JPS5811873B2 - Piperidylbenzimidazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (1) (wherein, Ar represents a halophenyl group, and R1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a benzoyl lower alkyl group, or a lower alkynyl group). The present invention relates to a method for producing the novel piperidylbenzimidazole derivatives or salts thereof.

〈For me, the formula (■) (In the formula, Ar and R1 are as described above.

The present invention relates to the production of a novel compound represented by formula (I) by treating a compound represented by formula (R2 represents a lower alkyl group) with an alkali or acid in a suitable solvent.

The reaction temperature of the present invention is room temperature to 200°C, and the reaction time is 20°C.
The reaction time ranges from minutes to 10 hours, and the reaction can generally be effectively promoted by increasing the temperature.

Reaction solvents include water, methanol, dioxane, acetone, dimethylformamide, acetonate, halogenated hydrocarbons, aromatic hydrocarbons, petroleum, etc., or mixtures thereof, which may interfere with the reaction raw materials and products. Non-toxic solvents can be used.

Examples of alkalis suitably used include sodium hydroxide and potassium hydroxide, and examples of acids include hydrochloric acid, sulfuric acid, and acetic acid.

After the reaction, the target product can be easily removed using conventional organic chemical techniques.

The compound (■) produced by the method of the present invention is hydrochloric acid,
They can be converted into therapeutically useful acid addition salts by reaction with inorganic acids such as sulfuric acid or organic acids such as acetic acid or citric acid.

In the compound of formula (I), when R1 is a hydrogen atom, it has a tautomeric relationship with the 2-benzimidazolinthione type.

The compounds produced according to the invention have interesting pharmacological effects.

For example, remarkable locomotor activity suppression effect (mice), methamphetamine group toxicity suppression effect (mice), methamphetamine lightning behavior suppression effect (rat), conditioned avoidance response suppression effect (
Apomorphine exhibits a behavioral inhibitory effect (in rats), and has properties that are useful as a medicine, especially as a psychotropic drug.

For example, in one of the representative compounds related to the present invention, Al 1-(1
The pharmacological effects of -C3-(4-fluorobenzf]v)propyl-4-piperidylco-2-mercaftobenzimidazole are as follows.

Incidentally, the raw material compound of the present invention can be easily produced, for example, by the method of the following reference example.

Reference example 1 (a) In 20 ml of n-butanol, 4-(2-
Nitroanilino)piperidine 3.32. ! li', ethylene bromohydrin i, sB, anhydrous sodium carbonate o, and r9slZ are added, and the mixture is refluxed for 3 hours.

After the reaction, the solvent was distilled off, water-chloroform was added and shaken, the organic layer was separated and dried over anhydrous sodium sulfate, and when the solvent was distilled off, a red oily substance, 1-hydroxyethyl-4-
(2-nitroanilino)piperidine is obtained.

To the resulting oil was added 7 ml of thionyl chloride under water cooling, and the mixture was stirred at room temperature for 1 hour and then refluxed for 30 minutes.

Thionyl chloride was distilled off under reduced pressure. A 10% aqueous sodium carbonate solution was added, and the mixture was extracted three times with 50 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain an oily residue.

This residue was subjected to silica gel chromatography using benzene and then chloroform, and the chloroform fraction was distilled off to give 1-(2-chloroethyl)-4-(2-nitroanilino)piperidine as a red oil.

(b) Dissolve 1.72 g of ethyl parafluorobenzoylacetate in 100 ml of xylene, add 190 μm of sodium metal, and heat and stir for 3 hours.

After cooling 2.32. 1-(2-chloroethyl)-4-( of p
Gradually add 2-nitroanilino)piperidine and add 5 more
Reflux for an hour.

After the reaction, ice water is added, and the xylene layer is separated and dried over anhydrous sodium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel chromatography using benzene and then chloroform. When the chloroform fraction was distilled off, a red oily 1-(3-(
4-fluorobenzoyl)-3-ethoxycarponylglobil)-4-(2-nitroanilino)piperidine is obtained.

Infrared absorption spectrum (liquid film method) Niji max 1700, 1670 cm-1 Nuclear magnetic resonance spectrum (deuterium chloroform solvent): TMS
Pl as internal standard, 30 (3H, triple line, J=7
Hz, C00CH2CH3), 425 (2H quartet J
=7 Hz, C00CH2CH3) 1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylph) in 50 ml of ethanol.

ropyru)-4-(2-nitroanilino)piperidine 5I
If catalytic reduction is carried out using 5 ml of Raney nickel catalyst and treated in a conventional manner, 1. -(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4-(2
-7minoanilino)piperidine is obtained.

Infrared absorption spectrum (liquid film method) 17001670cm-'' (C) 1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4-(2-
A mixture of aminoanilino)piperidine 470~, carbon disulfide 1501119, potassium hydroxide 67~, and ethanol solvent was heated in a sealed tube at 80°C for 1.5 hours. After the reaction, the solvent was distilled off and 5% sodium carbonate was added. Add the aqueous solution,
Extract 3 times with 501111 chloroform.

After drying the chloroform layer over anhydrous sodium ftte, the solvent was distilled off, and the residue was crystallized with ethanol and collected by filtration to give 1-(1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4 -piperidylco-2-
Obtain crystals of mercaptobenzimidazole.

Melting point 99-103°C (decomposed). Elemental analysis value C25H2
Calculated values for 8FN303S: C63,94, H6,
01, H8, 95 MIJ I Naoji C64, 15, H6
, 18, H8, 92 infrared absorption spectrum (liquid film method) Niji ml 700.1660 cIrL-' Reference example 2 (a) Normal butano-) In 20 ml of Li, 1-(
4-pi,beridyl)-2-methylthiobenzimidazole 7001r19 and ethylene bromohydrin 390
~ and 165~ of anhydrous sodium carbonate were added, and after refluxing for 3 hours, the solvent was distilled off, and the mixture was shaken with water-chloroform.

The organic layer is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain a colorless and transparent oil.

This is crystallized in ether and 1-(1-(2-
Colorless crystals of (hydroxyethyl)-4-piperidylco-2-methylthiobenzimidazole are obtained.

Melting point: 112-114.5°C.

(b) Add 5 Tll of thionyl chloride to the 1-[1-(2-hydroxyethyl)-4-piperidylco-2-methylthioben 1 diimidazole 600r/19 obtained above under water cooling, stir for 1 hour at room temperature, and then stir for 30 minutes. Perform reflux.

Thionyl chloride is distilled off under reduced pressure, 10% aqueous sodium carbonate is added, extracted three times with 50 ml of chloroform, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain a crystalline residue.

Recrystallization from ether-acetone yields 1-(1-(2-
Colorless crystals of zirco-2-methylthiobenzimidazole are obtained.

Melting point: 141-144°C. Elemental analysis value C15) (2
Be careful with oCIN3S: C58,14,
H6,51, N13.56 Actual value: C58,09, H6
, 52, N13.59 (C) In 100 ml of xylene, dissolve 1.71' of ethyl parafluorobenzoylacetate, add 1901 vol of sodium metal, and heat and stir for 3 hours.

After cooling 1-(1-(2-chloroethyl)-4-piperidylcy 2-methyl thiobenzimidazole 2.53.@
was gradually added and refluxed for 5 hours.

After the reaction, ice water was added, the xylene layer was separated and dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel chromatography using benzene and then chloroform. When the 7-lactone of chloroform was distilled off, a yellow oil was obtained. 1-.(1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4-piperidylco-2-methylthiobenzimidazole is obtained.

The infrared absorption spectrum, ultraviolet absorption spectrum, and nuclear magnetic resonance spectrum of this product are as follows.

Infrared absorption spectrum (e!, demethod) Niji ml 700, 1680 CrrL-'' Ultraviolet absorption spectrum (ethanol solvent): λ 284
292mμ nuclear magnetic resonance spectrum (deuterochloroform solvent): TMS
Pl, 29(3f(, triple line, J”7
Hz, C00CH2CH3), 2.77 (3H1 single line, S-CH5), 4.20 (2H, quartet, J=7Hz
tC00CH2CHs) Example 1 1-(1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4-piperidylcy2-
2.0 g of mercaptobenzimidazole are refluxed for 1 hour in 40 ml of a 3% methanol solution of sodium hydroxide.

