28973-47-9

Upstream product

• 1453167-99-1 dextromethorphan 
• 125-71-3 dextromethorphan 
• 113951-04-5 dextromethorphan N-oxide hydrochloride 
• 245407-53-8 2,2,2-trichloroethyl (9α,13α,14α)-3-methoxymorphinan-17-carboxylate 
• 1159-53-1 tri(p-tolyl)amine 
• 106-49-0 p-toluidine 
• 280-57-9 1,4-diaza-bicyclo[2.2.2]octane 
• 584-08-7 potassium carbonate 
• 144-55-8 sodium hydrogencarbonate 
• 125-70-2 dextromethorphan 
• 50893-53-3 carbonochloridic acid 1-chloro-ethyl ester 
• 28973-48-0 (+)-3-methoxy-N-formylmorphinan 
• 29144-31-8 (S)-2-Formyl-1-<(4-methoxyphenyl)methyl>-1,2,3,4,5,6,7,8-octahydroispquinoline 
• 94992-57-1 (-)-octabase mandelate salt 

Downstream Products

• 524713-56-2 N-CD3-dextromethorphan 
• 57969-05-8 (9α,13α,14α)-3-methoxy-17-methylmorphinan-10-one 
• 1079043-47-2 (4bS,8aS,9S)-ethyl 3-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate 

Relevant academic research and scientific papers

Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C

CYP2D6 is responsible for the oxidative metabolism of 20-25 % of clinical drugs and its genetic polymorphisms can significantly influence the drug metabolism. In this study, we analyzed the functional activities of four nonsynonymous single nucleotide polymorphisms from CYP2D652 allele, which were recently found, and one found frequently in CYP2D6 alleles. Recombinant variant enzymes of E418K, S486T, and R296C were successfully expressed in Escherichia coli and purified. However, a CYP holoenzyme spectrum of P34S variant was not detected in E. coli whole cell level. Structural analysis indicated that P34S mutation seemed to perturb a highly conserved proline-rich N-terminus of CYP2D6. Steady state kinetic analyses showed the significant reductions of enzymatic activities in E418K and R296C variants. In the case of bufuralol 1'-hydroxylation, a novel mutant, E418K, showed 32 % decrease in catalytic efficiency (k cat/K m) mainly due to the decrease of k cat value. R296C showed much greater reduction in the catalytic efficiency (9 % of wild-type) due to both of a decrease of k cat value and an increase of K m value. In the case of dextromethorphan O-demethylation, E418K showed both of a decrease of k cat value and an increase K m value to result in ～43 % reduction of catalytic efficiency. A highly decreased catalytic efficiency (～6 % of wild-type) in the mutant of R296C also was observed mainly due to the dramatic change of k cat value of dextromethorphan O-demethylation. These results suggested that individuals carrying these allelic variants are likely to have the altered metabolic abilities of many clinical drugs therefore, these polymorphisms of CYP2D6 should be much concerned for reliable drug treatment.

ANALOGS OF DEXTROMETHORPHAN WITH BALANCED RECEPTOR ACTIVITIES

Substituted analogs of dextromethorphan (DM) are disclosed, which are shown to have substantial binding affinity at both NMDA and sigma-1 receptors, and which are degraded by human liver enzymes more slowly than dextromethorphan. The analogs are useful as alternatives to dextromethorphan, and can provide the same benefits without requiring co-administration of a cytochrome P-450 enzyme inhibitor.

Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.

COMPOSITIONS AND METHODS THEREOF

Compounds of formula I, (I) or enantiomers thereof, metabolites thereof, derivatives thereof, deuterated derivatives thereof, halogenated derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N- oxides thereof, or a combination thereof, processes and intermediates for preparation thereof, compositions thereof, and uses thereof, are provided. Pharmaceutical compositions comprising a compound of formula I and a compound of Formula II: (IIa) (IIb) or enantiomers thereof, metabolites thereof, derivatives thereof, deuterated derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof. Compositions and methods for improving the efficacy of DEX, or providing beneficial pharmacokinetic effects to DEX, comprising co-administering a compound of formula I or SARPO, and a compound of Formula II or DEX to a subject in need thereof, and dosage forms, drug delivery systems, methods of treatment thereof.

CYP2D6 allelic variants *34, *17-2, *17-3, and *53 and a Thr309Ala mutant display altered kinetics and NADPH coupling in metabolism of bufuralol and dextromethorphan and altered susceptibility to inactivation by SCH 66712

Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of cytochrome P450–mediated drug metabolism but consists of more than 100 known varian

Utility of iron nanoparticles and a solution-phase iron species for the: N-demethylation of alkaloids

The N-demethylation of selected N-methylalkaloids using a modified Polonovski reaction can be accomplished using a novel green methodology employing nanoscale zero-valent iron, nZVI, in isopropanol. Use of nZVI promotes a much faster conversion to N-demethylated products due to much higher surface area on the metal surface as shown by SEM analysis. Rates of conversion can be further enhanced using catalytic quantities of the solubilised iron(0) species triiron dodecacarbonyl, Fe3(CO)12.

DEUTERATED MORPHINAN COMPOUNDS FOR USE IN TREATING AGITATION

This invention relates to methods of treating agitation comprising administering a morphinan compound or a pharmaceutically acceptable salt thereof. This invention also provides the use in methods of treating agitation and related disorders with such a morphinan compound in combination with quinidine, or pharmaceutically acceptable salt of either or both thereof.

Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3 Groups

We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+?, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C-H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure-activity relationships.

Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards α3β4 nicotinic acetylcholine receptor is determined using a patch-clamp technique and is in the micromolar range. Homology modeling, molecular docking and molecular dynamics of ligand-receptor complexes in POPC membrane are used to find the mode of interactions of N-alkylated dextromethorphan derivatives with α3β4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of α3β4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction.

An improved process for the preparation of (+)-3- Methoxy-N-formylmorphinan

Two major steps, N-formylation of (-)-octabase and cyclization of the N-formylated product, involved in synthesis of (+)-3-methoxy-N-formylmorphinan, a key intermediate for production of dextromethorphan (DXM), have been improved to achieve higher yields in shorter time with fewer effluents. Methods of analysis of chemical and enantiomeric purities of the intermediates by HPLC and strategies for easy recovery and recycle of the reagents have been devised.