KR840002242B1 - Method for preparing a novel imidazole compound - Google Patents

Abstract

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Description

Method for preparing a novel imidazole compound

The present invention relates to a method for preparing a novel imidazole derivative exhibiting excellent medicinal efficacy.

More specifically, the present invention relates to the preparation of imidazole derivatives represented by the following general formula (I).

라디칼(여기서 R₆는 수소원자, 저급알킬기 또는 저급 알킬설포닐기, A는 카보닐기 또는 설포닐기, R₇은 저급알킬기, 할로겐화 저급알킬기, 모노 또는 디-저급알킬아미노기, 모노 또는 디-저급알킬아미노알킬기, 미치환페닐기 또는 할로겐원자, 저급알킬기, 저급알콕시기 또는 트리플루오로 메틸기로 치환된 페닐기, 미치환페닐아미노기 또는 할로겐 원자, 저급알콕시기 또는 트리플루오로 메틸기로 치환된 페닐아미노기)를 나타내며, 단 (i)R₁이 메틸기, R₂,R₃,R₄,R₅가 수소원자인 경우, 또는 (ii)R₁은 메틸기, R₃는 올소-아미노기, R₂,R₄,R₅는 수소원자인 경우는 아니어야 한다.Wherein R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ , R ₄ , R ₅ may be the same or different and independently hydrogen atom, lower alkyl group, trifluoromethyl group, amino group, mono or di Lower alkyl amino groups, heterocyclic amino groups, halogen atoms or

Radicals wherein R ₆ is a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, A is a carbonyl or sulfonyl group, R ₇ is a lower alkyl group, a halogenated lower alkyl group, a mono or di-lower alkylamino group, a mono or di-lower alkylamino An alkyl group, an unsubstituted phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoro methyl group, an unsubstituted phenylamino group or a halogen atom, a lower alkoxy group or a trifluoro methyl group). Provided that (i) R ₁ is a methyl group, R ₂ , R ₃ , R ₄ , R ₅ is a hydrogen atom, or (ii) R ₁ is a methyl group, R ₃ is an oxo-amino group, R ₂ , R ₄ , R ₅ Should not be a hydrogen atom.

Lower alkyl group, lower alkoxy group, mono or di-lower alkylamino group, halogenated as defined in the definition of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ in the general formula (I) The term "lower alkyl" in a lower alkyl group, mono or di-lower alkyl amino group, halogenated lower alkyl group, mono or di-lower alkyl aminoalkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, Straight or branched alkyl groups such as 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like.

The term "heterocyclic amino group" means, for example, 1-piperidyl group, 1-pyrrolidyl group, 4-morpholinyl group, or the like.

According to the invention the compounds of general formula (I) can be readily converted into their acid addition salts upon reaction with pharmaceutically good inorganic, organic acids.

Such acid addition salts include inorganic acid salts such as hydrogen chloride, sulfate, nitrate, and the like, and organic acid salts such as oxalate, fumarate, maleate, malonate, methanesulfonate, and the like.

Typical examples of the compounds according to the invention are described below, but do not imply that the invention is limited thereto.

