CS242900B2 - Method of octahydro-1h-pyrrolo(2,3-g)-isoquinolines production - Google Patents

Description

R ₂ and R are independently alkyl of 1-7 carbon atoms, an alkyl group having 1-7 carbon atoms, a hydroxyalkyl group having 1-7 carbon atoms, fenylhydroxyalkylovou group having 1-7 carbon atoms in the alkyl part, halogenfenylhydroxyalkylovou C 1 -C 7 alkyl, C 1 -C 7 alkoxyalkyl, C 1 -C 7 aryloxyhydroxyalkyl, C 1 -C 7 arylcarbonyloxyalkyl, arylcarbonylalkyl (C 1 -C 7) alkyl group, (C 1 -C 7) alkoxycarbonylalkyl, (C 1 -C 7) arylalkyl, (C 3 -C 6) cycloalkyl (C 1 -C 7) cycloalkyl) C 1 -C 7 alkyl, C 1 -C 7 arylcarboxamidoalkyl; alkyl moieties, alkanoylalkyl having 1 to 7 carbon atoms in the alkanoyl and alkyl moieties, aroylalkyl having 1 to 7 carbon atoms in the alkyl moiety, alkenyloxyalkyl having 2 to 7 carbon atoms in the alkenyl moiety and having 1 to 7 carbon atoms in the alkyl moiety, arylalkenyl of 2 to 7 carbon atoms in the alkenyl moiety, aryloxyalkyl of 1 to 7 carbon atoms in the alkyl moiety, N-methylpyrrolidinylalkyl of 1 to 7 carbon atoms in the alkyl moiety or a group of the formula

where

R is C 1 -C 7 alkylene, and

Rg and R? independently of one another are hydrogen or C1-C8alkyl or together with the nitrogen atom they are morpholino, and

X represents an oxygen atom or, when R R represents an arylalkyl group having from 1 to 7 carbon atoms in the alkyl moiety, it also represents a sulfur atom, the aryl present in the radicals defined above being phenyl or phenyl substituted by 1 to 3 substituents selected from halogen, trifluoromethyl, C1-C7alkyl, C1-C7alkoxy, nitro, amino, C1-C7alkylamino and C1-C7alkylamino; furthermore, the optical and geometric isomers of these compounds and the pharmaceutically acceptable acid addition salts thereof.

The term alkyl, as used herein, refers to a straight or branched saturated C 1 -C 7 hydrocarbon group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl , a pentyl group, a heptyl group, and the like.

Alkoxy means an alkyl ether group in which the alkyl group is an alkyl group having 1 to 7 carbon atoms as described above, such as methoxy, ethoxy, propoxy, pentoxy, and the like.

Alkenyl is a straight or branched unsaturated hydrocarbon group having 2 to 7 carbon atoms, such as vinyl, allyl and the like.

The term halogen refers to halogen atoms bromine, chlorine, fluorine and iodine.

The term aryl means a phenyl group or a phenyl group having one to three substituents for halogen, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, nitro, amino, C 1 -C 7 alkylamino, and dialkylamino having 1 to 7 carbon atoms in the alkyl moieties.

The term arylalkyl preferably means a benzyl group and the like.

The term aryloxy means an aryl ether group in which the aryl group is a group as described above, such as a phenoxy group and the like.

Alkanoyl means a radical derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, such as, for example, formyl, acetyl, propionyl and the like.

An aroyl group is a group derived from an aromatic carboxylic acid such as a benzoyl group and the like.

The term cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Preferred compounds of formula (A) are those wherein C 1 -C 7 alkyl, C 1 -C 7 hydroxyalkyl, C 1 -C 7 phenylhydroxyalkyl, C 1 -C 7 halophenylhydroxyalkyl in the alkyl moiety, alkoxyalkyl of 1 to 7 carbon atoms in the alkoxy and alkyl moieties, aryloxyalkyl of 1 to 7 carbon atoms in the alkyl moiety, arylcarbonylalkyl of 1 to 7 carbon atoms in the alkyl moiety, or arylalkyl of 1 to 7 carbon atoms in the alkyl moiety, wherein the aryl in the above substituents is as defined above, and X is an oxygen atom.

The most preferred compounds of formula A wherein X is an oxygen atom produced by the process of this invention are the following:

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 (-) - 3-Ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline -4-one, (-) - 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [3,3] isoquinolin-4-one hydrochloride. 0.25 mol-hydrate,

2-methyl-3-ethyl-6- (2-hydroxy-2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2, 3-g] isoquinolin-4-one,

2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,3.6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride,

2-methyl-3-ethyl-6-benzyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- he,

2-methyl-3-ethyl-6-benzyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4 -one hydrochloride,

2-methyl-3-ethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, <

2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one.

2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, 5,6,7,8,8a-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline- 4-on hydrochloride.

2-methyl-3-ethyl-6- [4- (4-fluorophenyl) -4-oxobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H- pyrrolo [2,3-g] isoquinolin-4-one,

2-ethyl-3-ethyl-6- [3- (4-fluorophenyl) -3-oxopropyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-1H-pyrrolo [2] -3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (3-phenoxypropyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, _H

2-methyl-3-ethyl-6- (2-hydroxy-3-methylbutyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolof2,3- gIsoquinolin-4-one,

Μ

2-methyl-3-ethyl-6- (2-hydroxy-3,3-dimethylbutyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [ 2,3-g-isoquinolin-4-one a

2,6-dimethyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one- hydrochloride dihydrate.

Examples of other compounds of formula A wherein X is O are;

_3-t ety1-2 6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-pyrrolo £ 2,3-g] isoquinolin-4-one, (+) - 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, (+ -3-Ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- on-hydrochloride. 0.25 mol-hydrate,

3,6-dimethyl-2- (2-propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride,

3,6-dimethyl-2- (2-propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-3-butyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (2-hydroxy-2- (4-chlorophenyl) ethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo ~ 2,3 -g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (2-hydroxyethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-6-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one- hydrochloride. 0.25 mol, hydrate,

2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride-0,2 mol . hydrate,

2,6-dimethyl-3-cyclopropyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (2-dimethylaminoethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ-pyrrolop, 3-g] isoquinolin-4-one, ethyl ester 3 -ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-4-pyrrolo [2,3-g] isoquinolin-4-oxo-6-acetic acid,

2-benzyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4-pyrrolo [2,3-g] isoquinolin-4-one,

3,6-dimethyl-2- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-dimethyl-2- (2-propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-Ethyl-2-methyl-6- [2-hydroxy-3- (4-chlorophenoxy) propyl] -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3] -gJ-isoquinolin-4-one

3,6-diethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolof2,3-g] isoquinolin-4-one,

2-methyl-1-3-ethyl-6-propy 1-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6-butyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2-methyl-3-ethyl-6-pentyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,6-Dimethyl-3-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (2-hydroxy-3- (4-tert-butylphenoxy) propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2] 3-g] isoquinolin-4-one

3-ethyl-2-methyl-6- [2-hydroxy-2- (4-chloro-3-trifluoromethylphenyl) ethyl] -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolop 3-g] isoquinolin-4-one

3-ethyl-2-methyl-6- (2-hydroxy-2-adamantylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline- 4-on,

3-Ethyl-2-methyl-6- [2- (4-morpholino) ethyl] -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline -4-on,

3-ethyl-2-methyl-6- [2-oxo-2- (4-fluorophenyl) ethyl] -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (2-methylpropyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6-hexyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6-heptyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (4-methoxy-2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline,

2,6-dimethyl-3-ethyl-1- (1-oxobutyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolop, 3-g] isoquinolin-4-one,

3-ethyl-2-methyl-6- (4-chloro-2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline- 4-on,

2,6-dimethyl-3-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one,

2,3-dimethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-ΙΗ -pyrrolo [2,3-g] isoquinolin-4 -he,

2,3-dimethyl-6- [4- (4-fluorophenyl) -4-oxobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [ 2,3-g] isoquinolin-4-one,

2,6-dimethyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-cis-1H-pyrrolo [2,3-g] isoquinolin-4-one,

The most preferred compound of formula A produced by the process of the invention wherein:

X is a sulfur atom, is:

2-methyl-3-ethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4-thione.

The compounds produced by the process of the invention may exist as 4a, 8a-trans, or 4a, 8a-cis isomers or as mixtures thereof. Preferred are the 4a, 8a-trans isomers.

The compounds of the above general formula A, their optical and geometric isomers and their pharmaceutically usable acid addition salts are prepared according to the invention. wherein the compound of formula XV

H.

(XV) in which

^R 3 ^and X are as defined above, substituted on the nitrogen atom of the isoquinoline by reaction with a compound providing the remainder of the above meaning, the resulting mixture of cis and trans isomers optionally being isomerized to a final ratio in which the trans is predominantly the isomer, and / or the trans isomer is optionally separated from the obtained mixture, and / or the racemic mixture is optionally resolved into optical antipodes and / or the obtained compound or a pharmaceutically unusable acid addition salt thereof is optionally converted into a pharmaceutically usable acid addition salt .

