Pyrazolonaphthyridine derivatives

Abstract

The target is to provide PDE IV inhibitors which have a highly potent anti-asthmatic and/or COPD-prophylactic/therapeutic profile with unexpectedly excellent safety. A compound of the formula (1): wherein A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may be unsubstituted or optionally substituted with one or more members selected from the group consisting of hydroxyl, halogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl, lower alkoxy-carbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-lower alkylene, lower alkylsulfonyl, lower alkylsulfonyl-amino, and ureido; R 1 is a group selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and lower alkoxycarbonyl; R 2 is hydrogen or lower alkyl; and m is an integer of 1 to 3; or a pharmaceutically acceptable salt thereof, possesses highly excellent PDE IV-specific inhibitory actions and is useful as an anti-asthmatic drug and/or a prophylactic/therapeutic drug for COPD with high safety.

1 - 9 . (canceled) 
   
   
       10 . A compound of the formula (1): 
     
       
         
         
             
             
         
       
     
     wherein:
 A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may be unsubstituted or optionally substituted with one or more members selected from the group consisting of hydroxyl, halogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl, lower alkoxycarbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-lower alkylene, lower alkylsulfonyl, lower alkylsulfonylamino, and ureido; 
 R 1  is a group selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and lower alkoxycarbonyl; 
 R 2  is hydrogen or lower alkyl; and 
 m is an integer of 1 to 3; 
 with the proviso that 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one and 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one are excluded from said compound; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       11 . The compound according to  claim 10 , wherein A is phenyl; or a pharmaceutically acceptable salt thereof. 
   
   
       12 . The compound according to  claim 10 , wherein A is pyridyl or 1-oxypyridyl; or a pharmaceutically acceptable salt thereof. 
   
   
       13 . A compound, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
 5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,   5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one,   3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one,   3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one and   3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one.   
   
   
       14 . A pharmaceutical composition which comprises an effective amount of a compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. 
   
   
       15 . A method of inhibiting a phosphodiesterase IV comprising contacting an effective amount of a compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, with a phosphodiesterase IV. 
   
   
       16 . A method for treating a mammal with at least one respiratory disease selected from the group consisting of:
 bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease (COPD); and acute respiratory distress syndrome (ARDS)   
     comprising administering an effective amount of a compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       17 . A method for treating a mammal with asthma comprising administering an effective amount of a compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       18 . A pharmaceutical composition which comprises an effective amount of a compound according to  claim 11 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. 
   
   
       19 . A pharmaceutical composition which comprises an effective amount of a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. 
   
   
       20 . A pharmaceutical composition which comprises an effective amount of a compound according to  claim 13 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. 
   
   
       21 . A method of inhibiting a phosphodiesterase IV comprising contacting an effective amount of a compound according to  claim 11 , or a pharmaceutically acceptable salt thereof, with a phosphodiesterase IV. 
   
   
       22 . A method of inhibiting a phosphodiesterase IV comprising contacting an effective amount of a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, with a phosphodiesterase IV. 
   
   
       23 . A method of inhibiting a phosphodiesterase IV comprising contacting an effective amount of a compound according to  claim 13 , or a pharmaceutically acceptable salt thereof, with a phosphodiesterase IV. 
   
   
       24 . A method for treating a mammal with at least one respiratory disease selected from the group consisting of:
 bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease (COPD); and acute respiratory distress syndrome (ARDS)   
     said method comprising administering an effective amount of a compound according to  claim 11 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       25 . A method for treating a mammal with at least one respiratory disease selected from the group consisting of:
 bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease (COPD); and acute respiratory distress syndrome (ARDS)   
     said method comprising administering an effective amount of a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       26 . A method for treating a mammal with at least one respiratory disease selected from the group consisting of:
 bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease (COPD); and acute respiratory distress syndrome (ARDS)   
     said method comprising administering an effective amount of a compound according to  claim 13 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       27 . A method for treating a mammal with asthma comprising administering an effective amount of a compound according to  claim 11 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       28 . A method for treating a mammal with asthma comprising administering an effective amount of a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, to said mammal. 
   
   
       29 . A method for treating a mammal with asthma comprising administering an effective amount of a compound according to  claim 13 , or a pharmaceutically acceptable salt thereof, to said mammal.