MXPA96004030A - Azetidinone compounds substituted useful as agents hipocolesterolemi - Google Patents

Abstract

The present invention relates to a compound represented by the structural formula: or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is R 3 -substituted phenyl, Ar 2 is R 4 -substituted phenyl, Ar 3 is R 5 -substituted phenyl, Y and Z are -CH2-; A is -O-, -S-, -S (O) - or -S (O) 2-; R1 is selected from the group consisting of -OR6, -O (CO) R6, -O ( CO) OR9 and -O (CO) NR6R7; R2 is hydrogen; or R1 and R2 together are = O; q is 1, 2 or 3; p is 0, 1.2, 3 or 4; R3 is 1 to 3 substituents independently selected from the group consists of hydrogen, -CONR6R7, -COR6, -SO2NR6R7, SOo-2-alkyl, SOo-2-aryl, -NH2 and halogen, R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, lower alkyl, -OR6 , -OC (O) R6, -OC (O) OR9, -OC (O) NR6R7, -NR6R7, -COR6 and halogen; R5 is 1 to 3 substituents independently selected from the group consisting of -OR6, -O (CO ) R6, -O (CO) OR9, -O (CO) NR6R7, -NR6R7, (lower alkylene) -COOR6 and -CH = CH-COOR6; R6, R7 and R8 are selected independently of the group consisting of hydrogen and lower alkyl, and R9 is lower alkyl

Description

"SUBSTITUTE AZETIDINONE COMPOUNDS USEFUL AS HYPOCOLESTEROLEMIC AGENTS" BACKGROUND OF THE INVENTION The present invention relates to substituted azetidinones useful as hypocholesterolemic agents in the treatment and prevention of atherosclerosis, to the combination of a substituted azetidinone of this invention and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis, to pharmaceutical compositions comprising azetidinones, and combinations, to a process for preparing intermediates useful in the synthesis of azetidinones, and to the novel intermediate prepared by that process. Atherosclerotic coronary heart disease represents the leading cause of cardiovascular death and morbidity in the Western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, smoking cigarettes and serum cholesterol. A total cholesterol level in excess of 225 to 250 milligrams per deciliter is associated with a significant increase in risk.

Cholesteryl esters are a major component of atherosclerotic lesions and the predominant storage form of cholesterol in arterial wall cells. The formation of cholesteryl esters is also a key step in the intestinal absorption of dietary cholesterol. A few azetidinone compounds have been disclosed as being useful for lowering cholesterol and / or for inhibiting the formation of cholesterol-containing lesions in the arterial walls of mammals. . U.S. Patent No. 4,983,597 discloses N-sulfonyl-2-azetidinones as anti-cholesterolemic agents and Ram et al., In Indian J. Chem., Sect. B. 29B, 12 (1990), page 1134-7, and give a know the ethyl 4- (2-oxoazetidin-4-yl) phenoxy-alkanoates as hypolipidemic agents. European Patent Publication Number 264,231 discloses l-substituted-4-phenyl-3- (2-oxoalkylidene) -2-azetidinones as inhibitors of blood platelet aggregation. European Patent Number 199,630 and European Patent Application Number 337,549 disclose substituted elastase inhibitory azetidinones which are said to be useful in the treatment of inflammatory conditions resulting in tissue destruction that are associated with various disease states, v. gr, atherosclerosis. O93 / 02048 discloses substituted beta-lactams useful as hypocholesterolemic agents. In addition to the regulation of dietary cholesterol, the regulation of cholesterol hemostasis of the whole body of humans and animals involves the modulation of cholesterol biosynthesis, bile acid biosynthesis and catabolism of plasma lipoproteins containing cholesterol. The liver is the main organ responsible for the biosynthesis of cholesterol and catabolism and, because of this reason, it is a major determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) that are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the cholesterol-carrying lipoproteins that are predominant in plasma and an increase in their concentration is correlated with increased atherosclerosis. When the absorption of cholesterol in the intestines is reduced, whatever the means, the liver is given less cholesterol. The consequence of this action is a decreased production of hepatic lipoprotein (VLDL) and an increase in hepatic clearance of plasma cholesterol, mostly as LDL. Therefore, the net effect of an inhibition of the absorption of - Intestinal cholesterol is a decrease in plasma cholesterol levels. The inhibition of cholesterol biosynthesis by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (EC1.1.1: 34) has been shown to be an effective way to reduce plasma cholesterol (Witzum, Cirulation, 80 , 5 (1989), page 1101-1114) and reduce atherosclerosis. Combination therapy of a reductase inhibitor HMG CoA and a bile acid sequestrant has been shown to be more effective in human hyperlipidemic patients than any agent in monotherapy (Illingworth, Drugs, 36 (Suppl. 3) (1988), page 63 -71). * COMPENDIUM OF THE INVENTION The compounds of the present invention are represented by the formula I or a pharmaceutically acceptable salt thereof, wherein: Ar1 is R3-substituted aryl; Ar2 is R ^ -substituted aryl; Ar3 is R - ^ - substituted aryl; Y and Z are independently selected from the group consisting of -CH2-, -CH (lower alkyl) - and C (lower dialkyl) -; A is -0-, -S-, -S (O) - or -S (0) 2-; R1 is selected from the group consisting of -OR6, -0 (CO) R6, -0 (CO) OR9 and -0 (CO) NR6R7; R2 is selected from the group consisting of hydrogen, alkyl and lower aryl; or R1 and R2 together are = 0; q is 1, 2 or 3; p is 0, 1, 2, 3 or 4; R5 is substituents 1-3 which are independently selected from the group consisting of -OR6, 0 (C0) R6, -0 (C0) 0R9, -0 (CH2) I-5OR9, -0 (CO) NR6R7, -NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO ) NR7R8, -NR6S02-alkyl? lower, -NR6S02-aryl, -CONR6R7, -COR6, -S02NR6R7, S (0) 0-2alkyl ?, S (0) 0_2-aryl, -0 (CH2) Í-ÍQ-COOR6 '-0 (CH2) I_IOCONR6R7 'o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (lower alkylene) -C00R6, -CH = CH-C00R6; R3 and R4 are independently substituents 1-3 which are independently selected from the group consisting of R * ^, hydrogen, p-lower alkyl, aryl, -N02, -CF3 and p-halogen; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl. Preferred are compounds of formula I wherein Ar is R -substituted phenyl, especially phenyl (4-R3) -substituted. Ar 2 is preferably R 4 -substituted phenyl, especially phenyl (4-R 4) -substituted. Ar3 is preferably R- ^ - substituted phenyl, especially phenyl (4-R) -substituted. The mono-substitution of each of Ar ^, Ar2 and Ar3 is preferred. Y and Z each preferably is -CH2-. R 2 is preferably hydrogen, R 2 preferably -OR 6 wherein R 6 is hydrogen, or a group readily metabolizable to a hydroxyl (such as -0 (CO) R 6, -0 (CO) OR 9 and -0 (CO) NR 6 R- as defined above). Also preferred are compounds wherein R ^ and R2 together are = 0. The sum of q and p is preferably 1 or 2, more preferably 1. Compounds are preferred where p is zero, q is 1, compounds are more preferred where p is zero, q is 1, Y is -CH2 - and R ^ is -OR6, especially when R6 is hydrogen.

