PL126672B1 - Method for producing new octahydro-1h-pyrrole /2,3-g/isoquinolines - Google Patents

Description

The subject of the invention is a process for the preparation of new octane-1H-pyrrole (2.3 g] isoquinolines of the general formula A, in which Ra and R3 are identical or different and represent hydrogen, alkyl, cycloalkal, alkenyl, acyl radicals. , aryl, or aralkyl, and R4 is a farmer alkylating ether, hydroxyalkyl fenylohydroksyalkilowy, chlorofenylohydroksyalkilowy, alkilofenylohydroksy- alkyl alkoksyfenylohydroksyalkilowy, alkoxy alkyl aryloksyhydroksyalkilowy, alkoksyhydrok- syalkalowy, acylokisyalkilowy, arylokarbonyloalkilo¬ O, alkoksykarbonyloalkilowy, aralkyl, alkenyl ether, alkiiocylfcloalkilowy , alkynyl, thienylalkyl, furylalkyl, arylcarboxamidoalkyl, acylalkalic, cycloalkyloxyalkyl, cycloalkylhydroxyUril, alkenyloxyalkyl, aralfcenyl, aryloxyalkyl, N-alkylpyrrolidine or 2-alkylarylalkyl radicals where Re and R7 are the same or different and represent hydrogen atoms or alkyl radicals, or together with the nitrogen atom form a 5- or 6-membered heterocyclic ring, and X is oxygen or sulfur. The invention also relates to the optical and geometrical isomers of these compounds and their andanmatologically acceptable acid addition salts. As used herein, the term "alphylic" preferably denotes a lower alkyl radical, i.e. a saturated hydrocarbon radical of 1-7 atoms. carbon, having a straight or branched chain, for example a methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, neopentyl, pentyl, heptyl radical, etc. The term "alkoxy" essentially denotes a lower alkoxy radical The term "alkenyl" preferably denotes a lower alkenyl radical, i.e. an unsaturated hydrocarbyl radical, for example a methoxy, ethoxy, propoxy, pentotosyl radical, and the like. having 2 to 7 carbon atoms, having a straight or branched chain, e.g. vinyl, allyl, etc. The term "alkylene" preferably denotes the lower alkyl radical a kinyl radical, i.e. an unsaturated hydrocarbon radical having 2 to 7 carbon atoms, having a straight or branched chain, for example ethynyl, propargyl, methylbutinyl, etc. The term "halogen" * denotes bromine, chlorine, fluorine and iodine . The term "trifluoroalkyl radical of 2 to 6 carbon atoms" preferably denotes a 2,2,2-trifluoroethyl radical and the like. The term "aryl" denotes a phenyl or phenyl radical having one or more substitutions radicals such as halogens, trifluoromethyl, lower alkyl radicals, lower alkoxy radicals, nitro group, amino group, lower alkylamino groups and lower dialkylamino groups. The term "aralkyl" is preferably a benzyl and the like, and the term "lower aryloxy" denotes an aryl ether radical in which the aryl radical is as described above, for example a phenoxy radical, etc. . The term "acyl" denotes an alkanoyl radical derived from an aliphatic carboxylic acid with 1 to 7 carbon atoms, such as veneer, acetyl, propionyl and the like, or an aroyl radical derived from an aromatic carboxylic acid, such as such as benzoyl radical and the like. The term "acyloxy radical" denotes an alkanoyloxy radical derived from an aliphatic carboxylic acid having 1-7 carbon atoms, for example, a phyloxy, acetoxy, propionyloxy, and the like, or an aroyloxy radical derived from an aromatic acid The term "cycloalkyl" denotes a cycloalkyl radical of 3-6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or a dicycloalkyl radical such as a bornyl or a tricycloalkyl radical, such as adamanthyl. The 5 or 6 membered heterocyclic ring is derived from a saturated hetero * cyclic compound. ego containing 1 or 2 nitrogen atoms, or 1 nitrogen atom and 1 oxygen atom, in which the second nitrogen atom may be substituted with an alkyl or hydroxyalkyl radical, for example morpholino, N-methylpiperazine, piperazine, pyrrolidine, and the like. The compounds of formula A are those in which Rj and R3 are alkyl radicals, R4 is alkyl, hydaroxyalkyl, phenylhydroxyalkyl, halophenylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, arylcarbonylalkyl or aralkyl radicals, and X is more preferably an oxygen atom. compounds of formula A where X is oxygen sa: 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H -pyiiix) lo (2,3-g} isoquinolinone-4, N-3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-axirohydro-4a, 8a-9-trans-1H-pyrrolo [23 g] isoquinol) non-4, hydrochloric ether), V-3-ethyl-2.6, n-methyl-4.4a, 5.6.7; 8.8.8al9 -osmihydro-4a, 8a-'trans-1H-piii, olo [2,3Hg] isoquinone-4 · O, HjO, 2-methyl-3-ethyl-6H (2-hydroxy-2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-tranjs-1H-pyrrolo [2,3-g] β0 isoquinoneilinone-4,2,3- 6-trimethyl-4 , 4a, 5,6,7,8,8a, 9-esterhydro-4a, 8a-trans-1H-pyrrolo [2,3-g] 'isoquinolinone-4, 2,3,6-trimethyl-4 hydrochloride, 4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-1xansTlH-pyrrolo [2,3-g] isoquinone-4,2-methyl-3-ethyl-6-beinzyl-4, 4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo2,3-g] isoquinolinone-4, 2-methyl-3-ethyl-6-benzyl-4 hydrochloride , 4a, 5,6, 7,8,8a, 9-osmahydro-4a, 8a-1xa [and 4,2-methyl-3He-1-yl-6-y2-phenylethyl] -4.4a, 5.6 , 7,8,8a, 9-octahydro-4a, 8a-trans-1H-piTolo (2,3-g] isoquinone-4,2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, 5,6,7,8,8a, 9-os- * 45 hihydro-4a, 8a-trans-1H-pyrrolo {2,3-glisoquinolone-4, 2-methyl-3- hydrochloride ethyl-6H (2-ethoflosyethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-1a: ansnlH-pdjrolO ([2,3-g] isoquinolinone-4, 2 -methyl-3-ethyl-644n (4-fluorophenyl) -4-ketobutyl] -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans- (1Hypyrrolo [2.3 -g] isoquinone-4,2-me yl-3-ethyl-6-i [3- (4-fluorophenyl) -3-keto] -pyropyl] -4.4a, 5,6,7,8,8,8a, 9-octahydro-4a, 8a-translHipyrrolo [2, 3-g] isoquinolinone-4,2-methyl-3-ethyl-6V3-phenoxypropyl) -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trams-1H-pyrrolo [2 , 3g] isoquinolinone-4,2-methyl-3-ethyl-6- (2-hydroxy-3-methycbutyl) -4,4a, 5,6,7,8,8a, 9-octane-4a, 8a -trains-1H-pyrroloi [2,3-g] isoquinolinone-4,2-methyl-3-ethyl-6- (2-hydroxy-3,3-dimethylbutyl) -4.4a, 5.6.7 , 8,8a, 9-octahydro-4ai8a-1-ans-1H-pyrrolo [2,3-g] isoquinolinone-4 and 2,6-dimethyl-3-ethyl-4.4a, 5 hydrochloride dihydrate 6,7,8, Sa, 9-octahydro-4a, 8aHtrans-1H-pyrolo [23-g] isoquinolinone-4. Examples of compounds of formula A where X is oxygen are: 3-ethyl-2,6- dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrole [2,3-g] isoquinone-4,3-ethyl-2-methyl-6-i) 2-propynyl (n-4,4a, 5,6,7,8,8a, 9-axis-rhe-1H-pdnx) lo (2,3-g] isoquinolinone-4, / + / - 3- ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9HOS monohydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolinone-4, chloro hydride (+) 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8al9-octahydro-4a, 8a-trains-1H-pi] X) and 10 [2,3-g] 4-isohinoliinone • 0.25HiO, 3,6-dimethyl-2- (2-propyl) -4.4a, 5.6, 7.8.8a, 9-hydroxyhydro-1Hipolo [23ng] isoquinolion hydrochloride - -4,3,6H Dimethyl-2- (2-propyl) -4,4a, 5,6,7,8, da, 9,2 Hmiohydro-1H-pyrrolo [2,3-g] isochijiolinone-4 2 , 6-dimethyl-3-butyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3 g] isocmnoliiKn-4,2-methyl-3-ethyl-6 - (2N-hydroxy-2H (4-chloropheryl) -ethyl) -4.4a, 5,6,7,8,8,8a, 9-octahydroxy-1H- (pi (rolo [2,3-g] isoquinolimone-4 , 2-methyl-3-ethyl-6- (2-hydroxy-1-ccyethyl) -4,4a5,6,7,8,8a, 9-octane-1-pyrrolo [2,3-g] isoquinolinan-4, 2-methyl- 3-ethyl-6- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octane-1H-pyrrolo [1,3-g] -Ochdnolinone-4, 2-methyl hydrochloride -3-ethyl-6- 5,6,7,8,8a, 9-naphthinohydrin-1Hipiiix) 1- [2,3-g] isoquinone-4. 0.5H 2 O, 2-methyl-3-ethyl-6-i (cyclopsTopylmethyl) -4.4a, 5,6,7,8,8,8a, 9-octahydro-1H-piux) [2,3-g ]; isoquinone, hydrochloride -2Hinethyl-3-ethyl-6-i (cyclopropylmethyl) -4.4a, 5.6.7.8.8a, 9-osimine (r. ] 4-isoquinolinone, 0.2HaO, 2,6-dimethyl-3-cyclopropyl-4,4a, 5,6,7,8,8aJ 9, 6-dihydro-1H-pcol [2,3-g] isoquinolinone-4 , 3-ethyl-2-methyl-6- (2-dimethylaminoethyl) -4.4a, 5,6,7,8,8a, 9-osmdihydroix-1Hipiix) [2,3- [g] N -4, 3-ethyl-2H-methyl-4,4a, 5,6,7,8,8a (9-octahydro-1H-pyrrolo {2,3-g] isoquinol-4-iceto-4-6-acetic acid, ethyl ester, 2 -benzyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9H-dihydro * 126 672 6 ro-1H-pyro; [2,3-g] isoquinone-4,3,6 -dimethyl-2- (2-pro-phenyl) -4,4a, 5,6,7,8,8a, 9-octane-1H-pyrrolo {23-g] isoquinolinone-4, 2,6-dimethyl-3-) 2-propyl) -4,4a, 5,6,7,8,8a, 9-octohydro-1H-pyrrolo {2,3-g] isoquinolinone-4,3-ethyl-2-methyl-6-i [2-hydroxy-3- (4-chloirophe (oxy / propyl] -4.4a, 5,657.8.8a, 9-octahydro-1H-pyrrolo [2,3-g] iisoquinolinone-4, 3, 6-diethyl-2-methyl-4, 4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo (2,3-g] isoquinolinone-4, 2-methyl-3-ethyl-6-propyl-4,4a, 5.6 , 7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolinone-4,2-methyl-3-ethyl-6-butyl-4,4a, 5,6,7,8 , 8a, 9-octo-doxo-1H-pdroli [2,3-g] isoquinolinone-4,2-methyl-3-ethyl-6-pentyl-4,4a, 5,6,7,8,8a, 9 -8mmohydro-1H-pyrrolo [2,3-g] isoquinolinone-4,3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [23Hg ] dzoquinolinone-4,6-methyl-4,4a, 5,6,7,8,8a, 9- sirihydro-1H-pyrrolo [2,3-g] isoquinolinone-4,6-benzyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2.3 g] isoquinolinone-4,2,6-dimethyl-3-propyl-4,4a, 5,6,7,8, 8a, 9-octane-doiro-1H-parolo [2,3 ng] isoquinolinein-4,3-ethyl-2-methyl-6- (2-hydroxy-3n / 4-tertiary butylphenoxyByt / ipropyl] - 4J4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isochirole-Lnoin-4, 3-ethyl-2-methyl-6- {2-hydroxy-2V4- chloro-3-trifluoromethylphenyl) ethyl] 4,4a, 5,6,7,8,8a, 9-os'mio-daro-1H-pyrrolo [2,3-g] isoquinoline, n-4, 3 -ethyl-2-methyl-6- (2-hydroxy-2-adamantylethyl) - -4.4a, 5,6,7,8,8a, 9-osmhydro-1H- pyrrolo {2,3-g] isoquinolinone-4,3-ethyl-2-methyl-6-J2- (4-) morpholine / ethyl] -4,4a, 5,6,7, 8,8a, 9-octahydro-1H-pyrrolo (2,3-g] isoquinolinone-4,3-ethyl-2-methyl-6 [2] -oixo-2 (4-fluorophenyl) ethyl] -4} 4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolinone-4, 3- ethyl-2-methyl-6-i (2-methylpropyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2.3 g] isoquinolinone-4,3-ethyl -2-methyl-6-cyclobutylmethyl-4,4a, 5,6,7,8,8a, 9- simihydro-1H-pyrrolo [2,3-g] isoquinolinone-4,3-ethyl-2-methyl-6 -hexyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoliinoin-4,3-ethyl-2-methyl-6-heptyl-4 , 4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isochmolinan-4, 3-ethyl-2-methyl-6-[2-] lipyrrolidinyl n -ethyl] -4,4a, 5,6, 7,8,6a, 9-octane-1H-pyrrolo [2,3-g] isoquinolinone-4,3-ethyl-2-methyl-6- (4-) Methokisy-2-phenylethyl) -4,4a, 5, 6,7,8, Ba, 9-o-4-dihydro-1H-p (irolo [2J3-g] dzoquinolin-4, 2,6-dimethyl-3-ethyl -1- (1-oxobutyl) -4.4a, 5.6J 7.8, 8a, 9-octahydro-1H-pyrrolo! [2,3-g] isoquinolinone-4,3-ethyl-5-methyl-6H (4-chloro-2-phenylethyl (? - 4.4a, 5.6, 7; 8.8a, 9-osinihyde) - 1H-pyrrolo [2,3-g] dzoquinolinone-4,2,6-dimethyl-3-propyl-4,4a, 5,6,78,8a, 9-octadio-4a, 8a-trains-1H- pyrrolo (2,3-g] isoquinolinone-4,2,3-dimume, yl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-hydrogen-4a, 8a-trains-1H-1-pyrrolo [2,3-g] isoquinolinone-4,2,3-dimethyl-6- [4-f (4-fluorophenyl) -4-oxobutyl] -4, 4a, 5.6 , 7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinone-4,3-ethyl-2-methyl-6- (2,2,2-trifluoroethyl) -4,4a, 5,6,7,8,8,8a, 9-hydroxy-4a, 8a-1'-ain6-lH-pyrrolo [2,3-g] isoquinoldinone-4, 2,6-dimethyl-3 -ethyl-4.4a, 5.6 I, 8.8a, 9% hydrogen (r4a, 8a-cds-1H-pyrrole [2,3-g] isoquinolinone-4, 5 2-acetyl-3.6 -dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-picolo [2,3-g] nolmon-4,3-ethyl-2 -methyl-6- [2H (2-thienyl) -ethyl] -4.4a, 5,6,7,8,8a, 9-hydro-4a, 8a-trains-1H-pyrrolo-I2,3-g] i20- chdinoldsnon-4,10 3-ethyl-2-methyl-6 -, [2- (2-furyl) -ethyl] -4.4a, 5.6.7.8.8a, 9H) sm hydro-4a, 8aHtjnaaiiS-1H-pyrrolo [2,3] isoquinone-4-iinone-4 and 3-ethyl-2-methyl-6- [2- (1,3-dihydro) (rq-2 (/ 12H / 4benzo - imidazolonyl-ethyl] -4,4a, 