JPH075523B2 - Optically active 2-phenylethylamine derivative, method for producing the same, and analgesic containing the same as active ingredient - Google Patents

Description

TECHNICAL FIELD The present invention relates to an optically active 2-phenylethylamine derivative useful as a drug or an intermediate thereof, a method for producing the same, and an analgesic containing the same as an active ingredient.

[Conventional technology]

Morphine has been widely used as a central analgesic for many years, but on the other hand, due to its low drug resistance and drug dependence in the living body, its use must be greatly restricted. It is a drug. Therefore, in recent years, active attempts have been made to develop synthetic analgesics that have an analgesic effect comparable to that of morphine and are not drug-dependent (narcotic). Among them, for example, pentazocine (Pentazocine) is drug-dependent. It appeared as an analgesic that does not have. However, recently it has been found that pentazocine also has drug dependence [Medical Drugs Japan Pharmaceutical Collection, 5th Edition,
Pp. 694 to 695 (published by Yakuhin Jikho Co., Ltd. in 1979)], it has become a major clinical problem, and the development of new non-narcotic analgesics is desired.

[Problems to be solved by the invention]

The present invention has been made in view of the present situation, and in order to solve the restrictions found in the conventional synthetic analgesics such as the above, in particular, by using an optical isomer having an optical purity close to 100%, a pharmacological action is obtained. An attempt was made to create an analgesic with enhanced inflammatory response and reduced side effects.

[Means for solving problems]

In order to solve the above problems, according to the present invention, the general formula (I): (Wherein, R ₁ represents a hydrogen atom or a methyl group, R ₂ represents a C ₁ ~ ₄ alkyl group or a cyclopropylmethyl group, the absolute configuration of 1-position is either in the R or S configuration) represented by The optically active 2-phenylethylamine derivative and its acid addition salt, the production method thereof, and the analgesic containing them as active ingredients are provided. Hereinafter, the present invention will be specifically described. The alkyl group of C ₁ ~ ₄ represented by R ₂ in the compound represented by the general formula (I), a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group and the like.

Further, according to the production method of the present invention, the absolute configuration is (i) general formula (IA): (Wherein R ₁ and R ₂ have the same meanings as described above), and the optical isomer having the R configuration and (ii) the general formula (I
-B): (In the formula, R ₁ and R ₂ have the same meanings as described above) An optical isomer 2-phenylethylamine derivative having one of the S configurations represented by the above can be selectively and easily obtained.

Specific compounds of the present invention include the following. That is, (R) -N-methyl-1-cyclohexyl-2-phenylethylamine, (R) -N-ethyl-1-cyclohexyl-2-phenylethylamine, (R) -N-propyl-1-cyclohexyl-2-phenyl Ethylamine, (R) -N-isopropyl-1-cyclohexyl-2-
Phenylethylamine, (R) -N-isobutyl-1-cyclohexyl-2-phenylethylamine, (R) -N-cyclopropylmethyl-1-cyclohexyl-2-phenylethylamine, (R) -N, N-dimethyl-1 -Cyclohexyl-2-phenylethylamine, (R) -N-ethyl-N-methyl-1-cyclohexyl-2-phenylethylamine, (R) -N-propyl-N-methyl-1-cyclohexyl-2-phenylethylamine, (R) -N-isopropyl-N-methyl-1-cyclohexyl-2-phenylethylamine, (R) -N-isobutyl-N-methyl-1-cyclohexyl-2-phenylethylamine, (R) -N-cyclopropyl Methyl-N-methyl-1-
Cyclohexyl-2-phenylethylamine, and their optical antipodes (S configuration).

The acid addition salts of these 2-phenylethylamine derivatives include basic salts such as hydrochlorides, sulfates and phosphates, or citrates, oxalates, maleates, succinates, and fumarates. Examples thereof include organic acid salts such as methanesulfonate and acetate. The configuration of the compound of the present invention was confirmed by a crystal X-ray diffraction method.

The optically active 2-phenylethylamine derivative of the present invention can be easily obtained by the following method. That is, the general formula (II): (Wherein R ₁ represents a hydrogen atom or a methyl group, and the absolute configuration at the 1-position and the 1-position is either the R configuration or the S configuration) and the optically active 2-phenylethylamine compound is catalyzed. By hydrogenolysis in the presence of the general formula (Ii): The 2-phenylethylamine derivative of the present invention represented by the formula (wherein R ₁ represents the same thing and the absolute configuration at the 1-position has either the R configuration or the S configuration) is obtained, and further obtained -Phenylethylamine derivative (Ii), a) When R ₁ is a hydrogen atom, general formula (III): R ₃ CHO (III) (In the formula, R ₃ is a hydrogen atom or C ₁ to ₃₎ Represents an alkyl group of) and then undergoes a reduction reaction in the presence of a catalyst, or b) when R ₁ is a methyl group, a compound of the general formula (IV): R ₂ ′ X ( IV) (wherein, R ₂ 'is the general formula by reacting an alkyl group or a cyclopropylmethyl group of C ₁ ~ _4, X is a halogenated alkyl compound represented by a halogen atom) (I-ii): (Wherein R ₁ and R ₂ ′ represent the same as described above, and the absolute configuration at the 1-position is either R configuration or S configuration) to obtain the 2-phenylethylamine derivative of the present invention. Can be done.

