CN112174924A - Synthesis of deuterated pinocembrin and application of deuterated pinocembrin in preparation of anti-stroke medicine - Google Patents
Synthesis of deuterated pinocembrin and application of deuterated pinocembrin in preparation of anti-stroke medicine Download PDFInfo
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- CN112174924A CN112174924A CN201910583300.XA CN201910583300A CN112174924A CN 112174924 A CN112174924 A CN 112174924A CN 201910583300 A CN201910583300 A CN 201910583300A CN 112174924 A CN112174924 A CN 112174924A
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- pinocembrin
- deuterated
- cerebral
- stroke
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
The invention discloses a preparation method of deuterated pinocembrin and application of the deuterated pinocembrin in medicines for treating and preventing cerebrovascular diseases such as cerebral apoplexy. The invention discovers that deuterated pinocembrin can be prepared by adopting methods such as a catalytic reduction method, an addition synthesis method and the like, and can obviously improve the neurobehavioral impairment symptom of a cerebral ischemia reperfusion rat, obviously reduce the cerebral infarction volume of the cerebral ischemia reperfusion rat and obviously reduce the cerebral edema degree of the cerebral ischemia reperfusion rat. Meanwhile, the deuterated pinocembrin can obviously relieve the opening degree and permeability of the blood brain barrier of a cerebral hemorrhage rat and reduce cerebral hemorrhage injury. In addition, deuterated pinocembrin has superior pharmacokinetic properties and higher brain tissue concentrations than the proto-pinocembrin drug. The deuterated pinocembrin can be used for preparing medicaments for treating and preventing cerebral apoplexy, and has better effect than the original pinocembrin medicaments. The invention provides an effective solution for treating and preventing stroke diseases.
Description
Technical Field
The invention relates to a new application of deuterated pinocembrin in preparation of a medicine, mainly relates to an application of deuterated pinocembrin in preparation of a medicine for preventing and treating stroke, and belongs to the technical field of medicines.
Background
The stroke has the characteristics of high morbidity, high disability rate and high mortality rate, and is a global disease seriously threatening the health of human beings. The main categories of stroke include ischemic stroke, hemorrhagic stroke, and transient ischemic attack. Ischemic stroke is the damage to brain tissue caused by insufficient blood supply to brain tissue due to vascular embolism and/or arteriosclerosis. Hemorrhagic stroke is mainly caused by the fact that cerebral blood vessels are ruptured, blood permeates into the brain, and the blood flow of normal brain tissues is interrupted, so that the brain tissues are damaged. The pathogenesis and pathophysiology of stroke are complex, wherein multiple mechanisms such as oxidative stress, inflammatory reaction, calcium overload, excitotoxicity and the like participate in the occurrence and development process.
Currently, there are a limited number of clinically available anti-stroke drugs. FDA approved tissue plasminogen activator (tPA) is one of the more accepted therapeutic drugs for cerebral apoplexy. However, tPA has a narrow window of thrombolytic therapy time, a high risk of bleeding, and severe reperfusion injury, and thus it can only benefit a small fraction of clinical patients from thrombolytic therapy. Therefore, the development of novel drugs for treating cerebral apoplexy is imperative.
The deuterium-substituted drug replaces hydrogen in a drug active molecule group with isotope deuterium, and is non-toxic and non-radioactive, and is stabilized by about 6-9 times compared with a carbon-hydrogen bond, so that a metabolic site can be sealed to prolong the half-life period of the drug, the therapeutic dose is reduced, and the pharmacological activity of the drug is not influenced, so that the deuterium-substituted drug is considered to be an excellent modification method.
Disclosure of Invention
The invention aims to provide a synthetic method of deuterated pinocembrin and application of the deuterated pinocembrin in preparation of a medicine for preventing and treating stroke, thereby providing an effective solution for treating stroke.
The chemical name of Pinocembrin is (2S) -5,7-dihydroxy-2-phenyl-2,3-dihydrochromen-4-one, and the molecular formula is C15H12O4. Deuterated pinocembrin refers to a compound formed by substituting H atoms on the structure of pinocembrin by deuterium atoms, and part of deuterated pinocembrinThe chemical structure of sertraline is as follows:
therefore, the invention provides the following technical scheme:
the invention provides synthesis of deuterated pinocembrin and application of the deuterated pinocembrin in preparation of a medicine for preventing and treating stroke.
