CN112535682B

CN112535682B - Application of Shaerweike ketone derivative in preparation of medicine

Info

Publication number: CN112535682B
Application number: CN202011167212.0A
Authority: CN
Inventors: 梁广; 钱建畅; 李丽; 伍文奇; 王怡
Original assignee: Wenzhou Medical University
Current assignee: Wenzhou Medical University
Priority date: 2020-10-27
Filing date: 2020-10-27
Publication date: 2021-10-22
Anticipated expiration: 2040-10-27
Also published as: CN112535682A

Abstract

The invention discloses an application of a salwexone derivative or a salt thereof in preparation of a medicine, wherein the compound is used for treating or preventing chronic kidney disease, preferably nephropathy caused by hyperglycemia or hypertension, but not limited to the two inducing factors, and particularly, the medicine can inhibit or improve various types of kidney injury.

Description

Application of Shaerweike ketone derivative in preparation of medicine

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of a compound (code number 15a) shown in a formula (I) in preparation of a medicine for treating or preventing chronic kidney diseases.

Background

Chronic kidney disease is one of the most common complications of basic diseases such as hyperglycemia and hypertension. Stimulated by these risk factors, glomerular basement membrane thickens, and tubulointerstitial expansion progresses to fibrosis. As the disease progresses, it eventually progresses to end-stage renal disease, which severely affects the quality of life of the patient and even endangers life.

The inventor finds that the compound with the structure of the formula (I) can be used as an anti-acute lung injury medicament, but other purposes of the compound are not reported.

Disclosure of Invention

The invention aims toProvide C with₂₇H₂₃NO₃Novel use of (compound of formula (I), code 15 a).

In particular, the present invention provides the use of compound (15a) of formula (I) or a medicament for the treatment or prevention of chronic kidney disease.

The inventor finds that the compound with the structure shown in the formula (I) can be used as an anti-acute lung injury medicament, and can also be used for effectively treating chronic nephropathy induced by factors such as hyperglycemia, hypertension and the like, and related pathological changes induced by the chronic nephropathy can be remarkably improved.

Preferably, the use of the present invention is in the manufacture of a medicament for the treatment or prevention of chronic kidney disease.

The invention also provides the use of a compound (15a) of formula (I) in the manufacture of a medicament for the amelioration of chronic kidney disease.

Preferably, the use of the present invention is for the preparation of a medicament for ameliorating chronic kidney disease.

Nephropathy occurs as a result of many causes, including urinary system obstruction, hyperlipidemia, hypertension, autoimmunity, and drug toxicity. The treatment modes of different etiologies are different, and the invention aims at mainly diabetic nephropathy or hypertensive nephropathy as the preference, but is not limited to the two pathogenetic factors; most preferably, for the treatment of kidney damage and altered kidney tissue function.

Preferably, in the use of the present invention, the main pathological features of renal disease are glomerulosclerosis, dilation of the tubules, and the accumulation of collagen fibers in the interstitial spaces.

The renal tissue function changes include proteinuria, reduced renal function, tubular fibrosis, and basement membrane thickening.

Preferably, in the use according to the invention, the compound (15a) of formula (I) has no statistical significance for the influence on blood glucose or blood pressure.

The medicament in the use of the present invention contains an effective dose of the compound (15a) of the formula (I). The effective dose may be the amount in a unit dosage form (e.g., a tablet, a needle, a pill or a dose) of the drug, or may be a unit dose (e.g., a unit weight dose) of the patient to be treated/prevented. In the present invention, the effective dose (in terms of content) may be 10. mu.g to 1g, preferably 0.1mg to 500 mg, more preferably 1mg to 100 mg.

