RU2483724C2 - Combinations of activator (activators) of peroxisome proliferator-activated receptor (ppar), and inhibitor (inhibitors) of sterol absorption and treatment of vascular diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and deals with pharmaceutical composition or therapeutic combination for treatment of vascular pathological states, diabetes, obesity and reduction of concentration of sterols in plasma, which include: (a) at least, one activator of peroxisome proliferator-activated receptor, selected from group, consisting of fenofibrate, clofibrate, gemfibrozil, cyprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrole or their mixture, and (b) sterol absorption inhibitor, represented by formula

, or its pharmaceutically acceptable salt.

EFFECT: claimed are combinations of activator (activators) of peroxisome proliferator-activated receptor (ppar), and inhibitor (inhibitors) of sterol absorption and treatment of vascular diseases.

Description

Field of Invention

The present invention relates to compositions and therapeutic combinations comprising a peroxisome proliferator activated receptor activator (s) (PPAR) and some (some) sterol absorption inhibitor (s) for treating certain vascular and lipidemic pathological conditions, such as concomitant with atherosclerosis, hypercholesterolemia and other vascular pathological conditions in mammals.

State of the art

Atherosclerotic coronary heart disease (CHD) is the leading cause of death and the occurrence of vascular diseases in the Western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, a family history, male gender, smoking, and serum cholesterol concentration. A concentration of total cholesterol in excess of 225-250 mg / dl is associated with a significant increase in the risk of CHD.

Cholesterol esters are the main component of atherosclerotic lesions and the main form of storing cholesterol in the cells of the arterial walls. The formation of cholesterol esters is also a key step in the absorption of food cholesterol in the intestine. Thus, inhibition of the formation of cholesterol ester and a decrease in the concentration of cholesterol in serum can inhibit the progression of the formation of atherosclerotic lesions, reduce the accumulation of cholesterol esters in the walls of blood vessels and block the absorption of food cholesterol in the intestine.

Regulation of cholesterol homeostasis throughout the body of mammals and animals includes regulation of food cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of plasma lipoproteins containing cholesterol. The liver is the main organ responsible for the biosynthesis and catabolism of cholesterol, and for this reason it mainly determines the concentration of cholesterol in plasma. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL), which are then metabolized in the bloodstream to low density lipoproteins (LDL). LDL is the main plasma lipoprotein containing cholesterol and an increase in their concentration correlates with increased atherosclerosis. If, no matter by what means, the absorption of cholesterol in the intestine is reduced, less cholesterol enters the liver. The consequence of this is a decrease in the production of lipoprotein (VLDL) in the liver and an increase in hepatic clearance of plasma cholesterol, mainly in the form of LDL. Thus, the overall effect of inhibiting cholesterol absorption in the intestine is a decrease in plasma cholesterol concentration.

Fibric acid derivatives ("fibrates"), such as fenofibrate, gemfibrozil and clofibrate, are used to lower triglycerides, moderate LDL concentrations and increase HDL concentrations. Fibric acid derivatives are also known to be activators of the alpha receptor activated by the peroxisome proliferator.

US Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, respectively, describe hydroxy substituted azetidinone derivatives and substituted β-lactams suitable for use to lower cholesterol concentration and / or inhibit the formation of cholesterol-containing lesions in the walls of mammalian blood vessels. US Pat. Nos. 5846966 and 5661145, respectively, disclose hydroxy-substituted azetidinone derivatives and substituted β-lactams in combination with HMG CoA reductase inhibitors for preventing or treating atherosclerosis and lowering plasma cholesterol.

PCT Application No. WO 00/38725 describes cardiovascular therapeutic combinations, including an ileum bile acid transport inhibitor or a cholesterol ester carrier protein inhibitor in combination with a fibrin acid derivative, a nicotinic acid derivative, a cholesterol absorption antagonist, phytosterol, stanol, antihypertensive drug or sequestrant of bile acids.

US Pat. No. 5,698,527 describes ergostanone derivatives containing disaccharides as substituents for use as cholesterol absorption inhibitors that are used alone or in combination with certain other cholesterol lowering drugs that are suitable for use in the treatment of hypercholesterolemia and related diseases .

Despite recent advances in the treatment of vascular diseases, there remains a need in the art for improved compositions and methods for treating hyperlipidemia, atherosclerosis, and other vascular diseases.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (I):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (I) or their isomers, or prodrug forms of the compounds of formula (I) or their isomers, salts or solvates, moreover, in the above formula (I):

Ar ¹ and Ar ^{2 are} independently selected from the group consisting of aryl and R ⁴ -substituted aryl;

Ar ³ means aryl or R ⁵ -substituted aryl;

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

R and R ^{2 are} independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;

R ¹ 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 the group of values equal to 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 if p is 0 and r is 1, then the sum of m, q and n is 1, 2, 3, 4, or 5;

R ⁴ means 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 ) _1-5 OR ⁶ , - O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O ( CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ , -CH = CH-COOR ⁶ , -CF ₃ , -CN, -NO ₂ and halogen;

R ⁵ means 1-5 substituents independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , - COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent; and

R ⁹ means lower alkyl, aryl or lower alkyl containing an aryl substituent.

In another embodiment, the present invention relates to a composition comprising: (a) at least one fibric acid derivative; and (b) a compound representing a compound of the following formula (II):

or a pharmaceutically acceptable salt or solvate thereof, or a prodrug form of a compound of formula (II) or a salt or solvate thereof.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (III):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (III) or their isomers, or prodrug forms of the compounds of formula (III) or their isomers, salts or solvates, moreover, in the above formula (III):

Ar ¹ means R ³ -substituted aryl; Ar ² means R ⁴ -substituted aryl; Ar ³ means R ⁵ -substituted aryl;

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

A is selected from the group consisting of —O—, —S—, —S (O) - or —S (O) ₂ -;

R ^{1 is} selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;

R ² selected from the group comprising hydrogen, lower alkyl and aryl; or R ¹ and R ² together mean = O;

q is 1, 2 or 3;

p is 0, 1, 2, 3 or 4;

R ⁵ means 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 ⁹ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO _{2 -} lower alkyl, -NR ⁶ SO ₂ -aryl, -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (lower alkylene) -COOR ⁶ and -CH = CH-COOR ⁶ ;

R ³ and R ^{4 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of R ⁵ , hydrogen, p-lower alkyl, aryl, —NO ₂ , —CF _3, and p-halogen;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent; and

R ⁹ means lower alkyl, aryl or lower alkyl containing an aryl substituent.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (IV):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (IV) or their isomers, or prodrug forms of the compounds of formula (IV) or their isomers, salts or solvates, moreover, in the above formula (IV):

A is selected from the group consisting of R ² -substituted heterocycloalkyl, R ² -substituted heteroaryl, R ² -substituted heterocycloalkyl fused with a benzene ring and R ² -substituted heteroaryl fused with a benzene ring;

Ar ¹ means aryl or R ³ -substituted aryl;

Ar ² means aryl or R ⁴ -substituted aryl;

Q means a bond or forms a spiran group with the cyclic carbon atom in position 3 of azetidinone

and

R ¹ selected from the group including:

- (CH ₂ ) _q -, where q is 2-6 provided that if Q forms a spiran ring, then q can also be zero or 1;

- (CH ₂ ) _e -G- (CH ₂ ) _r -, where G is —O—, —C (O) -, phenylene, —NR ⁸ - or —S (O) _0-2 -, e is 0 -5 and r is 0-5, provided that the sum of e and r is 1-6;

- ((C ₂ -C ₆ ) alkenylene) -; and

- (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) cycloalkylene, f is 1-5 and g is 0-5 provided that the sum of f and g is 1- 6;

R ⁵ selected from the group including:

или

or

R ⁶ and R ^{7 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ⁵ together with neighboring R ⁶ , or R ⁵ together with neighboring R ⁷ form a —CH = CH— or —CH = C ((C ₁ –C ₆ ) alkyl) - group;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero; provided that if R ⁶ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1; with the proviso that if R ⁷ is —CH═CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1; provided that if a is 2 or 3, then R ⁶ may be the same or different; and provided that if b is 2 or 3, then R ⁷ may be the same or different;

and, if Q means a bond, then R ¹ can also be selected from the group including:

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

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

R ¹⁰ and R ^{12 are} independently selected from the group consisting of —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ¹⁶ and —O (CO) NR ¹⁴ R ¹⁵ ;

R ¹¹ and R ^{13 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl and aryl; or R ¹⁰ and R ¹¹ together mean = O, or R ¹² and R ¹³ together mean = O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1-6; provided that if p is 0 and t is 1, then the sum of m, s and n is 1-5; and provided that if p is 0 and s is 1, then the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5 provided that the sum of j, k and v is 1-5;

; и, если R² является заместителем у замещаемого атома азота цикла, то он означает водород, (С₁-С₆)алкил, арил, (С₁-С₆)алкоксил, арилоксил, (С₁-С₆)алкилкарбонил, арилкарбонил, гидроксил, -(CH₂)_1-6CONR¹⁸R¹⁸,R ² means 1-3 substituents on cyclic carbon atoms selected from the group consisting of hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, (C ₃ - C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkenyl, R ¹⁷ -substituted aryl, R ¹⁷ -substituted benzyl, R ¹⁷ -substituted benzyloxyl, R ¹⁷ -substituted aryloxyl, halogen, -NR ¹⁴ R ¹⁵ , NR ¹⁴ R ¹⁵ ((C ₁ -C ₆ ) alkylene) -, NR ¹⁴ R ¹⁵ C (O) ((C ₁ -C ₆ ) alkylene) -, -NHC (O) R ¹⁶ , OH, (C ₁ -C ₆ ) alkoxyl , -OC (O) R ¹⁶ , -COR ¹⁴ , hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, NO ₂ , -S (O) _{0- 2} R ¹⁶ , —SO ₂ NR ¹⁴ R ¹⁵ and - ((C ₁ -C ₆ ) alkylene) COOR ¹⁴ ; if R ² is a heterocycloalkyl ring substituent, then R ² is as defined, or is = O or

; and, if R ² is a substituent on the substituted nitrogen atom of the ring, then it means hydrogen, (C ₁ -C ₆ ) alkyl, aryl, (C ₁ -C ₆ ) alkoxyl, aryloxy, (C ₁ -C ₆ ) alkylcarbonyl, arylcarbonyl hydroxyl, - (CH ₂ ) _1-6 CONR ¹⁸ R ¹⁸ ,

where J is —O—, —NH—, —NR ¹⁸ - or —CH ₂ -;

R ³ and R ^{4 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ¹⁶ , -O (CH ₂ ) _1-5 OR ¹⁴ , -O (CO) NR ¹⁴ R ¹⁵ , -NR ¹⁴ R ¹⁵ , -NR ¹⁴ (CO) R ¹⁵ , -NR ¹⁴ (CO) OR ¹⁶ , -NR ¹⁴ (CO) NR ¹⁵ R ¹⁹ , -NR ¹⁴ SO ₂ R ¹⁶ , -COOR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -COR ¹⁴ , -SO ₂ NR ¹⁴ R ¹⁵ , S (O) _0-2 R ¹⁶ , -O (CH ₂ ) _1-10 -COOR ¹⁴ , -O (CH ₂ ) _1-10 CONR ¹⁴ R ¹⁵ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁴ , -CH = CH-COOR ¹⁴ , -CF ₃ , —CN, —NO ₂ and halogen;

R ⁸ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁴ or —COOR ¹⁴ ;

R ⁹ and R ¹⁷ independently mean 1-3 groups independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁴ R ¹⁵ , OH and halogen;

R ¹⁴ and R ^{15 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ¹⁶ means (C ₁ -C ₆ ) alkyl, aryl or R ¹⁷ -substituted aryl;

R ¹⁸ means hydrogen or (C ₁ -C ₆ ) alkyl; and

R ¹⁹ means hydrogen, hydroxyl or (C ₁ -C ₆ ) alkoxyl.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (V):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (V) or their isomers, or prodrug forms of the compounds of formula (V) or their isomers, salts or solvates, moreover, in the above formula (V):

Ar ¹ means aryl, R ¹⁰ -substituted aryl or heteroaryl;

Ar ² means aryl or R ⁴ -substituted aryl;

Ar ³ means aryl or R ⁵ -substituted aryl;

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

R is —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ or —O (CO) NR ⁶ R ⁷ ; R ¹ means hydrogen, lower alkyl or aryl; or R and R ¹ together mean = O;

q is 0 or 1;

r is 0, 1 or 2;

m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;

R ⁴ means 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 ) _1-5 OR ⁶ -, -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;

R ⁵ means 1-5 substituents independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , - COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , —CF ₃ , —CN, —NO ₂ , halogen, - (lower alkylene) COOR ⁶ and —CH = CH — COOR ⁶ ;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent;

R ⁹ means lower alkyl, aryl or lower alkyl containing an aryl substituent; and

R ¹⁰ means 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 ) _1-5 OR ⁶ , - O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , -S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , —CF ₃ , —CN, —NO ₂ and halogen.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (VI):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (VI) or their isomers, or prodrug forms of the compounds of formula (VI) or their isomers, salts or solvates, moreover, in the above formula (VI):

R ₁ means

R ₂ and R _{3 are} independently selected from the group consisting of: —CH ₂ -, —CH (lower alkyl) -, —C (di- (lower alkyl)) -, —CH = CH—, and —C (lower alkyl) = CH-; or R ₁ together with the neighboring R ₂ , or R ₁ together with the neighboring R ₃ form the group —CH = CH— or —CH = C (lower alkyl) -;

u and v are independently 0, 1, 2, or 3, provided that they are both non-zero; provided that if R ₂ is —CH = CH— or —C (lower alkyl) = CH—, then v is 1; provided that if R ₃ means —CH = CH— or —C (lower alkyl) = CH—, then u is 1; provided that if v is 2 or 3, then R ₂ may be the same or different; and provided that if u is 2 or 3, then R ₃ may be the same or different;

R _{4 is} selected from the group consisting of B- (CH ₂ ) _m C (O) -, where m is 0, 1, 2, 3, 4, or 5; B- (CH ₂ ) _q -, where q is 0, 1, 2, 3, 4, 5, or 6; B- (CH ₂ ) _e -Z- (CH ₂ ) _r -, where Z is —O—, —C (O) -, phenylene, —N (R ₈ ) - or —S (O) _0-2 - , e is 0, 1, 2, 3, 4, or 5, and r is 0, 1, 2, 3, 4, or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5, or 6 ; B - ((C ₂ -C ₆ ) alkenylene) -; B - ((C ₄ -C ₆ ) alkadienylene) -; B- (CH ₂ ) _t -Z - ((C ₂ -C ₆ ) alkenylene) -, where Z is as defined above, and where t is 0, 1, 2 or 3, provided that the sum of t and the amount carbon atoms in the alkenylene chain is 2, 3, 4, 5, or 6; B- (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) 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- (CH ₂ ) _t -V - ((C ₂ -C ₆ ) alkenylene) - or B - ((C ₂ -C ₆ ) alkenylene) -V- (CH ₂ ) _t -, where V and t are such 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- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d -, where 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; and T- (CH ₂ ) _s -, where T is cycloalkyl with 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or R ₁ and R ₄ together form a group

In the group selected from the group consisting of indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl, or W-substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxynyl, thienyl, oxynyl and for nitrogen-containing heterocycles, their N-oxides, or

в качестве заместителя для циклических атомов углерода, и заместители замещенных атомов азота гетероарильного кольца, если они имеются, выбраны из группы, включающей низший алкил, низший алкоксил, -C(O)OR₁₀, -C(O)R₁₀, ОН, N(R₈)(R₉)-низший алкилен-, N(R₈)(R₉)-низший алкиленилоксил-, -S(O)₂NH₂ и 2-(триметилсилил)-этоксиметил;W means 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkanedioyl, lower alkyl, lower alkanediyl —CF ₃ , —OCF ₃ , benzyl, R ₇ -benzyl, benzyloxy, R _7- benzyloxy, phenoxyl, R ₇ -phenoxyl, dioxolanyl, NO ₂ , -N (R ₈ ) (R ₉ ), N (R ₈ ) (R ₉ ) lower alkylene-, N (R ₈ ) (R ₉ ) lower alkylenyloxy-, OH, halogen, —CN, —N ₃ , —NHC (O) OR ₁₀ , —NHC (O) R ₁₀ , R ₁₁ O ₂ SNH-, (R ₁₁ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) _0-2 R ₈ , tert-butyldimethylsilyloxy tyl, -C (O) R ₁₂ , -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -CH = CHC (O) R ₁₂ , lower alkylene-C (O) R ₁₂ , R ₁₀ C ( O) (lower alkylenyloxy) -, N (R ₈ ) (R ₉ ) C (O) (lower alkylenyloxy) - and

as a substituent for cyclic carbon atoms, and substituents of substituted heteroaryl ring nitrogen atoms, if any, are selected from the group consisting of lower alkyl, lower alkoxyl, —C (O) OR ₁₀ , —C (O) R ₁₀ , OH, N (R ₈ ) (R ₉ ) lower alkylene-, N (R ₈ ) (R ₉ ) lower alkyleneyloxy-, -S (O) ₂ NH ₂ and 2- (trimethylsilyl) ethoxymethyl;

