Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-15
2002-12-10
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S363000
Reexamination Certificate
active
06492373
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the method for preparing 6-fluoro-1,4-dihydro-7-[4-(2-hydroxyiminoethyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid derivatives, and the pharmaceutical composition comprising the derivatives as the active ingredient for the treatment of bacterial infections and/or renal cancer diseases.
2. Description of the Prior Art
It is known that a number of 6-fluoro-1,4-dihydroquinoline-3-carboxylic acid derivatives are highly potent broad-spectrum antibacteial agents [G. Y. Lesher et. al.,
J. Med. Chem.,
5, 259 (1962); D. Kaminsky et. al.,
J. Med. Chem.,
11, 160 (1968); J. Matsumoto et. al.,
J. Med. Chem.,
18, 74 (1975); H. Koga et. al.,
J. Med. Chem.,
23, 1358 (1980); J. Matsumoto et. al.,
J. Med. Chem.,
27, 292 (1984); I. Hayakawa et. al.,
Chem. Pharm. Bull.,
32, 4907 (1984); D. T. W. Chu et. al.,
Drug. Fut.,
10, 543 (1985); H. Kondo et. al.,
J. Med. Chem.,
29, 2020 (1986); D. T. W. Chu et. al.,
J. Med. Chem.,
29, 1531 (1986); K. Grohe et. al.,
Liebigs Ann. Chem.,
1, 29 (1987); J. M. Domagala et. al.,
J. Med. Chem.,
31, 991 (1988); H. Kondo et. al.,
J. Med. Chem.,
32, 671 (1989)]. These agents are shown to be specific inhibitors of the bacterial DNA gyrase, an enzyme which is responsible for negatively supercoiling covalently closed circular DNA and also in catenation and decatenation reactions. Compounds of this type, which have a piperazinyl radical in the 7-position, are described in the above publications, in U.S. Pat. Nos. 4,292,317, 4,528,287; R.O.C. Patent No. 047,572; and in the Japan Patent No. JP58069880, JP63083083 etc.
The inventors have found that the introduction into the above-mentioned compounds of a substituted iminoalkyl side chain [in particular 2-hydroxyimino-2-(4-methoxyphenyl)-ethyl] in the 4-position of piperazine, or a halogen atom (in particular a fluorine) in the 8-position, or both, gives new derivatives which possess potent antibacterial activity. These new derivatives are active at low concentrations against both Gram positive and Gram negative bacteria, including certain resistant strains, and thus are valuable agents for the treatment of infectious diseases. Due to their selective cytotoxicity, these compounds are also valuable agents for the treatment of renal cancer diseases. The present invention describes the preparation of 6-fluoro-1,4-dihydro-7-[4-(2-hydroxyiminoethyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid derivatives by an efficient means. The products described herein are suitable for large-scale production and exhibit very strong antibacterial activity. They have also exhibited strong activity against the growth of renal cancer cells.
SUMMARY OF THE INVENTION
In one aspect, the present invention features a method for preparing a compound of formula I comprising the steps of (a) reacting 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid with a haloketon in a basic environment to form an intermidiate of formula II; and (b) treating said intermediate of formula with an amine to form said compound of formula I:
In another aspect, the present invention features a method for treating bacterial infections in a mammal, comprising administrating to the mammal an effective amount of a compound of fomula I.
In still another aspect, the present invention features a method for treating cancer diseases, especially renal cancer in a mammal, comprising administrating to the mammal an effective amount of a compound of fomula I.
In yet another aspect, the present invention features a pharmaceutical composition, which comprises an effective amount of a compound of formula I and a pharmaceutically aceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, new compounds of formula I can be prepared by the following reaction scheme:
wherein:
R
1
is a (C
1
-C
4
) alkyl or a phenyl group optionally substituted with one or two group selected from the group consisting of halide, (C
1
-C
4
) alkyl, (C
1
-C
4
) alkoxy, phenyl, nitro and amino;
R
2
represents hydroxyl, (C
1
-C
4
) alkoxy, amino, (C
1
-C
4
) alkyl or benzyl;
R
3
represents H or halide; and
R
4
represents (C
1
-C
4
) alkyl or a phenyl group optionally substituted with one or two group selected from the group consisting of halide, nitro and amino.
According to the method of the present invention, a compound of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid is first reacted with a haloketon in a basic environment to form an intermidiate of formula II. Then the intermidiate of formula II is treated with an amine to form the compound of formula I.
In this method, the basic environment may be created by adding basic compounds to the solution, the basic compounds including, but not limited to, NaHCO
3
, Na
2
CO
3
, NaOH etc. The haloketons useful in the present invention include, but are not limited to, chloroacetone (R
1
=CH
3
), 2-bromoacetophenone (R
1
=C
6
H
5
), 2-bromo-4′-fluoroacetophenone (R
1
=C
6
H
4
F), 2-bromo-4′-chloroacetophenone (R
1
=C
6
H
4
Cl), 2-bromo-4′-bromoacetophenone (R
1
=C
6
H
4
Br), 2-bromo-4′-nitroacetophenone (R
1
=C
6
H
4
NO
2
), 2-bromo-4′-methoxyaceto-phenone (R
1
=C
6
H
4
OCH
3
). The haloketon described above may be dissolved in an organic solvent. Suitable organic solvents include, but are not limited to, for example N,N-dimethyl-formamide (DMF) or acetone. The reaction of the treatment with amine is well known by those skilled in the art.
According to the present invention, these active compounds, either as free type or their pharmaceutically acceptable salts, may be administered parentally or orally in a suitable pharmaceutical form. They also may be administered along or in conjunction with other antibacterial and/or anticancer agents, in combination with any pharmaceutically acceptable carrier.
As used herein, the pharmaceutically acceptable salts include salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate and phosphate; salts with organic acids, such as acetate, maleate, tartrate, methanesulfonate; and salts with amino acids, such as arginine, aspartic acid and glutamic acid. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, tablets, troches, pills, capsules and the like. In addition, the active compounds may be incorporated into sustained-release preparations and formulations. The pharmaceutically acceptable carrier includes any and all solvents, disintegrating agents, binders, excipients, lubricants, absorption delaying agents and the like. Although the compound of the present invention may also be present as a hydrate or as a stereoisomer, it is a matter of course that these hydrates and stereoisomers are also included in the scope of the present invention.
Without intending to limit it in any manner, the present invention will be further illustrated by the following examples.
REFERENCES:
patent: 4292317 (1981-09-01), Pesson
patent: 4528287 (1985-07-01), Itoh et al.
patent: 4547503 (1985-10-01), Petersen et al.
patent: 58069880 (1983-04-01), None
patent: 63083083 (1988-04-01), None
Foroumadi et al., Chemical Abstracts, vol. 128, No. 164860 (1998).*
Chu et al., “Synthesis and Biological Activity of Benzothiazole[3,2-a]quinolone Antibacterial Agents”, J. Med. Chem. 29:1531-1534, 1986.
Domagala et al., “1-Substituted 7-[3-[(Ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acids. New Quantitative Structure-Activity Relationships at N1for the Quinolone Antibacterials”, J. Med. Chem. 31:991-1001, 1988.
Hayakawa et al., “Synthesis and Antibacterial Activities of Substituted 7-Oxo-2.3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acids”, Chem. Pharm. Bull. 32:4907-4913, 1984.
Koga et al., “Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubs
Chen Yeh-Long
Ko Feng-Nien
Tzeng Cherng-Chyi
Bernhardt Emily
Fish & Richardson P.C.
Pharmaceutical Industry Technology and Development Center
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