Pyridazin-3 (2h) -one derivatives as pde4 inhibitors

Abstract

New pyridazin-3(2H)-one derivatives having the chemical structure of general formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of phosphodiesterase 4.

1 - 21 . (canceled) 
     
     
         22 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents:
 a hydrogen atom; 
 a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; 
 an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups; or 
 a group of formula
   —(CH 2 ) n —R 6    
 
 wherein n is an integer from 0 to 4 and wherein 
 R 6  represents:
 a cycloalkyl group; 
 an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups; or 
 a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups; 
 
 
         R 2  represents a substituent chosen from R 1  and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group; 
         R 5  represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
 halogen atoms; 
 alkyl and alkylene groups,
 wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; and 
 
 phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups; 
 
         R 3  represents a monocyclic or bicyclic aryl group,
 wherein the monocyclic aryl group is substituted by one or more substituents chosen from:
 halogen atoms; 
 alkyl and alkylene groups,
 wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; and 
 
 phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups; 
 
 wherein the bicyclic aryl group is optionally substituted by one or more substituents chosen from:
 halogen atoms; 
 alkyl and alkylene groups,
 wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; and 
 
 phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups; 
 
 
         R 4  represents:
 a hydrogen atom; 
 a hydroxy, alkoxy, amino, mono- or di-alkylamino group; 
 an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; or 
 a group of formula
   —(CH 2 ) n —R 6    
 
 
         with the proviso that when simultaneously R 2  is H, and R 3  and R 5  are unsubstituted phenyl, R 1  is not methyl; 
         or a pharmaceutically acceptable salt of a compound of formula (I). 
       
     
     
         23 . A compound according to  claim 22 , wherein
 R 1  is
 a hydrogen atom; 
 a straight or branched C 1 -C 4  alkyl group, wherein the straight or branched C 1 -C 4  alkyl group is optionally substituted by one or more substituents chosen from halogen atoms, and 1 or 2 substituents chosen from hydroxy, alkoxy, amino, monalkylamino and dialkylamino groups; or 
 a group of formula —(CH 2 ) n —R 6 ,
 wherein n is an integer from 0 to 4 and wherein R 6  is an optionally substituted phenyl, cycloalkyl or a 5- to 6-membered heterocyclic ring comprising at least one nitrogen atom. 
 
   
     
     
         24 . A compound according to  claim 23 , wherein
 R 1  is
 an unsubstituted straight or branched C 1 -C 4  alkyl group, or 
 a group of formula —(CH 2 ) n —R 6 ,
 wherein n is 0 or 1 and wherein R 6  is cyclopropyl, phenyl or pyridyl. 
 
   
     
     
         25 . A compound according to  claim 22 , wherein
 R 2  is
 a hydrogen atom; 
 a group chosen from alkoxycarbonyl; carbamoyl; and a straight C 1 -C 4  alkyl group,
 wherein the straight C 1 -C 4  alkyl group is optionally substituted by a hydroxy group; or 
 
 a group of formula —(CH 2 ) n —R 6 ,
 wherein n is 0 and wherein R 6  is a phenyl ring, which is optionally substituted by 1 or 2 substituents chosen from halogen atoms and, alkyl, acyl, alkoxy, alkylthio and alkoxycarbonyl groups. 
 
   
     
     
         26 . A compound according to  claim 25 , wherein
 R 2  is
 a hydrogen atom, 
 an unsubstituted straight C 1 -C 4  alkyl group or 
 a phenyl ring, which is optionally substituted by 1 or 2 substituents chosen from halogen atoms and, alkyl, acyl, alkoxy, alkylthio and alkoxycarbonyl groups. 
   
     
     
         27 . A compound according to  claim 22 , wherein
 R 3  is a phenyl or naphthyl group,
 wherein the phenyl or the naphthyl group is substituted by 1 or 2 substituents chosen from halogen atoms and, hydroxy, alkoxy, cycloalkyloxy, alkylthio, cyano, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, acylamino, aminosulphonyl, carbamoyl, trifluoromethoxy, alkylenedioxy, alkyl and alkylene groups,
 wherein said alkyl and alkylene groups are optionally substituted by halogen atoms or by a group chosen from hydroxy, oxo, phenyl, amino and hydroxycarbonyl. 
 
   
     
     
         28 . A compound according to  claim 22 , wherein
 R 4  is
 a substituent chosen from a hydrogen atom and; hydroxy; alkoxy; amino; monoalkylamino; dialkylamino; and a straight and branched C 1 -C 6  alkyl groups,
 wherein the C 1 -C 6  alkyl group is optionally substituted by hydroxy, alkoxy, amino, monoalkylamino or dialkylamino groups; or 
 
 a group of formula —(CH 2 ) n —R 6 ,
 wherein n is 0, 1 or 2 and R 6  is a phenyl group. 
 
   
     
     
         29 . A compound according to  claim 28 , wherein R 4  is a substituent chosen from a hydrogen atom and, methoxy, unsubstituted straight C 1 -C 6  alkyl, unsubstituted branched C 1 -C 6  alkyl and phenyl groups. 
     
     
         30 . A compound according to  claim 22 , wherein R 5  is a phenyl group, which is optionally substituted by 1 or 2 substituents chosen from halogen atoms and, hydroxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, nitro, cyano, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, monalkylcarbamoyl, dialkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, an optionally substituted straight C 1 -C 6  alkyl, and an optionally substituted branched C 1 -C 6  alkyl groups. 
     
     
         31 . A compound according to  claim 30 , wherein R 5  is a phenyl group, which is optionally substituted by 1 or 2 substituents chosen from halogen atoms and, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl and nitro groups. 
     
     
         32 . A pharmaceutical composition comprising a compound as claimed in  claim 22  and at least one pharmaceutically acceptable carrier or diluent. 
     
     
         33 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by inhibition of phosphodiesterase 4, comprising administering to said subject an effective amount of a compound as claimed in  claim 22 . 
     
     
         34 . A method according to  claim 33 , wherein the pathological condition is chronic obstructive pulmonary disease. 
     
     
         35 . A method according to  claim 33 , wherein the pathological condition is rheumatoid arthritis. 
     
     
         36 . A method according to  claim 33 , wherein the pathological condition is psoriasis. 
     
     
         37 . A method according to  claim 33 , wherein the pathological condition is chosen from ulcerative colitis and Crohn's disease.