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Heterocycle compounds and methods of use thereof

A technology of heterocyclic compounds and compounds, applied to isoindoline compounds, tetrahydro-benzazepine derivatives, tetrahydro-isoquinoline compounds, isoindoline derivatives, and treatment of deacetylase Related diseases, packaging products for the treatment of deacetylase-related diseases, tetrahydro-isoquinoline derivatives, treatment of proliferative diseases, tetrahydro-benzazepine compounds, which can solve instability and are not suitable for anticancer drugs And other issues

Inactive Publication Date: 2009-12-23
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although trichostatin and Trapoxin have been studied for their anticancer activity, their in vivo instability makes them less suitable as anticancer agents

Method used

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  • Heterocycle compounds and methods of use thereof
  • Heterocycle compounds and methods of use thereof
  • Heterocycle compounds and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0236] Preparation of Arylbromide Heterocyclic Structural Units

[0237]

[0238] 5-Bromo-2,3-dihydro-1H-isoindoline

[0239]

[0240] To a solution of 5-bromophthalimide (44.2 mmol; 1.0 equiv) in THF (221 mL) was added BF under N2 3 -OEt 2 (265.5 mmol; 6.0 equiv), and the reaction was stirred at 25°C for 30 minutes. Will BH 3 -THF (353.6 mmol; 8.0 equiv) was added to the reaction mixture, which was then heated to 40° C. for 24 hours. The reaction was cooled to room temperature and quenched with 60 mL of MeOH until gas evolution ceased; 400 mL of HCl was added and the reaction was refluxed for 3 hours. The reaction was then cooled to room temperature and the aqueous layer was washed with ethyl acetate. The aqueous layer was then adjusted to pH 14 with 6N NaOH and extracted with ethyl acetate. The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give crude 5-bromo-2,3-dihydro-1H-isoindole, which was used in the next step without furth...

Embodiment 39

[0315]

[0316] To the cooled (0°C) (E)-3-{2-[2-(2-methyl-1H-indol-3-yl)-ethyl]-1,2,3,4-tetrahydro- Isoquinolin-7-yl}-methyl acrylate (100 mg, 0.264 mmol) in MeOH (2 mL) was added hydroxylamine (175 uL, 50% H 2 O solution, 2.65 mmol) and NaOMe (290 uL, 25% in MeOH, 1.34 mmol). The mixture was stirred at 0°C for 1.5 hours, neutralized with 1N HCl, some solid appeared and a gummy mass formed. The mixture was dissolved in MeOH and purified by preparative HPLC to afford 15 mg (yield: 15%) of (E)-N-hydroxy-3-{2-[2-(2-methyl-1H-ind Indol-3-yl)-ethyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-acrylamide.

[0317] Spectral data of prepared N-substituted 2,3-dihydro-isoindoline compounds:

Embodiment 1

[0318] Example 1: (E)-3-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yl)-N-hydroxy-acrylamide

[0319]

[0320] 1 H NMR (400MHz, CD 3 OD): 7.56(d, J=16Hz, 1H), 7.39(m, 8H), 6.45(d, J=16Hz, 1H), 4.21(s, 4H), 4.18(s, 2H), MS m / z 295.0(M +1) +

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Abstract

The invention relates to the use of compounds in the treatment of deacetylase-associated diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases.

Description

Background of the invention [0001] This application claims priority to US Serial No. 60 / 870176, filed December 15, 2006, which is incorporated herein by reference. In all eukaryotic cells, genomic DNA in chromatin associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer composed of two copies of various histones: H2A, H2B, H3 and H4. DNA wraps around the protein core, and the basic amino acids of the histones interact with the negatively charged phosphate groups of the DNA. The most common post-transcriptional modification of these core histones is the reversible acetylation of the ε-amino group of the highly conserved basic N-terminal lysine residue. The steady state of histone acetylation is established by the kinetic equilibrium of competing histone acetyltransferases and histone deacetylases, the latter referred to herein as HDACs. [0002] A dynamic balance of histone acetylation and deacetylation is essential for normal cell growth. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/165
CPCA61K31/165A61P1/04A61P1/16A61P7/02A61P9/10A61P9/14A61P13/08A61P13/12A61P15/00A61P17/02A61P17/06A61P19/02A61P25/00A61P25/02A61P27/02A61P27/06A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P43/00C07D209/10C07D209/16
Inventor 赵英伸L·江M·舒尔茨
Owner NOVARTIS AG
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