Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-26
2000-05-16
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514206, 540222, 540226, 540227, A61K 31546, C07D50124
Patent
active
060637781
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel cephalosporin derivatives of the formula(I) and pharmaceutically acceptable non-toxic salts thereof; and more particularly, to processes for preparing these compounds and to pharmaceutical compositions containing the same as active ingredients, which have broad antibacterial activities against both Gram-positive and Gram-negative bacteria.
SUMMARY OF THE INVENTION
An object of the present invention is to provide the novel cephalosporin derivatives of the formula(I) and pharmaceutically acceptable non-toxic salts thereof. ##STR2## wherein R.sub.1a is a hydrogen atom or an amino protecting group; R.sub.1b is a hydrogen atom, C.sub.1-4 alkyl group, C.sub.2-4 alkenyl group, C.sub.2-4 alkynyl group, fluoro-substituted C.sub.1-3 alkyl group or a substituted or unsubstituted carboxyalkyl group (preferably methyl group, ethyl group, allyl group, propargyl group, fluoromethyl group, 2-fluoroethyl group, --C(CH.sub.3).sub.2 COOH group, --CH.sub.2 COOH group); group selected from C.sub.1-3 alkyl group, C.sub.2-4 alkenyl group, C.sub.2-4 alkynyl group and hydroxyl-substituted C.sub.1-3 alkyl group; and ##STR3## wherein R.sub.5 is a hydrogen atom, C.sub.1-3 alkyl group or a hydroxyl-substituted C.sub.1-3 alkyl group; or an amino group; alkyl group;
DETAILED DESCRIPTION OF THE INVENTION
The cephalosporin compounds of the formula(I) can be prepared by the displacement reaction of the compounds of the formula(III) with the compounds of the formula(IV).
The compounds of the formula(III) can be prepared in accordance with known methods(J. of. Antibiotics., 43, 5, 533, 1990. European Patent No. 0333154). ##STR4## wherein R.sub.1a, R.sub.1b, R.sub.2, R.sub.3, R.sub.4 and Q are the same as defined above;
Also, the cephalosporin compounds of the formula(I) can be prepared by the acylation reaction of the compounds of the formula(VIII) with the activated form of the compounds of the formula(IX).
The compounds of the formula(IX) can be prepared in accordance with known methods (J. of. Antibiotics., 36, 8, 1020, 1983. J. of. Antibiotics., 45, 5, 709, 1992). ##STR5## wherein R.sub.1a, R.sub.1b, R.sub.2, R.sub.3, R.sub.4 R.sub.8, Q and L are the same as defined above; benzaldehyde group; and
Specific examples of the compounds of formula(I) provided by this invention are shown below:
7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-3-[(4- methylthiazol-5-yl)-methyldimethylammonio]-1-propen-1-yl]3-cephem-4-carboxy late or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-3-[(1- carbamoyl-1-propen-3-yl)-3-ethylmethylammonio]-1-propen-1-yl]3-cephem-4-car boxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-fluoroethoxyiminoacetamido]-3-[(E)-3 -[(4-methylthiazol-5-yl)-methyldimethylammonio]-1-propen-1-yl]3-cephem-4-ca rboxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-fluoroethoxyiminoacetamido]-3-[(E)-3 -[(1-carbamoyl-1-propen-3-yl)-3-ethylmethylammonio]-1-propen-1-yl]3-cephem- 4-carboxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[ (E)-3-[(1-carbamoyl-1-propen-3-yl)-3-ethylmethylammonio]-1-propen-1-yl]3-ce phem-4-carboxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(5-amnino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- [(E)-3-[(4-methylthiazol-5-yl)-methyldimethylammonio]-1-propen-1-yl]3-cephe m-4-carboxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoroethoxyiminoacetamido ]-3-[(E)-3-[(4-methylthiazol-5-yl)-methyldimethylammonio]-1-propen-1-yl]3-c ephem-4-carboxylate or pharmaceutically acceptable non-toxic salts thereof.
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoroethoxyiminoacetamido ]-3-[(E)-3-[(1-carbamoyl-1-propen-3-yl)-3-ethylmethylammonio]-1-propen-1-yl ]3-cephem-4-ca
REFERENCES:
patent: 3658649 (1972-04-01), Arnold et al.
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I. Csendes, B.W. Muller and W. Tosch, "The Journal of Antibiotics" vol. 36, p. 1020 Cephalosporin Antibiotics. Synthesis and Antimicrobial activity of 7.beta.-[2-(5-Amino-1,2,4-Thiadiazol-3-YL)-2-Oxyiminoacetamido]Cephalospor in Derivatives (Aug. 1983).
Hajime Kamachi, Masahisa Oka, Yukio Narita, Seiji Iimura, Shimpei Aburaki, Haruhiro Yamashita, Kozo Tomatsu, Jun Okumura and Takayuki Naito, "The Journal of Antibiotics" vol. 43, p. 533 Synthesis of a New Series of Cephalosporins Having 3-Substituted-Ammonio-1-Propenyl Group as the C-3 Side Chain May 1990.
Akio Miyake, Yoshinobu Yoshimura, Masayoshi Yamaoka, Tatsuo Nishimura, Naoto Hashimoto and Akira Imada, "The Journal Of Antibiotics" 45, p. 709 Studies on Condensed-Heterocyclic Azolium Cephalosporins, IV. Synthesis and Antibacterial Activity of 7.beta.-[2-(5-Amino-1,2,4-Thiadiazol-3-YL)-Alkoxyiminoacetamido]-3-(Conden sed-Heterocyclic Azolium)Methyl Cephalosporins Including SCE-2787.
Jang Moo-Soo
Kang Jae-Hoon
Kim Kee-Won
Yu Dong-Sik
Yu Seung-Woo
Berch Mark L.
Il-Dong Pharm. Co., Ltd.
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