JPS6328066B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel alkanoic acid derivatives and salts thereof. The alkanoic acid derivative of the present invention is a new compound and has the general formula [In the formula, R ¹ is a hydrogen atom, a hydroxyl group, or a lower alkyl group, and R ² is a hydroxyl group, a lower alkoxy group, or a group

[Formula] is shown, and R ³ and R ⁴ each represent a hydrogen atom, a lower alkyl group, or a cycloalkyl group. Further, A represents a lower alkylene group, and Z represents -N= or -CH=. However, when Z represents -CH= and ^R2 represents a hydroxyl group or a lower alkoxy group, A represents a trimethylene group. The compounds of the present invention have anti-ulcer and anti-inflammatory effects and are useful as anti-ulcer agents and anti-inflammatory agents. In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl,
Examples include butyl, tert-butyl, pentyl, and hexyl groups. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Furthermore, examples of lower alkylene groups include methylene, ethylene, trimethylene, tetramethylene,
Examples include pentamethylene, hexamethylene, methylethylene, 2-methyltrimethylene, 2,2-dimethyl-trimethylene, and 1-methyltrimethylene groups. Representative compounds of the present invention are listed below. 4-(2-pyridyl)thio-butyric acid 4-(4-pyridyl)thio-butyric acid 4-(3-pyridyl)thio-butyric acid 2-(2-pyridyl)thio-acetamide N-ethyl-2-(2-pyridyl )thio-acetamide N-ethyl-N-cyclohexyl-2-(2-
pyridyl)thio-acetamide N,N-diethyl-3-(2-pyridyl)thio-propionamide N-methyl-4-(2-pyridyl)thio-butyramide 4-(2-pyridyl)thio-butyric acid methyl ester N, N-dimethyl-4-(2-pyridyl)thio-butyramide N,N-diethyl-4-(2-pyridyl)thio-butyramide N-ethyl-N-hexyl-4-(2-pyridyl)thio-butyramide N- Cyclohexyl-4-(2-pyridyl)thio-butyramide N-methyl-N-cyclopentyl-4-(2-
pyridyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(2-
pyridyl)thio-butyramide N-ethyl-N-cyclooctyl-4-(2-
pyridyl)thio-butyramide N-ethyl-N-cyclohexyl-6-(2-
pyridyl)thio-hexanamide N,N-diethyl-3,3-dimethyl-4-
(2-pyridyl)thio-butyramide 4-(2-pyrimidyl)thio-butyric acid 2-(2-pyrimidyl)thio-acetic acid 4-(2-pyrimidyl)thio-butyric acid propyl ester 4-(2-pyrimidyl)thio-butyric acid Methyl ester N-ethyl-2-(2-pyrimidyl)thio-acetamide N,N-dicyclopentyl-2-(2-pyrimidyl)thio-acetamide N,N-diethyl-3-(2-pyrimidyl)thio-propionamide N-Methyl-4-(2-pyrimidyl)thio-butyramide N,N-dimethyl-4-(2-pyrimidyl)thio-butyramide N,N-diethyl-4-(2-pyrimidyl)thio-butyramide N-ethyl- N-pentyl-4-(2-pyrimidyl)thio-butyramide N-cyclohexyl-4-(2-pyrimidyl)
Thio-butyramide N-ethyl-N-cyclohexyl-4-(2-
pyrimidyl)thio-butyramide N,N-dicyclohexyl-4-(2-pyrimidyl)thio-butyramide N-methyl-N-cycloheptyl-4-(2-
pyrimidyl)thio-butyramide N,N-diethyl-6-(2-pyrimidyl)thio-hexanamide N-ethyl-N-cyclohexyl-2-methyl-4-(2-pyrimidyl)thio-butyramide N,N-diethyl- 4-(3-hydroxy-2
-pyridyl)thio-butyramide N,N-diethyl-4-(4-hydroxy-2
-pyridyl)thio-butyramide N,N-diethyl-4-(4-methyl-2-pyridyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
Ethyl-2-pyridyl)thio-butyramide N,N-dicyclohexyl-4-(6-methyl-2-pyridyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
hydroxy-2-pyrimidyl)thio-butyramide N,N-diethyl-4-(4-hydroxy-2
-pyrimidyl)thio-butyramide N,N-diethyl-4-(4-methyl-2-pyrimidyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
Methyl-2-pyrimidyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
Ethyl-2-pyrimidyl)thio-butyramide N,N-diethyl-4-(3-pyridyl)thio-butyramide N,N-diethyl-4-(2-hydroxy-4
-pyridyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(2-
Methyl-3-pyridyl)thio-butyramide N,N-diethyl-4-(4-pyrimidyl)thio-butyramide N,N-diethyl-4-(2-hydroxy-4
-pyrimidyl)thio-butyramide N,N-diethyl-4-(2-methyl-4-pyrimidyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(2-
Ethyl-4-pyrimidyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
Hydroxy-5-pyrimidyl)thio-butyramide N-ethyl-N-cyclohexyl-4-(4-
Methyl-5-pyrimidyl)thio-butyramide The compounds of the invention can be prepared in a variety of ways, ^e.g.

Compound (1a) represented by the formula can be produced by the method shown in the reaction formula below. Reaction formula- [In the formula, R ¹ , R ³ , R ⁴ , A and Z are the same as above] The method shown in the above reaction formula - is a method in which a carboxylic acid represented by general formula (2) and a carboxylic acid represented by general formula (3) are used. This is a method in which a known amine is reacted with a conventional amide bond forming reaction. In the above method, a compound whose carboxy group is activated may be used instead of the compound of general formula (2), and a compound whose amino group is activated may be used instead of the compound of general formula (3). Compounds may also be used. As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. For example, (a) mixed acid anhydride method, i.e., a method in which carboxylic acid (2) is reacted with a halocarboxylic acid alkyl ester to form a mixed anhydride, and this is reacted with amine (3), (b) active ester method, i.e. Carboxylic acid(2)
is used as an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and the amine (3) is reacted with the active ester. A method in which amine (3) is dehydrated and condensed with acid (2) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, and (ii) a carboxylic acid halide method, that is, a halide compound of carboxylic acid (2). (e) Another method is to convert carboxylic acid (2) into carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then react with amine (3).
Examples include a method in which an ester of a carboxylic acid (2) and, for example, a lower alcohol is reacted with an amine (3) under high pressure and high temperature. Among these, the mixed acid anhydride method and the carboxylic acid halide method are preferred. Examples of halocarboxylic acid alkyl esters used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate,
Examples include ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. Mixed acid anhydrides are obtained by the usual Schotten-Baumann reaction,
The compound of the present invention is produced by reacting this with an amine (3), usually without isolation. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used,
For example, triethylamine, trimethylamine,
Pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,5-diazabicyclo[5.4.0]
Examples include organic bases such as undecene-5 (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is carried out at about -20 to 100°C, preferably 0 to 50°C, and the reaction time is 5 minutes to 100°C.
It will take about 10 hours. The reaction between the obtained mixed acid anhydride and amine (3) is carried out at about -20 to 150°C, preferably 10 to 50°C, and the reaction time is 5 minutes to 50°C.
It is carried out under conditions of about 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 as the solvent, and specifically, halogenated hydrocarbons such as methylene chloride, chloroform, dichlorothane, etc.
Aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, and dimethoxydiethane; esters such as methyl acetate and ethyl acetate; Examples include protic polar solvents. Carboxylic acid in this method
(2), the proportion of halocarboxylic acid alkyl ester and amine (3) used is usually at least equimolar, preferably 1 to 1.5 times the molar amount of halocarboxylic acid alkyl ester and amine (3) to carboxylic acid (2). do. In the carboxylic acid halide method, carboxylic acid (2) is reacted with a halogenating agent to form a halide compound of carboxylic acid (2), and then the obtained carboxylic acid halide is isolated and purified, or without isolation and purification. This is carried out by reacting an amine (3). The reaction between the carboxylic acid (2) and the halogenating agent is 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 normal halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride,
Phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride,
Examples include phosphorus pentabromide. The ratio of the carboxylic acid (2) 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 with respect to 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 (3) is carried out in the presence of a dehydrohalogenating agent. As this dehydrohalogenating agent, a basic compound is usually used. A wide range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alkalis such as sodium and potassium. metals, alcoholates such as sodium methylate and 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-5 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Further, the amine (3) 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 proportions of carboxylic acid halide and amine (3) to be used are not particularly limited, 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. The compound of the present invention can also be produced by the method shown in the reaction formula below. Reaction formula- [In the formula, one of X ¹ and X ² is a halogen atom, and the other is a mercapto group or a group

[Formula] and R ¹ , R ² , Z and A are the same as above] In the reaction formula -, compounds (4) and (5) are known compounds, and this compound (4) and an alkanecarboxylic acid derivative ( The condensation reaction with 5) is usually carried out according to the above reaction formula -
It is carried out in the presence of the same basic compound used in the reaction shown in . 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; diethyl ether,
Ethers such as tetrahydrofuran, dioxane, monoglyme and diglyme, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and 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 (5) to compound (4) 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. Further, the reaction temperature is not particularly limited, but it is usually carried out at about -30°C to 200°C, preferably 0 to 160°C. The reaction time is usually about 1 to 30 hours. Furthermore, among the compounds of the present invention, the compound (1b) in which R ² represents a lower alkoxy group and the compound (2) in which R ² represents a hydroxyl group can be prepared by hydrolysis reaction or esterification of each compound as shown in the reaction formula below. They can be mutually converted by subjecting them to a chemical reaction. Reaction formula- [In the formula, R ⁵ represents a lower alkyl group, and R ¹ , Z and A are the same as above] The hydrolysis reaction of compound (1b) is carried out by a conventional method, such as sodium hydroxide, potassium hydroxide, hydroxide. Basic compounds such as barium, sulfuric acid,
It is carried out in the presence of mineral acids such as hydrochloric acid and nitric acid. This hydrolysis reaction generally proceeds advantageously in a solvent. As the solvent used at this time, any solvent that does not participate in the reaction can be used, and for example, lower alcohols such as water, methanol, ethanol, and isopropanol are preferred. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but is usually room temperature to about 150°C, preferably 50 to 150°C.
It is best to carry out the reaction at 110°C. The reaction is generally
It takes about 30 minutes to 10 hours to complete. Esterification of compound (2) is achieved by reacting it with a lower alcohol by a conventional method, and is usually carried out in the presence of a catalyst. As the catalyst used in this case, a wide variety of catalysts that are used in ordinary esterification reactions can be used. Typical examples include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, and p-tosylic acid. , organic acids such as benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trifluoromethanesulfonic anhydride,
Examples include thionyl chloride and acetone dimethyl acetal. Additionally, cation exchange resins can also be used as catalysts in the present invention. The amount of these catalysts used may be within a commonly used range and is not particularly limited. This reaction proceeds either without a solvent or in a solvent. As the solvent, those used in ordinary esterification reactions can be effectively used, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc. Examples include ethers such as halogenated hydrocarbons, diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. The ratio of compound (2) and lower alcohol to be used may be appropriately selected within a wide range, but in order to improve the production rate of the target product of the present invention, the former is usually used in the absence of a solvent. The latter is preferably used in large excess, and when a solvent is used, the latter is preferably used in an amount of equimolar to 5 times the former (especially preferably equimolar to 2 times). In addition, in this esterification reaction, the production rate can be further increased by removing the produced water from the reaction system using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, or phosphorus pentoxide. It is possible. The reaction temperature may be selected appropriately and is not particularly limited, but it is usually carried out in a range of about -20 to 200°C.
It is particularly preferable to carry out the reaction at a temperature of about 0 to 150°C.
Also, the reaction time depends on the type of raw materials and reaction conditions, but
Generally about 10 minutes to 20 hours. Further, in the esterification reaction of the present invention, a carboxy-activated derivative of compound (2), such as a carboxylic acid halide, a carboxylic acid anhydride, etc., can also be used. When a carboxylic acid halide is used, the reaction conditions of the carboxylic acid halide method shown in the above-mentioned reaction formula can be employed. Further, when using a carboxylic acid anhydride, the carboxylic acid anhydride may be converted to the carboxylic acid anhydride using a common dehydrating agent, and then a lower alcohol may be reacted with the carboxylic acid anhydride using a conventional method. 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, esters of higher alcohols, gelatin,
Examples include 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 commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. 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 The pharmacological activity of the compound represented by the general formula (1) was tested according to the pylorus ligation method of Shei Rat, which is the most common test method for testing gastric juice secretion suppressive action. 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 mg/Kg) was intraduodenally administered 30 minutes before pylorus ligation, and gastric fluid 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-4-(2
-pyridyl)thio-butyramide 2 N-ethyl-N-cyclohexyl-4-(4
-methyl-2-pyrimidyl)thio-butyramide

[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 the rat was restrained.
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 vehicle-administered control group × 100 (Test compound No.) 1 4-(4-hydroxy-2-pyrimidyl)thio-butyric acid methyl ester 2 4-(2-pyridyl)thio-butyric acid methyl ester 3 4-(2-pyridyl)thio-butyric acid hydrochloride 4 N-ethyl-N-cyclohexyl-4-(2
-pyridyl)thio-butyramide 5 N-ethyl-N-cyclohexyl-4-(4
-pyridyl)thio-butyramide 6 N,N-diethyl-4-(2-pyridyl)thio-butyramide 7 N-ethyl-4-(2-pyridyl)thio-butyramide 8 N-ethyl-N-cyclohexyl-4-( 4
-Methyl-2-pyrimidyl)thio-butyramide 9 N,N-diethyl-4-(4-hydroxy-
2-pyrimidyl)thio-butyramide 10 N-ethyl-N-cyclohexyl-4-(4
-Methyl-2-pyrimidyl)thio-butyramide 11 N,N-diethyl-4-(4-hydroxy-
2-pyrimidyl)thio-butyramide

[Table] Next, the compound of the present invention and its production method will be specifically explained with reference to Examples. Example 1 2-thiouracil 45g, methanol 500ml, water
200ml, mix and dissolve 25.4g of potassium hydroxide, 30
Heat to reflux for minutes. After cooling, 70 g of 4-bromobutyric acid methyl ester was added and the mixture was refluxed for 5 hours. After distilling off methanol, water was added, the pH was adjusted to about 7 with concentrated hydrochloric acid, the precipitated crystals were dried, and colorless plate-like crystals of 4-(4
83 g of -hydroxy-2-pyrimidyl)thio-butyric acid methyl ester are obtained. Melting point: 97.5-99.5℃ (recrystallized from hexane-ethyl acetate) Elemental analysis value: C ₉ H ₁₂ N ₂ O ₃ S Calculated value (%): C, 47.36; H, 5.30; N, 12.27 Analysis value (%) :C, 47.49;H, 5.41;N, 12.31 Example 2 The following compound is obtained in the same manner as in Example 1 above. 4-(2-pyridyl)thio-butyric acid methyl ester, pale yellow liquid, n ²⁰ _D = 1.5395 Example 3 10 g of 4-(2-pyridyl)thio-butyric acid methyl ester obtained in Example 2 was added to 150 ml of 20% aqueous hydrochloric acid solution. and stir for 3 hours at a bath temperature of 90°C. , under reduced pressure,
The water is distilled off, a small amount of water is added, the pH is adjusted to about 4 with sodium hydroxide, and the mixture is cooled. The precipitated crystals were collected, washed with cold water, and then recrystallized from ethanol to obtain colorless prismatic crystals of 4-(2-pyridyl)thio-
8 g of butyric acid salt are obtained. Melting point: 142.5-144.5℃ Elemental analysis value: C ₉ H ₁₂ NO ₂ SCl Calculated value (%): C, 46.25; H, 5.18; N, 5.99 Analysis value (%): C, 45.63; H, 5.16; N, 5.94 Example 4 2 g of 4-(2-pyridyl)thio-butyric acid hydrochloride are dissolved in 50 ml of N,N-dimethylformamide and 2.2 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. 1.5 g of N-ethylcyclohexylamine was added dropwise to this while stirring at room temperature, and the mixture was further stirred at room temperature for 3 hours. After distilling off N,N-dimethylformamide, water was added to the residue, and the mixture was extracted with chloroform. The chloroform solution is washed with dilute hydrochloric acid, saturated 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). Hexane-ether (4:1)
2 g of N-ethyl-N-cyclohexyl-4-(2-pyridyl)thio-butyramide is obtained as a pale yellow liquid. n ²⁰ _D = 1.5567 Elemental analysis value: C ₁₇ H ₂₆ N ₂ Calculated value (%) as OS: C, 66.63; H, 8.55; N, 9.14 Analysis value (%): C, 66.71; H, 8.59; N, 9.21 Example 5 1 mg of thionyl chloride is added to 1 g of 4-(4-pyridyl)thio-butyric acid and refluxed for 1 hour. Excess thionyl chloride is distilled off under reduced pressure to obtain crude acid chloride. Separately, N-ethylcyclohexylamine
Dissolve 0.8 g in 50 ml of acetone and 10 ml of water, and add 1.4 g of potassium carbonate. The above acid chloride is added dropwise to this while stirring while cooling on ice. Stir for 2 hours under ice cooling. After distilling off the acetone, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate.
Chloroform is distilled off, and the residue is purified by column chromatography (Wakogel C-200). Elute with chloroform to obtain pale yellow liquid N-ethyl-N.
-cyclohexyl-4-(4-pyridyl)thio-
0.7 g of butyramide is obtained. n ^28.5 _D = 1.5494 Elemental analysis value: C ₁₇ H ₂₆ N ₂ Calculated value (%) as OS: C, 66.63; H, 8.55; N, 9.14 Analysis value (%): C, 66.71; H, 8.63; N, 9.21 Examples 6 and 7 Analogously to Example 5, the following compounds are obtained. (6) N,N-diethyl-4-(2-pyridyl)thio-butyramide, colorless liquid, n ²⁰ _D = 1.5521 (7) N-ethyl-4-(2-pyridyl)thio-butyramide, pale yellow liquid, n ²⁸ _D = 1.5570 Example 8 2.1 g of 4-(4-methyl-2-pyrimidyl)thio-butyric acid was dissolved in 30 ml of tetrahydrofuran,
Add 1.3g of DBU. While cooling with ice and stirring, 1.2 g of isobutyl chloroformate is added dropwise, and the mixture is stirred at room temperature for 30 minutes.
1.2 g of N-ethylcyclohexylamine was added dropwise to this, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent,
The residue is extracted with chloroform. The chloroform solution is washed successively with water, 5% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. After distilling off the chloroform, the residue is purified by column chromatography (Wakogel C-200). N-ethyl-N-cyclohexyl-4-(4-methyl-2-pyrimidyl) is eluted with chloroform to give a colorless liquid.
1.5 g of thio-butyramide are obtained. n ¹⁹ _D = 1.5470 Elemental analysis value: C ₁₇ H ₂₇ N ₃ Calculated value (%) as OS: C, 63.51; H, 8.47; N, 13.07 Analysis value (%): C, 63.67; H, 8.53; N, 13.15 Example 9 The following compound is obtained in the same manner as in Example 8. N,N-diethyl-4-(4-hydroxy-2
-pyrimidyl)thio-butyramide, colorless liquid,
NMR (90MHz, _CDCl3 ) δ1.00-1.30 (6H, m),
1.90~2.30 (2H, m), 2.30~2.60 (2H, m), 3.10
~3.50 (6H, m), 6.17 (1H, d, J=6Hz),
7.78 (1H, d, J=6Hz) Example 10 1.1 g of 2-mercaptopyridine and 2.7 g of N,N-diethyl-4-brombutyramide are dissolved in 50 ml of methanol. In this, potassium hydroxide
Add 0.8 g and reflux for 3 hours. Methanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck, Kieselgel 60). Elution with hexane-ether (4:1) gave a colorless liquid N,N-diethyl-4-(2-pyridyl)thio-
1.7 g of butyramide is obtained. n ²⁰ _D = 1.5521 Elemental analysis value: C ₁₃ H ₂₀ N ₂ Calculated value (%) as OS: C, 61.87; H, 7.99; N, 11.10 Analysis value (%): C, 61.99; H, 8.06; N, 11.21 Examples 11 to 15 The following compounds are obtained in the same manner as in Example 10 above. (11) N-ethyl-N-cyclohexyl-4-(2
-pyridyl)thio-butyramide, pale yellow liquid, n ²⁰ _D = 1.5567 (12) N-ethyl-N-cyclohexyl-4-(4
-Methyl-2-pyrimidyl)thio-butyramide, colorless liquid, n ¹⁹ _D = 1.5470 (13) N-ethyl-N-cyclohexyl-4-
(4-Pyridyl)thio-butyramide, pale yellow liquid, n ^28.5 _D = 1.594 (14) N-ethyl-4-(2-pyridyl)thio-
Butyramide, pale yellow liquid, ^n28D = 1.5570 (15 ₎ N,N-diethyl-4-(4-hydroxy-2-pyrimidyl)thio-butyramide, colorless liquid, NMR (90MHz, _CDCl3 ) δ1.00-1.30
(6H, m), 1.90~2.30 (2H, m), 2.30~2.60
(2H, m), 3.10~3.50 (6H, m), 6.17 (1H,
d, J=6Hz), 7.78 (1H, d, J=6Hz) Formulation example 1 4-(4-hydroxy-2-pyrimidyl)thio-
Methyl butyrate 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, azevil, 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 4-(2-pyridyl)thio-butyric acid 150g Citric acid 1.0g Lactose 33.5g Dicalcium phosphate 70.0g Pluronik F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbowax 1500)
4.5g polyethylene glycol (Carbowax 6000)
45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol Appropriate amount The compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68, and sodium lauryl sulfate are mixed. The above mixture was sieved through a No. 60 screen, and polyvinylpyrrolidone, Carbowax 1500 and 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed. Pass through a No. 110 screen, place in a tray, and dry in an oven at 100℃ for 12 to 14 hours. Sieve the dry particles through a No. 16 screen, add dry sodium lauryl sulfate and dry magnesium stearate, mix,
Compress into desired shape using a tablet press. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth. Pigmented coatings are applied until the desired shade is obtained. After drying, the coated tablets are polished to a uniform gloss. Formulation example 3 N-ethyl-N-cyclohexyl-4-(2-pyridyl)thio-butyramide 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 hydroxyl group or a lower alkyl group, R ² represents a hydroxyl group, a lower alkoxy group or a group [Formula], and R ³ and R ⁴ each represent a hydrogen atom, a lower alkyl group or a cycloalkyl group. show. Furthermore, A is a lower alkylene group, Z is -N=,
Or indicates -CH=. However, when Z represents -CH= and ^R2 represents a hydroxyl group or a lower alkoxy group, A represents a trimethylene group.] Alkanoic acid derivatives and salts thereof.