Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-14
2004-01-13
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
06677331
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 imidazo[5,1-b]thiazole group 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 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 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 carbapenem 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 W98/023623 and, furthermore, the carbapenem derivatives having an imidazo[5,1-b]thiazole group directly at the 2-position of the carbapenem ring in WO98/032760.
Further, WO96/011932 and WO96/034868 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 specifictdata 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 imidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring have high anti-microbial activities against &bgr;-lactamase producing bacteria, MRSA, resistant-
Pseudomonas aeruginosa
, PRSP, enterococci, and influenza, and high stabilities to DHP-1. The present invention is based on such findings.
Accordingly, the object of the present invention is to provide novel compounds which have wide range of anti-gram-positive and gram-negative microbial activities, especially high anti-microbial activities against microorganisms including &bgr;-lactamase producing bacteria, MRSA, enterococci, PRSP, influenza, and high stabilities to DHP-1.
According to the present invention, there is provided a compound represented by the formula (I), or a pharmacologically acceptable salt thereof or an ester at the 3-position on the carbapeem ring thereof:
wherein
R
1
represents a hydrogen atom or a methyl group,
R
2
, R
3
, R
4
, and R
5
, either one of which represents the bonding to the 2-position on the carbapenem ring, and the other three of which may be the same or different, respectively represent
a hydrogen atom,
a halogen atom,
a nitro group,
a cyano group,
a lower alkyl group which may be'substituted,
a lower cycloalkyl group which may be substituted,
a lower alkylthio group,
an arylthio group,
a C
2-4
alkenyl group which may be substituted,
a formyl group,
a lower alkylcarbonyl group which may be substituted,
a lower alkoxycarbonyl group,
a lower alkylsulfonyl group,
an arylsulfonyl group which may be substituted,
an aminosulfonyl group,
an N-loweralkylaminosulfonyl group which may be substituted,
an N,N-di-lower alkylaminosulfonyl group which may be substituted,
an N-lower alkoxy-N-lower alkylaminosulfonyl group,
a lowerialkylsufinyl group
an arylsulfinyl group,
an aminosulfinyl group,
an arylcarbonyl group,
an arylgroup which may be substituted,
a carbamoyl group,
an N-lower alkylcarbamoyl group,
an N,N-di-lower alkylaminocarbonyl group,
a lowerialkoxyiminomethyl group,
a hydroxyiminomethyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and
R represents a hydrogen atom or a group which may be hydrolyzed in organisms.
DETAILED DESCRIPTION OF THE INVENTION
Definition
As used herein, the term “lower alkyl” or “lower alkoxy” as a group or a part of a group means a straight chain or branched chain alkyl of alkyloxy having 1-6 carbon atoms, preferably 1-4 carbonatoms. Theexamples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. Further, the lower alkoxy includes by way of example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, and the like.
The term “lower cycloalkyl” means monocyclic alkyl having 3-6 carbon atoms.
Further, the term “aryl” means an aromatic ring and aromatic polycyclic hydrocabon ring preferably phenyl or naphthyl.
The term “halogen” herein means fluorine, chlorine, bromine, or iodine.
Compound
In the formula (I), any one of R
2
, R
3
, R
4
, and R
5
represents the bond to the 2-position on the carbapenem ring. The remaining three groups, which may be the same or different, respectively represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a lower alkylthio group, an arylthio group, a C
2-4
alkenyl group which may be substituted, a formyl group, a lower alkylcarbonyl group which may be substituted, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, an arylsulfonyl group which may be substituted, an aminosulfonyl group, an N-loweralkylaminosulfonyl group which may be substituted, an N,N-di-lower alkylaminosulfonyl group which may substituted, an N-lower alkoxy-N-lower alkylaminosulfonyl group, a lower alkylsufinyl group, an arylsulfinyl group, an aminosulfinyl group, an arylcarbonyl group, an aryl group which may be substituted, a carbamoyl group, an N-lower alkylcarbamoyl group, an N,N-di-lower alkylaminocarbonyl group, a lower alkoxyiminomethyl group, a hydroxyiminomethyl group, or a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms.
According to the preferred embodiment of the present invention, the remaining three groups, which may be the same or different, respectively represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a lower alkylthio group, an arylthio group, a C
2-4
alkenyl group which may be substituted, a formyl group, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group, an arylsulfonyl group which may be substituted, an aminosulfonyl group, an N-loweralkylaminosulfonyl group which may be substituted, an N,N-di-lower alkylaminosulfonyl group which may be substituted, a lower alkylsufinyl group, an arylcarbonyl group, an aryl group which be substituted, a lower alkoxyiminomethyl group, a hydroxyiminomethyl group, or a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms. More preferably, the remaining three groups represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group (in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group cons
Aihara Kazuhiro
Akiyama Yoshihisa
Ando Takashi
Atsumi Kunio
Ida Takashi
Berch Mark L.
Meiji Seika Kaisha Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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