- Electrochemical behaviour of dipyrone (metamizole) and others pyrazolones
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The electrochemical oxidation of dipyrone (MTM) in aqueous medium was characterized using antipyrine (AA), 4-aminoantipyrine (4AA), 4-methyl-aminoantipyrine (MAA) and 4-dimethyl-aminoantipyrine (DMAA) as model molecules for the elucidation of all MTM voltammetric signals. The MTM and the other pyrazolones show up to four oxidation electrochemical processes. The voltammograms obtained in AA solutions presented an irreversible electrochemical oxidation process involving one electron at Eap3, which is common to all pyrazolone derivatives, while the amino pyrazolones present electrochemical oxidation processes at Eap0 or Eap1. The stabilization of the oxidation products depends on different effects: the proton release added to the thermodynamic stability, in the case of the imine formation at Eap0 (4AA and MAA) and the hyperconjugation (σ-stabilization) in the case of iminium formation (DMAA and MTM) at Eap1. The process observed at Epa0 corresponds to the pH-dependent oxidation of the primary and secondary enamines, while the process observed at Eap1 occurs in the tertiary enamines, is pH independent. The oxidation peak potential follows the order: MAA a linear range from 10 μmol L?1 to 100 μmol L?1 with a LOD of 1.94 and 2.97 μM for DMAA and MTM, respectively, LOQ of 6.48 and 9.91 μM (n = 10) and, sensitivity of 0.96 μA/μM for DMAA and 0.92 μA/μM; with a recoveries of 95–105% for MTM.
- Bacil, Raphael P.,Buoro, Rafael M.,Campos, Othon S.,Ramos, Matesa A.,Sanz, Caroline G.,Serrano, Silvia H.P.
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Read Online
- Preparation method of 4-methylaminoantipyrine
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The invention discloses a preparation method of 4-methylaminoantipyrine. The preparation method consists of: taking aminoantipyrene shown as formula (I) as the raw material, in a 1-methyl-3-butylimidazolium tetrafluoroborate ionic liquid reaction medium, and under the action of solid alkali, carrying out dimethyl carbonate methylation one-step reaction to obtain 4-methylaminoantipyrine shown as formula (II). The reaction equation is shown as the specification, and the solid alkali is macroporous weakly basic styrene type anion exchange resin. The technology has the characteristics of easy operation and high product purity, is a new synthetic technical route, and has the advantages of safety and easily available raw materials, thus being conducive to industrial production.
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Paragraph 0015
(2016/11/28)
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- Antinociceptive activity of metamizol metabolites in a rat model of arthritic pain
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Preclinical Research The aim of the present study was to evaluate the antinociceptive activity of the main metamizol (MET) metabolites, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA), and 4-acetylaminoantipyrine (AAA) using the "pain-induced functional impairment in rat" model (PIFIR model). The antinociceptive efficacies of MAA and AA were 288.3% h and 281.1% h, respectively, close to the efficacy of MET (333.80% h). The effective dose to attain 50% of the maximum response (ED50) values for MET, MAA and AA were 126.1, 124.9, and 110.7 mg/kg, respectively. FAA and AAA were essentially inactive in this experimental model. Part of the antinociceptive effect showed by MET in this study might be attributed to the effect of the metabolites MAA and AA on cyclooxygenases COX-1 and COX-2 activity.
- Lopez-Munoz, Francisco Javier,Soria-Arteche, Olivia,Lopez, Jose Raul Medina,Hurtado Y De La Pena, Marcela,Garcia, Ma. Concepcion Lozada,Moreno-Rocha, Luis Alfonso,Dominguez-Ramirez, Adriana Miriam
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p. 332 - 338
(2013/08/23)
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- NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation
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To understand the molecular basis of sequential N-dealkylation by cytochrome P450 2B enzymes, we studied the binding of amidopyrine (AP) as well as the metabolites of this reaction, desmethylamidopyrine (DMAP) and aminoantipyrine (AAP), using the X-ray crystal structure of rabbit P450 2B4 and two nuclear magnetic resonance (NMR) techniques: saturation transfer difference (STD) spectroscopy and longitudinal (T1) relaxation NMR. Results of STD NMR of AP and its metabolites bound to P450 2B4 were similar, suggesting that they occupy similar niches within the enzyme's active site. The model-dependent relaxation rates (RM) determined from T1 relaxation NMR of AP and DMAP suggest that the N-linked methyl is closest to the heme. To determine the orientation(s) of AP and its metabolites within the P450 2B4 active site, we used distances calculated from the relaxation rates to constrain the metabolites to the X-ray crystal structure of P450 2B4. Simulated annealing of the complex revealed that the metabolites do indeed occupy similar hydrophobic pockets within the active site, while the N-linked methyls are free to rotate between two binding modes. From these bound structures, a model of N-demethylation in which the N-linked methyl functional groups rotate between catalytic and noncatalytic positions was developed. This study is the first to provide a structural model of a drug and its metabolites complexed to a cytochrome P450 based on NMR and to provide a structural mechanism for how a drug can undergo sequential oxidations without unbinding. The rotation of the amide functional group might represent a common structural mechanism for N-dealkylation reactions for other drugs such as the local anesthetic lidocaine.
- Roberts, Arthur G.,Sjoegren, Sara E. A.,Fomina, Nadezda,Vu, Kathy T.,Almutairi, Adah,Halpert, James R.
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experimental part
p. 2123 - 2134
(2012/03/10)
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- Scavenging activity of aminoantipyrines against hydroxyl radical
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The pyrazolone derivatives antipyrine and 4-(N,N-dimethyl)-aminoantipyrine (aminopyrine) have long been used as analgesic, antipyretic and anti-inflammatory drugs. However, in spite of its recognized therapeutic benefits, the use of pyrazolones has been associated with agranulocytosis. Though the oxidation of aminopyrine by neutrophil-generated hypochlorous acid (HOCl), leading to the formation of a cation radical, has been considered responsible for the potential bone marrow toxicity, the reaction mechanisms of pyrazolones against other reactive oxygen species (ROS) remains elusive. Thus, the reactions of 4-aminoantipyrine and methylated derivatives with hydroxyl radicals (HO?) were studied as a model of their reactivity against ROS. The results show that 4-(N,N-dimethyl)-aminoantipyrine (aminopyrine) undergoes demethylation when reacting with HO· radical, leading to 4-(N-methyl)-aminoantipyrine, which is further demethylated to 4-aminoantipyrine. In addition, it was also observed that another favorable reaction of 4-aminoantipyrines in these conditions is the hydroxylation on the aromatic ring, a reaction that is common to aminopyrine, 4-(N-methyl)-aminoantipyrine, and 4-aminoantipyrine. Whether these reaction mechanisms give rise to harmful reactive intermediates requires further chemico-biological evaluation.
- Santos, Pedro M.P.,Antunes, Alexandra M.M.,Noronha, Jo?o,Fernandes, Eduarda,Vieira, Abel J.S.C.
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experimental part
p. 2258 - 2264
(2010/06/19)
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- MORPHINE COMPOUNDS FOR PHARMACEUTICAL COMPOSITIONS
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The invention relates to new morphine compounds of the formula: where R1 represents a C1-6 alkyl radical and the radicals R2 and R3 are independently selected from the group consisting of hydrogen atoms, methyl groups and acetyl groups.
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Page/Page column title page; 4; sheet 1; sheet 2
(2009/01/23)
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