Quinoline Derivatives As Phosphodiesterase Inhibitors

Abstract

There are provided according to the invention novel compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R19, R20, and R34 are as described in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.

1 .- 24 . (canceled) 
   
   
       25 . A method for the treatment of COPD (chronic obstructive pulmonary disease) in a human in need thereof, which comprises administration of a therapeutically effective amount of a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof 
     wherein:
 R 1  is C 1-6  alkyl; C 3-7 cycloalkyl or C 3-7 cycloalkyl(C 1-4 alkyl)- wherein the C 3-7 cycloalkyl is optionally substituted by one or more substituents selected from ═O and OH; C 4-7 cycloalkyl fused to an aryl ring; Aryl or aryl(C 1-6 alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 alkylCONR 6 —, C 1-6 alkylCO—, halogen, —CF 3 , —(CH 2 ) m OH, —OCF 3 , C 1-6 alkoxy-, C 1-6 alkoxy(C 1-4 alkyl)-, C 1-6 alkoxyC 2-6 alkoxy-, C 1-6 alkoxycarbonyl, —CN, R 4 R 5 NCO, R 7 R 3 N—, R 9 R 10 NCONR 11 —, HO(CH 2 ) 2-6 O—, R 12 R 13 NSO 2 (CH 2 ) m —, (4-morpholinyl)C 2-6 alkoxy, —NR 14 SO 2 C 1-6 alkyl, aryloxy, heteroaryl (optionally substituted by C 1-6 alkyl), CO 2 H, R 21 R 22 N(C 1-4 alkyl)-, C 1-6 alkoxyCONR 23 (CH 2 ) m —, aryl(optionally substituted by C 1-6 alkyl); Aryl fused to a C 4-7 cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted by one or more ═O; Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, —COC 1-4 alkyl, C 1-4 alkyl; Heteroaryl or heteroaryl(C 1-6 alkyl)- wherein the heteroaryl is optionally substituted by one or more substituents selected from: C 1-6 alkyl, aryl(C 1-4 alkyl), C 1-6 alkoxy, halogen, C 1-6 alkoxyCO; or Heterocyclyl optionally fused to an aryl or heteroaryl ring; 
 R 2  is hydrogen or C 1-6 alkyl; 
 R 34  is a group of formula: 
 
     
       
         
         
             
             
         
       
       R 3  is C 1-6 alkyl optionally substituted by one or more substituents selected from —OH, —NR 16 COR 15 , —NR 17 R 18 , —CO 2 R 24 , C 1-6 alkoxyCONR 25 —, —CONR 26 R 27 , C 1-6 alkoxy-, C 1-6 alkylSO 2 NR 33 —, or a group having one of the following formulae: 
     
     
       
         
         
             
             
         
       
       C 3-7 cycloalkyl; Aryl or aryl(C 1-6 alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C 1-6 alkyl-, halogen-, C 1-6 alkoxy-, —CO 2 R 28 , —CH 2 CO 2 H, —OH, aryl(optionally substituted by a C 1-6  alkoxy group), heteroaryl, —CONR 29 R 30 , C 3-7 cycloalkoxy, C 3-7 cycloalkyl(C 1-6 alkoxy)-, —CF 3 ; Heteroaryl or heteroaryl(C 1-6 alkyl)- wherein the heteroaryl is optionally substituted by one or more C 1-6 alkyl or —CONR 29 R 30  groups; or Heterocyclyl linked to the S(═O) n  moiety through a carbon atom which is optionally substituted by one of more substituents selected from C 1-6 alkyl-, C 1-6 alkylCO—, C 3-7 cycloalkylCO—, heteroarylCO— optionally substituted by one or more C 1-4 alkyl-groups, C 1-6 alkoxyCO—, arylCO—, R 31 R 32  NCO—, C 1-6 alkylSO 2 —, arylSO 2 , -heteroarylSO 2  optionally substituted by one or more C 1-4 alkyl or C 1-4 alkylCONH— groups; 
       m is 0-6; 
       n is 0, 1 or 2; 
       R 19  is hydrogen or C 1-6 alkyl; 
       R 20  is hydrogen, C 1-6 alkyl, halogen or C 1-6 alkoxy; 
       R 4-18 , R 21-25 , R 28  and R 31-33  all independently represent H, C 1-6  alkyl; 
       R 26  and R 27  independently represent H, C 1-6  alkyl, C 3-7 cycloalkyl or heterocyclyl; 
       R 29  and R 30  independently represent H, C 1-6 alkyl optionally substituted by OH; 
       R 7  and R 8  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; 
       R 9  and R 10  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; 
       R 17  and R 18  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; 
       R 21  and R 22  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; 
       R 26  and R 27  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; 
       R 29  and R 30  together with the nitrogen atom to which they are attached may form a heterocyclyl ring; and 
       R 31  and R 32  together with the nitrogen atom to which they are attached may form a heterocyclyl ring. 
     
   
   
       26 . The method of  claim 25  wherein the administration comprises inhaled administration. 
   
   
       27 . The method of  claim 25 , further comprising the administration of a second therapeutic agent selected from a β 2  adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent. 
   
   
       28 . The method of  claim 25 , wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
   
   
       29 . The method of  claim 25 , wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient. 
   
   
       30 . A method for the treatment of COPD (chronic obstructive pulmonary disease) in a human in need thereof, which comprises administration of a therapeutically effective amount of a compound of formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       31 . The method of  claim 30  wherein the administration comprises inhaled administration. 
   
   
       32 . The method of  claim 30 , further comprising the administration of a second therapeutic agent selected from a 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent. 
   
   
       33 . The method of  claim 30 , wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
   
   
       34 . The method of  claim 30 , wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient. 
   
   
       35 . A method for the treatment of COPD in a human in need thereof, which comprises administration of a therapeutically effective amount of 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide. 
   
   
       36 . The method of  claim 35  wherein the administration comprises inhaled administration. 
   
   
       37 . The method of  claim 35 , further comprising the administration of a second therapeutic agent selected from a 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent. 
   
   
       38 . The method of  claim 35 , wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
   
   
       39 . The method of  claim 35 , wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient.