1531-23-3Relevant academic research and scientific papers
ELECTRON-TRANSFER ACTIVATION. PHOTOCHEMICAL N-DEMETHYLATION OF TERTIARY AMINES
Santamaria, J.,Ouchabane, R.,Rigaudy, J.
, p. 2927 - 2928 (1989)
DAP(2+) sensitized photooxidation of some biologically active N-methylated alkaloids affords the corresponding secondary amines in excellent yields (80-95percent).
Comparative study of the metabolism of drug substrates by human cytochrome P450 3A4 expressed in bacterial, yeast and human lymphoblastoid cells
Andrews,Abd-Ellah,Randolph,Kenworthy,Carlile,Friedberg,Houston
, p. 937 - 947 (2002)
1. The aim was to compare the metabolic activity of human CYP3A4 expressed in bacteria (E. coli), yeast (S. cerevisiae) and human lymphoblastoid cells (hBl), with the native CYP3A4 activity observed in a panel of human livers. 2. Three CYP3A4 substrates were selected for study: dextromethorphan (DEM), midazolam (MDZ) and diazepam (DZ). The substrate metabolism in each of the four systems was characterized by deriving the kinetic parameters Km or S50, Vmax and intrinsic clearance (CLint) or maximum clearance (CLmax) from the kinetic profiles; the latter differing by 100-fold across the three substrates. 3. The Km or S50 for the formation of metabolites 3-methoxymorphinan (MEM), 1′-hydroxymidazolam (1′-OH MDZ) and 3-hydroxydiazepam (3HDZ) compared well in all systems. For CYP3A4-mediated metabolism of DEM, MDZ and DZ, the Vmax for hB1 microsomes were generally 2-9-fold higher than the respective yeast and human liver microsomes and E. coli membrane preparations, resulting in greater CLint or CLmax. In the case of 3HDZ formation, non-linear kinetics were observed for E. coli, hBl microsomes and human liver microsomes, whereas the kinetics observed for S. cerevisiae were linear. 4. The use of native human liver microsomes for drug metabolic studies will always be preferable. However, owing to the limited availability of human tissues, we find it is reasonable to use any of the recombinant systems described herein, since all three recombinant systems gave good predictions of the native human liver enzyme activities.
An improved process for the N-demethylation of opiate alkaloids using an iron(II) catalyst in acetate buffer
Kok, Gaik,Ashton, Trent D.,Scammellsa, Peter J.
, p. 283 - 286 (2009)
An improved process to N-demethylate opiate alkaloids utilising a solution of the ferrous porphyrin, tetrasodium 5,10,15,20-tetra(4-sulfophenyl) porphyrinatoiron(II) [=Fe(II)-TPPS (8)], in acetate buffer is described. This method provided the corresponding N-demethylated opiates in good yield with high reproducibility.
ANALOGS OF DEXTROMETHORPHAN WITH BALANCED RECEPTOR ACTIVITIES
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Paragraph 0073-0075, (2022/03/09)
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
Altman, Ryan A.,Ambler, Brett R.,Sorrentino, Jacob P.
, p. 5416 - 5427 (2020/05/19)
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.
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
Glass, Sarah M.,Martell, Cydney M.,Oswalt, Alexandria K.,Osorio-Vasquez, Victoria,Cho, Christi,Hicks, Michael J.,Mills, Jacqueline M.,Fujiwara, Rina,Glista, Michael J.,Kamath, Sharat S.
supporting information, p. 1106 - 1117 (2018/08/12)
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
COMPOSITIONS AND METHODS THEREOF
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Paragraph 00535, (2018/03/25)
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.
DEUTERATED MORPHINAN COMPOUNDS FOR USE IN TREATING AGITATION
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Page/Page column 25; 26, (2017/02/24)
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.
Utility of iron nanoparticles and a solution-phase iron species for the: N-demethylation of alkaloids
Awalt, Jon Kyle,Lam, Raymond,Kellam, Barrie,Graham, Bim,Scammells, Peter J.,Singer, Robert D.
, p. 2587 - 2594 (2017/07/17)
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.
Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3 Groups
Barham, Joshua P.,John, Matthew P.,Murphy, John A.
supporting information, p. 15482 - 15487 (2016/12/09)
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.