5,6,7,8,8a, 9HOSimyohydro-15 -4a, 8a-traris-1H ^ ixolo: [2,3-g] isoquinolinone-4. The most related compounds with formula A, where X is sulfur, sa: 2-methyl-3-ethyl-6- (2-pheoylethyl) -4.4a, 5,6,7,8,8a, O-octane-4a, 8a -trains-1H-pyrrolo [2,3-g] isoquinolyl-4,2,6-dimethyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a , 8a-trans-1H-pyrrolo [2,3-g] isoquinolto 2-methyl-3-ethyl-6-t4- (4-fluorophenyl) -4-ketobutyl] -4; 4a, 5,6.7, 8,8a, 9-octahydro-4a, 8a-toaais-1H-pyrrolo 25 [2,3-g] isoquinolinetidone-4 and 2-methyl-3-ethyl-6- (2-hydroxy-3,3H dimethylbutyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-tra! Ns-1H-pyrrolo [2,3-g] isoquinoliinthion-4. Examples of compounds of formula A, where X 30 is a sulfur atom sa: 2-methyl-3-ethyl-6- (2-hydroxy-2-phenylethyl-4,4a, 5.6J, 8.8a, 9-octane-4a, ea-trans-1H -pdrolot2,3-g] isochdinoliinotdon-4,2,3 , 6-trimethyl-4,4a, 5,6,7,8,8a, 9-osmdiooxo-4a, 8a-trans-lH-pyrrolo [2,3-g] isochi) noliinot] ion-4, 2 -methyl-3-ethyl-6-be (nzyl-4,4a, 5,6,7,8,8a, N - octahydro-4a, 8a-trans- 1H-pyrrole-p, -gloquinolinothioi ^, 2 -methyl-3-ethyl-6- (2-ethoxyethyl) -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-lH- p-pyrrolo [2,3-g] isoquinone-4,2-methyl-3-ethyl-6- [3-i (4-fluorophenyl] -3-oxopropyl] -4.4a, 5,6,7,8,8a, 9- Hydrogen-osmidoro-4a, 8a-traiis-1H-i) irolo [2.3 g] isoquinolinethlon-4,2-methyl-3-ethyl-6 ^ 3-feinoxyp (petroleum) -4.4a, 5.6.7 , 8,8a, 45 9-osimihydro-4a, 8a-tains-1Hypyrrolo2,3-g] isochm limothion-4,2-methyl-3-ethyl-6H (2-hydroxy-3H-methylbutyl) -4.4a, 5, 6,7,8,8a, 9-oxinehydro-4a, 8a-toans-1HH-pyrrolo [2,3-g] isochdnoliinotdone-4. The compounds according to the invention may be the 4a, 8a-phonance or 4a, 8a-c! Is isomers or mixtures thereof. The 4a, 8a-trans isomers are more preferred. According to the invention, compounds of formula A, their optical and geometric isomers and pharmacologically acceptable acid addition salts are prepared by substituting a compound of the general formula on the isoquinoline nitrogen atom. 15, in which R2, R3 and X are as defined above, and the mixture of the resulting cis and trans isomers is optionally isomerized so that the final product contains mainly the trans isomer and / or isomerized from the resulting mixture. trans and / or optionally resolves the resulting racemic mixture into optical antipodes and / or optionally converting the resulting compound or the resulting pharmacologically unacceptable acid addition salt into a pharmaceutically acceptable additive salt thereof. The preparation of the compounds of formula A, as described above, their optical and geometric isomers and their pharmaceutically acceptable compounds are described in more detail below. of these acid addition salts as well as of various intermediates. For example, compounds of formula A in which X is oxygen, i.e. compounds of formula I, in which Ra, R3 and R * have the above meanings, it is possible to prepare the process of which the course is shown in Scheme 1 in which Ra, R3 and R4 are as defined above. According to Scheme 1, compounds of Formula 1 are prepared from secondary amines of Formula 15 by substitution on the basic amine nitrogen (N-6). For example, treating a compound of Formula 15 with an alkyl halide such as ethyl bromide, an alkenyl halide such as allyl bromide, a cycloalkyl halide such as chloromethylcyclopropane, or an aralkyl halide such as benzyl bromide in the presence of a base, such as potassium carbonate, in the environment of acetone, 2-propanone or dimethylformamide, a suitably substituted compound of formula I is obtained, that is, where R * is an alkyl, alkenyl, cycloalMloalkyl or aoralkyl radical. When using reactive halides, it is possible to conduct a process at room temperature, and in the case of low reactivity halides, the mixture is boiled under reflux, and in some cases the reaction rate can be increased by adding 6ols of acid to the reaction mixture. Hydroiodic acid such as lithium iodide. Reaction of compounds of formula 15 with epoxyalkanes gives the compound of formula I with a hydroxyalkyl substituent and reacting with substituted epoxyalkanes gives the 2-substituted-2-hydroxyalkanoalalogs of formula I. For example, by reacting a compound of formula 15 with styrene oxide, a compound of formula I is obtained in which R 4 is 2-phenyl-2-hydroxyethyl. Reactions are usually conducted in the presence of an alcoholic solvent such as methanol at room temperature to the reflux temperature of the reaction mixture. The epoxylates are commercially available compounds or are prepared by epoxidation of the corresponding olefins, or by methylation of the ketone with sulfonium methylide or sulfoxonium methylide, for example dimethylsulfonium methylide. For example, by treating benzaldehyde with dimethylsulfonium methylide, styrene oxide is obtained. In the reaction shown in Scheme 1, both the trans-isomers of the formula I 'are obtained, in which Ra, R3 and R4 have the meanings given above, and the isomers cis of formula I ", in which Ra, Rt and Ri have the meaning given above, being isomers of the compounds of formula I, the trans isomers being mainly obtained. Pure trans isomer can be separated by chromatography or crystallization. In addition, the mixture may be separated by isomerized as described in relation to the trans and cis isomerization of oxo-compounds of the formulas la and l "a. Compounds of formula A, where X is sulfur, are represented by formula 2, in which Ri, R3 and R4 are the meaning given above. These compounds are prepared as described below, in accordance with Scheme 2, where R2, R3, and R4 are as defined above. In Scheme 2, the compound of Formula 15 is reacted with phosphorus pentasulfide, with If the compound of formula 15 has no other functional groups that can react with phosphorus pentasulfide in addition to the 4-oxo group, then it can be converted to the compound of formula 16 directly by heating with phosphorus pentasulfide in an inert organic solvent. If the compound of formula 15 also contains other functional groups capable of reacting with phosphorus pentasulfide, for example when Ra or R3 is an acyl group, these groups must be protected before the reaction and the protecting groups removed after the reaction. For example, ketone groups can be protected by the formation of ketals such as ethylene ketal. The resulting compound of formula 16 is then converted to the compound of formula 2 in an analogous manner to that given above in discussing Scheme 1 for analogous oxo-compounds of formula 15 and converting them to compounds of the formula 1. These reactions produce both the trans isomers of the formula II ', in which Ra, R3 and R4 are as defined above, and the cis isomers of the formula II "in which Ra, R3 and R4 are The meaning given above is the trans isomer in the product. The pure trans isomer can be separated by chromatography or crystallization. In addition, the resulting mixture can be isomerized, as described above in the trans-isomerization and cis-isomerization of the oxo compounds. compounds of Formula 15 used as starting material can be prepared as shown in Schemes 3, 4 and 5. According to Scheme 3, where Ra and Rs are as defined above. Compounds of formula IV are prepared by reacting a primary amine of formula 14 with ethyl chloroformate and reducing the resulting uretham of formula III with lithium aluminum hydride to give N-methylamine of formula 4. Compounds of formula 4 can also be prepared by the reductive alkylation of compounds of formula XI with formaldehyde and sodium cyanoborohydride under known conditions (e.g. R.F. Borch. J. Am. Chem. Soc., 93, 2897 (1971). Reduction of the amine of formula IV with the Birch method with lithium with ammonia containing tertiary butanol gives the dihydroamine of formula 5. Other modifications of the Birch reduction may also be used. For example, an amine of formula 50 65 60126 872 9 10 may be reacted with an alkali metal such as sodium, lithium, potassium or cesium in ammonia or an amine such as methylamine or ethylamine, in the presence of a lower alkanol such as ethanol, butanol or tertiary alcohol. butanol. The reactions are usually carried out at or below the boiling point of the solvent used, for example -78 ° C to 15 ° C. If a tube is used, the reactions are carried out under the boiling point of the reaction mixture under a reflux condenser. Optionally, it is also possible to add other solvents, such as diethyl ether or ozterohydrofuran. Hydrolysis of the dihydroamine of the formula 5 is easily carried out using the usual methods of hydrolysis of enol ethers, e.g. with an acid in an aqueous medium, e.g. hydrochloric acid, hydrobromic acid, formic, acetic, p-toluenesulfonic acid and perchloric. These acids can be used in the form of aqueous solutions or mixed solvents. For 1 mole of dihydroamine it is necessary to use at least 2 equivalents of water and more than 1 equivalent of acid. Examples of solvents that can be used are: tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane and acetonitrile. For example, by hydrolysis of the dihydroamine of formula V with 2N hydrochloric acid at room temperature or above, or with an aqueous acetic acid solution at a temperature of 40 ° C to reflux temperature, a ditone of the formula is obtained. 6. The dicetone of formula 6 is condensed by the Knorr method to give the dihydroindolone ethylamine of formula 9. Knarr condensation is a known method of producing pyrroles, and various known variations of this method may be used [see example conditions, JM Patterson , Synthesis, 281 (1976) and references cited therein]. For example, it is believed that the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, e.g. zinc, with an aqueous solution of acetic acid or hydrochloric acid to form an aminocarbonyl compound of formula VIII as an intermediate, which is then condensed with a di-ketone of formula VIII. Formula 6 yielding as the product a dihydroindolone ethylamine of formula 9. The condensations can also be carried out with the aminocarphinyl compound of formula 9 or a precursor thereof, Udam as aminocetone hydrochloride or acetal derivative of aminocetone or amdnoaldehyde. Preferably an aminocetone or aminoaldehyde precursor is used when such an amino aldehyde is used. the compounds are resistant to self-condensation. It is best to prepare them in situ as the aminocarbonyl component is then released in the presence of the formula 6 dichone. The formula 6 aiminocarbonyl component reacts immediately to form dihydroindoleethylamine 9. It is not necessary to isolate the dichone of formula 6 before carrying out the Knorr condensation. Since the reaction conditions are sufficient to carry out the hydrolysis of the dihydroamine of formula V to form the dicetone of formula 6. Knarr condensations are most preferably carried out at a pH of about 2 to 6. At a much higher pH value, than 6, considerable yield losses arise due to the formation of the self-condensation products of the aminocarbonyl compound of formula 8. Preferably the isonitrosoketone of formula 7 and zinc dust in aqueous acetic acid are condensed with dicetone of formula 6 to give the dihydroindole ethylamine of formula 9. Knorr condensations are preferably carried out at about room temperature to the boiling point of the reaction mixture under reflux. The isonitrosoketones of formula VII are known compounds [e.g. Ferris, J. Org. Chem. 24, 1726 (1959] or can be easily prepared by nitrosation of the corresponding ketones, e.g. with alkyl nitrite, or in the case of highly acidic O-diketones or O-ketoneesters with sodium nitrite. Examples of isonitrosoketones which can be used in condensation Knonr, sa: 2-isonitrosopentanone-3, 2,3,2-isonitroso-4-methylpentanone-3, 2-isonitrosoheptanone-3, 