JPH01500521A - imidazole derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] imidazole derivative The present invention is based on the general formula ■: [In the formula, R1 represents hydrogen or 0-lm- or p-position, and these four groups] -R7 may be present in the phenyl group 11 times or more times, and R4 is , Hs and R9 are hydrogen or a linear or branched chain having 1 to 6 carbon atoms. represents an alkyl group, R7 and R8 may be the same or different, hydrogen or represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms or R7 & R8 is a saturated heterocyclic 5^ with optionally a secondary heteroatom together with a divalent atom; represents a ring or a 6-membered ring, R5 is hydrogen, an alkyl group having 1 to 6 carbon atoms, or ZN activity of alkoxyalkylfit gold having 1 to 6 carbon atoms Concerning imidazole derivatives.

Halogen means fluorine, halogen, bromine or iodine, with fluorine and chlorine being preferred.

Alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms. group, such as methyl, ethyl, furopyru, ingropyru, butyl, penyl, ethyl and hexyl groups. Preferred form of alkoxyfurkyl of Ha as C1~, alkoxy-C,~, alkyl, especially 01-4 alkoxymethane. Chill is an example.

If R7 and R8 are saturated with other heteroatoms than Vc, Heterocyclic 5M block or 6^ ring t-syn, morpholine or biperazone.

Is it the center of vertebrates? 'Certain parts of the P system contain 1,4- and 1,5-benzodiazes. It is known that 5qui has a very unique affinity for pin binding. res, R, F.

and nraestrup+ cm Nature (London) K266 volume ( (1977), p. 764]. This site is called the benzodiazepine receptor.

Surprisingly, the t-substituted imidazole derivative according to the present invention has the following properties: Despite its chemical structure being strikingly similar to that of benzodiazepines, benzodiazepines It shows remarkable affinity and specificity for the binding of pin receptors, and has a slight affinity for #8. It was found that there was an insertion pressure.

In this way, the uninvented compound* is, for example, free from benzodiazepines. It can have mutually beneficial effects, conversely, mutually beneficial effects, and antagonistic effects on residential purchases.

Benzodiazepines, such as RF injections, 2-year-old women's relaxation and muscle 5'Ig relaxation. ! It exerts lE as well as headache effects.

The disadvantage of benzodiazepines is that they have a relatively broad spectrum of action with only modest selectivity. It is le.

That revision, there is still a requirement for sufficient Aiyani note quality to have an effect on the solution gZN. .

The compounds according to the invention, on the basis of their biological effects, can be used as psychotropic drugs in human medicine. It is appropriate. Class compounds can be used, for example, for oral and parenteral use. It can be used to formulate drugs.

Formulation auxiliaries include physiologically compatible organic and inorganic substances that are inert to the compounds of the invention. Support materials are suitable.

Examples of supporting substances include: water, salt M, alcohol , eryethylene glycol, polyhydroxyethoxylated castor oil, gelatin, latin Curcum, silicic acid, mono- and diglycerides of fatty acids, pentaerythritol fatty acids esters, hydroxymethylcellulose and polyvinylpyrrolidone.

Pharmaceutical information is sterilized and/or contains auxiliary agents, such as laminating agents, preservatives, stabilizers, and penetrants. Agents, emulsifiers, acidifying agents, and layer coloring agents may also be used.

For parenteral use, in particular injection solutions or suspensions, especially active compounds A bath solution dissolved in ethoxylated castor oil is suitable. Ore, Izume active as a support agent Adjuvants, such as bile salts or intravenous injections or a9B phospholipids, mixtures thereof You can also use cell fat tonic or its components.

For oral FFJ use, Merck and/or hydrocarbon carriers or binders, e.g. Tablets, dragees or capsules with cutose, corn or potato starch The text is appropriate. It can be used in 'tL-shaped form, for example, as a liquid; Add sweetener if necessary.

The compound according to the invention is physiologically compatible with the active substance in dosage units of 0.05 to 10 my. be sentenced to sexual assault.

