MC1285A1 - ISOQUINOLEIN DERIVATIVES - Google Patents

Description

-1-

The present invention relates to octahydro-1H-pyrrolo[2,3-g]isoquinolines of general formula

10

HAS

where R/j is a hydrogen, an alkoyl, an alcanoyl, an aroyl or an aralkoyl; Rg and R^, independently, represent a hydrogen, an alkoyl, a cycloalkoyl, an alkenyl, an acyl, an aryl or an aralkoyl; R^_ is a hydrogen, an alkyl, a hydroxyalkyl, a phenylhydroxyalkyl, a halophenylhydroxyalkyl, an al-coylphenylhydroxyalkyl, an alkoxyphenylhydroxyalkyl, an alkoxyalkyl, an aryloxyhydroxyalkyl, an alkoxyhyaroxyalkyl, an acyloxyalkyl, an arylcarbonylalkyl, an alkoxycarbonylalkyl, an aralcyl, an alkenyl, an alkylcycloalkyl, an alkylnye, a thienylalkyl, a furylalkyl, an arylcarbaminoalkyl, an acylalkyl, an cyclic alkyloxoalkyl, a cyclic alkylhydroxyalkyl, an alkenyloxyalkyl, an aralcyl, a aryloxyalcohol, un-alcohol-pyrrolidinylalcohol, a trifluoroalcohol having 2 to 6 carbon atoms, an aryl-N-imidazolo-nylalcohol, or 30 Rfi-^

N-alcohol, where R,- and R„, independently, R? ^ 0 <

represent a hydrogen/m an alkyl or, taken together with nitrogen, a heterocyclic ring with 5 or 6 members; and X represents 0 or S,

the optical and geometric isomers of these compounds and their pharmaceutically acceptable acidic addition salts.

As used here, the term "alcoyl" preferably denotes a "lower alcoyl", that is, a straight- or branched-chain saturated hydrocarbon containing 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, etc. The term "alkoxy" preferably denotes a "lower alkoxy," that is, an alkyl ether group where the lower alkyl group is as described above, for example, a methoxy, an ethoxy, a propoxy, a pentoxy, etc. The term "alkenyl" preferably denotes a "lower alkenyl," that is, a straight- or branched-chain unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, vinyl, allyl, etc. The term "alkynyl" preferably denotes a "lower alkynyl," that is, a straight- or branched-chain unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, ethynyl, propargyl, methylbutynyl, etc. The term "halogen" or "halo"

denotes halogens, bromine, chlorine, fluorine, and iodine. The term "trifluoroalkyl having 2 to 6 carbon atoms" preferably denotes 2,2,2-trifluoroethyl, etc. The term "aryl" denotes a phenyl or a phenyl with one or more substituents selected from the group consisting of halogens, trifluoromethyl, lower alkyls, lower alkoxys, nitro, amino, lower alkylaminos, and lower di-alkylaminos. The term "aralkyl" preferably denotes benzyl, etc. The term "aryloxy"

-3-

Deriote is an arylether group where the aryl group is as described above, for example, phenoxy, etc. The term "acyl" denotes an "alcanoyl" group derived from an aliphatic carboxylic acid having from 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, etc.; and an "aroyl" group derived from an aromatic carboxylic acid, such as benzoyl, etc. The term "acyloxy" denotes an "alcanoyloxy" group derived from an aliphatic carboxylic acid having from 1 to 7 carbon atoms, for example, formyloxy, acetoxy, propionyloxy, etc.; and an "aroyloxy" group derived from an aromatic carboxylic acid, such as benzoyloxy, etc. The term "cyclic alkyl" denotes a cycloalkyl group having 3 to 6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or a bicycloalkyl group such as bor-nyl, or a tricycloalkyl group such as adamantyl. The 5- or 6-membered heterocyclic nucleus is derived from a saturated heterocyclic compound comprising one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, where the second nitrogen atom may be substituted by an alkyl or a hydroxyalkyl, for example, morpholino, N-methylpiperazino, piperazino, pyrroli-dino, etc.

25 The preferred compounds of formula A are those where is a hydrogen, R£ and R^ are alkyls; R^_ is an alkyl, a hydroxyalkyl, a phenyl-hydroxyalkyl, a halophenyl-hydroxyalkyl, an alkoxyalkyl, an aryloxyalkyl, an arylcarbonylalkyl, or an aral-30 alkyl; and X is 0.

The most popular compounds of formula A of the invention where X is 0 are:

3-ethyl-2,6-dimethyl-4,4a,5,6,7 >818a,9-■octahydro-4a,8a-trans-1ïï-pyrrolo-[2,3-gjisoquinoline-35 4-one;

-4-

The (-)-3-ethyl-2,6-dimethyl-4,4a,5,6,7 >8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-[2,3-gjisoquinoline-4-one;

Hydrochloride of (-)-3-ethyl-2,6-dimethyl-5 4,5a,5i6,7j8,8a,9-oc tah.ydro-4a,8a-tran s -1H-pyrr ol o-[2,3-g]isoquinoline-4-one hydrate 0,25M;

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

10 2,3,6-trimethyl-4,4a,5,6,7i8,8a,9-octahydro-

4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one;

2,3,6-trimethyl-4,4a,5,6,7>8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquino-lein-4-one hydrochloride;

13 2-Methyl-3-ethyl-6-benzyl-4,4a,5,6T7»8,8a,9-

octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-

one;

2-methyl-3-ethyl-6-benzyl-4,4a,5 î 6,7 5 8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-20 [2,3"SJis°Q.uii10léiiie-4-one ;

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-one;

2-methyl-3-ethyl1-6-(2-ethoxyethyl1)-4,4a,5,6,257?8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-onc;

The hydrochloride of 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a:5,6,7? 8,8a,9-octahydro-4a,8a-trans-1αβ-pyrrolo[2,3-g]isoq-inoleine-4-one; 30 The 2-methyl-3-ethyl-6-[4-(4-fluorophenyl)-4-

oxobùtyl]-4,4a,5 î 6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-oiie;

2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3-oxopropyl]-4,4a,5,6,7? 8,8a,9-octahydro-4a,8a-trans-1H-35' pyrrolo[2;3-gJiso(d'u.inoleirie-4-orie ;

-5-

2-methyl-3-ethyl-6-(3-plienoxypropyl)-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-(2-hydroxy-3-methyl-5 butyl)-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-(2-hydroxy-3,3-dimethyl-butyl)-4,4a,5,6,7 i 8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one; and 10 2,6-dimethyl-3-ethyl-4,4a hydrochloride,

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

Examples of compounds with formula A where X is 0 include: 15 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octa-

hydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3-ethyl-2,6-dimethyl-4,4a,5,6,758,8a,9-octahydro-111-pyrrolo[2,3-g]isoquinoline--4-one;

3-ethyl-1,2,6-trimethyl-4,4a,5,6,7?8,8a,9-20 octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

The 1~benzoyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7i 8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3-ethyl-2-methyl-6-(2-propynyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo-[2,3-g]is°quinoline-4-25 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;

Hydrochloride of ( + )-3-ethyl-2',6-dimethyl-30 4,4a,5,6,7j8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo- -[2,3-gJisoquinoline-4-one hydrated 0,25M;

3i6-dimethyl-2-(2-propyl)-4,4a,5,6,7,8,8a,9'-octahydro-1H-pyrr ol o [2,3-g]isoquinoline-4-one;

35 La 3,6-dimethyl-2-(2-propyl)-4,4a,5,6,7»8,8a,9-

-6-

octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

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

2-methyl-3-ethyl-6-[2-hydroxy-2-(4-chloro-5 phenyl)ethyl]-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo-[2,3-gIsoquinoline-4-one;

2-methyl-3-ethyl-6-(2-hydroxyethyl)-4,4a, 5j6,7 »8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline~ 4-one;

10 2-Methyl-3-ethyl-6-(2-propenyl)-4,4a,5,6,

7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

2-methyl-3-ethyl-6-(2-propenyl)-4,4a, 5 j 6, 7,8,8a,9-octahydro-1H-pyrrolo[2,3-gJisoquinoline-4-one;

15 L® 2-methyl-3-ethyl-6-(2-

prope nyl)-4,4a,5,6,7 » 8,8a,9-octahydro-1H-pyrrolo[2.3g]-isoquinoline-4-one hydrate 0.5 M;

2-methyl-3-ethyl-6-(cyclopropylmethyl ethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-20-leine-4-one;

2-methyl-3-ethyl-6-(cyclo-propylmethyl)-4,4a,5,6,7 j 8,8a,9-octahydro-1H-pyrrolo-[2,3-g]isoquinoline-4-one hydrate 0.2 M;

The 2,6-dime thyl-3-ethyl-1-(2,2-dime thyl-1-oxo-25 propyl)-4,4a,5,6,7»8,8a,9-cctahydro-1H-pyrrolo[2,3-gj-isoquinoline-4-one;

2,6-dimethyl-3-cyclopropyl-4,4a,5,6,7i8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3-ethyl-2-methyl-6-(2-dimethylaminoethyl)~ 30 4,4a,5,6,7,8,8a,9-oct.ahydro-1H-pyrrolo[2,3-g]isoquino-leine-4-one;

1-benzyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7 > 8,8a,9-octahydro-.1H-pyrrolo[2,3-gIsoquinoline-4-one;

The ethyl ester of 3-ethyl-2-methyl-35 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-

-7-

leine-4-oxo-6-acetic acid;

2-benzyl-3-dimethyl-octahydro-pyrroloquinoline-octahydro-pyrroloquinoline-one;

The 3,6-dimethyl-2-(2-propenyl)-4,4a,5,6,7i8, 5 8a,9-octahydx,o-1H~pyrrolo[2,3-g]isoquinoline-4-one;

2,6-dimethyl-3-(2-propyl)-4,4a,5,6,7i8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3 -ethyl-2-methyl-6-[2-hydr oxy-3-(4-chlor o-phenoxy)propyl]-4,4a,5,6,7i8,8a,9-octahydro-1H-pyrrolo-

10 [2.3-g]isoqainoline-4-one;

3,6-Dieth-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

The 2-methyl~3-ethyl-6-propyl-4,4a,5,6,7 > 8,8a,9 octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

15 2-Methyl-3-ethyl-6-but3/l-4,4a,5,6,7j8,8a,9-

octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

2-methyl-3-ethyl-6-pentyl-4,4a,5,6,7i8,8a,9 octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-

20 1H-pyrrolo[2,3-gJisoquinoline-4-one;

6-methyl-4,4a,5,6,7)8,8a,9-octahydro-1H-pyrrolo[2,3~g]isoquinoline-4-one;

6-benzyl-4,4a,5,6,7 > 8,8a,9-octahydro-1H-

pyrrolo[2,3-o]is°Q.uiriOlLein-4-one;

25 La 2,6-dimethyl-3-propyl-4,4a,5,6,7*8,8a,9-

octahydro-1H-pyrrolo[2,3-gjisoquinoline-4-one;

3-ethyl-2-methyl-6-[2-hydroxy-3-(4-t-butylphenoxy)-propylJ -4,4a,5,6,7 ? 8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

30 The 3-ethyl-2-methyl-6-[2-hydroxy-2-(4-cliloro-

3-trifluoromethylphenyl).ethyl]-4,4a,5,6,7?8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-oae;

3-Ethyl-2-methyl-6-(2-hydroxy-2-adamantyl-

ethyl)-4,4a,5 56,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]-

35 isoquinoline-4-one;

-8-

The 3-ethyl-2-methyl-6-[2-(4-morpholino)ethyl]-4- »4-a, 5,6,7,8, 8a, 9-octahydro-l ti-pyrrolo[ 2,3-g J isoquino-leine-4-one;

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

3-ethyl-2-iaethyl-6-(2-methylpr opyl)-4, 4a, 5, 6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

10. 3-ethyl-2-meth:yl-6-cyclobutylmethyl-4,4a,5)

6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3-ethyl-2-methyl-6-hexyl-4,4a,5,6,7)8,8a,9-octahydro-1II-pyrrolo[2,3-g]isoquinoline-4-one;

15 3-ethyl-2-methyl-6-heptyl-4,4a,556,7î8,8a,

9-octahydro-1ïï-pyrrolo[2,3-gjisoquinoline-4-oneî

3-ethyl-2-methyl-6-L2-(1-pyrrolidinyl)-ethyl]-4,4a,5,6,718,8a,9-octahydro-1H-pyrrolo[2,3-g]-isoquinoline-4-one;

20 The 3-ethyl-2-methyl-6-(4-methcxy-2-phenyl-

ethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]-isoquinoline-4-one;

2,6-Dimethyl-3-ethyl-1-(l-oxobutyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo-[2,3-g]isoquinoline~4-

25 one;

3-ethyl-2-methyl-6-(4-chloru-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-leine-4-one;

2,6-dimethyl-3-propyl-4,4a,5,6,7,8,8a,9-

30 octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one; -

The 2,3-dimethyl-6-(2-phenylethyl)-4,4a,5,6,7»-8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquino-leine-4-one;

35 The 2,3-dimethyl-6-[4-(4-fluorophenyl)-4-oxo-

-9-

butyl] -4,4a, 5 5 6.7 58.8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one;

3-ethyl-2-methyl-6-(2,2,2-trifluoroethyl)-4,4a,5 j6,7»8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-5 [2,3-g]isoquinoline-4-one;

2,6-dime thyl-3-e thyl-4,4a,5,6,7 » 8,8a,9-octahydro-4a,8a-cis-1H-pyrrolo[2,3-g]isoquinoline-4-011e;

2-acetyl-3,6-dimethyl-4,4a,5»6,7»8,8a,9-10 octahydro-4a,8a-trans-1H-pyrrolo-[2,3-gIsoquinoline-4-one;

3-Ethyl-2-methyl-6-[2-(2-thiphenyl)ethyl]-4,4a; 5-6,7-8,8a,9-octahydro-4a,8a-trans-1H-pyrrol; 0-[2,3-g]isoquinoline-4-one; 15 3-Ethyl-2-methyl-6-[2-(2-furyl)ethyl]-4,4a,

5 *6.7 j8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-gJ-isoquinoline-4-one; And

3-ethyl-2-methyl-6-[2-(1,3-dihydro-2(2H)-benzoimidazolonyl)ethyl]-4,4a,516,7 ? 8,8a,9-octahydro-20 4a,8a-trans-1H-pyrrolo[2,3~gJisoquinoline-4-one.

Among the compounds of formula A of the invention where X is S, the most appreciated are:

The 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5 5 6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]-25 isoquinoline-4-thione;

2,6-dimethyl-3-ethyl-4,4a,5;6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-thione;

2-Methyl-3-ethyl-6-[4-(4-fluorophenyl)-4-30 oxobutyl]-4,4a,5*6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-thione; and

The 2-methyl-3-ethyl-6-(2-hydroxy-3,3-dimethyl-butyl)-4-4a,5,6,7,8,8a,9-oc tahydro-4a,8a-trans-1H-pyrrolo[2,3-gJisoquinoline-4-thione.

35 As examples of formula A where X is S, we

-10-

can cite:

2-methyl -3 - ethyl -6 - (2 -hy dr oxy -2 -phe ny 1 -ethyl)-4,4a,5*6,7*8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-gJisoquinoline-4-thione;

5 La ?,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-

4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-thione;

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-thione;

10 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,

6.7*8*8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2.3-g]~

isoquinoline-4-thione;

2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3~ oxopropyl]-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-15 pyrrolo[2,3-g]isoquinoline-4-thione;

2-Methyl-3-ethyl-6-(3-phenoxypropyl)-4,4a, ' 5,6,7*8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]—isoquinoline-4-thione;

2-Methyl-3-ethyl-6-(2-hydroxy-3-methyl-20-butyl)-4,4a,5,6,7*8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-thione; and

2-methyl-3-ethyl-4,4a,5,6,738,8a,9-octa-hydro-1H-pyrrolol_2,3-g]isoquinoline-4-thione.

The compounds of the invention can exist 25 in the form of the 4a,8a-trans or 4a,8a-cis isomers or mixtures thereof; the 4a,8a-tr&ns isomers are preferred.

