Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-24
2003-06-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C514S312000, C514S313000, C514S314000, C544S101000, C546S123000, C546S156000
Reexamination Certificate
active
06573260
ABSTRACT:
TECHNICAL FIELD
This invention relates to a synthetic quinolone antibacterial agent useful as a drug for humans, animals or fishes or an antibacterial preservative.
This invention also relates to a synthetic quinolone antibacterial agent in which the structure of substituent at the 7 position of 1,4-dihydro-4-oxoquinoline skeleton or at the 10-position of 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton exerts important influence upon the expression of pharmacological effects such as antibacterial activity, pharmacokinetics and safety, having a 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group which can provide excellent antibacterial activity, pharmacokinetics and safety, as a substituent at the 7- or 10-position, and also having excellent antibacterial activity, proper pharmacokinetics and high safety, namely to a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative or a 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid derivative, and to an antibacterial agent and an antibacterial preparation, which contain the compound.
BACKGROUND ART
Since the discovery of Norfloxacin, antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents have been improved, and many compounds are now used in the clinical field as chemotherapeutic agents which are effective in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to synthetic quinolone antibacterial agents has been increasing in the field of clinics. For example, like the case of Staphylococcus aureus (MRSA) and pneumococcus (PRSP) which are non-sensitive to &bgr;-lactam antibiotics and enterococcus (VRE) which is non-sensitive to aminoglycoside antibacterial agents, a case has been increasing in which a Gram-positive bacterium originally resistant to drugs other than synthetic quinolone antibacterial agents becomes low-sensitive to synthetic quinolone antibacterial agents too. In consequence, development of a drug having further high efficacy has been called for in the field of clinics. On the other hand, it has been revealed that synthetic quinolone antibacterial agents cause a side effect in which convulsion is induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity, so that development of a synthetic quinolone antibacterial agent having further high safety has also been called for in the field.
It is known that structures of substituents at the 7-position and 1-position have a great influence to the antibacterial activity, pharmcokinetics and safety of synthetic quinolone antibacterial agents. It is already known that quinolone derivatives having 3-aminamethylpyrrolidine as a substituent show strong antibacterial activity for Gram-negative and Gram-positive bacteria. For example, a 7-(3-ainomethylpyrrolidin-1-yl)quinolonecarboxylic acid derivative is described in
Journal of Medicinal Chemistry
, vol. 29, p. 445 (1986), a 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl)quinolonecarboxylic acid derivative is described in
Journal of Medicinal Chemistry
, vol. 37, p. 733 (1994), and a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative is described in
Chemical
&
Pharmaceutical Bulletin
, vol. 42, p. 1442 (1994). However, no compounds are known which have a 3-(1-amino-1-cycloalkyl)methylpyridin-1-yl group at the 7-position and are also related to the present invention.
On the other hand, quinolone derivatives having 3-aminomethylpyrrolidine as a substituent are compounds which show strong antibacterial activity, but, since most of these compounds have low selective toxicity, they act upon not only bacteria but also eucaryotic cells so that it is difficult to use them as medical drugs or animal drugs.
Also, it is known that quinolone derivatives having a 3-aminopyrrolidine derivative at the 7-position and 2-(S)-fluoro-1-(R)-cyclopropyl group at the 1-position of the quinoline skeleton have weaker micronucleus inducing toxicity than those corresponding 1-cyclopropylquinolone derivatives. Their examples are described in
Journal of Medicinal Chemistry
, vol. 37. P. 3344 (1994).
On the other hand, quinolonecarboxylic acid derivatives having a 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group as a substituent, which are related to the present invention, are exemplified for example in JP-W-3-502452 (the term “JP-W” as used herein means an “unexamined published Japanese international patent application”), and it describes compounds represented by a formula (a) or (b) shown below. However, substituent at the 5-position of these exemplified quinolones is limited to a straight, branched or cyclic lower alkyl having 1 to 3 carbon atoms, and JP-W-3-502452 does not describe compounds having the 1-[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton or 3-(S)-methyl-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton related to the present invention. In addition, JP-W-3-502452 does not disclose illustrative examples of the 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group.
[In the above formula, R
7
is an alkyl having 1 to 4 carbon atoms, a vinyl, a haloalkyl, a hydroxyalkyl having 2 to 4 carbon atoms, a cycloalkyl having 3 to 6 carbon atoms, a phenyl or a phenyl substituted with a halogen, an alkyl, NH
2
or OH, R
6
is a straight, branched or cyclic lower alkyl having 1 to 3 carbon atoms, and X
3
is CH, CF, CCl, CBr, N, CCF
3
, CNH
2
, CNO
2
, CR or COR′ (in these formulae, R is a lower alkyl and R′ is hydrogen or a lower alkyl). Definitions of substituents of the compound of formula (a) are independent to those the compound of the present invention.]
In the above formula, Z is a group represented by the following formula (b).
(In this formula, m is an integer of from 0 to 4, and the substituents R
9
and R
10
are each independently a hydrogen atom, a lower alkyl or a cycloalkyl. Definitions of substituents of the compound of formula (b) are independent to those the compound of the present invention.)
In addition, PCT WO 96/39407 discloses compounds represented by the following formula (c), but they are limited to 2-pyridone derivatives such as 4H-4-oxoquinotozone skeleton, and PCT WO 96/39407 does not describe compounds having the 1,4-dihydro-4-oxoquinoline skeleton or 2,3-dihydro-3-(S)-ethyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton related to the present invention. Also, PCT WO 96/39407 does not disclose illustrative examples of optically active 3-[1-amino-1-cyclopropyl]methylpyrrolidin-1-yl group.
In addition, PCT WO 96/39407 does not describe about safety of the compounds of formula (c).
DISCLOSURE OF INVENTION
In view of the above, the inventors of the present invention have conducted intensive studies with the aim of providing the field of clinics with a compound which has excellent antibacterial activity, high efficacy and excellent safety. As a result of the extensive investigation, it has been found absolutely unexpectedly that a cycloalkyl-substituted aminomethylpyrrolidine derivative represented by the formula (I) described below, its salts and hydrates thereof can show strong antibacterial activity upon broad range of Gram-negative and Gram-positive bacteria, can show particularly strong antibacterial activity upon resistant strains of Gram-positive bacteria including MRSA, PRSP and VRE, and also have excellent safety and good pharmacokinetics, thereby resulting in the accomplishment of the present invention.
Particularly, it has been found that a compound represented by the following formula (I) in which a cycloalkyl-substituted aminomethylpyrrolidine derivative is introduced at the 7position of the 1[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton, its salts and hydrates thereof show broad and excellent antibacterial activity upon any one of Gram-negative and Gram-positive bact
Hayakawa Isao
Miyauchi Rie
Takahashi Hisashi
Takeda Toshiyuki
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Raymond Richard L.
Sughrue & Mion, PLLC
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