Anti-hypercholesterolemic compounds

1. A compound of 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(OC)R 6 , —O(OC)OR 8 , —O(CO)OR 9 , —O(CO)NR 6 R 7 , a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue;

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 , —O(CO)OR 9 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;

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

m, n and p are integers each independently selected from 0, 1, 2, 3 and 4;

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 independently 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 —NR 10 R 11 , —C≡C—C(O)R 13 , and —(CH 2 ) 3 —NR 10 R 14 ;

R 10 is independently selected at each occurrence from —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:

R 13 is selected from the group consisting of —OH and —NR 10 R 11 ; and

R 14 is selected from the group consisting of —C(O)—C 1-3 alkyl, —C(O)—NR 10 R 10 , —SO 2 —C 1-3 alkyl and —SO 2 -phenyl.

2. The compound of claim 1 wherein R is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , and —O(CO)NR 6 R 7 , a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue; R 2 is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 and —O(CO)NR 6 R 7 ; and t is selected from 0 and 1.

3. The compound of claim 2 wherein m, n and p are each independently selected from 0, 1, 2, 3 and 4; 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.

4. The compound of claim 1 wherein 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.

5. The compound of claim 1 wherein R is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 8 , —O(CO)NR 6 R 7 , a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue; and 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 .

6. The compound of claim 5 wherein 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.

7. The compound of claim 1 of Formula Ia:

and the pharmaceutically acceptable salts and esters thereof.

8. The compound of claim 1 wherein R 9 is —C≡C—CH 2 —NR 10 R 11 .

9. The compound of claim 3 wherein R 9 is —C≡C—CH 2 —NR 10 R 11 .

10. The compound of claim 6 wherein R 9 is —C≡C—CH 2 —NR 10 R 11 .

11. The compound of claim 7 selected from the group consisting of:

Compound

R 12

R 9

 7a)

methyl ester glucuronide

 7b)

glucuronide

 7c)

methyl ester glucuronide

 7d)

glucuronide

 7e)

methyl ester glucuronide

 7f)

glucuronide

 7g)

methyl ester glucuronide

 7h)

glucuronide

 7i)

methyl ester glucuronide

 7j)

glucuronide

 7k)

methyl ester glucuronide

 7l)

glucuronide

 7m)

methyl ester glucuronide

 7n)

glucuronide

 8b)

glucuronide

—C≡CH

 9a)

glucuronide

—(CH 2 ) 3 —NHS0 2 CH 3

 9b)

glucuronide

—(CH 2 ) 3 —NHS0 2 CH 3

10e)

glucuronide

—C≡C—COOH

11b)

glucuronide

—C≡C—C(O)NHCH 2 CH 3

and the pharmaceutically acceptable salts and esters thereof.

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

13. The method of claim 12 comprising administering a therapeutically effective amount of the compound in combination with a therapeutically effective amount of a cholesterol biosynthesis inhibitor to a patient in need of such treatment.

14. The method of claim 13 wherein the cholesterol biosynthesis inhibitor is an HMG-CoA reductase inhibitor.

15. 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.

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

17. 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.

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

19. The pharmaceutical composition of claim 18 additionally comprising a cholesterol biosynthesis inhibitor.

20. The pharmaceutical composition of claim 19 wherein the cholesterol biosynthesis inhibitor is an HMG-CoA reductase inhibitor.

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

4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate; 4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)-4-oxoazetidin-2-yl]phenyl β-D-glucopyranosiduronic acid; and the pharmaceutically acceptable salts and esters thereof.

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

4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate;

4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenyl β-D-glucopyranosiduronic acid; and the pharmaceutically acceptable salts and esters thereof.

23. The compound of claim 22 selected from the group consisting of:

[ 35 S]4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate; [ 35 S]4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenyl β-D-glucopyranosiduronate; and the pharmaceutically acceptable salts and esters thereof.

24. The compound of claim 1 wherein:

R9 is selected from the group consisting of —C≡C—CH 2 —NR 10 R 11 ,—C≡C—C(O)R 13 wherein R 13 is —NR 10 R 11 , and —(CH 2 ) 3 —NR 10 R 14 ;

R 11 is selected from the group consisting of — 35 SO 2 —C 1-3 alkyl, and — 35 SO 2 -phenyl; and

R 14 is selected from the group consisting — 35 SO 2 —C 1-3 alkyl and — 35 S 2 -phenyl;

and the pharmaceutically acceptable salts and esters thereof.

25. The compound of claim 1 having the structural formula

wherein R 12 is selected from the group consisting of

and the pharmaceutically acceptable salts and esters thereof.

26. The compound of claim 25 wherein R 11 is selected from the group consisting of — 35 SO 2 —C 1-3 alkyl and — 35 SO 2 -phenyl; and the pharmaceutically acceptable salts and esters thereof.

27. The compound of claim 7 wherein R 9 is —C≡C—CH 2 —NR 10 R 11 , and the pharmaceutically acceptable salts and esters thereof.

28. The compound of claim 4 wherein R 9 is —C≡C—CH 2 —NR 10 R 11 , and the pharmaceutically acceptable salts and esters thereof.

29. The compound of claim 7 wherein:

R 9 is selected from the group consisting of —C≡C—CH 2 —NR 10 R 11 , —C≡C—C(O)R 13 wherein R 13 is —NR 10 R 11 , and —(CH 2 ) 3 -NR 10 R 14 ;

R 11 is selected from the group consisting of — 35 SO 2 —C 1-3 alkyl and — 35 SO 2 -phenyl; and

R 14 is selected from the group consisting of — 35 SO 2 —C 1-3 alkyl and — 35 SO 2 -phenyl;

and the pharmaceutically acceptable salts and esters thereof.