JPS6155495B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel phenylacetamide derivatives useful as pharmaceuticals and their pharmacologically acceptable salts. More specifically, the present invention discloses the general formula (R ₁ in the formula is an alkyl group having 1 to 3 carbon atoms or a hydroxyalkyl group having 2 to 4 carbon atoms,
R ₂ is a linear or branched alkenyl group having 3 to 6 carbon atoms, X is an alkoxy group having 1 to 3 carbon atoms, and Y is a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms; , n is an integer of 0 to 2) and pharmacologically acceptable salts thereof. The phenylacetamide derivative of the present invention represented by the above general formula () is a novel compound that has not been described in any literature, and it significantly suppresses the writhing reaction that occurs when acetic acid is administered to mice. This means that the phenylacetamide derivative represented by the general formula () of the present invention has a strong central depressant effect,
This indicates that it has an analgesic effect and is useful as a medicine. The phenylacetamide derivative of the present invention represented by the general formula () is, for example, (In the formula, Y, R ₁ and R ₂ have the same meanings as above) and a compound represented by the general formula Produced by reacting phenylacetic acid or a phenylacetic acid derivative or a reactive functional derivative thereof represented by the formula (wherein X and n have the same meanings as above) in the presence or absence of a condensing agent. I can do it. In this case, the compound represented by the general formula () used as a raw material is a new compound, and the compound represented by the general formula (wherein Y has the same meaning as above) is reacted with chloroacetic acid chloride in an inert solvent, such as water-dioxane, in the presence of a base, such as sodium hydrogen carbonate, The product is then dissolved in an inert solvent,
For example, by reacting an amine represented by the general formula R ₁ −NH ₂ (R ₁ in the formula has the same meaning as above) in alcohol, After obtaining a compound represented by (in the formula, Y and R ₁ have the same meanings as above), this compound is converted into the general formula R ₂ Z () (in the formula, Z is a halogen atom, and R ₂ is the above-mentioned (having the same meaning as ) in an inert organic solvent such as water-alcohol (in the presence of a base such as potassium carbonate), and (wherein Y, R ₁ and R ₂ have the same meanings as above) and then reducing this compound with lithium aluminum hydride in an inert organic solvent, such as ether. can. In the present invention, preferred compounds include N-phenethyl-N'-methyl-N'-arylethylenediamine, N-phenethyl-N'-methyl-N'-isopentenylethylenediamine, and N-(4-methoxyphenethylethylenediamine). Chill) -
These include N'-methyl-N'-isopentenylethylenediamine, N-phenethyl-N'-(2-hydroxyethyl)-N'-arylethylenediamine, and the like. Furthermore, phenylacetic acid or phenylacetic acid derivatives represented by the general formula () are known compounds and can be easily obtained by methods described in the literature; examples thereof include phenylacetic acid, 2-,
3- or 4-methoxyphenylacetic acid, 2-,3
- or 4-ethoxyphenylacetic acid, 2-, 3-
or 4-propoxyphenylacetic acid, 2,3-,
2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dimethoxyphenylacetic acid, 2,3-,
2,4-, 2,5-, 2,6-, 3,4- or 3,5-diethoxyphenylacetic acid, 2,3-,
Examples include 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dipropoxyphenylacetic acid. The reaction between the compound represented by the above general formula () and the phenylacetic acid or phenylacetic acid derivative represented by the above general formula () or a reactive functional derivative thereof is a known amidation reaction, and can be carried out by a known method. Therefore, it can be done easily. That is, a compound represented by the general formula () and a phenyl acetic acid represented by the general formula () or a derivative thereof are mixed in an inert organic solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran, chloroform, methylene chloride, etc. or in the presence or absence of a condensing agent such as phosphorous oxychloride in the absence of a solvent at room temperature to 150°C.
