JPH10287622A - Butadiene derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new butadiene derivative having excellent PAI-1 inhibiting activities and useful for prevention and treatment of myocardial infarction, various thrombosis, restenosis after percutaneous per tubam coronary arterioplasty (PTCA). SOLUTION: This new butadiene derivative is a compound of formula I [ring A and ring B are each a (substituted) heterocycle or a (substituted) benzene ring; R<1> and R<2> are each H or a lower alkyl; one of COR<32> and COR<42> is carboxyl and the other is an (esterified) carboxyl], e.g. (1Z,3E)-1-(4- cyclopentyloxy-3-methoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbu tadiene. The compound of formula I is obtained by treating a diester compound of formula II (COR<31> and COR<41> are each an esterified carboxyl) with an acid or a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel butadiene derivatives and pyrrolidine derivatives.

[0002]

2. Description of the Related Art Thrombus refers to a phenomenon in which blood coagulates in the heart and blood vessels of a living body. The thrombus causes stenosis or occlusion of a blood vessel, so that tissues under the control of the blood vessels are impaired in circulation. Cause necrosis or edema in response to myocardial infarction, atrial thrombus in atrial fibrillation, arteriosclerosis, angina, stroke, pulmonary embolism, deep vein thrombosis (D
VT), disseminated intravascular coagulation (DIC), diabetic complications,
It is well known to cause various diseases, such as restenosis after percutaneous transluminal coronary angioplasty (PTCA).

[0003] It is believed that the formation of a thrombus involves changes in the properties of the blood vessel wall, slow increase in blood flow, changes in plasma components, and the like. Platelets, red blood cells,
There are leukocytes and fibrin (fibrin).

[0004] In many cases, microthrombus generated in a living body is dissolved, so that the fibrinolysis phenomenon (fibrinolytic system) is secondarily enhanced. Specifically, plasminogen, which is an inactive precursor substance, is converted into plasminogen activator (PA; tissue type plasminogen activator (t-) having its specific activity.
PA), urokinase-type plasminogen activator (u-PA), etc.), plasmin (pl
asmin; a proteolytic enzyme mainly present in plasma), which dissolves the thrombus by cleaving the lysine bond of the fibrin polypeptide chain. On the other hand, the activity of PA is controlled by its specific inhibitor, type 1 plasminogen activator inhibitor (PAI-1).

Therefore, the activity of the fibrinolytic system is determined mainly by the quantitative balance between PA and PAI-1 secreted from vascular endothelial cells, and increases or decreases in PAI-1 production in the cells and PAI-1.
-1 Changes in the activity of the molecule itself are immediately reflected in the activity of the fibrinolytic system in blood.

In other words, it acts on vascular endothelial cells,
By inhibiting PAI-1 or its production and increasing PA activity, it is thought that the prevention and treatment of thrombotic diseases represented by the above-mentioned diseases will be possible.

Therefore, conventionally, t-PA, u-PA,
Although enzyme preparations such as streptokinase are widely used to prevent thrombosis, these drugs rapidly degrade in the blood and lose their efficacy, and have the drawback that they can only be used for pharmaceutical use by parenteral administration. .

On the other hand, as an antithrombotic agent, for example, EP-A-563798 discloses 3-[(E) -benzylidene]-
4-[(E) -3,4,5-trimethoxybenzylidene] -2,5-pyrrolidinedione and (E) -2-
[(E) -3,4,5-trimethoxybenzylidene]-
Although 3-carboxy-4-phenyl-3-butenoic acid methyl ester is described, these compounds have problems in bioavailability, safety and stability.
Specifically, (1) low water solubility, (2) easily metabolized in the liver, (3) toxicity to the liver and chromosomes, and (4) instability to light There are issues.

[0009] In addition, NOVOAU JOURNALDE CHIMI
E), Vol. 1, No. 5, 413-418 (19
No. 77) discloses benzylidene succinic acid as a product of an electrolyte reduction reaction, but no pharmacological activity of the compound is known.

[0010]

SUMMARY OF THE INVENTION The present invention provides novel butadiene derivatives and pyrrolidine derivatives which solve the above-mentioned problems. The present invention also provides a method for producing such a novel compound.

[0011]

Means for Solving the Problems In order to solve the problems, the present inventors have assiduously studied and, as a result, have developed novel butadiene derivatives and pyrrolidine derivatives which inhibit the production of PAI-1 and have an excellent antithrombotic effect. We have completed the present invention.

That is, the present invention provides a compound represented by the general formula (1-a):

[0013]

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(Wherein ring A is substituted or unsubstituted heterocyclic ring or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring which may be substituted with a group selected from a substituted or unsubstituted heterocyclic ring or a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group; R ¹ and R ² is the same or different and represents a hydrogen atom or a lower alkyl group, and includes a group -COR ³² and a group -COR
⁴² represents a carboxyl group on one side and a carboxyl group on the other side which may be esterified. However, Ring A and Ring B are not simultaneously unsubstituted benzene rings. When Ring A is a tri-lower alkoxybenzene ring, Ring B is a substituted or unsubstituted heterocyclic ring, or R ¹ and R ² At least one is a lower alkyl group. Or a pharmacologically acceptable salt thereof, represented by general formula (1-b):

[0015]

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(Wherein ring A is substituted or unsubstituted heterocyclic or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring which may be substituted with a group selected from a substituted or unsubstituted heterocyclic ring or a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group; R ¹ and R ² is the same or different and represents a hydrogen atom or a lower alkyl group, and includes a group -COR ³³ and a group -COR
⁴³ represents a carboxyl group that is amidated on one side and a carboxyl group or an amidated carboxyl group that may be esterified on the other side. However, Ring A and Ring B are not simultaneously unsubstituted benzene rings. When Ring A is a tri-lower alkoxybenzene ring, Ring B is a substituted or unsubstituted heterocyclic ring, or R ¹ and R ² At least one is a lower alkyl group. ) Or a pharmacologically acceptable salt thereof represented by the formula (2):

[0017]

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(Wherein ring A is substituted or unsubstituted heterocyclic ring or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring which may be substituted with a group selected from a substituted or unsubstituted heterocyclic ring or a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group; R ¹ and R ² is the same or different and represents a hydrogen atom or a lower alkyl group; R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic ring; Wherein ring A and ring B are not simultaneously unsubstituted benzene rings, and when ring A is a tri-lower alkoxybenzene ring, ring B is substituted or Or a substituted heterocyclic ring, or at least one of R ¹ and R ² is a lower alkyl group.) Relates to pyrrolidine derivative or a pharmaceutically acceptable salt represented by.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The butadiene derivative (1-
In the a), the amidobutadiene derivative (1-b) and the pyrrolidine derivative (2), the substituted or unsubstituted heterocyclic ring of the ring A and the ring B may be 5 to 6 such as a pyridine ring and a pyrimidine ring.
Membered nitrogen-containing monocyclic heterocycles and the like.Examples of the substituent of these heterocycles include an oxo group, a hydroxyl group,
Examples include a lower alkoxy group and a halogen atom.

Among the substituents on the benzene ring of ring A, the lower alkyl group includes, for example, a methyl group, an ethyl group, a propyl group and a butyl group, and the alkoxy group includes, for example, a methoxy group A ethoxy group, a lower alkoxy group such as a butoxy group, a lower alkylenedioxy group such as a methylenedioxy group, a cyclopropyloxy group, a cyclopentyloxy group, and a cycloalkyloxy group such as a cyclohexyloxy group. A cyclopentyloxy group is preferable, and the optionally substituted amino group includes, for example, a di-lower alkylamino group such as a dimethylamino group and a diethylamino group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferred.

The lower alkoxy group on the benzene ring of the ring B includes, for example, a methoxy group, an ethoxy group, a propyloxy group, a butoxy group and the like, and a methoxy group is preferred. Examples of the lower alkylenedioxy on the benzene ring of ring B include, for example, a methylenedioxy group and an ethylenedioxy group, and examples of the di-lower alkylamino group include a dimethylamino group and a diethylamino group. can give.

The lower alkyl group represented by R ¹ or R ² includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like, and a methyl group is particularly preferable.

A group -COR ³² , a group -COR ⁴² , a group -COR
^{When 33} and the group —COR ⁴³ are esterified carboxyl groups, the ester residue may be a lower alkyl group such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, a methoxymethyl group, A lower alkyl group substituted with a lower alkoxy group such as a methoxyethyl group is exemplified, but a methyl group, an isopropyl group, a 2-methoxyethyl group and the like are preferable, and a methyl group is particularly preferable. Group-
When COR ³³ and group —COR ⁴³ are amidated carboxyl groups, examples of such a group include an optionally substituted alkyl group, an optionally substituted phenyl group, and an optionally substituted amino group. A carbamoyl group which may be mono- or di-substituted by a group selected from a group and a nitrogen-containing heterocyclic ring which may be substituted;

[0024]

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Wherein the ring (a) in the formula is a 5- or 6-membered nitrogen-containing monocyclic heterocyclic ring which may be substituted.

The alkyl group which may be substituted in the group —COR ³³ , —COR ⁴³ and R ⁵ includes a lower alkyl group (for example, a methyl group, an ethyl group, an isopropyl group, a butyl group, etc.). Pyridyl- or 1-oxopyridyl-lower alkyl group (for example, pyridylmethyl group, pyridylethyl group, 1-oxopyridylmethyl group and the like), piperazinyl lower alkyl group (for example, piperazinylmethyl and the like), piperidyl lower alkyl group ( For example,
Piperidylmethyl), a hydroxy lower alkyl group (eg, a hydroxyethyl group), a di-lower alkylamino lower alkyl group (eg, a dimethylaminoethyl group, a diethylaminomethyl group, a diethylaminoethyl group, etc.) and the like. Examples of the phenyl group which may be used include a phenyl group, a di-lower alkylaminophenyl group (eg, a dimethylaminophenyl group), a morpholinophenyl group, a lower alkylpiperazinylcarbonylphenyl group (eg, a methylpiperazinylcarbonylphenyl group) And the like, and the optionally substituted amino group includes an amino group, a di-lower alkylamino group (for example,
Dimethylamino group, diethylamino group, etc.), morpholino lower alkylamino group (eg, morpholinomethylamino group, etc.), and the optionally substituted nitrogen-containing heterocycle includes an amino group, a lower alkoxy group, and an oxo group. A pyridine ring optionally substituted with a group selected from the group consisting of: a piperazine ring optionally substituted by a group selected from a lower alkyl group and an oxo group; a piperidine ring optionally substituted by a lower alkyl group; a lower alkyl group And a 5- or 6-membered nitrogen-containing monocyclic heterocyclic ring such as an isoxazole ring, a pyrazole ring, a triazole ring, and a pyrimidine ring which may be substituted.

