JP3466527B2 - New aconitine compounds and analgesic / anti-inflammatory agents - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel aconitine compound and an analgesic / anti-inflammatory agent containing the compound as an active ingredient.

[0002]

BACKGROUND ART It has already been reported that an aconitine alkaloid substance contained in tuberous roots of aconite plants has a strong analgesic action and anti-inflammatory action. However, aconitine alkaloids are highly toxic and therefore
It was said that the safety margin was narrow.

The present inventor has conducted various studies in order to obtain a novel aconitine alkaloid derivative which retains the analgesic / anti-inflammatory action of aconitine alkaloid substance and has low toxicity. Formula (I)
We have succeeded in providing a novel compound represented by. Further, the present inventors have found that the compound represented by the general formula (I) has a strong analgesic / anti-inflammatory activity, and further comprises mesaconitine,
It was found to be less toxic than aconitine, hypaconitine and jesaconitine. The present invention has been made based on such findings.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound represented by the following general formula (I), and an analgesic / anti-inflammatory agent containing the compound represented by the general formula (I). Is provided.

More specifically, the present invention has the general formula;

[Chemical 3] [Wherein, R ₁ is m-chlorobenzoyl or veratroyl or acetyl, 4-methylpentyl, crotyl or benzyl, R ₂ is methyl or ethyl, and R _{3 is}
And R ₄ are each hydrogen or a hydroxyl group, and R ₅ is
It is a hydroxyl group, and R ₆ is a hydroxyl group or a group forming a carbonyl group with the carbon atom at the 15-position.]
And an analgesic / anti-inflammatory agent containing the aconitine compound represented by the general formula (I) as an active ingredient.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the above formula (I) according to the present invention includes aconitine represented by the following formula (III), mesaconitine represented by the following formula (IV) and the following formula (V ) Hypaconitine represented by the following formula, Jesaconitine represented by the following formula (VI), 14-benzoylmethaconine represented by the following formula (VII), 14-benzoylaconine represented by the following formula (VIII), the following formula 14-benzoylhypaconine represented by (IX), 14-anisoylaconine represented by the following formula (X), pyrroaconitines and epipyroaconitines represented by the following formula (XI), etc. Using the aconitine alkaloid of as a starting material, performing a deoxygenation reaction at the 3-position, 8-position, 13-position or 15-position, or replacing the substituent bonded to the nitrogen atom or the 14-position with various substituents, Furthermore, the reaction of those combinations is performed. It can be produced by.

[0007]

[Chemical 4] R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 in} each formula of formulas (III) to (X)
Is as shown in the table below.

[0008]

[Chemical 5] [R ₁ is CH ₃ or C ₂ H ₅ , R ₂ is OH or H, and
₃ is Bz or An]

The above deoxidation reaction can be carried out by using an ionic reaction, a radical reaction, a reduction reaction or the like which is usually used in a chemical reaction, or by using a combination thereof. The ionic reaction can be carried out by heating under reflux with a dehydrating agent such as sulfuric acid or thionyl chloride as a solvent, and in a suitable solvent such as tetrahydrofuran in the presence of imidazole and sodium hydride. In, under appropriate temperature conditions, carbon disulfide and methyl iodide are stirred or heated under reflux to react to form a thioacylated compound, and tributyltin hydride or the like is added in a solvent such as benzene at room temperature or under reflux. It can be performed by stirring at.

In the reaction for substituting a substituent bonded to a nitrogen atom, first, a compound represented by each of formulas III to XI is treated with a suitable oxidizing agent such as potassium permanganate in a suitable solvent such as acetone. Reaction is performed to obtain an N-dealkylated product. It can be carried out by reacting the obtained N-dealkylated product with an alkylating agent, an acylating agent or the like, for example, an acid chloride, an alkyl halide, an aralkyl halide or the like. In the reaction for substituting the substituent bonded to the 14-position, first, the substituent present in the form of an ester bond at the 14-position is hydrolyzed, for example, deesterified by alkali hydrolysis to form a hydroxyl group, and then a normal chemical reaction is performed. The acid chloride used in the case of esterifying or etherifying the hydroxyl group, a halogen compound, etc.
It can be carried out by reacting the position-deesterified product with a suitable solvent, for example, in pyridine. The radical reaction can be carried out, for example, by using water and hexamethyltriamide phosphate as a solvent and irradiating a low-pressure mercury lamp at room temperature or under cooling. Further, for example, active substitution of the hydroxyl group with oxalyl chloride or the like is possible. As a group, a radical generating reagent such as αα′-azoisobutyronitrile and a reducing agent such as tributyltin hydride can be added to a solvent such as benzene, and the mixture can be heated under reflux or stirred at room temperature.

The reduction reaction is carried out by catalytic hydrogenation in a solvent such as ethanol or acetic acid using platinum oxide, palladium carbon or Raney nickel as a catalyst at room temperature or under heating. You can Further, in the above deoxygenation reaction, the hydroxyl group is converted into a ketone using an oxidant, such as sodium dichromate,
After introducing ethanedithiol or p-toluenesulfonylhydrazine etc. to thioketal or hydrazone, an organometallic reducing agent such as hydrogen at room temperature, with heating or cooling, using ether or tetrahydrofuran etc. as a solvent. It can be carried out by reduction with lithium aluminum chloride and its alkoxy derivative. Furthermore, the compound represented by the above formula (I) can be obtained by variously combining the above reactions.

The following are examples of producing compounds of the formula (I). Physical properties and analytical data of the compounds obtained in each example are listed after the description of the examples. Further, the pharmacological action, toxicity, etc. of the compounds are listed in Tables 1 to 3 below.

[0013]

EXAMPLES Example 1 70 mg of aconitine is dissolved in 5 ml of methanol, 1 ml of 5% potassium hydroxide is added, and the mixture is heated under reflux for 3 hours. The methanol in the reaction solution was distilled off under reduced pressure, 5 ml of water was added, and the mixture was extracted 3 times with 10 ml of methylene chloride. The extract is dried over Glauber's salt and concentrated to dryness under reduced pressure. The residue is subjected to thin layer chromatography (eluent: 10% methanol / ammonia saturated chloroform), separated and purified to obtain 32 mg of aconine. 30 mg of aconine is dissolved in 1 ml of pyridine, 30 mg of 3,4-dimethoxybenzoyl chloride is added, and the mixture is stirred at 80 ° C. for 4 hours.
After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (ammonia saturated ether), separated and purified to obtain 14 mg of 14-O-veratroyl aconine.

Example 2 The same operation as in Example 1 is carried out to obtain aconine. Dissolve 30 mg of aconine and 20 mg of p-toluenesulfonic acid in 1.5 ml of acetic anhydride, and stir at room temperature for 1 hour. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, ice water is added to the residue, the mixture is made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (ammonia saturated ether) to give 14-O-acetylaconine.
You get 28 mg.

Example 3 The same operation as in Example 1 is carried out to obtain aconine. Dissolve 30 mg of aconine in 1 ml of pyridine, add 30 mg of -m-chlorobenzoyl chloride, and stir at 80 ° C for 4 hours. After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure.
The residue was subjected to silica gel column chromatography (ammonia saturated ether), separated and purified, and 14-Om-
2.1 mg of chlorobenzoyl aconine are obtained.

