JPH085866B2 - Novel aconitine compounds and analgesic / anti-inflammatory agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel aconitine compound and an analgesic / anti-inflammatory agent.

More specifically, the invention has the general formula (In the formula, R ₁ represents benzoyl or anisoyl, R ₂ represents methyl or ethyl, R ₃ represents a hydroxyl group, acetyloxy or hydrogen, R ₄ represents a lower alkyl group or hydrogen, provided that R ₁ is benzoyl and R ₂ is ethyl. , R ₃ is acetyloxy, R ₄ is not ethyl R ₁ is benzoyl, R ₂ is methyl and R ₃ is a hydroxyl group R ₄ is not methyl, ethyl or hydrogen R ₁ is anisoyl , R ₂ is ethyl and R ₃ is a hydroxyl group,
R ₄ is not methyl, ethyl or hydrogen. R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is methyl and R ₃ is hydrogen.
R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is ethyl and R ₃ is a hydroxyl group. ) A novel aconitine compound represented by (In the formula, R ₁ represents benzoyl or anisoyl, R ₂ represents methyl or ethyl, R ₃ represents a hydroxyl group, acetyloxy or hydrogen, R ₄ represents a lower alkyl group or hydrogen, provided that R ₁ is benzoyl and R ₂ is methyl. Or ethyl, R ₄ when R ₃ is a hydroxyl group
Is not hydrogen. R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is methyl and R ₃ is hydrogen. R ₁ is Anisoyl, R ₂
Is ethyl and R ₃ is a hydroxyl group, R ₄ is not hydrogen. ) The present invention relates to an analgesic / anti-inflammatory agent containing a compound represented by

[Prior art]

It has already been reported that the aconitine-based alkaloid substances contained in tuberous roots of aconite plants have strong analgesic and anti-inflammatory effects. However, aconitine alkaloids are highly toxic, and therefore, the safety margin is said to be narrow.

[Disclosure of Invention]

The present inventor has conducted various studies to obtain a novel aconitine alkaloid derivative having an analgesic / anti-inflammatory action possessed by an aconitine alkaloid substance and having low toxicity. As a result, according to the present invention, the above general formula (II) We have succeeded in providing a compound represented by. It has been found that the substance according to the present invention has a strong analgesic / anti-inflammatory activity and is less toxic than maternal mesaconitine, aconitine, hipaconitine and jesaconitine.

The present invention is based on such findings. Therefore, the present invention provides a novel compound represented by the general formula (I) and an analgesic / anti-inflammatory agent containing the compound represented by the general formula (II).

The compound represented by the above formula (II) according to the present invention includes a mesaconitine represented by the following formula (III), an aconitine represented by the following formula (IV) or a gesaconitine represented by the following formula (V). The 3-position hydroxyl group is acetylated by a conventional method, and the 8-position acetyloxy group of the hypaconitine represented by the following formulas (III), (IV), (V) and (VI) is substituted with a lower alkoxy group, or It can be produced by hydrolysis.

In the above-mentioned acetylation, a chemical means usually adopted for converting a hydroxyl group usually present in a chemical structure into an acetyloxy group (acetic ester) can be optionally used. For example, the above-mentioned acetylation can be carried out by selecting and using an appropriate solvent and reacting the above-mentioned mesaconitine, aconitine or jesaconitine with an acetylating agent such as acetic anhydride. Further, the substitution of the acetyloxy group at the 8-position with the lower alkoxy group is carried out by using the corresponding lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-
Butanol and amyl alcohol can be used as a solvent.

The production examples of the compound according to the present invention are listed below.
The physical properties of the compounds obtained in each example, analytical data, pharmacological action, toxicity, etc. will be given later.

In addition, the silica gel column chromatography described in the production examples is based on Merck. Art 7734 Kieselgel 60 (70
~ 230 mesh).

[Example 1] 180 mg of aconitine is dissolved in 30 ml of methanol and stirred at an oil bath temperature of 60 to 70 ° C for 30 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified with 8-O-methyl-14-benzoylaconine 127.6 mg.
(Yield 72%) is obtained.

[Example 2] Aconitine (103 mg) was dissolved in ethanol (10 ml), and the mixture was stirred at an oil bath temperature of 70 to 80 ° C for 64 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified to give 8-O-methyl-14-benzoylaconine 71.6 mg (yield 71% ) Get.

Example 3 To 331 mg of aconitine, 8 ml of pyridine and 30 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 50 ml of chloroform, and the chloroform layer was mixed with 5 ml.
% NaHCO ₃ aqueous solution and then washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 300.9 mg of 3-O-acetylaconitine (yield 8
5.3%). 100.5 mg of 3-O-acetylaconitine is dissolved in 10 ml of methanol and stirred at an oil bath temperature of 70-80 ° C for 87 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified to 3-O-acetyl-8-.
75 mg of O-methyl-14-benzoyl aconine (yield 73%)
To get

Example 4 The procedure of Example 3 was repeated except that ethanol (10 ml) was used instead of methanol (10 ml) used in Example 3, and 3-O-acetyl-8-O-ethyl-14- was used. 71 mg (72% yield) of benzoyl aconine are obtained.

Example 5 8 ml of pyridine and 30 ml of acetic anhydride were added to 331 mg of aconitine, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform, the chloroform layer is washed with a 5% NaHCO ₃ aqueous solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 300.9 mg of 3-O-acetylaconitine (yield 85.3%). 3-O-acetylaconitine 100mg
Is heated to reflux in 10 ml of a dioxane-water (1: 1) mixture for 4 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. The obtained residue is separated and purified by column chromatography or thin layer chromatography (solvent: ammonia water saturated ether).
78 mg of -O-acetyl-14-benzoylaconine (yield 83
%).

[Example 6] 300 mg of mesaconitine is dissolved in 180 ml of methanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C for 168 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (solvent: ammonia water saturated ether),
Purified 8-O-methyl-14-benzoyl mesaconine 280 m
g (yield 97.6%) is obtained.

Example 7 300 mg of mesaconitine is dissolved in 180 ml of ethanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C. for 240 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (solvent: ammonia water saturated ether),
Purified 8-O-methyl-14-benzoyl mesaconine 285m
g (97% yield) are obtained.

Example 8 To 408 mg of mesaconitine was added 8 ml of pyridine and 30 ml of acetic anhydride, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure,
The residue is dissolved in 50 ml of chloroform, and the chloroform layer is washed with a 5% aqueous NaHCO ₃ solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 400.6 mg of 3-O-acetyl mesaconitine (yield 9
5%) 3-O-acetyl mesaconitine 131.0 mg in methanol 1
Dissolve in 0 ml and stir at an oil bath temperature of 70-80 ° C for 39 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified with 3-O-acetyl-8-O-methyl-14.
87.9 mg (70% yield) of benzoyl mesaconine are obtained.

[Example 9] 8 ml of pyridine and 30 ml of acetic anhydride were added to 408 mg of mesaconitine, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure,
The residue is dissolved in 50 ml of chloroform, and the chloroform layer is washed with a 5% aqueous NaHCO ₃ solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 400.6 mg of 3-O-acetyl mesaconitine (yield 9
Five%). 3-O-Acetylmethaconitine 136.0 mg in ethanol
Dissolve in 10 ml and stir at an oil bath temperature of 70-80 ° C for 87 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified to 3-O-acetyl-8-O-ethyl-14.
-Getting 98.2 mg of benzoyl mesaconine (74% yield).

[Example 10] To 408 mg of mesaconitine, 8 ml of pyridine and 30 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure,
The residue is dissolved in 50 ml of chloroform, and the chloroform layer is washed with a 5% aqueous NaHCO ₃ solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 400.6 mg of 3-O-acetyl mesaconitine (yield 9
Five%). 100 mg of 3-O-acetyl mesaconitine is heated under reflux for 4 hours in 10 ml of a dioxane-water (1: 1) mixture. After completion of the reaction, the solvent is distilled off under reduced pressure. The obtained residue is separated and purified by column chromatography or thin layer chromatography (solvent: ammonia water saturated ether) to obtain 3-O-acetyl-14-benzoylmesaconine 77.8 mg (yield 83%).

[Example 11] 100 mg of gesaconitine is dissolved in 30 ml of methanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C for 72 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (solvent: ammonia water saturated ether),
Purified 8-O-methyl-14-anisoylaconine 84.5 mg
(Yield 81%) is obtained.

[Example 12] 100 mg of gesaconitine is dissolved in 30 ml of ethanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C for 120 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to give 8-O-ethyl-14-anisoylaconine 7
3.5 mg (72% yield) are obtained.

Example 13 To 404 mg of jesaconitine, 8 ml of pyridine and 30 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform, the chloroform layer is washed with a 5% NaHCO ₃ aqueous solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: saturated aqueous ammonia) to obtain 411.7 mg of 3-O-acetylgesaconitine (yield 95.8%).

103.1 mg of 3-O-acetylgesaconitine is dissolved in 10 ml of methanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C. for 44 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified to 3-O-acetyl-8-O-.
72.3 mg (73% yield) of methyl-14-anisoylaconine are obtained.

[Example 14] To 404 mg of jesaconitine, 8 ml of pyridine and 30 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform, the chloroform layer is washed with a 5% NaHCO ₃ aqueous solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: saturated aqueous ammonia) to obtain 411.7 mg of 3-O-acetylgesaconitine (yield 95.8%). 3-O-acetyl gesaconitine 114.9m
g is dissolved in 10 ml of ethanol and stirred at an oil bath temperature of 60 to 70 ° C for 114 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified to give 3-O-acetyl-8-O-ethyl-14-anisoylaconine. 80.5 mg
(Yield 72%) is obtained.

Example 15 To 404 mg of jesaconitine, 8 ml of pyridine and 30 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform, the chloroform layer is washed with a 5% NaHCO ₃ aqueous solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: saturated aqueous ammonia) to obtain 411.7 mg of 3-O-acetylgesaconitine (yield 95.8%). 3-O-acetyl gesaconitine 100mg
Is heated to reflux in 10 ml of a dioxane-water (1: 1) mixture for 4 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. The obtained residue is separated and purified by column chromatography or thin layer chromatography (solvent: ammonia water saturated ether).
-O-acetyl-14-anisoylachonin 79.9 mg (yield
85%).

[Example 16] 55 mg of hypaconitine is dissolved in 5 ml of methanol, and the mixture is stirred at an oil bath temperature of 60 to 70 ° C for 72 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: saturated aqueous ammonia: ether: hexane = 4:
Separation and purification in 1) yielded 35.8 mg (yield 75%) of 8-O-methyl-14-benzoylhypaconine.

[Example 17] Hypaconitine (55 mg) is dissolved in ethanol (10 ml), and the mixture is stirred at an oil bath temperature of 70 to 80 ° C for 72 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: saturated aqueous ammonia: ether: hexane = 4:
Separation and purification in 1) yielded 35.2 mg (68% yield) of 8-O-ethyl-14-benzoylhypaconine.

Example 18 100 mg of aconitine was dissolved in 30 ml of amyl alcohol,
Stir at an oil bath temperature of 60-70 ° C for 240 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to give 8-O-ethyl-14-benzoylaconine 7
4.3 mg (71% yield) are obtained.

Example 19 To 331 mg of aconitine, 8 ml of pyridine and 30 ml of acetic anhydride are added, and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 50 ml of chloroform, and the chloroform layer was mixed with 5 ml.
% NaHCO ₃ aqueous solution and then washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) to obtain 300.9 mg of 3-O-acetylaconitine (yield 8
5.3%). 100 mg of 3-O-acetylaconitine is dissolved in 10 ml of amyl alcohol and stirred at an oil bath temperature of 70-80 ° C for 240 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ammonia water saturated ether) and purified with 3-O-acetyl-.
8-O-amyl-14-benzoyl aconine 78.3 mg (yield
74%).

Example 20 Mesaconitine (100 mg) was used in place of the aconitine (100 mg) used in Example 18, and the same operation as in Example 18 was carried out otherwise except that 76.2 mg of 8-O-amyl-14-benzoylmethaconine ( Yield 73%).

Example 21 Mesaconitine (408 mg) was used in place of aconitine (331 mg) used in Example 19, and the same procedure as in Example 19 was repeated except that 3-O-acetyl-8-O-amyl-
75.0 mg (yield 72%) of 14-benzoyl mesaconine is obtained.

[Example 22] Jesaconitine (100 mg) was used in place of the aconitine (100 mg) used in Example 18, and the other examples were used.
The same procedure as described in (8) -O-amyl-14-anisoylaconine (78.3 mg, yield 75%) was obtained.

[Example 23] In place of aconitine (331 mg) used in Example 19, gesaconitine (404 mg) was used.
The same procedure as described above was performed to obtain 74.0 mg (yield 71%) of 3-O-acetyl-8-O-amyl-14-anisoylaconine.

[Example 24] The same procedure as in Example 18 was carried out except that hypaconitine (100 mg) was used instead of aconitine (100 mg) used in Example 18, and 8-O-amyl-14-benzoylhypaconine 73.2 mg was used. (Yield 70%) is obtained.

[Example 25] 100 ml of methanol is added to 5 g of raw adzuki bean and heated under reflux for about 100 hours. Then, this extract is filtered, and the filtrate is distilled off under reduced pressure. The residue obtained is dissolved in 50 ml of 5% aqueous hydrochloric acid and distributed with 80 ml of hexane. Then, 10% aqueous ammonia is added to this 5% aqueous hydrochloric acid solution until the pH reaches about 9, and the aqueous layer is extracted three times with 100 ml of chloroform.

The chloroform layer was dried over Glauber's salt and evaporated under reduced pressure to give about 80
mg residue is obtained. 10 ml of this residue was added to acetonitrile.
To prepare a sample solution. For 10 μl of this sample solution, by high performance liquid chromatography (HPLC) under the following conditions,
Analyzes O-methyl-14-benzoylaconine, 8-O-methyl-14-benzoylmethaconine, 8-O-methyl-14-anisoylaconine, and 8-O-methyl-14-benzoylhypaconine And can be sorted.

(HPLC analysis conditions) Mobile phase: 0.05 M phosphate buffer (pH 2.5): Tetrahydrofuran: Acetonitrile = 80: 14: 6 Flow rate: 1.0 ml / min Detection wavelength: 247 nm Column: Chemcosorb ODS-H (4.6φ x 150 mm (HPLC preparative conditions) Mobile phase: Methanol: Water: Chloroform: Triethylamine = 80: 20: 2: 0.1 Flow rate: 10 ml / min Detection wavelength: 247 nm Column: Inertocyl ODS (22.5φ x 250 mm) [Example 26] Implementation Example 8 was repeated except that ethanol (100 ml) was used in place of methanol (100 ml) used in Example 25, and 8-O-ethyl-14-benzoylaconine and 8-O-ethyl-14-benzoyl were used. Mesaconine, 8-
O-ethyl-14-anisoylaconine and 8-O-ethyl-14-benzoylhypaconine can be analyzed and fractionated.

(1) Physical properties and analytical data of 8-O-methyl-14-benzoylaconine 1) Properties and solubility Colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, Soluble in dimethyl sulfoxide, insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3420,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.43 (5H, multiple line) (H of benzoyl group) 4.86 (1H, double line, J = 4.95Hz) (14th H) 4.60 (1H, double line, J = 5.60Hz) (15th place) H) 4.07 (1H, double line, J = 6.27Hz) (6th H) 1.16 (3 H, triplet, J = 6.93 Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

166.2 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.0,129.6,128.3 (C of benzoyl group) 93.2,83.0,82.4,82.1,79.2,77.2,74.6,71.3 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.7 (C of methoxy group bonded to 16,18,6,1) 49.9 (C of methoxy group bonded to 8 position) 49.0 (C of methylene group of N-ethyl group) 13.0 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 617 (M ⁺ ) (2) 8-O-ethyl-14- Physical Properties and Analytical Data of Benzoylaconine 1) Properties and Solubility A colorless amorphous powder, soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and soluble in hexane and water. It is insoluble.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3400,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.41 (5H, multiple line) (H of benzoyl group) 4.83 (1H, double line, J = 4.95Hz) (H in 14th position) 4.56 (1H, double line, J = 5.93Hz) (15th position) H) 4.09 (1H, double wire, J = 6.59Hz) (H in 6th place) 1.13 (3H, triplet, J = 7.26Hz) (H of N-ethyl group methyl group) 0.59 (3H, triplet, J = 6.29Hz) (H of methyl group of ethoxy group bonded to 8-position) 5 ) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.2,129.6,128.3 (C of benzoyl group) 93.2,83.3,82.3,82.2,79.4,76.8,74.7,71.5 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.7 (C of methoxy group bonded to 16,18,6,1 position) 57.2 (Ethoxy group methylene bonded to 8 position) Group C) 48.9 (C of methylene group of N-ethyl group) 15.3 (C of methyl group of ethoxy group bonded to 8-position) 13.1 (C of methyl group of N-ethyl group) 6) EI-mass spectrometry m / z 631 (M ⁺ ) (3) Physical property values and analytical data of 3-O-acetyl-8-O-methyl-14-benzoylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform , Soluble in benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3400,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.42 (5H, multiplet) (H of benzoyl group) 5.00 (1H, multiplet) (H of 3rd position) 4.84 (1H, doublet, J = 4.95Hz) (H of 14th position) 4.57 (1H , Double wire, J = 5.60Hz) (H in 15th place) 4.07 (1H, double wire, J = 6.27Hz) (H in 6th place) 2.08 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 1.16 (3H, triplet, J = 6.93Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic Resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

170.0 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.7, 130.1, 129.6, 128.3 (C of benzoyl group) 93.2, 83.0, 82.3, 81.9, 79.2,78.3,77.0,74.1,71.7 (1
6,6,1,8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.7 (C of methoxy group bonded to 16,18,6,1 position) 49.8 (8 position C) of bonded methoxy group 49.0 (C of methylene group of N-ethyl group) 21.2 (C of methyl group of acetyl group bonded to 3-position) 13.2 (C of methyl group of N-ethyl group) 6) EI- Mass spectrum analysis m / z 659 (M ⁺ ) (4) Physical properties and analytical data of 3-O-acetyl-8-O-ethyl-14-benzoylaconine 1) Properties and solubility In colorless amorphous powder It is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum analysis (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

