JPH0564143B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,2,4-oxadiazole derivatives.

More specifically, the present invention relates to the general formula () [In the formula, R-X- is a phenyl group, benzoyl group or isobutyl group, Y is a hydrogen atom or a halogen atom, T is a methylmethylene group, and U is a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkoxy carbonyl-lower alkyl group, carboxy-lower alkyl group, alkanoyl group or aryl-lower alkyl group, Z is -O-, -S-,
-S(O)- or -S( _O2 )-] This relates to a 3,5-disubstituted 1,2,4-oxadiazole derivative represented by the formula: -S(O)- or -S(O2)-.

In the above general formula (), The expressions alkyl and alkenyl include straight and branched carbon chains; lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl,
Examples include alkyl groups having 1 to 8 carbon atoms such as n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, and n-octyl. Examples of lower alkenyl groups include alkenyl groups having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 2-methylpropenyl, 2-butenyl, and prenyl (3,3-dimethylallyl). Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The halogen atom referred to in the present invention includes fluorine, chlorine, bromine and iodine. The expression alkanoyl has 1 to 1 carbon atoms.
It means a group produced by removing the hydroxyl group of the alkanoic acid of No. 8, and may contain a hydroxy group, a carboxy group, etc. For example, acetyl, propionyl, 2-methylpropionyl,
Examples include pivaloyl, hydroxyacetyl and 3-carboxypoonyl. The aryl group of the present invention is a substituted or unsubstituted phenyl group, and examples of the substituent include a halogen atom, a lower alkyl group, a lower alkoxy group, and/or a trifluoromethyl group. Therefore, examples of the aryl group include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl,
2,4-difluorophenyl, 2,3-dimethylphenyl, 3,4-dimethoxyphenyl and 3
-Includes trifluoromethylphenyl, etc.

1 represented by the general formula () of the present invention,
2,4-Oxadiazole derivatives have strong anti-inflammatory effects, have extremely low side effects such as gastrointestinal disorders, and are low in toxicity, so they are effective against inflammatory diseases in mammals.
For example, it is a useful compound that is expected to be applied to chronic rheumatoid arthritis, osteoarthritis, low back pain, etc.
Conventionally, general formula () [In the formula, R, X, Y and T have the same meanings as above. ] Carboxylic acid derivatives represented by include known non-steroidal anti-inflammatory drugs such as ibuprofen, flurbiprofen, ketoprofen, diclofenac, fuenbufuen, etc., which are currently not available. , widely used clinically. However, it is well known that these existing acidic anti-inflammatory agents cause considerable side effects including gastrointestinal disorders.

Surprisingly, although the 1,2,4-oxadiazole derivative of the present invention exhibits an anti-inflammatory effect comparable to that of the above-mentioned acidic anti-inflammatory agents, its gastrointestinal disorder effect is extremely weak, and its therapeutic index is low. It was found to be a highly excellent compound. For example, flurbiprofen (2-(2-fluoro-4-biphenylyl)propionic acid) and the compound of the present invention, 5
-(3-fluoro-4-phenyl-α-methylbenzyl)-3-ethylsulfonyl-1,2,4-
In comparison with oxadiazole, in a rat adjuvant arthritis treatment study, the minimum effective dose (oral) was 0.5 mg/Kg in both cases, and flurbiprofen had a small intestinal ulcer-inducing effect (oral) in rats. 5 mg/Kg administration and 50 mg/kg administration of the above-mentioned compound of the present invention.
mg/Kg administration showed comparable results. That is, when comparing the therapeutic index, flurbiprofen had a value of 10, whereas the compound of the present invention had a value of 100, indicating that the compound of the present invention is an extremely safe anti-inflammatory agent.

The compounds of the present invention can be administered orally or parenterally for the purpose of treating inflammatory diseases in mammals, including humans. Examples of dosage forms for oral administration include tablets, capsules, powders, granules, syrups, and troches. Dosage forms for parenteral administration include suppositories, ointments, creams, jellies, solutions, suspensions, patches, injections, and the like. The above pharmaceutical composition containing the compound of the present invention as an active ingredient can be prepared by known formulation techniques. The compound of the present invention is
It is usually preferable to administer a daily dose of 30 to 1500 mg to adults, but if symptoms occur, the dose may be increased or decreased as appropriate depending on the administration method.

The novel 1,2,4-oxadiazole derivative of the general formula () which is the object compound of the present invention is:
Publicly known literature (e.g. B., W. Nash et al., J.
(C), 1969 , 2794). That is, in order to produce the target compound of the present invention, (a) General formula () [In the formula, R, X, Y and T have the same meanings as above. ] An acylisothiocyanate derivative represented by the general formula () U ₂ -Z ₁ -H () [wherein U ₂ is a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower In the alkyl group or aryl-lower alkyl group, Z ₁ means an oxygen atom or a sulfur atom. ] By reacting with an alcohol or thiol derivative represented by the general formula () [In the formula, R, X, Y, T, U ₂ and Z ₁ have the same meanings as above. [In the formula, U ₁ is a lower alkyl group, a lower alkekenyl group, a lower alkoxycarbonyl- _lower alkyl group] , means a carboxy-lower alkyl group or an aryl-lower alkyl group. ] By reacting with a reactive derivative of alcohol represented by the general formula () [In the formula, R, X, Y, T, U ₁ , U ₂ and Z ₁ have the same meanings as above. ] After preparing the acyliminothie carbonate derivative represented by the formula (a), by further reacting this derivative with hydroxylamine, the derivative of general formula (a) is obtained. [In the formula, R, X, Y, T, U ₂ and Z ₁ have the same meanings as above. ] and general formula (b) [In the formula, R, X, Y, T, and U ₁ have the same meanings as above. ] Obtain a 1,2,4-oxadiazole derivative represented by (however, compound (b) is obtained only when Z ₁ is a sulfur atom), or (b) general formula (c) [In the formula, R, X, Y and T have the same meanings as above. ] The 3-methoxy-oxadiazole derivative represented by the general formula () R ₁ SNa () [wherein R ₁ is a lower alkyl group or an aryl-
means a lower alkyl group. ] By acting with sodium thioalcoside represented by the formula (d), [In the formula, R, X, Y and T have the same meanings as above. ] _A 3-hydroxy- _1,2,4 -oxadiazole derivative represented by It means an alkenyl group, a lower alkoxycarbonyl-lower ylkyl group, a carboxy-lower alkyl group, an alkanoyl group or an aryl-lower alkyl group. ] By reacting with a reactive derivative of an alcohol or carboxylic acid represented by the general formula (
e) [In the formula, R, X, Y, T and U ₃ have the same meanings as above. ] Or (c) obtain a 1,2,4-oxadiazole derivative represented by the general formula (b) [In the formula, R, X, Y, T and U ₁ have the same meanings as above. ] By reacting the 1,2,4-oxadiazole derivative represented by the formula (f) with an oxidizing agent, [In the formula, R, X, Y, T and U ₁ have the same meanings as above. ] and/or general formula (g) [In the formula, R, X, Y, T, and U ₁ have the same meanings as above. ] Obtain the 1,2,4-oxadiazole derivative represented by the formula (d), and if necessary, by reacting the compound of the above general formula (g) with an alkali, the 3-hydroxy- A method for obtaining a 1,2,4-oxadiazole derivative, etc. can be carried out.

Next, methods (a) to (c) for producing the compound of the present invention will be explained in detail.

In the method (a), first, an acid halide of a carboxylic acid of the general formula (), sodium thiocyanate,
With thiocyanates such as potassium thiocyanate, ammonium thiocyanate, and lead thiocyanate,
By heating in a solvent such as benzene, toluene, xylene, dioxane, acetonitrile, etc., the raw material compound of the general formula () is obtained. Next, N- of the general formula () is reacted with an alcohol or thiol derivative of the general formula () in an inert solvent at room temperature or under heating, with or without isolation. An acylthiocarbamate derivative is obtained.

Next, the compound of the general formula () is reacted with a reactive derivative of the alcohol of the general formula () in an inert solvent in the presence of a base to obtain an acylimino compound of the general formula (). A thiocarbonate derivative is obtained. The reactive derivatives of the alcohols mentioned above include chloride, bromide, iodide,
Examples include p-toluenesulfonic acid ester, methanesulfonic acid ester, and trichloromethanesulfonic acid ester. As a solvent for this reaction,
For example, alcohols such as methanol, ethanol, isopropanol, n-butanol, and tert-butanol, and ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and dimethylene glycol dimethyl ether are suitable. Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium metal, sodium hydride,
Sodium methoxide, sodium ethoxide, etc. are used.

This reaction usually proceeds at room temperature, but may be carried out under cooling or heating if necessary.

Finally, the target compound of the general formula () can be obtained by reacting the compound of the general formula () with hydroxylamine in a solvent such as methanol, ethanol, or isopropanol at room temperature or under heating. . When using an acid addition salt of hydroxylamine, such as hydroxylamine hydrochloride, it must be treated with an equivalent amount of an alcoholic solution of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc. to remove the free base. It is preferable to add it to the reaction system after the reaction. In this reaction, when Z ₁ of the starting compound () is an oxygen atom, that is, when it is an acyliminothiocarbonate derivative, only the compound of the general formula (a) (Z ₁ =O) is produced, but
When Z ₁ is a sulfur atom, that is, when it is an acyliminodithiocarbonate derivative, the general formula (
Since both compounds a) and (b) are produced, they can be isolated using known separation and purification means such as chromatography. However, in the case of U ₁ =U ₂ , there is naturally only one type of target compound.

In the method (b), first, the compound of the general formula (c) is reacted with a sodium thioalkoxide of the general formula () in an aprotic polar solvent. The 3-hydroxy-1,2,4-oxadiazole derivative of d) is obtained. Suitable solvents for this reaction include anhydrous solvents such as dimethylformamide, dimethylacetamide, and dimethylsulfoxide.
The reaction proceeds satisfactorily under ice-cooling or at room temperature, but can also be carried out under heating if necessary.

Next, the compound of the general formula (e) is reacted with a reactive derivative of the alcohol or carboxylic acid of the general formula () in an inert solvent in the presence of a basic substance. ) is obtained. As the reactive derivative of the above compound (), chloride, bromide, iodide, etc. are preferable. Examples of basic substances include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, metallic sodium, sodium hydride,
Examples include sodium methoxide, sodium ethoxide, triethylamine, N,N-dimethylaniline, and pyridine, which are appropriately selected and used depending on the reactivity of the raw material compound and the reaction solvent. Examples of solvents for this reaction include ethers such as ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl kent, dimethyl formamide, dimethyl acetamide, and dimethyl sulfoxide. etc. are appropriate.

In the method (c), the compound of the general formula (b) is oxidized with a suitable oxidizing agent in an inert solvent, so that the sulfoxide of the general formula (f) is generally oxidized under milder conditions. Under stronger conditions, the sulfone of general formula (g) can be obtained. Examples of the oxidizing agent for this reaction include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide,
Manganese dioxide, chromic acid, periodate, permanganate, etc. are suitable. The solvent for this reaction is
The oxidizing agent may vary depending on the oxidizing agent used, but may be appropriately selected from among, for example, methylene hydrochloride, chloroform, carbon tetrachloride, petroleum ether, hexane, methanol, ethanol, acetone, acetic acid, water, and the like. In order to obtain the above compound (f), the reaction is usually carried out at room temperature or under ice-cooling using an equimolar amount of an oxidizing agent. Furthermore, if the reaction is carried out for a long time using an excess oxidizing agent or by the reaction under heating, the above compound (g)
is obtained. When a reaction mixture of both is obtained, it can be separated and purified by chromatography or the like. Furthermore, by hydrolyzing the compound (g) obtained in this reaction in the presence of sodium hydroxide, potassium hydroxide, etc., 3-hydroxy-1,2,4- of the general formula (d) can be obtained. It is also possible to lead to oxadiazole derivatives.

Next, the method of the present invention will be explained in more detail with reference to Examples.

Example 1 5.3 g of 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) was suspended in 50 ml of dry benzene, 15 ml of thionyl chloride was added, and after refluxing for 3 hours, the reaction solution was poured under reduced pressure. Concentrated.
The residue was dissolved in 60 ml of dry toluene, 9 g of potassium thiocyanate powder was added, and the mixture was refluxed for 5 hours.
-(2-fluoro-4-biphenylyl)propionylisothiocyanate was produced. Next, add 9.8 ml of n-propyl mercaptan at room temperature and
After stirring at °C for 4 hours, the mixture was cooled and insoluble precipitates were removed at room temperature. The liquid was concentrated to dryness under reduced pressure, and the residue was
Recrystallization from hexane-benzene yields n-propyl N-[2-(2-fluoro-4
-biphenylyl)propionyl]dithiocarbamate was obtained. Melting point 109-110℃.

