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Substituted cycloalkenopyrazoles as BUB1 inhibitors for the treatment of cancer

a technology of cycloalkenopyrazole and bub1, which is applied in the field of substituting cycloalkenopyrazole compounds, can solve the problems of severe chromosomal missegregation, cell death, induction of apoptosis,

Inactive Publication Date: 2016-08-16
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast, inhibitors of Bub1 prevent the establishment and / or functionality of the mitotic checkpoint, which finally results in severe chromosomal missegregation, induction of apoptosis and cell death.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

examples

Synthetic Intermediates

Intermediate 1-1-1

Preparation of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carbonitrile

[1059]

[1060]3.40 g of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile (CAS-RN 851776-29-9) (25.5 mmol, 1.00 eq) were dissolved in 35 mL dry DMF under nitrogen atmosphere. 7.05 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (28.1 mmol, 1.10 eq.) and 9.98 g cesiumcarbonate (30.1 mmol, 1.20 eq.) were added and stirred over night at rt. DCM and water were added, the aqueous phase was washed twice with DCM, the organic phase was washed with brine and was dried with magnesiumsulfate, was concentrated in vacuo and purified by flash chromatography (hexane / tert-butyl methyl ether-gradient with hexane 100-70%) to provide 1.07 g (3.45 mmol, 14%) of the analytically pure target compound.

[1061]1H-NMR (300 MHz, DMSO-d6): δ [ppm]=1.27 (t, 3H), 2.11-2.23 (m, 1H), 2.38-2.45 (m, 1H), 2.54-2.68 (m, 4H), 4.02 (q, 2H), 5.22 (s, 2H), 6.71-6.79 (d, 2H).

[1062...

example 2-1-1

Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine

[1093]

[1094]1.74 g of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-4-1 (4.34 mmol, 1.00 eq.), 1.26 g of 4-bromopyridine hydrochloride (1:1) (6.50 mmol, 1.50 eq.), 540 mg of (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphtyl (0.867 mmol, 0.20 eq.), 1.66 g of sodium-tert-buylat (17.3 mmol, 4.00 eq.) and 198 mg of tris(dibenzylideneacetone)dipalladium(0) (0.867 mmol, 0.20 eq.) were suspended in 23 mL of dry DMF and stirred under nitrogen atmosphere at 100° C. bath temperature for 24 h. The reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM / isopropanol (4:1). The separated aqueous layer was extracted twice with DCM / isopropanol (4:1). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. To...

example 2-1-10

Preparation of N-{2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy-6-(pyridin-4-ylamino)pyrimidin-4-yl}-2-methoxyacetamide

[1098]

[1099]50 mg of N-{6-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}-2-methoxyacetamide 1-7-1 (0.12 mmol, 1.00 eq.), 25 mg of 4-bromopyridine hydrochloride (1:1) (0.13 mmol, 1.10 eq.), mg of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.02 mmol, 0.15 eq.), 115 mg of caesium carbonate (0.36 mmol, 3.00 eq.) and 2.6 mg of palladium diacetate (0.012 mmol, 0.1 eq.) were suspended in 0.5 mL of dry DMF and stirred under nitrogen atmosphere at 105° C. bath temperature for two h. The reaction mixture was diluted with water, the pH was adjusted to 7.5 using 4N aqueous hydrochloric acid and the crude product was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography yielding 29 ...

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Abstract

Compounds of formula (I), processes for their production and their use as Bub1 kinase inhibitors for the treatment of hyperproliferative diseases and / or disorders responsive to induction of cell death.

Description

FIELD OF APPLICATION OF THE INVENTION[0001]The invention relates to substituted cycloalkenopyrazole compounds, a process for their production and the use thereof.BACKGROUND OF THE INVENTION[0002]One of the most fundamental characteristics of cancer cells is their ability to sustain chronic proliferation whereas in normal tissues the entry into and progression through the cell division cycle is tightly controlled to ensure a homeostasis of cell number and maintenance of normal tissue function. Loss of proliferation control was emphasized as one of the six hallmarks of cancer [Hanahan D and Weinberg R A, Cell 100, 57, 2000; Hanahan D and Weinberg R A, Cell 144, 646, 2011].[0003]The eukaryotic cell division cycle (or cell cycle) ensures the duplication of the genome and its distribution to the daughter cells by passing through a coordinated and regulated sequence of events. The cell cycle is divided into four successive phases:[0004]1. The G1 phase represents the time before the DNA re...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/506C07D401/14C07D405/14A61K31/5377A61K31/695A61K45/06C07D403/04C07F7/18
CPCC07D401/14A61K31/506A61K31/5377A61K31/695A61K45/06C07D403/04C07D405/14C07F7/188C07F7/1856
Inventor HITCHCOCK, MARIONHILGER, CHRISTOPH-STEPHANMENGEL, ANNEBRIEM, HANSHOLTON, SIMONPÜTTER, VERASIEMEISTER, GERHARDPRECHTL, STEFANFERNÁNDEZ-MONTALVÁN, AMAURY ERNESTOSTEGMANN, CHRISTIANPREUΒE, CORNELIAGNOTH, MARK JEAN
Owner BAYER PHARMA AG
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