JP2983150B2 - Novel aconitine-type compounds and analgesic / anti-inflammatory agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound having an aconitine-type chemical structure and an analgesic / anti-inflammatory agent containing the compound as an active ingredient. More specifically, the present invention relates to a compound of the general formula (I)

[0002]

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[Wherein, R ₁ is (i) a hydrogen atom or a hydroxyl group, and R ₂ is (i) a hydroxyl group or (ii) acetyloxy or (iii) a carbonyl with a carbon atom at the 15-position. R ₃ is (i) a hydrogen atom or (ii) alkyl or acetyl or propionyl having 1 to 4 carbon atoms, and R ₄ is (i) a hydrogen atom or (ii) a hydroxyl group or ( iii) Acetyloxy. However, when R ₂ is a hydroxyl group or a group which forms a carbonyl together with the carbon atom at position 15, R ₄ is acetyloxy. And a salt thereof having an aconitine-type chemical structure represented by

The general formula (I)

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[Wherein, R ₁ is (i) a hydrogen atom or a hydroxyl group, and R ₂ is (i) a hydroxyl group or (ii) acetyloxy or (iii) a carbonyl with a carbon atom at the 15-position. R ₃ is (i) a hydrogen atom or (ii) alkyl or acetyl or propionyl having 1 to 4 carbon atoms, and R ₄ is (i) a hydrogen atom or (ii) a hydroxyl group or ( iii) Acetyloxy. However, when R ₂ is a hydroxyl group or a group which forms a carbonyl together with the carbon atom at position 15, R ₄ is acetyloxy. The present invention relates to an analgesic / anti-inflammatory agent comprising a novel compound having an aconitine-type chemical structure represented by the following formula or a salt thereof as an active ingredient.

[0006]

BACKGROUND ART It has already been reported that aconitine alkaloid substances contained in tuberous roots of Aconitum plants have strong analgesic and anti-inflammatory effects. However, aconitine alkaloids have been considered to be highly toxic and therefore have a narrow safety margin.

[0007]

DISCLOSURE OF THE INVENTION The present inventor has conducted various studies to obtain a novel aconitine-type alkaloid derivative which retains the analgesic / anti-inflammatory action of an aconitine alkaloid substance and has low toxicity. An aconitine compound and an analgesic / anti-inflammatory agent have been successfully provided (see JP-A-3-223255).

The present invention has been disclosed in Japanese Patent Application Laid-Open No. Hei 3-22325.
Among the compounds described in JP-A No. 5 (1999) -1995, 8-deoxy-14-O is a compound exhibiting particularly excellent activity in the pressure stimulation method which is an analgesic activity evaluation method other than the acetic acid licing method.
As a result of further study using benzoyl aconine as a comparative control, p-chlorobenzoyl was bonded to the oxygen atom bonded to the 14th carbon atom of the aconitine type chemical structure, and 3rd carbon atom It has been discovered that compounds having acetyloxy bonded to the carbon atom at position 15 and / or have particularly excellent pharmacological effects and high safety.

The above-mentioned pressure stimulation method used as an evaluation method of analgesic activity is a test method suitable for evaluating the activity of a compound having a strong analgesic effect such as morphine, and is a non-steroidal antipyretic / analgesic drug. In aspirin and indomethacin,
The analgesic effect is weaker than that of morphine, and no remarkable activity is recognized by the pressure stimulation method.

[0010] The compound of the present invention can be used in a pressure stimulation method using a subcutaneous administration method to provide 8-deoxy-14-O.
-A much stronger analgesic effect than benzoyl aconin is observed, and when both compounds are used in combination by subcutaneous administration of the compound of the present invention and intravenous administration of morphine, the compound of the present invention exerts an analgesic effect of morphine. A strong enhancement was found.

Therefore, the compounds according to the present invention greatly contribute to severe painful inflammatory diseases and inflammatory diseases. Furthermore, the analgesic effect of the compound according to the present invention is not suppressed even when used in combination with a morphine antagonist, and it is considered that the compound has a mechanism of action different from that of morphine. The combined use of provides the advantage that remission of pain can be reliably achieved, and the side effect of continuous use of morphine can be reduced by gradually reducing the dose of morphine. The present invention has been made based on such findings.

Accordingly, the present invention provides a novel compound having an aconitine-type chemical structure represented by the general formula (I), and further has an aconitine-type chemical structure represented by the general formula (I). An object of the present invention is to provide an analgesic / anti-inflammatory agent containing a compound or a salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail. The novel compounds represented by the above formula (I) according to the present invention include aconitine, mesaconitine, gesaconitine, hypoconitine, 14-O.benzoylaconine, and 14-O-benzoyl represented by the following formula (II). Mesaconin, 14-O-
Anisoyl aconin, 14-O-benzoylhypaconin, and pyroaconitine, pyromesaconitine, pyrogesaconitine, pyrohypaconitine, 16-epipyroaconitine, 16-epipyromesaconitine, 16 represented by the following formula (III): Compounds having an aconitine-type chemical structure described in the literature, such as -epipyrogesaconitine, 16-epipyrohypaconitine, and a compound represented by the following formula (III): And the like at the 3-position, 15-position or 1-position
It can be produced by replacing the substituent bonded to the 4-position or the nitrogen atom with various other substituents.

[0014]

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[0015]

[0016]

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[0017]

To acylate a hydroxyl group, the corresponding compound is reacted with an acid chloride or an acid anhydride usually used for esterifying a hydroxyl group in a suitable solvent, for example, pyridine. It can be carried out.
When hydroxyl groups are present at the 3-position and 15-position and no acetyl group is present at the 8-position in the structural formula, the above-mentioned acetylation reaction proceeds preferentially at the 15-position. In order to selectively convert the hydroxyl group at the 3-position to acetyloxy, a protecting group for the hydroxyl group usually used in a chemical reaction, such as tetrahydropyranyl, methylthiomethyl, benzoylmethyl, or benzyl, is bonded to the hydroxyl group at the 15-position. Then, by performing the above-mentioned acylation reaction, the hydroxyl group at the 3-position can be selectively acylated.

