CN113620889A - Ligustrazine memantine and application thereof - Google Patents
Ligustrazine memantine and application thereof Download PDFInfo
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- CN113620889A CN113620889A CN202110966441.7A CN202110966441A CN113620889A CN 113620889 A CN113620889 A CN 113620889A CN 202110966441 A CN202110966441 A CN 202110966441A CN 113620889 A CN113620889 A CN 113620889A
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- memantine
- ligustrazine
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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 127
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 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
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- 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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- 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: the structure of N- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide is shown in the 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 and the like, are common diseases seriously threatening the health of human beings, particularly middle-aged and elderly people. Therefore, it is very necessary to develop new drugs for preventing and treating cardiovascular and cerebrovascular diseases.
Ligustrazine (tetramethylpyrazine, TMP) is an alkaloid extracted from rhizoma Ligustici Chuanxiong (Ligusticum chuanxiong Hort.) belonging to Umbelliferae, is an effective component of rhizoma Ligustici Chuanxiong, and can be widely used for cardiovascular and cerebrovascular diseases, and TMP can obviously inhibit LPS-induced high expression of PA1-1 protein and mRNA thereof in vascular endothelial cells (Song, et al, Chinese medical J.113:136,2000). TMP inhibits the breakdown of plasma inositol and the formation of TXA2 at low doses and platelet aggregation by binding to glycoprotein Ilb/IIIa at high doses (Sheu, et al, Thromb Res.88:259,1997).
TMP can be thrombolytic directly. Both arterial and venous thrombosis models in rats demonstrated that TMP has antithrombotic effects (Liu and Sylvester, Thromb Res.58:129,1990) which may be associated with inhibition of platelet activity by TMP, including inhibition of intracellular Ca2+Activity, inhibition of phosphodiesterase activity, elevation of intracellular cAMP levels and reduction of the exposure of the cell membrane surface glycoprotein Ilb/IIIa etc. (Liu and Sylvester, Thromb Res.75:51,1994). TMP can remarkably reduce the death rate of ADP-induced acute pulmonary embolism mice, and intravenous injection of TMP can remarkably prolong the bleeding time of mesenteric artery cutting rats by 1.5 times, which proves that the TMP has remarkable in vivo antithrombotic activity (Sheu, et al, Thromb Res.88:259,1997).
The effect of TMP for protecting nerve cells is obvious. TMP significantly ameliorates rat brain cell damage caused by MCAO, and TMP significantly eliminates free radicals produced by human neutrophils. TMP also protects neuronal cells by modulating Bcl-2 and Bax expression to reduce apoptosis (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 influx, inhibits 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 treatments including ischemic diseases such as acute ischemic stroke, it is difficult to maintain effective blood concentration due to its short half-life and low bioavailability.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the ligustrazine memantine which has long half-life period and high bioavailability and is easy to maintain effective blood concentration.
The second purpose of the invention is to provide the application of ligustrazine memantine in preparing the medicine for preventing and treating vascular dementia.
The third purpose of the invention is to provide the application of ligustrazine memantine in preparing the medicine for treating ischemic stroke.
The fourth purpose of the invention is to provide a pharmaceutical preparation containing ligustrazine memantine.
The fifth purpose of the invention is to provide the application of the ligustrazine memantine-containing medicinal preparation in preparing the medicaments for preventing and treating vascular dementia.
The sixth purpose of the invention is to provide the application of the ligustrazine memantine-containing medicinal preparation in preparing the medicament for treating ischemic stroke.
The technical scheme of the invention is summarized as follows:
ligustrazine memantine with the chemical name: n- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide, wherein the structure is shown in a formula I:
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 medicine for treating ischemic stroke is provided.
A pharmaceutical preparation containing ligustrazine memantine of formula I.
The dosage form of the pharmaceutical preparation is preferably as follows: tablet, granule, injection, powder, capsule or suspension.
The application of the medicinal preparation in preparing medicaments for preventing and treating vascular dementia.
The application of the medicinal preparation in preparing medicines for treating ischemic stroke is provided.
The invention has the advantages that:
the ligustrazine memantine (TMPM) has amido bond, so that the tetramethylpyrazine memantine can enter a human body in a stable form, the half-life period is prolonged, and the drug effect is enhanced; has high stability, and can prevent the damage of the original core structure of the medicine, thereby improving the curative effect.
