CN104098497A - Novel amide compound - Google Patents
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- CN104098497A CN104098497A CN201410272593.7A CN201410272593A CN104098497A CN 104098497 A CN104098497 A CN 104098497A CN 201410272593 A CN201410272593 A CN 201410272593A CN 104098497 A CN104098497 A CN 104098497A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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Abstract
The invention provides a novel compound (as shown in the formula I) and salt thereof. Experimental results show that the novel compound can be applied to treating and preventing cerebral ischemic diseases and improving sleep; the novel amide compound can generate salt with alkali metal sodium, magnesium, kalium, calcium, organic base tris, diethyl amine, triethylamine and the like and has the functions of treating and preventing ischemic cardiovascular and cerebrovascular diseases and improving sleep.
Description
Technical field:
The invention belongs to the field of medicaments of compound, relate to a kind of new amides and salt thereof, and disclose its Preparation Method And The Use.
Background technology: be the cerebral infarction of broad sense, refer to that the local feeding artery blood perfusion minimizing of cerebral tissue or the blood flow of unexpected generation interrupts completely, stop blood supply, oxygen supply, supply sugar etc., this local brain tissue disintegration is destroyed.The major cause of cerebral infarction is: 1. thromboembolism due to atherosclerosis; 2. cerebral embolism due to the embolus that heart is originated; 3. a variety of causes causes vasculitis, blood vessel injury and wound etc.Cerebral infarction is generally fallen ill in nighttime sleep, and Chang Weici WA in morning is found limb adynamia or hemiplegia, how unconscious obstacle, and blood pressure can be normal or higher, can have arteriosclerosis history.Cerebral infarction accounts for 60%～70% of cerebral apoplexy patient sum, mainly comprises cerebral thrombosis and cerebral embolism.Because the atherosis and thrombosis in cerebral arteries system makes, arterial lumen is narrow or inaccessible to be caused cerebral tissue local intra-arterial blood perfusion to reduce or ends caused local brain tissue necrosis for the former.The medicine of cerebral infarction: the first kind is vasodilator (as dipyridamole etc.).Think in the past as long as medicine can make cerebral vasodilators, just can make blood multithread from the blood vessel stopping up go over.But find that not only Pimobendane do not accomplish this point, also can make the blood reflux of diseased region flow in healthy cerebral tissue and go (this is called steal syndrome in brain), so do not advocated to use this type of medicine.Equations of The Second Kind is the medicine (as low molecular dextran etc.) that improves microcirculation, expanding blood volume.This type of is morely medicinal at present, but has cardiopathic patient to be cautious use of, otherwise may cause heart failure.The 3rd class is thrombolytic medicine (as urokinase etc.).If apply this type of medicine, to reach the object of dissolving embolus be ideal, but often need heavy dose during systemic vein medication, causes sometimes hemorrhage danger.Present multidirectional patient's recommendation interventional therapy, embolus is dissolved at the position of by conduit, medicine directly being injected to infarct exactly, but take the front and back of this methods for the treatment of all will do cerebral angiograpathy one time, this itself just has again certain danger, in addition interventional therapy requires patient to carry out in obtaining 6 hours after being ill, has sometimes often missed opportunity.The 4th class is anticoagulant therapy (as heparin etc.).This class medicine can prevent blood coagulation, but will look into prothrombin time and mobility every day while using, and the poor hospital of condition cannot carry out.In addition anticoagulant therapy also has hemorrhage danger.The 5th class is to use calcium ion antagonist (as nimodipine etc.).This class medicine can prevent that calcium ion from flowing in cell from extracellular, plays slight expansion of cerebral vascular, and protection brain cell increases brain cell and utilizes the effects such as oxygen and glucose.The 6th class is the medicine (as acetylsalicylic acid etc.) that prevents platelet aggregation.Hematoblastic cohesion is the beginning of cerebral thrombosis often, if perhaps the cohesion of blocking platelet effectively can further form in anti-hemostasis osmanthus.This class medicine is applied very extensively in the world at present, not equal to but be to be more appropriate as prophylactic agent as medicine, because the acute phase of cerebral apoplexy, is used this class effect of drugs unsatisfactory.
Summary of the invention:
The object of this invention is to provide a kind of new amides for cerebral infarction, and its production and use.
