FR2827600A1 - New quinolone acid derivatives with aldose reductase inhibiting activity, useful for prevention and treatment of diabetes-related disorders - Google Patents

Abstract

Quinolone acid derivatives (I), their tautomers, enantiomers, diastereoisomers, epimers and their salts, are new. Quinolone acid derivatives of formula (I), their tautomers, enantiomers, diastereoisomers, epimers and their salts, are new: X = methylene (optionally substituted), N, O or S; R1 = OR2 or amine (optionally substituted by 1-5C alkyl or alkoxy, 3-8C cycloalkyl, (alkyl)aryl, and/or aralkyl, these groups being optionally interrupted by heteroatom(s) and optionally substituted by halogen(s), the N atom of the amine group optionally forming part of a heterocycle); R2 = H, 1-20C alkyl (optionally substituted by halogen, 1-5C alkyl or alkoxy, 3-8C cycloalkyl, optionally substituted amino, optionally substituted carbonyl, ester, amide, S or P), 2-20C alkylene or alkyne (optionally substituted by halogen, 1-5C alkyl or alkoxy or 3-8C cycloalkyl), 3-8C cycloalkyl (optionally substituted by 1-5C alkyl or alkoxy), 3-8C heterocycloalkyl (having heteroatoms of O, N or S, and optionally substituted by 1-5C alkyl or alkoxy), 6-14C aryl or 1-20C alkyl (optionally substituted by amino, OH, thio, halogen, 1-5C alkyl, alkoxy, alkylthio, alkylamino, 6-14C aryl(oxy), 6-14C aryl-1-5C alkoxy, CN, CF3, COOH, COO-methyl or COO-ethyl), or 1-13X=C heteroaryl (having heteroatom(s) of O, N or S, and optionally substituted by amino, OH, thio, halogen, 1-5C alkyl, alkoxy, alkylthio, alkylamino, 6-14C aryl(oxy), 6-14C aryl-1-5C alkoxy, CN, CF3, COOH, COO-methyl or COO-ethyl); and A = bond or 1-6C alkyl (optionally substituted by halogen, 3-8C cycloalkyl, 1-5C alkoxy, optionally substituted amino, optionally substituted carbonyl, ester, amide, S or P.

Description

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 The present invention provides quinolone acid derivatives useful in the treatment or prevention of diabetic complications.

 Diabetes is characterized by a high concentration of glucose in the blood. This glucose is normally metabolised by the enzyme hexokinase during the first step of glycolysis, resulting in degradation to pyruvate.

When the glucose concentration is too high, the hexokinase is saturated and a second pathway of glucose metabolism comes into play; it is the polyol route which successively involves two enzymes: aldose reductase, which converts glucose into sorbitol and sorbitol dehydrogenase which converts sorbitol into fructose. In diabetes, excess glucose accelerates the formation of sorbitol, which tends to accumulate. This leads to serious metabolic disturbances, such as an increase in osmotic pressure, which can lead to tissue degeneration. The aldose reductase inhibitors are therefore useful for treating or preventing some of the complications of diabetes.

dans laquelle : X représente indépendamment les uns des autres un radical méthylène éventuellement substitué, un atome d'azote, d'oxygène ou de soufre, R1 représente un groupement choisi parmi : - radical de formule OR2, The compounds of the invention have the following general formula (1):

in which: X independently of one another is an optionally substituted methylene radical, a nitrogen, oxygen or sulfur atom, R1 represents a group chosen from: - radical of formula OR2,

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Amine substitué ou non par un ou plusieurs des groupements suivants : alkyle (C1-C5), cyc ! oa ! ky ! e (Cs-Cs), aikoxy (Ci-Ce), ary ! e, alkylaryle ou aralkyle, ces groupements pouvant être interrompus par un ou plusieurs hétéroatomes et/ou pouvant être substitués, notamment par un ou plusieurs atome d'halogène, l'azote du groupement amine peut également faire partie d'un hétérocycloalkyle, R2, identique ou différent, représente un groupement choisi parmi : hydrogène, Alkyle (Cl-C20) substitué ou non par un ou plusieurs des groupements suivants : halogène, alkyle (C1-C5), cycloalkyle (C3-C8), alkoxy (C1-
C5), amino substitué ou non, carbonyle éventuellement substitué, ester, amide, un atome de soufre ou de phosphore, - Alkylène (C2-C2O) substitué ou non par halogène, alkyle (C1-C5), alkoxy (Ci-C5), cycloalkyle (C3-C8) - Alkyne (C2-C20) substitué ou non par halogène, alkyle (C1-C5), alkoxy (Ci-C5), cycloalkyle (C3-C8) - Cydoatkyie (Cs-Cg) substitué ou non par alkyle (C1-C5), alkoxy (C1-C5) - Hétérocycloalkyle (C3-C8) portant un ou plusieurs hétéroatomes choisis parmi N, 0 et S et substitué ou non par alkyle (C1-C5), alkoxy (C1-C5),

- Aryl (C6-C14) alkyle (C1-C20) substitué ou non par amino, hydroxy, thio, halogène, alkyle (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1- C5), aryle (C6-C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluorométhyle, carboxy, carboxyméthyle ou carboxyéthyle, - Aryle (C6-C14) substitué ou non par amino, hydroxy, thio, halogène, alkyle (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryle (C6-C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluorométhyle, carboxy, carboxyméthyle ou carboxyéthyle, - Hétéroaryie (d-Cis) portant un ou plusieurs hétéroatomes choisis parmi N, 0 et S et substitué ou non par amino, hydroxy, thio, halogène, alkyle (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryle (C6C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluorométhyle, carboxy, carboxyméthyle ou carboxyéthyle,

