CN113620889B - Ligustrazine memantine and application thereof - Google Patents
Ligustrazine memantine and application thereof Download PDFInfo
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- CN113620889B CN113620889B CN202110966441.7A CN202110966441A CN113620889B CN 113620889 B CN113620889 B CN 113620889B CN 202110966441 A CN202110966441 A CN 202110966441A CN 113620889 B CN113620889 B CN 113620889B
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- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 124
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960004640 memantine Drugs 0.000 title claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 14
- -1 3, 5-dimethyl adamantan-1-yl Chemical group 0.000 claims abstract description 4
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
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- 238000002360 preparation method Methods 0.000 claims description 6
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- 238000002347 injection Methods 0.000 claims description 4
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
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- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- WAYROSKAWWDSCA-UHFFFAOYSA-N 3,5,6-trimethylpyrazine-2-carbonyl chloride Chemical compound CC1=NC(C)=C(C(Cl)=O)N=C1C WAYROSKAWWDSCA-UHFFFAOYSA-N 0.000 description 1
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- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 229930013930 alkaloid Natural products 0.000 description 1
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- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
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- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses ligustrazine memantine and application thereof, wherein the chemical name of the ligustrazine memantine is as follows: n- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide has a structure shown in formula (I):
Description
Technical Field
The invention relates to ligustrazine memantine (TMPM) and application thereof, belonging to the field of pharmacy.
Background
Cardiovascular and cerebrovascular diseases, such as cerebral apoplexy, vascular dementia, etc., are common diseases that seriously threaten the health of humans, especially middle-aged and elderly people. Therefore, research and development of new drugs for preventing and treating cardiovascular and cerebrovascular diseases are very necessary.
Ligustrazine (TMP) is an alkaloid extracted from rhizoma Ligustici Chuanxiong of Umbelliferae, is an effective component of rhizoma Ligustici Chuanxiong, and is widely used for cardiovascular and cerebrovascular diseases, and TMP can significantly inhibit LPS-induced high expression of PA1-1 protein and its mRNA in vascular endothelial cells (Song, et al, chinese medical J.113:136,2000). TMP inhibits plasma inositol breakdown and TXA2 formation at low doses and platelet aggregation by binding glycoprotein Ilb/IIIa at high doses (Shea, et al, thromb Res.88:259,1997).
TMP can be directly thrombolytic. Both arterial and venous thrombosis models of rats demonstrated that TMP has an antithrombotic effect (Liu and Sylvester, thromb Res.58:129,1990), which might be associated with the inhibition of platelet activity by TMP, including the inhibition of intracellular Ca 2+ Activity, inhibition of phosphodiesterase activity, increase of intracellular cAMP levels, decrease of exposure of glycoprotein Ilb/IIIa on cell membrane surface, etc. (Liu and Sylvester, thromb Res.75:51,1994). TMP can significantly reduce the mortality of mice with ADP-induced acute pulmonary embolism, and intravenous injection of TMP can significantly prolong the bleeding time of mesenteric arterial-cut rats by 1.5 times, proving that TMP has significant in vivo antithrombotic activity (Shea, et al, thromb Res.88:259,1997).
TMP has obvious nerve cell protecting effect. TMP significantly ameliorates MCAO-induced brain cell damage in rats and TMP significantly eliminates free radicals produced by human neutrophils. TMP also protects nerve cells by reducing apoptosis through modulation of Bcl-2 and Bax expression (Hsiao, planta Med.72:411-417,2006; kao, neurochemInt. 48:166.2006).
TMP is a calcium channel blocker, and simultaneously promotes potassium channel opening, inhibits calcium ion inflow, inhibits free radical generation, enhances superoxide dismutase (SOD) activity, inhibits lipid peroxidation, and inhibits attenuation (Zhu, et al, eur. J. Pharmacol.510:187,2005).
Although ligustrazine is widely used in clinical treatment including ischemic diseases such as acute ischemic stroke, it is difficult to maintain an effective blood concentration due to the short half-life of ligustrazine and low bioavailability.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the ligustrazine memantine with long half-life period, high bioavailability and easy maintenance of effective blood concentration.
The second object of the invention is to provide the application of ligustrazine memantine in preparing the medicines for preventing and treating vascular dementia.
The third object of the invention is to provide the application of ligustrazine memantine in preparing the medicines for treating ischemic stroke.
A fourth object of the present invention is to provide a pharmaceutical formulation comprising ligustrazine memantine.
The fifth object of the invention is to provide the application of the pharmaceutical preparation containing ligustrazine memantine in preparing the medicines for preventing and treating vascular dementia.
The sixth object of the invention is to provide the application of the pharmaceutical preparation containing ligustrazine memantine in preparing the medicines for treating ischemic stroke.
The technical scheme of the invention is summarized as follows:
ligustrazine memantine, chemical name: n- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide has a structure shown in formula I:
the application of ligustrazine memantine shown in formula I in preparing medicine for preventing and treating vascular dementia is provided.
The application of ligustrazine memantine shown in formula I in preparing medicament for treating ischemic stroke is provided.
A pharmaceutical preparation contains ligustrazine memantine shown in formula I.
The dosage form of the above pharmaceutical formulation is preferably: tablets, granules, injections, powders, capsules or suspensions.
The application of the pharmaceutical preparation in preparing medicaments for preventing and treating vascular dementia.
The application of the pharmaceutical preparation in preparing medicaments for treating ischemic stroke.
The invention has the advantages that:
the ligustrazine memantine (TMPM) has amide bonds, so that the ligustrazine memantine enters a body in a stable form, the half life is prolonged, and the drug effect is enhanced; the stability is strong, the inherent mother nucleus structure of the medicine can not be destroyed, and the curative effect is improved.
Drawings
FIG. 1 shows NMR-H spectrum of ligustrazine memantine shown in formula I.
FIG. 2 shows a mass spectrum of ligustrazine memantine shown in formula I.
FIG. 3 shows the metabolic time of ligustrazine memantine of formula I.
FIG. 4 shows cytotoxicity of ligustrazine memantine on HT-22 cells of formula I.
FIG. 5 shows the protective effect of ligustrazine memantine on HT-22 cells.
FIG. 6 shows NMDA antagonism of ligustrazine memantine of formula I.
FIG. 7A shows the effect of ligustrazine memantine on the change of Arg-1 content in microglia, and FIG. 7B shows the effect of ligustrazine memantine on the change of IL-10 content in microglia.
FIG. 8 shows the protective effect of ligustrazine memantine on MCAO mice of formula I.
Detailed Description
The invention will be further described with reference to specific examples.
Example 1
The preparation method of the ligustrazine memantine I comprises the following steps:
(1) Ligustrazine (II)(1 eq) was dissolved in water, stirred at 60℃and KMnO was slowly added 4 (2 eq) after TLC monitored completion of the reaction, the mixture was filtered, the filter residue was washed with hot water (30-40 ℃), the filtrates were combined, the ethyl acetate extracted, the organic phase was discarded, and the aqueous phase was adjusted to ph=3 with 10% (w/w) aqueous hydrochloric acid, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3,5, 6-trimethylpyrazine-2-carboxylic acid (III) as a yellowish white solid. ESI-MS: [ M+H ]]*m/zl67.0;
(2) Oxalyl chloride (2.0 eq) was added dropwise to a dichloromethane solution (1 eq) of 3,5, 6-trimethylpyrazine-2-carboxylic acid (III) under ice bath, reacted for 1h, heated to room temperature for 2h, evaporated to dryness under reduced pressure to give 3,5, 6-trimethylpyrazine-2-carbonyl chloride (IV).
Dissolving memantine and 3,5, 6-trimethyl pyrazine-2-formyl chloride (IV) in dichloromethane, adding triethylamine serving as an acid binding agent which is 2 times of memantine in a molar ratio under ice bath, reacting for two hours at room temperature after dripping, filtering, evaporating filtrate to dryness, dissolving with ethyl acetate, washing with water for two times, washing with 1mol/L hydrochloric acid aqueous solution for two times, drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure to obtain a crude product, and recrystallizing to obtain the product. Hydrogen nuclear magnetic resonance spectroscopy and LC-MS identification were used, see fig. 1 and 2. The molar ratio of memantine to 3,5, 6-trimethyl pyrazine-2-formyl chloride (IV) is 1:1.5.
The product is of the chemical name: n- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide has a structure shown in formula (I):
the reaction formula is:
example 2
A pharmaceutical formulation comprising ligustrazine memantine of formula I.
The medicinal preparation comprises ligustrazine memantine and pharmaceutically acceptable auxiliary materials thereof. The specific dosage forms of the pharmaceutical preparation comprise tablets, granules, injection, powder, capsules or suspending agents. Other dosage forms are also possible.
EXAMPLE 3 in vivo Metabolic time of ligustrazine memantine (formula I)
SD rats 18, weight 240+ -20 g, fasted for 12 hours before experiment, free drinking water, randomly divided into two groups, respectively according to the dosage of 30mg/Kg,10mg/Kg after the stomach infusion of ligustrazine memantine, respectively in 1,2,4,6,8,12,24,36,48h through rat abdominal aorta place blood 6mL placed in a pre-heparinized test tube, through high speed centrifuge 3000rpm centrifugation for 10 minutes, separated plasma, placed at-20 ℃ for preservation test. Taking 100 mu L of rat plasma, placing into a 10mL plastic centrifuge tube, sequentially adding 100 mu L of internal standard reference substance solution, adding 3mL of ethyl acetate for liquid-liquid extraction, carrying out vortex oscillation for 3min, centrifuging at 5000rpm for 10min, sucking the supernatant, placing into another centrifuge tube, drying under a nitrogen flow at 35 ℃, adding 100 mu L of mobile phase into the residue, vortex dissolution, and finally taking 20 mu L of sample injection for analysis, wherein the result is shown in figure 3.
