Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-06-05
1989-01-10
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514195, 540310, C07D49900, A61K 31425
Patent
active
047973943
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
6-(1-Carbamoyl-1-hydroxymethyl)penicillanic acid derivatives, having the partial structure ##STR1## wherein n is 0, 1 or 2, are generally useful as antibacterials and/or beta-lactamase inhibitors. Some of these compounds possess excellent antibacterial activity per se, and so are valuable as industrial or medicinal antibacterial agents in their own right. Additionally, and more generally, they have particular value as beta-lactamase inhibitors; as such, they are useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to beta-lactam antibiotics through production of beta-lactamase enzymes.
beta-Lactamase inhibiting 6-(1-hydroxyalkyl)penicillanic acid 1,1-dioxides (sulfones) and 3-carboxylate esters thereof have been reported by Kellogg (U.S. Pat. Nos. 4,287,181; 4,342,768; European Pat. Publication No. 83977), while 6-(aminoacyloxymethyl)penicillanic acid 1,1-doxides have been reported by Barth (U.S. Pat. No. 4,503,040). Various antibacterial 6-(1-hydroxyalkyl)penicillanic acids and their 1-oxides (sulfoxides) have been disclosed by Beattie et al., (U.S. Pat. No. 4,207,323), but that disclosure encompasses no compounds containing the key 6-(1-carbamoyl-1-hydroxyalkyl)substituent of the present invention.
U.K. Patent Application No. 2,053,220 broadly discloses beta-lactamase inhibiting compounds of the formula ##STR2## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. Said infinity of compounds proposed might be construed to encompass some of the 1,1-dioxide compounds of the present invention. However, there is no specific mention of or preparative method provided for any compounds of the type of the present invention, let alone any hint or suggestion that the present compounds represent preferred compounds, having potent antibacterial and/or beta-lactamase inhibitory activity.
Sheehan et al. [J. Antibiotics Japan, vol. 37, pp. 1441-1448 (1984)] have reported that 6-[1-(N-phenylcarbamoyl)methyl]penicillanic, a compound lacking the present 1-hydroxy group, possesses only limited Gram-positive activity and no Gram-negative activity. Sheehan et al. do not list the latter compound among those having a modicum of beta-lactamase inhibitory activity.
SUMMARY OF THE INVENTION
The present invention is concerned with antibacterials, beta-lactamase inhibitors and/or intermediates containing the following partial structure: ##STR3## wherien n is 0, 1 or 2. Because of their excellent activity, the present invention is particularly concerned with antibacterial and/or beta-lactamase inhibitory compounds having the formula ##STR4## wherein
n is 0, 1 or 2;
R is hydrogen, a radical group forming an ester hydrolyzable under physiological conditions, or an acyloxymethyl or 1-(acyloxy)ethyl radical derived from a conventional beta-lactam antibiotic; and
R.sup.1 and R.sup.2 are taken separately and are each independently hydrogen, (C.sub.1 -C.sub.7)alkyl, phenyl, (C.sub.7 -C.sub.12)phenylalkyl, (C.sub.3 -C.sub.7)cycloalkyl, naphthyl, or ##STR5## where m is 1 or 2 and p is 2 or 3; or one of said groups substituted on aliphatic, aromatic or heterocyclic carbon with (C.sub.1 -C.sub.4)alkyl, phenyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.2 -C.sub.5)alkanoyloxy, carbamoyloxy, formamido, (C.sub.2 -C.sub.5) alkanecarboxamido, (C.sub.1 -C.sub.4)alkanesulfonamido, ##STR6## on heterocyclic nitrogen with (C.sub.1 -C.sub.4)alkyl,phenyl, (C.sub.7 -C.sub.9)phenylalkyl, pyridyl, 2-hyroxyethyl, formyl, (C.sub.2 -C.sub.5)alkanoyl or ##STR7## R.sup.1 and R.sup.2 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, perhydroazepine, morpholine, piperazine, homopiperazine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline or ##STR8## (1,4-diazabicyclo[3.2.2]non-4-yl) ring system; or one of said ring systems substituted on aliphatic, aromatic or heterocyclic carbon w
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Sheehan, J. Antibiotics Japan, vol. 37, pp. 1441-1448, 1984.
Blackwood Robert K.
Lumb J. Trevor
Pfizer Inc.
Richardson Peter C.
Rizzo Nicholas S.
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