Alternatively, the compound represented by the general formula () and the reactive functional derivative of phenyl acetic acid or its derivatives represented by the general formula () are mixed in an inert organic solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran, chloroform, methylene chloride,
If necessary, add an appropriate amount of 4-(N·N-dimethylamino)pyridine or 4-pyrrolidinopyridine in the presence of a base such as an organic tertiary base such as pyridine or triethylamine in
After heating at 0 to 100°C for 8 hours and cooling the reaction mixture, add an appropriate amount of an organic solvent such as benzene, wash with aqueous alkaline solution, dry the organic layer and concentrate under reduced pressure, and distill the residue under reduced pressure. The desired product can be obtained by purification using , column chromatography, etc. In this case, the reactive functional derivatives of phenylacetic acid or phenylacetic acid derivatives represented by the general formula () include acid chlorides, acid anhydrides, mixed acid anhydrides, esters, etc. It can be easily produced according to conventional methods. For example, an acid chloride can be produced by reacting phenyl acetic acid represented by the general formula () or a derivative thereof with thionyl chloride in benzene for several hours. The free form of the object compound of the present invention is a viscous oily substance, which can be used in common organic solvents such as methanol, ethanol, chloroform, methylene chloride,
Soluble in ether, ethyl acetate, benzene, etc. These free-form compounds can be converted into acid addition salts according to conventional methods. For example, the free form of the phenylacetamide derivative represented by the general formula () can be dissolved in ether, and then an appropriate amount of hydrochloric acid gas is added to this solution to form the hydrochloride. The acid addition salt of the object compound of the present invention is a colorless crystalline or glassy substance, and has strong central depressant and analgesic effects similar to the corresponding free form of the compound. The phenylacetamide derivative represented by the general formula () of the present invention is a new compound that has not been described in any literature, has strong central depression effect and analgesic effect, and is useful as a pharmaceutical. Reference examples and examples are shown below to further explain the present invention in detail. Note that the boiling points of the compounds in Reference Examples and Examples are uncorrected. Reference example 1 4-methoxyphenethylamine hydrochloride 59.5g,
120g of sodium hydrogen carbonate, 800ml of dioxane and water
Dissolve 60 chloroacetic acid chloride in 1000ml and cool on ice.
g was added dropwise and stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, water is added, and the crystals are collected by filtration. The crystals were recrystallized from chloroform-n-hexane to give N-(4
-methoxyphenethyl) chloracetamide 50.5
get g. Dissolve 8g of this in 50g of methylamine methanol solution (40%) and add it to Bombenroll.
Heat at 100℃ for 4 hours. After cooling, the solvent is distilled off under reduced pressure, a 10% aqueous sodium hydroxide solution is added to the residue, and the mixture is extracted with benzene. The benzene layer is washed with water and dried, and the benzene is distilled off under reduced pressure to obtain 7.5 g of N-(4-methoxyphenethyl)-α-(methylamino)acetamide. Next, 7.5 g of this product, 4 g of isopentenyl chloride, 13 g of potassium carbonate, and 0.5 g of sodium iodide were dissolved in 140 ml of ethanol and 50 ml of water, and heated under reflux for 5 hours. After cooling, the solvent is distilled off, a 10% aqueous sodium hydroxide solution is added, and the mixture is extracted with benzene. The benzene layer is washed with water and dried, and the benzene is distilled off under reduced pressure to obtain 6.8 g of N-(4-methoxyphenethyl)-α-(N-methyl-N-isopentenylamino)acetamide. Suspend 5.3 g of lithium aluminum hydride in 50 ml of ether, and add N-(4-methoxyphenethyl)-(N'-methyl-N'-isopentenyl) to this suspension.
