N-substituted azabicycloalkane derivatives, their preparation an

Details N-substituted azabicycloalkane derivatives, their preparation an N-substituted azabicycloalkane derivatives, their preparation an

1996-05-06

1999-06-01

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514259, 514272, 514275, 544253, 544278, 544282, 544284, 544285, 544286, 544287, 544320, 544321, 544330, 544331, A61K 31505, C07D40304, C07D40306

Patent

active

059088443

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel N-substituted azabicycloalkane derivatives, their preparation and use for preparing pharmaceutical active substances.
It is known that 5- or 6-membered heterocyclic nitrogen derivatives with basic substituents have neuroleptic effects (EP 196 132, EP 70 053, DE 42 43 287).
In this context the observed high affinities for serotonin receptors appear, besides the dopamine receptor subtype affinities, to be particularly important.
We have now found that N-substituted 3-azabicycloalkane derivatives of the formula I ##STR2## where B is a 3-, 5- or 6-membered ring which, in addition to carbon atoms, may contain 1 nitrogen atom and/or 1 oxygen atom and optionally a double bond, halogen atoms, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, unsubstituted or substituted by halogen, methoxy, hydroxyl or amino, -alkoxy or, together with the adjacent carbon atom, a C.dbd.O or C.dbd.S group, groups or nitrogen atoms, which one hydrogen atom can be replaced by a hydroxyl, amino or C.sub.1 -C.sub.4 -alkoxy group or a halogen atom, and di-C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 -alkylthio or C.sub.1 -C.sub.4 -alkoxy or, together with the adjacent carbon atom, a C.dbd.O group, or contain one or two non-cumulative double bonds and in which one CH or CH.sub.2 group may be replaced by a nitrogen or sulfur atom or an NH or N--CH.sub.3 group and where the ring may be mono-substituted either by a fluorine or chlorine atom or a methyl, methoxy, nitro or amino group or, in the case of a benzene ring, the latter may be mono-, di- or trisubstituted by fluorine or chlorine atoms or methyl, trifluoromethyl, nitro, hydroxyl, methoxy, amino, monomethyl- or dimethylamino groups, No. 1 hydrogen atom or a C.sub.1 -C.sub.4 -alkyl group and may contain 1-3 non-cumulative double bonds, and salts thereof with physiologically tolerated acids, have valuable pharmacological properties.
The following meanings of the substituents R.sup.1, R.sup.2, R.sup.3 and n should be particularly mentioned: methoxy, nitro, trifluoromethyl, hydroxyl or amino,
The bicyclic ring system on the left of formula I is, in particular, ##STR3##
The ring system on the right in formula I is, in particular, ##STR4##
Particularly preferred compounds are those where fluorine and chlorine or in the m position by fluorine or chlorine
The compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II ##STR5## where n, R.sup.3, X, Y, Z and A have the abovementioned meanings, and Nu is a nucleofugic leaving group, with a 3-azabicycloalkane derivative of the formula III ##STR6## where B, R.sup.1 and R.sup.2 have the abovementioned meanings, and converting the resulting compound where appropriate into the addition salt with a physiologically tolerated acid.
Suitable and preferred nucleofugic leaving groups Nu are halogen atoms, especially bromine or chlorine.
The reaction is expediently carried out in the presence of an inert base such as triethylamine or potassium carbonate as acid trap in an inert solvent such as a cyclic saturated ether, especially tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as toluene or xylene.
The reaction is, as a rule, carried out at from 20 to 150.degree. C., in particular from 80 to 140.degree. C., and is generally complete within 1-10 hours.
The compounds of the formula I according to the invention can either be recrystallized by recrystallization from conventional organic solvents, preferably from a lower alcohol, such as ethanol, or be purified by column chromatography.
Racemates can be fractionated into the enantiomers in a simple way by classical resolution using optically active carboxylic acids, e.g. tartaric acid derivatives, in an inert solvent, e.g. lower alcohols.
The free 3-azabicycloalkane derivatives of the formula I can be converted in a conventional way into the addition salt of a pharmacologically suitable acid, preferably by mixing a solutio

REFERENCES:
patent: 3960861 (1976-06-01), Danilewicz et al.
patent: 5049564 (1991-09-01), DeBernardis et al.

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