CN115212192A - Application of benzophenone derivative in preparation of anti-renal fibrosis medicine - Google Patents
Application of benzophenone derivative in preparation of anti-renal fibrosis medicine Download PDFInfo
- Publication number
- CN115212192A CN115212192A CN202210976333.2A CN202210976333A CN115212192A CN 115212192 A CN115212192 A CN 115212192A CN 202210976333 A CN202210976333 A CN 202210976333A CN 115212192 A CN115212192 A CN 115212192A
- Authority
- CN
- China
- Prior art keywords
- benzophenone
- tert
- renal fibrosis
- butyl
- application
- 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.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides an application of a benzophenone derivative in preparing an anti-renal fibrosis drug, wherein the benzophenone derivative is any one of 4,5,2' -trihydroxy-2, 5' -dibromo benzophenone, 3, 4-dihydroxy-4 ' -tert-butyl benzophenone, 4, 5-dihydroxy-2-bromo-4 ' -tert-butyl benzophenone and 2,3, 4-trihydroxy-6-chloro-4 ' -tert-butyl benzophenone. Pharmacological tests prove that the benzophenone derivative can effectively reduce the kidney fibrosis degree of UUO rats and reduce abnormal deposition of ECM, and the levels of main treatment indexes of Scr and BUN are superior to that of a first-line clinical medicament of losartan potassium.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, relates to a new pharmaceutical application of compounds, and particularly relates to applications of benzophenone compounds and derivatives thereof, including pharmaceutically acceptable salts thereof, in preparation of anti-renal fibrosis drugs.
Background
Fibrosis is defined as excessive deposition of Extracellular Matrix protein (ECM), scarring and thickening of tissue, and is essentially an excessive wound healing response that can lead to dysfunction, morbidity, and death of vital organs in the kidney, lung, liver, etc. of a patient. Therefore, inhibition of ECM deposition is important for improvement of fibrosis in body organs.
Chronic Kidney Disease (CKD) is a long-term Disease of abnormal renal tissue structure and function that affects about 10% of the adults worldwide, with about 120 million patients dying from CKD each year. Diabetes and hypertension are two major causes of CKD, the kidney having the ability to regenerate after acute injury, but in the case of chronic injury, regeneration and recovery are much more difficult. This process is therefore usually irreversible and can progress to end stage renal disease, which requires dialysis or kidney transplantation.
The pathological features of CKD are glomerular sclerosis and tubulointerstitial fibrosis due to excessive ECM deposition, and the presence of fibrosis in CKD is closely related to the future manifestations of renal failure and thus to a long-term poor prognosis.
At present, no medicine for effectively treating or preventing kidney fibrosis exists, clinical treatment mainly comprises controlling primary morbidity, eliminating related risk factors (anti-infection and the like), controlling symptoms and the like, and only can delay the progress of the disease. Therefore, the development of new therapeutic agents to reverse or eliminate renal fibrosis is imperative, and particularly the discovery of agents that reduce ECM deposition is a problem that needs to be addressed in current research and development.
The ECM primarily includes collagen and non-collagen. Collagen 1 (collagen 1, COL1) is the most abundant protein in the fibrotic matrix, fibronectin (FN) is a non-collagen glycoprotein, the degree of renal fibrosis is increased, and the expression of COL1 and FN is increased. Thus, COL1 and FN were used as indicators to evaluate the degree of renal fibrosis.
CN 101602657A discloses a halogenated hydroxyl aromatic ketone compound, a preparation method and an application thereof, wherein the compound is formed by respectively connecting one or more hydroxyl groups and halogen substituents on two phenyl groups of benzophenone, and typical compounds comprise 4-chloro-3 ',4' -dihydroxy benzophenone, 2, 3-dibromo-4, 5-dihydroxy benzophenone, 2, 6-dibromo-3, 3',4', 5-pentahydroxy benzophenone and the like. The halogenated hydroxyl arone compounds and non-toxic salts, esters and ethers thereof have the activities of resisting bacteria, tumors, oxidation and vascular endothelial cell injury and inhibiting proliferation of vascular smooth muscle cells.
Furthermore, CN 102423308A discloses the use of two bromophenol compounds 2, 3-dibromo-4, 5-dihydroxybenzophenone and 2,3 '-dibromo-4, 5,6' -trihydroxybenzophenone, and their pharmaceutically acceptable salts in the preparation of drugs for protecting myocardial ischemia-reperfusion injury, which defines the protection function of the compounds on myocardial ischemia-reperfusion injury.
