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

Abstract

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

1 - 20 . (canceled)  
     
     
         21 . A method for inhibiting pulmonary neutrophil infiltration in a patient comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of 
 N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient to inhibit pulmonary neutrophil infiltration in the patient.    
     
     
         22 . The method of  claim 21 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         23 . The method of  claim 21 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         24 . A method for treating a chronic obstructive pulmonary disease in a patient comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of 
 N-(3, 5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient having chronic obstructive pulmonary disease to treat the chronic obstructive pulmonary disease.    
     
     
         25 . The method of  claim 24 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         26 . The method of  claim 24 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         27 . A method for treating atopic dermatits comprising administering to a patient with atopic dermatitis a therapeutically effective amount of at least one compound selected from the group consisting of 
 N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient with atopic dermatitis to treat the atopic dermatitis.    
     
     
         28 . The method of  claim 27 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         29 . The method of  claim 27 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         30 . A method for inhibiting pulmonary neutrophil infiltration in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier, diluent, auxiliary agent and adjuvant; and 
 at least one compound selected from the group consisting of    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3, 5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient to inhibit pulmonary neutrophil infiltration in the patient.    
     
     
         31 . The method of  claim 30 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         32 . The method of  claim 30 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         33 . A method for treating a chronic obstructive pulmonary disease in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier, diluent, auxiliary agent and adjuvant; and at least one compound selected from the group consisting of 
 N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient having chronic obstructive pulmonary disease to treat the chronic obstructive pulmonary disease.    
     
     
         34 . The method of  claim 33 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[l -(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         35 . The method of  claim 33 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         36 . A method for treating atopic dermatits in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier, diluent, auxiliary agent and adjuvant; and 
 at least one compound selected from the group consisting of    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient with atopic dermatitis to treat the atopic dermatitis.    
     
     
         37 . The method of  claim 36 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         38 . The method of  claim 36 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         39 . A method for treating a disorder associated with neutrophils comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of 
 N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient to treat disorder associated with neutrophils in the patient.    
     
     
         40 . The method of  claim 39 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         41 . The method of  claim 39 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.  
     
     
         42 . A method for treating a disorder associated with neutrophils comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier, diluent, auxiliary agent and adjuvant; and 
 at least one compound selected from the group consisting of    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-propyl- 5 -hydroxyindol-3-yl)-2-oxyacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-4-flurobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;    N-(3,5-dicloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide; and    N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide;    or a pharmaceutically acceptable salt thereof to a patient to treat a disorder associated with neutrophils in the patient.    
     
     
         43 . The method of  claim 42 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide.  
     
     
         44 . The method of  claim 42 , wherein said at least one compound is N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide sodium salt.