U.S. patent application number 10/393981 was filed with the patent office on 2003-10-30 for cyanobiphenyl derivatives.
This patent application is currently assigned to TEIJIN LIMITED. Invention is credited to Hara, Takayuki, Nakada, Tomohisa, Takano, Yasunobu.
Application Number | 20030203935 10/393981 |
Document ID | / |
Family ID | 15156677 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203935 |
Kind Code |
A1 |
Nakada, Tomohisa ; et
al. |
October 30, 2003 |
Cyanobiphenyl derivatives
Abstract
Intermediates represented by the following formula: 1 (wherein
R.sup.1 is a hydrogen atom, an alkyl group, an aryl group, an
aralkyl group or the like; X is a carboxyl group, an alkoxycarbonyl
group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a
formyl group, --CH.sub.2--Y, --CHZ.sub.1Z.sub.2,
--CH(OR.sup.4)OR.sup.5 or the like), in the synthesis of
biphenylamidine derivatives to be used as inhibitors for an
activated blood coagulation factor X, and a process for preparing
the same.
Inventors: |
Nakada, Tomohisa; (Tokyo,
JP) ; Hara, Takayuki; (Yamaguchi, JP) ;
Takano, Yasunobu; (Tokyo, JP) |
Correspondence
Address: |
SUGHRUE, MION, ZINN, MACPEAK & SEAS, PLLC
Suite 800
2100 Pennsylvania Avenue, N.W.
Washington
DC
20037-3213
US
|
Assignee: |
TEIJIN LIMITED
|
Family ID: |
15156677 |
Appl. No.: |
10/393981 |
Filed: |
March 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10393981 |
Mar 24, 2003 |
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09959769 |
Nov 7, 2001 |
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6538137 |
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09959769 |
Nov 7, 2001 |
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PCT/JP00/03169 |
May 17, 2000 |
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Current U.S.
Class: |
514/317 ;
514/522; 546/230; 558/416 |
Current CPC
Class: |
C07D 211/26 20130101;
C07C 255/57 20130101; C07D 211/22 20130101; C07C 255/58
20130101 |
Class at
Publication: |
514/317 ;
514/522; 558/416; 546/230 |
International
Class: |
A61K 031/445; A61K
031/277; C07D 211/60; C07C 255/50 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 1999 |
JP |
11-135646 |
Claims
1. A cyanobiphenyl derivative represented by the following formula
(1): 161[wherein R.sup.1 is a hydrogen atom, a C.sub.1-C.sub.8
alkyl group, an aryl group or an aralkyl group; X is a carboxyl
group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl
group, an aralkoxycarbonyl group, a formyl group, the formula:
--CH.sub.2--Y {wherein Y is a chlorine atom, a bromine atom, an
iodine atom, an azide group, --OR.sup.2 (wherein R.sup.2 is a
hydrogen atom, a C.sub.1-C.sub.8 alkylsulfonyl group (wherein a
C.sub.1-C.sub.8 alkylsulfonyl group may be optionally substituted
with more halogen atoms)), an arylsulfonyl group or
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group), or --NHR.sup.3 (wherein R.sup.3 is
hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.1-C.sub.8
alkyl group, a C.sub.1. C.sub.8 alkylcarbonyl group, an
arylcarbonyl group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an
aryloxycarbonyl group or an aralkoxycarbonyl group))}, the formula:
162{wherein Z.sub.1 and Z.sub.2 are each independently a chlorine
atom, a bromine atom or an iodine atom}, or the formula:
163{wherein R.sup.4 and R.sup.5 are each independently a hydrogen
atom, a C.sub.1-C.sub.8 alkyl group or a C.sub.1-C.sub.8
alkylcarbonyl group or both together may form a ring when R.sup.4
and R.sup.5 are each a C.sub.1-C.sub.8 alkyl group}], or its salts
thereof.
2. The cyanobiphenyl derivative or its salts thereof according to
claim 1, wherein, in the above formula (1), R.sup.1 is a hydrogen
atom or a C.sub.1-C.sub.8 alkyl group; X is a C.sub.1-C.sub.8
alkoxycarbonyl group, a formyl group, the formula: --CH.sub.2--Y
{wherein Y is a chlorine atom, a bromine atom, an iodine atom, an
azide group, --OR.sup.2 (wherein R.sup.2 is a hydrogen atom or
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group)), or --NHR.sup.3 (wherein R.sup.3 is as
defined above), the formula: 164{wherein Z.sub.1 and Z.sub.2 are
each as defined above}, or the formula:, 165{wherein R.sup.4 and
R.sup.5 are each as defined above}.
3. The cyanobiphenyl derivative or its salts thereof according to
claim 2, wherein, in the above formula (1), X is a formyl group or
the formula: --CH.sub.2--Y {wherein Y is a chlorine atom, a bromine
atom, an iodine atom, --OR.sup.2 (wherein R.sup.2 is a hydrogen
atom or 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.1-C.sub.8
alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl
group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl
group or an aralkoxycarbonyl group)), or --NHR.sup.3 (wherein
R.sup.3 is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.1-C.sub.8
alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl
group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl
group or an aralkoxycarbonyl group))}.
4. The cyanobiphenyl derivative or its salt thereof according to
claim 3, wherein, in the above formula (1), X is a formyl group or
the formula: --CH.sub.2--Y {wherein Y is a chlorine atom, a bromine
atom, an iodine atom, a hydroxyl group or --NHR.sup.3 (wherein
R.sup.3 is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.1-C.sub.8
alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl
group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl
group or an aralkoxycarbonyl group))}.
5. The cyanobiphenyl derivative or its salts thereof according to
claim 4, wherein, in the above formula (1), X is the formula:
--CH.sub.2--Y {wherein Y is --NHR.sup.3 (wherein R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1. C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))}.
6. The cyanobiphenyl derivative or its salts thereof according to
claim 1, wherein, in the above formula (1), R.sup.1 is a hydrogen
atom, a CC.sub.1-C.sub.8 alkyl group, an aryl group or an aralkyl
group; X is a carboxyl group, a C.sub.1-C.sub.8 alkoxycarbonyl
group, an aryloxycarbonyl group, aralkoxycarbonyl group, formyl
group, the formula: --CH.sub.2--Y {wherein Y is a chlorine atom, an
iodine atom, --OR.sup.2 (wherein R.sup.2 is a C.sub.1-C.sub.8
alkylsulfonyl group (the C.sub.1-C.sub.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.sub.5-C.sub.8
alkoxycarbonyl group or an aryloxycarbonyl group)), --NHR.sup.3
(wherein R.sup.3 is 4-piperidinomethyl group (a nitrogen atom in
the 4-piperidinomethyl group may be substituted with a
C.sub.5-C.sub.8 alkoxycarbonyl group or an aryloxycarbonyl
group))}, the formula: 166{wherein Z.sub.1 and Z.sub.2 are each as
defined above}, or the formula: 167{wherein R.sup.4 and R.sup.5 are
each as defined above}.
7. The cyanobiphenyl derivative or its salts thereof according to
claim 6, wherein, in the above formula (1), R.sup.1 is a hydrogen
atom or a C.sub.1-C.sub.8 alkyl group; X is a carboxyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, a formyl group, or the
formula: --CH.sub.2--Y {wherein Y is --OR.sup.2 (wherein R.sup.2 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.5-C.sub.8 alkoxycarbonyl
group or an aryloxycarbonyl group)), --NHR.sup.3 (wherein R.sup.3
is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.5-C.sub.8
alkoxycarbonyl group or an aryloxycarbonyl group))}.
8. The cyanobiphenyl derivative or its salts thereof according to
claim 7, wherein, in the above formula (1), X is a formyl group or
the formula: --CH.sub.2--Y {wherein Y is --NHR.sup.3 (wherein
R.sup.3 is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group is substituted with a C.sub.5-C.sub.8
alkoxycarbonyl group or an aryloxycarbonyl group))}.
9. A process for preparing a cyanobiphenyl derivative represented
by the following formula (3): 168{wherein R.sup.1 is as defined in
the formula (2); Y.sup.1 is --NHR.sup.3 (wherein R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))} or its salt thereof, comprising
carrying out a dehydration condensation of a compound represented
by the following formula (2): 169(wherein R.sup.1 is a hydrogen
atom, a C.sub.1-C.sub.8 alkyl group, an aryl group or an aralkyl
group), with a compound represented by the formula: Y.sup.1--H
{wherein Y.sup.1 is --NHR.sup.3 (wherein R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))}, and subsequently conducting a
reducing reaction.
10. A process for preparing a cyanobiphenyl derivative represented
by the following formula (5): 170(wherein R.sup.1 is as defined in
the formula (4); Y.sup.1 is as defined in the above formula (3)) or
its salt, comprising reacting a compound represented by the
following formula (4): 171(wherein R.sup.1 is a hydrogen atom, a
C.sub.1-C.sub.8 alkyl group, an aryl group or an aralkyl group;
Y.sup.2 is a chlorine atom, a bromine atom or an iodine atom), with
a compound represented by Y.sup.1--H {wherein Y.sup.1 is
--NHR.sup.3 (wherein R.sup.3 is 4-piperidinomethyl group (a
nitrogen atom in the 4-piperidinomethyl group may be substituted
with a C.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl
group, an arylcarbonyl group, a C.sub.1-C.sub.8 alkoxycarbonyl
group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.
Description
TECHNICAL FIELD
[0001] 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
[0002] 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
[0003] 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).
[0004] 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.
[0005] That is, the present invention is cyanobiphenyl derivatives
represented by the following general formula (1): 2
[0006] [wherein R.sup.1 is a hydrogen atom, a C.sub.1-C.sub.8 alkyl
group, an aryl group or an aralkyl group; X is a carboxyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group, an
aralkoxycarbonyl group, a formyl group, the formula:
--CH.sub.2--Y
[0007] wherein Y is a chlorine atom, a bromine atom, an iodine
atom, an azide group, --OR.sup.2 (wherein R.sup.2 is a hydrogen
atom, a C.sub.1-C.sub.8 alkylsulfonyl group (the C.sub.1-C.sub.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.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl
group, an arylcarbonyl group, a C.sub.1-C.sub.8 alkoxycarbonyl
group, an aryloxycarbonyl group or an aralkoxycarbonyl group), or
--NHR.sup.3 (wherein R.sup.3 is a hydrogen atom or
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group), the formula: 3
[0008] {wherein Z.sub.1 and Z.sub.2 are each independently a
chlorine atom, a bromine atom or an iodine atom}, or the formula:
4
[0009] {wherein R.sup.4 and R.sup.5 are each independently a
hydrogen atom, a C.sub.1-C.sub.8 alkyl group or a C.sub.1-C.sub.8
alkylcarbonyl group or both together may form a ring when R.sup.4
and R.sup.5 are each a C.sub.1-C.sub.8 alkyl group}], or their
salts thereof (hereinafter referred to as the "cyanobiphenyl
derivatives").
[0010] Further, the present invention is a process for preparing
cyanobiphenyl derivatives represented by the following formula (3):
5
[0011] {wherein R.sup.1 is as defined in the formula (2); Y.sup.1
is --NHR.sup.3 (wherein R.sup.3 is 4-piperidinomethyl group (a
nitrogen atom in the 4-piperidinomethyl group may be substituted
with a C.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl
group, an arylcarbonyl group, a C.sub.1-C.sub.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): 6
[0012] (wherein R.sup.1 is a hydrogen atom, a C.sub.1-C.sub.8 alkyl
group, an aryl group or an aralkyl group), with a compound
represented by
Y.sup.1--H
[0013] {wherein Y.sup.1 is --NHR.sup.3 (wherein R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))}, and subsequent a reduction.
[0014] In addition, the present invention is a process for
preparing cyanobiphenyl derivatives, represented by the following
formula (5): 7
[0015] (wherein R.sup.1 is as defined in the formula (4); Y.sup.1
is as defined in the above formula (3)), or their salts, by
reacting a compound represented by the following formula (4): 8
[0016] (wherein R.sup.1 is a hydrogen atom, a C.sub.1-C.sub.8 alkyl
group, an aryl group or an aralkyl group; Y.sup.2 is a chlorine
atom, a bromine atom or an iodine atom), with a compound
represented by
Y.sup.1--H
[0017] {wherein Y.sup.1 is --NHR.sup.3 (wherein R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))}.
BEST MODE FOR CARRYING OUT THE INVENTION
[0018] 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.
[0019] The "C.sub.1-C.sub.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.
[0020] 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.
[0021] The "aralkyl group" means benzyl group, phenethyl group,
phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group
or the like, and benzyl group is preferable.
[0022] The "C.sub.1-C.sub.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.sub.1-C.sub.8 alkoxycarbonyl group" is preferably
methoxycarbonyl group or ethoxycarbonyl group.
[0023] 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.
[0024] The "aralkoxycarbonyl group" means benzyloxycarbonyl group,
4-methoxybenzyloxycarbonyl group,
3-trifluoromethylbenzyloxycarbonyl group,
3-oxohydroisobenzofuranyloxycarbonyl group or like, and
benzyloxycarbonyl group is preferable.
[0025] The "C.sub.1-C.sub.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.sub.1-C.sub.8 alkylsulfonyl group" includes for example
tifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group,
trichloromethylsulfonyl group, dichloromethylsulfonyl group,
monochloromethylsulfonyl group or the like. Trifluoromethylsulfonyl
group is preferable.
[0026] The "arylsulfonyl group" means benzenesulfonyl group,
p-toluenesulfonyl group, 4-nitrobenzenesulfonyl group,
1-naphthylsulfonyl group, 8-quinolinesulfonyl group or the like,
and p-toluenesulfonyl group is preferable.
[0027] The "C.sub.1-C.sub.8 alkyl group" substituted at the
nitrogen atom in the 4-piperidinomethyl group means a straight or a
branched carbon chain having 1 to 8 carbon atoms, and includes 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. The
"C.sub.1-C.sub.8 alkyl group" is preferably methyl group, ethyl
group or isopropyl group.
[0028] The "C.sub.1-C.sub.8 alkylcarbonyl group" substituted at the
nitrogen atom in the 4-piperidinomethyl group means a carbonyl
group having a straight or a branched carbon chain having 1 to 8
carbon atoms, and includes for example acetyl group, propionyl
group, butyryl group, isobutyryl group, valeryl group, isovaleryl
group, pivaloyl group, hexanoyl group, heptanoyl group, octanoyl
group or the like. The "C.sub.1-C.sub.8 alkylcarbonyl group" is
preferably acetyl group.
[0029] The "arylcarbonyl group" substituted at the nitrogen atom in
the 4-piperidinomethyl group means benzoyl group, 4-methoxybenzoyl
group or 3-trifluoromethylbenzoyl group and the like or a carbonyl
group to which a heteroaryl group is bound such as 2-furylcarbonyl
group, 3-pyridylcarbonyl group and the like. The "arylcarbonyl
group" is preferably benzoyl group.
[0030] The "C.sub.1-C.sub.8 alkoxycarbonyl group" substituted at
the nitrogen atom in the 4-piperidinomethyl 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 and the like. The
C.sub.1-C.sub.8 alkoxycarbonyl group" is preferably methoxycarbonyl
group, ethoxycarbonyl group or tert-butoxycarbonyl group.
[0031] The "C.sub.5-C.sub.8 alkoxycarbonyl group" substituted at
the nitrogen atom in the 4-piperidinomethyl group means an
alkoxycarbonyl group having a straight or branched carbon chain
having 5 to 8 carbon atoms, and includes for example
pentyloxycarbonyl group, isopentyloxycarbonyl group,
neopentyloxycarbonyl group, cyclopentyloxycarbonyl group,
hexyloxycarbonyl group, cyclohexyloxycarbonyl group,
heptyloxycarbonyl group, octyloxycarbonyl group,
2-ethylhexyloxycarbonyl group and the like. The "C.sub.5-C.sub.8
alkoxycarbonyl group" is preferably pentyloxycarbonyl group,
hexyloxycarbonyl group, heptyloxycarbonyl group or octyloxycarbonyl
group.
[0032] The "aryloxycarbonyl group" substituted at the nitrogen atom
in the 4-piperidinomethyl group means phenoxycarbonyl group,
naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group,
3-chlorophenoxycarbonyl group, 4-methoxyphenoxycarbonyl group and
the like. The "aryloxycarbonyl group" is preferably phenoxycarbonyl
group.
[0033] The aralkoxycarbonyl group" substituted at the nitrogen atom
in the 4-piperidinomethyl group means benzyloxycarbonyl group,
4-methoxybenzyloxycarbonyl group,
3-trifluoromethylbenzyloxycarbonyl group,
3-oxohydroisobenzofuranyloxycarbonyl group and the like. The
"aralkoxycarbonyl group" is preferably benzyloxycarbonyl group.
[0034] The "C.sub.1-C.sub.8 alkyl group" in R.sup.4 and R.sup.5
means a straight or a branched carbon chain having 1 to 8 carbon
atoms, and includes 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 and the like. The "C.sub.1-C.sub.8 alkyl group" is preferably
methyl group or ethyl group. In the case wherein R.sup.4 and
R.sup.5 together form a ring, it includes for example ethylene
group, propylene group, 2-methylenepropylene group,
2,2-dibromopropylene group and the like, and ethylene group or
propylene group is preferable.
[0035] The "C.sub.1-C.sub.8 alkylcarbonyl group" in R.sup.4 and
R.sup.5 means a carbonyl group having a straight-chain or a
branched carbon chain having 1 to 8 carbon atoms, and includes for
example acetyl group, propionyl group, butyryl group, isobutyryl
group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl
group, heptanoyl group, octanoyl group and the like. The
"C.sub.1-C.sub.8 alkylcarbonyl group" is preferably acetyl
group.
[0036] The cyanobiphenyl derivatives of the present invention may
form acid addition salts, and may form salts with bases depending
on the species of the substituents. These salts are not especially
restricted insofar as these salts are pharmaceutically acceptable,
and include for example mineral salts such as hydrochloride,
hydrobromide, hydroiodide, phosphate, nitrate or sulfate, organic
sulfonates such as methanesulfonate, 2-hydroxyethanesulfonate or
p-toluenesulfonate, organic carboxylates such as acetate,
trifluoroacetate, propionate, oxalate, malonate, succinate,
glutarate, adipate, tartrate, maleate, malate or mandelate, salts
with inorganic bases such as sodium salts, potassium salts,
magnesium salts, calcium salts or aluminum salts, or salts with
organic bases such as methylamine salts, ethylamine salts, lysine
salts or ornithine salts.
[0037] The preferred range of the cyanobiphenyl derivatives of the
present invention is as follows.
[0038] In the compounds represented by the above formula (1),
cyanobiphenyl derivatives [wherein R.sup.1 is a hydrogen atom or a
C.sub.1-C.sub.8 alkyl group in the above definition, and, in the
above definition, X is a C.sub.1-C.sub.8 alkoxycarbonyl group, a
formyl group, the formula:
--CH.sub.2--Y
[0039] {wherein, in the above definition, Y is a chlorine atom, a
bromine atom, an iodine atom, an azide group, --OR.sup.2 (wherein,
in the above definition, R.sup.2 is a hydrogen atom or
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group)) or --NHR.sub.3 (wherein R.sup.3 is as
defined as above)}, the formula: 9
[0040] {wherein Z.sub.1 and Z.sub.2 are each as defined above}, or
the formula: 10
[0041] {wherein R.sup.4 and R.sup.5 are each as defined as above}],
or their salts thereof.
[0042] The more preferred range is as follows.
[0043] In the compounds represented by the above formula (1), the
cyanobiphenyl derivatives [wherein R.sup.1 is a hydrogen atom or a
C.sub.1-C.sub.8 alkyl in the above definition and, in the above
definition, X is a formyl group or the formula:
--CH.sub.2--Y
[0044] {wherein, in the above definition, Y is a chlorine atom, a
bromine atom, an iodine atom, --OR.sup.2 (wherein, in the above
definition, R.sup.2 is a hydrogen atom or 4-piperidinomethyl group
(a nitrogen atom in the 4-piperidinomethyl group may be substituted
with a C.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl
group, an arylcarbonyl group, a C.sub.1-C.sub.8 alkoxycarbonyl
group, an aryloxycarbonyl group or an aralkoxycarbonyl group)), or
--NHR.sup.3 (wherein, in the above definition, R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group))}], or their salts thereof.
