JPH0276856A - Novel aconitine compound and analgesic and anti-inflammatory agent - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R1 is benzoyl or anisoyl; S2 is methyl or ethyl; R3 is OH or H; R4 is alpha-methoxy or beta-methoxy; etc.). EXAMPLE:8-Deoxy-15-oxo-16-alpha-methoxy-14-benzoylaconine. USE:An analgesic and anti-inflammatory agent having low toxicity and exhibiting strong activity. PREPARATION:The compound of formula can be produced by heating an aconitine-type alkaloid having hydroxyl group at 15-position and acyloxy group at 8-position (e.g., aconitine, mesaconitine, hypaconitine or jesaconitine). The heat-treatment may be carried out under arbitrary condition such as heating under normal pressure, heating under reduced pressure or heat-treatment in an autoclave.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to novel aconitine compounds and analgesic and anti-inflammatory agents.

More specifically, the present invention relates to the general formula (wherein R1 is benzoyl or anisoyl, R2 is methyl or ethyl, R□ is a hydroxyl group or water M, R4 is α-methoxy or β-methoxy, is benzoyl, R1 is a hydroxyl group, R1 is not methyl or ethyl, R1 is anisoyl, R3 is a hydroxyl group, and R4 is β-methoxy, R2 is not ethyl) and the general formula (In the formula, R□ is benzoyl or anisoyl, R2 is methyl or ethyl, R3 is a hydroxyl group or hydrogen, and R4 is α-methoxy or β-methoxy.) Analgesic containing an aconitine compound as an active ingredient. -Relates to anti-inflammatory drugs.

〔background〕

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

[Disclosure of the invention]

The present inventor has conducted various studies to obtain a novel aconitine alkaloid derivative that retains the analgesic and anti-inflammatory effects possessed by aconitine alkaloid substances and has low toxicity. We succeeded in providing a chemical compound represented by . It has been found that the compound represented by the general formula (■) has strong analgesic and anti-inflammatory activity, and is also less toxic than mesaconitine, aconitine, hivaconitine, and jesaconitine.

The present invention is based on this knowledge.

Therefore, the present invention provides an analgesic/anti-inflammatory agent containing a novel compound represented by the general formula (1) and a compound represented by the general formula (IT).

The compound represented by the above formula (n) according to the present invention is aconitine represented by the following formula (III).

Mesaconitine represented by the following formula (IV), the following formula (V)
It can be produced by heat treatment of an aconitine-type alkyloid having a hydroxyl group at the 15th position and an acyloxy group at the 8th position, such as hivaconitine represented by the following formula (Vl) and diesaconitine represented by the following formula (Vl).

In the above heat treatment, heating at normal pressure, heating at reduced pressure, heating using an autoclave, etc. can be arbitrarily used.

Two production examples of compounds according to the present invention are listed below. The physical property values and analytical data of the compounds obtained in each example are listed later. Moreover, the pharmacological action, m-property, and others regarding the compound are listed in Tables 1 to 3 below.

[Example 1] Aconitine 80B was adhered as uniformly as possible to the wall of 20-Meyer, and 20
Heat at 0°C for 30 minutes. Cold soaked, dissolved in chloroform.

At p-TLC (praparatlve TLC) (
Ammonia-saturated chloroform/ammonia-saturated ether = 1:1) separated and purified, 8-deoxy-15-oxo-16-α-methoxy-14-penzoylaconine 15
1 mg, 12 mg of 8-deoxy-15-oxo-16-β-methoxy-14-penzoylaconine are obtained.

[Example 2] Mesaconitine 1ooo instead of aconitine in Example 1
+g, and otherwise operated in exactly the same manner as in Example 1.

a-deoxy-15-oxo-16-α-methoxy-1
4-benzoylmethaconine 25mg, 8-deoxy-
20 mg of 15-oxo-16-β-methoxy-14-benzoylmesaconine is obtained.

[Example 3] Hivaconitine 200m instead of aconitine in Example 1
g, and otherwise operated in the same manner as in Example 1.

8-deoxy-15-oxo-16-α-methoxy-1
4-penzoylhypaconine 28 g, 8-deoxy-1
19 mg of 5-oxo-16-β-methoxy-14-penzoylhibaconine is obtained.

[Example 4] Jesaconitine 100 instead of aconitine in Example 1
Using 28 g of 8-deoxy-15-oxo-16-α-methoxy-14-anisoylaconine, 28 g of 8-deoxy-15-oxo-16- β-methoxy-14-anisoylaconine 2
Obtain 5 mg.

[Example 5] 500 g of Dzizi was pressurized and heated in an autoclave at 110° C. for 40 minutes, dried, crushed, and extracted five times with 1Ω methanol. After evaporating the methanol extract to dryness, 5
Dissolve in 300% hydrochloric acid and wash once with 200% hexane. The hydrochloric acid layer was adjusted to pH 9 with aqueous ammonia and extracted three times with 300% chloroform. After concentrating the chloroform layer to dryness under reduced pressure, it was repeatedly separated and purified using silica gel column chromatography (chloroform, 5% methanol/chloroform system) to obtain 8-deoxy-15-oxo-16-
α-methoxy-14-penzoylaconine, 8-deoxy-15-oxo-16-β-methoxy-14-penzoylaconine, 8-deoxy-15-oxo-16-
α-Methoxy-14-benzoylmesaconine.

8-deoxy-15-oxo-16-β-methoxy-1
4-benzoylmethaconine, 8-deoxy-15-oxo-16-α-methoxy-14-penzoylhypaconine, 8-deoxy-15-oxo-16-β-methoxy-
14-penzoylhypaconine, 8-deoxy-15-oxo-16-α-methoxy-14-anisoylaionine and 8-deoxy-15-oxo-16-β-methoxy-14-anisoylaconine are obtained. be able to. Furthermore, these compounds can also be obtained by separating and purifying crude fractions of the above compounds using liquid chromatography under the following conditions, and separating and purifying them using silica gel column chromatography.

