Pharmaceutically active isoindoline derivatives

Abstract

Isoindolin-1-one and Isoindoline-1,3-dione substituted in the 2-position with an α-(3,4-disubstituted phenyl)alkyl group and in the 4- and/or 5-position with a nitrogen-containing group are inhibitors of, and thus useful in the treatment of disease states mediated by, TNFα and phosphodiesterase. A typical embodiment is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-diaminoisoindoline-1,3-dione.

What is claimed is: 
     
       1. A method of reducing elevated levels of PDE IV in a mammal, which comprises administering thereto an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or an acid addition salt or a substantially chirally pure isomer thereof, 
         wherein:
 each of R 1  and R 2 , independently of the other, is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkylmethoxy in which cycloalkyl has from 3 to 18 carbon atoms; 
 one of X and X′ is ═C═O and the other of X and X′ is ═C═O or ═CH 2 ; 
 R 3  is —SO 2 —Y, —COZ, —CN, or hydroalkyl of 1 to 6 carbon atoms in which
 Y is alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; 
 Z is —NR 6″ R 7″ , alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; 
 R 6″  is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or alkanoyl of 2 to 5 carbon atoms, each of which is unsubstituted or substituted with halo, amino, or alkylamino of 1 to 4 carbon atoms; 
 R 7″  is alkyl of 1 to 4 carbon atoms; 
 
 n is 1, 2, or 3; 
 one of R 4  and R 5  is hydrogen and the other of R 4  and R 5  is imidazolyl, pyrrolyl, oxadiazolyl, triazolyl, or 
 
       
       
         
           
           
               
               
           
         
         
            in which z is 0 or 1;
 R 6 , when taken independently of R 7 , is selected from cycloalkanoyl whose cycloalkyl portion contains 3 to 6 carbon atoms, each of which is unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino in which each alkyl group contains 1 to 4 carbon atoms; and 
 R 7  is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl, or alkoxyalkylcarbonyl of 2 to 5 carbon atoms; or 
 R 6  and R 7 , taken together, are alkylidene of 1 or 2 carbon atoms substituted by amino, alkylamino, or dialkylamino, in which each alkyl group has from 1 to 4 carbon atoms, or, provided z is 1, —CH═CH—CH═CH—, or —CH═CH—N═CH—; and, 
 
           the carbon atom designated * constitutes a center of chirality. 
         
       
     
     
       2. A method of treating an inflammatory disease or an autoimmune disease in a mammal, which comprises administering thereto an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or an acid addition salt or a substantially chirally pure isomer thereof, 
         wherein:
 each of R 1  and R 2 , independently of the other, is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkylmethoxy in which cycloalkyl has from 3 to 18 carbon atoms; 
 one of X and X′ is ═C═O and the other of X and X′ is ═C═O or ═CH 2 ; 
 R 3  is —SO 2 —Y, —COZ, —CN, or hydroalkyl of 1 to 6 carbon atoms in which
 Y is alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; 
 Z is —NR 6″ R 7″ , alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; 
 R 6″  is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or alkanoyl of 2 to 5 carbon atoms, each of which is unsubstituted or substituted with halo, amino, or alkylamino of 1 to 4 carbon atoms; 
 R 7″  is alkyl of 1 to 4 carbon atoms; 
 
 n is 1, 2, or 3; 
 one of R 4  and R 5  is hydrogen and the other of R 4  and R 5  is imidazolyl, pyrrolyl, oxadiazolyl, triazolyl, or 
 
       
       
         
           
           
               
               
           
         
         
            in which z is 0 or 1;
 R 6 , when taken independently of R 7 , is selected from cycloalkanoyl whose cycloalkyl portion contains 3 to 6 carbon atoms, each of which is unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino in which each alkyl group contains 1 to 4 carbon atoms; and 
 R 7  is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl, or alkoxyalkylcarbonyl of 2 to 5 carbon atoms; or 
 R 6  and R 7 , taken together, are alkylidene of 1 or 2 carbon atoms substituted by amino, alkylamino, or dialkylamino, in which each alkyl group has from 1 to 4 carbon atoms, or, provided z is 1, —CH═CH—CH═CH—, or —CH═CH—N═CH—; and 
 
           the carbon atom designated * constitutes a center of chirality. 
         
       
     
     
       3. A method of reducing elevated levels of PDE IV in a mammal, which comprises administering thereto an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or an acid addition salt thereof. 
       
     
     
       4. A method of treating an inflammatory disease or an autoimmune disease in a mammal, which comprises administering thereto an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or an acid addition salt thereof. 
       
     
     
       5. The method of  claim 2 , wherein the inflammatory disease or autoimmune disease is an inflammatory respiratory condition. 
     
     
       6. The method of  claim 2 , wherein the inflammatory disease or autoimmune disease is asthma. 
     
     
       7. The method of  claim 4 , wherein the inflammatory disease or autoimmune disease is an inflammatory respiratory condition. 
     
     
       8. The method of  claim 4 , wherein the inflammatory disease or autoimmune disease is asthma. 
     
     
       9. The method of claim 2, wherein the inflammatory disease or an autoimmune disease is psoriasis. 
     
     
       10. The method of claim 2, wherein the inflammatory disease or an autoimmune disease is rheumatoid arthritis. 
     
     
       11. The method of claim 2, wherein the inflammatory disease or an autoimmune disease is osteoarthritis. 
     
     
       12. The method of claim 2, wherein the inflammatory disease or an autoimmune disease is Crohn's disease.