Huperzine A derivatives, their preparation and their use

Details Huperzine A derivatives, their preparation and their use Huperzine A derivatives, their preparation and their use

1997-06-27

1999-07-27

Huang, Evelyn Mei

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546 93, 546 97, A61K 3144, C07D22106, C07D22122

Patent

active

059290846

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/CN95/00100, filed Dec. 26, 1995, published as WO96/20176 on Jul. 4, 1996.
The present invention relates to semi-synthesis of natural product, and particularly to alkaloid and analogues thereof.
In the past ten years a lot of researches have been made in foreign countries about application of choline esterase inhibitor to enhance the function of the intracerebral cholinergic system for the treatment of presenile dementia. Although delightful results of research have been obtained, there still exist some defects; at the time of producing the treatment effect, there occurs a relatively serious toxic side reaction; and the duration of the effect is relatively short.
In recent years China has isolated from a Chinese herb Lycopodium serratum Thunb., a new alkaloid huperzine A (5R, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methylene ##STR4##
Upon a pharmacological study it is proved that it exhibits highly effective reversible anticholinesterase activity, and has selective inhibitory effect on intracerebral acetylcholinesterase (U.S. Pat. No. 5,177,082). In foreign countries modification of the structure of huperzine A has been carried out and analogues of huperzine A have been synthesized in hopes of Org. Chem. 56, 1991(4636-4645)! and finding a method of synthesizing an analogue having a better effect has been found so far.
The present invention has made use of the excellent resources of Chinese herbs in China to design a semi-synthesis starting from huperzine A, in the hope of finding among a great variety of huperzine A derivatives compounds having better treatment effect and lower toxicity than the existing huperzine A.
The present invention is carried out through the following steps:
1. Using alcohols such as ethanol as extraction solvent, from the plant Lycopodium serratum Thunb., the residue obtained is concentrated, and then treated with an inorganic acid (such as hydrochloric acid). The aqueous layer is neutralized with alkali (such as ammonia water, NaOH), after which an organic solvent (such as chloroform) is used to extract the total alkaloid. After the treatment, separation by layer chromatography is carried out to produce the compound of the formula (I).
2. After condensation is carried out between the compound of the formula (I), and the corresponding substituted aldehyde or the corresponding substituted acyl chloride or acid anhydride in anhydrous solvent, a compound of the formula (II) is obtained. ##STR5##
When Y is --C.dbd.O or --R", Y is .dbd.CH, ##STR6## n=0,1, X is hydrogen, C.sub.1 -C.sub.5 lower alkyl, C.sub.1 -C.sub.5 lower alkyloxy, nitro, halogen, carboxy, alkyloxycarbonyl, hydroxymethyl, hydroxy, amino substituted by bis-C.sub.1 -C.sub.5 lower alkyl; --(CH.sub.2).sub.m COOZ group, m=0-5, Z is hydrogen or C.sub.1 -C.sub.5 lower alkyl; --CH.dbd.CH--G group, G is phenyl, furanyl, carboxy, alkyloxycarbonyl; dihydro or tetrahydropyridyl substituted by C.sub.1 -C.sub.5 lower alkyl at the nitrogen atom; by C.sub.1 -C.sub.5 lower alkyloxy;
When Y is C.dbd.O, R is C.sub.1 -C.sub.5 lower alkyl, ##STR7## n=0,1, X is hydrogen, C.sub.1 -C.sub.5 lower alkyloxy, carboxy, alkyloxycarbonyl, pyridyl, dihydro or tetrahydropyridyl substituted by C.sub.1 -C.sub.5 lower alkyl at the nitrogen atom; --(CH.sub.2).sub.m COOZ group, m=0-5, Z is hydrogen or C.sub.1 -C.sub.5 lower alkyl; --CH.dbd.CH--G group, G is phenyl, furanyl, carboxy, alkyloxycarbonyl; by C.sub.1 -C.sub.5 lower alkyloxy;
When R", Y are .dbd.CH, R is ##STR8## n=0, X is hydrogen, C.sub.1 -C.sub.5 lower alkyl, C.sub.1 -C.sub.5 lower alkyloxy, nitro, halogen, hydroxy, hydroxymethyl, amino substituted by bis-C.sub.1 -C.sub.5 lower alkyl; --CH.dbd.CH--G group, G is phenyl, furanyl;


__________________________________________________________________________ No. Y R R' R" __________________________________________________________________________ No. 1 C.dbd.O HOOC--CH.sub.2 CH.sub.2 -- H H No. 2 C.dbd.O C.sub.6 H.sub.5 CH.sub.2 -- H H No. 3 C.dbd.O 1 #STR9## CH.sub.3 CH

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