Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-19
2001-06-26
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S350000
Reexamination Certificate
active
06251891
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel carbapenem (7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid) compounds, antibacterial agents containing such compounds as active ingredients, and a process for producing such compounds.
BACKGROUND ART
In recent years, new &bgr;-lactam antibiotic substances have been found in nature which have the same &bgr;-lactam rings as penicillins and as cephalosporins, but which have different basic structures.
For example, naturally derived carbapenem compounds such as thienamycin isolated from the fermentation of
Streptomyces cattleya
(J. Am. Chem. Soc., vol. 100, p. 6491 (1978)), may be mentioned. Thienamycin has an excellent antibacterial spectrum and strong antibacterial activities over a wide range against Gram-positive bacteria and Gram-negative bacteria. Therefore, its development as a highly useful &bgr;-lactam agent has been expected. However, thienamycin itself is chemically unstable, and it has been reported that it is likely to be decomposed by a certain enzyme in vivo such as renal dehydropeptidase I (hereinafter referred to simply as DHP-I), whereby the antibacterial activities tend to decrease, and the recovery rate in the urine is low (Antimicrob. Agents Chemother., vol. 22, p. 62 (1982); ibid., vol. 23, p. 300 (1983)).
Merck & Co., Inc. have synthesized many thienamycin analogs with an aim to maintain the excellent antibacterial activities of thienamycin and to secure chemical stability. As a result, imipenem: (5R,6S)-3-[[2-(formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monohydrate, obtained by formimidization of the amino group of thienamycin, has been practically developed as a pharmaceutical product (J. Med. Chem., vol. 22, p. 1435 (1979)).
Imipenem has antibacterial activities of an equal or higher level than thienamycin against various types of bacteria and has &bgr;-lactamase resistance. Especially against
Pseudomonas aeruginosa,
its antibacterial activities are superior to thienamycin by from 2 to 4 times. Further, the stability of imipenem in the solid form or in an aqueous solution is remarkably improved over thienamycin.
However, like thienamycin, imipenem is decomposed by DHP-I in the human kidney, and therefore, it does not exhibit sufficient treatment effect on urinary-tract infections. Therefore, imipenem can not be administered alone and is required to be used in combination with a DHP-I inhibitor like cilastatin (J. Antimicrob. Chemother., vol. 12 (Suppl. D), p. 1 (1983)). In recent years, imipenem has been frequently used for the treatment and prophylaxis of infectious diseases. Consequently, highly methicillin-resistant
Staphylococcus aureus
which is resistant to imipenem and imipenem resistant
Pseudomonas aeruginosa
are increasing in the clinical field. Imipenem does not show adequate treating effects against these resistant bacteria.
The characteristic of the compounds of the invention is having the partial structure of S—C(═S)N in the substituent at the 2-position of the carbapenem skeleton, and carbapenem compounds having the partial structure are novel compounds not disclosed in literatures. Prior art disclosing or suggesting the invention has not been known at all.
&bgr;-Lactam antibiotics exhibit selective toxicity against bacteria and show no substantial effects against animal cells. Therefore, they are widely used for treatment of infectious diseases caused by bacteria, as antibiotics having little side effects, and thus are highly useful drugs.
However, in recent years, highly methicillin-resistant
Staphylococcus aureus
(hereinafter, abbreviated as MRSA), methicillin-resistant coagulase negative Staphylococci (hereinafter, abbreviated as MRCNS) and resistant
Pseudomonas aeruginosa
have been isolated frequently from patients with the immunity decreased, as bacteria causing hardly curable infectious diseases. This has come into a large social problem. Further, recently, the strong toxicity of vancomycin, which is selectively used against MRSA, to the kidney, and the increasing resistance of pathogenic bacteria such as MRSA and MRCNS are becoming clinically serious problems. Accordingly, it is strongly desired to develop an antibacterial agent having improved antibacterial activities against such resistant bacteria, but &bgr;-lactam antibacterial agents meeting such requirement have not yet been developed. With respect to carbapenem compounds, it is strongly desired to develop medicaments which have improved antibacterial activities against bacteria causing hardly curable infectious diseases, particularly against MRSA and MRCNS, improved stability against DHP-I, reduced toxicity against the kidney, and no side effect on the central nervous system.
DISCLOSURE OF INVENTION
The present inventors intensely studied aiming to provide novel carbapenem compounds having wide antibacterial spectra and excellent antibacterial activities, and further being DHP-I-resistant. As a result, they found that the carbapenem compounds of the invention either which have, at the 2-position of the carbapenem skeleton, groups represented by the general formula:
wherein R
3
and R
4
may be the same or different, and each represent a hydrogen atom or a hydrocarbonic group optionally containing hetero atom(s) selected from the group consisting of oxygen atom(s), sulfur atom(s) and nitrogen atom(s), or they are combined together with the nitrogen atom to which they bound to form a heterocyclic group,
or in which the substituent R
1
at the 1-position of the carbapenem skeleton is bound to R
3
to form a heterocyclic group are novel compounds not disclosed in literatures, and have strong antibacterial activities against a wide range of Gram-positive bacteria and Gram-negative bacteria, and completed the invention.
This invention relates to a compound represented by the general formula:
wherein R
1
either represents a hydrogen atom or a lower alkyl group or is bound to R
3
to form a heterocyclic group, R
2
represents a hydrogen atom, an ester residue, an alkali metal or negative charge, and R
3
and R
4
are the same or different, and each represent a hydrogen atom or a hydrocarbonic group optionally containing hetero atom(s) selected from the group consisting of oxygen atom(s), sulfur atom(s) and nitrogen atom(s), or they are combined together with the nitrogen atom to which they bound to form a heterocyclic group,
a process for producing the compound and its use as an antibacterial agent.
Explanation is made on symbols and terms mentioned in the present description. The compounds of the invention have a basic structure of the formula:
which is systematically referred to as a 7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid. For the convenience sake, in the description, this basic structure will be referred to as a 1-carbapen-2-em-3-carboxylic acid by putting the numbers based on a commonly widely used carbapenem of the formula:
The invention includes optical isomers based on the asymmetrical carbon atoms at the 1-position, 5-position, 6-position and 8-position of the carbapenem structure and stereoisomers. Among these isomers, preferred is a compound of a (5R,6S,8R) configuration i.e. a compound having a steric configuration of (5R,6S) (5,6-trans) like thienamycin and in which the carbon atom at the 8-position takes a R-configuration, or a compound of a (1R,5S,6S,8R) configuration in a case where a methyl group is present at the 1-position.
The lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, etc., and preferred among them are a methyl group, an ethyl group, a t-butyl group, etc.
The cyclo-lower alkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohex
Imamura Hideaki
Jona Hideki
Kiyonaga Hideo
Nakagawa Susumu
Ogawa Masayuki
Banyu Pharmaceutical Co. Ltd.
Berch Mark L.
Nixon & Vanderhye
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