Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-08
2002-11-12
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S350000, C548S314700, C548S324100
Reexamination Certificate
active
06479478
ABSTRACT:
TECHNICAL FIELD
The present invention relates to carbapenem antibiotics and, more particularly, to carbapenem compounds having a &bgr;-orientated methyl group introduced at 1-position and 1-[(heterocyclyl)-azetidin-3-yl]thio group at the 2-position of carbapenem skeleton, and to antibacterial compositions containing the same as an active ingredient.
BACKGROUND ART
Since the discovery of thienamycin [U.S. Pat. No. 3,950,357; J. Am. Chem. Soc., 100, 313(1987)], there have been proposed many carbapenem antibiotic substances, and among them imipenem (INN) have been developed as a practically useful carbapenem antibiotic substance, and is widely used in clinical field.
Although the imipenem, developed at first as carbapenem antibiotic substance, exhibits wide antibacterial activities against gram positive or negative bacteria, it possesses the disadvantage that it is decomposed within a short period of time by renal dehydropeptidase (DHP) in the living body. For this reason, imipenem cannot be administered singly, and must be used in combination with a DHP inhibitor in order to control its decomposition leading to inactivation. Therefore, its formulation for clinical administration is a combination with cilastatin (INN) that is a DHP inhibitor.
An antibacterial agent preferred for practical clinical use; however, is one that alone can demonstrate antibacterial activity. Furthermore, the DHP inhibitor to be combined with the antibiotic could exert undesirable action on tissues of the living body. For these reasons, the combined use should be avoided wherever possible. Thus, there has been a growing demand for a carbapenem compound having sufficiently high degrees of both antibacterial activity and resistance to DHP.
There were proposed some carbapenem compounds of the type that could achieve the above-mentioned objectives. Such carbapenem compounds are 1-methylcarbapenem compounds in which a methyl group is introduced at the 1-position of the carbapenem skeleton, and it is reported that these carbapenem compounds are not only resistant to DHP but also more chemically stable than those having no methyl group at the 1-position of the carbapenem skeleton.
Under these circumstances, many researchers have specifically attempted to modify a side-chain substituent at 2-position of 1-methylcarbapenem compounds, and as a result, meropenem and biapenem are proposed for the carbapenem antibiotics that can be administered singly.
Although, the carbapenem compounds possess a potent antibacterial activity with a broad spectrum, it is anticipated that the resistant strain, which is a problem in the field of &bgr;-lactam antibiotics, will appear. That is, it is well anticipated for new carbapenem antibiotics to be effective at first, but long time clinical use of it will gradually cause the resistant to appear. Therefore, there always is constant demand for development of new compounds having excellent antibacterial activity in the antibacterial field.
Under these circumstances, it is the purpose of the present invention to provide new carbapenem compounds having high antibacterial activities and a strong action of inhibiting &bgr;-lactamase as well as improved resistance to DHP.
DISCLOSURE OF INVENTION
Accordingly, one subject of the present invention is to provide carbapenem compounds represented by the following formula (I):
wherein
R is hydrogen atom, or substituted or unsubstituted lower alkyl group; and,
n is an integer of 1 or 2,
or a pharmaceutically acceptable salt thereof.
Another subject of the present invention is to provide ester compounds of formula (I), in which carboxylic acid group at 3-position is converted to ester form by various kinds of ester residues. These ester residues may be conventional ester residues, which are widely used for ester moieties for carboxylic group in this field.
The carbapenem compounds according to the present invention are characterized in that the substituent at the 2-position of 1-methyl carbapenem skeleton is specific 1-heterocyclyl-azetidin-3-ylthio group, which is never demonstrated for substituent for 2-position, and have superior antibacterial activities.
Therefore, still another subject of the present invention is to provide an antibacterial agent containing the carbapenem compounds represented by the formula (I) above, ester thereof or pharmaceutically acceptable salt thereof claimed in claim 1 as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in more detail in the following. The terms used throughout the present specification have following meanings.
The term “lower” qualifying a group or a compound means that the group or the compound qualified has 1 to 7, preferably 1 to 4, carbon atoms.
The term “lower alkyl group” stands for a linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and so on.
Substituents, which can substitute to said lower alkyl group, are hydroxy group; lower alkoxy group; halogen atom such as chlorine, bromine, and so on; mono-substituted amino group; di-substituted amino group such as dimethylamino, diethylamino, methylethylamino, and the like; phenyl; substituted phenyl such as hydroxyphenyl, methylphenyl, dimethylphenyl, aminophenyl, aminomethylphenyl, nitrophenyl, and so on; nitro group; acetyl group, and the like.
When the carbapenem compounds of the present invention have an asymmetric carbon atom at the side chain of the 2-position, the isomers can be stereo-selectively obtained by using optically active starting materials, and each isomer can be isolated from the stereoisomeric mixture by usual method. Therefore, each isomer per se, as well as the stereoisomeric mixture, should be included in the compounds of the present invention.
The following are the typical carbapenem compounds of the present invention.
(1R,5S,6S)-2-[1-(1,3-imidazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carbolic acid;
(1R,5S,6S)-2-[1-(1-methy-2-imidazolin-2-yl)azetidin-3-yl]-thio -6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carbolic acid;
(1R,5S,6S)-2-[1-(1,4,5,6-tetrahydropyrimidin-2-yl)azetidin-3-yl]thio -6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carbolic acid;
(1R,5S,6S)-2-[1-(1-methyl-1,4,5,6-tetrahydropyrimidin-2-yl) azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carbolic acid;
(1R,5S,6S)-2-[1-(1-(4-aminomethylbenzyl)-2-imidazolin-2-yl) azetidin-3-yl]thio-6[-(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carbolic acid.
Examples of the pharmaceutically acceptable salt of carbapenem compound of the present invention include non-toxic inorganic or organic salts thereof. The inorganic salts may include alkali metal salt such as sodium, potassium and the like; alkali earth metal salt such as calcium, magnesium and the like; and ammonium salt thereof. The organic salts may include triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexyl amine, N,N′-dibenzyl-ethylenediamine and the like.
Furthermore, the carbapenem compounds of the present invention may be converted into a pharmaceutically acceptable acid addition salt thereof with organic or inorganic acids. Examples of inorganic acids include hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Examples of organic acids include organic acid such as formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and so on; and basic or acidic amino acid such as arginine, aspartic acid, glutamic acid and the like.
The ester compound of the present invention may include ester compound prepared by the ester residue mentioned later.
The carbapenem compound of the present invention may be prepared in accordance with the processes as illustrated by the reaction scheme A shown below.
wherein R
a
is acyl group; R
1
is carboxyl protecting
Abe Takao
Hayashi Kazuhiko
Kaneda soh-ichi
Berch Mark L.
Crowell & Moring LLP
Wyeth Lederle Japan, Ltd.
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