JPS6140227B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel imidazole derivative having excellent effects as a pharmaceutical, a method for producing the same, and a pharmaceutical containing the same. [In the formula, R ₁ represents a lower alkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group. R ₃ , R ₄ and R ₅ are the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, trifluoromethyl groups, amino groups, mono- or di-lower alkylamino groups, heterocyclic amino groups, or halogen atoms. However) R ₁ is a methyl group, R ₂ , R ₃ , R ₄ and R ₅
is a hydrogen atom, and) R ₁ is a methyl group,
R ₃ is an ortho-amino group, R ₃ , R ₄ and R ₅
Except when is a hydrogen atom. The present invention relates to an imidazole derivative represented by the following formula and a pharmacologically acceptable acid addition salt thereof; a method for producing the same; and an antidepressant containing the same. In the above general formula [], R ₁ , R ₂ , R ₃ , R ₄
and a lower alkyl group found in the definition of R ₅ ,
A lower alkoxy group, a mono- or di-lower alkylamino group means, for example, an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a lower alkoxy group based thereon, or a mono- or di-lower alkyl group. means an amino group. Moreover, the halogen atom specifically means chlorine, bromine, iodine, and fluorine. Further, the heterocyclic amino group means, for example, a piperidino group, a pyrrolyl group, a morpholino group, and the like. The compound [ ] of the present invention can be easily converted into an acid addition salt by reacting with a pharmacologically acceptable inorganic or organic acid. Such acid addition salts include, for example, mineral acid salts such as hydrochlorides, sulfates, and nitrates; organic salts such as oxalates, tartrates, fumarates, citrates, maleates, malonates, and methanesulfonates; Mention may be made of acid salts. The imidazole derivatives provided by the present invention are all new compounds that have not been described in any literature, and have extremely low toxicity and excellent antidepressant effects, and can be used as therapeutic and preventive agents for depression or depressive state. Useful. As antidepressants, conventional compounds with a tricyclic structure such as imipramine and amitriptyline are used clinically.
The compound of the present invention has a completely different structure from these compounds. Therefore, the object of the present invention is to provide a novel imidazole derivative that is extremely useful as an antidepressant and is highly safe. A further object of the present invention is to provide a method for producing a novel imidazole derivative that is extremely useful as an antidepressant and is highly safe. A further object of the present invention is to provide antidepressants containing novel imidazole derivatives. The compound [ ] of the present invention can be produced by various methods, and one of the commonly used methods is as follows. (1) Production method A In the target compound [], when R ₃ , R ₄ and R ₅ are not amino groups and R ₂ is a hydrogen atom, it can be produced by the following method. (In the formula, R ₁ , R ₃ , R ₄ and R ₅ have the above-mentioned meanings.) That is, an aniline compound represented by the general formula () is added to the oxazole-4-carboxylic acid compound represented by the general formula (), Approximately 160℃～
A melt reaction is carried out at 200°C to obtain the target compound (). (2) Production method B When one of R ₃ , R ₄ , and _{R 5} in the target compound () is an amino group, it can be produced by the following production method. As an example, the following general formula is used as a starting material:

A nitro group-substituted phenylimidazole compound represented by the formula (in which R ₁ , R ₂ , R ₄ and R ₅ have the above-mentioned meanings) is subjected to a catalytic reduction operation using palladium-carbon or Raney nickel as a catalyst, or By chemically reducing iron metal with zinc or tin chloride, the target compound () represented by the following formula is obtained. (3) Production method C In the target compound (), when R ₁ is a methyl group, it can also be produced by the following method. That is, a 2-position unsubstituted imidazole compound represented by () is reacted with formaldehyde in a sealed tube to form a 2-hydroxymethyl compound represented by (), and this is reacted with, for example, thionyl chloride to form a 2-hydroxymethyl compound represented by (). - a chloromethyl compound, which is further catalytically reduced to obtain the target compound (). At this time, if you want to obtain a compound in which R ₃ , R ₄ , and R ₅ are amino groups in the target compound ( Since the nitro group is reduced by the reduction operation in the final step in the formula to obtain an amino-substituted product, it can also be produced by this method. (4) Production method D In the target compound (), 1 of R ₃ , R ₄ , R ₅
When is a mono-lower alkylamino group, it can also be produced by the following method. In other words, the following general formula ()

[Formula] (wherein R ₁ , R ₂ , R ₄ and R ₅ have the above-mentioned meanings) is reacted with an amino group-substituted phenylimidazole compound with acetic anhydride, acetic chloride, or trifluoroacetic anhydride. General formula below ()

[Formula] (In the formula, Acyl represents a residue of acetic acid or trifluoroacetic acid), and by reacting this with a lower alkyl halide, the following general formula () is obtained.

