Note: Descriptions are shown in the official language in which they were submitted.
2092017
BUTADIENE DERIVATIVES AND PROCESS FOR PREPARING THE SAME
The present invention relates to novel butadiene
derivatives which are useful as an antithrombotic drug or as an
5 synthetic intermediate thereof, and further relates to processes
for preparing the same.
Prior A r t
It has been known that thrombus causes various
diseases such as myocardial infarction, cerebral infarction,
10 pulmonary infarction, and the like, and there have widely been
used enzyme preparations such as tissue plasminogen activator,
urokinase, streptokinase, and the like, for Iysis and prevention of
thrombus. These drugs have, however, some deficits, for
example, they are rapidly inactivated in blood and as a result they
15 lose their pharmacological activities, or they can be administered
only by parenteral route but not by oral route.
On the other hand, there have been disclosed
dibenzylidenesuccinic acid and N-methyl-dibenzylidene-
succinimide in Nouveau Journal De Chimie, Vol. 1, No. 5, 413-418
2 0 (1977), but their pharmacological activities have never been
disclosed hitherto.
Summary Description of the Invention
An object of the present invention is to provide novel
butadiene derivatives having excellent antithrombotic activity
2 5 which can be administered either orally or parenterally or are
useful as a synthetic intermediate for antithrombotic drug.
Another object of the present invention is to provide the
2092017
processes for preparing the same.
Detailed Description of the Invention
The desired butadiene derivatives of the present
invention have the following formula [I].
~R1
~R2 [I]
10 wherein Ring A is a tri-lower alkoxyphenyl group, R1 and R2
combine each other to form a group of the formula:
/N-R3
or one of R1 and R2 is a lower alkoxy group, and the other is a
15 group of the formula: -NHR3, in which R3 is hydrogen atom, a
substituted or unsubstituted lower alkyl group, a substituted or
unsubstituted lower alkoxy group, a substituted or unsubstituted
amino group, hydroxy group or pyridylcarbonyl group.
Suitable examples of the desired compounds [I] of the
20 present invention are compounds of the formula [I], wherein Ring
A is a tri-lower alkoxyphenyl group such as 3,4,5-tri-lower
alkoxyphenyl group, 2,3,4-tri-lower alkoxyphenyl group, 2,4,5-tri-
lower alkoxyphenyl group, 2,4,6-tri-lower alkoxyphenyl group,
and the like, and R3 is 1) hydrogen atom, 2) a lower alkyl group
2 5 which may optionally be substituted by 1 to 3 groups selected
from hydroxy group, a lower alkoxy group, carboxyl group, a lower
. . .
2~9201 7
alkoxycarbonyl group, an aralkyloxycarbonyl group (e.g. a phenyl-
lower alkoxycarbonyl group, etc.), a di-lower alkylamino group,
phenyl group and a nitrogen-containing 6-membered heterocyclic
group (e.g. pyridyl group, morpholino group, etc.), 3) a lower
5 alkoxy group which may optionally be substituted by a group
selected from a lower alkoxy group and phenyl group, 4) an amino
group which may optionally be substituted by a lower alkyl group,
5) hydroxy group, or 6) pyridylcarbonyl group.
The desired compounds [I] of the present invention
10 have four stereoisomers owing to two double bonds thereof, and
the present invention also includes these isomers and a mixture
thereof .
In the desired compounds [I] of the present invention,
the "lower alkyl group" and "lower alkoxy group" mean ones having
15 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms,
respectively, and the "aralkyl group" means phenyl-substituted
lower alkyl groups having 7 to 8 carbon atoms.
The preferable compounds [I] as a medicine are, for
example, compounds of the formula [I] wherein both two double
2 0 bonds have E-configuration, Ring A is a 3,4,5-tri-lower
alkoxyphenyl group, and R1 and R2 combine each other to form a
group of the formula:
\N-R3
/
25 wherein R3 is the same as defined above, among which the
compounds of the formula [I] wherein R3 is hydrogen atom, a
2092017
lower alkyl group, a lower alkoxy group, a hydroxy-lower alkyl
group, a morpholino-lower alkyl group or a pyridylcarbonyl group
are more preferable as a medicine. The other preferable
compounds as a medicine are compounds of the formula [I]
5 wherein one of R1 and R2 is a lower alkoxy group, and the other is
an amino group or a hydroxyamino group.
The desired compounds [I] of the present invention can
be used either in the free form or in the form of a
pharmaceutically acceptable salt thereof in clinical use.
The pharmaceutically acceptable salt includes, for
example, alkali metal salts (e.g. sodium salt, potassium salt,
etc.), alkaline earth metal salts (e.g. calcium salt, magnesium
salt, etc.), inorganic acid addition salts (e.g. hydrochloride,
hydrobromide, sulfate, etc.) and organic acid addition salts (e.g.
