CN101721408A - New application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone - Google Patents
New application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone Download PDFInfo
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- CN101721408A CN101721408A CN200910263042A CN200910263042A CN101721408A CN 101721408 A CN101721408 A CN 101721408A CN 200910263042 A CN200910263042 A CN 200910263042A CN 200910263042 A CN200910263042 A CN 200910263042A CN 101721408 A CN101721408 A CN 101721408A
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Abstract
The invention relates to a new application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone and/or tautomer thereof in the treatment and/or prevention of cerebrovascular diseases, in particular to a new application in the treatment and/or prevention of ischemic cerebrovascular diseases and a new application in the treatment and/or prevention of cerebral infarction. The invention also relates to a drug composition containing the 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone and/or the tautomer thereof.
Description
Technical field
The present invention relates to 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone and/or its tautomer and treating and/or preventing the new purposes of cerebrovascular, particularly treat and/or prevent the new purposes of ischemic cerebrovascular, particularly treat and/or prevent the new purposes of cerebral infarction.
Background technology
Cerebrovascular is the disease of one group of serious harm human health, has become at present that the mankind are disabled and one of dead major reason.
(cerebrovascular disease CVD) is meant because the brain lesions that cerebrovascular causes unusually cerebrovascular.Apoplexy (stroke) refers generally to acute cerebrovascular disease.
Cerebrovascular can simply be divided into two classes, and a class is owing to the minimizing of blood flow or the ischemic cerebrovascular that cutout causes, and another kind of is because angiorrhexis causes hemorrhagic apoplexy.Ischemic cerebrovascular mainly is cerebral infarction (comprising cerebral thrombosis and cerebral embolism), except cerebral infarction, also have and a kind ofly in 24 hours, can recover fully, do not stay the ischemic cerebrovascular of any sequela, be called as transient ischemic attack or transient cerebral ischemic attack, doctor's custom abbreviates TIA as, also is called transient apoplexy.Hemorrhagic apoplexy also is divided into two classes, and a class is an angiorrhexis, in the blood flow human brain essence, is called cerebral hemorrhage or cerebral hemorrhage.Another kind of is angiorrhexis, and the blood person who lives in exile holds the subarachnoid space around the brain, is called subarachnoid hemorrhage, and the doctor is called for short SAH.
3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, its structural formula:
Molecular formula: C
13H
14N
2O
2Molecular weight 230.26
There is isomerism in 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, and its tautomer has 3-methyl-4-(2-oxopropyl)-5-hydroxyl-1-phenyl-1H-pyrazoles, its structural formula:
And tautomer 4-(2-hydroxyl-1-acrylic)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5 (4H)-ketone, its structural formula:
And tautomer 4-(2-hydroxyl-1-acrylic)-3-methyl-5-hydroxyl-1-phenyl-1H-pyrazoles, its structural formula:
In above-mentioned four kinds of structures, comparatively common with 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone and 3-methyl-4-(2-oxopropyl)-5-hydroxyl-1-phenyl-1H-pyrazoles.
Summary of the invention
The present invention finds by a large amount of experiment, and a kind of have a following structure
3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (the 4H)-application of ketone in treating and/or preventing the medicine of cerebrovascular in have remarkable advantages.
The present invention also provides having of a kind of above-claimed cpd following structure
Tautomer: 3-methyl-4-(2-the oxopropyl)-5-hydroxyl-1-phenyl-application of 1H-pyrazoles in treating and/or preventing the medicine of cerebrovascular.
The present invention also provides having of a kind of above-claimed cpd following structure
Tautomer: 4-(2-hydroxyl-1-acrylic)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5 (the 4H)-application of ketone in treating and/or preventing the medicine of cerebrovascular.
The present invention also provides having of a kind of above-claimed cpd following structure
Tautomer: 4-(2-hydroxyl-1-the acrylic)-3-methyl-5-hydroxyl-1-phenyl-application of 1H-pyrazoles in treating and/or preventing the medicine of cerebrovascular.
The preferred ischemic cerebrovascular of cerebrovascular of the present invention, further preferred cerebral infarction.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone and pharmaceutically acceptable excipient or carrier.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, 3-methyl-4-(2-the oxopropyl)-5-hydroxyl-1-phenyl-blended compositions of 1H-pyrazoles and pharmaceutically acceptable excipient or carrier.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, 3-methyl-4-(2-oxopropyl)-5-hydroxyl-1-phenyl-1H-pyrazoles, 4-(2-hydroxyl-1-acrylic)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5 (4H)-ketone, 4-(2-hydroxyl-1-the acrylic)-3-methyl-5-hydroxyl-1-phenyl-blended compositions of 1H-pyrazoles and pharmaceutically acceptable excipient or carrier.
The present invention discovers that 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone and/or its tautomerism physical ability are improved rat neurological handicap symptom, dwindle infarct size, reduces brain water content, alleviates the brain injury degree.Particularly compare, reducing infarct size, alleviate brain injury, reduce the brain water content aspect and have the trend of certain improvement with listing medicine Edaravone.And improvement and Edaravone to the neurological handicap symptom are suitable.
The specific embodiment
Subordinate embodiment illustrates the present invention, is not limited to the present invention.For simplicity, refer to 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone with XS130.
Embodiment 1
Get XS130 solid 2g, add in the propylene glycol solution of 200g, stir and make dissolving fully, add slowly that water for injection makes it dissolving and, the 5ml ampoule filling to 1000ml.
Embodiment 2
1 materials and methods
1.1Sprague-Dawley (SD) rat is male, body weight 240-280g, cleaning level.
1.2 the XS130 injection (2mg/ml) of medicine and reagent embodiment 1 faces with before being diluted to desired concn.Commercially available Edaravone Injection.
1.3 method
1.3.1 the preparation of cerebral ischemic model adopts internal carotid artery line bolt legal system to be equipped with middle cerebral artery occlusion (Middle cerebralartery, MCAO) cerebral ischemia re-pouring model.Animal separates right carotid, external carotid artery, internal carotid artery after anaesthetizing with 10% chloral hydrate (3.5ml/kg), and ligation is also cut off external carotid artery, the tie wings arteria palatina.Folder closes the common carotid artery proximal part, make a kerf from the far-end of the ligature of external carotid artery, inserting external diameter is the nylon wire of 0.285mm, advances the common carotid artery bifurcated and enters internal carotid artery, slowly be inserted into then (from the about 20mm of crotch) till the slight resistance, all blood confessions of blocking-up middle cerebral artery are with laser-Doppler cerebral blood flow instrument monitoring cerebral blood flow, behind the right side cerebral ischemia 2.0h, extract nylon wire gently, recover blood for pouring into again, sew up scalp, sterilization.Sham operated rats is separating blood vessel only, does not insert nylon wire.
1.3.2 animal grouping and the pharmacodynamics test of this experimental observation of administration XS130 to cerebral ischemia, if 1.5mg/kg (dosage group 1) and 2 dosage groups of 0.75mg/kg (dosage group 2), model group is injected isopyknic solvent to rat tail vein, sham operated rats is injected isopyknic solvent to rat tail vein, positive drug control group with Edaravone Injection as positive control, adopt the dosage 1.5mg/kg of bibliographical information, totally 5 groups, animal is by impartial single blind each group that is dispensed to of probability.
1.3.3 the evaluation of neurological handicap symptom adopts 5 fens method for makings of improvement Bederson to carry out the evaluation of neurological handicap symptom.The neurological handicap symptom of rat behind the single blind method evaluation cerebral trauma of employing.
After 1.3.4 brain infarction area and brain injury are measured Animal Anesthesia, broken end is got brain, remove olfactory bulb, cerebellum and low brain stem, with normal saline flushing brain surface bloodstain, remained on surface water mark is removed in suction, place 7min in-80 ℃, make coronal section vertically downward in the optic chiasma plane immediately after the taking-up, and cut a slice every 2mm backward, the brain sheet is placed use in the freshly prepared TTC solution of PBS (0.2mol/L, pH 7.4～7.8) in 37 ℃ of incubation 90min, normal cerebral tissue dyes peony, ischemic tissue of brain then is pale asphyxia, behind normal saline flushing, rapidly the brain sheet is arranged in a row in the past backward in order, blot remained on surface water mark, take pictures, separate left and right sides cerebral tissue and weigh respectively, be expressed as W
A left sideAnd W
Right, (DMSO: ethanol 1: 1) 15 milliliters, in 25 ℃, lucifuge incubation 24 hours fully extracts replacing by the red material first moon of generating, and is white in color to the brain sheet respectively to add the extracting solution of fresh configuration to the left and right in the cerebral tissue.
(1) add up with the image analysis software comparison film, draw a circle to approve the right side ischemic areas (white portion) and the right side gross area, calculate the percentage ratio of brain infarction area with following formula:
(2) extract of left and right sides cerebral tissue is measured its absorbance (extract 100 μ l+ extracting solution 1900 μ l) respectively in the 485nm place, measured four times, get its average, be expressed as A
A left sideAnd A
Right, calculate the percentage ratio of brain injury degree with following formula:
After 1.3.5 mortality rate is rejected the animal of operative failure and cerebral hemorrhage, the animal dead rate of each group of record.
1.3.6 the statistical analysis quantitative data is expressed as means standard deviation.Brain infarction area, brain injury degree, neurological handicap symptom score adopt one factor analysis of variance, the significance of difference between the Scheffe`s check is measured two groups.The animal dead rate is with the significance of difference between X2 check mensuration group.Difference P＜0.05 is defined as significant difference.
2 results
2.1 influence to the neurological handicap symptom
The scoring of neurological handicap severity of symptom sees Table 1, and model group and sham operated rats more all have significant difference (F
5,35=10.42, P＜0.001), show that cerebral ischemia re-pouring causes serious neurological handicap symptom; XS130 dosage group 1 (F
5,35=10.42, P=0.015), dosage group 2 (F
5,35=10.42, P=0.039) with Edaravone group (F
5,35=10.42, P=0.039) compare with model group, the neurological handicap symptom all obviously alleviates.The result shows that XS130 can improve the neurological handicap symptom of cerebral ischemia re-pouring animal, and suitable with the Edaravone effect.
Table 1.XS130 is to the influence of neurological handicap symptom
X ± SD,
*Compare with sham-operation P＜0.05;
#Compare with model group P＜0.05.
2.2 influence to brain infarction area
Each is organized brain infarction area and sees Table 2, and model group and sham operated rats relatively have significant difference (F
5,35=5.95, P=0.001), show that cerebral ischemia re-pouring causes tangible cerebral infarction; XS130 dosage group 1 compares with model group, and infarct size significantly dwindles (F
5,35=5.95, P=0.034), to compare with the Edaravone group, infarction size has the trend that reduces.
Table 2.XS130 is to the influence of brain infarction area
X ± SD,
*Compare with sham-operation P＜0.05;
#Compare with model group P＜0.05.
2.3 influence to brain injury
Each is organized brain injury and sees Table 3, and model group and sham operated rats relatively have significant difference (F
5,35=5.39, P=0.004), show that cerebral ischemia re-pouring causes tangible brain injury; XS130 dosage group 1 compares with model group, and the brain injury degree obviously alleviates (F
5,35=5.39, P=0.010), to compare with the Edaravone group, brain injury has the trend that alleviates.The result shows that giving TR behind the cerebral ischemia re-pouring carries out acute treatment, can significantly alleviate the brain injury degree.
Table 3.XS130 is to the influence of brain injury
X ± SD, compare with sham-operation * P＜0.05; Compare with model group #P＜0.05.
2.4 influence to mortality rate
The ultimate mortality table 4 of each treated animal, the animal dead rate does not have significant difference between each group, shows that XS130 does not make significant difference to the mortality rate of cerebral ischemia animal.
Table 4.XS130 is to the influence of mortality rate
Embodiment 3
1 materials and methods
1.1Sprague-Dawley (SD) rat is male, body weight 240-280g, cleaning level.
1.2 the XS130 injection (2mg/ml) of medicine and reagent embodiment 1 faces with before being diluted to desired concn.Commercially available Edaravone Injection.
1.3 method
1.3.1 the preparation of cerebral ischemic model adopts internal carotid artery line bolt legal system to be equipped with middle cerebral artery occlusion (Middle cerebralartery, MCAO) cerebral ischemia re-pouring model.Animal separates right carotid, external carotid artery, internal carotid artery after anaesthetizing with 10% chloral hydrate (3.5ml/kg), and ligation is also cut off external carotid artery, the tie wings arteria palatina.Folder closes the common carotid artery proximal part, make a kerf from the far-end of the ligature of external carotid artery, inserting external diameter is the nylon wire of 0.285mm, advances the common carotid artery bifurcated and enters internal carotid artery, slowly be inserted into then (from the about 20mm of crotch) till the slight resistance, all blood confessions of blocking-up middle cerebral artery are with laser-Doppler cerebral blood flow instrument monitoring cerebral blood flow, behind the right side cerebral ischemia 2.0h, extract nylon wire gently, recover blood for pouring into again, sew up scalp, sterilization.Sham operated rats is separating blood vessel only, does not insert nylon wire.
1.3.2 animal grouping and the pharmacodynamics test of this experimental observation of administration XS130 to cerebral ischemia, if 3.0mg/kg (dosage group 1) and 2 dosage groups of 1.5mg/kg (dosage group 2), model group is injected isopyknic solvent to rat tail vein, sham operated rats is injected isopyknic solvent to rat tail vein, positive drug control group with Edaravone Injection as positive control, adopt the dosage 1.5mg/kg of bibliographical information, totally 5 groups, in operation process, it is all disallowable that the animal of abnormal conditions appears in all anesthesia, operation etc.Behind the cerebral ischemic model, animal is organized by impartial single blind being dispensed to respectively of probability.
1.3.3 the evaluation of neurological handicap symptom adopts 5 fens method for makings of improvement Bederson to carry out the evaluation of neurological handicap symptom.The neurological handicap symptom of rat behind the single blind method evaluation cerebral trauma of employing.
1.3.4 brain water content is measured animal and used 10% chloral hydrate anesthesia, broken end is got brain, removes olfactory bulb, cerebellum and low brain stem, with normal saline flushing brain surface bloodstain, inhale and remove remained on surface water mark, separate left and right brain rapidly, divide the another name weight in wet base, get left side weight in wet base (W
Left side weight in wet base) and right side weight in wet base (W
Right weight in wet base).In cerebral tissue placement surface ware, in 60 ℃ of oven dry, repeatedly weighing to double (at interval＞0.5 hour) weighing difference less than 0.0005g, left side dry weight (W
Left side dry weight) and right side dry weight (W
Right dry weight).Brain water content is calculated as follows:
Brain water content changing value (%)=damage side brain water content (%)-control sides brain water content (%)
1.3.5 statistical analysis
Quantitative data is expressed as means standard deviation.Neurological handicap symptom score, brain water content changing value all adopt one factor analysis of variance, the significance of difference between the Scheffe`s check is measured two groups.The animal dead rate is with the significance of difference between X2 check mensuration group.Difference P＜0.05 is defined as significant difference.
2 results
2.1 influence to the neurological handicap symptom
The scoring of neurological handicap severity of symptom sees Table 5, and model group and sham operated rats more all have significant difference (F
5,40=12.39, P＜0.001), show that cerebral ischemia re-pouring causes tangible neurological handicap symptom; XS130 dosage group 2 obviously alleviates (F with model group comparison neurological handicap symptom
5,40=12.39, P=0.004).The result shows that XS130 can improve the neurological handicap symptom of cerebral ischemia re-pouring animal, and suitable with the Edaravone effect.
Table 5.XS130 is to the influence of neurological handicap symptom
X ± SD,
*Compare with sham-operation P＜0.05;
#Compare with model group P＜0.05.
2.2 influence to brain water content
Each is organized brain water content and sees Table 6, and model group and sham operated rats relatively have significant difference (F
5,40=12.29, P＜0.001), show that cerebral ischemia re-pouring causes serious cerebral edema; XS130 dosage group 2 obviously reduces (F with model group comparison brain water content
5,40=12.29, P=0.006), to compare with the Edaravone group, cerebral edema has the trend that alleviates.The result shows that XS130 can alleviate cerebral edema.
Table 6.XS130 is to the influence of brain water content
X ± SD,
*Compare with sham-operation P＜0.05;
#Compare with model group P＜0.05.
2.3 influence to mortality rate
The ultimate mortality table 7 of each treated animal, the animal dead rate does not have significant difference between each group, shows that XS130 does not make significant difference to the mortality rate of cerebral ischemia animal.
Table 7.XS130 is to the influence of mortality rate
Claims (10)
1. one kind has following structure
3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (the 4H)-application of ketone in treating and/or preventing the medicine of cerebrovascular.
2. application according to claim 1 is characterized in that the following structure of having of the described chemical compound of claim 1
Tautomer: 3-methyl-4-(2-oxopropyl)-5-hydroxyl-1-phenyl-1H-pyrazoles.
3. application according to claim 1 is characterized in that the following structure of having of the described chemical compound of claim 1
Tautomer: 4-(2-hydroxyl-1-acrylic)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5 (4H)-ketone.
4. application according to claim 1 is characterized in that the following structure of having of the described chemical compound of claim 1
Tautomer: 4-(2-hydroxyl-1-acrylic)-3-methyl-5-hydroxyl-1-phenyl-1H-pyrazoles.
5. application according to claim 1 is characterized in that described cerebrovascular is an ischemic cerebrovascular.
6. application according to claim 1 is characterized in that described ischemic cerebrovascular is a cerebral infarction.
7. a pharmaceutical composition is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone and pharmaceutically acceptable excipient or carrier.
8. a pharmaceutical composition is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, 3-methyl-4-(2-the oxopropyl)-5-hydroxyl-1-phenyl-blended compositions of 1H-pyrazoles and pharmaceutically acceptable excipient or carrier.
9. a pharmaceutical composition is characterized in that comprising 3-methyl-4-(2-oxopropyl)-1-phenyl-1H-pyrazoles-5 (4H)-ketone, 3-methyl-4-(2-oxopropyl)-5-hydroxyl-1-phenyl-1H-pyrazoles, 4-(2-hydroxyl-1-acrylic)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5 (4H)-ketone, 4-(2-hydroxyl-1-the acrylic)-3-methyl-5-hydroxyl-1-phenyl-blended compositions of 1H-pyrazoles and pharmaceutically acceptable excipient or carrier.
10. each described pharmaceutical composition application in treating and/or preventing the cerebrovascular medicine in the claim 7～9.
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| CN200910263042A CN101721408A (en) | 2009-12-15 | 2009-12-15 | New application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102336710A (en) * | 2011-07-11 | 2012-02-01 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN108314652A (en) * | 2017-01-18 | 2018-07-24 | 周意 | Edaravone derivative and application thereof |
| WO2022037537A1 (en) * | 2020-08-17 | 2022-02-24 | 先声药业有限公司 | Stable pharmaceutical composition |
-
2009
- 2009-12-15 CN CN200910263042A patent/CN101721408A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102336710A (en) * | 2011-07-11 | 2012-02-01 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN102336710B (en) * | 2011-07-11 | 2014-03-12 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN108314652A (en) * | 2017-01-18 | 2018-07-24 | 周意 | Edaravone derivative and application thereof |
| WO2022037537A1 (en) * | 2020-08-17 | 2022-02-24 | 先声药业有限公司 | Stable pharmaceutical composition |
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