N-substituted 3-azabicyclo (3.2.0)heptane derivatives useful as

Details N-substituted 3-azabicyclo (3.2.0)heptane derivatives useful as N-substituted 3-azabicyclo (3.2.0)heptane derivatives useful as

1998-09-18

2000-02-22

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514259, 514269, 514270, 514271, 514312, 514414, 514387, 544285, 544282, 544319, 544320, 544321, 546157, 5483051, 548455, A61K 31505, C07D47102, C07D40106

Patent

active

060280735

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel N-substituted azabicycloheptane derivatives, and to their preparation and use for the preparation of pharmaceutical agents.
It is known that N-substituted azabicycloheptane derivatives have surprising affinity for dopamine and serotonin receptor subtypes (DE 42 43 287, DE 42 19 973). The observed high affinities for the D.sub.4 dopamine receptor subtype play a special role in this.
We have now found that N-substituted 3-azabicyclo[3.2.0]heptane derivatives of the formula I ##STR2## where .sup.1 is naphthyl or phenanthryl which is unsubstituted, mono- or disubstituted by halogen atoms, -alkoxy, or together with the adjacent carbon atom is C.dbd.O or C.dbd.S, groups or nitrogen atoms, one hydrogen atom can be replace d by hydroxyl, amino or C.sub.1 -C.sub.4 -alkoxy 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 is C.dbd.O, or contain one or two non-cumulative double bonds and in which one CH or CH.sub.2 group can be replaced by a nitrogen or sulfur atom or an NH or N--CH.sub.3 group and where the ring can be monosubstituted either by a fluorine or chlorine atom or by methyl, methoxy, nitro or amino, or in the case of a benzene ring the latter can be mono-, di- or trisubstituted by fluorine or chlorine atoms or methyl, trifluoromethyl, nitro, hydroxyl, methoxy, amino, monomethyl- or dimethylamino groups, -C.sub.4 -alkyl group on nitrogen atom No. 1 and contain 1 to 3 non-cumulative double bonds, pharmacological properties.
The following particular meanings of the substituents R.sup.1 and R.sup.2 and of n should be mentioned:
The ring system on the right in formula I is, in particular, ##STR3##
Preferred compounds are in particular those in which the ring system on the right of the molecule is derived from 7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 2,4(1H, 3H)-quinazolinedione, 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone, 2(1H)-quinolone, indolin-2-one or 2(3H)-benzimidazolone.
The compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II ##STR4## where n, R.sup.2, X, Y, Z and A have the abovementioned meanings, and Nu is a nucleofugic leaving group, with a 3-azabicyclo[3.2.0]heptane derivative of the formula III ##STR5## where R.sup.1 has the abovementioned meanings, and converting the resulting compound where appropriate into the salt with a physiologically tolerated acid.
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 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 be recrystallized [sic] either by recrystallization from conventional organic solvents, preferably from a lower alcohol such as ethanol, or purified 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.
The free 3-azabicyclo[3.2.0]heptane derivatives of the formula I can be 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 ne

REFERENCES:
patent: 5475105 (1995-12-01), Steiner et al.

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