15 maleate, oxalate, etc.).
The desired compounds [I] of the present invention and
a pharmaceutically acceptable salt thereof can be administered in
clinical use either orally or parenterally, and administered in the
form of a pharmaceutical composition mixed with a
2 0 pharmaceutical excipient suitable for oral administration or
parenteral administration. The pharmaceutical compositions are,
for example, solid preparations such as tablets, capsules,
powders, and the like, or liquid preparations such as solutions,
suspensions, emulsions, and the like. Moreover, when the desired
2 5 compounds [I] of the present invention are administered
parenterally, they may be used in the form of injection
preparations, dermatologic preparations, suppositories, and the
' ' ~ ~',.. .
: , ~
: .~
2~92017
like.
The dosage of the compounds [I] may vary depending on
age, weight, conditions of the patients, or severity of diseases to
be cured, but it is usually in the range of 0.1 to 100 mg/kg/day,
5 preferably 0.5 to 50 mg/kg/day in the case of oral administration.
In the case of parenteral administration, it is in the range of 0.01
to 10 mg/kg/day, preferably 0.05 to 5 mg/kg/day.
According to the present invention, the desired 3-
butenoic acid-type compounds [I] wherein one of R1 and R2 is a
10 lower alkoxy group and the other is a group of the formula:-NHR3,
that is, the compounds of the formula [I-a]:
~R11
~~ R21 [I-a]
wherein one of R11 and R21 is a lower alkoxy group and the other
is a group of the formula:-NHR3, and Ring A and R3 are the same
as defined above, can be prepared, for example, by subjecting a
20 compound of the formula [Il]:
~R12
2 5 ~ R22 [II]
2092017
wherein one of R12 and R22 is a lower alkoxy group, and the other
is hydroxy group, and Ring A is the same as defined above, or a
salt, or a reactive derivative thereof, to condensation reaction
with an amine compound of the formula [Ill]:
NH2R3 [Ill]
wherein R3 is the same as defined above.
Moreover, the desired 2,5-pyrrolidinedione-type
compounds [I] wherein R1 and R2 combine each other to form a
group of the formula:
'~.
wherein R3 is the same as defined above, that is, the compounds
of the formula [I-A]:
h~ o
~
N--R3 [I-A]
wherein Ring A and R3 are the same as defined above, can be
20 prepared, for example, by subjecting the compound [I-a] to
internal cyclization reaction.
The desired N-substituted 2,5-pyrrolidinedione-type
compounds [I], that is, the compounds of the formula [I-C]:
. :
2092017
N--R3l [I-C]
0~
O
wherein R31 is a substituted or unsubstituted lower alkyl group,
a substituted or unsubstituted lower alkoxy group, a substituted
or unsubstituted amino group or pyridylcarbonyl group, and Ring A
is the same as defined above, can be prepared, for example, by
subjecting an N-unsubstituted 2,5-pyrrolidinedione-type
compound [l], that is, a compound of the formula [I-B]:
N--H [I-B]
1 5 ~/
wherein Ring A is the same as defined above, to condensation
reaction with a compound of the formula [lV]:
X1-R31 [IV]
20 wherein X1 is a reactive residue, and R31 is the same as defined
above.
The 2,5-pyrrolidinedione-type compounds [l] wherein
R3 is a substituted or unsubstituted lower alkoxy group, that is,
the compound of the formula [I-D]:
. ~:
.
;' '~
2~92017
N--oR4 [I-D]
wherein R4 is a substituted or unsubstituted lower alkyl group,
and Ring A is the same as defined above, can be prepared by
subjecting a compound [I] wherein one of R1 and R2 is a lower
alkoxy group, and the other is a group of the formula: -NHOH, that
is, a compound of the formula [I-b]:
~ O
~ R13
~R23 [I-b]
wherein one of R13 and R23 is a lower alkoxy group, and the other
is a group of the formula: -NHOH, and Ring A is the same as
defined above, to condensation reaction and internal cyclization
reaction with a compound of the formula [V]:
2 0 X2-R4 [V]
wherein X2 is a reactive residue, and R4 is the same as defined
above.
Among the compounds [I] obtained above, the 2,5-
pyrrolidinedione-type compounds [I] can be converted from one
25 derivative to other derivative, if necessary.
For example, the compounds [I] wherein R3 is a
2~92017
carboxyl-substituted lower alkyl group, i.e. the compounds of the
formula [I-E]:
~ O
~,
I N--R32 [I-E]
~. '
wherein R32 is a carboxyl-substituted lower alkyl group, and Ring
A is the same as defined above, can be prepared by treating a
10 compound of the formula [I-F]:
~N--R33 [I-F]
~ O
wherein R33 is a lower alkoxycarbonyl-substituted lower alkyl
group, and Ring A is the same as defined above, with an acid.
