Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-15
2002-02-19
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...
C514S415000, C514S637000, C546S300000, C548S469000, C564S244000
Reexamination Certificate
active
06348478
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel selective activated blood coagulation factor X (hereinafter referred to as [FXa]) inhibitor represented by the general formula (1).
BACKGROUND ART
The anticoagulant therapy plays an important role for thromboembolic diseases such as cardiac infarction, cerebral thrombosis, peripheral arterial thrombosis, and deep venous thrombosis as a medical treating preventing method.
Especially for preventing chronic thrombosis, a safe and suitable oral anticoagulant capable of being administered for a long period is needed. However, potassium warfarin, which is difficult to control its anticoagulation ability, is only available now, and a more easily usable anticoagulant has therefore been demanded.
Antithrombin agents have been developed as anticoagulants, but it has been known that the agents have a risk of causing hemorrhagic diathesis as a side effect, for example, on hirudine. It has been clarified that the inhibition of FXa placed in the upstream of thrombin is systematically more effective than the inhibition of the thrombin on a blood coagulation cascade, and it has further been clarified that FXa inhibitors are clinically preferable because of being weak in the side effect.
Biphenylamidine compounds expressing FXa-inhibiting activities are described in The 17th Symposium on Medicinal Chemistry, The 6th Annual Meeting of Division of Medicinal Chemistry, Abstracts, 184-185, 1997. The compounds of the present invention are novel compounds which are structurally clearly different from the biphenylamidine compounds at a point that a heteroatom is used to link a biphenylamidine structure which may interact with a S1 pocket, to a cyclic structure which may interact with an aryl-binding site.
And, cyclic imino derivatives (Japanese Unexamined Patent Publication (Kokai) Number 4-264068) disclose biphenylamidine derivatives, but the present invention is clearly different at a point that a heteroatom is bonded to the benzyl position.
Accordingly, the object of the present invention is to provide a novel compound which can be used as a clinically applicable FXa inhibitor.
DISCLOSURE OF THE INVENTION
The inventors of the present invention have extensively and intensively studied for achieving the above-mentioned object, and the following 1 to 10 have consequently been found out and led to the completion of the present invention.
1. A biphenylamidine derivative represented by the general formula (1), or a pharmaceutically acceptable salt thereof:
[wherein, A represents an amidino group; R
1
represents a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a C
1
-C
8
alkyl group, or a C
1
-C
8
alkoxy group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C
1
-C
8
alkoxycarbonyl group, or a hydrogen atom (provided that Y is limited to a case represented by the below-mentioned formula (1-4) when X represents the hydrogen atom); Y represents a group of the following formula (1-1):
(wherein, n represents 0 or 1; Z represents C—H or a nitrogen atom; R
2
represents a hydrogen atom, an amino group, an amino C
1
-C
4
alkyl group, a C
1
-C
4
alkylamino group, or a di-C
1
-C
4
alkylamino group; R
3
represents a hydrogen atom or a C
1
-C
4
alkyl group; R
4
represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxide group, or a hydroxy C
1
-C
4
alkyl group), or a group of the following formula (1-2):
[wherein, k and m each represents an integer of from 0 to 2, provided that k+m≧2; R
5
represents a hydrogen atom, an amidino group, or a group of the following formula (1-3):
(wherein, R
6
represents a C
1
-C
4
alkyl group, an aralkyl group, or a phenyl group)], or a group of the following formula (1-4):
(wherein, the wavy line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; R
7
represents a hydrogen atom or a trifluoroacetyl group)].
2. The above-mentioned biphenylamidine derivative represented by the general formula (2) or a pharmaceutically acceptable salt thereof:
[wherein, A represents an amidino group; R
1
represents a hydrogen atom, a hydroxyl group, or a C
1
-C
4
alkoxy group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C
1
-C
8
alkoxycarbonyl group, or a hydrogen atom, (provided that Y is limited to a case represented by the below-mentioned formula (2-4) when X represents the hydrogen atom); Y represents a group of the following formula (2-1):
(wherein, n represents 0 or 1; Z represents C—H or a nitrogen atom; R
2
represents a hydrogen atom, an amino group, an amino C
1
-C
4
alkyl group, a methylamino group, or a dimethylamino group; R
3
represents a hydrogen atom or a C
1
-C
4
alkyl group; R4 represents a hydrogen atom, a chlorine atom, a hydroxyl group, a hydroxymethyl group, or a hydroxyethyl group), or a group of the following formula (2-2):
[wherein, k and m each represents an integer of from 0 to 2, (provided that k+m=2); R
5
is a hydrogen atom or a group of the following formula (2-3):
(wherein, R
6
represents a C
1
-C
4
alkyl group)], or a group of the following formula (2-4):
(wherein, the wavy line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; R
7
represents a hydrogen atom or a trifluoroacetyl group)].
3. The above-mentioned biphenylamidine derivative represented by the general formula (3) or a pharmaceutically acceptable salt thereof:
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C
1
-C
8
alkoxycarbonyl group; Z represents C—H or a nitrogen atom; R
2
represents a hydrogen atom, an amino group, an aminomethyl group, an aminoethyl group, a methylamino group, or a dimethylamino group; R
3
represents a hydrogen atom or a C
1
-C
4
alkyl group; R
4
represents a hydrogen atom, a chlorine atom, a hydroxyl group, a hydroxymethyl group, or a hydroxyethyl group).
4. The above-mentioned biphenylamidine derivative represented by the general formula (4) or a pharmaceutically acceptable salt thereof:
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C
1
-C
8
alkoxycarbonyl group; R
8
represents a hydrogen atom, an amino group, an aminomethyl group, an aminoethyl group, or a C
1
-C
4
alkyl group).
5. The above-mentioned biphenylamidine derivative represented by the general formula (5) or a pharmaceutically acceptable salt thereof:
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C
1
-C
8
alkoxycarbonyl group; R
5
represents a hydrogen atom or an acetimidoyl group).
6. The above-mentioned biphenylamidine derivative represented by the general formula (6) or a pharmaceutically acceptable salt thereof.
(wherein, the dashed line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C
1
-C
8
alkoxycarbonyl group, or a hydrogen atom; R
7
represents a hydrogen atom or a trifluoroacetyl group).
7. A prodrug compound which produces the mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof, in vivo.
8. An anticoagulant inhibitor which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. A thrombus or embolus-preventing agent which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10. A thrombus or embolus-treating agent which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically
Hara Takayuki
Nakada Tomohisa
Sugiura Satoshi
Takano Yasunobu
Takarada Reiko
Davis Zinna Northington
Teijin Limited
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