Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-07
2004-07-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S259410, C514S300000, C514S306000, C514S312000, C544S101000, C544S282000, C546S123000, C546S138000, C546S156000
Reexamination Certificate
active
06762181
ABSTRACT:
TECHNICAL FIELD
This invention relates to a synthetic quinolone antibacterial agent which is useful as a medicament, an animal drug, a drug for fishery use and an antibacterial preservative.
That is, the invention relates to a synthetic quinolone antibacterial agent in which the structure of a substituent at the 7-position of the quinolone mother skeleton or a corresponding position (e.g., the 7-position of the 1,4-dihydro-4-oxoquinoline skeleton; the 10-position of 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton or the like) exerts important influence upon the antibacterial activity, namely a quinolone derivative having a 3-[1-amino-1-aromatic group-substituted]methylpyrrolidin-1-yl group as a substituent which can provide excellent antibacterial activity, and to an antibacterial agent and an antibacterial pharmaceutical preparation, which contain the compound.
It further relates to a synthetic quinolone antibacterial drug, namely a 3-[1-amino-1-aromatic group-substituted]methylpyrrolidine, which has a structure that can provide excellent antibacterial activity and is useful as a production intermediate, and to a protected compound thereof.
BACKGROUND ART
Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents have been sharply 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 also became low-sensitive to synthetic quinolone antibacterial agents. In consequence, development of a drug having further high efficacy has been called for in the field of clinics.
Also, a side effect in which convulsions are induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity and the like, have been revealed, 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 are greatly concerned in the antibacterial activity, pharmacokinetics and safety of synthetic quinolone antibacterial agents. It is already known that a quinolone derivative having 3-(aminomethyl)pyrrolidinyl group as the 7-position substituent shows strong antibacterial activity for Gram-negative and Gram-positive bacteria. For example, there is a 7-[3-(aminomethyl)pyrrolidin-1-yl)quinolonecarboxylic acid derivative [
Journal of Medicinal Chemistry,
vol. 29, p. 445 (1986)]. Also, a 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [
Journal of Medicinal Chemistry,
vol. 36, p. 871 (1993)], a 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [
Journal of Medicinal Chemistry,
vol. 37, p. 733 (1994)], a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [
Chemical
&
Pharmaceutical Bulletin,
vol. 42, p. 1442 (1994)] and the like are known as quinolonecarboxylic acid derivatives having a substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group.
However, substituents on the aminomethyl group of currently known 3-(aminomethyl)pyrrolidin-1-yl group are only alkyl groups, and a quinolone compound having an aromatic group as a substituent, which is related to the present invention, is not known.
Also, as a reference in which quinolonecarboxylic acid derivatives having a cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group are exemplified, there is, for example, 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 two general formulae shown below. However, the cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group described in this document is limited to a cyclic alkyl, and there is no disclosure on the 3-[1-amino-1-aromatic group-substituted]methylpyrrolidin-1-yl group related to the invention.
[In the above formula, R
12
is an alkyl group having from 1 to 4 carbon atoms, a vinyl group, a haloalkyl group, a hydroxyalkyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, phenyl group or a phenyl group substituted with a halogen, an alkyl group, NH
2
or OH, R
14
is a straight, branched or cyclic lower alkyl group having from 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 group and R′ is hydrogen atom or a lower alkyl group).]
In the above formula, Z is
(wherein m is an integer of from 0 to 4, and R
15
and R
16
are each independently a hydrogen atom, a lower alkyl group or a cycloalkyl group). In this connection, the definitions of substituents and the like in the above two general formulae are unrelated to those of the compound of the invention, even if the same symbols are used.
In addition, JP-W-9-503783 discloses 2-pyridone carboxylic acid derivatives of 4H-4-oxoquinolizone skeleton and the like shown by the following formula. However, the quinolone compound of the invention having an aromatic substituent on the aminomethyl group moiety of 3-(aminomethyl)pyrrolidin-1-yl group related to the invention is not also exemplified in this document.
DISCLOSURE OF THE INVENTION
In view of the above, the inventors of the present application have conducted intensive studies with the aim of obtaining excellent quinolone compounds. As a result, it has been found absolutely unexpectedly that an aromatic group-substituted aminomethylpyrrolidine derivative represented by the formula (I) described below, its salts and hydrates thereof can show potent antibacterial activity upon a broad range of Gram-negative and Gram-positive bacteria including drug-resistant bacteria, thereby resulting in the accomplishment of the invention.
The inventors have found that a compound represented by the formula (I) in which an aromatic group-substituted aminomethylpyrrolidine derivatives is introduced onto the 10-position of 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton or the 7-position of 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline skeleton, its salts and hydrates thereof, having excellent safety, can show broad and excellent antibacterial activity upon any one of Gram-negative and Gram-positive bacteria. At the same time, it was found that it can exert potent antibacterial activity upon drug-resistant Gram-positive bacteria including MRSA, PRSP and VRE, which was not expected before the invention.
Accordingly, the invention relates to a compound represented by the following formula (I), its salts and hydrates thereof
(wherein R
1
represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkoxyl group having from 1 to 6 carbon atoms, an alkylth
Kawakami Katsuhiro
Miyauchi Rie
Takahashi Hisashi
Takeda Toshiyuki
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Raymond Richard L.
Sughrue & Mion, PLLC
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