CN1523003A - Novel 2-(alpha-hydroxyl amyl) and its preparing method and use - Google Patents

Novel 2-(alpha-hydroxyl amyl) and its preparing method and use Download PDF

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CN1523003A
CN1523003A CNA03156495XA CN03156495A CN1523003A CN 1523003 A CN1523003 A CN 1523003A CN A03156495X A CNA03156495X A CN A03156495XA CN 03156495 A CN03156495 A CN 03156495A CN 1523003 A CN1523003 A CN 1523003A
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杨文斌
秦华
赵兴凯
马喜生
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BEIJING TIANHENG DRUG RESEARCH INSTITUTE
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Abstract

The present invention relates to a new 2-(alpha-hydroxyamyl) benzoate and its preparation method, and medicine composition using said compound as active component, and also relates to its application for curing cardio-cerebral ischemia and cardio-cerebral arterial infarction.

Description

New 2-(Alpha-hydroxy amyl group) benzoate and method for making and purposes
Technical field the present invention relates to new 2-(Alpha-hydroxy amyl group) benzoate and method for making thereof and is the pharmaceutical composition of activeconstituents with this compound, also relates to the application of this compound at aspects such as treatment cardiac-cerebral ischemia, heart arter obstructions.
Background technology acute ischemic cerebral apoplexy and coronary heart disease and myocardial infarction, all be since arteriosclerosis until forming the disease that thrombus causes ischemia injury, such disease is brought great misery even life danger to patient.At present, the research of such medicine is the focus and the forward position of drug development research always.
Chinese patent CN1382682A, application number 01109795.7,2-(Alpha-hydroxy amyl group) benzoate and method for making and purposes are disclosed first, the salt that relates to monovalent metallic ion, divalent-metal ion and organic base specifically discloses the salt of potassium, sodium, calcium, magnesium, zinc, aniline, benzylamine, morpholine, diethylamine.The preparation of sylvite, sodium salt, lithium salts, calcium salt, benzylamine salt is disclosed in its specification sheets, but the concrete preparation method of zinc salt, aniline, morpholine, diethyl amine salt openly not.The influence of sylvite to local rats with cerebral ischemia cerebral infarct size also disclosed in its specification sheets; influence to rat platelet aggregation; and the provide protection of isolated rat heart ischemia-reperfusion heart disorder, prove that sylvite brought into play beneficial effect in above-mentioned experiment.Other salt compounds then do not carry out effect experiment proves its effect.
Summary of the invention the present inventor is when developing new cardio-cerebralvascular medicine, studied and comprised above-mentioned disclosed a large amount of 2-(Alpha-hydroxy amyl group) benzoate, discovery is according to prior art and the disclosed preparation method of Chinese patent CN1382682A, in the process of these salts of preparation, there is following phenomenon:
1, some alkali can not react at all, as aniline and similar compound, reason be amino benzenes compounds alkalescence too a little less than;
Though 2, some can react, and can not get solid, comprise simple organic amine or inorganic ammonia, as ammonia, methylamine, dimethylamine, diethylamine, quadrol, triethylamine etc., and simple nitrogen-containing heterocycle compound, as morpholine and piperidines, can only obtain heavy-gravity oily matter;
3, some alkali is according to existing disclosed preparation method, the solid that obtains is an amorphous substance, there are not fixed fusing point and good surface appearance and physical aspect, as sodium salt, magnesium salts, lithium salts, zinc salt, behind the decompressing and extracting solvent spumescence solid or jelly, no crystal formation, viscosity is very big, be difficult to pulverize, the flowability that is far from being is not suitable for pharmaceutical industry and processes.
Though 4, can obtain good solid behind some alkali reaction, toxicity is big, as benzylamine salt, tert-butylamine salt.
5, part mineral alkali has good crystal habit as sylvite, but exist draw moist very strong, to moist lability, labile shortcoming when under conventional environment, placing, sylvite shows bigger toxicity when intravenously administrable in addition.
Purpose of the present invention, just provide a kind of new 2-(Alpha-hydroxy amyl group) benzoate that can overcome the prior art shortcoming, have tangible platelet aggregation-against and improve cerebral circulation, and to the heart, cerebral ischemia, the heart, cerebral arteries emphraxis have the new compound of pharmaceutical activity, this compound has good surface appearance and physical aspect, and nothing is drawn moist, wet excellent in stability.
