JPS5811871B2 - Piperidylbenzimidazole - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (wherein Ar represents a halophenyl group and Q represents -CH(Ar)-
group or carbonyl group, R1 represents a hydrogen atom, a linear or branched lower alkyl group, an aralkyl group, a benzoyl lower alkyl group, a cyano lower alkyl group, a lower alkynyl group, an aryl group or a hydroxy lower alkyl group.

) A method for producing a novel piperidylbenzimidazole derivative or its salt.

The compound of formula (I) has the formula (■) (where Ar and R1 are as described above, and Ql is -CH(
Ar) A piperidinium salt having one group, a carbonyl group or a protected carbonyl group, R2 is an alkyl group or an aralkyl group, and X- is an anion is heated or treated with a base, and if necessary It can be produced by hydrolysis according to the requirements.

Examples of the alkyl group or aralkyl group used in the definition of the substituent salt include methyl group, ethyl group, isopropyl group, isobutyl group, benzyl group, 2-phenethyl group, 2-naphthylmethyl group, 2-naphthylethyl group. Examples include.

Examples of the anion of X- include halogens such as chlorine, bromine, and iodine, hydroxyl groups, sulfate groups, acetoxy,
It means an anion such as methanesulfonyloxy or paratoluenesulfonyloxy.

Examples of the "protected carbonyl group" include ketals such as dimethyl ketal and ethylene ketal, thioketals, hemithioketals, thiazolidines, enol ethers, enol esters, Schiff bases,
There are oximes and the like, among which ethylene ketal is preferably used because of its ease of handling.

The decomposition reaction of the piperidinium salt of the present invention can be carried out by heating it to 0 to 250°C or by contacting it with an appropriate base.

In this case, the reaction temperature may be low, but the reaction can be effectively promoted by increasing the reaction temperature.

Although the reaction of this invention can be carried out without a solvent, the reaction may be performed using water, alcohols, petroleum, aromatic hydrocarbons, ethers, acetonitrile, dimethylformamide, acetone, halogenated hydrocarbons, or mixtures thereof. It is also possible to use solvents that do not.

Examples of suitable bases include metal hydroxides such as sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride, sodium ethylate,
Examples include metal alcoholades such as potassium tert-butyralate, metal phenolates or thiophenolates such as sodium phenolate and sodium thiophenolate, and Grignard reagents such as silver oxide and methylmagnesium iodide.

After the reaction is completed, the target product can be isolated by conventional techniques.

When the carbonyl group is protected in the raw material compound of formula (■), the carbonyl protecting group may be removed at the same time as the reaction depending on the treatment method, but if the protecting group cannot be removed, a known conventional method such as rare mineral The carbonyl protecting group can also be removed by hydrolysis with acid.

The compound (■) produced by the method of the present invention can be converted into a therapeutically useful acid addition salt by reacting with an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or citric acid.

In addition, the compound of formula (■) in which R is a hydrogen atom is 2-
It has a tautomeric relationship with the benzimidacylinthion type.

The compound 2) produced according to the present invention has interesting pharmacological action.

For example, it exhibits remarkable locomotor activity suppressing activity, methamphetamine group toxicity suppressing effect, anti-methamphetamine effect, conditioned avoidance response suppressing effect, and anti-apomorphine effect, and has properties useful as a medicine, especially as a psychotropic drug.

For example, 1-(
1-(3-(4-fluorobenzoyl)propyl) -
The pharmacological effects of 4-hiheI)')-2-mercaptobenzimidazole are as follows.

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

Reference Example 1 5001v of 4-(2-=Troani IJ/)-1-ethylhyhelicine, 675~ of 3-(4-fluorobencyinolipropyl iodo ethylene ketal) and 80~ of sodium hydroxide were added to 50ml of water, and the mixture was stirred for 3 hours. Heat to reflux.

After the reaction, it was concentrated to dryness, crystallized by adding benzene, and recrystallized from methanol to obtain 1-ethyl-1-(3-(4-fluorobenzoyl)propyl)-41-(2-nitroanilino)piperidine ethylene ketal iodide. yellow crystals are obtained.