CN 103156829A discloses the application of polyhydroxy bromo-benzophenone compound 2,4',5' -trihydroxy-5, 2' -dibromo-benzophenone and its derivatives in the treatment and prevention of atherosclerosis, which proves that the compound inhibits the damage of vascular endothelium by reducing the expression of TG and LDL-C in serum, inhibiting the expression of inflammatory factors IL-6, TNF-alpha and adhesion molecule sICAM-1 in serum, and protecting vascular endothelium, thereby inhibiting the occurrence and development of AS pathological changes, and opening up a wider prospect for clinical medication.
CN 105193795A further discloses the application of two halogen phenol compounds, namely 2,4',5' -trihydroxy-5, 2 '-dibromobenzophenone and 2', 5-dibromo-2- (2-phenylimidazol-1-yl) methyl-4 ',5' -dihydroxybenzophenone, in the aspect of promoting angiogenesis, which can remarkably increase the length of damaged internode blood vessels of zebra fish, has a protective effect on the zebra fish with blood vessel damage, and has potential application prospects in the aspects of preventing and treating ischemic heart disease, stroke, muscle atrophy, distal limb necrosis and the like.
Furthermore, CN 105816446A and CN 107007610A respectively disclose the application of two halogen phenol compounds, 4,5,2 '-trihydroxy-2, 5' -dibromobenzophenone and 4,5,2 '-tri (4-morpholine formyloxy) -2,5' -dichlorobenzophenone in the preparation of anti-type II diabetic nephropathy drugs and the drugs for treating acute pyelonephritis and chronic nephritis, and show the important application prospect in the aspect of treating diabetic nephropathy and treating acute pyelonephritis and chronic nephritis.
Although the research shows that 4,5,2 '-trihydroxy-2, 5' -dibromobenzophenone and the like have good treatment effects on diabetic nephropathy rats, acute pyelonephritis rats and the like, the mechanism of the compound is strong anti-inflammatory effect, and inflammatory reaction of kidney tissue cells and vascular endothelial cells can be remarkably inhibited. Therefore, in view of the obvious difference between the pathogenesis of renal fibrosis and the pathogenesis of diabetic nephropathy, acute pyelonephritis and the like, the function of resisting renal fibrosis cannot be deduced from the fact that the benzophenone compounds can be used for treating diabetic nephropathy and acute pyelonephritis. In fact, the current drugs clinically used to treat the above-mentioned renal diseases have little effect on reversing or slowing down renal fibrosis.
In addition, CN 111393277A discloses 4-butyl polyhydroxy benzophenone derivatives and application thereof, which are used for preventing and treating oxidative stress injury, reducing blood fat and protecting liver. Most of the 4-butyl polyhydroxy benzophenone compound derivatives have the protection rate of higher than 90 percent on damaged cells, have obvious liver protection effect, have inhibition effect on lipogenesis and have obvious improvement effect on liver damage caused by NAFLD.
However, no reports related to the pharmacological action of the 4-butyl polyhydroxy benzophenone compound derivatives on the resistance to renal fibrosis are available at home and abroad.
Disclosure of Invention
The invention aims to provide a novel application of a benzophenone derivative in a medicine for resisting renal fibrosis, so as to solve the problem of lack of a medicine for resisting renal fibrosis in the prior art.
The invention firstly proves that the benzophenone derivative and the medicinal salt thereof obtained by screening can be used for resisting renal fibrosis through in vivo experiments, and provides the application of the benzophenone derivative and the medicinal salt thereof in preparing the medicament for resisting renal fibrosis.
Further, the benzophenone derivative of the present invention is specifically any one of 4,5,2' -trihydroxy-2, 5' -dibromobenzophenone, 3, 4-dihydroxy-4 ' -tert-butylbenzophenone, 4, 5-dihydroxy-2-bromo-4 ' -tert-butylbenzophenone, and 2,3, 4-trihydroxy-6-chloro-4 ' -tert-butylbenzophenone.
More specifically, in the above benzophenone derivatives:
the structural formula of the 4,5,2 '-trihydroxy-2, 5' -dibromo benzophenone is as follows:
abbreviated as HP1.
The structural formula of the 3, 4-dihydroxy-4' -tert-butyl benzophenone is as follows:
abbreviated as HP2.
The structural formula of the 4, 5-dihydroxy-2-bromo-4' -tert-butyl benzophenone is as follows:
abbreviated as HP3.
The structural formula of the 2,3, 4-trihydroxy-6-chloro-4' -tert-butyl benzophenone is as follows:
abbreviated as HP4.