Further, the synthesis of the deuterated pinocembrin comprises the following steps:
(1) carrying out catalytic reduction reaction on 5, 7-dihydroxyflavone serving as a raw material and deuterium gas serving as a deuterium donor under the condition of a catalyst to obtain deuterated pinocembrin I;
(2) reacting deuterated pinocembrin I with D under strong alkaline condition2Performing O reaction to obtain deuterated pinocembrin III;
(3) reacting deuterated pinocembrin III in an alcohol solvent under the condition of heating to generate deuterated pinocembrin II;
further, the alcoholic solvent in the step (3) of the preparation method is methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, pentanol, pentanediol, n-hexanol or octanol;
further, the effects of the deuterated pinocembrin comprise prevention and treatment effects after the stroke occurs;
furthermore, the treatment of the cerebral apoplexy is the treatment of acute ischemic cerebral apoplexy, transient ischemic attack, chronic cerebral circulation insufficiency and hemorrhagic cerebral apoplexy caused by various factors;
furthermore, the prevention of the cerebral apoplexy is the prevention of acute ischemic cerebral apoplexy, transient ischemic attack, chronic cerebral circulation insufficiency and hemorrhagic cerebral apoplexy caused by various factors;
further, the therapeutic effect of deuterated pinocembrin on stroke is characterized by treatment at any stage after the acute attack, including the acute stage, the subacute stage and the convalescent stage;
furthermore, the prevention effect of the deuterated pinocembrin on the stroke is characterized by aiming at high-risk people without acute symptoms and patients who have already suffered from stroke and are treated, and the purpose of the method is to avoid secondary attack;
furthermore, the deuterated pinocembrin can be prepared into anti-stroke drugs with various dosage forms with pharmaceutically acceptable auxiliary materials according to a conventional preparation method.
The invention therefore also relates to pharmaceutical compositions containing the compounds according to the invention as active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The deuterated pinocembrin can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary materials to be prepared into any dosage form for human or animal use. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of 0.1 to 99%.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the gastrointestinal or parenteral route, e.g., orally, intravenously, intramuscularly, subcutaneously, nasally, oromucosally, ocularly, pulmonary and respiratory, dermally, vaginally, rectally, etc.
The drug combination dosage form comprises an oral preparation, an injection administration dosage form and a skin mucosa route administration dosage form.
The oral preparation comprises tablets, capsules, sustained-release agents, controlled-release agents, dripping pills, powder, granules, solutions, emulsions and suspensions; the injection administration dosage forms comprise intramuscular injection, intravenous injection and intravenous drip; the administration forms of the skin mucosa route comprise external solution, lotion, liniment, ointment, plaster, cataplasm, patch, eye drop, nasal drop, eye ointment, gargle, sublingual tablet, sticking tablet and sticking film agent.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, carboxypropylmethylcellulose, ethylcellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The compounds of the invention may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the dosage unit, deuteroprimulin may be mixed with a diluent, glidant, and the mixture placed directly into a hard or soft capsule. Or mixing deuterated pinocembrin with diluent, adhesive, and disintegrating agent, making into granule or pellet, and placing into hard capsule or soft capsule. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, gallate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method. The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 400mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The invention has the beneficial effects that: the invention adopts a cerebral ischemia reperfusion and cerebral hemorrhage rat model to investigate the anti-stroke effect of deuterated pinocembrin. The result shows that the injection of the deuterated pinocembrin can obviously improve the neurobehavioral defect symptoms of the cerebral ischemic rats, reduce the cerebral infarction volume and the percent of cerebral edema of the cerebral ischemic rats, reduce the opening degree and permeability of the blood brain barrier of the rats, and the effect of the deuterated pinocembrin is better than that of the original pinocembrin drug. Meanwhile, the deuterated pinocembrin has better pharmacokinetic properties and higher brain tissue concentration compared with a pinocembrin prototype drug. The invention provides an effective solution for preventing and treating cerebral apoplexy.
Drawings
Figure 1 is a mass spectrum of deuterated pinocembrin.