[0045] The far more preferred range is as follows:
[0046] In the compounds represented by the above formula (1), the
cyanobiphenyl derivatives [wherein R.sup.1 is a hydrogen atom or a
C.sub.1-C.sub.8 alkyl group in the above definition and, in the
above definition, X is a formyl group or the formula:
--CH.sub.2--Y
[0047] {wherein, in the above definition, Y is a chlorine atom, a
bromine atom, an iodine atom, --OR.sup.2 (wherein, in the above
definition, R.sup.2 is hydrogen atom, that is, --OR.sup.2 is a
hydroxyl group), or --NHR.sup.3 (wherein, in the above definition,
R.sup.3 is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group may be substituted with a C.sub.1-C.sub.8
alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl
group, a C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl
group or an aralkoxycarbonyl group))}], or their salts thereof.
[0048] Examples of the cyanobiphenyl derivatives or their salts of
the presence invention are shown in the following table.
1 No. R.sup.1 X 1 H CHO 2 H CH.sub.2--Cl 3 H CH.sub.2--Br 4 H
CH.sub.2--I 5 H CH.sub.2--OH 6 H 11 7 H 12 8 H 13 9 H 14 10 H 15 11
H 16 12 H 17 13 H 18 14 H 19 15 H 20 16 H 21 17 H 22 18 H 23 19 H
24 20 H 25 21 H 26 22 H 27 23 H 28 24 H 29 25 H 30 26 H 31 27 H 32
28 H 33 29 H 34 30 H 35 31 H 36 32 H 37 33 H 38 34 H 39 35 H 40 36
H 41 37 H 42 38 H 43 39 H 44 40 H 45 41 H 46 42 Me CHO 43 Me
CH.sub.2--Cl 44 Me CH.sub.2--Br 45 Me CH.sub.2--I 46 Me
CH.sub.2--OH 47 Me 47 48 Me 48 49 Me 49 50 Me 50 51 Me 51 52 Me 52
53 Me 53 54 Me 54 55 Me 55 56 Me 56 57 Me 57 58 Me 58 59 Me 59 60
Me 60 61 Me 61 62 Me 62 63 Me 63 64 Me 64 65 Me 65 66 Me 66 67 Me
67 68 Me 68 69 Me 69 70 Me 70 71 Me 71 72 Me 72 73 Et 73 74 Et 74
75 Et 75 76 Me 76 77 Me 77 78 Me 78 79 Me 79 80 Me 80 81 Me 81 82
Me 82 83 Et CHO 84 Et CH.sub.2--Cl 85 Et CH.sub.2--Br 86 Et
CH.sub.2--I 87 Et CH.sub.2--OH 88 Et 83 89 Et 84 90 Et 85 91 Et 86
92 Et 87 93 Et 88 94 Et 89 95 Et 90 96 Et 91 97 Et 92 98 Et 93 99
Et 94 100 Et 95 101 Et 96 102 Et 97 103 Et 98 104 Et 99 105 Et 100
106 Et 101 107 Et 102 108 Et 103 109 Et 104 110 Et 105 111 Et 106
112 Et 107 113 Et 108 114 Et 109 115 Et 110 116 Et 111 117 Et 112
118 Et 113 119 Et 114 120 Et 115 121 Et 116 122 Et 117 123 Et
118
[0049] Among the compounds listed in the above table, compound Nos.
42, 44, 46, 47, 48, 51, 60, 73, 80, 83, 85, 87, 88, 89, 92, 101,
114 and 121 are preferred, and compound Nos. 42, 44, 46, 47, 51, 60
and 80 are more preferred.
[0050] Furthermore, the most preferred range of the cyanobiphenyl
derivatives of the present invention is as follows.
[0051] Cyanobiphenyl derivatives [wherein, R.sup.1 is hydrogen atom
or a C.sub.1-C.sub.8 alkyl group in the above definition, and, in
the above definition, X is the formula:
--CH.sub.2--Y
[0052] {wherein, in the above definition, Y is --NHR.sup.3
(wherein, in the above definition, R.sup.3 is 4-piperidinomethyl
group (a nitrogen atom in the 4-piperidinomethyl group may be
substituted with a C.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8
alkylcarbonyl group, an arylcarbonyl group, a C.sub.1-C.sub.8
alkoxycarbonyl group, an aryloxycarbonyl group or an
aralkoxycarbonyl group))}], or their salts thereof.
[0053] Among the compounds listed in the above table, compound Nos.
47 and 80 are most preferred.
[0054] On the other hand, the following cyanobiphenyl derivatives
are also within the preferred range of the present invention.
[0055] That is, cyanobiphenyl derivatives [wherein, in the above
formula (1), R.sup.1 is as defined above, and X is, in the above
definition, a carboxyl group, a C.sub.1-C.sub.8 alkoxycarbonyl
group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a
formyl group, the formula:
--CH.sub.2--Y
[0056] {wherein, in the above definition, Y is a chlorine atom, an
iodine atom, --OR.sup.2 (wherein, in the above definition, R.sup.2
is a C.sub.1-C.sub.8 alkylsulfonyl group (the C.sub.1-C.sub.8
alkylsulfonyl group may further be substituted with halogen
atoms)), an arylsulfonyl group or 4-piperidinomethyl group (a
nitrogen atom in the 4-piperidinomethyl group is substituted with a
C.sub.5-C.sub.8 alkoxycarbonyl group or an aryloxycarbonyl group),
--NHR.sup.3 (wherein, in the above definition, R.sup.3 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group is substituted with a C.sub.5-C.sub.8 alkoxycarbonyl group or
an aryloxycarbonyl group)), the formula:
[0057] 119
[0058] {wherein Z.sub.1 and Z.sub.2 are each as defined above}, or
the formula: 120
[0059] {wherein R.sup.4 and R.sup.5 are each as defined above}], or
their salts thereof.
[0060] The more preferred range is as follows.
[0061] That is, in the above formula (1), R.sup.1 is, in the above
definition, a hydrogen atom or a C.sub.1-C.sub.8 alkyl group, and X
is, in the above definition, a carboxyl group, a C.sub.1-C.sub.8
alkoxycarbonyl group, a formyl group, or the formula:
--CH.sub.2--Y
[0062] {wherein Y is, in the above definition, --OR.sup.2 (wherein
R.sup.2 is 4-piperidinomethyl group (a nitrogen atom in the
4-piperidinomethyl group is substituted with a C.sub.5-C.sub.8
alkoxycarbonyl group or an aryloxycarbonyl group)), --NHR.sup.3
(R.sup.3 is, in the above definition, 4-piperidinomethyl group (a
nitrogen atom in the 4-piperidinomethyl group is substituted with a
C.sub.1-C.sub.8 alkoxycarbonyl group or an aryloxycarbonyl
group))}, or their salts thereof.
[0063] The far more preferred range is as follows.
[0064] Cynobiphenyl derivatives [wherein, in the above formula (1),
R.sup.1 is, in the above definition, a hydrogen atom or a
C.sub.1-C.sub.8 alkyl group, and X is, in the above definition, a
formyl group or the formula:
--CH.sub.2--Y
[0065] {wherein, in the above definition, Y is --NHR.sup.3
(wherein, in the above definition, R.sup.3 is 4-piperidinomethyl
group (a nitrogen atom in the 4-piperidinomethyl group is
substituted with a C.sub.5-C.sub.8 alkoxycarbonyl group or an
aryloxycarbonyl group))}], or their salts thereof. Among these
compounds, the following compounds are especially preferred.
[0066] Methyl 3-(3-cyanophenyl)-5-formylbenzoate, methyl
3-(3-cyanophenyl)-5-[((N-n-pentyloxycarbonyl)piperidin-4-ylmethyl)aminome-
thyl]benzoate, methyl
3-(3-cyanophenyl)-5-[((N-n-hexyloxycarbonyl)piperidi-
n-4-ylmethyl]aminomethyl]benzoate, methyl
3-(3-cyanophenyl)-5-[((N-n-hepty-
loxycarbonyl)piperidin-4-ylmethyl)aminomethyl]benzoate, methyl
3-(3-cyanophenyl)-5-[((N-n-octyloxycarbonyl)piperidin-4-ylmethyl]aminomet-
hyl]benzoate and methyl
3-(3-cyanophenyl)-5-[((N-phenoxycarbonyl)piperidin-
-4-ylmethyl)aminomethyl]benzoate.
[0067] Among the compounds listed above, methyl
3-(3-cyanophenyl)-5-formyl- benzoate is further more preferred.
[0068] A representative process for synthesizing the cyanobiphenyl
derivatives of the present invention is detailed in the following
description.
[0069] In the present invention, when starting materials or
intermediates have substituents which may influence the reaction
such as a hydroxyl group, an amino group or a carboxyl group, it is
preferable to suitably protect such functional groups to carry out
the objective reaction and then eliminate the protecting groups.
The protecting group is not especially limited if it is the one
which is usually used for each of substituents without adverse
effects on other moieties in protecting and deprotecting steps. It
includes, for example, a trialkylsilyl group, a C.sub.1-C.sub.4
alkoxymethyl group, a tetrahydropyranyl group, an acyl group and a
C.sub.1-C.sub.4 alkoxycarbonyl group as a protecting group of a
hydroxyl group. It includes, for example, a C.sub.1-C.sub.4
alkoxycarbonyl group, a benzyloxycarbonyl group and an acyl group
as a protecting group of an amino group. It includes, for example,
a C.sub.1-C.sub.4 alkyl group as the protecting group of a carboxyl
group. The deprotecting reaction can be carried out according to
methods usually conducted for respective protecting groups.
[0070] The cyanobiphenyl derivatives of the present invention can
be synthesized according to, for example, the following reaction
formula (a): 121
[0071] wherein R.sup.1 is as defined in the above formula (1),
R.sup.6 is a hydrogen atom or a C.sub.1-C.sub.4 alkyl group and
W.sup.1 is a chlorine atom, a bromine atom, an iodine atom or a
trifluoromethylsulfonyloxy group.
