Carbapenem compounds, use thereof, and intermediate...

Details Carbapenem compounds, use thereof, and intermediate... Carbapenem compounds, use thereof, and intermediate...

1999-08-04

2002-01-29

Berch, Mark L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S350000

Reexamination Certificate

active

06342494

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel carbapenem compound and a pharmaceutically acceptable salt thereof, which are useful as agents for the prophylaxis and treatment of bacterial infectious diseases. More particularly, the present invention relates to a novel carbapenem compound and a pharmaceutically acceptable salt thereof, which have sufficient antibacterial activity and which permit oral absorption; an oral antibacterial agent containing said compound as an active ingredient; and an intermediate compound for the production of said carbapenem compound and a salt thereof.
BACKGROUND ART
Many compounds having a carbapenem skeleton have been found as agents for treating infectious diseases, from which some carbapenem compounds having superior antibacterial activity have been put to practical use or under development for practical application. For example, a carbapenem compound of the formula (A)
has been put to practical use and used in the clinical situations. This carbapenem compound has a broad antibacterial spectrum and potent antibacterial activity, and is free of instability to renal dehydropeptidase, which has been considered to be a drawback of conventional carbapenem compounds. It is a superior characteristic of this compound that it can be administered solely without using a stabilizer.
However, these carbapenem compounds show poor absorption from the digestive tract, which limits their clinical administration route to injection alone. An oral agent is easy and convenient to administer as compared to injections, and highly utilizable in clinical situations. Thus, there is a need for the development of a carbapenem compound for oral administration, which has potent antibacterial activity and broad antibacterial spectrum, and which shows superior absorption from the digestive tract.
It is therefore an object of the present invention to provide a carbapenem compound which has superior antibacterial activity and which shows superior absorption from the digestive tract.
Another object of the present invention is to provide use of said carbapenem compound.
A yet further object of the present invention is to provide an intermediate suitable for the production of said carbapenem compound.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects, and found that a novel carbapenem compound of the following formula (I) and a pharmaceutically acceptable salt thereof show superior absorption from the digestive tract, have sufficiently potent antibacterial activity and are extremely useful as oral antibacterial agents. Further, the present inventors have found a novel intermediate compound usable for the production of said compound, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) A carbapenem compound (I) of the formula (I)
wherein
R
1
and R
2
may be the same or different and each is a modifying group hydrolyzable in the body;
R
3
and R
4
may be the same or different and each is a lower alkyl; or
R
3
and R
4
form a cyclic amino together with the adjacent nitrogen atom, and a pharmaceutically acceptable salt thereof.
(2) The carbapenem compound of (1) above, wherein R
1
and R
2
may be the same or different and each is a modifying group hydrolyzable in the body, and R
3
and R
4
may be the same or different and each is a lower alkyl, and a pharmaceutically acceptable salt thereof.
(3) The carbapenem compound of (1) above, wherein R
2
is 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl and R
3
and R
4
are each methyl, and a pharmaceutical acceptable salt thereof.
(4) The carbapenem compound of (1) above, wherein R
1
is pivaloyloxymethyl and R
2
is 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, and a pharmaceutically acceptable salt thereof.
(5) The carbapenem compound of (1) above, wherein R
1
and R
2
are each pivaloyloxymethyl, and a pharmaceutically acceptable salt thereof.
(6) The carbapenem compound of (1) above, which is 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)methyl]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-pivaloyloxymethyl)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-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate hydrochloride,
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-diethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio }-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-N,N-methylethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio }-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-(1-pyrrolidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-(1-piperidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate, and
pivaloyloxymethyl (1R,5S,6S)-2-{(3S,5S)-[5-(1-azetidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate, and a pharmaceutically acceptable salt thereof.
(7) An antibacterial agent comprising the carbapenem compound of (1) above, which is represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(8) The antibacterial agent of (7) above, which is for oral administration.
(9) A carbapenem compound of the formula (II)
wherein
R
2
is a modifying group hydrolyzable in the body;
R
3
and R
4
may be the same or different and each is a lower alkyl; or
R
3
and R
4
form a cyclic amino together with the adjacent nitrogen atom; and
R
5
is a hydrogen atom or a carboxyl-protecting group, and a salt thereof.
(10) The carbapenem compound of (9) above, which is 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)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate and
sodium (1R,5S,6S)-2-{(3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl]pyrrolidin-3-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate,
and a salt thereof.
The modifying group hydrolyzable in the body at R
1
and R
2
is preferably hydrolyzed in intestine or blood, and is exemplified by optionally substituted aryl (e.g., phenyl, tolyl, xylyl, indanyl and the like), 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, phthalidyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl and the like. Particularly, 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl and 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl are preferable.
The optionally substituted aryl is preferably non-substituted or substituted by 1 to 3 substituents which may be the same or different. Examples of the substituent include alkyl having 1 to 4 carbon atoms such as methyl, ethyl and the like.
The number of the carbon atoms of the alkanoyl moiety of 1-alkanoyloxyalkyl is preferably 2 to 10, more preferably 2 to 7, and it may be linear, branched or cyclic. The number of the carbon atom of the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.
Examples of 1-alkanoyloxyalkyl include acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, p

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