JPH1135565A - Thiazole derivative, medicine containing the same and synthetic intermediate for the same - Google Patents

Abstract

PURPOSE: To obtain the subject novel compound that shows excellent activity to improve the enterokinesis with high safety and is useful for the prevention and treatment of a variety of enterokinesis disorder. CONSTITUTION: This compound is a thiazole derivative of formula I (R<1> is oxypyrrolidyl, hydroxymethylpyrrolidyl or a nitrogen-containing unsaturated heterocyclic ring) or its salt, typically N-methyl -N'-2-[2 -[1-[4-(2 -hydroxyethyl) piperazinyl] methyl]-4 -thiazoyl] methylthio]ethyl 2-nitro -1,1 -ethendiamine. The compound of formula I is prepared, for example, by condensation reaction between a compound of formula II (W is a halogen or an eliminating group; Z is H or a protecting group) and a thiol of formula III, deprotecting the protecting group for amino group as formyl group from the intermediate of formula IV in an organic solvent in the presence of an acid followed by reaction of the deprotection product with 1-methylamino -1-methylthio -2-nitroethylene.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel thiazole derivative, a medicament containing the same and an intermediate for producing the compound.

[0002]

2. Description of the Related Art
A number of gastrointestinal motility improving agents have been searched for the purpose of treating gastrointestinal motility disorders (JP-A-1-313424, JP-A-3-63074, JP-A-4-279581).
There is not always a drug that exerts a sufficient gastrointestinal motility improving effect, and the development of a drug that exhibits a stronger gastrointestinal motility improving effect and that has reduced side effects has been desired. On the other hand, as a thiazole derivative related to the compound of the present invention, a compound having histamine H ₂ antagonistic activity (Japanese Patent Application Laid-Open No. 57-91980) is known, but the compound of the present invention is not described at all. .

[0003]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of such circumstances, and as a result, have found that a specific thiazole derivative has an excellent gastrointestinal motility improving effect, and have completed the present invention. That is, the present invention relates to a novel thiazole derivative represented by the following general formula (I), a gastrointestinal motility improving agent containing the same, and an intermediate (II) for producing the compound.

[0004]

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[Wherein, R ¹ represents an oxopyrrolidyl group, a hydroxymethylpyrrolidyl group, a nitrogen-containing unsaturated heterocycle, a lower alkyl-substituted nitrogen-containing unsaturated heterocycle, a group represented by the formula A-NH- Inside, A is the following formula

[0006]

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Wherein B is a sulfur atom, an oxygen atom, a methylene group or NR ³ ; D is a sulfur atom or an imino group; E is a hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a cycloalkyl group, and benzyl A group, a phenyl group or a lower alkyl-substituted phenyl group; G represents a sulfur atom or NR ² ; n represents an integer of 1 or 2; R ² and R ³ simultaneously or differently represent a hydrogen atom or a lower alkyl group; .)] Or a group represented by the following formula:

[0008]

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[Wherein R ⁴ is a lower alkyl group (excluding a methyl group), a hydroxy lower alkyl group, a halogenated phenoxy lower alkyl group, a phenyl group, a benzyloxy group, a pyrimidyl group, an amino group or a lower alkyl substitution. An amino group; Y represents a nitrogen atom or a methine group. ]. ]

In the present invention, "lower" refers to a group having 1 to 1 carbon atoms.
And "lower alkyl group" means, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like, and "hydroxy lower group". "Alkyl group" specifically means hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxyisopropyl group, hydroxybutyl group, hydroxyisobutyl group, hydroxy-
sec-butyl group, hydroxy-tert-butyl group and the like, and the term "halogenated phenoxy lower alkyl group" means a group in which a hydrogen atom of the hydroxyl group of the "hydroxy lower alkyl group" is substituted with a halogenated phenyl group. I do.

The term "lower alkyl-substituted amino group" means a group in which one or two hydrogen atoms of an amino group are substituted with the above-mentioned "lower alkyl group", for example, a methylamino group, an ethylamino group, a propylamino group, a butyl group. Examples include an amino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group, a methylethylamino group, a methylpropylamino group, and isomers thereof. The “cycloalkyl group” represents a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
As the “oxopyrrolidyl group”, for example, 2-oxo-
A 1-pyrrolidyl group, a 3-oxo-1-pyrrolidyl group, and the "hydroxymethylpyrrolidyl group"
For example, 2-hydroxymethyl-1-pyrrolidyl group, 3-
And a hydroxymethyl-1-pyrrolidyl group.

The "nitrogen-containing unsaturated heterocyclic ring" is specifically 2
-Pyridyl group, 1,2,3,6-tetrahydro-1-pyridyl group, imidazol-1-yl group, imidazol-2-yl group, imidazol-4-yl group, imidazole-5-
Yl group, 1,2,3-triazol-1-yl group, 1,2,3-
Triazol-2-yl group, 1,2,3-triazole-4
-Yl group, 1,2,3-triazol-5-yl group, 1,2,4
-Triazol-1-yl group, 1,2,4-triazole-
2-yl group, 1,2,4-triazol-3-yl group, 1,
2,4-triazol-5-yl group, pyrazol-1-yl group, pyrazol-3-yl group, pyrazol-4-yl group, pyrazol-5-yl group, benzimidazole-1
-Yl group, benzimidazol-2-yl group, thiazolyl-2-yl group, thiazolyl-4-yl group, thiazolyl-5-yl group and the like. "Lower alkyl-substituted nitrogen-containing unsaturated heterocycle" means a group in which any hydrogen atom of the above-mentioned "nitrogen-containing unsaturated heterocycle" is substituted by the above-mentioned "lower alkyl group". Or a di-substituted product.
The term “protecting group” means a substituent usually used for protecting an amino group, and specific examples include a formyl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group.

In the present invention, when the group represented by R ⁴ in the general formulas (I) and (II) represents the aforementioned “lower alkyl-substituted amino group” or benzyloxy group,
The group represented by is preferably a methine group. Also,
The compound (I) of the present invention and the intermediate (II) for producing the compound can form a salt when operated according to a conventional method.
As the salt of the compound of the present invention and an intermediate for producing the compound,
For example, acid addition salts with inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, hydroiodide, or acetate, oxalate, malonate, succinate, Examples include acid addition salts with organic acids such as maleate, fumarate, lactate, malate, citrate, tartrate, salicylate, methanesulfonate, ethanesulfonate. The present invention also includes salts and various solvates of the compound (I) of the present invention and the intermediate (II) for producing the compound. The compound (I) of the present invention and the intermediate (II) for producing the compound include:
It can be synthesized by various manufacturing methods in consideration of the characteristics of the basic skeleton and the group, and for example, can be manufactured as follows. Manufacturing method A

[0014]

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(In the formula, W represents a halogen atom or a leaving group, and Z has the same meaning as described above.) In this reaction formula, the term “leaving group” specifically refers to p-toluenesulfonyl group, methyl It means a sulfonyl group. In the thiol derivative (IV), the group represented by Z is preferably a protecting group. That is, an intermediate (II) is produced by condensing a compound represented by the formula (III) and a thiol derivative represented by the formula (IV). For the condensation reaction, for example, an organic solvent such as methanol or ethanol or a solvent that does not participate in the reaction such as a mixed solvent of an organic solvent and water is used,
It is usually performed in the presence of a base. As the base, sodium hydroxide, potassium hydroxide and the like are suitable. The reaction time is appropriately selected depending on the properties of the reagents involved in the reaction, but usually 10 to 24 hours is sufficient. The reaction temperature is not particularly limited, but is preferably from 0 ° C to 70 ° C.

Since this condensation reaction is usually carried out in the presence of a base, a hydrolysis reaction of the ester group proceeds simultaneously with the condensation reaction. Therefore, in this reaction, the compound represented by the general formula (II)
Thus, an alcohol compound in which the group represented by R ¹ represents a hydroxyl group is obtained. This alcohol compound is reacted with a commonly used halogenating agent to form R ¹ in the general formula (II).
Can be converted into a compound in which the group represented by represents a halogen atom. Suitable halogenating agents include thionyl chloride, phosphorus pentachloride, carbon tetrachloride / triphenylphosphine, and the like. The reaction is carried out in an organic solvent such as methylene chloride, chloroform, carbon tetrachloride, n-hexane, benzene, etc., at a reaction temperature of 0 ° C to 60 ° C and a reaction time of 1 to 5 minutes.
Time is enough. Further, intermediates in which the group represented by R ¹ in the general formula (II) represents a halogen atom include pyrrolidine, piperazine, 1,2,3,6-tetrahydropyridine, imidazole, 1,2,3-triazole, 1 , 2,4-triazole,
By reacting with pyrazole, benzimidazole or a derivative thereof, they can be converted into the corresponding intermediates (II). The reaction is carried out, for example, in an organic solvent such as dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like, usually in the presence of a base, and as the base, sodium methylate, sodium ethylate , Potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, n-butyllithium and the like, and particularly, imidazole, 1,2,3-triazole,
When reacting with 2,4-triazole, pyrazole, benzimidazole or a derivative thereof, sodium methylate, sodium ethylate, sodium hydride, n-butyllithium is used in an organic solvent such as ethyl ether, isopropyl ether, and tetrahydrofuran. Is preferably performed in the presence of The reaction temperature is not particularly limited, but is usually set at 0 ° C to 100 ° C.

The intermediate (II) thus obtained can be prepared by a known method, for example, using an organic solvent such as dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, or the like, with hydrochloric acid, After deprotection of a protecting group for an amino group such as a formyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group in the presence of an acid such as hydrobromic acid, sulfuric acid, trifluoroacetic acid, and methanesulfonic acid, the method disclosed in Compound (I) of the present invention can be synthesized by reacting with 1-methylamino-1-methylthio-2-nitroethylene according to the method described in JP-A-91980. Manufacturing method B

[0018]

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(Wherein, M represents a hydrogen atom, a halogen atom or a lower alkylthio group, Q represents a halogen atom or an amino group, and R ^{1 ′} represents the R ¹ group or the general formula A). The compound represented by the general formula (V) and the 4-hydroxymethylthiazole derivative (VI) are prepared by using an organic solvent such as dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane or the like. The compound (VII) is produced by condensing at room temperature to under heating, preferably at 50 to 70 ° C. In this case, in the compound in which the group represented by Q in the general formula (VI) represents a halogen atom, the group represented by M in the general formula (V) represents a hydrogen atom,
In addition, it is preferable that the group represented by R ^{1 ′} is reacted with the compound showing the R ¹ group. Further, a compound in which the group represented by Q in the general formula (VI) represents an amino group is represented by M in the general formula (V).
It is preferred that the group represented by is a halogen atom or a lower alkylthio group, and the group represented by R ^{1 ′} is reacted with the compound represented by the general formula A. The condensation reaction is preferably carried out in the presence of a base, if necessary, depending on the properties of the reagents involved. The compound (VII) is heated with 2-aminoethyl mercaptan in a strongly acidic aqueous solution such as 47% hydrobromic acid or concentrated hydrochloric acid under heating, preferably at 80 ° C. to 110 ° C. for an appropriate time to obtain a compound of the formula (II) Intermediate (II-a) in which the group represented by Z represents a hydrogen atom can be synthesized. Intermediate (II-a) can be converted to compound (I) of the present invention by reacting with 1-methylamino-1-methylthio-2-nitroethylene according to a known method.