Another object of the present invention provides the synthetic method of a kind of preparation 2-(Alpha-hydroxy amyl group) benzoate.
Further purpose of the present invention provides a kind of prevention and treats the pharmaceutical composition of the heart, cerebral ischemia and the heart, cerebral arteries emphraxis.
Another object of the present invention provides above-claimed cpd and the application of composition in preparing the medicine that prevents and treat the heart, cerebral ischemia and the heart, cerebral arteries emphraxis and improve brain microcirculation.
In order to finish purpose of the present invention, the present inventor's preparation has also been studied large quantities of 2-(Alpha-hydroxy amyl group) benzoate, comprise the disclosed salt of Chinese patent CN1382682A, through physico-chemical property, drug effect, toxicity research, be surprised to find that compound with following formula structure, performance with each side excellence is not seen the report to this compound in the prior art.
Figure A0315649500041
2-(Alpha-hydroxy amyl group) benzoate N, N '-dibenzyl ethylenediamine salt
The compounds of this invention can prepare as follows:
(press existing known technology by 2-(Alpha-hydroxy amyl group) Sodium Benzoate, comprising the preparation of the described method of CN1382682A) acidifying obtains 2-(Alpha-hydroxy amyl group) phenylformic acid, be dissolved in behind the solvent at low temperatures and N, the solution reaction of N '-dibenzyl-ethylenediamin, temperature of reaction is-10 ℃ to 10 ℃, preferred-5 ℃ to 0 ℃.Stirred for several hour, suction filtration is used organic solvent drip washing, drains, and drying promptly obtains the The compounds of this invention of white solid.Above-mentioned solvent for use comprises ether, methylene dichloride, ethyl acetate, preferred ether.
The inventor finds that compound of the present invention has the performance of following excellence:
1, good crystal habit, the fixed fusing point only needs a simple aftertreatment can reach medicinal purity.
2, do not have and to draw moistly,, good outward appearance physical aspect is arranged, be fit to the storage and the processing of pharmaceutical industry wet stable.
3, animal acute toxicity test shows, compares with disclosed 2-(Alpha-hydroxy amyl group) benzoate, and toxicity of compound of the present invention is littler.
4, in animal drug effect model trial, to compare with disclosed 2-(Alpha-hydroxy amyl group) benzoate, the brain tissue impairment that under same dose cerebral arteries emphraxis is caused demonstrates excellent more provide protection and antiplatelet aggregative activity.Illustrate that The compounds of this invention has better prevention and therapeutic action to the heart, cerebral ischemia, and have platelet aggregation-against that the treatment heart, cerebral arteries emphraxis improve pharmacological actions such as the heart, brain microcirculation.
5, in animal drug effect model trial, compare with disclosed 2-(Alpha-hydroxy amyl group) benzoate, have littler significance dosage, promptly than under the low dosage, compound of the present invention can show the effect of significance.The molecular weight (656.86, sylvite 246.35, calcium salt 454.57) that further contemplates this compound is bigger, and therefore under the less dosage in mole number, this product can show the effect of significance.
It is activeconstituents that pharmaceutical composition of the present invention contains the The compounds of this invention for the treatment of significant quantity, and contains one or more pharmaceutically acceptable carriers.
Pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine, weighting agent such as starch, sucrose etc.; Tackiness agent such as derivatived cellulose, alginate, gelatin and polyvinyl pyrrolidone; Wetting agent such as ethanol, water; Disintegrating agent such as starch and derivative thereof, low-substituted hydroxypropyl cellulose, gas-producing disintegrant; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and magnesium, polyoxyethylene glycol; Also can in composition, add other auxiliary such as flavouring agent, sweeting agent etc. in addition.
Compound of the present invention and pharmaceutical composition can be used for preparation prevention and the treatment heart, cerebral ischemia diseases, and the heart, cerebral arteries emphraxis improve the medicine of diseases such as the heart, brain microcirculation disorder.
The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then, comprise tablet, capsule and granule.
The embodiment the following examples can help those skilled in the art more fully to understand the present invention, but do not limit the present invention in any way.
Embodiment 1:2-(Alpha-hydroxy amyl group) phenylformic acid N, the preparation of N '-dibenzyl ethylenediamine salt.