When the corresponding compound is a hydroxyl group which is difficult to be acylated due to steric hindrance due to a functional group in the three-dimensional structure, the corresponding compound is dissolved in an appropriate solvent, for example, tetrahydrofuran (THF), and Under a temperature condition, a hexane solution of an organometallic compound, for example, n-butyllithium or the like is added and stirred, and then a desired acid chloride is added and stirred, whereby the hydroxyl group can be acylated.

An acyl group present in the form of an ester bond is
Substitution with another acyl group can be carried out using a hydrolysis reaction, for example, a deesterification by alkali hydrolysis or the like to form a hydroxyl group, and then a reaction of acylating the hydroxyl group.

To replace the alkyl substituent attached to the nitrogen atom with another substituent, the corresponding compound is first reacted with a suitable oxidizing agent such as potassium permanganate in a suitable solvent such as acetone, N-dealkylated product, the obtained N-dealkylated product and an alkylating or acylating agent for introducing a desired alkyl group or acyl group, for example, an alkyl halide or an acid chloride or an acid anhydride. This can be done by reacting.

The carbonyl reduction reaction is carried out by dissolving the corresponding compound in an appropriate solvent, for example, ethanol or acetic acid, and catalytically hydrogenating the mixture with platinum oxide, palladium carbon or Raney nickel at room temperature or under heating. Can be performed. Alternatively, the corresponding compound is dissolved in a suitable solvent, for example, ether, and a metal hydride complex, for example, lithium aluminum hydride, sodium borohydride, lithium t-butoxyaluminum hydride or lithium trimethoxyaluminum hydride is added. By stirring under appropriate temperature conditions,
A carbonyl reduction reaction can be performed.

In order to obtain the compound represented by the above formula (I), the above reactions can be carried out in various combinations.

The compound according to the present invention may form a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or hydrobromic acid or an organic acid such as oxalic acid, succinic acid, tartaric acid, citric acid or ascorbic acid. Good.

Examples of the production of the compound represented by the formula (I) according to the present invention are described below. The analytical data of the compounds obtained in each example are listed after the description of the examples. The pharmacological action, toxicity, etc. of the compound are shown in Tables 2 to 6 below. In addition, compound No. in the following table | surface. Table 1 shows a control table of the compound names.

[0026]

【Example】

Example 1 500 mg of aconitine was dissolved in 5 ml of a 5% potassium hydroxide / methanol solution, and the mixture was stirred at room temperature for 10 hours. After distilling off the methanol in the reaction solution under reduced pressure,
5 ml of ice water was added to the residue to dissolve it, and Amberlite XAD-2 was washed with methanol and water in this order.
(Nippon Organo) Attached to a column filled with 100 ml,
Wash with water. After confirming that the washing solution does not show alkalinity, elution is carried out with 1000 ml of methanol. The eluate is concentrated to dryness under reduced pressure to obtain a residue containing 480 mg of aconine. 10 m of pyridine from which the residue has been distilled
and add 0.3 ml of p-chlorobenzoyl chloride and stir at -18 ° C for 10 minutes. After completion of the reaction, the reaction solution was subjected to silica gel column chromatography (50 g), and chloroform 150 ml, 5% methanol / chloroform 150 ml, 10% methanol / chloroform 1
50 ml, 15% methanol / chloroform 150 ml
And 20% methanol / chloroform.
The 0% methanol / chloroform eluate and the 15% methanol / chloroform eluate are combined and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (1
50 g), separated and purified (separated liquid: ammonia-saturated chloroform), and recrystallized from acetone / hexane to obtain 400 mg of 14-Op-chlorobenzoylaconine.

Example 2 14-Op-chlorobenzoyl aconine 30 obtained by the same operation as in Example 1
To 0 mg, 10 ml of acetic anhydride and 5 ml of pyridine were added,
Stir for 1 hour at room temperature. The reaction solution was poured into ice water and 10
After making the solution alkaline with aqueous ammonia, the solution is extracted three times with 100 ml of ether. The ether extract is washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was separated and purified by preparative silica gel thin-layer chromatography (separation liquid: chloroform / ether = 1: 1, saturated with ammonia vapor) to give 15-O-acetyl-14.
145 mg of Op-chlorobenzoylaconine are obtained.

Example 3 15-O-acetyl-14
208 mg of Op-chlorobenzoyl aconine was dissolved in 25 ml of acetone, and 25 ml of a solution of 127 mg of potassium permanganate dissolved in 25 ml of an acetone / water mixture (1: 1) was added to the solution, and the mixture was added at room temperature for 1.5 hours. Stir. After completion of the reaction, the reaction solution is acidified by adding 2N sulfuric acid under ice cooling, and sodium sulfite is added until the color of the reaction solution becomes transparent. Next, the reaction solution is concentrated under reduced pressure. After making this concentrated solution alkaline with 10% ammonia water,
Extract three times with 100 ml of chloroform. The chloroform layer is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (1
0 g, 5% methanol / ammonia saturated chloroform)
And purified by de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoyl aconine 93.4.
mg.

Example 4 In place of aconitine in Example 1, 500 mg of mesaconitine was used.
398 mg of 14-Op-chlorobenzoylmesaconin is obtained in the same manner as described above.

Example 5 To 100 mg of 14-Op-chlorobenzoylmesaconin was added 3.5 ml of acetic anhydride and 2 ml of pyridine, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution is poured into ice water, made alkaline with 10% aqueous ammonia, and extracted three times with 50 ml of ether.
The ether extract is washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was subjected to preparative silica gel thin layer chromatography (separation liquid: chloroform / ether = 1: 1).
1, ammonia vapor saturation) to separate and purify
50.3 mg of -acetyl-14-Op-chlorobenzoylmesaconine are obtained.

Example 6 De-N-ethyl-15-O-acetyl-14 obtained by the same procedure as in Example 3.
50 mg of Op-chlorobenzoyl aconine was dissolved in 2 ml of a methanol / ether mixture (1: 1), and 65 mg of calcium carbonate and 0.2 ml of propyl iodide were added.
Heat to reflux for 2 hours. After cooling, insolubles in the reaction solution are removed by filtration, and the reaction solution is concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (5 g, 5% methanol / ammonia-saturated chloroform) to give de-N-ethyl-N-propyl-15-O-acetyl-1.
28 mg of 4-Op-chlorobenzoyl aconine are obtained.

Example 7 De-N-ethyl-15-O-acetyl-14 obtained by the same operation as in Example 3.
50 mg of Op-chlorobenzoyl aconine was dissolved in 1 ml of methanol, and 50 mg of potassium carbonate and 0.1 m of water were dissolved.
and 20 μl of acetyl chloride, and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution is concentrated to dryness under reduced pressure. The residue was dissolved in 20 ml of chloroform, the chloroform layer was washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (5
g, 5% methanol / ammonia-saturated chloroform), and purified by de-N-ethyl-N-acetyl-15.
34 mg of -O-acetyl-14-Op-chlorobenzoylaconine are obtained.

Example 8 The procedure of Example 7 was repeated, except that 20 μl of propionyl chloride was used instead of the acetyl chloride of Example 7, except that de-N-ethyl-N-propionyl-15-O- 30 mg of acetyl-14-Op-chlorobenzoylaconine are obtained.

Example 9 100 mg of mesaconitine was placed under reduced pressure (1.5 to 2 mm).
Hg) Melt at 200 ° C. for 30 minutes. After cooling, the reaction mixture was subjected to silica gel column chromatography (10 g, 5%
(Methanol / chloroform) to obtain 56 mg of pyromesaconitine.

Dissolve 50 mg of pyromesaconitine in 5 ml of dry tetrahydrofuran. Separately, 144 mg of lithium aluminum hydride was suspended in 5 ml of tetrahydrofuran, and 0.46 ml of methanol was added thereto.
Stir at room temperature to obtain a solution of trimethoxylithium aluminum hydride in tetrahydrofuran. 5 ml of this liquid
Is slowly added dropwise to the above-mentioned solution of pyromesaconitine in tetrahydrofuran at -70 ° C, and then the reaction solution is stirred at this temperature for 1 hour and further at room temperature for 1 hour. Next, a tetrahydrofuran solution containing a small amount of water is gradually added to the reaction solution under ice-cooling, and insolubles are removed by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (15 g, 5% methanol / ammonia saturated chloroform) to obtain 46 mg of 8-deoxymesaconin.

45 mg of 8-deoxymesaconin was dissolved in 0.5 ml of pyridine, and 0.5 ml of a solution of p-chlorobenzoyl chloride / pyridine (0.05 ml / 0.5 ml) was added dropwise to this solution. Stir for 5 hours.
After completion of the reaction, the reaction solution is poured into ice water, acidified with 10% hydrochloric acid, and washed twice with 50 ml of ether. After making the hydrochloric acid layer alkaline with 10% aqueous ammonia, it is extracted three times with 50 ml of ether. The ether layer is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is separated and purified by alumina column chromatography (5 g, chloroform) to obtain 32-deoxy-14-Op-chlorobenzoylmesaconin (32 mg).

30 mg of 8-deoxy-14-Op-chlorobenzoylmesaconin was dissolved in 1 ml of anhydrous tetrahydrofuran, and the mixture was dissolved at room temperature in 3,4-dihydro-2H-.
Pyran 12 mg and boron trifluoride diethyl ether 1
After adding drops and stirring for 10 seconds, the solvent is distilled off. The residue was dissolved by adding 1.1 ml of acetic anhydride and 0.5 ml of pyridine, and the mixture was stirred at room temperature for 1 hour. Next, the reaction solution is poured into ice water, made alkaline with 10% aqueous ammonia, and extracted three times with 20 ml of ether. The extract is washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was separated by preparative silica gel thin layer chromatography (separation liquid:
Chloroform / methanol = 20: 1, saturated with ammonia vapor), and purified by 3-O-acetyl-8-deoxy-14-Op-chlorobenzoylmesaconin 2
1.2 mg are obtained.

[0038] 3-O-acetyl-8-deoxy-1
20 mg of 4-Op-chlorobenzoylmesaconin are dissolved in 0.4 ml of methylene chloride. Separately, a solution prepared by dissolving 37 mg of pyridinium chlorochromate in 0.3 ml of methylene chloride was prepared, and 0.3 ml of this solution was dissolved at 0 ° C. in the aforementioned 3-O-acetyl-8-deoxy-
Add to 14-Op-chlorobenzoylmesaconin in methylene chloride solution. After stirring this reaction solution at room temperature for 12 hours, 5 ml of chloroform is added and stirred. The solution is poured into ice water, the aqueous layer is made alkaline with 10% aqueous ammonia, mixed well, and the methylene chloride layer is separated. The methylene chloride layer is washed with water, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (5 g, 5% methanol / chloroform) to give 3-O-acetyl-14-O-.
17 mg of p-chlorobenzoylpyromesaconin are obtained.