Melting point 244-246°C (decomposed). Elemental analysis value C2,
Calculated value for H33FIN304: C51,28,H
5,68,H7,18 Actual value: C51,24,H5,8
3,H7,02 1-ethyl- obtained as described above
1-(3-(4-fluorobenzoyl)propyl)-4
1.2 g of (2-nitroanilino)piperidine ethylene ketal iodide was catalytically reduced in 9 ml of methanol with 2 ml of Raney nickel, and after hydrogen absorption was completed, the catalyst was filtered off, concentrated, crystallized by adding benzene, and methanol When recrystallized from 4-(2-aminoanilino)
-1-ethyl-1-[3=(4-fluorobenzoyl)
Obtain crystals of [propyl]hyperidine ethylene ketal iodide.

Melting point 215-216°C (decomposed). Elemental analysis value C,,
Calculated value for H3, FIN302: C54,06,
H6,35, H7,59 actual measurement value: C53,89, H6
, 41, H7, 74 4-(2
-aminoanilino)-1-ethyl-1-(3-(4-fluorohensoyl)furovir)hyperidine ethylene ketal iodide 1.10.9 and potassium hydroxide 22
5~, 305 mg of carbon disulfide, 5 ml of ethanol, and 0.5 ml of water are reacted for 3 hours in a total mixture of the infant mixture.

After the reaction, ether is added to obtain crude crystals, and the crystals are washed with ether and carbon disulfide.

When recrystallized from methanol, 1-[1-ethyl-1-(
3-[4-fluorobencyinolipropyl)-4-piperidylco-2-mercaptobenzimidazole ethylene ketal iodide is obtained.

Melting point 219-221°C (decomposed).

Elemental analysis value Calculated value for C76H33FIN302S: C52,26, H5,57, H7,03 Actual value: C
52,11, H5,50, H7,12 Reference Example 2 1-[1-ethyl-1-(3-(4
-fluorobencyinolipropyl]-4-piperidylco-2-mercaptobenzimidazole ethylene ketal iodide was dissolved in ethanol and hydrolyzed with hydrochloric acid,
1-(1-ethyl-(3-(4-fluorobenzoyl)
Propyl-4-piperidyl-2-mercaptobenzimidazole iodide is obtained.

Melting point 259-265°C (decomposition).

Elemental analysis value Calculated value for C24H29FIN30S: C52,08, H5,28, H7,59 Actual value: C5
1,81, H5,21, H7,46 Reference Example 3 1-[1-ethyl-1-(3-(4
-Fluorohensoyl)propylcou 4-piperidylco-2-mercaptobenzimidazole ethylene ketal iodide 598Tn9 and sodium hydroxide 80~
was added to a solution of 50 d of water and 50 ml of methanol, and 164 mg of dimethyl sulfate was added thereto for 3 hours while stirring at room temperature.

After that, heat under reflux for 2 hours.

After the reaction, it was concentrated, and 50 mJ of chloroform was added thereto for extraction three times.

Concentrate to dryness. The residue was recrystallized from methanol to give 1-(1-
Crystals of ethyl-1-(3-(4-fluorobenzoyl)propyl-4-piperidyl-2-methylthiobenzimidazole iodide are obtained).

Melting point 248-251°C (decomposition).

Elemental analysis value Calculated value for C27H3, FIN3O2S: C53,03, H5,77, H6,87 Actual value: C
52,91, H5,69, H6,85 Reference Example 4 A 20% aqueous sodium acetate solution was poured into a resin tower filled with 30 ml of strongly basic anion exchange resin Diaion PA-308 (chlor type), and after washing with water. , thoroughly washed with methanol, 1-[1-ethyl-1-(
550 m9 of 3-(4-fluorobenzoyl) furobil]-4-piperidyl]-2-mercaptobenzimidazole ethylene ketal iodide was added to 450 m1 of methanol.
! It dissolves in water and flows down.

Furthermore, 200 Tnl of methanol was allowed to flow down, and the flowing liquid was concentrated.

When recrystallized from methanol, 1-[1-ethyl-1-(
Colorless crystals of 3-(4-fluorobenzoyl)propyl-4-piperidylco-2-mercaptobenzimidazole ketal acetate are obtained.