In the above process of the present invention, the
2 0 condensation reaction between the butenoic acid ester-type
compound [Il] or a salt thereof with the amine compound [Ill] can
be carried out in the presence of dehydrating agent in a suitable
solvent. The dehydrating agent includes, for example, dicyclo-
hexylcarbodiimide, carbonyldiimidazole, and the like. The salt of
25 the butenoic acid ester [Il] may be any conventional ones such as
alkali metal salts, alkaline earth metal salts, and the like, and
these salts may preferably be converted in advance into a free
2092017
1 0
carboxylic acid and then used in the reaction with the amine
compound [Ill].
The condensation reaction between a reactive
derivative of the compound [Il] and the amine compound [Ill] can
be carried out in the presence or absence of an acid acceptor in a
suitable solvent. The reactive derivative may be any conventional
ones which are suitable for the acid-amide condensation reaction,
for example, acid halides, mixed acid anhydrides, active esters,
and the like. The acid acceptor includes, for example, alkali
metal hydroxides, alkali metal carbonates, alkali metal hydrogen
carbonates, trialkylamines, N,N-dialkylanilines, pyridine, and the
like.
The suitable solvent may be any inert solvent which
does not disadvantageously affect the reaction, for example,
ethers (e.g. tetrahydrofuran, dioxane, etc.), trichloromethane,
dichloromethane, and the like.
The condensation reaction can preferably be carried
out at a temperature from under cooling to a boiling point of the
solvent to be used, for example, at -20C to 100~C, more
2 0 preferably at -1 0C to 70~C.
The 3-butenoic acid-type compounds [I-a] thus
obtained can be used not only as a medicine but also as a
synthetic intermediate for the 2,5-pyrrolidinedione-type
compounds [I] having excellent antithrombotic activity.
2 5 The internal cyclization reaction of the 3-butenoic
acid-type compounds [I-a] can be carried out in the presence of a
base in a suitable solvent.
20912~17
The base includes, for example, alkali metals (e.g.
sodium, etc.), alkali metal hydroxides (e.g. sodium hydroxide,
etc.), alkali metal hydrides (e.g. sodium hydride, etc.), alkali
metal alcoholates (e.g. sodium methylate, etc.), lower alkyl-
substituted alkali metal amides (e.g. Iithium diisopropylamide,
etc.), lower alkyl alkali metals (e.g. n-butyllithium, etc.), organic
amines (e.g. tri-lower alkylamines, 1,8-diazabicyclo[5.4.0]undec-
7-ene, etc.).
The solvent may be any inert solvent which does not
disadvantageously affect the reaction, for example, organic
solvents such as ethers (e.g. tetrahydrofuran, dioxane, etc.),
alcohols (e.g. methanol, ethanol, etc.), dimethylformamide, and
the like, or a mixture of water and these organic solvents.
The internal cyclization reaction of the compounds
[I-a] can be carried out under cooling or with heating, for
example, at -60C to 1 50C, more preferably at a temperature
from room temperature to a boiling point of the solvent to be
used.
The condensation reaction between the N-
2 0 unsubstituted pyrrolidinedione-type compound [I-B] and the
compound [IV] can be carried out in the presence of an acid
acceptor in a suitable solvent.
The reactive residue represented by X1 is preferably a
halogen atom.
The acid acceptor may be any conventional ones which
are suitable in this kind of the reaction, for example, alkali metal
hydrides (e.g. sodium hydride, etc.), alkali metal hydroxides (e.g.
2092017
sodium hydroxide, etc.), alkali metal carbonates (e.g. potassium
carbonate, etc.), alkali metal alcoholates (e.g. sodium methylate,
etc.), lower alkyl-substituted alkali metal amides (e.g. Iithium
diisopropylamide, etc.) and alkali metals (e.g. sodium, etc.).
The solvent may be any inert solvent which does not
disadvantageously affect the reaction, for example, ethers (e.g.
tetrahydrofuran, etc.), dimethylformamide, dimethylsulfoxide,
and the like.
The condensation reaction can be carried out at a
temperature from under cooling to a boiling point of the solvent
to be used, for example, at -60C to 100C, more preferably at
-60 to 20 C.
The condensation reaction and the internal cyclization
reaction between the 3-butenoic acid-type compound [I-b] and the
compound [V] can be carried out in the presence of a base in a
suitable solvent.
The reactive residue represented by x2 is preferably a
halogen atom.
The base includes, for example, alkali metal
2 0 hydroxides (e.g. sodium hydroxide, etc.), alkali metal hydrides (e.g.
sodium hydride, etc.), alkali metal alcoholates (e.g. sodium
methylate, etc.), lower alkyl-substituted alkali metal amides (e.g.
