Anti-hypercholesterolemic compounds

1. A compound of structural Formula I

and the pharmaceutically acceptable salts and esters thereof, wherein

Ar 1 is selected from the group consisting of aryl and R 4 -substituted aryl;

X, Y and Z are independently selected from the group consisting of —CH 2 —, —CH(C 1-6 alkyl)— and —C(C 1-6 alkyl) 2 —;

R is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)O R 8 , and —O(CO)NR 6 R 7 ;

R 1 is selected from the group consisting of —H, —C 1-6 alkyl and aryl, or R and R 1 together are oxo;

R 2 is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 8 and —O(CO)NR 6 R 7 ;

R 3 is selected from the group consisting of —H, —C 1-6 alkyl and aryl, or R 2 and R 3 together are oxo;

q and r are integers each independently selected from 0 and 1 provided that at least one of q and r is 1;

m, n and p are integers each independently selected from 0, 1, 2, 3 and 4; provided that 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, then the sum of m, q and n is 1, 2, 3, 4, or 5;

t is an integer selected from 0, 1 and 2;

R 4 is 1-5 substituents independently selected at each occurrence from the group consisting of:

—OR 5 , —O(CO)R 5 , —O(CO)OR 8 , —O—C 1-5 alkyl-OR 5 , —O(CO)NR 5 R 6 , —NR 5 R 6 , —NR 5 (CO)R 6 , —NR 5 (CO)OR 8 , —NR 5 (CO)NR 6 R 7 , —NR 5 SO 2 R 8 , —COOR 5 , —CONR 5 R 6 , —COR 5 , —SO 2 NR 5 R 6 , —S(O) t R 8 , —O—C 1-10 alkyl-COOR 5 , —O—C 1-10 alkyl-CONR 5 R 6 and fluoro;

R 5 , R 6 and R 7 are independently selected at each occurrence from the group consisting of —H, —C 1-6 alkyl, aryl and aryl-substituted —C 1-6 alkyl;

R 8 is selected from the group consisting of —C 1-6 alkyl, aryl and aryl-substituted —C 1-6 alkyl;

R 9 is selected from the group consisting of —C≡C—(CH 2 ) y -NR 10 R 11 , —C═C—(CH 2 )y-NR 10 R 11 and —(CH 2 ) w -NR 10 R 11 ;

w is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; and

y is an integer selected from 1, 2, 3, 4, 5 and 6; and

R 10 is selected from the group consisting of —H and —C 1-3 alkyl;

R 11 is selected from the group consisting of —H, —C 1-3 alkyl, —C(O)—C 1-3 alkyl, —C(O)—NR 10 R 10 , —SO 2 —C 1-3 alkyl, and —SO 2 -phenyl;

R 12 is selected from the group consisting of —C 1-15 alkyl mono- or poly-substituted with —OH, —CH═CH—C 1-13 alkyl mono- or poly-substituted with —OH, —C≡C—C 1-13 alkyl mono- or poly-substituted with —OH, and

v is an integer selected from 0 and 1; and

R 13 is selected from the group consisting of —H and —OH.

2. The compound of claim 1 wherein r is zero and m is zero.

3. The compound of claim 2 wherein Ar 1 is selected from the group consisting of aryl and R 4 -substituted aryl wherein R 4 is 1-2 substituents independently selected at each occurrence from the group consisting of: —OR 5 , —O(CO)R 5 , —O(CO)OR 8 , —O—C 1-5 alkyl-OR 5 , —O(CO)NR 5 R 6 , —NR 5 R 6 , —NR 5 (CO)R 6 , —NR 5 (CO)OR 8 , —NR 5 (CO)NR 6 R 7 , —NR 5 SO 2 R 8 , —COOR 5 , —CONR 5 R 6 , —COR 5 , —SO 2 NR 5 R 6 , —S(O) t R 8 , —O—C 1-10 alkyl -COOR 5 , —O—C 1-10 alkyl-CONR 5 R 6 and fluoro.

4. The compound of claim 3 wherein R is —OR 6 and R 1 is —H.

5. The compound of claim 1 having structural Formula Ia

6. The compound of claim 5 wherein Ar 1 is selected from the group consisting of phenyl and R 4 -substituted phenyl wherein R 4 is 1-2 substituents independently selected at each occurrcnce from the group consisting of:

—OR 5 , —O(CO)R 5 , —O(CO)OR 8 , —O—C 1-5 alkyl-OR 5 , —O(CO)NR 5 R 6 , —NR 5 R 6 , —NR 5 (CO)R 6, —NR 5 (CO)OR 8 , —NR 5 (CO)NR 6 R 7 , —NR 5 SO 2 R 8 , —COOR 5 , —CONR 5 R 6 , —COR 5 , —SO 2 NR 5 R 6 , —S(O) t R 8 , —O—C 1-10 alkyl-COOR 5 , —O—C 1-10 alkyl-CONR 5 R 6 and fluoro.

7. The compound of claim 6 wherein R is —OR 6 and R 1 is —H.

8. The compound of claim 7 wherein R 9 is —(CH 2 ) w -NR 10 R 11 .

9. The compound of claim 1 having structural Formula Ib

10. The compound of claim 9 wherein R 9 is —(CH 2 ) w -NR 10 R 11 .

11. The compound of claim 1 selected from the group consisting of:

Example #

x

y

R 10

2

4

1

Methyl;

4

3

1

Methyl;

5

4

1

H;

6

1

1

H;

7

2

1

H;

8

3

4

H;

9

4

4

H;

10

1

4

H;

11

2

4

H;

12

2

2

H;

13

3

2

H;

14

4

2

H;

15

2

3

H;

16

3

3

H;

17

4

3

H;

18

1

2

H;

19

1

3

H;

and the pharmaceutically acceptable salts and esters thereof.

12. The compound of claim 1 selected from the group consisting of:

Example #

y

R 10

1

1

H;

20

2

H;

21

3

H;

22

4

H;

and the pharmaceutically acceptable salts and esters thereof.

13. The compound of claim 1 selected from the group consisting of:

Example #

y

R 13

R 10

3

1

OH

H;

23

2

OH

H;

24

3

OH

H;

25

4

OH

H;

26

2

OH

Methyl;

27

3

OH

Methyl;

28

4

OH

Methyl;

and the pharmaceutically acceptable salts and esters thereof.

14. A method of reducing plasma LDL-cholesterol levels comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

15. The method of claim 14 comprising administering a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of a cholesterol biosynthesis inhibitor to a patient in need of such treatment.

16. A method of treating hypercholesterolemia comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

17. A method of treating or reducing the risk for developing atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

18. A method of reducing the risk for having an atherosclerotic disease event comprising administering a prophylactically effective amount of a compound of claim 1 to a patient in at risk for such an event.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 additionally comprising a cholesterol biosynthesis inhibitor.