GB798847A - Novel quinolizine derivatives and a process for the manufacture thereof - Google Patents

Abstract

The invention comprises quinolizine derivatives of the general formula I: <FORM:0798847/IV (b)/1> wherein R1 and R2 are alkyl radicals each containing up to four carbon atoms, R3 stands for an alkyl radical containing up to ten carbon atoms, n is an integer from 1 to 4, m is 0 or an integer from 1 to 4, the broken lines denote that double bonds may be present in the positions indicated, two adjacent R1-O- and/or two adjacent R3-O- substituents may be linked to form an alkylenedioxy radical, and the optional double bond in ring C may be cyclically or semicyclically displaced, and a process for their manufacture. The compounds of formula I are prepared by condensing a compound of the formula II: <FORM:0798847/IV (b)/2> with a b -substituted ethylamine of the formula III: <FORM:0798847/IV (b)/3> cyclodehydrating the compound IV so obtained: <FORM:0798847/IV (b)/4> and hydrogenating the cyclization product V: <FORM:0798847/IV (b)/5> the use of various reduction techniques yields tereoisomeric products of the general formula I. Examples describe the preparation of the following compounds of the general formula I (as their acid addition salts) : 2-[{61,71-dimethoxy-11,21,31, 41 - tetrahydro - isoquinolyl - (11)] methyl} - 3 - methyl - 9,10 - dimethoxy-1,4,6,7 - tetrahydrobenzo[a]quinolizine, and the corresponding 3-ethyl (two stereoisomers), 3-isobutyl, 3 - n - butyl (two stereoisomers) and 3 - n - hexyl compounds; 2 - {[61,71 - methylenedioxy - 11,21,31,41-tetrahydroisoquinolyl - (11)]-methyl} - 3 - ethyl - 9,10 - dimethoxy - 1,4,6,7-tetrahydro - benzo [a] quinolizine; 2 - }[61-methoxy - 11,21,31,41 - tetrahydro - isoquinolyl-(11)] - methyl} -, 2 - {[61,71 - diethoxy - 11,21,31,41- tetrahydro - isoquinolyl - (11) - methyl]}-and 2 - {[61,71,81 - trimethoxy - 11,21,31,41-tetrahydro - isoquinolyl - (11)] - methyl} - 3-ethyl - 9,10 - dimethoxy - 1,4,6,7 - tetrahydrobenzo [a] quinolizine (two stereoisomers); 2-{[11,21,31,41,51,61,71, 81 - octahydro - isoquinolyl-(11) - methyl} - 3 - ethyl - 9,10 - dimethoxy-1,4,6,7 - tetrahydrobenzo [a] quinolizine; 2{[61,71 - dimethoxy - 11,21,31,41 - tetrahydroisoquinolyl - (11)] - methyl} - 3 - ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydrobenzo [a] quinolizine (two stereoisomers) and the corresponding 3-n-hexyl-, 3-isobutyl- and 3-n-butyl-compounds; 2 - {[61,71 - diethoxy - 11,21,31,41-tetrahydroisoquinolyl - (11) - methyl} - (two isomers), 2 - {[61,71,81 - trimethoxy - 11,21,31,41-tetrahydro - isoquinolyl - (11)] - methyl} -, 2-{[61,71 - methylenedioxy - 11,21,31,41 - tetrahydro - isoquinolyl - (11)] - methyl} - and 2-{[71 - methoxy - 11,21,31,41 - tetrahydroisoquinolyl - (11)] - methyl} - 3 - ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo [a] quinolizine. The preparation of the corresponding intermediates of formula IV and V is also described, starting from 3-R3-2-carboxymethylbenzo [a] quinolizines of the formula II. Compounds of formula II having a double bond in the 2,3-position are prepared by condensing an appropriately substituted 1-alkoxycarbonylmethyl - 1,2,3,4 - tetrahydroisoquinoline with a monosubstituted dimethylmalonate and formaldehyde, cyclizing the resulting tri-ester, hydrolysing, decarboxylating and condensing the resulting substituted 2-oxo-1,2,3,4,6,7-hexahydro-benzo [a] quinolizine with malonic acid dinitrile. The substituted 2-(dicyanomethylidene) - 3 - R2 - 1,2,3,4,6,7 - hexahydrobenzo [a] quinolizine so formed is then hydrolysed and decarboxylated. Starting materials of formula II having a single bond in the 2,3-position are prepared by condensing the foregoing substituted 2-oxo-1,2,3,4,6,7-hexahydrobenzo [a] quinolizine with ethyl cyanoacetate and hydrogenating, hydrolysing and decarboxylating the product.