A solution of 6.8 g of aminoacetamide in 25 ml of ether was added dropwise while stirring while cooling, and the mixture was stirred at room temperature for 1 hour and further heated under reflux overnight. After cooling, add an appropriate amount of
A 10% aqueous sodium hydroxide solution is added, then insoluble matter is filtered, and the ether layer is dried and concentrated. The residue was distilled under reduced pressure (130-135℃/0.5mmHg) and N-
(4-methoxyphenethyl)-N'-methyl-N'-
4.9 g of isopentenylethylenediamine are obtained. Infrared absorption spectrum (liquid film) νNH: 3300 cm ^-1 Elemental analysis value C ₁₇ H ₂₈ N ₂ O C% H% N% Theoretical value 73.86 10.21 10.14 Actual value 73.73 10.18 10.21 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.65 (s, 3H), 1.75 (s, 3H), 2.20
(s, 3H), 2.3-3.1 (m, 11H), 3.80 (s,
3H), 5.1-5.4 (m, 1H), 6.80 (d, 2H),
7.14(d, 2H) The following compounds can be produced by similar operations.

[Table] Example 1 3 g of N-phenethyl-N'-(β-hydroxyethyl)-N'-arylethylenediamine and 10 g of triethylamine were dissolved in 50 ml of benzene, and a benzene solution of 7 g of 4-methoxyphenylacetic acid chloride was added to this. Drip. The mixture was then stirred at room temperature for 1 hour, and then heated under reflux for 3 hours. After cooling, the reaction solution was
% aqueous sodium hydroxide solution, water, and drying. The solvent was distilled off under reduced pressure. A solution of 2 g of sodium hydroxide in 50 ml of ethanol was added to the residue, and the mixture was stirred overnight at room temperature. Then, it is concentrated under reduced pressure, water is added to the residue, extracted with benzene, and the benzene layer is washed with water and dried. Benzene was distilled off under reduced pressure, and the residue was purified by activated alumina column chromatography (benzene-ethyl acetate) to obtain N-phenethyl-N-2-
3 g of (N-2-hydroxyethyl-N-arylamino)ethyl-4-methoxyphenylacetamide are obtained. (Pale yellow oily substance) Infrared absorption spectrum (liquid film) νCO: 1640 cm ^-1 , νOH: 3400 cm ^-1 Elemental analysis value C ₂₄ H ₃₂ O ₃ N ₂ C% H% N% Theoretical value 72.69 8.13 7.07 Actual value 72.73 8.25 6.92 Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: 2.4-7.7 (m, 17H), 3.72 (s, 3H), 5.0
~5.3 (m, 2H), 5.5~6.0 (m, 1H), 6.7~
7.4 (m, 9H) Example 2 3.4 g of 4-methoxyphenylacetic acid is dissolved in 80 ml of benzene, 3.2 g of phosphorus oxychloride is added thereto, and the mixture is stirred at room temperature for 30 minutes. This reaction solution contains N-
Add 3 g of phenethyl-N'-methyl-N'-arylethylenediamine and heat under reflux for 3 hours. The reaction solution is made alkaline by adding an aqueous sodium hydroxide solution, and the reaction solution is extracted with benzene. After washing the benzene layer with water and drying, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure (170-180°C/0.5 mmHg) to obtain N-phenethyl-N-2-(N-methyl- 4.5 g of N-arylamino)ethyl-4-methoxyphenylacetamide are obtained. Infrared absorption spectrum (liquid film) νCO: 1640 cm ^-1 Elemental analysis value C ₂₃ H ₃₀ O ₂ N ₂ C% H% N% Theoretical value 75.37 8.25 7.64 Actual value 75.27 8.45 7.39 Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ: 2.15 (s, 3H), 2.2-3.7 (m, 12H),
3.75 (s, 3H), 4.9~5.3 (m, 2H), 5.5~
6.0 (m, 1H), 6.7-7.3 (m, 9H) Example 3 2.3 g of N-phenethyl-N'-methyl-N'-isopentenylethylenediamine, 2 g of triethylamine, 4-(N/N-dimethylamino)pyridine Dissolve 0.1 g in 50 ml of methylene chloride, add 2 g of phenyl acetic chloride dropwise under ice cooling, and stir at room temperature for 2 hours. The reaction solvent was concentrated under reduced pressure, a 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with benzene. After washing the benzene layer with water and drying, the solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure (213-216℃/0.85mmHg) to obtain N-phenethyl-N-2-(N- Methyl-N
2 g of -isopentenylamino)ethylphenylacetamide are obtained. Infrared absorption spectrum (liquid film) νCO: 1635cm ^-1 Elemental analysis value C ₂₄ H ₃₂ ON ₂ C% H% N% Theoretical value 79.08 8.85 7.69 Actual value 79.19 8.68 7.61 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.60 ( s, 3H), 1.70 (s, 3H), 2.1~3.9
(m, 15H), 5.0-5.3 (m, 1H), 6.9-7.4
(m, 10H) Example 4 3.2 g of N-phenethyl-N'-methyl-N'-isopentenylethylenediamine, 3 g of triethylamine, and 0.1 g of 4-(N·N-dimethylamino)pyridine were dissolved in 50 ml of methylene chloride, 2,5-dimethoxyphenyl acetic acid chloride under ice-cooling and stirring.
