JPH08337579A - Guanidinothiazole and its use as antiulcerous agent, h2-receptor antagonistic agent and antimicrobial agent - Google Patents

Abstract

PURPOSE: To obtain the subject new compound, a specific guanidinothiazole compound, having antiulcerous activity, H2 -receptor antagonistic activity and antimicrobial activity such as anti-Helicobacter pylori activity, thus useful as e.g. a therapeutic agent for human or animal ulcer and infectious diseases. CONSTITUTION: This compound, a new guanidinothiazole, is expressed by formula I [R<1> is a lower alkyl, higher alkyl, lower alkenyl, lower alkoxy(lower)alkyl, (substituted) aryl, etc.; R<2> is a lower alkyl or amino; Q is a lower alkylene, of the formula A-X-A (A is a lower alkylene; X is S, O, N, etc.), etc.], having antiulcerous activity, H2 -receptor antagonistic activity and antimicrobial activity (esp. anti-Helicobacter pylori activity), thus being useful for e.g. treating human or animal ulcer and infectious diseases. This compound is obtained by reaction of a compound of formula II (Y is a halogen) with a compound of the formula HX-A-NHCOR<2> .

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel guanidinothiazole derivative and a pharmaceutically acceptable salt thereof.
More specifically, the present invention relates to a guanidino thiazole derivative having anti-ulcer activity, H ₂ -receptor antagonistic activity and antibacterial activity (particularly anti-Helicobacter pylori activity) and a pharmaceutically acceptable salt thereof, a process for producing the same, The present invention relates to a pharmaceutical composition containing it as an active ingredient and a method for treating ulcers and infectious diseases in humans or animals.

[0002]

2. Description of the Related Art JP-A-55-55174 and JP-A-57
The JP and JP 57-54177 -4,977, antiulcer activity and H ₂ - Guanijinochiazo with receptor antagonistic activity - Le derivative.

[0003]

OBJECT OF THE INVENTION One object of the present invention is to provide antiulcer activity, H
A novel guanidino thiazole derivative having ₂ -receptor antagonistic activity and antibacterial activity (particularly anti-Helicobacter pylori activity) and a pharmaceutically acceptable salt thereof are provided. Another object of the present invention is to provide a method for producing the guanidinothiazole derivative and its salt. Still another object of the present invention is the guanidinothiazo-
Another object of the present invention is to provide a pharmaceutical composition containing a ru derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Still another object of the present invention is to provide a therapeutic method for treating ulcers and infections in humans or animals using the guanidinothiazole derivative or a pharmaceutically acceptable salt thereof.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The guanidinothiazole derivative which is the object compound of the present invention is novel, is represented by the following general formula (I), and includes a pharmaceutically acceptable salt thereof. formula: (In the formula, R ¹ is a lower alkyl group, a higher alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy (lower) alkyl group, a cyclo (lower) alkyl group, a cyclo (lower) alkyl (lower) alkyl group, suitably , An ar (lower) alkyl group which may have one or more substituents, an aryl group which may have one or more suitable substituents, and one or more suitable substituents Optionally arylamino (lower) alkyl group or heterocyclic (lower) alkyl group;
R ² is a lower alkyl group or an amino group; Q is a lower alkylene group, a lower alkenylene group or the formula: -AXA
-, -CONH-A-, -COO-A- (in the formula, A is a lower alkylene group; X is S, O, N or NR ³ , (R ³ is a lower alkanoyl group)), and a pharmaceutical agent thereof. Top acceptable salt.

The object compound (I) or a salt thereof can be produced by the method represented by the following reaction formula. Manufacturing method 1

Manufacturing method 2

Manufacturing method 3

Manufacturing method 4

Manufacturing method 5

A method for producing the starting compounds (II) and (III) will be described below. The other raw material compounds can be produced by the methods described in Production Examples below. Manufacturing method A

Manufacturing method B

(In the above formula, R ¹ , R ² , Q, A and X are as defined above; Y is halogen; Z is acid residue).

In the above and subsequent description of the present specification, suitable examples and explanations of various definitions included in the scope of the present invention will be explained in detail below.

The term "lower", unless stated otherwise, means a radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

The term "higher" unless otherwise specified, has 7 to 20 carbon atoms, preferably 12 to 1 carbon atoms.
A group having 8 is meant.

Suitable "lower alkyl group", "lower alkoxy (lower) alkyl group", "cyclo (lower) alkyl (lower) alkyl group", "arylamino (lower) alkyl group" and "heterocycle (lower)" Suitable lower alkyl moieties and (lower) alkyl moieties in ") alkyl groups" include 1 to 6 carbons such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl and the like. Straight-chain or branched-chain alkyl having an atom, preferably C1-C5 alkyl, more preferably methyl,
Ethyl, butyl and isopentyl.

Suitable "higher alkyl groups" include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the like.

Suitable "lower alkenyl group" includes vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl and the like.

Suitable "lower alkynyl group" includes ethynyl, propynyl, butynyl and the like.

The lower alkoxy moiety of a suitable "lower alkoxy (lower) alkyl group" is a straight chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like. Branched chain alkoxy is mentioned, preferably C1-C4 alkoxy, more preferably methoxy or ethoxy.

Preferable examples of "cyclo (lower) alkyl group" include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferable examples of "ar (lower) alkyl group" include benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl, trityl and the like. Among them, benzyl and phenethyl are preferable.

Preferable aryl moieties of "aryl group" and "arylamino (lower) alkyl group" include:
Examples thereof include phenyl, naphthyl, lower alkyl-substituted phenyl (eg, tolyl, mesityl, cumenyl, xylyl, diethylphenyl, diisopropylphenyl, di-tert-butylphenyl, etc.).

Suitable heterocyclic moiety in the preferable "heterocyclic (lower) alkyl group" includes oxygen atom, sulfur atom,
Mention may be made of saturated or unsaturated monocyclic or polycyclic heterocyclic groups having at least one heteroatom such as a nitrogen atom. Particularly preferred heterocyclic groups are 5- or 6-membered aromatic heteromonocyclic groups (eg, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5-membered or 6-membered An aliphatic heteromonocyclic group (for example, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, etc.),
An unsaturated condensed heterocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, etc.) and the like can be mentioned. The heterocyclic moiety thus defined is amino,
It may have an appropriate substituent such as oxo, halogen such as chlorine and lower alkyl as defined above. Preferable examples of the heterocyclic group having a substituent include a thiazolyl having a lower alkyl (eg, 4-methylthiazolyl etc.)
Is mentioned.

Preferable examples of "lower alkylene group" include 1 to 6 carbon atoms such as methylene, dimethylmethylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, pentamethylene, hexamethylene and the like. There may be mentioned a straight chain or branched chain alkylene group having 1 (preferably 1 to 4), and among them, methylene, ethylene, trimethylene and tetramethylene are preferable.

Preferable examples of "lower alkenylene group" include 1-propenyl, 1-butenyl, 2-butenyl and 2
-Pentenyl and the like are mentioned, and among them, 1-butenyl is preferable.

Preferable examples of "lower alkanoyl group" include formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, pivaloyl and the like, of which acetyl is preferable.

Suitable "halogen" includes fluorine, chlorine, bromine and iodine.

Suitable "acid residue" includes halogen atom (eg, fluorine, chlorine, bromine and iodine), allenesulfonyloxy (eg benzenesulfonyloxy, tosyloxy etc.), lower alkanesulfonyloxy (eg mesyloxy, (Ethanesulfonyloxy, etc.)
And the like. Among these, halogen is preferable.

"Ar (lower) alkyl group optionally having one or more suitable substituents", "aryl group optionally having one or more suitable substituents" and "suitable The “suitable substituent” of the “arylamino (lower) alkyl group which may have one or more substituents” is hydroxy,
Halogen (eg fluorine, chlorine, bromine and iodine), lower alkoxy (eg methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc.) and the like can be mentioned. Among these, lower alkoxy can be mentioned.

The pharmaceutically acceptable salt of the objective compound (I) is a conventional non-toxic salt, which is an inorganic acid salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.). , Organic acid salts (eg formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. ), A salt with an amino acid (eg, arginine salt, aspartate, glutamate, etc.) and the like.

The method for producing the object compound (I) will be described in detail below. Production Method 1 The object compound (Ia) or a salt thereof can be produced by reacting the compound (II) or a salt thereof with hydrazine monohydrate. Suitable salts of the compound (Ia) and the compound (II) may be the same as those shown for the compound (I).

The reaction is usually an alcohol (eg methanol).
, Ethanol, etc.), dioxane, tetrahydrofuran, diethyl ether, chloroform, methylene chloride,
It is carried out in a conventional solvent such as ethylene chloride, benzene, toluene, N, N-dimethylformamide, pyridine, or any other organic solvent that does not adversely influence the reaction.
The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature, under heating or under heating.

Production Method 2 The object compound (Ib) or its salt is the compound (III)
Alternatively, it can be produced by reacting the salt with compound (IV). Suitable salts of the compound (Ib) and the compound (III) may be the same as those shown for the compound (I).

The reaction is usually carried out in the presence of a base, in the presence of a solvent or without a solvent. Suitable bases used in this reaction include, for example, alkali metals (eg sodium, potassium, cesium etc.), alkaline earth metals (eg magnesium, calcium etc.), hydroxides or carbonates or bicarbonates of these metals. Salts, alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), alkali metal acetates, alkaline earth metal phosphates, alkali metal hydrogen phosphates (eg disodium hydrogen phosphate, dipotassium hydrogen phosphate). Etc.), tri (lower) alkylamines (eg trimethylamine, triethylamine etc.), pyridine or its derivatives (eg picoline, lutidine, 4-dimethylaminopyridine etc.), N-
Mention may be made of inorganic and organic bases such as (lower) alkylmorpholine and quinoline.

The reaction is usually an alcohol (eg methanol).
, Ethanol, etc.), N, N-dimethylformamide,
Diethyl ether, dioxane, tetrahydrofuran,
It is carried out in a conventional solvent such as benzene, toluene or any other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature, under heating or under heating.

Production Method 3 The object compound (Ic) or its salt is reacted with the compound (V) or its reactive derivative at the carboxyl group or its salt with the compound (VI) or its reactive derivative at the amino group or its salt. It can be manufactured by Compound (Ic) and compound (V
Suitable salts of I) may be the same as those shown for compound (I). Suitable salts of the compound (V) include salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt, cesium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt etc.). , Ammonium salts; salts with organic bases,
For example, organic amine salts (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethano-amine salt, etc.
Ruamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic Carboxylic acid addition salts or organic sulfonic acid addition salts (eg formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); Examples thereof include salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, lysine, etc.).

Suitable reactive derivatives at the carboxyl group of compound (V) include acid halides, acid anhydrides, active amides, active esters and the like. Suitable examples thereof include acid chloride; acid azide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Dibenzyl phosphoric acid, halogenated phosphoric acid, etc., dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, lower alkane sulfonic acid (eg methane sulfonic acid, ethane sulfonic acid etc.), aliphatic carboxylic acid (eg acetic acid, propionic acid, Butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or an aromatic carboxylic acid (for example, benzoic acid, etc.) and the like mixed acid anhydride; symmetrical acid anhydride; Active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazol or tetrazole; active esters (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, -Dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester etc.); or an N-hydroxy compound (eg N, N-
Dimethylhydroxylamine, 1-hydroxy-2-
(1H) -pyridone, N-hydroxysuccinimide,
Examples thereof include esters with N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and the like. These reactive derivatives may be appropriately selected from these depending on the type of compound (V) used. Suitable reaction derivative at the amino group of compound (VI) is a Schiff-base type imino compound produced by the reaction of compound (VI) with a carbonyl compound such as aldehyde, ketone or the like, or a tautomeric enamine type isomer thereof. , A silyl derivative formed by the reaction of a compound (VI) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [for example, N- (trimethylsilyl) acetamide], bis (trimethylsilyl) urea, etc .; Mention may be made of derivatives and the like formed by the reaction of VI) with phosphorus trichloride or phosgene.

In this reaction, when compound (V) is used in the form of a free acid or a salt thereof, the reaction is carried out by a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholino.Ethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-
Diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis- (2-methylimidazole); pentamethyleneketene-N- Cyclohexyl imine; diphenyl ketene-N
-Cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenylphosphoryl azide; diphenylphosphinic chloride; Thionyl chloride; oxalyl chloride; lower alkyl haloformate (eg ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m -Sulfophenyl) isoxazolium inner salt; 1- (p-chlorobenzenesulfonyloxy)-
6-chloro-1H-benzotriazol; N-hydroxybenzotriazole; so-called Vilsmeier prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is preferably carried out in the presence of reagents and the like.

The reaction is usually water, acetone, alcohol (for example, methanol, ethanol, etc.), dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, It is carried out in a conventional solvent such as pyridine or any other organic solvent that does not adversely influence the reaction. Among these solvents, the hydrophilic solvent can also be used as a mixture with water. The reaction in the presence of the condensing agent is usually performed under anhydrous conditions, but is not particularly limited. If the base or condensing agent used is a liquid,
It can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating.

This reaction is carried out by using alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), alkali metal bicarbonates (eg hydrogen carbonate). Sodium, potassium hydrogen carbonate, etc.), tri (lower) alkylamine (eg, trimethylamine, triethylamine, etc.), pyridine or its derivative (eg, picoline,
It can also be carried out in the presence of an inorganic or organic base such as lutidine, 4-dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like.

Production Method 4 The object compound (Id) or its salt is reacted with the compound (V) or its reactive derivative at the carboxyl group or its salt with compound (VII) or its reactive derivative at the hydroxy group or its salt. It can be manufactured by Suitable salt of the compound (Id) may be the same as those shown for the compound (I). Suitable reactive derivative at the hydroxy group of compound (VII) is, for example, halide such as chloride, bromide, iodide, etc., for example, sulfonic acid ester such as methanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc. And the like, and more preferable examples include sulfonic acid esters.

The reaction can be carried out by conventional esterification. Suitable reactive derivative at the carboxy group of compound (V) or a salt thereof may be the same as those exemplified in production method 3. In this reaction, when the compound (V) is used in the form of a free acid, it is desirable to carry out the reaction in the presence of the base described in the production method 3.

The reaction is usually a conventional solvent such as alcohol (eg, methanol, ethanol, etc.), dioxane, tetrahydrofuran, N, N-dimethylformamide, pyridine, dimethylsulfoxide or the like, or adversely affects the reaction. In any other organic solvent that does not The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating.

Production Method 5 The object compound (Ie) or its salt can be produced by reacting the compound (Ia) or its salt with potassium cyanate. Suitable salts of the compound (Ie) and the compound (Ia) may be the same as those shown for the compound (I).

The reaction is usually carried out in a water solvent under acidic conditions of hydrochloric acid. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating.

The starting compounds (III) and (II) of this method can be produced by the method described in the production method A or B, respectively. Production Method A Compound (III) or a salt thereof is compound (VIII)
Alternatively, it can be produced by reacting the salt with compound (IX). Suitable salts of the compound (VIII) may be the same as those shown for the compound (I).

This reaction is carried out by using alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), alkali metal bicarbonates (eg hydrogen carbonate). Sodium, potassium hydrogen carbonate, etc.), tri (lower) alkylamine (eg, trimethylamine, triethylamine, etc.), pyridine or its derivative (eg, picoline,
It can also be carried out in the presence of an inorganic or organic base such as lutidine, 4-dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. If the base used is a liquid, it can also be used as solvent.

The reaction is usually water, acetone, alcohol (for example, methanol, ethanol, etc.), dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, acetonitrile, chloroform, methylene chloride, ethylene chloride. , Ethyl acetate, N, N
Carried out in a conventional solvent such as dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, the hydrophilic solvent can also be used as a mixture with water. The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature, under heating or under heating.

Production Method B Compound (II) or a salt thereof can be produced by reacting compound (VIII) or a salt thereof with compound (X). For this reaction, the description of the above production method A may be referred to.

The compound obtained by each of the above production methods can be isolated and purified by a conventional method such as extraction, pulverization, recrystallization, column chromatography, recrystallization and the like.

[0052]

To show the usefulness of the object compound (I),
The pharmacological test data of the compound (I) are shown below.

Test Example: Gastric acid secretion from cavity-perfused stomach in anesthetized rats (1) Test method Sprague-Dawle
y) Male rats (body weight about 250 g) were used. Rats were fasted for 24 hours (with free access to water).
Rats were anesthetized by intraperitoneal administration of 1.25 g / kg urethane. The abdomen was opened and the stomach cavity was perfused with saline throughout the study. The perfusate was titrated using an automatic titrator with 25 mM sodium hydroxide as the titrant. Gastric acid secretion was induced by intravenous infusion of histamine (3 mg / kg / hour). After reaching the plateau, the test compound (1 mg
/ Kg) was administered intravenously. The drug efficacy was indicated by the maximum inhibition rate of acid secretion.

(2) Test compound: 2-[(amino) (n
-Butylamino) methyleneamino] -4- (3-acetylaminopropyl) thiazole oxalate

(3) Test result: Inhibition rate 100%

For the purpose of therapy, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are organic or inorganic solid, semisolid or liquid suitable for oral administration, parenteral administration and topical administration. It is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an excipient. The pharmaceutical preparation may be solid such as capsule, tablet, dragee, granule, suppository, or liquid such as solution, lotion, suspension, emulsion, gel, ointment and the like. If necessary, auxiliary agents, stabilizers, lubricants or emulsifiers, buffers and other commonly used additives may be contained in the above-mentioned preparation.

The dose of compound (I) varies depending on the age and condition of the patient, but the target compound (I) has an average of 1
Single dose about 0.1mg, 1mg, 10mg, 50mg,
It was found that 100 mg, 250 mg, 500 mg and 1000 mg were effective in treating the above diseases. Generally, an amount of between 0.1 mg and about 1000 mg per day may be administered.

[0058]

EXAMPLES The present invention will be described in more detail below with reference to production examples and examples.

Production Example 1 3-[(amino) (n-butylamino) methylene] thiourea (5.22 g) and sodium hydrogen carbonate (10
g) ethylene glycol dimethyl ether (75 m)
l) ethyl 3-bromopyruvate (7.1
5 g) is added at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture is refluxed for 20 minutes. The reaction mixture was cooled with ice-cold water (1
(00 ml) and extracted twice with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using 5% methanol / chloroform as an eluent to give 2-[(amino) (n-butylamino) methyleneamino] -4-ethoxycarbonylthiazole (5.6
8 g) are obtained. Melting point 102-104 ° C IR (nujol): 3400, 1695, 1590,
1570 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t,
J = 7.2 Hz), 1.28 (3H, t, J = 7.1H
z), 1.24-1.58 (4H, m), 3.06-
3.25 (2H, m), 4.23 (2H, q, J = 7.
1 Hz), 7.42 (2H, br.s), 7.60 (1
H, s)

Production Example 2 3-Bromopyruvic acid (5.0 g), 3-[(amino)
(N-Butylamino) methylene] thiourea (5.22
A mixture of g) and sodium hydrogen carbonate (10 g) in methanol (100 ml) is refluxed for 1 hour. After removing the solvent, the residue was dissolved in water (150 ml) and p-ionized with 6N hydrochloric acid.
Adjust H to 6.5. The resulting precipitate was collected by filtration and washed with water to give 2-[(amino) (n-butylamino) methyleneamino] thiazole-4-carboxylic acid (7.30 g).
Get. Melting point 247-250 ° C IR (nujol): 3200, 1660, 1620,
1500 cm ^-1 NMR (DMSO-d ₆ , δ): 0.89 (3H, t,
J = 7.1 Hz), 1.22-1.62 (4H, m),
3.06-3.24 (2H, m), 4.11 (3H, b
r. s), 7.52 (1H, s)

Production Example 3 1-Bromo-5-phthalimido-2-pentanone (1.
5 g) and 3-[(amino) (2-methoxypheneti)
Lumino) methylene] thiourea (1.1 g) in acetoni
The trilyl solution is refluxed for 2 hours with stirring. After removing the solvent,
The residue is dissolved in water (30 ml). Potassium carbonate solution
Alkalineized to pH 10 with 20% aqueous solution, ethyl acetate
Extract with. The extract was washed with saturated saline and washed with anhydrous sodium sulfate.
After drying over gnesium, concentrate under reduced pressure. 5% methano residue
-Silica gel column with eluent
After chromatographing, 2-[(amino) (2-meth
Ciphenethylamino) methyleneamino] -4- (3-f
Talimidopropyl) thiazole (1.48g) as an oil
Get as a thing. IR (film): 3350, 1770, 1705, 1
610,1540 cm ^-1 NMR (DMSO-d₆, Δ): 1.83-2.06
(2H, m), 2.48-2.60 (2H, m), 2.
79 (2H, t, J = 6.9Hz), 3.35-3.4.
6 (2H, m), 3.62 (2H, t, J = 6.9H
z), 3.77 (3H, s), 6.41 (1H, s),
6.84-7.00 (2H, m), 7.14-7.25
(2H, m), 7.49 (2H, br.s) MASS (m / Z): 464 (M⁺)

Production Example 4 The following compound was obtained in the same manner as in Production Example 3. 2-[(amino) (n-butylamino) methyleneamino] -4- (2-phthalimidoethyl) thiazole Melting point 176-178 ° C IR (nujol): 3320, 3250, 1770,
1720,1670,1640 cm ⁻¹ NMR (DMSO-d ₆ , δ): 0.93 (3H, t,
J = 7.2 Hz), 1.28-1.66 (4H, m),
2.96 (2H, t, J = 6.6Hz), 3.19-
3.38 (2H, m), 3.89 (2H, t, J = 6.
6 Hz), 7.01 (1H, br.s), 7.78-
7.90 (4H, m), 8.43 (2H, br.s)

Production Example 5 In the same manner as in Production Example 3, the following compound was obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (3-phthalimidopropyl) thiazole Melting point 75-82 ° C IR (nujol): 3400, 1765, 1705
1620,1600 cm ^-1 NMR (DMSO-d ₆ , δ): 0.88 (3H, t,
J = 7.2 Hz), 1.24-1.68 (4H, m),
1.88-2.04 (2H, m), 2.48-2.56
(2H, m), 3.08-3.22 (2H, m), 3.
63 (2H, t, J = 7.0Hz), 6.28 (1H,
s), 7.24 (2H, br.s), 7.8-7.9.
(4H, m)

Production Example 6 In the same manner as in Production Example 3, the following compound was obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (4-phthalimidobutyl) thiazole Melting point 80-85 ° C IR (nujol): 3400, 1768, 1720,
1700, 1650, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 0.88 (3H, t,
J = 7.2 Hz), 1.2-1.53 (4H, m),
1.54-1.72 (4H, m), 2.43-2.54
(2H, m), 3.05-3.15 (2H, m), 3.
59 (2H, t, J = 6.2Hz), 6.23 (1H,
s), 7.20 (2H, br.s), 7.77-7.9.
1 (4H, m)

Production Example 7 The following compound was obtained in the same manner as in Production Example 3. 2-[(amino) (n-butylamino) methyleneamino] -5- (4-phthalimidobutyl) thiazole (oil) IR (film): 3400, 3150, 1770, 1
700 cm ^-1 NMR (DMSO-d ₆ , δ): 0.67 (3H, t,
J = 6.8 Hz), 1.01-1.42 (8H, m),
2.41 (2H, t, J = 7.0Hz), 2.80-
3.01 (2H, m), 3.37 (2H, t, J = 6.
3Hz), 6.61 (1H, s), 7.09 (2H, b
r. s), 7.56-7.70 (4H, m)

Production Example 8 Bromine (0.51 g) was added dropwise to a solution of 4- (2-phthalimidoethoxy) -2-butanone (2.61 g) in methanol (30 ml) at room temperature with stirring. After stirring at the same temperature for 2 hours, the solution is concentrated to dryness. The resulting residue and 3
A solution of-[(amino) (n-butylamino) methylene] thiourea (1.74 g) in acetonitrile is refluxed with stirring for 2 hours. After removing the solvent, the residue is dissolved in water (20 ml), the solution is alkalinized to pH 10 with 20% aqueous potassium carbonate solution and extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform / methanol (20/1)
Silica gel column chromatography eluting with 2-[(amino) (n-butylamino) methyleneamino] -4-[(2-phthalimidoethoxy) ethyl]
Thiazol is obtained as an oil. IR (film): 3400, 3100, 1770, 1
710, 1640, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t,
J = 7.3 Hz), 1.27-1.60 (4H, m),
2.67 (2H, t, J = 6.4Hz), 3.05 (2
H, t, J = 6.9 Hz), 3.15-3.32 (2
H, m), 3.66 (2H, q, J = 6.9Hz),
3.73 (2H, q, J = 6.9Hz), 6.59 (1
H, s), 7.75-7.92 (4H, m) MASS (m / Z): 416 (M + 1)

Production Example 9 The following compound was obtained in the same manner as in Production Example 8. 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4-[(2-phthalimidoethoxy)
Ethyl] thiazole IR (nujol): 3400, 1770, 1710,
1630,1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.50-3.05
(4H, m), 3.56-3.83 (8H, m), 3.
79 (3H, s), 6.42 (1H, s), 6.81-
7.36 (4H, m), 7.76-7.91 (4H,
m)

Production Example 10 The following compound was obtained in the same manner as in Production Example 8. 2-[(amino) (isoamylamino) methyleneamino] -4- (3-phthalimidopropyl) thiazole IR (nujol): 3400, 1770, 1710,
1630, 1600, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.89 (6H, d,
J = 7.3 Hz), 1.25-1.93 (5H, m),
2.61 (2H, t, J = 7.5Hz), 3.08-
3.20 (2H, m), 3.50-3.72 (2H,
m), 6.29 (1H, s), 7.75-7.92 (4
H, m)

Production Example 11 The following compound was obtained in the same manner as in Production Example 8. 2-[(amino) (isoamylamino) methyleneami
No] -4- (4-phthalimidobutyl) thiazole IR (film): 3350, 1770, 1700, 1
600,1540 cm ^-1

Production Example 12 The following compound was obtained in the same manner as in Production Example 8. 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4- (4-phthalimidobutyl) thiazole IR (nujol): 3200, 1770, 1710,
1675, 1615, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.47-1.70.
(4H, m), 2.52 (2H, t, J = 7.1H
z), 2.84 (2H, t, J = 6.7 Hz), 3.4
7-3.66 (4H, m), 3.75 (3H, s),
6.83-7.30 (6H, m), 7.77-7.91
(4H, m)

Production Example 13 Bromine (3.2 g) was added dropwise to a solution of 5-phthalimido-2-pentanone (4.62 g) in methanol (25 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After removing the solvent, the residue is dissolved in acetonitrile (50 ml). To this 3-
[(Amino) (2-propoxybenzylamino) methylene] thiourea (3.73 g) and triethylamine (2.8 ml) are added and the mixture is refluxed for 1 hour. After removing the solvent, the residue is dissolved in water and ethyl acetate.
The mixture is basified to pH 10 with 20% aqueous potassium carbonate solution and extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using 5% methanol / chloroform as an eluent to give 2-
[(Amino) (2-propoxybenzylamino) methyleneamino] -4- (3-phthalimidopropyl) thiazole (1.96 g) is obtained as an oil. IR (film): 3400, 1770, 1705, 1
620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.00 (3H, t,
J = 7.3 Hz), 1.65-2.30 (4H, m),
2.45-2.57 (2H, m), 3.61 (2H,
t, J = 7.0 Hz), 3.90-4.03 (2H,
m), 4.36 (2H, d, J = 5.7Hz), 6.3
3 (1H, s), 6.85-7.28 (4H, m),
7.77-7.92 (4H, m)

Production Example 14 3-Chloro-2-oxopropyl triphenyl chloride
A solution of phosphonium (3.89 g), 3-phthalimidopropanal (2.03 g) and 1.8-diazabicyclo [5,4,0] undec-7ene (1.67 g) in acetonitrile (30 ml) was stirred. Reflux for 35 hours. 3-[(Amino) (2-methoxyphenethylamino) methylene] thiourea (1.51 g) is added to this solution and refluxed for 2 hours with stirring. After removing the solvent, the residue is dissolved in water. PH of the solution with 20% aqueous potassium carbonate
Alkalineize to 10 and extract with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using 3% methanol / chloroform as an eluent to give 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4- (4-phthalimido-1-).
Butenyl] thiazole (2.18 g) is obtained as an amorphous powder. IR (film): 3400, 3300, 1770, 1
650, 1620, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.48 (2H, t,
J = 6.4 Hz), 2.77 (2H, t, J = 7.0H
z), 3.2-3.4 (2H, m), 3.69 (2H,
t, J = 7.0 Hz), 3.79 (3H, s), 6.0
-6.3 (2H, m), 6.46 (1H, s), 6.8
-7.0 (2H, m), 7.3 (1H, br.s),
7.9 (4H, m)

Production Example 15 In the same manner as in Production Example 14, the following compound was obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (4-phthalimido-1-butenyl] thiazole melting point 143-145 ° C. IR (nujol): 3450, 1770, 1705.
1650, 1590, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.1 Hz), 1.22-1.63 (4H, m),
3.18-3.40 (4H, m), 3.70 (2H,
t, J = 6.9 Hz), 6.20-6.39 (2H,
m), 6.76 (1H, s), 7.80-8.10 (4
H, m)

Production Example 16 The following compound was obtained in the same manner as in Production Example 14. 2-[(amino) (2-ethoxyethylamino) methyleneamino] -4- (4-phthalimido-1-butenyl]
Thiazole, melting point 52-53 ° C IR (nujol): 3300, 1770, 1705.
1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.12 (3H, t,
J = 7.0 Hz), 2.37-2.54 (2H, m),
3.20-3.52 (6H, m), 3.69 (2H,
t, J = 7.1 Hz), 6.18-6.36 (2H,
m), 6.54 (1H, s), 7.45 (2H, br.
s), 7.77-7.82 (4H, m)

Production Example 17 In the same manner as in Production Example 14, the following compound was obtained. 2-[(amino) (isoamylamino) methyleneamino] -4- (4-phthalimido-1-butenyl] thiazole IR (nujol): 1770, 1710, 1620,
1600 cm ^-1 NMR (DMSO-d6, δ): 0.90 (6H, d,
J = 6.5 Hz), 1.31-1.56 (2H, m),
1.62-1.81 (1H, m), 2.46-2.53
(2H, m), 3.08-3.21 (2H, m), 3.
70 (2H, t, J = 7.0Hz), 6.04-6.3.
0 (2H, m), 6.44 (1H, s), 7.25 (2
H, br. s), 7.76-7.90 (4H, m)

Example 1 2-[(Amino) (2-methoxyphenethylamino) methyleneamino] -4- (3-phthalimidopropyl) thiazole (1.32 g) and hydrazine monohydrate in ethanol ( The solution (30 ml) is refluxed for 1 hour with stirring.
The insoluble matter is removed by filtration, and the filtrate is concentrated to dryness. Chloroform (30 m) of the obtained residue and acetic anhydride (2 ml)
l) The solution is stirred at room temperature for 2 hours. The resulting mixture was stirred for an additional hour and then pH adjusted with 20% aqueous potassium carbonate.
Alkalineize to 10 and extract with chloroform. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform / methanol (20/1) as an eluent to give 2-
[(Amino) (2-methoxyphenethylamino) methyleneamino] -4- (3-acetylaminopropyl) thiazole is obtained as an oil. The oil obtained is converted to the oxalate salt with oxalic acid, methanol and ethyl acetate. Melting point 99-101 ° C IR (nujol): 3300, 1685, 1635,
1550 cm ^-1 NMR (DMSO-d ₆ , δ): 1.58-1.82
(2H, m), 1.79 (3H, s), 2.45 (2
H, t, J = 7.1 Hz), 2.77 (2H, t, J =
7.1 Hz), 2.96-3.13 (2H, m), 3.
28-3.40 (2H, m), 3.79 (3H, s),
6.27 (1H, s), 6.76-6.90 (1H,
m), 6.84-6.98 (2H, m), 7.16-
7.40 (4H, m) MASS (m / Z): 376 (M + 1)

Example 2 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (2-acetylaminoethyl) thiazole
Oxalate melting point 82-84 ° C IR (nujol): 3250, 1680, 1650,
1590, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 0.69 (3H, t,
J = 7.1 Hz), 1.08-1.48 (4H, m),
1.57 (3H, s), 2.41-2.73 (2H,
m), 2.85-3.22 (4H, m), 6.11 (1
H, s), 7.76 (1H, br.s), 8.51 (2
H, br. s), 9.45 (1H, br.s) MASS (m / Z): 384 (M ⁺ ) Elemental analysis Calculated value: C; 41.75, H; 6.37, N; 1
6.23 Found: C; 41.60, H; 6.04, N; 1
5.96

Example 3 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (3-acetylaminopropyl) thiazole oxalate melting point 101-103 ° C IR (nujol): 3200, 3100, 1690,
1650, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.3 Hz), 1.28-1.61 (4H, m),
1.67-1.82 (2H, m), 1.80 (3H,
s), 2.56 (2H, t, J = 7.5Hz), 3.0
0-3.32 (4H, m), 6.72 (1H, s),
7.88 (1 H, t, J = 5.7 Hz) MASS (m / Z): 298 (M + 1) Elemental analysis Calculated value: C; 46.50, H; 6.50, N; 1
8.08 Found: C; 46.43, H; 6.74, N; 1
7.97

Example 4 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (n-butylamino) methyleneamino] -4- (4-acetylaminobutyl) thiazole
Oxalate Melting point 128-130 ° C IR (nujol): 3250, 1700, 1680,
1640, 1560 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.2 Hz), 1.35-1.62 (8H, m),
1.78 (3H, s), 2.57 (2H, t, J = 7.
0 Hz), 2.94-3.10 (2H, m), 3.20
-3.36 (2H, m), 6.73 (1H, s), 7.
81 (1H, br.s), 8.57 (2H, br.s) Elemental analysis Calculated value: C; 47.87, H; 6.78, N; 1
7.44 Found: C; 47.49, H; 6.81, N; 1
7.22

Example 5 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (n-butylamino) methyleneamino] -5- (4-acetylaminobutyl) thiazole
Oxalate melting point 150-152 ° C IR (nujol): 3250, 1680, 1630,
1560 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.2 Hz), 1.26-1.64 (8H, m),
1.78 (3H, s), 2.71 (2H, t, J = 7.
0 Hz), 2.97-3.11 (2H, m), 3.18
-3.36 (2H, m), 7.12 (1H, s), 7.
83 (1H, br.s), 8.63 (1H, br.s) MASS (m / Z): 312 (M ⁺ ) Elemental analysis Calculated value: C; 47.87, H; 6.78, N; 1
6.44 Found: C; 47.73, H; 6.78, N; 1
6.72

Example 6 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (n-butylamino) methyleneamino] -4- (4-acetylamino-1-butenyl) thiazole oxalate Melting point 176-177 ° C IR (nujol): 3250, 1710 , 1670,
1630 cm ^-1 NMR (DMSO-d ₆ , δ): 0.92 (3H, t,
J = 7.2 Hz), 1.30-1.66 (4H, m),
1.79 (3H, s), 2.20-2.35 (2H,
m), 3.08-3.36 (4H, m), 6.14-
6.37 (2H, m), 6.88 (1H, s), 7.9
2 (1H, t, J = 5.3Hz), 8.44 (2H, b
r. s) MASS (m / Z): 310 (M + 1) Elemental analysis Calculated value: C; 48.11, H; 6.31, N; 1
7.53 Found: C; 48.10, H; 6.62, N; 1
7.34

Example 7 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4- (4-acetylamino-1-butenyl) thiazole oxalate melting point 150-157 ° C IR (nujol): 3300, 1700, 1670,
1590 cm ^-1 NMR (DMSO-d ₆ , δ): 1.79 (3H,
s), 2.20-2.35 (2H, m), 2.86 (2
H, t, J = 6.9 Hz), 3.07-3.20 (2
H, m), 3.41-3.55 (2H, m), 3.77.
(3H, s), 6.02-6.37 (2H, m), 6.
77-7.00 (3H, m), 7.16-7.26 (2
H, m), 7.90 (1H, t, J = 5.6Hz)

Example 8 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (n-butylamino) methyleneamino] -4- [2- (2-acetylaminoethoxy) ethyl] thiazole oxalate mp 150-152 ° C IR (nujol): 3250 , 1720, 1680,
1630, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.2 Hz), 1.24-1.63 (4H, m),
1.79 (3H, s), 2.82 (2H, t, J = 6.
6 Hz), 3.12-3.35 (4H, m), 3.40
(2H, t, J = 5.6 Hz), 3.66 (2H, t,
J = 6.5 Hz), 6.80 (1H, s), 7.86
(1H, br.s), 8.52 (1H, br.s) MASS (m / Z): 382 (M + 1) Elemental analysis Calculated value: C; 46.03, H; 6.52, N; 1
6.78 Found: C; 45.87, H; 6.55, N; 1
7.04

Example 9 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (n-butylamino) methyleneamino] -4- (2-acetylaminoethoxycarbonyl)
Thiazol oxalate melting point 133-134 ° C IR (nujol): 3420, 3300, 1700,
1650, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t,
J = 7.2 Hz), 1.26-1.58 (4H, m),
1.82 (3H, s), 3.07-3.23 (2H,
m), 3.28-3.44 (2H, m), 4.16 (2
H, t, J = 5.7 Hz), 7.42 (2H, br.
s), 7.46 (1H, s), 8.04 (1H, t, J
= 5.7 Hz) MASS (m / Z): 328 (M + 1) Elemental analysis Calculated value: C; 47.69, H; 6.46, N; 2
1.39 Found: C; 47.84, H; 6.57, N; 2
1.33

Example 10 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (isoamylamino) methyleneamino] -4- (3-acetylaminopropyl) thiazole oxalate Melting point 104-105 ° C IR (nujol): 3330, 3100, 1690,
1650, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (6H, d,
J = 6.5 Hz), 1.40-1.56 (2H, m),
1.59-1.84 (3H, m), 1.80 (3H,
s), 2.57 (2H, t, J = 7.3Hz), 3.0
0-3.13 (2H, m), 3.20-3.36 (2
H, m), 6.75 (1H, s), 7.81 (1H,
t, J = 5.7 Hz) Elemental analysis calculated value: C; 47.87, H; 6.78, N; 1
7.44 Found: C; 47.93, H; 7.08, N; 1
7.33

Example 11 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4- [2- (2-acetylaminoethoxy) ethyl] thiazole oxalate mp 126-127 ° C IR (nujol): 3250, 3180, 1690,
1640 cm ^-1 NMR (DMSO-d ₆ , δ): 1.79 (3H,
s), 1.70-1.93 (4H, m), 3.10-
3.30 (2H, m), 3.34-3.67 (6H,
m), 3.77 (3H, s), 6.79 (1H, s),
6.83-7.03 (2H, m), 6.14-7.36
(2H, m) Elemental analysis Calculated value: C; 50.90, H; 5.90, N; 1
4.13 Found: C; 50.53, H; 5.99, N; 1
3.79

Example 12 The following compound is obtained in the same manner as in Example 1. 2-[(amino) (isoamylamino) methyleneamino] -4- (4-acetylamino-1-butenyl) thiazole oxalate Melting point 104-105 ° C IR (nujol): 3240, 1715, 1680 ，
1620 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (6H, d,
J = 6.5 Hz), 1.43 to 1.56 (2H, m),
1.59-1.75 (1H, m), 1.99 (3H,
s), 2.22-2.37 (2H, m), 3.03-
3.38 (4H, m), 6.22-6.39 (2H,
m), 6.92 (1H, s), 7.92 (1H, t, J
= 5.7 Hz) Elemental analysis calculated value: C; 49.38, H; 6.58, N; 1
6.94 Found: C; 49.34, H; 6.80, N; 1
6.43

Example 13 The following compound was obtained in the same manner as in Example 1. 2-[(amino) (2-ethoxyethylamino) methyleneamino] -4- (4-acetylamino-1-butenyl) thiazole oxalate melting point 130-132 ° C IR (nujol): 3280, 3100, 1740,
1710, 1680, 1630, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.14 (3H, t,
J = 7.0 Hz), 1.80 (3H, s), 2.20-
2.38 (2H, m), 3.08-3.23 (2H,
m), 3.40-3.68 (6H, m), 6.23-
6.42 (2H, m), 6.90 (1H, s), 7.9
1 (1H, t, J = 5.7 Hz), 8.49 (2H, b
r. s) Elemental analysis calculated value: C; 46.20, H; 6.06, N; 1
6.86 Found: C; 46.23, H; 6.25, N; 1
6.69

Example 14 In the same manner as in Example 1, the following compound is obtained. 2-[(amino) (2-propoxybenzylamino) methyleneamino] -4- (3-acetylaminopropyl)
Thiazol oxalate melting point 132-133 ° C IR (nujol): 3260, 1640, 1615,
1595 cm ^-1 NMR (DMSO-d ₆ , δ): 1.01 (3H, t,
J = 7.4 Hz), 1.60-1.87 (4H, m),
1.79 (3H, s), 2.45 (2H, t, J = 7.
5 Hz), 2.90-3.09 (2H, m), 3.96
(2H, t, J = 6.3 Hz), 4.36 (2H, d,
J = 5.7 Hz), 6.29 (1H, s), 6.83-
7.29 (4H, m), 7.44 (2H, br.s),
7.83 (1 H, t, J = 5.7 Hz) MASS (m / Z): 390 Elemental analysis Calculated value: C; 58.59, H; 6.99, N; 1
7.98 Found: C; 58.41, H; 7.14, N; 1
7.48

Example 15 2-[(amino) (n-butylamino) methyleneamino] -4-chloromethylthiazole hydrochloride (602 m
g), 3-acetylaminopropanethiol (532 m
g) and a 28% solution of sodium methoxide in methanol (1.54 g) in ethanol (10 ml) is stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, the residue is dissolved in water, the solution is alkalinized to pH 10 with 20% aqueous potassium carbonate solution and extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was subjected to silica gel column chromatography using 3% methanol / chloroform as an eluent to give 2-
[(Amino) (n-butylamino) methyleneamino]-
4- (3-Acetylaminopropylthiomethyl) thiazole (620 mg) is obtained as an oil. The oil obtained is converted to the oxalate salt with oxalic acid, methanol and ethyl acetate. Melting point 101-103 ° C IR (nujol): 3300, 1705, 1670,
1620 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.1 Hz), 1.30-1.70 (4H, m),
1.78 (3H, s), 2.40-2.55 (4H,
m), 3.02-3.37 (4H, m), 3.68 (2
H, s), 6.89 (1H, s), 7.48 (1H, b)
r. s), 8.50 (2H, br.s) MASS (m / Z): 344 (M + 1) Elemental analysis Calculated value: C; 44.33, H; 6.28, N; 1
6.15 Found: C; 44.40, H; 6.42, N; 1
5.90

Example 16 A mixture of 3-[(amino) (n-butylamino) methylene] thiourea (0.97 g) and 1,3-dichloroacetone (0.71 g) in ethanol (10 ml) was added. Reflux for 2 hours. After cooling to room temperature, the mixture was treated with 28% sodium methoxide in methanol (2.15 g) and 2-mercaptoethylamine (0.43 g) in ethanol.
Solution (5 ml). After stirring the mixture for 17 hours, acetic anhydride (0.57 g) is added and the resulting mixture is stirred for a further 3 hours. The solvent is evaporated under reduced pressure, and the residue is mixed with ethyl acetate and 20% aqueous potassium carbonate solution. The separated organic layer is dried over anhydrous magnesium sulfate and then concentrated to dryness. The residue is subjected to silica gel column chromatography using chloroform / methanol (50: 1) as an eluent. The obtained free base was converted into oxalate by a conventional method, and 4
-(2-Acetylaminoethylthiomethyl) -2-
[(Amino) (n-butylamino) methyleneamino] thiazole oxalate (0.45 g) is obtained. Melting point 106-108 ° C IR (nujol): 3320, 3250, 3100,
1730, 1625 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (3H, t,
J = 7.0 Hz), 1.32-1.55 (4H, m),
1.80 (3H, s), 2.49-2.63 (2H,
m), 3.16-3.26 (4H, m), 3.72 (2
H, s), 6.92 (1H, s), 8.01 (1H, b)
r. s), 8.58 (3H, br.s ) as elemental analysis _{C 13 H 23 N 5 OS 2} · C 2 H 2 O 4, calcd: C; 42.95, H; 6.00 , N; 1
6.69 Found: C; 42.89, H; 6.30, N; 1
6.96

Example 17 The following compound was obtained in the same manner as in Example 16. 4- (2-acetylaminoethylthiomethyl) -2-
[(Amino) (2-methoxyethylamino) methyleneamino] thiazole oxalate melting point 121-122 ° C IR (nujol): 3250, 1780, 1725,
1670, 1630, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.80 (3H,
s), 2.52 (2H, t, J = 7.8Hz), 3.1
6-3.25 (2H, m), 3.30 (3H, s),
3.35-3.53 (4H, m), 3.69 (2H,
s), 6.04 (4H, br.s), 6.91 (1H,
s), 8.00 (1H, t, J = 6.4Hz), 8.4
8 (1H, br.s)

Example 18 2-[(amino) (n-butylamino) methyleneamino] -4-chloromethylthiazole hydrochloride (1.50)
g) and 2-acetylaminoethylamine (1.50
A solution of g) in N, N-dimethylformamide (50 ml) is stirred at 50 ° C. for 2 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in chloroform (10 ml) and acetic anhydride (3 ml). After stirring at room temperature for 3 hours, the solvent is distilled off under reduced pressure. The residue is dissolved in water (20 ml), the solution is basified to pH 10 with 20% aqueous potassium carbonate solution and extracted with chloroform. The extract is dried over anhydrous sodium sulfate, concentrated to dryness, and the residue is subjected to silica gel column chromatography using 10% methanol / chloroform as an eluent. Thin layer chromatography (10% methanol / chloroform) was used to distill off the solvent from the fraction showing a high Rf value,
2-[(amino) (n-butylamino) methyleneamino] -4- [N- (2-acetylaminoethyl) -N-
Acetylaminomethyl] thiazole (533 mg) is obtained as an oil. The obtained oily substance was treated with oxalic acid and methanol.
Convert to the oxalate salt with ethyl acetate. Melting point 159-160 ° C IR (nujoule): 3250, 3100, 1740,
1670, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t,
J = 7.1 Hz), 1.30-1.60 (4H, m),
1.79 (3H, d, J = 6.4Hz), 2.06 (3
H, d, J = 5.0 Hz), 3.10-3.40 (6
H, m), 4.42 (2H, s), 6.85 (1H, b
r. s), 7.86 (1 / 2H, br.s), 8.02
(1/2 H, br.s) MASS (m / Z): 355 (M + 1) Elemental analysis Calculated value: C; 45.94, H; 6.35, N; 1
8.91 Found: C; 45.61, H; 6.45, N; 1
8.56

Example 19 2-[(Amino) (n-butylamino) methyleneamino] thiazol-4-carboxylic acid (1.21 g), 2-
N, N-dimethylformamide of acetylaminoethylamine (612 mg), N-hydroxybenzotriazole (918 mg) and N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride (1.15 g) The mixture in (15 ml) is stirred at room temperature for 5 hours. After evaporating the solvent under reduced pressure, the residue is dissolved in water (30 ml), the solution is alkalized to pH 10 with 20% aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using 5% methanol / chloroform as an eluent, and the obtained amorphous powder was crystallized from ethyl acetate and diethyl ether to give 2-[(amino) (n-butylamino). ) Methyleneamino] -4- (2-acetylaminoethylcarboxamido) thiazole (1.40 g) is obtained. Melting point 154-156 ° C IR (nujoule): 3400, 3300, 1640,
1605, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t,
J = 7.2 Hz), 1.24-1.53 (4H, m),
1.81 (3H, s), 3.10-3.32 (6H,
m), 7.30 (3H, s), 8.02-8.15 (1
H, m), 8.35-8.45 (1H, m) MASS (m / Z): 327 (M + 1) Elemental analysis Calculated value: C; 47.87, H; 6.79, N; 2
5.35 Found: C; 47.63, H; 6.80, N; 2
5.08

Example 20 2-[(amino) (isoamylamino) methyleneamino] -4- (4-phthalimidobutyl) thiazole (1
A solution of 1.5 g) and hydrazine monohydrate (10.0 g) in methanol (200 ml) is refluxed under stirring for 0.5 hours. The mixture obtained is evaporated to dryness, the residue is dissolved in 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The extract is washed with saturated saline, dried over anhydrous sodium sulfate, and then evaporated to dryness. Residue and potassium cyanate (8
92 mg) and water (20 ml) and 1N hydrochloric acid (10 m
Dissolve in l). The resulting mixture is stirred at room temperature for 3 hours, made alkaline with 10% aqueous potassium carbonate solution and extracted with chloroform. The extract is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography using methanol / chloroform (1:10) as an eluent. The obtained oily substance was converted into an oxalate by a conventional method to give 2-[(amino) (isoamylamino) methyleneamino] -4- (4-ureidobutyl) thiazole oxalate (483 mg). . Melting point 129-130 ° C IR (nujoule): 3350, 1735, 1690,
1640, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.91 (6H, d,
J = 6.5 Hz), 1.31-1.75 (7H, m),
2.56 (2H, t, J = 7.0Hz), 2.90-
3.05 (2H, m), 3.19-3.33 (2H,
m), 5.36 (2H, br.s), 5.95 (1H,
t, J = 5.7 Hz), 6.71 (1H, s), 8.4
6 (2H, br.s) MASS (m / Z): 327 (M ⁺ ) Elemental analysis Calculated value: C; 46.14, H; 6.78, N; 2
0.18 Found: C; 45.98, H; 7.03, N; 1
9.99

Example 21 The following compound was obtained as in Example 20. 2-[(amino) (2-methoxyphenethylamino) methyleneamino] -4- (4-ureidobutyl) thiazo-
Le oxalate Melting point 151-153 ° C IR (nujol): 3400, 3340, 1745,
1685, 1640, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 1.28-1.67.
(4H, m), 2.50 (2H, br.s), 2.75
-3.04 (4H, m), 3.48 (2H, br.
s), 3.77 (3H, s), 4.80 (4H, br.
s), 5.95 (1H, t, J = 5.7Hz), 6.7.
0 (1H, s), 6.81-7.14 (4H, m),
8.44 (1H, br.s) Elemental analysis (as 0.3H ₂ O) Calculated: C; 49.43, H; 5.93, N; 1
7.29 Found: C; 49.47, H; 5.86, N; 1
6.90

Claims (5)

[Claims] 1. The formula: (In the formula, R ¹ is a lower alkyl group, a higher alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy (lower) alkyl group, a cyclo (lower) alkyl group, a cyclo (lower) alkyl (lower) alkyl group, suitably , An ar (lower) alkyl group which may have one or more substituents, an aryl group which may have one or more suitable substituents, and one or more suitable substituents Optionally arylamino (lower) alkyl group or heterocyclic (lower) alkyl group;
R ² is a lower alkyl group or an amino group; Q is a lower alkylene group, a lower alkenylene group or the formula: -AX-A-, -CONH-A-, -COO-A- (wherein A is a lower alkylene group. X is a compound represented by S, O, N or NR ³ , (R ³ is a lower alkanoyl group) and a pharmaceutically acceptable salt thereof. 2. The formula: (In the formula, R ¹ is a lower alkyl group, a higher alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy (lower) alkyl group, a cyclo (lower) alkyl group, a cyclo (lower) alkyl (lower) alkyl group, suitably , An ar (lower) alkyl group which may have one or more substituents, an aryl group which may have one or more suitable substituents, and one or more suitable substituents Optionally arylamino (lower) alkyl group or heterocyclic (lower) alkyl group;
R ² is a lower alkyl group or an amino group; Q is a lower alkylene group, a lower alkenylene group or the formula: -AX-A-, -CONH-A-, -COO-A- (wherein A is a lower alkylene group. X is a process for producing a compound represented by S, O, N or NR ³ , (R ³ is a lower alkanoyl group) and a pharmaceutically acceptable salt thereof;
Formula (a): (Wherein R ¹ and Q have the same meanings as described above) or a salt thereof is reacted with hydrazine monohydrate to give a compound of the formula: (Wherein R ¹ and Q have the same meanings as described above) or a salt thereof, or (b) the formula: (In the formula, R ¹ and A have the same meanings as described above,
Y represents halogen) or a salt thereof is represented by the formula: HX-A-NHCO-R ² (IV) (wherein R ² , A and X have the same meanings as before). A compound of formula: (Wherein R ¹ , R ² , A and X have the same meanings as described above) or a salt thereof, or (c) formula: (Wherein R ¹ has the same meaning as described above), a reactive derivative of the carboxyl group or a salt thereof is represented by the formula: H ₂ N-A-NHCO-R ² (VI) (wherein R ² And A each have the same meaning as described above), and a compound represented by the formula: (Wherein R ¹ , R ² and A have the same meanings as defined above) or a salt thereof, or (d)
formula: (Wherein R ¹ has the same meaning as described above), or a reactive derivative of a carboxyl group or a salt thereof is represented by the formula: HO-A-NHCO-R ² (VII) (wherein R ² and A Each have the same meaning as described above), and the compound of the formula: (Wherein R ¹ , R ² and A have the same meanings as described above) or a salt thereof, or (e)
formula: (Wherein R ¹ and Q have the same meanings as described above) or a salt thereof is reacted with potassium cyanate to give a compound of the formula: (Wherein R ¹ and Q have the same meanings as defined above) or a salt thereof,
Method for producing a compound. 3. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. 4. A method for treating ulcer, which comprises administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a human or an animal. 5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an anti-ulcer agent, an H ₂ -receptor antagonist and an anti-Helicobacter pylori agent.