Example 4 The same operation as in Example 1 is carried out to obtain aconine. Dissolve 30 mg of aconine in 2 ml of 1,2-dimethoxyethane, add 60 mg of sodium hydride, and stir at room temperature for 30 minutes. Benzyl chloride 50
Add μl and heat to reflux for 3 hours. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (ammonia saturated chloroform) to give 14-O-
20 mg of benzylaconine are obtained.

Example 5 The same operation as in Example 1 is carried out to obtain aconine. Dissolve 30 mg of aconine in 3.6 ml of 1,2-dimethoxyethane, add 90 mg of sodium hydride, and stir at room temperature for 30 minutes. 0.9 ml of 1-bromo-4-methylpentane is added to this reaction solution, and the mixture is heated under reflux for 30 minutes. After completion of the reaction, the reaction solution is poured into ice water and extracted with chloroform.
The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (ammonia saturated chloroform),
20 mg of 14-O- (4-methyl) pentylaconine are obtained.

Example 6 The same operation as in Example 1 is carried out to obtain aconine. Dissolve 30 mg of aconine in 4 ml of 1,2-dimethoxyethane, add 50 mg of sodium hydride, and stir at room temperature for 30 minutes. Crotyl chloride 0.8 was added to this reaction solution.
Add ml and heat to reflux for 30 minutes. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (5
% Methanol / ammonia saturated chloroform) to separate and purify to obtain 14 mg of 14-O-crotylaconine.

Example 7 50 mg of 3,13-dideoxygesaconitine was added to 2 ml of dioxane.
Dissolve in a mixture of water and 2 ml of water, and heat to reflux for 4 hours. After cooling
The solvent is distilled off under reduced pressure. The residue was subjected to thin layer chromatography (eluent: 5% methanol / ammonia saturated chloroform), separated and purified to give 3,13-dideoxy-14-O-.
38 mg of anisoyl aconine are obtained. Dissolve 70 mg of 3,13-dideoxy-14-anisoylaconine in 5 ml of methanol and add 1 ml of 5% potassium hydroxide,
Heat to reflux for hours. The methanol in the reaction solution was distilled off under reduced pressure, 5 ml of water was added, and the mixture was extracted 3 times with 10 ml of methylene chloride. The extract is dried over Glauber's salt and concentrated to dryness under reduced pressure. The residue was subjected to thin layer chromatography (eluent: 10% methanol).
(30 ml of chloroform / ammonia saturated chloroform), separated and purified to obtain 30 mg of 3,13-dideoxyaconine. Dissolve 30 mg of 3,13-dideoxyaconine in 1 ml of pyridine, add 30 mg of 3,4-dimethoxybenzoyl chloride, and add at 80 ° C.
Stir for 4 hours. After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (ammonia saturated ether), separated and purified to give 3,13.
-Dideoxy-14-veratroyl aconine 18 mg is obtained.

Example 8 The same operation as in Example 7 was carried out to obtain 3,13-dideoxyaconine. 30 mg of 3,13-dideoxyaconine and 20 mg of p-toluenesulfonic acid are dissolved in 1.5 ml of acetic anhydride, and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, ice water is added to the residue, the mixture is made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated ether) to obtain 31 mg of 3,13-dideoxy-14-O-acetylaconine.

Example 9 The procedure of Example 7 was repeated except that 30 mg of m-chlorobenzoyl chloride was used in place of the 3,4-dimethoxybenzoyl chloride of Example 7,
3,13-Dideoxy-14-Om-chlorobenzoylaconine 1.
You get 5 mg.

[Example 10] The same operation as in Example 7 and carried out to obtain 3,13-dideoxyaconine. 30 mg of 3,13-dideoxyaconine is dissolved in 2 ml of 1,2-dimethoxyethane, 60 mg of sodium hydride is added, and the mixture is stirred at room temperature for 30 minutes. To this reaction solution, add 50 μl of benzyl chloride, and add 3
Heat to reflux for hours. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (ammonia saturated chloroform) to give 3,13-dideoxy-14.
16 mg of -O-benzylaconine are obtained.

[Example 11] By the same operation as in Example 7 and 3,3,3-dideoxyaconine was obtained. Dissolve 30 mg of 3,13-dideoxyaconine in 3.6 ml of 1,2-dimethoxyethane, add 90 mg of sodium hydride, and stir at room temperature for 30 minutes. 0.9 ml of 1-bromide-4-methylpentane was added to this reaction solution.
And heat to reflux for 30 minutes. After completion of the reaction, the reaction solution is poured into ice water and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated chloroform) to obtain 15 mg of 3,13-dideoxy-14-O- (4-methylpentyl) aconine.

[Example 12] The same operation as in Example 7 and carried out to obtain 3,13-dideoxyaconine. Dissolve 3,13-dideoxyaconine (30 mg) in 1,2-dimethoxyethane (4 ml), add sodium hydride (50 mg), and stir at room temperature for 30 minutes. To this reaction solution, add 0.8 ml of crotyl chloride,
Heat to reflux for minutes. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (5% methanol / ammonia saturated chloroform) to give 3,
17 mg of 13-dideoxy-14-O-crotylaconine are obtained.

Example 13 50 mg of 3-deoxygesaconitine is dissolved in a mixed solution of 2 ml of dioxane and 2 ml of water, and the mixture is heated under reflux for 4 hours. After cooling, the solvent is distilled off under reduced pressure. Thin layer chromatography of the residue
(Eluent: 5% methanol / ammonia-saturated chloroform), separated and purified to give 38 mg of 3-deoxy-14-anisoylaconine. 3,13-dideoxy-1 of Example 7
70 mg of 3-deoxy-14-anisoylaconine was used in place of 4-O-anisoylaconine, and the same operation as in Example 7 was carried out otherwise to obtain 35 mg of 3-deoxyaconine. Instead of the 3,13-dideoxyaconine of Example 7, 3
Using 30 mg of -deoxyaconine and otherwise the same operation as in Example 7, 20 mg of 3-deoxy-14-O-veratroylaconine is obtained.

Example 14 The same operation as in Example 13 gives 3-deoxyaconine. 3-deoxyaconine 30 mg and p-toluenesulfonic acid 20 mg are added to acetic anhydride 1.5 ml.
And stir at room temperature for 1 hour. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, ice water is added to the residue, the mixture is made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated ether) to obtain 22 mg of 3-deoxy-14-O-acetylaconine.

Example 15 In place of 3,4, -dimethoxybenzoyl chloride in Example 7, 30 mg of m-chlorobenzoyl chloride was used. 14-Om-chlorobenzoyl aconine 1.7
get mg.

[Example 16] The same operation as in Example 13 gives 3-deoxyaconine. Dissolve 30 mg of 3-deoxyaconine in 2 ml of 1,2-dimethoxyethane, add 60 mg of sodium hydride, and stir at room temperature for 30 minutes. To this reaction solution, add 50 μl of benzyl chloride and heat to reflux for 3 hours. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. Silica gel column chromatography of the residue (ammonia saturated chloroform)
Separated and purified with 3-deoxy-14-O-benzylaconine
You get 14 mg.

