1. Field of the Invention
The present invention relates to a novel 1,4-naphthoquinone derivative having a potent inhibitory activity against platelet aggregation. More specifically, the present invention relates to a novel 2-chloro-3-arylamino-1,4-naphthoquinone derivative represented by the following formula (I), which has a potent activity for inhibition of platelet aggregation and therefore, can be used as an agent for inhibition of blood coagulation and for treatment of thrombosis: ##STR2## in which X represents nitrogen (N) or carbon (C) atom and
R represents cyano, or PA1 R can further represent alkyl, carboxyl or acyl when X represents nitrogen (N) atom.
The present invention also relates to a process for preparation of the compound of formula (I), as defined above, and to a pharmaceutical composition for inhibition of blood coagulation which comprises the compound of formula (I) as an active ingredient.
2. Background Art
Platelets occupy the most small part of the cells constituting blood but are easy to respond even to any minute stimulus and therefore, play an important role in maintenance of biological homeostasis, for example, in blood coagulation. Further, the abnormality of platelet aggregation caused by a change in platelet function is one of the major negative factors responsible to blood rheology and thus can cause the abnormal hemostatic mechanism or microcirculation disorder. Particularly, it has been reported that the major cause of interruption in blood circulation which is frequently developed in geriatric diseases such as hypertension, arteriosclerosis, etc., and metabolic disorders such as diabetes mellitus, etc., which have been rapidly increased in modern society, is the abnormal acceleration of platelet aggregation. Accordingly, it has been expected that such related diseases can treat or prevent by normalizing the function of platelets.
1,4-Naphthoquinone derivatives generally have various pharmacological activities such as antimicrobial activity, antifungal activity, anticancer activity, anticoagulant activity, etc., and therefore, have been widely used as the leading compound for development of novel medicinal agents in the field of anticancer and antimicrobial agents. According to the result of numerous studies, it has been reported that vitamin K.sub.3 (menadione), which is one of the 1,4-naphthoquinone derivatives, has an effect on inhibition of platelet aggregation in human being. However, the mechanism of vitamin K.sub.3 for inhibition of platelet aggregation has not been clearly established yet (see, Blackwell, G. J., Radomski, M. and Moncada, S. Inhibition of human platelet aggregation by vitamin K. Thromb. Res. 37, 103-114, 1985). In addition, it has been disclosed that 2-chloro-3-methyl-1,4-naphthoquinone (CMN) inhibits the platelet aggregation in rabbit by inhibiting the metabolic pathway of phospholipids involving various platelet agonists (see, Ko, F. N., Sheu, S. J., Liu, Y. M., Huang, T. F. and Teng, C. M., Inhibition of rabbit platelet aggregation by 1,4-naphthoquinones, Thromb. Res. 57, 453-463, 1990).
Thus, the present inventors have synthesized various 1,4-naphthoquinone derivatives and examined their activity for inhibition of platelet aggregation. As a result, we have identified that a certain 1,4-naphthoquinone derivative having a different structure from those of presently known 1,4-naphthoquinone derivatives shows a potent activity for inhibition of platelet aggregation, and thus completed the present invention.
Therefore, it is an object of the present invention to provide a novel 2-chloro-3-arylamino-1,4-naphthoquinone derivative of formula (I), as defined above, which has a potent activity for inhibition of platelet aggregation.
It is another object of the present invention to provide a process for preparing the compound of formula (I).
It is a further object of the present invention to provide a pharmaceutical composition for inhibition of platelet aggregation, which comprises the compound of formula (I) as an active ingredient.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention and drawings, in addition to the scope of the invention defined by the claims.