Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry. In particular, the present invention relates to a class of alkynyl pyridine prolyl hydroxylase inhibitors (I). The experiments show that such a compound has good activity of inhibiting prolyl hydroxylase, and can enhance the generation and secretion of erythropoietin in cell or animal models, and thus can promote the generation of red cells, and can be used for the treatment or prevention of anemia, such as chronic kidney disease anemia, and ischemic diseases, including ischemic strokes, myocardial ischemia and other related diseases. The present invention also discloses a method for preparing such a compound.

What is claimed: 
     
         1 . A method for treating anemia or ischemic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier: 
       
         
           
           
               
               
           
         
         wherein X represents NH, NCH 3  or CH 2 ; 
         Y represents hydrogen, hydroxy, methoxy or ethoxy; 
         L represents —CH 2 —, —CH 2 O— or 
       
       
         
           
           
               
               
           
         
       
       R 6  represents hydrogen, C 1 -C 4  alkyl or phenyl;
 n represents 1; 
 R 1  represents C 1 -C 4  alkyl, phenyl, quinolinyl, benzofuranyl, naphthyl, substituted phenyl, 5- to 6-membered heteroaryl containing oxygen or nitrogen, or substituted 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein the substituent is C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, halogen, cyano, 
 
       
         
           
           
               
               
           
         
       
       phenyl or 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein R 7  represents C 1 -C 4  alkyl; R 8  and R 9  each independently represent hydrogen or C 1 -C 4  alkyl, or R 8  and R 9  are attached to form a 3- to 7-membered heterocyclyl containing nitrogen;
 R 2  represents hydrogen, halogen or methyl; 
 R 3  and R 4  each independently represent hydrogen, methyl or ethyl; and 
 R 5  represents hydroxy, C 1 -C 4  alkoxy, cyclopropoxy, or —NR 10 R 11 , wherein R 10  and R 11  each independently represent hydrogen, methyl or ethyl. 
 
     
     
         2 . The method according to  claim 1 , wherein X represents NH. 
     
     
         3 . The method according to  claim 1 , wherein L represents —CH 2 —, —CH 2 O— or 
       
         
           
           
               
               
           
         
       
       R 6  represents hydrogen, methyl, tert-butyl or phenyl. 
     
     
         4 . The method according to  claim 1 , wherein R 1  represents substituted phenyl, wherein the substituent is methyl, ethyl, isopropyl, tert-butyl, methoxy, tert-butoxy, phenyl, cyano, halogen, fluoromethyl, trifluoromethyl, imidazolyl, acetylamino, or 
       
         
           
           
               
               
           
         
       
       wherein R 8  and R 9  each independently represent hydrogen, methyl, butyl or tert-butyl, or R 8  and R 9  are attached to form aziridinyl, tetrahydropyrrolyl or N-methylhomopiperazinyl. 
     
     
         5 . The method according to  claim 1 , wherein R 1  represents phenyl, naphthyl, quinolinyl or benzofuranyl. 
     
     
         6 . The method according to  claim 1 , wherein R 3  or R 4  represents hydrogen. 
     
     
         7 . The method according to  claim 1 , wherein R 5  represents —NH 2 , —NHCH 3 , hydroxy, methoxy, isopropoxy, or cyclopropoxy. 
     
     
         8 . A method for treating anemia or ischemic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier: 
       
         
           
           
               
               
           
         
         wherein X represents NH, Y represents hydroxy, R 2 , R 3  and R 4  represent hydrogen, R 5  represents hydroxy or C 1 -C 4  alkoxy, L represents —CH 2 — or —CH 2 O—, n represents 0 or 1, and R 1  represents substituted phenyl, wherein the substituent is C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen. 
       
     
     
         9 . The method according to  claim 8 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 8 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 8 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method according to  claim 8 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method according to  claim 1 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease. 
     
     
         14 . The method according to  claim 8 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease. 
     
     
         15 . The method according to  claim 9 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease.