Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-26
1996-01-16
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544363, A61K 31495, C07D40110
Patent
active
054847850
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a 371 of PCT/KR93/00006 filed Jan. 21, 1993.
The present invention relates to novel organic acid addition salts of a quinolone-carboxylic acid and a process for preparing the same. More particularly, the present invention concerns 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car boxylic acid 5-oxotetrahydrofuran-2-carboxylate or 2-hydroxyglutarate, which is highly soluble in water giving an injectable solution, its preparation, and use in treating infectious diseases caused by bacteria.
BACKGROUND ART
The following quinolone-carboxylic acid of the formula: ##STR2## is known in the art as having potent antibacterial activities. This compound, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car boxylic acid, generally called "Ciprofloxacin" (hereinafter, referred to as "Ciprofloxacin") has been widely used for the treatment of infectious diseases in mammal caused by bacteria. See, P. B. Fernandes ed., International Symposium on Quinolones, pp. 1-134, J. R. Porous, S. A., Barcelona, Spain (1989).
Although Ciprofloxacin is very active in treating bacterial disease, the compound has certain disadvantages in that it is almost insoluble or sparingly soluble in water. This property bars the compound from formulating it into injectable solutions.
Aiming at overcoming these disadvantages, various acid and base addition salts of Ciprofloxacin have been developed, which can easily dissolve in water to a desired extent and do not cause occurrence of precipitation in the resulting solution during storage. For example, U.S. Pat. No. 4,705,789 to Grohe et al. discloses that hydrochloride, methanesulfonate, acetate, propionate, succinate and lactate of Ciprofloxacin are suitable to prepare highly stable injectables. These salts, however, cause some problems from the pharmaceutical point of view. That is, Ciprofloxacin hydrochloride is unstable in solution; methanesulfonate exhibits a very low value of pH; and acetate and propionate smell unpleasant. Ciprofloxacin lactate tends to occur precipitation in an injection when it is contained in the injection in an excessive amount.
European Patent Publication No. 0 067 666 A1 suggests to use galacturonic acid, aspartic acid, glutamic acid and gluconic acid as an acid for forming salts with Norfloxacin or Enoxacin which do not cause such precipitation in solution. The salts formed by adding these acids are proven to be pharmaceutically valuable.
German Patent Application Nos. P35 00 243.3 and P35 17 709.8 disclose sodium hydroxide, potassium hydroxide, ethanolamine, lysine, N-methyl glucamine and arginine as the bases which can form non-precipitating salts with Ciprofloxacin. However, an aqueous solution of each salt derived from those bases is not suitable to be administered parenterally owing to its high pH value.
DISCLOSURE OF THE INVENTION
According to the present invention, it has been surprisingly discovered that the solubility of Ciprofloxacin in water can be significantly enhanced by reacting it with certain organic acids, that is, 5-oxotetrahydrofuran-2-carboxylic acid or 2-hydroxyglutaric acid to give a novel salt thereof.
It is therefore an object of the invention to provide a novel salt of Ciprofloxacin which can easily dissolve in water resulting in highly stable injections without causing precipitation, even after a long-term period of storage.
It is another object of the invention to provide a process for preparing novel salts of Ciprofloxacin.
It is still another object of the invention to provide a pharmaceutical composition comprising the novel salt of the invention as an active ingredient.
It is still further object of the invention to provide a method for treating bacterial diseases by the novel salt of the invention.
Any additional objects of the invention will become apparent through reading the remainder of the specification.
According to the present invention, a novel compound is provided which is represented by the formula: ##STR3## wherein, Z is 5-oxotetrahydrofur
REFERENCES:
patent: 4705789 (1987-11-01), Grohe et al.
patent: 4772605 (1988-09-01), Naik et al.
patent: 4957922 (1990-09-01), Lammens et al.
Choi Kyung E.
Kim Dal H.
Kim Je H.
Lee Ki H.
Yeon Kyu J.
Bernhardt Emily
Cheil Foods & Chemicals Inc.
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