Cycloalkyl-hydroxyl compounds and compositions for cholesterol management and related uses

Abstract

The present invention relates to novel cycloalkyl-hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

1 - 57 . (canceled) 
     
     
         58 . A method of decreasing LDL levels in a patient having hypercholesterolemia or cardiovascular disease, comprising administering to the patient a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, wherein:
 (a) each occurrence of m is independently an integer ranging from 0 to 5; 
 (b) each occurrence of n is independently an integer ranging from 3 to 7; 
 (c) X is (CH 2 ) z  or Ph, wherein z is an integer from 0 to 4; 
 (d) R 1  and R 2  and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group; 
 (e) each occurrence of R 11  and R 12  and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group; and 
 (f) each occurrence of Y 1  and Y 2  is independently COOH, COOR 3 , SO 3 H, 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
           
           (i) R 3  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups, and 
           (ii) each occurrence of R 4  is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6  alkoxy, or phenyl groups. 
         
       
     
     
         59 . The method  claim 58 , wherein each occurrence of Y 1  and Y 2  is independently COOR 3  or COOH. 
     
     
         60 . The method of  claim 58 , wherein Y 1  and Y 2  are each COOH. 
     
     
         61 . The method of  claim 58 , wherein m is 0. 
     
     
         62 . The method of  claim 58 , wherein m is 1. 
     
     
         63 . The method of  claim 58 , wherein n is 4. 
     
     
         64 . The method of  claim 58 , wherein n is 5. 
     
     
         65 . The method of  claim 58 , wherein X is (CH 2 ) z  and z is 0. 
     
     
         66 . The method of  claim 58 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         67 . The method of  claim 58 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 58 , wherein the compound of formula I is orally administered to the patient in the form of a pharmaceutical composition comprising the compound of formula I, and a pharmaceutically acceptable vehicle. 
     
     
         69 . A method of decreasing LDL levels in a patient having hypercholesterolemia or cardiovascular disease, comprising administering to the patient a therapeutically effective amount of a compound of formula I, wherein formula I is represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         70 . The method of  claim 69 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         71 . The method of  claim 69 , wherein the compound of formula I is orally administered to the patient in the form of a pharmaceutical composition comprising the compound of formula I, and a pharmaceutically acceptable vehicle. 
     
     
         72 . The method of  claim 70 , wherein the compound is orally administered to the patient in the form of a pharmaceutical composition comprising the compound, and a pharmaceutically acceptable vehicle.