HK1049669B - New pyrimidin-4-one compounds a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Novel pyrimidin-4-one compounds, process for their preparation and pharmaceutical compositions containing them

Technical Field

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

Background

The invention also relates to the use thereof as alpha for co-applications₂/5-HT_2cA ligand.

1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c]Pyrrole compounds have been described in patent application EP 691342 on the basis of their serotonin-activation antagonist properties and according to their D₃Dopaminergic ligand characterization is described in patent application EP 887350.

Cortical limbic (corticoimbic) structures play a major role in controlling functional alterations in mental disorders. In particular, it is now recognized that disorders of monoaminergic transmission are strongly associated with the etiology of those different diseases. For example, in the case of depression, monoaminergic activity is reduced in the anterior cortex, hippocampus and nucleus accumbens.

Among the different types of mono-and hetero-receptors involved in the regulatory mechanisms, alpha has been found₂-AR (autoreceptor) and 5-HT_2cReceptors are of major importance. These two receptor subtypes are potentiated by inhibitionDopaminergic and adrenergic conduction act in the same direction. In one aspect, by alpha on noradrenergic neurons₂AR (autoreceptor) receptors exert reverse control (j. pharmacol. exp. ther., 1994,270958); and on the other hand, alpha₂-AR receptor and 5-HT_2cThe heterotypic receptors exert inhibitory control over dopaminergic and noradrenergic transmission (Neuropharmacology, 1997,36，609，J.Psychopharmacol.2000， 14(2)，114-138)。

the potential of compounds that bind to one or the other of those receptor subtypes to treat a number of pathological conditions has been demonstrated in the past.

For example, α has been studied₂AR antagonist compounds are useful in the treatment of cognitive disorders (j. pharmacol., 1992,6376), parkinson's disease (CNS Drugs, 1998,10189), schizophrenia (Science 1999,286105-,10suppl.3, 35-42), loss of libido and sexual dysfunction (j. pharmacol, 1997,1172) in the eye. Likewise, 5-HT2c receptor ligands have been demonstrated in the treatment of sexual dysfunction (j. pharmacol., supra) and parkinson's disease (Drug News department, 1999,12477) and anxiety (br.j. pharmacol., 1996,117427), depression (pharmacol. biochem. behav.1988,29819. quadrature. 820), impulsive diseases (biol. Psych.1993,333-14), appetite disorders (British j. pharmacol.1998,1231707-,33(3/4), 467-,18165).

Having a bidirectional alpha₂-AR and 5-HT_2cCompounds with antagonist properties are well suited to the requirements of the clinician to obtain a potentiation by administering a single compound while improving tolerability. Furthermore, such compoundsThere are distinct advantages over administration of two different compounds.

Disclosure of Invention

The compounds of the present invention have novel structures and are endowed with their bidirectional alpha₂/5-HT_2cAntagonist properties, whereby they are useful for the treatment of depression, impulsivity behavior disorders, anxiety, schizophrenia, parkinson's disease, cognitive disorders, sexual desire disorders, sexual dysfunction, appetite disorders and sleep disorders.

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

wherein:

R₁、R₂、R₃and R₄Which may be the same or different, each represent a hydrogen atom, a halogen atom or are selected from linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Polyhaloalkyl, hydroxy, cyano, nitro and amino groups;

or R₁And R₂、R₂And R₃Or R₃And R₄Together with the carbon atoms connecting them, form a benzene ring which may be substituted or unsubstituted or a heteroaromatic ring which may be substituted or unsubstituted;

x represents an oxygen atom or a methylene group;

a represents a linear or branched chain (C)₁-C₆) An alkylene chain;represents an unsaturated nitrogen-containing heterocycle which may or may not be substituted by one or two identical or different substituents, andthe substituents being selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) A polyhaloalkyl group, a cyano group, a nitro group, an amino group, a phenyl group which may be substituted or unsubstituted, a thienyl group which may be substituted or unsubstituted, a furyl group which may be substituted or unsubstituted, and a pyrrolyl group which may be substituted or unsubstituted; and is

R₅Represents a straight chain or branched chain (C)₁-C₆) An alkyl group.

It should be understood that:

the term "(C)₁-C₆) Alkyl "refers to a hydrocarbon chain containing 1 to 6 carbon atoms;

the term "(C)₁-C₆) Alkoxy "means (C) containing 1 to 6 carbon atoms₁-C₆) An alkyl-oxy group;

the term "(C)₁-C₆) Alkylene "refers to a divalent hydrocarbon chain containing 1 to 6 carbon atoms;

the term "(C)₁-C₆) Polyhaloalkyl "refers to a carbon chain containing 1 to 6 carbon atoms and 1 to 9 halogen atoms;

the term "heteroaromatic ring" refers to a 5-or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur;

the term "unsaturated nitrogen-containing heterocyclic ring" refers to a 5-to 7-membered unsaturated ring having 1, 2 or 3 unsaturations and containing 1, 2 or 3 heteroatoms, wherein one of those heteroatoms is a nitrogen atom and the other optionally present heteroatoms are selected from oxygen atoms, nitrogen atoms and sulfur atoms;

the term "optionally substituted" for the expressions "phenyl ring", "heteroaromatic ring", "phenyl", "thienyl", "furyl" or "pyrrolyl" means those radicals which may be substituted or unsubstituted by one or two identical or different substituentsA group selected from a halogen atom and a linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Polyhaloalkyl, cyano, nitro and amino.

Among the pharmaceutically acceptable acids, mention may be made, without being limited thereto, of 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, methanesulfonic acid, camphoric acid, oxalic acid and the like.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine and the like can be mentioned, but are not limited thereto.

In the heteroaromatic ring, mention may be made, but 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-dihydrooxazole.

It is understood that a (3a α, 9b α) or (3a β, 9b β) compound refers to a compound in which the relevant ring junction is in the cis configuration.

It is understood that a (3a α, 11c α) or (3a β, 11c β) compound refers to a compound in which the relevant ring junction is in the cis configuration.

It is understood that a (3a α, 9b β) or (3a β, 9b α) compound refers to a compound in which the relevant ring linkage is in the trans form.

