Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-02-03
1998-05-19
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514412, 514414, 514421, 548437, 548455, 548465, 548515, A61K 3140, C07D20956, C07D20902, C07D20944
Patent
active
057536902
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application is a 371 of PCT/EP95/02912 filed Jul. 22, 1995.
The present invention relates to novel N-substituted azabicycloheptane derivatives, and to their preparation and use for the preparation of drugs.
2. Description of Related Art
It is known that N-substituted azabicycloheptane derivatives have surprising affinity for dopamine and serotinin receptor subtypes (DE 42 43 287, DE 42 19 973). The observed affinities for the D.sub.4 dopamine receptor subtype play a special role in this.
SUMMARY OF THE INVENTION
derivatives of the formula I ##STR2## where R.sup.1 is naphthyl or phenanthryl which is unsubstituted, mono- or di-substituted by halogen atoms, ##STR3## or naphthyl which is unsubstituted or halogen-substituted, R.sup.2 is hydrogen, hydroxyl, C.sub.1 -C.sub.4 -alkyl, nitro or methoxy, or fluorine, chlorine, bromine or iodine, pharmacological properties.
DESCRIPTION OF PREFERRED EMBODIMENTS
The substituents R.sup.1 to R.sup.5, and n, in the formula I preferably have the following meanings:
The compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II ##STR4## where R.sup.1 is naphthyl or phenanthryl which is unsubstituted, mono- or disubstituted by halogen atoms, with physiologically suitable acids.
Suitable and preferred nucleofugic leaving groups Nu are halogen atoms, in particular bromine or chlorine.
The reaction is expediently carried out in the presence of an inert base such as triethylamine or potassium carbonate to trap acid, in an inert solvent such as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as toluene or xylene.
The reaction normally takes place at from 20.degree. to 150.degree. C., and is generally complete within 1-10 hours.
The compounds of the formula I according to the invention can be purified either by recrystallization from conventional organic solvents, preferably from a lower alcohol such as ethanol, or by column chromatography.
Racemates can be fractionated to the enantiomers in a simple way by classical resolution using optically active carboxylic acids, eg. tartaric acid derivatives, in an inert solvent, eg. lower alcohols. converted in a conventional way into the salt of a pharmacologically suitable acid, preferably by treating a solution with one equivalent of the appropriate acid. Examples of pharmaceutically suitable acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
The compounds according to the invention have valuable pharmacological properties. They can be used as neuroleptics (especially atypical), antidepressants, sedatives, hypnotics, CNS protectives or muscle relaxants. A compound according to the invention may display several of said types of action in combination. The pharmacological action is demonstrated both in vivo and in vitro, it being possible to characterize the substances in particular by the affinity, which is in some cases very high and selective, for receptor subtypes, especially dopamine D.sub.4 receptors.
The following methods have been used for the in vivo characterization:
a) Influence on orientation motility increased motor activity. This motor activity is measured in light barrier cages for 0-30 min after the animals (NMRI mice, female) have been placed in the cage. ED50: dose which reduces the motor activity by 50% compared with placebo-treated controls.
b) Apomorphine antagonism apomorphine leads to motor activation manifested by a permanent climbing when the animals are kept in wire mesh cages. The climbing is scored every 2 min for 30 min: compared with placebo-treated controls.
c) L-5-HTP antagonism animals then develop an agitation syndrome, of which the symptoms of from 20 to 60 min after administration of L-5-HTP. The average score after administration of L-5-HTP is 17. The test substances are given p.o. 60 min before L-5-HTP. The ED50 is calcula
REFERENCES:
patent: 5475105 (1995-12-01), Steiner et al.
patent: 5521209 (1996-05-01), Steiner et al.
Specification and claims from BASF 0050/44494, N-substituted Azabicycloheptane Derivatives, Their Preparation and Use.
Hoger Thomas
Munschauer Rainer
Steiner Gerd
Teschendorf Hans-Jurgen
Unger Liliane
BASF - Aktiengesellschaft
Coleman Brenda
Shah Mukund J.
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