Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-31
2002-06-25
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
Reexamination Certificate
active
06410525
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel carbapenem compound useful as an agent for the prophylaxis and treatment of bacterial infectious diseases. More particularly, the present invention relates to a novel carbapenem compound having sufficient antibacterial property and permitting oral absorption, an oral antibacterial agent containing this compound as an active ingredient and an intermediate compound for the production of the carbapenem compound.
BACKGROUND ART
A number of compounds having a carbapenem skeleton have been heretofore found to be a therapeutic agent for infectious diseases, and some of which have been put to practical use for the superior antibacterial activity they possess or have been developed for practical application. For example, a carbapenem compound of the formula (A)
has already been put to practical use in clinical situations. This carbapenem compound has a broad antibacterial spectrum and a strong antibacterial activity, and has overcome instability of the conventional carbapenem compound to renal dehydropeptidase, which was considered a defect of this compound. It has superior characteristic feature in that it can be administered alone without using a stabilizer.
On the other hand, this carbapenem compound shows poor absorption from the digestive tract and is now administered as an injection in clinical use. An oral agent is easily and conveniently administered and is clinically extremely useful as compared to injections. Therefore, there is a strong demand for the development of carbapenem compound for oral administration, that has a strong antibacterial activity and a broad antibacterial spectrum, and that shows superior absorption from the digestive tract.
DISCLOSURE OF THE INVENTION
It is therefore an object of the present invention to provide a carbapenem compound having a superior antibacterial property and showing superior absorption from the digestive tract. Another object of the present invention is to provide use of the carbapenem compound. A yet another object of the present invention is to provide an intermediate suitable for the production of the carbapenem compound.
The present inventor has conducted intensive studies in an attempt to achieve the above-mentioned objects and found that a novel carbapenem compound of the following formula (I) shows superior absorption from the digestive tract, that the compound has sufficiently strong antibacterial property and is extremely useful as an oral antibacterial agent. He has also found a novel intermediate compound usable for the production of this compound, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following (1) to (10).
(1) A carbapenem compound of the formula (I)
wherein R
1
is a modifier hydrolyzable in the living body, R
2
and R
3
are the same or different and each is a lower alkyl and R is a group of the formula (B)
or formula (C)
wherein R
4
and R
5
are the same or different and each is a hydrogen atom or a lower alkyl and R
6
is an alkyl having 1 to 10 carbon atoms.
(2) The carbapenem compound of (1) above, wherein R
2
and R3 are the same or different and each is a lower ally.
(3) The carbapenem compound of (1) above, wherein R
1
is pivaloyloxymethyl.
(4) The carbapenem compound of (1) above, wherein R
1
is 1-cyclohexyloxycarbonyloxyethyl.
(5) The carbapenem compound of (1) above, wherein R
1
is 1-ethoxycarbonyloxyethyl.
(6) The carbapenem compound of (1) above, which is a member selected from the group consisting of:
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
1-cyclohexyloxycarbonyloxyethyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2em-3carboxylate,
1-ethoxycarbonyloxyethyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-acetyloxymethyloxycarbonyl)pyrrolidin-3-ylthio[-6-(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2em-3carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-[hydroxyethyl]-1-methylcarbapen-2-em-3carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-isovaleryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-1-methylcarbapen-2em-3 carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-tert-butylacetyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
1-cyclohexyloxycarbonyloxyethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2em-3-carboxylate, and
1-ethoxycarbonyloxyethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2em-3-carboxylate.
(7) An antibacterial agent comprising the carbapenem compound of (1) above of the formula (I) as an active ingredient.
(8) The antibacterial agent of (7), which is for oral administration.
(9) A carbapenem compound of the formula (II)
wherein R
2
and R
3
are the same or different and each is a lower alkyl, R
7
is a hydrogen atom or a protecting group of carboxyl group and R is a group of the formula (B)
or formula (C)
wherein R
4
and R
5
are the same or different and each is a hydrogen atom or a lower alkyl and R
6
is an alkyl having 1 to 10 carbon atoms, or a salt thereof.
(10) The carbapenem compound of (9) above, which is a member selected from the group consisting of:
p-nitrobenzyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}-6-[(1R-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
(1R,5S,6S)-2{-(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
p-nitrobenzyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
p-nitrobenzyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
(1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid, and
(1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
or a salt thereof, particularly a sodium salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The definitions used in the present specification are explained in the following.
The “modifier hydrolyzable in the living body” at R
1
is preferably hydrolyzable in intestine or bloo
Berch Mark L.
Kyoto Pharmaceutical Industries, Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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