Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to quinoline-4-substituted derivatives of general formula:
• R 2 is hydrogen
• R 3 is in position -2 or -3 and represents alkyl (Cl-6) which may be optionally substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxy, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxy optionally substituted with alkyl
• R is a group -CH 2 -R S for which R 5 is selected from alkyl hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaroyl ..., n is 0 to 2, m is 1 or 2 and A and B are in particular oxygen, sulfur, sulfinyl, sul
• Ri, R'i, R ', R' 3 / R 'and R' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or heteroarylthio mono or bicyclic, OH, SH, alcoyloxy, difluoromethoxy, trifluoromethoxy, alcoylthio, trifluoromethylthio, cycloalcoyloxy, cycloalcoylthio, acyl, acyloxy, acylthio, cyano, carboxy, alcoyloxycarbonyl, cycloalcarloxy or cycloalcoyloxy represent hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl or Ra and Rb form together with the nitrogen atom to which they are linked a 5 or 6-membered heterocycle which may optionally contain another heteroatom chosen from 0, S or N and bearing
• R 2 represents a radical R, -C0 2 R, -CH 2 C0 2 R, -CH 2 -CH 2 C0 2 R, -CONH 2 , -CH 2 -CONH 2 , -CH 2 -CH 2 -CONH 2 , -CH 2 OH, -CH 2 -CH 2 OH, -CH 2 -NH 2 -CH 2 -CH 2 -NH 2 or -CH 2 -CH 2 -CH 2 -NH 2 , R being as defined above;
• R 3 represents a phenyl, mono or bicyclic heteroaryl radical, alk-R ° 3 for which alk is an alkylene radical and R ° 3 represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyloxy, cycloalkyloxy , cycloalkyllio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cycloalkyl) 2 , acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsuifinyl, phenylsuifinyl, phenylsuifinyl, phenylsu
• R4 represents a radical R, -CHO, -C0CH 3 -CH 2 C0 2 H or -COCH 2 NH 2 ; it being understood that the alkyl and acyl radicals and portions contain (except. special mention) 1 to 10 carbon atoms, in straight or branched chain, and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or where appropriate in syn or anti form or their mixture, as well as their salts, are very powerful anti-bacterial agents.
• the radicals represent or carry a halogen atom
• the halogen is chosen from fluorine, chlorine, bromine or iodine, and is preferably fluorine.
• the radicals represent or carry a mono or bicyclic heteroaryl substituent
• the latter contains 5 to 10 members and can be chosen (without limitation) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl , thiadiazolyle, oxadiazolyl, tetrazolyl, pyridyl, 'pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuranyl indazolyl, benzothiazolyl, naphthyridinyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, benzoxazolyl, benzimidazolyl which may be optionally substituted by the substituents mentioned above.
• Xi, X 2 , X 3 , X 4 and X 5 are as defined above,
• Ri, R'i, R ' 2 , R' 3 , R ' 4 , and R' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a radical alkyloxy-substituted methylene;
• n 1;
• n 1;
• R 2 is as defined above, and
• R 3 represents an alk-R ° 3 radical for which alk is an alkylene radical and R ° 3 represents alkyloxy, alkylthio, alkylamino, dialkoylamino, cycloalkyloyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cyclo) 2 , phenoxy, phenylthio, phenylamino, N-alkyl N-phenyl amino, N-cycloalkyl N-phenyl amino, phenylalkoyloxy, phenylalkoylthio, phenylalkoylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkylnoyloyloyloyloyloxy , heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalky
• R 4 is as defined above; it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above can be optionally substituted as envisaged above,
• Xi, X 2 , X 3 , X and X 5 respectively represent>C-R' ⁇ to> C-R ' S ,
• Ri, R'i, R ' 2 / R' 3 R ', - R' ⁇ are the same or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted by alkyloxy ; m is equal to al; n is 1;
• the subject of the invention is very particularly any one of those whose names follow: • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- fluoro-6-methoxy-4-quinoleinyl) -ethylamino] -3- acid carboxylic pyrrolidine; • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (6-methoxy-4 -quinolinyl) - ethylamino] -3 -pyrrolidine carboxylic acid; • 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3- fluoro-6-methoxy-4-quinoleinyl) -ethylamino] -3- pyrrolidine carboxylate methyl; • methyl 1- [(E) -3- (2,5-difluoro-phenyl)
• the products of general formula (I) can be obtained by condensation of the chain R 3 on the quinoline-4-substituted derivative of general formula:
• R 3 is defined as above and X represents a halogen atom, a methylsuifonyl radical, a trifluoromethylsulfonyl radical or p. toluenesulfonyl, operating in an anhydrous medium, preferably inert, in an organic solvent such as an amide (for example dimethylformamide), a ketone (for example acetone) or a nitrile (for example acetonitrile) in the presence of a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature between 20 ° C. and the reflux temperature of the solvent.
