Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-03-05
1994-07-19
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540581, C07D22122, C07D22314, A61K 31435
Patent
active
053309839
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel compound 14-O-p-chlorobenzoylaconine or a salt thereof, as well as to a novel analgesic/anti-inflammatory agent containing the 14-O-p-chlorobenzoylaconine or salt thereof as active ingredient.
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 activity. 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 already succeeded in providing "novel aconitine compounds and analgesic/anti-inflammatory agent comprising the same" (Japanese patent application No. 2-283553). As a result of further studies, we have now succeeded in providing 14-O-p-chlorobenzoylaconine, a compound with excellent pharmacological effects coupled with high safety.
Thus, the present invention provides a new compound, 14-O-p-chlorobenzoylaconine of the formula: ##STR1## as well as a salt thereof. It also provides an analgesic/anti-inflammatory agent containing 14-O-p-chlorobenzoylaconine or a salt thereof as active ingredient together with an excipient.
The present invention will now be described in detail in the following.
The compound according to the invention of the formula (I) shown above may be prepared by using as starting material aconitine compounds described in the literature, such as aconitine, mesaconitine, jesaconitine, 14-O-benzoylaconine, 14-O-benzoylmesaconine and 14-O-anisoylaconine shown below by the formulas (II) , (III), (IV) , (V) , (VI) and (VII), respectively.
Where the compounds of the formulas (II), (IV), (V) and (VII) are used as starting material, the compound of the formula (I) may be prepared by deesterification into hydroxyl group of the substituent present at the position 14 or 8 in the form of ester bond, through hydrolysis such as alkaline hydrolysis, followed by reaction with p-chlorobenzoyl chloride in an appropriate solvent such as pyridine.
Where the compounds of the formulas (III) and (VI) are used as starting material, the compound of the formula (I) may be prepared by following the same steps as in the case where the compounds of the formulas (II), (IV), (V) and (VII) are used as starting material, i.e. deesterification into hydroxyl group of the substituent present at the position 14 or 8 in the form of ester bond, through hydrolysis such as alkaline hydrolysis, followed by reaction with p-chlorobenzoyl chloride in an appropriate solvent such as pyridine, to give 14-O-p-chlorobenzoylmesaconine; reacting the product with an appropriate oxidizing agent such as potassium permanganate in an appropriate solvent such as acetone to give N-demethylated product; and reacting the N-demethylated product with an ethylating agent such as ethyl iodide.
______________________________________ ##STR2## (II)-(VII)
R.sub.1 R.sub.2 R.sub.3
______________________________________
II Bz CH.sub.2 CH.sub.3
OAc
III Bz CH.sub.3 OAc
IV An CH.sub.2 CH.sub.3
OAc
V Bz CH.sub.2 CH.sub.3
OH
VI Bz CH.sub.3 OH
VII An CH.sub.2 CH.sub.3
OH
______________________________________
Bz: COC.sub.6 H.sub.5,
An: COC.sub.6 H.sub.4 OCH.sub.3,
Ac: COCH.sub.3
The compound of the invention is a basic substance capable of forming salts with inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid or with organic acids such as oxalic acid, succinic acid, tartaric acid, citric acid and ascorbic acid.
In the following will now be given working examples and experiment examples regarding the compound of the invention for further illustration of the present invention Physicochemical parameters and analytical data of the compound of the formula (I) prepared in these working examples are given just after the description of the working examples. Pharmacolog
Rotman Alan L.
Sanwa Shoyaku Kabushiki Kaisha
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