Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-01
2001-04-10
Berch, Mark (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S224000, C540S225000, C546S274700, C546S275400, C546S276400, C546S279100, C546S280400, C546S328000, C546S341000
Reexamination Certificate
active
06214818
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel cephem compounds, a process for preparing the same, intermediates therefor, and pharmaceutical compositions containing the compounds.
BACKGROUND ART
Compounds having an optionally substituted pyridiniomethyl group at the 3-position of the cephem ring have been disclosed in patent applications such as Japanese Patent Publication (KOKAI) 60-237090 (WO 8505106, EP 160969A2), Japanese Patent Publication (KOKOKU) 1-44190 and also Japanese Patent Publication (KOKOKU) 6-70068 (EP 64740B1, U.S. Pat. No. 5,071,979), Japanese Patent Publication (KOKOKU) 2-44476 (EP 159011B1, U.S. Pat. No. 4,833,242), etc. However, there have not been reported compounds wherein a pyridinium ring is substituted with a heterocyclic group having a substituent of the formula —CONHCN or its analogues.
Although a huge number of antibiotics have been marketed so far, the development and characterization of compounds with higher antibiotic activity have been continuously demanded so as to cope with the appearance of multiple drug resistant bacteria and to provide for the diversification of therapy forms. In particular, it has been demanded to develop cephem compounds of broad spectrum which show a long blood half-life and have an excellent in vivo dynamics such as transfer to a tissue.
DISCLOSURE OF INVENTION
The present inventors have intensively studied with a purpose for developing novel cephem compounds with superior characteristics and found that cephem compounds wherein the cephem ring has a pyridiniomethyl group at the 3-position, and wherein the pyridinium ring is substituted with a heterocyclic group having a substituent -CONHCN or an analogue thereof have an excellent in vivo dynamics properties.
Thus, the present invention provides a cephem compound wherein the cephem ring has a substituent at the 3-position, which substituent is shown by the formula II:
wherein
Het is a mono- or polycyclic heterocyclic group comprising one or more hetero atoms selected from the group consisting of N, O and S which may be the same or different from each other; R
1
is hydrogen, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; A is an optionally substituted lower alkylene, an optionally substituted lower alkenylene or a single bond; B is an optionally substituted imino or a single bond; and D is a single bond or a group of the formula:
or a salt or a hydrate thereof. The above-mentioned cephem compounds, salts or hydrates may be hereinafter referred to as the compound of the present invention.
The compound of the present invention is preferably represented by the formula I:
wherein Acyl is an acyl, and Het, R
1
, A, B and D are as defined above, or an ester, a salt, or a hydrate thereof.
Acyl in the formula I is preferably a group of the formula III:
wherein X is CH or N; Y is an optionally protected amino; and Z is an optionally substituted hydrocarbon group.
Het in the formula I or II is preferably a 5- or 6-membered trivalent hetero cyclic group comprising one to four hetero atoms selected from the group consisting of N, O and S which may be the same or different from each other, and, more preferably, a pyrrolyl group of the formula IV:
Further, A in the formula I or II is preferably a single bond or a vinyl group; B is a single bond; and D is a single bond.
Example of preferable compounds of the formula I include those wherein Acyl is a group of the formula III:
(wherein X is CH or N, Y is an optionally protected amino and Z is hydrogen or an optionally substituted hydrocarbon group); Het is a 5- or 6-membered hetero cyclic group comprising one to four hetero atoms selected from the group consisting of N, O and S which may be the same or different from each other; A is a single bond or a vinyl group; B is a single bond; and D is a single bond, or an ester, a salt, or a hydrate thereof.
Terms herein used are defined below.
Throughout the present specification, the term “cephem compound” refers to a class of compounds having a double bond between the 3- and 4-positions of the cepham ring and named according to the nomenclature shown under the heading “cephem” in
The Journal of the American Chemical Society,
84, 3400 (1962). The present invention encompasses compounds of the formula I pharmaceutically acceptable esters, salts, or hydrates thereof (i.e., esters of Compound I, salts of Compound I, salts of an ester of Compound I, or hydrates thereof). The signal “
−
” in —COO
−
at the 4-position of a compound of the formula I indicates that a carboxylate anion forms an intramolecular salt by making a pair with the pyridinium cation on the substituent at the 3-position. When the carboxyl group is not ionized, the pyridinium cation can form a salt with an anion or a counter ion on a side-chain. The present invention encompasses all of these embodiments. The “S” at the 1-position of the cephem ring may be oxidized.
The term “mono- or polycyclic heterocyclic group” in the definition of “Het” includes the both aromatic and non-aromatic mono- or polycyclic heterocyclic groups, which is bound to the adjacent three groups. In the case of a monocyclic heterocyclic group, examples of a preferred aromatic heterocyclic group include 5- to 6-membered cyclic groups such as furan, thiophene, tetrazole, pyrrole, pyrazole, imidazole, oxazole, thiazole, pyridine, oxazine and triazine. Examples of a preferred non-aromatic heterocyclic group include 5- to 7-membered groups such as pyrrolidine, thiazolidine, oxazolidine, imidazolidine, thiazoline, oxazoline, imidazoline, piperidine, piperazine, morpholine, thiomorpholine, oxadiazoline, and dioxane. Among them, a monocyclic heterocyclic group comprising one or two hetero atoms selected from N and S is more preferable, and pyrrole is most preferred.
Preferred examples of polycyclic heterocyclic groups include those wherein benzene ring, pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring, or the like, is condensed to an above-mentioned monocyclic aromatic heterocyclic group, such as benzothiophene, indole, benzothiazole, benzofuran, and benzimidazole. Those wherein Het is bound to the 4-position of pyridinium ring are preferred.
The term “lower alkyl” in the definition of “R
1
” refers to a straight or branched C
1-6
alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. C
1-4
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like, are preferred. The lower alkyl group may be substituted by a substituent(s) selected from, for example, lower alkenyl group (e.g., C
2-6
alkenyl group such as vinyl, butenyl, propenyl, etc.); cycloalkyl group (e.g., C
3-7
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); aryl group (e.g., C
6-10
aryl group such as phenyl, naphthyl, etc., which aryl group may be further substituted by hydroxy, C
1-4
alkyl such as methyl or ethyl, or C
1-4
alkoxy such as methoxy or ethoxy); aromatic heterocyclic group (e.g., 5- or 6-membered aromatic heterocyclic group comprising 1 to 4 hetero atoms selected from N, O, S, and the like, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; bi- or tricyclic aromatic condensed heterocyclic group comprising 1 to 5 hetero atoms selected from N, O, S, and the like, which is formed by condensing one or two 5- or 6-membered aromatic heterocyclic groups comprising 1 to 4 hetero atoms selected from N, O, S, and the like or one or two benzene rings, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-inzdazolyl, bonzimidazolyl, benzoxazolyl,
Ishikura Koji
Nishitani Yasuhiro
Berch Mark
Foley & Lardner
Shionogi & Co. Ltd.
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