Figure 2 pharmacokinetic properties and brain tissue distribution of deuterated pinocembrin: (
n-6). FIG. 3 Effect of deuterated pinocembrin on neurobehavioral impairment symptoms in cerebral ischemia-reperfusion rats: (
n-10). And Sham: sham control group; I/R: a model group; I/R + Pino: pinocembrin treatment group (10 mg/kg); I/R + Pino-I: deuterated pinocembrin I treatment group (10 mg/kg); I/R + Pino-II: deuterated pinocembrin II treatment group (10 mg/kg); I/R + Pino-III: deuterated pinocembrin III treatment group (10 mg/kg).###P in comparison with sham-operated controls<0.001；***In comparison with the model group, P<0.001。
FIG. 4 Effect of deuterated pinocembrin on cerebral infarction volume of rats subjected to cerebral ischemia reperfusion
n-10). And Sham: sham control group; I/R: a model group; I/R +Pino: pinocembrin treatment group (10 mg/kg); I/R + Pino-I: deuterated pinocembrin I treatment group (10 mg/kg); I/R + Pino-II: deuterated pinocembrin II treatment group (10 mg/kg); I/R + Pino-III: deuterated pinocembrin III treatment group (10 mg/kg).###P in comparison with sham-operated controls<0.001；**In comparison with the model group, P<0.01；***In comparison with the model group, P<0.001。
FIG. 5 Effect of deuterated pinocembrin on percent brain Water content in rats subjected to cerebral ischemia-reperfusion (II)
n-10). And Sham: sham control group; I/R: a model group; I/R + Pino: pinocembrin treatment group (10 mg/kg); I/R + Pino-I: deuterated pinocembrin I treatment group (10 mg/kg); I/R + Pino-II: deuterated pinocembrin II treatment group (10 mg/kg); I/R + Pino-III: deuterated pinocembrin III treatment group (10 mg/kg).###P in comparison with sham-operated controls<0.001；**In comparison with the model group, P<0.01；***In comparison with the model group, P<0.001。
FIG. 6 influence of deuterated pinocembrin on the extent of opening of the blood brain barrier in cerebral-hemorrhagic rats (II)
n＝6)。
And Sham: sham control group; I/R: a model group; I/R + Pino: pinocembrin treatment group (10 mg/kg); I/R + Pino-I: deuterated pinocembrin I treatment group (10 mg/kg); I/R + Pino-II: deuterated pinocembrin II treatment group (10 mg/kg); I/R + Pino-III: deuterated pinocembrin III treatment group (10 mg/kg).###P in comparison with sham-operated controls<0.001；***In comparison with the model group, P<0.001。
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings.
Firstly, chemical synthesis experiment:
synthesis of deuterated pinocembrin
Experimental materials: 5, 7-dihydroxyflavone was prepared by pharmaceutical research of the academy of Chinese medical sciences, ethyl acetate was purchased from chemical reagents of the national drug group, Inc., palladium on carbon, sodium hydroxide (NaOH) and deuterium oxide (D)2O) were purchased from Sigma-Aldrich, deuterium gas generated from a deuterium gas generator, methanol (MeOH) as chromatographically pure reagent (Fisher, USA).
Example 1: synthesis of deuterated pinocembrin I
Taking 5, 7-dihydroxyflavone as a raw material, taking the 5, 7-dihydroxyflavone as a raw material with the dosage of 10.00g, taking ethyl acetate as a solvent and deuterium gas as a deuterium donor, carrying out addition reduction under the catalysis of palladium carbon, drying with anhydrous sodium sulfate after the reaction is stopped, carrying out rotary evaporation and evaporation to dryness, and finally carrying out silica gel column chromatography to obtain deuterated pinocembrin I with the weight of 7.82g and the yield of 78.2%.
Example 2: synthesis of deuterated pinocembrin III
10.00g deuterated pinocembrin I in NaOH and D2And (3) reacting O under a heating condition, performing replacement, drying the obtained product with anhydrous sodium sulfate after the reaction is stopped, performing rotary evaporation to dryness, and finally performing silica gel column chromatography to obtain deuterated pinocembrin III with the weight of 8.53g and the yield of 85.3%.
Example 3: synthesis of deuterated pinocembrin II
And finally, reacting 10.00g of deuterated pinocembrin III under the heating condition of MeOH for displacement reaction, drying the deuterated pinocembrin III by using anhydrous sodium sulfate after the reaction is stopped, evaporating the deuterated pinocembrin III by rotary evaporation, and finally obtaining deuterated pinocembrin II by using silica gel column chromatography, wherein the weight of the deuterated pinocembrin II is 9.32g, and the yield of the deuterated pinocembrin II is 93.2%.
The spectrograms of three deuterated pinocembrin detected by a mass spectrometer in a negative ion mode and corresponding m/z are shown in figure 1.