To achieve these goals, the present invention has adopted following technical scheme:
By animal experiment, prove, placebo does not reduce the effect of rat cerebral ischemia infarct volume, can not improve the symptom of cerebral ischemia, does not possess the effect that improves sleep yet, in the present invention, compound has the good effect that improves symptoms of cerebral ischemia, and can improve the sleep state of animal.
Because formula I compound is insoluble in water, therefore we make it and basic metal or organic bases salify, described alkali refer to sodium, potassium, magnesium, calcium and organic bases Trometamol, diethylamine, triethylamine, thanomin, quadrol,, dimethylamine, hydroxyethylethylene diamine, aminoethanolamine.
The first-selected sodium salt of compound shown in formula I and basic metal salify.
The present invention also provides the pharmaceutical composition that is used for the treatment of cerebral infarction, it is characterized in that containing general formula (1) compound or its salt and the pharmaceutically acceptable carrier for the treatment of significant quantity.Can be oral preparations or injection formulations.
Experimental results show that the injection liquid that adopts compound 1 preparation in embodiment 1, through haemolysis, irritant experiment, show, have good tolerance, the suitable injection liquid that is prepared into, in clinical use, is used for the treatment of the brain necrocytosis of patients with cerebral apoplexy and improves patient's sleep.
Specific embodiment:
Embodiment 1: the preparation of each compound:
Because compound described herein has very strong continuity, in order to describe in detail, accurately, easily each compounds process for production thereof, it is expressed with 1 embodiment, each compound below of following synthetic route shows the sequence number of compound, for simpler and clearer elaboration, in preparation method below, with sequence number, replace:
1, compound 3 is synthetic:
In ice-water bath, the sodium Metal 99.5 of 4.6 grams is joined in 200mL ethanol in batches, after sodium Metal 99.5 dissolves completely, by 29, digest after compound 2 is dissolved in 40mL ethanol and be added drop-wise in above-mentioned reaction solution, dropwise post-heating and reflux 4 hours.Stopped reaction, cooling reaction solution is to room temperature, after vacuum distillation recovered solvent, add 50.0mL saturated ammonium chloride saturated solution and 150mL distilled water, ethyl acetate extraction (100mL * 3), merges organic layer, underpressure distillation is digested compound 3 except obtaining 16.2 after desolventizing, and productive rate is 81.8%.HNMR(400Hz，DMSO)：8.10(s，1H)，4.32(s，2H)，3.32(s，2H)；MS(m/z)：100.2。2, compound 4 is synthetic:
By 14.85, digest compound 3 and 17.55 grams of pyridines are dissolved in the THF of 150mL, under room temperature, the THF solution that 100mL is dissolved with to 40.35 grams of anisoyl chlorides is slowly added drop-wise in above-mentioned reaction solution, in 30 minutes, dropwises, and then at room temperature continues reaction 5 hours.Stopped reaction, to the hydrochloric acid soln and the 150mL distilled water that add 50mL 1N in reaction solution, separate organic layer, water layer is extracted with ethyl acetate (0mL * 3), merge organic layer, underpressure distillation is except obtaining the crude product of compound 4 after desolventizing, with obtaining 25.6 sterlings after ethyl acetate and sherwood oil recrystallization, productive rate is 73.1%.HNMR(400Hz，CDCl
3)：7.87(d，J＝8.4Hz，2H)，6.95(d，J＝8.4Hz，2H)，4.36(s，2H)，3.74(s，3H)，3.34(s，2H)；MS(m/z)：234.2。
3, compound 5 is synthetic:
The compound of 25.0 grams 4 is dissolved in the methyl alcohol of 100mL, adds 5.02 grams of sodium borohydrides in batches on a small quantity under ice-water bath, in 10 minutes, add, continue reaction 2 hours.Stopped reaction, adds 10mL saturated ammonium chloride saturated solution, and solvent methanol is removed in underpressure distillation, adds 100mL distilled water and 100mL ethyl acetate, separates organic layer, and underpressure distillation is digested compound 5, productive rate 95% except obtaining 23.9 after desolventizing.MS(m/z)：236.2。
4, compound 6 is synthetic:
