FI67548C - REFRIGERATED FOR THERAPEUTIC USE OF THERAPEUTIC THERAPEUTIC HYDROGEN-1H-PYRROLO (2,3-G) Isoquinoline - Google Patents

Description

ESR ^ l ΓΒΐ ni> * ADVERTISING PUBLICATION, nrAn w πυ utlAggningsskrift 6/540 (51) K.Jt / 1-.σ.3 C 07 D 471/04 FINLAND — FINLAND (21) Pmnttlhilamui - PufntanuMming 793 1 83 (22) HtkMibplM — AiMBknlngidag 12.10.79 (23) AfcupUv · —GlkltMalag 12.10.79 (41) Tuikit JuIUmIoI - Mwit offamftg 1 ^ .0 ^ .80 ^ (44) NIhtMlolpiiio »] · kuL) utkalMM · pvm.— R.

patent · och registerstyralsan '' αμΜμ utlifd «* ucl ^ krtftwi pubikarad 31.12.04 (32) (33) (31) Pretty« welkn »—prtortut 13.10.78 10.09.79 USA (US) 9509 ^ 7, 73813 (71) F. Hoffmann-La Roche δ Co. Aktiengesel1schaft, Grenzacherstrasse 12A-18A, Basel, Switzerland-Switzerland (CH) (72) Leo Berger, Montclair, New Jersey, Gary Lee Olson, Westfield,

New Jersey, USA (US) (7i ») Oy Koi ster Ab (5ΙΟ Method for the preparation of therapeutically useful octahydro-1H-pyrrolo [2,3] / isoquinolines - Förfarande för framställning av tera-peutiskt användbara octahydro-1H-pyrrolo ^, 3-g7isokinoliner

The invention relates to a process for the preparation of therapeutically useful octahydro-1H-pyrrolo [2,3-g] isoquinolines of the formula A, their optical and geometric isomers and their pharmaceutically acceptable acid addition salts,

X

Μ "Ύΐΐ — if \ \ R9

B

wherein R 2 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 1-7 alkanoyl or phenyl-C 1-7 alkyl, R 3 is hydrogen, C 1-7 alkyl, C 3-7 cyclo-67548 alkyl or phenyl, R 3 is C 1-7 alkyl; alkyl, C 1-7 hydroxyalkyl, aryl-C 1-7 hydroxyalkyl, C 1-7 alkoxy-C 1-7 alkyl, aryloxy-C 1-7 hydroxyalkyl, arylcarbonyloxy-C 1-7 alkyl, arylcarbonyl-C 1-7 alkyl alkyl, C7-alkoxycarbonyl-C1-7-alkyl, aryl-C1-7-alkyl, C2-7-alkenyl, C8-7-cycloalkyl-C1-7-alkyl, C2-7-alkynyl, thienyl-C1-7-alkyl, furyl- -alkyl, arylcarboxamido-C 1-7 -alkyl, C 1-7 -alkanoyl-C 1-7 -alkyl, C 2-7 -alkenyloxy-C 1-7 -alkyl, aryl-C 2-7 -alkenyl, aryloxy-C 1-7 -alkyl, NC 1-7 -alkyl -alkyl-pyrrolidinyl-7-alkyl, N-benzimidazol-2-on-1-yl-C 1-7 -alkyl, di-C 1-7 -alkyl-N-C 1-7 -alkyl or morpholino-C 1-7 -alkyl, and X is O or S, wherein aryl means phenyl or phenyl monosubstituted with halogen, C 1-7 alkyl or C 1-7 alkoxy.

Japanese Kokai Publication No. 76,118,799 describes compounds having a similar basic structure to the compounds of formula A and having an effect on the central nervous system. The compounds of formula A differ from said known compounds in that they contain an oxo or thiono group in the middle, non-aromatic ring and the substituent combination is substantially different.

The term "alkyl", as used herein, means a straight-chain or branched, saturated hydrocarbon group having 1 to 7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, or heptyl. . The term "alkoxy" denotes an alkyl ether group in which the alkyl group is as previously described, e.g. methoxy, ethoxy or propoxy. The term "alkenyl" denotes a straight-chain or branched, unsaturated hydrocarbon group having 2 to 7 carbon atoms, e.g. vinyl or allyl. The term "alkynyl" denotes a straight-chain or branched, unsaturated hydrocarbon group having 2 to 7 carbon atoms, e.g. ethynyl, propargyl or methylbutynyl. The term "halogen" means bromine, chlorine, fluorine or iodine. The term "aryl" means phenyl, phenyl monosubstituted with halogen, C 1-7 alkyl or C 1-4 alkoxy. The term "aryl-C 1-7 alkyl" preferably means benzyl and the like. The term "aryloxy" means an aryl ether group in which the aryl group is as previously described,

II

67548 e.g. phenoxy and the like. The term "alkanoyl" means a group derived from an aliphatic C 1-4 carboxylic acid, e.g. formyl, acetyl or propionyl.

Preferred compounds of formula A are those wherein R 2 and R 3 are C 1-6 alkyl, C 1-7 alkyl, C 1-7 hydroxyalkyl, phenyl-C 1-7 hydroxyalkyl, halo-phenyl-C 1-7 hydroxyalkyl, C 1-7 alkylalkyl, N-alkoxy-C 1-4 alkyl, aryloxy-C 1-6 alkyl, arylcarbonyl-C 1-4 alkyl or aryl-C 1-4 alkyl and X is O.

The most preferred compounds of formula A are: 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-pyrrolo / 2,3 g / -isoquinolin 4-one hydrochloride · 1/4 H 2 O; 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-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] isoquinoline-4- one; 2-methyl-3-ethyl-6-benzyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-pyrrolo / 2,3 g / isoquinolin-4- one hydrochloride; 2-methyl-3-ethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octa-hydro-4a, 8a-trans-pyrrolo / 2,3- g / isoquinolin-4-one; 2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, 5,6,7,8,8a, 9-octa-hydro-4a, 8a-trans-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 hydrochloride; 2-methyl-3-ethyl-6- / 4- (4-fluorophenyl) -4-oxobutyl / -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-LH -pyrrolo / 2.3 g / iso-quinolin-4-one; 2-methyl-3-ethyl-6- / 3- (4-fluorophenyl) -3-oxopropyl / -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-LH pyrrolo [2,3-g] isoquinolin-4-one; "67548 I: ---- 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, 2-methyl-3-ethyl-6- (2-hydroxy-3-methylbutyl) -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-hydroxy-3,3-dimethylbutyl) -4, 4a, 5,6,7,8,8a, 9-octahydro-4α, 8α-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-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride dihydrate and 2,6-dimethyl-3-ethyl-4, 4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-pyrrolo / 2,3 g / butyl-4-thione.

The compounds of formula A may exist as 4a, 8a-trans or 4a, 8a-cis isomers or mixtures thereof; The 4a> 8a trans isomers are preferred.

