Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-22
2002-05-07
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C514S470000, C546S156000, C548S429000, C548S430000
Reexamination Certificate
active
06384050
ABSTRACT:
INDUSTRIAL FIELD
This invention relates to an antimicrobial compound useful as a drug for humans, animals or fishes or an antimicrobial preservative and an antimicrobial agent or preparation containing the same.
BACKGROUND ART
Since the discovery of Norfloxacin, synthetic quinolone antimicrobial agents have been improved in antimicrobial activity and pharmacokinetics, and many compounds have been launched for clinical use as a chemotherapeutic agent effective on all most all systemic infectious diseases.
However, bacteria having low sensitivity to the synthetic quinolone antimicrobial agents have recently been increasing in the clinical field. For example, bacteria which have not only resistance to drugs other than synthetic quinolone antimicrobial agents but low sensitivity to synthetic quinolone antimicrobial agents, as exemplified by
Staphylococcus aureaus
insensitive to &bgr;-lactam antibiotics (MRSA), have been increasing. Therefore, more effective drugs have been keenly demanded in the field of clinics.
Further, it has been revealed that synthetic quinolone antimicrobial agents tend to induce convulsion in a combined use with a non-steroid antiinflammatory agent or involve side effects such as phototoxicity. Therefore, development of safer synthetic quinolone antimicrobial agents has been sought.
DISCLOSURE OF THE INVENTION
In the light of these circumstances, the inventors have conducted extensive investigation for the purpose of providing excellent compounds fulfilling the above demands. As a result, they have found that tricyclic amine derivatives represented by formula (I) shown below and their salts and hydrates thereof have high antimicrobial activity broadly on Gram positive bacteria and Gram negative bacteria, exhibiting potent antimicrobial activity particularly on quinolone-resistant bacteria including MRSA, and also show satisfactory pharmacokinetics and safety.
The present invention relates to a compound represented by formula (I) shown below and its salt and their hydrates
wherein R
1
and R
2
each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents 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
3
represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R
4
and R
5
each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R
6
and R
7
each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X
1
represents an oxygen atom, a sulfur atom, a partial structure:
(wherein R
8
and R
9
each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2)
or a partial structure:
(wherein R
10
represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms);
n represents an integer 1 or 2; and
Q represents a partial structure represented by formula:
(wherein R
11
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 substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R
12
represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms;
R
11
and R
12
may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may have a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent;
R
13
represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the 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 5 carbon atoms;
X
2
represents a halogen atom or a hydrogen atom;
A
1
represents a nitrogen atom or a partial structure represented by formula (II):
wherein X
3
represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the 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 5 carbon atoms; and X
3
and R
11
may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent;
A
2
and A
3
each represents a nitrogen atom or a carbon atoms provided that A
2
, A
3
, and the carbon atom to which they are bonded form a partial structure:
>C═C(A
1
═)—N(R
11
)—
or a partial structure:
>N—C(A
1
═)═C(R
11
)—
wherein > indicates the carbon atom or the nitrogen atom has two bonds (hereinafter the same); and
Y 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).
The present invention also relates to:
(1) the compound of formula (I), wherein Q is a structure represented by formula:
or a structure represented by formula:
a salt or hydrate thereof, and a hydrate of the salt;
(2) the compound of formula (I), wherein Q is a structure represented by formula:
a salt or hydrate thereof, and a hydrate of the salt;
(3) the compound of formula (I), wherein Q is a 9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-6-carboxylic acid-10-yl group of formula:
a salt or hydrate thereof, and a hydrate of the salt;
(4) the compound of formula (I), wherein Q is a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula:
a salt or hydrate thereof, and a hydrate of the salt;
(5) the compound of formula (I), wherein Q is a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula:
a salt or hydrate thereof, and a hydrate of the salt;
(6) the compound of formula (I), wherein Q is a 5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula:
a salt or hydrate thereof, and a hydrate of the salt;
Kawakami Katsuhiro
Kimura Ken-ichi
Miyauchi Rie
Ohki Hitoshi
Takahashi Hisashi
Balasubramanian Venkataraman
Daiichi Pharmaceutical Co. Ltd.
Raymond Richard L.
Sughrue & Mion, PLLC
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