JPS6241224B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula () In the formula, R ₁ and R ₂ are hydrogen or lower alkyl groups, R ₃
is a lower alkyl group, a halogenated lower alkyl group,
A mono- or di-lower alkylamino group, a mono- or di-lower alkylaminoalkyl group, a phenyl group that is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, a phenyl moiety is an unsubstituted or optionally substituted phenylamino group with a halogen atom, lower alkyl group, lower alkoxy group, or trifluoromethyl group, R ₄ is a hydrogen atom, lower alkyl group, or lower alkylsulfonyl group, and R ₅ is a hydrogen atom, lower alkyl group, or lower alkylsulfonyl group. A represents a hydrogen atom, a lower alkyl group, or a trifluoromethyl group, and A represents a carbonyl group or a sulfonyl group.
The group represented by the formula -N( _R4 )-A- _R3 is located at the m or p position. The present invention relates to a novel imidazole compound represented by: and its pharmacologically acceptable acid addition salt. Furthermore, the present invention relates to antidepressants containing the imidazole compounds disclosed herein. The lower alkyl group in the compound () of the present invention is an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group,
It means a butyl group or an isobutyl group. As pharmacologically acceptable acid salts, inorganic acid salts include hydrochloride, sulfate, and nitrate; organic acid salts include oxalate, tartrate, citrate, fumarate, and methanesulfonate. This can be cited as an example. The compound of the present invention can be produced by various methods, but typical production methods are as follows. (i) In the target compound (), A is a carbonyl group or a sulfonyl group, R ₄ is a hydrogen atom or a lower alkylsulfonyl group, R ₃ is a lower alkyl group, a halogenated lower alkyl group, a mono- or di-lower alkylamino group, or a mono- or di-lower alkylamino group. or a di-lower alkylaminoalkyl group, a phenyl group that is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, a primary amino compound represented by the following general formula () (wherein R ₁ , R ₂ , R ₅ have the same meanings as defined above), carboxylic acid or sulfonic acid R ₃ -A-OH () represented by the following general formula () or its reactivity derivatives (e.g. acid halides, acid anhydrides, active esters, sulfonyl chlorides) in an insoluble solvent that does not participate in the reaction, such as chloroform, dichloromethane, benzene, toluene, xylene, etc., and if necessary, potassium carbonate, sodium carbonate, triethylamine, etc. The following target compound () is obtained by reacting at room temperature to about 150°C in the presence of a deoxidizing agent, or at about 0 to 40°C in pyridine. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and A have the same meanings as above) (ii) A is a carbonyl group, R ₄ is a hydrogen atom, and R ₃ is a lower alkylamino group , or a phenylamino group that is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, a primary amino compound represented by the following general formula () (In the formula, R ₁ , R ₂ and R ₅ have the same meanings as defined above.) Chloroform, dichloromethane, benzene,
An isocyanate compound represented by the following general formula () R ₆ NCO () (in the formula, R ₆ is a lower alkyl group, unsubstituted or halogen atom, lower (represents a phenyl group optionally substituted with an alkyl group, a lower alkoxy group, or a trifluoromethyl group)) at room temperature to about 100°C to obtain the target compound (). (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and A have the same meanings as above) (iii) In the target compound (), A is a carbonyl group or a sulfonyl group, and R ₄ is a lower alkyl group ,
R ₃ is a lower alkyl group, an unsubstituted or halogen atom, a lower alkyl group, a lower alkoxy group,
When it is a phenyl group optionally substituted with a trifluoromethyl group That is, a compound represented by the general formula (in which R ₁ , R ₂ , R ₄ , and R ₅ have the above meanings)
, the general formula R ₄ X (wherein R ₄ is a lower alkyl group,
represents a halogen atom) in the presence of an alkali carbonate, an alkali hydride, an alkoxy alkali, etc., with DMF (N/N-dimethylformamide),
HMPA (hexamethylphosphamide),
The target compound () is obtained by reacting in a solvent such as DMSO (dimethyl sulfoxide). The primary amino compound () used as a starting material in the above method can be replaced with the corresponding nitro compound () as shown below. (In the formula, R ₁ , R ₂ and R ₅ have the same meanings as defined above) can be obtained by performing a catalytic reduction operation using, for example, palladium/carbon or Raney nickel as a catalyst. Due to its chemical structure, the compound of the present invention is not expected to exhibit antidepressant action at all based on conventional knowledge, and its antidepressant action is specific and quite strong. The antidepressant effects of the compounds of the present invention are shown below. <Pharmacological test> Test compound The following compounds were selected from the compounds of the present invention () as test compounds. 1-[4-(3-chloropropionylamino)phenyl]imidazole (hereinafter referred to as compound A) 1-[4-(4-chlorobenzoylamino)phenyl]-2-methylimidazole (hereinafter referred to as compound B)
) 1-[4-(4-fluorobenzoylamino)phenyl]-2-methylimidazole (hereinafter referred to as compound C) 1-[4-(4-chlorobenzoylamino)phenyl]-2-ethylimidazole (hereinafter referred to as compound C) Compound D
1-[4-(4-methylbenzoylamino)phenyl]-2-ethylimidazole (hereinafter referred to as compound E)
) 1-[4-(4-chlorobenzoylamino)phenyl]-2-isopropylimidazole (hereinafter referred to as compound F) 1-[4-(4-methylbenzoylamino)phenyl]-2-methylimidazole (hereinafter referred to as compound F) Compound G
) However, the test compound used was its hydrochloride. Experimental method (1) Anti-reserpine effect A type of pharmacological screening method for antidepressants, the Askew and BM method (Life Science 4)
725-730, 1963) to investigate its antagonistic effect on reserpine-induced hypothermia. DD male mice (19-25
g), 2.5 mg/Kg of reserpine was intraperitoneally injected, and 18 hours later, the test compound was orally administered, and thereafter, changes in body temperature were measured over time. A thermistor type thermometer (MGA type manufactured by Shibaura Denshi Seisakusho) was used to measure body temperature. The test compound doses were 0.63, 1.25, 2.5...
40 mg/Kg and 2 to 4 doses of each compound were used to investigate the effect. All test compounds were used as aqueous solutions. Note that physiological saline was administered to the control group. The number of experimental cases was 4 per dose. Experimental animals with a body temperature of 24 to 25°C 18 hours after reserpine administration were used in the experiment. The experiment was conducted in a constant temperature environment of 23 to 25°C. (2) Effect on locomotor activity Locomotor activity was measured using the method of Sevensson, TH, et al. (Psychopharma-cologia 14 157, 1969). As a laboratory animal,
A group of 3 male dd mice (20-25 g)
Placed in a black acrylic resin observation box for 60 days.
The locomotor activity per minute was measured and recorded 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 was investigated when 100 and 400 mg/Kg of the test compound was orally administered to DD male mice. The number of experimental subjects was 5 for each dose, and 24 subjects were administered.
The mortality rate after hours was calculated. Experimental Results The antireserpine 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 test compound clearly exhibited antidepressant effects and had very low toxicity. As described above, the compound of the present invention (), represented by the test compound, has a completely different chemical structure from conventional tricyclic antidepressants (e.g. imipramine, amitriptyline), and exhibits highly specific antireserpine action. Since it has low toxicity, it is useful as a highly safe treatment for depression or depressive state. The clinical dose for the treatment of depression in patients with depression or visceral disease is 10-1000mg/
day, preferably 30 to 300 mg/day. The compounds of this invention can be prepared for administration using any conventional method of formulation. Therefore, the present invention also encompasses 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 include 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 lubricants 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, methylcellulose,
Glucose/sugar syrups, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, sorbitan monooleate, or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, 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 reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use. Next, the present invention will be explained with reference to examples. Example 1 1-[4-(4-chlorobenzoylamino)phenyl]-2-ethylimidazole 1.9 g of 1-(4-aminophenyl)-2-ethylimidazole and 2.6 g of P-chlorobenzoyl chloride were dissolved in 50 ml of toluene. The solution was stirred and refluxed for 7 hours. After the reaction is complete, let it cool,
After cooling, ethyl ether was added to precipitate crystals, which were thoroughly washed with ethyl ether and then recrystallized from ethanol and then water to obtain the desired product as a hydrochloride. Melting point 228-238℃ Yield 2.5g Elemental analysis value C ₁₈ H ₁₆ ClN ₃ O・HCl・1/2H ₂ O as C H N Theoretical value (%) 58.21 4.89 11.32 Actual value (%) 58.23 4.75 11.06 Example 2 1 -[2-(Dimethanesulfonylamino)phenyl]-2-methylimidazole To a solution of 1.5 g of 1-(2-aminophenyl)-2-methylimidazole dissolved in 30 ml of chloroform, 1.1 g of triethylamine and 1.2 g of methanesulfonyl chloride. The mixture was stirred and refluxed for 5 hours, and then 0.6 g of methanesulfonyl chloride was added and stirred and refluxed for 3 hours. After the reaction was completed, the mixture was allowed to cool, and after cooling, the solvent was distilled off under reduced pressure. Water was added to the resulting residue, and the liquid was then made alkaline with an aqueous sodium carbonate solution. The separated oily layer was collected, crystallized, washed with water, dried, and recrystallized from ethanol to obtain 0.9 g of the desired product. Hydrochloride (melting point
215-220℃). Elemental analysis value C ₁₂ H ₁₅ N ₃ S ₂ O ₄ As HCl C H N Theoretical value (%) 39.40 4.42 11.49 Actual value (%) 39.21 4.33 11.23 Example 3 2-ethyl-1-[4-(N') -Methylureide)] Phenylimidazole 0.8 g of methyl isocyanate was added to a solution of 1.5 g of 1-(4-aminophenyl)-2-ethylimidazole dissolved in 20 ml of dichloromethane, stirred at room temperature for 3 hours, and then stirred and refluxed for 3 hours. . After the reaction was completed, the mixture was allowed to cool, and after cooling, the solvent was distilled off under reduced pressure. Benzene was added to the resulting residue, and the resulting solidified product was collected. This was dissolved in a small amount of methanol and recrystallized from a mixed solvent of ethyl ether and benzene.