2-isonitrosoheptanone-3, 3-iz <^ trozo-4- methylpentanone-2, 2-isonitroso-1-cyclopropylpropanone-1,3-isonitrosohexanone-5-one-2, cyclopropyl-2-isonitrosopropanone-1 and 3-isonitroso-4-phenylbutanone-2. Examples of amino precursors Aminoacetaldehyde dimethylacetyl and 2-aminopentanone-3-amine hydrochloride are transformed into the compound of formula Ia via an intramolecular Mannich reaction. These reactions are usually carried out using a ketone and a dialkylamine salt as starting products, e.g. dimethylamines and formaldehyde (n p. as an aqueous solution, as paraformaldehyde or as trioxane) in an alcoholic solvent such as ethanol at the reflux temperature of the reaction mixture. In the embodiment described herein, the dihydroindole ethyl amide addition salt of formula 9 is reacted with formaldehyde added as paraformaldehyde, trioxane, or hydrated formaldehyde in a solvent. For example, a high boiling point hydroxyl solvent such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether, a polar high boiling aprotic solvent such as dimethylformamide, N-methylpyrrolidone or dimethyl ether. - ethyl diethyl glycol, or a polar solvent with a lower boiling point but under increased pressure, such as ethanol, butanol or 2-propanol, or an aprotic solvent with a lower boiling point but under increased pressure, such as dioxane or tetrahydrofuran can be used at a temperature of about 135 ° C to about 200 ° C to obtain the pyrrolo [2.3ng] isoquinoline of formula Ia. As a result of this reaction, especially when it leads to 10 M so »00 35 40 45 50 60126 672 11 12 is obtained at a temperature below 150 ° C, a mixture of cis and trans isomers is obtained, i.e. compounds of the formulas la and l are obtained. Longer heating of the reaction mixture or Heating of the mixture of hydrochlorides of the compounds of the formulas la and l, for example, in ethylene glycol, under reflux for 2 hours, may be used to form a mixture of cis and trans isomers ultimately containing mainly the trans isomer which can be easily isolated by crystallization or chromatographic separation. The relationship of dihydroindolone ethylamine hydrochloride of formula 9 with paraformaldehyde in ethanol at 180 ° C for 2 hours is preferable, since this reaction results in almost exclusively the trans isomer. Scheme 4 shows a process for the preparation of compounds of formula 15 where R2 and R3 are as defined above. The demethylation of a compound of formula Ia at the nitrogen atom can be carried out by known demethylation methods such as the von Braun method [H. A. Hageman, Org. Reactions, 7, 198 (1953)] or the acidic or basic hydrolysis of a urethane derivative, as mentioned by K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One route for dealkylation of compounds of formula Ia is through the urethane of formula 13 and acid hydrolysis, which gives the secondary amine of formula 15. For example, the compound of formula Ia wherein R2 is methyl and R3 is ethyl. is boiled under reflux in diethyl ketone with an excess of ethyl chloroformate and potassium bicarbonate for 3 hours, yielding the compound of formula (13) where Ra is methyl and R3 is ethyl. Hydrolysis of the obtained compound with concentrated hydrochloric acid in acetic acid at the boiling point of the reaction mixture for 24 hours gives the compound of formula 15 in which R2 is methyl and R3 is ethyl. The same compound is obtained by hydrolyzing a urethane of formula 13 with sodium hydroxide in boiling ethanol under reflux. A synthesis of compounds of formula Ia, in which Rj and Rs are much above, is shown in Scheme 5, according to which the isoquinoline ring is prepared by forming a pyrol ring. As indicated in this scheme, the (3,5-dimethoxy-enyl) -ethylamine of formula IV is maintained together with the aqueous solution of formaldehyde. boiling under reflux, yielding the tetrahydroisoquinoline of formula 10. This compound is subjected to Bircfra reduction with lithium in liquid ammonia containing tertiary butanol, "under conditions essentially the same as described above in the discussion above. The resulting crude hexahydroisoquinoline of formula 11 is subject to hydrolysis under substantially the same conditions as described above for the hydrolysis of dihydroamines of formula 5. The resulting dicetane compound of formula 12 is subjected to a condensation reaction. Knorr with an isonitrosoketone of formula 7 or an aminocarbonyl compound of formula 8 to give pyrrolisoquinoline of formula la. These condensations are carried out as described above for the preparation of dihydrogen indole ethyl amine of formula 9. Reactions in which the The order is shown in Scheme 5, preferably using the amine of formula IV as starting material, which gives the corresponding N-methylpyr oloiisoquinoline of formula Ia in the form of a mixture consisting of the trans isomer I'a and the cis isomer I "a. A mixture of these isomers can be isomerized as described above to produce the trans isomer I'a. The compounds of Formula A form acid addition salts with inorganic or organic acids and can therefore form pharmacologically acceptable acid addition salts with pharmacologically acceptable acids. organic or inorganic, e.g. with hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid and with other mineral acids such as sulfuric, nitric, phosphoric and the like with alkylsulfonic or monoarylsulfonic acids such as ethanesulfonic acid , toluem sulfonic acid, benzenesulfonic acid and the like and with other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid, and the like. Pharmacologically unacceptable addition salts of compounds of formula A can be converted into pharmaceutically acceptable acid addition salts Logically, using the known double-exchange reactions to replace an anion It is also possible to neutralize the pharmacologically unacceptable acid addition salt and react the resulting free base to form a pharmacologically acceptable acid addition salt. Acid addition salts may also exist in the form of hydrates. The compounds of formula A and their pharmacologically acceptable salts exhibit neuroleptic activity, but their important feature is that they do not have a hypotensive effect and therefore show only a weak cataleptic effect. Thus, the compounds of formula A are useful as agents against psychosis, e.g. in the treatment of early dementia. The properties of compounds of formula A, which make them suitable as agents against psychosis, can be demonstrated by known methods in warm-blooded animals. One of these methods is for example, trained rats are placed in experimental chambers equipped with responsive levers, a steel mesh floor to impart electric shock, and a loudspeaker for auditory stimulus. In each trial, a 15-second warning signal (conditioned stimulus) is used, continued for the next 15 seconds with an electric shock (stimulus 10 15 20 as 30 35 40 45 50 09 05 126 672 13 14 unconditioned, 1.0 mA, 350 V, fixed line) The rats can end the test at any time by pressing the reaction lever. Depressing the lever within the first 15 seconds of the warning signal interrupts the test before triggering the electric shock and is considered to be a reaction of the rat to avoid the shock, and pressing the / lever during the duration of the electric shock is a reaction to escape from the shock. this shock. The tests are carried out every 2 minutes for 1 hour (30 tests during one test cycle). The trained rats have a sufficient shock avoidance capacity (0-3 times not avoided in one test cycle). Test compounds are administered in advance to at least 2 to 3 rats for each dose within certain dose ranges. Some rats receive only the carrier simultaneously. Each week, one test is alternated between one avoidance test and one electric shock test, observing the behavior of the rats individually. The test cycle is divided into 3 consecutive steps of 20 minutes (10 trials). The rats' responses are summed up for each dose during each step. The number of trials in which the rats failed to show shock avoidance (AB) or the ability to break the shock duration (EB) was determined for the stage where the 30 rats' response was greatest with each dose. Dose required to achieve 50% evasion (AB 50) is calculated on the basis of the curve of declining efficiency determined by the least squares method. The smallest dose that achieves 35 20% shock load (EB 20) is read from the dose-effect plot. In order to obtain a value of this relationship on one axis, the logarithm of the dose is plotted and the percentage effect on the other axis. 40 The antipsychotic agents can be distinguished from drugs of other types that affect the behavior of rats in the test method described above, namely, there is a greater difference between the amount of antipsychotic agents required to induce avoidance responses and termination responses. shock. The clinical potency of these antipsychotic agents used in a medical manner and their properties are characteristically strongly related to their potency in the tests described above, so that the compounds of formula A can be used in therapy at doses corresponding to potency determined by this method. If 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octagon-4a, 8a-trans are used as the test substance -1HH-pyrrolo [2,3-g] isoquinolinone-4 showing an LD50 of e.g. 350 mg / kg when administered orally to mice, then its neuroleptic effect is observed at an AB50 of 0.7 mg / kg when administered orally. and 0.095 mg / kg for subcutaneous administration. In the case of the β-enantiomer of this compound, a neuroleptic effect is observed at an AB50 dose of 0.48 mg / kg when administered orally. 65 Similarly, if the hydrochloride of 2l3,6-trimethyl-4,4a, 5,6,7,8, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo (2 3-g] a) zoroquinolinone-4, the neuro-leptic activity is observed at an ABM dose of 0.48 mg / kg when administered orally. If N- [2- (3-ethyl-4,4a, 5,6,7A8a, 9-octahydro-2-methyl-4-keto-4a, 8a-trans-1H-pyrrolo [ 2,3-g] isoquinyl-6'-ethyl] -4-fluarobenzamide, the neuiroleptic activity occurs at an AB50 dose of 3.5 mg / kg orally, and in the case of 3-ethyl-2-methyl-6. - [4- (4-lluorophenyl) -4-ketobutyl] -4.4a, 5,6,7,8,8a, 9-oimio-4a, 8a-trans-1H-pyrrolo {2,3- g] isoquinolinone-4, the dose is 0.19 mg / kg when administered orally, while for 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8, 8a, 9-octane-4a , 8a-tranis-1H-pyrrolo [2,3-g] isoquinolinothio-4, the dose of AB50 at which neuro-activity is active is 0.94 mg / kg when administered orally. Compounds of formula A and their pharmacologically acceptable effects are active. The anti-psychotic acid addition salts are qualitatively similar to those of haloperidol, trifluoroperazine, and mollindone, which are therapeutic agents with known properties. For this reason, it can be concluded that the compounds of formula A exhibit activity inherent in anti-psychotic agents having known efficacy and safety in use. Compounds of formula A and their pharmacologically acceptable acid addition salts may be used. Wac in a form such as known pharmaceutical preparations. For example, a unit dose for oral administration contains or is 0.05-50 mg of a compound of formula A or a pharmacologically acceptable salt thereof, and a suitable daily dose for orally administered warm-blooded animals is from about 0.001 mg / kg to about 0.001 mg / kg. 10 mg / kg. However, in the case of individual warm-blooded animals the size of the doses can be varied and adapted to specific needs and in accordance with the expert judgment of the person administering the drug or supervising its administration. In addition, the frequency of doses can be changed depending on the activity of the substance. For the purposes described above, the compounds of formula A and their pharmacologically acceptable acid addition salts are used in the form of preparations also containing the known inert additives used in the formulations. pharmacological and suitable for oral or parenteral administration. Such preparations are in the form of tablets, suspensions, solutions and the like. The compound of formula A may also be incorporated into soft or hard capsules and used as such. As inert additives in the preparation of preparations containing the compounds of formula A or their pharmacologically acceptable acid addition salts, substances known to those skilled in the art and in amounts which will be clear to those skilled in the art are used. Such additives may be inorganic or organic substances and include, for example, water, gelatine, lactose *, starches, magnesium stearate, talc, vegetable oils, natural resins, polyalkylene glycols, etc. If desired, preservatives, stabilizers, wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, etc. can also be incorporated into the formulations, since the compounds of formula A and their pharmacologically acceptable acid addition salts have an asymmetric carbon atom, therefore they are usually kept in the form of racemic mixtures. Separation of such racemates into optically active isomers can be carried out by known methods. Some racemic mixtures can be lost as eutectics and then separated, but are preferably separated by chemical means. diastereoisomers are prepared from the racemic mixture with an optically active resolving agent, for example, using an optically active acid such as (+) tartaric acid to form a diastereoisomeric salt. The diastereoisomers formed are separated by fractionated crystallization and can be converted to the corresponding base being an optical isomer. Accordingly, the invention also includes the optically active isomers of the compounds of formula A and the racemates thereof. Moreover, due to the possible different spatial arrangement of the atoms, it is possible to prepare the compounds of the invention in more than one form of geometric isomers. The compounds of formula A prepared in accordance with the invention include all kinds of isomeric forms. Accordingly, it should be understood that the examples given below are illustrations of specific mixtures of geometric isomers or individual geometric isomers and are not intended to limit the scope of the invention. The following examples are illustrative of the subject matter of the invention. The temperatures in the examples are at ° C unless otherwise indicated. EXAMPLE I. N-2- (3,5-dimethoxyphenylcV-ethylcarbamic acid ethyl ester. For a 5-liter three-necked round bottom flask provided with A mechanical stirrer and a dropping funnel are charged with 32.63 g of 3,5-dimethoxyphenylZ-ethylamine hydrochloride, 600 ml of water, 600 ml of dichloromethane and 150 ml of 1N sodium hydroxide solution. To the mixture, while stirring and cooling in an ice bath, 16.28 g of ethyl hydroformate in 60 ml of dichloromethane were added dropwise over the course of 30 minutes. During the addition, 150 ml of sodium hydroxide solution in 8 portions are introduced in order to maintain the pH value between 8 and 9. After the addition is complete, the mixture is stirred in an ice bath for 1 hour. The mixture is then transferred to the separator and the phase separated. organic. The aqueous solution is extracted with 200 ml of dichloromethane and the organic solutions are combined and washed with 100 ml of water and 100 ml of brine, then dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated on a rotary evaporator to obtain 37.1 g of crude N-2- (3,5-dimethoxyphan-1cV-ethyl-carbamic acid ethyl ester) as a colorless oil. N-Methyl (3,5-dimethoxyphenyl) ethylamine hydrochloride. 180 ml of a 70% solution of sodium dihydro bis (2-methoxyethoxyethoxy telinate) and 700 ml of dry tetrahydrofuran are introduced into a 3 liter three-necked round bottom flask equipped with a mechanical stirrer, dropping funnel and coolers. The mixture is cooled in an ice bath and a solution of 37.1 g of crude N-2 (3,5-dimethoxyphenyl) -ethyl-carbamic acid ethyl ester in 100 ml of dry tetrahydrofuran is added within 15 minutes. After the addition was complete, the mixture was refluxed for 1 hour and then cooled in an ice bath. The excess hydride is destroyed by the dropwise addition of 100 ml of a 5,000 sodium hydroxide solution. After the base addition is complete, the organic layer is separated and the aqueous layer is extracted with 100 ml of ether. The combined organic solutions are concentrated on a rotary evaporator to yield an oil which dissolves in 300 ml of ether. The ethereal solution is washed with 50 ml of water, 50 ml of brine, dried over anhydrous sodium sulfate and filtered. 70 ml of ethereal hydrochloride solution are added to the filtrate, and the amine hydrochloride is precipitated. The solids are collected on a Buchner filter and crystallized from 180 ml of absolute ethanol and 270 ml of ether to give 28.9 g of N-methylH (3,5-dimethoxyphenyl) -ethylamine hydrochloride as a white crystalline solid at a temperature of mp 160-l64 ° C. Example II. N-methyl-1,5-dimethoxycyclo-hexa-1,4-diene-3-ethylamine. 185.2 g of N-methyl-γ-3,5-d hydrochloride, vumethoxyphenyl) -ethylamine is dissolved in 1600 ml of water and the solution is made alkaline with 160 ml of ammonium hydroxide. The mixture is extracted three times with 1000 ml of dichloromethane each and the combined extracts are washed with 1000 ml of brine and dried over anhydrous sodium sulfate. The solvent is evaporated on a rotary evaporator at 35 ° -40 ° to give 156.0 g of the free base. In a 12-liter three-necked flask equipped with a mechanical stirrer and two dry ice coolers, one with a gas inlet and the other with a drying tube containing soda lime, 4.0 liters of anhydrous ammonia are condensed. A solution of 156.0 g of the free base in 400 ml of 1L is added to the ammonia over 15 minutes. butanol and 400 ml of anhydrous ether. A total of 33.6 g of lithium wire is added to the stirred solution over a period of 50 minutes, in approximately 55 cm sections. The additional portions are added so that the wire is inserted in sections of about 12.5 cm per minute. After all the lithium has been turned blue, the mixture is stirred under reflux for 2 hours. 2.8 liters of anhydrous ether are then added to dilute the mixture, the drying tube is removed to allow the hydrogen to escape and a total of 280 g of powdered ammonium chloride is slowly introduced over 30 minutes until it disappears to a light blue color. Dry ice coolers are removed and the mixture is stirred and allowed to evaporate overnight for the ammonia. 2.8 liters of ice water are added to the residue. The mixture is transferred to a separating funnel, washed with 800 ml of ether and the layers are separated. The aqueous phase is extracted twice with 1.5 liters of dichloromethane and the extracts are combined, washed with 1 liter of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 40 ° C and heating at 40 ° / 1.0 mm for 1.5 hours yielded 150.7 g of crude product in the form of a yellow oil. The crude oil is distilled through a Goodloe column about 30 cm long, using a 150 ° bath, and the following fractions are collected: Fraction I Boiling point 1 2 3 4 40 80 ° / 0.45 mm SO2 ^ s— —0.15 mm 85 ^ 86 ° / 0.15 mm 86—87 ° / 0.15 mm Weight 7.9 g 6.2 g 21.2 g WA g Purity 4.0% 50% 92 % 100% j From the combined fractions 3 and 4, 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine are obtained in the form of a colorless oil. Example III. 6- [2- (N-Methylamino) -ethyl] -2-methyl-3-ethyl-6,7-dihydrogen (5H) -4 (1H, 5H) -indolone For a 1 liter three-neck round bottom flask equipped with a solution of 60.0 g of distilled N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine in 700 ml of 70% aqueous acetic acid is introduced into a mechanical stirrer and cooler. The reaction mixture was refluxed for 15 minutes and 59.5 g of zinc dust was added in 5 portions over 10 minutes, then the mixture was refluxed again for 15 minutes. To the heated solution, a solution of 42.1 g of 2-isonitroso-3-pentainone in 175 ml of 70% strength aqueous acetic acid is added over 1 hour. After the addition is complete, the mixture is refluxed for 2.5 hours and cooled. to room temperature. The zinc acetate precipitate is removed by filtering and the filter cake is washed with 500 ml of dichloromethane. The filtrate is concentrated on a rotary evaporator and the residue is heated at 100 ° / 1.0 mm for 30 minutes to remove residual acid. vinegar. The residue is dissolved in 500 ml of water and the solution is extracted twice with 150 ml of dichloromethane each. The dichlorometham extracts are discarded and the aqueous phase is made alkaline to pH 8-9 with 163 ml of ammonium hydroxide and 500 ml of brine are added. The mixture is extracted three times with 200 ml of dichloromethane, and the combined extracts are washed with 100 ml of brine and dried over anhydrous sodium sulphate. Evaporation of the solvent yielded 56.0 g of crude tetrahydroindolone, which was dissolved in 90 ml of a 2: 1 toluene-ethyl acetate mixture. The solution was stirred with a magnetic stirrer, seeded and left to stand. for crystallization overnight with agitation. The first crop of 20.8 g is isolated by the filtration path and the mother liquor is concentrated and recrystallized from the mixed solution, yielding 10.0 g of product in the second crop. The mother liquor is dissolved in 75 ml of methanol and a solution of 15.0 g of oxalic acid in 50 ml of methanol is added. The mixture is heated for 10 minutes on a steam bath and cooled. The solid oxalate salt is filtered off, washed with 10 ml of methanol and dissolved in 50 ml of water. The boron is made alkaline with ammonium hydroxide and is treated twice with 50 ml of dichloromethane. The extracts were washed once with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to give 4.5 g of additional crude product. Crystallization from a 2: 1 mixture of toluene and ethyl acetate gives 2.6 g of additional crystalline product. Both the crops and the oxalate-derived crystals are pooled and dried at 25 ° / l mm for 2 hours to yield 33.4 g of 6h [2 N (N-methylamino) -ethyl] -2-methyl-3-ethyl- 6,7-Dihydro (5H) -4 (1H, 5H) -indolone in the form of a pale yellow solid, mp 114-120 °, homogeneous according to thin layer chromatography. Example IV. 3-Ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-35-pyrrolo [2,3-g] isoquinoline hydrochloride -4- one. 17.0 g of 6- [2- (N-methylamino) -ethyl] -2-methyl-3-ethyl-6.7-dihydrogen (5H) - are introduced into a 500 ml round bottom flask. 4I (1H, 5H) -indole and 170 ml of methanol. 20 ml of a 4N solution of hydrochloride in diethyl ether (obtained by bubbling HCl gas through dimethyl ether in an ice bath and titration) are added to the solution. The solvent is removed on a rotary evaporator and the solid residue is dried at 50 ° / l mm for 2 hours, yielding 19.7 g of crude hydrochloride. To a 3 liter three-necked round bottom flask equipped with a mechanical stirrer, thermometer and the distillation overlay are charged with 19.7 g of hydrochloride 50, 21.8 g of paraformaldehyde and 1000: ml of octanol. The reaction mixture is heated under reflux and the water formed is removed by distillation as soon as the temperature of the octanol solution is 175-180 °, after which the distillation overlay is removed and the reflux condenser is replaced. The reaction mixture is heated at 175 ° -180 ° for 1 hour and 6.54 g of paraformaldehyde are added in three portions within 5 minutes. The water is distilled off as before until the reaction temperature reaches 175-180 ° and the mixture is heated at 175-180 ° for an additional 1 hour. The dark brown solution is cooled and poured into 1000 66 ml of water. The layers are separated and the organic phase is extracted twice with 400 ml of 5% hydrochloric acid each time. The combined aqueous extracts are washed twice with 150 ml of chloroform each and the chloroform solutions are discarded. 