JPS6135177B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to piperidine derivatives and methods for producing the same. The compound according to the present invention has the formula (): [In the formula, R is substituted with a substituent selected from the group consisting of hydrogen; C _1-4 alkyl; hydroxy-C _1-4 alkyl; C _1-4 alkoxycarbonyl; halogen and C _1-4 alkoxy may also represent benzyl; phenethyl or 3-phenylpropyl; X each represents one or more hydrogen; halogen; C _1-4 alkyl; C _1-4 alkoxy; Together with the phenyl nucleus, it may also represent naphthyl. However, R and X cannot be hydrogen at the same time. ] It is indicated by. Acid addition salts formed with a compound of formula () and an acid, particularly a pharmaceutically acceptable acid, are also encompassed by the present invention. Among the compounds of the present invention, preferred are those in which X represents one or more chlorine, represents naphthyl together with a phenyl nucleus, or represents trimethoxy. Among these compounds, those in which R is H are particularly preferred. The compound of formula () of the present invention is of formula (): [wherein R' represents R or a nitrogen protecting group such as 4-nitrobenzoyl, other optionally substituted benzoyl, optionally substituted benzyl or optionally substituted alkyl] Starting material is a compound represented by the formula (): [In the formula, Y represents a reactive group, such as chlorine or bromine.] When the protecting group R' does not correspond to R, this protecting group is removed or substituted. There is also a benzoyl protecting group that can be reduced, or formula (′): [In the formula, X has the same meaning as above] A compound included in () represented by the formula: It can be produced by reacting with a compound represented by the following. The present invention will be explained in more detail with reference to Examples below. The structure of the compound was confirmed by 1R, NMR and elemental analysis. Example 1 4-(4-fluorobenzyloxy)piperidine and its mandelate salt 1.1 1-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)piperidine 1.6 g of 50% aqueous sodium hydroxide solution, 10 ml of dichloromethane, 1-(4-nitrobenzoyl)-
2 g (0.008 mol) of 4-hydroxypiperidine,
4-fluorobenzyl bromide 2.32 g (0.012
A mixture of 0.15 g (4 x 10 ^-4 mol) of tetrabutylammonium iodide and
Stir for an hour. The reaction mixture is diluted with 20 ml of water and 30 ml of dichloromethane, the organic layer is decanted off, washed with water until neutral, dried over MgSO ₄ and evaporated under reduced pressure. The oily residue obtained is crystallized by stirring in ether to give 2.23 g of product. This product is dissolved in 11 ml of dimethylformamide (DMF) and reprecipitated by gradually adding 11 ml of water while stirring. After washing with water, it is dried under reduced pressure to obtain 1-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)piperidine. mp120℃ 1.2 4-(4-fluorobenzyloxy)piperidine (mandelate) 11.48 g (0.032 mol) of the compound obtained in 1.1, 96%
A mixture of 192 ml of ethanol and 48 ml of 10M aqueous potassium hydroxide solution was stirred under a nitrogen atmosphere, and
Keep at 50℃ for an hour. The alcohol is removed under reduced pressure and the residue is taken up in 200 ml of water, 72 g of sodium chloride and 200 ml of ether. After filtration, extract the aqueous layer twice with 200 ml of ether, combine the organic layers,
Dry with _MgSO4 and evaporate under reduced pressure. The obtained oil was dissolved in 100 ml of ether and d.
It is converted to d.l-mandelate by adding 4.57 g (0.03 mol) of l-mandelic acid. The salt obtained is filtered and recrystallized from isopropanol. mp146℃ Example 2 4-(3.4.5-trimethoxybenzyloxy)piperidine and its mandelate salt 2.1 1-(4-nitrobenzoyl)-4-(3.
4,5-trimethoxybenzyloxy)piperidine 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of dichloromethane, 1-(4-nitrobenzoyl)-
4-hydroxypiperidine 1g (0.004 mol),
3,4,5-trimethoxybenzyl chloride
A mixture of 1.30 g (0.006 mol) and 0.08 g (2×10 ⁻⁴ mol) of tetrabutylammonium iodide is stirred at 50° C. for 5 hours. After dilution with 10 ml of water and 15 ml of dichloromethane, the organic layer was decanted, washed with water until neutral, and diluted with MgSO ₄
and evaporate under reduced pressure. The oily residue obtained is stirred in ether to crystallize.
1.36 g (79%) of product are obtained in this way, which is dissolved in 7 ml of DMF and recrystallized by slowly adding 7 ml of water. After washing with water and drying under reduced pressure,
-(4-nitrobenzoyl)-4-(3・4・5
-trimethoxybenzyloxy)piperidine is obtained. mp124℃ 2.2 4-(3,4,5-trimethoxybenzyloxy)piperidine (mandelate) A mixture of 12 g (0.028 mol) of the product obtained in 2.1, 168 ml of 96% ethanol and 48 ml of 10 M aqueous potassium hydroxide solution was heated with nitrogen. Stir under atmosphere and keep at 50°C for 4 hours. Remove alcohol under reduced pressure;
The residue is taken up in 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous layer was extracted twice with 70 ml of chloroform, and all organic layers were combined.
Dry with _MgSO4 and evaporate under reduced pressure. Dissolve the obtained viscous solid in 120 ml of methanol,
4.26 g (0.028 mol) of d.l-mandelic acid are added, the mixture is stirred at ambient temperature overnight and then filtered to convert to the d.l-mandelate salt. The resulting precipitate is recrystallized from methanol. This product crystallizes with 1/2 molecule of water. mp114℃ Example 3 1-ethoxycarbonyl-4-benzyloxypiperidine 4-benzyloxypiperidine hydrochloride 6.83g
(0.03 mol), anhydrous K ₂ CO ₃ 7.74 g (0.056 mol), water
A mixture of 26 ml and 26 ml of chloroform is stirred and 3.4 g (0.033 mol) of ethyl chloroformate is gradually added. After stirring for 1 hour, chloroform
Dilute by adding 54 ml, decant the organic layer and add 20 ml of water.
ml three times, dried over MgSO ₄ and the solvent was evaporated under reduced pressure to give a liquid. This was distilled under reduced pressure. bp149-151℃/0.4mmHg, ^n21D ₌
1.5178 Example 4 1-Methyl-4-(4-chlorobenzyloxy)-piperidine and its hydrochloride 55% sodium hydride in oil in a 500 ml three-neck round bottom flask kept under an argon atmosphere 4.4
g (0.1 mol) are washed three times with petroleum ether.
Then 10.1 g (0.1 mol) of 1-methyl-4-hydroxypiperidine dissolved in 100 ml of DMF is added. The mixture is stirred for 1 hour at ambient temperature, then cooled in an ice-water bath and 19.3 g (0.12 mol) of p-chlorobenzyl chloride in 50 ml of DMF are added. Once the addition is complete, stir at ambient temperature for 4 hours.
Leave it overnight. The reaction mixture is poured into ice water and extracted three times with diethyl ether. The organic layer is washed with water and extracted with dilute HCl (1-2N). The aqueous phase is then made alkylated with NaOH, extracted with diethyl ether, and the ether extract is washed four times with water. This is dried over magnesium sulfate, filtered and concentrated. The resulting oil was distilled twice and 94~
Collect the fraction distilled off at 98°C/0.04mmHg. The resulting oil is taken up in diethyl ether and hydrogen chloride is added to precipitate the hydrochloride. Filter the hydrochloride and wash with diethyl ether. This is taken up in a minimum amount of warm isopropanol and 5 volumes of ethyl acetate are added to recrystallize the product. Melting point of hydrochloride = 149-151°C Example 5 1-Benzyl-4-(3,4,5-trimethoxybenzyloxy)piperidine and its fumarate salt In a nitrogen atmosphere, in a 250 ml three-neck round bottom flask, hydrogen 2.2 g of 55% suspension of sodium oxide in oil
(0.05 mol) was washed three times with petroleum ether.
