JPH0160026B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to isoxazole derivatives, particularly those having the following general formula () (In the formula, R is a hydrogen atom, a lower alkanoyl group,
A novel isoxazole derivative represented by a benzoyl group, a phenylacetyl group or a phenylalkyl group, R ⁰ is a piperidino group or a di-lower alkylamino group, and n is an integer of 2 to 6) and its acid addition Regarding salt and its manufacturing method. The present inventors have synthesized a large number of isoxazole derivatives and investigated their pharmacological actions, and found that the novel isoxazole derivative represented by the above general formula () and its acid addition salt have excellent central depressant action, especially in the central They discovered that it has a muscle relaxing effect and is useful as a medicine, and completed the present invention. Therefore, an object of the present invention is to provide a novel compound represented by the above general formula () that is useful as a medicine. Another object is to provide a new method for producing the compound represented by the general formula (). In the compound of the present invention of general formula (), among the groups represented by R, examples of the lower alkanoyl group include an acetyl group, propionyl group, butyryl group, and examples of the phenyl alkyl group include a benzyl group, phenethyl group, and a phenyl group. Examples include enylpropyl group. Examples of acid addition salts of the compounds of the present invention include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, fumaric acid, citric acid, maleic acid, and the like. Novel isoxazole derivatives of the present invention represented by the general formula () (when R ⁰ is a piperidino group)
is manufactured by any of the following methods. Method 1 (In the formula, R' represents a hydrogen atom or a phenylalkyl group, X represents a halogen atom, and n is the same as above.) That is, a compound represented by the general formula () is added to a compound represented by the general formula (). By reacting, a novel isoxazole derivative represented by the general formula () is produced. The reaction is carried out without a solvent or in a solvent such as benzene, toluene or xylene, preferably in the presence of a base such as sodium hydroxide, sodium amide or sodium hydroxide at a temperature of 50 to 150°C. Method 2 (In the formula, n is the same as above.) That is, by reducing the compound represented by the general formula (), a novel isoxazole derivative represented by the general formula () is produced. The reaction is carried out using a reducing agent such as lithium aluminum hydride in a solvent such as anhydrous ether or dioxane. Method 3 (In the formula, R″ represents a lower alkanoyl group, benzoyl group, or phenylacetyl group, X represents a halogen atom, and n is the same as above.) That is, the general formula obtained by method 1 or method 2 ( ) A novel isoxazole derivative represented by the general formula () is produced by reacting the compound represented by the general formula () with the compound represented by the general formula ().The reaction is carried out using a solvent such as methylene chloride, chloroform, acetonitrile, or benzene. Among them, it is preferably carried out at a temperature of -10 to 100°C in the presence of pyridine, triethylamine, etc. Also, when R ⁰ in the general formula () is a di-lower alkylamino group, the above methods 1 to 3 are carried out. It can be obtained in a similar manner. The novel isoxazole derivatives of the present invention obtained as in Methods 1 to 3 can be converted into acid addition salts with the above-mentioned acids by conventional methods. The compound represented by the general formula () used as a raw material in method 2 is 5-amino-3
- Obtained by reacting isoxazole with piperidinyl fatty acid halide under the reaction conditions shown in Method 3. It can also be obtained by the reaction of 3-(halogenoalkanoylamino)-5-phenylisoxazole and piperidine. The novel isoxazole derivative of the present invention obtained as described above was examined for its central muscle relaxing effect, that is, its effect on anemic decerebrate rigidity and its effect on spinal reflex action potentials. In addition, the acute toxicity of the compounds of the present invention was also investigated. Effect on anemic decerebrate rigidity A male Wistar rat weighing 270 to 350 g was anesthetized with ether, and the neck was incised to expose the trachea, esophagus, and bilateral common carotid arteries. A tracheal cannula was inserted into the trachea, and the esophagus and both common carotid arteries were double ligated and cut. Thereafter, a circular hole was made in the occipital bone to expose the basal artery, and this artery was double ligated with a needle suture and cut. Severe rigidity developed in the forelimbs as the rats recovered from anesthesia. The effects of the test compounds were examined using this forelimb rigidity as an indicator. That is, a concentric needle electrode was inserted into the triceps muscle of the upper arm of the forelimb to derive muscle discharge. After amplifying the muscle discharge, it was observed with an oscilloscope, and then introduced into a frequency integrator, and its output was recorded with a recticcorder. Test compounds were administered intravenously. The results are shown in Table 1, comparing the duration of the effect of tolperisone hydrochloride used as a control drug with that of the compound of the present invention. The duration of action was coded as follows. +: 3 to 5 minutes ++: 5 to 10 minutes +++: 10 minutes or more