1- (3,4-dimethyl phenyl) -2-methylimidazole,

1- (3,4-dichlorophenyl) -2-methyl imidazole,

1- (3,4-dichlorophenyl) -2-ethyl imidazole,

1- (4-aminophenyl) -2-methyl imidazole,

1- (4-amino phenyl) -2-ethyl amidazole,

1- (3-amino-4-methyl phenyl) -2-methylimidazole,

1- (4-n-butylamino phenyl) -2-methylimidazole,

1- (3,4,5-trimethoxyphenyl) -2-methyl imidazole,

1- (4-aminophenyl) -2,4-dimethyl imidazole,

1- (4-methoxy phenyl) -2-methyl imidazole,

1- (3,4-dimethoxy phenyl) -2-methylimidazole,

1- (2-methoxy phenyl) -2-methyl imidazole,

1- (4-fluorophenyl) -2-methylimidazole,

1- [4- (1-piperidinyl phenyl)]-2-methylimidazole,

1- (4-dimethyl aminophenyl) -2-methylimidazole,

1- (4-chlorophenyl) -2-methylimidazole,

1- (4-methyl phenyl) -2-methylimidazole,

1- (3,4-dimethylphenyl) -2-ethyl imidazole,

1- (3,4-dimethylphenyl) -2-n-propyl imidazole,

1- (3-trifluoromethyl-4-aminophenyl) -2-methylimidazole,

1- (2-amino-4-trifluoromethylphenyl) -2-methylimidazole,

1- (4-aminophenyl) -2-isopropyl imidazole,

1- (2-chloro-4-aminophenyl) -2-methyl imidazole,

1- (3-aminophenyl) -2-methylimidazole,

1- (4-aminophenyl) -2-n-propyl imidazole,

1-4- (1-pyrrolidinylphenyl) -2-methylimidazole,

1-4- (1-morpholinophenyl) -2-methylimidazole,

1- (4-methyl aminophenyl) -2-ethylimidazole,

1-4- (4-chlorobenzoylamino) phenyl-2-ethylimidazole,

1-2- (dimethanesulfonylamino) phenyl-2-methylimidazole,

1-4- (N'-methylureido) phenyl-2-ethylimidazole,

1- (4-methylsulfonylaminophenyl) -2-methylimidazole,

1- [4- (4-methylbenzoylamino) phenyl] -2-ethylimidazole,

1- [4- (4-chlorophenylsulfonyl amino) phenyl] -2-ethylimidazole,

1- (4 [N '-(4-chlorophenyl) ureido] phenyl) -2-methylimidazole,

1 [4- (4-chlorobenzoyl amino) phenyl] -2-methylimidazole,

1- [2-[(4-chlorobenzoylamino) -4-trifluoromethyl] phenyl] -2-methylimidazole,

1- [4- (4-chlorobenzoylamino) phenyl] -2,4-dimethylimidazole,

1- [4- (4-fluorobenzoylamino) phenyl] -2-methylimidazole,

1- [4- (3,4-dichlorobenzoylamino) phenyl] -2-ethylimidazole,

1- [4- (4-fluorobenzoylamino) phenyl] -2-ethylimidazole,

1- [2- (4-chlorobenzoylamino) phenyl] -2-methylimidazole,

1- [4- (4-chlorobenzoylamino) phenyl] -2-isopropylimidazole,

1- [4- (4-methoxybenzoylamino) phenyl] -2-ethyl imidazole,

1-[-(4-methylbenzoylamino) phenyl] -2-methylimidazole,

1- [4- (4-chlorobenzoylamino) phenyl] -2-n-propylimidazole,

1- [4- (4-chlorobenzoylmethylamino) phenyl] -2-methylimidazole,

1- (4-acetylaminophenyl) -2-methylimidazole,

1- [4- (3-trifluorobenzoylamino) phenyl] -2-ethylimidazole,

1- (3-aminophenyl) -2-ethylimidazole,

1- (3-amino-4-methoxyphenyl) -2-methylimidazole,

1- (3-dimethylaminophenyl) -2-methylimidazole,

1- (3-methylaminophenyl) -2-methylimidazole,

1- (4-propionylaminophenyl) -2-ethylimidazole,

1- (4-acetylaminophenyl) -2-methylimidazole,

1- (3-propionylaminophenyl) -2-methylimidazole,

1- (3-acetylamino-4-methoxyphenyl) -2-methylimidazole,

1- [3- (4-chlorobenzoylamino) phenyl] -2-methylimidazole,

1- [3- (4-chlorobenzoylamino) -4-methylphenyl] -2-methylimidazole,

The imidazole derivatives according to the present invention are new compounds which are not yet known which exhibit only minor toxicity and good antidepressant efficacy and are therefore useful for the treatment or prevention of depression or depressive conditions. As antidepressants, tricyclic compounds such as pramin and amitriptyline have been used clinically.

The compounds of the present invention are completely different in structure from such compounds.

Accordingly, an object of the present invention is to provide a method for preparing a novel imidazole derivative which is useful as an antidepressant and has high safety.

The compounds of general formula (I) according to the invention can be prepared in a number of ways, the typical of which is described in detail below.

(1) Method A

Compounds of formula (I) wherein R ₃ , R ₄ and R ₅ are not amino groups and R ₂ is a hydrogen atom can be prepared according to the following method.

(R ₁ , R ₃ , R ₄ , R ₅ are the same as defined above)

That is, the oxazole-4-carboxylic acid represented by general formula (II) is made to react with the aniline compound represented by general formula (III) at the temperature of about 160 degreeC-200 degreeC, and the compound of desired formula (I) is obtained.

