Verfahren zur Herstellung von therapeutisch wirksamen Chinolizinderivaten

摘要

The invention comprises compounds of the general formula and their non-toxic acid addition salts wherein R1 is a hydrogen atom or a C1- 7-alkyl. A halogenated-C1- 7-alkyl group, a monocyclic aryl group, an alkyl-, halogenor alkoxy-substituted monocyclic aryl group or a monocyclic aryl C1- 7-alkyl group, R2 is a hydrogen atom or a C1- 7-alkyl group and R5 is a bivalent radical which together with the adjoining carbon atoms of the quinolizine radical forms a substituted or unsubstituted benzene or indole radical which may have as substituents C1- 7-alkyl groups and/or C1- 7 alkoxy groups or a combination thereof or a methylenedioxy group and X is =C=O or =CH2 and the preparation thereof by cyclizing by heating under reflux conditions in an inert organic solvent a compound of the formula and if desired reducing the oxo group formed. Compounds of the invention where Z=CH2 are also prepared by reduction of the corresponding quinolizium quaternary salt or by reduction with subsequent ring closure of the reaction product of a glutaric aldehyde and tryptamine. Tetrahydro pyridine derivatives used as starting materials are prepared by reacting 3-R1R2-glutaric anhydrides with a phenyl ethylamine or a tryptamine to give an N-2-R3-3-R1R2-glutaramic acid (where R3 is a substituted phenyl or endolyl residue) and cyclizing this after esterification to give a dihydro pyridine derivative which is reduced. 3-(4-Methylphenyl) glutaric acid anhydride is prepared by reacting 4-methylbenzaldehyde with ethyl acetoacetate to form diethyl 2,4-diacetyl-3-(4-methylphenyl) glutarate, hydrolysing this to give 3-(4-methylphenyl) glutaric acid and forming the anhydride. Similarly are prepared the above 3-R1R2-glutaric anhydrides. Quaternary quinolizinium salts used as starting materials are prepared by reacting a 31-R1R2-5-bromovalerate with a phenylethylamine or a tryptamine to give a 1-(2-R3-ethyl)-4-R1R2-piperiol-2-one and cyclizing this with phosphorus oxychloride. Ethyl 5-bromo-3-methyl-valerate is prepared from 3-methyl-5-valerolactone and hydrogen bromide in ethanol. Ethyl 5-bromo-3-phenyl-valerate is also prepared.