Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-06
2002-05-21
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S156000
Reexamination Certificate
active
06391889
ABSTRACT:
TECHNICAL 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, improvements have been added to synthetic quinolone antimicrobial agents in antimicrobial activity and in pharmacokinatics, and many compounds have been launched for clinical use as a chemotherapeutic agent effective on all most all systemic infectious diseases.
However, low sensitive bacteria resistant to the synthetic quinolone antimicrobial agents have recently been increasing in the clinical field. For example, bacteria resistant to drugs other than synthetic quinolone antimicrobial agents have come to acquire resistance to synthetic quinolone antimicrobial agents, as exemplified by
Staphylococcus aureaus
insensitive to &bgr;-lactam antibiotics (MRSA). 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 involve side effects, such as induction of convulsion in a combined use with a non-steroid antiinflammatory agent, and 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 cis-substituted aminocyclopropane derivatives represented by the following formula (I) and their salts have broad antimicrobial spectra, exhibiting potent antimicrobial activity particularly on Gram positive bacteria, especially quinolone-resistant bacteria including MRSA, and also show satisfactory in pharmacokinatics and safety.
The present invention relates to a compound represented by formula (I) shown below, 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 alkyloxy group having 1 to 6 carbon atoms; n represents an integer of 1 to 3; Q represents a partial structure having formula:
wherein 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 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
4
represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; R
3
and R
4
may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain a sulfur atom as a ring constituting atom and/or may be substituted with an alkyl group having 1 to 6 carbon atoms; R
5
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 be substituted with one or more 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
1
represents a halogen atom or a hydrogen atom; and A represents a nitrogen atom or a partial structure represented by 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, in which the amino group may be substituted with one or more 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
2
and R
3
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 and/or may be substituted with an alkyl group having 1 to 6 carbon atoms;
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 having 1 to 6 carbon atoms in the alkyl moiety thereof;
and the two substituents on the cyclopropane ring,
are in a cis-configuration.
The present invention also relates to:
a compound of formula (I), wherein Q is a partial structure represented by formula:
wherein R
3
, R
4
, R
5
, X
1
, X
2
, and Y are as defined above, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein Q is a 6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl group of formula:
or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein Q is a 8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl group of formula:
or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein Q is a 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-yl group of formula:
or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein Q is a 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinolin-7-yl group of formula:
or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein Q is a 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-yl group of formula:
or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein n is 2, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
1
and R
2
are each a hydrogen atom, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
3
is a halogenocyclopropyl group, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
3
is a 1,2-cis-2-halogenocyclopropyl group, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
3
is a stereochemically pure substituent, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
3
is a (1R,2S)-2-halogenocyclopropyl group, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein R
3
is a (1R,2S)-2-fluorocyclopropyl group, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein X
1
is a halogen atom, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I), wherein X
1
is a fluorine atom, or a salt or hydrate thereof or a hydrate of the salt;
a compound of formula (I) which is a stereochemically pure compound, or a salt or hydrate thereof or a hydrate of the salt;
5-amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or a salt or hydrate thereof or a hydrate of the salt;
a drug containing any of the above-described compounds, hydrates ther
Ishida Yohhei
Kimura Youichi
Takahashi Hisashi
Takemura Makoto
Daiichi Pharmaceutical Co. Ltd.
Morris Patricia L.
Sughrue & Mion, PLLC
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