Secondly, pharmacological experiments:
experimental example 1: pharmacokinetic properties and brain tissue distribution of deuterated pinocembrin
Experimental materials: SPF male SD rats weighing 240-260 g were purchased from Beijing Wittingle laboratory animal technologies, Inc., and the certification numbers: SCXK (Jing) 2014-. Deuterated pinocembrin is prepared by the research of medicines of Chinese medical academy of sciences. Both methanol and acetonitrile were chromatographically pure (Fisher, USA), with the remainder of the reagents being commercially available analytically pure.
An experimental instrument: agilent 1200series hplc (G1379B on-line degasser, G1311A quaternary gradient pump, G1329A autosampler, G1316A DAD detector). Agilent 6110 single quadrupole mass spectrometry.
Grouping experiments: SD rats were randomly divided into 6 groups of Pino-synephrine (Pino, 10mg/kg), deuterated Pino-synephrine I (Pino-I, 10mg/kg), deuterated Pino-synephrine II (Pino-II, 10mg/kg), and deuterated Pino-synephrine III (Pino-III, 10mg/kg), each group was administered by intravenous injection.
SD rats were fasted for 12h before administration, then at different time points before and after administration, blood was taken from the intra-ocular angular venous plexus in heparinized EP tubes, centrifuged at 5000rpm for 10min at 4 ℃ and the supernatant plasma was stored at-80 ℃ for use. For detection, 150. mu.L of plasma was processed and used for HPLC-MS analysis. And data processing statistics are carried out by adopting DAS 2.0 software.
As a result: as shown in figure 2 and table 1, the pharmacokinetic properties of deuterated pinocembrin I, II, III were significantly improved upon intravenous injection of the drug compared to the proto-pinocembrin drug. AUC of deuterated pinocembrin I, II and III0-tRespectively equal to 1.56 times, 1.70 times and 2.23 times of the original drug of pinocembrin; AUC of deuterated pinocembrin I, II and III0-∞Respectively equal to 1.56 times, 1.70 times and 2.25 times of the original drug of pinocembrin; preparation of deuterated pinocembrin I, II and IIIThe half-life is equivalent to 2.05 times, 2.14 times and 2.21 times of the original drug of the pinocembrin respectively. Meanwhile, the brain tissue drug concentration of the deuterated pinocembrin I, II and III is obviously higher than that of the original pinocembrin drug within 30-360min after intravenous injection. Also, at 240 and 360min of intravenous drug injection, no proto-drug was detected in rat brain tissue, but the presence of deuterated pinocembrin could be detected. The above results suggest that deuterated pinocembrin has better pharmacokinetic properties and higher brain tissue concentrations than the proto-pinocembrin drug.
Table 1 pharmacokinetic parameters after intravenous injection of deuterated pinocembrin in rats: (
n＝10)
Experimental example 2: effect of deuterated pinocembrin on neurobehavioral impairment symptoms of cerebral ischemia-reperfusion rats
Experimental materials: SPF male SD rats weighing 240-260 g were purchased from Beijing Wittingle laboratory animal technologies, Inc., and the certification numbers: SCXK (Jing) 2014-. Deuterated pinocembrin is prepared by the research of medicines of Chinese medical academy of sciences.
Grouping experiments: SD rats were randomly divided into Sham-operated control group (Sham), model group (I/R), pinocembrin group (I/R + Pino, 10mg/kg), deuterated pinocembrin group I (I/R + Pino-I, 10mg/kg), deuterated pinocembrin group II (I/R + Pino + II, 10mg/kg), deuterated pinocembrin group III (I/R + Pino-III, 10mg/kg), and 10 rats each.
Establishing a cerebral ischemia reperfusion animal model: the middle cerebral artery occlusion/reperfusion (MCAO/R) model was prepared using a wire-embolus method. Rats were anesthetized with isoflurane, fixed in the supine position, incised at the median line of the neck, blunt dissection, muscle and fascia were dissected along the intramuscular margin of the sternocleidomastoid, and the right Common Carotid Artery (CCA), External Carotid Artery (ECA) and Internal Carotid Artery (ICA) were dissected. Tightening the CCA proximal end and the ICA with a No. 1 suture, ligating the ECA distal end, burying the thread under the ECA for fixing the thread bolt, cutting an oblique incision on the ECA, inserting the thread bolt into the incision with the size of about 18mm, and fixing the thread bolt. After 1.5h of ischemia, the plug was pulled out to achieve reperfusion, and the tail vein was administered simultaneously. After the wound is sutured layer by layer, the rat is raised in a cage, and 10mg/kg of the medicine is injected into the vein every 12 h.
