Aminoester derivatives

Abstract

Compounds of formula (I) are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is hydrogen halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, hydroxy, —SO 2 NR 6 R 7 , —CN, —NR 8 SO 2 R 9 , —NR 6 R 7 , —CONR 6 R 7 , or —NR 8 COR 9 , wherein said (C 1 -C 4 ) alkyl is optionally substituted by one or more groups selected from the group consisting of (C 3 -C 7 ) cycloalkyl, hydroxyl, and —NR 6 R 7  and wherein said (C 1 -C 4 ) alkoxy is optionally substituted by one or more halogens or (C 3 -C 7 ) cycloalkyl groups, wherein
 R 6  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 7  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 8  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 9  is hydrogen or (C 1 -C 6 ) alkyl; 
 
 n is an integer of 1 to 3; 
 each R 2  is hydrogen halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )haloalkyl, hydroxy, —SO 2 NR 10 R 11 , —CN, or —NR 12 SO 2 R 13 , wherein said (C 1 -C 4 ) alkyl and said (C 1 -C 4 ) alkoxy are optionally substituted by one or more (C 3 -C 7 ) cycloalkyl groups, wherein
 R 10  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 11  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 12  is hydrogen or (C 1 -C 6 ) alkyl; 
 R 13  is hydrogen or (C 1 -C 6 ) alkyl; 
 
 m is an integer of 1 to 3; 
 R 3  and R 4  are different or the same and are independently: 
 H; 
 (C 3 -C 7 ) cycloalkylcarbonyl; 
 (C 1 -C 6 ) alkyl, optionally substituted by one or more substituents selected from the group consisting of (C 1 -C 4  alkoxy), (C 3 -C 7 ) cycloalkyl, and (C 5 -C 7 ) cycloalkenyl; 
 (C 1 -C 6 ) haloalkyl; 
 (C 3 -C 7 ) cycloalkyl; 
 (C 5 -C 7 ) cycloalkenyl; 
 (C 2 -C 6 ) alkenyl; or 
 (C 2 -C 6 ) alkynyl; 
 each R 5 , whenever present, is independently CN, NO 2 , CF 3 , or a halogen atom; 
 k is 0 or an integer of 1 to 3; 
 L 1  is a bond 
 W 1  is a divalent arylene or heteroarylene group; 
 W 2  is aryl or heteroaryl; 
 L 2  is a group —(CH 2 ) q — wherein q is an integer of 1 to 4; 
 L 3  is a bond or a group —(CH 2 ),— wherein s is 1 or 2; 
 X is X1, X2, or X3: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 20  is H, OH, or (C 1 -C 4 ) alkyl optionally substituted by one or more hydroxyl group; 
         R 21  is hydrogen or (C 1 -C 6 ) alkyl optionally substituted by hydroxyl; 
         i is 1 or 2; 
         i′ is 1 or 2; 
         i″ is an integer of 1 to 4; 
         A is: 
         a group —(CH 2 ) s —NR 16 R 17  wherein s is an integer of 1 to 4 and R 16  and R 17  are independently hydrogen or (C 1 -C 4 ) alkyl; or 
         a saturated monocyclic, bicyclic, or tricyclic heterocyclic ring system containing one N heteroatom or NR 18  wherein R 18  is (C 1 -C 4 ) alkyl or benzyl; 
         an N-oxide on the pyridine ring, a deuterated derivative, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , which has formula (I)′: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , wherein
 W i  is heteroarylene;   W 2  is aryl or heteroaryl; and   L 2  is a group —(CH 2 ) q — wherein q is an integer of 1 to 4   
     
     
         4 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , wherein A is a group of formula (i), (ii), (iii), or (iv): 
       
         
           
           
               
               
           
         
       
       wherein
 f=1,2 or 3; and 
 g=1, 2 or 3. 
 
     
     
         5 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , wherein L 3  is a bond, X is a group X 2 , and i″ is 1, having formula (IA): 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , wherein L 3  is a bond and X is the group X 1 , having formula (IB): 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , wherein L3 is a bond, X is the group X3, and having formula (IE): 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 5 , wherein k is 2 and each R 5  is a halogen atom. 
     
