Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-03-26
1995-01-31
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546156, 560170, 560174, 544349, A61K 3147, C07D40110
Patent
active
053859138
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to new 1,4-dihydro-4-oxo-3-quinoline derivatives that are antibacterial agents suitable for the treatment of bacterial and mycoplasma infections in mammals, including humans. The compounds of the invention exhibit unexpectedly favorable selectivity against procaryotic cells, as measured by their activity against procaryotic DNA gyrase versus mammalian topoisomerase II.
U.S. Pat. Nos. 4,775,668 and 4,861,779 refer to antibacterial compounds having the formula ##STR2## wherein R.sup.1 is hydrogen, a pharmaceutically acceptable cation, or alkyl; A is CH, CF, CCl or N; Y is alkyl, haloalkyl, cyclopropyl, vinyl, methoxy, N-methylamino, p-flurophenyl, p-hydroxyphenyl or p-aminophenyl; or A is carbon and is taken together with Y and the carbon and nitrogen to which A and Y are attached to form a five to seven membered ring which is optionally substituted; and R.sup.2 is a bridged-diazabicycloalkyl group.
Derwent anonymous research disclosure no. 88-103269/15 refers to compounds of the formula ##STR3## wherein R.sup.1 is (C.sub.1 -C.sub.3)alkyl, cyclopropyl, vinyl, hydroxyethyl, fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl; R.sup.2 is hydrogen, (C.sub.1 -C.sub.4)alkyl or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl; R.sup.3 is methyl or one of eleven cyclic amino groups wherein one of said eleven cyclic amino groups is ##STR4## R.sup.4 is hydrogen, (C.sub.1 -C.sub.4) alkyl, hydroxyethyl, allyl, propargyl, CH.sub.2 COCH.sub.3, phenacyl, CHO, SCFCl.sub.2, SO.sub.2 CFCl.sub.2, SCOOMe, benzyl, 4-aminobenzyl or 5-methyl-2-oxo-1,3-dioxo-4-ylmethyl; R.sup.5 is hydrogen or methyl; R.sup.6 is hydrogen, (C.sub.1 -C.sub.4) alkyl, phenyl or CH.sub.2 OCH.sub.2 Ph; R.sup.7 is hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxy or hydroxymethyl; R.sup.8 is methyl, ethyl or chloro; X is fluyoro, chloro or nitro; Y is hydrogen, fluoro or amino; A is nitrogen or CR.sup.9 ; and R.sup.9 is hydrogen, alkoxy, (C.sub.1 -C.sub.3)alkylthio, halogen, methyl or nitro; or R.sup.1 and R.sup.9 are OCH.sub.2 CH(Me), SCH.sub.2 CH(Me), COCH.sub.2 CH(Me) or CH.sub.2 CH.sub.2 CH(Me). This broad generic disclosure includes several compounds of the present invention but does not teach or suggest their surprising and favorable selectivity as antibacterial agents against procaryotic versus eucaryotic cells.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR5## wherein Q is methyl, ethyl, hydroxyethyl or hydrogen;
R is hydrogen, (C.sub.1 -C.sub.3) alkyl, benzyl, (C.sub.1 -C.sub.3) alkanoyloxymethyl, (C.sub.1 -C.sub.3) alkanoyloxyethyl, benzoyloxymethyl, benzoyloxyethyl, or 5-[(C.sub.1 -C.sub.3)alkyl]-2-oxo-1,3-dioxolen-4-ylmethyl; and
Y is cyclopropyl or substituted cyclopropyl, wherein said substituted cyclopropyl is substituted with one to three substituents independently selected from the group consisting of (C.sub.1 -C.sub.3) alkyl, halo hydroxy, or (C.sub.1 -C.sub.3) alkoxy;
and the pharmaceutically acceptable salts and hydrates of such compounds.
As used herein, unless indicated otherwise, "halo" includes fluoro, chloro, bromo and iodo.
Examples of pharmaceutically acceptable salts of the compounds of formula I are the acid addition salts of acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, methanesulfonic, cinnamic, fumaric, phosphoric, hydrochloric, hydrobromic, hydroiodic, and sulfonic acids, and the cationic salts of alkali metals such as sodium or potassium, alkaline earth metals such as magnesium or calcium, ammonium, and organic amines such as diethanolamine and N-methylglucamine.
The term "pharmaceutically acceptable salts and hydrates", as used herein, includes pharmaceutically acceptable salts, hydrates, pharmaceutically acceptable salts of hydrates, and hydrates of such salts.
The present invention also relates to a pharmaceutical composition comprising an antibacterially effectiv
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Anonymous Research Disclosure No. 28737 "Rhinologic Containing Gyrase Retarder" (Mar. 1988).
Barrett, John F. et al. "Use of In Vitro Topiosomerase II Assays for Studying Quinolone Antibacterial Agents", Antimicrobial Agents and Chemotherapy, Oct. 1989, pp. 1697-1703.
Barrett et al., "Use of In Vitro Topoisomerase II Assays for Studying Quinolone Antibacterial Agents," Antimicrobial Agents and Chemotherapy, 33, No. 10, pp. 1697-1703 (1989).
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Bernhardt Emily
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Strassburger Philip C.
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