WO1999032485A1 - 3-oxazol-5-yl-1-oxo-1,2-dihydroisoquinoline-4-propanamide derivatives, preparation and therapeutic application - Google Patents

Abstract

The invention concerns compounds of formula (I) in which X represents a hydrogen or halogen atom or a methyl or methoxy group; R1 represents a methyl group; and R2 and R3 represent each, independently of each other, a hydrogen atom or a C1-C4 alkyl group. The invention is applicable in therapy.

Description

3-oxazol-5-yl-l-oxo-1,2,2-dihydroisoquinoline-4-propanamide derivatives, their preparation and their therapeutic use.

The subject of the present invention is compounds corresponding to the general formula (I)

X

dans laquelle

in which

X represents a hydrogen or halogen atom or a methyl or methoxy group,

R 1 represents a methyl group, and R ₂ and R ₃ each represent, independently of one another, a hydrogen atom or a (C 1 -C 4) alkyl group.

According to the invention, the compounds of general formula (I) can be prepared by a process illustrated by the scheme which follows.

The dianion of a benzamide of general formula (II), in which X and R _x are as defined above, is reacted with diethoxy-N, N-dimethylacetamide, of formula (III), in an ethereal solvent , for example tetrahydrofuran, at a temperature of -60 to + 60 ° C. This gives a hydroxyacetal of general formula (IV) which is dried, for example by means of Oxone ^® (potassium peroxymonosulfate), in an aromatic solvent, e.g. toluene, at a temperature of 70 to 110 ° CX is obtained a mixture of acetal of general formula (V) and of aldehyde of general formula (VI), which is completely transformed into aldehyde by treatment with a Diagram

acide, par exemple l'acide parâtoluènesulfonique dans

acid, for example paratoluenesulfonic acid in

1 acetone.

The aldehyde of general formula (VI) is then treated using (4-methylbenzenesulfonyl) methyl isocyanide ("TosMIC") in an alcoholic solvent, for example methanol, in the presence of a base, for example carbonate potassium, at a temperature of 20 to 65 ° C, to obtain a compound of general formula (VII).

The latter is treated with phosphorus oxychloride, in the presence of N, N-dimethylformamide, at a temperature of 20 to 95 ° C, to obtain, after hydrolysis, an aldehyde of general formula (VIII) which is reacted with methyl (dimethoxyphosphinyl) acetate (designated by DMPAcOMe in the diagram), in an ethereal solvent, for example tetrahydrofuran, at a temperature of 20 to 65 ° C, to obtain an ester of general formula (IX) which is subjected to a hydrogenation catalytically or chemically, for example by means of sodium borohydride in the presence of copper chloride, to obtain an ester of general formula (X). Finally, the latter is treated either directly with an amine of general formula (XI), in which R ₂ and R ₃ are as defined above, in a solvent such as a mixture of methanol and dichloromethane, or indirectly, by first preparing the corresponding acid by hydrolysis in basic medium, in a solvent such as methanol or ethanol, at a temperature of 60 to 80 ° C, then, by means of 1, 1 '-carbonylbis-1H- imidazole, by preparing the corresponding imidazolide, and finally by treating the latter with the amine of general formula (XI).

The isoquinolineones of general formula (VII), the esters of general formula (X) and the corresponding acids are new and form part of the invention as synthesis intermediates.

The starting amides of general formula (II) can be prepared by methods such as those described in Tet. Lett. (1994) 14 4149-4166 and J. Ara. Chem. Soc. (1962) 84 3410. The examples which follow illustrate the preparation of some compounds of the invention. Elementary microanalyses, and IR and NMR spectra confirm the structures of the compounds obtained. The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of Table 1 given below.

In the names of the compounds, the dash "-" is part of the word, and the dash "_" is only used for the break at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.

Example 1 (Compound No. 7).

N, 2, 7-Trimethyl- ₃ -oxazol-5-yl- ₁ -oxo-1,2,2-dihydroisoquinoline-4-propanamide.

1.1. 2, 7-Dimethyl-l-oxo-1,2,2-dihydroisoquinoline-3-carbox_ aldehyde.

