test method:
Medication preparation: after the forulic acid kurarinone become ether with 1: 1 molecule mol ratio, post separated and promptly gets A-, B-forulic acid kurarinone ether.Formula as follows:
Carry out [Liu Zhantao, Liu Sai, Wang Shoulan, Zhang Jian, Zhong Weizhen according to literature method.The comprehensive extract of seashells is to the therapeutic action of experimental atherosclerosis.2005 the 13rd the 3rd phases of volume of China's arteriosclerosis magazine; 305-308].
Get 140 of male quails, be divided into 7 groups at random, normal control group, model group, positive controls (sieve cut down its fourth 10mg/kg), the high, medium and low dosage group of oral control group of forulic acid (40mg/kg) and medicine (administration 10,20 respectively, 40mg/kg).Except that the normal control group is fed basal feed, set up high fat bait arteriosclerosis model according to literature method for all the other 5 groups.
Each medication group gastric infusion, once a day, 4 weeks of continuous use.Respectively at the 4th weekend after the medication, get 10 its serum lipid of zoometry for every group.Quail to survival when experiment finishes carries out the pathology detection.
The serum lipid assay: each organizes the 2nd, 4 weekend after medication, and fasting 12h is after jugular vein is got blood 2mL, and separation of serum adopts enzymatic assays serum cholesterol (TC), triglyceride level (TG) level.
The result: forulic acid kurarinone ether can obviously reduce arteriosclerosis model quail serum TC, TG level, and it acts on than the obvious enhancing of forulic acid (table 9).The most aortas of model group have tangible pathology, and most As pathologies are more than 2 grades, and forulic acid kurarinone ether group atherosclerosis of aorta lesion degree is lighter, how below 1～2 grade (table 10).Visible most arteries inner membrance is complete under the mirror, and part has slight lipid to soak into, and includes and is dispersed in foam cell.
Table 9. forulic acid kurarinone ether is to the influence of high blood lipid model quail blood fat
| Grouping | ??TC(mmol/L) | ??TG(mmol/L) |
| The normal control group | ??4.96±0.88 | ??0.87±0.21 |
| Model group | ??25.23±5.32 | ??5.66±1.21 |
| Sieve cuts down its fourth control group | ??10.19±2.07 | ??1.68±0.36 |
| The forulic acid control group | ??16.88±6.31 | ??3.52±0.73 |
| The test high dose group | ??11.43±4.38 | ??1.75±0.54 |
| Dosage group in the test | ??14.67±5.95 | ??2.87±0.45 |
| The test low dose group | ??15.86±6.67 | ??2.99±0.38 |
Table 10. forulic acid kurarinone ether is to the influence of high blood lipid model quail aorta artery sclerosis pathology
Embodiment nine, forulic acid matrine ketone emulsifiable paste are to the influence of acute rheumatic arthritis.
Medication preparation: after the forulic acid matrine become ketone with 1: 1 molecule mol ratio, post separated promptly.Make ointment according to practice of pharmacy.
30 couples of rheumatic arthritis patients, wherein 30 examples are control group, 30 examples are test group.The independent oral naproxen 200g of control group, forulic acid matrine ketone emulsifiable paste, every day 1 time, continuous use 5 days are smeared in treatment group affected part.
Observation of curative effect: swelling and pain disappear substantially, are produce effects; Mild swelling, pain disappear substantially for effectively; Swelling and pain all do not take a turn for the better, for invalid.
The result: test group produce effects 21 examples, effective 8 examples, total effective rate is 96.7%.Control group produce effects 12 examples, effective 11 examples, total effective rate is 76.7%.
Tens kinds of compounds of embodiment are to the therapeutic action of fash
Case is selected: the age is at 1825 years old, health bilateral fash, male or female, every kind of drug study 10 examples.Partial smearing 1% medicine is returned the ginseng emulsifiable paste on fash, the blind contrast of self list, and left limb is smeared medicine, and right side limbs physiological saline is smeared and was carried out evaluation of result in back 10 minutes.
