Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-08-07
2002-10-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S123000
Reexamination Certificate
active
06469023
ABSTRACT:
TECHNICAL FIELD
This invention relates to an antibacterial compound useful as medicines, animal drugs, fisheries drugs or antibacterial preservatives and to an antibacterial agent or preparations which contains the same.
BACKGROUND ART
Though quinolone derivatives having a 1-amino-5-azabispiro[2.4]heptyl group are disclosed in European Patent Publication Nos. 550,016A and 550,025A, nothing is known about the quinolone derivative of the present invention having a 1-amino-5-azabispiro[2.4]heptyl group at the 7-position and a halogenocyclopropyl group at the 1-position, which comprises a single isomer.
Synthetic quinolone antibacterial agents having not only antibacterial activities but also excellent biological distribution such as oral absorbability, distribution into organs, urinary excretion ratio and the like have been found in recent years, and a number of such compounds are now supplied to the clinical field as chemotherapeutic agents effective against various infectious diseases. However, the presence of bacterial strains having low sensitivity to these drugs has been increasing in recent years in the clinical field. Also, like the case of
Staphylococcus aureus
(MRSA) having less sensitivity against &bgr;-lactam antibiotics, strains having low sensitivity to synthetic quinolone antibacterial agents are increasing even among strains which are resistant to other drugs than synthetic quinolone antibacterial agents. In consequence, development of drugs having more higher efficacy has been called for in the clinical field.
DISCLOSURE OF INVENTION
The present inventors thought that structures of the 7-and 1-position substituent groups played important role for the antibacterial activity, efficacy and safety of synthetic quinolone antibacterial agents. In consequence, the present inventors have conducted intensive studies to obtain a compound having high antibacterial activity against a broad range of bacteria including quinolone-resistant strains, and as a result, have found that a quinolone derivative having at its 7-position a substituent group derived from a heterocyclic spiro-compound whose the hetero atom is nitrogen shows strong antibacterial activity against Gram-negative and Gram-positive bacteria, particularly quinolone-resistant bacteria including MRSA, and that not only the antibacterial activity but also excellent efficacy and safety can be obtained by a quinolone derivative in which the 1-position is substituted with a halogenocyclopropyl group, particularly fluorocyclopropyl group.
In the quinolone derivative of the present invention, only a pair of enantiomers is present attributable to the halogenocyclopropane ring moiety at the 1-position even in the absence of stereoisomerism in the substituents at the other positions. This is originated from a stereochemical relationship between pyridonecarboxylic acid moiety and halogen atom on the cyclopropane ring. When isomers formed in this way are racemic, such derivative is a mixture of antipodes and could be administered as a medicine as such.
On the other hand, when stereoisomerism is also present at the other positions, particularly at the 7-position substituent, in addition to the stereoisomerism of the halogenocyclopropene ring moiety, the quinolone derivative involves diastereomers, meaning that 4 or more stereoisomers are present. Since the mixture of diastereomers is a mixture of compounds having different physical properties, it is difficult to administer the mixture as a medicine.
The present inventors have made intensive efforts to obtain a quinoline compound consisting of a single stereoisomer even in the case of a 1-(1,2-cis-2-halogenocyclopropyl)-substituted quinolone derivative which involves diastereomers.
As the results, the present inventors have succeeded in obtaining each enantiomer of cis-2-fluorocyclopropylamine as a pure compound. The present inventors have also succeeded in obtaining each of the fluorocyclopropane ring configuration-originated enantiomers of the quinolone derivative as a compound of pure isomer, from the pure cis-2-fluorocyclopropylamine. The present inventors have also succeeded in obtaining each isomer of a heterocyclic spiro-compound having an asymmetric carbon atom and a nitrogen hetero atom, as a pure compound.
The success in obtaining such quinolone derivative and heterocyclic spiro-compound having a nitrogen atom as a hetero atom, both useful as intermediates, has rendered possible synthesis of an optically active quinolone derivative as a single diastereomer.
Thereafter, the present invention has been accomplished on the basis of a finding that the novel quinolone derivative of the present invention which has a group derived from the heterocyclic spiro-compound at the 7-position and the halogenocyclopropyl group at the 1-position is a compound of high safety and shows excellent activity against a broad range of bacterial species including quinolone-resistant strains.
Accordingly, the present invention relates to an N
1
-(halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative represented by formula (I):
wherein X
1
represents a halogen atom or a hydrogen atom;
X
2
represents a halogen atom;
R
1
represents a hydrogen atom, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an amino group (said amino group may have a substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and the amino group may be dialkyl-substituted when the substituents are alkyl groups which may be the same or different from each other);
R
2
represents a group having a structure derived from a heterocyclic spiro-compound, represented by formula (II):
wherein R
3
and R
4
independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and m is an integer of 1 or 2;
A represents a nitrogen atom or a partial structure of formula (III):
wherein X
3
represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, a halogenomethyl group, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group, an amino group (said amino group may have more than one substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms, and the amino group may be dialkyl-substituted when the substituents are alkyl groups which may be the same or different from each other); and
R represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidynyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group;
or a salt thereof.
The present invention also relates to the aforementioned compound or a salt thereof, in which the halogenocyclopropyl group in the formula (I) is a 1,2-cis-2-halogenocyclopropyl group.
The present invention also relates to the aforementioned compound or a salt thereof, in which R
2
in the formula (I) is a stereochemically pure substituent.
The present invention also relates to the aforementioned compound or a salt thereof, in which the halogenocyclopropyl group in the formula (I) is a stereochemically pure substituent.
The present invention also relates to the aforementioned compound or a salt thereof, in which the halogenocyclopropyl group is a (1R,2S)-2-halogenocyclopropyl group.
The present invention also relates to the aforementioned compound or a salt thereof, in which X
2
is a fluorine atom.
The present invention also relates to an antibacterial agent which contains the aforementioned compound of the formula (I) or a salt thereof as an active ingredient.
Other object
Kimura Youichi
Ohki Hitoshi
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Raymond Richard L.
Truong Tamthom N.
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