• a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature between 20 ° C. and the reflux temperature of the solvent.
• the nitrogen atom of the pyrrolidine ring of the derivative of general formula (II) is optionally protected according to the usual methods compatible with the rest of the molecule or the reaction; the protection is carried out for example by a protective radical chosen from the benzyl, t .butoxycarbonyl and benzyloxycarbonyl groups, and this nitrogen atom is released before condensation with the derivative of formula (IIa), in particular by acid hydrolysis.
• a derivative of general formula (IIa) is made to act for which X is a chlorine, bromine or iodine atom.
• X is a chlorine, bromine or iodine atom.
• Conditions under which the condensation between the derivatives of general formulas (II) and (IIa) can be carried out are also described in application WO 02/40474.
• R 3 is a radical -alk-R ° 3 in which R ° 3 is a group -C ⁇ C-Rd, in which Rd is as defined more above, an alkynyl halide is condensed, intermediate, then the desired radical is condensed on the alkyne thus obtained.
• R 3 represents a radical -alk-R ° 3 for which alk is an alkyl radical and R ° 3 represents a phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino radical
• the chain can also be constructed by first condensing an HO-alk-X chain for which X is a halogen atom, preferably iodine, under the conditions described above for the reaction of the product of general formula (IIa), then, if necessary, by transforming the hydroxyalkyl chain into a haloalkyl, methanesulfonylalkyl or p.
• toluenesulfonylalkyl and finally by acting in basic medium an aromatic derivative of structure R ° 3 H or R ° 3 H 2 .
• the transformation of the hydroxyl chain into a haloalkyl chain or p. toluenesulfonyl is carried out according to the usual methods of halogenation or sulfonylation, in particular a halogenating agent such as thionyl chloride, halogenated phosphorus derivatives (trichloride or phosphorus tribromide for example) or a sulfonylating agent is made to act for example methanesulfonyl chloride, p chloride.
• reaction is carried out in an organic solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature between 0 and 60 ° C. ⁇ In some cases it may be advantageous to operate in the presence of a base such as pyridine or triethylamine.
• organic solvent such as a chlorinated solvent (dichloromethane or chloroform for example)
• a base such as pyridine or triethylamine.
• the reaction of the aromatic derivative R 3 H or R 3 H 2 is advantageously carried out as described above for the action of the derivative of general formula (IIa), in an organic solvent such as an amide (dimethylformamide for example), a ketone (acetone for example), a nitrile (acetonitrile for example), in the presence of a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature included between 20 ° C and the reflux temperature of the reaction mixture. It may be advantageous to operate in presence of potassium iodide.
• an organic solvent such as an amide (dimethylformamide for example), a ketone (acetone for example), a nitrile (acetonitrile for example
• a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature included between 20 ° C and the reflux
• the protected carboxy radical carried by R 2 or R 4 can be chosen from easily hydrolyzable esters. By way of example, mention may be made of methyl, benzyl, tert-butyl esters, or else phenylpropyl or allyl esters. Possibly the protection of the carboxy radical takes place simultaneously with the reaction. Where appropriate, the protection of the amino radical is carried out by means of the usual protective radicals cited in the references above.
• the derivatives of general formula (I) for which R 2 is hydroxymethyl or hydroxyethyl can be prepared by the action of an appropriate reducing agent on a derivative for which R 2 is carboxy or carboxymethyl or protected carboxy or carboxy methyl protected. Any ketone function that may be present must then be protected.
• the products of general formula (I) for which R 2 is carboxymethyl or carboxyethyl can also be prepared from the derivatives for which R 2 is hydroxymethyl or hydroxyethyl, by action on the latter of an agent d halogenation or tosylation, then a cyanidation agent and finally a nitrile hydrolysis agent.
• the products of general formula (I) for which R 2 is -CONH 2 , -CH 2 -CONH 2 or -CH 2 -CH 2 -CONH 2 can be prepared from the corresponding acids or esters by amidification with ammonia.
• the products of general formula (I) for which R 2 is -CH 2 -NH 2 , - (CH 2 ) 2 -NH 2 or - (CH 2 ) 3 -NH 2 can be prepared from corresponding amides by reduction.
• the reduction of the protected carboxy can be carried out according to the usual methods which do not alter the rest of the molecule, in particular by the action of a hydride (aluminum and lithium hydride or diisobutyl aluminum hydride for example) in a solvent. such as an ether (tetrahydrofuran for example) at a temperature between 20 and 60 ° C.
• ketone function which may be present according to conventional methods known to those skilled in the art, in particular via an acetal, cyclic or not.
• the reduction of the free carboxy can be carried out according to methods also known to those skilled in the art, for example by hydrogenation in the presence of a catalyst based on rhodium or ruthenium, by the action of sodium hydroboride in the presence of Lewis or aluminum hydride and lithium in ether.
• the ketone function is also in this case temporarily protected.
• the transformation of the hydroxymethyl or hydroxyethyl radical into a carboxymethyl or carboxyethyl radical is carried out according to the usual methods which do not alter the rest of the molecule, in particular by the action of a halogenating agent such as, for example, thionyl chloride or phosphorus trichloride or phosphorus tribromide, or a tosylating agent, then an alkaline cyanide, for example (potassium cyanide or sodium cyanide, to prepare the corresponding cyanomethyl derivative, followed by hydrolysis of the nitrile.
• a halogenating agent such as, for example, thionyl chloride or phosphorus trichloride or phosphorus tribromide, or a tosylating agent
• an alkaline cyanide for example (potassium cyanide or sodium cyanide, to prepare the corresponding cyanomethyl derivative, followed by hydrolysis of the nitrile.
• the halogenation can be carried out
• the amidation reaction with ammonia is' made in • the usual conditions known to those skilled in the art.
• the operation is preferably carried out starting from the acid, for example in the presence of dicyclohexylcarbodiimide and of dimethylaminopyridine or of hydroxybenzotriazole, in an ether, for example tetrahydrofuran, of a chlorinated solvent, for example of dichloromethane, or dimethylformamide .
• the reduction to the amine is carried out, likewise, under conventional conditions, for example by the action of a hydride such as lithium aluminum hydride in an ether, for example tetrahydrofuran, or by the action of 'a borane in the presence of dimethylsulfide.
• R is a hydrogen atom
• the condensation of the chain R 3 on the nitrogen of pyrrolidine or of azetidine does not in principle require that the nitrogen carrying R 4 is protected taking into account the steric hindrance around this nitrogen.
• a conventional protective grouping of amino functions such as those described in the work by TWGreene and PGM Wuts cited above can be used.
• the preparation of the products of general formula (II) for which Y is a CH 2 group and m is equal to 1 or 2 is carried out by condensation of a heteroaromatic derivative of general formula:
• RI, XI, X2, X3, X4 and X5 are defined as above and m is equal to 1 or 2, on a derivative of general formula: • in which P is a protective group, n and R 2 are defined as above and R 2 represents a protected radical if R 2 represents or carries a carboxylic acid function, followed by the removal of the protective groups and / or followed by the transformation, by subsequent operation, substituents of the aromatic bicycle of general formula (II) thus obtained, to lead to the derivative carrying the radical R x , R '--- / R' i ⁇ • R ' 3 • R', R's expected, and if necessary elimination of the protective radical (s) still present on the molecule.
• P can be any protective group of the nitrogen atom compatible with the reaction (t-butyloxycarbonyl, benzyloxycarbonyl for example).
• the groups protecting from the acid functions are chosen from the usual groups, the establishment and elimination of which do not affect the rest of the molecule, in particular those mentioned in the references cited above.
• the reaction can be carried out in the presence of an amino base such as triethylamine, in a halogenated solvent such as chloroform or dichloroethane and then a reducing agent such as sodium triacetoxybrohydride in the presence of acetic acid, operating at room temperature.
• an amino base such as triethylamine
• a halogenated solvent such as chloroform or dichloroethane
• a reducing agent such as sodium triacetoxybrohydride
• the products of general formula (II) for which Y is a CHR group, R being an alkyl can be prepared starting from the corresponding compounds in which Y is CH 2 , by the action of an alkyl halide , preferably an iodide- on the anion in ⁇ of quinoline prepared by the action of a strong base, for example an alkaline tertbutylate. Such reactions are known to those skilled in the art.