Examples of the nitrogen-containing heteromonocyclic group represented by the ring (a) include 5- or 6-membered nitrogen-containing heteromonocyclic groups such as piperazinyl, piperidyl, morpholinyl and pyrazolyl. However, these heteromonocyclic groups may be substituted with an amino group, a lower alkyl group or the like.

Preferred compounds (1-a) include a group
A compound wherein COR ³² is an esterified carboxyl group and the group -COR ⁴² is a carboxyl group;
Preferred compounds (1-b) include compounds in which the group —COR ³³ is an esterified carboxyl group and the group —COR ⁴³ is an amidated carboxyl group.

Other preferred compounds (1-a), (1-
b) and (2) include a benzene ring in which ring A is substituted with a group selected from an alkoxy group, a nitro group, a hydroxy group, a di-lower alkylamino group and a halogen atom; Compounds which are a cyclic heterocyclic ring, a benzene ring or a lower alkylenedioxy group-substituted benzene ring are mentioned. More preferred compounds are those wherein ring A is a lower alkoxy group, a nitro group, a hydroxy group, a di-lower alkylamino group and a halogen atom. A benzene ring di- or tri-substituted with a group selected from the group consisting of a pyridine ring, a benzene ring or a benzene ring substituted with a lower alkylenedioxy group, a compound in which R ¹ is a lower alkyl group, and R ² is a hydrogen atom. .

More preferred compounds (1-b) include a group —COR ³³ having a lower alkoxycarbonyl group or a lower alkoxy group-substituted lower alkoxycarbonyl group, a group —COR ⁴³ having a pyridyl group, an oxo group-substituted pyridyl group, and an amino group. Group-substituted pyridyl group, lower alkoxy group-substituted pyridyl group, lower alkyl group-substituted piperidyl group, lower alkyl group-substituted piperazinyl group, piperazinyl group substituted by lower alkyl group and oxo group, lower alkyl group-substituted isoxazolyl group, pyrazolyl group, triazolyl Group, pyridyl group-substituted lower alkyl group, oxo group-substituted pyridyl-lower alkyl group, di-lower alkylphenyl group, morpholinophenyl group, lower alkylpiperazinylcarbonylphenyl group, hydroxy lower alkyl group and di-lower alkylamino group. A carbamoyl group which may optionally be mono-substituted with a group or formula:

[0031]

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Wherein the ring (a) in the formula is a 5- or 6-membered nitrogen-containing monocyclic heterocyclic ring which may be substituted, and more preferred compounds ( Examples of 2) include compounds in which R ⁵ is a pyridyl-substituted lower alkyl group, a di-lower alkylamino lower alkyl group, a hydroxy-lower alkyl group, a di-lower alkylamino group or a lower alkyl-substituted piperazinyl group.

More preferred compounds (1-a), (1-a)
The b) and (2), ring A is a methoxy group, a cyclopentyloxy group, a nitro group, hydroxy group, a dimethylamino group and di- or tri-substituted benzene ring with a group selected from a chlorine atom, R ¹ is a methyl group The compound which is is mentioned.

Further, more preferred compound (1-b) is a group -COR ³³ being a methoxycarbonyl group, an isopropyloxycarbonyl group or a 2-methoxyethoxycarbonyl group, a group -COR ⁴³ being a pyridyl group or a 2-aminopyridyl group. , 1-oxopyridyl, 4-methylpiperazinyl, 4-methyl-4-oxopiperazinyl, 1-
Methylpiperidyl group, 5-methylisoxazolyl group,
Carbamoyl optionally monosubstituted by a group selected from a 3-pyrazolyl group, a 1,3,4-triazolyl group, a pyridylmethyl group, a 1-oxopyridylmethyl group, a dimethylaminoethyl group, a hydroxyethyl group and a dimethylamino group And R ⁵ is a hydrogen atom, a pyridylmethyl group, a dimethylaminoethyl group, a hydroxyethyl group, a dimethylamino group or a 4-methylpiperazinyl group. Is mentioned.

The desired compounds (1-a), (1-
In b) and (2), there are four types of geometric isomers based on two double bonds, and the present invention includes both of these isomers and mixtures thereof.

Further, the objective compound (1-a) of the present invention,
(1-b) and (2) include a ring A, a ring B, a group -CO
R ³² , group —COR ³³ , group —COR ⁴² or group —COR
Depending on the type of substituent or R ⁵ in ^43, optical isomer based on an asymmetric carbon may also be present, but the present invention also includes any of these isomers and mixtures thereof.

Among the four types of geometric isomers, preferred are compounds in which the geometric isomerism based on the double bond to which ring B is bonded is trans (E).
A compound in which the geometric isomerism based on the double bond bonded to is cis (Z) is more preferred.

Preferred compounds among the target compounds of the present invention are compounds (1-b) and (2), among which compound (1-b) is particularly preferred.

Among the target compounds (1-b) of the present invention, particularly preferred are (1Z, 3E) -1-methyl-1
-(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-methylpiperazin-1-yl) aminocarbonyl] -4-phenylbutadiene,
(1Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N-
(4-pyridyl) aminocarbonyl] -4- (3,4-
Methylenedioxyphenyl) butadiene, (1Z, 3
E) -1-Methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-pyridylmethyl) aminocarbonyl] -4-phenylbutadiene, (1Z, 3E) -1 -Methyl-1- (3-chloro-4,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (3-pyridylmethyl) aminocarbonyl] -4-phenylbutadiene and (1Z, 3E)-
1-methyl-1- (3-chloro-4,5-dimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4- (4-pyridyl) butadiene and the like.

Among the desired compounds (2) of the present invention, particularly preferred are (3Z, 4E) -3- (3,5-dimethoxy-α-methylbenzylidene) -4-benzylidene-1- (4-pyridyl). Methyl) pyrrolidine-2,5-dione, (3Z, 4E) -3- (3-chloro-4,5-dimethoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5- Zeon, (3
Z, 4E) -3- (3-Methoxy-4-cyclopentyloxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5-dione, (3Z,
4E) -3- (3-Cyclopentyloxy-4-methoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5-dione and (3Z, 4
E) -3- (3,5-Dimethoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-
2,5-dione and the like.

The objective compounds (1-a) and (1-a) of the present invention
b) and (2) can be used in pharmaceutical form in free form or in the form of a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate and methanesulfonate. Is raised. Further, when it has a substituent such as a carboxyl group or an imide group, it can be used as a basic salt (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt). The compound of the present invention or a salt thereof also includes a hydrate or a solvate.

The objective compounds (1-a), (1-
b) and (2) or a salt thereof can be administered orally or parenterally, and may be administered in a conventional manner, for example, as tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as an appropriate pharmaceutical preparation.

The target compounds (1-a) and (1-
The dose of b) and (2) or a pharmacologically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient. About 0.1 to 100 mg / kg, and in the case of parenteral administration, about 0.01 to 10 mg / kg.

The target compound (1-a) of the present invention is, for example, a compound represented by the general formula (4)

[0045]

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Wherein the group —COR ³¹ and the group —COR ^31
41 represents the same or different esterified carboxyl group, and other symbols have the same meaning as described above. ) Can be produced by treating the diester compound represented by the formula (1) with an acid or a base.

The target compound (1-b) of the present invention is
Compound (1-a), a salt thereof or a reactive derivative thereof, and a compound represented by general formula (5) HR ⁴⁰ (5) (wherein R ⁴⁰ represents an amino group which may be substituted). Can be produced by reacting

The target compound (2) of the present invention has the general formula (1)
-C)

[0049]

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Wherein the group —COR ³⁴ and the group —COR
⁴⁴ has a carboxyl group which may be esterified on one side, an unsubstituted carbamoyl group, an alkyl group which may be substituted, a carbamoyl group which may be substituted, an amino group which may be substituted, or a carbamoyl group which may be substituted. Represents a carbamoyl group substituted with a nitrogen-containing heterocyclic group, and other symbols have the same meanings as described above. ) Or a salt thereof is subjected to an intramolecular ring closure reaction.

The target compound (2) wherein R ⁵ is an optionally substituted alkyl group, an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic group,
General formula (2-a)

[0052]

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(Wherein the symbols have the same meanings as described above) or a salt thereof, and a compound represented by the following general formula (3): R ⁵¹ -X (3) wherein R ⁵¹ may be substituted. An alkyl group, an amino group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted, and X represents a reactive residue.) .

The acid or base treatment of the diester compound (4) can be carried out in a suitable solvent or without a solvent.

The solvent is not particularly limited as long as it is an inert solvent which does not adversely affect the reaction. For example, ethylene glycol, N, N-dimethylformamide (DM
F), hexamethylphosphoramide, benzene, tetrahydrofuran (THF), dioxane, toluene, ethyl acetate, lower alcohol (methanol, ethanol, etc.), dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, 1,3- An organic solvent such as dimethyl-2-imidazolidinone, diethyl ether, dimethoxyethane, dimethyl sulfoxide, carbon disulfide, and acetone, or a mixed solvent of these organic solvents and water can be used as appropriate.

As the base, for example, an alkali metal, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alcoholate, lithium diisopropylamide (LD
Lower alkyl-substituted metal amides such as A), lower alkyl alkali metals such as n-butyllithium, tri-lower alkylamine or 1,8-diazabicyclo [5.4.0]
Organic amines such as undec-7-ene and the like can be suitably used, and as the acid, any of ordinary protonic acids and Lewis acids can be suitably used.

This reaction can be carried out widely under cooling to heating, for example, at -60 to 150 ° C, especially at 15 ° C.
〜 Properly proceeds at the boiling point of the solvent.

The condensation reaction between compound (1-a) or a salt thereof and compound (5) can be carried out in a suitable solvent in the presence of a dehydrating agent.

Examples of the dehydrating agent include 1,3-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI) and the like.

As the salt of the compound (1-a), conventional salts such as alkali metal salts and alkaline earth metal salts can be used, and these salts are used for the reaction with the compound (5). It is preferable to provide the compound in advance as a free compound.

The condensation reaction between the reactive derivative of the compound (1-a) and the compound (5) can be carried out in a suitable solvent in the presence of a deoxidizing agent.

As the reactive derivative, any of those commonly used in amide bond forming reactions such as acid halides, mixed acid anhydrides and active esters can be used.

Examples of the deoxidizing agent include alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogencarbonate, trialkylamine, N, N-dialkylaniline, pyridine and the like.

Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethylsulfoxide, toluene and benzene.

In this reaction, the compound (5) is reacted with 1 to 3 per mol of the compound (1-a), a salt thereof or a reactive derivative thereof.
It can be carried out using a molar amount, preferably 1.1 to 1.3 molar amount.

The intramolecular ring closure reaction of compound (1-c) can be carried out in a suitable solvent or without a solvent, in the presence of a base or an acid.

The solvent is not particularly limited as long as it is an inert solvent which does not adversely affect the reaction. For example, ethylene glycol, N, N-dimethylformamide (DM
F), hexamethylphosphoramide, benzene, tetrahydrofuran (THF), dioxane, toluene, ethyl acetate, lower alcohol (methanol, ethanol, etc.), dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, 1,3- An organic solvent such as dimethyl-2-imidazolidinone, diethyl ether, dimethoxyethane, dimethyl sulfoxide, carbon disulfide, and acetone, or a mixed solvent of these organic solvents and water can be used as appropriate.

As the base, for example, an alkali metal, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alcoholate, lithium diisopropylamide (LD
Lower alkyl-substituted metal amides such as A), lower alkyl alkali metals such as n-butyllithium, tri-lower alkylamine or 1,8-diazabicyclo [5.4.0]
Organic amines such as undec-7-ene and the like can be suitably used, and as the acid, any of ordinary protonic acids and Lewis acids can be suitably used.

This reaction can be carried out widely under cooling to heating, for example, at -60 to 150 ° C, especially at 15 ° C.
〜 Properly proceeds at the boiling point of the solvent.

The condensation reaction between compound (2-a) or a salt thereof and compound (3) can be carried out in a suitable solvent in the presence of a deoxidizing agent.

As the salt of the compound (2-a), an alkali metal salt or the like can be used.

Any deoxidizing agent can be used as long as it is used in this type of reaction. Examples thereof include alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as sodium hydroxide, potassium carbonate and the like. And alkali metal alkoxides such as sodium methylate, lower alkyl-substituted alkali metal amides such as lithium diisopropylamide, and alkali metals such as sodium.

As the reactive residue X, a halogen atom (for example, chlorine atom, bromine atom, iodine atom, etc.), a sulfonyloxy group (for example, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, toluenesulfonyloxy group, etc.) And the like.

As the solvent, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane, ethylene glycol,
N, N-dimethylformamide, dimethylsulfoxide, toluene, benzene and the like can be mentioned.

This condensation reaction suitably proceeds under cooling to the boiling point of the solvent, for example, -60 to 100 ° C, especially -60 to 20 ° C.

This reaction can be carried out using 1 to 5 mol of compound (3) per 1 mol of compound (2-a) or a salt thereof.

The starting compound (4) of the present invention has the general formula (6)

[0078]

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Wherein the symbols have the same meanings as described above, and a compound represented by the general formula (7):

[0080]

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(Wherein the symbols have the same meanings as described above).

The starting compound (4) of the present invention has the general formula (8)

[0083]

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Wherein the symbols have the same meanings as described above, and a compound represented by the general formula (9)

[0085]

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(Wherein the symbols have the same meanings as described above). The condensation reaction of compound (6) with compound (7) and compound (8) with compound (9) can be carried out in a suitable solvent in the presence of a base. As the base, for example, potassium tert-butoxide (t-BuO)
K), an alkyl-substituted alkali metal amide such as sodium methoxide and lithium diisopropylamide (LDA).

As the solvent, methanol, ethanol,
Lower alcohols such as tert-butyl alcohol (t-BuOH), dichloromethane, chloroform, 1,2-
Examples thereof include dichloroethane, diethyl ether, tetrahydrofuran, dioxane, ethylene glycol, N, N-dimethylformamide, dimethyl sulfoxide, toluene, and benzene.

This reaction is carried out under cooling to heating, for example, -3.
It proceeds suitably at 0 ° C to the boiling point of the solvent, especially 15 to 80 ° C.

Among the starting compounds (6) of the present invention, those which are trans (E) isomers include, for example, compounds (8) and (10)

[0090]

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(Wherein the symbols have the same meanings as described above), and can be obtained by condensation in a suitable solvent in the presence of a base.

Among the starting compounds (6) of the present invention, the cis (Z) isomer can be obtained by addition / elimination reaction of the corresponding trans (E) isomer. For example, it can be obtained by once adding a nucleophilic reagent such as thiophenol to the trans (E) isomer of the compound (6) and then removing the nucleophilic reagent in the presence of a base.

In the present invention, the alkyl group and the alkoxy group have 1 to 20 carbon atoms, especially 1 to 1 carbon atoms.
0, especially 1 to 6 alkyl groups and alkoxy groups. The lower alkyl group and the lower alkoxy group include those having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms.
The cycloalkyl group has 3 to 10 carbon atoms, especially 5 carbon atoms.
To 8 are mentioned. Examples of the lower alkylenedioxy group include an alkylenedioxy group having 1 to 4 carbon atoms.

[0094]

EXAMPLES Specific synthetic methods of the compounds of the present invention are shown below as examples.

Example 1 (1) To a solution of 50 g of vanillin in 600 ml of N, N-dimethylformamide (DMF), 13.9 g of 62.5% sodium hydride (NaH) and 38.8 ml of cyclopentyl bromide were added under ice cooling. Stir at 90 ° C. overnight. D
After evaporating the MF, water is added thereto, and the mixture is extracted with ethyl acetate. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane:
Ethyl acetate = 3: 1) was purified and 65 g of 4-cyclopentyloxy-3-methoxybenzaldehyde (yield: 90)
%, IR: 2960, 1683, 1583, 1506,
1266, 1135, 730 cm ^-1 ).

(2) 10 g of this product and dimethyl succinate
0 g of tert-butyl alcohol (t-BuOH) 2
0 ml solution is added to potassium tert-butoxide (t-BuO
K) Add 5.1 g of t-BuOH in 50 ml solution and stir at room temperature for 1 hour. The reaction solution is poured into ice water and washed with diisopropyl ether (iPr ₂ O). Extract with ethyl acetate after adjusting the pH to 1 with hydrochloric acid, washing and drying.
The solvent is distilled off. The residue obtained is diluted with dichloromethane 100
Then, 11.8 ml of diisopropylethylamine and 3.9 ml of methoxymethyl chloride are added to this solution under ice-cooling, and the mixture is stirred at room temperature for 1 hour. After adding water, the mixture is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give (E)-
10.9 g of methyl 3- (4-cyclopentyloxy-3-methoxyphenyl) -2- (methoxymethoxycarbonylmethyl) acrylate (yield: 63%, IR: 295)
7, 1741, 1710, 1599, 1513, 125
6, 1145 cm ^-1 ).

(3) 2.2 ml of a 15% n-butyllithium (n-BuLi) hexane solution was added to a solution of thiophenol (5.9 ml) in tetrahydrofuran (THF) (50 ml) under ice-cooling under a nitrogen stream, and then at room temperature. Stir for 30 minutes. To this solution was added 13.4 g of the compound obtained in (2).
Add 100 ml of HF solution and stir at room temperature overnight. After adding ethyl acetate, washing and drying, the solvent is distilled off, and silica gel column chromatography (elution solvent: hexane:
Ethyl acetate = 3: 1) Purified (2R ^* , 3R ^* )-3
14.5 g of methyl-(4-cyclopentyloxy-3-methoxyphenyl) -2-methoxymethoxycarbonylmethyl-3-phenylthiopropionate (yield: 84
%, IR: 2957, 1736, 1585, 1512,
1265, 1143 cm ^-1 ).

(4) 14.5 g of chloroform 30 of this product
3-chloroperbenzoic acid (mCPB)
A) Add 5.1 g little by little and stir at the same temperature for 30 minutes. After adding 10 g of calcium hydroxide, stirring and filtering, the solvent is distilled off. 300 ml of toluene is added to the obtained residue, and the mixture is heated under reflux for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1) to give (Z) -3- (4-cyclopentyloxy-3-methoxyphenyl) -2- (methoxymethoxycarbonyl) 8. methyl) methyl acrylate
0 g (Yield: 67%, IR: 2956, 1744, 17)
18, 1600, 1511, 1144 cm ^-1 ).

(5) This product 10.3 g of THF 100 ml
The solution was diluted with 4.6 ml of diisopropylamine, n-BuL
i in a lithium diisopropylamide (LDA) solution prepared from 20 ml and THF 60 ml under a nitrogen stream at −7
It is added dropwise at 8 ° C. and stirred at the same temperature for 30 minutes. 3.5 g of benzaldehyde in THF 30 at -100 ° C.
The solution was added dropwise and stirred at the same temperature for 20 minutes. An aqueous ammonium chloride solution is added, and the mixture is extracted with ethyl acetate, washed,
After drying, the solvent is distilled off. The resulting residue was dissolved in dichloromethane (50 ml), and triethylamine (11 m) was added under ice-cooling.
l and methanesulfonyl chloride (MSCl) 2.5 m
and stirred at room temperature for 1 hour. After adding water, the mixture is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give (1)
6. Z, 3E) -1- (4-Cyclopentyloxy-3-methoxyphenyl) -2-methoxycarbonyl-3-methoxymethoxycarbonyl-4-phenylbutadiene
3 g (Yield: 58%, IR: 2957, 1717, 15
97, 1509, 1264, 1160, 696c
m ^-1 ).

(6) To a solution of 7.3 g of this product in 50 ml of THF is added 5 ml of concentrated hydrochloric acid, and the mixture is stirred at room temperature for 1 hour. A saturated saline solution is added, and the mixture is extracted with ethyl acetate. After drying, the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 2).
0: 1) and purified to give (1Z, 3E) -1- (4-cyclopentyloxy-3-methoxyphenyl) -2-methoxycarbonyl-3-carboxy-4-phenylbutadiene 6.1 g (yield: 92%; IR: 3500-3000
(Br.), 2958, 1712, 1690, 160
0, 1509, 1270, 694 cm ^-1 ).

(7) 0.35 g of carbonyldiimidazole (CDI) is added to a solution of 0.75 g of this product in 20 ml of THF, and the mixture is stirred at room temperature for 30 minutes. 0.7 ml of 28% ammonia water is added to this solution, and the mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted with chloroform. After drying, the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: chloroform: acetone = 5:
1) Purification: 0.48 g of (1Z, 3E) -1- (4-cyclopentyloxy-3-methoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4-phenylbutadiene (yield: 64%, melting point) 158-159
° C) (see Table 1).

