Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-18
2004-03-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252010, C514S255020, C514S269000, C514S403000, C514S408000, C514S637000, C544S239000, C544S298000, C544S397000, C544S398000, C546S192000, C546S216000, C548S356100, C548S400000
Reexamination Certificate
active
06706745
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel, and selective, activated blood coagulation factor Xa (hereafter, “FXa”) inhibitors of the general formula (I).
Background Art
A therapy for anticoagulation plays an important part in the medical treatment and prophylaxis of thromboembolisms such as myocardial infarction, cerebral thrombosis, thrombosis of peripheral arteries, and thrombosis of deep veins.
In particular, for the prophylaxis of chronic thrombosis, harmless and appropriate oral anticoagulants which can be administrated over a long period of time are desired. However, to date, warfarin potassium agent which are difficult to control the extent of the anti-coagulation are the only above-mentioned anticoagulants, and thus a need for anticoagulants which are easy to use is left.
Though antithrombin agents have been developed as anticoagulants in the past, it is known that these agents, for example hirudin, have a risk of a tendency toward bleeding as a side effect. The fact that inhibition of FXa, located upstream of thrombin in the blood coagulation cascade is systematically more effective than inhibition of thrombin and that the FXa inhibitors do not cause the above significant side effect and is clinically preferable, has begun to be understood.
Biphenylamidine compounds, which exhibit FXa inhibition activity, were disclosed in The 17th Symposium on Medicinal Chemistry, The 6th Annual Meeting of Division of Medicinal Chemistry, Abstracts, 184-185, 1997. However, compounds of the present invention are novel compounds which differ distinctly in the use of a heteroatom in a linkage between the biphenylamidine structure which may interact with an S1 pocket and the cyclic structure which may interact with an aryl binding site, and in the presence of a substituent such as a carboxyl group on a linker benzene ring.
Further, Japanese Unexamined Patent Publication (Kokai) No. 4-264068 discloses biphenylamidine derivatives as cyclic imino-derivatives. However, compounds of the present invention differ in the presence of a bond, through a heteroatom, at a benzyl-position.
Therefore, an object of the present invention is to provide a novel compound which may be a FXa inhibitor having a clinical applicability.
Disclosure of the Invention
The inventors have made every effort to achieve the above purpose and, as a result, devised the following 1-10 inventions.
1. A biphenylamidine derivative of general formula (1):
wherein
R
1
is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom; a hydroxyl group, an amino group, a nitro group, a C
1-8
alkyl group, or a C
1-8
alkoxy group;
L is a direct bond or a C
1-4
alkylene group;
R
2
is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; a C
1-8
alkoxy group; a carboxyl group; a C
1-8
alkoxycarbonyl group; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom constituting the carbamoyl may be substituted with a mono- or di-C
1-8
alkyl group or may be a nitrogen atom in an amino acid; a C
1-8
alkylcarbonyl group; a C
1-8
alkylsulfenyl group; a C
1-8
alkylsulfinyl group; a C
1-8
alkylsulfonyl group; a mono- or di-C
1-8
alkylamino group; a mono- or di-C
1-8
alkylaminosulfonyl group; a sulfo group; a phosphono group; a bis(hydroxycarbonyl)methyl group; a bis(alkoxycarbonyl)methyl group; or a 5-tetrazolyl group;
R
3
is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C
1-8
alkyl group, a C
1-8
alkoxy group, a carboxyl group, or a C
1-8
alkoxycarbonyl group;
X is any of the formulae:
—O—, —S—, —SO—, —SO
2
—, —NH—CO—NH—, —N(R
4
)—, —CO—N(R
5
)—, —N(R
5
)—CO—, —N(R
5
)—SO
2
—, —SO
2
—N(R
5
)—,
wherein
R
4
is a hydrogen atom, a C
1-10
alkyl group, a C
1-10
alkylcarbonyl group, a C
1-10
alkylsulfonyl group, a C
3-8
cycloalkyl group, or an aryl group,
R
5
is a hydrogen atom, a C
1-10
alkyl group, a C
3-8
cycloalkyl group, or an aryl group,
wherein an alkyl group in the R
4
and R
5
may be substituted with an aryl group, a hydroxyl group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a C
1-8
alkoxy group, a carboxyl group, a C
1-8
alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazolyl group;
Y is a C
4-8
cycloalkyl group wherein a methylene group in the C
4-8
cycloalkyl may be replaced with a carbonyl group, or may be substituted with a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a C
1-8
alkyl group, a C
1-8
alkoxy group, a carbamoyl group, a C
1-8
alkoxycarbonyl-group, a carboxyl group, an aminoalkyl group, a mono- or di-alkylamino group, or a mono- or di-alkylaminoalkyl group; or the following 5-8-membered ring of the formulae I-1 or I-2:
wherein, in the formulae I-1 and I-2,
in each cyclic system, the methylene group may be replaced with a carbonyl group, and the cycle may have unsaturated bonds,
R
6
is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C
1-8
alkyl group, or a C
1-8
alkoxy group,
W is C—H, or a nitrogen atom, with the proviso that W is not a nitrogen atom when the cycle is 5-membered ring,
Z is a hydrogen atom; a C
1-10
alkyl group wherein the alkyl group may be substituted with a hydroxyl group except when Z is a C
1
alkyl, an amino group, a C
1-8
alkoxy group except when Z is a C
1
alkyl, a carboxyl group, a C
1-8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group; a C
1-8
alkylcarbonyl group; an arylcarbonyl group; an aralkylcarbonyl group; an amidino group; or the following group of the formula I-3:
wherein, in the formula I-3,
R
7
is a C
1-8
alkyl group wherein the alkyl group may be substituted with a hydroxyl group or a C
1-8
alkoxy group; an aralkyl group; or an aryl group;
m is an integer of 1-3;
n is an integer of 0-3, with the proviso that W is not a nitrogen atom when n is 0-1; or a pharmaceutically acceptable salt thereof.
2. A biphenylamidine derivative wherein, in said formula (1),
R
1
is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a C
1-4
alkyl group, or a C
1-4
alkoxy group;
L is a direct bond or a C
1-4
alkylene group;
R
2
is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; a C
1-8
alkoxy group; a carboxyl group; a C
1-8
alkoxycarbonyl group; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom in the carbamoyl group may be substituted with a mono- or di-C
1-8
alkyl group or may be a nitrogen atom in an amino acid; a C
1-8
alkylcarbonyl group; a C
1-8
alkylsulfenyl group; a C
1-8
alkylsulfinyl group; a C
1-8
alkylsulfonyl group; a mono- or di-C
1-8
alkylamino group; a mono- or di-C
1-8
alkylaminosulfonyl group; a sulfo group; a phosphono group; a bis(hydroxycarbonyl)methyl group; a bis(alkoxycarbonyl)methyl group; or a 5-tetrazolyl group;
R
3
is a hydrogen atom;
X is any of the formulae:
—O—; —S—, —N(R
4
)—, —CO—N(R
5
)—, —N(R
5
)—CO—, —N(R
5
)SO
2
—, or —SO
2
—N(R
5
)—;
wherein
R
4
is a hydrogen atom, a C
1-10
alkyl group, a C
1-10
alkylcarbonyl group, or a C
1-10
alkylsulfonyl group,
R
5
is a hydrogen atom, or a C
1-10
alkyl group,
wherein an alkyl group in the R
4
and R
5
may be substituted with an aryl group, a hydroxy group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a C
1-8
alkoxy group, a carboxyl group, a C
1-8
alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazoyl group;
Y is a C
4-8
cycloalkyl group wherein a methylene group constituting the C
4-8
cycloalkyl may be replaced with a carbonyl group, or may be substituted with a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a C
1-8
alkyl group, a C
1-8
alkoxy group, a carbamoyl group, a C
1-8
alkoxycarbonyl group, a carboxyl group, an aminoalkyl group, a mono- or di-alkylami
Hara Takayuki
Nakada Tomohisa
Sugiura Satoshi
Takano Yasunobu
Takarada Reiko
Raymond Richard L.
Sughrue & Mion, PLLC
Teijin Limited
Truong Tamthom N.
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