CN108864243B - For treating the pharmaceutical composition and its preparation of cerebral ischemia - Google Patents
For treating the pharmaceutical composition and its preparation of cerebral ischemia Download PDFInfo
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- CN108864243B CN108864243B CN201810600373.0A CN201810600373A CN108864243B CN 108864243 B CN108864243 B CN 108864243B CN 201810600373 A CN201810600373 A CN 201810600373A CN 108864243 B CN108864243 B CN 108864243B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of for treating the pharmaceutical composition and its preparation of cerebral ischemia, belongs to drug field.Comprising: compound of formula I.Apparent synergistic effect can also be can produce in terms for the treatment of cerebral ischemia comprising Edaravone, compound of formula I and Edaravone in described pharmaceutical composition.The present invention also provides the related preparations of described pharmaceutical composition and its applications.
Description
Technical field
The present invention relates to a kind of for treating the pharmaceutical composition and its preparation of cerebral ischemia, belongs to drug field.
Background technique
Ischemic cerebrovascular disease (Ischemic cerebrovascular disease) is one of common clinical, mainly
Refer to that disease incidence linearly rises with the growth at age, is since brain blood supply disorder causes one group of disease of corresponding mental symptom
Countries in the world adult's death and one of the main reason for disable.Currently, as China human mortality structure is increasingly aging, the cerebrovascular
Disease incidence number obviously increases.Therefore, it is that the whole society is of interest to the prevention and treatment of cerebral ischemia, how prevents and treats Imaging in Patients with Cerebral Ischemia Disease
And its caused cerebral injury, cause the domestic and international extensive concern in relation to scholar.
Currently, brain tissue is especially sensitive to ischemic according to the study of incident mechanism of ischemic cerebrovascular disease, ischemic is more than 6
Hour, ischemic region function is difficult to restore.Therefore, the patient for Ischemia Time lower than 6 hours generallys use recombinant tissue-type's fibre
The thrombolytic drugs such as lyase original rt-PA are treated, for such therapy once work, patient usually it is less leave after lose
Disease, but it is limited by the limitation of China's medical services, less patient can be effectively treated in 6 hours of onset, most of
Patient can miss thrombolytic treatment time window.And for the patient for missing therapeutic time window, generally use at this stage calcium from
The neuroprotective agents such as sub- antagonist, free radical scavenger are treated, and can be aided with traditional blood-activating and stasis-removing (example sometimes
Such as, wilsonii, Radix Salviae Miltiorrhizae or ginseng etc.), generally speaking curative effect is poor, and disability rate is higher, and can be less with drug.
CN2017101170041 discloses steroid saponin compound, to human muscle creatine kinase cell HL-60, people
Histocytic lymphoma's 3 tumor lines of cell U937 and human liver cancer cell HepG2 all have different degrees of tumor suppression and make
With showing that it can be further used as new anti-inflammatory, anti-tumor drug and be researched and developed, do not ground to its anti-cerebral ischemia
Study carefully.
Summary of the invention
The first aspect of the present invention is to provide a kind of compound of formula I, is used as anti-cerebral ischemia drugs, and structural formula is as follows:
The second aspect of the present invention is to provide a kind of for treating the pharmaceutical composition of cerebral ischemia comprising compound of formula I
And Edaravone.
Present inventors have unexpectedly found that above-mentioned compound of formula I while with treating cerebral ischemia, is combined with Edaravone
It can produce apparent synergistic therapeutic action, present invention discover that compound of formula I and the weight ratio of Edaravone are 1:0.01-0.5
Between can produce apparent synergistic effect, it is best with the synergy of 1:0.2.
The third aspect of the present invention is to provide a kind of pharmaceutical preparation comprising described pharmaceutical composition and can pharmaceutically connect
The carrier received.
In one embodiment, the pharmaceutical preparation is oral preparation or injection.
In another embodiment, the pharmaceutically acceptable carrier is selected from starch, beta-cyclodextrin, carbomer, micro-
Crystalline cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, calcium carboxymethylcellulose, polyethylene glycol (PEG), carboxylic
Sodium carboxymethylcellulose pyce, methylcellulose, ethyl cellulose, mannitol, lauryl sodium sulfate, croscarmellose sodium,
Lactose, polyvinylpyrrolidone (PVP), crosslinked polyvinylpyrrolidone, ethyl-para-hydroxybenzoate, magnesium stearate, talcum powder,
One or more of superfine silica gel powder, Aspartame, orange flavor, sodium bicarbonate, sodium carbonate, enteric coating powder.Above-mentioned preparation
Auxiliary material used and its conventional auxiliary material can be used for preparation method and preparation method is made.
The third aspect of the present invention is to provide application of the described pharmaceutical composition in preparation treatment brain ischemia medicament.
In above-mentioned medical usage, administration time and administration number of times for pharmaceutical composition of the present invention are needed according to disease
Depending on the specific diagnostic result of feelings, this is within the technical scope that those skilled in the art grasp.
