JPH024578B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antiulcer agent containing a novel alkanoic acid amide derivative or a salt thereof as an active ingredient. More specifically, the present invention relates to the general formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a phenyl group, an amino group or a group

[Formula] is shown, R ³ and R ⁴ are each a lower alkyl group, and R ² is a group

[Formula], R ⁵ and R ⁶ are a hydrogen atom, a lower alkyl group or a cycloalkyl group, A is a methine group or a nitrogen atom, B is an oxygen atom or a sulfur atom, and D and E each represent a lower alkylene group. The present invention relates to an anti-ulcer agent containing an alkanoic acid amide derivative or a salt thereof as an active ingredient. The alkanoic acid amide derivative represented by the general formula (1) and its salt, which is the active ingredient of the anti-ulcer agent of the present invention, is a new compound and has an anti-ulcer effect,
Useful as an anti-ulcer agent. In this specification, examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl, cycloheptyl and cyclooctyl groups. Examples of lower alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, and 1-methyltrimethylene. Representative compounds of the present invention are listed below. N,N-diethyl-2-(2-furyl)methylthio-acetamide N,N-diethyl-3-(2-furyl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(2-
furyl) methylthio-propionamide N,N-dimethyl-3-[2-(2-furyl)
Ethylthio]propionamide N-methyl-N-cyclohexyl-3-[2-
(2-furyl)ethylthio]propionamide N,N-dimethyl-3-[4-(2-furyl)
Butylthio]propionamide N,N-diethyl-4(2-furyl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(2-
Furyl) methylthio-butyramide 3-(2-furyl)methylthio-propionamide N-methyl-N-ethyl-3-(2-furyl)
Methylthio-propionamide N-methyl-N-ethyl-3-[2-(2-furyl)ethylthio]propionamide N,N-diethyl-3-(3-furyl)methylthio-propionamide N-ethyl-N-cyclohexyl -3- [2-
(3-furyl)ethylthio]propionamide N-ethyl-N-cyclohexyl-3-(3-
Furyl) methylthio-propionamide N-ethyl-3-(2-furyl)methylthio-
Propionamide N-cyclohexyl-3-(2-furyl)methylthio-propionamide N,N-dicyclohexyl-3-(2-furyl)methylthio-propionamide N,N-diethyl-3-[5-(N,N- dimethylaminomethyl)-2-furyl]methylthio-
Propionamide N-ethyl-N-cyclohexyl-3-[5-
(N,N-dimethylaminomethyl)-2-furyl]
Methylthio-propionamide N,N-dimethyl-3-{2-[5-(N,N
-dimethylaminomethyl)-2-furyl]ethylthio}propionamide N-methyl-N-cyclohexyl-3-{2-
[5-(N,N-dimethylaminomethyl)-2-
Furyl]ethylthio}propionamide N,N-diethyl-4-[5-(N,N-dimethylaminomethyl)-2-furyl]methylthio-
Butyramide N-ethyl-N-cyclohexyl-4-[5-
(N,N-dimethylaminomethyl)-2-furyl]
Methylthio-butyramide 3-[5-(N,N-dimethylaminomethyl)
-2-furyl] Methylthio-propionamide N-methyl-N-ethyl-3-[5-(N-methyl-N-ethylaminomethyl)-2-furyl]
Methylthio-propionamide N-methyl-N-ethyl-3-{2-[5-
(N-methyl-N-cyclohexylaminomethyl)
-2-furyl]ethylthio}propionamide N,N-diethyl-3-[4-(N,N-dimethylaminomethyl)-3-furyl]methylthio-
Propionamide N-ethyl-N-cyclohexyl-3-{2-
[3-(N,N-dimethylaminomethyl)-2-
Furyl]ethylthio}propionamide N-ethyl-N-cyclohexyl-3-[5-
(N,N-dimethylaminomethyl)-3-furyl]
Methylthio-propionamide N,N-diethyl-3-[5-(N,N-dicyclohexylaminomethyl)-2-furyl]Methylthio-propionamide N,N-diethyl-3-(5-methyl-2-furyl) Methylthio-propionamide N,N-dimethyl-3-(5-amino-2-furyl)methylthio-propionamide N,N-diethyl-3-(5-phenyl-2-
Furyl) methylthio-propionamide N,N-diethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(2-
Methylthiazol-4-yl) methylthio-propionamide N,N-dimethyl-3-[2-(2-methylthiazol-4-yl)ethylthio]propionamide N-methyl-N-cyclohexyl-3-[2-
(2-methylthiazol-4-yl)ethylthio]
Propionamide N,N-diethyl-4-(2-methylthiazol-4-yl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(2-
Methylthiazol-4-yl) methylthio-butyramide 3-(2-methylthiazol-4-yl)methylthio-propionamide N-methyl-N-ethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide N-Methyl-N-ethyl-3-[2-(2-methylthiazol-4-yl)ethylthio]propionamide N,N-dimethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide N , N-diethyl-3-(2-phenylthiazol-4-yl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(2-
Phenylthiazol-4-yl)methylthio-propionamide N,N-dimethyl-3-[2-(2-phenylthiazol-4-yl)ethylthio]propionamide N-methyl-N-cyclohexyl-3-[2 ―
(2-phenylthiazol-4-yl)ethylthio]propionamide N,N-diethyl-4-(2-phenylthiazol-4-yl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(2-
Phenylthiazol-4-yl)methylthio-butyramide 3-(2-phenylthiazol-4-yl)methylthio-propionamide N-methyl-N-ethyl-3-(2-phenylthiazol-4-yl)methylthio -Propionamide N-methyl-N-ethyl-3-[2-(2-phenylthiazol-4-yl)ethylthio]propionamide N-ethyl-N-cyclohexyl-3-(4-
Phenylthiazol-2-yl) methylthio-propionamide N,N-diethyl-3-(2-aminothiazol-4-yl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(2-
Aminothiazol-4-yl)methylthio-propionamide N,N-dimethyl-3-[2-(2-aminothiazol-4-yl)ethylthio]propionamide N-methyl-N-cyclohexyl-3-[2-
(2-aminothiazol-4-yl)ethylthio]
Propionamide N,N-diethyl-4-(2-aminothiazol-4-yl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(2-
aminothiazol-4-yl) methylthio-butyramide 3-(2-aminothiazol-4-yl)methylthio-propionamide N-methyl-N-ethyl-3-(2-aminothiazol-4-yl)methylthio-propionamide N-Methyl-N-ethyl-3-[2-(2-aminothiazol-4-yl)ethylthio]propionamide N-ethyl-N-cyclohexyl-3-(4-
aminothiazol-2-yl) methylthio-propionamide N,N-diethyl-3-(4-methylthiazol-2-yl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(4-
Methylthiazol-2-yl) methylthio-propionamide N,N-diethyl-4-(thiazol-4-yl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(thiazol-4-yl)methylthio-butyramide 3 -(4-ethylthiazol-2-yl)methylthio-propionamide N,N-diethyl-3-(thiazol-2-yl)methylthio-propionamide N,N-diethyl-3-(thiazol-5-yl)ethylthio -Propionamide N,N-diethyl-3-(2-thienyl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-(2-
thienyl)methylthio-propionamide N,N-dimethyl-3-[2-(2-thienyl)ethylthio]propionamide N-methyl-N-cyclohexyl-3-[2-
(2-thienyl)ethylthio]propionamide N,N-diethyl-4-(2-thienyl)methylthio-butyramide N-ethyl-N-cyclohexyl-4-(2-
thienyl)methylthio-butyramide 3-(2-thienyl)methylthio-propionamide N-methyl-N-ethyl-3-(2-thienyl)methylthio-propionamide N-methyl-N-ethyl-3-[2-(2 -thienyl)ethylthio]propionamide N,N-diethyl-3-(3-thienyl)methylthio-propionamide N-ethyl-N-cyclohexyl-3-[2-
(3-thienyl)ethylthio]propionamide N,N-diethyl-3-(5-methyl-2-thienyl)methylthio-propionamide N,N-diethyl-3-(5-amino-2-thienyl)methylthio-propion Amide N,N-diethyl-3-(5-phenyl-2-
thienyl)methylthio-propionamide N,N-diethyl-3-[2-(N,N-dimethylaminomethyl)oxazol-5-yl]methylthio-propionamide N,N-diethyl-3-[5-(N, N-dimethylaminomethyl)-2-thienyl]methylthio-propionamide N-ethyl-N-cyclohexyl-3-[5-
(N,N-dimethylaminomethyl)-2-thienyl]methylthio-propionamide N,N-dimethyl-3-{2-[5-(N,N
-dimethylaminomethyl)-2-thienyl]ethylthio]propionamide N-methyl-N-cyclohexyl-3-{2-
[5-(N,N-dimethylaminomethyl)-2-
Thienyl]ethylthio}propionamide N,N-diethyl-4-[5-(N,N-dimethylaminomethyl)-2-thienyl]methylthio-butyramide N-ethyl-N-cyclohexyl-4-[5-
(N,N-dimethylaminomethyl)-2-thienyl]methylthio-butyramide 3-[5-(N,N-dimethylaminomethyl)
-2-thienyl]methylthio-propionamide N-methyl-N-ethyl-3-[5-(N,N
-dimethylaminomethyl)-2-thienyl]methylthio-propionamide N-methyl-N-ethyl-3-{2-[5-
(N-methyl-N-ethylaminomethyl)-2-
Thienyl]ethylthio}propionamide N,N-diethyl-3-[4-(N,N-diethylaminomethyl)-3-thienyl]methylthio-propionamide N-ethyl-N-cyclohexyl-3-{2-
[3-(N,N-dimethylaminomethyl)-2-
thienyl]ethylthio}propionamide N,N-diethyl-3-(oxazole-5-
yl) methylthio-propionamide N,N-dimethyl-4-(oxazole-2-
yl) methylthio-butyramide N,N-diethyl-3-(oxazole-4-
yl) Methylthio-propionamide N-ethyl-N-cyclohexyl-3-(oxazol-5-yl)methylthio-propionamide N,N-diethyl-3-(2-methyloxazol-5-yl)methylthio-propionamide N -Ethyl-N-cyclohexyl-4-(2-
Aminoxazol-5-yl) methylthio-butyramide The compound of the present invention can be produced by various methods, for example, by the method shown in the following Fukai formula. [In the formula, either one of X and X ¹ represents a halogen atom, and the other represents a mercapto group or a group

[Formula] is shown. R ¹ , R ² , A, B, D and E are the same as above] In the reaction formula, compound (2) and compound (3)
is a known compound that is easily available, and this reaction is carried out in the presence of a conventional condensing agent. As this condensing agent, a wide range of basic compounds can usually be used. For example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, alkali metals such as sodium and potassium, alcoholates such as sodium methylate, sodium ethylate, Triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5
-Diazabicyclo [4.3.0] Nonene-5 (DBN),
1,5-diazabicyclo[5.4.0]undecene-
Examples include organic bases such as 5 (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO). The reaction is carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, N, N- Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. The ratio of compound (3) to compound (2) in the above method is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the latter is usually used relative to the former. When carrying out the reaction in a large excess amount in a solvent, it is usually desirable to use the latter in an equimolar to about 5 times the molar amount, preferably an equimolar to 2 times the molar amount of the former. Also,
The reaction temperature is also not particularly limited, but usually -
It is carried out at about 30°C to 200°C, preferably 0 to 160°C. The reaction time is usually about 1 to 75 hours. Compounds of the present invention, i.e., R ² is a group

Compound (1a) having the formula of the present invention has the general formula (1) of the compound of the present invention.
