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Pyrrolotriazinone derivatives

A pyrrolidinyl compound technology, applied in the field of preparing these compounds, treating diseases, and preparing drugs, achieving good tolerance

Active Publication Date: 2015-01-07
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Findings Provide Evidence for Antiangiogenic Targeting of PARP, Adding New Therapeutic Implications for Use of PARP Inhibitors in Cancer Treatment

Method used

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  • Pyrrolotriazinone derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] Synthesis of 2-p-tolyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one ("A1")

[0268]

[0269] Triethylamine (277 μl, 2.00 mmol) was added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (250 mg, 2.00 mmol) in acetonitrile (4.0 ml). A solution of 4-methylbenzoyl chloride (264 μl, 2.00 mmol) in dichloromethane (0.6 ml) was added dropwise under external cooling with ice. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and saturated NaHCO 3 solution. A precipitate formed which was filtered off, washed with water and dried under vacuum to give 1-(4-methyl-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as white crystals; HPLC / MS 1.57 min (A), [M+H] 244;

[0270] 1 H NMR (400 MHz, DMSO-d 6 ) δ [ppm] 11.42 (s, 1H), 7.83 (d, J =8.1, 2H), 7.42 (s, 1H), 7.32 (d, J=8.0, 2H), 6.96 (m, 1H), 6.83 (dd, J =4.2, 1.8, 1H), 6.78 (bs, 1H), 6.08 (dd, J =4.1, 2.8, 1H), 2.38 (s, ...

Embodiment 2

[0274] Synthesis of 4-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-benzoic acid methyl ester ("A2")

[0275] Triethylamine (554 μl, 4.00 mmol) was added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (501 mg, 4.00 mmol) in acetonitrile (8.0 ml). Then, a suspension of methyl 4-chlorocarbonylbenzoate (264 μl, 2.00 mmol) in dichloromethane (4.0 ml) was added slowly. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was triturated with water. The solid was filtered off, washed with water, and dried under vacuum to give methyl 4-[(2-carbamoylpyrrol-1-yl)carbamoyl]benzoate as white crystals; HPLC / MS 1.45 min (C) , [M+H] 288.

[0276] Sodium (65.3 mg, 2.84 mmol) was dissolved in methanol (5.0 ml). Then, 4-[(2-carbamoylpyrrol-1-yl)carbamoyl]benzoate (544 mg, 1.90 mmol) was added. The mixture was irradiated at 150 °C for 1 h in a microwave reactor. The solvent was evaporated and the residue was ...

Embodiment 3

[0287] 2-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one ("A5 ")Synthesis

[0288]

[0289] To 4-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-benzoic acid methyl ester (109 mg, 0.405 mmol) in THF (1.6 ml) was added cerium(III) chloride (110 mg, 0.445 mmol). The mixture was stirred at room temperature for 1 hour. Methylmagnesium chloride (20% solution in THF, 617 μl, 1.70 mmol) was then added and the reaction mixture was stirred at room temperature for another hour. Water was carefully added to the reaction mixture. The mixture was partitioned between 1 N HCl and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using cyclohexane / ethyl acetate as eluent to give 2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-pyrrolo[ 2,1-f][1,2,4]triazin-4-one, light brown powder; HPLC / MS 1.58 min (C), [M+H] 270;

[0290] 1 H NMR (400 MHz, DMSO-d 6 ) δ [ppm] 1...

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Abstract

Compounds of the formula (I) in which X, R1 and Y have the meanings indicated in Claim 1, are inhibitors of Tankyrase and PARP-1 and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of imflamination.

Description

Background of the invention [0001] The object of the present invention was to discover novel compounds having valuable properties, in particular those compounds which can be used for the preparation of medicaments. [0002] The present invention relates to bicyclic pyrazinone derivatives which inhibit the activity of tankyrase (TANK) and poly(ADP-ribose) polymerase PARP-1. Thus, the compounds of the present invention are useful in the treatment of diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injuries and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of treating diseases using pharmaceutical compositions comprising these compounds. [0003] The ribozyme poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family. This growing family of enzymes consists of PARPs such as PARP-1, PARP-2, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61P9/00A61P35/00A61P29/00
CPCC07D487/04A61K31/53A61P19/02A61P25/00A61P29/00A61P35/00A61P35/02A61P43/00A61P9/00
Inventor D.多施H-P.布赫斯塔勒
Owner MERCK PATENT GMBH
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