The compounds of formula A above, their optical and geometric isomers, and their pharmaceutically acceptable acid addition salts can be prepared according to the invention by a process in which a) To prepare a compound of formula A above-

above where R^ is a hydrogen, R^ is an alkyl, an alkoxyalcoyl^ or an alkylcycloalcoyl and where X is 0 35 and R2 and R, are as described above, that is-

-11-

10 where Rj£ is an alkyl, an alkoxyalcohol or an alkylcycloalcohol and where R2 and R^ are as described above,

we are dealing with a compound of general formula

15

20

0

IX

25

where R2, R^ and Ri{_ are as described above, with formaldehyde, or b) To prepare a compound of the formula above

above, we treat a compound with the general formula

30

R«-N

XII

where R^ is as described above, with a compound of general formula

-12-

10

E3

HON

VII

■R,

in the presence of a reducing agent or with a compound of general formula

°W-R3

h2N

VIII

where R2 and R^ are as described above,

or with a precursor of this body, or 15 c) To prepare a compound of formula A above-

above, where R^j and R^ are hydrogens and where X is O and where R^ and R^ are as described above, that is, a compound of general formula

20

25

Ib where R0 and R are as described above, d t> ~

one N-demethylates a compound of formula A above where R4" is a methyl, or 30 d) To prepare a compound of formula A above-

above where R^ and R^, independently, represent a hydrogen, an alkyl, a cycloalkyl, an alkenyl, an aryl or an aralalkyl, R^ is a hydrogen, an alkyl, an alkoxyalkyl, an aralalkyl, an alkenyl, an 35 alkylcycloalkyl, an alkynyl, a thienylalkyl,

-13-

a furyl alcohol, an alkenyloxy alcohol, an aralkenyl, an aryloxy alcohol, or a trifluoroalkoyl having 2 to 6 carbon atoms and where X represents S and is as described above, i.e., a compound of general formula

S

15

where R~' and R., ' independently represent a 2 3"

hydrogen, an alkyl, a cycloalkyl, an alkenyl, an aryl or an aralcyl, R^" is a hydrogen, an alkyl, an alkoxyalkyl, an aralcyl, an alkenyl, 20 an alkyl-cycloalkyl, an alkynyl, a thienyl-

an alkyl, a furyl-alkyl, an alkenyloxyalkyl, an aralkenyl, an aryloxyalkyl, or a trifluoroalkyl having from 2 to 6 carbon atoms and where R^ is as described above,

25. We treat a compound with the general formula

0

where R„, R', R' and R,. " ' are such as described herein.

35 above, with phosphorus pentasulfide, or

-14-

e) To prepare a compound of formula A, see below

above, where R^ is a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alcoylphenylhydroxyalcohol, an alkoxyphenylhydroxyalcohol, an aryloxyhydroxyalcohol, an alkoxyhydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an N-alcoylpyrrolidinylalcohol, an aryl-N-imidazolonylalcohol, or an N-alcohol, where Rg and R,-,, independently, ? represent a hydrogen or an alkyl group, or, taken together with nitrogen, represent a heterocyclic nucleus with 5 or 6 members, and X represents S and R^, and R^ are as described above, that is, a compound of general formula

S

25 where R^"^ is a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alkylphenylhydroxyalcohol, an alkoxyphenylhydroxyalcohol, an aryloxyhydroxyalcohol, an alkoxyhydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonyl-30 alcohol, an arylcarboxamidoalcohol, an acylalcohol,

a cyclic alkyloxoalkyl, a cyclic alkylhydroxyalkyl, an R-alkylpyrrolidinylalkyl, an aryl-N-

R

imidazolonyl alcohol or x,6^JT-alcohol where R^- and R,-, , of

J-LfO /

independently, represent a hydrogen or an alkyl group or, taken together with nitrogen, a hetero-

"s

-15-

cyclic with 5 or 6 links and where R^, R2 and R^ are as described above,

we separate the protecting group(s) in a compound with the general formula

10

il

15 where R2" and Rj" have the same meaning as R2 and R^ except that when R2 and R^ represent an acyl, R2"

and R," represent an acyl in protected form,

^V IV

and R^ has the same meaning as R^, but in protected form, and R^ is as described above,

20 or f) 'To prepare a compound of formula A below-

above, where R^ is an alkyl, an alkanoyl, an aroyl, or an aralcoyl, and where R^ is an alkyl, an alkoxy-alkyl, or an alkyl-cyclo-alkyl, and where R2, R^, and X25 are as described above, that is, a compound of general formula

X

-16-

aralcoyl and where R^, R^, R^" and X are as described above,

we substitute a compound with the general formula

10

X

Aa where R0,

R^, R^" and X are as described above,

to the nitrogen atom of pyrrole, or g) To prepare a compound of formula A ci-

15 above, where R^ is a hydrogen and where R^ is an alkyl, a hydroxyalcohol, a phenyl-hydroxyalcohol, a halo-phenyl-hydroxyalcohol, an alkylphenyl-hydroxyalcohol, an alkoxyphenyl-hydroxyalcohol, an alkoxyalcohol, an aryloxy-hydroxyalcohol, an alkoxy-hydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxy-

carbonyl, an arbonyl, an alkenyl, an alkoyl, a cycloalkoyl, an alkynyl, a thienylalkoyl, a furylalkoyl, an arylearboxamidoalkoyl, an acylalkoyl, a cyclic alkyloxoalkoyl, a cyclic 25-alkylhydroxyalkoyl, an aienyloxyalkoyl, an arkalkenyl, an aryloxyalkoyl, an N-alkoylpyrrolidinylalkoyl, a trifluoroalkoyl having 2 to 6 carbon atoms, a

R *

aryl-N-imidazoloayl alcohol or R6^N-alcoyl, where R^ and

R^, independently, represent a hydrogen 30 or an alkyl or, taken together with nitrogen, represent a heterocyclic nucleus with 5 or 6 members and where R,

that is, a compound with the general formula

Rj and X are as described above, that is-

-17-

R-

R,

Where R^' is an alkyl, a hydroxyalkyl, a phenyl-hydroxyalkyl, a halophenyl-hydroxyalkyl, a alkylphenyl-hydroxyalkyl, an alkoxyphenyl-hydroxyalkyl, an alkoxyalkyl, an aryloxy-hydroxyalkyl, an alkyloxyhydroxyalkyl, an ayl-

carbonyl alcohol, an aloeoxycarbonyl alcohol, an aral alcohol, an alkenyl, an alkoylcycloalcohol, an alkynyl, a thienyl alcohol, a furyl alcohol, an arylcarboxamido alcohol, an acyl alcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an alkenyloxyalcohol, an aralkenyl, an aryloxyalcohol, an N-alcoylpyrrolidinyl alcohol, a trifluoroalcohol having 2 to 6 carbon atoms, an aryl-N-imidazolonyl alcohol, or a

"R

RÉp^N-alcoyl, where R^ and R^, independently,

20 represent a hydrogen or an alkyl group or, taken together with nitrogen, a heterocyclic ring with 5 or 6 members, and R^, R^ and X are as described above,

we substitute a compound with the general formula

25

30

M-F

Ab

35

or R0,

R7 and X are as described above,

2V?

to the nitrogen atom of isoquinoline, or h) To prepare a compound of formula A ci-

above where R^ is an alkyl, an alkanoyl, an aroyle

-18-

10

15

20

25

or an aralcoyl and where R^ represents an alkyl, a hydroxyalcoyl, a phenylhydroxyalcoyl, a halophenylhydroxyalcoyl, an alcoylphenylhydroxyalcoyl, an alkoxyphenylhydroxyalcoyl, an alkoxyalcoyl, an aryloxyhydroxyalcoyl, an ayoxyhydroxyalcoyl, an ayyloxyalcoyl, an arylcarbonylalcoyl, an alkoxycarbonylalcoyl, an aralcoyl, an alkenyl, an alkylcycloalcoyl, an alkynyl, a thienylalcoyl, a furylalcoyl, an arylcarboxamidoaloyl, an acylalcoyl, a cyclic alkyloxoalcoyl, a cyclic alkylhydroxyalcoyl, an alkenyloxyalcoyl, an aralcoyl, an aryloxyalcoyl, a N-alcoyl-pyrrolidinylalcoyl, a trifluoroalcoyl having 2 to 6 carbon atoms, a

•p x aryl-N-imidazolonyl alcohol or a ^S^^N-alcoyl, where

Rg and R^, taken independently, represent a hydrogen or an alkyl group, or, taken together with nitrogen, represent a heterocyclic ring with 5 or 6 members, and R2, R^, and X are as described above, that is, a compound with the general formula

X

Af where R^1, R2î R-, R^' and X are as described above,

a compound of formula Ae below is substituted for the nitrogen atom of pyrrole, or i) To prepare a compound of formula A below-

above, where R^j is an alkyl, an alcanoyl, an aroyl 35 or an aralcoyl and where R^ is a hydrogen and where R2, R^

-19-

and X are as described above, that is, a compound with the general formula

10

15

20

H N

Ae where R^', Rg, R^ and X are as described above,

the protecting group is separated into a compound of general formula

Ah, where Z is a protecting group 25 and where Rxj', R2î^ sort: such as those described above,

or d)

To prepare a compound of formula A above, where R,j is an alkyl, an alcanoyl, an aroyl or an aralcoyl and where RZ(_ is a hydrogen, an alkyl, an alkoxyalcoyl, an acyloxyalcoyl, an alkylcarbonyl-alcoyl, an aliooxycarbonylalcoyl, an aralcoyl, an alkenyl, an alkylcycloalcoyl, an alkynyl, a thienyl-alkoyl, a furyl-alcoyl, an arylcarboxamido-alcoyl, an acylalcoyl, a cyclic alioyloxyalcoyl, an alkenyloxyalcoyl, an aralcenyl, an aryloxyalcoyl,

-20-

an N-alcoyl-pyrrolidinyl alcohol, a trifluoroalcohol having 2 to 6 carbon atoms, or an aryl-N-imidazolonyl alcohol, and where R^, x are as described above, that is, a compound of general formula

10

Af1

15

20

25

50

VT

where is a hydrogen, an alkyl, an alkoxyalkyl,

an acyloxyalcohol, an alcoylcarbonylalcohol, an alkoxy-carbonylalcohol, an aralcohol, an alkenyl, an alcoylcycloalcohol, an alkynyl, a thienylalcohol, a furylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alioyloxyalcohol, an alkenyloxyalcohol, an aralcohol, an aryloxyalcohol, an N-alcoylpyrrolidinylalcohol, a trifluoroalcohol having 2 to 6 carbon atoms or an aryl-N-imidazolonylalcohol, and 1, R25 and X are as defined above,

we substitute a compound with the general formula

X

R-

R,

A.d"

where R0,

H

R-j, R^"*" and X are as defined above,

35 to the nitrogen atom of pyrrole, or

-21-

k) To prepare a compound of formula A ci-

above, where R^ is an alkyl, an alkanoyl, an aroyl or an alkanoyl and where R2l is a hydroxyalkyl, a phenyl-hydroxyalkyl, a halophenyl-hydroxyalkyl, an alkoxyphenyl-

hydroxyalcohol, an aryloxy-hydroxyalcohol, an alkoxyhydroxyalcohol, a cyclic alkylhydroxyalcohol or Efi

■o N-alcohol, where Ec and En, independently,

9

represent a hydrogen or an alkyl or, taken in-

10 seems to be associated with nitrogen, a heterocyclic nucleus with 5 on 6

links and where E,

Ej and X are as defined below.

above, that is to say a compound of general formula

15

20

E;

VII

Af"

VIT

where R^ is a hydroxyalcohol, a phenyl-hydroxyalcohol, a halophenyl-hydroxyalcohol, an alcoylphenyl-hydroxyalcohol, an alkoxyphenyl-hydroxyalcohol, a 25-aryloxy-hydroxyalcohol, an alkoxyhydroxyalcohol, a cyclic alkoxyyl-hydroxyalcohol, or a

N-alcohol, where R,_ and R9, independently, Ry-^ b '

represent a hydrogen or an alkyl or, taken together with the nitrogen, a heterocyclic nucleus with 5 or 6 links and where R', R', R' and X are as defined above,

the protecting group is separated in a corresponding compound

VII

constituent of formula Af" ci-des.cus, but where R^ is 35 protected, that is to say in a compound of general formula ^

-22-

R

VIII

R1'

Af

He

10

15

20

25

30

WHERE,

VIII

VII

has the same meaning as R^, but in a protected form, and where R^', R2* R^ and X are as defined above,

Or

1) The mixture of cis and trans isomers obtained is isomerized in a final ratio predominantly comprising the trans isomer, or m) The trans isomer is separated from the mixture obtained,

or n) A racemic mixture obtained to give optical antipodes is resolved, and o) If desired, a compound is transformed

obtained or a non-pharmaceutical-acceptable acid addition salt into a pharmaceutically acceptable acid addition salt of this body.

More specifically, the compounds of formula A above, their optical and geometric isomers and their pharmaceutically acceptable acid addition salts, as well as various intermediates, can be prepared in the manner illustrated in more detail below.

Thus, for example, compounds with formula A where X is 0 are characterized by the formula

-23-

0

10 where R^ , R2, R^ and R^ are as described above, and can be prepared as shown in diagrams I, II, III and IV and as described in more detail.

-24-

FORMULA SCHEMA I

OCH,

I t>

OCH,

NH~ /V

ua

OCH-

XIV

V

r4"M

r4"nh

OCH

CoHc-0CÎIH

^ 2 5

III

where E., is CH-, 4 p

OCH-

OCH-

e4"nh

CH-

+Zn or

■B,

R0H - -^ ^ VIII ^

O

E4"RH

E,

IX

where E2» Ej and E^" are as described above.

-25-

According to formula scheme I, compounds of formula IV, where E is a methyl group, are prepared by reacting the primary amine of formula XIV with ethyl chloroformate to give urethane of formula III, which is then reduced with lithium aluminum hydride to give N-methylamine of formula IY. More broadly, compounds of formula IV can be prepared by a reductive alkoxylation of the compound of formula XIY using the corresponding aldehyde, for example acetaldehyde, etc., and sodium cyanoborohydride under known conditions [see, for example, E.F. Borch, J. Am. Chem. Soc., 93, 2897 (1971)]. The Birch reduction of the amine of formula IV with lithium in ammonia containing t-butanol gives dihydroamine of formula V. Other modifications of the reduction of Birch. Thus, an amine of formula IV can be reacted with an alkali metal, such as sodium, lithium, potassium, or cesium, in ammonia, or with an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, butanol, or β-butanol. The reaction generally takes place at or below the boiling point of the solvent, for example, between -78°C and 15°C. If 25% ammonia is used, the reaction is carried out under reflux. Co-solvents such as diethyl euher or tetrahydrofuran may optionally be added.

This is easily carried out by the usual methods for the hydrolysis of enolethers, for example with an aqueous acid. Examples of acids that can be used include hydrochloric acid, hydrobromidric acid, formic acid, acetic acid, p-toluenesulfonic acid, and perchloric acid. They can be used in aqueous solution or in solvents.

The hydrolysis of dihydroamine of formula V

-26-

10

15

20

25

30

mixed. At least 2 equivalents of water per mole of dihydroamine and more than one equivalent of acid are required. Examples of solvents that can be used include tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane, or acetonitrile. For example, the hydrolysis of dihydroamine of formula 7, where E^" is a methyl group, in 2 N hydrochloric acid at or above room temperature or in aqueous acetic acid at a temperature between 40°C and the reflux temperature, leads to diketone of formula 71, where E^" is a methyl group.

Diketone of formula 71 is condensed in a Knorr condensation to give dihydroindolone-ethylamine of formula IX. The Knorr condensation is a well-known process for the preparation of pyrroles and can be used in any of the well-known modifications [see, as an example of reaction conditions, J.M. Patterson, Synthesis, 281 (1976) and the references therein]. For example, the reaction of an isonitrosoketone of formula 711 in the presence of a reducing agent, for example with zinc in aqueous acetic acid or hydrochloric acid, is thought to proceed via the aminocarbonyl compound of formula 7III, which then condenses with diketone of formula 71 to give the dihydroindolone-ethylamine product of formula IX. Condensation can also be carried out with an aminocarbunyl compound of formula IX or a precursor of this compound, such as a hydrochloric salt of an aminoketone or an acetal derivative of an aminoketone or aminoaldehyde. It is preferable to use a precursor of the aminoketone or aminoaldehyde, as these substances have a tendency to self-condense. Ideally, they should be used in situ where the aminocarbunyl component is released in the presence of the diketone of formula 71.

-27-

The aminocarbonyl compound reacts immediately to form dihydroindolone-ethylamine, formula IX. It is not necessary to isolate the diketone, formula VI, before proceeding with the Knorr condensation, as the reaction conditions employed are sufficient to hydrolyze the dihydroamine, formula V, to give the diketone, formula VI. The Knorr condensation is best carried out between a pH of approximately 2 and 6. As soon as the pH is significantly exceeded (above 6), a considerable loss of yield is observed due to the formation of auto-condensation products of the aminocarbonyl compound, formula VIII.