Add 3.2 g dropwise and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with benzene. The benzene layer is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was purified by activated alumina column chromatography (benzene-ethyl acetate) to obtain a pale yellow oily N
4.2 g of -phenethyl-N-2-(N-methyl-N-isopentenylamino)ethyl-2,5-dimethoxyphenylacetamide are obtained. Infrared absorption spectrum (liquid film) νCO: 1640cm ^-1 Elemental analysis value C ₂₆ H ₃₆ O ³ N ₂ C% H% N% Theoretical value 73.55 8.55 6.60 Actual value 73.41 8.59 6.69 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.63 (s, 3H), 1.72 (s, 3H), 2.1~
3.8, (m, 15H), 3.75 (s, s, 3H, 3H),
5.0-5.3 (m, 1H), 6.7-7.4 (m, 8H) Example 5 8.3g of 4-methoxyphenyl acetic acid was added to 50% of benzene.
ml and dropwise added 7.7 g of phosphorus oxychloride.
After stirring at room temperature for 30 minutes, a solution of 9.2 g of N-(4-methoxyphenethyl)-N'-methyl-N'-isopentenylethylenediamine in 50 ml of benzene was added dropwise, stirring at room temperature for 1 hour, and heating for an additional 5 hours. Reflux. After cooling the reaction solution, add 10% aqueous sodium hydroxide solution and separate the benzene layer. After washing the benzene layer with water and drying, the solvent was distilled off under reduced pressure and the residue was purified by activated alumina column chromatography (benzene-ethyl acetate) to obtain N-(4-methoxyphenethyl) as a pale yellow oil. )-N-2-
10.6 g of (N-methyl-N-isopentenylamino)ethyl-4-methoxyphenylacetamide are obtained. Infrared absorption spectrum (liquid film) νCO: 1635 cm ^-1 Elemental analysis value C ₂₆ H ₃₆ O ₃ N ₂ C% H% N% Theoretical value 73.55 8.55 6.60 Actual value 73.42 8.60 6.50 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.60 (s, 3H), 1.70 (s, 3H), 2.1~3.7
(m, 15H), 3.8 (s, s, 3H, 3H), 5.0~
5.3 (m, 1H), 6.7-7.2 (m, 8H) Example 6 2.9 g of N-phenethyl-N'-methyl-N'-isopentenylethylenediamine, 3 g of triethylamine, 4-(N/N-dimethylamino)pyridine Dissolve 0.1 g in 30 ml of methylene chloride, add a solution of 3 g of 3,4-dimethoxyphenylacetic acid chloride in 10 ml of methylene chloride under ice-cooling and stirring, and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was
% aqueous sodium hydroxide solution and extracted with benzene. After washing the benzene layer with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by activated alumina column chromatography (benzene-ethyl acetate) to give N-phenethyl-N-2-(N
-Methyl-N-isopentenylamino)ethyl-
3,4-dimethoxyphenylacetamide 3.8g
get. Infrared absorption spectrum (liquid film) νCO: 1640cm ⁶¹ Elemental analysis value C ₂₆ H ₃₆ O ₃ N ₂ C% H% N% Theoretical value 73.55 8.55 6.60 Actual value 73.32 8.51 6.51 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.60 (s, 3H), 1.70 (s, 3H), 2.1~3.8
(m, 15H), 3.82 (s, s, 3H, 3H), 5.0~
5.3 (m, 1H), 6.5-7.4 (m, 8H) Example 7 Dissolve 5.6 g of 4-methoxyphenylacetic acid in 100 ml of benzene, add phosphorus oxychloride from 5.1 to this solution, and stir at room temperature for 30 minutes. . Then, a benzene solution of 5.5 g of N-phenethyl-N'-methyl-N'-isopentenylethylenediamine was added, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was made alkaline by adding 10% aqueous sodium hydroxide solution, extracted with benzene, washed with water, and dried. Benzene was distilled off under reduced pressure, and the residue was distilled under reduced pressure (220-230℃/1 mm
Hg) and N-phenethyl-N, which is a pale yellow substance.