This was made into a hydrochloride salt (melting point: 228-232°C) by a conventional method. Elemental analysis value C ₁₃ H ₁₆ N ₄ As O.HCl C H N Theoretical value (%) 55.60 6.11 19.96 Actual value (%) 55.53 5.86 20.00 Other compounds of the present invention are described as examples. [Table] [Table] [Table] [Table] [Table] [Table] Next, the present invention will be explained with reference to formulation examples. 1-[4'-N-(P-chlorobenzoyl)-aminophenyl]-2-ethyl-imidazole hydrochloride (hereinafter referred to as the main drug) was selected as the main drug. Example 31 Capsules Main drug 10g Corn starch 90g Total amount 100g The entire amount was thoroughly mixed and filled into hard gelatin capsules to the amount of 100mg. Main drug 10 in 1 capsule
Contains mg. Example 32 Tablet Main drug 10g Crystalline cellulose 100g Cornstarch 88g Calcium stearate 2g Total amount 200g The entire amount was thoroughly mixed and compressed into 1000 flat tablets. Each tablet contains 10mg of the main drug. Example 33 Injection Main drug 10g Sorbitol 20g Physiological saline Total amount 1 An injection was produced by a conventional method based on the above prescription. Buffers, PH regulators, and analgesics can be added as necessary.

Claims (1)

[Claims] 1. The following general formula [In the formula, R ₁ and R ₂ are hydrogen or lower alkyl groups, R ₃
is a lower alkyl group, a halogenated lower alkyl group,
A mono- or di-lower alkylamino group, a mono- or di-lower alkylaminoalkyl group, a phenyl group that is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, phenyl A phenylamino group in which the moiety is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, R ₄ is a hydrogen atom, a lower alkyl group, or a lower alkylsulfonyl group,
R ₅ represents a hydrogen atom, a lower alkyl group, or a trifluoromethyl group, and A represents a carbonyl group or a sulfonyl group. The -N( _R4 )-A- _R3 group is assumed to be substituted at the m or p position on the phenyl nucleus. ] An imidazole compound represented by these and its pharmacologically acceptable acid salt. 2 1-[4-(3-chloropropionylamino)
The compound according to claim 1, which is phenyl]imidazole. 3. The compound according to claim 1, which is 1-[4-(4-chlorobenzoylamino)phenyl]-2-methylimidazole. 4 1-[4-(4-fluorobenzoylamino)
The compound according to claim 1, which is phenyl]-2-methylimidazole. 5. The compound according to claim 1, which is 1-[4-(4-chlorobenzoylamino)phenyl]-2-ethylimidazole. 6. The compound according to claim 1, which is 1-[4-(4-methylbenzoylamino)phenyl]-2-ethylimidazole. 7. The compound according to claim 1, which is 1-[4-(4-chlorobenzoylamino)phenyl]-2-isopropylimidazole. 8. The compound according to claim 1, which is 1-[4-(4-methylbenzoylamino)phenyl-2-methylimidazole. 9 General formula below [In the formula, R ₁ and R ₂ are hydrogen or lower alkyl groups, R ₃
is a lower alkyl group, a halogenated lower alkyl group,
A mono- or di-lower alkylamino group, a mono- or di-lower alkylaminoalkyl group, a phenyl group that is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, phenyl A phenylamino group in which the moiety is unsubstituted or optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, R ₄ is a hydrogen atom, a lower alkyl group, or a lower alkylsulfonyl group,
R ₅ represents a hydrogen atom, a lower alkyl group, or a trifluoromethyl group, and A represents a carbonyl group or a sulfonyl group. The R ₅ and -N(R ₄ )-A-R ₃ groups may be substituted at any position on the phenyl nucleus. ] An antidepressant containing an imidazole compound represented by the following or a pharmacologically acceptable acid salt thereof. 10. The antidepressant according to claim 9, which is 1-[4-(3-chloropropionylamino)phenyl]imidazole. 11 1-[4-(4-chlorobenzoylamino)
The antidepressant according to claim 9, which is phenyl]-2-methylimidazole. 12. The antidepressant according to claim 9, which is 1-[4-(4-fluorobenzoylamino)phenyl]-2-methylimidazole. 13 1-[4-(4-chlorobenzoylamino)
The antidepressant according to claim 9, which is phenyl]-2-ethylimidazole. 14 1-[4-(4-methylbenzoylamino)
The antidepressant according to claim 9, which is phenyl]-2-ethylimidazole. 15 1-[4-(4-chlorobenzoylamino)
The antidepressant according to claim 9, which is phenyl]-2-isopropylimidazole. 16 1-[4-(4-methylbenzoylamino)
The antidepressant according to claim 9, which is phenyl]-2-methylimidazole.