MXPA01001781A - 6-amino- or 6-hydrazino-sulphonyl-3-quinolynyl-phosphonic acid compounds - Google Patents

Abstract

The invention relates to a compound of formula (I):wherein:R1 represents halogen or a group CF3, R2 represents hydrogen or alkyl or cycloalkyl, R3 is as defined in the description, R4 and R5 represent hydrogen or alkyl, cycloalkyl, aryl or arylalkyl a group Medicaments.

Description

NEW COMPOUNDS OF 6-AMINO- OR 6-HYDRAZINO-SULFONIL-3-UINOLINIL-PHOSPHONIC ACID, A PROCESS FOR YOUR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THE THEY CONTAIN The present invention relates to new compounds of 6-amino- or 6-hydrazino-sulphonyl-3-quinolinyl-phosphonic acid, to a process for their preparation and to compositions containing them. The prior art discloses compounds that are capable of counteracting the excitatory and toxic effects of excitatory amino acids (EAA) by blocking the initial activation of the AMPA receptor (a-amino-3-hydroxy-5-met il-4-isoxazolepropionic acid) / cainate (EP 0 640 612). Its utility is therefore recognized to inhibit pathological phenomena, especially neurotoxic phenomena associated with the hyperactivity of the neurotransmission pathways to excitatory amino acids. These compounds have serious problems of non-oxicity, however, since it has also been shown to be the case for other non-NMDA (N-met i 1-D-aspart at o) antagonists, such as, for example, 6-ni t ro-7-sul famoi 1-quinoxaline-2,3-dione (NBQX) (Journal of Cerebral Blood Flow and Metabolism, 1994, 14_, 251-261). The Applicant has discovered new compounds that have more powerful non-NMDA antagonist properties than the prior art compounds, with a greatly reduced associated oxidicity. These compounds are therefore novel and powerful therapeutic agents, potential for the acute and also chronic treatment of neurological and physiological disorders comprising these amino acids, for example, degenerative disorders such as stroke, brain or spinal trauma, epilepsy, diseases Chronic neurodegenerative diseases, such as Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis or Huntington's chorea. In particular, the present invention relates to compositions of Formula (I): wherein: - R 1 represents a halogen atom or a trifluoromethyl group, - R 2 represents a hydrogen atom or an alkyl or cycloalkyl group, R 3 represents an alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy group, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl or arylalkylcarbonyl or a group NHR6 (where R6 represents a hydrogen atom or an alkyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, arylalkyl or arylalkylcarbonyl group), or R2 and R3 together form with the atom of nitrogen that has a ring that has 5 or 6 carbon atoms, in which one of the carbon atoms can be replaced by an oxygen, nitrogen or sulfur atom, or by an SO or S02 group or by a group NRa (where Ra represents a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group), - R4 and R5, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group or a group (wherein R7 and R8, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group), it is understood that: "alkyl" is understood to mean a linear or branched alkyl group containing of 1 to 6 carbon atoms, - "alkoxy" is understood to mean a linear or branched alkoxy group containing from 1 to 6 carbon atoms, "cycloalkyl" is understood to mean an alkyl or cyclic group containing 3 to 6 carbon atoms. to 8 carbon atoms, "aryl" is understood to mean the phenyl or naphthyl groups, it being possible for these groups to be unsubstituted or substituted by 1 to 3 groups selected from alkyl, cycloalkyl, hydroxy, alkoxy, amino, alkylamino , dialkylamino, cyano, nitro, polyhaloalkyl, S02NR9R10 (where R9 and R10, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) and halogen atoms, its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. Among the pharmaceutically acceptable acids, mention may be made, by way of nonlimiting example, 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, et c. Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. The preferred compounds of the invention are compounds of Formula (I), wherein R 1 represents a chlorine atom. Preferred R3 groups are alkyl group (such as, for example, methyl or propyl), the dialkylaminoalkyl group (such as, for example, dimethylaminoethyl), the aryl group (such as, for example, phenyl), the arylcarbonyl group (such as for example, benzoyl) or the NHCOR group, wherein R represents an alkyl or aryl group. The nitrogen atom is the preferred meaning for the substituents of R4 and R5. Even more especially, the invention relates to compounds of the formula (I) which are: * 7-chloro-2-oxo-6- [(n-propylamino) sulfonyl] -1, 2 -dihydro-3- acid quinolylphos phonic. * 7-Chloro-6- [(methylamino) sulphonyl] -2 -oxo-1,2-dihydro-3-quinolyl phosphonic acid. * 6- (indigo inosul foni 1) -7-chloro-2-oxo-1,2-dihydro-3-quinolyl phosphonic acid. * 6- [(2-benzoylhydrazino) sulfonyl [-7-chloro-2-oxo-1,2-dihydro-3-quinolyl phosphonic acid] * 7-Chloro-β- [(2- {4- [(di-n-propylamino) sulfonyl] benzoyl} -2-oxo-1,2-dihydro-3-quinolylphosphonic acid, and * hydrobromide 7-Chloro-6- ( { [2 - (dimethylamino) ethyl] amino}. sulfonyl) -2-oxo-1,2-dihydro-3-quinol-1-phosphonic acid The enantiomers, diastereoisomers and salts of Pharmaceutically acceptable addition with an acid or a base of the preferred compounds of the invention form an integral part of the invention The invention also relates to a process for the preparation of compounds of the Formula (I), characterized in that it is used as start material a compound of Formula (II): wherein R1 is as defined for Formula I, which is condensed, in the presence of a base, such as, for example, pyridine, with a compound of Formula (III): to produce the compound of Formula (IV) wherein R1 is as defined above, which cyclizes in the presence of a catalytic amount of piperidine to obtain a compound of Formula (V): wherein R1 is as defined hereinabove, which is subjected to a mixture of nitric acid and sulfonic acid to produce a compound of Formula (VI): wherein R1 is as defined hereinabove, which is reduced using palladium on carbon in the presence of hydrogen or iron in a dilute alcoholic medium to produce a compound of Formula (VII): wherein R1 is as defined hereinabove, which is subjected, after conversion to the corresponding diazonium salt, to the action of sulfur dioxide in the presence of CuCl2 to produce a compound of Formula (VIII): wherein R is as defined hereinabove, which is condensed with a compound of the formula HNR2R3, wherein R2 and R3 are as defined for Formula (I) to produce a compound of the Formula (I / a) , a particular case of the compounds of the formula (I): wherein R1, R2 and R3 are as defined hereinbefore, which is partially or totally deprotected in the presence of for example, trimethylsilane bromide to produce a compound of the Formula (I / b), a particular case of the compounds of Formula (I): wherein R1, R2 and R3 are as defined hereinabove and R 'represents a hydrogen atom or an ethyl group, which can be condensed with a compound of the Formula (IX): R "-C1 (IX) wherein R "represents an alkyl, aryl or arylalkyl group or a group (wherein R7 and R8 are as defined for Formula (I)), to obtain a compound of Formula (I / c), a particular case of the compounds of Formula (I): wherein R1, R2, R3, R5 and R "are as defined hereinabove, compounds of the Formulas (I / a) to (I / c) which constitute all of the compounds of the Formula (I) , and can be purified according to a conventional separation technique, converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a technique conventional separation. The compounds of the invention have very valuable pharmacological properties since they are powerful inhibitors of the AMPA receptor, and in addition they are selective since they do not affect the NMDA receptor and therefore do not have any of the side effects described for NMDA antagonists, and especially do not have the nephrotoxicity associated with several AMPA / non-NMDA antagonists. The use of these compounds as inhibitors of the pathological phenomena associated with hyperactivity of the neurotransmission pathways to the excitatory amino acids will therefore be particularly appreciated in the acute and especially chronic treatment of neurological and physiological disorders comprising these amino acids, for example , degenerative disorders such as stroke, brain or spinal trauma, epilepsy, chronic neurodegenerative diseases such as Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis or Hunt ington chorea. The present invention also relates to pharmaceutical compositions comprising as an active ingredient at least one compound of the Formula (I) alone or in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal, percutaneous or rectal, rectal, perlingual, ocular or respiratory administration may be mentioned more especially., especially tablets or lozenges, sublingual tablets, sachets, packets, or gelatin capsules, glossetes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules. The doses vary according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatment and varies from 50 mg to 1 g per 24 hours in one or more administrations. The following examples illustrate the invention and do not limit it in any way.

