RESUMEN
BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.
Asunto(s)
Descubrimiento de Drogas/métodos , Receptores de Ghrelina/agonistas , Tetrazoles , Carbamatos , Humanos , Proyectos de InvestigaciónRESUMEN
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Asunto(s)
Carbamatos/síntesis química , Hormona del Crecimiento/metabolismo , Tetrazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Ésteres , Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/metabolismo , Humanos , Macaca fascicularis , Ratas , Solubilidad , Relación Estructura-Actividad , Tetrazoles/farmacocinética , Tetrazoles/farmacología , AguaRESUMEN
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
Asunto(s)
Azepinas/química , Azepinas/síntesis química , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/síntesis química , Neprilisina/antagonistas & inhibidores , Azepinas/farmacología , Inhibidores Enzimáticos/farmacología , Hidrogenación , EstereoisomerismoRESUMEN
The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 degrees C affords the chain-extended beta-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding alpha-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected alpha-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to alpha-chloroketones that avoids the use of toxic and explosive diazomethane.