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

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:
• Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl;
• Ar3 is aryl or R5-substituted aryl;
• X, Y and Z are independently selected from the group consisting of —CH2-, —CH(lower alkyl)- and —C(dilower alkyl)-;
• R and R2 are independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9 and —O(CO)NR6R7;
• R1 and R3 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;
• R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, —CH═CH—COOR6, —CF3, —CN, —NO2 and halogen;
• R5 is 1-5 substituents independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-50R6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
• R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
• and
• R9 is lower alkyl, aryl or aryl-substituted lower alkyl.