1-oxo- and 1,3-dioxoisoindolines and method of reducing inflammatory cytokine levels

Abstract

1-Oxo- and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines substituted in the 4- and/or 7-position of the isoindoline ring and optionally further substituted in the 3-position of the 2,6-dioxopiperidine ring reduce the levels of inflammatory cytokines such as TNFα in a mammal. A typical embodiment is 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline

What is claimed is:  
     
         1 . A compound selected from the group consisting of 
 (a) a 2-(2,6-dioxopiperidin-3-yl)-isoindoline of the formula:  
                 
    in which 
 Y is oxygen or H 2 ,  
 one of R 1  and R 2  is halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano, or carbamoyl, the other of R 1  and R 2  is independently hydrogen, halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano, or carbamoyl, and  
 R 3  is hydrogen, alkyl, or benzyl, and  
   (b) the acid addition salts of said 2-(2,6-dioxopiperidin-3-yl)-isoindolines which contain a nitrogen atom capable of being protonated.    
     
     
         2 . The compound according to    claim 1   , in which Y is oxygen.  
     
     
         3 . The compound according to    claim 1   , in which Y is H 2 .  
     
     
         4 . The compound according to    claim 1   , in which R 1  and R 3  are hydrogen.  
     
     
         5 . The compound according to    claim 4    in which R 2  is methyl, ethyl, chloro, or methoxy.  
     
     
         6 . The compound according to    claim 1   , in which R 2  and R 3  are methyl and R 1  is hydrogen.  
     
     
         7 . The compound according to    claim 1   , which is substantially chirally pure (S)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline, substantially chirally pure (R)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline, or mixtures thereof.  
     
     
         8 . The compound according to    claim 1   , which is substantially chirally pure (S)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-ethylisoindoline, substantially chirally pure (R)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-ethylisoindoline, or mixtures thereof.  
     
     
         9 . The compound according to    claim 1   , which is substantially chirally pure (S)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4,7-dimethylisoindoline, substantially chirally pure (R)-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4,7-dimethylisoindoline, or mixtures thereof.  
     
     
         10 . The compound according to    claim 1   , which is substantially chirally pure (S)-1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-methylisoindoline, substantially chirally pure (R)-1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-methylisoindoline, or mixtures thereof.  
     
     
         11 . The compound according to    claim 1   , which is substantially chirally pure (S)-1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,7-dimethylisoindoline, substantially chirally pure (R)-1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,7-dimethylisoindoline, ord mixtures thereof.  
     
     
         12 . The compound according to    claim 1   , which is substantially chirally pure (S)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline, substantially chirally pure (R)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline, or mixtures thereof.  
     
     
         13 . The compound according to    claim 1   , which is substantially chirally pure (S)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-ethylisoindoline, substantially chirally pure (R)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-ethylisoindoline, or mixtures thereof.  
     
     
         14 . The compound according to    claim 1   , which is substantially chirally pure (S)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,7-dimethylisoindoline, substantially chirally pure (R)-1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,7-dimethylisoindoline, or mixtures thereof.  
     
     
         15 . The compound according to    claim 1   , which is substantially chirally pure (S)-1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-methylisoindoline, substantially chirally pure (R)-1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-methylisoindoline, or mixtures thereof.  
     
     
         16 . The compound according to    claim 1   , which is substantially chirally pure (S)-1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,7-dimethylisoindoline, substantially chirally pure (R)-1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,7-dimethylisoindoline, or mixtures thereof.  
     
     
         17 . A method of reducing undesirable levels of inflammatory cytokines in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         18 . A pharmaceutical composition comprising a quantity of a compound according to    claim 1   , sufficient upon administration in a single or multiple dose regimen to reduce levels of inflammatory cytokines in a mammal in combination with a carrier.  
     
     
         19 . A method of treating inflammation in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         20 . A method of treating autoimmune diseases in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         21 . A method of treating in a mammal a disease selected from the group consisting of arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, aphthous ulcers, cachexia, graft versus host disease, asthma, adult respiratory distress syndrome, and acquired immune deficiency syndrome, which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         22 . A method of treating cancer in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         23 . A method of treating undesirable angiogenesis in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         24 . A method of reducing or inhibiting undesirable levels of TNFα in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         25 . A method of treating inflammatory diseases in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .  
     
     
         26 . The compound according to    claim 1   , which is substantially chirally pure (S)-isomer of a 2-(2,6-dioxopiperidin-3-yl)-isoindoline, a substantially chirally pure (R)-isomer of a 2-(2,6-dioxopiperidin-3-yl)-isoindoline, or mixtures thereof.  
     
     
         27 . A method of reducing or inhibiting undesirable levels of IL-1 in a mammal which comprises administering thereto an effective amount of a compound according to    claim 1   .