8.06-7.41 (5H, multiplex) (benzoyl group H) 4.97 (1H, multiplex) (3rd position H) 4.82 (1H, double line, J = 4.95Hz) (14th position H) 4.53 (1H , Double wire, J = 5.94Hz) (15th place H) 4.18 (1H, double wire, J = 6.59Hz) (6th place H) 2.07 (3H, singlet) (H of the methyl group of the acetyl group bonded to the 3-position) 1.11 (3H, triplet, J = 7.09Hz) (H of the methyl group of the N-ethyl group) 0.58 (3H, triplet , J = 6.76 Hz) (H of the methyl group of the ethoxy group bonded to the 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.7, 130.3, 129.6, 128.2 (C of benzoyl group) 93.6, 83.4, 82.3, 82.0, 79.5,78.5,77.0,74.8,71.5 (1
6,6,1,8,14,15,18,13,3 position C) 62.3,60.9,58.7,56.4 (C of methoxy group bonded to 16,18,6,1 position) 57.1 (8 position C. of the methylene group of the bound ethoxy group) 49.1 (C of the methylene group of the N-ethyl group) 21.2 (C of the methyl group of the acetyl group bound to the 3-position) 15.3 (of C) 13.5 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 673 (M ⁺ ) (5) Physical property value and analytical data of 3-O-acetyl-14-benzoylaconine 1 ) Properties and solubility It is a colorless amorphous powder which is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum analysis (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

8.06-7.41 (5H, multiple line) (H of benzoyl group) 4.98 (1H, multiple line) (H of 3rd position) 4.80 (1H, double line, J = 4.95Hz) (H of 14th position) 4.53 (1H , Double wire, J = 5.94Hz) (15th place H) 4.18 (1H, double wire, J = 6.59Hz) (6th place H) 2.07 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 1.11 (3H, triplet, J = 7.09Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic Resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.7, 130.3, 129.6, 128.2 (C of benzoyl group) 90.7, 83.5, 82.4, 81.3, 79.5,78.5,77.3,74.8,71.5 (1
6,6,1,15,14,8,18,13,3 position C) 62.0,59.9,58.7,56.2 (C of methoxy group bonded to 16,18,6,1) 49.1 (N-ethyl group Of the methylene group of 2) (C of the methyl group of the acetyl group bonded to the 3-position) 13.5 (C of the methyl group of the N-ethyl group) 6) EI-mass spectrum analysis m / z 645 (M ⁺ ) (6 ) Physical properties and analytical data of 8-O-methyl-14-benzoylmesaconine 1) Properties and solubility Colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide. Soluble in water and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.10-7.45 (5H, multiple line) (H of benzoyl group) 4.48 (1H, double line, J = 4.50Hz) (H at 14th position) 4.06 (1H, double line, J = 6.27Hz) (6th position) H) 2.37 (3H, singlet) (H of N-methyl group) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

166.2 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.1,129.6,128.3 (C of benzoyl group) 93.4,83.1,82.6,82.1,79.4,77.5,74.3,71.4 (16,6,1,
8,14,15,18,13,3-position C) 62.3,59.1,58.5,56.3 (C of methoxy group bonded to 16,18,6,1) 49.7 (C of methoxy group bonded to 8-position) 42.4 (C of N-methyl group) 6) EI-mass spectrum analysis m / z 603 (M ⁺ ) 7) Elemental analysis calculated value C, 53.22; H, 6.70; N, 1.94 (C ₃₂ H ₄₅ NO ₁₀ · HClO _Four
・ H ₂ O) Actual value C, 53.54; H, 6.62; N, 1.64 (7) Physical property value and analytical data of 8-O-ethyl-14-benzoylmethaconine 1) Property and solubility Colorless non-crystalline powder It is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.08-7.27 (5H, multiple line) (H of benzoyl group) 4.81 (1H, double line, J = 4.70Hz) (H at 14th position) 4.54 (1H, double line, J = 6.10Hz) (15th position) H) 4.08 (1H, double wire, J = 7.60Hz) (6th H) 2.34 (3H, singlet) (H of N-methyl group) 0.57 (3H, triplet, J = 6.00Hz) (H of methyl group of ethoxy group bonded to 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum ( CDCl ₃ ) analysis shows the following signals (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14th position) 132.8, 130.3, 129.6, 128.3 (C of benzoyl group) 93.4, 83.3, 82.7, 82.0, 79.4, 78.3, 76.4, 74.7, 71.3 (1
6,6,1,8,14,15,18,13,3 position C) 62.4,59.1,58.6,56.3 (C of methoxy group bonded to 16,18,6,1) 57.1 (bonded to 8 position Methylene group C of the ethoxy group 42.5 (C of the N-methyl group) 15.3 (H of the methyl group of the ethoxy group bonded to the 8-position) 6) EI-mass spectrum analysis m / z 617 (M ⁺ ) 7) high resolution mass spectrum _{calcd: 617.320 (C 33 H 47 NO} 10) Found: 617.321 (8) 3-O- acetyl--8-O-ethyl-14-benzoyl Mesako Nin of physical properties and analytical data 1) properties And Solubility A colorless amorphous powder that is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3420,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.02-7.45 (5H, multiple line) (H of benzoyl group) 4.97 (1H, multiple line) (H of 3rd position) 4.85 (1H, double line, J = 4.28Hz) (H of 14th position) 4.56 (1H , Double wire, J = 5.90Hz) (15th H) 4.16 (1H, double wire, J = 5.93Hz) (6th H) 2.09 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.8, 130.2, 129.7, 128.3 (C of benzoyl group) 93.3, 83.0, 82.2, 81.9, 79.2,77.6,77.0,74.8,71.5 (1
6,6,1,8,14,15,18,13,3 position C) 62.2,58.8,56.6,50.1 (C of methoxy group bonded to 16,18,6,1) 49.8 (bonded to 8 position C of methoxy group 42.7 (C of N-methyl group) 21.2 (H of methyl group of acetyl group bonded to 3-position) 6) EI-mass spectrum analysis m / z 645 (M ⁺ ) (9) 3- Physical properties and analytical data of O-acetyl-8-O-ethyl-14-benzoylmesaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine , Soluble in dimethylsulfoxide, insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.41 (5H, multiplet) (H of benzoyl group) 4.96 (1H, multiplet) (H of 3rd position) 4.82 (1H, doublet, J = 4.95Hz) (H of 14th position) 4.54 (1H , Double wire, J = 5.94Hz) (15th H) 4.14 (1H, double wire, J = 6.92Hz) (6th H) 2.08 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 0.57 (3H, triplet, J = 6.92Hz) (H of methyl group of ethoxy group bonded to 8-position) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.8,129.6,128.2 (C of benzoyl group) 93.3,82.0,79.3,78.3,77.0, 74.6,71.4 (16,6,1,8,14,
15,18,13,3-position C) 62.1,58.8,56.6 (C of methoxy group bonded to 16,18,6,1) 57.1 (C of methylene group of ethoxy group bonded to 8-position) 42.6 (N -C of methyl group 21.2 (C of methyl group of acetyl group bonded to 3-position) 15.2 (H of methyl group of ethoxy group bonded to 8-position) 6) EI-mass spectrum analysis m / z 659 (M ⁺ ) (10) Physical properties and analytical data of 3-O-acetyl-14-benzoylmesaconine 1) Properties and solubility Colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine , Soluble in dimethylsulfoxide, insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3420,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.43 (5H, multiplet) (H of benzoyl group) 4.96 (1H, multiplet) (H of 3rd position) 4.86 (1H, doublet, J = 4.95Hz) (H of 14th position) 4.60 (1H , Double wire, J = 5.60Hz) (H in 15th place) 4.07 (1H, double wire, J = 6.27Hz) (H in 6th place) 2.09 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (carbonyl group C of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.8,130.0,129.6,128.3 (C of benzoyl group) 91.0,83.0,82.4,82.5,79.3 , 77.2,74.6,71.3 (16,6,1,
15,14,8,18,13,3 position C) 62.3,59.0,58.5,55.7 (C of methoxy group bonded to 16,18,6,1) 42.7 (C of N-methyl group) 21.3 (3 H) of the methyl group of the acetyl group bonded to position 6) EI-mass spectrometric analysis m / z 631 (M ⁺ ) (11) Physical properties and analytical data of 8-O-methyl-14-anisoylaconine 1) Properties and solubility A colorless, amorphous powder that is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, and dimethyl sulfoxide, but insoluble in hexane and water.

