Satoshi Tamai

Novel efficient synthesis of 1-azabicyclo[1.1.0]butane and its application to the synthesis of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol useful for the pendant moiety of an oral 1β-methylcarbapenem antibiotic L-084

1-Azabicyclo[1.1.0]butane 2 was successfully synthesized by treatment of 2,3-dibromopropylamine hydrobromide 4 with organolithium compounds and was readily converted to 1-(1,3-thiazolin-2-yl)azetidine-3-thiol hydrochloride 1 and versatile azetidine derivatives 9 and 10.

Current Status of Oral Carbapenem Development

Since the discovery of thienamycin (1) in 1976, many studies on the synthesis and structure-activity relationships of parenteral-use drugs have been done and several carbapenems, imipenem (2), panipenem (3), and meropenem (7), have been marketed. The development of oral carbapenems, however, is a fairly slow process because carbapenems are considered unstable in the stomach and intestine. Recently, several orally active carbapenems without stability problems have been developed as prodrug esters or prodrug peptides, including GV-118819 (12), CS-834 (13), L-084 (14), DZ-2640 (15), and peptidic derivatives of CL 191,121 (16). The active forms (35), (41), (44), (45), (16) of these prodrugs exhibited potent and well balanced antibacterial activities as well as resistance to renal dehydropeptidase-I. The pharmacokinetic parameters of compounds (12), (13), (14), and ( 15) after oral administration to healthy volunteers were reported. The half-life (t1/2) of GV-118819 (12) was longer than that of the other compounds, while the Cmax, AUC and urinary excretion rate of L-084 (14) were higher than those of the others. In this review, the synthesis, chemical and biological properties, and pharmacokinetics of these oral carbapenems are described.

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-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.

A new enantiodivergent procedure utilising the chemoselective dieckmann-type cyclisation of chiral mono-thiol diesters

The chiral mono-thiol diester, 1 or 2, is converted to the corresponding enantiomeric cyclised products,(–)-7 and (+)-7 or (–)-9, and (+)-9, depending on whether LDA or AlCl3–Et3N is used.

A facile synthesis of mercaptopyrazolidine useful for construction of the pendant moiety of 1β-methyl-carbapenem L-627

A 4-mercaptopyrazolidine derivative (3), which is a synthetic intermediate of the pendant moiety of 1β-methylcarbapenem L-627 (2), was synthesized by a practical method starting from hydrazine hydrate