WO2020125478A1

WO2020125478A1 - Drug compound, preparation therefor, and application thereof

Info

Publication number: WO2020125478A1
Application number: PCT/CN2019/124182
Authority: WO
Inventors: 李大鹏
Original assignee: 上海槐丰生物科技有限公司
Priority date: 2018-12-18
Filing date: 2019-12-10
Publication date: 2020-06-25
Also published as: CN109384759B; CN109384759A

Abstract

The present invention relates to a drug compound, preparation therefor, and an application thereof. The drug has the structure as represented by formula I after being modified by a flavonol structure. Compared with current anticoagulant drugs, the present invention has the characteristics of high efficiency, low toxicity, long-acting, and stability; the drug has excellent physical and chemical stability, and has excellent stability to water, acid, and alkali.

Description

Pharmaceutical compound and its preparation and use

Technical field

The invention relates to a medicine, in particular to a medicine compound and its preparation and use.

Background technique

Cardiovascular disease is the first killer of human beings. In 2016, the number of deaths from cardiovascular disease worldwide was 17.65 million, far exceeding the number of tumors (various tumors) (8.93 million). In China, the number of deaths from ischemic heart disease (coronary heart disease) and ischemic stroke is much higher than the deaths from all tumors. The situation in the United States is similar. Although the clinical effect of antiplatelet drugs is positive, the side effects of bleeding are the biggest problems of existing antiplatelet drugs. Existing antiplatelet drugs have bleeding side effects of varying degrees. On the one hand, serious bleeding side effects (such as intracranial hemorrhage) can be fatal and more serious than the thrombus itself. On the other hand, bleeding side effects limit the possibility of increasing the antiplatelet and antithrombotic effects by increasing the dose. Therefore, we still need antiplatelet drugs with better antithrombotic effects and less bleeding side effects.

Take aspirin for example, which has anti-inflammatory, analgesic and antipyretic properties, and is widely used to combat cardiovascular diseases and to reduce mortality among all cardiovascular high-risk groups. It has been confirmed that aspirin has antipyretic, analgesic, anti-inflammatory, anti-rheumatic, anti-platelet aggregation, anti-thrombotic, thromboembolic diseases, cardiovascular and cerebrovascular diseases, stroke, Kawasaki disease, diabetes, diabetic complications, Alzheimer, Vascular dementia, tumors, reduction of morbidity and mortality of gastrointestinal malignant tumors, reduction of hearing damage caused by ototoxic antibiotics, roundworm of biliary tract, preeclampsia, cataract, contraception, infertility, miscarriage, multiple sclerosis, liver fibrosis, etc. Has a wide range of functions.

At present, the adverse reactions of aspirin are mainly the damage of the digestive system and the blood system, followed by allergic reactions, salicylic acid reactions, and liver and kidney function damage; of which the digestive system damage is mainly the gastrointestinal bleeding above, and the blood system damage is mainly due to thrombocytopenia. Performance, worsening bleeding tendency. Moreover, studies have shown that adverse reactions in the population of medium and small doses of aspirin mainly occur in people over 60 years of age, and the incidence of males is higher than that of women. Among them, the elderly aged 75 years or older have long-term adverse reactions of taking small doses of enteric-coated aspirin 100 mg/d The incidence rate was significantly higher than that of the adult group (43.8% vs 23.7%, nearly doubled), mainly manifested as upper abdominal pain or discomfort and upper gastrointestinal and cerebral hemorrhage. Therefore, the gastrointestinal hemorrhage and cerebral hemorrhage induced by it are increasingly concerned by public health, which limits the further clinical application.

In terms of gastrointestinal bleeding, current studies have shown that aspirin can triple the risk factor for gastrointestinal bleeding in almost half of patients, even at relatively low doses for the prevention of myocardial infarction, endoscopic controlled studies have shown that in all aspirin The dosage will increase the risk of bleeding. Cryer B found in a study that 10% of patients who took low-dose aspirin of 10-300 mg/day had endoscopic ulcers after 12 weeks. The risk of gastrointestinal side effects limits the use of aspirin in patient groups with a high probability of thrombotic events, and the risk of severe gastrointestinal bleeding in a random population is higher than the role of aspirin in preventing death from cardiovascular disease. Aspirin causes gastrointestinal bleeding mainly through two ways: (1) Chemical toxicity: Aspirin is a hydrophobic acid (pKa 3.5), it is fat-soluble at low pH, and it can destroy the hydrophobic layer covering epithelial cells to allow The cavity contents enter and cause irritation. When aspirin disintegrates in the stomach, the release of cytotoxic substances such as leukotriene increases, which in turn stimulates and damages the gastric mucosa. In addition, aspirin can also damage the intestinal mucosal barrier and eventually lead to ulcers. (2) Biological toxicity: Aspirin absorbs cyclooxygenase when it passes through the gastrointestinal tract during the systemic distribution and absorption process, weakens their protective effect, and causes the production of prostaglandins that regulate gastric acid secretion and blood flow. Causes damage to the digestive tract mucosa. Although enteric aspirin reduces its chemical damage toxicity in the stomach, it is still unavoidable that aspirin intestinal absorption leads to intestinal mucosal injury and bleeding, so the current solution is still not sufficiently effective. To address this defect , The industry has been trying to prepare aspirin as an aspirin ester prodrug. The theory of the prodrug is that it is inactive by itself but forms an active therapeutic agent when it is metabolized in the body. Because the carboxyl group of aspirin forms an ester, it blocks the carboxylic acid and the gastric mucosa. Chemical toxicity caused by direct contact until aspirin is released into the plasma after absorption into the gastrointestinal tract. However, after aspirin is esterified, it is easily degraded in the acidic environment of gastric juice and releases aspirin in the gastrointestinal tract. It is difficult to avoid aspirin on the stomach The damage to the intestinal mucosa, based on this design theory, still has not solved the side effects of gastrointestinal bleeding and cerebral hemorrhage caused by biochemistry, especially the side effects of cerebral hemorrhage are not fully considered.

In terms of cerebral hemorrhage, the risk of aspirin causing cerebral hemorrhage (CMB) has not been widely valued by the medical community until recently. The JPPP study published at the 2014 annual meeting of the American Heart Association was conducted in 1007 clinics in 47 regions in Japan. A total of 14,464 participants aged 60-85 years were included. Patients were treated for hypertension, dyslipidemia, or diabetes. Randomly received non-blind aspirin or non-aspirin treatment. The results showed that elderly patients with diabetes, hypertension or hypercholesterolemia taking low-dose aspirin daily (100 mg/day) for primary prevention failed to reduce the risk of cardiovascular disease and stroke, and the group taking aspirin significantly increased cerebral hemorrhage (Blood transfusion required) or hospitalization has an incidence of 85%. The stroke portion of the study was published at the International Stroke Conference (ISC) 2015 meeting, and the results showed that in Asian populations with vascular risk factors, aspirin did not produce any net clinical benefit in stroke primary prevention. At 5 years, the cumulative incidences of fatal and non-fatal strokes in aspirin and the control group were basically similar, 2.068% and 2.29 9%, respectively. Compared with the control group, although aspirin reduced the incidence of ischemic stroke, the incidence of cerebral hemorrhage increased, but there was no statistical difference between the two indicators. Dong Manli reported that compared with the elderly who did not take antithrombotic drugs, the elderly who took aspirin had more visible microbleeds in the brain when they were examined by MRI, and the higher the dose of these drugs, the greater the cerebral hemorrhage. Is more visible. Wong et al. studied the relationship between asymptomatic CMB and aspirin-related cerebral hemorrhage. GRE-MRI examination was performed on 21 patients with cerebral hemorrhage after aspirin application and 21 patients with aspirin without cerebral hemorrhage. The results showed that the incidence of cerebral microhemorrhage in the cerebral hemorrhage group was significantly higher than that in the non-cerebral hemorrhage group, and the number was larger, suggesting that cerebral microhemorrhage may be a risk factor for aspirin-related cerebral hemorrhage. Therefore, a large amount of research evidence has shown that aspirin no longer supports primary prevention of cardiovascular diseases.

In addition, antiplatelet drugs have increased the incidence of intracerebral hemorrhage while also increasing the incidence of intracerebral hemorrhage. Jianting Qiu and others reported in "Stroke" the meta-analysis of antiplatelet therapy with intracerebral hemorrhage and intracerebral hemorrhage. After 37 studies reported in 1997-2017 and the relevant literature reports of 20988 subjects, the researchers calculated the incidence and distribution of CMB in patients with antiplatelet therapy and those who did not receive antiplatelet therapy (local lobe, deep/behind the scene) The combined odds ratio (OR) and calculated the OR value of the incidence of intracranial hemorrhage in CMBs patients receiving antiplatelet therapy and CMBs patients not receiving antiplatelet therapy. Compared with patients who did not receive antiplatelet therapy, CMBs were more common in patients who received antiplatelet therapy. Antiplatelet therapy was significantly associated with local brain lobe MBs, but with deep/subcutaneous MBs. Compared with patients who did not receive antiplatelet therapy, patients who received antiplatelet therapy had a higher incidence of cerebral hemorrhage. These results indicate that antiplatelet drugs increase the risk of cerebral microhemorrhage and that the incidence of intracerebral hemorrhage associated with antiplatelet drugs is higher in patients with cerebral microhemorrhage. Due to the limited research on the relationship between antiplatelet therapy and cerebral hemorrhage, there are different opinions on the risk of aspirin causing cerebral hemorrhage, but the study includes a large number of samples from multiple studies in multiple countries. Based on a large number of clinical samples, the The study strongly confirms that antiplatelet drugs increase the risk of cerebral microbleeds. Therefore, how to avoid aspirin-induced cerebral hemorrhage is an urgent problem that needs to be solved in the treatment of stroke in the elderly. However, the current drug design lacks an effective solution.

Since the clinical symptoms of cerebral hemorrhage mainly depend on the location and number of CMB, in the study of ischemic diseases, CMB is associated with cognitive decline, CMB destroys the connection between the frontal lobe and the basal nucleus, which becomes cognitive function An independent risk factor for the disorder; in addition, the risk of secondary cerebral hemorrhage in patients with CMB is also significantly increased, and the risk of cerebral hemorrhage or recurrence of blood in patients with multiple CMB is significantly increased. CMB patients who take long-term anticoagulant drugs to prevent stroke The probability of bleeding complications is significantly increased, and a large number of studies have shown that CMB also increases the risk of hemorrhagic conversion after thrombolytic therapy in patients with acute ischemic stroke, and CMB is an independent risk factor for massive cerebral hemorrhage.

In addition, from the detection rate of cerebral hemorrhage in patients requiring antithrombotic therapy, Pasquin reported that the incidence of cerebral hemorrhage in the "healthy" population with no previous history of ischemic stroke is about 5%, and has occurred The incidence of ischemic stroke patients is 22.9% ~ 43.6%, of which, the incidence of ischemic stroke (lacunar cerebral infarction) involving small vessel disease is about 36%, and the incidence of arteriosclerotic thrombotic infarction The incidence rate is about 46%, the incidence rate in cardiogenic cerebral embolism is about 30%, the incidence rate in transient ischemic attack is 8%, and the incidence rate in ischemic peripheral vascular disease is about 13% , About 4% of patients with acute myocardial infarction. It can be seen that in patients with ischemic stroke, the incidence of cerebral hemorrhage is higher. At the same time, more and more studies have found that patients with asymptomatic cerebral hemorrhage are more likely to develop symptomatic cerebral hemorrhage. Most patients with cerebral hemorrhage are closely related to recurrent cerebral hemorrhage in Asian populations, while European and American populations are mostly Blood stroke is closely related, which shows that cerebral hemorrhage is more harmful to Asian people. Therefore, the actual damage of cerebral hemorrhage from cerebral hemorrhage to death has occurred and is occurring, and it is directly life-threatening, but so far there is no effective way to solve this problem, and cerebral hemorrhage has seriously increased the risk of oral aspirin to solve this One problem is urgent for pharmacists, and it is an urgent problem that needs to be solved in clinical medicine.