Conditions for liquid chromatography Column: Inertsil ODS (20X250+*m)
Mobile phase: 0.05M phosphate buffer (pH 2,35)
・Tetrahydrofuran・acetonitrile (80:15:
5) Flow rate: 10m1!7'+in.

(1) Physical properties and analytical data of 8-deoxy-15-oxo-16-α-methoxy-14penzoylaconine 1) Soluble ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide Soluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
It shows an absorption maximum at 717 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis λ[! t
Ol+ (10g')ndo230(4,15)4)"
Signal of H nuclear magnetic resonance spectroscopy (CDCI) analysis method is shown (δe ppm).

5.44 (Ill, double line, J=4.93Hz) (1
β-H at position 4) 3.81 (311, - doublet) (H of α-methoxy group at position 16) 3.25 (311, - doublet) J 1.03 (3+1. triplet, J= 7.0011z) (
The signal of the methyl H) s) 13c nuclear magnetic resonance spectroscopy (CDCI3) analysis method of the N-ethyl group is shown (δ* ppm).

211.7 (C of carbonyl group at 1,5 position) 165.9
(C of carbonyl of benzoyl group) 133.2,129
．． 8 (2C), 129.6, 128.6 (2C) (C of benzoyl group) 86.2, 84.0, 8.3.6, 78.6, 77.2
,77.0,71.7(16,6,1,14,18,1
3,3 position C) 4'3.0 (C of methylene of N-ethyl group) 13.5 (C of methyl of N-ethyl group) 6) EI-
Mass spectrum analysis lQ/z 585 (M+) 7) [α = +21.8° (C = 0° 22. Ethanol) (2) 8-deoxy-15-oxo-16-β-
Physical properties and analytical data of methoxy-14-penzoylaconine 1) Solubility Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-''.

3) Ultraviolet absorption spectrum (ethanol) analysis λ,...

,, (log t )n+*=230(4,15)4
) Shows the signal of 1H nuclear magnetic resonance spectroscopy (CDCI3) analysis method (δ* ppm).

5.18 (IH, double line, J=3.9711z) (1
4th position β-H) 3.64 (311, -@AfI) (1
H of β-methoxy group at position 6) 1.03 (311, triple line, J near, 0+1Z) (N
- H of methyl of ethyl group) 5) "C Nuclear Magnetic Resonance Spectrum (CDCI,) indicates the signal of analytical method (δ+ ppm).

211.8 (C of carbonyl group at position 15) 166.9 (
C) 133.8, 120. of carbonyl of benzoyl group.
7 (2C), 129.6, 128.5 (2C) (C of benzoyl group) 89.2, 84.0, 83.5, 79.5, 77.2,
77.0, 71.4 (16, 6, 1, 14, 18, 13
, C at position 3) 49.0 (C of methylene of N-ethyl group)
)13.4 (C of methyl of N-ethyl group)6) E
l-trade f non-vector analysis ra/z 585 (M”) (3) Physical properties and analytical data of 8-deoxy-15-oxo-16-α-methoxy-14benzoylmesaconine 1) Soluble ether, chloroform, Soluble in benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-''.

3) Ultraviolet absorption spectrum (ethanol) analysis λ[! ,
O1l (1o g i ) n m =230 (
4-05) 4) 1H nuclear magnetic resonance spectrum (CDCI3
) indicates the signal of the analytical method (δe PPIg) *5.4
4 (III, doublet, J = 4.9211z) (β-H at the 14th position) 3.79 (3+1.- doublet) (α- at the 16th position
H of methoxy group) 2.35 (311, - double line) (H of N-methyl group) 5)
"C Nuclear Magnetic Resonance Spectrum (CDC13') analysis method signal (6m ppm).

211.8 (C of carbonyl group at position 15) 166.0
(C of carbonyl of benzoyl group) 133.0.12
9.8 (2C), 129.5.128.5 (2C)
(C of benzoyl group) 86.2, 84.0. a3.5, 78.6, 77.2.
7? , 0,71.6 (16,6,1,14,18,13
, 3rd position (7)C) 42.4 (C of N-methyl group) 6) EI-Svector analysis ta/z 571 (M+) (4) 8-deoxy-15-oxo-16-β- Physical properties and analytical data of methoxy-14benzoyl mesaconine 1) Solubility Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm''.

3) Ultraviolet absorption spectrum (ethanol) analysis λ (
log i ) nm; 230 (4,05)! ! tOl+ 4) 1H Nuclear Magnetic Resonance Spectrum (CDCI, ) indicates the signal of the analytical method (δv PP11)
H, double line, J=4.011z) (β-H at position 14)
3.62 (311, - heavy g) (H of β-methoxy group at position 16) 2.35 (371, - heavy line) (H of N-methyl group) 5)
“C nuclear magnetic resonance spectroscopy (CDCI□) analysis method signal is shown (δt PP■).

211.7 (C of carbonyl group at position 15) 165.9 (
Carbonyl of benzoyl group C) 133.0,129.
7 (2G), 12L4, 128.5 (2C) (C of benzoyl group) 89.3, 84.1.83.6.7g, 7.77, I
,? 7.0, 71.5° (16, 6, 1, 14, 18
, 13,3 position C) 42.5 (N-methyl group C) 6) EI-Mass, spectrum analysis mHz 571 (M+) 7) [α coma = -79,5° (c = 0.44
, ethanol) (5) 8-deoxy-15-oxo-1
Physical properties and analytical data of 6-α-methoxy-14penzoylhypaconine 1) Soluble Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, insoluble in hexane and water It is.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
It shows an absorption maximum at 717 cm-'.

3) #External absorption spectrum (ethanol) analysis λ (
log i ) nm=230(4,10)! to11 4) Shows the signal of 1H nuclear magnetic resonance spectroscopy (CDCI) analysis method (6m ppm).

