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Novel N-substituted-pyrrolidines as inhibitors of MDM2-p53 interactions

A compound and alkyl technology, applied in the field of pyrrolidine-2-carboxamide derivatives I, can solve problems affecting the degradation of MDM2 protein

Inactive Publication Date: 2012-07-04
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, a recurrent molecular defect in the p16INK4 / p19ARF locus has been shown to affect the degradation of the MDM2 protein

Method used

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  • Novel N-substituted-pyrrolidines as inhibitors of MDM2-p53 interactions
  • Novel N-substituted-pyrrolidines as inhibitors of MDM2-p53 interactions
  • Novel N-substituted-pyrrolidines as inhibitors of MDM2-p53 interactions

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Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0225] Preparation of intermediate [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine

[0226]

[0227] Molecular weight 171.6 C 8 h 7 FClN

[0228] 3-Chloro-2-fluoro-benzaldehyde (Oakwood, 97%) (1.59 g, 10.0 mmol) and methylamine (2.0 M in THF (tetrahydrofuran), Aldrich, 7.5 mL, 15.0 mmol) were dissolved in CH 2 Cl 2 (20 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dried under reduced pressure to give [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (1.72 g, 100%) , which was a colorless oil which was used in the next step without further purification.

Embodiment 1b

[0230] Preparation of intermediate [1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine

[0231]

[0232] Molecular weight 153.6 C 8 h 8 ClN

[0233] 3-Chloro-benzaldehyde (Aldrich, 97%) (4.21 g, 30.0 mmol) and methylamine (2.0 M in THF, Aldrich, 22.5 mL, 45.0 mmol) were dissolved in CH 2 Cl 2 (50 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dried under reduced pressure to give [1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (4.60 g, 100%) as free A colored oil was used in the next step without further purification.

Embodiment 1c

[0235] Preparation of intermediate [1-(4-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine

[0236]

[0237] Molecular weight 171.6 C 8 h 7 FClN

[0238] 4-Chloro-2-fluoro-benzaldehyde (Matrix Sci, 3.17 g, 20.0 mmol) and methylamine (2.0 M in THF, Aldrich, 15 mL, 15.0 mmol) were dissolved in CH 2 Cl 2 (20 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dried under reduced pressure to give [1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.32 g, 97.0%) , which was a colorless oil which was used in the next step without further purification.

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PUM

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Abstract

There are provided compounds of the formula (I) wherein X, Y, R1, R2, R3, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof which are useful as anticancer agents.

Description

technical field [0001] The present invention relates to pyrrolidine-2-carboxamide derivatives I which are MDM2 interaction antagonists and are therefore useful as potent and selective anticancer agents. Background technique [0002] p53 is a tumor suppressor protein that plays an important role in preventing the development of cancer. It protects cellular integrity and prevents proliferation of permanently damaged cell clones by inducing growth arrest or apoptosis. At the molecular level, p53 is a transcription factor capable of activating genomes involved in the regulation of the cell cycle and apoptosis. p53 is a potent cell cycle inhibitor that is directly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 binds to p53 and inhibits the ability of p53 to transactivate genes regulated by p53. Additionally, MDM2 mediates ubiquitin-dependent degradation of p53. p53 is capable of activating the expression of the MDM2 gene, thereby inc...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07D401/06C07D401/12C07D403/12A61K31/402A61K31/4025A61P35/00
CPCC07D401/12C07D207/16C07D403/12C07D401/06A61P35/00A61P43/00C07D207/08A61K31/4025
Inventor D.J.巴特科维茨褚新阶刘进军T.M.罗斯张筑明
Owner F HOFFMANN LA ROCHE & CO AG
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