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 . 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%. 
     
     
         2 . The composition of  claim 1 , wherein the MNTX present in the composition is a cation of a salt, paired by an anion. 
     
     
         3 . The composition 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 fluoride. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . 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, and wherein the MNTX is not a bromide salt of MNTX. 
     
     
         7 . The composition of  claim 6 , wherein the MNTX present in the composition is a cation of a salt, paired by an anion, wherein the anion is selected from the group consisting of a halide, sulfate, phosphate, nitrate and an organic anionic species. 
     
     
         8 . (canceled) 
     
     
         9 . The composition 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 composition 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 composition 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 composition 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, bromide, chloride, iodide, and fluoride. 
     
     
         14 - 92 . (canceled) 
     
     
         93 . A pharmaceutical composition comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         94 . The pharmaceutical composition of  claim 93 , wherein the pharmaceutical composition comprises an enteric coating, a sustained release formulation, a lyophilized preparation, or a solution. 
     
     
         95 - 96 . (canceled) 
     
     
         97 . The pharmaceutical composition of  claim 93 , further comprising an opioid selected from the group consisting of alfentanil, anileridine, asimodiline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenyloxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, tramadol, and combinations thereof. 
     
     
         98 . (canceled) 
     
     
         99 . The pharmaceutical composition of  claim 93 , further comprising at least one pharmaceutical agent that is not an opioid or an opioid antagonist;
 optionally wherein the at least one pharmaceutical agent is an antiviral agent, an anti-infective agent, an anticancer agent, an antispasmodic agent, an anti-muscarinic agent, an 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, a herbal medicine, an anti-emetic agent, an anti-diarrheal agent, a laxative, a stool softener, a fiber or a hematopoietic stimulating agent; and   optionally wherein the anti-inflammatory agent is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), tumor necrosis factor inhibitors, basiliximab, daclizumab, infliximab, mycophenolate, mofetil, azothioprine, tacrolimus, steroids, sulfasalazine, olsalazine, mesalamine, and combinations thereof.   
     
     
         100 - 110 . (canceled) 
     
     
         111 . A method for treating or preventing opioid-induced side effects comprising administering to a patient in need of such treatment the composition of  claim 1  in an amount effective to treat or prevent 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 . A method for treating a patient receiving an opioid for pain resulting from surgery comprising administering to the patient a composition of  claim 1  in an amount effective to promote gastrointestinal motility, gastric emptying or relief of constipation. 
     
     
         115 . A method for treating or preventing endogenous opioid-induced gastrointestinal dysfunction, comprising administering to a patient in need of such treatment the composition of  claim 1  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 preventing or treating idiopathic constipation comprising administering to a patient a composition of  claim 1  in an amount effective to prevent or treat the idiopathic constipation. 
     
     
         118 . A method for treating irritable bowel syndrome comprising administering to a patient in need of such treatment the composition of  claim 1  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 the composition of  claim 1  in an amount effective to induce laxation 
     
     
         122 . A method for preventing or treating post-operative bowel dysfunction comprising administering to a patient in need of such prevention or treatment the composition of  claim 1  in an amount effective to prevent or ameliorate at least one symptom of post-operative bowel dysfunction; optionally wherein the post-operative bowel dysfunction is delayed gastric emptying or inhibition of gastrointestinal motility. 
     
     
         123 - 146 . (canceled) 
     
     
         147 . A patient-controlled injection device comprising the composition of  claim 1 . 
     
     
         148 . (canceled) 
     
     
         149 . A kit comprising a package containing a sealed container comprising the pharmaceutical composition of  claim 93  and instructions for use. 
     
     
         150 - 189 . (canceled) 
     
     
         190 . A method for manufacturing R-MNTX comprising the following steps,
 (a) obtaining a first composition containing R-MNTX,   (b) purifying the first composition by chromatography, recrystallization or a combination thereof,   (c) conducting HPLC on a sample of purified first composition using S-MNTX as a standard,   (d) determining the presence or absence of S-MNTX in the sample.   
     
     
         191 . The method of  claim 190 , wherein the purifying comprises multiple recryallization steps or multiple chromatography steps; optionally wherein the purifying is carried out until S-MNTX is less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05%, or is absent from the purified first composition as determined by HPLC with a detection limit of 0.02% and a quantitation limit of 0.05%. 
     
     
         192 - 199 . (canceled)