Alpha-aryl-N-alkylnitrones and pharmaceutical compositions containing the same

Abstract

Disclosed are novel α-aryl-N-alkylnitrone compounds and pharmaceutical compositions containing such compounds. The disclosed compositions are useful as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals.

1 - 44 . (canceled)  
     
     
         45 . A method for ameliorating a cause of a neurodegenerative disease in a patient at risk for developing the neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-cause-ameliorating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;  
 R 2  is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1  and R 2  are attached to adjacent carbon atoms, R 1  and R 2  may be joined together to form an alkylenedioxy group;  
 R 3  is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;  
 R 4  is selected from the group consisting of hydrogen and alkyl;  
 R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substituted alkyl having at least 3 carbon atoms and cycloalkyl;  
 provided that:  
 (i) when R 2  and R 3  are independently hydrogen or methoxy, R 1  is not methoxy;  
 (ii) when R 2 , R 3  and R 4  are hydrogen and R 5  is tert-butyl, then R 1  is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;  
 (iii) when R 2 , R 3  and R 4  are hydrogen and R 5 is isopropyl, then R 1  is not 4-ethoxy;  
 (iv) when R 1  and R 2  are joined together to form a 3,4-methylenedioxy group and R 3  are R 4  are hydrogen, then R 5  is not isopropyl or tert-butyl;  
 (v) when R 2 , R 3  and R 4  are hydrogen and R 5  is 1-hydroxy-2-methylprop-2-yl, then R 1  is not 2-ethoxy;  
 (vi) when R 1  is 4-methoxy, R 2  is 3-ethoxy, and R 3  and R 4  are hydrogen, then R 5  is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and  
 (vii) when R 3  and R 4  are hydrogen and R 5  is tert-butyl, then R 1  is not 4-methoxy when R 2  is 2-fluoro, and R 1  is not 2-methoxy when R 2  is 4-fluoro.  
 
     
     
         46 . The method according to  claim 45 , wherein the neurodegenerative disease is Alzheimer's disease.  
     
     
         47 . The method according to  claim 45 , wherein the neurodegenerative disease is Parkinson's disease.  
     
     
         48 . The method according to  claim 45 , wherein the neurodegenerative disease is HIV dementia.  
     
     
         49 . (canceled)  
     
     
         50 . A method for ameliorating a cause of an autoimmune disease in a patient at risk for developing the autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-cause-ameliorating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;  
 R 2  is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1  and R 2  are attached to adjacent carbon atoms, R 1  and R 2  may be joined together to form an alkylenedioxy group;  
 R 3  is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;  
 R 4  is selected from the group consisting of hydrogen and alkyl;  
 R 5  is selected from the group consisting of alkyl having at least 3 carbon atoms, substituted alkyl having at least 3 carbon atoms and cycloalkyl;  
 provided that:  
 (i) when R 2  and R 3  are independently hydrogen or methoxy, R 1  is not methoxy;  
 (ii) when R 2 , R 3  and R 4  are hydrogen and R 5  is tert-butyl, then R 1  is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;  
 (iii) when R 2 , R 3  and R 4  are hydrogen and R 5  is isopropyl, then R 1  is not 4-ethoxy;  
 (iv) when R 1  and R 2  are joined together to form a 3,4-methylenedioxy group and R 3  are R 4  are hydrogen, then R 5  is not isopropyl or tert-butyl;  
 (v) when R 2 , R 3  and R 4  are hydrogen and R 5  is 1-hydroxy-2-methylprop-2-yl, then R 1  is not 2-ethoxy;  
 (vi) when R 1  is 4-methoxy, R 2  is 3-ethoxy, and R 3  and R 4  are hydrogen, then R 5  is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and  
 (vii) when R 3  and R 4  are hydrogen and R 5  is tert-butyl, then R 1  is not 4-methoxy when R 2  is 2-fluoro, and R 1  is not 2-methoxy when R 2  is 4-fluoro.  
 
     
     
         51 . The method according to  claim 50 , wherein the autoimmune disease is systemic lupus.  
     
     
         52 . The method according to  claim 50 , wherein the autoimmune disease is multiple sclerosis.  
     
     
         53 . (canceled)  
     
     
         54 . A method for ameliorating a cause of an inflammatory disease in a patient at risk for developing the inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-cause-ameliorating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;  
 R 2  is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1  and R 2  are attached to adjacent carbon atoms, R 1  and R 2  may be joined together to form an alkylenedioxy group;  
 R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;  
 R 4 is selected from the group consisting of hydrogen and alkyl;  
 R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substituted alkyl having at least 3 carbon atoms and cycloalkyl;  
 provided that:  
 (i) when R 2  and R 3  are independently hydrogen or methoxy, R 1  is not methoxy;  
 (ii) when R 2 , R 3  and R 4  are hydrogen and R 5 is tert-butyl, then R 1  is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;  
 (iii) when R 2 , R 3  and R 4  are hydrogen and R 5  is isopropyl, then R 1  is not 4-ethoxy;  
 (iv) when R 1  and R 2  are joined together to form a 3,4-methylenedioxy group and R 3  are R 4  are hydrogen, then R 5  is not isopropyl or tert-butyl;  
 (v) when R 2 , R 3  and R 4  are hydrogen and R 5  is 1-hydroxy-2-methylprop-2-yl, then R 1  is not 2-ethoxy;  
 (vi) when R 1  is 4-methoxy, R 2  is 3-ethoxy, and R 3  and R 4  are hydrogen, then R 5  is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and  
 (vii) when R 3  and R 4  are hydrogen and R 5  is tert-butyl, then R 1  is not 4-methoxy when R 2  is 2-fluoro, and R 1  is not 2-methoxy when R 2  is 4-fluoro.  
 
     
     
         55 . The method according to  claim 54 , wherein the inflammatory disease is rheumatoid arthritis.  
     
     
         56 . The method according to  claim 54 , wherein the inflammatory disease is septic shock.  
     
     
         57 . The method according to  claim 54 , wherein the inflammatory disease is nodosum leprosy.  
     
     
         58 . The method according to  claim 54 , wherein the inflammatory disease is septicemia.  
     
     
         59 . The method according to  claim 54 , wherein the inflammatory disease is uveitis.  
     
     
         60 . The method according to  claim 54 , wherein the inflammatory disease is adult respiratory distress syndrome.  
     
     
         61 . The method according to  claim 54 , wherein the inflammatory disease is inflammatory bowel disease.