Amine substituted or not by one or more of the following groups: (C1-C5) alkyl, cyc! oa! ky! e (Cs-Cs), aikoxy (Ci-Ce), ary! e, alkylaryl or aralkyl, these groups may be interrupted by one or more heteroatoms and / or may be substituted, in particular by one or more halogen atom, the nitrogen of the amine group may also be part of a heterocycloalkyl, R2, identical or different, represents a group chosen from: hydrogen, alkyl (Cl-C20) optionally substituted with one or more of the following groups: halogen, (C 1 -C 5) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 8) alkoxy
C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, sulfur or phosphorus atom, - Alkylene (C2-C2O) substituted or unsubstituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy (C3-C8) -cycloalkyl (C2-C20) alkyl substituted or unsubstituted with halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C8) cycloalkyl-C4-C6 cycloalkyl (substituted or unsubstituted) by alkyl (C1-C5), (C1-C5) alkoxy-heterocycloalkyl (C3-C8) bearing one or more heteroatoms chosen from N, O and S and optionally substituted with (C1-C5) alkyl or (C1-C5) alkoxy )

- Aryl (C6-C14) alkyl (C1-C20) substituted or unsubstituted with amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino C5), (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - substituted (C6-C14) aryl or non-amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl ) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - heteroaryl (d-Cis) carrying one or more heteroatoms chosen from N, O and S and substituted or not by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6C14) aryl, (C6-C14) aryl, aryl (C6-C14) (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

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 A represents a single bond or an (C1-C6) alkyl group optionally substituted by one or more of the following groups: halogen, (C3-Cs) cycloalkyl, (C1-C5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester , amide, a sulfur or phosphorus atom, as well as tautomeric, enantiomeric, diastereoisomeric and epimeric forms and pharmaceutically acceptable salts.

dans laquelle R1, R2 et A sont tels que définis ci-dessus et R3 et R4, identiques ou différents, représentent les groupements choisis parmi : - l'atome d'hydrogène, - Alkyle (C1-C20) substitué ou non par un ou plusieurs des groupements suivants : halogène, alkyle (C1-C5), cycloalkyle (C3-C8), alkoxy (C1-C5), amino substitué ou non, carbonyle éventuellement substitué, ester, amide, un atome de soufre ou de phosphore, - Alkoxy (C1-C20) substitué ou non par un ou plusieurs des groupements suivants : halogène, alkyle (C1-C5), cycloalkyle (C3-C8), alkoxy (C1-C5), amino substitué ou non, - Alkylène (C2-C20) substitué ou non par halogène, alkyle (Ci-C5), alkoxy (Ci-C5), cycloalkyl (Cs-Cs) - Alkyne (C2-C20) substitué ou non par halogène, alkyle (Cl-C5), alkoxy (Ci-C5), cycloalkyle (C3-C8) A particular group of compounds of formula (1) is that wherein the compounds have a following general formula (II):

in which R1, R2 and A are as defined above and R3 and R4, which are identical or different, represent the groups chosen from: - a hydrogen atom, - (C1-C20) alkyl substituted or unsubstituted by one or several of the following groups: halogen, (C 1 -C 5) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, Alkoxy (C1-C20) substituted or not by one or more of the following groups: halogen, (C1-C5) alkyl, (C3-C8) cycloalkyl, (C1-C5) alkoxy, substituted or unsubstituted amino, -Alkylene (C2- C20) substituted or unsubstituted with halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C5-C5) cycloalkyl-(C2-C20) alkyl substituted or unsubstituted with halogen, (C1-C5) alkyl, alkoxy ( C 1 -C 5), cycloalkyl (C 3 -C 8)

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(C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryle (C6-
C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluorométhyle, carboxy, carboxyméthyle ou carboxyéthyle, R3 et R4 peuvent aussi former ensemble un hétérocycle adjacent au cycle phényle. - Cycloalkyl (C3-C8) substituted or unsubstituted by (C1-C5) alkyl, (C1-C5) alkoxy, - heterocycloalkyl (Cs-Cs) bearing one or more heteroatoms chosen from N, 0 and S and substituted or not by alkyl (C1-C5), (C1-C5) alkoxy, -Aryl (C6-C14) alkyl (C1-C20) substituted or unsubstituted with amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy ), (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl, (C6-C14) aryl, (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - Aryl (C6-C14) substituted or unsubstituted with amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino , (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, -Heteroaryl (C1-C13) bearing one or more heteroatoms selected from
N, O and S and optionally substituted with amino, hydroxy, thio, halogen, alkyl

(C1-C5), (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C6) aryl
C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, R3 and R4 may also together form a heterocycle adjacent to the phenyl ring.

dans laquelle R1, R2, R3, R4 et A sont tels que définis ci-dessus. A more particular group of compounds of formula (1) is that wherein the compounds have a following general formula (III):

wherein R1, R2, R3, R4 and A are as defined above.

 According to the present invention, the alkyl radicals have 1 to 20 carbon atoms, preferably 1 to 5 carbon atoms.

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 Mention may in particular be made, when they are linear, the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals.

méthylbutyle, 2-méthylpentyle, 1-méthylpentyle et 3-méthylheptyle. When they are branched or substituted by one or more alkyl radicals, mention may be made especially of isopropyl, tert-butyl and 2-ethylhexyl radicals.

methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl.

 The alkoxy radicals according to the present invention are radicals of formula -O-alkyl, the alkyl being as defined previously.

 Among the halogen atoms, mention is made more particularly of fluorine, chlorine, bromine and iodine atoms.

 The alkylene radicals comprise one or more ethylenic unsaturations. Among the alkylene radicals, mention may especially be made of allyl or vinyl radicals.

 The alkyl radicals include one or more acetylenic unsaturations. Among the alkylene radicals, there may be mentioned acetylene.

 The (C 3 -C 8) cycloalkyl radical is a cyclic hydrocarbon radical, such as in particular cyclopropyl, cyclopentyl or cyclohexyl.

 The aryl radical corresponds more particularly to an aromatic ring of 6 carbon atoms, such as the phenyl radical, optionally condensed by one or two other aromatic rings with 6 carbon atoms, such as the naphthyl radical.

Among the aryl radicals, mention may in particular be made of the phenyl radical, more particularly substituted by at least one halogen atom.

Among the ary radicals! (Ce-C) a! ky! e (Ci-Cso), there may be mentioned the benzyl or phenethyl radical.

 The heteroaryl radical corresponds more particularly to an aromatic heterocycle with 5 or 6 atoms containing one or two heteroatoms chosen from N, S and O, condensed or not by one or two aromatic rings with 6 carbon atoms or heteroaromatic rings with 5 or 6 atoms. .

 Among the heteroaryl radicals, mention may be made of the furyl, pyridyl, quinolinyl, indolyl, isoindolyl, quinolyl, imidazolyl, pyrimidinyl or carbazolyl radical.

 Among the heterocycles, mention may especially be made of the piperidine, morpholine, pyrrolidine, imidazolidine, pyrazolidine and piperazine rings.

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 When R 3 and R 4 together form a heterocycle adjacent to the phenyl ring, they may in particular represent the ring -O- (CH 2) n -O-, n an integer ranging from 1 to 4.

 When the nitrogen of the amine group represented by R 1 is part of a heterocycloalkyl, the latter is more particularly the piperidine ring.

 A particular group of compounds of formulas (1), (II) or (III), as defined above, are those in which A is an optionally substituted methylene group. More particularly, A represents an unsubstituted methylene radical.

 Another particular group of compounds of formula (II) or (III) is that wherein R4 is hydrogen and R3 is alkoxy.

 The invention also relates to tautomeric forms, enantiomers, diastereoisomers, epimers and organic or inorganic salts of the compounds of general formula (1).

 Compounds of the invention of formula (1) defined as above having a sufficiently acidic function or a sufficiently basic function or both, may include the corresponding salts of organic or inorganic acid or organic or inorganic base pharmaceutically acceptable.

 It may for example be salts such as hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palmate, aspartate, methanesulphonate, maleate, parachlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octodecanoate, benzenesulfonate, trimethoxybenzoate, para-toluenesulfonate, adamantanecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate, thioctate, hippurate, 3benzamidopropanoate, glucuronate, L pyrrolidone-5-carboxylate, cholate, α-glucose-1-phosphate, alginate, 4-amino-benzoate, chondroitin sulfate and alkali metal salts, such as sodium.

 The compounds of formula (1) can be chosen in particular from: - 3-carboxy-6-methoxy-4-oxo-1,4-dihydroquinoline-1-acetic acid - 3-carboxy-7-methoxy-4-oxoacid 1,4-dihydroquinoline-1-acetic acid,

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- Acide 3-carboxy-6, 7-méthylènedioxy-4-oxo-1, 4-dihydroquinoléine-1acétique - Acide 3-carboxy-8-méthoxy-4-oxo-1 A-dihydroquinoléine-1-acétique - Acide 1- [2- (1, 1-diméthy ! éthylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-1, 4dihydroqu ! no ! éine-3-carboxytique - Acide 1-[2- (4-méthylphénylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1 Adihydroquino) éine-3-carboxytique - Acide 1-[2- (4-chlorophénylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1 Adihydroquinotéine-3-carboxy) ique - Acide 1-[2- (3-chlorophénylamino) -2-oxoéthyl]-7 -méthoxy-4-oxo-1 Ad ! hydroquinotéine-3-carboxy ! ique - Acide 1-[2- (4-chlorophénylamino) -2-oxoéthyl]-7 -méthoxy-4-oxo-1 Adihydroquinoléine-3-carboxylique, - Acide 1- [2- (3-chlorophénylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-1, 4dihydroquino) éine-3-carboxy) ique - Acide 1- [2- (N-pipéridinoacéty))-2-oxoéthy)]-6-méthoxy-4-oxo-1, 4dihydroquinotéine-3-carboxytique - Acide 1- [2- (4-méthy) phénytamino)-2-oxoéthyt]-7-méthoxy-4-oxo-1, 4d ihyd roq uinoléine-3-carboxylique Les composés de formule générale (1) peuvent être préparés selon la méthode de Gould-Jacobs (J. Amer. Chem. Soc., 61, 2890, 1939) proposée en 1962 pour la synthèse de l'acide nalidixique (Schéma 1).

- 3-Carboxy-6,7-methylenedioxy-4-oxo-1,4-dihydroquinoline-1acetic acid - 3-carboxy-8-methoxy-4-oxo-1A-dihydroquinoline-1-acetic acid - Acid 1- [ 2- (1,1-dimethylaminoamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroxy; no! E-3-carboxylic acid - 1- [2- (4-methylphenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1-adihydroquinino) -3-carboxylic acid - 1- [2- (4-chlorophenylamino) - 2-oxoethyl] -6-methoxy-4-oxo-1-adihydroquinotein-3-carboxylic acid - 1- [2- (3-chlorophenylamino) -2-oxoethyl] -7-methoxy-4-oxo-1 Ad! hydroquinoteine-3-carboxy! 1 - [2- (4-chlorophenylamino) -2-oxoethyl] -7-methoxy-4-oxo-1-adihydroquinoline-3-carboxylic acid, 1- [2- (3-chlorophenylamino) -2-oxoethyl] ] -6-methoxy-4-oxo-1, 4-dihydroquinino-3-carboxy} - 1- [2- (N-piperidinoacetyl)) - 2-oxoethyl]] - 6-methoxy-4-oxo-1 4-Hydroquinoquinol-3-carboxylic acid - 1- [2- (4-methyl) phenylamino) -2-oxoethyl] -7-methoxy-4-oxo-1,4-dihydroquinolin-3-carboxylic acid The compounds of the general formula ( 1) can be prepared according to the method of Gould-Jacobs (J. Amer Chem Soc., 61, 2890, 1939) proposed in 1962 for the synthesis of nalidixic acid (Scheme 1).

The present invention therefore also relates to a process for the preparation of compounds of formula (1) comprising the following steps: a) the condensation of an arylamine or a heteroarylamine, optionally substituted, on diethyl ethoxymethylene malonate, l arylamine or heteroarylamine being of formula (1) below:

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 formula (1) in which X represents a nitrogen or carbon atom and R represents R3 or R4 as defined above, b) the heat treatment of the malonic derivative obtained in step a) under conditions allowing the cyclization, plus particularly by heating in a high boiling point solvent, preferably from 200 to 300 ° C., advantageously at 250 ° C., the solvent possibly being diphenyl oxide or Dowtherm, c) the N-alkylation reaction of the tautomeric form of the cyclized product obtained in step b) by condensation in the presence of an alkaline agent, d) optionally the saponification of the ester obtained in step c).