Toxicity test of ligustrazine Memantine on HT22 cells described in example 4
Single HT22 cell suspension is prepared by DMEM culture solution containing 10% fetal calf serum, 1000-10000 cells are inoculated into a 96-well plate, the volume of each hole is 200ul, different concentrations of ligustrazine memantine are added after 12h of culture, then MTT solution (5 mg/ml, prepared by PBS and pH=7.4) is added into each hole for 10ul, incubation is continued for 4h, culture is stopped, culture supernatant in each hole is carefully sucked and removed, 100ul of DMSO is added into each hole, and shaking is carried out for 10min, so that crystals are fully dissolved. The light absorption value of each well was measured on an ELISA monitor at 490nm wavelength, and the results were recorded as shown in FIG. 4.
Example 5 ligustrazine memantine vs. CoCl 2 Determination of the protective effect of induced ischemic and anoxic injury
Measurement of ischemic and anoxic injury protection: when HT-22 cells reached log phase, the complete medium in the flask was decanted and then the remaining complete medium in the flask was aspirated off before starving with serum free DMEM-H for 12-14H.
The cells are divided into normal groupsBlank), model group (CoC 1 2 ) Ligustrazine memantine group, ligustrazine group (100 μm) and memantine (5 μm) group.
The complete medium was given to the normal and model groups at 100 μl per well;
the tetramethylpyrazine memantine group was given 100. Mu.L per well at concentrations of 100, 75, 50. Mu.g/mL per group of 6 duplicate wells per group of tetramethylpyrazine memantine diluted in complete medium. Placing in a saturated humidity incubator with CO2 at 37 ℃ for 24 hours. 24h after administration, coC1 was added to each group except the normal group 2 100. Mu.L per well with a final concentration of 400. Mu. Mol/mL. The normal group is added with the equivalent complete culture medium and incubated for 12 hours in a saturated humidity incubator with 5% C02 at a constant temperature of 370 ℃. Cell viability was determined using the CCK-8 method. See fig. 5.
Example 6 NMDA (N-methyl-D-aspartate receptor) antagonistic Activity of ligustrazine memantine
When HT22 reaches logarithmic phase, HT22 cells in logarithmic phase are inoculated into 96-well plate as cell suspension with density of 5×10 per ml 4 Culturing in DMEM-FBS complete medium, and after adhering cells, adding 100 μg/ml ligustrazine memantine for 12 hr, and adding 50 μM NMDA for molding. After incubation for 2h with 10. Mu.L of CCK-8, the OD of each well was measured at 450 nm. In the experiment, a control hole and a zero setting hole are respectively set, and 5 compound holes are set in each group. See fig. 6.
Example 7 Effect of ligustrazine memantine on microglial M2 activation
When BV-2 cells reached the logarithmic growth phase, the complete medium in the flask was decanted and the remaining medium in the flask was aspirated off, and starved with serum-free DMEM-H for 12-14H.
The cells were divided into normal, model, ligustrazine memantine.
The complete medium was given to the normal and model groups at 100 μl per well; the ligustrazine memantine group was given 100. Mu.L per well with 100. Mu.g/mL concentration of 6 duplicate wells per group. Placing in a saturated humidity incubator with CO2 at 37 ℃ for 24 hours. 24h after administration, coC1 was added to the model group and ligustrazine memantine group 2 100. Mu.L per well with a final concentration of 400. Mu. Mol/mL. The normal group is added with the equivalent complete culture medium and incubated for 12 hours in a saturated humidity incubator with 5% C02 at a constant temperature of 370 ℃. The IL-10 and Arg-1 concentrations in the culture supernatant were determined by ELISA, and the results are shown in FIG. 7.
Example 8 protection of ligustrazine memantine against post-ischemia in rat MCAO
SD rats were weighed and 7% chloral hydrate (0.5 ml/100 g) was anesthetized. The rats were fixed on the console with medical tape and the neck was shaved. The alcohol cotton ball at the neck is sterilized, and the ophthalmic scissors make a vertical incision along the middle of the collarbone, and the length is about 3 cm to 4 cm. Separating subcutaneous muscle tissue, namely the common carotid artery when slight pulsation is seen below the bottom muscle, and passively separating the muscle covered above the common carotid artery, wherein after the common carotid artery is separated, the ophthalmic forceps carefully separate the vagus nerve accompanied with the common carotid artery, and continuously carefully separate and clean the mucosa tissue around the artery, wherein the separated common carotid artery is about 1-1.5 cm.