• RI, XI, X2, X3, X4 and X5 are defined as above, on a derivative of general formula IV) as defined above.
• This oxidation is carried out for example by means of potassium permanganate, optionally in a sodium hydroxide solution (for example 3N sodium hydroxide), at a temperature between -20 and 20 ° C., or else by the action of oxalyl chloride in the presence of dimethyl sulfoxide, followed by the addition of an amine such as triethylamine, in an inert solvent such as dichloromethane, dimethyl sulfoxide at a temperature between -60 and 20 ° C by analogy with the method described by D.
• a sodium hydroxide solution for example 3N sodium hydroxide
• RI, XI, X2, X3, X4 and X5 are defined as above.
• One operates for example in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole.
• the products of general formula (II) in which Y is a CROH group, R being an alkyl can be obtained from "products in which Y is a carbonyl group, by reaction of an appropriate alkyl magnesium halide, in conventional conditions known to those skilled in the art. This is done for example by the action of methyl magnesium chloride in an ether such as tetrahydrofuran.
• the products of general formula (II) in which Y is a CHR group, R being an alkyl can also be obtained from products in which Y is a CROH group, obtained as described above, by elimination of the alcohol via a xanthate.
• the alcohol is reacted with a strong base , for example sodium hydride, then add carbon sulfide and then methyl iodide, then heat the xanthate thus obtained in the presence of tributyltin hydride.
• a strong base for example sodium hydride
• carbon sulfide and then methyl iodide then heat the xanthate thus obtained in the presence of tributyltin hydride.
• the derivative of general formula (II) for which l Y is a CRNH 2 group can be prepared from the corresponding CROH derivative which is transformed into its tosylated derivative, on which ammonia is made to act.
• the reaction is carried out in an inert solvent such as N, N-dimethylformamide or dimethyl sulfoxide and preferably under pressure (2 to 20 atmospheres) at a temperature between 20 and 100 ° C.
• the tosyloxy derivative is obtained from the product of general formula (II) for which Y is CROH, by the action of tosyl chloride in pyridine, at a temperature between 5 . -10 and 20 ° C.
• the derivatives of general formula (II) for which Y is a CRF or CF 2 group can be prepared by fluorination respectively from the derivative for which Y is a CROH group and from that for which Y is a carbonyl group.
• reaction is carried out in the presence of a sulfur fluoride [for example in the presence of an amino sulfur trifluoride (diethylamino sulfur trifluoride (Tetrahedron, 44_, 2875 (1988), bis (2-methoxyethyl) amino trifluoride 'sulfur (Deoxofluor0), trifluoride
• a sulfur fluoride for example in the presence of an amino sulfur trifluoride (diethylamino sulfur trifluoride (Tetrahedron, 44_, 2875 (1988), bis (2-methoxyethyl) amino trifluoride 'sulfur (Deoxofluor0), trifluoride
• the fluorination reaction can also be carried out using a fluorinating agent such as hexafluoropropyl diethylamine (JP 2 039 546) or N- (2-chloro-trifluoro-1, 1, 2
• Ethyl) diethylamine Is carried out in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform) or in an ether (tetrahydrofuran or dioxane for example) at a temperature between -78 and 40 ° C (preferably '25 0 and 30 ° C). It is advantageous to operate under an inert atmosphere
• a chlorinated solvent e.g. dichloromethane, dichloroethane, chloroform
• ether tetrahydrofuran or dioxane for example
• RI, XI, X2, X3, X4 and X5 are defined as above, which is made to act with allyltributyltin in the presence of tetrakistriphenylphosphine palladium and copper iodide in dimethylfornamide at 60 °, to obtain the product allylé of formula .-
• the starting product of general formula (V) can be obtained as described in patent application WO 02.40474
• R x , Xi, X 2 , X 3 , X 4 and X 5 are defined as above, which are treated with a strong base, then act on the anion thus obtained dimethylformamide.
• the strong base is preferably butyllithium, sec-butyllithium, or lithium diisopropylamide, and the operation is carried out in a solvent such as an ether, tetrahydrofuran for example, at a temperature between -78 ° and -40 °. The condensation of this lithiated derivative on DMF takes place in the same solvent, at a temperature between -78 ° C and 0 ° C.
• the product of general formula (X) can be prepared according to a method described in patent application WO 02.40474.
• the product of formula (III ") can be obtained starting from the product of general formula (X) as defined above, the anion of which is prepared in position 4 as above, which is treated with acetaldehyde to obtain general formula alcohol
• the reducing agent for the ketone may in particular be boron hydride and the operation is carried out for example within tetrahydrofuran.
• the base used is in particular a carbonate or an alkali hydroxide and the operation is carried out, for example, in an alkanol.
• the product of- general formula (III '") can be obtained from the product of general formula (X) as defined above, the anion of which is prepared in position -4, which is treated with a chloroformate of alkyl, to obtain the ester of general formula
• products of formula (IN) not described can generally be obtained by methods described in these references or, starting from the products described, by methods known to those skilled in the art.
• products of general formula (I) for which R is different from hydrogen can be obtained either as described above, starting from a product of general formula (II) for which R has the corresponding value, different from hydrogen, either from a product of general formula (I) for which R 4 is hydrogen, by one or other of the methods described below.
• the products of general formula (II) for which R 4 is different from hydrogen can be obtained from a product of general formula (II) for which R 4 is hydrogen, by the same methods.
• the implementation of these methods requires the intermediate protection of the reactive functions, in particular amino and / or carboxy and / or hydroxy.
• This, as well as deprotection, can be carried out according to the methods described above.
• the products for which R 4 represents an alkyl radical can be obtained by the action of a corresponding aldehyde on the amine, in the presence of a reducing agent.
• a reducing agent may for example be sodium borohydride or sodium cyanoborohydride or alternatively sodium triacetoxy borohydride and it may be carried out in a conventional halogenated solvent or in an alcohol. It may be advantageous to operate at a slightly acid pH, for example in the presence of acetic acid.
• R represents a CHO radical
• the products for which R represents a CHO radical can be obtained by the action of formic acid in the presence of " acetic acid, or by the action of triethyl orthoformate in the presence of paratoluene sulfonic acid and triethylamine, on the amine.
• Formylation can also be carried out according to a Vilsmeyer type method.
• Products for . which R represents a COCH 3 radical can be obtained by the action of an acetyl halide or acetic anhydride on the amine. The operation is carried out in the presence of a base such as triethylamine.
• R 4 represents a CH 2 C0 2 H radical
• the products for which R 4 represents a CH 2 C0 2 H radical can be obtained by the action of bromoacetic acid on the amine, by operating under the same conditions as above, or by the action of glyoxaldehyde on the amine then reduction with sodium cyanoborohydride by operating in the same type of solvents.
• R represents a CO-CH 2 -NH 2 radical
• R represents a CO-CH 2 -NH 2 radical
• the products for which R represents a CO-CH 2 -NH 2 radical can be obtained by peptide coupling by action of glycine on the amine, in the presence for example of dicyclohexylcarbodiimide, and after having protected the amine function of the glycine, or also by action on the amine of the same protected glycine, the acid function of which is activated beforehand, in particular in the form of chloride, by the action of oxalyl chloride or of thionyl chloride. It is preferably carried out in a halogenated solvent or in tetrahydrofuran.
• XI), (XII), (XIII) and (XIV) are also new and, as such, are also part of the invention. It is understood that the derivatives of general formula (I) and (II) can exist in enantiomeric or diastereoisomeric forms or in syn or anti form, which of course fall within the scope of the present invention. These forms can be separated according to the usual methods known to those skilled in the art, in particular by chiral chromatography or by High Performance Liquid Chromatography (HPLC). This is illustrated below in the experimental part.
• the derivatives of general formula (I) can be purified if necessary by physical methods such as crystallization or chromatography.
• the derivatives of general formula (I) can, where appropriate, be converted into addition salts with acids or with bases, by known methods. It is understood that these salts with acids or bases also fall within the scope of the present invention.
• addition salts with pharmaceutically acceptable acids may be mentioned the salts formed with inorganic acids (e.g. hydrochlorides, hydrobromides, sulphates, nitrates or - phosphates) 'or with organic acids (e.g., succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p.
• inorganic acids e.g. hydrochlorides, hydrobromides, sulphates, nitrates or - phosphates
• organic acids e.g., succinates, fumarates, tartrates, acetates, propionates, maleates,
• the derivatives of general formula (I) carrying a carboxy radical can be transformed into metal salts or into addition salts with nitrogenous bases according to the methods known per se.
• the salts can be obtained by the action of a metal base (for example alkaline or alkaline-earth), ammonia or an amine, on a product according to the invention, in a suitable solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid.
• a metal base for example alkaline or alkaline-earth
• ammonia or an amine on a product according to the invention
• a suitable solvent such as an alcohol, an ether or water
• the salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or lyophilization.
• salts with alkali metals sodium, potassium, lithium
• alkaline earth metals magnesium, calcium
• the ammonium salt the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl- ⁇ -phenethylamine, NN '-dibenzylethylenediamine, diphenylenediamine, benzydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).
• the derivatives of general formula (I) according to the invention are particularly active antibacterial agents.
• the compounds of the invention have therefore been shown to be quite remarkable in at . both gram positive and negative germs.
• the products according to the invention are particularly advantageous because of their low toxicity. None of the products showed toxicity at a dose of 50 mg / kg subcutaneously or orally in mice (2 administrations / day).
• the subject of the present invention is therefore also, as medicaments and in particular medicaments intended for the treatment of bacterial infections in humans or animals, the compounds of general formula (I) as defined above as well as their pharmaceutically acceptable salts, and in particular the preferred compounds mentioned above.
• the present invention also relates to the pharmaceutical compositions containing at least one quinoline-4-substituted derivative according to the invention, where appropriate in the form of a salt, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.
• compositions according to the invention can be used orally, parenterally, topically, rectally or in aerosols.
• solid compositions for oral administration tablets, pills, capsules, powders or granules can be used.
• the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
• inert diluents or adjuvants such as sucrose, lactose or starch.
• These compositions can comprise substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for a controlled release.
• compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
• the compositions for parenteral administration can be sterile solutions or emulsions.
• solvent or vehicle there may be used water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate.
• compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• the compositions for topical administration can be, for example, creams, ointments, lotions or aerosols.
• compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• the compositions can also be aerosols.
• the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, in serum or any other pharmaceutically acceptable vehicle.
• the active ingredient is finely divided and associated with a water-soluble solid diluent or vehicle with a particle size of 30 to 80 ⁇ m, for example dextran, mannitol or lactose.
• the new quinoline-4-substituted derivatives according to the invention are particularly useful in the treatment of infections of bacterial origin.
• the doses depend on the desired effect and on the duration of the treatment. The doctor will determine the dosage he considers most appropriate based on the treatment, depending on the age, weight, degree of infection and other factors specific to the subject to be treated. Generally, the doses are between 750 mg and 3 g of active product in 2 or 3 taken per day by the oral route or between 400 mg and 1.2 g by the intravenous route for an adult.
• the following examples illustrate compositions according to the invention.
• a liquid composition intended for parenteral use is prepared according to the usual technique, comprising: • Acid -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- ( 3-fluoro- 6-methoxy-4-quinoleinyl) ethylamino] -3-pyrrolidine carboxylic 1 g
• a liquid composition intended for parenteral use is prepared according to the usual technique, comprising: • Acid -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] - 3- [2- (6-methoxy-4 -quinolinyl) -ethylamino] -3 -pyrrolidine carboxylic;
• Example 1 Enantiomers A and B of 1- [(E) -3- (2, 5-difluorophenyl) -allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) acid ) - ethylamino] -3 -pyrrolidine carboxylic:
• the A-enantiomer of 1- [(E) -3- (2,5-difluoro-phenyl) - allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) acid) ethylamino] - 3 -pyrrolidine carboxylic acid - can be prepared as follows:
• the reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure.
• the residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 15 cm of silica 20-45 ⁇ m at atmospheric pressure using as .eluent a chloroform / methanol / 28% aqueous ammonia mixture (12/3/0 , 5 by volume).
• the fractions containing the expected are combined and concentrated under reduced pressure to give 0.150 g of a pale yellow product which is taken up in 20 cm 3 of a dichloromethane / methanol mixture (9/1).
• the B-enantiomer of 1- [(E) -3- (2,5-difluoro-phenyl) - allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl)) acid ethylamino] - 3 -pyrrolidine carboxylic acid can be prepared as follows:
• the reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure.
• the residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 21 cm of silica 20-45 ⁇ m at atmospheric pressure using as eluent a chloroform / methanol / 28% aqueous ammonia mixture (12/3/0 , 5 by volume).
• the fractions containing .1 'expected are combined and concentrated under pressure reduced to give 0.150 g of a pale yellow product which is taken up in 20 cm 3 of a dichloromethane / methanol mixture (9/1).
• the yellow suspension thus obtained is brought to reflux for 5 hours, then brought to a temperature in the region of 20 ° C. and stirred for 18 hours.
• the reaction medium is then filtered, the residue is rinsed with 3 times 30 cm 3 of acetonitrile and the filtrate is concentrated under reduced pressure.
• the residue thus obtained is taken up in 250 cm 3 of ethyl acetate, the organic phase is washed with water, dried over anhydrous magnesium sulfate, filtered on paper and concentrated under reduced pressure.
• the orange oil thus obtained is purified by chromatography on a column 3.5 cm in diameter containing 26 cm of silica 20-45 ⁇ m at atmospheric pressure using as eluent a mixture of ethyl acetate / methanol (90/10), then a dichloromethane / methanol mixture (95/5).
• the fractions containing the expected product are combined and concentrated under reduced pressure to give 0.427 g of the methyl ester of 3- (RS) - l - [(E) -3- (2,5-difluoro-phenyl) acid.
• the latter product is ironed in its free base form by treatment of a solution in ethyl acetate containing it with an aqueous solution of sodium bicarbonate, decantation of the organic phase, drying over anhydrous magnesium sulfate and concentration under pressure. scaled down.
• the product thus obtained is mixed with the preceding fraction, then the two enantiomers are separated by chiral chromatography on the Chiracel OD 20 ⁇ m phase, eluting with a Heptane 95% iPrOH 5% TEA 0.5% mixture. Detection is carried out at 265 nm. Are thus obtained:
• the emulsion thus created is taken up in 100 cm 3 of brine, decanted, and the organic phases are dried over anhydrous magnesium sulfate, filtered on paper and then concentrated to dryness under reduced pressure to give 1.5 g of the expected product, in the form a pale yellow solid used as is in the next step.
• the solution thus obtained is stirred 15 minutes at a temperature close to 0 ° C., then diluted with 150 cm 3 of ethyl acetate.
• the organic phase is decanted and the aqueous phase is extracted with 3 times 100 cm 3 of ethyl acetate.
• the organic phases are combined, washed with 3 times 50 cm 3 of water, then s . dried over anhydrous magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure.
• the solid residue thus obtained is taken up in 50 cm 3 of ethyl acetate and stirred for 30 minutes at a temperature in the region of 20 ° C.
• the suspension thus obtained is filtered, the solid is washed with ethyl acetate, then with 1 isopropyl ether.
• the solid thus obtained is dried in a desiccator under vacuum for 2 hours to give 1.6 g of the expected product in the form of crystals of cream color, melting at 162 ° C.
• 4-allyl-3-fluoro-6-methoxy quinoline can be prepared as follows:
• the yellow suspension thus obtained is brought to reflux for 8 hours, then brought to a temperature in the region of 20 ° C. and stirred for 18 hours.
• the reaction medium is then filtered, the residue is rinsed with 3 times 15 cm 3 of acetonitrile and the filtrate is concentrated under reduced pressure.
• the residue thus obtained is taken up in 50 cm 3 of ethyl acetate, the organic phase is washed with 3 times 15 cm 3 of water, dried over anhydrous magnesium sulfate, filtered on paper and concentrated under reduced pressure.
• the orange oil thus obtained is. purified by chromatography on a column 2 cm in diameter containing 15 cm of silica.
• the reaction medium is then concentrated under reduced pressure, and the residue obtained East . taken up in 50 cm 3 of water, the pH of the solution is brought to a value close to 9 by an aqueous solution of NaHCO 3 , and the aqueous phase thus obtained is extracted with 3 times 100 cm 3 of ethyl acetate .
• the organic phases are combined, washed with 3 times 30 cm 3 of water, dried over anhydrous MgSO, filtered and concentrated under reduced pressure.
• the residue thus obtained is purified by chromatography on silica 20-45 ⁇ m at atmospheric pressure using as eluent dichloromethane / methanol (50/50). The fractions containing the product are combined and concentrated under reduced pressure. 0.240 g of expected ester is obtained in the form of an orange oil.
• Mass spectrum (CI): m / z 364 MH + (base peak).
• the reaction medium is then concentrated under reduced pressure, and the residue thus obtained is purified by chromatography on silica 20-45 ⁇ m at atmospheric pressure using dichloromethane as eluent, then a dichloromethane / ethyl acetate mixture (95/5).
• the fractions containing the product are combined and concentrated under reduced pressure. 0.550 g of the expected ester is obtained, in the form of an orange oil.
• the residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 21 cm of 20-45 Dm silica at atmospheric pressure using as eluent a dichloromethane / methanol / 28% aqueous ammonia mixture (40/5/0, 5).
• the fractions containing the expected are combined and concentrated under reduced pressure to give 0.360 g of a pale yellow meringue which is taken up in 25 cm 3 of a dichloromethane / methanol mixture (9/1).
• the resulting solution is filtered, the filter is washed with a dichloromethane / methanol mixture (9/1), the filtrates are combined and then concentrated to dryness under reduced pressure.
• the residue is taken up in 50 cm3 of isopropyl ether, stirred for 10 minutes, then the resulting suspension is concentrated to dryness under reduced pressure to give 0.330 g of the expected acid in the form of a pale yellow solid.
• the orange oil thus obtained is purified by chromatography on silica 70-200 ⁇ m at atmospheric pressure using as eluent a mixture of ethyl acetate / methanol (90/10), then a dichloromethane / methanol mixture (90/10). The fractions containing the expected product are combined and concentrated under reduced pressure. 0.460 g of the expected ester is obtained in the form of a yellow oil.
• the solution thus obtained is concentrated under reduced pressure to give a residue which is taken up in 60 cm 3 of dichloro-1, 2-dichloroethane and stirred at a temperature of 20 ° C.
• To the suspension thus obtained are added 1/4 g (6.3 mmol) of sodium triacetoxyborohydride, followed by 0.364 cm 3 (6.3 mmol) of acetic acid.
• the suspension thus obtained is stirred at a temperature in the region of 20 ° C for 18 hours.
• the reaction medium is then diluted with 250 cm 3 of dichloromethane, the organic phase is washed with 5 times 100 cm 3 of water, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure.
• the emulsion thus created is taken up in 1.00 cm 3 of brine, decanted, and the organic phases are dried over anhydrous magnesium sulphate, filtered on paper and then concentrated to dryness under pressure. reduced to give 1.1 g of the expected product in the form of a pale yellow solid used as it is in the next step.
• the solution thus obtained is stirred for 15 minutes at a temperature in the region of 0 ° C., then diluted with 150 cm 3 of ethyl acetate.
• the organic phase is decanted and the aqueous phase is extracted with 3 times 100 cm 3 of ethyl acetate.
• the organic phases are combined, washed with 3 times 50 cm 3 of water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
• the solid residue thus obtained is taken up in 50 cm 3 of ethyl acetate and stirred for 30 minutes at a temperature in the region of 20 ° C.
• 4-allyl-3-chloro-6-methoxy quinoline can be prepared as follows: To a suspension containing 8.2 g (30 mmol) of 4-bromo-3-chloro-6-methoxy quinoline (prepared according to the method described in patent application WO 0240474) in 250 cm 3 of DMF are added 14, 14 4 cm 3 (45 mmol) of allyl-tributyltin, 1.75 g (1.5 mmol) of tetrakis (triphenylphosphine) alladium and 1.2 g (6 mmol) of copper iodide (I). The suspension is stirred under an inert atmosphere (Argon) and at a temperature in the region of 60 ° C for 48 hours.
• an inert atmosphere ArArgon
• the reaction medium is then brought to a temperature in the region of 20 ° C, diluted with 500 cm 3 of ethyl acetate and washed with 3 times 300 cm 3 of water.
• the emulsion which has formed is filtered, and the residue is washed with 3 times 100 cm 3 of water, then with 3 times 100. cm 3 of ethyl acetate.
• the organic phases are combined and dried over anhydrous magnesium sulfate. It is filtered and concentrated to dryness under reduced pressure.
• the residue thus obtained is purified by chromatography on a column 6 cm in diameter containing 30 cm of 40-63 ⁇ m silica at atmospheric pressure using dichloromethane as eluent. The fractions containing the product were x; éunies and obtained 1.85 g of the expected product as an oil.

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