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Application of phthalazine derivative to treatment of hepatic fibrosis diseases

A technology of liver fibrosis and derivatives, which is applied in the field of phthalazine derivatives in the treatment of liver fibrosis, can solve the problems of unsatisfactory results in the targeted treatment of fibrosis, and achieve the effect of improving liver fibrosis

Active Publication Date: 2022-04-12
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Targeted treatment of fibrotic diseases has not yet achieved satisfactory results

Method used

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  • Application of phthalazine derivative to treatment of hepatic fibrosis diseases
  • Application of phthalazine derivative to treatment of hepatic fibrosis diseases
  • Application of phthalazine derivative to treatment of hepatic fibrosis diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The synthetic method of T-5-9:

[0041]

[0042]

[0043]

[0044] Among them: Boc is tert-butoxycarbonyl, PyBOP is 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate; DIEA is N,N -Diisopropylethylamine; (Cl 3 CO) 2 CO is triphosgene.

[0045] tert-butyl 4-((4-((2-fluorophenyl)carbamoyl)phenyl)carbamoyl)piperazine-1-carboxylate (2)

[0046] 4-amino- N -(2-Fluorophenyl)benzamide (1) (4.75 g, 20.64 mmol) was dissolved in 30 mL of anhydrous dichloromethane, and at room temperature, DIEA (7.19 mL, 41.28 mmol) and triphosgene (2.04 g, 6.88 mmol) in dichloromethane (20 mL), cooled to 0°C for 3 hours, then added N -Boc-piperazine (5.77 g, 30.96mmol), stirred overnight at room temperature, TLC detected that the raw materials were completely reacted, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (eluent: dichloromethane: methanol = 50:1 ), to obtain yellow solid 7.12g, productive rate 7...

Embodiment 2

[0055] Human semi-activated hepatic stellate cell line LX-2 cell test

[0056] The method of culturing LX-2 cells in this example: Take out the LX-2 cells from the -80 °C refrigerator, use DMEM medium containing 10% fetal bovine serum, and place them in a 10 cm 2 In a Petri dish, 37 °C, 5% CO 2 Cultivate in an incubator, change the medium, pass passage, and take the 3rd to 6th passage cells for experiments.

[0057] 1. Western Blot experiment

[0058] Human semi-activated hepatic stellate cells LX-2 (5*10 5 each well), and set up ① blank control group, ② TGF-β stimulation group, ③ T-5-9 (0.1 μM) group, ④ T-5-9 (1 μM) group, ⑤ T-5-9 (10 μM) group. When the cell density in the well was 70%, the cells were treated as shown in Table 1, and the lysed protein was quantitatively collected after 24 h, and the expression of Collagen I protein in LX-2 was detected by Western blot method, and the results were analyzed by comparing TGF-β The expression of Collagen I in the stimulatio...

Embodiment 3

[0078] Anti-hepatic fibrosis animal test

[0079] Modeling method of mouse liver fibrosis disease model in this example: 24 male mice (6 weeks old, body weight 18-22 grams) were randomly divided into 4 groups, 6 mice in each group. By injecting 10% carbon tetrachloride (CCl 4 , 0.5 ml / 100 g body weight) for 8 weeks (three times a week) to induce liver fibrosis in wild-type mice. The mice in the control group were intraperitoneally injected with the same amount of olive oil instead of carbon tetrachloride; the mice in the model group were intraperitoneally injected with carbon tetrachloride; the mice in the positive drug group were intraperitoneally injected with CCl 4 , and given colchicine (0.1 mg / kg, once a day, week 5-8); mice in the treatment group were intraperitoneally injected with CCl 4 , and given T-5-9 (12.5mg / kg, once a day, the 5th to 8th week); follow-up experiments and drawings were named: ① control group, ② model group, ③ positive drug group, ④ T-5 -9 groups....

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Abstract

The invention discloses an application of a phthalazine derivative in treatment of hepatic fibrosis diseases, relates to the field of biological medicines, and particularly relates to an application of the phthalazine derivative shown as a compound (I) in treatment of hepatic fibrosis diseases. Pharmacodynamic tests prove that the compound (I) can inhibit hepatic stellate cell activation caused by TGF-beta and has an obvious improvement effect on hepatic fibrosis of carbon tetrachloride modeling mice, so that the compound (I) has an inhibition effect on hepatic fibrosis, can be used for treating hepatic fibrosis, and can be used for preparing medicines for treating hepatic fibrosis diseases. (I).

Description

technical field [0001] The invention relates to the field of medicines, in particular to the application of phthalazine derivatives in treating liver fibrosis. Background technique [0002] Chinese patent CN201810140689.6 discloses a class of H )-ketone structure compounds, and disclosed that this type of compound has PARP (polyadenosine diphosphate-ribose polymerase) inhibitory effect, so it has anti-tumor activity, and this type of compound can be used in combination with other anti-tumor drugs to improve the anti-tumor effect. Tumor efficacy and reduced dose and toxicity effects. In the base excision repair pathway, PARP is a key DNA repair enzyme that regulates cell apoptosis and maintains genome stability. PARP inhibitors hinder the DNA repair process by affecting the function of PARP, and cause the death of cells lacking homologous recombination repair. In recent years, PARP has been widely studied as an antitumor target. Olaparib is the first marketed PARP inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/502A61P1/16
Inventor 徐强徐忆竹吴兴新黄磊翟冰新朱启华
Owner NANJING UNIV
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