- Preparative microfluidic electrosynthesis of drug metabolites
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In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. Electrochemistry can be used to simulate CYP450 oxidation, yet it is often confined to the analytical scale, hampering product isolation and full characterization. In an effort to replicate hepatic oxidations, while retaining high throughput at the preparative scale, microfluidic technology and electrochemistry are combined in this study by using a microfluidic electrochemical cell. Several commercial drugs were subjected to continuous-flow electrolysis. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. It is demonstrated that such metabolites can be synthesized by flow electrolysis at the 10 to 100 mg scale, and the purified products are fully characterized.
- Stalder, Romain,Roth, Gregory P.
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supporting information
p. 1119 - 1123
(2013/12/04)
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- Fluorescence immunoassays using fluorescent dyes free of aggregation and serum binding
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Fluorescence immunoassays methods are provided which use fluorescent dyes which are free of aggregation and serum binding. Such immunoassay methods are thus, particularly useful for the assay of biological fluids, such as serum, plasma, whole blood and urine.
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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- New chemical aspects of primidone metabolism
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Primidone is metabolized either into phenylethylmalondiamide or phenobarbital. 2-Hydroxyprimidone was synthesized and tested as a potential intermediate common to these two biodegradation pathways in dogs as well as in vitro. On the other hand, the mechanism of the formation of α-phenyl-γ-butyrolactone during intoxication was investigated and the role of precursor played by the phenobarbital generated in vivo was shown.
- Lafont,Cave,Menager,Miocque
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- Anticonvulsants in epileptic fowl
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The high seizure susceptibility in epileptic fowl is an autosomal recessive trait characterized in homozygotes by seizures that occur spontaneously and in response to photic stimulation or hyperthermia. Both of the latter stimuli can be used to evoke seizures in drug studies. Epileptic fowl have abnormal inter-ictal EEG activity. When exposed to photic stimulation spiking is apparent on the EEG at seizure onset. Phenobarbital, primidone, phenytoin, and valproic acid reduce seizure susceptibility at plasma concentrations approximating those used to control generalized and focal cortical tonic-clonic seizures in humans. Carbamazepine and the benzodiazepines also reduce seizure susceptibility. These data include that epileptic fowl provide a useful model for generalized and focal cortical tonic-clonic epilepsies. Ethosuximide was inactive in epileptic fowl. However, trimethadione had anticonvulsant activity indicating that this model is only relatively specific for the above seizure types. When seizures were evoked by hyperthermia phenobarbital but not phenytoin or valproate reduced seizure susceptibility. GABA (γ-aminobutyric acid), AOAA (amino-oxyacetic acid) and THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ole, a glial specific inhibitor of GABA uptake) all have anticonvulsant activity against seizures evoked by photic stimulation in young chicks. These data indicate that this model may be particularly useful for studies of the anticonvulsant activity of compounds designed to enhance GABAergic transmission.
- Johnson,Davis
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p. 1753 - 1757
(2007/10/02)
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- The Chemistry of Aryllead(IV) Tricarboxylates. Reaction with Derivatives of Malonic Acid: New Routes to α-Aryl Carboxylic Acids and Arylated Barbituric Acid Derivatives
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Derivatives of 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) and the sodium salts of substituted malonic esters undergo electrophilic C-arylation in high yield with aryllead triacetates, thus providing new routes to α-arylalkanoic acids.Syntheses of the antiflammatory compound 2-(p-isobutylphenyl)propanoic acid (Ibuprofen) have been carried out to demonstrate the method.The arylation reaction has been extended to 5-ethylbarbituric acid and to barbituric acid itself, which affords the 5,5-diarylated derivatives in good yield.A study of the effect of some tertiary bases on the reaction of p-methoxyphenyllead triacetate with the 5-isopropyl derivative of Meldrum's acid has shown that replacement of pyridine by 2,2'-bipyridyl results in an increase in yield and reaction rate, while a further marked improvement occurs in the presence of 1,10-phenanthroline.
- Kopinski, Richard P.,Pinhey, John T.,Rowe, Bruce A.
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p. 1245 - 1254
(2007/10/02)
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- HYDROLYSIS OF BARBITURIC ACID DERIVATIVES. PART V. HYDROLYSIS OF 1-BENZOYL-5-ETHYL-5-PHENYLBARBITURIC ACID
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The pathways of hydrolytic degradation of 1-benzoyl-5-ethyl-5-phenylbarbituric acid have been investigated.The profiles of log k - pH of hydrolyses of 1-benzoyl-5-ethyl-5-phenylbarbituric acid and the main hydrolytic product i.e. 1-benzoyl-3-(2-phenylbutyryl)urea have been determined and discussed.
- Paluchowska, Maria,Ekiert, Leszek,Jochym, Krystyna,Bojarski, Jacek
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p. 799 - 807
(2007/10/02)
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- THE REACTION OF t-BUTYL HYPOCHLORITE WITH THIOCARBONYL COMPOUND - A CONVENIENT METHOD FOR THE TRANSFORMATION
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The reaction of t-butyl hypochlorite with different thiocarbonyl compounds has been studied.Primary thioamides 1a-c give 1,2,4-thiadiazole derivatives.N-Phenylthiourea 4a gives 5-imino-4-phenyl-3-phenylamino-4,5-dihydro-1,2,4-thiadiazoline 15.Secondary and tertiary thioamides 2a-d, N-methyl-2-thiopyrrolidinone 3, N,N'-dicyclohexylthiourea 4b, N,N,N'-trimethylthiourea 4c, 5-ethyl-5-phenylthiobarbituric acid 5, xanthione 7a, Mischler's thioketone 7b, thiocoumarin 8, O-ethylthiobenzoate 9, O,O-diphenylthiocarbonate 10, di-p-tolyl and o-phenylene trithiocarbonates 11 and 12 have all afforded the oxigen analogues.N,N-Dimethyl-S-phenyldithiocarbonate 6 produces a mixture of di-, tri-, and tetrasulfides.A mechanism for the transformation is suggested in accordance with the Hard and Soft Acids and Bases (HSAB) principle.
- El-Wassimy, M.T.M.,Jorgensen, K.A.,Lawesson, S.-O.
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p. 1729 - 1734
(2007/10/02)
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- THE =C=S -> =C=O TRANSFORMATION USING THE SOFT NO(+)-SPECIES
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The reaction of NaNO2 in acidic solution with thiocarbonyl compounds has been studied.Secondary- and tertiary thioamides, 1-benzyl-hexahydro-2H-azepine-2-thione, 5-ethyl-5-phenyl thiobarbituric acid, certain thiourea derivatives, 2H-1-benzopyran-2-thione, O,O-diphenyl-thiocarbonic ester, O,S-diphenyl-dithiocarbonic ester, N,N-dimethyl-S-phenyl-dithiocarbamatic ester, N-ethyl-N-phenyl-O-ethyl-thiocarbamatic ester are all converted into the corresponding carbonyl-analogues. 4,4'-Bis(dimethylamino)-thiobenzophenone (Michler's thioketone) gives 3-nitro-4,4'-bis(dimethylamino)-benzophenone at room temperature.At (-10 deg C)-(-5 deg C) the expected oxo compound is obtained as the main product together with 4-(N-nitroso-methylamino)-4'-(dimethylamino)-benzophenone.
- Joergensen, K. A.,Ghattas, A.-B.A.G.,Lawesson, S.-O.
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p. 1163 - 1168
(2007/10/02)
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- THE α-ARYLATION OF DERIVATIVES OF MALONIC ACID WITH ARYLLEAD TRIACETATES. NEW SYNTHESES OF IBUPROFEN AND PHENOBARBITAL.
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Derivatives of Meldrum's acid and the sodium salts of substituted malonic acid esters undergo rapid arylation in high yield when treated with aryllead triacetates.These reactions have been applied to the synthesis of ibuprofen, an analgesic, and in a closely related reaction 5-ethylbarbituric acid has been reacted with phenyllead triacetate to give phenobarbital.
- Pinhey, John T.,Rowe, Bruce A.
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p. 965 - 968
(2007/10/02)
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- Spin labeled compounds
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Compounds are provided for use in assays of organic compounds, where organic compounds of biological interest are determined at extremely low concentrations by combining in a medium, the composition to be determined, hereinafter referred to as ligand, a high molecular weight material of at least 10,000 molecular weight, which has a site spatially characteristic of the ligand, hereinafter referred to as receptor, and an analog of the ligand having a free radical functionality, hereinafter referred to as "ligand analog". The ligand analog and ligand in the medium compete for the receptor site, the amount of ligand analog bound to the receptor, being dependent on the amount of ligand present in the medium. By following the change in electron spin resonance spectrum of the ligand analog and comparing it to the change in spectrum which would be obtained in the absence of any ligand, the amount of ligand can be determined.
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- Anticonvulsants. III. Phenobarbital and mephobarbital derivatives
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Several phenobarbital and mephobarbital derivatives were found to possess potent anticonvulsant activity and yet were either devoid of the marked hypnotic effects associated with the parent compounds or displayed very weak hypnotic activity. Particularly active compounds were the Mannich type derivatives, the bis(hexamethylenetetramine salt) of 1,3 bis(bromomethyl)phenobarbital and 1 methyl 3 methoxymethylphenobarbital.
- Vida,Hooker,Reinhard
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p. 602 - 605
(2007/10/09)
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