Iithium diisopropylamide, etc.) and alkali metals (e.g. sodium,
etc.), and the like.
The solvent may be any inert solvent which does not
disadvantageously affect the reaction, for example, ethers (e.g.
tetrahydrofuran, etc.), dimethylformamide, dimethylsulfoxide,
2092017
and the like.
These condensation reaction and cyclization reaction
can be carried out at a temperature from under cooling to a
boiling point of the solvent to be used, for example, at -60C to
1 00C, more preferably at -60C to 20C.
The acid treatment of the compound [I-F] can be
carried out in a suitable solvent by a conventional method.
The solvent includes, for example, ethyl acetate,
dichloromethane, benzene, and the like, and the acid may be any
one which is conventionally used in this type of the reaction, for
example, hydrogen chloride, p-toluenesulfonic acid, trifluoro-
acetic acid, hydrogen bromide in glacial acetic acid, and the like.
In the above reactions, when the desired compounds [I]
are obtained in the form of a mixture of stereoisomers, if
necessary, these isomers can be separated by a conventional
method such as silica gel column chromatography.
The starting compounds [Il] of the present invention
are a novel compound, and can be prepared by 1) condensation
reaction between benzaldehyde or a tri-lower alkoxybenzaldehyde
2 0 and a succinic acid di-lower alkyl ester to give a 3-lower alkoxy-
carbonyl-4-phenyl (or tri-lower alkoxyphenyl)-3-butenoic acid,
2) followed by conventional esterification of the product to give
a corresponding lower alkyl ester thereof, 3) and further reacting
the product with a tri-lower alkoxybenzaldehyde [or
2 5 benzaldehyde, in the case that a tri-lower alkoxybenzaldehyde is
used in process 1)].
The above condensation reactions 1) and 3) can be
20921017
14
carried out in the presence of a base (e.g. alkali metal alcoholate,
etc.) under cooling or with heating, for example, at a temperature
from -20C to a boiling point of the solvent to be used, in a
suitable solvent.
In the present specification and claims, the "lower
alkyl group" and the "lower alkoxy group" mean ones having 1 to 6
carbon atoms, preferably 1 to 4 carbon atoms, respectively, and
the "aralkyl group" means phenyl-substituted lower alkyl groups
having 7 to 8 carbon atoms.
Throughout the present description and claims, the
stereochemistries of the double bonds may be either cis-
configuration (Z) or trans-configuration (E) in the structures of
the compounds having double bonds (e.g. the compounds [I], the
compounds [Il], etc.), unless specified otherwise.
1 5 Examples
The present invention is illustrated in more detail by
the following Examples and Reference Examples, but should not be
construed to be limited thereto.
Example 1
2 0 (1 ) A solution of (E)-3-methoxycarbonyl-4-phenyl-3 -
butenoic acid methyl ester (23.1 g) and 3,4,5-trimethoxybenz-
aldehyde (19.4 g) in t-butyl alcohol (100 ml) is added dropwise
with stirring into a solution of potassium t-butoxide (11.1 g) in t-
butyl alcohol (100 ml) at room temperature, and the mixture is
stirred for one hour. The reaction mixture is poured into cold
water (200 ml), and the mixture is extracted with isopropyl
ether. The pH value of the aqueous layer is adjusted to pH 2-3,
2092017
1 5
and the aqueous layer is extracted with ethyl acetate. The ethyl
acetate layer is washed, dried, and evaporated to remove the
solvent. The resulting residue is crystallized from diethyl ether
to give (E)-2-[(E)-3,4,5-trimethoxybenzylidene]-3-carboxy-4-
5 phenyl-3-butenoic acid methyl ester (25.7 g) as pale yellow
crystals.
Yield: 65 %
M.p. 153-1 54C (recrystallized from ethyl
acetate/isopropyl ether)
(2) To a solution of the above product (25.7 g) in
trichloromethane (50 ml) is added thionyl chloride (4.7 ml)
dropwise under ice-cooling, and thereto is added a drop of
dimethylformamide. The mixture is refluxed for 30 minutes, and
cooled to a temperature below 25~C. The mixture is added
15 dropwise to conc. aqueous ammonia (20 ml) with vigorously
stirring, and the resulting mixture is stirred for 30 minutes. The
organic layer is separated, washed, dried, and evaporated to
remove the solvent. The resulting residue is crystallized from
diethyl ether, and collected by filtration to give (E)-2-[(E)-3,4,5-
20 trimethoxybenzylidene]-3-carbamoyl-4-phenyl-3-butenoic acid
methyl ester (24.9 g) as pale yellow crystals.