EXAMPLE 1: 7-Chloro-2-oxo-6- [(n-propylamino) sulfonyl] -1,2-dihydro-3-quinolylphosphonic acid diethyl ester Step A: [(5-Chloro-2-formyl-phenylcarbamoyl) methyl] phosphonic acid diethyl ester Pyridine (3.7 m, 45.7 mmol) is added to a solution of 2-amino-4-chlorobenzaldehyde (6.18 g, 39.7 mmol) in 170 ml anhydrous toluene, followed dropwise by a solution of diethyl ester of chlorocarbonylmethylphosphonic acid (9.8 g, 45.7 mmol) in 15 ml anhydrous toluene while maintaining the reaction mixture at a temperature of of 30 ° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with an IN solution of HCl, and then again with water. Finally, the mixture is washed with a saturated, aqueous solution of NaCl. The organic phase is dried over MgSO4 and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the next step.

Melting Point: 119 ° C My croanális is the emen ta 1% C% H% N Ca 1 culated 42.39 4.34 3.80 Found 42.31 4.12 3.69 Step B: Diethyl ester of the acid (7-chloro-2-oxo-1,2-dihydro-3-quinolyl) fon fo co In a round bottom flask in which a Dean-Stark apparatus is mounted, it is submitted at reflux for 4 hours, with vigorous stirring, all the compounds obtained in step A dissolved in 300 ml of toluene and 0.3 ml of piperidine. The batch is allowed to crystallize at room temperature and the resulting pale yellow solid is completely filtered.

Fusion Point: 210-213X Elemental microanalysis: Q, 0 C * H% N% Cl Calculated 49., 46 4.19 i.44 11.23 Found 49. 77 4.18 i .46 11.63 Step C: Diethyl ester of (7-chloro-6-nitro-2-oxo-l, 2-dihydro-3-quinolyl) fon fs are added dropwise 55 ml of nitric acid to a solution of 55 ml of 96% sulfuric acid cooled in an ice bath, and then diethyl ether (7-chloro-2-oxo-l, 2-dihydro-3) is added portionwise. -quinolyl) phosphonic (14.7 g, 46.6 mmol) while maintaining the temperature less than or equal to 5 ° C. When the addition is complete, stirring is continued for 15 minutes and then the ice bath is removed and the reaction mixture is brought to room temperature over a period of about 1 hour 30 minutes. The solution is poured onto ice and the precipitate is stirred to obtain a filterable solid. The filtration is carried out, followed by washing with water to neutralize and dry in vacuo. The solid is suspended in 210 ml of refluxing ethanol; the batch is allowed to cool and filtered to obtain the title product after drying.

Fusion Point: 258-262 ° C Mi c roana 1 is is elemen ta 1.:% C% H% N% Cl Ca 1 culated 43.29 3.91 7.77 9.83 Found 43.33 4.06 7.60 9.70 Step D: (6-Amino-7-chloro-2-oxo-l, 2-dihydro-3-quinolyl) phosphonic acid diethyl ester A suspension of the compound obtained in Step C (7.0 g, 19.4 mmol), iron in powder (10.8 g, 194 mmol) and ammonium chloride (10.4 g, 194 mmol) was stirred at reflux for 1 hour in a mixture of 270 ml of methanol and 90 ml of water. The suspension is filtered hot on Celite and the solid is rinsed several times with methanol. The filtrate is evaporated to dryness and the residue is suspended in water. The solid is completely filtered, rinsed with water and dried to obtain the title product in the form of orange crystals.

