Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-05
2002-01-01
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S137000, C546S153000, C546S155000
Reexamination Certificate
active
06335447
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel quinolonecarboxylic acid derivatives or salts thereof, particularly to quinolonecarboxylic acid derivatives or salts thereof exhibiting potent antibacterial activity against gram-positive bacteria, in particular Propionibacterium acnes.
BACKGROUND ART
4-Oxoquinoline-1,4-dihydro-3-carboxylic acid derivatives are known to have antibacterial activity. For example, 4-oxoquinoline-1,4-dihydro-3-carboxylic acid compounds having pyridine connected to the 7-position thereof through a carbon-to-carbon bond are described in Published Examined Japanese Patent Application (Kokoku) No. Sho-55-50591, Published Unexamined Japanese Patent Application No. Hei-1-100166, etc.
Furthermore, 4-oxoquinoline-1,4-dihydro-3-carboxylic compounds having a cyclopropyl group at the 1-position thereof include many known compounds including ciprofloxacin.
Moreover concerning 4-oxoqinoline-1,4-dihydro-3-carobxylic acid derivatives, i.e., so-called topical quinolone for skin, only nadifloxacin is used clinically.
Nadifloxacin and the compounds described in the above publications have insufficient activity against purulent disease-causing gram-positive bacteria such as staphylococci, in particular Propionibacterium acnes. Therefore, development of synthetic antibacterial agents having potent and broad antibacterial spectra against these bacteria is being desired.
On the other hand, the safety of quinolone antimicrobial agents, for example, phototoxicity and mutagenicity is being discussed [Journal of Antimicrobial Chemotherapy, 33, 685-706 (1994), Henigensei Shiken (Mutagenicity Tests), 2(3), 154-161 (1993)].
Accordingly, development of quinolone-based synthetic antibacterial agents having not only potent antibacterial activity and broad antibacterial spectrum but also increased safety is being desired.
DISCLOSURE OF THE INVENTION
Under the circumstances, the present inventors have made intensive research and as a result they have found that quinolonecarboxylic acid derivatives or salts thereof represented by general formula [1], which have a cycloalkyl group at the 1-position, a pyridine group connected through a carbon-to-carbon bond to the 7-position and an alkyl or alkoxy group at the 8-position of 4-oxoquinoline-3-carboxylic acid, have excellent antibacterial activity against various gram-positive bacteria such as staphylococci and gram-negative bacteria such as Escherichia coli, particularly excellent antibacterial activity against Propionibacterium acnes and have high safety. The present invention has been achieved based on this discovery.
That is, the present invention provides novel quinolonecarboxylic acid derivatives or salts thereof represented by the following general formula
(wherein R
1
represents a hydrogen atom or a carboxyl-protective group; R
2
represents an optionally substituted cycloalkyl group; R
3
represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, an optionally protected hydroxyl or amino group, or a nitro group; R
4
represents an optionally substituted alkyl or alkoxy group; and Z represents a pyridin-4-yl or pyridin-3-yl group which may be substituted with at least one group selected from a halogen atom and an optionally substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio or amino group and an optionally protected hydroxyl or amino group).
Hereinafter, the compounds of the present invention will be described in detail.
Unless otherwise indicated specifically herein, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkyl group means a straight chain or branched chain C
1-6
alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl; the alkenyl group means a straight chain or branched chain C
2-6
alkenyl group, such as vinyl or allyl; the cycloalkyl group means a C
3-6
cycloalkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl; the alkylene group means a C
1-6
alkylene group, such as methylene, ethylene or propylene; the alkoxy group means a straight chain or branched chain C
1-6
alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or pentyloxy; the alkylthio group means a straight chain or branched chain C
1-6
alkylthio group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio or pentylthio; the alkylamino group means an amino group substituted with one or more straight chain or branched chain C
1-6
alkyl groups, such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino or dipentylamino; the aryl group means phenyl, naphthyl or the like; the heterocyclic group means a 4-, 5-or 6-membered ring or condensed ring thereof including at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as hetero atom or atoms which constitutes or constitute the ring, for example, oxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl or morpholinyl group.
The cycloalkyl group in R
2
; the alkyl group, alkoxy group or alkylthio group in R
3
, the alkyl group or alkoxy group in R
4
; the alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio or amino group, which is a substituent group in pyridyl group in Z may be substituted with at least one group selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected alkylamino group, an alkyl group, an alkoxy group, an aryl group, a cycloalkyl group and an alkenyl group and an alkyl group substituted with a halogen atom.
The carboxyl-protective group may include all the groups that can be usually used as a protective group for a carboxyl group, for example, alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl and tert-butyl; aryl groups such as phenyl and naphthyl; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis(p-methoxyphenyl)methyl; acylalkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; halogenoalkyl groups such as 2,2,2-trichloroethyl; alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic alkyl groups such as phthalimidomethyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; alkoxyalkyl groups such as methoxymethyl, methoxyethoxymethyl and 2-(trimethylsilyl)ethoxymethyl; aralkoxyalkyl group such as benzyloxymethyl; alkylthioalkyl groups such as methylthiomethyl and 2-methylthioethyl; arylthioalkyl groups such as phenylthiomethyl; alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl and allyl; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl, and the like.
The protective groups for the amino group and alkyl amino group may include all the groups that can be usually used as protective groups for amino groups, for example, acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl a
Hayashi Kazuya
Kawafuchi Hiroyo
Kito Tokunori
Kuroda Hiroshi
Mitsuyama Junichi
Killos Paul J.
Toyama Chemical Co., Ltd.
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