The compounds of formula A, their optical and geometric isomers and their pharmaceutically acceptable acid addition salts can be prepared according to the invention by a) an isoquinoline nitrogen atom in a compound of formula

X

I R2

B

wherein R 1, R 2, R 2 and X are as defined above, are substituted using halide or aziridine, or b) a compound of formula 0 V-A * 3 NH r 1_ ^ d

IX

R

2

H Z

wherein R 2 and R 6 are as defined above and R 4 is alkyl, C 1-8 alkoxy-C 1-7 alkyl or C 3-8 cycloalkyl-C 1-6 alkyl, treated with formaldehyde to give a compound of formula 67548

'' CAT

"'' 'N' ^ R, I 2

B

wherein R 2, R 3 and R 2 "have the same meaning as above, or c) a compound of formula 0 R 1" -

H XII

o wherein R 1 "is as defined above is treated with a compound of formula ° R 3

VII R

HON K2 in the presence of a reducing agent, or with a compound of formula 0

VIII

H2N "" ^ 'R2 or a precursor thereof, wherein R2 and have the same meaning as above, to give a compound of formula Ia, or d) a compound of formula p R, -N \ Π ic "j R2'

B

6 67548 wherein R 2 'is hydrogen, C 1-7 alkyl, C 2-7 alkenyl or phenyl-C 1-6 alkyl, R 3' is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or phenyl and R 3-7 is C- C 1-7 alkyl, C 1-7 alkoxy-C 1-7 alkyl, aryl-C 1-7 alkyl, C 2-7 alkenyl, C 3-8 cycloalkyl-C 1-7 alkyl, C 2-7 alkynyl, thienyl-C 1-7 alkyl; C 1-7 alkyl, furyl-C 1-7 alkyl, C 2-7 alkenyloxy-C 1-7 alkyl, aryl-C 2-7 alkenyl or aryloxy-C 1-7 alkyl are treated with phosphorus pentasulfide to give a compound of formula

S

h öhX ,.

R2

B

wherein R 2 ', R 3' and R "'have the same meaning as above; and if desired 1) the resulting mixture of cis and trans isomers is isomerized to give a predominantly trans isomer 2) the trans isomer is separated from the resulting mixture 3) the resulting racemic mixture is decomposed into optical antipodes and / or 4) the resulting compound or pharmaceutically unacceptable acid adduct the thio salt is converted to a pharmaceutically acceptable acid addition salt.

The compounds of formula A above, their optical and geometric isomers, and pharmaceutically acceptable acid addition salts thereof, as well as various intermediates, can be prepared in particular as detailed below. Thus, for example, compounds of formula A wherein X is 0 and represented by formula I

0 and R2

B

wherein R ", R" and R. have the same meaning as above, can be prepared as shown in Reaction Schemes I-IV.

Il 7 67548

Reaction Scheme I

? CH3 OCH3 Γ "2 [" il -> C ^ NH kk XIV m och3 V yOossa R. "CU denotes OCH. 4 3 I ° CH3

R4'NH I

I | l _> v, NH

° CH3 ^ kk \ k \ IV V och3 0

r4 "NH

1 + v3 v> X- ^ N / Xq A + Zn 0 HON ^^ r> k VI 2 H2N R2

_____ ^ VIU

f 0 R "NH / R? k X JF ~ Tj ---> ** - [j jl — f I" "R2

B

IX la H

wherein R 2, R 3 and R 2 "have the same meaning as above.

8 67548

According to Reaction Scheme I, compounds of formula IV wherein R 1 is methyl are prepared by reacting a primary amine of formula XIV with a chloroformic acid ethyl ester to give a urethane of formula III which is reduced with lithium aluminum hydride to give a compound of formula IV as an N-methylamine. can be prepared by alkylation by reduction of a compound of formula XIV using the corresponding aldehyde, e.g. acetaldehyde and the like aldehyde, and sodium cyanoborohydride under known conditions (cf. e.g. RF Borch, J. Am. Chem.

Soc., 93, 2897 (1971). Birch reduction of the amine of formula IV using lithium in t-butanol-containing ammonia gives the dihydroamine of formula V. Other variations of Birch reduction are also useful. Thus, an amine of formula IV 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 t-butanol. The reaction generally takes place at or below the boiling point of the solvent, e.g. -78 ° to + 15 ° C. If ammonia is used, the reaction takes place at boiling temperature. The addition of additional solvents such as diethyl ether or tetrahydrofuran is possible.

The hydrolysis of the dihydroamine of formula V is readily carried out according to conventional methods for the hydrolysis of enol ethers, e.g. by means of an aqueous acid solution. Examples of useful acids are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid and perchloric acid. They can be used in aqueous solutions or mixed solvents. At least two equivalents of water and more than one equivalent of acid are required per mole of dihydroamine. Examples of useful solvents are tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile. For example, hydrolysis of a dihydroamine of formula V wherein R 1 is methyl in 2N hydrochloric acid at room temperature or higher in aqueous acetic acid between 40 ° and the boiling point produces a diketone of formula VI wherein R 1 is methyl.

Il 9 67548

The diketone of formula VI condenses in a Knorr condensation to the dihydroindolone-ethylamine of formula IX. Knorr condensation is a well-known method for preparing pyrroles, and the method can be used with all known variations (cf., for example, the conditions found in J. M. Patterson, Synthesis, 281, 1976 and references cited therein). Thus, it is assumed that e.g. the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, e.g. with zinc in aqueous acetic acid or hydrochloric acid, takes place via an aminocarbonyl compound of formula VIII which then condenses with a diketone of formula VI to dihydroindolone-ethyl On the other hand, condensation can occur with an aminocarbonyl compound of formula VIII or a precursor such as aminoketone hydrochloride or an acetal derivative of aminoketone or aminoaldehyde. The use of aminoketone or aminoaldehyde precursor is preferred, as such substances tend to self-condense. They are best used in situ under conditions in which the aminocarbonyl components are released in the presence of a diketone of formula VI. The aminocarbonyl components react immediately to the dihydroindolone-ethylamine of formula IX. It is not necessary to isolate the diketone of formula VI prior to performing the Knorr condensation because the reaction conditions used are sufficient to hydrolyze the dihydroamine of formula V to the diketone of formula VI. Knorr condensation is best performed at a pH of about 2-6. At pH substantially greater than 6, there is a significant reduction in yield due to the formation of self-condensation products of the aminocarbonyl compound of formula VIII.

The isonitrocoketone of formula VII is preferably condensed with zinc dust in aqueous acetic acid with a diketone of formula VI to give the product dihydroindolone-ethylamine of formula IX wherein R 1 is methyl.

Knorr condensation occurs primarily when the temperature range is approximately between room temperature and boiling temperature. The isonitrosoketones of the formula VII are known compounds (see e.g. Ferris, J. Org. Chem., 24, 1726 (1959)) or can be readily prepared by nitrosation of the corresponding ketones, e.g. with alkyl nitrite, or in the case of strongly acidic Λ -detokones or γ -ketoesters, with sodium nitrites.

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-heptanone; 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 precursors useful in Knorr condensation include aminoacetaldehyde dimethyl acetal and 2-amino-3-pentanone hydrochloride.

The amine of formula XX is converted to the compound of formula Ia by an intramolecular Mannich reaction. The Mannich reaction is usually carried out using as starting materials a ketone and a dialkylamine salt, e.g. dimethylamine hydrochloride and formaldehyde (e.g. as an aqueous solution, paraformaldehyde or trioxane) in an alcoholic solvent such as ethanol at reflux temperature. In the embodiment described herein, the acid addition salt of the dihydroindolone-ethylamine of formula IX is reacted with formaldehyde added in the form of an aqueous solution of paraformaldehyde, trioxane or formaldehyde in a solvent. To obtain pyrrolo [2,3-g] isoquinolines of formula Ia, for example, a high-boiling hydroxyl-containing solvent such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether diethylene-diethylamide, a high-boiling polar aprotic solvent such as dimethyl a low boiling polar solvent such as ethanol, butanol or 2-propanol under pressure, or a low boiling aprotic solvent under pressure such as

II

11,67548 dioxane or tetrahydrofuran at a temperature in the range of about 135 ° to about 200 °. In particular, at temperatures below 150 °, a mixture of cis and trans isomers is formed in the reaction, i.e. e.g. if R 2 is methyl, compounds of the formulas

Ctl3t I Jlit ch3-n Ί jl I

Hl ΰ 1 R2 H H h trans cis l’a ’.

