Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

Abstract

Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Z is selected from the group consisting of (CH 2 ) m ; (CH 2 ) n O; O(CH 2 ) p ; CH 2 SO 2 ; CHNR 6 ; CH 2 NR 6 ; NR 6 ; OCOR 4 R 5 ; and CR 4 R 5 , 
         wherein m=0, 1, or 2; n=1, 2, or 3; p=0, 1, 2 or 3; 
         R 4  is independently selected from H or a linear or branched (C 1 -C 4 ) alkyl, optionally substituted by a (C 1 -C 4 ) cycloalkyl; 
         R 5  is independently selected from the group consisting of linear or branched (C 1 -C 4 ) alkyl; phenyl; benzyl; NH 2 ; and HNCOOR′, wherein R′ is linear or branched (C y  C 4 ) alkyl; 
         R 6  is H or a linear or branched (C 1 -C 4 ) alkyl; 
         R 1  and R 2  are the same or different and are each independently selected from the group consisting of H; linear or branched (C 1 -C 6 ) alkyl, optionally substituted by one or more substituents selected from (C 3 -C 7 ) cycloalkyl and (C 5 -C 7 ) cycloalkenyl; (C 3 -C 7 ) cycloalkyl; (C 5 -C 7 ) cycloalkenyl; linear or branched (C 2 -C 6 ) alkenyl; and linear or branched (C 2 -C 6 ) alkynyl; 
         R 3  is one or more substituents independently selected from the group consisting of H, CN, NO 2 , CF 3  and a halogen atom; 
         A is a mono- or bicyclic, saturated, partially unsaturated, or unsaturated ring system, having 5 to 10 ring atoms, which may be optionally substituted with one or more R x  groups, wherein each R x  may be the same or different and each R x  is independently selected from the group consisting of: 
         linear or branched (C 1 -C 6 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl; 
         linear or branched (C 2 -C 6 ) alkenyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl; 
         linear or branched (C 2 -C 6 ) alkynyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl; 
         (C 5 -C 7 ) cycloalkenyl; 
         phenyl; 
         (C 3 -C 7 ) heterocycloalkyl; 
         OR 7 , wherein R 7  is selected from the group consisting of:
 H; 
 (C 1 -C 10 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl; 
 (C 3 -C 7 ) cycloalkyl; 
 (C 1 -C 4 ) alkylene-(C 3 -C 7 ) heterocycloalkyl; 
 CO(C 1 -C 6 ) alkyl; 
 COO(C 1 -C 6 ) alkyl; 
 phenyl; 
 benzyl; 
 (C 1 -C 10 ) alkylene-NR 8 R 9 , wherein R 8  and R 9  are each independently selected from the group consisting of H, linear or branched (C 1 -C 6 ) alkyl, or R 8  and R 9  together with the nitrogen atom to which they are linked form 
 a saturated, partially saturated, or unsaturated ring, optionally substituted by (C 1 -C 4 ) alkyl; 
 
         a halogen atom; 
         CN; 
         NO 2 ; 
         NR 10 R 11 , wherein R 10  and R 11  may be the same or different and are each independently selected from the group consisting of:
 H; 
 linear or branched (C 1 -C 6 ) alkyl, optionally substituted with phenyl or (C 3 -C 7 ) cycloalkyl; 
 COC 6 H 5 ; 
 CO—(C 1 -C 4 ) alkyl; 
 COO—(C 1 -C 4 ) alkyl; 
 CONH—(C 1 -C 6 ) alkylene-R 12 , wherein R 12  is selected from the group consisting of H; (C 1 -C 4 ) alkyl; and OR 4 R 5 ; and 
 CONH(C 1 -C 4 ) alkylene-N(C 1 -C 4 ) alkyl; 
 or R 10  and R 11  together with the nitrogen atom to which they are linked form a saturated or partially saturated ring; 
 
         (C 1 -C 4 ) alkylene-NR 10 R 11 ; 
         COR 12 , wherein R 12  is phenyl or linear or branched (C 1 -C 6 ) alkyl; 
         oxo; 
         HNSO 2 R 13 , wherein R 13  is (C 1 -C 4 ) alkyl or a phenyl optionally substituted with one or more halogen atoms or with a (C 1 -C 4 ) alkyl group; 
         SO 2 R 14 , wherein R 14  is (C 1 -C 4 ) alkyl, OH, or NR 10 R 11  wherein R 10  and R 11  are as defined above; 
         SOR 15 , wherein R 15  is phenyl or (C 1 -C 4 ) alkyl; 
         SR 16 , wherein R 16  is H, phenyl, or (C 1 -C 4 ) alkyl; 
         COOR 17 , wherein R 17  is H, (C 1 -C 4 ) alkyl, phenyl, or benzyl; and 
         (CH 2 )OR 18 , wherein q=1, 2, 3, or 4 and R 18  is H or (C 1 -C 4 ) cycloalkyl, 
       
       or a pharmaceutically acceptable salt thereof or a N-oxide of the pyridine ring thereof. 
     
