Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-23
2001-01-30
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210130, C540S350000
Reexamination Certificate
active
06180622
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to carbapenem derivatives which have potent antimicrobial activity against a wide range of bacteria. More particularly, the present invention relates to novel carbapenem derivatives which have a substituted or unsubstituted imidazo[5,1-b]thiazole or imidazo[5,1-b]thiazolium group at the 2-position of the carbapenem ring through a pyrrolidinylthio group.
2. Background Art
Carbapenem derivatives, by virtue of potent antimicrobial 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.
At the present time, 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. On the other hand, Meropenem, which has been recently put on the market, has increased stability against DHP-1 by virtue of the presence of a methyl group at the 1&bgr;-position and hence enabled the use as a single active ingredient in medicaments.
However, the stability against DHP-1 is not yet satisfactory. Further, the antimicrobial activity against methicillin-resistant
Staphylococcus aureus
(MRSA), penicillin-resistant
Streptococcus pneumoniae
(PRSP), and resistant
Pseudomonas aeruginosa
which have risen a serious clinical problem these days are also not always satisfactory. It is therefore strongly demanded to obtain novel carbapenem antibiotics which have improved antimicrobial activity against these bacteria.
WO 96/028455 discloses that carbapenem derivatives having an aromatic heterocyclic imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring have antimicrobial activity.
Japanese Patent Laid-Open Nos. 239058/1993 and 291973/1995, WO 95/10520, and WO 93/21186 disclose carbapenem derivatives wherein the 5-position of a pyrrolidinylthio group bonded to the 2-position of the carbapenem ring is bonded to the carbon atom on the aromatic heterocycle through a suitable spacer. None of these publications disclose carbapenem derivatives bonded to a bicyclic aromatic heterocycle.
SUMMARY OF THE INVENTION
The present inventors have now succeeded in synthesizing carbapenem derivatives having a substituted or unsubstituted imidazo[5,1-b]thiazole or substituted imidazo[5,1-b]thiazolium group at the 2-position of the carbapenem ring through a pyrrolidinylthio group (optionally through a pyrrolidinylthio group with a spacer).
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmacologically acceptable salt thereof:
wherein
A represents a bond, —(CH
2
)m—, —CHR
8
—, —(CH
2
)n—CH═CH—(CH
2
)n′—, —C(═O)N(—R
9
)CH
2
— wherein R
8
represents hydroxyl, methoxy, halogen, or amino, R
9
represents hydrogen or —(CH
2
)pCH
3
wherein p is an integer of 0 to 3, m is an integer of 1 to 3, and n and n′ each represent an integer of 0 to 3;
R
1
represents hydrogen or lower alkyl;
R
2
represents hydrogen, sodium, or potassium; and
any one of R
3
, R
4
, R
5
, and R
6
represents a bond and is bonded to A, and the remaining three substituents, which may be the same or different, represent hydrogen, halogen, nitro, cyano, lower alkyl, lower cycloalkyl, lower alkylthio, C
2-4
alkenyl, formyl, lower alkylcarbonyl, arylcarbonyl, or aryl (one or more hydrogen atoms in said lower alkyl, lower cycloalkyl, C
2-4
alkenyl, and aryl groups may be substituted by a group selected from the group consisting of halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxyl, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, (N-lower alkylamino)carbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, aminosulfonylamino, (N-lower alkylamino)sulfonylamino, and aryl);
or any two of R
3
, R
4
, R
5
, and R
6
may form together a five-membered heterocyclic saturated ring, containing one oxygen atom and one nitrogen atom, in which the ring may be substituted by oxo (═O), or any two of R
3
, R
4
, R
5
, and R
6
may form together C
3-6
alkylene in which one or more methylene groups in the alkylene group may be substituted by —NH—, —O—, —S—, or —CO—.
According to another aspect of the present invention, there is provided a compound represented by formula (II) or a pharmacologically acceptable salt thereof:
wherein
A represents a bond, —(CH
2
)m—, —CHR
8
—, —(CH
2
)n—CH═CH—(CH
2
)n′—, —C(═O)N(—R
9
)CH
2
— wherein R
8
represents hydroxyl, methoxy, halogen, or amino, R
9
represents hydrogen or —(CH
2
)pCH
3
wherein p is an integer of 0 to 3, m is an integer of 1 to 3, and n and n′ each represent an integer of 0 to 3;
R
1
represents hydrogen or lower alkyl;
R
2
represents hydrogen, sodium, or potassium;
any one of R
3
, R
4
, R
5
, and R
6
represents a bond and is bonded to A, and the remaining three substituents, which may be the same or different, represent hydrogen, halogen, nitro, cyano, lower alkyl, lower cycloalkyl, lower alkylthio, C
2-4
alkenyl, formyl, lower alkylcarbonyl, arylcarbonyl, or aryl;
R
7
represents lower alkyl, lower cycloalkyl, or aryl; and
one or more hydrogen atoms in said lower alkyl, lower cycloalkyl, C
2-4
alkenyl, and aryl groups each as a group or a portion of a group, which may be represented by R
3
, R
4
, R
5
, R
6
, and R
7
, may be substituted by a group selected from the group consisting of halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxyl, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, (N-lower alkylamino)carbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, aminosulfonylaminq, (N-lower alkylamino)sulfonylamino, and aryl; and
or any two of R
3
, R
4
, R
5
, and R
6
may form together a five-membered heterocyclic saturated ring, containing one oxygen atom and one nitrogen atom, in which the ring may be substituted by oxo (═O), or any two of R
3
, R
4
, R
5
, and R
6
may form together C
3-6
alkylene in which one or more methylene groups in the alkylene group may be substituted by —NH—, —O—, —S—, or —CO—.
The carbapenem derivatives represented by formulae (I) and (II) have potent antimicrobial activity against a wide range of bacteria including Gram-positive bacteria and Gram-negative acteria as well as have potent antimicrobial activity against various &bgr;-lactamase-producing bacteria, MRSA, and resistant
Pseudomonas aeruginosa
. Furthermore, they are very stable against DHP-1. Therefore, the compounds according to the present invention are useful as antimicrobial agents.
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 or branched chain C
1-6
alkyl or alkoxy, preferably a straight or branched chain C
1-4
alkyl or alkoxy. The term “lower cycloalkyl” means C
3-6
monocyclic alkyl.
The term “halogen” means a fluorine, chlorine, bromine, or iodine atom.
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, i-butoxy, s-butoxy, and t-butoxy.
Compounds
The group —(CH
2
)m— represented by A is preferably —(CH
2
)— (i.e., m=1).
—CHR
8
— represented by A is preferably —CHOH—.
—(CH
2
)n—CH═CH—(CH
2
)n′— represented by A is preferably —CH═CH— (i.e., n=n′=0).
—C(═O)N(—R
9
)CH
2
— represented by A is preferably —C(═O)N(—CH
3
)CH
2
— or —C(═O)NH—CH
2
—.
R
1
preferably represents hydrogen or methyl.
R
2
preferably represents hydrogen.
R
3
, R
4
, R
5
and R
6
preferably represent hydrogen, halogen, cyano,
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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