(2) Method B

Compounds of formula (I) wherein at least one of R ₃ , R ₄ , and R ₅ are amino groups, are prepared as follows.

For example, the nitro group-substituted phenylimidazole compound of the general formula (IV) used as starting material

(R ₁ , R ₂ , R ₄ , R ₅ are the same as before)

Catalytic reduction treatment with palladium-carbon and Raney Nickel catalysts or reduction with iron, metal zinc and stannous chloride yields the compound of formula (1).

The same method applies when R ₄ and R ₅ are amino groups.

(3) Method C

The compound of formula (I) wherein R ₁ is a methyl group is prepared according to the following method.

That is, the 2-unsubstituted imidazole compound represented by formula (V) is reacted with formaldehyde in a capped tube to form 2-hydroxymethyl compound represented by formula (VI), and then, for example, thionyl chloride and The reaction is carried out to form a 2-chloromethyl compound represented by formula (VII), followed by catalytic reduction to obtain a compound of formula (I). To obtain a compound of formula (I) wherein at least one of R ₃ , R ₄ , and R ₅ is an amino group, a nitro-substituted compound is used as starting material in Method B, where the nitro group is reduced in the final reduction stage of the reaction. Obtain an amino-substituted product.

(4) Method D

Compounds of the formula (I) in which one of R ₃ , R ₄ , and R ₅ are mono-lower alkylamino groups can be prepared according to the following method. Amino group substituted phenylimidazole compound represented by general formula (VIII)

(Wherein R ₁ , R ₂ , R ₄ , R ₅ are the same as electricity)

Is reacted with acetic anhydride, acetyl chloride or trifluoro acetic anhydride to form an intermediate of formula (IX).

(Acyl in this formula represents a residue of acetic acid or trifluoro acetic acid.)

It is then further reacted with a lower alkyl halide to give an N, N-di-substituted amino compound represented by formula (X).

(In this formula, alkyl stands for lower alkyl.)

The N, N-di-substituted amino compound is hydrolyzed with an inorganic acid or an alkali to obtain a compound of the general formula (I).

(5) Method E

Compounds of formula (I) in which none of R ₃ , R ₄ , and R ₅ are halogen atoms can be prepared according to the following method.

(Wherein X is a halogen atom, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are the same as above)

-콜리딘, 중탄산 알칼리, 탄산알칼리, 피리딘 등의 존재하에 가열하면서 반응시켜 식(I)의 화합물을 얻는다.In addition, the compound represented by the general formula (XI) and the compound represented by the general formula (XII) may be copper powder, copper oxide (II), copper halide (I),

The compound of formula (I) is obtained by reacting with heating in the presence of collidine, alkali bicarbonate, alkali carbonate, pyridine and the like.

They may be used alone or in combination. The heating temperature varies depending on the reaction conditions, but a range of about 190 ° -210 ° is appropriate. In the formula, X represents a halogen atom as described above, and bromine or chlorine are suitable.

(6) Method F

(여기서 R₆,R₇은 각기 상기와 동일함)로 나타낸식(I)의 화합물은 다음 방법에 따라 제조될 수 있다.One of R ₃ , R ₄ , and R ₅ is an expression

The compounds of formula (I) represented by each of R ₆ and R ₇ are the same as above, can be prepared according to the following method.

i) A is a carbonyl or sulfonyl group, R ₆ is a hydrogen atom or a lower alkyl sulfonyl group, R ₇ is a lower alkyl group, a halogenated lower alkyl group, a mono or di-lower alkyl amino group, a mono or di-lower alkyl aminoalkyl group, fine In the case of a substituted phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoro methyl group, a primary amino compound represented by the following formula (XIII),

In an inert solvent such as chloroform, dichloromethane, benzene, toluene, xylene, etc., not involved in the reaction, if necessary in the presence of a deoxidizing agent such as potassium carbonate, sodium carbonate, triethyl amine or pyridine, at 0 ° C.-150 ° C. Represented by (XIV)

Reaction with a carboxylic acid or sulfonic acid or with a reaction derivative thereof (e.g., acid halides, acid anhydrides, mixed anhydrides or sulfonyl halides) gives the intended compound of formula (I).

