Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-07
2001-06-05
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S227000, C544S346000
Reexamination Certificate
active
06242437
ABSTRACT:
This application is a 371 application of International Application No. PCT/JP97/04489 filed Dec. 8, 1997.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to cephem antibiotics useful as pharmaceuticals for human beings and animals.
2. Background Art
Cephem antibiotics possesses excellent antimicrobial activity and low toxicity in mammals and hence are medicaments which are very useful for treatment of infectious diseases of mammals.
The so-called onium salt type cephem antibiotics typified by cefozopran and cefpirome, which have aminothiazolyl (aminothiadiazolyl) acetyl at the 7-position and a quaternary salt substituent at the 3-position, are characterized by having potent antimicrobial activity and a wide spectrum of bacteria from Gram-positive bacteria to Pseudomonas aeruginosa. Therefore, numerous studies and developments in the antibiotics of this type have been made in many countries in the world.
However, even the onium-salt-type cephem compounds, such as cefozopuran and cefpirome, are not always satisfactory in terms of antimicrobial activity against Pseudomonas aeruginosa or Gram-positive bacteria such as Staphylococcus aureus which have brought about a clinical problem in recent years. In addition, infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA) or penicillin-resistant streptococcus pneumoniae (PRSP) have been a serious clinical problem these days. It is therefore strongly demanded to obtain novel onium salt type cephem antibiotics which have improved antimicrobial activity also against these bacteria (Chapter 11 by W. E. Wick, “Cephalosporins and Penicillins, Chemistry and Biology” edited by E. H. Flynn, Academic Press, New York, N.Y., 1972; 18.1 “Cephalosporins” by Hatsuo Aoki, “The Leading Studies in Antibiotics” edited by Masaji Ono and Satoshi Omura, Tokyo Kagaku Dojin Kabushiki Kaisha, Japan, 1987; and “Manifestation of Resistance and Molecular Genetics” by Ryoichi Okamoto and Matsuhisa Inoue, “
Sogo Rinsho”,
vol. 42, No. 2, 1993).
In recent years, cephem derivatives having both quaternary ammonium methyl at the 3-position of the cephem ring and 2-(2-aminothiazol-4-yl)- or 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxy(or substituted hydroxy)iminoacetamide group at the 7-position have been found to possess high antimicrobial activity and stability against &bgr;-lactamase, and numerous studies and developments on these cephem derivatives have been made in the art. Among others, cephem compounds having substituted or unsubstituted imidazo[5,1-b]thiazolium-6-yl at the 3-position of the cephem ring are described in WO 95/07912.
However, no compounds having sulfamidoalkyl or substituted sulfamidoalkyl on the imidazo[5,1-b]thiazole ring have been reported so far as the present inventors know.
SUMMARY OF THE INVENTION
The present inventors have now succeeded in synthesizing a novel cephem derivative having (substituted or unsubstituted sulfamido)alkylimidazo[5,1-b]thiazolium-6-yl at the 3-position. Furthermore, they have also found that this novel cephem derivative possesses potent antimicrobial activity against a wide spectrum of bacteria from Gram-positive bacteria to Gram-negative bacteria and, in addition, possesses high antimicrobial activity also against various &bgr;-lactamase-producing bacteria and significant antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococcus pneumoniae (PRSP), and imipenem-resistant Pseudomonas aeruginosa. The present invention has been made based on such finding.
Accordingly, an object of the present invention is to provide a novel onium salt type cephem antibiotic which possesses potent antimicrobial activity against a wide spectrum of bacteria from Gram-negative bacteria to Pseudomonas aeruginosa and improved antimicrobial activity against various resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant streptococcus pneumoniae (PRSP).
