JPH0125742B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel benzene derivatives and salts thereof. More specifically, the present invention relates to the general formula [In the formula, R ¹ is a phenyl group, a naphthyl group, or benzimidazolyl, 1,3,4-thiadiazolyl, imidazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, pyrimidinyl, pyridyl, benzoxazolyl A 5-membered or 6-membered unsaturated heterocyclic group selected from 1-3, thiazolyl, 4,5-dihydrothiazolyl, and 4,5-dihydrothiazolyl. It may have a substituent. A represents a trimethylene group] The present invention relates to a benzene derivative and a salt thereof. The benzene derivative of general formula (1) of the present invention is a new compound, has anti-ulcer and anti-inflammatory effects, and is useful as an anti-ulcer agent and an anti-inflammatory agent. In this specification, the lower alkyl group is
Examples include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups. Representative compounds of the present invention are listed below. 4-(1-naphthyl)thiobutyrophenone 4-(2-naphthyl)thiobutyrophenone 3-(1-naphthyl)thiopropiophenone 3-(2-naphthyl)thiopropiophenone 4-(benzimidazole- 2-yl)thiobutylphenone 3-(6-methylbenzimidazol-2-yl)thiopropiofenone 3-(benzimidazol-2-yl)thiopropiofenone 3-(1,3,4-thiadiazole- 2-il)
Thiopropiophenone 4-(5-amino-1,3,4-thiadiazol-2-yl)thiobutyrophenone 4-(5-methyl-1,3,4-thiadiazol-2-yl)thiobutyrophenone 4-(5-Hydroxy-1,3,4-thiadiazol-2-yl)thiobutylphenone 3-(5-amino-1,3,4-thiadiazol-2-yl)thiopropiophenone 3-(5 -Methyl-1,3,4-thiadiazol-2-yl)thiopropiophenone 3-(5-hydroxy-1,3,4-thiadiazol-2-yl)thiopropiophenone 4-(imidazol-2-yl) ) Thiobutylophenone 4-(1-methylimidazol-2-yl)thiobutylophenon 4-(1-methylimidazol-4-yl)thiobutylophenone 4-(1-methylimidazol-5-yl)thio Butylophenone 4-(1-ethylimidazol-2-yl)thiobutylphenone 3-(1-methylimidazol-5-yl)thiopropiofenone 3-(1-ethylimidazol-2-yl)thiopropiofenone Enone 3-(1-methylimidazol-5-yl)thiopropiofenone 3-(1-ethylimidazol-2-yl)thiopropiofenone 3-(1-isopropylimidazol-2-yl)-thiopropiofenone 4-Phenylthiobutyrophenone 3-Phenylthiobutyrophenone 3-(1,3,4-oxadiazol-2-yl)thiopropiophenone 4-(5-methyl-1,3,4- oxadiazol-2-yl)thiobutylphenone 4-(5-ethyl-1,3,4-oxadiazol-2-yl)thiobutylphenone 4-(5-isopropyl-1,3,4- oxadiazol-2-yl)thiobutylphenone 3-(5-methyl-1,3,4-oxadiazol-2-yl)thiopropiophenone 3-(5-ethyl-1,3,4- oxadiazol-2-yl)thiopropiophenone 4-(1,2,4-triazol-2-yl)
Thiobutyrophenone 4-(4,5-dimethyl-1,2,4-triazol-3-yl)Thiobutyrophenone 4-(4-methyl-5-ethyl-1,2,4-
Triazol-3-yl)thiobutylphenone 4-(4-ethyl-5-methyl-1,2,4-
triazol-3-yl)thiobutylphenone 3-(4,5-dimethyl-1,2,4-triazol-3-yl)thiopropiophenone 3-(4-methyl-5-ethyl-1,2, 4-
triazol-3-yl)thiopropiophenone 3-(4-ethyl-5-methyl-1,2,4-
Triazol-3-yl)thiopropiophenone 4-(4-methylpyrimidin-2-yl)thiobutylphenone 3-(pyrimidin-2-yl)thiopropiophenone 4-(5-methylpyrimidin-2-yl) ) Thiobutylphenone 4-(pyrimidin-2-yl)thiobutylphenone 4-(4-ethylpyrimidin-2-yl)thiobutylphenone 3-(4-aminopyrimidin-2-yl)thiopropiophenone 4-(5-ethylpyrimidin-2-yl)thiobutyrophenone 4-(2-methylpyrimidin-5-yl)thiobutyrophenone 4-(4-methylpyrimidin-5-yl)thiobutyrophenone 3- (1,2,4-triazol-5-yl)
Thiopropiophenone 4-(2-ethylpyrimidin-5-yl)thiobutyrophenone 4-(4-ethylpyrimidin-5-yl)thiobutyrophenone 4-(pyridin-2-yl)thiobutyrophenone 4 -(pyridin-3-yl)thiobutylphenone 4-(pyridin-4-yl)thiobutylphenone 3-(pyridin-2-yl)thiopropiophenone 3-(6-methylpyridin-2-yl) Thiopropiophenone 3-(pyridin-3-yl)thiopropiophenone 4-(4-aminopyridin-2-yl)thiobutylphenone 3-(pyridin-4-yl)thiopropiophenone 4-(4 -Hydroxypyridin-2-yl)thiobutyrophenone 4-(4,5-dihydrothiazol-2-yl)
Thiobutyrophenone 4-(4,5-dihydrothiazol-4-yl)
Thiobutyrophenone 4-(4,5-dihydrothiazol-5-yl)
Thiobutyrophenone 3-(4,5-dihydrothiazol-2-yl)
Thiopropiophenone 3-(4,5-dihydrothiazol-4-yl)
Thiopropiophenone 3-(4,5-dihydrothiazol-5-yl)
Thiopropiophenone 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone 4-(5-hydroxypyrimidin-2-yl)
Thiobutyrophenone 3-(4-hydroxypyrimidin-2-yl)
Thiopropiophenone 3-(5-hydroxypyrimidin-2-yl)
Thiopropiophenone 4-(2-hydroxypyrimidin-5-yl)
Thiobutyrophenone 4-(4-hydroxypyrimidin-5-yl)
Thiobutyrophenone 3-(2-hydroxypyrimidin-5-yl)
Thiopropiophenone 3-(4-hydroxypyrimidin-5-yl)
Thiopropiophenone 3-(benzoxazol-2-yl)thiopropiophenone 4-(benzoxazol-2-yl)thiobutylphenone 3-(6-hydroxybenzoxazole-2)
-yl)thiopropiophenone 3-(4-methylbenzoxazol-2-yl)thiopropiophenone 4-(4-aminobenzoxazol-2-yl)thiobutylphenone 4-(4-thiazole-2-yl) yl)thiobutylphenone 3-(4-thiazol-2-yl)thiopropiophenone 4-(4-methylthiazol-2-yl)thiobutylphenone 4-(4-hydroxythiazol-2-yl)
Thiobutyrophenone The compound of the present invention can be produced by various methods, for example, by the method shown in the following reaction formula. [In the formula, either one of X ¹ and X ² represents a halogen atom, and the other represents a mercapto group or a group

[Formula] is shown. R ¹ and A are the same as above] In the reaction formula -, instead of compound (3), compound
The compound (1) of the present invention can also be produced by reacting the compound (3) with a protected carbonyl group with the compound (2), and then removing the protecting group of the obtained compound.
In reaction formula -, the reaction between compound (2) and compound (3) is usually carried out in the presence of a condensing agent. A basic compound is usually used as this condensing agent. A wide variety 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, etc.
Alkali metals such as sodium and potassium, 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-diazacyclo[5,4,0]undecene-5 (DBU), 1,4-diazabicyclo[2,2,
2] Examples include organic bases such as octane (DABCO). The reaction is carried out without a solvent or in the presence of a solvent, and any inert solvent that does not adversely affect the reaction can be used, for example,
Alcohols such as methanol, ethanol, propanol, butanol, 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. Compound for compound (2) in the above method
The proportion of (3) to be used 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 in a large excess amount relative to the former in a solvent. Usually, the latter is about 5 times the mole of the former, preferably about 2 times the mole of the former.
It is desirable to use double the molar amount. In addition, the reaction temperature is not particularly limited, but is usually -30℃~
The temperature is about 200°C, preferably 0 to 160°C.
The reaction time is usually about 1 to 30 hours. As the protecting group for the ketone, any one that is stable under the above reaction conditions can be used, such as lower alcohols such as methanol and ethanol, ethylene glycol, lower alkylene diols such as 1,3-trimethyldiol, methanethiol, Lower alkanethiols such as ethanethiol, 1,2
Examples include lower alkylene dithiols such as -ethylene dithiol and 1,3-trimethylene dithiol. After the reaction, the protective group of the ketone is removed by a conventional method. For example, the ketal protected with the above-mentioned lower alcohol, lower alkylene diol, etc. can be easily converted into a carbonyl group by contacting with an acid. can. Examples of the acid catalyst used in this case include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, propionic acid, and p-toluenesulfonic acid. Examples of the solvent used in this reaction include:
Water, organic acids such as acetic acid and propionic acid, alcohols such as methanol and ethanol, acetone,
Examples include ketones such as methyl ethyl ketone, ethers such as dioxane, and aprotic solvents such as dimethyl sulfoxide and dimethyl formamide. In this case, if an organic acid is used as a solvent, no additional acid catalyst is required. This reaction is usually carried out at room temperature to 200℃, preferably 50 to 100℃ for 30 minutes to 12 minutes.
It will be done in about an hour. In addition, the thioketal protected with the lower alkanethiol, lower alkylene dithiol, etc.
Reaction conditions that can convert ordinary thioketals to carbonyl groups can be adopted. For example, mercuric chloride-
It is easily removed by treatment with mercury oxide, mercuric chloride-cadmium carbonate, silver nitrate-N-chlorosuccinimide, or the like. The protecting group removal reaction is carried out using a suitable solvent, for example, a mixed solvent of water and a water-soluble lower alcohol such as methanol or ethanol, or an organic solvent such as acetone or acetonitrile, at a temperature of 0 to 100°C, preferably 50 to 80°C. 1~ at °C
This is done by processing for about 5 hours. The compounds of the present invention also have the following reaction formula -
It can also be produced by the method shown below. [In the formula, R ¹ , A, X ¹ and X ² are the same as above.
