CN116768871A - Puerarin derivative and application thereof - Google Patents
Puerarin derivative and application thereof Download PDFInfo
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- CN116768871A CN116768871A CN202210220907.3A CN202210220907A CN116768871A CN 116768871 A CN116768871 A CN 116768871A CN 202210220907 A CN202210220907 A CN 202210220907A CN 116768871 A CN116768871 A CN 116768871A
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- puerarin
- preventing
- preparing
- medicament
- treating
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- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 21
- 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 4
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims abstract description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 4
- 206010008132 Cerebral thrombosis Diseases 0.000 claims abstract description 4
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims abstract description 4
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 4
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 150000002632 lipids Chemical class 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N flavone Chemical group O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 abstract description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 241000219780 Pueraria Species 0.000 description 1
- 235000010575 Pueraria lobata Nutrition 0.000 description 1
- 244000046146 Pueraria lobata Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention modifies the flavone structure in puerarin (8-beta-D-glucopyranose-4, 7-dihydroxyisoflavone) to obtain a new compound C 23 H 24 O 9 The lipid solubility of the medicine is increased, the biological activity is better, the lipid water distribution coefficient in the body is changed, the bioavailability is improved, the pharmacological activity is enhanced, and the medicine is expected to have better curative effects on cerebral thrombosis, cerebral hemorrhage sequelae, cerebral ischemia, coronary heart disease, angina pectoris and myocardial ischemia.
Description
Technical Field
The invention belongs to the field of compound medicines, and particularly relates to a puerarin derivative and application thereof.
Background
Puerarin is an active ingredient of Pueraria lobata (Willd.) Ohwi of genus Pueraria of family Leguminosae. The chemical name is 8-C-beta-D-glucosyl-7, 4-dihydroxyl-isoflavone (8-C-beta-D-Glucopyranosyl-7, 4-hydroxy-isolavone), which is white needle-like crystal and slightly soluble in water, and the water solution is colorless or yellowish. The structure is as follows.
Proved by researches, puerarin has strong anti-cardiovascular and cerebrovascular ischemia and hypoxia activity, and can dilate coronary artery and cerebral vessels, reduce myocardial oxygen consumption, improve myocardial contraction function, improve microcirculation, improve learning and memory and the like. Puerarin has been approved by the Ministry of health for clinical use since 1993 and has become one of the important clinical therapeutic drugs of traditional Chinese medicine extracts. In 2000, the puerarin overall market presents a stable development situation, and in 2004 puerarin sales reach the tripod flourishing period and the annual sales amount reach 10 hundred million yuan. With the wide clinical application of puerarin, the adverse reports of puerarin are also increasing. In 3 months of 2006, the national medicine adverse reaction monitoring center notifies serious adverse reactions caused by puerarin injection in a special form. The puerarin has the advantages of small solubility of the original structure, extremely low oral bioavailability and intravenous administration, and the intravenous administration of puerarin causes side effects such as hemolysis reaction and the like, which become main factors restricting the further development of the puerarin preparation market and lead the puerarin market to gradually slide down.
The low water-solubility and fat-solubility of puerarin are considered by a plurality of scholars at home and abroad to be the fundamental place of low oral bioavailability and great side effect of intravenous administration, and the original structure of puerarin is modified and improved to improve the water-solubility and fat-solubility, change the lipid-water distribution coefficient in vivo, improve the bioavailability and enhance the pharmacological activity of puerarin, thus being a key way for solving a plurality of problems in clinical application.
Disclosure of Invention
It is an object of the present invention to provide a novel puerarin derivative.
A puerarin derivative has a compound structural formula shown as follows:
it is a further object of the present invention to provide the use of the above compounds.
The application of the puerarin derivative in preparing the medicine for preventing and treating cerebral thrombosis.
The puerarin derivative is applied to the preparation of medicines for preventing and treating cerebral hemorrhage sequelae.
The puerarin derivative is applied to the preparation of medicines for preventing and treating cerebral ischemia.
The puerarin derivative is applied to the preparation of medicaments for preventing and treating coronary heart disease.
The application of the puerarin derivative in preparing medicines for preventing and treating angina pectoris.
The puerarin derivative is applied to the preparation of medicines for preventing and treating myocardial ischemia.
The invention modifies the flavone structure in puerarin (8-beta-D-glucopyranose-4, 7-dihydroxyisoflavone) and leads C to be 6 -C 3 -C 6 the-OH in the structure is replaced by-O-structure, and the C is obtained 23 H 24 0 9 The lipid solubility of the medicine is increased, the biological activity is better, the lipid water distribution coefficient in the body is changed, the bioavailability is improved, the pharmacological activity is enhanced, and the medicine is expected to have better curative effects on cerebral thrombosis, cerebral hemorrhage sequelae, cerebral ischemia, coronary heart disease, angina pectoris and myocardial ischemia.
