WO2002058732B1

WO2002058732B1 - Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications

Info

Publication number: WO2002058732B1
Application number: PCT/US2002/002009
Authority: WO
Inventors: Teddy Kosoglou; Harry R Davis; Gilles Jean Bernard Picard; Wing-Kee Philip Cho
Original assignee: Schering Corp
Priority date: 2001-01-26
Filing date: 2002-01-25
Publication date: 2003-09-12
Also published as: CZ301871B6; AU2002247019B2; CZ309209B6; CA2563051A1; BR0206654A; JP4777602B2; DK1353696T3; WO2002058732A2; RS20100015A; US20050153952A1; CZ2010307A3; CY1107045T1; US7612058B2; YU58603A; PL368653A1; MXPA03006725A; US20020151536A1; JP2004521893A; US20080058306A1; JP2008088184A

Abstract

The present invention provides compositions, therapeutic combinations and methods including: (a) at least one peroxisome proliferator-activated receptor activator; and (b) at least one substituted azetidinone or substituted b-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols.

Claims

163

AMENDED CLAIMS

[Received by the International Bureau on 15 May 2003 ( 15.05.03 ): original claims 1 to 101 replaced by new claims 1 to 86;

(75 pages)]

THEREFORE, WE CLAIM:

1. A composition comprising: (a) a compound represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof,

(b) lactose monohydrate;

(c) microcrystalline cellulose

(d) povidone;

(e) croscarmellose sodium;

(f) sodium lauryl sulfate; and

(g) magnesium stearate.

2. The composition according to claim 1 , wherein the compound represented by Formula (II) is:

(II). 164

3. The composition according to claim 1 , wherein the composition comprises:

Ingredient Weight percent of ingredient

Compound of Formula (II) 10 Lactose monohydrate 55 Microcrystalline cellulose 20 Povidone 4

Croscarmellose sodium 8 Sodium lauryl sulfate 2 Magnesium stearate 1

Total 100

4. The composition according to claim 1 , wherein the composition comprises:

Ingredient milligrams of ingredient

Croscarmellose sodium 8 Sodium lauryl sulfate 2 Magnesium stearate 1

Total 100 165

5. A composition comprising:

(a) a compound represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof,

(b) lactose;

(c) cellulose; and

(d) Povidone.

6. The composition according to claim 3, wherein the composition further comprises croscarmellose sodium.

7. A therapeutic combination comprising:

(a) a first amount of at least one cholesterol biosynthesis inhibitor;

(b) a second amount of a compound represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof; 166

(c) lactose monohydrate;

(d) microcrystalline cellulose;

(e) povidone;

(f) croscarmellose sodium;

(g) sodium lauryl sulfate; and (h) magnesium stearate, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

8. The therapeutic combination according to claim 7, wherein the at least one cholesterol biosynthesis inhibitor is administered concomitantly with the compound of Formula (II).

9. A therapeutic combination according to claim 7, wherein the at least one cholesterol biosynthesis inhibitor and the compound of Formula (II) are present in separate treatment compositions.

10. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 1000 milligrams of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof.

11. The composition or therapeutic combination according to claim 10, wherein the composition or therapeutic combination comprises about 0.25 to about 50 milligrams of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof.

12. The composition or therapeutic combination according to claim 11 , wherein the composition or therapeutic combination comprises about 10 milligrams of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof.

13. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of lactose monohydrate based upon total weight of the composition.

14. The composition or therapeutic combination according to claim 13, wherein the composition or therapeutic combination comprises about 55 milligrams of lactose monohydrate.

15. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of microcrystalline cellulose based upon total weight of the composition.

16. The composition or therapeutic combination according to claim 15, wherein the composition or therapeutic combination comprises about 20 milligrams of microcrystalline cellulose.

17. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of povidone based upon total weight of the composition.

18. The composition or therapeutic combination according to claim 17, wherein the composition or therapeutic combination comprises about 4 milligrams of povidone. 168

19. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of croscarmellose sodium based upon total weight of the composition.

20. The composition or therapeutic combination according to claim 19, wherein the composition or therapeutic combination comprises about 8 milligrams of croscarmellose sodium.

2 . The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of sodium lauryl sulfate based upon total weight of the composition.

22. The composition or therapeutic combination according to claim 21 , wherein the composition or therapeutic combination comprises about 2 milligrams of sodium lauryl sulfate.

23. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination comprises about 0.1 to about 90 weight percent of magnesium stearate based upon total weight of the composition.

24. The composition or therapeutic combination according to claim 23, wherein the composition or therapeutic combination comprises about 1 milligram of magnesium stearate.

25. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination further comprises at least one peroxisome proliferator-activated receptor activator. 169

26. The composition or therapeutic combination according to claim 25, wherein the at least one peroxisome proliferator-activated receptor activator is a fibric acid derivative selected from the group consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol and mixtures thereof.

27. The composition or therapeutic combination according to claim 26, wherein the fibric acid derivative comprises fenofibrate.

28. The composition or therapeutic combination according to claim 26, wherein the fibric acid derivative comprises gemfibrozil.

29. The composition or therapeutic combination according to any of claims 1 , 5 or 7, wherein the composition or therapeutic combination further comprises at least one cholesterol biosynthesis inhibitor.

30. The composition or therapeutic combination according to claim 29, wherein the at least one cholesterol biosynthesis inhibitor comprises at least one HMG CoA reductase inhibitor.

31. The composition or therapeutic combination according to claim 30, wherein the at least one HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, cerivastatin and mixtures thereof.

32. The composition or therapeutic combination according to claim 31 , wherein the at least one HMG CoA reductase inhibitor is simvastatin.

33. The composition or therapeutic combination according to claim 31 , wherein the at least one HMG CoA reductase inhibitor is atorvastatin. 170

34. The composition or therapeutic combination according to claim 31 , wherein the at least one HMG CoA reductase inhibitor is rosuvastatin.

35. The composition or therapeutic combination according to any of claims 1 , 5 or 7, further comprising at least one lipid-lowering agent selected from the group consisting of bile acid sequestrants, nicotinic acid or derivatives thereof, CETP inhibitors, IBAT inhibitors, AcylCoA:Cholesterol O-acyltransferase Inhibitors, probucol or derivatives thereof, low-density lipoprotein receptor activators, Omega 3 fatty acids, natural water soluble fibers, plant sterols, plant stanols and fatty acid esters of plant stanols.

36. The composition or therapeutic combination according to any of claims 1 , 5 or 7, further comprising at least one additive selected from the group consisting of antioxidants, vitamins, hormone replacement therapy compositions, obesity control medications, blood modifiers, cardiovascular agents different from the compound of Formula II and antidiabetic medications.

37. A pharmaceutical composition comprising a therapeutically effective amount of the composition or therapeutic combination of any of claims 1, 5 or 7.

38. A method of treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising the step of administering to a mammal in need of such treatment an effective amount of a composition or therapeutic combination of any of claims 1 , 5, 7 or 37 above.

39. The method of claim 38, further comprising the step of administering to a mammal in need of such treatment an effective amount of an HMG CoA reductase inhibitor. 171

40. The method of claim 39, wherein the HMG CoA reductase inhibitor is simvastatin.

41. The method of claim 39, wherein the HMG CoA reductase inhibitor is atorvastatin.

42. The method of claim 39, wherein the HMG CoA reductase inhibitor is rosuvastatin.

43. A composition comprising:

(a) at least one sterol absorption inhibitor selected from the group consisting of:

(1) a sterol absorption inhibitor represented by Formula (I):

(I)

or pharmaceutically acceptable salts or solvates thereof, wherein in Formula (I) above:

1 2

Ar and Ar are independently selected from the group consisting of aryl

4 and R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

X, Y and Z are independently selected from the group consisting of

-CH2-, -CH(lower alkyl)- and -C(diIower alkyl)-;

R and R are independently selected from the group consisting of -OR , -O(CO)R⁶, -O(CO)OR⁹ and -O(CO)NR⁶R⁷; 172

1 3

R and R 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;

4

R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -O CH^OR⁶, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO2R⁹, -COOR⁶, -CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, S(O)_0.2R⁹, -O^H^^^-COOR⁶,

-O(CH₂)_1.10CONR⁶R⁷, -(lower alkylene)COOR⁶, -CH=CH-COOR⁶, -CF₃, -CN, -NO₂ and halogen;

5

R is 1-5 substituents independently selected from the group consisting of -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -OtCH^OR⁶, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂R⁹, -COOR⁶, -CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, S(O)_0.2R⁹, -O^H^.^-COOR⁶, -O(CH₂)₁.₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

6 7 8

R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

9

R is lower alkyl, aryl or aryl-substituted lower alkyl;

(2) a sterol absorption inhibitor represented by Formula (III):

(HI) 173

or pharmaceutically acceptable salts or solvates thereof , wherein in Formula (III) above:

1 3

Ar is R -substituted aryl;

2 4

Ar is R -substituted aryl;

3 5

Ar is R -substituted aryl;

Y and Z are independently selected from the group consisting of -CH₂-, -CH(lower alkyl)- and -C(dilower alkyl)-;

A is selected from -O-, -S-, -S(O)- or -S(O)₂~;

R is selected from the group consisting of -OR , -O(CO)R , -O(CO)OR and -O(CO)NR⁶R⁷;

2

R is selected from the group consisting of hydrogen, lower alkyl and aryl;

1 2 or R and R together are =O; q is 1 , 2 or 3; p is O, 1 , 2, 3 or 4;

5

R is 1-3 substituents independently selected from the group consisting of

-OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂-lower alkyl, -NR⁶SO₂-aryl, -CONRV, -COR⁶, -SO₂NR⁶R⁷, S(O)₀.₂-alkyl, S(O)_0.2-aryl, -O(CH₂).,_₁₀-COOR , -O(CH₂)_1.10CONR R , o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR , and -CH=CH-COOR ;

3 4

R and R are independently 1-3 substituents independently selected from

5 the group consisting of R , hydrogen, p-lower alkyl, aryl, -NO₂, -CF₃ and p- halogeno;

.6 _7

R R⁶, , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; (3) a sterol absorption inhibitor represented by Formula (IV) 174

(IV)

or pharmaceutically acceptable salts or solvates thereof, wherein, in Formula (IV) above:

2

A is selected from the group consisting of R -substituted heterocycloalkyi,

2 2 2

R -substituted heteroaryl, R -substituted benzofused heterocycloalkyi, and R - substituted benzofused heteroaryl;

1 3

Ar is aryl or R -substituted aryl;

2 4

Ar is aryl or R -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone, forms

the spiro group

; and

1

R is selected from the group consisting of:

-(CH₂)_q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;

-(CH₂)_e-G-(CH₂)_r-, wherein G is -O-, -C(O)-, phenylene, -NR - or -S(O)_0.2_, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C₂-C₆ alkenylene)-; and

-(CH₂)_f-V-(CH₂)_g-, wherein V is C₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;

5

R is selected from:

I I I I I I I

-CH-, -C(C_rC₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R⁹)-, -N-, or -⁺NO^" ;

R 7

R and R are independently selected from the group consisting of 175

-CH₂-, -CH(C_rC₆ alkyl)-, -C(di-(C₁-C₆) alkyl), -CH=CH- and

5 6 5

-C^-Cg alkyl)=CH-; or R together with an adjacent R , or R together with an adjacent R , form a -CH=CH- or a -CH=C(C₁-C₆ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero;

6 provided that when R is -CH=CH- or -0(0,-0,₃ alkyl)=CH-, a is 1 ; provided that when R is -CH=CH- or -C(C C₆ alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R 's can be the same or different; and provided that when b is 2 or 3, the R 's can be the same or different;

1 and when Q is a bond, R also can be selected from:

-M

where M is -O-, -S-, -S(O)- or -S(O)₂-;

X, Y and Z are independently selected from the group consisting of -CH₂-, -CH(C_rC₆ alkyl)- and -C(di-(C_rC₆) alkyl);

10 12

R and R are independently selected from the group consisting of

14 14 16 14 15

-OR , -O(CO)R , -O(CO)OR and -O(CO)NR R ;

11 13

R and R are independently selected from the group consisting of

10 11 12 13 hydrogen, (C,-C₆)alkyl and aryl; or R and R together are =O, or R and R together are =O; d is 1 , 2 or 3; h is 0, 1 , 2, 3 or 4; s is 0 or 1; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; 176

2

R is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C.,-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,

17 17

(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R -substituted aryl, R -substituted

17 17 14 15 benzyl, R -substituted benzyloxy, R -substituted aryloxy, halogeno, -NR R ,

14 15 14 15 16

NR R (C_rC₆ alkylene)-, NR R C^^-C_β alkylene)-,-NHC(O)R ,

1 fi 14

OH, O,-C₆ alkoxy, -OC(O)R , -COR , hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-

16 14 15 14 2

C₆)alkyl, NO₂, -S(O)₀.₂R , -SO₂NR R and -(C,-C₆ alkylene)COOR ; when R

2 is a substituent on a heterocycloalkyi ring, R is as defined, or is =O

or

is a substituent on a substitutable ring nitrogen, it is hydrogen,

(C_j-C₈jalkyl, aryl, (O^C^alkoxy, aryloxy, (C_j-C^alkylcarbonyl, arylcarbonyl, hydroxy,

18 18

-(CH₂)₁.₆CONR R ,

18 wherein J is -O-, -NH-, -NR - or -CH₂-;

3 4

R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (O^C_gJalkyl,

14 14 16 14 14 15 14 15

-OR , -O(CO)R , -O(CO)OR , -O^H^._gOR , -O(CO)NR R , -NR R ,

14 15 14 16 14 15 19 14 16 14

-NR (CO)R , -NR (CO)OR , -NR (CO)NR R , -NR SO2R , -COOR ,

14 15 14 14 15 16 14

-CONR R , -COR , -SO2NR R , S(O)₀.₂R , -O(CH₂).,.₁₀-COOR ,

-O(CH₂)₁.₁₀CONR¹⁴R¹⁵, -(C_rC₆ alkylene)-COOR¹⁴, -CH=CH-COOR¹⁴, -CF₃, -CN, -NO₂ and halogen;

8 14 14

R is hydrogen, (C_rC₆)alkyl, aryl (C^C^alkyl, -C(O)R or -COOR ; 177

9 17

R and R are independently 1-3 groups independently selected from the group consisting of hydrogen, (O,-C₆)alkyl, (C^C^alkoxy, -COOH, NO₂,

14 15

-NR R , OH and halogeno;

14 15

R and R are independently selected from the group consisting of hydrogen, (C,-C₆)alkyl, aryl and aryl-substituted (C.,-C₆)alkyl;

16 17

R is (C₁-C₆)alkyl, aryl or R -substituted aryl;

18

R is hydrogen or (C_j-C^alkyl; and

19

R is hydrogen, hydroxy or (C.,-C₆)alkoxy;

(4) a sterol absorption inhibitor represented by Formula (V):

(V) or pharmaceutically acceptable salts or solvates thereof , wherein in Formula (V) above:

1 10

Ar is aryl, R -substituted aryl or heteroaryl;

2 4

Ar is aryl or R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

X and Y are independently selected from the group consisting of -CH₂-, -CH(lower alkyl)- and -C(dilower alkyl)-;

R is -OR⁶, -O(CO)R⁶, -O(CO)OR⁹ or -O(CO)NR⁶R^?; R is hydrogen, lower

1 alkyl or aryl; or R and R together are =O; q is 0 or 1 ; r is 0, 1 or 2; m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;

4

R 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 and -CH=CH-COOR⁶;

5

R is 1-5 substituents independently selected from the group consisting of -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -O(CH₂)_1.5OR⁶, -O(CO)NR⁶R⁷, -NR⁶R^?, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂R⁹, -COOR⁶, -CONR⁶R⁷, - COR⁶, -SO₂NR⁶R⁷, S(O)_0.2R⁹, -O(CH₂).,_₁₀-COOR⁶, -O(CH₂)₁.₁₀CONR⁶R⁷, -CF₃,

R R

-CN, -NO₂, halogen, -(lower alkylene)COOR and -CH=CH-COOR ;

R 7 ft

R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; and

10

R 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).,_₁₀-COOR⁶,

-O(CH₂)₁.₁₀CONR⁶R , -CF₃, -CN, -NO₂ and halogen;

(5) a sterol absorption inhibitor represented by Formula (VI):

(VI) or pharmaceutically acceptable salts or solvates thereof, wherein in Formula VI above:

_{R1 is} -CH-, -C(lower alkyl)-, -CF-, -C(OH>, -C(C₆H₅)-, -C(C₆H₄-R₁₅)-, 179

- N- or -⁺N O^" ;

R2 and R3 are independently selected from the group consisting of: -CH2-, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or

R1 together with an adjacent R2, or R together with an adjacent R3, form a -CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v is 1 ; provided that when R3 is -CH=CH- or -C(lower alkyl)=CH-, u is 1 ; provided that when v is 2 or

3, the R2's can be the same or different; and provided that when u is 2 or 3, the R3's can be the same or different;

R4 is selected from B-(CH2)mC(O)-, wherein m is 0, 1 , 2, 3, 4 or 5; B-(CH2)q-, wherein q is 0, 1 , 2, 3, 4, 5 or 6;

B-(CH2)e-Z-(CH2)r_> wherein Z is -O-, -C(O)-, phenylene, -N(Rδ)- or -S(O)θ-2-, e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B-(C2-C6 alkenylene)-; B-(C4-C6 alkadienylene)-;

B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1 , 2, 3, 4 or 5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6; B-(CH2)t-V-(C2-C6 alkenylene)- or

B-(C2-C6 alkenylene)-V-(CH2)t-, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3,

4, 5 or 6;

B-(CH2)a-Z-(CH2)b-V-(CH2)d-, wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d 180

is 0, 1 , 2, 3, 4, 5 or 6; or T-(CH2)s-, wherein T is cycloalkyi of 3-6 carbon atoms and s is 0, 1 , 2, 3, 4, 5 or 6; or