[Table] Effect on spinal reflex action potential Cats of both sexes weighing 2.5 to 3.5 kg were used. The spinal cord was cut between _C1 and _C2 under ether anesthesia.
Artificial respiration was performed and the cat was made into a spinal cat. The cat was fixed in a brain stereotaxic device of the University of Tokyo Brain Research Institute, and the spinal cord was exposed by performing a spinal arch resection according to the standard method. The sciatic nerve is cut distally, the central end of the nerve is stimulated with a digital stimulator, reflex action potentials are derived from the ipsilateral ventral root of L ₇ or S ₁ using a cathode ray tube oscilloscope, and a continuous imaging device Recorded. Furthermore, the reaction summation analysis device adds the reaction five times and calculates the average reaction.
Recorded with an XY recorder. For monosynaptic reflexes, the height of the potential amplitude was measured, and for polysynaptic reflexes, the area of the potential was measured using a planimeter, and compared with that before administration. Platinum wires were used as stimulation and recording electrodes, and the stimulation conditions were rectangular wave supermaximal stimulation with a period of 0.2 msec, once every 5 seconds. The temperature in the fluid paraffin pool of the spinal cord was maintained at 37±0.5°C using a thermistor controller during the experiment.
Test compounds were administered intravenously. The results are shown in Table 2 in comparison with the inhibition rate (%) of tolperisone hydrochloride used as a control drug. The inhibitory effect was symbolized as follows. +: 10-30% suppression ++: 30-60% suppression

[Table] Acute toxicity Using 20 ± 2 g of ddN male mice, up and
It was done using the down method. The results are shown in Table 3.

[Table] Tables 1 to 3 show that the compounds of the present invention and their acid addition salts have excellent central muscle relaxing effects, and their duration of action is longer than that of the currently commercially available tolperisone hydrochloride. Useful as a sexual muscle relaxant. EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto in any way. Example 1 5-(2-piperidinoethyl)amino-3-phenyl isoxazole: a A mixture of 200 mg of 5-chloroacetylamino-3-phenyl isoxazole, 170 mg of piperidine and 3 ml of benzene was heated under reflux for 2 hours.
After cooling, precipitated piperidine hydrochloride was separated and washed with benzene. The benzene layer of the liquid was washed with water and then dried with sodium sulfate. The solvent was distilled off and the residue was
-5-(Piperidinoacetyl) as a colorless crystalline powder with a melting point of 76-77℃ after recrystallization from hexane
Amino-3-phenyl isoxazole 190mg
(yield 78.8%). IRν ^KBr _nax cm ^-1 : 1610 (NHCO) NMR (CDCl ₃ ) δ: 1.40 to 2.00 (6H, m,

【formula】) 2.65 (4H, t,

[Formula]) 3.30 (2H, s, -CO-C H ₂ N) 7.05 (1H, s,

[Formula]) 7.80, 8.20 (5H, m, aromatic hydrogen) 10.00 (1H, broad, N H CO) b At room temperature, add 5 obtained in step a) to a suspension of 35 mg of lithium aluminum hydride and 9 ml of anhydrous ether. ―
350 mg of (piperidinoacetyl)amino-3-phenyl isoxazole was added as a crystalline powder and stirred overnight. 10 ml of water was carefully added and the ether layer was separated. The aqueous layer was extracted with 20 ml of ether, combined with the previous ether layer, washed twice with saturated brine, and dried over Glauber's salt. After distilling off the ether, the residue was subjected to silica gel column chromatography to obtain a pale yellow oil. This substance crystallizes when stimulated and has a melting point of 58-62
5-(2-piperidinoethyl) as crystals at °C
Amino-3-phenylisoxazole 200mg
I got it. Yield (60.1%) NMR ( _CDCl3 ) δ: 1.20-1.70 (6H, m,

【formula】) 2.10~2.45 (4H, m,

[Formula]) 2.43 (2H, t, J=7Hz,

[Formula]) 3.10 (2H, m, NHC H ₂ −) 5.19 (1H, broad s, N H ) 7.10 (3H, m, aromatic hydrogen) 7.45 (2H, m, aromatic hydrogen) The above crystals were dissolved in chloroform. and then bubbled with hydrogen chloride gas for about 10 minutes. After chloroform was distilled off, a small amount of ether was added to the residue for crystallization. This was recrystallized from ethanol-ether to give a pale yellow crystalline powder with a melting point of 155-158°C.
-(2-piperidinoethyl)amino-3-phenylisoxazole hydrochloride was obtained. Example 2 5-(2-piperidinoethyl)amino-3-phenyl isoxazole: 5-chloro-3-phenyl isoxazole
610 mg of 2-aminoethylpiperidine and 900 mg of 2-aminoethylpiperidine were heated under reflux for 5 hours with 6 ml of anhydrous toluene.
The solvent was distilled off, 20 ml of 10% hydrochloric acid was added to the residue, and the mixture was shaken twice with 20 ml of ether. Separate the aqueous layer and 10%
The mixture was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ether layer was washed with water and dried with Glauber's salt. The ether was distilled off, and the residue was subjected to silica gel column chromatography to obtain 30 mg of 5-(2-piperidinoethyl)amino-3-phenyl isoxazole as a pale yellow oil. NMR was consistent with Example 1. Example 3 5-(3-piperidinopropyl)amino-3-
Phenyl isoxazole: a 5-(β-bromopropionyl) synthesized by the reaction of 5-amino-3-phenylisoxazole and β-bromopropionic acid chloride
Amino-3-phenyl isoxazole 3.0g
and 2.6 g of piperidine in 40 ml of absolute ethanol.
The solution was heated to reflux for 1 hour. After cooling, ethanol was distilled off, 80 ml of chloroform was added to the residue, and water was added.
The mixture was washed three times with 50 ml of water, and the chloroform layer was dried with Glauber's salt. After chloroform was distilled off, the residue was subjected to silica gel column chromatography to obtain 3.05 g (quantitative) of 5-(β-piperidinopropionyl)amino-3-phenyl isoxazole as a pale yellow viscous oil. Ta. This oil was converted into a hydrochloride salt by the method of Example 1, and this was recrystallized from ethanol-ether to give a colorless powder with a melting point of 183°C (decomposition).
-(β-piperidinopropionyl)amino-3
- Phenyl isoxazole hydrochloride was obtained. IRν ^KBr _nax cm ^-1 : 1610 (NHCO) NMR (CD ₃ OD) δ: 1.50 to 2.00 (6H, m,

[Formula]) 2.70 to 3.20 (4H, m, -CH ₂ C H ₂ N) 3.30 to 3.60 (4H, m,

【formula】) 6.59 (1H, s,

[Formula]) 7.30 (3H, m, aromatic hydrogen) 7.60 (2H, m, aromatic hydrogen) b In a suspension of 390 mg of lithium aluminum hydride in 40 ml of dry ether, A solution of 3.05 g of (propionyl)amino-3-phenyl isoxazole in 30 ml of dry ether was added dropwise at room temperature over 1.5 hours. after that,
Stirring was continued overnight. Then add water to the reaction mixture.
10 ml was carefully added and the ether layer was separated.
The aqueous layer was extracted with 20 ml of ether, combined with the previous ether layer, washed twice with saturated brine, and dried over Glauber's salt. After distilling off the ether, the residue was subjected to silica gel column chromatography to obtain a pale yellow viscous oil. This thing has a small amount of n-
The mixture was crystallized by adding hexane and stimulating to obtain 2.0 g (yield 68.3%) of 5-(3-piperidinopropyl)amino-3-phenyl isoxazole as crystals with a melting point of 54 to 58°C. NMR ( _CDCl3 ) δ: 1.20-1.90 (8H, m,

[Formula] -C H ₂ -) 2.00 to 2.60 (6H, m,

[Formula]) 3.20 (2H, m, NHC H ₂ −) 5.09 (1H, s,

[Formula]) 6.60 (1H, broad s, N H ) 7.23 (3H, m, aromatic hydrogen) 7.55 (2H, m, aromatic hydrogen) This crystal was converted into a hydrochloride by the method of Example 1, and this was Recrystallize from ethanol-ether to obtain 5-(3-
Piperidinopropyl)amino-3-phenyl isoxazole hydrochloride was obtained. Example 4 5-{N-phenylacetyl-N-(3-piperidinopropyl)}amino-3-phenylisoxazole: 5-(3-piperidinopropyl)amino obtained in Example 3 3-Phenyl isoxazole 600
mg and triethylamine 430mg of chloroform
Add 630mg of phenyl acetate chloride to 10ml solution under ice cooling.
added. Thereafter, the ice bath was removed and stirring was continued overnight. Add 20 ml of chloroform to the reaction mixture and
20 ml of 2N aqueous sodium hydroxide solution was added and shaken. The chloroform layer was separated, washed three times with saturated brine, and then dried over Glauber's salt. After distilling off the solvent, the residue was subjected to silica gel column chromatography to obtain 5-{N-phenylacetyl-N-
700 mg (yield: 82.4%) of (3-piperidinopropyl)}amino-3-phenyl isoxazole was obtained as a pale yellow oil. This crystallized on standing to give crystals with a melting point of 73-75°C. IRν ^KBr _nax cm ^-1 : 1695 (NCO) NMR (CDCl ₃ ) δ: 1.20 to 1.70 (6H, m,

[Formula]) 1.80 (2H, m, -CH ₂ -CH ₂ N) 2.30 (6H, m,

[Formula]) 3.79 (2H, s, -C H ₂ ph) 3.80 (2H, t, J=7Hz,

【formula】) 6.38 (1H, broad s,

[Formula]) 7.20 (5H, m, aromatic hydrogen) 7.40 (3H, m, aromatic hydrogen) 7.69 (2H, m, aromatic hydrogen) Example 5 5-{N-benzoyl-N-(3-pi Peridinopropyl)}Amino-3-phenyl isoxazole: 5-(3-piperidinopropyl)amino-3-phenyl isoxazole obtained in Example 3 1.00
g was reacted and treated with 640 mg of benzoyl chloride in the same manner as in Example 4 to obtain 5-
{N-benzoyl-N-(3-piperidinopropyl)}amino-3-phenyl isoxazole 720
mg (yield 52.7%). IRν ^KBr _nax cm ^-1 : 1685 (N-CO- NMR (CDCl ₃ ) δ: 1.20 to 1.70 (6H, m,

[Formula]) 1.90 (2H, m, -CH ₂ -CH ₂ -N) 2.30 (6H, m,

【formula】) 3.96 (2H, t, J=7Hz,

【formula】) 6.10 (1H, s,

[Formula]) 7.32 (8H, m, aromatic hydrogen) 7.65 (2H, m, aromatic hydrogen) Example 6 5-{N-benzyl-N-(3-piperidinopropyl)}amino-3-ph Enyl isoxazole: 610 mg of N-(3-benzylaminopropyl)piperidine prepared from N-(3-chloropropyl)piperidine hydrochloride and benzylamine in benzene 4
ml solution was added with 110 mg of sodium amide and refluxed for 3 hours. To this was added 472 mg of 5-chloro-3-phenyl isoxazole and the mixture was refluxed for 16 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with benzene. After washing the benzene layer with water, it was dried with Glauber's salt.
By distilling off the benzene and subjecting the residue to silica gel column chromatography, 320 mg of 5-{N-benzyl-N-(3-piperidinopropyl)}amino-3-phenyl isoxazole was obtained as a pale yellow oil. (yield 32.5%). NMR ( _CDCl3 ) δ: 1.20-1.80 (6H, m,

[Formula]) 1.76 (2H, m, -CH ₂ CH ₂ N) 2.25 (6H, m,

【formula】) 3.35 (2H, t, J=7Hz,

[Formula]) 4.55 (2H, s, -CH ₂ ph) 5.30 (1H, s,

[Formula]) 7.40 (8H, m, aromatic hydrogen) 7.80 (2H, m, aromatic hydrogen) The above oil was treated in the same manner as in Example 1 to obtain a hydrochloride, which was regenerated from ethanol-ether. Crystallization gave 5-{N-benzyl-N-(3-piperidinopropyl)}amino-3-phenylisoxazole hydrochloride as a colorless powder with a melting point of 136-137°C. Example 7 5-{N-benzyl-N-(2-piperidinoethyl)}amino-3-phenylisoxazole: N-(2-piperidinoethyl) prepared from N-(2-chloroethyl)piperidine hydrochloride and benzylamine 5-{N-benzyl-N-(2- piperidinoethyl)}amino-
50 mg of 3-phenyl isoxazole was obtained. NMR (CDCl ₃ ) δ: 1.30-1.80 (6H, m,

【formula】) 2.45 (4H, m,

[Formula]) 2.60 (2H, t, J=8Hz, -C H ₂ N) 3.60 (2H, t, J=8Hz,

[Formula]) 4.75 (2H, s, ph-C H ₂ -) 5.40 (1H, s,

[Formula]) 7.40 to 7.90 (8H, m, aromatic hydrogen) 8.10 (2H, m, aromatic hydrogen) The above oil was treated in the same manner as in Example 1 to form a hydrochloride, and then converted from chloroform-ether. After recrystallization, 5-
{N-benzyl-N-(2-piperidinoethyl)}
Amino-3-phenyl isoxazole hydrochloride was obtained. When this product was further recrystallized from ethanol-ether, it became a colorless powder with a melting point of 161-164°C. Example 8 5-{N-phenethyl-N-(3-piperidinopropyl)}amino-3-phenylisoxazole: N-(3-phenyl) prepared from 1-(3-chloropropyl)piperidine hydrochloride and phenethylamine -piperidinopropyl)phenethylamine 1.37g, 5-
5-{N-phenethyl-N-(3
-piperidinopropyl)}Amino-3-phenyl isoxazole (100 mg) was obtained. NMR ( _CDCl3 ) δ: 1.20-1.80 (6H, m,

[Formula]) 1.70 (2H, m, -CH ₂ CH ₂ N) 2.25 (6H, m,

[Formula]) 2.90 (2H, t, J=8Hz, -C H ₂ ph) 3.24 (2H, t, J=7Hz,

[Formula]) 3.53 (2H, t, J=8Hz, -CH ₂ -CH ₂ -
ph) 5.15 (1H, s,

[Formula]) 7.20 (5H, m, aromatic hydrogen) 7.35 (3H, m, aromatic hydrogen) 7.70 (2H, m, aromatic hydrogen) Example 9 5-{N-Phenethyl-N-(3-Phenethyl-N- Peridinopropyl)}Amino-3-phenylisoxazole: 98 mg of sodium hydride was added to a solution of 550 mg of N-(3-piperidinopropyl)phenethylamine in 4 ml of benzene, and the mixture was refluxed for 3 hours. Add 400 mg of 5-chloro-3-phenyl isoxazole to this,
Reflux for 140 hours and treat as in Example 8 to obtain 5-
{N-phenethyl-N-(3-piperidinopropyl)}amino-3-phenylisoxazole 80
mg was obtained as a yellow oil. The NMR data of this product was consistent with Example 8. Example 10 5-{N-acetyl-N-(3-piperidinopropyl)}amino-3-phenylisoxazole: 5-(3-piperidinopropyl)amino-3- obtained in Example 3 Phenyl isoxazole 0.20
g and 0.11 g of triethylamine were dissolved in 15 ml of dry chloroform and stirred at 0° C. for 10 minutes.
0.082 g of acetyl chloride was added at 0°C, and the mixture was further stirred for 10 minutes. A 2N aqueous sodium hydroxide solution was added to the reaction mixture to make it basic, and the mixture was extracted with chloroform. The extract was washed twice with water and dried with Glauber's salt. After separating the sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a colorless oil, 5-{N-acetyl-N-(3-piperidinopropyl)}amino-3- 0.20 g of phenyl isoxazole was obtained. NMR ( _CDCl3 ) δ: 1.00-1.76 (6H, m,

[Formula]) 1.76 to 2.06 (2H, m, -CH ₂ CH ₂ N) 2.28 (3H, s, -COC H ₃ ) 2.08 to 2.56 (6H, m,

[Formula]) 3.90 (2H, t, J=7.2Hz,

【formula】) 6.60 (1H, s,

[Formula]) 7.42-7.68 (3H, m, aromatic hydrogen) 7.74-8.02 (2H, m, aromatic hydrogen) The above oil was treated in the same manner as in Example 1 to obtain a colorless substance with a melting point of 171-173°C. 5-{N-acetyl-N-(3-piperidinopropyl)}amino- as a powder
3-Phenyl isoxazole hydrochloride was obtained. Example 11 5-{N-benzyl-N-(4-piperidinobutyl)}amino-3-phenylisoxazole: N-(4-piperidinobutyl) prepared from N-(4-chlorobutyl)piperidine hydrochloride and benzylamine 1.03 g of benzylamine and 0.175 g of sodium amide were heated and stirred for about 1 hour without a solvent.
To this was added 1.125 g of 5-chloro-3-phenyl isoxazole, and the mixture was further stirred at 110°C for 16.5 hours. Chloroform was added to the reaction mixture, washed twice with water, and dried over Glauber's salt. After separating the Glauber's salt and distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 5-
{N-benzyl-N-(4-piperidinobutyl)}
0.35 g of amino-3-phenyl isoxazole was obtained. NMR ( _CDCl3 ) δ: 1.24-1.92 (10H, m,

[Formula]) 2.20~2.58 (6H, m,

【formula】) 3.50 (2H, t, J=7Hz,

[Formula]) 4.76 (2H, s, -CH ₂ ph) 5.47 (1H, s,

[Formula]) 7.68 (5H, s, aromatic hydrogen) 7.60-7.90 (3H, m, aromatic hydrogen) 8.04-8.24 (2H, m, aromatic hydrogen) Example 12 5-{N-benzyl-N- (2-Piperidinoethyl)}Amino-3-phenylisoxazole: 822 mg of N-(2-piperidinoethyl)benzylamine prepared from N-(2-chloroethyl)piperidine hydrochloride and benzylamine was mixed with 183 mg of finely ground sodium hydroxide. and heated at 110°C for 15 minutes. Add 500 mg of 5-chloro-3-phenyl isoxazole to this and heat at 110℃ without solvent.
Heating was continued for 48 hours. After cooling to room temperature, chloroform was added to the reaction mixture, washed twice with water, and dried over Glauber's salt. After separating the Glauber's salt and distilling off the chloroform under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 5-{N-benzyl-N-(2-piperidinoethyl)}amino-3- as a pale yellow oil. Phenyl isoxazole 670
mg (yield 81%). IR and
NMR data was consistent with Example 7. The above oil was treated in the same manner as in Example 1 to obtain a hydrochloride salt, and further recrystallized from ethanol-ether to obtain a colorless powder with a melting point of 161-164°C.
{N-benzyl-N-(2-piperidinoethyl)}
Amino-3-phenyl isoxazole hydrochloride was obtained. Example 13 5-{N-benzyl-N-(6-piperidinohexyl)}amino-3-phenylisoxazole: N-(prepared from N-(6-chlorohexyl)piperidine hydrochloride and benzylamine A mixture of 1.0 g of 6-piperidinohexyl)benzylamine and 170 mg of sodium amide was stirred at 90-95°C for about 20 minutes. To this was added 780 mg of 5-chloro-3-phenyl isoxazole, and the mixture was stirred at 100 to 110°C for 16.5 hours. The reaction product was extracted with benzene, and the benzene layer was washed with water and then dried with Glauber's salt. Benzene was distilled off, and the residue was subjected to silica gel column chromatography to obtain 5-{N-benzyl-N-
120 mg of (6-piperidinohexyl)}amino-3-phenyl isoxazole was obtained. NMR ( _CDCl3 ) δ: 1.10-1.80 (14H, m,

[Formula]) 2.10~2.50 (6H, m,

【formula】) 3.40 (2H, t, J=7Hz,

[Formula] 4.70 (2H, s, -C H ₂ ph) 5.40 (1H, s,

[Formula]) 7.40-7.80 (8H, m, aromatic hydrogen) 7.90-8.20 (2H, m, aromatic hydrogen) Example 14 5-{N-benzyl-N-(5-piperidinopentyl)}amino -3-Phenylisoxazole: N-(5-piperidinopentyl)benzylamine and 5-chloro-3- prepared from N-(5-chloropentyl)piperidine hydrochloride and benzylamine
Phenyl isoxazole was reacted in the same manner as in Example 13 to give 5-{N-benzyl-N as an oil.
-(5-piperidinopentyl)}amino-3-phenyl isoxazole was obtained. NMR ( _CDCl3 ) δ: 1.00-1.79 (12H, m,

[Formula] 2.00~2.42 (6H, m,

[Formula]) 3.25 (2H, t, J=6.6Hz,

[Formula]) 4.44 (2H, s, -CH ₂ ph) 5.08 (1H, s,

[Formula]) 7.18 (5H, s, aromatic hydrogen) 6.98-7.40 (3H, m, aromatic hydrogen) 7.42-7.72 (2H, m, aromatic hydrogen) Example 15 5-[N-benzyl-N- (3-N',N'-dimethylaminopropyl)]amino-3-phenyl isoxazole: N-benzyl- prepared from γ-(dimethylamino)propyl chloride hydrochloride and benzylamine.
N-(3-N',N'-dimethylaminopropyl)
1.15 g of amine and 0.351 g of sodium amide were stirred without solvent for about 1 hour. In this, 5-chloro-
Add 1.08g of 3-phenylisoxazole to 110
Stirred at ℃ for 16 hours. Chloroform was added to the reaction mixture, washed twice with water, and dried over Glauber's salt. After separating the Glauber's salt and distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 5-[N-benzyl-N-(3-N',
0.28 g of amino-3-phenyl isoxazole was obtained. NMR ( _CDCl3 ) δ: 1.64-2.03 (2H, m, -CH
₂ CH ₂ N) 2.30 (6H, s, -N ( CH ₃ ) ₂ ) 2.36 (2H, t, J _{= 7.2Hz, -CH 2} N ) 3.56 (2H, t, J = 7.2Hz,

[Formula]) 4.77 (2H, s, -CH ₂ ph) 5.50 (1H, s,

【formula】) 7.68 (5H,s, aromatic hydrogen) 7.60-7.90 (3H, m, aromatic hydrogen) 8.04-8.25 (2H, m, aromatic hydrogen)

Claims (1)

[Claims] 1. General formula (In the formula, R is a hydrogen atom, a lower alkanoyl group,
isoxazole derivatives represented by a benzoyl group, a phenylacetyl group, or a phenylalkyl group, R ⁰ is a piperidino group or a di-lower alkylamino group, and n is an integer of 2 to 6) and acid addition salts thereof . 2 General formula (In the formula, X represents a halogen atom) The compound represented by the general formula (In the formula, R′ represents a hydrogen atom or a phenyl alkyl group, R ⁰ represents a piperidino group or a di-lower alkylamino group, and n represents an integer of 2 to 6.) General formula, characterized in that the product is an acid addition salt (wherein R′R ⁰ and n are the same as above) A method for producing an isoxazole derivative and an acid addition salt thereof. 3 General formula (wherein n represents an integer of 2 to 6) is reduced, and if desired, the product is converted into an acid addition salt. (In the formula, n is the same as above.) A method for producing an isoxazole derivative and an acid addition salt thereof. 4 General formula (wherein, n represents an integer of 2 to 6), a compound represented by the general formula R''-X (wherein, R'' represents a lower alkanoyl group, benzoyl group, or phenylacetyl group, and X represents a halogen atom) ) is reacted, and the product is optionally converted into an acid addition salt. (wherein R'' and n are the same as above) A method for producing an isoxazole derivative and an acid addition salt thereof.