Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-02-09
1991-02-26
Nucker, Christine
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548421, C07D48706, A61K 3140
Patent
active
049962230
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new organic compounds having opioid properties, and to methods for their production.
It is known that eseroline, a hydrolysis product of physostigmine, has analgesic properties approximately equipotent with morphine but it also retains undesirable anticholinesterase activity.
Analogues of eseroline have been described in 1982 by Bartolini et al, in Canadian Patent Specification No. 1,137,489, but without presentation of any supporting pharmacological data.
Well known and potent analgesics include compounds having the molecular skeleton of morphine with addition of a substituted 2-carbon atom bridge between the 6 and 14 carbon atoms in the morphine structure, but this modification of the structure still has not taken away the high dependence liability.
It appears to be very difficult to identify, in any compound which possesses valuable opioid properties akin to those of morphine, exactly what causes the highly undesirable properties of respiratory depression, vomiting and dependence liability commonly associated with morphine.
The varied actions of morphine are mediated via a range of different types of receptors and it is believed that a particular action (for example analgesia) may be mediated via one type of receptor while a different type of receptor mediates another action, for example dependence liability. These different types of opioid receptors exist in peripheral tissues which can therefore serve as "models" for assessing opioid activity. In this way, the action of a drug on the intestinal muscle of the guinea pig, for example, is indicative of analgesic activity in man. The spectrum of sensitivity of different types of receptors (the receptor "profile") in a range of isolated tissues towards various opioids can thus be used as an indication of differences in properties which are of importance in practical use, for example the degree of dependence liability.
The existence of opioid antagonists at these receptors assist in the identification of novel mechanisms of drug action (i.e. receptor "profiles" that differ from morphine).
It is therefore very important to find compounds which do have opioid properties including the desired features but with the less desirable features removed or diminished, i.e. opioid compounds which have a different receptor "profile" from that of morphine itself.
We have now found that the opioid activity of eseroline can be retained to a substantial degree while the anticholinesterase activity appears to be substantially reduced or even removed, by incorporating a bridge structure in the eseroline ring system, namely a four-carbon atom bridge. Additionally, such compounds have opioid receptor "profiles" that differ from that of morphine and so are indicative of different qualitative actions in vivo, and offer an alternative to morphine.
Thus according to our invention we provide new organic compounds having opioid properties, namely new echiboline derivatives which are 6-hydroxy-9-methyl-echibolines with a hydrocarbon substituent of up to 4 carbon atoms in the 10-position.
The compounds of this invention, being bases, form salts with acids. Accordingly, the present invention includes the compounds in the form of the free bases or their salts, and the new compounds may be defined as new echiboline derivatives having, in their free-base form, the structure of a 6-hydroxy-9-methyl-echiboline with a hydrocarbon substituent of up to 4 carbon atoms in the 10-position.
The hydrocarbon substituent at the 10-position may contain up to four carbon atoms, and is preferably of the structure R.CH.sub.2 - wherein R represents a hydrogen atom or a hydrocarbon group of up to three carbons. When R is a hydrocarbon group, this may be for example a cyclopropyl group or an ethenyl group (CH.sub.2 .dbd.CH--), so that the 10-substituent is correspondingly a cyclopropyl-methyl or an allyl group. When R is a hydrogen atom, the 10-substituent is a methyl group. These compounds are especially useful and convenient to make.
Echiboline is the trivial name which has been g
REFERENCES:
Liebigs Annalen der Chemie, vol. 709, 1967, Fritz et al.: "Uber Ring-Ketten-Tautomerie . . . ", pp. 135-150.
Cox Brian
Rees John M. H.
Robinson Brian
Nucker Christine
The Victoria University of Manchester
Tsung Frederick F.
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