JP2595931B2 - 2,5-Pyrrolidinedione derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2,5-pyrrolidinedione derivative having an antithrombotic effect and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION It is well known that thrombus causes various diseases such as myocardial infarction, stroke, pulmonary embolism and the like. Widely used for thrombus prevention. However, these drugs have the disadvantage that they are rapidly degraded in the blood and lose their medicinal effect, and can be used for medical use only by parenteral administration. On the other hand, as a derivative of 2,5-pyrrolidinedione, an N-methyl-3,4-dibenzylidene derivative [NOUVEAU JOURNAL DE CHIMI
E), Vol. 1, No. 5,413-418 (197
7)] is known, but no pharmacological activity of the compound is known.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound which has an excellent antithrombotic effect and, unlike conventionally known enzyme preparations, can be used in both oral and parenteral administration. °

[0004]

The 2,5-pyrrolidinedione derivative according to the present invention has the general formula [I]

[0005]

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Wherein ring A is a tri-lower alkoxyphenyl group, R ¹ is 1) a hydroxyl group, a lower alkoxy group,
Sil group, lower alkoxycarbonyl group, aralkyloxy
Cicarbonyl group, di-lower alkylamino group, phenyl group
And a nitrogen-containing 6-membered heterocyclic group (eg, pyridyl
Group, morpholino group, etc.)
A lower alkyl group which may be present, 2) a lower alkoxy group and
Lower optionally substituted by a group selected from phenyl groups
An alkoxy group, 3) even if substituted with a lower alkyl group
Represents a good amino group or 4) a pyridinylcarbonyl group . ).

Specific examples of the object [I] of the present invention include:
Ring A is a 3,4,5-tri-lower alkoxyphenyl group,
2,3,4-tri-lower alkoxyphenyl group, 2,4
5-tri-lower alkoxyphenyl group, the compound is a tri-lower alkoxyphenyl group such as 2,4,6-tri-lower alkoxyphenyl group.

The object [I] of the present invention may have four types of stereoisomers based on two double bonds, and the present invention includes both of these stereoisomers and mixtures thereof.

In the object [I] of the present invention, specific examples of the lower alkyl group and the lower alkoxy group include an alkyl group and an alkoxy group having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples of the aralkyl group include a phenyl-substituted lower alkyl group having 7 to 8 carbon atoms.

The target compound [I] of the present invention can be used in a free form or a pharmaceutically acceptable salt thereof for pharmaceutical use. Pharmaceutically acceptable salts include, for example, sodium salts, alkali metal salts such as potassium salts,
Examples include hydrochloride, hydrobromide , sulfate, maleate, oxalate and the like.

The object [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be mixed with an excipient suitable for oral or parenteral administration. And can be used as a pharmaceutical preparation. The pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. In the case of parenteral administration, it can be used in the form of injection. The dose varies depending on the age, weight, condition and degree of disease of the patient, but the daily dose is usually 0.1 to 100 mg / k in the case of oral administration.
g, especially 0.5 to 50 mg / kg, for parenteral administration 0.01 to 10 mg / kg, especially 0.05
Preferably it is ５5 mg / kg.

According to the present invention, the target compound [I] is, for example, a compound represented by the general formula [II]:

[0013]

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(In the formula, one of R ² and R ³ represents a lower alkoxy group and the other represents a group represented by the formula: —NHR ¹ ,
R ¹ and ring A have the same meaning as described above. ) Is subjected to an intramolecular ring closure reaction, or a compound of the general formula [I
II]

[0015]

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(Wherein ring A has the same meaning as described above) by converting the compound represented by the general formula [IV]

[0017]

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(Wherein, X represents a reactive residue, and R ¹ has the same meaning as described above).

In the target compound [I], a compound wherein R ¹ is a lower alkoxy group which may be substituted with a group selected from a lower alkoxy group and a phenyl group, that is, a compound of the general formula [I
-A]

[0020]

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Wherein R ⁴ represents a lower alkyl group which may be substituted with a group selected from a lower alkoxy group and a phenyl group, and ring A has the same meaning as described above. General formula [II-a]

[0022]

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(Wherein R ²¹ and R ^{31 each} represent a lower alkoxy group and the other represents a group represented by the formula —NHOH, and ring A has the same meaning as described above). Formula [V]

[0024]

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(Wherein X ¹ represents a reactive residue and R ⁴ has the same meaning as described above), and can be produced by an intramolecular ring closure reaction.

In the above process of the present invention, the intramolecular ring-closure reaction of the butenoic acid derivative [II] can be appropriately carried out in a suitable solvent in the presence of a base. Examples of the base include an alkali metal hydroxide such as sodium hydroxide, an alkali metal hydride such as sodium hydride, an alkali metal alcoholate such as sodium methylate, a lower alkyl-substituted alkali metal amide such as lithium diisopropylamide, and n-butyl. Lower alkyl alkali metals such as lithium, triethylamine, 1,8-diazabicyclo [5.
4.0] Organic amines such as undec-7-ene and alkali metals such as sodium can be suitably used.

The solvent may be any inert solvent which does not adversely affect the reaction, and examples thereof include organic solvents such as tetrahydrofuran, dioxane, methanol, ethanol and dimethylformamide, and mixed solvents of these organic solvents and water. . This intramolecular ring closure reaction can be carried out widely under cooling to heating, and can be suitably carried out, for example, at -60 ° C to 150 ° C, especially at room temperature to the boiling point of the solvent.

N-unsubstituted pyrrolidinedione derivative [I
The condensation reaction of the compound [II] with the compound [IV] can be appropriately carried out in a suitable solvent in the presence of a deoxidizing agent. As an example of the deoxidizing agent, any one can be used as long as it is used in this type of reaction, for example, an alkali metal hydride such as sodium hydride, an alkali metal hydroxide such as sodium hydroxide, potassium carbonate and the like. Alkali metal carbonates, alkali metal alcoholates such as sodium methylate, lower alkyl-substituted alkali metal amides such as lithium diisopropylamide, and alkali metals such as sodium can be suitably used.

The solvent may be any inert solvent which does not adversely affect the reaction, and examples include dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. This condensation reaction is carried out under cooling to the boiling point of the solvent, for example, -6.
It can be suitably carried out at 0 ° C to 100 ° C, especially at -60 ° C to 20 ° C.

The condensation reaction and the intramolecular ring closure reaction between the butenoic acid derivative [II-a] and the compound [V] can be appropriately carried out in a suitable solvent in the presence of a base. Examples of the base include an alkali metal hydroxide such as sodium hydroxide, an alkali metal hydride such as sodium hydride, an alkali metal alcoholate such as sodium methylate, a lower alkyl-substituted alkali metal amide such as lithium diisopropylamide, and sodium. Alkali metals and the like can be suitably used.

The solvent may be any inert solvent which does not adversely affect the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. The condensation reaction and the ring closure reaction are carried out under cooling to the boiling point of the solvent,
For example, -60C to 100C, especially -60C to 20C
Can be suitably implemented.

The target product [I] thus obtained is
If necessary, they can be converted to each other. For example, in the target compound [I], a compound in which R ¹ is a carboxyl-substituted lower alkyl group, that is, a compound represented by the general formula [Ib]

[0033]

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(Wherein R ¹¹ represents a carboxyl-substituted lower alkyl group, and ring A has the same meaning as described above), and the compound represented by the general formula [Ic]

[0035]

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(Wherein R ¹² represents a lower alkoxycarbonyl-substituted lower alkyl group, and ring A has the same meaning as described above), and can be produced by treating the compound with an acid. The acid treatment of the compound [Ic]
It can be carried out according to a conventional method, and can be carried out as appropriate in a suitable solvent. As the solvent, ethyl acetate, dichloromethane, benzene, and the like can be used. As the acid, any acid can be used as long as it is used for this type of reaction. For example, hydrogen chloride, p-toluenesulfonic acid,
Trifluoroacetic acid, hydrogen bromide in glacial acetic acid, and the like can be suitably used.

In the above reaction, if the desired product [I] is obtained as a mixture of stereoisomers, it can be separated into the respective isomers by a conventional method such as silica gel column chromatography, if necessary.

The starting compound [II] of the present invention is a novel compound. For example, (1) 3-lower alkoxycarbonyl-4-phenyl (-) is obtained by a condensation reaction of benzaldehyde or tri-lower alkoxybenzaldehyde with di-lower alkyl succinate. Or (tri-lower alkoxyphenyl) -3-butenoic acid, and then (2) a corresponding lower alkyl ester is produced by a conventional method of esterification, and (3) this is converted to a tri-lower alkoxybenzaldehyde (or When a lower alkoxybenzaldehyde is used, benzaldehyde is used in this step) to react with a compound of the general formula [VI]

[0039]

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Wherein one of R ²² and R ³² represents a lower alkoxy group and the other represents a hydroxyl group, and ring A has the same meaning as described above. ) The compound [VI], a salt thereof or a reactive derivative thereof can be produced by reacting the compound with an amine represented by R ¹ NH ₂ . Condensation reaction steps (1) and (3)
Can be suitably carried out in a suitable solvent in the presence of a base (eg, an alkali metal alcoholate) under cooling to heating, for example, at −20 ° C. to the boiling point of the solvent. On the other hand, in the condensation reaction step (4), the compound [VI] or a salt thereof is used in the presence of a dehydrating agent (for example, dicyclohexylcarbodiimide). The reaction can be carried out in the presence or absence of, for example, an alkali metal hydroxide) in an appropriate solvent under cooling to the boiling point of the solvent, for example, -20 ° C to 100 ° C.
C. can be suitably carried out.

On the other hand, the starting compound [III] of the present invention is also a novel compound. For example, 2-tri-lower alkoxybenzylidene-3-carbamoyl- obtained by reacting ammonia in place of R ¹ NH _{2 by} the above method. It can be produced by subjecting a lower alkyl ester of 4-phenyl-3-butenoic acid to an intramolecular ring closure reaction in the presence of a base (for example, an alkali metal alcoholate).

In the present specification, compounds having a double bond (for example, compounds [I], [II], [III],
In the structural formula [VI], the configuration at the double bond site may be a cis configuration (Z), unless otherwise specified;
It also indicates that it may be in trans configuration (E).

[0043]

【Example】

Example 1 (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3-methylcarbamoyl-4-phenyl-
To a solution of 3.5 g of 3-butenoic acid methyl ester in 50 ml of tetrahydrofuran, 2 ml of a 2N aqueous sodium hydroxide solution
And reflux for 1 hour. After cooling the reaction solution to room temperature, 2
After adding 2 ml of N hydrochloric acid and concentrating under reduced pressure, ethyl acetate is added, washed and dried, and the solvent is distilled off. By crystallizing the residue from diethyl ether, (3E, 4E)
-1-methyl-3-benzylidene-4- (3,4,5-
2.8 g of (trimethoxybenzylidene) -2,5-pyrrolidinedione are obtained. Yield: 87% M.P. P. : 131-133 ° C (recrystallized from ethyl acetate-isopropyl ether)

Example 2-14 The corresponding starting compound was treated in the same manner as in Example 1 to give the following
And the compounds shown in Table 2 are obtained.

[0045]

[Table 1]

[0046]

[Table 2]

Example 15 (E) -2-[(E)-was added to a suspension of 62% sodium hydride (0.33 g) in dimethylformamide (10 ml) under ice-cooling.
A solution of 3.8 g of 3,4,5-trimethoxybenzylidene] -3-hydroxycarbamoyl-4-phenyl-3-butenoic acid methyl ester in 10 ml of dimethylformamide is added dropwise, and the mixture is stirred at room temperature for 2 hours. Next, 0.67 ml of methoxymethyl chloride is added dropwise under ice-cooling, and the mixture is stirred at room temperature for 2 nights. Ethyl acetate is added to the residue, and after washing and drying, the solvent is distilled off. The resulting residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: trichloromethane: ethyl acetate = 5: 5:
By purifying in 4), (3E, 4E) -1-methoxymethoxy-3-benzylidene-4- (3,4,5
1.25 g of (-trimethoxybenzylidene) -2,5-pyrrolidinedione are obtained as yellow crystals. Yield: 37% M.P. P. 175-177 ° C (recrystallized from ethyl acetate-n-hexane)

Example 16 (3E, 4E) -3 was added to a suspension of 63.2% sodium hydride (0.38 g) in dimethylformamide (10 ml) under ice-cooling.
A solution of 3.65 g of benzylidene-4- (3,4,5-trimethoxybenzylidene) -2,5-pyrrolidinedione in 10 ml of dimethylformamide is added dropwise, and the mixture is stirred at room temperature for 1 hour. Then, methoxymethyl chloride 0.8
4 ml is added dropwise under ice cooling, and the mixture is stirred at room temperature overnight, and then the solvent is distilled off. After adding ethyl acetate to the residue, washing and drying,
The solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane: trichloromethane: ethyl acetate = 5: 5: 4) to give (3E, 4E) -1-methoxymethyl-3-benzylidene. 3.0 g of 4- (3,4,5-trimethoxybenzylidene) -2,5-pyrrolidinedione are obtained as yellow crystals. Yield: 73% M.P. P. 127-128 ° C (recrystallized from ethyl acetate-n-hexane)

Examples 17-21 The corresponding starting compounds were treated in the same manner as in Example 16, to give the compounds shown in Table 3 below.

[0050]

[Table 3]

Example 22 (1) (3E, 4E) -1-t obtained in Example 18
-Butoxycarbonylmethyl-3-benzylidene-4-
(3,4,5-trimethoxybenzylidene) -2,5-
To a solution of 3.5 g of pyrrolidinedione in 40 ml of dichloromethane was added 10 ml of trifluoroacetic acid at room temperature. After leaving for 4 hours, the solvent was distilled off under reduced pressure. Trichloromethane was added to the residue, and the residue was washed and dried. Is distilled off. By crystallizing the residue from diethyl ether, (3E,
4E) -1-Carboxymethyl-3-benzylidene-4
-(3,4,5-trimethoxybenzylidene) -2,5
2.5 g of pyrrolidinedione are obtained as yellow prism crystals. Yield: 81% M.P. P. 183-185 ° C

(2) Dissolve 2.38 g of this product in a mixture of 10 ml of tetrahydrofuran and 10 ml of methanol, and add 2N
2.8 ml of an aqueous sodium hydroxide solution are added, and the solvent is distilled off. Trichloromethane is added to the residue, and after drying, the solvent is distilled off. By recrystallizing the crystalline residue from ethyl acetate and diethyl ether, (3E, 4E) -1-
Carboxymethyl-3-benzylidene-4- (3,4,
2.3 g of 5-trimethoxybenzylidene) -2,5-pyrrolidinedione sodium salt are obtained as yellow crystals. Yield: 74% M.P. P. : 190 ° C (decomposition)

Reference Example 1 (1) To a solution of 16.8 g of potassium t-butylate in 150 ml of t-butyl alcohol, benzaldehyde 15.
A solution of 9 g and 26.3 g of dimethyl succinate in 20 ml of t-butyl alcohol is added dropwise with stirring at room temperature, and then stirred for 30 minutes. The reaction solution was added to ice water 200
Pour into ml and extract with isopropyl ether. The aqueous layer is adjusted to pH 2-3, extracted with ethyl acetate, the ethyl acetate layer is washed, dried, and the solvent is distilled off. The residue was dissolved in 75 ml of methanol and thionyl chloride 1 was added under ice-cooling.
0.9 ml is added dropwise and left overnight at room temperature, after which the solvent is distilled off. After adding isopropyl ether to the residue, washing and drying, the solvent is distilled off. The residue is distilled under reduced pressure to obtain 23.2 g of (E) -3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester as a colorless oil. Yield: 66% B. P. : 135-137 ° C (0.3mmHg)

(2) A solution of 23.1 g of this product and 19.4 g of 3,4,5-trimethoxybenzaldehyde in 100 ml of t-butyl alcohol was mixed with potassium t-butyrate 1
It is added dropwise to a solution of 1.1 g of t-butyl alcohol in 100 ml at room temperature with stirring, and then stirred for 1 hour. The reaction solution is poured into 200 ml of cold water and extracted with isopropyl ether. The aqueous layer is adjusted to pH 2-3, extracted with ethyl acetate, the ethyl acetate layer is washed, dried, and the solvent is distilled off. By washing the residue with diethyl ether,
25.7 g of (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3-carboxy-4-phenyl-3-butenoic acid methyl ester are obtained as pale yellow crystals. Yield: 65% M.P. P. : 153-154 ° C (recrystallized from ethyl acetate-isopropyl ether)

(3) This product 6.0 g of trichloromethane 3
In a 0 ml solution, thionyl chloride (1.1 ml) was added under ice-cooling.
Is dropped. Then, after adding 2 drops of dimethylformamide, the mixture is refluxed for 30 minutes. After cooling the reaction solution to 25 ° C. or lower, it is dropped into 10 ml of a 40% aqueous solution of methylamine with vigorous stirring. After stirring for 30 minutes as it is, the organic layer is separated, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent: trichloromethane: acetone = 5: 1) to give (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3. 5.4 g of -methylcarbamoyl-4-phenyl-3-butenoic acid methyl ester are obtained as crystals. Yield: 87% M.P. P. : 155-157 ° C (recrystallized from ethyl acetate-n-hexane)

Reference Example 2-15 The corresponding starting compound was treated in the same manner as in Reference Example 1 to give the following
And the compounds described in Table 5 are obtained.

[0057]

[Table 4]

[0058]

[Table 5]

Reference Example 16 (1) To a solution of 25.7 g of the compound obtained in Reference Example 1- (2) in 50 ml of trichloromethane was added dropwise 4.7 ml of thionyl chloride under ice-cooling. Then, after adding 1 drop of dimethylformamide, the mixture is refluxed for 30 minutes. After cooling the reaction solution to 25 ° C. or lower, it is dropped into 20 ml of concentrated aqueous ammonia with vigorous stirring. After stirring for 30 minutes as it is, the organic layer is separated, washed, dried, and the solvent is distilled off.
By crystallizing the residue from diethyl ether,
24.9 g of (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3-carbamoyl-4-phenyl-3-butenoic acid methyl ester are obtained as pale yellow crystals. Yield: 97% M.P. P. 179-180 ° C (recrystallized from ethyl acetate)

(2) A 2N aqueous sodium hydroxide solution was added to a solution of 24.9 g of this product in 75 ml of tetrahydrofuran.
Add 6 ml and reflux for 1 hour. 2N after cooling to room temperature
After adding 15.6 ml of hydrochloric acid and concentrating under reduced pressure, trichloromethane is added, and after washing and drying, the solvent is distilled off. By crystallizing the residue from ethyl acetate, (3E, 4
E) -3-benzylidene-4- (3,4,5-trimethoxybenzylidene) -2,5-pyrrolidinedione
6 g are obtained as yellow platelets. Yield: 77% M.P. P. 158-159 ° C

[0061]

Industrial Applicability The 2,5-pyrrolidinedione derivative [I] and its pharmacologically acceptable salts, which are the object of the present invention, exhibit excellent antithrombotic effects in both oral and parenteral administration. As thrombotics, for example, myocardial infarction, stroke,
Pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, angina,
It can be used as a prophylactic and therapeutic agent for vascular diseases such as sepsis and other venous obstructions and diabetic complications. It can also be used as a preventive agent for reocclusion after percutaneous coronary angioplasty or thrombolytic therapy.

Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/44 A61K 31/44

Claims (5)

(57) [Claims] 1. A compound of the general formula [I] (Wherein ring A is a tri-lower alkoxyphenyl group, R ¹ is
1) hydroxyl group, lower alkoxy group, carboxyl group, lower
Alkoxycarbonyl group, aralkyloxycarbonyl
Group, di-lower alkylamino group, phenyl group and nitrogen atom
Having 1 to 3 groups selected from the group consisting of 6-membered heterocyclic groups
A lower alkyl group which may be 2) a lower alkoxy group and
Lower alkyl which may be substituted with a group selected from phenyl
Alkoxy group, 3) may be substituted with lower alkyl group
Represents an amino group or 4) a pyridinylcarbonyl group . Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein ring A is a 3,4,5-tri-lower alkoxyphenyl group. 3. A compound of the general formula [II] (Wherein ring A is a tri-lower alkoxyphenyl group, one of R ² and R ³ is a lower alkoxy group and the other is a compound of the formula: —NH
Groups represented by R ^1, R ¹ is 1) hydroxyl group, a lower alkoxy
Group, carboxyl group, lower alkoxycarbonyl group,
Lal Kill oxycarboxin group, di-lower alkylamino
Group, a phenyl group or a 6-membered heterocyclic group containing a nitrogen atom.
Lower alkyl group which may have 1 to 3 groups,
2) a group selected from a lower alkoxy group and a phenyl group
Lower alkoxy group which may be substituted, 3) lower alkyl
An amino group optionally substituted with a kill group, or 4) pyri
Represents a dinylcarbonyl group . (I) wherein the compound of formula (I) is subjected to an intramolecular ring closure reaction, and if desired, the product is converted into a pharmaceutically acceptable salt thereof. (Wherein the symbols have the same meanings as described above), or a method for producing a 2,5-pyrrolidinedione derivative or a pharmaceutically acceptable salt thereof. 4. A compound of the general formula [III] (Wherein ring A represents a tri-lower alkoxyphenyl group) by reacting a compound represented by the general formula [IV] (Wherein R ¹ is 1) a hydroxyl group, a lower alkoxy group,
Xyl group, lower alkoxycarbonyl group, aralkyl group
Xycarbonyl group, di-lower alkylamino group, phenyl
Group 1 or a group 1 selected from a nitrogen-containing 6-membered heterocyclic group
Lower alkyl group which may have 3 groups, 2) lower alkyl group
Substituted with a group selected from a oxy group and a phenyl group.
3) Substituted by lower alkyl group
An optionally substituted amino group, or 4) pyridinylcarbo
X represents a reactive group . Wherein the product is converted into a pharmacologically acceptable salt thereof, if desired, by reacting with a compound represented by the general formula [I]: (Wherein the symbols have the same meanings as described above), or a method for producing a 2,5-pyrrolidinedione derivative or a pharmaceutically acceptable salt thereof. 5. A compound of the general formula [II-a] (Wherein ring A represents a tri-lower alkoxyphenyl group;
One of R ²¹ and R ³¹ is a lower alkoxy group and the other is a group represented by the formula
Represents a group represented by NHOH. )
General formula [V] (Wherein R ⁴ represents a lower alkyl group which may be substituted with a group selected from a lower alkoxy group and a phenyl group, and X ¹ represents a reactive residue). General formula [Ia] wherein an intramolecular ring closure reaction is carried out to convert the product into a pharmaceutically acceptable salt thereof, if desired. (Wherein R ⁴ and ring A have the same meanings as described above) or a pharmacologically acceptable salt thereof.