Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors

Abstract

The present invention relates to substituted pyrrole derivatives, which can be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Compounds disclosed herein can function as cholesterol lowering agents and can be used for the treatment of cholesterol-related diseases and related symptoms. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and methods of treating cholesterol-related diseases and related symptoms.

1 . A compound of the structure of Formula Ib, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable tautomer, racemate, pure enantiomer, diastereoisomer or a lactone form or N-oxide thereof, wherein 
       
       
         
           
           
               
               
           
         
         R 1  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C 1 -C 6  alkyl, cyano and C 1 -C 3  perfluoroalkyl); 
         R 2  is optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino); 
         R 3  is optionally substituted C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C 1 -C 3  alkoxy, and protected hydroxyl); R 3  can also be —NR 6 R 7  wherein R 6  and R 7  are optionally substituted C 1 -C 6  alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C 1 -C 3  alkoxy, and protected hydroxyl); 
         R 4  is —COR 10  (wherein R 10  is selected from C 1 -C 2  alkoxy, hydroxyl and —NR 11 R 12  (wherein R 11  and R 12  are independently selected from hydrogen, alkyl, aryl, C 3 -C 7  cycloalkyl, aralkyl and R 11  and R 12  together form 5-7 membered ring with one or more optional heteroatom(s) wherein the heteroatom(s) is/are independently selected from nitrogen, oxygen and sulphur); and 
         R 5  is hydrogen, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, optionally substituted aryl or aralkyl [wherein the substituents are selected from halogens, cyano, optionally substituted C 1 -C 6  alkyl (wherein the substituents are independently selected from hydroxyl, protected hydroxyl, and halogen(s)], optionally substituted amino, acetyl, trifluoromethyl and C 1 -C 6  alkoxycarbonyl. 
       
     
     
         2 . The compound of  claim 1  wherein R1, R2, R3 and R5 are 4-fluorophenyl, phenyl, isopropyl and hydrogen, respectively. 
     
     
         3 . The compound according to  claim 1 , wherein R1 is phenyl substituted with one or more halogen. 
     
     
         4 . The compound according to  claim 3 , wherein R1 is phenyl substituted with one or more fluorine. 
     
     
         5 . The compound according to  claim 4 , wherein R1 is 4-fluorophenyl. 
     
     
         6 . The compound according to  claim 1 , wherein R2 and R5 are phenyl and hydrogen, respectively. 
     
     
         7 . The compound according to  claim 1 , wherein R3 is C1-C6 alkyl. 
     
     
         8 . The compound according to  claim 1 , wherein R3 is isopropyl. 
     
     
         9 . The compound according to  claim 1 , wherein R10 is hydroxyl. 
     
     
         10 . A compound according to  claim 1 , wherein R3 is alkyl of from one to six carbon atoms or cycloalkyl of from three to six carbon atoms. 
     
     
         11 . A compound of the chemical formula: 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A compound, which is (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A pharmaceutically acceptable salt of a compound of  claim 1 , wherein the salt is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, zinc, aluminium, amino acid, ammonium, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium and N-methyl glucamine. 
     
     
         14 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is sodium salt. 
     
     
         15 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is potassium salt. 
     
     
         16 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is hemicalcium salt. 
     
     
         17 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is hemimagnesium salt. 
     
     
         18 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is hemizinc salt. 
     
     
         19 . The pharmaceutically acceptable salt of  claim 13 , wherein the salt is N-methyl glucamine salt. 
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  together with a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         21 . A method of treating diabetes or a disease selected from the group consisting of arteriosclerosis, atherosclerosis, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, stroke, ischemia, peripheral vascular disease, peripheral arterial disease, coronary heart disease, myocardial infarction, cerebral infarction, myocardial microvascular disease, dementia, Alzheimer's disease, angina and restenosis in a mammal in need of such treatment comprising administering a therapeutically-effective amount of a compound of  claim 1  to the mammal. 
     
     
         22 . The method according to  claim 21 , wherein the disease is hyperlipidemia. 
     
     
         23 . The method according to  claim 21 , wherein the disease is hypercholesterolemia. 
     
     
         24 . The method according to  claim 21 , wherein the disease is hyperlipoproteinemia. 
     
     
         25 . The method according to  claim 21 , wherein the disease is hypertriglyceridemia. 
     
     
         26 . The method according to  claim 21 , wherein the disease is hypertension.