Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-20
2001-04-03
Morris, Patricia L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06211375
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel pyridonecarboxylic acid derivatives or their salts having excellent antibacterial activities and oral absorption, and antibacterial agents containing the same.
BACKGROUND TECHNOLOGY
Many compounds having a basic skeleton of pyridonecarboxylic acid are known to be useful synthetic antibacterials for their excellent antibacterial activities and wide antibacterial spectrum. Among such compounds, norfloxacin (Japanese Patent Application Laid-open No. 53-141286), enoxacin (Japanese Patent Application Laid-Open No. 55-31042), ofloxacin (Japanese Patent Application Laid-Open No. 57-46986), ciprofloxacin (Japanese Patent Application Laid-Open No. 58-74667), tosufloxacin (Japanese Patent Application Laid-Open No. 60-228479), and the like are widely used in clinical practice for treating infections.
These compounds, however, need further improvements in antibacterial activities, intestinal absorption, metabolic stability, and side effects, and in particular, in phototoxicity and cytotoxicity.
SUMMARY OF THE INVENTION
The present invention has been completed in view of such situation, and an object of the present invention is to provide novel pyridonecarboxylic acid derivatives or the salts thereof having satisfactory antibacterial activities, intestinal absorption and metabolic stability, and reduced side effects, in particular, phototoxicity and cytotoxicity; and antibacterial agents containing the same.
In order to achieve the above object, the inventors of the present invention have made an intensive study to find compounds which would be excellent synthetic antibacterial agents in clinical practice, and found that novel compounds represented by the following general formula (1) have good antibacterial activities to gram negative and positive bacteria as well as an extremely low toxicity, and therefore, would be very useful synthetic antibacterial agents. The present invention has been accomplished on the bases of such a finding.
According to the present invention, there is provided pyridonecarboxylic acid derivatives or their salts represented by the following formula (1):
[In the formula, R
1
represents hydrogen atom, a halogen atom or a lower alkyl group; R
2
represents hydrogen atom or a lower alkyl group; R
3
represents substituted or unsubstituted amino group or hydroxyl group; and R
4
represents hydrogen atom, a lower alkyl group, amino group or nitro group.]
According to the present invention, there is also provided antibacterial agents containing the pyridonecarboxylic acid derivatives or their salts as their effective components.
BEST MODE FOR CARRYING OUT THE INVENTION
The novel pyridonecarboxylic acid derivatives of the present invention are represented by the general formula (1) as shown above, and the term “lower” used for the substituents of the pyridonecarboxylic acid derivatives represented by the general formula (1) designates that the substituent comprises 1 to 7 carbon atoms, and preferably 1 to 5 carbon atoms in the case of a linear substituent, and that the substituent comprises 3 to 7 carbon atoms in the case of a cyclic substituent.
The halogen atoms represented by R
1
of the general formula (1) include fluorine, chlorine, bromine and iodine atoms, among which fluorine and chlorine atoms are preferred, and fluorine atom is most preferred.
The lower alkyl groups represented by R
1
, R
2
and R
4
include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group, and heptyl group, among which methyl group is preferred.
The substituents of the substituted amino group represented by R
3
include lower alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group, and heptyl group; lower alkenyl groups such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group, and heptenyl group; aralkyl groups containing 7 to 11 carbon atoms such as benzyl group and 1-phenylethyl group; aryl groups containing 6 to 14 carbon atoms such as phenyl group and naphthyl group; lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group and isobutyryl group; lower alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; aroyl groups containing 7 to 15 carbon atoms such as benzoyl group and naphthoyl group; amino acid residues such as amino acid residues or oligopeptide residues such as glycyl, leucyl, valyl, alanyl, phenylalanyl, alanyl-alanyl, glycyl-valyl, and glycyl-glycyl-valyl, and the amino acid residues or the oligopeptide residues wherein the functional group thereof is protected with an acyl, a lower aralkyl, or other protective groups which is commonly used in peptide chemistry; and cyclic amino group. One or two substituents which may be the same or different may be selected from the substituents as described above. The compound protected with the amino acid residue or the oligopeptide residue is expected to have an improved water solubility.
Preferable groups represented by R
3
include amino group, lower alkylamino groups, di-lower alkylamino groups, lower alkanoylamino groups, amino acid-substituted amino groups, oligopeptide-substituted amino groups, and hydroxyl group. More preferable groups of R
3
include amino group, methylamino group, ethylamino group, dimethyamino group, formylamino group, glycyl-amino group, leucyl-amino group, valyl-amino group, alanyl-amino group, alanyl-alanyl-amino group, and hydroxyl group among which the amino group being the most preferred.
Preferable combinations of the R
2
and R
3
are methyl group or hydrogen atom for the R
2
and amino group, methylamino group or hydroxyl group for the R
3
.
Preferable combinations of the R
1
, R
2
and R
3
in the general formula (1) is fluorine atom, chlorine atom or methyl group for the R
1
, hydrogen atom or methyl group for the R
2
, and amino group, methylamino group or hydroxyl group for the R
3
, and the most preferable combination is methyl group for the R
1
, hydrogen atom for the R
2
and amino group for the R
3
.
The pyridonecarboxylic acid derivatives of the formula (1) or the salts thereof as described above may form either an acid adduct salt or a base adduct salt. The term, salt used herein also includes a chelate salt with a boron compound. Exemplary acid adduct salts include (A) salts with a mineral acid such as hydrochloric acid or sulfuric acid; (B) salts with an organic carboxylic acid such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, or maleic acid; and (C) salts with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid; and exemplary base adduct salts include (A′) salts with an alkaline metal such as sodium or potassium; (B′) salts with an alkaline earth metal such as calcium or magnesium; (C′) ammonium salts; (D′) salts with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-&bgr;-phenethylamine, 1-ephenamine, or N,N′-dibenzylethylenediamine. Exemplary boron compounds include boron halides such as boron fluoride, and lower acyloxyborons such as acetoxyboron.
The pyridonecarboxylic acid derivatives of the formula (1) or the salts thereof may also be in the form of hydrates or solvates in addition to the non-solvated forms. Accordingly, the compounds of the present invention include all of the crystalline forms, the hydrate forms, and the solvate forms.
The pyridonecarboxylic acid derivatives of the formula (1) or the salts thereof as described above may also be present in the form of optically active substances, and such optically active substances are also within the scope of the compounds of the present invention. Still further, the
Amano Hirotaka
Hayashi Norihiro
Hirao Yuzo
Niino Yoshiko
Ohshita Yoshihiro
Birch & Stewart Kolasch & Birch, LLP
Morris Patricia L.
Wakunaga Pharmaceutical Co., Ltd.
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