Methods for the synthesis of pyridoxamine

Abstract

The invention provides non-oxidative methods for the large scale manufacture of pyridoxamine (I) (4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine): (I), and salts thereof. The invention also provides intermediate compounds for the synthesis of pyridoxamine, as well as compositions and methods for the treatment and/or prevention of conditions associated with the formation of post-Amadori advanced glycation end-products.

1 . A method for preparing pyridoxamine, or salt thereof, the method comprising the steps of: 
 (a) protecting the hydroxyls of a compound of formula (II), or salt thereof, to form a compound of formula (III), or salt thereof:                          wherein R at each occurrence is a hydroxyl protecting group;    (b) converting the compound of formula (III), or salt thereof, to a compound of formula (IV), or salt thereof:                          wherein                          represents a cyclic imide substituent;    (c) converting the compound of formula (IV), or salt thereof, to a compound of formula (V)                          wherein R 1  is H or is R,    wherein when R 1  is R, step (c) is followed by step (d), wherein step (d) comprises:    (d) converting the compound of formula (V), or salt thereof, to pyridoxamine (I), or a salt thereof:                          
   
   
       2 . A method according to  claim 1  wherein step (a) comprises treating the compound of formula (II) with a hydroxyl protecting reagent.  
   
   
       3 . A method according to  claim 1  wherein step (b) comprises treating the compound of formula (III) with a cyclic imide.  
   
   
       4 . A method according to  claim 1  wherein step (c) comprises treating the compound of formula (IV) with a deprotecting agent to form the compound of formula (V).  
   
   
       5 . A method according to  claim 1  wherein step (d) comprises treating to compound of formula (V) with a deprotecting agent.  
   
   
       6 . A method according to  claim 1  wherein R is selected from the group consisting of: alkanoyl, arylcarbonyl, lower alkoxycarbonyl; lower alkenyloxycarbonyl; aryl lower alkoxycarbonyl a sulfonyl derivative.  
   
   
       7 . A method according to  claim 1  wherein the cyclic imide substituent is selected from the group consisting of phthalimidyl, and succinimidyl.  
   
   
       8 . A method according to  claim 1  wherein the product of step (c) is isolated prior to carrying out step (d).  
   
   
       9 . A method according to  claim 1  wherein the product of step (c) is not isolated prior to carrying out step (d).  
   
   
       10 . A method for preparing pyridoxamine, the method comprising the steps of: 
 (a) acylating the hydroxyls of pyridoxine, to form an triester, or salt thereof, of the formula:                          (b) treating the triester formed in step (a) with phthalimide, or salt thereof, to form an phthalimido compound, or salt thereof, of the formula:                          (c) treating the phthalilimido compound formed in step (b) with a primary amine to form an amide compound, or salt thereof, of the formula:                          (d) treating the amide formed in step (c) with a deprotecting agent to form pyridoxamine, or salt thereof.    
   
   
       11 . A method according to  claim 10  wherein the product of step (c) is not isolated prior to carrying out step (d).  
   
   
       12 . A method according to  claim 10  wherein the product of step (c) is isolated prior to carrying out step (d).  
   
   
       13 . Pyridoxamine, or salt thereof, prepared according to the method of  claim 1 .  
   
   
       14 . A composition comprising pyridoxamine, or salt thereof, produced by the method of  claim 1 , in combination with a pharmaceutically acceptable carrier.  
   
   
       15 . A composition comprising pyridoxamine, or a pharmaceutically acceptable salt thereof, and a compound of the formula (X), or a pharmaceutically acceptable salt thereof:  
     
       
         
         
             
             
         
       
     
   
   
       16 . A composition comprising pyridoxamine, or a pharmaceutically acceptable salt thereof, and a compound of the formula (XX), or a pharmaceutically acceptable salt thereof:  
     
       
         
         
             
             
         
       
     
   
   
       17 . A composition comprising: pyridoxamine, or a pharmaceutically acceptable salt thereof; a compound of the formula (X), or a pharmaceutically acceptable salt thereof;  
     
       
         
         
             
             
         
       
     
     and a compound of the formula (XX), or a pharmaceutically acceptable salt thereof  
     
       
         
         
             
             
         
       
     
   
   
       18 . A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of pyridoxamine produced by the synthetic method of  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       19 . A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to  claim 15 .  
   
   
       20 . A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to  claim 16 .  
   
   
       21 . A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to  claim 17 .  
   
   
       22 . A zwitterion of the structure:  
     
       
         
         
             
             
         
       
     
   
   
       23 . A compound of formula (III), or salt thereof:  
     
       
         
         
             
             
         
       
     
     wherein R at each occurrence is a hydroxyl protecting group.  
   
   
       24 . A compound of formula (IV), or salt thereof:  
     
       
         
         
             
             
         
       
     
   
   
       25 . A compound of formula (V), or salt thereof:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a hydroxyl protecting group.