Another group of preferred compounds is that wherein Ar 1 is R -substituted phenyl, Ar 2 is R 4 -substituted phenyl, and Ar 3 is R 3 -substituted phenyl. Also preferred are compounds wherein Ar ^ is R3-substituted phenyl, Ar2 is phenyl, R ^ -substituted, Ar3 is R5-substituted phenyl and the sum of p and q is 1 or 2, especially 1. The especially preferred compounds are those in where r ^ is substituted phenyl R3, Ar2 is phenyl and substituted R4, Ar3 is phenyl, R ^ -substituted, p is zero and q is 1. A is preferably -0-. R3 preferably -COOR6, -CONR6R7, -COR6, -S0-2NR6R7, S (O) or-2 ~ alk? Ui-lc? s < °) 0-2"aryl ° 'N02 ° halogen.

An especially preferred definition for R3 is halogen, especially fluoro or chloro. R 4 is preferably hydrogen, lower alkyl, -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CO = NR6R7, -NR6R7, COR6 or halogen, wherein R6 and R7 are preferably independently hydrogen or lower alkyl, and R9 is preferably lower alkyl A particularly preferred definition for R 4 is hydrogen or halogen, especially fluoro or chloro R 5 is preferably -OR 6, -0 (CO) R 6, -0 (CO) OR 9, -0 (CO) NR6R7, -NR6R7, - (lower alkylene) -COOR6 or -CH = CH-COOR6, wherein R6 and R7 are preferably - independently hydrogen or lower alkyl, and R9 is preferably lower alkyl. An especially preferred definition for R * ^ is -OR6, - (lower alkylene) -COOR6 or -CH = CH-C00R6, wherein R6 is preferably hydrogen or lower alkyl. The invention also relates to a novel process for preparing chiral beta-amino ester intermediates of formula II wherein Ar20 is Ar2, a suitably protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl, Ar31- * is Ar3, an appropriately protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl, and -C (0) OR10 is an acyl radical of a chelal alcohol, useful in the preparation of the 3-unsubstituted azetidinones of the formula wherein Ar20 and Ar30 are as defined above.

- The process for preparing the compounds of the formula II comprises: reacting a bromoacetate of a chiral alcohol of the formula R10OC (0) CH2Br, wherein R10OH is an optically pure chiral alcohol-, an imine of the formula Ar 0-N = CH-Ar?, Where Ar2 * -1 and Ar (-) with as defined above, and zinc to obtain a beta-amino ester of formula II. The intermediate of formula II can be converted to the chiral 3-unsubstituted azetidinone of formula III by cyclizing the beta-amino ester of formula II with a Grignard reagent. This invention also relates to novel intermediates of formula II, ie, compounds of formula II wherein Ar 20 is R 4 -substituted aryl, suitably protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl; Ar ^ is R-^ - substituted aryl, an appropriately protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl; -C (0) ORlO is an acyl radical or an optically pure chiral alcohol selected from the group consisting of 1-menthyl, isopino-canphenyl, (lS) -endo-bornyl, isomenthyl, trans-2-phenylcyclohexyl or phenylmentil; R5 is substituents 1 to 3 independently selected from the group consisting of -OR6, 0 (CO) R6, -0 (CO) OR9, -0 (-CH2) 1_5OR9, -0 (CO) NR6R7, -NR6R7, -NR6 (CO) R7, -NR6 (COOR9, -NR6 (CO) NR7R8, -NR6S02-lower alkyl, -NR6S02-aryl, -CONR6R7- -COR6, -S02NR6R7, S (O) or -2_alkyl, S (O) 0-2-aryl, -O (CH2) 1_10-COOR6, -0 (CH2) i-ioCONR6R7, o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (lower alkylene) -COOR6 , -CH = CH-C00R6; R4 is substituents 1 to 3 which are independently selected from the group consisting of R5, H, p-lower alkyl, aryl, -N02, -CF3 and p-halogen; R6, R7 and R8 they are independently selected from the group consisting of H, lower alkyl, aryl and aryl-substituted lower alkyl, and R9 is lower alkyl, aryl or aryl-substituted lower alkyl.

This invention also relates to the use of a compound of the formula I as a hypocholesterolemic agent to reduce plasma cholesterol levels and to treat or prevent atherosclerosis in a mammal in need of this treatment. In another aspect, the invention relates to a pharmaceutical composition comprising a substituted azetidinone of the formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of the pharmaceutical composition as a hypocholesterolemic agent for reducing plasma cholesterol levels and for treating or preventing atherosclerosis and with a method for preparing the compositions by mixing a compound of the formula I, and the carrier pharmaceutically acceptable. The present invention also relates to a method for reducing plasma cholesterol levels and to a method for treating or preventing atherosclerosis, which comprises administering to a mammal in need of this treatment, an effective amount of a combination of an absorption inhibitor. of substituted azetidinone cholesterol of this invention and an inhibitor of cholesterol biosynthesis. That is, the present invention relates to the use of a substituted azetidinone cholesterol absorption inhibitor for combined use with a cholesterol biosynthesis inhibitor (and, in like manner, with the use of a cholesterol biosynthesis inhibitor for use combined with a substituted azetidinone cholesterol absorption inhibitor) to treat or prevent atherosclerosis or reduce plasma cholesterol levels. In yet another aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a substituted cholesterol absorption inhibitor of azetidinone, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier. The use of the composition to treat or prevent atherosclerosis or reduce plasma cholesterol levels is also proposed such as the preparation of the composition by mixing a substituted azetidinone cholesterol absorption inhibitor, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier. . In a final aspect, the invention relates to a kit comprising in a package an effective amount of a substituted azetidinone cholesterol absorption inhibitor in a pharmaceutically acceptable carrier, and in a separate package, an effective amount of a biosynthesis inhibitor. of cholesterol in a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION As used herein, the term "lower alkyl" means straight or branched alkyl chains of 1 to 6 carbon atoms. Similarly, "lower alkylene" means a straight or branched divalent alkyl chain of 1 to 6 carbon atoms. The term "aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl. "Halogen" refers to fluoro, chloro, bromo or iodo radicals. The above statement, wherein R6, R7 and R8 are said to be independently selected from a group of substituents, means that R6, R7 and R8 are independently selected, but also where a variable of R6, R7 or R8 occurs more than one Once in a molecule, those events are independently selected (eg, if R1 is -OR6 wherein R6 is hydrogen, R4 can be -OR6 where R6 is lower alkyl). Similarly, R3, R4 and R * ^ is independently selected from a group of substituents, and where more than one R3, R4 and / or R * ^ are present, the substituents are independently selected; those skilled in the art will recognize that the size and nature of the substituent (s) will affect the number of substituents that may be present. The compounds of the invention have at least one asymmetric carbon atom and are therefore all isomers including diastereomers and rotational isomers which are proposed as being part of this invention. The invention includes dimer isomers in both pure form and in mixture, including racemic mixtures. The isomers can be prepared using conventional techniques either by reacting optically pure or optically enriched starting materials or by separating the isomers of a compound of the formula I. Those skilled in the art will appreciate that for some compounds of the formula I, an isomer will show greater pharmacological activity than other isomers. The compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, ethanesulfonic and other carboxylic acids and minerals well known to those people skilled in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by treating the salt with an aqueous diluted basic solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form to some degree in certain physical properties such as solubility in polar solvents, but the salt otherwise is equivalent to its respective free base forms for the purposes of the invention. Certain compounds of the invention are acidic (e.g., those compounds that possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of these salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like. Cholesterol biosynthesis inhibitors for use in the combination of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin and Cl-981; HMG CoA synthetase inhibitors, for example L-659,699 ((E acid, E-ll- [3 'R- (hydroxy-methyl) -4' -oxo-2 'R-oxetanyl] -3,5, R-trimethyl -2, -undecadienoic), squalene synthesis inhibitors, for example, squaletostatin 1, and squalene epoxidase inhibitors, for example, NB-598 hydrochloride ((E) -N-ethyl-N- (6, 6 dimethyl-2-hepten-4-ynyl) -3 - [(3,3 '-bit? ofen-5-yl) methoxy] benzene-methamnam) The preferred HMG CoA reductase inhibitors are lovastatin, pravastatin and simvastatin. compounds of the formula I can be prepared by known methods, for example, the preparation of the compounds of the formula I, wherein Ar -'-, Ar2, Ar3, R2 and Zp are as described above, and -CH2-, q is 1, R1 is OH, and A is -O- or -S- (ie, a compound of the formula la), is described in Method 1: Method 1 the An epoxy-substituted azetidinone of the formula 1 can be treated with a compound of the formula Ar ^ -A'-M, wherein A * is -O- or -S-, wherein M is a metal eg sodium, potassium , lithium or magnesium, in an inert solvent such as tetrahydrofuran (THF) at room temperature and under an inert atmosphere such as N 2 in order to obtain a compound of the formula la. The compounds of the formula 1_ are prepared immediately before the reaction by treating a solution of Ar ^ -OH or AR ^ -SH in an inert solvent such as THF, with a suspension of alkali metal hydride, or, when M is magnesium, a solution of an alkyl Grignard reagent such as isopropylmagnesium bromide, in the same solvent. Alternatively, a compound of formula 1 can be treated with Ar ^ -OH or Ar ^ -SH in the presence of a reagent such as ZnCl to obtain a compound of formula la. The preparation of the starting materials of the formula 1_ is shown by the following processes (exemplification compounds where p is 0, ie Z is not present), wherein Process A prepares the compounds of the formula l_a, which have a relative "trans" orientation in beta-lactam at positions 3 and 4, and wherein Process B prepares the compounds of formula Ib, which has a relative "cis" orientation in beta-lactam at positions 3 and 4: Process A - - In the first step, the crotonyl chloride (2_) is refluxed with an imine of the formula, wherein Ar2 and Ar3 are as defined above, in an inert solvent such as CH2C12 or THF in the presence of a base such as tri-n-butylamine, triethylamine or diisopropylethylamine to obtain a trans-substituted 3-vinyl-2-azetidinone of the formula 4. The compound of the formula _ is then treated with an oxidation agent such as MCPBA in a solvent Inert such as CH2C12, the reaction is rapidly quenched with a reagent such as aqueous NaS? 3 and conventional extraction and separation techniques are used to obtain a mixture of 3-oxiranyl-2-azetidinone epimeros which can be separated by HPLC.

Process B: * 4a The 3-vinyl-2-azetidinone of the formula 4 ^ can be treated with a strong base such as lithium diisopropylamide (LDA) in an appropriate solvent such as THF at low temperatures, e.g., -78 ° C, followed by treatment with a bulky acid such as 2, β-di-tert-butyl-4-methylphenol (BHT), glacial acetic acid or isovaleric acid, to obtain the corresponding cis-3-vinyl-2-azetidinone (4a) ). The compound of the formula 4a can be oxidized in a manner similar to that described in Process A, to obtain the compound of the formula Ib. The following Method 2 describes the preparation of compounds of the formula I wherein Ar1, Ar2, Ar3, R1, R2, Yq and Zp are described above and A is -O- or -S- (ie, a compound of the formula le): Method 2 AG1-A Ar'-A-Y.- z ,. TO, An activated carboxylic acid derivative of the formula 5 / for example an acid chloride, wherein Q is chloro, and wherein L is a substituent group such as a halide, which can be reacted with an imine of the formula 3 ^ in presence of a base such as trialkylamine (e.g., triethylamine or tri-n-butylamine) at room temperature or at elevated temperature in an inert solvent such as CH C12 or toluene. The intermediate of formula 6 is then reacted with a compound of the formula Ar ^ -A'-M as described in Method 1 in order to obtain a compound of the formula le. Method 3 describes the preparation of the compounds of the formula Id wherein Ar1, Ar2, Ar3 and Yq are as described above, R1 is OH, R2 is H, p is zero and A 'is -0- or -S-: Method 3: A 3-substituted azetidinone of the formula 7 is treated with a strong base such as LDA or lithium dicyclohexylamide at low temperatures (e.g., -70 ° C to -78 ° C) in an inert solvent such as THF, followed by reaction with an aldehyde of the formula 8_. When 3-unsubstituted azetidinone is chiral, the reaction products with aldehyde 8 are non-racemic. The starting materials of formulas 2, 3, 5, 1_ and Q_ are known or prepared by methods known in the art. The chiral starting materials of the formula III, of which 7 is an example, can be prepared by cyclizing the chiral beta-amino ester intermediates of the formula II, which intermediates are prepared by the novel process described in what follows antece The process for preparing the compounds of the formula III is shown in the following reaction graph: R "&OC ( where Ar2 ?, r ^ and R11-1 are as defined above. Suitable protecting groups for the hydroxy- or amino-substituted aryl groups in Ar20 and Ar3 * -5 are exemplified in the table below. Typical optically pure chiral alcohols R10OH are selected from the group consisting of 1-menthyl, isopino-canphenyl, (1S) -endo-bornyl, isomenthyl, trans-2-phenylcyclohexyl and phenyl-butyl. To prepare the preferred compounds of formula III, preferred preferred pure alcohols are 1-menthyl, (-) isopino-canphenyl, (1S) -endo- (-) ornyl, (+) isomenthyl, (-) trans-2- phenylcyclohexyl and (-) phenylmentyl. In the first step, the equimolar amounts of a bromoacetate of the formula 9 and an i ina of the formula 3 ^ are reacted with fine zinc powder in an inert solvent such as anhydrous dioxane. THF or diethyl ether, preferably in the presence of a zinc activating agent such as iodine, at a temperature of 10 to 30 ° C, preferably 23 ° to 25 ° C, for about 24 to 48 hours. The reaction is also preferably carried out with ultrasonification. The resulting beta-amino ester is purified by conventional methods, for example the fine zinc powder is filtered, the excess imine is crystallized and the beta-amino ester is then crystallized: and a beta-amino ester can be recovered additional by flash chromatography. In the second step, the beta-amino ester is cyclized by treatment with a Grignard reagent such as isopropylmagnesium bromide or ethylmagnesium bromide in an ether solvent such as THF at -40 ° to 40 ° C, preferably at 0 °. C to room temperature. After cyclization, the protecting groups can be removed as necessary by methods well known to those skilled in the art. The starting materials of formula 9 are prepared by reacting the sodium alkoxide in the corresponding chiral alcohol with bromoacetyl chloride at -40 ° C to room temperature, preferably at -20 ° C to room temperature in an inert solvent such as THF or diethyl ether. be sent through the time difference addition circuit 23R and the level difference addition circuit 25R to the adder 26R. Referring to Figure 3, the functions hL] _, hLr, hp, hp > r of head transfer are considered as head transfer functions from sources 23, 24 of sound to both ears L, R of the listener M. The sound corresponding to the response of the impulse wound by the filters ljjj, 8Rf 9L 'R Diffitals are supplied by the handset 7 to the user, so that SLHL1 + SR ^ Rl and SRnRr + SLnLr will be supplied to the ears 1, left and right of the listener M. If the listener M moves the head to the left, for example , the left ear 1 moves away from the sound sources 2 \, 22 while the right r sound moves towards the sound sources 2, 22. Consequently, the time difference and the level difference occur in the input speech signal reaching ears 1, left and right r. It is the aforementioned second pair of circuits 23 ^, 23R of addition of time difference and of the second pair of circuits 25L, 25R of addition of level difference, respectively. The delay time added by the time difference addition circuits 23L of the L side is Table 1 We have found that the compounds of this invention decrease serum lipid levels, in particular serum cholesterol levels. The compounds of this invention have been found to inhibit the intestinal absorption of cholesterol and significantly reduce the formation of cholesteryl esters in the liver in animal models. Therefore, the compounds of this invention are hypocholesterolemic agents due to their ability to inhibit the esterification and / or intestinal absorption of cholesterol; they are therefore useful in the treatment and prevention of atherosclerosis in mammals, in particular in humans. In addition to the appearance of the compound, the present invention therefore also relates to a method for decreasing serum cholesterol levels, which method comprises administering to the mammal in need of this treatment, a hypocholesterolemic effective amount of a compound of formula I of this invention. The compound is preferably administered in a pharmaceutically acceptable carrier suitable for oral administration. The present invention also relates to a pharmaceutical composition comprising a compound of the formula I of this invention and a pharmaceutically acceptable carrier. The compounds of the formula I can be administered by any conventional oral dosage form such as capsules, pills, powders, wafers, suspensions or solutions. The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques and additives. These pharmaceutically acceptable excipients and additives include compatible non-toxic fillers or fillers, binders, disintegrants, stabilizers, preservatives and antioxidants, lubricants, flavoring agents, thickeners, coloring agents, emulsifiers and the like. The hypocholesterolemic daily dose of a compound of the formula I is from about 0.1 to about 30 milligrams per kilogram of body weight per day, preferably from about 0.1 to about 15 milligrams per kilogram. For an average body weight of 70 kilograms, the dosage level is therefore from about 5 to about 2000 milligrams of drug per day, preferably from about 5 to about 1000 milligrams, which is provided in a single dose or divided doses. in 2 to 4. The exact dose, however, is determined by the attending physician and depends on the potency of the compound administered, the age, weight, condition and response of the patient. For the combinations of this invention wherein the substituted azetidinone is administered in combination with a cholesterol biosynthesis inhibitor, the typical daily dose of the cholesterol biosynthesis inhibitor is 0.1 to 80 milligrams per kilogram of body weight of the mammal that is administered. in individual or divided dosages, usually once or twice a day; for example, for the HMG CoA reductase inhibitor, from about 10 to about 40 milligrams per dose is given 1 to 2 times per day, providing a total daily dose of about 10 to 80 milligrams per day, and for other biosynthesis inhibitors. of cholesterol, from about 1 to 1000 milligrams per dose is provided 1 to 2 times per day providing a total daily dose of about 1 milligram to about 2 grams per day. The exact dose of any component of the combination to be administered is determined by the attending physician and depends on the potency of the compound administered, the age, weight, condition and response of the patient. When the components of a combination are administered separately, the number of doses of each component that is provided daily may not necessarily be the same, eg, where a component may have a longer duration of activity, and therefore, it will need administered less frequently. Since the present invention relates to the reduction of plasma cholesterol levels, by treatment with a combination of active ingredients, wherein the active ingredients can be administered separately, the invention also relates to combining separate pharmaceutical compositions in the form of a case. That is, a kit wherein two separate units are combined is proposed: a pharmaceutical composition of the cholesterol biosynthesis inhibitor and a pharmaceutical composition of the substituted azetidinone absorption inhibitor. The preferential kit will include instructions for the administration of the separated compounds. The case form is particularly advantageous when the separate components must be administered in different dosage forms (e.g., oral and parenteral) or administered to different dosage intervlaos. The following are examples for preparing the 3-unsubstituted azetidinone starting materials and the compounds of the formula I. ' The stereochemistry listed is a relative stereochemistry unless otherwise mentioned. The terms cis and trans refer to the relative orientation in beta-lactam at positions 3 and 4.

Preparation 1 Step 1: Preparation of bromoacetate (+) - trans-2-phenyl-cyclohexyl. Dissolve (+) - trans-2-phenyl-cyclohexanol (0.0113 mol) in anhydrous THF, cool to -15 ° C, add NaH (1.2 equivalents) in portions and stir for 30 minutes. Bromoacetyl chloride is added dropwise (1.5 equivalents) and stir overnight at room temperature. The reaction mixture is cooled to 0 ° C and quenched with -t-butanol (5 milliliters) and water, dropwise (10 milliliters). The mixture is warmed to room temperature, diluted with ethyl acetate (EtOAc) and washed sequentially with water (2 x 50 milliliters) and brine (2 x 50 milliliters). The organic layer is dried through MgSO 4, filtered and concentrated. The resultresidue is purified by silica gel chromatography, elution with hexane > 5 percent of EtOAc / hexane.

Step 2: Preparation of A solution of fine powder of Zn (2.88 grams, 44 millimoles) and iodine (0.3 grams, 1.2 millimoles) in anhydrous dioxane (50 milliliters) is subjected to reflux for 1 hour, then cooled to room temperature. The flask is immersed in an ultrasonification bath, a mixture of the product of step 1 (7.4 millimoles) and (4-fluoro) aniline of 4-benzyloxybenzylidine (1.87 grams, 6 millimoles) is added and sonified for 48 hours at room temperature. . The fine zinc dust is filtered through celite and the filtrate is concentrated. The resultresidue is redissolved in a minimum amount of EtOAc; after 1 hour, and the unreacted imine is filtered crystallized. The filtrate is concentrated in vacuo and the resultresidue is redissolved in a minimum amount of CH3OH to crystallize the desired beta-amino ester (1.2 grams, 2.2 mmol). The mother liquor is concentrated and chromatographed on silica gel, elutwith 10 percent hexane / EtOAc to obtain additional beta-amino ester (0.3 gram). Melttemperature from 129 ° C to 131 ° C. The elemental analysis calculated for C34H34FNO3 is C, 78.01; H, 6.50; N, 2.67; Found C, 77.62; H, 6.65; N, 2.74. Step 3: Treat a solution of the product from step 2 (0.18 millimole) in THF (5 milliliters) at 0 ° C. with ethylmagnesium bromide (1.2 equivalents), stirrfor 4 hours and allowthe reaction mixture to warm to room temperature. The reaction mixture is quenched with aqueous NH 4 Cl (10 milliliters) and extracted with ether (50 milliliters). The organic layer is dried through MgSO 4 and concentrated. The product is isolated by chromatography - - of preparation on a silica gel plate elutwith 20 percent EtOAc / hexane. The product is analyzed usa chiral analytical HPLC AS column, elutwith i-propanol: hexane (20/80): the retention times for two enantiomers were 15.3 and 16.4 minutes at a flow rate of 0.5 milliliters per minute .

Step 1: A solution of crotonyl chloride (1.81 milliliters, 0.02 mol) in CH2C12 (50 milliliters) per drop is added, over a period of 1 hour, to a reflux solution of tri-n-butylamine (7.23 milliliters, 0.03 mol). ) and p-methoxybenzylidene aniline (3.19 grams, 0.015 mol) in CH C12 (100 milliliters). It is refluxed for 16 hours after the addition is complete and then cooled to room temperature. It is washed with water (2 times 100 milliliters) and a saline solution (1 time 100 milliliters) and then dried through Na 2 SO 4, filtered and concentrated. The resultoil is stirred with an excess of hexane and filtered to obtain a yellow solid (2.5 grams). The residue is purified by silica gel chromatography elutwith EtOAc / hexane (1: 5) to obtain a white solid (2.0 grams, 49 percent yield), melttemperature of 119 ° C to 120 ° C, EIMS: M + = 279. Step 2; To a stirred solution of the product from Step 1 (compound A) (1.0 gram, 0.0036 mol) in CH Cl2 (40 milliliters) at room temperature, MCPBA (1.9 grams, 0.01 mol) is added in portions. After 36 hours, the reaction mixture is rapidly cooled by the dropwise addition of 10 percent aqueous Na 2 SO 3, the aqueous layer is separated and the organic layer is washed consecutively with 5 percent NaHCO 3 (2 times 50 milliliters), water (1 time 50 milliliters) and a saline solution (1 time 50 milliliters), dried through Na S0 and concentrated. The resulting residue is purified by silica gel chromatography eluting with EtOAc / hexane (2: 1) to obtain a mixture of epoxide epimers as an off-white solid (1.00 gram, 96 percent yield). Purify further by HPLC, eluting with 5 percent EtO with CH2Cl2 to obtain: less polar epoxide: 0.27 gram, melting temperature of 85 ° C to 88 ° C, EIMS: M + 295. more polar epoxide: 0.54 gram, melting temperature from 138 ° C to 141 ° C, EIMS: M + 295. Step 3: To a suspension of NaH (0.53 gram of a dispersion in 60 percent oil, 0.013 mol) in THF (35 milliliters) at room temperature, add 4-fluorophenol (2.26 grams, 0.02 mol and stir for 30 minutes). minutes until a crystalline solution is obtained, add the larger product from Step 2 (compound Bl) (2.0 grams, 0.0067 mol) and stir at room temperature for 3 days, dilute the reaction mixture with EtOAc, wash with water (1 time 30 milliliters) and then with a saline solution (2 times 30 milliliters), dry through Na2SO4, filter and concentrate to obtain a brown oil (3.1 grams) .The oil is purified by gel chromatography. of silica eluting with EtOAc / hexane (1: 2) to obtain the title compound as a racemic mixture (1.23 grams, 45 percent yield) (Reld'S, 3S, 4S) -l-phenyl-3- [l -hydroxy-2- (4- fluorophen i) ethyl] -4- (4-methoxyphenyl) -2-azetidinone). The racemate from Step 3 is resolved using an HPLC Chiracel 'R column of preparation, eluting with hexane and isopropanol (80:20) to provide: : Enantio ero A: ura 9 ° C; High resolution MS: calculated side = 407.1533; observed = 407.1539 Enantiomero 3 72 ° C; n: calculated = 407.1533; observed = 4C7.1547 G Example 2 He passed To a solution of compound C (5.0 grams, 13.4 millimoles) in CH2Cl2 (70 milliliters), MCPBA (7 grams, 40 mmol) and aHC? 3 (3 grams) are added. Stir under N2 for 36 hours (approximately complete reaction in 95 percent), then add a small amount of (CH3) 2S (approximately 1 milliliter) and stir for 30 minutes. The acidic by-products are extracted to the aqueous aHC? 3 solution and discarded. The organic layer is washed with brine, dried through MgSO 4 and the solvent removed in vacuo. The crude residue is purified by silica gel chromatography eluting with 2 percent ethyl acetate (EtOAc) / hexane > 30 percent EtOAc / hexane to obtain: isomer 1 (compound D-1), 1.7 grams, EIMS: M + = 389; isomer 2 (compound D-2), 2.3 grams, EIMS: M + = 389; Step 2: To a solution of 4-fluorophenol (0.715 gram, 6. 38 millimoles) in THF (20 milliliters), a suspension of 80% NaH (100 milligrams, 3.5 ml Limols, pre-washed with hexane) in THF is added. After the bubbling ceases, a solution of the product from Step 1 (compound D-1) (= 0.45 gram, 0.00115 mol) in THF is added to this solution and the reaction is maintained under N 2 at room temperature for 2 days. The reaction mixture is treated with aqueous Na 2 C 3 (20 milliliters), the product is extracted with EtOAc, dried over MgSO 4 and the solvent is removed in vacuo. The resulting residue is purified by silica gel chromatography eluting with 5 percent EtOAc / CH2Cl2 - > 40 percent EtOAc / CH2Cl2.

Step 3: Treat a solution of the product from Step 2 (compound E) (0.185 gram, 0.00037 mol) in ethanol with 10 percent Pd / C (120 milligrams). It is stirred under a vacuum of the aspirator and then the N2 gas is introduced, repeating this procedure several times to eliminate the oxygen. Hydrogen gas is introduced and maintained at one atmosphere for 18 hours. Hydrogen is removed in vacuo and N2 reintroduced. The reaction mixture is filtered through Celite (R) and concentrated to a glass. Purify by preparative TLC eluting with 15 percent EtOAc / CH2Cl2 to obtain 0.102 gram of the header compound (rel (l'S, 3S, 4S) -l- (4-fluorophenyl) -3- [l-hydroxy-2- [4-fluorophenoxy] ethyl) -4- (4-hydroxyphenyl) -2-azetidinone). HRMS FAB: C 23 H 20 NO F 2 (M + 1) calculated 412.1360; found 412.1368. Elemental analysis: Calculated: C = 67.15, H = 4.64, N = 3.41, F = 9.25; Found: C = 67.00, H = 4.87, N = 3.26, F = 9.09. The racemic 1- (4-fluorophenyl) -3- [l-hydroxy-2- [4-fluorophenoxy] -ethyl) -4- (4-hydroxyphenyl) -2-azetidinone is resolved using a column of HPLC Chiracel HPLC (R ) of preparation eluting with hexane and isopropanol (70:30) to provide: Enantiomero A (l'R, 3R, 4R) 1 = + 33.2 ° (CHCI3) Example 3 0 Using the less polar isomer of Step 2 of Example 1 (compound B-2), the procedure of Step 3 of Example 1 is carried out to obtain the header compound (Reí (l'R, 3S, 4S) -l phenyl-3- [l-hydroxy-2- (4-fluorophenoxy) ethyl] -4- (4-methoxyphenyl) -2-azetidinone) co or a 5-racemate. Melting temperature of 125 ° to 129 ° C, HRMS FAB: M + l calculated = 408.1611, observed = 408.1600.

Example 4 A procedure similar to Example 1, Step 3 is used, substituting 4-fluorothiophenol for 4-fluorophenol and diluting with ether instead of EtOAc. After concentrating the extracted product, it is crystallized from ether-hexane to obtain a white solid (0.3 gram, 70 percent), melting temperature from 129 ° C to 130 ° C, MS: HRMS FAB: calculated 424.1383, found 424.1394 . , Example 5 To a solution of the product of Example 4 (0.27 gram, 0.637 millimole) in CH2C12 (20 milliliters) at 0 ° C is added MCBPA (0.12 gram, 0.695 millimole) in portions and stirred for 2 hours. The reaction is quenched with (CH3) 2S (0.5 milliliter), it is diluted with CH2Cl2, washed with 5 percent NaHCO3 (2 times 20 milliliters), water (1 time 20 milliliters) and a saline solution (1 time 20 milliliters), dried through Na2S4, filtered and concentrate. The resulting residue is purified by silica gel chromatography eluting with EtOAc / hexane (1: 1) and (2: 1) to obtain two components: 5A, the most polar component: 0.22 gram; 5B, the less polar component: 0.0259 gram, HRMS FAB: calculated 456.1281, observed 456.1280. 5A is further purified by HPLC eluting with 25 percent hexane / EtOAc to obtain isomers A and B: Isomer A (less polar, 5A-1): melting temperature of 141 to 143 ° C; HRMS FAB: calculated 440.1332, observed: 440.1348; Isomer B (more polar, 5A-2): melting temperature of 176 to 179 ° C; HRMS FAB: calculated 440.1332, observed 440.1352.

Example 6 - A solution of lithium dicyclohexylamide (5.7 mmol) in THF (40 milliliters) is prepared by treating a cold solution (0 ° C) of dicyclohexylamine in THF with one equivalent of n-butyllithium (5.7 millimoles, 3.6 milliliters of a solution of 1.6M hexane). The solution is cooled to -70 ° C and a pre-cooled solution (-70 ° C of compound F (1.74 grams, 5 mmol) in THF is added through a cannula, after 15 minutes, slowly, and with After stirring, a solution of 4-fluorophenoxy acetaldehyde (1 gram, 6.5 mmol) in THF is added after 30 minutes of stirring, a solution of 4-fluorophenoxy acetaldehyde (1 gram, 6.5 mmol) in THF is added. at -78 ° C, the reaction mixture is quenched with glacial acetic acid (0.6 milliliters), the product is exted into ether, washed with a layer of ether and aqueous aHC 3, dried over MgS. The solvent is evaporated under vacuum and the resulting residue is purified by chromatography on silica gel, eluting with 3: 1 hexane / EtOAc > 1: 1 EtOAc / hexane. The desired fions are concentrated to obtain three compounds, Gl, G2 and G3: Step 2: A procedure similar to that described in Example 2, Step 3 is used to remove the benzyl group of the compounds Gl, G2 and G3 in order to obtain compounds 6a, 6b and 6c: The mic compound 6a is separated into its enantiomers by chromatography on an HPLC column for preparation of Chil (R) AS, eluting with hexane / isopropyl alcohol (70:30). (Compound 6a is the same as the product of Example 2). t 6b: Melting temperature of 130 ° C to 131 ° C 6c: HRMS FAB: calculated 412.1360, observed 412.1364. Example 7 The azetidinone, compound H (1.7 grams, 7 mmol) is dissolved in anhydrous THF (50 milliliters) and cooled to -78 ° C. Fresh LDA (1.2 equivalents) is added as a THF solution (10 milliliters) and stirred for 45 minutes at -78 ° C. acetaldehyde of fluorophenoxy (1.3 grams, 1.2 equivalents) in THF (5 milliliters) is added dropwise and stirred for 4 hours. The reaction mixture is warmed to 0 ° C and quenched with aqueous NH 4 Cl (50 milliliters). Ext with ether (200 milliliters), dry the organic phase through MgSO 4, filter and concentrate. The resulting residue is purified by evaporation chromatography on silica gel, eluting with hexane > 15 percent of EtOAC / hexane. The chromatographic and Nuclear Magnetic Resonance analysis show that 7A is the same as the product of Example 1 and 7B is the same as the product of Example 3.

Example 8 , 0-13 OCHa •do not - - - It is a solution of the product of the example, Step 3 (0.15 gram, 0.37 millimole) with THF with a suspension of NaH (0.017 gram of 60 percent in oil, 0. 42 millimole) at room temperature. After 15 minutes CH3I (0.07 milliliter, 1.12 mmol) is added with stirring and maintained at room temperature for 16 hours. The mixture is diluted with EtOAc, exted with brine, the organic layer is dried through NaS? 4 and the solvent is evaporated in vacuo. The resulting oil is purified by thin layer chromatography of silica gel preparation, eluting with EtOAc / hexane (1: 3) in order to get 60 milligrams of the header compound. HRMS FAB (M + 1): calculated 422.1768; observed 422 1763 Example 9 A solution of the product of Example 1 is treated, Step 3 (0.3 gram, 0.7 millimole) in CH C12 with pyridinium chlorochromate (0.55 gram, 2.5 millimole) and basic alumina - (0.4 gram). It is stirred at room temperature for 3 days, filtered through a pad of celite and washed with CH2C12. Purify the product by silica gel chromatography eluting with EtOAc / hexane (1: 3) to obtain 0.23 gram of the header compound. HRMS FAB (M + 1): calculated 406.1455; observed 406.1422.

Example 10 The epoxide of Example 1, Step 2 is treated (compound Bl) in a manner similar to that described in Example 1, Step 3, substituting phenol for 4-fluorophenol to obtain the compound of the melting point heading 132 to 135 ° C, MS FAB: (M + l) 390. Example 11 - The azetidinone of Preparation 1 is treated according to the procedure described in Example 7 followed by removal of the benzyl protecting group, as described in Example 2, Step 3 in order to obtain the compounds of the heading. Isomer A: melting temperature from 147 ° C to 150 ° C; HRMS FAB (M + 1): calculated 426.1517, observed 426.1520. Isomer B: melting temperature of 146 ° C to 148 ° C; HRMS FAB (M + 1): calculated 426.1517, observed 426.1508.

Example 12 Treat the product of Example 2, Step 2, according to the procedure described in Example 9 followed by removal of the benzyl protecting group as described in Example 2, Step 3, in order to obtain the heading compound: Melting temperature 129 ° C to 130 ° C; HRMS FAB (M + 1): calculated 410.1216, observed 410.1204.

Example 13 To a solution of the enantiomer B of Example 2 (0.025 gram, 0.06 millimole) and pyridine (0.024 milliliter, 0.296 millimole) in CH2Cl2 (5 milliliters), the excite of acetyl chloride (0.01 milliliter, 0.14 millimole) is added and Stir for 2 hours at room temperature. The mixture is diluted with CH2C12, washed with water and brine, dried over Na2S4 and the solvent is evaporated. Purify in resulting oil by preparative HPLC eluting with EtOAc: hexane (1: 3) to obtain the title compound: calculated HRMS 496.1558; found: 496.1572. The following formulations exemplify some of the dosage forms of this invention. In each, the term "active compound" designates a compound of formula 1.

EXAMPLE A Pills Number Ingredient mg / mg / pill pill 1 Active Compound 100 500 2 Lactose from the United States Pharmacopeia 122 113 3 Corn Starch, Food Grade as a 10 percent paste in Purified Water 30 40 4 Corn Starch, Quality for Food 45 40 Magnesium Stearate 3 7 Total 300 700 Manufacturing Method Articles 1 and 2 are mixed in an appropriate mixer for 10 to 15 minutes. The mixture is granulated with Item Number 3. The wet granules are ground through a coarse screen (e.g., 0.63 cm) if necessary. The wet granules are dried, the dried granules are screened if necessary and mixed with Article Number 4 and mixed for 10 to 15 minutes. Article Number 5 is added and mixed for 1 to 3 minutes. The mixture is compressed to the appropriate size and weight in a suitable tablet-forming machine.

EXAMPLE B Capsules Number Ingredient mg / mg / pill pill 1 Active Compound 100 500 2 Lactose from the United States Pharmacopeia 106 123 3 Corn Starch, Quality for Food 40 70 4 Magnesium Stearate NF 4 7 Total 250 700 Manufacturing Method Articles 1, 2 and 3 are mixed in an appropriate mixer for 10 to 15 minutes. It adds the Article Number 4 and mix for 1 to 3 minutes. The mixture is filled into appropriate two-piece hard gelatin capsules in an appropriate encapsulation machine. Representative formulations comprising a cholesterol biosynthesis inhibitor are well known in the art. it is proposed that when two active ingredients are administered in a single composition, the dosage forms disclosed above for the substituted azetidinone compounds can be easily modified using the knowledge of a person skilled in the art. The in vivo activity of the compounds of the formula I can be determined by the following procedure.

In Vivo Assay of Hipolipidemic Agents Using the Hyperlipidemic Marmot The marmots are separated into two groups of six and administered to them a controlled cholesterol diet (Purina Chow # 5001, containing 0.5 percent cholesterol) for seven days. Diet consumption is monitored to determine exposure to dietary cholesterol in the presence of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of the diet. The dosage is by oral forced feeding of 0.2 milliliter of corn oil alone (control group) or a solution (or suspension) of the test compound in corn oil. All dying animals with bad physical condition are euthanized. After seven days, the animals are anesthetized by IM injection of ketamine and sacrificed by decapitation, the blood is collected in vacuum tubes containing EDTA for plasma lipid analysis and the liver is cut for tissue lipid analysis. The data is reported as a percentage of lipid reduction versus control. Using the live m-marmot test procedures, essentially as described above, the following data was obtained for the representative compounds of formula 1. The compounds will be referred to in the following table, by means of the numbers of corresponding examples; the data is known as the percentage of change versus control, therefore, negative numbers indicate a positive lipid decrease aspect.

Reduction Percentage Example Cholesterol Dose Esters Serum number cholesterol mg / kg 5A1 -12 -71 10 12 -. 12 - 9 -27 1 6b -39 10 For the racemic compounds of formula 1 or diastereomers or active enantiomers of the compounds of formula 1, the compounds administered as dosages of 1 to 10 milligrams per kilogram show a reduction scale of -96 percent to -15 percent in the esters of cholesterol and a reduction of -51 percent to 0 percent in serum cholesterol. The reduction in cholesterol esters is the most important measure of activity, and the active compounds preferably show a scale of -30 percent to -96 percent and more preferably a scale of -50 percent to -96 percent of reduction in cholesterol esters.

Claims (12)

- - R E I V I N D I C A C I O N E S;

1. A compound represented by the structural formula: or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is aryl R 4 -substituted; Ar2 is R4-substituted aryl; Ar ^ is R ^ -substituted aryl; Y and Z are independently selected from the group consisting of -CH2-, -CH (lower alkyl) - or -C (lower dialkyl) -; A is -O-, -S-, -S (0) - or -S (0) -; R1 is selected from the group consisting of -OR6, -0 (C0) R6, -0 (CO) OR9 and -0 (C0) NR6R7; R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R1 and R2 together are = 0; q is 1, 2 or 3; p is 0, 1, 2.3 or 4; R5 is the 1 to 3 substituents independently selected from the group consisting of -OR6, 0 (CO) R6, -0 (CO) OR9, -0 (CH2) I-5OR9, -0 (CO) NR6R7, -NR6R7, - NR6 (CO) R7, NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02-lower alkyl, -NR6S02-aryl, -CONR6R7, -COR6, -S02NR6R7, S (O) 0-2-alkyl, S (O) 0-2-aryl, -O (CH2) i ^ Q-COOR6 '-0 (CH2) I_; LOCONR6R7, o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (alkylene) lower) -COOR6 and -CH = CH-COOR6; R3 and R4 are independently from 1 to 3 substituents that are independently selected from the group consisting of R * ^, hydrogen, p-lower alkyl, aryl, -N02, -CF3 and p-halogen; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl.

2. A compound according to claim 1, wherein Ar1 is R- ^ - substituted phenyl, wherein R3 is -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (O) or -2-alkyl, S ( 0) o-2-aryl, N02 or halogen; Ar2 is R4-substituted phenyl, wherein R4 is hydrogen, lower alkyl, -OR6, -0 (CO) R6, -0 (CO) R6, -0 (CO) OR9, -0 (CO) NR6R7, -NR6R7, COR6 or halogen, wherein R6 and R7 are independently hydrogen or lower alkyl, and R9 is lower alkyl; and Ar3 is R5-substituted phenyl, wherein R5 is -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CO) NR6R7, -NR6R7, - (lower alkylene) -COOR6 or -CH = CH-COOR6, wherein R6 and R7 are independently hydrogen or lower alkyl and R9 is lower alkyl.

3. A compound according to claim 1 or 2, wherein Y and Z each is -CH2- and wherein the sum of p and q is 1 or 2.

4. A compound according to any of claims 1, 2 or 3, wherein R1 is -OR6, wherein R6 is hydrogen and R2 is hydrogen or wherein R1 and R2 together are = 0.

5. A compound according to claim 1, which is selected from the group consisting of: rel-3 (S) - [2- (4-fluorophenoxy) -1 (S) -hydroxyethyl] -4 (S) - ( 4-methoxy-phenyl) -l-phenyl-2-azetidinone; 3 (S) - [2- (4-fluorophenoxy) -1 (S) -hydroxyethyl] -4 (S) - (4-methoxyphenyl) -1-phenyl-2-azetidinone; rel-3 (S) - [2- (4-fluorophenoxy) -1 (S) -hydroxyethyl] -4 (S) - (4-hydroxyphenyl) -1- (4-fluorophenyl) -2-azetidinone; 3 (S) - [2- (4-fluorophenoxy) -1 (S) -hydroxyethyl] -4 (S) - (4-hydroxyphenyl) -1- (4-fluorophenyl) -2-azetidinone; rel-3- (S) - [2- (4-fluorophenoxy) -1- (R) -hydroxyethyl [-4 (S) - (4-methoxy-phenyl) -1-phenyl-2-azetidinone; rel-3 (S) - [2- (4-fluorophenyl) thio] -l (s) -hydroxyethyl] -4 (S) - (4-methoxy-phenyl) -l-phenyl-2-azetidinone; rel-3 (S) - [2- [(4-fluorophenyl) sulfinyl] -1- (S) -hydroxyethyl] -4 (S) - (4-methoxy-phenyl) -l-phenyl-2-azetidinone; rel-3 (S) - [2- (4-fluorophenyl) sulfinyl} -l (S) -hydroxyethyl] -4 (S) - (4-methoxyphenyl) -phenyl-2-azetidinone; rel-3 (S) - [2- (4-fluorophenyl) sulfonyl} -l (S) -hydroxyethyl] 4- (S) - (4-methoxyphenyl) -1-phenyl-2-azetidinone; rel-3 (S) - [2- (4-fluorophenoxy) -1 (S) -methoxyethyl] -4 (S) - (4-methoxy-phenyl) -l-phenyl-2-azet-dinone; rel-3 (S) - [2- (4-fluorophenoxy) -1-oxo-ethyl] -4 (S) - (4-methoxyphenyl) -l-phenyl-2-azetidinone; rel-3 (S) -hydroxy-2-phenoxyethyl) -4 (S) - (4-methoxyphenyl) -1-pheny1-2-azetidinone; rel-3 (S) - [3- (4-fluorophenoxy) -1 (R) -hydroxypropyl] -1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -2-azetidinone; rel-3 (S) - [3- (4-fluorophenoxy) -1 (S) -hydroxypropyl] -1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -2-azrtidinone; (3S, 4S) -3- [2- (4-fluorophenoxy) -l-oxoethyl] -4- (4-hydroxyphenyl) -1- (4-fluorophenyl) -2-azetidinone; rel-3 (S) - [2- (4-fluorophenoxy) -1 (R) -hydroxyethyl] -1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -2-azetidinone; and 3 (S) - [1 (s) - (acetyloxy) -2- (4-fluorophenoxy) ethyl] -4 (S) - [4- (acetyloxy) -phenyl] -1- (4-fluorophenyl) -2 -azetidinone.

6. A method for treating or preventing atherosclerosis or reducing plasma cholesterol levels in a mammal in need of this treatment, which comprises administering an effective amount of a compound of any one of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor.

A pharmaceutical composition comprising an effective amount of cholesterol lowering of a compound of any one of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, in a pharmaceutically acceptable carrier.

8. The use of a compound according to any of claims 1, 2, 3, 4 or 5, for the preparation of a medicament for the treatment or prevention of atherosclerosis, or for reduction of cholesterol levels in plasma , which comprises a compound of any of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

9. A kit comprising in separate packages in a single package, pharmaceutical compositions for use in combination to treat or prevent atherosclerosis or to reduce cholesterol levels in the plasma comprising in a package, an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier and in a second container, an effective amount of a compound of any one of claims 1, 2, 3, 4 or 5, in a pharmaceutically acceptable carrier.

10. A process for preparing the beta-amino chiral esters of formula II where Ar 20 is Ar 2 as defined in claim 1, an appropriately protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl, Ar 30 is Ar 3, in accordance with claim 1, an appropriately protected hydroxy-substituted aryl or an amino aryl -substituted appropriately protected, and -C (0) 0R10 is an acyl radical of a chiral alcohol, which comprises reacting a bromoacetate of a chiral alcohol of the formula R10OC (O) CH2Br, wherein R10OH is an optically pure chiral alcohol, an imine of the formula Ar < - * - NCH-Ar3 ^, wherein Ar20 and Ar30 are as defined above, and zinc in order to obtain a beta-amino ester of formula II.

11. A beta-amino ester of formula II wherein Ar21-1 is R ^ -substituted aryl, an appropriately protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl; • Ar3 * -1 is R ^ -substituted aryl, suitably protected hydroxy-substituted aryl or an appropriately protected amino-substituted aryl; -C (0) OR1 (^ is an acyl radical of an optically pure chiral alcohol selected from the group consisting of 1-menthyl, isopino-canphenyl, (lS) -endo-bornyl, isomenthyl, trans-2-phenylcyclo -hexyl or phenylmethyl; R5 is the 1 to 3 substituents independently selected from the group consisting of -OR6, -0 (CO) R6, -0 (CO) OR9, -O (CH2) i-sOR9, -0 (CO) NR6R7, -NR6R_7, -NR6 (CO> R7, -NR6 (C0) 0R9, -NR6 (CO) R7R8, -NR6S02-lower alkyl, -NR6S02-aryl, -CONR6R7, -COR6, -S02NR6R7, S (O ) n-2-alkyl, S (O) or-2-aryl ° -0 (CH2) i-io-COOR6, -0 (CH2)? -? oCONR6R7, o-halogen, m-halogen, o-alkyl lower, m-lower alkyl, - (lower alkylene) -COOR6, -CH = CH-COOR6; R4 is 1 to 3 substituents which are independently selected from the group consisting of R ^ 'H, p-lower alkyl, aryl, -N? 2_, -CF3- and p-halogen R6, R7 and R8 are independently selected from the group consisting of H, lower alkyl, aryl and aryl-substituted lower alkyl, and R9 is lower alkyl r, aryl or aryl-substituted lower alkyl. ,

12. A process for preparing a compound according to claim 1 comprising: Process A: the Treating an epoxy-substituted azetidinone of the formula 1, wherein Ar2, Ar3, R2 and Zp are as described in claim 1, with a compound of the formula Ar1-A'-M, wherein Ar1 is as described in Claim 1, A 'is -0- or -S-, and wherein M is a metal, for example, sodium, potassium, lithium, magnesium, in an inert solvent at room temperature and under an inert atmosphere to obtain a compound of formula 1, wherein Ar1, Ar2, Ar3, R2 and Zp are as described in claim 1, A 'is -0- or -S-, Y is -CH2-, q is 1 and R is OH ( that is, a compound of formula la); Process B: Treat a compound of formula 1 as defined in Process A with Ari-OH or Ar1-SH, wherein Ar1 is as defined in claim 1, in the presence of a reagent, such as ZnCl2 to obtain a composed of the formula la, as defined above in Process A; Process C: Reacting a compound of formula 6, wherein Ar2, Ar3, R1, R2, Yq and Zp are as described in claim 1, and L is a substituent group such as a halide, with a compound of the formula Ar1- A'-M, as described in Process A, in order to obtain a compound of formula I, wherein Ar1, Ar2, Ar3, R1 R2, Yq and Zp are as described above and A is - 0- or -S- (ie, a compound of the formula le); o Process D: A 3-unsubstituted azetidinone of the formula 7 is treated, wherein Ar 2 and Ar 3 are as defined in claim 1, with a strong base at low temperatures in an inert solvent, followed by reaction with an aldehyde of the formula 8, wherein Ar1 and Yq are as defined in claim 1 and A 'is -0- or -S-, in order to obtain a compound of the formula I wherein Ar1, Ar2, Ar3 and Yq are as described in above, R is OH, R2 is H, p is zero and A 'is -0- or -S- (ie, a compound of the formula Id). SUMMARY OF THE INVENTION The hypocholesterolemic substituted azetidinone agents of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is R 3 -substituted aryl; Ar2 is R4-substituted aryl; Ar3 is R ^ -substituted aryl; Y and Z are independently -CH2-, -CH (lower alkyl) - or -C (lower dialkyl); A is -0-, -S-, -S (0) - or -S (0) 2 ~; R1 is -OR6, -0 (C0) R6, -0 (C0) 0R9 or -0 (CO) NR6R7; R2 is hydrogen, lower alkyl or aryl, R1 and R2 together are = 0; q is 1, 2 or 3; p is 0, 1, 2, 3 or 4; R5 is the 1 to 3 substituents that are independently selected from -OR6, -0 (C0) R6, -0 (C0) 0R9, -0 (CH2) I-5OR9, -0 (CO) NR6R7, -NR6R7, -NR6 (CO) R7, NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02-lower alkyl, -NR6S02-aryl, -CONR6R7, -COR6, -S02NR6R7, S (0) 0-2_alc? Uil ° S (0) 0-2_aril0 '-0 (CH2) X-IQ-COOR6, -0 (CH2) O-10CONR6R7' o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - (lower alkylene) -C00R6 and -CH = CH-C00R6; R3 and R4 are the 1 to 3 substituents independently selected from R5, hydrogen, p-lower alkyl, aryl, -NO2, CF3 and p-halogen; R6, R7 and R8 are hydrogen, lower alkyl, aryl or aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl; it is harmed to know as well as a method for lowering the cholesterol administered serum of the compounds mentioned, the pharmaceutical compositions having the same, the combination of a substituted azetidinone and a cholesterol biosynthesis inhibitor for the treatment and prevention of asterosclerosis, the novel intermediates and the methods to prepare these intermediates.