Benzodiazepine derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C540S500000, C540S501000, C540S504000, C540S509000, C540S510000

Reexamination Certificate

active

06825191

ABSTRACT:

The present invention relates to new benzodiazepine derivatives which can be orally administrated to exhibit a strong anticoagulant effect by reversibly inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral stroke, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral arterial occlusive disease; deep vein thrombosis; disseminated intravascular coagulation; thrombus formation after an artificial blood vessel-forming operation or an artificial valve substitution; reocclusion and restenosis after a coronary artery bypass grafting; reocclusion and restenosis after a reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like fibrinolytic therapy and antiplatelet therapy.
Thrombin inhibitors were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and aggregation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when thrombin inhibitors are orally administered, the bioavailability thereof is low. At present, no thrombin inhibitors which can be orally administered is available on the market.
Since the activated blood coagulation factor X is positioned at the juncture of an extrinsic coagulation cascade reaction and an intrinsic coagulation cascade reaction and in the upstream of thrombin, it is possible to inhibit the coagulation system more efficiently and specifically, than the thrombin inhibition, by inhibiting the factor X (Tidwell, R.; Webster, W. P.; Shaver, S. R.; Geratz, J. D. THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds having an excellent effect of inhibiting the effect of activated blood coagulation factor X.
Another object of the present invention is to provide compounds having an effect of specifically inhibiting the effect of activated blood coagulation factor X, which can be orally administered.
Still another object of the present invention is to provide a pharmaceutical composition containing an above-described compound(s).
A further object of the present invention is to provide a blood-coagulation inhibitor or an agent for preventing or treating thrombosis or embolism, which contains one of the above-described compounds.
After intensive investigations made under these circumstances, the inventors have found that specified new benzodiazepine derivatives have an excellent effect of inhibiting activated blood coagulation factor X and are usable for preventing and treating various diseases caused by thrombi and emboli. The present invention has been completed on the basis of this finding.
Namely, the present invention provides benzodiazepine derivatives of following general formula (1) or pharmaceutically acceptable salts thereof:
wherein ring A represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms or a cycloalkyl group having 4 to 10 carbon atoms,
R1 represents hydrogen atom, a halogeno group, hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethyl group, trifluoromethoxyl group, trifluoromethanesulfonyloxyl group, methylenedioxyl group, carbamoyl group, thiocarbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, a mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, an alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, a mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms, which may have a substituent(s), a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s), an arylsulfonyl group having 6 to 10 carbon atoms, which may have a substituent(s), a heteroarylsulfonyl group having 4 to 10 carbon atoms, which may have a substituent(s), an acyl group having 1 to 8 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms and substituted with an aryl group(s) having 6 to 10 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms and substituted with a heteroaryl group(s) having 5 to 10 carbon atoms, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), a heteroaryl group having 5 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), an amino group, which may have a substituent(s), an aminoalkyl group having 1 to 7 carbon atoms, which may have a substituent(s), pyrrolidine group, which may have a substituent(s), pyrrolidyloxyl group, which may have a substituent(s), piperidine group, which may have a substituent(s), piperidyloxyl group, which may have a substituent(s), piperazine group, which may have a substituent(s), piperazinecarbonyl group, which may have a substituent(s), amidino group, which may have a substituent(s) or guanidino group, which may have a substituent(s),
when R1 has a substituent(s), the substituent is any of alkyl groups having 1 to 6 carbon atoms, halogeno groups, hydroxyl group, alkoxyl groups having 1 to 10 carbon atoms, trifluoromethyl group, trifluoromethoxyl group, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amino group, aminoalkyl groups having 2 to 7 carbon atoms, mono- or dialkylamino groups having 1 to 6 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, tetraalkylamidino groups having 5 to 8 carbon atoms, guanidino group, dialkylguanidino groups having 3 to 8 carbon atoms, trialkylguanidino groups having 4 to 9 carbon atoms, aryl groups having 6 to 10 carbon atoms, heteroaryl groups having 1 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms and substituted with an aryl group(s) having 6 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms and substituted with a heteroaryl group(s) having 5 to 10 carbon atoms, aryl groups having 6 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, heteroaryl groups having 5 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, arylsulfonyl groups having 6 to 10 carbon atoms, heteroarylsulfonyl groups having 4 to 10 carbon atoms, car

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