Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-25
2004-01-20
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S302000
Reexamination Certificate
active
06680313
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel carbapenem derivatives which have excellent antibiotic activity against a wide spectrum of bacteria, and more particularly to novel carbapenem derivatives which have a substituted imidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring.
2. Background Art
Carbapenem derivatives, by virtue of potent antibiotic activity against a wide spectrum of bacteria, have been energetically studied as a highly useful &bgr;-lactam agent, and Imipenem, Panipenem, and Meropenem have already been clinically used.
At the present time, both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 (hereinafter abbreviated to “DHP-1”) in the case of Imipenem 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 against DHP-1 and thus can be used alone. The stability against DHP-1, however, is still unsatisfactory. The antibiotic activity also is not necessarily satisfactory against methicillin resistant
Staphylococcus aureus
(hereinafter abbreviated to “MRSA”), penicillin resistant
Streptococcus pneumoneae
(hereinafter abbreviated to “PRSP”), resistant
Pseudomonas aeruginosa
, enterococci, and Influenzavirus which currently pose serious clinical problems. Therefore, drugs useful for these bacteria responsible for infectious diseases have been desired in the art.
WO 96/28455 describes carbapenem derivatives having a novel aromatic heterocyclic imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring, WO 98/23623 describes carbapenem derivatives having an imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the 2-position of the carbapenem ring, and WO 98/32760 describes derivatives with a carbon atom on an imidazo[5,1-b]thiazole group being attached to the 2-position of the carbapenem ring.
SUMMARY OF THE INVENTION
An object of the present invention is to provide carbapenem derivatives which have potent antibiotic activity against MRSA, PRSP, Influenzavirus, and &bgr;-lactamase-producing bacteria and are stable against DHP-1.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R
1
represents a hydrogen atom or methyl;
R
2
and R
3
, which may be the same or different, represent
a hydrogen atom,
a halogen atom,
lower alkyl on which one or more hydrogen atoms may be substituted by hydroxyl or amino,
lower alkylcarbonyl,
carbamoyl,
aryl, or
lower alkylthio; and
R
4
represents
substituted lower alkylthio wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, nitro, azido, cyano, lower cycloalkyl, isothioureido, hydroxyl, lower alkoxy, phosphonoxy, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, formylamino, lower alkylcarbonylamino, aminosulfonylamino, (N-lower alkylamino)sulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, formimidoylamino, acetimidoylamino, guanidino, amindsulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, aryl, a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms, which may be the same or different, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl wherein the lower alkyl portion may be substituted by one or more groups selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
lower cycloalkylthio wherein one or more hydrogen atoms of the cycloalkyl portion may be substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, hydroxyl, carbamoyl, and amino,
C
2-4
alkenylthio,
C
2-4
alkynylthio,
substituted arylthio wherein one or more substituents of the aryl portion, which may be the same or different, are selected from the group consisting of a halogen atom, nitro, cyano, hydroxyl, carbamoyl, and amino,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein, when the ring contains a nitrogen atom, lower alkyl optionally having carbamoyl may be attached to the nitrogen atom and the nitrogen atom may be in the form of a quaternary ammonium atom,
substituted lower alkylsulfinyl wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
substituted lower alkylsulfonyl wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino, or
sulfonyl substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein, when the ring contains a nitrogen atom, lower alkyl optionally having carbamoyl may be attached to the nitrogen atom and the nitrogen atom may be in the form of a quaternary ammonium atom.
The carbapenem derivatives represented by formula (I) have potent antibiotic activities against a wide spectrum of Gram-positive bacteria and Gram-negative bacteria. The compounds represented by formula (I) have potent antibiotic activity particularly against MRSA, PRSP, Influenzavirus, and &bgr;-lactamase-producing bacteria. The carbapenem derivatives of the present invention advantageously have low toxicity and high safety.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “lower alkyl” or “lower alkoxy” as a group or a part of a group means straight-chain or branched C
1-6
, preferably C
1-4
, alkyl or alkyloxy. Examples of the lower alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl. Examples of the lower alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.
The term “lower cycloalkyl” means C
3-6
monocyclic alkyl.
The term “halogen atom” means a fluorine, chlorine, bromine, or iodine atom.
The term “aryl” as a group or a part of a group means a six- to 10-membered monocyclic or bicyclic aromatic carbocyclic ring, and examples thereof include phenyl and naphthyl with phenyl being preferred.
The term “hetero atom” as used herein means a nitrogen atom, an oxygen atom, or a sulfur atom.
The “monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms” preferably means a five- to 12-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring containing 1 to 4 hetero atoms. The hetero atom constituting the heterocyclic ring is preferably one or two nitrogen atoms.
Examples of the heterocyclic ring include pyrrolidine, piperidine, and pyridine.
R
1
preferably represents methyl.
R
2
and R
3
, which may be the same or different, preferably represent a hydrogen atom or lower alkylthio, more preferably a hydrogen atom or methylthio, particularly preferably a hydrogen atom.
R
4
preferably represents
substituted lower alkylthio wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, azido, isothioureido, hydroxyl, phosphonoxy, lower alkylcarbonyl, carbamoyl, amino, formylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, formimidoylamino, acetimidoylamino amino, guanidino, aryl, a pyridine ring, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl in which lower alkyl may be substituted by one or more groups selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
thio substitu
Aihara Kazuhiro
Atsumi Kunio
Ida Takashi
Iwamatsu Kastuyoshi
Kano Yuko
Berch Mark L.
Meiji Seika Kaisha Ltd.
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