CN109875988B - Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia - Google Patents
Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia Download PDFInfo
- Publication number
- CN109875988B CN109875988B CN201811066452.4A CN201811066452A CN109875988B CN 109875988 B CN109875988 B CN 109875988B CN 201811066452 A CN201811066452 A CN 201811066452A CN 109875988 B CN109875988 B CN 109875988B
- Authority
- CN
- China
- Prior art keywords
- dhnb
- semicarbazone
- hyperuricemia
- xod
- gout
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of new drug development and application, in particular to application of a DHNB semicarbazone compound in the field of preventing and treating hyperuricemia and/or gout. The invention provides a synthesis method of a novel compound DHNB semicarbazone shown in a formula I and application of the novel compound DHNB semicarbazone in drugs for reducing blood uric acid level. Pharmacodynamic experiments show that the DHNB semicarbazone compound obtained by the invention is more efficient than DHNB and positive allopurinol, and is safe and nontoxic. The application provided by the invention is mainly to reduce the level of blood uric acid by inhibiting the activity of xanthine oxidase, effectively prevent and treat gout and hyperuricemia, and provide a new drug choice for clinical treatment of gout and hyperuricemia.
Description
Technical Field
The invention belongs to the field of new drug development and application, and relates to synthesis of a DHNB semicarbazone compound and application of the DHNB semicarbazone compound in the field of gout prevention and treatment and hyperuricemia prevention.
Background
Gout is a crystal-related arthropathy caused by deposition of monosodium urate (MSU) and is directly related to Hyperuricemia (HUA) caused by purine metabolic disorder or decreased uric acid excretion. The prevalence rate of Chinese HUA is on the rising trend year by year, the onset age is getting lower, the disease is the second most metabolic disease next to diabetes, and huge economic and mental burden is brought to the society and families. Epidemiological research in recent decade shows that the prevalence rate of the HUA in different areas of China is greatly different and is 5.46% -19.30%, wherein 9.2% -26.2% of males, 0.7% -10.5% of females and the total number of males is higher than that of females. Gout is a group of clinical syndromes of tissue damage caused by long-term purine metabolic disorder (or) reduction of uric acid excretion and increase of blood uric acid, and hyperuricemia is the most important biochemical basis of gout. Uric acid is produced in the liver by dietary intake and purine compounds decomposed in the body, and about 2/3 uric acid is excreted through the kidney, and the rest is excreted from the digestive tract. Gout comprises acute gouty arthritis and chronic tophus diseases, and the rise of blood uric acid can cause gout and is also related to the occurrence and development of systemic diseases such as kidney, endocrine metabolism, heart, cerebral vessels and the like.
At present, the conventional medicaments for treating gout mainly comprise colchicine, non-steroidal anti-inflammatory drugs, allopurinol, febuxostat, benzbromarone and the like. The medicines can inhibit the formation of uric acid or (and) promote the excretion of uric acid to achieve the aim of relieving and treating gout and hyperuricemia. The synthesis of uric acid in the body is associated with purine metabolism, and Xanthine Oxidase (XOD), which is a key enzyme in uric acid production in the body, catalyzes the conversion of hypoxanthine and xanthine into uric acid. Hyperuricemia can be caused by hyperuricemia in the body, and gout is caused. Allopurinol and febuxostat are inhibitors of XOD, and the two drugs can reduce synthesis of uric acid in vivo by inhibiting XOD, so that gout is effectively treated. However, they all have certain side effects in clinical use, for example, allopurinol can cause skin anaphylaxis and liver and kidney function damage, and severe patients can generate hypersensitivity syndromes such as lethal exfoliative dermatitis and the like; febuxostat can cause liver function impairment, nausea, rash, and the like. Adverse reactions of taking benzbromarone include gastrointestinal discomfort, diarrhea, rash and liver function damage; adverse reactions of colchicine include nausea, vomiting, diarrhea, abdominal pain, liver dysfunction, renal function injury and the like. Although more medicines for preventing and treating gout and hyperuricemia exist at present, most medicines have large side effects and influence the quality of life. Therefore, the development of new drugs for treating hyperuricemia and gout is still a hot spot of research in the medical field.
