Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1997-05-01
1999-01-05
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
514247, C07D23704, A61K 3150
Patent
active
058564802
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to optically active pyridazinone derivative effectual as an inhibitory agent of platelet aggregation and methods for manufacturing the said pyridazinone derivative.
BACKGROUND ART
It is well known in the art that pyridazinone compounds have an inhibitory effect on platelet aggregation, and the racemic modifications of the pyridazinone compound of the present invention are disclosed in WO 94/09784 corresponding to U.S. Pat. No. 5,663,172.
The said racemic modification has significant inhibitory effect on platelet aggregation, and the side effect caused thereby has been improved to an extent.
However, there is still such problems in the racemic modification that said racemic modifications is not enough chemically stable because of the noncrystalline state and further due to the influence generated from the remaining solvent and water therein, and therefore, the quality of the racemic modification have significantly varied in the industrial scale production. Therefore, it is an object of the present invention to provide optically active pyridazinone derivative which has an inhibitory effect on platelet aggregation, less side effect and higher physical stability.
The present invention is directed to a compound, ##STR1## the crystalline form thereof and methods for manufacturing the said compound and the crystalline form thereof. the present invention can be manufactured according to the method disclosed in WO 94/09784, for example.
The crystalline optically active compound of the present invention, enyl!-3(2H)-pyridazinone, can be prepared by firstly obtaining the racemic modification of said compound either by means of optical resolution by using column chromatography for optical isomers separation or by using modification, and subsequently conducting the crystallization of the racemic modification obtained in any of water, organic solvent or the admixture thereof according to a method generally known in the art, either after isolating the said optically active compound from the solvent or without such isolation. More specifically, the racemic modification can be prepared by taking a procedure, where firstly stirring the optically active compound in an solvent selected from a group consisting of water, hydrophilic organic solvent such as ethanol and the admixture thereof, at a temperature of from -20.degree. to 80.degree. C., more preferably from 0.degree. to 40.degree. C., then collecting the crystals precipitated, and finally drying said crystals according to a method generally-known in the art. In the procedure hereinabove, it is possible to hasten said crystallization by adding a piece of the crystals into the solvent as seed crystal. In case the admixture of water and an organic solvent is used for the solvent described above, it is preferable that the admixture contains water at a concentration of from 5 to 95%, and more preferably from 30 to 70%.
Whereas, in some cases, such crystalline optically active compound can be directly obtained from optical resolution by using column chromatography for optical isomers separation, however, it should be noted that such crystalline optically active compounds is naturally falling within the scope of the crystalline optically active compound of the present invention.
For the column chromatography for optical isomers separation, it is preferable to use CHIRALCEL OD, OJ, CHIRALPAK AD, AS (manufactured by Daicel Chemical industries, Ltd.) or SUMICHIRAL OA-25001 (manufactured by Sumika Chemical Analysis Service, Ltd.).
The manufacturing method of the crystalline optically active compound by using the optically active raw material (II) is shown as the following reaction formula. ##STR2##
The reaction is taken place in an inactive organic solvent, preferably in benzene, toluene, xylene, lower alcohols. DMF, DMSO or the like, in the presence of an acid catalyzer, such as hydrochloric acid, sulfuric acid, acetic acid, and p-toluenesulfonic acid, under applying heating to maintain temperature in a range of from room t
REFERENCES:
patent: 5110925 (1992-05-01), Kusase et al.
patent: 5663172 (1997-09-01), Mochizuki et al.
Mochizuki Nobuo
Uchida Seiichi
Umeda Nobuhiro
Daus Donald G.
Mason, Jr. Joseph C.
Nippon Soda Co. Ltd.
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