RESUMEN
Three products resulting from free-radical-induced oxidation of the oxahydrindene portion of 22,23-dihydroavermectin B1a (H2B1a) are 5-oxo-H2B1a, 8a-oxo-H2B1a, and 5,8a-bisoxo-H2B1a. The last of these compounds has not been reported previously.
Asunto(s)
Benzofuranos/química , Ivermectina/análogos & derivados , Química Farmacéutica , Estabilidad de Medicamentos , Radicales Libres , Ivermectina/química , Oxidación-Reducción , Peróxidos/química , terc-ButilhidroperóxidoRESUMEN
Substituted 5-amino-4-carbamoyl-1,2,3-triazoles 3a-w were prepared by two synthetic schemes and evaluated in vivo for anticoccidial activity. Both schemes proceeded by brominating appropriately substituted toluenes 4a-s,v to 5a-s,v. In Scheme I, the brominated benzyl analogues 5 were converted to the corresponding benzyl azides 6, which were treated with cyanoacetamide to yield 1-substituted-5-amino-4-carbamoyl-1,2,3-triazoles 3. In Scheme II, the benzyl halides 5 were employed to alkylate the sodium salt of 5-amino-4-carbamoyl-1,2,3-triazole (7). Preliminary screening data against Eimeria acervulina and E. tenella in chickens suggested structural requirements for maximizing activity. Further evaluation against a relatively resistant series of eight Eimeria field isolates revealed L-651,582 (3a) to be a highly effective coccidiostat. However, unacceptable tissue residues precluded further development. Mechanistic studies on this series of 5-amino-4-carbamoyl-1,2,3-triazoles and, in particular, on L-651,582 (3a) revealed that its mode of action does not involve inhibition of IMP dehydrogenase, but probably interferes with host cell calcium entry. In addition, L-651,582 has been found to have antiproliferative activity in several disease models and was recently reported to possess antimetastatic activity in a model of ovarian cancer progression.
Asunto(s)
Coccidiostáticos , Triazoles/farmacología , Alquilación , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Antineoplásicos/uso terapéutico , Pollos , Coccidiostáticos/química , Eimeria/efectos de los fármacos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Triazoles/químicaRESUMEN
Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroides dubius in mice. Preliminary screening indicated methyl 6-(1,2,2-trichloroethenyl)imidazo[1,2-alpha]pyridine-2-carbamate to be the most potent derivative in the series. However, evaluation in sheep indicated that its anthelmintic spectrum was inferior to methyl 6-(phenylsulfinyl)imidazo[1,2-alpha]pyridine-2-carbamate.
Asunto(s)
Antihelmínticos/síntesis química , Bencimidazoles/síntesis química , Imidazoles/síntesis química , Animales , Bencimidazoles/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Fenómenos Químicos , Química , Imidazoles/farmacología , Ratones , Infecciones por Nematodos/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/farmacología , Ovinos , Relación Estructura-ActividadRESUMEN
A series of methyl imidazo-[11,2-a]pyridine-2-carbamates was synthesized for anthelmintic testing. The preparation of this class of compounds was simplified by utilization of a novel one-step condensation of the appropriately substituted 2-aminopyridine and methyl chloroacetylcarbamate. The most potent compound, methyl 6-(phenylsulfinyl)-imidazo[1,2-a]pyridine-2-carbamate, was orally effective against a broad range of helminths in sheep and cattle, at a dosage of 2.5 mg/kg. Limited trials in swine and dogs demonstrated anthelmintic activity at higher dosages. Limited observations in sheep and cattle indicated that, in both species, a single oral dose of 200 mg/kg was well tolerated.
Asunto(s)
Antihelmínticos/síntesis química , Carbamatos/síntesis química , Piridinas/síntesis química , Animales , Antihelmínticos/uso terapéutico , Carbamatos/farmacología , Carbamatos/uso terapéutico , Bovinos , Perros , Ratones , Infecciones por Nematodos/tratamiento farmacológico , Piridinas/farmacología , Piridinas/uso terapéutico , Ovinos , PorcinosRESUMEN
Some 2-arylhydrazino- and 2-arylazo-2-thiazolines were synthesized for anthelmintic testing. The most potent compound, 2-(o-tolylazo)-2-thiazoline, was orally effective in sheep against a broad range of helminths.