Research shows that 3, 4-dihydroxy-5-nitrobenzaldehyde (DHNB) belongs to a derivative of protocatechualdehyde, is a strong XOD inhibitor, and can be used as a potential drug for treating hyperuricemia and gout. DHNB can reduce serum uric acid levels in hyperuricemic mice, and a large dose of DHNB has no side effect on the mice (500 mg/kg). However, DHNB has the defect of time dependence in inhibition of XOD activity, and the action time is short.
In view of the above, the invention provides a compound DHNB semicarbazone shown in formula I, which is prepared by performing aldehyde-amine condensation on DHNB and semicarbazone to synthesize DHNB phenylthiosemicarbazone, purifying the DHNB phenylthiosemicarbazone, repeatedly performing in vitro and in vivo pharmacodynamic experiments on the DHNB phenylthiosemicarbazone, and measuring the influence of the DHNB phenylthiosemicarbazone on serum XOD, liver XOD and serum uric acid of a hyperuricemic model mouse in vivo; the inhibition effect of the enzyme label on XOD is measured by a multifunctional enzyme label instrument in vitro, and the inhibition mechanism is discussed. And acute toxicity tests were performed. Thereby obtaining the DHNB semicarbazone which is an XOD inhibitor with high efficiency and low toxicity.
Disclosure of Invention
In view of the above background, the present invention provides a synthesis method of a novel DHNB semicarbazone compound represented by formula I and its application in drugs for reducing blood uric acid level. Pharmacodynamic experiments show that the DHNB semicarbazone compound obtained by the invention is more efficient than DHNB and positive allopurinol, and is safe and nontoxic. The application provided by the invention is mainly to reduce the level of blood uric acid by inhibiting the activity of xanthine oxidase, effectively prevent and treat gout and hyperuricemia, and provide a new drug choice for clinical treatment of gout and hyperuricemia.
A chemically synthesized DHNB semicarbazone represented by structural formula I:
formula I.
Drawings
FIG. 1 chemical synthesis route of DHNB semicarbazone.
FIG. 2 Infrared Spectrum of DHNB semicarbazone.
FIG. 3 hydrogen spectrum of DHNB semicarbazone.
FIG. 4 DHNB semicarbazone mass spectrum (positive ion).
FIG. 5 influence of the concentration of the enzyme on the speed of the enzymatic reaction.
FIG. 6 shows a Lineweaver-Burk curve of DHNB semicarbazone inhibition of xanthine oxidase catalysis.
FIG. 7 inhibition of serum XOD viability by DHNB semicarbazone in hyperuricemic model mice.
FIG. 8 the effect of DHNB semicarbazone on serum uric acid in hyperuricemic model mice.
FIG. 9 inhibition of liver XOD viability by DHNB semicarbazone in hyperuricemic mouse model.
Detailed Description
The following detailed description of specific embodiments of the invention refers to the accompanying drawings.
Synthesis, separation and purification of DHNB semicarbazone compound
The synthesis steps are as follows: 0.01 mol of semicarbazide is put into a 1000 ml three-neck flask, and 200 ml of methanol is added to be heated and refluxed until the semicarbazide is completely dissolved. 0.01 mol of DHNB was dissolved in 200 ml of methanol with antipyretic effect. After the semicarbazide is completely dissolved, slowly dripping methanol for dissolving the DHNB into the three-neck flask by using a constant pressure dropping funnel, finishing dripping within 20 min, and dripping 2 drops of glacial acetic acid into the three-neck flask to serve as a catalyst. The reaction was continued for 2 h under reflux and monitored by TLC until the starting material spot disappeared and the reaction was complete. The specific reaction formula is shown in figure 1. Isolation and purification of DHNB semicarbazone compounds: and after the reflux reaction is finished, naturally cooling to room temperature, sealing, placing in a refrigerator at 4 ℃ overnight until crystals are completely separated out, washing the product with glacial ethanol, and drying in vacuum to obtain a brick red powder product.
Structural characterization of DHNB semicarbazone compounds: DHNB semicarbazone, brick red powder (CH)3OH）IR (KBr)，νmax 3420, 2989, 1617.6, 1691,1540 cm–1The infrared spectrum is shown in FIG. 2.1HNMR(600HZ,DMSO-D6)δ10.175(S,1H,NH), δ7.718(S,1H,CH), δ6.438(S,2H,NH2) δ 9.458(S,1H, OH-Ph-H), δ 7.885,7.881(d,1H, OH-Ph-H), δ 7.626,7.623(d,1H, Ph-H), δ 7.390,7.387(d,1H, Ph-H); the hydrogen spectrum is shown in FIG. 3. ESI-MS (m/z Mr =240) (C8H8O5N4, M+H+) The mass spectrum is shown in FIG. 4.
Experimental materials DHNB semicarbazone, phosphate buffered saline PBS, xanthine oxidase, allopurinol, and the like.
Experimental methods
Enzyme activity detection and sample inhibition XOD determination: setting a normal group (without adding a sample) and a sample group in an experiment, sequentially adding 100 uL of xanthine substrate solution and the sample solution into a 96-well plate, replacing the others with PBS (phosphate buffer solution), keeping the volume (300 uL) of the whole system consistent, finally adding 3 mL of XOD solution to start reaction, measuring the absorbance value at 290nm, recording once at an interval of 10 s, measuring the absorbance change value within 2 min, taking time as an independent variable and the absorbance value as a dependent variable, obtaining an absorbance-time straight line, and calculating the slope Rate (dA/min) of the straight line. Each sample requires 3 parallel operations, and the inhibition rate of the sample is calculated by taking the average value.
The inhibition ratio (%) was calculated by calculating the change in absorbance with time, i.e., the linear slope K, in 2 min for the normal group and the sample group to calculate the degree of enzyme activity, thereby obtaining the inhibition ratio. The inhibition rate calculation formula is as follows: the inhibition ratio (%) [ (K1-K2)/K1 ] × 100%. Where K1 represents the slope of the line for the normal group and K2 represents the slope of the line for the sample group.
Median inhibitory concentration IC50The sample concentration is used as an independent variable X, the inhibition rate is used as a dependent variable Y, and an SPSS19.0 statistical software package is adopted to calculate a regression equation. Then calculating the sample concentration with the inhibition rate of 50 percent according to a regression equation, namely the half inhibition concentration IC50。
The inhibition mechanism of DHNB semicarbazone on XOD in a living system is characterized in that the concentration of a substrate xanthine is fixed, DHNB semicarbazone with different concentrations is added, the mass concentration of XOD is changed, and the influence of inhibitors with different concentrations on the ability of XOD to catalyze and oxidize xanthine is measured. Plotting the speed of the enzymatic reaction against the enzyme concentration, and if a series of straight lines through the origin are obtained, then the reversible inhibition is obtained; if a set of parallel lines is obtained, irreversible inhibition is indicated.
And (3) fixing the mass concentration of XOD by the inhibition type of DHNB semicarbazone on XOD, changing the concentration of substrate xanthine, and determining the influence of inhibitors with different concentrations on enzyme activity. By the Lineweaver-Burk equation: 1/v = Km/Vmax 1/[ S ] +1/Vmax mapping can lead to the type of inhibition.
Results of the experiment
Inhibition of xanthine oxidase by Each sample and allopurinol
The inhibition ratios of different samples on XOD are different through studying the inhibition effects of DHNB, DHNB semicarbazone and allopurinol on XOD, but the inhibition ratios all increase with the increase of concentration, namely the inhibition ratios are in positive correlation with the concentration, the samples have different IC50, the inhibition effect of DHNB on XOD IC50 is 32.12 mmol/L, the inhibition effect of DHNB semicarbazone IC50 is 0.29 mmol/L, the inhibition effect is more remarkable than that of DHNB, and the positive control allopurinol IC50 is 6.74 umol/L. The results of inhibition of XOD by the different samples are shown in table 1.