Fusion Point: 255-260X Elemental microanalysis% CH% N Calculado 47.22 3.47 Found 47.06 4.99 ..08 Step E: Diethyl ester of the acid (7-chloro-6-chlorosulfonyl-2-oxo-l, 2-dihydro- 3-quinolyl) fon fo co A solution of 13.4 ml of acetic acid and 2.25 ml of water is saturated with S02 by bubbling S02 gas for 15 minutes. In parallel, a solution of the compound obtained in Step D (3.34 g) is prepared at 5 ° C., 10.1 mmol) in a mixture of 10 ml of glacial acetic acid and 17 ml of concentrated HCl. To this solution is added dropwise a solution of sodium nitrite (767 mg, 11.11 mmol), previously dissolved in 5 ml of water, and the reaction mixture is stirred for 30 minutes at 5 ° C. CuCl22H20 (689 mg, 4.04 mmol) is added to the solution saturated with S02 and the resulting suspension is cooled to 5 ° C. The diazonium chloride solution prepared above is added dropwise to that solution. The mixture is stirred for 1 hour at 5 ° C, and then for 3 hours, it is allowed to return to room temperature. The reaction mixture is poured into ice and the precipitate is completely filtered and rinsed with water. Drying produces the title product in the form of a pale yellow powder.

Fusion Point: 190-200X Elemental microanalysis: Q? ~ (R _. * 5? - x ul N% S% Cl Calculated 37.70 3.41 3.38 7.74 17.12 Found 38.04 3.47 3.40 7.74 17.16 Step F: Diethyl ester of 7'-chloro-2-oxo-6- [(n-pr or p-ylamino) sulfonyl] -1,2-dihydro-3-quinolyl) fon fon a suspension of the compound obtained in Step E (1.26 g, 3.0 mmol) with n-propylamine (9.0 mmol) in 30 mL of acetonitrile is stirred for 3 hours. Evaporation to dryness was carried out, the residue was then taken up in IN HCl and the extraction was carried out with ethyl acetate. Drying over MgSO4 and evaporation of the organic phase produces a residue which is taken up in ether and filtered to yield the title product.

Fusion Point: > 300X My croanál isis the emen ta 1.% C% H% N% S Called 43.99 5.08 6.41 7.34 Found 43.99 5.08 6.24 7.07 EXAMPLE 2: 7-Chloro-2-oxo-6- [(n-propylamino) sulfonyl] -1,2-dihydro-3-quinolylphosphonic acid 25.3 mmol of bromot rimet-ilsilane are added to a suspension of the compound obtained in Example 1 (2.53 mmol) in 30 ml of anhydrous acetonitrile. The stirring is carried out at reflux for 1 hour, followed by evaporation to dryness. The residue is dried in vacuo and taken up in methanol. The suspension is stirred for 30 minutes and becomes increasingly thick. The precipitate is filtered completely and rinsed with a small amount of methanol to obtain the title product.

Fusion Point: > 300 X Microanalysis is elementary:% C * H% N% S% Cl Calculated 37.86 3.71 7.36 8.42 9.31 Found 37.60 3.83 7.07 7.78 10.06 The following examples are obtained according to procedures similar to those of Examples 1 and 2 starting from appropriate substrates.

EXAMPLE 3: 7-Chloro-6- [(di-n-propylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester The procedure is as for Example 1, replacing N-propylamine by dipropi lamina in Step F. Fusion Point: 172-175X EXAMPLE 4: 7-Chloro-6- [(di-n-propylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid The procedure is as for Example 2 starting with the compound obtained in Example 3.

Fusion Point: > 300 X Elemental microanalysis:% C * H% N% S% Cl Calculated 42.61 4.77 6.63 7.58 8.38 Found 42.40 4.78 6.48 7.35 8.95 EXAMPLE 5: 7-Chloro-6- [(methylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic diethyl ester The procedure is as for Example 1, replacing n-propylamine with methylamine in Step F.

Fusion Point: 261-265 ° C Elemental microanalysis:% C% H% N% S Calculated 41.13 4.44 6.85 7.84 Found 41.05 4.39 6.83 7.86 EXAMPLE 6: 7-Chloro-6- [(methylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid The procedure is as for Example 2 starting with the compound obtained in Example 5.

Fusion Point: > 300 X Elemental microanalysis: ~ 5 C s H s N s S ~ s Cl Calculated 34.06 2.86 7.94 9.09 10.05 Found 34.20 3.01 7.75 8.98 10.18 EXAMPLE 7: 7-Chloro-6- [(dimethylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester The procedure is as for Example 5, replacing n-propylamine with dimethylamine in Step F.

Fusion Point: 237-240X Microanalysis element:% C% H% N% S Cl Calculated 42.61 4.77 6.63 7.58 8. 38 Find 42.41 4.71 6.46 7.31 8., 12 EXAMPLE 8: 7-Chloro-6- [(dimethylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid The procedure is as for Example 2 starting with the compound obtained in Example 7.

Fusion Point: 256-259X Microanalysis element:% C% H% N% S% Cl Calculated 34.06 2.86 7.94 9.09 10.05 Found 34.20 3.01 7.75 8.98 10.18 EXAMPLE 9: 7-Chloro-6- (4-morpholinylsulfonyl) -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester The procedure is as for Example 1, replacing n-propylamine with morpholine in Step F.

EXAMPLE 10: 7-Chloro-6- (4-morpholinylsulfonyl) -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid The procedure is as for Example 2 starting from the compound obtained in Example 9.

Fusion Point: > 260X Microanalysis elemen tal:% C% H% N% S% Cl Called 38.20 3.45 6.85 7.84 8.67 Found 37.90 3.64 6.55 7.59 8.70 EXAMPLE 11: 7-Chloro-6- ( { [2- (dimethylamino) ethyl] amino} sulfonyl) -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester bromide The procedure is as for Example 1, replacing n-propylamine by dimethylaminoet and laminate in Step F.

Fusion Point: 166-171X Elemental Microanalysis:% C% H% N% S Calculated 43.83 5.41 9.02 6.88 Found 43.50 5.48 8.70 7.05 EXAMPLE 12: 7-Chloro-6- ( { [2- (dimethylamino) ethyl] amino} sulfonyl) -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid bromide procedure is as for Example 2 starting from the compound obtained in Example 11.

Fusion Point: 216-220X Elemental Microanalysis: ~ 5 C s H ~ Ó N s or s Br Calculated 31.82 3.70 8.26 6.53 16.28 Found 32.15 3.98 8.37 6.07 15.89 EXAMPLE 13: 6- (Anilinosulfonyl) -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid diethyl ester The procedure is as for Example 1, replacing n-propylamine with aniline in Step F.

Fusion Point: 139-141 X Elemental Microanalysis: ~ s C s s N ~ s S Calculated 48.47 4.28 5.95 6.81 Found 48.60 4.30 5.91 6.90 EXAMPLE 14: 6- (Anilinosulfonyl) -7-chloro-2-oxo-1,2-dihydro-3 -quinolylphosphonic acid The procedure is as for Example 2 starting from the compound obtained in Example 13.

Fusion Point: 249-253X Element microanalysis:% C% H% N% S% Cl Calculated 43.44 2.92 6.75 7.73 8.55 Found 43.53 2.87 6.64 7.82 9.06 EXAMPLE 15: 6 - [(2-Benzoylhydrazine) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester The procedure is as for Example 1, replacing n-propylamine with benzoylhydrazine in Step F.

Fusion Point: 202-20 X Elemental microanalysis:% C% H% N% S% Cl Calculated 46.75 4.12 8.18 6.24 6.90 Found 46.66 4.06 8.01 6.18 7.41 EXAMPLE 16: 6- [(2-Benzoylhydrazino) sulfonyl] -7- acid chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic The procedure is as for Example 2 starting from the compound obtained in Example 15.

Fusion Point: 242-244X Microanalysis element:% C% H% N% S% Cl Ca 1 culated 41.98 2.86 9.18 7.00 7.74 Found 42.12 2.80 8.95 7.05 7.92 EXAMPLE 17: 6 - [(2-Acetylhydrazino) -sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester The procedure is as for Example 15, replacing benzoylhydrazine with acetylhydrazine in Step F.

Fusion Point: 125-160X EXAMPLE 18: 6- [(2-Acetylhydrazino) -sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid The procedure is as for Example 2 starting from the compound obtained in Example 17.

Fusion Point: > 3 O O "C Microanalysis element:% C% H% N% S% Cl Calculated 33.39 2.08 10.62 8.10 8.96 Found 33.61 3.09 10.18 7.70 8.23 EXAMPLE 19: Diethyl ester of 7-chloro-6- [(2- {4- [(di-n-propylami) o) sulfonyl] benzoyl}. - hydrazino) sulfonyl] -2-oxo-l, 2 dihydro-3-quinolylphosphonic The procedure is as for Example 1, replacing n-propylamine with p- (dipropylamino-sulphonyl) benzoylhydrazine in Step F.

Fusion Point: 288-290X Element microanalysis:% C% H% N% S% Cl Ca 1 culated 46.12 5.06 8.27 9.47 5.24 Found 45.74 5.09 8.46 9.77 5.83 EXAMPLE 20: 7-Chloro-6- [(2- {4- [(di-n-propylamino) sulfonyl] benzoyl}. Hydrazino) sulfonyl] -2 -oxo-1,2-dihydro-3 acid -quinolylphosphonic. The procedure is as for Example 2 starting from the compound obtained in Example 19.

Fusion Point: 210-214X Microanalysis element:% C% H% N O s% Cl Calculated 42.55 4.22 9.02 10., 33 5.71 In contrast 42.35 4.45 8.69 10., 52 6.21 EXAMPLE 21: 7-Chloro-2-oxo-6- (. {2- [4- [(trifluoromethyl) benzoyl] hydrazino] -.sulfonyl) -1,2-dihydro-3-quinolylphosphonic acid diethyl ester procedure is as for Example 1, replacing benzoylhydrazine with p- (trifluoromethyl) -benzoylhydrazine in Step F.

Fusion Point: 281-282X Mícroanálísís elemen ta 1,; % C% H% N% S Calculated 43.35 3.46 7.22 5.51 Found 43.73 3.55 7.24 5.43 EXAMPLE 22: 7-Chloro-2-oxo-6- (. {2- [4- [(trifluoromethyl) benzoyl] -hydrazino] -sulfonyl) -1,2-dihydro-3-quinolyl-phosphonic acid. The procedure is as for Example 2 starting from the compound obtained from Example 21.

Fusion Point: 278-282 ° C Microanalysis elementa 1% c% H% N% S Calculated 38.83 2.30 7.99 6.10 Find 38.80 2.26 7.78 6.01 EXAMPLE 23: 6- [(Benzollamino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid diethyl ester. The procedure is as for Example 1, replacing n-propylamine with benzoylamino in Step F.