Example 2 (1) To a solution of 0.3 g of the compound obtained in Example 1 (6) in 10 ml of dichloromethane was added 0.15 ml of triethylamine and 0.14 ml of isobutyl chloroformate under ice-cooling, followed by stirring for 30 minutes. 0.11 ml of 4-picolylamine is added to this solution and stirred for 30 minutes. Add water,
After extraction with chloroform and drying, the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 50: 1) to give (1Z,
3E) -1- (3-Methoxy-4-cyclopentyloxyphenyl) -2-methoxycarbonyl-3- (4-pyridylmethylaminocarbonyl) -4-phenylbutadiene 0.29 g (yield: 80%) is obtained.

(2) To 0.29 g of this product was added a 4N hydrogen chloride-ethyl acetate solution, and the mixture was triturated with ether.
3E) -1- (3-Methoxy-4-cyclopentyloxyphenyl) -2-methoxycarbonyl-3- (4-pyridylmethylaminocarbonyl) -4-phenylbutadiene hydrochloride 0.29 g (yield: 93%, melting point) : 105-
130 ° C.) (listed in Table 1).

Examples 3 and 4 The corresponding starting compounds were treated in the same manner as in Example 2 to obtain the compounds shown in Table 1.

[0105]

[Table 1]

Example 5 To a solution of 0.28 g of the compound obtained in Example 1 (7) in 10 ml of tetrahydrofuran (THF) was added 1 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 10 minutes.
After neutralization with 2N hydrochloric acid, extraction with chloroform is performed, and after drying, the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2:
1) Purify (3Z, 4E) -4-benzylidene-3
0.24 g of-(4-cyclopentyloxy-3-methoxybenzylidene) pyrrolidine-2,5-dione (yield:
93%, melting point: 203-204 ° C.) (listed in Table 2).

Example 6 (1) To a solution of 0.25 g of the compound obtained in Example 2 (2) in 10 ml of tetrahydrofuran (THF) was added 1.1 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature. Water was added to the mixture, extracted with chloroform, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 1) to give (3Z, 4E) -3- (4-cyclopentyloxy-3-methoxybenzylidene) -4-benzylidene-
0.12 g (yield: 55%) of 1- (4-pyridylmethyl) pyrrolidine-2,5-dione is obtained.

(2) 4N hydrogen chloride-dioxane solution was added to 0.12 g of this product, and the mixture was triturated with ether.
4E) -3- (4-Cyclopentyloxy-3-methoxybenzylidene) -4-benzylidene-1- (4-pyridylmethyl) pyrrolidine-2,5-dione hydrochloride 90 m
g (yield: 76%, melting point: 117-130 ° C (decomposition))
(Described in Table 2).

Examples 7 to 8 The corresponding starting compounds were treated in the same manner as in Example 6 to give the compounds shown in Table 2.

Example 9 (1) To a solution of 0.3 g of the compound obtained in Example 1 (6) in 10 ml of dichloromethane was added 0.15 ml of triethylamine and 0.14 ml of isobutyl chloroformate under ice-cooling, followed by stirring for 30 minutes. 0.12 ml of N, N-dimethylethylenediamine is added to this solution and stirred for 30 minutes. Water is added, the mixture is extracted with chloroform, dried, and the solvent is distilled off. Tetrahydrofuran (THF) is added to the resulting residue.
5 ml and 0.7 ml of a 2N aqueous sodium hydroxide solution are added, and the mixture is stirred at room temperature for 10 minutes. Water is added and the mixture is extracted with chloroform. After drying, the solvent is distilled off. The resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1) to give (3Z, 4E)
-3- (4-Cyclopentyloxy-3-methoxybenzylidene) -4-benzylidene-1- (2- (N, N-
0.25 g (yield: 76%) of dimethylamino) ethyl) pyrrolidine-2,5-dione is obtained.

(2) 4N hydrogen chloride-ethyl acetate solution was added to 0.25 g of this product, and the mixture was triturated with ether.
4E) -3- (4-Cyclopentyloxy-3-methoxybenzylidene) -4-benzylidene-1- (2-
(N, N-dimethylamino) ethyl) pyrrolidine-2,
0.17 g of 5-dione hydrochloride (yield: 88%, melting point: 9
5-110 DEG C. (decomposition)) (see Table 2).

Example 10 The corresponding starting compound was treated in the same manner as in Example 9 to obtain the compounds shown in Table 2.

[0113]

[Table 2]

Example 11 (1) To a solution of magnesium methyl iodide (MeMgI) prepared from 2.9 g of magnesium (Mg) and 7.5 ml of methyl iodide (MeI) in 150 ml of diethyl ether was added 4-cyclopentyloxy-3-. 17.6 g of methoxybenzaldehyde in tetrahydrofuran (THF)
A 40 ml solution is added dropwise under ice cooling, and the mixture is stirred at room temperature for 1 hour. The reaction solution was cooled with ice, and a saturated aqueous ammonium chloride solution 20 was added.
Add ml and extract with ethyl acetate. After the solvent was distilled off, the residue was dissolved in 300 ml of acetonitrile, and 55 g of manganese dioxide (MnO ₂ ) was added under ice cooling. Warm to room temperature and stir for 3 days. 20 g of celite was added to the reaction solution, and 30
After stirring for minutes, the insolubles were removed by filtration, and the solvent was distilled off. The residue is crystallized from cold hexane to give 13.8 g of 4-acetyl-1-cyclopentyloxy-2-methoxybenzene (yield: 73.6%, melting point: 55-56 ° C).

(2) A solution of 9.7 g of this product and 10 g of dimethyl (E) -benzylidenesuccinate in 100 ml of THF was added at room temperature to potassium tert-butoxide (t-BuOK).
4.8 g of tert-butyl alcohol (t-BuO
H) Add dropwise to the 100 ml solution and stir at the same temperature for 1 hour.
200 ml of diisopropyl ether is added to the reaction solution, and the mixture is extracted with water. Concentrated hydrochloric acid is added to the aqueous layer to adjust the pH to 1 to 2, and the mixture is extracted again with ethyl acetate. The solvent was distilled off and the residue 2
And dissolve in 100 ml of chloroform. At room temperature, 2-3 drops of N, N-dimethylformamide (DMF) and 1.8 ml of thionyl chloride (SOCl ₂ ) are added, and the mixture is heated under reflux for 30 minutes. The reaction solution is ice-cooled, added dropwise to a solution of 20 ml of aqueous ammonia (NH ₄ OH) in 50 ml of chloroform and stirred for 30 minutes. 50 ml of water is added to the reaction solution, and extracted with chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform: acetone = 20: 1).
Crystallized from a mixture of ethyl acetate and 0.42 g of (1Z, 3E) -1-methyl-1- (4-cyclopentyloxy-3-methoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4-phenylbutadiene (melting point) : 1
33-134 ° C.) (listed in Table 3).

Examples 12 to 22 The corresponding starting compounds were treated in the same manner as in Example 11, and
5 can be obtained.

[0117]

[Table 3]

[0118]

[Table 4]

[0119]

[Table 5]

Example 23 (1) Potassium tert-butoxide (t-BuOK)
2.4 g of tert-butyl alcohol (t-BuO
H) In a 25 ml solution at 20-25 ° C, 3,4,5-
A solution of 5.0 g of trimethoxyacetophenone and 4.5 g of (E) -benzylidene-dimethyl succinate in 20 ml of tetrahydrofuran (THF) is added dropwise, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into water and washed with diisopropyl ether. The aqueous layer is adjusted to pH = 1 with hydrochloric acid and extracted with ethyl acetate. After drying the extract, the solvent is distilled off and the residue is subjected to silica gel column chromatography (elution solvent;
Chloroform: methanol = 50: 1 to 20: 1) Purified 1-methyl-1- (3,4,5-trimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-
6.5 g of 4-phenylbutadiene (yield: 66.3%,
IR: 3420, 2950, 1720, 1715, 16
90, 1585, 1240, 1125, 695 cm ^-1 )
(Mixture of (1E, 3E) -form and (1Z, 3E) -form).

(2) 6.5 g of this product in 30 m of chloroform
l, N, N-dimethylformamide (DMF)
3 drops and 1.15 ml of thionyl chloride are added,
Reflux for 0 minutes. This solution is added dropwise to 20 ml of a concentrated aqueous ammonia solution under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. After extracting with chloroform and drying, the solvent is distilled off and the residue is purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 to 1: 2). Further, ether was added, and the precipitated crystals were collected by filtration and recrystallized from a hexane-ethyl acetate mixed solution to give (1E, 3E) -1-methyl-1-methyl.
2.6 g of (3,4,5-trimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4-phenylbutadiene (yield: 40.1%, melting point: 155-1)
57 ° C.) (listed in Table 6).

(3) The solvent of the filtrate obtained in (2) was distilled off, and the filtrate was crystallized with diisopropyl ether.
Recrystallization from a mixed solution of ethyl acetate gave (1Z, 3E) -1-methyl-1- (3,4,5-trimethoxyphenyl) -2.
2.1 g of -methoxycarbonyl-3-aminocarbonyl-4-phenylbutadiene (yield: 32.4%, melting point:
118-120 ° C) (see Table 5).

Example 24 (1) Potassium tert-butoxide (t-BuOK) 1
4.5 g of tert-butyl alcohol (t-BuO
H) A mixture of 15.5 g of acetophenone and 27.1 g of dimethyl succinate is dropped into a 100 ml solution, and the mixture is stirred at room temperature overnight. The reaction solution is poured into ice water, washed with diisopropyl ether, and the aqueous layer is adjusted to pH = 2 to 3 with concentrated hydrochloric acid. After extracting with ethyl acetate and drying, the residue obtained by evaporating the solvent is dissolved in 150 ml of methanol, and 12.5 ml of thionyl chloride is added dropwise under ice cooling. After stirring at room temperature overnight, the solvent is distilled off, ethyl acetate is added, and the mixture is washed and dried, and then the solvent is distilled off. The resulting residue was separated by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1) to give (E) -2-benzylidene-α-
18.6 g of dimethyl methyl succinate (yield: 58%, property: oil, IR: 2970, 2940, 2860, 1
745, 1440, 1270, 1200, 1180, 1
135, 1060, 770, 705 cm ^-1 ) and 6.2 g of dimethyl (Z) -2-benzylidene-α-methylsuccinate (yield: 19%, properties: oil, IR: 29)
60, 2920, 2850, 1740, 1710, 14
40, 1320, 1250, 1195, 1170, 11
40, 765, 700 cm ^-1 ).