Yield: 97 %
M.p. 179-1 80C (recrystallized from ethyl acetate)
(3) To a solution of the above product (24.9 g) in
25 tetrahydrofuran (75 ml) is added 2N aqueous sodium hydroxide
solution (15.6 ml), and the mixture is refluxed for one hour. The
mixture is cooled to room temperature, and thereto is added 2N
,
:
2092017
1 6
hydrochloric acid (15.6 ml). The mixture is concentrated under
reduced pressure, and to the residue is added trichloromethane.
The mixture is washed, dried, and evaporated to remove the
solvent. The resulting residue is recrystallized from ethyl
5 acetate to give 3-[(E)-benzylidene]-4-[(E)-3,4,5-trimethoxy-
benzylidene]-2,5-pyrrolidinedione (17.6 g) as yellow plate
crystals.
Yield: 77 %
M.p. 158-159C
The mother liquor of the above recrystallization is
purified by silica gel column chromatography to give 3-[(E)-
benzylidene]-4-[(Z)-3,4,5-trimethoxybenzylidene]-2,5 -
pyrrolidinedione as orange crystals.
M.p. 193-1 95C (recrystallized from ethyl
1 5 acetate/n-hexane)
Example 2
(1 ) (Z)-3-Methoxycarbonyl-4-phenyl-3-butenoic acid
methyl ester is treated in the same manners as in Example 1-(1)
and 1-(2) to give (Z)-2-[(E)-3,4,5-trimethoxybenzylidene]-3-
2 0 carbamoyl-4-phenyl-3-butenoic acid methyl ester as colorless
crystals.
M.p. 144-1 46C (recrystallized from ethyl
acetate/n-hexane)
(2) The above product is treated in the same manner
2 5 as in Example 1-(3) to give 3-[(Z)-benzylidene]-4-[(E)-3,4,5 -
trimethoxybenzylidene]-2,5-pyrrolidinedione as yellow crystals.
M.p. 176-1 78C (recrystallized from ethyl
~ .
. :.
2~9201 7
acetate/n-hexane)
Example 3
(1 ) (E)-3-Methoxycarbonyl-4-phenyl-3-butenoic acid
methyl ester and 2,4,6-trimethoxybenzaldehyde are treated in the
same manner as in Example 1-(1) to give (E)-2-[(E)-2,4,6-
trimethoxybenzylidene]-3-carboxy-4-phenyl-3-butenoic acid
methyl ester (foam) and (E)-2-[(Z)-2,4,6-trimethoxybenzylidene]-
3-carboxy-4-phenyl-3-butenoic acid methyl ester (m.p. 208-
21 0C).
(2) (E)-2-[(E)-2,4,6-Trimethoxybenzylidene]-3-
carboxy-4-phenyl-3-butenoic acid methyl ester is treated in the
same manner as in Example 1-(2) to give (E)-2-[(E)-2,4,6-
trimethoxybenzylidene]-3-carbamoyl-4-phenyl-3-butenoic acid
methyl ester.
M.p. 173-174C
Further, (E)-2-[(Z)-2,4,6-trimethoxybenzylidene]-3-
carboxy-4-phenyl-3-butenoic acid methyl ester is treated in the
same manner as in Example 1-(2) to give (E)-2-[(Z)-2,4,6-
trimethoxybenzylidene]-3-carbamoyl-4-phenyl-3-butenoic acid
methyl ester.
M.p. 169-171~C (recrystallized from ethyl
acetate/n-hexane)
(3) (E)-2-[(E)-2,4,6-Trimethoxybenzylidene]-3-
carbamoyl-4-phenyl-3-butenoic acid methyl ester is treated in
the same manner as in Example 1-(3) to give 3-[(E)-benzylidene]-
4-[(E)-2,4,6-trimethoxybenzylidene]-2,5-pyrrolidinedione.
M.p. 246-248C
:
20920~ 7
1 8
Example 4
(1 ) (E)-3-Methoxycarbonyl-4-(3,4,5-trimethoxy -
phenyl)-3-butenoic acid methyl ester and benzaldehyde are
treated in the same manner as in Example 1-(1) to give (E)-2-[(E)-
benzylidene]-3-carboxy-4-(3,4,5-trimethoxyphenyl)-3-butenoic
acid methyl ester.
M.p. 131-1 33C
(2) The above product is treated in the same manner
as in Example 1-(2) to give (E)-2-[(E)-benzylidene]-3-carbamoyl-
4-(3,4,5-trimethoxyphenyl)-3-butenoic acid methyl ester.
M.p. 121-122C
(3) The above product is treated in the same manner
as in Example 1-(3) to give 3-[(E)-benzylidene]-4-[(E)-3,4,5-
trimethoxybenzylidene)-2,5-pyrrolidinedione.
