Phosphinylmethyl and phosphorylmethyl succinic and glutaric acid analogs as beta-secretase inhibitors

Abstract

The invention provides a compound of formula (I): or salts or hydrates thereof, useful as beta-secretase inhibitors. The invention further relates to a method of reducing plaque formation, particularly useful in the treatment of Alzheimer's disease.

1 . The compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or salts or hydrates thereof; 
 wherein n is 1 or 2;  
 wherein X is a phosphinylmethyl or phosphorylmethyl of the formula (II):  
                     
 wherein R 1  is H, OH, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R; wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl; and where m is 1 to 5;  
 wherein R 2  is H, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R with the proviso that R 2  is not OH;  
 wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C5-C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl, where m is 1 to 5.  
 
     
     
         2 . The compound of  claim 1  that comprises a phosphorylmethyl succinic acid having R 1 ═OH or a salt or hydrate thereof.  
     
     
         3 . The compound of  claim 1  that comprises a phosphorylmethyl glutaric acid having R 1 ═OH or a salt or hydrate thereof.  
     
     
         4 . The compound of  claim 1  that comprises a phosphorylmethyl succinic acid having R 1 ═OCH 2 CH 2 CHMe 2  or a salt or hydrate thereof.  
     
     
         5 . The compound of  claim 1  that comprises a phosphorylmethyl glutaric acid having R 1 ═OCH 2 CH 2 CHMe 2  or a salt or hydrate thereof.  
     
     
         6 . The compound of  claim 1  that comprises a phosphinylmethyl succinic acid having R 1 ═CH 2 CH 2 CHMe 2  or a salt or hydrate thereof.  
     
     
         7 . The compound of  claim 1  that comprises a phosphinylmethyl glutaric acid having R 1 ═CH 2 CH 2 CHMe 2  or a salt or hydrate thereof.  
     
     
         8 . The compound of  claim 1  that comprises a mixture of at least two of said phosphorylmethyl and/or phosphinylmethyl succinic and/or glutaric acid compound and wherein said composition regulates the processing of APP.  
     
     
         9 . The compound of  claim 1  that is in a form suitable for systemic, intravenous, intraperitoneal, or nasal administration.  
     
     
         10 . A method for treating conditions associated with β-amyloid plaque accumulation comprising administering an amount effective to reduce or prevent plaque accumulation of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or salts or hydrates thereof; 
 wherein n is 1 or 2;  
 wherein X is a phosphinylmethyl or phosphorylmethyl of the formula (II):  
                     
 wherein R 1  is H, OH, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R; wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl; and where m is 1 to 5;  
 wherein R 2  is H, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R with the proviso that R 2  is not OH;  
 wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl, where m is 1 to 5.  
 
     
     
         11 . The method of  claim 10  wherein said compound is administered to a subject.  
     
     
         12 . The method of  claim 10  wherein said compound reduces plaque accumulation.  
     
     
         13 . The method of  claim 10  wherein said condition is Alzheimer's disease.  
     
     
         14 . The method of  claim 10  wherein said compound inhibits β-amyloid protein accumulation to slow or prevent neurotoxicity.  
     
     
         15 . A method of inhibiting β-secretase comprising administering to a subject  
       
         
           
           
               
               
           
         
       
       an amount effective to reduce or prevent plaque accumulation of a compound of formula (I): 
 or salts or hydrates thereof;  
 wherein n is 1 or 2;  
 wherein X is a phosphinylmethyl or phosphorylmethyl of the formula (II):  
                     
 wherein R 1  is H, OH, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R; wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl; and where m is 1 to 5;  
 wherein R 2  is H, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R with the proviso that R 2  is not OH;  
 wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl, where m is 1 to 5.  
 
     
     
         16 . A method of increasing the (x-secretory pathway comprising administering to a subject an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or salts or hydrates thereof; 
 wherein n is 1 or 2;  
 wherein X is a phosphinylmethyl or phosphorylmethyl of the formula (II):  
                     
 wherein R 1  is H, OH, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R; wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl; and where m is 1 to 5;  
 wherein R 2  is H, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R with the proviso that R 2  is not OH;  
 wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl, where m is 1 to 5.  
 
     
     
         17 . A method for testing β-amyloid plaque production comprising administering an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or salts or hydrates thereof; 
 wherein n is 1 or 2;  
 wherein X is a phosphinylmethyl or phosphorylmethyl of the formula (II):  
                     
 wherein R 1  is H, OH, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R; wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl; and where m is 1 to 5;  
 wherein R 2  is H, R, OR, SR, N(R) 2 , (CH 2 ) m C(O)R, (CH 2 ) m COOR, (CH 2 ) m P(O)(OR) 2 , or (CH 2 ) m SO 2 R with the proviso that R 2  is not OH;  
 wherein each R is independently H, (C 1 -C 22 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C 2 -C 22 )alkenyl, (C 5 -C 8 )cycloalkenyl, (C 7 -C 32 )aralkyl, (C 7 -C 32 )alkylaryl, (C 9 -C 32 )aralkenyl, or (C 9 -C 32 )alkenylaryl, where m is 1 to 5.  
 
     
     
         18 . The method of  claim 17  wherein said testing is in vivo or in vitro.  
     
     
         19 . The method of  claim 18  wherein said compound is administered to a biological sample.  
     
     
         20 . The method of  claim 19  wherein said compound is administered to a cell.