(2) A solution of 5.0 g of dimethyl (E) -2-benzylidene-α-methylsuccinate and 4.0 g of 3,4,5-trimethoxybenzaldehyde in 20 ml of tetrahydrofuran (THF) was added to 2.3 g of t-BuOK. −
The solution is added dropwise to a solution of BuOH (20 ml) and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and after washing, the aqueous layer was concentrated with concentrated hydrochloric acid.
Adjust to H = 2-3 and extract with ethyl acetate. After drying the extract, the solvent was distilled off, and the resulting residue was treated with chloroform 30
and 1.5 ml of thionyl chloride and N, N
Add 3 drops of dimethylformamide and heat to reflux for 30 minutes. The solution is added dropwise to 20 ml of 28% aqueous ammonia under ice cooling, and the mixture is stirred at room temperature for 10 minutes. Water is added, the mixture is extracted with chloroform, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give (1E, 3E)-
1- (3,4,5-trimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4-methyl-
4.7 g of 4-phenylbutadiene (yield: 57%, melting point: 156-157 ° C.) are obtained (described in Table 6).

[0125]

[Table 6]

Example 25 In Example 24, 5.3 g of dimethyl (Z) -2-benzylidene-α-methylsuccinate obtained in (1) was used.
(1E, 3Z) -1- (3,3)
6.7 g of 4,5-trimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4-methyl-4-phenylbutadiene (yield: 76%, melting point: 141-
143 ° C.) (described in Table 7).

[0127]

[Table 7]

Example 26 To a solution of 0.32 g of the compound obtained in Example 11 (2) in 20 ml of tetrahydrofuran (THF) was added 2N under ice-cooling.
Add 3.6 ml of aqueous sodium hydroxide solution and stir for 10 minutes. To the reaction mixture is added 3.6 ml of 2N hydrochloric acid, and the mixture is extracted with ethyl acetate. The solvent was distilled off, and silica gel column chromatography (elution solvent: chloroform: acetone = 1)
0: 1) purified, crystallized from diethyl ether (3: 1
Z, 4E) -4-benzylidene-3- (4-cyclopentyloxy-3-methoxy-α-methylbenzylidene)
0.17 g of pyrrolidine-2,5-dione (yield: 58.
0%, melting point: 193-194 ° C) (described in Table 8 below).

Examples 27 to 38 The corresponding starting compounds were treated in the same manner as in Example 26, and
Compounds described in 10 can be obtained.

[0130]

[Table 8]

[0131]

[Table 9]

[0132]

[Table 10]

Examples 39 to 43 By treating the corresponding starting compounds in the same manner as in Example 1, the compounds shown in Table 11 can be obtained.

[0134]

[Table 11]

Examples 44 to 48 By treating the corresponding starting compounds in the same manner as in Example 5, the compounds shown in Table 12 can be obtained.

[0136]

[Table 12]

Example 49 (1) 100 g of vanillin was dissolved in 800 ml of chloroform, and chlorine was blown in at room temperature for about 1 hour to precipitate a white solid. After blowing in compressed air to remove dissolved chlorine, the precipitated solid is collected by filtration, washed and dried. The mother liquor is concentrated, powdered with diethyl ether, filtered, washed and dried. 115.25 g of 3-chlorovanillin (yield: 94.0%, melting point: 16)
3 ° C.).

(2) Dissolve 62 g of this product in 600 ml of N, N-dimethylformamide (DMF), add 91.8 g of potassium carbonate and 37.2 ml of methyl iodide at room temperature, and stir at the same temperature for 5 hours. After the reaction solution is concentrated, water is added, and the mixture is extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off to obtain 65.15 g of 3-chloro-4,5-dimethoxybenzaldehyde (yield: 97.7%, melting point: 54 ° C.).

(3) Magnesium (Mg) under a nitrogen stream
A solution of 30.4 ml of methyl iodide in 100 ml of diethyl ether is slowly added dropwise to a solution of 11.87 g of diethyl ether in 500 ml. It is 30 until the reflux subsides after dropping
After stirring for 40 minutes, a solution of 70 g of the compound obtained in (2) in 400 ml of tetrahydrofuran (THF) is added dropwise under ice-cooling. Warm to room temperature and stir for an additional 30 minutes. After quenching the reaction solution by adding a little water, an aqueous solution of ammonium chloride is added, and the mixture is extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent was distilled off and 3-chloro-4,5-dimethoxy-1- (1-hydroxyethyl) benzene 75
g.

This product (75 g) is dissolved in acetonitrile (500 ml), manganese dioxide (400 g) is added, and the mixture is stirred at room temperature overnight. Celite was added to the reaction solution, and the mixture was stirred for 1 hour, filtered through celite, and the mother liquor was concentrated. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) and then recrystallized from hexane to give 3-
62.0 g of chloro-4,5-dimethoxyacetophenone
(Yield: 82.8%, melting point: 47-49 ° C).

(4) A mixed solution of 11.3 g of this product, 11.54 g of dimethyl succinate and 50 ml of THF was added to ter
6.5 g of te-butoxy potassium (t-BuOK)
It is slowly added dropwise to a 30 ml solution of rt-butyl alcohol (t-BuOH) at room temperature. Stir at room temperature for 1 hour, 70 ° C. and 1 hour. After cooling the reaction mixture, the reaction mixture is poured into ice water, subjected to phase transfer purification with isopropyl ether, and extracted with water. Concentrated hydrochloric acid is added to the aqueous layer to adjust the pH to 2-3, and the released carboxylic acid is extracted with ethyl acetate. After drying the extract, the solvent was distilled off to give 4- (3-chloro-4,5-dimethoxyphenyl) -4-methyl-3-methoxycarbonyl-3.
-Butenoic acid (properties: amber oil) is obtained.

This product was dissolved in 100 ml of dichloromethane, and 11.0 ml of diisopropylethylamine was added under ice-cooling.
And methoxymethyl chloride (4.8 ml) were added, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution, an aqueous citric acid solution is added, and the mixture is extracted with ethyl acetate. The residue was separated by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 3 → 2: 3) to give (Z) -4- (3-chloro-4,5-dimethoxyphenyl) -4-methyl-3. -Methoxycarbonyl-3-
3.18 g of methoxymethyl butenoate (yield: 16.2)
%, IR: 1735, 1563, 1491, 1148,
932 cm ^-1 ) and (E) -4- (3-chloro-
Methoxymethyl 4,4-dimethoxyphenyl) -4-methyl-3-methoxycarbonyl-3-butenoate 9.12
g (Yield: 46.5%, IR: 1738, 1562, 1
491, 1146, 932 cm ^-1 ).

(5) 1.33 ml of diisopropylamine
Is slowly added dropwise to a solution of 1.6 ml of THF in ice-cooled solution under ice-cooling, and stirred at the same temperature for 30 minutes. The solution was cooled to -78 ° C and (Z) -4- (3-chloro-4,5-dimethoxyphenyl) -4-methyl-3-methoxycarbonyl-3
-Methoxymethyl butenoate 2.94 g in THF 20 ml
The solution is slowly added dropwise, and the mixture is further stirred at the same temperature for 30 minutes.
After cooling the reaction solution to -90 ° C, a solution of 1.01 g of isonicotinaldehyde in 10 ml of THF was slowly added dropwise, and-
Stir at 90 ° C. for 20 minutes. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After the organic layer was washed and dried, the solvent was distilled off and (Z) -4- (3-chloro-4,5-dimethoxyphenyl) -4-methyl-3-methoxycarbonyl-2- (4-pyridyl-hydroxy) was removed. Methyl) methoxymethyl-3-butenoate is obtained.

Dissolve the product in 50 ml of dichloromethane,
Under ice cooling, 7.54 ml of triethylamine and 0.977 ml of methanesulfonyl chloride (MSCl) are added, and the mixture is heated to room temperature and stirred overnight. Further, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) 1.
Add 18 ml and stir at room temperature for 3 hours. After the reaction solution is concentrated, water is added thereto, and the mixture is extracted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent; chloroform: acetone = 6: 1) to give (1Z, 3E) -1-methyl-1- (3-chloro-4,5-dimethoxyphenyl) -2-methoxycarbonyl. 2.007 g of -3-methoxymethoxycarbonyl-4- (4-pyridyl) butadiene (yield: 55.1%,
IR: 1720, 1594, 1563, 1490, 12
53, 1047, 927 cm ^-1 ).

(6) To a solution of 2.0 g of this product in 20 ml of THF was added 2.0 ml of 12N hydrochloric acid under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution is ice-cooled, a 2N aqueous sodium hydroxide solution is added thereto to adjust the pH to 4 to 5, and the mixture is extracted with ethyl acetate. After drying, the solvent was distilled off and (1Z, 3E) -1-methyl-1- (3-chloro-4,5-dimethoxyphenyl).
-2-methoxycarbonyl-3-carboxy-4- (4
-Pyridyl) butadiene (property: yellow solid) is obtained.

Dissolve the product in 20 ml of dichloromethane,
To this, triethylamine (0.67 ml) and isobutyl chloroformate (0.62 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Then, 2.8 ml of 28% aqueous ammonia was further added, and the mixture was stirred under ice cooling for 30 minutes. A 2-fold diluted saturated saline solution was added to the reaction solution, extracted with chloroform, dried, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 20: 1).
Purified 1-methyl-1- (3-chloro-4,5-dimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4- (4-pyridyl) butadiene 1.4
98 g (Yield: 83.0%, IR: 1720, 167)
6, 1595, 1240, 1047, 999, 855
cm ^-1 ). This product is a mixture of geometric isomers based on the 1-position double bond, and the ratio is Z-form: E-form = 2.
5: 1.

(7) This product was subjected to silica gel column chromatography (elution solvent: chloroform: acetone = 5:
1) Separated, (1Z, 3E) -1-methyl-1- (3
-Chloro-4,5-dimethoxyphenyl) -2-methoxycarbonyl-3-aminocarbonyl-4- (4-pyridyl) butadiene is obtained (described in Table 13).

Examples 50 to 53 The corresponding starting compounds were treated in the same manner as in Example 49, and
The compound described is obtained.

[0149]

[Table 13]

Example 54 (1) 800 mg of the compound obtained in Example 49 (7) was dissolved in 20 ml of tetrahydrofuran (THF), 0.48 ml of a 2N aqueous sodium hydroxide solution was added under ice-cooling, and the temperature was raised to room temperature for 1 hour. Stir. Water is added to the reaction solution, the mixture is extracted with chloroform, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 20: 1), and further recrystallized from a hexane-ethyl acetate mixed solution (3Z, 4E).
82 mg of -3- (3-chloro-4,5-dimethoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) -pyrrolidine-2,5-dione (yield: 11.1)
%, Melting point: 194 ° C. or more (decomposition), IR: 1721, 1
599, 1491, 1328, 1049 cm ^-1 ).

(2) 75 mg of this product was dissolved in a mixture of 1 ml of THF and 1 ml of dioxane, 0.054 ml of a 4N hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature.
A pale yellow solid crystallizes with stirring. The solvent was distilled off under reduced pressure, and the residue was triturated with diethyl ether.
The mixture was stirred and crystallized at room temperature in a diethyl ether mixed solution.
Z, 4E) -3- (3-Chloro-4,5-dimethoxy-
α-methylbenzylidene) -4- (4-pyridylmethylidene) -pyrrolidine-2,5-dione hydrochloride 70 mg
(Yield: 85.3%, melting point: 200 ° C. or more (decomposition), I
R: 1728, 1634, 1491, 1312 c
m ^-1 ) (see Table 14).

Examples 55 to 58 The corresponding starting compounds were treated in the same manner as in Example 54 to give Table 14.
The compound described is obtained.

[0153]

[Table 14]

Example 59 (1) Potassium tert-butoxide (t-BuOK) 1
6.8 g of tert-butyl alcohol (t-BuO
H) In 150 ml solution, 15.9 g of benzaldehyde and 26.3 g of dimethyl succinate in 20 ml of t-BuOH
The solution is added dropwise with stirring at room temperature and then stirred for 30 minutes. The reaction solution is poured into 200 ml of ice water and extracted with isopropyl ether. Adjust the aqueous layer to pH = 2-3,
After extraction with ethyl acetate, the organic layer is washed and dried, and the solvent is distilled off. The residue was dissolved in a mixture of 50 ml of toluene and 50 ml of ethylene glycol monomethyl ether, and cooled under ice-cooling.
After 16.4 ml of thionyl chloride is added dropwise and left overnight at room temperature, the solvent is distilled off. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give (E) -3-methoxycarbonyl-
26. 2-methoxyethyl 4-phenyl-3-butenoate
9 g (yield: 65%) are obtained.

(2) t of 14 g of this product and 11.1 g of 3-cyclopentyloxy-4-methoxybenzaldehyde
A solution of 100 ml of -BuOH is added dropwise to a solution of 6.2 g of t-BuOK in 40 ml of t-BuOH at room temperature, and the mixture is stirred at the same temperature for 1 hour. The reaction solution is poured into water and extracted with diisopropyl ether. The aqueous layer is adjusted to pH = 2 to 3 with hydrochloric acid, extracted with ethyl acetate, and the extract is washed, dried, and then the solvent is distilled off. The residue was washed with diethyl ether,
(E) -2-[(E) -3-cyclopentyloxy-4
-Methoxybenzylidene] -3-carboxy-4-phenyl-3-butenoate (23.4 g, yield: 67%)
Get.

(3) This product 5.0 g of chloroform 100
N, N-dimethylformamide (DMF) 2
Add ~ 3 drops and 0.82 ml of thiothionyl chloride and reflux for 30 minutes. The solution is added dropwise to 2-picolylamine with vigorous stirring under ice-cooling. 3 as it is
After stirring for 0 minutes, the organic layer was separated, washed and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: acetone = 5: 1).
(1E, 3E) -1- (3-cyclopentyloxy-4
2.7 g of -methoxybenzylidene) -2- (2-methoxyethoxycarbonyl) -3- (2-pyridylmethylaminocarbonyl) -4-phenylbutadiene (yield: 2
4%).

(4) 1.33 ml of 4N hydrogen chloride-dioxane solution was added to a solution of 2.7 g of this product in 20 ml of THF under ice-cooling.
And stir for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was crystallized from isopropyl ether to give (1E, 3E)
-1- (3-cyclopentyloxy-4-methoxybenzylidene) -2- (2-methoxyethoxycarbonyl)
-3- (2-Pyridylmethylaminocarbonyl) -4-
1.9 g of phenylbutadiene hydrochloride (yield: 66%, melting point: 167-168 ° C.) are obtained (described in Table 15).

Examples 60 to 85 The corresponding starting compounds were treated in the same manner as in Example 59, and
To 20 are obtained.

[0159]

[Table 15]

[0160]

[Table 16]

[0161]

[Table 17]

[0162]

[Table 18]

[0163]

[Table 19]

[0164]

[Table 20]

Example 86 (1) To a solution of 1.17 g of the compound obtained in Example 59 (4) in 10 ml of tetrahydrofuran (THF) was added 10 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 10 minutes. After adding 2N hydrochloric acid and concentrating under reduced pressure, chloroform was added, washed and dried, and the solvent was distilled off.
E, 4E) -3- (3-Cyclopentyloxy-4-methoxybenzylidene) -4-benzylidene-1- (2-
1.1 g of pyridylmethyl) pyrrolidine-2,5-dione
(Yield: 98%).

(2) To a solution of 1.1 g of this product in 10 ml of THF was added 0.7 ml of a 4N hydrogen chloride-dioxane solution under ice-cooling, followed by stirring for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was crystallized from ether to give (3E, 4E) -3- (3-cyclopentyloxy-4-methoxybenzylidene) -4.
1.1 g (yield: 88%, melting point: 134-135 ° C.) of benzylidene-1- (2-pyridylmethyl) pyrrolidine-2,5-dione hydrochloride are obtained (described in Table 21).

Examples 87 to 103 The corresponding starting compounds were treated in the same manner as in Example 86.
~ 24 are obtained.

[0168]

[Table 21]

[0169]

[Table 22]

[0170]

[Table 23]

[0171]

[Table 24]

Examples 104 to 107 The corresponding starting compounds were treated in the same manner as in Example 23 (1), and then subjected to silica gel column chromatography to give (1E,
The 3E) -isomer is separated and treated as in Example 2 to give the compounds listed in Table 25.

Example 108 The corresponding starting compound was treated in the same manner as in Examples 23 (1) and (2) to obtain the compounds shown in Table 25.

[0174]

[Table 25]

Examples 109 to 111 By treating the corresponding starting compounds in the same manner as in Example 6, the compounds shown in Table 26 can be obtained.

Example 112 The corresponding starting compound was treated in the same manner as in Example 5 to obtain the compounds shown in Table 26.

[0177]

[Table 26]

Examples 113 to 116 The corresponding starting compounds were treated in the same manner as in Example 11 to give Table 27.
The compounds described can be obtained.

[0179]

[Table 27]

Examples 117 to 130 The corresponding starting compounds are treated in the same manner as in Examples 1 (1) to (6) to obtain the compounds shown in Tables 28 to 29.

[0181]

[Table 28]

[0182]

[Table 29]

Examples 131 to 144 The corresponding starting compounds were treated in the same manner as in Examples 1 (1), (2), (5) and (6) or Example 23, and
31 can be obtained.

[0184]

[Table 30]

[0185]

[Table 31]

Example 145 (1) 246 g of 3,5-dimethoxyacetophenone and 320 g of dimethyl (E) -benzylidenesuccinate were added to t
tert-butyl alcohol (t-BuOH) 1300m
and 168.6 g of potassium tert-butoxide (t-BuOK) is added to the solution at room temperature and stirred.
After allowing to cool to room temperature, the mixture is stirred at the same temperature for 2 hours. 3 liters of water and 700 ml of diisopropyl ether are added to the reaction solution and mixed, and the aqueous layer is separated. Water is added to the remaining organic layer for further extraction, and the extracts are combined and concentrated with concentrated hydrochloric acid to pH2.
Adjust to ~ 3. The resulting oil was extracted with ethyl acetate, and the extract was dried and concentrated to give 1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4-phenylbutadiene. 580 g of an oily substance [mixture of (1Z, 3E) form and (1E, 3E) form] is obtained. The oil is dissolved in a mixture of diisopropyl ether and hexane, and the mixture is stirred at room temperature, and the resulting crystals are collected. After adding 1 liter of ethyl acetate to the crystals and heating to about 80 ° C., the remaining crystals were collected by filtration to give (1E, 3E) -1-methyl-1- (3,5
-Dimethoxyphenyl) -2-methoxycarbonyl-3
-Carboxy-4-phenylbutadiene (Example 135
117 g). The mother liquor (filtrate) is concentrated, 700 ml of ethyl acetate is added to the residue, and the (1Z, 3E) form is inoculated into this solution. The mixture was stirred, and the precipitated crystals were collected to obtain (1Z, 3E) -1-
192 g of methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (identical to the compound of Example 121) are obtained.

(2) (1Z, 3E) -1-methyl-1-
(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4-phenylbutadiene 487
g, was dissolved in 1000 ml of methylene chloride, 1 ml of N, N-dimethylformamide (DMF) was added, and then 133.3 ml of oxalyl chloride was added dropwise, followed by stirring for 1 hour. After concentration of the reaction solution, the residue is dissolved in 4 liters of tetrahydrofuran, and a mixture of 214 ml of triethylamine and 168 ml of 1-amino-4-methylpiperazine is added dropwise under ice cooling. The reaction mixture was extracted with ethyl acetate, the extract was dried, concentrated, and the residue was crystallized from diisopropyl ether to give (1Z, 3E) -1-methyl-1-methyl.
(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-methylpiperazin-1-yl)
Aminocarbonyl] -4-phenylbutadiene 490 g
(Yield: 81%, melting point: 117-121 ° C.).

(3) 268 g of this product was dissolved in chloroform, and 125 ml of a 4N hydrochloric acid-ethyl acetate solution was added under ice-cooling. Pour this solution into ice-cooled diethyl ether,
The (1Z, 3E)-
1-methyl-1- (3,5-dimethoxyphenyl) -2
278 g of -methoxycarbonyl-3- [N- (4-methylpiperazin-1-yl) aminocarbonyl] -4-phenylbutadiene monohydrochloride (yield: 97%, melting point:>
234 ° C. (decomposition)) (listed in Table 32).

Example 146 (1E, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4-phenylbutadiene obtained in Example 145 (1) 114 g is suspended in tert-butyl alcohol, and 40.1 g of t-BuOK is added to the suspension and stirred. After allowing the mixture to cool to room temperature, it is further stirred for 2 hours. The reaction solution was treated in the same manner as in Example 145 (1).
E, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-
32 g of 4-phenylbutadiene (same as the compound of Example 135) and (1Z, 3E) -1-methyl-1- (3,
5-dimethoxyphenyl) -2-methoxycarbonyl-
61.5 g of 3-carboxy-4-phenylbutadiene are obtained (identical to the compound of Example 121).