Evaluation of result: the detumescence itching-relieving action is estimated.Produce effects: fash obviously disappears, and itching-relieving action is obvious.Effectively: certain itching-relieving action is arranged, and papule has disappearing to a certain degree.Invalid: as not see obvious effect.
The results are shown in following table.
Several compounds of table 11. are to the therapeutic action therapeutic evaluation of fash
| Produce effects | Effective routine number | Invalid | |
| Kurarinone | ??10 | ||
| Forulic acid | ??3 | ??7 | |
| ??I | ??10 | ||
| ??II | ??8 | ??2 | |
| ??III | ??10 | ||
| ??IV | ??10 | ||
| ??V | ??10 |
Embodiment 11, Compound I I, III, X are to the therapeutic action of rat senile dementia
1. medicine and reagent: kurarinone, matrine and sophocarpine are produced by Ningxia Boertaili Pharmaceutical Co., Ltd, and the selagine sheet is produced by Shanghai red flag pharmaceutical factory.The D-semi-lactosi is that reagent two factories in Shanghai produce, and ibotenic acid (IBO) is analytical pure available from Sigma company.Whole blood and cerebral tissue TChE (TchE) detection kit are built up bio-engineering research by Nanjing to be provided.
2. animal grouping, modeling and administration: 57 of 15 monthly age young old female Wistar rats, body weight 300～450g provides by Qingdao City medicine inspecting institute animal center.Conventional sub-cage rearing, natural illumination is arbitrarily drunk water and is got food.Be divided into 6 groups at random, normal control group (abbreviation normal group) wherein, Meynert nuclear injecting normal saline in 6 weeks of intraperitoneal injection of saline and the brain, AD model group (abbreviation model group), bilateral Meynert nuclear injection IBO in abdominal injection D_ semi-lactosi (48mg/kg/d) 6 week and the brain, selagine control group (abbreviation selagine group) and tried all same model group of thing observation group modeling.Intracerebral injection carries out [1] with reference to relevant document behind abdominal injection.After modeling finished, the selagine group was irritated stomach and is given selagine 50ug/kg, and Compound I I, III, X group are irritated stomach medicine 50mg/kg respectively.Normal group, model group give the physiological saline with volume.Successive administration 7 days, carries out learning capacity and detects after 1 hour in the last administration, rat is anaesthetized with Sodital then, aorta abdominalis blood sampling 5ml on the ice platform, the rapid taking-up of dissection pallium as the homogenate medium, is made the homogenate of 10% (W/V) brain cortical tissue with physiological saline.According to the mensuration of test kit explanation carrying out acetylcholine esterase active, the mensuration of the acetylcholine esterase active of whole blood is carried out [2] according to literature method.
3. detection index: animal memory behavior test: the passive avoidance step down test, rat is put reaction box endoadaptation environment 3min.Pass to the 50V alternating-current then.After rat is shocked by electricity.Fugue reaction is for jumping onto platform to hide noxious stimulation.Record be subjected in the 5min number of shocks (errors number) as school grade with the response learning ability.Directly rat is placed on the platform behind the 24h.Write down latent period of jumping off for the 1st time with errors number in reaction memory capability and the 5min, surpass 5min person latent period in 5min.
Relatively t check between data processing employing group, with p＜0.05 as the statistical significance index.