8.10-7.26 (51 (, multiple M) (H of benzoyl group) 5.44 (111, doublet, J = 4.91112
) (β-H at position 14) 3.81 (311, - double line) (
H of α-methoxy group at position 16) 3.34 (6H, - double line) (3.18 (311, - double line) of positions 1, 6 and 18) H of methoxy group) 2.3
5 (311, - double line) (H of N-methyl group) 5) 13c
Nuclear Magnetic Resonance Spectrum (CDCI) analysis number signals are shown (δv ppm).

211.8 (C of carbonyl group at position 15) 166.0 (
C) 133.2, 129. of carbonyl of benzoyl group.
6,128.6 (2C), 129.9 (2C) (C of benzoyl group) 86.3, 86.0, 84.0, 81.4, 78.9.
77.0 (16th, 1st, 6th, 18th, 14th, 13th C) 4
2.6 (C of N-methyl group) 6) EI-Mass spectrometry + i/z 555 (M+) (6) Physical properties of 8-deoxy-15oxo-16-β-methoxy-14penzoylhypaconine and Analysis data 1) Solubility Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-1.

3) #External absorption spectrum (ethanol) analysis λ,,.

,, (log t )nm=230(4,10)4)
1H nuclear magnetic resonance spectrum (CDCI3) analysis number signals are shown (δr ppm).

8.08-7.25 (511, multiplet) (H of benzoyl group) 5.20 (III, doublet, J = 4.01lz)
(β-H at position 14) 3.64 (311, - double line) (1
H of β-methoxy group at position 6) 2.35 (311, - double line) (H of N-methyl group) 5)
The i3c nuclear magnetic resonance spectrum (CDCI, ) indicates the signal of the analysis number (δ, ρpm).

211.7 (C of carbonyl group at position 15) 16L1 (C of carbonyl of benzoyl group) 133.2, 129.
9 (2C), 129.6, 128.6 (2C) (C of benzoyl group) 89.3, 85.9, 84.0, 81.4, 78.9,
77.0 (16th, 1st, 6th, 18th, 14th, 13th place + 7)C
)42.6 (C of N-methyl group) (3) EI-mass spectrometry + i/z 555 (M”) 7) [α]v=-65.6@(c=0.18.ethanol) ( 7) Physical properties and analytical data of 8-deoxy-15-oxo-16-α-methoxy-14-anisoylaconine 1) Properties and solubility Colorless needle-like crystals that can be used in ether, chloroform, benzene, ethanol, methanol, Soluble in acetone, ethyl acetate, pyridine, dimethyl sulfoxide, insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3456, 1
The maximum absorption is shown at 715 cm-''.

3) Ultraviolet absorption spectrum (ethanol) analysis λ [lt
o,, (log i )nm=257(4,00)4
) 1H nuclear magnetic resonance spectrum (CDC1,) indicates the signal of the analysis number (δy PP[O).

5.39 (Ill, double line, J=4.9511z) (
β-H at position 14) 3.87 (311,-heavy a) C7 di) a) H of methoxy group of Ii group) 3.80 (311,-heavy line) (α-methoxy at position 16) Group H) 1.05 (311, triple line, J=7.25+1z) (
(H of methyl of N-ethyl group) 5) 13G nuclear magnetic resonance spectrum (CDC1,) Showing the signal of the analysis number (δ* PPII) a211.7 (1
C of carbonyl group at position 5) 165.8 (C of carbonyl of anisoyl group) 164.0, 131.7 (2C), 1
21.6,113.8 (2C) (C of anisoyl group) 86, 1,84.0,83.6.7g, 3,77.4,
77.0, 71. fl(16, 6, 1, 14, 18, 1
C at position 3,3) 49.1 (C of methylene of N-ethyl group)
) 13.4 (N-ethyl group methyl C) 6) EI-mass spectrometry analysis trr/z 615 (8) (8) 8-deoxy-15oxo-16-β-methoxy-14-anisoylaco Physical properties and analytical data of nin
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3484, 1
The maximum absorption is shown at 711 cm-1.

3) #External absorption spectrum (ethanol) analysis λato
++ (log i )nm=258(4,00)4)
The signal of 1H nuclear magnetic resonance spectroscopy (CDC13) analysis method is shown (δ+ ppm).

5.14 (Ill, double line, J=3.9611z) (
β-H at position 14) 3.86 (311, - double line) (H of methoxy group of anisoyl group 3,63 (311, - double line) (H of β-methoxy group at position 16) 1.03 ( 311, triple line, J=7.2511z) (
(δ'+ PPII) a211.9(
C of carbonyl group at position 15) 166.8 (C of carbonyl of anisoyl group) 163.6, 131.0 (2C),
121.9, 113.7 (2C) (C of anisoyl group) 89.2, 84.1, 83.5. ．． 79.2, 77.4
,76.6,71.5(16,6,1,14,Ill,
c) 49.1 (C of methylene of N-ethyl group) 13.3 (C of methyl of N-ethyl group) 6) at position 13.3
EI-Mass Spectrometry rrr/z 615 (M+) \'', 7'7-'7'/'' An experimental example on the pharmacological action and acute toxicity of the compound according to the present invention is shown.

[Experiment Example IF (Analgesic effect) ■For an experiment to measure analgesic activity based on the acetic acid rising method, 5
tdSddY male mice (20-25 g) were used. Animals were kept at room temperature 24-25°C, fed ad libitum, with raw water and 1
The animals were reared under light and dark conditions with a 2-hour cycle. The test drug was used as a 3% gum arabic suspension. Test drug administration (s, c,)
After 30 minutes, add 10 tons of 0.7% acetic acid and 10.9% physiological saline.
Injected intraperitoneally at a rate of 2/kg, 10 minutes after injection.
The number of writhing events occurring in 0 minutes was counted. A 3% gum arabic 10.9% physiological saline solution was used as a negative control.

In addition, the EDs value is 1 of the rising number of the negative control group.
72 or less is considered positive for analgesic activity, and Litchfia
It was calculated based on the ld-li coxon method. The results are shown in Table 1.

As shown in Table 1, nine compounds according to the present invention were found to have dose-dependent analgesic activity.

[Experiment Example 2 (Anti-inflammatory effect) ■For the measurement experiment of carrageenan paw edema, Std:ddY male mice (2-0 to 25g
)It was used. 30 minutes after oral administration of the drug, carrageenin (0.5 x 725 μQ) suspended in 0.9% physiological saline
5 μQ was injected subcutaneously into the right hind leg footprint of the mouse as an inflammatory agent.

As a control, 25μ of 0.9% physiological saline was applied subcutaneously to the left hind leg.
I injected Q. The thickness of the foot was measured using a dial gauge caliper, and the thickness was measured at 1° 2.3, 4.
Measurements were taken at 5 and 6 hours. Result is.

It is expressed as the difference in thickness between the left and right feet. The results are shown in Table 2.

As shown in Table 2, nine compounds according to the present invention were found to have carrageenan footprint edema inhibitory effects.

[Experiment Example 3] (Acute toxicity) Experiment 2 LtStdSddY male 7 mice (20-25g
)It was used. Li from the number of deaths 72 hours after administration of the test drug
LD based on the tchflald-Wilcoxon method,
. The value was calculated. The results are shown in Table 3.

As shown in Table 3, the two compounds according to the present invention were found to have lower toxicity than mesaconitine, aconitine, hivaconitine, and jesaconitine.

It has been revealed that the above two compounds according to the present invention have lower toxicity than mesaconitine, aconitine, hivaconitine and jesaconitine, and also have strong analgesic and anti-inflammatory activities.

The clinical dosage of the analgesic/anti-inflammatory agent according to the present invention is preferably 0.1 to 100 x 7 days for adults as the active ingredient. The preparations of the present invention can be used in a conventional manner with any necessary pharmaceutical carriers or excipients.

Tablets, powders, granules, capsules, etc. for oral administration may be prepared using conventional excipients such as calcium carbonate, magnesium carbonate, calcium phosphate, corn starch.

Potato starch, sugar, lactose, talc.

It may contain magnesium stearate, gum arabic, etc. Tablets may be coated by known methods. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, and the like.

For injection preparations, the compound according to the present invention may be used in the form of a salt, and is preferably dissolved at the time of use.

l! ! It may contain formulation agents such as clouding agents, stabilizers or dispersants, sterile distilled water, essential oils such as peanut oil, corn oil or non-aqueous solvents.

It may contain polyethylene glycol, polypropylene glycol, etc.

For rectal administration, the composition may be provided in the form of a suppository composition and may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, coconut oil, and the like.

For topical application, it may be provided in the form of ointment or plaster compositions, and may contain pharmaceutical carriers well known in the art, such as petrolatum, paraffin, hydrated lanolin, plastibase, parent petrolatum, macrogols, waxes, etc. It may contain resin, purified lanolin, rubber, etc.

0.01 1g, 3±2.5φ-0.06 Aconitine 0.03 14.9
±2.4$1 (0,017-0,208)0.1
09.3±1.6 out of 0.01 16.7±1.5. , 0.0
39 Menaconitine 0.0313
．． S±2. Cape a (0,019-0,079)0.
107.4±2.0 Umbrella Umbrella 0.03 20.8±1.9-- 0.10
Hivaconitine 0.10
13.2±1.2 happiness - (0,043-0,233)0.
30 7.2±1.31- 0.01 17.11±lJ** 0.
032 Diesaconitine 0.03
13.6±2.2 happy umbrella (0,012-0,0
89) 0.10 9.2±2. 8-deoxy-15-oxo-16α-0,315,2
±0.訃ψ 1.70 Methoxy-14-penzoylaconine 1.8 11.4±3.0・Umbrella (
1,04-2,78) 3.0 11.2±2.81 8-deoxy-! 5-oxo 16α-0,317,0
-1,10 Me1-xy-14-benzoylmesaconine 1.0 in ±3.0 13. a±3.6-* (
0,38-3,19) 3.0 10.8±
8-deoxy-15-oxo-[6α-0,
318,0±2.1・Umbrella 2.70 Methoxy-1
4-Penzoylhypaconin 1.0 16.0±2
．． 7** (0,56-12,96)3.0
14. Z±4.4-11 8-deoxy-15-oxo-16α-0,314,6
±3,6*umbrella 0.74methoxy-14-anisoylaconine 1.0 +3.2±2.7ψumbrella
(0,28-1,96) 3.09.6±2.5 umbrella ψ Table 3 Control -Aconitine 0.55
(0,30-1,01) Mesaconitine
0.25 (0,20-0,31) Hibaconitine 1.90 (
1,52-2,37) Jesaconitine
0.23 (0,18-0,29)8-deoxy-15-oxo-16-α-methoxy-20<1
4-penzoylaconine 8-deoxy-15-oxo-16-α-methoxy-3
0<14-benzoylmesaconine 8-deoxy-15-oxo-16-α-methoxy-1
0<14-penzoylhibaconine 8-deoxy-15-oxo-16-α-methoxy-3
0<14-anisoylaconine 8-deoxy-15-oxo-16-β-methoxy-3
0<14-penzoylaconine 8-deoxy-15-oxo-16-β-methoxy-3
0<14-penzoylhypaconine 8-deoxy-15-oxo-16-β-methoxy-3
0〈14-Anisoylaconine Procedural Amendment September 8, 1999 Director General of the Patent Office Yoshi 1) Tsuyoshi Moon1, Indication of the case 1988 Patent Application No. 2269982, Title of the invention Novel aconitine compound and analgesic/anti-inflammatory agent 3, relationship with the amended case Patent applicant address 6-1 Hiraide Industrial Park, Utsunomiya City, Tochigi Prefecture Name 4 Sanwa Herbal Medicine Co., Ltd. Agent address 3-2 Kojimachi, Chiyoda-ku, Tokyo Address Sogo Daiichi Building Telephone (265) 9649 Full text correction statement ■1 Name of the invention Novel aconitine compound and analgesic/anti-inflammatory agent 2 Claim 1 General formula (wherein R1 is benzoyl or anisoyl Tomorrow, R2
is methyl or ethyl, R3 is a hydroxyl group or a hydrogen atom, and F? , is α-methoxy or β-methoxy. However, when R1 is benzoyl and R3 is a hydroxyl group, R2 is not methyl or ethyl, and R1
is anisoyl, R3 is a hydroxyl group, and R4 is β-methoxy, R2 is not ethyl).

2. General formula (wherein R1 is benzoyl or anisoyl, R2
is methyl or ethyl, R1 is a hydroxyl group or a hydrogen atom, and N R4 is α-methoxy or β-methoxy.

3. Detailed Description of the Invention [Technical Field] The present invention relates to a novel aconitine compound and an analgesic/anti-inflammatory agent.

More specifically, the present invention relates to the general formula (wherein R1 is benzoyl or anisoyl and R2
is methyl or ethyl, R3 is a hydroxyl group or a hydrogen atom, and R4 is α-methoxy or β-methoxy.

However, when R1 is benzoyl and R3 is a hydroxyl group, R2 is not methyl or ethyl, and when R1 is anisoyl, R3 is a hydroxyl group, and N R4 is β-methoxy, R3 is ethyl. It relates to an aconitine compound ° represented by the general formula - (wherein R1 is benzoyl or anisoyl, and R2
is methyl or ethyl, R1 is a hydroxyl group or a hydrogen atom, and % R4 is α-methoxy or β-methoxy. ) This relates to an analgesic/anti-inflammatory agent containing an aconitine compound represented by the following as an active ingredient.

[Background technology]

It has already been reported that aconitine-based alkaloid substances contained in the tuberous roots of plants of the genus Tricapto have strong analgesic and anti-inflammatory effects.

However, aconitine-based alkaloids are highly toxic.
Therefore, the margin of safety was considered narrow.

[Disclosure of the invention]

The present inventor has conducted various studies to obtain a novel aconitine alkaloid derivative that retains the analgesic and anti-inflammatory effects possessed by aconitine alkaloid substances and has low toxicity. We have succeeded in providing a compound represented by It has been found that the compound represented by the general formula (If) has strong analgesic and anti-inflammatory activity, and is also less toxic than mesaconitine, aconitine, hivaconitine, and diesaconitine.

The present invention is based on this knowledge.

Therefore, the present invention provides a novel compound represented by the general formula (I), and further provides a novel compound represented by the general formula (I[
) provides an analgesic/anti-inflammatory agent containing the compound represented by:

The compound represented by the formula (I) (ff) according to the present invention includes aconitine represented by the following formula (I[I), mesaconitine represented by the following formula (IV), and the following formula (V). It can be produced by heat treatment using an aconitine type alkaloid having a hydroxyl group at the 15th position and an acyloxy group at the 8th position, such as hibaconitine represented by the formula (Vl) below, and hyaconitine represented by the following formula (Vl). can.

// OCHr (lI[): CH2CH2BZ (IV) : CH, Bz (■): CH2CH2An Bz-COCsHs An= COCa Ha OCHs (p) The above heat treatment includes heat treatment at normal pressure, heat treatment at reduced pressure, or Heat treatment using an autoclave, etc. can be optionally performed.

Examples of manufacturing the compounds according to the present invention are listed below. The physical property values and analytical data of the compounds obtained in each example are listed after the description of the example. In addition, the pharmacological effects, toxicity, and other information regarding the compounds are listed in Table 1 below.
~ Listed in 3.

[Example l]

80 mg of aconitine was deposited as evenly as possible on the wall of 20 m (l) of Meyer, and under reduced pressure (1-1-5 im Hg 1-
Heat at 5i° C. for 30 minutes. Cold immersion, dissolving in chloroform, p-TLC (preparative TLC)
(ammonia saturated chloroform/ammonia saturated ether - 1:1) to separate and purify 8-deoxy-15-
Oxo-16-・α-methoxy-14-penzoylaconine 15111 g, 8-deoxy-15-oxo-16
12 mg of -β-methoxy-14-penzoylaconine is obtained.

[Example 2] Mesaconitine l 00 instead of aconitine in Example 1
Using +11g, the other operations were exactly the same as in Example 1, and 8
-deoxy-15-oxo-16-α-methoxy-14
-Benzoylmethaconine 25 mg, 8-deoxy-15
20 m9 of -oxo-16-β-methoxy-14-benzoylmesaconine are obtained.

[Example 3] Hibaconitine 20C1 instead of aconitine in Example 1
+g, and otherwise operated in the same manner as in Example 1 to obtain 281+g of 8-deoxy-15-oxo-16-α-methoxy-14-penzoylhibaconine, 8-deoxy-15-
19111 g of oxo-16-β-methoxy-14-benzoylmesaconine are obtained.

[Example 4] Diesaconitine loO instead of aconitine in Example 1
8-deoxy-15-oxo-16-α-methoxy-14-anisoylaconine 28m9.8-deoxy-15-oxo-16-β- Methoxy-14-anisoylaconine 2
Obtain 5 mg.