Digest 5,10.1 grams of triethylamines of compound by 23.5,12.0 grams of Succinic anhydrieds and 0.12 gram of DMAP are dissolved in the THF of 150mL, react 6 hours at 70 ℃.Stopped reaction, cooling reaction solution is to room temperature, the hydrochloric acid soln and the 100mL distilled water that add 100mL 1.0N, separate organic layer, water layer is extracted with ethyl acetate (50mL * 3), merges organic layer, with saturated common salt water washing (50mL * 3), underpressure distillation is digested compound 6, productive rate 82% except desolventizing obtains 27.6.MS(m/z)：336.2。
5, compound 1 is synthetic:
By 27.0, digest compound 6 and join in the distilled water of 100mL, under room temperature, add on a small quantity 8.12 can sodium bicarbonate in batches, has bubble to emerge in solution, adds rear continuation reaction 1 hour.Stopped reaction, reaction solution is extracted with ethyl acetate (50mL * 3), discard organic layer, water layer is concentrated into 1/2nd of original volume through underpressure distillation, slowly drip the acetone of certain volume, there is Precipitation, suction filtration, after dry, obtain 21.2 and digest compound 1, productive rate is 73.8%.HNMR (400Hz, CD3OD): 7.87 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 4.56-4.53 (m, 1H), 4.12-4.10 (m, 2H), 3.73 (s, 3H), 2.72-2.70 (m, 2H), 2.62 (t, J=4.8Hz, 2H), 2.52 (t, J=4.8Hz, 2H), MS (m/z): 357.2.
Embodiment 2: the impact of compound 1 on local rats with cerebral ischemia cerebral infarct volume in embodiment 1
(1) experiment material and method
Wistar rat, body weight 250-280g.Perioperatively is raised separately, and room temperature keeps 23-25 ℃, own feed and water inlet.Method according to longa etc. is prepared tMCAO model.10% chloral hydrate anesthesia (350mg/kg, i.p.) for rat, body temperature maintains 37 ± 0.5 ℃, and dorsal position is fixed on operating table.Along neck median line, cut skin, careful separated right carotid (CCA), external carotid artery (ECA), internal carotid artery (ICA).ECA ligation is cut off, and stretching and ICA are in line.On ECA, cut an osculum, by a long 4.0cm, the round end silication nylon rope of diameter 0.26mm (coated with 0.1% poly-lysine) thus opening inserts the about 1.85-2.00cm of ICA, refers to rat brain prerolandic artery Rolando section start, the supply of blood flow of blocking-up arteria cerebri media.Ischemic is the careful nylon wire of extracting out after 2 hours, ligation ECA opening suture operation otch, and animal is put back in cage and fills with 24 hours again.
(2) experiment grouping and administration
Minutes 12 groups at random of rats: model control group, water for injection (100ml/kg), the compound 1 administration group in embodiment 1 (25,50,100mg/kg), oral administration when MCA blocking-up causes after ischemic 10 minutes.
(3) mensuration of cerebral infarct volume
After rat reperfusion injury 24 hours, broken end is got brain at once, removes tractus olfactorius, cerebellum and low brain stem, and it is crownly cut into 6 (first to the 5th 2mm/ sheet, the 6th 4mm), is placed in rapidly 5ml and contains 1.5ml4%TTC and 0.1ml1MK
2hPO
4solution in dyeing (37 ℃, lucifuge) 20-30 minute, every 5 minutes, stir once therebetween.After TTC dyeing, healthy tissues engrain takes on a red color, and infarction tissue is white in color.By every group of brain sheet marshalling, the preservation of taking pictures.Ask the infarct size of calculating every, and final stack is converted into infarct volume.Infarct volume represents with shared Interhemispheric percentage, to eliminate the impact of cerebral edema.
The volume * 100% of cerebral infarct volume (%)=(operation offside hemisphere volume-operation side hemisphere does not block the volume of part)/operation offside hemisphere
(4) experimental result
Ischemic poured into after 24 hours for 2 hours again, and the cerebral infarct volume of solvent control group (%) is 33.8%.Sham operated rats occurs without any cerebral infarction.Other group cerebral infarct volume results are as shown in table 1:
Table 1: the impact of gastric infusion on local cerebral ischemic rats cerebral infarct volume (%)
With solvent control group ratio, 1 group of oral administration of compound all can significantly dwindle cerebral infarct volume.
Embodiment 3: the impact of compound 1 on Sleep in Rats effect in embodiment 1:
(1) improve sleep Experiment on Function
Animal-origin: Kunming kind small white mouse, 18-22 gram, male, the clean level animal being provided by Guangdong Experimental Animal Center.22 ± 2 ℃ of laboratory animal breeding room's temperature, relative humidity 50-70%, animal rearing material, is provided by Guangdong Experimental Animal Center.
It is 25mg/kg that compound 1 dosage is established in this experiment, separately establishes distilled water control group.
Sample preparation: each sample thief 25mg respectively adding distil water, to 20ml, makes into even suspension, for examination.
Give sample approach: gavage
Experimental technique:
(2) above threshold dosage hypnosis of vetanarcol test:
Select 40 of body weight 18-22g male mices, be divided at random four groups, every group 10, give continuously sample 30 days, in the 30th day sample gavage, after 15 minutes, give the vetanarcol abdominal injection of each treated animal 50mg/kg.b.w, injection volume is 0.2ml/20g.b.w, the mouse righting reflex loss of usining reach 1 minute above as the judging criterion of falling asleep, observation is to time for falling asleep and the length of one's sleep of each treated animal in vetanarcol 60 minutes.
Result:
Table 2: the impact of sample on the weight of animals
As seen from the above table, each dosage treated animal body weight of sample is compared with control group, difference that there are no significant.
Table 3: the above threshold impact of vetanarcol inducing mouse length of one's sleep of dosage
* P<0.05 compares (Analysis of variance) with control group
As seen from the above table, the time for falling asleep of 1 group of sample animal of compound under above threshold dosage vetanarcol induction compared with control group with the length of one's sleep, had significant difference.
(3) vetanarcol sub-threshold dose hypnosis test:
Select 40 of body weight 18-22g male mices, be divided at random four groups, every group 10, give continuously sample 28 days, in the 28th day sample gavage after 15 minutes, the vetanarcol abdominal injection of giving each treated animal 30mg/kg.b.w, injection volume is 0.2ml/20g.b.w, the mouse righting reflex loss of usining reaches 1 minute and as the judging criterion of falling asleep, observes the number of animals of sleeping to each treated animal in vetanarcol 25 minutes occurs above.
Result:
Table 4: the impact of the vetanarcol inducing mouse sleep incidence of sub-threshold dose
* P<0.05 compares (through chi square test) with control group
As seen from the above table, 1 group of compound with control group fall asleep animal and the incidence of sleeping under the induction of sub-threshold dose vetanarcol compare with control group, all have significance poor.
Sum up: per os gave mouse sample after 30 days 1 group of effect with improvement sleep of compound.
Embodiment 4: the injection liquid that adopts compound 1 preparation in embodiment 1:
The compound 1 that accurately takes embodiment 1 preparation by recipe quantity is put in a container, add appropriate water for injection, be stirred to entirely molten, and regulate pH to 8.5-8.8, and inject water to 4000ml, add 2g needle-use activated carbon, boil 15min, suction filtration decarburization, solution is through 0.22 μ m filtering with microporous membrane, solution embedding in glass ampoule (every containing compound 1:94mg) preparation through 115 ℃ of pressurization sterilizing 30min.
Embodiment 5: injection liquid hemolytic and irritation test in embodiment 4
The test of liquid hemolytic:
External hemolytic test: to the lower concentration and the high density (0.63mg/mL and 1.88mg/mL) that fill the injection liquid of embodiment 4 preparations that add respectively inequality in each drug liquid tube of 2% red blood corpuscle suspension, each drug liquid tube did not produce hemolytic action in 3 hours.The outer hemolytic negative of injecting fluid of embodiment 4 preparations is described.Concrete experimental technique and experimental result are as follows:
1, the preparation of tested medicine:
(1) high dose group: get 1 bottle of the injection liquid (4mL:94mg/ bottle) of embodiment 4 preparation, be diluted to 6.25mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 0.5mL, make into the solution that concentration is 1.88mg/mL.
(2) low dose group: getting above-mentioned concentration is the solution 2mL of 1.88mg/mL, is diluted to 6mL with 0.9% (0.9g/100ml) sodium chloride injection, is diluted to the solution that concentration is 0.63mg/mL.