Fusion Point: > 300 X The compound of Example 23 can also be obtained in the following manner: Step A: 6- (Aminosulfonyl) -7-chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic acid diethyl ester A suspension of the compound obtained in Step E of Example 1 is stirred (1.26 g, 3.0 mmol) in 18 ml of 28% ammonium hydroxide solution. After a few minutes, the batch is observed to pass in solution. Stirring is maintained for 30 minutes and the reaction mixture becomes acidic with 4N HCl. A few ml of ethyl acetate are added with stirring and precipitation occurs. The precipitate is filtered completely and dried in vacuo to yield the title product in the form of a cream colored powder.

Fusion Point: 288-290X Step B: 6- [(Benzoyl-amino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid diester. A solution of benzoic acid (111 mg, 0.912 mmol) in 3 ml of anhydrous THF containing 173 mg (1.06 mmol) of carbonyldiimide zol is stirred for 45 minutes under reflux. In parallel, a suspension of 300 mg (0.760 mmol) of the compound obtained in Step a is prepared in 3 ml of THF, to which 0.125 ml (0.836 mmol) of DBU are added. The stirring is carried out for 15 minutes at room temperature, and then the benzoic acid solution prepared above is added thereto. The mixture is heated for 3 hours at 60 ° C. The reaction mixture is cooled in an ice bath and made acidic by the addition of IN HCl. The extraction was carried out with ethyl acetate. The organic phases were combined and washed with a saturated NaCl solution and then dried over MgSO4. After evaporation, the residue was chromatographed on a silica column while eluting with a gradient (95 / 5-90 / 10) of CH2Cl2 / MeOH. The title product is obtained in the form of a white solid.

EXAMPLE 24: 6- [(Benzoylamino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid. The procedure is as for Example 2 starting from the compound obtained from Example 23.

Melting Point: 236-241X Elemental microanalysis:% C% Cl% H% N% S Calculated 43.40 8.01 2.73 6.33 7.24 Found 43.38 8.18 2.86 6.17 7.20 EXAMPLE 25: Diethyl ester of 7-chloro-6- [( { 4- [(Dipropylamino) sulfonyl] benzoyl.}. Amino) -sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as in example 1 by replacing n-propylamine with p (dipropy laminosul-fonyl) -benzolamine, or as for Example 23, replacing benzoic acid with 4- [(di-n-propylamino) -sulfonyl] -benzoic acid.

Fusion Point: 197-200X Elemental microanalysis: O "o- pO 9" d- t Ti% N% S Calculated 47.17 5.02 6.35 9.69 Found 46.83 5.07 6.24 9.84 EXAMPLE 26: 7-Chloro-6- [(. {4 - [(dipropylamino) sulfonyl] benzoyl} - amino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid. The procedure is for Example 2 starting from the compound obtained in Example 25.

Fusion Point: 202-206X Elemental Microanalysis: s C ~ o H ~ o N s S ~ & Cl Calculated 43.60 4.16 6.93 10.58 5.85 Found 43.81 4.27 6.72 10.62 5.96 EXAMPLE 27: Diethyl ester of 7-chloro-6- [(methoxyamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is for Example 1, replacing n-propylamine with methoxyamine hydrochloride.

Fusion Point: 176-180X Microanalysis elementa 1:% C% H% N% S% Cl Calculated 39.58 4.21 6.59 7.55 8.35 Found 39.43 4.35 6.39 7.41 8.89 EXAMPLE 28_: 7-Chloro-6- [(methoxyamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained from Example 27.

Fusion Point: 259-260X Elemental microanalysis: ~ 6 C ~ s H s N. S Calculated 32.58 2.73 7.60 8.70 Found 32.78 2.74 7.40 8.73 EXAMPLE 29: Diethyl ester of 6- [(n-dipropylamino) sulfonyl] -2-oxo-7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The protocols of Steps AG of Example 29 are identical to those of Example 1, replacing 2-amino-4-chlorobenzaldehyde with 2-amino-4-tri f luoromet ilbenzaldehyde in Step A of Example 29, carrying out the step of reduction of Step D with the couplet Pd-C / -formiat or ammonium instead of the couplet Fe / NH4C1 in a diluted alcoholic medium.

Step A: Diethyl ester of acid [(5-tr i f luoromet i 1 -2-formyl-phenyl 1 carbamoi 1) -methyl] -phosphonium co.

Fusion Point: 62-64X Elemental Microanalysis:% C% H% N Calculated 45.79 4.67 3.81 Found 45.89 4.66 3.76 Step B: Diethyl ester of the acid (7-trif luoromet il-2 -oxo- 1, 2-dihydro-3-quinoli 1) phosphonium co.

Fusion Point: 151"C My croanális is elemen ta 1% C% H% N Ca 1 culated 48.15 4.33 4.01 Found 48.19 4.32 3.92 Step C. Diethyl ester of the acid (7-trif luoromet i l-6-nitro-2-oxo-1,2-dihydro-3-quinol i 1) -phosphonic acid Melting Point: 209-215X Mi ero anal is is elemen ta 1% C% H% N Calculated 42.65 3.58 7.11 Find 42.86 3.58 6.78 Step D: Diethyl ester of the acid (6-amino-7-tr if luoromet il-2-oxo-1,2-dihydro-3-quinolylphosphonium) A mixture of 490 mg (1.24 mmol) of the compound obtained in Step D, 650 mg, (12.4 mmol) of ammonium formate and 120 mg of 10% Pd / C in 50 ml of ethanol is stirred at reflux for 1 hour. dihydro-3-quinolylphosphonic. The procedure is as for Step F of Example 1, replacing n-propylamine with dipropylamine.

EXAMPLE 30: 6- [(Di-n-propylamino) sulfonyl] -2-oxo-7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The procedure is for Example 2 starting from the compound obtained in Example 29.

Fusion Point: > 26Q ° C Elemental microanalysis:% C% H% N% S Calculated 42.11 4.42 6.14 7.03 Found 41.87 4.19 6.03 6.79 EXAMPLE 31: Diethyl ester of 2-oxo-6- (l-piperidylsulfonyl) -7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 29, replacing dipropylamine with piperidine in Step F.

Fusion Point: 132-135 X a membrane, filtered, the filtrate was evaporated to dryness and the residue is taken up in water. The suspension is filtered, rinsed with water, filtered by suction and dried in vacuo to obtain the title product in the form of a yellow solid.

Fusion Point: 240-244X Elemental Microanalysis:% C% H% N Calculated 46.16 4.43 7.69 Found 46.26 4.37 7.62 Step Diethyl ester of the acid (7- tr i -fluoromet il-6-c lor or sulf Onyl-2-oxo-1,2-dihydro-3-quinolyl) phosphonic acid.

Fusion Point: 165-171 X Mícroanális is elemen tal:% C% H% N% S "O Cl Calculated 34.56 3.15 3.13 7.16 7. 92 Found 37.54 3.20 3.18 7.05 7. 97 Step F: 6- [(di-n-propylamino) sulfonyl] -2-oxo-7 - (tr i fl uoromethyl) -1,2-diethyl ester: EXAMPLE 32: 2-Oxo-6- (1- piperidylsulfonyl) -7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid.

Fusion Point: > 260 ° C Elemental microanalysis: "5 C" or H s N s S Calculated 40.92 3.66 6.36 7.28 Found 40.96 3.64 6.31 7.25 EXAMPLE 33: Diethyl acid ester 6-. { [(benzyloxy) amino] sulfonyl} -7-chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 27, replacing methoxyamine hydrochloride with benzyloxyamine hydrochloride.

Fusion Point: 233-236X Elemental microanalysis:% C% H% N% S Calculated 47.96 4.43 5.59 6.40 Found 47.84 4.83 5.56 6.24 EXAMPLE 34: Diethyl ester of 7-chloro-6- [(hydroxyamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. 1.35 ml (1.35 mmol) of a solution of BBr3, M, CH2C12 are added dropwise to a suspension of 310 mg (0.655 mmol) of the product from the previous step in 30 ml of CH2C12 cooled to -60 ° C. The reaction mixture was allowed to return to -20 ° C over a period of about 1 hour and then poured into ice. The gelatinous white suspension is stirred and then filtered. The white solid is rinsed several times with water and then with ether. It is then dispersed hot in acetonitrile and the resulting solid, which corresponds to the title compound, is completely filtered.

Fusion Point: 285-290X Elemental Microanalysis:% C% H% N% Cl Calculated 38.01 3.93 6.82 7.81 Found '38.01 3.97 6.48 7.86 EXAMPLE 3_5: 7-Chloro-6- [(hydroxyamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 34 Fusion Point: 285-290X Elemental microanalysis: O 5- C- '95- 1 U1 * N% S% Cl Calculated 30.48 2.27 7.90 9.04 10.00 Found 30.76 2.58 7.35 9.03 10.04 EXAMPLE 36: Diethyl ester of 7-chloro-6- [(cyclopropylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 1, replacing n-propylamine with cyclopropylamine in Step F.

Fusion Point: 261-263 ° C Microanalysis elemen tal:% C% H% N% S% Cl Called 44.20 4.64 6.44 7.37 8.15 Found 44.13 4.75 6.03 6.82 8.70 EXAMPLE 37: 7-Chloro-6- [(cyclopropylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 36.

Fusion Point: > 300 Elementary microanalysis:% C% H% N% S% Cl Calculated 38.06 3.19 1.40 8.47 9.36 Found 38.05 3.18 7.08 8.27 10.47 EXAMPLE 38: Diethyl ester of 7-chloro-6-t (isopropylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 1, replacing n-propylamine by i sopropylamine in Step F.

Fusion Point: 239-240X Microanalysis element:% C% H% N% S Q, "O Cl Calculated 43.99 5.08 6.41 7.34 8. 12 Found 44.13 5.13 6.24 7.25 9. 76 EXAMPLE 39: 7-Chloro-6- [(isopropylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 38.

Fusion Point: > 300 ° C Microanalysis elemen tal:% C% H% N% S% Cl Called 37.86 3.71 7.36 8.42 9.31 Found 37.56 3.83 7.09 7.98 9.85 EXAMPLE 40: 6- [(n-Butylamino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid diethyl ester. The procedure is as for Example 1, replacing n-propylamine with n-butylamine in Step F.

Fusion Point: 229-230X EXAMPLE 41: 6- [(n-Butylamino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl-phosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 40.

Fusion Point: > 300"C Elementary microanalysis: ~ s C ~ 5 n ~ s N ~ s S ~ s Cl Calculated 39.55 4.08 7.10 8.12 Found 39.25 4 4..0055 6 6..8866 7 7..6633 9.77 EXAMPLE 42: 7-Chloro-6- [(ethylamino) sulfonyl] -2-oxo-l, 2-diethyl ester -dihydro-3-quinolylphosphonic. The procedure is as for Example 1, replacing n-propylamine with ethylamine in Step F.

Fusion Point: 225 X.

EXAMPLE 43: 7-Chloro-6- [(ethylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 42.

Fusion Point: > 300"C Microanalysis elemen tal:% C% H% N% S% Cl Calculated 36.03 3.30 7.64 8.74 9.67 Found 35.95 3.44 7.31 8.16 10.51 EXAMPLE 44: Diethyl ester of 7-chloro-2-oxo-6- acid. { [(2-phenylethyl) amino] sulfonyl} -l, 2-dihydro-3-quinolylphosphonic. The procedure is as for Example 1, replacing n-propylamine with phenethylamine in Step F.

Fusion Point: 267-268X Elemental Microanalysis:% C% H% N% S% Cl Calculated 50.56 4.85 5.61 6.43 7.11 Found 50.71 4.94 5.68 6.22 7.92 EXAMPLE 45: 7-Chloro-2-oxo-6- acid. { [(2-phenylethyl) amino] sulfonyl} -l, 2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 44.

Fusion Point: > 300"C Microanalysis elemen tal:% C% H% N% S% Cl Calculated 46.11 3.64 6.33 7.24 8.01 Find 45.60 3.65 6.18 7.06 8.53 EXAMPLE 46: Diethyl ester of 2-oxo-6 - [(n-propylamino) sulfonyl] -7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The procedure is as for Step F of Example 29, replacing dipropylamine with n-propylamine.

Fusion Point: 218-220 ° C My croanális is elemen tal. % C% H% N% S Calculated 43.41 4.71 5.96 6.82 Found 43.39 4.65 5.82 6.80 EXAMPLE 47: 2-0x0-6- [(n-propylamino) sulfonyl] -7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 46.

Fusion Point: 277 ° C Elementary microanalysis g, or C% H N. Calculated 37. 69 3.41 6.76 7.74 Found 37. 74 3.57 6.74 8.10 EXAMPLE 48: 6- [(Methylamino) sulfonyl] -2-oxo-7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid diethyl ester. The procedure is as for Step F of Example 29, replacing dipropylamine by melamine.

Merger Point: 142-145X Mycroanal is is elementary:% C% H% N% S Calculated 40.73 4.10 6.33 7.25 Found 40.64 4.01 6.18 7.11 EXAMPLE 49: 6- [(Methylamino) sulfonyl] -2-oxo-7- (trifluoromethyl) -1,2-dihydro-3-quinolylphosphonic acid. The procedure is as for Example 2 starting from the compound obtained in Example 48.

Fusion Point: > 300 ° C Elemental microanalysis:% C% H% N% S Calculated 34.21 2.61 7.25 8.30 Found 34.56 2.66 7.34 8.59 PHARMACOLOGICAL STUDY EXAMPLE A: Inhibition of the current induced by administration of (R, S) -AMPA (10 μM) of Xenopus oocytes injected into the mRNAs of the rat cortex. Xenopus oocytes were injected with 50 ng of poly (A +) mRNA isolated from the rat cerebral cortex incubated for 2 to 3 days at 18 ° C to allow their protein expression. The influx currents induced by administration of (R, S) -AMPA (10 μM) are measured in a medium having the composition: NaCl (82.5 mM), KCl (2.5 m), CaCl2 (1 mM), MgCl2 (1 mM), NaH2P04 (1 mM), HEPES (5 m), pH 7.4, by the 2-electrode voltage clamp method (potential = -60 mV). The products of the present invention are administered in a concentration-dependent manner, 30 seconds before and during the administration of (R, S) -AMPA agonists. Its ability to inhibit the current induced by (R, S) -AMPA is determined by the IC50 values (μM), which represents the concentrations that 50% inhibit the current induced by an administration of (R, S) -AMPA (10). μM). The compounds of the invention demonstrate excellent inhibitory properties with IC5o values (μM) of the order of 1.

EXAMPLE B: Audiogenic convulsion test in DBA / 2 mice. In immature DBA / 2 mice, seizures can be triggered by subjecting the animal to stimulation with high frequency and high intensity sound. Antagonists of the AMPA-type glutamate receptor antagonize this type of seizure in a dose-dependent manner (Chapman et al., Epilepsy Res., 1991, _9, 92-96). This test is used to study the anti-convulsive effects of the compounds of the present invention. In summary, immature DBA / 2 mice (21-28 days) were exposed for 60 seconds at a noise of 105 dB and 18 kHz. This causes the appearance of clonic seizures. The products that are studied and the solvent are administered by the i.p route. 30 minutes before the start the test in a volume of 0.1 ml / 10 g. The ED50 (dose that inhibits the occurrence of seizures by 50%) is determined for each compound using the method of Litchfield and icoxon (J. Pharmacol, Exp. Ther., 1949, 9_6, 99-113). The compounds of the invention demonstrate an excellent ability to inhibit seizures with ED50 values of the order of 10 mg / kg i.p.

EXAMPLE C: Fischer rat nephrotoxicity test. The evaluation of the renal impact of the compounds of the present invention is carried out in an adult Fischer rat weighing 200-250 g. Fischer rats are anesthetized using pantobarbital (Nembutal®, 60 mg / kg i.p.). 90 minutes after the anesthesia has been induced, the test compounds are administered by the intravenous route in doses of 3 to 10 mg / kg. 24 hours after administration, the animals are sacrificed, the plasma is removed and the creatinine and uremia measurements are made. Statistical analysis is carried out using analysis of variance of individual factor followed by a Newman-Keuls test, which compares treated animals and animals that have received only the carrier. The compounds of the invention exhibit excellent renal tolerance, no toxic effect obtained for doses less than or equal to 10 mg / kg i.v.

EXAMPLE D: Pharmaceutical composition 1000 tablets containing a dose of 5 mg of 7-chloro-2-oxo-6- [(n-propylamino) sulfonyl] -l, 2-dihydro-3-quinolyl phosphonic acid (Example 2) 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

Claims (15)

1. CLAIMS 1. Compounds of the Formula (I) wherein: - R 1 represents a halogen atom or a trifluoromethyl group, - R 2 represents a hydrogen atom or an alkyl or cycloalkyl group, R 3 represents an alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy group , aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl or arylalkylcarbonyl or a group NHR6 (where R6 represents a hydrogen atom or an alkyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, arylalkyl or arylalkylcarbonyl group), or R2 and R3 together form with the nitrogen atom that has a ring that has 5 or 6 carbon atoms, in which one of the carbon atoms can be replaced by an oxygen, nitrogen or sulfur atom, or by an SO or S02 group or by a group NRa (where Ra represents a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group), R4 and R5, which may be identical or different, represent a hydrogen atom. or an alkyl, cycloalkyl, aryl or arylalkyl group or a group (wherein R7 and R8, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group), it is understood that: "alkyl" is understood to mean a linear or branched alkyl group containing of 1 to 6 carbon atoms, - "alkoxy" is understood to mean a linear or branched alkoxy group containing from 1 to 6 carbon atoms, - "cycloalkyl" is understood to mean an alkyl or cyclic group containing 3 to 8 carbon atoms, "aryl" is understood to mean the phenyl or naphthyl groups, it being possible for these groups to be insubstituted or substituted by 1 to 3 groups selected from alkyl, cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, polyhaloalkyl, S02NR9R10 (where R9 and R10, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) and halogen atoms, their enantiomers and diastereomer s and addition salts thereof with a pharmaceutically acceptable acid or base.
2. 2. The compounds of Formula (I) according to claim 1, wherein R1 represents a chlorine atom, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
3. 3. The compounds of Formula (I) according to claim 1, wherein R3 represents an alkyl group, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base.
4. 4. The compounds of the Formula (I) according to claim 1, wherein R 3 represents an aryl group, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
5. 5. The compounds of Formula (I) according to claim 1, wherein R3 represents a NHCOR group wherein R represents an alkyl or aryl group, their isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
6. 6. The compounds of Formula (I) according to claim 1, wherein R2 represents a hydrogen atom, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
7. 7. The compounds of Formula (I) according to claim 1, wherein R4 and R5 simultaneously represent a hydrogen atom, its isomers and their pharmaceutically acceptable addition salts thereof with an acid or a base.
8. 8. The compounds of Formula (I) according to claim 1, which are 7-chloro-2-oxo-6- [(propyl amino) sulfonyl] -1,2-dihydro-3-quinolyl phosphonic acid, and -chloro-6- [(methylamino) sulfonyl] -2-oxo-l, 2-dihydro-3-quinolyl phosphonic acid, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
9. 9. The compound of Formula (I) according to claim 1, which is 7-chloro-6- [(2- {4- [(dimethylamino) sulfonyl] benzoyl} hydrazine) sulfonyl hydrobromide. ] -2 -oxo-1, 2-dihydro-3-quinolylphos phonic its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base.
10. 10. The compound of Formula (I) according to claim 1, which is 7-chloro-6- ( { [2- (dimethylamino) ethyl] amino.} Sulfonyl) -2-oxo-1 hydrobromide. , 2-dihydro-3-quinolyl phosphonic acid, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base. The compound of Formula (I) according to claim 1, which is 6- (anilinosulfonyl) -7-chloro-2-oxo-l, 2-dihydro-3-quinolylphosphonic acid, its isomers and pharmaceutically addition salts acceptable from it with an acid or a base. 12. The compound of Formula (I) according to claim 1, which is 6 - [(2-benzoylhydrazino) sulfonyl] -7-chloro-2-oxo-l, 2-dihydro-3-quinolyl phosphonic acid, its isomers and pharmaceutically acceptable addition salts thereof with an acid or a base. 13. Process for the preparation of the compounds of the Formula (I) according to claim 1, characterized in that a compound of the Formula (II) is used as the starting material: wherein R1 is as defined for Formula I, which is condensed, in the presence of a base, such as, for example, pyridine, with a compound of Formula (III): to produce the compound of Formula (IV) wherein R1 is as defined above, which cyclizes in the presence of a catalytic amount of piperidine to obtain a compound of Formula (V): wherein R is as defined hereinabove, which is subjected to a mixture of nitric acid and sulfonic acid to produce a compound of Formula (VI): wherein R1 is as defined hereinabove, which is reduced using palladium on carbon in the presence of hydrogen or iron in a dilute alcoholic medium to produce a compound of Formula (VII): wherein R1 is as defined hereinabove, which is subjected, after conversion to the corresponding diazonium salt, to the action of sulfur dioxide in the presence of CuCl2 to produce a compound of Formula (VIII): wherein R1 is as defined hereinabove, which is condensed with a compound of the formula HNR2R3, wherein R2 and R3 are as defined for Formula (I) to produce a compound of the Formula (I / a) , a particular case of the compounds of the Formula (I): wherein R1, R2 and R3 are as defined hereinabove, which is partially or totally deprotected in the presence of, for example, trimethyl-bromide bromide to produce a compound of the Formula (I / b), a particular of the compounds of Formula (I): wherein R1, R2 and R3 are as defined hereinabove and R 'represents a hydrogen atom or an ethyl group, which may be condensed with a compound of the Formula (IX) R "-C1 (IX) wherein R "represents an alkyl, aryl or arylalkyl group or a group (wherein R7 and R-8 are as defined for Formula (I)), to obtain a compound of Formula (I / c), a particular case of the compounds of Formula (I): wherein R1, R2, R3, R5 and R "are as defined hereinabove, compounds of the Formulas (I / a) to (I / c) which constitute all of the compounds of the Formula (I) , and can be purified according to a conventional separation technique, converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a technique conventional separation. 14. Pharmaceutical compositions comprising as active ingredient at least one compound of Formula (I) according to any of claims 1 to 12 or a pharmaceutically acceptable addition salt thereof with an acid or a base, alone or in combination with one or more pharmaceutically acceptable excipients. 15. The pharmaceutical compositions according to claim 14, for use in the manufacture of a medicament for the acute or chronic treatment of pathological phenomena associated with hyperactivity of the neurotransmission pathways to excitatory amino acids, such as stroke, brain trauma. or spinal, epilepsy, chronic neurodegenerative diseases, such as Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis or Huntington's chorea.