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Proteasome Inhibitors and Methods of Using the Same

A technology of medicinal salts and alkyl groups, applied in the field of boronic acid and boronic ester compounds, can solve problems such as reducing the degradation rate of animal p53 protein

Inactive Publication Date: 2012-07-25
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

[0503] (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2-benzodi Synthesis of borolan-2-yl]-3-methylbutylamine hydrochloride

[0504] Step 1: 2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3,2 -Benzodi Borolane e

[0505]

[0506] A mixture of (+)-pinanediol (23.9g, 0.140mol) and 2-methylpropylboronic acid (15g, 0.147mol) in diethyl ether (300ml) 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 90:10 mixture of hexane:ethyl acetate. A clear oily product was obtained (32.6 g, yield 94%).

[0507] 1 H NMR(DMSO-d 6 ): 4.28 (1H, dd, J = 8.8 Hz, 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); 0.81 ( 3H, s); 0.69 (2H, m).

[0508] Step 2: 2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7...

Embodiment A2

[0521] 2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl4,6-methylene-1,3,2-benzodioxa Alternate synthesis of borocyclopentane e

[0522] Step 1: 2-(1-Methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene-1,3, 2-benzodi Borolane e.

[0523]

[0524] To a solution of (1S, 2S, 3R, 5S)-(+)-pinanediol (50.0g, 0.293mol) in anhydrous tetrahydrofuran (350ml) was slowly added triisopropoxyborane while maintaining at 0°C Stir under nitrogen. After 2 hours, the solvent was removed by rotary evaporation. The oily residue was redissolved in hexane (150 ml), 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%).

[0525] 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); 1.74-1.67 ( 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, ...

Embodiment B1

[0530] N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methylene- 1,3,2-benzodi Borolan-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl-carbamic acid 1,1-dimethyl Ethyl ester

[0531]

[0532] Method A: HOAt / HATU

[0533] To BocNH(NO 2 ) ArgOH (15.7g, 49.3mmol) in anhydrous DMF (100ml) solution was added 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, add (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5trimethyl-4,6-methylene-1 of Example A.1, 3,2-benzodi Borolan-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), with 2% citric acid solution (2×150ml), 2% NaHCO 3 Wash with so...

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Abstract

The invention relates to a proteasome inhibitors and methods of using the same. 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

[0001] This application is a divisional application in which the international application PCT / US2004 / 026407 entered the Chinese national phase on April 14, 2006, the application number is 200480030152.0, and the invention title is "proteasome inhibitors and methods of use". Technical field [0002] The present invention relates to boronic acid and boronic acid ester compounds that are effective as proteasome inhibitors and regulate apoptosis. Background technique [0003] Proteasome, (also called multi-catalytic protease (MCP), multi-catalytic protease, multi-catalytic protease complex, multi-catalytic endopeptidase complex, 20S, 26S, or ingensin) is present in the cytoplasm and nucleus of all eukaryotic cells Large multi-protein complexes within. It is a highly conserved cell structure responsible for ATP-dependent proteolysis of most cellular proteins (Tanaka, Biochem Biophy. Res. Commun., 1998, 247, 537). The 26S proteasome is composed of a 20S core catalytic complex, which i...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07F5/04
CPCC07F5/025A61K31/69A61P1/04A61P11/06A61P17/02A61P17/06A61P19/02A61P19/10A61P21/04A61P25/00A61P3/12A61P31/00A61P31/04A61P31/18A61P35/00A61P35/02A61P37/00A61P37/06A61P43/00A61P9/10C07F5/02C07F5/00A61K45/06
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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