Drawings
FIG. 1 shows the NMR-H spectrum of ligustrazine memantine of formula I.
FIG. 2 shows the mass spectrum of ligustrazine memantine shown in formula I.
FIG. 3 shows the metabolism time of ligustrazine memantine shown in formula I.
FIG. 4 is a graph showing the cytotoxicity of ligustrazine memantine of formula I on HT-22 cells.
FIG. 5 shows the protective effect of ligustrazine memantine shown in formula I on HT-22 cells.
FIG. 6 is a graph of the 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 of formula I on MCAO mice.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
The preparation method of the ligustrazine memantine I comprises the following steps:
(1) dissolving ligustrazine (II) (1eq) in water, stirring at 60 deg.C, and slowly adding KMnO4(2eq), after TLC monitoring the reaction was complete, the mixture was filtered, the filter residue was washed with hot water (30-40 ℃), the filtrates were combined, extracted with ethyl acetate, 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 yellow-white solid. ESI-MS: [ M + H ]]*m/zl67.0;
(2) Oxalyl chloride (2.0eq) is added dropwise to a dichloromethane solution (1eq) of 3,5, 6-trimethylpyrazine-2-carboxylic acid (III) under ice bath, the reaction is carried out for 1h, the temperature is increased to room temperature for 2h, and the reduced pressure is evaporated to dryness to obtain 3,5, 6-trimethylpyrazine-2-formyl 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 the memantine in mol in an ice bath, heating to room temperature to react for two hours after dropwise addition, filtering, dissolving filtrate in ethyl acetate after solvent evaporation, washing with water twice, washing with 1mol/L hydrochloric acid aqueous solution twice, drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure to obtain a crude product, and recrystallizing to obtain the product. Identified using hydrogen nuclear magnetic resonance spectroscopy and LC-MS, see FIGS. 1 and 2. The molar ratio of memantine to 3,5, 6-trimethylpyrazine-2-carbonyl chloride (IV) is 1: 1.5.
The product has the chemical name: the structure of N- (3, 5-dimethyl adamantan-1-yl) -3,5, 6-trimethyl pyrazine-2-formamide is shown in the formula (I):
the reaction formula is as follows:
example 2
A pharmaceutical formulation comprising ligustrazine memantine of formula I.
The medicinal preparation contains ligustrazine memantine and pharmaceutically acceptable auxiliary materials thereof. The pharmaceutical preparation can be made into tablet, granule, injection, powder, capsule or suspension. Other dosage forms are also possible.
Example 3 in vivo Metabolic time of ligustrazine memantine (formula I)
18 SD rats with body weight of 240 +/-20 g are fasted for 12 hours before the experiment, freely drink water, are randomly divided into two groups, are respectively gavaged with ligustrazine memantine according to the dose of 30mg/Kg and 10mg/Kg, and then are respectively placed in a heparinized centrifuge tube after 6mL of blood is taken from the abdominal aorta of the rat for 1,2,4,6,8,12,24,36 and 48 hours, and are centrifuged for 10 minutes at 3000rpm of a high-speed centrifuge, and then plasma is divided and is placed at-20 ℃ for storage to be tested. 100 mu L of rat plasma is taken and placed in a 10mL plastic centrifuge tube, 100 mu L of internal standard reference substance solution is sequentially added, 3mL of ethyl acetate is added for liquid-liquid extraction, vortex oscillation is carried out for 3min, centrifugation is carried out for 10min at 5000rpm, supernatant liquid is absorbed and placed in another centrifuge tube, drying is carried out under 35 ℃ nitrogen flow, 100 mu L of mobile phase is added into residue, vortex dissolution is carried out, and finally 20 mu L of sample injection analysis is taken, and the result is shown in figure 3.
Toxicity test of ligustrazine memantine on HT22 cells as described in example 4
Preparing a single HT22 cell suspension by using a DMEM culture solution containing 10% fetal calf serum, inoculating 1000-10000 cells per well to a 96-well plate, adding ligustrazine memantine with different concentrations after culturing for 12h in 200-200 ul. per well, adding 10ul of MTT solution (5mg/ml, prepared by PBS and with the pH being 7.4) per well, continuing to incubate for 4h, stopping culturing, carefully sucking and removing culture supernatant in the wells, adding 100ul DMSO per well, and shaking for 10min to fully melt crystals. The 490nm wavelength was selected, the absorbance of each well was measured on an enzyme linked immunosorbent instrument and the results were recorded, see FIG. 4.