In particular, the compounds of the above general formula (A), their optical and geometric isomers, and their pharmaceutically usable acid addition salts, as well as the various intermediates, as illustrated below, can be prepared.

Thus, for example, compounds of formula A in which X is oxygen are characterized by formula I

in which

R ₂ , R ₃ and are as defined above, and can be prepared as outlined in Scheme I below.

Reaction Scheme I

(XVI (i)

H f

wherein in the above scheme the symbols and R 1 are as defined above.

According to Reaction Scheme I, compounds of formula (X) are prepared from a secondary amine of formula (XV '), i.e., starting materials for the preparation of numerous derivatives of formula (I), by substitution at the basic nitrogen atom of the amine (N-6). Thus, for example, reacting a compound of formula XV '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 acetone, 2-propanone or dimethyl an appropriately substituted compound of formula (I) wherein R 1 is alkyl, alkenyl, cycloalkylalkyl, or aralkyl.

The reaction with reactive halides can be carried out at room temperature. The reaction with less reactive halides is carried out at reflux and in many cases the reaction rate can be increased by adding an iodide such as lithium iodide to the reaction mixture.

Reaction of a compound of formula XV with epoxyalkanes provides a hydroxyalkyl substituted compound of formula I. Reaction with a substituted apoxyalkane provides 2-substituted 2-hydroxyalkylderivatives of a compound of formula I, for example reaction of a compound of formula XV 'with styrene oxide 2-phenyl-2-hydroxyethyl. The reaction is generally carried out in the presence of an alcoholic solvent, such as methanol, at a temperature from about room temperature to the reflux temperature of the reaction mixture.

Epoxyalkanes are either commercially available or are produced by epoxidizing the respective olefins or methylating the ketone with a sulfonium methylide or a sulfoxonium methylide, for example dimethylsulfonium methylide. Thus, for example, the reaction of benzaldehyde with dimethylsulfonium methylide provides styrene oxide.

In the reaction described in Reaction Scheme I, both trans-isomers of Formula I 'may be formed

HQ _(I \ x wherein

R ^, R ₃ and R ^ are as defined above, as well as the cis-isomers of Formula I *

wherein ^R 2, ^R 3 ^{and R} 4 are as defined above for compounds of Formula I, the trans-isomer predominating in the mixture. The pure trans-isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described below for the isomerization of the trans- and cis-isomers of the oxo compound of formula I'a and Ia.

Compounds of formula A wherein X is sulfur are characterized by formula II

»

WITH

Němž in which

R ₂ and R 1 are as defined above and are arylalkyl group having 1 to 7 carbon atoms in the alkyl moiety, wherein aryl is as defined above, may be prepared as follows:

Reaction Scheme II

(XVV (XV) (II) where

R _2, R and R are as defined above,

According to Reaction Scheme II, a compound of formula XV is reacted with phosphorus pentasulfide to form a thione of formula XV. If the compound of formula XV contains no functional group that can react with phosphorus pentasulfide, except for the 4-oxo group, the compound of formula XV can be converted to the compound of formula XV 'directly by heating with phosphorus pentasulfide in an inert organic solvent.

Following! Conversion of compounds of formula XV to compounds of formula II is carried out similarly as described in Reaction Scheme I for an analogous oxo compound of formula XV when converted to compounds of formula I.

In these reactions, both trans-isomers of formula (II ') may be formed,

in which

R _2, R and R are as defined above, (II) and cis-isomers of formula II

Η H in which

R ₂ and R are as defined above, compounds of formula II, wherein the predominant trans-isomer. The pure trans-isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described below for the isomerization of the trans- and cis-isomers of the oxo compound of formula I'a and Ia.

Compounds of formula XV which are used as starting materials can be prepared by the methods outlined in Reaction Schemes III, IV and V, as well as in the following.

Reaction Scheme III

_.— ->

CH.

R3

Rj (Ia) wherein

R. and R1 have the above-mentioned meanings.

According to Reaction Scheme III, compounds of formula IV are prepared by reacting a primary amine of formula XIV with ethyl chloroformate to give a urethane of formula III which is reduced with luthium aluminum hydride to the N-methylamine of formula IV. In addition, compounds of formula IV can be prepared by reductive alkylation of compounds of formula XIV using formaldehyde and sodium cyanoborohydride under known conditions (cf., for example, R. F. Borch, J. Am. Chem. Soc., 93, 2897 (1971)). Birch reduction of amine (IV) with lithium in the target. butanol containing ammonia provides the dihydroamine of formula V.

Other variations of the Birch reduction may also be used. Thus, an amine of formula IV can 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 tert-butanol. The reaction is generally carried out at or below the boiling point of the solvent, for example at -78 to 15 ° C. If ammonia is used, the reaction is carried out under reflux. Optionally, co-solvents such as diethyl ether or tetrahydrofuran may be added.

The hydrolysis of the dihydroamine (V) is readily accomplished by conventional methods of hydrolysis of enol ethers, for example by treatment with aqueous acid. Examples of useful acids include hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid, and perchloric acid. These acids can be used in aqueous solutions or in mixed solvents.

At least two equivalents of water per mole of dihydroamine and more than one equivalent of acid are required. Examples of useful solvents include tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile. For example, hydrolysis of the dihydroamine V in 2N hydrochloric acid at room temperature or higher in aqueous acetic acid is carried out at temperatures between 40 ° C and reflux to give the diketone VI.

The diketone of formula VI is condensed to a dihydroindoloneethylamine of formula IX by Knor condensation. Knorr condensation is a well-known process for producing pyrroles and can be carried out in various variations (see, for example, J. M. Patterson, Synthesis, 281, 1976 and references cited therein). This process is carried out, for example, by reacting an isonitrosoketone of formula VII in the presence of a reducing agent, for example zinc in aqueous acetic acid or hydrochloric acid, and proceeding via an aminocarbonyl compound of formula VIII which is then condensed with a diketone of formula VI to a dihydroindoloneethylamine of formula IX.

Further, the condensation can be carried out using an aminocarbonyl compound of formula VIII or intermediates (precursors) thereof, such as an aminoketone hydrochloride or an acetal derivative of aminoketone or aminoaldehyde. The use of aminoketone or aminoaldehyde intermediates is advantageous since such substances readily tend to self-condense. They can be produced preferably in situ, where the aminocarbonyl component is released in the presence of diketone of formula VI.

The aminocarbonyl component reacts immediately to form the dihydroindolonethylamine of formula IX. The dihydroketone VI does not necessarily have to be isolated before the Knorre condensation is performed, since the reaction conditions used are sufficient to hydrolyze the dihydroamine V to the diketone VI. The Knorr condensation is preferably carried out at a pH of from about 2 to 6. At a pH substantially greater than 6, there is a significant loss in yield due to the formation of products resulting from the self-condensation of the aminocarbonyl compound of formula VIII.

Preferably, the isonitrosoketone of formula VII and the zinc powder are condensed in aqueous acetic acid with a diketone of formula VI to form the dihydroindoloneethylamine of formula IX.

The Knorr condensation is preferably carried out at temperatures ranging from about room temperature to the boiling point of the reaction mixture. Isonitrosoketones of formula VII are known compounds (see, for example, Ferris, J. Org. Chem., 24, 1726 (1959)) or can be readily prepared by nitrosation of the corresponding ketones, such as alkyl nitrite, or in the case of strongly acidic β-diketones or β. -ketoesters with sodium nitrite. Examples of isonitrosoketones useful in Knorr condensation include:

2-Isonitroso-3-pentanone

2,3-butanedione monoxime,

2-Isonitroso-4-methyl-3-pentanone

2-Isonitroso-3-hexanone

2-Isonitroso-3-heptannone

3-Isonitroso-4-methyl-2-pentanone

2-Isonitroso-1-cyclopropyl-1-propanone

3-isonitroso-5-hexen-2-one, cyclopropyl-2-isonitroso-1-propanone and 3-isonitroso-4-phenyl-2-butanone.

Examples of aminocarbonyl compound intermediates useful in Knorr condensation include the following:

aminoacetaldehyde dimethylacetal; and 2-amino-3-pentanone hydrochloride.

The amine of formula IX is converted to the compound of formula Ia by an intramolecular Mannich reaction. The Mannich reaction is usually carried out using a ketone and a dialkylamine salt, for example dimethylamine hydrochloride and formaldehyde (for example in the form of an aqueous solution such as paraformaldehyde or as trioxane) in an alcoholic solvent such as ethanol at reflux. In an embodiment described herein, the acid addition salt of the hydroindolone ethylamine of formula IX is reacted with formaldehyde, which is added in the form of paraformaldehyde, trioxane or in the form of aqueous formaldehyde in a solvent.