Example 17 The same operation as in Example 13 gives 3-deoxyaconine. Dissolve 30 mg of 3-deoxyaconine in 3.6 ml of 1,2-dimethoxyethane, add 90 mg of sodium hydride, and stir at room temperature for 30 minutes. 0.9 ml of 1-bromo-4-methylpentane is added to this reaction solution, and the mixture is heated under reflux for 30 minutes. After completion of the reaction, the reaction solution is poured into ice water and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated chloroform) to give 3-deoxy-14-O- (4-methylpentyl) aconine 16 mg.

Example 18 The same operation as in Example 13 gives 3-deoxyaconine. 30 mg of 3-deoxyaconine is dissolved in 4 ml of 1,2-dimethoxyethane, 50 mg of sodium hydride is added, and the mixture is stirred at room temperature for 30 minutes. 0.8 ml of crotyl chloride is added to this reaction solution, and the mixture is heated under reflux for 30 minutes. After completion of the reaction, the reaction solution is poured into ice water and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (5% methanol / ammonia saturated chloroform) to give 3-deoxy-14-O-.
Obtain 15 mg of crotyl aconine.

Example 19 70 mg of pyrogesaconitine was added to 5 ml of 90% aqueous methanol solution.
15 mg of potassium carbonate, and the mixture is stirred at room temperature for 40 hours. After distilling off the methanol in the reaction solution under reduced pressure, water was added.
Add 5 ml and extract 3 times with 10 ml of methylene chloride. The extract is dried over Glauber's salt and concentrated to dryness under reduced pressure. The residue was subjected to thin layer chromatography (eluent: 10% methanol / ammonia saturated chloroform), separated and purified to obtain 30 mg of 16-epi-pyroaconine. 30 mg of 16-epi-pyroaconine is dissolved in 1 ml of pyridine, 20 mg of m-chlorobenzoyl chloride is added, and the mixture is stirred at 80 ° C for 4 hours. After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure.
The residue was subjected to silica gel column chromatography (ammonia saturated ether), separated and purified, and 14-Om-
1.2 mg of chlorobenzoyl-16-epi-pyroaconine are obtained.

Example 20 The same operation as in Example 19 gives 16-epi-pyroaconine. Acetic anhydride was added to 16 mg of 16-epi-pyroaconine and 20 mg of p-toluenesulfonic acid.
Dissolve in 1.5 ml and stir at room temperature for 1 hour. After the reaction,
Acetic anhydride was distilled off under reduced pressure, ice water was added to the residue, the mixture was made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. After washing the chloroform layer with water and drying with Glauber's salt,
Concentrate to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated ether) to obtain 14 mg of 14-O-acetyl-16-epi-pyroaconine.

Example 21 100 mg of pyrogesaconitine is dissolved in 1.5 ml of thionyl chloride and heated under reflux for 3 hours. After cooling, thionyl chloride is distilled off under reduced pressure. Ice water was added to the residue, and the mixture was made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then with 30 ml of chloroform.
Extract 3 times. The chloroform layers are combined, washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: ammonia saturated ether: n-hexane = 4: 1), separated and purified to obtain 35 mg of 3-deoxypyrrogesaconitine. Next, 70 mg of anhydrogesaconitine is dissolved in 10 ml of ethanol, 33 mg of platinum oxide is added, and the mixture is vigorously stirred under a hydrogen stream for 1.5 hours. After completion of the reaction, the catalyst is filtered and the filtrate is concentrated to dryness under reduced pressure. Silica gel column chromatography of the residue
(Eluent: ammonia saturated ether: n-hexane = 4: 1)
Then, isolate, purify, and add 37 mg of 3-deoxygesaconitine.
To get Dissolve 35 mg of 3-deoxypyrrogesaconitine in 3 ml of 90% aqueous methanol solution, add 10 mg of potassium carbonate, and stir at room temperature for 40 hours. After distilling off the methanol in the reaction solution under reduced pressure, 5 ml of water was added, and 3 ml of 10 ml of methylene chloride was added.
Extract twice. The extract is dried over Glauber's salt and concentrated to dryness under reduced pressure. Thin layer chromatography of the residue (eluent: 10%
Isolate and purify to obtain 20 mg of 3-deoxy-16-epi-pyroaconine. 20 mg of 3-deoxy-16-epi-pyroaconine and 1 of pyridine
Dissolve in 80 ml, add 20 mg of m-chlorobenzoyl chloride,
Stir at ℃ for 4 hours. After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. Silica gel column chromatography of the residue
(Ammonia saturated ether), separated and purified,
1.0 mg of deoxy-14-Om-chlorobenzoyl-16-epi-pyroaconine are obtained.

Example 22 The same operation as in Example 21 gives 3-deoxy-16-epi-pyroaconine. 3-
20 mg of deoxy-16-epi-pyroaconine and 20 mg of p-toluenesulfonic acid are dissolved in 1.5 ml of acetic anhydride and stirred at room temperature for 1 hour. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, ice water is added to the residue, the mixture is made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated ether) to obtain 10 mg of 3-deoxy-14-O-acetyl-16-epi-pyroaconine.

Example 23 100 mg of pyrogesaconitine was dissolved in 10 ml of pyridine,
0.5 ml of trifluoromethanesulfonic anhydride was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution is poured into ice water to make it ammonia alkaline, and then extracted three times with 50 ml of chloroform. The chloroform layers are combined, washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ammonia saturated ether: n-hexane = 4: 1), separated,
Purification gives 13-O-trifluoromethanesulfonyl-anhydrogesaconitine 98 mg. Next, 90 mg of 13-O-trifluoromethanesulfonyl-anhydrogesaconitine was mixed with hexamethylphosphoric triamide and water (95:
5) Dissolve it in 100 ml, and irradiate it with a 2537Å low-pressure mercury lamp for 1 hour at 0 ° C under a nitrogen stream. After completion of the reaction, the reaction solution is diluted with 5 volumes of water to make it ammonia alkaline, and then extracted with 500 ml of ether three times. The ether layers are combined, washed with water, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ammonia saturated ether: n-hexane = 4: 1), separated and purified to obtain 41 mg of 13-deoxyanhydrogesaconitine. Next, 13-deoxyanhydrogesaconitine 40mg
Was dissolved in 7 ml of ethanol, 15 mg of platinum oxide was added, and the mixture was vigorously stirred under a hydrogen stream for 1.5 hours. After completion of the reaction, the catalyst is filtered and the filtrate is concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ammonia saturated ether: n-hexane = 4: 1) to separate and purify the product, which was then added to 3,1.
35 mg of 3-dideoxypyrrogesaconitine are obtained. Dissolve 35 mg of 3,13-dideoxypyrogesaconitine in 3 ml of 90% aqueous methanol solution, add 10 mg of potassium carbonate, and add 40 mg at room temperature.
Stir for hours. The methanol in the reaction solution was distilled off under reduced pressure, 5 ml of water was added, and the mixture was extracted 3 times with 10 ml of methylene chloride.
The extract is dried over Glauber's salt and concentrated to dryness under reduced pressure. The residue was subjected to thin layer chromatography (eluent: 10% methanol /
Ammonia saturated chloroform), separated and purified,
20 mg of 3,13-dideoxy-16-epi-pyroaconine is obtained. 20 mg of 3,13-dideoxy-16-epi-pyroaconine is dissolved in 1 ml of pyridine, 20 mg of m-chlorobenzoyl chloride is added, and the mixture is stirred at 80 ° C for 4 hours. After completion of the reaction, pyridine is distilled off under reduced pressure, water is added to the residue, the mixture is made alkaline with 5% aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is subjected to silica gel column chromatography (ammonia saturated ether), separated and purified to obtain 1.0 mg of 3,13-dideoxy-14-Om-chlorobenzoyl-16-epi-pyroaconine.

