Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-06-07
1995-04-04
Rizzo, Nicholas
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540227, 540225, C07D50136, A61K 31545
Patent
active
054038359
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a cephem compound useful as a curing agent for bacterial infections in the field of medicine, particularly, optically active 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[[(S)-.alpha.-carboxy-3,4-dihydroxybenzyl ]oxyimino]acetamido]-3-[(1-carboxymethyl-4-pyridinio)thiomethyl]-3-cephem-4 -carboxylate or its pharmaceutically acceptable salt or ester, a process for the production thereof and a use thereof.
BACKGROUND ART
The present inventors have found that 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(.alpha.-carboxy-3,4-dihydroxybenzyl)oxy imino]acetamido]-3-[(1-carboxymethyl-4-pyridinio)thiomethyl]-3-cephem-4-car boxylate (hereinafter referred to simply as BO-1463) has good antibacterial activities against Gram-positive bacteria and Gram-negative bacteria, and have filed a U.S. patent application (Ser. No. 07/028,576, now U.S. Pat. No. 4,880,797) concerning BO-1463. BO-1463 is a cephem compound expected to practically be used as a curing agent for bacterial infections.
However, the description of the specification of the U.S. patent application refers nothing about optically active compounds based on the asymmetric carbon of a (.alpha.-carboxy-3,4-dihydroxybenzyl)oxyimino group substituting at the acyl side chain, and such optically active compounds have not been synthesized.
.beta.-lactam antibiotics exhibit selective toxicity against bacteria only and present no substantial effects against animal cells, and they have been widely used for the treatment of infectious diseases caused by bacteria as antibiotics having no substantial side effects. Thus, they are highly useful drugs.
However, in recent years, glucose non-fermentative Gram-negative rods, particularly Pseudomonas aeruginosa have been frequently isolated from immuno-compromised patients, as causative organisms of refractory infections and have posed various problems. Therefore, it has been desired to develop an antibacterial agent having an improved activity against such bacteria.
DISCLOSURE OF INVENTION
It is an object of the present invention to provide novel cephalosporin derivatives having excellent antibacterial activities, and the present inventors have conducted extensive researches concerning novel cephalosporin derivatives having a 1-carboxymethylpyridinio-4-ylthiomethyl group at the 3-position of the cephem nucleus and a 2-(2-aminothiazol-4-yl)-2-(substituted oxyimino)acetamide group at the 7-position of the cephem nucleus. As a result, acylation was conducted by using (Z)-2-(2-aminothiazol-4-yl)-2-[[(S)-.alpha.-carboxy-3,4-dihydroxybenzyl]ox yimino]acetic acid derivative wherein the asymmetric carbon of the (.alpha.-carboxy-3,4-dihydroxybenzyl)oxyimino group substituting at the acyl side chain took S-configuration, to synthesize the S-isomer of BO-1463 which was the compound of the present invention, i.e. 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[[(S)-.alpha.-carboxy-3,4-dihydroxybenzyl ]oxyimino]acetamido]-3-[(1-carboxymethyl-4-pyridinio)thiomethyl]-3-cephem-4 -carboxylate (hereinafter referred to simply as BO-1463S). The present inventors have found that BO-1463S has antibacterial activities apparently superior to BO-1463 which is the racemic compound and the R-isomer (hereinafter referred to simply as BO-1463R), and it is further useful as a medicine used for the treatment and prevention of human infectious diseases. The present invention has been accomplished on the basis of such discoveries.
The present invention relates to a compound represented by the structural formula: ##STR2## or its pharmaceutically acceptable salt or ester, which is a novel optically active compound useful as a curing agent for bacterial infections, a process for production thereof and a use thereof.
Now, the symbols and terms used in the present description will be explained.
Each of R.sup.1, R.sup.2 and R.sup.4 is a hydrogen atom or a carboxyl-protecting group selected from the group consisting of a benzhydryl group, a tert-butyl group and a p-methoxybenzyl group, particularly preferably a benzhydryl group or a p-methoxybenzyl gr
REFERENCES:
patent: 4880797 (1989-11-01), Nakagawa et al.
patent: 5134138 (1992-07-01), Onoue et al.
patent: 5275816 (1994-01-01), Branch et al.
Angewandte Chemie, International Edition in English, 24 Mar. 1985, W. Durkheimer, J. Blumbach, R. Lattrell, K. H. Scheunemann, "Recent Developments in the Field of B-Lactam Antibiotics", pp. 180-185.
Asai Akira
Kuroyanagi Satoru
Mitomo Ryuji
Nakagawa Susumu
Ushijima Ryosuke
Banyu Pharmaceutical Co. Ltd.
Rizzo Nicholas
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