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)OR 8 , —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 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;

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 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 ) y —NR 10 R 11 , —(CH 2 ) 2 —(CH 2 ) y NR 10 R 11 and —C≡C—C(O)R 16 ;

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; and

R 12 is selected from the group consisting of R 13 , —C 1-8 alkyl-R 13 , —CH═CH—(CH 2 ) w —R 13 and —C≡C—(CH 2 ) w —R 13 , provided that when R 12 is —C 1-8 alkyl-R 13 then R 9 is —(CH 2 ) 2 —(CH 2 ) y NR 10 R 11 ;

w is an integer independently selected at each occurrence from 0, 1, 2, 3, 4, 5 and 6;

y is an integer independently selected at each occurrence from 1, 2, 3, 4, 5 and 6;

R 13 is

R 14 is selected from the group consisting of —COOH, —COOC 1-6 alkyl, —CH 2 OH, —CH 2 O(CH 2 ) y —R 15 , —CONR 10 R 10 and

R 15 is independently selected at each occurrence from the group consisting of —H, —OH, —COOR 10 , —NR 10 R 17 , —NR 10 COR 17 , —NR 10 COOR 17 , —NR 10 —SO 2 R 17 and —NR 10 —CONR 10 R 17 ;

R 16 is selected from the group consisting of —OH, —OC 1-6 alkyl and —NR 10 R 11 ; and

R 17 is selected from the group consisting of —H, —C 1-3 alkyl, phenyl and —CH 2 -phenyl.

2. The compound of claim 1 having structural Formula Ia

and the pharmaceutically acceptably salts and esters thereof.

3. The compound of claim 2 having structural Formula Ib

4. The compound of claim 1 wherein R 9 is selected from —C≡C—(CH 2 ) y —NR 10 R 11 and —(CH 2 ) 2 —(CH 2 ) y NR 10 R 11 .

5. The compound of claim 4 wherein R 9 is selected from —C≡C—CH 2 —NR 10 R 11 and —(CH 2 ) 3 —NR 10 R 11 .

6. The compound of claim 5 wherein R 9 is selected from —C≡C—CH 2 —N(R 10 )(SO 2 —C 1-3 alkyl), —C≡C—CH 2 —N(R 10 )(SO 2 -phenyl), —(CH 2 ) 3 —N(R 10 )(SO 2 —C 1-3 alkyl) and —(CH 2 ) 3 —N(R 10 )(SO 2 -phenyl).

7. The compound of claim 1 wherein R 12 is selected from R 13 , —CH 2 —R 13 , —CH 2 —CH 2 —R 13 and —C≡C—R 13 .

8. The compound of claim 4 wherein R 12 is selected from R 13 , —CH 2 —R 13 , —CH 2 —CH 2 —R 13 and —C≡C—R 13 .

9. The compound of claim 5 wherein R 12 is selected from R 13 , —CH 2 —R 13 , —CH 2 —CH 2 —R 13 and —C≡C—R 13 .

10. The compound of claim 6 wherein R 12 is selected from R 13 , —CH 2 —R 13 , —CH 2 —CH 2 —R 13 and —C≡C—R 13 .

11. The compound of claim 8 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.

12. The compound of claim 11 wherein R is —OR 6 and R 1 is —H.

13. The compound of claim 1 selected from:

N-[3-(4-{(2S,3R)-2-(-(4-{[(2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl-2-yl}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]-N-methylmethanesulfonamide;

N-[3-(4-{(2S,3R)-2-(4-{[(2S, 5S, 3R, 4R, 6S)-3,4,5-trihydroxy-6-(carboxy)perhydro-2H-pyran-2-yl]ethyl-2-yl}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]-N-methylmethanesulfonamide;

N-[3-(4-{(2S,3R)-2-(-(4-{[2S, 5S, 3R, 4R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl-2-yl}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]methanesulfonamide;

2,6-anhydro-7,8-dideoxy-8-{4-[(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[methyl(methylsulfonyl)amino]propyl}phenyl)-4-oxoazetidin-2-yl]phenyl}-L-gulo-octonic acid;

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

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

19. The pharmaceutical composition of claim 15 additionally comprising a cholesterol biosynthesis inhibitor.