The mucosa tissue covered on the arteries is carefully removed, and at this time, the external carotid artery, the internal carotid artery and the common carotid artery are distributed in a Y shape, and two independent arteries (external carotid artery and internal carotid artery) are separated. After vessel separation, the common carotid artery was ligated (more caudally, better). And ligating the external carotid artery, preparing a wire between the two ligatures, and loosening the knot.
The arterial clip temporarily clips the internal carotid artery. A V-shaped incision is cut between the standby wire and the common carotid artery ligation, the V-shaped incision is cut at the right front part of a blood vessel at the position which is about 0.8mm away from the Y-shaped bifurcation, so that the blood vessel is in a natural state, a bolt wire is clamped by using an ophthalmic forceps and slowly enters into the internal carotid artery, when the internal carotid artery reaches an arterial clamp, the reserved wire is slightly tensioned (the reflux and the blood seepage of a distal end are prevented), the arterial clamp is loosened, the common carotid artery is slightly pulled to the right to continue to insert the bolt wire, and when the black mark of the special bolt wire reaches the position which is near the Y-shaped bifurcation, the bolt wire enters into the middle cerebral artery and cannot continue to advance.
After the bolt wire is inserted, the reserved ligature wire is tensioned and fixed. Medical small cotton swabs are used for cleaning neck blood clots, skin is sewn layer by layer, alcohol cotton balls are sterilized, and rats are put back into the cage. After 1.5 hours, the anaesthetized rat is disinfected at the neck, a small opening is opened, the bolt line is pulled out to the head end of the bolt line by clamping the bolt line fixing position by using ophthalmic forceps, redundant bolt lines are cut off, and the rat is sutured layer by layer and disinfected (MCAO/R group); the sham group (Control) only dissects the common carotid artery and immediately sutures the wound. The cage was returned after the operation, and sufficient feed and water were given.
After waking, rats were scored with reference to the Zea Longa 5 scoring standard: score 0 represents no neurological deficit symptoms; score 1 represents incomplete extension of the contralateral forelimb; 2 points represent turns to the hemiplegia side when walking; 3 represents tilting to the hemiplegia side during walking; a score of 4 represents failure to walk spontaneously and disturbance of consciousness; score 5 represents death. Accumulating for 1 minute or more to obtain successful molding; whenever 5 minutes were reached, dissection and the subarachnoid hemorrhage or no symptom of neurological deficit (0 minutes) were found, all were considered as failure to model.
The rats after successful molding are given with 30mg/Kg of ligustrazine memantine solution and 50mg/Kg of ligustrazine (TMP) solution, and the brains are quickly taken after the animals are sacrificed by a decapitation method, and are placed in a PBS solution at 0-4 ℃ for transferring, and are frozen for 30min at-20 ℃. Cutting brain or heart into slices with thickness of 2mm, placing slices into 2% red tetrazolium solution, and placing in 37 deg.C light-proof water bath for 30min, slightly shaking the container every 5min to make the slices fully dyed. Taking out brain slice or heart slice, washing with PBS for 3-5min, immediately photographing, and fixing brain slice with 10% neutral formaldehyde for 6 hr. And selecting the tail side surface of each slice to carry out image analysis by using a pathological image-text analysis system, measuring the dead area and the total area of each slice, wherein the infarct volume of each layer is the product of the infarct area and the layer thickness of the layer, and the sum of the infarct volumes of all layers is the total infarct volume. See fig. 8.
The compounds of the invention, methods of making and using the same, are described herein in connection with certain specific embodiments, and the description and illustration are presented for the purposes of illustration in many detail. Indeed, it will be apparent to those skilled in the art that the present invention may be practiced in other embodiments, and that any modification and adjustment that does not depart from the spirit and scope of the invention is intended to be included therein.
Claims (7)
1. Ligustrazine memantine, characterized by the chemical name: n- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide has a structure shown in formula (I):
2. use of ligustrazine memantine according to claim 1 for the preparation of a medicament for the prevention and treatment of vascular dementia.
3. Use of ligustrazine memantine according to claim 1 for the preparation of a medicament for the treatment of ischemic stroke.
4. A pharmaceutical formulation comprising the tetramethylpyrazine memantine of claim 1.
5. The pharmaceutical preparation according to claim 4, wherein the pharmaceutical preparation is in the form of a tablet, granule, injection, powder, capsule or suspension.
6. Use of a pharmaceutical formulation according to claim 4 or 5 for the preparation of a medicament for the prevention and treatment of vascular dementia.
7. Use of a pharmaceutical formulation according to claim 4 or 5 for the preparation of a medicament for the treatment of ischemic stroke.
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