Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-10
2001-01-16
Raymond, Richard 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
06174877
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel carbapenem compound having excellent antibacterial activities and oral absorbability or its esters or salts. The carbapenem compounds or their esters or salts of this invention can be used as an antibacterial agent.
BACKGROUND ART
There have been known a variety of carbapenem compounds, some of those compounds have been put on practical use and commercially available. For example, in JPA S60(1985)-233076, there is disclosed (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthio]-6-[((R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid, i.e. Meropenem.
And, in EP-A-289801, there is disclosed (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a]pyrazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate, i.e. Biapenem.
These compounds are regarded to improve the stability to renal dehydropeptitase (DHP-I) which is considered as a drawback of conventional carbapenem compounds, thus these compounds have now come to be administered singly without combination with an enzyme inhibitor.
On the other hand, on carbapenem substituted with 2-(N-containing aromatic heterocyclic ring) ethylthio group at 2-position, there are several reports.
For example, in AU-A-8319342, there is disclosed compounds represented by the formula
wherein R
1
stands for, e.g. H, R
8
stands for, e.g. H, R
15
stands for, e.g. H, R
2′
stands for a conventional carboxyl-protecting group which is readily removable, A stands for C
1-6
straight-chain or branched alkylene, and
stands for mono-, bi or polycyclic aromatic heterocyclic group, and the ring is linked with A through carbon atom constituting the ring, or their salts. As specific examples, however, only the following three compounds are disclosed,
and, these compounds are described only as intermediates for synthesizing a carbapenem compound having, at 2-position of the carbapenem skeleton, a monocyclic or polycyclic N-containing aromatic heterocyclic alkylthio group quaternarized by N-alkylation, but no use of these compounds as antibacterial agents is disclosed.
And, while, in EP-A-170073 and EP-A-242134, there are disclosed compounds having formulae:
having N-containing aromatic heterocyclic alkylthio group at 2-position of the carbapenem skeleton, these compounds are described only as synthetic intermediates, and no use as antibacterial agents is disclosed at all. And, no specific examples of carbapenem compounds, whose 2-position is substituted with 2-(non-quaternary nitrogen-containing aromatic heterocycle) ethylthio group, are disclosed.
And, in JPA S63(1988)-63680, a (1R)-1-methyl carbapenem compound of the formula:
having, at 2-position of the carbapenem skeleton, aromatic ring alkylthio group, or alicyclic or aromatic heterocyclic alkylthio group is described. However, as specific example of the compound having, at its 2-position, an aromatic heterocyclic alkylthio group, disclosed in the above-mentioned official gazette, only a carbapenem compound having 2-(1H-imidazol-1-yl)ethylthio group is given, and the ethylthio group of this compound has the linkage through nitrogen atom on the aromatic heterocyclic ring.
Further, in AU 9336488, a (1R)-1-methyl carbapenem compounds of the formula:
wherein R is hydrogen, anion charge or an ester residue, and
wherein X, Y is the same or different, N or —CH═, one of the portion of dotted line is a single bond and the other portion of dotted line is a double bond, is a bicyclic heterocyclic ring, is described. However, this reference does not show the compound having at 2-position of carbapenem skelton, a bicyclic heterocyclic ring-ethylthio group.
Carbapenem compounds now commercially available are poor in absorbability from digestive canal, which are used only as injectable preparations and are not put on practical use as orally administrable preparations.
Circumstances being such as above, clinically useful carbapenem compounds having, besides a broad antibacterial spectrum, strong antibacterial activities and stability to DHP-I, good oral absorbability have been ardently desired.
DISCLOSURE OF INVENTION
As a result of extensive studies diligently conducted, the present inventors synthesized, for the first time, a carbapenem represented by the formula:
wherein R
1
stands for an optionally substituted lower alkyl group, R
2
stands for H or a lower alkyl group, R
3
stands for H, an optionally substituted hydrocarbon group, cyano group, a lower alkyloxy group or a lower alkylthio group and ring A stands for an optionally substituted non-quaternarized N-containing aromatic heterocyclic ring, provided that when A is unsubstituted 2-pyridyl group, R
3
stands for a group other than H, or its ester or salt [sometimes abbreviated as Compound (I)], and found that this novel carbapenem compound, based on its specific chemical structure, shows unexpectedly excellent antibacterial activities against a broad range of pathogenic bacteria from gram-positive bacteria to gram-negative bacteria, and has clinically useful properties, for example, excellent oral absorbability. Based on these findings, the present invention has been accomplished.
More specifically, the present invention relates to
(1) Compound (I),
(2) a method of producing Compound (I), which comprises reacting a compound of the formula:
wherein L is a group capable of leaving, and other symbols are of the same meaning as defined above, or its ester or salt with a compound of the formula:
wherein symbols are of the same meaning as defined above, or its salt, or reacting a compound of the formula:
wherein symbols are of the same meaning as defined above, or its ester or salt with a compound represented by the formula:
wherein L′ stands for a group capable of leaving and other symbols are of the same meaning as defined above, and
(3) a medicinal agent containing Compound (I).
Compound (I) of this invention shows excellent antibacterial activities against a broad range of pathogenic bacteria from gram-positive to gram-negative bacteria, and shows antibacterial activity not only by subcutaneous injection but also by oral administration.
In the above-mentioned formulae, as lower alkyl group of the optionally substituted lower alkyl group shown by R
1
, use is made of C
1-4
alkyl groups. Examples of the substituents include cyano group, amino group, mono- or di- C
1-4
alkylamino group, hydroxyl group, C
1-4
alkyloxy group, carbamoyloxy group, C
1-4
alkylthio group, C
1-4
alkyl-sulfonyl group, halogen, sulfamoyl group, C
1-4
alkyloxy-carbonyl group and sulfoxy group. Number of these substituents ranges preferably from 1 to 3, and, when the number of these substituents is 2 or more, they may be the same as or different from one another.
In the case where the alkyl group is substituted with amino group or hydroxyl group, these substituents may optionally be protected with a readily removable protective group, preferably exemplified by a silyl group such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; and alkoxycarbonyl group such as allyloxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl.
More preferable examples of R
1
include groups representable by the formula:
wherein R
1′
stands for H, halogen, or, respectively optionally substituted hydroxyl group or amino group. As substituents of the hydroxyl group or amino group shown by R
1′
, use is made of, for example, removable protective groups mentioned as above. More preferable examples of R
1′
include hydroxyl group. Especially preferable examples of R
1
include (1R)-hydroxyethyl group.
As R
2
of the above-mentioned formula, use is made of H or a lower alkyl group. As the lower alkyl group, use is made of, for example, C
1-4
alkyl group, preferably methyl group.
As R
3
of the above-mentioned formula, use is made of H, an optionally substituted hydrocarbon group, cyano group, a lower alkyloxy group or a lower alkylthio group. As hydrocarbon group of the optionally substituted hydroc
Imamura Shinichi
Ishibashi Yukio
Miwa Tetsuo
Raymond Richard L.
Sripada Pananaram K
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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