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Substituted acetophenones useful as PDE4 inhibitors

A kind of substituent and representative technology, applied in the field of preparing medicine, can solve the problems such as limiting the clinical application of theophylline

Inactive Publication Date: 2009-12-23
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, treatment with theophylline may cause moderate and severe side effects, such as cardiac arrhythmias and convulsions, limiting theophylline's clinical use (Kroegel and Foerster, supra)

Method used

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  • Substituted acetophenones useful as PDE4 inhibitors
  • Substituted acetophenones useful as PDE4 inhibitors
  • Substituted acetophenones useful as PDE4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0064] In one or more embodiments of the present invention, ring B represents pyridyl, pyrazinyl, quinolinyl, pyrimidinyl or pyridazinyl, which is optionally selected from one or more, the same or different Substituted by the following substituents: fluorine, chlorine, bromine, cyano, methoxy, -NH 2 or C 1-4 Amino.

[0065] In one or more embodiments of the invention, optionally R 11 The substituted ring B represents 2-(6-chloro-pyrazinyl), 2-pyrazinyl, 4-(3-bromo-pyridyl), 4-(3,5-dibromo-pyridyl), 4 -(6-chloro-pyrimidinyl), 2-(4-chloro-pyridyl), 3-(2-chloro-pyridyl), 4-(2-methoxy-pyridyl), 4-(2- cyano-pyridyl), 3-pyridazinyl, 4-(2-tert-butylamino-3,5-dichloro-pyridyl), 4-(2-amino-3,5-dichloro-pyridyl ), 4-(3,5-dichloro-pyridyl), 2-(3-bromo-pyrazinyl), 4-pyridyl, 4-quinolyl or 4-(3,5-dichloro-1 -oxy-pyridyl).

[0066] In one or more embodiments of the invention, formula I represents the general formula Iz,

[0067]

[0068] where X 3 represents -CH- or N, and where ...

Embodiment 1

[0409] Example 1 (compound 101)

[0410] 2-(3,5-Dichloro-pyridin-4-yl)-1-(2-hydroxy-3,4-dimethoxy-phenyl)-ethanone

[0411]

[0412] 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone (20 g, 56 mmol) was dissolved in DCM (75 mL). Add BCl slowly over 2 hours at room temperature 3 (95 mL of 1M in DCM). Water (50 mL) was added slowly, followed by EtOH (200 mL). The white precipitate was filtered and recrystallized from EtOH. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2-hydroxy-3,4-dimethoxy-phenyl)-ethanone was obtained as a white solid. 1 H NMR (CDCl 3 )δ=11.92(1H,s), 8.54(2H,s), 7.68(1H,d), 6.60(1H,d), 4.67(2H,s), 3.98(3H,s), 3.90(3H,s ). Yield 14.2 g (74%)

[0413] Preparation 3 (Compound 503)

[0414] 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3-dihydroxy-4-methoxy-phenyl)-ethanone

[0415]

[0416] 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone (1.25 g , 3.5 mmol) was dissolved in AcOH (100%, 9.25 mL). HI (55-58%, 4.55 mL) was added and...

Embodiment 2

[0421] Example 2 (compound 102)

[0422] 2-(3,5-dichloro-pyridin-4-yl)-1-(3-hydroxy-2,4-dimethoxy-phenyl)-ethanone LC / MS (method B): (m / z) 342.1 (MH+); RT = 3.34 min; Purity (UV) = 100%; Alkyl halide: methyl iodide

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Abstract

The present invention relates to a compound according to formula (I); wherein X1, X2, X3, X4 and X5 independently of each other represent -CH- or N; or X3, X4 and X5 independently of each other represent -CH- or N, and Xi and X2 independently of each other represent C and form part of an additional 6- membered aromatic ring; R1 represents hydrogen, alkyl, alke nyl, alkynyl, haloalkyl, hydroxyalkyl, or alkylcarbonyl, all of which are optionally substituted; R2 and R3 independently represent hydrogen, -CH2-C(O)NR-R', alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, alkylalkoxycarbonyl, alkylcarbonyloxy, or alkoxyalkyl, all of which are optionally substituted; R11 represents hydrogen, halogen, cyano, amino, alkoxy or alkylamino, X1-X5 represent -CH- or N, including N-oxides, enantiomers and diastereomers; and pharmaceutically acceptable salts, hyd rates, or solvates thereof. The invention relates further to processes for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases, e.g. dermal diseases, with said compounds, and to the use of said compounds in the manufacture of medicaments.

Description

field of invention [0001] The present invention relates to novel substituted acetophenones and derivatives thereof, processes for their preparation, said compounds for use in therapy, pharmaceutical compositions comprising said compounds, methods of treating diseases with said compounds, and said compounds Use in the preparation of medicines. Background of the invention [0002] Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic AMP and / or cyclic GMP into 5-AMP and 5-GMP, respectively, in cells, so they are very important for cellular regulation of cAMP or cGMP levels. Among the 11 phosphodiesterases identified so far, phosphodiesterase (PDE) 4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important regulator of cAMP expressed by immune cells and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z. Huang and J.A. Mancini, Current Med. Chem. 13, 2006, pp. 3253-3262 ). Since cAMP is a key second messenger in regulating infla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61C07D413/12C07D417/12A61K31/44A61K31/4427A61P25/00A61P29/00A61P31/00A61P35/00
Inventor J·费尔丁S·F·尼尔森
Owner LEO PHARMA AS
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