AU2007201970B2 - Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: Schering Corporation Invention Title: COMBINATIONS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) ACTIVATOR(S) AND STEROL ABSORPTION INHIBITOR(S) AND TREATMENTS FOR VASCULAR INDICATIONS The following statement is a full description of this invention, including the best method of performing it known to me/us: 00 -la-

O

SCOMBINATIONS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR S(PPAR) ACTIVATOR(S) AND STEROL ABSORPTION INHIBITOR(S) AND TREATMENTS FOR VASCULAR INDICATIONS

O

FIELD OF THE INVENTION The present invention relates to compositions and therapeutic combinations for treating vascular and lipidemic conditions such as are associated with Satherosclerosis, hypercholesterolemia and other vascular conditions in mammals.

BACKGROUND OF THE INVENTION Atherosclerotic coronary heart disease (CHD) represents the major cause for death and vascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, cigarette smoke and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk of CHD.

Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol can inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.

The regulation of whole-body cholesterol homeostasis in mammals and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteins. The liver is the major organ responsible for cholesterol biosynthesis and catabolism and, for this reason, it is a prime determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the predominant cholesterol-carrying lipoproteins in the plasma and an increase in their concentration is correlated with increased atherosclerosis. When intestinal cholesterol absorption is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is decreased hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in plasma cholesterol levels.

Fibric acid derivatives ("fibrates"), such as fenofibrate, gemfibrozil and clofibrate, have been used to lower triglycerides, moderately lower LDL levels and increase HDL levels. Fibric acid derivatives are also known to be peroxisome proliferator-activated receptor alpha activators.

U.S. Patents Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, respectively, disclose hydroxy-substituted azetidinone compounds and substituted 3lactam compounds useful for lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Patents Nos.

5,846,966 and 5,661,145, respectively, disclose hydroxy-substituted azetidinone compounds or substituted p-lactam compounds in combination with HMG CoA reductase inhibitors for preventing or treating atherosclerosis and reducing plasma cholesterol levels.

PCT Patent Application No. WO 00/38725 discloses cardiovascular therapeutic combinations including an ileal bile acid transport inhibitor or cholesteryl ester transport protein inhibitor in combination with a fibric acid derivative, nicotinic acid derivative, microsomal triglyceride transfer protein inhibitor, cholesterol absorption antagonist, phytosterol, stanol, antihypertensive agent or bile acid sequestrant.

U.S. Patent No. 5,698,527 discloses ergostanone derivatives substituted with disaccharides as cholesterol absorption inhibitors, employed alone or in combination with certain other cholesterol lowering agents, which are useful in the treatment of hypercholesterolemia and related disorders.

00 (O -3- Despite recent improvements in the treatment of vascular disease, there remains a need in the art for improved compositions and treatments for hyperlipidaemia, atherosclerosis and other vascular conditions.

3a- 00 oO SUMMARY OF THE INVENTION

(N

The present invention provides the following items 1 to 13: 1. A composition comprising at least one Omega 3 fatty acid and c at least one substituted azetidinone sterol absorption inhibitor or substituted p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or Sthe at least one substituted p-lactam sterol absorption inhibitor.

(N

2. A therapeutic combination comprising a first amount of at least one Omega 3 fatty acid and a second amount of at least one substituted azetidinone sterol absorption inhibitor or substituted p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or the at least one substituted p-lactam sterol absorption 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.

3. The composition or therapeutic combination according to item 1 or 2, wherein the at least one substituted azetidinone sterol absorption inhibitor or substituted p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or the at least one substituted p-lactam sterol absorption inhibitor is administered to a mammal in an amount ranging from about 0.1 to about 1000 milligrams per day.

4. The composition according to item 3, further comprising at least one HMG CoA reductase inhibitor.

The composition according to item 4, 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.

3b- 00 6. The composition according to item 5, wherein the at least one c HMG CoA reductase inhibitor is simvastatin.

7. The composition according to item 5, wherein the at least one HMG CoA reductase inhibitor is atorvastatin.

8. The composition according to item 5, wherein the at least one HMG CoA reductase inhibitor is rosuvastatin.

o 9. The composition or therapeutic combination according to item 1 or 2, further comprising at least one lipid lowering agent selected from the group 0 consisting of bile acid sequestrants, nicotinic acid or derivatives thereof, CETP inhibitors, IBAT inhibitors, AcylCoA:Cholesterol O-acyltransferase Inhibitors, probucol or a derivative 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.

The composition or therapeutic combination according to item 1 or 2, 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.

11. 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 item 1 or 2.

12. 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 item 1 or 2.

3c- 00 0 13. Use of a composition or therapeutic combination according to item 1 C1 or 2, 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.

s Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula R

R

2 Ar 1 -Xm-(C)q-Yn-(C)r-Zp Ar 3 R

R

O \Ar 2

(I)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula or of the isomers thereof, or prodrugs of the compounds of Formula (I) or of the isomers, salts or solvates thereof, wherein in Formula above: Ar and Ar are independently selected from the group consisting of aryl and 4 R -substituted aryl; 3 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)-; R and R are independently selected from the group consisting of -OR,

-O(CO)R

6

-O(CO)OR

9 and -O(CO)NR6R R and R are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is0 or 1; 00 (O O-4- C 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 Sprovided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 4 R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR 6 -O(CO)R -O(CO)OR 9

-O(CH

2 1 5 OR -O(CO)NR R -NR6R 7 -NR6(CO)R -NR (CO)OR -NR (CO)NR R 8 -NR6SO2R -COOR,

-CONRR

7

-COR

6 -SO2NR 6

R

7 S(0)02R 9

-O(CH

2 1 0

-COOR

6

-O(CH

2 1 0 CONR R -(lower alkylene)COOR 6

-CH=CH-COOR

6

-CF

3

-CN,

-NO

2 and halogen;

R

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

-OR

6

-O(CO)R

6

-O(CO)OR

9

-O(CH

2 )1-5OR 6 -O(CO)NR6R 7 -NR6R 7

-NR

6

(CO)R

7

-NR

6

(CO)OR

9

-NR

6

(CO)NR

7

R

8 -NR SO 2 R -COOR 6

-CONRR,

-COR6, -SO2NR 6R S(O)o 2 R -O(CH 2 1 1 0

-COOR

6

-O(CH

2 1 10

CONR

6 R, -(lower alkylene)COOR 6 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 R is lower alkyl, aryl or aryl-substituted lower alkyl.

Also described herein is a composition comprising: at least one fibric acid derivative; and a compound represented by Formula (II) below: OH

F

OH N

(II)

or pharmaceutically acceptable salt or solvate thereof, or prodrug of the compound of Formula (II) or of the salt or solvate thereof.

00 Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and c at least one sterol absorption inhibitor represented by Formula (111):

R,

Arl-A-Y'-C-Zp Ar 3 12 o A r 2 S(ill) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (III) or of the isomers thereof, or prodrugs of the compounds of Formula (III) or of the isomers, salts or solvates thereof, wherein, in Formula (III) above: Ar is R -substituted aryl; Ar is R4-substituted aryl; Ar is Rs-substituted aryl; Y and Z are independently selected from the group consisting of -CH 2 -CH(lower alkyl)- and -C(dilower alkyl)-; A is selected from or is R is selected from the group consisting of-OR -O(CO)R 6

-O(CO)OR

9 and -O(CO)NR R R 2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R and R 2 together are =0; q is 1, 2 or 3; p is 0, 1,2, 3 or 4;

R

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

-OR

6

-O(CO)R

6

-O(CO)OR

9

-O(CH

2 1 5 OR -O(CO)N R -NR R 7 -NR (CO)R 7 -NR6(CO)OR 9 -NR6(CO)NR R 8 -NR SO,-lower alkyl, -NR SO 2 -aryl, -CONRR 7

-COR

6

-SO

2 NR6R S(0)o-2-alkyl, S(O) 0 2-aryl,

-O(CH

2 1 o 1 0

-COOR

6

-O(CH

2 1 1 0 CONR R 7 o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR 6 and -CH=CH-COOR6;

R

3 and R 4 are independently 1-3 substituents independently selected from the group consisting of Rs, hydrogen, p-lower alkyl, aryl, -NO 2

-CF

3 and 00 (O -6p-halogeno; 6 7 8 R R and R are independently selected from the group consisting of Shydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R is lower alkyl, aryl or aryl-substituted lower alkyl.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula (IV): N^

R

19 Ar'-R'-Q

A

0 'Ar 2

(IV)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IV) or of the isomers thereof, or prodrugs of the compounds of Formula (IV) or of the isomers, salts or solvates thereof, wherein, in Formula (IV) above: 2 2 A is selected from the group consisting of R -substituted heterocycloalkyl, R 2 substituted heteroaryl, R -substituted benzofused heterocycloalkyl, and R2-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 R5-(R6)a I I

(R

7 spiro group b and R is selected from the group consisting of:

-(CH

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

-(CH

2 )e-G-(CH 2 wherein G is phenylene, -NR 8 or -7e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6 alkenylene)-; and wherein V is C 3 cycloalkylene, f is 1-5 and g is provided that the sum of f and g is 1-6;

R

s is selected from: I I I I I II -C(Cl-C6 alkyl)-, -C(C 6

H

4

-R

9 or -NO R6 and R are independently selected from the group consisting of

-CH

2

-CH(C

1

-C

6 alkyl)-, -C(di-(C 1

-C

6 alkyl), -CH=CH- and -C(C1-C6 alkyl)=CH-; or R 5 together with an adjacent R or R 5 together with an adjacent R form a -CH=CH- or a -CH=C(C,-C 6 alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R 6 is -CH=CH- or -C(C,-C6 alkyl)=CH-, a is 1; provided that when R 7 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; and when Q is a bond, R also can be selected from: RiO R 12 R1i RiO I I I I -M -Yd-C-Zh-, -Xm-(C)s-Yn-(C)t-Zp- or 0 R R3 R" R where M is or-S(0)2-; X, Y and Z are independently selected from the group consisting of

-CH

2 -CH(C1-C 6 alkyl)- and -C(di-(C,-C 6 alkyl); R and R 12 are independently selected from the group consisting of

-OR

14

-O(CO)R

1 4

-O(CO)OR

1 6 and -O(CO)NR1 R; R and R 13 are independently selected from the group consisting of hydrogen,

(C,-C

6 )alkyl and aryl; or R and R together are or R 12 and R 13 together are =0; d is 1, 2 or 3; h is 1, 2, 3 or 4; -8s 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 isi1, the sum of m, s and n is 1-5; and provided that when p isO0 and s is 1, the sum of m, t and n is v is 0ori1; and k are independently 1-5, provided that the sum of j, k and v is 2 R is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C 1 -Cl 0 )alkyl, (C 2

-C

10 )alkenyl, (C 2 -Cl 0 )alkynyl, 17_ 17_

(C

3

-C

6 )cycloalkyl, (C 3 -0 6 )cycloalkenyl, R -ubstituted aryl, R -substituted benzyl, R -7substituted benzyloxy, R -7substituted aryloxy, halogeno, -NR 14R 15 NR14R5(1 14 1516 C. alkylene)-, NR R15C(O)(C 1

-C

6 alkylene)-,-NHC(O)R OH, C1_C6 alkoxy, -OC(O)Rlr, -COR 14, hydroxy(Cl-C 6 )alkyl, (C_6akx(C_6akl N0'~2' -S(O) 0 2 R 1, -SO 2 NR 14R1 and

-(C

1

-C

6 alkylene)COOR 14; when R 2is a substituent on a heterocycloalkyl ring, R2is a L (cH 2 12 2 as defined, or is =0 or and, where R 2is a su bstituent on a substitutable ring nitrogen, it is hydrogen, (C 1

-C

6 )alkyl, aryl, (C 1

-C

6 )alkoxy, aryloxy, 18 18

(C

1

-C

6 )alkylcarbonyl, arylcarbonyl, hydroxy, H 2 1 6 C0N R R 0

R

18 j or

(CH

2 0 4 0 wherein J is -NR18- or -OH 2 R 3and R 4are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Cl-C 6 )alkyl, 14 14 16 14 14 15 14 -OR O(CO)R O(CO)OR -O(CH 2 15 0R O(CO)NR R NR R -NR 14(CO)R 15 NR 14(CO)OR -NR 1 4

(CO)NR

1 5 R19, -NR 14S02R 1, -COOR14 14 15 14 14 15 16 14 -CONR R COR S02NR R S(0) 0 2 R1 O(CH 2 110

-COOR,

00 -9- -O(CH2,) 1 1 CONR R 15 -(C-C6 alkylene)-COOR 1 4 -CH=CH-COOR 1

-CF

3 -CN,

NO

2 and halogen; R is hydrogen, (Cl-Cs)alkyl, aryl (C,-C,)alkyl, -C(O)R 14 or -COOR14 9 17 O R and R 1 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C,-C 6 )alkyl, (C,-C 6 )alkoxy, -COOH, NO 2 14 -NR R OH and halogeno; R14 0 R and R are independently selected from the group consisting of hydrogen, S(C,-C6)alkyl, aryl and aryl-substituted (C,-C 6 )alkyl; R is (C,-C 6 )alkyl, aryl or R -substituted aryl; R is hydrogen or (C,-C,)alkyl; and R is hydrogen, hydroxy or (Cl-C 6 )alkoxy.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula

R

I Y 1O Ar 3

(V)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula or of the isomers thereof, or prodrugs of the compounds of Formula (V) or of the isomers, salts or solvates thereof, wherein, in Formula above: 1 Ar is aryl, R -substituted aryl or heteroaryl; Ar is aryl or R -substituted aryl; Ar is aryl or R -substituted aryl; X and Y are independently selected from the group consisting of -CH 2 -CH(lower alkyl)- and -C(dilower alkyl)-; 00 R is -OR6, -O(CO)R 6 -O(CO)0R 9 or -O(CO)NR 6 R 7

R

1 is hydrogen, lower alkyl or aryl; or R and R1 together are =0; q is 0ori1; r is 0, 1 r 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 R4 is 1-5 substituents independently selected from the group consisting of 6 6 96 6 7 lower alkyl, -OR -O(CO)R -O(CO)OR9, -0(CH 2 15 0R -O(CO)NR R -NR R 7 -NR -NR 6 (CO)0R', -NR (CO)NR 7 R -NR S02R -COOR 6 6 7 6 6 7 96 -CONR R -COR -S0 2 NR R S(O) 0 2 -O(CH9 110 -COQR 6 7 6 6 -O(0H 2 1 1 0 00NRR, -(lower alkylene)COOR and -CH=CH-COOR R 5is 1-5 substituents independently selected from the group consisting of 6 6 96 6 7 6 7 -OR -O(CO)R ,-O(CO)OR -O(CH 2 15 0R -O(CO)NR R -NR R 6 7 6 9 6 7 8 6 9 6 6 7 -NR (CO)R -NR (CO)OR ,-NR (CO)NR R -NR S0 2 R ,-COOR ,-CONRR 6 6 7 9 6 7 -COR -S0 2 NR R, S(O) 0 2 R9, -O(CH 2 1 1 0 -COOR -O(0H 2 110 00NR R -F 3 -CN, -NO 2 halogen, -(lower alkylene)COOR 6and -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; R 9is lower alkyl, aryl or aryl-substituted lower alkyl; and R 10is 1-5 substituents independently selected from the group consisting of 6 6 9 6 6 7 lower alkyl, -OR -O(CO)R 6 -O(CO)OR -O(0H 2 15 0R -O(OO)NR R -NR 6R 7, -NR 6 (CO)R 7 -NR 6 (CO)0R 9 -NR 6 (O)NR 7 -NR 6 2 R 9,-COOR6, 6 7 6 2' 7SO 0 2 9 6 -CONR R -COR S02NR 6

