Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-06
2003-05-13
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C514S322000, C514S394000, C514S318000, C514S367000, C514S213010, C546S145000, C546S194000, C546S199000, C544S328000, C544S333000, C540S593000, C548S159000, C548S306100
Reexamination Certificate
active
06562828
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel amidine compound having a blood coagulation factor Xa inhibitory activity. The present invention also relates to a pharmaceutical composition, a factor Xa inhibitor and a therapeutic agent for the diseases caused by blood coagulation or thrombus, which comprises this compound.
BACKGROUND OF THE INVENTION
One of the etiologies of thrombosis, such as unstable angina, deep vein thrombosis and disseminated intravascular coagulation (DIC), is promotion of blood coagulation. For the prophylaxis and treatment of thrombus, heparin and warfarin have been conventionally used. Heparin acts on antithrombin III (ATIII) to indirectly inhibit the coagulation system and, therefore, may show a weak action on arterial thrombus. Heparin is associated with generation of an antibody against platelet factor (PF4), which promotes coagulation in some patients, and a propensity toward hemorrhage as a side effect. Warfarin requires longer time for the expression of the drug effect and is not necessarily an easy and safe drug. Under the circumstances, a new anticoagulant is desired to overcome these problems.
The factor X is a glycoprotein having a molecular weight of 58,000, and in an intrinsic pathway, the factor X is activated on a phospholipid membrane in the presence of a factor IXa/factor VIIIa/Ca
2
+ complex and becomes factor Xa. In the coagulation system called extrinsic pathway, factor X is activated by factor VIIa in the presence of a tissue factor and becomes factor Xa. The factor Xa generated in the both pathways activates prothrombin to give thrombin. The generated thrombin further activates the upstream of this cascade to produce a large amount of thrombin. Consequently, fibrinogen becomes fibrin and coagulation of blood occurs.
Inasmuch as the blood coagulation system is an amplification reaction, inhibition of generation of thrombin in the early stage is considered to be more efficient than direct inhibition of the activity of the generated thrombin. In addition, since factor Xa is the confluence of intrinsic and extrinsic coagulation pathways, inhibition of factor Xa is considered to be extremely effective. Some reports have documented that low molecular weight heparin showed a lower tendency of bleeding than heparin in clinical applications, and in a test using baboon (Thrombosis and Haemostas, 74, 464 (1995)), it was found that inhibition of factor Xa rather than thrombin showed less tendency of bleeding. Therefore, a factor Xa inhibitor has a potential of showing antithrombus effect without influencing the bleeding time observed in the use of conventional anticoagulants.
As a factor Xa inhibitor, WO97/08165 discloses a compound of the formula
wherein R
1
, R
2
and R
3
are each hydrogen atom, hydroxy, halogen atom, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkoxy, aralkyloxy, alkenyloxy, alkynyloxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkenyloxycarbonylalkyl or alkynyloxycarbonylalkyl, A is alkylene optionally substituted by hydroxy, carboxy, alkoxycarbonyl or halogen atom, X is a bond, alkylene or alkyleneoxy, Y is a single bond, chalcogen atom or CO, Z is a saturated or unsaturated optionally substituted hetero ring or carbon ring, optionally substituted amino, hydroxy, carboxy, alkoxycarbonyl or alkyl, n is an integer of 1 or 2, and m is an integer of 0 to 4. In addition, Japanese Patent Unexamined Publication No. 5-208946 (U.S. Pat. No. 5,620,991, EP No. 540051) discloses a compound of the formula
wherein R
1
is hydrogen atom or lower alkoxy, R
2
is hydrogen atom, lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, R
3
is hydrogen atom, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, carboxyalkoxy or alkoxycarbonylalkoxy, R
4
is hydrogen atom, hydroxy, lower alkyl or lower alkoxy, n is an integer of 0 or 1, A is C
1
-C
4
alkylene optionally substituted by 1 or 2 substituents from hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl, X is a single bond, oxygen atom, sulfur atom or carbonyl, Y is optionally substituted saturated or unsaturated 5 or 6-membered heterocyclic group or cyclic hydrocarbon group, optionally substituted amino or optionally substituted aminoalkyl, and a group of the formula
is selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl. Furthermore, WO96/16940 discloses a compound of the formula
wherein R
1
is hydrogen atom or a group of the formula —A—W—R
4
wherein A is a group of the formula
or —SO
2
— wherein X
2
is oxygen atom or sulfur atom, and W is a single bond or —NR
5
—, R
4
is hydroxy, lower alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, with the proviso that when W is a group of the formula —NR
5
—, R
4
may be hydrogen atom but is not hydroxy or lower alkoxy; wherein R
5
is hydrogen atom, carbamoyl, lower alkoxycarbonyl, mono- or di(lower)alkylaminocarbonyl, lower alkylsulfonyl, mono- or di(lower)alkylaminothiocarbonyl, optionally substituted lower alkyl or optionally substituted lower alkanoyl; R
2
is lower alkyl; R
3
is hydrogen atom, halogen atom, carboxy, amino, cyano, nitro, hydroxy, lower alkoxy, lower alkyl or lower alkoxycarbonyl; B is lower alkylene or carbonyl; and n is an integer of 0 or 1.
DISCLOSURE OF THE INVENTION
The present invention aims at providing a novel compound useful as a factor Xa inhibitor. The present invention also aims at providing a novel factor Xa inhibitor.
In view of the above situation, the present inventors conducted intensive studies in an attempt to find a compound useful as a factor Xa inhibitor and found the amidine compound of the following formula [I]. They have further found that the compound can be a superior factor Xa inhibitor and completed the present invention.
The compound of the present invention specifically inhibits blood coagulation factor Xa and shows strong anticoagulation action. Therefore, the compound is useful as an agent for the prophylaxis and/or treatment of various diseases caused by blood coagulation or thrombus, namely, cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (TIA), subarchnoid hemorrhage and the like; ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis and the like; pulmonary vascular diseases such as pulmonary infarction, pulmonary embolism and the like; and diseases caused by various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after recanalization such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR) and the like, thrombosis due to extracorporeal circulation and the like, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger disease, tumor thrombosis, thrombus by atrial fibrillation, and the like.
As is evident from Experimental Example 2 to be mentioned later, since the compound of the present invention does not have inhibitory activity against thrombin, namely, factor IIa (FIIa), hemorrhage as a side effect is considered to be noticeably less. Experimental Examples 6 and 7 to be mentioned later reveal striking factor Xa inhibitory effect by oral administration.
There is also a finding that factor Xa is involved in the growth of influenza virus (Japanese Patent Unexamined Publication No.6-227971). Thus, the compound of the present invention is expected to be useful for the prophylaxis and/or treatment of influenza.
The present invention relates to a compound of the following formula [I&rsqb
Hayashi Mikio
Katoh Susumu
Yokota Katsuyuki
Bernhardt Emily
Foley & Lardner
Japan Tobacco Inc.
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