R ₇ means 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxyl, —COOH, NO ₂ , —N (R ₈ ) (R ₉ ), OH, and halogen;

R ₈ and R _{9 are} independently selected from the group consisting of H and lower alkyl;

R _{10 is} selected from the group consisting of lower alkyl, phenyl, R ₇ -phenyl, benzyl or R ₇ -benzyl;

R _{11 is} selected from the group consisting of OH, lower alkyl, phenyl, benzyl, R _{7 is} phenyl or R _{7 is} benzyl;

R _{12 is} selected from the group consisting of H, OH, alkoxyl, phenoxyl, benzyloxyl,

-N (R ₈ ) (R ₉ ), lower alkyl, phenyl or R ₇ phenyl;

R _{13 is} selected from the group consisting of —O—, —CH ₂ -, —NH—, —N (lower alkyl) - or —NC (O) R ₁₉ ;

R ₁₅ , R ₁₆ and R _{17 are} independently selected from the group consisting of H and the groups indicated in the definition of W; or R ₁₅ is hydrogen and R ₁₆ and R _17, together with the adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

R ₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and

R ₂₀ and R _{21 are} independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl condensed with a benzene ring, heteroaryl, W-substituted condensed with a benzene ring heteroaryl and cyclopropyl, where heteroaryl is as defined above.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (VII):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (VII) or their isomers, or prodrug forms of the compounds of formula (VII) or their isomers, salts or solvates, moreover, in the above formula (VII):

And means -CH = CH-, -C≡C- or - (CH ₂ ) _p -, where p is 0, 1 or 2;

B means

E means alkyl from C ₁₀ to C ₂₀ or —C (O) - (C ₉ to C ₁₉ ) -alkyl, where the alkyl is linear or branched, saturated or containing one or more double bonds;

R is hydrogen, (C ₁ -C ₁₅ ) alkyl, linear or branched, saturated or containing one or more double bonds, or B- (CH ₂ ) _r -, where r is 0, 1, 2 or 3;

R ₁ , R ₂ , and R _{3 are} independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxyl, carboxyl, NO ₂ , NH ₂ , OH, halogen, (lower alkyl) amino group, (di- (lower alkyl)) an amino group, -NHC (O) OR ₅ , R ₆ O ₂ SNH- and -S (O) ₂ NH ₂ ;

R ₄ means

where n is 0, 1, 2 or 3;

R ₅ means lower alkyl; and

R ₆ means OH, lower alkyl, phenyl, benzyl or substituted phenyl, in which the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxyl, carboxyl, NO ₂ , NH ₂ , OH, halogen, (lower an alkyl) amino group and (di- (lower alkyl)) an amino group.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor, which is a compound of formula (VIII):

or its isomers, or pharmaceutically acceptable salts or solvates of compounds of the formula (VIII) or their isomers, or prodrug forms of the compounds of the formula (VIII) or their isomers, salts or solvates thereof, in the above formula (VIII):

R ²⁶ means H or OG ¹ ;

G and G ^{1 are} independently selected from the group including

H

with the proviso that if R ²⁶ is H or OH, then G is not H;

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl and —WR ³⁰ ;

W is independently selected from the group consisting of —NH — C (O) -, —O — C (O) -, —O — C (O) —N (R ³¹ ) -, —NH — C (O) —N ( R ³¹ ) - and -OC (S) -N (R ³¹ ) -;

R ² and R ^{6 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^{4a are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) ( C ₁ -C ₆ ) alkyl and -C (O) aryl;

R ^{30 is} selected from the group consisting of R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl;

R ^{31 is} selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;

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

R ^{32 is} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of halogen, (C ₁ -C ₄ ) alkyl, —OH, phenoxyl, —CF ₃ , —NO ₂ , (C ₁ —C ₄ ) alkoxy, methylenedioxy, oxo, (C ₁ -C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O) - (C ₁ -C ₄ ) alkyl, -C (O) - (C ₁ -C ₄ ) alkoxyl and pyrrolidinylcarbonyl; or R ³² is a covalent bond and R ³¹ , the nitrogen atom to which it is attached, and R ³² form a pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group, or a (C ₁ -C ₄ ) alkoxycarbonyl substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group;

Ar ¹ means aryl or R ¹⁰ -substituted aryl;

Ar ² means aryl or R ¹¹ -substituted aryl;

Q means a bond or forms a spiran group with the cyclic carbon atom in position 3 of azetidinone

and

R ^{1 is} selected from the group consisting of - (CH ₂ ) _q -, where q is 2-6, provided that if Q forms a spiran ring, then q can also be zero or 1; - (CH ₂ ) _e —E— (CH ₂ ) _r -, where E is —O—, —C (O) -, phenylene, —NR ²² - or —S (O) _0-2 -, e is 0 -5 and r is 0-5, provided that the sum of e and r is 1-6; - (C ₂ -C ₆ ) alkenylene-; and - (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) cycloalkylene, f is 1-5 and g is 0-5 provided that the sum of f and g is 1 -6;

R ¹² means

R ¹³ and R ^{14 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ¹² together with the neighboring R ¹³ , or R ¹² together with the neighboring R ¹⁴ form a group —CH = CH— or —CH = C ((C ₁ -C ₆ ) alkyl) -;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero;

provided that if R ¹³ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1;

provided that if R ¹⁴ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1;

provided that if a is 2 or 3, then R ¹³ may be the same or different; and provided that if b is 2 or 3, then R ¹⁴ may be the same or different;

and, if Q means a bond, then R ¹ may also mean:

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

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

R ¹⁰ and R ^{11 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O (CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , —CN, —NO ₂ and halogen;

R ¹⁵ and R ^{17 are} independently selected from the group consisting of —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ^21, and —O (CO) NR ¹⁹ R ²⁰ ;

R ¹⁶ and R ^{18 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and aryl; or R ¹⁵ and R ¹⁶ together mean = O, or R ¹⁷ and R ¹⁸ together mean = O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;

provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1-6;

provided that if p is 0 and t is 1, then the sum of m, s and n is 1-5; and

provided that if p is 0 and s is 1, then the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5 provided that the sum of j, k and v is 1-5;

and if Q means a bond and R ¹ means

then Ar ¹ may also mean 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, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ²¹ means (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;

R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;

R ²³ and R ²⁴ independently mean 1-3 groups independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁹ R ²⁰ , -OH and halogen; and

R ²⁵ means H, -OH or (C ₁ -C ₆ ) alkoxyl.

In another embodiment, the present invention relates to a composition comprising: (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one sterol absorption inhibitor of the formula (IX):

or its isomers, or pharmaceutically acceptable salts or solvates of the compounds of formula (IX) or their isomers, or prodrug forms of the compounds of formula (IX) or their isomers, salts or solvates, moreover, in the above formula (IX):

R ^{26 is} selected from the group including:

a) OH;

b) OCH ₃ ;

c) fluorine and

d) chlorine.

R ¹ selected from the group including

H

-SO ₃ H; natural and unnatural amino acids.

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl and —WR ³⁰ ;

W is independently selected from the group consisting of —NH — C (O) -, —O — C (O) -, —O — C (O) —N (R ³¹ ) -, —NH — C (O) —N ( R ³¹ ) - and -OC (S) -N (R ³¹ ) -;

R ² and R ^{6 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^{4a are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) ( C ₁ -C ₆ ) alkyl and -C (O) aryl;

R ^{30 is} independently selected from the group consisting of R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl;

R ^{31 is} independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;

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

R ^{32 is} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of H, halogen, (C ₁ -C ₄ ) alkyl, —OH, phenoxyl, —CF ₃ , —NO ₂ , (C ₁ —C ₄ ) alkoxyl, methylenedioxy, oxo group, (C ₁ -C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O) - (C ₁ -C ₄ ) alkyl, -C (O) - ( C ₁ -C ₄ ) alkoxyl and pyrrolidinylcarbonyl; or R ³² is a covalent bond and R ³¹ , the nitrogen atom to which it is attached, and R ³² form a pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group, or a (C ₁ -C ₄ ) alkoxycarbonyl substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group;

Ar ¹ means aryl or R ¹⁰ -substituted aryl;

Ar ² means aryl or R ¹¹ -substituted aryl;

Q means - (CH ₂ ) _q -, where q is 2-6, or with a cyclic carbon atom in position 3 of azetidinone forms a spiran group

R ¹² means

R ¹³ and R ^{14 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ¹² together with the neighboring R ¹³ , or R ¹² together with the neighboring R ¹⁴ form a group —CH = CH— or —CH = C ((C ₁ -C ₆ ) alkyl) -;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero; provided that if R ¹³ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1; provided that if R ¹⁴ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1; provided that if a is 2 or 3, then R ¹³ may be the same or different; and provided that if b is 2 or 3, then R ¹⁴ may be the same or different;

R ¹⁰ and R ^{11 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O (CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , —CN, —NO ₂ and halogen;

Ar ¹ may 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, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ²¹ means (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;

R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;

R ²³ and R ²⁴ independently mean 1-3 groups independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁹ R ²⁰ , -OH and halogen; and

R ²⁵ means H, -OH or (C ₁ -C ₆ ) alkoxyl.

Also provided are therapeutic combinations comprising (a) a first amount of at least one peroxisome proliferator activated receptor activator; and (b) a second amount of at least one sterol absorption inhibitor, which is a compound of the above formulas (I-XI), or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of formulas (I-XI), or isomers thereof, or prodrug forms of the compounds of formulas (I-XI) or their isomers, salts or solvates in which the first amount and the second amount together are a therapeutically effective amount for treating or preventing a vascular disease state, diabetes, obesity, or decrease in the concentration of sterol in the plasma of a mammal.

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

Methods are also provided for treating or preventing a vascular pathological condition, diabetes, obesity, or lowering the concentration of sterol in a plasma of a mammal, comprising the steps of administering to a mammal in need of such treatment an effective amount of the above compositions or therapeutic combinations.

With the exception of working examples or other indications, in all cases it should be understood that all numbers characterizing the amounts of components, reaction conditions, etc., used in the description and claims are changed so that the term “about” is in front of them .

DETAILED DESCRIPTION OF THE INVENTION

Compositions or therapeutic combinations of the present invention include at least one (or more) peroxisome proliferator activated receptor activators (PPARs). These activators act as agonists of receptors activated by the peroxisome proliferator. Three subtypes of RAPP were found and are designated as receptor-alpha activated by the peroxisome proliferator (RAPPα), gamma-receptor activated by the peroxisome proliferator (RAPPγ), and receptor-delta activated by the peroxisome proliferator (RAPPδ). It should be noted that RAPPδ are often referred to in the literature as RAPPβ and NUC1, and all these names refer to the same receptor.

RAPPa regulates lipid metabolism. RAPPα is activated by fibrates and certain medium and long chain fatty acids and it is involved in stimulating β-oxidation of fatty acids. RAPPγ receptor subtypes are involved in the activation of adipocyte differentiation programs and are not involved in stimulating proliferation of peroxisomes in the liver. It has been found that RAPPδ is useful for increasing the concentration of high density lipoproteins (HDL) in human liver. See, for example, WO 97/28149.

Compounds that activate RAPPα are, inter alia, useful for lowering triglyceride concentrations, moderate lowering LDL concentrations, and increasing HDL concentrations. Examples of suitable activators of RAPPα include fibrates.

Non-limiting examples of suitable fibric acid derivatives (“fibrates”) include clofibrate (such as ethyl 2- (p-chlorophenoxy) -2-methylpropionate, for example, ATROMID-S® capsules sold by Wyeth-Ayerst); gemfibrozil (such as 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanecarboxylic acid, for example, LOPID® tablets sold by Parke Davis); ciprofibrate (registration No. C.A.S. (Chemical Abstracts journal database) 52214-84-3, see US Pat. No. 3,948,973, which is incorporated herein by reference); bezafibrate (registration number C.A.S. 41859-67-0, see US patent No. 3781328, which is incorporated into this invention by reference); clinofibrate (registration No. C.A.S. 30299-08-2, see US patent No. 3716583, which is incorporated into this invention by reference); binifibrate (Registration No. C.A.S. 69047-39-8, see BE 884722, which is incorporated herein by reference); liffrol (registration number C.A.S. 96609-16-4); fenofibrate (such as the finely divided fenofibrate TRICOR® (2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanecarboxylic acid 1-methylethyl ester) sold by Abbott Laboratories or the finely divided LIPANTHYLo® fenofibrate sold , France) and mixtures thereof. These compounds can be used in a variety of forms, including (without limitation) the acid form, salt form, racemates, enantiomers, zwitterions and tautomers.

Other examples of RAPPα activators suitable for use in the practice of the present invention include suitable fluorophenyl compounds disclosed in US Pat. No. 6,028,109, which is incorporated herein by reference; certain substituted phenylpropionic compounds, such as those disclosed in WO 00/75103, which is incorporated herein by reference; and RAPPα activator compounds disclosed in WO 98/43081, which is incorporated herein by reference.

Non-limiting examples of suitable RAPPγ activators suitable for use in the compositions of the present invention include suitable glitazone and thiazolidinedione derivatives such as troglitazone (such as troglitazone REZULIN® (5 - [[4- [3,4-dihydro-6-hydroxy- 2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione), sold by Parke-Davis); rosiglitazone (such as AVANDIA® rosiglitazone maleate (5 - [[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione, (Z) -2-butenedioate) (1 : 1) sold by SmithKline Beecham) and pioglitazone (such as ACTOS ™ pioglitazone hydrochloride (5 - [[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -2,4- ] thiazolidinedione monohydrochloride) sold by Takeda Pharmaceuticals). Other useful thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653, disclosed in WO 98/05331, which is incorporated herein by reference; RAPPγ activator compounds disclosed in WO 00/76488, which is incorporated herein by reference; and RAPPγ activator compounds disclosed in US Pat. No. 5,994,554, which is incorporated herein by reference.

Other useful RAPPγ activator compounds include some acetylphenols disclosed in US Pat. No. 5,859,051, which is incorporated herein by reference; certain quinolinophenyl compounds disclosed in WO 99/20275, which is incorporated herein by reference; aryl compounds disclosed in WO 99/38845, which is incorporated herein by reference; certain 1,4-disubstituted phenyl compounds disclosed in WO 00/63161; certain aryl compounds disclosed in WO 01/00579, which is incorporated herein by reference; benzoic acid derivatives disclosed in WO 01/12612 and WO 01/12187, which are incorporated herein by reference; and substituted 4-hydroxyphenylalkonic acid derivatives disclosed in WO 97/31907, which is incorporated herein by reference.

RAPP activator compounds δ are particularly suitable for lowering triglyceride concentrations or increasing HDL concentrations. Non-limiting examples of suitable activators of RAPPδ suitable for use in the compositions of the present invention include suitable thiazole and oxazole derivatives, such as the compound with registration No. C.A.S. 317318-32-4, disclosed in WO 01/00603, which is incorporated herein by reference); certain fluoro, chloro and thiophenoxyphenylacetic acids disclosed in WO 97/28149, which is incorporated herein by reference; suitable non-oxidizable β-position fatty acid analogues disclosed in US Pat. No. 5,093,365, which is incorporated herein by reference; and RAPP activator compounds δ disclosed in WO 99/04815, which is incorporated herein by reference.

In addition, in the compositions of the present invention, compounds which contain many functional groups activating various combinations of RAPPα, RAPPγ and RAPPδ are also suitable for use. Non-limiting examples include certain substituted aryl compounds, such as those disclosed in US Pat. No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, which are incorporated herein by reference, and are described as suitable activator compounds RAPPα and / or RAPPγ. Other non-limiting examples of useful RAPPα and / or RAPPγ activator compounds include activator compounds disclosed in WO 97/25042, which is incorporated herein by reference; activator compounds disclosed in WO 00/63190, which is incorporated herein by reference; activator compounds disclosed in WO 01/21181, which is incorporated herein by reference; biaryl oxa (thia) ash compounds disclosed in WO 01/16120, which is incorporated herein by reference; activator compounds disclosed in WO 00/63196 and WO 00/63209, which are incorporated herein by reference; substituted 5-aryl-2,4-thiazolidinediones disclosed in US patent No. 6008237, which is incorporated into this invention by reference; arylthiazolidinediones and aryloxazolidinediones disclosed in WO 00/78312 and WO 00 / 78313G, which are incorporated herein by reference; GW2331 or derivatives of (2- (4- [difluorophenyl] -1-heptylureido) ethyl] phenoxy) -2-methylbutyric acid disclosed in WO 98/05331, which is incorporated herein by reference; aryl compounds disclosed in US patent No. 6166049, which is incorporated into this invention by reference; oxazole derivatives disclosed in WO 01/17994, which is incorporated herein by reference; and dithiolane derivatives disclosed in WO 01/25225 and WO 01/25226, which are incorporated herein by reference.

Other useful RAPP activator compounds include substituted benzylthiazolidine-2,4-dione disclosed in WO 01/14349, WO 01/14350 and WO / 01/04351, which are incorporated herein by reference; mercaptocarboxyl compounds disclosed in WO 00/50392, which is incorporated herein by reference; ascofuranones disclosed in WO 00/53563, which is incorporated herein by reference; carboxyl compounds disclosed in WO 99/46232, which is incorporated herein by reference; compounds disclosed in WO 99/12534, which is incorporated herein by reference; benzene derivatives disclosed in WO 99/15520, which is incorporated herein by reference; o-anisamide derivatives disclosed in WO 01/21578, which is incorporated herein by reference; and RAPP activator compounds disclosed in WO 01/40192, which is incorporated herein by reference.

The activator (s) of the receptor (s) activated by the peroxisome proliferator, for the treatment of these pathological conditions, are administered in a therapeutically effective amount, for example, in a daily dose, which can be from about 0.1 to about 1000 mg / day, preferably in the range from about 0.25 to about 50 mg / day, and more preferably about 10 mg / day, administered as a single dose or 2-4 divided doses. However, the exact dose is determined by the attending physician and it depends on factors such as the activity of the administered compound, age, weight, condition and reaction of the patient.

The term “therapeutically effective amount” means an amount of a therapeutic drug contained in a composition, such as a peroxisome proliferator-activated receptor activator (s), sterol absorption inhibitor (s), and other pharmacological or therapeutic drugs described below that will provide a biological or medical tissue response, a system, of an animal or mammal, that the prescriber seeks to manifest (such as a researcher, doctor or veterinarian), including partial understanding the symptoms of a pathological condition or disease being treated, and preventing, slowing or stopping the progression of one or more pathological conditions, such as vascular pathological conditions, such as hyperlipidemia (e.g., atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and / or a decrease in plasma concentrations of sterol (sterols) (such as cholesterol).

When used in the present invention, “combination therapy” or “therapeutic combination” means the administration of two or more therapeutic drugs, such as a peroxisome proliferator activated receptor activator (s) and sterol absorption inhibitor (s), for preventing or treating a pathological condition for example, a vascular pathological condition such as hyperlipidemia (e.g. atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and / or a decrease in plasma concentrations of sterol (sterols) (such as cholesterol). As used herein, “vascular” means cardiovascular, cerebrovascular, and combinations thereof. Compositions, combinations, and preparations of the present invention can be administered by any suitable means that allows these compounds to interact with a site of exposure in the body, for example, in a plasma, liver, or small intestine of a mammal or human. Such administration includes coadministration of these therapeutic agents substantially simultaneously, such as in a single tablet or capsule having a constant ratio of the amounts of active ingredients, or in several, separate capsules for each therapeutic agent. Such administration also includes the use of each type of therapeutic drug in a consistent manner. In any case, treatment using combination therapy will lead to beneficial effects in the treatment of a pathological condition. A potential advantage of the combination therapy disclosed in the present invention may be a reduction in the required amount of a single therapeutic compound or the total total amount of therapeutic compounds that are effective in treating a pathological condition. Compared to the case of monotherapy, using a combination of therapeutic drugs can reduce the side effects of individual drugs, which can help patients to better adhere to the treatment regimen. In addition, you can choose therapeutic drugs that provide a wide range of additional effects or additional directions of exposure.

As shown above, the compositions, pharmaceutical compositions and therapeutic combinations of the present invention include one or more azetidinone derivatives or β-lactams, cholesterol 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 (without limitation) cholesterol, phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), 5α-stanols (such as cholestanol , 5α-campestanol, 5α-sitostanol) and mixtures thereof when administered to a mammal or human in a therapeutically effective (inhibiting absorption of sterol) amount.

In a preferred embodiment, sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (I):

or isomers of compounds of formula (I), or pharmaceutically acceptable salts or solvates of compounds of formula (I) or isomers of compounds of formula (I), or prodrug forms of compounds of formula (I) or isomers, salts or solvates of compounds of formula (I), where in the above above formula (I):

Ar ¹ and Ar ^{2 are} independently selected from the group consisting of aryl and R ⁴ -substituted aryl;

Ar ³ means aryl or R ⁵ -substituted aryl;

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

R and R ^{2 are} independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;

R ¹ 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 the group of values equal to 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 if p is 0 and r is 1, the sum of m, q, and n is 1, 2, 3, 4, or 5;

R ⁴ means 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 ) _1-5 OR ⁶ , - O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O ( CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ , -CH = CH-COOR ⁶ , -CF ₃ , -CN, -NO ₂ and halogen;

R ⁵ means 1-5 substituents independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , - COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent; and

R ⁹ means lower alkyl, aryl or lower alkyl containing an aryl substituent.

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

As used in the present invention, the terms “alkyl” or “lower alkyl” mean straight or branched alkyl chains containing from 1 to 6 carbon atoms, and “alkoxyl” in the same way means alkoxyl groups containing from 1 to 6 carbon atoms. Non-limiting examples of suitable lower alkyl groups include, for example, methyl, ethyl, propyl and butyl groups.

"Alkenyl" means a linear or branched carbon chain containing in the chain one or more double bonds, conjugated or non-conjugated. Similarly, "alkynyl" means a linear or branched carbon chain containing in the chain one or more triple bonds. If an alkyl, alkenyl or alkynyl chain connects two other groups and is therefore divalent, the terms alkylene, alkenylene and alkynylene are used.

“Cycloalkyl” means a saturated carbon ring containing from 3 to 6 carbon atoms, and “cycloalkylene” means a corresponding divalent ring in which the attachment positions to other groups include all positional isomers.

"Halogen" means fluorine, chlorine, bromine or iodine radicals.

“Aryl” means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

“Phenylene” means a divalent phenyl group, including ortho, meta, and para substitution.

A statement in which, for example, states that R, R ¹ , R ² and R ^{3 are} independently selected from the group of substituents, means that R, R ¹ , R ² and R ³ are independently selected, and also that when the groups R, R ¹ , R ² and R ³ are contained in the molecule more than once, they are independently selected (for example, if R is —OR ⁶ , where R ⁶ is hydrogen, then R ² can be —OR ⁶ in which R ⁶ means lower alkyl). Specialists in the art should understand that the size and shape of the substituent (s) will affect the number of substituents that may be contained in the molecule.

The compounds of the present invention possess at least one asymmetric carbon atom and it is therefore assumed that all isomers, including enantiomers, stereoisomers, rotational isomers, tautomers, racemates of compounds of formulas (I-XI) (if any) are part of the present invention. The present invention includes the d- and l-isomers, both in pure form and in a mixture, including racemic mixtures. The isomers can be obtained using conventional methods or by introducing into the reaction optically pure or enriched in any optical isomer starting materials, or by separating the isomers of the compounds of formulas I-XI. Isomers may include geometric isomers, for example, when a double bond is present.

Specialists in the art should understand that for some compounds of formulas I-XI, one isomer will have greater pharmacological activity than other isomers.

Compounds of the invention that contain an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of acids suitable for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other inorganic and carboxylic acids, well known to specialists in this field of technology . Salts are prepared by reacting the free base with the amount of acid needed to produce a salt. Free bases can be isolated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous sodium bicarbonate solution. The free bases differ slightly from the corresponding salts in some physical characteristics, such as solubility in polar solvents, but for the purposes of the present invention, the salts are equivalent to the corresponding free bases.

Some compounds of the present invention are acidic in nature (for example, compounds that contain a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are sodium, potassium, calcium, aluminum, gold and silver salts. It is also contemplated that the present invention encompasses salts formed with pharmaceutically acceptable amines, such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine, and the like.

As used in the present invention, “solvate” means a molecular or ionic complex of molecules or solvent ions with molecules or ions of a solute (for example, one or more compounds of formulas I-XI, isomers of compounds of formulas I-XI, or prodrug forms of compounds of formulas I- Xi). Non-limiting examples of suitable solvents include polar, protic solvents such as water and / or alcohols (e.g. methanol).

When used in the present invention, a “prodrug form" means compounds that are precursors of drugs that, after administration to a patient, release the drug in vivo through some chemical or physiological process (for example, the prodrug form under physiological pH or when converted by the enzyme dosage form).

Preferred compounds of formula (I) are those in which Ar ¹ is phenyl or R ⁴ -substituted phenyl, more preferably (4-R ⁴ ) -substituted phenyl. Ar ² preferably means phenyl or R ⁴ -substituted phenyl, more preferably - (4-R ⁴ ) -substituted phenyl. Ar ³ preferably means R ⁵ -substituted phenyl, more preferably - (4-R ⁵ ) -substituted phenyl. If Ar ¹ is (4-R ⁴ ) -substituted phenyl, then R ^{4 is} preferably halogen. If Ar ² and Ar ^{3 are} R ⁴ and R ^{5 are} substituted phenyl, respectively, then R ^{4 is} preferably halogen or —OR ⁶ and R ^{5 is} preferably —OR ⁶ , where R ⁶ is lower alkyl or hydrogen. Particularly preferred are compounds in which Ar ¹ and Ar ^{2 are} 4-fluorophenyl and Ar ³ is 4-hydroxyphenyl or 4-methoxyphenyl.

X, Y and Z are preferably —CH ₂ -. R ¹ and R ^{3 are} preferably hydrogen. R and R ^{2 are} preferably —OR ⁶ , where R ⁶ is hydrogen, or a group which is easily metabolized to hydroxyl (such as —O (CO) R ⁶ , —O (CO) OR ⁹ and —O (CO) NR ⁶ R ⁷ as defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. The preferred compounds are those in which m, n and r are zero, q is 1 and p is 2.

Also preferred are compounds of formula (I) in which p, q and n are zero, r is 1 and m is 2 or 3. More preferred are compounds in which m, n and r are zero, q is 1, p is 2, Z is —CH ₂ - and R is —OR ⁶ , especially if R ⁶ is hydrogen.

Also preferred are compounds of formula (I) wherein p, q and n are zero, r is 1, m is 2, X is —CH ₂ - and R ² is —OR ⁶ , especially if R ⁶ is hydrogen.

Another group of preferred compounds of formula (I) are those wherein Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl and Ar ³ is R ⁵ -substituted phenyl. Also preferred are compounds in which Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl and the sum of m, n, p, q and r is 2 , 3 or 4, more preferably 3. Compounds in which Ar ¹ is phenyl or R ⁴ -substituted phenyl, Ar ² is phenyl or R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, and in of which m, n and r are zero, q is 1 and p is 2, or where all p, q and n are zero, r is 1 and m is 2 or 3.

In a preferred embodiment of the invention, the sterol absorption inhibitor of formula (I), suitable for use in the compositions, therapeutic combinations and methods of the present invention, is a compound of the following formula (II) (ezetimibe):

or pharmaceutically acceptable salts or solvates of a compound of formula (II), or prodrug forms of a compound of formula (II) or salts or solvates of a compound of formula (II).

The compounds of formula I can be obtained in many ways well known to specialists in this field of technology, for example, such as described in US patent No. 5631365, 5767115, 5846966, 6207822, provisional application for US patent No. 60/279288, filed March 28, 2001 ., and PCT patent application WO 93/02048, which are incorporated herein by reference, and in the Example below. For example, usable compounds of formula I can be prepared by a process comprising the steps of:

(a) treating the lactone of formula A or B with a strong base:

where R 'and R ^2' mean R and R ² respectively or mean hydroxyl groups containing suitable protective groups; Ar ¹⁰ means Ar ¹ containing suitable protecting groups, hydroxy-substituted aryl or containing suitable protecting groups, amino-substituted aryl; and the remaining substituents are as defined above for formula I, provided that if the parameters n and r are zero in the lactone of formula B, then p is 1-4;

(b) introducing the product obtained in stage (a) into a reaction with an imine of the formula

where Ar ²⁰ means Ar ² containing suitable protecting groups, hydroxy-substituted aryl or containing suitable protecting groups, amino-substituted aryl; and Ar ³⁰ means Ar ³ containing suitable protecting groups, hydroxy-substituted aryl, or containing suitable protecting groups, amino-substituted aryl;

c) stopping the reaction with an acid;

d) optionally removing protecting groups from R ', R ^2' , Ar ¹⁰ , Ar ²⁰ and Ar ³⁰ , if any; and

e) optional functionalization of hydroxy or amino substituents at R, R ² , Ar ¹ , Ar ² and Ar ³ .

Using the above lactones, the following compounds of formulas IA and IB are prepared:

where the designations are as defined above; and

where the designations are as defined above.

Alternative sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (III):

or isomers of compounds of formula (III), or pharmaceutically acceptable salts or solvates of compounds of formula (III) or isomers of compounds of formula (III), or prodrug forms of compounds of formula (III) or isomers, salts or solvates of compounds of formula (III), where in the above above formula (III):

Ar ¹ means R ³ -substituted aryl;

Ar ² means R ⁴ -substituted aryl;

Ar ³ means R ⁵ -substituted aryl;

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

A is selected from the group consisting of —O—, —S—, —S (O) - or —S (O) ₂ -;

R ^{1 is} selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ^9, and —O (CO) NR ⁶ R ⁷ ;

R ² selected from the group comprising hydrogen, lower alkyl and aryl; or R ¹ and R ² together mean = O;

q is 1, 2 or 3;

p is 0, 1, 2, 3 or 4;

R ⁵ means 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 ⁹ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO _{2 -} lower alkyl, -NR ⁶ SO ₂ -aryl, -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (lower alkylene) -COOR ⁶ and -CH = CH-COOR ⁶ ;

R ³ and R ^{4 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of R ⁵ , hydrogen, p-lower alkyl, aryl, —NO ₂ , —CF _3, and p-halogen;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent; and R ⁹ is lower alkyl, aryl or lower alkyl containing an aryl substituent.

Preferred compounds of formula I include those in which Ar ¹ is R ³ -substituted phenyl, especially (4-R ³ ) -substituted phenyl. Ar ² preferably means R ⁴ -substituted phenyl, in particular (4-R ⁴ ) -substituted phenyl. Ar ³ preferably means R ⁵ -substituted phenyl, in particular (4-R ⁵ ) -substituted phenyl. Monosubstitution of all Ar ¹ , Ar ² and Ar ³ is preferred.

Y and Z are preferably —CH ₂ -. R ² preferably means hydrogen. R ¹ preferably means —OR ⁶ , where R ⁶ is hydrogen, or a group which is readily metabolized to hydroxyl (such as —O (CO) R ⁶ , —O (CO) OR ⁹ and —O (CO) NR ⁶ R ⁷ defined above). Also preferred are compounds in which R ¹ and R ² together mean = O.

The sum of q and p is preferably 1 or 2, more preferably 1. The preferred compounds are those in which p is zero and q is 1. The more preferred compounds are those in which p is zero, q is 1, Y is —CH ₂ - and R ¹ is —OR ⁶ , especially if R ⁶ is hydrogen.

Another group of preferred compounds are those in which Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl and Ar ³ is R ⁵ -substituted phenyl.

Also preferred are compounds in which Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, and the sum of p and q is 1 or 2, in particular 1. More preferred are compounds in which Ar ¹ is R ³ -substituted phenyl, Ar ² is R ⁴ -substituted phenyl, Ar ³ is R ⁵ -substituted phenyl, p is zero and q is 1.

A preferably means —O—.

R ³ preferably means —COOR ⁶ , —CONR ⁶ R ⁷ , —COR ⁶ , —SO ₂ NR ⁶ R ⁷ , S (O) _0-2 -alkyl, S (O) _0-2 -aryl, NO ₂ or halogen . A more preferred value of R ³ is halogen, in particular fluorine or chlorine.

R ⁴ preferably means hydrogen, lower alkyl, —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CO) NR ⁶ R ⁷ , —NR ⁶ R ⁷ , COR ⁶ or halogen, where R ⁶ and R ⁷ preferably independently mean hydrogen or lower alkyl, and R ⁹ preferably means lower alkyl. A more preferred value of R ⁴ is hydrogen or halogen, in particular fluorine or chlorine.

R ⁵ preferably means —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CO) NR ⁶ R ⁷ , —NR ⁶ R ⁷ , - (lower alkylene) —COOR ^6, or - CH = CH-COOR ⁶ , where R ⁶ and R ⁷ preferably independently mean hydrogen or lower alkyl, and R ⁹ preferably means lower alkyl. More preferred R ⁵ values are —OR ⁶ , - (lower alkylene) —COOR ⁶ or —CH = CH — COOR ⁶ , where R ^{6 is} preferably hydrogen or lower alkyl.

Methods for preparing compounds of formula III are well known to those skilled in the art. Non-limiting examples of suitable methods are described in US Pat. No. 5,688,990, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (IV):

or isomers of compounds of formula (IV), or pharmaceutically acceptable salts or solvates of compounds of formula (IV) or isomers of compounds of formula (IV), or prodrug forms of compounds of formula (IV) or isomers, salts or solvates of compounds of formula (IV), where in the above above formula (IV):

A is selected from the group consisting of R ² -substituted heterocycloalkyl, R ² -substituted heteroaryl, R ² -substituted heterocycloalkyl fused with a benzene ring and R ² -substituted heteroaryl fused with a benzene ring;

Ar ¹ means aryl or R ³ -substituted aryl;

Ar ² means aryl or R ⁴ -substituted aryl;

Q means a bond or forms a spiran group with the cyclic carbon atom in position 3 of azetidinone

and

R ¹ selected from the group including:

- (CH ₂ ) _q -, where q is 2-6 provided that if Q forms a spiran ring, then q can also be zero or 1;

- (CH ₂ ) _e -G- (CH ₂ ) _r -, where G is —O—, —C (O) -, phenylene, —NR ⁸ - or —S (O) _0-2 -, e is 0 -5 and r is 0-5, provided that the sum of e and r is 1-6;

- ((C ₂ -C ₆ ) alkenylene) -; and

- (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) cycloalkylene, f is 1-5 and g is 0-5 provided that the sum of f and g is 1- 6;

R ⁵ selected from the group including:

R ⁶ and R ^{7 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ⁵ together with neighboring R ⁶ , or R ⁵ together with neighboring R ⁷ form a —CH = CH— or —CH = C ((C ₁ –C ₆ ) alkyl) - group;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero; provided that if R ⁶ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1; with the proviso that if R ⁷ is —CH═CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1; provided that if a is 2 or 3, then R ⁶ may be the same or different; and provided that if b is 2 or 3, then R ⁷ may be the same or different;

and, if Q means a bond, then R ¹ can also be selected from the group including:

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

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

R ¹⁰ and R ^{12 are} independently selected from the group consisting of —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ¹⁶ and —O (CO) NR ¹⁴ R ¹⁵ ;

R ¹¹ and R ^{13 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl and aryl; or R ¹⁰ and R ¹¹ together mean = O, or R ¹² and R ¹³ together mean = O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1-6; provided that if p is 0 and t is 1, then the sum of m, s and n is 1-5; and provided that if p is 0 and s is 1, then the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5 provided that the sum of j, k and v is 1-5;

и, если R² является заместителем у замещаемого атома азота цикла, то он означает водород, (С₁-С₆)алкил, арил, (С₁-С₆)алкоксил, арилоксил, (С₁-С₆)алкилкарбонил, арилкарбонил, гидроксил, -(CH₂)_1-6CONR¹⁸R¹⁸,R ² means 1-3 substituents on cyclic carbon atoms selected from the group consisting of hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, (C ₃ - C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkenyl, R ¹⁷ -substituted aryl, R ¹⁷ -substituted benzyl, R ¹⁷ -substituted benzyloxyl, R ¹⁷ -substituted aryloxyl, halogen, -NR ¹⁴ R ¹⁵ , NR ¹⁴ R ¹⁵ ((C ₁ -C ₆ ) alkylene) -, NR ¹⁴ R ¹⁵ C (O) ((C ₁ -C ₆ ) alkylene) -, -NHC (O) R ¹⁶ , OH, (C ₁ -C ₆ ) alkoxyl , -OC (O) R ¹⁶ , -COR ¹⁴ , hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, NO ₂ , -S (O) _{0- 2} R ¹⁶ , —SO ₂ NR ¹⁴ R ¹⁵ and - ((C ₁ -C ₆ ) alkylene) COOR ¹⁴ ; if R ² is a heterocycloalkyl ring substituent, then R ² is as defined, or is = O or

and, if R ² is a substituent on the substituted nitrogen atom of the ring, then it means hydrogen, (C ₁ -C ₆ ) alkyl, aryl, (C ₁ -C ₆ ) alkoxyl, aryloxy, (C ₁ -C ₆ ) alkylcarbonyl, arylcarbonyl hydroxyl, - (CH ₂ ) _1-6 CONR ¹⁸ R ¹⁸ ,

where J is —O—, —NH—, —NR ¹⁸ - or —CH ₂ -;

R ³ and R ^{4 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁴ , —O (CO) R ¹⁴ , —O (CO) OR ¹⁶ , -O (CH ₂ ) _1-5 OR ¹⁴ , -O (CO) NR ¹⁴ R ¹⁵ , -NR ¹⁴ R ¹⁵ , -NR ¹⁴ (CO) R ¹⁵ , -NR ¹⁴ (CO) OR ¹⁶ , -NR ¹⁴ (CO) NR ¹⁵ R ¹⁹ , -NR ¹⁴ SO ₂ R ¹⁶ , -COOR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -COR ¹⁴ , -SO ₂ NR ¹⁴ R ¹⁵ , S (O) _0-2 R ¹⁶ , -O (CH ₂ ) _1-10 -COOR ¹⁴ , -O (CH ₂ ) _1-10 CONR ¹⁴ R ¹⁵ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁴ , -CH = CH-COOR ¹⁴ , -CF ₃ , —CN, —NO ₂ and halogen;

R ⁸ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁴ or —COOR ¹⁴ ;

R ⁹ and R ¹⁷ independently mean 1-3 groups independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁴ R ¹⁵ , OH and halogen;

R ¹⁴ and R ^{15 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ¹⁶ means (C ₁ -C ₆ ) alkyl, aryl or R ¹⁷ -substituted aryl;

R ¹⁸ means hydrogen or (C ₁ -C ₆ ) alkyl; and

R ¹⁹ means hydrogen, hydroxyl or (C ₁ -C ₆ ) alkoxyl.

When used in the above formula (IV), “A” preferably means an R ² -substituted, 6-membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred heterocycloalkyl rings are piperidinyl, piperazinyl and morpholinyl groups. Preferably, ring “A” is connected to the phenyl ring via a cyclic nitrogen atom. Preferred R ² substituents are hydrogen and lower alkyl. R ¹⁹ preferably means hydrogen.

Ar ² preferably means phenyl or R ⁴ phenyl, in particular (4-R ⁴ ) substituted phenyl. Preferred R ⁴ values are lower alkoxyl, in particular methoxy, and halogen, in particular fluorine.

Ar ¹ preferably means phenyl or R ³ -substituted phenyl, in particular (4-R ³ ) -substituted phenyl.

There are several preferred meanings for the combination of —R ¹ —Q— groups:

Q is a bond and R ¹ is lower alkylene, preferably propylene;

Q is a spiran group as defined above, wherein it is preferred that R ⁶ and R ^{7 are} ethylene and R ^{5 is}

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —O — CH ₂ —CH (OH) -;

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —CH (OH) - (CH ₂ ) ₂ -; and

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —CH (OH) —CH ₂ —S (O) _0-2 -.

Methods for preparing compounds of formula IV are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Pat. No. 5,656,624, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (V):

or isomers of compounds of formula (V), or pharmaceutically acceptable salts or solvates of compounds of formula (V) or isomers of compounds of formula (V), or prodrug forms of compounds of formula (V) or isomers, salts or solvates of compounds of formula (V), where in the above above formula (V):

Ar ¹ means aryl, R ¹⁰ -substituted aryl or heteroaryl;

Ar ² means aryl or R ⁴ -substituted aryl;

Ar ³ means aryl or R ⁵ -substituted aryl;

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

R is —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ or —O (CO) NR ⁶ R ⁷ ; R ¹ means hydrogen, lower alkyl or aryl; or R and R ¹ together mean = O;

q is 0 or 1;

r is 0, 1 or 2;

m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5;

R ⁴ means 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 ) _1-5 OR ⁶ -, -O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , - (lower alkylene) COOR ⁶ and -CH = CH-COOR ⁶ ;

R ⁵ means 1-5 substituents independently selected from the group consisting of —OR ⁶ , —O (CO) R ⁶ , —O (CO) OR ⁹ , —O (CH ₂ ) _1-5 OR ⁶ , —O (CO ) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , - COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH ₂ ) _1-10 CONR ⁶ R ⁷ , —CF ₃ , —CN, —NO ₂ , halogen, - (lower alkylene) COOR ⁶ and —CH = CH — COOR ⁶ ;

R ⁶ , R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl containing an aryl substituent;

R ⁹ means lower alkyl, aryl or lower alkyl containing an aryl substituent; and

R ¹⁰ means 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 ) _1-5 OR ⁶ , - O (CO) NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -NR ⁶ (CO) R ⁷ , -NR ⁶ (CO) OR ⁹ , -NR ⁶ (CO) NR ⁷ R ⁸ , -NR ⁶ SO ₂ R ⁹ , -COOR ⁶ , -CONR ⁶ R ⁷ , -COR ⁶ , -SO ₂ NR ⁶ R ⁷ , -S (O) _0-2 R ⁹ , -O (CH ₂ ) _1-10 -COOR ⁶ , -O (CH _{2) 1-10} CONR ⁶ R ^7, - CF _3, -CN, -NO ₂ and halogen;

Of the systems described by Formula V, two preferred structures are included. In the formula VA q is equal to zero and the remaining parameters are as defined above, and in the formula VB q is 1 and the remaining parameters are as defined above:

all R ⁴ , R ⁵ and R ¹⁰ preferably mean 1–3 independently selected substituents, as indicated above. Preferred are compounds of formula (V) in which Ar ¹ is phenyl, R ^{10 is} substituted phenyl or thienyl, especially (4-R ¹⁰ ) is substituted phenyl or thienyl. Ar ² preferably means R ⁴ -substituted phenyl, in particular (4-R ⁴ ) -substituted phenyl. Ar ³ preferably means phenyl or R ⁵ -substituted phenyl, in particular (4-R ⁵ ) -substituted phenyl. If Ar ¹ is R ¹⁰ -substituted phenyl, then R ^{10 is} preferably halogen, especially fluorine. If Ar ² is R ⁴ -substituted phenyl, then R ^{4 is} preferably —OR ⁶ , especially if R ⁶ is hydrogen or lower alkyl. If Ar ³ is R ⁵ -substituted phenyl, then R ^{5 is} preferably halogen, especially fluorine. Particularly preferred are compounds of formula (V) in which Ar ¹ is phenyl, 4-fluorophenyl or thienyl, Ar ² is 4- (alkoxy or hydroxy) phenyl and Ar ³ is phenyl or 4-fluorophenyl.

X and Y are preferably —CH ₂ -. The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. If q is 1, then n is preferably 1 to 5.

Preferred values of X, Y, Ar ¹ , Ar ² and Ar ³ in formulas (VA) and (VB) are the same.

In the compounds of formula (VA), the sum of m and n is preferably 2, 3 or 4, more preferably 2. The compounds in which the sum of m and n is 2 and r is 0 or 1 are also preferred.

In the compounds of formula (VB), the sum of m and n is preferably 1, 2 or 3, more preferably 1. In particular, compounds in which m is zero and n is 1. R ^{1 is} preferably hydrogen and R is preferably OR ⁶ where R ⁶ is hydrogen, or a group that is readily metabolized to hydroxyl (such as —O (CO) R ⁶ , —O (CO) OR ⁹ and —O (CO) NR ⁶ R ⁷ as defined above), or R and R ¹ together form a group = O.

Methods for preparing compounds of formula V are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US patent No. 5624920, which is incorporated into this invention by reference.

In another embodiment, sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (VI):

or isomers of compounds of formula (VI), or pharmaceutically acceptable salts or solvates of compounds of formula (VI) or isomers of compounds of formula (VI), or prodrug forms of compounds of formula (VI) or isomers, salts or solvates of compounds of formula (VI), where

R ₁ means

R ₂ and R _{3 are} independently selected from the group consisting of:

-CH ₂ -, -CH (lower alkyl) -, -C (di- (lower alkyl)) -, -CH = CH- and -C (lower alkyl) = CH-; or R ₁ together with the neighboring R ₂ , or R ₁ together with the neighboring R ₃ form the group —CH = CH— or —CH = C (lower alkyl) -;

u and v are independently 0, 1, 2, or 3, provided that they are both non-zero; with the proviso that if R ₂ is —CH═CH— or —C (lower alkyl) = CH—, then v is 1; provided that if R ₃ means —CH = CH— or —C (lower alkyl) = CH—, then u is 1; provided that if v is 2 or 3, then R ₂ may be the same or different; and provided that if u is 2 or 3, then R ₃ may be the same or different;

R _{4 is} selected from the group consisting of B- (CH ₂ ) _m C (O) -, where m is 0, 1, 2, 3, 4, or 5; B- (CH ₂ ) _q -, where q is 0, 1, 2, 3, 4, 5, or 6; B- (CH ₂ ) _e -Z- (CH ₂ ) _r -, where Z is —O—, —C (O) -, phenylene, —N (R ₈ ) - or —S (O) _0-2 - , e is 0, 1, 2, 3, 4, or 5, and r is 0, 1, 2, 3, 4, or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5, or 6 ; B - ((C ₂ -C ₆ ) alkenylene) -; B - ((C ₄ -C ₆ ) alkadienylene) -; B- (CH ₂ ) _t -Z - ((C ₂ -C ₆ ) alkenylene) -, where Z is as defined above, and where t is 0, 1, 2 or 3, provided that the sum of t and the amount carbon atoms in the alkenylene chain is 2, 3, 4, 5, or 6; B- (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) 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- (CH ₂ ) _t -V - ((C ₂ -C ₆ ) alkenylene) - or B - ((C ₂ -C ₆ ) alkenylene) -V- (CH ₂ ) _t -, where V and t are such 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- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d -, where 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; and T- (CH ₂ ) _s -, where T is cycloalkyl with 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or R ₁ and R ₄ together form a group

In the group selected from the group consisting of indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl, or W-substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxynyl, thienyl, oxynyl and for nitrogen-containing heterocycles, their N-oxides, or

в качестве заместителя для циклических атомов углерода, и заместители замещенных атомов азота гетероарильного кольца, если они имеются, выбраны из группы, включающей низший алкил, низший алкоксил, -C(O)OR₁₀, -C(O)R₁₀, ОН, N(R₈)(R₉)-низший алкилен-, N(R₈)(R₉)-низший алкиленилоксил-, -S(O)₂NH₂ и 2-(триметилсилил)-этоксиметил;W means 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkanedioyl, lower alkyl, lower alkanediyl —CF ₃ , —OCF ₃ , benzyl, R ₇ -benzyl, benzyloxy, R _7- benzyloxy, phenoxyl, R ₇ -phenoxyl, dioxolanyl, NO ₂ , -N (R ₈ ) (R ₉ ), N (R ₈ ) (R ₉ ) lower alkylene-, N (R ₈ ) (R ₉ ) lower alkylenyloxy-, OH, halogen, —CN, —N ₃ , —NHC (O) OR ₁₀ , —NHC (O) R ₁₀ , R ₁₁ O ₂ SNH-, (R ₁₁ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) _0-2 R ₈ , tert-butyldimethylsilyloxy tyl, -C (O) R ₁₂ , -COOR ₁₉ , -CON (R ₈ ) (R ₉ ), -CH = CHC (O) R ₁₂ , lower alkylene-C (O) R ₁₂ , R ₁₀ C ( O) (lower alkylenyloxy) -, N (R ₈ ) (R ₉ ) C (O) (lower alkylenyloxy) - and

as a substituent for cyclic carbon atoms, and substituents of substituted heteroaryl ring nitrogen atoms, if any, are selected from the group consisting of lower alkyl, lower alkoxyl, —C (O) OR ₁₀ , —C (O) R ₁₀ , OH, N (R ₈ ) (R ₉ ) lower alkylene-, N (R ₈ ) (R ₉ ) lower alkyleneyloxy-, -S (O) ₂ NH ₂ and 2- (trimethylsilyl) ethoxymethyl;

R ₇ means 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxyl, —COOH, NO ₂ , —N (R ₈ ) (R ₉ ), OH, and halogen;

R ₈ and R _{9 are} independently selected from the group consisting of H and lower alkyl;

R _{10 is} selected from the group consisting of lower alkyl, phenyl, R ₇ -phenyl, benzyl or R ₇ -benzyl;

R _{11 is} selected from the group consisting of OH, lower alkyl, phenyl, benzyl, R _{7 is} phenyl or R _{7 is} benzyl;

R _{12 is} selected from the group consisting of H, OH, alkoxyl, phenoxyl, benzyloxyl,

-N (R ₈ ) (R ₉ ), lower alkyl, phenyl or R _{7 is} phenyl;

R _{13 is} selected from the group consisting of —O—, —CH ₂ -, —NH—, —N (lower alkyl) - or —NC (O) R ₁₉ ;

R ₁₅ , R ₁₆ and R _{17 are} independently selected from the group consisting of H and the groups indicated in the definition of W; or R ₁₅ is hydrogen and R ₁₆ and R _17, together with the adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

R ₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and

R ₂₀ and R _{21 are} independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl condensed with a benzene ring, heteroaryl, W-substituted condensed with a benzene ring heteroaryl and cyclopropyl, where heteroaryl is as defined above.

One group of preferred compounds of formula VI are those compounds wherein R _{21 is} selected from the group consisting of phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, or cyclopropyl, where W is lower alkyl, lower alkoxyl, OH, halogen, -N (R ₈ ) (R ₉ ), -NHC (O) OR ₁₀ , -NHC (O) R ₁₀ , NO ₂ , -CN, -N ₃ , -SH, -S ( O) _0-2 - (lower alkyl), —COOR ₁₉ , —CON (R ₈ ) (R ₉ ), —COR ₁₂ , phenoxyl, benzyloxy, —OCF ₃ , —CH = C (O) R ₁₂ or tert- butyldimethylsilyloxy, where R ₈ , R ₉ , R ₁₀ , R ₁₂ and R ₁₉ are as defined for formula IV. If W is 2 or 3 substituents, then the substituents may be the same or different.

Another group of preferred compounds of formula VI are those compounds wherein R ₂₀ is phenyl or W-substituted phenyl, wherein preferred values of W are as defined above for preferred values of R ₂₁ .

More preferred are compounds of formula VI in which R ₂₀ is phenyl or W-substituted phenyl and R ₂₁ is phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; where W is lower alkyl, lower alkoxyl, OH, halogen, —N (R ₈ ) (R ₉ ), —NHC (O) OR ₁₀ , —NHC (O) R ₁₀ , NO ₂ , —CN, —N ₃ , —SH, —S (O) _0-2 - (lower alkyl), —COOR ₁₉ , —CON (R ₈ ) (R ₉ ), —COR ₁₂ , phenoxyl, benzyloxyl, —CH = CHC (O) R ₁₂ , —OCF ₃ or tert-butyldimethylsilyloxy, where if W is OCF ₃ or tert-butyldimethylsilyloxy, where if W is 2 or 3 substituents, then the substituents may be the same or different, and where R ₈ , R ₉ , R ₁₀ , R ₁₂ and R ₁₉ are as defined for formula VI.

или

.Also preferred are compounds of formula VI in which R ₁ means

or

.

Another group of preferred compounds of formula VI are those compounds in which R ₂ and R _{3 are} —CH ₂ and the sum of u and v is 2, 3 or 4, with u = v = 2 being more preferred.

R ₄ preferably means B- (CH ₂ ) _q - or B- (CH ₂ ) _e -Z- (CH ₂ ) _r -, where B, Z, q, e and r are as defined above. In preferably means

where R ₁₆ and R ₁₇ mean hydrogen and where R ₁₅ preferably means H, OH, lower alkoxyl, in particular methoxyl, or halogen, in particular chlorine.

Preferably, when Z is —O—, e is 0, and r is 0.

Preferably, when q is 0-2.

R ₂₀ preferably means phenyl or W-substituted phenyl.

Preferred W substituents for R ₂₀ are lower alkoxyls, especially methoxyl and ethoxyl, OH and —C (O) R ₁₂ , where R _{12 is} preferably lower alkoxyl.

Preferably, R _{21 is} selected from the group consisting of phenyl, lower alkoxy-substituted phenyl and F-phenyl.

или

, R₂ и R₃ означают -СН₂-, u=v=2, R₄ означает B-(CH₂)_q-, где В означает фенил или фенил, замещенный низшим алкоксилом или хлором, q равно 0-2, R₂₀ означает фенил, ОН-фенил, (низший алкоксил)-замещенный фенил или (низший алкоксилкарбонил)-замещенный фенил, и R₂₁ означает фенил, (низший алкоксил)-замещенный фенил или F-фенил.Particularly preferred are compounds of formula VI in which R ₁ means

or

, R ₂ and R _{3 are} —CH ₂ -, u = v = 2, R ₄ is B- (CH ₂ ) _q -, where B is phenyl or phenyl substituted with lower alkoxyl or chloro, q is 0-2, R ₂₀ is phenyl, OH-phenyl, (lower alkoxy) substituted phenyl or (lower alkoxycarbonyl) substituted phenyl, and R ₂₁ is phenyl, (lower alkoxy) substituted phenyl or F-phenyl.

Methods for preparing compounds of formula VI are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Pat. No. 5,698,548, which is incorporated herein by reference.

In another embodiment, sterol absorption inhibitors suitable for use in the compositions, therapeutic combinations and methods of the present invention are compounds of the following formula (VII):

or isomers of compounds of formula (VII), or pharmaceutically acceptable salts or solvates of compounds of formula (VII) or isomers of compounds of formula (VII), or prodrug forms of compounds of formula (VII) or isomers, salts or solvates of compounds of formula (VII), where in the above above formula (VII):

And means -CH = CH-, -C≡C- or - (CH ₂ ) _p -, where p is 0, 1 or 2;

B means

E means alkyl from C ₁₀ to C ₂₀ or —C (O) - (C ₉ to C ₁₉ ) -alkyl, where the alkyl is linear or branched, saturated or containing one or more double bonds;

R is hydrogen, (C ₁ -C ₁₅ ) alkyl, linear or branched, saturated or containing one or more double bonds, or B- (CH ₂ ) _r -, where r is 0, 1, 2 or 3;

R ₁ , R ₂ , and R _{3 are} independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxyl, carboxyl, NO ₂ , NH ₂ , OH, halogen, (lower alkyl) amino group, (di- (lower alkyl)) an amino group, -NHC (O) OR ₅ , R ₆ O ₂ SNH- and -S (O) ₂ NH ₂ ;

R ₄ means

where n is 0, 1, 2 or 3;

R ₅ means lower alkyl; and

R ₆ means OH, lower alkyl, phenyl, benzyl or substituted phenyl, in which the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxyl, carboxyl, NO ₂ , NH ₂ , OH, halogen, (lower an alkyl) amino group and (di- (lower alkyl)) an amino group.

Preferred compounds of formula (VII) are those in which R is hydrogen, methyl, ethyl, phenyl or phenylpropyl. Another group of preferred compounds of formula (VII) are those wherein R ₄ is p-methoxyphenyl or 2,4,6-trimethoxyphenyl. Another group of preferred compounds of formula (VII) are compounds in which A is ethylene or a bond. Another group of preferred compounds of formula (VII) are compounds in which E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably, R ₁ , R ₂ and R _{3 are} hydrogen.

More preferred are those compounds of formula (VII) in which R is hydrogen, methyl, ethyl, phenyl or phenylpropyl; R ₄ means p-methoxyphenyl or 2,4,6-trimethoxyphenyl; A means ethylene or a bond; E is decyl, oleoyl or 7-Z-hexadecenyl; and R ₁ , R ₂ and R _{3 are} hydrogen.

Preferred are those compounds of formula (VII) in which E is decyl, R is hydrogen, BA is phenyl and R ₄ is p-methoxyphenyl.

In another embodiment, sterol inhibitors suitable for use in the compositions and methods of the present invention are compounds of formula (VIII):

or isomers of compounds of formula (VIII), or pharmaceutically acceptable salts or solvates of compounds of formula (VIII) or isomers of compounds of formula (VIII), or prodrug forms of compounds of formula (VIII) or isomers, salts or solvates of compounds of formula (VIII), where in the above above formula (VIII):

R ²⁶ means H or OG ¹ ;

G and G ^{1 are} independently selected from the group including

H

with the proviso that if R ²⁶ is H or OH, G is not H;

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl and —WR ³⁰ ;

W is independently selected from the group consisting of —NH — C (O) -, —O — C (O) -, —O — C (O) —N (R ³¹ ) -, —NH — C (O) —N ( R ³¹ ) - and -OC (S) -N (R ³¹ ) -;

R ² and R ^{6 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^{4a are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) ( C ₁ -C ₆ ) alkyl and -C (O) aryl;

R ^{30 is} selected from the group consisting of R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl;

R ^{31 is} selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;

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

R ^{32 is} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of halogen, (C ₁ -C ₄ ) alkyl, —OH, phenoxyl, —CF ₃ , —NO ₂ , (C ₁ —C ₄ ) alkoxy, methylenedioxy, oxo, (C ₁ -C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O) - (C ₁ -C ₄ ) alkyl, -C (O) - (C ₁ -C ₄ ) alkoxyl and pyrrolidinylcarbonyl; or R ³² is a covalent bond and R ³¹ , the nitrogen atom to which it is attached, and R ³² form a pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group, or a (C ₁ -C ₄ ) alkoxycarbonyl substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group;

Ar ¹ means aryl or R ¹⁰ -substituted aryl;

Ar ² means aryl or R ¹¹ -substituted aryl;

Q means a bond or forms a spiran group with the cyclic carbon atom in position 3 of azetidinone

R ^{1 is} selected from the group consisting of - (CH ₂ ) _q -, where q is 2-6, provided that if Q forms a spiran ring, then q can also be zero or 1; - (CH ₂ ) _e —E— (CH ₂ ) _r -, where E is —O—, —C (O) -, phenylene, —NR ²² - or —S (O) _0-2 -, e is 0 -5 and r is 0-5, provided that the sum of e and r is 1-6; - (C ₂ -C ₆ ) alkenylene-; and - (CH ₂ ) _f -V- (CH ₂ ) _g -, where V is (C ₃ -C ₆ ) cycloalkylene, f is 1-5 and g is 0-5 provided that the sum of f and g is 1 -6;

R ¹² means

R ¹³ and R ^{14 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ¹² together with the neighboring R ¹³ , or R ¹² together with the neighboring R ¹⁴ form a group —CH = CH— or —CH = C ((C ₁ -C ₆ ) alkyl) -;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero;

provided that if R ¹³ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1;

provided that if R ¹⁴ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1;

provided that if a is 2 or 3, then R ¹³ may be the same or different; and provided that if b is 2 or 3, then R ¹⁴ may be the same or different;

and, if Q means a bond, then R ¹ may also mean:

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

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

R ¹⁰ and R ^{11 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O (CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , —CN, —NO ₂ and halogen;

R ¹⁵ and R ^{17 are} independently selected from the group consisting of —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ^21, and —O (CO) NR ¹⁹ R ²⁰ ;

R ¹⁶ and R ^{18 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and aryl;

or R ¹⁵ and R ¹⁶ together mean = O, or R ¹⁷ and R ¹⁸ together mean = O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;

provided that at least one of s and t is 1 and the sum of m, n, p, s and t is 1-6;

provided that if p is 0 and t is 1, then the sum of m, s and n is 1-5; and provided that if p is 0 and s is 1, then the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5 provided that the sum of j, k and v is 1-5;

and if Q means a bond and R ¹ means

then Ar ¹ may also mean 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, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ²¹ means (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;

R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;

R ²³ and R ²⁴ independently mean 1-3 groups independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁹ R ²⁰ , -OH and halogen; and

R ²⁵ means H, -OH or (C ₁ -C ₆ ) alkoxyl.

Ar ² preferably means phenyl or R ^{11 is} phenyl, in particular (4-R ¹¹ ) substituted phenyl. Preferred R ¹¹ values are lower alkoxyl, in particular methoxy, and halogen, in particular fluorine.

Ar ¹ preferably means phenyl or R ¹⁰ -substituted phenyl, in particular (4-R ¹⁰ ) -substituted phenyl. A preferred value of R ¹⁰ is halogen, more preferably fluorine.

There are several preferred meanings for the combination of —R ¹ —Q— groups:

Q is a bond and R ¹ is lower alkylene, preferably propylene;

Q is a spiran group as defined above, wherein it is preferred that R ¹³ and R ^{14 are} ethylene and R ^{12 is}

and R ¹ is - (CH ₂ ) _q , where q is 0-6;

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —O — CH ₂ —CH (OH) -;

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —CH (OH) - (CH ₂ ) ₂ -; and

Q means a bond and R ¹ means

wherein the substituents are selected so that R ^{1 is} —CH (OH) —CH ₂ —S (O) _0-2 -.

Therefore, a preferred compound of formula (VIII) is a compound in which G and G ¹ are as defined above, and in which the remaining substituents have the following meanings:

Ar ¹ is phenyl or R ^{10 is} substituted phenyl, where R ¹⁰ is halogen;

Ar ² is phenyl or R ^{11 is} phenyl, where R ¹¹ is 1 to 3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkoxyl and halogen;

Q is a bond and R ¹ is lower alkylene; Q with a cyclic carbon atom in position 3 of azetidinone forms a group

where it is preferred that R ¹³ and R ^{14 are} ethylene and a and b are 1, and where R ¹² is

Q is a bond and R ¹ is —O — CH ₂ —CH (OH) -; Q is a bond and R ¹ is —CH (OH) - (CH ₂ ) ₂ -; or Q is a bond and R ¹ is —CH (OH) —CH ₂ —S (O) _0-2 -.

The preferred values of the groups G or G ¹ in the formula:

are the following:

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl.

The preferred values of the groups G or G ¹ in the formula:

are the following:

R ³ , R ^3a , R ⁴ and R ^4a are selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl;

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl, and —WR ³⁰ , where W is —O — C (O) - or —OC (O) —NR ³¹ -, R ³¹ is H and R ³⁰ is (C ₁ -C ₆ ) alkyl, —C (O) - (C ₁ -C ₄ ) alkoxy - (C ₁ -C ₆ ) alkyl, T, T- (C ₁ -C ₆ ) alkyl, or T or T- (C ₁ -C ₆ ) alkyl, where T contains one or two halogens or (C ₁ -C ₆ ) alkyl groups.

Preferred R ³⁰ substituents are selected from the group consisting of 2-fluorophenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxycarbonylethyl, thiazol-2-ylmethyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl.

Preferred combinations of R, R ^a and R ^b are as follows:

1) R, R ^a and R ^b independently mean —OH or —OC (O) —NH — R ³⁰ , in particular if R ^a means —OH and R and R ^b mean —OC (O) —NH — R ³⁰ and R ^{30 is} selected from the group of preferred substituents described above, or if R and R ^{a are} —OH and R ^b is —OC (O) —NH — R ³⁰ , where R ³⁰ is 2-fluorophenyl, 2,4-difluorophenyl, 2 6-dichlorophenyl;

2) R ^a means —OH, halogen, azido group or (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy, R ^b means H, halogen, azido group or (C ₁ -C ₆ ) alkoxy (C ₁ —C ₆ ) alkoxy, and R is —OC (O) —NH — R ³⁰ , in particular compounds in which R ^a is —OH, R ^b is H and R ³⁰ is 2-fluorophenyl;

3) R, R ^a and R ^b independently mean —OH or —OC (O) —R ³⁰ and R ³⁰ means (C ₁ -C ₆ ) alkyl, T, or T, containing one or two halogens as substituents or ( C ₁ -C ₆ ) alkyl groups, especially compounds in which R is —OH and R ^a and R ^{b are} —OC (O) —R ³⁰ , where R ³⁰ is 2-furyl; and

4) R, R ^a and R ^b independently mean —OH or halogen. Three additional classes of preferred compounds are those in which the oxy group at the anomeric C ^{1 ′} atom is in beta configuration, in which the oxy group at the anomeric C ^{2 ′} atom is in beta configuration, and in which the R group is in alpha configuration.

G and G ^{1 are} preferably selected from the group including:

where Ac is acetyl and Ph is phenyl.

Preferably, R ^{26 is} H or OH, more preferably N. It is preferred that the —OG substituent is in position 4 of the phenyl ring to which it is attached.

In another embodiment, sterol inhibitors suitable for use in the compositions and methods of the present invention are compounds of the following formula (IX):

or isomers of compounds of formula (IX), or pharmaceutically acceptable salts or solvates of compounds of formula (IX) or isomers of compounds of formula (IX), or prodrug forms of compounds of formula (IX) or isomers, salts or solvates of compounds of formula (IX), where in the above above formula (IX):

R ^{26 is} selected from the group including:

a) OH;

b) OCH ₃ ;

c) fluorine and

d) chlorine.

R ¹ selected from the group including

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl and —WR ³⁰ ;

W is independently selected from the group consisting of —NH — C (O) -, —O — C (O) -, —O — C (O) —N (R ³¹ ) -, —NH — C (O) —N ( R ³¹ ) - and -OC (S) -N (R ³¹ ) -;

R ² and R ^{6 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ³ , R ⁴ , R ⁵ , R ⁷ , R ^3a and R ^{4a are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, -C (O) ( C ₁ -C ₆ ) alkyl and -C (O) aryl;

R ^{30 is} independently selected from the group consisting of R ³² -substituted T, R ³² -substituted-T- (C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₂ -C ₄ ) alkenyl, R ³² -substituted- ( C ₁ -C ₆ ) alkyl, R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl and R ³² -substituted- (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl;

R ^{31 is} independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl;

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

R ^{32 is} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of H, halogen, (C ₁ -C ₄ ) alkyl, —OH, phenoxyl, —CF ₃ , —NO ₂ , (C ₁ —C ₄ ) alkoxyl, methylenedioxy, oxo group, (C ₁ -C ₄ ) alkylsulfanyl, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, -N (CH ₃ ) ₂ , -C (O) -NH (C ₁ -C ₄ ) alkyl, -C (O) -N ((C ₁ -C ₄ ) alkyl) ₂ , -C (O) - (C ₁ -C ₄ ) alkyl, -C (O) - ( C ₁ -C ₄ ) alkoxyl and pyrrolidinylcarbonyl; or R ³² is a covalent bond and R ³¹ , the nitrogen atom to which it is attached, and R ³² form a pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group, or a (C ₁ -C ₄ ) alkoxycarbonyl substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group;

Ar ¹ means aryl or R ¹⁰ -substituted aryl;

Ar ² means aryl or R ¹¹ -substituted aryl;

Q means - (CH ₂ ) _q -, where q is 2-6, or with a cyclic carbon atom in position 3 of azetidinone forms a spiran group

R ¹² means

R ¹³ and R ^{14 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 ((C ₁ -C ₆ ) alkyl) = CH—; or R ¹² together with the neighboring R ¹³ , or R ¹² together with the neighboring R ¹⁴ form a group —CH = CH— or —CH = C ((C ₁ -C ₆ ) alkyl) -;

a and b are independently 0, 1, 2, or 3, provided that they are both non-zero; provided that if R ¹³ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then a is 1; provided that if R ¹⁴ means —CH = CH— or —C ((C ₁ -C ₆ ) alkyl) = CH—, then b is 1; provided that if a is 2 or 3, then R ¹³ may be the same or different; and provided that if b is 2 or 3, then R ¹⁴ may be the same or different;

R ¹⁰ and R ^{11 are} independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, —OR ¹⁹ , —O (CO) R ¹⁹ , —O (CO) OR ²¹ , -O (CH ₂ ) _1-5 OR ¹⁹ , -O (CO) NR ¹⁹ R ²⁰ , -NR ¹⁹ R ²⁰ , -NR ¹⁹ (CO) R ²⁰ , -NR ¹⁹ (CO) OR ²¹ , -NR ¹⁹ (CO) NR ²⁰ R ²⁵ , -NR ¹⁹ SO ₂ R ²¹ , -COOR ¹⁹ , -CONR ¹⁹ R ²⁰ , -COR ¹⁹ , -SO ₂ NR ¹⁹ R ²⁰ , S (O) _0-2 R ²¹ , -O (CH ₂ ) _1-10 -COOR ¹⁹ , -O (CH ₂ ) _1-10 CONR ¹⁹ R ²⁰ , - ((C ₁ -C ₆ ) alkylene) -COOR ¹⁹ , -CH = CH-COOR ¹⁹ , -CF ₃ , —CN, —NO ₂ and halogen;

Ar ¹ may 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, (C ₁ -C ₆ ) alkyl, aryl and containing an aryl substituent (C ₁ -C ₆ ) alkyl;

R ²¹ means (C ₁ -C ₆ ) alkyl, aryl or R ²⁴ -substituted aryl;

R ²² is H, (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, —C (O) R ¹⁹ or —COOR ¹⁹ ;

R ²³ and R ²⁴ independently mean 1-3 groups independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl, —COOH, NO ₂ , —NR ¹⁹ R ²⁰ , -OH and halogen; and

R ²⁵ means H, -OH or (C ₁ -C ₆ ) alkoxyl.

Ar ² preferably means phenyl or R ^{11 is} phenyl, in particular (4-R ¹¹ ) substituted phenyl. Preferred R ¹¹ values are lower alkoxyl, in particular methoxy, and halogen, in particular fluorine.

Ar ¹ preferably means phenyl or R ¹⁰ -substituted phenyl, in particular (4-R ¹⁰ ) -substituted phenyl. A preferred value of R ¹⁰ means halogen, in particular fluorine.

Preferably, Q is lower alkyl or a spiran group as defined above, wherein it is preferred that R ¹³ and R ^{14 are} ethylene and R ^{12 is}

Therefore, a preferred compound of formula IX is one in which R ¹ is as defined above, and in which the remaining substituents have the following meanings:

Ar ¹ is phenyl or R ^{10 is} substituted phenyl, where R ¹⁰ is halogen;

Ar ² is phenyl or R ^{11 is} phenyl, where R ¹¹ is 1 to 3 substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkoxyl and halogen;

Q is lower alkyl (i.e., C-1 to C-2) and Q = C-2 is preferred, or Q with a cyclic carbon atom in position 3 of azetidinone forms a group

where it is preferred that R ¹³ and R ^{14 are} ethylene and a and b are 1, and where R ¹² is

The preferred values of the groups R ¹ in the formulas

are the following:

R ² , R ³ , R ⁴ , R ⁵ R ⁶ and R ^{7 are} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl.

The preferred values of the group R ¹ in the formula

are the following:

R ³ , R ^3a , R ⁴ and R ^4a are selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, benzyl and acetyl;

R, R ^a and R ^{b are} independently selected from the group consisting of H, —OH, halogen, —NH ₂ , an azido group, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxyl, and —WR ³⁰ , where W is —O — C (O) - or —OC (O) —NR ³¹ -, R ³¹ is H and R ³⁰ is (C ₁ -C ₆ ) alkyl, —C (O) - (C ₁ -C ₄ ) alkoxy - (C ₁ -C ₆ ) alkyl, T, T- (C ₁ -C ₆ ) alkyl, or T or T- (C ₁ -C ₆ ) alkyl, where T contains one or two halogens or (C ₁ -C ₆ ) alkyl groups.

Preferred R ³⁰ substituents are 2-fluorophenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxycarbonylethyl, thiazol-2-ylmethyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl.

Preferred combinations of R, R ^a and R ^b are as follows:

1) R, R ^a and R ^b independently mean —OH or —OC (O) —NH — R ³⁰ , in particular if R ^a means —OH and R and R ^b mean —OC (O) —NH — R ³⁰ and R ^{30 is} selected from the group of preferred substituents described above, or if R and R ^{a are} —OH and R ^b is —OC (O) —NH — R ³⁰ , where R ³⁰ is 2-fluorophenyl, 2,4-difluorophenyl, 2 6-dichlorophenyl;

2) R ^a means —OH, halogen, azido group or (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy, R ^b means H, halogen, azido group or (C ₁ -C ₆ ) alkoxy (C ₁ —C ₆ ) alkoxy, and R is —OC (O) —NH — R ³⁰ , in particular compounds in which R ^a is —OH, R ^b is H and R ³⁰ is 2-fluorophenyl;

3) R, R ^a and R ^b independently mean —OH or —OC (O) —R ³⁰ and R ³⁰ means (C ₁ -C ₆ ) alkyl, T, or T, containing one or two halogens as substituents or ( C ₁ -C ₆ ) alkyl groups, especially compounds in which R is —OH and R ^a and R ^{b are} —OC (O) —R ³⁰ , where R ³⁰ is 2-furyl; and

4) R, R ^a and R ^b independently mean —OH or halogen. Three additional classes of preferred compounds are those in which the oxy group at the anomeric C ^{1 ′} atom is in beta configuration, in which the oxy group at the anomeric C ^{2 ′} atom is in beta configuration, and in which the R group is in alpha configuration.

R ^{1 is} preferably selected from the group including:

where Ac is acetyl and Ph is phenyl.

An example of a compound suitable for use in the present invention is a compound representing a compound of formula X:

where R ¹ is as defined above, or pharmaceutically acceptable salts or solvates of a compound of formula (X), or prodrug forms of a compound of formula (X) or salts or solvates of a compound of formula (X).

More preferred is a compound representing a compound of formula XI:

or pharmaceutically acceptable salts or solvates of a compound of formula (XI), or prodrug forms of a compound of formula (XI) or salts or solvates of a compound of formula (XI).

In another embodiment, compositions, pharmaceutical compositions, therapeutic combinations, kits and treatment methods described above are provided that include (a) at least one peroxisome proliferator activated receptor activator; and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers of at least one substituted azetidinone or at least one substituted β-lactam or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam, in which the first amount and the second amount taken together in their entirety completeness (administered together or sequentially), are a therapeutically effective amount for the treatment or prevention of a vascular pathological condition, diabetes, obesity or a decrease in the concentration of sterol in the plasma of a mammal.

Suitable substituted azetidinones or substituted β-lactams can be selected from any of the compounds described above by formulas I-XI. Other suitable substituted azetidinones include N-sulfonyl-2-azetidinones, such as those disclosed in US Pat. No. 4,983,597 and ethyl 4- (2-oxoazetidin-4-yl) phenoxyalkanoates, such as those disclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, which are incorporated herein by reference.

The compounds of formulas I-XI can be obtained by known methods, including the methods described above; and, for example, in, WO 93/02048 describes the preparation of compounds in which —R ¹ —Q— is alkylene, alkenylene or alkylene containing a heteroatom, phenylene or cycloalkylene; WO 94/17038 describes the preparation of compounds in which Q is a spirocyclic group; WO 95/08532 describes the preparation of compounds in which —R ¹ —Q— is a hydroxy substituted alkylene group; PCT / US95 / 03196 describes compounds in which —R ¹ —Q— is hydroxy substituted alkylene attached to the Ar ¹ moiety through an —O— or S (O) _0-2 - group; and US patent application serial number 08/463619, filed June 5, 1995, describes the preparation of compounds in which -R ¹ -Q- means a hydroxy-substituted alkylene group attached to the azetidinone ring using the group -S (O) _{0 -2} -.

The daily dose of sterol absorption inhibitor (s) can be from about 0.1 to about 1000 mg / day, preferably from about 0.25 to about 50 mg / day, and more preferably about 10 mg / day, and administered as a single doses or 2-4 divided doses. However, the exact dose is determined by the attending physician and it depends on the activity of the administered compound, age, weight, condition and reaction of the patient.

When pharmaceutically acceptable salts of the above compounds are administered, the weights indicated above refer to the mass of the acidic equivalent or basic equivalent of the therapeutic compound formed from the salt.

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

In another embodiment, the composition or preparation may further include one or more cholesterol biosynthesis inhibitors administered together or in combination with a peroxis proliferator-activated receptor activator (s), sterol absorption inhibitor (s) discussed above.

Non-limiting examples of sterol biosynthesis inhibitors for use in the compositions, therapeutic combinations and methods of the present invention include competitive HMG CoA reductase inhibitors that determine the limiting stage of cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors, and mixtures thereof. Non-limiting examples of HMG CoA reductase inhibitors include statins such as lovastatin (e.g. MEVACOR® manufactured by Merck & Co.), pravastatin (e.g. PRAVACHOL® manufactured by Bristol Meyers Squibb), fluvastatin, simvastatin (e.g. ZOCOR®, manufactured by Merck & Co.), atorvastatin, cerivastatin, CI-981, rivastatin (7- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethylpyridin-3-yl) -3,5-dihydroxy-6-heptanoate sodium), rosuvastatin, pitavastatin (such as NK-104 from Negma Kowa of Japan); HMG CoA synthetase inhibitors, for example, L-659699 ((E, E) -11- [3'R- (hydroxymethyl) -4'-oxo-2'R-oxetanyl] -3,5,7R-trimethyl-2 , 4-undecadienocarboxylic 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'-bithiophen-5-yl ) -methoxy] -benzenemethanamine hydrochloride) 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.

Typically, the total daily dose of the cholesterol biosynthesis inhibitor (s) can be from about 0.1 to about 160 mg / day, preferably from about 0.2 to about 80 mg / day, and administered as a single dose or 2-3 divided doses .

In another preferred embodiment, the composition or preparation comprises a compound of formula (II) in combination with one or more peroxisome proliferator activator (s) activated and one or more cholesterol biosynthesis inhibitors. In this embodiment, the preferred activator (s) of the peroxisome proliferator-activated receptor are fibric acid derivatives selected from the group consisting of gemfibrozil, clofibrate and / or fenofibrate. A preferred cholesterol biosynthesis inhibitor includes one or more HMG CoA reductase inhibitors, such as, for example, lovastatin, pravastatin and / or simvastatin. More preferably, the composition or preparation comprises a compound of formula (II) in combination with simvastatin and gemfibrozil or fenofibrate.

In another alternative embodiment, the compositions, therapeutic combinations or methods of the present invention may further include one or more bile acid sequestrants (insoluble anion exchange resins) that are administered together or in combination with an RAPP activator (s) and a absorption inhibitor (s) sterol discussed above.

Bile acid sequestrants bile bile acids in the intestine, interrupting the enterohepatic circulation of bile acids and causing increased excretion of steroids with feces. The use of bile acid sequestrants is desirable because their effects are unsystematic. Bile acid sequestrants can lower the concentration of cholesterol in the liver and stimulate the synthesis of apo-B / E (LDL) receptors (LDL - low density lipoprotein), which bind plasma LDL and thereby further lower blood cholesterol.

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® manufactured by Bristol-Myers Squibb), colestipol (diethylene tetra-1 copolymer -2,3-epoxypropane, such as COLESTID® tablets manufactured by Pharmacia, wheel cyclohydrochloride (such as WelChol® tablets (poly (allylamine hydrochloride) crosslinked with epichlorohydrin and alkylated with 1-bromodecane and (6-b Romhexyl) -trimethylammonium bromide), manufactured by Sankyo), water-soluble derivatives such as 3,3-yoyen, N- (cycloalkyl) -alkylamines and polyglys, insoluble, containing quaternary main groups of polystyrenes, saponins and mixtures thereof. Other suitable bile acid sequestrants are disclosed in PCT patent applications Nos. WO 97/11345 and WO 98/57652 and in US patents Nos. 3692895 and 5703188, which are incorporated herein by reference. Suitable inorganic cholesterol sequestrants include bismuth salicylate with added montmorillonite clay, antacids aluminum hydroxide and calcium carbonate.

Typically, the daily dose of sequestrant (sequestrants) of bile acids can be from about 1 to about 50 g / day, and more preferably from about 2 to about 16 g / day in a single dose or 2-4 divided doses.

In an alternative embodiment of the present invention, the compositions or treatment of the present invention may further include one or more ileal bile acid transport inhibitors (TFAs) (or apical sodium dependent bile acid transport inhibitors (ANFAs)) administered together or in combination with activator (s) of the receptor activated by the peroxisome proliferator; and sterol absorption inhibitor (s) discussed above. TLCA inhibitors can inhibit bile acid transport to lower LDL cholesterol concentrations. Non-limiting examples of usable TFA inhibitors include benzothiepines, such as therapeutic compounds containing 2,3,4,5-tetrahydro-1-benzithiepin-1,1-dioxide structures, such as those disclosed in PCT patent application WO 00/38727, which is included in the present invention by reference.

Typically, the total daily dose of the TFA inhibitor (s) may be from about 0.01 to about 1000 mg / day, and preferably from about 0.1 to about 50 mg / day, and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or preparations of the present invention may further include nicotinic acid (niacin) and / or its derivatives, which are administered together or in combination with an activator (s) of a receptor activated by a peroxisome proliferator and an absorption inhibitor (s) sterol discussed above.

As used herein, a “nicotinic acid derivative” means a compound containing a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, if any. Examples of nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide). Niacin and its derivatives inhibit the production of VLDL and its LDL metabolite in the liver and increase the concentrations of HDL and apo-A-1. An example of a suitable product containing nicotinic acid is NIASPAN® (sustained release niacin tablets) manufactured by Kos.

Typically, the total daily dose of nicotinic acid or its derivative may be from about 500 to about 10,000 mg / day, preferably from about 1000 to about 8000 mg / day, more preferably from about 3000 to about 6000 mg / day, and administered as a single or divided doses.

In another alternative embodiment, the compositions or preparations of the present invention may further include one or more AcylCoA inhibitors: O-acyltransferase cholesterol (AHAT), which can lower LDL and VLDL concentrations and which are administered together or in combination with an activator (s) peroxisome proliferator-activated receptor and sterol absorption inhibitor (s) discussed above. AHAT is an enzyme that provides the esterification of excess intracellular cholesterol, and it can reduce the synthesis of VLDL, which is a product of cholesterol esterification, and the excessive production of lipoproteins containing apo-B-100.

Non-limiting examples of suitable AChT inhibitors include avasimibe (2,6-bis- (1-methylethyl) phenyl ester [[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamic acid, previously CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (N- (2,4-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 into the present invention by reference.

Typically, the total daily dose of AChAT inhibitor (s) can be from about 0.1 to about 1000 mg / day and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or preparations of the present invention may further include one or more cholesterol ester transfer protein (BPEC) inhibitors that are administered together or in combination with a peroxis proliferator-activated receptor activator (s) and an inhibitor (inhibitors) of sterol absorption discussed above. BPEC provides for the exchange or transport of HDL containing cholesterol ester and triglycerides in VLDL.

Non-limiting examples of useful BPEC inhibitors are disclosed in PCT Patent Application No. WO 00/38721 and in US Pat. No. 6,147,090, which are incorporated herein by reference. Cholesterol ester pancreatic hydrolase inhibitors (pECS), such as WAY-121898, can also be administered together or in combination with an activator of the receptor (s) activated by the peroxisome proliferator and the sterol absorption inhibitor (s) discussed above.

Typically, the total daily dose of the BPHE inhibitor (s) may be from about 0.01 to about 1000 mg / day, and preferably from about 0.5 to about 20 mg / (kg body weight) / day, and administered as a single dose or divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the present invention may further include probucol or its derivatives (such as AGI-1067 and other derivatives disclosed in US Pat. Nos. 6121319 and 6147250), which can reduce LDL concentrations administered together or in combination with a peroxisome proliferator-activated receptor activator (s) and a sterol absorption inhibitor (s) discussed above.

Typically, the total daily dose of probucol or its derivatives can be from about 10 to about 2000 mg / day, and preferably from about 500 to about 1500 mg / day, and administered in a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the present invention may further include low density lipoprotein receptor (LDL) activators that are administered together or in combination with a peroxisome proliferator activated receptor activator (s) and a absorption inhibitor (s) sterol discussed above. Non-limiting examples of useful LDL receptor activators include HOE-402, an 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.

Typically, the total daily dose of the activator (s) of the LDL receptor can be from about 1 to about 1000 mg / day and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or treatment of the present invention may further include fish oil containing omega-3 fatty acids (3-PUFAs), which can lower the concentrations of VLDL and triglycerides and which is administered together or in combination with an activator (s) ) a receptor activated by the peroxisome proliferator and the sterol absorption inhibitor (s) discussed above. Typically, the full daily dose of fish oil or omega-3 fatty acids can be from about 1 to about 30 g / day and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or treatment of the present invention may further include natural water-soluble fibers, such as psyllium, guar gum, oats and pectin fibers, which can lower cholesterol concentrations and that are administered together or in combination with an activator (activators) ) a receptor activated by the peroxisome proliferator and the sterol absorption inhibitor (s) discussed above. Typically, the total daily dose of natural water-soluble fiber can be from about 0.1 to about 10 g / day and administered in a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or treatment of the present invention may further include plant sterols, plant stanols and / or esters of fatty acids and plant stanols, such as the sitostanol ester used in BENECOL® margarine, which can lower cholesterol and which are administered together or in combination with an activator (activators) of a receptor activated by a peroxisome proliferator and an inhibitor (inhibitors) of sterol absorption, reviewed above. Typically, the total daily dose of plant sterols, plant stanols and / or esters of fatty acids and plant stanols can be from about 0.5 to about 20 g / day and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or treatment of the present invention may further include antioxidants such as probucol, tocopherol, ascorbic acid, β-carotene and selenium, or vitamins such as vitamin B ₆ or vitamin B ₁₂ , which are administered together or in combination with the peroxisome proliferator-activated receptor activator (s) and the sterol absorption inhibitor (s) discussed above. Typically, a full daily dose of antioxidants or vitamins can be from about 0.05 to about 10 g / day and administered as a single dose or 2-4 divided doses.

In another alternative embodiment, the compositions or treatment of the present invention may further include monocyte or macrophage inhibitors such as polyunsaturated fatty acids (PUFAs), thyroid hormones, including troxin analogs such as CGS-26214 (a fluorinated ring thyroxine derivative), drugs used in gene therapy and recombinant proteins, such as recombinant apo-E, which are administered together or in combination with activator (s) of the receptor activated by by peroxisome inhibitor, and sterol absorption inhibitor (s) discussed above. Typically, the total daily dose of these drugs can be from about 0.01 to about 1000 mg / day and administered as a single dose or 2-4 divided doses.

Compositions or therapeutic combinations may also be used in the present invention, which may further comprise hormone-replacing preparations and compositions. Suitable hormonal preparations and compositions for hormone replacement therapy of the present invention include androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives. Combinations and compositions of these preparations are also suitable.

The dosage of the combinations of androgens and estrogens is preferably from about 1 to about 4 mg of androgen and from about 1 to about 3 mg of estrogen. Examples (without limitation) include combinations of androgens and estrogens, such as a combination of esterified estrogens (sodium estronsulfate and sodium equilinsulfate) and methyltestosterone (17-hydroxy-17-methyl-, (17B) -androst-4-en-3-one) manufactured by Solvay Pharmaceuticals, Inc., Marietta, GA, under the trade name Estratest.

The dosage of estrogens and estrogen combinations may be from about 0.01 to about 8 mg, preferably from about 0.3 to about 3.0 mg. Examples of usable estrogens and estrogen combinations include:

(a) a mixture of nine (9) synthetic estrogens, including sodium estrone sulfate, sodium equiline sulfate, sodium 17α-dihydroequiline sulfate, sodium 17α-dihydroequiline sulfate, 17β-sodium dihydroequiline sulfonate, 17β-sodium disodium dihydroquin sulfate, dihydrodisquinine sulfate dihydrodisinhydrosine dihydrodinhydrin ; manufactured by Duramed Pharmaceuticals, Inc., Cincinnati, OH, under the trade name Cenestin;

(b) ethinyl estradiol (19-nor-17α-pregna-1,3,5 (10) -trien-20-yn-3,17-diol; manufactured by Schering Plow Corporation, Kenilworth, NJ, under the trade name Estinyl;

(c) combinations of esterified estrogens such as sodium estronsulfate and sodium equilinsulfate; sold by Solvay under the trade name Estratab and Monarch Pharmaceuticals, Bristol, TN, under the trade name Menest;

(d) estropipate (piperazine-estra-1,3,5 (10) -trien-17-one, 3- (sulfooxy) -estronsulfate); manufactured by Pharmacia & Upjohn, Peapack, NJ, under the trade name Ogen and Women First Health Care, Inc., San Diego, CA, under the trade name Ortho-Est; and

(e) conjugated estrogens (17α-dihydroequiline, 17α-estradiol and 17β-dihydroequiline); manufactured by Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA, under the trade name Premarin.

Progestins and estrogens can be administered in different doses, usually from about 0.05 to about 2.0 mg of progestin and from about 0.001 to about 2.0 mg of estrogen, preferably from about 0.1 to about 1 mg of progestin and from about 0 01 to about 0.5 mg of estrogen. Examples of combinations of progestin and estrogen, the dosage and regimen of which may vary, include:

(a) a combination of estradiol (estra-1,3,5 (10) -triene-3,17β-diol hemihydrate) and norethindrone (17β-acetoxy-19-nor-17α-pregn-4-en-20-in-3 -she); manufactured by Pharmacia & Upjohn, Peapack, NJ, under the trade name Activella;

(b) a combination of levonogestrel (d (-) - 13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one) and ethinyl estradial; sold by Wyeth-Ayerst under the trade name Alesse, Watson Laboratories, Inc., Corona, CA, under the trade names Levora and Trivora, Monarch Pharmaceuticals, under the trade name Nordette, and Wyeth-Ayerst under the trade name Triphasil;

(c) a combination of ethinodiol diacetate (19-nor-17α-pregn-4-en-20-yn-3β, 17-diol diacetate) and ethinyl estradiol; manufactured by G. D. Searle & Co., Chicago, IL, under the trade name Demulen and Watson under the trade name Zovia;

(d) a combination of desogestrel (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and ethinyl estradiol; sold by Organon under the trade names Desogen and Mircette and Ortho-McNeil Pharmaceutical, Raritan, NJ, under the trade name Ortho-Cept;

(e) a combination of norethindrone and ethinyl estradiol; manufactured by Parke-Davis, Morris Plains, NJ, under the trade names Estrostep and femhrt, Watson under the trade names Microgestin, Necon and Tri-Norinyl, Ortho-McNeil under the trade names Modicon and Ortho-Novum, and Warner Chilcott Laboratories, Rockaway, NJ, under the trade name Ovcon;

(f) a combination of norgestrel ((±) -13-ethyl-17-hydroxy-18,19-dinor-17α-preg-4-en-20-yn-3-one) and ethinyl estradiol; manufactured by Wyeth-Ayerst under the trade names Ovral and Lo / Ovral, and Watson under the trade names Ogestrel and Low-Ogestrel;

(g) a combination of norethindrone, ethinyl estradiol and mestranol (3-methoxy-19-nor-17α-pregna-1,3,5 (10) -trien-20-in-17-ol); manufactured by Watson under the trade names Brevicon and Norinyl;

(h) a combination of 17β-estradiol (estra-1,3,5 (10) -trien-3,17β-diol) and finely ground norgestimate (17α-17- (acetyloxy) -13-ethyl-18,19-dinorpregn-4 en-20-in-3-one-3-oxime); manufactured by Ortho-McNeil under the trade name Ortho-Prefest;

(i) a combination of norgestimate (18,19-dinor-17-pregn-4-en-20-yn-3-one, 17- (acetyloxy) -13-ethylloxim, (17 (α) - (+) -) and ethinyl estradiol; manufactured by Ortho-McNeil under the trade names Ortho Cyclen and Ortho Tri-Cyclen; and

(j) a combination of conjugated estrogens (sodium estronsulfate and sodium equilinsulfate) and medroxyprogesterone acetate (20-dione, 17- (acetoxy) -6-methyl-, (6 (α)) pregn-4-ena-3); manufactured by Wyeth-Ayerst under the trade names Premphase and Prempro.

Typically, the dose of progestins may be from about 0.05 to about 10 mg, or to about 200 mg if finely ground progesterone is administered. Examples of progestins include norethindrone manufactured by ESI Lederle, Inc., Philadelphia, PA, under the trade name Aygestin, Ortho-McNeil under the trade name Micronor and Watson under the trade name Nor-QD; norgestrel, manufactured by Wyeth-Ayerst under the trade name Ovrette; finely ground progesterone (pregn-4-en-3,20-dione), manufactured by Solvay under the trade name Prometrium; and medroxyprogesterone acetate sold by Pharmacia & Upjohn under the trade name Provera.

Compositions, therapeutic combinations or methods of the invention may further include one or more drugs for the treatment of obesity. Suitable drugs for treating obesity include (without limitation) drugs that lower energy intake or suppress appetite, drugs that increase energy expenditure, and agents that share nutrients. Suitable medications for treating obesity include, but are not limited to, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, fendimethrazine, fendiaminartartrat, methamphetamine and fendimetrazintartrat); serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtin); thermogenic agents (such as ephedrine, caffeine, theophylline and selective β3-adrenergic agonists); alpha blocking agents; Cainite or AMPA receptor antagonists; liptin lipolysis stimulating receptors; phosphodiesterase enzyme inhibitors; compounds containing the nucleotide sequence of the mahogany gene; fibroblast growth factor 10 polypeptides; monoamine oxidase inhibitors (such as befloxatone, moclobenimide, brofaromine, phenoxatin, esupron, befol, toloxatone, pirlindole, amiflamine, sercloremin, bazinaprine, lazabemide, mimacemide and caroxanzone); lipid metabolism enhancing compounds (such as evodiamine compounds); and lipase inhibitors (such as orlistat). Typically, the full dose of the above medications intended for the treatment of obesity may be from 1 to 3000 mg / day, preferably from about 1 to 1000 mg / day, and more preferably from about 1 to 200 mg / day and administered as single dose or 2-4 divided doses.

Compositions, therapeutic combinations or methods of the present invention may further include one or more blood modifiers that are chemically different from the substituted azetidinones and substituted β-lactams discussed above (such as the above compounds I-XI) and the above-described RAPP receptor activators for example, they contain one or more other atoms, have a different arrangement of atoms or a different number of one or more atoms than the inhibitor p (s), sterol absorption or PPAR receptor activators discussed above. Suitable blood modifiers include (without limitation) anticoagulants (argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, sodium liapolate, nafamostamezylate, fenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic preparations (anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxybenhydrochloride, efegatransulfate, enoxaparin sodium, fluuretophen, ifetroban, nifibanibibanibibanofibanibanibibanibanibibanibanibibanibanibibanibanibibanibanibibanibanibibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibanibaniban and triphenagrel, absiximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors (kilostazol, clopidogrelbisulfate, epoprostenol, epoprostenol sodium, tiklopidining hydrochloride, aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate, droxicam, diclofenipyrampyridone, sulfinopyramidone; platelet aggregation inhibitors (acadesine, beraprost, berabrost-sodium, cyprosten-calcium, itazigrel, lifarisine, lotrafiban hydrochloride, orbofibanacetate, oxagrelate, fradafiban, orbofiban, tirofiban, xemilofiban); agents that change the rheological characteristics of the blood (pentoxifylline); lipoprotein-associated blood coagulation inhibitors; factor VIIa inhibitors (4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-4-ones, quinazolin-4-ones, quinazolin-4-thions, benzothiazin-4-ones, peptide analogues - imidazolylboronic acid derivatives , peptides are derivatives of IMTP, {1- [3- (aminoiminomethyl) benzyl] -2-oxopyrrolidin-3- (S) -yl} -amide trifluoroacetate naphthalene-2-sulfonic acid, {1- [3- (aminomethyl) - benzyl] -5-oxo-pyrrolidin-3-yl} -amiddibenzo-furan-2-sulfonic acid, {1- [3- (aminoiminomethyl) benzyl] -2-oxopyrrolidin-3- (S) -yl} -amide trifluoroacetate toluene-4-sulfonic acid, {1- [3- (aminoiminomethyl) benzyl] -2-oxopyrrolin-3- (S) 3,4-dihydro-1H-isoquinoline-2-sulfonic acid -yl} -amide trifluoroacetate); factor Xa inhibitors (disubstituted pyrazolines, disubstituted triazolines, substituted n - [(aminoiminomethyl) phenylpropylamides, substituted n - [(aminomethyl) phenylpropylamides, tissue factor pathway inhibitors (IMTP), low molecular weight heparins, heparinoids, benzimide , benzopiperazinones, indanones, dibasic (amidinoaryl) derivatives of propanecarboxylic acid, amidinophenylpyrrolidines, amidinophenylpyrrolines, amidinophenylisoxazolidines, amidinoindoles, amidinoazoles, derivatives of bis-arylsulfonylaminobenzamide, ngibitory peptide factor Xa).

Compositions, therapeutic combinations or methods of the present invention may further include one or more cardiovascular preparations that are chemically different from the substituted azetidinones and substituted β-lactams discussed above (such as compounds I-XI above) and those contemplated higher RAPP receptor activators, for example, they contain one or more other atoms, have a different arrangement of atoms or a different amount of one or more more atoms than the sterol absorption inhibitor (s) or RAPP receptor activators discussed above. Suitable cardiovascular agents include, but are not limited to, calcium channel blockers (such as clentiazemmaleate, amlodipinebesilate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipinghydrochloride, diltia-zemhydrochloride chloride, whitewashed chloride, whitewashed chloride, adrenergic blockers (fenspiridgidrohlorid, labetalolgidrohlorid, proroksan, alfuzodingidrohlorid, acebutolol, atsebutololgidrohlorid, alprenololgidrohlorid, atenolol, bunolol hydrochloride, karteololgidrohlorid, tseliprololgidrohlorid, tsetamololgidrohlorid, tsikloprololgidrohlorid, dekspropranololgidrohlorid, diatsetololgidrohlorid, dilevalolgidrohlorid, estmololgidrohlorid, eksaprololgidrohlorid, flestololsulfat, labetalolgidrohlorid, levobeksatololgidrohlorid, levobunololgidrohlorid, metalolgidrohlorid, metoprolol, me toprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, praktolol, propranolol hydrochloride, solatol hydrochloride, timolol, timolol maleate, tiprenol hydrochloride, tolamolol, bisoprolol, bisoprolololum); adrenergic stimulants; inhibitors of angiotensin converting enzyme (ACE) (benazeprilgidrohlorid, benazeprilat, captopril, delaprilgidrohlorid, fosinopril sodium, libenzapril, moeksiprilgidrohlorid, pentopril, perinodopril, kvinaprilgidrohlorid, kvinaprilat, ramipril, spiraprilgidrohlorid, spiraprilat, teprotide, enalaprilmaleat, lisinopril, zofenopril calcium, perindopril erbumine) ; antihypertensive agents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, klonidingidrohlorid, cyclothiazide, delaprilgidrohlorid, dilevalolgidrohlorid, doksazosinmezilat, fosinopril sodium, gvanfatsingidrohlorid, methyldopa, metoprololsuktsinat, moeksiprilgidrohlorid, monatepilmaleat, pelanserin hydrochloride, fenoksibenzamingidrohlorid, prazosingidrohlorid, primidolol, kvinaprilgidrohlorid , quinaprilat, ramipril, terazosine hydrochloride, candesartan, candesartan-cilexetil, thermisartan, amlodipinebesilate, amlodipinmale t, bevantololgidrohlorid); angiotensin II receptor antagonists (candesartan, irbesartan, losartan-potassium, candesartan cilexetil, telmisartan); anti-stenocarditis drugs (amlodipinebesilate, amlodipine maleate, betaxol hydrochloride, bevantol hydrochloride, butoprozine hydrochloride, carvedilol, cinopazetmaleate, metoprolol succinate, molsidomine, ranole aziderolidrolide; coronary vasodilators (fostedil, azaklorzingidrohlorid, hromonargidrohlorid, klonitrat, diltiazemgidrohlorid, dipyridamole, droprenilamid, eritritiltetranitrat, izosorbiddinitrat, izosorbidmononitrat, lidoflazina, mioflazingidrohlorid, miksidin, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oksprenololgidrohlorid, pentrinitrol, pergeksilinmaleat, prenylamine, propatilnitrat, terodyning hydrochloride, tolamolol, verapamil); diuretics (a product that is a combination of hydrochlorothiazide and spirolactone, and a product that is a combination of hydrochlorothiazide and triamterene).

Compositions, therapeutic combinations or methods of the present invention may further include one or more antidiabetic drugs intended to lower glucose concentrations in human blood. Various antidiabetic drugs include (without limitation) drugs that lower energy intake or suppress appetite, drugs that increase energy expenditure, and drugs that share nutrients. Suitable antidiabetic drugs include, but are not limited to, sulfonylurea (such as acetohexamide, chlorpropamide, glutamilide, glyclazide, glimepiride, glipizide, gliburide, glibenclamide, tolazamide and tolbutamide), meglitinide (such as napglinidinum and biblideum) and buformin); an alpha glucosidase inhibitor (such as acarbose, miglitol, camiglibose and voglibose), certain peptides (such as amlintide, pramlintide, exendin and GLP-1 agonistic peptides), and orally administered insulin or insulin compositions intended to be excreted in the intestine. Typically, the full dose of the antidiabetic drugs described above may be from about 0.1 to about 1000 mg / day and administered as a single dose or 2-4 divided doses.