Specific embodiment
Also the present invention further can be understood by embodiment, wherein the embodiment illustrates some preparations or user
Method.It is to be appreciated, however, that these embodiments do not limit the present invention.The change of the invention of currently known or further exploitation
Change is considered within the scope of the invention described herein and claimed below.
The preparation of 1 compound of formula I of embodiment
Dry black nightshade Chinese olive medicinal material 1kg is taken twice with hexamethylene refluxing extraction to discard hexamethylene extracting solution.Ungrease treatment
Medicinal material afterwards is with 10 times of 70% methanol heating and refluxing extraction 3 times measured, and 2 hours every time, combined extract was concentrated under reduced pressure to give leaching
Cream.Medicinal extract is suspended with water, through D101 macroporous resin column (1000 × 100mm), respectively with water, 10% methanol, 30% methanol,
50% methanol, 70% methanol and the elution of 100% methanol, wherein 50% methanol-eluted fractions pass through silica gel column chromatography, reverse phase repeatedly
MPLC column chromatography, Sephadex LH-20 column chromatography and the means such as reversed-phase HPLC column chromatography are partly prepared, isolated Formulas I chemical combination
Object.
2 compound of formula I of embodiment and pharmaceutical composition lack the influence of pool model to PC12 cell hypoxia
Cell culture: it takes and freezes the recovery of PC12 cell strain in centrifuge tube, after centrifuging and taking supernatant, with containing 10%FBS's
RPMI1640 culture medium is suspended, and is inoculated in culture dish and carries out subculture with incubator, cell is harvested in logarithmic growth phase, uses
Culture medium, which is suspended, adjusts concentration to 1 × 104A/ml is laid in 24 orifice plates, is used for follow-up test.
Experimental group: Normal group persistently passes to 95%O2And 5%CO2Gaseous mixture, be changed without culture solution；Deficiency
Sugared (OGD) model group: nerve cell removes normal culture solution, change without glucose HBSS solution (140mM NaCl,
3.5mM KCl,12mM MgSO4, 5mM NaHCO3,1.7mM CaCl2,0.4mM KH2PO4, 10mM Hepes), it is put into dedicated
Anoxic tank passes to 95%N2And 5%CO2Gaseous mixture, Anoxia 6h；Administration group, cell is with including different pharmaceutical composition
After DMEM liquid pre-processes 3h, cell is again through above-mentioned OGD model 6h；Specific dosage regimen is as follows:
| Group | Compound of formula I | Edaravone |
| Administration group 1 | 0.1mg/L | - |
| Administration group 2 | 1mg/L | - |
| Administration group 3 | 2mg/L | - |
| Administration group 4 | - | 2mg/L |
| Administration group 5 | 1mg/L | 0.1mg/L |
| Administration group 6 | 1mg/L | 0.2mg/L |
| Administration group 7 | 1mg/L | 0.5mg/L |
Concrete outcome is as follows:
1) cytoactive detection (MTT)
It is examined through Oneway-ANOVA, ## represents p < 0.01 compared with Normal group；* represent compared with model group p <
0.01
2) LDH and SOD determination of activity
| Group | LDH(U/L) | SOD(U/ml) |
| Normal group | 107.1±17.47 | 111.1±10.35 |
| Model group | 360.3±18.99## | 49.6±4.98## |
| Administration group 1 | 315.1±16.38 | 54.3±7.14 |
| Administration group 2 | 249.7±19.89** | 72.5±9.40** |
| Administration group 3 | 178.8±18.16** | 84.2±7.65** |
| Administration group 4 | 221.7±21.64** | 93.7±8.53** |
| Administration group 5 | 197.9±19.74** | 89.1±6.17** |
| Administration group 6 | 140.6±18.92** | 104.9±7.61** |
| Administration group 7 | 151.3±20.17** | 103.2±6.26** |
The influence of 3 compound of formula I of embodiment and pharmaceutical composition to MCAO models in rats
According to the cell experiment of embodiment 2 as a result, the present invention has further investigated compound of formula I and its joined with Edaravone
With the influence to substantially animal model.
Experimental animal selection male Wistar rat, about 200 grams of weight, secondary animal.Operation consent 1 hour and Reperfu- sion it
2 hours intraperitoneal injection of drugs afterwards.Blank control group and model control group intraperitoneal injection of saline；Each administration group composition is as follows:
| Group | Compound of formula I | Edaravone |
| Administration group 1 | 5mg/kg | - |
| Administration group 2 | - | 5mg/kg |
| Administration group 3 | 4.2mg/kg | 0.8mg/kg |
Modeling method: selecting diameter is that the nylon yarn of 0.23mm is moulded into linear and is cut into the line segment of 5cm, and front end is with carefully
Sand paper polishing is dipped in glue and is allowed to smoothly, spare marking at front end 1.6cm, 1.8cm, 2.0cm, faces the used time for nylon yarn
Front end dips heparin.10% chloral hydrate anesthesia is injected intraperitoneally in 400mg/kg.Neck midsection, exposure left common carotid
(CCA), external carotid artery (ECA), internal carotid (ICA).Ligature the proximal end CCA, the root ECA.Distal end cuts one tiltedly at CCA ligation
Mouthful, it is inserted into nylon yarn, cranium is entered to arteria cerebri anterior (ACA) by ICA through CCA crotch, blocks the blood flow of MCA.Nylon yarn is flat
Equal insertion depth is 18.5 ± 0.5mm, ligatures ICA.Skin suture, exposure nylon yarn end.By nylon yarn after ischemic 2 hours
It extracts, observes the variation of different time course after Reperfu- sion.Blank control group does not insert nylon yarn.
By daily single, and daily Neurological deficits are carried out to each group rat；Specific standards of grading: rat-tail is 1. proposed
Forelimb buckling situation is observed, such as double forelimbs symmetrically stretch to ground, are denoted as 0 point, and wrist buckling occurs in opposite side forelimb of such as performing the operation, elbow is bent
Bent, shoulder inward turning, is calculated as 1,2,3 points respectively.2. animal is placed on plane earth, both shoulders are pushed away respectively to opposite side movement, check resistance,
Such as bilateral resistance equity and effectively, it is calculated as 0 point, drop in resistance when such as pushing to the opposite side of operation, according to decline degree difference point
For it is light, in, severe, be calculated as 1,2,3 points respectively.3. the double forelimbs of animal are set on a metal mesh, the Muscle tensility of double forelimbs is observed, such as
Double forelimb Muscle tensilities are reciprocity and strong, are calculated as 0 point, are calculated as 1,2,3 points according to operation opposite side Muscle tensility decline degree difference.4. moving
Object is ceaselessly turn-taked to side, is calculated as 1 point.Full marks are 10 points, and score is higher, and animal behavior obstacle is more serious.
Administration put to death rat after 3 days, and mouse brain longitudinal gap 2mm is taken to be sliced, and calculated each group rat cerebral infarction after TTC dyeing
Unleavened dough product.
Concrete outcome is as follows:
1) TTC coloration result
| Group | Number of animals (only) | Cerebral infarct volume (%) |
| Normal group | 10 | 0 |
| Model group | 10 | 32.3±4.2 |
| Administration group 1 | 10 | 14.4±3.3** |
| Administration group 2 | 10 | 12.6±2.9** |
| Administration group 3 | 10 | 8.1±2.7** |
2) Neurological deficits result
| Group | Number of animals (only) | Neurological deficits |
| Normal group | 10 | 0 |
| Model group | 10 | 8.8±0.9 |
| Administration group 1 | 10 | 5.4±0.8** |
| Administration group 2 | 10 | 4.6±0.7** |
| Administration group 3 | 10 | 2.1±0.9** |
The content of present invention merely illustrates claimed some specific embodiments, one of them or more skill
Documented technical characteristic can be combined with arbitrary one or more technical solutions in art scheme, these are combined and obtain
Technical solution also in the application protection scope, the technical solution just as obtained from these are combined is disclosed in the present invention
It is specifically recorded in content the same.
Claims (5)
1. a kind of for treating the pharmaceutical composition of cerebral ischemia, which is characterized in that it includes compound of formula I and Edaravone, institute
It is as follows to state compound of formula I structure:
The compound of formula I and the weight ratio of Edaravone are 1:0.2.
2. a kind of pharmaceutical preparation comprising claim 1 described pharmaceutical composition and pharmaceutically acceptable carrier.
3. pharmaceutical preparation according to claim 2, which is characterized in that the pharmaceutical preparation is oral preparation or injection.
4. pharmaceutical preparation according to claim 3, which is characterized in that the pharmaceutically acceptable carrier be selected from starch,
Beta-cyclodextrin, carbomer, microcrystalline cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose
Calcium, polyethylene glycol (PEG), sodium carboxymethylcellulose, methylcellulose, ethyl cellulose, mannitol, lauryl sodium sulfate,
Croscarmellose sodium, lactose, polyvinylpyrrolidone (PVP), crosslinked polyvinylpyrrolidone, P-hydroxybenzoic acid second
Ester, magnesium stearate, talcum powder, superfine silica gel powder, Aspartame, orange flavor, sodium bicarbonate, sodium carbonate, in enteric coating powder
It is one or more of.
5. application of claim 1 described pharmaceutical composition in preparation treatment brain ischemia medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810600373.0A CN108864243B (en) | 2018-06-12 | 2018-06-12 | For treating the pharmaceutical composition and its preparation of cerebral ischemia |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810600373.0A CN108864243B (en) | 2018-06-12 | 2018-06-12 | For treating the pharmaceutical composition and its preparation of cerebral ischemia |
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| CN108864243B true CN108864243B (en) | 2019-07-05 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1218701C (en) * | 2002-12-27 | 2005-09-14 | 成都地奥制药集团有限公司 | Use of spirosterol type steroid saponin in preparing medicine for treating cardio-cerebral vascular disease |
| CN103319409B (en) * | 2013-07-12 | 2015-09-09 | 四川省惠达药业有限公司 | A kind of edaravone compound, its pharmaceutical composition and preparation method thereof |
| CN106866776B (en) * | 2017-03-01 | 2018-12-07 | 广东药科大学 | Novel steroid saponin compound and its application |
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