Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1994-12-16
1995-12-12
Datlow, Philip I.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
544278, 544279, 544282, 544285, 544286, 544287, 544311, 544312, 544319, 544320, 544281, 5483051, 548454, 548455, 548465, C07D40304, C07D40306, C07D40314, C07D41714
Patent
active
054751055
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel N-substituted azabicycloheptane derivatives, the preparation and use thereof for preparing pharmaceutical agents.
It is known that 5- or 6-membered heterocyclic nitrogen derivatives with basic substituents have neuroleptic effects (EP 196 132, EP 70 053, EP 110 435).
It appears that the high affinities for serotonin receptors, in addition to the dopamine affinities, are particularly important for this.
We have now found that N-substituted 3-azabicyclo[3.2.0]heptane derivatives of the formula I ##STR2## where R.sup.1 is phenyl, pyridyl, thienyl or pyrrole [sic], each of which is unsubstituted or mono- or disubstituted by halogen, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro, halogen, methoxy, hydroxyl or amino, -alkoxy, or together with the adjacent carbon atom is C.dbd.O or C.dbd.S, replaced by hydroxyl, amino, C.sub.1 -C.sub.4 -alkoxy or halogen, 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 can be replaced by N, S, NH or N-CH.sub.3, and where the ring can be either mono-substituted by fluorine, chlorine, methyl, methoxy, nitro or amino or, in the case of a benzene ring, mono-, di- or trisubstituted by fluorine, chlorine, methyl, trifluoromethyl, nitro, hydroxyl, methoxy, amino, monomethylamino or dimethylamino, -alkyl, allyl or benzyl attached to N-1 and can contain 1-3 non-cumulative double bonds, and the salts thereof with physiologically tolerated acids have valuable pharmacological properties.
The following meanings may be particularly mentioned for R.sup.1, R.sup.2, R.sup.3 and n: chlorine, iodine, methoxy, nitro, trifluoromethyl, hydroxyl or amino,
The ring system on the right in formula I is, in particular, ##STR3##
Particularly preferred compounds are those where fluorine and chlorine or in the m position by fluorine or chlorine
The following compounds are particularly preferred: yl-5H-thiazolo[3,2-a]pyrimidin-5-one, yl-5H-thiazolo[3,2-a]pyrimidin-5-one, yl-2,3-dihydro-5H-thiazolo[3,2-a]-pyrimidin-5-one, yl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, H,3H)-quinazolinedione, yl-2,4-(1H,3H)-quinazolinedione, yl-4H-pyrido-[1,2-a]pyrimidin-4-one, 9-tetrahydro-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, ylamino-3,6-dimethyl-4(3H)-pyrimidinone, lamino-3,6-dimethyl-4(3H)-pyrimidinone.
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.3, 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 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 for the nucleofugic leaving group Nu are halogens, especially bromine or chlorine.
The reaction is expediently carried out in the presence of an inert base such as triethylamine or potassium carbonate to bind the acid and 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 usually carried out at from 20.degree. to 150.degree. C. in particular from 80.degree. to 140.degree. C., and is generally complete after from 1 to 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 resolved into the enantiomers in a straightforward way by classical methods 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 c
REFERENCES:
patent: 4540318 (1985-09-01), Hornung et al.
Kenms, Chemical Abstract 102: 6522t (1985) for EP 110,435 (Jun. 13, 1984).
Behl Berthold
Munschauer Rainer
Steiner Gerd
Teschendorf Hans-Juergen
Unger Liiane
BASF - Aktiengesellschaft
Datlow Philip I.
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