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Pyrrolo-triazinone derivatives

A compound and solvate technology, applied in the field of pyrrolotriazinone derivatives, can solve problems such as inability to repair DNA fragments

Active Publication Date: 2016-06-08
NANJING GEAR PHARMA & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that in the homologous recombination repair after DNA damage, some key gene proteins (including BRCA1, BRCA2, XRCC1, XRCC2, RAD51, NBS1, FANCA, FANCC, CHK1, MRE11, RAD50, ATM, ATR, etc. ) cells are highly sensitive to PARP inhibitors, and cannot effectively repair damaged DNA fragments in the presence of PARP inhibitors (KummarS, ChenA, ParchmentRE.etal.BMCMed, 2012, 10, 25)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] 1-[3-(4-Cyclopentylcarbonyl-1-piperazine-1-formyl)-benzyl]-3H-pyrrolo[1,2-d][1,2,4]triazine-4 -Synthesis of ketone (1)

[0082]

[0083] 3-(4-Oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl-methyl)benzoic acid (2.0 g, 7.43 mmol) , cyclopentyl-piperazin-1-yl-methanone (1.4g, 7.68mmol), O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoroborate ( TBTU) (3.6g, 11.21mmol) and N,N-diisopropylethylamine (2.9g, 22.44mmol) were added to dimethylformamide (20ml) and stirred for 3 hours. Water (100ml) was added, and the pH of the reaction solution was adjusted with 1N HCl under stirring. A large amount of solids were precipitated, and hydrochloric acid was continued to be added dropwise until no solids precipitated. Filter, wash the filter cake successively with a large amount of water and a small amount of ethanol, and dry in vacuum to obtain 1-[3-(4-cyclopentylcarbonyl-1-piperazine-1-formyl)-benzyl]-3H-pyrrolo [1,2-d][1,2,4]triazin-4-one (1) white solid (3.0 g, 93.0%...

Embodiment 2

[0088] 1-[3-(4-Cyclopropylcarbonyl-1-piperazine-1-formyl)-4-fluorophenyl]-3H-pyrrolo[1,2-d][1,2,4]tri Synthesis of oxazin-4-one (4)

[0089]

[0090] 2-Fluoro-5-(4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl-methyl)benzoic acid (1.5g , 5.22mmol), cyclopropyl-piperazin-1-yl-methanone (0.48g, 5.58mmol), O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoro Borate ester (TBTU) (2.5g, 7.79mmol) and N,N-diisopropylethylamine (2.0g, 15.50mmol) were added to dimethylformamide (15ml), and stirred for 2-3 hours. Water (100ml) was added, and the pH of the reaction solution was adjusted with 1N HCl under stirring. A large amount of solids were precipitated, and hydrochloric acid was continued to be added dropwise until no solids precipitated. Filtration, the filter cake was successively rinsed with a large amount of water and a small amount of ethanol, and dried in vacuum to obtain 1-[3-(4-cyclopentylcarbonyl-1-piperazine-1-formyl)-4-fluorophenyl]-3H - pyrrolo[1,2-d][1,2,4]...

Embodiment 3

[0095] To assess the inhibitory effect of compounds, the IC was determined using the following assay 50 value.

[0096] Using the Alarmblue method to determine the IC of the test sample and positive control AZD2281 in MDA-MB-436 tumor cells 50 , 9 concentration gradients (including 0 concentration) were set up for each compound, and 2 replicate wells were used.

[0097] MDA436 cells were cultured in MEM complete medium (containing 10% fetal bovine serum, 100 U·mL -1 Penicillin, 100 μg mL -1 Streptomycin), at 37°C, 5% CO 2 , 2 to 3 generations under 95% air culture conditions.

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PUM

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to pyrrolo-triazinone derivatives and the application thereof in drugs. More specifically, the related compounds can restrain the activity of poly(ADP-ribose)polymerase, and the poly ADP-ribose polymerase is also named poly(ADP-ribose)synthetase and poly ADP-ribosyltransferase and is generally called PARP. The compounds are characterized in that for the compound shown in the formula (1), X can be NRX or CRXRY; if X is NRX, n is 1 or 2; if X is CRXRY, n is 1; RX can be H, substitutional C1-20 alkyl, C5-20 aryl, C3-20 heterocyclic radical, acylamino, thioamide, ester, acyl or sulfonyl; RY can be H, hydroxyl or amino; or RX and RY can form spiro-C3-7-hydrocarbon radical or heterocyclic radical together; R2 and R3 are both H, or when X=CRXRY, R2, R3, RX and RY and carbon atoms connected with R2, R3, RX and RY form substitutional dense aromatic nucleus; R1 is H or halogen; R4 is H or halogen.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to pyrrolotriazinone derivatives and their use in medicine. Background technique [0002] The compounds of the present invention are useful for inhibiting the activity of poly(ADP-ribose) polymerase, also known as poly(ADP-ribose) synthetase and poly ADP-ribosyltransferase, commonly known as PARP. [0003] This enzyme is a protease that exists in most eukaryotic cells and has polyadenylate diphosphate-ribose (PAR) catalytic activity, and is involved in the perception and repair of single-strand DNA damage. There are about 18 subtypes of this enzyme family, which can be divided into three groups according to the degree of homology: PARP-1 group, including PARP-1~PARP-4, PARP-6, PARP-8 and PARP- 16; tankyrase group, including PARP-5a~PARP-5c; Group III, including PARP-7, PARP-9~PARP-15 (NguewaPA, FuertesMA, ValladaresB, etal.ProgBiophysMolBiol, 2005, 88 (1): ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61K45/06A61P9/00A61P9/10A61P31/12A61P7/04A61P35/00A61P25/00
CPCC07D487/04
Inventor 王小龙李福卫
Owner NANJING GEAR PHARMA & TECH CO LTD
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