9.6 g (0.05 mol) of 1-benzyl-4-hydroxypiperidine dissolved in 30 ml of DMF are added.
Once the addition is complete, the mixture is stirred for 1 hour at ambient temperature. Then 13 g (0.06 mol) of 3,4,5-trimethoxybenzyl chloride in 30 ml of DMF.
Add while cooling in an ice water bath. The mixture is stirred at ambient temperature for 5 hours and left overnight. Pour the reaction mixture into ice water and extract with diethyl ether. The product is then extracted with dilute HCl. The aqueous phase is made alkylated with NaOH, extracted with diethyl ether, the ethereal extract is washed with water, dried over MgSO ₄ , filtered and evaporated. Take the resulting oil in warm pentane. The product crystallizes and is removed.
Recrystallize from isopropanol. Dissolve the base obtained in this way in 70 ml of ethanol, and
Add the filtered solution of 2.9 g (0.025 mol) of fumaric acid to 140 ml. The generated fumarate is collected and dried. mp160～161℃ Example 6 1-(4-chlorobenzyl)-4-(3・4・5
-trimethoxybenzyloxy)piperidine and its fumarate 6(1) 1-(4-chlorobenzoyl)-4-hydroxypiperidine 30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHCl ₃ , 57.3 g of K ₂ CO ₃ ( 0.414 mol) and 260 ml of water into Erlenmeyer flask 1. 51.8 g (0.296 mol) of p-chlorobenzoyl chloride dissolved in 50 ml of CHCl ₃ are added over 15 minutes while cooling in an ice-water bath. After stirring the mixture overnight at ambient temperature, the organic layer was decanted and
Extract the aqueous layer with CHCl ₃ and extract the CHCl ₃ extract with pH 6~
Rinse with water until it reaches 7. Dry with _MgSO4 ,
Filter and concentrate. The product is recrystallized from ethyl acetate. 6(2) 1-(4-chlorobenzoyl)-4-(3.
4,5-trimethoxybenzyloxy)piperidine in a three-necked round-bottomed flask kept under nitrogen atmosphere,
0.96 g of 55% suspension of sodium hydride in oil
(0.022 mol) was washed three times with petroleum ether.
Then, the 1-(4-
4.8 g (0.02 mol) of chlorobenzoyl)-4-hydroxypiperidine are added. After the addition is complete, the mixture is stirred for 1 hour at ambient temperature. It was then cooled in an ice water bath and dissolved in 10 ml of DMF.
5-trimethoxybenzyl chloride 5.4g
(0.025 mol) is added. The mixture is stirred at ambient temperature for 3 hours and left overnight. Pour this into an ice water bath and extract with ethyl acetate. Wash the ethyl acetate extract with water, dry with _MgSO4 , filter, and concentrate. Take the obtained oil in diethyl ether,
Filter this solution. Concentrate the solution and pass through an alumina column (eluent: CHCl ₃ ). The product does not crystallize but is used as is in the next step. 6(3) 1-(4-chlorobenzyl)-4-(3.
4,5-trimethoxybenzyloxy)piperidine and its fumarate salt in a round bottom flask kept under nitrogen atmosphere, 6(2)
A solution of 7 g (0.0167 mol) of the product obtained in 70 ml of dry diethyl ether is added at ambient temperature to a suspension of 0.38 g (0.01 mol) of AlLiH ₄ in 30 ml of dry diethyl ether. This mixture is heated at reflux temperature for 3 hours. This is hydrolyzed with 2.6 ml of isopropanol and 3.3 ml of a saturated aqueous solution of NaCl. The mixture is filtered and the material on the filter is washed with diethyl ether. The product was extracted with dilute hydrochloric acid and the mixture was diluted with _NH4OH
The mixture is made alkyl and extracted with diethyl ether. The ethereal extract is washed with water, dried over MgSO ₄ , filtered and concentrated. Dissolve the obtained oil in 30 ml of ethanol, and add this solution to 60 ml of ethanol.
Add 1.2 g (0.0105 mol) of fumaric acid to the filtered solution. Fumarate gradually precipitates. This is taken, washed with a small amount of ethanol and diethyl ether, and dried. mp178
-180°C Representative compounds of the present invention prepared by the methods described in the above examples are listed in Table 1 below.

【table】

【table】

[Table] When the piperidine derivatives of the general formula () according to the present invention were subjected to pharmacological experiments, it was found that these compounds had antidepressant effects. When the toxicity of the compound was investigated by intraperitoneal administration to mice, the LD ₅₀ was 30-1000 mg/Kg (body weight). Antidepressant activity was investigated in a culture test against blepharoptosis induced by reserpine (C. Gouret
et al., J. Pharmacol. (Paris) 8 333-350, 1977
Year). Test compound (or vehicle) was administered to mice (male, CD1 Charles River strain, France, 18-22 g).
and reserpine (4 mg/Kg (body weight)) were administered simultaneously (the former was administered intraperitoneally, and the latter was administered subcutaneously). 60
Minutes later, each mouse was graded for degree of ptosis (0-4). For each dose, the average grade and % deviation when compared to the control group were determined. For each compound, the _AD50 , ie, the dose that would reduce the average ptosis value by 50% compared to the control group, was determined by a graphical method. For intraperitoneal administration
_AD50 was 4-10 mg/Kg (body weight). Antidepressant activity is also associated with head spasm induced by L-5-hydroxytryptophan.
(H.Van
Riezen (1972) Arch.Int.Pharmacology 198 256~
269). The procedure is as follows: Animals are placed in the operating room 24 hours before the experiment. On the day of the experiment, weigh the mice and let them sleep. suspended in tween
The test compound is injected intraperitoneally before L5-HTP is injected subcutaneously at a rate of 125 mg/Kg (body weight). L5
- Reduce the number of head spasms to 60 30 minutes after injecting HTP.
Count seconds. The mean head twitch counts and % deviation when compared to the control group are calculated for each dose. Calculate the 50% effective dose from the curve. The AD ₅₀ for intraperitoneal administration was 0.1-5 mg/Kg (body weight). As a result of the above pharmacological experiments, it was found that the piperidine derivative of the present invention is useful for treating depression. The compounds of the present invention can be administered in any dosage form suitable for oral or parenteral administration, such as tablets, sugar-coated tablets, capsules, oral or injectable solutions, etc., together with suitable excipients. The daily dose can be 5-200 mg.

Claims (1)

[Claims] 1 Formula (): [In the formula, R is substituted with a substituent selected from the group consisting of hydrogen; C _1-4 alkyl; hydroxy-C _1-4 alkyl; C _1-4 alkoxycarbonyl; halogen and C _1-4 alkoxy may also represent benzyl; phenethyl or 3-phenylpropyl; X each represents one or more hydrogen; halogen; C _1-4 alkyl; C _1-4 alkoxy; Together with the phenyl nucleus, it may also represent naphthyl. However, R and X cannot be hydrogen at the same time. ] Piperidine derivatives and salts thereof. 2. A compound according to claim 1, wherein X represents naphthyl together with one or more chlorine, three methoxy or phenyl nuclei. 3. The compound according to claim 2, wherein 3R is hydrogen or _C1-4 alkoxycarbonyl. 4 Formula (′): [In the formula, X each represents one or more halogen; C _1-4 alkyl; C _1-4 alkoxy; trifluoromethyl or methylenedioxy, or together with a phenyl nucleus, it can represent naphthyl. good. ] A method for producing a piperidine derivative or a salt thereof represented by the formula (): [wherein R' represents a nitrogen protecting group such as 4-nitrobenzoyl, other optionally substituted benzoyl, optionally substituted benzyl or optionally substituted alkyl] The compound represented by the formula (): [Wherein, Y is a reactive group such as chlorine or bromine,
has the same meaning as in the case of formula (')] A method consisting of reacting with a compound of formula (') and then removing R'.