Drawings
FIG. 1 is a diagram showing the results of carbon-based nuclear magnetic resonance spectroscopy detection synthesis of puerarin modifier C23H 2409.
FIG. 2 is a diagram showing the results of the detection and synthesis of the puerarin modifier C23H2409 hydrogen nuclear magnetic resonance spectrum.
FIG. 3 is a graph showing plasma concentration results of plasma concentration detection in example 2.
FIG. 4 is a graph showing the relationship between time and logarithmic concentration in the blood concentration measurement in example 2.
Detailed Description
The following examples of the invention do not address the specific conditions of the experimental procedure, and are generally conducted under conventional conditions, or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an associated object, and means that there may be three relationships, for example, a and/or B, and may mean: there are three cases, a alone, a and B together, and B alone. The character "/" generally indicates that the context associated with the object is an "or" relationship.
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. The following examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the following examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and basic idea of the present invention should be considered as equivalent substitutions, and are included in the scope of the present invention.
Example 1
C 23 H 24 0 9 The preparation method of (2) comprises the following steps:
(1) The puerarin powder was dissolved with warm water at 50 degrees celsius.
(2) Adding acetone (2.0 eq) to selectively protect four hydroxyl groups on puerarin glycosyl;
(3) Anhydrous potassium carbonate (2.0 eq) was added to N, N-dimethylformamide and stirred at room temperature for 1 hour;
(4) Methyl iodide (1.2 eq) is added dropwise into the reaction system, incubated overnight at room temperature, and used for converting two hydroxyl groups on a benzene ring into methoxy groups;
(5) The hydroxy protection on the glycosyl groups was removed under weakly acidic conditions (pH 5.5). Obtaining the said
Example 2: drug metabolism detection
Blood concentration detection was performed by single oral administration of 1mmol/kg puerarin or puerarin modification to adult mice, and by orbital venous plexus blood collection, 0,15,30,45,60min, and 1.5,2,4,6,8,12h blood samples. The peak time (Tmax), half-life (T1/2) of the plasma concentration was calculated.
1. The research method comprises the following steps:
1) Purchasing and raising animals: c57BL/6 wild type mice were purchased from university laboratory animal centers at the center and were kept in a 12-hour alternating-light and dark environment and were fed with water.
2) Healthy adult male mice were randomly divided into 2 groups of 120. No water was allowed for 12 hours before the experiment. Each group of mice was single orally administered 1mmol/kg puerarin or puerarin modifier aqueous solution suspension. Blood samples were collected for 0,15,30,45,60min, and 1.5,2,4,6,8,12h with 5ml of each blood sample. After the blood sample was allowed to stand at room temperature for 30 minutes, serum was separated by centrifugation at 3000rpm X15 minutes at room temperature.
3) To 500. Mu.L of serum sample was added 2000. Mu.L of methanol (4:1, v/v) and mixed by vortexing at room temperature for 1 minute. After centrifugation at 3000rpm X15 min, the supernatant was removed, dried using liquid nitrogen, dissolved in 200. Mu.L of methanol, vortexed for 1 min and centrifuged at 10,000rpm for 10 min. The final supernatant was transferred to a 1.5ml polypropylene tube. The supernatant was aliquoted into an analytical column at 20. Mu.L and examined.
Study results: puerarin drug half-life is 274 minutes, about 4.5 hours. The half life of puerarin modifier drug is 231 minutes, about 4 hours. AUC (AUC) A38 /AUC A0 = 593.69407/382.10087 = 1.553763. The results are shown in FIG. 3 and FIG. 4.
The above examples represent only a few embodiments of the present invention, which are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (7)
1. A puerarin derivative is characterized in that the compound structural formula is shown as follows:
2. the use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating cerebral thrombosis.
3. The use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating cerebral hemorrhage sequelae.
4. The use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating cerebral ischemia.
5. The use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating coronary heart disease.
6. The use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating angina pectoris.
7. The use of puerarin derivatives according to claim 1 for preparing a medicament for preventing and treating myocardial ischemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210220907.3A CN116768871A (en) | 2022-03-08 | 2022-03-08 | Puerarin derivative and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210220907.3A CN116768871A (en) | 2022-03-08 | 2022-03-08 | Puerarin derivative and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116768871A true CN116768871A (en) | 2023-09-19 |
Family
ID=88012114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210220907.3A Pending CN116768871A (en) | 2022-03-08 | 2022-03-08 | Puerarin derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116768871A (en) |
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2022
- 2022-03-08 CN CN202210220907.3A patent/CN116768871A/en active Pending
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