Phthalazine derivatives as phosphodiesterase 4-inhibitors

Abstract

A process for preparing a compound of formula I: wherein G is methylene, ethylene, CONH, amino or a bond; R is H, phenyl or a (C 1-4 )alkyl group optionally substituted by phenyl; Cy is phenyl or a 5- or 6-membered heterocycle of the group consisting of pyrrole, imidazole, pyrazole, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, piperidine, and triazine, the Cy residue being optionally substituted by one or more substituent(s) selected from the group consisting of keto, nitro, carboxy, fluorine, chlorine, bromine, or iodine; R 1 is a (C 1-6 )alkyl or polyfluoro(C 1-6 )alkyl group; and R 2 is aryl, aryl-(C 1-10 )-alkyl, (C 4-7 )cycloalkyl or (C 4-7 )heterocycle wherein the heteroatom is an oxygen atom.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 B is methylene, ethylene, amino, CONH or a bond;  
 Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s), being both the residues optionally substituted by one or more substituent(s);  
 R is H, phenyl or a (C 1-4 )alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members:  
 R 1  is a (C 1-6 )alkyl or polyfluoro(C 1-6 )alkyl group;  
 R 2  is aryl, aryl-(C 1-10 )-alkyl or a (C 4-7 )cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent;  
 and the N→O derivatives and pharmaceutically acceptable salts thereof,  
 with the proviso that when R is H, R 2  is not aryl-methyl.  
 
     
     
         2 . A compound according to  claim 1  wherein B is methylene or amino; Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s), being both the residues substituted by one or two halogen(s); R is H, phenyl or a (C 1-4 )alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members; R 1  is a (C 1-6 )alkyl or polyfluoro(C 1-6 )alkyl group; R 2  is a (C 4-7 )cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent; and the N→O derivatives and pharmaceutically acceptable salts thereof.  
     
     
         3 . A compound according to  claim 1  wherein B is methylene; Cy is phenyl or a 6-membered heterocycle containing 1 nitrogen atom, being both the residues substituted by one or two halogen(s); R is phenyl or a (C 1-4 )alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members; R 1  is a (C 1-6 )alkyl or polyfluoro(C 1-6 )alkyl group; R 2  is a (C 4-7 )cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent; and the N→O derivatives and pharmaceutically acceptable salts thereof.  
     
     
         4 . A process for preparing a compound according to  claim 1  wherein B is methylene, ethylene, ammo or a bond, characterized in that a benzaldehyde of formula II  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined in  claim 1  is oxidised to give an acid of formula III  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, which is transformed into the corresponding acyl halide of formula IV  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above and X is chlorine or bromine; this compound is reacted with diethylamine to give a benzamide of formula V  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, which reacted with dimethylformamide in the presence of a strong base yields a compound of formula VIa  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, and R 1  is hydrogen which, when a compound of formula I wherein R is hydrogen is desired, is reacted with tert.butylcarbazole to give the compound of formula VIIa  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 1  and R 2  are as defined above, and R′ is a protecting group of the carboxy moiety; instead when a compound of formula I wherein R is over then hydrogen is desired, the compound of formula VIa is treated with a R II -magnesium halide or R II -lithium, wherein R II  is phenyl or a (C 1-4 )alkyl group optionally substituted by an aromatic or hydrogenated ring having from 5 to 7 members, to give a compound of formula XIII  
       
         
           
           
               
               
           
         
       
       wherein R II , R 1  and R 2  are as defined above, which treated with a suitable oxidising agent, yields a compound of formula VIb  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R II  are as defined above, which is treated with tert.butylcarbazole to give the compound of formula VIIb, differing from the compound VIIa in that R has the meanings of formula I hydrogen excluded; the compound of formula VIIa or VIIb is reacted with trifluoroacetic acid to give the phthalazinone of formula VIII  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R 2  are as defined above; this is reacted with a halogenating agent to give the phthalazine of formula IX  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R 2  are as defined above, and X 1  is a halogen atom, which by treatment with a compound of formula XIV 
       Cy-B′-Y  (XIV) 
       wherein Cy is as defined in  claim 1 , B′ is methylene, ethylene, amino or a bond and Y is hydrogen or halogen, provides the desired compound.  
     
     
         5 . A process for preparing compounds according to  claim 1  wherein B is methylene, ethylene, amino or a bond characterized in that a compound of formula VIa or VIb  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined in  claim 1 , R I  is hydrogen and R II  is phenyl or a (C 1-4 )-alkyl group optionally substituted by an aromatic or hydrogenated ring of from 5 to 7 members, is reacted with acetic acid in acidic medium to give a compound of formula X  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are as defined above and R′ 2  is hydrogen, aryl, aryl-(C 1-10 )-alkyl or a (C 4-7 )cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent, which in turn is reacted with hydrazine to give a phthalazinone of formula XI  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R′ 2  are as defined above, which only when R′ 2  is hydrogen, is treated with the suitable compound of formula XIa or XIIb 
       R 2 OSO 2 CH 3   (XIIa)R 2 X  (XIIb) 
       wherein R 2  and X are as defined above, and yields a compound of formula VIII  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R 2  are as defined above; this is reacted with a chlorinating agent to give the phthalazine of formula IX  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R 2  are as defined above, and X′ is a halogen atom, which by treatment with a compound of formula XIV 
       Cy-B′-Y  (XIV) 
       wherein Cy is as defined above, B′ is methylene, ethylene, amino or a bond and Y is hydrogen or halogen, provides the desired compound.  
     
     
         6 . A process for preparing a compound according to  claim 1  wherein B is CONH, characterized in that a compound IX is reacted with carbon monoxide and methanol in the presence of a metal catalyst, to give a compound of formula XV  
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and R 2  are as defined in  claim 1 , which is converted in the desired compound of formula I by amidation.  
     
     
         7 . A process for preparing a compound according to  claim 1  wherein B is other than amino, characterized in that the acid of formula III  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined in  claim 1 , is reacted with formaldehyde/HCl to give a compound of formula XVI  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, which is oxidized, then hydrolyzed to give a compound of formula XVII  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, which with an hydrohalide acid and triphenylphosphine gives a compound of formula XVIII  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above, which treated with an aldehyde of formula XIX 
       Cy-B″-CHO  (XIX) 
       wherein Cy is as defined in  claim 1  and B″ is methylene or is absent, in the presence of an organic base, gives a compound of formula XX  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , B″ and Cy are as defined above; this is reacted with hydrazine to give a compound of formula XXI  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and Cy are as defined above and B is other than amino, which is treated with a halogenating agent to give a compound of formula XXII  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , X and Cy are as defined above and B is other than amino, which is subdued to a coupling reaction with the suitable metal-organic derivative in the presence of a catalyst, or to a nucleophilic substitution.  
     
     
         8 . A pharmaceutical composition containing a therapeutically effective amount of a compound according to  claim 1  in admixture with a suitable carrier.  
     
     
         9 . A pharmaceutical composition according to  claim 8  for the treatment of allergic and inflammatory pathologies.  
     
     
         10 . A pharmaceutical composition according to  claim 8  for the treatment of respiratory diseases.