Examples 5-8
(1) The corresponding starting compounds obtained in
Reference Examples 1 and 4 - 5 are treated with a corresponding
benzaldehyde derivative in the same manner as in Example 1-(1)
to give the compounds of Table 1. The stereochemistries of the
double bonds are both E-configuration.
20g2017
1 9
Table 1
_
~CORl2
5 ~ ~COFI'~
Ex. No. Ring A R22 R12 Physica!
propertles
-- ;1 c~ -OH -OCH2CH3 ~M3P8.lc37
1 06- ( 1 ) CH30 -OH -OCH(CH3)2 Foam
CH,C(~=}
7 - ( 1 ) C~H3 -OH -OCH3 M . p. 93-94 C
~ ~ -OH -OCH3 1 5P9
(2) The above products are treated in the same
manner as in Example 1-(2) to give the compounds of Table 2. The
stereochemistries of the double bonds are both E-configuration.
.
: ~
2092017
Table 2
~COR1
~COR2
Ex. No. Ring A R2 R1 Physical
properties
5 - ( 2 ) CH3O -N H2 -OCH2cH3 M p 129 -
CH3C~
1 0 ~ E~ ~I H 2 ~ C ~3)2 M~ ~ -
¦ 7-(2T~ l-NH2 -OCH3 !1M4P2 l ~
8 - ( 2 ) OCH3 -NH2 -OCH3 2 0 1 C
r~
(3) The above products are treated in the same
15 manner as in Example 1-(3) to give the compounds of Table 3. The
stereochemistries of the double bonds are both E-configuration.
- 2~2~17
21
Table 3
~ ~N--H
Ex. No.Ring A ¦ Physical properties
5-(3) CH ( The same product as
CH3~ ~ Example 1-(3)
1 0 6- ( 3 ) . The same product as
CH3Q>=~ Example 1-(3)
CH3C~
7 ~ ( 3 )C~H3 M . p. 183-1 84C
8 - ( 3 )OCH3 M . p . 224-225 ~ C
CH30
Example 9
(1) To a solution of the compound (6.0 g) obtained in
Example 1-(1 ) in trichloromethane (30 ml) is added dropwise
2~21~17
thionyl chloride (1.1 ml) under ice-cooling, and thereto is added
two drops of dimethylformamide. The mixture is refluxed for 30
minutes, and cooled to a temperature below 25C. The mixture is
added dropwise into 40 % aqueous methylamine solution (10 ml)
5 with vigorously stirring. The mixture is stirred for 30 minutes
as it is, and the organic layer is separated, washed, dried, and
evaporated to remove the solvent. The resulting residue is
purified by silica gel column chromatography (solvent;
trichloromethane : acetone = 5 : 1 ) to give (E)-2-[(E)-3,4,5-
i 0 tri meth oxy be nzylid ene]-3- methylcarbamoyl-4-pheny 1-3-bute noic
acid methyl ester (5.4 g) as crystals.
Yield: 87 %
M.p. 155-1 57C (recrystallized from ethyl
acetate/n-hexane)
(2) To a solution of the above product (3.5 g) in
tetrahydrofuran (50 ml) is added 2N aqueous sodium hydroxide
solution (2 ml), and the mixture is refluxed for one hour. The
reaction solution is cooled to room temperature, and thereto is
added 2N hydrochloric acid (2 ml). The mixture is concentrated
under reduced pressure, and to the residue is added ethyl acetate.
The mixture is washed, dried, and evaporated to remove the
solvent, and the resulting residue is crystallized from diethyl
ether to give (3E,4E)-1-methyl-3-benzylidene-4-(3,4,5-
trimethoxybenzylidene)-2,5-pyrrolidinedione (2.8 g).
Yield: 87 %
M.p. 131-1 33'C (recrystallized from ethyl
acetate/isopropyl ether)
~0920~7
Examples 1 0-25
The corresponding starting compounds are treated in
the same manner as in Example 9-(1) to give the compounds of
Table 4. The stereochemistries of the double bonds are both E-
5 configuration.
Table 4
C H30
C H30~COOCH3
CH30 l
~CoNHR3
_
Ex. No. R3 Physical properties
1 0 -CH2CH2CH2CH3 M.p. 86-88C
11 -CH(CH3)2 Foam
1 2 M.p. 130-1 32C
_ --CH2~
1 3 -CH2CH20H M . p. 1 1 0-1 1 1 C
1 4 -C(CH3)(CH20H)2 M.p. 116-1 17C
1 5 -C(CH20H)3 M .p. 130-131 C
2 0 1 6 -CH(CH20H)2 Foam
17 -CH2CH20CH3 M . p . 88-90 C
?
. - - `~; - - .