Example 10 Aconitine (100 mg) was placed under reduced pressure (1.5 to 2 mmH).
g) Melt at 200 ° C. for 30 minutes. After cooling, the reaction mixture is separated and purified by silica gel column chromatography (10 g, 5% methanol / chloroform) to obtain 60 mg of pyroaconitine.

The procedure of Example 9 was repeated, except that 50 mg of pyroaconitine was used instead of pyromesaconitine in Example 9, and 47 mg of 8-deoxyaconine was used.
Get.

The same procedure as in Example 9 was repeated, except that 45 mg of 8-deoxyaconine was used instead of 8-deoxymesaconin of Example 9, and the same procedure as in Example 9 was repeated.
36 mg of 14-Op-chlorobenzoyl aconine are obtained.

The 8-deoxy-14 of Example 9
Instead of Op-chlorobenzoylmesaconin, 8-
Deoxy-14-Op-chlorobenzoyl aconine 3
Using 0 mg, operate as in Example 9 except for 3 mg.
22.4 mg of -O-acetyl-8-deoxy-14-Op-chlorobenzoylaconine are obtained.

3-O-acetyl-8 of Example 9
-Instead of deoxy-14-Op-chlorobenzoylmesaconine, 3-O-acetyl-8-deoxy-14
Using the same procedure as in Example 9 except that 20 mg of -Op-chlorobenzoylaconine was used, 3-O-acetyl-14-Op-chlorobenzoylpyroconine 17
mg.

Example 11 Instead of 15-O-acetyl-14-Op-chlorobenzoylaconine in Example 3, 3-O-acetyl-8-deoxy-14-Op-chlorobenzoyl The same procedure as in Example 3 was repeated except that 200 mg of aconine was used, and 95.2 m of de-N-ethyl-3-O-acetyl-8-deoxy-14-Op-chlorobenzoylaconine was used.
g.

The de-N-ethyl-15-O of Example 7
De-N-ethyl-3-O-acetyl-8- instead of -acetyl-14-O-p-chlorobenzoylaconine
Deoxy-14-Op-chlorobenzoyl aconine 5
The same procedures as in Example 7 were carried out except for using 0 mg, and de-N
-Ethyl-N-acetyl-3-O-acetyl-8-deoxy-14-Op-chlorobenzoylaconine 33.
Obtain 2 mg.

3-O-acetyl-8 of Example 9
-Instead of deoxy-14-O-p-chlorobenzoylmesaconine, de-N-ethyl-N-acetyl-3-O
-Acetyl-8-deoxy-14-O-p-chlorobenzoylaconine, using the same procedure as in Example 9, except for using 20 mg, to give de-N-ethyl-N-acetyl-3-O
12 mg of -acetyl-14-Op-chlorobenzoylpyroaconine are obtained.

Example 12 50 mg of pyroaconitine was dissolved in 5 ml of a 5% potassium hydroxide / methanol solution and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution is concentrated to dryness under reduced pressure, and the residue is dissolved in 10 ml of water. Amberlite XA
The mixture is applied to a column packed with 100 ml of D-2 (Nippon Organo) and washed with water until the eluate no longer shows alkalinity. Next, elution is performed with methanol, and the methanol eluate is concentrated to dryness under reduced pressure. The residue is separated and purified by silica gel column chromatography (10 g, 10% methanol / ammonia saturated chloroform) to obtain 43 mg of 16-epipyroaconin.

The procedure of Example 9 was repeated, except that 40 mg of 16-epipiroaconin was used in place of the 8-deoxymesaconin of Example 9, except that 16-epi-1 was used.
30 mg of 4-Op-chlorobenzoylpyroaconine are obtained.

In place of 14-Op-chlorobenzoylmesaconine in Example 5, 16-epi-14-O-
Using 30 mg of p-chlorobenzoylpyroaconin,
Otherwise, operating as in Example 5, 3-O-acetyl-16
23 mg of epi-14-Op-chlorobenzoylpyroaconine are obtained.

3-O-acetyl-16-epi-14
20 mg of -Op-chlorobenzoylpyroaconin was dissolved in 2.5 ml of acetone, and 12 mg of potassium permanganate was added to 2.5 ml of an acetone / water mixture (1: 1) in 2.5 ml of acetone.
2.5 ml of a solution dissolved in
Stir for hours. After completion of the reaction, add 2
Acidify with N sulfuric acid and add sodium sulfite until the color of the reaction becomes clear. The solution is concentrated under reduced pressure, made alkaline with 10% aqueous ammonia, and extracted three times with 10 ml of chloroform. The chloroform layer is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was separated by preparative silica gel thin layer chromatography (separation liquid:
5% methanol / ammonia-saturated chloroform) for separation and purification, and de-N-ethyl-3-O-acetyl-16.
-Obtain 10.3 mg of epi-14-Op-chlorobenzoylpyroaconine.

Example 13 The procedure of Example 12 was repeated, except that 50 mg of pyromesaconitine was used in place of the pyroaconitine of Example 12, except that 45 mg of 16-epipyromesaconin was obtained.

The procedure of Example 9 was repeated, except that 40 mg of 16-epipyromesaconin was used in place of the 8-deoxymesaconin of Example 9.
14-Op-chlorobenzoylpyrromesaconin 30m
g.

The 16-epi-14 of Example 12
Instead of Op-chlorobenzoylpyroaconin, 1
The same procedure as in Example 12 was followed, except using 30 mg of 6-epi-14-O-p-chlorobenzoylpyrromesaconin, to give 3-O-acetyl-16-epi-14-O-p-.
21 mg of chlorobenzoylpyrromesaconin are obtained.

