Cyanobiphenyl derivatives

Details Cyanobiphenyl derivatives Cyanobiphenyl derivatives

2001-11-07

2003-03-25

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S230000, C558S416000

Reexamination Certificate

active

06538137

ABSTRACT:

This application is a 371 of PCT/JP00/03169 filed May 17, 2000.
TECHNICAL FIELD
The present invention relates to novel cyanobiphenyl derivatives and more particularly it relates to cyanobiphenyl derivatives or their salts useful as intermediates for biphenylamidine derivatives which are capable of providing selective inhibitors for an activated blood coagulation factor X (hereinafter abbreviated to “FXa”) and a process for producing the same.
BACKGROUND ART
Thrombin inhibitors have been developed as antithrombotic agents in the past. Since these agents, however, inhibit the thrombin induced platelet aggregation as well as blood coagulation, therefore they have a risk of tendency towards bleeding as a side effect, it is difficult to control the extent of the anticoagulation.
DISCLOSURE OF THE INVENTION
The present inventors, therefore, have conducted intensive studies to find out anticoagulants based on the mode of action other than inhibition of thrombin which has a risk in such side effects. As a result of such effects, the inventors have found that biphenylamidine derivatives have excellent FXa inhibitory activity and can clinically be applied as an anticoagulant (WO99/26918).
Furthermore, the present inventors have continued studies on the biphenylamidine derivatives, then have found out novel compounds useful as intermediates for the biphenylamidine derivatives. The present invention has been accomplished on the basis of these findings.
That is, the present invention is cyanobiphenyl derivatives represented by the following general formula (1):
[wherein R
1
is a hydrogen atom, a C
1
-C
8
alkyl group, an aryl group or an aralkyl group; X is a carboxyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a formyl group, the formula:
—CH
2
—Y
wherein Y is a chlorine atom, a bromine atom, an iodine atom, an azide group, —OR
2
(wherein R
2
is a hydrogen atom, a C
1
-C
8
alkylsulfonyl group (the C
1
-C
8
alkylsulfonyl group may further be substituted with a halogen atom)), an arylsulfonyl group or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C
1
-C
8
alkyl group, a C
1
-C
8
alkylcarbonyl group, an arylcarbonyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group), or —NHR
3
(wherein R
3
is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C
1
-C
8
alkyl group, a C
1
-C
8
alkylcarbonyl group, an arylcarbonyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group), the formula:
{wherein Z
1
and Z
2
are each independently a chlorine atom, a bromine atom or an iodine atom}, or the formula:
{wherein R
4
and R
5
are each independently a hydrogen atom, a C
1
-C
8
alkyl group or a C
1
-C
8
alkylcarbonyl group or both together may form a ring when R
4
and R
5
are each a C
1
-C
8
alkyl group}], or their salts thereof (hereinafter referred to as the “cyanobiphenyl derivatives”).
Further, the present invention is a process for preparing cyanobiphenyl derivatives represented by the following formula (3):
{wherein R
1
is as defined in the formula (2); Y
1
is —NHR
3
(wherein R
3
is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C
1
-C
8
alkyl group, a C
1
-C
8
alkylcarbonyl group, an arylcarbonyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, or their salts, which is carried out a condensation reaction of a compound represented by the following formula (2):
(wherein R
1
is a hydrogen atom, a C
1
-C
8
alkyl group, an aryl group or an aralkyl group), with a compound represented by
Y
1
—H
{wherein Y
1
is —NHR
3
(wherein R
3
is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C
1
-C
8
alkyl group, a C
1
-C
8
alkylcarbonyl group, an arylcarbonyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, and subsequent a reduction.
In addition, the present invention is a process for preparing cyanobiphenyl derivatives, represented by the following formula (5):
(wherein R
1
is as defined in the formula (4); Y
1
is as defined in the above formula (3)), or their salts, by reacting a compound represented by the following formula (4):
(wherein R
1
is a hydrogen atom, a C
1
-C
8
alkyl group, an aryl group or an aralkyl group; Y
2
is a chlorine atom, a bromine atom or an iodine atom), with a compound represented by
Y
1
—H
{wherein Y
1
is —NHR
3
(wherein R
3
is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C
1
-C
8
alkyl group, a C
1
-C
8
alkylcarbonyl group, an arylcarbonyl group, a C
1
-C
8
alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.
BEST MODE FOR CARRYING OUT THE INVENTION
The cyanobiphenyl derivatives of the present invention are represented by the above formula (1), wherein the definitions of substituents in the formula (1) are described as follows.
The “C
1
-C
8
alkyl group” means a straight or a branched carbon chain having 1 to 8 carbon atoms, and include for example methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, isoheptyl group, octyl group, isooctyl group or the like. Among them, one having 1 to 4 carbon atoms is preferable, and methyl group or ethyl group is especially preferable.
The “aryl group” means a carbocyclic aromatic group including for example phenyl group or naphthyl group, etc. or a heteroaryl group including for example pyridyl group or furyl group, etc., and phenyl group is preferable.
The “aralkyl group” means benzyl group, phenethyl group, phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group or the like, and benzyl group is preferable.
The “C
1
-C
8
alkoxycarbonyl group” means an alkoxycarbonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group or the like. The “C
1
-C
8
alkoxycarbonyl group” is preferably methoxycarbonyl group or ethoxycarbonyl group.
The “aryloxycarbonyl group” means phenoxycarbonyl group, naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group, 3-chlorophenoxycarbonyl group, 4-methoxyphenoxycarbonyl group or the like, and phenoxycarbonyl group is preferable.
The “aralkoxycarbonyl group” means benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, 3-oxohydroisobenzofuranyloxycarbonyl group or like, and benzyloxycarbonyl group is preferable.
The “C
1
-C
8
alkylsulfonyl group” means a sulfonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes, for example, methylsulfonyl group, ethylsulfonyl group, butylsulfonyl group, hexylsulfonyl group, octylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, heptylsulfonyl group or the like, and methylsulfonyl group is preferable. The alkyl group moiety may further be substituted with a halogen atom, and the “C
1
-C
8
alkylsulfonyl group” includes for example tifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, trichloromethylsulfonyl group, dichloromethylsulfonyl group, monochloromethylsulfonyl group or the like.

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