Methods and therapeutic combinations for the treatment of hypercholesterolemia and xanthoma using sterol absorption inhibitors

Abstract

The present invention provides therapeutic combinations and methods including at least one sterol or 5α-stanol absorption inhibitor that can be useful for treating xanthomas and hypercholesterolemia.

1 . A method of treating hypercholesterolemia and decreasing the incidence of xanthomas in a subject comprising the step of administering to a subject in need of such treatment an effective amount of a combination of (i) at least one sterol absorption inhibitor, at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof and (ii) at least one HMG CoA reductase inhibitor as a cholesterol biosynthesis inhibitor, to treat hypercholesterolemia and decrease the incidence of xanthomas in the subject, wherein the at least one sterol or 5α-stanol absorption inhibitor is represented by Formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein: 
 Ar 1  and Ar 2  are independently selected from the group consisting of aryl and R 4 -substituted aryl;  
 Ar 3  is aryl or R 5 -substituted aryl;  
 X, Y and Z are independently selected from the group consisting of —CH2-, —CH(lower alkyl)- and —C(dilower alkyl)-;  
 R and R 2  are independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9  and —O(CO)NR 6 R 7 ;  
 R 1  and R 3  are independently selected from the group consisting of hydrogen, lower alkyl and aryl;  
 q is 0 or 1;  
 r is 0 or 1;  
 m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;  
 R 4  is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO2R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6 , —CH═CH—COOR 6 , —CF 3 , —CN, —NO 2  and halogen;  
 R 5  is 1-5 substituents independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-50 R 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6  and —CH═CH—COOR 6 ;  
 R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and  
 R 9  is lower alkyl, aryl or aryl-substituted lower alkyl.  
 
   
   
       2 . The method according to  claim 1 , wherein the sterol or 5α-stanol absorption inhibitor is represented by Formula (II) below:  
     
       
         
         
             
             
         
       
     
   
   
       3 . The method according to  claim 1 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, rosuvastatin, atorvastatin, cerivastatin, and combinations thereof.  
   
   
       4 . The method according to  claim 1 , further comprising the step of co-administering probucol or derivatives thereof.  
   
   
       5 . The method according to  claim 1 , further comprising the step of co-administering at least one low-density lipoprotein receptor activator.  
   
   
       6 . The method according to  claim 1 , further comprising the step of co-administering at least one Omega 3 fatty acid.  
   
   
       7 . The method according to  claim 1 , further comprising the step of co-administering nicotinic acid or a derivative thereof.  
   
   
       8 . The method according to  claim 1 , further comprising the step of co-administering at least one AcylCoA:Cholesterol O-acyltransferase Inhibitor.  
   
   
       9 . The method according to  claim 1 , further comprising the step of co-administering at least one natural water soluble fiber.  
   
   
       10 . The method according to  claim 1 , further comprising the step of co-administering at least one of plant sterols, plant stanols or fatty acid esters of plant stanols.  
   
   
       11 . The method according to  claim 1 , further comprising the step of co-administering at least one antioxidant or vitamin.  
   
   
       12 . A therapeutic combination comprising (a) a first amount of at least one sterol absorption inhibitor, at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof and (b) a second amount of at least one HMG CoA reductase inhibitor as a cholesterol biosynthesis inhibitor, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment of hypercholesterolemia and xanthomas in a subject, wherein the at least one sterol or 5α-stanol absorption inhibitor is represented by Formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein: 
 Ar 1  and Ar 2  are independently selected from the group consisting of aryl and R 4 -substituted aryl;  
 Ar 3  is aryl or R 5 -substituted aryl;  
 X, Y and Z are independently selected from the group consisting of —CH2-, —CH(lower alkyl)- and —C(dilower alkyl)-;  
 R and R 2  are independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9  and —O(CO)NR 6 R 7 ;  
 R 1  and R 3  are independently selected from the group consisting of hydrogen, lower alkyl and aryl;  
 q is 0 or 1;  
 r is 0 or 1;  
 m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;  
 R 4  is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO2R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6 , —CH═CH—COOR 6 , —CF 3 , —CN, —NO 2  and halogen;  
 R 5  is 1-5 substituents independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6  and —CH═CH—COOR 6 ;  
 R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and  
 R 9  is lower alkyl, aryl or aryl-substituted lower alkyl.  
 
   
   
       13 . The method according to  claim 1 , wherein the at least one sterol absorption inhibitor, at least one 5a-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof is administered in an amount ranging from about 0.1 to about 1000 mg per day.  
   
   
       14 . The method according to  claim 13 , wherein the at least one sterol absorption inhibitor, at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 10 mg per day.  
   
   
       15 . The method according to  claim 1 , wherein the HMG CoA reductase inhibitor is administered in an amount of about 0.2 to about 80 mg per day.  
   
   
       16 . The method according to  claim 15 , wherein the HMG CoA reductase inhibitor is administered in an amount of about 20 mg per day.  
   
   
       17 . The method according to  claim 1 , wherein the HMG CoA reductase inhibitor is simvastatin.  
   
   
       18 . The method according to  claim 12 , wherein the at least one sterol absorption inhibitor, at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof is administered in an amount ranging from about 0.1 to about 1000 mg per day.  
   
   
       19 . The method according to  claim 18 , wherein the at least one sterol absorption inhibitor, at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 10 mg per day.  
   
   
       20 . The method according to  claim 12 , wherein the HMG CoA reductase inhibitor is administered in an amount of about 0.2 to about 80 mg per day.  
   
   
       21 . The method according to  claim 20 , wherein the HMG CoA reductase inhibitor is administered in an amount of about 20 mg per day.  
   
   
       22 . The method according to  claim 12 , wherein the HMG CoA reductase inhibitor is simvastatin.  
   
   
       23 . A method of treating hypercholesterolemia and decreasing the incidence of xanthomas in a subject comprising the step of administering to a subject in need of such treatment an effective amount of a combination of (i) a sterol absorption inhibitor of Formula (II):  
     
       
         
         
             
             
         
       
     
     and (ii) simvastatin, to treat hypercholesterolemia and decrease the incidence of xanthomas in the subject.  
   
   
       24 . A therapeutic combination comprising (a) a first amount of a sterol absorption inhibitor of Formula (II):  
     
       
         
         
             
             
         
       
     
     and (b) a second amount of simvastatin, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment of hypercholesterolemia and xanthomas in a subject.