In the compositions and therapeutic combinations of the present invention, mixtures of any pharmacological or therapeutic agents described above can be used.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one AcylCoA inhibitor: O-acyltransferase cholesterol and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β- lact ma or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) probucol or a derivative thereof and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one low density lipoprotein receptor activator and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one omega-3 fatty acid and (b) at least one substituted azetidinone or at least one substituted β -lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers, by cr at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least , one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one natural water-soluble fiber and (b) at least one substituted azetidinone or at least one substituted β- lactams, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam and and isomers of at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates thereof at least one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one of plant sterols, plant stanols or esters of fatty acids and plant stanols, and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers of at least one substituted azetidinone or at least one substituted β-lactam or prodrugs of at least one substituted azetidinone or at least at least one substituted β-lactam or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam.

In another embodiment, the present invention relates to a composition or therapeutic combination comprising (a) at least one antioxidant or vitamin and (b) at least one substituted azetidinone or at least one substituted β-lactam, or isomers of at least one substituted azetidinone or at least one substituted β-lactam, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or isomers, by at least one substituted azetidinone or at least one substituted β-lactam, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or isomers, salts or solvates of at least , one substituted azetidinone or at least one substituted β-lactam.

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

The compositions or therapeutic combinations of the present invention can be administered to a mammal in need of such treatment in a therapeutically effective amount for treating one or more pathological conditions, for example, vascular pathological conditions such as atherosclerosis, hyperlipidemia (including (without limitation) hypercholesterolemia, hypertriglyceridemia, sitosterolemia), vascular inflammation, stroke, diabetes, obesity and / or to reduce the concentration of sterol (sterols) in the plasma. Compositions and preparations can be administered by any suitable means that allow the interaction of these compounds with the site of exposure in the body, for example, in the plasma, liver or small intestine of a mammal or human.

The daily dose of the various compositions and therapeutic combinations described above, if necessary, can be administered to the patient in the form of a single dose or multiple divided doses. The divided doses may be administered, for example, from 2 to 6 times per day. You can use doses, for example, from 2 to 6 times a day. Slow release doses may be used. If the activator of the receptor (s) activated by the peroxisome proliferator and the sterol absorption inhibitor (s) are administered in separate doses, then the number of doses of each component administered per day is not necessarily the same, for example, one component may have a longer duration of action and therefore it is necessary inject less frequently.

The pharmaceutical therapeutic compositions and therapeutic combinations of the present invention may further comprise one or more pharmaceutically acceptable carriers, one or more inert 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 filler in the treatment composition may be from about 5 to about 99% by weight of the total weight of the treatment composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable inert excipients and additives include non-toxic compatible excipients, binders such as starch, disintegrants, buffering systems, preservatives, antioxidants, lubricants, flavoring agents, thickeners, coloring agents, emulsifiers, etc. . The amount of inert filler or additive may be from about 0.1 to about 90 wt.% Of the total weight of the treatment composition or therapeutic combination. One skilled in the art should understand that the amounts of carrier (s), inert fillers, and additives (if any) may vary.

The therapeutic compositions of the present invention may be administered in any conventional dosage form, preferably an oral dosage form, such as a capsule, tablet, powder, cachet, suspension or solution. Formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional methods. The following are some examples of the preparation of dosage formulations.

The formulations below are examples of certain dosage forms of the present invention. In each formulation, the term “active compound I” means substituted azetidinone, β-lactam or any of the compounds of formulas I-XI described above in the present invention, or isomers of at least one substituted azetidinone or at least one substituted β -lactam or any of the compounds of formulas I-XI, or pharmaceutically acceptable salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or any of the compounds of formulas I-XI or isomers, at least one substituted azetidinone or at least one substituted β-lactam or any of the compounds of formulas I-XI, or prodrugs of at least one substituted azetidinone or at least one substituted β-lactam or any of the compounds of formulas I- XI or isomers, salts or solvates of at least one substituted azetidinone or at least one substituted β-lactam or any of the compounds of formulas I-XI, and the term “active compound II” means the activator RAPP described above in the present invention.

EXAMPLE

Pills

No. Component mg / tablet one Active compound I 10 2 Lactose Monohydrate NF * 55 3 Microcrystalline Cellulose NF twenty four Povidone (K29-32) US Pharmacopoeia four 5 Croscarmellose sodium salt NF 8 6 Sodium Lauryl Sulfate 2 7 Magnesium Stearate, NF one Total one hundred * National Pharmaceutical Directory.

In the present invention, the tablet described above can be administered together with a tablet, capsule and the like containing a dose of the active compound II, for example, the TRICOR® capsule described above.

Preparation method

Component No. 4 is mixed in a suitable mixer with purified water to form a binder solution. To granulate the components, a binder solution, and then water, is sprayed onto components No. 1, 2, 6 and part of component No. 5 located in the fluidized bed apparatus. Fluidization is carried out before drying the wet granules. The dried granules are passed through a sieve and mixed with component No. 3 and the remainder of component No. 5. Add component No. 7 and mix. The mixture is compressed into tablets of the appropriate size and weight on a suitable tablet machine.

Typical compositions containing a cholesterol absorption inhibitor, such as those discussed above, and intended for co-administration in separate tablets or capsules, are well known in the art and typical compositions containing a peroxisome proliferator-activated receptor activator, such as those discussed above, are well known in this technical field. It is understood that if these two active components are administered as a single composition, the dosage forms disclosed above for substituted azetidinones or β-lactams can be easily modified using the knowledge of a person skilled in the art.

Since the present invention relates to the treatment of pathological conditions discussed above, such as reducing plasma concentrations or levels of sterol (especially cholesterol) by treatment with a combination of active components, in which the active components can be administered separately, the present invention also relates to combining individual pharmaceutical compositions as a kit. This means that the scope of the present invention includes a kit in which two elements are combined: a pharmaceutical composition comprising at least one peroxisome proliferator activated receptor activator, and a separate pharmaceutical composition containing at least one sterol absorption inhibitor, described above. Preferably, the kit includes instructions for administering the individual components. The kit form is particularly useful when the individual components must be administered in various dosage forms (e.g., oral and parenteral) or taken at different time intervals.

As shown in the Example below, the therapeutic compositions and therapeutic combinations of the present invention can inhibit cholesterol absorption in the intestines of mammals and therefore can be used to treat and / or prevent pathological conditions, such as vascular pathological conditions such as atherosclerosis, hypercholesterolemia and sitosterolemia, stroke and obesity, and lowering the concentration of cholesterol in the plasma of mammals, in particular humans.

In another embodiment of the present invention, the compositions and therapeutic combinations of the present invention can inhibit sterol absorption or reduce plasma concentrations of at least one sterol selected from the group consisting of phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), 5α-stanols (such as cholestanol, 5α-campestanol, 5α-sitostanol), cholesterol and mixtures thereof. Plasma concentrations can be reduced by administering to a mammal in need of such treatment an effective amount of at least one therapeutic composition or therapeutic combination containing at least one RAPP activator and at least one sterol absorption inhibitor described above . The decrease in the concentration of sterols in plasma and / or tissues can be from about 1 to about 70%, and preferably from about 10 to about 50%. Methods for measuring the concentration of total cholesterol and total LDL cholesterol in blood serum are well known to those skilled in the art and, for example, include disclosed in PCT WO 99/38498 p.11, which is incorporated herein by reference. Methods for determining the concentrations 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), which is incorporated herein by reference.

The present invention is illustrated by the following examples, and the details given therein should not be construed as limiting the present invention. Unless otherwise specified, all of the values presented in the examples below, as well as throughout the application, expressed in parts and percent, are massive.

EXAMPLES

SYNTHESIS OF COMPOUND OF FORMULA (II)

Step 1): To a solution of (S) -4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH ₂ Cl ₂ (200 ml) 4-dimethylaminopyridine (2.5 g, 0.02 mol) is added. and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to 0 ° C.

Methyl 4- (chloroformyl) butyrate (50 g, 0.3 mol) is added dropwise in water in CH ₂ Cl ₂ (375 ml) in water over 1 hour and the reaction mixture is allowed to warm to 22 ° C. After 17 hours, water and H ₂ SO ₄ (2 N, 100 ml) were added, the layers were separated, and the organic layer was washed successively with NaOH (10%), NaCl (saturated solution) and water. The organic layer was dried over MgSO ₄ and concentrated to give a semi-crystalline product.

Step 2): To a solution of TiCl ₄ (18.2 ml, 0.165 mol) in CH ₂ Cl ₂ (600 ml), titanium isopropoxide (16.5 ml, 0.055 mol) is added at 0 ° C. After 15 min, the product obtained in stage 1 (49.0 g, 0.17 mol) was added as a solution in CH ₂ Cl ₂ (100 ml). After 5 min, diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was stirred for 1 h at 0 ° C, the reaction mixture was cooled to -20 ° C and 4-benzyloxybenzylidine- was added as a solid (4 fluorine) aniline (114.3 g, 0.37 mol). The reaction mixture was stirred vigorously for 4 hours at −20 ° C., then acetic acid was added dropwise over 15 minutes as a solution in CH ₂ Cl ₂ , the reaction mixture was allowed to warm to 0 ° C. and the layers were separated, washed with water, and the organic layer was separated are dried. The crude product is recrystallized from ethanol / water to give a pure intermediate.

Stage 3): To a solution of the product obtained in stage 2 (8.9 g, 14.9 mmol) in toluene (100 ml) at 50 ° C are added N, O-bis (trimethylsilyl) -acetamide (BSA) (7 50 ml, 30.3 mmol). After 0.5 hours, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture was stirred at 50 ° C. for another 3 hours. The reaction mixture was cooled to 22 ° C and CH ₃ OH (10 ml) was added. The reaction mixture was washed with HCl (1 N), NaHCO ₃ (1 N) and NaCl (saturated solution) and the organic layer was dried over MgSO ₄ .

Stage 4): To a solution of the product obtained in stage 3 (0.94 g, 2.2 mmol) in water, CH ₃ OH (3 ml) was added water (1 ml) and LiOH · H ₂ O (102 mg, 2, 4 mmol). The reaction mixture was stirred for 1 h at 22 ° C and then an additional amount of LiOH · H ₂ O (54 mg, 1.3 mmol) was added. After a total time of 2 hours, HCl (1 N) and EtOAc were added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the obtained product (0.91 g, 2.2 mmol) in CH ₂ Cl ₂ at 22 ° C was added ClCOCOCl (0.29 ml, 3.3 mmol) and the mixture 16 was stirred. The solvent is removed in vacuo.

Stage 5): With vigorous stirring to a suspension of 4-fluorophenylzinc chloride (4.4 mmol) obtained from 4-fluorophenylmagnesium bromide (1 M solution in THF (tetrahydrofuran), 4.4 ml, 4.4 mmol) and ZnCl ₂ (0 6 g, 4.4 mmol), tetrakis (triphenylphosphine) palladium (0.25 g, 0.21 mmol) is added at 4 ° C, and then the product obtained in stage 4 (0.94 g, 2.2 mmol) ), as a solution in THF (2 ml). The reaction mixture was stirred for 1 h at 0 ° C and then 0.5 h at 22 ° C. HCl (1N solution, 5 ml) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to give an oil and purified by silica gel chromatography to give 1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -3 (R) - (3-oxo-3-phenylpropyl) -2-azetidinone : HRMS (high resolution mass spectroscopy): calculated for C ₂₄ H ₁₉ F ₂ NO ₃ = 408.1429, found 408.1411.

Step 6): (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H was added to a solution of the product of step 5 (0.95 g, 1.91 mmol) in THF (3 ml) -pyrrole- [1,2-s] [1,3,2] -oxazaborol (120 mg, 0.43 mmol) and the mixture is cooled to -20 ° C. After 5 minutes, a borohydride-dimethyl sulfide complex (2 M solution in THF, 0.85 ml, 1.7 mmol) was added dropwise over a period of 0.5 hours. After a total time of 1.5 hours, CH ₃ OH and then HCl (1 N solution) were added and the reaction mixture was extracted with EtOAc to give 1- (4-fluorophenyl) -3 (S) - [3 (S ) - (4-fluorophenyl) -3-hydroxypropyl)] - 4 (S) - [4- (phenylmethoxy) phenyl] -2-azetidinone (compound 6A-1) as an oil. ¹ H in CDCl ₃ d H3 = 4.68. J = 2.3 Hz. CI (chemical ionization) (M ⁺ H) 500.

The use of (S) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo- [1,2-c] [1,3,2] -oxazaborol gives the corresponding 3 (R) -hydroxypropylazetidinone (compound 6B -one). ¹ H in CDCl ₃ d H3 = 4.69. J = 2.3 Hz. CI (M ⁺ H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml) was added 10% Pd / C (0.03 g) and the reaction mixture was stirred for 16 hours at a pressure of gaseous H ₂ equal to 60 pounds / inch ² . The reaction mixture was filtered and the solvent was removed to give compound 6A. Melting point 164-166 ° C; CI (M ⁺ H) 410. [α] ²⁵ _D = -28.1 ° (s3, CH ₃ OH). Elemental analysis: calculated for C ₂₄ H ₂₁ F ₂ NO ₃ : C, 70.41; H 5.17; N 3.42; found C, 70.25; H 5.19; N, 3.54.

A similar treatment of compound 6B-1 gives compound 6B.

Melting point 129.5-132.5 ° C; CI (M ⁺ H) 410. Elemental analysis: calculated for C ₂₄ H ₂₁ F ₂ NO ₃ : C, 70.41; H 5.17; N 3.42; found C, 70.30; H 5.14; N, 3.52.

Stage 6 '(alternative method): To a solution of the product obtained in stage 5 (0.14 g, 0.3 mmol) in ethanol (2 ml), add 10% Pd / C (0.03 g) and the reaction mixture 16 hours stirred at a pressure of gaseous H ₂ equal to 60 pounds / inch ² . The reaction mixture was filtered and the solvent was removed to give a 1: 1 mixture of compounds 6A and 6B.

In vivo tests

In a randomized blind trial for researchers in a parallel group with placebo control, 32 healthy patients suffering from hypercholisterinemia (LDL-X screening ≥130 mg / dL), stabilized and kept on an NCEP diet (National Cholesterol Education Program) Stage 1, randomly They are divided into the following four treatment groups:

Treatment A - placebo is administered orally in the form of 1 dose per day;

Treatment B - 10 mg of compound II is orally administered as 1 dose per day;

Treatment C - 200 mg of finely ground fenofibrate LIPANTHYL® (manufactured by Labortoire Fournier of France) is orally administered as 1 dose per day;

Treatment D - 200 mg of finely ground fenofibrate LIPANTHYL® and 10 mg of compound II are administered orally as 1 dose per day every morning for 14 days.

Serum lipid concentrations are determined before the dose is taken (after fasting for at least 10 hours) on the 1st day (baseline), the 7th day and the 14th day.

Results: Mean changes expressed as a percentage (%) (in parentheses are standard deviations) of serum lipid concentrations (n = 8) are shown below in table 1:

Treatment LNP-X * General x HDL-X TG * BUT -10.1 (4.9) -8.38 (4.0) -14.1 (2.2) 19.1 (13.9) AT -22.3 (5.7) -19.6 (4.0) -13.3 (4.4) -4.57 (12.8) FROM -13.5 (3.1) -13.0 (2.4) -6.1 (3.6) 0.28 (11.4) D -36.3 (3.5) -27.8 (1.7) -1.97 (4.7) -32.4 (4.5) * X - cholesterol, TG - triglycerides.

Concomitantly administered 10 mg of compound II and 200 mg of fenofibrate (treatment D) are well tolerated and lead to a statistically significant (p <0.03) decrease in LDL-X concentration compared with the cases of taking one of the two drugs or placebo. In this in-patient test, in which the physical activity of the subjects is limited, there is a general tendency to a decrease in HDL-X concentration and an increase in triglyceride concentration. In the group treated with C, the decrease in HDL-X concentrations was the smallest, and the decrease in triglyceride concentrations was the largest.

Those skilled in the art will appreciate that changes can be made to the above described embodiments without departing from the broadly understood essence of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to encompass modifications that are within the scope and spirit of the present invention described in the appended claims.

Claims (4)

1. A pharmaceutical composition for treating or preventing a vascular pathological condition, diabetes, obesity, or lowering the concentration of sterol in a plasma of a mammal, including:
(a) at least one peroxisome proliferator activated receptor activator selected from the group consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol, or a mixture thereof, and
(b) a sterol absorption inhibitor represented by the formula (II)

or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition according to claim 1, in which the activator of the receptor activated by the peroxisome proliferator is fenofibrate. 3. A therapeutic combination for treating or preventing a vascular pathological condition, diabetes, obesity, or lowering the concentration of sterol in a plasma of a mammal, including:
(a) at least one peroxisome proliferator activated receptor activator selected from the group consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol, or a mixture thereof, and
(b) a sterol absorption inhibitor represented by the formula (II)

or a pharmaceutically acceptable salt thereof. 4. The therapeutic combination according to claim 3, in which the activator of the receptor activated by the peroxisome proliferator is fenofibrate.