RESUMO
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.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/química , Compostos de Espiro/química , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacocinética , Benzazepinas/administração & dosagem , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Ratos , Ratos Long-Evans , Receptores de Vasopressinas/metabolismo , Receptores de Vasopressinas/fisiologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Vasopressinas/metabolismoRESUMO
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.