4. result: 3 kinds of compounds all can reduce whole blood and cerebral tissue Pseudocholinesterase level, improve learning and memory in rats achievement (table 12,13)
Table 12 Compound I I, III, X are to the influence of TChE level in rat whole blood and the cerebral tissue
| Group | ??N | Whole blood TchE (mmol/L) | Inhibiting rate | Cerebral tissue TchE (umol/g) | Inhibiting rate |
| Normal control | ??10 | ??76±28 | ??- | ??3.4±0.7 | ??- |
| The model contrast | ??10 | ??84±32 | ??- | ??3.8±0.9 | ??- |
| The selagine group | ??8 | ??48±35* | ??42.86％ | ??2.0±0.6* | ??41.18％ |
| ??II | ??10 | ??37±29* | ??55.95％ | ??1.4±0.7** | ??58.82％ |
| ??III | ??9 | ??26±35* | ??69.05％ | ??1.6±0.8** | ??52.94％ |
| ??X | ??10 | ??33±27* | ??60.71％ | ??1.8±0.9** | ??47.06％ |
Compare * p＜0.05 with model group; * p＜0.01
Table 13 Compound I I, III, X are to the influence of rat step down test learning and memory ability
| Group | Errors number in the 5min | Latent period (s) | Errors number in the 5min behind the 24h |
| Normal control | ??0.9±0.7 | ??237±86 | ??0.3±0.2 |
| The model contrast | ??16±7.6 | ??78±27 | ??9±4.2 |
| The huperzine A contrast | ??4±2.3* | ??135±55* | ??2±1.6* |
| ??II | ??5±1.9* | ??187±43* | ??4±2.1* |
| ??III | ??3±2.2* | ??222±78* | ??3±1.0* |
| Group | Errors number in the 5min | Latent period (s) | Errors number in the 5min behind the 24h |
| ??X | ??4±2.7* | ??112±41* | ??2±1.5* |
Compare * p＜0.05 with model group
Claims (10)
1. the present invention relates to forulic acid with the matrine compound chemistry esterification, amidation, salify takes place, becomes ether, becomes the formed salt of reactive ketone, amides, ketone, ethers or ester compound.
2. the present invention relates to forulic acid and matrine compound chemistry the formed ester compound of esterification takes place.
3. the present invention relates to forulic acid salify takes place, becomes the formed salt of amidate action, amides with the matrine compound chemistry.
4. the present invention relates to forulic acid becomes ether, becomes the formed ketone of reactive ketone, ether compound with the matrine compound chemistry.
5. according to claim 1-4, the forulic acid that the present invention relates to comprises positive forulic acid and isoferulic acid and their isomers and the inorganic salts compound of being formed.Constitutional features is seen relevant document [Zhang Juan etc.Synthetic and the pharmacological research progress of forulic acid and derivative thereof, grain and grease, 2007 the 1st phases, 43-45].Esterification, amidation, salify, one-tenth ether can take place on its forulic acid, become reactive ketone can be phenolic hydroxyl group and/or carboxyl (formula R1 as follows, R2).After the reaction of its phenolic hydroxyl group and/or carboxyl and matrine alkaloid, all the other groups can by chemical reactions such as group generation electrophilic substitution such as pharmacy acceptable salt or hydrogen, hydroxyl, carboxyl, carbonyl or addition (formula as follows, R3-6).For example R1 is with after matrine becomes ether, and all the other groups can chemical reaction take place with the isomer sophorine of methyl, ethyl, glycosyl, sodium, potassium, calcium, magnesium, phosphorus, iron, zinc, selenium, iodine, amino, carbonyl, carboxyl, phenyl, styroyl, phenmethyl and matrine, Oxymatyine (kurarinone), sophocarpine, Sophocarpidin, sophoranol, supanine and matrine, Iosmatrine etc.
6. according to claim 1-5, matrine compound involved in the present invention mainly comprises isomer sophorine, Iosmatrine of matrine, Oxymatyine (kurarinone), sophocarpine, Sophocarpidin, sophoranol, supanine and matrine etc. and their isomers or inorganic salts.Its basic structural feature is to have a tetracyclic quinolizine pyridine, as shown in the formula: the esterification that it took place, amidation, salify, one-tenth ether, become reactive ketone can occur on the tetracyclic quinolizine pyridine ring on arbitrary carbon atom.
The basic structure of matrine alkaloid
7. according to claim 1-6, salt, amides, ketone, ethers or ester compound that forulic acid can react and form with a kind of matrine alkaloid, also salt, amides, ketone, ethers or the ester compound that can react and form with matrine alkaloid more than 2 kinds or 2 kinds, all the other groups can be by group generation electrophilic substitution reaction or addition reactions such as pharmacy acceptable salt or hydrogen, hydroxyl, carboxyl, carbonyls.