It can be produced from compound (1b) in which R ² corresponds to a hydroxyl group by the method shown in the following reaction formula. [In the formula, R ¹ , R ⁵ , R ⁶ , A, B, D, and E are the same as above] The method shown in the above reaction formula is a method in which a carboxylic acid represented by the general formula (1b) and a general formula (4 ) is reacted with an amine represented by ) in a conventional amide bond forming reaction. In the above method, instead of the compound of general formula (1b),
A compound whose carboxy group is activated may be used, and a compound whose amino group is activated may be used instead of the compound of general formula (4).
As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied.
For example, (a) mixed acid anhydride method, that is, a method of reacting carboxylic acid (1b) with a halocarboxylic acid alkyl ester to form a mixed acid anhydride, and reacting this with amine (4), (b) active ester method, That is, carboxylic acid (1b) is converted into, for example, P-nitrophenyl ester, N-hydroxysuccinimide ester,
A method in which an active ester such as 1-hydroxybenzotriazole ester is reacted with an amine (4), and (3) a carbodiimide method, in which an amine (4) is added to a carboxylic acid (1b), such as dicyclohexylcarbodiimide or carbonyldiimidazole. A method of dehydration condensation in the presence of a dehydrating agent such as (d)
Carboxylic acid halide method, that is, a method of reacting an amine (4) with a halide compound of carboxylic acid (1b), (e) Other methods include carboxylic acid (1b)
is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with an amine (4), or an ester of a carboxylic acid (1b) with, for example, a lower alcohol is produced by adding an amine (4) to the carboxylic acid anhydride under high pressure and high temperature. Examples include a method of causing a reaction. Among these, the mixed acid anhydride method and the carboxylic acid halide method are preferred. Examples of the halocarboxylic acid alkyl ester used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound of the present invention is produced by reacting it with the amine (4) without isolation. The Schotten-Baumann reaction is carried out in the presence of a basic compound.
As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, for example,
Triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]nonene-5
(DBN), 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), and organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO),
Examples include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction temperature is about -20 to 100℃, preferably 0
The reaction is carried out at a temperature of ~50°C, and the reaction time is approximately 5 minutes to 10 hours. The reaction between the obtained mixed acid anhydride and amine (4) is carried out at about -20 to 150°C, preferably at 10°C.
The reaction is carried out at ~50°C for a reaction time of approximately 5 minutes to 10 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, and specifically, methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran,
Examples include ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The proportion of carboxylic acid (1b), halocarboxylic acid alkyl ester and amine (4) used in this method is usually that of carboxylic acid (1b).
The amount of halocarboxylic acid alkyl ester and amine (4) is at least about equimolar, preferably 1
Use ~1.5 times the molar amount. Carboxylic acid halide method uses carboxylic acid (1b)
By reacting with a halogenating agent, carboxylic acid (1b)
This is carried out by converting the obtained carboxylic acid halide into a halide compound, and then reacting the obtained carboxylic acid halide with an amine (4) without isolation or purification. The reaction between carboxylic acid (1b) and halogenating agent is
It can be carried out without a solvent or in the presence of a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, Examples include ethers such as tetrahydrofuran and diethyl ether, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. As the halogenating agent, a usual halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide. The ratio of the carboxylic acid (1b) and the halogenating agent to be used is not particularly limited and is selected as appropriate, but when the reaction is carried out without a solvent, the latter is usually used in large excess of the former under the solvent. When the reaction is carried out, the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. Further, the reaction temperature and reaction time are not particularly limited, but it is usually carried out at room temperature to about 100°C, preferably 50 to 80°C, for about 30 minutes to 6 hours. The reaction between the carboxylic acid halide and the amine (4) is usually carried out in the presence of the same condensing agent as used in the reaction represented by the above reaction formula. Further, the amine (4) itself may be used in excess to serve as a dehydrohalogenating agent. The reaction is carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction are used, such as halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride; Ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric acid Examples include aprotic polar solvents such as triamide. The ratio of carboxylic acid halide and amine (4) to be used is not particularly limited and is appropriately selected, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, and when the reaction is carried out in a solvent. In general, the latter may be used in at least an equimolar amount, preferably an equimolar to twice the molar amount. Further, the reaction temperature and reaction time are not particularly limited, but usually -
30°C to 100°C, preferably 0 to 50°C
It takes about 12 minutes to 12 hours. Furthermore, among the compounds of the present invention, R ¹ is a group

Some compounds (1d) among the compounds represented by [Formula] are compounds (1c) in which R ¹ is a hydrogen atom.
Therefore, it can be produced by the method shown in the reaction formula below. [In the formula, R ² , R ³ , R ⁴ , A, B, D and E are the same as above] The reaction of compound (1c) with formaldehyde (5) and the amine represented by general formula (6) is In a solvent or suitable solvent, 25-150℃, preferably 50-100℃
The reaction is carried out by heating at a temperature of about 30 minutes to 10 hours. The solvent used in this reaction is
For example, water, lower alcohols such as methanol, ethanol, propanol, and isoamyl alcohol, and lower fatty acids such as acetic acid and propionic acid are used. The proportions of formaldehyde (5) and amine (6) to be used relative to the starting material (1c) are usually at least equimolar, preferably equimolar to 3 times the molar amount, respectively. Among the compounds represented by the general formula (1), those having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such basic compounds include metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal alcoholates such as sodium methylate and potassium ethylate. Furthermore, among the compounds represented by the general formula (1), those having a basic group can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. Can be mentioned. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation, extraction, recrystallization, distillation, column chromatography, and preparative thin layer chromatography. The compounds of the present invention are useful as anti-ulcer agents and are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. class ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, amines of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those customary in this field can be used, such as water, ethyl alcohol, propylene glycol,
Examples include ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and the anti-ulcer agent may also contain conventional solubilizing agents, buffers, soothing agents, etc. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. . There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly alone.
Administered intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the anti-ulcer agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 50 mg/kg body weight per day. It is better. Also,
The dosage unit form preferably contains 10 to 1000 mg of the active ingredient. Pharmacological Test 1: Suppressive Effect on Gastric Juice Secretion The pharmacological activity of the compound represented by general formula (1) was tested according to the pyloric ligation method of Shay Rat, which is the most common test method for testing the suppressive effect on gastric juice secretion. Male Wistar rats weighing approximately 170 g were used in this test. The rats were fasted for 24 hours and the compound to be tested 100 minutes before pylorus ligation.
mg/Kg was administered into the duodenum, and gastric juice volume, total acidity, and pepsin activity were measured 4 hours after ligation. The inhibition rate was determined in %, setting the physiological saline administration group as 0. The results are shown in Table 1 below. In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 10% to less than 50% ++: 50% or more Test compound 1 N-ethyl-N-cyclohexyl-3-(2
-furyl) methylthio-propionamide 2 N-ethyl-N-cyclohexyl-3-[5
-(N,N-dimethylaminomethyl)-2-furyl]methylthio-propionamide 3 N-ethyl-N-cyclohexyl-3-(2
-Methylthiazol-4-yl)methylthio-
Propionamide 4 N,N-diethylamino-3-(2-methylthiazol-4-yl)methylthiopropionamide 5 N-ethyl-N-cyclohexylamino-3
-(2-aminothiazol-4-yl)methylthiopropionamide 6 N-ethylamino-3-(2-furyl)methylthiopropionamide 7 N-ethylamino-3-(2-aminothiazol-4-yl)methylthiopropion Amide 8 N-ethylamino-3-(2-methylthiazol-4-yl)methylthiopropionamide 9 N-ethyl-N-cyclohexylamino-3
-(2-thienyl)methylthiopropionamide 10 N-ethyl-N-cycloheptylamino-3
-(2-Methylthiazol-4-yl)methylthiopropionamide 11 N,N-diethylamino-3-(2-furyl)methylthiopropionamide 12 N-ethyl-N-cyclohexylamino-3
-(2-phenylthiazol-4-yl)methylthiopropionamide 13 N,N-dimethyl-3-(2-methylthiazol-4-yl)methylthiopropionamide

[Table] Pharmacological test 2: Stress ulcer experiment After fasting male Wistar rats (approximately 170 g in weight) for 24 hours, they were restrained in a stress cage and immersed in a water tank with a water temperature of 23°C up to the lower edge of the sternum. Slaughtered after 7 hours,
8 ml of 10% formalin was injected into the collected stomach and fixed. The stomach was incised from the greater curvature side, the length of each ulcer formed on the mucosa was measured, and the sum of the lengths was defined as the ulcer index (UI). The test drug was administered immediately before rat restraint.
300 mg/Kg was orally administered in the form of a 0.5% CMC suspension.
The stress ulcer inhibition rate of the test drug was calculated using the following formula. The results are shown in Table 2. Inhibition rate = UI of vehicle-administered control group - UI of test drug-administered group /
UI of the vehicle-administered control group x 100 In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 30-60% ++: 60% or more

[Table] Pharmacological test 3: Suppression of acetic acid ulcer The abdomen of a male Wistar rat was opened under anesthesia to expose the stomach.
0.015 ml of 30% acetic acid aqueous solution was injected, the abdomen was closed, and an acetic acid ulcer was created. The test drug was dissolved or suspended in 0.5% CMC and administered twice a day for 12 days starting from the day after ulcer creation.
The drug was administered orally in divided doses (20 mg/Kg/day). The ulcer area was determined by measuring the area of the opening using a micrometer, excluding the area of mucosal regeneration from around the ulcer, and using it as the ulcer index (UI). The acetic acid ulcer inhibition rate of the test drug was calculated using the following formula. Inhibition rate = UI of vehicle-administered control group - UI of test drug-administered group /
UI×100 of vehicle-administered control group The results are shown in Table 3.

[Table] Example 1 5.7 g of furfuryl mercaptan is dissolved in 150 ml of 1N aqueous sodium hydroxide solution. A solution of 6 g of 3-chloropropionic acid in 50 ml of methanol is added dropwise to this. After stirring at room temperature for 3 hours, leave to stand for 3 days. Acidify with concentrated hydrochloric acid and extract with chloroform. Further, back-extract with saturated sodium bicarbonate solution. The aqueous layer is acidified with concentrated hydrochloric acid, extracted again with chloroform, dried over magnesium sulfate, and the chloroform is distilled off to obtain 7.2 g of 3-(2-furyl)methylthio-propionic acid as a brown liquid. NMR (90MHz, _CDCl3 ): δ 2.40-2.90 (4H,
m, -S- (CH ₂ ) ₂ -), 3.72 (2H, s, -CH ₂ -
S-), 6.10-7.40 (3H, m,

[Formula]), 10.43 (1H, br.s, -COOH) Elemental analysis value: C ₈ H ₁₀ O ₃ S Calculated value (%): C, 51.60; H, 5.41 Analysis value (%): C, 51.62 ; H, 5.42 Example 2 5.4 g of 3-mercaptopropionic acid is dissolved in 150 ml of 1N aqueous sodium hydroxide solution. A solution of 8.5 g of furfuryl chloride in 50 ml of methanol is added dropwise to this. After stirring at room temperature for 3 hours, leave to stand for 3 days. Acidify with concentrated hydrochloric acid and extract with chloroform. Further, back-extract with saturated sodium bicarbonate solution. The aqueous layer was acidified with concentrated hydrochloric acid, extracted again with chloroform, dried over magnesium sulfate, and the chloroform was distilled off.
6.9 g of 3-(2-furyl)methylthio-propionic acid are obtained as a brown liquid. NMR (90MHz, _CDCl3 ): δ 2.40-2.90 (4H,
m), 3.72 (2H, s), 6.10-7.40 (3H, m), 10.43
(1H, br.s) Elemental analysis value: C ₈ H ₁₀ O ₃ S Calculated value (%): C, 51.60; H, 5.41 Analysis value (%): C, 51.78; H, 5.50 Examples 3 to 6 The following compounds are obtained in the same manner as in Examples 1 and 2. (3) N-ethyl-N-cyclohexyl-3-(2
-furyl) methylthio-propionamide, pale yellow liquid, n ¹⁸ _D = 1.5329 (4) N-ethyl-N-cyclohexyl-3-[5
-(N,N-dimethylaminomethyl)-2-furyl]methylthio-propionamide, brown liquid, n ¹⁸ _D = 1.5263 (5) N,N-diethyl-3-(2-furyl)methylthio-propionamide, light yellow liquid, n ²⁶ _D
=1.5199 (6) N,N-diethyl-3-[5-(N,N-dimethylaminomethyl)-2-furyl]methylthio-propionamide, brown liquid, n ²⁶ _D =
1.5160 Example 7 3-(2-furyl)methylthio-propionic acid
Dissolve 3.7 g in 50 ml of tetrahydrofuran and add 2.2 g of triethylamine. While cooling with ice and stirring, 3 g of isobutyl chloroformate is added dropwise, and the mixture is stirred at room temperature for 30 minutes. 3 g of N-ethylcyclohexylamine was added dropwise to the mixture while stirring at room temperature, and the mixture was further stirred for 3 hours. After evaporating the solvent, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off, and the residue was subjected to column chromatography (Merck, Kieselgel).
60). n-hexane-ether (4:
1) eluted with pale yellow liquid N-ethyl-N-cyclohexyl-3-(2-furyl)methylthio-
3.7 g of propionamide are obtained. n ¹⁸ _D = 1.5329 Elemental analysis value: C ₁₆ H ₂₇ NO ₂ S Calculated value (%): C, 64.61; H, 9.15; N, 4.71 Analysis value (%): C, 64.60; H, 9.14; N, 4.70 Example 8 3-(2-furyl)methylthio-propionic acid (45 mmol) obtained in Example 1 was dissolved in 50 ml of tetrahydrofuran, DBU (50 mmol) was added,
Isobutyl chloroformate (50 mmol) is added dropwise under ice-cooling and stirring, and the mixture is stirred at room temperature for 30 minutes. Ethylamine (54 mmol) was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform, washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the chloroform, it was isolated by column chromatography (Wako Gel C-200, eluent: chloroform) to obtain pale yellow liquid N-ethyl-3-(2-furyl)methylthio-propionamide (yield: 40 %). n ²⁹ _D = 1.5238 Elemental analysis value: C ₁₀ H ₁₅ NO ₂ Calculated value (%): C, 56.31; H, 7.09; N, 6.57 Analysis value (%): C, 56.30; H, 7.19; N, 6.58 Examples 9 to 11 The following compounds are obtained in the same manner as in Example 8. (9) N-ethyl-N-cyclohexyl-3-[5
-(N,N-dimethylaminomethyl)-2-furyl]methylthio-propionamide, brown liquid, n ¹⁸ _D = 1.5263 (10) N,N-diethyl-3-(2-furyl)methylthio-propionamide, light yellow liquid, n ²⁶ _D
=1.5199 (11) N,N-diethyl-3-[5-(N,N-dimethylaminomethyl)-2-furyl]methylthio-propionamide, brown liquid, n ²⁶ _D =
1.5160 Example 12 3-(2-furyl)methylthio-propionic acid
Add 1 ml of thionyl chloride to 0.9 g and reflux for 1 hour. Thionyl chloride is distilled off, and benzene is added to the residue and evaporated under reduced pressure to completely remove thionyl chloride. The residue was diluted with N,N-diethylamine.
Add dropwise to a solution of 0.8 g in 10 ml of benzene while cooling with ice and stirring. Stir for 1 hour under ice cooling. The reaction solution is diluted with benzene, washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (Merck Kieselgel 60). Elution with chloroform yields 0.5 g of N,N-diethyl-3-(2-furyl)methylthio-propionamide as a pale yellow liquid. n ²⁶ _D = 1.5199 Elemental analysis value: C ₁₂ H ₁₉ NO ₂ Calculated value (%): C, 59.72; H, 7.94; N, 5.80 Analysis value (%): C, 59.72; H, 7.95; N, 5.82 Example 13 The following compound is obtained in the same manner as in Example 12. N-ethyl-N-cyclohexyl-3-(2-
Furyl) methylthio-propionamide, pale yellow liquid, n ¹⁸ _D = 1.5329 Example 14 N-ethyl-N-cyclohexyl-3-(2-
(furyl) methylthio-propionamide (2.9 g) is dissolved in 4 ml of acetic acid. Add 1.5 ml of 40% dimethylamine aqueous solution and 35% formalin to this and heat on a water bath for 1 hour. After cooling, sodium hydroxide 2.5
Pour into 10 ml of water solution and extract with chloroform. The chloroform aqueous solution is washed with saturated saline and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck, Kieselgel 60). Elute with chloroform:methanol (50:1) to obtain N-ethyl-N-cyclohexyl-3-[5-(N,N-
1.1 g of dimethylaminomethyl)-2-furyl]methylthio-propionamide are obtained. brown liquid,
n ¹⁸ _D =1.5263 Example 15 The following compound is obtained in the same manner as in Example 14. N,N-diethyl-3-[5-(N,N-dimethylaminomethyl)-2-furyl]methylthio-
Propionamide, brown liquid, n ²⁶ _D = 1.5160 Example 16 5 g of β-mercaptopropionic acid are dissolved in 150 ml of 1N aqueous sodium hydroxide solution. To this was added dropwise a solution of 7.4 g of 2-methyl-4-chloromethylthiazole in 50 ml of acetone while stirring on ice. Stir for 2 hours under ice cooling. Acetone is distilled off, the residue is adjusted to pH 3-4 with concentrated hydrochloric acid, and extracted with chloroform. The chloroform solution was dried over magnesium sulfate and the chloroform was distilled off to obtain 10.5 g of 3-(2-methylthiazol-4-yl)methylthio-propionic acid as a colorless liquid. NMR (90MHz, _CDCl3 ): δ2.50~3.00 (4H,
m), 2.69 (3H, s), 3.84 (2H, s), 6.99 (1H,
s), 9.90 (1H, br.s) Elemental analysis value: C ₈ H ₁₁ NO ₂ S ₂ Calculated value (%): C, 44.22; H, 5.10; N, 6.45 Analysis value (%): C, 44.20 ; H, 5.08; N, 6.44 Example 17 2-Methyl-4-mercaptomethylthiazole
Dissolve 6.8 g in 150 ml of 1N aqueous sodium hydroxide solution. To this was added dropwise a solution of 5.4 g of 3-chloropropionic acid in 50 ml of acetone while stirring on ice. Stir for 2 hours under ice cooling. Acetone is distilled off, the residue is adjusted to pH 3-4 with concentrated hydrochloric acid, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and the chloroform is distilled off to obtain 10 g of 3-(2-methylthiazol-4-yl)methylthio-propionic acid as a colorless liquid. NMR (90MHz, _CDCl3 ): δ2.50~3.00 (4H,
m), 2.69 (3H, s), 3.84 (2H, s), 6.99 (1H,
s), 9.90 (1H, br.s) Elemental analysis value: C ₈ H ₁₁ NO ₂ S ₂ Calculated value (%): C, 44.22; H, 5.60; N, 6.45 Analysis value (%): C, 44.21 ; H, 5.59; N, 6.43 Examples 18-24 The following compounds are obtained in the same manner as in Examples 16 and 17. (18) 3-(2-phenylthiazol-4-yl)methylthio-propionic acid, colorless liquid,
NMR (60MHz, _CDCl3 ): δ2.60~3.00 (4H,
m), 3.90 (2H, s), 7.05 (1H, s), 7.20~
7.50 (3H, m), 7.70-8.00 (2H, m), 10.33
(1H, br.s) (19) N-ethyl-N-cyclohexyl-3-
(2-Methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ¹⁸ _D =
1.5423 (20) N,N-diethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ¹⁸ _D = 1.5323 (21) N-ethyl-N-cyclohexyl-3-
(2-Phenylthiazol-4-yl)methylthio-propionamide, pale yellow liquid, n ²⁷ _D =
1.5919 (22) N-ethyl-N-cyclohexyl-3-
(2-Aminothiazol-4-yl)methylthio-propionamide, pale yellow liquid, n ²⁷ _D =
1.5667 (23) N,N-dimethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D = 1.5377 (24) N-ethyl-N-cycloheptyl-3-
(2-Methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D =
1.5425 Example 25 2.2 g of 3-(2-methylthiazol-4-yl)thio-propionic acid was dissolved in 50 ml of tetrahydrofuran.
and add 1.1 g of triethylamine. While cooling with ice and stirring, add 1.5 g of isobutyl chloroformate dropwise.
Stir for 30 minutes at room temperature. While stirring at room temperature, 1.5 g of N-ethylcyclohexylamine is added dropwise, and the mixture is further stirred for 5 hours. After distilling off tetrahydrofuran, water is added to the residue and extracted with chloroform.
The chloroform solution is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck Kieselgel 60). Elution with chloroform yields 2.3 g of N-ethyl-N-cyclohexyl-3-(2-methylthiazol-4-yl)methylthio-propionamide as a colorless liquid. n ¹⁸ _D = 1.5423 Elemental analysis value: C ₁₀ H ₂₆ N ₂ Calculated value (%) as OS ₂ : C, 58.86; H, 8.03; N, 8.58 Analysis value (%): C, 58.85; H, 8.02; N , 8.56 Example 26 12.6 g of 3-(2-phenylthiazol-4-yl)methylthio-propionic acid obtained in Example 18 was dissolved in 50 ml of tetrahydrofuran, 7.6 g of DBU was added, and chloroformic acid was dissolved under stirring under ice cooling. Isobutyl 6.8g
dropwise and stir at room temperature for 30 minutes. 5.3g of cyclohexylamine was added dropwise to this, and
Stir for an hour. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform, washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After chloroform was distilled off, N-cyclohexyl-3-
5.9 g of (2-phenylthiazol-4-yl)methylthio-propionamide are obtained. Elemental analysis value: C ₁₉ H ₂₄ N ₂ OS ₂ Calculated value (%): C, 63.50; H, 6.71; N, 7.77 Analysis value (%): C, 63.45; H, 6.68; N, 7.76 Example 27 ~31 The following compound is obtained in the same manner as in Example 25. (27) N,N-diethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ¹⁸ _D = 1.5323 (28) N-ethyl-N-cyclohexyl-3-
(2-Phenylthiazol-4-yl)methylthio-propionamide, pale yellow liquid, n ²⁷ _D =
1.5919 (29) N-ethyl-N-cyclohexyl-3-
(2-Aminothiazol-4-yl)methylthio-propionamide, pale yellow liquid, n ²⁷ _D =
1.5667 (30) N,N-dimethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D = 1.5377 (31) N-ethyl-N-cycloheptyl-3-
(2-Methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D =
1.5425 Example 32 2.2 g of 3-(2-methylthiazol-4-yl)methylthio-propionic acid and 5 ml of thionyl chloride
was added and refluxed for 1 hour. After evaporating excess thionyl chloride under reduced pressure, anhydrous benzene is added to the residue, and a small amount of thionyl chloride is removed by azeotroping. The residue is dissolved in 50 ml of anhydrous pyridine. To this was added dropwise 1.5 g of N,N-diethylamine while stirring on ice.
Stir for 1 hour at room temperature. Add chloroform to the reaction mixture, wash successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dry over sodium sulfate. Chloroform was distilled off, and the residue was isolated by column chromatography (Merck, Kieselgel 60, eluent, chloroform) to obtain colorless liquid N,N-diethyl-
1.7 g of 3-(2-methylthiazol-4-yl)methylthio-propionamide are obtained. n ¹⁸ _D =
1.5323 Elemental analysis value: C ₁₂ H ₂₀ N ₂ OS ₂ Calculated value (%): C, 52.91; H, 7.40; N, 10.28 Analysis value (%): C, 52.93; H, 7.42; N, 10.27 Example 33-36 The following compounds are obtained in the same manner as in Example 32. (33) N-ethyl-N-cyclohexyl-3-
(2-Methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ¹⁸ _D =
1.5423 (34) N-ethyl-N-cyclohexyl-3-
(2-Phenylthiazol-4-yl)methylthio-propionamide, pale yellow liquid, n ²⁷ _D =
1.5919 (35) N,N-dimethyl-3-(2-methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D = 1.5377 (36) N-ethyl-N-cycloheptyl-3-
(2-Methylthiazol-4-yl)methylthio-propionamide, colorless liquid, n ²⁶ _D =
1.5425 Example 37 5.3 g of 3-mercaptopropionic acid is dissolved in 150 ml of 1N aqueous sodium hydroxide solution. Add 6.5 liters of 2-thienylmethyl chloride to this while stirring on ice.
50 ml of acetone solution was added dropwise to the mixture, and the mixture was stirred for 2 hours under ice-cooling. After distilling off the acetone under reduced pressure, the mixture is extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform solution is washed with saturated saline and dried over magnesium sulfate. After distilling off the chloroform, a pale brown liquid of 3-(2-thienyl) was obtained.
6 g of methylthio-propionic acid are obtained. Elemental analysis value: C ₈ H ₁₀ O ₂ S ₂ Calculated value (%): C, 47.50; H, 4.98 Analysis value (%): C, 47.45; H, 4.98 Example 38 The following was carried out in the same manner as Example 37. The compound is obtained. N-ethyl-N-cyclohexyl-3-(2-
thienyl)methylthio-propionamide, pale yellow liquid, n ²⁵ _D = 1.5534 Example 39 2 g of 3-(2-thienyl)methylthio-propionic acid are dissolved in 50 ml of tetrahydrofuran and 1.1 g of triethylamine are added. While cooling with ice and stirring, 1.5 g of isobutyl chloroformate is added dropwise, and the mixture is stirred at room temperature for 30 minutes. To this was added dropwise 1.5 g of N-ethylcyclohexylamine while stirring at room temperature, and the mixture was stirred at room temperature for 3 hours. After distilling off tetrahydrofuran, water is added to the residue, and the mixture is extracted with chloroform. Wash the chloroform solution with saturated saline and dry with sodium sulfate. After chloroform was distilled off, the residue was purified by column chromatography (Wako Gel C-200, eluent, chloroform), and a pale yellow liquid N-
1.5 g of ethyl-N-cyclohexyl-3-(2-thienyl)methylthio-propionamide are obtained.
n ²⁵ _D = 1.5534 Elemental analysis value: C ₁₆ H _{27 NOS} Calculated value (%): C, 61.30; H, 3.22; N, 4.47 Analysis value (%): C, 61.25; H, 3.20; N, 4.49 Example 40 2 g of 3-(2-thienylmethylthio)propionic acid obtained in Example 37 was added to 50 ml of tetrahydrofuran.
Add 2.5 g of DBU, add 2.3 g of isobutyl chloroformate dropwise under stirring under ice-cooling, and stir at room temperature for 30 minutes. Add 0.6g of ethylamine dropwise to this,
The mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform, washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After chloroform distillation, column chromatography (Wakou Gel C-
200, eluent, chloroform) and isolated with N-
1.0 g of ethyl-3-(2-thienylmethylthio)propionamide is obtained. Elemental analysis value: C ₁₀ H ₁₅ NS ₂ O Calculated value (%): C, 52.37; H, 6.59; N, 6.11 Analysis value (%): C, 52.40; H, 6.61; N, 6.05 Example 41 3 Add 5 ml of thionyl chloride to 2 g of -(2-thienylmethylthio)propionic acid and reflux for 1 hour. Excess thionyl chloride is distilled off under reduced pressure. Dissolve the residue in 50 ml of dry pyridine. Add N-ethylcyclohexylamine to this while stirring on ice.
Add 1.5 g dropwise and stir at room temperature for 2 hours. After diluting with chloroform, it is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. Chloroform was distilled off and the residue was subjected to column chromatography (Wako Gel C-200, eluent chloroform)
to give N-ethyl-N-cyclohexyl-3-(2-thienyl)methylthio- as a pale yellow liquid.
1.5 g of propionamide is obtained. n ²⁵ _D = 1.5534 Elemental analysis value: C ₁₆ H _{27 NOS} Calculated value (%): C, 61.30; H, 3.22; N, 4.47 Analysis value (%): C, 61.35; H, 3.20; N, 4.46 Example 42 S-(2-carboxyethyl)isothiourea
Dissolve 8.1 g in 150 ml of 1N aqueous sodium hydroxide solution. A solution of 8.5 g of furfuryl chloride in 50 ml of methanol is added dropwise to this. After stirring at room temperature for 3 hours, leave to stand for 3 days. Acidify with concentrated hydrochloric acid and extract with chloroform. Further, back-extract with saturated sodium bicarbonate solution. The aqueous layer is acidified with concentrated hydrochloric acid and extracted again with chloroform. After drying over magnesium sulfate, chloroform was distilled off to obtain 6.5 g of 3-(2-furyl)methylthio-propionic acid as a brown liquid. NMR (90MHz, _CDCl3 ): δ2.40~2.90 (4H,
m), 3.72 (2H, s), 6.10-7.40 (3H, m),
10.43 (1H, br.s) Elemental analysis value: C ₈ H ₁₀ O ₃ S Calculated value (%): C, 51.60; H, 5.41 Analysis value (%): C, 51.76; H, 5.52 Example 43~ 46 The following compound is obtained in the same manner as in Example 42. (43) N-ethyl-N-cyclohexyl-3-
(2-furyl)methylthio-propionamide,
Pale yellow liquid, n ¹⁸ _D = 1.5329 (44) N-ethyl-N-cyclohexyl-3-
[5-(N,N-dimethylaminomethyl)-2
-furyl] methylthio-propionamide, brown liquid, n ¹⁸ _D = 1.5263 (45) N,N-diethyl-3-(2-furyl)methylthio-propionamide, pale yellow liquid,
n ²⁶ _D =1.5199 (46) N,N-diethyl-3-[5-(N,N-
dimethylaminomethyl)-2-furyl]methylthio-propionamide, brown liquid, n ²⁶ _D =
1.5160 Formulation example 1 3-(2-furyl)methylthio-propionic acid
150g Avicel (trade name: manufactured by Asahi Kasei Corporation) 40g Cornstarch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g After mixing and polishing the compound of the present invention, Avicel, cornstarch and magnesium stearate, sugar coating
Compress the tablets with an R10mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets. Formulation example 2 N-ethyl-N-cyclohexyl-3-(2-
Methylthiazol-4-yl) Methylthio-propionamide 5g Polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml Dissolve the above parabens, sodium metabisulfite and sodium chloride in about half the amount of distilled water above at 80°C with stirring. do. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper to prepare an injection.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl group, an amino group, or a group [Formula], R ³ and R ⁴ each represent a lower alkyl group, R ² represents a group [Formula], R ⁵ and R ⁶ are a hydrogen atom, a lower alkyl group or a cycloalkyl group, A is a methine group or a nitrogen atom, B is an oxygen atom or a sulfur atom, D and E each represent a lower alkylene group] An anti-ulcer agent characterized by containing an acid amide derivative or a salt thereof as an active ingredient.