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 . The method of  claim 111 , 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%. 
     
     
         2 . The method of  claim 111 , wherein the MNTX present in the composition is a cation of a salt, paired by an anion. 
     
     
         3 . The method of  claim 2 , wherein the anion is selected from the group consisting of a halide, sulfate, phosphate, nitrate, an organic-charged anionic species, bromide, chloride, iodide, and flouride. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 111  comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen, and wherein the MNTX is not a bromide salt of MNTX. 
     
     
         7 . The method of  claim 6 , wherein the MNTX present in the composition is a cation of a salt, paired by an anion, optionally, wherein the anion is selected from the group consisting of a halide, sulfate, phosphate, nitrate, an organic anionic species, chloride, iodide, and flouride. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 6  further comprising one or more of a buffering agent, a chelating agent, a cryoprotecting agent, a lubricating agent, a preservative, an anti-oxidant, or a binding agent. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 6 , wherein at least 99.85% of the MNTX in the composition is in the R configuration with respect to nitrogen. 
     
     
         12 . The method of  claim 6 , wherein the composition is free of HPLC detectable S-MNTX at a detection level of 0.02% and at a quantitation level of 0.05%. 
     
     
         13 . The method of  claim 11 , wherein the MNTX present in the composition is a cation of a salt, paired by an anion, optionally, wherein the anion is selected from the group consisting of a halide, sulfate, phosphate, nitrate, an organic anionic species, chloride, iodide, and flouride. 
     
     
         14 - 110 . (canceled) 
     
     
         111 . A method for treating an opioid-induced peripheral side effect comprising administering to a patient in need of such treatment a composition comprising R-MNTX, 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% or a composition comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen in an amount effective to treat the side effect; optionally wherein the patient is chronically administered opioids. 
     
     
         112 . (canceled) 
     
     
         113 . The method of  claim 111 , wherein the side effect is selected from a group consisting of constipation, immune suppression, inhibition of gastrointestinal motility, inhibition of gastric emptying, nausea, emesis, incomplete evacuation, bloating, abdominal distension, increased gastroesophageal reflux, hypotension, bradycardia, gastrointestinal dysfunction, pruritus, dysphoria, and urinary retention. 
     
     
         114 . (canceled) 
     
     
         115 . A method for treating endogenous opioid-induced gastrointestinal dysfunction, comprising administering to a patient in need of such treatment a composition comprising R-MNTX, 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% or a composition comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen in an amount effective to treat the endogenous opioid-induced gastrointestinal dysfunction; optionally wherein the gastrointestinal dysfunction is selected from a group consisting of inhibition of gastrointestinal motility, constipation and postoperative bowel dysfunction. 
     
     
         116 . (canceled) 
     
     
         117 . A method for treating idiopathic constipation comprising administering to a patient a composition comprising R-MNTX, 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% or a composition comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen in an amount effective to treat the idiopathic constipation. 
     
     
         118 . A method for treating irritable bowel syndrome comprising administering to a patient in need of such treatment a composition comprising R-MNTX, 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% or a composition comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen in an amount effective to ameliorate at least one symptom of the irritable bowel syndrome; optionally further comprising administration of at least one irritable bowel syndrome therapeutic agent to the patient; and optionally wherein the irritable bowel syndrome therapeutic is selected from the groups consisting of an antispasmodic agent, an anti-muscarinic agent, a non-steroidal or steroidal anti-inflammatory agent, a pro-motility agent, a 5HT 1  agonist, a 5HT 3  antagonist, a 5HT 4  antagonist, a 5HT 4  agonist, a bile salt sequestering agent, a bulk-forming agent, an alpha2-adrenergic agonist, a mineral oil, an antidepressant, an herbal medicine, an anti-diarrheal agent and combinations thereof. 
     
     
         119 - 120 . (canceled) 
     
     
         121 . A method for inducing laxation in a patient in need of laxation comprising administering to a patient in need of such treatment a composition comprising R-MNTX, 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% or a composition comprising MNTX, wherein at least 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition is in the R configuration with respect to nitrogen in an amount effective to induce laxation. 
     
     
         122 - 199 . (canceled)