I R1 and R4 together form the group B-CH=C- ;

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or

W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, -N(R8)(R9), N(Rδ)(R9)-lower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3, -NHC(O)ORιo, -NHC(O)Rio, R11O2SNH-, (Rnθ2S)2N-, -S(O)2NH2, -S(O)o-2R8> tert-butyldimethyl-silyloxymethyl, -C(O)Ri2, -COORig, -CON(Rδ)(R9), -CH=CHC(O)Ri2, -lower alkylene-C(O)Ri2, R θC(O)(lower alkylenyloxy)-, N(Rδ)(R9)C(O)(lower alkylenyloxy)- and

- CH₂- N R₁₃

^ — for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy,

-C(O)ORιo, -C(O)Rιo, OH, N(Rs)(R9)-lower alkylene-,N(R8)(R9)-lower alkylenyloxy-, -S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;

R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO2, -N(Rδ)(R9), OH, and halogeno; 181

Rδ and Rg are independently selected from H or lower alkyl; R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl; R 1 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7- benzyl;

R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,

^~ R₁₃

— , -N(Rδ)(R9), lower alkyl, phenyl or R7-phenyl;

R13 is selected from -O-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)R 9;

R15. R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R 6 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

R g is H, lower alkyl, phenyl or phenyl lower alkyl; and

R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above;

(6) a sterol absorption inhibitor represented by Formula (VII):

(VII) or pharmaceutically acceptable salts or solvates thereof, wherein in Formula (VII):

A is -CH=CH-, -C≡C- or -(CH2)p- wherein p is 0, 1 or 2; B is 182

E is C10 to C20 alkyl or -C(O)-(Cg to Cιg)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;

R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -, wherein r is 0, 1 , 2, or 3;

Rl , R2. and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR5, R6O2SNH- and -S(O)2NH2;

R4 is

wherein n is 0, 1, 2 or 3;

R5 is lower alkyl; and R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino;

(7) a sterol absorption inhibitor represented by Formula (VIII):

(VIII) or pharmaceutically acceptable salts or solvates thereof, wherein in Formula

(VIII) above:

R26 j_S H or OGl ; 183

G and G1 are independently selected from the group consisting of

H or

OH, G is not H;

R, R^a and R^D are independently selected from the group consisting of H, OH, halogeno, -NH2, azido, (Cι-C6)alkoxy(Cι-C6)-alkoxy or -W-R³⁰;

W is independently selected from the group consisting of -NH-C(O)-, -O-

C(O)-, -O-C(O)-N(R³¹)-, -NH-C(0)-N(R31 )- _and -0-C(S)-N(R31 )-;

R2 and R^ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl(C -C6)alkyl;

R³, R4, R5_; 7_ R3a _and R^a are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl(Cι-C6)alkyl, -C(O)(Cι-C6)alkyl and -C(O)aryI;

R³⁰ is selected from the group consisting of R³²-substituted T, R³²-substituted-T-(Ci-C6)alkyl, R³ -substituted-(C2-C4)alkenyl, R³²-substituted-(C -C6)alkyl, R³²-substituted-(C3-C7)cycloalkyl and R³²-substituted-(C3-C7)cycloalkyl(Cι-C6)alkyl;

R^3"! is selected from the group consisting of H and (C -C4)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; 184

R³² is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C -C4)alkyl, -OH, phenoxy, -CF3, -NO2, (C -C4)alkoxy, methylenedioxy, oxo, (C -C4)alkylsulfanyl, (Cι-C-4)alkylsulfinyl, (Cι-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(O)-(Cι-C4)alkyl, -C(O)-(C -C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³1 , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C -C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar^"! is aryl or Rl°-substituted aryl;

Ar² is aryl or R11 -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,

forms the spiro group

and

R1 is selected from the group consisting of

-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;

-(CH2)e-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR²²- or -S(O)o-2-. β is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6)alkenylene-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; Rl² is l l I ' i ,, I I

-CH-, -C(C,-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -⁺NO^' ;

R^³ and R14 are independently selected from the group consisting of - CH2-, -CH(C1-C6 alkyl)-, -C(di-(Cι-Ce) alkyl), -CH=CH- and 185

-C(C -C6 alkyl)=CH-; or R^"!² together with an adjacent R^³, or R¹² together with an adjacent R^'l4_j form a -CH=CH- or a -CH=C(Cι-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R1³ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, a is 1 ; provided that when R14 j_s -CH=CH- or -C(Cι-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R^³'s can be the same or different; and provided that when b is 2 or 3, the R^4's can be the same or different; and when Q is a bond, R^"! also can be:

-M -Y_d- -Y_k-S(O)_0.2-;

M is -O-, -S-, -S(O)- or -S(O)2-;

X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C1-C6)alkyl- and -C(di-(Cι-C6)alkyl);

R10 and R^"! 1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Cι-C6)alkyl, -OR 9, -O(CO)R¹⁹, -O(CO)OR²1 , -O(CH2)1-5OR19_J -O(CO)NR19R²0_; __NR19R20_J -NR19(CO)R²0, -NR19(C0)0R²1 , -NR19(CO)NR²OR²5, -NR1 _S02R²¹ , -COOR19, -CONR19R²0_J -COR19, -SO2NR1 R²0₇ S(O)O-2R²¹ , -O(CH2)1-10-COOR ⁹, -O(CH2)1-10CONR19R²0₇ -(C1-C6 alkyleneJ-COORlθ, -CH=CH-COOR¹⁹, -CF3, -CN, -NO2 and halogen;

R15 and R1⁷ are independently selected from the group consisting of - OR19, -O(CO)R¹⁹, -O(CO)OR²1 and -O(CO)NR ⁹R²⁰; 186

R16 and R^"!³ are independently selected from the group consisting of H, (Cι-C6)alkyl and aryl; or R^"l⁵ and R¹⁶ together are =O, or R ⁷ and R¹⁸ together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R¹⁵ -X_r(C)_v-Y_k-S(O)₀.₂- and when Q is a bond and R^ is R¹⁶ , Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R1 and R^2υ are independently selected from the group consisting of H, (C -C6)alkyl, aryl and aryl-substituted (Cι-C6)alkyl;

R²¹ is (Cι-C6)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R19 OΓ -COOR19_;

R²³ and R²4 are independently 1-3 groups independently selected from the group consisting of H, (C -C6)alkyl, (C -C6)alkoxy, -COOH, NO2,

-NR19R²0_I _OH and halogeno; and

R²⁵ is H, -OH or (Cι-C6)alkoxy; and

(8) a sterol absorption inhibitor represented by Formula (IX): 187

or pharmaceutically acceptable salts or solvates thereof, wherein, in Formula (IX) above,

R² is selected from the group consisting of: a) OH; b) OCH₃; c) fluorine and d) chlorine;

R¹ is selected from the group consisting of

tural

R, R^a and Rb are independently selected from the group consisting of H, OH, halogeno, -NH2, azido, (Cι-C6)alkoxy(C -C6)-alkoxy and -W-R³⁰;

W is independently selected from the group consisting of

-NH-C(O)-, -O-C(O)-, -O-C(O)-N(R³1 )-, -NH-C(O)-N(R 1)- and

-O-C(S)-N(R 1 )-;

R² and R⁶ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl(C -C6)alkyl; 188

R³, R4, R5, R7₍ R3a _anc| R4a _are independently selected from the group consisting of H, (C -C6)alkyl, aryl(Cι-C6)alkyl, -C(O)(Cι-C6)alkyl and -C(O)aryl;

R³⁰ is independently selected form the group consisting of R³²-substituted T, R³²-substituted-T-(C -C6)alkyl, R³ -substituted-(C2- C4)alkenyl, R³²-substituted-(Cι-C6)alkyl, R³²-substituted-(C3-C7)cycloalkyl and R³²-substituted-(C3-C7)cycIoalkyl(Cι-C6)alkyi;

R³1 is independently selected from the group consisting of H and (Cι-C )alkyl;

T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (C -C4)alkyl, -OH, phenoxy, -CF3, -NO2, (C -C4)alkoxy, methylenedioxy, oxo, (C -C4)alkylsulfanyl, (C -C4)alkylsulfinyl, (Cι-C4)alkylsulfonyI, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(O)-(Cι-C4)alkyl, -C(O)-(Cι-C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³^ , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Cι-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar^"! is aryl, R^ °-substituted aryl; pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

Ar² is aryl or Rl 1 -substituted aryl;

Q is -(CH2)q-, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone,

forms the spiro group (R )t> R ² is 189

I I I I I ₉, I . 1

-CH-, -C(C,-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -⁺NO^" ;

R^³ and R^'l are independently selected from the group consisting of - CH₂-, -CH(Cι-C6 alkyl)-, -C(di-(Cι-C6) alkyl), -CH=CH- and -C(Ci-C6 alkyl)=CH-; or

R^'l together with an adjacent R^'l³, or R^'l ² together with an adjacent R^'14, form a -CH=CH- or a -CH=C(Cι-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R ³ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, a is 1 ; provided that when R14 j_s -CH=CH- or -C(C -C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R1³'S can be the same or different; and provided that when b is 2 or 3, the Rl4's can be the same or different;

RlO and R^'l ^"I are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C -C6)alkyl,

-OR¹9, -O(CO)Rl9, -O(CO)OR²1 , -0(CH2)1-50R19, -O(CO)NR19R20, __NR19R20_J -NR19(CO)R²0, -NR19(C0)0R 1 , -NR19(CO)NR²0R25_> -NR19SO2R²¹ , -COOR19, -CONR^{1 9}R20, -C0R19, -SO2NR19R 0_J -S(O)o-2R²¹. -O(CH2)1-10-COOR¹⁹, -O(CH2)1-10CONR19R²0_J -(C1-C-6 alkylene)-COORl , -CH=CH-COORl9, -CF3, -CN, -NO2 and halogen;

R19 and R²^ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl-substituted (Cι-C6)alkyl;

R²1 is (Cι-C6)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R19 OΓ -COOR19_;

R²³ and R²4 are independently 1-3 groups independently selected from the group consisting of H, (Cι-C6)alkyl, (C -C6)alkoxy, -COOH, NO2, -

NR¹⁹R²⁰, -OH and halogeno; and

R25 js H, -OH or (Cι-C6)alkoxy; 190

(b) lactose monohydrate;

(c) microcrystalline cellulose;

(d) povidone;

(e) croscarmellose sodium;

(f) sodium lauryl sulfate; and

(g) magnesium stearate.

44. The composition according to claim 43, wherein the sterol absorption inhibitor is represented by Formula (X):

(X) or pharmaceutically acceptable salts or solvates of the compound of Formula (X), wherein R¹ is defined as in Formula (IX).

45. The composition according to claim 43, wherein the sterol absorption inhibitor is represented by Formula (XI):

or pharmaceutically acceptable salts or solvates of the compound of Formula (XI). 191

46. A pharmaceutical composition for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising a therapeutically effective amount of the composition of claim 43.

47. A method of treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising the step of administering to a mammal in need of such treatment an effective amount of the composition of claim 43.

48. A therapeutic combination comprising:

(a) a first amount of the composition of claim 43; and

(b) at least one cholesterol biosynthesis inhibitor, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

49. A method of treating or preventing a vascular condition, obesity, diabetes or lowering a concentration of a sterol in plasma of a mammal, comprising the step of administering to a mammal in need of such treatment an effective amount of the therapeutic combination of claim 48.

50. Use of a composition or therapeutic combination of any of claims 1 , 5, 7 or 43 for preparation of a medicament for treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

51. A composition comprising:

(a) at least one peroxisome proliferator-activated receptor activator; and 192

(b) at least one sterol absorption inhibitor represented by Formula (I):

(I) or pharmaceutically acceptable salts or solvates thereof, wherein in Formula (I) above:

1 2

Ar and Ar are independently selected from the group consisting of aryl

4 and R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

X, Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;

2 fi

R and R are independently selected from the group consisting of -OR , -O(CO)R⁶, -O(CO)OR⁹ and -O(CO)NR⁶R⁷;

1 3

4

R 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, -©(CH^^-COOR⁶,

-O(CH₂)₁.₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶, -CH=CH-COOR⁶, -CF₃, -CN, -NO₂ and halogen; 193

R is 1-5 substituents independently selected from the group consisting of -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 and -CH=CH-COOR⁶; fi ^"7 ft

R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and g

R is lower alkyl, aryl or aryl-substituted lower alkyl.

52. The composition according to claim 51 , wherein the sterol absorption inhibitor is represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof.

53. A therapeutic combination comprising:

(a) a first amount of at least one peroxisome proliferator-activated receptor activator; and

(b) a second amount of at least one sterol absorption inhibitor represented by Formula (I): 194

(0 or pharmaceutically acceptable salts thereof, wherein:

1 2

Ar and Ar are independently selected from the group consisting of aryl

4 and R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

1 3

R and R 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;

4

R 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;

5

R is 1-5 substituents independently selected from the group consisting of 195

-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 and

-CH=CH-COOR⁶; fi 7 ft

9

R is lower alkyl, aryl or aryl-substituted lower alkyl wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

54. The therapeutic combination according to claim 53, wherein the sterol absorption inhibitor is represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof.

54. A therapeutic combination according to claim 53, wherein the at least one peroxisome proliferator-activated receptor activator is administered concomitantly with the at least one sterol absorption inhibitor. 196

55. A therapeutic combination according to claim 53, wherein the at least one peroxisome proliferator-activated receptor activator and the at least one sterol absorption inhibitor are present in separate treatment compositions.

56. A composition comprising:

(a) at least one fibric acid derivative; and

(b) a compound represented by Formula (II) below:

or pharmaceutically acceptable salt or solvate thereof.

57. A composition comprising:

(a) at least one peroxisome proliferator-activated receptor activator; and

(b) at least one sterol absorption inhibitor selected from the group consisting of:

(1) a sterol absorption inhibitor represented by Formula (III):

(IN) 197

1 3

Ar is R -substituted aryl;

2 4

Ar is R -substituted aryl;

3 5

Ar is R -substituted aryl;

A is selected from -O-, -S-, -S(O)- or -S(O)₂-;

R is selected from the group consisting of -OR , -O(CO)R , -O(CO)OR⁹ and -O(CO)NR⁶R^?;

2

R is selected from the group consisting of hydrogen, lower alkyl and aryl;

1 2 or R and R together are =O; q is 1 , 2 or 3; p is O, 1, 2, 3 or 4;

5

R is 1-3 substituents independently selected from the group consisting of -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -O CH-^OR⁹, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂-lower alkyl, -NR⁶SO₂-aryl, -CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, S(O)₀.₂-alkyl, S(O)_0.2-aryl,

R R 7

-O(CH₂)_1-10-COOR , -O(CH₂)_1.10CONR R , o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR , and -CH=CH-COOR ;

3 4

R and R are independently 1-3 substituents independently selected from

6 7 8

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; (2) a sterol absorption inhibitor represented by Formula (IV) 198

(iv)

2

A is selected from the group consisting of R -substituted heterocycloalkyi,

2 2 2

1 3

Ar is aryl or R -substituted aryl;

2 4

Ar is aryl or R -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone, forms — ⁽R⁶⁾ >aa the spiro group ⁽R⁷) ^Ji^b ; and

1

R is selected from the group consisting of:

-(CH₂)_q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ; o

-(CH₂)_e-G-(CH₂)_r-, wherein G is -O-, -C(O)-, phenylene, -NR - or -S(O)₀_₂-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C₂-C₆ alkenylene)-; and

-(CH₂)fV-(CH₂)_g-, wherein V is C₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;

5

R is selected from:

I I I I I I J

-CH-, -C(C_rC₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R⁹)-, -N-, or -⁺NO^" ;

R and R are independently selected from the group consisting of 199

-CH₂-, -CH(C C₆ alkyl)-, -C(di-(C₁-C₆) alkyl), -CH=CH- and

5 6 5

-C(C.,-C₆ alkyl)=CH-; or R together with an adjacent R , or R together with an adjacent R , form a -CH=CH- or a -CH=C(C₁-C₆ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero;

6 provided that when R is -CH=CH- or -C^-C₈ alkyI)=CH-, a is 1 ; provided that when R is -CH=CH- or -C(C.,-C₆ alkyl)=CH-, b is 1 ; provided that when a is 2 or

6

3, the R 's can be the same or different; and provided that when b is 2 or 3, the R 's can be the same or different;

1 and when Q is a bond, R also can be selected from:

-M -Y_d- -Y_k-S(O)₀.₂-;

where M is -O-, -S-, -S(O)- or -S(O)₂-;

10 12

R and R are independently selected from the group consisting of

14 14 16 14 15

-OR , -O(CO)R , -O(CO)OR and -O(CO)NR R ;

11 13

R and R are independently selected from the group consisting of

1 Ω 11 19 1 ^ hydrogen, (C,-C₆)alkyl and aryl; or R and R together are =O, or R and R together are =O; d is 1, 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1 -5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; 200

2

R is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C^O^alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,

17 17

14 15 14 15 16

NR R (C.,-C₆ alkylene)-, NR R C(O)(C₁-C₆ alkylene)-,-NHC(O)R ,

16 14

OH, C_rC₆ alkoxy, -OC(O)R , -COR , hydroxy(C₁-C₆)aIkyl, (C₁-C₆)alkoxy(C₁-

16 14 15 14 2

C₆)alkyl, NO₂, -S(O)₀.₂R , -SO₂NR R and -(C_rC₆ alkylene)COOR ; when R

2 is a substituent on a heterocycloalkyi ring, R is as defined, or is =O

or o' ; and, where R is a substituent on a substitutable ring nitrogen, it is hydrogen,

(C_j-C₈jalkyl, aryl, (C C^alkoxy, aryloxy, (C^C_gJalkylcarbonyl, arylcarbonyl, hydroxy,

18 18

-(CH₂)₁.₆CONR R ,

18 wherein J is -O-, -NH-, -NR - or -CH₂-;

