Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-28
2001-10-30
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S302000, C540S200000, C548S103000
Reexamination Certificate
active
06310056
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a carbapenem compound which has excellent antimicrobial activity and wide range of anti-microbial spectrum, and can be administered not only as an injection but also orally. More particularly, the present invention relates to a novel carbapenem derivative which has a substituted or unsubstituted imidazo[5,1-b]thiazole group or a substituted or unsubstituted imidazo[5,1-b]thiazolium group at the 2-position on the carbapenem ring, or a salt thereof.
2. Background Art
Carbapenem derivatives, by virtue of potent antibacterial activity against a wide spectrum of bacteria, have been energetically studied as a highly useful &bgr;-lactam agent, and Imipenem, Panipenem, and Meropenem have been clinically used.
Both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 (“DHP-1”) in the case of Impenem and in order to reduce nephrotoxicity in the case of Panipenem. Meropenem which has recently been marketed has a methyl group at the 1&bgr;-position, so that it has increased stability to DHP-1 and thus can be used alone.
However, a need still exists for a drug having higher stability to DHP-1. Furthermore, drugs effective for methicillin resistant
Staphylococcus aureus
(“MRSA”), penicillin resistant
Streptococcus pneumoneae
(“PRSP”), resistant
Pseudomonas aeruginosa
and enterococci which have recently become serious problems as well as influenza have been demanded as well.
Some of the present inventors have previously reported the carbapenem derivatives having a novel heteroaromatic ring imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position on the carbapeneni ring in WO 96/028455 and the carbapenem derivatives having an imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the 2-position of the carbapenem ring in PCT/JP 97/04270.
Further, WO 96/034868 and Japanese Patent Laid-Open Publication No. 273876/1992 disclose the carbapenem derivatives in which a carbon atom on the heteroaromatic ring is bonded to the 2-position of the carbapenem ring. However, there have been described no specific data on the anti-microbial activities or effectiveness for these derivatives. There have been described neither bicyclic heteroaromatic rings nor carbapenem rings having imidazo[5,1-b]thiazole group.
SUMMARY OF THE INVENTION
The present inventors have now found that novel carbapenem derivatives having a substituted or unsubstituted imidazo[5,1-b]thiazole group or a substituted or unsubstituted imidazo[5,1-b]thiazolium group at the 2-position on the carbapenem ring have high anti-microbial activities against MRSA, PRSP, enterococci, influenza and &bgr;-lactamase producing bacteria, and high stabilities to DHP-1. The present invention is based on such findings.
Thus, the object of the present invention is to provide novel compounds which have wide range of anti-microbial activities, especially high anti-microbial activities against microorganisms including MRSA, PRSP, enterococci, influenza and &bgr;-lactamase producing bacteria, and high stabilities to DHP-1.
Thus, the present invention provides a compound represented by the formula (I), or a pharmacologically acceptable salt thereof:
wherein,
R
1
represents hydrogen or methyl,
R
2
, R
3
, R
4
, and R
5
, either one of which represents the bond to the 2-position on the carbapenem ring, and the remaining three groups, which may be the same or different, respectively represent
hydrogen,
halogen,
nitro,
cyano,
lower alkyl, in which one or more hydrogen atoms on the alkyl may be substituted by a group selected by the group consisting of halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbarnoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,
lower cycloalkyl, in which one or more hydrogen atoms on the cycloalkyl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alko)rycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylainino, aiminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, lower alkylthio,
C
2-4
alkenyl, in which one or more hydrogen atoms on the alkenyl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,
formyl,
lower alkylcarbonyl,
lower alkoxycarbonyl,
lower alkylsulfonyl,
arylsulfonyl,
aminosulfonyl,
arylcarbonyl,
aryl, in which one or more hydrogen on the aryl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, and
(N,N-di-lower alkylamino)sulfonylamino, carbamoyl,
N-lower alkylcarbamoyl,
N,N-di-lower alkylaminocarbonyl,
lower alkoxyiminomethyl, or hydroxyiminomethyl,
R
6
is not present, or represents lower alkyl, in which one or more hydrogen atoms on the alkyl may be substituted by a group selected from the group consisting of halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylainino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,
lower cycloalkyl, in which one or more hydrogen atoms on the cycloalkyl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, or
C2-4 alkenyl, in which one or more hydrogen atoms on the alkenyl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfony
Aihara Kazuhiro
Atsumi Kunio
Fushihara Kenichi
Ida Takashi
Iwamatsu Katsuyoshi
Berch Mark L.
Meiji Seika Kaisha Ltd.
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