RESUMEN
A facile and efficient method has been developed for the synthesis of a small library of dibenzo[b,f][1,4]thiazepin-11(10H)-ones via Smiles rearrangement. Compounds were obtained in excellent isolated yields (70%-92%) under metal-free conditions. More specifically, this transition metal-free process relates to an environmentally friendly, economical, and efficient method for preparing benzoic-fused seven-membered lactams.
Asunto(s)
Dibenzotiazepinas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Dibenzotiazepinas/química , Estructura Molecular , EstereoisomerismoRESUMEN
The mycothiol biosynthesis enzyme MshC catalyzes the ligation of cysteine with the pseudodisaccharide GlcN-Ins and has been identified as an essential enzyme in Mycobacterium tuberculosis. We now report on the development of NTF1836 as a micromolar inhibitor of MshC. Using commercial libraries, we conducted preliminary structure-activity relationship (SAR) studies on NTF1836. Based on this data, NTF1836 and five structurally related compounds showed similar activity towards clinical strains of M. tuberculosis. A gram scale synthesis was developed to provide ample material for biological studies. Using this material, we determined that inhibition of M. tuberculosis growth by NTF1836 was accompanied by a fall in mycothiol and an increase in GlcN-Ins consistent with the targeting of MshC. We also determined that NTF1836 kills non-replicating M. tuberculosis in the carbon starvation model of latency.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Dibenzotiazepinas/química , Inhibidores Enzimáticos/química , Mycobacterium tuberculosis/enzimología , Animales , Proteínas Bacterianas/metabolismo , Chlorocebus aethiops , Cisteína/biosíntesis , Dibenzotiazepinas/síntesis química , Dibenzotiazepinas/toxicidad , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/toxicidad , Glicopéptidos/biosíntesis , Inositol/biosíntesis , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Células VeroRESUMEN
As a part of an integrated quality concept in drug development, the multidimensional evaluation of impurity profiles by LC-MS/MS is presented for quetiapine--an active pharmaceutical ingredient (API). LC-UV is commonly employed for the determination of impurities and degradation products. In this work LCMS/MS technique is proposed as a modern alternative for the characterization of these compounds. The use of this technique allowed to develop methods for the separation and identification of the impurities resulting from both, synthesis and degradation processes.
Asunto(s)
Antipsicóticos/análisis , Cromatografía Liquida , Dibenzotiazepinas/análisis , Contaminación de Medicamentos , Espectrometría de Masas en Tándem , Tecnología Farmacéutica/métodos , Antipsicóticos/síntesis química , Dibenzotiazepinas/síntesis química , Fumarato de QuetiapinaRESUMEN
A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).
Asunto(s)
Dibenzotiazepinas/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiazepinas/síntesis química , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Depresores del Apetito/síntesis química , Depresores del Apetito/química , Depresores del Apetito/farmacología , Línea Celular , Técnicas Químicas Combinatorias , Dibenzotiazepinas/química , Dibenzotiazepinas/farmacología , Agonismo Inverso de Drogas , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipotermia/inducido químicamente , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Solubilidad , Relación Estructura-Actividad , Tiazepinas/química , Tiazepinas/farmacologíaRESUMEN
Seven potential impurities, including by-products, starting materials and intermediates were identified in pharmaceutical substance quetiapine fumarate and characterized by spectroscopic methods (MS, IR, NMR). Based on these methods the structures of the impurities were assigned or confirmed as: impurity I: 2-(phenylthio)aniline; impurity II: phenyl N-[2-(phenylthio)phenyl]carbamate; impurity III: N,N'-bis[2-(phenylthio) phenyl]urea; impurity IV: N-[2-(phenylthio)phenyl]-1-piperazinecarboxamide hydrochloride; impurity V: N,N'-bis[(2-phenylthio)phenyl]-1,4-piperazinedicarboxamide; impurity VI: 11-(1-piperazinyl) dibenzo[b,f][1,4]thiazepine fumarate; impurity VII: 1,4-bis(dibenzo[b,f][1,4] thiazepin-11-yl)piperazine. Structural elucidation of compounds, proposed MS fragmentation pathway and possible ways of formation of the impurities are also discussed.
Asunto(s)
Antipsicóticos/análisis , Dibenzotiazepinas/análisis , Contaminación de Medicamentos , Compuestos de Anilina/análisis , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Antipsicóticos/síntesis química , Carbamatos/análisis , Carbamatos/síntesis química , Carbamatos/química , Dibenzotiazepinas/síntesis química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Compuestos de Fenilurea/química , Piperazinas/análisis , Piperazinas/síntesis química , Piperazinas/química , Fumarato de Quetiapina , Espectrofotometría Infrarroja , Sulfuros/química , Tiazepinas/análisis , Tiazepinas/síntesis química , Tiazepinas/química , Urea/análisis , Urea/síntesis químicaRESUMEN
A number of 2,5-disubstituted benzothiazepines were synthesized and screened for their ability to inhibit arginine vasopressin binding to the human V(2) and V(1a) receptor subtypes. The more active compounds were subsequently analyzed for their antagonist activity in in vitro functional assays. The SAR showed a preference for an acidic unit appended from the benzothiazepine scaffold. This substitution pattern afforded the most potent and selective analogues in the series. The carboxymethyl analogue 4, showed a 140-fold greater selectivity for the V(2) over the V(1a) receptor in the binding assay. In the cell-based functional assays this analogue was a potent and selective antagonist of the V(2) receptor. The in vitro SAR of the series and a description of the in vivo studies around compound 4 is described.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Dibenzotiazepinas/síntesis química , Dibenzotiazepinas/farmacología , Animales , Azepinas/síntesis química , Azepinas/química , Azepinas/farmacología , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Benzazepinas/síntesis química , Benzazepinas/química , Benzazepinas/farmacología , Diuresis/efectos de los fármacos , Diseño de Fármacos , Cinética , Masculino , Pirroles , Ratas , Relación Estructura-ActividadRESUMEN
A new series of 11-substituted 6,11-dihydro-6-methyl-dibenzo[c,f]-[1,2]thiazepine S,S-dioxides was synthesized. Some of the components show significant anticonvulsant activity in the MES, pentetrazol and strychnine tests. The more active compounds are devoid of neurotoxic effects.
Asunto(s)
Anticonvulsivantes/síntesis química , Dibenzotiazepinas/síntesis química , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidad , Dibenzotiazepinas/farmacología , Dibenzotiazepinas/toxicidad , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Espectrofotometría InfrarrojaRESUMEN
The synthesis of several 8-carboxy-6-sulfamyldibenz[b,f][1,4]oxazepines and -thiazepines is described. The results of diuretic screening lend support to the thesis that activity is strongly dependent on the conformational mobility of 4-substituents in the 3-amino-5-sulfamylbenzoic acids.