Preferably, an isonitroso-ketone of formula VII and zinc powder are condensed in aqueous α-15 acetic acid with a diketone of formula VI where R^" is a methyl to give the dihydro-indolone-ethylamine product of formula IX where R^" is a methyl.

The Knorr condensation is preferably carried out within a temperature range of approximately 20 degrees above room temperature to the reflux temperature. Isonitrosoketones of formula VII are known compounds [see for example Ferris, J. Org. Chem., 24, 1726 (1959)] or can easily be prepared by nitrosation of the corresponding ketones, for example with an alkali-nitrite or, in the case of the very acidic p-dicetones or (3-ketoesters), with sodium nitrite.

Examples of isonitroketones that can be used in Knorr condensation include: 2-isonitroso-3-pentanone-;

2,3-frutanedione monoxime; 2-isonitroso-4-methyl-5-pentanone; 2-isonitroso-5-hexanone; 35 2-isonitroso-3-heptanone;

-28-

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 amino-carbonyl precursor compounds that can be used in the Knorr condensation include: 1'aminoacetaldehyde-dimethylacetal; and 10 2-amino-3-pentanone hydrochloride.

The amine of formula IX is transformed to give the compound of formula 1a by means of an intramolecular Mannich reaction. The Mannich reaction is generally carried out starting from a ketone and a dialcoylamine salt, for example dimethylamine hydrochloride, and formaldehyde (for example, in aqueous solution, as paraformaldehyde or trioxane) in an alcoholic solvent such as ethanol, under reflux. In the modification described here, an acid addition salt of dihydroindolone-ethylamine of formula IX is reacted with formaldehyde, added as paraformaldehyde, trioxane, or as aqueous formaldehyde in a solvent. For example, a high-boiling hydroxyl solvent 25, such as amyl alcohol, octanol, ethylene glycol, or diethylene glycol monoethyl ether; a high-boiling polar aprotic solvent, such as dimethylformamide, N-methylpyrrolidinone, or diethylene glycol dimethyl ether; 30 a lower-boiling polar solvent, such as ethanol, butanol, or 2-propanol under pressure; or a lower-boiling aprotic solvent under pressure, such as dioxane or tetrahydrofuran, can be used at a temperature between approximately 135°C and approximately 200°C to give the pyrrolo(2,3-s)is°Quin°-

-29-

The reaction, particularly when carried out at temperatures below 150°C, leads to a mixture of cis and trans isomers; for example, when R is a methyl group, to compounds of the formulas

10

15

ch5-:

H

h trans

H,

ir\

R,

h l a'

20

chj— ï

R-

R,

I"a'

25

cis

One can resort to longer heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloric salts of formulas 30l'a and I"a, for example in ethylene glycol at reflux for 2 hours, to equilibrate the cis and trans isomers to a final ratio predominantly comprising the trans isomer, which is easily isolated by crystallization or chromatographic separation. 35 The reaction of the hydrochloric salt is preferred.

-30-

of dihydroindolone-ethylamine of formula IX where R^" is a methyl with paraformaldehyde in octanol at 180° for 2 hours, by which the product is isolated almost exclusively in the form of the trans isomer l'a.

FORMULA SCHEMA II

0

where R~ and R are as described above, and or R.'

2 5 '

is an alkyl, an alcanoyl, or aroyl or an aralcoyl

-31-

According to formula scheme II, O11 prepares compounds of formula le1 by alkoylation or acylation of the nitrogen of the pyrrole of a compound of formula la1 and other N-6-alkyl derivatives by formation of the α-5 pyrrole anion with a strong base, for example sodium amide, potassium hydride, sodium methylsulfonylmethane, or butyllithium, or with an alkali metal, followed by immersion with an alkyl or acyl halide in a solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethylformamide, or dimethyl sulfoxide. For example, treatment of a compound of formula la1, where R^ is a methyl and R^ is an ethyl, with sodium in ammonia followed by quenching with methyl iodide gives the 1-methyl derivative, that is, a compound of formula le' where R^ is a methyl, R^ is an ethyl, and R^' is a methyl. Similarly, the reaction of a compound of formula la' where is a methyl and R^ is an ethyl with butyllithium in tetrahydrofuran 20 at -30° followed by extinction with benzoyl chloride gives the 1-benzoyl derivative, that is, a compound of formula le' where ' is a benzoyl, R^ is a methyl, and R^ is an ethyl.

The K-demethylation of the compound of formula la' 25 can be carried out by classical IT-dealcoylation processes, such as the von Braun process [H. A. Hageman, Org. Reactions, 7, 198 (1953)] or via the acid or basic hydrolysis of a urethane derivative such as those listed in K. C. 30 Eice [J. Org. Chem., 40, 1850 (1975)]. One of the dealcoylation processes of the compound of formula la' involves passing through urethane of formula XIII and acid hydrolysis to give the secondary α-amine of formula Ib. For example, a compound of formula la', where R^ is a methyl group, is refluxed.

-32-

and Rj is an ethyl, in diethylketone with an excess of ethyl chloroformate and potassium bicarbonate for 3 hours to give a compound of formula XIII where R2 is a methyl and R^ is an ethyl.

5. Hydrolysis of the preceding compound with concentrated hydrochloric acid in refluxing acetic acid for 24 hours yields a compound of formula Ib, where R2 is a methyl group and R^ is an ethyl group. The same compound is obtained by hydrolysis of urethane of formula XIII 10 with sodium hydroxide in refluxing ethanol.

FORMULA SCHEME III

where R^', R2, R7 and R^' are as described above,

-33-

According to formula scheme III, the compounds of formulas le, Id and le are prepared from the secondary a-mine of formula Ib, starting product for the preparation of many derivatives included in formula I, by substitution at the basic nitrogen of the a-mine (IT-6) and/or at the nitrogen of the pyrrole (N-1). For example, treating a compound of formula Ib with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalkoyl halide, such as chloromethylcyclopropane, or an aralkyl halide, such as benzyl bromide, in the presence of a base, for example potassium carbonate, in acetone, 2-propanone, or dimethylformamide, gives the corresponding substituted compound of formula Id, i.e., where R' is an alkyl, an alkenyl, a cycloalkoyl alkyl, or an aralkyl, respectively. With reactive halides, the reaction can be carried out at room temperature; With less reactive halides, reflux temperatures are used, and in some cases the reaction rate can be accelerated by adding an iodide salt, for example lithium iodide, to the reaction mixture.

The reaction of a compound of formula Ib with epoxyalkanes gives the substituted hydroxyalkaoyl compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkaoyl analogs of a compound of formula Id; thus, the reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, where R' is a 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol, at a temperature approximately between room temperature and the reflux temperature of the mixture. Epoxyalkanes are commercially available.

-34-

or are prepared by epoxidation of the corresponding olefins, or by methylenation of a ketone with a sulfonium methylide or sulfo-xonium methylide reagent, for example dimethylsulfonium methyl.

5 Thus, for example, the treatment of benzaldehyde with dimethylsulfonium methyl gives styrene oxide.

The compound of formula Ih can be transformed to give the compound of formula le by a process in which, successively, the basic nitrogen of the amine (N-6) of the compound of formula Ib is protected by a hydrolyzable or hydrogenolyzable protecting group, substituted for the nitrogen of the pyrrole (I-T-1), and deprotected. Typical protecting groups include acetyl, β-butoxycarbonyl, benzenesulfonyl, or benzyl. The reaction of the protected intermediate is carried out in a manner practically analogous to that described for the transformation of the compound of formula la giving the compound of formula le'. The substituted intermediate is deprotected by basic or acid hydrolysis or hydrogenolysis processes appropriate to the protecting group. Thus, the compound of formula Ib, where E2 is a methyl and E^ is an ethyl, is treated with Formic-acetic anhydride is used to give the 6-formyl derivative. Treatment of the derivative with sodium hydride in dimethyl sulfoxide followed by treatment with methyl iodide and acid hydrolysis gives the compound of formula Ib, where E1 is a methyl, E2 is a methyl, and E1 is an ethyl. Treatment of a compound of formula Ib with a haloalkoylamiria in the presence of a base, for example potassium carbonate, or an aziridine, gives the amino-substituted analogs of a compound of formula Id, respectively. The reaction conditions are those described for the preparation of the alkyl derivatives.

-35-

In some cases, when R' in the compound of formula Id does not contain functional groups capable of undergoing alkoylation or acylation, the processes shown in Scheme III can be used directly to prepare the N-1-substituted analogs of formula I. Alkylations can occur in compounds where R' is a hydroxyalkoyl, a phenylhydroxyalkoyl, a halophenylhydroxyalkoyl, an alkylphenylhydroxyalkoyl, an alkoxyphenylhydroxyalkoyl, an aryloxyhydroxyalkoyl, an alkoxyhydroxyalkoyl, or a cy-

•p clique or ^6^: K-alcoyle, where R^ and R^, in an independent way.

The pendant groups are either a hydrogen or an alkyl group, or, together with nitrogen, form a heterocyclic 15-membered ring with 5 or 6 members. The functional groups included within them, for example, hydroxyl or secondary amine, must be protected by a base-stable protecting group, such as tetrahydropyranyl. After N-1-alkylation, the protecting group is removed by acid hydrolysis.

The compound of formula le is transformed to give the compound of formula le using practically the same process as is used in the transformation of the compound of formula Ib to give the compound of formula Id.

In the reactions described in the formula diagrams I, II and III, both trans isomers of formula can be formed

-36-

where R,,, R2, R^ and R^ are as described above, and the cis isomers of formula

I"

10

15

where R^j, R2j, R3, and R^ are as described above, compounds of formula I, the trans isomer being predominant. The pure trans isomer can be separated by chromatography or crystallization. Furthermore, the mixture can be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formulas I'a' and I'a'.

\

\

-37-

SniffA OF FORMULAS IV

och

OCH-

r4"ke

-> v-f

H2ikXR2

YIII

where R~, R, and R,, " are as described above cL? • H-

-38-

Scheme IV describes an alternative synthesis of compounds of formula 1a, where the isoquinoline ring is formed before the formation of the pyrrole ring. According to Scheme IV, 5(3,5-dimethoxyl3-ethylamine <3-e formula IV> is refluxed with aqueous formaldehyde to give tetrahydroisoquinoline of formula X. Birch reduction of tetrahydroisoquinoline of formula X with lithium in ammonia containing β-butanol under conditions 10 practically identical to those described for the Birch reduction of the compound of formula IV gives 11hexahydroisoquinoline of formula XI. Hydrolysis of 11hexahydroisoquinoline of formula XI under conditions practically identical to those 15 described for the hydrolysis of dihydroamine of formula V gives diketone of formula XII. The compound of formula XII is reacted in a Knorr condensation, as described in the preparation of dihydroindolone-ethylamine of formula IX with iso-20 nitrosoketone of formula VII or with the amino-carbonyl compound of formula VIII to give pyrrolo-isoquinoline of formula 1a. The reaction sequence according to the scheme of formula IV is preferred, starting from the amine of formula IV, where 1^" is a methyl, and giving the corresponding N-methylpyrroloisoquinoline of formula 1a', in the form of a mixture containing the trans isomer 1a1 and the cis isomer of formula 1"a'.

The same processes as described above can be used for the isomerization of the mixture of 30 pyrroloisoquinolines of formulas l'a' and l'a' to give especially the trans isomer of formula l'a'.

Compounds with formula A where X is S are characterized by the formula

-39-

's

"l where R^, R^, R^ and R^ are as described above, 10 and can be prepared as stated below.

Thione compounds of formula ii are generally prepared by the reaction of phosphorus pentasulfide on keto compounds of formula I. When the compound of formula I has no functional groups capable of reacting with phosphorus pentasulfide other than the 4-oxo group, the compound of formula i can then be directly converted into the compound of formula ii by heating with phosphorus pentasulfide in an inert organic solvent. On the other hand, when the compound 20 of formula I actually contains functional groups capable of reacting with phosphorus pentasulfide, for example when R^ is different from a hydrogen, an alkyl, an alkoxyalkyl, an aralkyl, an alkenyl, an alioyl-cyclo,alkyl, an alkynyl, a thienyl-alkyl, a furyl-alkyl, an alkenyloxyalkyl, an aralkyl, an aryloxyalkyl, or a trifluoroalkyl having 2 to 6 carbon atoms or when R2 or R^ is an acyl, these groups must be protected before the reaction and then unprotected. 30 Thus, keto groups can be protected in the form of ketals such as 11-ethylene ketal, and alcohol groups can be protected in the form of ether derivatives, such as benzyl ether. Thiones of formula ii can also be prepared by suitable processes described in 35 the formula schemes v and vi.

-40-

FORMULA SCHEME V

IIc:

V

where R^', R25, Rj and R^" are as described above,

-41-

In formula scheme V, the compound of formula Ia is transformed into the compound of formula Ia by heating in an inert organic solvent with phosphorus pentasulfide. Preferred solvents are tetrahydrofuran, benzene, and dioxane, and the reaction is generally carried out at reflux temperature. The compound of formula Ia can then be alkylated or acylated to give the compound of formula Ie' in the same way as described in formula scheme II for the transformation of the compound of formula Ia1 into the compound of formula Ie1.

Other compounds of formula II can be prepared as described in the formula scheme VI.

-42-

where R-, R, . R' and R., 1 are as described above. 2 O I 4 A

-4-3-

In formula scheme VI, the compound of formula Ib is reacted with phosphorus pentasulfide as described above, to give the thione of formula Hb. The subsequent transformations of the compound of formula Ilb into compounds of formulas Ile, Ild and Ile are carried out in the same way as described in formula scheme III for the analogous compound oxo Ib in its transformations giving the compounds of formulas le, Id and le.

In these reactions, both trans isomers with the formula can be formed

15

20

25

30

where R^, R2, Rj and R^ are as described above,

compounds of formula II, with a predominance of the trans isomer. The pure trans isomer 35 can be separated by chromatography or crystallization. Furthermore, one

5

10

ii'

where R^, R^, R^ and R^ are as described above, and the cis isomers of formula

-44-

can isomerize the mixture as is said for the isomerization of the trans and cis isomers of the oxo compound of formulas l'a1 and T'a'.

Compounds of formula A form acidic addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acidic addition salts with both pharmaceutically acceptable organic and inorganic acids, for example with halohydric acids such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, other salts of mineral acids, such as sulfuric acid, nitric acid, phosphoric acid, etc., alkyl- and mono-aryl-sulfonic acids, such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, etc., other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid, etc. The non-pharmaceutically acceptable acid addition salts of compounds of formula A can be transformed into pharmaceutically acceptable acid addition salts via classical double decomposition reactions where the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable pharmaceutical anion; or alternatively, by neutralizing the non-pharmaceutically acceptable acid addition salt and then reacting the resulting free base with a reagent to yield a pharmaceutically acceptable acid addition salt. Acid addition salts can also form hydrates.

Compounds of formula A and their pharmaceutically acceptable acidic addition salts exhibit neuroleptic activity. However, it is significant that they lack hypotensive activity, 35 and exhibit only weak cataleptic activity.

-45-

Tick. Compounds of formula A are therefore useful as antipsychotic agents, for example in the treatment of schizophrenia. The activity of compounds of formula A that makes them useful as antipsychotic agents can be demonstrated in homeothermic animals using known methods.

For example, according to one procedure, trained rats are placed in experimental chambers equipped with a response lever, a wire-mesh floor for transmitting electric shocks, and a loudspeaker for communicating auditory stimuli. Each trial consists of a 15-second warning tone (conditioned stimulus), continuing for another 15 seconds while accompanied by an electric shock (unconditioned stimulus; 1.0 mA, 350 volts AC). The rats can terminate the trial at any time by lowering the response lever. A response during the initial 15-second warning tone ends the trial before the shock is transmitted and is considered an avoidance response, while a response occurring during the shock transmission is an escape response. Trials are conducted every two minutes during a 1-hour experimental session (30 trials per session). 25 Trained rats maintain a reliable baseline of avoidance behavior (zero to three avoidance failures per session). The compounds are administered at suitable times before treatment to a minimum of 3 to 4 rats for each dose over a certain dosing interval. Rats receive the excipient alone during control sessions. A control session and an experimental session are alternated weekly; each animal serves as its own control.