2, medication:
The preparation of (1) 2% red blood corpuscle suspension:
Get rabbit blood number milliliter, put into and fill containing the triangular flask jolting of granulated glass sphere 10 minutes, remove Fibrinogen, make into defibrinated blood.Then be divided in several centrifuge tubes, 0.9% sodium chloride injection of 10 times of amounts of every Guan Jiayue, shakes up, centrifugal (1500 revs/min, 15 minutes), remove supernatant liquor, the red blood corpuscle of precipitation is again with 0.9% sodium chloride injection washing 2-3 time, until the not aobvious redness of supernatant liquor.Gained red blood corpuscle is made into 2% suspension with 0.9% sodium chloride injection, is for experiment.
Get 7 of the uniform clean tube of caliber size (every Guan Junshe parallel pipe), after numbering, with transfer pipet, by proportional quantity shown in table 9, add successively 2% red blood corpuscle suspension, 0.9% sodium chloride injection, water for injection and tested liquid, after mixing, put immediately in 37 ℃ of thermostat containers and carry out incubation, beginning was observed once every 15 minutes, after 1 hour, every 1 hour, observe once, observe altogether 3 hours.
The preparation numbering of table 5:2% red blood corpuscle suspension
Note: wherein 1-5 pipe is trial-product pipe, the negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
(2) result is observed:
As solution in test is clear and bright redness, the pipe end, is acellular residual or have a small amount of red corpuscle residual, indicates haemolysis generation; As red corpuscle all sinks, supernatant liquid achromatism and clarity, shows to occur without haemolysis.As having red-brown or reddish-brown flocks in solution, after jolting, do not disperse, show to have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, need further to judge to be true cohesion or pseudo agglutination.If condensation product can be uniformly dispersed again after test tube vibration, or aggregation is placed on wave carrier piece, at cover glass edge, drip 2 0.9% sodium chloride injections, to examine under a microscope, cohesion red corpuscle can be pseudo agglutination by the person of breaking up; If condensation product is not shaken loose or is not true cohesion by the person of breaking up on slide.
3, result is judged
When negative control pipe occurs without haemolysis and cohesion, when positive control pipe has haemolysis to occur, if the solution in tested property management did not produce haemolysis and cohesion in 3 hours, tested material can be injected use; If the solution in tested property management produced haemolysis and (or) cohesion in 3 hours, tested material should not be injected use.
4, test-results
Adding respectively lower concentration is that each drug liquid tube of 0.63mg/mL and the high density injection liquid solution that is 1.88mg/mL did not all produce hemolytic action, external hemolytic negative in 3 hours.Refer to following table 6 and table 7.
Table 6: injection liquid (high dose group) hemolytic test-results (visual inspection)
Note: "+" represents full haemolysis, "-" represents not haemolysis; The negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
Table 7: injection liquid (low dose group) hemolytic test-results (visual inspection)
Note: "+" represents full haemolysis, "-" represents not haemolysis; The negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
Injection liquid vascular stimulation tests
Rabbit vascular stimulation tests: 8 of healthy new zealand rabbits are selected in test, adopt consubstantiality left and right sides ear self-contrast method, left side auricular vein is injected tested medicine, administration volume 5ml/kg body weight, each administration group gives the injection liquid of embodiment 4 preparations of corresponding dosage, low dose group and high dose group dosage are respectively 3.15mg/kgbw and 9.4mg/kgbw, (by concentration, calculate its lower concentration and high density is respectively 0.63mg/mL and 1.88mg/mL, that 0.7-1.4 times and 2-4 times by concentration intended in a clinical intravenous drip), auris dextra gives equal-volume 0.9% (0.9g/100ml) sodium chloride injection and compares, once a day, for three days on end.8 rabbits are subject to after the high density and lower concentration of reagent successively, then give respectively 0.9% sodium chloride injection.Respectively get 2 rabbits of low dosage and high dosage and within 48 hours after last administration, cut open inspection, 4 rabbits of remaining lower concentration and high density are cutd open inspection after 2 week decubation of last administration finishes.8 animal ears blood vessel profiles are more clear as a result, and rabbit ear thickness is even, has no obvious change; Histopathologic examination, animal ears blood vessel is there are no the change of toxicology meaning.The injection liquid vascular stimulation tests that embodiment 4 preparations are described is up to specification.Concrete experimental technique and experimental result are as follows:
1, the preparation of tested material:
(1) high dose group: get 2 bottles of the injection liquids (4mL:94mg/ bottle) of embodiment 4 preparation, be diluted to 100.0mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 8mL, make into the solution that concentration is 1.88mg/mL.