In the above-mentioned production method, the catalyst used for hydrogenolysis of the optically active 2-phenylethylamine compound represented by the general formula (II) in the presence of a catalyst is preferably palladium-carbon, for example. The reaction is usually performed in an organic solvent under hydrogen pressure. Examples of the solvent used include acetic acid. Appropriate hydrogen pressure is 5 to 100 atm. Although the reaction temperature and the reaction time are not particularly limited, the reaction may be performed usually at a temperature of about 15 to 30 ° C. for about 12 to 24 hours. Isolation and purification of the target compound may be carried out by usual processing means. 2-obtained as described above
The phenylethylamine derivative (I-i) was converted into R ₃ CHO (III)
When the Schiff base compound is obtained by reacting with the aldehyde compound represented by, the catalyst used is, for example, paratoluenesulfonic acid. The reaction is usually performed in an organic solvent. Examples of the solvent used include benzene and the like. Although the reaction temperature and the reaction time are not particularly limited, the reaction is usually carried out under reflux for about 3 to 6 hours. Isolation and purification of the Schiff base compound may be carried out by an ordinary treatment means. NaBH ₄ , LiAlH _{4 and the} like are suitable as the catalyst to be used for reducing the Schiff base compound obtained as described above to obtain the 2-phenethylamine derivative (I-ii). The reaction is usually performed in an organic solvent. Examples of the solvent used include methanol and tetrahydrofuran. The reaction temperature and reaction time are not particularly limited, but usually 3 to 5
The reaction may be performed for about 5 hours.

Isolation and purification of the target compound may be performed by ordinary means.

In addition, the 2-phenylethylamine derivative (Ii)
When the ₂ -phenethylamine derivative (I-ii) is obtained by reacting with a halogenated alkyl compound represented by R ₂ ′ X (IV), for example, in the presence of potassium carbonate in an organic solvent such as dimethylformamide, 20 to 12 ~ 80 ℃
The reaction may be performed for 24 hours.

Isolation and purification of the target compound may be performed by ordinary means.

The optically active 2-phenylethylamine derivative (I) of the present invention is produced by the above method. For example, an example of the production method in the case of the R configuration is represented by the reaction formula as follows.

The optically active 2-phenylethylamine derivative (II) used as a starting material in the production method of the present invention
Is the method by Takahashi et al. (Chem.Pharm.Bull.32 Vol. 7
2714-2723 1984), it can be easily obtained by the following manufacturing process.

By using L-α-phenylglycine in place of D-α-phenylglycine which is the starting material in the above production process, an optical isomer having a configuration of (1S, 1 ′S) can be obtained.

As is clear from the pharmacological test examples and toxicity test examples described below, the 2-phenylethylamine derivative of the present invention has a powerful analgesic activity comparable to or higher than pentazocine,
It can also be used as an excellent analgesic that is not antagonized by naloxone. Examples of such applications include various guns,
Pain such as gastric / duodenal ulcer, renal / urinary tract stones, arteritis obliterans, etc. Pain analgesics, preanesthetic medications and anesthesia aids after surgery, when using gastric / ureteral / bladder test instruments To be

Examples of the dosage form of the analgesic of the present invention include (i) oral administration preparations: tablets, capsules, granules, powders, etc. (ii) parenteral administration preparations: injection solutions, suppositories, etc. The preparation of these preparations can be carried out according to a usual method, and an auxiliary drug (for example, a stabilizer etc.) usually used in the technical field may be appropriately blended.

Further, the analgesic of the present invention is preferably administered to an adult at a dose of 1 to 50 mg / dose in order to exert the effect.

〔Example〕

Next, the 2-phenylethylamine derivative of the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.

Reference Example 1 (1R, 1′R) -N- (2′-hydroxy-1′-phenylethyl) -1-cyclohexyl-2-phenylethylamine, (i) Obtained by reducing D-α-phenylglycine (R) -2-amino-2-phenylethanol 1.37 g (1
1.12 g (10 mM) cyclohexylaldehyde are added over 5 minutes with stirring to a solution of 0 mM) in 10 ml dichloromethane. Further, 2 g of anhydrous magnesium sulfate is added and stirring is continued at room temperature for 1 hour. After the reaction was completed, the solid matter was filtered off, the filtrate was concentrated, and the residue was distilled under reduced pressure (2S, 4R).
2.22 g of 2-cyclohexyl-4-phenyl-1,3-oxazolidine was obtained as a colorless oil.

Boiling point: 160 ° C./2 mmHg. MS m / e: CI, 232 (M · H ⁺ ); EI, 149 (base peak, M ⁺ −C ₆ H ₁₁ ) (ii) (i) Oxazolidine compound 1.85 g (8
(mM) dissolved in 30 ml of tetrahydrofuran, 4.53 g (30 mM) of benzylmagnesium chloride suspended in 30 ml of tetrahydrofuran is added dropwise in a nitrogen stream. Then, stirring is continued at room temperature for 4 hours. After completion of the reaction, a small amount of water is added, the precipitate is filtered off and then extracted with ether. The ether extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By subjecting the residue to silica gel column chromatography (developing solvent: dichloromethane) (1
2.24 g of R, 1′R) -N- (2′-hydroxy-1′-phenylethyl) -1-cyclohexyl-2-phenylethylamine was obtained as a colorless oil.