[Example 5] 500 g of Fushizi was pressurized and heated in an autoclave at 110'C for 40 minutes, dried and crushed, and mixed with 1Q of methanol,
Extract 5 times. After the methanol extract is evaporated to dryness, it is dissolved in 300 mQ of 5% hydrochloric acid and washed once with 200 mQ of hexane. The hydrochloric acid layer was adjusted to pH 9 with aqueous ammonia and extracted three times with chloroform 300+ml2. After concentrating the chloroform layer to dryness under reduced pressure, it was repeatedly separated and purified using silica gel column chromatography (chloroform, 5% methanol/chloroform system) to obtain 8-deoxy-15-oxo-16-a-methoxy-14-penzoylaconine. ,
8-deoxy-15-oxo-16-β-methoxy-1
4-penzoylaconine, 8-deoxy-15-oxo-16-α-methoxy-14-benzoylmesaconine, 8-deoxy-15-oxo-16-β-methoxy-
14-benzoylmethaconine, 8-deoxy-15-oxo-16-α-methoxy-14-penzoylhypaconine, 8-deoxy-15-oxo-16-β-methoxy-14-penzoylhybaconine, 8-deoxy -15-
Oxo-16-σ-methoxy-14-anisoylaconine and 8-deoxy-15-oxo-16-β-methoxy-14-anisoylaconine can be obtained.

Further, these compounds can also be obtained by separating and purifying the crude fraction of the above compound using liquid chromatography under the following conditions and using silica gel column chromatography.

Conditions for liquid chromatography Column: Inertsil ODS (20X 250+m)
Mobile phase: (LO5M phosphate buffer (pH 2,35)
・Tetrahydrofuran-acetonitrile (80:15:5) Flow rate = 1Om (1/In1n.

(1) Physical properties and analytical data of 8-deoxy-15-oxo-16-α-methoxy-14-penzoylaconine l) Properties and solubility Colorless needle-like crystals with a melting point of 4166-167°C. Soluble in , chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
It shows an absorption maximum at 717 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis λ
u(logt)nm-230(4,15)4)
'H Nuclear Magnetic Resonance Spectrum (CDC(23)) analysis method signal is shown (δ, ppm).

5.44 (LH, double line, J□4.93Hz) (14
β-H at position) 3.81 (3H, - double line) (α-H at position 16)
H of methoxy group) 1.03 (3H, triple line, J = 7.0OHz) (N
- H of methyl of ethyl group) 5) Signal of 13C nuclear magnetic resonance spectroscopy (CDC et al.) analysis method is shown (δ+ ppm).

211.7 (C of carbonyl group at position 15) 165.9 (
C) 133.2.129 of carbonyl of benzoyl group.
8(2C), 129.6.128.6(2C) (C of benzoyl group) 86.2.84.0.83.6.78.6.77.2.
77.0.71.7 (16, 6, 1, 14, 18, 13
, C at position 3) 49.0 (C of methylene of N-ethyl group)
13.5 (C of methyl of N-ethyl group)6) El-
Mass spectrum analysis m/z 585 (M”) 7) [α]y −-64,3° (c-0,23, ethanol) 8) High-resolution mass spectrometry calculated value C5xH4sNOs 585.2938 Actual value 585.2925 ( 2) Physical properties and analytical data of 8-deoxy-15-oxo-16-β-methoxy-14-penzoylaconine l) Properties and solubility Colorless amorphous powder that can be used in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate,
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm''.

3) Ultraviolet absorption spectrum (ethanol) analysis: g
l((log g)nm-230(4,15)4)
'H Nuclear Magnetic Resonance Spectroscopy (CDCQx) analysis method signals are shown (δl I) I) m).

5.18 (IH, doublet, J = 3.97 Hz , J□7.OHzXN -x
5) "C nuclear magnetic resonance spectroscopy (CDC43) analysis method signal (δ, ppm).

211.8 (C of carbonyl group at position 15) 166.9 (
C) 133.0.129 of carbonyl of benzoyl group.
7 (2G), 129.6.128.5 (2C) (C of benzoyl group) 89.2.84.0.83.5.79.5.77.2.
77.0.71.4 (16,6,l, 14.18.
C at position 13.3) 49.0 (C of methylene in N-ethyl group) 13.4 (C of methyl in N-ethyl group) 6) E
l-Mass spectrum analysis m/z 585 (M") 7) [α]",' = + 21.8' (c -0,2
2, Ethanol) 8) High-resolution mass spectrometry calculation value C1H, 3NO! 585.2938 actual measurement value
585.2945 (3) Physical properties and analytical data of 8-deoxy-15-oxo-16-σ-methoxy-14-benzoylmethaconine l) Properties and solubility Colorless amorphous powder, soluble in ether, chloroform, benzene, ethanol , methanol, acetone, ethyl acetate,
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis λ elbow gH
CIog t ) nm = 230 (4,05) 4)
'H Nuclear Magnetic Resonance Spectroscopy (CDCQ,) indicates the signal of the analytical method (δ+ ppm).

5.44 (LH, doublet, J□4.92Hz β-H at the 14th position) 3.79 (3H, - doublet) (H of the α-methoxy group at the 16th position) 2.35 (3I (, - Heavy line) (H of N-methyl group) 5)
The signals of C nuclear magnetic resonance spectroscopy (CDCL) analysis are shown (δ, ppm).

211.8 (C of carbonyl group at position 15) 166.0 (
Carbonyl C of benzoyl group) 133.0.129°8 (2G), 129.5.128.5 (2G) (C of benzoyl group) 86.2.84.0.83.5.78.6. 77.2.
77.0.71.6 (16, 6, 1, 14, 18, 13
, C at position 3) 42.4 (C at N-methyl group) 6) El-Mass spectrum analysis m/z 571 (M 7) [α) H' = -79,5' (c = 0.44
．． Ethanol) 8) High-resolution mass spectrometry calculated value Cs+HatNO* 571.2781 Actual value 571.2799 (4) Physical property values and analytical data of 8-deoxy-15-oxo-16-β-methoxy-14-benzoylmesaconine■) Properties and solubility Colorless amorphous powder in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate,
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis λ loading gH
<lOg t )nm-230(4,05)4)'
Signals of H nuclear magnetic resonance spectroscopy (CDC12s) analysis method are shown (ar ppm).

