Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-21
1998-08-04
Clardy, S. Mark
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514310, C07D21700, A61K 3142
Patent
active
057895953
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel tetrahydroisoquinoline derivative and a medical preparation containing the same.
BACKGROUND ART
Agglutination of platelets plays a significant role in the formation of thrombus and blood coagulation. In the final stage of the platelet agglutination, GPIIb/IIIa receptor on the surface of platelets is activated before its binding to fibrinogen. Therefore, an agent capable of inhibiting the binding of the GPIIb/IIIa receptor with the adhesive protein like fibrinogen should be useful in preventing the formation of the thrombus and the blood coagulation. The active site for the binding of the GPIIb/IIIa receptor and the fibrinogen has been reported to be Arg-Gly-Asp-Ser (RGDS) of the fibrinogen (Phillips et al., Blood, vol. 71, 831-843 (1988)). In view of such finding, RGDS analogues have been developed for use as an antagonist for the GPIIb/IIIa receptor (Patent Publications: EP 512831, EP 445796, EP 372486, and EP 513675). There is a demand for a highly active antagonist which exhibits excellent oral absorption.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a tetrahydroisoquinoline derivative which has an activity to compete with GPIIb/IIIa receptor, and hence, which exhibits platelet agglutination-inhibitory action and antithrombotic action; and medical preparations such as platelet agglutination-inhibitory agent, fibrinogen receptor-inhibitory agent and antithrombotic agent which contain the tetrahydroisoquinoline derivative as their effective component.
More illustratively, the present invention is directed to a novel tetrahydroisoquinoline derivative having the structure as shown in Formula 1: ##STR3##
In formula 1, B and G independently represent a (C: 0-10) alkylene optionally substituted with a substituent (said substituent being a (C: 1-10) alkyl, an aryl (C: 0-8) alkyl, a (C: 0-10) alkylamino, an acylamino, a (C: 1-10) alkoxy, an aryl (C: 0-8) alkoxy, an (aryl (C: 0-8) alkyl)amino, hydroxy, or halogeno); aryl (C: 0-8) alkoxycarbonyl, a (C: 1-10) alkylcarbonyloxy (C: 1-10) alkoxycarbonyl, or an aryl (C: 0-10) alkylcarbonyloxy (C: 1-10) alkoxycarbonyl; alkylcarbonyloxy (C: 1-10) alkoxycarbonyl; substituents R.sub.1, R.sub.2, R.sub.3 and R.sub.4, and which binds to G at position 2 (said substituents R.sub.1, R.sub.2, R.sub.3 and R.sub.4 independently representing a (C: 1-10) alkyl, an aryl (C: 0-8) alkyl, a (C: 0-10) alkylamino, an acylamino, a (C: 1-10) alkoxy, an aryl (C: 0-8) alkoxy, an (aryl (C: 0-8) alkyl)amino, hydroxy, or halogeno); (aryl (C: 1-10) alkyl)amino, a (C: 1-10) alkoxy, an aryl (C: 0-8) alkoxy, a (C: 1-10) alkylcarbonyloxy (C: 1-10) alkoxy, or an aryl (C: 1-10) alkylcarbonyloxy (C: 1-10) alkoxy; carbon. ##STR4##
In formula 2, M represents hydrogen, a (C: 1-10) alkyl, a (C: 1-10) alkoxycarbonyl, or an aryl (C: 0-8) alkoxycarbonyl, a (C: 1-10) alkylcarbonyloxy (C: 1-10) alkoxycarbonyl, or an aryl (C: 0-10) alkylcarbonyloxy (C: 1-10) alkoxycarbonyl; and (C: 1-10) alkyl, an aryl (C: 0-8) alkyl, a (C: 0-10) alkylamino, an acylamino, (C: 1-10) alkoxy, an aryl (C: 0-8) alkoxy, hydroxy, or halogeno, and C represents carbon.
The present invention is also directed to a medical preparation containing the tetrahydroisoquinoline derivative represented by formula 1.
The present invention is also directed to a platelet agglutination-inhibitory agent containing the tetrahydroisoquinoline derivative represented by formula 1.
The present invention is also directed to an antagonist for fibrinogen receptor containing the tetrahydroisoquinoline derivative represented by formula 1.
The present invention is also directed to an antithrombotic agent containing the tetrahydroisoquinoline derivative represented by formula 1.
It should be noted that the tetrahydroisoquinoline derivative of the present invention may be used in the form of a salt.
Typical, but non-limited illustrating salts that may be formed with its acidic functional group include salts with an alkaline metal or an alkaline earth metal such as lithium,
REFERENCES:
Phillips et al., Blood, vol. 71, 831-843 (1988).
M. Folkmann et al., Synthesis, 1159 (1990).
H.C. Brown et al., Journal of Organic Chemistry, vol. 50, 1582-9 (1985).
H.H. Friedman (Tetrahedron Letters No. 38, 3251 (1975).
Ajao, J.F. et al., Journal of Heterocyclic Chemistry, vol. 22, 329-31 (1985).
Paul, R. et al., Journal of Medicinal Chemistry, vol. 15, 720-6 (1972).
Kohama Hiromasa
Nakata Nobuyuki
Suzuki Masahiro
Terajima Youko
Clardy S. Mark
Qazi Sabiha N.
Terumo Kabushiki Kaisha
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