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Benzimidazole derivatives and their use as protein kinase inhibitors

a technology of benzimidazole and derivatives, applied in the field of pyrazole compounds, can solve the problems of mitotic abnormalities, cell cycle arrest and/or cell apoptosis, and cyclin e in solid tumours, and achieve the effects of improving the prognosis of patients

Inactive Publication Date: 2011-09-15
ASTEX THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Failure to satisfy the pre-requisite biochemical criteria at a given cell cycle checkpoint, i.e. failure to form a required cdk / cyclin complex, can lead to cell cycle arrest and / or cellular apoptosis.
Conversely over expression of cyclin E in solid tumours has been shown to correlate with poor patient prognosis.
Furthermore, it has been found (Adams, 2001) that mutation or disruption of the Aurora A gene in various species leads to mitotic abnormalities, including centrosome separation and maturation defects, spindle aberrations and chromosome segregation defects.
Hyperphosphorylation of Tau disrupts its normal binding to microtubules and may also lead to the formation of intra-cellular Tau filaments.
It is believed that the progressive accumulation of these filaments leads to eventual neuronal dysfunction and degeneration.

Method used

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  • Benzimidazole derivatives and their use as protein kinase inhibitors
  • Benzimidazole derivatives and their use as protein kinase inhibitors
  • Benzimidazole derivatives and their use as protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 2-(4-Nitro-1H-pyrazol-3-yl)-1H-benzimidazole

[0558]

[0559]A mixture of o-phenylenediamine (1.51 g, 14.0 mmol), 4-amino-1H-pyrazole-3-carboxylic acid (2.00 g, 12.7 mmol), EDC (2.93 g, 15.3 mmol) and HOBt (2.08 g, 15.3 mmol) in DMF (70 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the residue dissolved in AcOH (150 ml) and heated at reflux for 3 h. The solvent was removed in vacuo, water (100 ml) added and the resultant solid collected by filtration washing with water. The solid was dried through azeotrope with toluene (3×150 ml) yielding 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole as a yellow solid (1.44 g, 50%). A 100 mg portion was purified by preparative LC / MS and following evaporation of product containing fractions gave 70 mg of the title compound. (LC / MS: Rt 1.72, [M+H]+ 229.61).

example 2

Synthesis of 3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-ylamine

[0560]

[0561]A mixture of 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (1.34 g, 5.85 mmol) and 10% Pd / C (0.13 g) in DMF (200 ml) was subjected to an atmosphere of hydrogen at room temperature for 36 h. The reaction mixture was filtered through a plug of Celite and reduced in vacuo. The residue was partitioned between EtOAc and water and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was azeotroped with toluene (3×150 ml) yielding 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a purple solid (0.32 g, 26%). (LC / MS: Rt 0.97, [M+H]+ 199.62).

example 3

Synthesis of N-[3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide

[0562]

[0563]A mixture of benzoic acid (34 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (5 ml) was stirred at room temperature for 24 h. The solvent was removed in vacuo, the crude product purified by preparative LC / MS and following reduction of the product-containing fractions N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide was obtained as a brown solid (23 mg, 30%). (LC / MS: Rt 3.66, [M+H]+ 303.67).

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Abstract

The invention provides compounds of the formula (I):The compounds have activity against cyclin dependent kinases, glycogen synthase kinase and Aurora kinases and are therefore useful to treat cancer and viral diseases.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 10 / 564,166, which published as U.S. 2007-0135477 A1 on Jun. 14, 2007, the contents of which are incorporated herein by reference. U.S. application Ser. No. 10 / 564,166 is a Section 371 national phase application of PCT International Application No. PCT / GB2004 / 002824, filed Jul. 5, 2004, and published in English as WO 2005 / 002552 on Jan. 13, 2005. PCT / GB2004 / 002824 claims the priority of GB Application No. 0315657.7, filed Jul. 3, 2003; GB Application No. 0324919.0, filed Oct. 24, 2003; U.S. Provisional Application No. 60 / 484,685, filed Jul. 3, 2003; and U.S. Provisional Application No. 60 / 514,374, filed Oct. 24, 2003.FIELD OF THE INVENTION[0002]This invention relates to pyrazole compounds that inhibit or modulate the activity of Cyclin Dependent Kinases (CDK), Glycogen Synthase Kinases (GSK) and Aurora kinases to the use of the compounds in the treatment or prophylax...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61P35/04A61P35/02A61K31/00A61K31/4184A61P31/10A61P35/00C07D401/14C07D405/14C07D409/14C07D413/14
CPCA61K31/00A61K31/4184C07D401/14C07D403/04C07D405/14C07D409/14C07D413/14A61P25/00A61P31/00A61P31/10A61P31/12A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P43/00A61K31/5377A61K45/06C07D471/04C07D513/04
Inventor BERDINI, VALERIOO'BRIEN, MICHAEL ALISTAIRCARR, MARIA GRAZIAEARLY, THERESA RACHELNAVARRO, EVA FIGUEROAGILL, ADRIAN LIAMHOWARD, STEVENTREWARTHA, GARYWOOLFORD, ALISON JO-ANNEWOODHEAD, ANDREW JAMESWYATT, PAUL GRAHAM
Owner ASTEX THERAPEUTICS LTD
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