Synthesis of (r)-n-methylnaltrexone

Abstract

This invention relates to stereoselective synthesis of R-MNTX and intermediates thereof, pharmaceutical preparations comprising R-MNTX or intermediates thereof and methods for their use.

What is claimed is: 
     
         1 . An aqueous pharmaceutical composition suitable for parenteral delivery comprising a solution of R-MNTX, or a salt thereof, a chelating agent, a buffering agent and an isotonicity agent, wherein the composition is characterized by at least one of (a), (b), or (c):
 (a) the composition is free of HPLC detectable S-MNTX at a detection limit of 0.02% and at a quantitation limit of 0.05%;   (b) at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen; or   (c) less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05% of the MNTX in the composition is in the S configuration with respect to the nitrogen.   
     
     
         2 . The aqueous pharmaceutical composition of  claim 1 , wherein the solution has a pH of between about 3.0 and about 3.5. 
     
     
         3 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition has a pH of about 3.5. 
     
     
         4 . The aqueous pharmaceutical composition of  claim 1 , wherein the solution comprises methylnaltrexone bromide. 
     
     
         5 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition is free of HPLC detectable S-MNTX at a detection limit of 0.02% and at a quantitation limit of 0.05%. 
     
     
         6 . The aqueous pharmaceutical composition of  claim 1 , wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen. 
     
     
         7 . The aqueous pharmaceutical composition of  claim 1 , wherein less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05% of the MNTX in the composition is in the S configuration with respect to the nitrogen. 
     
     
         8 . The aqueous pharmaceutical composition of  claim 1 , wherein at least 99.85% of the MNTX in the composition is in the R configuration with respect to nitrogen. 
     
     
         9 . The aqueous pharmaceutical composition of  claim 1 , wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid, or combinations thereof. 
     
     
         10 . The aqueous pharmaceutical composition of  claim 1 , wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a derivative thereof. 
     
     
         11 . The aqueous pharmaceutical composition of  claim 1 , wherein the isotonicity agent is selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, sorbitol, and a combination thereof. 
     
     
         12 . The aqueous pharmaceutical composition of  claim 11 , wherein the isotonicity agent is sodium chloride. 
     
     
         13 . A method for treating an opioid-induced peripheral side effect comprising administering to a patient the composition of  claim 1  in an amount effective to treat the side effect. 
     
     
         14 . The method of  claim 13 , wherein the peripheral side effect is constipation. 
     
     
         15 . The method of  claim 14 , wherein the composition is administered parenterally. 
     
     
         16 . The method of  claim 14 , wherein the subject experiences a bowel movement within 4 hours of administration. 
     
     
         17 . The method of  claim 14 , comprising administering R-MNTX at between about 0.01 to about 1.0 mg/kg body weight. 
     
     
         18 . The method of  claim 14 , comprising administering R-MNTX at between about 0.01 to about 0.45 mg/kg body weight. 
     
     
         19 . The method of  claim 14 , wherein the composition is administered subcutaneously. 
     
     
         20 . A product comprising a syringe or a vial comprising the composition of  claim 1 .