RESUMEN
The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Pirazolonas/química , Pirazolonas/farmacología , Receptores Purinérgicos P2X3/metabolismo , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , Pirroles/química , Pirroles/farmacología , Receptores Purinérgicos P2X3/química , Relación Estructura-ActividadRESUMEN
The reaction of 1-(p-hydroxyaryl)cyclobutanols and phenyl iodide(III) diacetate in hexafluoroisopropanol and water produced spiro cyclohexadienone lactones via a domino reaction.
Asunto(s)
Ciclohexenos/síntesis química , Yodo/química , Lactonas/síntesis química , Compuestos de Espiro/síntesis química , Ciclohexenos/química , Lactonas/química , Compuestos de Espiro/químicaRESUMEN
The domino reaction of 2,3-epoxy-1-alcohol derivatives, namely tetrasubstituted 2,3-epoxy-1-alcohols and 2- or 3-alkyl trisubstituted 2,3-epoxy-1-alcohols, with PhI(OCOCF(3))(2) in the presence of H(2)O is described in detail. In this reaction, several types of lactol derivatives can be directly obtained from the 2,3-epoxy-1-alcohol derivatives in a single operation. The obtained lactols were successively converted into the corresponding lactones. This reaction is applicable to the construction of optically active lactone compounds. The asymmetric total synthesis of (+)-tanikolide, an antifungal marine natural product, has been effectively achieved by using this reaction.
Asunto(s)
Alcoholes/química , Antifúngicos/síntesis química , Productos Biológicos/síntesis química , Compuestos Epoxi/química , Yodo/química , Lactonas/síntesis química , Biología Marina , Modelos Químicos , Estereoisomerismo , Agua/químicaRESUMEN
The oxidation of non-phenolic alkanoic acid derivatives to oxygen heterocycles was investigated; a new oxidative route to dienone lactones has been developed using a combination of hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate)(PIFA), and heteropoly acid (HPA).
Asunto(s)
Fluoroacetatos , Yodo/química , Lactonas/química , Ciclización , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Indicadores y Reactivos , Yodobencenos , Oxidación-Reducción , Ácido Trifluoroacético/químicaRESUMEN
The combination of the water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) and the surfactant, cetyltrimethyl-ammonium bromide (CTAB), was found to be the most suitable condition for the effective and direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water. In addition, the direct amidation of aldehydes was achieved by the addition of the amines to the thioesterification reaction mixture in water.
Asunto(s)
Aldehídos/química , Amidas/síntesis química , Ésteres/síntesis química , Cetrimonio , Compuestos de Cetrimonio , Indicadores y Reactivos , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de Fourier , Agua/químicaRESUMEN
Intramolecular oxidative coupling reaction of N-protected benzyltetrahydroisoquinoline derivatives using hypervalent iodine(III) reagents was investigated. The use of remarkable combination of phenyliodine bis (trifluoroacetate) (PIFA) and heteropoly acid (HPA) in wet acetonitrile smoothly afforded morphinandienone alkaloids, while neospirinedienone alkaloids were obtained in high yield under anhydrous conditions.
Asunto(s)
Alcaloides/síntesis química , Compuestos de Espiro/síntesis química , Tetrahidroisoquinolinas/química , Acetonitrilos , Catálisis , Indicadores y Reactivos/química , Estructura Molecular , Morfinanos/química , Oxidación-ReducciónRESUMEN
The non-phenolic coupling reaction of benzyltetrahydroisoquinolines (laudanosine derivatives) by using a hypervalent iodine(III) reagent is described. In general, chemical oxidation of laudanosine gives glaucine. In contrast to general chemical oxidizing reagent systems, the novel use of reagent combination of phenyliodine bis(trifluoroacetate) (PIFA), and heteropoly acid (HPA) afforded morphinandienone alkaloids in excellent yields. In order to achieve the coupling reaction with simple reaction procedure, the use of HPA supported on silica gel instead of HPA was demonstrated and sufficient yield was exerted again. The present reagent system, PIFA/HPA, was also applied to the oxidation of other non-phenolic benzyltetrahydroisoquinolines and the high yield conversion to morphinandienones was accomplished.
Asunto(s)
Ácidos/química , Alcaloides/química , Yodo/química , Morfinanos/química , Isoquinolinas/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
The combination of the water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044), and surfactant, cetyltrimethylammonium bromide (CTAB), was found to be the most suitable condition for the effective direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water.