[0072] That is, cyanophenylboronic acid derivatives (6) which are
precursors are reacted with aryl halides or aryl
trifluoromethylsulfonate- s (7) in the presence of a base and a
transition metal catalyst such as palladium or nickel and, if
necessary, a phase-transfer catalyst to thereby produce the
cyanobiphenyl derivatives of the present invention.
[0073] Ethers such as tetrahydrofuran, 1,4-dioxane or
dimethoxyethane, hydrocarbons such as benzene or toluene,
halogenated hydrocarbons such as dichloromethane or chloroform,
alcohols such as methanol or ethanol, acetonitrile,
dimethylformamide, water or the like or mixed solvents thereof are
used as the solvent usually used in this reaction.
[0074] Inorganic bases such as potassium carbonate or sodium
carbonate, alkoxides such as tert-butoxypotassium and organic
tertiary amines such as triethylamine or pyridine are used as the
base used in the reaction.
[0075] A zerovalent palladium such as
tetrakis(triphenylphosphine)palladiu- m, a bivalent palladium such
as palladium acetate or diphenylphosphinobutanepalladium
dichloride, a bivalent nickel such as
[bis(diphenylphosphino)ferrocene]nickel dichloride and the like are
used in an amount of 0.001 to 100 mol % as the transition metal
catalysts, and tetra-C.sub.1-C.sub.8 alkylammonium halides or the
like in an amount of 0.001 to 100 mol % is used as the
phase-transfer catalysts in combination.
[0076] Among them, a combination of dimethylformamide as the
solvent with potassium carbonate as the base and zerovalent
palladium such as tetrakis(triphenylphosphine)palladium as the
transition metal catalyst or a combination of water as the solvent,
potassium carbonate as the base, palladium acetate as the
transition metal catalyst and tetrabutylammonium bromide as the
phase-transfer catalyst or a combination of a mixed solvent of
toluene-methanol as the solvent, potassium carbonate as the base
and palladium acetate as the transition metal catalyst is
preferred. The reaction is usually carried out at room temperature
or under heating for 0. 1 to 100 hours.
[0077] When X is represented by --CH.sub.2--Y.sup.2 described below
in the cyanobiphenyl derivatives of the present invention, the
cyanobiphenyl derivatives can be synthesized even according to, for
example, the following reaction formula (b): 122
[0078] wherein R.sup.1 is as defined in the above formula (1), and
Y.sup.2 is a chlorine atom, a bromine atom or an iodine atom.
[0079] That is, the cyanobiphenyl derivatives (1a-1) prepared
according to the above reaction formula (a) are reacted with
halogenating agents in the presence or absence of bases to thereby
produce the cyanobiphenyl derivatives (1b) which are the compounds
of the present invention.
[0080] Ethers such as tetrahydrofuran or diethyl ether,
hydrocarbons such as toluene or hexane, halogenated hydrocarbons
such as dichloromethane or chloroform or mixed solvents thereof are
used as the solvent usually used in the reaction.
[0081] Inorganic bases such as potassium carbonate or sodium
carbonate or organic tertiary amines such as triethylamine or
pyridine are used as the base. Furthermore, phosphorus trihalides,
phosphorus pentahalides, thionyl halides and the like are used as
the halogenating agents. The reaction is usually carried out at
room temperature or under heating for 0.5 to 100 hours.
[0082] Among them, a combination of diethyl ether as the solvent
with phosphorus tribromide as the halogenating agent is
preferred.
[0083] When X is represented by --CH.sub.2--Y.sup.3 described below
in the cyanobiphenyl derivatives of the present invention, the
cyanobiphenyl derivatives can be synthesized even according to, for
example, the following reaction formula (c): 123
[0084] wherein R.sup.1 is as defined in the above formula (1), and
Y.sup.3 is --OR.sup.2 (wherein R.sup.2 may be substituted with a
C.sub.1-C.sub.8 alkylsulfonyl group (the alkyl group may further be
substituted with halogen atoms) or an arylsulfonyl group).
[0085] That is, the cyanobiphenyl derivatives (1a-1) prepared
according to the above reaction formula (a) are reacted with
sulfonyl halides or sulfonic acid anhydrides in the presence of
bases to thereby produce the cyanobiphenyl derivatives (1c) which
are the compounds of the present invention.
[0086] Ethers such as tetrahydrofuran or diethyl ether,
hydrocarbons such as toluene or hexane, halogenated hydrocarbons
such as dichloromethane or chloroform, or mixed solvents thereof
are used as the solvent usually used in the reaction.
[0087] Sulfonyl halides such as methylsulfonyl chloride,
p-toluenesulfonyl chloride and the like and sulfonic acid
anhydrides such as methylsulfonic acid anhydride,
trifluoromethylsulfonic acid anhydride and the like are used.
[0088] Inorganic bases such as potassium carbonate or sodium
carbonate or organic tertiary amines such as triethylamine or
pyridine are used as the base.
[0089] The reaction is usually carried out at room temperature,
under cooling with ice or under heating for 0.5 to 100 hours.
[0090] When X is represented by --CH.sub.2--Y.sup.4 described below
in the cyanobiphenyl derivatives of the present invention, the
cyanobiphenyl derivatives can be synthesized even according to, for
example, the following reaction formula (d): 124
[0091] wherein R.sup.1 is as defined in the formula (1), Y.sup.2
and R.sup.6 are each as defined in the above reaction formulae (a)
and (b), Y.sup.4 is --OR.sup.2 (wherein R.sup.2 is
4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl
group may be substituted with a C.sub.1-C.sub.8 alkyl group, a
C.sub.1-C.sub.8 alkylcarbonyl group, an arylcarbonyl group, a
C.sub.1-C.sub.8 alkoxycarbonyl group, an aryloxycarbonyl group or
an aralkoxycarbonyl group)), and W.sup.2 is a bromine atom or a
trifluoromethylsulfonyloxy group. That is, iodobenzene derivatives
(8), which are starting materials, are mixed with alcohols
represented by Y.sup.4--H in the presence of bases to provide ether
derivatives (9), which are then monocarbonylated to introduce a
substituent group CO.sub.2R.sup.1. Thereby, benzoic acid
derivatives (10) are obtained. Further, a coupling reaction with
cyanophenylboronic acid derivatives (6) are carried out to produce
cyanobiphenyl derivatives (1d) which are the compounds of the
present invention.
[0092] The etherification shown in the first step of the reaction
formula (d) is carried out by using ethers such as tetrahydrofuran
or diethyl ether, hydrocarbons such as benzene or toluene, aprotic
polar solvents such as dimethylformamide or hexamethylphosphoric
triamide or mixed solvents and the like thereof. Metal oxides such
as barium oxide or zinc oxide, metal hydroxides such as sodium
hydroxide or potassium hydroxide, metal hydrides such as sodium
hydride and the like are used as such a base. The reaction usually
proceeds at 0 to 100.degree. C. for 3 to 72 hours with stirring.
The reaction is preferably carried out at 20 to 80.degree. C. for 8
to 36 hours by using sodium hydride in anhydrous ethers such as
tetrahydrofuran or diethyl ether.
[0093] The reaction for introducing the substituent group
CO.sub.2R.sup.1 shown in the second step of the reaction formula
(d) can be carried out by dissolving the ether derivatives (9)
obtained in the first step in alcohols represented by R.sup.1--OH,
adding bivalent palladium catalysts and bases such as tertiary
amines, for example, triethylamine and, if necessary, phosphine
ligands such as triphenyiphosphine and stirring the resulting
mixture at room temperature or under heating in an atmosphere of
carbon monoxide for 3 to 48 hours to convert the iodine atom into
the group CO.sub.2R.sup.1. The reaction is preferably carried out
at 60 to 80.degree. C. for 12 to 36 hours by using
bistriphenylphosphinepalladium chloride or palladium acetate as the
catalyst, diisopropylethylamine or tributylaluminum as the base and
methanol as the solvent.
[0094] The coupling reaction shown in the third step of the
reaction formula (d) is carried out by reacting benzoic acid
derivatives (10) with cyanophenylboronic acid derivatives (6) in
the presence of transition metal catalysts to thereby produce the
cyanobiphenyl derivatives (1d) which are the compounds of the
present invention.
[0095] Ethers such as tetrahydrofuran, 1,4-dioxane or
dimethoxyethane, hydrocarbons such as benzene or toluene,
halogenated hydrocarbons such as dichloromethane or chloroform,
alcohols such as methanol or ethanol, acetonitrile,
dimethylformamide, water or the like or mixed solvents thereof are
used as the solvent usually used in the reaction. Inorganic bases
such as potassium carbonate or sodium carbonate, alkoxides such as
tert-butoxypotassium or organic tertiary amines such as
triethylamine or pyridine are used as such a base. A zerovalent
palladium such as tetrakis(triphenylphosphine)palladium, a bivalent
palladium such as palladium acetate or
diphenylphosphinobutanepalladium dichloride or a bivalent nickel
such as [bis(diphenylphosphino)ferrocene]nickel dichloride is used
as the transition metal catalyst in an amount of 0.001 to 100 mol
%. Furthermore, a tetra-C.sub.1-C.sub.8 alkylammonium halide or the
like is used as a phase-transfer catalyst together in an amount of
0.001 to 100 mol %.
[0096] Among them, a combination of dimethylformamide as the
solvent, potassium carbonate as the base and a zerovalent palladium
such as tetrakis(triphenylphosphine)palladium as the transition
metal catalyst, a combination of water as the solvent, potassium
carbonate as the base, palladium acetate as the transition metal
catalyst and tetrabutylammonium bromide as the phase-transfer
catalyst, or a combination of a mixed solvent of toluene-methanol
as the solvent, potassium carbonate as the base and palladium
acetate as the transition metal catalyst, is preferred. The
reaction is usually carried out at room temperature or under
heating for 0.1 to 100 hours.
