Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-05
2004-03-23
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C307S328000, C307S328000, C307S328000, C307S402000, C307S651000, C546S146000, C546S168000, C546S187000, C548S309400, C548S200000, C562S440000, C564S169000
Reexamination Certificate
active
06710056
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new amidinophenylpyruvic acid derivatives antagonistic to activated blood coagulation factor VII (FVIIa) and pharmaceutically acceptable salts thereof. The amidinophenylpyruvic acid derivatives and salts thereof of the present invention are usable as active ingredients of blood anticoagulants, pharmaceutical composition for preventing or treating a thrombus or embolus, intimal thickening inhibitors or pharmaceutical composition for preventing or treating angiostenosis and vascular occlusion.
When a thrombus or embolus is formed in a blood vessel, the normal blood flow becomes impossible to cause various diseases. The anticoagulation therapy is one of internal medical treatment methods for treating and preventing thrombosis like fibrinolytic therapy and antiplatelet therapy.
Anticoagulants available on the market are warfarin capable of inhibiting the formation of coagulation factors, thrombin inhibitors, etc. However, they often have undesirable side effects such as causing of serious hemorrhage and, therefore, they cannot easily control of the coagulating property. Now, it is demanded in the art to find a compound having an anticoagulating activity based on a new function mechanism and free of the undesirable side effects of the existing anticoagulants. It is also demanded in the art to find an anticoagulating compound having a high peroral activity and free of undesirable side effects.
The blood coagulation paths are roughly divided into intrinsic path and extrinsic path. Although the relative importance of each of the two coagulation paths has not yet been elucidated, it is said that the extrinsic coagulating reaction is deeply concerned in the acceleration of coagulation. The origin of the extrinsic coagulating reaction is the incidence of glycoprotein tissue factor (TF) on the surface of a cell membrane. When FVIIa and TF form a complex (FVIIa/TF) together, the activation is further accelerated. The complex having serine protease-type activity specifically reacts on blood coagulation factors X and IX to activate the respective factors. As a result, thrombin is activated to form a thrombus. The term “inhibition of activated blood coagulation factor VII (FVIIa inhibition)” herein indicates the inhibition of the activity of FVIIa/TF complex enzyme.
Thus, compounds having the FVIIa inhibition activity have an excellent blood anticoagulating activity, and they will be possibly used as medicines free of the defects of ordinary anticoagulants. Further, medicines capable of selectively inhibiting FVIIa will be possibly used as excellent anticoagulating medicines substantially free from side effects.
Disseminated intravascular coagulation is usually caused because a tissue factor forms a complex with FVIIa in the blood, and an FVIIa inhibitor is possibly particularly effective against generalized intravascular blood coagulation syndrome.
It is known that thrombi are hardly formed in the blood of patients lacking in VII factor at a high shear rate. The FVIIa inhibitor is possibly effective in controlling the thrombus formation particularly in narrowed arteries (R. Bastad et al., Blood. 84, 3371 (1994)).
The FVIIa inhibitor is possibly effective in controlling the restenosis after angioplasty with, for example, a balloon catheter (Y. Jang et al., Circulation 92, 3041 (1995) and D. W. Courtman et al., Circ Res. 82, 996 (1998)).
It is known that FVIIa/TF causes the migration of smooth muscle cells of blood vessels. The activity of a compound to inhibit this effect can be examined by a method described in Sato Y et al., Thromb Haemost. 78, 1138 (1997). FVIIa inhibitor might be effective in not only inhibiting the thrombus formation but also controlling the thickening of intima by inhibiting the migration of smooth muscles to control the narrowing or occlusion of the blood vessels.
However, compounds clinically usable as FVIIa inhibitor have not been obtained yet.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide compounds having an excellent effect of inhibiting the action of activated blood coagulation factor VII.
Another object of the present invention is to provide compounds capable of selectively inhibiting activated blood coagulation factor VII.
A third object of the present invention is to provide peroral compounds selectively inhibiting the action of activated blood coagulation factor VII.
A fourth object of the present invention is to provide a pharmaceutical composition.
A fifth object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by the blood coagulation, thrombus or embolus, intimal thickening or angiostenosis.
A sixth object of the present invention is to provide a pharmaceutical composition for preventing or treating disseminated intravascular coagulation, deep vein thrombosis, diseases caused by pulmonary vascular disorder, diseases caused by an ischemic heart disease, diseases caused by a cerebrovascular disorder, occlusion of blood vessel and angiostenosis after an operation for forming a bypass in coronary artery, coronary artery intervention after percutaneous transluminal coronary angioplasty (PTCA), occlusion of blood vessel and angiostenosis after percutaneous transluminal coronary recanalization (PTCR), formation of thrombi after artificial blood vessel-forming operation or artificial valve replacement, peripheral embolism, formation of thrombi in the course of the extracorporeal circulation and antiphospholipid antibody syndrome.
A seventh object of the present invention is to provide a pharmaceutical composition for preventing or treating cerebral infarction or cerebral stroke.
A eighth object of the present invention is to provide an antagonist against activated blood coagulation factor VII (FVIIa).
Under these circumstances, the inventors made investigations on FVIIa inhibiting activity of benzamidine derivatives disclosed in WO 98/31661 as compounds having an effect of inhibiting activated blood coagulation factor X (FXa). As a result, the inventors found that only specified amidinophenylpyruvic acid derivatives have a high activity of inhibiting FVIIa. After synthesizing the new amidinophenylpyruvic acid derivatives and examining the effect thereof on extrinsic blood coagulation factors on the basis of these facts, the inventors have found that they are highly useful new compounds having an activation profile different from that of ordinary ones. Namely, these compounds have a high activity of inhibiting FVIIa and a high selectivity toward thrombin. The present invention has been completed on the basis of these findings.
The present invention provides amidinophenylpyruvic acid derivatives of the following general formula (1) or (1-2), pharmaceutically acceptable salts thereof and an antagonist against activated blood coagulation factor VII (FVIIa), which contains such a compound(s) as the active ingredient:
wherein W represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
X represents a hydrogen atom, a carboxyalkyl group having 2 to 5 carbon atoms, or
a methyl or ethyl group having a substituent(s) selected from the group consisting of alkoxycarbonyl groups having 2 to 8 carbon atoms, carbamoyl group, tetrazolyl group, sulfo group, sulfamoyl group, phosphono group and hydroxyl group,
a benzyl group which may have a substituent(s) selected from the group consisting of hydroxyl group, carboxyl group, tetrazolyl group, sulfo group, sulfamoyl group, phosphono group, halogeno groups and alkyl groups having 1 to 3 carbon atoms, or
an alkyl group having 1 to 4 carbon atoms, phenyl group, guanidinopropyl group, mercaptomethyl group, imidazolylmethyl group, aminobutyl group, aminopropyl group, (methylthio)ethyl group or indolylmethyl group, X and W may be bonded together to form a ring, and in this case, —W—X— represents ethylene group, trimethylene group or tetramethylene group, V represents any of the following groups (1) to (8):
(1) benzimidazolecarbonyl, quinolinecarbonyl, benzothiazolecarbony
Fujita Kohichi
Kayahara Takashi
Sagi Kazuyuki
Sakurai Kuniya
Sugiki Masayuki
Ajinomoto Co. Inc.
Davis Zinna Northington
LandOfFree
Amidinophenylpyruvic acid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Amidinophenylpyruvic acid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amidinophenylpyruvic acid derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3286600