MS m / e: CI324 (M · H +); ET240 (M + -C 6 H 11), 232 (base peakM + -CH 2 C 6 H 5) 1 H-NMR: 2.56 (1H, d, J = 3.7,6.6, NC H C ₆ H ₁₁ ) 2.65 (1H, dd, J = 6.6,13.4, C ₆ H ₅ C H ₂ CH) 2.73 (1H, dd, J = 6.6,13.4, C ₆ H ₅ C H ₂ CH) 3.39 (1H, dd, J = 8.3,10.7, O−C H ₂ —CH) 3.53 (1H, dd, J = 4.4,10.7, O−C H ₂ —CH) 3.71 (1H, dd, J _{= 4.4,8.3.N-C H -C 6 H} 5) Optical rotation: [α] _D -5.29 ° (c = 0.46, ethanol) reference example 2 (1R, 1'R) -N- methyl -N- ( 2'-hydroxy-
1′-phenylethyl) -1-cyclohexyl-2-phenylethylamine, (1R, 1′R) -N- (2 ′) obtained in Reference Example 1- (ii).
-Hydroxy-1'-phenylethyl) -1-cyclohexyl-2-phenylethylamine (3.23 g), potassium carbonate (2 g) and methyl iodide (10 ml) were added to dimethylformamide (40 ml) and stirred at room temperature for 12 hours, water (50 ml) was added, and ether (50 ml) was added. It was extracted twice with and the ether layer was washed with 50 ml of water three times. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (developing solvent: dichloromethane) to give (1R, 1′R) -N-methyl-N- (2′-hydroxy-1). ′ -Phenylethyl)
-1-Cyclohexyl-2-phenylethylamine 3.14
g was obtained as a colorless oil.

MS m / e: CI, 338 (M · H +); EI, 254 (M + -C 6 H 11) 246 (base peak, M + -CH 2 C 6 H 5) 1 H-NMR (CDCL 3) δ: 2.33 (3H, s, NCH ₃ ), 2.62 (1H, dd, J = 5.6,13.9Hz, PhC H ₂ CH), 2.67 (1H, dd, J = 8.3,13.9Hz, PhC H ₂ CH), 2.77 (1H, ddd, J = 4.2,5.6,8.3Hz CHC H CH ₂ ), 3.43 (1H, dd, J = 4.9,10.6Hz, OC H ₂ CH), 3.58 (1H, dd, J = 4.9,8.2Hz , PhC H CH ₂ ), 3.68 (1H, dd, J = 8.2,10.6Hz, OC H ₂ CH). Recrystallization of this oil from n-heptane gave a melting point of 77-78.
Colorless needle-shaped crystals of ℃ are obtained.

Elemental analysis: Calculated as _{C 23 H 31 NO (%)} : C81.85 H9.26 N4.15 Found (%): C81.66 H9.25 N4.03 that was treated by a conventional method The crystals The hydrochloride salt was obtained.

Melting point: 164-166 ° C. Optical rotation: [α] _D + 10.5 ° (c = 0.55, ethanol) Reference Example 3 (1S, 1 ′S) -N- (2′-hydroxy-1′-phenylethyl) -1-Cyclohexyl-2-phenylethylamine (S) -2-amino-2-phenyl obtained by reducing L-α-phenylglycine in place of D-α-phenylglycine in Reference Example 1- (i). (1S, 1 ′S) -N- (2′-hydroxy-1′-phenylethyl) -1-reacted in the same manner as in Reference Examples 1- (i) and (ii) except that ethanol was used. Cyclohexyl-2-phenylethylamine was obtained. The physical property values are the same as those described in Reference Example 1 except the optical rotation.

Optical rotation: [α] _D + 52.7 ° (c = 0.44, ethanol) Reference Example 4 (1S, 1 ′S) -N-methyl-N- (2′-hydroxy-)
1′-phenylethyl) -1-cyclohexyl-2-phenylethylamine In Reference Example 2, (1R, 1′R) -N- (2′-hydroxy-1′-phenylethyl) -1-cyclohexyl-
In place of 2-phenylethylamine, (1S, 1'S) -N- (2'-hydroxy-1'-phenylethyl) -1-cyclohexyl-2-phenylethylamine obtained in Reference Example 3 was used. In the same manner as in Reference Example 2 (1S, 1 ′
S) -N-Methyl-N- (2'-hydroxy-1'-phenylethyl) -1-cyclohexyl-2-phenylethylamine was obtained. The physical property values are the same as those described in Reference Example 2 except for the optical rotation.

Optical rotation: [α] _D −10.6 ° (c = 0.56, ethanol) Reference Example 5 (R) -1-Cyclohexyl-2-phenylethylamine (1R, 1′R) -N- (obtained in Reference Example 1 2'-hydroxy-1'-phenylethyl) -1-cyclohexyl-
3.23 g of 2-phenylethylamine (10 mM) was added to 100 ml of glacial acetic acid.
Add 1 g of 10% palladium on carbon to the one dissolved in ml and add 10
Shake at room temperature under a hydrogen pressure of 0 kg / cm ² for 24 hours. After completion of the reaction, the catalyst is filtered off, the residue is made alkaline with an aqueous sodium carbonate solution, and then extracted with ether. After the ether was distilled off, the residue was subjected to silica gel chromatography (developing solvent: dichloroethane) to give (R) -1-cyclohexyl-
1.94 g of 2-phenylethylamine was obtained as a colorless oil.

