RESUMO
A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 µM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Descoberta de Drogas , Hidantoínas/química , Uracila/química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo , Estereoisomerismo , Traqueia/efeitos dos fármacosRESUMO
Two original chiral diphosphines, SYNPHOS and DIFLUORPHOS, have been synthesized on multigram scales. Their steric and electronic profiles have been established in comparison with the commonly used 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl ligands. A screening study of the four ligands in Ru(II)-catalyzed asymmetric hydrogenation of prochiral ketones and olefins has been performed. It revealed that the stereoelectronic features of the ligand and the substrate deeply influenced the enantioselectivities obtained in asymmetric hydrogenation, SYNPHOS and DIFLUORPHOS being fully complementary in terms of enantioselectivity for this reaction.
RESUMO
Alkylation of the enolate of the Seebach (R)-methionine oxazolidinone with benzyl bromide gave the expected benzylated product in low yield. The major product was a novel amine arising from oxazolidinone cleavage, decarboxylation, alkylation and finally hydrolysis. The rearrangement could be suppressed by using a more reactive electrophile or by using the N-Cbz instead of the N-benzoyl protecting group, and the required (R)-alpha-benzyl-methionine was obtained in 78% yield and in an enantiomeric ratio of 90:10.
