Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-30
2002-09-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S299000, C546S153000, C546S156000
Reexamination Certificate
active
06448266
ABSTRACT:
INDUSTRIAL FIELD
This invention relates to an antibacterial compound useful for a medicament, a veterinary drug, a drug for fisheries or an antibacterial preservative, and to an antibacterial agent and an antibacterial preparation, which contain the compound.
BACKGROUND ART
Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics after administration 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, 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 antibacterial agents becomes low-sensitive to 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 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.
DISCLOSURE OF THE INVENTION
In view of the above, the inventors of the present invention have conducted intensive studies with the aim of providing an excellent compound which can satisfy the aforementioned requirements. As a result of the efforts, it was found that a substituted cyclobutylamine derivative represented by the formula (I) described below, a salt thereof and a hydrate thereof are possessed of excellent antibacterial action upon broad range of Gram-negative and Gram-positive bacteria, can show particularly strong antibacterial activity upon quinolone-resistant bacteria including MRSA, and have excellent pharmacokinetics and safety, thereby resulting in the accomplishment of the present invention.
Accordingly, the present invention relates to a compound represented by the following formula (I), its salt or hydrates thereof:
{wherein R
1
and R
2
, each independently 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 (excluding a case in which R
1
and R
2
are both hydrogen atoms),
wherein the alkyl group may have one or more substituent selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms,
R
3
and R
4
, each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
wherein the alkyl group may have one or more 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,
n is an integer of 1 or 2,
Q is a partial structure represented by the following formula:
[wherein R
5
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, an aryl group 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,
R
6
represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R
6
and the aforementioned R
5
may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R
7
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,
wherein the amino group may have one or more substituent(s) 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
1
represents a halogen atom or a hydrogen atom,
A
1
represents a nitrogen atom or a partial structure represented by the following formula (II):
(wherein X
2
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,
wherein the amino group may have one or more substituent 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
2
and the aforementioned R
5
may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom, and the ring may also have 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 atom,
wherein A
2
and A
3
together with carbon atoms to which they are linked form a partial structure:
or a partial structure:
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 phenyl group]}.
The present invention also relates to:
the aforementioned compound, its salt or hydrates thereof in which a partial structure resulting from the exclusion of Q from the formula (I) is a stereochemically pure compound;
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a compound having a structure represented by the following formula:
{wherein R
5
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, an aryl group 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,
R
6
represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R
6
and the aforementioned R
5
may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain a sulfur atom as a ring consituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R
7
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,
wherein the amino group may have one or more substituent 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
1
represents a halogen atom or a hydrogen atom,
A
1
represents a nitrogen atom or a partial structure represented by the following formula (II):
(wherein X
2
represents a hydrogen atom, an amino grou
Miyauchi Rie
Sugita Kazuyuki
Takahashi Hisashi
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Patel Sudhaker B.
Shah Mukund J.
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