KR840000060B1 - Process for preparing isoquinoline derivatives - Google Patents

Abstract

Isoquinolines a (R2, R3 independently = H, alkyl, cycloalkyl, alkenyl, acyl, aryl, aralkyl; R4=alkyl, hydroxy-, phhydroxy-, halophenylhydroxy-, alkylphenylhydroxy-, aryloxyhydroxy- alkoxyhydroxy-, acyloxy-, arylcarbonyl-, alkoxycarbonyl-, alkylcyclo-, thienyl-, furyl-, aryl carbox amido-, cyclic alkylox-, cyclic alkylhydroxy-, alkenyloxy-, aryloxy-, N-alkylpyrrolidinyl-, aryl-N-imidazolonyl-alkyl, alkynyl, alkenyl; X=O, S) were prepd. Thus, a mixt. contg. 3-ethyl-2-methyl-4, 4a,5,6,8,8a,9-octahydro-lH-pyrrolo[2,3-g -isoquinolin4-thione, K2CO3, and 2-bromoethylbenzene was refluxed for 3 hrs. to give 3-etyl-2 methyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a, 9-octahydro-4a, 8a trans-lH-pyrrolo[2,3-g isoquinolin-4-thione.

Description

Method for preparing isoquinoline derivative

The present invention relates to a novel octahydro-1H-pyrrolo [2,3-g] -isoquinoline of formula (A), optical and geometrical isomers thereof, and a pharmaceutically acceptable acid addition salt thereof. .

(여기에서, R₆및 R₇은 독립적으로 수소 또는 알킬이거나, 질소와 함께는 5-또는 6-원 헤테로 사이클릭 환을 형성한다)이며 ; X는 0 또는 S이다.Wherein R ₂ and R ₃ are independently hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl; R ₄ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxyalkyl, acyloxyalkyl, arylcarbonylalkyl , Alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxalkyl, cyclic-alkyl Hydroxyalkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alkyl-pyrrolidinylalkyl-trifluoroalkyl of 2 to 6 carbon atoms, aryl-N-imida zoloylalkyl, or

Wherein R ₆ and R ₇ are independently hydrogen or alkyl, or together with nitrogen form a 5- or 6-membered heterocyclic ring; X is 0 or S.

The term "alkyl" as used herein preferably means "lower alkyl", ie straight or branched chain saturated hydrocarbons of 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tertiary -Butyl, neopentyl, pentyl, heptyl and the like. The term "alkoxy" is preferably "lower alkoxy", meaning that the lower alkyl group is an alkylether group as described above, for example methoxy, ethoxy, propoxy, pentoxy and the like. The term "alkenyl" is preferably "lower alkenyl" to mean straight or branched chain unsaturated hydrocarbons having 2 to 7 carbon atoms, such as vinyl, allyl and the like. The term "alkynyl" preferably refers to "lower alkynyl" linear or branched unsaturated hydrocarbons having 2 to 7 carbon atoms, such as ethynyl, propargyl, methylbutynyl and the like.

The term "halogen" or "halo" means halogen such as bromine, chlorine, fluorine and iodine. The term "trifluoroalkyl having 2 to 6 carbon atoms" preferably denotes 2,2,2-trifluoroethyl and the like. The term "aryl" means phenyl or phenyl containing one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, lower alkylamino and di-lower alkylamino. The term "aralkyl" preferably means benzyl and the like. The term "aryloxy" means an arylether group in which the aryl group is as described above, for example phenoxy. The term "acyl" refers to "alkanoyl" groups derived from aliphatic carboxylic acids having 1 to 7 carbon atoms such as formyl, acetyl, propionyl and the like, and "aroyl" groups derived from aromatic carboxylic acids such as benzoyl and the like.

The term "acyloxy" refers to "alkanoyloxy" groups derived from aliphatic carboxylic acids having 1 to 7 carbon atoms such as formyloxy, acetoxy, propionyloxy and the like, and "aroyloxy" derived from aromatic carboxylic acids such as benzoyloxy and the like. Means a group. The term "cyclic-alkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, that is, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or a bicycloalkyl group such as bornyl or a tricycloalkyl group such as adamantyl it means. 5- or 6-membered heterocyclic rings are derived from saturated heterocyclic compounds consisting of one or two nitrogen atoms or one nitrogen atom and one oxygen atom, wherein the second nitrogen atom is selected from alkyl or hydroxyalkyl And morpholino, N-methyl-piperazino, piperazino, pyrrolidino and the like.

Preferred compounds of formula (A) are those in which R ₂ and R ₃ are alkyl and R ₄ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, arylcarbonyl Alkyl or aralkyl and X is zero.

Among the compounds of formula (A) of the present invention wherein X is 0, the most preferred compounds are as follows:

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

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

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

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

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

2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinoline-4- Warm, hydrochloride;

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

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

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

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

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

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

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] -isoquinolin-4-one;

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

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

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

2,6-dimethyl-3-pentyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2, 3-g] -isoquinoline- 4-on; Hydrochloride, dihydrate.

Examples of the compound of formula (A) wherein X is 0 include the following compounds:

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

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

(+)-3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2, 3-g] -Isoquinolin-4-one;

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

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

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

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

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

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

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, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2, 3-g] -isoquinoline 4-one, hydrochloride, 0.5 mole hydrate;

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

2-methyl-3-ethyl-6- (cyclopropylmethyl) -4,4a, 5,6,7,8, a, 9-octahydro-1H-pyrrolo [2, 3-g] isoquinoline-4 -On ; Hydrochloride, 0.2 mol hydrate;

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

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

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinoline-4-oneok-6-acetic acid, Ethyl ester;

2-benzyl-3,6-dimethyl-4, a4,5,6,7, 8, 8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3-ethyl-2-methyl-6-heptyl-4,4a, 5,6,7,, 88a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one;

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

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

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

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

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

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

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

3-ethyl-2-methyl-6- (2,2,2-trifluoroethyl) -4,4a, 5,6,7,8, 8a, 9-octahydro-4a, 8a-trans-1H- Pyrrolo [2,3-g] isoquinolin-4-ones;

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

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

3-ethyl-2-methyl-6- [2- (2-thienyl) ethyl] -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-P Rolo [2,3-g] isoquinolin-4-one;

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

3-ethyl-2-methyl-6- [2- (1,3-dihydro-2 (2H) -benzoimidazolonyl) ethyl] -4,4a, 5,6,7, 8, 8a, 9 -Octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one;

Among the compounds of formula (A) of the present invention wherein X is S, the most preferred compounds are as follows:

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

Examples of the compound of formula (A) wherein X is S include the following compounds:

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

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

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

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

2-methyl-3-ethyl-6- [3- (4-fluorophenyl) -3-oxopropyl] -4,4a ,, 56,7,8,8a, 9-octahydro-4a, 8a-trans -1H-pyrrolo [2,3g] 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, 3g] isoquinoline-4-thione; And

2-methyl-3-6-ethyl- (2-hydroxy-3-methylbutyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-P Rolo [2,3 g] isoquinolin-4-thione.

The compounds of the present invention may exist as 4a, 8a-trans or 4a, 8a-cis isomers or mixtures thereof, with 4a, 8a-trans isomers being preferred.

The compound of formula (A), its optical and geometric isomers and pharmaceutically acceptable acid addition salts thereof cause a substitution reaction at the isoquinoline nitrogen atom of the compound of formula (XV);

If desired, the mixture of cis and trans isomers obtained is isomerized to obtain a mixture in which the trans isomer predominates at the final ratio;

If desired, the trans isomer is separated from the mixture obtained; If desired, the racemic mixture obtained is isolated in an optical colon and / or;

If desired, it may be prepared by a process characterized by the conversion of the obtained compound or pharmaceutically unacceptable acid addition salt to its pharmaceutically acceptable acid addition salt.

In the above formula,

R ₂ , R ₃ and X are as described above.

More particularly the compounds of formula (A), their optical isomers and geometric isomers and their pharmaceutically acceptable acid addition salts as well as their various intermediates can be prepared as described in more detail below.

Thus, for example, a compound of general formula (A) in which X is 0 is characterized by the following general formula (I) and can be prepared as described in Scheme I.

Wherein R ₂ , R ₃ and R ₄ are as described above.

Scheme Ⅰ

Wherein R ₂ , R ₃ and R ₄ are as described above.

According to Scheme I, the compound of general formula (I) is derived from the secondary amine of general formula (XV), which is a starting material for the preparation of various derivatives contained in general formula (I). It can be prepared by the substitution reaction in basic amine nitrogen (N-6). For example, a compound of general formula (XV) may be prepared in the presence of a base such as potassium carbonate, in an acetone, 2-propanone or dimethylformamide, an alkyl halide such as ethyl bromide, an alkenyl halide such as allyl bromide, chloromethyl A compound of general formula (I), each substituted with a correspondingly substituted compound, i.e., R _4, is alkyl, alkenyl, cycloalkyl-alkyl or aralkyl by treatment with a cycloalkyl-halide such as cyclopropane or an aralkyl halide such as benzyl bromide Obtain the compound. Reactions with reactive halides can be carried out at room temperature, reactions with less reactive halides can be carried out at reflux, and sometimes reaction rates can be increased by adding iodide salts such as lithium iodide to the reaction mixture. .

The reaction of the compound of formula (XV) with an epoxyalkane yields a hydroxyalkyl substituted compound of formula (I). Treatment with a substituted epoxyalkane yields a 2-substituted-2-hydroxyalkyl homologue of the compound of formula (I), e.g., R ₄ is 2 The compound of general formula (I) which is -phenyl-2-hydroxyethyl is produced. The reaction is generally carried out in the presence of an alcoholic solvent such as methanol, at about room temperature to the reflux temperature of the mixture. Epoxyalkanes may use commercially available products, or may be prepared by epoxidizing the corresponding olefins or by methyleneization of ketones with sulfonium methylide or sulfoxium methylide reagents, for example dimethylsulfonium methylide. Thus, for example, benzaldehyde is treated with dimethylsulfonium methylide to produce styrene oxide.

In the reaction described in Scheme I, both the trans isomer (I ') and the cis isomer (I' ') of the general formula (I) compound can be formed, mainly the trans isomer is formed.

In the above formula

R ₂ , R ₃ and R ₄ are as described above. Pure trans isomers can be separated by chromatography or crystallization methods. In addition, the mixture can be isomerized in the same manner as the method for isomerizing the trans and cis isomers of the oxo compounds of the general formulas (Ia ') and (Ia'') described below.

The compound of Formula A, wherein X is S, may be represented by the following Formula (II) and may be prepared as described below.

Wherein R ₂ , R ₃ and R ₄ are as described above.

Scheme Ⅱ

Wherein R ₂ , R ₃ and R ₄ are as described above.

In Scheme II, the compound of general formula (XV) is reacted with phosphorus pentasulfide to form thion of general formula (XVI). If the compound of formula (XV) does not have a functional group capable of reacting with phosphorus pentadisulfide in addition to the 4-oxo group, the compound of formula (XV) is heated directly with phosphorus pentadisulfide in an inert organic solvent to directly Can be converted into a compound. On the other hand, when the general formula (XV) compound contains a functional group capable of reacting with phosphorus pentasulfide, for example when R ₂ or R ₃ is acyl, these groups must be protected before the reaction and then deprotected. Ketogroups, for example, can be protected with ketals such as ethylene ketal. Subsequently, the compound of formula (XVI) is converted to the compound of formula (II) in the same manner as described in Scheme I, in which a similar oxo compound (XV) is converted to a compound of formula (I). Let's do it.

In this reaction, both the trans isomer (II ') and the cis isomer (II') of the general formula (II) compound can be formed, and mainly the trans isomer is formed.

In the above formula,

R ₂ , R ₃ and R ₄ are as described above.

Pure trans isomers can be separated by chromatography or crystallization. The mixture may also be isomerized by isomerizing trans and cis isomers of the general formulas (Ia ') and (Ia ") oxo compounds described below. The compounds of general formula (XV) used as starting materials are It may be prepared by the method described in III, VI and V and described in more detail below.

Scheme Ⅲ

Wherein R ₂ and R ₃ are as described above.

According to Scheme III, the compound of general formula (IV) reacts the primary amine of general formula (XIV) with ethyl chloroformate to give urethane of general formula (III) which is reduced to lithium aluminum hydride to general It is prepared by obtaining N-methylamine of formula (iii). In addition, the compound of the general formula (IV) can be prepared under the known conditions using formaldehyde and sodium cyanoborohydride [Reference Example R. F. Borch, J. Am. Chem. Soc., 93,2897 (1971)] can be prepared by reductive alkylation of a compound of formula (XIV). Birch reduction reaction of the amine of formula (IV) using lithium in ammonia containing tert-butanol affords the dihydroamine of formula (V). Other variations of the Birch reduction reaction may be used. Therefore, the amines of general formula (IV) are combined with alkali metals such as sodium, lithium, potassium or cesium in ammonia or amines such as methylamine or ethylamine in the presence of lower alkanols such as ethanol, butanol or tert-butanol. Can react. The reaction is generally carried out at temperatures 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. Optionally, a cosolvent such as diethyl ether or tetrahydrofuran may be added.

Hydrolysis of the dihydroamine of general formula (V) is easily carried out by methods commonly used for hydrolysis of enol ethers, for example using aqueous acids. Examples of acids that can be used are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, P-toluenesulfonic acid and perchloric acid. Such acids can be used as aqueous solutions or as mixed solvents. At least two equivalents per mole of dihydroamine and at least one equivalent of acid are required. Examples of solvents that can be used are tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile. For example, dihydroamine of general formula (V) is hydrolyzed with 2N hydrochloric acid at room temperature or higher, or hydrolyzed with aqueous acetic acid at 40 ° C. to reflux temperature to obtain diketone of general formula (VI).

The diketone of formula (VI) is condensed by Knorr condensation to produce dihydroindolone-ethylamine of formula (VII). The knor condensation reaction is a well-known method for preparing pyrrole, which can also be used as a well-known variant. [Reference example for reaction conditions. J. M Patterson, synthesis, 281 (1976) and references thereof.

For example, the reaction of isonitrosoketone of the general formula in the presence of a reducing agent such as aqueous acetic acid or zinc in hydrochloric acid is carried out after the formation of the aminocarbonyl compound of the general formula It is thought to proceed with the process of condensation with tones to produce the product dihydroindolone-ethylamine of the general formula. The condensation reaction may also be carried out using an aminocarbonyl compound of general formula or a precursor thereof such as aminoketone hydrochloride, or an acetal derivative of aminoketone or aminoaldehyde. It is preferred to use aminoketones or precursors of aminoaldehydes because these materials tend to self-condense. They are best used in the reaction system itself in which the aminocarbonyl component is released in the presence of the diketone of the general formula (VI). The aminocarbonyl component reacts immediately to form dihydro indlon-ethylamine of the general formula. The diketone of formula (VI) does not need to be separated before the knorp condensation reaction. The reaction conditions used are such that the dihydroamine of formula (V) is hydrolyzed to remove the diketone of formula (VI). It's enough to generate. The knorcondensation reaction is best performed at about pH 2 to pH6. When the pH is exceeded, the yield is considerably reduced because a self-condensation product of the aminocarbonyl compound of general formula is formed.

Preferably, the isonitrosoketone of the general formula (IV) and zinc powder in aqueous acetic acid are condensed with the diketone of the general formula (VI) to give the product dihydroindolone-ethylamine of the general formula (VII).

The knor condensation reaction is preferably carried out in a temperature range between room temperature and reflux temperature. Isonitrosoketone of the general formula is a known compound [Reference Examples. Ferris, J. Org Chem., 24, 1726 (1959)], or the corresponding ketones, for example, by nitrosolication with alkyl nitrites, or for highly acidic β-diketones or β-ketoesters It can be easily prepared by nitrosing with sodium nitrite.

Examples of isonitrosoketones that can be used in the knorr condensation reaction include the following compounds.

2-isonitroso-3-pentanone; 2,3-butanedione monooxime; 2-isonitroso-4-methyl-3-pentanone; 2-isonitroso-3-hexanone; 2-isonitroso-3-heptanone; 3-isonitroso-4-methyl-2-pentanone; 2-isonitroso-1-cyclopropyl-1-propanone; 3-isonitroso-5-hexen-2-one; Cyclopropyl-2-sonytroso-1-propanone; And 3-isonnitroso-4-phenyl-2-butanone.

Examples of aminocarbonyl precursor compounds that can be used in the knor condensation reaction include aminoacetaldehyde dimethylacetal and 2-amino-3-pentanone hydrochloride.

Amines of general formula are converted to compounds of general formula (Ia) through an intramolecular Mannich reaction. The Mannich reaction is generally refluxed with ketones and dialkylamine salts, for example dimethylamine hydrochloride in an alcoholic solvent such as ethanol and formaldehyde (for example as an aqueous solution, paraformaldehyde or trioxane) as a starting material. Perform under In the modification described herein, the acid addition salt of dihydro indlon-ethylamine of general formula is reacted with formaldehyde added in the form of paraformaldehyde, trioxane or aqueous formaldehyde in a solvent. High boiling point hydroxyl solvents such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether; High boiling point polar aprotic solvents such as dimethylformamide, N-methylpyrrolidinone or diethylene glycol dimethyl ether; Low boiling point polar solvents such as ethanol, butanol or 2-propanol under pressure; Or by using a low boiling aprotic solvent such as dioxane or tetrahydrofuran under pressure at a temperature ranging from about 135 ° to about 200 ° C. to obtain pyrrolo [2,3-g] -isoquinoline of formula (Ia). Can be. The reaction, especially when carried out at temperatures below 150 ° C., produces a mixture of cis and trans isomers, ie, compounds of the general formulas (I′a) and (I ″ a).

The reaction mixture is heated for a long time or an isomeric mixture of the hydrochloride salts of formulas (I'a) and (I "a) is separated and heated, for example, for 2 hours at reflux in ethylene glycol, for example, the cis and trans isomers at final ratio Equilibrate the trans isomer so that the trans isomer can be easily separated by crystallization or chromatographic separation methods.

It is preferable to react the hydrochloride salt of dihydroindolone-ethylamine of the general formula and paraformaldehyde in octanol at 180 ° C. for 2 hours, and most of the products here are trans isomers (I′a). To be separated.

Scheme Ⅳ

Wherein R ₂ and R ₃ are as described above.

The N-demethylation reaction of the general formula (Ia) compound was carried out by Von Braun method HA Hageman, Org. Reactions, 7, 198 (1953)] or standard N-dealkylation processes. city. Rice [KC Rice, J. Org. Chem., 40, 1850 (1975), by acid or base hydrolysis of urethane derivatives as described. One process for dealkylation of compounds of formula (Ia) is to obtain secondary amines of formula (XV) via urethanes of formula (XV) and acid hydrolysis. For example, a compound of formula (Ia) wherein R ₂ is methyl and R ₃ is ethyl is refluxed in diethyl ketone with excess ethyl chloroformate and potassium bicarbonate for 3 hours, where R ₂ is methyl and R ₃ is To yield a compound of formula (XIII), which is ethyl. The above compound is hydrolyzed with concentrated hydrochloric acid for 24 hours under reflux in acetic acid to give a compound of formula (XIII) wherein R ₂ is methyl and R ₃ is ethyl. The same compound may be obtained by hydrolyzing the urethane of general formula (XIII) with sodium hydroxide in reflux ethanol.

Scheme Ⅴ

Wherein R ₂ and R ₃ are as described above.

Scheme V describes another method for synthesizing a compound of formula (Ia) that forms isoquinoline before forming a pyrrole ring. According to Scheme V, (3,5-dimethoxyphenyl) -ethylamine of formula (IV) is refluxed with aqueous formaldehyde to produce tetrahydroisoquinoline of formula (VII). In the liquid ammonia containing tert-butanol under almost the same conditions as the Birch reduction method of the general formula (IV) compound, the reaction of the tetrahydroisoquinoline and lithium of the general formula Hexa-hydroisoquinoline is obtained. The diketone of the general formula (XII) is obtained by hydrolysis of the crude hexahydroisoquinoline of the general formula (XI) under almost the same conditions as the hydrolysis of the dihydroamine of the general formula (V).

The compound of general formula (XII) is isonitroso ketone of general formula or aminocarbonyl of general formula as described in the manufacturing method of dihydroindolon-ethylamine of general formula (Xi). Knorr condensation reaction with the compound yields pyrroloiso-quinoline of formula (la). In the reaction sequence according to Scheme V, a mixture containing the trans isomer (I'a) and the cis isomer (I "a), starting with the amine of formula (IV), is the corresponding N- of formula (Ia). Preference is given to producing methylpyrroloisoquinoline.

The trans isomer of general formula (I'a) can be obtained mainly using the same process as described above for the isomerization of a mixture of general formulas (I'a) and (I "a) pyrroloisoquinoline.

Compounds of formula (A) form acid addition salts with inorganic or organic acids. In addition, they are pharmaceutically acceptable organic and inorganic acids such as hydrochloric acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid. Other inorganic acids such as nitric acid, phosphoric acid, etc., other alkyl- and mono-arylsulfonic acids such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, etc., acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid, etc. It is possible to form pharmaceutically acceptable acid addition salts with organic acids. Pharmaceutically unacceptable acid addition salts of the compounds of general formula (A) may be obtained by conventional substitution reactions in which pharmaceutically unacceptable anions are substituted with pharmaceutically acceptable anions or by pharmaceutically unacceptable acid addition salts. After neutralizing, the free base obtained can be converted into a pharmaceutically acceptable acid addition salt by reacting with a reactant capable of obtaining a pharmaceutically acceptable acid addition salt. Acid addition salts may also form hydrates.

Compounds of general formula (A) and pharmaceutically acceptable acid addition salts thereof exhibit neuroleptic action. However, it is important that these compounds have no hypotensive action and only show weak catalepsy action. Therefore, the compound of formula (A) is useful as a therapeutic agent for mental disorders, for example, schizophrenia is useful for treatment. Useful activity of the compound of formula (A) as an agent for treating mental disorders can be demonstrated in warm-blooded animals according to known methods.

For example, in one method, trained mice are placed in an experimental chamber equipped with a response lever, a wire mesh floor for the delivery of electrical shock, and a loudspeaker for the representation of auditory stimuli. Each experiment gives 15 seconds of warming (conditional stimulus) followed by an additional 15 seconds of electric shock (unconditional stimulus: 10mA, 350V AC). If the reaction lever drops to a certain point, the experiment on the rat can be stopped. The response to the first 15 seconds of alertness ends the experiment before shock delivery, which is thought to be an avoidance response, while the response during shock delivery is an escape response. Experiments are carried out every 2 minutes during the 1 hour test period (30 experiments per test period).

Trained mice maintain reliable baseline avoidance (0 to 3 evasion failures per test). The compound is administered at an appropriate pretreatment time in at least three to four mice per dose at the dose level. In the control trial, rats receive only excipients. Each week, control and actual tests are alternated, with each animal itself being used as a control.

The test is divided into three thermal segments of 20 minutes each (10 experiments). The response number is the sum of all animal responses to doses in each quarter.

The number of experiments in which rats do not show an evasion response (avoidance: AB) or do not show an escape response (evacuation: EB) is measured for the branches that exhibit the maximum of this effect at each dose. This number is expressed as a percentage of the total number of tests in the quarter. The dose (AB50) calculated to block the avoidance response (50%) is obtained from the dose-effect regression line by the Method of Least Squares. The minimum dose (EB20) that blocks the escape response 20% is read from the dose-effect plot graphically. The percentage effect in obtaining these values is shown against log capacity.

Therapeutic agents for mental illness show a large difference between the dose-blocking dose and the dose-blocking dose and can be distinguished from other types of medications that affect the behavior of rats in this test method. The clinical potency of a psychiatric agent for its known therapeutic uses and properties is very closely related to the potency of the drug in these test methods. Thus, the compound of formula (A) may be used as a therapeutic agent in a dosage range consistent with the dose that is effective in this test method.

In mice, for example 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-, representing 350 mg / kg (oral) of LD ₅₀ When trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride was used as the test substance, the neuroleptic activity was 0.7 mg / kg (oral) and 0.095 mg / kg (subcutaneously) AB _50. Is observed. The (-)-enantiomer of the compound exhibits neurolactic activity at 0.48 mg / kg (oral) of AB ₅₀ .

Similarly, 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo- [2,3-g] -iso Quinoline-4- shows neuroleptic activity at 0.48 mg / kg (oral) of AB ₅₀ when hydrochloride is used as a test substance.

Furthermore, N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-1H-pyrrolo [ When 2,3-g] isoquinolin-6-yl) ethyl] -4-fluorobenzamide was used as the test substance, neuroleptic activity was observed at AB ₅₀ of 3.5 mg / kg (oral).

Similarly, 3-ethyl-2-methyl-6- [4- (4-fluorophenyl) -4-oxobutyl] -4,4,5,6,7,8,8a, 9-octahydro-4a In the case of using, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as the test substance, neuroleptic activity is observed at AB ₅₀ 0.19 mg / kg (oral).

In addition, 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] was used as a test substance. Isoquinoline-4-thione results in neuroleptic activity at 0.94 mg / kg AB ₅₀ (oral).

The compound of formula (A) and its pharmaceutically acceptable acid addition salts have the effect of treating mental disorders similar to those of haloperidol, trifluoroperazine and molindone, whose therapeutic uses and properties are known. Therefore, the general formula (A) compound exhibits a mode of action related to the treatment of mental disorders with known efficacy and stability.

Formula (A) compounds and their pharmaceutically acceptable acid addition salts can be used in the form of conventional pharmaceutical preparations. For example, suitable oral dosage units range from 0.05 to 50 mg, and suitable oral administration methods for warm-blooded animals range from about 0.001 mg / kg to about 10 mg / kg per day. Individual methods of administration to certain warm-blooded animals, however, may vary and should be adjusted at the discretion of each subject and at the discretion of the expert administering or supervising the administration of Compound (A) or its pharmaceutically acceptable acid addition salts. . In addition, the frequency of administration of the dosage form to be administered varies depending on the amount of active agent contained in the dosage form and the pharmacological need.

For this purpose the compounds of formula (A) and their pharmaceutically acceptable acid addition salts are formulated in dosage forms suitable for oral or parenteral administration using conventional inert pharmaceutical adjuvants. Such dosage forms include tablets, suspensions, solutions and the like. Formula (A) compounds may also be formulated in suitable hard or soft capsules. Inert auxiliaries used to formulate compounds of Formula (A) and their pharmaceutically acceptable acid addition salts in oral or parenteral dosage forms are well known to those skilled in the art. Such adjuvants include inorganic or organic substances and include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, and the like. In some cases, such formulations may also contain preservatives, stabilizers, wetting agents, emulsifiers, osmotic salts, buffers and the like.

Formula (A) compounds and their pharmaceutically acceptable acid addition salts are usually obtained in racemic mixtures because they contain asymmetric carbon atoms. Such racemates can be isolated into optically active isomers according to known processes. Some racemic mixtures may be separated after precipitation into eutectic mixtures. However, chemical isolation is preferred. By this method, diastereomers from racemic mixtures are formed into diastereoisomeric salts by optically active isolators such as optically active acids (eg, (+)-tartaric acid). The diastereomers formed can be separated by fractional crystals and converted to the corresponding optical isomeric bases. The present invention therefore encompasses not only the optically active isomers of the compounds of general formula (A) but also racemates thereof.

In addition, because their atoms may have different spatial arrangements, the compounds of the present invention may be obtained in one or more possible geometric isomeric forms. The general formula (A) compounds described and claimed are those containing all of these forms of isomers. Thus, the examples described herein are to be understood as specific descriptions of mixtures or single geometric isomers of racemates and are not intended to limit the scope of the invention.

The following examples illustrate the invention in detail. All temperatures are degrees Celsius (° C.) unless otherwise indicated.

Example 1

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

To a 5-liter three-necked round bottom flask equipped with a mechanical stirrer and dropwise addition, 32.63 g of (3,5-dimethoxyphenyl) -ethylamine hydrochloride, 600 ml of water, 600 ml of dichloromethane and 150 ml of 1N sodium hydroxide solution were added. 16.28 g of ethylchloroformate in 60 ml of dichloromethane is added dropwise over 30 minutes while stirring the mixture and cooling in an ice bath. During the dropwise addition, a total of 150 ml of 1N sodium hydroxide solution is added eight times to maintain a pH of 8-9. After the addition is complete, the mixture is stirred for 1 hour in an ice bath. The mixture is transferred to a separatory funnel to separate the organic layer. The aqueous solution is extracted with 200 ml of dichloromethane, the combined organic solution is washed with 100 ml of water and 100 ml of brine, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated on a rotary evaporator to give 37.1 g of crude N-2- (3,5-dimethoxyphenyl) -ethyl carbamic acid ethyl ester as colorless oil.

Example 1a

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

In a 3-liter three-neck round bottom flask equipped with a mechanical stirrer, dropping filter and condenser, 180 ml of 70% sodium dihydrobis- (2-methoxyethoxy) -aluminate solution and 700 ml of anhydrous tetrahydrofuran are added. The solution is cooled in an ice bath and a solution of 37.1 g of crude N-2- (3,5-dimethoxyphenyl) -ethyl carbamic acid, ethyl ester in 100 ml of anhydrous tetrahydrofuran is added over 15 minutes. After addition, the mixture is heated to reflux for 1 hour and then cooled in an ice bath. 100 ml of 5% sodium hydroxide solution is added dropwise to decompose the excess hydride. After adding all the bases, the organic layer was separated and the aqueous layer was extracted with 100 ml of ether. The combined organic solutions are concentrated to oil on a rotary evaporator and the resulting oil is dissolved in 300 ml of ether. The ether solution is washed with 50 ml of water and 50 ml of brine, dried over anhydrous sodium sulfate and filtered. 70 ml of ethereal hydrogen chloride is added to the filtrate to precipitate the amine hydrochloride. The solids were collected in a Buchner funnel and crystallized from 180 ml of anhydrous ethanol and 270 ml of ether to give 28.9 g of N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride as a white crystalline solid with a melting point of 160 to 164 °. To obtain.

Example 2

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

185.2 g of N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride are dissolved in 1600 ml of water and the solution is made alkaline with 160 ml of ammonium hydroxide. The mixture is extracted three times with 1000 ml of dichloromethane and the extracts are combined, washed with 1000 ml of brine and dried over anhydrous sodium sulfate. Evaporate the solvent on a 35-40 ° rotary evaporator to yield 156.0 g of free base.

Condensate 4.0 L of anhydrous ammonia in a 12 L three-necked flask equipped with a mechanical stirrer and two dry ice condensers, one attached to the gas inlet and the other to the soda-lime dryer tube. To ammonia is added a solution of 156.0 g of free base in 400 ml of tert-butanol and 400 ml of anhydrous ether over 15 minutes. To the stirred solution is added a total of 33.6 g of lithium wire cut 2.5 inches long over 50 minutes. The addition rate is adjusted to add 5 inches of lithium wire per minute. After all the lithium has been added, the dark blue mixture is stirred at reflux for 2 hours. 2.8 L of anhydrous ether is then added to dilute the mixture, the drying tube is removed to introduce hydrogen, and a total of 280 g of ammonium chloride powder is added over 30 minutes until blue disappears. Remove the dry ice condenser and stir the mixture to evaporate ammonia overnight. 2.8 liters of ice water is added to the residue. The mixture is transferred to a separatory funnel, washed with 800 ml of ether and the layers separated. The aqueous layer was extracted twice with 1.5 L of dichloromethane, the extracts were combined, washed with 1 L of brine and dried over anhydrous sodium sulfate. The solvent is evaporated on a rotary evaporator at 40 ° and finally at 40 ° / 1.0 mm for 1.5 hours to afford 150.7 g of crude product on yellow oil. The resulting crude oil is distilled through a 12 inch Goodloe column (150 ° bath) to collect the following fractions:

Fractions 3 and 4 were combined to give 120.6 g of N-methyl-1,5-dimethoxy-cyclohexa-1,4-diene-3-ethylamine as a colorless oil.

Example 3

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

Into a 1 L three-necked round bottom flask equipped with a mechanical stirrer and a condenser was placed a solution of 60.0 g of distilled N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine in 700 ml of 70% aqueous acetic acid. . The reaction mixture was refluxed for 15 minutes, 59.5 g of zinc powder was added in 5 portions over 10 minutes, and then the mixture was refluxed for an additional 15 minutes. To the reflux solution is added a solution of 42.1 g of 2-isonitroso-3-pentanone in 175 ml of 70% aqueous acetic acid over 1 hour. After addition, the mixture is refluxed for 2.5 hours and cooled to room temperature. The precipitated zinc acetate is filtered off and the filter cake is washed with 500 ml of dichloromethane. The filtrate is concentrated on a rotary evaporator and the residue is heated at 100 ° / 1.0 mm for 30 minutes to remove traces of acetic acid. The residue is dissolved in 500 ml of water and the solution is extracted twice with 150 ml of dichloromethane. Discard the dichloromethane extract and add the aqueous layer to 165 ml of ammonium hydroxide to make it basic (pH 8-9), and add 500 ml of brine. The mixture is extracted three times with 200 ml of dichloromethane, the extracts are combined, washed with 100 ml of brine and dried over anhydrous sodium sulfate. The solvent is evaporated to give 56.0 g of crude tetrahydroindolelon, which is dissolved in 90 ml of 2: 1 toluene-ethyl acetate. The solution is magnetically stirred and crystallized with stirring overnight with stirring. 20.8 g of the first crop was collected by filtration, and the mother liquor was concentrated to crystallize again from the stirred solution to obtain 10.0 g of the second crop. The mother liquor is dissolved in 75 ml of methanol and a solution of 15.0 g of oxalic acid in 50 ml of methanol is added. The mixture is warmed and cooled in a steam bath for 10 minutes. The solid oxalate salt is filtered off, washed with 10 ml of methanol and dissolved in 50 ml of water. The solution is made basic by adding ammonium hydroxide and extracted twice with 50 ml of dichloromethane. The extract is washed once with 20 ml brine, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give 4.5 g additional crude product. Crystallization with 2: 1 toluene-ethyl acetate affords 2.6 g of additional crystalline product. The two obtained and oxalate-derived crystals were combined and dried at 25 ° / 1 mm for 2 hours to give 6- [2- (N-methylamino as a pale yellow solid with a melting point of 114-120 ° which was confirmed to be homogeneous by TLC. 33.4 g)) ethyl] -2-methyl-3-ethyl-6,7-dihydro- (5H) -4 (1H, 5H) indolone is obtained.

Example 4

3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinoline- Preparation of 4-silver hydrochloride.

In a 500 ml round bottom flask, 17.0 g of 6- [2- (N-methylamino) ethyl] -2-methyl-3-ethyl-6, 7-dihydro- (5H) -4 (1H, 5H) -indoleon and methanol Add 170 ml. To this solution is added 20 ml of 4N hydrogen chloride in diethyl ether (prepared by titration after introducing HCl gas into diethyl ether in an ice bath). The solvent is removed on a rotary evaporator and the residual solid is dried at 50 ° / 1 mm for 2 hours to give 19.7 g of crude hydrochloride.

In a 3-liter three-neck round bottom flask equipped with a mechanical stirrer, thermometer and distilling head, 19.7 g of hydrochloride, 21.8 g of paraformaldehyde and 1000 ml of octanol were added. The reaction mixture is heated to reflux, and the free water is distilled off until the octanol solution temperature in the flask reaches 175 to 180 °, then the distillation head is removed and replaced with a reflux capacitor. The reaction mixture is heated at 175-180 ° for 1 hour and 6.54 g of paraformaldehyde is added in three portions over 5 minutes. As above, the water is distilled off until the temperature reaches 175 to 180 ° and the mixture is heated at 175 to 180 ° for an additional hour. Cool the dark brown solution and pour into 1000 ml of water. The layers are separated and the organic layer is extracted twice with 400 ml of 5% hydrochloric acid. The aqueous extracts were combined and washed twice with 150 ml of chloroform and discarded the chloroform solution. 120 ml ammonium hydroxide and 400 ml chloroform are added to the aqueous layer. The layers were separated and the aqueous solution was extracted four times with 200 ml of chloroform. The combined chloroform extracts are washed with 200 ml brine and dried over anhydrous sodium sulfate. The solvent is evaporated to give 12.0 g of crude pyrrolo [2,3-g] isoquinoline, which is a 4a, 8a-trans, 4a, 8a-cis mixture (about 8: 1) as a dark tan solid. The crude solid is dissolved in 100 ml of 9: 1 dichloromethane-methanol and 300 ml of diethyl ether are added. Fine solid precipitates, predominantly 4a, 8a-trans isomers, are collected by filtration and the filtrate is concentrated and crystallized to give the second and third yields as tan solids. The product was combined and dried at 25 ° / 1 mm for 1 hour to yield 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octane as a light gray solid with a melting point of 203 to 226 °. Hydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4- yields 8.20 g. The partially purified gray solid is suspended in 80 ml of methanol and 12 ml of 4N hydrogen chloride in diethyl ether is added. The solvent is removed and the residue is crystallized from 25 ml of heat anhydrous ethanol. The first crop is collected by filtration and the mother liquor is concentrated and crystallized to give second and third crystals. The combined solids are dissolved in 120 ml of methanol and 2.4 g of activated carbon (Darco-G-60) is added. The mixture is warmed in a steam bath for 10 minutes and the carbon is filtered off through celite. The filtrate is concentrated and recrystallized from 15 ml of ethanol to give three yields of white crystals. The combined solids were dried under vacuum at 80 ° / 0.05 mm for 18 hours to yield 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, white solids with melting points of 196-198 °. 5.4 g of 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride are obtained (oxime 1/2 hydrate has a melting point of 131 to 133 °).

Example 4a-c

According to the process of Examples 3 and 4, the compounds described in Table I were prepared by the indicated method using an appropriate isonitroso ketone as a starting material. Each compound exhibits spectral characteristics consistent with the described structure. Melting point is for free base or hydrochloride (HCl) as indicated.

Isonitroketones are prepared by nitrosing appropriate ketones as described in Ferris et al., J Org Chem., 24, 1726 (1959). The isolated compound is the 4a, 8a-trans isomer.

TABLE I

Example 5

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

3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3] prepared in Example 4 in diethylketone (100 ml) -g] A mixture of isoquinolin-4-one (4.92 g, 20 mmol), ethyl chloroformate (19.55 g, 180 mmol) and potassium bicarbonate (6.0 g, 60 mmol) is heated to reflux for 3 hours. The mixture is cooled and filtered, the filtrate is concentrated to dryness on a rotary evaporator and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous hydrochloric acid and brine and dried over anhydrous sodium sulfate. The solvent was evaporated to yield 4.90 g of crude carbamate, which was purified by chromatography on alumina III to give pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4,4a, 5,6,7,8, 3.70 g of 8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-one are obtained.

Carbamate (3.7 g, 12.2 mmol), glacial acetic acid (45 ml) and concentrated hydrochloric acid (60 ml) are concentrated on a rotary evaporator for 24 hours under reflux heating and cooling. After the residue is dissolved in water and extracted with chloroform (discarded), the aqueous layer is made alkaline with ammonium hydroxide and extracted with chloroform. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2.72 g of crude secondary amine. The crude amine in ethanol was treated with ethanolic hydrogen chloride to give the hydrochloride, which was crystallized with thermal ethanol to give 2-methyl-3-ethyl-4,4a, 5,6,7,8, 2.18 g (yield 47%) of 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinolin-4-one hydrochloride are obtained.

Elemental analysis: C ₁₄ H ₂₀ N ₂ O. HCl

Calculated Value: C 62.56 H 7.88 N 10.42 Cl 12.19

Found: C 62.50 H 7.90 N 10.19 Cl13.13

From 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-one according to a similar method Preparation of 2,3-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one can do.

Example 6

Preparation of 3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline hydrochloride.

A solution of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride (15.0 g, 64.7 mmol) in 30 ml of water is treated with 35 ml of 2N sodium hydroxide and extracted with dichloromethane. The extracts are combined and concentrated on a rotary evaporator and mixed with aqueous formaldehyde (65 ml, 37% solution). The mixture is refluxed for 2 hours, added with 2N sodium hydroxide (15 ml) to make alkaline and extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5 g). This oil is dissolved in 100 ml of ethanol and treated with ethanolic hydrogen chloride. Ether (75 ml) is added and the salt is crystallized to give 10.15 g (64% yield) of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride.

Example 7

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

Ammonia (150 ml) is condensed in a flask containing tert-butanol (9.1 g; 123 mmol) and diethyl ether (50 ml). To the solution is added 3,4-dihydro-1N-6,8-dimethoxy-2-methylisoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring for 2-3 minutes, lithium wire (0.57 g, 82 mmol) is added in portions over 30 minutes. The blue solution is stirred at reflux for 2.5 h and solid ammonium chloride (4.5 g) is added until blue disappears. Ether (100 ml) is added and ammonia is evaporated overnight. Ice water (100 ml) is added and the organic phase is separated. The aqueous layer is extracted with ethyl acetate and chloroform. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58g, 68% yield).

The crude product (1.05 g) in 20 ml of 70% aqueous acetic acid is refluxed for 5 hours and acetic acid is removed on a rotary evaporator. The residue is dissolved in water and washed with chloroform. The aqueous phase was concentrated to a volume of 10 ml, chromatographed on Dowex AG 50wx8 and eluted with 2 molar aqueous pyridine to yield octahydro-2-methylisoquinoline-6,8-dione 0,11 g as a pale yellow solid (yield). 11.6%). The product is treated with hydrochloric acid in methanol to give hydrochloride at melting point 193-196 °.

Example 8

3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octa-hydro-1H-P via octahydro-2-methylisoquinoline-6,8-dione Preparation of Rolo [2,3-g] isoquinolin-4-one.

1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.68 mmol) was heated to 90-100 ° in 70% aqueous acetic acid (10 ml) Hydrolysis of bis (enolether) yields octahydro-2-methylisoquinoline-6,8-dione. To the thermal solution was added zinc powder (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The mixture is refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate is concentrated to dryness on a rotary evaporator and the residue is dissolved in dichloromethane. Ammonium hydroxide was added to the solution to separate the layers. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The resulting crude product was chromatographed on Alumina III to give 3-ethyl-2,6-dimethyl-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-1H-pyrrolo as a white solid. [2,3-g] -isoquinolin-4-one (0.19 g, yield 29%) is obtained.

Example 9

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

A solution of crude octahydro-2-methyl-isoquinoline-6,8-dione (about 12.5 mmol) and 2.4 g (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 ml of 70% aqueous acetic acid Was treated with 2.6 g (40 mmol) of zinc powder and slowly heated to reflux. After 1 hour, the mixture is cooled slightly and further 0.4 g of isonitrosoketone and 1.0 g of zinc are added and the mixture is stirred under reflux for 1.5 hours. The mixture is then cooled and filtered to concentrate the filtrate at 50 ° / 20 mmHg to give a yellow oil which is diluted with 50 ml of water and made ammonium hydroxide to make alkaline (pH 8-9). The mixture is extracted with chloroform and the extract is washed with brine, dried over sodium sulfate and concentrated to give 2.6 g of crude product. The product was chromatographed (dry column) on 100 g of silica gel to elute into the organic phase of the mixture prepared by equilibrating 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 and diluted with water to make alkaline (pH 8-9) with ammonium hydroxide and extracted with chloroform. The extract was dried over sodium sulfate and evaporated to afford 1.0 g of a solid product, which was recrystallized twice with ethyl acedate to give pure 2,6-dimethyl-3-isopropyl-4,4a as a crystalline solid with a melting point of 244 to 274 °. 470 mg of 5,6,7,8,8a, 9-octa-hydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinolin-4-one are obtained.

Example 10

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

3, having a melting point of 221 to 223 ° from 3-isonitroso-5-hexen-2-one and 2-methyl-octahydroisoquinolin-6,8-dione, according to a method analogous to that described in Example 9 6-dimethyl-2- (2-propenyl) -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g]- Isoquinolin-4-one is obtained.

Example 11

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

Melting point 258 to 259 ° (decomposition) from cyclopropyl-2-isonitroso-1-propanone and 2-methyl-octachahydroisoquinoline-6,8-dione according to methods analogous to those described in Example 9 3-cyclopropyl-2,6-dimethyl-4,4a5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinoline-4 To obtain -on.

Example 12

2-benzyl-3,6-4,4a, 5,6,7,8,8a, 9-dimethyloctahydro-4a, 8a-trans-1H-pyrrolo- [2,3-g] isoquinoline-4 Preparation of the -one.

2, with a melting point of 234-235 ° from 3-isonitroso-4-phenyl-2-butanone and 2-methyl-octahydroisoquinoline-6,8-dione, according to methods analogous to those described in Example 9 -Benzyl-3,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinoline-4 To obtain -on.

Example 13

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

6- with a melting point of 208-210 ° from aminoacetaldehyde dimethylacetal and 2-methyl-octahydroisoquinoline-6,8-dione, according to a method analogous to that described in Example 9 except that no zinc is used. Methyl-4,4a, 5,5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3g] isoquinolin-4-one is obtained.

Example 14

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

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-one in acetone (35 ml) (0.470 g, 2.03 mmol), a mixture of allyl bromide (0.5 g, 4.13 mmol) and potassium carbonate (0.85 g, 6.16 mmol) is stirred at room temperature for 2 hours and filtered. The filtrate is concentrated and the residue (0.53 g) is chromatographed on alumina III to give the product (0.40 g).

The product was treated with ethereal hydrogen chloride to form hydrochloride and recrystallized from ethanol-ethyl acetate to give 3-ethyl-2-methyl-6- (2-propenyl) -4,4a, as a white solid with a melting point of 214-217 °. 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one hydrochloride is obtained.

Elemental analysis: C ₁₇ H ₂₄ N ₂ OHCl0.5 H ₂ O

Calculated Value: C64.24 H8.25 N8.81 Cl 11.15

Found: C64.50 H8.48 N8.96 Cl 11.37

Example 14a-dd

From the indicated 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3g] -isoquinolin-4-one and the indicated halides, according to the process of Example 14 Prepare the compounds listed in Table II. Each compound exhibits spectral characteristics consistent with the structure shown. Melting point is for free base or hydrochloride (HCl) as indicated. The isolated compound is the 4a, 8a-trans isomer.

TABLE II

Example 15

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

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-one in methanol (25 ml) (0.83 g, 3.58 mmol) and styrene oxide (0.51 g, 4.22 mmol) were refluxed for 2.5 hours, cooled and filtered. The filtrate is concentrated and the residue is chromatographed on alumina III to yield 0.69 g of crude product. Recrystallized from ethyl acetate-ethanol to give 3-ethyl-2-methyl-6- (2-hydroxy-2-phenylethyl) -4,4a, 5,6,7, as a white solid having a melting point of 218.5 to 220 °. 0.195 g of 8, 8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one is obtained.

Elemental Analysis C ₂₂ H ₂₈ N ₂ O ₂

Calc .: C 74.97; H 8.01; N 7.95

Found: C 74.87; H 7.92; N 7.95

Example 15a-15f

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo- [2,3-g] isoquinoline-4 according to the process of Example 15 Compounds linked to Table III are prepared from -on and indicated epoxides. Each compound exhibits spectral characteristics consistent with the structure shown. Melting point is for free base or hydrochloride (HCl) as indicated. The isolated compound is the 4a, 8a-trans isomer.

TABLE III

Example 16

Racemate 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g]- Isolation of Isoquinolin-4-one

The racemate freebase (prepared 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 liberate a free base and the free base is treated with anhydrous hydrogen chloride to give the hydrochloride. After recrystallization twice with ethanol and drying at 80 ° / 0.005 mm, 0.15 g of (-)-enantiomer is obtained as a white crystalline solid having a melting point of 240 to 245 °.

-120.78°(C 0.81%, 물)Radiance:

-120.78 ° (C 0.81%, water)

Elemental Analysis C ₁₅ H ₂₂ N ₂ O · HCl · 0.25H ₂ O

Calc .: C 62.70; H 8.24; N 9.75

Found: C 62.44; H 8.33; N 9.67

The mother liquor obtained from the crystallization of the d-(+)-tartrate salt is treated with ammonium hydroxide to liberate a free base which is treated with a solution of l-(-)-tartaric acid (0.46 g) in methanol. The solution is concentrated and recrystallized twice with methanol and then converted to free base and hydrochloride as described above to yield 0.10 g of (+)-enantiomer as a white crystalline solid with a melting point of 240 to 244 °.

+121.38°(C 0.44%, 물)Radiance:

+ 121.38 ° (C 0.44%, water)

Elemental Analysis C ₁₅ H ₂₂ N ₂ O · HCl · 0.25H ₂ O

Calc .: C 62.70; H 8.24; N 9.75

Found: C 63.02; H 8.20; N 9.88

Example 17

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

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo- [2,3-g] -isoquinoline-4 in a mixture of benzene and methanol -One and 1- (4-fluorobenzoyl) -aziridine were heated for 2 hours to form N- [2- (3-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro- 2-Methyl-4-oxo-4a, 8a-trans-1 H-pyrrolo [2,3-g] isoquinolin-6-yl) ethyl] -4-fluorobenzamide is prepared. The crude product is crystallized with ethanol to give a white solid with a melting point of 252 to 253 °. Starting aziridine is prepared from aziridine, p-fluorobenzoylchloride and sodium bicarbonate in water

Example 18

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

3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-one 1.45 in 60 ml dioxane A mixture of g (6 mmol) and 1.77 g (4 mmol) of phosphorus sulphide is stirred under reflux for 10 hours. After cooling to the mixture and dioxane solution is decanted from the brown residue, the residue is dissolved in 75 ml of water. Ammonium hydroxide is added to make the solution alkaline (pH 8-9) and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The solvent is evaporated to give 420 mg of jothion which is subjected to chromatography (dry column, silica gel) with 100 mg of additional crude product obtained by the same chloroform extraction process which is first treated with hot water. The dry column was evaporated by evaporation into an organic phase of a mixture prepared by equilibrating (volumeically) 90 parts of chloroform, 30 parts of methanol, 10 parts of water and 6 parts of acetic acid, dissolved in water and neutralized to pH 8-9 with ammonium hydroxide. And extracted with chloroform to obtain purified thion. After washing with water and drying with sodium sulfate, chloroform was evaporated to 3-ethyl-2-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H as a yellow solid having a melting point of 190 to 194 °. 250 mg of -pyrrolo [2,3-g] -isoquinoline-4-thione is obtained. Recrystallization with acetonitrile yields pure 4a, 8a-trans isomers with melting points of 203-205 °.

Example 19

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

3-ethyl-2-methyl-4,4a, 5,6,, 8,8a, 9-octahydro-1H-pyrrolo [2,3-g] -isoquinolin-4-thione in 15 ml of 3-pentanone A mixture of 248 mg (1 mmol), 276 mg potassium carbonate and 222 mg 2-bromoethylbenzene was stirred at reflux for 3 hours. The solvent is removed on a rotary evaporator and 25 ml of water are added and the mixture is extracted with chloroform. Purification by dry column chromatography as described in Example 18 gave 100 mg of the purified product which was recrystallized from acetonitrile to 3-ethyl-2-methyl-6- (2-phenylethyl) having a melting point of 164 to 166 °. 50 mg of -4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] -isoquinoline-4-thione are obtained.

Example 20

Capsule

Manufacturing process: The active ingredient, lactose and starch are mixed in a suitable mixer and ground using an appropriate grinder. It is mixed with talc and magnesium stearate to fill the capsule.

Example 21

Tablets (Direct Tableting)

Preparation Process: The active ingredient, lactose, Avicel and modified starch are mixed in a suitable mixer for 10-15 minutes. Magnesium stearate is added to the premix and mixed for 4 minutes and tableted on a suitable tabletting machine.

Example 22

Tablets (Wet Granulation)

Manufacturing process: The active ingredient, lactose, modified starch and pregelatinized starch are mixed in a suitable mixer and granulated with water. After drying and pulverizing, the mixture is mixed with magnesium stearate and compressed into a suitable tabletting machine.

Claims (1)

Octahydro-1H-pyrrolo [2,3-g] -isoquinoline of formula (A), the optical and geometrical isomers thereof, characterized by a substitution reaction at the isoquinoline nitrogen atom of the formula (XV) Method for preparing a pharmaceutically acceptable acid addition salt.

In the above formula R ₂ and R ₃ are independently hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl; R ₄ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxy Alkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarbox-amidoalkyl, acylalkyl, Cyclic-alkyloxoalkyl, cyclic-alkylhydroxyalkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alkyl-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms, aryl- N-imidazolonylalkyl or

Wherein R ₆ and R ₇ are independently hydrogen or alkyl and together with nitrogen form a 5- or 6-membered heterocycle ring; X is O or S.