3 4

R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C^-C₆)a\ky\,

14 14 16 14 14 1 *1 14 15

-OR , -O(CO)R , -O(CO)OR , -O(CH₂)_1-5OR , -O(CO)NR R , -NR R ,

14 15 14 16 14 15 19 14 16 14

-NR (CO)R , -NR (CO)OR , -NR (CO)NR R , -NR SO2R , -COOR ,

14 15 14 14 15 16 14

-CONR R , -COR , -SO2NR R , S(O)₀.₂R , -O CH_g ^-COOR ,

14 15 14 14

-O(CH₂)_1-10CONR R , -(0,-C₈ alkylene)-COOR , -CH=CH-COOR , -CF₃, -CN, -NO₂ and halogen;

8 14 14

R is hydrogen, (C^C_gJalkyl, aryl (C.,-C₆)alkyl, -C(O)R or -COOR ; 201

9 17

R and R are independently 1-3 groups independently selected from the group consisting of hydrogen,

(O,-C₆)alkoxy, -COOH, NO₂,

14 15

-NR R , OH and halogeno;

14 15

R and R are independently selected from the group consisting of hydrogen, (C,-C₆)alkyl, aryl and aryl-substituted

16 17

R is (C,-C₆)alkyl, aryl or R -substituted aryl;

1R

R is hydrogen or (C,-C₆)alkyl; and

19

R is hydrogen, hydroxy or (C_|-C₆)alkoxy;

(3) a sterol absorption inhibitor represented by Formula (V):

(V)

or pharmaceutically acceptable salts or solvates thereof , wherein, in Formula (V) above:

1 10

Ar is aryl, R -substituted aryl or heteroaryl;

2 4

Ar is aryl or R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

R fi Q R 7 1

R is -OR , -O(CO)R , -O(CO)OR or -O(CO)NR R ; R is hydrogen, lower

1 alkyl or aryl; or R and R together are =O; q is 0 or 1; r is 0, 1 or 2; m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1 , 2, 3, 4 or 5; 202

4

R 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 and -CH=CH-COOR⁶;

5

R is 1-5 substituents independently selected from the group consisting of -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 CH^.^-COOR⁶, -O(CH₂)₁.₁₀CONR⁶R⁷, -CF₃, fi R

-CN, -NO₂, halogen, -(lower alkylene)COOR and -CH=CH-COOR ;

R 7 ft

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; and

10

R 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, -NRV, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂R⁹, -COOR⁶, -CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, -S(O)₀.₂R⁹, -OfCH^.^-COOR⁶,

R 7

-O(CH₂)_1.10CONR R , -CF₃, -CN, -NO₂ and halogen;

(4) a sterol absorption inhibitor represented by Formula (VI):

(VI) or pharmaceutically acceptable salts or solvates thereof , wherein in Formula VI above: 203

R1 is

-CH-, -C(lower alkyl)-, -C-F-, -C(OH)-, -C(C₆H₅)-, -C-(C₆H₄-R₁₅)-,

- N- or -⁺N O^" ;

Rl together with an adjacent R2, or R1 together with an adjacent R3, form a -CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently 0, 1, 2 or 3, provided both are not zero; provided that when R2 is -CH=CH- or -C(Iower alkyl)=CH-, v is 1 ; provided that when R3 is -CH=CH- or -C(lower alkyl)=CH-, u is 1 ; provided that when v is 2 or 3, the R2's can be the same or different; and provided that when u is 2 or 3, the R3's can be the same or different;

B-(CH2)e-Z-(CH2)r, wherein Z is -O-, -C(O)-, phenylene, -N(Rs)- or -S(O)rj-2-_> e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B-(C2-C6 alkenylene)-; B-(C4-C6 alkadienylene)-;

B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1 , 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1 , 2, 3, 4 or 5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6; B-(CH2)t-V-(C-2-C6 alkenylene)- or 204

4, 5 or 6;

B-(CH2)a-Z-(CH2)b-V-(CH2)d-. wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1 , 2, 3, 4, 5 or 6; or T-(CH2)s-_> wherein T is cycloalkyi of 3-6 carbon atoms and s is 0, 1 , 2, 3, 4, 5 or 6; or

I R1 and R4 together form the group B-CH=C- ;

W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, -N(R8)(Rg), N(Rδ)(R9)-lower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3, -NHC(O)ORιo, -NHC(O)Rιo, R11O2SNH-, (Rnθ2S)2N-, -S(O)2NH2, -S(O)o-2R8_> tert-butyldimethyl-silyloxymethyl, -C(O)Ri2, -COORig, -CON(R8)(R9), -CH=CHC(O)Ri2, -lower alky!ene-C(O)Ri2, RlθC(O)(lower alkylenyloxy)-, N(Rs)(R9)C(O)(lower alkylenyloxy)- and

- CH₂" N R₁₃

^ — ^/ for substitution on ring carbon atoms, 205

and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C(O)OR o, -C(O)Rιo, OH, N(R8)(Rg)-lower alkylene-,N(R8)(R9)-lower alkylenyloxy-, -S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;

R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO2, -N(R8)(Rg), OH, and halogeno;

R8 and Rg are independently selected from H or lower alkyl;

R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;

R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7- benzyl;

R 2 is selected from H, OH, alkoxy, phenoxy, benzyloxy,

~ N R₁₃ — ^/ , -N(R8)(Rg), lower alkyl, phenyl or R7-phenyl;

R13 is selected from -O-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)Rιg;

R15. R16 and R17 are independently selected from the group consisting of H and the groups defined forW; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

Rig is H, lower alkyl, phenyl or phenyl lower alkyl; and

(5) a sterol absorption inhibitor represented by Formula (VII): 206

A is -CH=CH-, -C≡C- or -(CH2)p- wherein p is 0, 1 or 2;

B is

E is Cιo to C20 alkyl or -C(O)-(Cg to C g)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;

Rl , R2_> and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR5, R6O2SNH- and -S(O)2NH2;

R4 is

wherein n is 0, 1 , 2 or 3;

R5 is lower alkyl; and R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of 207

lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino;

(6) a sterol absorption inhibitor represented by Formula (VIII):

(VIII) or pharmaceutically acceptable salts or solvates thereof , wherein, in Formula (VIII) above,

R26 j_S H or OG¹ ;

G and C¹ are independently selected from the group consisting of

H or

OH, G is not H;

R, R^a and R are independently selected from the group consisting of H, - OH, halogeno, -NH2, azido, (Cι-C-6)alkoxy(Cι-C6)-alkoxy or -W-R³⁰;

W is independently selected from the group consisting of -NH-C(O)-, -O-

C(O)-, -O-C(O)-N(R31)-, -NH-C(O)-N(R³¹)- and -O-C(S)-N(R³¹)-;

R2 and R⁶ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl(Cι-C6)alkyl; 208

R³, R⁴, R⁵, RJ, R^3a and R^a are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl(Cι-C6)alkyl, -C(O)(Cι-C6)alkyl and -C(O)aryl;

R³0 is selected from the group consisting of R³ -substituted T, R³ -substituted-T-(Cι-C6)alkyl, R³²-substituted-(C2-C4)alkenyl, R³ -substituted-(Cι -C6)alkyl, R -substituted-(C3-C7)cycloalkyI and R³²-substituted-(C3-C7)cycloalkyl(Cι-C6)alkyl;

R³^ is selected from the group consisting of H and (Cι-C4)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C -C4)alkyl, -OH, phenoxy, -CF3, -NO2, (Cι-C4)alkoxy, methylenedioxy, oxo, (Cι-C4)alkylsulfanyl, (Cι-C4)alkylsulfinyl, (Cι-C4)alkylsulfonyt, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(O)-(Cι-C4)alkyl, -C(O)-(Cι-C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³^ , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Cι-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl or Rl°-substituted aryl;

Ar² is aryl or R¹1 -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,

forms the spiro group

and

Rl is selected from the group consisting of

-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ; 209

-(CH2)e-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR²²- or -S(O)o-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C2-C6)alkenylene-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;

Rl² is i l i i i „ I J

-CH-, -C(C_rC₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -⁺NO^" ;

R^'l³ and R^⁴ are independently selected from the group consisting of - CH₂-,

-CH(C1-C6 alkyl)-, -C(di-(Cι-C6) alkyl), -CH=CH- and -C(Cι-C6 alkyl)=CH-; or R¹² together with an adjacent R^'l³ or R¹² together with an adjacent R^'l , form a -CH=CH- or a -CH=C(C -C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, a is 1 ; provided that when R^'l⁴ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the Rl³'s can be the same or different; and provided that when b is 2 or 3, the R^'s can be the same or different; and when Q is a bond, R¹ also can be:

-M -Y_d- S(O)₀.₂-;

is -O-, -S-, -S(O)- or -S(O)2-;

X, Y and Z are independently selected from the group consisting of -CH2-, -CH(Cι-C6)alkyl- and -C(di-(Cι-C6)alkyl);