The medicament in the use of the invention will generally also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier used refers to nontoxic fillers, stabilizers, diluents, adjuvants or other formulation adjuvants. For example, diluents, excipients, such as water, physiological saline, and the like; fillers, such as starch, sucrose, and the like; binders, such as cellulose derivatives, alginates, gelatin and/or polyvinylpyrrolidone; humectants, such as glycerol; disintegrating agents, such as agar, calcium carbonate and/or sodium bicarbonate; absorption accelerators, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and/or bentonite clay; lubricants, such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition of the invention can further comprise other auxiliary materials, such as flavoring agents, sweetening agents and the like. According to the well-known technology in the field, the pharmaceutical composition can be prepared into various dosage forms according to the requirements of treatment purposes and administration routes, preferably the composition is in a unit administration dosage form, such as a freeze-dried preparation, a tablet, a capsule, powder, emulsion, a water injection or a spray, and more preferably the pharmaceutical composition is in an injection dosage form (such as a freeze-dried powder injection) or an oral dosage form (such as a tablet and a capsule). The medicaments can be administered by the customary routes, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, topically, for example in the form of lotions or gels, or in the form of nasal or nasal preparations.

The invention will be described in detail below by means of specific embodiments and the accompanying drawings. It is to be expressly understood that the description is only a partial illustration and is not intended as a definition of the limits of the invention. Many variations and modifications of the present invention will be apparent to those skilled in the art in light of the teachings of this specification.

Description of the drawings:

FIG. 1 shows the effect of compound (15a) of formula (I) on blood glucose and body weight in diabetic mice and on the improvement of urine protein and kidney function in model.

FIG. 2 is a graph showing the inhibitory effect of compound (15a) of formula (I) on renal fibrosis in diabetic mice.

FIG. 3 is a graph showing the inhibitory effect of compound (15a) of formula (I) on renal tubular epithelial cell fibrosis in vitro caused by high concentration of glucose.

FIG. 4 shows the therapeutic effect of compound (15a) of formula (I) on angioII-induced hypertensive glomerular fibrosis and enlargement.

The specific implementation mode is as follows:

the invention is further illustrated in the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1 the compounds of the present invention did not affect blood glucose and body weight in mice.

The C57L/B6 mice were randomly divided into 3 groups (6 per group) of:

control group (Control group): healthy C57L/B6 mice;

type 1 diabetes model mouse (STZ): constructing a type 1 diabetes mouse model by utilizing Streptozotocin (STZ);

compound treatment group (STZ +15a 20 mg/kg): after completion of the construction of type 1 diabetes model mice, the mice were gavaged with the compound of formula (I) (15a), 1% CMC-Na suspension, starting at week 9 and administered for 8 weeks at a dose of 20 mg/kg/day.

Blood glucose (Serum glucose) and Body weight (Body weight) were recorded weekly in each group of mice during a 16-week period following molding. As shown in FIGS. 1A-B, the blood glucose levels of the mice in the treated group were not different from those in the STZ group. Meanwhile, the use of compound (15a) did not affect the body weight of the diabetic mouse model.

Mice were sacrificed after the dosing period was completed and urine and blood samples were collected and assayed for urine protein, urine creatinine, and blood urea nitrogen levels using biochemical analysis. FIGS. 1C-E show that compound (15a) of formula (I) significantly ameliorates high-sugar induced urinary protein and renal dysfunction.

Example 2 Compounds of the invention significantly inhibit hyperglycemia-induced renal fibrosis

Animal groups were performed as in example 1, and 8 weeks after dosing, mice were sacrificed and kidney tissue was obtained. Fixed with 4% formalin, paraffin-embedded, sliced to a thickness of 5 μm, and then stained with hematoxylin & eosin (H & E), sirius Red (Sirus Red), Masson (Masson), glycogen (PAS) and microscopic. FIG. 2A shows that hyperglycemia causes glomerular hypertrophy, thickening of glomerular basement membrane, and tubular dilation; at the same time, tubulointerstitial fibrosis and carbohydrate deposition were induced, but the pathological features were significantly alleviated after 15a treatment, fig. 2B-2D.

In addition, collagen 4(COL-4) and the fibrosis marker TGF-. beta.were detected by Western blotting. FIG. 2E shows that COL-4 and TGF- β were significantly increased in the STZ group, while 15a significantly inhibited the expression of these proteins (p < 0.05).

Crushing the tissue, extracting RNA, and detecting connective tissue growth factor CTGF by a real-time quantitative PCR method; fibrosis-associated markers COL-4, TGF- β; . As shown in FIG. 2F, 15a significantly suppressed the expression of CTGF, COL-4 and TGF-. beta.in the kidney due to hyperglycemia.

Example 3 the compounds of the present invention significantly improve hyperglycemia-induced fibrosis of renal tubular epithelial cells in vitro.

NRK-52E cells were stimulated with high concentrations of glucose (HG, 33mM) for 24 hours, followed by lysis of the cells to obtain total protein and detection of fibrosis-associated proteins COL-4, TGF-. beta.by Western blotting, with GAPDH as an internal control. As shown in FIG. 3A, increased expression of COL-4 and TGF- β induced by HG was significantly inhibited by 15 a. Furthermore, HG was used to stimulate NRK-52E cells for 10 hours, total cellular RNA was extracted using TRIzol, and RNA expression levels of COL-4, TGF-. beta.and CTGF were detected by a real-time quantitative PCR method. The results are shown in fig. 3B-D, and 15a also significantly inhibited HG-induced increase in fibrotic RNA levels in vitro.

Example 4 the compounds of the present invention did not affect blood pressure in mice but significantly improved glomerular fibrosis and enlargement caused by hypertension

The C57BL/6 mice were divided into 3 groups of 6 mice each, which were:

blank control (Ctrl): a healthy mouse;

renal hypertension model group (AngII): injecting with AngII subcutaneous micro pump (1000 ng/kg/min) for 4 weeks;

treatment group (Ang II +15a 20 mg/kg): injecting with Ang II subcutaneous micro pump (1000 ng/kg/min) for 2 weeks; the compound of formula (I) was gavaged to mice at a dose of 20mg/kg/day on day 15 for 2 consecutive weeks.

The results are shown in fig. 4A, the blood pressure of the treated mice was not significantly different from that of AngII, indicating that formula (I) did not affect the blood pressure of the model mice, and that its pharmacological effects were not achieved by lowering blood pressure. After administration, mice were sacrificed and kidney tissues were taken, fixed with 4% formalin, paraffin-embedded, sectioned at 5 μm thickness, and subjected to hematoxylin & eosin (H & E) staining, sirius Red (Sirus Red) staining, Masson staining (Masson) and microscopic examination. Fig. 4B shows that AngII causes glomerular hypertrophy, dilation of the tubules; at the same time, tubulointerstitial fibrosis was induced, and the pathological features were significantly improved after 15a treatment, fig. 4C and 4D.

Claims

1. Use of a salwexone derivative in the manufacture of a medicament for the treatment or prevention of a renal disorder;

the salwexone derivative is a compound with a structure shown in a formula (I) or a pharmaceutically acceptable salt thereof:

（І）

the kidney disorder is caused by hyperglycemia or hypertension.

2. Use of the salmonellone derivative of claim 1 in the preparation of a medicament, wherein the medicament does not affect blood glucose or blood pressure.

3. The use of salmonenone derivative according to claim 1, wherein the renal affection is caused by hyperglycemia and the renal affection is: hyperglycemia-induced urine protein, renal dysfunction, glomerular hypertrophy, thickening of glomerular basement membrane, tubular dilation, tubular interstitial fibrosis, and carbohydrate deposition.

4. The use of a salmonenone derivative according to claim 1, wherein the medicament is effective to inhibit the expression of CTGF, COL-4, TGF- β in the kidney due to hyperglycemia.

5. The use of salmonenone derivative according to claim 1, wherein the renal affection is caused by hypertension and the renal affection is: glomerular hypertrophy, tubular dilation, tubulointerstitial fibrosis.