TABLE 1 results of inhibition of xanthine oxidase by different samples (n ═ 3)
Mechanism of inhibition of XOD by DHNB semicarbazones
The concentration of XOD is changed by fixing the concentration of the substrate, DHNB semicarbazones with different concentrations are added, and the inhibition effect of the DHNB semicarbazones with different concentrations on the XOD and the inhibition results of the DHNB semicarbazones with four different concentrations on the XOD are respectively measured. As shown in fig. 5, the four lines are not parallel, but intersect at a point, indicating that DHNB semicarbazone is a reversible inhibitor of XOD.
Type of inhibition of XOD by DHNB semicarbazone in the XOD system, under the same XOD concentration condition, the volume of the substrate xanthine in the total system 300 mL was changed [50 mL (3.8 mg/mL), 60 mL (4.564 mg/mL), 70 mL (5.32 mg/mL), 80 mL (mg/mL), 100mL (7.6 mg/mL) ], i.e., the mass concentration of the substrate XOD in the system was changed, and the inhibition of XOD by inhibitors at different concentrations (0 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.15 mg/mL) at 290nm was determined. The inhibition pattern of DHNB semicarbazone against XOD is shown in figure 6. The lines of the double reciprocal plot have a common intersection point in the second quadrant, the intersection point does not fall on the coordinate axis, the reaction rate is reduced along with the increase of the concentration of the inhibitor under the same substrate concentration, and the Michaelis constant Km and the maximum reaction rate Vm both change along with the change of the concentration of the inhibitor, which indicates that the inhibition mechanism of the DHNB semicarbazone on the XOD is not competitive or anti-competitive, so that the inhibition mechanism of the DHNB semicarbazone on the XOD can be preliminarily judged to be mixed.
Effect of DHNB semicarbazone on hyperuricemic mouse model
The experimental animal is selected from 40 healthy male Kunming mice with the weight of 18-22 g, and is provided by the scientific and technological center of the experimental animal of Jiangxi traditional Chinese medicine university (the production license number of the experimental animal: SCXK (gan) 2018-. Raising for one week before experiment to adapt to environment. Feeding conditions are as follows: the room temperature is 25 +/-2 ℃, and the relative humidity is 60-70%.
The liquid medicine is prepared into medicine-containing suspension by using 0.9 percent CMC-Na solution for preparing various groups of intragastric administration medicines and animal modeling substances.
Animal modeling reference literature methods potassium oxonate and uric acid ip mice were used to increase serum uric acid levels, resulting in a mouse model of hyperuricemia. After the male Kunming mice are adaptively fed for one week, the male Kunming mice are randomly divided into 4 groups of normal saline, hyperuricemia model group, DHNB semicarbazone and allopurinol, and each group contains 10 mice. Except the normal saline group, other groups were modeled with Potassium Oxonate and uric acid ip mice for 2 days in succession to increase serum uric acid levels, resulting in a mouse hyperuricemia model.
The experimental operation physiological saline group and the hyperuricemia model group are 20 mL/kg per day -1Dosage of ig physiological saline, 6 days continuously, allopurinol group (10 mg. kg)-1) Administration of ig 1 time per day for 6 days with 10 mg/kg in all DHNB semicarbazone groups-1The dosage of ig is given 1 time per day for 6 days, from the 5 th day of administration, except for the normal saline group, the other groups need to take potassium oteroxide and uric acid 1h before ig administration, and the dosages of the potassium oteroxide and the uric acid are respectively 0.3 g-kg-1And 0.25 g.kg-1The molding was carried out 1 time per day for 2 consecutive days. Collecting blood from femoral artery of mouse after 1h of ig administration on day 6, placing blood sample into 1.5mL centrifuge tube, coagulating in 4 deg.C refrigerator for 2 h, and performing coagulation at 3000 r.min -1Centrifuging at low temperature for 5 min. Serum uric acid levels and serum XOD viability were determined for each blood sample serum. After blood is taken, the liver of the dissected mouse is wrapped by the tin foil paper, and then is quickly frozen by liquid nitrogen and placed in a refrigerator at the temperature of 20 ℃ below zero to be tested for the activity of XOD.
Biochemical index detection separately measures mouse blood uric acid level, XOD activity in blood and liver. The phosphotungstic acid method is adopted to detect the blood uric acid of each group of mice, and the enzymatic colorimetric method is adopted to detect the XOD activity. The specific operation is carried out according to the kit instruction.
Results of the experiment
Inhibition effect of DHNB semicarbazone on serum XOD (x-ray activating degree) vitality of hyperuricemia model mouse
The phosphotungstic acid method is adopted to detect the activity of the serum XOD of mice in a normal saline group, a hyperuricemic model group, a DHNB semicarbazone group and an allopurinol group, as shown in figure 7, the activity of the model group XOD is very different from that of a normal saline control group, which indicates that the experimental modeling is successful. After modeling, the DHNB semicarbazone and the positive allopurinol can inhibit the activity of mouse serum XOD, and show significant difference compared with a model group. In addition, DHNB semicarbazone inhibits XOD slightly more strongly than allopurinol, but there was no significant difference between the two. The results show that the DHNB semicarbazone has a good inhibition effect on the mouse serum XOD activity.
Effect of DHNB semicarbazone on blood uric acid of hyperuricemic mouse
After the mice are modeled by hyperuricemia, the serum uric acid levels of the mice in a normal saline group, a hyperuricemia model group, a DHNB semicarbazone group and an allopurinol group are detected. As shown in FIG. 8, the serum content of the model mice showed a significant difference from that of the normal saline control group, indicating that the modeling was successful. The DHNB semicarbazone and the allopurinol which are positive drugs can reduce the serum uric acid level of mice, and have significant difference compared with a model group. Mouse serum uric acid levels were lower after DHNB semicarbazone administration compared to the positive drug allopurinol, and showed significant differences between the two. The results show that the DHNB semicarbazone has better effect of reducing the serum uric acid level of mice and better effect than that of a positive allopurinol.
Inhibition effect of DHNB semicarbazone on liver XOD (x-ray activating degree) vitality of hyperuricemia model mouse
The viability of the liver XOD of mice in the normal saline group, the hyperuricemia model group, the DHNB semicarbazone and allopurinol group was detected by phosphotungstic acid method, as shown in FIG. 9, the viability of the model group XOD was enhanced with the viability of the normal saline control group, indicating that the model building was successful. After modeling, the DHNB semicarbazone and the positive allopurinol can inhibit the XOD activity of the liver of a mouse. In addition, DHNB semicarbazone inhibits XOD slightly more strongly than allopurinol, but there was no significant difference between the two. The results show that the DHNB semicarbazone has a good inhibition effect on the mouse liver XOD activity.
Toxicity study of DHNB semicarbazone on animals
In the mouse acute poisoning experiment, 24 healthy Kunming mice (32 +/-2 g) are selected, half each male and female are divided into two groups, a DHNB semicarbazone group and an allopurinol group are selected, 12 mice are selected in each group, half each male and female are subjected to intragastric administration (ig) once according to the weight mass of 500 mg/kg, and the activity and death condition of the mice are observed and recorded after administration. As a result, the mice in the DHNB semicarbazone group administered within one week had no toxic reaction, no death, and good status; and 12 mice in allopurinol group died 6 mice, wherein 2 female mice and 4 male mice. Preliminary toxicity tests indicate that DHNB semicarbazone is extremely low in toxicity, or non-toxic.
Claims (4)
1. A chemical synthetic drug 3, 4-dihydroxy-5-nitrobenzaldehyde (DHNB) semicarbazone for preventing and treating gout and hyperuricemia is synthesized by carrying out an aldehyde-amine condensation reaction on DHNB and semicarbazone, and the reaction formula is as follows:
2. the medicine DHNB semicarbazone for preventing and treating gout and hyperuricemia according to claim 1, wherein the DHNB semicarbazone is used as a chemical medicine and is formulated into tablets, capsules, granules, liposomes, injections and sustained-release and controlled-release preparations.
3. The DHNB semicarbazone according to claim 1, wherein the DHNB is used for the prevention and treatment of gout and hyperuricemia in combination with allopurinol, febuxostat and colchicine which are clinical gout prevention and treatment drugs.
4. The DHNB semicarbazone according to claim 1, wherein the metal complex synthesized by the metal ions is used for preventing and treating gout and hyperuricemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811066452.4A CN109875988B (en) | 2018-09-13 | 2018-09-13 | Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811066452.4A CN109875988B (en) | 2018-09-13 | 2018-09-13 | Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109875988A CN109875988A (en) | 2019-06-14 |
| CN109875988B true CN109875988B (en) | 2021-08-27 |
Family
ID=66924829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811066452.4A Active CN109875988B (en) | 2018-09-13 | 2018-09-13 | Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109875988B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017156513A1 (en) * | 2016-03-11 | 2017-09-14 | Selecta Biosciences, Inc. | Formulations and doses of pegylated uricase |
-
2018
- 2018-09-13 CN CN201811066452.4A patent/CN109875988B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017156513A1 (en) * | 2016-03-11 | 2017-09-14 | Selecta Biosciences, Inc. | Formulations and doses of pegylated uricase |
Non-Patent Citations (2)
| Title |
|---|
| Investigation of the interaction between benzaldehyde thiosemicarbazone compounds and xanthine oxidase;Mengrong Li等;《Journal of Molecular Structure》;20180202;第1159卷;23-32 * |
| 茶树根抗痛风活性部位的筛选研究;余雄英等;《江西中医药大学学报》;20151231;第27卷(第6期);52-56 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109875988A (en) | 2019-06-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110801452B (en) | Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof | |
| CN109678715B (en) | Salt, the preparation method and the usage that 2- (1- acyl-oxygen n-pentyl) benzoic acid and basic amino acid or aminoguanidine are formed | |
| US20220362249A1 (en) | Methods for treating hyperphenylalaninemia | |
| CN102086172A (en) | Medicinal salts of saxagliptin and preparation methods of medicinal salts | |
| CN111249283A (en) | Pyrimidine derivatives having anticancer effect | |
| CN111533770A (en) | Preparation method of arbutin in sparrow tea and application of arbutin in treating hyperuricemia | |
| WO2015188609A1 (en) | New use of a benzopyran derivative in preparation of medicament for treating hyperuricemia | |
| CN109096190B (en) | Sinomenine derivative, preparation method, application and pharmaceutical composition thereof | |
| CN109875988B (en) | Synthesis of compound DHNB semicarbazone and application of compound DHNB semicarbazone in preventing and treating gout and hyperuricemia | |
| CN109260182B (en) | Application of cannabidiol in preparation of medicine for treating pulmonary hypertension | |
| JPS6112622A (en) | Agent for promoting differentiation and proliferation of hemopoietic stem cell | |
| CN108403729B (en) | Preparation method of agrocybe cylindracea extract and application of agrocybe cylindracea extract in preparation of uric acid reducing medicine | |
| CN109336800B (en) | DHNB (dehydroepiandrosterone) condensed phenylthiosemicarbazide compound as well as preparation method and application thereof | |
| CN110938025B (en) | Application of catechaldehyde condensed phenyl thiosemicarbazide compound in preventing and treating gout and hyperuricemia | |
| CN111417632B (en) | Thiazole-5-formic acid derivative and preparation method and application thereof | |
| CN105012294B (en) | New application of the ellagic acid compounds in treatment antihyperuricemic disease drug is prepared | |
| CN110204493B (en) | Tricyclic XOR inhibitor and preparation method and application thereof | |
| EP3904335A1 (en) | Acetylsalicylic acid derivative and application thereof | |
| CN112402410A (en) | Application of oridonin in preparing medicine for treating hyperuricemia and anti-gout | |
| WO2021135665A1 (en) | Application of tetrahydrocannabivarin in prevention and/or treatment of pulmonary arterial hypertension | |
| JPH06135830A (en) | Antihypertensive medicine composition containing flavonoid derivative | |
| CN110731979A (en) | Application of rhus chinensis total phenolic acid pellets in preparation of medicines for preventing and/or treating cardiovascular diseases | |
| CN113197907B (en) | Application of gardenia acetic acid and derivatives thereof in preparing medicine for treating diabetes | |
| JP3834089B2 (en) | Asthma treatment containing a benzimidazole derivative | |
| CN109394798B (en) | Preparation method of dried extract of xanthobacter guidongensis and application of dried extract in reducing uric acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |