4-biarylyl-1-phenylazetidin-2-ones

Abstract

4-Biarylyl-1-phenylazetidin-2-ones useful for the treatment of hypercholesterolemia are disclosed. The compounds are of the general formula in which represents an aryl or heteroaryl residue; Ar represents an aryl residue; U is a two to six atom chain; and the R's represent substituents.

1 - 139 . (canceled) 
     
     
         140 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1i  and R 2i  are chosen from H, Cl and F; and 
 R 5i  is chosen from OH and SO 3 H. 
 
     
     
         141 . A compound according to  claim 140  of formula 
       
         
           
           
               
               
           
         
       
       wherein the substituent at position 3 of the azetidin-2-one is of the R absolute configuration, the substituent at position 4 of the azetidin-2-one is of the S absolute configuration and the benzylic hydroxyl is of the S absolute configuration. 
     
     
         142 . A compound according to  claim 141  wherein R 5i  is OH. 
     
     
         143 . (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one according to  claim 142 . 
     
     
         144 . A compound according to  claim 141  wherein R 5i  is SO 3 H. 
     
     
         145 . 4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-sulfonic acid; 4′-{(2S,3R)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid; or 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid according to  claim 144 . 
     
     
         146 . Sodium 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate. 
     
     
         147 . A pharmaceutical formulation comprising a compound according to  claim 140  and a pharmaceutically acceptable carrier. 
     
     
         148 . A pharmaceutical formulation according to  claim 147  additionally comprising an inhibitor of cholesterol biosynthesis. 
     
     
         149 . A method for treating a disorder of lipid metabolism comprising administering to a mammal a therapeutically effective amount of a compound having the formula shown in  claim 140 , wherein said disorder is chosen from hypercholesterolemia, hyperlipidemia, arteriosclerosis and sitosterolemia. 
     
     
         150 . A pharmaceutical formulation according to  claim 148  wherein said inhibitor of cholesterol biosynthesis is an HMG-CoA reductase inhibitor. 
     
     
         151 . A pharmaceutical formulation according to  claim 150  wherein said HMG-CoA reductase inhibitor is chosen from the group consisting of lovastatin, simvastatin, pravastatin, rosuvastatin, mevastatin, atorvastatin, cerivastatin, pitavastatin, fluvastatin, bervastatin, crilvastatin, carvastatin, rivastatin, sirrivastatin, glenvastatin and dalvastatin. 
     
     
         152 . A pharmaceutical formulation according to  claim 147  additionally comprising at least one bile acid sequestrant. 
     
     
         153 . A pharmaceutical formulation according to  claim 152  wherein the at least one bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam hydrochloride and mixtures thereof. 
     
     
         154 . A pharmaceutical formulation according to  claim 147  additionally comprising at least one nicotinic acid or derivative thereof selected from the group consisting of nicotinic acid, niceritrol, nicofuranose, acipimox and mixtures thereof. 
     
     
         155 . A pharmaceutical formulation according to  claim 147  additionally comprising at least one peroxisome proliferator-activated receptor alpha activator. 
     
     
         156 . A pharmaceutical formulation according to  claim 155  wherein said peroxisome proliferator-activated receptor alpha activator is a fibric acid derivative. 
     
     
         157 . A pharmaceutical formulation according to  claim 156  wherein said fibric acid derivative is selected from the group consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol and mixtures thereof. 
     
     
         158 . A pharmaceutical formulation according to  claim 147  additionally comprising at least one cholesterol ester transfer protein (CETP) inhibitor. 
     
     
         159 . An article of manufacture comprising a container, instructions, and a pharmaceutical formulation according to  claim 147 , wherein the instructions are for the administration of the pharmaceutical formulation for a purpose chosen from: the prevention or treatment of a disorder of lipid metabolism; reducing the plasma or tissue concentration of at least one 5α-cholestanol or cholest-5-enol other than (3β)-cholest-5-ene-3-ol; reducing the blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum; increasing the fecal excretion of cholesterol; reducing the incidence of coronary heart disease-related events; reducing blood plasma or serum concentrations of C-reactive protein (CRP); treating or preventing vascular inflammation; reducing blood plasma or serum concentrations of triglycerides; increasing blood plasma or serum concentrations of HDL cholesterol; reducing blood plasma or serum concentrations of apolipoprotein B. 
     
     
         160 . A method according to  claim 149 , wherein said disorder of lipid metabolism is hyperlipidemia. 
     
     
         161 . A method according to  claim 149 , wherein said disorder of lipid metabolism is arteriosclerosis. 
     
     
         162 . A method according to  claim 149 , wherein said disorder of lipid metabolism is sitosterolemia. 
     
     
         163 . A method for inhibiting the absorption of cholesterol from the intestine of a mammal, which comprises administering an effective cholesterol-absorption-inhibiting amount of a compound according to  claim 140  to the mammal. 
     
     
         164 . A method of reducing plasma or tissue concentration of at least one 5α-cholestanol or cholest-5-enol other than (3β)-cholest-5-ene-3-ol, comprising administering to a mammal in need of such treatment an effective amount of a compound according to  claim 140 . 
     
     
         165 . A method for reducing the blood plasma or serum concentrations of LDL cholesterol in a mammal, which comprises administering an effective cholesterol reducing amount of a compound according to  claim 140  to the mammal. 
     
     
         166 . A method for reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a mammal, which comprises administering an effective cholesterol and cholesterol ester reducing amount of a compound according to  claim 140  to the mammal. 
     
     
         167 . A method for increasing the fecal excretion of cholesterol in a mammal, which comprises administering an effective cholesterol fecal excretion increasing amount of a compound according to  claim 140  to the mammal.