Assuntos
Antidepressivos Tricíclicos/síntese química , Valina/química , beta-Lactamases/química , Antidepressivos Tricíclicos/química , Domínio Catalítico , Química Farmacêutica/métodos , Desenho de Fármacos , Hidrogênio/química , Hidrólise , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Software , Tiazepinas/química , beta-Lactamases/metabolismoRESUMO
We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036.
Assuntos
Antibacterianos/farmacocinética , Carbapenêmicos/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/farmacologia , Disponibilidade Biológica , Carbapenêmicos/administração & dosagem , Carbapenêmicos/síntese química , Carbapenêmicos/farmacologia , Ésteres , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , RatosRESUMO
A novel and mild method was established to synthesize 6-methylidene penem compounds. This method entails a MgBr(2)/Et(3)N-promoted aldol-type condensation on 6-bromopenem 12 with an appropriately substituted aldehyde to yield the intermediate acetylated bromohydrin, which was smoothly converted to the final product with simultaneous deprotection of C3 carboxylic acid ester using activated zinc dust and phosphate buffer at pH 6.5. This process provides a useful variation of C-C bond formation method for penem derivatives and also serves as a practical synthetic method to prepare 6-exomethylenepenem derivatives without racemization at the C5 position.