I 'al

Heating the reaction mixture for a longer period of time or heating the isolated isomeric mixture of the hydrochlorides of formulas I'a and I "a, e.g. by boiling in ethylene glycol for 2 hours, can be used to equilibrate the cis and trans isomers so that the majority of the isomeric mixture is trans. which can be easily isolated by crystallization or chromatographic separation.

Preferred is the reaction of the hydrochloride of the dihydroindolone-ethylamine of formula IX, wherein R 2 "is methyl, with paraformaldehyde in octanol at 180 ° for a reaction time of 2 hours, isolating the product almost exclusively as the trans isomer of Ena.

0 12 67548

Reaction Scheme II

__S Rz CH3 “n ^ Il Ia '

i * 2 / H

L / 0 9 ^ C 2ii5CHj-N | |

B

XIII

v o H-N | j L X- JX XVa I 2

B

wherein R2 and R3 are as defined above.

Il 67548

N-demethylation of a compound of formula Ia1 can be accomplished by standard methods commonly used for N-dealkylation, such as the Braun method (HA Hageman, Org. Reactions, 7, 198 (1953)) or by hydrolysis with acids or bases of a urethane derivative as described by KCRice ( J. Org. Chem. 40, 1850 (1975)). In one dealkylation of a compound of formula Ia1, the synthesis takes place via a urethane of formula XIII by hydrolysis with an acid of formula XVa sec. amine. For example, a compound of formula Ia 'wherein R 2 is methyl and R 1 is ethyl is refluxed for 3 hours with excess chloroformic acid ethyl ester and potassium bicarbonate in diethyl ketone to give a compound of formula XIII wherein R 2 is methyl and R 1 is ethyl. Hydrolysis of the above compound with concentrated hydrochloric acid in acetic acid boiling for 24 hours gives a compound of formula XVa wherein R 1 is methyl and R 2 is ethyl. The same compound is obtained by hydrolysis of urethane of formula XIII with sodium hydroxide in refluxing ethanol.

Reaction Scheme III

0 H-N ^ 3 I 1 f li 1 \ 2 u \ XVa

V

'€ & ("I R2

B

Id where and R 1 have the same meaning as above.

14 67548 Treatment of a compound of formula XVa 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 a propylamide in the presence of a base such as potassium carbonate provides Id compound, i.e. a compound having C 1-6 alkyl, C 2-6 alkenyl, C 1-6 cycloalkyl-C 1-6 alkyl or aryl-C 1-7 alkyl. When reactive halides are used, the reaction can take place at room temperature, when less reactive halides are used, the reaction is carried out at reflux temperature, and in many cases the reaction rate can be increased by adding iodide, such as lithium iodide, to the reaction mixture.

Reaction of a compound of formula XVa with epoxy alkanes gives a hydroxyalkyl-substituted compound of formula Id. Treatment with a substituted epoxyalkane provides 2-substituted 2-hydroxyalkyl analogs of a compound of formula Id, e.g., reacting a compound of formula XVa with styrene oxide provides a compound of formula Id wherein R 1 is 2-phenyl-2- hydroxy-ethyl. The reaction usually takes place in the presence of an alcoholic solvent such as methanol at a temperature between about room temperature and the reflux temperature of the mixture. Epoxyalkanes are either commercially available or are prepared by epoxidation of the corresponding olefins or by methylenation of the ketone with sulfonium methyldi or sulfoxonium methylide, e.g. dimethylsulfonium methyldi. Thus, for example, treatment of benzaldehyde with dimethylsulfonium methylide gives styrene oxide.

Treatment of a compound of formula XVa with a haloalkylamine in the presence of a base, e.g. potassium carbonate or aziridine, affords amine-substituted analogs of a compound of formula Id. The reaction conditions are described in connection with the preparation of alkyl derivatives.

The reactions described in Reaction Schemes I, II and III may form compounds of formula I as well as trans isomers of formula 15,67548

-cfcC

2 ί 2

B

where R, R and R have the same meaning as above, so that the 2 3 4 cis isomers of the formula

H ° R

"diet: - H I 2

B

wherein R 2, R 2 and R 2 are as defined above, the trans isomer being the predominant type. The pure trans isomer can be isolated by chromatography or crystallization. The mixture may further be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula I'a and I "a.

16 67548

Reaction Scheme IV

° 0Η3 OCH3 V «« __ >> V-N ^ Yll OCH3 IV / x och3

R4M ~ Ni ^ XI

^^^ och3 v- "yV * V \ zn ° yRs hon ^ \ r K2 Hon · XII 2 2

VII VIII

Ψ _r / R3 r “" 1 I in, a

B

wherein, R 1 and R 2 "have the same meaning as above.

17 6754 8

A second synthesis for the preparation of compounds of formula Ia is described in Reaction Scheme IV, in which an isoquinoline ring is formed prior to pyrrole ring formation. According to Reaction Scheme IV, (3,5-dimethoxyphenyl) ethylamine of formula IV is boiled with an aqueous solution of formaldehyde under reflux to give a tetrahydroisoquinoline of formula X. In the Brich reduction, reduction of a tetrahydroisoquinoline of formula X with lithium in liquid ammonia containing t-butanol under substantially the same conditions as described for Birch reduction of a compound of formula IV gives a hexahydroisoquinoline of formula XI. Hydrolysis of the crude hexahydroisoquinoline of formula XI under substantially the same conditions as described for the hydrolysis of the dihydroamine of formula V gives the diketone of formula XII. The compound of formula XII is reacted using Knorr condensation as described for the preparation of dihydroindolone-ethylamine of formula IX with an isonitrosoketone of formula VII or an aminocarbonyl compound of formula VIII to give a pyrroloisoquinoline of formula Ia. Preferred is the reaction sequence of Reaction Scheme IV starting from an amine of formula IV wherein R 1 is methyl to form the corresponding N-methylpyrroloisoquinoline of formula Ia * and in particular the trans-isomer I'a and formula I, (a *). as a mixture of the cis isomer.

In order to obtain the trans isomer mainly of the formula I'a ', the same procedures can be used as for the isomerization of the mixture of pyrroloisoquinolines of the formulas I'a' and I "a 'as previously described.

Compounds of formula A wherein X is S are represented by the formula __ r ~.:.

18 67548 s uux, \ R2

B

wherein R 2, R 3 and R 2 are as defined above and can be prepared as follows.

Thions of formula II are generally prepared by reacting phosphorus pentasulfide in keto compounds of formula I.

If the compound of formula I does not have any functional groups which can react with phosphorus pentasulfide, with the exception of the 4-oxo group, the compound of formula I can be converted directly to the compound of formula II by heating with phosphorus pentasulfide in an inert organic solvent. On the other hand, thions of formula II can be prepared as shown in Reaction Schemes V and VI.

Reaction Scheme V

i ΙΠ N R „- y.

V il R

| R2 Ha H

wherein R, R3 and R3 "have the same meaning as above.

19 67548

In Reaction Scheme V, a compound of formula Ia is converted to a compound of formula IIa by heating in an inert organic solvent with phosphorus pentasulfoxide. Preferred solvents are tetrahydrofuran, benzene and dioxane, and the reaction generally takes place at reflux temperature.

Other compounds of formula II can be prepared as described in Reaction Scheme VI:

Reaction Scheme VI

n '' 'l [^ XVa

B

S

H V "3 n i l | XVc I v 2 H \ s R \ n / xA — R3

i R

I 2

Ild H

wherein R 2 and R 2 are as defined above.

20 67548

In Reaction Scheme VI, a compound of formula XVa is reacted with phosphorus pentasulfide as described above to form a thione of formula XVc. The compound of formula XVc is then converted to the compound of formula IId in the same manner as in Reaction Scheme III for the conversion of the analogous oxo compound XVa to compound Id.

These reactions can form compounds of formula II as well as trans isomers of formula

S

R ψλ R

I j | ^ II.

H I R2

B

wherein R 2, R 3 and R 2 have the same meaning as above, so do the cis isomers of the formula f X J-1!

H I

B

wherein R 2, R 3 and R 2 are as defined above, wherein the trans isomer predominates. The pure trans isomer can be isolated by chromatography or crystallization. The mixture may further be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula I'a and I "a '.

The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acid addition salts of both pharmaceutically acceptable organic and inorganic salts.

II

21 67548 with organic acids, e.g. hydrohalic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, other salts of inorganic acids such as salts with sulfuric acid, nitric acid, phosphoric acid or the like, toluenesulfonic acid, alkyl and monoaryl sulfonic acids such as ethyl and monoaryl sulfonic acids with such acids, with other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like. The pharmaceutically unacceptable acid addition salts of the compounds of formula A may be converted into pharmaceutically acceptable acid addition salts by conventional exchange reactions whereby the pharmaceutically unacceptable anion is replaced by a pharmaceutically acceptable anion, an acceptable acid addition salt. Acid addition salts can also form hydrates.

The compounds of formula A and their pharmaceutically acceptable acid addition salts exhibit stress-releasing activity. However, they surprisingly lack an antihypertensive effect and show only weak cataleptic activity. Thus, the compounds of formula A are useful as medicaments for the prevention of mental illness, e.g. in the treatment of appendicitis. The activity of the compounds of formula A, which makes them useful as drugs for the prevention of mental illness, can be demonstrated by known methods in warm-blooded animals.

According to one method of operation, e.g., trained rats are placed in test chambers equipped with a reaction lever, a steel-wire base to deliver an electric shock, and a loudspeaker to deliver an acoustic stimulus. Each experiment includes a 15-second warning sound (conditional stimulus) that continues for another 15 seconds. and followed by electric shock (absolute stimulus; 1.0 mA, 350 V AC). Rats can stop the experiment at any point by pushing down the reaction lever. Reaction first 15 sec. during the sustained warning sound terminates the experiment, prior to the administration of the shock, and 22 67548 is considered an avoidance reaction, whereas the reaction that occurs during the shock delivery is an escape reaction. The experiments are performed every other minute for an hour-long experiment (30 experiments per test period).

In trained rats, the baseline level of avoidance behavior is reliable (0-3 missed avoidance responses per experimental time). At least 3-4 rats receive compounds for each dose amount in the dosing range at appropriate pretreatment times. During control periods, rats receive the vehicle only. Control and trial times change weekly; each animal acts as its own control.

The duration of each experiment is divided into three consecutive 20-minute periods (10 experiments). The numbers of reactions of individuals who received a given dose during each period are added together.

The number of experiments in which the rats did not show an avoidance reaction (avoidance-retardation, VB) or an escape reaction (escape-retardation, FB) is determined by the period in which the effect of each dose was greatest. This figure is expressed as a percentage of the total number of trials performed during the period. For a 50% avoidance path (VB 50), the calculated dose is obtained from the dose-response regression curve constructed by the least squares method.

The lowest dose that caused a 20% escape reaction patency (FB 20) is read from the dose / effect diagram. To obtain these values, the effect is expressed as a% of the logarithm of the dose

Mental antidepressants are distinguishable from other species that, when used in this mode of action, have a detrimental effect on the behavior of rats, on the grounds that the difference between doses that dampen the avoidance reaction and doses that dampen the escape reaction is greater than the previous one. The clinical efficacy of anti-mental agents, the therapeutic use and properties of which are known, is substantially and strictly dependent on their efficacy in this method. Thus, the compounds of formula A may be used therapeutically in dosages consistent with their efficacy in these experimental methods.

When 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, which was found to have an LD50 of e.g. 350 mg / kg orally when administered to mice,

II

23 6 7 5 4 8 for VB ^ Q is 0.7 mg / kg orally and 0.095 mg / kg subcutaneously; the stress-triggering activity of the (-) enantiomers of the above compound for VBj is 0.48 mg / kg given orally. Similarly used as a test substance is 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, the excitatory activity for VB ^ Q is 0.48 mg / kg orally.

When N- [2- (3-ethyl-4,4a, 5,6,7,8,8 * 8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo) is used as a test substance 2,3-g-((isoquinolin-6-yl) -ethyl] -4-fluorobenzamide, the tension-triggering activity for VB (R) is 3.5 mg / kg given orally.

When 3-ethyl-2-methyl-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, the excitatory activity for VBcn is 0.19 mg / kg orally

b U

given through.

Similarly, 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 the substance, quinoline-4-thione, the excitatory activity for VBj.Q is 0.9 4 mg / kg orally.

The following table summarizes the VB1 values for some of the compounds of formula A.

24 67548

Compound VB of formula A.

5 O

mg / kg p.o.

3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -0.73 isoquinoline 4-one (-) - 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g / iso-0.48 quinolin-4-one 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2 , 3-g / iso-0.47 quinolin-4-one 2-methyl-3-ethyl-6- (2-ethoxyethyl) -4,4a, -5,6,7,8,8a, 9-octahydro- 4α, 8α-trans-1H-pyr-0,78 rolo [2,3-g] isoquinolin-4-one 2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7, 8,8a, 9-octahydro-1H-pyrrolo-1,64 / 2,3-g / isoquinolin-4-one

Ras · 2,3-dimethyl-6- [4- (4-fluorophenyl) -4-octobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro-0.08 4a, 8a-trans -1H-pyrrolo [2,3-g] isoquinolin-4-one

Ras. 2-methyl-3-ethyl-6- [4- (4-fluorophenyl) -4-octobutyl] -4,4a, 5,6,7,8,8a, 9-octahydro-0.19 4a, 8a-trans -1H-pyrrolo [2,3-g] isoquinolin-4-one. 2,3-dimethyl-6- (2-phenylethyl) -4,4a, -t5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrro-0.3410 / 2, 3 g / isoquinolin-4-one

Ras. 2-methyl-3-ethyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans - 0,37 1H-pyrrolo [2, 3 g / isoquinolin-4-one

Ras. 3-ethyl-2-methyl-6- (3-phenoxypropyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-0.48 1H-pyrrolo [2,3 -g / isoquinolin-4-one

Ras. 3-ethyl-2-methyl-6- [2- (methoxyphenyl) ethyl] -4,4a, 5,6,7,8,8a, 9-octa-0,54 hydro-4a, 8a-trans 1H-pyrrolo [2,3-g] isoquinolin-4-one 67548 25

Compound of formula A VB ^ q mg / kg p.o.

Ras. 2-methyl-3-ethyl-6- (2-hydroxy-3,3-dimethyllibutyl) -4,4a, 5,6,7,8,8a, - 0,62 9-octahydro-4a, 8a- trans-1H-pyrrolo [2,3-g] isoquinolin-4-one

Ras. 2-methyl-3-ethyl-6- (2-hydroxy-3-methylbutyl) -4,4a, 5,6,7,8,8a, 9-octa-0.71 hydro-4a, 8a-trans-1H -pyrrolo [2,3-g] isoquinolin-4-one

Ras. 2-methyl-3-ethyl-6- [3- (fluorophenyl) -3-oxopropyl] -4,4a, 5,6,7,8,8a, -855 9-octahydro-4a, 8a- trans-lH-pyrrolo / 2,3 g / isoquinolin-4-one

Ras. 3-ethyl-2-methyl-6- [2- (2-thienyl) ethyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-0.87 trans-1H pyrrolo / 2,3 g / isoquinolin-4-one

Ras. 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8, -8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo-0,94 / 2,3-g / isoquinoline -4-thione

Ras. 3-ethyl-2-methyl-6- [2- (4-chlorophenyl) ethyl] -4,4a, 5,6,7,8,8a, 9-1,50 octahydro-4a, 8a-trans- H-pyrrolo / 2,3 g / isoquinolin-4-one

Ras. 2-methyl-3-ethyl-6-benzyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-1,70 trans-1H-pyrrolo [2,3-g] isoquinoline -4-one

Ras. 3-ethyl-2-methyl-6- [2- (ethenyloxy) ethyl] -4,4a, 5,6,7,8,8a, 9-octa-hydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -1,55 quinolin-4-one 26 6 7 5 4 8

The compounds of formula A and their pharmaceutically acceptable acid addition salts have anti-mental effects which are qualitatively similar to the effects of Haloperodol, Trifluorperazine and Molindon, which are known for their therapeutic use and properties. Thus, the pattern of activity of the compounds of formula A is in accordance with the pattern of anti-mental agents of known potency and safety.

