- ELECTRON-TRANSFER ACTIVATION. PHOTOCHEMICAL N-DEMETHYLATION OF TERTIARY AMINES
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DAP(2+) sensitized photooxidation of some biologically active N-methylated alkaloids affords the corresponding secondary amines in excellent yields (80-95percent).
- Santamaria, J.,Ouchabane, R.,Rigaudy, J.
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- Comparative study of the metabolism of drug substrates by human cytochrome P450 3A4 expressed in bacterial, yeast and human lymphoblastoid cells
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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.
- Andrews,Abd-Ellah,Randolph,Kenworthy,Carlile,Friedberg,Houston
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- An improved process for the N-demethylation of opiate alkaloids using an iron(II) catalyst in acetate buffer
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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.
- Kok, Gaik,Ashton, Trent D.,Scammellsa, Peter J.
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- ANALOGS OF DEXTROMETHORPHAN WITH BALANCED RECEPTOR ACTIVITIES
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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.
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Paragraph 0073-0075
(2022/03/09)
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- Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues
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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.
- Altman, Ryan A.,Ambler, Brett R.,Sorrentino, Jacob P.
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p. 5416 - 5427
(2020/05/19)
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- COMPOSITIONS AND METHODS THEREOF
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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.
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Paragraph 00535
(2018/03/25)
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- 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
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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
- 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.
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supporting information
p. 1106 - 1117
(2018/08/12)
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- DEUTERATED MORPHINAN COMPOUNDS FOR USE IN TREATING AGITATION
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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.
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- Utility of iron nanoparticles and a solution-phase iron species for the: N-demethylation of alkaloids
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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.
- Awalt, Jon Kyle,Lam, Raymond,Kellam, Barrie,Graham, Bim,Scammells, Peter J.,Singer, Robert D.
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p. 2587 - 2594
(2017/07/17)
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- Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3 Groups
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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.
- Barham, Joshua P.,John, Matthew P.,Murphy, John A.
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p. 15482 - 15487
(2016/12/09)
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- Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor
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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.
- Jozwiak, Krzysztof,Targowska-Duda, Katarzyna M.,Kaczor, Agnieszka A.,Kozak, Joanna,Ligeza, Agnieszka,Szacon, Elzbieta,Wrobel, Tomasz M.,Budzynska, Barbara,Biala, Grazyna,Fornal, Emilia,Poso, Antti,Wainer, Irving W.,Matosiuk, Dariusz
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p. 6846 - 6856
(2015/02/02)
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- An improved process for the preparation of (+)-3- Methoxy-N-formylmorphinan
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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.
- Kumaraguru, Thenkrishnan,Fadnavis, Nitin W.
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p. 174 - 178
(2014/05/20)
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- METHODS FOR TREATING DEPRESSIVE SYMPTOMS
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The present application relates methods for treating a depressive symptom comprising administering an effective amount of a μ opioid receptor agonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. Non-limiting examples of such agonist include the compounds of Formulas I, II, III, and IV, as well as the compounds of Table A.
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Page/Page column 62
(2014/12/12)
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- Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C
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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.
- Kim, Joohwan,Lim, Young-Ran,Han, Songhee,Han, Jung-Soo,Chun, Young-Jin,Yun, Chul-Ho,Lee, Chang Hoon,Kim, Donghak
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p. 1500 - 1506
(2014/01/06)
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- Polonovski-type N-demethylation of N-methyl alkaloids using substituted ferrocene redox catalysts
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Various substituted ferrocenes have been trialed as catalysts in the nonclassical Polonovski reaction for N-demethylation of N-methyl alkaloids. Earlier studies suggest that conditions facilitating a higher ferrocenium ion concentration lead to superior outcomes. In this regard, the bifunctional ferrocene FcCH2CO2H, with electron donor and acceptor moieties in the same molecule, has been shown to be advantageous for use as a catalyst in the N-demethylation of a number of tertiary N-methylamines such as codeine, thebaine, and oripavine. These substrates are readily N-demethylated under mild conditions, employing sub-stoichiometric amounts of the substituted ferrocene at ambient temperature. These reactions are equally efficient in air and may also be carried out in one pot. Georg Thieme Verlag Stuttgart · New York.
- Kok, Gaik B.,Scammells, Peter J.
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experimental part
p. 2587 - 2594
(2012/09/22)
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- N-Demethylation of N-methyl alkaloids with ferrocene
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Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.
- Kok, Gaik B.,Scammells, Peter J.
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supporting information; experimental part
p. 4499 - 4502
(2010/09/15)
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- Two-step iron(0)-mediated N-demethylation of N -methyl alkaloids
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(Figure Presented) A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.
- Kok, Gaik B.,Pye, Cory C.,Singer, Robert D.,Scammells, Peter J.
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experimental part
p. 4806 - 4811
(2010/10/19)
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- Combinatorial alanine substitution enables rapid optimization of cytochrome P450BM3 for selective hydroxylation of large substrates
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Made for each other: Combinatorial alanine substitution of active site residues in a thermostable cytochrome P450BM3 variant was used to generate an enzyme that is active with large substrates. Selective hydroxylation of methoxymethylated monosaccharides, alkaloids, and steroids was thus made possible (see Scheme). This approach could be useful for improving the activity of enzymes that show only limited activity with larger substrates.
- Lewis, Jared C.,Mantovani, Simone M.,Fu, Yu,Snow, Christopher D.,Komor, Russell S.,Wong, Chi-Huey,Arnold, Frances H.
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scheme or table
p. 2502 - 2505
(2011/10/01)
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- MORPHINAN COMPOUNDS
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This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ1 receptor agonist that also has NMDA antagonist activity.
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Page/Page column 29; 30
(2010/04/25)
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- Morphinan Compounds
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This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ1 receptor agonist that also has NMDA antagonist activity.
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Page/Page column 12
(2008/12/08)
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- New methodology for the N-demethylation of opiate alkaloids
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(Chemical Equation Presented) N-Demethylation is a key step in the preparation of a number of semisynthetic opiate pharmaceuticals. Herein we report a high-yielding, catalytic procedure for the N-demethylation of opiates which has a number of advantages over existing methods. For example, tetrasodium 5,10,15,20-tetra(4-sulfophenyl)-porphyrinatoiron(II) (0.3 molar equiv) effected the transformation of codeine methyl ether to the corresponding N-nor analogue in 91% yield. The catalyst was readily removed and recycled.
- Dong, Zemin,Scammells, Peter J.
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p. 9881 - 9885
(2008/09/18)
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- ELECTRON-TRANSFER ACTIVATION. SALT EFFECTS ON THE PHOTOOXADIDATION OF TERTIARY AMINES : A USEFUL N-DEMETHYLATION METHOD
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Photooxidation of tertiary methylamines sensitized by electron acceptors like 9,10-dicyanoanthracene is shown to proceed by two distinct ways depending on the presence of added salts.In the absence of added salt both nor and N-formyl compounds were obtained while with added salt the nor-derivative is obtained highly efficiently.
- Santamaria, J.,Ouchabane, R.,Rigaudy, J.
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p. 3977 - 3980
(2007/10/02)
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