2) [α] ▲ ²⁴ _D ▼ = + 7.5 ° (c = 0.93, ethanol) 3) Infrared absorption spectrum (KBr) analysis 3450,1720 cm ^-1 shows the maximum absorption.

4) Ultraviolet absorption spectrum (ethanol) analysis 5) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

4.55 (1H, double line, J = 6.00Hz) (H at 14th position) 3.87 (3H, single line) (H at methoxy group of anisoyl group) 1.13 (3 H, triplet, J = 7.26 Hz) (H of methyl group of N-ethyl group) 6) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

165.7 (C of carbonyl group derived from 14th anisoyl group) 163.2,131.6,122.4,113.5 (C of anisoyl group) 93.3,83.1,82.2,82.2,79.4,76.9,74.7,71.5 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.4,55.6 (C of methoxy group bonded to 16,18,6,1) 55.3 (C of methoxy group of anisoyl group) 49.8 ( C of methoxy group bonded to 8-position 48.8 (C of methylene group of N-ethyl group) 13.0 (C of methyl group of N-ethyl group) 7) EI-mass spectrum analysis m / z 647 (M ⁺ ) 8 ) High resolution mass spectrum analysis Calculated value: 647.330 (C ₃₄ H ₄₉ NO ₁₁ ) Actual value: 647.328 (12) Physical properties and analytical data of 8-O-ethyl-14-anisoylaconine 1) Property and solubility Colorless It is a non-crystalline powder, soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water.

2) [α] ²⁴ _D ▼ = + 5.8 ° (c = 1.80, ethanol) 3) Infrared absorption spectrum (KBr) analysis 3450,1720 cm ⁻¹ shows the maximum absorption.

4) Ultraviolet absorption spectrum (ethanol) analysis 5) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

4.60 (1H, doublet, J = 6.00Hz) (H at 14th position) 3.88 (3H, singlet) (H of methoxy group of anisoyl group) 1.11 (3H, triplet, J = 7.00Hz) (H of methyl group of N-ethyl group) 0.64 (3H, triplet, J = 6.00Hz) (H of methyl group of ethoxy group bonded to 8-position) 6 ) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

165.8 (C of carbonyl group derived from 14th anisoyl group) 163.1,131.6,122.7,113.6 (C of anisoyl group) 93.3,83.4,82.5,82.1,79.2,77.3,74.2,71.6 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.8 (C of the methoxy group bonded to 16,18,6,1) 55.3 (C of the methoxy group of anisoyl group) 57.1 ( Methylene group of the ethoxy group bonded to the 8-position C) 48.8 (C of the methylene group of the N-ethyl group) 15.3 (Methyl group of the ethoxy group bonded to the 8-position) 13.0 (Methyl group of the N-ethyl group) C) 7) EI- mass spectrometry ^{m / z 661 (M +)} 8) high resolution mass spectrum _{calcd: 661.349 (C 35 H 51 NO} 11) Found: 661.346 (13) 3-O- acetyl -8 Physical properties and analytical data of -O-methyl-14-anisoylaconine 1) Properties and solubility Colorless amorphous powder in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide. Soluble and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

4.95 (1H, multiple line) (3rd H) 4.81 (1H, double line, J = 4.95Hz) (14th H) 4.53 (1H, double line, J = 5.94Hz) (15th H) ) 4.11 (1H, doublet, J = 6.60Hz) (H at 6th position) 3.86 (3H, singlet) (H of methoxy group of anisoyl group) 2.07 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 1.11 (3H, triplet, J = 7.26Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic Resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

170.3 (C of carbonyl group of acetyl group bonded to 3-position) 166.0 (C of carbonyl group derived from anisoyl group of 14-position) 163.2,131.8,122.8,113.6 (C of anisoyl group) 93.6,83.3,82.2,79.2, 77.8,77.0,74.9,71.3 (16,6,1,
8,14,15,18,13,3 position C) 62.4,58.8,55.4 (C of methoxy group bonded to 16,18,6,1) 55.4 (C of anisoyl group methoxy group) 49.8 (8 position C of methoxy group bound to 4) (C of methylene group of N-ethyl group) 21.3 (C of methyl group of acetyl group bound to 3-position) 13.5 (C of methyl group of N-ethyl group) 6) EI - mass spectrometry ^{m / z 689 (M +)} 7) high resolution mass spectrum _{calcd: 689.340 (C 36 H 51 NO} 12) Found: 689.339 (14) 3-O- acetyl--8-O-ethyl - Physical properties and analytical data of 14-anisoylaconine 1) Properties and solubility A colorless amorphous powder soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and hexane. , Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450, 1705 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

4.96 (1H, multiple line) (3rd H) 4.81 (1H, double line, J = 4.95Hz) (14th H) 4.53 (1H, double line, J = 5.94Hz) (15th H) ) 4.11 (1H, doublet, J = 6.60Hz) (H at 6th position) 3.86 (3H, singlet) (H of methoxy group of anisoyl group) 2.08 (3H, singlet) (H of the methyl group of the acetyl group bonded to the 3-position) 1.13 (3H, triplet, J = 7.26Hz) (H of the methyl group of the N-ethyl group) 0.64 (3H, triplet , J = 7.26 Hz) (H of the methyl group of the ethoxy group bonded to the 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.0 (C of carbonyl group derived from anisoyl group of 14-position) 163.2,131.7,122.8,113.6 (C of anisoyl group) 93.5,83.3,82.1,79.1, 78.3,77.0,74.8,71.7 (16,6,1,
8,14,15,18,13,3 position C) 62.2,58.7,55.4 (C of methoxy group bonded to 16,18,6,1) 56.4 (C of anisoyl group methoxy group) 57.1 (8 position Methylene group C of ethoxy group bound to 4) (Methylene group C of N-ethyl group) 21.2 (Acetyl methyl group C bound to 3-position) 15.4 (Ethoxy group methyl group bound to 8th position) C) 13.3 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 703 (M ⁺ ) 7) High resolution mass spectrum analysis Calculated value: 703.356 (C ₃₇ H ₅₃ NO ₁₂ ) Actual measurement Value: 703.359 (15) Physical properties and analytical data of 3-O-acetyl-14-anisoylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, acetone, acetic acid. Soluble in ethyl, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3420,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

4.97 (1H, double wire, J = 4.95Hz) (14th H) 4.55 (1H, double wire, J = 5.60Hz) (15th H) 4.07 (1H, double wire, J = 6.27Hz ) (H at 6th position) 3.85 (3H, singlet) (H at methoxy group of anisoyl group) 1.16 (3 H, triplet, J = 6.93 Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.3 (C of carbonyl group of acetyl group bonded to 3-position) 165.9 (C of carbonyl group derived from anisoyl group of 14-position) 163.5,131.8,122.1,113.6 (C of anisoyl group) 90.7,83.5,82.4,81.9, 79.5,78.6,77.3,78.8,71.3 (1
6,6,1,15,14,8,18,13,3 position C) 62.2,58.7,55.4 (C of methoxy group bonded to 16,18,6,1) 56.4 (of methoxy group of anisoyl group) C) 49.0 (C of methylene group of N-ethyl group) 21.1 (C of methyl group of acetyl group bonded to 3-position) 13.0 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 675 (M ⁺ ) (16) Physical properties and analytical data of 8-O-methyl-14-benzoylhypaconine 1) Properties and solubility Colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, Soluble in acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500,1710 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.10-7.45 (5H, multiple line) (H of benzoyl group) 4.70 (1H, double line, J = 4.50Hz) (H at 14th position) 4.54 (1H, double line, J = 5.93Hz) (15th position) H) 4.06 (1H, double wire, J = 6.70Hz) (6th H) 2.37 (3H, singlet) (H of N-methyl group) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

166.2 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.1,129.6,128.3 (C of benzoyl group) 93.4,83.1,82.6,82.1,79.4,77.5,74.3 (16,6,8,14,1
5,18,13 position C) 62.3,59.1,58.5,56.3 (C of methoxy group bonded to 16,18,6,1 position) 49.9 (C of methoxy group bonded to 8 position) 42.4 (N-methyl Group C) 6) EI-mass spectrum analysis m / z 587 (M ⁺ ) (17) 8-O-ethyl-14-benzoylhypaconine physical properties and analytical data 1) Properties and solubility Colorless non-crystalline It is a soluble powder, soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.07-7.26 (5H, multiple line) (H of benzoyl group) 4.82 (1H, double line, J = 4.50Hz) (14th H) 4.55 (1H, double line, J = 5.93Hz) (15th place) H) 4.08 (1H, double line, J = 6.70Hz) (6th H) 2.34 (3H, singlet) (H of N-methyl group) 0.58 (1H, triplet, J = 6.00Hz) (H of ethoxy group bonded to 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) Analysis The following signals are shown (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.3,129.6,128.3 (C of benzoyl group) 93.5,83.2,82.6,81.9,79.4,78.3,74.7 (16,6,8,14,1
5,18,13 position C) 62.4,59.1,58.6,56.3 (C of methoxy group bonded to 16,18,6,1 position) 57.2 (C of methylene group of ethoxy group bonded to 8 position) 42.5 ( C of N-methyl group) 15.3 (C of methyl group of ethoxy group bonded to 8-position) 6) EI-mass spectrum analysis m / z 599 (M ⁺ ) (18) 8-O-amyl-14-benzoyl aco Physical properties and analytical data of nin 1) Properties and solubility It is a colorless amorphous powder, soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water. is there.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3400,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.41 (5H, multiple line) (H of benzoyl group) 4.83 (1H, double line, J = 4.95Hz) (H in 14th position) 4.56 (1H, double line, J = 5.93Hz) (15th position) H) 4.09 (1H, double wire, J = 6.59Hz) (H in 6th place) 1.13 (3H, triplet, J = 7.26Hz) (H of methyl group of N-ethyl group) 0.57 (3H, triplet, J = 6.29Hz) (H of methyl group of amyl group bonded to 8th position) 5 ) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.2,129.6,128.3 (C of benzoyl group) 93.2,83.3,82.3,82.2,79.4,76.8,74.7,71.5 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.7 (C of methoxy group bonded to 16,18,6,1) 57.5 (methylene group of amyl group bonded to 8 position) C) 48.9 (C of methylene group of N-ethyl group) 15.0 (C of methylene group of amyl group bonded to 8-position) 13.1 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 675 (M ⁺ ) (19) 3-O-acetyl-8-O-amyl-14-benzoylaconine physical properties and analytical data 1) Properties and solubility Colorless amorphous powder of ether, chloroform, Soluble in benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.41 (5H, multiplex) (benzoyl group H) 4.97 (1H, multiplex) (3rd position H) 4.82 (1H, double line, J = 4.95Hz) (14th position H) 4.53 (1H , Double wire, J = 5.94Hz) (15th place H) 4.18 (1H, double wire, J = 6.59Hz) (6th place H) 2.07 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 1.11 (3H, triplet, J = 7.09Hz) (H of methyl group of N-ethyl group) 0.55 (3H, triplet , J = 6.76 Hz) (H of the methyl group of the amyl group bonded to the 8-position) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.7, 130.3, 129.6, 128.2 (C of benzoyl group) 93.6, 83.4, 82.3, 82.0, 79.5,78.5,77.0,74.8,71.5 (1
6,6,1,8,14,15,18,13,3 position C) 62.3,60.9,58.7,56.4 (C of methoxy group bonded to 16,18,6,1) 57.0 (bonded to 8 position 49.1 (C of methylene group of N-ethyl group) 21.2 (C of methyl group of acetyl group bonded to 3-position) 15.0 (C of methyl group of amyl group bonded to 8-position) ) 13.5 (C of methyl group of N-ethyl group) 6) EI-mass spectrum analysis m / z 717 (M ⁺ ) (20) 8-O-amyl-14-benzoyl mesaconiine physical properties and analytical data 1) Properties and solubility A colorless, amorphous powder that is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, and dimethyl sulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.08-7.27 (5H, multiple line) (H of benzoyl group) 4.81 (1H, double line, J = 4.70Hz) (H at 14th position) 4.54 (1H, double line, J = 6.10Hz) (15th position) H) 4.08 (1H, double wire, J = 7.60Hz) (6th H) 2.34 (3H, singlet) (H of N-methyl group) 0.55 (3H, triplet, J = 6.00Hz) (H of methyl group of amyl group bound to 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum ( CDCl ₃ ) analysis shows the following signals (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.3,129.6,128.2 (C of benzoyl group) 93.4,83.3,82.7,82.0,79.4,78.3,76.4,74.7,71.3 (1
6,6,1,8,14,15,18,13,3 position C) 62.4,59.1,58.6,56.3 (C of methoxy group bonded to 16,18,6,1) 57.0 (bonded to 8 position Methylene group C of amyl group 42.5 (C of N-methyl group) 15.1 (C of amyl group methyl group attached to 8-position) 6) EI-mass spectrum analysis m / z 661 (M ⁺ ) (21 ) Physical properties and analytical data of 3-O-acetyl-8-O-amyl-14-benzoylmethaconine 1) Properties and solubility Colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, acetone, acetic acid. Soluble in ethyl, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 3500 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.06-7.41 (5H, multiplet) (H of benzoyl group) 4.96 (1H, multiplet) (H of 3rd position) 4.82 (1H, doublet, J = 4.95Hz) (H of 14th position) 4.54 (1H , Double wire, J = 5.94Hz) (15th H) 4.14 (1H, double wire, J = 6.92Hz) (6th H) 2.08 (3H, singlet) (H of methyl group of acetyl group bonded to 3-position) 0.55 (3H, triplet, J = 6.92Hz) (H of methyl group of amyl group bonded to 8-position) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.2 (C of carbonyl group derived from benzoyl group of 14-position) 132.8,129.6,128.2 (C of benzoyl group) 93.3,82.0,79.3,78.3,77.4, 74.6,71.4 (16,6,1,8,14,
15,18,13,3 position C) 62.1,58.8,56.6 (C of methoxy group bonded to 16,18,6,1) 57.0 (C of amyl group methylene group bonded to 8 position) 42.6 (N -C of methyl group 21.2 (C of methyl group of acetyl group bonded to 3-position) 15.2 (C of methyl group of amyl group bonded to 8-position) 6) EI-mass spectrum analysis m / z 703 (M ⁺ ) (22) Physical properties and analytical data of 8-O-amyl-14-anisoylaconine 1) Properties and solubility A colorless amorphous powder of ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, Soluble in pyridine and dimethyl sulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450 and 1720 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

4.60 (1H, doublet, J = 6.00Hz) (H at 14th position) 3.88 (3H, singlet) (H of methoxy group of anisoyl group) 1.11 (3H, triplet, J = 7.00Hz) (H of methyl group of N-ethyl group) 0.54 (3H, triplet, J = 6.00Hz) (H of methyl group of amyl group bonded to 8-position) 5 ) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm).

165.8 (C of carbonyl group derived from 14th anisoyl group) 163.1,131.6,122.7,113.6 (C of anisoyl group) 93.3,83.4,82.5,82.1,79.2,77.3,74.2,71.6 (16,6,1,
8,14,15,18,13,3 position C) 62.3,59.0,58.5,55.8 (C of the methoxy group bonded to 16,18,6,1) 55.3 (C of the methoxy group of anisoyl group) 57.1 ( C8 of the methylene group of the amyl group bonded to the 8-position 48.8 (C of the methylene group of the N-ethyl group) 15.3 (C of the methyl group of the amyl group bonded to the 8-position) 13.0 (of the methyl group of the N-ethyl group) C) 6) EI-mass spectrum analysis m / z 705 (M ⁺ ) (23) 3-O-acetyl-8-O-amyl-14-anisoylaconine Physical properties and analytical data 1) Properties and solubility It is a colorless amorphous powder that is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450, 1705 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

4.96 (1H, multiple line) (3rd H) 4.81 (1H, double line, J = 4.95Hz) (14th H) 4.53 (1H, double line, J = 5.94Hz) (15th H) ) 4.11 (1H, doublet, J = 6.60Hz) (H at 6th position) 3.86 (3H, singlet) (H of methoxy group of anisoyl group) 2.08 (3H, singlet) (H of the methyl group of the acetyl group bonded to the 3-position) 1.13 (3H, triplet, J = 7.26Hz) (H of the methyl group of the N-ethyl group) 0.55 (3H, triplet , J = 7.26 Hz) (H of the methyl group of the amyl group bonded to the 8-position) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm).

170.2 (C of carbonyl group of acetyl group bonded to 3-position) 166.0 (C of carbonyl group derived from anisoyl group of 14-position) 163.2,131.7,122.8,113.6 (C of anisoyl group) 93.5,83.3,82.1,79.1, 78.3,77.0,74.8,71.7 (16,6,1,
8,14,15,18,13,3 position C) 62.2,58.7,55.4 (C of methoxy group bonded to 16,18,6,1) 56.4 (C of anisoyl group methoxy group) 57.1 (8 position Methylene group C of the amyl group bonded to 4) (methylene group C of the N-ethyl group) 21.2 (acetyl group methyl group C bonded to the 3-position) 15.1 (amyl group methyl group bonded to the 8-position) C) 13.3 (C of methyl group of N-ethyl group) 6) EI-mass spectroscopic analysis m / z 733 (M ⁺ ) (24) 8-O-amyl-14-benzoylhypaconine Data 1) Properties and solubility It is a colorless amorphous powder which is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 3450,1715 cm ^-1 .

3) Ultraviolet absorption spectrum (ethanol) analysis 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis Shows the following signals (δ, ppm).

8.07-7.26 (5H, multiple line) (H of benzoyl group) 4.82 (1H, double line, J = 4.50Hz) (14th H) 4.55 (1H, double line, J = 5.93Hz) (15th place) H) 4.08 (1H, double line, J = 6.70Hz) (6th H) 2.34 (3H, singlet) (H of N-methyl group) 0.55 (3H, triplet, J = 6.00Hz) (H of methyl group of amyl group bound to 8-position) 5) ¹³ C Nuclear magnetic resonance spectrum ( CDCl ₃ ) analysis shows the following signals (δ, ppm).

166.1 (C of carbonyl group derived from benzoyl group at 14-position) 132.8,130.3,129.6,128.3 (C of benzoyl group) 93.5,83.2,82.6,81.9,79.4,78.3,76.4,74.7 (16,6,8,
C at 14,15,18,13 position) 62.4,59.1,58.6,56.3 (C at methoxy group bonded to 16,18,6,1 position) 57.0 (C at methylene group of amyl group bonded at 8 position) 42.5 (C of N-ethyl group) 15.0 (C of methyl group of amyl group bonded to 8-position) 6) EI-mass spectrum analysis m / z 643 (M ⁺ ) Pharmacological action and acute toxicity of the compound according to the present invention An example of the experiment will be shown.

[Experimental Example 1] (Analgesic action) Measurement of analgesic activity based on acetic acid lysing method Male Std: ddY mice (20 to 25 g) were used for the experiment. The animals were kept at room temperature 24 to 25 ° C. under free feeding, watering and light / dark conditions with a 12-hour cycle. The test drug was used as a 3% gum arabic suspension. 30 minutes after test drug administration (sc)
0.7% acetic acid / 0.9% physiological saline solution was intraperitoneally injected at a rate of 10 ml / kg, and the number of licings developed 10 to 10 minutes after the injection was counted. As a negative control, 3% gum arabic / 0.9% saline solution was used. The ED ₅₀ value was determined to be positive for analgesic activity when the licing number of the negative control group was 1/2 or less.
It was calculated based on the ld-Wilcoxon method. The results are shown in Table 1.

As shown in Table 1, the compound of the present invention was found to have a dose-dependent analgesic activity.

[Experimental Example 2] (Anti-inflammatory action) Measurement of carrageenin footpad edema Std: ddY male mice (20 to 25 g) were used in the experiment. Thirty minutes after oral administration of the drug, 25 μl of carrageenin (0.5 mg / 25 μl) suspended in 0.9% physiological saline was injected subcutaneously into the footpad of the right hind leg of a mouse as an inflammatory agent. As a control, 25 μl of 0.9% physiological saline was injected subcutaneously in the footpad of the left hind leg. The paw thickness was measured using a dial gauge caliper, and 1, 2, 3, 4, and 6 hours after carrageenin administration. The results were expressed as the difference in the thickness of the left and right feet. The results are shown in Table 2.

As shown in Table 2, it was confirmed that the compound according to the present invention has a carrageenin footpad edema inhibitory action.

[Experimental Example 3] (Acute toxicity) Male Std: ddY mice (20 to 25 g) were used in the experiment. Litchfield-Wilco from 72 hours after administration of the test drug
The LD ₅₀ value was calculated based on the xon method. Table 3 shows the results.

As shown in Table 3, it was confirmed that the compound according to the present invention had reduced toxicity as compared with mesaconitine, aconitine, hypaconitine and gesaconitine.

As described above, it was revealed that the compound according to the present invention is less toxic than mesaconitine, aconitine, hypaconitine and jesaconitine, and has a strong analgesic / anti-inflammatory activity.

The clinical dose of the analgesic / anti-inflammatory agent according to the present invention is preferably 0.01 to 10 mg / day for an adult as an active ingredient. The preparation of the present invention is provided for use in a conventional manner with any desired carrier or excipient for preparation.

Tablets, powders, granules, capsules, etc. for oral administration include conventional excipients such as calcium carbonate, magnesium carbonate,
It may contain calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate, gum arabic and the like. The tablets may be coated by well known methods. Liquid oral preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, and the like.

In the injectable preparation, the compound according to the present invention may be used in the form of a salt, and the soluble form at the time of use is preferable. It may also contain formulating agents such as suspending, stabilizing or dispersing agents,
It may contain sterile distilled water, essential oil such as peanut oil, corn oil or non-aqueous solvent, polyethylene glycol, polypropylene glycol and the like.

Provided for the rectal administration in the form of a suppository composition,
It may contain a carrier for formulation well known in the art, such as polyethylene glycol, lanolin, coconut oil and the like.

For topical application, provided in the form of an ointment composition or a plaster composition, a carrier for formulation well known in the art,
For example, petrolatum, paraffin, hydrolanolate, plastibase, hydrophilic petrolatum, macrogol, wax, resin,
It may contain purified lanolin, rubber and the like.

Claims (2)

[Claims] 1. A general formula, (In the formula, R ₁ represents benzoyl or anisoyl, R ₂ represents methyl or ethyl, R ₃ represents a hydroxyl group, acetyloxy or hydrogen, R ₄ represents a lower alkyl group or hydrogen, provided that R ₁ is benzoyl and R ₂ is ethyl. , R ₃ is acetyloxy, R ₄ is not ethyl R ₁ is benzoyl, R ₂ is methyl and R ₃ is a hydroxyl group R ₄ is not methyl, ethyl or hydrogen R ₁ is anisoyl , R ₂ is ethyl and R ₃ is a hydroxyl group,
R ₄ is not methyl, ethyl or hydrogen. R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is methyl and R ₃ is hydrogen.
R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is ethyl and R ₃ is a hydroxyl group. ) An aconitine compound represented by: 2. General formula (In the formula, R ₁ represents benzoyl or anisoyl, R ₂ represents methyl or ethyl, R ₃ represents a hydroxyl group, acetyloxy or hydrogen, R ₄ represents a lower alkyl group or hydrogen, provided that R ₁ is benzoyl and R ₂ is methyl. Or ethyl, R ₄ when R ₃ is a hydroxyl group
Is not hydrogen. R ₄ is not hydrogen when R ₁ is benzoyl, R ₂ is methyl and R ₃ is hydrogen. R ₁ is Anisoyl, R ₂
Is ethyl and R ₃ is a hydroxyl group, R ₄ is not hydrogen. ) An analgesic / anti-inflammatory agent containing an aconitine compound represented by