Example 5 Tetramethylpyrazine Memantine on CoCl2Determination of protective Effect of induced ischemic and hypoxic Damage
Determination of protection against ischemic and hypoxic injury: when HT-22 cells reached logarithmic growth phase, the complete medium in the flask was decanted and then after aspiration of the remaining complete medium in the flask, starved for 12-14H with serum-free DMEM-H.
The cells were divided into a normal group (blank group) and a model group (CoC 1)2) Ligustrazine memantine group, ligustrazine group (100 μ M) and memantine group (5 μ M).
The normal group and the model group were given complete medium at 100. mu.L per well;
the ligustrazine memantine group is given with ligustrazine memantine diluted by complete culture medium, each hole is 100 mu L, the concentration is 100, 75 and 50 mu g/mL in turn, and each group has 6 multiple holes. Placing in a incubator with constant temperature of 37 ℃, 5% CO2 and saturated humidity for 24 h. After 24h of administration, CoC1 was added to each group except the normal group 2100 μ L per well, final concentration 400 μmol/mL. The normal group was incubated for 12 hours with the same amount of complete medium in a 5% C02 saturated humidity incubator at 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 reached logarithmic growth phase, HT22 cells in logarithmic growth phase were prepared into cell suspension and inoculated into 96-well plate at density of 5X 10/ml4And (3) culturing by using a DMEM-FBS complete culture medium, after the cells are attached to the wall, respectively adding 100 mu g/ml ligustrazine memantine for 12h, and then adding 50 mu M NMDA for molding. After addition of 10. mu.L of CCK-8 and incubation for 2h, the OD of each well was measured at 450 nm. Control holes and zero setting holes are respectively arranged in the experiment, and each group is provided with 5 multiple holes. See fig. 6.
Example 7 Effect of ligustrazine memantine on microglial M2 type activation
When BV-2 cells reached logarithmic growth phase, the complete medium in the flask was decanted, and then after the remaining medium in the flask was aspirated, starved for 12-14H with serum-free DMEM-H.
The cells were divided into normal group, model group, and ligustrazine memantine group.
The normal group and the model group were given complete medium at 100. mu.L per well; the ligustrazine memantine group is given with ligustrazine memantine diluted by complete culture medium, each hole is 100 mu L, the concentration is 100 mu g/mL in turn, and each group has 6 multiple holes. Placing in a incubator with constant temperature of 37 ℃, 5% CO2 and saturated humidity for 24 h. After 24h of administration, CoC1 was added to the model group and the ligustrazine memantine group 2100 μ L per well, final concentration 400 μmol/mL. The normal group was incubated for 12 hours with the same amount of complete medium in a 5% C02 saturated humidity incubator at 370 ℃. The concentrations of IL-10 and Arg-1 in the culture supernatants were determined by ELISA and the results are shown in FIG. 7.
Example 8 protective Effect of ligustrazine memantine on rat MCAO after ischemia
SD rats were weighed and 7% chloral hydrate (0.5ml/100g) was anesthetized. Rats were fixed to the operating table with medical tape and shaved on the neck. Disinfecting a neck with an alcohol cotton ball, and making a vertical incision along the center of a clavicle by an ophthalmic scissors, wherein the length of the incision is about 3-4 cm. And (3) separating subcutaneous muscle tissue, namely, a slight pulsation is seen below bottom muscle, namely, a common carotid artery, carrying out blunt separation on the muscle covering the common carotid artery, after the common carotid artery is separated, carefully separating vagus nerve accompanying the common carotid artery by using an ophthalmic forceps, continuously and carefully separating and cleaning mucosa tissue around the artery, and obtaining the separated common carotid artery with the length of about 1-1.5 cm.