Examples 147 to 174 By treating the corresponding starting compounds in the same manner as in Example 11, the compounds shown in Tables 32 to 36 are obtained.

[0191]

[Table 32]

[0192]

[Table 33]

[0193]

[Table 34]

[0194]

[Table 35]

[0195]

[Table 36]

Examples 175 to 179 By treating the corresponding starting compounds in the same manner as in Example 49, the compounds shown in Table 37 are obtained.

[0197]

[Table 37]

Example 180 (1) Potassium tert-butoxide (t-BuOK) 1
4.2 g of tert-butyl alcohol (t-BuO)
H) Dissolve in 120 ml, add 20 g of 3,5-dimethoxybenzaldehyde and 21.1 dimethyl succinate to this solution.
g in tetrahydrofuran (THF) is added dropwise. After stirring at room temperature for 30 minutes, isopropyl ether (IPE) and water are added to the reaction solution, and the aqueous layer is separated. Water is added to the remaining organic layer for further extraction, and the extracts are combined and adjusted to pH 2-3 with concentrated hydrochloric acid. The resulting oil was extracted with ethyl acetate, and the extract was dried and concentrated under reduced pressure to obtain 42 g of methyl 4- (3,5-dimethoxyphenyl) -3-carboxy-3-butenoate as an oil.

(2) This product is dissolved in 200 ml of methanol, 2 ml of concentrated sulfuric acid is added to this solution, and the mixture is refluxed for 13 hours. After concentrating the reaction solution, water and diethyl ether are added, and the organic layer is separated. The organic layer is washed, dried and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 4) to give (E) -2- (3,5-dimethoxybenzylidene)
18.4 g of dimethyl succinate (yield: 52%) are obtained.

(3) 18.4 g of this product and 11.83 g of 3,5-dimethoxyacetophenone were added to 70 m of t-BuOH.
and 8.42 g of t-BuOK is added to this solution and stirred. After stirring at room temperature for 2 hours, water and isopropyl ether are added to the reaction solution, and the aqueous layer is separated. Water is added to the remaining organic layer for further extraction, and the extracts are combined and concentrated with concentrated hydrochloric acid.
Prepare H2-3. The resulting oil is extracted with ethyl acetate, and the extract is dried and concentrated under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give (1Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4- (3 4.74 g (yield: 17.1%) of (, 5-dimethoxyphenyl) butadiene are obtained.

(4) The mother liquor (filtrate) is concentrated, isopropyl ether is added to the residue, and the mixture is stirred at room temperature. By collecting the precipitated crystals, 1-methyl-1- (3,5-
Dimethoxyphenyl) -2-methoxycarbonyl-3-
9.2 g (yield: 33.3%) of a mixture of (1Z, 3E) and (1E, 3E) forms of carboxy-4- (3,5-dimethoxyphenyl) butadiene is obtained.

(5) 9.0 g of this mixture was added to t-BuOH
Suspended in 50 ml, and t-BuOK2.51 was added to this suspension.
g and stirred at room temperature for 2 hours. Water and 12
The mixture is acidified with N hydrochloric acid and extracted with ethyl acetate. After the extract is dried and concentrated, 30 ml of isopropyl ether is added to the residue.
And stirred under ice-cooling. By collecting the precipitated crystals, (1Z, 3E) -1-methyl-1- (3,5-
Dimethoxyphenyl) -2-methoxycarbonyl-3-
3.6 g of carboxy-4- (3,5-dimethoxyphenyl) butadiene (yield: 13.0%, melting point: 137-1)
40 ° C, IR: 1724, 1670, 1591, 142
3, 1206, 1156 cm ^-1 ).

(6) (1Z, 3E) -1-methyl-1-
1.70 g of (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-carboxy-4- (3,5-dimethoxyphenyl) butadiene was added to 20 ml of dichloromethane.
And a catalytic amount of N, N-dimethylformamide (DMF) and 0.4 ml of oxalyl chloride are added to the solution, and the mixture is stirred at room temperature for 1 hour. After concentration of the reaction solution, 20 ml of tetrahydrofuran (THF) is added to the residue. This solution is added dropwise to a solution of 462 mg of 1-methylpiperazine and 0.65 ml of triethylamine in 20 ml of THF, and the mixture is stirred under ice cooling for 30 minutes. Water and ethyl acetate are added to the reaction solution, and the organic layer is separated. Ethyl acetate is added to the remaining aqueous layer for further extraction, and the extracts are combined, dried and concentrated.
The residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 30: 1),
(1Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (3,5
-Dimethoxyphenyl) butadiene 2.0 g (yield: 9
9.2%, IR: 1727, 1591, 1425, 12
00, 1155 cm ^-1 ).

(7) This product 2.0 was added to 10 ml of chloroform.
The solution was added with 1.05 ml of a 4N hydrochloric acid-ethyl acetate solution under ice-cooling and stirred for several minutes. Dimethyl ether was added to the reaction solution, the mixture was stirred, and the precipitated crystals were collected by filtration to give (1Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3-.
(4-methylpiperazin-1-yl) carbonyl-4-
1.70 g of (3,5-dimethoxyphenyl) butadiene monohydrochloride (yield: 79.5%, melting point:> 133 ° C. (decomposition), IR: 3436, 1725, 1591, 142
5, 1206, 1156 cm ^-1 ) are obtained (described in Table 38).

Examples 181 to 183 The corresponding starting compounds were treated in the same manner as in Example 180.
The compound described in 8 is obtained.

[0206]

[Table 38]

Example 184 The corresponding starting compounds were treated in the same manner as in Example 26, to give Table 39.
The compound described is obtained.

[0208]

[Table 39]

Examples 185 to 189 The corresponding starting compounds were treated in the same manner as in Example 11 to give Table 40.
The compound described is obtained.

[0210]

[Table 40]

[0211]

The butadiene derivative (1-a) of the present invention,
Since the amidobutadiene derivative (1-b) and the pyrrolidine derivative (2) or their pharmacologically acceptable salts have an excellent PAI-1 inhibitory effect and the like, they are used in myocardial infarction, atrial thrombosis in atrial fibrillation, and stroke. Prevention of various thrombosis such as pulmonary embolism, deep vein thrombosis (DVT), disseminated intravascular coagulation (DIC), diabetic complications and restenosis after percutaneous transluminal coronary angioplasty (PTCA) or Useful as a therapeutic. The target compounds (1-a), (1-
b) and (2) are excellent in bioavailability and stability and have low toxicity and high safety when used as a pharmaceutical compound.
Compounds in which the geometric isomer based on the double bond bonded to ring B is trans (E) and the compound whose geometric isomer based on the double bond bonded to ring A is cis (Z) among -b) are water-soluble. It is particularly excellent in terms of stability in the liver, low toxicity to the liver and chromosomes, and photostability.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 69/734 C07C 69/734 Z 231/02 231/02 235/34 235/34 237/20 237/20 241/04 241/04 243 / 32 243/32 C07D 207/448 C07D 207/448 207/452 207/452 207/456 207/456 211/58 211/58 213/40 213/40 213/55 213/55 213/56 213/56 213 / 64 213/64 213/68 213/68 213/73 213/73 213/75 213/75 213/89 213/89 239/42 239/42 Z 261/14 261/14 401/06 207 401/06 207 405 / 06 213 405/06 213 // A61K 31/215 ABN A61K 31/215 ABN ABS ABS 31/44 AED 31/44 AED 31/495 ACB 31/495 ACB C07M 9:00 (72) Inventor Jun Murakami Saitama 2-385 Kitabukurocho, Omiya City Tanabe Pharmaceutical Omiya Dormitory 308

Claims (21)