Example 24 The same operation as in Example 23 gives 3,13-dideoxy-16-epi-pyroaconine. 3,13-Dideoxy-16-epi-pyroaconine 20 mg and p-
Dissolve 20 mg of toluenesulfonic acid in 1.5 ml of acetic anhydride and stir at room temperature for 1 hour. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, ice water is added to the residue, the mixture is made alkaline with 5% sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried over Glauber's salt, and concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (ammonia saturated ether) to obtain 3,13-dideoxy-14-O-acetyl-16-epi-pyroaconine 10 mg.

Next, the physical property values and analytical data of the compounds of each Example are shown. The number of each compound corresponds to the example number. (1) Physical properties and analytical data of 14-O-veratroylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, 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 1720 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 6.89-7.68 (3H, m) (H of veratroyl group) 4.97 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.92 (6H, s) (H of methoxy group of veratroyl group) 3.71 (3H, s) (H of 1, 6, 16 and 18 methoxy groups) 3.31 (3H, s) (〃) 3.29 (3H, s) (〃) 3.25 (3H, s) (〃) 1.10 (3H, t J = 7.0 Hz) (H of methyl N-ethyl) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 166.0 (carbonyl C of veratroyl group) 122.5, 110.6, 153.1, 148.3, 112.3 (C of veratroyl group) 90.8, 83.5, 82.4, 81.9, 79.5, 78.6, 77.3, 74.8, 71.
9 (C in 16,6,1,15,14,8,18,13,3 position) 55.8 (C in methoxy group of veratroyl group) 60.9, 59.1, 58.0, 55.6 (16,18,6,1 position C of methoxy group 48.4 (C of methylene of N-ethyl) 13.5 (C of methyl of N-ethyl) 6) Mass spectrum analysis m / z 663 (M ⁺ ) 7) Elemental analysis C ₃₄ H ₄₉ NO ₁₂ , calculation Value C: 61.52, H: 7.44, N: 2.11 Actual value C: 61.80, H: 7.56, N: 2.09

(2) Physical properties and analytical data of 14-O-acetylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol , Soluble in ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1713 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 4.95 (1H, d, J = 4.8 Hz) (βH at 14th position) 3.71 (6H, s) (H at methoxy group at 1, 6, 16 and 18th position) 3.31 (3H, s) (〃) 3.29 (3H , s) (〃) 3.25 (3H, s) (〃) 2.01 (3H, s) (methyl H of acetyl group) 1.10 (3H, t J = 7.0 Hz) (H of methyl N-ethyl) 4) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 171.5 (C of carbonyl of acetyl group) 90.7, 83.5, 82.4, 79.9, 79.5, 78.6, 77.3, 74.8, 7
1.9 (16,6,1,15,14,8,18,13,3
C at position 60.9, 59.1, 58.0, 55.6 (C at methoxy group at positions 16, 18, 6, 1) 49.0 (C at methylene of N-ethyl) 13.3 (C at methyl of N-ethyl) 21.5 (acetyl group C) 5) Mass spectral analysis of methyl of m / z 541 (M ⁺ )

(3) Physical properties and analytical data of 14-Om-chlorobenzoylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol, Soluble in methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.98-7.31 (4H, m) (H of m-chlorobenzoyl group) 4.89 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.71 (3H, s) (1,6, 16 and 18th position) H of methoxy group 3.31 (3H, s) (〃) 3.28 (3H, s) (〃) 3.24 (3H, s) (〃) 1.02 (3H, t J = 7.0 Hz) (H of N-ethyl methyl) ) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis 166.0 (C of carbonyl of m-chlorobenzoyl group) 131.5, 130.0, 129.5, 135.1, 128.3 (C of m-chlorobenzoyl group) 90.7, 83.4, 82.3, 82.0, 79.4, 78.6, 77.3, 74.7, 7
2.0 (16,6,1,15,14,8,18,13,3
Position C) 60.9, 59.1, 57.9, 55.6 (C of methoxy group at position 16, 18, 6, 1) 48.8 (C of N-ethyl methylene) 13.0 (C of N-ethyl methyl) 6) Mass spectrum Analysis m / z 637,639 (M ⁺ ) 7) Elemental analysis C ₃₂ H ₄₄ NO ₁₀
Cl, Calculated value C: 60.23, H: 6.95, N: 2.19 Measured value C: 60.33,
H: 7.11, N: 1.97

(4) Physical properties and analytical data of 14-O-benzylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol. , Soluble in ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.28 (5H, s) (H of benzyl group) 4.50 (2H, s) (H of methylene of benzyl group) 3.70 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) 3.31 (3H , s) (〃) 3.29 (3H, s) (〃) 3.25 (3H, s) (〃) 1.09 (3H, t, J = 7.0 Hz) (N-ethyl methyl H) 5) ¹³ C nuclear magnetism Resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 126.7, 127.0, 128.6, 141.7 (benzyl group C) 64.0 (benzyl group methylene C) 90.8, 83.4, 82.1, 81.9, 79.5, 78.8, 77.3, 74.6, 7
1.9 (16,6,1,15,14,8,18,13,3
Position C) 60.9, 59.1, 57.9, 55.6 (C of methoxy group at position 16, 18, 6, 1) 49.0 (C of N-ethyl methylene) 13.1 (C of N-ethyl methyl) 6) Mass spectrum Analysis m / z 589 (M ⁺ )

(5) Physical properties and analytical data of 14-O- (4-methyl) pentylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethano- Soluble in methanol, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water. 2) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 3.70 (3H, s) (H of 1, 6, 16 and 18 methoxy groups) 3.30 (3H, s) (〃) 3.28 (3H, s) (〃) 3.25 (3H, s) (〃) 1.09 ( 3H, t, J = 7.0 Hz) (H of methyl N-ethyl) 1.02 (6H, d, J = 7.0 Hz) (H of methyl 4-methylpentyl) 3) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) Analysis The following signals are shown (δ, ppm). 90.8, 83.4, 82.1, 81.9, 79.5, 78.9, 77.4, 74.5, 7
2.0 (16,6,1,15,14,8,18,13,3
C at position 60.8, 59.0, 58.0, 55.5 (C at methoxy group at position 16, 18, 6, 1) 49.0 (C at methylene of N-ethyl) 13.1 (C at methyl of N-ethyl) 21.1 (4- C) 4) Mass spectral analysis of methyl of methylpentyl m / z 583 (M ⁺ ).

(6) Physical properties and analytical data of 14-O-crotylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, acetic acid. Soluble in ethyl, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.68 (2H, m) (H of double bond of crotyl group) 4.10 (2H, m) (H of methylene of crotyl group) 3.70 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) ) 3.35 (3H, s) (〃) 3.29 (3H, s) (〃) 3.25 (3H, s) (〃) 1.70 (3H, d, J = 6.3 Hz) (H of methyl of crotyl group) 0.90 (3H , t, J = 7.0 Hz) (H of methyl N-ethyl) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 130.7, 123.5 (C of double bond of crotyl group) 90.7, 83.5, 82.3, 82.0, 79.4, 78.8, 77.5, 74.6, 7
2.0 (16,6,1,15,14,8,18,13,3
C at position 60.8, 59.0, 58.1, 55.6 (C at methoxy group at position 16, 18, 6, 1) 49.1 (C at methylene of N-ethyl) 13.9 (C at methyl of N-ethyl) 12.9 (crotyl group C) 6) Mass spectrum analysis of methyl group of m / z 553 (M ⁺ )

(7) 3,13-Dideoxy-14-O-
Physical Properties and Analytical Data of Veratroylaconine 1) Properties and Solubility A colorless amorphous powder which can be used in ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethyl sulfoxide. Soluble and insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1720 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 6.89-7.70 (3H, m) (H of veratroyl group) 5.03 (1H, t, J = 4.8 Hz) (βH of 14th position) 3.92 (6H, s) (H of veratroyl group) 3.58 (3H, s) ( 1,6,16 and 18th H) 3.29 (3H, s) (〃) 3.27 (3H, s) (〃) 3.21 (3H, s) (〃) 1.10 (3H, t, J = 7.0 Hz) ( N-Ethyl methyl H) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 166.0 (C of veratroyl group carbonyl) 122.7, 110.4, 153.2, 148.1 112.4 (C of veratroyl group) 89.7, 85.2, 83.6, 81.7, 79.9, 78.6, 77.5 (16,
C at 1,6,18,15,8,14 position) 55.8 (C of methoxy group of veratroyl group) 59.1, 57.9, 57.6, 55.6 (C of methoxy group of 18,16,6,1 position) 49.0 (N -Ethyl methylene C) 13.2 (N-ethyl methyl C) 6) mass spectral analysis m / z 631 (M ⁺ ).

(8) 3,13-dideoxy-14-O-
Physical properties and analytical data of acetylaconine 1) Properties and solubility A colorless amorphous powder, applicable to ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethyl sulfoxide. It is soluble and insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 4.93 (1H, t, J = 4.8 Hz) (βH at 14th position) 3.59 (3H, s) (H at methoxy groups at 1, 6, 16 and 18th positions) 3.30 (3H, s) (〃) 3.27 (3H , s) (〃) 3.21 (3H, s) (〃) 2.02 (3H, s) (acetyl-methyl H) 1.10 (3H, t, J = 7.0 Hz) (N-ethyl-methyl H) 4 ) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis 171.4 (carbonyl C of acetyl group) 89.8, 85.2, 83.6, 81.7, 79.9, 78.6, 77.5 (16,
1,6,18,15,8,14 position C) 59.2, 57.8, 57.6, 55.5 (18,16,6,1 position methoxy group C) 49.0 (N-ethyl methylene C) 13.2 (N -Ethyl methyl C) 21.4 (methyl acetyl group C) 5) mass spectral analysis m / z 509 (M ⁺ ).

(9) 3,13-Dideoxy-14-O-
Physical properties and analytical data of m-chlorobenzoyl aconine
1) Properties and solubility A colorless amorphous powder, soluble in ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. . 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.95-7.28 (4H, m) (H of m-chlorobenzoyl) 5.01 (1H, t, J = 4.9 Hz) (βH at 14th position) 3.59 (3H, s) (methoxy at 1, 6, 16 and 18th positions) H) 3.30 (3H, s) (〃) 3.27 (3H, s) (〃) 3.21 (3H, s) (〃) 1.12 (3H, t, J = 7.0 Hz) (H of N-ethyl methyl 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 165.5 (C of carbonyl of m-chlorobenzoyl group) 131.4, 130.0, 129.5, 135.1, 128.4 (C of m-chlorobenzoyl group) 89.6, 85.0, 83.6, 81.8, 80.0, 78.5, 77.5 (16,
1,6,18,15,8,14 position C) 59.0, 57.8, 57.6, 55.6, (18,16,6,1 position methoxy C) 49.1 (N-ethyl methylene C) 13.0 (N C) 6) Mass spectrometric analysis of methyl ethyl-m / z 605,607 (M ⁺ )

(10) 3,13-dideoxy-14-O
-Physical properties and analytical data of benzylaconine 1) Properties and solubility A colorless amorphous powder, which can be used in ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethyl sulfoxide. Soluble and insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.28 (5H, s) (benzyl H) 4.50 (2H, s) (benzyl methylene H) 3.61 (3H, s) (1, 6, 16 and 18 methoxy H) 3.31 (3H , s) (〃) 3.28 (3H, s) (〃) 3.26 (3H, s) (〃) 1.09 (3H, t, J = 7.0 Hz) (N-ethyl methyl H) 5) ¹³ C nuclear magnetism Resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 126.7, 127.0, 128.6, 141.6 (benzyl group C) 64.1 (benzyl group methylene C) 89.8, 85.3, 83.7, 81.8, 79.7, 78.5, 77.4 (16,
1,6,18,15,8,14 position C) 59.3, 58.0 57.6, 55.5 (18,16,6,1 position methoxy C) 49.3 (N-ethyl methylene C) 14.0 (N-ethyl C) 6) Mass spectrometric analysis of methyl of m / z 557 (M ⁺ )

(11) 3,13-dideoxy-14-O
Physical properties and analytical data of-(4-methyl) pentylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, ethyl acetate, Soluble in pyridine and dimethyl sulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis A maximum absorption is shown at 3450 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 3.61 (3H, s) (H of 1, 6, 16 and 18-position methoxy groups) 3.30 (3H, s) (〃) 3.29 (3H, s) (〃) 3.26 (3H, s) (〃) 1.10 ( 3H, t, J = 7.0 Hz) (H of methyl group of N-ethyl group) 1.02 (6H, t, J = 7.0 Hz) (H of methyl of 4-methylpentyl) 4) ¹³ C Nuclear magnetic resonance spectrum ( CDCl ₃ ) analysis shows the following signals (δ, ppm). 89.7, 85.2, 83.5, 81.7, 79.8, 78.6, 77.3 (16,
1,6,18,15,8,14 position C) 59.3,58.0,57.6,55.4 (18,16,6,1 position methoxy group C) 49.3 (N-ethyl group methylene C) 14.0 (C of methyl of N-ethyl group) 21.3 (C of methyl of 4-methylpentyl) 5) Mass spectrum analysis m / z 551 (M ⁺ ).

(12) 3,13-dideoxy-14-O
-Physical properties and analytical data of crotylaconine 1) Properties and solubility A colorless amorphous powder, soluble in ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethyl sulfoxide. It is insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.68 (2H, m) (H of double bond of crotyl group) 4.09 (2H, m) (H of methylene of crotyl group) 3.58 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) ) 3.30 (3H, s) (〃) 3.27 (3H, s) (〃) 3.23 (3H, s) (〃) 1.72 (3H, d, J = 6.3 Hz) (H for methyl of crotyl group) 0.90 (3H , t, J = 7.0 Hz) (H of methyl group of N-ethyl group) 4) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 130.8, 123.6 (C of double bond of crotyl group) 89.7, 85.0, 83.5, 81.5, 79.8, 78.7, 77.5 (16,
1,6,18,15,8,14 position C) 59.1,58.1,57.7,55.6 (18,16,6,1, methoxy group C) 49.2 (N-ethyl group methylene C) 14.0 (C of methyl of N-ethyl group) 12.8 (C of methyl of crotyl group) 5) Mass spectrum analysis m / z 521 (M ⁺ )

(13) Physical properties and analytical data of 3-deoxy-14-O-veratroylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethano- Soluble in methanol, ethyl acetate, pyridine and dimethyl sulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1720 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 6.88-7.68 (3H, m) (H of veratroyl group) 4.98 (1H, d, J = 4.7 Hz) (βH at 14th position) 3.92 (6H, s) (H of methoxy group of veratroyl group) 3.70 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) 3.31 (3H, s) (〃) 3.29 (3H, s) (〃) 3.24 (3H, s) (〃) 1.10 (3H, t, J = 7.0 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). 165.9 (carbonyl carbonyl C) 122.5, 110.5, 153.1, 148.2, 112.3 (veratroyl C) 90.8, 85.2, 83.6, 81.9, 81.7, 79.5, 78.6, 74.8
(C at 16,1,6,15,18,14,8,13 position) 55.8 (C at methoxy group of veratroyl group) 60.9, 59.1, 58.0, 55.7 (of methoxy group at 16,18,6,1 position) C) 49.0 (C of methylene of N-ethyl group) 13.2 (C of methyl of N-ethyl group) 6) Mass spectrum analysis m / z 647 (M ⁺ ) 7) Elemental analysis C ₃₄ H ₄₉ NO ₁₁ , calculated value C: 63.04, H: 7.62, N: 2.16 Actual value C: 63.22, H: 7.59, N: 2.13

(14) Physical properties and analytical data of 3-deoxy-14-O-acetylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol , Soluble in methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1713 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 4.96 (1H, d, J = 4.8 Hz) (βH at 14th position) 3.70 (3H, s) (H at methoxy groups at 1, 6, 16 and 18th positions) 3.31 (3H, s) (〃) 3.29 (3H , s) (〃) 3.24 (3H, s) (〃) 4) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 171.6 (C of carbonyl of acetyl group) 90.8, 85.2, 83.3, 81.8, 81.6, 79.5, 78.6, 74.8
(C at 16,1,6,15,18,14,8,13 position) 60.9, 59.0, 58.1, 55.6 (C at methoxy group at 16,18,6,1 position) 49.0 (methylene at N-ethyl group) C) 13.2 (C of methyl of N-ethyl group) 21.5 (C of methyl of acetyl group) 6) Mass spectrum analysis m / z 525 (M ⁺ )

(15) Physical properties and analytical data of 3-deoxy-14-O-m-chlorobenzoylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, It is soluble in ethanol, methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.98-7.30 (4H, m) (H of m-chlorobenzoyl group) 4.87 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.71 (3H, s) (1,6, 16 and 18th position) Methoxy group H) 3.31 (3H, s) (〃) 3.29 (3H, s) (〃) 3.25 (3H, s) (〃) 1.11 (3H, t, J = 7.0 Hz) (N-ethyl group methyl H) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis of the group shows the following signals (δ, ppm). 165.3 (Carbonyl C of m-chlorobenzoyl group) 131.5, 129.9, 129.4, 135.1, 128.4 (C of m-chlorobenzoyl group) 90.7, 85.2, 83.6, 82.0, 81.6, 79.5, 78.6, 74.8
(C at 16,1,6,15,18,14,8,13 position) 60.9, 59.2, 58.1, 55.6 (C at methoxy group at 16,18,6,1 position) 49.1 (methylene at N-ethyl group) C) 13.0 (C of methyl of N-ethyl group) 6) Mass spectrum analysis m / z 621, 623 (M ⁺ )

(16) Physical properties and analytical data of 3-deoxy-14-O-benzylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol , Soluble in methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.28 (5H, s) (H of benzyl group) 4.49 (2H, s) (H of methylene of benzyl group) 3.70 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) 3.31 (3H , s) (〃) 3.29 (3H, s) (〃) 3.27 (3H, s) (〃) 1.10 (3H, t, J = 7.0 Hz) (H of methyl group of N-ethyl group) 5) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 126.6, 127.0, 128.5, 141.7 (benzyl group C) 64.0 (benzyl group methylene C) 90.8, 85.3, 83.7, 81.8, 81.6, 79.5, 78.6, 74.9 (1
6,1,6,15,18,14,8,13 C) 60.7, 59.1, 58.0, 55.6, (16,18,6,1 methoxy C) 49.4 (N-ethyl group C) 14.0 of methylene (C of methyl of N-ethyl group) 6) Mass spectrum analysis m / z 573 (M ⁺ )

(17) 3-deoxy-14-O- (4-
Physical properties and analytical data of (methyl) pentylaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine, dimethyl sulfoxide Soluble in water and insoluble in hexane and water. 2) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 3.71 (3H, s) (H of 1, 6, 16 and 18 methoxy groups) 3.30 (3H, s) (〃) 3.28 (3H, s) (〃) 3.25 (3H, s) (〃) 1.09 ( 3H, t, J = 7.0 Hz) (H of methyl group of N-ethyl group) 1.02 (6H, d, J = 7.0 Hz) (H of methyl of 4-methylpentyl) 5) ¹³ C nuclear magnetic resonance spectrum ( CDCl ₃ ) analysis shows the following signals (δ, ppm). 90.7, 85.4, 83.7, 81.7, 81.5, 79.2, 78.5, 74.8 (1
6,1,6,15,18,14,8,13 position C) 60.8, 59.1, 58.0, 55.5 (16,18,6,1 methoxy group C) 49.4 (N-ethyl group methylene) C) 13.5 (C of methyl of N-ethyl group) 21.0 (C of methyl of 4-methylpentyl) 6) Mass spectrum analysis m / z 567 (M ⁺ )

(18) Physical properties and analytical data of 3-deoxy-14-O-crotylaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, ethanol, methano -Soluble in ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis Absorption maximum is shown at 3300 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.69 (2H, m) (H of double bond of crotyl group) 4.10 (2H, m) (H of methylene of crotyl group) 3.68 (3H, s) (H of methoxy group at 1, 6, 16 and 18 positions) ) 3.40 (3H, s) (〃) 3.29 (3H, s) (〃) 3.25 (3H, s) (〃) 1.71 (3H, d, J = 6.3 Hz) (H of methyl of crotyl group) 0.89 (3H , t, J = 7.0 Hz) (H of methyl N-ethyl group) 4) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 130.8, 123.6 (C of double bond of crotyl group) 90.6, 85.0, 83.5, 82.0, 81.7, 79.5, 78.6, 74.8 (1
6,1,6,15,18,14,8,13 position C) 60.9, 59.2, 57.9, 55.7 (16,18,6,1 position methoxy group C) 49.3 (N-ethyl group methylene C) 13.9 (C of methyl of N-ethyl group) 12.7 (C of methyl group of crotyl group) 5) Mass spectrum analysis m / z 537 (M ⁺ )

(19) Physical properties and analytical data of 16-epi-14-Om-chlorobenzoyl-pyroaconine 1) Properties and solubility A colorless amorphous powder, ether, chloroform, benzene, It is soluble in ethanol, methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.98 to 7.30 (4H, m) (H of m-chlorobenzoyl group) 5.40 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.80 (3H, s) (1,6, 16 and 18th position) H of methoxy group) 3.30 (3H, s) (〃) 3.28 (3H, s) (〃) 3.26 (3H, s) (〃) 1.05 (3H, t, J = 7.0 Hz) (N-ethyl methyl H) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 211.6 (C of carbonyl at 15-position) 165.0 (C of carbonyl of m-chlorobenzoyl group) 131.6, 129.8, 129.5, 135.0, 128.4 (C of m-chlorobenzoyl group) 86.1, 84.1, 83.6, 78.3, 77.4, 76.8 , 71.9 (16,
6,3,14,13,18,3 position C) 62.3,59.2,57.8,56.1 (16,18,6,1 position methoxy group C) 49.1 (N-ethyl methylene C) 13.4 (N -Ethyl methyl C) 6) Mass spectrum analysis m / z 619, 621 (M ⁺ ) 7) Elemental analysis C ₃₂ H ₄₂ NO ₉ Cl, calculated value C: 61.98, H: 6.83, N: 2.26 measured value C : 62.05, H: 6.91, N: 2.05

(20) Physical properties and analytical data of 16-epi-14-O-acetyl-pyroaconine 1) Properties and solubility Colorless, non-crystalline powder, ether, chloroform, benzene, ethanol , Soluble in methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1713 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.24 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.81 (3H, s) (H at methoxy groups at 1, 6, 16 and 18th positions) 3.29 (3H, s) (〃) 3.25 (6H , s) (〃) 1.03 (3H, t, J = 7.0 Hz) (Methyl H of N-ethyl) 2.04 (3H, s) (H of methyl of acetyl group) 4) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) Analysis The following signals are shown (δ, ppm). 211.5 (C of carbonyl at 15-position) 171.3 (C of carbonyl of acetyl group) 86.1, 84.0, 83.5, 78.3, 77.5, 76.8, 71.9 (16,
C at 6,1,14,13,18,3 position 62.4, 59.1, 57.8, 56.1 (C at methoxy group at 16,18,6,1 position) 49.1 (C at methylene N-ethyl) 13.4 (N -Ethyl methyl C) 21.4 (Acetyl methyl C) 5) Mass spectrum analysis m / z 523 (M ⁺ ) 6) Elemental analysis C ₂₇ H ₄₁ NO ₉ , calculated value C: 61.93, H: 7.89, N: 2.67 Actual value C: 61.88, H: 7.77, N: 2.45

(21) 3-deoxy-16-epi-14
Physical properties and analytical data of -Om-chlorobenzoylpyroaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, ethyl acetate , Soluble in pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDC ₁₃ ) analysis The following signals are shown (δ, ppm). 7.97 to 7.30 (4H, m) (H of m-chlorobenzoyl group) 5.39 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.81 (3H, s) (1,6, 16 and 18th position) H of methoxy group) 3.30 (3H, s) (〃) 3.27 (3H, s) (〃) 3.25 (3H, s) (〃) 1.04 (3H, t, J = 7.0 Hz) (of N-ethyl methyl H) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 211.6 (C of carbonyl at the 15-position) 165.1 (C of carbonyl of m-chlorobenzoyl group) 131.8, 129.7, 129.5, 135.0 128.4 (C of m-chlorobenzoyl group) 86.2, 85.0, 83.7, 80.2, 78.4, 77.4, (16, 1,
6,18,14,13 position C) 62.3, 59.2, 57.8, 56.0 (16,18,6,1 position methoxy group C) 49.0 (N-ethyl methylene C) 13.5 (N-ethyl methyl) C) 6) Mass spectrum analysis m / z 603, 605 (M ⁺ ) 7) Elemental analysis C ₃₂ H ₄₂ NO ₈ Cl, calculated value C: 63.62, H: 7.01, N: 2.32 measured value C: 63.41, H : 6.94, N: 2.22

(22) 3-deoxy-16-epi-14
Physical properties and analytical data of -O-acetyl-pyroaconine 1) Properties and solubility Colorless amorphous powder, ether, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine, dimethyl. Soluble in sulfoxide, insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1713 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.20 (1H, d, J = 5.0 Hz) (βH at 14th position) 3.80 (3H, s) (H at methoxy groups at 1, 6, 16 and 18th positions) 3.30 (3H, s) (〃) 3.24 (6H , s) (〃) 1.05 (3H, t, J = 7.0 Hz) (H of methyl N-ethyl) 2.05 (3H, s) (H of methyl acetyl group) 4) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) Analysis The following signals are shown (δ, ppm). 211.6 (C of carbonyl at position 15) 171.2 (C of carbonyl of acetyl group) 86.3, 85.1, 83.5, 80.3, 78.4, 77.2 (16, 1,
6,18,14,13 position C) 62.4, 59.1, 57.9, 56.0 (16,18,6,1 position methoxy group C) 49.1 (N-ethyl methylene C) 13.2 (N-ethyl methyl) C) 21.4 (C of methyl of acetyl group) 5) Mass spectrum analysis m / z 507 (M ⁺ ) 6) Elemental analysis C ₂₇ H ₄₁ NO ₈ , calculated value C: 63.89, H: 8.14, N: 2.76 actual measurement Value C: 64.11, H: 8.36, N: 2.51