Next, 4.0 g of this dithiocarbamate compound was dissolved in 100 ml of dry tetrahydrofuran (THF), 0.87 g of potassium hydroxide powder was added, and a solution of 2.24 g of n-propyl iodide in 20 ml of THF was added dropwise with stirring under ice-cooling. The mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure, ice water was added, extracted with chloroform, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily di-n-propyl 2-
(2-fluoro-4-biphenylyl)propionyliminodithiocarbonate was obtained.

NMR (CDCl ₃ ) δ: 0.95 (6H, triplet, J=7
Hz), 1.53 (3H, double line, J=7Hz), 1.30-1.95
(4H, multiplet), 2.93 (4H, triplet, J=7Hz),
3.90 (1H, quartet, J=7Hz) 6.96-7.66 (8H,
multiplet).

Further, the entire amount of the above iminodithiocarbonate was dissolved in 100 ml of methanol, a mixture of 1.0 g of hydroxylamine hydrochloride and 2.64 g of a 28% sodium methoxide methanol solution was added, and the mixture was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, a small amount of water was added to the residue, extracted with chloroform, washed with water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. This residue was adsorbed on a silica gel column, and n-hexane-
Purification by elution with chloroform (2:1) yields
Colorless oily 5-(3-fluoro-4-phenyl-
α-methylbenzyl)-3-(n-propylthio)
3.0 g of -1,2,4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 1560, 1480, 1420, 1255,
1240.

NMR (CDCl ₃ ) δ: 1.03 (3H, triplet, J=7
Hz), 1.45 to 2.13 (2H, multiplet, 1.76 (3H, doublet J = 7Hz), 3.10 (2H, triplet, J = 7Hz) 4.38
(1H, quartet, J=7Hz) 6.96-7.65 (8H, multiplet).

Example 2 By operating according to the method of Example 1, using ethyl mecaptan and ethyl iodide in place of n-propyl mercaptan and n-propyl iodide in Example 1, a colorless oil was prepared. 3-ethylthio-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole was obtained. n ¹⁹ _D 1.5882 IR ν ^neat _nax cm ^-1 : 1560, 1485, 1420, 1270,
1245.

NMR (CDCl ₃ ) δ: 1.43 (3H, triplet, J=7
Hz), 1.75 (3H, triple line, J=7Hz), 3.13 (2H,
quartet, J=7Hz) 4.35 (1H, quartet, J=7
Hz) 7.00-7.60 (8H, multiplet).

Example 3 By operating in the same manner as in Example 1, 2-
(2-Fluoro-4-biphenylyl)propionyl isothiocyanate is obtained, which is reacted with a THF solution of methyl mercaptan at room temperature in a sealed tube.
Methyl N-[2-(2-fluoro-4-biphenylyl)propionyl]dithiocarbamate was obtained. Next, in the same manner as in Example 1, 5-(3-
fluoro-4-phenyl-α-methylbenzyl)
-3-methylthio-1,2,4-oxadiazole was obtained. Melting point 73.5-74°C Example 4 In place of flurbiprofen, n-propyl mercaptan and n-propyl iodide in Example 1, ketoprofen (2-(3-beozoylphenyl)propionic acid) and ethyl mercaptan were used, respectively. By operating according to the method of Example 1 using ethyl iodide and ethyl iodide, 5-
(3-Benzoyl-α-methylbenzyl)-3-ethylthio-1,2,4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 1665, 1565, 1450, 1325,
1285, 1250.

Example 5 Colorless prismatic crystals were prepared by operating according to the method of Example 1, using benzyl mercaptan and benzyl bromide in place of n-propyl mercaptan and n-propyl iodide in Example 1, respectively. 3-benzylthio-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,
2,4-oxadiazole was obtained. Melting point 80.5
-81°C Example 6 2.0 g of 2-(4-isobutylphenyl)propionic acid (ibuprofen) was dissolved in 30 ml of dry benzene, 5 ml of thionyl chloride was added, and the mixture was refluxed for 2 hours, and then the reaction solution was concentrated under reduced pressure. Dissolve the residue in 30 ml of dry toluene and add 1.7 ml of potassium thiocyanate powder.
When the mixture was refluxed for 8 hours, 2-(4-isobutalphenyl)propionyl isothiocyanate was produced. Then n-octanethiol 2.52
ml was added at room temperature and stirred at 70°C for 3 hours. After cooling, the insoluble precipitate was removed, the liquid was concentrated under reduced pressure, the residue was adsorbed on a silica gel column, and n-hexane-
Purification by elution with chloroform (2:1) yields
2.2 g of n-octyl N-[2-(4-isobutylphenyl)propionyl]dithiocarbamate was obtained as pale yellow crystals.