[0097] When X is shown by --CH.sub.2--Y.sup.1 described below in
the cyanobiphenyl derivatives of the present invention, the
cyanobiphenyl derivatives can be synthesized even according to, for
example, the following reaction formula (e): 125
[0098] wherein R.sup.1 is as defined in the formula (1), and
Y.sup.1 is as defined in the above formula (3).
[0099] That is, the cyanobiphenyl derivatives (1a-2) prepared
according to the above reaction formula (a) are mixed with amines
represented by Y.sup.1--H, if necessary, in the presence of a
catalytic amount of acids or dehydrating agents to produce imine
intermediates which are subsequently reduced to produce the
cyanobiphenyl derivatives (1e) which are the compounds of the
present invention.
[0100] Ethers such as tetrahydrofuran, 1,4-dioxane or
dimethoxyethane, hydrocarbons such as benzene or toluene,
halogenated hydrocarbons such as dichloromethane or chloroform,
alcohols such as methanol or ethanol, aprotic polar solvents such
as dimethylformamide, acetonitrile, water and the like, or mixed
solvents thereof are used as the solvent usually used in the
reaction.
[0101] Toluene is preferred for the reaction for preparing the
imine intermediates, and methanol is preferred for the subsequent
reduction. Metal hydride complex compounds such as sodium
borohydride or lithium aluminum hydride are used as the reducing
agent. The reduction is also achieved by hydrogenation in the
presence of transition metal catalysts such as palladium-carbon,
platinum oxide or Raney nickel. Inorganic acids such as
hydrochloric acid or sulfuric acid or organic acids such as
benzenesulfonic acid or p-toluenesulfonic acid are used as the acid
catalysts used in the preparation of the imine intermediates.
Molecular sieves 4A, anhydrous sodium sulfate and the like are used
as the dehydrating agents.
[0102] The reaction is usually carried out at room temperature or
under heating for 1 to 100 hours. The reaction for preparing the
imine intermediates is preferably carried out at 100 to 200.degree.
C., and the reduction is preferably carried out at room
temperature.
[0103] When X is shown by --CH.sub.2--Y.sup.4 or
--CH.sub.2--Y.sup.1 in the cyanobiphenyl derivatives of the present
invention, the cyanobiphenyl derivatives can be synthesized
according to, for example, the following reaction formula (f):
126
[0104] wherein R.sup.1 is as defined in the formula (1), and
Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.1 are each as defined in the
above reaction formulae (b), (c), (d) and (e).
[0105] That is, the cyanobiphenyl derivatives (1b) or (1c) prepared
according to the above reaction formula (b) or (c) are mixed with
alcohols represented by Y.sup.4--H in the presence of bases to
thereby synthesize the cyanobiphenyl derivatives (1d) of the
present invention. Furthermore, amines represented by Y.sup.1--H
are mixed therewith in the presence of bases to thereby synthesize
the cyanobiphenyl derivatives (1e) of the present invention.
[0106] Ethers such as tetrahydrofuran or diethyl ether,
hydrocarbons such as toluene or hexane, halogenated hydrocarbons
such as dichloromethane or chloroform, aprotic polar solvents such
as dimethylformamide, or mixed solvents thereof are used as the
solvent usually used in the reaction. Metal hydrides such as sodium
hydride, inorganic bases such as potassium carbonate or sodium
carbonate or organic tertiary amines such as triethylamine or
pyridine are used as such a base. The reaction is usually carried
out at room temperature or under heating for 0.5 to 100 hours.
[0107] When X is shown by --CH.sub.2--N.sub.3 in the cyanobiphenyl
derivatives of the present invention, the cyanobiphenyl derivatives
can be synthesized even according to, for example, the following
reaction formula (g): 127
[0108] wherein R.sup.1 is as defined in the formula (1), Y.sup.2
and Y.sup.3 are each as defined in the above (b) and (c) and M is
an alkali metal atom such as lithium atom, sodium atom or potassium
atom or a trialkylsilyl group.
[0109] That is, the cyanobiphenyl derivatives (1b) or (1c) prepared
according to the above reaction formula (b) or (c) are mixed with
azides represented by M-N.sub.3 to thereby synthesize the
cyanobiphenyl derivatives (1g) of the present invention.
[0110] Aprotic polar solvents such as dimethylformamide or
hexamethylphosphoric triamide, ethers such as tetrahydrofuran or
diethylene glycol dimethyl ether, halogenated hydrocarbons such as
chloroform or dichloromethane, alcohols such as methanol or
ethanol, water, or mixed solvents thereof are used as the solvent
usually used in the reaction. Alkali metal azides such as sodium
azide or potassium azide, trialkylsilyl azides and the like are
used as the azides. A combination of dimethylformamide as the
solvent with sodium azide as the azide is preferred.
[0111] When X is represented by --CH.sub.2--NH.sub.2 in the
cyanobiphenyl derivatives of the present invention, the
cyanobiphenyl derivatives can be synthesized even according to, for
example, the following reaction formula (h): 128
[0112] wherein R.sup.1 is as defined as in the formula (1).
[0113] That is, the cyanobiphenyl derivatives (1g) prepared
according to the above reaction formula (g) are reduced with
suitable reducing agents to thereby synthesize the cyanobiphenyl
derivatives (1h) of the present invention.
[0114] Aprotic polar solvents such as dimethylformamide or
hexamethylphosphoric triamide, ethers such as tetrahydrofuran or
diethylene glycol dimethyl ether, halogenated hydrocarbons such as
chloroform or dichloromethane, alcohols such as methanol or ethanol
and water are used as the solvent usually used in the reaction.
[0115] Metal hydride complexes such as sodium borohydride or
lithium aluminum hydride, metal hydrides such as trialkyltin
hydrides, a metal such as zinc or chromium or salts thereof are
specifically used as the reducing agent. Otherwise, hydrogenation
may be used in the presence of a catalyst such as palladium. A
combination of methanol as the solvent with sodium borohydride as
the reducing agent is preferred.
[0116] The cyanobiphenyl derivatives (1d) or (1e) of the present
invention synthesized according to the above reaction formula (a),
(d), (e) or (f) can be converted into the biphenylamidine
derivatives described in WO99/26918 by carrying out an amidination
as shown in the following reaction formula (i): 129
[0117] wherein R.sup.1 is as defined in the formula (1), Y.sup.4
and Y.sup.1 are each as defined in the above reaction formulae (d)
and (e), R.sup.7 is a C.sub.1-C.sub.4 alkyl group, Y.sup.5 is a
group in which a nitrogen atom in the 4-piperidinomethyl group is
unsubstituted or substituted with a C.sub.1-C.sub.8 alkyl group or
a C.sub.1-C.sub.8 alkylcarbonyl group or an arylcarbonyl group in
the above Y.sup.4, Y.sup.6 is a group in which a nitrogen atom in
the 4-piperidinomethyl group is unsubstituted or substituted with a
C.sub.1-C.sub.8 alkyl group, a C.sub.1-C.sub.8 alkylcarbonyl group
or an arylcarbonyl group in the above Y.sup.1, and W.sup.3 is a
chlorine atom, a bromine atom or an iodine atom.
[0118] The amidination is carried out under reaction conditions
shown in the following (i-1) or (i-2).
[0119] (i-1) Amidination Through Imidate Intermediates Using a
Solution of Hydrogen Halides in Alcohols
[0120] The reaction is carried out by dissolving the cyanobiphenyl
derivatives (1d) or (1e) of the present invention in alcohols
represented by R.sup.7--OH having 1 to 4 carbon atoms, which
contain hydrogen halides represented by, for example, H--W.sup.3
such as hydrogen chloride or hydrogen bromide. The reaction is
usually carried out at -20 to +30.degree. C. for 12 to 96 hours and
is preferably carried out in a solution of hydrogen chloride in
methanol or ethanol at -10 to +30.degree. C. for 24 to 72
hours.
[0121] The reaction of the imidates (11) with ammonia proceeds by
stirring the imidates (11) in alcohols having 1 to 4 carbon atoms
such as methanol or ethanol, aliphatic ethers such as diethyl ether
or halogenated hydrocarbons such as dichloromethane or chloroform
or mixed solvents thereof containing the ammonia or amines such as
hydroxylamines, hydrazines or carbamic acid esters to synthesize a
biphenylamidine derivatives (12). The reaction is usually carried
out at -10 to +50.degree. C. for 1 to 48 hours and is preferably
carried out in methanol or ethanol at 0 to 30.degree. C. for 2 to
12 hours.
[0122] (i-2) Amidination Through Imidate Intermediates Prepared by
While Directly Bubbling Hydrogen Halides
[0123] The reaction proceeds by dissolving the cyanobiphenyl
derivatives (1d) or (1e) of the present invention in ethers such as
diethyl ether, halogenated hydrocarbons such as chloroform or
aprotic solvents such as benzene, adding an equivalent amount or an
excess of alcohols represented by R.sup.7--OH having 1 to 4 carbon
atoms, bubbling hydrogen halides represented by H--W.sup.3 such as
hydrogen chloride or hydrogen bromide under stirring at -30 to
0.degree. C. for 30 minutes to 6 hours, then stopping the bubbling
and more stirring the solution at 0 to 50.degree. C. for 3 to 96
hours.
[0124] Preferably, the reaction is carried out by bubbling hydrogen
chloride at -10 to 0.degree. C. for 1 to 3 hours with stirring
thereof in halogenated hydrocarbons containing an equivalent amount
or an excess of methanol or ethanol and then stirring the solution
at 10 to 40.degree. C. for 8 to 24 hours without bubbling. The
imidates (10) thus obtained can be converted into the
biphenylamidine derivatives (12) by carrying out the stirring
thereof in alcohols having 1 to 4 carbon atoms such as methanol or
ethanol, aliphatic ethers such as diethyl ether or halogenated
hydrocarbons such as chloroform or mixed solvents thereof which
contain ammonia or amines such as hydroxylamine, hydrazine or
carbamic acid esters. The reaction is usually carried out at -20 to
+50.degree. C. for 1 to 48 hours and is preferably carried out in
saturated ethanol solution of ammonia at 0 to 30.degree. C. for 2
to 12 hours.
[0125] The compounds represented by the above formula (1) can
respectively and mutually be synthesized by optional combination of
other processes such as known oxidation, reduction, esterification
or hydrolysis which are usually adoptable by those skilled in the
art.
