MXPA99006173A - TRICYCLIC BENZO[e]ISOINDOLES AND BENZO[h]ISOQUINOLINES - Google Patents

Abstract

The present invention is concerned with novel benzo[e]-isoindoles and benzo[h]isoquinolines. Since the compounds in accordance with the invention can bind to serotonin receptors (5HT2), they are especially suitable for the treatment or prevention of central nervous disorders such as depressions, bipolar disorders, anxiety states, sleep and sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or pain of a different kind, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, mental organic disorders, mental disorders in childhood, aggressivity, age-related memory disorders and behavioural disorders, addiction, obesity, bulimia, etc., nervous system damage caused by trauma, stroke, neurodegenerative diseases, etc.;cardiovascular disorders such as hypertension, thrombosis, stroke, etc;and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.

Description

BENZO COMPOUNDS [e] ISOINDOLES AND BENZO [h] TRICICLIC ISOQUINOLINES FIELD OF THE INVENTION The present invention relates to tricyclic compounds. In particular it refers to benzo [e] isoindoles and benzo [h] isoquinolines of the general formula wherein ^ ^-R4 signifies, each independently, hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or phenyl or R2 and R3 together represent -0-CH2-0-; R5 means hydrogen, lower alkyl or benzyl; and n means O or 1 thus or pharmaceutically acceptable acid addition salts of the compounds of formula I, with the Ref .: 30597 except for racemic 2-methyl-l, 3,4-, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one.

BACKGROUND OF THE INVENTION The compounds of the formula I are new with the exception of 2-methyl-l, 3, 4a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one (DE 19 26 022). The compounds described herein have aptiplastic properties for use against inflammations, as well as edema following contusions, distortions or fractures. Because the compounds according to the invention can be linked to serotonin receptors (5HT2), they are especially suitable for the treatment or prevention of central nervous system disorders such as depressions, dipolar disorders, anxiety states, sleep disorders and sexual, psychosis, schizophrenia, migraine and other conditions associated with head pain or pain of a different type, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, mental disorders, mental disorders in children, aggression, Memory related to age and behavior disorders, addiction, obesity, bulimia, etc., injury of the nervous system caused by trauma, attack, neurodegenerative diseases, etc .; cardiovascular disorders such as hypertension, thrombosis, attack, etc .; and gastrointestinal disorders such as motility dysfunction of the gastrointestinal tract.

DESCRIPTION OF THE INVENTION Objects of the present invention are compounds of the formula I and pharmaceutically acceptable acid addition salts, their racemic mixtures and their corresponding enantiomers per se and as pharmaceutically active substances, the preparation of these compounds and salts, medicaments containing a compound of the Formula I or a respective pharmaceutically acceptable acid addition salt, the production of these medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of diseases, especially diseases and disorders of the aforementioned type and , respectively, for the production of corresponding medications. Only the cited compound itself, as previously defined, is excluded from the object of the present invention.

The term "lower" denotes radicals with a maximum of 7, preferably up to 4, carbon atoms; "alkyl" denotes straight or branched chain saturated hydrocarbon radicals such as methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl or t-butyl and "alkoxy" denotes an alkyl group linked through a hydrogen atom. oxygen, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy. "Halogen" can mean Cl, Br, F or l. The term "pharmaceutically acceptable acid addition salts" encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, malic acid, acetic acid , succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Preferred are those compounds wherein R 4 hydrogen, R 5 signifies methyl and n means 1. Then those compounds where R 1 hydrogen, hydroxy, halogen or methyl, R 2 means hydrogen or ethyl and R 3 means hydrogen, methyl or methoxy are considered. Some particularly preferred representatives of the class of substance defined by the General formula I in the scope of the present invention are: rac-trans-8-ethyl-7-hydroxy-methoxy-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h ] isoquinolin-6-one; rac-cis-7-methoxy-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-2, 9-dimethyl-l, 3,4,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-7-chloro-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-7-fluoro-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-2, 7, 9-trimethyl-l, 3,4, 4a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one; (+) -trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; (+) - cis-2, 7-dimethyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one; (+) - cis-2, 7, 9-trimethyl-l, 3,4, a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one and (+) - cis-2-methyl- 1, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] -isoquinolin-6-one. The compounds of the general formula I, as well as their pharmaceutically acceptable acid addition salts can be prepared according to the invention in the form already known cyclizing a compound of the general formula wherein R6 means lower alkyl, to a compound of the general formula 1A or b) cyclizing a compound of the general formula to a compound of the general formula c) alkylating or benzylating a compound of the general formula I wherein R5 means hydrogen, or d) dealkylating a compound of the general formula I wherein R5 means alkyl or benzyl, or e) in a compound of the general formula I wherein at least one of R1-R4 signifies an alkoxy group, converting this / these into a hydroxy group (s), and f) if desired, converting the compound of the formula I obtained into a pharmaceutically acceptable acid addition salt.

According to variant a) of the process, the cyclisation of a correspondingly substituted acetic ester of the general formula II can be carried out with polyphosphoric acid at a reaction temperature of about 120 ° C. Toluene is especially suitable as the solvent. Another method of cyclization comprises the reaction of a corresponding ester with phosphorus oxychloride in the presence of a strong base. Cyclization of a compound of formula III to compounds of formula IB (see scheme 2) according to variant b) is carried out analogously to variant a). A mixture of polyphosphoric acid and toluene is reacted with an acetic acid ester for several hours at about 120 ° C and the product is then purified following known methods. According to variant c) of the process, the alkylation or benzylation at the N atom of the ring nitrogen is carried out with an alkyl or benzyl halide, preferably with methyl bromide, ethyl bromide, propyl bromide or benzyl bromide. . Conveniently a compound of the general formula I, wherein R5 signifies hydrogen, is reacted with an aforementioned alkyl or benzyl halide in the presence of an alkaline salt, for example K2CO3, in anhydrous DMF and at about 125 ° C. The dealkylation at the N atom of the ring nitrogen is carried out according to variant d) of the process by treating a compound of the general formula I wherein R5 means alkyl in anhydrous chloroform and at room temperature with a cyanogen halide, preferably bromide of cyanogen, subsequently heating under reflux and, after concentration under reduced pressure, boiling again under reflux with hydrochloric acid for several hours. Another possibility comprises treating a corresponding compound with 2,2,2-trichloroethyl chloroformate. In accordance with variant e) of The process is a compound of the general formula I wherein one of R1-R4 means an alkoxy group in a compound of formula I wherein one of R1-R4 means a hydroxy group. This is done, conveniently, converting the corresponding compound of the formula I to the hydrochloride and subsequently converting the latter to the corresponding hydroxy compound at about -70 ° C using a solution of BBr3 in methylene chloride. It has been found that their acid addition salts are particularly suitable for the pharmaceutical use of these compounds. The addition of the corresponding acids to the compounds of formula I is conveniently carried out before their final isolation at the end of the preparation variants described. The compounds required as precursors for the preparation of the compounds of formula I can be prepared according to Schemes 1 and 2. Scheme 1 describes the preparation of the compounds of formula I wherein n means O. The steps for the synthesis are described with detail in the example la-lh as an example for the preparation of cis-7-ethyl-6-hydroxy-8-methoxy-2-methyl-1, 2, 3, 3a, 4, 9b-hexahydro-benzo [e ] isoindol-5-one.

The preparation of compounds of the general formula I wherein n means 1 is set forth in the Formulation Scheme 2. A detailed description for the preparation of compounds of the formulas IBa and IBb from a compound of the general formula IV is described in Example 8a-8i as a specific example for trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [h] isoquinoline-6 -one Scheme 1 (in accordance with example 1) Scheme 2 (in accordance with example 8 XII XIII The binding of compounds of formula I according to the invention to serotonin receptors was determined in vitro with standard methods. The compounds were investigated in accordance with the tests offered below: a) for binding to the 5HT2c receptor in accordance with the [3 H] -5-HT binding assay according to the method of S. J. Peroutka et al., Brain Research 584, 191-196 (1992). b) for binding to the 5HT2A receptor in accordance with the [3 H] -DOB binding assay according to the method of T. Branchek et al., Molecular Pharmacology 3_8, 604-609 (1990). The (Pkl, Pkl = -log 10 Ki) values of the test compounds are offered. The ki value is defined by the following formula: Ki = [] 1+ Kn wherein the IC50 values are those concentrations of the test compounds in nM with which 50% of the ligands bound to the receptor are displaced. [L] is the ligand concentration and the KD value is the ligand dissociation constant. The activity thus determined of some compounds according to the invention will be evident from the following Table: A = rac-trans-8-ethyl-7-??-idroxy-9-methoxy-2-methyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one B = rac-7-methoxy-2-methyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one C rac-cis-2,9-dimethyl-1,3 , 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one D = rac-cis-7-chloro-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro- 2H-benzo [h] isoquinolin-6-one E rac-cis-7-fluoro-2-methyl-1,3,4,4,4a, 5, l-hexahydro-2H-benzo [h] isoquinolin-6-one F = rac-cis-2, 7, 9-trimethyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one (+) -trans-8-ethyl-7- hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one H = (+) - cis-7-methoxy-2-methyl -l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one (+) - cis-2,7,7-dimethyl-l, 3,4, 4a, 5, 10b- hexahydro-2H-benzo [h] isoquinolin-6-one J = (+) - cis-2,7,9-trimethyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinoline -6-one K = (+) - cis-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one The compounds of formula I and the pharmaceutically acceptable acid addition salts of the Compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, parenterally, for example in the form of injection solutions or nasally. The compounds of formula I and pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. As these vehicles, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used for tablets, coated tablets, dragees and hard gelatine capsules. Suitable vehicles for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance no vehicles are required in the case of soft gelatine capsules. Suitable vehicles for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid polyols and the like. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also still contain other therapeutically valuable substances. It is also an object of the present invention the medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt and a therapeutically inert carrier, as well as a process for its production comprising administering a galenic form to one or more compounds of formula I and / or pharmaceutically acceptable acid addition salts together with one or more therapeutically inert carriers. According to the invention, the compounds of the general formula I, as well as their pharmaceutically acceptable acid addition salts, can be used in the treatment or prevention of disorders of the system. administered as a single dose or divided into several independent doses. The following examples illustrate the present invention in greater detail. However, they are not intended to limit your scope in any way. All temperatures are offered in degrees Celsius.

EXAMPLE 1 cis-7-ethyl-6-hydroxy-8-methoxy-2-methyl-1, 2, 3, 3a, 4, 9b, hexahydro-benzo [e] isoindol-5-one a) During a period of 15 minutes and while stirring at -40 ° C, 39.4 ml (63 mmol) of a solution was added. 1. 6 N of n-butyl lithium in hexane to a suspension of 28. 3 g (66 mmol) of ethoxycarbonylmethyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran. The reaction mixture was stirred at 0 ° for one hour, cooled to -70 ° and treated dropwise for 30 minutes with a solution of 11.6 g (60 mmol) of 4-ethyl-3,5-dimethoxy-benzaldehyde in 100 ml. ml of tetrahydrofuran.

The mixture was then stirred at room temperature for a further 16 hours, poured into 600 ml of saturated sodium chloride solution and extracted twice with central nervous system such as depressions, dipolar disorders, anxiety states, sleep and sexual disorders, psychosis, schizophrenia, migraine and other conditions associated with head pain or pain of a different type, personality disorders or obsessive-compulsive disorders, social phobias or panic states, mental organic disorders, mental disorders in children, aggressiveness, memory disorders related to age and behavioral disorders, addiction, obesity, bulimia, etc., injury to the nervous system caused by trauma, attack, neurodegenerative diseases, etc.; cardiovascular disorders such as hypertension, thrombosis, attack, etc .; and gastrointestinal disorders such as motility dysfunction of the gastrointestinal tract and, respectively, for the production of corresponding drugs. The dose can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. In the case of oral administration the dose is in a range of about O.01 mg to about 500 mg of a compound of general formula I or the corresponding amount of a respective pharmaceutically acceptable acid addition salt, although it may be exceed the upper limit when indicated. The daily dose can 800 ml of diethyl ether each time. The combined organic phases were washed once with 600 ml of saturated sodium chloride solution, dried (MgSO) and concentrated in vacuo. The obtained crude product was purified by column chromatography on silica gel (hexane / ethyl acetate 5: 1). There were obtained 12.5 g (79%) of 3- (4-ethyl-3,5-dimethoxy-phenyl) -ethyl acrylate in the form of a white solid. b) A mixture of 12.5 g was stirred at 60 ° for 15 hours. (47.3 mmol) of (4-ethyl-3,5-dimethoxy-phenyl) -ethyl acrylate, 40 ml of nitromethane and 10 ml of a 40% solution of Triton B in methanol. The reaction mixture was then poured onto 50 ml of ice and 50 ml of 3N sulfuric acid and extracted twice with 300 ml of ethyl acetate each time. The combined organic phases were washed twice with 100 ml of saturated sodium chloride solution, dried (MgSO) and concentrated in vacuo. 15.1 g (98%) of ethyl 3- (4-ethyl-3, 5-dimethoxy-phenyl) -4-nitrobutanoate was obtained as a yellow oil.

C) 15.1 g (46.4 mmol) of ethyl 3- (4-ethyl-3, 5-dimethoxyphenyl) -4-nitrobutanoate dissolved in 300 ml of ethanol was hydrogenated on Raney nickel while I waved for a period of 2 and a half hours. The catalyst was filtered off, washed several times with ethanol and the combined ethanolic phases concentrated in vacuo to a volume of 200 ml. The reaction mixture was treated with 1.7 g of sodium acetate and 50 mg of p-toluenesulfonic acid and heated under reflux for 24 hours. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel (methylene chloride / methanol 19: 1). 8.85 g (76%) of 4- (4-ethyl-3,5-dimethoxy-phenyl) -pyrrolidin-2-one was obtained in the form of a beige solid with a melting point of 156 °. d) 3.12 g (78 mmol) of a sodium hydride dispersion (60% in oil) were added using a spatula and while stirring a suspension of 8.85 g. (35.5 mol) of 4- (4-ethyl-3,5-dimethoxyphenyl) -pyrrolidin-2-one in 250 ml of tetrahydrofuran and 2 ml of dimethylformamide and the mixture was stirred at room temperature for an additional hour. The reaction mixture was then treated with 3.52 ml (106.5 mmol) of methyl iodide and allowed to stir at room temperature for a further 16 hours. The reaction mixture was then poured over 400 ml of ice-water and extracted twice with 600 ml of ethyl acetate each time. The organic phases were washed combined twice with 300 ml of saturated sodium chloride solution each time, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (methylene chloride / methanol 39: 1). 8.08 g (66%) of 4- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-pyrrolidin-2-one was obtained in the form of a beige solid. e) A solution of LDA in 20 ml of anhydrous tetrahydrofuran, freshly prepared at 0 ° from 1.35 ml (9.5 mmol) of diisopropylamine and 5.93 ml (9.5 mmol) of a 1.6 N solution of n-butyllithium in hexane added dropwise while stirring to a solution, cooled to -70 °, of 2 g (7.6 mmol) of 4- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-pyrrolidin-2-one in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred at -70 ° for an additional 30 minutes and then a solution of 1.23 ml (8.35 mmol) of tert-butyl bromoacetate in 20 ml of tetrahydrofuran was added dropwise over 30 minutes. The mixture was then stirred for a further 22 hours without separation from the cooling bath, with the temperature slowly reaching room temperature. The mixture was poured into 150 ml of ice-water and 250 ml of ethyl acetate was extracted twice each time. The combined organic phases were washed once with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuum. The obtained crude product was purified by column chromatography on silica gel (ethyl acetate). In addition to 0.54 g of educt there were obtained 1.23 g (43% and, respectively, 58% based on the conversion) of terbutyl- (4- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-2 -oxo-pyrrolidin-3-yl) -acetate in the form of a pale yellow oil. f) A solution of 1.23 g (3.26 mmol) of (4- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-2-oxo-pyrrolidin-3-yl) -acetic acid tert-butyl ester in 20 ml of tetrahydrofuran was treated at room temperature while stirring with 32.6 ml (32.6 mmol) of a complex solution of borane-THF and then heated under reflux for 7 hours. The reaction mixture was then cooled to 0 °, 10 ml of methanol were slowly added dropwise and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate). 0.9 g (76%) of 4- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-pyrrolidin-3-yl) -acetic acid ester was obtained as a colorless oil. g) A mixture of 1.08 g (2.97 mmol) of 4- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-pyrrolidin-3-yl) -tert-butyl acetate and 11 g of polyphosphoric acid it was stirred at 120 ° for 75 minutes. The reaction mixture was then adjusted to pH 6 with 28% NaOH and saddic acetate and extracted three times with 100 ml of methylene chloride each time. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried (MgSO 4) and concentrated in vacuo. The obtained crude product was purified by column chromatography on silica gel (methylene chloride / methanol / NH40H 15: 1: 0.1). 0.4 g (49%) of cis 7-ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a, 4,9b-hexahydro-benzo [e] isoindol-5-one in form of a colorless oil. h) 168 mg (1.45 mmol) of fumaric acid and 50 ml of diethyl ether were added while stirring to a solution of 0.4 g (1.45 mmol) of cis-7-ethyl-6-hydroxy-8-methoxy-2-methyl -l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one in 0.5 ml of ethanol. The mixture was stirred at room temperature for a further 17 hours and then the solid was filtered off. 0.55 g (97%) of 7-ethyl-6-hydroxy-8-methoxy-2-methyl-l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one fumarate was obtained. (1: 1) in the form of a white solid with a melting point of 195 °.

EXAMPLE cis-7-ethyl-6,8-dimethoxy-2-methyl-1, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one a) A mixture of 150 mg (0.4 mmol) of (4- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-pyrrolidin-3-yl) -acetate, 1.5 ml of trifluoroacetic acid and 0.15 ml of trifluoroacetic acid anhydride was stirred at room temperature for 2 hours. The reaction mixture was then poured into 50 ml of ice-water, basified with 28% NaOH and extracted twice with 100 ml of methylene chloride each time. The combined organic phases were washed once with 50 ml of saturated sodium chloride solution, dried (MgSO) and concentrated in vacuo. The crude product obtained was purified by column chromatography on silica gel (methylene chloride / methanol / NH 4 OH 15: 1: 0.1). 15 mg (13%) of cis-7-ethyl-6,8-dimethoxy-2-methyl-1, 2, 3, 3a, 4, 9b-hexahydro-benzo- [e] isoindol-5-one was obtained in form of a colorless oil. b) 6 mg (0.05 mmol) of fumaric acid, 10 ml of hexane and 10 ml of diethyl ether were added while stirring to a solution of 15 mg (0.05 mmol) of cis-7-ethyl-6,8-dimethoxy- 2-methyl-1, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one in 0.1 ml of ethanol. The mixture was stirred room temperature for a further 2 hours and then the solid was filtered off. 15 mg (75%) of cis-7-ethyl-6,8-dimethoxy-2-methyl-1, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one fumarate were obtained (1: 1) in the form of a beige solid, melting point 148 °.

EXAMPLE 3 cis-8-methoxy-2-methyl-l, 2,3, 3a, 4, 9b-hexahydro-benzo [e] -isoindol-5-one Analogous to that described in Example 1 d) -h), 4- (3-methoxy-phenyl) -pyrrolidin-2-one was obtained from cis-8-methoxy-2-methyl-1, 2 fumarate. , 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one (1: 1) as a white solid with a melting point of 193 °.

EXAMPLE cis-2, 8-dimethyl-l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one In a similar way to that described in example 1 b) h), from 3- (3-methyl-phenyl) -ethyl acrylate was obtained cis-2, 8-dimethyl-l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindole fumarate -5-one (1: 1) in the form of a white solid with a melting point of 153 °.

EXAMPLE 5 cis-8-chloro-2-methyl-l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one In a manner analogous to that described in example 1 b) -h), 3- (3-chloro-phenyl) -ethyl acrylate was obtained from cis-8-chloro-2-methyl-l, 2, 3 fumarate , 3a, 4, 9b-hexahydro-benzo [e] -isoindol-5-one (1: 0.5) as a white solid with a melting point of 213 °.

EXAMPLE cis-2-methyl-l, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one In a manner analogous to that described in example 1 e) -h), from l-methyl-4-phenyl-pyrrolidin-2-one was obtained cis-2-methyl-l, 2, 3, 3a, 4 fumarate , 9b-hexahydro-benzo [e] - Isoindol-5-one (1: 0.5) as a white solid with a melting point of 203 °.

EXAMPLE 7 cis-7-methoxy-2-methyl-l, 2,3, 3a, 4, 9b-hexahydro-benzo [e] -isoindol-5-one In a manner analogous to that described in example 1 e) -h, 4- (4-methoxy-phenyl) -l-methyl-pyrrolidin-2-one was obtained from cis-7-methoxy-2-methyl fumarate. 1, 2, 3, 3a, 4, 9b-hexahydro-benzo [e] isoindol-5-one (1: 1) as a white solid with melting point 173 °.

EXAMPLE 8 trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2-H-benzo [h] isoquinolin-6-one a) 130 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol (Triton B) were added to a solution of 126.5 g (651.2 mmol) of 4-ethyl-3,5-dimethoxy-benzaldehyde and 80.89 g. (651.2 mmol) of methyl methylthiomethyl sulfoxide in 300 ml of tetrahydrofuran and the mixture was heated under reflux for 5 hours. After the addition of 300 ml of methylene chloride, the mixture was extracted with 200 ml of 0.5 M sulfuric acid. The organic phase was dried (MgSO), filtered and evaporated. Chromatography of the resulting residue (silica gel, ethyl acetate / hexane 1: 1) gave 134.6 g (69%) of (E) -2-ethyl-5- (2-methylsulfanyl-2-methylsulfinyl-vinyl) -1 , 3-dimethoxybenzene in the form of a colorless oil, which gave colorless crystals of melting point 82-830 by crystallization from hexane. b) 400 ml of a concentrated methanolic hydrochloric acid solution was added to a solution of 130. 0 g (433 mmol) of (E) -2-ethyl-5- (2-methylsulfanyl-2-methylsulfinyl-vinyl) -1,3-dimethoxybenzene in 200 ml of methanol and the mixture was stirred at 50 ° for 4 hours . The methanol was then evaporated and the residue was partitioned between 300 ml of methylene chloride and 200 ml of saturated sodium bicarbonate solution. The aqueous phase was washed two times with 200 ml of methylene chloride and the organic phases were dried (MgSO 4), filtered and evaporated. Chromatography of the residue (silica gel, ethyl acetate / hexane 1: 9) gave 100.5 g (94%) of (4-ethyl- 3,5-dimethoxy-phenyl) -acetic acid methyl ester in the form of a colorless wax, Rf = 0.345 (silica gel, ethyl acetate / hexane 1: 9). c) A solution of 80.43 g (337.5 mmol) of methyl (4-ethyl-3,5-dimethoxy-phenyl) -acetate in 400 ml of toluene was added dropwise to a suspension of 22.1 g (506 mmol) of NaH (55% in mineral oil) in 400 ml of tetrahydrofuran and 40.86 g (346 mmol) of dimethyl oxalate and the mixture was stirred at room temperature for 65 hours. The reaction mixture was poured into 500 ml of ice-water and washed twice with 250 ml of diethyl ether. The aqueous phase was adjusted to pH 1 with 25% HCl and extracted three times with 300 ml of diethyl ether. The combined phases were dried (MgSO4), filtered and evaporated. The dimethyl 2- (4-ethyl-3, 5-dimethoxy-phenyl) -3-oxo-succinate thus obtained (101.9 g, 314.3 mmol) was suspended in 150 ml of water and treated with 61 ml (812 mmol) of formaldehyde solution (37% in water). A solution of 43.4 g of potassium carbonate in 150 ml of water was then slowly added dropwise and the mixture was stirred at room temperature for 12 hours and then extracted three times with 250 ml of diethyl ether. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography of the resulting residue (gel silica, hexane / methylene chloride 1: 2) gave 44.5 g (53%) of methyl 2- (4-ethyl-3,5-dimethoxy-phenyl) -acrylate in the form of a colorless wax, Rf = 0.635 ( silica gel, methylene chloride / hexane 2: 1). c 2) 18.9 g (630 mmol) of paraformaldehyde, 92.8 g (672 mmol) of potassium carbonate and 3.1 g (8.4 mmol) of tetrabutylammonium iodide were added to a solution of 100 g (420 mmol) of 2- (4- ethyl-3, 5-dimethoxy-phenyl) -acrylate in 200 ml of toluene and the mixture was heated to 80 ° for 6 hours and then cooled and treated with 150 ml of water. The phases were separated and the aqueous phase was extracted twice with 120 ml of toluene. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography of the resulting residue (silica gel, hexane / methylene chloride 2: 1) gave 70.5 g (67%) of methyl 2- (4-ethyl-3, 5-dimethoxy-phenyl) acrylate in the form of a wax colorless, Rf = 0.635 (silica gel, methylene chloride / hexane 2: 1). d) A solution of 78.4 g (313 mmol) of methyl 2- (4-ethyl-3,5-dimethoxy-phenyl) -acrylate and 47.7 g (364 mmol) of ethyl 3-methylamino-propionate was stirred at room temperature. environment for 48 hours. Chromatography of the reaction mixture (silica gel, ethyl acetate / hexane 1: 1) and crystallization from hexane gave 71.1 g (59%) of methyl 3 - [(2-ethoxycarbonyl-ethyl) -methyl-amino] -2- (4-ethyl-3, 5-dimethoxy-phenyl) -propionate in the form of colorless crystals of melting point 74-75 °. e) A solution of 53.51 g (140.3 mmol) of methyl 3- [(2-ethoxycarbonyl-ethyl) -methyl-amino] -2- (4-ethyl-3,5-dimethoxyphenyl) -propionate in 150 ml of toluene 80 ° drops were added to a suspension of 11.62 g (266.3 mmol) of sadist hydride (55% in mineral oil) in 150 ml of toluene and the mixture was then heated under reflux for 15 hours. The solution was cooled to room temperature and adjusted to pH 1 with 6N hydrochloric acid. The toluene was separated and extracted once with 150 ml of 6N hydrochloric acid. The acid phases were heated under reflux for 20 hours. After cooling to room temperature, the mixture was adjusted to pH 14 with 28% NaOH and extracted three times with 250 ml of methylene chloride. The organic phases were washed once with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried (MgSO 4), filtered and evaporated. Chromatography (silica gel methylene chloride / methanol 19: 1) and recrystallization from hexane gave 34.4 g (88%) of 3- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-piperidin-4. -one in fo-rma de yellow crystals dß * melting point 84-85 °. # f) A solution of 39 ml (262.4 mmol) of trimethyl phosphonacetate in 450 ml of tetrahydrofuran was added dropwise at 0 ° to a suspension of 9.54 g (238.5 mmol) of sadist hydride (55% in mineral oil) in 450 ml. of tetrahydrofuran and the mixture was stirred for 30 minutes. The white suspension was then treated with a solution of 33.15 g (119.5 mmol) of 3- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-piperidin-4-one in 450 ml of tetrahydrofuran and stirred the mixture at 50 ° for 2 hours. After cooling to room temperature, the mixture was poured onto 500 ml of ice-water and extracted three times with 400 ml of diethyl ether. The organic phases were washed with 400 ml of water and 400 ml of saturated sodium chloride solution, dried (Na 2 SO), filtered and evaporated. Chromatography (silica gel, methylene chloride / methanol 19: 1) and recrystallization from hexane gave 36.33 g (91%) of (E) - [3- (4-ethyl-3,5-dimethoxy-phenyl) -l methyl-piperidin-4-ylidene] methyl acetate in the form of pale yellow crystals of melting point 110-112 °. g 1) 25.76 g (1060 mmol) of magnesium turnings were added to a solution of 35.33 g (106 mmol) of (E) - [3- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-piperidin-4-ylidene] methyl acetate in 850 ml of methanol and the mixture was stirred at room temperature for 2 hours. The solution was filtered over Dicalite and evaporated. The residue was partitioned between 300 ml of methylene chloride and 500 ml of saturated ammonium chloride solution. The aqueous phase was extracted three times with 250 ml of methylene chloride. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, ethyl acetate / methanol / NH 4 OH 200: 10: 1) gave 7.16 g (20%) of cis- [3- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl methyl-piperidin-4-yl] -acetate in the form of a colorless oil, Rf = 0.23 ((silica gel, ethyl acetate / methanol / NH 4 OH 200: 10: 1) and 23.51 g (66%) of methyl- [3- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-piperidin-4-yl] -acetate as a colorless oil, Rf = 0.12 (silica gel, ethyl acetate / methanol / NH 4 OH 200: 10: 1). g 2) A solution of 11.7 g (35.3 mmol) of methyl (E) - [3- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-piperidin-4-ylidene] acetate in 100 ml of methanol was treated with 500 mg of Pd on carbon and hydrogenated with hydrogen at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated. Chromatography (silica gel, acetate ethyl / methanol / NH 4 OH 200: 10: 1) gave 9.14 g (77%) of cis- [3- (4-ethyl-3,5-dimethoxy-phenyl) -l-methyl-piperidin-4-yl] -acetate of methyl in the form of a colorless oil, Rf = 0.23 (silica gel, ethyl acetate / methanol / NH4OH 200: 10: 1) and 2.56 g (21%) of trans- [3- (4-ethyl-3, Methyl 5-dimethoxy-phenyl) -l-methyl-piperidin-4-yl] -acetate in the form of a colorless oil, Rf = 0.12 (silica gel, ethyl acetate / methanol / NH 4 OH 200: 10: 1). g 3) A solution of 6.4 g (19.3 mmol) of methyl (E) - [3- (4-ethyl-3, 5-dimethoxy-phenyl) -l-methyl-piperidin-4-ylidene] acetate in 100 ml of methanol was treated with 1.08 g (20 mmol) of sodium methylate and the mixture was heated under reflux for 6 hours. The solution was evaporated and the residue was partitioned between 50 ml of methyl acetate and 50 ml of water. The organic phases were dried (MgSO 4), filtered and evaporated. The colorless oil was dissolved in 50 ml of methanol, treated with 125 mg of Pd on carbon and hydrogenated with hydrogen at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated. Chromatography (silica gel, ethyl acetate / methanol / NH40H 200: 10: 1) gave 5.68 g (88%) of cis- [3- (4-ethyl-3,5-dimethoxy-phenyl) -1-methyl. methylpiperidin-4-yl] -acetate in the form of a colorless oil, Rf = 0.23 (silica gel, ethyl acetate. ethyl / methanol / NH-jOH 200: 10: 1) h) A mixture of 140 g of polyphosphoric acid and 50 ml of toluene was heated to 120 ° and treated with a solution of 13.9 g (41.5 mmol) of cis- [3- (4-ethyl-3,5-dimethoxy). methyl phenyl) -l-methyl-piperidin-4-yl] -acetate in 120 ml of toluene. The reaction mixture was stirred at 120 ° for 3 hours and poured slowly into 500 ml of water at 80 °. The mixture was adjusted to pH = 12 with 28% sodium hydroxide solution and extracted three times with 300 ml of ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride / methanol / NH40H 110: 1) gave 8.64 g (68%) of trans-8-ethyl-7,9-dimethoxy-2-methyl-1,3,4,4a, 5, -10b-hexahydro-2H-benzo [h] isoquinolin-6-one as a colorless oil, Rf-0.32 (silica gel, methylene chloride / methanol / NH40H 110: 10: 1), which became with fumaric acid in the fumarate (1: 1) with melting point 194-195.5 °. i) 3.9 g (13 mmol) of trans-8-ethyl-7-, 9-dimethoxy-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one they were converted with HCl into ethyl acetate in the hydrochloride and the latter was subsequently dissolved in 280 ml of methylene chloride. The solution was cooled to -70 ° and it was treated with 15.4 ml of a solution of BBr3 IT in methylene chloride. After 15 minutes the cooling bath was removed. After the solution reached room temperature, it was stirred for one hour, then poured into 200 ml of ice / saturated sodium bicarbonate solution and extracted three times with 250 ml of methylene chloride. The organic phases were dried (Na 2 SO 4), filtered and evaporated. Chromatography (silica gel, methylene chloride / methanol / NH0H 110: 10: 1) gave 2.50 g (67%) of trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3, 4, 4a, 5, 10b-hexahydro-2H-benzo (h) isoquinolin-6-one, which was converted with fumaric acid to the fumarate (1: 1) with melting point 201-203 °.

EXAMPLE 9 cis-8-ethyl-7-hydroxy-9-methoxy-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to the one described in Example 1 h) and i), from cis-8-ethyl-7,9-dimethoxy-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one cis-8-ethyl-7-hydroxy-9-methoxy-2-methyl-l, 3, 4, 4a, 5 was obtained 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with fumaric acid to the fumarate (1: 1) with melting point 221-223 °.

EXAMPLE 10 trans-8-bromo-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, a) 2 ml of 1N NaOH solution was added to a solution of 0.726 g (1.87 mmol) of trans- [3- (4-bromo-3,5-dimethoxy-phenyl) -l-methyl-piperidin-4-yl. ] -methyl acetate in 3 ml of ethanol and the mixture was stirred at 50 ° for 30 minutes. The solution was evaporated and the residue was dried in a high vacuum. The sodium salt thus obtained was suspended in 5 ml of acetonitrile. After the addition of 278 mg (2 mmol) of potassium carbonate the suspension was treated at 0 ° with 0.913 ml (10 mmol) of phosphorus oxychloride and the mixture was subsequently stirred at 50 ° for 2 hours. The mixture was then poured into 10 ml of water, adjusted to pH = 12 with 28% NaOH and extracted three times with 15 ml of ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, chloride methylene / methanol 95: 5) gave 0.385 g (58%) of trans-8-bromo-7,9-dimethoxy-2-methyl-1,3,4,4, 5, 10b-hexahydro-2H-benzo [ h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point 226-228 °. b) A solution of 0.421 g (1:11 mmol) trans-8-bromo-7,9-dimethoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo hydrochloride [h] ] isoquinolin-6-one in 40 ml of methylene chloride was treated at -70 ° C with 1.23 ml of a solution of BBr3 IT in methylene chloride. After 15 minutes the cooling bath was separated. After the solution reached room temperature, it was stirred for one hour, then poured into 80 ml of ice / saturated sodium bicarbonate solution and extracted three times with 60 ml of methylene chloride. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride / methanol 9: 1) gave 0.315 g (83%) of trans-8-bromo-7-hydroxy-9-methoxy-2-methyl-1, 3, 4, 4a, 5, 10-b-hexahydro-2H-benzo [h] isoquinolin-6-one which was converted with HCl in methanol into the hydrochloride with melting point 257-259 °. The methyl [3 (4-bromo-3, 5-dimethoxy-phenyl) -1-methyl-piperidin-4-yl] acetate used was prepared from 4-bromo-3,5-dimethoxybenzole aldehyde so analogous to that described in example 8a), b), c 1), d) e), f) and g 1).

EXAMPLE 11 trans-7-hydroxy-9-methoxy-2-methyl-l, 3,4, 4a, 5, IQb-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to the one described in example 8 cl), d), e), f), gl), h) and i), trans-7-hydroxy was obtained from methyl (3,5-dimethoxyphenyl) -acetate. -9-methoxy-2-methyl-1, 3,4, 4a, 5, -10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 12 cis-2-methyl-l, 3, 4, 4a, 5, llb-hexahydro-2H-8, 10-dioxa-2-aza-cyclopenta [b] phenanthren-6-one In a manner analogous to that described in example 10 a), cis- (3-benzo [1,3] dioxol-5-yl-l-methyl-piperidin-4-yl) -acetic acid methyl ester was obtained from cis- 2-methyl- 1,3,4, 4a, 5, llb-hexahydro-2H-8, 10-dioxa-2-aza-cyclopenta [b] -phenanthren-6-one, which was converted with fumaric acid in the fumarate (1: 0.75 ) with melting point > 250 °. The methyl cis- (3-benzo [l, 3] dioxol-5-yl-l-methyl-piperidin-4-yl) -acetate used was prepared analogously to that described in example 8 f) and g 3) a from 3-benzo- [1,3] dioxol-5-yl-l-methyl-piperidin-4-one.

EXAMPLE 13 cis-9-methoxy-2-ethyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one? _ cis-7-methoxy-2-methyl-1, 3 , 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in example 8 f), g 3) and h), from 3- (3-methoxy-phenyl) -1-methyl-piperidin-4-one cis-9-methoxy-2- was obtained methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and cis-7-methoxy-2-methyl-1, 3, 4, 4a, 5, 10b- hexahydro-2H-benzo [h] -isoquinolin-6-one, which was converted with HCl in methanol into its hydrochlorides with melting point > 250 °.

EXAMPLE 14 trans-9-methoxy-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in example 8 f), g 1) and h), from 3- (3-methoxy-phenyl) -1-methyl-piperidin-4-one was obtained trans-9-methoxy-2-methyl-1,3,4,4, 5a, 5, 10b-hexahydro -2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 250 °.

EXAMPLE 15 cis-2, 9-dimethyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] -isoquinolin-6-one In a manner analogous to that described in example 8 d) e), f), g 3) and h), from 2-m-tolyl-methyl acrylate, cis-2,9-dimethyl-1,3,4 was obtained , 4a, 5, lOb-hydro-2H-benzo [b] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 250 °.

EXAMPLE 16 trans-2, 9-dimethyl-l, 3,4, 4a, 5, 10b-hydro-2H-benzo [h] -isoquinolin-6-one Analogously to that described in Example 8 d), e), f), gl) and h), trans-2,9-dimethyl-1,3,4 was obtained from methyl 2-m-tolyl acrylate. 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 17 cis-9-chloro-2-methyl-lr 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, trans-9-chloro-2-methyl-l, 3, 4 , 4a, 5, 10b-hydro-2H-benzo- [h] isoquinolin-6-one, cis-7-chloro-2-methyl-1, 3, 4, 4a, 5, 10b-hydro-2H-benzo [ h] -isoquinolin-6-one and trans-7-chloro-2-methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one Analogous to that described in example 8 d), e), f), g 1) and h), from 2 - (3-chloro-phenyl) -methyl methacrylate was obtained cis-9-chloro-2- methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, trans-9-chloro- 2-methyl-l, 3,4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, cis-7-chloro-2-methyl-l, 3,4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one and trans-7-chloro-2-methyl-1, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinoline-6 ona that was converted with HCl into methanol in its hydrochlorides with melting point > 250 °.

EXAMPLE 18 trans-8-fluoro-2-methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo- [h] isoquinolin-6-one In a manner analogous to that described in example 8 d), e), f), g 1) and h), trans-8-tluoro-2- was obtained from 2- (4-fluoro-phenyl) -methyl methacrylate. methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo- [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 19 cis-8-fluoro-2-methyl-1, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in Example 8 d), e), f), g and h), cis-8-fluoro-2-methyl-1, 3 was obtained from 2- (4-fluoro-phenyl) -acrylate. , 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 250 °.

EXAMPLE 20 trans-2, 8-dimethyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] -isoquinolin-6-one In a manner analogous to that described in example 8 d), e), f), g 1) and h), trans-2,8-dimethyl-1,3 was obtained from methyl 2-o-tolyl acrylate. 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 250 °.

EXAMPLE 21 cis-2, 8-dimethyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in Example 8 d), e), f), g 3) and h), from 2-a-tolyl-methyl acrylate cis-2,8-dimethyl-1,3 was obtained, 4, 4a, 5, lOb-hydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 250 °.

EXAMPLE 22 trans-8-methoxy-2-methyl-1,3,4,4a, 5, 10b-hydro-2H-benzo- [h] isoquinolin-6-one In a manner analogous to that described in example 8 f), g 1) and h), from 3- (4-methoxy-phenyl) -1-methyl-piperidin-4-one trans-8-methoxy-2- was obtained methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo- [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point 222 °.

EXAMPLE 23 cis-8-methoxy-2-methyl-1,3,4,4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in Example 8 f), g 3) and h), 3- (4-methoxy-phenyl) -1-methyl-piperidin-4-one gave cis-8-methoxy-2- methyl-l, 3, 4, 4a, 5, 10b-hydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 24 trans-8-ethyl-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in Example 8 d), e), f), g 1) and h), trans-8-ethyl-2-methyl was obtained from 2- (4-ethyl-phenyl) -acrylate. 1, 3, 4, 4a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point 226 °.

EXAMPLE 25 cis-8-ethyl-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 8 d), e), f), g 3) and h), 2- (4-ethyl-phenyl) -acrylic acid was obtained from cis-8-ethyl-2 methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 26 trans-8-chloro-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] -isoquinolin-6-one and cis-8-chloro-2-methyl-1, 3 , 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogous to that described in example 8 d), e), f), g 1) and h), 2- (4-chloro-phenyl) -acrylic acid ester was obtained trans-8-clear-2 -methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and cis-8-chloro-2-methyl-l, 3, 4, 4a, 5, 10b -hexahydro-2H-benzo [h] -isoquinolin-6-one, which was converted with HCl in methanol into its hydrochlorides with melting point > 250 °.

EXAMPLE 27 cis-7, 9-difluoro-2-methyl-l, 3,4,4,4, 5, 10b-hexahydro-2H-benzo - [h] -isoquinolin-6-one Analogously to that described in example 8 c 2 ), d), e), f), g 3) and h), from methyl 3,5-di-fluoro-phenylacetate, cis-7,9-difluoro-2-methyl-1,3,4,4a was obtained. , 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 230 °.

EXAMPLE 28 trans-7, 9-difluoro-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 8 c 2), d), e), f), g 1) and h), from methyl 3,5-difluorophenylacetate trans-7,9-difluoro-2- was obtained methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 220 °.

EXAMPLE cis-7, 9-dichloro-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one and trans-7, 9-dichloro-2-methyl -l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in Example 8 c 2), d), e), f), g 1) and h), from ethyl 3,5-dichlorophenylacetate, cis-7,9-dichloro-2- was obtained methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and trans-7, 9-dichloro-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into its hydrochlorides with melting point > 250 °.

EXAMPLE 30 trans-9-fluoro-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one y_ trans-7-fluoro-2-methyl-l, 3 , 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in example 8 c 2), d), e), f), g 1) and h), trans-9-fluoro-2-methyl-1 was obtained from ethyl 3-fluorophenylacetate; 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and trans-7-fluoro-2-methyl-1,3,4,4a, 5, 10b-hexahydro-. 2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into its hydrochlorides with melting point > 250 °.

EXAMPLE 31 cis-9-fluoro-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] -isoquinolin-6-one and cis-7-fluoro-2-methyl-1, 3 , 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one Analogously to that described in example 8 c 2), d), e), f), g 3) and h), cis-9-fluoro-2-methyl-1 was obtained from ethyl 3-fluorophenyl acetate. , 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and cis-7-fluoro-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H -benzo [h] -isoquinolin-6-one, which were converted with HCl in methanol into their hydrochlorides with melting point > 250 °.

EXAMPLE 32 cis-2-methyl-8-phenyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a similar way to that described in the example c 2), d), e), f), g 3) and h), from (4-phenyl) -phenyl methyl acetate was obtained cis-2-methyl-8-phenyl-1,3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 33 trans-2-methyl-8-phenyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one In a manner analogous to that described in example 8 c 2), d), e), f), g 1) and h), trans-2-methyl-8 was obtained from methyl (4-phenyl) -phenyl acetate. phenyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 34 cis-8, 9-difluoro-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo - [h] isoquinolin-6-one In a manner analogous to that described in example 8 c 2), d), e), f), g 3) and h), cis-8,9-difluoro- was obtained from methyl 3,4-difluorophenyl acetate. 2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 35 trans-8, 9-difluoro-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 8 c 2), d), e), f), g 1) and h), from 3,3-difluoro-phenyl methyl acetate, trans-8, 9-difluoro was obtained -2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 36 cis-10-fluoro-2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one Analogously to that described in example B f), g 3) and h), from 3- (2-fluorophenyl) -1-methyl-piperidone cis-10-fluoro-2-methyl-1,3 was obtained, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 220 °.

EXAMPLE 37 trans-10-fluoro-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one Analogously to that described in example 8 f), g 1) and h), from 3 (2-fluorophenyl) -1-methyl-piperidone, trans-10-fluoro-2-methyl-1,3 was obtained, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 220 °.

EXAMPLE 38 cis-10-methoxy-2-methyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzo- [h] isoquinolin-6-one y_ trans-10-methoxy-2-methyl-1, 3 , 4, 4a, , 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 8 d), e), f), g 2) and h), from 2 - (2-methoxy-phenyl) -methyl methacrylate was obtained cis-10-methoxy-2- methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and trans-10-methoxy-2-methyl-l, 3,, 4a, 5, 10b-hexahydro -2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into its hydrochlorides with melting point > 220 °.

EXAMPLE 39 cis-2, 10-dimethyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in Example 8 d), e), f), g 3) and h), from 2 - (2-methyl-phenyl) -methyl methacrylate was obtained cis-2, 10-dlmethyl- 1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 220 °.

EXAMPLE 40 trans-2, 10-dimethyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] -isoquinolin-6-one In a manner analogous to that described in example 8 d), e), f), g 1) and h), from 2- (2-methyl-phenyl) -methyl methacrylate trans-2, 10-dimethyl- 1, 3, 4, 4a, 5, 10-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with melting point > 220 °.

EXAMPLE 41 trans-2, 7, 9-trimethyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 8 c 2), d), e), f), g 3) and h), trans-2 was obtained from methyl (3, 5-dimethyl-phenyl) -acetate. 7, 9-trimethyl-1,4,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 42 cis-2, 7, 9-trimethyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] -isoquinolin-6-one In a manner analogous to that described in Example 8 c 2), d), e), f), g 1) and h), cis-2 was obtained from (3,5-dimethyl-phenyl) -acetic acid methyl ester. 7,9-trimethyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride with melting point > 250 °.

EXAMPLE 43 (-) -trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one 3.08 g (8.6 mmol) of (+) - O, 0-dibenzoyltartaric acid were added to a solution of 2.58 g (8.6 mmol) of trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one in 40 ml of ethanol and the mixture was stirred at room temperature for 15 minutes. It was then heated to reflux and sufficient ethanol was added in order to give a clean solution (about 80 ml). After cooling to room temperature they will be separated by Filter the resulting crystals (2.52 g) and dissolve in a mixture of 50 ml of methylene chloride and 50 ml of 2N sodium carbonate solution. The sodium carbonate solution was washed once with methylene chloride. The organic phases were dried (MgSO 4), filtered and evaporated. The yellow oil obtained (1.18 g) was converted with HCl into methanol in the hydrochloride. After recrystallization from diisopropyl ether / ethanol, 0.86 g of (+) - trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4, 5, l-hexahydro-2H hydrochloride was obtained. -benzo [h] isoquinolin-6-one with melting point 261-263, The mother liquors of the crystallization were evaporated with (+) - O, O-dibenzoyltartaric acid and the residue was partitioned between methylene chloride and a 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried (MgSO 4), filtered and evaporated. The light yellow oil thus obtained (1.39 g (4.8 mmol)) was dissolved in 20 ml of ethanol and treated with 1.72 g (4.8 mmol) of (-) -0, O-dibenzoyltartaric acid. The mixture was then heated to reflux and sufficient ethanol was added to give a clean solution (about 40 ml) After cooling to room temperature they were separated by Filter the resulting crystals (2.26 g) and dissolve in a mixture of 50 ml of methylene chloride and 50 ml of 2N sodium carbonate solution. The sodium carbonate solution was washed once with methylene chloride. The organic phases were dried (MgSO 4), filtered and evaporated. The yellow oil thus obtained (1.22 g) was converted with HCl into methanol in the hydrochloride. After recrystallization from diisopropyl ether / ethanol, 0.82 g of (-) - trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro hydrochloride was obtained. -2H-benzo [h] isoquinolin-6-one with melting point 261-263 °, [a] 589 = -29.2 (c = 0.5, H20).

EXAMPLE 44 (+) - cis-7-methoxy-2-methyl-l, 3,4,4,4a, 5,10b-hexahydro-2H-benzo [hj isoquinolin-6-one (-) - cis-7-methoxy-2- methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in Example 43, starting from cis-7-methoxy-2-methyl-1,3,4,4,4, 5, 10-hexahydro-2H-benzo [h] isoquinolin-6-one by crystallization with (+) -O, O-dibenzoyltartaric acid was obtained (+) - Cis-7-methoxy-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo - [h] -isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride. After recrystallization from ethanol, (+) - cis-7-methoxy-2-methyl-1, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one hydrochloride was obtained. fusion > 250 °, [a] 589 = +2.6 (c = 0.5, H20). Crystallization with (-) - 0,0-dibenzoyltartaric acid gave (-) - cis-7-methoxy-2-methyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinoline -6-one, which was converted with HCl into methanol in the hydrochloride. After recrystallization from ethanol, (-) cis-7-methoxy-2-methyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one hydrochloride was obtained with fusion > 250 °, [a] 589 = -2.4 (c = 0.5, H20).

EXAMPLE 45 (-) -trans-7-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in Example 43, starting from trans-7-methoxy-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one by crystallization with (+) - O, 0 '-dibenzoyltartaric acid is obtained (+) - trans-7-methoxy-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride. After recrystallization from ethanol, (+) - trans-7-methoxy-2-methyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one hydrochloride was obtained with dot fusion > 250, +39.5 (c = 0.5, methanol). Crystallization with (-) - 0.0 '-dibenzoyltartaric acid gave (-) - cis -7-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with HCl into methanol in the hydrochloride. After recrystallization from ethanol, (-) -trans-7-methoxy-2-methyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one hydrochloride was obtained fusion > 250 °, [? T] 589 = -41.2 (c = 0.5, methanol).

EXAMPLE 46 (+) - cis-2, 7-dimethyl-l, 3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] -isoquinolin-6-one (-) - cis-2,7-dimethyl- l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [hj isoquinolin-6-one] In a similar way to that described in example 43, a Starting from cis-2,7-dimethyl-l, 3,4,4,4a, l, l-hexahydro-2H-benzo [h] isoquinolin-6-one by crystallization with (+) -O, O-dibenzoyltartaric acid was obtained (+) - cis-2,7-dimethyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with fumaric acid in ethanol in the fumarate. After recrystallization from ethanol, (+) - cis-2,7,7-dimethyl-l, 3,4-, 4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one fumarate (1: 1) was obtained. ) with a melting point of 230.5-232 °, 0. 5, H20). Crystallization with (-) - 0,0-dibenzoyltartaric acid gave (-) - cis-2,7-dimethyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinoline-6 -one, which was converted with fumaric acid into ethanol in the fumarate. After recrystallization from ethanol, (-) - cis-2,7,7-dimethyl-l, 3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one fumarate (1: 1) was obtained. ) with melting point 230.5-232 °, [a] 589 = -5.6 (c = 0.5, H20).

EXAMPLE 47 (+) - cis-2, 7, 9-trimethyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [hj-isoquinolin-6-one (-) - cis-2,7, 7-trimethyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] -isoquinolin-6-one Analogously to that described in Example 43, starting from cis-2, 7, 9-trimethyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one by crystallization with (+) - O, O '-dibenzoyltartaric acid was obtained (+) - cis-2,7-, 9-trimethyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo- [h] isoquinoline -6-one, which was converted with fumaric acid into ethanol in the fumarate. After recrystallization from ethanol, (+) - cis-2,7,9-trimethyl-1,3,4,4,4-, 10,10-hexahydro-2H-benzo [h] -isoquinalin-6-one fumarate ( 1: 1) with melting point 219-220 °, [a] 589 = +22.8 (c = 0.5, H20). Crystallization with (-) - 0,0-dibenzoyltartaric acid gave (-) - cis-2,7,7-trimethyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinoline -6-one, which was converted with fumaric acid into ethanol in the fumarate. After recrystallization from ethanol, (-) - cis-2,7-, 9-trimethyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo [hj isoquinolin-6-one (1: 1) with melting point 219-220 °, [a] 589 = -22.8 (c = 0.5, H20).

EXAMPLE 48 (-) -cis-2-methyl-1, 3, 4, 4a, 5, 10b, hexahydro-2H-benzo [h] isoquinolin-6-one (+) - cis-2-methyl-l, 3, 4, 4a, 5-10b, hexahydro-2H-benzo [h] -isoquinolin-6-one Analogously to that described in example 43, starting from cis-2-methyl-1,3,4,4,4, 5,10b-hexahydro-2H-benzo- [h] isoquinolin-6-one by crystallization with acid ( -) -O, 0'-di-p-toluyltartaric was obtained (-) - cis-2-methyl-1,3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one , which was converted with fumaric acid into ethanol in the fumarate. After recrystallization from ethanol, (-) -cis-2-methyl-1-fumarate was obtained, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [hj isoquinolin-6-one (1: 1) with melting point 206.5-208.5 °, [aj589 = -21.6 (c = 0.5, H20). Crystallization from (+) - O, 0'-di-p-toluoyltartaric acid gave (+) - cis-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with fumaric acid in ethanol in the fumarate. After recrystallization from ethanol, (+) - cis-2-methyl-1,3,4,4,4,5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one fumarate (1: 1) was obtained. melting point 207-209 °, [a] 589 = +20.8 (c = 0.5, H20).EXAMPLE 49 cis-8-fluoro-2-propyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] isoquinolin-6-one a) 0.45 g (1.92 mmol) of 8-fluoro-2-methyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one was dissolved in 6 ml of anhydrous chloroform and it was added dropwise at room temperature for 15 minutes to a solution of 244 mg (2.3 mmol) of cyanogen bromide in 2 ml of anhydrous chloroform. The mixture was then heated under reflux for a further 75 minutes, concentrated in vacuo, taken up in 12 ml of 2N hydrochloric acid and heated under reflux for 6 hours. The mixture was then basified with 3N sodium hydroxide solution and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed once with 70 ml of saturated sodium chloride solution, dried (MgSO 4) and concentrated in vacuo. 0.29 g (69%) of cis-8-fluoro-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one was obtained as a yellow oil. b) A mixture of 0.29 g (1.32 mmol) of cis-8-fluoro-1,3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, 0.12 ml (1.39 mmol) of bromopropane, 0.2 g (1.45 mmol) of potassium carbonate and 20 ml of anhydrous DMF are heated to 125 ° C for 1 hour. The mixture was then poured into 3 ml of water and extracted once with 50 ml of ethyl acetate. The organic phase was washed once with 40 ml of saturated sodium chloride solution, dried (MgSO 4) and concentrated in vacuo. The obtained crude product was purified by column chromatography on silica gel (methylene chloride / methanol / NH40H 9: 1: 0.2). 220 mg (63%) of cis-8-fluoro-2-propyl-1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [hj isoquinolin-6-one in the form of a yellow oil was obtained, which was converted with MeOH / HCl into the hydrochloride with melting point > 220 °.

EXAMPLE 50 cis-8-fluoro-2-ethyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [hj • isoquinolin-6-one In a manner analogous to that described in example 49 b), from cis-8-fluoro-1,3,4,4,4-, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one by alkylation with bromide of ethyl was obtained cis-8-fluoro-2-ethyl-l, 3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted with MeOH / HCl into the hydrochloride with melting point > 220 °.

EXAMPLE 51 cis-2-benzyl-8-fluoro-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [h] -isoquinolin-6-one In a manner analogous to that described in example 49 b), starting from cis-8-fluoro-1,3,4,4,4-, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one by alkylation with bromide of benzyl was obtained cis-2-benzyl-8-fluoro-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo- [hj isoquinolin-6-one, which was converted with MeOH / HCl into the hydrochloride with melting point > 220 °.

EXAMPLE 52 (+) -7, 9-dimethyl-2-propyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one In a manner analogous to that described in example 49 b), starting from (+) - 7, 9-dimethyl-l, 3, 4, 4a, 5, 10b-hexahdiro-2H-benzo [h] isoquinolin-6-one by alkylation with bromopropane, (+) - 7,9-dimethyl-2-propyl-l, 3,4,4,4,7,10b-hexahydro-2H-benzo [h] isoquinolin-6-one, which was converted to fumaric acid in the fumarate (1: 1) with melting point 220.5-226.5 °, [a] 569 = +33.7 (c = 0.5, H20). The (+) - 7, 9-dimethyl-1,3,4,4,4a, 5,10b-hexahydro-2H-benzofhj isoquinolin-6-one used was prepared as follows: a 2.1) 100% 0.76 ml of 2,2,2-trichloroethyl chloroformate was added to a suspension of 500 mg (2.26 mmol) of (+) - cis-2,7,7-trimethyl-1,3,4. , 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one and 120 mg of K2C03 in 20 ml of toluene and the mixture was heated under reflux for 16 hours. The solution was then cooled to room temperature and poured into 40 ml of ice-water. The aqueous phase was extracted twice with 50 ml of ethyl acetate, dried (MgSO 4), filtered and evaporated. Chromatography of the residue (silica gel, hexane / ethyl acetate 4: 1) gave 890 mg (97%) of 2,2,2-trichloroeti 1 7,9 d imet il ~ 6-oxo-3, 4, 4a , 5, 6, lOb-hexahydro-lH-benzo [h] isoquinoline-2-carboxylate in the form of a colorless oil. a 2.2) 250 mg of Zn powder was added to a solution of 890 mg (2.2 mmol) of 2,2,2-trichloroethyl-7,9-dimethyl-6-OXO-3, 4, 4a, 5, 6, lOb hexahydro-lH-benzo [h] isoquinoline-2-carboxylate in 10 ml of glacial acetic acid and the mixture was stirred at room temperature for 16 hours. The solution was filtered and adjusted to pH 10 with 28% NaOH.

The aqueous phase was extracted twice with the 30 ml of methylene chloride, dried (Na 2 SO 4), filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride / methanol / NH 4 OH 200: 10: 1) yielded 420 mg (83%) of 7,9-dimethyl-1,3,4,4a, 5,10b-hexahydro- 2H-benzo- [h] isoquinolin-6-one as a colorless oil.

EXAMPLE A In the usual way, tablets of the following composition were produced: g / compressed Active ingredient 100 Lactose powder 95 White cornstarch 35 Polyvinylpyrrolidone 8 Carboxymethyl starch of Na 10 Magnesium stearate 2 Tablet weight 250 EXAMPLE B In the usual way tablets of the following composition are produced: mg / tablet Active ingredient 200 Lactose powder 100 White corn starch 64 Polyvinylpyrrolidone 12 Carboxymethyl starch of Na 20 Magnesium stearate 4 Tablet weight 400 EXAMPLE C Encapsulates of the following composition are produced: mg / capsule Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talcum 5 Magnesium stearate 1 Weight of encapsulation 150 The active substance having an appropriate particle size, the crystalline lactose and the microcrystalline cellulose are mixed homogeneously with each other, sieved and then the talc and the magnesium stearate are added. The final mixture is filled into hard gelatin capsules of appropriate size.

It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (9)

1. Compounds of the general formula characterized in that R 1 -R 4, each independently, means hydrogen, halogen, hydroxy, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy or phenyl or R 2 and R 3 together represent -0-CH 2-0-; R5 means -C? -C7 alkyl or benzyl; and n means 0 or 1, as well as pharmaceutically acceptable acid addition salts of the compounds of formula I, with the exception of 2-methyl-1,3,4, a, 5, 10b-hexahydro-2H-benzo [h] racemic -isoquinolin-6-one.

2. Compounds of general formula I, according to claim 1, characterized in that R4 means hydrogen, R5 means methyl and n means 1

3. Compounds according to claim 2, characterized in that R 1 is hydrogen, hydroxy, halogen or methyl, R is hydrogen or ethyl and R 3 is hydrogen, methyl or methoxy.

4. Compounds according to claims 1 to 3, characterized in that they are: rae-trans-8-eti1-7-hydroxy-9-methoxy-2-methyl-1,3,4, 4a, 5, 10b-hexahydro-2H- benzo [h] isoquinolin-6-one; rac-cis-7-methoxy-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [hj isoquinolin-6-one; rac-cis-2, 9-dimethyl-l, 3,4,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-7-chloro-2-methyl-1,3,4,4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-7-fluoro-2-methyl-l, 3,4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one; rac-cis-2, 7, 9-trimethyl-l, 3, 4, 4a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one; (+) - trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo [h-isoquinoline; (+) -cis-8 - getoxi-2-methyl-l, 3, 4, 4a, 5, 10b- hexahydro-2H-benzo [h] isoquinolin-6-one; (+) - cis-2, 7-dimethyl-l, 3,4,4,4a, 5,10b-hexahydro-2H-benzo [h] isoquinolin-6-one; (+) - cis-2, 7, 9-trimethyl-l, 3,4, 4a, 5, lOb-hexahydro-2H-benzo [h] isoquinolin-6-one and (+) - cis-2-methyl- 1, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [h] isoquinolin-6-one.

5. A medicament characterized in that it contains a compound according to any of claims 1-4 and a therapeutically inert carrier material.

6. A medicament based on a compound of formula I, in accordance with the claim 1, and its pharmaceutically acceptable acid addition salts characterized for the treatment or prevention of central nervous system disorders such as depressions, dipolar disorders, anxiety states, sleep and sexual disorders, psychosis, schizophrenia, migraine and other conditions associated with cephalic pain or pain of a different type, personality disorders or obsessive-compulsive disorders, social phobias or panic states, mental disorders, mental disorders in children, aggression,. memory disorders related to age and behavior disorders, addiction, obesity, bulimia, etc., injury to the nervous system caused by trauma, attack, neurodegenerative diseases, etc .; cardiovascular disorders such as hypertension, thrombosis, attack, etc .; and gastrointestinal disorders such as motility dysfunction of the gastrointestinal tract.

7. A process for the preparation of compounds according to any of claims 1-4, characterized in that the method comprises a) cyclizing a compound of the general formula wherein R means C-C7-alkyl, to give a compound of the general formula 1A wherein the substituents Rx-R5 have the meaning set forth in claim 1, or cyclize a compound of the general formula to give a compound of the general formula wherein R1-Rs have the meaning set forth in claim 1 and R6 has the meaning set forth above in this claim, or c) alkylating or benzylating a compound of the general formula I wherein R, 5 means hydrogen, or d) dealkylating a compound of general formula I wherein R means alkyl or benzyl, or e) in a compound of the general formula I wherein at least one of R- ^ R4 signifies an alkoxy group, converting this / these to a hydroxy group (s), and f) if desired, converting the compound of formula I obtained to a pharmaceutically acceptable addition salt acceptable.

8. Compounds according to any of claims 1-4, as well as pharmaceutically acceptable salts thereof for use as therapeutically active substances.

9. The use of compounds according to any of claims 1-4 and rae. -2-methyl-l, 3, 4, 4a, 5, 10b-hexahydro-2H-benzo [hj-isoquinolin-6-one and its pharmaceutically usable salts, especially for the treatment or prevention of central nervous system disorders such such as depressions, dipolar disorders, anxiety states, sleep and sexual disorders, psychosis, schizophrenia, migraine and other conditions associated with head pain or pain of a different type, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks , mental organic disorders, mental disorders in children, aggressiveness, memory disorders related to age and behavior disorders, addiction, obesity, bulimia, etc., injury to the nervous system caused by trauma, attack, neurodegenerative diseases, etc .; disorders cardiovascular diseases such as hypertension, thrombosis, attack, etc .; and gastrointestinal disorders such as motility dysfunction of the gastrointestinal tract, and, respectively, for the production of corresponding drugs.