Under a nitrogen atmosphere, 16 g (98 mmol) of N, 2,5-tri_ methylbenzamide are placed in solution in 250 ml of dry tetrahydrofuran, the solution is cooled to -70 ° C. and 100 ml are added dropwise. of 2.5 M butyllithium (250 mmol) in hexane, and the mixture is stirred while allowing the temperature to rise to 0 ° C. After 15 min at 0 ° C., it is again cooled to -60 ° C. and 160 g (148 mmol) of diethoxy-N, N-dimethylacetamide are added, the mixture is warmed to room temperature then, for a few minutes, at 60 ° vs.

It is cooled to 0 ° C., it is hydrolyzed by adding 200 ml of water, the organic phase is separated, the aqueous phase is extracted with dichloromethane, all of the organic phases are combined and the solvent is evaporated under pressure scaled down.

The residue is taken with 200 ml of toluene, 3 g (22 mmol) of Oxone ^® and the mixture was heated under reflux by trapping the water formed using a Dean-Stark apparatus.

The solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 50/50 mixture of cyclohexane and dichloromethane, then with a 100/0 to 95/5 mixture of dichlo_ romethane and ethyl acetate.

About 15 g of a mixture of acetal and aldehyde are obtained. It is dissolved in 250 ml of acetone, 0.8 g of 4-methylbenzenesulfonic acid is added and the mixture is heated at reflux for 18 h.

It is concentrated under reduced pressure, dichloromethane, water and a saturated aqueous solution of sodium hydrogencarbonate are added, the organic phase is separated, washed with water, dried over sodium sulfate , it is filtered, the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 0/100 mixture of cyclohexane and dichloromethane, then with a 90/10 mixture dichlo_ romethane and methanol. After recrystallization from a mixture of dichloromethane and cyclohexane, 10.59 g (52.3 mmol) of aldehyde are obtained in the form of a white solid. Melting point: 171-173 ° C.

1.2. 2,7-Dimethyl-3-oxazol-5-yl-isoquinoline-1 - (2H) -one. In a 500 ml flask were placed 16 g (79.12 mmol) of _{2,7-dimethyl-l -oxo-l,} 2-dihydroisoquinoline-3-carboxaldehyde dissolved in 250 ml of methanol are successively added 15.44 g (79.13 mmol) of (4-methylbenzene_sulfonyl) methyl isocyanide ("TosMIC") and 13 g (94.05 mmol) of anhydrous potassium carbonate, the mixture is heated very gradually to the temperature reflux and is maintained there for 3 h 30 min. It is cooled to room temperature, the solvent is evaporated off under reduced pressure, water and dichloromethane are added to the residue, the organic phase is separated, washed with water, dried over sodium sulfate, the filter, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 0/100 mixture of dichloromethane and ethyl acetate.

After evaporation of the solvents under reduced pressure and recrystallization from ethyl acetate, 10.01 g (41.66 mmol) of yellow solid are obtained. Melting point: 163-164, 5 ° C.

By concentrating the mother liquors under reduced pressure, a second jet of 5.87 g (24.43 mmol) of orange solid is isolated.

1.3. 2, 7-Dimethyl-3-oxazol-5-yl-1-oxo-1, 2-dihydroiso_ quinoline-4-carboxaldehyde. Under a nitrogen atmosphere, 56.64 g (775 mmol) of dry N, N-dimethylformamide are cooled to 0 ° C., 32.9 g (214.6 mmol) of phosphorus oxychloride are added dropwise then , at room temperature, 13.87 g (57.7 mmol) of 2, 7-dimethyl-3-oxazol-5-yl-isoquinoline-1 - (2H) -one, and the mixture is heated to 95 ° C. for 4 a.m.

It is allowed to cool, it is poured onto 200 g of crushed ice, 30% aqueous sodium hydroxide is added until pH = 10, while cooling, it is diluted with water to a volume d 'about 1 1 and extracted with dichloromethane. The organic phase is washed four times with water, dried over sodium sulfate, filtered, the solvents are evaporated off under reduced pressure, and the residue is purified by chromatography on a silica gel column, eluting with a 100/0 to 0/100 mixture of dichloromethane and ethyl acetate.

After evaporation of the solvents under reduced pressure and recrystallization from a mixture of dichloromethane and cyclohexane, 7.81 g (29.11 mmol) of yellowish amorphous solid are obtained. Melting point: 147-149 ° C.