The session is divided into three consecutive 20-minute parts (10 trials). The summation of

-46-

responses for all subjects receiving a given dose " during each period.

The number of trials in which rats fail to exhibit an avoidance response (avoidance block; BE) or fail to exhibit an escape response (escape block; EB) is determined for the period in which this effect is maximum, for each dose. This number is expressed as a percentage of the total number of trials during the period. The dose calculated to produce a 50% avoidance block (BE 50) is obtained from the least-squares fitted regression line. The lowest dose producing a 20% escape block (EB 20) is read from a dose-response plot. Once these 15 values are obtained, the effect is plotted as a percentage against the logarithm of the dose.

Antipsychotic agents can be distinguished from other types of drugs that affect rat behavior in this procedure by the greater separation between doses that block the avoidance response and doses that block the escape response. The clinical efficacy of antipsychotic drugs with known uses and therapeutic properties is closely and significantly correlated with their

25. Efficacy in this process. Therefore, compounds of formula A can be used therapeutically at dose intervals compatible with their efficacy in the experimental process.

When 3-ethyl-2,6-dimethyl-4,4α,5β6,7β8,8α,9βα-octahydro-4α,8α-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one, which has an LD50 of 350 mg/kg orally, is used as the experimental substance, for example, in mice, neuroleptic activity is observed at a BE50 of 0.7 mg/kg orally and 0.095 mg/kg subcutaneously. In the (-) enantiomer of the preceding compound,

-47-

Neuroleptic activity is observed at a BE^Q of 0.48 mgAg P.o.

Similarly, when 2,3,6-trimethyl-5 4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-[2,3-g]isoquinoline-4-one hydrochloride is used as the experimental substance, neuroleptic activity is observed at a BE^q of 0.48 mg/kg p.o.

Similarly, when N-[2-(3-ethyl-4,4a,5,6,7*8,8a,9-10 octahydro-2-methyl-4-oxo-4a,8a-trans-1H-pyrrolo[2,3-g]-isoquinoline-6-yl)ethylJ-4-fluorobenzamide is used as the experimental substance, neuroleptic activity is observed at a BE^Q of 3.5 mg/kg p.o.

Similarly, when 3-ethyl-2-methyl-6-[4-(4~fluorophenyl)-15 4-oxobutyl J-4,4a,5 *6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one is used as the experimental substance, neuroleptic activity is observed at a BE^q of 0.19 mg/kg p.o.

Similarly, when 3-ethyl-2,6-dimethyl-4,4a,5,6,7*8,8a,9-20 octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-thione is used as the experimental substance, "neuroleptic activity is observed at a BE^Q of 0.94 mg/kg p.o.

Formula A compounds and their pharmaceutically acceptable acidic addition salts have antipsychotic effects that are qualitatively similar to those of haloperidol, trifluoroperazine, and molindone, known for their therapeutic uses and properties. Thus, formula A compounds exhibit a pattern of activity associated with antipsychotic drugs of known efficacy and safety.

Compounds of formula A and their pharmaceutically acceptable acidic addition salts can be used in the form of conventional pharmaceutical preparations. For example, unit doses

-48-

Suitable oral doses range from 0.05 metric tons to 50 mg, and suitable oral dosing regimens for homeothermic animals range from approximately 0.001 mg/kg per day to approximately 10 mg/kg per day. However, depending on the homeothermic animal in question, the specific dosing regimen may vary and should be adjusted according to the individual need and the professional judgment of the person administering or controlling the administration of a compound of formula A or one of its pharmaceutically acceptable salt additions. Furthermore, the frequency of administration of the administered doses varies according to the quality of the active drug they contain and the needs and requirements of the pharmacological situation.

15 For the application described here, compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated using conventional inert pharmaceutical adjuvants to give suitable pharmaceutical forms for oral or parenteral administration. These pharmaceutical forms include tablets, suspensions, solutions, etc. In addition, compounds of formula A can be included in, and administered in the form of suitable hard or soft capsules. The identity of the inert adjuvants used to formulate compounds of formula A and their pharmaceutically acceptable acid addition salts into oral and parenteral pharmaceutical forms will be immediately apparent to specialists. These adjuvants, of inorganic or organic nature, include, for example, water, gelatin, lactose, etc.

starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Furthermore, preservatives, stabilizers, wetting agents, emulsifying agents, can be incorporated into these formulations if desired.

-49-

salts intended to modify osmotic pressure, buffers, etc.

Since compounds of formula A and their pharmaceutically acceptable acidic addition salts possess an asymmetric carbon atom, they are usually obtained as racemic mixtures. The resolution of these racemates to give optically active isomers can be carried out by conventional methods. Some racemic mixtures can be precipitated as eutectics and then separated. However, chemical resolution is preferred. By this method, diastereomers are formed from the racemic mixture with an optically active separating agent, for example, an optically active acid, such as α-15 (+)-tartaric acid, to form a diastereoisomeric salt.

The diastereomers formed by fractional crystallization are separated and can be transformed to give the corresponding optical isomeric base. Thus, the invention covers the optically active isomers of the 20 compounds of formula A as well as their racemates.

Furthermore, given the various possible spatial arrangements of their atoms, it must be understood that the compounds of the invention can be obtained in more than one possible geometric isomeric form. The compounds of formula A, as described and claimed, are understood to include all such isomeric compounds. The examples included herein should therefore be understood as practical embodiments of particular mixtures of geometric isomers or isolated geometric isomers, and not as limitations of the scope of the invention.

The following examples give other practical embodiments of the invention. Unless otherwise indicated, all temperatures are given in degrees Celsius.

-50-

Example 1

Preparation of the ethyl ester of N-2-(3-.5--dimethoxypheriyl)-ethyl carbamic acid.

In a 5-liter, round-bottom, three-necked flask equipped with a mechanical stirrer and an addition funnel, 32.63 S of (3,5-dimethoxyphenyl)ethylamine hydrochloride, 600 mL of water, 600 mL of dichloromethane, and 150 mL of 1 N sodium hydroxide solution are placed. The mixture is stirred and cooled in an ice bath by adding 16.28 g of ethyl chloroformate in 60 mL of dichloromethane dropwise for 30 minutes. During the addition, a total of 150 mL of 1 N sodium hydroxide solution is added in 8 fractions to maintain the pH between 8 and 9. After the addition is complete, the mixture is placed in an ice bath for 1 hour. The mixture is then transferred to a separating funnel, and the organic layer is separated. The aqueous solution is extracted with 200 ml of dichloromethane, then the organic solutions are combined and washed with

100 ml of water and 100 ml of brine are dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated on a rotary evaporator to give 37.1 g of crude ethyl ester of IT-2-(3,5-dimethoxyphenyl)-25 ethylcarbamic acid in the form of a colorless oil.

Example 1a

Preparation of N-methyl-(5,5-dimethoxyphenyl)ethylamine hydrochloride 30 In a 3 L round-bottom flask with 3 beakers equipped with a mechanical stirrer, an addition funnel, and a condenser, 180 mL of 70% sodium dihydrobis(2-methoxyethoxy)aluminate solution and 700 mL of dry tetrahydrofuran are placed. 35 The solution is cooled in an ice bath and the following is added

-51-

For 15 minutes, a solution of 37.1 g of crude 11-2-(3,5-dimethoxyphenyl)-ethylcarbamic acid ethyl ester was added to 100 mL of dry tetrahydrofuran. After the addition, the mixture was heated under reflux for 1 hour and then cooled in an ice bath. The excess hydride was decomposed by adding 100 mL of 5°A sodium hydroxide solution dropwise. After all the base had been added, the organic layer was separated, and the aqueous layer was extracted with 100 mL of ether. The combined organic solutions were concentrated to give 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 and 50 mL of brine, dried over anhydrous sodium sulfate, and filtered. 15. 70 ml of ethereal hydrochloric acid is added to the filtrate to precipitate the amino hydrochloride. The solid is 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-20 (3,5-μimethoxyphenyl)-ethylamine hydrochloride as a white crystalline solid, Pf 160-154°.

Example 2

Preparation of N-methyl-1,'p-dimethoxycyclohexa-1,4-digne-5-ethylanine 25 185>2 g of N-methyl-

(3,5-dimethoxyphenyl)ethylamine is dissolved in 1600 mL of water and the solution is made alkaline with 160 mL of ammonium hydroxide. The mixture is extracted with 3 x 1000 mL of dichloromethane, and the combined extracts are washed with 30 x 1000 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35°C yields 156.0 g of free base.

In a 12-liter, 1- to 3-necked flask equipped with a mechanical stirrer and two 35% dry ice condensers, one equipped with a gas inlet and the other

-52-

From a soda lime drying tube, 4.0 L of anhydrous ammonia is condensed. To the ammonia, a solution of 156.0 g of the free base in 400 ml of t-butanol and 400 ml of anhydrous ether is added for 15 minutes.

5. To the stirred solution, a total of 55.6 g of lithium wire, cut into 63.5 mm lengths, is added over 50 minutes. The addition rate is controlled to add 127 mm of wire per minute. After all the lithium has been added, the dark blue mixture is stirred under reflux for 2 hours. Then, 2.8 L of anhydrous ether is added to dilute the mixture, the drying tube is removed to allow the hydrogen to escape, and a total of 280 g of ammonium chloride powder is slowly added over 30 minutes until the blue color has dissipated. The dry ice condenser is removed, the mixture is stirred, and the ammonia is allowed to evaporate overnight. 2.8 L of ice water is added to the residue. The mixture is transferred to a 20 mm separating funnel, rinsed with 800 ml of ether, and the layers are separated. The aqueous layer is extracted with 2 x 1.5 L of dichloromethane, then the extracts are combined and washed with 1 L of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40°C and finally at 40°C/1.0 mm for 1.5 hours yields 150.7 g of crude product in the form of a yellow oil. The crude oil is distilled through a 304.8 mm Goodloe column (150°C bath), collecting the fractions as follows:

Feb fraction

Weight

Purity (CG)

1

40-80°/0.45

mm

7.9 g

4.6%

2

80-85°/0.45

at 0.15 mm

6.2 g

50%

3

85-86° /0.15-

mm

21.2g

92%

4

86-87°/0.15

mm

99.4g o o

•vÇl

r

-53-

The fractions 3 and 4 combined give 120.6 g

10

15

20

25

30

of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine in the form of a colorless oil.

Example 3

Preparation of 6-f2-(N-methylamino)ethyl 1-2-methyl-3-ethyl-6,7-dihydro-(5H)-4(1J1,5H)-indolone: In three necked flasks equipped with a mechanical stirrer and a condenser, a solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine distilled in 700 mL of 70% aqueous acetic acid is placed. The reaction mixture is refluxed for 15 minutes, and 59.5 g of zinc powder is added in 5 fractions for 10 minutes, followed by refluxing the mixture for another 15 minutes. A solution of 42.1 g of 2-isonitroso-3-pentanone in 175 mL of 70% aqueous acetic acid is added to the refluxed solution for one hour. After the addition, the mixture is refluxed for 2.5 hours and cooled to room temperature. The precipitated zinc acetate is removed by filtration, and the filter cake is washed with 500 mL of dichloromethane. The filtrate is concentrated on a rotary evaporator, and the residue is heated to 100°C/1.0 mm for 30 minutes to remove the last traces of acetic acid. The residue is dissolved in 500 mL of water, and the solution is extracted with 2 x 150 mL of dichloromethane. The dichloromethane extracts are discarded, and the aqueous layer is made basic (pH 8-9) with 165 mL of ammonium hydroxide and 500 mL of brine is added. The mixture is extracted with 3 x 200 mL of dichloromethane, and the combined extract is washed with 100 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent yields 56.0 g of crude tetrahydroindolone, which is dissolved in 90 mL of 2:1 ethyl toluene acetate. The solution is stirred with a

In a one-liter round-bottomed flask and

-54-

Using a magnetic medium, it is inoculated and left to crystallize overnight while being agitated. A first harvest of 20.8 g is collected by filtration, then the mother liquor is concentrated and crystallized again from a stirred solution to give

10.0 g in the second harvest. The mother liquor is dissolved in 75 mL of methanol, and a solution of 15 × 50 S of oxalic acid in 50 mL of methanol is added. The mixture is heated for 10 minutes in a 10 µg steam bath and cooled. The solid oxalate salt is separated by filtration and washed with 10 mL of methanol and dissolved in 50 mL of water. The solution is made basic with ammonium hydroxide and extracted with 2 × 50 mL of dichloromethane. The 15 extracts are washed with 1 × 20 mL of brine, then dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give an additional 4.5 g of crude product. Crystallization from toluene-ethyl acetate 2:1 gives an additional 2.6 g of crystalline product. The two harvests and the oxalate-derived crystals are combined and dried at 25°/1 mm to give 33 54 g of 6-[2-(N-methylamino)ethyl]-2-methyl-3-ethyl-6,7~ciihydro-(5H)-4(1H,5H)-indolone as a pale yellow solid, 114-120°, homogeneous 25 by thin layer chromatography.

Example 4

Preparation of 3-ethyl-2,6-dimethyl-4,4a,5,6,7^8,8a,9-^ctahydro~4a,8a--trans-1H-^pyrrolo-^2,5-g1isocuinoleine-4-one hydrochloride

50 In a 500 ml round-bottom flask, 170 g of 6-[2-(N-methylamino)ethyl]-2-methyl-3-ethyl-6,7-dihydro-(5H)-4(1H,5H)-indolone and 170 ml of methanol are placed. 20 ml of 4 N hydrochloric acid in diethyl ether (obtained by bubbling hydrochloric acid through diethyl-

S

-55-

ether in an "ice bath and titration). The solvent is removed on a rotary evaporator and the residual solid is dried at 50° under 1 mm for 2 hours to give 19» 7 S of crude hydrochloric salt.

5. In a round-bottom, 3-gauge round-bottom flask equipped with a mechanical stirrer, a thermometer, and a distillation head, 19.7 S of hydrochloric acid, 21.8 g of paraformaldehyde, and 1000 mL of octanol are placed. The reaction mixture is heated under reflux, and the released water is removed by distillation until the temperature of the octanol solution in the flask reaches 175–180°C. The distillation head is then removed and replaced with a reflux condenser. The reaction mixture is heated to 175–180°C for 1 hour, and 6.54 S of paraformaldehyde is added in 3 fractions over 5 minutes. The water is removed by distillation as before until the temperature reaches 175-180°C, and the mixture is heated to 175-180°C for another hour. The dark brown solution is then cooled and poured into

1000 ml of water. The layers are separated, and the organic layer is extracted with 2 x 400 ml of 5% hydrochloric acid. The aqueous extract is then washed with 2 x 150 ml of chloroform, and the chloroform solutions are discarded. To the aqueous layer, 120 ml of ammonium hydroxide and 400 ml of chloroform are added. The layers are separated, and the aqueous solution is extracted with 4 x 200 ml of chloroform. The chloroform extracts are then mixed with 200 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent yields 12.0 g of crude pyrrolo(2.3-g)-isoquinoline as a 4a,8a-trans, 4a,8a-cis (approximately 8:1) mixture, a dark ochre solid. The crude solid is dissolved in 100 ml of 9:1 dichloromethane-methanol solution, and 300 ml of diethyl ether is added. The solution is collected by filtration.

-56-

The fine solid precipitate, in which the 4a,8a-trans isomer predominates, is concentrated, and the filtrate is crystallized to give a second and third harvest of ochre solid. The combined product is dried at 525°/1 mm for 1 hour to give 8.20 g of a pale gray solid, 3-ethyl-2,6-dimethyl-4,4-a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1E-pyrrolo[2,3-g]isoquinoline-4-one, P203-226°. The partially purified gray solid is suspended in 80 mL of methanol, and 12 mL of 4 N hydrochloric acid in diethyl ether are added. The solvent is removed, and the residue is crystallized from 23 mL of hot absolute ethanol. The first harvest is collected by filtration, then the mother liquor is concentrated and crystallized to yield the second and third harvests of crystals. The collected solid is dissolved in 120 ml of methanol and 2.4 g of activated charcoal (Darco-G-60) is added. The mixture is heated in a steam bath for 10 minutes and the charcoal is separated by filtration through Celite. The filtrate is concentrated and recrystallized from 15 ml of ethanol to yield three harvests of white crystals. The collected solid is dried under vacuum at 80°/ 0.05 mm for 18 hours to give 5*4 g of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octa-25 hydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one hydrochloride in the form of a white solid, P^ 196-198°; oxime serahydrate, Pf 131-133°.