MS m / e: CI, 204 (M · H +); EI, 112 (pase peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 2.38 (1H, dd, J = 9.8,13.2, C ₆ H ₅ C H ₂ CH) 2.78 (1H, dt, J = 3.9,9.8, N−C H −C ₆ H ₁₁ ) 2.88 (1H, dd, J = 3.9,13.2, C ₆ H ₅ C H ₂ CH) This oily substance was treated with methanol hydrochloric acid by a conventional method, and recrystallized from ethanol to give colorless needle crystals (R)-
1-Cyclohexyl-2-phenylethylamine hydrochloride was obtained.

Melting point: 223 to 225 ° C. Elemental analysis: Calculated as _{C 14 H 21 N · HCl (} %): C70.13 H9.25 N5.84 Found (%): C70.19 H9.47 N5.89 Optical rotation Degree: [α] _D + 28.7 ° (c = 0.54, water) Example 1 (R) -N-methyl-1-cyclohexyl-2-phenylethylamine Obtained in Reference Example 2 (1R, 1′R). -N-methyl-N-
3.38 g of (2'-hydroxy-1'-phenylethyl) -1-cyclohexyl-2-phenylethylamine (10 m
M) is dissolved in 100 ml of glacial acetic acid, 1 g of 10% palladium carbon is added, and the mixture is shaken at room temperature under hydrogen pressure of 6 kg / cm ² for 12 hours. After completion of the reaction, the catalyst is filtered off, the residue is made alkaline with an aqueous sodium carbonate solution, and then extracted with ether. After the ether was distilled off, the residue was subjected to silica gel chromatography (developing solvent: dichloroethane) to obtain 2.1 g of (R) -1-cyclohexyl-2-phenylethylamine as a colorless oil.

MS m / e: CI, 218 (M · H +); EI, 126 (pase peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 2.17 (3H, s, NCH 3), 2.43 ( 1H, dt, J = 4.4,8.6Hz, CH ₂ CH H CH), 2.49 (1H, dd, J = 8.6,13.2Hz, PhC H ₂ CH), 2.64 (1H, dd, J = 4.4,13.2Hz, (PhC H ₂ CH) This oily substance was treated with methanol hydrochloric acid by a conventional method, and recrystallized from ethanol to give colorless needle crystals (R)-
1-Cyclohexyl-2-phenylethylamine hydrochloride was obtained.

Melting point: 239 to 241 ℃ Elemental analysis value: As C ₁₅ H ₂₃ N ・ HCl Theoretical value (%): C70.98 H9.53 N5.52 Actual value (%): C71.00 H9.73 N5.44 Optical rotation Degree: [α] _D + 8.4 ° (c = 0.38, ethanol) Example 2 (R) -N-ethyl-1-cyclohexyl-2-phenylethylamine (R) -1-cyclohexyl obtained in Reference Example 5 -2-
Add phenylethylamine (1.02g) and acetaldehyde (0.5g) to benzene (30ml) and use a Dear Stark-type water separation tube.
Reflux for hours. Benzene was distilled off under reduced pressure and methanol 30 ml
Add 0.5 g of sodium borohydride to this, and add
Stir for hours. After distilling off the methanol under reduced pressure, 20 ml of water was added, the mixture was extracted twice with 30 ml of ether, and the ether layer was washed with 20 ml of water.
After washing twice with water and drying over anhydrous magnesium sulfate, the ether was distilled off under reduced pressure, and the residue was subjected to column chromatography (methychro) to give 0.97 g of (R) -N-ethyl-1-cyclohexyl-2-phenylethylamine as colorless. Was obtained as an oily substance.

MS m / e: CI, 232 (M · H +) EI, 140 (pase peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 0.96 (1H, t, J = 7,1, N −CH ₂ C H ₃ ), 2.47 (1H, dq, J = 7.1,11.2, NC−C H ₂ —CH ₃ ), 2.58 (1H, dq, J = 7.1,11.2, NC−C H ₂ —CH ₃ ) This oily substance is treated with hydrochloric acid methanol by a conventional method and recrystallized from ethanol to give colorless needle-shaped (R) -N.
-Ethyl-1-cyclohexyl-2-phenylethylamine hydrochloride was obtained.

Melting point: 194-197 ° C Elemental analysis value: As C ₁₆ H ₂₅ N HCl Theoretical value (%): C71.75 H9.78 N5.23 Actual value (%): C71.90 H10.06 N5.25 Optical rotation: [Α] _D + 18.1 ° (c = 0.59, water) Examples 3 to 6 In Example 2, a series of analogs could be obtained by reacting with the corresponding alkyl aldehyde instead of acetaldehyde. . The obtained compound is shown together with its physical property values.

(R)-N-propyl-1-cyclohexyl-2-phenylethylamine (Example 3 Compound) Typical Properties: colorless oil MS m / e: CI, 246 (M · H +) EI, 154 (M + -CH ₂ C ₆ H ₅ ) ¹ H-NMR δ: 0.78 (3H, t, J = 7.3, CH ₂ —CH ₂ —C H ₃ ), 2.39 (1H, ddd, J = 6.6,7.8,11.2, N−C _{H 2 -CH 2), 2.51 (} 1H, ddd, J = 6.6,7.8 11.2, N-C H 2 -CH 2) ( hydrochloride) Typical properties: colorless needle crystals melting point: 163-165 ° C. (ethanol Recrystallization) Elemental analysis value: As C ₁₇ H ₂₇ N HCl Theoretical value (%): C72.44 H10.01 N4.97 Actual value (%): C72.36 H10.19 N4.94 Optical rotation: [α] _D + 19.8 ° (c = 0.57, water) (R) -N-isopropyl-1-cyclohexyl-2-
Phenylethylamine (Example 4 Compound) Typical Properties: colorless oil MS m / e: CI, 246 (M · H +) EI, 154 (bese peak, M + -CH 2 -C 6 H 5) 1 H-NMR δ: 0.83 (3H, d, J = 6.1, NCH (C H ₃ ) ₂ ), 0.95 (3H, d, J = 6.1, NCH (C H ₃ ) ₂ ), 2.25 (1H, dd, J = 7.7, 12.9, C ₆ H ₅ C H ₂ CH), 2.60 (1H, ddd, J = 3.7,5.4,7.7, N-C H- C ₆ H ₁₁ ), 2.67 (1H, 7th, J = 6.1, N-C _{H (CH 3) 2),} 2.75 (1H, dd, J = 5.4,12.9, C 6 H 5 C H 2 -CH) ( hydrochloride) Typical properties: colorless needle crystals melting point: 170-172 ° C. (ethanol Elemental analysis value: As C ₁₇ H ₂₇ N HCl Theoretical value (%): C72.44 H10.01 N4.97 Actual value (%): C72.60 H10.25 N4.97 Optical rotation: [α] _D + 18.0 ° (c = 0.69, water) (R) -N-isobutyl-1-cyclohexyl-2-phenylethylamine (Compound of Example 5) Properties: colorless oil MS m / e: CI, 260 (M・ H ⁺ ) EI, 168 (base peak, M ⁺ −CH ₂ C ₅ H ₅ ) ¹ H −NMr δ: 0.7 5 (3H, d, J = 6.6, CH 2 CH (C H 3) 2), 0.76 (3H, d, J = 6.6, CH 2 C H (CH 3) 2), 1.56 (1H, 9th, J = _{6.6, CH 2 C H (CH} 3) 2) 2.22 (1H, dd.J = 6.6,11.4, N-C H 2 -CH), 2.35 (1H, dd.J = 6.6,11.4, N-C H 2 −CH), 2.51 (1H, dd.J = 8.5,14.7, C ₆ H ₅ −C H ₂ CH), 2.53 (1H, dd.J = 8.5,14.7, C ₆ H ₅ −C H ₂ CH) ( hydrochloride) Typical properties: colorless needle crystals melting point: 153-154 ° C. (ethanol recrystallization) elemental analysis: C ₁₈ H ₂₉ theory as NHCl (%): C73.07 H10.22 N4.73 Found (%): C73.19 H10.41 N4.70 Optical rotation: [α] _D + 26.8 ° (c = 0.73, water) (R) -N-cyclopropylmethyl-1-cyclohexyl-2-phenylethylamine ( example 6 compound) Typical properties: colorless oil MS m / e: CI, 258 (M · H +) EI, 166 (base peak, M + -CH 2 -C 6 H 5) 1 H-NMR δ: 2.19 (1H, dd.J = 7.1,11.8, N -C H 2 -CH), 2.44 (1H, dd.J = 6.6,11.8, N-C H 2 -CH), 2.54 (1H, dd.J _{8.8,12.2, C 6 H 5 -CH 2} -CH), 2.57 (1H, dd.J = 8.8,4.2, C 6 H 5 -C H 2 -CH) ( hydrochloride) Typical Properties: colorless needle crystals melting point: 146 to 148 ° C. (ethanol recrystallization) elemental analysis: C ₁₈ H ₂₇ theory as NHCl (%): C73.57 H9.60 N4.77 Found (%): C73.59 H9.86 N4 .79 Optical rotation: [α] _D + 23.3 ° (c = 0.60, water) Example 7 Example in (R) -N-ethyl-N-methyl-1-cyclohexyl-2-phenylethylamine DMF (10 ml). 1.08 g (5 mM) of (R) -N-methyl-1-cyclohexylamine obtained in 1 above, 2.4 g of ethyl iodide and 1 g of anhydrous potassium carbonate were added, and the mixture was stirred at 70 ° C. for 4 hours. This was poured into 50 ml of water, extracted twice with 50 ml of ether, and washed 3 times with 50 ml of water. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (R) -N-ethyl-N-.
2.27 g of methyl-1-cyclohexyl-2-phenylethylamine was obtained as a colorless oil.

Sexual shape: colorless oil MS m / e: CI246 (M · H +) EI, 154 (base peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 0.96 (3H, t, J = 7.1 _{N-CH 2 -C H 3)} , 2.27 (3H, s, N-C H 3) ( hydrochloride) Typical properties: colorless needle crystals melting point: 154-155 ° C. elemental analysis: as C ₁₇ H ₂₇ NHCl Theoretical value (%): C72.44 H10.01 N4.97 Actual value (%): C72.42 H10.22 N4.96 Optical rotation: [α] _D + 11.3 ° (c = 0.67, water) Example 8-12 A series of compounds could be obtained by reacting in Example 7 with the corresponding alkyl halide instead of ethyl iodide. The obtained compound is shown together with its physical property values.

(R) -N, N-dimethyl-1-cyclohexyl-2-phenylethylamine (Example 8 Compound) Typical Properties: colorless oil MS m / e: CI232 (M · H +) EI140 (base peak, M + - CH ₂ C ₆ H ₅ ) ¹ H-NMR δ: 2.26 (6H, s, N (C H ₃ ) ₂ ) 2.56 (1H, dd, J = 5.4,13.9, C ₆ H ₅ —C H ₂ —CH) 2.82 (1H, dd, J = 6.1,13.9, C 6 H 5 -C H 2 -CH), ( hydrochloride) melting point: 193~194 ℃ (recrystallized from EtOH) elemental analysis: C ₁₆ H ₂₅ NHCl Theoretical value (%): C71.75 H9.78 N5.23 Actual value (%): C71.95 H10.07 N5.24 Optical rotation: [α] _D + 11.2 ° (c = 0.53, water) ( R) -N-Propyl-N-methyl-1-cyclohexyl-2-phenylethylamine (Compound of Example 9) Properties: colorless oil MS m / e: CI260 (MH) ⁺ EI168 (base peak, M ^{+ _{-CH 2 C 6 H 5) 1}} H-NMR δ: 0.79 (3H, t, J = 7.3CH 2 CH 2 C H 3) 2.56 (3H, s, N- H 3) ( hydrochloride) Typical properties: colorless Needle crystal Melting point: 171-174 ℃ Element analysis: C ₁₈ H ₂₉ theory as NHCl (%): C73.07 H10.22 N4.73 Found (%): C73.13 H10.49 N4.73 Optical rotation: [α] _{D +15.7} ° (c = 0.68, water) (R) -N-isopropyl-N-methyl-1-cyclohexyl-2-phenylethylamine (Compound of Example 10) Properties: colorless oil MS m / e: CI260 (MH) ^{+) EI168 (base peak, M} + -CH 2 C 6 H 5) 1 H-NMR δ: 0.88 (3H, d, J = 6.6-CH (C H 3) 2), 0.95 (3H, d, J = _{6.4-CH (C H 3)} ), 2.27 (3H, s, N-CH 3) (R) -N- isobutyl -N- methyl-1-cyclohexyl-2-phenylethylamine (example 11 compound) Typical properties: colorless oil MS m / e: CI274 (M · H +) EI182 (base peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 0.73 (3H, d, J = 6.6-CH 2 CH ( _{C H 3) 2), 0.76} (3H, d, J = 6.6CH 2 CH (C H 3) 2), 2.11 (1H, dd, J = 7.2,12.5N-C H 2 -CH), 2.15 (1H , dd, J = 7.2,12.5N-C H 2 -CH), 2.20 (3H, s, N- CH 3), 2.52 (1H.q, J = 6.1N-C H -C 6 H 11), 2.59 (1H, dd, J = 6.1,13.9C 6 H 5 -C H ₂ CH), 2.79 (1H, dd, J = 6.1,13.9C ₆ H ₅ -C H ₂ CH) (hydrochloride) Property: colorless needle crystal Melting point: 176-177 ℃ Elemental analysis value: C ₁₉ H Theoretical value (%) as ₃₁ N HCl: C73.63 H10.41 N4.52 Actual value (%): C73.56 H10.68 N4.47 Optical rotation: [α] _D + 20.6 ° (c = 0.56, water) ) (R) -N-Cyclopropylmethyl-N-methyl-1-
Cyclohexyl-2-phenylethylamine (Example 12
Compound) Typical Properties: colorless oil MS m / e: CI272 (M · H +) EI180 (base peak, M + -CH 2 C 6 H 5) 1 H-NMR δ: 2.24 (1H, dd, J = 6.4 _{, 12.7N-C H 2 -CH)} , 2.32 (1H, dd, J = 6.3,12.7N-C H 2 -CH), 2.34 (3H, s, N-C H 3), 2.59 (1H, dd, J = 6.1,13.4C ₆ H ₅ −C H ₂ CH), 2.66 (1H, q, J = 6.1, N−C H −C ₆ H), 2.77 (1H, dd, J6.1,13.4C ₆ H _5- C H ₂ -CH) (hydrochloride) Properties: colorless needle crystals (benzene) Melting point: 165-167 ° C Elemental analysis: C ₁₉ H ₂₉ Theoretical value as N HCl (%): C74.12 H9. 82 N4.55 Actual value (%): C74.35 H10.08 N4.54 Optical rotation: [α] + 13.2 ° (c = 0.79, water) Reference Example 6 (S) -1-cyclohexyl-2-phenyl Ethylamine (1S, 1'S) -N- (2'-hydroxy-1'-phenylethyl) -1-cyclohexyl-obtained in Reference Example 3
The reaction was performed in the same manner as in Reference Example 5 except that 2-phenylethylamine was used to obtain (S) -1-cyclohexyl-2-phenylethylamine and its hydrochloride. The physical properties thereof were the same as those described in Reference Example 5 except for the following.

