Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-20
2001-09-25
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S205000, C540S224000, C540S225000, C540S226000, C540S227000
Reexamination Certificate
active
06294527
ABSTRACT:
BACKGROUND OF THE INVENTION
TECHNICAL FIELD
1. Field of the Invention
The present invention relates to cephem derivatives or pharmaceutically acceptable salts thereof useful as antibacterial agents and represented by the formula I:
wherein
represents benzene ring, pyridine ring, pyrazine ring or 5-membered aromatic heterocycle (having one oxygen or sulfur atom as ring-constituting atom);
X and Y respectively represent hydrogen atom or CXY represents C═N—OR
5
wherein R
5
represents hydrogen atom, halo C
1
-C
6
alkyl or C
3
-C
7
cycloalkyl;
R
1
represents phenyl, furyl, thienyl, thiazolyl (which may be substituted with amino group), tetrazolyl or thiadiazolyl,
R
2
, R
3
and R
4
respectively represent hydrogen atom, halogen, hydroxyl group, nitro, C
1
-C
6
alkoxy, trifluoromethyl, isothiuronium C
1
-C
6
alkyl, amino C
1
-C
6
alkyl, halo C
1
-C
6
alkyl, morpholino, piperidino or piperazinyl, there being no R
4
where
represents 5-membered aromatic heterocycle; or synthetic intermediates of the compounds of the formula I and represented by the formula II
wherein Z represents a protective group for a carboxyl group and
R
2
, R
3
and R
4
are as defined above.
2. Description of the Background
In recent years, hardly-curable infections due to pathogenic bacteria having resistance against antibiotics such as methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococci (VRE) have caused serious problems. Vancomycin, which was the only agent against which no resistant bacteria had been found, was frequently used as medicine against MRSA; however, recently, vancomycin-resistant
Staphylococcus aureus
(MU3) was found.
Among the above-mentioned resistant bacteria, MRSA are typical as hospital infecting bacteria and there are MRSA-carriers in healthy humans. Usually, these healthy MRSA-carriers are not sick with MRSA; however, they may tend to become sick with MRSA when they have come into compromised hosts with reduced vital resistance due to operations or other diseases. Once they become sick, a remedy for their sickness is difficult to effect. Nowadays, arbekacin, which is an aminoglycoside, and vancomycin, which is a glycopeptide, are used for such diseases. However, already, there are resistant bacteria against arbekacin; and resistant bacteria such as the above-mentioned MU3 have been found also as to vancomycin only against which there were no resistant bacteria. Such vancomycin-resistant MRSA are found all over Japan so that there is a fear that, in near feature, MRSA infectious diseses will increase which cannot be treated with vancomycin.
Although VRE provide world-shaking issues, though they have not been found in Japan yet. VRE are bacteria which have resistance against various antibacaterial agents just as MRSA and which derive from enterococci (
E. faecalis
and
E. faecium
) against which in turn only vancomycin was effective and which have gained high resistance against vancomycin, too. It is highly feared that, in the future, VRE will appear in Japan or prevail as imported infections. However, no effective medicines are present now and have been developed yet.
Coming of such medical crisis is readily predicted and urgent development of medicines effective for the resistant bacteria is desired to avert such crisis.
Cephem-type antibiotics have been proposed as new antibiotics effective for MRSA. More specifically, cephem derivatives having cyclic ammoniothiovinyl group at the 3-position have been proposed (Japanese Patent Provisional publication (Kokai) Nos. 6-206886 and 7-304779). These compounds are defective both in terms of antibacterial force and toxicity, perhaps, due to the cyclic ammoniothiovinyl group, thus failing to provide new medicines.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present, the inventors, who made devoted researches to pursue cephem derivatives effective for MRSA and VRE and not having the above-mentioned defective ammonio group in structure, have discovered cephem derivatives of the formula I having at the 3-position thiopyranylthiovinyl group with condensed aromatic ring and having excellent antibacterial activities against MRSA and vancomycin-resistant
E. faecalis,
thus accomplishing the present invention.
Conventionally known 3-thiovinyl cephem derivatives having antibacterial activities are, for example, compounds disclosed in the above-mentioned Publications as well as in Japanese Patent Provisional Publication (Kokai) No. 62-17592 and Japanese Patent Publication (Kokoku) No. 6-39475. There is no disclosure in the publications on compounds having at the 3-position thiopyranylthiovinyl group with condensed aromatic ring, nor disclosed is the fact that they are effective for MRSA and vancomycin-resistant
E. faecalis.
The compounds and synthetic intermediates of the present invention are respectively represented by the formulae I and II. The terms used for definition of letters in these formulae will be defined and exemplified in the following.
The term “C
1
-C
6
” refers to a group having 1 to 6 carbon atoms.
The term “C
3
-C
7
” refers to a group having 3 to 7 carbon atoms.
The “C
1
-C
6
alkyl group” refers to a straight- or branched-chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl.
The “C
3
-C
7
cycloalkyl group” refers to cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopeptyl.
The “C
1
-C
6
alkoxy group” refers to a straight- or branched-chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy or n-hexyloxy.
The “isothiuronium C
1
-C
6
alkyl group” refers to the above-mentioned “C
1
-C
6
alkyl group” with isothiuronium group coupled to any of the carbon atoms.
The “amino C
1
-C
6
alkyl group” refers to the above-mentioned “C
1
-C
6
alkyl group” with amino group coupled to any of the carbon atoms.
The “halo C
1
-C
6
alkyl group” refers to the above-mentioned “C
1
-C
6
alkyl group” with halogen atom connected to any of the carbon atoms.
The “halogen atom” may be fluorine, chlorine, bromine or iodine atom.
The “5-membered aromatic heterocycle” may be aromatic 5-membered heterocycle having one oxygen or sulfur atom as ring-constituting atom other than carbon atoms such as furan or thiophene.
When
is 5-membered aromatic heterocycle, the thiopyranyl group with condensed ring may be a group with any of the following structures.
wherein R
2
and R
3
are as defined above.
The “protective group for the carboxyl group” may be a group which may be ordinarily utilized in the art and which may be readily removed. For example, it may be tri C
1
-C
6
alkylsilyl such as trimethylsilyl, benzhydryl, p-methoxybenzyl, tert-butyl, p-nitrobenzyl.
The compounds according to the present invention may be as follows, though the present invention is not limited to these compounds.
7-[2-(2-Thienyl)acetamido]-3-[2-(4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-(2-Thienyl)acetamido]-3-[2-(7-fluoro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-Cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(7-fluoro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-Fluoromethyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(7-fluoro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-(2-Thienyl)acetamido]-3-[2-(7-chloro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-Hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(7-chloro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-Cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(7-chloro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid
7-[2-Fluoromethyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(7-chloro-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic
Hanaki Hideaki
Hiramatsu Keiichi
Kawashima Seiichiro
Sato Hideki
Tsuchida Yoshio
Berch Mark L.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Zenyaku Kogyo Kabushiki Kaisha
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