CN104098497B - A kind of new amides - Google Patents
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- CN104098497B CN104098497B CN201410272593.7A CN201410272593A CN104098497B CN 104098497 B CN104098497 B CN 104098497B CN 201410272593 A CN201410272593 A CN 201410272593A CN 104098497 B CN104098497 B CN 104098497B
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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
A kind of new compound (shown in formula I) and salt thereof, experiment proof may be used for treatment and prevention cerebral ischemia diseases, improving water flood, salt can be generated with alkali metallic sodium, magnesium, potassium, calcium and organic bases tris, diethylamine, triethylamine etc., there is the effect for the treatment of and prevention ischemic cardio cerebrovascular diseases and improving water flood.
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: the cerebral infarction being broad sense, refers to that the cerebral tissue local feeding artery blood perfusion occurred suddenly reduces or blood flow interrupts completely, stops blood supply, oxygen supply, for sugar etc., this local brain tissue disintegration is destroyed.The major cause of cerebral infarction is 1. thromboembolism caused by atherosclerosis; 2. heart source embolus caused by cerebral embolism; 3. vasculitis, blood vessel injury and the wound etc. that cause of a variety of causes.Cerebral infarction is generally fallen ill in nighttime sleep, and Chang Weici WA in morning finds limb adynamia or hemiplegia, and how unconscious obstacle, 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.The former make the narrow or obturation of arterial lumen cause cerebral tissue local intra-arterial blood perfusion to reduce due to the atherosis and thrombosis in cerebral arteries system or local brain tissue caused by stopping downright bad.The medicine of cerebral infarction: the first kind is vasodilator (as dipyridamole etc.).As long as think that medicine can make cerebral vasodilators in the past, blood multithread from the blood vessel of blocking just can be made to go over.But find that not only Pimobendane does not accomplish this point, the blood reflux of diseased region also can be made to 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.) improving 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.3rd class is thrombolytic medicine (as urokinase etc.).If apply this type of medicine can reach that to dissolve the object of embolus be ideal, but often need heavy dose during systemic vein medication, cause hemorrhage danger sometimes.Present multidirectional patient's recommendation interventional therapy, by conduit, embolus is dissolved at the position that medicine directly injects infarct exactly, but take the front and back of this methods for the treatment of all will do a cerebral angiograpathy, this inherently has again certain danger, in addition interventional therapy requires that patient carries out in obtaining 6 hours after being ill, sometimes often misses opportunity.4th class is anticoagulant therapy (as heparin etc.).This kind of medicine can prevent blood coagulation, but will look into prothrombin time and mobility every day when using, and the poor hospital of condition cannot carry out.In addition anticoagulant therapy also has hemorrhage danger.5th class uses calcium ion antagonist (as nimodipine etc.).This kind of medicine can prevent calcium ion from flowing in cell from extracellular, plays the mild dilation cerebrovascular, protection brain cell, increases brain cell and utilizes the effect such as oxygen and glucose.6th class is the medicine (as acetylsalicylic acid etc.) preventing platelet aggregation.At the beginning of hematoblastic cohesion cerebral thrombosis often, if can the cohesion of blocking platelet effectively, perhaps can be formed further in anti-hemostasis osmanthus.Current this kind of medicine is applied very extensive in the world, not equal to but be more appropriate as prophylactic agent as medicine, because the acute phase of cerebral apoplexy, uses this kind of 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, present invention employs following technical scheme:
Proved by animal experiment, 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 of improving water flood yet, in the present invention, compound then has the effect well improving symptoms of cerebral ischemia, and can improve the sleep state of animal.
Because formula I 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.
Compound shown in formula I and the first-selected sodium salt of basic metal salify.
Present invention also offers the pharmaceutical composition being used for the treatment of cerebral infarction, it is characterized in that general formula (1) compound or its salt containing treatment significant quantity and pharmaceutically acceptable carrier.Can be oral preparations or injection formulations.
Experiment proves to adopt the injection liquid that in embodiment 1 prepared by compound 1, show through haemolysis, irritant experiment, there is good tolerance, be suitable for being prepared into injection liquid at Clinical practice, be used for the treatment of the brain necrocytosis of patients with cerebral apoplexy and improve the sleep of patient.