(Hydrochloride) Optical rotation: [α] _D −27.9 ° (c = 0.50, water) Example 13 (S) -N-methyl-1-cyclohexyl-2-phenylethylamine Obtained in Reference Example 4 (1S, 1'S) -N-methyl-N-
(S'-N-methyl-1-cyclohexyl-) was reacted in the same manner as in Example 2 except that (2'-hydroxy-1'-phenylethyl) -1-cyclohexylamine was used.
2-Phenylethylamine and its hydrochloride salt were obtained. Their physical properties were similar to those described in Example 2 except for the following.

(Hydrochloride) Optical rotation: [α] _D -13.8 ° (c = 0.61, water) Examples 14 to 17 In Examples 2 to 12, the starting compound is the R-configuration isomer, and Reference Example 6 to A series of compounds could be obtained by reacting in the same manner as in Examples 2 to 12 except that the S-configuration isomer obtained in Example 13 was replaced. The obtained compound and its physical properties are shown below. In addition, the physical property values other than those described below correspond to the corresponding R values described in Examples 2 to 12.
-Similar to that of the configurational isomer.

(S) -N-Propyl-1-cyclohexyl-2-phenylethylamine (Compound of Example 14) (hydrochloride) Optical rotation: [α] _D -19.5 ° (c = 0.52, water) (S) -N-isopropyl -1-cyclohexyl-2-
Phenylethylamine (Compound of Example 17) (Hydrochloride) Optical rotation: [α] _D- 17.2 ° (c = 0.73, water) (S) -N-Cyclopropylmethyl-1-cyclohexyl-2-phenylethylamine (Example) 16 compound) (hydrochloride) Optical rotation: [α] _D −22.9 ° (c = 0.53, water) (S) -N-cyclopropylmethyl-N-methyl-1-
Cyclohexyl-2-phenylethylamine (Example 17
Compound) (Hydrochloride) Optical rotation: [α] _D -12.5 ° (c = 0.65, water) Next, the pharmacological activity and toxicity test of the 2-phenylethylamine derivative of the present invention will be described.

Pharmacological Test Example 1 (Analgesic Activity Test by Acetic Acid Rising Method) Eight male ddY mice were used as a group for the experiment.
The acetic acid rising method was adopted as the analgesic activity test method. That is, the test compounds shown in Table 1 were subcutaneously administered, and
After 20 minutes, 0.7% acetic acid aqueous solution was intraperitoneally administered at a rate of 0.1 ml / 10 g body weight. A 50% inhibitory dose (ID ₅₀
The value (mg / kg)) was calculated. As a comparative example, the same operation was performed using pentazocine. The obtained results are shown in Table 1.

As is clear from the results shown in Table 1, the 2-
Phenylethylamines have potent analgesic activity comparable or superior to pentazocine.

Pharmacological Test Example 2 (Naloxone Antagonism in Analgesic Activity Expression) The same method as in the above Pharmacological Test 1 except that naloxone 5 mg / kg body weight was subcutaneously administered 15 minutes after subcutaneous administration of the test compound in the method of the aforementioned Pharmacological Test 1. According to the experiment, the suppression rate of writhing at a specific dose was examined. Naloxone antagonism is evaluated by observing the change in the rate of inhibition of writhing with and without naloxone. Morphine was used as a comparative example.

The obtained results are shown in Table 2.

As is clear from the results shown in Table 2, the 2-phenylethylamine derivative of the present invention is not significantly or almost not antagonized by naloxone.

Example of toxicity test (acute toxicity test) Using 5 to 6 ddY male mice as one group,
The test compound was intraperitoneally administered to the cells, and the test was conducted according to the method of examining the number of deaths 8 days later. Table 3 shows the LD ₅ values of each test compound obtained from the test results.

Next, formulation examples of the analgesic of the present invention will be given. However, in the following formulation examples, the bulk powder is (S) -N-propyl-
1-Cyclohexyl-2-phenylethylamine hydrochloride was used. In addition, other compounds can be similarly prepared.

Formulation Example 1 (Injection: 10 mg / ampoule = 10mg / 2ml = 0.5% Formulation) (component) (usage) bulk powder _{0.5g Na 2 HPO 4 · 12H 2} O 2.28g NaH 2 PO 4 0.51g chlorobutanol 0.1g Sterilized purified water Total amount that can be 100 ml (Preparation method) Add 0.1 g of chlorobutanol to reduced sterilized purified water (about 80 ml) equivalent to 80% of the total amount heated to about 60 ° C, and mix appropriately. Then it was dissolved. Next, cool it with water to bring the solution temperature to about 40
After lowering to ℃, add 0.51 g of sodium phosphate and 2.28 g of disodium phosphate dodecahydrate to dissolve,
0.5 g was added and dissolved. The temperature was further lowered to room temperature, and purified water was added so that the total amount was 10 ml. Add this preparation to 0.
The cells were sterilized and filtered with a membrane filter having a pore size of 45 μm. Separately, 2 ml of a glass ampoule for injection which had been washed with water and sterilized by heating at 180 ° C. for 1 hour at high temperature was filled with the sterilized filter-prepared solution, and then sealed. This ampoule was subjected to high-pressure sterilization treatment at 115 ° C for 10 minutes to give an isotonic injection solution having a pH of 6.8.