     
         2 . The compound, salt, or N-oxide of  claim 1 , wherein R 4  is methyl. 
     
     
         3 . The compound, salt, or N-oxide of  claim 1 , wherein R 5  is methyl. 
     
     
         4 . The compound, salt, or N-oxide of  claim 1 , wherein R′ is t-butyl. 
     
     
         5 . The compound, salt, or N-oxide of  claim 1 , wherein A is an aryl group, a (C 3 -C 8 ) cycloalkyl group, or a heteroaryl. 
     
     
         6 . The compound, salt, or N-oxide of  claim 1 , wherein in A at least one ring atom is a heteroatom. 
     
     
         7 . The compound, salt, or N-oxide of  claim 1 , wherein in A at least one ring atom is a heteroatom selected from N, S, and O. 
     
     
         8 . The compound, salt, or N-oxide of  claim 1 , wherein R 8  and R 9  together with the nitrogen atom to which they are linked form a piperidine ring optionally substituted by (C 1 -C 4 ) alkyl, an oxazine ring optionally substituted by (C 1 -C 4 ) alkyl, or an imidazole ring optionally substituted by (C 1 -C 4 ) alkyl. 
     
     
         9 . The compound, salt, or N-oxide of  claim 1 , wherein R 10  and R 11  together with the nitrogen atom to which they are linked form a piperidyl ring. 
     
     
         10 . The compound, salt, or N-oxide of  claim 1 , wherein A is a phenyl optionally substituted with one or more R x  groups. 
     
     
         11 . The compound, salt, or N-oxide of  claim 1 , wherein A is a heteroaryl ring optionally substituted with one or more R x  groups. 
     
     
         12 . The compound, salt, or N-oxide of  claim 11 , wherein A is a heteroaryl ring selected from the group consisting of pyrrole, pyrazole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, and pyran. 
     
     
         13 . The compound, salt, or N-oxide of  claim 1 , wherein R 3  is a halogen atom. 
     
     
         14 . The compound, salt, or N-oxide of  claim 13 , wherein R 3  is chlorine. 
     
     
         15 . The compound, salt, or N-oxide of  claim 14 , which has the formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or a N-oxide of the pyridine ring thereof. 
     
     
         16 . The compound, salt, or N-oxide of  claim 15 , wherein Z is (CH 2 ) m  with m equal to 0. 
     
     
         17 . The compound, salt, or N-oxide of  claim 1 , which is 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester. 
     
     
         18 . The compound, salt, or N-oxide of  claim 1 , which is 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester. 
     
     
         19 . The compound, salt, or N-oxide of  claim 15 , wherein Z is CHR 5  where R 5  is a linear or branched C 1 -C 4  alkyl, preferably methyl. 
     
     
         20 . The compound, salt, or N-oxide of  claim 15 , wherein Z is CR 4 R 5  where R 4  and R 5  are the same or different and are each independently linear or branched C 1 -C 4  alkyl and they form a ring with the carbon atom to which they are linked having 3, 4, 5 or 6 carbon atoms, preferably having 3 carbon atoms. 
     
     
         21 . The compound, salt, or N-oxide of  claim 15 , wherein Z is CR 4 R 5  where R 4  and R 5  together with the carbon atom to which they are linked form a ring having 3 carbon atoms. 
     
     
         22 . A process for the preparation of a compound, salt, or N-oxide according to  claim 1 , comprising:
 (a) adding an acid of formula AZCOOH or an acyl chloride of formula AZCOCl or an isocyanate of formula AZNCO, wherein A and Z are as defined above, to a solution of an alcohol of formula (2):   
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined above. 
     
     
         23 . A pharmaceutical composition, comprising at least one compound, salt, or N-oxide of  claim 1  and one or more pharmaceutically acceptable carriers and/or excipients. 
     
     
         24 . The pharmaceutical composition of  claim 23 , which is suitable for administration by inhalation. 
     
     
         25 . The pharmaceutical composition of  claim 23 , wherein said composition further comprises an additional active ingredient selected from the group consisting of a beta 2 -agonist, a corticosteroid, an anticholinergic agent, and an antimuscarinic agent. 
     
     
         26 . A method for the prevention and/or treatment of a disease mediated by phosphodiesterase 4 (PDE4) overactivity and/or in which an inhibition of PDE4 activity is desirable, said method comprising administering an effective amount of a compound, salt, or N-oxide of  claim 1  to a subject in need thereof. 
     
     
         27 . The method of  claim 26 , wherein said disease is a disease of the respiratory tract characterized by airway obstruction. 
     
     
         28 . The method of  claim 26 , wherein said disease is selected from the group consisting of asthma, chronic bronchitis, and chronic obstructive pulmonary disease. 
     
     
         29 . A method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response or induced by or associated with an excessive secretion of TNF-α and PDE4, said method comprising administering an effective amount of a compound, salt, or N-oxide of  claim 1  to a subject in need thereof.