Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-23
2000-06-13
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514450, 546 89, A01N 4342
Patent
active
060750359
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Stage under 35 U.S.C. 371 of International Application No. PCT/JP96/02352, filed Aug. 23, 1996, and claims priority of Japanese Application No. 7-248591, filed Sep. 1, 1995.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel dihydrate crystal of amphoteric tricyclic compound: 3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperid ino]propionic acid which has antihistaminic activity and antiallergic activity and is useful as an active ingredient of medicaments for therapeutic and/or preventive treatment of bronchial asthma, allergic rhinitis, dermatosis, urticaria and other, and also relates to a process for preparing thereof.
2. Description of Background Information
3-[4-(8-Fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperidi no]propionic acid represented by the following formula (I), first synthesized by the inventor of the present invention, is disclosed in Example 2 of Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 6-192263/1994. This compound was found to have antihistaminic activity and antiallergic activity, and revealed to be useful as active ingredients of medicaments for therapeutic and/or preventive treatment of bronchial asthma, allergic rhinitis, dermatosis, urticaria and other. In the above publication, an anhydride of the compound is specifically disclosed with its physicochemical properties and is described to have a melting point of 160-161.degree. C. ##STR1##
The inventors of the present invention conducted various researches on processes for recrystallization and purification of a crystalline substance of the compound represented by the aforementioned formula (I), and as a result, they found that the crystalline substances of the compound exist as distinguishable crystalline forms (an anhydride crystal and a dihydrate crystal). The inventors of the present invention recognized that the anhydride of the above compound was susceptible to environmental conditions during storage and not satisfactory from a viewpoint of stability. On the other hand, they revealed that the above dihydrate crystal did not substantially have these problems and had properties highly suitable for active ingredients of medicaments. The existence of the crystalline dihydrate of the compound has not been known so far, and no specific disclosure of the crystal is given in Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 6-192263/1994.
While the inventors of the present invention continued further researches, they were confronted with a problem that, when a crystalline substance of the above compound was isolated and purified in a usual manner, the aforementioned different crystalline forms (anhydride crystal and dihydrate crystal) deposited separately or as a mixture thereof depending on minute fluctuations of manufacturing conditions, and consequently, crystals with constant quality were not obtainable.
When crystalline substances containing a single compound exist as plural forms such as anhydride and hydrate, each of the crystals usually has different physicochemical properties. In particular, when these crystals are used as active ingredients of medicaments, each of the crystalline substances has different characteristics as to absorbability, blood concentration or other, and may often exhibit different bioavailability, which is one of the factors responsible for an effect of a medicament. Therefore, in order to manufacture a medicament which can always achieve constant effect, it is necessary to use a crystalline substance with constant quality as an active ingredient of the medicaments. It is also required to choose a crystalline substance as most suitable form for a medicament from various viewpoints of, for example, effect and stability, and to selectively produce the crystalline substance.
As explained above, the compound represented by the aforementioned formula (I) exist as the aforementioned two crystalline forms, i.e., anhydride and dihy
REFERENCES:
patent: 5334594 (1994-08-01), Ito et al.
Chemical Abstract No. 121:205230p, vol. 121, p. 1161, 1994.
Iwasaki et al., Journal of Medicinal Chemistry, vol. 38, No. 3, pp. 496-507, 1995.
Chemical Abstract No. 121:157634z, vol. 121, p. 1026, 1994.
Ito Yasuo
Iwasaki Nobuhiko
Kado Noriyuki
Kato Hideo
Nishino Hiroyuki
Hokuriku Seiyaku Co. Ltd.
Jones Dwayne C.
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