Niacin mimetics, and methods of use thereof

Abstract

Disclosed are 6-(morpholinoalkyl)-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

1 - 59 . (canceled) 
     
     
         60 . A pharmaceutical composition, comprising a compound represented by structure I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         an agent that lowers the serum level of low-density lipoprotein cholesterol (LDL-C) or triglycerides in a mammal; and a pharmaceutically acceptable carrier, 
         wherein
 R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; 
 R 4  is selected independently for each occurrence from the group consisting of deuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; 
 R 5  is selected independently for each occurrence from the group consisting of hydrogen and lower alkyl; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and 
 m is 2, 3, or 4. 
 
       
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein R is hydrogen or lower alkyl. 
     
     
         62 . The pharmaceutical composition of  claim 60 , wherein R is hydrogen. 
     
     
         63 . The pharmaceutical composition of  claim 60 , wherein R is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         64 . The pharmaceutical composition of  claim 60 , wherein R 5  is hydrogen. 
     
     
         65 . The pharmaceutical composition of  claim 60 , wherein n is 0. 
     
     
         66 . The pharmaceutical composition of  claim 60 , wherein the compound represented by structure I is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         67 . The pharmaceutical composition of  claim 60 , wherein R is hydrogen; R 5  is hydrogen; n is 0; and m is 2. 
     
     
         68 . The pharmaceutical composition of  claim 60 , wherein the agent lowers the mammalian serum level of LDL-C. 
     
     
         69 . The pharmaceutical composition of  claim 68 , wherein R is hydrogen; R 5  is hydrogen; n is 0; and m is 2. 
     
     
         70 . The pharmaceutical composition of  claim 69 , wherein the agent is selected from the group consisting of cholesteryl ester transfer protein (CETP) inhibitors, ezetimibe, a combination of ezetimibe and simvastatin, a combination of ezetimibe and atorvastatin, fibrates, HMG CoA reductase inhibitors, niacin, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. 
     
     
         71 . The pharmaceutical composition of  claim 70 , wherein the agent is an HMG CoA reductase inhibitor. 
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin. 
     
     
         73 . The pharmaceutical composition of  claim 72 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of simvastatin and atorvastatin. 
     
     
         74 . The pharmaceutical composition of  claim 70 , wherein the agent is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. 
     
     
         75 . The pharmaceutical composition of  claim 60 , wherein the agent lowers the mammalian serum level of triglycerides. 
     
     
         76 . The pharmaceutical composition of  claim 75 , wherein R is hydrogen; R 5  is hydrogen; n is 0; and m is 2. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the agent is selected from the group consisting of niacin, omega-3 fatty acids, and fibrates. 
     
     
         78 . The pharmaceutical composition of  claim 77 , wherein the agent is an omega-3 fatty acid. 
     
     
         79 . The pharmaceutical composition of  claim 77 , wherein the agent is a fibrate. 
     
     
         80 . A method of treating a disease, disorder, or condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, lipodystrophy, dyslipidemia, and fatty liver disease, comprising the step of coadministering to a subject in need thereof a pharmaceutically effective amount of a compound represented by structure I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         and an agent that lowers the serum level of low-density lipoprotein cholesterol (LDL-C) or triglycerides in a mammal, 
         wherein
 R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; 
 R 4  is selected independently for each occurrence from the group consisting of deuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; 
 R 5  is selected independently for each occurrence from the group consisting of hydrogen and lower alkyl; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and 
 m is 2, 3, or 4. 
 
       
     
     
         81 . The method of  claim 80 , wherein R is hydrogen or lower alkyl. 
     
     
         82 . The method of  claim 80 , wherein R is hydrogen. 
     
     
         83 . The method of  claim 80 , wherein R is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . The method of  claim 80 , wherein R 5  is hydrogen. 
     
     
         85 . The method of  claim 80 , wherein n is 0. 
     
     
         86 . The method of  claim 80 , wherein the compound represented by structure I is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         87 . The method of  claim 80 , wherein R is hydrogen; R 5  is hydrogen; n is 0; and m is 2. 
     
     
         88 . The method of  claim 80 , wherein the agent lowers the mammalian serum level of LDL-C. 
     
     
         89 . The method of  claim 88 , wherein R is hydrogen; R 5  is hydrogen;
 n is 0; and m is 2.   
     
     
         90 . The method of  claim 89 , wherein the agent is selected from the group consisting of cholesteryl ester transfer protein (CETP) inhibitors, ezetimibe, a combination of ezetimibe and simvastatin, a combination of ezetimibe and atorvastatin, fibrates, HMG CoA reductase inhibitors, niacin, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. 
     
     
         91 . The method of  claim 90 , wherein the agent is an HMG CoA reductase inhibitor. 
     
     
         92 . The method of  claim 91 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin. 
     
     
         93 . The method of  claim 92 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of simvastatin and atorvastatin. 
     
     
         94 . The method of  claim 90 , wherein the agent is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. 
     
     
         95 . The method of  claim 80 , wherein the agent lowers the mammalian serum level of triglycerides. 
     
     
         96 . The method of  claim 95 , wherein R is hydrogen; R 5  is hydrogen; n is 0; and m is 2. 
     
     
         97 . The method of  claim 96 , wherein the agent is selected from the group consisting of niacin, omega-3 fatty acids, and fibrates. 
     
     
         98 . The method of  claim 97 , wherein the agent is an omega-3 fatty acid. 
     
     
         99 . The method of  claim 97 , wherein the agent is a fibrate. 
     
     
         100 . The method of  claim 80 , wherein the disease, disorder, or condition is hyperlipidemia. 
     
     
         101 . The method of  claim 80 , wherein the disease, disorder, or condition is hypercholesterolemia. 
     
     
         102 . The method of  claim 80 , wherein the disease, disorder, or condition is lipodystrophy. 
     
     
         103 . The method of  claim 80 , wherein the disease, disorder, or condition is dyslipidemia. 
     
     
         104 . The method of  claim 80 , wherein the disease, disorder, or condition is fatty liver disease. 
     
     
         105 . The method of  claim 80 , wherein the coadministration is simultaneous. 
     
     
         106 . The method of  claim 80 , wherein the coadministration is sequential or staggered. 
     
     
         107 . The method of  claim 80 , wherein the compound represented by structure I and the agent that lowers the mammalian serum level of low-density lipoprotein cholesterol (LDL-C) or triglycerides are formulated together in a dosage form. 
     
     
         108 . The method of  claim 107 , wherein the dosage form is a solid dosage form. 
     
     
         109 . The method of  claim 80 , wherein the agent is administered by injection. 
     
     
         110 . The method of  claim 109 , wherein the agent is administered by subcutaneous injection. 
     
     
         111 . The method of  claim 110 , wherein the agent is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.