Amidinonaphthyl derivative or salt thereof

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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Details

514424, 546205, 546221, 548541, 548550, A61K 31445, C07D21144

Patent

active

058695010

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/JP95/02458, filed on Dec. 1, 1995, published as WO 96/16940 on Jun. 6, 1996.
1. Technical Field
This invention relates to an amidinonaphthyl derivative or a salt thereof, which is useful as medicine, particularly as an activated blood coagulation factor X inhibitor.
2. Background Art
With the changes in European and American life styles and the increase in aged population in recent years, the number of patients with thromboembolic diseases including myocardial infarction, cerebral thrombosis and peripheral arterial thrombosis have been increasing from year to year, and social importance of their treatment has been increasing more and more. As well as the fibrinolysis therapy and antiplatelet therapy, the anticoagulation therapy takes a part of the medical therapy in treating and preventing thrombosis (Sogo Rinsyo, 41: 2141-2145, 1989). In particular, the safety which withstands long-term administration and accurate and proper expression of the anticoagulation activity are essential in the prevention of thrombosis.
Warfarin potassium is frequently used in the world as the sole oral anticoagulant. However, this drug is extremely difficult to use clinically, because it is difficult to control the anticoagulation capacity due to the characteristics based on its action mechanism (J. Clinical Pharmacology, 32, 196-209, 1992, and N. Eng. J. Med., 324 (26), 1865-1875, 1991), so that great concern has been directed toward the development of a more useful and easily usable anticoagulant.
Since thrombin controls conversion of fibrinogen into fibrin, which is the final step of coagulation, and is also concerned deeply in the activation and aggregation of platelets (T-PA and Pro-UK, edited by O. Matsuo, published by Gakusai Kikaku, pp. 5-40 Blood Coagulation, 1986), its inhibitor has been the center of anticoagulant studies as a target of drug developments. However, thrombin inhibitors which can be administered orally have not been reported until now because of their low bioavailability by oral administration and problems from the safety point of view (Biomed. Biochim. Acta, 44, 1201-1210, 1985).
Activated blood coagulation factor X is a key enzyme which is located at the joining point of the extrinsic and intrinsic coagulation cascade reactions and locates upstream to thrombin, so that there is a possibility that inhibition of this factor is more efficient than the thrombin inhibition and such an inhibitor can inhibit the coagulation system in a specific fashion (THROMBOSIS RESEARCH (19), 339-349, 1980).
As a patent which discloses a compound having an activated blood coagulation factor X inhibiting action, an unexamined published Japanese patent application (kokai) No. 5-208946 discloses an amidinonaphthylbenzene derivative represented by the following general formula or a salt thereof; ##STR4## (in the formula, an omission, A: an alkylene group having 1 to 4 carbon atoms which may be substituted with 1 to 2 of hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxylalkyl or alkoxycarbonylalkyl group, Y represents a saturated or unsaturated 5 to 6 membered heterocyclic group or cyclic hydrocarbon group or the like, which may have a substituent group, the rest omitted).
However, the compound of the present invention is a novel compound which is clearly different from the aforementioned compound in the structure since the amidinonaphthylalkyl group or amidinonaphthylcarbonyl group is linked to a substituted phenyl group via a nitrogen atom. In addition, as will be described later, the compound of the present invention is a compound having markedly excellent activated blood coagulation factor X inhibiting action in comparison with the aforementioned compound.


DISCLOSURE OF THE INVENTION

With the aim of providing a compound having excellent activated blood coagulation factor X inhibiting action, the inventors of the present invention carried out extensive studies. As the result, it was found unexpectedly that a compound in which an amidinonaphthylalkyl group or amidinonaphthylcarb

REFERENCES:
patent: 4563527 (1986-01-01), Fujii et al.
patent: 4634783 (1987-01-01), Fujii et al.
patent: 5576343 (1996-11-01), Nagahara
Delgado JN and Remers WA. Textbook of Organic Medicinal and Pharmaceutical Chemistry. Ninth Edition. pp. 30-31, 1991.

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