- MEANS AND METHODS FOR THE N-DEALKYLATION OF AMINES
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The invention relates to improved means and methods for N- dealkylation of alkylated amines. Provided is a method for the catalytic N- dealkylation of an N-alkylated amine substrate, comprising incubating said amine substrate in a suitable solvent in the
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Page/Page column 18; 19
(2017/11/10)
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- Drug Oxidation by Cytochrome P450BM3: Metabolite Synthesis and Discovering New P450 Reaction Types
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There is intense interest in late-stage catalytic C-H bond functionalization as an integral part of synthesis. Effective catalysts must have a broad substrate range and tolerate diverse functional groups. Drug molecules provide a good test of these attributes of a catalyst. A library of P450BM3 mutants developed from four base mutants with high activity for hydrocarbon oxidation produced human metabolites of a panel of drugs that included neutral (chlorzoxazone, testosterone), cationic (amitriptyline, lidocaine) and anionic (diclofenac, naproxen) compounds. No single mutant was active for all the tested drugs but multiple variants in the library showed high activity with each compound. The high conversions enabled full product characterization that led to the discovery of the new P450 reaction type of oxidative decarboxylation of an α-hydroxy carboxylic acid and the formation a protected imine from an amine, offering a novel route to α-functionalization of amines. The substrate range and varied product profiles suggest that this library of enzymes is a good basis for developing late-stage C-H activation catalysts.
- Ren, Xinkun,Yorke, Jake A.,Taylor, Emily,Zhang, Ting,Zhou, Weihong,Wong, Luet Lok
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p. 15039 - 15047
(2015/10/20)
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- Iron-catalyzed Cα-H oxidation of tertiary, aliphatic amines to amides under mild conditions
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De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe-catalyzed Cα-H functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild Cα-H cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis. Let′s iron it out! The title reaction enables the oxidative synthesis of amides directly from tertiary, noncyclic alkyl amines under synthetically useful, mild conditions through a biologically inspired approach employing oxidative iron catalysis. Mechanistic studies suggest that hemiaminals are likely intermediates in this reaction and that the catalytic system can be employed for other Cα-H oxidations of amines.
- Legacy, Christopher J.,Wang, Anqi,O'Day, Brian J.,Emmert, Marion H.
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supporting information
p. 14907 - 14910
(2016/02/05)
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- 2, 6 XYLIDINE DERIVATIVES FOR THE TREATMENT OF PAIN
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The disclosure herein provides a composition compound of formula 1. The disclosure also provides a method of synthesizing the compound of formula 1. The compound of formula 1 or its pharmaceutical acceptable salts, as well as polymorphs, solvates, and hydrates thereof may be formulated as pharmaceutical composition to be used for treatment of pain. The pharmaceutical composition of compound of formula 1 or the final compound may be formulated for non-invasive peroral, topical (example transdermal), enteral, transmucosal, targeted delivery, sustained release delivery, delayed release, pulsed release and parenteral methods. Such compositions may be used to treat chronic pain manifested with chronic diseases or its associated complications. The compound of formula 1 may also be offered as a kit.
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- Preparation of human drug metabolites using fungal peroxygenases
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The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus radians catalyzed the H2O2-dependent selective monooxygenation of diverse drugs, including acetanilide, dextrorphan, ibuprofen, naproxen, phenacetin, sildenafil and tolbutamide. Reactions included the hydroxylation of aromatic rings and aliphatic side chains, as well as O- and N-dealkylations and exhibited different regioselectivities depending on the particular APO used. At best, desired HDMs were obtained in yields greater than 80% and with isomeric purities up to 99%. Oxidations of tolbutamide, acetanilide and carbamazepine in the presence of H218O2 resulted in almost complete incorporation of 18O into the corresponding products, thus establishing that these reactions are peroxygenations. The deethylation of phenacetin-d1 showed an observed intramolecular deuterium isotope effect [(kH/kD) obs] of 3.1 ± 0.2, which is consistent with the existence of a cytochrome P450-like intermediate in the reaction cycle of APOs. Our results indicate that fungal peroxygenases may be useful biocatalytic tools to prepare pharmacologically relevant drug metabolites.
- Poraj-Kobielska, Marzena,Kinne, Matthias,Ullrich, Rene,Scheibner, Katrin,Kayser, Gernot,Hammel, Kenneth E.,Hofrichter, Martin
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experimental part
p. 789 - 796
(2012/07/14)
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- Electrochemical oxidation by square-wave potential pulses in the imitation of oxidative drug metabolism
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Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wa
- Nouri-Nigjeh, Eslam,Permentier, Hjalmar P.,Bischoff, Rainer,Bruins, Andries P.
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experimental part
p. 5519 - 5525
(2012/02/15)
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- OLIGOMER CONJUGATES OF LIDOCAINE AND ITS DERIVATIVES
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The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer.
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Page/Page column 41; 43
(2009/05/30)
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- SUBSTITUTED ACETANILIDES AND BENZAMIDES FOR THE TREATMENT OF ASTHMA AND PULMONARY INFLAMMATION
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Substituted acetanilide or benzamide compositions or formulations for delivery by aerosolization are described. The formulation contains an efficacious amount of acetanilide or benzamide compound able to inhibit inflammation in asthmatic lungs. Compounds of the invention are formulated in 5 ml solution of a quarter normal saline having pH between 5.0 and 7.0. The method for treatment of respiratory tract inflammation by a formulation delivered as an aerosol having mass medium average diameter predominantly between 1 to 5 μ, produced by nebulization or dry powder inhaler.
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Page/Page column 41
(2008/06/13)
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- Application of Predictive QSAR Models to Database Mining: Identification and Experimental Validation of Novel Anticonvulsant Compounds
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We have developed a drug discovery strategy that employs variable selection quantitative structure-activity relationship (QSAR) models for chemical database mining. The approach starts with the development of rigorously validated QSAR models obtained with
- Shen, Min,Béguin, Cécile,Golbraikh, Alexander,Stables, James P.,Kohn, Harold,Tropsha, Alexander
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p. 2356 - 2364
(2007/10/03)
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- Studying drug metabolic oxidation with biomimetic metalloporphyrin systems : Problems and solutions in the case of lidocaine
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The oxidation of the drug lidocaine 1 (2,2-diethylamino-2',6'-dimethylacetanilide) by various metalloporphyrin systems mimicking cytochrome P450 was studied.Systems using H2O2 or PhIO as oxidants and several homogeneous or supported Fe(III)- or Mn(III)-po
- Carrier, M. N.,Battioni, P.,Mansuy, D.
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p. 405 - 416
(2007/10/02)
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- Simultaneous quantitation of lidocaine and its four metabolites by high-performance liquid chromatography: Application to studies on in vitro and in vivo metabolism of lidocaine in rats
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A convenient and sensitive high-performance liquid chromatographic assay for the simultaneous quantitation of lidocaine and its four metabolites has been developed. The samples containing lidocaine and its metabolites were eluted from a microparticulate octadecylsilane column using a mobile phase of 0.1 M phosphate buffer (pH 3.0) containing 10% acetonitrile. This method was applied to studies on in vitro metabolism and in vivo pharmacokinetics of lidocaine in rats. Kinetic studies of in vitro microsomal metabolism of lidocaine indicated that the apparent K(m) and V(max) for aromatic hydroxylation were smaller than those for N-deethylation. Lineweaver-Burk plots of the N-deethylation of lidocaine and those of its two primary metabolites indicated that at least two isozymes are taking part in these reactions. In in vivo lidocaine pharmacokinetics, the area under the blood concentration-time curve for the monodeethylated product, ω-ethylamino-2,6-dimethylacetanilide (1), varied considerably depending on the route of administration.
- Kawai,Fujita,Suzuki
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p. 1219 - 1224
(2007/10/02)
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