Z represents a halogen atom] For the reaction between compound (2) and compound (4) in the above reaction formula -, the same reaction conditions as in the reaction in the above reaction formula - can be employed. The reaction between compound (5) and Grignard reagent (6) is carried out in a suitable inert solvent at about -70°C to 50°C, preferably at -30°C.
This can be achieved by processing for about 1 to 6 hours at a temperature of .degree. C. to room temperature. As the inert solvent, solvents customary for Grignard reactions can be used, such as ethers such as diethyl ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and saturated solvents such as pentane, hexane, heptane, and cyclohexane. Examples include hydrocarbons. The amount of Grignard reagent (6) to be used is at least equimolar, preferably equimolar to compound (5).
A 1.5-fold molar amount is used. The reaction product of compound (5) and compound (6) thus produced is subjected to conventional hydrolysis to obtain compound (1) of the present invention. The hydrolysis reaction is carried out in an appropriate manner in the presence of acids such as mineral acids such as hydrochloric acid and sulfuric acid, aliphatic carboxylic acids such as formic acid, acetic acid, and propionic acid, and perhalogenated acids such as perchloric acid and periodic acid. The reaction can be carried out in a suitable solvent at a temperature of about 0 to 100°C, preferably 50 to 80°C, for about 1 to 5 hours. Examples of the solvent include lower alcohols such as methanol and ethanol that are soluble in water, ethers such as tetrahydrofuran and dioxane, and mixed solvents of water and solvents such as acetone and acetonitrile. The amount of acid used is
It is used in at least an equimolar amount to (5). A method in which the reactive groups of compound (5) and Grignard reagent (6) in the above reaction formula - are exchanged, that is,
Compound (1) of the present invention can also be produced by the method shown in the following reaction formula. [In the formula, R ¹ , A and Z are the same as above. Y is a mercapto group or a group

[Formula] is shown. Z ¹ represents a halogen atom] The reaction between the above compound (2a) and the compound (7) can be carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above reaction formula -. compound
(8), according to the reaction conditions used for the production of Grignard reagents, for example, in an appropriate solvent from room temperature to
Compound (9) can be easily led to compound (9) by acting with magnesium at 100°C for 30 minutes to several hours. In this case, magnesium is used in at least an equimolar amount, preferably an equimolar to 1.5 times the molar amount of compound (8). Furthermore, the same reaction conditions as for the reaction between compound (5) and compound (6) in the above reaction formula - are employed for the reaction between compound (9) and compound (10). [In the formula, R ¹ , A, X ¹ _and The same reaction conditions as in (3) can be adopted. The hydrolysis reaction of compound (12) is carried out in a suitable inert solvent in the presence of a conventional catalyst such as a basic compound such as sodium hydroxide or potassium hydroxide, or a mineral acid such as hydrochloric acid or sulfuric acid at 50°C or more. This can be advantageously carried out at 110°C for about 30 minutes to several hours. An example of the solvent is water. The reaction between compound (13) and compound (14) is carried out in a suitable inert solvent at about -70°C to room temperature, preferably -
It can be carried out in about 1 to 6 hours at 30°C to room temperature. Examples of the solvent used include ethers such as diethyl ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and saturated hydrocarbons such as hexane, heptane, pentane, and cyclohexane.
The amount of compound (14) used in this reaction is at least twice the molar amount of compound (13), preferably 2 to 3 times the molar amount. [In the formula, R ¹ , A and Z are the same as above. M represents a metal atom such as zinc, cadmium, magnesium, etc.] The reaction between compound (13) and the halogenating agent in the above reaction formula - can be carried out without a solvent or in an appropriate inert solvent at room temperature to about 100°C. Preferably,
It is carried out at 50 to 80°C for about 30 minutes to 6 hours.
Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide, and examples of the solvent include chloroform, methylene chloride, carbon tetrachloride, etc. Examples include halogenated hydrocarbons, dioxane, tetrahydrofuran, ethers such as diethyl ether, and the like. The amount of the halogenating agent to be used is usually a large excess amount when the reaction is carried out without a solvent, and at least an equimolar amount when the reaction is carried out in a solvent.
