Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-10-18
1991-05-07
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540310, 514192, C07D49900, A61K 31425
Patent
active
050137298
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to antibacterial compounds which are diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxyl ic acids, viz., the 2-(1S-oxo-3R-thiolanylthio) variant of the formula (I) below, and the 2-(1R-oxo-3S-thiolanylthio) variant of the formula (II) below; the pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof; and intermediates and processes useful in the preparation of said diastereoisomers.
Antibacterial 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxyl ic acid, which is a diastereomeric mixture of two compounds, was earlier disclosed as a valuable antibacterial substance by Hamanaka, U.S. Pat. No. 4,619,924 and European patent application No. 130,025. Although detectable by analytical methods, the pure diastereomeric compounds of assigned structure have heretofore been unavailable. Disclosure of an improved process for that diastereomeric mixture from racemic cis-3-(acetylthio)thiolane 1-oxide, which employs mixed diastereomeric intermediates otherwise analogous to those presently used, will be found in a European patent application by Volkmann et al., scheduled for publication on May 27, 1987 under the No. 223,397.
Concerning the present optically active precursors, Brown et al., J. Am. Chem. Soc., vol. 108, pp. 2049-2054 (1986) have reported the synthesis of (S)-3-hydroxythiolane [inadvertently depicted as the (R)-isomer, but actually of configuration opposite to that of the present (R)-3-hydroxythiolane, of the formula (XI) below]by asymmetric hydroboration of 2,3-dihydrothiophene. Partial enzymic oxidation of racemic 3-hydroxythiolane by Jones et al., Can. J. Chem., vol. 59, pp. 1574-1579 (1981) permitted recovery of 3-hydroxythiolane containing the (R)-isomer in slight excess. Present optically active precursors (R)-(2-methanesulfonyloxyethyl)oxirane [of the formula (XIII) below wherein R.sup.9 =CH.sub.3 ] and (S)-2-bromo-1,4-di(methanesulfonyloxy)butane [of the formula (Xa) below wherein R.sup.8 =CH.sub.3 ] are known compounds; both preparable according to Shibata et al., Heterocycles, vol. 24, pp. 1331-1346 (1986); the former also according to Boger et al., J. Org. Chem., vol. 46, pp. 1208-1210 (1981).
SUMMARY OF THE INVENTION
We have now discovered methods for preparing the diastereomeric penem compounds, 5R, 6S-6-(1R-hydroxy-ethyl)-2-(1S-oxo-3R-thiolanylthio)-3-carboxylates, of the absolute stereochemical formula ##STR1## and 5R, 6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanyl-thio)-3-carboxylates, of the absolute stereochemical formula ##STR2## wherein R is hydrogen or a radical forming an ester hydrolyzable under physiological conditions; and the pharmaceutically-acceptable cationic salt thereof when R is hydrogen.
Because each of these compounds, and their several immediate precursors, are single, homogeneous compounds, the quality of the final products is much better controlled relative to the previously reported diastereomeric mixture of these compounds, an important factor in clinical use. Based on in vitro studies of the presently isolated compounds (I) and (II), both show about the same intrinsic antibacterial activity. However, it is surprising that, in the form of their pivaloyloxymethyl esters, the isomer of the formula (II) is better absorbed orally than the isomer (I); and, evidently as a result of a lowered level of metabolic destruction, the isomer (II) shows virtually twice the urine recovery as the isomer (I) whether administered parenterally as the sodium salt or orally as the pivaloyloxymethyl ester. For these reasons, the present pure diastereoisomers are preferred over the earlier diastereomeric mixture, and the isomers of the formula (II) are most preferred.
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
REFERENCES:
patent: 4619924 (1986-10-01), Hamanaka
Boger, J. Org. Chem., vol. 46, pp. 1208-1210 (1981).
Jones et al., Can. J. Chem., vol. 59, pp. 1574-1579 (1981).
Brown et al., J. Am. Chem. Soc., vol. 108, pp. 2049-2054 (1986).
Shibata et al., Heterocycles, vol. 24, pp. 1331-1346 (1986).
Blackwood Robert K.
Lumb J. Trevor
Pfizer Inc.
Richardson Peter C.
Rizzo Nicholas S.
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