Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-23
2003-12-02
Seaman, D. Margaret (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S156000, C548S557000
Reexamination Certificate
active
06656952
ABSTRACT:
TECHNICAL FIELD
This invention relates to an 8-(substituted)alkoxy-4-oxoquinoline-3-carboxylic acid derivative having 3-(S)-amino-4-(S)-fluoromethylpyrrolidin-1-yl group at the 7-position of the quinoline nucleus as a substituent, which has excellent antibacterial activity, good pharmacokinetics and high safety, and to an antibacterial agent and an antibacterial preparation, which contain the compound.
This invention also relates to a compound which is useful for introducing a substituent at the 7-position that has such a structure that excellent antibacterial activity, pharmacokinetics and safety can be added to synthetic quinolone antibacterial agents in which the structure of the substituent at the 7-position exerts important influences upon the antibacterial activity, pharmacokinetics and safety.
BACKGROUND ART
Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics of quinolone synthetic 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 quinolone synthetic antibacterial agents has been increasing in the field of clinics. For example, like the case of
Staphylococcus aureus
(MRSA) which is non-sensitive to &bgr;-lactam antibiotics, a case has been increasing in which a bacterium originally resistant to drugs other than quinolone synthetic antibacterial agents becomes low-sensitive to quinolone synthetic 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 quinolone synthetic antibacterial agents cause a side effect in which severe convulsion is induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity and the like, so that development of a quinolone synthetic antibacterial agent having higher safety has also been called for in the field.
Quinolone-carboxylic acid derivatives which has the cis-3-amino-4-fluoromethylpyrrolidin-1-yl group related to the present invention as a substituent are disclosed for example in JP-A-62-19583, JP-A-63-45261 and JP-A-63-152318 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”), and these patents describe compounds represented by the following formula. However, though the substituent at the 7-position of these disclosed quinolones is a cis-3-amino-4-fluoromethylpyrrolidin-1-yl group, they are compounds which have the 8-fluoroquinoline nucleus in which the 8-position substituent is a halogen atom, and nothing is described about a compound which has the 8-methoxyquinoline nucleus related to the present invention. In addition, there is no illustrative disclosure in these specifications concerning an optically active compound 3-(S)-amino-4-(S)-fluoromethylpyrrolidine or 3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.
(In the above formula, R
5
is a hydrogen atom or a fluorine atom. Definition of the substituent of the compound represented by the formula (III) is unrelated to the compound of the present invention.)
In addition, JP-A-3-188074 discloses a compound represented by the following formula (IV), but it does not disclose a compound which has the 1-cyclopropyl-8-methoxyquinoline nucleus related to the present invention. Also, there is no illustrative disclosure in the specification concerning an optically active compound 3-(S)-amino-4-(S)-fluoromethylpyrrolidine or 3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.
(In the above formula, R
6
is a hydrogen atom or an amino group. Definition of the substituent of the compound represented by the formula (IV) is unrelated to the compound of the present invention.)
Also, JP-A-4-211077 discloses a compound which has the 1-cyclopropyl-8-methoxyquinoline nucleus, represented by the following formula (V). However, there is no illustration in the specification concerning a compound substituted with 3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.
(In the above formula, R
7
is methyl, ethyl or the like lower alkyl group. Definition of the substituent of the compound represented by the formula (V) is unrelated to the compound of the present invention.)
In addition, there is no description in the just described specification about safety of a compound represented by the following formula (VI) in which R
7
is a methyl group.
DISCLOSURE OF INVENTION
The inventors of the present invention have carried out tests on the safety of the compound represented by the formula (VI) and found as the result that its mouse peripheral blood micronucleus test was positive (micronucleus inducing action).
The present inventors have conducted intensive studies with the aim of providing a compound which has excellent antibacterial activity, high efficacy and excellent safety in the clinical field. As the result, it has been found that an 8-methoxyquinoline compound substituted with 3-(S)-amino-4-(S)-fluoromethylpyrrolidin-1-yl group, represented by the following formula (I), is superior to its corresponding 8-methoxyquinoline compound substituted with 3-(S)-amino-4-(S)-methylpyrrolidin-1-yl group, represented by the aforementioned formula (VI), thereby resulting in the accomplishment of the present invention.
That is, it has been found that the compound represented by the following formula (I) is possessed of excellent antibacterial activity upon a broad range of Gram-negative and Gram-positive bacteria and have excellent safety and pharmacokinetics, such as its micronucleus test-negative property.
[In the above formula, R
1
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituent(s) selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms,
R
2
represents a halogenomethoxyl group or an alkoxyl group having 1 to 6 carbon atoms,
R
3
represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and
R
4
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 phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylmethyl 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.
In this connection, the substituent R
4
may also be a boron-containing group represented by the following formula:
−B(Y
11
)Y
12
wherein Y
11
and Y
12
, each independently represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms.]
Accordingly, the present invention relates to a compound represented by the aforementioned formula (I), its salts or hydrates thereof.
The present invention also relates to the aforementioned 8-methoxyquinolone-carboxylic acid derivative, its salts or hydrates thereof in which the compound of formula (I) is a stereochemically pure compound;
the aforementioned compound, its salts or hydrates thereof, wherein R
1
in the formula (I) is a hydrogen atom;
the aforementioned compound, its salts or hydrates thereof, wherein R
2
in the formula (I) is a methoxyl group; 7-[3-(S)-amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof, wherein R
3
in the formula (I) is a cyclopropyl group;
the aforementioned compound, its salts or hydrates thereof,
Kimura Ken-ichi
Miyauchi Rie
Ohki Hitoshi
Takahashi Hisashi
Takeda Toshiyuki
Daiichi Pharmaceutical Co. Ltd.
Seaman D. Margaret
LandOfFree
Cis-substituted fluoromethylpyrrolidine derivative does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cis-substituted fluoromethylpyrrolidine derivative, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cis-substituted fluoromethylpyrrolidine derivative will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3158153