R

7 ,SO029 -O(0H 2 11 0

-COOR,

6 7 -O(0H 2 110 00NR R -OF 3 -ON, -NO 2 and halogen.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula (VI): -11 R-(R 2 )v

/R

2 0 I

A

(R

3

)U

/-N

0

R

21

(VI)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VI) or of the isomers thereof, or prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates thereof, wherein in Formula (VI) above: R1 is -C(lower alkyl)-, 6

-C(C

6

H

5

-(C

6

H

4

-R

15 I I orN 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 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 -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(0)-, 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 phenylene, or e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 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 -12sum 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 is 0, 1, 2, 3, 4, 5 or 6; or T-(CH2)s-, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or 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

R

1

R

16

R

17 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, N02, N(R8)(Rg)-lower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3, -NHC(O)OR10, -NHC(O)R10o, R1102SNH-, (R1102S)2N-, -S(0)2NH2, -S(O)0-2R8, tert-butyldimethyl-silyloxymethyl, -C(O)R12, -COOR19, -CON(R8)(R9), -CH=CHC(O)R12, -lower alkylene-C(O)R1 2, R1 OC(O)(lower alkylenyloxy)-,

CH

2 N R 13 N(R8)(Rg)C(O)(lower alkylenyloxy)- and 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,

CA

-13- -C(O)R10, OH, N(R8)(Rg)-lower alkylene-, N(R8)(Rg)-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, N02, OH, and halogeno; R8 and R9 are independently selected from H or lower alkyl; 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; R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy, -N

R

13 lower alkyl, phenyl or R7-phenyl; R13 is selected from -CH2-, -N(lower alkyl)- or -NC(O)R19; R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring; R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and 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.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and(b) at least one sterol absorption inhibitor represented by Formula (VII):

(VII)

00 O -14-

O

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VII) or of the isomers thereof, or prodrugs of the compounds of Formula m (VII) or of the isomers, salts or solvates thereof, wherein in Formula (VII) above: A is -CH=CH-, or -(CH2)p- wherein p is 0, 1 or 2; B is R1 SR3 E is C10 to C20 alkyl or to C19)-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; R1, R2, and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower s1 alkylamino, dilower alkylamino, -NHC(O)OR5, R602SNH- and -S(O)2NH2; R4 is a (OR 5 )n wherein n is 0, 1, 2 or 3; 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, N02, NH2, OH, halogeno, lower alkylamino and dilower alkylamino.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula (VIII):

O-G

Arl-R'-Q O Ar 2

(VIII)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VIII) or of the isomers thereof, or prodrugs of the compounds of Formula (VIII) or of the isomers, salts or solvates thereof, wherein, in Formula (VIII) above,

R

2 6 is H or OG 1 G and G 1 are independently selected from the group consisting of

OR

4 T5 OR 4

O

0 R 7 H, ROIOR3 R OOR3 -CH2 IIOR H,

CO

2

R

2

CH

2

OR

6

OR

3

OR

4

OR

3 a R4aQ9: QR R j and

OR

3 CH Rb provided that when R 2 6 is H or 1O

CH

2 Ra OH, G is not H; R, R a and Rb are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or W is independently selected from the group consisting of

-O-C(O)-N(R

3 1

-NH-C(O)-N(R

3 1 and -O-C(S)-N(R 3 1

R

2 and R 6 are independently selected from the group consisting of H, (Cl- C6)alkyl, aryl and aryl(C1-C6)alkyl;

R

3

R

4

R

5

R

7 R3a and R 4 a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, -C(O)(C1-C6)alkyl and -C(O)aryl;

R

3 0 is selected from the group consisting of R 3 2 -substituted T, 16-

R

32 -substituted-T-(Cli-C6)alkyI, R 32 -substituted-(C2-C4)alkenyl,

R

32 -substituted-(Ci -C6)alkyl, R 32 -su bstituted-(C3-C7 )cycloa Ikyl and

R

32 -substituted-(C3-C7)cycloalkyl(CI -C6)alkyl;

R

31 is selected from the group consisting of H and (C1-C4)alkyl; T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosth lazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R

32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, -OH, phenoxy, -CF3, -N02, (Cl -C4)alkoxy, methylenedioxy, oxo, (Cl -C4)alkylsulfanyl, (Ci -C4)alkylsulfinyl, (Ci -C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C4)alkyl)2, -C4)alkyl, -C4)alkoxy and pyrrolidinylcarbonyl; or R 32 is a covalent bond and R 3 1 the nitrogen to which it is attached and R 32 form a pyrrolidinyl, pipenidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci -C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, Nmethylpiperazinyl, indolinyl or morpholinyl group; Ar 1 is aryl or R 1 O-substituted aryl; Ar 2 is aryl or R 1 1 -substituted aryl; Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group (R4bi and

R

1 is selected from the group consisting of 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 phenylene, -NR 22 or e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6)aikenylene-; and -(CH2)f-V-(CH2)g-, wherein V is 03-C6 cycloalkylene, f is 1-5 and g is provided that the sum of f and g is 1-6; -17-

R

12 is -C(0 1

-C

6 alkyl)-, -C(C 6

H

4 -R 23 or -+O

R

13 and R 14 are independently selected from the group consisting of -0H2-, -CH(CI-C6 alkyl)-, -C(di-(Oi -06) alkyl), -CH=CH- and -0(01 -06 alkyl)=CH-; orR1 together with an adjacent R 13 or R 12 together with an adjacent R 14 form a -OH=CH- or a -OH=O(C1-06 alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R 13 is -CH=CH- or -0(01-06 alkyl)=OH-, a is 1; provided that when R 14 is -CH=CH- or -0(01-06 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R 1 3 s can be the same or different; and provided that when b is 2 or 3, the R 14 's can be the same or different; and when Q is a bond, R 1 also can be: 1R17 15 1

R

1 I R 1

R

I I I -MYdC -4 -XM(O)s-Yn(CTt ZP- or 2 R16 R118 R1 R16 M is or X, Y and Z are independently selected from the group consisting of -CH2-, -CH(Ci -C6)alkyl- and -O(di-(Oi -06)alkyl);

R

10 and R 1 1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, -ORl 9, -0(CO)Rl 9, -0(CO)OR 2 1, -0(0H2)1 -5OR 1 9, -0(OO)NR1 9

R

2 0, -NR 19

R

20

-NR

19

(CO)R

20 -NR1 9

(CO)OR

2 1,

-NR

19

(CO)NR

20

R

2 5

-NR

1 9 S02R 2 1 -C00R 1 9, -00 NR 1 9

R

20 -00R 1 9, -SO2NR 1 9

R

20 S(0)O..2R 21 -0(0H2)1 -1 -C00R 1 9, -0(0H2)1 -1 OCONR 1 9

R

20 -(Ci -06 alkylene)-COORl 9, -CH=OH-COOR 1 9, -0F3, -ON, -N02 and halogen;

R

15 and R 17 are independently selected from the group consisting of -18-

-OR

1 9

-O(CO)R

1 9

-O(CO)OR

2 1 and -O(CO)NR1 9

R

2 0;

R

1 6 and R 18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R 1 5 and R 16 together are or R 1 7 and R 18 together are =0; d is 1, 2 or 3; his 1, 2, 3or4; 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 v is 0 or 1; j and k are independently 1-5, provided that the sum of j, k and v is -Xi-(C)v-Yk-S(0)o.2and when Q is a bond and R 1 is R 16 Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R

1 9 and R 2 0 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;

R

2 1 is (C1-C6)alkyl, aryl or R 2 4 -substituted aryl;

R

2 2 is H, (Ci-C6)alkyl, aryl (Cl-C6)alkyl, -C(O)R1 9 or -COOR 19

R

2 3 and R 2 4 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, -COOH, N02,

-NR

1 9

R

2 0 -OH and halogeno; and

R

2 5 is H, -OH or (C1-C6)alkoxy.

Also described herein is a composition comprising: at least one peroxisome proliferator-activated receptor activator; and at least one sterol absorption inhibitor represented by Formula (IX): -19- Ar

(IX)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IX) or of the isomers thereof, or prodrugs of the compounds of Formula (IX) or of the isomers, salts or solvates thereof, wherein, in Formula (IX) above,

R

26 is selected from the group consisting of: a) OH; b) OCH 3 c) fluorine and d) chlorine.

R

1 is selected from the group consisting of

OR

5

OR

4

OR

5

OR

4

OR

7 H, V.IIOR 3

.,,IIOR

3

,-CH

2 "11OR H, 0 0

CO

2

R

2

CH

2

OR

6

R

3 O R

OR

3 a

R

4 aO, -SO 3 H; natural and unnatural

OR

3 O CH 2 Rb amino acids.

R40/0 O CH 2 Ra R, Ra and Rb are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy and -W-R 30 W is independently selected from the group consisting of

-O-C(O)-N(R

3 1

-NH-C(O)-N(R

3 1 and -O-C(S)-N(R 3 1

R

2 and R 6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(Ci-C6)alkyl; 20

R

3

R

4

R

5

R

7

R

3 a and R 4 a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, -C(O)(C1-C6)alkyl and -C(O)aryl;

R

30 is independently selected form the group consisting of R 32 -substituted T,

R

32 -substituted-T-(Cl1-C6)alkyl, R 32 -substituted-(C2-C4)aIke nyl, R 32 -substituted- (Ci -C6)alkyl, R 32 -substituted-(C3-C7)cycloalkyI and R 32 -su bstituted-(C3- C7)cycloalkyl(Ci -C6)alkyl;

R

31 is independently selected from the group consisting of H and (Ci -C4)alkyl; T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R

32 is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (CI-C4)alkyl, -OH, phenoxy, -CF3, -N02, (Ci -C4)al koxy, methylenedioxy, oxo, (Ci -C4)alkylsulfanyl, (CI -C4)alkylsulfinyl, (Ci -C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C4)alkyl)2, *C(O)-(Cl-C4)alkyl, -C(O)-(Cl-C4)alkoxy and pyrrolidinylcarbonyl; or R 32 is a covalent bond and R 31 the nitrogen to which it is attached and R 32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci- C4)alkoxyca rbonyl-substituted pyrrolidi nyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar 1 is aryl or R 1 O-substituted aryl; Ar 2 is aryl or R 1 1 -substituted aryl; Q is wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, R 12

(R

13 )a forms the spiro group bR4),

R

12 is -0(01-06 alkyl)-, -C(0 6

H

4

-R

23 or -+NO- 00 -21-

R

13 and R 14 are independently selected from the group consisting of -0H2-, -CH(C1-06 alkyl)-, -O(di-(01-06) alkyl), -CH=CH- and -0(01-06 alkyl)=OH-; orR1 together with an adjacent R 13 or R 12 together with an adjacent R 14 form a -OH=OH- or a -OH =0(01-06 alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R 13 is -OH=CH- or -0(01-06 alkyl)=CH-, a is 1; provided that when R 14 is -CH=OH- or -0(01 -06 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the RI 3 's N can be the same or different; and provided that when b is 2 or 3, the R 14 's can be the same or different;

R

1 0 and R 1 1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting Of (C-W6alkyl, -OR1 9 ,-O(CO)Rl 9, -O(COOR 2 1 -O(0H2)1 5 OR1 9, -O(CO)NRi 9

R

20

-NR

1 9

R

20

-NR

1 9

(CO)R

20

-NR

1 9

(COOR

2 1

-NR

19

(CO)NR

20

R

25

-NR

19 S02R 2 1 -000R 1 9,

-CONR

1 9

R

20 -C0R 1 9, -SO2NR 1 9

R

20 S(O)0-2R 21 -O(CH2)1 -1 o-C0R 1 9, -O(0H2)1 -1 oOONR 1 9

R

2 0 -(Ci -06 alkylene)-C00R 1 9, -CH=CH-OOORl 9, -CF3, -ON, -NO2 and halogen; Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidlazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R

19 and R 20 are independently selected from the group consisting of H, (Ci -C6)alkyl, aryl and aryl-substituted (0-06alkyl;

R

21 is (O1-06)alkyl, aryl or R 24 -substituted aryl;

R

22 is H, (CII -06)alkyl, aryl (C1 -06)alkyl, -O(O)R 1 9 or -OOOR1 9

R

2 3 and R 24 are independently 1-3 groups independently selected from the group consisting of H, (OI-Oe)alkyl, (O-06alkoxy, -OOOH, N02, -NR 19

R

2 0

-OH-

and halogeno; and

R

25 is H, -OH- or (01-C6)alkoxy.

Therapeutic combinations also are described comprising: a first amount of at least one peroxisome proliferator-activated receptor activator; and a second 00 0 -22amount of at least one sterol absorption inhibitor represented by Formulae (I-XI) i above or isomers thereof, or pharmaceutically acceptable salts or solvates of the Scompounds of Formula (I-XI) or of the isomers thereof, or prodrugs of the compounds of Formula (I-XI) or of the isomers, salts or solvates thereof, 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 0concentration of a sterol in plasma of a mammal.

Pharmaceutical compositions for the treatment or prevention of a vascular Scondition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising a therapeutically effective amount of the above compositions or therapeutic combinations and a pharmaceutically acceptable carrier also are described.

Methods 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 above compositions or therapeutic combinations also are described.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." DETAILED DESCRIPTION The compositions and therapeutic combinations described herein comprise at least one (one or more) activators for peroxisome proliferator-activated receptors (PPAR). These activators act as agonists for the peroxisome proliferatoractivated receptors. Three subtypes of PPAR have been identified, and these are designated as peroxisome proliferator-activated receptor alpha (PPARa), peroxisome proliferator-activated receptor gamma (PPARy) and peroxisome proliferator-activated receptor delta (PPAR6). It should be noted that PPAR6 is also referred to in the literature as PPARP and as NUC1, and each of these names refers to the same receptor.

PPARa regulates the metabolism of lipids. PPARa is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating p- 00 -23oxidation of fatty acids. The PPARy receptor subtypes are involved in activating the Z program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. PPAR6 has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, WO 97/28149.

PPARa activator compounds are useful for, among other things, lowering triglycerides, moderately lowering LDL levels and increasing HDL levels. Examples of SPPARa activators useful in the compositions described herein include fibrates.

Non-limiting examples of suitable fibric acid derivatives ("fibrates") include Sclofibrate (such as ethyl 2 -(p-chlorophenoxy)-2-methyl-propionate, for example ATROMID-S® Capsules which are commercially available from Wyeth-Ayerst); gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, for example LOPID® tablets which are commercially available from Parke Davis); ciprofibrate Registry No. 52214-84-3, see U.S. Patent No. 3,948,973 which is incorporatec herein by reference); bezafibrate Registry No. 41859-67-0, see U.S. Patent No. 3,781,328 which is incorporated herein by reference); clinofibrate Registry No. 30299-08-2, see U.S. Patent No. 3,716,583 which is incorporated herein by reference); binifibrate Registry No. 69047-39-8, see BE 884722 which is incorporated herein by reference); lifibrol Registry No. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester) which is commercially available from Abbott Laboratories or LIPANTHYL® micronized fenofibrate which is commercially available from Labortoire Founier, France) and mixtures thereof. These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enantiomers, zwitterions and tautomers.