[Formula] (In the formula, Alkyl represents a lower alkyl group) N,N-disubstituted amino compound is prepared, and this is hydrolyzed with mineral acid or alkali to obtain the target compound () expressed by the following general formula. get. Due to its chemical structure, the compound of the present invention is not expected to exhibit antidepressant effects at all based on conventional knowledge, and its antidepressant effects are specific and quite strong. The experimental results of pharmacological effects are described below. <Pharmacological test> Test compound The following compounds were selected from the compounds of the present invention () as test compounds. 1-(3,4-dimethylphenyl)-2-methyl-imidazole (hereinafter referred to as compound A) 1-(4-dimethylaminophenyl)-2-methyl-imidazole (hereinafter referred to as compound B) 1-( 3,4-diclophenyl)-2-ethyl-imidazole (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
-Methiimidazole (hereinafter referred to as compound G) 1-(3-aminophenyl)-2-methylimidazole (hereinafter referred to as compound H) 1-(3-amino-4-methylphenyl)-2
-Methylamidazole (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) However, the hydrochloride of each compound was used as the test compound. Experimental method 1 Antireserpine effect A type of pharmacological screening method for antidepressants.
Askew, BM method (Life Science 4 725~
730, 1963) to investigate the anti-inflammatory effect on reserpine-induced hypothermia. DD male mice (19-25 g) were used as experimental animals, and 2.5 mg/Kg of reserpine was intraperitoneally injected, and 18 hours later, the test compound was orally administered.
Changes in body temperature were measured over time. To measure body temperature, use a thermistor thermometer (manufactured by Shibaura Electronics Manufacturing Co., Ltd.).
MGA type) was used. Test compound doses are 0.63, 1.25, 2.5...40
mg/Kg and 2 to 4 doses of each compound were used to study the effects. All test compounds were used as aqueous solutions. Note that a control group was given physiological saline. The number of experimental cases was 4 per dose. For the experiment, the body temperature 18 hours after reserpine administration was 24-25.
Experimental animals were used at ℃. The experiment was conducted in a constant temperature environment of 23 to 25°C. 2 Effect on locomotor activity Using the method of Sevensson, TH et al. (Psychopharmacologia 14 157, 1969),
Locomotor activity was measured. As experimental animals, groups of three DD male mice (20 to 25 g) were placed in an observation box made of black acrylic resin, and their locomotor activity was measured and recorded for the next 60 minutes using Animex (manufactured by Farad, Sweden). The test compound was orally administered 60 minutes before the start of locomotor activity measurement, and the dose was 40 mg/Kg. Note that physiological saline was administered to the control group, and the number of experimental samples was 5 for each dose (15 mice per group). 3. Acute Toxicity The lethal effect of the test compound when 100 and 400 mg/Kg was orally administered to DD male mice was investigated. The number of experimental cases was 5 per dose, and the mortality rate 24 hours after administration was calculated. Experimental results The anti-reserpine effect of the test compound, the effect on locomotor activity, and the acute toxicity test results are summarized in Table A below.

[Table] As is clear from this table, the anti-reserpine effects of the test compounds were generally strong, and with the exception of compound G, the anti-reserpine effects on reserpine hypothermia were exhibited at doses of 1.25 to 5.0 mg/Kg. On the other hand, the locomotor activity enhancing effect was not necessarily observed in all test compounds, but was observed in about half of the test compounds, and a slight decrease in locomotor activity was observed in some compounds (compounds E and I). Regarding acute toxicity, for compound K the dose 100
Deaths occurred at mg/Kg (oral), making it the most toxic and strongest of the test compounds. On the other hand, dosage 40mg/Kg
Among the compounds that did not exhibit a locomotor activity-promoting effect, compounds C, E, H, and I exhibited weak toxicity and highly specific antireserpine activity. As described above, the compound of the present invention has a strong and specific antireserpine effect and is also low in toxicity, so it is highly safe and is an extremely excellent agent for treating and preventing depression or depressive state. Moreover, the compound of the present invention has a completely different chemical structure from existing tricyclic antidepressants (e.g., imipramine, amitriptyline, etc.), so it is a completely different type of drug from conventional antidepressants. be. The clinical dose for the treatment of depression in patients with depression or visceral disease is 10 to 1000 mg/day, preferably 30 mg/day.
~300mg/day is used. The compounds of this invention can be prepared for administration using any conventional method of formulation. Therefore, the present invention also includes pharmaceutical compositions containing at least one compound of the present invention suitable as a human medicine. Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients. Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract. Tablets and capsules for oral administration are in unit dosage form and contain binders such as syrup, acacia, gelatin, sorbitate, tragacanth, or polyvinylpyrrolidone,
Excipients such as lactose, corn starch, calcium phosphate, sorbitate or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. It may also contain conventional excipients. The tablets may be coated by methods well known in the art. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products that are redissolved in water or other suitable vehicle before use. good. Such liquid formulations contain commonly used additives such as suspending agents,
For example, sorbitol syrup, methyl cellulose,
Glucose/sugar syrups, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, sorbitan monoolefinate, or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil,
It may also contain oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl P-hydroxybenzoate, propyl P-hydroxybenzoate or sorbic acid. Injectable compositions are presented in unit dose ampoules or vials with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and/or dispersing agents. good. Alternatively, the active ingredient may be in powder form for redissolution with a suitable vehicle, eg sterile pyrogen-free water, before use. Next, the present invention will be explained with reference to Examples, but it goes without saying that the present invention is not limited thereto. Example 1 Synthesis of 1-(3,4-dimethylphenyl)-2-methyl-imidazole 2-methyl-oxazole-4-carboxylic acid
2.0g and 6.0g of 3,4-xylidine in an oil bath at an external temperature of 180℃.
Stir and heat at ℃ for 40 minutes. The reaction product was purified by silica gel column chromatography (eluent: ethyl ether) to obtain 2.6 g of the target product (melting point: 84-85°C).
The hydrochloride salt (melting point: 255°C decomposition) was obtained by a conventional method. Elemental analysis value C ₁₂ H ₁₄ N ₂・HCl as C H N Theoretical value (%) 64.69 6.80 12.58 Actual value (%) 64.77 6.77 12.52 Example 2 Synthesis of 1-(3.4-dichlorophenyl)-2-ethylimidazole 2-ethyl-oxazole-4-carboxylic acid
1.5 g of 3,4-dichloroaniline and 5.2 g of 3,4-dichloroaniline were stirred and heated in an oil bath at an external temperature of 170 to 180°C for 40 minutes. The reaction product was purified by silica gel column chromatography (eluent: ethyl ether, benzene/ethanol mixture) to obtain 1 g of the target product (melting point: 95-6°C). Hydrochloride (melting point ~ 250℃) Elemental analysis value C ₁₁ H ₁₀ Cl ₂ N ₂・HCl C H N Theoretical value (%) 47.57 4.00 10.09 Actual value (%) 47.78 3.90 10.01 Example 3 1-(4-aminophenyl ) - Synthesis of 2-methylimidazole Dissolve 13.5g of 2-methyl-1-(4-nitrophenyl)imidazole in 160ml of ethanol, add 1g of 10% palladium on carbon, and add hydrogen at an initial pressure of 40Kg/cm ² , 30 A catalytic reduction operation was performed at ~40°C for 3 hours. After the reaction was completed, the catalyst was removed, the liquid ethanol was distilled off under reduced pressure, and the resulting residue was dissolved in benzene/n-
Recrystallize from a hexane mixed solvent to obtain the desired product (melting point 112
~3°C) 9.8g was obtained. Elemental analysis value C ₁₀ H ₁₁ N ₃ C H N Theoretical value (%) 69.33 6.41 24.26 Actual value (%) 69.31 6.46 23.96 Example 4 1-(3-amino-4-methylphenyl)-2
-Synthesis of methylimidazole 1-(4-methyl-3-nitrophenyl)-
Synthesis of 2-hydroxymethylimidazole 12 g of 1-(4-methyl-3-nitrophenyl)imidazole and 12 ml of 37% formalin were placed in a sealed tube and reacted by heating at 140°C for 10 hours.
6 ml of formalin was added and reacted under the same conditions for 9 hours. After cooling, water was added to the reaction product, and the precipitated crystals were dried and recrystallized from dimethylformamide to obtain 10.2 g of the desired product (melting point: 185°C). Elemental analysis value as C ₁₁ H ₁₁ N ₃ O ₄ C H N Theoretical value (%) 56.64 4.76 18.02 Actual value (%) 56.42 4.69 17.93 1-(4-methyl-3-nitrophenyl)-
Synthesis of 2-chloromethylimidazole 25.5 ml of thionyl chloride was added to 8 g of 1-(4-methyl-3-nitrophenyl)-2-hydroxyimidazole obtained in 2-chloromethylimidazole, stirred and refluxed for 5 hours, and after cooling, ethyl was added to the reaction product. Add ether, remove the precipitated crystals, and collect 9.6 g of the desired product (hydrochloride).
I got it. 1-(3-amino-4-methylphenyl)-
Synthesis of 2-methylimidazole 1-(4-methyl-3-nitrophenyl)-2-chloromethylimidazole hydrochloride obtained by
4.3 g was dissolved in a mixed solvent of 40 ml of water and 100 ml of ethanol, 0.4 g of 10% palladium on carbon was added thereto, and a catalytic reduction operation was performed at 50° C. and an initial hydrogen pressure of 40 Kg/cm ² for 4 hours. After the reaction was completed, the catalyst was removed, the solvent of the liquid was distilled off under reduced pressure, and an aqueous sodium carbonate solution was added to the resulting residue to adjust the liquid to alkaline, followed by extraction with chloroform. The chloroform layer was washed with water, dried with Glauber's salt, and chloroform was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of benzene/n-hexane to obtain 2.2 g of the desired product (melting point: 126-8°C).
This was made into a hydrochloride (melting point: 234°C). Elemental analysis value C ₁₁ H ₁₃ N As ₃・2HCl C H N Theoretical value (%) 50.76 5.82 16.15 Actual value (%) 50.59 5.91 15.92 Example 5 1-(4-n-butylaminophenyl)-2-
Synthesis of methylimidazole Synthesis of 1-(4-acetaminophenyl)-2-methylimidazole 6 g of 1-(4-aminophenyl)-2-methylimidazole and 30 ml of acetic anhydride were stirred and refluxed for 3 hours, and then the reaction mixture was refluxed under reduced pressure. Distilled. Add water to the obtained residue, collect the precipitated crystals, and then purify with silica gel chromatography (eluent: benzene/ethanol solvent) to obtain the desired product (melting point: 177°C).
Obtained 2.1g. Elemental analysis value C ₁₄ H ₁₉ N ₃ C H N Theoretical value (%) 73.36 8.30 18.34 Actual value (%) 73.33 8.27 18.29 1-(4-n-butylaminophenyl)-2
-1-(4-acetaminophenyl) obtained in the synthesis of methylimidazole-
1.7 g of 2-methylimidazole was dissolved in 15 ml of dimethylformamide under a nitrogen stream, 0.38 g of 55% sodium hydrate was added, and the mixture was stirred at room temperature for 20 minutes and further stirred at 60 to 70°C for 10 minutes. Then n
- A solution of 1.5 g of butyl iodite dissolved in a small amount of dimethylformamide was added dropwise. 60~ after dripping
The mixture was stirred at 70°C for 2 hours, and after the reaction was completed, the solvent dimethylformamide was distilled off under reduced pressure. Add 20 ml of 10% hydrochloric acid to the obtained residue, stir and reflux for 2 hours, and after cooling, wash the reaction solution with chloroform, separate the aqueous layer,
Make the liquid alkaline with an aqueous sodium carbonate solution, extract with chloroform, wash the chloroform layer with water, dry with sodium sulfate, remove the solvent chloroform under reduced pressure, and apply the resulting residue to silica gel chromatography (eluent benzene/ethanol solvent). Purified target product 0.9g
I got it. This was made into a hydrochloride (melting point: 18-192°C). Elemental analysis value C ₁₄ H ₁₀ N ₃ · HCl · 1/6 H ₂ O C H N Theoretical value (%) 62.54 7.76 15.63 Actual value (%) 62.42 7.85 15.37 The following other compounds of the present invention are described as examples. .

【table】

【table】

【table】

[Table] Next, the present invention will be explained by showing formulation examples. 1-(3′,4′-dichlorophenyl) as the main drug
-2-Ethyl-imidazole hydrochloride (hereinafter referred to as the main drug) was selected. Formulation Example 1 Capsule Main Drug 10g Cornstarch 90g Total Amount 100g The entire amount was thoroughly mixed and filled into hard gelatin capsules at 100 mg per capsule. Main drug 10 in 1 capsule
Contains mg. Formulation Example 2 Tablet Main drug 10g Crystalline cellulose 100g Corn starch 80g Calcium stearate 2g Total amount 200g The total amount was thoroughly mixed and compressed into 1000 flat tablets. Each tablet contains 10mg of the main drug. Formulation Example 3 Injection Main Drug 10g Sorbitol 20g Physiological Saline Total Volume 1l Based on the above prescription, an injection was prepared by a conventional method. Buffers, pH adjusters, and analgesics can be added as necessary.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a lower alkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group. R ₃ , R ₄ and R ₅ are the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, trifluoromether groups, amino groups, mono- or di-lower alkylamino groups, heterocyclic amino groups, or halogen atoms. (However) R ₁ is a methyl group, R ₂ , R ₃ , R ₄ and
Cases in which R ₅ is a hydrogen atom and) R ₁ is a methyl group, R ₃ is an ortho-amino group, and R ₂ , R ₄ and R ₅ are hydrogen atoms are excluded. ] and its pharmacologically acceptable acid addition salts. 2 Imidazole derivative according to claim 1 which is 1-(3,4〓dimethylphenyl)-2-methylimidazole 3 1-(4-dimethylaminophenyl)-2-
Imidazole derivative 4 according to claim 1 which is methylimidazole Imidazole derivative 5 according to claim 1 which is 1-(3,4-dichlorophenyl)-2-ethylimidazole 1-(4 -aminophenyl)-2,4-dimethylimidazole The imidazole derivative 6 according to claim 1, which is 1-(3-trifluoromethyl-4-aminophenyl)-2-methylimidazole, claim 1 Imidazole derivative 7 according to Claim 1 Imidazole derivative 8 according to Claim 1 which is 1-(4-aminophenyl)-2-ethylimidazole 1-(2-chloro-aminophenyl)-2-
Imidazole derivative 9 according to Claim 1 which is methylimidazole Imidazole derivative 10 according to Claim 1 which is 1-(3-aminophenyl)-2-methylimidazole 1-(3-amino-4 -methylphenyl)
-Imidazole derivative 11 according to claim 1 which is 2-methylimidazole 1-(4-n-butylaminophenyl)-
Imidazole derivative 12 according to Claim 1 which is 2-methylimidazole Imitazole derivative 13 according to Claim 1 which is 1-(4-aminophenyl)-2-methylimidazole General formula [In the formula, R ₁ represents a lower alkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group. R ₃ , R ₄ and R ₅ are the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, trifluoromethyl groups, amino groups, mono- or di-lower alkylamino groups, heterocyclic amino groups, or halogen atoms. However) R ₁ is a methyl group, R ₂ , R ₃ , R ₄ and R ₅
is a hydrogen atom, and) R ₁ is a methyl group,
R ₃ is an ortho-amino group, R ₂ , R ₄ and R ₅
Except when is a hydrogen atom. ] Antidepressant containing an imidazole derivative or a pharmacologically acceptable acid addition salt thereof 1-(3,4-dimethylphenyl)-2-
Claim 13 which is methylimidazole
Antidepressant described in Section 15 1-(4-dimethylaminophenol)-2
-Claim 1 which is methylimidazole
Antidepressant 16 according to item 3 1-(3,4-dichlorophenyl)-2-
Claim 13 which is ethylimidazole
Claim 13, which is the antidepressant described in 17 1-(4-aminophenyl)-2,4-dimethylimidazole
Antidepressant 18 of Claim 18 Antidepressant 19 of Claim 13 which is 1-(3-trifluoromethyl-4-aminophenyl)-2-methylimidazole 1-(4-aminophenyl)-2- Antidepressant 20 according to claim 13, which is ethylimidazole 1-(2-chloro-4-aminophenyl)
Antidepressant 21 according to claim 13, which is -2-methylimidazole Antidepressant 22 according to claim 13, which is 1-(3-aminophenyl)-2-methylimidazole 1-( 3-amino-4-methylphenyl)
-Antidepressant according to claim 13 which is 2-itilimidazole 23 1-(4-n-butylaminophenyl)-
The antidepressant according to claim 13 which is 2-methylimidazole 24 The antidepressant according to claim 13 which is 1-(4-aminophenyl)-2-methylimidazole