5.20 (IH, double line, J・4.0Hz014th β
-H) 3.62 (3H, - double line) (H of β-methoxy group at position 16) 2.35 (3H, - double line) (H of N-methyl group) 5)
"C Nuclear Magnetic Resonance Spectrum (CDC(23)) shows the signal of analysis method (δ, apHl).

211.7 (C of carbonyl group at position 15) 165.9 (
C) 133.8.129 of carbonyl of benzoyl group.
7(2C), 129.4.128.5(2C) (C of benzoyl group) 89.3.84.1.83.6.78.7.77.1.
77.0.71.5 (16, 6, 1, 14, 18, 13
, C at position 3) 42.5 (C at N-methyl group) 6) El-mass spectrometry analysis m/z 571 (M”) 7) [α] = −+ 15.4° (c = 0.48 .ethanol) 8) High-resolution mass spectrometry calculation value C3,H,, NOI 57t, 2781 actual value 571.2777 (5) Physical properties of 8-deoxy-15-oxo-16-α-methoxy-14-benzoylhypaconine Values and analytical data l) Properties and solubility Colorless amorphous powder in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate,
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
The maximum absorption is shown at 717 cm-''.

3) Ultraviolet absorption spectrum (ethanol) analysis λi:”
, on (log t )nm-230(4-10)4)
The signal of 1H nuclear magnetic resonance spectroscopy (CDCL) analysis is shown (δ* ppm).

8.10-7.26 (5H, multiplet) (H of benzoyl group) 5.44 (IH, doublet, J = 4.91Hz01
β-H at position 4) 3.81 (3H, - double line) (σ at position 16
- H of methoxy group) 2.35 (3H, - double line) (H of N-methyl group) 5)
Signals of 13C nuclear magnetic resonance spectroscopy (CDCI23) analysis method are shown (δ, ppm).

211.8 (C of carbonyl group at position 15) 166.0 (
C) 133.2.129 of carbonyl of benzoyl group.
6.128.6 (2C), 129.9 (2G) (C of benzoyl group) 86.3.86.0.84.0.81.4.78.9.
77.0 (16th, 1st, 6th, 18th, 14th, 13th c) 4
2.6 (C of N-methyl group) 6) El-Mass spectrometry m/z 555 (M 7) (a) F = -65,0° (c -0,1
8, ethanol) 8) High-resolution mass spectrometry calculation value C5JssNOt (M”-0CHs) 52
4.2648 Actual value 524.2853 (6) Physical properties and analytical data of 8-deoxy-15-oxo-16-β-methoxy-14-penzoylhypaconine l) Properties and solubility Colorless amorphous powder Ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate,
Soluble in pyridine, dimethyl sulfoxide, hexane,
Insoluble in water.

2) Infrared absorption spectrum (KBr) analysis 3450, 1
It shows an absorption maximum at 717 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis λ”x(
log t ) n+++-230(4,10)tOH 4) 1H nuclear magnetic resonance spectrum (CDCI23) analysis method signal is shown (δ+ ppn+).

8.08-7.25 (5H, multiplet) (H of benzoyl group) 5.20 (IH, doublet, J = 4.0Hz814
β-H at position) 3.64 (3H, - double line) (β-H at position 16)
H of methoxy group) 2.35 (3H, - double line) (H of N-methyl group) 5)
"C nuclear magnetic resonance spectroscopy (CDCI23) analysis method signal is shown (δ, ppm).

211.7 (C of carbonyl group at position 15) 166.1 (
C) 133.2.129 of carbonyl of benzoyl group.
9(2C), 129.6.128.6(2G) (C of benzoyl group) 89.3.85.9.84.0.81.4.78.9.
77.0 (16th, 1st, 6th, 18th, 14th, 13th C) 4
2.6 (C of N-methyl group) 5) El-Mass spectrometry m/z 555 (M”) 7) Cff) r-+15.6° (c = 0.18.
8) High-resolution mass spectrometry calculation value C5oHssNOt (M”-0CH3) 5
24-2648 actual value 524.2625 (7) Physical properties and analytical data of 8-deoxy-15-oxo-16-α-methoxy-14-anisoylaconine 1) Properties and solubility Colorless with a melting point of 181-182°C It has needle-like crystals and is soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, and dimethyl sulfoxide, and insoluble in hexane and water.

2) Infrared absorption spectrum (KBr) analysis 3456, 1
It shows an absorption maximum at 715 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis A i'
:gl((logt)nm-257(4,00)4
) 'H Nuclear Magnetic Resonance Spectroscopy (CDCL) analysis method signal is shown (δ, ppm).

6.94 (2H, double line, J-8,91) J of H) 5.39 (IH, double line, J=4.95HzX1
β-H at position 4) 3.87 (3H, - line) (H of methoxy group of anisoyl group) 3.80 (3H, - double line) (H of α-methoxy group at position 16) 1.05 (3H, triple line, J=7.25Hz) (
Methyl H of N-ethyl group) 5) 13C nuclear magnetic resonance spectrum (CDCQ3)
The signal of the analytical method is shown (δ, ppm).

211.7 (C of carbonyl group at position 15) 1,65,
8 (C of carbonyl of anisoyl group) 164.0.1
31.7 (2C), 121.6.113.8 (2C)
(C of anisoyl group) 86.1.84.0.83.6.78.3.77.4.
77.0.71.9 (16,6,l, 14.18.
C at position 13.3) 49.1 (C of methylene in N-ethyl group) 13.4 (C of methyl in N-ethyl group) 6) E
l-Mass spectrum analysis m/z 615 (M"") 7) [α] = -58,9° (c-0,55, ethanol) 8) High-resolution mass spectrometry calculation value C33H4, NO, 6615, 3043 Actual value 615.3050 (8) Physical properties and analytical data of 8-deoxy-15-oxo-16-β-methoxy-14-anisoylaconine l) Properties and solubility Colorless amorphous powder ether, chloroform, Soluble in benzene, ethanol, methanol, acetone, ethyl acetate, pyridine, dimethyl sulfoxide, insoluble in hexane and water.

2] Infrared absorption spectrum (KBr) analysis 3484,
The maximum absorption is shown at 1711 cm-'.

3) Ultraviolet absorption spectrum (ethanol) analysis A iM
HgH"gt ) nm -258(4,00)4)1H
Signals of nuclear magnetic resonance spectroscopy (CDCQx) analysis method are shown (δ, ppm).

5.14 (IH, doublet, J 3.96HzX β-H at position 14) 3.86 (3H, -double line) (H of methoxy group of anisoyl group) 3.63 (3H, -double line) (!()1.03(3)T of β-methoxy group at position 16, triplet, J=7..25H
zXN-H of methyl of ethyl group) 5) "Signal of C nuclear magnetic resonance spectroscopy (CDCL) analysis method is shown (δ, ppm).

211.9 (C of carbonyl group at position 15) 166.8 (
C) 163.6.131. of carbonyl of anisoyl group.
9(2G), 121.9.113.7(2C) (C of anisoyl group) 89.2. '84.1.83.5.79.2.77.4
．． 76.6.71.5 (16, 6, 1, 14, 18, 1
C at position 3,3) 49.1 (C of methylene of N-ethyl group)
)13.3(C of methyl of N-ethyl group)5) El
-Mass spectrum analysis m/z 615 (M7) Ca ) F − + 20.5' (c = 0.
43. 8) High-resolution mass spectrometry calculation value C33H,INO,t+ 615.3043 Actual measurement value 615.3042 Experimental examples regarding the pharmacological action and acute toxicity of the compound according to the present invention are shown below.

[Experiment Example 1) (Analgesic effect) ■S
td:ddY male mice (20-25 g) were used. Animals were kept at room temperature 24-25°C, fed ad libitum, with raw water and 1
The animals were reared under light and dark conditions with a 2-hour cycle.

The test drug was used as a 3% gum arabic suspension.

0.7% acetic acid 10 minutes after test drug administration (s, c,).
A 9% physiological saline solution was injected intraperitoneally at a rate of 10 raQ/kg, and the number of writhings that appeared within 10 minutes after the injection was counted. 3% gum arabic/Q as a negative control;
9% physiological saline was used. Also, EDi. The value was calculated based on the Litchf 1eld-Wilcoxon method, with 1/2 or less of the number of risings in the negative control group being considered positive for analgesic activity. The results are shown in Table 1.

As shown in Table 1, the compounds according to the invention were found to have dose-dependent analgesic activity.

[Experiment Example 2] (Anti-inflammatory effect) ■For the measurement experiment of carrageenan footprint edema, Std: ddY male mice (20 to 25
9) was used. 30 minutes after oral administration of the drug, carrageenan suspended in 0.9% physiological saline (0,5 rx 9/2
5μA) was injected subcutaneously into the right hind leg of the mouse as an inflammatory agent. As a control, 25 μQ of 0.9% physiological saline was injected subcutaneously into the hoof of the left hind leg. Paw thickness was measured using a dial gauge caliber and measured 1 day after carrageenan administration.
．． Measurements were taken at 2.3.4.5 and 6 hours. The results were expressed as the difference in thickness between the left and right feet. The results are shown in Table 2.

As shown in Table 2, the compounds according to the present invention were found to have a carrageenan footpad edema suppressing effect.

[Experiment Example 3] (Acute toxicity) Std:ddY male mice (20-25g) were used for the experiment.
It was used. LiL is determined from the number of deaths 72 hours after administration of the test drug.
LDio based on the chfield-Wilcoxon method
The value was calculated. The results are shown in Table 3.

As shown in Table 3, the compounds according to the present invention were found to have lower toxicity than mesaconitine, aconitine, hibaconitine, and diesaconitine.

As described above, it has been revealed that the compound according to the present invention has lower toxicity than mesaconitine, aconitine, hivaconitine, and deesaconitine, and also has strong analgesic and anti-inflammatory activities.

The clinical dosage of the analgesic/anti-inflammatory agent according to the present invention is preferably 0.1=100119/day for adults as the active ingredient.

The preparations of the present invention can be used in a conventional manner with any necessary pharmaceutical carriers or excipients.

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

For injection preparations, the compound according to the present invention may be used in the form of a salt, preferably a form dissolved before use. It may also contain formulation agents such as suspending, stabilizing or dispersing agents, sterile distilled water, essential oils such as peanut oil, corn oil or non-aqueous solvents, polyethylene glycol, polypropylene glycol, etc. It's okay.

For rectal administration, it may be provided in the form of a suppository composition and may contain pharmaceutical carriers well known in the art, such as evaporated polyethylene glycol, lanolin, coconut oil, and the like.

For topical application, it may be provided in the form of ointment compositions or ointment compositions, using pharmaceutical carriers well known in the art, such as petrolatum, paraffin, hydrated lanolin, plastibase, parent petrolatum, macrogols, waxes, It may contain resin, purified lanolin, rubber, etc.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is benzoyl or anisoyl, R_2 is methyl or ethyl, R_3 is a hydroxyl group or hydrogen, R_4 is α-methoxy or β-methoxy. However, when R_1 is benzoyl and R_3 is a hydroxyl group, R_2 is not methyl or ethyl. When R_1 is anisoyl, R_3 is a hydroxyl group, and R_4 is β-methoxy, R_2 is not ethyl.) Aconitine compound represented by 2. General formula, ▲Mathematical formula, chemical formula, table, etc.▼(II) (In the formula, R_1 is benzoyl or anisoyl, R_2 is methyl or ethyl, R_3 is hydroxyl group or hydrogen, R_4 is α-methoxy or β-methoxy. An analgesic/anti-inflammatory agent containing an aconitine compound represented by (shown below) as an active ingredient.