Examples include high boiling solvents containing hydroxyl groups such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether, high boiling polar aprotic solvents such as dimethylformamide, N-methylpyrrolidinone or diethylene glycol dimethyl ether, low boiling polar solvents such as ethanol, butanol, or ethanol; or low boiling aprotic solvents under pressure, such as dioxane or tetrahydrofuran, at a temperature in the range of about 135 ° C to about 200 ° C to give the pyrrolo [2,3-g] isoquinolines of Formula Ia. This reaction leads, in particular at temperatures below 150 ° C, to a mixture of cis- and trans-isomers, i.e. to compounds of formulas I'a and Ia.

Longer heating of the reaction mixture or separate heating of the mixture of isomers of hydrochlorides of formulas I'a and Ia, for example in ethylene glycol for two hours under reflux, can achieve the final balance of cis and trans isomers, where the trans isomer is predominantly present. , which can be easily isolated by crystallization or chromatographic separation.

Preference is given to reacting dihydroindolone ethylamine hydrochloride XI with paraformaldehyde in octanol at 180 DEG C. for 2 hours, whereby the product is isolated almost exclusively in the form of the trans-isomer of formula I'a.

Reaction sc '‘' 2 3

(la) (XIII) (XV)

Demethylation at the nitrogen atom of the compound of formula Ia can be carried out according to conventional standard procedures for dealkylaoi at the nitrogen atom, such as by the Braun method (HA Hageman, Org. Reactions, 7, 198 (1953)) or via hydrolysis with acids or bases of urethane derivatives. Rice (J. Org. Chem. 40: 1850 (1975)). The process for dealkylaoi of a compound of formula Ia proceeds through urethane of formula XIII and hydrolysis with acids to form the sec-amine of formula XV '. Thus for example a compound of formula Ia wherein R ₂ is methyl and R represents an ethyl group, boiled in diethyl ketone with an excess of ethyl chloroformate and potassium bicarbonate for 3 hours under reflux, to afford a compound of Formula XIII wherein R ₂ is and R a represents an ethyl group.

Hydrolysis of the above compound with concentrated hydrochloric acid in acetic acid at reflux for 24 hours affords a compound of formula XV wherein R ₂ is methyl and R 1 is ethyl. The same compound is obtained by hydrolyzing the urethane of formula XIII with sodium hydroxide in refluxing ethanol.

Reaction Scheme V

(la) wherein

R ₂ and R ₃ are as defined above.

A further synthesis for the preparation of compounds of formula Ia is described in Reaction Scheme V, whereby an isoquinoline ring is formed prior to the formation of the pyrrole ring. According to Reaction Scheme V, the (3,5-dimethoxyphenyl) ethylamine of formula IV is refluxed with aqueous formaldehyde to give the tetrahydroisoquinoline of formula X. The Birch reduction of the tetrahydroisoquinoline of formula X with lithium in target. of butanol containing liquid ammonia under virtually the same conditions as described for the Birch reduction of the compound of formula IV provides the hexahydroisoquinoline of formula XI.

Hydrolysis of the crude hexahydroisoquinoline of formula XI under the same conditions as described for the hydrolysis of the dihydroamine of formula V provides a diketone of formula XII. The compound of formula XII is reacted with a Knor condensation as described in the preparation of the dihydroindolonethylamine of formula IX with an isonitrosoketone of formula VII or an aminocarbonyl compound of formula VIII to give a pyrroloisoquinoline of formula Ia.

Preferably, the reaction is in the order of Reaction Scheme V, starting from an amine of formula IV, which leads to the corresponding N-methylpyrroloisoquinoline of formula Ia, namely in the form of a mixture comprising a trans isomer of formula I'a and a cis isomer of formula of formula Ia.

In order to obtain mainly the trans-isomer of the formula I * and the same operating procedures can be used for the isolation of the mixture of pyrroloisoquinolines of the formulas I‘a and Ia.

The compounds of formula (A) form addition salts with inorganic or organic acids. Thus, the compounds form framaceutically useful addition salts with both pharmaceutically usable organic acids and inorganic acids, for example with hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, other mineral acids such as sulfuric acid, nitric acid, phosphoric acid, or with similar acids, alkyl and monoarylsulfonic acids such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like .

Pharmaceutically unusable acid addition salts of the compounds of Formula A can be converted into pharmaceutically usable acid addition salts using conventional exchange reactions to replace the pharmaceutically unusable anion with a pharmaceutically usable anion, or on the other hand by neutralizing the pharmaceutically unusable acid addition salts and subsequent reaction. the free base thus obtained with an agent providing a pharmaceutically acceptable acid addition salt. Acid addition salts may also form hydrates.

The compounds of formula A and their pharmaceutically usable acid addition salts show neuroleptic activity. However, these compounds are not markedly hypotensive and exhibit only weak cataleptic activity. Consequently, the compounds of formula A are useful as antipsychotic agents, for example in the treatment of schizophrenia. The activity of the compounds of formula A, based on which can be used as antipsychotic agents, can be demonstrated by known methods on warm-blooded animals.

For example, according to one method, trained rats are placed in experimental cages equipped with a reaction lever, a steel wire bottom to impart an electric shock, and a loudspeaker for acoustic stimulation.

Each experiment consists of a warning tone of 15 seconds (conditional reflex), which continues for a further 15 seconds and is accompanied by an electric shock (unconditional reflex;

1.0 mA, 350 V AC). Rats can terminate the experiment at any point by depressing the reaction lever. The reaction during the first 15 seconds of the warning tone terminates the experiment before a shock occurs and is considered a defensive reaction, while the reaction that occurs during the shock is an escape reaction. The experiments are performed every 2 minutes during the one-hour duration of the experiment (30 experiments per test duration).

Trained rats show a reliable baseline in defense behavior (0 to 3 negative defense reactions over the duration of the experiment). At least 3 to 4 rats are dosed with the compounds at each dosing amount over the appropriate dosage range at appropriate time intervals. During the test, only the vehicle alone is administered to control rats. Every week, the check changes per attempt and vice versa.

Each experiment time is divided into 3 consecutive 20-minute intervals (10 trials). The number of responses for all specimens are added at a given dose within each Time Interval.

The number of experiments in which the rats showed no defense response (defense blocking, VB), or no escape target (escape blocking, FB) was determined for the time interval at which the maximum effect was achieved at each dose. This number is a percentage of all experiments that are performed over a period of time.

The dose calculated for 50% blockade of the defense effect (VB 50) sc is obtained from a regression curve indicating the ratio of the dose to effect values determined by the least squares method.

The lowest dose that elicits 20% of the escape reaction block (FB 20) is read from the diagram that shows the ratio of the effect value in percent versus the logarithm of the dose.

Antipsychotic agents differ from other types of active ingredients that adversely affect the behavior of rats in this test, by the greater difference between doses that block the defense response and doses that block the escape reaction. The clinical intensity of action of antipsychotic drugs with known therapeutic applications and properties depends very much on the intensity of their action in this test. As a result, the compounds of formula A can be used therapeutically at dosages that correspond to their effect in the above described assay.

When 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] is used as test substance] isoquinolin-4-one hydrochloride, which has a value of, for example, 350 mg / kg po in mice, then neuroleptic activity in

VB, -q 0.7 mg / kg po and 0.095 mg / kg sc, the neuroleptic activity of the (-) - enantiomer of the above compound can then be observed at νΒ ₅ θ 0.48 mg / kg po

Similarly when 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4 is used as the test substance -on-hydrochloride, then neuroleptic activity was observed at VB _{50 Q} 0.48 mg / kg po

When N-2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo) is used as test substance [2,3-g] isoquinolin-6-yl) ethyl] -4-fluorobenzamide, then neuroleptic activity can be observed at νΒΒ 3,5 3.5 mg / kg after

When 3-ethyl-2-methyl-6- [4- (4-fluorophenyl) -4-oxobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a is used as test substance -trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, then neuroleptic activity can be observed at νΒ, -θ 0.19 mg / kg po

Also when 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] ] isoquinoline-4-thione, neuroleptic activity can be observed at νΒ ^ θ 0,94 mg / kg after

The compounds of formula A and their pharmaceutically usable acid addition salts have antipsychotic effects which are qualitatively similar to those of haloperidol, trifluorperazine and molindone, which are known for their therapeutic use and properties.

Thus, the compounds of formula A exhibit activity comparable to the efficacy and safety of known antipsychics.

The compounds of formula A and their pharmaceutically usable acid addition salts can be used in the form of conventional pharmaceutical preparations. These preparations contain, for example, suitable dosage units for oral administration or contain the active ingredient in the range of 0.05 to 50 mg. Suitable dosages for oral administration in warm-blooded animals range from about 0.001 mg / kg per day and about 10 mg / kg per day. However, for any particular warm-blooded animal, the specific dose may vary and should be determined according to individual requirements and expert judgment by the person administering the compounds of formula A or the pharmaceutically acceptable addition salt or by the supervisor. >

Further, the frequency at which each such dosage form is administered will vary depending upon the amount of active drug present and the requirements of the pharmacological situation.

For use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are admixed with conventional inert pharmaceutical excipients in dosage forms suitable for oral or parenteral administration.

Such dosage forms include tablets, suspensions, solutions and the like. Further, the compounds of formula A may be formulated in the form of suitable hard or soft capsules and are thus administered.

The kind of inert excipients which are used for formulating the compounds of formula A and their pharmaceutically usable acid addition salts for oral and parenteral dosage forms is well known to those skilled in the art. These auxiliary materials are represented by either inorganic or organic substances such as water, gelatin, lactose, starch, magnesium stearic acid, talc, vegetable oils, resins, polyalkylene glycols, etc. Additionally, preservatives, stabilizers, wetting agents may optionally be added to such mixtures. , emulsifiers, salts for influencing osmotic pressure, buffers and the like.

Since the compounds of formula A and their pharmaceutically usable acid addition salts have an asymmetric carbon atom, they are usually in the form of a racemate. The resolution of these racemates into the optically active isomers can be carried out by known methods. Many racemates can be obtained in the form of a eutectic and then resolved. However, chemical cleavage is preferred. The diastereomeric salt is formed from the racemic mixture of diastereomers by the action of a dptically active resolving agent, for example by the action of an optically active acid such as (+) - tartaric acid. The resulting diastereomers can be separated by fractional crystallization and converted to the corresponding optically isomeric bases. The present invention encompasses both optically active isomers of the compounds of Formula A as well as their racemates.

Further, due to possible different spatial arrangements of atoms, it is evident that the compounds of the invention can be obtained in more than one possible geometric isomeric form. The compounds of formula A as described herein and as formulated in the subject invention include all such isomeric forms. Thus, the examples herein are understood to mean mixtures of geometric isomers or individual geometric isomers, and the invention is not limited in this respect.

The following examples illustrate the process of the invention in more detail. All temperatures are in degrees Celsius unless otherwise indicated.

Example 1

Preparation of N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester.

To a 5 L 3-neck round bottom flask equipped with a mechanical stirrer and dropping funnel was added 32.63 g of (3,5-dimethoxyphenyl) ethylamine hydrochloride, 600 mL of water, 600 mL of methylene chloride and 150 mL of 1N sodium hydroxide solution. The mixture was stirred and cooled in an ice bath, 16.28 g of ethyl chloroformate in 60 ml of methylene chloride were added dropwise over 30 minutes. A total of 150 ml of 1N sodium hydroxide solution was added in 8 portions during the dropwise addition to maintain the pH between 8 and 9. After the addition was complete, the mixture was stirred in an ice bath for 1 hour. The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous solution was extracted with 200 ml of methylene chloride and the organic solutions were combined and washed with 100 ml of water and 100 ml of brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator to 37.1 g of crude N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester as a yellow oil.

Example 1a

Preparation of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride

A 3-liter 3-neck round bottom flask equipped with a mechanical stirrer, dropping funnel and condenser was charged with 180 ml of a 70% solution of sodium dihydro-bis (2-methoxyethoxy) aluminate and 700 ml of absolute tetrahydrofuran. The solution is cooled in an ice bath and a solution of 37.1 g of crude N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester in 100 ml of absolute tetrahydrofuran is added over 15 minutes. After the addition, the mixture was heated under reflux for 1 hour and then cooled in an ice bath, the excess hydride was quenched by dropwise addition of 100 ml of 5% sodium hydroxide solution and after all the base had been added, the organic layer was separated and the aqueous layer was extracted. ml of ether.

The combined organic solutions were concentrated to an oil on a rotary evaporator and this oil was dissolved in 300 mL of ether. The ethereal solution was washed with 50 ml of water, 50 ml of brine, dried over anhydrous sodium sulfate, and filtered. Ether (70 ml) was added to the filtrate to precipitate the amine hydrochloride. The solid is collected on a Buchner funnel and crystallized from a mixture of 180 ml of absolute ethanol and 270 ml of ether. 28.9 g of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride are obtained in the form of a white crystalline solid, m.p. 160-164 ° C.

Example 2

Preparation of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine

185.2 g of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride were dissolved in 1600 ml of water and basified with 160 ml of ammonium hydroxide. The mixture was extracted three times with 1000 ml of methylene chloride each time, the combined extracts were washed with 1000 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at a temperature of 35 to 40 ° gave 156.0 g of the free base.

A 12-liter, three-necked flask equipped with a mechanical stirrer and two solid carbon dioxide coolers, a gas supply tube and another tube (driers) filled with soda lime condenses 4.0 liters of anhydrous ammonia. To this ammonia was added a solution of 156.0 g of the free base in 400 ml of tert-butanol and 400 ml of anhydrous ether over 15 minutes.

A total of 33.6 g of 6.35 cm long lithium wire cut into pieces is added to the stirred solution over 50 minutes. The rate of addition is controlled to add 12.7 cm of wire within a minute. After all of the lithium was added, the deep blue mixture was stirred at reflux for 2 hours. Thereafter, 2.8 liters of anhydrous ether was added to dilute the mixture, the drying tubes were removed to allow hydrogen to escape, and a total of 280 g of ammonium chloride powder was slowly added over 30 minutes until the blue color disappeared.

The solid carbon dioxide condenser was removed and the mixture was stirred while ammonia was evaporated overnight. 2.8 liters of ice water are added to the residue. The mixture was transferred to a separatory funnel, rinsing with 800 mL of ether and separating the layers. The aqueous layer was extracted twice with 1.5 L of methylene chloride each time, the extracts were combined, washed with 1 L of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 40 ° and then at 40 ° / 13.3 Pa for 1.5 hours afforded 150.7 g of crude product as a yellow oil. The crude oil was distilled through a 30.5 cm Goodloe column (150 ° bath), collecting the following fractions:

Fractions Boiling point ° C / Pa Mass Purity* 1 40-80 ° / 5.6 Pa 7.9 g 4.6% 2 80-85 ° / 5.6-20 Pa 6.2 g 50,% 3 85-86 ° / 20 Pa 21,2 g 92% 4 86-87 ° / 20 Pa 99.4 g 100%

according to gas chromatography

Combined fractions 3 and 4 gave 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine as a colorless oil.

Example 3

Preparation of 6- [2- (N-methylamino) ethyl-3,2-methyl-3-ethyl-6,7-dihydro- (5H) -4 (1H, 5H) -indolone

A 1 liter round bottom flask equipped with a mechanical stirrer and condenser was charged with a solution of 60.0 g of distilled N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine in 700 ml 70% aqueous acetic acids. The reaction mixture is refluxed for 15 minutes and 59.5 g of zinc dust are added in 5 portions over 10 minutes and the mixture is refluxed for a further 15 minutes, and a solution of 42.1 is added over 1 hour. g of 2-isonitroso-3-pentanone in 175 ml of 70% aqueous acetic acid.

After the addition, the mixture was refluxed for 2 1/2 hours and then cooled to room temperature. The precipitated zinc acetate is filtered off and the filter cake is washed with 500 ml of methylene chloride. The filtrate is concentrated on a rotary evaporator and the residue is heated at 100 ° / 133.3 Pa for 30 minutes to remove the last traces of acetic acid. The residue was dissolved in 500 ml of water and extracted twice with 150 ml of methylene chloride each time.

The methylene chloride extracts are set aside and the aqueous layer is made basic with 165 ml of ammonium hydroxide (pH 8-9), and 500 ml of sodium chloride solution are added. The mixture was extracted three times with 200 ml of methylene chloride each time, and the combined extracts were washed with 100 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 56.0 g of crude tetrahydroindolone dissolved in 90 ml of toluene / ethyl acetate (2: 1). The solution was stirred with a magnetic stirrer and seeded, then crystallized overnight with stirring. The first crop isolated by filtration is 20.8 g of product.

The mother liquor was concentrated and the stirred solution was crystallized again to give an additional product of 10.0 g. The mother liquor was dissolved in 75 ml of methanol and a solution of 15.0 g of oxalic acid in 50 ml of methanol was added. The mixture was heated on a steam bath for 10 minutes and then cooled. The solid oxalate is filtered off and washed with 10 ml of methanol and dissolved in 50 ml of water. The solution was basified with ammonium hydroxide and extracted twice with 50 ml methylene chloride. The extracts were washed with brine (1 x 20 ml) and dried over anhydrous sodium sulfate, and then concentrated on a rotary evaporator to give 4.5 g of additional product (crude product). Crystallization from toluene / ethyl acetate (2: 1) gave 2.6 g of additional crystalline product. Both these amounts and oxalate crystals were combined and dried for 2 hours at 25 ° / 133.3 Pa. 33.4 g of 6- [2- (N-methylamino) ethyl] -2-methyl-3-ethyl-6,7-dihydro (5H) -4 (1H, 5H) indolone are obtained in the form of a slightly yellow solid. Melting point 114-120 °. The product is a homogeneous substance according to thin-layer chromatography.

Example 4 *

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 -hydrochloride

A 500 ml round bottom flask was charged with 17.0 g of 6- [2- (N-methylamino) ethyl-3 '-2-methyl-3-ethyl-6,7-dihydro- (5H) -4 (1H, 5H) indolone and 170 ml methanol. To the solution was added 20 mL of 4N hydrogen chloride in diethyl ether (produced by introducing hydrogen chloride gas into diethyl ether on an ice bath and titrating). The solvent was removed by rotary evaporation and the residue was dried at 50 ° / 133.3 Pa for two hours to give 19.7 g of crude hydrochloride.