The compounds of formula A and their pharmaceutically acceptable acid addition salts may be used in the form of conventional pharmaceutical preparations. For example, suitable oral dosage units range from 0.05 to 50 mg, and suitable oral dosages for warm-blooded animals range from about 0.001 mg / kg per day to about 10 mg / kg per day. However, the specific dosage for each particular warm-blooded animal may vary and should meet individual needs and the judgment of a person performing or supervising the administration of a compound of formula A or a pharmaceutically acceptable salt thereof. Also, the frequency of administration of each such dosage form will vary depending on the amount of active drug contained in the dosage and the requirements of the pharmacological situation.

For the stated use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are combined, with the addition of a number of conventional neutral pharmaceutical excipients, into dosage forms suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, and the like. Further, suitable hard or soft capsules can be prepared from the compounds of formula A and administered in these forms. The nature of the neutral excipients used in connection with the compounds of formula A and their pharmaceutically acceptable acid addition salts for the preparation of oral and parenteral dosage forms will be readily apparent to those skilled in the art. These excipients, either inorganic or organic, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, resins, polyalkylene glycols, etc. If desired, preservatives, stabilizers, humectants, humectants, emulsifiers, emulsifiers may be added to such formulations. and the like.

27 ... 67548

Because the compounds of formula A and their pharmaceutically acceptable acid addition salts have an asymmetric carbon atom, they are usually formed as racemates. Separation of such racemates into optically active isomers can be accomplished by known procedures. Several racemates can be precipitated as eutectic mixtures and then separated. However, chemical separation is considered a priority. It forms diastereomers from a racemic mixture with an optically active resolving agent, e.g. an optically active acid such as (+) - tartaric acid, to form a diastereomeric salt. The diastereomers formed are separated by fractional crystallization and can be converted into the corresponding optical base isomer. Thus, the invention includes optically active isomers of the compounds of formula A as well as their racemates.

Due to the possible three-dimensional differences between their atoms, it is further understood that the compounds of formula A can be obtained in more than one possible geometric form.

The following examples illustrate the invention. All temperatures are in degrees Celsius unless otherwise noted.

Example 1 a) Preparation of N-2- (3,5-dimethoxyphenyl) -ethylcarbamic acid ethyl ester To a 5-liter three-necked flask equipped with a mechanical stirrer and addition funnel was charged 32.63 g of (3,5-dimethoxyphenyl) -ethylamine hydrochloride, 600 ml of water, 600 ml of methylene chloride and 150 ml of 1-norm. sodium hydroxide-O. The mixture was stirred and cooled in an ice bath by the dropwise addition of 16.28 g of chloroformic acid ethyl ester in 60 ml of methylene chloride over 30 minutes. During the addition, a total of 150 ml of 1-norm was added. sodium hydroxide solution in eight portions to maintain the pH between 8-9. After the addition was complete, the mixture was stirred for one hour in an ice bath. 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, and dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated on a rotary evaporator to give 37.1 grams of crude N-2- (3,5-dimethoxyphenyl) -ethylcarbamic acid ethyl ester as a colorless oil.

67548 28 b) Preparation of N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride In a 3-liter three-necked beaker equipped with a mechanical stirrer, addition funnel and condenser, 180 ml of 70% sodium dihydrobis- (2-methoxyethoxy) was added. ) aluminate solution and 700 ml of dry tetrahydrofuran. The solution was cooled in an ice bath, and a solution of 37.1 g of crude N-2- (3,6-dimethoxyphenyl) -ethylcarbamic acid ethyl ester in 100 ml of dry tetrahydrofuran was added over 16 minutes. After the addition, the mixture was heated at reflux for 1 hour and then cooled in an ice bath, the excess hydride being discarded by dropwise addition of 100 ml of 5% sodium hydroxide solution. After all the base was added, the organic layer was separated and the aqueous layer was extracted with 100 ml of ether. The combined organic solutions were evaporated to an oil on a rotary evaporator and the oil was dissolved in 300 ml of ether. The ether solution was washed with 50 mL of water, 50 mL of brine, dried over anhydrous sodium sulfate and filtered. To precipitate the amine hydrochloride, 70 ml of ethereal hydrogen chloride solution was added to the filtrate. The solid was collected on a Buchner funnel and crystallized from 180 mL of absolute ethanol and 270 mL of ether to give 28.9 g of N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride as a white crystalline solid, m.p. . 160-164 °.

c) 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 the solution made alkaline with 160 ml of ammonium hydroxide. The mixture was extracted with 3 x 1000 mL of methylene chloride, and 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 35-4 ° gave 156.0 g of the free base.

In a 12-liter three-necked cooking flask equipped with a mechanical stirrer and two dry ice-coolers.

II

29 67548 ice, one equipped with a gas supply line, the other with a drying line containing soda-lime, was condensed with 4.0 l of anhydrous ammonia. A solution of 156.0 g of the free base in 400 ml of t-butanol and 400 ml of dry ether was added to the ammonia mixture over 15 minutes. A total of 33.6 g of lithium wire cut into 6.35 cm (2.5 inch) pieces was added to the stirred solution over 50 minutes. The insertion rate was adjusted so that yarn was added 12.7 cm per minute. After all the lithium was added, the deep blue mixture was stirred at reflux for 2 hours. To dilute the mixture, 2.8 L of dry ether was then added, the drying tube was removed to release hydrogen, and a total of 280 g of ammonium chloride powder was slowly added over 30 minutes until the blue color disappeared. The dry ice-cooler was removed and the mixture was stirred, allowing ammonia to evaporate overnight. To the residue was added 2.81 ice water. The mixture was transferred to a separatory funnel where it was rinsed with 800 mL of ether and the layers were separated. The aqueous layer was extracted with 2 x 1.5 L of methylene chloride, and the extracts were combined and washed with one L of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 40 and finally at 40 ° under a 1.0 mm vacuum for 1.5 hours gave 150.7 g of crude product as a yellow oil. The crude oil was distilled on a 30.5 cm (12 inch) Goodloe column (bath 150) to collect the following fractions:

Fraction _Sp._ Weight GC purity 1 40-80 ° / 0.45 mm 7.9 g 4.6% 2 80-85 ° / 0.45-0.15 mm 6.2 g 50% 3 85-86 ° / 0.15 mm 21.2 g 92% 4 86-87 ° / 0.15 mm 99.4 g 100%.

From the combined fractions 3 and 4, 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine were obtained as a colorless oil.

30 6 7 5 4 8 d) Preparation of 6- [2- (N-methylamino) ethyl] -2-methyl-3-ethyl-6,7-dihydro- (5H) -4 (1H, 5H) -indolone in 1 liter A three-necked beaker equipped with a mechanical stirrer and condenser was charged with a solution of 60 μg of distilled N-methyl-1,5-dimethoxycyclohexa-1,4-dien-3-ethylamine 7U (J in 70 mL). aqueous reaction solution of acetic acid. The reaction mixture was refluxed under reflux for 15 minutes, and 59.5 g of zinc dust was added in five portions over 10 minutes and then. The mixture was further refluxed for 15 minutes. The refluxing solution was added over one hour. containing 42.1 g of 2-iso-nitroso-3-pentanone in 175 ml of a 70% aqueous acetic acid solution, the mixture was refluxed for 2.5 hours and cooled to room temperature, and the precipitated silica acetate was filtered off and the filter cake was washed with 50 ml. 11a methylene chloride The filtrate was evaporated to dryness swirled on rotational evaporation and the residue was heated at 100 ° under a 1.0 mm vacuum for 30 minutes to remove the last residual acetic acid. The residue was dissolved in 500 ml of water, and the solution was extracted with 2 x 150 ml of methylene chloride. The methylene spiral extracts were discarded and the aqueous layer was basified with 165 mL of ammonium hydroxide (pH 8-3), and 500 mL of brine was added.

The mixture was extracted with 3 x 200 mL of methylene chloride, and the combined extracts were washed with 100 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 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 and seeded, and allowed to crystallize with stirring overnight. The first batch of 20.8 g was collected by filtration, and the mother liquor was evaporated to dryness and recrystallized from the stirred solution to give a second batch of 10.0 g. The mother liquor was dissolved in 75 ml of methanol and a solution of 15.0 oxalic acid in 50 ml of methanol was added. The mixture was heated for 10 min. in a water bath and then cooled. The solid oxalate was 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 with 2 x 50 ml of 31,67548 methylene chloride. The extract was washed once with 20 ml of brine and dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give an additional 4.5 g of crude product. Crystallization from toluene / ethyl acetate 2: 1 gave an additional 2.6 g of crystalline product. Both batches and crystals from the oxalate were combined and the mixture was dried at 25 ° under 1 mm vacuum for 2 hours to give 33.4 g of 6- [2- (N-methylamino) ethyl] -2-methyl-3-ethyl- 6,7-dihydro- (5H) -4 (1H, 5H) -indolone as a pale yellow solid, m.p. 114-120 °, homogeneous after thin layer chromatography.

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- Preparation of onion hydrochloride 17.0 g of 6- [2- (N-methylamino) ethyl] -2-methyl-3-ethyl-6,7-dihydro- (5H) -4 (1H) was placed in a 500 ml round bottom flask. , 5H) -indolone and 170 ml of methanol. To the solution was added 20 ml of 4-norm. diethyl ether solution of hydrogen chloride (prepared by introducing HCl gas into diethyl ether in an ice bath and titrating). The solvent was removed on a rotary evaporator and the remaining residue was dried at 50 ° under 1 mm vacuum for 2 hours to give 19.7 g of crude hydrochloride.

A 3-liter three-necked flask equipped with a mechanical stirrer, thermometer, and distillation head was charged with 19.7 g of hydrochloride, 21.8 g of paraformaldehyde, and 1000 mL of octanol. The reaction mixture was heated to reflux, and the liberated water was removed by distillation until the temperature of the octane solution in the flask had risen to 175-180 °, after which the distillation head was removed and replaced with a reflux condenser. The reaction mixture was heated at 175-180 ° for 1 hour, and 6.54 g of paraformaldehyde was added in three portions over 5 minutes. Water was distilled off as before until a temperature of 175-180 ° was reached, and the mixture was heated for another hour at 175-180 °. The dark brown solution was cooled and poured into 1000 ml of water. The layers were separated and the organic layer was extracted with 2 x 400 mL of 5% hydrochloric acid. The combined aqueous extracts were washed with 2 x 150 mL of chloroform and the chloroform solutions were discarded. To the aqueous layer were added 120 ml of ammonium hydroxide and 400 ml of chloroform. The layers were separated and the aqueous solution was extracted with 4 x 200 mL of chloroform. The combined chloroform extracts were washed with 200 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 12.0 g of crude pyrrolo [2,3-g] isoquinoline as a mixture of 4a, 8a-trans, 4a, 8a-cis (about 8: 1) as a dark yellow-brown solid. The crude solid was dissolved in 100 mL of methylene chloride / methanol (9: 1) and 300 mL of diethyl ether was added. A fine solid precipitate, mainly the 4α, 8α-trans isomer, was collected by filtration, and the filtrate was concentrated and crystallized to give a second and third crop of a tan solid. The combined material was dried at 25 ° under 1 mm vacuum for 1 hour to give 8.20 g of a light gray solid, 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. 203-226 °. The partially purified gray solid was suspended in 80 mL of methanol, and 12 mL of 4-norm was added. diethyl ether solution of hydrogen chloride. The solvent was removed and the residue was crystallized from 25 ml of hot, absolute ethanol. The first batch was collected by filtration, and the mother liquor was concentrated and crystallized to obtain the second and third batches. The combined solid was dissolved in 120 mL of methanol, and 2.4 g of activated carbon (Darco-G-60) was added. The mixture was heated on a water bath for 10 minutes and the charcoal was filtered off with Celite. The filtrate was concentrated and recrystallized from 15 ml of ethanol to give 3 portions of white crystals. The combined solid was dried under 0.05 mm vacuum at 80 ° for 18 hours to give 5.4 g 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 as a white solid, m.p. 196-198 °; oxime semihydrate, m.p. 151-133 °.

33 67548

Following the procedure of Examples Id and 1e, the compounds shown in Table I were prepared from the appropriate isonitrosoketone with the indicated changes. The spectral values of each compound were consistent with the described structure. Melting points refer to the melting points of the free base or hydrochloride as indicated. Isonitrosoketones were prepared as described in the literature (e.g., Ferris et al., J. Org. Chem., 24, 1726 (1959)) by nitrosating the appropriate ketone. The isolated compounds are 4α, 8α trans isomers.

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67548

Example 2 a) 2-Methyl-3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- Preparation of 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 according to Example 4 (4.92 g, 20 mmol), chloroformic acid ethyl ester (19.55 g, 180 mmol) and potassium hydrogen carbonate (6.0 g, 60 mmol) in diethyl ketone (100 mL) were heated at reflux for 3 hours. The mixture was cooled, filtered and the filtrate was evaporated to dryness on a rotary evaporator and the residue was dissolved in chloroform. The chloroform solution was washed with 5% aqueous hydrochloric acid, 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-III to give 3.70 g of pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4,4a, 5,6 , 7,8,8a, 9-octahydro-lH-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) were heated at reflux for 24 hours, cooled and evaporated to dryness on a rotary evaporator. The residue was dissolved in water and extracted with chloroform (discarded), and the aqueous layer was made alkaline with ammonium hydroxide, extracted with chloroform. The combined extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated to dryness to give 2.72 g of crude sec. amine. Treatment of the crude amine in ethanol with ethanolic hydrogen chloride gave the hydrochloride which was crystallized from hot ethanol to give 2.18 g (47% yield) of 2-methyl-3-ethyl-4,4a, 5,6,7,8,8a 1,9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride as white crystals, m.p. 250 °. Analysis calculated for compound 0. HCl: 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 manner, 2,3-dimethyl-4,4a, 5,6, -7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one can be prepared. 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-pyrrolo / 2,3 g / isoquinolin-4-one.

36 67548 b) 3-Ethyl-2-methyl-6- (2-propenyl) -4,4a, 5,6,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo Preparation of [2,3-g] isoquinolin-4-one A mixture of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo / 2,3 g / isoquinolin-4-one (0.470 g, 2.03 mmol), allyl bromide (0.5 g, 4.13 mmol) and potassium carbonate (0.85 g, 6.16 mmol) in acetone (35 mL). , stirred for 2 hours at room temperature and filtered. The filtrate was concentrated and the residue (0.53 g) was chromatographed on alumina to give product III (0.40 g). This product was treated with ethereal hydrogen chloride to give the hydrochloride, which was 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 °.