The four benzophenone derivatives listed above in the present invention are all compounds reported in the literature, and the preparation method thereof is well known to those skilled in the art. For example, CN 103156829A shows a specific preparation of 4,5,2 '-trihydroxy-2, 5' -dibromobenzophenone (HP 1) and its sodium salt.
Furthermore, the invention also provides application of the benzophenone derivative in preparing a medicine for reducing extracellular matrix deposition.
In the medicine for resisting renal fibrosis prepared by the benzophenone derivative, the pharmaceutical active ingredient can be the benzophenone derivative or the pharmaceutically acceptable salt thereof.
Further, the pharmaceutically acceptable salt thereof is specifically a sodium salt, a potassium salt or an ammonium salt.
The medicine for resisting renal fibrosis, disclosed by the invention, comprises necessary auxiliary materials besides the active pharmaceutical ingredients, as well as conventional medicines. The adjuvant may include, but is not limited to, at least one of diluents, excipients, fillers, binders, wetting agents, absorption enhancers, surfactants, lubricants, stabilizers, flavoring agents, sweeteners, pigments, etc., which are conventional in the pharmaceutical field.
Furthermore, the medicament of the invention can be prepared into any pharmaceutically acceptable dosage form, and the dosage form comprises but is not limited to any one of tablets, capsules, granules, pills, dripping pills, powder, oral liquid, sustained release preparations or controlled release preparations.
Pharmacological tests on the four benzophenone derivatives provided by the invention prove that the derivatives can be used as an anti-renal fibrosis drug to remarkably reduce serum creatinine (Scr) and serum urea nitrogen (BUN) levels of UUO rats and improve renal functions.
Specifically, the drug can obviously reduce the area of collagen fibers of the kidney of a UUO rat and reduce the expression quantity of COL1 and FN in ECM protein, thereby inhibiting the ECM deposition of kidney tissues and playing a role in resisting renal fibrosis.
The test result also shows that the effect of the medicine for resisting the kidney fibrosis is better than that of losartan potassium.
Drawings
Figure 1 is the results of Masson staining of benzophenone derivatives to reduce fibrosis in the kidney tissue of UUO rats.
Figure 2 is the results of COL1 and FN protein expression by benzophenone derivatives to reduce ECM deposition in kidney tissue of UUO rats.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are provided only for more clearly illustrating the technical solution of the present invention so that those skilled in the art can well understand and utilize the present invention, and do not limit the scope of the present invention.
The production process, experimental method or detection method related in the embodiments of the present invention are all conventional methods in the prior art, and the names and/or short names thereof all belong to the conventional names in the field, and are clearly and clearly understood in the related fields of use, and those skilled in the art can understand the conventional process steps and apply corresponding equipment according to the names, and implement the processes according to the conventional conditions or conditions suggested by manufacturers.
The various instruments, equipments, raw materials or reagents used in the examples of the present invention are not particularly limited in their sources, and are all conventional products commercially available from normal commercial sources, and can be prepared by conventional methods well known to those skilled in the art.
Example 1: and (3) researching the anti-rat kidney fibrosis effect of the benzophenone derivative.
Male SD rats, weight 180-220 g, animal origin: sbeft (beijing) biotechnology limited, license number: SCXK- (Jing) 2019-0010, certificate number: 110324220102652614.
the animals and related treatment used in the experiment meet the requirements of animal welfare, and the animal welfare committee of the institution has been subjected to ethical examination before the experiment is carried out.
Losartan potassium tablet, zhejiang huahai pharmaceutical industry gmbh; the determination kit (sarcosine oxidase method, microplate method) for the creatinine (Cr) of a rat, the urea nitrogen (BUN) test kit (urease method) and Nanjing are built into a bioengineering research institute.
72 SD rats were selected, 8 were randomly selected as Sham surgery groups (Sham), and the other rats were operated with Unilateral Ureteral Obstruction (UUO).
After 3% pentobarbital sodium solution (dose is 0.15mL/100 g) is injected into the abdominal cavity of an SD rat for anesthesia, the SD rat is fixed in a supine position, the middle position of the left abdominal cavity is opened, and a ureter is found downwards along the renal gate; dissociating the left ureter, permanently ligating at the opening of the renal pelvis and 1/3 of the ureter with 4-0 surgical sutures, and cutting off the left ureter from the middle of two ligation points; and (4) suturing layer by layer, closing the abdomen, and preparing a Unilateral Ureteral Obstruction (UUO) rat model.
In the sham operation group, SD rats were subjected to abdominal release and direct abdominal closing without ligaturing.
Successfully prepared UUO model rats are randomly divided into 8 groups, namely a model group (UUO), a positive drug group (UUO + losartan potassium, 10 mg/kg/d), an HP1 low-dose group (22.5 mg/kg/d), an HP1 medium-dose group (45 mg/kg/d), an HP1 high-dose group (90 mg/kg/d), an HP2 high-dose group (90 mg/kg/d), an HP3 high-dose group (90 mg/kg/d) and an HP4 high-dose group (90 mg/kg/d), wherein each group contains 8 mice.
Each drug group was given the respective concentration of drug by continuous gavage for 21 days. The sham operation group and the model group were given equal doses of physiological saline.
After the model-making administration, the patient is fasted overnight on the 20 th day and is anesthetized in the abdominal cavity on the 21 st day, and related indexes of abdominal aortic blood detection are extracted. The kidneys were washed with physiological saline, and the same portion of the kidney tissue (including glomeruli and tubules) from the left kidney was longitudinally cut and immersed in 4% paraformaldehyde for pathomorphological analysis.
The data were analyzed using SPSS Statistics 20 software, all values were expressed in terms of
Showing that comparisons between groups were performed by one-way analysis of variance (ANOVA), based on results of homogeneity of variance tests, such as the homogeneous variance test by LSD test, and the heterogeneous variance test by Dunnett's T3 testPDifferences < 0.05 are statistically significant.
Masson staining is one of the main methods for judging pathological staining of renal fibrosis. The Masson staining results of figure 1 show that the blue collagen fiber area of tubulointerstitis of the UUO rats was significantly increased compared to the Sham group, while HP1 dose-dependently decreased the collagen fiber area compared to the UUO group, indicating that HP1 was able to reduce kidney fibrosis in UUO rats. And as can be seen from fig. 1, the effect of high doses of HP1, HP2, HP3 and HP4 on reducing renal fibrosis is superior to that of the current first-line clinical medicament of losartan potassium for CKD.
Collagen 1 (COL 1) and Fibronectin (FN) are the main indicators for determining ECM deposition changes. Immunohistochemistry was used to detect the expression levels of COL1 and FN in pathological sections of kidney tissues, and from the results of fig. 2, it was found that the expression levels of COL1 and FN were significantly increased in the UUO group compared to the Sham group, whereas the expression levels of COL1 and FN were significantly lower in the HP 1-treated group than in the UUO group, indicating that HP1 was effective in reducing ECM deposition in kidney tissues. And as can be seen from fig. 2, the effect of reducing the expression of COL1 and FN proteins by high doses of HP1, HP2, HP3 and HP4 is better than that of losartan potassium, which is a positive drug.
Serum creatinine (Scr) and serum urea nitrogen (BUN) are important indicators reflecting kidney function. The results of blood biochemical tests in table 1 show that compared with the Sham group, the Scr and BUN contents of the UUO group are significantly increased, HP1 can significantly reduce the levels of the kidney injury markers Scr and BUN, and significantly improve the kidney function, and compared with the UUO group, the difference of the Scr reduction level of losartan potassium has no statistical significance.
Meanwhile, the high-dose HP1, HP2, HP3 and HP4 group has a function of improving the kidney function obviously better than that of the losartan potassium group.
Note: compared to the Sham group, # c,Pless than 0.01; in comparison with the set of UUOs, # ，P＜0.05， ## ，Pless than 0.01; compared with the UUO + losartan potassium group, Δ ，P＜0.05。
the above embodiments of the present invention are not intended to be exhaustive or to limit the invention to the precise form disclosed. Various changes, modifications, substitutions and alterations to these embodiments will be apparent to those skilled in the art without departing from the principles and spirit of this invention.
Claims (5)
1. The application of the benzophenone derivative in preparing the anti-renal fibrosis drug is that the benzophenone derivative is any one of 4,5,2' -trihydroxy-2, 5' -dibromo benzophenone, 3, 4-dihydroxy-4 ' -tert-butyl benzophenone, 4, 5-dihydroxy-2-bromo-4 ' -tert-butyl benzophenone and 2,3, 4-trihydroxy-6-chloro-4 ' -tert-butyl benzophenone.
2. Use of a benzophenone derivative according to claim 1 for the preparation of a medicament for reducing extracellular matrix deposition.
3. The use according to claim 1 or 2, wherein the medicament further comprises a pharmaceutically acceptable salt thereof.
4. Use according to claim 3, characterized in that the pharmaceutically acceptable salt is a sodium, potassium or ammonium salt.
