Spiroindolinone pyrrolidines

A technology of pyrrolidine and alkyl, applied in organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems affecting MDM2 protein degradation, etc.

Active Publication Date: 2012-10-17
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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  • Spiroindolinone pyrrolidines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0287] Preparation of intermediate [3,3-dimethyl-but-(E)-imino]-tert-butyl acetate

[0288]

[0289] M.W.213.32 C 12 H 23 NO 2

[0290] Combine tert-butyl glycine (Alfa) (2.71g, 20.0mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21g, 21.0mmol) in CH 2 Cl 2 (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-butyl-(E)-iminoamino]-acetic acid tert-butyl ester (4.29 g, 100%) as a colorless oil The oil was used in the next step without further purification.

Embodiment 2

[0292] Preparation of intermediate E / Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one

[0293]

[0294] M.W.308.14 C 15 H 8 Cl 2 FNO

[0295] To a mixture of 6-chloro-2-hydroxyindole (11g, 65.6mmol) (Crescent) and 3-chloro-2-fluorobenzaldehyde (12g, 75.7mmol) (Aldrich) in methanol (140mL) was added dropwise Pyridine (5.59 g, 65.6 mmol) (Aldrich). The mixture was then heated at 50°C for 3 hours. After cooling to 4°C, the mixture was filtered and the resulting precipitate was collected and dried to obtain E / Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro- Indole-2-one, which is a yellow solid (yield 18 g, 89%).

Embodiment 3

[0297] Intermediate racemic-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl -Propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid tert-butyl ester

[0298]

[0299] M.W.521 C 27 H 31 Cl 2 FN 2 O 3

[0300] To [3,3-dimethyl-butyl-(E)-imino]-tert-butyl acetate (3.37g, 15.8mmol) prepared in Example 1 and E / Z-6 prepared in Example 2 -Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (4g, 13mmol) in dichloromethane (100mL) was added three Ethylamine (6.6mL, 47.4mmol) and AgF (2g, 15.8mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate and brine. Separate the organic layer, wash with water and use MgSO 4 Dry and concentrate. The residue was dissolved in tert-butanol (30 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, Fluka) (7.2 g, 47.4 mmol) was added. The reaction mixture was heated at 120°C for 2 hours. The mixture was ...

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Abstract

There are provided compounds of the formula (I) wherein X, Y and R1 to R8 are described herein along with the enantiomers, pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

Description

Technical field [0001] The present invention relates to spiroindolinone pyrrolidine I, which acts as an MDM2 interaction antagonist and can therefore be used as a potent and selective anticancer agent. The compounds of the present invention and their enantiomers and pharmaceutical salts have the general formula I: [0002] [0003] Where X, Y and R 1 To R 8 As described in this application. Background technique [0004] p53 is a tumor suppressor protein that plays an important role in preventing the development of cancer. It protects cell integrity and prevents permanently damaged cell clones from proliferating by inducing growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate the genome involved in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor, which is directly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind to p53 and inhibit the ability of p53 t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10A61P35/00A61K31/407
CPCC07D487/10A61P35/00A61P43/00A61K31/407
Inventor D.J.巴特科维茨褚新阶丁庆杰B.J.格雷夫斯姜楠张静张筑明
Owner F HOFFMANN LA ROCHE & CO AG
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