Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1997-06-23
1999-03-09
Sham, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D40110, C07D40104
Patent
active
058802835
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid sesquihydrate with excellent stability and process for producing the same.
BACKGROUND TECHNOLOGY
Antibacterial agents of the quinolonecarboxylic acid class have achieved a striking progress in recent years. Because of broad antibacterial spectrum and potent bactericidal activity ranging from Gram-positive bacteria to negative bacteria, they have become to be used for surgical infectious diseases as well as urinary tract infectious disease and their usefulness is highly appreciated, leading to great contribution in the clinical practice.
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-o xo-3-quinolinecarboxylic acid is particularly noted because of not only its potent antibacterial activity but also higher selectivity against bacteria from mammalian cells, which brings on an excellent selective toxicity.
In Japanese Unexamined Patent Publication No. Sho 62-252772, hemihydrate of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid represented by a formula (2) is disclosed. ##STR2##
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-o xo-3-quinolinecarboxylic acid tends to make a hydrate because of its strong hygroscopicity, and it easily forms a hemihydrate when recrystallizing from water-containing organic solvent or when drying crystals obtained by the recrystallization method by neutralization according to acid-alkali recrystallization.
It was revealed by us, however, that the measured weight of this hemihydrate increases with the rise of environmental humidity. It was further revealed by us that the tablet containing the hemihydrate has poor disintegration and dissolution rates, leading to disadvantages in pharmaceutical manufacturing.
Moreover, in Japanese Unexamined Patent Publication No. Sho 63-198664, hydrochloride of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid represented by a formula (3) is disclosed. ##STR3##
However, with respect to this hydrochloride (3), too, the instability due to the hygroscopicity of drug substance same as or more than that of hemihydrate (2) and the problems of poor disintegration and dissolution rate when converted to tablets have become evident.
DISCLOSURE OF THE INVENTION
As a result of studies for the purpose of solving the problems of said 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid hemihydrate and hydrochloride, the inventors have found that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid sesquihydrate is a stable compound and excellent also in pharmaceutical manufacturing. Namely, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid sesquihydrate has been found to be stable under different conditions of humidity, and the disintegration and dissolution rates of the tablets manufactured have also found to be good.
In addition, as a means to obtain 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid sesquihydrate, we have found that the target compound can be obtained efficiently by heating an aqueous suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid under stirring, leading to the completion of the invention.
Here, the aqueous suspension represents a suspension after neutralization in the acid-alkali recrystallization during the process for purification, a suspension of isolated crystals added with water, or the like, and it is possible to manipulate with amount of water 3 to 20 times as much as crystals, but it is preferable to use 3 to 5 times for obtaining the target compound in high yield.
It is optimum to stir for 10 to 30 minutes at a temperature of, f
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Hara Masamoto
Kato Yukihiro
Matsumoto Toyomi
Miyashita Kunio
Kessinger Ann
Kyorin Pharmaceutical Co. Ltd.
Sham Mukund J.
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