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Compound as apoptosis protein inhibitor, and application thereof

A compound and solvate technology, applied to compounds as apoptotic protein inhibitors and their application fields, can solve the problems of difficult to achieve oral administration, toxic side effects, serious problems, etc.

Active Publication Date: 2018-08-24
NANJING SANHOME PHARM RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, Smac mimics have entered clinical research, but they have some obvious defects, such as difficulty in oral administration and serious side effects

Method used

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  • Compound as apoptosis protein inhibitor, and application thereof
  • Compound as apoptosis protein inhibitor, and application thereof
  • Compound as apoptosis protein inhibitor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: (2S,2'S)-N,N'-((2S,2'S)-((5R,5'R)-((6,6'-difluoro-1H,1'H-[2, 2'-biindole]-3,3'-bismethylene))bis(3,3-difluoropyrrolidine-5,1-diyl))bis(1-butyryl-1,2-di base)) bis(2-methylaminopropionamide)

[0117]

[0118] Step 1: Preparation of (2S,4R)-1-(benzyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid

[0119]

[0120] Dissolve L-N-Cbz-hydroxyproline (53.0 g, 200 mmol) in N,N-dimethylformamide (300 mL), then add imidazole (68.0 g, 1000 mmol) to its solution, followed by t-butyl Dimethylchlorosilane (60.0 g, 400 mmol) was stirred at room temperature for 16 h, water and ethyl acetate were added to the reaction solution, and the pH was adjusted to 3-4 with 6N hydrochloric acid. The organic phase was washed with water (500 mL×2), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by column chromatography to obtain the title compound.

[0121] Step 2: Preparation of...

Embodiment 3

[0180] Example 3: (2S, 2'S)-N, N'-((2S, 2'S)-((3S, 3'S, 5R, 5'R)-((6,6'-difluoro-1H, 1'H -[2,2'-biindole]-3,3'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-butyryl- 1,2-diyl)) dimethylamino) propionamide)

[0181]

[0182] Step 1: Preparation of (2R,4R)-4-acetoxy-2-(6-fluoro-1H-indol-3-yl)methylpyrrolidine-1-carboxylic acid benzyl ester

[0183]

[0184] (2R,4R)-2-(6-fluoro-1H-indol-3-yl)methyl-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (3.70g, 10.0mmol ), 4-dimethylaminopyridine (61.0mg, 0.500mmol) was dissolved in dichloromethane (50mL), then added acetic anhydride (2.00g, 20.0mmol), reacted overnight, then added methanol to quench (3mL), the reaction The system was successively washed with 10% aqueous sodium carbonate solution (30mL), 1N hydrochloric acid (30mL), and 10% aqueous sodium carbonate solution (30mL), and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (PE:EA =3:1-2:1)...

Embodiment 4

[0212] Example 4: (2S,2'S)-N,N'-((1S,1'S)-((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H -[2,2'-biindole]-3,3'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-cyclohexyl- 2-oxoethane-2,1-diyl)(2-methylaminopropionamide)

[0213]

[0214] Step 1: ((1S,1'S)-((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H-[2,2'-biindole]- 3,3'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-cyclohexyl-2-oxoethane-2,1-di base)) preparation of tert-butyl dicarbamate

[0215]

[0216] The preparation method is the same as ((2S,2'S)-((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H-[2,2' -biindole]-3,3'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-butyryl-1,2-diyl) )) The preparation method of tert-butyl dicarbamate, the difference is that the raw material (S)-2-(tert-butoxycarbonylamino)butanoic acid is replaced by tert-butoxycarbonyl-L-cyclohexylglycine to obtain the title compound.

[0217] Step 2: (2S,2'S)-1,1'-((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H-[2,2'-link Indole]-3...

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Abstract

The present invention belongs to the field of medical chemistry, relates to a class of compounds of apoptosis protein inhibitors, and applications thereof, and particularly provides a compound represented by a formula I, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, preparation methods of the compounds, pharmaceutical compositions containing the compounds, and uses of the compounds or the compositions in treatment and / or prevention of IAPs overexpression related diseases such as viral infections, cancer, hyperblastosis diseases or inflammatory diseases. According to the present invention, the compound has good inhibitory activity against IAPs, and is highly expected to be used as the treatment drug for viral infection, cancer, hyperblastosis diseases or inflammatory diseases. The formula I is defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of peptide mimetics or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs as inhibitors of apoptosis proteins (IAPs), and their preparation methods As well as pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating and / or preventing diseases related to the overexpression of IAPs, such as viral infection, cancer, tissue proliferative diseases or inflammatory diseases. Background technique [0002] The apoptosis protein (IAPs) family is an endogenous inhibitor of programmed cell death (apoptosis). The subtypes of IAPs found in humans include XIAP, c-IAP1, c-IAP2, NAIP, Livin, and Survivin. In general, IAPs contain one to three baculovirus repeat domains (BIRs). The BIR domain is thought to exert an anti-apoptotic effect by inhibiting caspases and thereby inhibiting apoptosis. ...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D413/14C07D519/00C07D209/14A61K31/404A61K31/496A61K31/438A61K31/5377A61K31/5383A61P31/12A61P35/00A61P29/00
CPCC07D209/14C07D403/14C07D413/14C07D519/00
Inventor 王勇赵立文葛崇勋张先杨圣伟喻佳孙坤杰张志杰邱杨成
Owner NANJING SANHOME PHARM RES & DEV CO LTD
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