120 ml of ammonium hydroxide and 400 ml of chloroform are added to the aqueous phase. The layers are separated and the aqueous phase is extracted four times with 200 ml of chloroform each. The combined chloroform extracts are washed with 200 ml of brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, 12.0 g of crude pyrrolo [2,3-g] isoquinoline are obtained as a mixture of 4a, 8a-trans and 4a, 8a-cis (about 8: 1) as a dark brown solid. the solid is dissolved in 100 ml of a 9: 1 mixture of dichloromethane-methanol and 300 ml of dimethyl ether are added. A fine solid precipitate, mainly the 4a, 8a-trans isomer, separate the filtration path and the effluent is concentrated and crystallized to give a second and third crop of brown solid. The combined material was dried at 25 ° / l mm for 1 hour, yielding 8.20 g of a light gray solid, representing 3-ethyl-2,6-dimethyl-4.4a, 5.6.7.8 , 8a, 9-hydrogen-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, mp 203-226 °. The partially purified gray solids are suspended in 80 ml of methanol and 12 ml of a 4N solution of hydrogen chloride in diethyl ether are added. The solvent is removed and the residue is crystallized with 25 ml of hot absolute ethanol. The first crop is distinguished by the filtration path and the mother liquor is concentrated and crystallized to give the second and third crops of crystals. The combined substances are continuously dissolved in 120 ml of methanol and 2.4 g of activated carbon (Darco-G-GO) are added. The mixture is heated in a steam bath for 10 minutes and the carbon is filtered off through celite. The filtrate is concentrated and recrystallized from 15 ml of ethanol to give three crops of white crystals. The combined substances were continuously vacuum dried at 80 ° V0.05 mm for 18 hours to give 5.4 g of 3-eityl-2,6-dimethyl-4.4a, 5.6.7.8, 8a, 9-octahydro-4a, 8a-traris-1H-pyrrolo2, 3Hg] isoquinoline-4-one as a white solid, with a melting point of 196-198 °, oxime half-titre, having a melting point of 131-133 °. IVa — c. By following the procedure described in Examples 3 and 4, the compounds in Table 1 are prepared starting from the corresponding isonitrosoketone with the changes indicated. Each compound exhibits spectral characteristics consistent with the structure described. The melting points were determined with the free bases or the hydrochlorides (.HCl) as given in the table. The isonitrosoketones are prepared by the nitrosation of the appropriate ketone (for example, Ferris et al., J. Org. Chem., 24, 1726 (1959)). The isolated compounds are the 4a, 8a-trans isomers. The procedure is as in the scheme 6. Example lVa | 3,6-dimethyl-2-i (12-H-propyl) -4,4a, 5,6,7,8,8,8a, 9-osmhydro-1H-pyrrolo [2,3-g] isohinolin-4- on IV b 2,6-dJ Wuxnetyl-3-phenyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-H-pyrrolo [2,3-g] isoquinoline-4-one IVc 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one 1 Rb • CH (CH3 * CH3 CH3 Table 1 R3 CH3 formula 18 CHs Analysis calculated (.HCl) C 64.74 H 8.49 N 9.44 CI 1.1.94 C 77.23 H 7.53 N 9.52 (.HCl) C 62.56 H 7.88 N 10.42 Cl 13.1 © found C 64.53 H 8.38 N 9.36 Cl 12.16 C 77.23 H 7.50 N 9.54 C 62.19 H 7.97 N 10.20 Cl 13.41 Melting point (.HCl) 0080 ° decomposition <240 ° 275-280 ° decomposition Crystallized from methanol ethanol ethyl acetate ethanol ether Changes in process Procedure - Mannich reaction in diethylene glycol monoethyl ether - gol 55 ° 1 hour | Knorr reaction in n-butanol at 170 ° / 50 kg / ohm * | 126 672 21 22 Example V. 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-tranis-1H-pyrrolo [2,3-g] isOquinoline -4-on.Mixing 4.92 g (20 mmol) 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo {2,3-g] isoquinolin- 4-one prepared as described in Example IV, 19.55 g (180 mmol) of ethyl chloroformate and 6.0 g (60 mmol) of acidic potassium carbonate in 100 ml of diethyl ketone are refluxed for 3 hours. . The mixture is cooled, filtered, the filtrate is concentrated to dryness on a rotary evaporator and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous hydrochloric acid, brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, 4.90 g of crude carbamate was obtained, which was purified by chromatography on alumina III to give 3.70 g of pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4.4a, 5.6, 7,8,8a, 9-octahydro TO-1H-pyrrolo [2,3-g] isoquinolin -4-one. Carbamate 3.7 g (12.2 mmol), 45 ml glacial acetic acid and 60 ml conc. hydrochloric acid is heated under reflux for 24 hours, cooled and concentrated on a rotary evaporator. The residue is dissolved in water and extracted with chloroform (the extracts are discarded) and the aqueous phase is made alkaline with ammonium hydroxide and extracted with chloroform. The combined extracts are washed with brine, dried over anhydrous sodium sulphate and concentrated to 2.72 g of crude secondary amine. The crude amine in ethanol is treated with an ethanolic solution of hydrogen chloride to obtain a hydrochloride which is recrystallized from hot ethanol to give 2.18 g (47 "yield) of 2-methyl-3-ethyl-4-hydroxy hydrochloride. , 4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo (2,3-g] isoquinolinone-4-one in the form of white crystals, mp 250 °, Analysis for C 14 H 20 N 2 O HCl Calculated C 62.56; H 7.88; N 10.42; Cl 12.19 Found C 62.50; H 7.90; N 10.19; Cl 12.33 W an analogous method is prepared for 2,3-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin- 4-one with 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one. Example VI 3,4-dihydro-2-H-6,1-dimethoxy-2-methyl-isoquinolma hydrochloride. Solution of 15.0 g (64.7 mmol) N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride in 30 ml of water are mixed with 35 ml of 2N sodium hydroxide solution and extracted with dichloromethane. The combined extracts are concentrated to a rotary evaporator and is mixed with 65 ml of 37% aqueous formaldehyde solution. The mixture is refluxed for 2 hours, made alkaline with 15 ml of 2N sodium hydroxide solution and extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give 15.5 g of product as a yellow oil. The oil is dissolved in 100 ml of ethanol and treated with ethanolic hydrogen chloride. 75 ml of ether are added, and 10.15 g (64% yield) of 3,4-dihydrogen-1H-6.8H-dimethoxy-2-4 hydrochloride crystallize out. methylisoquinoline. 5 Example VII. 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline and octane-2 -methylisoquinoline-6,8-dione. 150 ml of ammonia are introduced into a flask containing 9.1 g (123 mmol) of tertiary butanol and 50 ml of diethyl ether. 1.0 g (4.1 mmol) of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride are added to the solution. It is stirred for 2-3 minutes, then 0.57 g (82 mmoles) of the lithium wire is introduced in short lengths for 30 minutes. The blue solution was stirred under reflux for 2.5 hours and 4.5 g of solid ammonium chloride was added until it disappeared. light blue color. 100 ml of ether is added and the ammonia is allowed to evaporate overnight. 100 ml of ice water are added and the organic phase is separated. The aqueous layer is extracted with ethyl acetate and chloroform. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.58 g (68.9 / tonne yield) 1,2,3,4,4a, 7-hexahydro-6,8-dimume. Toxy-2-methyl-isoquinoline in the form of a yellow oil. The crude product of 1.05 g in 20 ml of 70 P / e aqueous acetic acid solution is heated under reflux for 5 hours and the acetic acid is removed on a rotary evaporator. The residue is dissolved in water and washed with chloroform. The aqueous phase is concentrated to a volume of 10 ml, chromatographed on Dowex AG 50 WX 8, eluting with a 2M aqueous solution of pyridine and yields 0.11 g (11.6% yield) of octahydrogen-2-methylisoquinolin-6,8-dione in light yellow solid. Treatment with hydrochloric acid in methanol gives the hydrochloride, mp 193 ° -196 °. «0 Example VIII. 3-ethyl-2,6-dimethyl-4,4a, 5,6, 7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one via octahydro-2-methylisoquinoline -6.8-dione. 0.56 g (2.68 mmol) 1,2,3,4,4a, 7-hexahydro-6.8-45-dimethoxy-2-methylisoquinoline is heated at 90 ° C to 100 ° C in 10 ml 70 ° C. o aqueous acetic acid for hydrolysis of the bis (enol ether) into the octane-2-methylisoquinoline-6,8-dione. To the hot solution is added 0.6 g (9.25 mmoles) of zinc dust and 0.7 g (6.1 mmoles) of 2-isonitroso-3-penis. The mixture is heated under reflux for 3 hours, cooled and sucks to remove zinc and zinc acetate. The filtrate is concentrated to dryness on a rotary evaporator and the residue is dissolved in dichloromethane. Ammonium hydroxide is added to the solution and the layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated to give a crude product. Chromatography of the crude product on alumina III gives 0.19 g - (29% yield) of 3-ethyl-2,6-dimethyl-4.4a, 5,6,7,8, 8a, 9-octane -1H4pyrrolo [2,3-g] isoquinolin-4-one [mu] U in the form of a white solid. 65 P r z y k l a d IX. 2,6-dimethyl-3-isopropyl-4,4a, 126 672 23 24 5,6,7 £, 8a, 9-octahydro-4a, 8a-trans-1H-piix) lo [2,3-g] isochrnoline -4-on. For a solution of about 12.5 mmol of crude octahydrogen-2-methyl-isoquinolin-6.8-dione and 2.4 g (18 mmol) of 2-isotroso-4-methyl-3-pentanone in 40 ml of a 7 g / l aqueous acetic acid solution are treated with 2.6 g (40 mmoles) of zinc dust and slowly heated to reflux. After 1 hour, the mixture is cooled a little and again 0.4 g of mmitro-ketone and 1.0 g of zinc are added and the mixture is stirred for 1.5 hours under reflux. The mixture is then cooled and dried. and the porridge is concentrated at 50 ° / 20 mm Hg to give a yellow oil which is diluted with 50 ml of wtJfly and alkaline to pH 8-9 with ammonium hydroxide. The mixture is extracted with dfloroftarm and the extracts washed with brine, dried over sodium sulphate and concentrated to give 2.6 g of crude product. This product is chromatographed on a dry column on 100 g of silica gel, eluting with the organic phase of a mixture made of (by volume) 90 parts of chloroform, 30 parts of methanol, 10 parts of water and 6 parts of acetic acid. The eluted product fractions are evaporated, diluted water, basified to pH 8-9 with ammonium hydroxide and extracted with chloroform. The extracts were dried over sodium sulfate and evaporated to give 1.0 g of a solid which was recrystallized twice from ethyl acetate to give 470 mg of pure 2,6-dimethyl-3-isopropyl-4.4a, 5. 6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo {2,3 g] isoquinolin-4-one as a crystalline solid, mp 244-247 °. X. 3,6-dimethyl-2-y2-propenyl) -4,4a, 5,6,7,8, Sa, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one. Following a procedure analogous to that described in Example IX, 3-isonitroso-5-hexen-2-one is reacted with 2-methyl-octahydroisoquinoline-6,8-dione to give 3, 6-dimethyl-2H (2-prophenyleth) 4,4a, 5,6,7,858a, 9-oSMIO-4a, 8a-trans-1H-7 * pyrrolo [2,3-g] isoquinolines! -4-one with a melting point of 221 ° -223 °. Example XI. 3-cyclopropyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one Proceeding analogously to that described in Example IX, cyclopropyl-2-isonitroso-1-propanone is reacted with 2-methyl-octahydro-isoquinoline-6,8-dione to give 3-cyclopropyl-2,6. -dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo (2,3-g] isoquinolin-4-one, m.p. 256 to 59 ° C (decomposition). Example XII. 2nbenzyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g ] isoquinolin-4-one. Following a procedure analogous to that described in Example IX, 3-isonitroso-4-phenyl-2-butanone is reacted with 2-methyl-octahydroisoquinoline-6,8-dione to give 2-benzyl -3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-osmk) hydro-4a ^ a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- it has a melting point of 234-235 °. EXAMPLE XIII. 6-methyl-4,4a, 5,6,7,8,8a, 9-octahydrogen-4a8a-traris-1H-pyrrolo [2,3-g] isoquinolin-4-one. * Proceeding in a similar manner to described in Example IX, except that no zinc is used, the aminocetaldehyde dimethyl acetal is reacted with 2-methyl-octahinoquinoline-6,8-dione to give 6-methyl-4,4a, 5,6, 7,8,8a, 9-10-octahydro-4a, 8a-th, ans-1H-pyrrolo (2,3-g] isoquinoline-4-one, mp 208-210 °. Example XIV. ethyl-2-methyl-6- (2-propenyl) -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-pyrrolo [2,3-g] isoquinolin- 4-one. 15 A mixture of 0.470 g (2.03 mmol) of 3-ethyl-2-methyl-4.4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo (2,3- g] isoquinolin-4-one, 0.5 g (4.14 mmoK) of allyl bromide and 0.85 g (6.16 mmol) of potassium carbonate in 35 ml of acetate are stirred at room temperature. after 2 hours and sucked. The filtrate is concentrated, and the residue, 0.53 g, is chromatographed on aluminum oxide III to give 0.40 g of product. This product is treated with an ethereal solution. with hydrogen chloride to give the hydrochloride, which is recrystallized from ethanol-ethyl acetate to give 3-ethyl-2-methyl-6 - ((2-propenyl) -4.4a, 5.6 , 7,8,8a, 9-octahydro-4a, 8a-tirans-1H-pyrrolo [2,3-g] isoohinolin-4-one as a white solid, mp 214-217 °. Analysis for C 17 HmN4O.HCl 0.5 H 2 O Calculated: C 64.24; H 8.25; N 8.81; CI 11.15 Found: C 64.50; H 8.48; N 8.96; Cl 11.37. Examples XIV a- ^ dd. Following the procedure described in example 14, the compounds listed in Table 2 are obtained from the given 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrole [2,3 the -g] -isoquinolin-4-one and the indicated halide. Each compound exhibits spectral characteristics consistent with the given structure. Table 40 lists the melting points of the free base or hydrochloride (.HCl). The isolated compounds are 4a, 8a-trans isomers. Example XV. 3-ethyl-2-methyl-6V2-hydroxy--2-phenyl-ethyl) -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-40-trans-1H-pyrrolo [ 2, α-g] isoquinolin-4-one .. A mixture of 0.83 g (3.58 mmol) of 3-ethyl-2-methyl-4.4a, 5.6,7,8,8a, 9-octane -1H-pyrrolo [2,3-g] isoquinolin-4-one and 0.51 g (4.22 mmol) of styrene oxide in 25 ml of methanol were heated under reflux for 2.5 hours, cooled 1 The filtrate is concentrated and the residue is chromatographed on alumina III to give 0.69 g of crude product. After recrystallization from ethyl acetate-ethanol, 0.195 g of 3-ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -4.4a, 5, ", 7.8, 8a are obtained. 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a white solid, mp 218.5-220 °. Analysis for C22H28N /) 2: 60 Calculated: C 74.97, H 8.01, N 7.95 Found: C 74.87, H 7.92, N 7.95. Examples XVa — XVI By following the procedure described in example XV, the compounds listed in Table 3 are obtained starting from 3-ethyl-2-methyl-4a, 5,6,7,8,8a-8-octane-1Hrpy: olo [2,3-g] iso-Table 2 Example 1 XIV a 2-methyl -3-ethyl-6- (cyclopropyl-methyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo {2,3-g] isoquinolin-4- n.HCl 0.2 HjO XIVb 2-methyl-3-ethyl-6-ben-1-yl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g ] isoohinolin-4-one..HCl XIVc racemic 2-methyl-3-ethyl-6-i [2-dimethyl-1 arrmo] -ethyl) -4.4a, 5.6.7, 8.8a, 9 - octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one XIVd racemic 2-methyl-3-ethyl-6 - '[4V4-fluoro-phenyl' / - 4-o'x abutyl] -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3 -g] isoquinolin-4-one XIV e racemic 2-methyl-3-ethyl-6- (2-panylethyl) - -4.4a, 5,6,7,8,8a, 9-octahydrogen-4a , 8a-tranis-1H-pyrrolo [2,3-g] isoquinolin -4-one Ri 2 HHHHH Re 3. CH3 CHj CH3 CH3 CHs Ra 4 CH2CH3 CH2CH3 CHaCH3 CH2CH3 CH2CH3 Ri 5 Formula 19 Formula 20 (CH32N— ^^ CHgCHa Formula 21 Formula 22 X 6 Cl Cl Cl Br Analysis calculated found 7 (.HCl) C 66.22 H 8.15 N 8.58 Cl 10.85 (.HCl) C 70.27 H 7.58 N 7.81 Cl 9.88 C 71.25 H 9.63 N 13.85 C 72.70 H 7.37 N 7 , 07 P 4.79 C 78.53 H 8.39 N 8.33 C 66.24 H 8.35 N 8.36 Cl 10.51 C 70.49 H 7.33 N 7.72 Cl 10.03 C 71.03 H 9.73 N 13.66 C 72.47 H 7.47 N 7.09 P 4.75 C 78.53 H 8.40 N 8.35 Melting point 8 215-219 ° 193 —197 ° 184—166 ° 210-212 ° 230—240 ° Crystallization from 9 ethanol ethyl acetate ethanol ethyl acetate ethyl acetate ethyl acetate ethanol Reaction conditions 1 temperature 10 heating under reflux in acetone heating under reflux in acetone heating for reflux condenser heating for reflux condenser heating time 11 16 hours 2 hours 20 hours in 3-pentynone 24 hours in 3-pentynone 2 hours in 3-penta-nonecd. table 2 1 * 1 2 1 XIVf racemic 2-methyl hydrochloride 1-3-ethyl-61 (2-ethoxyethyl) -4,4a, 5,6,7, 8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4 -one XIVg racemic 3,6-diethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-ttrans-1H-pyrrolo [2,3-g ] isoquinolin-4-one XIVh racemic 3-ethyl-2-methyl-6-propyl-4,4a, 5, 6,7,8,8a, 9-octane-4a, 8a-trans-1H-pyrrolo [ 2,3-g] isoquinolin-4-one XIV and 4a, 8a-trans-3-ethyl-4-oxo-1, 5,7,8,8a, 9-hexahydro-2-methyl-acid ethyl ester 1H, 4H-pyrrole {2,3-a] isoquinoline-6-acetic acid XIVj 4a, 8a-trans-1- [3-ethyl-4a, 5,7,8,8a, 9-hexahydro-2 -methyl-4-oxo-1H-4-H-pyrrolo [2,3-g] isoquinolin-6-yl] -2-propanone HHHHH 3 CH3 CH3 CH3 CH3 CH3 4 | 5 | 6 CH2CH3 CH2CH3 CH3CH3 CH2CH3 CH2CH3 CH3 CHa — O— —CH3CH2 CH3CH2 CH3CH2 CHsCH5O— —OCCHa CH3COCH2 Br Br Br Br Cl 7 | 6 C 63.42 H 8.57 N 8.21 Cl 10.40 C 73.81 H 9.29 N 10.76 C 73.41 H 9.55 N 10.21 C 67.90 H 8.23 N 8.80 C 70.80 H 8.39 N 9.71 C 63.13 H 8.71 N 8.17 Cl 10.64 C 73.9 (1 H 9.30 N 10.84 C 74.29 H 9.40 N 10.21 C 68.09 H 8.28 N 8.80 C 71.10 H 8.30 N 9.93 213—215 ° 228 ^ 230 ° 226—228 ° 215—216 ° 192 ^ 195 ° 9 | 10 | U | ethanol ethyl acetate ethanol ethanol ethanol ethyl acetate ethanol heating (reflux heating reflux heating | reflux heating | reflux heating 2 hours in 3 pentanone 3 hours in acetone 13 hours in 3-pentanon 2 hours in 3-pentynone 2 hours in 3-pentynecon.d. table 2 [1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 0 | 10 | 11 | XIVk racemiezny 2-methyl-3-ethyl-6- [2- (4-fluorophenyl) -2-oxoethyl] -4,4a, 5,6,7,8,8a, 9-osinihydro-1H- -pyrrolo [2,3-g] isoquinolin -4-one XIV1 racemates of 2-methyl-3-ethyl-6- [3- (4-fluorophenyl) -3-oxo-propyl] -4,4a, 5,6,7,8,8a, 9-octane-4a, 8a-trans-1H-pyrrolo [2,3-g] and zoquinolin-4-one XIVm 3-ethyl-2-methyl-6- (3-phenoxypropyl) -4,4a, 5,6,7,8,8a, 9-hydro-1H-4a racemates, 8a-trans-pyrrolo [2,3-g] isoquinolin-4-one XIVn racemias 6- (3-diphenylpropyl) -3-ethyl-2-methyl-4.4a, 5.6, 7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoehinolin-4-one XIV with 3-ethyl-6- [2- - / 4-methoxyphenyl racemates n-ethyl] -2-methyl-4,4a, 5,6,7,8,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo ([2,3-g] -isoehinolin -4-one HHHHH CH3 CH3 CH3 CH3 CH3 CH2CH3 CHzCHs CHaCH3 CH2CH3 CH2CH3 formula 23 formula 24 formula 25 formula 26 formula 27 Cl Cl Br Cl Cl C 71.72 H 6.84 N 7.60 and C 72.23 H 7, 12 N 7.32 C 75.37 H 8.24 N 7.64 C 81.65 H 8.03 N 6.57 C 75.37 H 8.25 N 7.64 C 71.44 H 6.80 N 7.47 C 72.24 H 7.00 N 7.19 C 75.64 H 8.18 N 7.52 C 81.60 H 7.85 N 6.72 C 75.65 H 8.41 N 7, 73 209-213 ° 208-210 ° 202-203 ° 220-222 ° 255-257 ° ethanol ethanol ethanol ethanol heating to reflux condenser heating to reflux condenser heating to reflux condenser heat water under reflux condenser 3 hours in 3-pentynone 3 hours in 3-pentynone 2 hours in 3-pentynone 17 hours in 3-pentynone 24 hours in 3-pentynone126 672 31 32 1 1 " Si .s% .H fi - * 8.1 CO H • i-2 Hi Wig CO fi O ^ 3 c ^ co 6 O 0) liii W) o ^ O .fi d fi O i PSS § goal io C © 1 3 O li i co oo ~ cp * OW 55 OW Iz; a s s f-T c-T t »O W S5 i-H OJ co m i-H 00 d- 10 CN OJ o w £ O W fc O« jz; CD OJ i-H ° 1 ^ ^ ^ OJ OJ r- o w & ^ 4 Tl <10 CN CO 10 O W Iz; OJ t * CO t * CO CN o W Iz; c »o ^ ° i '" l A OJ 00 00 ow Iz; un OUN 3 .a $ ^ w Bff oo 8 8 a 8 8 wwww H. 5 ° I it * 4 cm <° «o 4f * r SX ci? "fi £ 1 M có 73 5« 1 * O fi ca 00 3. ^ what About csf W) J? OD i, »rH" 5 ge »co W ci V ^ $ eó N» I1 cf fi có nf h ° fi o <fi ¦ § p, 'i ocT ^ co -P t * -fi T * ^ 5 ^ A ^ T! I2 h! ¦ G * «" O CO l * ifI Bafil ^ ax co ^ £ 1 ooa? I 0Qk0O 'fi cd 5 ^ XI co "7 * f * § fi <ó ^ .2 y ó fi fi' Tl" 52 ^ 15 1! ? -s 0 * 1 § I-i Oc.d. array 2 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 XIV u, 8a-trans-3-ethyl-4a, 5,7, 8a-trans-3-ethyl-4a, 5,6,7, 8.8a, 9-hexahydro-2- and -methyl-4- oxo-1H, 4H- 4-pyrrolo [2,3-g] isoquinoline-6-propane XIVv racemic 6-cyclobutyl-methyl) -3-ethyl-2-methyl-4.4a, 5.6 , 7,8,8a, 9-hydrogen-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one XIV to racemic 6- (4-diphenylbutyl) - 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one : XlVx trans42- (3-ethyl-4.4a, 5,6,7,8,8a, 9-octahydrogen-2-imethyl-4-oxo-1H-pyrrolo [2,3-g] ester isoquinoline-6-yl) -ethyl benzoic acid XIVy racemiosine 3-ethyl-2-methyl-642- (N-methyl--2-pyrrolidinyl) -ethyl] -4,4a, 5,6,7,8 , 8a, 9-octohydro-4a, 8a-trams-1Hnpyrrolo [2,3-g] isoquinolin-4-one HHHHH CH3 CH3 CH3 CH, CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3CH2— —OOCCH2— —CH2 formula 31 formula 32 formula 33 formula 34 Br Cl Cl Br Cl C 68.65 H 8.49 N 8.43 C 75.96 H 9.39 N 9.32 C 81.78 H 8.24 N 6.36 C 72.60 H 7.42 N 7.36 C 73.43 H 9.68 N 12.23 C 68.59 H 8.50 N 8.55 C 75.70 H 9.34 N 9.23 C 81.88 H 8.16 N 6.36 C 72.31 H 7.58 N 7.22 C 73.25 H 9.54 N 12 , 41 180-184 ° 222-224 ° 236-238 ° 206-208 ° 192-494 ° ethyl acetate ethanol ethanol ethanol ethyl acetate heating to reflux heating to reflux heating! To reflux condenser heating ipod reflux condenser 11 | 3 hours in 3-pentynone 18 hours in 3-pentynone 18 hours in 3-pentynone 6 hours in 3-pentynone 20 hours in 3-pentynetin d. array 2 1 | 2 | 3 | 4 | 5 XIV z trans- {3- (3-ethyl-4.4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-1H-pyrrolo [2,3) benzoate -g] isoquinoline-6-yl) -propyl] XIV aa racemic 3-ethyl-2-methyl-6- (2,3-dihydroxypropyl) -4.4a, 5.6.7, 8y8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one XIVbb 3-ethyl-2-methyl-6 [[2,2-dimethyl-1,3-dioxo- lan-4-yl) -methyl] -4.4a, 5, 6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- on XIV cc racemic 3-ethyl-6- [2-y4-morpholinyl] -ethyl] -2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans- 1H-pyrrolo [2,3-g] isoquinolin-4-one XIVdd racemic 6-benzyl-2,3-dimethyl-4,4a, 5,6,7,8, 8a, 9-octahydro-1H-4a 8a trans-pyrrolo [2,3-glisoquinolin-4-one HHHHH CH3 CHa CH3 CH3 CH, CH2CH3 CH2CH3 CH2CHJ CH2CH3 CHa formula 35 formula 36 formula 37 formula 38 formula 39 6 Br Cl Br Cl Cl 7 | 6 C 73.07 H 7.67 N 7.10 C 66.64 H 8.55 N 9.14 C 69.33 H 8.73 N 8.09 C 69.53 H 9.04 N 12.16 C 77.89 H 7.84 N 9.08 C 73.12 H 7.63 N 7.07 C 66.32 H 9.07 N 9.07 C 69.29 H 8.74 N 8.12 C 69, 59 H 9.12 N 12.12 C 77.61 H 7.63 N 9.13 189-190.5 ° 210-212 ° 233-235 ° 206-208 ° 245.5-246 ° 9 ethanol ethanol ethanol ethanol ethanol 10 heating to reflux condenser heating to reflux condenser heating to reflux condenser heating to reflux 11 4 hours in 3-pentynone 20 hours in 3-pentanone 20 hours in 3-pentinone 8 hours in 3- pentinone 3 hours in acetone Table 3 Example 1 XVa 2-methyl-3-ethyl-6 [2-hydroxy-2- (4-chlorophenylcV-ethyl] -4,4a, 5,6,7,8 , 8a, 9-octadoro-1H-pyrrolo [2,3-g] isoquinolin-4-one XVb 2-methyl-3-ethyl-6- (2-hydroxyethyl) -4.4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2-ng] isoquinolin-4-one XVc racemic 2-methyl-3-ethyl-6- 2-hydroxy-3- [4-] 1,1-dimethyl) -4,4a, 5,6,7,8,8a, 9-05 hmihydro-4a, 8a-trans-1H-pyrrolo [2,3- g] isoquinolin -4-one XV d racemic 2-methyl-3-ethyl-6V2-hydroxy-3-methylbutyl) -4.4a, 5,6,7,8,8a, 9-os- hydro-4a, 8a-trans-1H- -pyxyl [2,3-g] isoquinolin-4-one XV e racemic 2-methyl-3-ethyl-6- / 2-hydroxy-3,3-dimethylbutyl [Beta] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pixolo (2,3-g] isoquinolin-4-one - a 2 HHHHH Rb 3 CH3 CH3 CH3 CH3 CH3 R1 4 CHjCH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 Rs 5 1 Formula 40 H Formula 41 Formula 42 Formula 43 Amalysis calculated found 6 C 68.29 H 7.03 N 7.24 Cl 9.16 C 69.53 H 8, 75 N 10.14 C 73.94 H 8.73 N 6.39 C 71.66- H 9.50 N 8.80 C 72.25 H 9.70 N 8.43 C 68.11 H 7.03 N 7.18 Cl 9.38 C 68.93 H 8.78 N 9.96 C 73.83 H 8.84 N 6.30 C 71.49 H 9.72 N 8.77 C 72.31 H 9 , 73 N 8.20 m.p. 7 214-215 ° 215-218 ° 225-227 ° 197-199 ° 232-234 ° Crystallization from 8 ethanol ethyl acetate ethanol ethanol ethyl acetate ethanol ethyl acetate ethanol ethyl acetate Conditions Reaction temperature 9 heating under reflux 25 ° heating under reflux heating under cooling reflux condenser heating under chlorine reflux time 10 3 hours in methanol 2 hours in methanol 2 hours in methanol 5 hours in ethanol overnight in methanol quinolin-4-one and a suitable epoxy compound. Each compound exhibits spectral characteristics consistent with the given structure. The table lists the melting points of the free base or the hydrochloride (.HC1). The isolated compounds are the 4a, 8a-trans isomers. The process follows the scheme 8. Example XVI. Decomposition of racemic-3-ethyl--2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-4srans-1H-pyrrolo [2,3-g] isoquinolines -4-one. 1.20 g of racemic free base (prepared as described in Example IV) is dissolved in methanol and 0.74 g of d - (+) - tartaric acid in methanol is added. The solution is concentrated and recrystallized twice from methanol. The crystalline d - (+) - tartrate is treated with ammonium hydroxide to liberate the base and the free base is treated with anhydrous ethereal hydrogen chloride solution to obtain the hydrochloride. After recrystallization of the resin twice from ethanol and drying at 80 ° / 0.005 mm, 0.15 g of the (-) - enantiomer is obtained as a white solid, mp 240 to 245 ° [* Analysis for CigHaNjA HCl. 0.25 Kfi calculated: C 62.70, H 8.24, N 9.75 Found: C 62.44, H 8.33, N 9.67. Mother Lug after crystallization d - <+) - tartrate * treated ammonium hydroxide to free the base, which is treated with a solution of 0.46 g of l- / n-tartaric acid in methanol. The solution is concentrated and recrystallized twice from methanol, converting the compound as described above into the free base and the hydrochloride. 0.10 g of the (H -) - enantioner is obtained as a white solid, mp 240-244 °, [a] 25 = + 1121.38 ° (c = 0.44 "/" in water). Analysis for Cis H ^ NaCHCl. 0.25 H * O Calculated: C 62.70 H 8.24 N 9.75 Found: C 63.02 H 8.20 N 9.88. Example XVII. [2n / 3'-ethyl-4,4a, 5,6,7A8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-6 -yl) -ethyl] -4-fluorobenzaniide. N- [2- (3-ethyl-, 4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a , 8a-trans-1H-pyrrolo2,3-g] isoquinolin-6-yl-i-ethyl] -4-fluorobenzamide is prepared by heating 3-ethyl-2-methyl-4,4a, 5,6,7, 8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-3-one and 1- (4-fluoroibenzoyl) aziridine in a mixture of benzene and methanol for 2 hours. The crude product crystallizes from ethanol as a white solid, mp 252-253 ° C. The starting aziridine is prepared from azidimine, p-fluorobenzoyl chloride and acidic sodium carbonate in water. 3-ethyl-2-methyl-4,4a, 5,6,7,8,8,8a, 9-octane-1Hipiix) lc {2.3 g] isO (Chinolin-4-thion. Mixture 1.45 g (6 mmol ) 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydroHlHnpyrrolo [2,3 g] isoquin-60 lin-4-one and 1.77 g <4 nimol) phospho pentasulfide The ¬ ru in 60 ml of dioxane is stirred and heated to reflux for 10 hours. The mixture is cooled and the dioxane solution is decanted from the dark residue which dissolves in * 75 ml of water. The solution is basified to pH 8-9 with ammonium hydroxide and the aqueous mixture is extracted with chloroform. The extracts are washed with water and dried over sodium sulfate. After evaporation of the solvent, 420 mg of crude thionium are obtained, which is chromatographed on a dry silica gel column together with 100 mg of additional crude product obtained by treating with hot water on the residue after initial isolation and an analogous extraction with chloroform. The dry column containing the organic phase is eluted with a mixture (parts by volume) of 90 parts of chloroform, 30 parts of methanol, 10 parts of water and 6 parts of acetic acid, and the product is evaporated, dissolved in water, neutralized to a pH of 8-9 per with ammonium hydroxide and extracted with chloroform to give pure thion. This product was washed with water, dried over sodium sulfate, and evaporated with chloroform to give 250 mg of 3-ethyl-2-methyl-4.4a, 5,6,7,8,8,8a, 9-octahydro-1H. -pyrrolo [2,3-g] isoquinoline-4H thione as a yellow solid, m.p. 190 ° 194 °. After recrystallization from acetonitrile, the pure 4a, 8a-trans isomer is obtained, mp 203-205 °. Example XIX. 3-ethyl-2-methyl-6-y2-phenyl-ethyl) -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3- g] isoquinoline-4-thion. Mixture 248 mg (1 mmol) of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g ] isoquinoline-4-thionium, 276 mg of potassium carbonate and 22 mg of 2-bromoethylbenzene in 15 ml of 3-pentanone are stirred and refluxed for 3 hours. The solvent is removed on a rotary evaporator, 25 ml of water are added and the mixture is extracted with chloroform. The product is chromatographed on a dry column as described in Example 21 to give 100 mg of a substance which, after recrystallization from acetonitrile, yields 50 mg of 3-ethyl-2-methyl-6- ((2-phenylethyl) -4.4a. , 5,6,7,8,8,8a, 9-octane TO-4a, 8a-thiraniS-1H-pyrrolo [2,3-g] isoquinoline-4-thionium, m.p. 164-166 ° (decomposition). XX. In a manner analogous to the example XIV, the compounds listed in Table 4 can be prepared. Table 4 Compound 1 * 2,6-dimethyl-3-isopropyl-4,4a, 5,6,7,8,8a, 9-eight- hydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin -4-one 3,6-dimethyl-3 (2-propenyl) -4.4a, 5,6,7,8,8a , 9-Honeydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin -4-one 3-cyclopropyl-2,6-dimethyl-4,4a, 5,6,7,8 , 8a, 9-axis dihydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4-one 2-benzyl-3,6-dimethyl-4,4a, 5,6,7 , 8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin -4-one. 6-methyl-4,4a, 5,6,7,8, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo (2,3-g1) isoChinolin-4-one rac. thio-2- (lo-xo-ethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-ittransylH-pyrrolo (2,3-g) isoquinolin-4- he flares 2,6-dimethyl-3-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole (2,3-g) isoquinoline- 4-on and rac. 2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole / 2,3-g / lzochmolin-4-one 3,6- dimethyl-2-2-propyl) -4,4a, 5,6,7,8,8a, 9-os-hydro-1H-pyrrole (2,3-g) isoquinoline-4-one (hydrochloride) 2.6 -dimethyl-3-phenyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo (2,3-g) isoquinolin-4-one Analysis calculated found 2 C 69.20 H 7.74 N 10.76 C 73.81 H 9.29 N 10.76 C 71.53 H 8.31 N 12.83 C 64.74 H 8.49 N 9.44 Cl 11.94 C 77 , 23 H 7.53 N 9.52 • C 68.97 H 7.77 N 10.47 C 73.56 H 9.30 N 10.91, C 71.44 H 8.44 N 12.98 C 64 , 53 H 8.38 N 9.36 Cl 12.16 C 77.23 H 7.50 N 9.54 Melting point 3 244 247 ° C ethyl acetate 221-223 ° C 258-259 ° C (decomposition) 234 —235 ° C 208-210CC 243—245 ° C 250—251 ° C 251—263 ° C 280 ° C (decomposition, methanol> 40 ° C (decomposition) ethanol / ethyl acetate | 43 126 672 44 1 x 2, 3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrole (2,3-g) isoquinolin-4-one (hydrochloride) 3-ethyl-2 hydrochloride, 6-dimethyl-4,4a, 5,6,7,8, 8a, 9-oHydro-4a, 8a-trans-1H-pyrrole / 2.3 g of isoquinolin-4-one 3-ethyl -2, 6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole / 2,3- (0) isoquinolin-4-thion 3-ethyl- 2-methyl-6- (2, phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a, trans-1H-pyrrole (2,3 g) isoquinolin-4 -tion rac. 6- benzyl-4.4a, 5,6,7,8,8a, 9-octahydro-1H-4a, 8a-trans-pyrrolo (2,3-g!) Isoquinolin-4-one rac. 2,3-dimethyl-6- (2-phenyl-ethyl) -4,4a, 5,6,7,8,8,8a, 9-octahydro-4a, 3a-tranis-1H-pyrrole (2,3-g / isoquinolin-4-one rac. 2,3-dimethyl-6- (4- (4-fluoforenyl) -4-oxo-ibutyl) -4.4a, 5,6,7,8,8a, 9-octane-4a, 8a-trans-1Hnpyrrole (2,3-g) isoquinolin-4-one rac. 3-ethyl-2-methyl-6-i [2 - N -2-thienyl] -ethyl] -4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-tranis-1H- pyrrole (2, & rg1) isoquinol-4-one rac. 3-ethyl-2-methyl-6- [2-i / 2-furylZ-ethyl] -4,4a, &, 6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole 1 (2,3-g) isoquinolin-4-Oin rac. S-ethyl- [beta] -methyl-[alpha] -tP- [beta] -s-dihydrogen-oxo-[beta] -benzimidazol-1-yl [alpha] -ethyl] -4.4a ^ 5.6.7, fi, 8a, 9-octane 4a, 8a-trans-1H-pyroio (2,3-g) and z <) quinolin-4-one rac. 3-ethyl-2-methyl-6- [3-i (2,3-dihydro-2-oxo-. 1H-benzimidazol-1-yl-propyl] -4.4a, 5.6.7.8, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo (2,3-g) isoquinol-4-0 (n 2-methyl-3-ethyl-6- [4- (4-fluorophenyl )- 4-oxobutyl] -4,4a, 5,6,7,8,8a, 9-osnihydro-4a, 8a-trans-1H-pyrrolo (2,3-g) isoquinolin-4-one 2 | 3 C 62.56 H 7.88 N 10.42 Cl 13.19 * C 77.11 H 7.19 N 0.99 C 78.22 H 8.13 N 8.69 C 72.23 H 7.12 N 7.32 C 70.19 H 7.65 N 8.18 C 73.59 H 8.03 N 8.58 C 70.38 H 7.19 N 14.27 C 70.91 H 7.44 N 13, 78 C 69.87 H 7.09 N 6.79 C 62.19 H 7.97 N 10.20 Cl 13.41 C 77.15 H 7.20 N 10.04 C 77.90 H 6.14 N 8.67 C 72.1Z H 7.23 N 7.54 C 70.24 H 7.83 N 8.0S C 73.48 H 8.15 N 8.68 C 70.15 H 7.04 N 14, 35 C 70.73 H 7.43 N 13.54 C 69.60 H 7.14 N 6.80 275-80 ° C (decomposition) ethanol / ether 196-198 ° C ethanol 194-196 ° C (decomposition) acetonitrile 164 ° -166 ° C (decomposition) acetonitrile 266—268 ° C 207-209 ° C 235—237 ° C 230—232 ° C 253—255 ° C 240—242 ° C 159—161 ° C Patent claims 1. Preparation method the novel octane-1H-pyrrolo [2,3-g] isoquinolines o general formula A, in which R2 and R3 independently of each other represent hydrogen atoms, alkyl, cycloalkyl, alkenyl radicals, acyl, aryl or aralkyl groups, and R4 is an arylcarbonamidoalkyl radical, acylalkyl, cyclic alkyloxyalkyl radical, cyclic alkylhydroxy radical 60 alkenyloxyalkyl, aralkenyl, aryloxyalkyl, Ncalkylpyrrolidinylalkyl, trifluoroalkyl with 2 to 6 carbon atoms or an aryl-N-imidazolonylalkyl radical, and in the case that R2 and / or R3 are also acyl or aryl groups alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, chloro-phenyl-hydroxyalkyl, alkylphenylhydroxyalkyl, alkoxyphenylhydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl, acyloxyalkyl, arylcarbonyl, alkylcarbonyl tocycloalkyl, alkynyl, thienylalkyl, furylalkyl, or group b formula e 17, in which Ra and R7 independently of each other represent hydrogen or alkyl radicals, or together with the nitrogen atom form a 5- or 6-membered heterocyclic ring, and X represents an oxygen or sulfur atom, as well as isomers the optical and geometrical compounds of these compounds and their pharmaceutically acceptable acid addition salts, characterized in that the compound of general formula 15, in which Ra, R3 and X are as defined above, is substituted on the isochlinoline nitrogen atom and the resulting mixture of cis and trans isomers is optionally trans-isomerized to the final product containing the predominance of the trans isomer and / or possibly the trans isomer is isolated from the mixture obtained and / or the racemic mixture obtained, if any, splits into optical antipodes and / or or the resulting compound or a pharmaceutically non-tolerated acid addition salt is optionally converted into a pharmaceutically acceptable acid addition salt. 2. The method for the preparation of the new octane-1H-ipyrrole (2,3-g) isoquinolines of formula A, in which R 1 and R j, independently of each other, represent hydrogen, alkyl, cycloalkyl, alkenyl or aralkyl radicals, and R * denotes an alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halogen-phenylhydroxyalkyl, alpha-phenyl-hydroxyalkyl, alkoxyphenyl and hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl, ararylalkylalkyl, arylalkylalkyl, acyloxyalkyl radicals alkenyl, alkylcycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl or the group of formula 17, where R 'and R7 independently of each other represent hydrogen or alkyl radicals, or together with the nitrogen atom represent 5- or 6-6 a member heterocyclic ring and X represents the oxygen or sulfur atom of the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized in that the compound of general formula 15, in which R *, R 3 and X are as defined above, are substituted at the isoquinoline nitrogen atom and the resulting mixture of cis and trans isomers is optionally isomerized to the final product containing predominance of the trans isomer and / or optionally with the trans isomer is isolated from the mixture obtained and / or the resulting racemic mixture is cleaved into optical antipodes and / or the compound obtained or the pharmaceutically incompatible acid addition salt is optionally converted into a pharmaceutically acceptable acid addition salt. acid. 3. The method according to p. Z, characterized in that for the preparation of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo / 2 , 3-g (isoquinolin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8, 8a, 9-octahydro "-4a, 8a-trans-1H-pyrrole) 2 The 3-g (isoquinolin-4-one) is substituted on the isoquinoline nitrogen atom. 4. The process according to claim 2, characterized in that in the preparation of 2-ethyl-3-ethyl-6- ^ 2- - phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole (2,3-gi) isoquinolin-4-one, 2-methyl-3- Ethyl-4,4a, 5,6,7,8,8a, 4-octahydro-4a, 8a-trans-1Hyprolo (2,3-g) isoquinolin-4-one is displaced on the isoquinoline nitrogen atom. 5. Process according to claim 2, characterized in that in the preparation of 2-methyl-3-ethyl-6-i (2-ethoxyethylcV-4.4a, 5,6,7,8,8a, 9-octane 4a, 8a-trans-1H-pyrrolo (2,3-g) isoquinolin-4-one, 2-methyl-3-25-ethyl-4,4a, 5,6,7,8,8,8a, 9-octane The -4a, 8a-trans-1H-pyrroleV2,3-g!) Isoquinolin-4-one is substituted on the isoquinoline nitrogen atom. characterized in that for the preparation of 2-methyl-3-ethyl-6- [4- (4- 3'-fluoro-phenyl-M-oxobutyl] -4.4a, 5, e, 7.8.8a, 9-octal 4a, 8a, trans-1H-pixolo (2,3-g) isochi.noiin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octane 4a, 8a-trans-1H-pyrrolo (2,3-g) isoquinolin-4-one is substituted on the isoquinoline nitrogen atom. 2. A process according to claim 2, characterized in that for the preparation of 2-methyl-3-ethyl-6V2-hydroxy-3,3-dimethylbutyl) -4,4a, 5,6,7,8i8a, 9-hydrogen-4a, 8a -trans-1H-pyrrole (2,3-g) isoquinolin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octane-4a, 8a-trans-1H-pyrrole (2,3-g) isoquinolin-4-one is substituted at the isoquinoline nitrogen atom. 126 872 CIS FORMULA A FORMULA 1 "a R" CCrt "! IZH FORMULA 1 O CH3T" |, "R- HIH trans FORMULA Ta N ^ R- R, N R- N" RH FORMULA 2 H FORMULA 1 "R / H" N -rR- 1 XN ^ RHH FORMULA 2 'fy. HN R. 1 L H ^ R2 H PATTERN 2 "K 0 N PATTERN 15 'X' N ^ RI 'HH ~ N. R- PATTERN 16 N ^ R ^ IHR,' NO: N ^ RH PATTERN 2 SCHEME 2 C2H5OCNH OCH CH3NH PATTERN 6 H: PATTERN 3 OCH3 PATTERN 5 SCHEME 3 (C7.I) O CHQNH + X + Zn O HON "R2 I ^ N R2 PATTERN 6 PATTERN 7 PATTERN 8 O CH3NH Ro 1 II - ^ Lh3 OXI 2 H R-: nC" I 2 H PATTERN 9 PATTERN la SCHEME 3 (czJI) C- CH O 2 126 672 CH. PATTERN 23 PATTERN 20 OC CrUCrU PATTERN 2k CCH2CH2CH2 O PATTERN 21 OCH2CH2CH2 PATTERN 25 HN X RX H PATTERN 15 Rf R .; N - aLkiL FORMULA 17 CH2CH2 FORMULA 22 D ^ CH, FORMULA 18 FORMULA 19126 672 C6H5 C6H5; CHCH2CH2 HX - H3C; ch-ch2 FORMULA 26 FORMULA 29: H30_CVCH2CH2 CL- MODEL 27 FORMULA 30 O II C6-CH5 ^ CHCrU CHo CHn H2CN CH2 TH2 ': hch. in VZ0R 31 FORMULA 32 COOCH2CH2 FORMULA 33 N 'CH2CH2 AND CH3 FORMULA 3 /, 126 672 C00CH2CH2CH2 0 N-CH2-CH2 FORMAT 35 FORMAT 38 CH2CH CH2 II OH OH 7 Vch.CL / \ FORMAT 36 FORMAT 39 FORMAT 40 CH9 — CH - 1 1 1 1 0 0 \ / c / \ 3C CH3 PATTERN 37 -CH2 CH- CH CH3 PATTERN 42 H3C CH3 C CH ~ PATTERN 43 'Cl OCH2- OCH- PATTERN 41 OH -N PATTERN 15 R- N ^ RH PATTERN 1 MODEL 44 SCHEME 1126 672 O CH3-N MODEL la ^ KN ^ R and HOO C2H50-CN R, MODEL 13 HN 1 li i ^ HOR 3 and IN ^ R: H MODEL 15 SCHEME OCH, OCH, CH3NI CH3-N OCH3 PATTERN 4 OCH, OCH3 PATTERN 10 CH3-N OCH: PATTERN 11 O CH3N 0cV ^ R3 ° "V ^ R3 O HON R2 H2N R2 PATTERN 12 O * CH3- N PATTERN 1a PATTERN 7 Or PATTERN 8 R3 1 1 1 with H DIAGRAM 5 Y5 HON R2 OCH, CH3NH sv- Knorr reaction OCH- O CHoNH. R3 Mannich reaction N- ^ Ro 1 with H a'i ± ix: N ^ R- 1 H SCHEME 6126 672 O o «cca3 -». «^ - "cóx! Ri 2 i * 2 R, SCHEME 7 r ^ o-tA /: - rvAx3 N ^ R2 OH ^^^ N ^ R2 R1 Ri SCHEMAT 8 National Printing House, Plant No. 6, 440/85 Price PLN 100 PL

Claims (7)

Claims 1. Process for the preparation of new octahydro-1H-pyrrolo [2,3-g] isoquinolines of the general formula A, in which R2 and R3 independently of each other represent hydrogen atoms, alkyl, cycloalkyl, alkenyl radicals, acyl groups , aryl or aralkyl, and R4 is an arylcarbonamidoalkyl, acylalkyl, cyclic alkyloxyalkyl radical, cyclic alkylhydroxyalkyl radical, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, Ncalkylpyrrolidinylalkylalkyl, Ncalkylpyrrolidinylalkyl or tri? and in case R2 and / or R3 are acyl or aryl groups, R465 is also alkyl, hydroxyalkyl, phenylhydroxyalkyl, chlorophenyl hydroxyalkyl, alkylphenylhydroxyalkyl, alkoxyphenylhydroxyalkyl, alkoxyalkyl, ryloxyhydroxyalkyl, alkoxyhydroxyalkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, araltolic, alkenes alkyl, alkylcycloalkyl, alkynyl, thienylalkyl, furylalkyl, or group b of formula 17, where Ra and R7 independently of each other represent hydrogen or alkyl radicals, or together with the nitrogen atom form 5- or A 6-membered heterocyclic ring and X is oxygen or sulfur, as well as the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized by a compound of general formula 15, wherein Ra, R3 and X are as defined above, they are substituted at the isocholin nitrogen atom, and the resulting mixture of cis and isomers is transiently isomerized to the final product containing predominantly the trans isomer and / or optionally isolated from the resulting mixture. the trans-isomer and / or the racemic mixture obtained, if any, is cleaved into optical antipodes and / or the compound obtained or the pharmaceutically untolerated acid addition salt is optionally converted including a pharmaceutically acceptable acid addition salt. 2. The method for the preparation of the new octane-1H-ipyrrole (2,3-g) isoquinolines of formula A, in which R 1 and R j, independently of each other, represent hydrogen, alkyl, cycloalkyl, alkenyl or aralkyl radicals, and R * denotes an alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halogen-phenylhydroxyalkyl, alpha-phenyl-hydroxyalkyl, alkoxyphenyl and hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl, ararylalkylalkyl, arylalkylalkyl, acyloxyalkyl radicals alkenyl, alkylcycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl or the group of formula 17, where R 'and R7 independently of each other represent hydrogen or alkyl radicals, or together with the nitrogen atom represent 5- or 6-6 a member heterocyclic ring and X represents the oxygen or sulfur atom of the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized in that the compound of general formula 15, in which R *, R 3 and X are as defined above, are substituted at the isoquinoline nitrogen atom and the resulting mixture of cis and trans isomers is optionally isomerized to the final product containing predominance of the trans isomer and / or optionally with the trans isomer is isolated from the mixture obtained and / or the resulting racemic mixture is cleaved into optical antipodes and / or the compound obtained or the pharmaceutically incompatible acid addition salt is optionally converted into a pharmaceutically acceptable acid addition salt. acid. 3. The method according to p. Z, characterized in that for the preparation of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo / 2 , 3-g (isoquinolin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8, 8a, 9-octahydro "-4a, 8a-trans-1H-pyrrole) 2 The 3 g. Isoquinolin-4-one is displaced by the isoquinoline nitrogen atom. 4. The method according to p. 2. A process according to claim 2, characterized in that for the preparation of 2-ethyl-3-ethyl-6- [beta] 2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a - trans-1H-pyrrole (2,3-gi) isoquinolin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, N-octahydro-4a, 8a-trans-1Hipi - rolo (2,3-g) isoquinolin-4-one is substituted on the isoquinoline nitrogen atom. 5. The method according to p. 2. A process according to claim 2, characterized in that for the preparation of 2-methyl-3-ethyl-6-i (2-ethoxyethylcV-4.4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans -1H-pyrrole (2,3-g) isoquinolin-4-one, 2-methyl-3-25-ethyl-4.4a, 5,6,7,8,8a, 9-octane-4a, 8a-trans The -1H- -pyrroloV2,3-g!) isoquinolin-4-one is substituted on the isoquinoline nitrogen atom. 6. The method according to p. 2. A process as claimed in claim 2, characterized in that for the preparation of 2-methyl-3-ethyl-6- [4- (4-3- fluorophenyl-M-oxobutyl] -4.4a, 5, e, 7.8.8a, 9-octal) hydro-4a, 8a, trans-1H-pixolo (2,3-g) isoquin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9- octahydro-4a, 8a-trans-lH-pyrrolo (2,3-g) isoquinolin-4-one is displaced at the isoquinoline nitrogen atom. M. 7. The method according to p. 2. A process according to claim 2, characterized in that for the preparation of 2-methyl-3-ethyl-6V2-hydroxy-3,3-dimethylbutyl) -4,4a, 5,6,7,8i8a, 9-hydrogen-4a, 8a -trans-1H-pyrrole (2,3-g) isoquinolin-4-one, 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octane-4a, 8a-trans-1H-pyrrole (2,3-g) isoquinolin-4-one is substituted at the isoquinoline nitrogen atom. 126 872 CIS FORMULA A FORMULA 1 "a R" CCrt "! IZH FORMULA 1 O CH3T" |, "R- HIH trans FORMULA Ta N ^ R- R, N R- N" R. H FORMULA 2 H FORMULA 1 "R / H" N -rR- 1 XN ^ RHH FORMULA 2 'fy. HN R. 1 L H ^ R2 H PATTERN 2 "K 0 N PATTERN 15 'X' N ^ R. I 'H H ~ N. R- PATTERN 16 N ^ R ^ I H R,' N R: N ^ R H PATTERN 2 SCHEME 2 C2H5OCNH OCH. CH3NH PATTERN 6 H: PATTERN 3 OCH3 PATTERN 5 SCHEME 3 (C7.I) O CHQNH + X + Zn O HON "R2 I ^ N R2 PATTERN 6 PATTERN 7 PATTERN 8 O CH3NH Ro 1 II - ^ Lh3 OXI 2 H R- : nC "I 2 H PATTERN 9 PATTERN la SCHEME 3 (czJI) C- CH O 2 126 672 CH. PATTERN 23 PATTERN 20 O C CrUCrU PATTERN 2k CCH2CH2CH2 P PATTERN 21 OCH2CH2CH2 PATTERN 25 H-N X R. X H PATTERN 15 Rf; N - aLkiL FORMULA 17 CH2CH2 FORMULA 22 D ^ CH, FORMULA 18 FORMULA 19126 672 C6H5 C6H5; CHCH2CH2 HX - H3C; ch-ch2 FORMULA 26 FORMULA 29: H30_CVCH2CH2 CL- MODEL 27 FORMULA 30 O II C6-CH5 ^ CHCrU CHo CHn H2CN CH2 TH2 ': hch. in VZ0R 31 FORMULA 32 COOCH2CH2 FORMULA 33 N 'CH2CH2 AND CH3 FORMULA 3 /, 126 672 C00CH2CH2CH2 0 N-CH2-CH2 FORMAT 35 FORMAT 38 CH2CH CH2 I I OH OH 7 Vch. CL / \ PATTERN 36 PATTERN 39 PATTERN 40 CH9 — CH - 1 1 1 1 0 0 \ / c / \ 3C CH3 PATTERN 37 -CH2 CH- CH CH3 PATTERN 42 H3C CH3 C CH ~ PATTERN 43 'Cl OCH2- OCH- PATTERN 41 OH -N MODEL 15 R- N ^ RH MODEL 1 MODEL 44 SCHEME 1126 672 O CH3-N MODEL la ^ KN ^ R and HOO C2H50-CN R, FORMULA 13 HN 1 li i ^ HOR 3 i IN ^ R: H PATTERN 15 SCHEME OCH, OCH, CH3NI CH3-N OCH3 FORMAT 4 OCH, OCH3 FORMULA 10 CH3-N OCH: FORMULA 11 O CH3N 0cV ^ R3 ° "V ^ R3 O HON R2 H2N R2 FORMULA 12 O * CH3- N MODEL 1a FORMULA 7 Or FORMULA 8 R3 1 1 1 with H SCHEME 5 Y5 HON R2 OCH, CH3NH sv- Knorr reaction OCH- O CHoNH. R3 Mannich reaction N- ^ Ro 1 with H a'i ± ix: N ^ R- l H SCHEME 6126 672 O o «cca3 -». «^ -" cóx! Ri 2 i * 2 R, SCHEME 7 r ^ o-tA /: - rvAx3 N ^ R2 OH ^^^ N ^ R2 R1 Ri SCHEMAT 8 National Printing House, Plant No. 6, 440/85 Price PLN 100 PL