The compound according to the VC of the present invention can be used for 0.1 to 300 η7 days, preferably 1 to 30 η7 days. Use in doses.

The preparation of compounds of the general formula I according to the present invention includes those of the general formula I: Aniline with the general formula m [In the formula, R4 and R5 represent the above-mentioned fr: X and YrI.

In the presence of 2-abbutadiene (representing a group to be replaced by f) and an acid, at a temperature of 0 to 150"C. to transesterify the ester groups present in the molecule or to transesterify V′i , saponified, optionally esterified free carboxyl groups, amidated or is the formula: R,'-C(-NOH)NH2 reacted with amidoxime to form 5-oxa zoazolyl derivatives and optionally hydrolyze the nitrile group present in the molecule. carbonylamide group or carboxyl group, or via an imidiester group. Amidoxime is converted into a stellate group (COOR’) or converted into a hydroxylamine. followed by activation induction of an alkane carboxylic acid or acid of the formula: u'-cooH This is carried out by converting the compound into a 3-oxazoazolyl derivative in the body.

According to the present invention, aniline of the formula (1) is reacted with 2-abbutadiene (2) of the formula I. The reaction resulting in the midazole derivative is carried out in the presence of an acid at a temperature of 0 to 150°C.

As ft-substituted groups X and Y, in particular sialkylamines, such as dimethylamine and diethylamine and cyclic amines such as pyrrolysine.

The reaction can be carried out, for example, by combining an aniline derivative and abbutadiene with an organic compound such as formic acid, acetic acid, etc. , stirred in propionic acid or trifluoroacetic acid at temperature, then the reaction mixture This is done by heating it up to a temperature of about 120°C (approximately 120°C).

The acid can serve simultaneously as a reactant and as a bath agent. however Bath agents such as alcohols, ethers, ketones, esters such as ethyl acetate, charcoal hydrogenated hydrocarbons, such as doluol or halogenated hydrocarbons, such as urea tetrachloride. You can also add

The amount of acid used can vary within a wide range, but is used in "weekly" amounts. preferably Choose a 6 to 10 times excess of acid over aniline and 7 degtadiene.

The molar ratio of aniline to 7-debutadiene is not critical to the outcome of the reaction. one Generally, V equimolar amounts of the reactants are used, in this case 1 aniline and 7 degtazoene 1 ．． The molar ratio with 1 is very close. The reactive ore according to the invention is in principle contacted in the bath agent mentioned above. It is carried out with small amounts of mineral acids such as sulfuric acid, salt, perchloric acid or p-dololsulfonic acid. You can also

The Jl different origin of the method of the present invention is that the imidazole that forms only the A body in a single step Chemical interpretation synthesis of derivatives.

Transesterification Kr that governs depending on the case! :, all the commonly used methods are unwarranted. example reaction of a carboxylic ester with a suitable alcohol in the presence of an alcoholate or By reaction with a suitable alcohol with titanium-tetraalcoholate or in the presence of relatives Examples include reaction with alcohol. Transesterification occurs at temperatures of approximately 0 to 120'0 Do it.

The optional subsequent saponification of the ester groups is preferably carried out bare-alkaline and in this case Synthetic esters can be prepared using a diluted alkaline water bath solution, such as potassium hydroxide or sodium hydroxide. Heat to reflux temperature in a thorium bath.

Esterification of the carboxyl group is carried out in a well-known manner with a suitable alcohol. Carry out in the presence of injection acid derivatives. As activated acid derivatives, for example, Midazolid or anhydride are suitable.

For amidation, imidazole-4-carboxylic acid or the corresponding ester, N, N '-Carbonylzimidazole #also using Hzocyclohexyllupozoimide, The reaction is carried out by chlorination with activated acid derivatives, e.g. anhydrides or mixed hydrates, in a known manner. iii ester. Amidation is usually carried out using neutral bath agents, e.g. Temperature with methylformamide, tetrahydrofuran, doluol or methylene chloride The temperature is 0 to 100"C.