It is understood that a (3a α, 11c β) or (3a β, 11c α) compound refers to a compound in which the relevant ring linkage is in the trans form.

In preferred compounds of the formula (I), R₁、R₂、R₃And R₄Which may be the same or different, each represent a hydrogen atom or a linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy or hydroxy.

Preferred compounds of the invention are those wherein R is₁And R₂Together with the carbon atom to which they are attached form a phenyl ring and R₃And R₄Each represents a hydrogen atom.

X preferably represents an oxygen atom.

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

The invention relates more particularly to compounds of the general formula (I), in whichRepresents the following groups:it may be substituted or unsubstituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (_C-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Polyhaloalkyl, cyano, nitro, amino and thienyl.

Other preferred compounds of the invention are compounds of the general formula (I), whereinRepresents the following groups:it may be substituted or unsubstituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C)₁-C₆) Alkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, straight or branched chain (C)₁-C₆) Polyhaloalkyl, cyano, nitro and amino.

The invention relates more particularly to compounds of general formula (I) in which A represents an ethylene chain, X represents an oxygen atom, R₅Represents methyl andrepresents the following groups:it may be substituted in the 2' -position by a halogen atom or selected from linear or branched (C)₁-C₆) Alkyl, cyano and thienyl are substituted or unsubstituted at that position by these groups.

Among the preferred compounds of the invention, there may be mentioned more particularly:

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

3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6] chromeno [3, 4-c ] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one, and enantiomers thereof and salts for addition with pharmaceutically acceptable acids;

and 3- [2- ((3a β, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6] chromeno [3, 4-c ] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one, and enantiomers thereof and salts for addition with pharmaceutically acceptable acids.

The invention also relates to a process for the preparation of a compound of general formula (I), which process is characterized in that:

subjecting the compound of formula (II) to catalytic hydrogenation to give a compound of formula (III):

wherein R is₁、R₂、R₃、R₄And X is as defined for formula (I);

wherein R is₁、R₂、R₃、R₄And X is as defined above; reacting a compound of formula (III) with a compound of formula (IV):

wherein A, B and R₅As defined for general formula (I) and Y₁Represents a leaving group such as: such as a halogen atom or a tosylate, triflate or mesylate group;

or

Reacting a compound of formula (III) with a compound of formula (V) under reductive amination conditions:

wherein B and R₅As defined for formula (I) and A' represents a bond or a linear or branched chain (C)₁-C₅) An alkylene chain;

to give a compound of formula (I), which is purified, if necessary, according to conventional purification techniques; if desired, it is separated into its stereoisomeric forms according to conventional separation techniques; and if necessary, converting it into a salt to which a pharmaceutically acceptable acid or base is added.

The compound of the general formula (II) (the compound of the general formula (IIa)) in which X represents an oxygen atom can be obtained from the compound of the general formula (VI) as a starting material:

wherein R is₁、R₂、R₃And R₄As defined above; in K.achiwa, et al (chem. pharm. bull.1985,33(7) 2762-66) with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine to give a compound of the general formula (VII):

wherein R is₁、R₂、R₃And R₄As defined above;

the compound of formula (VII) is then converted into a compound of formula (VIII) by reduction followed by deprotection of the phenolic function:

wherein R is₁、R₂、R₃And R₄As defined above;

the compound of formula (VIII) is subsequently converted to the compound of formula (IIa) by a Mitsunobu reaction.

The configuration (Z or E) of the compound of the formula (VI) used determines the ring-linking configuration of the compound of the formula (IIa) thus obtained.

The compounds of the general formula (IIa) can also be obtained starting from compounds of the general formula (IX):

wherein R is₁、R₂、R₃And R₄As defined above;

oxidizing the compound of formula (IX) to a compound of formula (X):

wherein R is₁、R₂、R₃And R₄As defined above;

reacting a compound of formula (X) with methyl propiolate to give a coumarin of formula (XI):

wherein R is₁、R₂、R₃And R₄As defined above;

the coumarin of the general formula (XI) is subjected to the following reaction:

when it is desired to prepare compounds of the formula (IIa) in which the ring linkage is in trans, reaction with sodium methoxide and subsequent reaction with a suitable catalyst in the reaction mixture of K.Achiwa et al (chem.pharm.Bull.1985,33(7) 2762-66) under the conditions described above with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine followed by reduction to give the compound of the general formula (VIII) in the configuration trans, which is then converted to the trans compound of the general formula (IIa) by Mitsunobu reaction;

or, when it is desired to prepare compounds of formula (IIa) in which the ring linkage is cis, as described in K.Achiwa et al (chem.pharm.Bull.1985,33(7) 2762-66) with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine under the conditions described for the cycloaddition reaction to give a compound of the general formula (XII) in which the ring linkage is cis,

wherein R is₁、R₂、R₃And R₄As defined above;

the compound of formula (XII) is then reduced to a compound of formula (VIII) whose configuration is cis, followed by conversion of the compound of formula (VIII) to the cis compound of formula (IIa) by a Mitsunobu reaction.

The compound of the general formula (II) (the compound of the general formula (IIb)) wherein X represents a methylene group can be obtained from the compound of the general formula (XIII):

wherein R is₁、R₂、R₃And R₄As defined above;

reacting a compound of formula (XIII) with ethyl acrylate to give a compound of formula (XIV):

wherein R is₁、R₂、R₃And R₄As defined above;

(XIV) converting the compound of formula (XIV) to a compound of formula (XV) by reduction reaction followed by hydrolysis:

wherein R is₁、R₂、R₃And R₄As defined above;

cyclizing a compound of formula (XV) to a compound of formula (XVI):

wherein R is₁、R₂、R₃And R₄As defined above;

the compound of formula (XVI) is then converted to a compound of formula (XVII):

wherein R is₁、R₂、R₃And R₄As defined above;

and subsequently converting the compound of formula (XVII) to the compound of formula (XVIII) by addition of lithium hydride:

wherein R is₁、R₂、R₃And R₄As defined above;

converting the cyano group in the compound of formula (XVIII) to a carboxyl group, and thereafter condensing the compound to a compound of formula (XIX):

wherein R is₁、R₂、R₃And R₄As defined above;

followed by reacting a compound of formula (XIX) with benzylamine to give a compound of formula (XX):

wherein R is₁、R₂、R₃And R₄As defined above;

converting the compound of formula (XX) to a compound of formula (IIb) by a reduction reaction.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) as active ingredient together with one or more inert, non-toxic pharmaceutically acceptable excipients. Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration in the form of tablets or lozenges, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injections, suspensions which may be cited, and the like.