[Claims] 1. A compound of the general formula (1-a) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. The benzene ring and ring B are a substituted or unsubstituted heterocyclic ring, or a benzene ring which may be substituted with a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group, and R ¹ and R ² are the same. or different, represent a hydrogen atom or a lower alkyl group, a group -COR ³² or group -COR ^42, one is a carboxyl group, the other is a carboxyl group which may be esterified. However, rings a and B Are not simultaneously unsubstituted benzene rings, and when ring A is a tri-lower alkoxybenzene ring, ring B is a substituted or unsubstituted heterocyclic ring, or Or at least one of R ¹ and R ² is a lower alkyl group) or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula (1-b) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. The benzene ring and ring B are a substituted or unsubstituted heterocyclic ring, or a benzene ring which may be substituted with a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group, and R ¹ and R ² are the same. Or differently, represents a hydrogen atom or a lower alkyl group, and a group —COR ³³ and a group —COR ⁴³ are one of an amidated carboxyl group and the other an optionally esterified carboxyl group or an amidated carboxyl group. Wherein ring A and ring B are not simultaneously unsubstituted benzene rings, and when ring A is a tri-lower alkoxybenzene ring, Wherein ring B is a substituted or unsubstituted heterocyclic ring, or at least one of R ¹ and R ² is a lower alkyl group.) Or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, wherein the group —COR ³³ is an esterified carboxyl group and the group —COR ⁴³ is an amidated carboxyl group. 4. The group —COR ^{43 comprises an} optionally substituted alkyl group, an optionally substituted phenyl group, an optionally substituted amino group and an optionally substituted nitrogen-containing heterocyclic group. The compound according to claim 2 or 3, which is a carbamoyl group which may be mono- or di-substituted by the selected group. 5. A benzene ring in which ring A is substituted with a group selected from an alkoxy group, a nitro group, a hydroxy group, a di-lower alkylamino group and a halogen atom, ring B is a nitrogen-containing monocyclic heterocycle, a benzene ring or 5. The compound according to claim 2, which is a benzene ring substituted with a lower alkylenedioxy group. 6. A benzene ring wherein ring A is di- or tri-substituted by a group selected from a lower alkoxy group, a nitro group, a hydroxy group, a di-lower alkylamino group and a halogen atom, and ring B is a pyridine ring, a benzene ring or a lower ring. An alkylenedioxy group-substituted benzene ring, R ¹ is a lower alkyl group, R ² is a hydrogen atom, a group —COR ³³ is a lower alkoxycarbonyl group or a lower alkoxy group-substituted lower alkoxycarbonyl group, a group —COR ⁴³ is a pyridyl group, an oxo group Substituted pyridyl group, amino group-substituted pyridyl group, lower alkoxy group-substituted pyridyl group, lower alkyl group-substituted piperidyl group, lower alkyl group-substituted piperazinyl group, piperazinyl group substituted by lower alkyl group and oxo group, lower alkyl group-substituted isoxazolyl group , Pyrazolyl, triazolyl, pyridyl group-substituted lower alkyl Group, an oxo group-substituted pyridyl-lower alkyl group, a di-lower alkylphenyl group, a morpholinophenyl group, a lower alkylpiperazinylcarbonylphenyl group, a hydroxy lower alkyl group and a di-lower alkylamino group. A carbamoyl group or a compound represented by the formula: And the ring (a) in the formula is a 5- or 6-membered nitrogen-containing monocyclic heterocyclic ring which may be substituted. . 7. A ring A is a benzene ring di- or tri-substituted by a group selected from a methoxy group, a cyclopentyloxy group, a nitro group, a hydroxy group, a dimethylamino group and a chlorine atom; R ¹ is a methyl group; ³³ is a methoxycarbonyl group, an isopropyloxycarbonyl group or a 2-methoxyethoxycarbonyl group, the group -COR ⁴³ is a pyridyl group, a 2-aminopyridyl group, a 1-oxopyridyl group,
-Methylpiperazinyl group, 4-methyl-4-oxopiperazinyl group, 1-methylpiperidyl group, 5-methylisoxazolyl group, 3-pyrazolyl group, 1,3,4-triazolyl group, pyridylmethyl A carbamoyl group which may be monosubstituted with a group selected from a group, a 1-oxopyridylmethyl group, a dimethylaminoethyl group, a hydroxyethyl group and a dimethylamino group.
Or the compound according to 6. 8. General formula (2) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. The benzene ring and ring B are a substituted or unsubstituted heterocyclic ring, or a benzene ring which may be substituted with a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group, and R ¹ and R ² are the same. Or differently, represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic group. However, Ring A and Ring B are not simultaneously unsubstituted benzene rings, and when Ring A is a tri-lower alkoxybenzene ring, Ring B is a substituted or unsubstituted heterocyclic ring. Or some, or at least one of R ¹ and R ² is a lower alkyl group.) Pyrrolidine derivative or a pharmaceutically acceptable salt represented by. 9. A benzene ring in which ring A is substituted with a group selected from an alkoxy group, a nitro group, a hydroxy group, a di-lower alkylamino group and a halogen atom, ring B is a nitrogen-containing monocyclic heterocycle, a benzene ring or The compound according to claim 8, which is a benzene ring substituted with a lower alkylenedioxy group. 10. Ring A is a lower alkoxy group, a nitro group,
A benzene ring di- or tri-substituted with a group selected from a hydroxy group, a di-lower alkylamino group and a halogen atom,
Ring B is a pyridine ring, a benzene ring or a lower alkylenedioxy group-substituted benzene ring, R ¹ is a lower alkyl group, R ² is a hydrogen atom, R ⁵ is a pyridyl group-substituted lower alkyl group, di-lower alkylamino lower alkyl group, hydroxy 10. The compound according to claim 8, which is a lower alkyl group, a di-lower alkylamino group or a lower alkyl group-substituted piperazinyl group. 11. Ring A is a benzene ring di- or tri-substituted by a group selected from methoxy, cyclopentyloxy, nitro, hydroxy, dimethylamino and chlorine, R ¹ is methyl, and R ⁵ is Hydrogen atom, pyridylmethyl group, dimethylaminoethyl group, hydroxyethyl group,
The compound according to claim 8, 9 or 10, which is a dimethylamino group or a 4-methylpiperazinyl group. 12. The geometric isomer based on the double bond to which ring B is bonded is trans (E), and the geometric isomer based on the double bond to which ring A is bonded is cis (Z). 5,
8. The compound according to 6 or 7. 13. The geometric isomer based on the double bond to which ring B is bonded is trans (E).
2. The compound according to 1. 14. (1Z, 3E) -1-methyl-1-
(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-methylpiperazin-1-yl)
Aminocarbonyl] -4-phenylbutadiene, (1
Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-
Pyridyl) aminocarbonyl] -4- (3,4-methylenedioxyphenyl) butadiene, (1Z, 3E) -1
-Methyl-1- (3,5-dimethoxyphenyl) -2-
Methoxycarbonyl-3- [N- (4-pyridylmethyl) aminocarbonyl] -4-phenylbutadiene;
(1Z, 3E) -1-methyl-1- (3-chloro-4,
5-dimethoxyphenyl) -2-methoxycarbonyl-
3- [N- (3-pyridylmethyl) aminocarbonyl]
-4-phenylbutadiene, (1Z, 3E) -1-methyl-1- (3-chloro-4,5-dimethoxyphenyl)
-2-methoxycarbonyl-3-aminocarbonyl-4
The compound according to claim 2, wherein the compound is selected from-(4-pyridyl) butadiene or a pharmaceutically acceptable salt thereof. 15. (1Z, 3E) -1-methyl-1-
(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-methylpiperazin-1-yl)
Aminocarbonyl] -4-phenylbutadiene or a pharmaceutically acceptable salt thereof. 16. (1Z, 3E) -1-methyl-1-
(3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-pyridyl) aminocarbonyl]
-4- (3,4-methylenedioxyphenyl) butadiene or a pharmaceutically acceptable salt thereof. 17. (3Z, 4E) -3- (3,5-dimethoxy-α-methylbenzylidene) -4-benzylidene-1- (4-pyridylmethyl) pyrrolidine-2,5-dione, (3Z, 4E ) -3- (3-Chloro-4,5-dimethoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5-dione, (3
Z, 4E) -3- (3-Methoxy-4-cyclopentyloxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5-dione, (3Z,
4E) -3- (3-Cyclopentyloxy-4-methoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-2,5-dione, (3Z, 4
E) -3- (3,5-Dimethoxy-α-methylbenzylidene) -4- (4-pyridylmethylidene) pyrrolidine-
9. The compound according to claim 8, wherein the compound is selected from 2,5-dione or a pharmaceutically acceptable salt thereof. 18. A compound of the general formula (4) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring, ring B is a substituted or unsubstituted heterocyclic ring, or a benzene ring optionally substituted with a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group, R ¹ and R ² are The same or different, and represent a hydrogen atom or a lower alkyl group, and the groups -COR ³¹ and -COR ⁴¹ represent the same or different esterified carboxyl groups, provided that ring A and ring B are simultaneously unsubstituted benzene that they are not ring, when ring a is a tri-lower alkoxybenzene ring, or ring B is a substituted or unsubstituted heterocyclic ring, or R ¹ and R ² less Wherein one of them is a lower alkyl group.) Wherein the diester compound is treated with an acid or a base, and if desired, the product is converted into a pharmaceutically acceptable salt thereof. Embedded image Butadiene (wherein the radicals -COR ³² and group -COR ^42, one carboxyl group and the other represents a carboxyl group which may be esterified, and the other symbols having. The same as defined above) represented by A method for producing a derivative or a pharmaceutically acceptable salt thereof. 19. A compound of the general formula (1-a) (Wherein ring A is a substituted or unsubstituted heterocyclic ring, or a lower alkyl group, an alkoxy group, a nitro group, a hydroxyl group,
A benzene ring which may be substituted with a group selected from an amino group and a halogen atom which may be substituted, a ring B is a substituted or unsubstituted heterocycle, or a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino A benzene ring which may be substituted with a group selected from the group, R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkyl group, and one of the groups —COR ³² and —COR ⁴² is a carboxyl group; And the other represents a carboxyl group which may be esterified. However, Ring A and Ring B are not simultaneously unsubstituted benzene rings. When Ring A is a tri-lower alkoxybenzene ring, Ring B is a substituted or unsubstituted heterocyclic ring, or R ¹ and R ² At least one is a lower alkyl group. ), A salt or a reactive derivative thereof, and a general formula (5) HR ⁴⁰ (5) (wherein R ⁴⁰ represents an optionally substituted amino group). Reacting the compound with a compound and, if desired, converting the product into a pharmaceutically acceptable salt thereof, characterized by the general formula (1-b): (Wherein, R ³³ and R ^{43 each} represent an amidated carboxyl group, the other represents an optionally esterified carboxyl group or an amidated carboxyl group, and the other symbols have the same meanings as described above.) ) Or a pharmacologically acceptable salt thereof. 20. A compound of the general formula (1-c) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring, ring B is a substituted or unsubstituted heterocyclic ring, or a lower alkoxy group, a benzene ring which may be substituted with a lower alkylenedioxy group and a di-lower alkylamino group, R ¹ and R ² are the same or different, Represents a hydrogen atom or a lower alkyl group;
R ³⁴ and the group —COR ⁴⁴ are one of a carboxyl group which may be esterified, the other an unsubstituted carbamoyl group,
An alkyl-substituted carbamoyl group which may be substituted,
It represents an optionally substituted amino-substituted carbamoyl group or an optionally substituted nitrogen-containing heterocyclic group-substituted carbamoyl group. However, Ring A and Ring B are not simultaneously unsubstituted benzene rings. When Ring A is a tri-lower alkoxybenzene ring, Ring B is a substituted or unsubstituted heterocyclic ring, or R ¹ and R ² At least one is a lower alkyl group. Wherein the compound represented by the formula (I) or a salt thereof is subjected to an intramolecular ring closure reaction, and if desired, the product is converted into a pharmaceutically acceptable salt thereof. (Wherein, R ⁵ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group, or an optionally substituted nitrogen-containing heterocyclic group, and other symbols are the same as those described above. ) Or a pharmacologically acceptable salt thereof. 21. The general formula (2-a) (Wherein, ring A may be substituted or unsubstituted heterocyclic, or substituted with a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, an optionally substituted amino group and a halogen atom. A benzene ring, ring B is a substituted or unsubstituted heterocyclic ring, or a lower alkoxy group, a benzene ring which may be substituted with a lower alkylenedioxy group and a di-lower alkylamino group, R ¹ and R ² are the same or different, Represents a hydrogen atom or a lower alkyl group, provided that
Ring A and ring B are not simultaneously unsubstituted benzene rings, and when ring A is a tri-lower alkoxybenzene ring, ring B is a substituted or unsubstituted heterocyclic ring, or at least ^one of R ¹ and R ² One is a lower alkyl group. ) Or a salt thereof, and R ⁵¹ -X (3) wherein R ⁵¹ is an optionally substituted alkyl group, an optionally substituted amino group or a substituted A nitrogen-containing heterocyclic group, and X represents a reactive residue), and if necessary, converting the product into a pharmaceutically acceptable salt thereof. Equation (2-
b) embedded image (Wherein the symbols have the same meanings as described above), or a pharmaceutically acceptable salt thereof.