Example 14 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 6, de-N-ethyl-3-O-acetyl- Using the same procedure as in Example 6 except that 50 mg of 16-epi-14-O-p-chlorobenzoylpyroaconine was used, de-N-ethyl-N-propyl-3-O-acetyl-16-epi. 18.8 mg of 14-Op-chlorobenzoylpyroaconine are obtained.

Example 15 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 7, de-N-ethyl-3-O-acetyl- The procedure of Example 7 was repeated, except that 50 mg of 16-epi-14-O-p-chlorobenzoylpyroaconine was used, to give de-N-ethyl-N-acetyl-3-O-acetyl-16-epi. 14 mg of 14-Op-chlorobenzoylpyroaconine are obtained.

Example 16 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 7, de-N-ethyl-3-O-acetyl- Using 50 mg of 16-epi-14-O-p-chlorobenzoylpyroaconine and using 20 ul of propionyl chloride instead of the acetyl chloride of Example 7,
Otherwise operating as in Example 7, de-N-ethyl-N-propionyl-3-O-acetyl-16-epi-14-O
26.5 mg of p-chlorobenzoylpyroaconin are obtained.

Example 17 The same operation as in Example 12 was carried out to obtain 45 mg of 16-epipiroaconin.

The procedure of Example 9 was repeated, except that 40 mg of 16-epipiroaconin was used instead of pyromesaconitine of Example 9, and 8-deoxy-16-
36 mg of epiaconin are obtained.

Instead of 8-deoxymesaconin of Example 9, 8-deoxy-16-epiaconin 36
The same procedures as in Example 9 were carried out except for using
28.6 mg of deoxy-16-epi-14-O-p-chlorobenzoylaconine are obtained.

The 8-deoxy-14 of Example 9
Instead of Op-chlorobenzoylmesaconin, 8-
Using the same procedure as in Example 9 except that 28 mg of deoxy-16-epi-14-O-p-chlorobenzoylaconine was used, 3-O-acetyl-8-deoxy-16-epi-14-O -P-chlorobenzoylaconine 22mg
Get.

The 3-O-acetyl- of Example 12
Instead of 16-epi-14-O-p-chlorobenzoylpyroaconine, 3-O-acetyl-8-deoxy-1
6-epi-14-Op-chlorobenzoyl aconine 2
Using 0 mg, otherwise operate as in Example 12,
De-N-ethyl-3-O-acetyl-8-deoxy-1
6-epi-14-Op-chlorobenzoyl aconine 1
1.3 mg are obtained.

Example 18 The procedure of Example 12 was repeated, except that 50 mg of pyromesaconitine was used in place of the pyroaconitine of Example 12, and 42 mg of 16-epipyromesaconin was obtained.

Instead of pyromesaconitine of Example 9, 42 mg of 16-epipyromesaconin was used,
Otherwise, operating as in Example 9, 8-deoxy-16
-Obtain 37.6 mg of epimesaconin.

Instead of 8-deoxymesaconin of Example 9, 8-deoxy-16-epimesaconin 3
Using 7 mg, operate as in Example 9 except for 8
33 mg of -deoxy-16-epi-14-Op-chlorobenzoylmesaconin are obtained.

The 8-deoxy-14 of Example 9
Instead of Op-chlorobenzoylmesaconin, 8-
Using the same procedure as described in Example 9 but using 30 mg of deoxy-16-epi-14-O-p-chlorobenzoylmesaconine, 3-O-acetyl-8-deoxy-16-
Epi-14-Op-chlorobenzoylmesaconin 2
0.8 mg is obtained.

Example 19 In place of de-N-ethyl-15-O-acetyl-14-op-chlorobenzoylaconine in Example 6, de-N-ethyl-3-O-acetyl- Using 50 mg of 8-deoxy-16-epi-14-O-p-chlorobenzoylaconine, otherwise use Example 6
The same operation as described above was carried out, and de-N-ethyl-N-propyl-3-
O-acetyl-8-deoxy-16-epi-14-O-
26 mg of p-chlorobenzoylaconine are obtained.

Example 20 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 7, de-N-ethyl-3-O-acetyl- Using 50 mg of 8-deoxy-16-epi-14-O-p-chlorobenzoylaconine, otherwise use Example 7
The same operation as described above was performed to obtain de-N-ethyl-N-acetyl-3-.
O-acetyl-8-deoxy-16-epi-14-O-
23 mg of p-chlorobenzoylaconine are obtained.

Example 21 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 7, de-N-ethyl-3-O-acetyl- Using 50 mg of 8-deoxy-16-epi-14-O-p-chlorobenzoylaconine, the method of Example 7 was repeated.
20 μl of propionyl chloride instead of acetyl chloride
And operating in the same manner as in Example 7, except that de-N-ethyl-N-propionyl-3-O-acetyl-8-deoxy-16-epi-14-op-chlorobenzoylaconine 24 was used. 0.7 mg is obtained.

Example 22 0.5 ml of acetic anhydride and 1 ml of pyridine were added to 100 mg of 14-Op-chlorobenzoyl aconine, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution is poured into ice water, made alkaline with 10% aqueous ammonia, and extracted three times with 50 ml of ether. The ether layer is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to preparative silica gel thin layer chromatography (separation liquid: chloroform / methanol = 5).
(0: 1, ammonia vapor saturation).
74 mg of 15-di-O-acetyl-14-Op-chlorobenzoylaconine are obtained.

Embodiment 23 14-Op of Embodiment 22
-Instead of chlorobenzoyl aconine, 14-Op
Using the same procedure as in Example 22 except that 65 mg of -chlorobenzoylmesaconin was used, 3,15-di-O-acetyl-14-Op-chlorobenzoylmesaconin 32m
g.

Example 24 Instead of aconitine in Example 1, hypoconitine 5 was used.
The same procedures as in Example 1 were repeated except for using
380 mg of -Op-chlorobenzoylhypaconin are obtained.