Preferably it is 2 to 4 times the molar amount. For the reaction between compound (15) and compound (16) or compound (17), the same reaction conditions as for the reaction between compound (13) and compound (14) in the reaction formula - can be employed. In this case, the usage amounts of compound (16) and compound (17) are as follows:
At least equimolar, preferably equimolar to
1.5 times the molar amount. [In the formula, R ¹ , A and Z ¹ are the same as above. B represents a lower alkylene group] The reaction between compound (8) and compound (18) in the above reaction formula - is the same as the reaction between compound (15) and compound (16) or compound (17) in the above reaction formula -. The same reaction conditions can be adopted. In addition, the reaction from compound (19) to compound (1) is expressed by the above reaction formula -
The same reaction conditions as in the reaction for converting a thioketal protected with a lower alkanethiol, lower alkylene dithiol, etc. into a carbonyl group can be adopted. [In the formula, Z ² is a halogen, a hydroxyl group, or a group

[Formula] is shown. R ¹ and A are the same as above] The reaction between compound (15) and benzene (20) in the reaction formula proceeds advantageously in the presence of a catalyst. The catalysts include aluminum chloride, antimony pentachloride, ferric chloride, titanium tetrachloride, boron trifluoride, tin chloride, zinc chloride, mercuric chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid, and pentoxide. Examples include phosphorus, and aluminum chloride, stannic chloride, and zinc chloride are preferred. Although the catalyst is not particularly limited, it is usually used in an amount equivalent to or more, preferably 1 to 3 times the molar amount of benzene (20). The reaction is carried out without a solvent or in the presence of a solvent. As a solvent, any inert solvent that does not adversely affect the reaction can be used. For example, nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, 1, Examples include 2-dichloroethane. The ratio of benzene (20) to compound (15) is usually an equimolar amount to an excess amount, preferably 1 to 3 times the molar amount. This reaction can be carried out at 0°C to 150°C, preferably 0°C to room temperature, for about 1 to 5 hours. 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. It will be done. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Such separation methods include precipitation methods, extraction methods,
Examples include recrystallization method, distillation method, 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, binders such as carboxymethylcellulose, ceramic, methylcellulose, potassium phosphate, polyvinylpyrrolidone,
Dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cocoa butter, Decay inhibitors such as hydrogenated oils, quaternary ammonium bases,
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 pyloric 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 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 1,4-(1-methylimidazol-2-yl)
Thiobutyrophenone 2,4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone 3,4-(4,5-dimethyl-1,2,4-triazole- 3-yl)thiobutylphenone 4,4-(4,5-dihydrothiazole-2-
Ilthiobutylophenone

[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 the 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 at 0.5 ml immediately before rat restraint.
300 mg/Kg was administered orally in the form of a %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 x 100 In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 30-60%: 60% or more In addition to the above-mentioned compounds, the following compounds were used as test compounds in this pharmacological test and the following pharmacological tests. 5,4-(5-amino-1,3,4-thiadiazol-2-yl)thiobutyrophenone 6,4-phenylthiobutyrophenone 7,4-(4-methylpyrimidin-2-yl)
Thiobutylphenone 8,4-(pyridin-2-yl)thiobutylphenone 9,4-(benzoxazol-2-yl)thiobutylphenone 10,4-(4-hydroxypyrimidin-2-yl)thio Butyrophenone 11,4-(4-methylthiazol-2-yl)
Thiobutylophenone

[Table] Pharmacological test 3: Indomesacin ulcer experiment After fasting for 24 hours, male Wistar rats (body weight approximately 160 g) were treated with indomesacin 20 mg/Kg (0.5% CMC).
+ used as a suspension in a small amount of Tween 80)
100mg/Kg was administered subcutaneously. After 5 hours, the animals were sacrificed, and 8 ml of 10% formalin was injected into the collected stomach to fix it. The stomach was incised from the greater curvature side, the length of the ulcer formed on the mucous membrane was measured, and the ulcer inhibition rate of indometacin was determined in the same manner as in Pharmacological Test 2 above. The test drug was administered at 0.5% 30 minutes before administration of indomethacin.
100 mg/Kg was administered orally in the form of CMC suspension. The results are shown in Table 3. In addition, the suppression rate (%) in the table
The evaluation is as follows. +: 30-60%: 60% or more

[Table] Pharmacological test 4 The abdomen of a male Wistar rat was opened under anesthesia to expose the stomach, and 30% of the stomach was placed under the serosa at the boundary between the fundic membrane and the pyloric membrane.
0.015 ml of acetic acid aqueous solution was injected, the abdomen was closed, and an acetic acid ulcer was formed. 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 formation.