Analysis calculated for 0.1 H 2 O 2 · 0.5 H 2 O 5 H 2 O: C, 64.24; H 8.25; N 8.81; Cl "11.15; found: C 64.50; H 8.48; N 8.96; Cl" 11.37.

In a manner similar to Example 2b, the compounds shown in Table II were prepared from said 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one and the indicated halide. The spectral values of each compound were consistent with the described structure. Melting points refer to the melting points of the free base or hydrochloride. The isolated compounds are the 4a, 8a trans isomers.

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Example 3 a) Preparation of 3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline 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 2-norm. sodium hydroxide and extracted with methylene chloride. The combined extracts were evaporated to dryness on a rotary evaporator and mixed with aqueous formaldehyde (65 ml, 37% solution). The mixture was refluxed for 2 hours, made alkaline at 2-norm. sodium hydroxide (15 ml) and extracted with methylene chloride. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and evaporated to a yellow product oil (15.5 g). The oil was dissolved in 100 ml of ethanol and treated with ethanolic hydrogen chloride solution. Ether (75 ml) was added and the salt crystallized apart to give 10.15 g of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (64% yield).

b) 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 into a beaker containing t-butanol (9.1 g, 123 mmol) and diethyl ether (50 mL). To the solution was added 3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring for 2-3 minutes, lithium wire (0.57 g, 82 mmol) was added in short portions over 30 minutes. The blue solution was stirred at reflux for 2.5 hours and solid ammonium chloride (4.5 g) was added until the blue color disappeared. Ether (100 mL) was added and the ammonia was allowed to evaporate overnight. Ice water (100 ml) was 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 and concentrated to give 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, 68% yield) as a yellow oil. .

The crude product (1.05 g) was refluxed in 20 ml of 70% aqueous acetic acid for 5 hours,

II

67548 47 and the acetic acid was removed on a rotary evaporator. The residue was dissolved in water and washed with chloroform. The aqueous phase was concentrated to 10 mL and chromatographed on Dowex AG 50WX 8 eluting with 2M aqueous pyridine to give 0.11 g of octahydro-2-methylisoquinoline-6,8-dione (11.6% yield) as a pale yellow. as a solid. Treatment with hydrogen chloride solution in methanol gave the hydrochloride, m.p. 193-196 °.

c) Preparation of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one octahydro-2- via methyl isoquinoline-6,8-dione 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.68 mmol) heated at 90-100 ° C in 70% aqueous acetic acid (10 mL) to hydrolyze the bis (ethanol ether) to octahydro-2-methylisoquinoline-6,8-dione. To the hot solution was added zinc dust (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The mixture was refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate was evaporated 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 brine and dried over anhydrous sodium sulfate and evaporated to a crude product. Chromatography of the crude product on alumina gave 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octa-hydro-1H-pyrrolo [2,3-g] isoquinoline. -4-one as a white solid (0.19 g, 29% yield).

Example 4 2,6-Dimethyl-3-isopropyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- onion Preparation of a solution of crude octahydro-2-methyl-isoquinoline-6,8-dione (about 12.5 mmol) and 2.4 g (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 ml: in 70% aqueous acetic acid, treated with 2.6 g (40 mmol) of zinc dust and slowly heated to boiling. After 1 hour, the mixture was cooled slightly and an additional 0.4 g of isonitrocoketone and 1.0 g of zinc 48 67548 were added and the mixture was stirred at reflux for 1.5 hours. The mixture was then cooled and filtered and the filtrate was concentrated at 50 ° under a vacuum of 20 mm Hg to a yellow oil which was diluted with 50 mL of water and made alkaline with ammonium hydroxide (pH 8-9). The mixture was extracted with chloroform, and the extracts were washed with brine and dried over sodium sulfate, and concentrated to 2.6 g of a crude product. The material was chromatographed on 100 g of silica gel (dry column) eluting with a mixture of 90 (v / v) chloroform, 30 parts methanol, 10 parts water and 6 parts acetic acid in an organic phase. The product-containing eluate fractions were evaporated to dryness, diluted with water, made alkaline with ammonium hydroxide (pH 8-9) and extracted with chloroform. The extracts were dried over sodium sulfate and evaporated to 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, 8α, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a crystalline solid, m.p. 244-247 °.

Example 5 3,6-Dimethyl-2- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo / 2,3- Preparation of g / isoquinolin-4-one from 3-isonitroso-5-hexen-2-one and 2-methyl-octahydroisoquinoline-6,8-dione was obtained as described in Example 4 to give 3,6-dimethyl-2- (2-propenyl ) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 221-223 °.

Example 6 3-Cyclopropyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4- Preparation of cyclopropyl-2-isonitroso-1-propanone and 2-methyl-octahydroisoquinoline-6,8-dione was obtained as described in Example 14 with 3-cyclopropyl-2,6-dimethyl-4,4a, 5,6,7,8, 8α, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 258-259 ° (dec.).

Il 67548 49

Example 7 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 3-Isonitroso-4-phenyl-2-butanone and 2-methyl-octa-hydroisoquinoline-6,8-dione were obtained as described in Example 4 to give 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, m.p. 234-235 °.

Example 8 Preparation of 6-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a, -trans-1H-pyrrolo [2,3-g] isoquinolin-4-one from aminoacetaldehyde dimethyl acetal and 2-methyl-octahydroisoquinoline-6,8-dione was obtained in the same manner as described in Example 4, except that no zinc was used, 6-methyl-4,4a, 5,6,7,8,8a, 9 -octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 208-210 °.

Example 9 3-Ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -4,4a, 5-6, 7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo / Preparation of 2,3-g / isoquinolin-4-one

A mixture of 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one (0.83 g , 3.58 mmol) and styrene oxide (0.51 g, 4.22 mmol) in methanol (25 mL) were refluxed for 2.5 h, cooled and filtered. The filtrate was evaporated to dryness and the residue was chromatographed on alumina III to 0.69 g of crude product. 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 , 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a white solid, m.p. 218.5 - 220 °.

Analysis calculated for ^ 22 ^ 28 ^ 2 ^ 21 C 74.97; H 8.01; N 7.95; Found: C, 74.87; H 7.92; N 7.95.

As described in Example 9, the compounds shown in Table III were prepared from 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one and the indicated epoxide. The spectral values of each compound were consistent with the described structure. Melting points refer to the melting points of the free base or hydrochloride. The isolated compounds are 4a, 8a trans isomers.

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Example 10

Racemic 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 decomposition

The racemic free base (prepared as in Example 1) (1.20 g) was dissolved in methanol, and a solution of d - (+) - tartaric acid (0.74 g) in methanol was added. The solution was evaporated to dryness and recrystallized twice from methanol. Crystalline d - (+) - tartrate was treated with ammonium hydroxide to liberate the free base, and the free base was treated with anhydrous ethereal hydrogen chloride to prepare the hydrochloride.

Recrystallization twice from ethanol and drying at 80 ° under a vacuum of 0.005 mm gave 0.15 g of the (-) - enantiomer as a white crystalline solid, m.p. 240-> 245 °.

Rotation: ζ-120.78 ° (c 0.81%, water)

Analysis, calc. for 2 O · HCl.0.2 0: C, 62.70; H 8.24; N 9.75; Found: C, 62.44; H 8.33; N 9.67. The mother liquors obtained in the crystallization of d - (+) - tartrate were treated to liberate the free base with ammonium hydroxide, which was treated with a solution of 1 - (-) - tartaric acid (0.46 g) in methanol. The solution was evaporated to dryness and recrystallised twice 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 °.

