A Substituted Acethydrazide Derivative, Preparation Method and Use Thereof

Abstract

The present invention pertains to the field of pharmaceutical chemicals, and relates to a substituted acethydrazide derivative, preparation method and use thereof; preferably, relates to a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof can effectively inhibit proline hydroxylase, stabilize HIF-α, particularly HIF-1α, and has potency in the manufacture of a medicament for treatment and/or prophylaxis and/or adjuvant therapy of anemia, acute ischemic reperfusion injury.

1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         n is 1, 2, 3, 4 or 5; 
         A is O or S; 
         R 3  is selected from hydrogen, and C 1 -C 4  alkyl; 
         Ar 1  is an aryl substituted with R 1 , wherein R 1  is selected from: hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, trifluoromethyl and cyano; 
         Ar 2  is an aryl substituted with R 2 , R 4 , and R 5 , wherein R 2 , R 4 , and R 5  are independently selected from: hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, allyl, halogen and C 1 -C 4  dialkylamino; wherein R 2 , R 4 , and R 5  are not hydrogen simultaneously. 
       
     
     
         2 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein
 the aryl is independently selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, fluorenyl and acenaphthenyl.   
     
     
         3 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 n is 1 or 2;   A is O;   R 3  is hydrogen;   Ar 1  is phenyl or naphthyl substituted with R 1 , wherein R 1  is selected from: hydrogen, C 1 -C 4  alkyl, methoxy, ethoxy, trifluoromethyl and cyano;   Ar 2  is phenyl or naphthyl substituted with R 2 , R 4 , and R 5 , wherein R 2 , R 4 , and R 5  are independently selected from: hydrogen, hydroxy, C 1 -C 4  alkyl, methoxy, ethoxy, allyl, halogen, dimethylamino, diethylamino and methylethylamino; wherein R 2 , R 4 , and R 5  cannot be hydrogen simultaneously.   
     
     
         4 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , which is selected from:
 (E)-N-(3-methoxy-2-hydroxybenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3,5-di-tert-butyl-2-hydroxybenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-ethoxy-2-hydroxybenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-[(2-hydroxynaphthalen-1-yl)methylene]-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-bromo-4-hydroxybenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-bromobenzal)-2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3,5-di-tert-butyl-2-hydroxybenzal)-2-{N-{2-[N-(3-trifluoromethylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-ethoxy-2-hydroxybenzal)-2-{N-{2-[N-(3-trifluoromethylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{2-[N-(3-trifluoromethylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(2,3-dihydroxybenzal)-2-{N-{2-[N-(3-trifluoromethylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-methoxy-2-hydroxybenzal)-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-[(3-ethoxy-2-hydroxybenzal)methylene]-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-[(2-hydroxynaphthalen-1-yl)methylene]-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3,5-di-tert-butyl-2-hydroxybenzal)-2-{N-{2-[N-(4-isopropylbenzyl)-N-methyl amino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(2,3-dihydroxybenzal)-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-bromo-6-hydroxybenzal)-2-{N-{2-[N-(4-isopropylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-methoxy-2-hydroxybenzal)-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3, 5-di-tert-butyl-2-hydroxybenzal)-3-(N-(2-(N-(4-tert-butylbenzyl)-N-methylamino)propyl)N-methylamino)acethydrazide,   (E)-N′-[(2-hydroxynaphthalen-1-yl)methylene]-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3,5-di-tert-butyl-2-hydroxybenzal)-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(2,3-dihydroxybenzal)-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-bromo-6-hydroxybenzal)-2-{N-{2-[N-(3-methoxybenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-[(2-hydroxynaphthalen-1-yl)methylene]-2-{N-{2-[N-(4-cyanobenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3,5-di-tert-butyl-2-hydroxybenzal)-2-{N-{2-[N-(4-cyanobenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-methoxy-2-hydroxybenzal)-2-{N-{2-[N-(4-cyanobenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-ethoxy-2-hydroxybenzal)-2-{N-{2-[N-(4-cyanobenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{2-[N-(4-cyanobenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-methoxy-2-hydroxybenzal)-2-{N-{2-[N-(4-tert-butylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(3-ethoxy-2-hydroxybenzal)-2-{N-{2-[N-(4-tert-butylbenzyl)-N-methylamino]ethyl}N-methylamino}acethydrazide,   (E)-N′-(4-N,N-diethylamino-2-hydroxybenzal)-2-{N-{3-[N-(4-tert-butylbenzyl)-N-methylamino]propyl}N-methylamino}acethydrazide;   and pharmaceutically acceptable salts of the above compounds.   
     
     
         5 . A method for preparing the compound of Formula I according to  claim 1 , comprising the following steps:
 1) dissolving N,N′-dimethylethanediamine or N,N′-dimethylpropanediamine in tetrahydrofuran, heating to reflux, then slowly adding benzyl chloride dropwise, generating and separating a compound of Formula 1;   
       
         
           
           
               
               
           
         
         2) adding the compound of Formula 1, NaHCO 3  into acetone, refluxing, then adding methyl chloroacetate or methyl chloroethanesulfonate, generating and separating a compound of Formula 2; 
       
       
         
           
           
               
               
           
         
         3) using ethanol as solvent, adding hydrazine hydrate or a corresponding substituted hydrazine, refluxing and then adding dropwise the compound of Formula 2, performing hydrazinolysis to generate a compound of Formula 3; 
       
       
         
           
           
               
               
           
         
         4) reacting the compound of Formula 3 with a corresponding salicylic aldehyde or aromatic ketone to generate a compound of Formula I; 
       
       
         
           
           
               
               
           
         
         wherein n, A, R 1 , R 2 , R 3 , R 4 , R 5 , Ar 1  and Ar 2  are as defined in  claim 1 . 
       
     
     
         6 . The method according to  claim 5 , which is characterized in any one or more of following items (1) to (3):
 (1) in step 1), the molar ratio of benzyl chloride to N,N′-dimethylethanediamine or N,N′-dimethylpropanediamine is 1:6;   (2) in step 1), the reaction is monitored by using TLC;   (3) in step 1), after the benzyl chloride is completely reacted, heating is stopped, cooling is performed and then rotary evaporation is conducted to dry out the solvent, the products is washed by using NaOH aqueous solution, then is extracted by using CH 2 Cl 2  and a pH≧12 is maintained during extraction; organic layers are combined and is subjected to column chromatography to obtain the compound of Formula 1.   
     
     
         7 . A pharmaceutical composition, which comprises the compound of  claim 1  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         8 .- 9 . (canceled) 
     
     
         10 . A method for inhibiting proline hydroxylase or stabilizing HIF-1 in vivo or in vitro, comprising a step of administering to a subject or a cell in need thereof an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         11 .- 13 . (canceled) 
     
     
         14 . A method for treatment and/or prophylaxis and/or adjuvant therapy of anemia, acute ischemic reperfusion injury, comprising a step of administering to a subject in need thereof an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the C 1 -C 6  alkyl is independently C 1 -C 4  alkyl. 
     
     
         16 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the C 1 -C 6  alkoxy is independently C 1 -C 4  alkoxy. 
     
     
         17 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the C 1 -C 4  dialkylamino is independently C 1 -C 3  dialkylamino. 
     
     
         18 . The compound, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the halogen is selected from fluorine, chlorine, bromine, and iodine. 
     
     
         19 . The method according to  claim 10 , wherein the proline hydroxylase is a prolyl-4-hydroxylase or EC 1.14.11.2. 
     
     
         20 . The method according to  claim 10 , wherein the HIF-1 is HIF-α. 
     
     
         21 . The method according to  claim 20 , wherein the HIF-α is HIF-1α, HIF-2α or HIF-3α.