Other examples of PPARa activators useful with the practice described herein include suitable fluorophenyl compounds as disclosed in U.S. No. 6,028,109 which is incorporated herein by reference; certain substituted phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated herein by reference; and PPARa activator compounds as disclosed in WO 98/43081 which is incorporated herein by reference.

Non-limiting examples of suitable PPARy activators useful in the compositions described herein include suitable derivatives of glitazones or thiazolidinediones, such 00 D -24- 4 as, troglitazone (such as REZULIN® troglitazone (-5-[[4-[3,4-dihydro-6-hydroxy- 2,5,7,8-tetramethyl-2H- 1-benzopyran-2-yl)methoxy]phenyl] methyl]-2,4c thiazolidinedione) commercially available from Parke-Davis); rosiglitazone (such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate) commercially available from SmithKline Beecham) and pioglitazone (such as ACTOSTM pioglitazone hydrochloride (5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride) commercially available from Takeda Pharmaceuticals). Other useful thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653 as disclosed in WO 98/05331 which is incorporated herein by reference; PPARy activator compounds disclosed in WO 00/76488 which is incorporated herein by reference; and PPARy activator compounds disclosed in U.S. Patent No.

5,994,554 which is incorporated herein by reference.

Other useful PPARy activator compounds include certain acetylphenols as disclosed in U.S. Patent No. 5,859,051 which is incorporated herein by reference; certain quinoline phenyl compounds as disclosed in WO 99/20275 which is incorporated herein by reference; aryl compounds as disclosed by WO 99/38845 which is incorporated herein by reference; certain 1,4-disubstituted phenyl compounds as disclosed in WO 00/63161; certain aryl compounds as disclosed in WO 01/00579 which is incorporated herein by reference; benzoic acid compounds as disclosed in WO 01/12612 and WO 01/12187 which are incorporated herein by reference; and substituted 4-hydroxy-phenylalconic acid compounds as disclosed in WO 97/31907 which is incorporated herein by reference.

PPAR6 compounds are useful for, among other things, lowering triglyceride levels or raising HDL levels. Non-limiting examples of suitable PPAR6 activators useful in the compositions described herein include suitable thiazole and oxazole derivates, such as C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which is incorporated herein by reference); certain fluoro, chloro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149 which is incorporated herein by reference; suitable non-B-oxidizable fatty acid analogues as disclosed in U.S. Patent No. 5,093,365 which is incorporated herein by reference; and PPAR6 00 activator compounds disclosed in WO 99/04815 which is incorporated herein by Sreference.

SMoreover, compounds that have multiple functionality for activating various combinations of PPARa, PPARy and PPAR6 also are useful in compositions described herein. Non-limiting examples include certain substituted aryl compounds as disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are t incorporated herein by reference, which are described as being useful PPARa and/or O PPARy activator compounds. Other non-limiting examples of useful PPARa and/or PPARy activator compounds include activator compounds as disclosed in WO 97/25042 which is incorporated herein by reference; activator compounds as disclosed in WO 00/63190 which is incorporated herein by reference; activator compounds as disclosed in WO 01/21181 which is incorporated herein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is incorporated herein by reference; activator compounds as disclosed in WO 00/63196 and WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4thiazolidinediones compounds as disclosed in U.S. Patent No. 6,008,237 which is incorporated herein by reference; arylthiazolidinedione and aryloxazolidinedione compounds as disclosed in WO 00/78312 and WO 00/78313G which are incorporated herein by reference; GW2331 or (2-(4-[difluorophenyl]-1heptylureido)ethyl]phenoxy)-2methylbutyric compounds as disclosed in WO 98/05331 which is incorporated herein by reference; aryl compounds as disclosed in U.S. Patent No. 6,166,049 which is incorporated herein by reference; oxazole compounds as disclosed in WO 01/17994 which is incorporated herein by reference; and dithiolane compounds as disclosed in WO 01/25225 and WO 01/25226 which are incorporated herein by reference.

Other useful PPAR activator compounds include substituted benzylthiazolidine- 2,4-dione compounds as disclosed in WO 01/14349, WO 01/14350 and WO/01/04351 which are incorporated herein by reference; mercaptocarboxylic compounds as disclosed in WO 00/50392 which is incorporated herein by reference; ascofuranone compounds as disclosed in WO 00/53563 which is incorporated herein by reference; carboxylic compounds as disclosed in WO 99/46232 which is incorporated herein by reference; compounds as disclosed in WO 99/12534 which is incorporated herein by -26reference; benzene compounds as disclosed in WO 99/15520 which is incorporated herein by reference; o-anisamide compounds as disclosed in WO 01/21578 which is incorporated herein by reference; and PPAR activator compounds as disclosed in WO 01/40192 which is incorporated herein by reference.

The peroxisome proliferator-activated receptor(s) activator(s) are administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose can range from about 0.1 to about 1000 mg per day, preferably about 0.25 to about 50 mg/day, and more preferably about 10 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.

The term "therapeutically effective amount" means that amount of a therapeutic agent of the composition, such as the peroxisome proliferator-activated receptor activator(s), sterol absorption inhibitor(s) and other pharmacological or therapeutic agents described below, that will elicit a biological or medical response of a tissue, system, animal or mammal that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more conditions, for example vascular conditions, such as hyperlipidaemia (for example atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and/or to reduce the level of sterol(s) (such as cholesterol) in the plasma.

As used herein, "combination therapy" or "therapeutic combination" means the administration of two or more therapeutic agents, such as peroxisome proliferatoractivated receptor activator(s) and sterol absorption inhibitor(s), to prevent or treat a condition, for example a vascular condition, such as hyperlipidaemia (for example atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and/or reduce the level of sterol(s) (such as cholesterol) in the plasma. As used herein, "vascular" comprises cardiovascular, cerebrovascular and combinations thereof. The compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver 00 0 -27- Sor small intestine of a mammal or human. Such administration includes coadministration of these therapeutic agents in a substantially simultaneous manner, Ssuch as in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each therapeutic agent. Also, such administration includes use of each type of therapeutic agent in a sequential manner. In either case, the treatment using the combination therapy will provide beneficial effects in treating the condition. A potential advantage of the combination therapy disclosed herein may be a reduction in the required amount of an individual therapeutic compound or the Soverall total amount of therapeutic compounds that are effective in treating the condition. By using a combination of therapeutic agents, the side effects of the individual compounds can be reduced as compared to a monotherapy, which can improve patient compliance. Also, therapeutic agents can be selected to prov1df'a broader range of complimentary effects or complimentary modes of action.

The compositions, pharmaceutical compositions and therapeutic combinations of the present invention comprise one or more substituted azetidinone or substituted p-lactam sterol absorption inhibitors discussed in detail below. As used herein, "sterol absorption inhibitor" means a compound capable of inhibiting the absorption of one or more sterols, including but not limited to cholesterol, phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), stanols (such as cholestanol, 5-campestanol, 5a-sitostanol), and mixtures thereof, when administered in a therapeutically effective (sterol absorption inhibiting) amount to a mammal or human.

In a preferred embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula below: R

R

2 1 R 3 Ar -Xm-(C)q-Yn-(C)r-Zp Ar 3 R1 R -28-

(I)

or isomers of the compounds of Formula or pharmaceutically acceptable salts or solvates of the compounds of Formula or of the isomers of the compounds of Formula or prodrugs of the compounds of Formula or of the isomers, salts or solvates of the compounds of Formula wherein, in Formula above: Ar and Ar 2 are independently selected from the group consisting of aryl and

R

4 -substituted aryl; Ar 3 is aryl or Rs-substituted aryl; X, Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-; R and R are independently selected from the group consisting of -OR

-O(CO)R

6 -O(CO)OR and -O(CO)NR6R; R and R 3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or

R

4 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR 6

-O(CO)R

6

-O(CO)OR

9

-O(CH

2 5 0R -O(CO)NR6R -NR R -NR (CO)R 7 -NR (CO)OR -NR (CO)NR R -NR S02R -COOR 6 -CONR R, -COR 6

-SO

2 NR R 7 S(0) 0 2

R

9

-O(CH

2 )110-COOR,

-O(CH

2 1 1 0 CONR6R 7 -(lower alkylene)COOR 6

-CH=CH-COOR

6 -CF3, -CN,

-NO

2 and halogen; R is 1-5 substituents independently selected from the group consisting of

-OR

6

-O(CO)R

6

-O(CO)OR

9

-O(CH

2 1 -5OR 6 -O(CO)NR6R -NRR -NR (CO)R 7 -29- -NR (CO)OR 9 -NR6(CO)NR 7 R, -NR S0 2

R

9

-COOR

6

-CONR

6

R

7

-COR

6

SO

2 NR R S(0)0 2

R

9

-O(CH

2 )1- 1 o-COOR -O(CH 2 )1 10 oCONR6R 7 -(lower alkylene)COOR 6 and -CH=CH-COOR6; 6 7 8

R

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

Preferably, R 4 is 1-3 independently selected substituents, and R 5 is preferably 1-3 independently selected substituents.

to As used herein, the term "alkyl" or "lower alkyl" means straight or branched alkyl chains having from 1 to 6 carbon atoms and "alkoxy" means alkoxy groups having 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups include, for example methyl, ethyl, propyl, and butyl groups.

"Alkenyl" means straight or branched carbon chains having one or more double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means straight or branched carbon chains having one or more triple bonds in the chain. Where an alkyl, alkenyl or alkynyl chain joins two other variables and is therefore bivalent, the terms alkylene, alkenylene and alkynylene are used.

"Cycloalkyl" means a saturated carbon ring of 3 to 6 carbon atoms, while "cycloalkylene" refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional isomers.

"Halogeno" refers to fluorine, chlorine, bromine or iodine radicals.

"Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

"Phenylene" means a bivalent phenyl group, including ortho, meta and parasubstitution.

The statements wherein, for example, R, R R 2 and R 3 are said to be independently selected from a group of substituents, mean that R, R R 2 and R are independently selected, but also that where an R, R 1

R

2 and R variable occurs more than once in a molecule, each occurrence is independently selected if R is 00 0 -OR wherein R is hydrogen, R 2 can be -OR wherein R is lower alkyl). Those skilled in the art will recognize that the size and nature of the substituent(s) will affect Sthe number of substituents that can be present.

Compounds useful in the invention may have at least one asymmetrical carbon atom and therefore all isomers, including enantiomers, stereoisomers, rotamers, tautomers and racemates of the compounds of Formula (I-XI) (where they exist) are contemplated, e.g. d and I isomers in both pure form Sand in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of the Formulae I-XI. Isomers may also include geometric isomers, when a double bond is present.

Those skilled in the art will appreciate that for some of the compounds of the Formulae I-XI, one isomer will show greater pharmacological activity than other isomers.

Compounds with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.

Certain compounds are acidic those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

-31 As used herein, "solvate" means a molecular or ionic complex of molecules or ions of solvent with those of solute (for example, one or more compounds of Formulae I-XI, isomers of the compounds of Formulae I-XI, or prodrugs of the compounds of Formulae I-XI). Non-limiting examples of useful solvents include polar, protic solvents such as water and/or alcohols (for example methanol).

As used herein, "prodrug" means compounds that are drug precursors which, following administration to a patient, release the drug in vivo via some chemical or physiological process a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).

Preferred compounds of Formula are those in which Ar is phenyl or R -substituted phenyl, more preferably (4-R 4 )-substituted phenyl. Ar 2 is preferably 4 3 phenyl or R -substituted phenyl, more preferably (4-R 4 )-substituted phenyl. Ar is preferably R -substituted phenyl, more preferably (4-R )-substituted phenyl. When Ar is (4-R4-substituted phenyl, R 4 is preferably a halogen. When Ar 2 and Ar 3 are R- and R -substituted phenyl, respectively, R is preferably halogen or -OR 6 and R s is preferably -OR wherein R is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar and Ar is 4-fluorophenyl and Ar 3 is 4-hydroxyphenyl or 4-methoxyphenyl.

X, Y and Z are each preferably -CH 2

R

1 and R 3 are each preferably 2 6 r hydrogen. R and R are preferably -OR wherein R 6 is hydrogen, or a group readily metabolizable to a hydroxyl (such as -O(CO)R 6

-O(CO)OR

9 and -O(CO)NR 6

R

7 defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2.

Also preferred are compounds of Formula in which p, q and n are each zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are each 6 6 zero, q is 1, p is 2, Z is -CH 2 and R is -OR especially when R is hydrogen.

Also more preferred are compounds of Formula wherein p, q and n are each zero, r is 1, m is 2, X is -CH 2 and R 2 is -OR especially when R is hydrogen.

-32- Another group of preferred compounds of Formula is that in which Ar is phenyl or R 4 -substituted phenyl, Ar 2 is phenyl or R 4 -substituted phenyl and Ar 3 is R substituted phenyl. Also preferred are compounds in which Ar is phenyl or R 4 2 4 3 substituted phenyl, Ar is phenyl or R 4 -substituted phenyl, Ar is R -substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more preferably 3. More preferred are 1 4 2 4 compounds wherein Ar is phenyl or R -substituted phenyl, Ar is phenyl or R substituted phenyl, Ar is R -substituted phenyl, and wherein m, n and r are each zero, q is 1 and p is 2, or wherein p, q and n are each zero, r is 1 and m is 2 or 3.

In a preferred embodiment, a sterol inhibitor of Formula useful in the compositions, therapeutic combinations and methods of the present invention is represented by Formula (II) (ezetimibe) below: OH F

N

OH

F

(II)

or pharmaceutically acceptable salts or solvates of the compound of Formula or prodrugs of the compound of Formula (II) or of the salts or solvates of the compound of Formula (II).

Compounds of Formula I can be prepared by a variety of methods well know to those skilled in the art, for example such as are disclosed in U.S. Patents Nos.

5,631,365, 5,767,115, 5,846,966, 6,207,822, U.S. Provisional Patent Application No.

60/279,288 filed March 28, 2001, and PCT Patent Application WO 93/02048, each of which is incorporated herein by reference, and in the Example below. For example, suitable compounds of Formula I can be prepared by a method comprising the steps of: treating with a strong base a lactone of the Formula A or B: -33- R O OoE Y O n0n

I

n or

(CR'R

1 )q

R

1 Ar A Aro B wherein R' and R 2 are R and R 2 respectively, or are suitably protected hydroxy groups; Ar 10 is Ar 1 a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl; and the remaining variables are as defined above for Formula I, provided that in lactone of formula B, when n and r are each zero, p is 1-4; reacting the product of step with an imine of the formula Ar 30

N

wherein Ar 20 is Ar 2 a suitably protected hydroxy-substituted aryl or a suitably 0o protected amino-substituted aryl; and Ar 30 is Ar 3 a suitably protected hydroxysubstituted aryl or a suitably protected amino-substituted aryl; c) quenching the reaction with an acid; d) optionally removing the protecting groups from R 2 Ar 10 Ar 20 and Ar 3 0 when present; and e) optionally functionalizing hydroxy or amino substituents at R, R 2 Ar 1 Ar 2 and Ar 3 Using the lactones shown above, compounds of Formula IA and IB are obtained as follows: Zp R OH R3 Ar30 1 1 R3 O Ar Ar-Xm(C) qYn CZ Ar 3 Y 0 i 1-I I1 I N

R

1 R3 (CR'R' )q Ar2 I IA \Ar 2 Ar I m

A

-34wherein the variables are as defined above; and

R

2

R

3 AH R 2 CrZp Ar30

I

Y r Ar'-Xm-C-Yn- C)rZ Ar3 (I 1n3 RN

R

1

R

3 O Ar IlB \Ar 2 Ar 10

B

wherein the variables are as defined above.

Alternative sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (III) below:

R

1 Arl-A-Y'C'-Zp Ar 3 R2 Ar2 0 (Ill) or isomers of the compounds of Formula (III), or pharmaceutically acceptable salts or solvates of the compounds of Formula (III) or of the isomers of the compounds of Formula (III), or prodrugs of the compounds of Formula (111) or of the isomers, salts or solvates of the compounds of Formula (III), wherein, in Formula (III) above: Ar is R3-substituted aryl; 2 4 Ar is R -substituted aryl; Ar is R -substituted aryl; Y and Z are independently selected from the group consisting of -CH 2 -CH(lower alkyl)- and -C(dilower alkyl)-; A is selected from or R is selected from the group consisting of -OR -O(CO)R -O(CO)OR 9 and 6 7 2 -O(CO)NR R R is selected from the group consisting of hydrogen, lower alkyl and 1 2 aryl; or R and R together are =0; O q is 1,2 or 3; p is 0, 1,2, 3 or 4; R is 1-3 substituents independently selected from the group consisting of -OR -O(CO)R 6

-O(CO)OR

9

-O(CH

2 )1 5 0R 9 -O(CO)NR6R -NR R -NR (CO)R, -NR (CO)OR -NR (CO)NR R -NR SO 2 -lower alkyl, -NR SO 2 -aryl, -CONR R.

-COR

6

-SO

2

NR

6

R

7 S(O)0-2-alkyl, S(O)02,-aryl, -O(CH 2 1 10 -COOR -O(CH2) 1 10 CONR6R o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-

COOR

6 and -CH=CH-COOR 6

R

3 and R are independently 1-3 substituents independently selected from the group consisting of R hydrogen, p-lower alkyl, aryl, -NO 2

-CF

3 and p-halogeno; 6 7 8

R

6 R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R 9 is lower alkyl, aryl or aryl-substituted lower alkyl.

1 Preferred compounds of Formula I include those in which Ar is 3 3 4 4 R -substituted phenyl, especially (4-R )-substituted phenyl. Ar is preferably R 4 substituted phenyl, especially (4-R 4 )-substituted phenyl. Ar 3 is preferably R 5 substituted phenyl, especially (4-Rs)-substituted phenyl. Mono-substitution of each of 1 2 3 Ar, Ar and Ar is preferred.

Y and Z are each preferably -CH 2

R

2 is preferably hydrogen. R 1 is preferably -OR wherein R is hydrogen, or a group readily metabolizable to a hydroxyl (such as -O(CO)R -O(CO)OR 9 and -O(CO)NR R defined above). Also preferred are compounds wherein R and R 2 together are =0.

The sum of q and p is preferably 1 or 2, more preferably 1. Preferred are compounds wherein p is zero and q is 1. More preferred are compounds wherein p is zero, q is 1, Y is -CH 2 and R is -OR 6 especially when R 6 is hydrogen.

-36- Another group of preferred compounds is that in which Ar is R -substituted phenyl, Ar 2 is R 4 -substituted phenyl and Ar is R -substituted phenyl.

1 3 2 4 Also preferred are compounds wherein Ar is R -substituted phenyl, Ar is R 3 substituted phenyl, Ar is R -substituted phenyl, and the sum of p and q is 1 or 2, especially 1. More preferred are compounds wherein Ar is R -substituted phenyl, Ar is R4-substituted phenyl, Ar is R -substituted phenyl, p is zero and q is 1.

A is preferably

R

3 is preferably -COOR 6 -CONRR 7, -COR 6 -SO2NR6R 7 S(0)o2-alkyl, S(O).

2 aryl, NO 2 or halogeno. A more preferred definition for R 3 is halogeno, especially fluoro or chloro.

R is preferably hydrogen, lower alkyl, -OR -O(CO)R 6

-O(CO)OR

9 -O(CO)NR R -NR R COR or halogeno, wherein R and R are preferably independently hydrogen or lower alkyl, and R 9 is preferably lower alkyl. A more preferred definition for R is hydrogen or halogeno, especially fluoro or chloro.

R

5 is preferably -OR 6

-O(CO)R

6

-O(CO)OR

9 -O(CO)NR6R 7 -NR R -(lower alkylene)-COOR or -CH=CH-COOR wherein R 6 and R are preferably independently hydrogen or lower alkyl, and R is preferably lower alkyl. A more preferred definition for R 5 is -OR 6 -(lower alkylene)-COOR 6 or

-CH=CH-COOR

6 wherein R 6 is preferably hydrogen or lower alkyl.

Methods for making compounds of Formula III are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No.

5,688,990, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (IV): -37-

(IV)

or isomers of the compounds of Formula or pharmaceutically acceptable salts or solvates of the compounds of Formula (IV) or of the isomers of the compounds of Formula or prodrugs of the compounds of Formula (IV) or of the isomers, salts or solvates of the compounds of Formula wherein, in Formula (IV) above: 2 2 A is selected from the group consisting of R -substituted heterocycloalkyl, R 2 2 2 substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl; 1 is aryl or R3substituted aryl; 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 R 5-R 6 )a spiro group (R )bJ ;and R is selected from the group consisting of:

-(CH

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

-(CH

2 )e-G-(CH 2 wherein G is phenylene, -NR 8 or e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6 alkenylene)-; and

-(CH

2 )f-V-(CH 2 wherein V is C3-C6 cycloalkylene, f is 1-5 and g is provided that the sum of f and g is 1-6; R is selected from: -C I I I I I -0 -C(C1-C6 alkyl)-, -C(C 6

H

4

-R

9 or NO;

I

-38- R and R are independently selected from the group consisting of -CH2-, -CH(C 1

-C

6 alkyl)-, alkyl), -CH=CH- and -C(C,-C6 alkyl)=CH-; or R together with an adjacent R 6 or R together with an adjacent R form a -CH=CH- or a 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,-C6 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R6'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, R 1 also can be selected from: RiO R 12 RiO R 10 I I 1 -M -Yd -Zh t Zp- or -Xj-(C)V-Yk-S(0) 0 2

R

1 R13 Rl

R

where M is or X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C 1

-C

6 alkyl)- and -C(di-(C,-C 6 alkyl); 12 R0 and R12 are independently selected from the group consisting of

-OR

14

-O(CO)R

1

-O(CO)OR

1 6 and -O(CO)NR1 R R and R 3 are independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl and aryl; or R 10 and R together are or R 12 and R13 together are =0; 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 v is 0 or 1; j and k are independently 1-5, provided that the sum of j, k and v is -39- R 2is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (Cl-C 10 )alkyl, (C 2

-C

10 )alkenyl, (C 2

-C

16 )alkynyl, 17 17

(C

3 -0 6 )cycloalkyl, (C 3

-C

6 )cycloalkenyl, R -Substituted aryi, R -Substituted benzyl, 17 17 14 15 14 1 R -substituted benzyloxy, R -substituted aryloxy, halogeno, -NR R1 NR R 5 (0 1 06 alkylene)-, NR 14R1Co( -6akln),NCOR1,OH, 1l-06 alkoxy, 16

OC(O)R

14 1 -COR ,hydroxy(C 1 -0 6 )alkyl, (C 1

-C

6 )alkoxy(Cj-0 6 )alkyl, NO 2 S(O) .R 1 14 and 14 2 S0 2 NR R an -(01-06 alkylene)COOR when R is a substituent on a 0 heterocycloalkyl ring, R 2is as defined, or is =0 or -01 and, where R 2is a substituent on a substitutable ring nitrogen, it is hydrogen, (0 1

-C

6 )alkyl, aryl, 0 6 )alkoxy, a ryloxy, (0 1 -0 6 )alkylcarbonyl, arylcarbonyl, hyd roxy, H 2 1 6 C0NRl 8

R

j~ or (C H 2 0A 0 18 wherein J is -NR or -OH 2-; R 3and R 4are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (0 1 -0 6 )alkyl, 14 14 16 14 14 15 14 -OR O(CO)R -O(CO)OR ,-O(CH 2 15 0R -O(O)NR R NR R 14 15 14 16 14 15 19 14 16 14 -NR (CO)R NR (OO)OR1 ,NR (CO)NR R NR S02R -COOR 14 15 14 14 15 16 14 -CONR R COR S02NR R S(0) 0 2 R -0(CH 2 1 1

,-COOR

14 15 14 14

-O(CH

2 110 00ONRI R -(01-06 alkylene)-COOR -CH=CH-OOOR -OF 3 -ON, N0 2 and halogen; 8 14 14 R is hydrogen, (0 1 -0 6 )alkyl, aryl (0 1 -0 6 )alkyl, -C(O)R or -OOR R 9and R 17are independently 1-3 groups independently selected from the group consisting of hydrogen, (C 1 -0)allkyl, (0 1 -0 6 )alkoxy, -COOH, NO 2 14 -NR R OH and halogeno; 14

R

14 and R are independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl, aryl and aryl-substituted (C,-C 6 )alkyl; 16 .17 R is (C,-C 6 )alkyl, aryl or R -substituted aryl; R is hydrogen or (C 1

-C

6 )alkyl; and

R

1 9 is hydrogen, hydroxy or (Cl-C 6 )alkoxy.

2 As used in Formula (IV) above, is preferably an R -substituted, 6membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred heterocycloalkyl rings are piperidinyl, piperazinyl and morpholinyl groups. The ring is preferably joined to the phenyl ring through a ring nitrogen. Preferred R 2 substituents are hydrogen and lower alkyl. R 9 is preferably hydrogen.

Ar is preferably phenyl or R 4 -phenyl, especially (4-R 4 )-substituted phenyl.

Preferred definitions of R 4 are lower alkoxy, especially methoxy, and halogeno, especially fluoro.

1 3 Ar is preferably phenyl or R -substituted phenyl, especially (4-R 3 )-substituted phenyl.

There are several preferred definitions for the -R1-Q- combination of variables: Q is a bond and R is lower alkylene, preferably propylene; Q is a spiro group as defined above, wherein preferably R 6 and R are each I I ethylene and R is -CH- or -C(OH)-

I

Q is a bond and R 1 is -M-Yd-C-Zh- wherein the variables R11 are chosen such that R is -O-CH 2

-CH(OH)-;

R12 Rio Q is a bond and Rlis C)s-Y-(I)t-Zp- wherein the

R

13

R

R

variables are chosen such that Rlis -CH(OH)-(CH 2 2 and -41- Q is a bond and R 1 is 0 2 wherein the

R"

1 variables are chosen such that R is -CH(OH)-CH 2 -S(O)0 2 Methods for making compounds of Formula IV are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No.

5,656,624, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula

R

Ar, S(O) Ar 2 Xm 1 Y I;ji 0 Ar 3

(V)

or isomers of the compounds of Formula or pharmaceutically acceptable salts or solvates of the compounds of Formula or of the isomers of the compounds of Formula or prodrugs of the compounds of Formula or of the isomers, salts or solvates of the compounds of Formula wherein, in Formula above: Ar is aryl, R 10 -substituted aryl or heteroaryl; 2 4 Ar is aryl or R -substituted aryl; 3 Ar is aryl or R -substituted aryl; X and Y are independently selected from the group consisting of -CH 2 -CH(lower alkyl)- and -C(dilower alkyl)-; R is -OR 6

-O(CO)R

6 -O(CO)OR or -O(CO)NR R R 1 is hydrogen, lower alkyl or aryl; or R and R together are =0; q is 0 or 1; risO, 1 or 2; -42 m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is1, 2, 3,4or 4 R is 1-5 substituents independently selected from the group consisting of 6 6 9 6 67 lower alkyl, -OR -O(CO)R -O(CO)OR -O(CH 2 15 0R6, -O(OO)NR R -N R ,NR (CO)R NR(O), -NR 6

(CO)NR

7 -RS2R' -COOR', 6 7 6 6 7 96 -CONR R -COR -S0 2 NR R 2 R9, -O(CH 2 110

,-COOR,

6 7 6 6 6

-O(CH

2 110 00NR R -(lower alkylene)COOR and -OH=CH-COOR R 5is 1-5 substituents independently selected from the group consisting of 6696 6 7 6 7 6 7

-OR

6

-O(OO)R

6 -O(CO)0R, -O(CH 2 1 5 OR O (CO)NR R, -NR R -NR (OO)R, 67 6 9 6 6 7 6 -NR (CO)0R', -NR 6 (CO)NR -NR S02R CORCNR CR, 6 7 96 6 7 S0 2 NR R, S(O)a- 2 R9, -O(0H 2 1 10 000R 0O(CH 2 )iiaOCONR R _CF3 -ON, -NO 2 halogen, (lower alkylene) OOR6 and H=CH- OOR6 R R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; R 9is lower alkyl, aryl or aryl-substituted lower alkyl; and R 0is 1-5 substituents independently selected from the group consisting of 6 6 9 6 6 7 lower alkyl, -OR -O(CO)R -O(CO)OR -O(0H 2 15 0R -O(OO)NR R 676 7 6 9 6 7 8 6 9 6 -NR R -NR (OO)R -NR (CO)OR', -NR (CO)NR R -NR S 2 R ,-COOR, 6 7 6 6 7 9 6 OCONR R, -COR -S0 2 NR R S(O) 0 2 R 0(CH 2 )iia0COOR OC21 6 7 10 00NR R

-OF

3 -ON, -NO 2 and halogen.

Within the scope of Formula V, there are included two preferred structures. In Formula VA, q is zero and the remaining variables are as defined above, and in Formula VB, q is 1 and the remaining variables are as defined above: -43-

R

N R

N,

Ar Xm y OS( Ar2 ArkR Y 3 O0 Ar 3 0 Ar3 VA VB 4 5 R R and R are each preferably 1-3 independently selected substituents as set forth above. Preferred are compounds of Formula wherein Ar 1 is phenyl, R 1 substituted phenyl or thienyl, especially (4-R )-substituted phenyl or thienyl. Ar 2 is preferably R 4 -substituted phenyl, especially (4-R 4 )-substituted phenyl. Ar 3 is preferably phenyl or R5-substituted phenyl, especially (4-R )-substituted phenyl.

When Ar is R -substituted phenyl, R10 is preferably halogeno, especially fluoro.

When Ar 2 is R4-substituted phenyl, R 4 is preferably -OR especially wherein R is hydrogen or lower alkyl. When Ar 3 is R -substituted phenyl, R 5 is preferably halogeno, to especially fluoro. Especially preferred are compounds of Formula wherein Ar is phenyl, 4-fluorophenyl or thienyl, Ar 2 is 4-(alkoxy or hydroxy)phenyl, and Ar is phenyl or 4-fluorophenyl.