(2) low dose group: getting above-mentioned concentration is the solution 30mL of 1.88mg/mL, is diluted to 90.0mL with 0.9% sodium chloride injection, is diluted to the solution that concentration is 0.63mg/mL.
2, animal is weighed: before administration and after last administration, within 48 hours and 14 days, respectively weigh once.
3, overview and animal are drawn materials:
Before administration every day, observe and record the reaction at animal and intravascular injection position, after last administration 48 hours, the high density of the tested medicine of difference sacrificed by exsanguination and 2 new zealand rabbits of lower concentration, visual inspection is also recorded after the reaction of vascular tissue, from basal part of the ear portion cut two rabbit ears (first cut left ear, after cut auris dextra, and mark), then one section of rabbit ear sample of clip is fixed on that in 10% neutral formalin solution, (sample is about 8cm, wide about 1cm respectively; Distal end otch is apart from the about 0.5cm of the first pinprick place, and proximal part otch is apart from the about 2cm of the 3rd pinprick place, and hanging wire end is proximal part).Respectively leave the high density of tested medicine and 2 animals of lower concentration and continue to observe to after last administration 14 days, carry out following pathologic finding: take the first pinprick as boundary, far-end is cut one section; The 3rd pinprick of take is boundary, and near-end is cut two sections; Blood vessel crosscut during film-making, routine paraffin wax flaking, the about 4-5 μ of slice thickness m, H-E dyeing, then carries out histopathologic examination.
4, result is judged
According to the result of visual inspection and pathologic finding, comprehensively judge.
5, test-results
5.1 visual inspections:
The front visual inspection of administration every day the reaction of recording animal blood vessels injection site, during administration, in the Some Animals administration side of the visible tested medicine high density of naked eyes and lower concentration and control sides rabbit ear inserting needle position vascular epidermis, outside takes on a red color, and area is by 0.1cm * 0.2cm to 0.2cm * 1.0cm.After last administration 48 hours, the bilateral rabbit ear blood vessel profile of 4 rabbits of the high density of tested medicine and lower concentration was more clear, and rabbit ear thickness is even, has no obvious change, refers to table 12 and table 13.Within after last administration 14 days, cut open the inspection high density of tested medicine and 4 rabbits of lower concentration, bilateral rabbit ear blood vessel profile is more clear, and rabbit ear thickness is even, has no obvious change.
5.2 pathologic findings:
4 rabbits of the high density of tested medicine and lower concentration are cutd open inspection for 48 hours after last administration, and 4 rabbits of the high density of remaining tested medicine and lower concentration are cutd open inspection after 2 week decubation finished.Histopathologic examination is showed no vascular tissue the significant stimulation reactions such as sex change or necrosis.The results are shown in Table 8 and table 9:
Table 8: injection liquid (high dose group) is to rabbit ear vascular stimulation reaction (48 hours visual inspection results after last administration)
Table 9: injection liquid (low dose group) is to rabbit ear vascular stimulation reaction (48 hours visual inspection results after last administration)
The injection liquid that these results suggest that compound 1 preparation adopting in embodiment 1 shows to have good security through hemolytic and vascular stimulation tests, and the suitable injection liquid that is prepared into is in clinical use.
Claims (4)
1. there is a compound for prevention and treatment cerebrovascular ischemia disease, as shown below:
2. compound as claimed in claim 1 reacts generated salt with basic metal, from pharmaceutically acceptable sodium, potassium, magnesium, calcium and organic bases Trometamol, diethylamine, triethylamine, thanomin, quadrol,, dimethylamine, hydroxyethylethylene diamine, aminoethanolamine etc.
3. the application of compound in preparation treatment cerebral ischemia diseases medicine described in claim 1-2.
4. described in claim 1-2, compound improves the application in sleep medicine in preparation.
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- 2014-06-17 CN CN201410272593.7A patent/CN104098497B/en not_active Expired - Fee Related
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| CN104098497B (en) | 2016-04-13 |
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