Examples 4a-c

Following the procedure of Examples 3 and 4, the compounds listed in Table I are prepared from the appropriate isonitroketone with the variations mentioned. Each compound exhibits spectral characteristics that are consistent with the described structure. The melting points for the free base or the hydrochloric acid salt (.IIC1) are those that are h

-57-

indicated. Isonitrosoketones are prepared as described in the literature [e.g., Ferris et al., JOrg. Chenu, 24, 1726 (1959)] by nitrosation of the appropriate ketone. The isolated compounds are the five 4α,8α-trans isomers.

\

\

TABLE I

och-

c^v/r3 ch hon^^r

Example 4a

3,6-dimethyl-2-(2-propyl)-4,4a,5,6,7,

8,8a,9-octahydro-

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

isoquinoline-4-one

4b

2,6-dimethyl-3-phe-ny1-4,4a,5,6,758,8a, 9-octahydro-1H-pyr-rolo[2,3-g]isoquino-lein-4-one

Reaction of

OCH-

R„

ch(ch5)2

ch.

ch-

W //

ch,hh

-> ■ 5.

Knorr

CH- reaction

Mannich

Analysis

Calculated

Find

(

;HC1)

c

64.74

C

64.53

H

8.49

H

8.38

N

Q Zul

N

9.36

Cl

11.94

Cl"

12.12

C

77.23

C

77.23

H

7.53

H

7.50

N

9.52

N

9.54

Crystallized Variation from process

(•HC1) methanol >280°,d

>240°, of ethanol-ethyl acetate

Mannich reaction in diethylene glycol monoethyl ether, 155°, 1 hour i

vj1 03 i

PAINTING

I (Continued)

Example

4c

2,3,6-trimethyl-4,4a, 5,6,7 »8,8a,9-octahydro-1 H-pyrrolo-[2,3-s]i£oquinoline-4-one

R,

CH-

h

Analysis

Calculate

CH, (.HC1)

C

H n

Cl"

Find

62.56 C 7.88.H 10.42 N 13.19 Cl"

62.19 7.97

10.20 13.41

3. Crystallized Variation of f from process

275- ethanol-80°, ether

Knorr reaction in n-butanol at 170°/3.5 kg/cm³

i vjl vX> i i

-60-

Example 5

Preparation of 2-methyl-5-ethyl-4,4a..'5<6<7,8.,8a,9-octahydro-4a,8a~trans-1H-pyrrolo[" 2,3-g~l isoquinoline-4-

one

5. Heat a mixture under reflux for 3 hours.

a mixture of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octa-hydro-1H-pyrrolo[2,3-g]isoquinoline-4-one prepared as in Example 4 (4.92 g, 20 mmols), ethyl chloroformate (19.55 S ≈ 180 mmols) and potassium bicarbonate (6.0 g, 60 mmols) in diethyl ketone

(100 ml). The mixture is cooled, filtered, and the filtrate is concentrated to dryness on a rotary evaporator. The residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous hydrochloric acid, brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent yields 4.90 g of crude carbamate, which is 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,9-20 octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one.

Carbamate (3.7 g, 12.2 mmol), glacial acetic acid (45 mL), and concentrated hydrochloric acid (60 mL) are heated under reflux for 24 hours, cooled, and concentrated on a rotary evaporator. The residue is dissolved in water and extracted with chloroform (which is discarded). The aqueous layer is then made alkaline with ammonium hydroxide and extracted with chloroform. The combined extracts are washed with brine and dried over anhydrous sodium sulfate, then concentrated to give 2.72 g of crude secondary amine. Treatment of crude a-mine in ethanol with ethanolic hydrochloric acid gives the hydrochloric salt, which is crystallized from hot ethanol to give 2.18 g 35 (yield 47%) of 2-methyl-3-ethyl-

-61-

4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-[2,3-g]isoquinoline-4-one in the form of white crystals, above 250°.

Analysis: Calculated for C^E^qI^O.HCI:

C 62.56, H 7.77; N 10.42; Cl 12.19 Found: C 62.50; H 7.90; N 10.19; Cl 13.53

Similarly, 2,3-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one can be prepared from 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-a isoquinoline-4-one.

Example 6

Preparation of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride 15 A hydrochloride solution is treated

N-methyl-(3,5-dimethoxyphenyl)ethylamine (15.0 g, 54.7 mmol) in 30 mL of water with 35 mL of 2 N sodium hydroxide and extracted with dichloromethane. The combined extracts are concentrated on a rotary evaporator and mixed with aqueous formaldehyde.

(65 ml, 37% solution) • The mixture is refluxed for 2 hours, made alkaline with 2 N sodium hydroxide (15 ml), and extracted with dichloromethane. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5 s). • The oil is dissolved in 100 ml of ethanol and treated with ethanolic hydrochloric acid. Ether (75 ml) is added, and the salt crystallizes to give 10.15 s of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (yield: 64%).

Example 7

Preparation of 1,2,3-,4,4a,7-hexahydro-6,8-dimethoxy 35 2-ineth7/risoquinoline and octah,hydro-2-methylisoquinoline-6,8-dione

5

10

-62-

Ammonia (150 mL) is condensed in a flask containing t-butanol (9.1 g; 123 mmol) and diethyl ether (50 mL). 3,4-dihydro-1E-6,8-dimethoxy-2-methylisoqui-5-nolein hydrochloride (1.0 g, 4.1 mmol) is added to the solution. After stirring for 2–3 minutes, lithium wire (0.37 g, 82 mmol) is added in small batches over 30 minutes. The blue solution is refluxed for 2.5 hours, and solid ammonium chloride (4.5 g) is added until the blue color dissipates. Ether (100 mL) is added, and the ammonia is allowed to evaporate overnight. Ice-cold water (100 mL) is added, and the organic phase is separated. The aqueous layer is extracted with ethyl acetate and chloroform. 13 The combined extracts are washed with brine, then dried over anhydrous magnesium sulfate and concentrated to give 1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, yield 68%) as a yellow oil.

20. The crude product (1.05 g) is refluxed for 5 hours in 20 mL of 70% aqueous acetic acid, and the acetic acid is removed on a rotary evaporator. The residue is dissolved in water and washed with chloroform. The aqueous phase is concentrated to a 10 mL volume and chromatographed on a Dowex AG 50WX 8, eluting with 2 M aqueous pyridine to give 0.11 g of octahydrc-2-methylisoquinoline-6,8-dione (yield: 11.6%) as a pale yellow solid. Treatment with hydrochloric acid in methanol gives the hydrochloride, 193-196°. Example 8

Preparation of 3-ethyl-2,6-dimethyl-4,4a,5-6,7-8-,8a,9-octahydro-1II-P7/[rrolor2,3-g]isoauinoleine-4-one via octahydro-2-methylisoauinoleine-6,8-35-di one

-63-

Oel heats 1,2,3,4-,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.68 mmol) in 70% aqueous acetic acid (10 mL) to 90-100°C to hydrolyze the bis(enol-ether) to give 5-octahydro-2-methylisoquinoline-6,8-dione. Zinc powder (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol) are added to the hot solution. The mixture is refluxed for 3 hours, cooled, and filtered to remove the zinc and zinc acetate. The filtrate is concentrated to dryness on a rotary evaporator, and the residue is dissolved in the Dichloromethane. Ammonium hydroxide is added to the solution and the layers are separated. The organic layer is washed with brine, then dried over anhydrous sodium sulfate and concentrated to give the crude product. Chromatography of the crude product on alumina(III) gives 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-gIsoquino-4-one as a white solid (0.19 g, yield 29 Example 9)

Preparation of 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,Sa,9-octahydr o-4a,8a-trans-1H-pyrrolo|" 2,3-g lis oauino-leine-4-one

25. A solution of octahydrb-2-methyl-

Crude isoquinoline-6j8-dione (approximately 12.5 mmols) and 2.4 g (18 mmols) of 2-isonitroso-4-methyl-3-pentanone are mixed in 40 ml of 70% aqueous acetic acid with 2.6 g (40 mmols) of zinc powder and heated slowly under reflux. After one hour, the mixture is slightly cooled, and 0.4 g of isonitrosoketone and 1.0 g of zinc are added. The mixture is stirred for 1.5 hours under reflux. The mixture is then cooled and filtered, and the filtrate is concentrated to 50°/35° 20 mmHg to give a yellow oil, which is then diluted.

-64-

with 50 ml of water and made alkaline (pH 8-9) with ammonium hydroxide. The mixture is extracted with chloroform and the extracts are washed with brine and dried over sodium sulfate, then concentrated to give 2.6 g of crude product. The product is chromatographed (dry column) on 100 g of silica gel by eluting with the organic phase of a mixture prepared by equilibrating (by volume) 90 parts of chloroform, 30 parts of methanol, 10 parts of water, and 6 parts of acetic acid. The eluate fractions containing the product are evaporated, diluted with water, made alkaline (pH 8-9) with ammonium hydroxide, and extracted with chloroform. The extracts are dried on sodium sulfate and evaporated to give 1.0 g of solid product which is recrystallized twice from ethyl acetate to give 470 mg of pure 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,8a,9-oc tahydr o-4a,8 a-trans-1H-pyrr ol o [ 2.3 -g ] -isoquinoline-4-one as a crystalline solid, 244-247°.

Example 10

Preparation of 516-dimethyl-?-(2-propenyl)-4,4a,5«> 6,7 -, 8, 8a, Q-octahydro-4a, 8a-trans-1H-pyrrolo[ 2,3-g l -isoquinoline-4-one 25 In a manner analogous to that described in Example 9, 3-isonitroso-5-hexen-2-one and 2-methyl-octahydroisoquinoline-6,8-dione give 3,6-dimethyl-2-(2-propenyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[ 2, 3-g]isoquinoline-4-30 one, Pf 221-223°.

Example 11

Preparation of 3-c.vclopropyl-2,6-dimethyl-4,4a,5-6,7,8,8a,9-octahydro-4a,8a-tran-1H-pyrrolo f" 2,3-g "I-

-isoquinoline-4-one .

35 In a manner analogous to what is described in

-65-

Example 9* cyclopropyl-2-isonitroso~1-propanone and 2-methyl-octahydroisoquinoline-6,8-dione give 3-cyclopropyl-2,6-dimethyl-4,4a,5,6,7,2,8a,9-octahydr o-4a,8a-trans-1H-pyrrolo[2,3-g]is oquinolei ne-4-one, Pf 258-259° (dec.).

Example 12

-^repair of 2-benzyl-3,6-dimethyl-4,4a,5-.6,7,8, 8a,9-octahydro-4a,8a-trans-1H-pyrroloT2,5-g~iisoquino-

leine-4-one

10. In a manner analogous to that described in example 9, 3-isonitroso-4-phenyl-2-butanone and 2-methyl-octahydroisoquinoline-6,8-dione give 2-benzyl-3,6-dimethyl-4,4a,5,6,7-8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one,

15 Pf 234-235°.

Example 15

Preparation of 6-methyl-4,4a,5i6,7,S,8a,9-octahydro-4a,8a-trans-1H-pyrrolor2,3-flisoquinoline-4-one

Similar to what is described in example 9? except that zinc is not used, aminoacetaldehyde di-methylacetal and 2-methyl-octa-hydroisoquinoline-6,8-dione give 6-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-[2,3-g]isoquinoline-4-one, Pf 208-210°.

25 Example 14

Preparation of 3-ethyl-1,2,6-trimethyl-4,4a,516,718,8a,9-octahydro-4a,8a-trans-1H-pyrrolof 2,3-g]isoquino-

leine-4-one

Ammonia (80 ml) is condensed in a 30-balloon containing a suspension of 2,6-dimethyl-3-

ethyl-4,4a,5,6,7)8,8a,9-octahydro-1H-pyrrolo[2,3-g]-isoquinoline-4-one (0.984 g, 4.0 mmols) in ether (24 mL). Metallic sodium (0.138 g, 6.0 mmols) is added and the solution is stirred until all the sodium has dissolved. Iodide solution is added.

-66-

1.28 g of methyl ammonia (90 mmols) is dissolved in 16 mL of ether, and the mixture is stirred at room temperature until the ammonia evaporates. Water and chloroform are added, and the aqueous layer is separated and extracted with chloroform. The combined extracts are washed with brine and dried over anhydrous sodium sulfate. The mixture is concentrated to give 1.14 g of crude product, which is then chromatographed over alumina(III) to give 0.572 g of white solid product. Trans-10 forms the chromatographed free base to give the hydrochloric salt with etheric hydrochloric acid and crystallizes from ethyl-ethanol acetate and ethanol to give the pure 3-ethyl-1,2,6-trimed thyl-4,4-a,5,6,7,8,8a,9-octahydr o-4a,8a-15 trans-1H-pyrrolo[2,3-g]isoauinoleine-4-one hydrochloride (0.33 S5 yield 28%) as white crystals, 241-243°C.

Analysis: Calculated for C^gHg^l^O.HCl:

C 64.74; H 8.49; N 9.44; Cl 11.94 20 Found C 64.72; H 8.63; N 9.29; Cl 12.03.

Example 15

Preparation of 1-benzoyl-2,6-dimethyl-5-ethyl-4,4a, 5% 6,7,8,8a,9-oc tahydr o-4a,8a-trans -1H-pyrrolo j" 2.5 -g 1 -

isoquinoline-4-one 25 A a suspension of 3-ethyl-2,6-dimethyl-4,4a,

5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one (492.7 mg, 2.0 mmols) is mixed with dry tetrahydrofuran (10 mL) at -30°C. Butyllithium (1.6 mL, 2.4 mmols, 1.5 M solution in hexane) is added for 2 to 30 minutes using a syringe. The solution is stirred at -30°C for 1 hour, and benzoyl chloride (336 mg, 2.4 mmols) is added for 2 to 3 minutes. The resulting solution is stirred for 1 hour between -25 and -35°C and for 30 minutes at room temperature. The solution is then poured into ice water (30 mL) and

-67-

It is extracted with chloroform. The combined extracts are washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the crude product (0.9 g), which is chromatographed (dry column, silica gel, eluting with a solution of chloroform, water, methanol, and acetic acid). The column fractions are treated with ammonium hydroxide, then extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. Evaporation of the solvent gives 1-benzoyl-2,6-dimethyl-3-ethyl-4,4a,5 >6,7,8,8a,9-octa-hydro-4a,8a-trans-1H-pyrrolo[2,3-g]is°quinoline-4-one in the form of a solid which is recrystallized from cyclohexane to give the pure product, P^ 144-13 146°.

Analysis: Calculated for ^22^26^2^2;

C 75.4-0; H 7.48; N 7.99 Found C 75.63; H 7.79; N 8.01 Using the process of Example 15, or 20 prepares the following compounds. The isolated compounds are the 4a,8a-trans isomers.

From 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one and benzoyl chloride, we obtain 1-benzyl-25 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one.

7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one and 1-trimethylacetyl chloride, we obtain 30 2,6-dimethyl-3-ethyl-1-(2,2-dimethyl-1-oxopropyl)-

4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-lein-4-one, P^ 110°-112°.

From 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]-35 isoquinoline-4-one and methyl iodide, we obtain-

From 2,6-dimethyl-3-ethyl-4,4a,5,6,

-68-

holds the 3-ethyl-1,2-dimethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrr olo [2,3-g j -isoquinoline-4-one, 180-181°.

Example 16

5. Preparation of 5-ethyl-2-methyl-6-(2-propenyl)-4,4a,5,6,7-octahydro-4a,8a-trans-1H-pyrrolo-1-2,3-g-lisoauinolein-4-one

A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,8,108a,9-octahydro-1H-pyrrolo[2,3-g]isO<ruinolein-4—one (0.470 g, 2.03 mmols), allyl bromide (0.5 g, 4.13 mmols), and potassium carbonate (0.85 g, 6.16 mmols) is shaken at room temperature for 2 hours in acetone (35 mL) and filtered. The filtrate is concentrated, and residue 15 (0.53 g) is chromatographed on alumina(III) to give the product (0.40 g). This product is treated with ethereal hydrochloric acid to form the hydrochloric salt, which is recrystallized from ethyl ethanol-acetate to give 3-ethyl-2-methyl-20 6-(2-propenyl)-4,4a,5,6,7 >8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one hydrochloride as a white solid, Pf 214-217°.

Analysis: Calculated for C^E24N2O.HCL.0.5^0

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

Examples 16a-dd

Following the procedure in Example 16, the compounds listed in Table II are prepared from the indicated 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-30-lein-4-one and the indicated halide. Each compound exhibits spectral characteristics consistent with the described structure. The melting points are those indicated for the free base or the hydrochloric acid salt (HCl). The isolated compounds are the 35 4a,8a-trans isomers.

