Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-06-03
1993-11-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544349, 544362, 544363, 546123, 546156, A61K 31495, C07D40104
Patent
active
052624170
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to new quinolone compounds useful as antibacterial agents. Various quinolone type structures are known for their antibacterial properties, however new antibacterials are continually sought especially those which exhibit both gram positive and gram negative activity.
INFORMATION DISCLOSURE
International Application No. PCT/US87/02556 (International Publication No. WO 88/02627) discloses naphthyridine- and quinoline-carboxylic acids having a 1-tertiary-alkyl substituent, compositions containing them, and their use in treating bacterial infections in warm-blooded animals and man. 1-tertiary-alkyl substituents disclosed include 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-methyl-1-phenylethyl, 1-phenylcyclopropyl, 2-methyl-1-phenylcyclopropyl, 1-methylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methylcyclobutyl, 1-methylethenyl and 1-adamantyl. There are disclosed numerous N-heterocyclic ring substituents in the 7-position including piperazinyl, piperidinyl, 3-amino-1-pyrrolidinyl, 3-aminoalkyl-1-pyrrolidinyl, 2-aminoalkyl-morpholin-4-yl, 2-aminoalkyl-thimorpholin-4-yl, and diazabicycloalkyl groups containing 7-9 atoms in the diazobicycloalkyl ring system. Also disclosed are amines and intermediates used in the preparation of the naphthyridine- and quinoline-carboxylic acids.
International Application No. PCT/US87/02556 (International Publication No. WO 88/02627) describes additional background references including:
R. Albrecht, Progress in Drug Research, 21:9-104 (1977); Egawa, et al., J. Med. Chem. 27:1543-1548 (1984); M. P. Wentland and J. B. Cornett, Annual Reports in Medicinal Chemistry, 20:145-154 (1985); U.S. Pat. Nos. 3,590,036, 4,146,719, 4,284,629, 4,341,784, 4,352,803, 4,359,578, 4,556,658, 4,559,341, 4,559,342, 4,563,448, 4,571,396, 4,578,473, and 4,705,788; German Offen. DE 3142854; GB A 2,160,519 and GB A 937,183; EP 0,132,845, EP 0,134,165, EP 0,153,163, EP 0,166,939, and EP 0,167,763; Spanish Patent 8504767; and South African Patent Application Publication No. 853954.
At the 28th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy) held Oct. 23-26, 1988 in Los Angeles, Calif. the antibacterial activity of 7-(1R,4R-2,5-diazabicyclo-[2,2,1]-heptan-2-yl)-6-fluoro-1-t-butyl-1,4-dihy dro-4-oxo-1,8-naphthyridine-3-carboxylic acid (BMY 40062) was disclosed in poster abstracts (#962 and #963). The synthesis and structure-activity relationships of related quinoline and naphthyridine carboxylic acids incorporating 1-tertiary-alkyl substituents is described by D. Bouzard, et al., in J. Med. Chem. 32:537-542 (1989).
The synthesis and structure-activity relationships of various 1-aryl-6-fluoroquinolone, 1-aryl-6-fluoronaphthyridine and 1-aryl-6,8-difluoroquinolone antibacterial agents is described by D. T. Chu, et al., in J. Med. Chem. 28:1558-1564 (1985); J. Med. Chem. 29:2363-2369 (1986); and J. Med Chem. 30:504-509 (1987).
The synthesis of a variety of 1- and 2-substituted bicyclo[1.1.1]pentanes is described by K. B. Wiberg and V. Z. Williams in J. Org. Chem., 35:369-373 (1970).
The synthesis of a variety of 1,3-disubstituted bicyclo[1.1.1]pentanes is described by D. E. Applequist, et al., in J. Org. Chem. 47:4985-4995 (1982).
Various quinolone-carboxylic acids are disclosed in U.S. Pat. No. 4,563,448 for combating plant-pathogenic bacteria. Other quinolone acids suitable for treating bacteria infection are disclosed in U.S. Pat. No. 4,559,342 and in German Patent DE 3,615,303. In one aspect the present compounds, Formual IA also exhibit antibacteria properties but unlike the disclosed compounds possess a unique substituent on the piperazinyl ring.
The preparation of various piperazinyl and 3-amino-1-pyrrolidinyl naphthyridine derivatives, including 2-(4-(1-cyclopropyl-3-carboxy-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-p iperazinyl)-2-butanedioic acid, 2-(4-(1-cyclopropyl-3-carboxyethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl )-1-piperazinyl)-2-butanedioic acid, dimethyl ester, 2-(4-(1-ethyl-3-carboxy-6-fluoro-1,4-dihydro-4-oxo-7
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Egawa et al., J. Med. Chem., 27, pp. 1543-1548 (1984).
M. P. Wentland and J. B. Cornett, Annual Reports in Medicinal Chemistry, 20, pp. 145-154 (1985).
D. Bouzard et al., J. Med. Chem., 32, pp. 537-542 (1989).
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Poster Abstract #962.
Poster Abstract #963.
Barbachyn Michael R.
Bisaha Sharon N.
Gammill Ronald B.
Judge Thomas M.
Kim Kyoung S.
Corneglio Donald L.
Ivy C. Warren
The Upjohn Company
Turnipseed James H.
Wootton Thomas A.
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