The dosage employed may vary depending upon the nature and severity of the disease, the route of administration, and the age and weight of the patient and any associated therapeutic measures. The dose per 24 hours varies from 0.5mg to 2g and is administered in one or more doses.

Detailed Description

The following examples illustrate the invention without limiting it in any way.

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

The structures of the compounds described in the examples have been determined by conventional spectroscopic techniques (infrared, NMR, mass spectrometry).

Example 1: 3- [2- ((3a α, 9b α) -9-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one dihydrochloride

Step A: (3 α, 4 α) -1-benzyl-4- (2, 6-dimethoxyphenyl) -3-pyrrolidine-carboxylic acid methyl ester

To a solution of 120mmol of methyl cis- (2, 6-dimethoxy) cinnamate and 0.1ml of trifluoroacetic acid in 150ml of ethyl acetate cooled to 5 ℃ was slowly added 100mmol of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine. The reaction mixture was heated from 30 ℃ to 55 ℃ over 75 minutes. 0.75g of potassium carbonate was then added and the mixture was stirred for 15 minutes. After filtration and evaporation of the solvent, the residue is dissolved in 100ml of ethyl acetate and the solution is heated at 50 ℃. 110mmol of oxalic acid dissolved in 100ml of acetone are then added while stirring vigorously for 15 hours. After filtration and then washing with diethyl ether, the oxalate salt obtained was treated with 2 equivalents of 1N potassium hydroxide solution to give the expected product.

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

To 120mmol of lithium aluminium hydride suspended in 800ml of tetrahydrofuran at +5 ℃ are added 100mmol of the compound obtained in the above step dissolved in 400ml of tetrahydrofuran. After stirring for 1 hour at this temperature, the mixture was worked up by slowly adding 11ml of water, 15ml of 2N sodium hydroxide solution and 26ml of water. The mixture was stirred for 10 hours and then filtered. The solvent was evaporated to give the expected product.

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

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

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

To 80mmol of the compound obtained in the above step dissolved in 1 liter of tetrahydrofuran, 120mmol of diethyl azodicarboxylate and 120mmol of triphenylphosphine were sequentially added. The mixture was stirred at ambient temperature for 15 hours. The solvent was evaporated off and the crude product was dissolved in 1 liter of isopropyl ether and heated under 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 is converted into a salt using hydrochloric acid.

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

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

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 68.776.884.2210.68

Measured value 68.664.484.4510.97

Step F: (3a α, 9b α) -9-methoxy-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c)]-azoles

50mmol of the compound obtained in the above step are dissolved in a mixture of 200ml of methanol and 50ml of water. A solution of 50mmol of 5N hydrochloric acid in ethanol was added. After addition of 2g of palladium dihydroxide, the reaction mixture is placed under a hydrogen atmosphere. After the theoretical volume of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is evaporated. The residue obtained was treated with 1N sodium hydroxide solution and extracted with dichloromethane to give the expected product.

Step G: 3- [2- ((3a α, 9b α) -9-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido[1，2-a]Pyrimidin-4-one dihydrochloride

To 7mmol of the compound obtained in the above step dissolved in 100ml of acetonitrile was added 7mmol of potassium carbonate. The mixture was heated to 60 ℃. Then immediately 7mmol of 3- (2-chloroethyl) -2-methylpyrido [1, 2-a ] pyrimidin-4-one (prepared as described in Liebigs Ann. chem.1973, 103-l 110) were added in one portion. The mixture was heated at 80 ℃ for 18 hours. After cooling and addition of water, the mixture was extracted with dichloromethane and then washed and dried. After filtration and evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (eluent: dichloromethane/methanol 95/5). The product obtained is converted into a salt using hydrochloric acid.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 59.495.869.0515.27

Measured value 59.575.899.0915.41

Example 2: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one sesquifumarate

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

To 416mmol of 2, 4-dimethoxy-3-methyl-benzaldehyde dissolved in 100ml of dichloromethane was added 624mmol of m-chloroperbenzoic acid. The reaction mixture was heated under reflux for 5 hours, after which it was filtered. 200ml of saturated NaHCO are used each time₃The filtrate was washed 3 times with water and then dried over magnesium sulfate. After evaporation of the solvent, the crude product is dissolved in 400ml of methanol. 624mmol of 10% KOH solution were added. The mixture was stirred for 1 hour and then the pH was adjusted to pH 4 using 1N hydrochloric acid solution. After stirring for 1 hour, the volume was reduced to 1/3. Will be provided withThe crude product was dissolved in 400ml water and extracted with dichloromethane. The organic phase was collected and dried. After evaporation of the solvent, the residue obtained is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 90/10) to give the expected product.

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

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

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

The expected product was obtained following the procedure described in example 1, steps a and B, starting from the compound obtained in the above step.

Step D: (3 alpha, 4 alpha) -2-benzyl-6, 8-dimethoxy-7-methyl-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c)]Pyrrole hydrochloride

The expected product was obtained by following the procedure described in step D of example 1, starting from the compound obtained in the above step.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 67.106.973.739.43

Measured value 66.907.003.929.57

Step E: (3a α, 9b α) -6, 8-dimethoxy-7-methyl-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c]Azole compounds

The expected product was obtained following the procedure described in step F of example 1, starting from the compound obtained in the above step.