8. according to claim 1-7, the formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound had not only increased the biological effect of forulic acid but also can increase the biological effect of matrine compound.The effect of for example anti-internal organs fibrosis improves hemorheology, antivirus action, anti-inflammatory action suppresses the effect of Pseudocholinesterase, pain relieving and itching-relieving action, anti thrombotic action, anti-microbial effect, antitumor action, antioxygenation, reducing blood lipid, arteriosclerosis, rheumatism, increase immunity, increase motility of sperm and motion, antihypertensive function etc.
9. the formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound can obviously increase the water-soluble and fat-soluble of forulic acid and matrine alkaloid.
10. the formed salt of forulic acid that the present invention relates to and matrine compound, amides, ketone, ethers or ester compound can adopt the method for pharmaceutics to make oral preparations, injection and the mucocutaneous preparation of using.Its anti-internal organs fibrosis, the hemorheology of improving, antiviral, anti-inflammatory, inhibition Pseudocholinesterase, pain relieving and antipruritic, antithrombotic, platelet aggregation-against, antibiotic, antitumor, anti-oxidant, reducing blood-fat, arteriosclerosis, rheumatism, increase immunity, increase motility of sperm and motion, antihypertensive function etc.It is low to be used for antitumor, arteriosclerosis, the treatment heart, cerebro-vascular diseases, bone and joint diseases, flu, senile dementia, the inflammation of skin, eczema, acne, maculopapule, urticaria, psoriasis, gastrointestinal tract dynamia, the acute and chronic inflammation that the inflammation of internal organs such as hepatitis, ephritis and internal organs fibrosis and whole body and/or internal organs take place.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810304902A CN101723944A (en) | 2008-10-13 | 2008-10-13 | Compound formed from ferulic acid and matrine compound and purpose thereof |
| PCT/CN2009/073837 WO2010028596A1 (en) | 2008-09-11 | 2009-09-09 | The pharmaceutical composition containing ferulic acid and matrine compounds, the preparation and the use thereof |
| JP2011520315A JP5538386B2 (en) | 2008-09-11 | 2009-09-09 | Drug composition containing ferulic acid and matrine compounds, and production method and use thereof |
| CA2734309A CA2734309C (en) | 2008-09-11 | 2009-09-09 | Preparation and usage of a pharmaceutical composition containing ferulic acid and matrine compounds |
| EP09812662A EP2343065A4 (en) | 2008-09-11 | 2009-09-09 | The pharmaceutical composition containing ferulic acid and matrine compounds, the preparation and the use thereof |
| US13/058,738 US8785471B2 (en) | 2008-09-11 | 2009-09-09 | Pharmaceutical composition containing ferulic acid and matrine compounds, the preparation and the use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810304902A CN101723944A (en) | 2008-10-13 | 2008-10-13 | Compound formed from ferulic acid and matrine compound and purpose thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101723944A true CN101723944A (en) | 2010-06-09 |
Family
ID=42445564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810304902A Pending CN101723944A (en) | 2008-09-11 | 2008-10-13 | Compound formed from ferulic acid and matrine compound and purpose thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101723944A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309156A (en) * | 2016-10-31 | 2017-01-11 | 成都远睿生物技术有限公司 | Ferulic acid acne fading solution and preparation method thereof |
| CN108840871A (en) * | 2018-07-18 | 2018-11-20 | 陕西科技大学 | 13- hydroxyl sparteine cinnamate derivative compound with anti-tumor activity and preparation method thereof |
| WO2018228430A1 (en) * | 2017-06-13 | 2018-12-20 | 首都医科大学附属北京地坛医院 | Use of isoferulic acid, isoferulic acid-containing traditional chinese medicine extract and cimicifugae foetidae |
| CN111253401A (en) * | 2020-03-17 | 2020-06-09 | 珠海萱嘉君行健康产业发展有限公司 | Non-steroidal aryl alkanoic acid ionic salt and preparation method and application thereof |
-
2008
- 2008-10-13 CN CN200810304902A patent/CN101723944A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309156A (en) * | 2016-10-31 | 2017-01-11 | 成都远睿生物技术有限公司 | Ferulic acid acne fading solution and preparation method thereof |
| WO2018228430A1 (en) * | 2017-06-13 | 2018-12-20 | 首都医科大学附属北京地坛医院 | Use of isoferulic acid, isoferulic acid-containing traditional chinese medicine extract and cimicifugae foetidae |
| CN108840871A (en) * | 2018-07-18 | 2018-11-20 | 陕西科技大学 | 13- hydroxyl sparteine cinnamate derivative compound with anti-tumor activity and preparation method thereof |
| CN108840871B (en) * | 2018-07-18 | 2021-12-17 | 西安泰科迈医药科技股份有限公司 | 13-hydroxy cytisine cinnamate compound with anti-tumor activity and preparation method thereof |
| CN111253401A (en) * | 2020-03-17 | 2020-06-09 | 珠海萱嘉君行健康产业发展有限公司 | Non-steroidal aryl alkanoic acid ionic salt and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nair et al. | Traditional usage, phytochemistry and pharmacology of the South African medicinal plant Boophone disticha (Lf) Herb.(Amaryllidaceae) | |
| CN106905313B (en) | Nitric oxide donator type protoberberine analog derivative and its preparation method and application | |
| CA2734309C (en) | Preparation and usage of a pharmaceutical composition containing ferulic acid and matrine compounds | |
| CN101721400A (en) | Action of ferulic acid on enhancing drug effect of some medicaments and purpose thereof | |
| CN101732417B (en) | Preparation method and application of ion pair mixture of macleaya cordata total alkaloid | |
| CN101723944A (en) | Compound formed from ferulic acid and matrine compound and purpose thereof | |
| CN101732299A (en) | Medicinal composition containing ferulic acid and matrine compounds and application thereof | |
| Shi et al. | The untapped potential of spermidine alkaloids: Sources, structures, bioactivities and syntheses | |
| CN101012227A (en) | Novel 13-n-octylberberine derivative with antineoplastic action | |
| Guadarrama-Enríquez et al. | Broccoli sprouts produce abdominal antinociception but not spasmolytic effects like its bioactive metabolite sulforaphane | |
| CN101591337A (en) | Compound formed by splicing ferulic acid and matrine compound and application thereof | |
| Kundu et al. | Exploration of in vivo and in vitro biological effects of Sonneratia caseolaris (L.) fruits supported by molecular docking and ADMET study | |
| CN103405494A (en) | Bauhinia championii n-butyl alcohol extract and preparation method and application thereof | |
| CN113248525B (en) | Extract of cibotium plant, extraction and separation method and application thereof | |
| CN103044377B (en) | Compounds and composition with effects of inhibiting xanthine oxidase and reducing uric acid | |
| CN101463079A (en) | Calf chondroprotein, preparation and use thereof | |
| CN104497077B (en) | The extraction separation method of chromone ketoside compounds and the application in easing pain and diminishing inflammation medicine is prepared | |
| CN101824061B (en) | Baicalin ion pair medicine from traditional Chinese medicine of baikal skullcap root as well as preparation method and application thereof | |
| Kundu et al. | Research Article Exploration of In Vivo and In Vitro Biological Effects of Sonneratia caseolaris (L.) Fruits Supported by Molecular Docking and ADMET Study | |
| Hunegnaw et al. | In vivo antidiarrheal activity evaluation of the seeds of Sorghum bicolor L.(Poaceae) | |
| KR20070008228A (en) | Composition for the prevention and treatment of obesity and type 2 diabetes comprising a tussilago farfara extract or tussilagone | |
| CN103623038A (en) | Preparation method and purpose of total phenolic acid in pithecellobium clypearia | |
| Das et al. | The analgesic and acute anti-inflammatory effect of the ethanolic extract of the leaves of Paederia foetida (EEPF) on experimental animal models. | |
| CN113214154B (en) | Tribenzyl isoquinoline alkaloid, preparation method, pharmaceutical composition and application thereof | |
| KR20110038386A (en) | Pharmaceutical composition comprising extract of pulsatilla koreana for alalgesic |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100609 |