Specific embodiment:
Embodiment 1: the preparation of each compound:
Because compound described herein has very strong continuity, in order to describe each compounds process for production thereof in detail, accurately, easily, it is expressed with 1 embodiment, the sequence number of compound is shown below each compound of following synthetic route, for simpler and clearer elaboration, replace with sequence number in preparation method below:
1, the synthesis of compound 3:
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, be added drop-wise in above-mentioned reaction solution after 29 g of compound 2 are dissolved in 40mL ethanol, 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, extraction into ethyl acetate (100mL × 3), merge organic layer, underpressure distillation obtains 16.2 g of compound 3 except 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, the synthesis of compound 4:
14.85 g of compound 3 and 17.55 grams of pyridines are dissolved in the THF of 150mL, under room temperature, THF solution 100mL being dissolved with 40.35 grams of anisoyl chlorides is slowly added drop-wise in above-mentioned reaction solution, dropwises in 30 minutes, then at room temperature continues reaction 5 hours.Stopped reaction, hydrochloric acid soln and the 150mL distilled water of 50mL1N is added in reaction solution, separate organic layer, aqueous layer with ethyl acetate extraction (0mL × 3), merge organic layer, underpressure distillation is except the crude product obtaining compound 4 after desolventizing, and obtain 25.6 sterlings with 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, the synthesis of compound 5:
The compound 4 of 25.0 grams 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, add in 10 minutes, continue reaction 2 hours.Stopped reaction, adds 10mL saturated ammonium chloride saturated solution, and underpressure distillation removing solvent methanol, add 100mL distilled water and 100mL ethyl acetate, separate organic layer, underpressure distillation obtains 23.9 g of compound 5, productive rate 95% except after desolventizing.MS(m/z)：236.2。
4, the synthesis of compound 6:
By 23.5 g of compound, 5,10.1 grams of triethylamines, 12.0 grams of Succinic anhydrieds and 0.12 gram of DMAP are dissolved in the THF of 150mL, react 6 hours at 70 DEG C.Stopped reaction, cooling reaction solution is to room temperature, add hydrochloric acid soln and the 100mL distilled water of 100mL1.0N, separate organic layer, aqueous layer with ethyl acetate extraction (50mL × 3), merges organic layer, with saturated common salt water washing (50mL × 3), underpressure distillation removes desolventizing and obtains 27.6 g of compound 6, productive rate 82%.MS(m/z)：336.2。
5, the synthesis of compound 1:
Join in the distilled water of 100mL by 27.0 g of compound 6, add 8.12 under room temperature on a small quantity can sodium bicarbonate in batches, has bubble to emerge, add rear continuation reaction 1 hour in solution.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, the acetone of slow dropping certain volume, there is Precipitation, suction filtration, 21.2 g of compound 1 are obtained after drying, 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: in embodiment 1, compound 1 is on the impact of local rats with cerebral ischemia cerebral infarct volume
(1) experiment material and method
Wistar rat, body weight 250-280g.Perioperatively is raised separately, and room temperature keeps 23-25 DEG C, own feed and water inlet.TMCAO model is prepared according to the method for longa etc.Rat 10% chloral hydrate anesthesia (350mg/kg, i.p.), body temperature maintains 37 ± 0.5 DEG C, and dorsal position is fixed on operating table.Cut skin along neck median line, be carefully separated right carotid (CCA), external carotid artery (ECA), internal carotid artery (ICA).ECA ligation is cut off, stretching with ICA in line.ECA cuts an osculum, by a long 4.0cm, the round end silication nylon rope (with 0.1% poly-lysine bag quilt) of diameter 0.26mm thus opening inserts ICA and is about 1.85-2.00cm, refers to rat brain prerolandic artery Rolando section start, blocks the supply of blood flow of arteria cerebri media.Ischemic carefully extracted nylon wire 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
Rat divides 12 groups at random: model control group, water for injection (100ml/kg), compound 1 administration group in embodiment 1 (25,50,100mg/kg), and MCA blocks oral administration when causing after ischemic 10 minutes.
(3) mensuration of cerebral infarct volume
Rat reperfusion injury is after 24 hours, and broken end gets brain at once, removes tractus olfactorius, cerebellum and low brain stem, it to be crownly cut into 6 (first to the 5th 2mm/ sheet, the 6th 4mm), to be placed in rapidly 5ml and to contain 1.5ml4%TTC and 0.1ml1MK
2hPO
4solution in dyeing (37 DEG C, lucifuge) 20-30 minute, stirred once every 5 minutes therebetween.After TTC dyeing, healthy tissues engrain takes on a red color, and infarction tissue is in white.Often will organize brain sheet marshalling, preservation of taking pictures.Ask the infarct size calculating every sheet, and final superposition 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 (%)=(volume of operation contralateral hemisphere volume-non-infarcted portion of operation side hemisphere)/operation contralateral hemisphere
(4) experimental result
Ischemic 2 hours of reperfusion is after 24 hours, 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: gastric infusion is on the impact of ischemic rat cerebral infarct volume (%)
With solvent control group ratio, compound 1 group of oral administration all significantly can reduce cerebral infarct volume.
Embodiment 3: in embodiment 1, compound 1 is on the impact of Sleep in Rats effect:
(1) improving water flood Experiment on Function
Animal-origin: Kun Ming mice, 18-22 gram, male, the cleaning grade animal provided by Guangdong Experimental Animal Center.Laboratory animal breeding room's temperature 22 ± 2 DEG C, relative humidity 50-70%, animal rearing material, is provided by Guangdong Experimental Animal Center.
This experiment sets compound 1 dosage as 25mg/kg, separately establishes distilled water control group.
Sample preparation: each sample thief 25mg respectively adding distil water, to 20ml, makes uniformly suspension, for examination.
To sample approach: gavage
Experimental technique:
(2) vetanarcol above threshold dosage hypnosis test:
Select body weight 18-22g male mice 40, be divided into four groups at random, often organize 10, give sample 30 days continuously, in the 30th day sample gavage after 15 minutes, to the vetanarcol abdominal injection of each treated animal 50mg/kg.b.w, injection volume is 0.2ml/20g.b.w, reach more than 1 minute as sleep judging criterion using mouse righting reflex loss, observe to the time for falling asleep of each treated animal in vetanarcol 60 minutes and the length of one's sleep.
Result:
Table 2: sample is on the impact of the weight of animals
As seen from the above table, sample each dosage treated animal body weight 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 (Analysis of variance) compared with control group
As seen from the above table, the time for falling asleep of compound 1 group of sample animal under above threshold dose of sodium pentobarbitone induction compared with control group, has significant difference with the length of one's sleep.
(3) vetanarcol sub-threshold dose hypnosis test:
Select body weight 18-22g male mice 40, be divided into four groups at random, often organize 10, give sample 28 days continuously, in the 28th day sample gavage after 15 minutes, to the vetanarcol abdominal injection of each treated animal 30mg/kg.b.w, injection volume is 0.2ml/20g.b.w, reaches observe the number of animals that sleep occurs to treated animal each in vetanarcol 25 minutes as sleep judging criterion in more than 1 minute using mouse righting reflex loss.
Result:
Table 4: the impact of the vetanarcol inducing mouse sleep incidence of sub-threshold dose
* P<0.05 (through chi square test) compared with control group
As seen from the above table, compound 1 group and the control group sleep animal under the induction of sub-threshold dose vetanarcol compared with control group, all has significance poor with sleep incidence.
Sum up: per os gave mouse samples after 30 days, and compound 1 group has the effect of improving water flood.
Embodiment 4: adopt the injection liquid that in embodiment 1 prepared by compound 1:
The compound 1 accurately taking 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, inject water to 4000ml, add 2g needle-use activated carbon, boil 15min, suction filtration decarburization, solution is through 0.22 μm of filtering with microporous membrane, and solution embedding (often props up containing compound 1:94mg) preparation through 115 DEG C of pressurization sterilizing 30min in glass ampoule.
Embodiment 5: injection liquid hemolytic and irritation test in embodiment 4
Liquid hemolytic is tested:
Hemolysis in vitro is tested: the lower concentration of injection liquid prepared by the embodiment 4 adding inequality in each the drug liquid tube filling 2% red blood corpuscle suspension respectively and high density (0.63mg/mL and 1.88mg/mL), each drug liquid tube did not produce hemolytic action in 3 hours.The outer hemolytic negative of injecting fluid prepared by embodiment 4 is described.Concrete experimental technique and experimental result as follows:
1, the preparation of test medicine:
(1) high dose group: injection liquid (4mL:94mg/ bottle) 1 bottle prepared by Example 4, is diluted to 6.25mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 0.5mL, makes into the solution that concentration is 1.88mg/mL.
(2) low dose group: get the solution 2mL that above-mentioned concentration is 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 the triangular flask jolting 10 minutes filled containing granulated glass sphere, removing Fibrinogen, makes into defibrinated blood.Then be divided in several centrifuge tubes, 0.9% sodium chloride injection of every Guan Jiayue 10 times amount, shakes up, centrifugal (1500 revs/min, 15 minutes), removing supernatant liquor, the red blood corpuscle of precipitation washs 2-3 time with 0.9% sodium chloride injection again, till the aobvious redness of supernatant liquor.Gained red blood corpuscle is made into the suspension of 2% with 0.9% sodium chloride injection, is for experiment.
Get the uniform clean tube of caliber size 7 (every Guan Junshe parallel pipe), after numbering, 2% red blood corpuscle suspension, 0.9% sodium chloride injection, water for injection and tested liquid is added successively by proportional quantity shown in table 9 with transfer pipet, put immediately after mixing in 37 DEG C of thermostat containers and carry out incubation, start to observe once every 15 minutes, after 1 hour, observed once every 1 hour, observe 3 hours altogether.
The preparation numbering of table 5:2% red blood corpuscle suspension
Note: wherein 1-5 pipe is trial-product pipe, the 6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
(2) result is observed:
As in test, solution be clear and bright redness, acellular residual or have a small amount of red corpuscle residual at the bottom of pipe, namely indicate that haemolysis occurs; As red corpuscle all sinks, supernatant fluid achromatism and clarity, shows to occur without haemolysis.As having red-brown or reddish-brown flocks in solution, not disperseing after jolting, showing have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, need to judge further to be true cohesion or pseudo agglutination.If condensation product can be uniformly dispersed again after test tube vibration, or is placed on wave carrier piece by aggregation, drip 2 0.9% sodium chloride injections, examine under a microscope at cover glass edge, 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 judges
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, then tested material can inject use; If the solution in tested property management produced haemolysis and (or) cohesion in 3 hours, then tested material should not inject use.
4, test-results
To add lower concentration be respectively 0.63mg/mL and high density is that each drug liquid tube of the injection liquid solution of 1.88mg/mL did not all produce hemolytic action, hemolysis in vitro 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; 6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
Table 7: injection liquid (low dose group) hemolytic test-results (visual inspection)
Note: "+" represents full haemolysis, "-" represents not haemolysis; 6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
Injection liquid vascular stimulation tests
Rabbit vascular stimulation tests: healthy new zealand rabbit 8 is selected in test, adopt consubstantiality left and right sides ear self-contrast method, left side auricular vein injection test medicine, administration volume 5ml/kg body weight, injection liquid prepared by the embodiment 4 that each administration group gives corresponding dosage, low dose group and high dose group dosage are 3.15mg/kgbw and 9.4mg/kgbw respectively, (calculate its lower concentration by concentration and high density is respectively 0.63mg/mL and 1.88mg/mL, it is 0.7-1.4 times and 2-4 times of a clinical intravenous drip plan concentration), 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 give successively by after the high density of reagent and lower concentration, then give 0.9% sodium chloride injection respectively.2 rabbits of respectively getting low dosage and high dosage cut open inspection in 48 hours after last administration, and 4 rabbits of remaining lower concentration and high density cut open inspection after 2 week decubation of last administration terminates.8 animal ears vessel profile 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 toxicological significance.Illustrate that injection liquid vascular stimulation tests prepared by embodiment 4 conforms with the regulations.Concrete experimental technique and experimental result as follows:
1, the preparation of tested material:
(1) high dose group: injection liquid (4mL:94mg/ bottle) 2 bottles prepared by Example 4, is diluted to 100.0mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 8mL, makes into the solution that concentration is 1.88mg/mL.
(2) low dose group: get the solution 30mL that above-mentioned concentration is 1.88mg/mL, be diluted to 90.0mL with 0.9% sodium chloride injection, be diluted to the solution that concentration is 0.63mg/mL.
2, animal is weighed: within 48 hours and 14 days, respectively weigh once before administration and after last administration.
3, overview and animal are drawn materials:
Observe before administration every day and record the reaction at animal and intravascular injection position, after last administration 48 hours, the high density of sacrificed by exsanguination test medicine and 2 new zealand rabbits of lower concentration respectively, visual inspection after recording the reaction of vascular tissue, cut from basal part of the ear portion two rabbit ear (first cut left ear, after cut auris dextra, and mark), then clip one section of rabbit ear sample is fixed in 10% neutral formalin solution that (sample is about 8cm, wide about 1cm respectively; Distal end otch is about 0.5cm place apart from the first pinprick, and proximal part otch is about 2cm place apart from the 3rd pinprick, and hanging wire end is proximal part).Respectively leave the high density of test medicine and lower concentration 2 animals to continue to observe to last administration 14 days, carry out following pathologic finding: with the first pinprick for boundary, far-end cuts one section; With the 3rd pinprick for boundary, near-end cuts two sections; Blood vessel crosscut during film-making, routine paraffin wax flaking, slice thickness is about 4-5 μm, and H-E dyes, and then carries out histopathologic examination.
4, result judges
Result according to visual inspection and pathologic finding carries out comprehensive descision.
5, test-results
5.1 visual inspections:
Visual inspection before administration every day also records the reaction of animal blood vessels injection site, during administration, in the Some Animals administration side of the visible test 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 vessel profile of the high density of test medicine and 4 of lower concentration rabbits 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 test medicine and 4 rabbits of lower concentration, bilateral rabbit ear vessel profile is more clear, and rabbit ear thickness is even, has no obvious change.
5.2 pathologic findings:
The high density of test medicine and 4 of lower concentration rabbits cut open inspection in 48 hours after last administration, and the high density of remaining test medicine and 4 of lower concentration rabbits cut open inspection after 2 week decubation terminated.Histopathologic examination is showed no vascular tissue has the significant stimulation such as sex change or necrosis to react.The results are shown in Table 8 and table 9:
Table 8: injection liquid (high dose group) is to rabbit ear vascular stimulation reaction (after last administration 48 hours visual results)
Table 9: injection liquid (low dose group) is to rabbit ear vascular stimulation reaction (after last administration 48 hours visual results)
These results suggest that the injection liquid adopting the compound 1 in embodiment 1 to prepare shows to have good security through hemolytic and vascular stimulation tests, be suitable for being prepared into injection liquid at Clinical practice.
Claims (4)
1. there is a compound for prevention and therapy cerebrovascular ischemic disease, as shown below:
2. the salt that generates of compound as claimed in claim 1 and sodium, potassium, magnesium, calcium, Trometamol, diethylamine, triethylamine, thanomin, quadrol, dimethylamine, hydroxyethylethylene diamine, aminoethanolamine.
3. the application of compound described in any one of claim 1-2 in preparation treatment cerebral ischemia diseases medicine.
4. compound described in any one of claim 1-2 is preparing the application in improving water flood medicine.
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| ES2184145T3 (en) * | 1996-12-13 | 2003-04-01 | Aventis Pharma Inc | SULPHONIC ACID OR SULFONYLAMINE ACIDS-N- (HETEROARALQUIL) -AZAHETEROCICLILAMIDA. |
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