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N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses

A compound and alkyl technology, applied in the field of N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical applications, can solve problems such as limitations, effectiveness and side effects

Inactive Publication Date: 2008-10-22
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its effectiveness is limited by side effects, especially when used systemically, such as nausea and vomiting

Method used

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  • N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses
  • N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses
  • N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses

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Experimental program
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preparation example Construction

[0132] 4.1. Preparation of compounds

[0133] The compounds can be prepared using known methods generally used for the preparation of imides and 2,3-dihydro-1H-isoindolinones. However, the present invention also relates to improvements in the formation of the final compounds, which are described in more detail below.

[0134] Reaction of N-alkoxycarbonyldiimides with amines in the presence of a base such as sodium carbonate or sodium bicarbonate yields N-substituted imides essentially as described in: Shealy et al., Chem . & Ind., (1965) 1030-1031 and Shealy et al., J. Pharm. Sci. 57, 757-764 (1968). Alternatively, cyclic anhydrides can be reacted with appropriate amines to form imides. Cyclic imides can also be formed by refluxing an anhydrous tetrahydrofuran solution of a suitably substituted dicarboxylic acid monoamide with N,N'-carbonyldiimidazole. Alternatively, 2-bromomethyl-benzoate esters can be reacted with appropriate amines to give 2,3-dihydro-1H-isoindolinones a...

Embodiment 2

[0226] (1R)-2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindole- 1-keto

[0227]

[0228] According to the method of Example 1, from (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (3.0g, 13mmol), 2-bromo Preparation of methyl-6-nitro-benzoate (3.6g, 13mmol) and triethylamine (2ml, 14mmol) in DMF (40ml) (1R)-2-[1-(3-ethoxy-4 -methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-one to give a yellow solid (4.1 g, yield 81%):

[0229] 1 H NMR (CDCl 3 )δ1.44(t, J=7Hz, 3H, CH 3 ), 2.13-2.31 (m, 2H, CH 2 ), 3.54-3.59(m, 1H, CHH), 3.71-3.77(m, 1H, NCHH), 3.87(s, 3H, CHH 3 ), 3.94(d, J=16Hz, 1H, NCHH), 4.06(q, J=7Hz, 2H, CH 2 ), 4.26 (d, J=16Hz, 1H, NCHH), 5.70 (dd, J=4, 11Hz, 1H, NCH), 6.85-6.99 (m, 3H, Ar), 7.55-7.77 (m, 3H, Ar ); 13 C NMR (CDCl 3 )δ14.76, 33.92, 45.80, 51.30, 55.98, 58.65, 64.63, 65.84, 111.39, 113.22, 119.75, 122.91, 124.13, 126.74, 130.66, 132.11, 143.84, 146.63, 2.468.682

Embodiment 3

[0231] (3R)-(tert-butoxy)-N-{3-(3-ethoxy-4-methoxyphenyl)-3-[7-nitro-1-oxodihydroisoindole- 2-yl]-propyl}carbonylamino(tert-butoxy)formate

[0232]

[0233] At room temperature, to (1R)-2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro - Isoindol-1-one (4.1g, 11mmol), (tert-butoxy) carbonylamino (tert-butoxy) formate (3.0g, 13mmol) and triphenylphosphine in THF (40ml) solution, Diisopropyl azodicarboxylate (2.6ml, 13mmol) was added. After 30 min, the solvent was removed in vacuo. The residue was purified by chromatography (silica gel) to give (3R)-(tert-butoxy)-N-{3-(3-ethoxy-4-methoxyphenyl)-3-[7-nitro -1-Oxodihydroisoindol-2-yl]-propyl}carbonylamino(tert-butoxy) formate (5 g, yield 78%):

[0234] 1 H NMR (CDCl 3 )δ1.41(s, 9H, 3CH 3 ), 1.42(t, J=7Hz, 3H, CH 3 ), 1.51(s, 9H, 3CH 3 ), 2.39-2.52 (m, 2H, CH 2 ), 3.59-3.69 (m, 2H, CH 2 ), 3.84 (s, 3H, CH 3 ), 4.06 (q, J=7Hz, 2H, CH 2 ), 4.11 (d, J = 16Hz, 1H, NCHH), 4.43 (d, J = 16Hz, 1H, NCHH)...

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Abstract

The invention encompasses novel N-alkyl-hydroxamic acid-isoindolyl compounds of formula (I) with the definition X1-X4, Z1, Z2, R1, R2, R7 and Y according to claim 1, pharmaceutical compositions of these compounds, and methods of using these compounds and compositions for treatment or prevention of various diseases and disorders mediated by PDE4 inhibition, associated with abnormal TNA-alpha levels, and / or mediated by MMP inhibition.

Description

[0001] This application claims the benefit of US Provisional Application No. 60 / 454,149, filed March 12, 2003, which is hereby incorporated by reference in its entirety. 1. Field of invention [0002] The present invention includes novel N-alkyl-hydroxamic acid-isoindolyl compounds, pharmaceutical compositions of these compounds and methods of using these compounds and compositions for the treatment, prevention and management of various diseases and disorders in mammals , such as diseases and disorders mediated by inhibition of PDE4, diseases associated with abnormal TNF-α levels, and / or diseases mediated by inhibition of MMPs. 2. Background of the invention [0003] 2.1. TNF-α [0004] Tumor necrosis factor alpha (TNF-α) is a cytokine released primarily by inflammatory and mononuclear phagocytes in response to immune stimuli. TNF-α is capable of enhancing most cellular processes such as differentiation, recruitment, proliferation and protease degradation. At low levels, T...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/46A61K31/4035A61K31/4178A61K31/4196A61K31/4245A61K31/454A61K31/496A61K31/5377C07D209/48C07D413/02C07D417/02
CPCC07D209/46
Inventor H·-W·曼G·W·穆勒
Owner CELGENE CORP