ABSTRACT
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.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemistry , Spiro Compounds/chemistry , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacokinetics , Benzazepines/administration & dosage , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Drug Evaluation, Preclinical , Female , Humans , Male , Rats , Rats, Long-Evans , Receptors, Vasopressin/metabolism , Receptors, Vasopressin/physiology , Spiro Compounds/administration & dosage , Spiro Compounds/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Vasopressins/metabolismABSTRACT
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.