The procedure of Example 2 was repeated, except that 100 mg of 14-Op-chlorobenzoylhypaconin was used in place of 14-Op-chlorobenzoylaconine in Example 22.
2 and 15-O-acetyl-14-Op
-53 mg of chlorobenzoylhypaconin are obtained.

Example 25 Instead of 8-deoxy-14-Op-chlorobenzoylmesaconine in Example 9, 14-Op-chlorobenzoylmesaconin 30
The same procedures as in Example 9 were carried out, except for using 3-mg.
18 mg of O-acetyl-14-Op-chlorobenzoylmesaconine are obtained.

Example 26 The procedure of Example 12 was repeated, except that 30 mg of 8-deoxy-14-O-p-chlorobenzoylmesaconine was used instead of 16-epi-14-O-p-chlorobenzoylpyrocononine. The other operations were the same as in Example 12, except that 15-O-acetyl-8-deoxy-1 was used.
21 mg of 4-Op-chlorobenzoylmesaconine are obtained.

Example 27 The procedure of Example 12 was repeated, except that 30 mg of 8-deoxy-14-Op-chlorobenzoylaconine was used instead of 16-epi-14-Op-chlorobenzoylpyroaconine. The other operations were the same as in Example 12, except that 15-O-acetyl-8-deoxy-14 was used.
22 mg of -Op-chlorobenzoyl aconine are obtained.

Example 28 In place of 15-O-acetyl-14-Op-chlorobenzoylaconine in Example 3, 15-O-acetyl-8-deoxy-14-Op-chlorobenzoyl The same operation as in Example 3 was carried out except that 22 mg of aconine was used, and 12 mg of de-N-ethyl-15-O-acetyl-8-deoxy-14-Op-chlorobenzoylaconine was used.
Get.

The de-N-ethyl-15-O of Example 7
De-N-ethyl-15-O-acetyl-8 instead of -acetyl-14-O-p-chlorobenzoylaconine
-Deoxy-14-O-p-chlorobenzoyl aconine was treated in the same manner as in Example 7 except for using 11 mg.
N-ethyl-N-acetyl-15-O-acetyl-8-
Deoxy-14-Op-chlorobenzoyl aconine 7
mg.

Example 29 The same procedure as in Example 17 was carried out to obtain 30 mg of 8-deoxy-16-epi-14-Op-chlorobenzoylaconine.

The 16-epi-14 of Example 12
Instead of Op-chlorobenzoylpyroaconine, 8
-Deoxy-16-epi-14-O-p-chlorobenzoylaconine, using the same procedure as in Example 12 except for using 30 mg, to give 15-O-acetyl-8-deoxy-1.
6-epi-14-Op-chlorobenzoyl aconine 2
Obtain 4 mg.

[Example 30] 15-O-acetyl-8-deoxy-16-epi-14-O- Using the same procedures as in Example 3 except that 24 mg of p-chlorobenzoylaconine was used, de-N-ethyl-15-O-acetyl-8-deoxy-16-epi-1 was used.
12 mg of 4-Op-chlorobenzoyl aconine are obtained.

Example 31 The same procedure as in Example 18 was carried out to obtain 35 mg of 8-deoxy-16-epi-14-op-chlorobenzoylmesaconin.

16-epi-14 of Example 12
Instead of Op-chlorobenzoylpyroaconine, 8
-Deoxy-16-epi-14-O-p-chlorobenzoyl mesaconine, operated in the same manner as in Example 12 except for 35 mg, to give 15-O-acetyl-8-deoxy-
27 mg of 16-epi-14-Op-chlorobenzoylmesaconine are obtained.

[Example 32] Instead of de-N-ethyl-15-O-acetyl-14-op-chlorobenzoylaconine of Example 6, de-N-ethyl-15-O-acetyl- The same procedure as in Example 6 was repeated except that 50 mg of 8-deoxy-16-epi-14-Op-chlorobenzoylaconine was used, and de-N-ethyl-N-propyl-1 was used.
5-O-acetyl-8-deoxy-16-epi-14
25 mg of Op-chlorobenzoylaconine are obtained.

Example 33 In place of de-N-ethyl-15-O-acetyl-14-Op-chlorobenzoylaconine in Example 7, de-N-ethyl-15-O-acetyl- The same procedure as in Example 7 was followed except for using 50 mg of 8-deoxy-16-epi-14-Op-chlorobenzoylaconine to obtain de-N-ethyl-N-acetyl-1.
5-O-acetyl-8-deoxy-16-epi-14
36 mg of Op-chlorobenzoyl aconine are obtained.

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Next, experimental examples on the pharmacological action and acute toxicity of the compound represented by the formula (I) according to the present invention will be described.

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[Experimental example]

Example 1 (1) Measurement of Analgesic Activity Based on Pressure Stimulation Method Std: ddY male mice (20 to 25 g) fasted all day and night were used in the experiment. Among the compounds shown in Table 1, (5), (6), (9), (14), (15),
Compounds (18), (23), (24), (31) and (36) were prepared by adding gum arabic to them (final concentration: 3).
%), 10 mg / 10 ml using 0.9% physiological saline
Was used as a sample solution. Among the compounds shown in Table 1, the compounds other than the above were converted into tartrate salts, and then dissolved in a concentration of 10 mg / 10 ml using 0.9% physiological saline to prepare a sample solution. As controls,
0.9% saline was used. The experiment was performed using a pressure stimulator. The pain threshold was measured twice at 30 minute intervals before administration of the sample solution, and mice with a pain threshold of 50 to 100 mmHg were selected and used in the experiment. 10 ml / kg of the above sample solution
1 hour after subcutaneous administration at a rate of 1%, the pain threshold was measured using a pressure stimulator. 0.9% as control
Physiological saline was subcutaneously administered at a rate of 10 ml / kg. The result was represented by the inhibition rate (%) shown in the following equation. Cutoff pressure is set at 230 to prevent damage to mouse ridge tissue.
mmHg. The results are shown in Table 2 below. As shown in Table 2, the compounds according to the present invention have strong analgesic activity, and the strength of the action is 8-deoxy-14-
It was found to be much stronger than O-benzoyl aconine. Inhibition rate (%) = (AB) × 100 / (CB) A: Pain threshold (mmHg) after administration of test compound B: Pain threshold (mmHg) before administration of test compound C: cutoff pressure ( 230mmHg)

