New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases

A hepatitis B virus and inhibitor technology, applied in the treatment of diseases related to hepatitis B virus infection, phthalazinone compounds for the treatment or prevention of diseases related to hepatitis B virus infection, liver cancer field

Inactive Publication Date: 2015-09-09
THE WEST CHINA SECOND UNIV HOSPITAL OF SICHUAN +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A series of patent applications for phthalazinone-based PARP inhibitors have been published, including WO2002036576, WO2004080976 and WO200602. It is believed that phthalazinone and its derivatives may be used for the above metabolic, degenerative, inflammatory and tumor diseases However, so far, there has been no discovery that phthalazinones PARP inhibitors have been applied to the treatment and / or prevention of hepatitis virus infection-related diseases

Method used

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  • New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases
  • New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases
  • New application of multi-poly ADP RNA polymerase inhibitor in treating HBV-related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Olaparib increases the probability of chromosome breakage in HL02-H1 cells.

[0049] 1. Hepatitis B virus (HBV) genome-wide transgenic human liver cell line HL02-H1

[0050] HL-7702 cells were cultured in 5cm×5cm culture flasks until the density reached 90%. After trypsinization, re-spread to 6cm petri dishes for a total of 3 dishes and culture overnight. Transfect 10 μg of pcDNA3.1-HBV-wholeGenome plasmid into each plate of cells, and the transfection process is as follows: Add 10 μg of plasmid and TurboFect transfection reagent (Thermo, #R0531) into Opti-MEM serum-free medium, mix well, and let stand for 20 minutes. The mixture was added to the overnight cultured cells, and G418 was added 48 hours later for selection (final concentration 800 μg / ml). Continue to screen for one month, digest the surviving cells, dilute to 4 cells / ml with complete medium, add the diluted cell culture to a 96-well plate, 200 μl per well, to ensure that each well in the 96-well...

Embodiment 2

[0056] Example 2 Olaparib significantly inhibits the proliferation of hepatitis B virus genome-wide transgenic human liver cell line HL02-H1

[0057] In order to further confirm the inhibitory effect of olaparib on the proliferation of HBV-positive cells, the inhibitory effect of olaparib on HBx-positive malignant liver cells HL02-H1 was tested by colony formation assay.

[0058] Cells HL-7702 as the control group and HBV-positive HL02-H1 cells were inoculated into 10 cm diameter culture dishes, and drugs or the same volume of DMSO were added as controls after the cells adhered to the wall. 37°C, 5% CO 2 After culturing for 10 days, the cells were fixed with methanol, stained according to the instructions of the Giemsa stain kit, and the number of clones was counted. The total number of plates required is determined according to the concentration of the drug gradient. The final concentration of olaparib single drug is 0, 0.25, 0.5, 1, 1.5 μM, the dose of cisplatin combined wit...

Embodiment 3

[0060] Example 3. The killing effect of olaparib on hepatitis B virus-positive liver cancer cells (HepG2.2.15) Experimental method: collect logarithmic phase liver cancer cells HepG2 and HepG2.2.15 cells, use a cell counting board to count, adjust the concentration of the cell suspension, The two kinds of cells were respectively added to two 96-well plates, 100ul was added to each well, and the cell density was adjusted to 1000 cells / well, and the edge wells were filled with sterile PBS. Incubate at 37°C in 5% CO2 until the cell monolayer covers the bottom of the well, then add gradient concentrations of olaparib so that the final drug concentration in each well is 0, 2, 2.5, 3.5, 4.5 μM. Three replicate wells were set up for each well. At the same time set the zero well (medium, MTT, dimethyl sulfoxide). After incubating for 16-48 hours under the condition of 5% CO2 and 37° C., 20 μl of MTT solution (5 mg / ml, ie 0.5% MTT) was added to each well, and the culture was continued...

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Abstract

The invention relates to a drug combination of a multi-poly (ADP-ribose) polymerase (PARP) inhibitor, a method of treating or preventing HBV-related diseases by utilizing the drug combination, and the application of the drug combination. More specifically, the invention relates to a drug combination comprising 1-(ciprofloxacin formyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro benzoyl] piperazine, a method of treating or preventing HBV, liver cancer, liver cirrhosis and other HBV-related diseases by utilizing the drug combination, and the application of the drug combination.

Description

1. Technical field [0001] The present invention generally relates to poly(ADP ribose) polymerase (PARP) inhibitors as therapeutic agents for the treatment or prevention of hepatitis virus-associated diseases. Specifically, the present invention relates to phthalazinone compounds for treating or preventing hepatitis B virus infection-related diseases, compositions containing them, treatment methods and uses thereof. More specifically, the present invention relates to 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1) for treating or preventing diseases related to hepatitis B virus infection -phthalazinyl)methyl]-2-fluorobenzoyl]piperazine (also known as Olaparib, Chinese Olaparib), a pharmaceutical composition comprising the inhibitor, and using it to treat hepatitis B virus (Hapatitis BVirus, Hereinafter abbreviated as HBV) Infection-related diseases, especially methods and uses of liver cancer. 2. Background technology [0002] Acute HBV infection often transforms into chr...

Claims

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Application Information

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IPC IPC(8): A61K31/502A61P31/20A61P1/16A61P35/00A61K31/282
Inventor 不公告发明人
Owner THE WEST CHINA SECOND UNIV HOSPITAL OF SICHUAN
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