The drug was administered orally in divided doses (20 mg/Kg/day). The results are shown in Table 4. 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 of vehicle-treated control group x 100

【table】

[Table] Next, the compound of the present invention and its production method will be explained with reference examples and examples. Reference example 1 16.0g of 2-mercaptonaphthalene in acetone
Dissolve in 100ml. To this were added 21.7 g of 4-bromobutyric acid methyl ester and 15 g of potassium carbonate, and the mixture was refluxed for 4 hours. Acetone was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing the chloroform solution with saturated saline, dry over magnesium sulfate. Chloroform was distilled off, and the residue was recrystallized from hexane to obtain 24 g of 4-(naphthalen-2-yl)thio-butyric acid methyl ester in colorless granular crystals. Melting point: 65.5-66.5°C Reference Example 2 150 ml of 20% hydrochloric acid was added to 20 g of 4-(naphthalen-2-yl)thio-butyric acid methyl ester and refluxed for 2 hours. After cooling, the reaction solution was diluted with water and extracted with chloroform. After washing the chloroform solution with saturated saline, dry over magnesium sulfate. The chloroform is distilled off to obtain colorless needle-like crystals of 4-(naphthalen-2-yl)thio-butyric acid. Melting point 86~
87°C (Ligroin) Reference Example 3 6.3 g of 2-mercaptonaphthalene and 9.4 g of 1-bromo-3-chloropropane are dissolved in 100 ml of acetone. Add 6.8g of potassium carbonate to this and
Reflux for an hour. Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. Wash the chloroform solution with saturated saline and dry with magnesium sulfate. Chloroform was distilled off and the residue was subjected to column chromatography (Merck Kieselgel 60-,
The eluent was purified with benzene:ether=5:1) to obtain 10 g of 2-(3-chloropropyl)thionaphthalene as a colorless liquid. NMR (90MHz, _CDCl3 ) δ: 1.90-2.40 (2H,
m), 3.12 (2H, t, J=7.5Hz), 3.62 (2H, t,
J=6Hz), 7.30~7.50 (3H, m), 7.50~7.90
(4H, m) Reference Example 4 2.2 g of mercaptobenzene and 3.6 g of 4-brombutyronitrile are dissolved in 50 ml of acetone. Add 3 g of potassium carbonate to this and reflux for 3 hours. 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 was distilled off, and the residue was purified by column chromatography (Merck Kieselgel 60, eluent: chloroform) to obtain 3.4 g of 4-phenylthio-butyronitrile as a colorless liquid. The structure was confirmed by NMR, IR, elemental analysis, etc. Example 1 2 g of γ-chlorobutylphenone in 30 ml of acetone
dissolve in Add 2.3 g of sodium iodide to this and reflux for 3 hours. After distilling off the acetone, the residue is dissolved in 30 ml of N,N-dimethylformamide. This was mixed with 0.7 g of powdered potassium hydroxide and 2-
Add 1.6g of mercaptonaphthalene and heat to 80-90℃
Stir for 8 hours. After distilling off dimethylformamide, water is added to the residue and extracted with chloroform.
The chloroform solution is washed with saturated brine and dried over magnesium sulfate. Distill the chloroform,
The residue was subjected to column chromatography (Wakogel C-
200) to obtain 1.8 g of 4-(2-naphthylthio)butylophenone in the form of colorless scales. melting point 55
~56°C (ethanol-water) Example 2 The following compound is obtained in the same manner as in Example 1. 4-(benzimidazol-2-yl)thiobutylphenone, colorless needles (hexane-ethyl acetate), melting point 158-159°C 4-(5-amino-1,3,4-thiadiazol-2-yl) Thiobutyrophenone, light yellow scale crystals (water-ethanol), melting point 140.5-143°C 4-(1-methylimidazol-2-yl)thiobutyrophenone, light yellow needle crystals (hexane-ether), melting point 73-74℃ 4-phenylthiobutyrophenone, colorless scaly crystals (petroleum ether), melting point 36℃ 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone , colorless needle crystals (hexane), melting point 56-57°C 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless platelet crystals (hexane-ether), Melting point 64-67℃ 4-(4-methylpyrimidin-2-yl)thiobutyrophenone, pale yellow plate crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether),
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutyrophenone, white powder crystal (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point: 163-165.5°C 4-(4-methylthiazol-2-yl)thiobutylphenone, colorless flaky crystals (hexane), melting point: 53-55°C Example 3 1.8 g of 4-mercaptothiobutylphenone was dissolved in 50 ml of methanol. and add 10 ml of 10% aqueous sodium hydroxide solution. Add 1.7 g of 2-chlorobenzimidazole while stirring at room temperature, and add 5 g of 2-chlorobenzimidazole while stirring.
Stir for an hour. After distilling off the methanol, water is added to the residue and extracted with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off and the residue was subjected to column chromatography (Wakogel C-
200). After elution with chloroform, the resulting crystals were recrystallized from hexane-ethyl acetate to give colorless needle-like crystals of 4-(benzimidazole-2).
0.5 g of thiobutyrophenone is obtained. melting point
158-159°C Example 4 The following compound was obtained in the same manner as in Example 3. 4-(2-naphthyl)thiobutyrophenone, colorless flaky crystals (ethanol-water), melting point 55-56°C 4-(5-amino-1,3,4-thiadiazol-2-yl)thiobutyrophenone , pale yellow scaly crystals (water-ethanol), melting point 140.5-143°C 4-(1-methylimidazol-2-yl)thiobutyphophenone, pale yellow needle crystals (hexane-ether), melting point 73-74°C 4-Phenylthiobutyrophenone, colorless scaly crystals (petroleum ether), melting point 36°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone, colorless needles 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless plate crystals (hexane-ether), melting point 64-67 °C 4-(4-methylpyrimidin-2-yl)thiobutyrophenone, pale yellow platelet crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point 163-165.5°C 4-(4-methylthiazol-2-yl)thiobutyrophenone, colorless flaky crystals (hexane), melting point 53-55°C Example 5 5-(3-benzoylpropyl)isothiourea hydrochloride Dissolve 2.6g in 50ml of ethanol. Add 1.4 g of 2-amino-5-chloro-1,3,4-thiadiazole and 10 ml of 10% sodium hydroxide aqueous solution.
was added and refluxed for 3 hours. Ethanol 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 sodium sulfate. Chloroform was distilled off, the residue was purified by column chromatography (Merck Kieselgel 60, eluent chloroform), and then recrystallized from water-ethanol to obtain 4-(5
0.6 g of -amino-1,3,4-thiadiazol-2-yl)thiobutylophenone is obtained. Pale yellow flaky crystals (water-ethanol), melting point 140.5-143°C Example 6 The following compound was obtained in the same manner as in Example 5. 4-(Benzimidazol-2-yl)thiobutylphenone, colorless needles (hexane-ethyl acetate), melting point 158-159°C 4-(1-methylimidazol-2-yl)thiobutylphenone, pale yellow Needles (hexane-ether), melting point 73-74°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutylphenone, colorless needles (hexane), melting point 56 ~57℃ 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless needles (hexane-ether), melting point 64-67℃ 4-(4-methyl pyrimidin-2-yl) thiobutyrophenone, pale yellow platelets (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point 163-165.5°C 4-(4-methylthiazol-2-yl)thiobutyrophenone, colorless flaky crystals (hexane), melting point 53-55°C Example 7 2-(pyridin-2-yl)isothiourea hydrochloride Dissolve 1.9 g of salt in 30 ml of ethanol. 10 for this
Add 10 ml of % aqueous sodium hydroxide solution and reflux for 2 hours. After distilling off the ethanol, water is added to the residue and extracted with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off and the residue was subjected to column chromatography (Wakogel C-200).
Refine with. Elution with chloroform yields 0.8 g of 4-(2-pyridyl)thiobutylphenone as a colorless liquid.
get. n ^23.5 _D = 1.5854 Elemental analysis value: C ₁₅ H ₁₅ Calculated value (%) as NOS: C, 70.01; H, 5.88; N,
5.44 Analysis value (%): C, 69.95; H, 5.90; N,
5.45 Example 8 The following compound is obtained in the same manner as in Example 7. 4-(benzimidazol-2-yl)thiobutylphenone, colorless needles (hexane-ethyl acetate), melting point 158-159°C 4-(5-amino-1,3,4-thiadiazol-2-yl) Thiobutyrophenone, light yellow scale crystals (water-ethanol), melting point 140.5-143°C 4-(1-methylimidazol-2-yl)thiobutyrophenone, light yellow needle crystals (hexane-ether), melting point 73-74℃ 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone, colorless needles (hexane), melting point 56-57℃ 4-(4,5- Dimethyl-1,2,4-triazol-3-yl)thiobutyrophenone, colorless platelets (hexane-ether), melting point 64-67°C 4-(4-methylpyrimidin-2-yl)thiobutyrophenone , pale yellow plate crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutyrophenone, white powder crystal (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point 163-165.5°C 4-(4-methylthiazol-2-yl)thiobutylphenone, colorless flakes (hexane), melting point 53-55°C Example 9 0.25 g magnesium, 1.7 g bromobenzene and 10 ml dry tetrahydrofuran. Phenylmagnesium bromide is made from. To this, under ice-cooling stirring, 4
-(1-methylimidazol-2-yl)thiobutyronitrile 1.8 g dry tetrahydrofuran 10
ml solution dropwise. After dropping, stir at room temperature for 3 hours. Add 50 ml of IN hydrochloric acid under ice cooling and stir for 1 hour.
The reaction solution was diluted with water and extracted with chloroform.
The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. Chloroform was distilled off, and the residue was recrystallized from hexane-ether to obtain 0.6 of 4-(1-methylimidazol-2-yl)thiobutylphenone in the form of pale yellow needles. Melting point: 73-74°C Example 10 The following compound was obtained in the same manner as in Example 9. 4-(benzimidazol-2-yl)thiobutylphenone, colorless needles (hexane-ethyl acetate), melting point 158-159°C 4-(5-amino-1,3,4-thiadiazole, 2-yl) Thiobutyrophenone, pale yellow flakes (water-ethanol), melting point 140.5-143℃ 4-(2-naphthyl)thiobutyrophenone, colorless flakes (ethanol-water), melting point 55-56℃ 4- Phenylthiobutyrophenone, colorless scaly crystals (petroleum ether), melting point 36°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone, colorless needle crystals ( hexane), melting point 56-57°C 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless needles (hexane-ether), melting point 64-67°C 4 -(4-methylpyrimidin-2-yl)thiobutylphenone, pale yellow platelets (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutyrophenone, white powder crystal (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point 163-165.5°C Example 11 0.3 g of magnesium is suspended in 5 ml of dry tetrahydrofuran. A small piece of iodine is added to this under stirring in a nitrogen stream, and then 0.4 g of 2-(3-chloropropyl)thio-naphthalene is added. Add 0.1 ml of ethyl bromide and heat externally to start the reaction. The remaining 2-(3-chloropropyl)thio-
2.2g naphthalene 15ml dry tetrahydrofuran
Drop the solution. After dropping, reflux is performed for 1 hour.
A solution of 0.9 g of benzonitrile in 5 ml of dry tetrahydrofuran is added dropwise to the resulting Grignard reagent under ice-cooling and stirring, and the mixture is stirred at room temperature for 3 hours. Under ice-cooling, add 20 ml of IN hydrochloric acid and stir for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The ether was distilled off, and the residue was recrystallized from water-ethanol to obtain 0.7 g of 4-(2-naphthyl)thiobutylphenone. Colorless scaly crystals, melting point 55-56°C Example 12 The following compound was obtained in the same manner as in Example 11. 4-Phenylthiobutyrophenone, colorless scaly crystals (petroleum ether), melting point 36°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone, colorless needles 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless plate crystals (hexane-ether), melting point 64-67 °C 4-(4-methylpyrimidin-2-yl)thiobutyrophenone, pale yellow platelet crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutyrophenone, white powder crystals (methanol-water), melting point 53-54°C Example 13 2 g of 4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyric acid anhydrous benzene
Dissolve in 20ml. 13.3 ml of a 1.5N phenyllithium ether solution was added dropwise under stirring at −70° C. under an argon stream. Stir for 3 hours while gradually raising the temperature to room temperature. The mixture was further stirred overnight at room temperature, and the reaction mixture was poured into ice water and extracted with ether. The ether solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. The ether was distilled off, and the residue was recrystallized from hexane to give colorless needle-shaped 4-
(5-methyl-1,3,4-oxadiazole-
0.6 g of 2-yl)thiobutylphenone is obtained. Melting point: 56-57°C Example 14 The following compound was obtained in the same manner as in Example 13. 4-(2-naphthyl)thiobutylphenone, colorless scaly crystals (ethanol-water), melting point 55-56°C 4-(benzimidazol-2-yl)thiobutylphenone, colorless needle-like crystals (hexane-acetic acid) ethyl), melting point 158-159°C 4-(1-methylimidazol-2-yl)thiobutyrophenone, pale yellow needles (hexane-ether), melting point 73-74°C 4-phenylthiobutyrophenone, Colorless flaky crystals (petroleum ether), melting point 36°C 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless platelet crystals (hexane-ether), melting point 64 ~67℃ 4-(4-methylpyrimidin-2-yl)thiobutylphenone, pale yellow needles (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylophenone, white powder crystals (methanol-water), melting point 53-54°C Example 15 2.1 g of 2-phenyl-1,3-dithiane are dissolved in 20 ml of dry tetrahydrofuran and cooled to -78°C. To this, 1.6Nn− was added under stirring in an argon stream.
Add dropwise 6.5 ml of n-hexane solution of butyllithium. Stir for 30 minutes at -78°C. 4,5-
dimethyl-3-(3-chloropropyl)thio-1,
A solution of 2 g of 2,4-triazole in 5 ml of dry tetrahydrofuran is added dropwise. After stirring at -78℃ for 1 hour,
Stir for 4 hours while gradually increasing the temperature to 0°C. Pour the reaction solution into ice water and extract with ether.
The ether solution is washed with water and saturated saline, and then dried over magnesium sulfate. Distill the ether,
Dissolve the residue in 20 ml of acetonitrile. Separately, 7 g of silver nitrate and 4.9 g of N-chlorosuccinimide
Dissolve in 40ml of water and 100ml of acetonitrile. The above dithiane solution was added dropwise to the solution while stirring at 0° C. in a nitrogen stream. After stirring at 0°C for 30 minutes, warm to room temperature and stir for an additional 30 minutes. Dilute with water and extract with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off, and the residue was recrystallized from hexane-ether to give colorless plate-like 4-
0.4 g of (4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone is obtained.
Melting point: 64-67°C Example 16 The following compound was obtained in the same manner as in Example 15. 4-(2-naphthyl)thiobutylphenone, colorless scaly crystals (ethanol-water), melting point 55-56°C 4-(benzimidazol-2-yl)thiobutylphenone, colorless needle-like crystals (hexane-acetic acid) ethyl), melting point 158-159°C 4-(5-amino-1,3,4-thiadiazol-2-yl)thiobutylphenone, pale yellow flaky crystals (water-ethanol), melting point 140.5-143°C 4- Phenylthiobutyrophenone, colorless scaly crystals (petroleum ether), melting point 36°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone, colorless needle crystals ( hexane), melting point 56-57°C 4-(4-methylpyrimidin-2-yl)thiobutylphenone, pale yellow plate crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol),
Melting point: 163-165.5°C Example 17 5 ml of thionyl chloride is added to 1.9 g of 4-phenylthio-butyric acid and stirred at 40-50°C for 1 hour. Excess thionyl chloride is distilled off under reduced pressure. Dry benzene is added and water is removed by azeotroping, and 4-phenylthio-butyric acid chloride is obtained from the resulting mixture. Separately, 571 mg of copper iodide is added to a sealed two-necked flask, and after degassing under reduced pressure, the flask is filled with nitrogen. 10 ml of anhydrous ether was poured into this, and the whole was cooled to -40°C. Add 5 ml of ether solution of 1.32M phenyllithium to this.
was added, stirred at -40°C for 5 minutes, and then cooled to -78°C. 5 ml of a cold anhydrous ether solution containing 0.23 g of the 4-phenylthio-butyric acid chloride obtained above was poured into the mixture, and the mixture was stirred at -78 DEG C. for 15 minutes. 35 ml of anhydrous methanol is poured into this reaction solution, and the flask is returned to room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is distilled off. The residue was recrystallized from petroleum ether to give colorless scaly crystals.
- Obtain 0.1 g of phenylthiobutyrophenone. Melting point: 36°C Example 18 The following compound was obtained in the same manner as in Example 17. 4-(2-naphthyl)thiobutylphenone, colorless scales (ethanol-water), melting point 55-56°C 4-(1-methylimidazol-2-yl)thiobutylphenone, pale yellow needles ( hexane-ether), melting point 73-74°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutylphenone, colorless needles (hexane), melting point 56-57°C 4 -(4,5-dimethyl 1,2,4-triazol-3-yl)thiobutylphenone, colorless platelet crystals (hexane-ether), melting point 64-67°C 4-(4-methylpyrimidin-2-yl) ) Thiobutylophenone, pale yellow platelets (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C Example 19 4 g of benzene was dissolved in 20 ml of carbon disulfide, and 4-
Add 2.1 g of phenylthio-butyric acid chloride. 1.8 g of aluminum chloride is gradually added while stirring on ice. After stirring at room temperature for 1 hour, the reaction solution was poured into cold hydrochloric acid and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Wakogel C-200). Elution with benzene-ether (10:1) gives 0.6 g of 4-phenylthiobutylphenone. Colorless flaky crystals (petroleum ether), melting point 36°C Example 20 The following compound was obtained in the same manner as in Example 19. 4-(2-naphthyl)thiobutylphenone, colorless scales (ethanol-water), melting point 55-56°C 4-(1-methylimidazol-2-yl)thiobutylphenone, pale yellow needles ( hexane-ether), melting point 73-74°C 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutylphenone, colorless needles (hexane), melting point 56-57°C 4 -(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless platelet crystals (hexane-ether), melting point 64-67°C 4-(4-methylpyrimidine-2- il) thiobutylophenone, pale yellow platelet crystals (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C Example 21 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutylphenone ethylene ketal Dissolve 0.5 g in 5 ml of acetic acid. Water 2.5 to this
ml and 0.5 ml of concentrated hydrochloric acid and heat on a water bath for 1 hour. Add water to the reaction solution and extract with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Elute with chloroform, 4
0.3 g of -(5-methyl-1,3,4-oxadiazol-2-yl)thiobutylphenone is obtained.
Colorless needle crystals (hexane), melting point 56-57°C Example 21 The following compound was obtained in the same manner as in Example 20. 4-(2-naphthyl)thiobutylphenone, colorless scaly crystals (ethanol-water), melting point 55-56°C 4-(benzimidazol-2-yl)thiobutylphenone, colorless needle-like crystals (hexane-acetic acid) ethyl), melting point 158-159°C 4-(5-amino-1,3,4-thiadiazol-2-yl)thiobutylphenone, pale yellow flaky crystals (water-ethanol), melting point 140.5-143°C 4- (1-Methylimidazol-2-yl)thiobutylphenone, pale yellow needles (hexane-ether), melting point 73-74°C 4-phenylthiobutylphenone, colorless scales (petroleum ether), melting point 36℃ 4-(4,5-dimethyl-1,2,4-triazol-3-yl)thiobutylphenone, colorless platelet crystals (hexane-ether), melting point 64-67℃ 4-(4-methylpyrimidine) -2-yl)thiobutyrophenone, pale yellow needles (petroleum ether),
Melting point 61-63°C 4-(pyridin-2-yl)thiobutylphenone, colorless liquid, n ^23.5 _D = 1.5854 4-(benzoxazol-2-yl)thiobutylphenone, white powder crystal (petroleum ether) ,
Melting point 63-64℃ 4-(4,5-dihydrothiazol-2-yl)
Thiobutylphenyl, white powder crystals (methanol-water), melting point 53-54°C 4-(4-hydroxypyrimidin-2-yl)
Thiobutyrophenone, white granular crystals (ethanol)
Melting point: 163-165.5°C Formulation example 1 4-(5-methyl-1,3,4-oxadiazol-2-yl)thiobutyrophenone 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 4-(4,5-dihydrothiazol-2-yl)
Thiobutylophenone 150g Citric acid 1.0g Lactose 33.5g Dicalcium phosphate 70.0g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbovacs 1500) 4.5g Polyethylene glycol (Carbovacs 6000) 45.0 g Cornstarch 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 it through a No. 10 screen, put it in a tray, and put it in a 100℃ oven for 12~
Dry for 14 hours. The dry particles are sieved through a No. 16 screen, dried sodium lauryl sulfate and dry magnesium stearate are added and mixed, and compressed into the desired shape using a tablet machine. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish enough 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 4-(2-pyridyl)thiobutylphenone 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 passing through a suitable filter paper to prepare an injection solution.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a phenyl group, a naphthyl group, or benzimidazolyl, 1,3,4-thiadiazolyl, imidazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, pyrimidinyl, pyridyl, benzoxazolyl A 5-membered or 6-membered unsaturated heterocyclic group selected from 1-3, thiazolyl, 4,5-dihydrothiazolyl, and 4,5-dihydrothiazolyl. It may have a substituent. A represents a trimethylene group] A benzene derivative and a salt thereof.