Figure 1 is as follows:

Schéma 1 L'étape a) est la condensation d'une arylamine ou d'une hétarylamine (1) éventuellement substituée sur de l'éthoxyméthylène malonate de diéthyle selon Claisen (Liebiegs Annal. Chem, 297, 1, 1897).

Scheme 1 Step a) is the condensation of an arylamine or a hetarylamine (1) optionally substituted on diethyl ethoxymethylene malonate according to Claisen (Liebiegs Annal Chem, 297, 1, 1897).

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Step b) is the thermal cyclization of the malonic derivative (2) obtained. It is carried out by heating in a high-boiling point solvent, preferably at 250 ° C. in diphenyl ether or Dowtherm. The tautomeric form (4) of the cyclized product (3) is then N-alkyl classically: step (c). This condensation, well known under the name of Hoffman alkylation, may be carried out in the usual solvents, preferably dimethylformamide or anhydrous toluene, in the presence of an alkaline agent such as potassium carbonate. The ester (5) obtained is conventionally saponified in (6).

 The compounds of the present invention exhibit activity as aldose reductase inhibitors.

 IN VITRO STUDY: INHIBITION OF ALDOSE REDUCTASE Aldose reductase is partially purified from crystalline male rats (Wistar, 200-240g).

The extract is prepared by centrifugation and ammonium sulfate precipitation from W. H. J. WARD et al. (1990, Biochem Pharmacol 39.2, 337-346) The enzyme is preincubated at 37 ° C with or without the test products and NADPH (0.125 mM) in phosphate buffer for 10 min. The reaction is started by adding L-glyceraldehyde (5 mM) as a substrate.

Aldose reductase
L-Glyceraldehyde + NADPH + H + Glycerol + NADP The enzymatic activity is measured spectrophotometer at 340 nm.

The measured values are shown in the table below:

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<Tb>
<tb> TEST <SEP> OF INHIBITION <SEP> DALDOSE <SEP> REDUCTASE
<tb> .. <SEP> l <SEP> l
<tb> Compound <SEP> IC <SEP> 50 <SEP> (nM)
<tb><SEP> 1-Carboxymethyl-6-methoxy-4-oxo-1,4-dihydroquinoline-3- acid
<tb> 15
<tb> carboxylic
<tb><SEP> 1-Carboxymethyl-7 <SEP> -methoxy-4-oxo-1 acid. <SEP> 4-dihydroquinoline-3- <SEP> 10
<tb> carboxylic
<tb> Acid <SEP> 1-Carboxymethyl-6, <SEP> 7 <SEP> -methylenedioxy-4-oxo-1. <SEP> 4- <SEP> 5
<tb> dihydroquino <SEP>! <SEP> Eine-3-carboxy) <SEP>
<tb> Acid <SEP> 1-Carboxymethyl-7 <SEP> -methyl-4-oxo-1, <SEP> 4-dihydro- <SEP> 50
<tb> [1, <SEP> 8] naphthyridine-3-carboxylic acid
<Tb>

Les composés de formule (1) peuvent donc être utilisés à titre de médicaments en tant qu'inhibiteurs d'aldose réductase, et notamment dans le traitement des complications du diabète, ces complications pouvant être la cataracte, les rétinopathies, les neuropathies, les néphropathies ou certaines maladies vasculaires.

The compounds of formula (1) can therefore be used as medicaments as aldose reductase inhibitors, and in particular in the treatment of complications of diabetes, these complications being able to be cataract, retinopathies, neuropathies, nephropathies or certain vascular diseases.

 The present invention therefore also relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.

 The pharmaceutical compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration.

 They will therefore be presented in the form of injectable solutes or suspensions or multi-dose vials, in the form of naked or coated tablets, coated tablets, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules. , solutions or suspensions, for percutaneous use in a polar solvent, for permselective use.

 Suitable excipients for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.

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 For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.

 For parenteral use, water, aqueous solutes, physiological saline, isotonic solutes are the most conveniently used vehicles.

 The dosage may vary within the important limits (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as the age and weight of the subject.

The present invention also relates to the use of compounds of general formula (1) for the preparation of pharmaceutical compositions intended to treat or prevent a complication induced by diabetes.

 The following examples illustrate the invention without limiting it. The starting materials used are known products or prepared according to known procedures.

 Percentages are by weight unless otherwise indicated.

Example 1: 3-carboxy-6-methoxy-4-oxo-1 acid. 4-dihydroquinoline-1-acetic acid - 2- (4-Methoxyphenylaminomethylene) diethyl malonate: In 400 ml of toluene are introduced: 120g (0.97M) of para anisidine and 199ml (0, 97M) of diethyl ethoxymethylenemalonate. The mixture is refluxed with the solvent. The ethanol formed is entrained by azeotropic distillation. When the reflux temperature reaches 110 ° C., reflux is maintained for an additional 45 minutes. After cooling, the solution is purified by passage over silica and then evaporated under reduced pressure.

280.8 g of red oil is obtained.

4, 16-4, 22 (4H, 2xq) ; 3, 75 (3H, s) ; 1, 24-1, 29 (6H, 2xt) - 6-Méthoxy-4-oxo-1, 4-dihydroquinoléine-3-carboxylate d'éthyle : Yield: 98% 1 H NMR (CDCl 3): 10.87 (1H, d); 8.35 (1H, d); 7.00 (2H, d); 6.82 (2H, d,);

4, 16-4, 22 (4H, 2xq); 3.75 (3H, s); Ethyl 1, 24-1, 29 (6H, 2xt) -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate:

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 300 ml of dowtherm-A are brought to reflux (about 2500C) under a nitrogen atmosphere. Then, 124.1 g (0.43M) of diethyl 2- (4-methoxyphenylaminomethylene) malonate are introduced dropwise. The reflux is maintained 10 minutes after the end of introduction. The reaction mixture is then cooled to 15 ° C.: a brown solid precipitates. It is drained, washed with petroleum ether and then dried under vacuum.