(23) Physical properties and analytical data of 3,13-dideoxy-16-epi-14-Om-chlorobenzoylpyroaconine 1) Properties and solubility A colorless amorphous powder, -Soluble in tellurium, chloroform, benzene, ethanol, methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The absorption maximum is shown at 1715 cm ^-1 . 4) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 7.96 to 7.35 (4H, m) (H of m-chlorobenzoyl group) 5.50 (1H, t, J = 5.0 Hz) (βH at 14th position) 3.63 (3H, s) (1,6, 16 and 18th position) H of methoxy group) 3.30 (3H, s) (〃) 3.27 (3H, s) (〃) 3.25 (3H, s) (〃) 1.04 (3H, t, J = 7.0 Hz) (of N-ethyl methyl H) 5) ¹³ C nuclear magnetic resonance spectrum (CDCl ₃ ) analysis shows the following signals (δ, ppm). 211.6 (C of carbonyl at 15-position) 165.0 (C of carbonyl of m-chlorobenzoyl group) 131.8, 129.7, 129.5, 135.0, 128.4 (C of m-chlorobenzoyl group) 85.2, 85.0, 83.7, 80.2, 78.4 (16 , 1, 6, 1
C at the 8,14 position 61.1, 59.2, 57.8, 56.0 (C of the methoxy group at the 16,18,6, 1 position) 49.0 (C of methylene of N-ethyl) 13.4 (C of methyl of N-ethyl) 6 ) Mass spectrum analysis m / z 587, 589 (M ⁺ ) 7) Elemental analysis C ₃₂ H ₄₂ NO ₇ Cl, calculated value C: 65.35, H: 7.20, N: 2.38 measured value C: 65.51, H: 7.25, N : 2.09

(24) Physical properties and analytical data of 3,13-dideoxy-16-epi-14-O-acetyl-pyroaconine 1) Properties and solubility Colorless, non-crystalline powder, ether and chloroform. , Soluble in benzene, ethanol, methanol, ethyl acetate, pyridine and dimethylsulfoxide, but insoluble in hexane and water. 2) Infrared absorption spectrum (KBr) analysis The maximum absorption is shown at 1713 cm ^-1 . 3) ¹ H nuclear magnetic resonance spectrum (CDCl ₃ ) analysis The following signals are shown (δ, ppm). 5.38 (1H, t, J = 5.0 Hz) (βH at 14th position) 3.65 (3H, s) (H at methoxy groups at 1, 6, 16 and 18th positions) 3.30 (3H, s) (〃) 3.25 (6H , s) (〃) 1.05 (3H, t, J = 7.0 Hz) (H of methyl N-ethyl) 2.05 (3H, s) (H of methyl acetyl group) 4) ¹³ C Nuclear magnetic resonance spectrum (CDCl ₃ ) Analysis The following signals are shown (δ, ppm). 211.6 (C of carbonyl at 15-position) 171.2 (C of carbonyl of acetyl group) 85.3, 85.1, 83.5, 80.3, 78.4 (16, 1, 6, 1
C at the 8,14 position 61.4, 59.1, 57.9, 56.0 (C at the methoxy group at the 16,18,6,1 position) 49.1 (C at methylene in N-ethyl) 13.1 (C at methyl in N-ethyl) 21.4 (C of methyl of acetyl group) 5) Mass spectrum analysis m / z 491 (M ⁺ ) 6) Elemental analysis C ₂₇ H ₄₁ NO ₇ , calculated value C: 65.96, H: 8.41, N: 2.85 measured value C: 66.26 , H: 8.55, N: 2.97

Experimental examples of the pharmacological action and acute toxicity of the compound represented by the above formula (I) are shown below. [Experimental Example 1] (Analgesic action) Std: ddY male mice (20 to 25 g) were used for the measurement of the analgesic activity based on the acetic acid lysing method. Animals should be at room temperature 24-25 ° C, ad libitum, water and 1
The animals were raised under light and dark conditions with a 2-hour cycle. The test drug was used as a 3% gum arabic suspension. 30 after administration of test drug (sc)
0.7% acetic acid / 0.9% physiological saline solution was intraperitoneally injected at a rate of 10 ml / kg per minute, and the number of licing expressed 10 to 10 minutes after the injection was counted. As a negative control, 3% gum arabic / 0.9% saline solution was used. In addition, the ED ₅₀ value was calculated based on the Litchfield-Wilcoxon method, assuming that one having a licing number of 1/2 or less in the negative control group was positive for analgesic activity. The results are shown in Table 1. The compounds according to the present invention show a dose-dependent analgesic activity, and as shown in Table 1, it was found that they have a strong analgesic activity.

[Experimental Example 2] (Anti-inflammatory action) Male Std: ddY mice (20 to 25 g) were used in the experiment for measuring carrageenin footpad edema.
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, subcutaneously in the left hind footpad
25 μl of 0.9% saline was injected. The paw thickness was measured using a dial gauge caliper, and 1, 2, 3, 4, 5 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. Litchfie from the lethality 72 hours after subcutaneous administration of the test drug
The LD ₅₀ value was calculated based on the ld-Wilcoxon method. The results are shown in Table 3. As shown in Table 3, the compounds according to the present invention were found to be less toxic than mesaconitine, aconitine, hypaconitine and gesaconitine.

[0064]

[Table 1]

[0065]

[Table 2]

[0066]

[Table 3]

[0067]

[Table 4]

[0068]

[Table 5]

[0069]

As described above, it was revealed that the compound represented by the above formula (I) 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 1 to 1000 mg / day for an adult as the compound of the formula (I). 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 and the like for oral administration include conventional excipients such as calcium carbonate, magnesium carbonate, calcium phosphate, corn starch,
It may contain potato starch, sugar, lactose, talc, magnesium stearate, gum arabic and the like. The tablets may be coated by well known methods.
Liquid oral formulations may be aqueous or oily suspensions, solutions, syrups, elixirs and the like. In the injectable preparation, the compound represented by the above formula (I) may be used in the form of a salt, and a soluble form at the time of use is preferable. It may also contain a formulation such as a suspending agent, stabilizer or dispersant,
It may contain sterilized distilled water, essential oils such as peanut oil, corn oil or non-aqueous solvent, polyethylene glycol, polypropylene glycol and the like.

For rectal administration, it may be provided in the form of a suppository composition and may contain a carrier for formulation well known in the art such as polyethylene glycol, lanolin, coconut oil and the like. For topical application, it is provided in the form of an ointment composition or a plaster composition, and carriers for formulation well known in the art, such as petrolatum, paraffin, hydrolanolin, plastibase, hydrophilic petrolatum, macrogol, It may contain wax, resin, refined lanolin, rubber and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 221/22 A61K 31/435 A61P 25/04 A61P 29/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A general formula; [Wherein, R ₁ is m-chlorobenzoyl or veratroyl or acetyl, 4-methylpentyl, crotyl or benzyl, R ₂ is methyl or ethyl, and R _{3 is}
And R ₄ are each hydrogen or a hydroxyl group, and R ₅ is
It is a hydroxyl group, and R ₆ is a hydroxyl group or a group forming a carbonyl group with the carbon atom at the 15-position.]
An aconitine compound represented by. 2. A general formula; [Wherein R ₁ is m-chlorobenzoyl or peratroyl or acetyl or 4-methylpentyl or crotyl or benzyl, R ₂ is methyl or ethyl, R ₃
And R ₄ are each hydrogen or a hydroxyl group, and R ₅ is
It is a hydroxyl group, and R ₆ is a hydroxyl group or a group forming a carbonyl group with the carbon atom at the 15-position.]
An analgesic / anti-inflammatory agent containing an aconitine compound represented by the following as an active ingredient.