CS242899B2 - Method of octahydro-1h-pyrrolo(2,3-g)-isoquinolines production - Google Patents

Description

The term alkenyl means a straight or branched chain alkenyl group containing 2 to 7 carbon atoms, such as vinyl, allyl and the like.

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

Preferred are those compounds of formula (A) wherein ^R 3 is C 1 -C 7 alkyl.

Particularly preferred are the following individual compounds of formula (A):

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 [3,3-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 hydrochloride. 0.25 mol hydrate,

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

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

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

Examples of compounds of formula (A) include the following:

3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrrolo [2,3-g] isoquinolin-4-one, (+) -3- ethyl-2,6-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-lH-pyrrolo [2,3-g ^-] isoquinolin - 4-on-hydrochloride-0,25 mol hydrate,

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

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

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

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

2-benzyl-3,6-dimethyl-4,4a, 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] isoquinolin-4-one,

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

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

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

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

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

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

The compounds of the above general formula A, their optical and geometric isomers and their pharmaceutically usable acid addition salts can be produced according to the invention by reacting the compound of the general formula XII

N '(XII) in which it is as defined above with a compound of formula VII

‘3

HUNT

R, (VII), 2 wherein

R2 and R1 have the meanings given above, in the presence of a reducing agent, the resulting mixture of cis- and trans-isomers is optionally isomerised to a final ratio in which the trans-isomer is predominantly present, and / or the trans- the isomer, and / or the racemic mixture obtained is optionally resolved into optical antipodes, and / or the compound or pharmaceutically unacceptable acid addition salt obtained is optionally converted into a pharmaceutically usable acid addition salt.

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

Reaction Scheme I

OCH,

OCH, (XI)

(VII)

wherein R ^, Rj and R ^ are as defined above.

According to Reaction Scheme I, compounds of formula IV in which they are methyl are prepared by reacting a primary amine of formula XIV with ethyl chloroformate to give a urethane of formula III which is reduced with lithium aluminum hydride to the N-methylamine of formula IV. In a broader aspect, compounds of formula IV may be prepared by reductive alkylation of compounds of formula XIV using the corresponding aldehyde, e.g. acetaldehyde and the like, and sodium cyanoborohydride under known conditions (cf., for example, RF Borch, J. Am. Chem. Soc., 93, 2). 897 (1971)).

The synthesis of compounds of formula (A) is described in Reaction Scheme II, whereby an isoquinoline ring is formed prior to formation of the pyrrole ring. According to Reaction Scheme IX, the (3,5-dimethoxyphenyl) ethylamine of formula IV is refluxed with aqueous formaldehyde to give the tetrahydroisoquinoline of formula X. The Birch reduction of the tetraisoquinoline of formula X with lithium in tert-butanol containing ammonia affords hexahydroisoquinoline of formula XX. Other variations of the Birch reduction may also be used. Thus, the compound of formula X can be reacted with an alkali metal such as sodium, lithium, potassium or cesium in ammonia or an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, butanol or tert-butanol. The reaction is generally carried out at or below the boiling point of the solvent, for example at -78 ° C to 15 ° C.

If ammonia is used, the reaction is carried out under reflux. Optionally, co-solvents such as diethyl ether or tetrahydrofuran may be added.

The hydrolysis of the crude hexahydroisoquinoline of formula XI is carried out by readily conventional methods of hydrolysis of enol ethers, for example by treatment with aqueous acid. Examples of useful acids include hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid, and perchloric acid.

These acids can be used in aqueous solutions or in mixed solvents. At least 2 equivalents of water per mole of hexahydroisoquinoline and more than one equivalent of acid are required. Examples of useful solvents include tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile.

For example, hydrolysis of a compound of formula XI in which R 1 is a methyl group in 2N hydrochloric acid at room temperature or higher in aqueous acetic acid at temperatures between 40 ° C and reflux to give the diketone of formula XII, wherein R 1 is methyl.

The diketone of formula XII is condensed by Knor condensation to pyrroloisoquinoline of formula A. Knor condensation is a well-known process for producing pyrroles and can be carried out in various known variations (see, for example, JM Patterson, Synthesis, 281 (1976) and references cited therein). . This process is carried out, for example, by reacting an isonitrosoketone of formula VII in the presence of a reducing agent, such as zinc, in aqueous acetic acid or hydrochloric acid, and passing through the corresponding aminocarbonyl compound, which is then condensed with a diketone of formula XII to pyrroloisoquinoline of formula A.

The diketone of formula (XII) does not necessarily have to be isolated prior to Knorre condensation, since the reaction conditions used are sufficient to hydrolyze the compound of formula (XI) to the diketone of formula (XII).

The Knorr condensation is preferably carried out at a pH of about 2 to 6. At a pH substantially greater than 6, a significant loss of yield occurs due to the formation of the products resulting from the self-condensation of the corresponding carbonyl compound.

Preferably, the isonitrosoketone of formula VII and the zinc powder are condensed in aqueous acetic acid with a diketone of formula XII in which R 1 is methyl to give N-methylpyrroloisoquinoline of formula A in which R 1 is methyl.

The Knorr condensation is preferably carried out at temperatures ranging from about room temperature to the boiling point of the reaction mixture. The isonitrosoketones of formula VII are known compounds (see, for example, Ferris, J. Org. Chem., 24, 1 726 (1959)) or can be readily prepared by nitrosating the corresponding ketones, such as alkyl nitrite, or in the case of strongly acidic δ-diketones or $ -ketoesters with sodium nitrite.

Examples of isonitrosoketone useful in the Korr condensation include:

2-Isonitroso-3-pentanone

2,3-butanedione monoxime,

2-Isonitroso-4-methyl-3-pentanone

2-Isonitroso-3-hexanone

2-Isonitroso-3-heptanone

3-Isonitroso-4-methyl-2-pentanone

2-Isonitroso-1-cyclopropyl-1-propanone

3-Isonitroso-5-hexen-2-one, cyclopropyl-2-isonitroso-1-propanone, and

3-Isonitroso-4-phenyl-2-butanone.

In the reactions described in Reaction Schemes I and II, both the trans-isomers of formula I 'may be formed in which R ₄ and R ₄ are as defined above, as well as the cis-isomers of formula I

H 9

H

H (I) wherein

are as defined above for compounds of formula (A), with the trans-isomer predominating in the mixture. The pure trans-isomer may be separated by chromatography or crystallization.

Longer heating of the reaction mixture or separate heating of the mixture of isomers of the hydrochlorides of formulas 1 ' and I ', for example in ethylene glycol for two hours under reflux, can achieve final equilibrium of the cis and trans isomers where the trans isomer is predominant. , which can be easily isolated by crystallization or by chromatographic separation.

The compounds of formula (A) form addition salts with inorganic or organic acids. Thus, the compounds form pharmaceutically acceptable addition salts with both pharmaceutically usable organic acids and inorganic acids such as hydrohalic acid, hydroiodic acid, other mineral acids such as sulfuric acid, nitric acid, phosphoric acid or the like, with alkyl- and monoarylsulfonic acids such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like. The compounds of formula A with acids can be converted to pharmaceutically usable acid addition salts using conventional exchange reactions to replace the pharmaceutically unusable anion of the pharmacist. or by neutralizing pharmaceutically unusable acid addition salts and subsequently reacting the free base thus obtained with an agent providing a pharmaceutically usable acid addition salt. Acid addition salts may also form hydrates.

The compounds of formula A and their pharmaceutically usable acid addition salts show neuroleptic activity. However, these compounds do not exhibit noticeable hypotensive activity and show only weak cataleptic activity. Consequently, the compounds of formula A are useful as antipsychotic agents, for example in the treatment of schisophrenia. The activity of the compounds of formula A, on the basis of which they can be used as antipsychotic agents, can be demonstrated by known warm-blood tests.

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

Each experiment consists of a warning tone of 15 seconds (conditional reflex), which continues for a further 15 seconds and is accompanied by an electric eye (unconditional reflex? 1.0 mA, 350 V AC).

242899 8

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

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

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

The number of experiments in which the rats show no defensive response (defense blocking, VB), or no escape target (escape blocking, FB) is determined for the time interval at which maximum effect is achieved at each dose. This number is the percentage of all attempts made during the time period. The dose calculated for 50% blockade of the defense effect (VB 50) is obtained from a regression curve indicating the dose-to-effect ratio determined using the least squares method. The lowest dose that elicits 20% of the escape reaction block (FB 20) is read from the diagram that shows the ratio of the effect value in percent versus the logarithm of the dose.

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

When 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] is used as test substance isoquinolin-4-one hydrochloride, which has an LDjjq value of, for example, 350 mg / kg po in mice, then neuroleptic activity is observed at νΒ, -θ 0.7 mg / kg po and 0.095 mg / kg s.c., for the (-) -enantiomer of the above compound, neuroleptic activity can then be observed at νΒ, -θ 0.48 mg / kg p.o.

Similarly when 2,3,6-trimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] is used as the test substance isoquinolin-4-one hydrochloride, neuroleptic activity can be observed at νΒθθ 0.48 mg / kg after

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

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

The compounds of formula A and their pharmaceutically usable acid addition salts can be used in the form of conventional pharmaceutical preparations. These preparations contain, for example, suitable dosage units for oral administration or contain the active ingredient in the range of 0.05 to 50 mg. Suitable dosages for oral administration in warm-blooded animals range from about 0.001 mg / kg per day and about 10 mg / kg per day. However, for any particular warm-blooded animal, the specific dose may vary and should be determined according to individual requirements and expert judgment by the person administering the compound of formula A or the pharmaceutically acceptable addition salt or by the person supervising it. Further, the frequency at which each such dosage form is administered will vary depending upon the amount of active drug present and the requirements of the pharmacological situation.

For use, the compounds of formula A and their pharmaceutically usable acid addition salts are mixed with conventional inert pharmaceutical excipients into dosage forms suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions and the like.

Further, the compounds of formula A may be formulated in the form of suitable hard or soft capsules and applied in this manner. The kind of inert excipients to be used for mixtures of the compounds of formula A and their pharmaceutically acceptable acid addition salts for oral and parenteral dosage forms is well known to those skilled in the art. These auxiliary materials are either inorganic or organic substances such as water, gelatin, lactose, starch, magnesium stearic acid, talc, vegetable oils, resins, polyalkylene glycols, etc.

Further, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers and the like can optionally be added to such mixtures.

Since the compounds of formula A and their pharmaceutically usable acid addition salts have an asymmetric carbon atom, they are usually in the form of a racemate. The resolution of these racemates into the optically active isomers can be carried out by known methods. Many racemates can be obtained in the form of a eutectic and then resolved. However, chemical cleavage is preferred. The diastereomeric salt is formed from the racemic mixture of diastereomers by treatment with an optically active resolving agent, for example by treatment with an optically active acid such as (+) - tartaric acid.

The resulting diastereomers can be separated by fractional crystallization and converted to the corresponding optically isomeric bases. The present invention encompasses both the preparation of optically active isomers of the compounds of Formula A and their racemates.

Further, due to possible different spatial arrangements of atoms, it is evident that the compounds of the invention can be obtained in more than one possible geometric isomeric form. The compounds of formula A as described herein and as formulated in the subject invention include all such isomeric forms.

Thus, the examples herein are understood to mean mixtures of geometric isomers or individual geometric isomers, and the invention is not limited in this respect.

The following examples illustrate the process according to the invention. All temperatures are in degrees Celsius unless otherwise indicated.

Example 1

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

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

Example 1a

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

A 3-liter, 3-necked round-bottomed flask equipped with a mechanical stirrer, dropping funnel and condenser was charged with 180 ml of a 70% solution of sodium dihydro-bis- (2-methoxyethoxy) aluminate and 700 ml of absolute tetrahydrofuran. The solution is cooled in an ice bath and a solution of 37.1 g of crude N-2- (3,5-dimethoxyphenyl) ethylcarbamic acid ethyl ester in 100 ml of absolute tetrahydrofuran is added over 15 minutes. After addition, the mixture was heated at reflux for 1 hour and then cooled in an ice bath, the excess hydride was quenched by dropwise addition of 100 ml of 5% sodium hydroxide solution and after all the base had been added, the organic layer and the aqueous layer were separated. extract with 100 ml of ether. The combined organic extracts were concentrated on a rotary evaporator to an oil and dissolved in 300 mL of ether. The ethereal solution was washed with 50 ml of water, 50 ml of brine, dried over anhydrous sodium sulfate, and filtered. 70 ml of ethereal hydrogen chloride were added to the filtrate to precipitate the amine hydrochloride. The solid is collected on a Buchner funnel and crystallized from a mixture of 180 ml of absolute ethanol and 270 ml of ether. 28.9 g of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride are obtained in the form of a white crystalline solid, m.p. 160-164 ° C.

Example 2

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

A solution of 15.0 g (64.7 mmol) of N-methyl- (3,5-dimethoxyphenyl) ethylamine hydrochloride in 30 ml of water is treated with 35 ml of 2N sodium hydroxide solution and then extracted with methylene chloride. The combined extracts are concentrated on a rotary evaporator and the residue is mixed with 65 ml of 37% aqueous formaldehyde solution.

The reaction mixture was refluxed for 2 hours, basified with 15 ml of 2N sodium hydroxide solution and extracted with methylene chloride. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate to give 15.5 g of the product as an oil. This oil was dissolved in ethanol (100 mL) and ethanolic hydrogen chloride was added. Ether (75 ml) was then added to crystallize the salt. 10.15 g of 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride are obtained (yield 64%).

Example 3

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

150 ml of ammonia were condensed in a flask containing 9.1 g (123 mmol) of tert-butanol and 50 ml of diethyl ether. To this solution was added 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring for 2-3 minutes, 0.57 g (82 mmol) of lithium wire is added, which is cut into small pieces over a period of 30 minutes.

The blue solution was stirred at reflux for 2 1/2, and then 4.5 g of solid ammonium chloride was added until the blue color disappeared. Ether (100 ml) was added and the ammonia was evaporated overnight. 100 ml of ice-water are then added and the organic phase is separated.

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

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

Example 4

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

0.56 g (2.68 mmol) of 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline were heated to 90-100 ° C in 70% aqueous acetic acid ( 10 ml) to hydrolyze the bis- (enol ether) to octahydro-2-methylisoquinoline-6,8-dione. To the hot solution was added 0.6 g (9.25 mmol) of zinc powder and 0.7 g (6.1 mmol) of 2-isonitroso-3-pentanone.

The reaction mixture was refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate was concentrated to dryness on a rotary evaporator and the residue was dissolved in methylene chloride. Ammonium hydroxide was added to the solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Concentration gives the crude product. Chromatography of the crude product on alumina (Grade III activity) gave 0.19 g (29% yield) of 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro -1H-pyrrolo [2,3-g] isoquinolin-4-one as a white solid.

Example 5

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

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

The reaction mixture was then stirred at reflux for 1 1/2 hours. The mixture was then cooled and filtered. The filtrate was concentrated in vacuo at 50 ° C / 25 mm Hg to give a yellow oil. This oil was diluted with 50 mL of water and basified with ammonium hydroxide to pH 8-9.

The resulting mixture was extracted with chloroform, and the extracts were washed with brine and dried over sodium sulfate. 2.6 g of crude product are obtained (concentration). The product obtained is chromatographed on 100 g of silica gel (dry column), using an organic phase of a mixture made to obtain equilibrium between 90 parts by volume of chloroform, parts by volume of methanol, 10 parts by volume / OD and 6 parts by volume of acetic acid. The eluate fractions containing the desired product were evaporated, the residue was diluted with water, basified with ammonium hydroxide (pH 8-9) and extracted with chloroform.

The extracts were dried over sodium sulfate and evaporated to give 1.0 g of a solid which was recrystallized twice from ethyl acetate to give 470 mg of pure 2,6-dimethyl-3-isopropyl-4,4a, 5,6,7,8 8α, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one as a crystalline solid. Mp 244-247 ° C.

Example 6

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

In a similar manner to that described in Example 5, 3,6-dimethyl-2- (2-propenyl) -4,4a, 5, 5-dimethyl-2- (2-propenyl) -4,4a, 5 is obtained from isonitroso-5-hexen-2-one and 2-methylooctahydroisoquinolin-6,8-dione. 6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 221-223 ° C.

Example 7

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

In a similar manner to that described in Example 5, 3-cyclopropyl-2,6-dimethyl-4,4a, 5,6,7, 3-cyclopropyl-2,6-dimethyl-4,4a, 8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 258-259 ° C.

Example 8

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

In a similar manner to that described in Example 5, 2-benzyl-3,6-dimethyl-4,4a, 5,6-dione was obtained from 3-isonitroso-4-phenyl-2-butanone and 2-methylooctahydroisoquinoline-6,8-dione. 7,8,8a, 9-octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one, m.p. 234-235 ° C.

Example 9

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

In a similar manner to that described in Example 5 except that zinc was not used, 6-methyl-4,4a, 5,6,7,8,8a, 9 was prepared from aminoacetaldehyde dimethylacetal and 2-methylooctahydroisoquinoline-6,8-dione. -octahydro-4α, 8α-trans-1H-pyrrolo [2,3-g] isoquinolin-4-one. Mp 208-210 ° C.

Example 10

Resolution of racemic 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a, trans-1H-pyrrolo [2,3-g] isoquinolin-4- onu

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

[a] θ ⁵ = -120.78 (c = 0.81%, water)

Analysis: for ^C 15 ^H 22 ^N 2 ° calculated: 62.70% C found: 62.44% C. HCl. 0.25 H ₂ O

H, 8.24; N, 9.75; 8.33% H 9.67% N.

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

Optical rotation:

M + 121.38 ° (c = 0.44%, water).

Analysis for: ^C 15 ^H 22 ^N 2®

HCl. 0.25 H ₂ O Calculated: C, 62.70 i Found: C 63.02%

H, 8.24; N, 9.75; H, 8.20; N, 9.88.

The following examples illustrate in more detail the composition and preparation of pharmaceutical compositions containing, as an active ingredient, a compound of formula A produced by the process of the invention:

Example 11

Preparation of capsules

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

Workflow:

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

Example 12

Preparation of tablets by direct compression

Composition mg / tablet

0,5 5,0 10,0

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

0.5

5.0

10.0 ί ⁴

Continuation

Ingredients mg / tablet 10.0 0.5 5.0 lactose 85.5 81.0 103.0 microcrystalline cellulose (Avicel) 30.0 30.0 45.0 modified starch 7.5 7.5 10.0 magnesium salt of stearic acid 1.5 1.5 2,0 total weight 125 mg 125 mg 170 mg

Workflow:

The active ingredient, lactose, microcrystalline cellulose (Avicel) and modified starch are mixed in a suitable blender for 10-15 minutes. The magnesium stearate salt is then admixed and the mixture is further stirred for 4 minutes. The tablets are then compressed from a mixture on a suitable press.

Example 13

Preparation of tablets (wet granules)

Composition mg / tablet

0,5 5,0 10,0

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

-hydrochloride 0.5 5.0 10.0 lactose 103.5 99.0 148.0 modified starch 10.0 10.0 20.0 pregelatinized starch 10.0 10.0 20.0 magnesium salt of stearic acid 1.0 1.0 2,0 total weight 125 mg 125 mg 200 i

Workflow:

The active ingredient, lactose, modified and pregelatinized starch is mixed in a suitable blender and granulated using water. The granulate is then dried and ground. Finally, the magnesium salt of stearic acid is admixed and the mixture is compressed into tablets using a suitable press.

Claims (3)

VYNALEZU A process for the preparation of octahydro-1H-pyrrolo [2,3-g] isoquinolines of the general formula A in which R (a) independently of one another are hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms or benzyl and R 4 represents an alkyl group having 1 to 7 carbon atoms, optical and geometric isomers of the compounds as well as pharmaceutically usable acid addition salts thereof, characterized in that the compound of formula XII (XII) wherein: R1 is as defined above, reacts with a compound of formula VII (VII) in which and R3 is as defined above, in the presence of a reducing agent, the resulting mixture of cis and trans isomers is optionally isomerized to a final ratio in which and / or the resulting racemic mixture is optionally resolved into optical antipodes and / or the resulting compound or pharmaceutically unusable acid addition salt is optionally converted into a pharmaceutically usable addition salt. acid salt. 2. A process according to item 1 for the preparation of octahydro-1 H -pyrrolo [2,3- g] isoquinolines of the general formula A, in which R ₃ and R ₃ have the meanings given in item 1 and R 6 is methyl, optical and geometric isomers of these the compounds as well as the pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula XII 'h ₃ c (xii') is treated with a compound of formula VII wherein R 1 and R ₃ are as defined in point 1, in the presence of zinc, the resulting mixture of cis and trans isomers is optionally isomerised to a final ratio in which it is predominantly represented. the trans-isomer, and / or optionally the trans-isomer is separated from the resulting mixture, and / or the racemic mixture obtained is optionally resolved into optical antipodes and / or the resulting compound or pharmaceutically unacceptable acid addition salt is optionally converted into a pharmaceutically usable acid addition salt acid. 3. The process of item 2 for producing 3-ethyl-2,6-dimethyl-4,4a, 5,6,7,8,8a, 9-octahydro-4a, 8a-trans-1H-pyrrolo [2,3- Isoquinolin-4-one, characterized in that octahydro-2-methylisoquinolin-6,8-dione is treated with 2-lsonitroso-3-pentanone in the presence of zinc. Severography, n. P., MOST Price 2,40 Kčs