To convert the 5-oxazoazolyl group, imidazole-4-carboxylic acid is added. , formula: Rg-C(-NOH)NH.

The amidoxime of [formula R9 represents the compound in formula 1] and the reaction between d and d in the inactive bath additive Complementation can also be carried out at the fouling temperature of the reaction mixture. Examples of inert solvents include Luol and trimethylformamide are suitable. Preferably the free carboxylic acid is , -activated in an unreasonable manner before the synthesis reaction. For this purpose, free sulfuric carboxylic acids are The combined anhydride, tIi-formed ester or chloride VC is transformed. Imidazole/thichloride neutral bath agents such as dioxane, tetrahydro7rane, dimethylform Activation in amide or N-methyl birolide at temperatures between 0 and 50 °C is sufficient. It turned out that there is one thing.

The optional subsequent conversion of the nitrile group can be carried out by known methods. example For example, a nitrile group can be converted into a carbonylamide group by acidic or alkaline water decomposition. Or change it to a carboxyl group, or add hydrogen chloride gas with a suitable alcohol. can be converted into an ester group via an imidiester group.

IC for converting 3-oxadiazolyl foundation is imidazole-4-carbonitri is reacted with hydroxylamine to amidoxime in a known manner followed by formula: R9-C0OH (Rρ is of formula I t- of the flucancarboxylic acid or acid represented by Condensate with the activated derivative in an inert cleavage. Condensation is a 5-oxadiazolyl compound Do it in the same way as for the lift.

The 7-niline of the general formula layer and the 2-7 degutazoene of the general formula vagina used as raw materials are publicly available. It can be manufactured by the knowledge method or the method. 2-7 degutazo x7 is, for example, d Liebigs Annalander Ch amie (1980) g344M and German cargo eaves stripe 2919891 @ii -It is written in the book.

Next, t-B5 for producing fr2-7 degtazoene 2-4 used in Examples will be explained.

7zu getadien 1 1.4-bis(dimethylamino)-2-az-1゜5-getadiene-5-carbo acid ethyl ester.

L engineering a1ga Annalen dar Checnte (1980) No. 3 According to 44jjK.

Azubtagen 2 1.4-bis(dimethylamino)i-(+-ethyl-1,2,4)-oxaqua Sol-5-yl)-2-7de-1,3-butadiene.

5-7minomethyl-6-ethyl-1.2.4-oxadiazole 11.5&andzome A mixture of chillform 7 and midozomethyl acetal 24d was heated at 80°C for 7 hours. Ru. The methanol 101jt-W produced in this process is removed. Furthermore, DMF-acetal 1 After boiling 281, the mixture is boiled for 3 hours under overflow and then fractionally distilled.

7, 7 distillation at 155-160° & 0-05 mBg 2) is obtained with a concentration of 72 f/=(D-1-5908).

The raw material is made using the following method.5: 3-ethyl-5-(7talimidomethane)-1゜2.4-oxazoazo Le.

Phthalimide R65,711k Tetrahydro22F (THF) 5 LI Carbonylciimidazole 26 at 40°C to 0ajrC and 27≧vtjg ．． Add a 1° suspension of 0&’t” THF250ajC to the side. After about 1 hour, Catfish no longer produce gas. Therefore, propioamidoxime 28.2 gk D) Add 1R of IP5Qajr bath solution and stir at room temperature for 24 hours. Shen After filtration of the precipitate, the alg was washed in vacuo and dried kijiroll soomtt-4 Then heat in a water separator under rapid flow for 6 hours. Separation of oily residue from still ripe liquid and condense in vacuo. Melting point 106-107°C after crystallization from ethanol Phthalimide with 31.51/(76 for carbonyldiimidazole) ．． 5%) is obtained.

佽) 5-amitsumethyl-3-ethyl-1,2,4-oxadiazole.

Phthalimide: 52.211't To a suspension dissolved in methanol 250#j, Hydrazine 4.5, f (140 moles) tJ) 0, its wAw quality Dissolves quickly. Boil the reaction mixture eta for 6 hours to form a precipitate! absorb wisdom Filter, add methanol to +9 [, #shi, and test filtrate. After suspending the IC, it is filtered again, diluted with mkgV"ram, and the boiling point is 90~ 100°C (0.31 liters Hg).

Yield 3114.87N (91.6+%) a “20” +4691° Adegtazo E15 1.4-bis(dimethylamino)-6-cy7no-2-azobutadiene.

Amino-7tonitrile 45.9 and dimethylformamide-dimethyl acetal 1 Mixed with 90J/4! rV for 4 hours at 100°C (bath m degrees) with humidity tgtr. Heat for 3 hours at 120°C at f, -. At that time, volatile sodium chloride* (methanol) ) Approximately 90d was exported, and 1ooazt- of DMF-dimethyl acetal was newly added. and further heated at 150"C (bath temperature) for 5 hours.Following fractional steaming in vacuum fIV rc gives the following 7 rakions: hook stain/1 (f9 points 64-74 °C/　0-04　am　Hg): Zomethylaminomethyleneamino 77tonitrile 59.9# (67.4%).

7 Luxion 2 (boiling point 115-125"C10,03 1Hg): title 511C25, 5q6).

The title compound vlJ is crystallized from hexane. Melting point: 78-81°C.

Azobutadiene 4 6-dia2-1-dimethylamino-4-vicrizono-2-azo-1,3-penta Jen.

dimethylaminomethyleneamino7cetonitrile22Isdimethyl77doamidedi Methyl acetal 2iA baboon r:s! 7 So714 Noff1@t-% 8 Heat at 0'Cj (bath d degree) for 488 hours. X It shrinks in the air, and then the original tube becomes a fish. After heating (160-185℃ 10-08mHg rich), the title compound was obtained. It is crystallized from hexene. M point 49-55-QCffi% Z-d *).

Azobutadiene 5 1-dimethylamino-5-(5-ethyl-1,2゜4-oxazoazo-5-y Leku 4-pyrrolisino 2-fupene/-1,5-diene (g%2).

ω 5-Aminomethyl-3-ethyl-1,2,4-oxazol 71-ol 261 and sol 6. The mixture w of methylformua Z and dozomethyla heptatal 3Qaj was heated at 80°C. Heat for 5 hours.

Subsequently, the methanol 16al was removed with WI, and the shaped product was purified by distillation of a bulb. make 3-Ethyl-5-(N-dimethylaminomethyleneaminomethyl)-1° 27.9 g (74,81) of 2,4-oxadiazole are obtained.

Node 130~150℃/　0-05　am　Hg　o　nj'　1-4924( b) Product obtained in 1g) 13.6, 9. Zomethylacetamidosimethyla Setal 15.0 and pyrrolidine 8. OIi was heated at 80°C under nitrogen for 21 hours. do. The alcohol formed by the reaction is distilled off, and the reaction product 'il! On 21, Ichigen tube steaming Purify by distillation. Distilled at 215-230"CE/0.04jJHg 7 traction of 15.4N is obtained. Recondensed from n-hexane, melting point The title compound 9.5.9 (45.7%) having 59-61C'i is obtained.

abbutagen 6 1-dimethylamino-6-(6-nityl-1.2゜4-oxazo7sol-5-y )-5-methoxy-4-(1-pyrrolizonyl)-2-7 depenter-1,3-di en (3%Z).

) Methoxyacetic acid-zomethylamidozomethyl acetal.

trimethyloxonium-tetrafluoroborate 53.4 & with cooling. Add 42.4 # of methoxyacetic acid-dimethylamide in three portions. Then anti The reaction mixture was stirred at mold temperature for 2 hours and left overnight. Dichloromethane 40dVC dissolved After that, the salt formed is dissolved in a solution of sodium methoxide in methanol. Thorium 10.4. ? was dissolved in methanol 225H and gradually added to Ru. Then, stir at mold temperature for 2 hours. For post-treatment, suction filter all the precipitate that has formed. Filter and wash with a small amount of ethanol. The filtrate forms an IC2 phase after distillation of the solvent. . The desired product '@9゜08.9 (15 cm) was obtained from the upper phase by the steam droplet of the bulb. It will be done.

Node 54-57-0/14aaHgo n,,': 1-4204°(b) The product w8-8# obtained in (transformation) was converted into 6-nityl-5-(N-dimethylamino Methyleneaminoethyl>-i.

2.4-oxazazole 6.62 and pyrrolidine 4.5d with abbutadiene The reaction is carried out in the same manner as in the production of 5. Abbutagen 6 due to urine collection in the bulb ii, agcii%) are served.

m11220~240''C/0.05xxHg Example Example 1 (a) 1-(3-chlorophenyl)-imidazole-4-carboxylic acid-ethyl ether Stell.

While cooling, add Abbutagene 1 2.2 Nk glacial acetic acid 8 atK drops, followed by 6 -Kroll 7 Nirin i! It-add. blend? 1 Stir for 30 minutes at mold temperature, then continue. Heat at 80'''C (bath temperature) for 5 hours. Treat with sodium hydrogen carbonate bath solution. After that, the crystalline residue is crystallized from diisopropyl ether. Title compound 1 ．． 65& (81% relative to chloraniline) is obtained. Melting point 104-106℃ .

Analogously to example (1a), the following is obtained: (b) 3,4-dichlora Nilin to 1-(3,4-dichlorophenyl)-imidazole-4-carboxylic acid -Ethyl ester.

(C) 4-Chloraniline, C'' et al. 1-(4-chlor7enyl)-iotasole Ru-4-carvone is monoethyl ester.

((1) 4-fluoroaniline to 1-(4-,yluol7znyl)-'f mir’l”-ru 4-carboxylation-ethyl (transformation) 1-(3-/lorphenyl )-Imi I’! -4-carboxylic acid-isoglobil ester.

1-(3-chlorophenyl)-imitasol-4-carvone-ethyl ester 0.4.9ki-7' lovanol 40a or 1-bath m't-, titanium-tet Lysopropal) Q, 5aj and boil for 8 hours. Reduced the bath liquid It is then treated with silicic acid and crystallized from diisopropyl ether. Jii From sopropyl ether, the title compound '41J267Mk?, melting point 109°C. C6 5ch) is obtained.

In the same way, manufacture: (b) 1-(4-fluorophenyl)-imidazole-4-carboxylic acid-imp Lobil ester.

Example 3 ←) 1-(3-chlorophenyl)-imifole-4-carboxylic acid.

1-(3-chlorophenylcouimidazole-4-carboxylic acid-ethyl ester A suspension of 11 in 2N-xOHloaj't-,IioC (bath temperature) Heat for an hour. After cooling for 4 hours, the precipitate 91J was acidified to -6~4 with 4N HCl, and the precipitate 91J was converted to 1- Crystallize from the propa tool. Table t4v compound with melting point 195-C'ft *0. 737 (82%) were obtained.

In the same way you get: (b) 1-(4-fluorophenyl)-imidazole-4-carboxylic acid.

Example 4 (transformation) 1-(3-chlorophenyl)-(midazole-4-carvone cough-zoethyl Ruamide.

MC Example 3a) 0-56. ! / in a bath solution of 10 dic of dimethylformamide , drop N, di-carbonyldiimidazole 0.5.9 dissolved in pMip5aj. The solution was heated at 60°C for 60 minutes until the gas evolution stopped, and then Add to 1.3jLg1 of diethylamine. Heat the mixture at 90°C for 2 hours and apply vacuum It shrinks in water and precipitates with water.

The crude product is crystallized from diisopropyl ether.

The title compound with melting point 105°C (from diisopropyl ether) 0.48.9 ( 70chi) is obtained.

In the same way you get: (1-(4-fluorophenylcouimidazole-4-carboxylic acid-diyl) Sopropylamide.

Example 5 France) 1-(3-chlorophenyl)-4-(5-ethyl-1,2,4-oxadi Azol-5-yl)-imidazole.

3-chloroaniline and azogetadiene 2 were prepared in the same manner as in Example 1 (Company). Let's do it from 60% compound cutting of the plate axis with a melting point of 164-165℃ (ethyl acetate) was obtained. It will be done.

In the same way, the following can be served from the corresponding aniline: Cb) 1-(3-4-zo10ruphenyl)-4-(3-ethyl-1,2,4- 5-yl)-imidazole.

Stem) 1-(4-chlorophenyl)-4-(3-ethyl-1,2,4-oxazo Azol-5-yl)-imidazole.

(d) 1-(4-fluorophenyl)-4-(3-ethyl-1,2,4-, oxy Thadiazol-5-ylzimidazole.

(θ) 1-(3-bromphenyl)-4-(3-ethyl-1,2,4-oxa Diazol-5-yl)-yl (a) 1-(3-chlorophenyl)-imidazole -4-carbonitrile.

The preparation is analogous to Example 1(a) from 6-chloroaniline and azogetadiene 6. Let's do it. By chromatography, 1-C5-chlorophenyl)-yl 55% of the title compound is obtained along with 25% of the fsol-4-carboxylic acid amide. .

Example 7 (a) 1-(3-chlorophenyl)-5-methyl-yl-sol-4-carboni Trill.

Preparation t1 Same as in Example 1) 5 & 3-Chloraniline and azogetadiene 4 Let's do it from By silica chromatography, 60 molecules of the title compound were obtained. is obtained.

Melting point 117-118°C (diisopropyl ether).

(匈　1-(6-chlorophenyl)-5-methyl-ylfsol-4-carvone Acid amide.

Melting point 179-181°C (fraud ester). Yield: 3.4 cm.

In the same way you get: ←) 1-(4-fluorophenyl)-5-methyl-imidazole-4-carbo Nitrile.

Example 8 ω 1-(3-chlorophenyl)-4-(5-ethyl-1,2,4-oxazoa Sol-3-yl)-5-methyl-imidazole.

Example 7 (1-(3-chlorophenyl)-5-meth-fk-imyl from aj -4-Carbonitrile 655'R9, [chemical compound]" loxyl ammonium 695 da and m [Potassium 690 IV prepared in 32 d of ethanol at 110° C. for 1.5 h. heat. It is then concentrated, the pores are stirred with water, and the solids formed are filtered with suction. drying Later, it is crystallized from ethanol.

1-(6-chlorophenyl)-5-methane having a melting point of 206-209 °ci Tyl-imidazole-4-formamidoxime 6U 0U9C79.8%).

(b) Formamidoxime 577~ prepared in Example 8(a) was mixed with anhydrous tetrahydrochloride. 7 runs 4 Q ttl VC charged, propionyl chloride 286~'fJ4JL Add to. This is followed by stirring for 16 hours at Arashi. Distilled into tetrahydro7ran' Afterwards, the residue is filtered into 25-g of quid roll and the batch is refluxed for 6.5 hours. − Doluol/md ester (1:1)-c chloride was prepared using a crude WiN silicon derivative. After performing the 1-(3-chlorophenyl)-4-(5-ethyl -1,2,4-oxadiazol-6-yl)-5-methyl-imidazole [J , 74y are obtained.

Melting point 71-72E (diisopropyl ether).

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Claims (7)

[Claims] 1. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is hydrogen, o-, m- or Represents a halogen at the p-position, in which case one or several halogens are present in the phenyl group. R4 is -COOR6, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, -CN, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Represents R6 and R 9 represents hydrogen or a linear or branched alkyl group having 1 to 6 carbon atoms; R7 and R8 may be the same or different and have hydrogen or 1 to 6 carbon atoms. represents a straight-chain or branched alkyl group, or R7 and R8 together with a nitrogen atom represents a saturated 5- or 6-membered heterocyclic ring optionally containing other heteroatoms; , R5 is hydrogen, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. represents an alkoxyalkyl group]. 2. 1-(3-chlorophenyl)-imidazole-4-carboxylic acid ethyl ester . 1-(3,4-dichlorophenyl)-imidazole-4-carboxylic acid-ethyl ether Stell. 1-(4-chlorophenyl)-imidazole-4-carboxylic acid ethyl ester . 1-(4-fluorophenyl)-imidazole-4-carboxylic acid-ethyl ester Le. 1-(3-chlorophenyl)-imidazole-4-carboxylic acid-isopropyle Stell. 1-(4-fluorophenyl)-imidazole-4-carboxylic acid-isopropyl ester. 1-(3-chlorophenyl)-imidazole-4-carboxylic acid and 1-(4-fluorophenyl)-imidazole-4-carboxylic acid. 3. 1-(3-chlorophenyl)-imidazole-4-carboxylic acid-diethylamide as well as 1-(4-fluorophenyl)-imidazole-4-carboxylic acid-diinpropyl Ruamide. 1-(3-chlorophenyl)-5-methyl-imidazole-4-carboxylic acid amide Do. 4. 1-(3-chlorophenyl)-4-(3-ethyl-1,2,4-oxadiazole -5-yl)-imidazole. 1-(3,4-dichlorophenyl)-4-(3-ethyl-1,2,4-oxadi Azol-5-yl)-imidazole. 1-(4-chlorophenyl)-4-(3-ether-1,2,4-oxadiazole -5-yl)-imidazole. 1-(4-fluorophenyl)-4-(3-ethyl-1,2,4-oxadiazo (5-yl)-imidazole and 1-(3-bromphenyl)-4-(3-ether-1,2,4-oxadiazole -5-yl)-imidazole. 1-(3-chlorophenyl)-4-(3-ethyl-1,2,4-oxadiazole -5-yl)-5-methyl-imidazole. 1-(3-chlorophenyl)-4-(5-ethyl-1,2,4-oxadiazole -3-yl)-5-methyl-imidazole. 1-(3-chlorophenyl)-4-(3-ethyl-1,2,4-oxadiazole -5-yl)-5-methoxy-methyl-imidazole. 5. 1-(3-chlorophenyl)-imidazole-4-carbonitrile. 1-(3-chlorophenyl)-5-methyl-imidazole-4-carbonitri le and 1-(4-Fluorphenyl)-5-methyl-imidazole-4-carbonite Lil. 6. A drug whose substrate is a compound according to any one of claims 1 to 5. 7. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is hydrogen, o-, m- or Represents a halogen at the p-position, in which case one or several halogens are present in the phenyl group. R4 is -COOR6, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, -CN, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼、▲There are mathematical formulas, chemical formulas, tables, etc.▼or▲There are mathematical formulas, chemical formulas, tables, etc. ▼, R6 and R9 are hydrogen or a straight chain having 1 to 6 carbon atoms or represents a branched alkyl group, and R7 and R8 may be the same or different. , hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms; is a saturated complex with R7 and R8 optionally containing other heteroatoms along with the nitrogen atom. Represents a 5- or 6-membered ring, R5 is hydrogen or an alkyl group having 1 to 6 carbon atoms. Representing a kill group or an alkoxyalkyl group having 1 to 6 carbon atoms] In a method for producing a sol derivative, the general formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1 represents the above] The aniline of general formula III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R4 and R5 are the above and X and Y represent substituting groups] in the presence of 2-azabutadiene and an acid. The reaction is carried out at a temperature of 0 to 150°C, and in some cases, the ester group present in the molecule is converted into an ester. exchange or saponification, optionally esterifying free carboxyl groups, and or by reacting with amidoxime of formula: R9-C(=NOH)NH2 - Oxadiazolyl derivative and optionally hydrolyze the nitrile group present in the molecule. into a carbonylamide group or carboxyl group, or an iminoester group. to an ester group (COOR6) or to an amide with hydroxylamine. via xime followed by activation of an alkane carboxylic acid or acid of formula: R9-COOH An imidazole characterized by being converted into a 3-oxadiazolyl derivative as a derivative Method for producing derivatives.