Hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and process for their preparation

a technology of phosphodiesterase and hydroxyindoles, which is applied in the field of new, substituted hydroxyindoles, can solve the problems of reducing the life expectancy of patients, affecting the quality of life of patients, and obvious respiratory distress of patients

Inactive Publication Date: 2004-10-12
ARZNEIMITTELWERK DRESDEN GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the course of the disease, the lung function continuously decreases, the lungs become increasingly emphysematous and the respiratory distress of the patients is obvious.
This disease clearly adversely affects the quality of life of the patients (dyspnoea, low exercise tolerance) and significantly reduces their life expectancy.
The therapy of this disease is unsatisfactory as yet, particularly with respect to the continuous decrease in lung function.
Until now, it was not possible to use any of these compounds clinically.
It had to be established that the known PDE 4 inhibitors also have various side-effects such as nausea and emesis, which it was not possible to suppress adequately until now.

Method used

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  • Hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and process for their preparation
  • Hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and process for their preparation
  • Hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and process for their preparation

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-o xoacetamide

1.4 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2- oxoacetamide (3 mmol) is dissolved in 100 ml of dichloromethane. The solution is heated to reflux and treated with a solution of 14 mmol of BBr.sub.3 in 15 ml of dichloromethane with stirring. The reaction mixture is refluxed for 3 hours. After cooling, the solution is intensively stirred for 3 hours at 20.degree. C. with 200 ml of an aqueous sodium hydrogencarbonate solution. The product crystallizes out, it is isolated, dried at 60.degree. C. and recrystallized from 80 ml of ethanol. Yield: 1.1 g (80% of theory) Melting point: 213-214.degree. C.

example 2

N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-]2- oxoacetamide

5 g (38 mmol) anhydrous aluminium chloride is introduced into 50 ml ethane-1,2,-dithiol. A solution of 4.7 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2- oxoacetamide (10 mmol) in 50 ml of dichloromethane is added at 0.degree. C. The mixture is stirred at 0.degree. C. for 4 hours. 50 ml of 10% hydrochloric acid is added dropwise at from 0 to 10.degree. C. with stirring. The crystallizing product is isolated, washed with water and dried at 20.degree. C. A pure product is obtained by recrystallization from ethanol (180 ml). Yield: 3.1 g (67% of theory) Melting point: 212-214.degree. C.

Exemplary preparative process as follows for compounds of Formula (1) from starting substances of the type described, in which R.sup.7 is an acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulfonyl residue.

example 3

N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-o xoacetamide Na salt

5 g of N-(3,5-dichloropyridin-4-yl)-2-[5-acetoxy-1-(4-fluorobenzyl)-indol-3-yl]2- oxoacetamide (10 mmol) are stirred at 40.degree. C.-50.degree. C. for 1 hour in 50 ml dilute sodium hydroxide solution. The solution is neutralized with 10% hydrochloric acid while cooling with ice, and is concentrated to dryness. The residue is dissolved in 80 mle acetone and insoluble constituents are removed. The clear solution is treated with a solution of 0.4 g NaOH in 3 ml of water and stirred at 20.degree. C. for 2 hours. The crystallized product is isolated, washed with acetone and dried at 60.degree. C. Yield: 2.44 g (51% of theory) Melting point: 265.degree. C.

An exemplary preparation process follows for compounds of Formula (1) from other compounds of Formula (1).

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Abstract

The invention relates to new hydroxyindoles of the Formula, ##STR1## their use as inhibitors of phosphodiesterase 4 and processes for their preparation.

Description

FIELD OF THE INVENTIONThe present invention relates to novel, substituted hydroxyindoles processes for their preparation, pharmaceutical preparations containing these compounds, and a method for the use of these compounds which are phosphodiesterase 4 inhibitors, as active compounds for the treatment of disorders which can be affected by inhibition of phosphodiesterase 4 activity in immunocompetent cells (e.g. macrophages and lymphocytes).BACKGROUNDThe activation of cell membrane receptors by transmitters leads to the activation of the second messenger system. Adenylate cyclase synthesizes active cyclic AMP (cAMP) or cyclic GMP (cGMP) from AMP and GMP. These lead, for example, to relaxation in smooth muscle cells or to inhibition of mediator release or synthesis in inflammatory cells. The breakdown of the second messenger cAMP and cGMP is carried out by the phosphodiesterases (PDE). To date, 7 families of PDE enzymes (PDE1-7) are known, which differ by their substrate specificity (c...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4439A61K31/4427C07D401/06C07D401/00A61K31/00A61K31/40A61K31/403A61K31/404A61K31/496A61K31/5377A61K31/541A61P11/00A61P11/06A61P19/02A61P29/00A61P43/00C07D209/22C07D209/24C07D209/42C07D401/12C07D413/02C07D417/02
CPCC07D209/22C07D401/12C07D209/24A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P11/08A61P13/04A61P13/08A61P13/10A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P19/00A61P19/02A61P19/08A61P21/00A61P25/00A61P25/02A61P25/16A61P25/24A61P25/28A61P25/36A61P27/14A61P29/00A61P3/10A61P31/04A61P31/18A61P33/06A61P37/00A61P37/02A61P37/06A61P43/00A61P7/12A61P9/00A61P9/08A61P9/10
Inventor HOFGEN, NORBERTEGERLAND, UTEKUSS, HILDEGARDMARX, DEGENHARDSZELENYI, STEFANKRONBACH, THOMASPOLYMEROPOULOS, EMMANUELHEER, SABINE
Owner ARZNEIMITTELWERK DRESDEN GMBH
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