     
         9 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 8 , wherein R 5  are two chlorine atoms at positions 3 and 5 of the pyridine ring. 
     
     
         10 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 5 , wherein R 4  is a (C 1 -C 6 ) alkyl and R 3  is (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 ) alkyl which is optionally substituted by (C 3 -C 7 ) cycloalkyl. 
     
     
         11 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1  of formula (IC): 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 11  of formula (ID): 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 12 , wherein:
 both L 1  and L 3  are a bond;   m is 0;   W 1  is phenylene-1,4-diyl, phenylene-1,3-diyl, or thienylene-2,5-diyl;   n is 0;   W 2  is phenyl;   X is a group of formula X 1  wherein both i and i′ are 1 or 2, or a group of formula X 2  wherein i″ is 1, and R 20  and R 21  are each independently H or methyl, or X is a group of formula X 3  wherein both i and i′ are 1 and R 21  is H;   A is a group of formula (i) or (ii):   
       
         
           
           
               
               
           
         
         wherein f is 1 and g is 1 or f is 1 and g is 2 and the asterisk (*) represents the point of attachment to the oxygen atom of Formula (I); or A is the group —CH 2 CH 2 N(CH 3 ). 
       
     
     
         14 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , represented by formula (I)” wherein the absolute configuration of carbon (1) is that shown below: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1  which is selected from the group consisting of:
 [(3,5)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 4-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]benzoate; 
 [(3R)-quinuclidin-3-yl] 1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-4-phenyl-piperidine-4-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[[3[(3R)-1-methylpyrrolidin-3-yl]oxy-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5- [[[3-(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5- [[methyl-[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(3R)-quinuclidin-3-yl]-1-[[4-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]-carbonylphenyl]methyl]-4-phenyl-piperidine-4-carboxylate; 
 [(3R)-quinuclidin-3-yl]-1-[2-[4-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]ethyl]-4-phenyl-piperidine-4-carboxylate; 
 [(3R)-quinuclidin-3-yl] 1-[2-[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]ethyl]-4-phenyl-piperidine-4-carboxylate; 
 [(3R)-quinuclidin-3-yl]-1-[[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]methyl]-4-phenyl-piperidine-4-carboxylate; 
 [(3R)-quinuclidin-3-yl]-1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-3-phenyl-azetidine-3-carboxylate; 
 [(3R)-1-methylpyrrolidin-3-yl] 1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-3-phenyl-azetidine-3-carboxylate; 
 Single diastereoisomer of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-hydroxy-3-oxo-3-[(3R)-quinuclidin-3 -yl]oxy-2-(2-thienyl)proply]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxypropyl]amino]-methyl]thiophene-2-carboxylate (diastereoisomer 1); 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)]-5- [[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxypropyl]amino]-methyl]thiophene-2-carboxylate (diastereoisomer 2); 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-hydroxy-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5- [[[2-hydroxy-3 -oxo-2-phenyl-3-[(3R)-quinuclidin-3 -yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5- [[[3 -(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propy]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5 -[[[3 -(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1 -ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[methyl-[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5- [[methyl-[2-methyl-3-oxo-2-phenyl-3 -[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3 -(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3 -[(3R)-quinuclidin-3 -yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate; 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate; 
 [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yl]oxycarbonyl-cyclobutyl]amino]methyl]thiophene-2-carboxylate; 
 Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxypheny)ethyl] 5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yl]oxycarbonyl-cyclobutyl]amino]methyl]thiophene-2-carboxylate; and 
 Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yl]oxycarbonyl-cyclobutyl]amino]methyl]thiophene-2-carboxylate. 
 
     
     
         16 . A pharmaceutical composition, comprising a compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 , in admixture with one or more pharmaceutically acceptable carriers. 
     
     
         17 . A pharmaceutical composition according to  claim 16 , further comprising another active ingredient. 
     
     
         18 . A method for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction, comprising administering to a subject in need thereof an effective amount of a compound, N-oxide, deuterated derivative, or pharmaceutically acceptable salt according to  claim 1 . 
     
     
         19 . A method according to  claim 18 , wherein said disease of the respiratory tract is asthma or COPD.