1, Alpha-hydroxy n-amylbenzene formic acid preparation
Operation:
Alpha-hydroxy n-amylbenzene sodium formiate (by the CN1382682A preparation) 80g (0.348mol) and water 500ml are joined in the beaker of 2.5L, be chilled to-10 ℃ after the stirring and dissolving, add cold 5% hydrochloric acid in batches, temperature is at 0 to-10 ℃ in the control, transfer PH=2～3, with ether 500ml * 3 extractions, ether layer is washed in water 300ml * 3, is washed till neutrality, the ether layer drying, the filtering siccative, decompression eliminates ether, gets white solid 64g.
2,2-(Alpha-hydroxy n-pentyl) phenylformic acid N, N '-dibenzyl ethylenediamine salt preparation
Figure A0315649500061
Operation
(1) add N in reaction flask, N '-dibenzyl-ethylenediamin 37.2g (0.155mol) and ether 1.0L is after stirring is molten entirely down, add the benzoic diethyl ether solution 1.0L (64g of 2-(Alpha-hydroxy n-pentyl) in batches, 0.31mol), become muddy gradually, separate out a large amount of white solids after adding.
(2) stir suction filtration after 3～4 hours, filter cake is with ether 1500ml washing, after draining with solid transfer in the beaker of 2.5L, with ether 2.0L washed twice, filter, filter cake is put into the vacuum drier drying, the 92g white solid, mp:105～106 ℃, yield: 90.2%
Infrared absorption spectrum, KBr, 3419cm -1' (γ NH), 3040,3070cm -1' (γ Ar-H) .1763cm -1' (γ C=O)
Proton nmr spectra (300MHz, CD 3Cl) δ (ppm)
7.13-7.60 (m, 14H), 4.93 (t, 2H, two Ar-CH), 3.92 (S, 4H, two Ar-CH 2), 2.99 (s, 4H, N-CH 2CH 2-N), 1.63-1.70 (m, 4H, two CH 2), 1.14-1.36 (m, 8H, two CH 2CH 2) 0.76-0.83 (m, 6H, two CH 3)
ESI-MS：Negative??M/Z?207??
Figure A0315649500062
Positive??M/Z?241??
Ultimate analysis: C 40H 52N 2O 6FW656.86
????C ????H ????N
Theoretical value % ????73.14 ????7.98 ????4.26
Measured value % ????73.10 ????8.05 ????4.28
Embodiment 2: the appearance character of various 2-(Alpha-hydroxy amyl group) benzoate and fusing point contrast
The appearance character of the various 2-of table one (Alpha-hydroxy amyl group) benzoate and fusing point contrast.
Compound Lithium salts * Sodium salt * Sylvite * Calcium salt * Zinc salt ** Magnesium salts ** Benzylamine salt * Alkylbenzyldimethylasaltsum saltsum * The diethyl amine salt * Aniline * N, N '-dibenzyl-ethylenediamin TERTIARY BUTYL AMINE ***
Appearance character Spumescence Spumescence Crystalline powder Pressed powder Colloidal solid The spumescence solid Crystalline powder Thick liquid Thick liquid Do not react Crystalline powder Crystalline powder
??m.p. ??(℃) ??— ??— ??156- ??157 260 (decomposition) ??— ??— ??83- ??84.5 ??— ??— ??— ???105- ???106 ??119- ??120
*: press the CN1382682A preparation. *: press the calcium salt method preparation among the CN1382682A * *: according to the method preparation of embodiment 1
The result shows: lithium salts, sodium salt, magnesium salts, zinc salt are spumescence or colloidal solid, do not have tangible fusing point.Morpholine and diethyl amine salt are thick liquid.They all do not meet the requirement of pharmaceutical industry.Sylvite, calcium salt, benzylamine salt, N, N '-dibenzyl ethylenediamine salt, tert-butylamine salt have good surface appearance physical aspect and fixed fusing point.Aniline is not reaction then.
Embodiment 3: wet stability relatively
According to " high humidity test method " described method test under 2000 editions two appendix XIX C of Chinese Pharmacopoeia " medicine stability governing principle " item, the time is 10 days.Result such as table two.
Table di-potassium, calcium salt, benzylamine salt, N, N '-dibenzyl ethylenediamine salt, the wet stability of tert-butylamine salt are relatively
Relative humidity Project N, N '-dibenzyl ethylenediamine salt Sylvite Calcium salt Benzylamine salt Tert-butylamine salt
??75％ Changes in weight % ????+0.080 ????+2.442 ??+0.418 ????+0.125 ????+0.026
Appearance character No change The moisture absorption caking No change No change No change
Degradation production % ????＜0.5 ????2.7 ??＜0.5 ????＜0.5 ????1.7
??92.5％ Changes in weight % ????+0.091 ????+67.817 ??+0.441 ????+7.14 ????+0.309
Appearance character No change Liquefaction fully No change Partial liquefaction No change
Degradation production % ????＜0.5 ????32.1 ??＜0.5 ????61 ????3.9
*The mensuration of degradation production adopts the HPLC method, according to 2000 editions two appendix VD tests of Chinese Pharmacopoeia, and the C18 post, the moving phase acetonitrile: 0.02M SODIUM PHOSPHATE, MONOBASIC=40: 60, detect wavelength 230nm, flow velocity 1ml/min.
Experimental result shows that the moisture absorption of sylvite, benzylamine salt is more serious, and decomposes after the moisture absorption seriously, N, and N '-dibenzyl ethylenediamine salt and calcium salt moisture absorption are less and stable.The tert-butylamine salt moisture absorption is little, but stability is poor slightly.
Embodiment 4: acute toxicity test
Present embodiment is selected for use:
1, animal
The ICR mouse, male and female half and half, body weight 18-20g is provided by Beijing Vital River Experimental Animals Technology Co., Ltd..Conformity certification number is: SCXK (capital) 2002-0003.
2, be subjected to reagent
Oral: N, N '-dibenzyl ethylenediamine salt, sylvite, calcium salt, benzylamine salt, tert-butylamine salt, being the Tianheng Medicinal Inst., Beijing provides, and uses the 0.5%CMC suspendible, is mixed with different concns; Quiet notes: sylvite, with the preparation of injection physiological saline.
3, test method
60 of ICR mouse are divided into 6 groups at random by body weight and sex, and 10 every group, male and female half and half according to the trial test result, are respectively organized dosage by the design in 1: 0.8 of group spacing.The administration capacity was 0.2ml/10g body weight (the administration capacity is the 0.1ml/10g body weight during sylvite intravenous injection) when per os was irritated stomach, fasting be can't help water 12 hours before the test, the conventional raising after the administration, observed 14 days continuously, reaction of record animal toxicity and death condition, dead group performs an autopsy on sb, and the visual inspection pathological change is calculated LD with the Bliss method 50Value and 95% fiducial limit.
4, test-results
Table three The acute toxicity tests
Compound title LD 50Be worth 95% fiducial limit
N, N '-dibenzyl ethylenediamine salt 3.1910g/kg 2.7851～3.656g/kg
Calcium salt 1.5498g/kg 1.3015～1.8546g/kg
Benzylamine salt 1.4537g/kg 1.316～1.6057g/kg
Tert-butylamine salt 1.2635g/kg 1.1188～1.427g/kg
Sylvite (oral) 1.1735g/kg 1.0559～1.3041g/kg
Sylvite (quiet notes) 0.382g/kg 0.3513～0.4154g/kg
The result shows that each compound is followed successively by N to the acute toxicity (oral) of mouse, N '-dibenzyl ethylenediamine salt＜calcium salt＜benzylamine salt＜tert-butylamine salt＜sylvite, N wherein, the toxicity minimum of N '-dibenzyl ethylenediamine salt.
Embodiment 5: to arteria cerebri media thrombus model (Middle Cerebral Artery Thrombosis, MCAT) influence of rat nervous symptoms and cerebral infarction scope
Present embodiment is selected for use:
One, animal
The SD rat, the male and female dual-purpose, body weight 190～210g is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., conformity certification number: SCXK 11-00-0008.
Two, medicine and reagent:
Be subjected to reagent: N, N '-dibenzyl ethylenediamine salt, sylvite, calcium salt, being the Tianheng Medicinal Inst., Beijing provides, and uses the 0.5%CMC suspendible, is mixed with different concns.
Reagent: FeCl 36H 2O (A.R.), the Beijing Chemical Plant produces, with the preparation of 1mol/L hydrochloric acid; TCC (TTC), the Beijing Chemical Plant produces.