0

Example 16a 2-methyl-J-ethyl-6-(cyclopropyl-methyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-gJi3oquinoline-4-one hydrate 0.2M

16b

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

J

TABLE II

KoC0-,

^ 3

+ r4x r/| r2 r^

H CH5 CÏÏ2CH5

H CH-, CH0CH,

3 ^3

Example

16c rac.2-methyl-3-ethyl-6-[2-dime thylamino) ethyl]-4-,4-a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one

1od rac.2-methyl-3-ethyl-6-[4-(4-fluorophenyl)-4-oxohutyl]-4,4a,5,6,7,8,8a,9-octahydro-, 4a,8a-trans-1H-pyrrolo[2,3-gJ isoquinoline-4-one

16th rac.2-methyl-3-ethyl-6-(2-

phenylethyl)-4,4a,5,6,7,8,8a, 9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquino2 eine-4-one

16f

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

II (Continued)

h. -2: —

ch2ch5 (ch5)2nch2ch2 Cl

P

ch2ch5 c[;ch2ch2ch2 ci

0

ch2ch5 ^ ch2ch2 Br

I

Cïï2CH5

ch5ch20ch2ch2

Br

Example R^j

16s rac.3,6-diethyl-2-methyl-4,4a, H 5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]iso~ quinoline-4-one

16h rac.3-ethyl-2-methyl-6-propyl- H 4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]~ isoquinoline-4-one

16i

Ethyl ester of acid h

4a,8a-trans-3-ethyl-4-oxo-4a, 5,7,8,8a,9-hexahydro-2-methyl-111?4H-pyrrolo[2,3-g]isoquino-6-acetic acid

16d

4a,8a-trans-1-[3-ethyl-4a,5,7,h 8,8a,9-hexahydro-2-methyl-4-oxo-1H,4H-pyrrolo[2,3-gJiso-quinoline-6-yl]-2-propanone

TABLE II (Continued)

ch- ch0ch, 5 25

crj . ch2ch ch5 CH2CH5

ch5 ch2ch.

a_ jl

CH^CHg Br

CH5CH2CH2 Br

CH5CH2OOCCH2 Br h,ccch0 3 il 2 0

Cl

Example

Ry

TABLE II (Continued)

r,

i

R,

16k rac.2-methyl-3-ethyl-6-[2-(4-fluorophenyl)-2-oxoethyl]-4,4a,5,6,7i8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one

16^

rac.2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3-oxopropyl]-4,4a,5,6,7,8,8a,9-octahydro-

4a,8a-trans~1H-pyrrolo[2,3-g] isoquinoline-4-one

16m rac.3-ethyl-2-methyl-6-(3-

phenoxypropyl)-4,4a,5,6,7,8

8a,9-octahydro-1H-4a,8a-trans-pyrrolo[2,3-g]isoquinoline-4-ono

H • CH, CH0CH, 3 2 3

H

H

CH^ ' ch2CH5

ch5 CH2CH5

e

P

C-CH-Il 2

0

0

CCH2CH2

0CH2CH2CH2

Cl

Cl

Bri

-o you i

16n rac. ô-O-diphenylpropy^^-ethyl^-methyl-^-^a^ ,6,7 ,8, 8a,9-octahydro~4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline -4-one

H

CH, CH0CH, 3 2 3

C6H5. O5H5'

\

CHCH2CH2

Cl

Example

16° rac.3-ethyl-6-[2-(4-methoxyphenyl)-ethyl]-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one

16p

3-ethyl-4,4a,5,6,7,8,8a,9-

octahydro-2-methyl-6-[2-[tricyclo[3.3.1.1/3,7/]decan-1-ylJ-2-oxoethyl-4a,8a-trans-1H-pyrrolo[2,3-Sjisoquinoline-

4-one

16q rac.3-ethyl-2-methyl-6-(2-methylpropyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo [2,3-g]isoquinoline-4-one

16r rac.3-ethyl-6-[2-(4-chlorophenyl)-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-gIsoquinoline-4-one

J

(Following)

ch2ch5

ch0ch, 2 3

ch2ch5

H3C\

hjc"

ch-ch,

Br ch2ch5

ci-^>-ch2ch2

Cl

Example

16s rac.3-ethyl-6-[2-(ethenyloxy)-ethyl]-2-methyl-4,4a,5,6,7,8,8a,9-octah.hydro-4a,8a-trans-1H-pyrrolo[2.3~g]isoquinoline-4-one

16t rac.3-e thyl-2-methyl-6(3-phenyl-2-propenyl]-4,4a,5,6, 7,8,8a,9-octahydro-4a,8a-trans in-pyrrolo[2,3-g]isoquinoIein3 4-one

16u

Ethyl ester of 4a,8a-trans-3-ethyl-4a,5,7,8,8a,9-hexahydro-2-methyl-4-oxo-1H?4H-pyrrolo[2,3-g]isoquino-leine-6-propanoic acid

16v rac.6-(cyclobutylmethyl)-3-ethyl-2-methyl-4,4a,5,6,7,8, 8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one

II (Continued)

■^3 ^4.

CH2CH5 CH2=CH0GH2CH2 Cl

CH2CH5 C6H5CH=CHCH2 Br

CH2CH5 CH5CH200CCH2CH2 Br

/X

CH0CHX H0CV CHCH0 Cl

2 3 2 \ / d ch27

Example 1 6v-t rac. 6- (4-diphenbutyl ) -3 -

ethyl-2-methyl-4,4a,5,6,7 >8,

8a,9-octahydro-4a, 8a-trans-1H-pyrroloL2,3-g]isoquino-lein-4-one

16x

Ester of trans-[2-[3-ethyl-4,4a,5,6,7,8,8a,9-octahydr o-2-methyl-4-oxo-. 1H-pyrrolo[ 2,3-g leine-6-yljethyl_

isooumo-benzoic

16y rac.3-ethyl-2-methyl-6-[2~ (K-methyl-2-pyrrolidinyl)-ethyl-2-pyrrolidinyl)-ethyl-4,4-hydroxypyrrolidinyl]-4,4-hydroxypyrrolidinyl,5,6,7,8,8-hydroxypyrrolidinyl,9-octahydro-4,8-hydroxypyrrolidinyl,1-isoquinoline-4-one

16z trans-[3-[3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-2-methyl-4-oxo-IH-pyrrolo[2,3-g]isoquinoline-6-yl]propyl]benzene

II (Continued)

jh_ a. jl

C6H5.

CH0CH, OIICH„CH„CH_ 01

d $ y 2 2 2

6:05 AM

CHgOH, COOOH2OH2 Br

-n' ch20h2

in.

i

-o \j1 i

Cïï2CH5 , 1 Cl ch2ch5

C00CH2CH2CH2

Br

Example

16aa rac.-3-ethyl-2-methyl-6-(2,3-dihydroxypropyl) -4,4a, 5,6,7 î 8,8a,9~octahydro-4a,8a-trans-1Iî-pyrrolo[2,3-g]isoquino-lein-4-one

16bb

3-ethyl-2-methyl-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-

methylJ-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H~ pyrrolo[2,3-g]isoquinoline-

4-one

16cc rac,3-ethyl-6-[2-(4-morpho-li nyl)ethyl]-2-methyl-4,4a, 5,6,718,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-, L2,3-g]isoquinoline-4-one

16dd rac.6-benzyl-2,3-dimethyl-4, 4a,5,6,7 î 8,8a,9-octahydro-

1H-4a,8a-trans-pyrrolo[2,3-g]

isoquinoline-4-one

II (Continued)

R4 JL

CH2CH2 CH2CH-CH2 Cl

OH OH

ch2CH3

ch2-ch-ch2

Br h,c 3

°x/°

HAS

CH-

i

-o 0> i ch2ch5

V_7

n-ch2-ch2

cl

CH-

0 \

CH,

Cl

Example 16a

Analysis

Calculated (.HCl)

Find

TABLE II (Continued)

P„ Crystallized

- from

C

66.22

C

66.24

215-9°

Ethanol-

H

8.15

H

8.35'

acetate

N

8.58

H

8.36

ethyl

Cl"

10.85

Cl"

10.51

16b

(.HCl)

s

C'

70.27

C

70.49

193-7°

Ethanol

H

7.58

H

7.33

N

7.81

N

7.72

Cl"

9.88

Cl"

10.03

16c

C

71.25

C

71.03

184-6°

acetate

H

9.63

H

9.73

d* ethyl

N

13.85

N

13.66

16d

C

72.70

C

72.47

210-12°

acetate

H

7.37

H

7.47

ethyl

N

7.07

N

7.09

F

4.79

F

4.75

16th

C

78.53

C

78.53

239-40°

acetate

H

8.39

H

8.40

d1ethyl

N

8.33

N

8.35

ethanol

16f

C

63.42

C

63.13

213-5°

ethanol

H

8.57

H

8.71

acetate

>

N

8.21

N

8.17

ethyl

Cl"

10.40

Cl"

10.64

reaction conditions duration temp.

reflux in 16 hours, acetone reflux in 2 hours

1'acetone reflux reflux

20 hours in 3-pentanone

24 hours in the 3-pentanone reflux

2 hours in the 3-pentanone reflux

2 hours in 3-pentanone

Example Analysis

Calculated

Find

16g

C

73.81

C

73.91

H

9.29

H

9.30

N

10.76

N

10.84

4 p.m.

C

74.41

C

74.29

H

9.55

H

9.40

.N

10.21

N

10.21

16i

C

67.90

C

68.09

H

8.23

H

8.28

N

8.80

N

8.80

16 days

C

70.80

C

71.10

H

8.39

H

8.30

N

9.71

N

9.93

16k

C

71.72

C

71.44

H

6.84

H

6.80

N

7.60

N

7.47

160

C

72.23

C

72.24

H

7.12

H

7.00

N

7.32

N

7.19

16m

C

75.37

C

75.64

H

8.24

H

8.18

N

7.64

N

7.52

TABLE II (Continued)

p Crystallized

f starting from

228-30° ethanol

Reaction conditions: temperature, reflux, duration

3 hours in acetone

226-8°

ethanol reflux

13 hours in 3-pentanone

215-6°

192-5<

ethanol ethyl acetate

ethanol reflux

2 hours in 3-Pentanone

2 hours in 3-pentanone i

-o

00

1

209-13° ethanol refluxed for 3 hours in 3-pentanone

208-10°

ethanol reflux

3 hours in 3-pentanone

202-3°

ethanol reflux

2 hours in 3-pentanone

PAINTING

II (Continued)

Example

Analysis

Pf

Crystallized

Reactive conditions

Calculated

Find

I

from temp.

duration

16n

C

81.65

C

81.60

220-2°

backflow

17

hours in

H

8.03

H

7.85

there

3-pentanone

N

6.57

N

6.72

16th

C

75.37

C

75.65

255-7°

ethanol reflux

24

hours in

H

8.25

H

8.41

there

3-pentanone

N

7.64

î!

7.73

16p

C

76.43

C

76.34

2$7~40o

N ethanol reflux

3

hours in

H

8.88

H

8.75

there

3-pentanone

N

6.86

N

6.62

16q

C

74.96

C

75.24

213-15°

ethanol reflux

10

hours in

H

9.79

H

9.89

there

3-pentanone

N

9.71

N

9.70

16r

C

71.24

C

71.25

264-7°

1,4-dioxane reflux

20

hours in

H

7.34

H

7.16

there

3-pentanone

N

7.55

N

7.63

16s

C

71,^-9

C

71.31

174-7°

acetonitrile reflux

10

hours in

H

8.67

H

3.59

there

3-pentanone

N

9.26

N

9.25

16t

C

79.27

C

79.10 ^

218-20°

ethanol reflux

4

hours in

H

8.10

H

8.04

there

3-pentanone

N

8.04

N

8.10

rp>16u

C

68.65

C

68.59

180-4°

acetonitrile reflux

3

hours in

7

H

8.49

H

8.50

there

3-pentanone

J

N

8.43

N

8.55

TABLE II (Continued)

Example Analysis Crystallized Reaction Conditions rt„ 1 X ...i A 4-_* _ J _ J > _

Calculated

Find

x

from temp.

duration

16v

C

75.96

C

75.70

222-4°

ethanol reflux

18

hours in

H

9.39

H

9.34

there

3-pentanone

N

9.32

H

9.23

16w

C

81.78

C

81.88

236-8°

ethanol reflux

18

hours in

II

8.24

H

8.16

there

3-pentanone

N

6.36

N

6.36

16x

C

72.60

H

72.31

206-8°

s

ethanol reflux

6

hours in

H

7.42

H

7.58

there

3-pentanone

N

7.36

N

7.22

16y

C

73.43

C

73.25

192-4°

acetate reflux

20

hours in

H

9.68

H

9.54

ethyl

there

3-pentanone

N

12.23

N

12.41

16z

C

75.07

C

73.12

189-90.5°

ethanol reflux

8

hours in

H

7.67

H

7.63

there

3-pentanone

N

7.10

N

7.07

16aa

C

66.64

C

66.32

210-12°

ethanol reflux

20

hours in

H

8.55

H

9.07

there

3-pentanone

N

9.14

N

9.07.

16bb

C

69.33

C

69.29

233-5°

ethanol reflux

20

hours in

H

8.73

H

8.74

there

3-pentanone

N

8.09

N

8.12

I

TABLE II (Continued)

Analysis ^ p„ Crystallized

Example Calculate Find -=• from

16cc

C

69.53

C

69.59

206-8°

ethanol

h

9.04-

h

9.12

N

12.16

N

12.12

16dd

C

77.89

C

77.61

24-5.5-6°

- ethanol

h

7.84-

h

7.63

N

9.08

N

9.13

reaction conditions duration temp.

reflux

8 hours in 3-pentanone

3 hours in 11 acetone

-82-

Example 17

Preparation of 3-ethyl-2-methyl-6-(2-hydroxy-2-phenylethyl)-4,4a,5 16,7 •> 8,8a,9-octahydro-4a,8a-trans-1H-pyrrolof 2,3-g]isoouinolein-4-one

5. A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one (0.83 g, 3.58 mmol) and styrene oxide (0.51 g, 4.22 mmol) is refluxed in methanol (25 mL) for 2.5 hours, then cooled and filtered. The filtrate is concentrated and the residue is chromatographed on alumina(III) to give 0.69 g of crude product. Recrystallization from ethyl-ethanol acetate • gives 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-15 1H-pyrrolo[2,3-g]isoquinoline-4-one as a white solid, P^. 218-220°.

Analysis: Calculated for £22^28^2^2:

'C 74.97; H 8.01; N 7.95 Found C 74.87; H 7.92; N 7.95 20 Examples 17a-17f

Following the procedure in Example 17, the compounds listed in Table III are prepared from 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one and indi-25 epoxide. Each compound exhibits spectral characteristics consistent with the described structure. The melting points are those indicated for the free base or for the hydrochloric acid salt (HCl). The isolated compounds are the 4a,8a-trans isomers.

0

Rr

<J

H

Example R^

17a

2-methyl-3-ethyl-6-[2-:H hydroxy-2-(4-chloropheryl)-6-ethyl]-4,4a,5,6,7,8",8a,9-octahydro-1H-pyrrolol 2,3-gJ isoquinoline-4-one

TABLE III

r.

CH-

5pm

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

H

cïï-

2s.