IR ν ^neat _nax cm ^-1 :3260, 2960, 2930, 2850,
1720, 1465, 1200.

Next, 990 mg of this dithiocarbamate compound was dried.
Dissolved in 20ml of THF, added 200mg of potassium hydroxide powder, stirred under ice cooling, and then added 1-bromooctane.
580 mg was added and stirred at room temperature overnight. Ice water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give di-n-octyl 2-(4-isobutyl fluoride) as a pale yellow oil. 1.21 g of enyl) propionyliminodithiocarbonate were obtained.

IR ν ^neat _nax cm ^-1 :2950, 2925, 2850, 1675,
1570, 1460 Further, the entire amount of the above iminodithiocarbonate was dissolved in 25 ml of methanol, a mixture of 0.22 g of hydroxylamine hydrochloride and 0.58 g of 28% sodium methoxide methanol solution was added, and the mixture was refluxed for 3 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, the organic layer was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was adsorbed onto a silica gel column and purified by elution with n-hexane-ether (80:1) to give 5-(4-isobutyl-α-methylbenzyl)-3-(n-oxytylthio)-1 as a colorless oil. ,2,
0.83 g of 4-oxadiazole was obtained. n ¹⁹ _D
1.5159.

Example 7 n-octyl N-[2-(4-isobutylphenyl)propionyl]dithiocarbamate 1.13 g
Dissolve potassium hydroxide powder in 20ml of dry THF.
After adding 0.23 g and cooling on ice, 0.49 g of methyl iodide was added and stirred for 4 hours. The reaction solution was diluted with water, extracted with chloroform, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to yield methyl octyl 2-(4-isobutylphenyl) propionyliminodithio as a pale yellow oil. 1.03 g of carbonate was obtained.

NMR ( _CDCl3 ) δ: 0.83-1.0 (3H, multiplet),
0.87 (6H, double line, J=7Hz), 1.10~1.70 (12H,
multiplet), 1.52 (3H, doublet, J=7Hz) 1.70~
2.00 (1H, multiplet) 2.36 (3H, singlet), 2.42 (2H,
double line, J=7Hz), 2.93 (2H, triple line, J=8
Hz), 3.85 (1H, quartet, J=7Hz), 7.04 (2H,
double line, J=9Hz), 7.21 (2H, double line, J=9
Hz).

Next, dissolve the entire amount of iminodithiocarbonate in 25 ml of methanol, add 0.23 g of hydroxylamine hydrochloride and 0.60 g of 28% sodium methoxide.
A mixture of these was added and the mixture was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with chloroform, washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was adsorbed onto a silica gel column and treated with n-hexane-ether (40:1).
When eluted and purified, each colorless oily 5-
(4-isobutyl-α-methylbenzyl)-3-
(n-octylthio)-1,2,4-oxadiazole 0.45 g and 5-(4-isobutyl-α-methylbenzyl)-3-methylthio-1,2,4-
0.22 g of oxadiazole was obtained. the latter
The NMR data were as follows.

NMR (CDCl ₃ δ: 0.89 (6H, doublet, J=7
Hz), 1.71 (3H, double line, J=7Hz), 1.62-2.10
(1H, multiplet), 2.43 (2H, doublet, J=7Hz)
2.57 (3H, singlet) 4.30 (1H, quartet, J=7
Hz), 7.07 (2H, double line, J=9Hz), 7.21 (2H,
Double line, J=9Hz)).

Example 8 By operating in the same manner as in Example 6, 2-
(4-isobutylphenyl)propionic acid to 2
-(4-isobutylphenyl)propionylisothiocyanate was obtained, using a silica gel column,
0.93 g of a colorless oily product obtained by elution with n-hexane-chloroform (3:1) was added to 20 g of toluene.
ml and sealed in an autoclave with 0.9 ml of allyl mercaptan. Heat this at 50 to 60℃ for 5
After heating for an hour, the mixture was allowed to cool, and the reaction solution was concentrated under reduced pressure. The residue was adsorbed on a silica gel column and n-
Purification by elution with hexane-chloroform (3:2) yielded 0.46 g of allyl N-[2-(4-isobutylphenyl)propionyl]dithiocarbamate as a yellow oil.

IR ν ^neat _nax cm ^-1 : 3270, 2950, 2925, 1720,
1465, 1210.

Next, dry the entire amount of this dithiocarbamate.
Dissolved in THF10ml, potassium hydroxide powder 0.11g
and 0.21 g of allyl bromide were added and stirred at room temperature for 4 hours. The reaction solution was diluted with water, extracted with chloroform, washed with water, dried, and then the solvent was distilled off under reduced pressure to obtain 0.52 g of diallyl 2-(4-isobutylphenyl)propionyliminodithiocarbonate. Further, this entire amount was dissolved in 15 ml of methanol, a mixed solution of 0.13 g of hydroxylamine hydrochloride and 0.35 g of 28% sodium methoxide was added, and after refluxing for 2.5 hours, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extracted with chloroform, washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by adsorption on a silica gel column and eluted with n-hexane-ether (20:1) to give 3-allylthio-
5-(4-isobutyl-α-methylbenzyl)-
0.11 g of 1,2,4-oxadiazole was obtained. n ²² _D 1.5360.

Example 9 1.17 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylthio-1,2,4-oxadiazole was dissolved in 100 ml of methylene chloride, and 0.68 g of m-chloroperbenzoic acid was dissolved. g was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, washed with brine, and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was adsorbed on a silica gel column, and purified by elution with chloroform to give 5-(3-fluoro-4-phenyl-α) as a colorless oil.
-methylbenzyl)-3-methylsufinyl-1,
0.94 g of 2,4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 1555, 1480, 1260, 1080.

Example 10 Dissolve 2.15 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylthio-1,2,4-oxadiazole in 80 ml of methylene chloride, and dissolve 3.54 g of m-chloroperbenzoic acid. Add g and at room temperature
After stirring for 1.5 hours, the mixture was further refluxed for 2 hours. After cooling, the mixture was washed with saturated sodium bicarbonate solution, water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from n-hexane-benzene to give colorless fine crystals of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylsulfonyl-1,2,
2.1 g of 4-oxadiazole was obtained. Melting point 102
−103℃.

Example 11 2.6 g of 3-ethylthio-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole was dissolved in 60 ml of methylene chloride, and m-chloro was added under ice cooling. 1.4 g of perbenzoic acid was added and stirred at room temperature for 3 hours. Then, by treating in the same manner as in Example 9, 3-ethylsulfinyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole was obtained as a colorless oil. 2.2g was obtained.

IR ν ^neat _nax cm ^-1 : 1555, 1485, 1420, 1270,
1081.

Example 12 3-ethylsulfinyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,
1.5 g of 4-oxadiazole in 30 ml of methylene chloride
Dissolve 1.1 g of m-chloroperbenzoic acid under ice-cooling.
was added and stirred for 3 hours. Then, by treating in the same manner as in Example 9, 1.1 g of 3-ethylsulfonyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole was obtained as a colorless oil. was gotten.

IR ν ^neat _nax cm ^-1 : 1555, 1485, 1420, 1340,
1150.

NMR (CDCl ₃ ) δ: 1.43 (3H, triplet, J=7
Hz), 1.81 (3H, double line, J=7Hz), 3.41 (2H,
quartet, J=7Hz), 4.48 (1H, quartet, J=7
Hz), 7.00-7.60 (8H, multiplet).

Example 13 By operating according to the method of Example 10, 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-n-propylthio-1,2,
4-oxadiazole to 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-n
-Propylsulfonyl-1,2,4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 1550, 1480, 1460, 1420,
1340, 1145.

NMR (CDCl ₃ ) δ: 1.12 (3H, triplet, J=7
Hz), 1.86 (3H, double line, J=7Hz), 1.80-2.14
(2H, multiplet), 3.33 (2H, triplet, J=7Hz),
4.46 (1H, quartet, J=7Hz), 7.00~7.53 (8H,
multiplet).

Example 14 5-(4-isobutyl-α-methylbenzyl)-
Dissolve 0.76 g of 3-(n-octyl)-1,2,4-oxadiazole in 30 ml of methylene chloride, add 0.38 g of m-chloroperbenzoic acid under ice cooling, and dissolve at room temperature.
Stir for 15 minutes. Then, by treating in the same manner as in Example 9, 5-(4-isobutyl-α-methylbenzyl)-3-n-(octylsulfinyl)-1,2,4-oxadiazole was obtained as a colorless oil.
0.78g was obtained.

IR ν ^neat _nax cm ^-1 : 1555, 1515, 1460, 1260,
1175.

Example 15 5-(4-isobutyl-α-methylbenzyl)-
3-(n-octylsulfinyl)-1,2,4-
0.78 g of oxadiazole was dissolved in 30 ml of methylene chloride, 0.38 g of m-chloroperbenzoic acid was added at room temperature, and the mixture was stirred for 24 hours. Then, by treating in the same manner as in Example 9, 5-(4-isobutyl-α-methylbenzyl)-3-n-(octylsulfonyl)-1,2,4-oxadiazole was obtained as a colorless oil.
0.78g was obtained.

n ²¹ _D 1.5056 Example 16 Flurbiprofen 10.6g dried benzene 100
After adding 40 ml of thionyl chloride and refluxing for 3 hours, the reaction solution was concentrated under reduced pressure. 12.6g of potassium thiocyanate and 100ml of toluene to the residue
was added and refluxed for 5 hours, and 20 ml of methanol was added to the reaction system without isolating the produced 2-(2-fluoro-4-biphenylyl)propionyl isothiocyanate, followed by stirring at 100°C for 30 minutes. After cooling, insoluble matter was removed, and the liquid was concentrated to dryness under reduced pressure. The residue was recrystallized from n-hexane-benzene to give colorless needles of o-methyl N-[2-(2-
9.6 g of fluoro-4-biphenylyl)propionyl monothiocarbamate were obtained. Melting point 132.5
~133℃.

Next, 9.0 g of this thiocarbamate body was dried.
Dissolved in 70ml of THF and cooled with ice 2.4g of potassium hydroxide
A solution of 5.2 g of methyl iodide in 10 ml of THF was added and stirred for 1.5 hours. Dilute the reaction solution with ice water,
The extract was extracted with chloroform, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 9.2 g of dimethyl 2-(fluoro-4-biphenylyl)propionyliminothiocarbonate as a colorless oil.

NMR (CDCl ₃ ) δ: 1.52 (3H, triplet, J=7
Hz), 2.28 (3H, singlet), 3.82 (3H, singlet),
3.86 (1H, quartet, J=7Hz), 6.90~7.65 (8H,
multiplet).

Further, the entire amount of iminothiocarbonate was dissolved in 150 ml of methanol, and a mixture of 2.5 g of hydroxylamine hydrochloride, 50 ml of methanol, and 6.7 g of a 28% methanol solution of sodium methoxide was added, and the mixture was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, cold water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. This residue was adsorbed onto a silica gel column and purified by elution with n-hexane-ether (5:1), yielding 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methoxy-1,
7.36 g of 2,4-oxadiazole was obtained. When this product is recrystallized from n-hexane, the melting point is
It became colorless needle crystals at 63.5-64℃.

Example 17 A colorless oily 5 −(3
-benzoyl-α-methylbenzyl)-3-methoxy-1,2,4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 1660, 1595, 1555, 1390.

NMR (CDCl ₃ ) δ: 2.75 (3H, doublet, J=7
Hz), 4.00 (3H, singlet), 4.36 (1H, quartet, J
=7Hz), 7.30−7.95 (9H multiplet).

Example 18 0.67 g of 60% sodium hydride was suspended in 20 ml of dry dimethylformamide (DMF), and a solution of 1.2 ml of ethyl mercaptan in 10 ml of DMF was added dropwise under ice cooling. After the evolution of hydrogen has stopped, add 1.99 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methoxy-1,2,4-oxadiazole to 8 ml of DMF under ice cooling in a nitrogen stream. The solution was added and stirred for 1.5 hours. The reaction solution was diluted with brine, 1N hydrochloric acid was added to adjust the pH to about 4, and the mixture was extracted with ether. Wash the ether layer with saturated saline and water,
After drying over magnesium sulfate and removing the solvent under reduced pressure, 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-hydroxy-1,2,4-
1.76 g of crude crystals of oxadiazole were obtained. This was recrystallized from n-hexane-ethyl acetate to give colorless needles with a melting point of 153-154°C.

Example 19 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-n-propylsulfonyl-1,
0.75 g of 2,4-oxadiazole in 8 ethanol
ml and 10ml of 2N sodium hydroxide aqueous solution.
was added and stirred at room temperature for 5 hours. Add to the reaction solution under ice cooling.
The mixture was made weakly acidic by adding 2N hydrochloric acid, extracted with chloroform, washed with water, dried, and the solvent was distilled off under reduced pressure. When the residue is recrystallized from benzene, colorless needle crystals of 5-
(3-fluoro-4-phenyl-α-methylben)
0.25 g of -3-hydroxy-1,2,4-oxadiazole was obtained. Melting point 151-153℃.

Example 20 By operating in the same manner as in Example 18, 5-
From (3-benzoyl-α-methylbenzyl)-3-methoxy-1,2-4-oxadiazole, colorless oily 5-(3-benzoyl-α-methylbenzyl)-3-hydroxy-1,2, 4-oxadiazole was obtained.

IR ν ^neat _nax cm ^-1 : 2300~3500, 1650, 1595,
1540, 1320, 1280.

Example 21 100 mg of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-hydroxy-1,2,4-oxadiazole was dissolved in 3 ml of dry THF,
Under ice-cooling, 0.1 ml of triethylamine and 50 mg of pivaloyl chloride were added and stirred for 1 hour. The reaction solution was diluted with water, extracted with chloroform, washed with aqueous sodium bicarbonate, dried, and the solvent was distilled off under reduced pressure. Residue n-
Recrystallization from hexane-benzene gives colorless needles of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-pivaloyloxy-1,2,
4-oxadiazole was obtained. Melting point 105.5−
106.5℃.

Example 22 120 mg of 60% sodium hydride was suspended in 10 ml of dry DMF, and 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-hydroxy-
1,2,4-oxadiazole 800mg in DMF 10ml
The solution was added gradually and stirred for a while. Next, 500 mg of ethyl 2-bromoacetate was added under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid and aqueous sodium bicarbonate, dried over magnesium sulfate, and then evaporated under reduced pressure. The residue was adsorbed on a silica gel column and purified by elution with n-hexane-chloroform (1:4) to give a colorless oil of 3-ethoxycarbonylmethoxy-5-(3-fluoro-4-phenyl-α-
methylbenzyl)-1,2,4-oxadiazole was obtained.

n ²⁴ _D 1.5487.

Example 23 3-ethoxycarbonylmethoxy-5-(3-
fluoro-4-phenyl-α-methylbenzyl)
-Dissolve 390 mg of 1,2,4-oxadiazole in 2 ml of methanol, and dissolve 180 mg of potassium hydroxide in 2 ml of water.
ml solution was added and stirred for a while at room temperature.

The reaction solution was made weakly acidic by adding 1N hydrochloric acid, extracted with chloroform, washed with water, dried, and then the solvent was distilled off under reduced pressure to obtain 3-carboxymethoxy-5 as a colorless oil.
274 mg of -(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole was obtained.

n ²⁴ _D 1.5562.

Claims (1)

[Claims] 1. General formula [In the formula, R-X- is a phenyl group, benzoyl group or isobutyl group, Y is a hydrogen atom or a halogen atom, T is a methylmethylene group, and U is a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkoxy carbonyl-lower alkyl group, carboxy-lower alkyl group, alkanoyl group or aryl-lower alkyl group, Z is -O-, -S-,
-S(O)- or -S( _O2 )-. ] 3,5-disubstituted 1,2,4-oxadiazole derivative 2 represented by U is a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkyl group, or an aryl-lower alkyl group and Z is a group represented by the general formula -S(O) _o - (n means 0, 1 or 2), 3,5-disubstituted 1, 2,4-oxadiazole derivative 3 3,5- according to claim 2, wherein R-X- is a p-phenyl group and Y is a m-fluoro group.
Disubstituted 1,2,4-oxadiazole derivatives. 4 3,5-disubstituted 1,2,4-oxadiazole derivative according to claim 2, wherein R-X- is m-benzoyl group and Y is hydrogen atom 5 R-X- is p- 3,5-disubstituted 1,2,4-oxadiazole derivative according to claim 2, wherein the isobutyl group and Y are hydrogen atoms.