In a 3-liter 3-neck flask equipped with a mechanical stirrer, thermometer and distillation head was charged 19.7 g of hydrochloride, 21.8 g of para-formaldehyde and 1000 ml of octanol. The reaction mixture is heated to reflux and the water released is removed by distillation until the octanol solution in the flask reaches 175-180 °, after which the distillation head is removed and replaced by a reflux condenser. 175 DEG-180 DEG C. and 6.54 g of paraformaldehyde are added in 3 portions over 5 minutes. The water was distilled off as before to reach 175-180 ° and the mixture was heated at 175-180 ° for 1 hour.

The dark brown solution was cooled and poured into 1000 ml of water. The layers were separated and the organic layer was extracted twice with 400 ml of 5% hydrochloric acid each. The combined aqueous extracts are washed twice with 150 ml of chloroform each and the chloroform solutions are discarded. The aqueous layer was mixed with 120 ml of ammonium hydroxide and 400 ml of chloroform. The layers were separated and the aqueous solution was extracted four times with 200 ml of chloroform each. The combined chloroform extracts were washed with 200 ml of sodium chloride and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 12.0 g of crude pyrrolo [2,3-g] isoquinoline as a trans-, 4a, 8a-cis (about 8: 1) mixture as a dark yellow-brown solid. The crude solid was dissolved in 100 mL of a 9: 1 mixture of methylene chloride and methanol and then 300 mL of diethyl ether was added.

The fine, solid precipitate, predominantly the 4α, 8α-trans-isomer, was isolated by filtration, and the filtrate was concentrated and crystallized to give an additional portion of a tan solid (second and third fractions). The combined material was dried at 25 ° / 133.3 Pa for 1 hour to give 8.20 g of a light gray solid, i.e. 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, m.p. 203 DEG-226 DEG. The partially purified gray solid was suspended in 80 mL of methanol and 12 mL of a 4N solution of hydrogen chloride in diethyl ether was added.

The solvent was removed and the residue crystallized from 25 ml of hot, absolute ethanol. The first crop is isolated by filtration and the mother liquor is concentrated and crystallized to give the second and third crop crystals. The combined solid was dissolved in 120 mL of methanol and 2.4 g of activated carbon was added. The mixture was heated on a steam bath for 10 minutes and the activated carbon was filtered through diatomaceous earth. The filtrate was concentrated and the residue was recrystallized from 15 ml of ethanol to give an additional white crystal.

The combined solids were dried under vacuum at 80 ° / 6.7 Pa for 18 hours to give 5.4 g of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4α, 8α-trans-1H-pyrrolo {2,3-g] isoquinolin-4-one hydrochloride as a solid, m.p. 196-198 ° C; oxime semi-hydrate, m.p. 131-133 °.

Examples 4a to c

Following the procedures described in Examples 3 and 4, the compound shown in Table 1 is prepared from aqueous isonitrosoketone with the indicated variations. Each compound exhibits spectral features that are consistent with the disclosed structure. Melting points apply to the free base or hydrochloride as indicated. Isonitrosoketones are prepared as described in the literature [e.g., Ferris et al., J. Org, Chem., 24, 1726 (1959) 3] by nitrosation of a suitable ketone. The isolated compounds are the 4α, 8α-trans-isomers.

Table I

OCH,

HUNT

CH ₃ NH

Knorr reaction and ₃

Example

4a

3,6-dimethyl-2- (2-propyl) -4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one ₃ ) ₂

4b

2,6-dimethyl-3-phenyl-4,4a, 5,6,7,8, CH 2

8α, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one

4c

CH,

2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one

Analysis - Temperature calculated by melting

CH, (.HCl)

64.74

8.49

9.44

Cl, 11.94

64.53

8.38

9.36

12.16

Mannich reaction

Crystallizes from

(.HCl) methanol 280280 ° (decomposition)

Production method differences

77.23

7.53

9.52

77.23

7.50

9.54-240 of a mixture of ethanol (decomposition) and ethyl acetate

CH ₃ (.HCl)

C 62.56 H 7.88 N 10.42

C13,19

62.19 7,97

10.20 13,41

275-80 from a mixture (decomposition) of ethanol and ether

Mannich reaction in diethylene glycol monoethyl ether, 155 °, h

Knorr reaction in butanol at 170 ° / 0.35 MPa

Example 5

Preparation of 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one

A mixture of 3 ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one, prepared as in Example 4 ( 4.92 g, 20 mmol), chloroformic acid ethyl ester (19.55 g, 180 mmol) and potassium bicarbonate (6.0 g, 60 mmol) in diethyl ketone (100 mL) were refluxed for 3 hours. Then the reaction mixture was cooled, filtered and the filtrate was concentrated to dryness on a rotary evaporator and the residue was dissolved in chloroform. The chloroform solution was washed with 5% aqueous hydrochloric acid solution, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 4.90 g of crude carbamate which was purified by chromatography on alumina (Stage III activity) to give 3.70 g of pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4,4a, 5 6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one.

The carbamate (3.7 g, 12.2 mmol), glacial acetic acid (45 mL) and concentrated hydrochloric acid (60 mL) was heated at reflux for 24 hours, then the reaction mixture was cooled and concentrated on a rotary evaporator. The residue was dissolved in water and extracted with chloroform (removed), and the aqueous layer was basified with ammonium hydroxide and extracted with chloroform.

The combined extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated to give 2.72 g of crude sec.amine. Treatment of the crude amine in ethanol with ethanolic hydrogen chloride yields the hydrochloride which crystallizes from hot ethanol to give 2.18 g (47% of theory) of 2-methyl-3-ethyl-4,4a, 5,6,7,8, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride as white crystals, m.p. &gt; 250 DEG.

Analysis for C- ^ I ^ q qH O:

calculated: C: 62.56%, H: 7.88%, N: 10.42%, Cl: 12.19%;

Found: C: 62.50%, H: 7.90%, N: 10.19%, Cl: 13.33%.

In a similar way, 2,3-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one can be prepared and from 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one.

Example 6

Preparation of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride

A solution of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride (15.0 g, 64.7 mmol) in 30 mL of water was treated with 35 mL of 2N sodium hydroxide solution and then made with methylene chloride. The combined extracts were concentrated on a rotary evaporator and the residue was treated with aqueous formaldehyde (65 ml, 37% solution). The mixture was refluxed for 2 hours, basified with 2N sodium hydroxide solution (15 mL) and extracted with methylene chloride. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate to give the title compound as an oil (15.5 g).

This oil was dissolved in 100 ml of ethanol and treated with ethanolic hydrogen chloride. Ether (75 ml) was then added, whereupon the salt crystallized out. 10.15 g of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride is obtained (yield 64%).

Example 7

Preparation of 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline and octahydro-2-methylisoquinoline-6,8-dione

Ammonia (150 mL) was condensed in a flask containing tert-butanol (9.1 g, 123 mmol) and diethyl ether (50 mL). To this solution was added 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring for 2-3 minutes, lithium wire (0.57 g, 82 mmol) cut into small pieces is added over 30 minutes. The blue solution was stirred at reflux for 2 1/2 hours, and then solid ammonium chloride (4.5 g) was added until the blue stain disappeared; Ether (100 mL) was then added and the ammonia could be evaporated overnight.

Ice water (100 ml) was then added and the organic phase was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate to give 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, 68% yield). ) in the form of a yellow oil.

The crude product (1.05 g) in 20 ml 70% aqueous acetic acid was refluxed for 5 hours and then the acetic acid was removed on a rotary evaporator. The residue was dissolved in water and washed with chloroform. The aqueous phase is concentrated to a volume of 10 ml and chromatographed (Dowex AG 50WX 8) using 2M aqueous pyridine as eluent to give 0.11 g of octahydro-2-methylisoquinoline-6,8-dione (11.6 yield). %) as a light yellow solid. Treatment with hydrogen chloride in methanol gives the hydrochloride, m.p. 193-196 °.

Example 8

Preparation of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolof2,3-g] isoquinolin-4-one via octahydro-2-methylisoquinolin-6 , 8-dione

1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.68 mmol) was heated to 90-100 ^° in 70% aqueous acetic acid ( 10 ml) to hydrolyze the bis (enol ethers) to octahydro-2-methylisoquinoline-6,8-dione. To the hot solution was added zinc powder (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The reaction mixture was refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate was concentrated to dryness on a rotary evaporator and the residue was dissolved in methylene chloride. Ammonium hydroxide was added to the solution and the layers were separated.

The organic layer was washed with sodium chloride and dried over anhydrous sodium sulfate. Concentration gives the crude product. Chromatography of the crude product on alumina (Stage III activity) gave 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3- gisoquinolin-4-one as a white solid (0.19 g, 29% yield).

Example 9

Preparation of 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

A solution of about 12.5 mmol of crude octahydro-2-methylisoquinoline-6,8-dione and 2.4 g (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 mL of 70% aqueous acetic acid was heated with 2.6 g (40 mmol) of zinc powder are slowly heated to reflux. After 1 hour, the reaction mixture was cooled slightly and an additional 0.4 g of isonitrosoketone and 1.0 g of zinc were added. The reaction mixture was stirred at reflux for 1 1/2 hours. The reaction mixture was then cooled and filtered.

The filtrate was concentrated in vacuo at 50 ° C / 2670 Pa to a yellow oil. This oil was diluted with 50 mL of water and basified with ammonium hydroxide to pH 8-9. The mixture was extracted with chloroform, and the chloroform extracts were washed with brine, dried over sodium sulfate and concentrated to give 2.6 g of crude product. The product thus obtained is chromatographed on 100 g of silica gel (dry column), eluting with an organic phase of a mixture which has been prepared to equilibrate between 90 parts by volume of chloroform, 30 parts by volume of methanol, 10 parts by volume of water and 6 parts by volume of acetic acid.

The eluate fractions containing the product were evaporated, the residue was diluted with water, basified with ammonium hydroxide (pH 8-9) 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-4α, .alpha.-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a crystalline solid, m.p. 244-2.7 °.

242

Example 10

Preparation of 3,6-dimethyl-2- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline -4-one

Similar to Example 9, 3,6-dimethyl-2- (2-propenyl) -474a, 5,6a is obtained from 3-isonitroso-5-hexen-2-one and 2-methyl-octahydroisoquinolin-6,8-dione. 7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 221-223

Example 11

Preparation of 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

Similar to Example 9, 3 cyclopropyl-2,6-dimethyl-4,4a, 5,6,7,8, 3-cyclopropyl-2,6-dimethyl-4,4a, 2-methyl-octahydroisoquinoline-6,8-dione are obtained from cyclopropyl-2-isonitroso-1-propanone, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 258 DEG-259 DEG (dec.).

Example 12

Preparation of 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 onu

In analogy to Example 9, 2-benzyl-3,6-dimethyl-4,4a, 5,6,7-dione is obtained from 3-isonitroso-4-phenyl-2-butanone and 2-methyl-octahydroisoquinoline-6,8-dione. 8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 234-235 ° C.

Example 13

Preparation of 6-methyl-4,4a, 5,6,7,8,8a, 8,9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one

Similarly to Example 9, except that zinc was used to produce 6-methyl-4,4a, 5,6,7,8,8a-octahydro-, from aminoacetaldehyde dimethyl acetal and 2-methoxyoctahydroisoquinoline-6,8-dione. 4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one. Mp 208-210 ° C.

Example 14

Preparation of 3-ethyl-2-methyl-6- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-a] - gisoquinolin-4-one

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 (4.13 mmol) of allyl bromide and 0.85 g (6.16 mmol) of potassium carbonate in 35 ml of acetone are stirred at room temperature for 2 hours and then the reaction mixture is filtered. The filtrate is concentrated and the residue is chromatographed on activity III alumina (0.53 g). degree. 0.40 g of product is obtained. This product is converted to the hydrochloride with ethereal hydrogen chloride, which is recrystallized from ethanol / ethyl acetate to give 3-ethyl-2-methyl-6- (2-propenyl) -4,4a, 5,6,7,8, 8α, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride as a white solid, m.p. 214-217 ° C.

Analysis for ^C 24 ^H i7 ^N ° 2 * ^HC1 * θ ^'5H 2 ° Calculated: 64.24% C, 8.25% H, 8.81% N, 11.15% Cl;

found: C 64.50, H 8.48, N 8.96, Cl 11.37.

Examples 14a to 14dd

Following the procedure described in Example 14 above, from the -4,4a, 5,6,7,8,8a, 9 octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-ones and said halide, the above compounds are obtained. following Table II. The spectral data of the individual compounds were consistent with the structure. Melting points are given either for the free base or for the hydrochloride. The isolated compounds are the 4α, 8α-trans-isomers.

Table II

H> 1 λ:

β w Ή d ε> □

Ό

Ο a

or d β -Ρ> 0 ο 44 Η d and Φ Φ Ρ5 + J β

rd d

4-1 ω ν> 1

D Φ d · γί d

4J

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N d Φ N rd *> · d rd β β

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Φ a

I m

>

β β

Ο β

d «Ρ τί

Ο

Λ

Μ d

>

ε + j> φ a

Ν ι

ο

-Ρ φ

ϋ d

>

Ί3

Ο a

Ρ d

>

ε β

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I ο

4-1

Φ

Ο d

>

• Η> Φ β

4-1 d 'd 4->

β d Ο>>>>>>>>

ιη σ>

ι — Ι 'ι — 1 <\ | CM

Ν * η κο ι-ι cn η η ιη l £> what co ο \ Ο ι-Ι &>

cn ιη co ιη m ι - ι ιη co (Α οο ω ο kO rd β

rd

Ο β

d

4-3

Φ

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ω γ · σ> σι> Ν d

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Γ-Ι <Γι <*>

Γ 1-4

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Φ

I ΐ £>

Ό d

rd

Ή> Ρ βι and ιη 44 0 * 0 Ρ d I and ν σ »0 rd ν * d

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Ν '

Ν '

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Ν β

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β

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9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinoline242900> 1 Λί β (

I β

• μ β

β • μ β

φ β »

Β β β + J> Ο Ο Λ4 Η (β β Φ φ 05 -μ> 1 • μ

Φ ω ν> 1 μΦ · · π + J

Ο rH μ & β ΦΜΰ υ

# '> Ι β η β —κ ιΰ <# <Ο β Φ> υ ο

β »£

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Η> ι • μ

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μ > 1 TO β Ο • Η > 1 κ μ C m 0 4- » 00 μ Λ 4-> WHAT « μ Η 3 3 to μ Ο Φ fc > 1 Λ Γ— ( γΜ X r * O > p 0 rH γ — 1 Γ- Λ □ > 1 Μ-Ι O μ β » IN) > 1 > 1 fc O Ο 4J X <0 Ό • Η Ρ β <0 μ β Φ O fc > 1 and 1 β Φ φ fc Ό γΗ • μ ό β · - m Λ ι — 1 ΓΖ3 θ β m m > 1 ΓΠ β fc β 3 »1 «. X! W tn rd CN χ »· β μ ω 1 CN <Ν β β β β Λ4 • U_1 ί · Λί β Μ 1 > * 3 * μ β WHAT 0 Ή Ό Ο r — t Ο β - β Φ υ fc AND! μ fc 1 Mm β \ Ο > 1 μ CM Ή β \ £> Ί * Ο +4 <Ν -φ Οι τΗ μ β σ> μ 1 — ί Η γΜ μ IF 1

β μ

'β> Ν β ο co m <-I γΚ CN (Ν m οο οο <3 * LT> NN (Ό 00 CO β φ I I (Ν CM □ I β <ο μ ι

-octahydro-4α, 8α-Cl: 10.40, 10.64

-trans-1H-pyrrolo [2,3-g] isoquinoline27

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I -Prolo [D] * - i-octahydro-4a, 8a-tra 1H-pyrrolo-2,3-g]

Example R R R. Y Analysis Crystal Temperature - The reaction conditions calculated melting point is from temperature t i

ti • μ fi o

Oj

Ό

O

X!

fi

0)

J ko r r CM <<<cm cm cm cm CM CM CM CM CM CM CM

CM 00 m σ \ kO Ok Ok r <· Ok in ko msi <*> in

I fi cd Φ> i m +>

O

X β O + J CM V I ε ΓΊ rr? 7

Ol I 1 fi

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fi ti rX

0)

Ό * 0> 1 43 n

O ¹ O 1 (0 r μ O cd O O O j j j j O IO> 1 Λ! Β ι

Β β C -Ρ> υ ο Η β Οι φ φ Ρ Λ Λ Λ Λ Φ

Ρ

Ο

Η Μ Οι β Φ * β Η Ρ Ο

Ο β

Φ

Β β φ Ν «-Ι '> 1 β Η β _

2

Φ

Ρ

Μ> Ρ &

β

Ή

Ό

Ο

X!

η οο σι ΓΟΕ £ ι — I Ο

Ε ο

ο m

ο ιι> 1

Ρ φ

> ♦

Ρ

Φ

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Φ

Λ

Ρ

Φ

Ρ β

φ

<ι <η οο οο σ> οο οο

Ε υ

Ε υ

II

Ε ο

ι ο

Μ

Ό> ι ή Λ I CO CO CO £ 3 * »

I 00 β σ> ι ι w ro β * β <Ν Ρ> —4 Ρ ο I Η β ο> 1

Ρ

Φ e

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CN

AND

Ο> Ρ * Οι Χ> I> 1 β Ρ φ φ Ρ ro ro

Ο I ο

Ρ

Ό

WITH

XJ β

Ρ

Λ4

Ο> Ί β

Φ

Οι

I • χ χ:

ο ο

> 1 β

Ή

Ό

Ο χί m m m «κ ιη

00 lo lo σ m <Χ> 3 <Μ ¹

00 00

Ε υ

υ

Ο

Ο

-hexahydro-2-methyl-4-oxo-1 ', 4H-pyrrolo [2,3-g] isoquinolines:

>.

Λί β w M β ε> υ Τ 3 ο ίλ

Ρ <0 CU Φ Φ Ρ ω ν> ι

Φ φ ·4 · η β

Ρ ο

1 Μ & β φ χ Η Ρ ίΰ φ Ν Ρ '> 1 <0 <-1 β β β <Ο β φ Ρ> υ ο Λ>. >

ι (0

Ρ β

φ

Λ ο

β cd

Ρ η σι σι σι m σι σι>

ύ «ζ ι — ι υ

kO 00 Γ9 ΓΟ (Ν (Ν ω φ ie co ρ η

Η CO Φ

WHAT

C0 Ρ k £>

> (Ν η η ω ω nj ρ

β φ

&

ΟΊ

Κ

AT

W υ

m «υ υ p

AT

WITH

U / \

1 γ-1 AND td ρ 1 • Η Ρ 1 AND φ 1 1 AND 1 00 1 0 > 1 r- 1 0 0 γ — 1 ε X β 0 0 1 X 1 ω > 1 Ρ 1 0 Ρ β >. AND 00 ρ Ρ β Ρ r- ΓΊ 1 • Ρ Ρ β Γ \) kO Ρ Ρ Η β (Ν X 1 Ρ • Η V_4 X 1 » Γ ~ Χ φ Ρ 1 κ τ3 > 1 Χ3 φ AND Γ- 0 > 1 Χ3 1 kO ο Ρ σ> 1 — X 0 ι — 1 ιη > 1 & 0 Ρ Ρ Ρ Λ υ , <Ν Ρ 1 1 'ρ ¹ ι— ( Λ 1 0 • Ρ > 1 kD * 0 1 0 U-J ιη Ό 0 Ρ > 1 Λί Ρ ίΰ ίΰ « w Τ3 Ρ X > 1 « ω 1 X > 1 X X r > 1 Φ ρ Ρ Ρ • Η 1 Φ ιη XJ ίΉ • ρ ω β -β 0 Ρ. kO Ο 1 «. λ; 1 Γ ~ Ρ ρ 1 X β 1 ř-p β Ρ β 1 (___J AND what ρ 0 ω ρ β Ρ ω ’Σι β β Ρ Ρ 0 β 'φ > 1 1 1 ι » β 1 1 ι Ρ * β I 0 Ρ Ρ Λ! AND Ρ • Ρ > β kO γ — 1 σι σί ΓΩ k £> X 0 β Ρ 1 Ρ 1 0 Ρ 0 Ρ 0 • Ρ 1 Ρ ÍP X ρ X β 1 Ρ Ρ 1 ρ * ρ Ρ Ρ 1 > 1 Ρ 0 0 Ρ > 1 Ρ ίΰ Ρ , ΙΝ, 0 > Ί 1 σι Ρ , Ρ 1 φ > 1 σι Ρ Ρ β Ν φ φ Ρ Φ C0 1 L-P 1 5 υ Ρ Ρ X 1 β X Ρ Ρ X φ > 1 • Ρ β ω ίΰ φ ε χ ιΰ 0 ρ ρ ίΰ β > 1 β β 0 · Ρ Ρ W φ β ε ÍX Λ Φ > 1 Ρ ε AND C0 00 ι-1 1 Ρ Ρ Λ Ρ 00 00 Ρ Ρ Ρ φ 1 00 AND 1 υ Ρ Λ4

Example R, R-R. Y Analysis Crystal Temperature - The reaction conditions calculated melting point is from temperature time s

•Him

Λ o

CM «3 +3

Φ

AND

H 3> 1 P P MTJ Φ P> N d

CM σι

O * 4 · σι tfl Μ- H cs ň t t coι cm i — I

ΓΟ CO fO tO CM co σι cm

Fl- fl • H

Ό

O

Λ what

H

O c

d

P

Φ

I d

P

0) &

I co

S>

o> N d m σι o oo <n

O cm what r>

Μ tO About co r- Γ · r * r- r- ©

O tO i-H rr * rr * f1

About d

P

Φ> N d O i i — I CM

CM

WHAT IT DO THAT IT DO

u tc u

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Ethyl-6- (2,3-dihydro- _QH H: 8.55 9.07 212 xypropyl) -4.4a, 5.6, N: 9.14 9.07

7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolof2,3-giso33

Example R @ ₃ R @ ₃ R. Y Analysis Crystal Temperature - The reaction conditions calculated melting point is from temperature time

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Example 15

Preparation of 3-ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo £ 2 3-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-octahydro-1H-pyrrolo (2,3-g) isoquinolin-4 -one and 0.51 g (4.22 mmol) of styrene oxide in 25 ml of methanol are refluxed for 2.5 hours, cooled and filtered, and the filtrate is concentrated and the residue is chromatographed on an alumina activity in stage III, recrystallization from ethyl acetate-ethanol gave 0.195 g of 3-ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -4,4a, 5,6,7, 8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a white solid, m.p. 218.5-220 ° C.

Analysis for ^C 22 ^H 28 ^N 2 ° 2: calculated: 74.97% C, 8.01% H, 7.95 SN;

Found:% C, 74.87;% H, 7.92;% N, 7.95.

Examples 15a to 15f

As described in Example 15, 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one and Each of said compounds exhibits spectral data that is consistent with the structure described. Melting points are given either for the free base or for the hydrochloride. The isolated compounds are represented by the 4α, 8α-trans-isomers.

Table III

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1) The reflux temperature

Example 16

Racemic cleavage 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- onu

The racemic free base (produced as in Example 4) (1.20 g) was dissolved in methanol and a solution of d - (+) - tartaric acid (0.74 g) in methanol was added. The solution was concentrated and recrystallized twice from methanol. The crystalline d - (+) - tartrate was treated with ammonium hydroxide to liberate the free base and then treated with anhydrous ethereal hydrogen chloride to give the hydrochloride. Recrystallization twice from ethanol and drying at 80 ° / 0.67 Pa gave 0.15 g of the (-) enantiomer as a white crystalline solid. Mp 240-245 ° C.

Rotation: MpS -120.78 ° (c = 0.81%, water)

Analysis for C ₃ H ₂₂ N ₂ O ₂ O.HC1.0,25H Calculated: C: 62.70% H: 8.24% N: 9.75 i;

found C: 62.44%, H: 8.33%, N: 9.67%.

Ammonium hydroxide was added to the mother liquors from the crystallization of d - (+) - tartrate to liberate the free base, which was treated with a solution of (? - (-) - tartaric acid (0.46 g) in methanol). The product was recrystallized from methanol, converted to the free base and hydrochloride as described above to give 0.10 g of the (+) - enantiomer as a white crystalline solid, m.p. 240-244 °.

Optical rotation: + 121.38 ° (c = 0.44%, water)

Analysis for: ^C 15 ^H 22 ^N 2 ^O · ^HCl · 0.25H ₂ O:

calculated: C: 62.70, H: 8.24, N: 9.75%;

Found: C: 63.02%, H: 8.20%, N: 9.88%.

Example 17

Preparation of N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo [2,3] - isoquinolin-6-yl-ethyl-4-fluorobenzamide

Heating with 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one and 1- (4-fluorobenzoyl) aziridine for 2 hours N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H) was prepared in a mixture of benzene and methanol pyrrolo [2,3-g] isoquinolin-6-yl) ethyl] -4-fluorobenzamide. The crude product crystallized from ethanol in a white solid, m.p. 252-253 ° C. The starting aziridine is prepared from aziridine and p-fluorobenzoyl chloride and sodium bicarbonate in water.

Example 18

Preparation of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline-4-thione

A mixture of 1.45 g (6 mmol) of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one and 1.77 g (4 mmol) of phosphorus pentasulfide in 60 ml of dioxane are stirred at reflux for 10 hours. The mixture was cooled and the dioxane solution separated by decantation from a dark residue which was dissolved in 75 ml of water. The solution was basified by addition of ammonium hydroxide to pH 8-9 and the aqueous mixture was extracted with chloroform. The extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent gave 420 mg of crude thion which was chromatographed on a silica gel column together with 100 mg of the additional crude product obtained by treatment with hot water on the residue from the original isolation followed by the same extraction with chloroform. Washing the dry column with the organic phase, a mixture prepared by equilibrating between 90 parts by volume of chloroform, 30 parts by volume of methanol, 10 parts by volume of water and 6 parts by volume of octo242900 acid, after evaporation of the eluate, dissolve the residue in water to pH 8-9 and extraction with chloroform gives pure thion. After washing with water and drying over sodium sulfate, the chloroform was evaporated to give 250 g of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-a]. g] isoquinoline-4-thione as a yellow solid, m.p. 190-194 ° C. Recrystallization from acetonitrile gave pure 4α, the trans-isomer, mp 203-205 ° C.

Example 19

Preparation of 3-ethyl-2-methyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-c] isoquinoline-4-thione

A mixture of 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-thione, 276 mg of potassium carbonate and 222 mg of 2-bromomethylbenzene in 15 ml of 3-pentanone are stirred for 3 hours and then refluxed. The solvent was removed on a rotary evaporator, water (25 ml) was added and the mixture was extracted with chloroform.

Purification by column chromatography as described in detail in Example 18 gave 100 mg of pure product which, after recrystallization from acetonitrile, afforded 50 mg of 3-ethyl-2-methyl-6- (2-phenylethyl) -4,4a, 5,6 7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4-thione, m.p. 164-166 ° C.

Example 20

Preparation of capsules

0.5 mg / capsule 5.0 10.0 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-a] - g] isoquinolin-4-one hydro-chloride 0.5 5.0 10.0 lactose 183.5 179.0 218.0 starch 30.0 30.0 50.0 talc 5.0 5.0 10.0 magnesium stearic acid 1.0 1.0 2,0 total 220 mg 220 mg 290 mg

Workflow:

The active ingredient, lactose and starch are mixed in a suitable mixer and the mixture is ground in a suitable mill. Finally, the talc and the magnesium salt of stearic acid are added and the resulting mixture is machine filled into capsules.

Example 21

Tablet preparation (direct compression)

Ingredients 0.5 mg / tablet 0.5 10.0 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 hydrochloride 0.5 5.0 10.0 lactose 85.5 81.0 103.0 microcrystalline cellulose (Avicel) 30.0 30.0 45.0 modified starch 7.5 7.5 10.0 magnesium stearate salt 1.5 1.5 2,0 total 125 mg 125 mg 170 mg Workflow: Active ingredient, lactose, microcrystalline are mixed in a suitable mixer over a period of 10 to 15 minutes The mixture was stirred for 4 minutes. Then pressing. cellulose (Avicel) and modified starch • i. The magnesium stearate is then admixed and the tablets are prepared from the mixture on a suitable press Example 22 Tablet preparation (wet granulation) Ingredients 0.5 mg / tablet 5.0 10.0 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- hydrochloride 0.5 5.0 10.0 lactose 103.5 99.0 148.0 modified starch 10.0 10.0 20.0 pregelatinized starch 10.0 10.0 20.0 magnesium stearate salt 1.0 1.0 2,0 total 125 mg 125 mg 200 mg Workflow: The active ingredient, lactose, modified starch and pre-mixer and the mixture are granulated using water. Then the gelatinized starch is dried is mixed in and grind.

Finally, the magnesium salt of stearic acid is admixed and the resulting mixture is compressed into a suitable tablet press.

Claims (7)

(C 1 -C 7), (C 1 -C 7) phenylhydroxyalkyl, (C 1 -C 7) halophenyl (C 1 -C 7) alkyl, (C 1 -C 7) alkoxyalkyl, (C 1 -C 7) aryloxyhydroxyalkyl (C 1 -C 7) carbon atoms in the alkyl moiety, arylcarbonyloxyalkyl of 1 to 7 carbon atoms in the alkyl moiety, arylcarbonylalkyl of 1 to 7 carbon atoms in the alkyl moiety, alkoxycarbonylalkyl groups of 1 to 7 carbon atoms in both the alkyl and alkoxy moieties, arylalkyl groups of 1 to 7 carbon atoms in the alkyl moiety, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and having 1 to 7 carbon atoms in the alkyl moiety, or a group of the formula wherein R is C 1 -C 7 alkylene, and Rg and R.? each independently represents a hydrogen atom or an alkyl group having from 1 to 7 carbon atoms or together with the nitrogen atom it is a morpholino group, wherein the aryl group mentioned in the abovementioned radicals is in each case phenyl or phenyl substituted with 1 to 3 substituents selected from halogen; trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms and dialkylamino of 1 to 7 carbon atoms in the alkyl moieties, optical and geometric isomers of these compounds as and pharmaceutically acceptable acid addition salts thereof, characterized in that the compounds of formula XV 'wherein í <2 and as defined in point 1 are substituted on the nitrogen atom of the isoquinolines by reaction with a compound giving the remainder of the meanings defined above, obtained cis mixture - and the trans-isomers, respectively if desired, it is isomerized to a final ratio in which the trans isomer is predominantly present, and / or the trans isomer is optionally separated from the resulting mixture, and / or the racemic mixture obtained is optionally resolved into optical antipodes and / or compound obtained or pharmaceutically unusable optionally, the acid addition salt is converted to a pharmaceutically acceptable acid addition salt. C 1-7, or together with the nitrogen atom, are morpholino, and is oxygen or, when R 6 is a C 1-7 arylalkyl group in the alkyl moiety, it is also a sulfur atom, wherein aryl is as defined above the radicals are in each case phenyl or phenyl substituted by 1 to 3 substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 atoms carbon and dialkylamino having 1 to 7 carbon atoms in the alkyl moieties, optical and geometric isomers of these compounds, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula XV (XV) wherein: R ₂ , R ₃ and X are as defined above, substituted on the nitrogen atom of the isoquinoline by reaction with a compound giving the remainder of the meanings defined, the resulting mixture of cis- and trans-isomers optionally being isomerized to a final ratio in which the trans- the trans-isomer is optionally separated from the mixture obtained, and / or the racemic mixture obtained is optionally resolved into optical antipodes and / or the compound or pharmaceutically unacceptable acid addition salt obtained is optionally converted into a pharmaceutically usable acid addition salt. A process for the preparation of octahydro-1H-pyrrolo-2,3-g] isoquinolines of the general formula A OBJECT OF THE INVENTION H in which R ₂ and R are independently alkyl of 1 to 7 carbon atoms, R ₄ represents a C 1 -C 7 alkyl group, a C 1 -C 7 hydroxyalkyl group, a C 1 -C 7 phenylhydroxyalkyl group, in the alkyl moiety, a C 1 -C 7 halophenylhydroxyalkyl group in the alkyl moiety, a C 1 alkoxyalkyl group C 7 -C 7 alkyl and alkoxy, C 1 -C 7 aryloxyhydroxyalkyl, C 1 -C 7 arylcarbonyloxyalkyl, C 1 -C 7 arylcarbonylalkyl, C 1 alkoxycarbonylalkyl up to 7 carbon atoms in the alkoxy and alkyl moieties, arylalkyl group having 1 to 7 carbon atoms in the alkyl moiety, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 7 carbon atoms in the alkyl moiety, arylcarboxamidoalkyl group having 1 to 7 atoms carbon in the alkyl moiety, alkanoylalkyl having 1 to 7 carbon atoms in alkanoyl an alkyl moiety, an arylalkyl group having 1 to 7 carbon atoms in the alkyl moiety, an alkenyloxyalkyl having 2 to 7 carbon atoms in the alkenyl moiety and having 1 to 7 carbon atoms in the alkyl moiety, an arylalkenyl group having 2 to 7 carbon atoms in the alkenyl moiety, aryloxyalkyl C 1 -C 7 alkyl, N-methylpyrrolidinylalkyl C 1 -C 7, or formula N-R-, where R is C 1 -C 7 alkylene, and Rg and R-? each independently represents a hydrogen atom or an alkyl group with s 2. The process of item 1 for the preparation of octahydro-1H-pyrrolo-2,3-g-isoquinolines of the general formula A 'wherein: R ₂ and R ₃ are as defined in Item 1 R 'is C 1 -C 7 alkyl, hydroxyalkyl 3. The process of item 2 for producing 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, characterized in that 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one is substituted on the nitrogen atom of isoquinolines with methyl halide. 4. The process of item 2 for producing 2-methyl-3-ethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H- pyrrolo [2,3-g] isoquinolin-4-one, characterized in that 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a- trans-1H-pyrrolo [1,3-g] isoquinolin-4-one is substituted at the nitrogen atom of the isoquinolines by the action of the compound providing the 2-phenylethyl group. 5. The process of item 2 for producing 2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H- pyrrolo [2,3-g] isoquinolin-4-one, characterized in that 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans- 1H-pyrrolo [2,3-g] isoquinolin-4-one is substituted at the nitrogen atom of the isoquinolines by the action of the compound affording the 2-ethoxyethyl group. 6. The process of item 1 for the preparation of 2-methyl-3-ethyl-6- [4- (4-fluorophenyl) -4-oxobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro- 4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, characterized in that 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one is substituted at the nitrogen atom of the isoquinolines by the action of the compound giving the 4- (4-fluorophenyl) -4-oxobutyl group. 7. The process of item 2 for producing 2-methyl-3-ethyl-6- (2-hydroxy-3,3-dimethylbutyl) -4,4a, 56,7,8,8a, 9-octahydro-4a, 8α- trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, characterized in that 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro- 4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one is substituted on the isoquinoline nitrogen by the action of a 2-hydroxy-3,3-dimethylbutyl group introducing epoxide.