CN115947716B - Nur 77-targeted indole derivative and application thereof - Google Patents
Nur 77-targeted indole derivative and application thereof Download PDFInfo
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- -1 2- (1H-indol-3-yl) -6-methyl nicotinyl Chemical group 0.000 claims description 35
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
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- Indole Compounds (AREA)
Abstract
The invention discloses an indole derivative targeting Nur77 and application thereof, which is characterized in that: the structure is as followsWherein R is Cl, F, CH3 or OCH3. The indole derivative takes the orphan nuclear receptor Nur77 as an action target point, and inhibits hepatic stellate cell activation by inducing the expression of the orphan nuclear receptor Nur77, so that hepatic fibrosis can be effectively inhibited. The indole derivative has the advantages of low reaction cost, high yield, simple and easily controlled reaction process and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of liver fibrosis treatment medicines, and particularly relates to an indole derivative targeting Nur77 and application thereof.
Background
In recent years, the incidence of liver fibrosis and cirrhosis has rapidly increased, however, there is currently no drug specifically treating liver fibrosis available in the market. The most effective treatment means for liver fibrosis in clinic is liver transplantation, and the treatment effect of liver fibrosis is not ideal because patients are easy to cause immune rejection and high medical cost. Hepatic stellate cells are effector cells of hepatic fibrosis, and hepatic stellate cell activation is the onset of hepatic fibrosis formation. At present, the pathological mechanism of liver fibrosis is mainly concerned with a cell signal path such as TGF-beta which influences the activity of hepatic stellate cells, and a drug target is also mainly an active molecule of the signal path. Many small or large molecule drugs designed for these targets have been tested in preclinical or new drug clinical trials, and most of them have not achieved ideal results. Therefore, the method has important clinical value for searching a new therapeutic molecular target of hepatic fibrosis, clarifying a new action mechanism of hepatic fibrosis activation and developing a targeted anti-hepatic stellate cell activation medicament.
Nur77, also known as NR4A1 or TR3, belongs to a member of the orphan nuclear receptor subfamily 4A (NR 4A). Nur77 has been shown to play an important role in liver fibrosis. In the TGF-beta pathway, nur77 can interact with SMAD7 and AXIN2, and induce the degradation of SMAD7 through AXIN2-RNF12/ARKADIA dependent modes, so that the TGF-beta/SMAD signal pathway is activated, and the continuously activated TGF-beta signal can inactivate Nur77 protein functions through AKT phosphorylation and HDAC apparent silencing modification modes to cause fibrosis diseases. Taken together, the results indicate that NR4A1 is a potentially important target for the treatment of liver fibrosis. However, research on how Nur77 regulates hepatic stellate cell activation is not reported at present. The study of this example found that in liver fibrosis mice, nur77 was induced and that knockout of Nur77 resulted in sustained activation of TGF- β signaling, exacerbating liver fibrosis, whereas Nur77 agonists could overcome this defect, rebalance TGF- β signaling and inhibit liver fibrosis. This suggests that agonists targeting Nur77 could be a direction of development of therapeutic drugs against liver fibrosis. Therefore, the designed and synthesized targeted nuclear receptor Nur77 small molecular compound can elucidate a new mechanism of Nur77 mediated anti-hepatic stellate cell activation, provides theoretical basis for anti-hepatic fibrosis clinical treatment and anti-hepatic fibrosis drug research and development, and has great research significance and clinical value.
Indole compounds are one of a plurality of structural units with physiological activity, and have great attention because of great structural flexibility, high modifiable degree, low toxicity to human bodies and good anticancer activity. Many natural and synthetic indole derivatives have good anti-fibrotic, anti-tumor activity, including 2-indolinone derivatives (PMID) inhibiting progression of lung fibrosis in silica (SiO 2) mice, indole derivatives nilamide (Nintedanib) have become first-line drugs for lung fibrosis, while indole derivatives C-DIM5 act as novel Nur77 agonists, mediating expression of tumor cell apoptosis proteins (TRAIL) by inducing expression of Nur77, thereby promoting tumor cell apoptosis and inhibiting tumor growth in vivo. This indicates that indole derivatives can be developed as medicines for treating fibrosis and cancer targeting Nur77, but no anti-hepatic fibrosis medicines targeting Nur77 are reported so far.
Disclosure of Invention
The invention aims to provide an indole derivative targeting Nur 77.
It is a further object of the present invention to provide the use of the above indole derivatives.
The technical scheme of the invention is as follows:
nur 77-targeted indole derivative with structural formula ofWherein R is Cl, F, CH 3 Or OCH (optical wavelength) 3 。
In a preferred embodiment of the present invention it is at least one of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-methylphenyl semicarbazide and 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-methylphenyl semicarbazide.
Use of an indole derivative as described above for the preparation of a composition for the treatment of liver fibrosis diseases, the active ingredient of the composition comprising said indole derivative or a pharmaceutically acceptable salt, ester or hydrate thereof.
In a preferred embodiment of the present invention, the active ingredient of the composition is the indole derivative or a pharmaceutically acceptable salt, ester or hydrate thereof.
In a preferred embodiment of the present invention, the composition is in the form of a tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated wine, tincture, lotion or film.
In a preferred embodiment of the invention, the indole derivative or a pharmaceutically acceptable salt, ester or hydrate thereof is in an in vivo dose of 15-30mg/kg.
A composition for treating liver fibrosis, characterized by: the active ingredients of the composition comprise the indole derivatives or pharmaceutically acceptable salts, esters or hydrates thereof.
In a preferred embodiment of the present invention, the indole derivative as claimed in claim 1 or 2 or a pharmaceutically acceptable salt, ester or hydrate thereof is used as an active ingredient.
In a preferred embodiment of the present invention, the dosage form is a tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated wine, tincture, lotion or film.
In a preferred embodiment of the invention, the indole derivative or a pharmaceutically acceptable salt, ester or hydrate thereof is in an in vivo dose of 15-30mg/kg.
The beneficial effects of the invention are as follows:
1. the indole derivative takes the orphan nuclear receptor Nur77 as an action target point, and inhibits hepatic stellate cell activation by inducing the expression of the orphan nuclear receptor Nur77, so that hepatic fibrosis can be effectively inhibited.
2. The indole derivative has the advantages of low reaction cost, high yield, simple and easily controlled reaction process and suitability for industrial production.
Drawings
FIG. 1 is a graph showing the experimental results of example 6 of the present invention.
FIG. 2 is a graph showing the experimental results of examples 7 and 8 of the present invention.
FIG. 3 is a graph showing the experimental results of example 9 of the present invention.
Detailed Description
The technical scheme of the invention is further illustrated and described below by the specific embodiments in combination with the accompanying drawings.
Example 1: preparation of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-p-fluorophenyl semicarbazide (J5)
(1) Intermediate 3-N, N-dimethylamino-1H-indol-3-yl-2-propen-1-one: to a dry round bottom flask was added 0.318g (0.002 mol) of 3-acetylindole and 5.5mL (0.04 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) in this order, followed by stirring, heating to 110℃and refluxing, incubating for 8h, and monitoring by TLC. After the reaction is completed, cooling to room temperature, precipitating yellow crystals, and carrying out suction filtration and drying to obtain yellow solid 3-N, N dimethylamino-1H-indol-3-yl-2-propylene-1-one. Yield 75%80％。 1 H-NMR(DMSO-d 6 )：δ11.60(s，1H)，8.26(d，J＝7.7Hz，1H)，8.14(s，1H)，7.53(d，J＝12.5Hz，1H)，7.40(d，J＝8.0Hz，1H)，7.13(dt，J＝7.1&1.2Hz，1H)，7.09(dt，J＝8.0&1.2Hz，1H)，5.77(d，J＝12.5Hz，1H)，2.97(s，6H，)；MS(ESI)m/z[M+H]+calcd.for C 13 H 15 N 2 O + ，215.12；found 215.12。
(2) Preparation of intermediate 6- (1H-indol-3-yl) -2-methylnicotinic acid ethyl ester: to a dry round bottom flask was added 1.07g (5 mmol) of 3-N, N-dimethylamino-1H-indol-3-yl-2-propen-1-one prepared in step (1), 0.7mL (5.5 mmol) of ethyl acetoacetate, 0.42g (5.5 mmol) of ammonium acetate, 15mL of glacial acetic acid, followed by stirring and heating to 125℃and refluxing for 5H, followed by TLC monitoring. After the reaction is completed, cooling to room temperature, extracting 3 times by using 30mL of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering, purifying a crude product by column chromatography (ethyl acetate petroleum=1:4), and obtaining yellow solid 6- (1H-indol-3-yl) -2-methylnicotinic acid ethyl ester, wherein the yield is 70% -75%; 1 H NMR(600MHz，DMSO-d 6 )：δ11.73(brs，1H)，8.59(d，J＝7.3Hz，1H)，8.27(d，J＝2.5Hz，1H)，8.13(d，J＝8.4Hz，1H)，7.80(d，J＝8.0Hz，1H)，7.47(d，J＝7.3Hz，1H)，7.24-7.07(m，2H)，4.32(q，J＝7.0Hz，2H)，2.83(s，3H)，1.35(t，J＝7.1Hz，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ166.5，159.1，158.1，138.7，137.6，128.5，125.8，122.5，122.4，120.9，120.4，116.8，115.0，112.4，61.0，25.5，14.6；HRMS(+)calcd for C 17 H 17 N 2 O 2 [M+H] + 281.1285 found 281.1277。
(3) Preparation of intermediate 6- (1H-indol-3-yl) -2-methylnicotinyl hydrazide: to a dry round bottom flask was added 2.80g (10 mmol) of ethyl 6- (1H-indol-3-yl) -2-methylnicotinate prepared in step (2), 10mL of ethanol, 0.42g (5.5 mmol) of ammonium acetate, 5mL of hydrazine hydrate (100 mmol) in sequence, heated to 78℃with stirring, refluxed for 5H and monitored by TLC. Cooling to room temperature after the reaction is completed, filtering, and drying 6- (1H-indol-3-yl) -2-methyl nicotinyl hydrazide, wherein the yield is 70% -75%; 1 H NMR(600MHz，DMSO-d 6 )：δ11.61(brs，1H)，9.54(s，1H)，8.55(d，J＝7.7Hz，1H)，8.17(d，J＝1.8Hz，1H)，7.74-7.69(m，1H)，7.69-7.64(m，1H)，7.46(d，J＝7.7Hz，1H)，7.24-7.08(m，2H)，4.54(brs，2H)，2.64(s，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ168.1，156.0，155.6，137.5，136.0，127.1，126.3，125.8，122.3，120.6，116.4，115.3，112.3，23.7；HRMS(+)calcd for C 15 H 15 N 4 O[M+H] + 267.124 found 267.1232。
(4) 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-p-fluorophenyl semicarbazide (J5): in a dry reaction bottle, 6- (1H-indol-3-yl) -2-methyl nicotinyl hydrazide (0.266 g,1 mmol) prepared in the step (3) is added sequentially, ethanol (5 mL) and p-fluorophenyl isocyanate (0.137 g,1 mmol) are heated to 70-80 ℃ under stirring, and the temperature is kept for reaction for 8-10H. TLC detects completion of the reaction and stops the reaction. Cooled, filtered, washed with toluene and dried. To obtain 0.32g of white solid product 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-o-methylphenyl thiosemicarbazide with the yield of 77%; a yellow solid was used as the starting material, 1 H NMR(600MHz，DMSO-d 6 )：δ11.63(brs，1H)，10.08(brs，1H)，8.95(brs，1H)，8.56(d，J＝7.5Hz，1H)，8.26(brs，1H)，8.21(brs，1H)，7.83(brs，1H)，7.77(d，J＝8.1Hz，1H)，7.55-7.50(m，2H)，7.46(d，J＝7.5Hz，1H)，7.22-7.09(m，4H)，2.70(s，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ168.7，168.4，156.4，156.1(d，J＝23Hz)，137.5，136.5，136.4，127.4，125.8，125.3，122.3，120.7，119.3，116.3，115.7，115.6，115.2，112.3，107.4，23.8；HRMS(+)calcd for C 22 H 19 FN 5 O 2 + [M+H] + 404.1517，found：404.1524.
example 2: preparation of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-p-methoxyphenyl semicarbazide (J9)
Steps (1) to (3) are as in example 1
(4) In a dry reaction flask, 6- (1H-indol-3-yl) -2-methylnicotinyl hydrazide (0.266 g,1 mmol) prepared in step (3), ethanol (5 mL) was added sequentially toMethoxy phenyl isocyanate (0.149 g, lmmol) is heated up to 70-80 ℃ under stirring, and the reaction is carried out for 8-10h with heat preservation. TLC detects completion of the reaction and stops the reaction. Cooled, filtered, washed with toluene and dried. To obtain 0.32g of white solid product 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-o-methylphenyl thiosemicarbazide with the yield of 77%; a white solid was used as a solid, 1 H NMR(600MHz，DMSO-d 6 )：δ11.61(d，J＝1.7Hz，1H)，10.05(d，J＝1.5Hz，1H)，8.70(s，1H)，8.57(d，J＝7.7Hz，1H)，8.20(d，J＝2.8Hz，1H)，8.14(d，J＝1.5Hz，1H)，7.84(d，J＝7.9Hz，1H)，7.76(d，J＝8.3Hz，1H)，7.47(d，J＝7.5Hz，1H)，7.43-7.38(m，2H)，7.21-7.12(m，2H)，6.88(d，J＝9.0Hz，2H)，3.36(s，3H)，2.71(s，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ168.7，156.4，156.2，156.1，155.0，137.5，136.4，133.2，127.4，125.8，125.4，122.3，120.8，120.7，116.3，115.3，114.3，114.3，112.3，55.6，23.8；HRMS(+)calcd for C 23 H 22 N 5 O 3 + [M+H] + 416.1717，found 416.1717.
example 3: preparation of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-chlorophenyl semicarbazide (J14)
Steps (1) to (3) are as in example 1
(4) In a dry reaction bottle, 6- (1H-indol-3-yl) -2-methyl nicotinyl hydrazide (0.266 g,1 mmol) prepared in the step (3) is added sequentially, ethanol (5 mL) and o-chlorophenyl isocyanate (0.153 g,1 mmol) are heated to 70-80 ℃ under stirring, and the reaction is carried out for 8-10H under heat preservation. TLC detects completion of the reaction and stops the reaction. Cooled, filtered, washed with toluene and dried. To obtain 0.32g of white solid product 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-o-methylphenyl thiosemicarbazide with the yield of 77%; a white solid was used as a solid, 1 H NMR(600MHz，DMSO-d 6 )：δ11.62(d，J＝1.7Hz，1H)，10.23(s，1H)，8.99(brs，1H)，8.57(d，J＝7.5Hz，1H)，8.35(brs，1H)，8.21(d，J＝2.8Hz，1H)，8.15(d，J＝7.7Hz，1H)，7.83-7.80(m，1H)，7.79-7.75(m，1H)，7.50-7.42(m，2H)，7.35-7.29(m，1H)，7.18(dtd，J＝1.2，7.2，18.1Hz，2H)，7.06(dt，J＝1.5，7.7Hz，1H)，2.71(s，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ168.7，156.6，156.0，155.5，137.6，136.3，129.7，128.1，127.5，125.8，125.2，124.0，122.5，122.4，121.8，121.7，121.6，120.7，116.4，115.2，112.3，23.7；HRMS(+)calcd for C 22 H 19 ClN 5 O 2 + [M+H] + 420.1222，found：420.1220.
example 4: preparation of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-methylphenyl thiosemicarbazide (J20)
Steps (1) to (3) are as in example 1
(4) In a dry reaction bottle, 6- (1H-indol-3-yl) -2-methyl nicotinyl hydrazide (0.266 g,1 mmol) prepared in the step (3) is added sequentially, ethanol (5 mL) and o-tolylthioisocyanate (0.149 g,1 mmol) are heated to 70-80 ℃ under stirring, and the temperature is kept for reaction for 8-10H. TLC detects completion of the reaction and stops the reaction. Cooled, filtered, washed with toluene and dried. To obtain 0.32g of white solid product 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-o-methylphenyl thiosemicarbazide with the yield of 77%; 1 H NMR(400MHz，DMSO-d 6 )：δ11.63(brs，1H)，10.36(s，1H)，9.73-9.60(m，1H)，9.55(brs，1H)，8.57(d，J＝7.1Hz，1H)，8.22(brs，1H)，8.06(brs，1H)，7.77(d，J＝8.1Hz，1H)，7.47(d，J＝7.3Hz，1H)，7.32-7.11(m，6H)，2.72(s，3H)，2.24(brs，3H)； 13 C NMR(100MHz，DMSO-d 6 )：δ168.2，164.5，159.8，156.5，147.7，137.5，136.9，130.6，130.5，129.6，127.5，127.2，126.3，125.8，124.7，122.4，122.3，120.7，116.1，115.2，112.3，24.1，18.2；HRMS(+)calcd for C 23 H 22 N 5 OS[M+H] + 416.154 found 416.1546。
example 5: preparation of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-methylphenyl semicarbazide (J25)
Steps (1) to (3) are the same as in example 1.
(4) In a dry reaction flask, 6- (1H-indol-3-yl) -2-methylnicotinyl hydrazide (0.266 g,1 mmol) prepared in step (3), ethanol (5 mL), o-methylbenzene were added sequentiallyThe isocyanate (0.133 g,1 mmol) was then heated to 70-80℃with stirring and incubated for 8-10h. TLC detects completion of the reaction and stops the reaction. Cooled, filtered, washed with toluene and dried. To give 0.30g of 1- (2- (1H-indol-3-yl) -6-methylnicotinyl) -4-o-methylphenyl semicarbazide (J25) as a white solid in 77% yield; 1 H NMR(600MHz，DMSO-d 6 )：δ11.62(brs，1H)，10.13(brs，1H)，8.57(d，J＝7.5Hz，1H)，8.51(brs，1H)，8.20(brs，1H)，8.09(s，1H)，7.84(d，J＝7.0Hz，1H)，7.77(d，J＝7.9Hz，1H)，7.72(brs，1H)，7.47(d，J＝7.5Hz，1H)，7.23-7.06(m，4H)，7.02-6.94(m，1H)，2.71(s，3H)，2.26(s，3H)； 13 C NMR(150MHz，DMSO-d 6 )：δ169.8，168.7，166.8，156.5，156.2，156.0，137.7，137.5，136.4，130.7，127.4，126.6，125.8，125.3，123.7，122.2，120.7，116.3，115.3，112.3，23.8，18.3；HRMS(+)calcd for C 23 H 22 N 5 O 2 [M+H] + 400.1768 found 400.1773。
example 6: orphan nuclear receptor Nur77 can be used as a drug target for resisting hepatic fibrosis
Hepatic Stellate Cells (HSCs) act as pharmacophore cells for liver fibrosis, HSCs activation being the onset of liver fibrosis formation. In hepatic stellate cells LX2, this example shows that the lack of active Nur77 in LX2 cells results in the expression of HSCs activation standard α -SMA protein by over-expressing and knocking out Nur77, and inducing LX2 activation by TGF- β1, whereas over-expression of Nur77 significantly inhibits HSCs activation, as shown in fig. 1 (a-C), consistent with the results reported by Palumbo-Zerr K et al, indicating that Nur77 is a good target for anti-hepatic fibrosis treatment.
Example 7: drug efficacy screening of J20 and J25 for TGF- β1 induced activation of HSCs
(1) In LX2 cells, this example can be used to effectively inhibit hepatic stellate cell activation by creating a stable transfection-based CAGA (12) - α -SMA reporter plasmid as a lead compound for high throughput screening systems. In TGF-. Beta.1 (5 ng/mL) induced LX2 cells, the compounds prepared in examples 1 to 5 were allowed to act at 10. Mu.M for 24h, and the results of the α -SMA-Luciferase Assay reporter gene experiments showed that J5, J9, J14, J20 and J25 all had good α -SMA transcriptional activity, with J20 and J25 inhibitory activities greater than 50%, and were subsequently studied further with the leads J20 and J25.
TABLE 1 alpha-SMA luciferase reporter drug screening
(2) Compounds were tested for in vitro toxicity using the MTT method. In this experiment, the compound was set at 5 concentrations of 0.625. Mu.M, 1.25. Mu.M, 2.5. Mu.M, 5. Mu.M, 10. Mu.M, and the dosing time was 24 hours, the OD value thereof was measured, and the IC50 value was calculated from the measured absorbance value (OD value). Results both the J20 prepared in example 1 and the J25 prepared in example 2 have IC 50's of greater than 79. Mu.M in normal hepatocytes and hepatic stellate cells LX2, indicating less toxicity, as shown in Table 2.
Table 2 MTT method for compound cytotoxicity screening (IC 50 μM)
(3) And establishing a luciferase reporter gene drug screening system for the hepatic fibrosis marker gene alpha-SMA, namely an alpha-SMA luciferase reporter gene drug screening system, and carrying out reporter gene detection on the compounds J20 and J25 with smaller cytotoxicity. After stimulation with TGF- β1 using LX2 cells and treatment with the concentrations of the candidate drugs J20 and J25 (10 μm) for 24 hours, the results show that compounds J20 and J25 can significantly inhibit α -SMA luciferase activity by reporter gene detection, indicating that J20 and J25 can significantly inhibit transcription activity of hepatic stellate cell activation markers α -SMA, as shown in fig. 2.
Example 8: j20 and J25 inhibit hepatic stellate cell activation depending on Nur77 induced expression
This example investigated the expression of Nur77 under conditions of TGF-beta pathway activation of J20 and J25 by treating LX2 cells with TGF-beta 1 alone or in combination with J20 or J25. The results show that the separate treatment of J20 can obviously induce Nut77 to express, J25 is weaker, and interestingly, both J20 and J25 induce Nur77 to express in a large amount under the condition that cells are added with TGF-beta, and the antagonism of J20 and J25 on TGF-beta induced alpha-SMA is reversed if Nur77 is knocked down, so that J20 and J25 depend on Nur77 to express, inhibit hepatic stellate cell activation, and the results are shown in figure 2.
Example 9: anti-hepatic fibrosis in J20 and J25
The present embodiment is implemented by CCl 4 Mice liver fibrosis model was induced to evaluate the anti-liver fibrosis in vivo activity for J20 and J25 prepared in examples 4 and 5: first 20% CCl was used 4 Model for inducing liver fibrosis in mice, CCl4 alone treatment group, CCl using normal mice as control 4 +J20，CCl 4 +J25 dosing group, dosing time and dosing concentration were determined based on drug passage and drug passage, J20 and J25 were dosed in high and low doses (low dose 15mg/kg, high dose 30 mg/kg) and compound J20 and J25 were shown to improve mouse hepatocyte inflammation dose-dependently by HE staining results, reducing CCl 4-induced liver injury and fibrosis. Meanwhile, the sirius red staining results show that J20 and J25 significantly improve CCl 4-induced collagen deposition. These results indicate that J20 and J25 have good anti-liver fibrosis effects in mice, as shown in figure 3.
In conclusion, the results show that the indole derivatives prepared in the embodiments 1 to 5 have certain anti-hepatic fibrosis effects, wherein J20 and J25 have good effects on hepatic fibrosis, have no adverse reaction, can obviously induce Nur77 expression, thereby inhibiting TGF-beta 1-induced in vitro Hepatic Stellate Cell (HSCs) activation and slowing CCl 4-induced mouse hepatic fibrosis, and have good application prospects in the aspects of treating, relieving or improving hepatic fibrosis diseases.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, i.e., the invention is not to be limited to the details of the invention.
Claims (10)
1. Nur 77-targeted indoleAn indole derivative characterized in that: the structure is as followsWherein R is Cl, F, CH 3 Or OCH (optical wavelength) 3 。
2. An indole derivative according to claim 1, characterized in that: which is at least one of 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-R-phenylsemicarbazide and 1- (2- (1H-indol-3-yl) -6-methyl nicotinyl) -4-o-methylphenyl thiosemicarbazide.
3. Use of an indole derivative according to claim 1 or 2 for the preparation of a composition for the treatment of liver fibrosis diseases, characterized in that: the active ingredients of the composition comprise the indole derivative or pharmaceutically acceptable salts thereof.
4. A use according to claim 3, wherein: the effective component of the composition is the indole derivative or pharmaceutically acceptable salt thereof.
5. Use according to claim 3 or 4, characterized in that: the composition is in the form of tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, medicated wine, tincture, distillate or film.
6. Use according to claim 3 or 4, characterized in that: the in vivo dose of the indole derivative or the pharmaceutically acceptable salt thereof is 15-30mg/kg.
7. A composition for treating liver fibrosis, characterized by: an indole derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The composition of claim 7, wherein: an indole derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The composition of claim 7 or 8, wherein: the preparation is in the form of tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, medicated wine, tincture, distillate or film.
10. The composition of claim 7 or 8, wherein: the in vivo dose of the indole derivative or the pharmaceutically acceptable salt thereof is 15-30mg/kg.
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| CN110156672A (en) * | 2019-05-22 | 2019-08-23 | 浙江师范大学 | A kind of application of semicarbazide compound preparation method and obtained compound |
| CN112679409A (en) * | 2021-01-11 | 2021-04-20 | 浙江师范大学行知学院 | 4-indole-substituted thiosemicarbazide derivative and preparation method and application thereof |
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| CN110156672A (en) * | 2019-05-22 | 2019-08-23 | 浙江师范大学 | A kind of application of semicarbazide compound preparation method and obtained compound |
| CN112679409A (en) * | 2021-01-11 | 2021-04-20 | 浙江师范大学行知学院 | 4-indole-substituted thiosemicarbazide derivative and preparation method and application thereof |
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| Title |
|---|
| Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators;Hongyu Hu;Molecules;第27卷(第5期);1698 * |
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