KR100491596B1 - New pyrimidin-4-one compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to compounds of formula (I), enantiomers and diastereomers thereof, and addition salts thereof with pharmaceutically acceptable acids and to medicaments comprising the same:

Where

R ₁ , R ₂ , R ₃ and R ₄ may be the same or different and each of them represents a hydrogen atom, a halogen atom or a group selected from alkyl, alkoxy, polyhaloalkyl, hydroxy, cyano, nitro and amino Or

R ₁ and R ₂ , R ₂ and R ₃ or R ₃ and R ₄ together with the carbon atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring,

X represents an oxygen atom or a methylene group,

A represents an alkylene chain,

Represents a substituted or unsubstituted unsaturated nitrogen-containing heterocycle,

R ₅ represents an alkyl group.

Description

Pyrimidin-4-one compounds, methods of making them, and pharmaceutical compositions containing them {NEW PYRIMIDIN-4-ONE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}

The present invention relates to novel pyrimidin-4-one compounds, methods for their preparation and pharmaceutical compositions containing them.

The invention also relates to their use as mixed α ₂ / 5-HT _2c ligands.

1,2,3,3a, 4,9b-hexahydrochromeno [3,4- c ] pyrrole compounds are described in patent application EP 691 342 for their serotonin functional antagonist properties and patent application EP 887 350 describes their D ₃ dopaminergic ligand properties.

Cortical marginal structures are an integral part of the process of controlling altered function in psychiatric diseases. In particular, current disturbances in monoamine stimulatory delivery are known to be significantly associated with the pathogenesis of these various diseases. For example, in the case of depression, monoamine stimulatory activity is reduced in the frontal cortex, hippocampus, and the left nucleus.

Among the various classes of self- and hetero-receptors of monoamines involved in the regulatory mechanisms, α ₂ -AR (autoreceptor) and 5-HT _2c receptors have been found to be very important. These two receptor sub-types act in the same direction by inhibiting dopaminergic and adrenergic delivery. On the one hand, retro-control is exerted by the α ₂ -AR (autoreceptor) receptor on noradrenergic neurons (J. Pharmacol. Exp. Ther., 1994, 270 , 958), on the other hand, α ₂ -AR receptors and 5-HT _2c heteroreceptors affect inhibitory control for dopaminergic and noradrenergic delivery. Neuropharmacology, 1997, 36 , 609, J. Psychopharmacol. 2000, 14 (2), 114-138.

Compounds that bind to one or the other of these receptor sub-types, in the past, have demonstrated the therapeutic potential of numerous pathologies.

For example, beneficial roles of α ₂ -AR antagonist compounds include cognitive impairment (J. Pharmacol., 1992, 6 , 376), Parkinson's disease (CNS Drugs, 1998, 10 , 189), schizophrenia (Science) 1999, 286 , 105-107), in the treatment of depression (J. Psychopharmacol. 1996, 10 Suppl. 3, 35-42), libido disorders, and sexual dysfunction (J. Pharmacol., 1997, 11 , 72). Was studied. In addition, 5-HT _2c receptor ligands can be used for anxiety (Br. J. Pharmacol., 1996, 117 , 427), depression (Pharmacol. Biochem. Behav. 1988, 29 , 819-820), impulsive disorder ( Biol. Psych. 1993, 33 , 3-14), anorexia (British J. Pharmacol. 1998, 123 , 1707-1715), sleep disorders (Neuropharmacology 1994, 33 (3/4), 467-471) ) And schizophrenia (Neursci. Lett., 1996, 181 , 65), as well as sexual dysfunction (J. Pharmacol., Ibid .) And Parkinson's disease (Drug News Perspect., 1999, 12 , 477) Their usefulness in the treatment of has been demonstrated.

Compounds with dual α ₂ -AR and 5-HT _2c antagonist properties can be very useful to clinicians in enhancing tolerance while enhancing action by administration of a single compound. In addition, compounds of this kind have significant advantages over the administration of two different compounds.

The compounds of the present invention are novel structures that provide dual α ₂ / 5-HT _2c antagonist properties and are characterized by depression, impulsive behavior disorders, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, anorexia and Useful for the treatment of sleep disorders.

More specifically, the present invention relates to compounds of formula (I), their enantiomers and diastereomers, and addition salts thereof with pharmaceutically acceptable acids or bases:

Where

R ₁ , R ₂ , R ₃ and R ₄ may be the same or different, each of which is a hydrogen atom, a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxy, cyano, nitro and amino, or

R ₁ and R ₂ , R ₂ and R ₃ or R ₃ and R ₄ together with the carbon atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring,

X represents an oxygen atom or a methylene group,

A represents a linear or branched (C ₁ -C ₆ ) alkylene chain,

Is a halogen atom and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cyan Substituted or substituted by one or two identical or different substituents selected from no, nitro, amino, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl and substituted or unsubstituted pyrrolyl group Unsaturated nitrogen-containing heterocycles,

R ₅ represents a linear or branched (C ₁ -C ₆ ) alkyl group,

here,

The term “(C ₁ -C ₆ ) alkyl” refers to a hydrocarbon chain containing 1 to 6 carbon atoms,

The term “(C ₁ -C ₆ ) alkoxy” refers to a (C ₁ -C ₆ ) alkyl-oxy group containing 1 to 6 carbon atoms,

The term “(C ₁ -C ₆ ) alkylene” refers to a divalent hydrocarbon chain containing 1 to 6 carbon atoms,

The term (C ₁ -C ₆ ) polyhaloalkyl denotes a carbon chain containing 1 to 6 carbon atoms and 1 to 9 halogen atoms,

The term “heteroaromatic ring” denotes a five or six membered aromatic ring containing one, two or three hetero atoms selected from oxygen, nitrogen and sulfur,

The term "unsaturated nitrogen-containing heterocycle" has one, two or three unsaturated groups and contains one, two or three hetero atoms, one of these hetero atoms being a nitrogen atom and oxygen, nitrogen and A 5-7 membered unsaturated ring, with or without additional hetero atom (s) selected from sulfur atoms,

-The term "substituted or unsubstituted" as applied to "benzene ring", "heteroaromatic ring", "phenyl", "thienyl", "furyl" or "pyrrolyl" means "benzene ring", "heteroaromatic" Ring, “phenyl”, “thienyl”, “furyl” or “pyrrolyl” group is a halogen atom and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ Unsubstituted or substituted by one or two identical or different substituents selected from alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cyano, nitro and amino groups.

Pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methane Sulphonic acid, camphoric acid, oxalic acid and the like can be mentioned, but are not limited to these.

Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, and the like.

Heteroaromatic rings may include, but are not limited to, thiophene, pyridine, furan, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine.

Preferred unsaturated nitrogen-containing heterocycles are 1,2-dihydropyridine, 2,3-dihydro-1,3-thiazole and 2,3-dihydro-oxazole.

A (3aα, 9bα) or (3aβ, 9bβ) compound is understood to mean a compound whose associated ring linkage is cis stereoconfiguration.

(3a [alpha], 11c [alpha]) or (3a [beta], 11c [beta]) compounds are understood to mean compounds in which the related ring linkages are cis stereoconfiguration.

(3aα, 9bβ) or (3aβ, 9bα) compounds is understood that the associated connecting ring means that the compound trans (trans).

(3a [alpha], 11c [beta]) or (3a [beta], 11c [alpha]) compounds are understood to mean compounds in which the related ring linkage is trans.

In preferred compounds of formula (I), R ₁ , R ₂ , R ₃ and R ₄ may be the same or different, each of which is a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched A (C ₁ -C ₆ ) alkoxy or hydroxy group.

Preferred compounds of the present invention are compounds in which R ₁ and R ₂ together with the carbon atom to which they are bonded form a benzene ring and R ₃ and R ₄ each represent a hydrogen atom.

X preferably represents an oxygen atom.

The present invention advantageously relates to compounds of formula (I) in which A represents ethylene, propylene or butylene chains.

More particularly, the present invention Divalent halogen atoms and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cya Groups unsubstituted or substituted by one or two identical or different substituents selected from no, nitro, amino and thienyl groups It relates to a compound of formula (I).

Other preferred compounds of the invention Divalent halogen atoms and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cya Groups unsubstituted or substituted by one or two identical or different substituents selected from no, nitro and amino groups Is a compound of formula (I).

More particularly, in the present invention, A represents an ethylene chain, X represents an oxygen atom, R ₅ represents a methyl group, Are unsubstituted or substituted at the 2'-position by a halogen atom or a group selected from linear or branched (C ₁ -C ₆ ) alkyl, cyano and thienyl The present invention relates to a compound of formula (I).

Preferred compounds of the invention may more particularly be mentioned the following compounds:

3- [2-((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] pyrrole-2 ( 3H ) -yl) -ethyl] -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one and its enantiomers, diastereomers and addition salts thereof with pharmaceutically acceptable acids,

● 3- [2 - ((3aα , 11cα) -1,3a, 4,11c- tetrahydro-benzo [5,6] chroman Agate [3,4-c] pyrrol -2 (3 H) - yl) - ethyl ] -2-methyl- 4H -pyrido [1,2-a] pyrimidin-4-one and its enantiomers and addition salts thereof with pharmaceutically acceptable acids, and

● 3- [2 - ((3aβ , 11cα) -1,3a, 4,11c- tetrahydro-benzo [5,6] chroman Agate [3,4- c] pyrrole -2 (3 H) - yl) ethyl] 2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one and its enantiomers and addition salts thereof with pharmaceutically acceptable acids.

The present invention further provides a compound of formula (III) by catalytically hydrogenating a compound of formula (II), reacting a compound of formula (III) with a compound of formula (IV), or reducing Reaction with a compound of formula (V) to give a compound of formula (I) under conditions of amination, if necessary purifying according to conventional purification techniques, and, if desired, stereoisomers thereof according to conventional separation techniques. , And, if desired, to convert to addition salts with pharmaceutically acceptable acids or bases thereof, to produce a compound of formula (I):

Where

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, B, X are as defined for formula (I) and Y ₁ represents a halogen atom or leaving group such as tosylate, triflate or mesylate group , A 'represents a single bond or a linear or branched (C ₁ -C ₅ ) alkylene chain.

A compound of formula (II) wherein X represents an oxygen atom (a compound of formula (IIa)) is a compound of formula (VI) K. Achiwa et al., Chem. Pharm. Bull. Cycloaddition reaction with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine under the conditions described in 1985, 33 (7), 2762-66 to give a compound of formula (VII) The compound of formula (VII) is then converted to the compound of formula (VIII) by reduction followed by deprotection of the phenol functional group, and then the compound of formula (VIII) is subjected to Mitsunobu reaction. It can be obtained by converting to a compound of formula (IIa):

Where

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

The stereoconfiguration of the ring linkages of the obtained compound of formula (IIa) was determined by the stereoconfiguration (Z or E) of the compound of formula (VI) used.

Further, the compound of formula (IIa) is oxidized to a compound of formula (X) by using a compound of formula (IX) as a starting material, and reacting a compound of formula (X) with methyl propiolate to Coumarin)

If coumarin of formula (XI) is to be prepared with a compound of formula (IIa) in which the ring linkage is trans, it is reacted with sodium methanolate and then K. Akiwa et al., Chem. Pharm. Bull. 1985, 33 (7), 2762-66, under an addition ring reaction with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine, followed by a reduction reaction, wherein the steric configuration is trans. Obtaining the compound of VIII) and then converting it to a trans compound of formula (IIa) by Mitsunobu reaction,

If it is desired to prepare a compound of formula (IIa) wherein the ring linkage is cis, k. Akiwa et al., Chem. Pharm. Bull. 1985, 33 (7), 2762-66 under cycloaddition reaction with N-benzyl-N- (methoxymethyl) -trimethyl-silylmethylamine, wherein the ring linkage is cis. Compounds can be obtained and then reduced to form compounds of formula (VIII) with stereoconfiguration cis, and then converted to cis compounds of formula (IIa) by Mitsunobu reaction:

Where

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

A compound of formula (II), wherein X represents a methylene group (a compound of formula (IIb)), uses a compound of formula (XIII) as a starting material and reacts with ethyl acrylate to obtain a compound of formula (XIV) And converting the compound of formula (XIV) to a compound of formula (XV) by reduction followed by hydrolysis and cyclizing the compound of formula (XV) to form a compound of formula (XVI) XVI) is converted into a compound of formula (XVIII) by converting the compound of formula (VI) to a compound of formula (XVII) and then adding lithium cyanide and condensing the cyano group of the compound of formula (XVIII) To obtain a compound of formula (XIX), and then reacting a compound of formula (XIX) with benzylamine to obtain a compound of formula (XX), and a compound of formula (XX) to ring By converting a compound of formula (IIb) can be obtained by:

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) together with one or more inert and nontoxic pharmaceutically acceptable excipients as active ingredients. The pharmaceutical compositions according to the invention more particularly those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, Dermal gels, injectable preparations, drinking suspensions and the like can be mentioned.

Useful dosages may vary depending on the nature and severity of the disease, the route of administration and the age and weight of the patient and any associated therapy. Dosages vary from 0.5 mg to 2 g per 24 hours in one or more administrations.

The following examples illustrate the invention but do not limit the invention in any way.

The starting materials used are known products or prepared according to known production methods.

The structure of the compound described in the Examples was determined by conventional spectroscopic techniques (infrared, NMR, mass spectroscopy).

Example 1 : 3- [2-((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one dihydrochloride

Step A : Methyl (3α, 4α) -1-benzyl-4- (2,6-dimethoxyphenyl) -3-pyrrolidine-carboxylate

N-benzyl-N- (methoxymethyl) trimethylsilyl in a solution of 120 mmol of cis- (2,6-dimethoxy) cinnamic acid methyl ester and 0.1 ml of trifluoroacetic acid in 150 ml of ethyl acetate, cooled to 5 ° C 100 mmol of methylamine was added slowly. The reaction mixture was heated from 30 ° C. to 55 ° C. over 75 minutes. Then 0.75 g of potassium carbonate was added and the mixture was stirred for 15 minutes. After filtration and evaporation of the solvent, the residue was dissolved in 100 ml of ethyl acetate and the solution was heated at 50 ° C. Then 110 mmol of oxalic acid dissolved in 100 ml of acetone were added with vigorous stirring for 15 hours. After filtration and washing with ether, the resulting oxalate was treated with 2 equivalents of 1N potassium hydroxide solution to afford the title product.

Step B : (3α, 4α) -1-benzyl-3-hydroxymethyl-4- (2,6-dimethoxyphenyl) -pyrrolidine

To 120 mmol of lithium aluminum hydride suspended in 800 ml of tetrahydrofuran at 5 ° C., 100 mmol of the compound obtained in the previous step dissolved in 400 ml of tetrahydrofuran was added. After stirring for 1 hour at the same temperature, the mixture was treated by slowly adding 11 ml of water, 15 ml of 2N sodium hydroxide and 26 ml of water. The mixture was stirred for 10 hours and then filtered. Evaporation of the solvent gave the title product.

Step C : (3α, 4α) -1-benzyl-3-hydroxymethyl-4- (2,6-dihydroxyphenyl) -pyrrolidine

To 8.9 mmol of the compound obtained in the previous step in 170 ml of dichloromethane, 44.5 ml of a 1M solution of boron tribromide in dichloromethane was added. The reaction mixture was heated at reflux for 8 hours and then treated with concentrated sodium hydroxide solution for 1 hour. The mixture was then neutralized with hydrochloric acid. After extraction with dichloromethane, the title product is obtained after purification of the residue by chromatography on silica (eluent: dichloromethane / methanol 95/5).

Step D : (3aα, 9bα) -2-benzyl-9-hydroxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] -pyrrole hydrochloride

To 80 mmol of the compound obtained in the previous step in 1 liter of tetrahydrofuran, 120 mmol of diethyl azodicarboxylate and 120 mmol of triphenylphosphine were added successively. The mixture was stirred at ambient temperature for 15 hours. The solvent was evaporated and the crude product was dissolved in 1 liter of isopropyl ether and heated at reflux for 1 hour. The resulting precipitate was removed and the filtrate was concentrated and then chromatographed (eluent: cyclohexane / ethyl acetate 70/30). The product obtained was converted to salt using hydrochloric acid.

Step E : (3aα, 9bα) -benzyl-9-methoxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] -pyrrole hydrochloride

11.6 mmol of the compound obtained in the previous step in 50 ml of dimethylformamide was added to a solution containing 14 mmol of sodium hydride in 50 ml of dimethylformamide. After stirring for 30 minutes, 11.6 mmol of methyl iodide was added. After being left at ambient temperature for 1 hour and then hydrolyzed, the solvent was evaporated. The residue was dissolved in water. After extraction with ether, drying and evaporation, the residue was purified by chromatography on a silica column using a mixture of cyclohexane / ethyl acetate (75/25) as eluent to afford the title product.

Elemental Trace Analysis :

C% H% N% Cl% Calculation 68.77 6.68 4.22 10.68 Found 68.66 4.48 4.45 10.97

Step F : (3aα, 9bα) -9-methoxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole

50 mmol of the compound obtained in the previous step were dissolved in a mixture of 200 ml of methanol and 50 ml of water. 50 mmol of a 5N solution of hydrochloric acid in ethanol was added. After adding 2 g of palladium hydroxide, the reaction mixture was placed under hydrogen atmosphere. After the theoretical volume of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The resulting residue was treated with 1N sodium hydroxide solution and extracted with dichloromethane to afford the title product.

Step G : 3- [2-((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4-c] -pyrrol-2- (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one dihydrochloride

To 7 mmol of the compound obtained in the previous step in 100 ml of acetonitrile 7 mmol of potassium carbonate was added. The mixture was heated to 60 ° C. 3- (2-chloroethyl) -2-methylpyrido [1,2-a] pyrimidin-4-one [prepared according to Liebigs Ann. Chem. 1973, 103-110] 7 mmol was added all at once. The mixture was heated at 80 ° C. for 18 h. After cooling and adding water, the mixture was extracted with dichloromethane and then washed and dried. After filtration and evaporation of the solvent, the resulting residue was purified by chromatography on silica (eluent: dichloromethane / methanol 95/5). The resulting product was converted to salt using hydrochloric acid.

Elemental Trace Analysis :

C% H% N% Cl% Calculation 59.49 5.86 9.05 15.27 Found 59.57 5.89 9.09 15.41

Example 2 : 3- [2-((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H -Pyrido [1,2- a ] -Pyrimidin-4-one sesquifumarate

Step A : 2,4-dimethoxy-3-methyl-phenol

To 416 mmol of 2,4-dimethoxy-3-methyl-benzaldehyde dissolved in 200 ml of dichloromethane, 624 mmol of meta-chloroperbenzoic acid was added. The reaction mixture was heated at reflux for 5 hours and then filtered. The filtrate was washed three times with 200 ml of saturated NaHCO ₃ solution and then dried over magnesium sulfate. After evaporating the solvent, the crude product was dissolved in 400 ml of methanol. 624 mmol of 10% KOH solution was added. The mixture was stirred for 1 hour and then adjusted to pH = 4 with 1N hydrochloric acid solution. After stirring for 1 hour, the volume was reduced to 1/3. The crude product was dissolved in 400 ml of water and extracted with dichloromethane. The organic phase was collected and dried. After evaporation of the solvent, the resulting residue was purified by chromatography on a silica column (eluent: cyclohexane / ethyl acetate 90/10) to afford the title product.

Step B : 6,8-dimethoxy-7-methyl-coumarin

270 mmol of methyl propiolate was added to 270 mmol of the compound obtained in the previous step dissolved in 500 ml of anhydrous methanesulfonic acid. The reaction mixture was heated at 90 ° C. for 30 minutes and then cooled to 0 ° C. After the slow addition of water, the mixture was extracted with dichloromethane. The organic phase was collected, washed with 1N sodium hydroxide solution and dried. After evaporation of the solvent, the resulting residue was triturated in ethyl ether and then filtered to afford the title product.

Step C : (3α, 4α) -1-benzyl-3-hydroxymethyl-4- (3,5-dimethoxy-2-hydroxy-4-tolyl) -pyrrolidine

According to the preparation described in steps A and B of Example 1, the compound obtained in the previous step was used as starting material to give the title product.

Step D : (3aα, 9bα) -2-benzyl-6,8-dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydro-chromeno [3,4-c] pyrrole hydrochloride

According to the preparation described in Step D of Example 1, the title product was obtained using the compound obtained in the previous step as starting material.

Elemental Microanalysis :

C% H% N% Cl% Calculation 67.10 6.97 3.73 9.43 Found 66.90 7.00 3.92 9.57

Step E : (3aα, 9bα) -6,8-dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno- [3,4-c] pyrrole

According to the preparation described in step F of example 1, using the compound obtained in the previous step as starting material, the title product was obtained.

Step F : 3- [2-((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromeno- [3,4-c] pyrrole-2- (3H ) -Yl) -ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one sesquifumarate

According to the preparation described in Step G of Example 1, the compound obtained in the previous step was used as starting material to give the title product. The resulting product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 61.07 5.80 6.89 Found 61.73 6.03 7.19

Example 3 3- [2- (1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A : 1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Following the preparation described in steps C to F of Example 2, benzo [ f ] chromen-3-one was used as starting material to afford the title product.

Step B : 3- [2- (1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) -ethyl] -2-methyl-4H -Pyrido [1,2-a] pyrimidin-4-one fumarate

According to the preparation described in Step G of Example 1, the compound obtained in the previous step was used as starting material to give the title product.

Elemental Microanalysis :

C% H% N% Calculation 68.30 5.54 7.96 Found 67.87 5.57 7.79

Example 4 : 6- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) -ethyl] -7-methyl-5 H -[1,3] thiazolo [3,2- a ] Pyrimidine-5-one fumarate

The compound described in step A of example 3 and 6- (2-chloro-ethyl) -7-methyl-thiazolo [3,2-a], according to the preparation described in step G of example 1, as a starting material Pyrimidin-5-one was used to give the title product.

Elemental Microanalysis :

C% H% N% S% Calculation 63.03 5.10 7.87 6.01 Found 62.91 5.08 7.77 5.83

Example 5 : 3- [3-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) propyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one hemifumarate

Step A 3- (2-methyl) -4-oxo-pyrido [1,2-a] pyrimidin-3-yl) -propionaldehyde

3- (2-Chloro-ethyl) -2-methyl-pyrido [1,2-a] pyrimidin-4-one in 140 ml of dimethyl sulfoxide [Liebigs Ann. Chem. 1973, 103-110 120 mmol potassium cyanide was added to 60 mmol. The reaction mixture was heated at 100 ° C. for 3 hours. After evaporation of dimethyl sulfoxide, the crude product was dissolved in dichloromethane and water and extracted with dichloromethane. The organic phase was washed and dried. The residue was purified by chromatography on silica (eluent: dichloromethane / methanol 95/5) and the resulting product was dissolved in 100 ml of dichloromethane. The mixture is cooled to −70 ° C .; 120 mmol of diisobutyl aluminum hydride was introduced. After stirring for 2 hours at the same temperature, the mixture was treated with 50 ml of methanol and 100 ml of water; The organic phase was then washed and dried to give the title product.

Step B : 3- [3-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) propyl]- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one hemifumarate

To 10 mmol of the compound described in Step A of Example 3 dissolved in 1,2-dichloroethane, 10 mmol of the compound obtained in the previous step, followed by 14 mmol of sodium triacetoxyborohydride. After stirring for 4 hours, water is added; The reaction mixture was then separated and extracted with dichloromethane. The combined organic phases were dried then filtered and evaporated. The resulting residue was purified by chromatography on silica (eluent: dichloromethane / methanol 95/5) to give the title product after conversion to the salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 72.03 6.04 8.69 Found 71.68 5.95 8.59

Example 6 : 3- {2-[(3aα, 11cα) -1,3,3a, 4,5,11c-hexahydro-2 H Naphtho [1,2- e ] -Isoindol-2-yl] ethyl} -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A : 2-chloromethyl-naphthalene

3.8 mol of thionyl chloride was slowly added to 1.26 mol of naphth-2-yl-methanol in 1.5 liters of toluene. Then the mixture was heated at reflux for 2 hours. After cooling, the solvent was evaporated. The crude product was dissolved twice in toluene and evaporated. The resulting oil was dissolved in dichloromethane, washed and dried. After filtration and evaporation, the resulting oil was distilled off to give the title product.

Boiling Point : 118 ° C under Hg 0.09 mm

Step B : Ethyl 4- (2-naphthyl) -2-butenoate

To 863 mmol of the compound obtained in the previous step in 206 ml of tri-butylamine, 1.07 mol of ethyl acrylate and 10 mmol of palladium acetate were added. The reaction mixture was heated at reflux for 5 hours. After cooling, the mixture was hydrolyzed and extracted once with dichloromethane. The organic phase was washed with 1N hydrochloric acid solution and then with water and then dried. The product was purified by chromatography on silica (eluent: cyclohexane / ethyl acetate 95/5) to afford the title product.

Step C : Ethyl 4- (2-naphthyl) -2-butanoate

To 490 mmol of the compound obtained in the previous step in 3 liters of ethanol was added 7 g of 10% palladium-on-carbon. The mixture was then placed under hydrogen atmosphere. After the theoretical amount of hydrogen has been absorbed, the mixture is filtered and the solvent is evaporated to yield the title product.

Step D : 4- (2-naphthyl) -2-butanoic acid

To 484 mmol of the compound obtained in the previous step in 1.5 liters of ethanol, 490 ml of a titrated 2N sodium hydroxide solution was added. The mixture was heated and kept under reflux for 1 hour. Then ethanol was evaporated. The pH was adjusted to 5-6 with 1N hydrochloric acid. The precipitate formed was filtered off and washed with water to afford the title product.

Step E : 2,3-dihydro-4 (1H) -phenanthrenone

To 550 g polyphosphoric acid was added 240 mmol of the compound obtained in the previous step. The reaction mixture was heated at 80 ° C. for 3 hours and then poured on ice. After stirring for 1 hour, the formed precipitate was filtered, washed with water and dried to give the title product.

Step F : 1,2-dihydro-4-phenanthrene-carbonitrile

To 207 mmol of the compound obtained in the previous step in 500 ml of tetrahydrofuran were added successively 243 mmol of trimethylsilane cyanide, followed by 16 mmol of a 0.5 M solution of lithium cyanide in dimethylformamide. The reaction mixture was stirred for 2 hours and then poured onto ice and extracted four times with ether. The organic phase was collected, washed with water and dried. After filtration, the solvent was evaporated. The residue was dissolved in 325 ml of pyridine. 42 ml of POCl ₃ were added. The mixture was heated at 100 ° C. for 3 hours and then cooled and poured onto 400 ml of ice cold hydrochloric acid. After addition of dichloromethane, the mixture was separated and then extracted with dichloromethane. The combined organic phases were washed and dried. After filtration, the solvent was evaporated. The resulting residue was purified by chromatography on silica (eluent: cyclohexane / dichloromethane: 70/30) to afford the title product.

Step G : 1,2,3,4-tetrahydro-phenanthrene-3,4-dicarbonitrile

To 87 mmol of acetic acid was added 105 mmol of a 0.5 M solution of lithium cyanide followed by 82 mmol of the compound obtained in the previous step dissolved in 500 ml of dimethylformamide at 5 ° C. The reaction mixture was heated at 100 ° C. for 2 hours, then cooled and dried and poured on ice. The resulting precipitate was filtered off and washed to give the title product.

Step H : 1,2,3,4-tetrahydro-phenanthrene-3,4-dicarboxylic acid

To 68 mmol of the compound obtained in the previous step, 42 ml of acetic acid followed by 84 ml of concentrated hydrochloric acid were added successively. The reaction mixture was heated at reflux for 5 days, then cooled and poured into 1 liter of water. The product was extracted with ethyl acetate. The organic phase was collected and dried. After filtration and evaporation of the solvent, the resulting residue was purified by chromatography (eluent: dichloromethane / methanol / acetic acid: 95/5 / 0.5) to afford the title product.

Step I : (3aα, 11cα) -3a, 4,5,11c-tetrahydrophenanthro [3,4-c] furan-1,3-dione

To 37 mmol of the compound obtained in the previous step, 1.67 mol of acetic anhydride was added. The reaction mixture was heated at reflux for 2 hours and then evaporated to dryness. The resulting residue was triturated in ether to afford the title product in crystalline form.

Step J : (3aα, 11cα) -2-benzyl-3a, 4,5,11c-tetrahydro-1H-naphtho [1,2-e] isoindole-1,3 (2H) -dione

18 mmol of benzylamine was added to 18 mmol of the compound obtained in the previous step in 400 ml of toluene. The reaction mixture was heated at reflux for 30 hours. 70 ml of 0.1N hydrochloric acid solution was added. The mixture was separated. The organic phase is dried, filtered and then evaporated. The resulting residue was purified by chromatography on silica (eluent: dichloromethane / cyclohexane: 60/40) to afford the title product.

Step K : (3aα, 11cα) -2-benzyl-2,3,3a, 4,5,11c-hexahydro-1H-naphtho [1,2-e] -isoindole hydrochloride

180 ml of anhydrous ether was poured into 93 mmol of lithium aluminum hydride. After cooling to 10 ° C., 15.5 mmol of the compound obtained in the previous step dissolved in 250 ml of dichloromethane was added. The reaction mixture was stirred at ambient temperature for 2 hours and then cooled to -10 ° C. 90 ml of water were added slowly. The resulting gel was filtered and washed with a large amount of dichloromethane. The organic phase and filtrate were combined and separated. The organic phase is dried, filtered and then evaporated. The resulting residue was purified by chromatography on silica (eluent: cyclohexane / ethyl acetate 80/20). The resulting product was converted to salt using hydrochloric acid.

Elemental Microanalysis :

C% H% N% Cl% Calculation 78.95 6.91 4.00 10.13 Found 78.60 6.99 4.28 10.04

Step L : 3- {2-[(3aα, 11cα) -1,3,3a, 4,5,11c-hexahydro-2H-naphtho [1,2-e] isoindol-2-yl] ethyl} -2 -Methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

According to the preparation described in steps F and G of Example 1, the compound obtained in the previous step was used as starting material to give the title product. The resulting product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 70.49 5.88 7.85 Found 70.84 5.94 7.99

Example 7 : 3- [2-((3aα, 9bβ) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H -Pyrido [1,2- a ] -Pyrimidin-4-one sesquifumarate

Step A Trans- (3,5-dimethoxy-6-hydroxy-6-methyl) -cinnamic acid methyl ester

To 70 mmol of the compound obtained in step B of Example 2 in 100 ml of methanol was slowly added 205 mmol of a 30% solution of sodium methylate in methanol. The reaction mixture was heated at reflux for 4 hours and then hydrolyzed with 1N hydrochloric acid solution. The precipitate was filtered off, washed with water and dried to afford the title product.

Step B : (3aα, 9bβ) -2-benzyl-6,8-dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydro-chromeno [3,4-c] pyrrole hydrochloride

According to the preparation described in steps C and D of Example 2, the title product was obtained using the compound obtained in the previous step as starting material.

Elemental Microanalysis :

C% H% N% Cl% Calculation 67.10 6.97 3.73 9.43 Found 67.15 7.13 3.76 9.73

Step C : 3- [2-((3aα, 9bβ) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4-c] pyrrole-2 (3H) -Yl) -ethyl] -2-methyl-4H-pyrido [1,2-a] -pyrimidin-4-one sesquifumarate

According to the preparation described in steps F and G of Example 1, the compound obtained in the previous step was used as starting material to give the title product. The resulting product was converted to salt using fumaric acid.

Example 8 3- [2- (1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c Pyrrole-2 (3) H ) -Yl) ethyl] -7-chloro-2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A : 7-chloro-3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

The product was prepared according to the preparation described in Liebigs Ann. Chem. 1973, 103-110, using 2-amino-5-chloropyridine as starting reaction.

Step B : 3- [2- (1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl] -7-chloro-2- Methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

Following the preparation described in Step G of Example 1, the title product was obtained using the compound described in the previous step and the compound obtained in Step A of Example 3 (the product was converted to a salt using fumaric acid). .

Elemental Microanalysis :

C% H% N% Cl% Calculation 63.21 4.97 7.18 6.08 Found 62.98 5.08 7.03 6.19

Example 9 : 3- [2-((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

According to the preparation described in Example 2, instead of 3- (2-chloroethyl) -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one as starting material The title product was obtained using 7-chloro-3- (2-chloroethyl) -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one prepared in Step A. The resulting product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Cl% Calculation 59.44 5.5 7.17 6.05 Found 58.94 5.43 6.97 6.34

Example 10 : 6- [2-((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-methyl-5 H -[1,3] thiazolo [3,2- a ] Pyrimidine-5-one fumarate

Step A : (3aα, 9bα) -6-methoxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole

The product was prepared following the preparation of steps A to F of Example 1 using cis- (2,3 dimethoxy) cinnamic acid as starting material.

Step B : 6- [2-((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl] -7 -Methyl-5H- [1,3] thiazolo [3,2-a] pyrimidin-5-one fumarate

Using the compound prepared in the previous step as a starting material and following the method used in step G of the example 1, 6- (2-chloroethyl) -7-methyl-5 H- [1,3] thiazolo [3 , 2- a ] pyrimidin-5-one gave the title product. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% S% Calculation 58.47 5.30 8.18 6.24 Found 58.78 5.22 8.27 6.20

Example 11 : 3- [2-((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

The compound described in step A of example 10 and 3- (2-chloroethyl) -2-methyl-4 H -pyrido [1,2- as a starting material according to the preparation described in step G of example 1 a ] pyrimidin-4-one was used to give the title product.

Elemental Microanalysis :

C% H% N% Calculation 63.90 5.76 8.28 Found 63.03 5.77 7.91

Example 12 : 3- [2-((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-bromo-2-methyl-4 H -Pyrido [1,2- a ] -Pyrimidin-4-one fumarate

Step A 3- (2-chloroethyl) -7-bromo-2-methyl-4H-pyrido- [1,2-a] pyrimidin-4-one

The product was prepared following the preparation described in Step A of Example 8 using 2-amino-5-bromopyridine as the starting reactant.

Step B : 3- [2-((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl] -7 -Bromo-2-bromo-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

Following the preparation described in Example 11, the title product was obtained using the compound of Example 10 and the pyrimidinone prepared in the previous step as starting material. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Br% Calculation 55.30 4.81 7.17 13.63 Found 55.02 4.75 7.12 13.81

Example 13 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2,7-dimethyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A 3- (2-chloroethyl) -2,7-dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one

Following the preparation described in step A of Example 8, the product was prepared using 2-amino-5-methylpyridine as starting reactant.

Recipe B : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl]- 2,7-dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

According to the preparation described in Step G of Example 1, using the compound prepared in the previous step and the compound of Step A of Example 3 as starting materials, the title product was obtained. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 68.75 5.77 7.76 Found 67.96 5.60 7.67

Example 14 : 3- [2-((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) ethyl] -2,7-dimethyl-4 H -Pyrido- [1,2- a ] Pyrimidin-4-one fumarate

According to the preparation described in step G of example 1, the title product was obtained using the compound obtained in step A of example 13 and the product of step E of example 2 as starting materials. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 63.70 6.24 7.43 Found 63.57 6.09 7.36

Example 15 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-bromo-2-methyl-4 H -Pyrido [1,2- a ] -Pyrimidin-4-one fumarate

The title product was obtained using the compound obtained in step A of example 3 together with the product obtained in step A of example 12 as a starting material, according to the preparation described in step G of example 1. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Br% Calculation 59.41 4.65 6.93 13.18 Found 59.04 4.69 6.81 12.93

Example 16 : 3- [2-((3aα, 9bα) -6-hydroxy-8-methoxy-7-methyl-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A : (3aα, 9bα) -2-benzyl-8-methoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno- [3,4-c] pyrrole-6-ol

At 0 ° C., 64 ml of a 1 molar solution of boron tribromide in dichloromethane were added to a solution of 20 g of the compound described in Step D of Example 2. After stirring at 20 ° C. for 3 hours, 200 ml of saturated sodium hydrogen carbonate solution was hydrolyzed and the organic phase was separated. The resulting residue was purified by chromatography on silica gel using a mixture of dichloromethane / methanol: 98/2 as eluent.

Step B : (3aα, 9bα) -8-methoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] -pyrrole-6-ol

The product prepared in the previous step was dibenzylated by applying the recipe described in step F of Example 1.

Step C : 3- [2-((3aα, 9bα) -6-hydroxy-8-methoxy-7-methyl-1,3a, 4,9b-tetrahydro-chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl] -2-methyl-4H-pyrido [1,2-a] -pyrimidin-4-one fumarate

The compound described in the previous step and the 3- (2-chloroethyl) -2-methyl-4 H -pyrido [1,2- a ] pyrimidine according to the preparation described in step G of Example 1, but as starting reactants 4-one was used to yield the title product. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 62.56 5.81 7.82 Found 61.61 5.97 7.42

Example 17 : 3- [4- (3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) butyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one, fumarate

Step A 3- (3-butenyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

5.7 g of methyl 2-acetyl-5-hexenoate, 3.15 g of 2-aminopyridine and 0.65 g of polyphosphoric acid were heated at 160 ° C. for 2 hours. Then, under cooling conditions, 30 ml of water were added and the mixture was extracted using dichloromethane. After evaporation of the solvent the resulting residue was purified by chromatography on silica gel using a mixture of dichloromethane / methanol: 98/2 as eluent.

Step B : 3-butyl-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

55.2 ml of a 1 molar solution of borane in tetrahydrofuran were added to a solution of 5.4 g of product obtained in the previous step in 100 ml of tetrahydrofuran. After 1 hour, cooled to 0 ° C. and 10 ml of water followed by 25.4 g of sodium borate. Stirred for 1 hour and then the mixture was concentrated; The residue was dissolved in 100 ml of water and dichloromethane was extracted. After evaporation of the solvent, the resulting residue was purified by chromatography on silica gel using a mixture of dichloromethane / methanol: 98/2 as eluent.

Step C 4- (2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) butanal

A mixture of 4.5 g of the product obtained in the previous step with 8.1 g of 1-hydroxy-1-oxo-benzo [ d ] [1,2] iodoxol-2-one in 200 ml of tetrahydrofuran under reflux for 3 hours Heated. Filtered on cool and concentrated the filtrate.

Step D : 3- [4- (3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) -butyl]- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

The rest of the synthesis was carried out by applying the recipe described in step B of Example 5, using the aldehyde obtained in the previous step as starting material. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 68.06 5.89 7.26 Found 67.25 5.85 6.82

Example 18 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one, fumarate

Step A (3aα, 11cα) -1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Separation of racemate 1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4- c ] pyrrole: the product obtained in step A of Example 3 in 450 ml of ethanol 53.6 g were dissolved and heated to reflux. 85.2 g of (+) 2,3-dibenzoyl-D-tartaric acid in 450 ml of ethanol were added. After 12 hours the precipitate was filtered off. The booker precipitate was recrystallized three times with a mixture of ethanol / water: 85/15. The compound was obtained in the form of base after treatment with aqueous sodium hydroxide solution.

Step B : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl]- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

Enantiomer and 3- (2-chloroethyl) -2-methyl- 4H -pyrido [1,2- a ] prepared in the previous step as starting material, according to the preparation described in step G of Example 1 Pyrimidin-4-one was used to give the title product.

The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 68.30 5.54 7.96 Found 68.24 5.41 8.12

Example 19 : 3- [2-((3aβ, 11cβ) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one, fumarate

Step A (3aβ, 11cβ) -1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Isolation of racemates: 1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

In 200 ml of ethanol 10.3 g of the product obtained in step A of Example 3 were dissolved and heated under reflux. A solution of 16.4 g of (-) 2,3-dibenzoyl-L-tartaric acid in 200 ml of ethanol was added. After 12 hours the precipitate was filtered off. Ethanol / water: The precipitate was recrystallized three times from a mixture of 85/15. The compound was obtained in the form of base after treatment with aqueous sodium hydroxide solution.

Step B : 3- [2-((3aβ, 11cβ) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl]- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

Enantiomer and 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyridine, prepared according to the preparation described in Step G of Example 1, as a starting material Midin-4-one was used to give the title product.

The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 68.30 5.54 7.96 Found 68.85 5.45 7.81

Example 20 : 3- [2-((3aα, 9bα) -6,8-dimethoxy-7-propyl-1,3a, 4,9b-tetrahydro-chromeno [3,4- c ] Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] -Pyrimidin-4-one fumarate

Step A : 2-allyloxy-4-methoxybenzaldehyde

To a solution of 100 g of 2-hydroxy-4-methoxybenzaldehyde in 2 liters of acetone, 79.5 ml of allyl bromide were added slowly followed by 272 g of potassium carbonate. Heated at reflux for 4 hours and then filtered; The filtrate was concentrated in vacuo, the residue dissolved in 1 liter of chloromethane and the solution washed with 1N sodium hydroxide solution followed by saturated sodium chloride solution. Dry over magnesium sulfate and concentrate in vacuo.

Step B : 3-allyl-2-hydroxy-4-methoxybenzaldehyde

The solution of 125 g of the product obtained in step A in 300 ml of N, N -dimethylaniline was heated at 200 ° C. for 15 hours. Then evaporate the solvent under vacuum and dissolve the residue in 1 liter of isopropyl ether; The solution was extracted 10 times with 100 ml of 1N sodium hydroxide and then the combined extracts were acidified with 3N hydrochloric acid. Then acidic aqueous solution was extracted with dichloromethane, dried and the organic phase was concentrated.

Step C : 3-allyl-2,4-dimethoxybenzaldehyde

A mixture of 108 g of the product obtained in the previous step in 2 liters of acetone, 74.4 g of dimethyl sulfate and 233 g of potassium carbonate was heated at reflux for 5 hours. Filtered on cool and concentrated the resulting solution. The residue was dissolved in isopropyl ether and washed with saturated sodium bicarbonate followed by water. Dry over magnesium sulfate and evaporate the solvent under vacuum. The residue was purified by chromatography on silica gel using a mixture of cyclohexane / ethyl acetate: 96/4 as eluent.

Step D 2,4-dimethoxy-3-propylbenzaldehyde

64 g of the product obtained in step C at ambient temperature under atmospheric pressure were hydrogenated using 35 g of Wilkinson's catalyst [tris (triphenylphosphine) rhodium chloride] in 500 ml of benzene. The product was purified by chromatography on silica gel using a mixture of cyclohexane / ethyl acetate: 92/8 as eluent.

Step E : 3- [2 ((3aα, 9bα) -6,8-dimethoxy-7-propyl-1,3a, 4,9b-tetrahydrochromeno- [3,4-c] pyrrole-2 (3H)- Yl) ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

The remaining synthesis was carried out by applying the formulation described in Example 2 (Steps A to F), but using the aldehyde obtained in the previous step as starting reactant.

The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 64.24 6.43 7.25 Found 63.33 6.30 7.05

Example 21 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

Step A : (7-chloro-2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde

7-chloro-3- (2-hydroxyethyl obtained according to the preparation described in Step C of Example 18, but obtained according to the preparation described in Liebigs Ann. Chem. 1973, 103-110 as starting substrate. The product was prepared using) -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one.

Step B : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl]- 7-chloro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

According to the preparation described in Step B of Example 5, the title product was obtained using the compound prepared in Step A of Example 19 and the aldehyde prepared in the previous step. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Cl% Calculation 64.11 5.02 7.48 6.31 Found 63.82 5.02 7.35 6.63

Example 22 : 3- [2-((3aβ, 11cβ) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one fumarate

According to the preparation described in step B of example 5, the compound prepared in step A of example 20 and the aldehyde prepared in step A of example 22 were used to obtain the title product. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Cl% Calculation 64.11 5.02 7.48 6.31 Found 64.30 4.92 7.53 6.56

Example 23 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromano [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4-oxo-4 H -Pyrido [1,2- a ] Pyrimidine-7-carbonitrile fumarate

To a solution of 1.83 mmol of the compound obtained in Example 15 in 12 ml of dimethylformamide was added 1.1 mmol of zinc cyanide and 0.073 mmol of tetrakis (triphenylphosphine) palladium under inert atmosphere. The reaction mixture was heated on celite and then evaporated. The resulting residue was purified by chromatography on silica (eluent: dichloromethane / methanol: 95/5). The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% Calculation 68.52 5.18 10.58 Found 68.63 5.05 10.58

Example 24 : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-7- (2-thienyl) -4 H -Pyrido [1,2- a ] -Pyrimidin-4-one fumarate

Step A 3- (2-hydroxyethyl) -2-methyl-7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one

In a round bottom flask under argon atmosphere, 5 g of 7-bromo-3- (2-hydroxyethyl) -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one, tri 6.2 ml of butyl-thiophen-2-yl-stanan, 1 g of tetrakis (triphenylphosphine) palladium and 250 ml of N -methylpyrrolidone were mixed. The solution is heated at 130 ° C. for 2 hours and then the solvent is evaporated under vacuum; The residue was dissolved in 200 ml of dichloromethane and the solution was washed with 10% potassium fluoride solution, filtered and the organic phase was separated and washed with water. After drying over magnesium sulfate and evaporation, the resulting residue was purified by chromatography on silica gel using a mixture of dichloromethane / methanol: 95/5 as eluent.

Step B 3- (2-chloroethyl) -2-methyl-7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one

The product of the previous step was converted to a chlorinated compound by applying the recipe described in Liebigs Ann. Chem. 1973, 103-110.

Step C : 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno

[3,4-c] pyrrole-2 (3H) -yl) ethyl] -2-methyl-7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one fuma Rate

The remainder of the synthesis is subjected to the preparation described in Example 1 (step G), but in the previous step instead of 3- (2-chloroethyl) -2-methylpyrido [1,2-a] pyrimidin-4-one This was done by using the product obtained. The product was converted to salt using fumaric acid.

Elemental Microanalysis :

C% H% N% S% Calculation 66.98 5.12 6.89 5.26 Found 66.02 5.07 6.85 4.94

Example 25 : 3- [2-((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one hemifumarate

Step A (3aβ, 11cα) -1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Compounds were obtained according to the same experimental protocol as described in patent application EP 691 342 (Example 33).

Step B : 3- [2-((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 (3H) -yl) ethyl]- 7-chloro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one hemifumarate

Following the recipe described in step G of example 1, the title product was obtained using the compound described in the previous step and the compound obtained in step A of example 8 (the product was converted to a salt using fumaric acid). .

Elemental Microanalysis :

C% H% N% Cl% Calculation 66.16 5.16 8.15 6.88 Found 66.33 5.10 8.31 7.40

Example 26 : 6- [2-((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -7-methyl-5 H -[1,3] thiazolo [3,2- a ] Pyrimidine-5-one hemifumarate

According to the preparation described in Step G of Example 1, with 6- (2-chloroethyl) -7-methyl-5H- [1,3] thiazolo [3,2-a] pyrimidin-5-one The title product was obtained using the compound obtained in step A of Example 26 (product was converted to salt using fumaric acid).

Elemental Microanalysis :

C% H% N% Cl% Calculation 65.09 5.26 8.63 6.58 Found 64.98 5.28 8.61 6.67

Example 27 : 3- [2-((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] -Pyrrole-2 (3 H ) -Yl) ethyl] -2-methyl-4 H -Pyrido [1,2- a ] Pyrimidin-4-one hemifumarate

Obtained in step A of example 26 with the procedure described in step G of example 1 with 3- (2-chloroethyl) -2-methylpyrido [1,2-a] pyrimidin-4-one Compound was used to give the title product (product was converted to salt using fumaric acid).

Elemental Microanalysis :

C% H% N% Calculation 70.90 5.74 8.73 Found 70.99 5.70 8.77

Pharmacological Research

Example A Penile erection test in rats

This test assessed the ability of pharmacological agents to inhibit penile erection caused by administration of the selective 5-HT _2c agonist, RO 60-0175.

Male rats of Wistar strain weighed from 120 to 140 g on the day of the experiment were individually placed in a plexiglass observation box immediately after administration of the test compound or vehicle. After 30 minutes, RO 60-0175 (1.25 mg / kg, subcutaneously) was administered to the animal and the number of erections occurring for the next 30 minutes was counted.

Results : It was observed that the compounds of the present invention can inhibit penile erection caused by the administration of selective 5-HT _2c agonists. Thus, the compounds of the present invention have antagonist properties for the 5-HT _2c receptor. By way of example, the compound of Example 3 subcutaneously had an inhibitory dose 50 (ID ₅₀ ) of 2.6 mg / kg.

Example B : Testing for Aggression by Quarantine in Mice

The animals used were male CD-1 mice. From the arrival time of the mice, the mice were isolated in individual cages and free access to food and drink. One month after isolation, pairs of mice that were stable to aggressiveness were selected by observing the latency and number and duration of incubation when the mice were placed together.

The test was performed once a week. On the day of testing, each pair of mice (residents and invaders) was injected intraperitoneally with vehicle (control) or test compound (treated animals) in a volume of 10 ml / kg. After 30 minutes, invader mice were placed in cages of resident mice. The incubation period and the number and duration of attacks until the first attack were then measured over three minutes.

The compound determined that this was particularly anti-aggressive when it reduced the number and duration of attacks at non-sedative doses.

Results : The compounds of the present invention were observed to significantly reduce the number and duration of attacks. By way of example, the compound of Example 3 had an inhibitory dose 50 (ID ₅₀ ) of 7 mg / kg intraperitoneally.

Example C : Marble-burying test in mouse

This test evaluated the ability of pharmacological agents to inhibit spontaneous marble-berring behavior in mice, which inhibits antidepressant and / or anti- impulsive behavior.

Male mice of NMRI strain weighed from 20 to 25 g on the day of the experiment were individually placed in Macrolon boxes containing 5 cm of sawdust and covered with perforated plexiglass plates. Twenty-four "tiger's eye" glass marbles were evenly distributed on sawdust around the box. After 30 minutes of free searching, the animals were removed from the box and the embedded marble counted.

Results : The compounds of the present invention were observed to inhibit spontaneous marble-bering behavior in mice. By way of example, the compound of Example 3 had an inhibitory dose 50 (ID ₅₀ ) of 4.1 mg / kg subcutaneously.

Example D : Α in rat ₂ Determination of affinity for adrenergic receptors

Affinity was determined by competition experiments using [ ³ H] -RX 821,002. Membranes were prepared from rat cerebral cortex and incubated with 0.4 nM [ ³ H] -RX 821,002 and the compound to be tested in a final volume of 1.0 ml at 22 ° C. for 60 minutes. Culture buffers included 50 nM TRIS-HCl (pH 7.5), 1 mM EDTA and 100 μM GppNHp. Nonspecific binding was determined using 10 μM phentolamine.

Data Analysis: After incubation, the medium was filtered through a WHATMAN GF / B filter infiltrated with 0.1% polyethyleneimine and washed three times with 5 ml of cold buffer. Radioactivity retained on the filter was determined by liquid scintillation counting. Binding isotherms were analyzed by nonlinear regression curves.

Results : Compounds of the present invention interacted with α ₂ -adrenergic receptors by specific means, eg the compound of Example 3 had a pK _i of 7.5.

Example E Pharmaceutical Composition

Composition for preparing 1000 tablets each containing 10 mg of active ingredient

Compound of Example 3 ... 10 g

Hydroxypropyl Cellulose ........................ 2 g

Wheat starch ......................................... 10 g

Lactose ......................................... 100 g

Magnesium Stearate ......................... 3 g

talc................................................. 3 g

The compounds of the present invention are novel structures that provide dual α ₂ / 5-HT _2c antagonist properties, and include depression, impulsive behavior disorders, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, anorexia and Useful for the treatment of sleep disorders.

Claims (12)

Compounds of formula (I), enantiomers or diastereomers thereof, or addition salts thereof with pharmaceutically acceptable acids or bases: Where R ₁ , R ₂ , R ₃ and R ₄ may be the same or different, each of which is a hydrogen atom, a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxy, cyano, nitro and amino, or R ₁ and R ₂ , R ₂ and R ₃ or R ₃ and R ₄ together with the carbon atoms bonded thereto form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring, X represents an oxygen atom or a methylene group, A represents a linear or branched (C ₁ -C ₆ ) alkylene chain, Is a halogen atom and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cyan Substituted by one or two identical or different substituents selected from no, nitro, amino, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl and substituted or unsubstituted pyrrolyl group Unsubstituted unsaturated nitrogen-containing heterocycle, R ₅ represents a linear or branched (C ₁ -C ₆ ) alkyl group, here, The term “(C ₁ -C ₆ ) alkyl” refers to a hydrocarbon chain containing 1 to 6 carbon atoms, The term “(C ₁ -C ₆ ) alkoxy” refers to a (C ₁ -C ₆ ) alkyl-oxy group containing 1 to 6 carbon atoms, The term “(C ₁ -C ₆ ) alkylene” refers to a divalent hydrocarbon chain containing 1 to 6 carbon atoms, The term (C ₁ -C ₆ ) polyhaloalkyl denotes a carbon chain containing 1 to 6 carbon atoms and 1 to 9 halogen atoms, The term “heteroaromatic ring” denotes a five or six membered aromatic ring containing one, two or three hetero atoms selected from oxygen, nitrogen and sulfur, The term "unsaturated nitrogen-containing heterocycle" has one, two or three unsaturated groups and contains one, two or three hetero atoms, one of these hetero atoms being a nitrogen atom and oxygen, nitrogen and A 5-7 membered unsaturated ring, with or without additional hetero atom (s) selected from sulfur atoms, -The term "substituted or unsubstituted" as applied to "benzene ring", "heteroaromatic ring", "phenyl", "thienyl", "furyl" or "pyrrolyl" means "benzene ring", "heteroaromatic" Ring, “phenyl”, “thienyl”, “furyl” or “pyrrolyl” group is a halogen atom and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ Unsubstituted or substituted by one or two identical or different substituents selected from alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cyano, nitro and amino groups. The compound of claim ₁ , wherein R ₁ , R ₂ , R ₃ and R ₄ may be the same or different, each of which is a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) Compounds of formula (I) characterized in that they represent an alkoxy or hydroxy group, enantiomers or diastereomers thereof, or addition salts thereof with pharmaceutically acceptable acids or bases. A compound of formula (I) according to claim 1, wherein R ₁ and R ₂ together with the carbon atom to which they are attached form a benzene ring and R ₃ and R ₄ each represent a hydrogen atom Addition salts of thiomers or diastereomers, or pharmaceutically acceptable acids or bases thereof. A compound of formula (I), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable acid thereof according to any one of claims 1 to 3, wherein X represents an oxygen atom. Or addition salts with bases. A compound of formula (I), an enantiomer or diastereomer thereof, or a medicament thereof according to any one of claims 1 to 3, wherein A represents ethylene, propylene or butylene chains. Addition salts with acids or bases, which are scientifically acceptable. The method according to any one of claims 1 to 3, Divalent halogen atoms and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cya Groups unsubstituted or substituted by one or two identical or different substituents selected from no, nitro, amino and thienyl groups Compounds of formula (I), their enantiomers or diastereomers, or addition salts thereof with pharmaceutically acceptable acids or bases, characterized in that The method according to any one of claims 1 to 3, Divalent halogen atoms and linear or branched (C ₁ -C ₆ ) alkyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, cya Groups unsubstituted or substituted by one or two identical or different substituents selected from no, nitro and amino groups Compounds of formula (I), their enantiomers or diastereomers, or addition salts thereof with pharmaceutically acceptable acids or bases, characterized in that: The compound according to any one of claims 1 to 3, wherein A represents an ethylene chain, X represents an oxygen atom, R ₅ represents a methyl group, Is an unsubstituted or substituted at the 2'-position by a halogen atom or a group selected from linear or branched (C ₁ -C ₆ ) alkyl, cyano and thienyl Compounds of formula (I), their enantiomers or diastereomers, or addition salts thereof with pharmaceutically acceptable acids or bases, characterized in that: The compound of claim 1 or 2, wherein 3- [2-((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- c ] pyrrole-2 ( 3H ) -yl) -ethyl] -2-methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one, a compound of formula (I), enantiomer or diastereomer thereof Isomers, or addition salts with pharmaceutically acceptable acids thereof. 4. The compound of claim 1 or 3, wherein 3- [2-((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrole-2 ( 3H ) -yl) -ethyl] -2-methyl- 4H -pyrido [1,2-a] pyrimidin-4-one and 3- [2-((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] pyrrole-2 ( 3H ) -yl) ethyl] -2-methyl- 4H -pyrido [1,2- a ] Compounds of formula (I), their enantiomers, or addition salts thereof with pharmaceutically acceptable acids, characterized in that they are pyridin-4-ones. Catalytically hydrogenating a compound of formula (II) to afford a compound of formula (III) Reacting a compound of formula (III) with a compound of formula (IV) By reacting with a compound of formula (V) under reductive amination conditions, Obtain a compound of formula (I) and, if necessary, purify the compound of formula (I) according to conventional purification techniques, if desired, separate it into its stereoisomer according to conventional separation techniques, and if desired, A process for preparing a compound of formula (I) according to claim 1, characterized in that it is converted to an addition salt with a pharmaceutically acceptable acid or base. Where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, B and X are as defined for Formula (I), Y ₁ represents a leaving group comprising a halogen atom or tosylate, triflate or mesylate group, and A ′ represents a single bond or a linear or branched (C ₁ -C ₅ ) alkylene chain. 3- [2- (1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] pyrrole-2 ( 3H ) -yl) -ethyl] -2- as active ingredient Depression, impulsive behavior disorder, anxiety, comprising methyl- 4H -pyrido [1,2- a ] pyrimidin-4-one fumarate, together with one or more inert and nontoxic pharmaceutically acceptable excipients or carriers , Pharmaceutical compositions for use in the treatment of schizophrenia, Parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, and sleep disorders.