Methods for the treatment of atherosclerosis, using substituted phenethylsulfones

Abstract

Methods and compositions for the prevention and treatment of all forms of atherosclerosis are described. Administration of compounds such as thalidomide, its analogs, hydrolysis products, metabolites, derivatives and precursors as well as additional compounds capable of inhibiting tumor necrosis factor α (TNF-α) are used in the invention. Also disclosed is the coating of prosthetic devices, such as stents, with the compounds of the invention for the prevention and/or treatment of restenosis.

1 .- 42 . (canceled)  
     
     
         43 . A method of treating atherosclerosis in a mammal comprising administering to a mammal having atherosclerosis an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       in which 
 the carbon atom designated * constitutes a center of chirality;  
 Y is C═O, CH 2 , SO 2 , or CH 2 C═O;  
 each of R 1 , R 2 , R 3 , and R 4 , independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR 8 R 9 ; or any two of R 1 , R 2 , R 3 , and R 4  on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene;  
 each of R 5  and R 6 , independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;  
 R 7  is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR 8′  R 9′ ;  
 each of R 8  and R 9  taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R 8  and R 9  is hydrogen and the other is —COR 10  or —SO 2 R 10 , or R 8  and R 9  taken together are tetramethylene, pentamethylene, hexamethylene, or CH 2 CH 2 X 1 CH 2 CH 2  in which X 1  is —O—, —S— or —NH—;  
 each of R 8′  and R 9′  taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R 8′  and R 9′  is hydrogen and the other is —COR 10′  or —SO 2 R 10′ , or R 8′  and R 9′  taken together are tetramethylene, pentamethylene, hexamethylene, or CH 2 CH 2 X 2 CH 2 CH 2  in which X 2  is —O—, —S—, or —NH—; R 10  is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and R 10′  is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl;  
 or a physiologically acceptable salt or an optically active enantiomer thereof.  
 
     
     
         44 . A method of  claim 43  wherein the compound is of the formula:  
       
         
           
           
               
               
           
         
         or a physiologically acceptable salt thereof.  
       
     
     
         45 . The method of  claim 43  or  44  wherein the atherosclerosis is in the aorta, coronary artery, mesenteric arteries, or carotid arteries.  
     
     
         46 . The method of  claim 43  or  44  wherein the atherosclerosis is in a renal artery.  
     
     
         47 . The method of  claim 43  or  44  wherein the mammal is a human.  
     
     
         48 . The method of  claim 43  or  44  wherein approximately 0.01 mg/kg to 300 mg/kg of body weight is administered per day.  
     
     
         49 . The method of  claim 48  wherein approximately 0.1 mg/kg to 100 mg/kg of body weight is administered per day.  
     
     
         50 . The method of  claim 43  or  44  wherein the administration is oral.  
     
     
         51 . The method of  claim 43  or  44  wherein the atherosclerosis is in the common iliac arteries, internal iliac arteries, external iliac arteries, or the pulmonary arteries.  
     
     
         52 . The method of  claim 43  or  44 , wherein the compound is administered in the form of a capsule, a tablet, a cachet, a solution, a suspension, an emulsion, a granule, a powder or a bolus.  
     
     
         53 . The method of  claim 44 , wherein the compound is of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         54 . The method of  claim 44 , wherein the compound is a physiologically acceptable salt.  
     
     
         55 . The method of  claim 44 , wherein the compound is an optically active enantiomer.