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Novel phosphodi esterase inhibitors

A technology of diclopyridine and dioxide, which is applied in the direction of anti-inflammatory agents, non-central analgesics, active ingredients of heterocyclic compounds, etc., and can solve problems such as adverse reactions and restrictions on the clinical application of theophylline

Active Publication Date: 2010-01-20
UNION THERAPEUTICS AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, treatment with theophylline can produce mild and severe adverse effects, such as cardiac arrhythmias and convulsions, limiting the clinical use of theophylline (Kroegel and Foerster, supra)

Method used

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Experimental program
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Embodiment approach

[0047] In one or more embodiments of the invention, both E and G are oxygen.

[0048] In one or more embodiments of the invention, both m and n are one.

[0049] In one or more embodiments of the invention, both m and n are zero.

[0050] In one or more embodiments of the invention, R 1 and R 2 Together with the carbon atom to which it is attached, it contains one or two selected from -O-, -S-, -S(O)-, -S(O 2 )-, -N= and -N(R 5 )-heteroatom heterocyclic ring; one or more carbon atoms in the heterocyclic ring are optionally replaced by one or more identical or different selected from R 4 of substituents.

[0051] In one or more embodiments of the invention, R 1 and R 2 Together with the carbon atom to which it is attached, it contains one or two selected from -O-, -S-, -S(O)-, -S(O 2 )-and-N(R 5 )- heteroatom heterocycloalkyl ring; one or more carbon atoms in the heterocycloalkyl ring are optionally replaced by one or more same or different R 4 of substituents.

[00...

Embodiment 1

[0194] 2-(3,5-dichloropyridin-4-yl)-1-(7-methoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodiox Heterocyclopentene-2,4'-(4H)-pyran]-4-yl)ethanone (compound 101)

[0195]

[0196] 7-methoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodioxole-2,4'-(4H)-pyran]- A solution of methyl 4-carboxylate (1.80 g, 6.42 mmol) and 3,5-dichloro-4-methylpyridine (1.46 g, 8.99 mmol) in tetrahydrofuran (33 mL) was cooled to 0°C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (19.3 mL, 19.3 mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Add saturated NH 4 Aqueous Cl solution (70 mL). The aqueous phase was extracted with dichloromethane (3 x 100 mL). The combined organic phases were washed with water (50 mL), washed with MgSO 4 Dry and evaporate to dryness under reduced pressure. Standard silica gel column chromatography followed by recrystallization from isopropanol afforded 2-(3,5-dichloropyridin-4-yl)-1-(7-methoxy-2',3',5', 6'-...

Embodiment 2

[0199] N-(3,5-dichloropyridin-4-yl)-7-methoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodioxolane En-2,4'-(4H)-pyran]-4-carboxamide (compound 102)

[0200]

[0201] Oxalyl chloride (92 μL, 1.1 mmol) and a catalytic amount of N,N-dimethylformamide were added to 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3 - Benzodioxole-2,4'-(4H)-pyran]-4-carboxylic acid (48 mg, 0.18 mmol) in suspension in dichloromethane (2 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and the crude acid chloride was redissolved in tetrahydrofuran (2 mL). A suspension of 3,5-dichloropyridin-4-amine (67 mg, 0.40 mmol) and NaH (60% in mineral oil, 16 mg, 0.40 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 3 hours, It was then added dropwise to a solution of the crude acid chloride in tetrahydrofuran at room temperature. After having been stirred overnight at room temperature, the reaction mixture was diluted with diethyl ether (30 mL), and...

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Abstract

The present invention relates to a compound according to formula I, wherein X, A, G, E, R1, R2, R3 are as shown herein; and pharmaceutically acceptable salts, hydrates, N-oxides or solvates hereof. The invention further relates 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 compounds having phosphodiesterase inhibitory activity and their use as therapeutic agents in the treatment of inflammatory diseases and disorders. Background of the invention [0002] Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic AMP and / or cyclic GMP in cells to 5-AMP and 5-GMP, respectively, and as such, they are essential for cellular regulation of cAMP or cGMP levels. Of the 11 phosphodiesterases identified so far, phosphodiesterase (PDE) 4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important regulator of cAMP, which is expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z. Huang and J.A. Mancini, Current Med. Chem. 13, 2006, 3253- 3262 pages). Since cAMP is a key second messenger in the regulation of inflammatory responses, PDE4 has been found to regulate the inflammatory response of inflammatory cells by regulating pro-infl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/10C07D493/10A61K31/36A61P29/00C07D495/10
Inventor J·费尔丁S·F·尼尔森J·C·H·拉尔森B·R·巴布
Owner UNION THERAPEUTICS AS
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