In addition, antiplatelet drugs generally have resistance problems. For example, aspirin resistance causes the antiplatelet effect of patients to be ineffective after medication, which makes bleeding more likely. Although enteric-coated aspirin preparations reduce stomach irritation, studies have reported that in patients with type 2 diabetes, the bioavailability of enteric-coated aspirin is reduced compared to taking ordinary aspirin, and enteric solubility is an important cause of aspirin resistance. Therefore, the use of enteric aspirin did not really solve the bleeding problem. In some cases, enteric coating caused aspirin resistance, but increased the bleeding.

In summary, for the gastrointestinal hemorrhage and cerebral hemorrhage, if the appropriate structural modification of aspirin can not only prevent local gastrointestinal hemorrhage of aspirin, but also greatly reduce or even prevent cerebral hemorrhage and substantial cerebral hemorrhage, while still Being able to retain the antithrombotic activity of aspirin is undoubtedly of great clinical value.

In addition to the above-mentioned adverse reactions, aspirin's salicylic acid reaction is also one of the main side effects of aspirin. Studies have found that taking aspirin at a dose greater than 100 mg/kg/day for more than 2 days can cause chronic toxicity and potentially life-threatening. Acute poisoning (overdose), accidental ingestion by children leads to poisoning. Chronic salicylate poisoning can manifest as recessive and no specific symptoms. Mild chronic salicylate poisoning, or salicylic acid reaction, usually occurs after repeated large doses. Symptoms include dizziness, dizziness, tinnitus, deafness, sweating, nausea and vomiting, headache, and confusion. The plasma concentration of salicylic acid further increases and more serious adverse reactions can occur. In addition, animal experiments have shown that high doses of salicylic acid cause kidney damage, and salicylates may be teratogenic in different kinds of animals. On the other hand, aspirin is quickly hydrolyzed to salicylate in the gastrointestinal tract, liver and blood, and then metabolized in the liver. The metabolites are mainly conjugates of salicylic acid and glucuronic acid, and a small portion is oxidized to dragon Bile acid, salicylic acid reaches the peak of blood medicine 1 to 2 hours after taking the medicine. Aspirin only exists in a very low proportion in the body, mostly in the form of salicylic acid. The high concentration of salicylic acid in the body further leads to the reaction of salicylic acid. Therefore, how to reduce the salicylic acid reaction while reducing the concentration of salicylic acid while ensuring the effective concentration of aspirin is also an unsolved problem in the improvement of aspirin drugs.

As the effect of aspirin, including anti-thrombotic effects, depends on its absorption into the blood as prototype aspirin, not its hydrolysate salicylic acid. Aspirin is rapidly degraded to salicylic acid after oral absorption. The peak time of aspirin and salicylic acid plasma concentrations are 10-20 minutes and 0.3-2 hours, respectively. Only a small part of the body exists in the form of aspirin prototype, which makes it impossible Efficient use of aspirin activity. Current clinical medications still need to be taken daily.

It can be seen that the current aspirin drugs have the following problems: low efficacy, low safety, short effect, and poor stability. In order to solve these problems of aspirin, people have tried a lot of prodrug design for aspirin, but due to the influence of aspirin prodrug structure, aspirin's own structure and metabolic complex factors in the body, many prodrugs have failed. Nielsen reported on the metabolic pathway of aspirin ester prodrugs of phenol in the body. Studies have found that aspirin esters are converted to salicylic acid instead of aspirin in the body. Aspirin ester prodrugs have two possible metabolic pathways in human tissues and blood: pathways (1 ), after the aspirin ester prodrug is absorbed into the blood, under the action of blood and plasma, the ester bond between the aspirin and the carrier is cleaved, and then the aspirin is released. This is the ideal metabolic pathway for the design of prodrug; pathway (2), aspirin ester prodrug After being absorbed into the blood, under the action of blood and plasma, the acetyl group of aspirin itself is cleaved to generate salicylate, and eventually salicylic acid is further generated without releasing aspirin. When salicylic acid is generated, anticoagulant activity is lost. Therefore, approach 2 should be avoided as much as possible. However, none of the 26 different prodrug compounds designed by Nielsen's research institute released more than 0.5% of aspirin when incubated in the relevant blood or plasma. Therefore, compounds of aspirin prodrugs actually do not have the effect of aspirin in vitro or in vivo, but instead they release the corresponding salicylates.

In order for aspirin esters to function as prodrugs, the design challenge was to avoid the wrong ester group hydrolysis of aspirin esters in the presence of human plasma. Nielsen further clarified one of the possible pathways of aspirin's esterase metabolism in the body. For example, when aspirin enters the blood, its acetyl group is hydrolyzed to salicylic acid by the dominant esterase-butyrylcholinesterase in human plasma. . Aspirin is negatively charged at blood pH, but butyrylcholinesterase is not actually in the most effective state when processing negatively charged substrates. The negative charge of aspirin after esterification is removed, and the acetyl group becomes As a more suitable substrate for butyrylcholinesterase, the introduction of new ester groups will greatly accelerate the metabolic rate of acetyl esters on aspirin. The study shows that the half-life of aspirin in diluted plasma is about one hour, but the half-life of aspirin ester undergoing the same deacetylation process is less than one minute. Natural phenyl acetate such as aspirin ester is the most effective hydrolysis of butyrylcholinesterase One of the substrate types. In order for the hydrolysis of the ester bond to occur at the correct position, the carrier group that forms an ester with aspirin must have a competitive structure that is complementary to the acetyl group, that is, it must be at least as attractive as the BuChE enzyme substrate as the acetyl group. It even appears to promote their own hydrolysis while simultaneously inhibiting the hydrolysis of adjacent acetyl groups. In designing 26 prodrugs, Neilsen found that only the 2-hydroxyacetamide ester of aspirin can successfully compete with acetyl hydrolysis, but it was only partially successful, and only 50% was hydrolyzed according to route (1). Therefore, because the actual metabolism in the body is far more complicated than that simulated by this esterase, such an ester-forming carrier group has to be designed. Many studies have shown that aspirin ester prodrugs are metabolized in the body according to pathway (1). Proving is extremely difficult.

Among the known aspirin prodrugs, the aspirin ester of acetaminophen-benoate has been on the market for about 30 years, but a large number of studies have found that the dose administered to humans does not produce aspirin release in the body. In addition, the research of NO-aspirin prodrug esters is the most extensive. It is based on NO to promote mucosal defense and offset the gastrointestinal damage caused by aspirin. Nitric oxide and aspirin also have complementary pharmacological effects, sometimes with synergistic pharmacological effects. It is theoretically foreseeable that this prodrug design can show better pharmacological effects and smaller side effects. NCX-4016 is a prototype compound of NO-aspirin drug, it is one of the most widely promoted drug development in the past decade, and has been expected by the biomedical community. It can produce NO in vivo and has antiplatelet effect. In animal models, NCX-4016 also shows greater gastric tolerance than aspirin, but the key evaluation index for aspirin ester prodrugs is its temperature in human plasma or blood. Whether it can be hydrolyzed into aspirin during childbirth. NCX-4016 is an aspirin ester substituted for phenol. The current study also does not have the hydrolytic metabolism data of NCX-4016 in human plasma. Corazzi et al. reported in 2005 that the drug can directly act on its target Click without releasing aspirin. NCX-4016's clinical trials started in 2002, and ultimately because of drug absorption and clinical trials, its inhibition of COX is not as strong as that of aspirin to inhibit COX. There is no significant advantage, which leads to the failure of clinical trials. While other NO-aspirin prodrug designs may release nitric oxide in the body, the prodrugs are hydrolyzed along the typical salicylic acid pathway and cannot release a large amount of aspirin.

In an effective aspirin prodrug disclosed in WO2009/080795A1, it discloses a series of 25 aspirin isosorbide compound prodrugs, although the parent structures of these prodrugs are the same, only the 5-position substituents of isosorbide are different , Leading to huge differences in the metabolic pathways of these prodrugs, such as several compounds exemplified in the following formula, where compound 17 is substituted in the absence of the 5-position, 99% of the prodrug is metabolized to salicylate according to pathway 2 , Only 1% is metabolized to aspirin; even if compound 7 is substituted with a six-membered heterocyclic ring at the 5 position, 82% of the prodrug is metabolized to salicylate according to route 2; when the 5 position substitution is a benzoic acid analog substitution , Compound 20 is 80% metabolized to aspirin according to pathway 1, and only 20% is metabolized to salicylate according to pathway 2; even if the 5-position substitutions are all benzoic acid analog substitutions, the metabolism between

compounds

1 and 20 is also significant In difference, only 60% of compound 1 is metabolized to aspirin according to route 1, while 40% is metabolized to salicylate according to route 2. It can be seen that small changes in the carrier group structure of aspirin esters can lead to huge differences in metabolic pathways, which in turn affects the effective release of aspirin in the body.

Although WO2009/080795A1 obtained the majority of aspirin isosorbide compound prodrugs that release aspirin according to route 1, there are still many shortcomings in the structural design. First, the in vitro experiments of the prodrugs in 50% and 80% human plasma, It is not whole plasma, so the experiment does not reflect the actual metabolism of the prodrug in the body; in addition, the prodrug disappears in about 10 minutes in the human plasma experiment, and the action time is short. Therefore, after 10 minutes Aspirin has fewer prototypes and fewer proportions, and it cannot play the role of aspirin prototype drugs in actual clinical application. Secondly, the release of NO can only offset the gastrointestinal damage caused by aspirin through mucosal defense, and cannot solve the problem of aspirin cerebral hemorrhage. ; Finally, the ester bond of the isosorbide carrier group is extremely unstable in an aqueous medium, acid and alkali, and is prone to hydrolysis, so the prodrug has the following potential risks, that is, the ester of isosorbide is stored for a period of time in the prodrug Most of the bonds are wet or hydrolyzed in the gastrointestinal environment, which eventually leads to changes in the metabolic pathway of the prodrug after absorption into the blood, but the prodrug has not proved its superior resistance to hydrolysis and is difficult to form a drug. Therefore, no matter whether it is the drug drugability or the current demand for aspirin clinical treatment, the aspirin prodrug provided by this method is still far from meeting the stable, safe and effective clinical needs.

On the other hand, the stability of aspirin ester prodrugs to water and moisture also has many challenges. Aspirin's acetyl group is quite unstable to the hydrolysis of water and other nucleophiles. Aspirin's instability is mainly due to autocatalysis. Aspirin has carboxyl and acetyl groups. The carboxyl group can activate nearby water molecules to produce hydroxides that attack the acetyl group. Theoretically, aspirin carboxyl formation can mask the carboxyl group, thereby inhibiting autocatalysis, but the introduction of the second chemically active ester has the effect of improving the acetyl reaction activity (and adding another unstable position), which brings new ester bonds in It is easy to hydrolyze in water environment, which will cause new instability. Bundgaard reported on the hydrolytic stability of the following three compounds of 2-acetoxybenzoic acid N-hydroxyalkylamide:

Among them, the three primary aspirin prodrugs have large differences in the rate of first-order hydrolysis. For example, the hydrolysis rates of compounds I and II are similar between pH 0.15 and 6.02, while compound III is significantly different from compounds I and II. Even if the compounds I and II with similar structure are in a neutral or slightly alkaline environment, the hydrolysis rates of the two are quite different. Therefore, the water stability and acid-base stability of aspirin ester prodrugs will also be significantly affected by small changes in the structure of the ester-forming carrier group. These unfavorable factors have led to the development of aspirin ester prodrugs full of uncertain factors, and these effects are difficult to accurately predict through theory, and the actual effect is far from the theoretical prediction.

In the selection of aspirin-forming carrier groups, most of the flavonoids have various pharmacological activities such as anti-oxidation. For example, quercetins have antioxidant and scavenging oxygen free radicals, protect myocardial ischemia, protect blood vessels, and enhance immune function. , Lowering blood pressure, improving capillary resistance, reducing capillary permeability, reducing capillary fragility, reducing blood fat, dilating coronary arteries, increasing coronary blood flow, antibacterial, antiviral, anti-inflammatory, anti-allergic, anti-tumor, reversal The multidrug resistance and antithrombotic effect of tumor cells. However, due to the poor water solubility and fat solubility of quercetin, the drug preparation and absorption in the body are extremely unsatisfactory. Current research reports that in the rat in vivo experiment, the dose of quercetin was administered by oral gavage at 40mg/kg, and the highest blood concentration of ordinary quercetin suspension was only 3.5ng/ml, which was distributed in tissues. Among them, quercetin has the highest distribution in gastric tissue, followed by blood, liver, kidney, heart, lung, and spleen, but it has not been detected in brain tissue and muscle. It can be seen that quercetin is difficult to penetrate the blood-brain barrier and cannot enter Brain tissue plays a role.

In recent years, there have also been studies on the formation of esters with flavonoids and aspirin. For example, Xu Jun reported the preparation of puerarin esters of aspirin. The effects of puerarin and aspirin on platelets are different and the antithrombotic mechanism is different. According to the combination principle of drug design With puerarin as the parent, the hydroxy structure of puerarin B ring was modified by acylation to combine the two drugs into esters. Although studies have shown that esterification reduces the side effects of gastrointestinal bleeding, the inhibitory effect of ester-forming drugs on ADP-induced platelet aggregation in vitro is comparable to aspirin, and the efficacy has not been improved. At the same time, this study did not further study aspirin puerarin ester In vivo metabolism, whether aspirin puerarin ester is released in the body in accordance with pathway 1 in the body has not been clarified. In the body, its protective effect on gastric mucosa can only be determined that aspirin esters mask the acidity in its structure Carboxyl groups reduce chemical stimulation of the gastric mucosa. The study also showed that the water solubility of aspirin puerarin ester was somewhat reduced, only 0.87 times that of puerarin, which is far from the theoretical prediction, and the improvement of the water solubility of flavonoid-puerarin is far from the expected effect. Therefore, the prodrug design of aspirin and flavonoids cannot achieve the expected effect according to theory, and the complex factors of in vivo metabolism make the prodrug design difficult to predict.

In addition, the current research on the formation of flavonoids is more concerned with the overall anti-cancer effect of the ester-forming drugs and the improvement of the drug's water solubility. It does not improve the actual absorption, distribution, metabolism and other problems of flavonoids in the body, as well as the actual effect. For example, CN101591318A discloses 3,5,7-trihydroxy derivatives and uses, and the C1-C5 acylation of the hydroxy groups on the A and C rings of flavonoids is selected, but the study did not study the physical and chemical properties of esters including Water solubility, stability, and metabolism in vivo, but only the in vitro activity of ester-forming derivatives on human tumor cells was investigated. For example, CN 107163096A discloses troxerutinamide derivatives and uses. The hydroxyethyl ester of this structure on the B ring of troxerutin forms esters. Similarly, this study did not design it as a prodrug, but investigated ester formation. The cytotoxic activity of derivatives on HT-29 (human colon cancer cells) and MCF-7 (human breast cancer cells) in vitro. Therefore, the current research on aspirin and flavonoid prodrugs is not in-depth, nor does it involve whether the body metabolism can produce an effective amount of aspirin, whether it can increase the absorption of flavonoids in the body, whether the prodrug is stable, and whether it can reduce the gastrointestinal tract of aspirin Side effects of hemorrhage and microhemorrhage

Although aspirin and flavonoid esters face great challenges as prodrugs, natural flavonoid products have improved platelet function, can adjust the balance of PGI2 and TXA2, increase PGI2 levels, reduce TXA2/PGI2 ratio, inhibit platelet aggregation, and promote damaged blood vessels Endothelial function is restored, and aspirin and flavonoids are esterified to achieve synergistic antithrombotic effects. They are still very attractive for clinical research and development, but so far, there is no real hydrolysis, absorption, and metabolism in the body that meets antiplatelet The aspirin ester drug research required by the aggregation design was successful.

Esterification of aspirin and flavonol is a good idea, but the challenging goal is that after absorption, the compound should be able to release aspirin in accordance with route 1 as well as flavonol (3′,4′,7-tri(- O-hydroxyethyl) quercetin) to achieve the therapeutic effect, while avoiding gastrointestinal bleeding, especially the side effects of cerebral hemorrhage, reduce the salicylic acid reaction, reduce the aspirin resistance effect, and improve 3′,4′,7-three The effect of (-O-hydroxyethyl) quercetin. To obtain the above advantages, the prodrug ester must first be an ester that can be converted to aspirin in the blood or plasma, and at the same time it can resist the hydrolysis of water and gastric juice to ensure its pharmaceutical stability, and can also be used in human plasma Rapid hydrolysis releases aspirin and 3′,4′,7-tris (-O-hydroxyethyl) quercetin, increases 3′,4′,7-tris (-O-hydroxyethyl) quercetin Blood concentration, so as to achieve the goals of high efficiency, low toxicity, long-term and stable.

Summary of the invention

The present invention provides a pharmaceutical compound and its preparation and use. Compared with current antiplatelet drugs, the drug has the outstanding characteristics of high efficiency, low toxicity, long-acting, and stability.

In terms of high efficiency, the medicine of the present invention can effectively release aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin in vivo, and can maintain a high effective blood drug concentration. Furthermore, the medicine of the present invention can effectively release the aspirin prototype according to route 1, reduce the release of salicylic acid, and can effectively release the high blood concentration of 3′,4′,7-tri(-O-hydroxyethyl) Quercetin and reduce the aspirin resistance effect.

Compared with aspirin, the blood concentration and bioavailability of aspirin of the drug of the present invention are significantly improved. At the same molar dose, the highest blood concentration of the aspirin of the drug of the present invention is more than 3 times that of aspirin alone, and can still be maintained at 2h-12h The blood concentration is higher, and aspirin alone is very low in blood concentration after 2h, and is rapidly metabolized and eliminated after 2h, making it difficult to exert the efficacy of the aspirin prototype drug.

At the same time, compared with 3′,4′,7-tris (-O-hydroxyethyl) quercetin alone, the medicine of the present invention significantly improves 3′,4′,7-tris (-O-hydroxyethyl) Base) Quercetin bioavailability, and maintain a higher plasma concentration for a longer period (after 12h). It solves the problem that quercetin is difficult to exert clinical effect because of low bioavailability and rapid metabolism.

Another outstanding advantage of the present invention lies in its higher safety. The medicine of the present invention can significantly reduce bleeding tendency and effectively avoid gastrointestinal bleeding of aspirin including gastrointestinal bleeding. Especially, aspirin has prominent clinical advantages in cerebral microhemorrhage and intracerebral hemorrhage. , Can significantly reduce the point of cerebral hemorrhage, safer medication in elderly groups. At the same time, the drug effectively releases 3′, 4′, 7-tris (-O-hydroxyethyl) quercetin at the same time in the body, which synergistically improves the safety of the drug.

In terms of salicylic acid reaction, the cumulative concentration of salicylic acid in the body of the present invention is significantly reduced, and the highest blood concentration of salicylic acid does not exceed 1/3 of aspirin metabolism in the body. Therefore, the salicylic acid brought by the medicine of the present invention The side effects of the reaction are also significantly reduced.

In terms of long-term effect, the drug of the present invention can continuously and stably release aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin in the body for a long time; from the perspective of the duration of antithrombotic action, and Compared with aspirin, the antithrombotic effect of the drug of the present invention exceeds 12 hours, and the antithrombotic effect of aspirin basically disappears after 12 hours.

In terms of stability, the prodrug esters of the present invention have excellent stability compared to other ester drugs, which not only can resist the hydrolysis of water to ensure its pharmaceutical stability, but also has excellent resistance to hydrolysis in acidic and alkaline environments Stability, but at the same time, the prodrug can be quickly hydrolyzed in the blood or plasma after being absorbed into the blood to release aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin.

In addition, the medicine of the present invention can effectively cross the blood-brain barrier and carry 3′,4′,7-tri(-O-hydroxyethyl) quercetin to cross the blood-brain barrier, which truly realizes the quercetin-like substances in the body. Distribution of high concentrations in brain tissue.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof has the following structure:

Where R1 is (CH ₂ )n, where n is an integer of 1-10, n is more preferably 1, 2, 3, 4, 5, more preferably 2;

R2 and R3 are selected from H or O-(CH ₂ )n-OH, where n is an integer of 1-10, n is more preferably 1, 2, 3, 4, 5, preferably 2, even more preferably R2 is H, And R3 is O-(CH ₂ )n-OH;

R4 is selected from H or (CH ₂ )n-OH, where n is an integer of 1-10, n is further preferably 1, 2, 3, 4, 5, preferably 2.

Wherein -(CH ₂ )n- includes straight chain or branched chain structure.

In the compound of the present invention, R1 is preferably (CH ₂ )n, R2 is O-(CH ₂ )n-OH, R3 is H, R4 is H or (CH ₂ )n-OH, n is more preferably 1, 2, 3 , 4, 5, more preferably 2;

In the compound of the present invention, R1 is preferably (CH ₂ )n, R2 is H, R3 is O-(CH ₂ )n-OH, R4 is H, n is more preferably 1, 2, 3, 4, 5, more preferably 2 ;

In the compound of the present invention, R1 is preferably (CH ₂ )n, R2 is H, R3 is O-(CH ₂ )n-OH, R4 is (CH ₂ )n-OH, and n is more preferably 1, 2, 3, 4 , 5, more preferably 2;

Preferably, R1 is CH ₂ , R2 is H, R3 is OCH ₂ OH, and R4 is CH ₂ OH;

Preferably, R1 is CH ₂ , R2 is H, R3 is OCH ₂ OH, and R4 is (CH ₂ ) ₂ OH;

Preferably, R1 is CH ₂ , R2 is H, R3 is O(CH ₂ ) ₂ OH, and R4 is (CH ₂ ) ₂ OH;

Preferably, R1 is CH ₂ , R2 is H, R3 is O(CH ₂ ) ₂ OH, and R4 is CH ₂ OH;

Preferably, R1 is CH2, R2 is H, R3 is OCH2OH, and R4 is (CH2)3OH;

Preferably, R1 is CH ₂ , R2 is H, R3 is O(CH ₂ ) ₃ OH, and R4 is (CH ₂ ) ₃ OH;

Preferably, R1 is (CH ₂ ) ₂ , R2 is H, R3 is O(CH ₂ ) ₃ OH, and R4 is (CH ₂ ) ₃ OH;

Preferably, R1 is (CH ₂ ) ₂ , R2 is H, R3 is OCH ₂ OH, and R4 is (CH ₂ ) ₂ OH;

Preferably, R1 is (CH ₂ ) ₂ , R2 is H, R3 is OCH ₂ OH, and R4 is CH ₂ OH;

Preferably, R1 is (CH ₂ ) ₂ , R2 is H, R3 is O(CH ₂ ) ₂ OH, and R4 is (CH ₂ ) ₂ OH;

Preferably, R1 is (CH ₂ ) ₃ , R2 is H, R3 is O(CH ₂ ) ₃ OH, and R4 is (CH ₂ ) ₃ OH;

Preferably, R1 is (CH ₂ ) ₂ , R2 is H, R3 is O(CH ₂ ) ₂ OH, and R4 is (CH ₂ ) ₃ OH;

Preferably, R1 is CH ₂ , R2 is H, R3 is O(CH ₂ ) ₂ OH, and R4 is (CH ₂ ) ₃ OH;

The compound of the present invention most preferably R1 is (CH ₂ ) ₂ , R2 is H, R3 is O-(CH ₂ ) ₂ -OH, and R4 is (CH ₂ ) ₂ -OH.

The complex is a metal complex or an amino acid complex.

The present invention further provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt or a 5-hydroxy, 4-keto complex or a solvate thereof, and a pharmaceutical adjuvant.

The present invention further provides a pharmaceutical composition comprising the above-mentioned compound or pharmaceutically acceptable salt or 5-hydroxy, 4-keto complex or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt or a 5-hydroxy, 4-keto complex or a solvate thereof, a pharmaceutical adjuvant and a pharmaceutically acceptable carrier .

The present invention also provides a pharmaceutical composition or pharmaceutical preparation comprising the above compound as an active ingredient, and less than 0.2% of 3-O-acetyl-3',4',7-tri(-O-hydroxyethyl Base) Quercetin impurities. Where less than 0.2% refers to 3-O-acetyl-3', 4', 7-tris (-O-hydroxyethyl) quercetin accounting for the compounds of the present invention and 3-O-acetyl-3', 4 ', 7-tris (-O-hydroxyethyl) quercetin weight percent.

The pharmaceutical composition of the present invention can be further prepared into an oral solid preparation, an oral liquid preparation, an injection, or a topical external preparation. The oral solid preparation is selected from tablets, capsules and granules.

The present invention further provides a method for preparing the above compound, which includes the following main steps: using an esterification reaction to prepare the flavonol of formula II and aspirin by esterification,

Where R1, R2, R3, R4 are as described above.

The preparation method of the present invention includes the following main steps: adding flavonol of formula II and aspirin in a molar ratio of 1:1 to 3, and adding a catalyst 4-dimethylaminopyridine (DMAP) and a water-absorbing agent N,N'-di Cyclohexylcarbodiimide (DCC), where the molar amount of N,N'-dicyclohexylcarbodiimide (DCC) is 1 to 3 times the flavonol of formula II, and the ester is at a temperature of -30 to 5°C Chemical reaction for 10 to 72 hours, filtered and crystallized.

More preferably, the molar amount of DMAP is 0.05-1 times that of DCC, preferably 0.1 times.

Among them, the flavonol of formula II is preferably 3′,4′,7-tri(-O-hydroxyethyl)quercetin.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate can be metabolized in the body into aspirin and 3′,4′,7-tri(-O- Hydroxyethyl) quercetin, corresponding to the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof also has aspirin and 3′,4′,7- in the body The biological activity of tri(-O-hydroxyethyl) quercetin or its activity in treating diseases.

The present invention further provides the use of the above compound or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or its pharmaceutical composition in the preparation of a medicament for treating diseases.

The present invention further provides the use of the above compound or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or its pharmaceutical composition in the preparation of a medicament for treating diseases, preferably in the preparation of prophylactic or therapeutic solutions Use of heat, analgesic, anti-inflammatory, anti-rheumatic, Kawasaki disease, ototoxic antibiotics on hearing impairment, biliary roundworm, gallstones, preeclampsia, cataract, contraception, infertility, abortion drugs.

The analgesia includes headache, toothache, neuralgia, muscle pain, and menstrual pain.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of a medicament for preventing or treating cognitive decline and dementia; said dementia Alzheimer's disease, vascular dementia.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of multiple sclerosis and liver fibrosis.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of drugs for preventing or treating tumors and reversing multidrug resistance of tumor cells.

The tumor is a digestive system tumor (including esophageal cancer, gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, colon cancer, rectal cancer), breast cancer, lung cancer, non-small cell cancer, cervical cancer, brain tumor, preferably colon Cancer, rectal cancer, liver cancer, or preferably brain tumor. The brain tumor is a glioma.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of a medicament for preventing or treating diabetes and diabetic complications, preferably in the preparation of treatment The use of diabetic retinopathy, diabetic ulcer, diabetic progressive necrosis ulcer, diabetic nephropathy medicine.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of a medicament for preventing or treating vascular diseases.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of drugs for cardiovascular and cerebrovascular diseases.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition can also be used in the preparation of drugs for primary and secondary prevention of cardiovascular and cerebrovascular diseases .

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of drugs for primary prevention and secondary prevention of cerebrovascular diseases.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of drugs for coronary heart disease, angina pectoris and myocardial infarction.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of drugs for arteriosclerosis, atrial fibrillation, and ventricular enlargement.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of a medicament for ischemic disease is preferably ischemic cerebrovascular disease.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition is used in the preparation of cerebral infarction, cerebral ischemia (such as transient cerebral ischemia), stroke Use in disease medicine. The stroke is an ischemic stroke.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof in the preparation of anti-platelet aggregation drugs.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of antithrombotic and antithromboembolic drugs.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof is used in the preparation or prevention of thromboembolic stroke, venous thrombosis, arterial thrombosis, cerebral thrombosis, Pulmonary embolism, cerebral embolism, peripheral arterial occlusive disease, thromboembolism caused by surgery or interventional therapy, thromboembolism caused by drugs, complications of thromboembolism during pregnancy, artificial surfaces (such as stents, blood oxygenators, shunts, vascular access, Thrombosis on vascular grafts, artificial valves, etc.), thrombosis caused by hemodialysis, coagulopathy (e.g., disseminated intravascular coagulation), coagulation syndrome, Ka-May syndrome, type I membrane proliferative nephritis, and glomus Renal nephritis patients with worsening renal function and end-stage renal disease, restenosis use.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of tumor-induced anti-platelet aggregation drugs, preferably in the preparation of prevention or treatment Use of tumor-related venous thrombosis and pulmonary embolism drugs.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of a medicament for preventing or treating micro-bleeding Bleeding, microbleeding of the digestive tract, microcapillary bleeding. Cerebral microbleeds are preferred.

The present invention further provides the use of the above compound or pharmaceutical composition in the preparation of antithrombotic drugs after cerebral hemorrhage.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition is used in the preparation of antioxidant and scavenging oxygen free radicals, protecting myocardial ischemia, protecting blood vessels, enhancing Immune function, lower blood pressure, improve capillary resistance, reduce capillary permeability, reduce capillary fragility, reduce blood fat, dilate coronary artery, increase coronary blood flow, antibacterial, antiviral, anti-inflammatory, anti-allergic, thrombosis Use of phlebitis, central retinitis, edema caused by increased vascular permeability.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition can also be used in the preparation or prevention or treatment of brain iron metabolic deposition and regulation of brain iron in the central nervous system Metabolic protein, neuronal and/or microglia brain iron metabolic protein, brain nervous system injury, brain neuroinflammatory injury, microglia inflammation, brain iron overload neuroinflammatory diseases medicine application.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition in the preparation of a medicament for preventing or treating osteoporosis.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition has a hydrolytic stability against water and a stability against acid-base hydrolysis.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or pharmaceutical composition has the ability to rapidly release aspirin and 3′,4′,7- in blood or plasma The role of tri (-O-hydroxyethyl) quercetin.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof can reduce the release of salicylic acid in the body.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof has the effect of preventing or treating cerebral microbleed or cerebral hemorrhage.

The compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate or pharmaceutical composition thereof is released into aspirin in the body at least 50%, more preferably 55% or more, 60% or more, More than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 99 are released into aspirin.

At the same time, the present invention further provides the use of therapeutically active metabolites of the above-mentioned compounds or their pharmaceutically acceptable salts or their 5-hydroxy, 4-keto complexes or solvates thereof in the preparation of drugs for the treatment of diseases, preferably in the preparation of prevention or treatment Antipyretic, analgesic, anti-inflammatory, anti-rheumatic, Kawasaki disease, ototoxic antibiotics for hearing loss, biliary roundworm, gallstones, pre-eclampsia, cataract, contraception, infertility, abortion medicine use.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a medicament for the prevention or treatment of cognitive decline and dementia; Dementia is Alzheimer's disease, vascular dementia.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a drug for preventing or treating tumors and reversing multidrug resistance of tumor cells .

The tumor of the digestive system (including esophageal cancer, gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, colon cancer, rectal cancer), breast cancer, lung cancer, non-small cell cancer, cervical cancer, brain tumor, preferably colon cancer , Rectal cancer, liver cancer, or preferably brain tumors. The brain tumor is a glioma.

The use of the compound of the present invention or a pharmaceutically acceptable salt thereof or its 5-hydroxy, 4-keto complex or a solvate thereof as a therapeutically active metabolite in the preparation of a medicament for the prevention or treatment of diabetes and diabetic complications is preferably used in the preparation Use in the treatment of diabetic retinopathy, progressive necrosis ulcer, diabetic nephropathy.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a medicament for preventing or treating vascular diseases.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or a solvate thereof in the preparation of a medicament for cardiovascular and cerebrovascular diseases.

The therapeutically active metabolite of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate can also be used in the preparation of primary and secondary preventive drugs for cardiovascular and cerebrovascular diseases application.

The use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of drugs for primary prevention and secondary prevention of cerebrovascular diseases.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of drugs for coronary heart disease, angina pectoris, and myocardial infarction.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a drug for arteriosclerosis, atrial fibrillation, and ventricular enlargement.

The use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a medicament for ischemic disease is preferably ischemic cerebrovascular disease.

The compounds of the present invention or their pharmaceutically acceptable salts or their 5-hydroxy, 4-keto complexes or solvates thereof are active metabolites in the preparation of cerebral infarction, cerebral ischemia (such as transient cerebral ischemia), brain Use in stroke disease medicine. The stroke is an ischemic stroke.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of antiplatelet aggregation drugs.

Use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or its solvate or therapeutically active metabolite in the preparation of antithrombotic and antithromboembolic drugs.

The compounds of the present invention or their pharmaceutically acceptable salts or their 5-hydroxy, 4-keto complexes or their solvate therapeutically active metabolites are used in the prevention or treatment of thromboembolic stroke, venous thrombosis, arterial thrombosis, cerebral thrombosis , Pulmonary embolism, cerebral embolism, peripheral arterial occlusive disease, thromboembolism caused by surgery or interventional therapy, thromboembolism caused by drugs, complications of thromboembolism during pregnancy, artificial surfaces (such as stents, blood oxygenators, shunts, vascular access , Vascular grafts, artificial valves, etc.), thrombosis caused by hemodialysis, coagulopathy (such as disseminated intravascular coagulation), coagulation syndrome, Kamei syndrome, type I membrane proliferative nephritis and blood vessels Glomerulonephritis patients with worsening renal function and end-stage renal disease, restenosis use.

The use of the compound of the present invention or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate therapeutically active metabolite thereof in the preparation of tumor-induced antiplatelet aggregation drugs is preferably used in the preparation of prophylaxis or Use in the treatment of tumor-related venous thrombosis and pulmonary embolism.

Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in a medicament for preventing or treating micro-bleeding Bleeding, microbleeding of the digestive tract, microcapillary bleeding.

The compounds of the present invention or their pharmaceutically acceptable salts or their 5-hydroxy, 4-keto complexes or solvates are active metabolites in the preparation of antioxidants and scavenging oxygen free radicals, protecting myocardial ischemia, protecting blood vessels, Enhance immune function, lower blood pressure, improve capillary resistance, reduce capillary permeability, reduce capillary fragility, reduce blood fat, dilate coronary artery, increase coronary blood flow, antibacterial, antiviral, anti-inflammatory, anti-allergic, thrombosis Use of phlebitis, central retinitis, edema caused by increased vascular permeability.

The therapeutically active metabolites of the compounds of the present invention or their pharmaceutically acceptable salts or their 5-hydroxy, 4-keto complexes or their solvates can also be used in the preparation of the brain to prevent or treat the deposition of iron metabolism in the brain and regulate the brain of the central nervous system Iron metabolic proteins, neurons and/or microglia brain iron metabolic proteins, brain nervous system damage, brain neuroinflammatory damage, microglia inflammation, brain iron overload neuropathic diseases medicine application.

The use of the compound of the present invention or a pharmaceutically acceptable salt or a therapeutically active metabolite of its 5-hydroxy, 4-keto complex or solvate thereof in the preparation of a medicament for preventing or treating osteoporosis.

Wherein the above-mentioned therapeutically active metabolites are selected from the metabolites of the drug of the present invention, and aspirin, salicylic acid, 3′,4′,7-tri(-O-hydroxyethyl)quercetin and 3′,4′,7 -One or more of the active metabolites of tri(-O-hydroxyethyl) quercetin further metabolized, or the therapeutically active metabolites of the present invention do not include aspirin, salicylic acid, 3′,4′,7- Tri-(-O-hydroxyethyl) quercetin and 3′,4′,7-tri(-O-hydroxyethyl) quercetin are active metabolites for further metabolism.

Beneficial effect

1. The compound of the present invention is more efficient than existing aspirin drugs. It can effectively release the aspirin prototype according to route 1 and reduce the release of salicylic acid; at the same time, it can reduce the aspirin resistance effect and significantly improve the effectiveness of aspirin.

2. Compared with existing aspirin drugs, the compounds of the present invention can significantly improve the safety of clinical medication. The drugs of the present invention can significantly reduce bleeding tendency and effectively avoid gastrointestinal bleeding including gastrointestinal bleeding of aspirin, especially in preventing aspirin from causing Hemorrhage and intracerebral hemorrhage have outstanding clinical advantages, can significantly reduce cerebral microbleeds, and make the elderly group medication safer.

3. The cumulative concentration of salicylic acid in the body of the present invention is significantly reduced, and the side effects of its salicylic acid reaction are also significantly reduced.

4. The compound of the present invention greatly improves the absorption of quercetin-like substances in the body, and correspondingly greatly improves the body of 3′,4′,7-tri(-O-hydroxyethyl)quercetin The therapeutic activity provides an effective solution for quercetin-like substances to truly achieve clinical and effective application.

5. The medicine of the present invention is more long-acting. The medicine of the present invention can continuously and stably release aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin in the body for a long time; compared with aspirin, The antithrombotic effect of the invented drug exceeds 12 hours, and the antithrombotic effect of aspirin basically disappears after 12 hours.

6. The medicine of the present invention can effectively cross the blood-brain barrier, and at the same time, the released 3′,4′,7-tri(-O-hydroxyethyl) quercetin can also cross the blood-brain barrier, and the quercetin is really realized in the body The high concentration distribution of glucocorticoids in brain tissue solves the problem that quercetin has difficulty entering brain tissue for a long time.

7. The drug of the present invention has stable properties and is more suitable for the preparation of medicines. The prodrug ester of the present invention has excellent stability compared with other ester drugs, which not only can resist the hydrolysis of water to ensure its pharmaceutical stability, but also is acidic and alkaline. It still has excellent resistance to hydrolysis under environmental conditions.

BRIEF DESCRIPTION

Figure 1: H-NMR spectrum of Compound 1 of the present invention

Figure 2: C-NMR spectrum of Compound 1 of the present invention

Figure 3: Infrared spectrum of Compound 1 of the present invention

Figure 4: Serum salicylic acid concentration curve after oral administration of aspirin in rats

Figure 5: Aspirin plasma concentration curve of rats after oral administration of aspirin

Figure 6: Blood concentration of 3', 4', 7-tris (-O-hydroxyethyl) quercetin after oral administration of 3', 4', 7-tris (-O-hydroxyethyl) quercetin in rats Graph

Figure 7: Rat 3', 4', 7-tris (-O-hydroxyethyl) quercetin plasma concentration curve after oral administration of Compound 1 of the present invention

Figure 8: The concentration curve of salicylic acid in rats after oral administration of Compound 1 of the present invention

Figure 9: Aspirin blood concentration curve of rats after oral administration of Compound 1 of the present invention

Figure 10: Rats after oral administration of a mixture of aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin of the present invention 3′,4′,7-tri(-O-hydroxyethyl) Quercetin plasma concentration curve

Figure 11: The concentration curve of salicylic acid in rats after oral administration of a mixture of aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin of the present invention

Figure 12: Aspirin blood concentration curve of rats after oral administration of the mixture of aspirin and 3′,4′,7-tris (-O-hydroxyethyl)quercetin

Figure 13: Percentage of drug clotting time extension curve

Figure 14: Anti-brain micro-bleeding experiment blank group of mice on the surface of the brain

Figure 15: Anti-cerebral micro-hemorrhage test Aspirin group of mice with micro-hemorrhage on the surface of the brain

Figure 16: Micro-hemorrhage spots on the surface of the brain of mice in the experimental model group

Figure 17: Spot of cerebral microhemorrhage on the surface of the brain of group 1 mice

Figure 18: Anti-cerebral microbleeding experiment combined treatment group mouse brain microbleeds on the surface

Figure 19: HE staining diagram of cerebral microhemorrhage sections of the experimental model group (Figure 19A), compound 1 group (Figure 19B), aspirin group (Figure 19C), and combination medication group (Figure 19D)

detailed description

Example 1: Preparation of 3-O-((2-acetoxy)-benzoyl)-3′,4′,7-tri(-O-hydroxyethyl)quercetin

1) Dissolve troxerutin (10g=10.9mmol, chromatographic purity of troxerutine 85%, content 81%), dissolve it in 380ml of water, then add 20ml of concentrated sulfuric acid, heat to reflux for 3 hours, stop the reaction and cool down to After room temperature, the filter cake was washed and neutralized with water to obtain a filter cake, which was dried under vacuum at 65° C. to obtain 5.66 g of 3′,4′,7-tri(-O-hydroxyethyl)quercetin, and the chromatographic purity was 90.2%. The yield was 56.6%.

2) In a 100ml three-necked reaction bottle, dry 3', 4', 7-tris (-O-hydroxyethyl) quercetin (2g = 4.6mmol, water content less than 0.1%) was stirred and dissolved at room temperature To DMF (40ml), add aspirin (1.66g = 9.2mmol), and then add DCC (1.9g = 9.2mmol) and 10% DMAP, stir the reaction at -5 ~ 5 ℃, after 12 hours the reaction is complete, The reaction solution was filtered, 10 times saturated ice brine was added, stirred, and a solid was precipitated, which was filtered with suction to obtain a wet filter cake.

3) Add 40ml of methanol to the filter cake, heat to reflux to dissolve in the water bath, heat filter, add anhydrous sodium sulfate to the filtrate, let stand for 1 hour, filter, concentrate and recover methanol to obtain a sticky substance, then add 30ml of ethanol, and heat to reflux for half an hour. After filtration and crystallization at room temperature overnight, 1.5 g of crude product was obtained. The crude product was separated by silica gel column chromatography using dichloromethane-methanol (volume ratio of 100:3) as eluent. Fractions were collected in sections and detected by TLC and HPLC. , Combined, concentrated and dried under reduced pressure to obtain compound 1: 3-O-((2-acetoxy)-benzoyl)-3′,4′,7-tri(-O-hydroxyethyl)quercetin (3′,4′,7-tri(-O-hydroxyethyl)quercetin-3-O-o-acetoxybenzoate), ESI-MS: 597.1[M+H] ⁺ ; ¹ H NMR (150MHZ, CDCl ₃ ) δ 12.06 (s, 1H, 5-OH), 4.16 (t, 2H, Ar OCH ₂ ), 4.08 (t, 2H, Ar OCH ₂ ), 3.92 (t, 2H, Ar OCH ₂ ), 4.97 (t, 1H, C ₂ H ₄ OH), 4.87 (t, 1H, C ₂ H ₄ OH), 4.84 (t, 1H, C ₂ H ₄ OH), 2.19 (s, 3H, COCH ₃ ), 7.52～7.84(t, 2H, ArH), 7.37～8.27(br.d, 2H, ArH), 6.48(br.s, 1H, 6-ArH), 6.90(br.s, 1H, 8-ArH) ), 7.51 (br.s, 1H, 2'-ArH), 7.16 (d, 1H, 5'-ArH), 7.54 (br.d, 1H, 6'-ArH).

¹³ C NMR (600 MHz, DMSO) δ 174.7, 168.9, 165.1, 160.9, 160.8, 156.6, 156.0, 151.6, 151.0, 148.1, 135.8, 132.0, 130.0, 126.7, 124.7, 122.0, 120.6, 120.6, 113.1, 112.8, 104.4, 98.8, 93.5, 70.6, 70.5, 70.3, 59.29, 59.25, 59.2, 20.5.

Example 2: Preparation of 3-O-((2-acetoxy)-benzoyl)-3′,4′,7-tri(-O-hydroxyethyl)quercetin

(1) Dissolve troxerutin (100g=119.9mmol, chromatogram purity of troxerutin 92%, content 89%), dissolve in 3800ml water, then add 200ml concentrated sulfuric acid, heat and reflux for 3 hours, stop the reaction, keep the temperature 90 Filtration above ℃, then washed with hot water until neutral, to obtain a filter cake, vacuum drying at 65 ℃, to obtain 3′, 4′, 7-tris (-O-hydroxyethyl) quercetin 55.4g, chromatographic purity 93.8%, The yield was 55.4%.

(2) In a 500 ml glass reaction bottle, dissolve 10 g (23.0 mmol) of 3′,4′,7-tri(-O-hydroxyethyl)quercetin obtained in (1) in DMF (200 ml) for use, 12.4g (68.9mmol) of aspirin was added, 12g of DCC and 12% DMAP were added thereto, and the reaction was stirred at -5 to -15°C. After 18 hours, the reaction was completed, and the reaction solution was filtered. The filtrate was added with 15 times saturated ice brine, stirred, and precipitated The solid was filtered with suction to obtain a wet crude product.

(3) The crude product obtained in (2) was added to 200 ml of methanol, and the water bath was heated to reflux to dissolve under stirring, and hot filtered. The filtrate was added with anhydrous sodium sulfate, and allowed to stand for 2 hours, filtered, and concentrated to recover methanol to obtain a viscous substance. Add 200ml of ethanol, stir to dissolve with heating, reflux for 1 hour, filter, and crystallize at room temperature overnight to obtain 9.33g of crude product. The crude product is separated by silica gel column chromatography and eluted with dichloromethane-methanol (volume ratio 100:6). Fractions were collected in fractions, detected by TLC and HPLC, combined, concentrated and dried under reduced pressure to obtain compound 1: 3-O-((2-acetoxy)-benzoyl)-3′,4′,7- Tri(-O-hydroxyethyl) quercetin (3′,4′,7-tri(-O-hydroxyethyl)quercetin-3-O-o-acetoxybenzoate), its chromatogram The purity is 97.5%.

Example 3: Preparation of 3-O-((2-acetoxy)-benzoyl)-3′,4′,7-tri(-O-hydroxyethyl)quercetin

(1) Dissolve troxerutin (100g = 121.3mmol, chromatogram purity of troxerutin 93%, content 90%), dissolve in 3800ml water, add 200ml concentrated sulfuric acid, heat and reflux for 3 hours, stop the reaction, keep warm 80 Filter above ℃, then wash to neutrality with hot water to obtain a filter cake, add 4500ml of ethanol-water (40:60) mixed solvent to the filter cake, stir and heat to reflux for 30 minutes, hot filter, filter cake is dried under vacuum at 65 ℃ to obtain 3′ , 4',7-tris (-O-hydroxyethyl) quercetin 53.1g, chromatographic purity 95.1%, yield 53.1%.

(2) In a 500 ml glass reaction bottle, dissolve 10 g (23.0 mmol) of 3′,4′,7-tri(-O-hydroxyethyl)quercetin obtained in (1) in DMF (200 ml) for use, Add 8.3 g (46.1 mmol) of aspirin, then add 15 g of DCC and 15% DMAP, and stir the reaction at -15 to -25°C. After 26 hours, the reaction is completed. The reaction solution is filtered, and the filtrate is added with 15 times saturated ice brine and stirred. The solid precipitated and was filtered with suction to obtain a wet crude product.

(3) Crude product (2) Add 200ml of methanol, heat to dissolve under reflux in a water bath, heat filter, add anhydrous magnesium sulfate to the filtrate, let stand for 2 hours, filter, concentrate and remove methanol to obtain a viscous substance, then add 250ml of ethanol and stir Heat to dissolve, reflux for 1 hour, filter, and crystallize at room temperature overnight to obtain 9.01 g of crude product. The crude product was separated by silica gel column chromatography, using dichloromethane-methanol (volume ratio of 100:3) as eluent, fractions were collected, TLC and HPLC detection, combined, concentrated under reduced pressure and dried to obtain compound 1: 3-O-((2-acetoxy)-benzoyl)-3′,4′,7-tri(-O-hydroxyethyl)quercetin (3′,4′,7-tri(- O-hydroxyethyl) quercetin-3-O-o-acetoxybenzoate), its chromatographic purity is 98.6%, and the final product of Compound 1 also contains about 0.17% 3-O- Acetyl-3', 4', 7-tris (-O-hydroxyethyl) quercetin.

Example 4: Stability experiment

4.1 Hydrolytic stability experiment of compound:

The compound 1 was measured separately in water, artificial gastric juice, hydrochloric acid solution, and artificial intestinal juice in a 37°C water bath: 0h, 1h, 3h, 5h, 7h, and then sampled to determine the content of compound 1 to analyze the hydrolytic stability of compound 1.

Among them, the configuration of artificial gastric juice: take 23.4ml of concentrated hydrochloric acid and 100ml of water to prepare dilute hydrochloric acid. Take 1.64ml of the above dilute hydrochloric acid, add about 80ml of water and mix with 1g of pepsin, and dilute with water to 100ml to obtain artificial gastric juice;

Artificial intestinal juice configuration: take 0.68g of potassium dihydrogen phosphate, add 50ml of water to dissolve, adjust to pH=6.8 solution with 0.1mol/L sodium hydroxide solution, take another 1g trypsin, add appropriate amount of water to dissolve The solution is mixed evenly and diluted with water to 100ml to obtain artificial intestinal juice.

The hydrochloric acid solution is 0.1 mol/L.

High performance liquid chromatography detection method: chromatographic column: 0.25m×4.6mm, stationary phase is octadecylsilane bonded silica gel; mobile phase: acetonitrile: sodium dihydrogen phosphate solution is 35:65, detection wavelength: 254nm.

Table 1 Experimental results of hydrolytic stability

The above results indicate that the general ester compounds are easily broken and degraded in aqueous, acidic, and alkaline environments. However, Compound 1 of the present invention not only resists aqueous, acidic, and alkaline degradation, but also resists pepsin. 2. The degradation of trypsin, even after being placed in an aqueous solution, artificial gastric juice, or hydrochloric acid solution for 7 hours, Compound 1 does not degrade substantially and has unexpected hydrolytic stability. And even under artificial intestinal fluid, its content can still be maintained at about 70% after 7 hours.

Since the compound 1 of the present invention is stable and does not degrade in gastric juice, it will not produce acidic substances such as aspirin and salicylic acid, and accordingly will not cause irritation to the stomach and the risk of gastric bleeding, and no enteric coating of the drug is required. Compared with the existing aspirin drugs, the drug of the present invention can effectively reduce gastrointestinal irritation and side effects of gastrointestinal bleeding without enteric coating, and can also avoid the problem of aspirin resistance caused by the use of enteric preparations. Significantly improve the effectiveness of drugs.

4.2 Stability experiment under high humidity, high temperature and light conditions

High temperature test: take a small amount of compound 1, place it in a suitable open clean container, spread it into a thin layer of ≤5mm thickness, and place it in a 60°C oven for sampling on the 5th and 10th days to detect the content of compound 1.

High humidity test: Take a small amount of compound 1 and place it in a closed container with constant humidity. Sample it at the temperature of 25°C and relative humidity of 75% ± 5% on day 5 and day 10 to detect the content of compound 1.

Illumination test: A small amount of compound 1 was taken, the opening was placed under the sunlight for 10 days, and samples were taken on the 5th and 10th days to detect the content of compound 1.

Table 2 Experimental results of high temperature, high humidity and light stability

The above results indicate that the compound of the present invention does not substantially degrade under moisture, heat, and light, and it can be seen that Compound 1 has excellent stability under high temperature, high humidity, and light conditions.

Example 5: Absorption and metabolism experiments in rats

Twenty-four SD male rats (with a body weight of about 300g) were randomly divided into 4 groups of 6 rats in each group: Group A: Aspirin group, dose 40mg/kg; Group B: 3′, 4′, 7- Tris (-O-hydroxyethyl) quercetin group, dose 96.44mg/kg; Group C: Compound 1 group, dose 132.66mg/kg; Group D: combination group (aspirin: 3', 4' , 7-tris (-O-hydroxyethyl) quercetin molar ratio = 1:1), the administered dose of aspirin 40mg/kg + 3', 4', 7-tris (-O-hydroxyethyl) quercetin Cortex 96.44mg/kg. Animals were fasted and deprived of water 12 hours before administration.

Before administration, blank blood is taken for 0 min. Rats were given intragastrically with the above-mentioned liquids, and the blood was collected according to the blood sampling point: 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, (blood sampling After 4h, rats can be given appropriate water to maintain blood volume). Take about 0.5mL of whole blood in a 1.5mL heparinized centrifuge tube (the first drop of blood is discarded) and centrifuge at 3000r/min for 15min at 4°C; take 100μL of plasma supernatant plus 2% acetonitrile phosphate (containing internal standard: benzene Formic acid) 500 μL, vortex for 1 min, centrifuge at 4 °C, 13000 r/min for 10 min, accurately draw 500 μL of supernatant, and blow dry with nitrogen.

Preparation of 2% acetonitrile phosphate (including internal standard): ① 16mg benzoic acid was dissolved in methanol, and made up to 10mL with methanol, ② 0.5mL benzoic acid internal standard, made up to 100mL with 2% acetonitrile phosphate, ③ 2% acetonitrile phosphate : 2ml phosphoric acid was made up to 100mL with acetonitrile.

Chromatographic mass spectrometry conditions:

1. Liquid chromatography conditions: chromatographic instrument: Agilent 1200 Series, chromatographic column: Agilent ZORBAX SB-C18, 3.5μm, 2.1×150mm. Column temperature: room temperature

Table 3 Liquid chromatography mobile phase conditions

2. Mass spectrometry conditions: Mass spectrometer model: AB SCIEX API 4000, MRM negative mode

Table 4 Mass spectrometry conditions

Entrance Potential (EP): -10

Collision Cell Exit Potential (CXP): -20

CollisionGas(CAD): 6

CurtainGas(CUR): 30

IonSourceGas1(GS1): 40

IonSourceGas2GS2): 30

IonSprayVoltage(IS): -4500.00

Temperature(TEM): 550.0

The experimental results are shown in Figures 4-12. At the same molar dose, aspirin alone and compound 1 of the present invention have a similar peak time of aspirin in plasma compared to group C, but compound 1 of the present invention has the highest blood level of aspirin The drug concentration was more than 3 times that of group A, and the aspirin blood concentration of compound 1 has been maintained at a relatively high level (above 40 ng/ml), which has been about twice the highest blood concentration of group A. In terms of time, the blood concentration of aspirin in group A was less than 5ng/ml after 2h (close to the lower limit of detection limit), while the blood concentration of compound after 12h was still above 40ng. Therefore, the prototype aspirin metabolized by Compound 1 of the present invention is significantly higher in blood concentration and bioavailability than aspirin alone, and can maintain a higher blood concentration for a long time.

On the other hand, the highest cumulative blood concentration of salicylic acid in group A was nearly 3 times that of group C, and within 24 hours, the blood concentration of salicylic acid in group A had been more than twice that of group C, while C The group maintained below 1000ng/ml for a long time. Therefore, compared with aspirin alone, the blood concentration of salicylic acid metabolized by Compound 1 of the present invention is low, and the corresponding salicylic acid reaction is much lower than that of aspirin alone, and it is safer.

From the perspective of 3′,4′,7-tris (-O-hydroxyethyl) quercetin, 3′,4′,7-tris (-O-hydroxyethyl) quercetin alone in blood concentration ( (Approximately 250ng/ml) reached the peak at 1h, and the blood drug concentration rapidly dropped to only about 20ng/ml at 2h, and the blood drug concentration was basically at 20ng/ml in 2-12 hours; and the compound 1 of the present invention (Group C ), at the same molar dose, the highest blood concentration of 3', 4', 7-tris (-O-hydroxyethyl) quercetin is nearly 400ng/ml (3', 4', 7-tris is used alone) -O-hydroxyethyl) 1.6 times of quercetin), and between 1h-6h, the blood concentration of the drug is above 150ng/ml (3', 4', 7-tri (-O-hydroxyl is used alone (Ethyl) Quercetin more than 7 times), 8h-12h blood concentration is still above 100ng/ml (see Figure 6-7). Therefore, compared with the single use of 3′,4′,7-tris (-O-hydroxyethyl) quercetin, the compound 1 of the present invention significantly improved the 3′,4′,7-tris (-O-hydroxyl The absorption of ethyl) quercetin, the bioavailability is also significantly improved, and maintain a higher plasma concentration for a longer period of time (after 12h), can play a long-term effect.

There was no synergistic effect in the combination group D. Aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin were similar to their absorption and metabolism when used alone.

Example 6: In vitro metabolism experiment of human plasma

After eating, take human blood in a blood vessel containing heparin, centrifuge for 15min, remove the supernatant plasma for use, take 1ml of plasma, add 0.5ml of aspirin and compound 1 drug solution, vortex for 30s, and stand in a 37°C water bath to keep warm. Samples were taken at 1 min, 10 min, and 30 min, and the contents of aspirin and salicylic acid were determined by HPLC.

Table 5 In vitro plasma experiment results

Since the prototype aspirin is rapidly degraded to salicylic acid in the plasma environment, the prototype drug aspirin decomposed in the plasma environment of the present invention will also be quickly converted into salicylic acid and gradually accumulate to increase the concentration of salicylic acid. The experimental results show that the drug of the present invention mainly decomposes the prototype drug aspirin (basically 100% decomposes the prototype aspirin) at the initial stage of 1min, but salicylic acid is not detected, but as the decomposition of aspirin increases, the aspirin also transforms Into salicylic acid, the concentration of salicylic acid also increases, and even at 10 minutes, the proportion of aspirin in the plasma in the metabolite is more than 54% (based on the molar sum of aspirin and salicylic acid as a benchmark), therefore, this The invention of the drug mainly cleaves the ester bond of the aspirin and the carrier under the action of blood and plasma according to the route (1), thereby realizing the degradation pathway mainly based on the release of the prototype aspirin. In addition, the drug of the present invention can continuously and stably release the prototype aspirin in human plasma for a long time, thereby making the drug of the present invention both efficient and long-acting.

Example 7: Anticoagulation experiment

20±2g body weight ICR male mice are divided into: blank group, aspirin group, compound 1A group, compound 1B group. Blank group: Gavage blank solvent; Aspirin group: 5mg/ml aspirin (0.028mmol/ml); Compound 1A group: 16.5mg/ml (0.028mmol/ml); Compound 1B group: 8.5mg/ml (0.014mmol/ml) ). The mice in each group were administered by intragastric administration once, and the dosage was 0.1ml/20g body weight.

Using the capillary method to measure the coagulation time: fasting overnight (about 12h), after a single administration, insert a capillary glass tube with an inner diameter of 1mm into the venous plexus of the mouse to take blood according to the set time to the blood column in the capillary At 5cm (at least 5cm), break the capillary for a short period every 30s and check for the presence of coagulation columns. Calculate the time from capillary blood collection to the appearance of the coagulation column, which is the coagulation time. The blood clotting time was measured at 1 hour, 3 hours, 4 hours, 8 hours, 12 hours, 16 hours, 18 hours, and 24 hours after administration (the mice in each group did not repeat blood collection at each time point, that is, the mice in each group only Blood collection once at the corresponding time point).

The following are the results of clotting time experiments at 1 hour, 3 hours, 4 hours, 8 hours, 12 hours, 16 hours, 18 hours, and 24 hours after a single administration.

Table 6 Clotting time 1 hour after single administration

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1111	221±35.23221±35.23
阿司匹林组Aspirin group	1313	247±34.97247±34.97
化合物1A组Compound 1A	1313	256±51.40256±51.40
化合物1B组Compound 1B	1313	275±36.43##275±36.43##

## means comparing with blank group P<0.01

Experimental results show that aspirin and Compound 1 of the present invention have obvious anticoagulant and antithrombotic effects 1 hour after administration. Compared with the blank group, P>0.05 in the aspirin group and the compound 1A group was not significantly different, but P<0.01 in the compound 1B group was very significantly different. Compared with the aspirin group, the compound 1A group and the compound 1B group had P>0.05, that is, there was no significant difference in the anticoagulant and antithrombotic effects of aspirin and the compound 1 of the present invention within 1 hour.

Table 7 Clotting time 3 hours after single administration

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1111	215±20.56215±20.56
阿司匹林组Aspirin group	1313	263±32.76##263±32.76##
化合物1A组Compound 1A	1313	270±32.40##270±32.40##
化合物1B组Compound 1B	1313	265±24.02##265±24.02##

## means comparing with blank group P<0.01

The experimental results show that at 3 hours after administration, compared with the blank group, P<0.01 in the aspirin group, the compound 1A group and the compound 1B group of the present invention all have obvious anticoagulant and antithrombotic effects. Compared with the aspirin group, the compound 1A group and the compound 1B group had P>0.05, that is, there was no significant difference in the anticoagulant and antithrombotic effects of aspirin and the compound 1 of the present invention at 3 hours.

Table 8 Clotting time 4 hours after single administration

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1313	235±47.19235±47.19

阿司匹林组Aspirin group	1313	286±59.52#286±59.52#
化合物1A组Compound 1A	1313	330±73.48##330±73.48##
化合物1B组Compound 1B	1313	332±73.95##＊332±73.95##＊

# Means P<0.05 compared to the blank group, ## means P<0.01 compared to the blank group, * means P<0.05 compared to the aspirin group

The experimental results show that at 4 hours after administration, compared with the blank group, P<0.05 in the aspirin group, the compound 1A group and the compound 1B group of the present invention all have obvious anticoagulant and antithrombotic effects. Compared with the aspirin group, P<0.05 in the compound 1B group, that is, at 4 hours, the anticoagulation and antithrombotic effects of aspirin and the compound 1 of the present invention are significantly different, and the anticoagulant and antithrombotic effects of the compound 1 of the present invention are significantly better than aspirin .

Table 9 8-hour clotting time after a single dose

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1111	196±33.23196±33.23
阿司匹林组Aspirin group	1313	221±30.38##221±30.38##
化合物1A组Compound 1A	1313	245±48.40##245±48.40##
化合物1B组Compound 1B	1313	254±37.83##＊254±37.83##＊

## means comparing with blank group P<0.01, * means comparing with aspirin group P<0.05

The experimental results showed that, at 8 hours after administration, compared with the blank group, P<0.01 in the aspirin group, the compound 1A group and the compound 1B group of the present invention all had significant anticoagulant and antithrombotic effects. Compared with the aspirin group, P<0.05 in the compound 1B group, that is, at 8 hours, the anticoagulant and antithrombotic effects of aspirin and the compound 1 of the present invention are significantly different, and the anticoagulant and antithrombotic effects of the compound 1 of the present invention are significantly better than aspirin .

Table 10 12-hour clotting time after a single dose

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1313	230±18.71230±18.71
阿司匹林组Aspirin group	1313	258±45.06258±45.06
化合物1A组Compound 1A	1313	323±81.36##＊323±81.36##＊
化合物1B组Compound 1B	1313	305±64.61##＊305±64.61##＊

The experimental results show that at 12 hours after administration, compared with the blank group, P>0.05 in the aspirin group, while P<0.01 for the compound 1A group and compound 1B group of the present invention, that is, 12 hours after the administration, the compound of the present invention It still has anticoagulant and antithrombotic effects, while the anticoagulant and antithrombotic effects of the aspirin group disappeared. Compared with the aspirin group, the P<0.05 of the compound 1A group and the compound 1B group, that is, at 12 hours, the anticoagulant and antithrombotic effects of aspirin and the compound 1 of the present invention are significantly different, and the anticoagulant and antithrombotic effects of the compound 1 of the present invention Significantly superior to aspirin.

Table 11 Clotting time at 16 hours after a single dose

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1313	203±24.96203±24.96
阿司匹林组Aspirin group	1313	217±34.97217±34.97
化合物1A组Compound 1A	1313	247±49.22##＊247±49.22##＊
化合物1B组Compound 1B	1313	238±41.46#238±41.46#

The experimental results showed that at 16 hours after administration, compared with the blank group, P>0.05 in the aspirin group, while P<0.01 for the compound 1A group of the present invention and P<0.05 for the compound 1B group, that is, 16 hours after administration, The compound of the present invention still has anticoagulant and antithrombotic effects, while the anticoagulant and antithrombotic effects of the aspirin group disappear. Compared with the aspirin group, the anticoagulant and antithrombotic effects of Compound 1 of the present invention at 16 hours are still significantly better than that of aspirin.

Table 12 18-hour clotting time after a single dose

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1313	185±22.52185±22.52
阿司匹林组Aspirin group	1313	187±20.90187±20.90
化合物1A组Compound 1A	1313	199±25.26##＊199±25.26##＊
化合物1B组Compound 1B	1313	208±14.24##＊208±14.24##＊

The experimental results showed that at 18 hours after administration, compared with the blank group, P>0.05 in the aspirin group and P<0.01 at the compound 1B group of the present invention, that is, at 18 hours after administration, the compound of the present invention still had anticoagulation Antithrombotic effect, while the anticoagulant and antithrombotic effect of the aspirin group disappeared.

Table 13 Clotting time 24 hours after a single dose

组别Group	例数Number of cases	凝血时间(s)Clotting time (s)
空白blank	1111	131±24.27131±24.27
阿司匹林组Aspirin group	1414	132±21.56132±21.56
化合物1A组Compound 1A	1414	133±28.13133±28.13
化合物1B组Compound 1B	1414	137±19.39137±19.39

The experimental results show that, at 24 hours after administration, compared with the blank group, P>0.05 in the aspirin group, Compound 1A group, and Compound 1B group, that is, after 24 hours after administration, at the above doses, Compound 1 and Compound 1 of the present invention There was no significant difference in the anticoagulant and antithrombotic effects of aspirin.

Based on the above experimental results, further calculate the percentage of drug clotting time extension A at each time point, where A = (coagulation time of the drug group-clotting time of the blank group) / clotting time of the blank group * 100%, and A is the vertical axis, time For the horizontal axis, make a graph, see Figure 13 for details.

The compound 1 of the present invention has an equivalent anticoagulant and antithrombotic effect at the same molar dose and half the molar dose of aspirin in the early period of administration, but after 4 hours, the anticoagulant and antithrombotic effect of the compound 1 of the present invention is significantly better than that of aspirin, thus The compound of the present invention is more effective in anticoagulation and antithrombotic. In addition, aspirin's anticoagulant and antithrombotic effects gradually decrease between 8-12 hours, and it basically disappears after 12 hours, while the compound 1 of the present invention still maintains a stable anticoagulant after 12 hours, 16 hours, and 18 hours. 3. Antithrombotic effect. Therefore, in terms of the duration of anticoagulant and antithrombotic effects, the compound 1 of the present invention has a longer effect.

Example 8: Anti-cerebral microbleeding experiment

The animal model of acute cerebral hemorrhage induced by LPS was used, and C57BL/6 mice aged 10-12 weeks were selected. The mice were divided into: blank group, model group, aspirin group, compound 1 group, aspirin and 3′,4′,7 -Tris(-O-hydroxyethyl) quercetin combination group. Aspirin group: 60 mg/kg aspirin by gavage, Compound 1 group: 189.49 mg/kg Compound 1, gavage, aspirin and 3′,4′,7-tri(-O-hydroxyethyl)quercetin combination: gavage Stomach 60mg/kg aspirin + 144.67mg/kg 3', 4', 7-tris (-O-hydroxyethyl) quercetin, blank group, model group: gavage blank matrix solution. The mice in the above groups were given intragastrically once a day, and the dosage was 0.1ml/10g body weight.

Mice in each group were given LPS 3 mg/kg intraperitoneally at 0, 6, and 24 hours (except for the blank group) after continuous administration for 3 days (therapeutic drugs were still given after LPS administration), and 48 hours after the first injection, hydrated intraperitoneally Chloraldehyde was sacrificed, pre-chilled PBS heart perfusion for 5min, and the brain was taken to observe the number of microbleeds on the surface of the brain (including olfactory bulb, brain, cerebellum and brain stem, literature: cerebellar/brain stem hemorrhage points> olfactory bulb> cerebral cortex). Frozen slices, 15 μm thick, 1 slice every 12-13 slices of the olfactory bulb and cerebellum, 1 slice every 24-25 slices of the brain, about 60 slices each, and HE staining to detect the number of cerebral hemorrhage.

Table 14 Effect of compound 1 on acute cerebral hemorrhage caused by LPS

*Compared with model group, P<0.05

#Compared with Compound 1 group P<0.05

The experimental results show that compared with the compound 1, the use of aspirin alone or aspirin in combination with 3′,4′,7-tri(-O-hydroxyethyl)quercetin has significant differences in cerebral hemorrhage points. Groups will cause increased cerebral microbleeds. Compared with the model group, there was no significant difference in the cerebral microhemorrhage point of the compound 1 group, and the compound 1 of the present invention can significantly reduce the cerebral microhemorrhage point.

Figures 14-18 are pictures showing the microbleed points of the brain of the same batch of mice. There is no microbleed on the surface of the brain in the blank group, there are 5 bleeding points on the surface of the brain in the model group, and 10 bleeding points on the surface of the brain in the aspirin group. The 3′,4′,7-tri(-O-hydroxyethyl) quercetin combination group had 12 hemorrhages on the surface of the brain, while the compound 1 group had only 2 hemorrhages on the surface of the brain. In order to further verify the actual situation of the above cerebral microhemorrhage points, the results of HE staining of the slices (see FIG. 19) also confirmed that the compound of the present invention can reduce cerebral microhemorrhage, and aspirin can increase the increase of cerebral microhemorrhage.

Therefore, the application of aspirin is likely to cause cerebral hemorrhage and increase the point of cerebral hemorrhage, even when combined with 3′,4′,7-tris (-O-hydroxyethyl) quercetin Slow or reduce cerebral hemorrhage, therefore, aspirin or aspirin in combination with 3′,4′,7-tris (-O-hydroxyethyl) quercetin will increase the risk of cerebral hemorrhage, however, the compound of the present invention is compared with aspirin Can significantly reduce the point of cerebral hemorrhage. Therefore, through this experiment, the present invention unexpectedly found that the compound of the present invention can significantly reduce cerebral hemorrhage, and have certain preventive and repairing effects on cerebral hemorrhage, effectively reducing the fatal risk of aspirin causing cerebral hemorrhage in the clinic. In addition, even aspirin combined with vasoprotective substances such as 3', 4', 7-tris (-O-hydroxyethyl) quercetin, can not effectively fight the side effects of aspirin cerebral hemorrhage.

Example 9: Antithrombotic experiment

Wistar rats 200±20g: blank group, aspirin group, compound 1A group, compound 1B group. Blank group: Gavage blank solvent; Aspirin group: 9 mg/ml aspirin; Compound 1A group: 59.6 mg/ml; Compound 1B group: 29.8 mg/ml. The rats were administered for 7 consecutive days, once a day, and on the 8th day for 3 hours. The abdominal aorta was bled to measure the weight of thrombus.

Push 1.5ml whole blood into the syringe in each tube, set time 16min, temperature 37℃, thrombometer beep sound, pour the thrombus in the tube in a beaker filled with pure water, after cleaning, the filter paper is dried and placed in The weighed filter paper is dried in an oven at 60°C for 1 hour, placed at room temperature for 10 minutes, and weighed.

Table 15 Compound 1 antithrombotic test results

分组Grouping	血栓干重mgThrombus dry weight mg
空白blank	25.40±6.7625.40±6.76
阿司匹林aspirin	20.63±13.0020.63±13.00
化合物1ACompound 1A	20.26±10.4520.26±10.45
化合物1BCompound 1B	21.98±6.9121.98±6.91

The experimental results show that, under the experimental conditions, after administration of Compound 1A for 7 consecutive days, its antithrombotic effect is comparable to that of aspirin.

Example 10: Brain tissue distribution experiment

Administration method for rats: oral gavage, rats (200g): Each time a concentration of 5.6mg/ml Compound 1 solution 1ml was given twice a day (once in the morning and evening).

Brain extraction: Rats were anesthetized with ether, the heart was perfused and washed with physiological saline, the blood vessels of the brain were cleaned, then methanol (containing internal standard) was added, ground and extracted, centrifuged, the supernatant was taken, and compound 1 was determined by HPLC And the content of 3′,4′,7-tris (-O-hydroxyethyl) quercetin in brain tissue.

Table 16

Compound

1 and 3′,4′,7-tri(-O-hydroxyethyl)quercetin content in rat brain tissue

时间time	化合物1(μg/g)Compound 1 (μg/g)	三羟乙基槲皮素(μg/g)Trihydroxyethyl quercetin (μg/g)
130min130min	0.5400.540	0.2110.211
225min225min	0.2160.216	0.3010.301
300min300min	0.1970.197	0.1210.121
400min400min	0.1730.173	0.1000.100

The above experimental results show that the

compound

1 and 3′,4′,7-tri(-O-hydroxyethyl) quercetin of the present invention have a higher distribution content in brain tissue, and compound 1 is effective in brain tissue Metabolism produces high concentrations of 3′,4′,7-tri(-O-hydroxyethyl)quercetin. Therefore, the compound 1 of the present invention can effectively enter the brain tissue through the blood-brain barrier, and at the same time, 3′,4′,7-tri(-O-hydroxyethyl)quercetin also passes through the blood-brain barrier and is carried into Brain tissue and exert curative effects, and the current distribution of quercetin-like substances in the brain tissue is extremely low, it is difficult to cross the blood-brain barrier into the brain tissue, which greatly improves the role of quercetin-like substances in the body, especially Protective effect on the brain. On the other hand, combined with the above anti-brain microbleeding experiment,

compound

1 and 3′,4′,7-tri(-O-hydroxyethyl)quercetin entered the brain tissue and the presence of high concentration further confirmed the compound 1 of the present invention Outstanding role and advantages in anti-cerebral microbleed

references

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6. Niels Mmk Nielsen, Hans Bundgaard, Evaluation of Glycolamide Esters and Various Other Esters of Aspirin as True Aspirin Prodrugs, Journal of Medicinal Chemistry, 1989, 32(3), 727-734.

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Claims

A compound of formula I or a pharmaceutically acceptable salt or 5-hydroxy, 4-keto complex or solvate thereof, the structure is as follows:

Where R1 is (CH 2 )n, R2 and R3 are selected from H or O-(CH 2 )n-OH, and R4 is selected from H or (CH 2 )n-OH,

Where n is an integer of 1-10, n is more preferably 1, 2, 3, 4, 5, and 2 is more preferable.
The compound of formula I or a pharmaceutically acceptable salt or 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, wherein R2 is O-(CH 2 )n-OH, R3 is H.
The compound of formula I or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, wherein R2 is H and R3 is O-(CH 2 ) n-OH.
The compound of formula I or a pharmaceutically acceptable salt or 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, wherein R1 is (CH 2 )n and R2 is H, R3 is O-(CH 2 )n-OH, R4 is (CH 2 )n-OH, n is 1, 2, 3, 4 or 5, more preferably 2, the complex is a metal complex or an amino acid Complex.
The compound of formula I or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, wherein R1 is CH 2 , R2 is H, and R3 is OCH 2 OH, R4 is CH 2 OH; or R1 is CH 2 , R2 is H, R3 is OCH 2 OH, R4 is (CH 2 ) 2 OH; or R1 is CH 2 , R2 is H, R3 is O(CH 2 ) 2 OH, R4 is (CH 2 ) 2 OH; or R1 is CH 2 , R2 is H, R3 is O(CH 2 ) 2 OH, R4 is CH 2 OH; or R1 is CH 2 , R2 is H, R3 Is O(CH 2 ) 3 OH, R4 is (CH 2 ) 3 OH; or R1 is (CH 2 ) 2 , R2 is H, R3 is O(CH 2 ) 3 OH, R4 is (CH 2 ) 3 OH; Or R1 is (CH 2 ) 2 , R2 is H, R3 is OCH 2 OH, R4 is (CH 2 ) 2 OH; or R1 is (CH 2 ) 2 , R2 is H, R3 is OCH 2 OH, R4 is CH 2 OH; or R1 is (CH 2 ) 2 , R2 is H, R3 is O(CH 2 ) 2 OH, R4 is (CH 2 ) 2 OH; or R1 is (CH 2 ) 3 , R2 is H, R3 is O(CH 2 ) 3 OH, R4 is (CH 2 ) 3 OH; or R1 is (CH 2 ) 2 , R2 is H, R3 is O(CH 2 ) 2 OH, R4 is (CH 2 ) 3 OH; or R1 is CH 2 , R2 is H, R3 is OCH 2 OH, R4 is (CH 2 ) 3 OH; or R1 is CH 2 , R2 is H, R3 is O(CH 2 ) 2 OH, R4 is (CH 2 ) 3 OH.
The compound of formula I or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, wherein R1 is (CH 2 ) 2 and R2 is H, R3 is O-(CH 2 ) 2 -OH, and R4 is (CH 2 ) 2 -OH.
The method for preparing the compound of formula I or its pharmaceutically acceptable salt or its 5-hydroxy, 4-keto complex or solvate thereof according to claim 1, characterized in that it includes the following main steps: using an esterification reaction, Prepared by esterification reaction of flavonol of formula II and aspirin,

Wherein R1, R2, R3 and R4 are as described in claim 1 above.
The method according to claim 7, characterized in that: the flavonol of formula II and aspirin are added in a molar ratio of 1:1-3, and the catalyst 4-dimethylaminopyridine (DMAP) and the water-absorbing agent N, N'are added -Dicyclohexylcarbodiimide (DCC), in which the molar amount of N,N'-dicyclohexylcarbodiimide (DCC) is 1-3 times the flavonol of formula II, at a temperature of -30～5℃ The next esterification reaction is 10-72 hours, filtered and crystallized.
The method according to claim 8, wherein the molar amount of DMAP is 0.05-1 times the DCC.
The method according to claim 7, wherein the temperature of the esterification reaction is -30 to 5°C.
The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation for the prevention or treatment of antipyretic, analgesic, headache, toothache , Neuralgia, muscle pain, menstrual pain, anti-inflammatory, anti-rheumatic, Kawasaki disease, ototoxic antibiotics for hearing loss, biliary roundworm, gallstones, pre-eclampsia, cataracts, contraception, infertility, abortion medicine use.
The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation for the prevention or treatment of cognitive decline, dementia, Alz Uses in medicines such as Haimer, vascular dementia, diabetes, diabetic complications, diabetic retinopathy, diabetic ulcer, progressive necrosis of diabetes, diabetic nephropathy, multiple sclerosis, and liver fibrosis.
The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation for preventing or treating tumors and reversing multidrug resistance of tumor cells , Digestive system tumors (including esophageal cancer, gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, colon cancer, rectal cancer), breast cancer, lung cancer, non-small cell cancer, cervical cancer, brain tumors, glioma drugs Use in.
The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation for the prevention or treatment of vascular diseases, cardiovascular and cerebrovascular diseases, coronary Heart disease, angina, myocardial infarction, arteriosclerosis, atrial fibrillation, ventricular enlargement, ischemic disease, ischemic cerebrovascular disease, cerebral infarction, cerebral ischemia (such as transient cerebral ischemia), stroke, ischemia Stroke, antiplatelet aggregation, antithrombotic, antithromboembolic, thromboembolic stroke, venous thrombosis, arterial thrombosis, cerebral thrombosis, pulmonary embolism, cerebral embolism, peripheral arterial occlusive disease, thromboembolism caused by surgery or interventional therapy, Drug-induced thromboembolism, complications of thromboembolism during pregnancy, thrombosis on artificial surfaces, thrombosis caused by hemodialysis, coagulopathy, coagulation syndrome, Ka-Mei syndrome, type I membrane proliferative nephritis and glomerulonephritis Patients with worsening renal function and advanced renal disease, restenosis, tumor-induced anti-platelet aggregation, tumor-associated venous thrombosis and pulmonary embolism, microhemorrhage, cerebral microhemorrhage, gastrointestinal microhemorrhage, capillary microhemorrhage, resistance after cerebral hemorrhage Use in thrombotic drugs.
The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation of primary and secondary prophylactic drugs for cardiovascular and cerebrovascular diseases Application.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a 5-hydroxy, 4-keto complex or a solvate thereof, in the preparation of drugs for primary prevention and secondary prevention of cerebrovascular diseases Applications.
The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof or a 5-hydroxy, 4-keto complex or a solvate thereof in the preparation of antioxidants and scavenging oxygen free radicals, protecting myocardial ischemia , Protect blood vessels, enhance immune function, lower blood pressure, improve capillary resistance, reduce capillary permeability, reduce capillary fragility, lower blood fat, dilate coronary arteries, increase coronary blood flow, antibacterial, antiviral, anti-inflammatory, Anti-allergy, thrombophlebitis, central retinitis, edema due to increased vascular permeability, brain iron metabolism deposits, brain iron metabolism proteins that regulate central nervous system, brain iron metabolism of neurons and/or microglia Uses in proteins, brain nervous system damage, brain neuroinflammatory damage, microglia inflammation, brain iron overload neuroinflammatory diseases, osteoporosis drugs.