Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-18
2001-02-20
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230200, C544S101000, C544S102000
Reexamination Certificate
active
06191129
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pyridobenzoxazine derivative having 1-amino-3-azabicyclo[3.1.0]hexan-3-yl group as its substituent, which has an excellent antibacterial activity, good pharmacokinetics and high safety, and to a drug, an antibacterial agent and an antibacterial preparation, which contain said compound.
BACKGROUND ART
Since the discovery of Norfloxacin, antibacterial activity and pharmacokinetics of 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, increasing of bacteria having low sensitivity to quinolone antibacterial agents is becoming a problem 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 antibacterial agents becomes low-sensitive to quinolone antibacterial agents. In consequence, development of a drug having also the higher efficacy has been called for in the field of clinics.
On the other hand, it has been revealed that quinolone antibacterial agents cause a side effect in which convulsion is induced when a non-steroidal anti-inflammatory drug is simultaneously taken, as well as other side effects such as phototoxicity and the like, so that development of a quinolone antibacterial agent having the higher safety has also been called for in the field.
Quinolonecarboxylic acid derivatives having a substituent derived from 3-azabicyclo[3.1.0]hexylamine, which relates to the present invention, have been disclosed for example in JP-A-64-56673 and JP-A-7-48367 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”). Although these disclose a compound represented by the following formula, they describe only about compounds having quinoline skeleton but do not describe about compounds having pyridobenzoxazine skeleton of the present invention which will be described later.
Also, JP-A-3-86875 and JP-A-7-149758 disclose compounds represented by the following formula, but they do not concretely disclose any compound of the present invention.
(In the above formula, A, R
3
, R
6
, R
7
, R
9
, R
10
, R
25
, R′, W and Y are various substituents such as an alkyl group. In this connection, definition of the substituents related to the above compound is independent to that of the compound of the present invention.)
In addition, JP-A-3-86875 and JP-A-7-149758 disclose compounds represented by the following formula (A), which have pyridobenzoxazine skeleton. However, though pyridobenzoxazine derivatives having 6-amino-3-azabicyclo[3.1.0]hexan-3-yl group as a substituent at the 10-position are concretely described in these publications, there is no concrete description about pyridobenzoxazine derivatives of the present invention having 1-amino-3-azabicyclo[3.1.0]hexan-3-yl group as a substituent at the 10-position. What is more, nothing is described therein about the excellent pharmacokinetics and safety of the pyridobenzoxazine compounds of the present invention having the 1-amino-3-azabicyclo[3.1.0]hexan-3-yl group as the substituent at the 10-position.
(In the compounds of formula (A), definition of the substituents related to the above compound is independent to that of the compound of the present invention.)
DISCLOSURE OF INVENTION
In view of the above, the inventors of the present invention have conducted intensive studies with the aim of providing a compound which has an excellent antibacterial activity, high efficacy and excellent safety. As a result of the efforts, it was found that a pyridobenzoxazine compound represented by the following formula (I) is superior to a corresponding compound represented by the foregoing formula (A), thereby resulting in the accomplishment of the present invention.
That is, it was found that the compound represented by the formula (I) is possessed of broad and excellent antibacterial activity upon both Gram-negative and Gram-positive bacteria, particularly shows strong antibacterial activity against quinolone-resistant bacteria and also has excellent pharmacokinetics and safety.
A compound represented by formula (I):
wherein
R
1
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, in which said alkyl group may have a substituent 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 hydrogen atom or an amino group, in which said amino group may have one or two substituents 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 6 carbon atoms; and
R
3
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, 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, a salt thereof, or a hydrate thereof.
Accordingly, the present invention relates to a compound represented by the aforementioned formula (I), a salt thereof, or a hydrate thereof.
The present invention also relates to the aforementioned compound, a salt thereof, or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound; a compound of formula (I), a salt thereof, or a hydrate thereof, wherein R
2
is a hydrogen atom;
10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazine-6-carboxylic acid (a compound represented by the following formula), an ester thereof, a salt thereof (of carboxylic acid or ester) or a hydrate thereof (of the carboxylic acid, ester, salt of carboxylic acid and salt of ester)
10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof (of carboxylic acid or ester), or a hydrate thereof (of carboxylic acid, ester, salt of carboxylic acid or salt of ester), which comprises a pure isomer;
a compound of formula (I), a salt thereof, or a hydrate thereof, wherein R
2
is an amino group;
8-amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]-benzoxazine-6-carboxylic acid (a compound represented by the following formula), an ester thereof, a salt thereof (of carboxylic acid or ester), or a hydrate thereof (of carboxylic acid, ester, salt of carboxylic acid or salt of ester);
8-amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]-benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof (of carboxylic acid or ester), or a hydrate thereof (of carboxylic acid, ester, salt of carboxylic acid or salt of ester), which comprises a pure isomer;
a pharmaceutical preparation which comprises as an active ingredient the compound represented by formula (I), a salt thereof, or a hydrate thereof;
a pharmaceutical preparation which comprises as an active ingredient the compound represented by formula (I), a salt thereof, or a hydrate thereof, wherein the compound of formula (I) is stereochemically pure compound;
a pharmaceutical preparation which comprises as an active ingredient the compound represented by formula (I), a salt thereof, or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound and R
2
is a hydrogen atom;
a pharmaceutical preparation which comprises as an active ingredient 10-(1-amino-3-azabicyclo[3.1.0]hexan-
Kawakami Katsuhiro
Takahashi Hisashi
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Schroeder Ben
Shah Mukund J.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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