Three, instrument
The XTT stereomicroscope: Beijing electric light scientific instrument factory produces; Water bath with thermostatic control vibrator SHZ-22 type: Da Cang medical apparatus and instruments factory in Jiangsu produces; Electronic analytical balance: the AEG-220 type, produce in a day island proper Tianjin.
Four, test method and result
(1) to the influence of MCAT rat nervous symptoms
1, grouping and administration: animal is divided into 14 groups at random, it is sham operated rats, the MCAT model group, N, N '-dibenzyl ethylenediamine salt 340mg/kg, 200mg/kg, 170mg/kg, 100mg/kg, 85mg/kg, 50mg/kg group, sylvite 200mg/kg, 100mg/kg, 50mg/kg group, calcium salt 200mg/kg, 100mg/kg, 50mg/kg group.Prevention administration before the modeling, every day, gastric infusion was 1 time, successive administration 3 days, modeling in the 4th day is irritated stomach at once and is given once to set dosage after the modeling, irritated stomach again in 12 hours after the modeling to give once to set dosage.Control group gives the equivalent solvent.
2, implement the modeling operation: the anesthesia of rats by intraperitoneal injection 12% Chloral Hydrate solution (350mg/kg).Method (Tamura A with reference to Tamura etc., Graham DI, McCulluoch J et al.Focal cerebral ischemia in therat.1.Description of technique and early neuropathological consequences following middleCerebral artery occlusion.J Cereb Blood Flow Metab, 1981,1:53) also improved, the rat right arm reclining is fixed, make an arc incision at paropia and external auditory meatus line mid point, be about 1.5cm, the pinch off temporalis also cuts, expose temporal bone, make a diameter 2.5mm bone window at cheekbone and temporo squamosum joint to oral-lateral 1mm place with dental burr, the cleaning residue exposes arteria cerebri media (between tractus olfactorius and venae cerebri inferiores).Have the small pieces quantitative paper of 50% ferric chloride Solution, 10 μ l to apply on this section arteria cerebri media suction, about 30min treats to take off filter paper after the blackening of blood vessel color, uses the normal saline flushing local organization, and layer-by-layer suture steams again and raises.
3, behavior detects: with reference to method (the Bederson JB of Bederson etc., Pitts LH, Tsuji M et al.Rat middlecerebral artery occlusion:evaluation of the mode and development of a neurologicexamination.Stroke, 1986,17:472) also improved, (6h 24h) carries out behavior scoring to animal to different time points after surgery.(1) carries the about chi of mouse tail built on stilts, observe forelimb flexing situation.Stretch to ground as two forelimb symmetries, be designated as 0 fen; As the flexing that shoulder flexing, elbow flexing, shoulder inward turning or existing wrist elbow appear in the offside forelimb of performing the operation has inward turning person again, is designated as 1 fen.(2) animal is placed on the level and smooth ground, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and be designated as 0 fen effectively; As resistance descender when the operation offside promotes, be designated as 1 fen.(3) animal two forelimbs are put on the wire netting, observed the muscular tension of two forelimbs.Bilateral muscular tension equity and strong person are 0 minute; Operation offside muscle of anterior limb tension force descends and is designated as 1 fen.(4) carry the about chi of mouse tail built on stilts, animal has ceaselessly to operation offside revolver, is designated as 1 fen.According to above standard scoring, full marks are 4 minutes, and mark is high more, and the behavior disorder of animal is serious more.
4, interpretation of result: relatively, the results are shown in Table four between employing t check is organized behavior detection score value.
The influence of table four pair MCAT rat nervous symptoms
Group Dosage (mg/kg) Number of animals (n) Score value Effect in 24 hours suppresses percentage (%)
????????6h ?????????24h
Model group ????— ????10 ????3.50±0.53 ????3.70±0.48 ??????—
Sham operated rats ????— ????10 ????0.00±0.00 *** ????0.00±0.00 *** ??????—
N, N '-dibenzyl ethylenediamine salt group ????340 ????10 ????2.60±0.70 ** ????2.40±0.52 *** ??????35.1
????200 ????10 ????2.80±0.42 ** ????2.50±0.53 *** ??????32.4
????170 ????10 ????2.80±0.79 * ????2.60±0.52 *** ??????29.7
????100 ????10 ????2.90±0.57 * ????2.80±0.42 *** ??????24.3
????85 ????10 ????3.20±0.92 ????2.90±0.57 ** ??????21.6
????50 ????10 ????3.30±0.67 ????3.10±0.32 ** ??????16.2
The sylvite group ????200 ????10 ????3.00±0.67 ????2.70±0.48 *** ??????27.0
????100 ????10 ????3.10±0.74 ????3.00±0.67 * ??????18.9
????50 ????10 ????3.50±0.53 ????3.20±0.79 ??????13.5
The calcium salt group ????200 ????10 ????3.10±0.57 ????2.80±0.42 *** ??????24.3
????100 ????10 ????3.20±0.63 ????3.10±0.57 * ??????16.2
????50 ????10 ????3.40±0.52 ????3.30±0.48 ??????10.8
Annotate: compare with model group, * *P＜0.001, *P＜0.01, *P＜0.05
The result shows that sham operated rats behavior no abnormality seen changes, and hemiplegia sample symptom all appears in model group rat 6h, 24h after surgery, mainly show as in the operation offside forelimb to receive, and the shoulder inward turning, muscle of anterior limb tension force reduces, and the shoulder resistance descends.Compare with model group, postoperative 6h, N, the nervous symptoms of N '-dibenzyl ethylenediamine salt 100～340mg/kg group rat all significantly improves, and the nervous symptoms of each dosage group rat of sylvite and calcium salt does not all have remarkable improvement the (P＞0.05); Postoperative 24h, N, the nervous symptoms of N '-dibenzyl ethylenediamine salt 50～340mg/kg group, sylvite and calcium salt 100mg/kg, 200mg/kg group rat all significantly improves, and tangible dose-effect relationship is arranged, and sylvite and calcium salt 50mg/kg organize all not have significantly and improve (P＞0.05).The significance dosage that N, N '-dibenzyl ethylenediamine salt improve MCAT rat nervous symptoms is 50mg/kg, is lower than sylvite and calcium salt (100mg/kg).Under the same dose, N, N '-dibenzyl ethylenediamine salt is better than sylvite and calcium salt to the improvement effect of MCAT rat nervous symptoms.
(2) to the influence of MCAT rat cerebral infarction scope
Behind the animal via last behavior scoring, broken end is got brain.Remove olfactory bulb, cerebellum and low brain stem, residue partly is cut into 5 crown below 4 ℃.(every 5ml dye liquor contains 4%TTC 1.5ml, 1M K rapidly the brain sheet to be placed the TTC dye liquor 2HPO 40.1ml), 37 ℃ of lucifuge temperature were incubated 30 minutes, took out again, placed 10% formalin to keep in Dark Place.The non-ischemic region in dyed back is a rose, and infarct is a white.White organized carefully to dig down weigh, the per-cent that accounts for total brain weight with blocking tissue's weight is as the cerebral infarction scope.Adopt the t check that result between group is compared, the results are shown in Table five.
The influence of table five pair MCAT rat cerebral infarction scope
Group Dosage (mg/kg) Number of animals (n) Blocking tissue's weight accounts for the white proportion by subtraction (%) of total brain weight Infraction inhibiting rate (%)
Model group ????— ????10 ????7.79±2.40 ????—
Sham operated rats ????— ????10 ????0.00±0.00 *** ????—
N, N '-dibenzyl ethylenediamine salt group ????340 ????10 ????4.97±1.34 ** ????36.2
????200 ????10 ????5.14±1.66 * ????34.0
????170 ????10 ????5.16±1.80 * ????33.8
????100 ????10 ????5.26±2.32 * ????32.5
????85 ????10 ????5.30±2.37 * ????32.0
????50 ????10 ????5.46±1.74 * ????29.9
The sylvite group ????200 ????10 ????5.36±1.81 * ????31.2
????100 ????10 ????5.60±1.67 * ????28.1
????50 ????10 ????6.11±1.91 ????21.6
The calcium salt group ????200 ????10 ????5.39±2.66 * ????30.8
????100 ????10 ????5.62±2.17 * ????27.9
????50 ????10 ????6.27±2.28 ????19.5
Annotate: compare with model group, * *P＜0.001, *P＜0.01, *P＜0.05
The result shows that tangible focus of infarct has appearred in the model group rat behind the intraluminal middle cerebral artery occlusion in rats infraction 24h, and sham operated rats does not have any change.Compare with model group, N, the cerebral infarction scope of N '-dibenzyl ethylenediamine salt 50～340mg/kg group, sylvite, calcium salt 100mg/kg, 200mg/kg group rat all significantly alleviates, and tangible dose-effect relationship is arranged; Sylvite and calcium salt 50mg/kg group all do not have remarkable restraining effect (P＞0.05).The significance dosage that N, N '-dibenzyl ethylenediamine salt suppress MCAT rat cerebral infarction scope is 50mg/kg, is lower than sylvite and calcium salt (100mg/kg).Under the same dose, N, N '-dibenzyl ethylenediamine salt is better than sylvite and calcium salt to the restraining effect of MCAT rat cerebral infarction scope.
Embodiment 6: to the influence of rat platelet aggregation
Present embodiment is selected for use:
One, animal
The SD rat, male, body weight 220～250g is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., conformity certification number: SCXK11-00-0008.
Two, medicine and reagent
N, N '-dibenzyl ethylenediamine salt, sylvite, calcium salt, being the Tianheng Medicinal Inst., Beijing provides.Positive control drug: acetylsalicylic acid (ASA) is produced by the sub-great mansion chemical pharmaceutical in Mudanjiang company limited, lot number 010622015.Said medicine is all used the 0.5%CMC suspendible, is mixed with different concns.Adenosine diphosphate (ADP) (ADP) is available from Sigma company.
Three, instrument: TYXN-91 intelligence platelet aggregation instrument (Shanghai General Machinery ﹠ Electric technology Inst.'s production)
Four, test method
Rat is divided into 11 groups at random, that is: solvent control group, ASA 100mg/kg, N, N '-dibenzyl ethylenediamine salt 200mg/kg, 100mg/kg, 50mg/kg group, sylvite 200mg/kg, 100mg/kg, 50mg/kg group, calcium salt 200mg/kg, 100mg/kg, 50mg/kg group.Every day gastric infusion once, continuous three days, the solvent control group gave the equivalent solvent.Got blood from arteria carotis communis in 1 hour after the last administration, mixed anti-freezing with whole blood by 1: 9, prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) according to a conventional method with Sodium Citrate (3.8%), with PPP accent PRP to platelet count be 6～7 * 10 11L -1With reference to BornShi turbidimetry (G.V.R.Born and M.J.CROSS:The Aggregation of Blood Platelets, J.Physiology, 1963,168:178), get the PRP of 200 μ l through regulating and add in the opacity tube, 37 ℃ of incubations add inductor ADP to final concentration 5 μ molL after 5 minutes -1, measure to add behind the ADP in 5 minutes hematoblastic MA and assemble inhibiting rate.
Assemble inhibiting rate=(solvent control group aggregation rate-administration group aggregation rate)/solvent control group aggregation rate * 100%
Five, test-results
The result shows, N, the platelet aggregation rate of N '-dibenzyl ethylenediamine salt 50～200mg/kg group, sylvite and calcium salt 100mg/kg, 200mg/kg group rat compares with the solvent control group that all there were significant differences, and sylvite is compared with the solvent control group with the platelet aggregation rate of calcium salt 50mg/kg group rat does not all have significant difference.Under the same dose, N, N '-dibenzyl ethylenediamine salt is better than sylvite and calcium salt to the restraining effect of rat platelet aggregation.The results are shown in Table six.
The influence of table six pair ADP inductive rat platelet aggregation
Group Dosage (mg/kg) Number of animals (n) MA (%) Assemble inhibiting rate (%)
The solvent control group ????— ????10 ????58.14±11.51 ?????—
N, N '-dibenzyl ethylenediamine salt group ????200 ????10 ????41.57±8.33 ** ?????28.5
????100 ????10 ????45.86±9.41 * ?????21.1
????50 ????10 ????48.78±7.30 * ?????16.1
The sylvite group ????200 ????10 ????43.25±9.01 ** ?????25.6
????100 ????10 ????49.04±6.65 * ?????15.7
????50 ????10 ????51.62±9.02 ?????11.2
The calcium salt group ????200 ????10 ????46.98±9.54 * ?????19.2
????100 ????10 ????49.26±5.76 * ?????15.3
????50 ????10 ????52.32±11.51 ?????10.0
The ASA group ????100 ????10 ????27.27±9.51 *** ?????53.1
Annotate: compare with the solvent control group, * *P＜0.001, *P＜0.01, *P＜0.05
Embodiment 7: tablet
Composition Quantity (mg/ sheet)
N, N '-dibenzyl ethylenediamine salt 200
Starch 50
Microcrystalline Cellulose 35
Magnesium Stearate 0.5
Talcum powder 1
Xylo-Mucine 5
The preparation method: press proportioning with N, N '-dibenzyl ethylenediamine salt, starch, Microcrystalline Cellulose, Xylo-Mucine mixing, water is evenly wetting, the system particle, drying, whole grain adds Magnesium Stearate, talcum powder, then the mixture compressing tablet is promptly got this product tablet.
Embodiment 8: capsule
Composition Quantity (mg/ capsule)
N, N '-dibenzyl ethylenediamine salt 200
Starch 50
Methylcellulose gum 3
Commissure PVP 1
The preparation method: by proportioning with N, N '-dibenzyl ethylenediamine salt and auxiliary materials and mixing, wet method system particle, drying, whole, then with mixture by in the gastric solubility hard capsule of quantitatively packing into, promptly get this product capsule.
Embodiment 9: granule
Composition Quantity (mg/ bag)
N, N '-dibenzyl ethylenediamine salt 200
Starch 1000
Dextrin 150
Icing Sugar 150
The preparation method: press proportioning with N, wet granulation after N '-dibenzyl ethylenediamine salt and the auxiliary materials and mixing, drying, the classification of whole grain, sub-dose packaging promptly gets this product granule.

Claims (9)

1,2-(Alpha-hydroxy amyl group) phenylformic acid N, N '-dibenzyl ethylenediamine salt, structural formula is as follows:
Figure A031564950002C1
2, according to the preparation method of compound in the claim 1, it is characterized in that 2-(Alpha-hydroxy amyl group) phenylformic acid is dissolved in the organic solvent, then at low temperatures with N, the solution reaction of the organic solvent of N '-dibenzyl-ethylenediamin.
3,, it is characterized in that organic solvent comprises ether, methylene dichloride, ethyl acetate according to the preparation method of compound in the claim 1.
4,, it is characterized in that organic solvent is an ether according to the preparation method of compound in the claim 1.
5,, it is characterized in that temperature of reaction is-10 ℃ to 10 ℃ according to the preparation method of compound in the claim 1.
6,, it is characterized in that temperature of reaction is-5 ℃ to 0 ℃ according to the preparation method of compound in the claim 1.
7, the application of compound in preparing treatment and the prevention heart, cerebral ischemia diseases and the heart, cerebral arteries emphraxis medicine in the claim 1.
8, be used for the treatment of and prevent the heart, cerebral ischemia diseases, the heart, cerebral arteries emphraxis, improve the pharmaceutical composition of brain microcirculation, it is characterized in that containing the compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
9,, it is characterized in that to make tablet, capsule, granule according to the pharmaceutical composition in the claim 8.
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CN103992219A (en) * 2013-02-19 2014-08-20 石药集团中奇制药技术（石家庄）有限公司 Potassium-hydroxypentyl benzoate crystal and preparation method thereof
CN104086399A (en) * 2013-07-17 2014-10-08 郑州大学 Different crystal forms of sodium 5-bromo-2-(alpha-hydroxyamyl)benzoate and preparation method thereof
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CN103992219B (en) * 2013-02-19 2017-09-26 石药集团中奇制药技术（石家庄）有限公司 Hydroxyl amyl group Potassium Benzoate crystal and preparation method thereof
CN103127025A (en) * 2013-03-06 2013-06-05 石家庄鸯星科技有限公司 Racemic 2-(alpha-hydroxyl amyl) benzoate tablets and preparation method thereof
CN103127025B (en) * 2013-03-06 2016-03-09 石家庄鸯星科技有限公司 The preparation method of racemization 2-(Alpha-hydroxy amyl group) benzoate sheet
CN103142513A (en) * 2013-03-25 2013-06-12 石家庄鸯星科技有限公司 Racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and preparation method thereof
CN103142513B (en) * 2013-03-25 2016-01-20 石家庄鸯星科技有限公司 A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof
CN104086399A (en) * 2013-07-17 2014-10-08 郑州大学 Different crystal forms of sodium 5-bromo-2-(alpha-hydroxyamyl)benzoate and preparation method thereof
WO2021185356A1 (en) 2020-03-20 2021-09-23 石药集团恩必普药业有限公司 Use of butylphthalide and derivative thereof

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