209~0~7
24
18 -OH M.p. 1 93DC (decomposed)
t 9 -OCH3 M . p. 1 63-1 64C
2 0 -NH2 M.p. 175-1 76C
21 -N(CH3)2 M.p. 124-1 26C
2 2 Foam
--C H2~N
23 --CH,~ M.p. 108-1 10C
24 M.p. 143-144C
C H2CH2N~O . .
2 S OCH2~ Oi I
Examples 26-38
The corresponding starting compounds are treated in
the same manner as in Example 9-(2) to give the compounds of
Table 5. The stereochemistries of the double bonds are both E-
configuration .
2~20~
Table 5
CH30
CH30~,,~
CH30 ¦ N--R3
Ex. No. R3 Salt Physical
properties
t O ~ ~ Free lM3P4 1C2 -
2 7 -CH2CH20H Free 1 0 5 ' C
2B -C(CH3)(cH20H)2 Free M p 125 -
2 9 -C(CH20H)3 Free 1M6p2 o1C61 -
3 0 -CH(cH20H)2 Free Foam
1 5 31 -CH2CH20CH3 Free lM4pgO1c8 -
3 2 -OCH3 Free 1M3p3 o1C31 -
33 -NH2 Hydrochloride M.p. 108C
(decomposed)
3 4 -N (C H3)2 Free 1M6p~ o1C59 -
.
20~2~7
26
Hydrochloride M.p. 204C
--C H2~N (decomposed)
36 Hydrochloride M;p. 203C
--CH2~ (decomposed)
3 7 Hyd rochloride M .p. 1 95C
C H2C H2N~O
~ Free M.p 137
5
Example 3 9
To a suspension of 62 % sodium hydride (0.33 g) in
dimethylformamide (10 ml) is added dropwise a solution of (E)-2-
[(E)-3,4,5-trimethoxybenzylidene]-3-hydroxycarbamoyl-4-phenyl -
3-butenoic acid methyl ester (3.8 g) in dimethylformamide (1 0
ml) under ice-cooling, and the mixture is stirred at room
temperature for two hours. To the mixture is added dropwise
methoxymethyl chloride (0.67 ml) under ice-cooling, and the
mixture is stirred at room temperature for two days, and then
15 evaporated to remove the solvent. To the residue is added ethyl
acetate, and the mixture is washed, dried, and evaporated to
remove the solvent. The resulting residue is purified by silica gel
column chromatography (solvent; n-hexane: trichloromethane:
ethyl acetate = 5: 5: 4) to give (3E,4E)-1-methoxymethoxy-3-
,
.
2092017
benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidine-
dione (1.25 g) as yellow crystals.
Yield: 37 %
M.p. 175-1 77C (recrystallized from ethyl
5 acetate/n-hexane)
Example 4 0
To a suspension of 63.2 % sodium hydride (0.38 g) in
dimethylformamide (10 ml) is added dropwise a solution of (3E,
4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-
pyrrolidinedione (3.65 g) in dimethylformamide (1 0 ml) under ice-
cooling, and the mixture is stirred at room temperature for one
hour. To the mixture is added dropwise methoxymethyl chloride
(0.84 ml) under ice-cooling, and the mixture is stirred at room
temperature overnight. The mixture is evaporated to remove the
15 solvent, and to the residue is added ethyl acetate. The mixture is
washed, dried, and evaporated to remove the solvent. The
resulting residue is purified by silica gel column chromatography
(solvent; n-hexane: trichloromethane: ethyl acetate = 5: 5: 4) to
give (3E,4E)-1-methoxymethyl-3-benzylidene-4-(3,4,5-
2 0 trimethoxybenzylidene)-2,5-pyrrolidinedione (3.0 g) as yellow
crystals.
Yield: 73 %
M.p. 127-1 28C (recrystallized from ethyl
acetate/n-hexane)
Examples 41-45
The corresponding starting compounds are treated in
the same manner as in Example 40 to give the compounds of Table
-, -
. . -
2~92017
28
6. The stereochemistries of the double bonds are both E-
configuration.
Table 6
CH30
CH30~
CH30 ¦ N--R3
0~ ..
Ex. R3 Salt Physical
No. properties
41-CH2CH2N(CH3)2 Hydrochloride M.p. 202C
(decomposed)
4 Z-CH2C00C(CH3)3 Free Foam
43 Hydrochloride M.p. 200~C
--Co{~N (decomposed)
44 Hydrochloride M.p. 1 96C
co~? (decomposed)
4 5 Free M.p. 127-1 29C
_C H2COOCH2~
Example 4 6
(1 ) To a solution of (3E,4E)-1 -t-butoxycarbonyl -
methyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-
~OC~2017
29
pyrrolidinedione (3.5 g) obtained in Example 42 in dichloro-
methane (40 ml) is added trifluoroacetic acid (10 ml) at room
temperature, and the mixture is allowed to stand for 4 hours. The
mixture is evaporated under reduced pressure to remove the
5 solvent, and to the residue is added trichloromethane. The
mixture is washed, dried, and evaporated to remove the solvent.