Melting point 183, 5-185°C (decomposition).

Elemental analysis value Calculated value for C28H36FN304S: C63,49, H6,85, H7,93 Actual value: C6
3,26, H6,79, H7,82 Example 1 1-[1-ethyl-1-(3-(4-fluorobenzoyl)propyl)-4-piperidylcy 2-mercaptobenzimidazole ethylene ketal iodide 1 .21
was added to a solution of 157 m9 of potassium and 407 nl of tertiary butanol, and the mixture was heated under reflux for 2 hours with stirring.

After the reaction, the mixture was concentrated, acidified with hydrochloric acid in supported methanol, and refluxed for 10 minutes.

Then, add 10% aqueous sodium carbonate solution and extract 3 times with 50 ml of chloroform.

Dry with anhydrous sodium sulfate and concentrate. The precipitate was collected by filtration and recrystallized from acetone to give 1-(1-(3-(4
-fluorobenzoyl)propylcy 4-piperidylco-2-mercaptobenzimidazole colorless crystals are obtained.

Melting point: 201-203°C.

Calculated value 2C for elemental analysis value C22H24FN30S
66, 47, H6, 09, N10.57 Actual value: C66
, 53, H6,21, N10.49 Dissolve this in ethanol, add hydrogen chloride saturated ethanol, concentrate, and recrystallize from methanol to obtain 1-(1-(3-(4-fluorobenzoyl)propyl)-4-piperidylco - Obtain colorless prism crystals of 2-mercaptobenzimidazole hydrochloride.

Melting point 242-244°C (decomposition).

Elemental analysis value C22H24FN30S-HCt-)H2
Calculated value for 0 2 C60,27, H5,86, H9,59 Actual value: C60,22, H5,85, H9,63 Example 2 1-[1-ethyl-1-(3-(4- 550 μl of 4-piperidyl-2-mercaptobenzimidazole iodide were added to a solution of 80 μl of potassium and 20 ml of tert-butanol and stirred for 2 hours.
Heat to reflux for an hour.

After the reaction, the solvent was distilled off, a 10% aqueous sodium carbonate solution was added, and the mixture was extracted with 50 ml of chloroform three times.

Dry over anhydrous sodium sulfate and concentrate.

The precipitate was collected by filtration and recrystallized from acetone.
Colorless crystals of 3-(4-fluorobenzoyl)propyl-4-piperidyl-2-mercaptobenzimidazole are obtained.

Melting point: 201-203°C. Infrared absorption spectrum of crystal (
KBr tablet method) was completely consistent with that of the free base obtained in Example 1.

Example 3 If 1-[1-benzyl-1-(3-(4-fluorobenzoyl)furobyl]-4-piperidyl]-2-mercaptobenzimidazole iodide is reacted and treated in the same manner as in Example 2, Colorless crystals of 1-(1-(3-(4-fluorobenzoyl)propyl)=4-piperidyl]-2-mercaptobenzimidazole are obtained.

Melting point: 201-203°C. Infrared absorption spectrum of crystal (
KBr tablet method) was completely consistent with that obtained in Example 2.

Example 4 1-[1-ethyl-1-(3-(4-fluorobenzoyl)propyl-4-piperidylco-2-methylthiobenzimidazole ethylene ketal iodide 612~
was added to a solution of 80 molar potassium and 20 ml of tertiary butanol, and the mixture was heated under reflux for 2 hours with stirring.

After the reaction, the mixture was concentrated, acidified with hydrochloric acid in supported methanol, and refluxed for 10 minutes.

Then, add 10% aqueous sodium carbonate solution and extract with chloroform at 50 mA' three times.

Dry over anhydrous sodium sulfate and concentrate. The precipitate was collected by filtration and recrystallized from ether to give 1-(1-(3-(4-fluorobenzoyl)propyl)-4-piperidyl]-2
- Colorless crystals of methylthiobenzimidazole are obtained.

Melting point 98-985°C.