X and Y are each preferably -CH 2 The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. When q is 1, n is preferably 1 to Preferences for X, Y, Ar Ar 2 and Ar 3 are the same in each of Formulae (VA) and (VB).

In compounds of Formula the sum of m and n is preferably 2, 3 or 4, more preferably 2. Also preferred are compounds wherein the sum of m and n is 2, and r is 0 or 1.

In compounds of Formula the sum of m and n is preferably 1, 2 or 3, more preferably 1. Especially preferred are compounds wherein m is zero and n is 1.

R is preferably hydrogen and R is preferably -OR wherein R is hydrogen, or a group readily metabolizable to a hydroxyl (such as -O(CO)R

-O(CO)OR

9 and -O(CO)NR6R 7 defined above), or R and R 1 together form a =0 group.

-44- Methods for making compounds of Formula V are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No.

5,624,920, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (VI): R4

R

1 -(R 2 )v /R 2 I A

(R

3 )u

N

0 R21

(VI)

or isomers of the compounds of Formula or pharmaceutically acceptable salts or solvates of the compounds of Formula (VI) or of the isomers of the compounds of Formula or prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates of the compounds of Formula wherein: R1 is I I -C(lower alkyl)-, 6

-C(C

6

-C(C

6

H

4

-R

15 N- or -C NO 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 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 -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(0)-, wherein m is 0, 1, 2, 3,4 or B-(CH2)q-, wherein q is 0, 1, 2, 3, 4, 5 or 6; B-(CH2)e-Z-(CH2)r-, wherein Z is phenylene, or e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B-(C2-C6 alkenylene)-; B-(C4- 06 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- 06 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 is 0, 1, 2, 3, 4, 5 or 6; or T-(CH2)s-, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or Ri 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

R

1 R16 R17 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, R7benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, N02, N(R8)(R9)-lower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3, -46- R1102SNH-, (R1102S)2N-, -S(0)2NH2, -S(0)0-2R8, tertbutyldimethyl-silyloxymethyl, -C(O)R12, -COOR19, -CON(R8)(Rg), -CH=CHC(O)R12.

-lower alkylene-C(O)R12, R1 C(O)(lower alkylenyloxy)-, N(R8)(Rg)C(O)(lower CH2_ R13 alkylenyloxy)- and 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, OH, N(R8)(Rg)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, -S(0)2NH2 and 2-(trimethylsilyl)-ethoxymethyl; R7 is 1-3 groups independently selected from the group consisting of lower to alkyl, lower alkoxy, -COOH, NO2, OH, and halogeno; R8 and R9 are independently selected from H or lower alkyl; 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; R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy, N

R

13 lower alkyl, phenyl or R7-phenyl; R13 is selected from -CH2-, -N(lower alkyl)- or -NC(O)R19; R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring; R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and 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.

-47- One group of preferred compounds of Formula VI is that in which R21 is selected from phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl, wherein W is lower alkyl, lower alkoxy, OH, halogeno, -N(R8)(R9), -NHC(O)OR10, -NHC(O)R10, NO2, -CN, -N3, -SH, -S(0)0-2-(lower alkyl), -COOR19, -CON(R8)(R9), -COR12, phenoxy, benzyloxy, -OCF3, -CH=C(O)R12 or tert-butyldimethylsilyloxy, wherein R8, R9, R10, R12 and R19 are as defined for Formula IV. When W is 2 or 3 substituents, the substituents can be the same or different.

Another group of preferred compounds of Formula VI is that in which R20 is phenyl or W-substituted phenyl, wherein preferred meanings of W are as defined above for preferred definitions of R21.

More preferred are compounds of Formula VI wherein R20 is phenyl or Wsubstituted phenyl and R21 is phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; W is lower alkyl, lower alkoxy, OH, halogeno, -N(R8)(Rg), -NHC(O)R1 0, NO2, -CN, -N3, -SH, -S(O)0-2-(ower alkyl), -COOR19, -CON(R8)(R9), -COR12, phenoxy, benzyloxy, -CH=CHC(O)R12, -OCF3 or tert-butyldimethyl-silyloxy, wherein when W is 2 or 3 substituents, the substituents can be the same or different, and wherein R8, Rg, R10, R12 and R19 are as defined in Formula

VI.

Also preferred are compounds of Formula VI wherein R1 is -CH- or Another group of preferred compounds of Formula VI is in which R2 and R3 are each -CH2- and the sum of u and v is 2, 3 or 4, with u=v=2 being more preferred.

R4 is preferably B-(CH2)q- or B-(CH2)e-Z-(CH2)r-, wherein B, Z, q, e and r are

R

1 R16 as defined above. B is preferably R 17 ,wherein R16 and R17 are each hydrogen and wherein R15 is preferably H, OH, lower alkoxy, especially methoxy, or halogeno, especially chloro.

-48- Preferably Z is e is 0, and r is 0.

Preferably q is 0-2.

is preferably phenyl or W-substituted phenyl.

Preferred W substituents for R20 are lower alkoxy, especially methoxy and ethoxy, OH, and -C(O)R12, wherein R12 is preferably lower alkoxy.

Preferably R21 is selected from phenyl, lower alkoxy-substituted phenyl and Fphenyl.

I

Especially preferred are compounds of Formula VI wherein R1 is or R2 and R3 are each -CH2-, u=v=2, R4 is B-(CH2)q-, wherein B is phenyl or phenyl substituted by lower alkoxy or chloro, q is 0-2, R20 is phenyl, OH-phenyl, lower alkoxy-substituted phenyl or lower alkoxycarbonyl-substituted phenyl, and R21 is phenyl, lower alkoxy-substituted phenyl or F-phenyl.

Methods for making compounds of Formula VI are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No.

5,698,548, which is incorporated herein by reference.

In another embodiment, sterol inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (VII):

B

R I

E

N

0 R4

(VII)

or isomers of the compounds of Formula (VII), or pharmaceutically acceptable salts or solvates of the compounds of Formula (VII) or of the isomers of the compounds of Formula (VII), or prodrugs of the compounds of Formula (VII) or of the isomers, salts or solvates of the compounds of Formula (VII), wherein in Formula (VII) above: -49- A is -CH=CH-, -C C- or -(CH2)p- wherein p is 0, 1 or 2; B is

R,

E is C10 to C20 alkyl or to C19)-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; R1, 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, R602SNH- and -S(O)2NH2; R4 is Q (OR 5 wherein n is 0, 1,2 or 3; 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.

Preferred compounds of Formula (VII) are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpropyl. Another group of preferred compounds of Formula (VII) is that wherein R4 is p-methoxyphenyl or 2,4,6-trimethoxyphenyl. Still another group of preferred compounds of Formula (VII) is that wherein A is ethylene or a bond. Yet another group of preferred compounds of Formula (VII) is that wherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably R1, R2 and R3 are each hydrogen.

More preferred compounds of Formula (VII) are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpropyl; R4 is p-methoxyphenyl or 2,4,6trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoyl or 7-Z-hexadecenyl; and R1, R2 and R3 are each hydrogen.

A preferred compound of Formula (VII) is that wherein E is decyl, R is hydrogen, B-A is phenyl and R4 is p-methoxyphenyl.

In another embodiment, sterol inhibitors useful in the compositions and methods of the present invention are represented by Formula (VIII):

-O-G

Arl-R 1

-Q

(VIll) or isomers of the compounds of Formula (VIII), or pharmaceutically acceptable salts or solvates of the compounds of Formula (VIII) or of the isomers of the compounds of Formula (VIII), or prodrugs of the compounds of Formula (VIII) or of the isomers, salts or solvates of the compounds of Formula (VIII), wherein, in Formula (VIII) above,

R

2 6 is H or OG 1 G and G 1 are independently selected from the group consisting of Or 5

OR

4 H, .11OR 3

CO

2

R

2

OP

5

OR

4 .'llOR 3 -C1

CH

2

OR

6

OR

3

OR

OR

3 a R4a(;

R

OR3 "o CH Rb; and 2 0O CH 2 Ra OH, G is not H; provided that when R 2 6 is H or 51 R, Ra and Rb are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (Cl -06)alkoxy(Cl -C6)-alkoxy or WR0 W is independently selected from the group consisting of

-O-C(O)-N(R

3 1 -NH-C(O)-N(R 3 i and -O-C(S)-N(R 3 1

R

2 and R 6 are independently selected from the group consisting of H, (Ci C6)alkyl, aryl and aryl(CI-C6)alkyl;

R

3

R

4

R

5

R

7

R

3 a and R 4 a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(Cl-C6)alkyl, -C(O)(Cl-06)alkyl and -C(0)aryl;

R

30 is selected from the group consisting of R 32 -substituted T,

R

3 2 -su bstituted-T-(Ci -C6)alkyl, R 32 -su bstituted-(02-C4)alkenyl,

R

32 -substituted-(Cl1-06)alkyl, R 32 -substituted-(C3-C7)cycloal kyl and

R

32 -substituted-(C3-C7)cycloalkyl(C1 -C6)alkyl;

R

31 is selected from the group consisting of H and (CI1-C4)alkyl; T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyi and pyridyl;

R

32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (Cl-C4)alkyl, -OH, phenoxy, -CF3, -N02, (Ci -C4)alkoxy, methylenedioxy, oxo, (Cl-C4)alkylsulfanyl, (Ci -C4)alkylsulfinyl, (Ci -C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C4)alkyl)2, -C4)alkyl, -C4)alkoxy and pyrrolidinylcarbonyl; or R 32 is a covalent bond and R 31 the nitrogen to which it is attached and R 32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Cl-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, Nmethylpiperazinyl, indolinyl or morpholinyl group; Ar 1 is aryl or R 10 -substituted aryl; Ar 2 is aryl or R 1 1 -substituted aryl; Q is a bond or, with the 3-position ring carbon of the azetidinone, -52-

R

1 2

-(R

13 )a forms the spiro group (R14) and

O

R

1 is selected from the group consisting of S-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q 0can also be zero or 1; -(CH2)e-E-(CH2)r-, wherein E is phenylene, -NR 2 2 or e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; S-(C2-C6)alkenylene-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is provided that the sum of f and g is 1-6;

R

1 2 is I I I I I II alkyl)-, -C(C 6

H

4

-R

23 or

R

1 3 and R 14 are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(C1-C6 alkyl)=CH-; or R 12 together with an adjacent R 1 3 or R 1 2 together with an adjacent R 14 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; provided that when R 1 3 is -CH=CH- or -C(C1-C6 alkyl)=CH-, a is 1; provided that when R 14 is -CH=CH- or -C(C1-C6 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R 1 3 's can be the same or different; and provided that when b is 2 or 3, the R 1 4 's can be the same or different; and when Q is a bond, R 1 also can be:

R

17 R15

R

1 a I I I -M-Yd -Xm-(C)s-Yn-(C)t-Zp- or 2

R

16 R8 R16 R16 M is or X, Y and Z are independently selected from the group consisting of 53 -CH2-, -CH(Ci -06)alkyl- and -C(di-(Ci -C6)alkyl);

R

1 0 and R 11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, -OR 1 9, -O(CO)R 19 -O(CO)0R 2 1 -O(CH2)1 ORl 9, .O(CO)NRI 9

R

20

-NR

1 9

R

20

-NR

1 9

(CO)R

20

-NR

1 9

(CO)OR

2 1, -NR1 9

(CO)NR

20

R

25

-NR

19 S02R 2 1 -000R 19 -00NR 19

R

20 -00R 19 -SO2NR 1 9

R

20 S(O)0-2R 21 -O(CH2)1 -1 Q-COOR 1 9, -O(CH2)1 -1 OCONR 1 9

R

20 -(Ci -06 alkylene)-COOR1 9, -CH=CH-COOR 1 9, -CF3, -CN, -N02 and halogen;

R

1 5 and R 1 7 are independently selected from the group consisting of

-OR

1 9, -O(CO)Ri 9, -O(CO)0R 21 and -O(CO)NRi 9

R

20

R

1 6 and R 1 8 are independently selected from the group consisting of H, (C-C6alkyl and aryl; or R 15 and R 16 together are or R 17 and R 18 together are =0; d is1, 2or 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 isO0 and t is 1, the sum of m, s and n is 1-5; and provided that when p isO0 and s is 1, the sum of m, t and n is v is 0Qor 1; j and k are independently 1-5, provided that the sum of j, k and v is and when Q is a bond and R 1 is R 16 Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R

19 and R 20 are independently selected from the group consisting of H, (Cl- C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;

R

21 is (C1-C6)alkyl, aryl or R 24 -substituted aryl; -54-

R

2 2 is H, (Cl-C6)alkyl, aryl (C1-C6)alkyl, -C(O)R 1 9 or-COOR 19

R

2 3 and R 2 4 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, -COOH, N02,

-NR

1 9

R

2 0 -OH and halogeno; and

R

2 5 is H, -OH or (C1-C6)alkoxy.

Ar 2 is preferably phenyl or R 1 1 -phenyl, especially (4-R 1 1 )-substituted phenyl.

Preferred definitions of R 1 1 are lower alkoxy, especially methoxy, and halogeno, especially fluoro.

Ar 1 is preferably phenyl or R 10 -substituted phenyl, especially (4-R 10 substituted phenyl. Preferably R 1 0 is halogeno, and more preferably fluoro.

There are several preferred definitions for the -R 1 combination of variables: Q is a bond and R 1 is lower alkylene, preferably propylene; Q is a spiro group as defined above, wherein preferably R 1 3 and R 1 4 are each I I ethylene and R 12 is -CH- or and R 1 is -(CH2)q wherein q is 0-6; Q is a bond and R 1 is -M Yd- Zh- wherein the variables R16 are chosen such that R 1 is -O-CH2-CH(OH)-;

R

17

R

1 I I Q is a bond and R 1 wherein the is

R

8

R

1 6 variables are chosen such that R 1 is -CH(OH)-(CH2)2-; and Q is a bond and R 1 is 2 wherein the X -(C)-kS002 variables are chosen such that R 1 is -CH(OH)-CH2-S(O)0-2-.

A preferred compound of Formula (VIII) therefore, is one wherein G and G 1 are as defined above and in which the remaining variables have the following definitions: Ar 1 is phenyl or R 10 -substituted phenyl, wherein R 10 is halogeno; Ar 2 is phenyl or R 1 1 -phenyl, wherein R 1 1 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkoxy and halogeno; Q is a bond and R 1 is lower alkylene; Q, with the 3-position R12 (R13)a 1 4| (R )a ring carbon of the azetidinone, forms the group (R1)b wherein preferably

R

1 3 and R 14 are each ethylene and a and b are each 1, and wherein R 1 2 is I I -CH- or Q is a bond and R 1 is -O-CH2-CH(OH)-; Q is a bond and R 1 is -CH(OH)-(CH2)2-; or Q is a bond and R 1 is -CH(OH)-CH2-S(O)0-2-.

Preferred variables for G and G 1 groups of the formulae

OR

5

OR

4

OR

5

OR

4

R

7 0n4 SRR IOR 3 and -CH 2

"OR

C0 2

R

2

CH

2

OR

6 OR3 OR are as follows:

R

2

R

3

R

4

R

5

R

6 and R 7 are independently selected from the group consisting of H, (Cl-C6)alkyl, benzyl and acetyl.

