Methods and therapeutic combinations for the treatment of demyelination

1. A method of treating demyelination in a subject, comprising the step of administering to a subject in need of such treatment an effective amount of at least one sterol absorption inhibitor or a pharmaceutically acceptable salt or solvate thereof, wherein the at least one sterol absorption inhibitor is:

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 —CH 2 —, —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 substitutents 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 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 , —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.

2. The method according to claim 1 , wherein the at least one sterol 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 —C 2 —, —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 substitutents 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 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 CONRR 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.

3. The method according to claim 1 , wherein the at least one sterol absorption inhibitor is administered to a subject in an amount ranging from about 0.1 to about 1000 milligrams of sterol absorption inhibitor per day.

4. The method according to claim 1 , further comprising the step of administering at least one antidemyelination agent to the subject.

5. The method according to claim 4 , wherein the antidemyelination agent is selected from the group consisting of beta interferon, glatiramer acetate and corticosteroids.

6. The method according to claim 1 , further comprising the step of administering at least one HMG CoA reductase inhibitor to the subject.

7. The method according to claim 6 , wherein the at least one HMG CoA reductase inhibitor is atorvastatin.

8. The method according to claim 6 , wherein the at least one HMG CoA reductase inhibitor is simvastatin.

9. The method according to claim 1 , wherein the subject has multiple sclerosis.

10. A method of treating demyelination in a subject is provided, comprising the step of administering to a subject in need of such treatment an effective amount of at least one sterol absorption inhibitor represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof.

11. A method of treating multiple sclerosis in a subject, comprising the step of administering to a subject in need of such treatment an effective amount of at least one sterol absorption inhibitor of Formula (I) or (II) of claims 1 and 10 or a pharmaceutically acceptable salt or solvate thereof.