-2-(N-methyl-N-isopentenylamino)ethyl-4-methoxyphenylacetamide
Obtain 3.2g. Infrared absorption spectrum (liquid film) νCO: 1640cm ^-1 Elemental analysis value C ₂₅ H ₃₄ O ₂ N ₂ C% H% N% Theoretical value 76.10 8.69 7.10 Actual value 76.10 8.41 7.30 Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ: 1.59 (s, 3H), 1.70 (s, 3H), 2.0~4.0
(m, 15H), 3.70 (s, 3H), 5.0~5.3 (m,
1H), 6.7-7.3 (m, 9H) Example 8 N-phenethyl-N-2-(N-methyl-N-
Dissolve 1 g of arylamino)ethyl-4-methoxyphenylacetamide in 30 ml of ether, and blow an appropriate amount of hydrochloric acid gas into this solution. When ether and excess hydrochloric acid gas were removed from the reaction solution under reduced pressure, N-phenethyl-N, a colorless and transparent glassy substance, was obtained.
1 g of -2-(N-methyl-N-arylamino)ethyl-4-methoxyphenylacetamide hydrochloride is obtained.

Claims (1)

[Claims] 1. General formula (R ₁ in the formula is an alkyl group having 1 to 3 carbon atoms or a hydroxyalkyl group having 2 to 4 carbon atoms,
R ₂ is a linear or branched alkenyl group having 3 to 6 carbon atoms, X is an alkoxy group having 1 to 3 carbon atoms, and Y is a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms; , n is an integer of 0 to 2) and pharmacologically acceptable salts thereof. 2 General formula The phenylacetamide derivative according to claim 1, represented by the formula (wherein R ₁ and R ₂ have the same meanings as above). 3 General formula The phenylacetamide derivative according to claim 1, represented by the formula (wherein X, R ₁ and R ₂ have the same meanings as above). 4 General formula The phenylacetamide derivative according to claim 1, represented by the formula (wherein X, R ₁ and R ₂ have the same meanings as above). 5 General formula (Y ₁ in the formula is an alkoxy group having 1 to 3 carbon atoms, and X, R ₁ and R ₂ have the same meanings as above)
The phenylacetamide derivative according to claim 1, which is represented by: 6 General formula The phenylacetamide derivative according to claim 3, represented by the formula (wherein R ₁ and R ₂ have the same meanings as above). 7 General formula The phenylacetamide derivative according to claim 4, represented by the formula (wherein R ₁ and R ₂ have the same meanings as above). 8 General formula The phenylacetamide derivative according to claim 5, represented by the formula (wherein R ₁ and R ₂ have the same meanings as above). 9 formula The phenylacetamide derivative according to claim 2, which is represented by: 10 formula The phenylacetamide derivative according to claim 6, which is represented by: 11 formula The phenylacetamide derivative according to claim 6, which is represented by: 12 formula The phenylacetamide derivative according to claim 6, which is represented by: 13 formula The phenylacetamide derivative according to claim 7, which is represented by: 14 formula The phenylacetamide derivative according to claim 7, which is represented by: 15 formula The phenylacetamide derivative according to claim 8, which is represented by: