Prolyl hydroxylase inhibitors and methods of use

Abstract

The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.

1 - 32 . (canceled) 
     
     
         33 . A method for treating a patient having ischemia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), or heart failure, comprising administering to the patient a compound having a structure: 
       
         
           
           
               
               
           
         
         wherein
 R is selected from
 i) 3-chlorophenyl; and 
 ii) 2,3-dihydrobenzo[1,4]dioxin-6-yl; 
 
 R 2  is selected from
 i) OR 6 ; and 
 ii) NR 7a R 7b ; 
 
 R 6  is selected from hydrogen, methyl, and ethyl; 
 R 7a  and R 7b  are each independently selected from:
 i) hydrogen; and 
 ii) methyl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 33 , wherein the patient has ischemia. 
     
     
         35 . The method of  claim 33 , wherein the patient has Peripheral Vascular Disease (PVD). 
     
     
         36 . The method of  claim 33 , wherein the patient has Coronary Artery Disease (CAD). 
     
     
         37 . The method of  claim 33 , wherein the patient has heart failure. 
     
     
         38 . The method of  claim 35 , wherein the PVD results from atherosclerosis. 
     
     
         39 . The method of  claim 38 , wherein the atherosclerosis presents as asymptomatic PVD, intermittent claudication, or critical limb ischemia. 
     
     
         40 . A method of vascularizing ischemic tissue, improving blood flow, improving oxygen delivery, improving energy utilization, enhancing the ability to revascularize damaged tissues, or increasing vasculature in a patient in need thereof, comprising administering to the patient a compound having a structure: 
       
         
           
           
               
               
           
         
         wherein
 R is selected from
 i) 3-chlorophenyl; and 
 ii) 2,3-dihydrobenzo[1,4]dioxin-6-yl; 
 
 R 2  is selected from
 i) OR 6 ; and 
 ii) NR 7a R 7b ; 
 
 R 6  is selected from hydrogen, methyl, and ethyl; 
 R 7a  and R 7b  are each independently selected from:
 i) hydrogen; and 
 ii) methyl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . The method of  claim 33  or  40 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         wherein
 R 2  is selected from
 i) OR 6 ; and 
 ii) NR 7a R 2b ; 
 
 R 6  is selected from hydrogen, methyl, and ethyl; 
 R 7a  and R 7b  are each independently selected from:
 i) hydrogen; and 
 ii) methyl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The method of  claim 33 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         wherein
 R 2  is selected from
 i) OR 6 ; and 
 ii) NR 7a R 7b ; 
 
 R 6  is selected from hydrogen, methyl, and ethyl; 
 R 7a  and R 7b  are each independently selected from:
 i) hydrogen; and 
 ii) methyl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 41 , wherein the compound is selected from:
 {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester;   {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid;   5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;   5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; and   5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide.   or a pharmaceutically acceptable salt thereof.   
     
     
         44 . The method of  claim 43 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         45 . The method of  claim 43 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . The method of  claim 43 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . The method of  claim 43 . wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         48 . The method of  claim 43 . wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         49 . The method of  claim 42 , wherein the compound has a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.