5. Use according to claim 1 or 2, characterized in that the medicament further comprises necessary excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210976333.2A CN115212192B (en) | 2022-08-15 | 2022-08-15 | Application of diphenyl ketone derivative in preparation of kidney fibrosis resisting medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210976333.2A CN115212192B (en) | 2022-08-15 | 2022-08-15 | Application of diphenyl ketone derivative in preparation of kidney fibrosis resisting medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115212192A true CN115212192A (en) | 2022-10-21 |
| CN115212192B CN115212192B (en) | 2023-09-08 |
Family
ID=83615686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210976333.2A Active CN115212192B (en) | 2022-08-15 | 2022-08-15 | Application of diphenyl ketone derivative in preparation of kidney fibrosis resisting medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115212192B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010077101A (en) * | 2008-09-29 | 2010-04-08 | Toray Ind Inc | Curative or preventive agent for kidney fibrosis |
| CN106420680A (en) * | 2016-09-30 | 2017-02-22 | 广东轻工职业技术学院 | Benzophenone derivatives serving as tyrosinase activating agents and applications thereof |
| CN107007610A (en) * | 2017-04-25 | 2017-08-04 | 山西医科大学 | Application of the benzophenone compound in pharmacy |
| CN110856716A (en) * | 2018-08-22 | 2020-03-03 | 龙海波 | Application of compound and pharmaceutical composition thereof in prevention and treatment of renal fibrosis |
-
2022
- 2022-08-15 CN CN202210976333.2A patent/CN115212192B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010077101A (en) * | 2008-09-29 | 2010-04-08 | Toray Ind Inc | Curative or preventive agent for kidney fibrosis |
| CN106420680A (en) * | 2016-09-30 | 2017-02-22 | 广东轻工职业技术学院 | Benzophenone derivatives serving as tyrosinase activating agents and applications thereof |
| CN107007610A (en) * | 2017-04-25 | 2017-08-04 | 山西医科大学 | Application of the benzophenone compound in pharmacy |
| CN110856716A (en) * | 2018-08-22 | 2020-03-03 | 龙海波 | Application of compound and pharmaceutical composition thereof in prevention and treatment of renal fibrosis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115212192B (en) | 2023-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20090005424A9 (en) | Composition and Method for Treating Fibrotic Diseases | |
| KR102140910B1 (en) | Composition comprising chp (cyclo-his pro) for preventing, improving or treating of fibrosis | |
| WO2017088775A1 (en) | Use of benzenesulfonamido benzamide compounds for inhibiting liver fibrosis | |
| AU2002315814B2 (en) | Medicinal composition for treatment of interstitial cystitis | |
| JP2017524663A (en) | PPAR compounds used for the treatment of fibrotic diseases | |
| CN110960671A (en) | New application of Elabela polypeptide and medicine thereof | |
| JP4951530B2 (en) | Pharmaceutical composition for the treatment of renal disorders and health foods containing herbal extracts | |
| Bond et al. | Treatment of hemorrhage and traumatic shock by the intravenous use of lyophile serum | |
| WO2020175817A1 (en) | Composition for preventing, ameliorating, or treating fibrosis | |
| US4448788A (en) | 11-Deoxoglycyrrhetinic acid hydrogen maleate, process for its production, and its use as a medicine | |
| CN115212192A (en) | Application of benzophenone derivative in preparation of anti-renal fibrosis medicine | |
| WO2014063660A1 (en) | Naringenin and asiatic acid combination treatment of fibrosis | |
| EP1806136B1 (en) | Medicinal composition for prevention of transition to operative treatment for prostatic hypertrophy | |
| CN108685907B (en) | Compound for preventing and treating kidney injury | |
| CN110372800B (en) | Fusion polypeptide with multifunctional activity and application thereof | |
| CN101837007B (en) | Medicinal composition for curing hemorrhoids and preparation method thereof | |
| JP2001139483A (en) | Protecting agent for brain cell or nerve cell, consisting of ginseng | |
| CN113908161A (en) | Use of koumine for the treatment of sepsis | |
| CN111840512A (en) | Composition for treating cartilage repair and/or osteoarthritis | |
| CN108295067B (en) | Compound for preventing and treating renal interstitial fibrosis | |
| JP2007084459A (en) | Composition for treating fibrotic disease | |
| CN114569601B (en) | Application of neogambogic acid in preparation of medicines for preventing and/or treating kidney diseases | |
| CN110604735B (en) | Compound for treating hepatic fibrosis and scleroderma and application thereof | |
| CN113304163B (en) | Application of trifolium pterocarpus santalin in treating arthritis | |
| CN107050025A (en) | Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis |
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 |