ii) when A is a carbonyl group, R ₆ is a hydrogen atom, R ₇ is a lower alkyl amino group or an unsubstituted phenyl amino group or a halogen atom, a lower alkyl group, a lower alkoxy group or a phenylamino group substituted with a trifluoromethyl group, Compounds represented by the formula (XIII) represented by the formula R ₈ NCO (XV) at a temperature from room temperature to 100 ° C. in an inert solvent not involved in the reaction, for example chloroform, dichloromethane, benzene, toluene, xylene or pyridine R ₈ represents a lower alkyl group or an unsubstituted phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trilomethyl group, and reacted with an isocyanate represented by a compound of formula (I) Get

iii) when A is a carbonyl or sulfonyl group, R ₆ is a lower alkyl group, R ₇ is a lower alkyl group or an unsubstituted phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, The compound of the following general formula (I) can be produced as follows.

In addition, compounds of the general formula (XVI), wherein R ₁ , R ₂ , R ₄ , and R ₅ are the same as those described above, may be DMF (N, N-dimethyl formamide), HMPA (hexamethylphosphoramide), Or reacted with a compound of formula (XVII), wherein R ₆ represents lower alkali and X represents a halogen atom, in the presence of an alkali carbonate, an alkali halide or an alkoxy alkali in a solvent such as DMSO (dimethyl sulfoxide) To prepare a compound of formula (I).

Given the chemical structure of the compounds according to the invention, but from the point of view of the prior art, it is not predictable that the compounds of the invention will exert antidepressant efficacy.

However, the antidepressant efficacy of the compounds of the invention is special and very potent.

The antidepressant efficacy of the compounds of the present invention will now be described.

(Pharmaceutical test)

Test compound

The following compounds were selected for testing among the compounds of the general formula (I) of the present invention.

1- (3,4-dimethylphenyl) -2-methylimidazole (hereinafter referred to as "Compound A")

1- (4-dimethylaminophenyl) -2-methylimidazole (hereinafter referred to as "Compound B")

1- (3,4-dichlorophenyl) -2-ethylimidazole (hereinafter referred to as `` Compound C '')

1- (4-aminophenyl) -2,4-dimethylimidazole (hereinafter referred to as "Compound D")

1- (3-trifluoromethyl-4-aminophenyl) -2-methylimidazole (hereinafter referred to as "Compound E")

1- (4-aminophenyl) -2-ethylimidazole (hereinafter referred to as "Compound F")

1- (2-chloro-4-aminophenyl) -2-methylimidazole (hereinafter referred to as "Compound G")

1- (3-aminophenyl) -2-methylimidazole (hereinafter referred to as "Compound H")

1- (3-amino-4-methylphenyl) -2-methylimidazole (hereinafter referred to as "Compound I")

1- (4-n-butylaminophenyl) -2-methylimidazole (hereinafter referred to as "Compound J")

1- (4-aminophenyl) -2-methylimidazole (hereinafter referred to as "Compound K")

1- [4- (4-chlorobenzoylamino) phenyl] -2-methylimidazole (hereinafter referred to as `` Compound L '')

1- [4- (4-fluorobenzoylamino) phenyl] -2-methylimidazole (hereinafter referred to as "Compound M")

1- [4- (4-chlorobenzoylamino) phenyl] -2-ethylimidazole (hereinafter referred to as "Compound N")

1- [4- (4-methylbenzoylamino) phenyl] -2-ethylimidazole (hereinafter referred to as "Compound O")

1- [4- (4-chlorobenzoylamino) phenyl] -2-isopropylimidazole (hereinafter referred to as "Compound P '')

1- [4- (4-methylbenzoylamino) phenyl] -2-methylimidazole (hereinafter referred to as "Compound Q")

Each test compound is used in the form of hydrogen chloride.

Experimental procedure

(1) anti-reserpin action

Antagonism against hypothermia caused by reserpin has been described in B.M. Measured according to the Askew (Life Sciences, 4,725-730, 1963) method.

Males of ddy mice weighing 19-25 g are used as test animals. Reserpin is injected in the peritoneum at a dose of 2.5 mg / kg, and the test compound is orally injected 18 hours after the injection, thereby changing the temperature of thermistor type thermometer (model MGA III). , Shibaura Denshi).

The effect of each compound is measured by two to four doses.

Each test compound is used in the form of an aqueous solution.

Test animals are treated with physiological salt solutions.

The test compound is administered to animals at a body temperature of 24-25 ° C. and 18 hours after injection of riserpin. The experiment is carried out in a laboratory at 23-25 ° C.

(2) effect on spontaneous motility

Spontaneous motility was T.H. It is measured according to the Sevensson method (psychopharmacologia 14, 157, 1969).

Three Didy Wye males, weighing 20-25 g, were placed in a group in an acrylic resin box and measured for 60 minutes spontaneous motility and recorded with Animex (Farrod Co., Sweden). .

A single dose of 40 mg / kg of test compound is administered orally 6 minutes prior to determination of spontaneous motility. Test animals are treated with physiological salt solutions. Five groups (15) are used for each dose.

(3) acute toxicity

To determine lethality, the test compound is administered orally to rats at a single dose of 100 or 400 mg / kg.

The mortality rate is measured 24 hours after oral administration.

Experiment result

The antiriserpin action, the effect on spontaneous motility and the results of acute toxicity experiments are shown in Table A.

TABLE A

a) the minimum dose required to significantly increase body temperature in reserpin-treated mice compared to the control group;

(p <0.05)

b) 10 mg / kg P.O. (oral).

As is apparent from Table A, it is found that the compounds of the present invention exhibit potential anti-reserpin action and have very low toxicity. The present inventors also studied the efficacy of the compounds of the present invention (compounds H and I) on the level of dopamine and its metabolism in the rat brain.

The researchers found that these compounds act to reduce dopamine turnover in the brain.

This means that the compound of the present invention antagonizes against reserpin-induced depression in a completely different way from known tricyclic antidepressants.

As such, the compounds of the present invention exhibit potential and unique anti-reserpin action and are highly safe due to their mild toxicity, and are therefore very good at treating and preventing depression or depression. In addition, the compounds of the present invention are considered to be completely different from existing antidepressants (imimipramine, amitriptyline, etc.) both chemically and pharmacologically.

In other words, the compound of the present invention is a unique type of medicine which is completely different from known antidepressants.

The compound of the present invention is administered at a dose of 10-1000 mg / day, preferably at a dose of 30-300 mg / day, for clinical treatment of patients suffering from depression or suffering from depression due to visceral diseases. do.

The compounds of the present invention can be formulated in a variety of formulations to be suitable for administration in any manner.

As such, the present invention is a medicament suitable for the human body, and includes a pharmaceutical composition containing one or more compounds of the present invention. This pharmaceutical composition can be formulated using a suitable pharmaceutical weight or excipient and can be administered according to conventional methods.

The pharmaceutical composition is preferably administered in a form suitable for absorption in the digestive tract.

Units for oral administration include tablets and capsules, which are syrups. Arabian rubber. gelatin. Binders such as sorbitol tragacanth and polyvinyl alcohol, lactose. Cornstarch. Calcium phosphate. Excipients such as sorbitol and glycine, magnesium stearate. Talc. Lubricants such as polyethylene glycol and silica, wetting agents such as potato starch trapped disintegrant sodium lauryl sulfate and other common preparations.

Tablets may be coated on their surface by known methods commonly used in the art.

Liquid preparations for oral administration include trustees, emulsions, solvents, syrups, elixirs and the like.

It may also be used as a dry agent that dissolves again in water or other suitable excipients before administration.

Such agents are combinations commonly used in the art, for example sorbitol syrup. Methyl cellulose. Glucose / sugar syrup. gelatin. Hydroxyeryl cellulose. Carboxy methylcellulose. Suspending agents such as aluminum stearate and cooking oil, Lexitan. Emulsifiers such as mono-oleic acid sorbitol and gum arabic, almond oil. Carbonized Coconut Oil. Oily ester. Water insoluble excipients such as propylene glycol and ethyl alcohol, methyl p-hydroxy benzoate. Preservatives such as propyl p-hydroxy benzoate and sorbic acid.

Injectable compositions are prepared in the form of ampoules or vials containing unit dosages with preservatives.

Injectable compositions may be prepared in the form of suspensions, solutions, or emulsions in oily or aqueous excipients, including suspending, stabilizing and / or dispersing agents.

The active ingredient may be powder which is redissolved in a suitable excipient such as disinfectant water free of pyrogenic substances prior to administration.

The present invention will be described in more detail according to the following examples, but the present invention is not limited to these examples.

Example 1

Synthesis of 1- (3,4-dimethylphenyl) -2-merylimidazole:

A mixture of 2 g of 2-methyl-oxazole-4-carboxylic acid and 6.0 g of glycyridine is heated in an oil bath with stirring for 40 minutes at an external temperature of 180 ° C.

The reaction product was purified using silica gel column chromatography (using ethyl ether as eluent) to obtain 2.6 g of the target compound having a melting point of 84 to 85 ° C.

The product was changed into hydrochloric acid addition salt at melting point of 255 占 폚 by a conventional method.

Elemental analysis of C ₁₂ H ₁₄ N ₂ ㆍ HCl was as follows.

Theory

C = 64.69%, H = 6.80%, N = 12.58%

Found

C = 64.77%, H = 6.77%, N = 12.52%

Example 2

1- (3,4-dichlorophenyl) -2-ethyl imidazole:

A mixture of 1.5 g of 2-ethyl-oxazole-carboxylic acid and 5.2 g of 3,4-dichloroarylene is heated in an oil bath with stirring for 40 minutes at an external temperature of 170-180 ° C.

The reaction product was purified using silica gel column chromatography (using a liquid mixture of ethyl ether, benzene and ethanol as eluent) to obtain 1 g of the desired compound having a melting point of 95 to 96 ° C.

The hydrochloric acid addition product had melting | fusing point 250 degreeC.

Elemental analysis for C ₁₁ H ₁₀ Cl ₂ N ₂ ㆍ HCl was as follows.

Theory

C = 47.57%, H = 4.00% N = 10.99%

Found

C = 47.48% H = 3.90%, N = 10.01%

Example 3

Synthesis of 1- (4-aminophenyl) -2-methylimidazole:

13.5 g of 2-methyl-1- (4-nitrophenyl) imidazole was hydrogenated at an initial pressure of 40 kg / cm ² temperature at 30 ° -40 ° C. in the presence of 10% Pd / C in 160 ml of ethanol.

After 3 hours, the reduced mixture was filtered and the solvent was removed from the filtrate under reduced pressure.

The residue was recrystallized from a mixed solvent of benzene and n-hexane to give 9.8 g of the desired compound at a melting point of 112-113 占 폚.

Elemental analysis for C ₁₀ H ₁₁ N ₃ was as follows.

Theory

C = 69.33%, H = 6.41%, N = 24.26%

Found

C = 69.31%, H = 6.46%, N = 23.96%

Example 4

Synthesis of 1- (3-amino-4-methylphenyl) -2-merylimidazole:

i) Synthesis of 1- (4-methyl-3-nitrophenyl) -2-hydroxy-methylimidazole:

In a stoppered in vitro tube, 12 g of 1- (4-methyl-3-nitrophenyl) -imidazole was reacted with 12 ml of 37% formalin for 12 hours at 140 ° C., and 6 ml of 37% formalin was added, followed by the above-described conditions. The reaction was continued for 9 hours.

After cooling the reaction mixture, water was added thereto.

The precipitated crystals were collected by filtration, dried and recrystallized from dimethylformamide to obtain 10.2 g of the target compound having a melting point of 185 ° C.

Elemental analysis for C ₁₁ H ₁₁ N ₃ O ₄ was as follows.

Theory

C = 56.64%, H = 4.76%, N = 18.02%

Found

C = 56.4%, H = 4.69%, N = 17.93%

ii) Synthesis of 1- (4-methyl-3-nitrophenyl) -2-chloromerimidazole:

25.5 ml of thionyl chloride was added to 8 g of 1- (4-methyl-3-nitrophenyl) -2-hydroxymerimidazole, and the mixture was refluxed with stirring for 5 hours.

The reaction mixture was cooled down and diaryl ether was added thereto.

The precipitated crystals were filtered to give 9.6 g of the target compound hydrochloric acid addition salt.

iii) Synthesis of 1- (3-amino-4-methylphenyl) -2-merylimidazole:

3 g of 1- (4-methyl-3-nitrophenyl) -2-chloromerimidazole hydrochloride addition salt obtained in ii) was added to 40 ml of water and 100 ml of ethanol, containing 10 ml of 10% Pd / c. It was added to the solution made of hydrogen reaction to 50 ℃ at an initial pressure of 40kg / cm ² .

After 4 hours, the reaction mixture was filtered and the solvent was removed from the filtrate under reduced pressure.

An aqueous sodium carbonate solution was added to the residue to alkalinize the final solution.

The solution was then extracted with chloroform.

The chloroform layer was washed with water then dried over MgSO ₄ and the chloroform was evaporated under reduced pressure.

The residue was recrystallized with a mixed solvent of benzene and n-hexane to obtain 2.2 g of the target compound at a melting point of 126-128 占 폚. The compound thus obtained is converted to hydrochloric acid addition salt having a melting point of 234 占 폚 (decomposition).

Elemental analysis for C ₁₁ H ₁₃ N ₃ ㆍ 2HCl was as follows.

Theory

C = 50.76%, H = 5.82%, N = 16.15%

Found

C = 50.59%, H = 5.91%, N = 15.92%

Example 5

Synthesis of 1- (4-butylaminophenyl) -2-methylimidazole:

i) Synthesis of 1- (4-acetoaminophenyl) -2-methylimidazole:

6 g of 1- (4-aminophenyl) -2-merimidazole and 30 ml of acetic anhydride were refluxed with stirring for 3 hours, and the reaction mixture was distilled off under reduced pressure.

Water was added to the residue, followed by filtration to recover the precipitated crystals. Purification by silica gel chromatography using a mixed solvent of benzene and ethanol as eluent gave 2.1 g of the desired compound at a melting point of 177 ° C.

Elemental analysis for C ₁₄ H ₁₉ N ₃ was as follows.

Theory

C = 73.36%, H = 8.30%, N = 18.34%

Found

C = 73.33%, H = 8.27%, N = 18.29%

ii) Synthesis of 1- (4-n-butylaminophenyl) -2-methylimidazole:

1- (4-acetoaminophenyl) -2-methylimidazole was redissolved in 15 ml of dimethylformamide in the presence of N ₂ and 0.38 g of 55% sodium hydroxide was added to the solution.

The solution was stirred at room temperature for 20 minutes and at 60 ° C.-70 ° C. for 10 minutes.

Then a solution containing 1.5 g of n-butyl iodine in a small amount of dimethyl formamide was added dropwise to the reaction mixture.

The mixture was then stirred at 60 ° C.-70 ° C. for 2 hours. Dimenylformamide was evaporated under reduced pressure, and 20 ml of 10% hydrochloric acid was added to the residue.

The mixture was stirred at reflux for 2 hours, cooled to reflux and washed with chloroform.

The solution layer was recovered, alkalized with an aqueous sodium carbonate solution and extracted with chloroform.

The chloroform layer was washed with water and dried over MgSO ₄ to evaporate off the chloroform used as solvent.

The residue was purified by silica gel chromatography using a benzene-ethanol mixed solvent as the eluent to obtain 0.9 g of the target compound. The compound thus obtained is converted to hydrochloric acid addition salt having a melting point of 189-192 占 폚.

Elemental analysis for C ₁₄ H ₁₀ N ₃ , 1 / 6H ₂ O was as follows.

Theory

C = 62.54%, H = 7.76%, N = 15.6%

Found

C = 62.42%, H = 7.85%, N = 15.37%

Example 6

Synthesis of 1- [4- (4-chlorobenzoylamino) phenyl] -2-ethylimidazole:

1.9 g of 1- (4-aminophenyl) -2-ethylimidazole was added to a solution containing 2.6 g of P-chlorobenzoyl chloride in 50 ml of toluene, and the mixture was refluxed with stirring for 7 hours.

The reaction mixture was naturally cooled and diethyl ether was added thereto. The precipitated crystals were collected by filtration, washed sufficiently with ethyl ether, recrystallized from ethanol, and recrystallized from water to obtain 2.5 g of the target compound in the form of hydrochloric acid addition salt.

Melting point was 265-267 degreeC.

Elemental analysis for C ₁₈ H ₁₆ Cl N ₃ O.HCl 1 / 2H ₂ O was as follows.

Theory

C = 58.21%, H = 4.89%, N = 11.32%

Found

C = 58.23%, H = 4.75%, N = 11.06%

Example 7

Synthesis of 1- [2- (N, N-dimethylsulfonylamino) phenyl] -2-methylimidazole:

A mixture of 1.1 g of triethylamine and 1.2 g of methylsulfonyl chloride was added to a solution of 1.5 g of 1- (2-aminophenyl) -2-methylimidazole dissolved in 30 ml of chloroform, and the mixture was stirred for 5 hours. It was refluxed.

Then, 0.6 g of methanesulpotyl chloride was added to the reaction mixture, and the mixture was refluxed with stirring for 3 hours.

After completion of the reaction, the reaction mixture was cooled naturally and the solvent was removed by evaporation under reduced pressure.

Water was added to the residue, and an aqueous sodium carbonate solution was added so that the final solution became alkaline.

The precipitated crystals were collected by filtration, washed with water and recrystallized from ethanol to obtain 0.9 g of the target compound.

The compound thus obtained is converted to an addition salt of an acid having a melting point of 215-220 ° C. according to a conventional method.

Elemental analysis for C ₁₂ H ₁₅ N ₃ S ₂ O ₄ ㆍ HCl is as follows.

Theory

C = 39.40%, H = 4.42%, N = 11.49%

Found

C = 39.21%, H = 4.33%, N = 11.23%

Example 8

Synthesis of 2-ethyl-1- [4- (N'-methylureido) phenyl] imidazole:

0.8 g of methyl isocyanate was added to a solution containing 1.5 g of 1- (4-aminophenyl) -2-ethylimidazole in 20 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours and then stirred at reflux for 3 hours. .

After completion of the reaction, the reaction mixture was cooled naturally and the solvent was removed by evaporation under reduced pressure.

Benzene was added to the residue, and the solid thus produced was collected by filtration. The recovered solid was redissolved in a small amount of methanol and recrystallized from a mixed solvent of ethyl ether / benzene.

The compound thus obtained is converted to hydrochloric acid addition salt at melting point of 228-232 ° C. according to customary methods.

Elemental analysis for C ₁₃ H ₁₆ N ₄ O.HCl is as follows.

Theory

C = 55.60%, H = 6.11%, N = 19.96%

Found

C = 55.53%, H = 5.8%, N = 20.00%

Example 9

Synthesis of 1- (3-amino-4-methylphenyl) -2-methylimidazole:

A mixture of 4.5 g of 2-methylimidazole, 6.9 g of 2-amino-4-chlorotoluene 7.5 g of potassium carbonate and 0.5 g of copper powder was stirred at 200 ° C. for 5 hours.

After cooling, dilute hydrochloric acid was added to the reaction compound until the solution was acidified and the insoluble material was filtered off. The filtrate was again alkaline with sodium carbonate, extracted with chloroform (50 ml × 3), washed with water and dried over MgSO ₄ .

Thereafter, chloroform was evaporated under reduced pressure and the final residue was purified by silica gel chromatography (eluted with chloroform-methanol) to obtain 2.1 g of the target compound.

This compound was normally converted to its hydrochloric acid addition salt (melting point 234 ° C.) by explosion.

Elemental Analysis for C ₁₁ H ₁₃ N ₃ ㆍ 2HCl

Theory

C = 50.76%, H = 5.82%, N = 16.15%

Found

C = 50.56%, H = 5.85%, N = 16.85%

Other compounds according to the invention are listed in the following table by way of example.

TABLE 1

EXAMPLE

Injection drugs were prepared from the composition according to a conventional method.

Buffers, pH constituents, and analgesics may be formulated into the injectables as needed.

Claims (1)

A primary amino compound represented by formula (VIII) is reacted with a carboxylic acid and sulfonic acid of formula (XIV), a reactive derivative thereof, or an isocyanate of formula (XV). The manufacturing method of the imidazole compound represented by (I).

In the above formulas R ₁ represents a lower alkyl group, R ₂ represents a hydrogen atom or a lower alkyl group, R ₄ and R ₅ are the same or different and each represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group, an amino group, a mono- or di-lower alkylamino group, a heterocyclic amino group, a halogen atom or a general formula

Represents a group represented by R ₆ represents a hydrogen atom or a lower alkylsulfonyl group, A represents a carbonyl group or a sulfonyl group, R ₇ is substituted with a lower alkyl group, a halogenated lower alkyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkylaminoalkyl group, an unsubstituted phenyl group, or a halogen atom or a lower alkyl group or a lower alkoxy group or a trifluoro methyl group. Represents a phenyl group, R ₈ represents a lower alkyl group or an unsubstituted phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group.