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Proteasome inhibitors and methods of using the same

A medicinal salt and alkyl technology, applied in the field of boric acid and boric acid ester compounds, can solve the problems of reducing the degradation rate of p53 protein in animals

Active Publication Date: 2012-03-28
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 degradation rate of 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 A1

[0507] (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

[0508] Step 1: 2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2 - Benzodioxin borole

[0509]

[0510] 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).

[0511] 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).

[0512] Step 2: 2-[(1S)-1-Chloro-3-methy...

Embodiment A2

[0525] 2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl4,6-methylene-1,3,2-benzodioxaborole alternate synthesis of

[0526] Step 1: 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3, 2-Benzodioxin borole.

[0527]

[0528] To a solution of (1S, 2S, 3R, 5S)-(+)-pinanediol (50.0g, 0.293mol) in anhydrous tetrahydrofuran (350ml) was slowly added triisopropoxyborane while at 0°C Stir under nitrogen. After 2 hours, the solvent was removed by rotary evaporation. The oily residue was redissolved in hexane (150ml), and the solution was filtered to remove a small amount of white solid. The filtrate was concentrated by rotary evaporation to obtain a clear oily product (62.6 g, yield 90%).

[0529] 1 H NMR (DMSO-d6): 4.31-4.20 (2H, m); 2.34-2.16 (2H, m); 1.96 (1H, t, J=5.5); 1.90-1.85 (1H, m); 1H, m); 1.32(3H, s); 1.31(1H, d, J=7.6); 1.25(3H, s); 1.14(3H, d, J=6.1); 1.13(3H, d, J=6.1 ); 0.81 (3H, s).

[0530] Step 2: 2-(2-Methylpropyl...

Embodiment B1

[0534] 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

[0535]

[0536] Method A: HOAt / HATU

[0537] 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 from Example A.1 was added, 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% ...

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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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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00
Inventor 阿尔贝托·贝尔纳雷吉保罗·G·卡萨拉桑卡尔·查特吉埃德蒙多·费雷蒂穆罕默德·伊克巴勒埃内斯托·门塔帕特里西亚·A·梅西纳·麦克劳克林安布罗焦·奥利娃热尔马诺·达拉斯莫塞尔吉奥·德·穆纳里拉法埃拉·贝尔纳迪尼
Owner CEPHALON INC
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