R

CH2CÏÏ5

Cl ch2ch5

H

Example 17c rac.2-methyl-3-ethyl-6-[2-hydroxy-3-[4-(1,1-dimethylethyl)phenoxy]propyl] 4,4a,5,6,7 5 8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-gIsoquinoline-4-one

17^.

rac.2-methyl-3-ethyl-6-(2-hydroxy-3-methylbutyl)-4,4a,5,6,7 ? 8,8a,9-octahydr o-4a,8a-tran s-1H-pyrr olo[2,3-g]-isoquinoline-4-one

17th rac.2-methyl-3-ethyl-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7 ?8,8a,9-octa hydro-4a,8a-trans-1H-pyrrolo[2.3~g]~ isoquinoline-4-one

17f rac.2-methyl-3-ethyl-6-[2-hydroxy-3-(4-chlorophenoxy)-propyl]-4,4a;5 56,7 > 8,8a,9-octahydro-3a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one

(Continued) r2 r3

CH, CH-CH, 3 2 3

OCH,

ch5 CH2CH5

ch,

/ 3

CH

CH-

ch2CH5

H,C CH,

5 / 5

HAS

CH-

CH-

ch2ch5

Clocho-

Example Analysis

17a

17b

17c

17d

17th

17f

Calculated

Find

C

68.29

C

68.11

214-5

H

7.03

H

7.03

N

7.24

N

7.18

Cl

9.16

Cl

9.38

C

69.53

C

68.93

215-8

H

8.75

H

8.78

N

10.14

N

9.96

C

73.94

C

73.83

225-7

H

8.73

H

8.84

N

6.39

N

6, 30

C

71.66

C

71.49

197-9

H

9.50

H

9.72

N

8.80

N

8.77

C

72.25

C

72.31

232-4

H

9.70

H

9.73

N

8.43

N

8.20

C

66.26

C

66.11

211-13

H

7.01

H

7.05

N

6.72

N

6.81

Cl

8.50

Cl

8.26

TABLE III (Continued)

Crystallized from

Reaction conditions (temperature),

duration

ethanol-ethyl acetate reflux

3 hours in methanol

ethanol

25

2 hours in refluxing methanol and ethyl ethanol acetate

2 hours in methanol

ethanol-ethyl acetate reflux

5 hours in methanol

ethanol-ethyl acetate reflux overnight in methanol

ethanol reflux

3 hours in

11ethanol

-85-

Example 18

Resolution of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolor 2,5-g"lisoquinoline-

4-one racemigue 5 The racemic free base (prepared as in Example 4) (1.20 g) is dissolved in methanol, and a solution of d-(+)-tartaric acid (0.74 g) in methanol is added. The solution is concentrated and recrystallized twice from methanol. The crystalline d-(+)-tartrate salt is treated with ammonium hydroxide to release the free base, and the free base is treated with anhydrous etheric hydrochloric acid to give the hydrochloric acid salt. After two recrystallizations from ethanol and drying at 80°C/15°C, 0.005 mm, 0.15 g of the (-) enantiomer is obtained as a white crystalline solid, 240-245°C. Rotation: [a]^p -120.78° (c 0.81%, water)

Analysis: Calculated for C^^22^2®'HC1.0,2^2°

C 62.70; H 8.24; N 9.75 20 Found: C 62.44; H 8.33; N 9.67

The mother liquors of the crystallization of d-(+)-tartrate salt are treated with ammonium hydroxide to release the free base, which has been previously treated with a solution of 1-(-)-tartaric acid 25 (0.46 g) in methanol. The solution is concentrated and recrystallized twice from methanol, then transformed to give the free base and the hydrochloric acid sol as described above, yielding 0.10 g of the enantiomer(+) as a white crystalline solid, P 240-244°.

Rotation: [a]jp +121.38° (c 0.4-4%, water)

Analysis: Calculated for C^rHU^^O.HCl.0.25^0

C 62.70; H 8.24; N 9.75 Found C 63.02; H 8.20; N 9.88

-86-

Example 19

Preparation of N-r2-(5-ethyl-4,4a,5^,7,8-,8a,9-octahydr o-2-methyl-4-oxo-4a,8a-trans-1H-pyrrolor 2,3-g

- isoquinoline-6,7/1)ethyl j-4-fluorobenzamide 5 We prepare 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]-

isoquinoline-6-yl)ethyl-4-fluorobenzamide is prepared by heating 3-ethyl-2-methyl-4,4a,5,6,7j8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-one and 1-(4-fluoro-10-henzoyl)-aziridine in a mixture of benzene and methanol for 2 hours. The crude product crystallizes from ethanol as a white solid, P 252-253°. The starting aziridine is prepared from aziridine, p-fluorobenzoyl chloride, and sodium bicarbonate in water.

Example 20

Preparation of 3-ethyl-2,6-dimethyl-4,4a,i:3-l6,7,8,Sa, 9-octahydro-4a,8a-trans-1H-P7/rrrolor 2, ^-glisoauinoleine-

4-Thione A mixture of 2.48 g (0.01 mol) of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahyaro-1H-pyrrolo[2,3-g]isoquinoline-4-one and 2.44 g (0.008 mol) of 4-thione is stirred and refluxed for 17 hours. The dioxane is evaporated under reduced pressure, and 150 ml of water and sufficient sodium hydroxide to bring the pH to 8-9 are added. The mixture is extracted with chloroform, and the extracts are washed with water and then dried over sodium sulfate. Evaporation of the solvent gives crude thione (313 g) as a gummy product. Dry column chromatography gives 1.2 g of solid thione which is recrystallized twice from acetonitrile to give 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9~octahydro-4a,8a-trans-1H-pyrrolo[2,3-gIso-quinoline-4-thione pure, P^ 194-196° (dec.).

-87-

Example 21

Preparation of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolor2,5-g]-isoquinoline-4-thione

A mixture of 1.4-5 S (6 mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquino-lein-4-one and 1.77 g (4 mmol) of phosphorus pentasulfide is stirred and refluxed for 10 hours in 60 mL of dioxane. The mixture is cooled, and the dioxane solution is decanted from a dark residue, which is then dissolved in 75 mL of water.

The solution is made alkaline (p11 8-9) with ammonium hydroxide, and the aqueous mixture is extracted with chloroform. The extracts are washed with water and dried over sodium sulfate. Evaporation of the sol-13 yields 4-20 mg of crude thione, which is rechromatographed (dry column, silica gel) along with 100 mg of crude product obtained by hot water treatment of the residues from the initial isolation, followed by the same chloroform extraction process. 20 Elution of the dry column with the organic phase of a mixture prepared by balancing (by volume) 90 parts of chloroform, 30 parts of methanol, 10 parts of water, and 6 parts of acetic acid gives the purified thione after evaporation, dissolution in water, 25 neutralization at pH 8-9 with ammonium hydroxyae, and extraction with chloroform. After washing with water and drying on sodium sulfate, evaporation of chloroform gives 250 mg of 3-ethyl-2-methyl-4,4-a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline-4-30 thione as a yellow solid, T 190-194°. Recrystallization from acetonitrile gives the pure 4a,8a~trans isomer, P 203-205°.

Example 22

Preparation of 3-ethyl-2-methyl-6-(2-phenyl6thyl)-35 4,4a,5i6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo-1-F.1 soquinoline-4-thione

-88-

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]isoquino-leine-4-thione, 276 mg of potassium carbonate, and 5222 mg of 2-dromoethylbenzene in 15 mL of 3-pentanone is shaken and refluxed for 3 hours. The solvent is removed on a rotary evaporator, 25 mL of water is added, and the mixture is extracted with chloroform. Purification by dry column chromatography as detailed in Example 2110 yields 100 mg of purified product, which gives 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~gjisoquinoline-

4-thione, P^ 164-166° (dec.) after recrystallization from acetonitrile.

15 Example 23

Formulation of a capsule mg/capsule

Composition

0.5

5.0

10.0

3-Ethyl-2,6-Dimethyl-4,4a,5,6,7-8,8a,9-Octahydro-4a,8a-Trans-1H-Pyrrol[2,3-g]Isoquinoline-4-one

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 stearate

1.0

1.0

2.0

Total

220 mg

220 mg

290 mg

30. Procedure:

Mix the active ingredient, lactose, and starch in a suitable mixer. Grind through a suitable mill. Mix with talc and magnesium stearate and feed into a encapsulating machine.

-89-

Example 24

Tablet formulation (direct compression)

mg/tablet

Composition

0^

iiû

10.0

5

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 hydrochloride

0.5

5.0

10.0

10

Lactose

85.5

81.0

103.0

Avicel

30.0

30.0

45.0

Modified starch

7.5

7.5

10.0

Magnesium stearate

1^5

1.5

2.0

15

Total

125 mg 125 mg

170 mg

Procedure:

Mix the active ingredient, lactose, avicel, and modified starch in a suitable mixer for 10 to 15 minutes. Add magnesium stearate 20 at premix strength and mix for 4 minutes. Compress using a suitable press.

Example 25

Tablet formulation (moist granules)

mg/tablet

25 Composition 0.5 5 >0, 10.0

3-Ethyl-2,6-Dimethyl-4,4a,5,6,7,8,8a,9-Octahydro-4a,8a-Trans-1H-Pyrrol[2,3-g]Isoquinoline-

4-one

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

1.0

1.0

2.0

Total 125 mg 125 mg 200 mg

-90-

Procedure:

Mix the active ingredient, lactose, modified starch, and pre-gelatinized starch in a suitable mixer, then granulate with water. Dry and grind. Mix with magnesium stearate and compress using a suitable press.

Claims (1)

-91- - DEMANDS - 10 1 - Process for preparing octahydro-1H-pyrrolo[2,3-g]isoquinolines of general formula R, r, r, a where R^ is a hydrogen, an alkoyl, an alcanoyl, an aroyl or an aralkoyl; R2 and R^, independently, represent a hydrogen, an alkoyl, a cycloalkoyl, an alkenyl, an acyl, an aryl or an aralkoyl; R^ is a hydrogen, an alkyl, a hydroxyalkyl, a phenylhydroxyalkyl, a halophenylhydroxyalkyl, an alkylphenylhydroxyalkyl, a 20-alkyloxyphenylhydroxyalkyl, an alkoxyalkyl, an aryloxyhydroxyalkyl, an alkoxyhydroxyalkyl, an acyloxyalkyl, an arylcarbonylalkyl, an alkoxycarbonylalkyl, an aralalkyl, an alkenyl, an alkylcycloalkyl, an alkynyl, a thienylalkyl, a 25-furylalkyl, an arylcarboxamidoalkyl, an acylalkyl, a cyclic alkyloxoalkyl; a cyclic alkylhydroxyalkyl, an alkenyloxyalkyl, an aralkenyl, an aryloxyalkyl, a N-alccyl-pyrrolidinyl-alcohol, a trifluoroalcohol having 2 to 6 t3 atoms 30 carbon, an aryl-N-imidazolonyl alcohol, or N-alcohol *7" where Rg and R,-,, independently represent a hydrogen or an alkyl or, taken together with nitrogen, a heterocyclic nucleus with 5 or 6 members; and X represents O or S, 35 the optical and geometric isomers of these compounds -92- 10 15 20 and their pharmaceutically acceptable acid addition salts, characterized in that a) To prepare a compound of formula A above- above, where R is a hydrogen, R^ is an alkyl, an alkoxyalcohol, or an alkylcycloalcohol, and where X is 0 and R2 and Rj are as described above, i.e., a compound with the general formula 0 where is an alkyl, an alkoxyalcohol, or an alkylcycloalcohol, and where R2 and R^ are as described above, we are dealing with a compound of general formula 25 IX 30 35 where R2, R^ and R^" are as described above, with formaldehyde, or b) To prepare a compound of the formula above above, we treat a compound with the general formula XII -93- where R^" is as described above, with a compound of general formula o R. VII HON r, 10 13 in the presence of a reducing agent or with a compound of general formula 0. h2n R- VIII r, 20 25 where R^ and R^ are as described above, or with a precursor of this substance, or c) To prepare a compound of formula A above above where R^ and R^ are hydrogens and where X is 0 and where R^ and R^ are as described above, that is, a compound of general formula 0 Ib 30 where R^ and R^ are as described above, a) N-demethylates a compound of formula A above where R^" is a methyl group, or d) To prepare a compound of formula A above- above, where R2 and Rj, independently, represent 35 a hydrogen, an aloeyl, a cycloalkoyl, an alkenyl, -94- an aryl or an aralcoyl, R^ is a hydrogen, an alcoyl, an alkoxyalcoyl, an aralcoyl, an alkenyl, an alkylcycloalcoyl, an alkynyl, a thienyl-alcoyl, a furyl-alcoyl, an alkenyloxy-alcoyl, an aralkenyl, an aryloxyalcoyl, or a trifluoroalcoyl having 2 to 6 carbon atoms, where X represents S and R^ is as described above, i.e., a compound with the general formula 10 15 island" 20 25 30 where R2' and R^' independently represent a hydrogen, an alkyl, a cycloalkyl, an alkenyl, an aryl, or an aralalkyl, R^" is a hydrogen, an alkyl, an alkoxyalkyl, an aralalkyl, an alkenyl, an alkyl-cycloalkyl, an alkynyl, a thienylalkyl, a furylalkyl, an alkenyloxyalkyl, an aralalkyl, an aryloxyalkyl, or a trifluoroalkyl having from 2 to 6 carbon atoms and where is as described above, we are dealing with a compound of general formula the" 35 -95- 10 15 20 25 30 or R. h2', V and R^"' are as described above. above, with phosphorus pentasulfide, or e) To prepare a compound of formula A above above, where R^_ is a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alcoylphenylhydroxyalcohol, an alkoxyphenylhydroxyalcohol, an aryloxyhydroxyalcohol, an alkoxyhydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an N-alcoylpyrrolidinylalcohol, an aryl-N-imidazolonylalcohol or a γ,6-N-alcohol, where Rg and R,.,, independently, represent a hydrogen or an alcohol or, taken together with the nitrogen, represent a 5- or 6-membered heterocyclic ring and X represents S and R^, R2 and R^ are as described above, that is, a compound with the general formula R- iic m r. IV where R^_ is a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, a ioylphenylhydroxyalcohol, an alkoxyphenylhydroxyalcohol, an aryloxyhydroxyalcohol, an alkoxyhydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an N-alcoylpyrrolidinylalcohol, an aryl-N- of R, 35 imidazolonyl alcohol or ^5 _N-alcoyl where R^ and R^, independently, represent a hydrogen or a -96- alkyl or, taken together with nitrogen, a heterocyclic ring with 5 or 6 members and where R1, R2 and R1 are as described above, we separate the protecting group(s) in a compound with the general formula 10 il 15 20 25 30 where R2" and R^" have the same meaning as R2 and R^ except that when R2 and R^ represent an acyl, R2" and R" represent an acyl in protected form, 3y tv and R^ have the same meaning as R^, but in protected form, and R^ is as described above. or f) "To prepare a compound of formula A above- above, where R^ is an alkyl, an alkanoyl, an aroyl or an aralcoyl and where R^ is an alkyl, an alkoxyalcoyl or an alkoxycycloalcoyl, and where R2, R^ and X are as described above, that is to say a compound of general formula Ac 35 where R^j' is an alkyl, an alkanoyl, an aroyl or a -97- aralcoyl and where R^, R/j." e"b x are as described above, we substitute a compound with the general formula 10 15 20 25 30 V. R- Aa R, H or RQ, v V and X are as described above, to the nitrogen atom of pyrrole, or g) To prepare a compound of formula A above- above, where R^j is a hydrogen and where R^ is an alkyl, a hydroxyalcohol, a phenyl-hydroxyalcohol, a halo-phenyl-hydroxyalcohol, an alkylphenyl-hydroxyalcohol, an alkoxyphenyl-hydroxyalcohol, an alkoxyalcohol, an aryloxy-hydroxyalcohol, an alkoxy-hydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxy-carbonylalcohol, an aralcohol, an alkenyl, an alkyl, a cycloalcohol, an alkynyl, a thienylalcohol, a furylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an alkenyloxyalcohol, an aralcenyl, an aryloxyalcohol, a N-alcoyl-pyrrolidinyl-al'coyl, a trifluoroalcoyl having 2 to 6 carbon atoms, a "d ^ aryl-IT-imidazolonyl alcohol or -p6 N-alcohol, where F_ and R, -, independently, represent hydrogen or an alkyl group, or, taken together with nitrogen, represent a heterocyclic ring with 5 or 6 members, and where R0, R, and X are as described above, that is, a compound of general formula -98- Ad 10 15 20 25 30 35 where R^' is an alkyl, a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alkylphenylhydroxyalcohol, an alkoxyphenylhydroxyalcohol, an alkoxyalcohol, an aryloxyhydroxyalcohol, an alkoxyhydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonylalcohol, an aralcohol, an alkenyl, an alkylcycloalcohol, an alkynyl, a thienylalcohol, a furylalcohol, an arylcarboxamidoalcohol, an acylalcohol, a cyclic alkyloxoalcohol, a cyclic alkylhydroxyalcohol, an alkenyloxyalcohol, an aralcohol, an aryloxyalcohol, a N-alcoyl-pyrroli-dinyl-alcohol, a trifluoroalcohol having 2 to 6 carbon atoms, an aryl-N-imidazolonyl alcohol, or a t5^ £6 N-alcohol, where Rr and R„, independently, c* f represent a hydrogen or an alkyl or, taken together with the nitrogen, a heterocyclic ring, at 5 or 6 links and R0, R^ and X are as described above, we substitute a compound with the general formula X R. H-N ' Ab where R~, R. and X are as described above, at the nitrogen atom of isoquinoline, or -99- h) To prepare a compound of formula A above- above where R^ is an alkyl, an alkanoyl, an aroyl, or an aralcoyl, and where R^ represents an alkyl, a hydroxyalcoyl, a phenyl-hydroxyalcoyl, a hydroxyphenyl-hydroxyalcoyl, an alooxyphenyl-hydroxyalcoyl, an alkoxyalcoyl, an aryloxy-hydroxyalcoyl, an alkoxy-hydroxyalcoyl, an acyloxyalcoyl, an arylcarbonylalcoyl, an alkoxycarbonylalcoyl, an aralcoyl, an alkenyl, an alkylcycloalcoyl, an alkynyl, a thienyl-alcoyl, a furyl-alcoyl, an arylcarboxamidoalcoyl, an acyl-alcoyl, a cyclic alkyloxoalcoyl, a cyclic alkylhydroxyalcoyl, an alooxyphenyloxyalcoyl, a aralcenyl, an aryloxyalcohol, an N-alcohol-pyrrolidinylalcohol, a trifluoroalcohol having 2 to 6 carbon atoms, a ■p x aryl-N-imidazolonyl alcohol or a T?6~~'^N-alcoyl, where ? Rg and R^, taken independently, represent a hydrogen or an alkyl group, or, taken together with nitrogen, represent a heterocyclic nucleus with 5 or 6 links and R^, ^ R^ and X are as described above, that is, a compound with the general formula Af where R^', R2, Rj, R^1 and X are as described above, a compound of formula Ae below is substituted for the nitrogen atom of pyrrole, or i) . To prepare a compound of formula A below- -100- 5 10 where R^j1, R2, R^ and X are as described above, 15. The protecting group is separated in a compound with the general formula X 25 where Z is a protecting group and where R^1, R^, Rj and X are as described above, or O) To prepare a compound of formula A, see below- 30 sus, where R^ is an alkyl, an alcanoyl, an aroyl or an aralcoyl and where R^ is a hydrogen, an alkyl, an alkoxyalcoyl, an acyloxyalcoyl, an alioylcarbonyl-alcoyl, an alkoxycarbonylalcoyl, an aralcoyl, an alkenyl, an alkylcycloalcoyl, an alkynyl, a 35 thienyl-alcoyl, a furyl-alcoyl, an arylcarboxamido- dôssus, where R^ is an alkyl, an alcanoyl, an aroyl, or an aralcoyl, and where R^ is a hydrogen, and where R2, R^, and X are as described above, i.e., a compound of general formula x -101- an alkoyl, an acyl alcohol, a cyclic alkoyloxy alcohol, an alkenyloxy alcohol, an aralkenyl, an aryloxy alcohol, an N-alkoyl-pyrrolidinyl alcohol, a trifluoroalkoyl having 2 to 6 carbon atoms, or an aryl-N-imidazolonyl alcohol, and where R0, R^, and X are as described above, i.e., a compound of general formula 10 15 20 25 Af ' where R^^* is a hydrogen, an alkyl, an alkoxyalkyl, an acyloxyalkyl, an alkylcarbonylalkyl, an alkoxy-carbonylalkyl, an aralkyl, an alkenyl, an alkylcycloalkyl, an alkynyl, a thienylalkyl, a furylalkyl, an arylcarboxamidoalkyl, an acylalkyl, a cyclic alioyloxyalkyl, an alkenyloxyalkyl, an aralkyl, an aryloxyalkyl, an N-alkylpyrrolidinylalkyl, a trifluoroalkyl having 2 to 6 carbon atoms or an aryl-N-imidazolonylalkyl and R^', R2, R^ and X are such as defined above, we substitute a compound of general formula 30 ad' 35 where R^j R^ 5 % are as defined above, -102- to the nitrogen atom of pyrrole, or k) To prepare a compound of formula A ci- above, where R^ is an alkyl, an alkanoyl, an aroyl or an aralcoyl and where R^ is a hydroxyalcoyl, a phenyl-hydroxyalcoyl, a halophenyl-hydroxyalcoyl, an alkylphenyl-hydroxyalcoyl, an alkoxyphenyl-hydroxyalcoyl, an aryloxy-hydroxyalcoyl, an alkoxyhydroxyalcoyl, a cyclic alkylhydroxyalcoyl or •d £6 j;ïï-alcoyle, where Rc and Rn, independently, ■"ri— o / 10 represent a hydrogen or an alkyl group or, taken together with nitrogen, a heterocyclic ring with 5 or 6 links and where R„, R^ and X are such as defined below- above, that is to say a compound of general formula 15 20 R, VII Af" VII where R^ is a hydroxyalcohol, a phenyl-hydroxyalcohol, a halophenyl-hydroxyalcohol, an alkylphenyl-25-hydroxyalcohol, an alkoxyphenyl-hydroxyalcohol, an aryloxy-hydroxyalcohol, an alkoxyhydroxyalcohol, a cyclic alkylhydroxyalcohol, or a T? ^6 J^^N-alcoyle, where Rg and R,-,, independently, represent a hydrogen or an alkyl or, taken together with nitrogen, a heterocyclic nucleus with 5 or 6 links and where R^1, R2, R^ and X are as defined above, we separate the protecting group in the corresponding compound of formula Af" above, but where R"^ is protected, that is to say in a compound of general formula -103- rale x 10 VTTT VII where R; has the same meaning as R^, but in a protected form, and where R^1, R25, R^ and X are as defined above, Or 15 1) The mixture of cis and trans isomers obtained is isomerized in a final ratio predominantly comprising the trans isomer, or m) The trans isomer is separated from the mixture obtained, Or 20 n) A racemic mixture obtained is resolved to give the optical antipodes and o) If desired, a compound is transformed obtained or a non-pharmaceutical-acceptable acid addition salt in a pharmaceutically-25 acceptable acid addition salt of this body. 2 - A process according to claim 1, characterized in that compounds of formula A are prepared, where R^ is a hydrogen, an alkyl, an alkanoyl, an aroyl, or an aralcoyl; R^ and R^, independently, represent a hydrogen, an alkyl, a cycloalcoyl, an alkenyl, or an aralcoyl; R^ is a hydrogen, an alkyl, a hydroxyalcoyl, a phenhydroxyalcoyl, a halophenylhydroxyalcoyl, a ioylphenylhydroxyalcoyl, a iooxyphenylhydroxyalcoyl, an alkoxy-35 alkyl, an aryloxyhydroxyalcoyl, an iooxyhydroxy- -104- an alkool, an acyloxyalcohol, an arylcarbonylalcohol, an alkoxycarbonylalcohol, an aralcohol, an alkenyl, an alcoylcycloalcohol, an alkynyl, a thienylalcohol, a furylalcohol, or a 5 ^N-alcohol, where R^ and R^, independently, V represent a hydrogen or an alkyl, or, taken together with nitrogen, a heterocyclic ring with 5 or 6 10 links, and X is 0, the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, process which involves preparing said compounds according to practical embodiments c), l), m), n) and o) of claim 1, or by a practical embodiment a) or b) where a starting material is used a compound of formula IX or XII where R^" is a methyl, or by a practical embodiment f) where a starting material is used a compound of formula Aa where R^" is a 20 methyl and where X is 0, or by a practical embodiment g), h), i), j) or k) where a starting material is used a compound of formula Ab, Ae, Ah, Ad1 or Af1" where X is 0. 3 - Method according to claim 1 or 2, 25 characterized in that Ryj is a hydrogen.. 4 - A process according to any one of claims 1 to characterized in that R2 and R^ represent an alkyl. 5 - A process according to any one of claims 30 1 to 4, characterized in that R^ is an alkyl, a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alkoxyalcohol, an aryloxyalcohol, an arylcarbonylalcohol or an aralcohol. 6 - Method according to any one of claims 1 to 35 and 3 to 55 characterized in that X is 0. -105- 7 - A process according to any one of claims 1 to 6, characterized in that the compound is the trans isomer. 8 - Process according to claim 2, characterized in that 3-ethyl-2,6-dimethyl- is prepared 4,4a,5,6,7? 8 i8a,9-octahydro-4a,8a-trans-1H-pyrrolo-'[2,3-g] isoquinoline-4-one. 9 - Process according to claim 1, characterized in that 2-methyl-3-ethyl-6- is prepared 10 (2-phenylethyl)-4,4a,5,6,7 » 8,8a,9-cctahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one. 10 - Process according to claim 1, characterized in that 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5 >6,7 > 8,8a,9~octahydro~4a,8a-15 trans-1H-pyrrolo[2,3-g]isoauinoleine-4-one is prepared. 11- Process according to claim 1, characterized in that 2-methyl-3-ethyl-6~ [4-(4-fluorophenyl)-4-oxobutyl]-4,4a,5 5 6,718,8a,9-octahydro~4a,8a-trans-1H~pyrrolo[2,3-g]isoquinoline-4-20 one is prepared. 12 - A process according to claim 1, characterized in that it prepares 2-methyl-3-ethyl-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7 > 8,8a,9-octa-hydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one. 25 13 - A process for preparing a medicinal product, particularly intended for use as a neuroleptic/antipsychotic agent, characterized in that an ocbahydro-1H-pyrrolo[2,3-g]is°quinoline of formula A given in claim 1, an optical or geometric isomer or a pharmaceutically acceptable acid addition salt of this substance is put in galenic form. 14 - Medicinal product containing an octahydro-1H-pyrrolo[2,3-g]isoquinoline of formula A given in claim 1, an optical or geometric isomer -106- or a pharmaceutically acceptable acidic addition salt of that body. 15 - Neuroleptic/antipsychotic drug containing an octahydro-1H-pyrrolo[2,3-gIsoquinoline] 5 of formula A given in claim 1, an optical or geometric isomer or a pharmaceutically acceptable acid addition salt of this substance. 16 - Drug containing 3-ethyl-2,6-dimethyl-4,4a,5,6,7 5 8,8a,9-octahydro-4a,8a-trans-1H- 10 pyrrolo[2,3-g]i soquinolei ne-4-one. 17 - Antipsychotic neuroleptic drug containing 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. 15 18 - 0ctahydro-1H-pyrrolo[2,3-gIsoquinoline of general formula x 25 where R/j is a hydrogen, an alkyl, an alkanoyl, an aroyl or an aralcoyl; R2 and R^, independently, represent a hydrogen, an alkyl, a cycloalcoyl, an alkenyl, an acyl, an aryl or an aralcoyl; R^ is a hydrogen, an alkyl, a hydroxyalcoyl, a 30 phenyl-hydroxyalcoyl, a halophenyl-hydroxyalcoyl, an alioylphenyl-hydroxyalcohol, an alkoxyphenyl-hydroxyalcohol, an alkoxyalcohol, an aryloxy-hydroxyalcohol, an aliooxy-hydroxyalcohol, an acyloxyalcohol, an arylcarbonylalcohol, an aliooxycarbonylalcohol, an aralcohol, 35 an alkenyl, an alkylcycloalcohol, an alkynyl, an -107- thienyl alcohol, a furyl alcohol, an aryl carboxamido alcohol, an acyl alcohol, a cyclic alkyloxoalkoyl, a cyclic alkylhydroxyalkoyl, an alkenyloxyalkoyl, an aralkenyl, an aryloxyalkoyl, an N-alkylpyrrolidinyl alcohol, a trifluoroalkoyl having 2 to 6 carbon atoms, an aryl-N-imidazolonyl alcohol, or V N-alcohol, where and R^, independently, h" represent a hydrogenated or alkyl group or, taken together with nitrogen, a heterocyclic ring with 5 or 6 members; and X represents O or S, the optical and geometric isomers of these compounds and their pharmaceutically acceptable acidic addition salts, prepared according to the process claimed in claim 1 or according to an obvious chemical equivalent of this process. 19 - Compound according to claim 18 where R^ is a hydrogen, an alkool, an alkanoyl, an aroyl or an aralcoyl; R^ and R^, independently, represent a hydrogen, an alkool, a cycloalcoyl, an alkenyl, or an aralcoyl; R^ is a hydrogen, an alkyl, a hydroxyalkyl, a phenylhydroxyalkyl, a halophenylhydroxyalkyl, a ioylphenylhydroxyalkyl, an alkoxyphenylhydroxyalkyl, an alkoxyalkyl, an aryloxyhydroxyalkyl, a ioyloxyhydroxyalkyl, an acyloxyalkyl, an arylcarbonylalkyl, an alkoxycarbonylalkyl, an aralcyl, an alkenyl, a ioylcycloalkyl, an alkynyl, a thienylalkyl, a furylalkyl or 6 ^.N-alcohol, where R^ and R^ independently, represent a hydrogen or an alkyl or, taken in- h, 7 -108- seems to be with nitrogen, a heterocyclic nucleus with 5 or 6 links, and where X is 0, an optical isomer, a geometric isomer, or a pharmaceutically acceptable acidic addition salt of this 5th substance, whether prepared according to the process claimed in claim 2 or according to an obvious chemical equivalent of this process. 20 - Compound according to claim 18 or 19, where is a hydrogen, prepared according to the process of the 10 claim 3i °u according to an obvious chemical equivalent of this process. 21 - Compound according to any one of claims 18- to 20, where Eg and E^ represent an alkyl, either prepared according to the process of claim 4 or by an equi- 15 obvious chemical values of this process. 22 - Compound according to any one of claims 18 to 21, where E^ is an alkyl, a hydroxyalcohol, a phenylhydroxyalcohol, a halophenylhydroxyalcohol, an alkoxyalcohol, an aryloxyalcohol, an arylcarbonyl- 20 alkyl or an aralcoyl, prepared according to the process of claim 5 or according to an obvious chemical equivalent of this process. 2J - Compound according to any one of claims 18 and 20 to 22 where X is 0, prepared according to the process of 25 claim 6 or according to an obvious chemical equivalent of this process. 24 - Compound according to any one of claims 18 to 23, which is the trans isomer, prepared according to the process of claim 7 or according to a chi- equivalent 30 obvious mique of this process. 25 - 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-gIsoquinoline-4-one, prepared according to the process of claim 8 or according to an obvious chemical equivalent of this process. -109- 26 - 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-one, prepared according to the process of claim 9 or according to a chemical equivalent 5. This process is evident. 27 - 2-Methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5 » 6,718,8a,9-oc tahydro-4a,8a-trans-1H-pyrrolo-[2,3-g]isoquinoline-4-one, prepared according to the process of claim 10 or according to a chemical equivalent 10 is evident from this process. 28 - 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]isoquinoline-4-one, prepared according to the process of claim 11 or according to an obvious chemical equivalent of this process. 29 - 2-methyl-3-ethyl-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7)8,8a,9-octahydro-4a,8.a-trans-1H-pyrrolo[2,3-g]isoquinoline-4-one, prepared according to the process of claim 12 or according to an obvious chemical equivalent of this process. 30 - The invention as described above. 31 - Formula compound 25 R4"NH V och7 3 30 where R^" is an alkyl, an alkoxyalcoyl or an alkylcycloalcoyl. 32 - Compound according to claim 31, characterized in that •RZj_n is a methyl. 33 - Formula compound -110- 0 r4"nh VI 10 15 characterized in that R^" is an alkyl, an alkoxyalcoyl or an alkylcycloalcoyl. 34. _ Compound according to claim 33, characterized in that R^ " is a methyl. 35 - Formula compound OCH- XI OCH- 20 25 •30 where R^" is an alkyl, an alkoxyalcoyl or an alkylcycloalcoyl. 36 - Compound according to claim 351 characterized in that R^" is a methyl. 37 - Compound of formula ix h where R^ and R^, independently, represent a 35 hydrogen, an alkyl, an alkenyl, an alkenyl, a -111- acyl, an aryl or an aralcoyl and where R^" is an alcoyl, an alkoxyalcoyl or an alkylcycloalcoyl. 38 - Compound according to claim 37» characterized in that R2 ^3» independently represent a hydrogen, an alkyl, a cycloalkyl, an alkenyl or an aralcyl and where R^" is a methyl. 39 - Formula compound 10 XII 15 where R^" is an alkyl, an alkoxyalcoyl or an alkylcycloalcoyl. 40 - Compound according to claim 39» characterized in that R^" is a methyl. a to 1 s i n a i- page* containing References word added word crossed out null ^/^José Cyrau Industrial Property Attorney 26bl1, Princess Charlotte Blvd. MONTE-CARLO By power of attorney - 4i\ IloeUe