Carbapenem derivatives

Details Carbapenem derivatives Carbapenem derivatives

1996-08-23

1998-01-13

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540350, 540302, A61K 3140, C07D48704

Patent

active

057079870

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This application is a 371 of PCT/JP95/00280 Feb. 24, 1995.
The present invention relates to novel carbapenem antibacterial agents containing such compounds as active ingredients, and a process for producing such compounds.


BACKGROUND ART

In recent years, new .beta.-lactam antibiotic substances have been found in nature which have the same .beta.-lactam rings as penicillin derivatives and as cephalosporin derivatives, 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 .beta.-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); ditto, vol. 23, p.300 (1983)).
Merck & Co., Inc. have synthesized many thienamycin analogues with an aim to maintain the excellent antibacterial activities of thienamycin and to secure chemical stability. As a result, imipenem, formimidation 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 .beta.-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 likely to be decomposed by DHP-I in the human kidney. Therefore, it can not be used for treatment of the urinary-tract infection. Further, it presents toxicity against the kidney due to the decomposition products. Therefore, imipenem can not be administered alone and is required to be used in combination with a DEP-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 prevention 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.
As the prior arts closest to the present invention, Japanese Unexamined Patent Publication No. 179876/1988 (hereinafter referred to as publication A) and Japanese Unexamined Patent Publication No. 204490/1990 (hereinafter referred to as publication B) may be mentioned. Publication A describes carbapenem compounds having at the 2-position of the carbapenem structure a pyrrolidinylthio group substituted with a group of A--X--R.sup.4. Publication B describes carbapenem compounds having at the 2-position of the carbapenem structure a pyrrolidinylthio group substituted with a group of A--O--R.sup.4.
However, according to publication A, the definition of R.sup.4 in the substituent is restricted to an optionally substituted lower alkyl group, a heterocyclic group which may be optionally substituted or a-lower alkylsulfonyl group. Similarly, publication B mentions that the definition of R.sup.4 in the substituent is restricted to a substituted lower alkyl group such as a monohalo(lower)alkyl group, a mono- or di-(lower)alkylamino(lower)alkyl group, a protected mono(lower)alkylamino(lower)alkyl group, a mono- or di-(lower)alkylcarbamoyl(lower)alkyl group or a protected or unprotected car

REFERENCES:
patent: 5571805 (1996-11-01), Jung et al.
patent: 5583218 (1996-12-01), Takemura et al.

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