Preferred variables for group G or G 1 of the formula:

OR

3 a R4a,

R.R

OR

3

OCH

2 Rb

R

4 O y ,O CH 2 Ra are as follows:

R

3

R

3 a, R 4 and R 4 a are selected from the group consisting of H, (C1- C6)alkyl, benzyl and acetyl; R, R a and Rb are independently selected from the group consisting of H, -56- -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy and -W-R 30 wherein W is or -O-C(O)-NR 3

R

31 is H and

R

30 is (C1-C6)alkyl, -C(O)-(C1-C4)alkoxy-(C1-C6)alkyl, T, T-(C1-C6)alkyl, or T or T- (C1-C6)alkyl wherein T is substituted by one or two halogeno or (C1-C6)alkyl groups.

Preferred R 30 substituents are selected from the group consisting of: 2fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonyl ethyl, thiazol-2-yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl.

Preferred combinations of R, Ra and Rb are as follows: 1) R, Ra and Rb are independently -OH or -O-C(O)-NH-R 3 0 especially wherein Ra is -OH and R and Rb are -O-C(O)-NH-R 3 0 and R 3 0 is selected from the preferred substituents identified above, or wherein R and Ra are each -OH and Rb is-O-C(O)-NH-R 3 0 wherein R 3 0 is 2-fluorophenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl; 2) Ra is -OH, halogeno, azido or (C1-C6)-alkoxy(C1-C6)alkoxy, Rb is H, halogeno, azido or (C1-C6)alkoxy(C1-C6)-alkoxy, and R is -O-C(0)-NH-R 3 0 especially compounds wherein Ra is -OH, Rb is H and R 3 0 is 2-fluorophenyl; 3) R, Ra and Rb are independently -OH or -O-C(O)-R 3 0 and R 3 0 is (C1-C6)alkyl, T or T substituted by one or two halogeno or (C1-C6)alkyl groups, especially compounds wherein R is -OH and Ra and Rb are

R

3 0 wherein R 3 0 is 2-furyl; and 4) R, Ra and Rb are independently -OH or halogeno. Three additional classes of preferred compounds are those wherein the Cl' anomeric oxy is beta, wherein the C2' anomeric oxy is beta, and wherein the R group is alpha.

G and G1 are preferably selected from: 57 OH OH 1(I IOH 0 C02H OH

OH

'IIOH

CH20H ICO2CH 3

-IIOCH

2 Ph, 0 OAC OHI sIlOAc, 00

CH

2 OAc

OH

OH 0 i0 CH 2 0H A )\CH 2

OH

OH OCH 3 -110H -CH 2 1H

ZO

2

CH

3 OH OH OAc Ac c

CH

2 OAc Ac/kL O\'C2Ac and O CH 2 0H wherein Ac is acetyl and Ph is phenyl.

Preferably, R 26 is H or OH, more preferably H. The -0-G substituent is preferably in the 4-position of the phenyl ring to which it is attached.

In another embodiment, sterol inhibitors useful in the compositions and methods of the present invention are represented by Formula (IX) below:

OR

1 Ar 1 -CH-Q- 7R2

(IX)

-58or isomers of the compounds of Formula or pharmaceutically acceptable salts or solvates of the compounds of Formula (IX) or of the isomers of the compounds of Formula or prodrugs of the compounds of Formula (IX) or of the isomers, salts or solvates of the compounds of Formula wherein in Formula (IX) above:

R

2 6 is selected from the group consisting of: a) OH; b) OCH 3 c) fluorine and d) chlorine.

R

1 is selected from the group consisting of

OR

5

OR

4

OR

5

OR

4

OR

7

OR

3 4, IlOR 3

-CH

2 )lOR H, 0 OC 4 CO2R 2

CH

2 0R 6 R3 OR

OR

3 a

R

4 aO,, R -SO 3 H; natural and unnatural

OR

3 O CH 2 Rb amino acids.

O CH 2 Ra R, R a and Rb are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy and -W-R 3 0 W is independently selected from the group consisting of

-O-C(O)-N(R

3

-NH-C(O)-N(R

3 1 and

-O-C(S)-N(R

3 1

R

2 and R 6 are independently selected from the group consisting of H, (Ci-C6)alkyl, aryl and aryl(Cl-C6)alkyl;

R

3

R

4

R

5

R

7

R

3 a and R 4 a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, -C(O)(C1-C6)alkyl and -C(O)aryl; 59-

R

30 is independently selected form the group consisting of

R

32 -substituted T, R 32 -su bstituted-T-(Ci -C6)alkyl, R 32 -substituted-(02-C4)aIke nyl,

R

32 -substituted-(O 1-C6)alkyI, R 32 -substituted-(C3-C7)cycloalky and R 32 -substituted- (C3-C7)cycloalkyl(C1 -C6)alkyl;

R

31 is independently selected from the group consisting of H and (C1-C4)alkyl; T is independently selected from the group consisting of phenyt, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R

32 is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (C1-C4)alkyl, -OH, phenoxy, -CF3, -N02, (Ci -C4)alkoxy, methylenedioxy, oxo, (C1-04 )al kylsulfanyl, (Ci -C4)alkylsulfinyl, (Ci C4)alkylsulfonyl, -N(0H3)2, -C(O)-NH(01-C4)alkyl, -04)alkyl)2, (Ci-C4)alkyl, -O(O)-(C1-04)alkoxy and pyrrolidinylcarbonyl; or R 32 is a covalent bond and R 31 the nitrogen to which it is attached and R 32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci- C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar 1 is aryl or R 10 -substituted aryl; Ar 2 is aryl or R 1 1 -substituted aryl; Q is wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone, R 2R1)a forms the spiro group

R

12 is -0(01-06alkyl)-, -O(0 6

H

4

-R

23

I-

R

13 and R 14 are independently selected from the group consisting of -0H2-, OH(O1-06 alkyl)-, -O(di-(Oi-06) alkyl), -CH=OH- and -0(01-06 alkyl)=CH-; orR1 together with an adjacent R 13 or R 12 together with an adjacent R 14 form a -OH=CHor a -CHOC(C1-06 alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R 13 is -OH=OH- or -0(01-06 alkyl)=OH-, a is 1; provided that when R 14 is -OH=CH- or -0(01 -06 alkyl)=OH-, b is 1; provided that when a is 2 or 3, the R 1 3's can be the same or different; and provided that when b is 2 or 3, the R 14 's can be the same or different;

R

1 0 and R 1 1 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting Of (01 -C6)alkyl, -OR 1 9 -O(OO)Rl 9, -O(COOR 2 1, -O(0H2)1 -5OR 1 9, -O(CO)NRl 9

R

2 0

-NR

19

R

20

-NR

19

(CO)R

20 -NR1 9

(CO)OR

2 1, -NR 19

(CO)NR

20

R

2 5

-NR

19 ,S02R 2 1 -000R 1 9,

-OONR

1 9

R

20

-OR

1 9, -SO2NR 1 9

R

20 S(O)O..2R 2 1 -O(0H2)1-1 o-COOR 1 9, -O(CH2)1-10C0NR 19

R

2 0, -(01-06 alkylene)-C00R 19 -OH=CH-C00R 19 -CF3,

ON,

-N02 and halogen; Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R

1 9 and R 20 are independently selected from the group consisting of H, (Cl 06)alkyl, aryl and aryl-substituted (01-C6)alkyl;

R

21 is (O1 -C6)alkyl, aryl or R 24 -substituted aryl;

R

22 is H, (O1-06)alkyl, aryl (01-06)alkyl, -O(O)R 19 or -000R 19

R

23 and R 24 are independently 1-3 groups independently selected from the group consisting of H, (01-06)alkyl, (O1-06)alkoxy, -OOOH, N02, -NR 19

R

20

-OH

and halogeno; and

R

2 5 is H, -OH or (O1-06)alkoxy.

Ar 2 is preferably phenyl or R 1 1 -phenyl, especially (4-R 1 l)-substituted phenyl.

Preferred definitions of R 11 are lower alkoxy, -61 especially methoxy, and halogeno, especially fluoro.

Ar 1 is preferably phenyl or R 1 0 -substituted phenyl, especially (4-R10)substituted phenyl. A preferred definition of R 1 0 is halogeno, especially fluoro.

Preferably Q is a lower alkyl or a spiro group as defined above, wherein I

I

preferably R 1 3 and R 14 are each ethylene and R 12 is -CH- or A preferred compound of formula IX, therefore, is one wherein R 1 is as defined above and in which the remaining variables have the following definitions: Arl is phenyl or R 1 0 -substituted phenyl, wherein R 1 0 is halogeno; Ar 2 is phenyl or R 1 1 -phenyl, wherein R 1 1 is 1 to 3 substituents independently to selected from the group consisting of C1-C6 alkoxy and halogeno; Q is a lower alkyl C-1 to C-2) with Q C-2 being preferred, or Q, with the R12-(R 13 )a 3-position ring carbon of the azetidinone, forms the group (R1 )b wherein preferably R 13 and R 14 are each ethylene and a and b are each 1, and I I wherein R 12 is -CH- or-C(OH)- Preferred variables for R 1 groups of the formula

O

5

OR

4

O

5

R

4

R

0

OR

3

-*IOR

3 and -CH 2

'-OR

CO

2

R

2 CH20R 6

OR

3

OR

4 are as follows:

R

2

R

3

R

4

R

5

R

6 and R 7 are independently selected from the group consisting of H, (Cl-C6)alkyl, benzyl and acetyl.

Preferred variables for group R 1 of the formula

OR

3 a

'CH

2 Ra -62are as follows:

R

3

R

3 a, R 4 and R4a are selected from the group consisting of H, (Cl- C6)alkyl, benzyl and acetyl; R, Ra and Rb are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy and -W-R 30 wherein W is -0or -O-C(O)-NR 3 1

R

31 is H and R 30 is (CI-C6)alkyl, -C(O)-(C1-C4)alkoxy-(C1- C6)alkyl, T, T-(C1-C6)alkyl, or T or T-(C1-C6)alkyl wherein T is substituted by one or two halogeno or (C1-C6)alkyl groups.

Preferred R 30 substituents are 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl, thiazol-2yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl. Preferred combinations of R, Ra and Rb are as follows: 1) R, Ra and Rb are independently -OH or -O-C(O)-NH-

R

30 especially wherein Ra is -OH and R and Rb are -O-C(O)-NH-R 3 0 and R 30 is selected from the preferred substituents identified above, or wherein R and Ra are OH and Rb is-O-C(O)-NH-R 30 wherein R 30 is 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6dichlorophenyl; 2) Ra is -OH, halogeno, azido or (C1-C6)-alkoxy(C1-C6)alkoxy, Rb is H, halogeno, azido or (C1-C6)alkoxy(C1-C6)-alkoxy, and R is -O-C(O)-NH-R 3 0, especially compounds wherein Ra is -OH, Rb is H and R 30 is 2-fluorophenyl; 3) R, Ra and Rb are independently -OH or -O-C(O)-R 3 0 and R 30 is (C1 -C6)alkyl, T or T substituted by one or two halogeno or (C1-C6)alkyl groups, especially compounds wherein R is -OH and Ra and Rb are -O-C(O)-R 3 0 wherein R 30 is 2-furyl; and 4) R, Ra and Rb are independently -OH or halogeno. Three additional classes of preferred are compounds are those wherein the C1' anomeric oxy is beta, wherein the C2' anomeric oxy is beta, and wherein the R group is alpha.

R

1 is preferably selected from: OH OH OH -OH Ac OAc C-110H CH20-H O, -COH IIOAc cOH CH 2 OH OH OH CO 2

CH

3 63 Ph CH 2

OCH

2 Ph PhCH 2 9- OCH 2 Ph 110lcH 2 Ph IOCH2 Ph

CO

2

CH

2 Ph CH 2 00H 2 Ph OA p QAc O OHC 0 CH 2 OAc C0 2

CH

3

OH

OH

HC), ,\0 OH A CH 2 0H o CH 2 0H

OHC

and

OH

OAc Ac c 0

CH

2 OAc ACO2 Oc

~H

2 0H

CH

2 0H wherein Ac is acetyl and Ph is phenyl.

An example of a useful compound of this invention is one represented by the formula X: OR'

OH

FN

FF

X

wherein R' is defined as above, or pharmaceutically acceptable salts or solvates of the compound of Formula or prodrugs of the compound of Formula or of the pharmaceutically acceptable salts or solvates of the compound of Formula 00 -64- 00

(OH

Sor solvA more preferred compound is one represented by formula XI: SHO O F O-N F (Xl) CI or pharmaceutically acceptable salts or solvates of the compound of Formula or prodrugs of the compound of Formula (XI) or of the pharmaceutically acceptable salts or solvates of the compound of Formula (XI).

Compositions, pharmaceutical compositions, therapeutic combinations, kits and methods of treatment as described above are provided which comprise: at least one peroxisome proliferator-activated receptor activator; and at least one substituted azetidinone compound or at least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted p1-lactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, wherein the first amount and the second amount together in their totality (whether administered concurrently or consecutively) 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.

Suitable substituted azetidinone compounds or substituted p-lactam compounds can be selected from any of the compounds discussed above in Formulae 1-XI. Other useful substituted azetidinone compounds include N-sulfonyl-2azetidinones such as are disclosed in U.S. Patent No. 4,983,597 and ethyl 4-(2- 00 0 (Ni Soxoazetidin-4-yl)phenoxy-alkanoates such as are disclosed in Ram et al., Indian J.

Chem. Sect. B. 29B, 12 (1990), p. 1134-7, which are incorporated by reference n herein.

The compounds of Formulae I-XI can be prepared by known methods, including the methods discussed above and, for example, WO 93/02048 describes the preparation of compounds wherein -R 1 is alkylene, alkenylene or alkylene interrupted by a hetero atom, phenylene or cycloalkylene; WO 94/17038 describes Sthe preparation of compounds wherein Q is a spirocyclic group; WO 95/08532 N describes the preparation of compounds wherein -R 1 is a hydroxy-substituted alkylene group; PCT/US95/03196 describes compounds wherein -R 1 is a hydroxy-substituted alkylene attached to the Arl moiety through an or S(0)o-2group; and U.S. Serial No. 08/463,619, filed June 5, 1995, describes the preparation of compounds wherein -R 1 is a hydroxy-substituted alkylene group attached the azetidinone ring by a group.

15 The daily dose of the sterol absorption inhibitor(s) can range from about 0.1 to about 1000 mg per day, preferably about 0.25 to about 50 mg/day, and more preferably about 10 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

For administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.

In one embodiment of the present invention, the compositions or therapeutic combinations can further comprise one or more pharmacological or therapeutic agents or drugs such as cholesterol biosynthesis inhibitors and/or lipid-lowering agents discussed below.

In another embodiment, the composition or treatment can further comprise one or more cholesterol biosynthesis inhibitors coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

00 -66-

O

Non-limiting examples of cholesterol biosynthesis inhibitors for use in the C compositions, therapeutic combinations and methods of the present invention include Scompetitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof. Non-limiting examples of suitable HMG CoA reductase inhibitors include statins such as lovastatin (for example MEVACOR® which is available from O Merck pravastatin (for example PRAVACHOL® which is available from Bristol Meyers Squibb), fluvastatin, simvastatin (for example ZOCOR® which is available 0 from Merck atorvastatin, cerivastatin, CI-981, rivastatin (sodium 7-(4fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6heptanoate), rosuvastatin, pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoA synthetase inhibitors, for example L-659,699 1-[3'R-(hydroxymethyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophenhydrochloride) and other sterol biosynthesis inhibitors such as DMP-565. Preferred HMG CoA reductase inhibitors include lovastatin, pravastatin and simvastatin. The most preferred HMG CoA reductase inhibitor is simvastatin.

Generally, a total daily dosage of cholesterol biosynthesis inhibitor(s) can range from about 0.1 to about 160 mg per day, and preferably about 0.2 to about 80 mg/day in single or 2-3 divided doses.

Described herein is a composition or treatment comprising the compound of Formula (II) in combination with one or more peroxisome proliferatoractivated receptor(s) activator(s) and one or more cholesterol biosynthesis inhibitors.

Preferably the peroxisome proliferator-activated receptor activator(s) is a fibric acid derivative selected from gemfibrozil, clofibrate and/or fenofibrate. Preferably the cholesterol biosynthesis inhibitor comprises one or more HMG CoA reductase inhibitors, such as, for example, lovastatin, pravastatin and/or simvastatin. More preferably, the composition or treatment comprises the compound of Formula (II) in combination with simvastatin and gemfibrozil or fenofibrate.

00 C0 -67-

(N

SIn another alternative embodiment, the compositions, therapeutic combinations Sor methods of the present invention can further comprise one or more bile acid n sequestrants (insoluble anion exchange resins), coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

Bile acid sequestrants bind bile acids in the intestine, interrupting the Senterohepatic circulation of bile acids and causing an increase in the faecal excretion of steroids. Use of bile acid sequestrants is desirable because of their non-systemic mode of action. Bile acid sequestrants can lower intrahepatic cholesterol and promote the synthesis of apo B/E (LDL) receptors that bind LDL from plasma to further reduce cholesterol levels in the blood.

Non-limiting examples of suitable bile acid sequestrants include cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof. Other useful bile acid sequestrants are disclosed in PCT Patent Applications Nos. WO 97/11345 and WO 98/57652, and U.S. Patents Nos. 3,692,895 and 5,703,188 which are incorporated herein by reference. Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.

Generally, a total daily dosage of bile acid sequestrant(s) can range from about 1 to about 50 grams per day, and preferably about 2 to about 16 grams per day in single or 2-4 divided doses.

In an alternative embodiment, the compositions or treatments of the present invention can further comprise one or more ileal bile acid transport ("IBAT") inhibitors (or apical sodium co-dependent bile acid transport ("ASBT") inhibitors) coadministered 00 -68-

(N

Swith or in combination with the sterol absorption inhibitor(s) Sdiscussed above. The IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol levels. Non-limiting examples of suitable IBAT inhibitors include benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure such as are disclosed in PCT SPatent Application WO 00/38727 which is incorporated herein by reference.

SGenerally, a total daily dosage of IBAT inhibitor(s) can range from about 0.01 to about 1000 mg/day, and preferably about 0.1 to about 50 mg/day in single or 2-4 Sdivided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise nicotinic acid (niacin) and/or derivatives thereof coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

As used herein, "nicotinic acid derivative" means a compound comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Examples of nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit hepatic production of VLDL and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos.

Generally, a total daily dosage of nicotinic acid or a derivative thereof can range from about 500 to about 10,000 mg/day, preferably about 1000 to about 8000 mg/day, and more preferably about 3000 to about 6000 mg/day in single or divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise one or more AcylCoA:Cholesterol

O-

acyltransferase ("ACAT") Inhibitors, which can reduce LDL and VLDL levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. ACAT is an enzyme responsible for esterifying excess intracellular cholesterol and may reduce the 00 00 -69synthesis of VLDL, which is a product of cholesterol esterification, and overproduction Sof apo B-100-containing lipoproteins.

Non-limiting examples of useful ACAT inhibitors include avasimibe tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, S 5 formerly known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea). See P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1); 55-93, which is incorporated by reference herein.

SGenerally, a total daily dosage of ACAT inhibitor(s) can range from about 0.1 to about 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise one or more Cholesteryl Ester Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

Non-limiting examples of suitable CETP inhibitors are disclosed in PCT Patent Application No. WO 00/38721 and U.S. Patent No. 6,147,090, which are incorporated herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors such as WAY-121898 also can be coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

Generally, a total daily dosage of CETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20 mg/kg body weight/day in single or divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise probucol or derivatives thereof (such as AGI- 1067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319 and 6,147,250), which can reduce LDL levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

00 Generally, a total daily dosage of probucol or derivatives thereof can range Sfrom about 10 to about 2000 mg/day, and preferably about 500 to about 1500 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the 0 5 present invention can further comprise low-density lipoprotein (LDL) receptor 0activators, coadministered with or in combination with the 0sterol absorption inhibitor(s) discussed above.

Non-limiting examples of suitable LDL-receptor activators include HOE-402, an 0 0 imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.

Generally, a total daily dosage of LDL receptor activator(s) can range from about 1 to about 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise fish oil, which contains Omega 3 fatty acids (3- PUFA), which can reduce VLDL and triglyceride levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. Generally, a total daily dosage of natural water soluble fibers can range from about 0.1 to about 10 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostanol ester used in BENECOL® margarine, which can reduce cholesterol levels, coadministered with or in combination with the sterol absorption 00 00 -71- Sinhibitor(s) discussed above. Generally, a total daily dosage of plant sterols, plant Sstanols and/or fatty acid esters of plant stanols can range from about 0.5 to about grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise antioxidants, such as probucol, tocopherol, Sascorbic acid, p-carotene and selenium, or vitamins such as vitamin B6 or vitamin 812, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. Generally, a total daily dosage of antioxidants or vitamins can range from about 0.05 to about grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise monocyte and macrophage inhibitors such as polyunsaturated fatty acids (PUFA), thyroid hormones including throxine analogues such as CGS-26214 (a thyroxine compound with a fluorinated ring), gene therapy and use of recombinant proteins such as recombinant apo E, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. Generally, a total daily dosage of these agents can range from about 0.01 to about 1000 mg/day in single or 2-4 divided doses.

Also useful with the present invention are compositions or therapeutic combinations which further comprise hormone replacement agents and compositions.

Useful hormone agents and compositions for hormone replacement therapy of the present invention include androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives thereof. Combinations of these agents and compositions are also useful.

The dosage of androgen and estrogen combinations vary, desirably from about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mg estrogen.

Examples include, but are not limited to, androgen and estrogen combinations such as the combination of esterified estrogens (sodium estrone sulfate and sodium equilin sulfate) and methyltestosterone (17-hydroxy-1 7-methyl-, (17B)- androst-4-en-3-one) available from Solvay Pharmaceuticals, Inc., Marietta, GA, under the tradename Estratest.

-72- Estrogens and estrogen combinations may vary in dosage from about 0.01 mg up to 8 mg, desirably from about 0.3 mg to about 3.0 mg. Examples of useful estrogens and estrogen combinations include: the blend of nine synthetic estrogenic substances including sodium estrone sulfate, sodium equilin sulfate, sodium 17 a -dihydroequilin sulfate, sodium 17 a -estradiol sulfate, sodium 17 p -dihydroequilin sulfate, sodium 17 a -dihydroequilenin sulfate, sodium 17 p -dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17 p -estradiol sulfate; available from Duramed Pharmaceuticals, Inc., Cincinnati, OH, under the tradename Cenestin; ethinyl estradiol (19-nor-17 a -pregna-1,3,5(10)-trien-20-yne-3,17-diol; available by Schering Plough Corporation, Kenilworth, NJ, under the tradename Estinyl; esterified estrogen combinations such as sodium estrone sulfate and sodium equilin sulfate; available from Solvay under the tradename Estratab and from Monarch Pharmaceuticals, Bristol, TN, under the tradename Menest; estropipate (piperazine estra-1,3,5(10)-trien-1 7-one, 3-(sulfooxy)estrone sulfate); available from Pharmacia Upjohn, Peapack, NJ, under the tradename Ogen and from Women First Health Care, Inc., San Diego, CA, under the tradename Ortho-Est; and conjugated estrogens (17 a-dihydroequilin, 17 a-estradiol, and 17 1dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA, under the tradename Premarin.

Progestins and estrogens may also be administered with a variety of dosages, generally from about 0.05 to about 2.0 mg progestin and about 0.001 mg to about 2 mg estrogen, desirably from about 0.1 mg to about 1 mg progestin and about 0.01 mg to about 0.5 mg estrogen. Examples of progestin and estrogen combinations that may vary in dosage and regimen include: the combination of estradiol (estra-1, 3, 5 (10)-triene-3, 17 P-diol hemihydrate) and norethindrone (17 p-acetoxy-19-nor-17 a-pregn-4-en-20-yn-3-one); which is available from Pharmacia Upjohn, Peapack, NJ, under the tradename Activella; -73the combination of levonorgestrel 1-ethyl-17 a-ethinyl-17 Phydroxygon- 4-en-3-one) and ethinyl estradial; available from Wyeth-Ayerst under the tradename Alesse, from Watson Laboratories, Inc., Corona, CA, under the tradenames Levora and Trivora, Monarch Pharmaceuticals, under the tradename Nordette, and from Wyeth-Ayerst under the tradename Triphasil; the combination of ethynodiol diacetate (19-nor-17 a-pregn-4-en-20-yne- 3 1, 17-diol diacetate) and ethinyl estradiol; available from G.D. Searle Co., Chicago, IL, under the tradename Demulen and from Watson under the tradename Zovia; the combination of desogestrel (13-ethyl-l 1- methylene-18,19-dinor-17 a-pregn- 4-en- 20-yn-17-ol) and ethinyl estradiol; available from Organon under the tradenames Desogen and Mircette, and from Ortho-McNeil Pharmaceutical, Raritan, NJ, under the tradename Ortho-Cept; the combination of norethindrone and ethinyl estradiol; available from Parke-Davis, Morris Plains, NJ, under the tradenames Estrostep and femhrt, from Watson under the tradenames Microgestin, Necon, and Tri-Norinyl, from Ortho-McNeil under the tradenames Modicon and Ortho-Novum, and from Warner Chilcott Laboratories, Rockaway, NJ, under the tradename Ovcon; the combination of norgestrel 3-ethyl-1 7-hydroxy-18, 19-dinor-17 a-preg-4-en-20-yn-3-one) and ethinyl estradiol; available from Wyeth-Ayerst under the tradenames Ovral and Lo/Ovral, and from Watson under the tradenames Ogestrel and Low-Ogestrel; the combination of norethindrone, ethinyl estradiol, and mestranol (3methoxy-19-nor-17 a-pregna-1,3,5(1 O)-trien-20-yn-17-ol01); available from Watson under the tradenames Brevicon and Norinyl; the combination of 17 P-estradiol (estra-1 ,3,5(10)-triene-3,17 P-diol) and micronized norgestimate (17 a- 17-(Acetyloxyl)-13-ethyl-1 8,19-dinorpregn-4-en-20-yn- 3-one3-oxime); available from Ortho-McNeil under the tradename Ortho-Prefest; the combination of norgestimate (18,19-dinor-l 7-pregn-4-en-20-yn-3one, 17--(acetyloxy)-1 3-ethyl-,oxime, and ethinyl estradiol; available from Ortho-McNeil under the tradenames Ortho Cyclen and Ortho Tri-Cyclen; and -74the combination of conjugated estrogens (sodium estrone sulfate and sodium equilin sulfate) and medroxyprogesterone acetate (20-dione, 17-(acetyloxy)-6methyl-, pregn-4-ene-3); available from Wyeth-Ayerst under the tradenames Premphase and Prempro.

In general, a dosage of progestins may vary from about .05 mg to about 10 mg or up to about 200 mg if microsized progesterone is administered. Examples of progestins include norethindrone; available from ESI Lederle, Inc., Philadelphia, PA, under the tradename Aygestin, from Ortho-McNeil under the tradename Micronor, and from Watson under the tradename Nor-QD; norgestrel; available from Wyeth-Ayerst under the tradename Ovrette; micronized progesterone (pregn-4-ene-3, available from Solvay under the tradename Prometrium; and medroxyprogesterone acetate; available from Pharmacia Upjohn under the tradename Provera.

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more obesity control medications. Useful obesity control medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrientpartitioning agents. Suitable obesity control medications include, but are not limited to, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and tartrate); serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine, theophylline, and selective P3-adrenergic agonists); alpha-blocking agents; kainite or AMPA receptor antagonists; leptin-lipolysis stimulated receptors; phosphodiesterase enzyme inhibitors; compounds having nucleotide sequences of the mahogany gene; fibroblast growth factor-10 polypeptides; monoamine oxidase inhibitors (such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); compounds for increasing lipid metabolism (such as evodiamine compounds); and lipase inhibitors (such as orlistat). Generally, a total dosage of the above-described obesity control medications can range from 1 to 3,000 mg/day, desirably from about 1 to 1,000 mg/day and more desirably from about 1 to 200 mg/day in single or 2-4 divided doses.

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more blood modifiers which are chemically different from the substituted azetidinone and substituted p-lactam compounds (such as compounds l-XI above) and the PPAR receptor activators discussed above, for example, they contain one or more different atoms, have a different arrangement of atoms or a different number of one or more atoms than the sterol absorption inhibitor(s) or PPAR receptor activators discussed above. Useful blood modifiers include but are not limited to anti-coagulants (argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran, ortbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine, beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban, xemilofiban); hemorrheologic agents (pentoxifylline); lipoprotein associated coagulation inhibitors; Factor Vila inhibitors (4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-4-thiones, quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4ones, imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides, naphthalene-2-sulfonic acid (1 -[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)yl) amide trifluoroacetate, dibenzofuran-2-sulfonic acid (1-[3-(aminomethyl)-benzyl]-5oxo-pyrrolidin-3-yl}-amide, tolulene-4-sulfonic acid {1-[3-(aminoiminomethyl)-benzyl]- 2-oxo-pyrrolidin-3-(S)-yl)-amide trifluoroacetate, 3,4-dihydro-1 H-isoquinoline-2-sulfonic acid {1 -[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl)-amide trifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines, disubstituted triazolines, substituted n- [(aminoiminomethyl)phenyl] propylamides, substituted n-[(aminomethyl)phenyl] -76propylamides, tissue factor pathway inhibitor (TFPI), low molecular weight heparins, heparinoids, benzimidazolines, benzoxazolinones, benzopiperazinones, indanones, dibasic (amidinoaryl) propanoic acid derivatives, amidinophenyl-pyrrolidines, amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles, amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidic Factor Xa inhibitors).