R10 and R^ 1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of 210

(Ci-C6)alkyl, -OR1 , -O(CO)Rl9, -O(CO)OR²1 , -O(CH2)l-5OR¹⁹, -O(CO)NR19R20_J ._{N R}19R20_J -NR19(CO)R²0, -NR19(C0)0R 1 , -NR19(CO)NR²OR²5, -NR19SO2R²¹ , -COOR19, -CONR19R²0_> -COR19, -SO2NR19R²0_J S(O)O-2R²¹ , -O(CH2)1-10-COOR19, -O(CH2)1-10CONR19R20_J -(C1-C-6 alkylene)-COORl9, -CH=CH-COORl9, -CF3, -CN, -NO2 and halogen;

R^'l 5 and R^ are independently selected from the group consisting of - OR19, -O(CO)R¹⁹, -O(CO)OR²1 and -O(CO)NR19R20_;

R16 and R^"*⁸ are independently selected from the group consisting of H, (Cι-C6)alkyl and aryl; or R1⁵ and R¹⁶ together are =O, or R¹⁷ and R¹⁸ together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R¹⁵ -X_r(C)_v-Y_k-S(O)₀.₂- and when Q is a bond and R^'l is R¹⁶ , Arl can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R^ and R^2u are independently selected from the group consisting of H, (C -C6)alkyl, aryl and aryl-substituted (C -C6)alkyl;

R^2"! is (Cι-C6)alkyl, aryl or R² -substituted aryl; 211

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R¹⁹ or -COORl9;

R²³ and R²⁴ are independently 1-3 groups independently selected from the group consisting of H, (Cι-C6)alkyl, (Ci-C6)alkoxy, -COOH, NO2,

-NR^{1 9}R20_I _OH and halogeno; and

R²⁵ is H, -OH or (Cι-C6)alkoxy; and

(7) a sterol absorption inhibitor represented by Formula (IX):

R²⁶ is selected from the group consisting of: a) OH; b) OCH₃; c) fluorine and d) chlorine;

R¹ is selected from the group consisting of

ral

R, R^a and R^D are independently selected from the group consisting of H, OH, halogeno, -NH2, azido, (Ci-C6)alkoxy(Cι-C6)-alkoxy and -W-R³⁰; 212

W is independently selected from the group consisting of

-NH-C(O)-, -O-C(O)-, -O-C(O)-N(R³1 )-, -NH-C(O)-N(R³1)- and

-O-C(S)-N(R³1 )-;

R² and R^ are independently selected from the group consisting of H, (Cι-C6)alkyi, aryl and aryl(C -C6)alkyl;

R³, R⁴, R5, R7_I R3a _ancj R4a _are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl(Cι-C6)alkyl, -C(O)(Cι-C6)alkyl and -C(O)aryl;

R^3u is independently selected form the group consisting of

R³²-substituted T, R³²-substituted-T-(C -C6)alkyl, R³ -substituted-(C2-

C4)alkenyl, R³²-substituted-(Cι-C6)alkyl, R³²-substituted-(C3-C7)cycloalkyl and

R³²-substituted-(C3-C7)cycloalkyl(Cι-C6)alkyl;

R^3*! is independently selected from the group consisting of H and (Cι-C4)alkyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (Cι-C-4)alkyl, -OH, phenoxy, -CF3, -NO2, (C -C4)alkoxy, methylenedioxy, oxo, (Cι-C4)alkylsulfanyl, (Cι-C4)alkylsulfinyl, (Cι-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(O)-(Cι-C4)aIkyl, -C(O)-(Ci-C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³1 , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Cι-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar¹ is aryl, Rl°-substituted aryl; pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

Ar² is aryl or R^{1 1} -substituted aryl; 213

forms the spiro group

;

Rl² is

-

-N-, or -⁺NO^" ;

R¹³ and R¹⁴ are independently selected from the group consisting of - CH₂-, -CH(C1-C6 alkyl)-, -C(di-(Cι-C6) alkyl), -CH=CH- and -C(Cι-C6 alkyl)=CH-; or

R^² together with an adjacent Rl³, or R^² together with an adjacent R^'l⁴, form a -CH=CH- or a -CH=C(Cι-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R^'l³ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, a is 1 ; provided that when R is -CH=CH- or -C(C -C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R^"l³'s can be the same or different; and provided that when b is 2 or 3, the R^'s can be the same or different;

RiO and R^'l ^"I are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C -C6)alkyl,

-OR19, -O(CO)Rl9, -O(CO)OR 1 , -0(CH2)1-50R19, -O(CO)NR¹9R²0, __NR19R20_I -NR19(CO)R²0, -NR19(C0)0R 1 , -NR19(CO)NR OR²5, -NR19SO2R²¹ , -COOR 9, -CONR19R20_J -_C0R19, -SO2NR19R20_> -S(O)o-2R²¹ , -O(CH2)1-10-COOR19_J -O(CH2)1 -10CONR19R 0, -(C1-C6 alkylene)-COOR¹⁹, -CH=CH-COORl9, -CF3, -CN, -NO2 and halogen;

R¹⁹ and R²⁰ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl-substituted (Cι-C6)alkyl;

R²1 is (Cι-C6)alkyl, aryl or R² -substituted aryl; 214

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R19 or -COOR ;

R²³ and R²⁴ are independently 1-3 groups independently selected from the group consisting of H, (Cι-C6)alkyl, (Cι-C6)alkoxy, -COOH, NO2, -

NR19R20_J _OH and halogeno; and

R²⁵ is H, -OH or (Cι-C6)alkoxy.

58. A therapeutic combination comprising:

(a) at least one peroxisome proliferator-activated receptor activator; and

(1) a sterol absorption inhibitor represented by Formula (III):

(III) or pharmaceutically acceptable salts or solvates thereof , wherein in Formula (III) above:

1 3

Ar is R -substituted aryl;

2 4

Ar is R -substituted aryl;

3 5

Ar is R -substituted aryl;

A is selected from -O-, -S-, -S(O)- or -S(O)₂-;

R is selected from the group consisting of -OR , -O(CO)R , -O(CO)OR and -O(CO)NR⁶R⁷; 215

2

R is selected from the group consisting of hydrogen, lower alkyl and aryl;

1 2 or R and R together are =O; q is 1 , 2 or 3; p is O, 1 , 2, 3 or 4;

5

R is 1-3 substituents independently selected from the group consisting of -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -OfCH^_.gOR⁹, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO₂-lower alkyl, -NR⁶SO₂-aryl, -CONRV, -COR⁶, -SO₂NR⁶R⁷, S(O)_0.2-alkyI, S(O)_0.2-aryl, fi fi 7

-O CH^o-COOR , -O(CH₂)₁.₁₀CONR R , o-halogeno, m-halogeno, fi fi o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR , and -CH=CH-COOR ;

3 4

R and R are independently 1-3 substituents independently selected from

5 the group consisting of R , hydrogen, p-lower alkyl, aryl, -NO₂, -CF₃ and p- halogeno; fi "7 ft

R R°, , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; (2) a sterol absorption inhibitor represented by Formula (IV)

(IV)

or pharmaceutically acceptable salts or solvates thereof, wherein, in Formula (IV) above: 216

2

A is selected from the group consisting of R -substituted heterocycloalkyi,

2 2 2

1 3

Ar is aryl or R -substituted aryl;

2 4

Ar is aryl or R -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone, forms

the spiro group

; and

1

R is selected from the group consisting of:

-(CH₂)_e-G-(CH₂)_r-, wherein G is -O-, -C(O)-, phenylene, -NR⁸- or -S(O)₀_₂-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C₂-C₆ alkenylene)-; and

-(CH₂)_rV-(CH₂)_g-, wherein V is C₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;

5

R is selected from:

I I I I i _ I . I

-CH-, -C(C_rC₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R⁹)-, -N-, or -⁺NO^" ;

6 7

R and R are independently selected from the group consisting of -CH₂-, -CH(C.,-C₆ alkyl)-,

alkyl), -CH=CH- and

5 6 5

-C(C_|-C₆ alkyI)=CH-; or R together with an adjacent R , or R together with an adjacent R , form a -CH=CH- or a -CH=C(C_rC₆ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R is -CH=CH- or -C(C,-C₆ alkyl)=CH-, a is 1 ; provided that when R is -CH=CH- or -C(C_rC₆ alkyl)=CH-, b is 1; provided that when a is 2 or 217

fi

1 and when Q is a bond, R also can be selected from:

-M -Y_d- -Y_k-S(O)₀.₂-;

where M is -O-, -S-, -S(O)- or -S(O)₂-;

X, Y and Z are independently selected from the group consisting of -CH₂-, -CH(C_rC₆ alkyl)- and -C(di-(C₁-C₆) alkyl);

10 12

R and R are independently selected from the group consisting of -OR¹⁴, -O(CO)R¹⁴, -O(CO)OR¹⁶ and -O(CO)NR¹⁴R¹⁵;

11 13

R and R are independently selected from the group consisting of

10 11 12 13 hydrogen, (C C^alkyl and aryl; or R and R together are =O, or R and R together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

2

17 17

14 15 14 15 16

NR R (C.,-C₆ alkylene)-, NR R C(O)(C C₆ alkylene)-,-NHC(O)R , 218

16 14

OH, O,-C₈ alkoxy, -OC(O)R , -COR , hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-

