MC1377A1 - ISOQUINOLEIN DERIVATIVES - Google Patents

Description

1

The present invention relates to cycloalkali/5,57py-rrolo/2,3-g7-isoquinolines of general formula

X

where is a hydrogen, an alkyl, an acyl or an aral-coyl; 1Lp is a hydrogen, an alkyl, a hydroxyalcoyl, an arylhydroxyalcoyl, an arylhydroxyalcoyl, an alkoxyalcoyl, an acyloxyalcoyl, an acylacoyl, an aralcoyl, an alkenyl, a cycloalcoyl-alcoyl, an alkynyl, thienyl-alcoyl, furyl-alcoyl, an arylcarboxamidoalcoyl, an ar-alkenyl, alkenyloxyalcoyl, an aryloxyalcoyl, an aral-kyloxyalcoyl, or an aryl-N-imidazolonylalcoyl; X is 0 or S; and n is 3, 4, 5 or 6;

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

As used here, the term "alcohol" preferably denotes a "lower alkyl," that is, a straight- or branched-chain saturated hydrocarbon containing 1 to 7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, etc. The term "cycloalkyl" denotes a cyclic alkyl group of 3 to 6 carbon atoms, e.g., cyclopropyl, cyclohexyl, etc. The term "alkoxy" preferably denotes a "lower alkyl," that is, an alkyl ether group where the lower alkyl group is as described above, e.g., methoxy, ethoxy, propoxy, pentoxy, etc. The term "alkenyl" preferably denotes a "lower lacenyl," that is, an unsaturated hydrocarbon with a straight or branched chain containing 2 to 7 carbon atoms, e.g., vinyl, allyl, etc. The term "alkenyloxy" preferably denotes a "lower alkenyloxy," that is,

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To say an alkenyl ether group where the lower alkenyl group is as described above, e.g., ethenyloxy, etc. The term "alkynyl" preferably denotes a "lower alkynyl," that is, an unsaturated hydrocarbon with a straight or branched chain having from 2 to 7 carbon atoms, e.g., ethynyl, propargyl, methylbutynyl, etc. The term "halogen" or "halo" denotes all halogens, that is, bromine, chlorine, fluorine, and iodine. The term "aryl" denotes a phenyl or a phenyl group bearing one or more substituents selected from the group consisting of the halogens, trifluoromethyl, lower alkyls, lower alkoxys, nitro, amino, lower alkylamino, and lower di-alkylamino. The term "aralcoyl" preferably denotes an aryl group bonded to an alkoylene chain having 1 to 4 carbon atoms, such as 2-phenylethyl, 4-chlorobenzyl, benzyl, etc. The term "aralkenyl" preferably denotes 3-phenyl-2-propenyl, etc. The term "aralcoyloxy" denotes an aralcoyl ether, e.g., benzyloxy, etc. The term "aryloxy" denotes an aryl ether group where the aryl group is as described above, e.g., phenoxy, etc. The term "acyl" denotes an "alcanoyl" group derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, e.g., formyl, acetyl, propionyl, etc.; and an "aroyl" group derived from an aromatic carboxylic acid, such as benzoyl, 4-fluorobenzoyl, etc. The term "acyloxy" denotes an "alkanoyloxy" group derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, e.g., formyloxy, acetoxy, propionyloxy, etc.; and an "aroyloxy" group derived from an aromatic carboxylic acid, such as benzoyloxy, etc. Examples of "acylal-coyl" include 2-oxopropyl, 4-(4-fluorophenyl)-4-oxobutyl, etc. Examples of "alkyloxyalcoyl" include 2-acetoxyethyl, 3-benzoyloxypropyl, etc. Examples of "hydroxyalcoyl" include 1'-hydroxyethyl, 2-hydroxy-3,3-dimethylbutyl, etc. An example of "cycloalcoyl-alcoyl" is...

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Cyclopropylmethyl, cyclobutylmethyl, etc. Examples of "arylcarboxamidoalkoyl" include benzamide, etc. Examples of "aryloxyalkoyl" include 3-phenoxypropyl, etc. Examples of "aralkoyloxyalkoyl" include 2-benzyloxyethyl, 3-benzyloxypropyl, etc. Examples of "aryl-N-imidazolonylalkoyl" include 2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl, 3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl, etc. Examples of "arylhydroxyalkoyl" include 2-hydroxy-2-phenylethyl, 2-hydroxy-2-(4-chlorophenyl)ethyl, etc. Examples of "alkoxyalkyl" include 2-ethoxyethyl, 3-methoxypropyl, etc. Examples of "alkenyloxyalkyl" include 2-ethenyloxyethyl, etc.

Preferred compounds of formula A are those where n is 3, 4, 5 or 6, is a hydrogen, R2 is an alkyl, a hydroxyalkyl, an arylhydroxyalkyl, an alkoxyalkyl, an aryloxyalkyl, an acylalkyl or an aralalkyl; and X represents 0 or S.

The most appreciated compounds of formula A are those where n is 3 or 4, is a hydrogen, R2 is an alkyl, a hydroxyalkyl, an arylhydroxyalkyl, an alkoxyalkyl, an aryloxyalkyl, an acylalkyl or an aralalkyl; and X represents 0.

The most popular compounds of formula A of the invention are:

2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/C,_57pyrrolo/2,3-£7isoquinolin-10(10H)-one;

2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7~ isoquinolin-10(l0H)-one, hydrated 0.5 molar;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/ïï,57pyrrolo/2,3-g7isoquinolin-10-(1OH)-one;

4

2-/5-(4-fluorophenyl)-4-oxot>utyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo-/2,3-g7isoquinolin-10(10H)-one;

(-)-2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,-5 10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinolin-10-

(lOH)-one;

2-methyl-2,3,4,4a-5,7,8,9,10,11a-decahydro-4a,11a-trans-1 H, 6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinolin-1 1 ( 11 H) — one;

10 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-

trans-IHjôH-cyclohexa/îj^/pyrrolo/S^-^isoquinolin-l 1 ( 11H)-one, hydrated 0.75 molar;

2-(2-phenylethyl)~2,3,4,4a-5,7,8,9,10,11a-decahy-dro-4a,11a-trans-1H,6H-cyclohexa/4,57pyrrolo/2,3-g7i so-15 quinolin-11 (HH)-one;

2-/5-(4-fluorophenyl)-4-oxobutyl7-2,3,4,4a,5,7,8,-9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrro-lo/2,3-g7isoquinolin-11(11H)-one; and 2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-20 trans-6H-cyclopenta/5,57pyrrolo/2J3-g7isoquinolin-10(1OH)-thione.

Examples of compounds with formula A where n equals 3, that is, compounds with formula R, |, R£ and X are as described above, include:

2-ethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,1Oa-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinolin-10(10H) -

5

one

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25

2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahy-dro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquino-lin-10H)-one;

2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans~6H-cyclopenta/ïï, 57-pyrrolo/2,3-^7-

i soquinolin-10(10H)-one;

2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-^7isoquinolin-10(1 OH)-one;

2-(2-acetoxyethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahy-dro-4a,10a-trans-6H-cyclopenta/î,57pyrrolo/2,3-g7isoquino-lin-10(1OH)-one;

2-/3-(4-fluorophenyl)-3-oxopropyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo-/2,3-g7isoquinolin-10(1 OH)-one;

2-/2-(4-methoxyphenyl)ethyl7-1,2,3,4,4a,5,7,8,9, 10a-de cahydro-4a, 10a-trans-6H-cyclopenta/ïï, ^pyrrolo/S^-^-isoquinolin-10(10H)-one;

2-allyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4to,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-£7isoquinolin-10(10H)-one;

2~cyclopropylmethyl-1,2,3,4,4a,5,7,8,9,1Oa-decahy-dro-4a,10a-trans-6H-cyclopenta/ïï,57pyrrolo/2,3-g7isoqui-nolin-10(10H)-one;

2-propargyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-_g7isoquinolin-10-(1OH)-one;

.2-/2-(2-thienyl)ethyl7-1,2,3,4,4a,5,7,8,9,1Oa-de-cahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-gJlso-quinolin-10(10H)-one;

2-/2-(2-furyl)ethyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahy-dro-4a, 10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquino-lin-10(10H)-one;

2-JjL-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl/-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopen-ta/4,57pyrrolo/2,3-£7isoquinolin-10(1OH)-one;

2-/2-(benzyloxy)ethyl7~1,2,3,4,4a,5,7,8,9,10a-de-cahydro-4a, 10a-trans-6H-cyclopenta/5, j^pyrrolo/^^-g/iso-quino lin- 10(10H)-one;

2-(3-phenyl-2-propenyl)-1,2,3,4,4a,5,7,8,9,1Oa-de-cahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7-iso-quinolin-10(1OH)-one;

2-/2-(4-fluorobenzamido)ethyl7-1,2,3,4,4a,5,7,8,9,

1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/5,57pyrrolo-/2,3-^7i s o quinolin-10(10H)-one;

2-/2-(ethenyloxy)ethyl7-1,2,3,4,4a,5,7,8,9,1Oa-

decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7-

isoquinolin-10(10H)-one;

2-benzyl-1,2,3,4,4a,5,7,8,9,1Oa-de cahydro-4a,10a-trans-6H-cyclop enta/5,57pyrro 1 o /2 3-g7i so quinolin-10(1 OH)-

9

one;

1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyFrolo/2,3-g7isoquinolin-1 0(10H)-one;

6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahy-dro-4a, 10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-_g7isoquino-lin-10(10H)-one;

2,6-dimethyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinolin-10-(1OH)-one;

6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahy-dro-4a, 10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-_g7isoquino-lin-10(10H)-one;

6-methyl1-2-/5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta-/?» 57pyrrolo/2,3-_g7isoquiholin-10(10H) - one;

the 1,2,3,4,4a,5,7,8,9,1Oa-de cahydro-4a,10a-trans-6H-cy c lop ent a/5,57py ^ro lo/2,3-_g7i s o quino 1 in-10 (10H)-t hi one;

7

2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/5,57pyrrolo-/2,3-g7isoquinolin-10(1OH)-thione;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahy-5 dro-4a, 10a-trans-6H-cyclopenta/5, 57pyrrolo/2,3-g7isoquino-

lin-10(10H)-thione; and 2-/5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7, 8,9,10a-de cahydro-4a, 10a-trans-6H-cyclopenta/5, _57pyrrolo-/2,3-g7i soquinolin-10(10H)-thione.

10. As examples of compounds of formula A where n equals

4, that is to say, compounds of formula

20 where R2 and X are as described above, we can cite:

2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo-/2,3-^7isoquinolin-11(11H)-one;

25. 2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11a-decahy-

dro-4a,11a-trans-1H,6H-cyclohexa/5,57pyFrolo/2,3-g7isoqui-nolin-11(11H)-one;

2-cyclobutylmethyl-2,3,4,4a,5,7,8,9,10,11a-decahy-dro-4a, 11 a-trans-1 H, 6H-cyclohexa/5,57pyrrolo _/2,3-_g7isoqui-30 nolin-11(11H)-one;

2-/2-(2-thienyl)ethyl7-2,3,4,4a,5,7,8,9,10,11a-de-cahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinolin-1 1(11H)-one;

2-/2~(2-furyl)ethyl7-2,3,4,4a,5,7,8,9,10,11a-deca-35 hydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-£7iso-

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20

25

quinolin-11 (HH)-one;

2-/3-(4-fluorophenyl)-3-oxopropyl7~2,3,4,4a,5, 7,8,9,10,11a-decahydro-4a, 11 a-trans-1 H, 6H-cyclohexa/4, 57_ pyrrolo/2,3-g7isoquinolin-11(11H)-one;

2-(2-propenyl)-2,3,4,4a,5,7,8,9,10,11 a-de cahydro-4a, 11 a-trans-1 H, 6H~cyclohexa/5,j)7pyrrolo/2,3-_g7i soquinolin-11 (11H)-one;

2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11a-de-cahydro-4a,11a-trans-1H,6H~cyclopenta/ïï,57pyrrolo/2,3-£/~ isoquinolin-11(11H)-one;

2-/p-(2,3-dihydro-2-oxo-III-benzimidazol-l-y)pro-pyl7-2,3,4,4a,5,758,9,10,11 a-decahydro-4a,11a-trans-1 H, 6H-cyclohexa/5,57pyrrolo/2,3-£7isoquinilin-11 ( 11H)-one;

2-benzyl-2,3,4,4a,5,7,8,9,10,11 a-de cahydro-4a,11a-trans-1H, 6H, cyclohexa/4, ^pyrrolo/^^-g/isoquinolin-l 1-(11H)-one;

2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinolin-11(11H)-one;

6-benzoyl-2- /5-(4-fluorophenyl) -4-oxobutyl7-2,3,4-4a, 5,.7,8,9,10,11 a-decahydro-4a, 11 a-trans-1 H, 6H-cy clohexa-Z^^Tpyrrolo/^^-^isoquiûolin-l 1 (11H)-one;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahy-dr o-4a, 11 a-trans-1 H, 6H-cyclohexaJJi, 57py rr o lo /2,3-_g7 i s o qui-nolin-11 (HH)-thione;

2,3,4,4a,5,7,8,9,10,11 a-de cahydro-4a,11a-trans-1 H, 6H-cyclohexa/4,57pyrrolo/~ 2,3-g7isoquinolin-11 (HH)-thione; and 2-fpr- (4-fluorophenyl) -4-oxobutyl7~2,3,4,4a,5,7,8, 9,10,11 a-de cahydr o-4a, 11 a-trans-1 H, 6H-cyclohexa/5,57pyrro-lo/2,3-£7isoquinolin-11 (11H)-thione.

In compounds of formula A-2 where X represents 0, another nomenclature can be used. Thus, for example, 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7i soquinolin-11(11 H) -

9

one; and 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-pyrido/4,3-b7carbazol-11(1H,6H)-one are one and the same compound.

5. As examples of compounds of formula A where n equals

5, that is to say, compounds of formula

X

A-3

15 where R2 and X are as described above, we can cite:

2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahy-■ dro-4a,12a-trans-6H-cyclohepta/4,57pyrrolo/2,3-^7isoqui-nolin-12(12H)-one;

20 2-/ï-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,

7,8,9,10,11,12-dodecahydro-4a,12a-trans-6H-cyclohepta-fpr57pyrr o 1 o /2,3 -£Ji s o quino 1 in-12 (12H) - one;

2-(3-phenoxypropyl)-1,2,3,4,4a-5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta/11,57pyrrolo/2,3-g7-

25 isoquinoline-12(12H)-one;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta/5,57pyrrclo/2,3-g7-. isoquinolin-12(12H)-one;

2r-/4-(4-fluorophenyl)-4-"xobutyl7-1,2,3,4,4a,5,7,

8,9,10,11,12a-dode cahydro-4a,12a-trans-6H-cyclohepta-/5,57pyrrolo/2,3-^7isoquinolin-12(12H)-thione;

2-(3-phenoxypropyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta/4,57pyrrolo/2,3-^7-isoquinolin-12(12H)-thione; And

35 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-

10

10

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20

25

30

dodecahydro-4a-12a-trans-6H~cyclohepta/5,57pyrrolo/2,3-g7~isoquinolin-12(12H)-thione.

Examples of compounds with formula A where n equals 6, i.e., compounds with formula R^, R2 and X are as described above, include:

2-fpr~ (4-fluorophenyl) - 4- oxobut yl72,3,4,4a, 5,7,8, 9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta-fpc, 57pyrrolo /2,3-g7 isoquinolin-13(13H) -one ;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/4,57pyrrolo-/2,3-g7i s o quinolin-13(13H)-one;

2-(2-hydroxy-3,3-dimethylpropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta-U±,57pyrro1o/2,3-g7i soquino1in-13(13H)-one;

2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/5,57pyrrolo/2,3-_g7isoquino-lin-13(13H)-one;

2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycXoocta/5,57pyrrolo-/2,3-g7isoquinolin-13(13H)-one;

2-/4- (4-fluorophenyl) -4-oxobutyl7-2,3,4,4a,5,7,8, 9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta-/5,57pyrrolo/2,3-_g7isoquinolin-13(13H)-thione;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/4,57pyrrolo-

A-4

11

10

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20

25

J2,3-_g7i soquinolin-13 (13H)-thi one;

2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/5,57purrolo-/2,3-_g7isoquinolin-13(13H)-thione; and 2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/ïï,57pyrrolo-/2,3-g7isoquinolin-13(13H)-thione.

The compounds of the invention where n is 3 can exist in the form of the 4a,10a-trans or 4a,10a-cis isomers or mixtures thereof; the 4a,10a-trans isomers are preferred.

The compounds of the invention where n is 4 can exist in the form of the 4a,11a-trans or 4a,11a-cis isomers or mixtures thereof; the 4a,11a-trans isomers are preferred.

The compounds of the invention where n is 5 can exist in the form of the 4a,12a-trans or 4a,12a-cis isomers or mixtures thereof; the 4a,12a-trans isomers are preferred.

The compounds of the invention where n is 6 can exist in the form of the 4a,13a-trans or 4a,13a-cis isomers or mixtures thereof; the 4a,13a-trans isomers are preferred.

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

30

(C.HA

where R£ is an alkyl, an alkoxyalcoyl, or a cycloalcoylalcoyl, and where n is as described above,

to treat a compound of general formula

12

(C1I2'n t. ...

IX

10

where and n are as described above,

with formaldehyde, or b) To prepare a compound of the general formula above, to treat a compound of the general formula

15

20

O

V-N

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

XII

25

O

GO

HOls^ ^^

yil.. :

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

35

13

(ChVn

VIII

10

15

20

25

30

or one of its precursors, in which formula n is such as described above, or c) To prepare a compound of general formula

" "0 "

II-N "

(RESUME"

Ib where n is as described above,

to N-demethylate a compound of formula a above where R is a methyl, or d) To prepare a compound of general formula - ' ^

where Rî| is a hydrogen, an alkyl, or an aralcoyl, R£' is a hydrogen, an alkyl, an alkoxyalkyl, an aralcoyl, an alkenyl, a cycloalkyl-alkyl, an alkynyl, a thienylalkyl, a furylalkyl, an alkenyloxyalkyl, an aralcoyl, an aryloxyalkyl, or a thienylalkyl, and n is as described above,

to treat a compound of general formula

14

(CIVn the

10

15

20

25

30

35

where R!| , R^1 and n are as described above, with phosphorus pentasulfide, or e) To prepare a compound of general formula ~~ X

(CIVn

A d where R£ is an alkyl, hydroxyalcohol, arylhydroxyalcohol, alkoxyalcohol, acyloxyalcohol, acylalcohol, aralcohol, alkenyl, cycloalcohol, thienylalcohol, alkynyl, furylalcohol, arylcarboxamidoalcohol, aralkenyl, alkenyloxyalcohol, aryloxyalcohol, aralcoyloxyalcohol, or aryl-N-imi-dazolonylalcohol, and X and n are as described above, to substitute a compound of general formula

H —N

<CIVn

A b where X and n are as described above, to the nitrogen atom of isoquinoline, or

15

10

15

20

25

30

35

f) To prepare a compound of general formula

X

(CH2)n A ' c where is an alkyl, an acyl or an aralcoyl, R^ is an alkyl, an alkoxyalcoyl, an acyloxyalcoyl, an acyl, an aralcoyl, an alkenyl, a cycloalcoyl-alcoyl, a thienylalcoyl ion, an alkynyl, a furylalcoyl, an arylcar-boxamidoalcoyl, an aralkenyl, an alkenyloxyalcoyl, an aryloxyalcoyl, an aralcoyloxyalcoyl or xm aryl-N-imida-zolonylalcoyl and where X. and n are as described above,

to substitute xin compound of general formula

<ClVn

A d'

i where R^, X and n are as described above, to the nitrogen atom of pyrrole, or g) To prepare xin compound of general formula - ~ "X"

(CHÀ

Ac"

JV

where Ri;v is a hydroxyalkoyl or an arylhydroxyalkoyl, and where Ri, X and n are as described above,

N

16

15

20

to detach the protecting group in a compound of general formula

(CH2)n XIV

,v

10 where Rg is a protected hydroxyalkoyl or aryl-hydroxyalkoyl group and RJj, X and n are as described above,

or h) To prepare a compound of general formula

X

(cH2)n Ad"

tIV

2

where Ro", X and n are as described above,

to reduce the acyl alcohol group in a compound of general formula

25

30

X

(CrÇn Ad'

B.

j

VII

where R2 is an acyl alcohol, and where X and n are as described above, or i) To prepare a compound of general formula

17

10

H

(CH2>n

Ah

15

20

where X, n and RJj are as described above, to separate the urethane group in a compound of general formula

Y —N

(CH2'n

XIII

where X, n and RJj are as described above and Y is a urethane group,

and j) If desired, to isomerize the mixture of cis and trans isomers obtained in a final ratio which predominantly comprises the trans isomer, and/or k) If desired, to separate the trans isomer from the mixture obtained, and/or l) If desired, to decouple a racemic mixture obtained into its optical antipodes and/or m) If desired, to transform a compound obtained or an acid addition salt not pharmaceutically acceptable into one of its pharmaceutically acceptable acid addition salts.

"h

18

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 for obtaining them, can be prepared in the manner more fully specified below.

Thus, for example, compounds of formula A where X represents 0 are characterized by the formula i

I

O

where n, FL] and R2 are as described above, and can be prepared as shown in diagrams I, II, III and IV given later.

19

FORMULA SCHEMA I

OCII

OCII,

where n is as described above, and R£ is an alkyl, 35 an alkoxyalcoyl or a cycloalcoyl-alcoyl.

According to formula scheme I, the compo- are prepared

20

compounds of formula Ia are derived from known compounds of formula IV, where R2" is an alkyl, an alkoxyalkyl, or a cycloalcoylalkyl. The Birch reduction of the amine of formula IV with lithium in ammonia containing β-butanol gives the dihydroamine of formula V. Other modifications of the Birch reduction can also be used. Thus, the 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 is usually carried out at or below the boiling point of the solvent, for example, between -78 and 15°C. If ammonia is used, the reaction is carried out under reflux. Co-solvents such as diethyl ether or tetrahydrofuran.

The hydrolysis of dihydroamine V is easily carried out by the usual methods for the hydrolysis of enolethers, e.g., with an aqueous acid. Examples of acids that can be used include hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid, and perchloric acid. These can be used in aqueous solutions or in mixed solvents. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane, or acetonitrile are examples of solvents that can be used. For example, the hydrolysis of dihydroamine of formula V where R2" is a methyl in 2 N hydrochloric acid at room temperature or above or in aqueous acetic acid between 40° and reflux results in diketone of formula VI, where R2" is a methyl.

Diketone VI is condensed in a Knorr condensation to give methylaminoethyl ketone IX. The Knorr condensation is a well-known process for the preparation of pyrroles, and the process can be used in any of its well-known modifications (see the conditions given as examples in

21

10

15

20

25

30

J.M. Patterson, Synthesis, 281 (1976) and the references therein). Thus, it is thought that the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, for example with zinc in aqueous acetic acid or hydrochloric acid, proceeds via the aminocarbonyl compound of formula VIII, which then condenses with the diketone of formula VI to give the methylaminoethyl ketone product of formula IX. The condensation can also be carried out with an aminocarbonyl compound of formula VIII or one of its precursors, such as an aminoketone hydrochloride salt or a ketal derivative of an aminoketone. The use of an aminoketone precursor is preferred because its substances have a tendency to self-condense. It is best to use them in situ where the aminocarbonyl component is released in the presence of the diketone of formula VI. The aminocarbonyl component reacts immediately to form the compound of formula IX. It is not necessary to isolate the diketone of formula VI before performing the Knorr condensation because the reaction conditions used are sufficient to hydrolyze the dihydroamine of formula V to give the diketone of formula VI. The Knorr condensation is best carried out at a pH of approximately 2 to 6. When pH is significantly exceeded, there is a considerable loss of yield due to the formation of autocondensation products of the aminocarbonyl compound of formula VII.

Preferably, an isonitrosoketone of formula VII and zinc powder are condensed in aqueous acetic acid with a diketone of formula VI where R^" is a methyl to give the methylaminoethyl-ketone product of formula IX where R2" is a methyl.

The Knorr condensation preferably takes place within a temperature range from approximately room temperature to reflux. Isonitrosoketones of formula VII are known compounds or can be readily prepared by nitrosation of the corresponding beta-ketoester, for example with sodium nitrite.

22

(see, for example, T. A. Geissman & M. J. Schlatter, J. Org.Chem., 1J_, 771 (1946)).

Examples of isonitroketones of formula VII that can be used in Knorr condensation,

5. We can cite:

2-isonitrosocyclopentanone; 2-isonitrosocyclohexanone; 2-isonitrosocycloheptanone; and 2-isonitrosocyclooctanone.

10. Examples of aminocarbonyl precursor compounds of formula VIII that can be used in the Knorr condensation include:

2-aminocyclohexanone hydrochloride;

2-aminocyclopentanone hydrochloride;

15 2-aminocycloheptanone hydrochloride; and 2-aminocyclooctanone hydrochloride.

The said compounds are known or can be prepared by reduction of the corresponding isonitroketone, for example by catalytic hydrogenation in the presence of hydrochloric acid.

The amine of formula IX is transformed to give the compound of formula la by an intramolecular Mannich reaction. The Mannich reaction is generally carried out starting from a ketone and a dialcoylamine salt, 25 for example dimethylamine hydrochloride and formaldehyde (e.g. as an aqueous solution, as paraformaldehyde or as trioxane).

in an alcoholic solvent such as ethanol, at the reflux temperature of the reaction mixture. In modification 30 described here, an acid addition salt of methylaminoethyl ketone of formula IX is reacted with formaldehyde, added as paraformaldehyde, trioxane, or aqueous formaldehyde in a solvent. For example, a high-boiling hydroxyl solvent, 35 such as amyl alcohol, octanol, ethylene glycol, or mono-

23

diethylene glycol ethyl ether; a high-boiling polar aprotic solvent, such as dimethylformamide, N-methylpyrrolidinone, or diethylene glycol dimethyl ether; 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, within a temperature range of about 135°C to about 200°C to give cycloalkali,57-pyrrolo/2,3-g7isoquinolines of formula 1a. The reaction, particularly when carried out at temperatures below 150°C, results in a mixture of cis and trans isomers, i.e., for example, when R^" is a methyl group, in compounds of formulas

O

h trans

H

If'

O

ch3-]

(ch2)

h h

cis

24

The reaction mixture can be heated for a longer time, or the isomeric mixture of hydrochloric salts of formulas If' and Ig' can be heated separately, for example, in ethylene glycol under reflux for 2 h to equilibrate the 5 cis and trans isomers to a final ratio which predominantly includes the trans isomer, which is easily isolated by crystallization or by chromatographic separation.

For example, when the hydrochloride salt of the amine of formula IX where R2" is a methyl a- is reacted with paraformaldehyde in butanol at 180° for 2 h, the product is isolated in the form of the trans isomer If'.

25

10

c H O-C-N ^2 5

15

xnrâ

20

H-N •

25

FORMULA SCHEMA II O

30

35

where n is as described above, and where R^ ' is an alkyl, an acyl_ or an aralcoyl.

According to formula scheme II, compounds of formula l'c are prepared by alkylation or acylation of the nitrogen of the pyrrole of a compound of formula la' and other derivatives

26

N-2-Alkyl is formed by the formation of the pyrrole anion with a strong base, for example sodium amide, potassium hydride, sodium methylsulfinyl carbanion, potassium t-butoxide, 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 tallow oxide. For example, treating a compound of formula Ia', where n is 3, with potassium t-butoxide in tetrahydrofuran followed by immersion with methyl iodide gives the 6-methyl derivative, i.e., a compound of formula I'c where n is 3 and ' is a methyl group. Similarly, the reaction of a compound of formula la', where n is 4, with butyllithium in tetrahydrofuran at -30° followed by immersion with benzoyl chloride gives the 6-benzoyl derivative, i.e. a compound of formula I'c where R^' is a benzoyl and where n is 4. Similarly, the reaction of a compound of formula la', where n is 3, with methylsulfynyl sodium carbanion in dimethyl tallow oxide followed by immersion with benzyl chloride gives the 6-benzyl derivative, i.e. a compound of formula I'c where R^' is a benzyl and n is 3.

The N-demethylation of the compound of formula IaT can be carried out by classical N-dealcoylation processes, such as the von Braun process (H.A. Hageman, Org. Reactions, 7, 198 (1953)), or by acid or basic hydrolysis of a urethane derivative such as those listed in K.C. Rice (J. Org. Chem, 40, 1850 (1975)). A desalcoylation process for the compound of formula la' consists of passing it through urethane of formula XIIIa and acid hydrolysis to give the secondary amine of formula Ib. For example, a compound of formula la', where n is 4, when refluxed through dioxane with an excess of ethyl chloroformate and potassium bicarbonate for 6 h gives a compound of formula XIII, where n is 4.

27

10

15

20

Hydrolysis of the previous compound with 30% aqueous sodium hydroxide in refluxing ethanol-dioxane for 24 h gives the compound of formula Ib, where n is 4.

used as starting compounds for the preparation of derivatives substituted on the pyrrole ring by alkoylation or acylation on the pyrrole nitrogen, followed by cleavage of the urethane. The alkoylation or acylation is carried out following the procedure given for the preparation of the compounds of formula I'c, and the urethane derivatives and the procedures for their cleavage are given, as indicated above, in K.C. Rice (ibid). For example, according to the scheme of formulas II, the treatment of ethoxycarbonyl urethane of formula XlIIa, in which n is equal to 4, with sodium methylsulfinyl carbanion in dimethyl sulfoxide, followed by treatment with benzyl chloride, gives the compound of formula XlIIb where n is equal to 4 and R' is a benzyl. Hydrolysis with sodium hydroxide gives the 6-benzyl derivative, i.e. a compound of formula Ih where R^' is a benzyl and n is equal to 4e. In the case where R^' is an acyl group that could be hydrolyzed under strongly alkaline or strongly acidic conditions, a urethane group such as 2,2,2-trichloroethoxy-carbonyl, which can be cleaved under mild conditions with zinc in aqueous acetic acid, can be used to give compounds of formula Ih where R^' is an acyl.

Urethane derivatives can also

28

FORMULA SCHEME III

10

Ib

15

20

25

(CH2}n

ID

I'c where n is as described above, and R^' is an alkyl, an acyl, or an aralcoyl, and R2' is an alkyl, a hydroxyalcoyl, an arylhydroxyalcoyl, an alkoxyalcoyl, an acyloxyalcoyl, an acylalcoyl, an aralcoyl, an alkenyl-30, a cycloalcoyl-alcoyl, a thienylalcoyl, an alkynyl, a furylalcoyl, an arylcarboxamidoalcoyl, an aralcenyl, an alkenyloxyalcoyl, an aryloxyalcoyl, an aralcoyloxyalcoyl, or an aryl-N-imidazolonylalcoyl.

According to formula III, the compo-

29

10

15

20

■25

30

its formulas Id and the from the secondary amine of formula Ib, starting product for the preparation of many derivatives included in formula I, by substitution at the nitrogen of the basic amine (N-2) and/or at the nitrogen of pyrrole (N-6). For example, the treatment of a compound of formula Ib with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalcoylalcoyl halide, such as chloromethylcyclopropane, an aralcoyl halide, such as benzyl bromide, or an acylalcoyl halide such as gamma-chloro-p-fluorobutyrophenone, in the presence of a base, e.g. Potassium carbonate, in acetone, 2-propanone, or dimethylformamide, gives the compound of formula Id substituted in the corresponding manner, i.e., where R2' is an alkyl, an alkenyl, a cycloalkoyl-alkyl, an aralkoyl, or an acylalkoyl, respectively. With reactive halides, the reaction can be carried out at room temperature; with less reactive halides, reflux temperature is used, and in some cases, the reaction rate can be increased by adding an iodide salt, such as lithium iodide, to the reacting mixture.

The reaction of a compound of formula Ib with epoxyalkanes gives the substituted hydroxyalkyl compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogs of a compound of formula Id; e.g., the reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, where R2' is a 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol, from around room temperature up to the reflux temperature of the mixture. Epoxyalkanes are commercially available or are prepared by epoxidation of the corresponding olefins, or by methylation of a ketone with a sulfonium methylide or sulfoxonium methylide reagent, for example...

30

10

15

20

25

30

35

dimethylsulfonium methylide. Thus, e.g., the treatment of benzaldehyde with dimethylsulfonium methylide gives styrene oxide.

In some cases, when the compound of formula Id does not contain functional groups capable of undergoing alkoxylation or acylation, the processes shown in Scheme II for the preparation of compounds of formula Ie' can be used directly to prepare N-6-substituted analogs of formula Ie, as seen in Scheme III. Alkylations can take place in compounds where Ie' is a hydroxyalkoyl or an arylhydroxyalkoyl. The hydroxyl groups contained therein must be protected by a base-stable protecting group, such as tetrahydropyranyl. After N-6-alkoxylation, the protecting group is removed by acid hydrolysis.

Compounds of formula Id, where Rp1 is a hydroxyalkyl or an aryl-hydroxyalkyl, can also be prepared by reducing the corresponding compounds of formula Id, where Rg' is an acylalkyl. In particular, the preceding reduction can be carried out, for example, with an alkali metal borohydride reducing agent, such as sodium borohydride or lithium borohydride, at room temperature, for example, and in a solvent, for example, an alkanol, such as ethanol, etc.

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

(c-'9„

If

31

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

O

11

I '

n

H

10

15

20

where n, R^ and Rr are such as described above, compounds of formula I, the trans isomer being predominant. The pure trans isomer can be separated by chromatography or crystallization. In addition, the mixture can be isomerized as described for the isomerization of the cis and trans isomers of the oxo compound of formulas I1 and I1, or by base-catalyzed equilibration, for example with sodium hydroxide in ethanol.

When the substituent groups R1 and R2 in compounds of formula I contain additional asymmetry centers, a mixture of diastereomers can be obtained. For example, the number of possible isomers is 2n, where n is the total number of asymmetry centers in the compound. The enantiomers and/or diastereomers of the compound of formula I described above are preferred.

32

FORMULA SCHEMA IV

]t2" —NH

10

15

20

Ro"— N

XII

25

30

OCJI.

OCII

(CH2)n «n vii

OCH.

(OH2>n the

(CIVn wine

J

35

where n is as described above, and R2" is an alkyl, an alkoxyalcoyl or a cycloalcoyl-alcoyl.

Another synthesis of compounds of formula Ia is described in formula scheme IV where the isoquinoline ring is formed before the pyrrole ring. According to the scheme

33

From formula IV, (3,5-dimethoxyphenyl)ethylamine of formula IV is refluxed with aqueous formaldehyde to give tetrahydroisoquinoline of formula X. The Birch reduction of tetrahydroisoquinoline of formula X with lithium in ammonia containing t-butanol under conditions practically identical to those described for the Birch reduction of the compound of formula IV gives hexahydroisoquinoline of formula XI. The hydrolysis of crude hexahydroisoquinoline of formula XI under conditions practically identical to those 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 methylaminoethyl ketone of formula IX with isonitroketone of formula VII or with the aminocarbonyl compound of formula VIII to give cycloalka-5,57pyrroloisoquinoline of formula 1a. The reaction sequence according to the scheme of formula IV, starting from the amine of formula IV, where R2" is a methyl group, is preferred, giving the corresponding N-methylcycloalka-5,57pyrroloisoquinoline of formula 1a, in the form of a mixture containing the trans isomer 11' and the cis isomer of formula 11'.

The same processes as described above can be used for the isomerization of the mixture of cycloalka-/5,57pyrroloisoquinolines of formulas If and Ig to give mainly the trans isomer of formula If'.

Compounds with formula A, where X represents S, are characterized by the formula

34

II

10

where n, FLj and are as described above,

and can be prepared as shown in formula diagrams V and VI, and described in more detail below.

15

FORMULA SCHEME V

20

25

P2S5

•V

(C'Vr,

THE

30

35

<CIV„

Island

35

where n is as described above; " is a hydrogen,

an alkyl or an aralcoyl; and R2" is a hydrogen, an alkyl, an alkoxyalcoyl, an aralcoyl, an alkenyl, an aryloxyalcoyl, a thienylalcoyl, a furylalcoyl, an alkynyl, an aralkenyl, an alkenyloxyalcoyl, an aralcoyloxyalcoyl ion or a cycloalcoyl-alcoyl.

According to the scheme of formula V, compounds of formula Ile are prepared by heating compounds of formula le with phosphorus pentasulfide in an inert organic solvent. Preferred solvents are tetrahydrofuran, benzene, toluene, or dioxane, and the reaction is generally carried out at re- temperature

Other compounds of formula II are prepared, as shown in formula scheme VI0. According to formula scheme VI, a compound of formula 11b is reacted to give a compound of formula IId by following the procedures detailed in formula scheme III for the preparation of the corresponding oxo compounds of formula flux

Id.

36

FORMULA SCHEME VI

10

15

20

25

(C1I2}n

(C.H2}n

«?H2>n

11b

Ild

Island

V

where n, R,j' and R2' are as described above.

30 Similarly, a compound of formula Ild is reacted to give a compound of formula Ile by following the processes shown in Scheme III for the preparation of the corresponding oxo compounds of formula le.

Other compounds of formula II are prepared by following the procedures detailed in the formula II diagram for the preparation of the corresponding compounds.

37

of formula Ih.

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

5

10

15

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

20

25

30

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

compounds of formula II, 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 isomers.

R

2

(CH2)n iig

.j

38

10

15

20

25

30

trans and cis of the oxo compound with formulas If' and Ig'.

As stated above for compounds of formula I, when the substituent groups R1 and R2 in compounds of formula II contain additional centers of asymmetry, a mixture of diastereomers can be obtained. The enantiomers and/or diastereomers of the compounds of formula II, described above, are preferred.

Compounds of formula A form acidic addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acidic addition salts with pharmaceutically acceptable organic or inorganic acids, e.g., with halohydric acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, other salts of mineral acids, such as sulfuric acid, nitric acid, phosphoric acid, etc., alkyl- and mono-alkylsulfonic 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. Non-pharmaceutical-acceptable acidic addition salts of compounds of formula A can be transformed into pharmaceutically acceptable acidic addition salts by conventional double decomposition reactions, in which the non-pharmaceutical-acceptable anion is replaced by a pharmaceutically acceptable anion; or alternatively, by neutralizing the non-pharmaceutical-acceptable acidic addition salt and then reacting the resulting free base with a reagent to yield a pharmaceutically acceptable acidic addition salt. The addition salts can also form hydrates.

The compounds of general formulas IX and XIII are new and are also part of the invention.

Compounds of formula A and their addition salts

39

Pharmaceutically acceptable acids exhibit neuroleptic activity. Compounds of formula A are therefore useful as antipsychotic agents, e.g., in the treatment of schizophrenia. The activity of compounds of formula A, which makes them useful as antipsychotic agents, can be demonstrated in homeothermic animals using known methods.

For example, according to one method, trained rats are placed in an experimental chamber equipped with a response lever, a floor made of a steel grid to transmit electric shocks, and a loudspeaker to present auditory stimuli. Each trial consists of a 15-second warning tone (conditioned stimulus), which continues for another 15 seconds accompanied by an electric shock (unconditioned stimulus).

1.0 mA, 350 volt-amperes). Rats can end a trial at any time by pressing the response lever. A reaction during the initial 15-second warning time ends the experiment 20 seconds before the shock is delivered and is considered an avoidance response, while a reaction that occurs during the delivery of the shock is a flight response. Trials are conducted every two minutes over a 1-hour experimental run (30 ± 25 trials per run).

Trained rats maintain a reliable baseline avoidance behavior (0 to 3 avoidance failures per series). Compounds are administered at appropriate pretreatment times to a minimum of 3 to 4 rats at each dose level over a dosing interval. Rats receive the vehicle alone during control series. A control series and an experimental series are alternated weekly.

The series is divided into three constituent segments of 20 minutes each (10 trials). The total number of reactions is calculated for all subjects at a given dose in each segment.

40

10

15

20

25

30

The number of trials in which rats fail to exhibit an avoidance response (avoidance block; AB) or fail to exhibit an escape response (escape block; EB) is determined for the segment exhibiting the maximum such effect at each dose. This number is expressed as a percentage of the total number of trials in the segment. The dose calculated to produce a 50% avoidance block (ABD 50) is obtained from the dose-response regression line fitted by the least-squares method. The lowest dose that produces a 20% escape block (EBD 20) is read from a dose-response curve. To obtain these values, the effect percentage is plotted against the logarithm of the dose.

Antipsychotic agents can be distinguished from other types of drugs that affect rat behavior in this experimental procedure by the greater difference between the doses that block avoidance responses and those that block escape responses. The clinical potency of antipsychotic drugs with known uses and therapeutic properties is significantly and strongly correlated with their potency in this experimental procedure. Therefore, compounds of formula A can be used therapeutically at dose ranges consistent with their potency in the experimental procedure.

When 2-methyl-1,2,3,4,4a,5,7,8,9,10,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-7™ isoquinolin-10(10H)-one is used as the experimental substance, neuroleptic activity is observed at an ABD^q of 0.98 mg/kg p.o.

Similarly, when 2-/5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-jg7i s o quino 1 in-10 ( 10H ) -one is used as the experimental substance, neuroleptic activity is observed at an ABD^q of 0.15 mg/kg p.o.

41

Similarly, when using 2-/£-(4-fluorophenyl)-4-oxobutyl7-2,3,4,4a,5,7,8,9,10,11a-de cahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinolin-11(11 H) — one as the experimental substance, a neuroleptic activity is observed at an ABD^q of 0.73 mg/kg p.o.

Similarly, when using the hydrochloride of 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,_57pyrrolo/2,3-g7isoquinoline-11(11H)-one,

hydrated 0.75 molar, which showed an LD^q of, e.g. 10 pie, 650 mg/kg p.o. in mice, as an experimental substance, neuroleptic activity is observed at an •ABD^q of 5.5 mg/kg p.o.

Similarly, when 2-methyl-2,3,4,4a,5,7>8,9, 10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta-15/4,57pyrrolo/2,3-g7isoquinoline-13(l3H)-one is used as the experimental substance, neuroleptic activity is observed at 8 mg/kg orally where the avoidance blockade is 63%.

Similarly, when using 2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta-£P* » 57py r r o 1 o /2,3 -£J i s o quino 1 é in-12 ( 12H ) - one as the experimental substance, neuroleptic activity is observed at 16 mg/kg p.o. where the avoidance blockade is 50%.

The compounds of formula A and their pharmaceutically acceptable acidic addition salts have antipsychotic effects that are qualitatively similar to those of haloperidol and trifluoroperazine, known for their therapeutic applications and properties. Thus, the compounds of formula A exhibit a pattern of activity associated with that of 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, suitable oral dose units (AP-35) range from 0.05 to 50 mg, and appropriate oral dosing regimens in animals

42

Homeothermic ailments range from approximately 0.001 mg/kg per day to approximately 10 mg per kg/day. However, for a given homeothermic animal, the specific dosage regimen may vary and should be adjusted according to individual needs and the professional judgment of the person administering or supervising the administration of a Formula A compound or one of its pharmaceutically acceptable acidic addition salts. Furthermore, the frequency with which such a dosage form is administered varies depending on the amount of active drug present and the needs and requirements of the pharmacological situation.

For the application described, compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated using conventional inert pharmaceutical excipients in dosage forms suitable for oral or parenteral administration. These dosage forms include tablets, suspensions, solutions, etc. In addition, the compounds of formula A may be included in, and administered in, suitable hard or soft capsules. The identity of the inert excipients used to formulate the compounds of formula A and their pharmaceutically acceptable acid addition salts in oral and parenteral dosage forms will be immediately apparent to specialists. These excipients, of inorganic or organic origin, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. In addition, wetting agents, emulsifying agents, salts to modify osmotic pressure, buffers, etc. can be incorporated if desired.

Since compounds of formula A and their pharmaceutically acceptable acidic salts possess asymmetric carbon atoms, they are usually obtained

43

in the form of racemic mixtures. If desired, the mixtures of diastereomers can be separated when obtained. The resolution of the various racemates to give the optically active isomers can be carried out by known processes. Optically active isomers can also be prepared using, in the processes described here, corresponding optically active starting materials. Some racemic mixtures can be precipitated as eutectic mixtures and can then be separated. However, chemical resolution is preferred. By this process, diastereomers are formed from the racemic mixture with an optically active resolution agent, e.g., an optically active acid, such as (+)-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (+)-d-10-cam-

phosulfonic acid, (-)-3-pinanecarboxylic acid, etc.

to form a diastereomeric salt. The diastereomers formed are separated by fractional crystallization and can be transformed to give the corresponding optical isomeric base. Thus, the invention covers the optically active isomers of 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 intended to encompass all such isomeric forms. The examples included herein should therefore be understood as specifying particular mixtures of geometric isomers or isolated geometric isomers, and not limiting the scope of the invention.

The following examples further clarify the invention. All temperatures are in degrees Celsius, unless otherwise indicated.

44

10

15

20

25

Example 1

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

185.2 g of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydrochloride 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 1000 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35–40°C yields 156.0 g of free base.

In a 12¹ to 3-necked flask equipped with a mechanical stirrer and dry ice condensers, one with a gas inlet and the other with a soda lime desiccation tube, 4.0 liters of anhydrous ammonia are condensed. A solution of 156.0 g of the free base in 400 mL of t-butanol and 400 mL of anhydrous ether is added to the ammonia for 15 minutes. A total of 33.6 g of lithium wire, cut into 63.5 mm segments, is added to the stirred solution over 50 minutes. The addition rate is controlled so that 127 mm of wire is added per minute. Once 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, and the mixture is stirred and then allowed to evaporate overnight. 2.8 liters of ice water are added to the residue. The mixture is transferred to a 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, and the extracts are combined and washed with 1 liter of brine and dried on anhydrous sodium hydroxide. The evaporation...

45

The solvents are heated on a rotary evaporator at 40°C and then at 400/1.0 mm for 1 h, yielding 150.7 g of crude product in the form of a yellow oil. The crude oil is distilled through a 504.8 mm Goodloe column (150°C bath), collecting the fractions as follows:

Peb fraction Weight purity (cG)

1 40-80°/0.45 mm 7.9 g 4.6%

2 80-85°/0.45 to 0.15 mm 6.2 g 50%

3 85-86°/0.15mm 21.2g 92% 10 4 86-87°/0.15mm 99.4g 100%

Fractions 3 and 4 combined give 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene~3-ethylamine in the form of a colorless oil.

Calculated for CHNO2: C,66,97; H,9,71; N,7,10 15 Found: C,66,84; H,9,62; N,6,93

Example 2

Preparation of 1,2,3,5,6,7,8>9-octahydro-2-/2-(methylamine)ethyl7-4H-carbazol-4-one

A mixture of 15.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (79 mmol), 16.7 g of 2-isonitrosocyclohexanone (131 mmol), and 19.5 g of zinc powder (300 mg atoms) is heated under reflux for 5 h in 300 mL of aqueous acetic acid, then cooled and filtered. The filtrate is concentrated under vacuum, and an excess of dioxane is added. The dioxane-acetic acid azeotrope is removed by distillation, and the process is repeated until all the acetic acid is removed. The residue was chromatographed on alumina(III) by eluting with 10% methanol in dichloromethane to give 10.730 g of crude 1,2,3,5,6,7,8,9-octahydro-2-/2-(methylamino)ethyl7-4H-carbazol-4-one. The crude product was dissolved in methanol and treated with methanolic HCl, and the solvent was evaporated to give 12.2 g of 1,2,3,5,6,7,8,9-octahydro-2-/2-(methylamino)ethyl7-354H-carbazol-4-one hydrochloride.

46

Example 3

Preparation of 2-methyl-2,3,4,4a,5,7,8,9f10,11a-deca-hydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinoline-11(11H)-one

5. The mixture is heated in a glass bomb immersed in an oil bath at 180°C at an internal pressure of

2

5.6 kg/cm³ for 1 h of a mixture of 2.3 g of 1,2,3,5,6,7,8,9-octahydro-2-/2-(methylamino)ethyl7-4H-carbazol-4-one hydrochloride (8.14 mmol) and 2.3 g of paraformald-10 hyde (76 mmol) in 100 mL of n-butanol. The solution is cooled and the solvent is withdrawn under reduced pressure. The residue is then dissolved in water and washed with dichloromethane (which is discarded). The aqueous solution is made alkaline with ammonium hydroxide and extracted with dichloromethane. The extracts are dried over sodium sulfate, filtered, and evaporated to a volume of 10 mL. The mixture is diluted with 10 g of alumina, filtered, and evaporated to dryness. The residue is chromatographed on 80 g of alumina 20 III by eluting with 10% methanol in dichloromethane to give 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/4,57pyrrolo/2,3-g7isoquinoline-. 1L(1H)-one crude containing a small amount of the corresponding 4a,11a-cis isomer. The crystallization of the crude product from methanol-dichloromethane-ether gives 2-methyl-2,3,4,4a,5,7,8,9,10,11 a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinoline-11(11H)-one as an off-white solid. The free base is treated with HCl in methanol and the hydrochloride is recrystallized twice from ethanol to give 0.46 g of 2-methyl~2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo-/2,3-g7isoquinoline-11(11H)-one pure hydrated 0.75 molar in crystal form, P^ 217-220°C .(yield 19%).

35 Anal, calculated for C^gH^^O.HCl.0.75 ^0

Found: C, 62.56; H, 8.01; N, 9.09; Cl, 11.50

47

Example 4

Preparation of 5,4-dihydro-1H-6,8-dimethox-2-methylisoquinoline hydrochloride,

A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydrochloride (15.0 g, 64.7 mmol) in 30 mL of water is treated with 35 mL of 2N 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 h, made alkaline with 2N sodium hydroxide (15 mL), and extracted with dichloromethane. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. They are then concentrated to yield the crude product in the form of a yellow oil (15.5 g). The oil is dissolved in 100 ml of ethanol and treated with ethanolic hydrochloric acid. Ether (75 ml) is added, and the salt is crystallized to give 10.15 g of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (64% yield).

Example 5

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

Ammonia (150 mL) is condensed in a flask containing t-butanol (9.1 g, 123 mmol) and diethyl ether (50 mL). 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (1.0 g, 4.1 mmol) is added to the solution. After stirring for 2–3 min, lithium wire (0.57 g, 82 mmol) in small pieces is added over 30 min. The blue solution is refluxed for 2 h, 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.

48

The aqueous layer is extracted with ethyl acetate and chloroform. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate and concentrated to give 1,2,3,4,4a,7-hexahydro-6,8-5-dimethoxy-2-methylisoquinoline (0.58 g, crude) in the form of a yellow oil.

The crude product (1.05 g) is refluxed for 5 h 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 volume of 1 mL and chromatographically analyzed on a Dowe AG 50 WX8, eluting with 2 M aqueous pyridine to give 0.11 g of octahydro-2-methylisoquinoline-6,8-diore (yield 11.6%) as a pale yellow solid. Treatment with hydrochloric acid in methanol gives the hydrochloride, Pf 193-196°.

Example 6

Preparation of 2-methyl-2,3,4-4a,5,7-8,9,10,11a-decahy-20 dro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinolin-1 (1 1H)~o via octahydro-2-methylisoquinoline-6,8-dione

A mixture of 72 g of crude 2-octahydro-2-methylisoquinoline-6,8 (approximately 25-30% pure, approximately 0.1 M), 21.1 g of crude 2-isonitrosocyclohexanone (approximately 60% pure, approximately 0.1 M), and 19.5 g of zinc powder (0.3 gram-atoms) is heated under reflux for 1 h in 500 mL of 70% aqueous acetic acid. A second portion of 10.5 g of 2-isonitrosocyclohexanone and 6.5 g of zinc powder is added, and the mixture is refluxed for another 2 h. The solution is cooled, filtered, and concentrated under vacuum. The residue is dissolved in water and washed with chloroform (which is then discarded). -The aqueous solution is made alkaline with ammonium hydroxide 35 and extracted with chloroform. The extracts are washed with brine, dried over sodium sulfate, and

49

Concentrate. Crude 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/4,57pyrrolo-/2,3-jg7isoquinoline-11,11H-one is chromatographed on silica gel (dry column) by eluting with the organic phase of a mixture prepared by shaking (by volume) 90 parts of chloroform, 30 parts of methanol, 10 parts of water, and 6 parts of acetic acid to give 7.8 g of 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinoline-11(11) H)-one 10 in the form of a white amorphous solid after dilution with hot ethanol, 273-275°C (dec.)

Calculated analysis for C16H22N20: C, 74.38; H, 8.58; N, 10.84. Found: C, 74.21; H, 8.39; N, 10.61

Example 7

15 Following the process of Example 6, starting from 2-isonitrosocyclopentanone and 1'ocathydro-2-methylsoquinolin-6,8-dione, we obtain 2-methyl-1,2,3,-4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-/4,57pyrrolo/2,3-117isoquinoline-10(10H)-one, P^ 296-297°C 20 (dec.) crystallized from 11ethanol-methanol.

Calculated analysis for C^H2ON2O: C, 73.74; H, 8.25; N, 11.47 Found: C, 73.93; H, 8.41; N, 11.46

Hydrochloride crystallizes from water as hemihydrate, P^ 256-258°C (dec.)

25. Calculated analysis for C^H20N20.HC1 0.5H20:

C, 61.17; H, 7.65; N, 9.67; Cl, 12.23 Found C, 62.16; H, 7.71; N, 9.54; Cl, 12.37

Example 8

Following the procedure of example 6, starting with 30 of 2-isonitrosocycloheptanone and 1'octahydro-2-methyl-

isoquinolin-6,8-dione, we obtain 2-methyl-1,2,3,4,4a,-, 5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta-/5,57pyrrolo/~~2,3-ig7isoquinoline-12(l2H)-one, Pf 293-296°C, crystallized from ethanol.

35. Calculated analysis for C17H24N20: C, 74.96; H, 8.88; N, 10.28. Found: C, 74.79; H, 8.74; N, 10.33

50

Example 9

Following the process of Example 6, starting from 2-isonitrosocyclooctanone and 1'ocathydro-2-methylsoquinoline-6,8-dione, we obtain 2-methyl-2,3,4,~ 4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H, 6H-cycloocta^,57pyrrolo/~2,3-g7isoquinoline-13(13H)-one, P^ 298-300°C, crystallized from dimethylformamide water.

Calculated analysis for 8^26^2°* C, 75,48; H,9,15; N,9,78 Found C, 75,29; H,9,04; N,9,70

Example 10

Preparation of 2,5,4,4a,5,7,8,9,10,11a-decahydro-4a 5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa-fpr, 57pyrrolo f2., 3-g7isoquinoline-11 (11H)-one

A mixture of 2-methyl-2,3,4,4a,5,7,8,9,10,11 α-decahydro-4a,11a-trans-1H,6H-cyclohexa/4,57pyrrolo α-2,3-β7isoquinoline-1(1H)-1, 2.6 g of ethyl chloroformate, and 3.2 g of potassium bicarbonate in 100 ml of dioxane is heated under reflux for 8 h, cooled, and filtered. The filtrate is concentrated under reduced pressure, dissolved in chloroform, and extracted with 5% aqueous hydrochloric acid. It is washed with water and brine and dried over sodium sulfate. Evaporation of the solvent gives 1.4 g of carbamate, the 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinoline-11-(HH)-one. From the aqueous extracts, 0.45 g of the starting material is recovered by treatment with ammonium hydroxide and chloroform extraction.

The crude carbamate (1.4 g) is heated under reflux for 24 h with 15 mL of 30% aqueous sodium hydroxide in a mixture of 15 mL of ethanol and 5 mL of dioxane. The mixture is concentrated under vacuum, and the residue is dissolved in 5% aqueous hydrochloric acid and washed with chloroform. The aqueous solution is made alkaline with ammonium hydroxide and extracted with

S

51

chloroform. The extracts are washed with brine, dried, and concentrated to give 0.65 g of 2,3,4,4a,5,7,-

8,9,10,11 a-de cahydro-4a, 11 a-trans-1 H, 6H-cyclohexa/5, 57pyr-roloy2,3-jg7isoquinolin-11 (11H)-one.

Example 11

Following the process of Example 10, starting from 2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline~10-(1 OH)-one, we obtain, via carbamate, 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinoline-10(10H)-one, 242-245°C (dec.), crystallized from ethyl ethanol-acetate.

Calculated analysis for CH₃gO: c, 73.01; H, 7.88; N, 12.16 Found: C, 72.84; H, 7.78; N, 12.30

Example 12

Following the process of Example 10, starting from 2-methyl-2,3,4,4a,5,7,8,9,10,11,12,12a-dodeca-hydro-4a,13a-trans-1H,6H-cyclopenta/5,f7pyrrolo/2,3-g7isoquinoline-13(13H)-one, we obtain, via carbamate, 1,2,3,4,4a,5,6,7,8,9,10,11,12,13a-tetrade~ cahydro-4a,13a-trans-cycloocta/4-,57pyrrolo/2,3-g7isoquino~ lein-4-one, P^ 283-5°C., crystallized from ethanol.

Calculated for ciyH24N2°: 0.74.96; H, 8.88; N, 10.28. Found: 0.74.71; H, 8.65; N, 10.24

Example 13

Preparation of 2-/5-(4-fluoropheryl)-4-oxobutyl7~2,3,4,-4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa-IF > 57pyrrolo/2,3-S7isoquinoline-11(11H)-one

A mixture of 0.68 g of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquinoline-11 (HH)-one, 1.68 g of γ-chloro-p-fluorobutyrophenone, and 1.55 g of potassium carbonate is heated under reflux for 24 h in 15 ml of diethyl ketone.

52

cools the mixture, filters and concentrates. The residue is chromatographed (dry column) by eluting with the organic phase of a mixture prepared by stirring (by volume) 90 parts of chloroform, 30 parts of methanol, 510 parts of water, and 6 parts of acetic acid to give 0.85 g of a crude amine, which is recrystallized from ethanol to give 0.42 g of pure 2-/4~(4-fluorophenyl)-4-oxobutyl7~2,3,4,4a,5,7,8,9,10,11 α-decahydro-4α,11α-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7isoquino-10 lein-11(11H)-one in the form of a crystalline solid, Pf 220-222°.

Calculated analysis for C25H29W2°2F:

C, 73.50; H, 7.16; N, 6.86; F, 4.65 Found: C, 73.46; H, 7.08; N, 7.16; F, 4.61

15 Example 14

Following the process of Example 13, the alkoxylation of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,1a-trans-1H,6H-cyclohexa/^, 57py^0l°/2,3-cr7isoquinoline-11 (11H)-one with (2-bromoethyl)benzene gives 2-(2-phenylethyl)-2, 20 3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohe-xa/^jSTpy^olo/S^-^isoquinoline-11 (11H)-one, 250-256°C

(Dec.), in the form of a crystalline solid after recrystallization from ethanol.

Calculated analysis for C23H28N20: C, 79.27; H, 8.10; N, 8.04 25 ■ Found: C, 79.29; H, 8.40; N, 7.97

Example 15

Following the process of Example 13, the alkoylation of 2,3,4,4a-5,7,8,9,10,11a-decahydro-4a,11a~trans-1H,6H-cyclohexa/4,57pyrrolo/2,3-β7isoquinoline-11(11H)-one 30 with benzyl chloride gives 2-benzyl-2,3,4,4a-5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa-A,57pyrrolo/2,3-β7isoquinoline-11(HH)-one , P^ 266-268°C, in the form of a crystalline solid after recrystallization from ethanol.

35. Calculated analysis for C22^26^2^* C,79,00; H,7,84; N,8,38 Found: C,79,27; H,8,03; N,8,60

53

Example 16

Following the process of Example 13, the alkoxylation of 1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/5,57pyrrolo/2,3-_g7isoquinoline-10(10H)-one 5 with benzyl chloride gives 2-benzyl-1,2,3,4,4a,-

5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta /5,57py^~ rolo/2,3-_g7isoquinoline-10(l0H)-one, 258-260°C. (dec. ), in the form of a crystalline solid after recrystallization from ethanol.

10. Calculated analysis for C21H24N20: C, 78.71; H, 7.55; N, 8.74. Found; C, 78.97; H, 7.54; N, 8.63

Example 17

Following the process of Example 13, the alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-15 6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one with γ-chloro-p-fluorobutyrophenone gives 2-/5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one, at 225-227°C as a crystalline solid ion after recrystallization from ethanol

Calculated analysis for £24^27^2^2:

C, 73.07; H, 6.90; N, 7.10; F, 4.82 Found: C, 72.76; H, 6.86; N, 7.24; F, 4.71

Example 18

25 Following the process of Example 13, the alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one with (2-bromoethyl)benzene gives 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a~trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one, P^ 251-254°C (dec.) in the form of a crystalline solid after recrystallization from ethanol.

Calculated analysis for C22H2gN2O: C, 79.00; H, 7.84; N, 8.38 Found: C, 78.68; H, 7.72; N, 8.28

h

54

Example 19

Following the process of example 13, the alkoxylation of 1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/4,57pyrrolo/2,3-γ7isoquinoline-10(10H)-one with 4-methoxybenzyl chloride gives 2-(4-methoxybenzyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-γ7isoquinoline-4-one,

236-8° (dec.), in the form of a crystalline solid after recrystallization from ethanol.

Calculated analysis for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99 Found: C, 75.39; H, 7.41; N, 8.03

Example 20

Following the process of Example 13, the alkylation of 1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/C,57pyrrolo/2,3-g7isoquinoline-10(10H)-one with 4-chlorobenzyl chloride gives 2-(4-chlorobenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/C,57pyrrolo/2,3-g7isoquinoline-10(10H)-one as a crystalline monohydrate, P^ 254-256°

after recrystallization from ethanol.

Calculated analysis for C^H^NgO: C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; N, 10.36

Example 21

Following the process of Example -13, the alkoylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-/5,57pyri,olo/2,3-β7isoquinoline-10(10H)-one with allyl bromide gives 2-(4-chlorobenzyl)-1,2,-3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-/5,57pyri,olo/2,3-β7isoquinoline-10(10H)-one, after recrystallization from ethyl ethanol acetate.

Calculated analysis for C^H22N2O: C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; N, 10.36

Example 22

Following the process of example 12, the alkoxylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-

55

6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(1OH)-one with 2-bromoethyl ether gives 2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinoline-10(1OH)-one, P^ 236-8° (dec.)

in the form of a crystalline solid after recrystallization from ethanol.

Calculated analysis for c-j8^26^2°2: C' 71.49; H, 8.67; N, 9.26 Found: C, 71.35; H, 8.47; N, 9.23

Example 23

Following the process of Example 13, the alkylation of 2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,-13a-trans-1H,6H,cycloocta/5,57pyrrolo/2,3-γ7isoquinoline-13(13H)-one with the ethylene ketal of gamma-chloro-p-fluorobutyrophenone followed by acid hydrolysis gives 2-fpc-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,6,7,8,-9,10,11,12,13a-tetradecahydro-4a,13a-trans-cycloocta/4,57-pyrrolo/2,3-γ7isoquinoline-13( 13H)-one.

Example 24

Following the procedure of Example 13, the compounds listed in Table I can be prepared from the indicated cycloalca/5,57pyFrolo/2,3-g7isoquinoline and the indicated halide.

NJ

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TABLE I

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Example, Name '

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2-[3-(4-fluoropher.yl)-3-oxopropyl] -1,2,3,4,4a, 5,7,8,9,10a-dicahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo-{2,3-gî iscquinnléin-10(10H)-bne

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Example 49

Preparation of 2-methyl-1,2,3,4,4a-5,7,8,9,1Oa-decahy-dro-4a,10a-trans-6H-cyclopenta,57pyrrolo fz,3-g7isoquinoline-10(10H)-thione

A mixture of 244 mg (1.0 mmol) of 2-methyl-1,2,3,4,4a,5,7,8,-9,10a-decahydro-4a,10a-trans-6H-cyclopenta/¥,57pyrrolo-/2,3-_g7isoquinoline-10(10H)-one and 222 mg (1.0 mmol) of phosphorus pentasulfide is stirred and allowed to settle for 17 h in 15 mL of dioxane. The dioxane solution is decanted, and water (20 mL) and sufficient ammonium hydroxide to adjust the pH to 8-9 are added to the residue. The mixture is extracted with chloroform, and the extracts are washed with brine, dried, and evaporated. The crude thione is chromatographed as stated in Example 13 to give 65 mg of crude solid thione which is recrystallized from acetonitrile to give 2-methyl-1,2,3.4,4a,5,-7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrro-lo/2,3-g7isoquinoline-10(1 OH)-thione, 224-227°C (dec.).

Calculated analysis for C^^qN^S: C, 69.19; H, 7.74; N, 10.76 Found: C, 68.97; H, 7.59; N, 10.97

Example 50

The process of Example 49 is used to prepare 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a~ trans-1H,6H-cyclohexa/5,fppyrrolo/2,3-g7isoquinoline-11(11H)-thione from 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/^,3-g7isoquinoline-11(HH)-one.

Example 51

The process of Example 49 is used to prepare 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-β7isoquinoline-10(10H)-thione from 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-β7isoquinoline-10(10H)~ one.

Example 52

63

The process of Example 13 is used to prepare 2-/5-(4-fluorophenyl-4-oxobutyl7-1,2,3,4,4a,5,7,-8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo-/2,3-107isoquinoline-10(10H)-thione from 1,2,-3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta-/5,57pyrrolo/2,3-107isoquinoline-10(10H)-thione and 1-chloro-p-fluorobutyrophenone.

Example 53

The process of Example 13 is used to prepare 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/1,57pyrrolo/2,3-g7isoquinoline-10(1OH)-thione from 1,2,3,4,4a,5,7,8,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/5,57pyrrolo-/2,3-g7isoquinoline-10(1OH)-thione and (2-bromoethyl)benzene.

Example 54

Preparation of 6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,-10a-decahydr o-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7-isoquinoline-10(10H)-one

To a mixture of 244 mg (1.0 mmol) of 2-methyl-1,-2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cydopenta-/2+,.57pyrrolo/2,3-ig7isoquinoline-10(10H)-one in 10 mL of dry tetrahydrofuran at -30°C, 0.5 mL of n-butyllithium (1.1 mmol) of a 2.2 M solution in hexane is added for 2 to 3 min using a syringe. The solution is stirred for 30 min at -30°C and 168 mg of benzoyl chloride (1.2 mmol) is added for 2 to 3 min. The solution is stirred for 1 h at -30°C and for 30 min at room temperature. The mixture is poured onto ice and extracted with chloroform. The extracts are washed with brine, dried (sodium sulfate), concentrated and chromatographed to give 6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta/5,57py^rolo/~2,3-g7isoquinoline-10(10H)-one.

Example 55

Following the procedure in example 54, we prepare ts

64

2,6-dimethyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-_g7isoquinoline-10(1OH)-one using methyl iodide instead of benzoyl chloride.

Example 56

Preparation of 2-(2-hydroxy~3,3-dimethylbutyl)-2,3,4,-4a,5;7>8>9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa-fU,57pyrrolo/2>3-g7isoquinoline-11(11H)-one

488 mg (2.0 mmol) of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,^7pyrrolo/2,3-g7isoquino-lein-11(11H)-one and 300 mg (3.0 mmol) of 3,3-dimethyl-1,2-epoxybutane in 15 ml of methanol and concentrated. The residue is chromatographed, and the crude product (350 mg) is crystallized from ethanol to give 200 mg of 2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,-8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57-pyrrolo/2,3-jg7isoquinoline-11 (11H)-one, P^ 276-278°C (dec.).

Calculated analysis for C21H32N2°2: C' 73.22; H, 9.36; N, 8.13 found: C, 73.39; H, 9.31; N, 8.15

Example 57

The process of Example 56 is used to prepare 2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7,8,-9,10a-decahydro-4a,10a-trans-6H-cyclopenta/11,57pyrrolo-/2,3-g7isoquinoline-10(10H)-one from 1,2,3,-4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one and styrene oxide.

Example 58

Following the process of Example 56, the alkoxylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10-(1OH)-one with ethylene oxide at room temperature gives 2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,-10a-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo-

A solution of

65

/2,3-g7isoquinoline-10(l0H)-one, 237-9° (dec.) as a crystalline solid after recrystallization from ethanol.

Calculated analysis for 5*^22^2^2 * 70.04; H, 8.08; N, 10.21 5 Found: C, 69.66; H, 8.17; N, 10.19

Example 59

Following the process of Example 56, the alkoxylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cy c 1 op enta/5,57py rr o 1 o /2,3 -_g7 isoquinolated in- 10(l0H)-one 10 with 3,3-dimethyl-1,2-epoxubutane gives 2-(2-hydroxy-

3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one, 284-6° (dec.) as a crystalline solid after recrystallization from ethanol.

15. Calculated analysis for C2q^q^^z: 0 72.69; H, 9.15; N, 8.48

Found: C 72.80; H 9.02; N 8.55

Example 60

A mixture of 30 mg of sodium hydride dispersion (5%, freed from all oil by washing) and 2 ml of dimethyl tallow (DMSO) is heated to 65-70° for 1 h.

The solution is cooled, and a solution of 244 mg of 2-methyl-1,2,3,4,4a,5,7,-8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta/11,57pyirolo-/2,3-_g7isoquinoline-10(10H)-one is added in 1 ml of dry DMSO. The mixture is stirred for 2 h at room temperature.

A solution of 160 mg of benzyl chloride is added to 1 ml of dry DMSO, and the mixture is stirred for 2 h at room temperature and then poured into ice water. The mixture is extracted with chloroform, the extracts are washed with brine, dried, and concentrated to give 560 mg of crude solid. Silica gel chromatography using the system given in Example 62 gives 60 mg of 6-benzyl-2-methyl-1,2,-3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-35/5,57pyrrolitol/2,3g7isoquinoline-10(10H)-one as a crystalline solid, ± 169-171° after recrystallization

66

tion from ethyl-ethanol acetate.

Calculated analysis for ^22^26^2^: 79.00; H, 7.84; N, 8.35

Example 61

In a solution of 2.35 g of rac.-2-methyl-1,-2,3,4,4a,5,7,8,9,10a-decahydro-4a,1Oa-trans-6H~cyclopenta-/5,57pyrrolo/2,3-g7isoquinoline-10(10H)-one in 20 mL of methanol, a solution of 3.62 g of (+)-dibenzoyl-(D)-tartaric acid monohydrate in 20 mL of methanol is added. The mixture is concentrated and crystallized three times from the methanol, then converted to the free base with ammonium hydroxide. Recrystallization of the base from ethanol yields 0.18 g of (-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinoline-10(10H)-one, 270° (dec.). The hydrochloric acid salt gives -101.17° in methanol (1%).

Example 62

Preparation of 2-4-fluorophenyl)-4-hydroxybutyl7-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta/5,57pyrrolo/2,3-isoquinoline-10(10H)-one: a mixture of 394 mg (1.0 mmol) of 2-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta/5,57pyrrolo/2,3-isoquinoline-10(10H)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol. A second fraction of sodium borohydride (150 mg, 4.0 mmol) is added, and the mixture is stirred again at room temperature for 24 h. The mixture is poured into 50 ml of water and filtered to remove the white solid product containing a certain amount of the starting material. Dry column chromatography on silica gel, eluting with the lower phase of a mixture of 90 ml of chloroform, 30 ml of methanol, 10 ml of water, and 6 ml of acetic acid, gives 220 mg of a solid, which is recrystallized from aqueous dimethylformamide.

Find :

C, 78.92; H, 7.84; N, 8.55

Shake at room temperature for 24 hours

to give 2-/5-(4-fluorophenyl)-4-hydroxybutyl~7-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,1Oa-trans-cyclo-penta/5,57pyrrolo/2,3-^71soquinoline-10(10H)-one, P~ 243-5°, in the form of a mixture of diastereomers.

Calculated analysis for C24H2gN2O2: C, 72.70; H, 7.37; N, 7.07 Found: C, 72.68; H, 7.56; N, 7.33

Example 63

Following the process of Example 62, the reduction by sodium borohydride of 2-J/4-(4-f luorophenyl)-4-oxobutyl7-2,3,4,4a,5,7,8,9,10,11 α-decahydro-4a,11a-trans-1H,6H-cyclohexa/4,57pyrrolo/2,3-β7isoquinoline-11(11H)-one gives 2-JJi-(4-f luorophenyl)-4-hydroxybutyl7~2,3,4,-4a,5,7,8,9,10,11 α-decahydro-4a,11a-trans-1H,6H-cyclohexa-/4,57pyrrolo/2,3-β7isoquinoline-11(HH)-one under the form of a mixture of diastereomers, 239-241°, crystallized from 1,4-dioxane.

Calculated analysis for C^H^N^F: C, 73.14; H, 7.61; N, 6.82 Found: C, 73.18; H, 7.72; N, 6.82

Example 64

Following the process of Example 62, the reduction of 2-/5-(4-fluorophenyl)-4-oxobutyl7-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/5,57pyrrolo/2,3-g7isoquino-lein-13(13H)-one with sodium borohydride gives 2-/5-(4-fluorophenyl)-4-hydro-oxobutyl7-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta/5,57pyrrolo/2,3-g7isoquino-lein-13-(13H)-one in the form of a mixture of diastereomers, P^ 219-251°, crystallized from 1,4-dioxane.

Calculated analysis for C2yH^N2O2F: C, 73.94; H, 8.04; N, 6.39 Found: C, 73.71; H, 8.05; N, 6.37

Example 65

Preparation of the 5-,/T2-methylamino)ethyl7-cyclohexane-1,3-dione

To a shaken solution of N-methyl-1,5-dimethoxy-cyclohexa-1,4-diene-3-ethylamine (5.5 g, 27.9 mmol) in 20 ml of tetrahydrofuran, 10 ml of chlorhy-

b

68

6N pyridine is extracted in a fraction. The hot solution is heated for 15 min at 50°C and concentrated to give a light yellow oil. The crude oil is dissolved in 25 mL of water, and the solution is mixed with 50 g of Dov/ex 5 50X8 resin (previously washed with 2 N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution is extracted by suction, and the resin is rinsed with four 50 mL fractions of water, then with eight 35 mL fractions of 10² M aqueous pyridine. The pyridine fractions 3-8 are combined and concentrated to give 3.9 g of 5-(1,2-methylamino)ethylcyclohexane-1,3-dione. An analytical sample crystallizes from water and has a boiling point of 171-174°C.

Calculated analysis for CHNOg: C, 63.88; H, 8.93; N, 8.28 Found: C, 63.50; H, 8.87; N, 8.15

Example 66

Preparation of 6-benzyl-2,3,4,4a,5,7,8,9,10>11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,57pyrrolo/2,3-g7i soquinoline-11(11H)-one

20 Following the procedure of example 60, we will use alcohol.

316 mg of 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/11a,57pyrrolo/2,3-g7isoquinoline-11(11H)-one with 190 mg of benzoyl chloride to give 6-benzyl-2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa/5,11a-pyrrolo/2,3-g7isoquinoline-11(11H)-one (220 mg), Pf 54°-60°C which is hydrolyzed following the process of Example 10 with sodium hydroxide to give 6-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a, 11 a-trans-1 H, 6H-cyclohexa/5,57pyrrolo/5,3-£I~ 30 isoquinoline-11 (HH)-one.

>

Example A Capsule Formulation mg/capsule

Ingredients

0.1

0.5

5.0

10.0

25.0

2-/5-(4-fluorophenyl)-4-oxybutyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta-75,57-pyrrolo/2,3-g7isoquinolin~ 10(T0H)-one

0.1

0.5

5.0

10.0

25.0

Lactose

183.9

183.5

179.0

218.0

257.0

Starch

30.0

30.0

30.0

50.0

70.0

Talc

5.0

5.0

5.0

10.0

15.0

Magnesium stearate

1.0

1.0

1.0

2.0

3.0

Total

220 mg.

220 mg

0.220 mg.

190 mg.

370 mg.

Procedure: Mix the 2-/5-(4-fluorophenyl)-4-oxobutyl7--i ,2,3,4,4a,5,7,8,9,10a-

trans-6H-cyclopenta/5,57pyrrolo/2,3-g7isoquinoline~10(10H)-one, lactose and starch in a suitable mixer, grind in a suitable mill, mix with talc and magnesium stearate and introduce into an encapsulating machine.

Example B

Tablet formulation (Direct compression)

. }

.y mg/tablet

Ingredients

-0*1

0? 5

-5^0

10.0

25.0

2-f5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-

4a,10a-trans-6H-cyclopenta/4,57-

pyr r ol o {2., 3-g7 i so quino lin-T 0 (10H) -one

0.1

0.5

5.0

10.0

25.0

Lactose

85.4

85.5

81.0

103.0

112.5

Avicel

30.0

30.0

30.0

45.0

60.0

Modified starch

8

7.5

7.5

10.0

15.0

■ Magnesium stearate

1.5

1.5

1.5

2? 0

2.5

Total

125 mg.

125 mg.

125 mg.

170 mg.

215 mg.

Procedure: Mix the 2-/5-(4-fluorophenyl)-4-oxobutyl7-1,2,3,4,4a,5,7,8,9,10a-

trans-6H-cyclopenta/5,37pyrrolo/2,3-£7isoquinolin-10(10Hj-one), lactose, avicel, and modified starch are blended in a suitable mixer for 10 to 15 minutes. Magnesium stearate is added as a premix and blended for 4 minutes. Compress using a suitable press.

Example C

Tablet formulation (moist granulation)

mg/Tablet

Ingredients 0.1

0.5

5.0

10.0

25.0

2-/7+- (4-fluorophenyl) -4-oxobutyl7-1,5,3,4,4a,5,7,8,9,10a-decahy-dro-4a,10a-trans-6H-cyclopenta-Pl,57pyrrolo/2,3-g7isoquinolin-T0(TQH)-one ~ 0.1

0.5

5.0

10.0

25.0

Lactose 103.9

103.5

99.0

148.0

197.0

Modified starch 10.0

10.0

10.0

20.0

30.0

Pregelatinized starch 10.0

10.0

10.0

20.0

30.0

Magnesium stearate 1.0

1.0

1.0

2.0

3.0

Total 125 mg.

125 mg.

125 mg.

200 mg.

285 mg.

Procedure: Mix the 2-(4-fluorophenyl)-4-oxobutyl7-1,2^3,4,4a,5,7,8,9,10a-

Decahydro-4a,10a-trans-6H-cyclopenta/4,57pyrrolo/2,3-g7isoquinolin-10(10H)-one, lactose, modified starch, and pregelatinized starch in a suitable mixer, granulate with water. Dry, grind. Mix with magnesium stearate and compress on a suitable press.

72

Claims (23)

DEMANDS 1. Process for preparing cycloalcaQ4,5]pyrrolo[2,3-g3-isoquinolines of general formula X *2- HAS R. 1 where R^ is a hydrogen, an alkyl, an acyl, or an aralcoyl; R£ is a hydrogen, an alkyl, a 5-hydroxyalkyl, an arylhydroxyalkyl, an alkoxyalkyl, a . acyloxyalcoyl, an acylalcoyl, an aralcoyl, an alkenyl, - a cyclo-alcoyl-alcoyl, an alkynyl, thienyl-alcoyl, furyl-alcoyl, an arylcarboxamidoalcoyl, an aralcenyl, alkenyloxyalcoyl, an aryloxyalcoyl, an aralcoyloxvalcoyl 10 or an aryl-N-imidazolonylalcoyl; X is O or S; and n is 3, 4, 5 or 6; the geometric optical isomers of these compounds and their pharmaceutically acceptable acidic addition salts, a process which consists of: 15 _ • a) To prepare a compound with general formula 0 . there I H 73 where 1*2 is an alkyl, an alkoxyalkyl, or a cycloalkyl-alkyl, and where n is as described above, to treat a compound of general formula O I H IX where R2 and n are as described above, 5 with formaldehyde, or b) To prepare a compound of the general formula above, to treat a compound of the general formula O where is as described above, 10 with a compound of general formula in the presence of a reducing agent or with a general formula composed of t 74. 'O H2N CCK2)n YIII or one of its precursors, in which formula n is such as described above, or c) To prepare a compound of general formula H-N • (CIVn ib: 10 where n is as described above, to N-demethylate a compound of formula a above where R!J is a methyl, or d) To prepare a compound of general formula "S tCIVn Island where there is a hydrogen, an alkyl, or an aralcoyl. 75 10 1*21 is a hydrogen, an alkyl, an alkoxyalkyl, an aralalkyl, an alkenyl, a cycloalkyl-alkyl, an alkynyl, a thienylalkyl, a furylalkyl, an alkenyloxyalkyl, an aralkenyl, an aryloxyalkyl, or an aralcoyloxyalkyl, and n is as described above, to treat a compound of general formula <CII2V THE- where R', R1 and n are as described above, with phosphorus pentasulfide, or e) To prepare a compound of general formula (CH2>„ A d where RJ^ is an alkyl, a hydroxyalcohol, an arylhydroxyalcohol, an alkoxyalcohol, an acyloxyalcohol, an acylalcohol, an aralcohol, an alkenyl, a cycloalcohol-alcohol, a thienylalcohol, an alkynyl, a furylalcohol, a 15-arylcarboxamidoalcohol, an aralkenyl, an alkenyloxyalcohol, an aryloxyalcohol, an aralcoyloxyalcohol, or an aryl-N-imidazolonylalcohol, and X and n are as described above, to substitute a compound of general formula ■ ' 76 X H - H or X and n are as described above, to the nitrogen atom of isoquinoline, or f) To prepare a compound of general formula where R| is an alkyl, an acyl or an aralcoyl, is 5 an alkyl, an alkoxyalcoyl, an acyloxyalcoyl, an acyl, an aralcoyl, an alkenyl, a cycloalcoyl-alcoyl, a thienylalcoyl, an alkynyl, a furylalcoyl, an aryl-carboxamidoalcoyl, an aralcenyl, an alkenyl-oxyalcoyl, an aryloxyalcoyl, an aralcoyloxyalcoyl, or an aryl-N-10 imidazolonylalcoyl, and where X and n are as described above, to substitute a compound of general formula X VI X VI K2~ 77 where R^1 / X and n are as described above, to the nitrogen atom of pyrrole, or g) To prepare a compound of general formula X <CH2>n A c* where R^V is a hydroxyalkoyl or an arylhydroxyalkoyl, and where R|, X and n are as described above, to detach the protecting group in a compound of general formula X <CVn XIV where R^ is a hydroxyalkyl or aryl-hydroxyalkyl group 10 O-protected and , X and n are as described above, or h) To prepare a compound of general formula 78 where R^V / X and n are as described above, to reduce the acyl alcohol group in a compound of general formula X <CH2>n Ad' H VII or R2 is an acyl alcohol, and where X and n are as described above or i) To prepare a compound of general formula H-N «'•Vn Ah, where X, n and R^ are as described above, to separate the urethane group in a compound of general formula (CH) XIII. where X, n and R^ are as described above and Y is a urethane group, And 79 j) If desired, to isomerize the mixture of cis and trans isomers obtained in a final ratio predominantly comprising the trans isomer, and/or k) If desired, to separate the trans isomer from the mixture obtained, and/or 1) If desired, to split a racemic mixture obtained into its optical antipodes and/or m) If desired, to transform a compound obtained or an acid addition salt not pharmaceutically acceptable into one of its pharmaceutically acceptable acid addition salts. 2. A method according to claim 1, wherein embodiments a), b), c), d), e), f), , g) / j) / k), , l) and m) are carried out. 15 3. Method according to claim 1, wherein embodiment h is carried out). 4. A method according to any one of claims 1 to 3, where R is hydrogen. 5. A method according to any one of claims 1 to 4, 20 where R2 is an alkyl, a hydroxyalcohol, an arylhydroxyalcohol, an alkoxyalcohol, an aryloxy-alcohol, an acylalcohol, or an aralcohol. 6. A method according to any one of claims 1 to 5, where n is 3 or 4. 25 7. A method according to any one of claims 1 to 6, where X represents 0. 8. A method according to any one of claims 1-7, wherein the trans isomers of the compounds of general formula A given in claim 1 are prepared. 30 9. Procedure according to the, içs^ançlication 2, where one pre par the 2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta [4,5]pyrrolo[2,3-g]isoquinoline-10, .(10H) -one .• t) 80 10. A process according to claim 2, wherein the hydrochloride of 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo is prepared [2, 3-g3isoguino]ein-l0 (10H) -one hydrated 0.5 molar. 11. A process according to claim 2, wherein the 2-α-4-(4-fluorophenyl)-4-oxobutyl3α, 2,3,4,4α,5,7,8,9,10α-decahydro-4α,10α-trans-6H-cyclopenta is prepared [4,5 Jpyrrolo [2, 3-g]isoquinoline-10(10H)-one. 12. A process according to claim 2, wherein 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo is prepared [2,3-g]isoquinoline-10(10H)-one. 13. Process according to claim 2, wherein the (-)-2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,53pyrrolo [2,3-g]isoquinoline-10(10H)-one is prepared. 14. Process according to claim 2, wherein 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,Ila-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g3isoquinoline-11(11H)-one is prepared. 15. Process according to claim 2, wherein 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a,11a-trans-1H, 6H-cyclohexa[4,5]pyrrolo 2,3-gIsoquinolein-11(11H)-one hydrated 0.75 molar is prepared. 16. A process according to claim 2, wherein 2-4-(4-fluorophenyl)-4-oxobutyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa is prepared [4,5jpyrrolo[2,3-gJisoquinolin-11(11H)-one. 17. A process according to claim 2, wherein 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9;10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo is prepared [2, 3-g]isoquinoline-ll (11H)-one. 81 10 18. Proceed according to claim 2, wherein 2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro- is prepared 4a,10a-trans-6H-cyclopenta[4,5 3pyrrolo[2,3-g]isoquinoline-10(10H)-thione. 19. A method for preparing a medicinal product, in particular intended for use as a neuroleptic/antipsychotic agent, which involves putting a compound of general formula A given in claim 1, one of its optical or geometric isomers or one of its pharmaceutically acceptable acidic addition salts, into a pharmaceutical dosage form. 20. The invention as described above. 21. Compounds of general formula IX where 1*2 is 1111 alkyl, an alkoxyalkyl or a cycloalkyl-15 alkyl and n is 3, 4, 5 or 6. 22. Compounds according to claim 21, where is a methyl. 23. Compounds of general formula y —M (CH2)n H" 82 where X is S or 0, n is 3, 4, 5 or 6, R is a hydrogen, an alkyl, an acyl or an aralcoyl and Y is a urethane group. ORIGF NAL in 30 pages 'containing ....Zl RenvorS me added —y/snoi crossed out nuf ^ / J Intellectual Property Advice» By proctirsiio-a ci® ■Q.', ->1 # « * *)