After the reaction, the formed insoluble matter is removed by filtration, the solvent is distilled off, diluted hydrochloric acid is added to make the mixture weakly acidic, and the mixture is neutralized with a 5% aqueous sodium carbonate solution.

Extract three times with 50 ml of chloroform, dry the extract over anhydrous sulfuric acid, and concentrate.

The precipitate was collected by filtration and recrystallized from acetone to give 1-(1-(
Colorless crystals of 3-(4-fluorobenzoyl]propyl, 1-4-piperidylco-2-mercaptobenzimidazole are obtained.

Melting point: 2.01-203°C.

Elemental analysis value Calculated value for C22H24FN30S:
C66,47, H6,09, N10.57 Actual value: C6
6,29,H5,99,N10.58Example 2 1-(1-(3-(4-fluorobenzoyl)-3-ethoxycarbonylpropyl)-4-piperidylcy2-
2.0 g of methylthiobenzimidazole is refluxed for 1 hour in 40 ml of a 3% methanol solution of sodium hydroxide.

After the reaction, the formed insoluble matter is removed by filtration, the solvent is distilled off, water and chloroform are added and distributed, the chloroform layer is taken, dried over anhydrous sulfuric acid, and the solvent is distilled off.

The residue was subjected to silica gel chromatography using benzene and then chloroform, the chloroform fraction was distilled off, and recrystallization from ether yielded 1-
Colorless crystals of CI-C, 3-(4-fluorobenzoyl)propyl-4-piperidylco-2-methylthiobenzimidazole are obtained.

Melting point: 98-98.5°C. Elemental analysis value C23H26FN
Calculated value 2C67,12,H6,37,N for 30S
10.21 Actual measurement value: C67, 27, H6, 39, N10
．． 19 This product is converted into a hydrochloride salt by a conventional method, and recrystallized from methanol to obtain colorless crystals of 1-(1-(3-(4-fluorobenzoyl)propyl)-4-piperidylco-2-methylthiobenzimidazole hydrochloride. .

Melting point 179-180'C (decomposed). Elemental analysis value C23
Calculated value for H26FN30S/2HCt-TE01: 56.50, H5,88, H8,60 Actual value: 56.48, H5,89, H8,71 Example
3 According to Example 2, the following compound is obtained.

(a) 2-ethylthio-1-(1-[3-(4-fluorobenzoyl)propyl-4-piperidyl]penduimidazole hydrochloride: colorless crystals: recrystallized from methanol,
Melting point 210-211°C (decomposition).

(b) 2-Benzylthio-1-(1-C3-(4-fluorobenzoyl)propyl]-4-piperidyl]benzimidazole: Colorless prism crystals: Recrystallized from a chloroform-ether mixture, melting point 124-126°C.

(c) 1-(1-(3-(4-fluoropencyinolipropyl)-4-piperidylco-2-isopropylthiobenzimidazole hydrobromide: colorless scaly crystals: recrystallized from chloroform-ethanol mixture, melting point 222~
224.5°C (decomposed).

(d) 1-(1-(3-(4-fluorobenzoyl)propyl-4-piperidyl-2-parachlorophenacylthiobenzimidazole hydrate): colorless needle crystals: recrystallized from benzene, melting point 68-70 ℃.

(e) 1-(1-[3-(4-fluorobenzoyl)propyl)-4-piperidyl)-2-propalkylthiobenzimidazole dihydrochloride: Colorless crystals: Ethanol-
Recrystallized from a mixture of acetone, melting point 156-158°C (
Disassembly).

Claims (1)

[Claims] 1 In the general formula (wherein, Ar represents a halophenyl group, R1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a benzoyl lower alkyl group, or a lower alkynyl group), and R2 represents a lower alkyl group. A method for producing a piperidylbenzimidazole derivative or a salt thereof represented by the general formula (wherein Ar and R1 are the same as above), which comprises treating the represented compound with an acid or an alkali.