58.8g of solid brown is obtained.

Yield: 59% Mp> 270 C (melting point) 1H NMR (DMSO-d6):
8.38 (1H, s); 7.51 (1H, d); 7.50 (1H, d); 7.25 (1H, dd); 4.14 (2H, q); 3.78 (3H, s); 1.21 (3H, t) -3-Ethoxycarbonyl-6-methoxy-4-oxo-1,4-dihydroquinoline-1-ethyl acetate: In 100 ml of DMF are introduced: 10, Og (0, 041 M) from Ethyl 6-methoxy-4-oxo-1,4dihydroquinoline-3-carboxylate and 11.0 g (0.080M) of potassium carbonate. The reaction mixture is stirred for 15 minutes at room temperature.

After addition of 5 .0 ml (0.045M) of ethyl bromoacetate and 2 hours of heating at 60oC, the solvent is evaporated under vacuum, and the solid obtained is taken up in demineralised water with stirring. The suspended solid is filtered, washed extensively with water and then with ethyl ether and finally dried under vacuum.

 13.4 g of beige powder is obtained.

8, 62 (1 H, s) ; 7, 62 (1 H, d,) ; 7, 47 (1 H, d,) ; 7, 33 (1 H, dd) ; 5, 31 (2H, s) ; 4, 18 (2H, q) ; 4, 13 (2H, q) ; 3, 82 (3H, s) ; 1, 24 (3H, t) ;
1,17 (3H, t) - Acide 3-carboxy-6-méthoxy-4-oxo-1. 4-dihydroquinoléine-1-acétique : Une suspension de 10, Og (0, 030M) de 1- (2-ethoxy-2-oxoéthyl) -6-méthoxy-1. 4dihydroquinoléine-3-carboxylate d'éthyle dans 10ml d'une solution d'hydroxyde Yield: 95% Mp = 207 C 1 H NMR (DMSO-d6):

8, 62 (1H, s); 7, 62 (1H, d,); 7, 47 (1H, d,); 7, 33 (1H, dd); 5, 31 (2H, s); 4, 18 (2H, q); 4, 13 (2H, q); 3.82 (3H, s); 1, 24 (3H, t);
1.17 (3H, t) - 3-Carboxy-6-methoxy-4-oxo-1-acid. 4-dihydroquinoline-1-acetic acid: A suspension of 10, Og (0, 030M) of 1- (2-ethoxy-2-oxoethyl) -6-methoxy-1. 4dihydroquinoline-3-carboxylic acid ethyl ester in 10 ml of a solution of hydroxide

<Desc / Clms Page number 13>

 10% sodium is refluxed for 2 hours. The solution which has become clear is cooled and then acidified to pH = 1 with a 10% hydrochloric acid solution.

The white precipitate formed is filtered, washed with demineralized water until the filtrate is neutral, and then dried under vacuum.

7.5 g of white solid is obtained.

15, 15 (1 H, s) ; 13, 50 (1 H, s) ; 8, 94 (1 H, s) ; 7, 68 (1 H, d) ; 7, 65 (1 H, d) ;
7,48 (1 H, dd) ; 5,37 (2H, s) ; 3,84 (3H, s) A titre d'exemples, les composés suivants sont préparés selon le mode opératoire de l'exemple 1 : - Acide 3-carboxy-6, 7-méthylènedioxy-4-oxo-1. 4-dihydroquinoléine-1- acétique - Acide 3-carboxy-8-méthoxy-4-oxo-1. 4-dihydroquinoléine-1-acétique Exemple 2 : Acide 1-[2-(1,1-dimethyléthylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-

1A-dihydroquinoléine-3-carboxylique - 1-[2- (1, 1-dimethyléthylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1 Adihydroquinoléine-3-carboxylate d'éthyle A 200ml de toluène anhydre, sont ajoutés : 10g (0, 04M) de 6-Méthoxy-4-oxo-1, 4- dihydroquinoléine-3-carboxylate d'éthyle, 11,2g (0,08M) de carbonate de potassium, 8,4g (0, 05M) de iodure de potassium et 7,6g (0, 05M) de N- (1, 1diméthyléthyl) chloroacétamide. Le mélange réactionnel est agité 24 heures à reflux du solvant. Après refroidissement, le solide précipité est repris par 50ml d'eau déminéralisée. Yield: 91% Mp = 250 C 1 H NMR (DMSO-d6):

15, 15 (1H, s); 13.50 (1H, s); 8, 94 (1H, s); 7, 68 (1H, d); 7, 65 (1H, d);
7.48 (1H, dd); 5.37 (2H, s); 3.84 (3H, s) By way of examples, the following compounds are prepared according to the procedure of Example 1: - 3-Carboxy-6,7-methylenedioxy-4-oxo-1 acid. 4-dihydroquinoline-1-acetic acid - 3-carboxy-8-methoxy-4-oxo-1. 4-Dihydroquinoline-1-acetic acid Example 2: 1- [2- (1,1-Dimethylethylamino) -2-oxoethyl] -6-methoxy-4-oxoacetate

1A-Dihydroquinoline-3-carboxylic acid ethyl 1- [2- (1,1-dimethylethylamino) -2-oxoethyl] -6-methoxy-4-oxo-1-adihydroquinoline-3-carboxylate A 200 ml of anhydrous toluene are added: 10 g (0.04 M) of ethyl 6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate, 11.2 g (0.08 M) of potassium carbonate, 8.4 g (0.05M) ) of potassium iodide and 7.6 g (0.05M) of N- (1,1-dimethylethyl) chloroacetamide. The reaction mixture is stirred for 24 hours at reflux of the solvent. After cooling, the precipitated solid is taken up in 50 ml of demineralized water.

<Desc / Clms Page number 14>

 The suspension is stirred 45 minutes. The solid is filtered, washed with demineralised water, dried under reduced pressure.

12.6 g of brown solid is obtained.

8, 4 (1 H, s) ; 8, 1 (1 H, s) ; 7, 5 (1 H, s) ; 7, 3 (2H, m) ; 4. 8 (2H, s) ; 4. 1 (2H, q) ; 3, 7 (3H, s) ; 1. 1 (12H, s) - Acide 1- [2- (1, 1-dimethyléthylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-1. 4- dihydroquinoléine-3-carboxylique Dans 120ml d'eau déminéralisée, sont ajoutés : 15ml d'éthanol, 1,4g (0, 034M) de soude en pastille puis 12,4g (0. 034M) de 1-[2- (1, 1-dimethyléthylamino) -2- oxoéthyl]-6-méthoxy-1,4-dihydroquinoléine-3-carboxylate d'éthyle. Le milieu réactionnel est chauffé 2 heures à reflux du solvant. Après refroidissement, le milieu est filtré. La solution est acidifiée à pH=1 par une solution d'acide chlorhydrique concentrée. Un solide précipite. Pf = 250 C
Yield: 87% 1H NMR (DMSO-d6):

8, 4 (1H, s); 8, 1 (1H, s); 7.5 (1H, s); 7, 3 (2H, m); 4. 8 (2H, s); 4. 1 (2H, q); 3, 7 (3H, s); 1. 1 (12H, s) - 1- [2- (1,1-Dimethylethylamino) -2-oxoethyl] -6-methoxy-4-oxo-1-acid. 4-Dihydroquinoline-3-carboxylic acid In 120 ml of demineralised water, 15 ml of ethanol, 1.4 g (0.034 M) of pelletized sodium hydroxide and then 12.4 g (0. 034M) of 1- [2- ( Ethyl 1,1-dimethylethylamino) -2-oxoethyl] -6-methoxy-1,4-dihydroquinoline-3-carboxylate. The reaction medium is heated for 2 hours at reflux of the solvent. After cooling, the medium is filtered. The solution is acidified to pH = 1 with a concentrated hydrochloric acid solution. A solid precipitates.

Stirring is continued for 30 minutes, then the solid is filtered, washed with demineralised water and dried under reduced pressure.

11 g of creamy white solid is obtained.

Pf .: 250 C
Yield: 87% 1H NMR (DMSO-d6):
7.8 (3H, m); 5.5 (2H, s); 3.9 (3H, s); 1.2 (9H, s) Example 3: 1- [2- (4-Methylphenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

<Desc / Clms Page number 15>

 Ethyl 1- [2- (4-methylphenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate A suspension containing 6 g (0.024M) of 6-methoxy Ethyl 4-oxo-1,4dihydroquinoline-3-carboxylate, 5g (0.036M) of potassium carbonate and 5.3g (0.029M) of N- (4-methylphenyl) chloroacetamide in 50ml of N, N- dimethylformamide is heated at 50 ° C. for 5 hours. The reaction mixture is cooled to -5 C.

The solid is drained, washed with 10 ml of N, N-dimethylformamide, impregnated with demineralized water until the filtrate is neutral and dried under reduced pressure.

6.9 g of whitish solid is obtained.

7, 37 (1H, dd) ; 7, 10 (2H, d) ; 5, 23 (2H, s) ; 4, 21 (2H, q) ; 3, 83 (3H, s) ; 2, 22 (3H, s) ; 1, 27 (3H, t) - Acide 1-[2- (4-méthylphénylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1, 4- dihydroquino) éine-3-carboxy ! ique On agite 16 heures à température ambiante une suspension de 6,9g (0, 017M) de 1-[2-(4-metylphenylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-1,4-dihydroquinoléine-3- carboxylate d'éthyle dans 70ml de solution de soude à 10% et 70ml de méthanol. Le mélange est ensuite acidifié par 15 ml d'acide chlorhydrique 12N à 10 C, puis agité 3 heures. Le solide précipité est essoré, lavé abondamment à l'eau déminéralisée puis séché sous pression réduite. Yield: 72%
Mp = 266 C NMRH (DMSO-dr)
10.42 (1H, s); 8.65 (1H, s); 7.66 (1H, d); 7.51 (1H, d); 7.43 (2H, d);

7, 37 (1H, dd); 7, 10 (2H, d); 5, 23 (2H, s); 4, 21 (2H, q); 3.83 (3H, s); 2.22 (3H, s); 1, 27 (3H, t) - 1- [2- (4-methylphenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxy! A suspension of 6.9 g (0.017M) of 1- [2- (4-metylphenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline is stirred for 16 hours at room temperature. 3- ethyl carboxylate in 70 ml of 10% sodium hydroxide solution and 70 ml of methanol. The mixture is then acidified with 15 ml of 12N hydrochloric acid at 10 ° C. and then stirred for 3 hours. The precipitated solid is drained, washed extensively with demineralized water and then dried under reduced pressure.

6.4g of solid cream is obtained.

Yield: 100%
Mp> 270 C 1H NMR (DMSO-d6):
10.76 (1H, s); 8.97 (1H, s); 7.80 (2H, m); 7.53 (1H, dd); 7.49 (2H, d);
7.11 (2H, d); 5.51 (2H, s); 3.90 (3H, s); 2.24 (3H, s);

<Desc / Clms Page number 16>

Acide 1-[2- (4-chlorophenylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1, 4dihydroquinoiéine-3-carboxyiique Acide 1-[2- (3-chlorophenylamino) -2-oxoéthyl]-7 -méthoxy-4-oxo-1, 4dihydroquino) éine-3-carboxyiique Acide 1-[2- (4-chlorophenylamino) -2-oxoéthyl]-7 -méthoxy-4-oxo-1, 4- dihydroquinotéine-3-carboxytique Exemple 4 : Acide 1-[2-(3-chlorophenylamino)-2-oxoéthyl]-6-méthoxy-4-oxo-1,4-

d ihyd roqu inoléine-3-carboxylique - 1-[2- (3-Chlorophenylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1, 4dihyd roquinoléine-3-carboxylate d'éthyle Une suspension contenant 5g (0, 02M) de 6-méthoxy-4-oxo-1, 4- dihydroquinoléine-3-carboxylate d'éthyle, 4,2g (0, 03M) de carbonate de potassium et 5, 1g (0, 025M) de N- (3-chlorophényl) chloroacétamide dans 50ml de N, N-diméthylformamide est chauffée à 500C pendant 5 heures. Le mélange réactionnel est refroidi à température ambiante puis versé sur 450ml d'eau déminéralisée froide. Le précipité obtenu est essoré, lavé abondamment à l'eau déminéralisée. Le solide se sublimant au séchage est engagé humide à l'étape suivante. By way of example, the following compounds are prepared according to the procedure of Example 3:

1- [2- (4-Chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinolein-3-carboxylic acid 1- [2- (3-chlorophenylamino) -2-oxoethyl] -7-acid Methyl-4-oxo-1,4-dihydroquinino-3-carboxylic acid 1- [2- (4-Chlorophenylamino) -2-oxoethyl] -7-methoxy-4-oxo-1,4-dihydroquinotein-3-carboxylic acid Example 4 1- [2- (3-Chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-

Dihydrochloride-3-carboxylic acid - Ethyl-1- [2- (3-chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate A suspension containing 5 g (0 g. , 02M) of ethyl 6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate, 4.2g (0.03M) of potassium carbonate and 5.1g (0.025M) of N- ( 3-chlorophenyl) chloroacetamide in 50ml of N, N-dimethylformamide is heated at 500C for 5 hours. The reaction mixture is cooled to ambient temperature and then poured onto 450 ml of cold demineralized water. The precipitate obtained is filtered off and washed thoroughly with deionized water. The solid sublimating on drying is wet in the next step.

15.4 g of wet solid is obtained.

- Acide 1-[2- (3-clorophenylamino) -2-oxoéthyl]-6-méthoxy-4-oxo-1 Adihydroquino ! éine-3-carboxy ! ique Mp = 228 C 1H NMR (DMSO-d6):
10.71 (1H, s); 8.67 (1H, s); 7.76 (1H, s); 7.68 (1H, d, J = 2.6); 7,58-
7.33 (4H, m); 7.14 (1H, dd, J = 6.8); 5.29 (2H, s); 4.22 (2H, q, J = 6.9); 3.85 (3H, s); 1.29 (3H, t, J = 6.9)

1- [2- (3-Clorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1-adihydroquininoic acid; Eine-3-carboxy! ic

<Desc / Clms Page number 17>

 The preceding ester is hydrolysed according to the method described in Example 3.

4.4g of beige solid is obtained.

15, 25 (1H, s) ; 10, 75 (1H, s) ; 9, 05 (1H, s) ; 7, 77 (3H, m) ; 7, 56 (1 H, dd, J=9,5, J=2,6) ; 7,45 (1 H, d, J=7.7) ; 7,36 (1 H, t, J=7.7) ; 7.15 (1 H, d, J=8, 6) ; 5,50 (2H, s) ; 3,91 (3H, s) ; A titre d'exemple, les composés suivants sont préparés selon le mode opératoire de l'exemple 3 :

Acide 1-[2- (N-pipéridinoacétyl) -2-oxoéthyl]-6-méthoxy-4-oxo-1, 4d ihyd roqu inoléine-3-carboxylique Acide 1-[2- (4-méthylphenylamino) -2-oxoéthyl]-7-méthoxy-4-oxo-1, 4- dihydroquino) éine-3-carboxy ! ique Les composés ci-dessus mentionnés ont été caractérisés par les techniques analytiques suivantes : RMN : Les spectres RMN ont été effectués à l'aide d'un spectromètre RMN Brücker Advanced DPX 200mHz Points de fusion : Les points de fusion (Pf) ont été mesurés sur un banc de type Kofler Leica VMHB.Overall yield: 57% Pf> 270 C 1H NMR (DMSO-d6):

15, 25 (1H, s); 10, 75 (1H, s); 9.05 (1H, s); 7.77 (3H, m); 7.56 (1H, dd, J = 9.5, J = 2.6); 7.45 (1H, d, J = 7.7); 7.36 (1H, t, J = 7.7); 7.15 (1H, d, J = 8, 6); 5.50 (2H, s); 3.91 (3H, s); By way of example, the following compounds are prepared according to the procedure of Example 3:

1- [2- (N-Piperidinoacetyl) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1- [2- (4-methylphenylamino) -2-oxoethyl acid ] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxy! The above-mentioned compounds were characterized by the following analytical techniques: NMR: The NMR spectra were carried out using a Brücker Advanced DPX 200mHz NMR spectrometer. Melting points: The melting points (Pf) were measured on a Leica VMHB Kofler type bench.

Claims (14)

 - Alkyl (Cl-C20) optionally substituted with one or more of the following groups: halogen, (C 1 -C 5) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 8) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, - Alkylene (C2-C20) substituted or unsubstituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C8) cycloalkyl-Alkyne (C2- C20) substituted or unsubstituted with halogen, (C1-C5) alkyl, (C1-CS) alkoxy, (C3-CS) cycloalkyl

 following: alkyl (C1-C5), cyc! oa! ky! e (Cs-Cs), alkoxy (Ci-Cs), aryl, alkylaryl or aralkyl, these groups may be interrupted by one or more heteroatoms and / or may be substituted, especially by one or more halogen atom, nitrogen the amine group may also be part of a heterocycloalkyl, R2, identical or different, represents a group chosen from: - hydrogen,

 in which: X represents independently of each other an optionally substituted methylene radical, a nitrogen, oxygen or sulfur atom, R1 represents a group chosen from: - radical of formula OR2, - amine substituted or unsubstituted by one or several of the groupings

 1-Compounds of general formula (1) <Desc / Clms Page number 19> Heteroaryl (C1-C13) carrying one or more heteroatoms selected from N, O and S and optionally substituted with amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio ), (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl, (C6-C14) aryl, (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, A represents a single bond or a (C1-C6) alkyl group optionally substituted with one or more of the following groups: halogen, (C3-Cg) cycloalkyl, (C1-C5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, as well as tautomeric, enantiomeric, diastereoisomeric and epimeric forms and pharmaceutically acceptable salts. Aryl (C6-C14) alkyl (C1-C20) substituted or unsubstituted with amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino ), aryl (C6-C14), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - Aryl (C6-C14) substituted or unsubstituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl oxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, Heterocycloalkyl (C3-C8) carrying one or more heteroatoms selected from N, O and S and optionally substituted with (C1-C5) alkyl, (C1-C5) alkoxy, Cycloalkyl (C3-C8) substituted or unsubstituted with (C1-C5) alkyl, (C1-C5) alkoxy 2-Compounds according to claim 1, characterized in that they have the following general formula (II): <Desc / Clms Page number 20>  - Aryl (C6-C14) alkyl (C1-C20) substituted or not with amino, hydroxy, thio, halogen, alkyl (C1-CS), alkoxy (C1-Cs), alkylthio (C1-CS), alkylamino (CI- C5), (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - substituted (C6-C14) aryl or non-amino, hydroxy, thio, halogen,

 in which R 1, R 2, X and A are as defined in claim 1 and R 3 and R 4, which may be identical or different, represent the groups chosen from: the hydrogen atom, C 1 -C 20 alkyl substituted or unsubstituted by a one or more of the following groups: halogen, (C 1 -C 5) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, - Alkoxy (C1-C20) substituted or not by one or more of the following groups: halogen, (C1-C5) alkyl, (C3-C8) cycloalkyl, (C1-C5) alkoxy, substituted or unsubstituted amino, - Alkylene (C2 -C20) substituted or unsubstituted by halogen, (C 1 -C 5) alkyl, (C 1 -C 5) alkoxy, (C 3 -C 8) cycloalkyl (C 3 -C 8) -alkyl (C 2 -C 20) substituted or otherwise by halogen, (C 1 -C 5) alkyl , (C1-C5) alkoxy, (C3-C8) cycloalkyl-(C3-C8) -cycloalkyl substituted or unsubstituted by (C1-C5) alkyl, (C1-C5) alkoxy, -Heterocyctoatkyte (Cs-Cs) bearing one or more heteroatoms selected from N, O and S and substituting whether or not C 1 -C 5 alkyl, C 1 -C 5 alkoxy,

<Desc / Clms Page number 21>  (C1-C5), (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl, (C6-C14) aryl, (C6-C14) aryl ( C 1 -C 5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, R 3 and R 4 may also together form a heterocycle adjacent to the phenyl ring.

N, O and S and optionally substituted with amino, hydroxy, thio, halogen, alkyl  (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryl, (C6-C14) aryl, (C6-C14) aryl, alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, - heteroaryl (Ci-Cis) carrying one or more heteroatoms selected from  wherein R1, R2, R3, R4 and A are as defined in claim 1 or 2.

 3- compounds according to claim 2, characterized in that they have the following general formula (III): 4-Compounds according to claim 2 or 3, characterized in that, when R3 and R4 together form a heterocycle adjacent to the phenyl ring, they represent the -O- (CH2) nO- ring, n being an integer ranging from 1 to 4 .  5. Compounds according to claim 2 or 3, characterized in that R4 is a hydrogen atom and R3 represents an alkoxy radical. 6-Compounds according to one of the preceding claims, characterized in that A is a methylene group, optionally substituted. <Desc / Clms Page number 22>  7-Compounds according to any one of the preceding claims, characterized in that when the nitrogen of the amine group represented by R1 is part of a heterocycloalkyl, the latter is the piperidine ring.  1- [2- (1,1-Dimethylethylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, - 1- [2- (4-methylphenylamino) - 2-oxoethyl] -6-methoxy-4-oxo-1. 4-Hydroquinoline-3-carboxylic acid, 1- [2- (4-chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1- [1- [2- (4-chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo- (3-Chlorophenylamino) -2-oxoethyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1- [2- (4-chlorophenylamino) -2-oxoethyl] -7-methoxy- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1- [2- (3-chlorophenylamino) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, - Acid 1- [2- (N-Piperidinoacetyl) -2-oxoethyl] -6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1- [2- (4-methylphenylamino) -2-oxoethyl ] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

 8- Compounds according to any one of the preceding claims, characterized in that they are chosen from: - 3-carboxy-6-methoxy-4-oxo-1, 4-dihydroquinoline-1-acetic acid, -3-carboxy Acid 7-methoxy-4-oxo-1,4-dihydroquinoline-1-acetic acid, 3-carboxy-6,7-methylenedioxy-4-oxo-1,4-dihydroquinoline-1-acetic acid, 3-carboxy acid 8-methoxy-4-oxo-1,4-dihydroquinoline-1-acetic acid, 9-Process for the preparation of compounds of formula (1), as defined in claim 1, comprising the following steps: a) the condensation of an arylamine or an optionally substituted heteroarylamine with ethoxymethylene malonate of diethyl, arylamine or heteroarylamine being of formula (1) below: <Desc / Clms Page number 23>  formula (1) in which X represents a nitrogen or carbon atom and R represents R3 or R4 as defined in claim 2, b) the heat treatment of the malonic derivative obtained in step a) under conditions allowing the cyclization, more particularly by heating in a high-boiling solvent, preferably from 200 to 300 ° C., advantageously at 250 ° C., c) the N-alkylation reaction of the tautomeric form of the cyclized product obtained in step b) by condensation in the presence of an alkaline agent, d) optionally the saponification of the ester obtained in step c).

10-Pharmaceutical composition comprising, as active principle, a compound according to any one of claims 1 to 8. 11-Composition according to claim 10 for presenting an inhibitory activity on aldose reductase. 12-Composition according to claim 10 for treating or preventing complications caused by diabetes. 13-Composition according to claim 12, characterized in that the complications induced by diabetes are selected from retinopathy, nephropathy, neuropathy and vascular diseases. 14-Use of at least one compound according to one of claims 1 to 8 for the preparation of a pharmaceutical composition for treating or preventing a complication induced by diabetes.