Rotation: + 121.38 ° (c 0.44%, water)

Analysis calculated for 2 O · HCl.0.2 0: C, 62.70; H 8.24; N 9.75; Found: C, 63.02; H 8.20; N 9.88.

Example 11 N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo / 2, Preparation of 3-g (isoquinolin-6-yl) -4-fluorobenzamide N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo) -4a, 8a-trans-1H-pyrrolo [2,3-g (isoquinolin-6-yl) ethyl] -4-fluorobenzamide was prepared by heating 3-ethyl-2-methyl-

II

67548 53 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 in a mixture of was benzene and methanol. The crude product crystallized from ethanol as a white solid, m.p. 252-253 °. The aziridine starting material was prepared from aziridine and p-fluorobenzoyl chloride and sodium carbonate in water.

Example 12 3-Ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4 Preparation of a mixture of 2.48 g (0.01 mol) of 3-ethyl-2,2-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo (2,3-g) isoquinolin-H-one and 2.44 g (0.008 mol) of P 2 S 2 in 100 ml of dioxane were stirred and refluxed for 17 hours. The dioxane was evaporated off in vacuo and 150 ml of water and enough ammonium hydroxide were added to bring the pH to between 8-9. The mixture was extracted with chloroform, and the extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent gave crude thione (3.3 g) as a gum. Chromatography on a dry column gave 1.2 g of solid thione which was recrystallized twice from acetone to give pure 3-ethyl-2,6-dimethyl-2,6-dimethyl-4,4a, 5,6,7,8, 8α, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinoline-4-ion, m.p. 194-196 ° (dec.).

Example 13 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] isoquinoline 4-one and 1.77 g (4 mmol) of phosphorus pentasulfide in 60 ml of dioxane were stirred and refluxed for 10 hours. The mixture was cooled and the dioxane solution was decanted off from the dark residue which was dissolved in 75 money in water. The solution was made alkaline (pH 8-9) with ammonium hydroxide, 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 g of crude thione, which was chromatographed (dry column, silica gel) together with 100 mg of the other crude product obtained by treating the residues remaining in the initial isolation with hot water and then extracting at the same time. chloroform. Elution of the dry column mixture prepared by equilibrating a mixture of 90 (v / v) chloroform, 30 parts methanol, 10 parts water and 6 parts acetic acid with the organic phase gave pure thion to dryness, dissolving in water, ammonium hydroxide to pH 8. -9 after neutralization and extraction with chloroform. After washing with water and drying over sodium sulfate and evaporation of chloroform, 250 mg of 3-ethyl-2-methyl-9,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquino were obtained. -lin-4-thione as a yellow solid, m.p. 190-194 °. Recrystallization from acetonitrile gave the pure 4a, 8a trans isomer, m.p. 203-205 °.

Example 14 3-Ethyl-2-methyl-6- (2-phenylethyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrole [2,3 Preparation of -g / 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- thion, 276 mg of potassium carbonate and 222 mg of 2-bromoethylbenzene in 15 ml of 3-pentanone, were stirred and refluxed for 3 hours. The solvent was removed on a rotary evaporator, 25 ml of water was added, and the mixture was extracted with chloroform. Purification by dry column chromatography as detailed in Example 15 gave 100 mg of purified product, yielding 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 ° (decomposed) after recrystallization from acetonitrile.

The compounds shown in Table IV were prepared by the methods described in Examples 1e) and 2b).

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Claims (6)

1 R3 'Ru' 'J- -if ί, Jl H "c" H where R2', Rg * and R '' denote the same as above, and if desired 1. Isomerize the obtained mixture of cis- and trans isomers, such that substantially the obtained trans isomer 2. separates the trans isomer from the obtained mixture 3. divides a obtained racemic mixture into optical antipodes, and / or 4. converts a obtained compound or a pharmaceutically unacceptable acid addition salt into a pharmaceutically acceptable acid addition salt. 1 A. H where R 2 is hydrogen, C 1-6 alkyl, C 2-7 alkenyl, C 1-6 alkanoyl or phenyl C 1-7 alkyl, is hydrogen, C 1-7 alkyl, C 3-6 cycloalkyl or phenyl, is C 1-7 alkyl, C 1-7 hydroxyalkyl, aryl C 1-7 hydroxyalkyl, C 1-7 alkoxy-C 1-7 alkyl, aryloxy-C 1-6 hydroxyalkyl, aryl carbonyloxy-C 1-7 alkyl, arylcarbonyl -C 1-7 alkyl, C 1-7 alkoxy-carbonyl-C 1-7 alkyl, aryl C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl-C 1-7 alkyl, C 2-7 alkynyl, thienyl-C 7-alkyl, furyl-C 1-7 alkyl, aryl carboxamido-C 1-7 alkyl, C 1-7 alkanolyl-C 1-7 alkyl, C 2-7 alkenyloxy-C 1-7 alkyl, aryl C 2-7 alkenyl , aryloxy-C 1-7 alkyl. N, N-benzimimidazole-2-oa-1-yl-C 1-7 -alkyl di-C 1-7 -alkyl-MC 1-7 alkyl or morpholino-C 1-6 -alkyl-pyrrolidinyl-C 1-7 -alkyl Alkyl and X are 0 or S, wherein aryl represents phenyl or a halogen, C 1-7 alkyl or C 1-7 alkoxy monosubstituted phenyl, characterized in that a) the isoquinoline nitrogen atom in a compound of the formula X 3 l | xv N / R2 H where, R2, Rg and X are taken together as above, substituted using a halide, epoxide or aziridine, or b) a compound of formula (V) H (-R3) lΧ / νΛ Where R 2 and R 3 are the same as above and R 2 is C 1-6 alkyl, C 1-7 alkoxy-C 1-7 alkyl or C 3-6 cycloalkyl C 1-7 alkyl, treated with formaldehyde, whereby obtains a compound of formula R R, _______, R i in I Ji ia, N N R2 R0 IZH where R₂, R3 and R ^ "are the same as above, or c) a compound of formula O V X XII where R ^ "represents the same as above treated with a compound of formula 0. 2, R 2, 3 VII HON 2 R 2 in the presence of a reducing agent or with a compound of formula" R 3 VIII H 2 N - 2 r 2 or a precursor thereof, in which Formulas R 2 and R 3 are the same as above to give a compound of formula Ia, or d) a compound of formula R 4, R 1 is hydrogen, C 1-4 alkyl, C 2. 7-alkenyl or phenyl-C 1-7 alkyl, is hydrogen, C ^^ - alkyl alkyl, C3_g cycloalkyl or phenyl and R ^ "are C1_7 alkyl, C ^^ - alkoxy-C. ^ Alkyl, aryl C C ^ alkyl, C₂_7 alkenyl, C3_ cycloalkyl C C17 - alkyl, C2-6 alkynyl, thienyl C1-7 alkyl, furyl C1-7 alkyl, C2-7 ~ alkenyloxy-C1-7 alkyl, aryl-C2-7 alkenyl or aryloxy-C1-7 alkyl are treated with phosphorus pentasulfide, wherein a compound of the formula is obtained A process for the preparation of therapeutically useful octahydro-1H-pyrroloZ.2,3-gisoquinolines of Formula A, optical icebergs and geometric isomers thereof, and pharmaceutically acceptable acid addition salts thereof, X./R3 Rh- N j, Γ) A process according to claim 1 for the preparation of 3-ethyl-2,6-dimethyl-U, 4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo / 2,3 -gisoquinolin-4-one, characterized in that, as a starting material, a correspondingly substituted compound of formula XV, IX or XII is used. A process according to claim 1 for the preparation of 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, as a starting material, a compound of formula XV is substituted in a corresponding manner.