RESUMEN
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/química , Compuestos de Espiro/química , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/química , Antihipertensivos/metabolismo , Antihipertensivos/farmacocinética , Benzazepinas/administración & dosificación , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratas , Ratas Long-Evans , Receptores de Vasopresinas/metabolismo , Receptores de Vasopresinas/fisiología , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Vasopresinas/metabolismoRESUMEN
An efficient process to produce kilogram quantities of a key argininylbenzo[d]thiazole intermediate was developed for the preparation of the tryptase inhibitor RWJ-56423. A variety of activated arginine esters and benzo[d]thiazole nucleophiles were evaluated as coupling partners. Our work led to the selection and optimization of an argininyl imidazolide ester and benzothiazol-2-yl MgCl nucleophile. This paper focuses on the preparation, use, and stability of the benzothiazol-2-yl Grignard reagents.