16 14 15 14 2

2 is a substituent on a heterocycloalkyi ring, R is as defined, or is =O

or

; and, where R is a substituent on a substitutable ring nitrogen, it is hydrogen,

(C C_gJalkyl, aryl, (C^C_gJalkoxy, aryloxy, (C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy,

-(CH^_gCONR^R¹⁸,

18 wherein J is -O-, -NH-, -NR - or -CH₂-;

3 4

R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C.,-C₈)alkyl,

14 14 16 14 14 15 14 15

-OR , -O(CO)R , -O(CO)OR , -O^H^._gOR , -O(CO)NR R , -NR R ,

14 15 14 16 14 15 19 14 16 14

-NR (CO)R , -NR (CO)OR , -NR (CO)NR R , -NR SO2R , -COOR , -CONR¹⁴R¹⁵, -COR¹⁴, -SO2NR¹⁴R¹⁵, S(O)₀.₂R¹⁶, -O CH^_Q-COOR¹⁴,

14 15 14 14

-OfCH^oCONR R , -(0,-C₈ alkylene)-COOR , -CH=CH-COOR , -CF₃, -CN, -NO₂ and halogen;

8 14 14

R is hydrogen, (C_rC₆)alkyl, aryl (C.,-C₈)alkyl, -C(O)R or -COOR ;

9 17

R and R are independently 1-3 groups independently selected from the group consisting of hydrogen, (C^C_gJalkyl, (C₁-C₆)alkoxy, -COOH, NO₂,

-NR¹⁴R¹⁵, OH and halogeno;

14 15

R and R are independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

R is (C.,-C₈)alkyl, aryl or R -substituted aryl; 219

R is hydrogen or (C₁-C₆)alkyl; and

19

R is hydrogen, hydroxy or (C^C^alkoxy;

(3) a sterol absorption inhibitor represented by Formula (V):

(V)

1 10

Ar is aryl, R -substituted aryl or heteroaryl;

2 4

Ar is aryl or R -substituted aryl;

3 5

Ar is aryl or R -substituted aryl;

X and Y are independently selected from the group consisting of -CH₂-, -CH(lower alkyl)- and -C(dilower alkyl)-; fi fi Q fi 7 1

R is -OR , -O(CO)R , -O(CO)OR or -O(CO)NR R ; R is hydrogen, lower

1 alkyl or aryl; or R and R together are =O; q is 0 or 1 ; r is O, 1 or 2; m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1 , 2, 3, 4 or 5;

4

R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, -O CH^OR⁶, -O(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO2R⁹, -COOR⁶, -CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, S(O)₀.₂R⁹, -O CH^_Q-COOR⁶, -O(CH₂)_1.10CONR⁶R⁷, -(lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

5

R is 1-5 substituents independently selected from the group consisting of 220

-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, -CONRV, - COR⁶, -SO₂NR⁶R⁷, S(O)_0.2R⁹, -O(CH₂)_1.10-COOR⁶, -O(CH₂)_1.10CONR⁶R⁷, -CF₃, fi fi

-CN, -NO₂, halogen, -(lower alkylene)COOR and -CH=CH-COOR ; fi 7 ft

9

R is lower alkyl, aryl or aryl-substituted lower alkyl; and

10

R 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,

-CN, -NO₂ and halogen;

(4) a sterol absorption inhibitor represented by Formula (VI):

(VI) or pharmaceutically acceptable salts or solvates thereof , wherein in Formula VI above:

R1 is

-CH-, -C(lower alkyl)-, -CF-, -C(OH)-, -C(C₆H₅)-, -b(C₆H₄-R₁₅)-,

I I

- N- or -⁺N O^" ;

R2 and R3 are independently selected from the group consisting of: -CH2-, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or 221

Rl together with an adjacent R2, or R1 together with an adjacent R3, form a -CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v is 1 ; provided that when R3 is -CH=CH- or -Cøower alkyl)=CH-, u is 1 ; provided that when v is 2 or

B-(CH2)e-Z-(CH2)r-> wherein Z is -O-, -C(O)-, phenylene, -N(Rs)- or -S(O)n-2~, e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1 , 2, 3, 4, 5 or 6; B-(C2-C6 alkenylene)-; B-(C4-C6 alkadienylene)-;

4, 5 or 6;

B-(CH2)a-Z-(CH2)b-V-(CH2)d-, wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1 , 2, 3, 4, 5 or 6; or T-(CH2)s-_> wherein T is cycloalkyi of 3-6 carbon atoms and s is 0, 1 , 2, 3, 4, 5 or 6; or

I

R and R4 together form the group B-CH=C- ; 222

W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, -N(Rδ)(R9), N(R8)(Rg)-lower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3, -NHC(O)ORιo, -NHC(0)Rio, R11O2SNH-, (Rnθ2S)2N-, -S(O)2NH2, -S(O)o-2R8_> tert-butyldimethyl-silyloxymethyl, -C(O)Ri2, -COORig, -CON(R8)(R9). -CH=CHC(O)Ri2, -lower alkylene-C(O)Ri2, R θC(O)(lower alkylenyloxy)-, N(Rδ)(R9)C(O)(Iower alkylenyloxy)- and

- CH₂- N R₁₃ — for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C(O)ORιo, -C(O)Rιo, OH, N(Rs)(Rg)-lower alkylene-,N(R8)(R9)-lower alkylenyloxy-, -S(O)2NH2 and 2-(trimethyIsilyl)-ethoxymethyl;

R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO2, -N(Rs)(Rg), OH, and halogeno;

R8 and Rg are independently selected from H or lower alkyl;

R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl; 223

R1 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7- benzyl;

R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,

- N R13

^N — ' , -N(Rδ)(Rg), lower alkyl, phenyl or R7-phenyl; R13 is selected from -O-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)Rιg; R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R 6 and R 7, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

Rig is H, lower alkyl, phenyl or phenyl lower alkyl; and

(5) a sterol absorption inhibitor represented by Formula (VII):

A is -CH=CH-, -C≡C- or -(CH2)p- wherein p is 0, 1 or 2;

B is 224

E is C 0 to C20 alkyl or -C(O)-(Cg to Cιg)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;

R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -. wherein r is 0, 1 , 2, or 3;

Rl _> R2. and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR5, R6O2SNH- and -S(O)2NH2;

R4 is

wherein n is 0, 1 , 2 or 3;

(6) a sterol absorption inhibitor represented by Formula (VIII):

(VIII) or pharmaceutically acceptable salts or solvates thereof , wherein, in Formula

(VIII) above,

R²⁶ is H or OGl ; 225

G and Gl are independently selected from the group consisting of

s H or

OH, G is not H;

R, R^a and R^D are independently selected from the group consisting of H, - OH, halogeno, -NH2, azido, (Cι-C6)alkoxy(Cι-C6)-alkoxy or -W-R³⁰;

W is independently selected from the group consisting of -NH-C(O)-, -O-

C(O)-, -O-C(O)-N(R³1)-, -NH-C(O)-N(R³¹)- and -O-C(S)-N(R³¹)-;

R² and R⁶ are independently selected from the group consisting of H, (C -C6)alkyl, aryl and aryl(Cι-C6)alkyl;

R³, R⁴, R⁵, R⁷, R^3a and R^4a are independently selected from the group consisting of H, (C -C6)alkyl, aryl(Cι-C6)alkyl, -C(O)(Cι-C6)alky) and -C(O)aryl;

R³⁰ is selected from the group consisting of R³ -substituted T, R³²-substituted-T-(Cι-C6)alkyl, R³²-substituted-(C2-C4)alkenyl, R³²-substituted-(C -C6)alkyl, R³ -substituted-(C3-C7)cycloalkyl and R³²-substituted-(C3-C7)cycloalkyl(Ci-C6)alkyl;

R³¹ is selected from the group consisting of H and (C -C4)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; 226

R³² is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (Cι-C4)alkyl, -OH, phenoxy, -CF3, -NO2, (Cι-C4)alkoxy, methylenedioxy, oxo, (Cι-C4)alkylsulfanyl, (C -C-4)alkylsulfinyl, (Cι-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(0)-(Cι-C4)alkyl, -C(O)-(Cι-C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³^ , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C -C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar^ is aryl or Rl°-substituted aryl;

Ar² is aryl or R11 -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,

forms the spiro group

; and

R^'l is selected from the group consisting of

-(CH2)e-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR²²- or -S(O)o-2-_> e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6)alkenylene-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; Rl² is

I I I I I | |

-CH-, -C(C C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -"^"NO^" ;

RI³ and Rl⁴ are independently selected from the group consisting of - CH₂-, -CH(Cι-C6 alkyl)-, -C(di-(C1-C6) alkyl), -CH=CH- and 227

-C(Cι-C6 alkyl)=CH-; or R^"12 together with an adjacent R^³, or R¹² together with an adjacent R¹⁴, form a -CH=CH- or a -CH=C(Cι-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, a is 1 ; provided that when R¹ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R^³'s can be the same or different; and provided that when b is 2 or 3, the Rl⁴'s can be the same or different; and when Q is a bond, R^'l also can be:

-M -Y_d- -γ_k-s(θ)₀.₂-;

M is -O-, -S-, -S(O)- or -S(O)2-;

R10 and R1 ^"I are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C6)alkyl, -OR19, -0(00^9, -O(CO)OR²1 , -0(CH2)1-50R19, -O(CO)NR19R20_J __NR19R20_J -NR19(CO)R²0, -NR19(C0)0R²1 , -NR19(CO)NR 0R²5, -NR19SO2R²¹, -COOR19, -CONR19R20₇ _COR19, -SO2NR 9R20_ S(O)o-2R²¹ , -O(CH2)1 -10-COOR19_J -O(CH2)1-10CONR19R20₇ -(C1-C6 aIkylene)-COORl9, -CH=CH-C00R19, -CF3, -CN, -NO2 and halogen;

R15 and R^ are independently selected from the group consisting of - OR19, -©(COJR^'IΘ, -O(CO)OR²¹ and -O(CO)NR19R20_; 228

Rl6 and R¹⁸ are independently selected from the group consisting of H, (Cι-C6)alkyl and aryl; or R¹⁵ and R^"16 together are =O, or R ⁷ and R^'l⁸ together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R¹⁵ -X_r(C)_v-Y_k-S(O)₀.₂- and when Q is a bond and R1 is R¹⁶ , Ar^"! can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R²¹ is (Cι-C6)alkyl, aryl or R² -substituted aryl;

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R19 or -COOR ⁹;

R²³ and R²⁴ are independently 1-3 groups independently selected from the group consisting of H, (Cι-C6)alkyl, (Cι-C6)alkoxy, -COOH, NO2,

-NR19R20_] _OH and halogeno; and

R²⁵ is H, -OH or (Cι-C6)alkoxy; and

(7) a sterol absorption inhibitor represented by Formula (IX): 229

R²^ is selected from the group consisting of: a) OH; b) OCH₃; c) fluorine and d) chlorine;

R¹ is selected from the group consisting of

ral

R, R^a and Rb are independently selected from the group consisting of H, OH, halogeno, -NH2, azido, (Cι-C6)alkoxy(Cι-C6)-alkoxy and -W-R³⁰;

W is independently selected from the group consisting of

-NH-C(O)-, -O-C(O)-, -O-C(O)-N(R³1)-, -NH-C(O)-N(R³1)- and

-O-C(S)-N(R³¹ )-;

R² and R6 are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryI(C -C6)alkyl; 230

R³, R⁴, R5, R7_; R3a _anc| R4a _are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl(C -C6)alkyl, -C(O)(C -C6)alkyl and -C(O)aryl;

R^3υ is independently selected form the group consisting of R³²-substituted T, R³²-substituted-T-(Cι-C6)alkyl, R³²-substituted-(C2- C4)alkenyl, R³²-substituted-(Ci-C6)alkyl, R³²-substituted-(C3-C7)cycloalkyl and R³²-substituted-(C3-C7)cycloalkyl(Cι-C6)alkyI;

R^3"! is independently selected from the group consisting of H and (Cι-C )alkyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (Cι-C4)alkyl, -OH, phenoxy, -CF3, -NO2, (Cι-C4)alkoxy, methylenedioxy, oxo, (Cι-C4)alkylsulfanyl, (Cι-C4)alkylsulfinyl, (Cι-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Cι-C4)alkyl, -C(O)-N((Cι-C4)alkyl)2, -C(O)-(Cι-C4)alkyl, -C(O)-(Cι-C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹ , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Cι-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar1 is aryl, R¹ °-substituted aryl; pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

Ar² is aryl or R1¹ -substituted aryl;

forms the spiro group

Rl² is 231

I I I I I | |

R¹³ and R^'l⁴ are independently selected from the group consisting of - CH₂-, -CH(Cι-C6 alkyl)-, -C(di-(Cι-C6) alkyl), -CH=CH- and -C(Cι-C6 alkyl)=CH-; or

R1² together with an adjacent R¹³, or R^² together with an adjacent R^⁴, form a -CH=CH- or a -CH=C(Cι-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R^'l³ is -CH=CH- or -C(Cι-C6 alkyI)=CH-, a is 1 ; provided that when R¹ is -CH=CH- or -C(Cι-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R¹³'s can be the same or different; and provided that when b is 2 or 3, the R¹⁴'s can be the same or different;

R¹⁰ and R¹1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Cι-C6)alkyl,

-OR19, -O(CO)Rl9, -O(CO)OR²1 , -O(CH2)1-5OR19_J

-NR19R20_J -NR19(CO)R²0, -NR¹9(CO)OR²1 , -NR19(CO)NR 0R²5, -NR19SO2R²¹ , -COOR19, -CONR1 R20_J -COR19, -SO2NR19R20, -S(O)0-2R²¹ , -O(CH2)1-10-COOR¹⁹, -O(CH2)1-10CONR19R20_J -(C1-C6 alkyleneJ-COORlθ, -CH^H-COORlθ, -CF3, -CN, -NO2 and halogen;

R¹9 and R²^ are independently selected from the group consisting of H, (Cι-C6)alkyl, aryl and aryl-substituted (Cι-C6)alkyi;

R²1 is (Cι-C6)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (Cι-C6)alkyl, aryl (Cι-C6)alkyl, -C(0)R19 OΓ -COOR19_;

NR19R20_I _OH and halogeno; and

R²⁵ is H, -OH or (Cι-C6)alkoxy. 232

59. A composition comprising (a) at least one AcylCoA:Cholesterol O- acyltransferase Inhibitor and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

60. A therapeutic combination comprising (a) a first amount of at least one AcylCoA:Cholesterol O-acyltransferase Inhibitor; and (b) a second amount at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

61. A composition comprising (a) probucol or a derivative thereof and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

62. A therapeutic combination comprising (a) a first amount of probucol or a derivative thereof and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal. 233

63. A composition comprising (a) at least one low-density lipoprotein receptor activator and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

64. A therapeutic combination comprising (a) a first amount of at least one low-density lipoprotein receptor activator and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

65. A composition comprising (a) at least one Omega 3 fatty acid and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

66. A therapeutic combination comprising (a) a first amount of at least one Omega 3 fatty acid and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal. 234

67. A composition comprising (a) at least one natural water soluble fiber and (b) at least one substituted azetidinone compound or substituted β- lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

68. A therapeutic combination comprising (a) a first amount of at least one natural water soluble fiber and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

69. A composition comprising (a) at least one of plant sterols, plant stanols or fatty acid esters of plant stanols and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

70. A therapeutic combination comprising (a) a first amount of at least one of plant sterols, plant stanols or fatty acid esters of plant stanols and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β- lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a 235

vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

71. A composition comprising (a) at least one antioxidant or vitamin and (b) at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound.

72. A therapeutic combination comprising (a) a first amount of at least one antioxidant or vitamin and (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted β-lactam compound, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

73. The composition or therapeutic combination according to any of claims 51, 53, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, wherein the fibric acid derivative is fenofibrate.

74. The composition or therapeutic combination according to any of claims 51, 53, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, wherein the fibric acid derivative is gemfibrozil.

75. The composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, wherein the at least one peroxisome proliferator-activated receptor activator is administered to a mammal in an amount ranging from about 50 to about 3000 milligrams of peroxisome proliferator-activated receptor activator per day. 236

76. The composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, wherein the at least one sterol absorption inhibitor is administered to a mammal in an amount ranging from about 0.1 to about 1000 milligrams of sterol absorption inhibitor per day.

77. The composition according to claim 76, further comprising at least one HMG CoA reductase inhibitor.

78. The composition according to claim 77, wherein the at least one HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, cerivastatin and mixtures thereof.

79. The composition according to claim 78, wherein the at least one HMG CoA reductase inhibitor is simvastatin.

80. The composition according to claim 78, wherein the at least one HMG CoA reductase inhibitor is atorvastatin.

81. The composition according to claim 78, wherein the at least one HMG CoA reductase inhibitor is rosuvastatin.

82. The composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, further comprising at least one lipid lowering agent selected from the group consisting of bile acid sequestrants, nicotinic acid or derivatives thereof, CETP inhibitors, IBAT inhibitors, AcylCoA:Cholesterol O-acyltransferase Inhibitors, probucol or a derivatives thereof, low-density lipoprotein receptor activators, 237

Omega 3 fatty acids, natural water soluble fibers, plant sterols, plant stanols and fatty acid esters of plant stanols.

83. The composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72, further comprising at least one additive selected from the group consisting of antioxidants, vitamins, hormone replacement therapy compositions, obesity control medications, blood modifiers, cardiovascular agents different from the compound of Formula II and antidiabetic medications.

84. A pharmaceutical composition for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising a therapeutically effective amount of the composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72.

85. A method of treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising the step of administering to a mammal in need of such treatment the composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72.

86. Use of a composition or therapeutic combination according to any of claims 51 , 53, 56, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72 for preparation of a medicament for treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.