Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-06
1997-12-30
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514302, 514412, 546113, 546115, 548452, 548453, A61K 3139
Patent
active
057030910
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel N-substituted azabicycloalkane derivatives, their preparation and use for preparing pharmaceutical active compounds.
It has been disclosed that basically substituted butyrophenone derivatives or benzamide derivatives have neuroleptic or cerebro-protective activity (U.S. Pat. No. 4,605,655, EP 410 114, DE 12 89 845, EP 400 661, DE 29 41 880, EP 190 472, DE 42 19 973).
The observed high affinities to dopamine and serotonin receptor subtypes appear to play a particular role in this context.
It has now been found that N-substituted 3-azabicycloalkane derivatives of the formula I ##STR2## where B is a 3-, 5- or 6-membered ring which can contain 1 nitrogen atom and/or 1 oxygen atom and possibly one double bond, by halogen atoms or C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, group which is unsubstituted or substituted by halogen, methoxy, hydroxyl or amino, --CO--R.sup.7, by fluorine, chlorine, bromine or a hydroxyl, nitro, amino, C.sub.1-4 -alkanoylamino, C.sub.1-4 -alkylamino, C.sub.1 -C.sub.4 -alkyl or methoxy group or a naphthyl group which is unsubstituted or substituted by fluorine or chlorine, chlorine, bromine, C.sub.1 -C.sub.4 -alkyl, hydroxyl or methoxy or monosubstituted by nitro, cyano, trifluoromethyl, amino, C.sub.1 -C.sub.4 -alkylamino or di-C.sub.1 -C.sub.4 -alkylamino or a thienyl, naphthyl, benzothienyl or indenyl group which is unsubstituted or substituted by fluorine, chlorine or nitro, pharmacological properties.
In the formula I, the substituents R.sup.1 to R.sup.6 and n preferably have the following meanings: methoxy, trifluoromethyl, nitro, hydroxyl or amino, 5-chlorothien-1-yl, 1-naphthyl, 3-indenyl, 3-chloro-1-benzothien-2-yl.
The bicyclic ring system in the left moiety of the formula I is particularly ##STR3##
Preferred compounds are in particular those where fluorine or chlorine or in the m-position by fluorine or chlorine and
The compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II group, with a 3-azabicycloalkane derivative of the formula III ##STR4## where B, R.sup.1 and R.sup.2 have the meaning given above, removing any protective groups present and if desired converting the compound thus obtained into the acid addition salt of a physiologically tolerable acid.
Suitable nucleofugic leaving groups for Nu are preferably 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, as acid acceptor in an inert solvent, such as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or a benzene hydrocarbon, such as toluene or xylene.
The reaction is in general carried out at from 20.degree. to 150.degree. C., in particular from 80.degree. to 140.degree. C., and is in general complete within from 1 to 10 hours.
The compounds of the formula I according to the invention can either be purified by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by column chromatography.
Racemates can be resolved into the enantiomers in a simple manner by classical cleavage 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 to the acid addition salt of a pharmacologically tolerable acid in a customary manner, preferably by treating a solution with an equivalent of the corresponding acid. Pharmaceutically tolerable acids are, for example, 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 useful pharmacological properties. They can be used as neuroleptics (in particular atypical), antidepressants, sedatives, hypnotics, CNS protectants or muscle relaxants. Several o
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patent: 4605655 (1986-08-01), Yevich et al.
patent: 5216018 (1993-06-01), Ciganek
patent: 5532243 (1996-07-01), Gilligan
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Hoger Thomas
Munschauer Rainer
Steiner Gerd
Teschendorf Hans-Jurgen
Unger Liliane
BASF - Aktiengesellschaft
Reamer James H.
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