RESUMO
A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Isoquinolinas/síntese química , Cinética , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Inibidores de Fosfodiesterase/metabolismo , Quinolinas/síntese química , Rolipram/metabolismo , Estereoisomerismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.
Assuntos
Técnicas de Química Combinatória , Diltiazem/química , Compostos de Epóxi/síntese química , Propionatos , Silanos/química , Catálise , Compostos de Epóxi/análise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Silanos/síntese química , EstereoisomerismoRESUMO
The dihydrobenzoxazone 9e, which is easily prepared from salicylamide 11 and cyclohexanone, serves as an efficient auxiliary in the synthesis of the 1-beta-methylcarbapenem key intermediate 10. The stereocontrolled Reformatsky-type reactions of the acetoxyazetidinone 2 with the carboximides 6 gave the intermediates 7 with high diastereoselectivities in high chemical yields. The auxiliary 9e also acts as a good leaving group in the TMSCl-promoted Dieckmann-type cyclization leading to a 1-beta-methylcarbapenem skeleton. By using this auxiliary, 10 was synthesized in 58% overall yield and four steps from 2.