The resulting residue is crystallized from diethyl ether to give
(3E,4E)-1 -carboxymethyl-3-benzylidene-4-(3,4,5-trimethoxy-
benzylidene)-2,5-pyrrolidinedione (2.5 g) as yellow prisms.
Yield: 81 %
M.p. 183-1 85C
(2) The above product (2.38 g) is dissolved in a
mixture of tetrahydrofuran (10 ml) and methanol (10 ml), and
thereto is added 2N aqueous sodium hydroxide solution (2.8 ml).
15 The mixture is evaporated to remove the solvent, and to the
residue is added trichloromethane. The mixture is dried and
evaporated to remove the solvent, and the resulting crystalline
residue is recrystallized from a mixture of ethyl acetate and
diethyl ether to give (3E,4E)-1-carboxymethyl-3-benzylidene-4-
(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione sodium salt
(2~3 g) as yellow crystals.
Yield: 74 %
M.p. 1 90C (decomposed)
Reference Example 1
2 5 To a solution of potassium t-butoxide (16.8 g) in t-
butyl alcohol (150 ml) is added dropwise with stirring a solution
of benzaldehyde (15.9 g) and succinic acid dimethyl ester (26.3 g)
2~2~7
in t-butyl alcohol (20 ml) at room temperature, and the mixture
is stirred for 30 minutes. The reaction mixture is poured into ice-
water (200 ml), and the mixture is extracted with isopropyl
ether. The pH value of the aqueous layer is adjusted to pH 2-3,
5 and the mixture is extracted with ethyl acetate. The ethyl
acetate layer is washed, dried, and evaporated to remove the
solvent. The residue is dissolved in methanol (75 ml), and thereto
is added dropwise thionyl chloride (10.9 ml) under ice-cooling.
The mixture is allowed to stand at room temperature overnight,
10 and then evaporated to remove the solvent. To the residue is
added isopropyl ether, and the mixture is washed, dried, and
evaporated to remove the solvent. The resulting residue is
distilled under reduced pressure to give (E)-3-methoxycarbonyl-4-
phenyl-3-butenoic acid methyl ester (23.2 g) as colorless oil.
Yield: 66 %
B.p. 135-1 37C (0.3 mmHg)
Reference Example 2
Benzaldehyde (21.2 g) and succinic acid dimethyl ester
(40.9 g) are treated in the same manner as in Reference Example
20 1, and the resulting product is purified by silica gel column
chromatography to give (Z)-3-methoxycarbonyl-4-phenyl-3-
butenoic acid methyl ester (2.3 g) as colorless syrup.
Reference Example 3
3,4,5-Trimethoxybenzaldehyde and succinic acid
25 dimethyl ester are treated in the same manner as in Reference
Example 1 to give (E)-3-methoxycarbonyl-4-(3,4,5-trimethoxy-
phenyl)-3-butenoic acid methyl ester as pale yellow syrup.
2~92017
Reference Examples 4-5
The corresponding starting compounds are treated in
the same manner as in Reference Example 1 to give the compounds
of Table 7. The stereochemistry of the double bond is E-
5 configuration.
Table 7
1 0 ~ ~COR6
Ref. Ex. ¦R6 ¦ R5 ¦ Physical properties
4 -OCH2cH3 ¦-OCH2CH3 Pale yellow syrup
-OCH(CH3)2 ¦ -OCH3 Pale yellow syrup
Effects of the Invention
The desired butadiene derivatives [I] of the present
2 0 invention and pharmaceutically acceptable salts thereof enhance
fibrinolysis and show excellent antithrombotic activity by either
oral administration or parenteral administration. Hence, they can
be used as antithrombotic drug in the prophylaxis or treatment of
various blood vessel diseases such as myocardial infarction,
2 5 cerebral infarction, pulmonary infarction, deep venous
thrombosis, peripheral arterial embolism, angina pectoris,
. .- . . :. . -
-
209~17
dissminated intravascular coagulation containing septicemia and
other venous embolism, and diabetic complications. Moreover, the
butadiene derivatives [I] of the present invention and
pharmaceutical acceptable salts thereof can also be used as
5 preventive for re-occulusion of the blood vessel after a
pecutaneous transluminal coronary angioplasty or thrombolytic
therapy.
Among the desired butadiene derivatives [I] of the
present invention, the 3-butenoic acid-type compounds per se
10 have antithrombotic activity, but they can also be used as an
intermediate for preparing the 2,5-pyrrolidinedione-type
compounds having excellent antithrombotic activity.