Elemental analysis value C23H26FN30S Calculated value: C67,12, H6,37, N10.21 Actual value: C67,30, H6,36, N10.26 Example 5 1-[1-ethyl-1-(3-(4- fluorobenzoyl) propylcy 4-piperidylycy 2-mercaptobenzimidazole ethylene kecool acetate 530
1n9 in 10ml of xylene and 2ml of acetonyl
ml of solution and heated under reflux for 48 hours while stirring.

After the reaction, the solvent was distilled off, the solution was dissolved in methanol and refluxed for 10 minutes under acidic hydrochloric acid.

Then, 10% aqueous sodium carbonate solution was added and extracted three times with 50 ml of chloroform.

Dry over anhydrous sodium sulfate and concentrate.

The precipitate was collected by filtration and recrystallized from acetone.
Colorless crystals of 3-(4-fluorobenzoyl)furobylcy, 4-piperidylycy, 2-mercaptobenzimidazole are obtained.

Melting point: 201-203°C.

The infrared absorption spectrum (KBr tablet method) of the crystal completely matched that of the free base obtained in Example 1.3 Example 6 The following compound was obtained according to Example 1.

1) 2-Ethylthio-1-(1-(3-(4-fluorobenzoyl)propyl)-4-piperidylcobenzimidazole hydrochloride; colorless crystals, recrystallized from methanol, mp 210-211°C (decomposition).

2) 2-cyanomethylthio-1-(1-[3-(4-fluorobenzoyl)furovir)-4-piperidylcobenzimidazole hydrochloride; colorless crystals, recrystallized from a methanol-ethanol mixture, melting point 201-202. 5°C (
Disassembly).

3) 1-(1-C3-(4-fluorobencyinolipropyl)-4-piperidyl)-2-7” lovargylthiobenzimidazole dihydrochloride; colorless crystals, recrystallized from a mixture of ethanol and acetone, melting point 156 ~158°C
(Disassembly).

4) 1-(1-(3-(4-fluorobenzoyl)
Propylcy 4-piperidylco-2-inpropylthiobenzimidazole hydrobromide; colorless scaly crystals, recrystallized from a chloroform-ethanol mixture, melting point 222~
224.5°C (decomposition).

Example 7 According to Example 2, the following compound is obtained.

1) 1-CI-C3-(4-fluorobenzoyl)
Propylcy 4-piperidyl]-2-hydroxyethylthiobenzimidazole: colorless prismatic crystals, acetone-
Recrystallized from a mixture of ether, melting point 103-104°C8 2) 1-(1-C4,4-bis(4-fluorophenyl)phthyl]-4-piperidyl]-2-mercaptobenzimidazole; colorless prismatic crystals, ether Recrystallized from, melting point 224-227°C.

3) 1-[1-(4,4-bis(4-fluorophenyl)phthyl]-4-piperidyl)-2-methylthiobenzimidazole; colorless prism crystals, recrystallized from a mixture of ether-n-hexane, melting point 110. 5-111
．． 5℃.

4) 2-Benzylthio-1-(1-(3-(4-fluorobenzoyl)propyl]-4-piperidyl)benzimidazole; colorless prism crystals, recrystallized from a chloroform-ether mixture, melting point 124-126°C.

5) 1-(1-C3-(4-fluorobenzoyl)
Propyl-4-piperidyl-2-parachlorophenacilthiobenzimidazole hydrate; colorless needle crystals, recrystallized from benzene, melting point 68-70°C.

6) 1-(1-(3-(4-fluorobenzoyl)
Propyl (4-piperidyl)-2-(2-nitrophenylthio)benzimidazole; yellow crystals, recrystallized from ethanol, mp 124-127°C.

Claims (1)

[Claims] 1 General formula (wherein Ar represents a halophenyl group, Ql represents -CH(Ar)
one group, a carbonyl group or a protected carbonyl group, R
1 is a hydrogen atom, a linear or branched lower alkyl group,
An aralkyl group, a benzoyl lower alkyl group, a cyano lower alkyl group, a lower alkyl group, an aryl group or a hydroxy lower alkyl group, a bird represents an alkyl group or an aralkyl group, and X- represents an anion. ) is heated or treated with a base and optionally hydrolyzed.
r and R1 are the same as above. ) A method for producing a piperidylbenzimidazole derivative or a salt thereof.