Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-25
2004-11-30
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
06825187
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. Related 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, each independently represent
a hydrogen atom,
a halogen atom,
lower alkyl on which one or more hydrogen atoms are optionally substituted by hydroxyl or amino,
lower alkylcarbonyl,
carbamoyl,
aryl, or
lower alkylthio;
R
4
represents
lower alkylthio on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of: a halogen atom; nitro; azido; cyano; lower cycloalkyl; lower alkylthio; 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; aminosulfonyl; (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 one or more hydrogen atoms of the lower alkyl portion are optionally substituted by a group 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 are optionally 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,
arylthio,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different,
lower alkylsulfinyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, and amino,
lower alkylsulfonyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a group selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
lower alkylcarbonyl, or
arylcarbonyl or
R
4
and R
5
together form —R
4
—R
5
— which represents —S—(CH
2
)
n
— wherein n is an integer of 2 to 4;
R
5
represents
lower alkyl on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of: a halogen atom; nitro; azido; cyano; lower cycloalkyl; lower alkylthio wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino; thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein one or more hydrogen atoms of the ring are optionally substituted by carbamoyl, hydroxymethyl, aminosulfonylamino, or aminosulfonylaminomethyl; isothioureido; hydroxyl; lower alkoxy on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino; phosphonoxy; formyl; lower alkylcarbonyl; arylcarbonyl wherein one or more hydrogen atoms of the aryl portion are optionally substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, lower alkyl on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino, hydroxyl, lower alkoxy, benzyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, and hydroxyamino; carboxy; lower alkoxycarbonyl; carbamoyl; N-aminocarbamoyl; N-lower alkylcarbamoyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; N,N-di-lower alkylcarbamoyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; alicyclic aminocarbonyl in which one or more hetero atoms may be contained as the member atom of the ring; N-arylcarbamoyl; N-hydroxycarbamoyl; N-benzyloxy-carbamoyl; N-lower alkyl-N-lower alkoxycarbamoyl; hydrazinocarbonyl; amino; N-lower alkylamino wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; N,N-di-lower alkylamino wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino)sulfonylamino; (N,N-di-lower alkylamino)sulfonylamino; piperazinyl-carbonylamino; N-lower alkylpiperazinylcarbonylamino; N-arylpiperazinylcarbonylamino; formimidoylamino; acetimidoylamino; guanidino; lower alkylsulfonyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a halogen atom, amino, or hydroxyl; arylsulfonyl wherein one or more hydrogen atoms of the aryl portion are optionally substituted by a halogen atom, amino, or hydroxyl; aminosulfonyl; (N-lower alkylamino)sulfonyl; (N,N-di-lower alkylamino)sulfonyl; aryl on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, lower alkyl on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, N,N-di-lower alkylcarbamoyl, amino, or amino-substituted lower alkyl, hydroxyl, lower alkoxy, benzyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl N,N-di-lower a
Aihara Kazuhiro
Atsumi Kunio
Ida Takashi
Iwamatsu Katsuyoshi
Kano Yuko
Berch Mark L.
Meiji Seika Kaisha Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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