Production Method C Further, the compound (I) of the present invention can also be produced by the following method. That is, the thiourea derivative, the isothiocyanate compound or the compound represented by the general formula (V) used in the above-mentioned production method B can be produced according to the method described in JP-A-57-91980. N-methyl-N'-2-[(2-aminomethyl-4-thiazolyl)
The compound (I) of the present invention is produced by condensation with methylthio] ethyl 2-nitro-1,1-ethenediamine. As the thiourea derivative, a thiourea derivative or thiourea substituted with a protecting group or a lower alkyl group is used, and in particular, the compound of the present invention in which the group represented by R ¹ in the general formula (I) represents a guanidino group is produced. It is suitable for the case. The isothiocyanate compound lower alkyl ester isothiocyanate, lower alkoxy-substituted lower alkyl esters, benzyl esters, phenyl esters, lower alkyl-substituted phenyl ester or cycloalkyl ester is used, the medium R ¹ especially general formula (I)
The group represented by is preferably a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a benzyl group, a phenyl group, a compound of the present invention having a thiourea group substituted with a lower alkyl-substituted phenyl group or a cycloalkyl group. is there. The compound having a thiourea group obtained here is reacted with a lower alkyl halide to obtain a compound of the general formula (I)
In the compound of the present invention, the group represented by R ¹ has an S-alkylisothiourea group. Further, the S-alkylisothiourea derivative is reacted with a lower alkylamine, a lower alkoxy-substituted lower alkylamine, a benzylamine, a phenylamine, a lower alkyl-substituted phenylamine or a cycloalkylamine to obtain R in the general formula (I). ^The group represented by ¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a benzyl group,
The compound of the present invention showing a guanidino group substituted by a phenyl group, a lower alkyl-substituted phenyl group or a cycloalkyl group can be produced. Further, as the compound represented by the general formula (V), a compound in which the group represented by M represents a halogen atom or a lower alkylthio group and the group represented by R ^{1 ′} represents the aforementioned general formula A is used. It is preferable to use a compound having a lower alkoxy group, a lower alkylsulfonyl group or a lower alkylsulfinyl group. Each reaction is, for example, dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, methanol, ethanol, propanol, ethyl ether,
Using an organic solvent such as isopropyl ether, tetrahydrofuran, or dioxane, particularly when reacting an isothiocyanate compound, methanol, ethanol,
When the compound represented by the general formula (V) is reacted with an organic solvent such as dimethylformamide, chloroform and methylene chloride, the compound does not participate in the reaction such as an organic solvent such as methanol or ethanol or a mixed solvent of an organic solvent and water. It is preferable to use a solvent. When reacting with a thiourea derivative, a condensing agent is used as necessary, and examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide and the like. The reaction time and reaction temperature of each reaction are not particularly limited.

The compound (I) of the present invention thus obtained has an excellent action of improving gastrointestinal motility as described below. Compound (I) of the present invention is blended with a pharmaceutically acceptable auxiliary,
It can be made into a preparation for oral administration or parenteral administration. As a preparation for oral administration, the compound (I) of the present invention can be prepared by adding an appropriate additive such as lactose, mannitol, corn starch, excipients such as crystalline cellulose, a cellulose derivative, a binder such as gum arabic or gelatin, carboxymethyl cellulose. Tablets, powders, granules, and capsules can be prepared by appropriately using a disintegrating agent such as calcium, a lubricant such as talc, magnesium stearate, and the like. In addition, these solid preparations can be made into enteric preparations using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate co-polymer. Formulations for parenteral administration include, for example, water, ethanol,
A suppository can be prepared by combining glycerin, a common surfactant and the like into a liquid preparation for injection and a suppository base. The dose of the compound (I) of the present invention varies depending on the age, body weight, symptom, therapeutic effect, administration method and administration period, but is usually 0.1 to 2000 mg / day, preferably 1 to 300 mg / day for oral administration. Is administered in a range of 1 to 3 times a day.

[0022]

[Action]

Gastrointestinal motility enhancer Itoh et al.'S method (Am. J. Dig. Dis. 22, 117-124, 1977)
It went according to. Under pentobarbital anesthesia (30mg / k
g, iv), a force transducer was chronically sewn to the gastric body, gastric antrum, duodenum and jejunum of a male dog (body weight 9-10 kg). An amplifier (UG-5, 7; manufactured by Nihon Kohden) that receives the contraction signal obtained from each transducer
And recorded on a recorder as well as a computer. The test drug is dissolved in physiological saline and fed (30
g / Kg, Gaines, Ajinomoto General Foods Co., Ltd.) 2 hours after intravenous administration. Analysis program for the area obtained by the contraction wave and the contraction baseline in the antrum vestibule (DSSFF
T, V.21, manufactured by Nihon Kohden) to calculate the kinetic coefficient. The results were calculated according to the following formula, and are shown in Table 1 as the kinetic coefficient rate (%).

[0023]

(Equation 1)

[0024]

[Table 1]

Toxicity test ICR mice 4-5 weeks old were used as a group of 6 mice.
After suspending each Example compound in a 5% gum arabic solution, each was orally administered at 1000 mg / kg, and observed for one week. No death was observed in any of the administration groups.

[0026]

The present invention will be described more specifically with reference to the following examples and reference examples, but the present invention is not limited to these examples. Reference Example is a production example of production intermediate (II). In addition, Tables 2 to 10 show the chemical structural formulas and the obtained physicochemical values of each Example and Reference Example. Reference Example 1 N-benzyloxycarbonyl-2- [2- [1- [4
-(2-hydroxyethyl) piperazinyl] methyl]-
4-Thiazolylmethylthio] ethylamine Step 1 Preparation of benzoyloxythioacetamide 707 g of benzoyloxyacetonitrile in 1,4-dioxane: 4N hydrochloric acid in 1,4-dioxane = 1000 ml: 3500 ml
Dissolved in a mixture of the above, and added 616 g of thioacetamide
After stirring at 80 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure. After ice was added to the residue and left overnight, ether was added for extraction, and the obtained ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with a mixed solution of ether: n-hexane = 1: 5 to give the title compound
592 g were obtained. 74% yield.

Step 2 Preparation of 2-benzoyloxymethyl-4-chloromethylthiazole 592 g of the benzoyloxythioacetamide obtained above was dissolved in 4000 ml of anhydrous 1,4-dioxane, and 393 g of 1,3-dichloroacetone was added thereto. Refluxed for hours. The reaction solution was concentrated under reduced pressure, ether was added to the residue to dissolve, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 745 g of the title compound. Yield 92%.

Step 3 Preparation of N-benzyloxycarbonyl-2- (2-hydroxymethyl-4-thiazolyl) methylthioethylamine 350 g of 2-benzoyloxymethyl-4-chloromethylthiazole obtained above was dissolved in methanol, and N 340 g of benzyloxycarbonylcysteamine were added. 700 ml of water containing 136 g of 96% sodium hydroxide under ice-cooling and stirring
Was slowly added and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 391 g of the title compound. . yield
88%.

Step 4 Production of N-benzyloxycarbonyl-2- (2-chloromethyl-4-thiazolyl) methylthioethylamine N-benzyloxycarbonyl-2- (2
-Hydroxymethyl-4-thiazolyl) methylthioethylamine (317 g) was dissolved in anhydrous methylene chloride, and triethylamine (158 ml) was added.
30 ml of anhydrous methylene chloride containing was added dropwise. After stirring at room temperature for 2.5 hours, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain 170 g of the title compound.
55% yield.

Step 5 N-benzyloxycarbonyl-2- [2- [1- [4
-(2-hydroxyethyl) piperazinyl] methyl]-
Production of 4-thiazolylmethylthio] ethylamine N-benzyloxycarbonyl-2- obtained in step 4
[(2-Chloromethyl-4-thiazolyl) methylthio]
1.0 g of ethylamine was dissolved in 5 ml of dimethylformamide, and 387 mg of piperazine ethanol and potassium carbonate 3
90 mg was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.20 g of the title compound. 95% yield.

Reference Examples 2 to 9 The starting compounds were appropriately selected, and the compounds of Reference Examples 2 to 9 as intermediates of the compound (I) of the present invention were produced according to the method of Reference Example 1. Hereinafter, the names of the compounds of each Reference Example are shown. Reference Example 2 N-benzyloxycarbonyl-2- [2- [1- (
1,2,3,6-tetrahydropyridyl) methyl] -4-thiazolylmethylthio] ethylamine Reference Example 3 N-benzyloxycarbonyl-2- [2- [1- (2
-Oxopyrrolidyl) methyl] -4-thiazolylmethylthio] ethylamine Reference Example 4 N-benzyloxycarbonyl-2- [2- [1- (4
-Phenylpiperazinyl) methyl] -4-thiazolylmethylthio] ethylamine Reference Example 5 N-benzyloxycarbonyl-2- [2- [1- (4
-Ethylpiperazinyl) methyl] -4-thiazolylmethylthio] ethylamine Reference Example 6 N-benzyloxycarbonyl-2-[[2- [1-
(4-Dimethylamino) piperidinomethyl] -4-thiazolyl] methylthio] ethylamine Reference Example 7 N-benzyloxycarbonyl-2-[[2- [1-
[4- (2-pyrimidyl) piperazinyl] methyl] -4
-Thiazolyl] methylthio] ethylamine Reference Example 8 N-benzyloxycarbonyl-2-[[2- [1-
[4- (4-Fluorophenoxy) propylpiperazinyl] methyl] -4-thiazolyl] methylthio] ethylamine Reference Example 9 N-benzyloxycarbonyl-2-[[2- [1-
(2-hydroxymethylpyrrolidino) methyl] -4-thiazolyl] methylthio] ethylamine

Reference Example 10 N-benzyloxycarbonyl-2- [2- (1-imidazolylmethyl) -4-thiazolylmethylthio] ethylamine imidazole (190 mg) was suspended in tetrahydrofuran (12 ml), and 60% sodium hydride (111 mg) was added. Stirred at room temperature for 20 minutes. Further, 8 ml of tetrahydrofuran in which 1.0 g of N-benzyloxycarbonyl-2- (2-chloromethyl-4-thiazolyl) methylthioethylamine obtained in Step 4 of Reference Example 1 was added dropwise, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into water and extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.05 g of the title compound. 97% yield.

Reference Examples 11 to 13 Starting compounds were appropriately selected, and the compounds of Reference Examples 11 to 13 which were intermediates of the compound (I) of the present invention were produced according to the method of Reference Example 10. Hereinafter, the names of the compounds of each Reference Example are shown. Reference Example 11 N-benzyloxycarbonyl-2-[[2- [1-
(1,2,4-triazolyl) methyl] -4-thiazolyl]
Methylthio] ethylamine Reference Example 12 N-benzyloxycarbonyl-2-[[2- (1-pyrazolylmethyl) -4-thiazolyl] methylthio] ethylamine Reference Example 13 N-benzyloxycarbonyl-2-[[2- (1- Benzimidazolylmethyl) -4-thiazolyl] methylthio] ethylamine

Reference Example 14 N-benzyloxycarbonyl-2- [2- (2-thiazolylaminomethyl) -4-thiazolyl] methylthio]
Ethylamine Step 1 N-benzyloxycarbonyl-2- [2- [1- (3
Preparation of -benzoylthioureido) methyl] -4-thiazolyl] methylthio] ethylamine Ammonium thiocyanate (2.1 g) was dissolved in acetone (30 ml), and benzoyl chloride (3.5 g) was added. After stirring at room temperature for 30 minutes, N-benzyloxycarbonyl-2-
[(2-aminomethyl-4-thiazolyl) methylthio]
Acetone in which 7.0 g of ethylamine was dissolved was added dropwise, and the mixture was further refluxed for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7.8 g of the title compound. 74% yield.

Step 2 Preparation of N-benzyloxycarbonyl-2- [2- (1-thioureidomethyl) -4-thiazolyl] methylthio] ethylamine N-benzyloxycarbonyl-2- [2-
[1- (3-benzoylthioureido) methyl] -4-
7.8 g of thiazolyl] methylthio] ethylamine was dissolved in 20 ml of ethanol, 25 ml of a 15% sodium hydroxide solution was added, and the mixture was stirred at 60 ° C. for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound.
5.7 g were obtained. Yield 92%.

Step 3 N-benzyloxycarbonyl-2- [2- (2-thiazolylaminomethyl) -4-thiazolyl] methylthio]
Production of ethylamine N-benzyloxycarbonyl-2- [2-
5.7 g of (1-thioureidomethyl) -4-thiazolyl] methylthio] ethylamine was suspended in 50 ml of water, and 2.9 g of bromoacetaldehyde dimethyl acetal was added.
Stirred at C for 3 hours. After cooling, 5% sodium hydroxide solution
15 ml was added, extracted with methylene chloride, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.5 g of the title compound. yield
75%.

Reference Example 15 2- [2- [2- (2-Imidazolinylamino) methyl] -4-thiazolyl] methylthio] ethylamine Step 1 [2- [2- (2-Imidazolinylamino) methyl] methyl −
Production of 4-thiazolyl] methanol / hydroiodide 2-aminomethyl-4-hydroxymethylthiazole 2.
16 g was dissolved in 5 ml of ethanol, and 3.66 g of 2-methylthioimidazoline hydroiodide was added, followed by stirring at 100 ° C. for 2 hours. The mixture was further stirred at 100 ° C. under reduced pressure for 8 hours, and allowed to cool to give 3.4 g of the title compound. Yield 100%.

Step 2 Preparation of 2- [2- [2- (2-imidazolinylamino) methyl] -4-thiazolyl] methylthio] ethylamine [2- [2- (2-imidazolinylamino) methylamine] )
Methyl] -4-thiazolyl] methanol / hydroiodide (340 mg) was dissolved in 47% hydrobromic acid (2 ml), 2-aminoethylmercaptan / hydrochloride (136 mg) was added, and the mixture was stirred at 100 ° C for 10 hours. The solvent is distilled off, the residue is dissolved in 10 ml of water,
After adding potassium carbonate to make the mixture basic, water was distilled off.
The residue was subjected to silica gel column chromatography (Chroma
Purification by torex-NH 2) gave 170 mg of the title compound. 63% yield.

[0039]

[Table 2]

[0040]

[Table 3]

[0041]

[Table 4]

Example 1 N-methyl-N'-2- [2- [1- [4- (2-hydroxyethyl) piperazinyl] methyl] -4-thiazoyl] methylthio] ethyl 2-nitro-1,1- Ethenediamine N-benzyloxycarbonyl-2- obtained in Reference Example 1
5.7 g of [2- [1- [4- (2-hydroxyethyl) piperazinyl] methyl] -4-thiazoylmethylthio] ethylamine was suspended in 100 ml of 4N hydrochloric acid in 1,4-dioxane and stirred at 100 ° C. for 8 hours. . After cooling, the reaction solution was concentrated under reduced pressure, the residue was washed with ether, suspended in 60 ml of dimethylformamide, and 5 ml of water in which 1.52 g of sodium hydroxide was dissolved was added. Further, 1.8 g of 1-methylamino-1-methylthio-2-nitroethylene was added, and the mixture was stirred at 70 ° C. for 8 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (methylene chloride: methanol = 30: 1) to obtain 1.2 g of the title compound.

Examples 2 to 14 Starting compounds were appropriately selected, and the compounds of Examples 2 to 14 were produced according to the method of Example 1. The names of the compounds of the examples are shown below (salts are omitted). Example 2 N-methyl-N'-2-[[2- [1- (4-dimethylamino) piperidylmethyl) -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Example 3 N -Methyl-N'-2- [2- [1- (4-phenylpiperazinyl) methyl] -4-thiazolyl] methylthio]
Ethyl 2-nitro-1,1-ethenediamine Example 4 N-methyl-N'-2- [2- [1- (4-ethylpiperazinyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro -1,1-ethenediamine Example 5 N-methyl-N'-2-[[2- [1- [4- (2-pyrimidyl) piperazinyl] methyl] -4-thiazolyl]
Methylthio] ethyl 2-nitro-1,1-ethenediamine Example 6 N-methyl-N′-2-[[2- [1- [4- (4-fluorophenoxy) propylpiperazinyl] methyl]-
4-thiazolyl] methylthio] ethyl 2-nitro-
1,1-ethenediamine Example 7 N-methyl-N'-2- [2- [1- (1,2,3,6-tetrahydropyridylmethyl) -4-thiazolyl] methylthio] ethyl 2-nitro-1 , 1-ethenediamine Example 8 N-methyl-N'-2-[[2- [1- (2-oxopyrrolidyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethene Diamine Example 9 N-methyl-N'-2-[[2- [1- (2-hydroxymethylpyrrolidyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Example 10 N-Methyl-N'-2-[[2- [1- (4-benzyloxypiperidino) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Example 11 N -Methyl-N'-2-[[2- [1- (1,2,4-to Azolyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Example 12 N-methyl-N′-2-[[2- (1-pyrazolylmethyl) -4-thiazolyl] methylthio Ethyl 2-nitro-1,1-ethenediamine Example 13 N-methyl-N'-2-[[2- (1-benzimidazolylmethyl) -4-thiazolyl] methylthio] ethyl
2-nitro-1,1-ethenediamine Example 14 N-methyl-N'-2- [2- (1-imidazolylmethyl) -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine

Example 15 N-methyl-N'-2-[[2- (4 (5) -methyl-
5 (4) -imidazolylmethyl) -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Step 1 2- (4 (5) -methyl-5 (4) -imidazolylmethyl) -4-thiazole Production of ethyl carboxylate 5.21 g of 4 (5) -cyanomethyl-5 (4) -methylimidazole was dissolved in 10 ml of dimethylformamide, and 6.46 g of thioacetamide and 50 ml of 4N hydrochloric acid in 1,4-dioxane were added.
Then, the mixture was stirred at 80 ° C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was washed with 50 ml of tetrahydrofuran, dissolved in 100 ml of ethanol, added with 13.65 g of ethyl bromopyruvate, and refluxed for 1 hour. After cooling, ethanol was distilled off under reduced pressure. To the residue was added 200 ml of a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The obtained chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound 8.3
g was obtained. Yield 77%.

Step 2 Preparation of 2- (4 (5) -methyl-5 (4) -imidazolylmethyl) -4-thiazolemethanol Under ice-cooling, 2- (4 (5) -methyl-5 ( 4)
6 g of ethyl (imidazolylmethyl) -4-thiazolecarboxylate was gradually added to 50 ml of a suspension of 0.9 g of lithium aluminum hydride in anhydrous tetrahydrofuran. After stirring for 1 hour, water 0.9 ml, 15% sodium hydroxide solution 0.9 ml,
2.7 ml of water was added in order and filtered. The filtrate is concentrated under reduced pressure,
The residue was purified by alumina column chromatography (chloroform: methanol = 10: 1) to give the title compound
2.1 g were obtained. Yield 42%.

Step 3 Preparation of 2-[[2- (4 (5) -methyl-5 (4) -imidazolylmethyl) -4-thiazolyl] methylthio] ethylamine 2- (4 (5) -methyl -5 (4) -imidazolylmethyl) -4-thiazolemethanol (1.52 g)
The mixture was dissolved in 20 ml of 20% hydrobromic acid, 823 mg of 2-aminoethanethiol hydrochloride was added, and the mixture was stirred at 100 ° C for 18 hours. After cooling, potassium carbonate was added for neutralization, and the mixture was concentrated under reduced pressure. The residue was purified by alumina column chromatography (chloroform: methanol = 7: 1) to give the title compound (1.07).
g was obtained. 55% yield.

Step 4 N-methyl-N'-2-[[2- (4 (5) -methyl-
Production of 5 (4) -imidazolylmethyl) -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine 2-[[2- (4 (5) -methyl-5 (4)]
0.94 g of -imidazolylmethyl) -4-thiazolyl] methylthio] ethylamine was dissolved in 50 ml of methanol.
-Methylamino-1-methylthio-2-nitroethylene
0.62 g was added, and the mixture was refluxed for 12 hours. The reaction solution was concentrated under reduced pressure,
The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain 0.5 g of the title compound. Yield 39%.

Example 16 N-methyl-N'-2-[[2- (pyridylmethyl)-
4-thiazolyl] methylthio] ethyl 2-nitro-
1,1-Ethenediamine hydrochloride The title compound was produced according to the procedure of Example 15.

Example 17 N-methyl-N'-2-[(2-guanidinomethyl)-
4-thiazolyl] methylthio] ethyl 2-nitro-
1,1-ethenediamine hydrochloride Step 1 N-methyl-N′-2-[[2- [2- (1,3-di-t
-Butoxycarbonyl) guanidinomethyl] -4-thiazolyl] methylthio] ethyl Preparation of 2-nitro-1,1-ethenediamine N-methyl-N'-2-[(2-aminomethyl-4-thiazolyl) methylthio] ethyl 3.57 g of 2-nitro-1,1-ethenediamine was dissolved in 50 ml of dimethylformamide, and 1,3-di-tert-butoxycarbonylthiourea 2.9
g and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.01 g) were added, and triethylamine (2.12 g) was added dropwise with stirring, followed by stirring at room temperature for 1 hour. The reaction solution was poured into 200 ml of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain 3.8 g of the title compound. Yield 66%.

Step 2 N-methyl-N'-2-[(2-guanidinomethyl)-
4-thiazolyl] methylthio] ethyl 2-nitro-
Production of 1,1-ethenediamine hydrochloride N-methyl-N′-2-[[2- [2- (
3.8 g of 1,3-di-t-butoxycarbonyl) guanidinomethyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine is dissolved in 30 ml of chloroform, and 4N hydrochloric acid 1,4-dioxane is stirred under stirring. The solution was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to give 1.93 g of the title compound. 73% yield.

Example 18 N-methyl-N'-2-[[2- [3- (1-methylthioureylene) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine N -Methyl-N'-2-[(2-aminomethyl-4-thiazolyl) methylthio] ethyl 4.2 g of 2-nitro-1,1-ethenediamine was dissolved in 20 ml of methanol, and 1.2 g of methyl isothiocyanate was added. For 4.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain 3.6 g of the title compound. Yield 69%.

Example 19 N-methyl-N'-2-[[2- [3- (1,2-dimethyl-2-thiopsoidureylenyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro -1,1-ethenediamine N-methyl-N′-2-[[2- [3-
Dissolve 3.6 g of (1-methylthioureylene) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine in 50 ml of methanol, and add methyl iodide.
1.48 g was added and stirred overnight. The reaction solution was concentrated under reduced pressure, 100 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. After the obtained chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 5:
Purification was performed in 1) to obtain 2.86 g of the title compound.

Example 20 N-methyl-N'-2-[[2- (N "-methyl-
N "'-methylguanidinomethyl) -4-thiazolyl]
Methylthio] ethyl 2-nitro-1,1-ethenediamine hydrobromide N-methyl-N′-2-[[2- [3-
(1,2-Dimethyl-2-thiopseudoureylenyl) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine (4.23 g) was suspended in ethanol (45 ml) and mixed with 30% methylamine / methanol. Add 2 g of solution,
The mixture was stirred at 70 ° C. for 3.5 hours. The solvent was distilled off, and the residue was purified by alumina column chromatography (chloroform: methanol = 9: 1) to obtain 2.6 g of the title compound.
Yield 64%.

Example 21 N-methyl-N'-2-[[2- [2- (2-thiazolinylamino) methyl] -4-thiazolyl] methylthio]
7.45 g of ethyl 2-nitro-1,1-ethenediamine oxalate N-methyl-N'-2-[(2-aminomethyl-4-thiazolyl) methylthio] ethyl 2-nitro-1,1-ethenediamine Dissolve in 100 ml of ethanol and add 2-
3.33 g of (methylthio) -2-thiazoline was added and refluxed for 4 days. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol =
5: 1). 3.7 g of the obtained oil was dissolved in 30 ml of methanol, and 0.9 g of oxalic acid was added. The solvent was concentrated under reduced pressure, and the precipitated crude crystals were recrystallized from methanol to obtain 3 g of the title compound. Yield 26%.

Example 22 N-methyl-N'-2-[[2- [2- (1-methyl-
2-imidazolinylamino) methyl] -4-thiazolyl] merylthio] ethyl 2-nitro-1,1-ethenediamine maleate The title compound was prepared by operating according to the method of Example 21.

Example 23 N-methyl-N'-2-[[2- [2- (2-imidazolinylamino) methyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1-ethenediamine Hydrochloride 271 mg of 2- [2- [2- (2-imidazolinylamino) methyl] -4-thiazolyl] methylthio] ethylamine obtained in Reference Example 15 was dissolved in 1 ml of methanol, and 1-methylamino-1-methylthiol was dissolved. 148 mg of -2-nitroethylene was added, and the mixture was refluxed for 2 days. The reaction solution was poured into water, washed with chloroform, and the aqueous layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-butanol: acetic acid: water = 2: 1: 2) and silica gel column chromatography (Chromatorex-NH) to obtain 248 mg of the title compound. Yield 67%. The obtained title compound was dissolved in 1 ml of methanol, 2 ml of a saturated ethereal hydrochloric acid solution was added, and the precipitated crystals were collected by filtration to obtain a hydrochloride.

Example 24 N-methyl-N'-2- [2- (2-thiazolylaminomethyl) -4-thiazolyl] methylthio] ethyl 2-
Nitro-1,1-ethenediamine N-benzyloxycarbonyl-2- obtained in Reference Example 14
2.4 g of [2- (2-thiazolylaminomethyl) -4-thiazolyl] methylthio] ethylamine in 30 ml of ethanol
, And 1.76 g of 1-methylamino-1-methylthio-2-nitroethylene was added, followed by stirring at 60 ° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 15: 1) to obtain 950 mg of the title compound. 30% yield.

Example 25 N-methyl-N'-2-[[2- [2- (5,6-dihydro-4H-1,3-thiazyl) aminomethyl] -4-thiazolyl] methylthio] ethyl 2- Nitro-1,1-ethenediamine N-methyl-N'-2-[(2-aminomethyl-4-thiazolyl) methylthio] ethyl 4.55 g of 2-nitro-1,1-ethenediamine was dissolved in 10 ml of dimethylformamide. Then, 50 ml of methylene chloride in which 2.67 g of 1,1'-thiocarbonylimidazole was dissolved was added, and the mixture was stirred for 30 minutes. further,
3.28 g of bromopropylamine hydrobromide and 1.94 g of diisopropylethylamine were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 100 ml of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The obtained methylene chloride layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (chloroform: methanol = 10: 1) to obtain 3.53 g of the title compound. Yield 58%.

Examples 26 to 28 Starting compounds were appropriately selected, and the compounds of Examples 26 to 28 were produced according to the method of Example 21. Hereinafter, the names of the compounds in each example are shown. Example 26 N-methyl-N'-2-[[2- [2- (5,6-dihydro-4H-1,3-oxazinyl) aminomethyl] -4-
Thiazolyl] methylthio] ethyl 2-nitro-1,1-
Ethenediamine Example 27 N-methyl-N'-2-[[2- [2- (3,4-dihydro-2H-pyrrolyl) aminomethyl] -4-thiazolyl] methylthio] ethyl 2-nitro-1,1 -Ethenediamine Example 28 N-methyl-N'-2-[[2- [2- (3,4,5,6-tetrahydropyridinyl) aminomethyl] -4-thiazolyl] methylthio] ethyl 2-nitro − 1,1-ethenediamine

[0059]

[Table 5]

[0060]

[Table 6]

[0061]

[Table 7]

[0062]

[Table 8]

[0063]

[Table 9]

[0064]

[Table 10]

Formulation Example 1 Compound of Example 2 20 g Lactose 315 g Maize starch 125 g Crystalline cellulose 25 g The above components were uniformly mixed, and 200 ml of a 7.5% aqueous solution of hydroxypropylcellulose was added. The granules were used, immediately rounded with a marmellaizer, and dried to obtain granules.

Formulation Example 2 Compound of Example 15 20 g Lactose 100 g Maize starch 36 g Crystalline cellulose 30 g Carboxymethylcellulose calcium 10 g Magnesium stearate 4 g The components of the above composition were uniformly mixed, and the diameter was adjusted with a single tableting machine.
One tablet was weighed 200 mg with a 7.5 mm punch.

Formulation Example 3 Compound of Example 17 100 mg Sodium acetate 2 mg Acetic acid (for adjusting to pH 5.8) Appropriate amount Distilled water Appropriate amount Total 10 ml / vial The above formulation was used as an injection in a conventional manner.

[0068]

Industrial Applicability The compounds of the present invention improve gastrointestinal motility by significantly enhancing gastrointestinal motility, and exhibit high safety. Therefore, the compounds of the present invention are useful in the field of medicine such as prevention and treatment of various gastrointestinal motility disorders. Useful.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/505 A61K 31/505 31/54 31/54 C07D 417/06 C07D 417/06 (72) Inventor Shigeru Ueki Shigeru Konan, Osato-gun, Saitama 2512-1 Municipal Oshikiri Numagami 1 Central Research Laboratory of Zeria Shinyaku Kogyo Co., Ltd. (72) Inventor Yugo Matsunaga 2512-1 Oshikiri Character Numagami Larger Enishi Town of Osato-gun, Saitama Yoshiaki 2512-1 Numagami, Oshikiri, Konan-cho, Osato-gun, Saitama 1 Zeria Shinyaku Kogyo Co., Ltd.

Claims (3)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ represents an oxopyrrolidyl group, a hydroxymethylpyrrolidyl group, a nitrogen-containing unsaturated heterocycle, a lower alkyl-substituted nitrogen-containing unsaturated heterocycle, a group represented by the formula A-NH-, wherein Is the following formula: (Where B is a sulfur atom, an oxygen atom, a methylene group or N
R ^3; D is a sulfur atom or an imino group; E is a hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a cycloalkyl group, a benzyl group, a phenyl group or a lower alkyl-substituted phenyl group; G is a sulfur atom or NR ² N represents an integer of 1 or 2; R ² and R ³ simultaneously or differently represent a group represented by a hydrogen atom or a lower alkyl group; )] Or a group represented by the following formula: Wherein R ⁴ is a lower alkyl group (excluding a methyl group), a hydroxy lower alkyl group, a halogenated phenoxy lower alkyl group, a phenyl group, a benzyloxy group, a pyrimidyl group, an amino group or a lower alkyl-substituted amino group;
Y represents a nitrogen atom or a methine group. ]. Or a salt thereof. 2. A gastrointestinal motility improving agent comprising the thiazole derivative according to claim 1 or a salt thereof as an active ingredient. 3. A compound of the general formula (II) [In the formula, Z represents a hydrogen atom or a protecting group, R ¹ is an oxopyrrolidyl group, a hydroxymethylpyrrolidyl group, a nitrogen-containing unsaturated heterocycle, a lower alkyl-substituted nitrogen-containing unsaturated heterocycle,
A group represented by the formula A-NH-, wherein A is the following formula: (Where B is a sulfur atom, an oxygen atom, a methylene group or N
R ^3; D is a sulfur atom or an imino group; E is a hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a cycloalkyl group, a benzyl group, a phenyl group or a lower alkyl-substituted phenyl group; G is a sulfur atom or NR ² N represents an integer of 1 or 2; R ² and R ³ simultaneously or differently represent a group represented by a hydrogen atom or a lower alkyl group; )] Or a group represented by the following formula: Wherein R ⁴ is a lower alkyl group (excluding a methyl group), a hydroxy lower alkyl group, a halogenated phenoxy lower alkyl group, a phenyl group, a benzyloxy group, a pyrimidyl group, an amino group or a lower alkyl-substituted amino group;
Y represents a nitrogen atom or a methine group. ]. Or a salt thereof.