[0126] The cyanobiphenyl derivatives (1) synthesized as described
above can be isolated and purified according to known methods, for
example, extraction, precipitation, fractional chromatography,
fractional crystallization or recrystallization. A salt of the
compounds of the present invention can be synthesized by carrying
out a usual salt-forming reaction.
[0127] The cyanobiphenyl derivatives of the present invention can
effectively be used as synthetic intermediates for the
biphenylamidine derivatives described in WO99/26918.
EXAMPLES
[0128] The present invention will be illustrated using the
following Productive Examples, Examples and Reference Examples. The
scope of the present invention, however, is not restricted by the
Productive Examples, Examples and Reference Examples.
Productive Example 1
Preparation of 3-cyanophenylboronic Acid
[0129] 130
[0130] In 100 ml of anhydrous tetrahydrofuran, was dissolved 20 g
of 3-bromobenzonitrile. To the resulting solution, was added 37.6
ml of triisopropoxyborane under a nitrogen atmosphere. The formed
solution was cooled to -78.degree. C., and 98.3 ml of a 1.6 M
solution of n-butyllithium in hexane was dropped thereinto under
stirring for about 30 minutes. After stirring the resulting mixture
at room temperature for 30 minutes, the mixture was then cooled to
0.degree. C., and 220 ml of a 4 M sulfuric acid was added. The
prepared solution was refluxed overnight and subsequently recooled
to 0.degree. C. To the cooled solution, was added 340 ml of a 5 M
aqueous solution of sodium hydroxide. The resulting solution was
extracted with 200 ml of diethyl ether, and an aqueous layer was
separated. To the aqueous layer, was added a 6 M hydrochloric acid
until pH attained 2. The resulting mixture was extracted with 300
ml of ethyl acetate twice. The extract was dried over magnesium
sulfate, and the solvent was then evaporated. The resulting crude
product was recrystallized from dimethylformamide-water to provide
11.6 g (72%) of the title compound as a needlelike light-yellow
crystal.
[0131] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 7.6-8.3 (m,
4H), 8.5 (brs, 2H).
Productive Example 2
Preparation of Methyl 3-bromo-5-(hydroxymethyl)benzoate
[0132] 131
[0133] In 25 ml of tetrahydrofuran, was dissolved 10.00 g of
dimethyl 3-bromoisophthalate. 1.66 g of sodium borohydride was
added to the above solution and thereby a suspension was obtained.
A mixed solution of 7.4 ml of methanol and 25 ml of tetrahydrofuran
was slowly dropped into the resulting suspension. After completing
the dropping, the reaction solution was refluxed for 30 minutes. A
1 M hydrochloric acid was added to the solution to quench the
reaction. The resulting solution was extracted with ethyl acetate,
and the organic layer was dried over magnesium sulfate. The solvent
was removed under reduced pressure to afford 9.30 g of the title
compound as a colorless oil quantitatively.
[0134] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 3.9 (s, 3H), 4.73
(d, 2H, J=5.4 Hz), 7.7-8.1 (m, 3H).
Example 1
Synthesis of Methyl 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoate
[0135] 132
[0136] In 50 ml of anhydrous dimethylformamide, was dissolved 3.08
g of the compound obtained in Productive Example 2. To the
resulting solution, were added 2.32 of the compound obtained in
Productive Example 1, 2.18 g of potassium carbonate and 456 mg of
tetrakis(triphenylphosphine) palladium. The prepared mixture was
stirred at 90.degree. C. under heating overnight. Water was added
to quench the reaction, and the resulting solution was extracted
with ethyl acetate. The obtained extract was dried over magnesium
sulfate, and the solvent was evaporated. The obtained crude product
was purified by silica gel column chromatography to provide 2.05 g
(73%) of the title compound as a white crystal.
[0137] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 2.1 (brs, 1H),
3.96 (s, H), 4.84 (d, 2H, J=3.7 Hz), 7.5-8.2 (m, 7H).
Example 2
Synthesis of Methyl 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoate
[0138] 133
[0139] In 35 ml of ion exchange water, were dissolved 6.31 g of the
compound obtained in Productive Example 1, 10.01 g of the compound
obtained in Productive Example 2, 13.23 g of tetrabutylammonium
bromide, 14.02 g of potassium carbonate and 0.021 g of palladium
acetate under a nitrogen stream. The resulting solution was stirred
under heating at 60.degree. C. for 40 minutes. The reaction
solution was extracted with ethyl acetate, and the organic layer
was washed with saturated brine and then dried over sodium sulfate.
The solvent was evaporated. The obtained crude product was purified
by silica gel column chromatography to afford 8.58 g (79%) of the
title compound as a white crystal.
[0140] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 2.1 (brs, 1H),
3.96 (s, 3H), 4.84 (d, 2H, J=3.7 Hz), 7.5-8.2 (m, 7H).
Example 3
Synthesis of Methyl 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoate
[0141] 134
[0142] To a mixed solvent of 1260 ml of toluene with 290 ml of
methanol, were added 140 g of the compound obtained in Productive
Example 1 and 88 g of the compound obtained in Productive Example
2. To the resulting mixture, were further added 0.95 g of palladium
acetate and 648 g of a 25% aqueous solution of potassium carbonate.
The obtained mixture was stirred under heating at 55.degree. C. for
2 hours. The resulting reaction mixture was filtered and separated,
and the aqueous layer was extracted with 300 ml of toluene. Organic
layers were combined, washed with a dilute hydrochloric acid, dried
and then concentrated. The obtained crude product was purified by
silica gel column chromatography to provide 90 g (94%) of the title
compound as a white crystal.
[0143] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 2.1 (brs, 1H),
3.96 (s, 3H), 4.84 (d, 2H, J=3.7 Hz), 7.5-8.2 (m, 7H).
[0144] The following compound of Example 4 was synthesized
according to the same method as that in Example 2 or 3:
Example 4
Synthesis of Dimethyl 3-(3-cyanophenyl)isophthalate
[0145] 135
[0146] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 4.00 (s, 6H),
7.5-8.0 (m, 4H), 8.44 (s, 2H), 8.72 (s, 1H).
Example 5
Synthesis of Methyl 3-(3-cyanophenyl)-5-(bromomethyl)benzoate
[0147] 136
[0148] To 20 ml of diethyl ether, was added 1.0 g of the compound
obtained in Example 1, 2 or 3. Into the prepared suspension, was
slowly dropped 0.5 ml of phosphorus tribromide. The resulting
solution was stirred at room temperature for 19 hours. Water was
added to the reaction solution to quench the reaction, and the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The solvent was then removed under reduced pressure to
afford 1.2 g (98%) of the title compound as a light-yellow
crystal.
[0149] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 3.97 (s, 3H),
4.58 (s, 2H), 7.5-7.9 (m, 5H), 8.1-8.2 (m, 2H).
Example 6
Synthesis of Methyl
3-(3-cyanophenyl)-5-[((N-t-butoxycarbonyl)piperidin-4--
ylmethyl)aminomethyl]benzoate
[0150] 137
[0151] In 150 ml of anhydrous tetrahydrofuran, was dissolved 5.5 g
of the compound obtained in Example 5. To the resulting solution,
was added 7.92 g of 4-aminomethyl-(N-t-butoxycarbonyl)piperidine.
The obtained mixture was stirred at room temperature overnight. The
resulting reaction solution was poured into a 0.5 M aqueous
solution of potassium hydrogensulfate to quench the reaction. The
reaction solution was extracted with ethyl acetate and dried over
sodium sulfate, and the solvent was then evaporated to provide 10 g
(as a potassium hydrogensulfate salt, quantitatively) of the title
compound.
[0152] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-1.3 (m, 2H),
1.43 (s, 9H), 1.7-2.0 (m, 3H), 2.6-2.8 (m, 4H), 3.95 (s, 3H),
4.0-4.2 (brs, 4H), 7.5-7.7 (m, 2H), 7.9-8.0 (m, 2H), 8.20 (s,
2H).
[0153] The compounds of Examples 7 to 8 described below were
synthesized according to the same method as that in Example 6, with
the proviso that sodium hydride was used as a base.
Example 7
Synthesis of Methyl
3-(3-cyanophenyl)-5-[((N-t-butoxycarbonyl)piperidin-4--
yl)methoxymethyl]benzoate
[0154] 138
[0155] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-1.3 (m, 2H),
1.45 (s, 9H), 1.5-1.6 (m, 1H), 1.6-1.9 (m, 2H), 2.71 (t, 2H, J=12.2
Hz), 3.38 (d, 2H, J=5.9 Hz), 3.97 (s, 3H), 4.0-4.2 (m, 2H), 4.60
(s, 2H), 7.5-7.9 (m, 4H), 7.90 (s, 1H), 8.03 (s, 1H), 8.16 (s,
1H).
Example 8
Synthesis of Methyl
3-(3-cyanophenyl)-5-[(N-isopropylpiperidin-4-yl)methox-
ymethyl]benzoate
[0156] 139
[0157] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.04 (d, 6H,
J=6.6 Hz), 1.6-1.9 (m, 4H), 2.13 (dt, 2H, J=11.6 Hz, 2.3 Hz), 2.70
(quint, 1H, J=6.6 Hz), 2.90 (d, 2H, J=11.6 Hz), 3.38 (d, 2H, J=6.6
Hz), 3.96 (s, 3H), 4.60 (s, 2H), 7.5-7.7 (m, 2H), 7.74 (s, 1H),
7.8-7.9 (m, 1H), 8.03 (s, 1H), 8.15 (s, 1H).
Example 9
Synthesis of Methyl 3-(3-cyanophenyl)-5-(azidomethyl)benzoate
[0158] 140
[0159] In 33 ml of dimethylformamide, was dissolved 1.1 g of the
compound obtained in Example 5. To the resulting solution, was
slowly added 325 mg of sodium azide. The obtained reaction solution
was stirred at room temperature for 2 hours, and 80 ml of water and
120 ml of ethyl acetate were then added thereto to extract organic
substances. The aqueous layer was extracted with 100 ml of ethyl
acetate twice. The resulting extract was washed with saturated
brine and dried with anhydrous sodium sulfate. The solvent was
removed under reduced pressure to afford 925 mg (95%) of the title
compound as a light-yellow oil.
[0160] GC-MS (M-N.sub.2)=264.
Example 10
Synthesis of Methyl 3-(3-cyanophenyl)-5-(aminomethyl)benzoate
[0161] 141
[0162] The compound obtained in Example 9 was dissolved in 66 ml of
ethanol. To the resulting solution, was added 1.1 g of
palladium-barium carbonate. The interior of the flask was then
replaced with hydrogen. The solution was stirred at room
temperature for 6 hours, and then the catalyst was filtered through
Celite. The resulting filtrate was concentrated and then purified
by silica gel column chromatography to provide 794 mg (94%) of the
title compound.
[0163] GC-MS (M-H)=265.
Example 11
Synthesis of Methyl 3-(3-cyanophenyl)-5-(formyl)benzoate
[0164] 142
[0165] In 200 ml of dichloromethane, was dissolved 9.05 g of the
compound obtained in Example 1, 2 or 3. To the resulting solution,
was added 20.6 g of manganese dioxide. The obtained mixture was
stirred at room temperature for 40 hours. The reaction solution was
filtered through Celite, and the Celite was further washed with
dichloromethane. Each filtrate was combined into one portion, and
the solvent was removed under reduced pressure to afford 7.65 g
(85%) of the title compound as a white crystal.
[0166] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 4.02 (s, 3H),
7.5-8.7 (m, 7H), 10.16 (s, 1H).
Example 12
Synthesis of Methyl
3-(3-cyanophenyl)-5-(dimethoxymethyl)benzoate
[0167] 143
[0168] In 200 ml of methanol, were dissolved 2.00 g of the compound
obtained in Example 11, 0.86 ml of methyl orthoformate and 0.004 g
of p-toluenesulfonic acid monohydrate. The resulting solution was
refluxed for 12 hours. After completing the reaction, 0.03 ml of
triethylamine was added to the reaction solution, and the solvent
was then removed under reduced pressure. Ethyl acetate was added to
the residue, and the resulting solution was extracted with ethyl
acetate. The organic layer was dried over sodium sulfate. The
solvent was removed under reduced pressure to provide 2.35 g
(quantitatively) of the title compound.
[0169] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 3.35 (s, 6H),
3.90 (s, 3H), 5.85 (s, 1H), 7.5-8.7 (m, 7H) ; GC-MS (M+H)=312.
Example 13
Synthesis of Methyl 3-(3-cyanophenyl)-5-(dibromomethyl)benzoate
[0170] 144
[0171] In 10 ml of dichloromethane, was dissolved 6.2 g of
triphenyl phosphite. The resulting solution was cooled to 0.degree.
C., and then 3.2 g of bromine was slowly dropped. The reaction
solution was cooled to -15.degree. C., and 5 ml of a solution of
2.65 g of the compound obtained in Example 11 in dichloromethane
was slowly dropped therein. After completing the dropping, the
temperature was returned to room temperature, and subsequently the
reaction solution was filtered through basic alumina. The solvent
was removed under reduced pressure. The resulting residue was
purified by silica gel column chromatography to afford 3.48 g (85%)
of the title compound.
[0172] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 4.02 (s, 3H),
6.80 (s, 1H), 7.5-8.7 (m, 7H) GC-MS (M+H)=408.
Example 14
Synthesis of Methyl
3-(3-cyanophenyl)-5-[(piperidin-4-ylmethyl)aminomethyl-
]benzoate
[0173] 145
[0174] In 30 ml of toluene, were dissolved 3.00 g of the compound
obtained in Example 11 and 1.50 g of 4-aminomethylpiperidine. The
resulting solution was refluxed for 3 hours to remove the produced
water. The solvent was evaporated from the reaction solution under
reduced pressure, and 10 ml of tetrahydrofuran and 20 ml of
methanol were added to the residue to provide a solution. To the
resulting solution, was added 0.500 g of sodium borohydride under
cooling with ice. The mixture was stirred at this temperature for 1
hour, then returned to room temperature and stirred for another
hour. To the resulting solution was added a 1 M hydrochloric acid
to quench the reaction. The resulting solution was washed with
ethyl acetate. A 1 M aqueous solution of sodium hydroxide was added
to the obtained aqueous layer until the pH attained 10. The
resulting solution was extracted with ethyl acetate. The resulting
organic layer was washed with saturated brine and subsequently
dried over sodium sulfate, and the solvent was removed under
reduced pressure to provide 2.9 g (71%) of the title compound as an
oil.
[0175] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-3.5 (m, 11H),
3.90 (s, 2H), 3.96 (s, 3H), 7.5-8.5 (m, 7H).
Example 15
Synthesis of Methyl
3-(3-cyanophenyl)-5-[(piperidin-4-ylmethyl)aminomethyl-
]benzoate
[0176] 146
[0177] In 20 ml of toluene, were added 1.0 g of the compound
obtained in Example 11 and 500 mg of 4-aminomethylpiperidine. The
resulting mixture was refluxed using a Dean-Stark device under
heating for 2 hours to remove the produced water. The solvent was
then evaporated, and 20 ml of anhydrous methanol was added to
dissolve the residue. To the obtained solution, was added 100 mg of
5% palladium-carbon. The mixture was stirred at room temperature
under hydrogen atmosphere. After 4 hours, 200 mg of the 5%
palladium-carbon was further added, and the reaction mixture was
stirred for another 65 hours. The catalyst was separated by
filtration, and the reaction mixture was concentrated. The
resulting concentrate was then dissolved in a mixed solvent of
water-dichloromethane, and the aqueous layer was separated and
concentrated to afford 0.82 g (60%) of the title compound as a
light-yellow oily substance.
[0178] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-3.5 (m, 11H),
3.90 (s, 2H), 3.96 (s, 3H), 7.5-8.5 (m, 7H).
Example 16
Synthesis of Methyl
3-(3-cyanophenyl)-5-[(piperidin-4-yl)methoxymethyl]ben- zoate
[0179] 147
[0180] In 20 ml of methanol, was dissolved 400 mg of the compound
obtained in Example 7. To the resulting solution, was added 20 ml
of a 2 M hydrochloric acid under cooling with ice and stirring.
After stirring at 0.degree. C. to room temperature for 7 hours, the
resulting solution was then concentrated to provide 298 mg (95%) of
the title compound.
[0181] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-3.4 (m, 11H),
3.97 (s, 3H), 4.05 (s, 2H), 7.5-8.5 (m, 7 H).
Example 17
Synthesis of Methyl
3-(3-cyanophenyl)-5-[(1-acetylpiperidin-4-yl)methoxyme-
thyl]benzoate
[0182] 148
[0183] In 20 ml of dichloromethane, was dissolved 298 mg of the
compound obtained in Example 16. To the resulting solution, was
added 3.0 ml of triethylamine. To the obtained mixture, 0.46 ml of
acetyl chloride was added under cooling with ice and stirring. The
mixture was stirred at 0.degree. C. to room temperature for 18
hours. The obtained mixture was poured into a saturated aqueous
solution of sodium hydrogensulfate and extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium hydrogencarbonate and saturated brine and
subsequently dried over magnesium sulfate. The solvent was removed
under reduced pressure, and the obtained crude product was purified
by silica gel column chromatography to afford 260 mg (78%) of the
title compound.
[0184] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-1.3 (m, 2H),
1.7-2.0 (m, 3H), 2.09 (s, 3H), 2.56 (td, 1H, J=12.8, 2.9 Hz), 3.06
(td, 1H, J=13.2, 2.0 Hz), 3.2-3.5 (m, 2H), 3.83 (brd, 1H, J=13.5
Hz), 3.97 (s, 3H), 4.65 (s, 2H), 4.5-4.8 (m, 1H), 7.58 (t, 1H,
J=7.8 Hz), 7.6-7.8 (m, 1H), 7.72 (s, 1H), 7.85 (d, 1H, J=7.9 Hz),
7.90 (s, 1H), 8.03 (s, 1H), 8.17 (s, 1H).
Example 18
Synthesis of Methyl
3-(3-cyanophenyl)-5-[2-(N-t-butoxycarbonylpiperidin-4--
yl)methoxymethyl]benzoate
[0185] 149
[0186] In 20 ml of methanol, was dissolved 1.43 g of the compound
obtained in Example 7. To the resulting solution, was added 2 ml of
water. To the prepared mixture, was added 1.54 ml of a 4 M aqueous
solution of lithium hydroxide. The obtained mixture was stirred at
room temperature for 3 hours. A saturated aqueous solution of
ammonium chloride was added to acidify the mixture. The acidified
mixture was then extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over magnesium sulfate.
The solvent was evaporated, and the obtained crude product was
purified by silica gel column chromatography to provide 1.03 g
(74%) of the title compound.
[0187] .sup.1H-NMR (270 MHz, CDCl.sub.3): .delta. 1.0-1.3 (m, 2H),
1.46 (s, 9H), 1.7-2.0 (m, 3H), 2.56 (td, 1H, J=12.8, 2.9 Hz), 3.05
(td, 1H, J=13.2, 2.0 Hz), 3.2-3.5 (m, 2H), 3.83 (brd, 1H, J=13.5
Hz), 4.65 (s, 2H), 4.6-4.8 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 7.6-7.8
(m, 1H), 7.74 (s, 1H), 7.85 (d, 1H, J=7.9 Hz), 7.90 (s, 1H), 8.03
(s, 1H), 8.16 (s, 1H).
Reference Example 1
Synthesis of Methyl
3-(3-amidinophenyl)-5-[((4-piperidinylmethyl)amino)met-
hyl]-5-benzoate
[0188] 150
[0189] In 60 ml of dichloromethane, was dissolved 6.0 g of the
compound obtained in Example 6. To the resulting solution, was
added 3.0 ml of methanol. Gaseous hydrogen chloride was bubbled
into the solution with stirring under cooling with ice for 30
minutes. After stirring the solution at 0.degree. C. for 30 minutes
and at room temperature for 20 hours, the resulting solution was
concentrated. To the residue, was added 30 ml of a saturated
ammonia-ethanol solution, and the resulting solution was stirred at
room temperature for 5 hours and then concentrated. The obtained
crude product was purified by using HP-20 column chromatography (30
g, eluting solvent: water-methanol) to afford 4.89 g (99%) of the
title compound.
[0190] .sup.1H-NMR (270 MHz, DMSO-d.sub.6+D.sub.2O): .delta.
1.3-1.5 (m, 2H), 1.96-2.00 (m, 2H), 2.1 (brs, 1H), 2.7-3.0 (m, 4H),
3.97 (s, 3H), 4.32 (s, 2H), 7.76 (t, 1H, J=7.8 Hz), 7.89 (d, 1H,
J=7.8 Hz), 8.1-8.5 (m, 5H).
[0191] The following compounds of Reference Examples 2 to 5 were
synthesized according to the same method as that in Reference
Example 1.
Reference Example 2
Synthesis of Methyl
3-(3-amidinophenyl)-5-[((4-piperidinylmethyl)amino)met-
hyl]-5-benzoate
[0192] 151
[0193] The compound obtained in Example 14 or 15 was used as a
starting material to provide the title compound. (The spectral data
were the same as those in Reference Example 1.)
Reference Example 3
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(4-piperidinyl)methoxymethyl]-5-
-benzoate
[0194] 152
[0195] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.3-1.5 (m,
2H), 1.7-2.0 (m, 3H), 2.7-2.9 (m, 2H), 3.15-3.3 (m, 2H), 3.38 (d,
2H, J=6.3 Hz), 3.91 (s, 3H), 4.64 (s, 2H), 7.69 (t, 1H, J=7.9 Hz),
7.86 (d, 1H, J=7.9 Hz), 7.99 (s, 1H), 8.02 (s, 1H), 8.07 (d, 1H,
J=7.6 Hz), 8.15 (s, 1H), 8.28 (s, 1H), 8.55-8.85 (brs, 1H),
9.19-9.52 (s, 2H).
Reference Example 4
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(N-isopropyl-4-piperidinyl)meth-
oxymethyl]-5-benzoate
[0196] 153
[0197] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.26 (d, 6H,
J=6.9 Hz), 1.6-2.0 (m, 5H), 2.8-3.0 (m, 2H), 3.1-3.5 (m, 5H), 3.92
(s, 3H), 4.65 (s, 2H), 7.74 (t, 1H, J=7.8 Hz), 7.90 (d, 1H, J=7.9
Hz), 7.98 (s, 1H), 8.07 (s, 1H), 8.07 (d, 1H, J=7.6 Hz), 8.08 (d,
1H, J=8.3 Hz), 8.18 (s, 1H), 8.27 (s, 1H), 9.40-9.62 (brs, 3H).
Reference Example 5
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(N-acetylpiperidin-4-yl)methoxy-
methyl]-5-benzoate
[0198] 154
[0199] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 0.9-1.3 (m,
2H), 1.6-2.0 (m, 3H), 1.97 (s, 3H), 2.4-2.65 (m, 1H), 3.00 (brt,
1H, J=11.7 Hz), 3.2-3.5 (m, 2H), 3.80 (brd, 1H, J=14.9 Hz), 3.91
(s, 3H), 4.37 (brd, 1H, J=4.4 Hz), 4.63 (s, 2H), 7.71 (t, 1H, J=7.7
Hz), 7.83 (d, 1H, J=7.9 Hz), 7.98 (s, 2H), 8.02 (d, 1H, J=7.9 Hz),
8.11 (s, 1H), 8.17 (s, 1H), 8.25 (s, 1H), 9.40-10.0 (br, 3H).
Reference Example 6
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(((N-acetimidoylpiperidin-4-yl)-
methyl)amino)methyl]benzoate
[0200] 155
[0201] To 4.79 g of the compound obtained in Reference Example 1 or
2 and 3.10 g of ethyl acetimidate monohydrochloride, were added 50
ml of ethanol. To the resulting solution, was dropped 5.25 ml of
triethylamine with stirring under cooling with ice. The resulting
mixture was warmed up from 0.degree. C. to room temperature,
stirred for 36 hours and then concentrated. The obtained crude
product was purified by HPLC (ODS, eluent: water-methanol) to
afford 4.37 g (82%) of the title compound.
[0202] .sup.1H-NMR (270 MHz, DMSO-d.sub.6+D.sub.2O): .delta.
1.2-1.5 (m, 2H), 1.8-2.0 (m, 2H), 2.1 (brs, 1H), 2.26 (s, 3H),
2.9-3.2 (m, 4H), 3.94 (s, 3H), 3.9-4.1 (m, 2H), 4.35 (s, 2H),
7.8-8.2 (m, 6H), 8.43 (s, 1H).
[0203] The following compound of Reference Example 7 was
synthesized according to the same reaction as that in Reference
Example 6.
Reference Example 7
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(1-acetimidoyl-4-piperidinyl)me-
thoxymethyl]benzoate
[0204] 156
[0205] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.1-1.4 (m,
2H), 1.7-2.1 (m, 3H), 2.50 (s, 3H), 3.0-3.5 (m, 4H), 3.8-4.0 (m,
1H), 3.91 (s, 3H), 4.0-4.2 (m, 1H), 4.64 (s, 2H), 7.74 (t, 1H,
J=7.8 Hz), 7.87 (d, 1H, J=7.6 Hz), 8.00 (s, 1H), 8.03 (s, 1H), 8.07
(d, 1H, J=7.6 Hz), 8.16 (s, 1H), 8.28 (s, 1H), 8.64-9.20 (brs, 1H),
9.25-9.54 (brs, 2H).
Reference Example 8
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(((N-acetimidoylpiperidin-4-yl)-
methyl)amino)methyl]benzoate
[0206] 157
[0207] In 27 ml of a 2 M hydrochloric acid, was dissolved 2.71 g of
the compound in Reference Example 6. The resulting solution was
stirred at 70.degree. C. for 24 hours and then concentrated. The
obtained crude product was purified by HPLC (ODS, eluent:
water-methanol) to provide the title compound (2.00 g, yield:
76%).
[0208] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.2-1.5 (m,
2H), 1.9-2.0 (m, 2H), 2.28 (s, 3H), 2.1-2.3 (m, 1H), 2.9-3.4 (m,
4H), 4.02 (dd, 2H, J=5.3 Hz, 13.5 Hz), 4.34 (s, 2H), 7.7-8.0 (m,
2H), 8.1-8.3 (m, 3H), 8.41 (s, 1H), 8.47 (s, 1H).
[0209] The following compounds of Reference Examples 9 to 11 were
synthesized according to the same reaction as that in Reference
Example 8.
Reference Example 9
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(N-acetimidoyl-4-piperidinyl)me-
thoxymethyl]benzoate
[0210] 158
[0211] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.2-1.6 (m,
2H), 1.9-2.2 (m, 3H), 2.31 (s, 3H), 3.0-3.4 (m, 2H), 3.47 (d, 2H,
J=5.9 Hz), 3.9-4.1 (m, 2H), 4.65 (s, 2H), 7.6-7.8 (m, 3H), 8.0-8.1
(m, 2H), 8.10 (s, 1H), 8.24 (s, 1H).
Reference Example 10
Synthesis of Methyl
3-(3-amidinophenyl)-5-[(N-isopropylpiperidin-4-yl)meth-
oxymethyl]benzoate
[0212] 159
[0213] .sup.1H-NMR (270 MHz, DMSO-d.sub.6): .delta. 1.18 (d, 6H,
J=6.6 Hz), 1.4-1.65 (m, 2H), 1.75-1.95 (m, 3H), 2.6-2.9 (m, 2H),
3.1-3.5 (m, 5H), 4.33 (m, 2H), 4.62 (s, 2H), 7.73 (t, 1H, J=7.9
Hz), 7.84 (d, 1H, J=7.6 Hz), 7.94 (s, 1H), 7.97 (s, 1H), 8.06 (d,
1H, J=7.6 Hz), 8.18 (s, 1H), 8.27 (s, 1H), 9.45 (brs, 3H).
Reference Example 11
Synthesis of Methyl
3-(3-amidinophenyl)-5-[((4-piperidinylmethyl)amino)met-
hyl]benzoate
[0214] 160
[0215] .sup.1H-NMR (270 MHz, DMSO-d.sub.6+D.sub.2O): .delta.
1.3-1.5 (m, 2H), 1.96 (d, 2H, J=14 Hz), 2.11 (brs, 1H), 2.7-3.0 (m,
4H), 4.30 (s, 2H), 7.74 (t, 1H, J=7.7 Hz), 8.1-8.5 (m, 5H).
Reference Example 12
Determination of Inhibitory Activity of Activated Blood Coagulation
Factor X (FXa)
[0216] A test substance was dissolved in water or water containing
organic solvents (DMSO, ethanol or methanol) at a suitable
concentration to provide a specimen. To 70 .mu.l each of the
resulting specimens serially diluted with water, were added 90
.mu.l of a 100 mM Tris buffer (pH 8.4), 20 .mu.l of a 50 mM Tris
buffer (pH 8.4) containing 50 mU/ml human FXa and 2 mM of a
substrate (S-2765 manufactured by Daiichi Pure Chemicals Co.,
Ltd.). Incubation was carried out for 30 minutes. To the incubated
mixture, was then added 50 .mu.l of a 50% acetic acid. The
absorbance (A.sub.405) was determined. A mixture prepared by adding
the Tris buffer instead of the FXa was used as a blank, and a
mixture containing water instead of the specimen was used as a
control. The 50% inhibitory activity (IC.sub.50) was determined as
the indication of FXa inhibitory activity.
[0217] As a result, the inhibitory activity of IC.sub.50=0.01 to
0.1 .mu.M was found in the compounds of Reference Examples 6, 7 and
9, and the inhibition activity of IC.sub.50=0.1 to 1 .mu.M was
found in the compounds of Reference Examples 3, 4, 5, 8 and 10.
INDUSTRIAL APPLICABILITY
[0218] The cyanobiphenyl derivatives of the present invention can
be used as useful intermediates for biphenylamidine derivatives
used as inhibitors of FXa.
* * * * *