Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
  • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms

Definitions

• the present invention relates to 4-substituted-quinolines derivatives of the general formula:
• the invention also relates to their process and preparation intermediates and pharmaceutical compositions containing them.
• R 1 is in particular alkoxy (Cl-6)
• 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 4 is -CH 2 -R 5 wherein R 5 is selected from 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, sulphinyl, sulphonyl, NR 11
• EP 30044 which discloses related derivatives active in another field. All these applications describe compounds having a chain attached to the 4-position of quinoline and which contain a substituted nitrogenous heterocycle.
• R 1 , R ' 1 , R' 2 , R ' 3 , R' 4 and R ' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or mono- or bicyclic heteroarylthio, OH, SH, alkyloxy, difluoromethoxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, acyl, acyloxy, acylthio, cyano, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, nitro, -NRaRb or -CONRaRb (for which Ra and Rb may represent a hydrogen atom, an alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl radical or Ra and Rb together with the nitrogen atom to which they are
• R 5 may also represent trifluoroacetyl; n is 0, 1 or 2; m is 0, 1 or 2;
• Z is CH 2 or Z is oxygen, sulfur or NH when n and m are 1 or 2 and Y is CROH, CRNH 2 , CRF, or CF 2 ;
• R 2 represents a radical -CO 2 R, -CH 2 CO 2 R, -CH 2 -CH 2 OH, CH 2 OH, CH 2 -CH 2 CO 2 R, - CONH 2, -CH 2 -CONH 2, - CH 2 -CH 2 -CONH 2 , -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 radical, heteroaryl, alk-R ° 3 for which alk is an alkylene radical and
• R 3 is hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfmyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N -alkylamino, N- (cycloalkyl) 2 , acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino, N- (phenyl) 2 , phenylalkyloxy, phenylalkylthi
• R 1 , R ' 1 , 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 substituted methylene radical by alkyloxy; m and n are 1 or 2; and
• R 3 represents an alk-R 3 radical for which alk is an alkylene radical and R 3 represents alkyloxy, alkylthio, alkylamino, dialkylamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N -alkylamino, -N- (cyclohexyl), alkyl) 2 , phenyl, phenoxy, phenylthio, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino, phenylalkyloxy, phenylalkylthio, phenylalkylamino, N-alkyl N-phenylaminoalkyl, N-cycloalkyl N-phenylaminoalkyl amino, heteroaryloxy, heteroarylthio, heteroarylamino, N-alkyl N-heteroaryl amino,
• N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N-heteroaryl aminoalkyl, (the heteroaryl moieties mentioned above being mono or bicyclic), -NRaRb or -CO-NRaRb for which Ra and Rb are defined as in item 1, or R 3 is -CR'b CR'c-R'a wherein R'a is phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl , N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, (the heteroaryl moieties mentioned above being mono or bicyclic), or phenylthio, and wherein R'b and R
• R 2 , R 4 , R 5 , Y and Z are as defined in point 1; in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in E or Z form or mixtures thereof, and also their salts.
• R 2 represents a radical COOR, CH 2 -COOR, CH 2 OH or CH 2 CH 2 OH, R being as defined in point 1;
• Z represents a CH 2 group
• R 3 represents an alk-R 3 radical for which alk is an alkylene radical and R 3 represents cycloalkyloxy, cycloalkylthio, phenyl, phenoxy, phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryloxy, heteroarylthio, heteroarylalkyloxy, heteroarylalkylthio,
• R 4 represents a hydrogen atom or an alkyl radical optionally substituted with R 6 , where
• R 6 represents an OH radical or a fluorine atom
• R 5 is a hydrogen atom or an alkyl group; it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above may be optionally substituted as envisaged above; in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in Z or E form or mixtures thereof, and also their salts.
• R 1 , R ' 1 , 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 substituted methylene radical by alkyloxy; m and n are 1; Y and Z are CH 2 ;
• R 2 represents a radical COOR or CH 2 -COOR, R being as defined in point 1;
• R 3 and R 4 are as defined in point 3;
• R 5 is a hydrogen atom; in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in Z or E form or mixtures thereof, and also their salts.
• the products of general formula (I) can be obtained according to the process in which the R 3 chain defined above is condensed on the 4-substituted quinoline derivative of general formula II
• X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , Y, Z, m, n R 4 and R 5 are as defined above, R 2 being protected when it bears a carboxy radical, then if necessary eliminates the protective group of the carboxy radical, optionally the enantiomeric or diastereoisomeric forms and / or, where appropriate, the Z or E forms are separated off and, if appropriate, the product obtained is converted to a salt.
• the condensation of the chain R 3 on the nitrogen is carried out by action of a derivative of general formula (IIa): R 3 -X (IIa) in which R 3 is defined as above and X represents an atom halogen, a methylsulfonyl radical, a trifluoromethylsulfonyl radical, or a toluenesulfonyl radical.
• R 3 is defined as above and X represents an atom halogen, a methylsulfonyl radical, a trifluoromethylsulfonyl radical, or a toluenesulfonyl radical.
• R 3 represents a radical -alk-R ° 3 for which alk is an alkyl radical and R 3 represents a radical -C ⁇ C-Rd in which Rd is as defined above
• Rd represents a condensation of an alkynyl halide HC ⁇ C-alk-X for which alk is defined as above and X is a halogen atom, then a substitution of the chain by a radical Rd appropriate.
• R 3 represents a radical -alk-R ° 3 for which wing is an alkyl radical and R 3 represents a radical phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino
• the reaction is carried out by construction of the chain by first condensing an HO-alk-X chain for which X is a halogen atom, and then either by transforming the hydroxyalkyl chain obtained into a haloalkyl, methanesulphonylalkyl or toluenesulphonylalkyl chain and finally by acting in a basic medium a aromatic derivative of structure R 3 H or R 3 H 2 , or by directly acting aromatic derivative under dehydration conditions.
• a product of general formula (I) wherein R 4 represents a hydrogen atom to the action of a suitable alkylating reagent for the preparation of the compounds of general formula (I) in which R 4 represents an alkyl group optionally substituted with R 6 , a product of general formula (I) wherein R 4 represents a hydrogen atom to the action of a suitable alkylating reagent.
• R 2 represents a protected radical if R 2 represents or carries a carboxylic acid function, followed by elimination protecting groups and / or followed by the conversion, by subsequent operation, of the substituents of the aromatic bicycle of general formula (II) thus obtained, to yield the derivative carrying the radical R 1 , R ' 1; R ' 2 , R' 3 , R ' 4 , R' 5 expected, and optionally removal of the protective radical (s) still present on the molecule.
• the subject of the invention is also the derivatives of general formula (II) and (IV) as defined above.
• the subject of the invention is also, as medicaments, the derivatives of general formula (I) as defined above.
• the invention also relates to a pharmaceutical composition which contains at least one drug of general formula (I) in pure form or in combination with one or more compatible and pharmaceutically acceptable diluents and / or adjuvants.
• the compounds of general formula (I) can be prepared by condensation on a compound of general formula (II)
• R 1 , X 1 , X 2 , X 3 , X 4 , X 5 , Y, n, Z, R 5 , R 2 , m and R 4 are defined as previously, of the chain R 3 , R 2 being protected when it bears a carboxyl radical, optionally followed by the elimination of the carboxy-protecting group, optionally the separation of the enantiomeric or diastereomeric forms and / or, where appropriate, the syn or anti forms and, optionally, the transformation of the product obtained in a salt.
• R 3 is defined as above and X represents a halogen atom, a methylsulfonyl radical or a trifluoromethylsulfonyl or p-toluenesulphonyl radical, operating in an anhydrous medium, preferably an inert medium, in an organic solvent such as an amide (dimethylformamide for example), a ketone (acetone for example) or a nitrile (acetonitrile for example) in the presence of a base such as a nitrogenous organic base (for example triethylamine) or a mineral base (for example an alkaline carbonate such as potassium carbonate) at a temperature of between 20 ° C. and the reflux temperature of the solvent.
• a base such as a nitrogenous organic base (for example triethylamine) or a mineral base (for example an alkaline carbonate such as potassium carbonate) at a temperature of between 20 ° C. and the reflux temperature of the solvent.
• the amino function is optionally protected according to the usual methods compatible with the rest of the molecule or the reaction; the protection taking place for example by a protective radical chosen from benzyl, t-butoxycarbonyl and benzyloxycarbonyl groups, and this function is released prior to condensation with the derivative of formula (IIa), in particular by acid hydrolysis.
• a derivative of general formula (IIa) is used for which X is a chlorine, bromine or iodine atom.
• X is a chlorine, bromine or iodine atom.
• R 3 is a radical -alk-R ° 3 in which R ° 3 is a group -C ⁇ C-Rd, in which Rd is as defined above, an alkynyl halide is intermediate-condensed and the radical is then condensed. desired 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
• 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
• X is a halogen atom, preferably iodine
• the conversion of the hydroxyl chain into a haloalkyl or p-toluenesulfonyl chain is carried out according to the usual halogenation or sulphonylation methods, in particular a halogenating agent such as thionyl chloride, halogenated phosphorus derivatives (trichloride or phosphor tribromide for example) or a sulfonylating agent such as, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulphonic anhydride.
• a halogenating agent such as thionyl chloride, halogenated phosphorus derivatives (trichloride or phosphor tribromide for example) or a sulfonylating agent such as, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane
• the 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.
• 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 a nitrogenous organic 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 reaction mixture. It may be advantageous to operate in the 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 a nitrogenous organic base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature between 20 ° C and
• the protected carboxy radical carried optionally by R 2 may be chosen from esters easily hydrolyzable. By way of example, mention may be made of methyl, benzyl or tert-butyl esters or of phenylpropyl or allyl esters.
• Optionally protection of the carboxy radical is carried out simultaneously with the reaction. The establishment of the elimination of these protective radicals is carried out according to the methods known to those skilled in the art.
• the condensation of the chain R 3 on the nitrogen atom can be carried out by the action of a precursor derivative of R 3 comprising at the end of the chain an aldehyde function, the carbon atom of this molecule. as an integral part of R 3 .
• the reaction is carried out in an anhydrous medium in an inert solvent such as an ether, for example diethyl ether, or a halogenated solvent, for example dichloromethane, under reductive amination conditions, in the presence of a base as described. above, and a reducing agent such as a borohydride, for example sodium borohydride or sodium triacetoxyborohydride.
• the reaction is carried out by the action of hydrogen in the presence of a suitable catalyst, in particular palladium. An example is given later in the experimental section.
• the products of general formula (I) in which R 4 represents an alkyl group optionally substituted with R 6 can be prepared by action on a product of general formula (I) in which R 4 represents a hydrogen atom of a suitable alkylation reagent.
• the alkylation reagent may in particular be a halide or, more generally, a product of formula X-CH 2 -R 6 in which X and R 6 are as defined above, which are reacted in the presence of a base for example an alkali carbonate, or a suitable aldehyde which is reacted under reductive amination conditions such as those described above.
• the derivatives of general formula (I) for which R 2 is hydroxymethyl or hydroxyethyl may 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.
• a ketone function that may be present must then be intermediately protected.
• the products of general formula (I) for which R 2 is carboxymethyl or carboxyethyl may also be prepared from derivatives for which R 2 is hydroxymethyl or hydroxyethyl, by action on it of an agent halogenation or tosylation, then a cyanidation agent and finally a nitrile hydrolysis agent.
• 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 under conditions known to those skilled in the art.
• the reduction of the protected carboxy can be carried out according to the usual methods which do not affect the rest of the molecule, in particular by the action of a hydride (lithium aluminum hydride and diisobutyl hydride for example) in a solvent such as an ether (tetrahydrofuran, for example) at a temperature of between 20 and 60 ° C.
• a hydride lithium aluminum hydride and diisobutyl hydride for example
• a solvent such as an ether (tetrahydrofuran, for example) at a temperature of between 20 and 60 ° C.
• ether tetrahydrofuran
• 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.
• a ketone function optionally present is in this case also intermediately protected.
• the conversion of the hydroxymethyl or hydroxyethyl radical into a carboxymethyl or carboxyethyl radical is carried out according to the usual methods which do not affect 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, and 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
• an alkaline cyanide for example (potassium cyanide or sodium cyanide
• the halogenation may be carried out in a chlorinated solvent (dichloromethane or chloroform for example) at a temperature between 0 ° C. and the reflux temperature of the solvent.
• a chlorinated solvent dichloromethane or chloroform for example
• the amidification reaction with ammonia is carried out under the usual conditions known to those skilled in the art.
• the reaction is preferably carried out starting from the acid, for example in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine or of hydroxybenzotriazole, in an ether, for example tetrahydrofuran, with a chlorinated solvent, for example dichloromethane or dimethylformamide. .
• the reduction in amine is carried out, likewise, under conventional conditions, for example by action of a hydride such as lithium hydride and aluminum in an ether, for example tetrahydrofuran, or by action of a borane in the presence of dimethylsulfide.
• a hydride such as lithium hydride and aluminum in an ether, for example tetrahydrofuran
• a borane in the presence of dimethylsulfide.
• the products of general formula (I) in which R 5 represents an alkyl radical can be prepared by the action of an alkylation reagent in the presence of a base, on a product of general formula (I) in which R 5 represents a hydrogen atom and R 2 preferably represents a COOalkyl radical.
• the alkylating reagent may in particular be an alkyl iodide and the base is a strong base and may in particular be an alkali metal amide such as lithium diisopropylamide.
• the base is a strong base and may in particular be an alkali metal amide such as lithium diisopropylamide.
• the molecule has an alkylation position other than that involved in the foregoing reaction, in particular a secondary or primary nitrogen, an alcohol or a carbon bearing a carboxylic acid function, it will be necessary to protect it in a suitable manner. .
• R 2 in which m, R 2 , R 5 , n and R are defined as above or R 2 represents a corresponding protected radical if R 2 represents or carries a carboxylic acid function
• P represents a protecting group for the amino function, followed by eventual elimination of the protecting groups and / or followed by conversion, by subsequent operation of the substituents of the aromatic bicycle of general formula (II) thus obtained, to yield the derivative carrying the radical R 1, R 'l5 R' 2 , R ' 3 , R' 4 , R ' 5 expected, and, where appropriate, removal of the protective radical (s) still present on the molecule.
• P may be any protective group of the nitrogen atom compatible with the reaction (t-butyloxycarbonyl, benzyloxycarbonyl for example).
• the protective groups of the acidic functional groups are chosen from the usual groups whose introduction and elimination do not affect the rest of the molecule, in particular those mentioned in the references cited above.
• the reaction may in particular be carried out by successive action on the derivative of general formula (IV) of an organoborane (9-borabicyclo [3.3, 1] nonane for example) in a solvent such as an ether (tetrahydrofuran, dioxane by example) at a temperature between -20 and 20 ° C and then bicyclic derivative of general formula (III) for which HaI represents a chlorine atom or preferably a bromine or iodine atom, by analogy with the methods described by Suzuki et al. Pure and Appl. Chem., 57, 1749 (1985).
• the reaction is generally carried out in the presence of a palladium salt (palladium diphenylphosphinoferrocene chloride for example) and a base such as potassium phosphate at a temperature between 20 ° C and the reflux temperature of the solvent.
• a palladium salt palladium diphenylphosphinoferrocene chloride for example
• a base such as potassium phosphate
• the products of general formula (II) for which Y represents a CHOH group may be prepared by oxidation in a basic medium of the corresponding derivative for which Y is a CHR group. Oxidation is carried out by the action of oxygen, preferably in an inert solvent such as dimethylsulfoxide in the presence of tert-butanol and a base such as potassium tert-butoxide or sodium at a temperature between 0 and 100 ° C.
• the derivatives of general formula (II) for which Y is a CRF or CF 2 group may be prepared by fluorination respectively from the derivative for which Y is a group CROH and that for which Y is a carbonyl group.
• the reaction is carried out in the presence of a sulfur fluoride [for example in the presence of an aminosulfur trifluoride (diethylamino trifluoride sulfur (Tetrahedron, 44, 2875 (1988), bis (2-methoxyethyl) amino trifluoride sulfur (Deoxofluor®), morpholino sulfur trifluoride, for example) or alternatively in the presence of sulfur tetrafluoride (J. Org Chem., 40, 3808 (1975)].
• fluorinating agent such as hexafluoropropyl diethylamine (JP 2,039,546) or N- (2-chloro-1,1,2-trifluoroethyl) diethylamine.
• an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform) or in an ether (tetrahydrofuran, dioxane, for example) at a temperature of between -78 and 40 ° C. (preferably between 0 and 30 ° C. ° C). It is advantageous to operate in an inert medium (argon or nitrogen in particular).
• a chlorinated solvent for example dichloromethane, dichloroethane, chloroform
• an ether tetrahydrofuran, dioxane, for example
• the derivatives of general formula (II) for which Y is a carbonyl group can be prepared by oxidation of the corresponding derivative of general formula (II) for which Y is a CHOH group.
• This oxidation is carried out for example by means of potassium permanganate, optionally in a solution of sodium hydroxide (for example 3N sodium hydroxide), at a temperature of between -20 and 20 ° C., or else by action of oxalyl chloride in the presence of dimethylsulfoxide, followed by the addition of an amine such as triethylamine, in an inert solvent such as dichloromethane, dimethylsulfoxide at a temperature between -60 and 20 ° C. by analogy with the method described by D. SWERN et al. , J. Org. Chem., 44, 4148 (1979).
• the derivative of general formula (II) for which Y is a CRNH 2 group may be prepared from the corresponding CHOH derivative which is converted into its tosylated derivative, on which ammonia is reacted. It is carried out in an inert solvent such as N, N-dimethylformamide or dimethylsulfoxide and preferably under pressure (2 to 20 atmospheres) at a temperature between 20 and 100 ° C.
• an inert solvent such as N, N-dimethylformamide or dimethylsulfoxide
• the tosyloxy derivative is obtained from the product of general formula (II) for which Y is CROH, by action of tosyl chloride in pyridine, at a temperature of between -10 and 20 ° C.
• R 2 in which P, m, R 2 and R 5 are defined as above, R 2 preferably represents a COOalkyl or COOp radical, p being a protective group, on a compound of general formula (IV) Hal- (CH 2 ) n -CH CHR (VI)
• Hal represents a halogen atom, preferably a bromine atom.
• the procedure is preferably carried out in the presence of a strong base, in particular an alkaline amide, for example lithium bis (trimethylsilyl) amide, or a lithien, for example butyllithium, in an organic solvent which may in particular be an ether. such as tetrahydrofuran or dioxane.
• a strong base in particular an alkaline amide, for example lithium bis (trimethylsilyl) amide, or a lithien, for example butyllithium
• organic solvent which may in particular be an ether.
• ether such as tetrahydrofuran or dioxane.
• R is defined as above, and then the product obtained is dehydrobromide by a method known to those skilled in the art. For example, one can refer to the method described by R. A. Bunce et al, Organic Preparations International Procedure 1999-31 (1) p.99-106.
• the compounds of general formula (V) in which R 5 represents an alkyl radical may be prepared by the action of an alkylating reagent in the presence of a base on the corresponding compounds in which R 5 is a hydrogen atom, in conditions identical to those described above for the preparation of the compounds of general formula (I).
• the alkylation reaction can also be carried out on the compound of general formula (TV), that is to say by alkylation of a compound of formula IV in which R 5 represents an atom of hydrogen, under the same conditions as above.
• TV general formula
• the compound of general formula (II) for which Z is an oxygen atom may be prepared starting from the compound of formula (VII)
• the compound of formula (X) may be prepared by condensation of the lithiated derivative at the 4-position of the heteroaromatic compound of general formula (III '):
• n is defined as above.
• the formation of the lithiated derivative at the 4-position of the compound (III ') is carried out using a strong lithiated base such as butyllithium, sec-butyllithium, or preferably lithium diisopropylamide, in a solvent such as an ether tetrahydrofuran, for example, at a temperature between -78 ° and -40 °.
• a strong lithiated base such as butyllithium, sec-butyllithium, or preferably lithium diisopropylamide
• a solvent such as an ether tetrahydrofuran
• the derivative of formula (HF) may be prepared according to a method described in patent application WO 02/40474.
• reaction of the compound of formula (X) with the compound of formula (IX) may be carried out in the presence of a basic agent such as sodium hydride in a solvent such as acetonitrile.
• the compound of general formula (II) for which Z is a sulfur atom may be prepared starting from a compound of general formula IX as defined above, the corresponding thiol of which is prepared, firstly preparing the corresponding mesylate of formula (XII)
• the preparation of the mesylate of formula (XII) can be carried out within pyridine.
• reaction of the compound of formula (XII) can be carried out in a solvent such as dimethylformamide.
• the compound of general formula (II) for which Z is an NH group may be prepared starting from a compound of general formula (XIV)
• the compound of formula (XIV) may be prepared starting from a compound of formula
• P 5 m and p are defined as above and P 'is a protective group different from P and removable under conditions different from P.
• the compound of formula (XV) may be prepared from the corresponding acid.
• Such acids are known or can be prepared by known methods and for some commercial.
• the compound of formula (II) as defined above in which R 1 , X 1 , X 2 , X 3 , X 4 , X 5, Z, n, R 2 , R 5 , m and R 4 are defined as previously and Y is a CHR group in which R is an alkyl radical can be prepared from the corresponding compound wherein R is a hydrogen atom by preparing the quinoline azide under the conditions analogous to those indicated above for the compound of formula (IH '), an anion on which a reactant of RX type is reacted, X being a halogen such as chlorine or, preferably, bromine or iodine or else a leaving group such as a mesyl or tosyl.
• Such a compound may also be prepared starting from a compound in which Y is a CO group by the action of a suitable magnesium under conditions known to those skilled in the art, followed, if appropriate, by deoxygenation under conditions also known to those skilled in the art, in particular described by Barton et al. J. Chem. Sac, Perkin trans.l, 1574 (1975) and Synthesis, 743 (1981) and by N. Hartwig, Tetrhedron, 39, 2609 (1983). ).
• 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) may optionally be converted into addition salts with acids or with bases, by known methods. It is understood that these salts with acids or bases are also within the scope of the present invention.
• salts formed with the mineral acids for example the hydrochlorides, hydrobromides, sulphates, nitrates or phosphates
• organic acids for example the succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates
• substitution derivatives of these acids for example the hydrochlorides, hydrobromides, sulphates, nitrates or phosphates
• succinates for example the succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulf
• the derivatives of general formula (I) carrying a carboxy radical may be converted into metal salts or addition salts with nitrogenous bases according to methods known per se.
• the salts may 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
• ammonium salt nitrogen base salts
• nitrogen base salts ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl- ⁇ -phenethylamine, N, N'-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 dilutions method in agar medium in accordance with the NCCLS recommendations is used for the determination of the minimum inhibitory concentrations (C.M.I.) expressed in mg / 1.
• the products according to the invention are particularly interesting because of their low toxicity, most of the products having shown no toxicity at the dose of 50 mg / kg (DC 50) both subcutaneously and by Oral route in mice (2 administrations / day). These properties make it possible for said products, as well as their pharmaceutically acceptable acid and base salts, to be used as medicaments in the treatment of diseases caused by susceptible bacteria caused by gram-positive bacteria, and in particular those with staphylococci, such as staphylococcal septicemia, malignant staphylococcal disease of the face or cutaneous, pyoderma, septic or suppurative wounds, anthrax, phlegmons, erysipelas, acute primitive or post-influenza staphylococci, bronchopneumonia, pulmonary suppuration, as well as in those with streptococci or enterococci.
• staphylococci such as staphylococcal septicemia, malignant staphylococcal disease of the face
• 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 salts. pharmaceutically acceptable, and especially the preferred compounds mentioned above.
• the present invention also relates to pharmaceutical compositions containing at least one quinoline-4-substituted derivative according to the invention, where appropriate in salt form, in the pure form or in the form of an association with one or more diluents or compatible and pharmaceutically acceptable adjuvants.
• compositions according to the invention can be used orally, parenterally, topically, rectally or in aerosols.
• solid compositions for oral administration may be used tablets, pills, capsules, powders or granules.
• the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
• these compositions may comprise substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.
• compositions for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used.
• inert diluents such as water or paraffin oil
• These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
• compositions for parenteral administration may be sterile solutions or emulsions.
• a solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, may be used.
• These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.
• Sterilization can be done in several ways, for example using a bacteriological filter, irradiation or heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• compositions for topical administration may be, for example, creams, ointments, lotions or aerosols.
• compositions for rectal administration are suppositories or rectal capsules, which contain in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions may also be aerosols.
• the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in pyrogen-free sterile water, in serum or other pharmaceutically acceptable carrier.
• the active principle is finely divided and combined with a water-soluble solid diluent or carrier with a particle size of 30 to 80 ⁇ m, for example dextran, marmitol or lactose.
• novel 4-substituted quinoline derivatives of the invention are particularly useful in the treatment of bacterial infections.
• a liquid composition intended for parenteral use is prepared according to the usual technique, comprising:
• a liquid composition intended for parenteral use is prepared according to the usual technique, comprising:
• Ethyl (RS) -2-aminomethyl-5- (3-fluoro-6-methoxy-quinolin-4-yl) pentanoate hydrochloride can be prepared in the following manner:
• Ethyl (RS) -2- (tert-butyloxycarbonylamino-methyl) -5- (3-fluoro-6-methoxy-quinol-4-yl) -pentanoate can be prepared in the following manner:
• 3-Fluoro-4-iodo-6-methoxyquinoline can be prepared according to the method described in patent WO200240474-A2.
• Ethyl (RS) -2- (tert-butyloxycarbonylamino-methyl) pent-4-enoate can be prepared in the following manner:
• Ethyl 3-tert-butyloxycarbonylamino-propionate can be prepared in the following manner:
• (E) -3- (2,5-difluoro-phenyl) -propenal can be prepared as follows: 22.7 g (74.6 mmol) of (triphenylphosphoranylidene) acetaldehyde dissolved in 650 cm3 of toluene, 10.6 g of 2,5-difluorobenzaldehyde are added at a temperature in the region of 20 ° C. After stirring for 4 hours at a temperature in the region of 80 ° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give 28.42 g of a brown residue which is taken up with 120 cm 3 of diisopropyl ether. .
• the elution is carried out with a mobile phase [heptane / ethanol / methanol (96 1 2 1 2 in volumes)] at a flow rate of 140 ml / min, the detection is carried out by UV at 254 nm.
• the enantiomer A levorotatory
• the enantiomer B (dextrorotatory), of undetermined absolute configuration, eluted in the second position is recovered and then concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C.
• the lower phase is removed and the upper phase is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 5 cm3 of water and 20 cm3 of dichloromethane.
• the aqueous phase is acidified with 1N hydrochloric acid to a pH value of about 7.
• the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 3 cm3 of water. and 15 cm3 of acetonitrile.
• the reaction mixture is filtered. The residue is washed with acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35 ° C.
• Ethyl (RS) -2 - ⁇ [3- (2,5-difluoro-phenyl) -propylamino] -methyl ⁇ -5- (3-fluoro-6-methoxyquinolin-4-yl) -pentanoate may be prepared in the following way: To 0.043 g (0.405 mmol) of 10% palladium on carbon is added at room temperature, under an argon atmosphere, 31 cm3 of ethanol and 0.4 g (0.822 mmol) of (RS) -2 - ⁇ [ Ethyl (E) -3- (2,5-difluoro-phenyl) -allylamino] -methyl ⁇ -5- (3-fluoro-6-methoxy-quinolin-4-yl) -pentanoate.
• reaction medium is purged five times with argon and then hydrogenated under pressure at 2 bars of hydrogen at room temperature for 6 hours.
• the catalyst is filtered through Celite®, Celite® is rinsed with 3 times 5 cm 3 of ethanol and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.459 g of (RS) -2 - ⁇ [ Ethyl 3- (2,5-difluoro-phenyl) -propylamino] -methyl ⁇ -5- (3-fluoro-6-methoxy-quinolin-4-yl) -pentanoate as a colorless oil.
• MS IE spectrum m / z 488 [M +], m / z 204 (base peak).
• the lower phase is removed and the upper phase is concentrated at dry under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 cm3 of ethyl acetate and 10 cm3 of water.
• the pH of the aqueous phase is adjusted to 1 by addition of an aqueous solution of 1N hydrochloric acid.
• Ethyl (RS) -5- (3-fluoro-6-methoxy-iminolin-4-yl) -2 - ⁇ [2- (thiophen-2-ylsulfanyl) -ethylamino] -methyl ⁇ -pentanoate can be prepared 0.4 g (1.079 mmol) of ethyl (RS) -2-aminomethyl-5- (3-fluoro-6-methoxypinolin-4-yl) -pentanoate hydrochloride, obtained at 0 ° C.
• the solution of (thiophen-2-ylsulfanyl) acetaldehyde (1.079 mmol) in toluene can be prepared as follows. 0.106 cm3 (1.079 mmol) of thiophen-2-thiol in solution in 4 cm3 of toluene is added at a temperature in the region of 15 ° C., under an argon atmosphere, 0.18 cm 3 (1.079 mmol) of N, N-diisopropylethylamine. . After stirring for 0.5 hour at room temperature, the reaction medium is cooled to a temperature in the region of 5 ° C. and 0.167 cm 3 (1.316 mmol) of a 50% aqueous solution of chloroacetaldehyde is added.
• Ethyl (RS) -2- ⁇ [2- (2,5-difluoro-phenylsulfanyl) -ethylamino] -methyl ⁇ -5- (3-fluoro-6-methoxy-quinolin-4-yl) -pentanoate may be prepared in the following manner: 0.5 g (1.35 mmol) of (RS) -2-aminomethyl-5- (3-fluoro-6-methoxyquinolin-4-yl) -pentanoate hydrochloride ethyl obtained in Example 1 in solution in 15 cm3 of acetonitrile is added at a temperature of 20 ° C under an argon atmosphere, 0.377 g
• Ethyl (RS) -2- ⁇ [2- (2,5-difluoro-phenoxy) -ethylamino] -methyl ⁇ -5- (3-fluoro-6-methoxyquinolin-4-yl) -pentanoate may be prepared in the following way
• 2- (2-Bromo-ethoxy) -1,4-difluoro-benzene may be prepared according to the method described in the patent application WO200240474.

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