Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

a technology of azetidinone and hydroxysubstituted azetidinone, which is applied in the field of hydroxysubstituted azetidinone, can solve the problems of significant elevation of the risk of chd, and achieve the effects of reducing plasma cholesterol, preventing atherosclerosis, and lowering serum cholesterol levels
USRE37721E1Inactive Publication Date: 2002-05-28MERCK SHARP & DOHME CORP
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Patent Information

Authority / Receiving Office
US · United States
Patent Type
Patents(United States)
Current Assignee / Owner
MERCK SHARP & DOHME CORP
Publication Date
2002-05-28
Estimated Expiration
Not applicable · inactive patent

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Abstract

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formulaor a pharmaceutically acceptable salt thereof, wherein:Ar1 and Ar2 are aryl or R4-substituted aryl;Ar3 is aryl or R5-substituted aryl;X, Y and Z are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-;R and R2 are -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7;R1 and R3 are H or lower alkyl;q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5;R4 is selected from lower alkyl, R5, -CF3, -CN, -NO2 and halogen R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6;R6, R7 and R8 are H, lower alkyl or aryl-substituted IcR9 is lower alkyl, aryl or aryl-substituted lower alkyl;are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them.
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Description

BACKGROUND OF THE INVENTIONThe present invention relates to hydroxy-substituted azetidinones useful as hypocholesterolemic agents in the treatment prevention of atherosclerosis, and to the combination of a hydroxy-substituted azetidinone of this invention and a cholesterol bioxynthesis inhibitor for the treatment and prevention of atherosclerosis. The invention also relates to a process for preparing hydroxy-substituted azetidinones.Atherosclerotic coronary heart disease (CHD) represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, cigar smoke and serum cholesterol. A total cholesterol level in excess of 225-250 mg / dl is associated with significant elevation of risk of CHD.Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholestery...

Claims

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