Step F: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one sesquifumarate

The expected product was obtained following the procedure described in step G of example 1, starting from the compound obtained in the above step. The obtained product is converted into a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 61.075.806.89

Measured value 61.736.037.19

Example 3: 3- [2- (1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: 1, 2, 3, 3a, 4, 11 c-hexahydrobenzo [5, 6]]Chromeno [3, 4-c]Azole compounds

The expected product was obtained as described in example 2, steps C-F starting from benzo [ F ] chromen-3-one.

Step B: 3- [2- (1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in step G of example 1, starting from the compound obtained in the above step.

Elemental microanalysis：

C％ H％ N％

Calculated value 68.305.547.96

Measured value 67.875.577.79

Example 4: 6- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) -ethyl]-7-methyl-5H- [1, 3]Thiazolo [3, 2-a]Pyrimidin-5-one fumarate

The expected product was obtained by the method described in example 1, step G, using the compound described in example 3, step a and 6- (2-chloro-ethyl) -7-methyl-thiazolo [3, 2-a ] pyrimidin-5-one as starting materials. The obtained product is converted into a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ S％

Calculated value 63.035.107.876.01

Measured value 62.915.087.775.83

Example 5: 3- [3- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) propyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one hemifumarate

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

To 60mmol of 3- (2-chloro-ethyl) -2-methyl-pyrido [1, 2-a ] pyrimidin-4-one (prepared as described in Liebigs Ann. chem.1973, 103-110) dissolved in 140ml of dimethyl sulfoxide was added 120mmol of potassium cyanide. The reaction mixture was heated at 100 ℃ for 3 hours. After evaporation of the dimethyl sulfoxide, the crude product is dissolved in dichloromethane and water and extracted with dichloromethane. The organic phase is washed and dried. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 95/5) and the product obtained was then dissolved in 100ml dichloromethane. Cooling the mixture to-70 ℃; 120mmol of diisobutylaluminum hydride was added. After stirring at this temperature for 2 hours, the mixture is treated with 50ml of methanol and 100ml of water; the organic phase is then washed and dried to give the expected product.

Step B: 3- [3- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) propyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one hemifumarate

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

Elemental microanalysis：

C％ H％ N％

Calculated value 72.036.048.69

Measured value 71.685.958.59

Example 6: 3- {2- [ (3a α, 11c α) -1, 3, 3a, 4, 5, 11 c-hexahydro-2H-naphtho [1, 2-e ] naphthalene]-isoindol-2-yl]Ethyl } -2-methyl-4H-pyrido [1, 2-a ]]Pyrimidin-4-one fumarate

Step A: 3-chloromethyl-naphthalene

To 1.26mol of naphthalen-2-yl-methanol dissolved in 1.5 l of toluene was added 3.8mol of thionyl chloride. The mixture was then heated under reflux for 2 hours. After cooling, the solvent evaporated. The crude product was dissolved twice in toluene and evaporated. The oil obtained is dissolved in dichloromethane, washed and dried. After filtration and evaporation of the solvent, the oil obtained is distilled to give the expected product.

Boiling point: 118 ℃ at 0.09mm Hg

Step B: 4- (2-naphthyl) -2-butenoic acid ethyl ester

To 863mmol of the compound obtained in the above step dissolved in 206ml of tributylamine were added 1.07mol of ethyl acrylate and 10mmol of palladium acetate. The reaction mixture was heated under reflux for 5 hours. After cooling, the mixture was hydrolyzed and extracted once with dichloromethane. The organic phase is washed with a 1N hydrochloric acid solution and then with water and thereafter dried. The product was purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 95/5) to give the expected product.

Step C: 4- (2-naphthyl) -2-butanoic acid ethyl ester

To 490mmol of the compound obtained in the above step dissolved in 3L of ethanol was added 7g of 10% palladium on carbon. The mixture was then placed in a hydrogen atmosphere. After absorption of the theoretical amount of hydrogen, the mixture was filtered and the solvent was evaporated to give the expected product.

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

490ml of a 2N titrated sodium hydroxide solution were added to 484mmol of the compound obtained in the above step dissolved in 1.5 l of ethanol. The mixture was heated and maintained at reflux for 1 hour. The ethanol is then evaporated. The pH was adjusted to pH 5-6 using 1N hydrochloric acid. The precipitate formed was filtered off and washed with water to give the expected product.

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

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

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

To 207mmol of the compound obtained in the above step dissolved in 500ml of tetrahydrofuran were added 243mmol of trimethylsilylcyanide and 16mmol of a 0.5M solution of lithium cyanide in dimethylformamide in that order. The reaction mixture was stirred for 2 hours and then poured onto ice and extracted 4 times with ether. The organic phase was collected and washed with water before drying. After filtration, the solvent was evaporated. The residue was dissolved in 325ml of pyridine. 42ml of POCl were added₃. The compound was heated at 100 ℃ for 3 hours and then cooled, after which the system was poured into 400ml of ice-cold hydrochloric acid. After addition of dichloromethane, the mixture was separated and then extracted with dichloromethane. The combined organic phases are washed and then dried. After filtration, the solvent was evaporated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane 70/30) to give the expected product.

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

To 87mmol of acetic acid was added 105mmol of a 0.5M lithium cyanide solution and then 82mmol of the compound obtained in the above step dissolved in 500ml of dimethylformamide at 5 ℃. The reaction mixture was heated at 100 ℃ for 2 hours, after which it was cooled and dried and the system was poured onto ice. The precipitate obtained is filtered off and washed to give the expected product.

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

To 68mmol of the compound obtained in the above step were added 42ml of acetic acid and 84ml of concentrated hydrochloric acid in this order. The reaction mixture was heated under reflux for 5 days, after which it was cooled and dried and the system was 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 residue obtained is purified by chromatography (eluent: dichloromethane/methanol/acetic acid: 95/5/0.5) to give the expected product.

Step I: (3a alpha, 11c alpha) -3a, 4, 5, 11 c-tetrahydrophenanthro [3, 4-c)]Furan-1, 3-diones

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

Step J: (3a alpha, 11c alpha) -2-benzyl-3 a, 4, 5, 11 c-tetrahydro-1H-naphtho [1, 2-e]Isoindole-1, 3(2H) -diones

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

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

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

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 78.956.914.0010.13

Measured value 78.606.994.2810.04

Step L: 3- {2- [ (3a α, 11c α) -1, 3, 3a, 4, 5, 11 c-hexahydro-2H-naphtho [1, 2-e ] naphthalene]-isoindol-2-yl]Ethyl } -2-methyl-4H-pyrido [1, 2-a ]]Pyrimidin-4-one fumarate

The expected product was obtained following the procedure described in example 1, steps F and G, using the compound obtained in the above procedure as starting material. The obtained product is converted into a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 70.495.887.85

Measured value 70.845.947.99

Example 7: 3- [2- ((3a α, 9b β) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydro-chromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one sesquifumarate

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

To 70mmol of the compound obtained in step B of example 2 dissolved in 100ml of methanol was slowly added 205mmol of 30% sodium methoxide in methanol. The reaction mixture was heated under reflux for 4 hours, after which the reaction mixture was hydrolyzed using a 1N hydrochloric acid solution. The precipitate was filtered off, washed with water and dried to give the expected product.

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

The expected product was obtained by following the procedure described in example 2, steps C and D, using the compound obtained in the above step as starting material.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 67.106.973.739.43

Measured value 67.157.133.769.73

Step C: 3- [2- ((3a α, 9b β) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydro-chromeno [3, 4-c)]Pyrrol-2 (3H) -yl) -ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one sesquifumarate

The expected product was obtained following the procedure described in example 1, steps F and G, using the compound obtained in the above procedure as starting material. The obtained product is converted into a salt using fumaric acid.

Example 8: 3- [2- (1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

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

This product was prepared according to the procedure described in the literature (Liebigs Ann. chem.1973, 103-110) using 2-amino-5-chloropyridine as starting reagent.

Step B: 3- [2- (1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumaric acidSalt (salt)

The procedure described in step G of example 1 was followed using the compound obtained in the above step and the compound obtained in step a of example 3 as starting materials to obtain the expected product (which was converted into a salt using fumaric acid).

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 63.214.977.186.08

Measured value 62.985.087.036.19

Example 9: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The procedure described in example 2 was followed using 7-chloro-3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one prepared in step a of example 8 instead of 3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one as the starting reagent to prepare the expected product. The obtained product is converted into a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 59.445.57.176.05

Measured value 58.945.436.976.34

Example 10: 6- [2- ((3a alpha, 9b alpha) -6-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-7-methyl-5H- [1, 3]Thiazolo [3, 2-a]Pyrimidin-5-one fumarate

Step A: (3a alpha, 9b alpha) -6-methoxy-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c)]Azole compounds

The product was prepared as described in example 1, steps a-F, using cis- (2, 3-dimethoxy) cinnamic acid as starting material.

Step B: 6- [2- ((3a alpha, 9b alpha) -6-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-7-methyl-5H- [1, 3]Thiazolo [3, 2-a]Pyrimidin-5-one fumarate

The expected product is obtained by the procedure of example 1 step G using the compound obtained in the above step as starting material and subsequently 6- (2-chloroethyl) -7-methyl-5H- [1, 3] thiazolo [3, 2-a ] pyrimidin-5-one. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ S％

Calculated value 58.475.308.186.24

Measured value 58.785.228.276.20

Example 11: 3- [2- ((3a alpha, 9b alpha) -6-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by the method described in step G of example 1 using the compound described in step A of example 10 and 3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one as starting materials. The obtained product is converted into a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 63.905.768.28

Measured value 63.035.777.91

Example 12: 3- [2- ((3a alpha, 9b alpha) -6-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-7-bromo-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: 3- (2-chloroethyl) -7-bromo-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-ones

This product was prepared following the procedure described in example 8, step a, using 2-amino-5-bromopyridine as starting reagent.

Step B: 3- [2- ((3a alpha, 9b alpha) -6-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-7-bromo-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The procedure described in example 11 was followed using the compound described in example 10 and the pyrimidinone prepared in the above procedure as starting materials to obtain the expected product. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ Br％

Calculated value 55.304.817.1713.63

Measured value 55.024.757.1213.81

Example 13: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2, 7-dimethyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: 3- (2-chloroethyl) -2, 7-dimethyl-4H-pyrido [1, 2-a]Pyrimidin-4-ones

This product was prepared following the procedure described in example 8, step a, using 2-amino-5-methylpyridine as starting reagent.

Step B: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2, 7-dimethyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained following the procedure described in step G of example 1, using the compound prepared in the above procedure and the compound described in step a of example 3 as starting materials. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 68.755.777.76

Measured value 67.965.607.67

Example 14: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2, 7-dimethyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in step G of example 1, using the compound obtained in step a of example 13 and the product in step E of example 2 as starting materials. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 63.706.247.43

Measured value 63.576.097.36

Example 15: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-bromo-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in step G of example 1, using the compound obtained in step a of example 3 and the product obtained in step a of example 12 as starting materials. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ Br％

Calculated value 59.414.656.9313.18

Measured value 59.044.696.8112.93

Example 16: 3- [2- ((3a α, 9b α) -6-hydroxy-8-methoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: (3a alpha, 9b alpha) -2-benzyl-8-methoxy-7-methyl-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c)]Pyrrole-6-ols

To a solution of the 20g compound described in step D of example 2 was added a molar solution of 64ml boron trifluoride in dichloromethane at 0 ℃. After stirring at 20 ℃ for 3 hours, 200ml of saturated sodium bicarbonate solution were used for hydrolysis and the organic phase was separated off. The residue obtained was purified by chromatography on silica gel using a mixture of dichloromethane/methanol 98/2 as eluent.

Step B: (3a α, 9b α) -8-methoxy-7-methyl-1, 2, 3, 3a, 4, 9 b-hexahydrochromeno [3, 4-c]Pyrrole-6-ols

The product prepared in the above step was debenzylated by using the procedure described in step F of example 1.

Step C: 3- [2- ((3a α, 9b α) -6-hydroxy-8-methoxy-7-methyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in step G of example 1 using the compound obtained in the above-mentioned step and 3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one as starting reagents. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 62.565.817.82

Measured value 61.615.977.42

Example 17: 3- [4- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) butyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: 3- (3-butenyl) -2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-ones

A mixture of 5.7g of methyl 2-acetyl-5-hexenoate, 3.15g of 2-aminopyridine and 0.65g of polyphosphoric acid was heated at 160 ℃ for 2 hours. Then 30ml of water were added in the cooled state and the mixture was extracted with dichloromethane. The residue obtained after evaporation of the solvent 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-ones

To a solution of 5.4g of the product obtained in the above step in 100ml of tetrahydrofuran was added 55.2ml of a molar solution of borane in tetrahydrofuran. After 1 hour, cool to 0 ℃ and add 10ml of water and then 25.4g of sodium borate. Stirred for 1 hour and then the mixture was concentrated; the residue was dissolved in 100ml of water and extracted with dichloromethane. After evaporation of the solvent, the residue obtained is 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 4.5g of the product obtained in the above step and 8.1g of 1-hydroxy-1-oxo-benzo [ d ] [1, 2] iodosyl alcohol (iodoxol) -3-one in 200ml of tetrahydrofuran was heated under reflux for 3 hours. The filtrate was filtered and concentrated under cooling.

Step D: 3- [4- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) -butyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-ones

The remaining synthesis steps were carried out by using the method described in step B of example 5, starting with the aldehyde obtained in the above step. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 68.065.897.26

Measured value 67.255.856.82

Example 18: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A：(3a alpha, 11c alpha) -1, 2, 3, 3a, 4, 11 c-hexahydrobenzo [5, 6]]Chromeno [3, 4-c]Azole compounds

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

Step B: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in example 1, step G, using the enantiomer prepared in the above step and 3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one as starting materials.

The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 68.305.547.96

Measured value 68.245.418.12

Example 19: 3- [2- ((3a beta, 11c beta) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: (3a beta, 11c beta) -1, 2, 3, 3a, 4, 11 c-hexahydrobenzo [5, 6]]Chromeno [3, 4-c]Azole compounds

Separation of the racemate 1, 2, 3, 3a, 4, 11 c-hexahydrobenzo [5, 6] chromeno [3, 4-c ] pyrrole: 10.3g of the product obtained in step A of example 3 are dissolved in 200ml of ethanol and the mixture is heated under reflux. A solution of 16.4g (-)2, 3-dibenzoyl-L-tartaric acid in 200ml ethanol was added. After 12 hours the precipitate was filtered off. The precipitate was recrystallized three times from a mixture of ethanol/water 85/15. The compound was obtained in base form after treatment with aqueous sodium hydroxide solution.

Step B: 3- [2- ((3a beta, 11c beta) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained by following the procedure described in example 1, step G, using the enantiomer prepared in the above step and 3- (2-chloroethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one as starting materials.

The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 68.305.547.96

Measured value 68.855.457.81

Example 20: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-propyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

Step A: 2-allyloxy-4-methoxybenzaldehyde

To a solution of 100g of 2-hydroxy-4-methoxybenzaldehyde in 2 l of acetone was added 79.5ml of allyl bromide and then 272g of potassium carbonate was added stepwise. Heated under reflux for 4 hours and then filtered; the filtrate was concentrated in vacuo, the residue was dissolved in 1 l dichloromethane and washed with 1N aqueous sodium hydroxide solution and then with saturated sodium chloride solution. Dried over magnesium sulfate and concentrated in vacuo.

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

A solution of 125g of the product obtained in step A in 300ml of N, N-dimethylaniline was heated at 200 ℃ for 15 hours. The solvent is then evaporated off in vacuo and the residue is dissolved in 1 l of isopropyl ether; the solution was extracted 10 times with 1N sodium hydroxide, 100ml of aqueous sodium hydroxide solution each time; and then the combined extracts were acidified using 3N hydrochloric acid. The aqueous acidic solution was then extracted with dichloromethane and the organic phase was dried and concentrated.

Step C: 3-allyl-2, 4-dimethoxy benzaldehyde

A mixture of 108g of the product obtained in the above step, 74.4g of dimethyl sulfate and 233g of potassium carbonate was heated under reflux for 5 hours. The obtained solution was filtered and concentrated under cooling. The residue was dissolved in isopropyl ether and washed with saturated sodium bicarbonate solution and then with water. Dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of cyclohexane/ethyl acetate 96/4 as eluent.

Step D: 2, 4-dimethoxy-3-propylbenzaldehyde

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

Step E: 3- [2- ((3a α, 9b α) -6, 8-dimethoxy-7-propyl-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c)]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The remaining synthesis steps were carried out by using the method described in example 2 (steps a-F), with the aldehyde obtained in the above steps as starting material.

The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％

Calculated value 62.246.437.25

Measured value 63.336.307.05

Example 21: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-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

This product was prepared by the method described in example 18, step C, using 7-chloro-3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one obtained according to the method described in the literature (Liebigs Ann. chem.1973, 103-110) as starting material.

Step B: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained following the procedure described in step B of example 5, using the compound prepared in step a of example 19 and the aldehyde prepared in the above step. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 64.115.027.486.31

Measured value 63.825.027.356.63

Example 22: 3- [2- ((3a beta, 11c beta) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The expected product was obtained following the procedure described in example 5, step B, using the compound prepared in example 20, step a and the aldehyde prepared in example 22, step a. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 64.115.027.486.31

Measured value 64.304.927.536.56

Example 23: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4-oxo-4H-pyrido [1, 2-a]Pyrimidine-7-carbonitrile fumarate

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

Elemental microanalysis：

C％ H％ N％

Calculated value 68.525.1810.58

Measured value 68.635.0510.58

Example 24: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-7- (2-thienyl) -4H-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-ones

5g of 7-bromo-3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one, 6.2ml of tributyl-thiophen-2-yl-stannane, 1g of tetrakis (triphenylphosphine) palladium and 250ml of N-methylpyrrolidone were mixed in a round-bottomed flask under a stream of argon. The solution was heated at 130 ℃ for 2 hours and then the solvent was evaporated in vacuo; the residue is dissolved in 200ml of dichloromethane, the solution is washed with 10% potassium fluoride solution, filtered, the organic phase is separated off and washed with water. After drying over magnesium sulfate and evaporation, the residue obtained is 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-ones

The product of the above step is converted into the chlorinated compound by using the method described in the literature (Liebigs Ann. chem.1973, 103-110).

Step C: 3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-7- (2-thienyl) -4H-pyrido [1, 2-a]Pyrimidin-4-one fumarate

The remaining synthesis steps were carried out by using the method described in example 1 (step G) replacing 3- (2-chloroethyl) -2-methylpyrido [1, 2-a ] pyrimidin-4-one as starting material with the product obtained in the above step. The product is converted to a salt using fumaric acid.

Elemental microanalysis：

C％ H％ N％ S％

Calculated value 66.985.126.895.26

Measured value 66.025.076.854.94

Example 25: 3- [2- ((3a beta, 11c alpha) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidine-4-

Ketone hemifumarate

Step A: (3a beta, 11c alpha) -1, 2, 3, 3a, 4, 11 c-hexahydrobenzo [5, 6]]Chromeno [3, 4-c]Azole compounds

This compound was obtained according to the same experimental protocol as patent application EP 691342 (example 33).

Step B: 3- [2- ((3a beta, 11c alpha) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-chloro-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-4-one hemifumarate

The expected product (which was converted to a salt using fumaric acid) was obtained according to the procedure described in step G of example 1 using the compound described in the above step and the compound obtained in step a of example 8.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 66.165.168.156.88

Measured value 66.335.108.317.40

Example 26: 6- [2- ((3a beta, 11c alpha) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-7-methyl-5H- [1, 3]Thiazolo [3, 2-a]Pyrimidine-5-

Ketone hemifumarate

The expected product (which was converted to a salt using fumaric acid) was obtained by the method described in step G of example 1 using the compound obtained in step A of example 26 and 6- (2-chloroethyl) -7-methyl-5H- [1, 3] thiazolo [3, 2-a ] pyrimidin-5-one.

Elemental microanalysis：

C％ H％ N％ Cl％

Calculated value 65.095.268.636.58

Measured value 64.985.288.616.67

Example 27: 3- [2- ((3a beta, 11c alpha) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6]]Chromeno [3, 4-c]Pyrrol-2 (3H) -yl) ethyl]-2-methyl-4H-pyrido [1, 2-a]Pyrimidin-5-one moieties

Fumarate salt

The expected product (which was converted to a salt using fumaric acid) was obtained by following the procedure described in step G of example 1 using the compound obtained in step a of example 26 and 3- (2-chloroethyl) -2-methylpyrido [3, 2-a ] pyrimidin-4-one.

Elemental microanalysis：

C％ H％ N％

Calculated value 70.905.748.73

Measured value 70.995.708.77

Pharmacological study

Example A: rat penile erection test

This test was used to evaluate drug versus factor administration selectivity for 5-HT_2cThe stimulant RO 60-0175 can inhibit penile erection.

Male rats of the Wistar strain weighing 120-. After 30 minutes, the animal was given RO 60-0175(1.25mg/kg, subcutaneously) and counted for the number of erections that occurred over the next 30 minutes.

Results: it appears that the compounds of the invention are capable of inhibiting the selective 5-HT due to administration_2cPenile erection by stimulant. They thus have a 5-HT response_2cAntagonist properties of the receptor. Illustratively, the compound of example 3 has a subcutaneous inhibitory dose of 50 (ID)₅₀) It was 2.6 mg/kg.

Example B: assays for challenge by isolation in mice

The animals used were male CD-1 mice. Mice were placed in separate cages from the time they were shipped to the laboratory so that they were free to eat and drink. After a period of 1 month of isolation, pairs of challenge stable mice were selected by observing the latency of the challenge and the number and duration of challenges when the mice were placed together.

The test was performed once a week. On the day of the experiment, each mouse in each pair (both the dwellers and the invaders) was injected intraperitoneally with vehicle (control animals) or compound under test (treated animals) in an amount of 10 ml/kg. After 30 minutes, the invader mice were placed in cages of the resident mice. The latency and number and duration of attacks up to the first attack were then determined over a period of 3 minutes.

A compound is considered particularly anti-challenge when it reduces the number and duration of challenges at non-sedative doses.

Results: it appears that the compounds of the present invention significantly reduce the number and duration of attacks. By way of illustration, the compound of example 3 has an intraperitoneal inhibitory dose of 50 (ID)₅₀) It was 7 mg/kg.

Example C: marble burying test for mouse

This test was used to evaluate the inhibitory ability of the drug on the spontaneous marbleizing behaviour of the mice, from which an antidepressant and/or antishock effect could be deduced.

On the day of the experiment, 20-25g of NMRI strain male mice were individually placed in a Macrolon box filled with 5cm sawdust and covered with a perforated plexiglas plate. 24 pieces of "tiger-eye" glass-like marble were evenly distributed on the sawdust in the inner edge area of the box. At the end of the 30 minute free exploration, animals were removed from the box and the number of buried marbles counted.

Results: it appears that the compounds of the present invention inhibit the spontaneous marbles burying behaviour in mice. Illustratively, the compound of example 3 has a subcutaneous inhibitory dose of 50 (ID)₅₀) It was 4.1 mg/kg.

Example D: for rat alpha₂Determination of the affinity of the adrenergic receptors

The term "PAS" or "PAS³H]-RX 821,002 competition experiments to determine said affinity. A membrane was prepared from the cerebral cortex of rat and one of its formula was admixed with 0.4nM [ sic ], [ solution of ] A³H]RX 821,002 was incubated with the test compound in a final volume of 1.0ml at 22 ℃ for 60 minutes. The incubation buffer contains50nM TRIS-HCl (pH7.5), 1mM EDTA and 100. mu.M GppNHp. Nonspecific binding was determined using 10 μ M phentolamine.

Data analysis: at the end of the incubation, the incubation medium was filtered through an WHATMAN GF/B filter impregnated with 0.1% polyethylenimine and washed 3 times with 5ml cold buffer. The radioactivity retained on the filters was determined by liquid scintillation counting. Binding isotherms were analyzed by non-linear regression.

Results: it appears that the compounds of the invention react in a specific manner with alpha₂-adrenergic receptor interaction, e.g. where the compound of example 3 has a pK_iIt was 7.5.

Example E: pharmaceutical composition

1000-tablet formulation containing 10mg of active ingredient per tablet

Example 3 Compound 10g

Hydroxypropyl cellulose 2g

Wheat starch 10g

Lactose 100g

Magnesium stearate 3g

Talc 3g

Claims (13)

1. A compound of the general formula (I), its enantiomers and diastereomers and their salts with a pharmaceutically acceptable acid or base:

wherein:

R₁、R₂、R₃and R₄Which may be identical or different, each represent a hydrogen atom or are chosen from linear or branched C₁-C₆Alkyl, straight or branched C₁-C₆Alkoxy, hydroxy groups;

or R₁And R₂、R₂And R₃Or R₃And R₄Together with the carbon atom to which they are attached form a benzene ring;

x represents an oxygen atom or a methylene group;

a represents a linear or branched C₁-C₆An alkylene chain;

represents an unsaturated nitrogen-containing heterocycle optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched C₁-C₆Alkyl, cyano and thienyl; and is

R₅Represents a straight or branched chain C₁-C₆An alkyl group, a carboxyl group,

it should be understood that:

the term "C₁-C₆Alkyl "refers to an alkyl chain containing 1 to 6 carbon atoms;

the term "C₁-C₆Alkoxy "means (C) containing 1 to 6 carbon atoms₁-C₆) An alkyl-oxy group;

the term "C₁-C₆Alkylene "refers to a divalent alkyl chain containing 1 to 6 carbon atoms;

the term "unsaturated nitrogen-containing heterocyclic ring" refers to a 5-to 7-membered unsaturated ring having 1 or 2 unsaturations and containing 1 or 2 heteroatoms, wherein one of those heteroatoms is a nitrogen atom and the other, optionally present, heteroatoms is a sulfur atom.

2. A compound of formula (I) according to claim 1, wherein R is R, enantiomers and diastereomers thereof, and salts thereof with pharmaceutically acceptable acids or bases₁、R₂、R₃And R₄Which may be the same or different, each represent a hydrogen atom or a linear or branched C₁-C₆Alkyl, straight or branched C₁-C₆Alkoxy or hydroxy.

3. A compound of formula (I) according to claim 1, wherein R is R, enantiomers and diastereomers thereof, and salts thereof with pharmaceutically acceptable acids or bases₁And R₂Together with the carbon atom to which they are attached form a phenyl ring and R₃And R₄Each represents a hydrogen atom.

4. Compounds of general formula (I) according to claim 1, wherein X represents an oxygen atom, their enantiomers and diastereoisomers and their addition salts with pharmaceutically acceptable acids or bases.

5. Compounds of general formula (I), the enantiomers and diastereomers thereof, and the salts thereof added with a pharmaceutically acceptable acid or base, according to claim 1, wherein a represents an ethylene, propylene or butylene chain.

6. A compound of general formula (I), its enantiomers and diastereomers and its addition salts with a pharmaceutically acceptable acid or base according to claim 1, whereinRepresents the following groups:it is optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched C₁-C₆Alkyl, cyano and thienyl.

7. A compound of general formula (I), its enantiomers and diastereomers and its addition salts with a pharmaceutically acceptable acid or base according to claim 1, whereinRepresents the following groups:it is optionally substituted by one or two identical or different substituentsSubstituted, the substituents being selected from halogen atoms and straight or branched C₁-C₆Alkyl and cyano.

8. A compound of general formula (I) according to claim 1, wherein a represents a methylene, an enantiomer or diastereomer thereof, and a salt thereof with a pharmaceutically acceptable acid or base

An ethyl chain, X represents an oxygen atom, R₅Represents methyl andrepresents the following groups:optionally substituted in the 2' -position by halogen atoms or selected from straight or branched C₁-C₆Alkyl, cyano and thienyl.

9. A compound of formula (I) according to claim 1 which is 3- [2- ((3a α, 9b α) -9-methoxy-1, 3a, 4, 9 b-tetrahydrochromeno [3, 4-c ] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one, its enantiomers and diastereoisomers and salts thereof with pharmaceutically acceptable acids.

10. A compound of the formula (I) according to claim 1, which is

3- [2- ((3a α, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6] chromeno [3, 4-c ] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one and 3- [2- ((3a β, 11c α) -1, 3a, 4, 11 c-tetrahydrobenzo [5, 6] chromeno [3, 4-c ] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidin-4-one, enantiomers thereof and salts thereof with pharmaceutically acceptable acids.

11. A process for the preparation of a compound of general formula (I) according to claim 1, characterized in that:

subjecting the compound of formula (II) to catalytic hydrogenation to give a compound of formula (III):

wherein R is₁、R₂、R₃、R₄And X is as defined in claim 1;

wherein R is₁、R₂、R₃、R₄And X is as defined in claim 1;

reacting a compound of formula (III) with a compound of formula (IV):

wherein A, B and R₅As defined in claim 1 and Y₁Represents a leaving group halogen atom or a tosylate, triflate or mesylate group;

or

Reacting a compound of formula (III) with a compound of formula (V) under reductive amination conditions:

whereinAnd R₅As defined in claim 1 and A' represents a bond or a straight or branched chain C₁-C₅An alkylene chain;

to produce a compound of formula (I), optionally purified according to conventional purification techniques; optionally, it is separated into its stereoisomeric forms according to conventional separation techniques; and optionally converting it into a salt to which it is added with a pharmaceutically acceptable acid or base.

12. A pharmaceutical composition comprising a compound of claim 1 as an active ingredient in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.

13. Use of a pharmaceutical composition according to claim 12 for the preparation of a medicament for the treatment of alpha₂/5-HT_2cReceptor-induced depression, impulsiveness behavior disorders, anxiety, schizophrenia, parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, appetite disorders and sleep disorders.