The mucosal tissues covering the arteries were carefully removed, and then the external carotid artery, the internal carotid artery and the common carotid artery were observed to be distributed in a "Y" shape, and two independent arteries (external carotid artery and internal carotid artery) were isolated. After the vessel separation is completed, the common carotid artery is ligated (the closer to the tail, the better). Then the external carotid artery is ligated, and a thread is prepared between the two ligations, and the knot is loosened.
The arterial clamp temporarily clamps the internal carotid artery. Between the prepared thread and the ligation part of the common carotid artery, a V-shaped incision is made by an ophthalmic scissors, a V-shaped incision is cut at the position about 0.8mm away from the Y-shaped bifurcation and positioned right in front of the blood vessel, so that the blood vessel is in a natural state, the thrombus thread is clamped by an ophthalmic forceps and slowly enters the internal carotid artery, when the blood vessel reaches the artery forceps, the reserved thread is slightly tensioned (the blood seepage caused by the backflow of the telecentric end is prevented), the artery forceps are loosened, the common carotid artery is slightly pulled rightwards to continue to be inserted into the thrombus thread, and when the black mark part of the special thrombus thread reaches the position near the Y-shaped bifurcation, the thrombus thread enters the middle cerebral artery and cannot continue to move forwards.
After the bolt wire is inserted, the reserved ligature is tensioned and fixed. The neck blood clot was cleared with a small medical cotton swab, the skin was sutured layer by layer, the alcohol cotton ball was sterilized and the rat was returned to the cage. After 1.5h, anesthetizing the rat, disinfecting the neck, opening a small opening, clamping the fixing position of the plug thread by using ophthalmologic forceps, pulling out the plug thread to the head end of the fixing position, cutting off the redundant plug thread, suturing layer by layer, and disinfecting (MCAO/R group); the sham group (Control) only dissected the common carotid artery and immediately sutured the wound. After surgery, the cages were returned and given sufficient feed and water.
After the rats were awakened, the rats were scored according to the Zea Longa 5 scoring standard: score 0 represents no neurological deficit symptoms; score 1 indicates that the contralateral forelimb cannot be fully extended; 2 points represent turning to the side of hemiparalysis when walking; 3 points represent the falling to the side of hemiparalysis when walking; 4 points represent that the walking cannot be performed spontaneously and the disturbance of consciousness cannot be achieved; and 5 points represent death. Accumulating 1 minute or more to obtain the success of molding; however, when the score reaches 5 points, the subarachnoid hemorrhage or the symptom without neurological deficit (score 0) is found by dissection, the model is considered to fail.
The rats after successful molding are given 30mg/Kg of ligustrazine memantine solution and 50mg/Kg of ligustrazine (TMP) solution, animals are killed by decapitation, and then brains are taken out quickly and placed in PBS solution at 0-4 ℃ for transfer and refrigerated in a refrigerator at-20 ℃ for 30 min. Cutting brain slice or heart slice with thickness of 2mm, placing the slice in 2% red tetrazole solution, and water bathing at 37 deg.C in dark place for 30min, and slightly shaking the container every 5min to dye completely. Taking out brain slice or heart slice, washing with PBS solution for 3-5min, immediately taking picture, and fixing brain slice with 10% neutral formaldehyde for 6 h. And selecting the caudal side of each slice, carrying out image analysis by using a pathological image-text analysis system, and measuring the infarct 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, and the sum of the infarct volumes of all layers is the total infarct volume. See fig. 8.
The compounds of the present invention, methods of preparation and uses thereof, are described herein with reference to specific embodiments, and are illustrated and described in considerable detail for the purpose of description. Indeed, it will be apparent to those skilled in the art that the present invention may be embodied in other specific forms and that any changes or modifications which do not depart from the spirit and intent of this invention are deemed to be within the scope of the invention.
Claims (7)
2. the use of ligustrazine memantine according to claim 1 for the preparation of a medicament for the prevention and treatment of vascular dementia.
3. The 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 ligustrazine memantine according to claim 1.
5. The pharmaceutical preparation according to claim 4, wherein the pharmaceutical preparation is in the form of tablet, granule, injection, powder, capsule or suspension.
6. Use of the pharmaceutical preparation according to claim 4 or 5 for the manufacture of a medicament for the prevention or treatment of vascular dementia.
7. Use of a pharmaceutical formulation according to claim 4 or 5 in the manufacture of a medicament for the treatment of ischemic stroke.
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