Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-09-24
1994-06-14
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540350, 540310, C07D48704, A61K 3140
Patent
active
053210204
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to antibacterial 5R,6S-6-(1R-hydroxyethyl)-2-(3-thiolanyl)thio-2-carbapenem-3-carboxylic acids, as depicted by the for below; the pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof; and intermediates useful in the preparation of said compounds.
There are numerous reports in the literature concerning antibacterial 2-(alkylthio)-2-carbapenems and related compounds. See, for example, Andrus et al , J. Am. Chem. Soc., vol. 106, pp. 1808-1811, 1984; Afonso et al., ibid., vol. 104, pp. 6139-6140, 1982; DiNinno et al., Tetrahedron Letters, vol. 23, pp. 3535-3538 (1982); Ganguly et al., J. Antimicrobial Chemotherapy, vol. 9, suppl. C, pp. 1-5 (1982); Ghosez et al., Tetrahedron, vol. 39, pp. 2493-2503, 1983; Girijavallabhan et al., J. Antibiotics, vol. 39, pp. 1182-1190, 1986; Girijavallabhan et al., Tetrahedron Letters, vol. 24, pp. 3179-3182, 1979; Leanza et al., Tetrahedron, vol. 39, pp. 2505-2513, 1983; and Shih et al., Heterocycles, vol. 21, pp. 29-40, 1984.
In addition, antibacterial 5R, 6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acid and 5R,6S-6-(1R-hydroxyethyl)-2-(1,1-dioxo-3thiolanylthio)-2-penem-3-carboxyli c acid have been disclosed by Hamanaka, U.S. Pat. No. 4,619,924. More recently, the preferred diastereoisomer, 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-acid, was identified by Volkmann in International Application No. PCT/US87/01114, designating inter alia the United States of America, published on Nov. 17, 1988 as WO-88/08845.
SUMMARY OF THE INVENTION
It has now been discovered that carbapenems substituted in analogy to the above-noted penems of Hamanaka and Volkmann are especially valuable antibacterial agents. These novel compounds are of the formula ##STR2## wherein n is 0 or 1; R is hydrogen or a radical forming an ester hydrolyzable under physiological conditions; and R.sup.1 is hydrogen or methyl; including the pharmaceutically-acceptable cationic salts thereof when R is hydrogen.
Said pharmaceutically-acceptable cationic salts include, but are not limited to, those of sodium, potassium, calcium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) and diethanolamine. The preferred cationic salts are those of potassium and sodium.
The reference to esters which are hydrolyzable under physiological conditions refers to those esters frequently referred to as "pro-drugs." Such esters are now as well-known and common in the penicillin art as pharmaceutically-acceptable salts. Such esters are generally used to enhance oral absorption, but in any event are readily hydrolyzed in vivo to the parent acid. The more preferred ester forming radicals are those wherein R is:
(5-methyl-1,3-dioxol-2-on-4-yl)methyl;
1H-isobenzofuran-3-on-1-yl;
gamma-butyrolacton-4-yl;
--CHR.sup.2 OCOR.sup.3 ; or
--CHR.sup.2 OCOOR.sup.3 ;
wherein R.sup.2 is hydrogen or methyl; and R.sup.3 is (C.sub.1 -C.sub.6)alkyl. The most preferred radicals are pivaloyloxymethyl and 1-(ethoxycarbonyloxy)ethyl.
For ease of preparation, the preferred value of R.sup.1 is hydrogen. When n is 0, it is preferred that the groups attached to the thiolane ring be cis to one another, most preferably in the 1R,3S-configuration, i.e., ##STR3##
The present invention is also directed to intermediate compounds of the formula ##STR4## wherein n is 0 or 1; R.sup.1 is hydrogen or methyl, and R.sup.4 is a conventional carboxylic acid protecting group such as benzyl, p-nitrobenzyl, or --CH.sub.2 CX.dbd.CH.sub.2 where X is H or C1. For their ease of preparation and the facile removal of the protecting group, the preferred compounds of the formula (II) are those wherein R.sup.4 is --CH.sub.2 CX.dbd.CH.sub.2, most preferably with X as hydrogen
Detailed Description of the Invention
The antibacterial compounds of the present invention, having the formula (I), are readily and conventionally prepared from the ketonic compound of the formula ##STR5## wherein R.sup.1 is as defined above and R.sup.5 is a conventional carbo
REFERENCES:
patent: 4619924 (1984-11-01), Hamanaka
patent: 4665169 (1987-05-01), Martel et al.
patent: 4739047 (1988-04-01), Volkmann et al.
patent: 4757066 (1988-07-01), Shiokari et al.
Chemical Abstracts vol. 115; 182945K (1991).
Chemical Abstracts vol. 114; 81420J (1991).
Miyadera T., et al., "Synthesis and In Vitro Activity of a New Carbapenem", Journal of Antibiotics, vol. 36, No. 8, 1983 pp. 1034-1038.
Benson Gregg C.
Brokke Mervin E.
Pfizer Inc.
Richardson Peter C.
Rizzo Nicholas S.
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