Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1997-07-17
1999-03-23
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D47720, A61K 3140
Patent
active
058861726
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/03540, filed Dec. 04, 1996.
1. Technical Field
The present invention relates to orally administrable carbapenem antibiotics and, more particularly, to carbapenem-3-carboxylic acid ester derivatives which are highly absorbable through digestive tract.
2. Background Art
Heretofore, there have been proposed a lot of carbapenem compounds having a strong antibacterial activity. For example, Japanese Patent Kokai No. 202886/1985 discloses a carbapenem-3-carboxylic acid derivative having (N-methylacetoimidoyl-azetidin-3-yl)thio group at the 2-position represented by the following formula (A): ##STR2##
The inventors of the present invention also disclosed carbapenem derivatives having a methyl group introduced at the 1-position in the beta-configuration and (1-heterocyclyl-azetidin-3-yl)thio group at the side chain of the 2-position as represented by the formula (B) below, which showed a high antibacterial activity, a strong action of inhibiting beta-lactamase as well as improved resistance to kidney dehydropeptidase (Japanese Patent Kokai No. 53453/1996): ##STR3##
Because of poor absorbability through digestive tract, however, most of the carbapenem compounds proposed so far, including the compounds of the formulae (A) and (B) above, are clinically thought to be administrable as an injection only.
In clinical practice, however, it is desirable that a suitable administration route can be selected case by case in view of the purpose of therapy or circumstances on the side of patients. Compared with injections, oral drugs are especially preferable and clinically quite useful since they can be taken easily and conveniently, even in a patient's own home. Accordingly, there have been strong demands for the development of orally administrable carbapenem compounds which have a wide range of antibacterial spectrum and strong antibacterial activity.
DISCLOSURE OF INVENTION
Through extensive investigations, the present inventors discovered that an ester derivative produced by esterifying the carboxyl group at the 3-position of the compound represented by the following formula (II): ##STR4## which is one of the compounds of formula (B) wherein the R is a hydrogen atom and the X is a sulfur atom, was highly absorbable through digestive tract and that the ester derivative was rapidly hydrolyzed in the body and thereby returned to the compound of formula (II). Consequently, the present inventors found that said ester derivative, as a pro-drug of the compound of formula (II), can be a clinically excellent antibiotic which can be administered orally.
Accordingly, the present invention provides (1R, !-1-methyl-carbapen-2-em-3-carboxylic acid ester derivatives represented by the following formula (I): ##STR5## wherein R.sup.1 is a hydrogen atom or a lower alkyl group; having 4 to 7 carbon atoms which may further be substituted by a lower alkyl group, or a cycloalkyl group having 4 to 7 carbon atoms which may be substituted by a lower alkyl group; and,
More specifically, the present invention provides the respective compounds of formula (I) wherein: carbon atoms which may further be substituted by an lower alkyl group; substituted by a lower alkyl group;
Most specifically, the present invention provides (1-methylcyclohexanecarboxy)methyl thyl!-1-methyl-carbapen-2-em-3-carboxylate represented by the following formula (I-a): ##STR6##
The compound of formula (I-a) is excellent both in physical stability and chemical stability, and is highly absorbable through digestive tract when administered orally. This compound is rapidly hydrolyzed in the body to turn to the active compound (II) to show a strong antibacterial activity. Therefore, its usefulness is superior to that of other carbapenem antibiotics proposed so far.
The present invention is described in more detail in the following.
The term "lower", used throughout the present specification and claims to qualify a group or a compound, means that the group or the compound so qualified has 1 to 7, preferably 1 to 4, carbon atoms.
The term "alkyl
REFERENCES:
Kawamoto, Chem. Abs 121: 179400, 1994.
Mihara, Chem Abs 126: 31219, 1996.
Abe Takao
Kumagai Toshio
Berch Mark L.
Lederle (Japan) Ltd.
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