Neurobehavioral impairment score (Neurological deficits score): reperfusion was performed for 48h and neuro-behavioral impairment scoring was performed prior to sacrifice. The method comprises the following specific operations: lifting the rat tail out of the ground, observing the stretching condition of two forelimbs of the rat, then placing the rat on the horizontal ground, observing the crawling condition of the rat, pushing the shoulders of the rat, and observing whether the resistance of the two sides is different. A five-grade scoring method (0-4 points) is adopted, and the higher the score is, the more serious the neurobehavioral injury is.
As a result: as shown in fig. 3, the neurobehavioral impairment score of the model group rats was 3.80 ± 0.42; the neurobehavioral impairment score of the pinocembrin group rats was 2.90 ± 0.74, which was significantly reduced compared to the model group (P < 0.01); the neurobehavioral impairment score of the deuterated pinocembrin I group rats is 2.60 +/-0.52, and is remarkably reduced compared with that of a model group (P < 0.001); the neurobehavioral impairment score of the deuterated pinocembrin high II group rats is 2.20 +/-0.42, and the neurobehavioral impairment symptom is improved more obviously compared with that of a model group (P < 0.001); the neurobehavioral impairment score of the deuterated pinocembrin high III group rats is 2.00 +/-0.47, and the neurobehavioral impairment symptom is improved more obviously compared with that of the model group (P < 0.001). Meanwhile, the data suggest that the deuterated pinocembrin has more remarkable effect of improving the nerve function damage caused by cerebral ischemia-reperfusion compared with the pinocembrin.
Experimental example 3: effect of deuterated pinocembrin on cerebral ischemia reperfusion rat cerebral infarction volume (infarcct volume)
Experimental materials: TTC (2, 3, 5-Triphenyltetrazolium chloride) was purchased from Sigma Aldrich (Sigma-Aldrich). Other relevant experimental materials were the same as those in experimental example 1.
Grouping experiments: SD rats were randomly divided into a sham-operated control group, a model group, a pinocembrin group (10mg/kg), a deuterated pinocembrin group I (10mg/kg), a deuterated pinocembrin group II (10mg/kg), and a deuterated pinocembrin group III (10mg/kg), each group containing 10 rats.
Determining the cerebral infarction volume: placing rat brain tissue in a refrigerator at-20 deg.C, taking out after 15min, placing in rat brain slice mold, cutting olfactory bulb, cerebellum and lower brain stem, and cutting into coronal slices with 2mm interval. Brain sections were then quickly placed in 0.5% TTC solution and incubated at 37 ℃ in the dark for 20 min. After TTC staining, normal tissue was rose-red, while ischemic infarcted tissue was pale. Taking out brain slices, and fixing in 4% paraformaldehyde solution. Finally, the brain slices of each rat are arranged in order and stored by taking a picture. And calculating the total area and the infarct area of each brain slice by using Image J Image analysis software, and then converting according to the thickness of the brain slice and the measured area to obtain the cerebral infarction volume.
As a result: TTC is a fat-soluble photosensitive compound, reacts with succinate dehydrogenase in living cell mitochondria to generate red formazan, is used for reacting the activity of histiocytes, and is pale due to the fact that the activity of the succinate dehydrogenase in ischemic tissues is reduced and cannot react with TTC. As shown in fig. 4, the volume percentage of cerebral infarction of the model group rats was 42.12 ± 6.55%; the percent volume of cerebral infarction of the rats in the pinocembrin treatment group is 33.23 +/-3.19 percent, and the cerebral infarction is obviously reduced compared with that in the model group (P < 0.001); the cerebral infarction volume percentage of the deuterated pinocembrin I group rats is 27.68 +/-5.27%, and is remarkably reduced compared with that of a model group (P < 0.001); the volume percentage of cerebral infarction of the deuterated pinocembrin II group rats is 24.63 +/-4.05%, and the cerebral infarction state is improved more obviously compared with that of a model group (P < 0.001); the volume percentage of cerebral infarction of the deuterated pinocembrin III group rats is 19.14 +/-2.23%, and the cerebral infarction state is improved more obviously compared with that of a model group (P < 0.001). This suggests that deuterated pinocembrin can significantly reduce cerebral infarction volume more than pinocembrin.
Experimental example 4: effect of deuterated pinocembrin on brain Water content (cerebral Water content) of rats subjected to cerebral ischemia reperfusion
Grouping experiments: SD rats were randomly divided into a sham-operated control group, a model group, a pinocembrin group (10mg/kg), a deuterated pinocembrin group I (10mg/kg), a deuterated pinocembrin group II (10mg/kg), and a deuterated pinocembrin group III (10mg/kg), each group containing 10 rats. Other relevant experimental materials and experimental protocols were the same as in experimental example 1.
And (3) detecting cerebral edema: after the brain tissue of the rat is taken out, the rat is weighed wet, and then the brain tissue is placed in a constant temperature drying oven at 100 ℃ and dried for 24 hours until the constant weight is the dry weight. Percent brain water content ═ wet weight-dry weight/wet weight x 100%.
As a result: as shown in FIG. 5, the percent brain water content of the model group rats was 80.93. + -. 3.73%; the percent brain water content of the rats in the pinocembrin group is 76.74 +/-1.70%, and the percent brain water content is obviously reduced compared with that in the model group (P < 0.01); the percentage of the brain water content of the deuterated pinocembr I rats is 75.60 +/-2.20%, and the percentage is remarkably reduced compared with that of a model group (P < 0.001); the percentage of brain water content of the deuterated pinocembr II rats is 75.15 +/-2.74%, and the rats have a remarkable reduction (P <0.001) compared with the model group. The percentage of brain water content of deuterated pinocembr group III rats was 74.43 ± 1.77%, which was more significantly reduced compared to the model group (P < 0.001). Meanwhile, the data indicate that the deuterated pinocembrin can more remarkably inhibit the cerebral edema state of a cerebral ischemia reperfusion rat and reduce the brain tissue damage compared with the pinocembrin.
Experimental example 5: influence of deuterated pinocembrin on blood brain barrier opening degree of cerebral hemorrhage rats
Experimental materials: evans Blue (Evans Blue) was purchased from Sigma-Aldrich. Other relevant experimental materials were the same as those in experimental example 1.
Grouping experiments: SD rats were randomly divided into a sham-operated control group, a model group, a pinocembrin group (10mg/kg), a deuterated pinocembrin group I (10mg/kg), a deuterated pinocembrin group II (10mg/kg), and a deuterated pinocembrin group III (10mg/kg), and 6 rats were selected. After anesthetizing, fixing in prone position, incising the skin along the middle of the skull, exposing the anterior chimney, vertically arranging the anterior chimney on the surface of the right tail shell nucleus for 3mm, laterally opening the position for 1mm, drilling the position with the skull, injecting 2 mu L collagenase at a constant speed by using a microsyringe, keeping the needle for 5min, taking out the microsyringe, suturing the incision, and injecting penicillin into the abdominal cavity after operation to prevent infection.
Rats were injected intravenously with 4% Evans blue (0.2mL/100g) at the end of the experiment at 48h every 12h with 10mg/kg of therapeutic drug, followed by 20mL of 10U/mL heparin sodium to flush out the blood. The brains were then separated, weighed, and homogenized with 50% trichloroacetic acid solution. After centrifugation at 400 Xg for 20min, the measurement was carried out spectrophotometrically at 620 nm. The content of the cerebral ischemic hemisphere Evans blue is expressed in ng/g.
As a result: evans blue is a commonly used azo dye reagent, and has a molecular weight similar to that of plasma albumin, and has high affinity with the plasma albumin in blood. Under normal conditions, plasma albumin cannot cross the Blood Brain Barrier (BBB), and Evans blue cannot stain it. During stroke, the blood brain barrier is disrupted and Evans blue enters the nervous system and stains it. As shown in FIG. 6, the Evans blue penetration of the model group rats was significantly increased (4240.0 + -337.6 ng/g), indicating that the blood-brain barrier was severely damaged and the degree of opening of the blood-brain barrier was increased. The Evans blue penetration of the pinocembrin rats is obviously reduced compared with that of the model group (3109.6 +/-546.9 ng/g, P <0.001), and the blood brain barrier opening degree is reduced. The Evans blue permeation amount of the rats in the deuterated pinocembrin I group is (2740.3 +/-618.7 ng/g), the Evans blue permeation amount of the rats in the deuterated pinocembrin II group is (2285.4 +/-282.3 ng/g), the Evans blue permeation amount of the rats in the deuterated pinocembrin III group is (1926.1 +/-224.6 ng/g), each group is obviously reduced compared with the model group (P <0.001), the Evans blue permeation amount of each group is lower than that of the pinocembrin group, and the blood brain barrier damage degree is obviously reduced. This suggests that deutero-pinocembrin can inhibit the blood brain barrier injury of cerebral hemorrhage rat more obviously than pinocembrin, reduce its opening degree and permeability, and exert the blood brain barrier protection effect.
In conclusion, the invention adopts a cerebral ischemia reperfusion and cerebral hemorrhage rat model to investigate the effect of the deuterated pinocembrin on resisting the cerebral apoplexy, and the result shows that the injection of the deuterated pinocembrin can obviously improve the neurobehavioral defect symptoms of the cerebral apoplexy rat, obviously reduce the cerebral infarction volume and the cerebral edema degree of the cerebral apoplexy rat and reduce the permeability and the openness degree of a blood brain barrier. Therefore, the deuterated pinocembrin has the effect of resisting cerebral apoplexy, and the therapeutic effect of the deuterated pinocembrin is better than that of a pinocembrin prototype drug. Meanwhile, the deuterated pinocembrin has better pharmacokinetic properties and higher brain tissue concentration compared with a pinocembrin prototype drug. Deuterated pinocembrin is taken as an active substance, is singly used or/and is combined with other compounds or extracts with pharmacological activity for compound use, and is prepared into anti-stroke medicaments in various dosage forms according to the conventional preparation method in the pharmaceutical field, or is prepared into compound preparations with other medicaments and the like, so that adverse reactions in the medicament action are reduced under the condition of keeping the curative effect, and an effective solution is provided for the prevention and treatment of stroke.
Finally, while the present invention has been described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. Deuterated pinocembrin or a pharmaceutically acceptable salt thereof, wherein the deuterated pinocembrin has a structure represented by formula I, formula II, or formula III:
2. the method of claim 1, comprising the steps of:
(1) taking 5, 7-dihydroxyflavone as a raw material, taking deuterium gas as a deuterium donor, and carrying out catalytic reduction reaction in a solvent under the condition of a catalyst to obtain deuterated pinocembrin I;
(2) reacting deuterated pinocembrin I with D under strong alkaline condition2Performing O reaction to obtain deuterated pinocembrin III;
(3) reacting deuterated pinocembrin III in an alcohol solvent under the condition of heating to generate deuterated pinocembrin II;
3. the method according to claim 2, wherein the solvent used in step (1) is ethyl acetate, and the catalyst is palladium on carbon.
4. The method according to claim 2, wherein the reaction condition in step (2) is heating at a temperature of 60-100 ℃, preferably 80 ℃, and the strong base is sodium hydroxide.
5. The process according to claim 2, wherein the reaction condition in the step (3) is heating at 60 to 100 ℃, preferably 80 ℃, and the alcoholic solvent is methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, pentanol, pentanediol, n-hexanol, or octanol.
6. A pharmaceutical composition comprising an effective amount of deuteroprimulin of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition according to claim 6, wherein the formulation type is selected from the group consisting of oral formulation, injectable administration and administration by the mucocutaneous route.
8. The pharmaceutical composition of claim 7, wherein the oral preparation comprises a tablet, a capsule, a sustained release agent, a controlled release agent, a drop pill, a powder, a granule, a solution, an emulsion or a suspension, the injection dosage form comprises intramuscular injection, intravenous injection or intravenous drip, and the administration dosage form of the mucocutaneous route comprises a topical solution, a lotion, a liniment, an ointment, a plaster, a paste, a patch, an eye drop, a nasal drop, an ophthalmic ointment, a gargle, a sublingual tablet, a patch or a patch.
9. Use of deuterated pinocembrin or a pharmaceutically acceptable salt thereof as defined in claim 1 or a pharmaceutical composition as defined in claim 6 for the preparation of a medicament for the prevention and/or treatment of stroke and stroke sequelae.
10. The use according to claim 9, wherein the stroke is acute ischemic stroke, transient ischemic attack, chronic cerebral ischemia, or hemorrhagic stroke.
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| 宋瑞捧等: "氘标记药物分子的合成进展", 《中国医药工业杂志》 * |
| 张寅生: "氘代药物研发的过去、现在与未来", 《药学进展》 * |
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