By evaporating the mother liquors under reduced pressure, a second jet of 3.83 g (14.27 mmol) of compound is obtained.

1.4. 3- (2,7-Dimethyl-3-oxazol-5-yl-1-oxo-1,2,2-dihydroiso_ quinoline-4-yl) methyl prop-2-enoate. 2.6 g (65 mmol) of sodium hydride suspended in 60% suspension in oil are introduced into a 500 ml three-necked flask placed under an argon atmosphere, washed with pentane and replaced. suspended in 300 ml of dry tetrahydrofuran, the suspension is cooled to 0 ° C., 10 g (59.4 mmol) of (dimethoxyphosphiny1) methyl acetate dissolved in 20 ml of tetrahydrofuran are added dropwise, then 11 , 64 g (43.4 mmol) of 2, 7-dimethyl-3-oxazol-5-yl-1-oxo-1,2, dihydroisoquinoline-4-carboxaldehyde, and the mixture is heated at reflux for 6 h.

It is allowed to cool, 10 ml of methanol are added slowly to destroy the excess hydride, the solvent is evaporated off under reduced pressure, the residue is taken up in 250 ml of dichloromethane, hydrochloric acid is added until that the pH is between 1 and 2, the organic phase is separated, washed with water, dried over sodium sulfate, filtered and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 0/100 mixture of dichloromethane and ethyl acetate, then with a 95/5 to 90/10 mixture of dichloromethane and methanol. After evaporation of the solvents under reduced pressure and recrystallization from a mixture of cyclohexane and dichloromethane, 10.91 g (33.64 mmol) of compound are obtained. Melting point: 104.5-108 ° C.

1.5. Methyl 2,7-Dimethyl-3-oxazol-5-yl-1-oxo-1,2,2-dihydroiso_ quinoline-4-propanoate. To a solution of 10.91 g (33.64 mmol) of 3- (2, 7-dimethyl-3-oxazol-5-yl-1-oxo-1, 2-dihydroisoquinoline-4-yl) prop-2- methyl enoate in 180 ml of acetic acid 5 g of 5% palladium on carbon are added, and the suspension is subjected to hydrogenation in a Parr apparatus under a pressure of approximately 0.3 MPa for 4 h at 40 ° C. , then for 4 h at room temperature. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure, 300 ml of dichloromethane are added to the residue and then a saturated aqueous solution of sodium hydrogencarbonate, the organic phase is separated, washed with water, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The product obtained is subjected to a new catalytic hydrogenation under the conditions described above and the operations of separation of the product obtained are repeated. The latter is purified by chromatography on a column of silica gel, eluting with a 100/0 to 0/100 mixture of dichloro_ methane and ethyl acetate, then with a mexange y: -. / -aa 90/10 of dichloromethane and methanol. After evaporation of the solvents under reduced pressure and recrystallization from a mixture of dichloromethane and ethyl acetate, 4 g (12.26 mmol) of compound are obtained. Melting point: 119-121.5 ° C.

1.6. N, 2, _{7-Trimethyl-3-oxazol-5-yl-l} -oxo-l, 2-dihydroiso_ quinoline-4-propanamide. 150 ml of methanol and 20 ml of dichloromethane are added to 2.1 g (6.49 mmol) of 2, 7-dimethyl-3-oxazol-5-yl-l-oxo-1,2, dihydroisoquinoline-4-propanoate methyl and passed through the solution of methylamine gas until saturation. After 3 hours of stirring at room temperature, the mixture is saturated again, then it is left to stand for 24 hours. The volatile compounds are evaporated under reduced pressure, 250 ml of dichloromethane and 100 ml of water are added to the residue, the organic phase is separated, washed with water, dried over sodium sulphate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 0/100 mixture of dichloromethane and ethyl acetate, then with a 95/5 mixture 90/10 of dichloro. methane and methanol.

After evaporation of the solvents and recrystallization from a 95/5 mixture of ethyl acetate and dichloromethane, 1.58 g (4.85 mmol) of white amorphous compound are obtained. Melting point: 208-209, 5 ° C.

Example 2 (Compound Ν ° 9).

2, 7-Dimethyl-3-oxazol-5-yl-1-oxo-W, N-dipropyl-1,2-dihydroiso_ quinoline-4-propanamide.

2.1. 2, 7-dimethyl-3-oxazol-5-yl-1-oxo-1, 2-dihydroiso_ quinoline-4-propanoic acid. In a 250 ml flask, 5.9 g (18.08 mmol) of 2, 7-dimethyl-3-oxazol-5-yl-1-oxo-1, 2-dihydroisoquinoline-4-methyl propanoate are dissolved in 80 ml of ethanol, 5 ml of 35% aqueous sodium hydroxide solution and the mixture is heated to reflux for 1 h.

It is cooled, the solvent is evaporated off under reduced pressure, the residue is taken up in 60 ml of water, 37% hydrochloric acid is added dropwise while the mixture is cooled with an ice bath. insoluble by filtration, washed with water and dried. 4.97 g of crude acid are obtained in the form of a white solid which is used as it is in the following stage.

2.2. 2, 7-Dimethyl-3-oxazol-5-yl - 1 -oxo-N, N-dipropyl-1,2-dihydroisoquinoline-4-propanamide. 1.85 g (5.92 mmol) of 2,7-dimethyl-3-oxazol-5-yl-l-oxo-1,2,2-dihydroiso-quinoline-4-propanoic acid are introduced into a 250 ml flask. solution in 60 ml of dichloromethane, 1.9 g (11.72 mmol) of 1,1 '-carbonylbis-1H-imidazole are added, the mixture is stirred at room temperature for 1 h, 1.11 g (10 , 94 mmol) of dipropylamine and the mixture is allowed to stir for 24 h.

110 ml of dichloromethane and then 1 M hydrochloric acid are added, then 0.1 M until pH = 2, the organic phase is separated, washed with water and then with a saturated aqueous solution of hydrogen carbonate. sodium, dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 50/50 to 0/100 mixture of dichloromethane and d ethyl acetate, then with a 95/5 mixture of dichloromethane and methanol. After evaporation of the solvents and recrystallization from a mixture of diethyl ether and ethyl acetate, 1.41 g (3.56 mmol) of white solid are obtained. Melting point: 160-161 ° C.

The following table illustrates the chemical structures and the physical properties of some compounds of the invention. Board

The compounds of the invention have been subjected to pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.

Study of the membrane bond with respect to a population of ω (benzodiazepine) receptors associated with GABA _A receptors containing the ce subunit.

These receptors can be selectively labeled in rat hippocampus membranes incubated in the presence of [ ³ H] flumazenil and 5 μM zolpidem (in order to mask the other ω receptor subtypes).

The compounds have been the subject of an in vitro study as to their affinity for these receptors labeled with [ ³ H] flumazenil. The animals used are OFA male rats (Iffa Credo) weighing 200 to 250 g. After decapitation, the hippocampus is removed and ground using an Ultra-Turrax ™ or Polytron ™ device for 20 s at 6/10 of maximum speed in 80 volumes of 50 mM Tris buffer at a pH adjusted to 7, 4 with hydrochloric acid, and containing 120 mM of sodium chloride and 5 mM of potassium chloride (5 mM).

The binding with [ ³ H] flumazenil (1 nM; specific activity: 80-87 Ci / mmole; Du Pont de Nemours / New England Nuclear) is determined by incubation of 200 μl of suspension of membranes in a final volume of 1 ml of buffer containing 5 μM of zolpidem and the compound to be tested. After a 45 min incubation at 0 ° C., the membranes are recovered by filtration on Whatman GF / B ™ filters which are washed twice with 5 ml of ice-cold buffer. The amount of radioactivity retained by the filter is measured by liquid scintigraphy.

The specific binding of [ ³ H] flumazenil is defined as the amount of radioactivity retained on the filters and which can be inhibited by co-incubation with flunitrazepam 1 μM. For each concentration of compound studied, the percentage of inhibition of [ ³ H] flumazenil binding is determined, then the concentration CI _S0 , a concentration which inhibits 50% of the specific binding.

The most active compounds of the invention have an IC ₅₀ of between 10 and 100 nM. Study of the membrane bonds with respect to récepteurs receptors (benzodiapapine type II) associated with GABA receptors, containing ma orarily the α subunits _? and α ₃ . The affinity of the compounds for the ω ₂ receptors of the spinal cord was determined according to a variant of the method described by SZ Langer and S. Arbilla in Fund. Clin. Pharmacol. (1988) 2 159-170, using [ ³ H] flumazenil instead of [ ³ H] diazepam as radioligand.

The spinal cord tissue is homogenized for 60 s in 30 volumes of ice-cold buffer (50 ml Tris / HCl, pH 7.4, 120 mM NaCl, 5 mM KCl) and then, after dilution to 1/3, the cell is incubated. suspension with [ ³ H] flumazenil (specific activity: 78 Ci / mmol; New England Nuclear) at a concentration of 1 nM and with the compounds of the invention, at different concentrations, in a final volume of 525 μl. After 30 min of incubation at 0 ° C., the samples are vacuum filtered on hatman GF / B ™ filters and washed immediately with ice-cold buffer. The specific binding of [ ³ H] flumazenil is determined in the presence of unlabelled 1 μM diazepam. The data are analyzed according to the usual methods and the IC ₅₀ is calculated, a concentration which inhibits 50% of the binding of the

[ ³ H] flumazenil.

The IC ₅₀ values of the compounds of the invention are, in this test, between 50 and 500 nM.

Study of the membrane bonds with respect to the ω ₁ receptors (benzoriiaτ: epinic type I) associated with GABA receptors "containing the α subunit ^ The affinity of the compounds for the ω _x receptors of the cerebellum was determined according to a variant of the method described by SZ Langer and S. Arbilla in Fund. Clin. Pharmacol. (1988) 2 159-170, using [ ³ H] flumazenil instead of [ ³ H] diazepam as radioligand. The cerebellum tissue is homogenized for 60 s in 120 volumes of ice-cold buffer (50 ml Tris / HCl, pH 7.4, 120 mM NaCl, 5 mM KCl) then, after dilution to 1/3, the suspension is incubated with [ ³ H] flumazenil (specific activity: 78 Ci / mmol; New England Nuclear) at a concentration of 1 nM and with the compounds of the invention, at different concentrations, in a final volume of 525 μl. After 30 min of incubation at 0 ° C., the samples are vacuum filtered on hatman GF / B ™ filters and washed immediately with ice-cold buffer. The specific binding of [ ³ H] flumazenil is determined in the presence of unlabelled 1 μM diazepam. The data are analyzed according to the usual methods and the IC ₅₀ is calculated, a concentration which inhibits 50% of the binding of [ ³ H] flumazenil. The IC ₅₀ values of the compounds of the invention are, in this test, between 100 and 1000 nM.

Study of the membrane bonds of PHl flumazenil vis-à-vis stable transfected cells expressing the GABA receptor subtype „recombinant α ₃ β ₂ γ ₂ .

The affinity of the compounds for the GABA _A receptor containing the subunits α ₂ β ₃ γ ₂ is studied after stable expression thereof in HEK 293 cells A membrane preparation of such cells is obtained by homogenisation for 60 s in a frozen pad

(K ₂ HP0 ₄ / KH ₂ P0 ₄ 10 mM, pH 7.2) then centrifugation for 10 min at 43,000 g. The pellet is then taken up by homogenization in an ice-cold incubation buffer (K ₂ HP0 ₄ / KH ₂ P0 ₄ 10 mM, KCl 100 mM, pH 7.2). This membrane preparation is incubated, at a rate of approximately 150 μg of protein, with [ ³ H] flumazenil (specific activity: 70-87 Ci / mmol; New England Nuclear) at a concentration of 1 nM and with the compounds of the invention, at different concentrations, in a final volume of 1000 μl. After 90 min of incubation at 0 ° C. the samples are vacuum filtered on Whatman GF / B ™ filters and washed immediately with ice-cold buffer. The specific binding of [ ³ H] flumazenil is determined in the presence of unlabeled 10 μM diazepam. The data are analyzed according to the usual methods and the IC ₅₀ is calculated, a concentration which inhibits 50% of the binding of [ ³ H] flumazenil. The IC ₅₀ values of the most active compounds are, in this test, between 1 and 100 nM. The results of the tests carried out on the compounds of the invention show that in vitro, they selectively displace [ ³ H] flumazenil from its membrane-binding sites with respect to a population of associated ω (benzodiazepine) receptors to GABA _A receptors containing the α ₃ and / or _s subunits, compared to the ω _x receptor subtypes associated with GABA _A receptors containing the α _x subunit, and compared to a population of ω ₂ receptors (benzodiazepine type II) associated with GABA _A receptors mainly containing the α ₂ and α ₃ subunits.

In other words, the compounds have an affinity

^• strong for the membrane binding sites of ^[3 H] flu- mazénil vis-à-vis a population ω receptors (benzodiazepine receptors) associated with GABAA _receptors containing the subunits α ₃ and / or ₅ cc,

^• medium or low for receptor subtypes ^ (benzodiazepine type I) associated with GABA _A receptors containing the α _lf subunit

^• medium or low for a population of ω ₂ receptors (benzodiazepine type II) associated with GABA _A receptors mainly containing the subunits α ₂ and α ₃ .

The selectivity represented by the ratio (CI ₅₀ o ^ -cervelet / CI ₅₀ ω _5- hippocampus) is between 10 and 20 and that represented by the ratio (CI ₅₀ G ^ -cervelet / CI ₅₀ recombinant receptor α ₃ β ₂ γ ₂ ) is between 10 and 60.

The compounds of the invention can be used in the treatment of conditions linked to disorders of GABAergic transmission in general, such as anxiety, sleep disorders, epilepsy, and linked in particular to GABA _A receptors associated with sub - units α ₃ and / or α ₅ . The preferential distribution of ω receptors, associated with the α ₅ subunit of the GABA _A receptor complex, in the olfactory bulb, in limbic structures such as the hippocampus and the hypothalamus, and in the spinal cord, suggests that the compounds of the invention can be used in the process olfaction disorders, cognitive disorders, hormonal disorders related to dysfunction of the hypothalamus, certain emotional disorders and pain perception.

The preferential distribution of ω receptors associated with the cc ₃ subunit of the GABA _A receptor complex in the spinal cord suggests that the compounds of the invention can also be used in the treatment of spasticity and muscle contractures.

This subunit is also present in the brain structures containing the noradrenergic and serotonergic cell bodies, which suggests that the compounds of the invention may find an application in the treatment of diseases associated with a malfunction of these systems, such as depression, anxiety and cognitive impairment.

To this end, the compounds of the invention can be presented in all galenical forms, associated with suitable excipients, for enteral or parenteral administration, for example in the form of tablets, dragees, capsules, capsules, solutions or suspensions which are drinkable or injectable. , suppositories, transdermal patches, etc., dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims

claims 1. Compound corresponding to the general formula (I)

in which X represents a hydrogen or halogen atom or a methyl or methoxy group, Ri represents a methyl group, and R ₂ and R ₃ each represent, independently of one another, a hydrogen atom or a group (C ^ C alkyl. 2. Process for the preparation of compounds according to claim 1, characterized in that the dianion of a benzamide of general formula (II) is reacted

in which X and R _x are as defined in claim 1, with diethoxy-N, N-dimethylacetamide, to obtain a hydroxyacetal of general formula (IV)

which is dehydrated, to obtain a mixture of acetal of general formula (V) and of aldehyde of general formula (VI)

then the acetal is transformed into an aldehyde by treatment with an acid, then the aldehyde of general formula (VI) is treated with (4-methylbenzenesulfonyl) methyl isocyanide to obtain a compound of general formula (VII)

the latter is treated with phosphorus oxychloride in the presence of N, N-dimethylformamide, to obtain, after hydrolysis, an aldehyde of general formula (VIII)

which is reacted with methyl (dimethoxyphosphinyl) acetate to obtain an ester of general formula (IX)

which is subjected to hydrogenation to obtain an ester of general formula (X)

and finally we treat the latter either directly with an amine of general formula (XI) R, HN (XI) in which R ₂ and R ₃ are as defined in claim 1, either indirectly, by first preparing the corresponding acid by hydrolysis in basic medium, then, by means of 1, 1 ′ -carbonylbis-1H-imidazole, by preparing the corresponding imidazolide, and finally by treating the latter with the amine of general formula (XI). 3. Medicament, characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it contains a compound according to claim 1, associated with an excipient. 5. Esters of general formula (X) X

in which X and R _x are as defined in claim 1, as well as the corresponding acids, as synthesis intermediates in the process according to claim 2. 6. Isoquinoleinones of general formula (VII)

in which X and R are as defined in claim 1, as synthesis intermediates in the process according to claim 2.