Formulation Example 2 (tablets) (ingredient) (blending amount per tablet) Bulk powder 20 mg Aerosil # 200 0.02 mg Lactose 78.68 mg Avicel 30 mg Magnesium stearate 1.3 mg Total 130 mg Aerosil # 200 and bulk powder are mixed and ground. , Then lactose,
Avicel and magnesium stearate were added and mixed thoroughly. This mixture was tabletted with a 7 mmφ rod.

Formulation example 3 (capsule) (ingredient) (blending amount in 1 capsule) Bulk powder 20 mg Lactose 77 mg Avicel 52 mg Magnesium stearate 1 mg Total amount 150 mg Lactose and bulk powder are mixed and ground, and then Avicel and magnesium stearate are mixed. In addition, mixed well. 150 mg of this mixture was filled into size 4 hard capsules.

Formulation Example 4 (Granule) (Ingredient) (Blending amount) Bulk powder 40 mg Lactose 630 mg HPC-L 20 mg Avicel 300 mg Magnesium stearate 10 mg Total amount 1000 mg Part of lactose (for example, 200 mg in total amount used 630 mg), bulk powder and HPC-L (hydroxypropyl cellulose of Nippon Soda Co., Ltd., L type) was mixed and pulverized, and then the remaining amounts of lactose, Avicel and magnesium stearate were added and thoroughly mixed. Next, this mixture was made into a core by a known slug machine, then crushed, and further sized into predetermined particles (20 to 45 mesh).

Formulation Example 5 (Suppository) (Ingredient) (Amount to be mixed in one bottle) Bulk powder 20 mg Witepsol H-15 1264 mg Witepsol E-85 316 mg Total amount 1600 mg Witepsol H-15 and E-85 are melted at about 60 ° C. Then, the bulk powder was added thereto, and then uniformly dispersed by a homomixer. This solution was poured into a suppository type plastic container (1.9 ml hole), then cooled and solidified to obtain a suppository.

〔The invention's effect〕

The 2-phenylethylamine derivative (I) of the present invention has an excellent analgesic action, and its optical purity is
Since it is an optical isomer close to 100%, it can be used as an excellent analgesic because its pharmacological action is enhanced and side effects are reduced as compared with the generally used racemate.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07C 209/62 // B01J 23/44 C07B 61/00 300

Claims (7)

[Claims] 1. General formula (I): In (wherein, R ₁ represents a hydrogen atom or a methyl group, R ₂ represents an alkyl group or a cyclopropylmethyl group of C ₁ ~ _4, the absolute configuration of 1-position is one of a R or S configuration) The optically active 2-phenylethylamine derivative or its acid addition salt shown. 2. In the general formula (I), the absolute configuration at the 1-position is R.
The optically active 2-coupling according to claim 1, which is an arrangement.
Phenylethylamine derivatives or acid addition salts thereof. 3. In the general formula (I), the absolute configuration at the 1-position is S
The optically active 2-coupling according to claim 1, which is an arrangement.
Phenylethylamine derivatives or acid addition salts thereof. 4. General formula (II): (Wherein R ₁ represents a hydrogen atom or a methyl group, and the absolute configuration at the 1-position and the 1'-position is either the R configuration or the S configuration), and an optically active 2-phenylethylamine compound represented by the following formula: It is hydrolyzed in the presence of a catalyst to give a compound of the general formula (I-
i): (Wherein R ₁ has the same meaning as described above, and the absolute configuration at the 1-position has either the R configuration or the S configuration), and is further optionally obtained by obtaining the 2-phenylethylamine derivative. In the case where a) R ₁ is a hydrogen atom, the following formula (III): R ₃ CHO (III) (wherein R ₃ is a hydrogen atom or C ₁ ~ ₃ represents an alkyl group), and then the reduction reaction is carried out in the presence of a catalyst, or b) when R ₁ is a methyl group, the compound represented by the general formula (IV): R ₂ ' X (IV) (wherein, R ₂ 'represents an alkyl group or a cyclopropylmethyl group of C ₁ ~ _4, X represents a halogen atom) general formula by reacting with an alkyl halide compound represented by (I-ii ): (In the formula, R ₁ and R ₂ ′ represent the same as above,
A compound of formula (I), wherein the absolute configuration of the position is either the R configuration or the S configuration). In (wherein, R ₁ represents a hydrogen atom or a methyl group, R ₂ represents an alkyl group or a cyclopropylmethyl group of C ₁ ~ _4, the absolute configuration of 1-position is one of a R or S configuration) A method for producing the indicated optically active 2-phenylethylamine derivative or an acid addition salt thereof. 5. General formula (I): In (wherein, R ₁ represents a hydrogen atom or a methyl group, R ₂ represents an alkyl group or a cyclopropylmethyl group of C ₁ ~ _4, the absolute configuration of 1-position is one of a R or S configuration) An analgesic containing the optically active 2-phenylethylamine derivative or its acid addition salt shown as an active ingredient. 6. The analgesic according to claim 5, which comprises, as an active ingredient, a 2-phenylethylamine derivative whose absolute configuration at the 1-position is R configuration in the general formula (I) or an acid addition salt thereof. 7. The analgesic according to claim 5, which comprises a 2-phenylethylamine derivative or an acid addition salt thereof having the S-configuration as the absolute configuration at the 1-position in the general formula (I).