Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

Abstract

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

1 - 352 . (canceled)  
     
     
         353 . A compound of formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         q is 1 or 2; n is 2; R 1  and R 2  are each alkyl; R 3  is hydroxy; R 4  and R 6  are hydrogen; and  
         R 5  has the formula (ii)  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         t is an integer from 0 to 5;  
         one or more R y  are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , SO 2 R 13 , SO 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 CO 2 R 14 , OC(O)R 13 , OC(O)R 13 R 14 , NR 13 SOR 14 , NR 13 SO 2 R 14 , NR 13 SONR 14 R 15 , NR 13 SO 2 NR 14 R 15 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A − , P(OR 13 )OR 14 , S + R 13 R 14 A − , and N + R 9 R 11 R 12 A − ; and  
         A −  is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and  
         said R y  alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups selected from the group consisting of OR 7 , NR 7 R 8 , SR 7 , S(O)R 7 , SO 2 R 7 , SO 3 R 7 , CO 2 R 7 , CN, oxo CONR 7 R 8 , N + R 7 R 8 R 9 A − , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 A − , and P(O)(OR 7 )OR 8 ; and  
         said R y  alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 , N + R 7 R 8 A − , S, SO, SO 2 , S + R 7 A − , PR 7 , P(O)R 7 , P + R 7 R 8 A − , or phenylene; and  
         R 13 , R 14 , and R 15  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, and  
         said R 13 , R 14 , and R 5  alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9 , N + R 9 R 10 A − , S, SO, SO 2 , S + R 9 A − , PR 9 , P + R 9 R 10 A − , P(O)R 9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide, and  
         R 13 , R 14 , and R 15  are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A − , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 2 R 9 , CN, halogen, CONR 9 R 10 , SO 2 OM, SO 2 NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R 11 A − , S + R 9 R 10 A − , and C(O)OM; or  
         R 13  and R 14 , together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or  
         R 14  and R 15 , together with the nitrogen atom to which they are attached, form a cyclic ring; and  
         R 9  and R 10  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; and  
         R 11  and R 12  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , CO 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9  and R 10  are as defined above; or  
         R 11  and R 12  together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and  
         R 16  and R 17  are independently selected from the substituents constituting R 9  and M; and  
         R 7  and R 8  are hydrogen; and  
         one or more R x  are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or  
         a pharmaceutically acceptable salt, solvate, or prodrug thereof.  
       
     
     
         354 . A compound of  claim 353  wherein R 1  and R 2  are each n-butyl.  
     
     
         355 . A compound of  claim 354  wherein t is 1, R y  is OR 13 .  
     
     
         356 . A compound of  claim 355  wherein one or more R x  are independently selected from methoxy and dimethylamino.  
     
     
         357 . A compound of  claim 355  wherein R x  is dimethylamino.  
     
     
         358 . A compound of  claim 355  wherein: 
 R y  is para-OR 13  or meta-OR 13 .  
 
     
     
         359 . A compound of  claim 355  having the 4R,5R configuration.  
     
     
         360 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         361 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         362 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         363 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         364 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         365 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         366 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         367 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         368 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         369 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         370 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         371 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         372 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         373 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         374 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         375 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         376 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         377 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         378 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         379 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         380 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         381 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         382 . The compound of  claim 353  having the structural formula:  
       
         
           
           
               
               
           
         
         wherein R is PEG having a molecular weight of 5000 g/mol.