JPH0432826B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel oxazole derivatives and salts thereof, more specifically, the general formula [In the formula, R ¹ means a lower alkyl group or phenyl group, R ² means a lower alkyl group or cycloalkyl group, and A means a lower alkylene group. however
When R ² represents a lower alkyl group, A is a trimethylene group] and salts thereof. The oxazole 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 particular, the compounds of the present invention are effective at low doses and have a long duration. In this specification, lower alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 2-methyltrimethylene, 2,2
-C 1-6 straight chain or branched alkylene groups such as -dimethyltrimethylene and 1-methyltrimethylene groups. Lower alkyl groups include methyl, ethyl, propyl, isopropyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as butyl and tert-butyl groups. In addition, cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
3 carbon atoms such as cycloheptyl and cyclooctyl
~8 cycloalkyl groups are mentioned. The compound of the present invention can be manufactured by various methods, for example, by the method shown in Reaction Scheme-I below. [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 , R ² and A are the same as above] In Reaction Formula-I, instead of Compound 3, a compound in which the carbonyl group of Compound 3 is protected is used to react with Compound 2, and then protection of the obtained compound Compound (1) of the present invention can also be produced by removing the group.
In Reaction Formula-I, 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
-Diazabicyclo[5.4.0]Undecene-5
(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and other organic bases.
The reaction is carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. The ratio of compound 3 to compound 2 in the above method is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the latter is usually used in a large excess of the former. When carrying out in a solvent, it is usually desirable to use the latter in an amount of about 1 to 5 times the mole of the former, preferably about 1 to 2 times the mole of the former. Also, the reaction temperature is not particularly limited, but is usually about -30℃ to 200℃,
It is preferably carried out at a temperature of 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, lower alkylene diols such as ethylene glycol and 1,3-trimethylene diol, and methane. thiol,
lower alkanethiols such as ethanethiol,
Examples include lower alkylene dithiols such as 1,2-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 in -. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above. Z represents a halogen atom] The reaction between compound 2 and compound 4 in the above reaction formula - can employ the same reaction conditions as the reaction in the above reaction formula -I. 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 prepared 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 at least equimolar to Compound 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 , R ² , 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 same reaction conditions as for the reaction between compound 2 and compound 3 in the reaction formula-I can be used for the reaction between compound 2a and compound 7, and the obtained compound 8
For example, in a suitable solvent at room temperature to
Compound 9 can be easily obtained by using magnesium at 100°C for 30 minutes to several hours. In this case, the amount of magnesium used is at least equimolar, preferably 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 reaction formula - above are employed for the reaction between compound 9 and compound 10. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above. R ³ represents a lower alkyl group] Compound 2 and compound 11 in the above reaction formula -
The reaction with Compound 2 in the above reaction formula-I
The same reaction conditions as for compound 3 can be adopted. The hydrolysis reaction of compound 12 is carried out using conventional catalysts, such as sodium hydroxide, in a suitable inert solvent.
It can be advantageously carried out in the presence of a basic compound such as potassium hydroxide or a mineral acid such as hydrochloric acid or sulfuric acid at 50°C to 110°C for about 30 minutes to several hours. As the solvent,
For example, water can be used. The reaction between compound 13 and compound 14 is carried out in a suitable inert solvent at about -70°C to room temperature, preferably at -30°C.
~Can be carried out at room temperature for about 1 to 6 hours. Examples of the solvent used include diethyl ether,
Examples include ethers such as 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
The amount is at least twice the amount, preferably 2 to 3 times the amount. [In the formula, R ¹ , R ² , 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-V can be carried out without a solvent or in an appropriate inert solvent at room temperature to about 100°C, preferably. is 50
It is carried out at ~80°C for about 30 minutes to 6 hours. Examples of the halogenating agent include thionyl chloride,
Phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride,
Examples include phosphorus pentabromide, and as a solvent,
Examples include halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and ethers such as dioxane, tetrahydrofuran, and diethyl ether. The amount of the halogenating agent to be used is usually a large excess of compound 13 when the reaction is carried out in the absence of a solvent, and at least an equimolar amount when the reaction is carried out in a solvent. It is 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 amount of Compound 16 and Compound 17 used is at least equimolar, preferably equimolar to 1.5 times the molar amount of Compound 15. [In the formula, R ¹ , R ² and Z ¹ are the same as above. B represents a lower alkylene group] Compound 8 and compound 18 in the above reaction formula -
The reaction with Compound 1 in the above reaction formula-V
The same reaction conditions as for the reaction of 5 with compound 16 or compound 17 can be employed. Further, for the reaction from Compound 19 to Compound 1, the same reaction conditions as those for converting a thioketal protected with lower alkanethiol, lower alkylene dithiol, etc. into a carbonyl group in Reaction Formula-I described above can be employed. 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. 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, carlim phosphate, polyvinylpyrrolidone and other binders, 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% by weight based on the total composition.
~50% by weight. 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 10 minutes after pyloric ligation.
mg/Kg or 100 mg/Kg was administered into the duodenum, and the amount of gastric juice was measured 4 hours after ligation. The inhibition rate was determined in %, setting the physiological saline administration group as 0. Its suppression rate%
The evaluation is as follows. +: 10% to less than 50% ++: 50% or more As a test compound, 5-(5-methyl-1,3,
In an experiment using 4-oxadiazol-2-yl)thio-2-pentanone, the dose was 10 mg/
The inhibition rate is ++ for both Kg and 100mg/Kg,
It showed high activity even at low doses. Pharmacological Test 2: Stress Ulcer Experiment After fasting male Wistar rats (weighing approximately 170 g) 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. Inhibition rate = UI of vehicle-administered control group - UI of test drug-administered group /
UI of the vehicle-administered control group x 100 The evaluation of the inhibition rate (%) is as follows. +: 30 to less than 60% ++: 60% or more When the same compound as in Pharmacological Test 1 was used as the test compound, the inhibition rate was ++. Next, the method for producing the compound of the present invention will be described in more detail with reference to Examples. Example 1 Dissolve 1.8 g of 5-chloro-2-pentanone in 50 ml of acetonitrile, and add sodium iodide to this.
Add 3.4g and react by heating at 60°C for 1 hour. Then, 1.4 g of 5-methyl-2-mercapto-1,3,4-oxadiazole and 2 g of potassium carbonate were added to this reaction mixture, and the mixture was further refluxed for 3 hours.
After distilling off the acetonitrile, water is added to the residue and extracted with chloroform. Add the chloroform layer to water,
Wash sequentially with 1N aqueous sodium hydroxide solution and saturated saline, and dry with magnesium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5-(5-
1.6 g of methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone are obtained. n ^26.5 _D =
1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.88; H, 6.13; N, 13.90 Examples 2 to 4 The above implementation Analogously to Example 1, using appropriate starting materials, the compounds in Table 1 below are obtained.

[Table] Example 5 Dissolve 1.18 g of 5-mercapto-2-pentanone in 50 ml of methanol, and add 10 ml of 10% aqueous sodium hydroxide solution. While stirring this mixture at room temperature, 2-methyl-5-chloro-1,3,4-
Add 1.32 g of oxadiazole and stir for an additional 5 hours. After distilling off methanol, water was added to the residue,
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 purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5-(5-methyl-1,3,4-oxadiacetate) as a pale yellow oil. 0.3 g of azol-2-yl)thio-2-pentanone are obtained. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.89; H, 6.14; N, 13.91 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 6 1.9 g of 2-(3-acetylpropyl)isothiourea hydrochloride is dissolved in 50 ml of ethanol. Add to this 1.2 g of 2-methyl-5-chloro-1,3,4-oxadiazole and 10% aqueous sodium hydroxide solution.
ml 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, and the residue was chromatographed on a silica gel column (eluent; hexane: ethyl acetate = 1:
Purification in step 1) yields 0.3 g of 5-(5-methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone as a pale yellow oil. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.90; H, 6.12; N, 13.92 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 7 2 g of 4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyric acid was dissolved in anhydrous benzene.
Dissolve in 20ml. 13.3 ml of a 1.5N methyllithium ether solution is added dropwise under stirring at -70°C under an argon stream. Stir for 3 hours while gradually raising the temperature to room temperature. Further, the mixture was 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 subjected to silica gel column chromatography (eluent;
5-(5-Methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone was purified with hexane:ethyl acetate=1:1) to give pale yellow oil.
Obtain 0.5g. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.93; H, 6.08; N, 13.92 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 8 0.3 g of magnesium is suspended in 5 ml of dry tetrahydrofuran. A small piece of iodine was added to this under stirring in a nitrogen stream, and further 2-methyl-5-(3-
Add 0.33 g of chloropropyl)thio-1,3,4-oxadiazole. Add 0.1ml of ethyl bromide,
The reaction is initiated by external heating. remaining 2-
Methyl-5-(3-chloropropyl)thio-1,
A solution of 1.79 g of 3,4-oxadiazole in 15 ml of dry tetrahydrofuran is added dropwise. After dropping, reflux is performed for 1 hour. A solution of 0.36 g of acetonitrile in 5 ml of dry tetrahydrofuran was added dropwise to the resulting Grignard reagent under ice-cooling and stirring, and the mixture was stirred at room temperature for 3 hours.
Add 20 ml of 1N 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 then dried over sodium sulfate. Ether was distilled off, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 1:
1) to produce pale yellow oily 5-(5-methyl-
0.2 g of 1,3,4-oxadiazol-2-yl)thio-2-pentanone is obtained. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.91; H, 6.09; N, 14.03 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 9 Methylmagnesium iodide is prepared from 0.25 g of magnesium, 1.5 g of methyl iodide and 10 ml of dry tetrahydrofuran. To this, 4-
(5-methyl-1,3,4-oxadiazole-
A solution of 1.8 g of 2-yl)thiobutyronitrile in 10 ml of dry tetrahydrofuran is added dropwise. After dropping, stir at room temperature for 3 hours. Add 50 ml of 1N 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 a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over sodium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1:1) to obtain 5-(5-methyl-1,3,4-oxane) as a pale yellow oil. Diazol-2-yl)thio-2-pentanone 0.3g
get. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 48.04; H, 6.01; N, 14.05 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 10 1.4 g of 2-methyl-1,3-dithiane is dissolved in 20 ml of dry tetrahydrofuran and cooled to -78°C. To this, 6.5 ml of a solution of 1.6N n-butyllithium in n-hexane was added dropwise under stirring in an argon stream. Stir for 30 minutes at -78°C. To this, 5-methyl-3-(3-chloropropyl)thio-1,3,4
- A solution of 1.9 g of oxadiazole in 5 ml of dry tetrahydrofuran is added dropwise. After stirring for 1 hour at -78℃,
Stir for 4 hours while gradually raising 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 40 ml of water and 100 ml of acetonitrile. The above dithiane solution was added dropwise to this under 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 purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1:1) to obtain 5-(5-methyl-1,3,4-oxane) as a pale yellow oil. Diazol-2-yl)thio-2-pentanone 0.2
get g. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 48.03; H, 5.99; N, 14.06 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 11 5 ml of thionyl chloride is added to 2.0 g of 4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-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 azeotropic distillation, and 4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-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 is poured into this, and the whole is cooled to -40°C.
Add 5 ml of 1.32M methyllithium ether solution to this.
was added, stirred at -40°C for 5 minutes, and then cooled to -78°C. This was added to the 4-(5-methyl-
5 ml of cold anhydrous ether solution of 0.24 g of 1,3,4-oxadiazol-2-yl)thio-butyric acid chloride
and stir for 15 minutes at -78°C. 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 purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5-(5-methyl-1,3,4) as a pale yellow oil.
0.05 g of -oxadiazol-2-yl)thio-2-pentanone is obtained. n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 48.05; H, 6.01; N, 14.04 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 12 0.5 g of 5-(5-methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone ethylene ketal is dissolved in 5 ml of acetic acid. This and water
Add 2.5 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 was distilled off, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5- as a pale yellow oil.
(5-methyl-1,3,4-oxadiazole-
0.3 g of 2-yl)thio-2-pentanone is obtained.
n ^26.5 _D = 1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual value: C, 47.92; H, 6.07; N, 13.93 Same as above Using appropriate starting materials, the compounds shown in Table 1 above are obtained. Example 13 1.8 g of 2-(5-methyl-1,3,4-oxadiazol-2-yl)isothiourea hydrochloride is dissolved in 30 ml of ethanol. In this, 5-chloro-2
- Add 1.2 g of pentanone and 10 ml of 10% 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 purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 5-(5-methyl-1,3,4-oxadiacetate) as a pale yellow oil. 0.7 g of azol-2-yl)thio-2-pentanone are obtained. n ^26.5 _D =
1.5024 Elemental analysis value: C ₈ H ₁₂ N ₂ O ₂ S Calculated value: C, 47.99; H, 6.04; N, 13.99 Actual measurement value: C, 47.91; H, 6.08; N, 13.92 As above, appropriate Using the following starting materials, the compounds shown in Table 1 above are obtained. Formulation example 1 5-(5-methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone
150g Avicel (trade name: manufactured by Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methyl cellulose 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 5-(5-methyl-1,3,4-oxadiazol-2-yl)thio-2-pentanone
150g Citric acid 1.0g Lactose acid 33.5g Dicalcium phosphate 70.0g Pluronic 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 3.0 g Dry magnesium stearate 3.0 g 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 an oven at 100℃ for 12 hours.
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 8-(5-methyl-1,3,4-oxadiazol-2-yl)thio-2-octanone 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 means a lower alkyl group or phenyl group, R ² means a lower alkyl group or cycloalkyl group, and A means a lower alkylene group. however
When R ² represents a lower alkyl group, A is a trimethylene group.] An oxazole derivative or a salt thereof.