Thus, according to one aspect of the present invention, there is provided a cephem derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:
wherein
X represents CH or N;
R
1
represents a hydrogen atom,
C
1-6
alkyl in which one or more hydrogen atoms in the alkyl is optionally substituted by a halogen atom, a hydroxyl group, carboxyl, C
1-6
alkoxy-carbonyl, carbamoyl, N—C
1-6
alkylcarbamoyl, cyano, amino, or C
1-6
alkylamino,
C
2-6
alkenyl,
C
2-6
alkynyl, or
cycloalkyl;
any one of R
2
, R
3
, R
4
, and R
5
represents R
6
R
7
NSO
2
NH—C
1-6
alkyl where R
6
and R
7
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl, and
the other substituents of R
2
, R
3
, R
4
, and R
5
, which may be the same or different, each independently represents a hydrogen atom; C
1-6
alkoxy; C
1-6
alkylthio; cyano; carboxyl; C
1-6
alkoxy-carbonyl; carbamoyl; C
1-6
alkyl-carbamoyl; formyl; amino; formylamino; acetylamino; methanesulfonylamino; a halogen atom; C
1-6
alkyl (in which one or more hydrogen atoms in the alkyl is optionally substituted by a hydroxyl group, C
1-6
alkoxy, mercapto, C
1-6
alkylthio, cyano, a halogen atom, carboxyl, C
1-6
alkoxy-carbonyl, carbamoyl, N—C
1-6
alkyl-carbamoyl, formyl, acetyl, acetoxy, hydroxyimino, C
1-6
alkoxyimino, amino, formylamino, acetylamino, trifluoroacetylamino, carbamoyloxy, N—C
1-6
alkyl-carbamoyloxy, methanesulfonylamino, ureido, N—C
1-6
alkylureido, C
1-6
alkoxy-carbonylamino, or iminomethylamino); C
3-6
alkylene; C
3-6
cycloalkyl; C
2-6
alkenyl; or C
2-6
alkynyl,
or any two of R
2
, R
3
, R
4
, and R
5
may combine with each other to represent C
1-6
alkylene, thereby forming a ring, one or more methylene groups in the alkylene being optionally substituted by NH, O, or S, the ring optionally having oxo (═O) as a substituent; and
n is 0 or 1.
DETAILED DESCRIPTION OF THE INVENTION
Definition
As used herein, the term “C
1-6
alkyl” as a group or a part of a group means any straight-chain or branched C
1-6
alkyl, preferably C
1-4
alkyl. The term “halogen” means a fluorine, chlorine, bromine, or iodine atom.
Compounds
In the formula (I), X represents CH or N, preferably N, and n is 0 or 1, preferably 0.
R
1
represents a hydrogen atom, C
1-6
alkyl, C
2-6
alkenyl (for example, 2-propenyl), C
2-6
alkynyl, or cycloalkyl (preferably C
3-7
cycloalkyl, for example, cyclopentyl).
One or more hydrogen atoms in the alkyl represented by R
1
is optionally substituted by a halogen atom, a hydroxyl group, carboxyl, C
1-6
alkoxy-carbonyl, carbamoyl, N—C
1-6
alkylcarbamoyl, cyano, amino, or C
1-6
alkylamino. A fluorine atom is preferred as the substituent. Substituted or unsubstituted alkyls represented by R
1
include methyl, ethyl, propyl, 1-methylethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, cyanomethyl, (S)-1-carboxyethyl, carbamoylmethyl, and 1-carboxy-1-methylethyl.
According to a preferred embodiment of the present invention, R
1
preferably represents optionally substituted C
1-6
alkyl.
In the formula (I), any one of R
2
, R
3
, R
4
, and R
5
represents R
6
R
7
NSO
2
NH—C
1-6
alkyl wherein R
6
and R
7
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl. Examples of R
6
R
7
NSO
2
NH—C
1-6
alkyls include sulfamido C
1-6
alkyls (for example, sulfamidomethyl, sulfamidoethyl, (R)-1-(sulfamido)ethyl, and (S)-1-(sulfamido)ethyl), N—C
1-6
alkyl sulfamido C
1-6
alkyls (for example, (N-methylsulfamido)methyl), N′—C
1-6
alkyl sulfamido C
1-6
alkyls (for example, (N′-methylsulfamido)methyl), and N′,N′-di-C
1-6
alkyl sulfamido C
1-6
alkyls (for example, (N′,N′-dimethylsulfamido)methyl), and preferred examples thereof include sulfamido C
1-6
alkyl, N—C
1-6
alkyl sulfamido C
1-6
alkyls, N′,N′-di-C
1-6
alkylsulfamido C
1-6
alkyl.
The other substituents of R
2
, R
3
, R
4
, and R
5
, which do not represent R
6
R
7
NSO
2
NH—C
1-6
alkyl, may be the same or different and each i
Atsumi Kunio
Ida Takashi
Kobayashi Kazuko
Umemura Eijirou
Berch Mark L.
Meiji Seika Kaisha Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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