Proteasome inhibitors and methods of using the same

A technology of stereoisomerism and compounds, applied in chemical instruments and methods, extracellular fluid diseases, compounds containing elements of group 3/13 of the periodic table, etc., can solve problems such as reducing the degradation rate of p53 protein

Inactive Publication Date: 2006-09-27
CEPHALON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound is also said to reduce the rate of degradation of the p53 protein in animals

Method used

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  • Proteasome inhibitors and methods of using the same
  • Proteasome inhibitors and methods of using the same
  • Proteasome inhibitors and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2-benzodioxanborol- Synthesis of 2-yl]-3-methylbutylamine hydrochloride

[0163] Step 1: 2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2 - Benzodioxin borole

[0164]

[0165] A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and 2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 mL) was stirred at room temperature for 24 hours. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (silica gel 230-400 mesh), eluting with a mixture of hexane:ethyl acetate 90:10. The product was obtained as a clear oil (32.6 g, 94% yield).

[0166] 1 H NMR (DMSO-d 6 ): 4.28 (1H, dd, J = 8.8Hz, 2.0); 2.30 (1H, m); 2.18 (1H, m); 1.96 (1H, t, J = 5.3); 1.86 (1H, m); 1.78 ( 1H, set, J = 6.8); 1.68 (1H, m); 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J = 6.6); 3H, s); 0.69(2H, m).

[0167] Step 2: 2-[(1S)-1-Chloro-3-methyl...

Embodiment 2

[0180] N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)hexahydro-3a,5,5-trimethyl-4,6-methylene-1 , 3,2-Benzodioxanborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl-carbamic acid 1 , 1-Dimethylethyl Ester

[0181]

[0182] Method A: HOAt / HATU

[0183] To BocNH(NO 2 ) ArgOH (15.7g, 49.3mmol) in anhydrous DMF (100ml) solution, add HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium Hexafluorophosphate; 18.7 g, 49.3 mmol) and HOAt (1-hydroxy-7-azabenzotriazole; 6.71 g, 49.3 mmol). The mixture was cooled to 0°C and N-methylmorpholine (13.6ml, 0.123mol) was added. After 10 minutes, (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5trimethyl-4,6-methylene-1,3, 2-Benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride (12.4 g, 41.1 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate (800ml), washed with 2% citric acid solution (2×150ml), 2% NaHCO 3 solution (2 x 150ml...

Embodiment 3

[0188] N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2-benzobis Oxaborol-2-yl]-3-methylbutyl]-(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide hydrochloride

[0189]

[0190] Method A

[0191] A solution of 4N hydrochloric acid in dioxane (15ml) was added to N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a ,5,5-trimethyl-4,6-methylene-1,3,2-benzodioxanborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[ 1,1-Dimethylethyl imino(nitroamino)methyl]amino]butyl]-carbamate (4.04g, 7.06mmol) in dioxane (40ml) and diethyl ether (7ml) solution of the mixture while maintaining cooling at 0 °C. The reaction mixture was warmed to room temperature and stirring was continued for 4 hours. The solvent was removed by rotary evaporation, the residue was treated with diethyl ether (50ml) and the mixture was stirred at room temperature for 3 days. The resulting solid was collected by filtration to yield 3.18 g of pure product (90% yield).

[0192] Method B ...

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Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Description

field of invention [0001] The present invention relates to boronic acids and boronate compounds that are effective as proteasome inhibitors and modulate apoptosis. Background of the invention [0002] The proteasome, (also called multicatalytic protease (MCP), multicatalytic protease, multicatalytic protease complex, multicatalytic endopeptidase complex, 20S, 26S, or ingensin) is a cytoplasmic and nuclear large multiprotein complexes. It is a highly conserved cellular structure responsible for the ATP-dependent proteolysis of most cellular proteins (Tanaka, Biochem Biophy. Res. Commun., 1998, 247, 537). The 26S proteasome consists of a 20S core catalytic complex capped at each end by a 19S regulatory subunit. The archaeal 20S proteasome contains 14 copies of two different types of subunits α and β, forming a cylindrical structure consisting of four stacked rings. The top and bottom rings each contain 7 α subunits, while the inner ring contains 7 β subunits. The more comp...

Claims

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Application Information

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IPC IPC(8): C07F5/04C07F5/02A61K31/69A61P35/00
CPCC07F5/025A61P1/00A61P1/16A61P1/18A61P11/00A61P13/08A61P13/12A61P15/00A61P17/00A61P19/00A61P21/00A61P35/00A61P35/02A61P43/00A61P7/00
Inventor 桑卡尔·查特吉穆罕默德·伊克巴勒埃内斯托·门塔安布罗焦·奥利瓦
Owner CEPHALON INC
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