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4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogue as PARP inhibitor

A compound, CH3 technology, applied in anti-inflammatory agents, organic chemistry, drug combination, etc., can solve problems such as unrealized treatment

Active Publication Date: 2015-10-14
HUBEI BIO PHARMA IND TECHCAL INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] While efforts to develop PARP-1 inhibitors for the treatment of cancer and other diseases have continued, satisfactory treatments have not been achieved, thus necessitating the development of new PARP-1 inhibitors

Method used

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  • 4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogue as PARP inhibitor
  • 4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogue as PARP inhibitor
  • 4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogue as PARP inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] 6-Fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

[0265]

Embodiment 1A

[0267] tert-butyl 4-(p-toluenesulfonyloxymethyl)piperidine-1-carboxylate

[0268]

[0269] Under nitrogen protection at 0°C, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol), triethylamine (5.64 g, 55.8 mmol) and DMAP (1.13 g, 9.3 mmol) in dichloromethane (100 ml) was added in portions to TosCl (9.73 g, 51.2 mmol), stirred at 17 °C for 2 hours, quenched by adding water (100 ml), and the aqueous layer was washed with dichloromethane (100 mL × 2) extraction, the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to obtain the title compound (white solid, 17 g, 99% yield). LCMS(ESI)m / z:370(M+1).

Embodiment 1B

[0271] tert-Butyl 4-(cyanomethyl)piperidine-1-carboxylate

[0272]

[0273] Example 1A (19 g, 55.7 mmol), a mixture of sodium cyanide (8.19 g, 167 mmol) in dimethyl sulfoxide (100 ml) was reacted at 100°C for 16 hours. After cooling to room temperature, dilute with water (200 mL), extract the aqueous layer with ethyl acetate (100 mL × 3), wash the combined organic layer with water (50 mL), brine (50 mL), dry over sodium sulfate, filter and evaporate , provided the title compound (11 g) which was used directly in the next step without further purification. LCMS(ESI)m / z:225(M+1)

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Abstract

The invention discloses a series of 4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogues as a PARP inhibitor and particularly discloses the compound represented as the formula (I) as the PARP inhibitor or pharmaceutically acceptable salts thereof.

Description

technical field [0001] The present invention relates to a series of analogs of 4H-pyrazolo[1,5-α]benzimidazole compounds as PARP inhibitors. Specifically, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as a PARP inhibitor. Background technique [0002] PARP is a family of enzymes that catalyze the addition of ADP-ribose residues to various target proteins. Up to 18 subtypes have been identified and characterized so far. Despite the large number of enzymes in this family, PARP-1 is responsible for more than 90% of ADP-ribosylation in cells. [0003] PARP-1 has been associated with DNA repair and maintenance of genome function. Following DNA damage, PARP-1 is activated transiently by binding to DNA breaks. After the structural change, it begins to use NAD+ to synthesize poly(ADP) ribose as a signal for other repair enzymes (eg, DNA ligase III, DNA polymerase beta). The binding and activation of PARP-1 (...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61P35/00A61P25/00A61P9/10A61P29/00A61P3/10
CPCC07D487/04C07D519/00
Inventor 丁照中陈曙辉李刚王才林张志博
Owner HUBEI BIO PHARMA IND TECHCAL INST
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