Sesquiterpenes, their preparation and their use as inhibitors ac

Details Sesquiterpenes, their preparation and their use as inhibitors ac Sesquiterpenes, their preparation and their use as inhibitors ac

1995-08-29

1996-10-15

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549383, 435119, A61K 3135, C07D31194

Patent

active

055654860

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB93/02632 filed Dec. 22, 1993.
The present invention relates to novel benzodiazepine-receptor binding compounds. The invention further relates to the preparation of said compounds, to pharmaceutical and veterinary compositions containing them and to the microorganism from which they are obtained.
Benzodiazepine (Bz) is the conventional term used to describe the structurally related compounds with the basic benzo-1,4-diazepine structure (Haefely et al, Advances in Drug Res. 14 165-322 (1985)). Pharmacological screening of some of the early synthetic analogues of this novel ring system showed the benzodiazepines to have tranquillizing and anticonvulsant activity. Further investigation resulted in the launch of chlordiazepoxide (Librium) for therapeutic use in 1960.
Extensive electrophysiological and binding studies have established that the benzodiazepine mechanism of action involves allosteric modulation of the major inhibitory neuro-transmitter, gamma-aminobutyric acid (GABA). More specifically, this effect results in the hyperpolarisation of neurons by increased Cl.sup.- ion flux through the GABA-Bz-Cl.sup.- ionophore receptor complex. This receptor complex has been designated subtype A, or GABA.sub.A.
The majority of the currently prescribed benzodiazepines are agonists and act by potentiation of the GABA inhibitory effect. They therefore exert sedative, hypnotic, anticonvulsant and anxiolytic effects. Partial (low efficacy) agonists are also of interest since their use can reduce the undesirable effects of benzodiazepine therapy such as sedation, tolerance and addiction yet maintain their clinical effect. Inverse agonists having biological activity opposite to the classical benzodiazepine effects, i.e. convulsants, also have a postulated role in memory enhancement. Antagonists are devoid of biological activity but have applications in counteracting an excess of the above effects, i.e. overdose.
Structure activity relationships (SAR) for benzodiazepines have been fully characterised and the pharmacophore identified. Emphasis has therefore shifted to the identification of the endogenous receptor ligand, or novel structures as potential new drug candidates. Various chemical classes (e.g. benzazepines, .beta.-carbolines, cyclopyrrolones, phenylquinolines, triazolopyridazines and imidazopyridines) have been shown to be active at this site. Zopiclone (a cyclopyrrolone derivative) and zolpidem (an imidizopyridine) have been launched as hypnotics.
It has now been found that fermentation of a nutrient medium with a strain of the fungus Acremonium strictum (Xenova organism X06/15/458, IMI 354451) produces novel compounds which inhibit the binding of benzodiazepine to the benzodiazepine receptor present on the GABA-Bz-Cl.sup.- ionophore receptor complex. These compounds are sesquiterpenes which, together with their synthetic derivatives, form a novel class.
Accordingly the present invention provides a sesquiterpene of formula I: ##STR1## wherein each of ##STR2## is a single bond or one is a single bond and the other is a double bond;
A, together with ##STR3## and the carbon atoms to which it is attached forms a ring selected from: ##STR4## wherein R is H or OH; ##STR5## and Y is a double bond or, when A is a ring (a) as defined above Y is either a double bond or forms, together with the carbon atoms to which it is attached, an epoxide linkage; ##STR6## and the pharmaceutically or veterinarily acceptable salts thereof.
In one embodiment, the sesquiterpene of formula I has the following structure II: ##STR7## wherein --Y-- is a double bond or forms, together with the carbon atoms to which it is attached, an epoxide linkage ##STR8## .
In another embodiment the sesquiterpene of formula I has the following structure III: ##STR9## wherein R is H or OH.
In a further embodiment, the sesquiterpene of formula I is a compound of the following formula IV: ##STR10## wherein X represents ##STR11##
The sesquiterpene of formula II wherein Y is a double bond is hereinafter referred to as compound

REFERENCES:
Patent Abstracts of Japan, vol. 12, No. 263 Jul. 1988 & JP, A, 63 048 284 (Yamanouchi Pharmaceutical Co. Ltd.) 29 Feb. 1988.
Advances in Drug Research vol. 14, 1985, pp. 165-322, Haefly W, et al 'Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their et al' see the whole document.

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