(2) Comparison with morphine Std: ddY male mice (20-25 g) fasted all day and night were used in the experiment. In this experiment, the tartrate salt of the compound shown in Table 1 (3) was used as the compound according to the present invention, and morphine hydrochloride was used as a control. The tartrate salt of compound (3) was dissolved in 0.9% physiological saline and adjusted to concentrations of 5 mg / 2 ml, 3 mg / 2 ml, and 1 mg / 2 ml. Morphine hydrochloride
Dissolve using 0.9% saline, 5mg / 2ml,
It was adjusted to a concentration of 3 mg / 2 ml and 1 mg / 2 ml.
0.9% physiological saline was used as a negative control. The experiment was performed using a pressure stimulator. The pain threshold was measured twice at 30-minute intervals before administration of the test compound, and mice with a pain threshold of 50 to 100 mmHg were selected and used in the experiment. The pain threshold was measured using a pressure stimulator 10 minutes, 20 minutes and 30 minutes after the above test compound solution was intravenously administered at a rate of 2 ml / kg, respectively. As a control, the same 0.9% physiological saline was intravenously administered.
The results were represented by the inhibition rate (%) shown in the preceding section (1). The results are shown in Table 3 below. As shown in Table 3, the compounds according to the present invention were found to have analgesic activity as strong as morphine.

(3) Combination experiment with morphine Std: ddY male mice (20 to 25 g) fasted all day and night were used in the experiments. In this experiment, the tartrate salt of the compound shown in (3) of Table 1 and morphine hydrochloride were used as the compound according to the present invention. Compound (3)
Tartrate is dissolved in 0.9% saline solution, 7m
g / 10 ml. Morphine hydrochloride is 0.1%.
Dissolve using 9% physiological saline, 5mg / 2ml, 3m
The concentrations were adjusted to g / 2 ml and 1 mg / 2 ml. 0.9% physiological saline was used as a control. The experiment was performed using a pressure stimulator.

Before administration of the test compound, the pain threshold was measured twice at 30-minute intervals, and mice having a pain threshold of 50 to 100 mmHg were selected and used in the experiment. The mice were divided into a control group, a compound (3) tartrate administration group, a morphine hydrochloride administration group, and a compound (3) tartrate / morphine hydrochloride combination group.
In the tartrate group of the compound (3), 0.9% saline solution of the above-mentioned compound (3) tartrate was subcutaneously administered at a rate of 10 ml / kg at a rate of 30 ml. It was administered intravenously at a rate of 2 ml / kg. In the morphine administration group, 0.9% physiological saline was subcutaneously administered at a rate of 10 ml / kg, and then 30 minutes later, the above-mentioned physiological saline solution of morphine hydrochloride was intravenously administered at a rate of 2 ml / kg. In the combined use of the compound (3) tartrate and morphine, a 0.9% physiological saline solution of the compound (3) tartrate was subcutaneously administered at a rate of 10 ml / kg, and then 30 minutes after the administration of the morphine hydrochloride. 2 ml of physiological saline solution
It was administered intravenously at a rate of kg. In the control group,
After 30 minutes of subcutaneous administration of 0.9% physiological saline at a rate of 10 ml / kg, 0.9% physiological saline was intravenously administered at a rate of 2 ml / kg. Pain threshold plants were measured at 10, 20, and 30 minutes after intra-static administration.

The results are shown in Table 4 in terms of the suppression rate (%) obtained by the same equation as in the preceding section (1). As shown in Table 4, the compounds according to the present invention were found to strongly enhance the analgesic effect of morphine.

(4) Combination experiment with morphine antagonist Stud: ddY male mice (20-25 g) fasted all day and night were used in the experiments. In this experiment, the tartrate salt of the compound (3) shown in Table 1 was used as the compound according to the present invention, and morphine hydrochloride and levallorphan hydrochloride, a narcotic antagonist, were used. The tartrate salt of compound (3) was dissolved in 0.9% physiological saline, and 10 mg / 2
It was adjusted to a concentration of ml. Morphine hydrochloride was dissolved in 0.9% physiological saline and adjusted to a concentration of 10 mg / 2 ml. Levallorphan hydrochloride was adjusted to a concentration of 1 mg / 10 ml using 0.9% physiological saline. 0.9% physiological saline was used as a control. The experiment was performed using a pressure stimulator.

Before the administration of levallorphan hydrochloride, the pain threshold was measured twice at 30 minute intervals, and the pain threshold was 50/100 mmH
g mice were selected and used in the experiments. After subcutaneous administration of the above-mentioned levallorphan hydrochloride solution at a rate of 10 ml / kg, 3
At 0 minutes, a 0.9% saline solution or a morphine hydrochloride solution of the tartrate of the above compound (3) was added at 2 ml / k each.
g, then 10 minutes, 20 minutes and 3 minutes
At 0 minutes, the pain threshold was measured using a pressure stimulator. As a control, 0.9% physiological saline was added at 10 ml / kg.
30 minutes after the subcutaneous administration at a rate of 0.9%, 0.9% physiological saline was intravenously administered at a rate of 2 ml / kg. In the group administered with levallorphan hydrochloride alone, 30 minutes after subcutaneous administration of the above levallorphan hydrochloride solution at a rate of 10 ml / kg,
0.9% physiological saline was intravenously administered at a rate of 2 ml / kg.

The results are shown in Table 5 as suppression rates (%) determined by the same equation as in the preceding section (1). As shown in Table 5, the analgesic effect of morphine was suppressed by the combined use of levallorphan, whereas the analgesic effect of the compound of the present invention was not suppressed by the combined use of levallorphan.

Experimental Example 2 Measurement of Anti-inflammatory Activity Based on Carrageenan Footpad Edema Method Std: ddY male mice (20 to 25 g) fasted all day and night were used in the experiments. Among the compounds shown in Table 1, (5), (6), (9), (14), (15),
Compounds (18), (23), (24), (31) and (36) were prepared by adding gum arabic to them (final concentration: 3).
%) And sterilized distilled water to a concentration of 30 mg / 10 ml to prepare a sample solution. Among the compounds shown in Table 1, the compounds other than the above were converted into a tartrate salt, dissolved using sterile distilled water, and adjusted to a concentration of 30 mg / 10 ml for use. As a control, sterilized distilled water was used. One hour after orally administering an aqueous solution of the above-mentioned test compound at a rate of 10 ml / kg, one hour after suspension in 0.9% physiological saline,
25 mg of carrageenin (0.5 mg / 25 μl) was administered subcutaneously to the right hind footpad of mice, and 0.5 μl to the left hind footpad.
25 μl of 9% saline was administered. Paw thickness measurements were made using a dial cage caliper, 3 hours and 5 hours after carrageenin administration. In the control, 25 μl of λ-carrageenin (0.5 mg / 25 μl) suspended in 0.9% saline was administered 1 hour after oral administration of sterile distilled water at a rate of 10 ml / kg in the right hind foot of the mouse. The test compound was administered subcutaneously to the pad, and 25 μl of 0.9% physiological saline was subcutaneously administered to the subcutaneous footpad of the left hind leg.

The results were expressed as an edema rate based on the following equation. (RL) × 100 / L = Edema rate (%) R: Thickness of right hind leg L: Thickness of left hind leg The results are shown in Table 6 below. As shown in Table 6, the compounds according to the present invention were found to have a carrageenan foot pad edema inhibitory action.

[Experimental Example 3] (Acute toxicity) Male Std: ddY mice (20-25 g) fasted all day and night were used in the experiments. The sample solution of the test compound was prepared in the same manner as in Experimental Example 2 (30 mg).
/ 10 ml). After orally administering the sample solution at a rate of 10 ml / kg, the lethal number for 72 hours was observed. as a result,
The compounds according to the present invention each contain 30 mg / k.
No oral death was observed in the oral administration of g, and low toxicity was observed.

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The clinical dose of the analgesic / anti-inflammatory agent according to the present invention is as follows:
An amount of mg / day is preferred. The drug according to the present invention is prepared into a desired dosage form by a conventional method using a commonly used pharmaceutical carrier or excipient, and is provided for use.
In addition, the compound of the present invention may be used as any required salt in order to achieve a pharmaceutical effect or to facilitate formulation.

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

In the preparation for injection, the compound represented by the formula (I) may be used in the form of a salt, and the dissolution form at the time of use is preferred. It may also contain various formulating agents such as suspending agents, stabilizers or dispersants, and sterile distilled water, essential oils such as peanut oil, corn oil or non-aqueous solvents, polyethylene glycol, polypropylene glycol, etc. May be contained.

Formulations for rectal administration are provided in the form of suppository compositions and may contain formulation carriers well known in the art, for example, polyethylene glycol, lanolin, coconut oil and the like.

Formulations for topical application are provided in the form of ointments, plasters, or cataplasms, and are well-known in the art for pharmaceutical carriers such as petrolatum, paraffin, Lanolin, plastibase, kaolin, bentonite, talc, aluminum silicate, propylene glycol, sorbitol,
Hydrophilic petrolatum, macrogol, wax, resin, purified lanolin, rubber, glycerin, gelatin, polyacrylic acid,
It may contain a polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, or the like.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 221/22 A61K 31/44

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) [Wherein, R ₁ is (i) a hydrogen atom or a hydroxyl group, and R ₂ is (i) a hydroxyl group or (ii) acetyloxy or (iii) a group which forms a carbonyl with a carbon atom at the 15-position. , R ₃ are (i) a hydrogen atom or (ii) an alkyl or acetyl or propionyl having 1 to 4 carbon atoms, and R ₄ is (i) a hydrogen atom or (ii) a hydroxyl group or (iii) acetyl. Oxy. However, when R ₂ is a hydroxyl group or a group which forms a carbonyl together with the carbon atom at position 15, R ₄ is acetyloxy. And a salt thereof having an aconitine-type chemical structure represented by the formula: [Solution 2] General formula (I) [Wherein, R ₁ is (i) a hydrogen atom or a hydroxyl group, and R ₂ is (i) a hydroxyl group or (ii) acetyloxy or (iii) a group which forms a carbonyl with a carbon atom at the 15-position. , R ₃ are (i) a hydrogen atom or (ii) an alkyl or acetyl or propionyl having 1 to 4 carbon atoms, and R ₄ is (i) a hydrogen atom or (ii) a hydroxyl group or (iii) acetyl. Oxy. However, when R ₂ is a hydroxyl group or a group which forms a carbonyl together with the carbon atom at position 15, R ₄ is acetyloxy. An analgesic / anti-inflammatory agent comprising, as an active ingredient, a compound having an aconitine-type chemical structure represented by the formula: