Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-07-21
1997-01-28
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
A61K 3147, C07D215233, C07D21538
Patent
active
055979238
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 93/00109, filed 29 Jan. 1993.
TECHNICAL FIELD
This invention relates to 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid dihydrate that is useful as an antimicrobial agent and which has satisfactory stability.
BACKGROUND ART
The official gazette of Japanese Patent Public Disclosure (KOKAI) No. Hei 3-95177 discloses 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid (hereunder designated "Q-35"). The official gazette further teaches that Q-35 is the product of recrystallization from acetonitrile and that it has satisfactory antimicrobial activity.
However, as continued research was undertaken to commercialize it as a medicine, the Q-35 recrystallized from acetonitrile turned out to have only low stability due to the drawback that its weight would increase with increasing humidity. Under the circumstances, it was impossible to administer the Q-35 in well-defined doses and this, combined with other problems of the Q-35 made it difficult to develop said compound as a medicine. Hence, there was the need to develop a technique by which stable Q-35 could be produced even under humid conditions.
DISCLOSURE OF INVENTION
The present inventors conducted intensive studies with a view to eliminating the above-described drawback of Q-35 recrystallized from acetonitrile. As a result, they found that Q-35 had four crystal forms, a crystal with a variable water content (which is hereunder referred to as "crystal III" or "type III crystal"), a monohydrate crystal (which is hereunder referred to as "crystal II" or "type II crystal"), a dihydrate crystal (which is hereunder referred to as "crystal I" or "type I crystal"), and an anhydride crystal, and that the specific type of crystal to be produced is determined by the type of solvent used for recrystallization. As a result of closer studies conducted on the physical properties of the respective crystal forms, the inventors found the following: the Q-35 recrystallized from acetonitrile was a type III crystal; type I crystal, namely, the dihydrate of Q-35, was the most stable under humid conditions and, although it turned to an anhydride under drying or heating conditions, it reverted to the dihydrate when left to stand. The present invention has been accomplished on the basis of this finding. Stated briefly, the invention relates to a 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid dihydrate having the following formula: ##STR2##
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows the weight change of type I crystal of Q-35 when it was stored under atmospheric conditions after heating;
FIG. 2 shows the weight change of type I crystal of Q-35 when it was first stored under dried conditions at room temperature, then stored under atmospheric conditions;
FIG. 3 shows the weight change of dehydrated type I crystal of Q-35 when it was stored under dried conditions (6% R.H.) at room temperature;
FIG. 4 shows TG and DTA curves obtained when type I crystal of Q-35 was heated from room temperature up to 170.degree. C. at a rate of 3.degree. C./min;
FIG. 5 shows a DSC curve obtained when type I crystal of Q-35 was heated from room temperature up to 170.degree. C. at a rate of 3.degree. C./min;
FIG. 6 shows infrared absorption spectra for type I crystal of Q-35 in both the initial and heated states;
FIG. 7 shows infrared absorption spectra for type I crystal of Q-35 both in the heated state and after cooling in an anhydrous atmosphere followed by storage at room temperature;
FIG. 8 shows infrared absorption spectra for type I crystal of Q-35 both in the initial state and after heating followed by storage under atmospheric conditions;
FIG. 9 shows infrared absorption spectra for type I crystal of Q-35 both in the heated state and after storage in an anhydrous atmosphere at room temperature;
FIG. 10 shows infrared absorption spectra for type I crystal of Q-35 both in t
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Nagano Hiroyuki
Suzuki Nobuyuki
Chugai Seiyaku Kabushiki Kaisha
Ivy C. Warren
M. Mach D. Margaret
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