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more cardiovascular agents which are chemically different from the substituted azetidinone and substituted p-lactam compounds (such as compounds I-XI above) and the PPAR receptor activators discussed above, for example, they contain one or more different atoms, have a different arrangement of atoms or a different number of one or more atoms than the sterol absorption inhibitor(s) or PPAR receptor activators discussed above. Useful cardiovascular agents include but are not limited to calcium channel blockers (clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate, nebivolol); adrenergic stimulants; angiotensin converting enzyme (ACE) inhibitors (benazepril hydrochloride, benazeprilat, captopril, delapril hydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride, pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril, spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate, lisinopril, zofenopril calcium, perindopril erbumine); antihypertensive agents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine -77hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium, guanfacine hydrochloride, methyldopa, metoprolol succinate, moexipril hydrochloride, monatepil maleate, pelanserin hydrochloride, phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate, bevantolol hydrochloride); angiotensin II receptor antagonists (candesartan, irbesartan, losartan potassium, candesartan cilexetil, telmisartan); anti-anginal agents (amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride); coronary vasodilators (fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatyl nitrate, terodiline hydrochloride, tolamolol, verapamil); diuretics (the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene).

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more antidiabetic medications for reducing blood glucose levels in a human. Useful antidiabetic medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient-partitioning agents. Suitable antidiabetic medications include, but are not limited to, sulfonylurea (such as acetohexamide, chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide, glyburide, glibenclamide, tolazamide, and tolbutamide), meglitinide (such as repaglinide and nateglinide), biguanide (such as metformin and buformin), alpha-glucosidase inhibitor (such as acarbose, miglitol, camiglibose, and voglibose), certain peptides (such as amlintide, pramlintide, exendin, and GLP-1 agonistic peptides), and orally administrable insulin or insulin composition for intestinal delivery thereof. Generally, a total dosage of the above-described 00 00 -78antidiabetic medications can range from 0.1 to 1,000 mg/day in single or 2-4 divided Sdoses.

Mixtures of any of the pharmacological or therapeutic agents described above can be used in the compositions and therapeutic combinations of the present 0 5 invention.

O Described herein is a composition or Stherapeutic combination comprising at least one AcylCoA:Cholesterol Oacyltransferase Inhibitor and at least one substituted azetidinone compound or at 0 least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or at least one substituted p-lactam compound.

Described herein is a composition or therapeutic combination comprising probucol or a derivative thereof and at least one substituted azetidinone compound or at least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted plactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

Described herein is a composition or therapeutic combination comprising at least one low-density lipoprotein receptor activator and at least one substituted azetidinone compound or at least one -79- 0 79 substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically ¢n acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, Sor prodrugs of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

cN The present invention provides a composition or therapeutic combination comprising at least one Omega 3 fatty acid and at least one substituted azetidinone compound or at least one substituted p-lactam compound or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

Described herein is a composition or therapeutic combination comprising at least one natural water soluble fiber and (b) at least one substituted azetidinone compound or at least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted plactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

00 00 Described herein is a composition or therapeutic combination comprising at least one of plant sterols, plant stanols or fatty acid esters of plant stanols and at least one substituted azetidinone compound or at least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

Described herein is a composition or therapeutic combination comprising at least one antioxidant or vitamin and at least one substituted azetidinone compound or at least one substituted p-lactam compound, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound, or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or of the isomers of the at least one substituted azetidinone compound or the at least one substituted P-lactam compound, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted plactam compound or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound.

Mixtures of any of the pharmacological or therapeutic agents described above can be used in the compositions and therapeutic combinations of these other embodiments of the present invention.

The compositions and therapeutic combinations of the present invention can be administered to a mammal in need of such treatment in a therapeutically effective amount to treat one or more conditions, for example vascular conditions such as atherosclerosis, hyperlipidaemia (including but not limited to hypercholesterolemia, hypertriglyceridaemia, sitosterolemia), vascular inflammation, stroke, diabetes, -81 obesity, and/or reduce the level of sterol(s) in the plasma. The compositions and treatments can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human.

The daily dosage for the various compositions and therapeutic combinations described above can be administered to a patient in a single dose or in multiple subdoses, as desired. Subdoses can be administered 2 to 6 times per day, for example. Sustained release dosages can be used. Where the peroxisome proliferator-activated receptor(s) activator and sterol absorption inhibitor(s) are administered in separate dosages, the number of doses of each component given per day may not necessarily be the same, one component may have a greater duration of activity and will therefore need to be administered less frequently.

The pharmaceutical treatment compositions and therapeutic combinations of the present invention can further comprise one or more pharmaceutically acceptable carriers, one or more excipients and/or one or more additives. Non-limiting examples of pharmaceutically acceptable carriers include solids and/or liquids such as ethanol, glycerol, water and the like. The amount of carrier in the treatment composition can range from about 5 to about 99 weight percent of the total weight of the treatment composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders such as starch, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. The amount of excipient or additive can range from about 0.1 to about 90 weight percent of the total weight of the treatment composition or therapeutic combination. One skilled in the art would understand that the amount of carrier(s), excipients and additives (if present) can vary.

The treatment compositions of the present invention can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. Several examples of preparation of dosage formulations are provided below.

00 8 -82- The following formulations exemplify some of the dosage forms described i herein. In each formulation, the term "Active Compound I" designates a substituted tC azetidinone compound, p-lactam compound or any of the compounds of Formulae I-XI described herein above, or isomers of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or any of the compounds of Formulae I-XI, or pharmaceutically acceptable salts or solvates of the N at least one substituted azetidinone compound or the at least one substituted p-lactam r- Scompound or any of the compounds of Formulae I-XI or of the isomers of the at least CN one substituted azetidinone compound or the at least one substituted p-lactam compound or any of the compounds of Formulae I-XI, or prodrugs of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or any of the compounds of Formulae I-XI or of the isomers, salts or solvates of the at least one substituted azetidinone compound or the at least one substituted p-lactam compound or any of the compounds of Formulae I-XI, and the term "Active Compound is II" designates a PPAR activator described herein above.

EXAMPLE

Tablets No. Ingredient mg/tablet 1 Active Compound I 2 Lactose monohydrate NF 3 Microcrystalline cellulose NF 4 Povidone (K29-32) USP 4 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate 2 7 Magnesium stearate NF 1 Total 100 The above-described tablet can be coadministered with a tablet, capsule, etc. comprising a dosage of Active Compound II, for example a TRICOR® capsule as described above.

-83- Method of Manufacture Mix Item No. 4 with purified water in suitable mixer to form binder solution.

Spray the binder solution and then water over Items 1, 2, 6 and a portion of Item 5 in a fluidized bed processor to granulate the ingredients. Continue fluidization to dry the damp granules. Screen the dried granules and blend with Item No. 3 and the remainder of Item 5. Add Item No. 7 and mix. Compress the mixture to appropriate size and weight on a suitable tablet machine.

For coadministration in separate tablets or capsules, representative formulations comprising a cholesterol absorption inhibitor such as are discussed above are well known in the art and representative formulations comprising a peroxisome proliferator-activated receptor activator such as are discussed above are well known in the art. It is contemplated that where the two active ingredients are administered as a single composition, the dosage forms disclosed above for substituted azetidinone or P-lactam compounds may readily be modified using the knowledge of one skilled in the art.

The matter described above relates to treating conditions as discussed above, such as reducing the plasma sterol (especially cholesterol) concentrations or levels by treatment with a combination of active ingredients wherein the active ingredients may be administered separately. Also described herein is a combination of separate pharmaceutical compositions in kit form. For example, a kit is contemplated wherein two separate units are combined: a pharmaceutical composition comprising at least one peroxisome proliferator-activated receptor activator and a separate pharmaceutical composition comprising at least one sterol absorption inhibitor as described above.

The kit will preferably include directions for the administration of the separate components. The kit form is particularly advantageous when the separate components must be administered in different dosage forms oral and parenteral) or are administered at different dosage intervals.

The treatment compositions and therapeutic combinations of the present invention can inhibit the intestinal absorption of cholesterol in mammals, as shown in the Example below, and can be useful in the treatment and/or prevention of 00 00 -84conditions, for example vascular conditions, such as atherosclerosis, Shypercholesterolemia and sitosterolemia, stroke, obesity and lowering of plasma levels of cholesterol in mammals, in particular in mammals.

The compositions and therapeutic combinations described herein can inhibit sterol absorption or reduce plasma concentration of at least one sterol selected from the group consisting Sof phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), stanols (such as cholestanol, 5a-campestanol, 5a-sitostanol), cholesterol and Smixtures thereof. The plasma concentration can be reduced by administering to a mammal in need of such treatment an effective amount of at least one treatment composition or therapeutic combination comprising at least one PPAR activator and at least one sterol absorption inhibitor described above. The reduction in plasma concentration of sterols can range from about 1 to about 70 percent, and preferably about 10 to about 50 percent. Methods of measuring serum total blood cholesterol and total LDL cholesterol are well known to those skilled in the art and for example include those disclosed in PCT WO 99/38498 at page 11, incorporated by reference herein. Methods of determining levels of other sterols in serum are disclosed in H.

Gylling et al., "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999), incorporated by reference herein.

Illustrating the invention are the following examples which, however, are not to be considered as limiting the invention to their details. Unless otherwise indicated, all parts and percentages in the following examples, as well as throughout the specification, are by weight.

EXAMPLES

PREPARATION OF COMPOUND OF FORMULA (II) Step To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2CI2 (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to 00C. Methyl- 4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2CI2 (375 ml) dropwise over 1 h, and the reaction was allowed to warm to 220C. After 17 h, water and H2S04 (2N, 100 ml), was added the layers were separated, and the organic layer was washed sequentially with NaOH NaCI (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product.

Step To a solution of TiCI4 (18.2 ml, 0.165 mol) in CH2CI2 (600 ml) at 0oC, was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2CI2 (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was stirred at 0OC for 1 h, the reaction mixture was cooled to -200C, and 4benzyloxybenzylidine(4-fluoro)aniline (114.3 g. 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -200C, then acetic acid was added as a solution in CH2C12 dropwise over 15 min, the reaction mixture was allowed to warm to OoC, and H2S04 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.

Step To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 ml) at 500C, was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 500C for an additional 3 h. The reaction mixture was cooled to 220C, (10 ml), was added. The reaction mixture was washed with HCI (1N), NaHCO3 (1N) and NaCI and the organic layer was dried over MgSO4.

Step To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 ml), was added water (1 ml) and LiOH-H20 (102 mg, 2.4 mmole). The reaction mixture was stirred at 220C for 1 h and then additional LiOH-H20 (54 mg, 1.3 mmole) was added. After a total of 2 h, HCI (1N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2CI2 at 220C, was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.

-86- Step To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 40C, was added tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). The reaction was stirred for 1 h at OoC and then for 0.5 h at 220C. HCI (1N, 5 ml) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3phenylpropyl)-2-azetidinone: HRMS calc'd for C24H19F2NO3 408.1429, found 408.1411.

Step To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), was added (R)-tetrahydro-l-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to -200C. After 5 min, borohydridedimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) was added dropwise over h. After a total of 1.5 h CH3OH was added followed by HCI (1 N) and the reaction mixture was extracted with EtOAc to obtain 1-(4-fluorophenyl)-3(R)-[3(S)-(4fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone (compound 6A-1) as an oil. 1 H in CDCl3 d H3 4.68. J 2.3 Hz. Cl 500.

Use of (S)-tetra-hydro-1 -methyl-3,3-diphenyl-1 H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone (compound 6B-1). 1H in CDCI3 d H3 4.69. J 2.3 Hz. Cl 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), was added Pd/C (0.03 g) and the reaction mixture was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to obtain compound 6A. Mp 164-1660C; Cl 410. [cf2o 5 -28.10 (c 3, CH 3

OH)

Elemental analysis calc'd for C24H21F2N03: C 70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.

Similarly treat compound 6B-1 to obtain compound 6B.

Mp 129.5-132.50C; CI (M+H)410. Elemental analysis calc'd for C24H21F2NO3: C70.41; H5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

-87- Step 6' (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to afford a 1:1 mixture of compounds 6A and 6B.

In Vivo Evaluation In a randomized, evaluator-blind, placebo-controlled, parallel-group study 32 healthy hypercholesterolemic humans (screening LDL-C 2 130 mg/dL) stabilized and maintained on a NCEP Step I Diet were randomized to one of the following four treatments: Treatment A placebo given orally as 1 dose per day, Treatment B 10 mg of Compound II given orally as 1 dose per day, Treatment C 200 mg of LIPANTHYL® micronized Fenofibrate (available from Labortoire Foumier of France) given orally as 1 dose per day, or Treatment D 200 mg of LIPANTHYL® micronized Fenofibrate plus 10 mg of Compound II given orally as 1 dose per day every morning for 14 days.

Serum lipids were assessed predose (after a minimum of a 10-hour fast) on Day 1 (Baseline), Day 7 and Day 14.

Results: The mean Day 14 percent change from Baseline in serum lipids are shown in Table 1 below: Table 1 Treatment LDL-C Total-C HDL-C TG A -10.1 -8.38 -14.1 19.1 (13.9) B -22.3 -19.6 -13.3 -4.57 (12.8) C -13.5 -13.0 -6.1 0.28 (11.4) D -36.3 -27.8 -1.97 -32.4 The coadministration of 10 mg of Compound II and 200 mg of Fenofibrate (Treatment D) was well tolerated and caused a significant (p 0.03) reduction in LDL-C compared to either drug alone or placebo. In this inpatient study where the subjects' physical activity was restricted, in general HDL-C concentrations tended to -88decrease and triglycerides tended to increase. The group receiving Treatment C had the least decrease in HDL-C and the greatest decrease in triglyceride levels.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications which are within the spirit and scope of the invention, as defined by the appended claims.

It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims (14)

1. A composition comprising at least one Omega 3 fatty acid and at least one substituted azetidinone sterol absorption inhibitor or substituted CS p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or the at least one substituted p-lactam sterol absorption inhibitor.

S2. A therapeutic combination comprising a first amount of at least one Omega 3 fatty acid and a second amount of at least one substituted S0o azetidinone sterol absorption inhibitor or substituted p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or the at least one substituted p-lactam sterol absorption 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.

3. The composition or therapeutic combination according to claim 1 or 2, wherein the at least one substituted azetidinone sterol absorption inhibitor or substituted p-lactam sterol absorption inhibitor or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone sterol absorption inhibitor or the at least one substituted p-lactam sterol absorption inhibitor is administered to a mammal in an amount ranging from about 0.1 to about 1000 milligrams per day.

4. The composition according to claim 3, further comprising at least one HMG CoA reductase inhibitor.

The composition according to claim 4, 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. 00

6. The composition according to claim 5, wherein the at least one HMG CoA reductase inhibitor is simvastatin.

7. The composition according to claim 5, wherein the at least one SHMG CoA reductase inhibitor is atorvastatin.

8. The composition according to claim 5, wherein the at least one HMG CoA reductase inhibitor is rosuvastatin.

9. The composition or therapeutic combination according to claim 1 or 2, further comprising at least one lipid lowering agent selected from the Sgroup consisting of bile acid sequestrants, nicotinic acid or derivatives thereof, CETP inhibitors, IBAT inhibitors, AcylCoA:Cholesterol O-acyltransferase Inhibitors, probucol or a derivative 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.

The composition or therapeutic combination according to claim 1 or 2, 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.

11. 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 claim 1 or 2.

12. 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 claim 1 or 2. 00 -91-

13. Use of a composition or therapeutic combination according to claim 1 or 2, for preparation of a medicament for treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of Sa mammal. s

14. A composition according to claim 1, a therapeutic combination according to claim 2, a method according to claim 12, or use according to Sclaim 13, substantially as herein described with reference to the Examples.