ACONITINE COMPOUND AND ANALGESIC/ANTIINFLAMMATORY AGENT

Abstract: A novel aconitine compound represented by general formula (I) and analgesic/antiinflammatory agent containing said compound or its salt as the active ingredient; wherein each symbol is as defined in the text of specification.

Description: Technical Field This invention relates to novel aconitine compounds as well as to an analgesic/anti-inflammatory agent containing the same. Background Art Aconitine alkaloids contained in the tuberous root of plants of the genus Aconitium have already been reported to have a potent analgesic and anti-inflammatory action. They, however, are supposed to show a narrow safety margin because of their high toxicity. Disclosure of Invention As a result of extensive studies in an attempt to develop novel aconitine alkaloid derivatives which are low in toxicity but maintain the analgesic/anti-inflammatory activity that aconitine alkaloids have, we have now succeeded in providing novel compounds of the general formula (I) according to the present invention: wherein R 2 and R 7 are the same and represent: butanoyl or p-chlorobenzoyl, R 5 group. We have also found that the compounds of the general formula (I) have a potent analgesic/anti-inflammatory action as well as a lower toxicity than mesaconitine, aconitine, hypaconitine and jesaconitine. The present invention has been accomplished based on these findings. Thus, the present invention provides novel compounds of the general formula (I) mentioned above as well as an analgesic/anti-inflammatory agent containing as active ingredient one or more of the compounds of the general formula (I) or salts thereof. The compounds according to the invention of the general formula (I) shown above may be prepared from neoline of the formula (X) shown below as starting material by way of replacement of substituents attached to the position 1 and 14 by other substituents In formula (X), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are defined to mean the following: R 1 R 2 R 3 R 4 R 5 R 6 R 7 X H CH 2 CH 3 H H OH H H Acylation of the hydroxyl group may be carried out by reacting the corresponding compound with an acid chloride, which is conventionally used for esterification of the hydroxyl group, in an appropriate solvent such as pyridine. Replacement of an acyl group present in the form of ester bond with another acyl group may be carried out by deesterification into a hydroxyl group through hydrolysis such as alkaline hydrolysis, followed by acylation of the hydroxyl group. In the following will now be given examples of preparation of compounds of the formula (I). Physicochemical parameters and analytical data of the compounds prepared in these examples are given just after the description of the examples. Pharmacological activity, toxicity etc. of the compounds are shown in Tables 1 - 3 mentioned below. Example 1 Neoline 8 mg was dissolved in 1 ml of pyridine. To this solution, 0.08 ml of butyryl chloride was added and the mixture was permitted to stand at room temperature for 30 min. To the reaction mixture, 20 ml of water and 10 ml of 1N sodium carbonate were added and the mixture was extracted three times with 30 ml of ether. After the extract was concentrated to dryness, the residue was subjected to column chromatography on silica gel (7g) with 30 ml of a mixture of chloroform / methanol (99.5 : 0.5) as a washing solvent and with 30 ml of a mixture of chloroform / methanol (98 : 2) as an eluting solvent. The elute was concentrated to dryness to give 1,14-di-butanoylneoline (8 mg). Example 2 Neoline 8 mg was dissolved in 1 ml of pyridine. To this solution, 0.04 ml of p-chlorobenzoyl chloride was added and the mixture was permitted to stand at room temperature for 30 min. To the reaction mixture, 20 ml of water and 10 ml of 1N sodium carbonate were added and the mixture was extracted three times with 30 ml of ether. The extract was concentrated to dryness and the residue was subjected to column chromatography on silica gel (7g) with 30 ml of a mixture of chloroform / methanol (99.5 : 0.5) as a washing solvent and with 30 ml of a mixture of chloroform / methanol (98 : 2) as an eluting solvent. The elute was concentrated to dryness to give 1,14-di-p-chlorobenzoylneoline (8 mg). (1) Physicochemical parameters and analytical data of 1,14-di-butanoylneoline 1) Solubility Colorless powder. Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethylacetate, pyridine and dimethyl sulfoxide. Very poorly soluble in hexane. Insoluble in water. 2) Analysis of IR spectra (CHCl 3 ) IR ν KBr / max : 3580, 1720 cm -1 . 3) Analysis of 1 H-NMR spectra (CDCl 3 ) The following signals are shown (δ, ppm). 4.86 (1H, t, J=4.6 Hz, C14-H), 4.30 (1H, t, J=3.1 Hz, C1-H), 3.31, 3.30 and 3.26 (each 3H, s, methoxy group), 1.05 and 1.07 (each 3H, t, J=7.0 Hz, CH 3 of butanoyl group), 1.10 (3H, t, J=7.2 Hz, CH 3 of C 2 H 5 at the nitrogen atom). 4) Analysis of 13 C-NMR spectra (CDCl 3 ) The following signals are shown (δ, ppm). 170.4 and 170.1 (each carbonyl of butanoyl group), 83.4, 83.3, 80.2, 77.4, 75.0 and 74.3 (C6, C16, C18, C1, C14 and C8), 59.1, 58.0 and 56.1 (methoxy group), 48.9 (CH 2 of C 2 H 5 at the nitrogen atom), 13.8 and 13.6 (CH 3 of butanoyl group), 13.5 (CH 3 of C 2 H 5 at the nitrogen atom). 5) Analysis of EI-Mass spectra m/z: 577 (M + ). 6) Elemental analysis Calculated for C 32 H 51 NO 8 : C: 66.52; H: 8.90; N: 2.42. Found: C: 66.73; H: 8.87; N: 2.33. (2) Physicochemical parameters and analytical data of 1,14-di-p-chlorobenzoylneoline 1) Solubility Colorless powder. Soluble in ether, chloroform, benzene, ethanol, methanol, acetone, ethylacetate, pyridine and dimethyl sulfoxide. Very poorly soluble in hexane. Insoluble in water. 2) Analysis of IR spectra (CHCl 3 ) IR ν KBr / max : 3580, 1720 cm -1 . 3) Analysis of UV spectra (ethanol) UV λ EtOH / max (log ε): 246 nm (4.10). 4) Analysis of 1 H-NMR spectra (CDCl 3 ) The following signals are shown (δ, ppm). 7.90 and 7.35 (each 4H, d, J=8.5 Hz, p-chlorobenzoyl group), 5.25-4.96 (2H, m, 1,14-H), 3.37, 3.33 and 3.10 (each 3H, s, methoxy group), 1.18 (3H, t, J=7.2 Hz, CH 3 of C 2 H 5 at the nitrogen atom). 5) Analysis of 13 C-NMR spectra (CDCl 3 ) The following signals are shown (δ, ppm). 166.0 and 165.8 (carbonyl of p-chlorobenzoyl group), 140.1, 139.7, 131.7, 131.3, 129.3, 128.9, 128.7 and 128.4(p-chlorobenzoyl group), 83.5, 83.0, 79.9, 77.8, 75.4 and 74.2 (C6, C16, C18, C14, C1 and C8), 59.0, 57.8 and 56.6 (methoxy group), 48.2 (CH 2 of C 2 H 5 at the nitrogen atom), 13.2 (CH 3 of C 2 H 5 at the nitrogen atom). 6) Analysis of EI-Mass spectra m/z: 714, 716, 718 (M + ). 7) Elemental analysis Calculated for C 38 H 45 NO 8 Cl 2 : C: 63.86; H: 6.35; N: 1.96. Found: C: 63.62; H: 6.38; N: 2.01. Examples of experiment with respect to the pharmacological properties and acute toxicity of the compound shown in formula (I) mentioned above are described below. Experiment example 1 (Analgesic action) Measurement of analgesic activity by the acetic acid-induced writhing method. Male mice of the Std:ddY Strain (20 - 25g) were used. All mice were maintained at room temperature of 24 - 25 °C on a 12 hours light and dark cycle and were given food and water ad libitum . The test compound was used in 3 % suspension in gum arabic. 0.7 % acetic acid in 0.9 % physiological saline solution was injected i.p. (10ml / kg) at 30 minutes after the test compound was administered s.c. After 10 minutes, the number of writhing movements was counted for a period of 10 minutes. 3 % gum arabic solution in 0.9 % physiological saline solution was used as a negative control. The ED 50 values were calculated in accordance with the Litchfield-Wilcoxon's method based on judging to be positive in case of half and below the writhing number of the negative control group. The results are shown in Table 1. It was demonstrated in Table 1 that the compounds of this invention had a dose-dependent potent analgesic activity. Experiment example 2 (Antiinflammatory action) Measurement of the antiinflammatory activity on the carrageenin-induced hind paw edema in mice. Male mice of Std:ddY strain (20 - 25g) were used. Thirty minutes after the oral administration of test compound, 25 µl of carrageenin (0.5mg / 25 µl) was injected s.c. under the plantar surface of the right hind paw. To the control group, 25 µl of 0.9 % physiological saline solution was injected s.c. under the plantar surface of the left hind paw. The volume of the paw was measured at one hour intervals for 6 hours with a dial gauge calliper. The results were described as a difference in foot pad thickness between the right and left feet. The results are shown in Table 2. As shown in Table 2, it was demonstrated that the compound of this invention had an inhibitory action against the carrageenin-induced hind paw edema. Experiment example 3 (Acute toxicity) Male mice of the Std:ddY Strain (20 - 25g) were used. The LD 50 values were calculated using the method of Litchfield-Wilcoxon from the mortality during 72 hours after- test compound was administered s.c. The results are shown in Table 3. As shown in Table 3, it was demonstrated that the compound of this invention was found to be lower in toxicity than mesaconitine, aconitine, hypaconitine and jesaconitine. As mentioned above, it was indicated that the compound shown in formula (I) had lower toxicity than mesaconitine, aconitine, hypaconitine and jesaconitine and had potent analgesic and antiinflammatory activity. The dose of the compound of the general formula (I) for clinical use as analgesic/anti-inflammatory agent according to the invention is preferably 1-1,000 mg/day for adults. The agent according to the present invention is presented for actual application after having been formed into any desired dosage form by conventional methods using customarily used carriers or excipients. Oral preparations such as tablets, powders, granules and capsules may contain conventional excipients such as calcium carbonate, magnesium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate and gum arabic. Tablets may be coated by conventional methods. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs etc. For injectable preparations, the compounds of the formula (I) may be used in the form of a salt thereof, and preferably reconstituted upon use. Such preparations may contain different adjuvants such as suspending, stabilizing or dispersing agents. They may contain sterilized distilled water, refined oils such as peanut oil and corn oil, non-aqueous solvents, polyethylene glycol, polypropylene glycol, etc. Preparations for rectal administration are presented in the form of compositions for suppository and may contain pharmaceutical carriers well known in the art such as polyethylene glycol, lanolin and coconut oil. Preparations for topical application are presented in the form of compositions for ointment, plaster or poultice and may contain pharmaceutical carriers well known in the art such as vaseline, paraffin, hydrous lanolin, plastibase, kaolin, bentonite, talc, aluminum silicate, propylene glycol, sorbitol, hydrophilic petrolatum, macrogols, wax, resin, purified lanolin, gum, glycerin, gelatin, polyacrylic acid, polyacrylic acid salt, polyvinyl alcohol, polyvinyl pyrrolidone and polyethylene oxide. Test compound ED 50 value, mg/kg (95 % confidence limit) 1,14-di-O-butanoylneoline 29.5 (10.3-83.90) 1,14-di-p-chlorobenzoylneoline 27.6 (9.32-81.70) n=6. Test compound LD 50 value, mg/kg (95 % confidence limit) 1,14-di-butanoylneoline 30< 1,14-di-p-chlorobenzoylneoline 30<

Claims: An aconitine compound of the general formula (I) or a salt thereof: wherein R 1 and R 7 are the same and represent : butanoyl or p-chlorobenzoyl. An aconitine compound of the general formula (I) or a salt thereof as claimed in claim 1 for use as an active therapeutic substance. An analgesic/anti-inflammatory composition containing as an active ingredient an aconitine compound of claim 1 or a salt thereof together with an excipient. The use of an aconitine compound of claim 1 for the preparation of a pharmaceutical composition having analgesic/anti-inflammatory activity.

Inventors: MORI TAKAO, MURAYAMA MITSUO, MORI, TAKAO, MURAYAMA, MITSUO
Applicants: SANWA SHOYAKU KK, SANWA SHOYAKU KABUSHIKI KAISHA
Application year: 1991
Main classification: C07D221
IPC codes: C07D221