EA010403B1 - 4-substituted quinonoline derivatives, preparation methods and intermediates and pharmaceutical composition comprising same - Google Patents

Abstract

The invention concerns 4-substituted quinoline derivatives active as antimicrobial agents, of general formula (I),wherein: X, X, X, Xand Xrespectively represent >C-R'to >C-R', Rrepresents (C-C)-alkyloxy group; R', R'and R'represent a hydrogen atom; R'represents phenyl or 5- or 6- membered heterocycle, which may optionally contain another heteroatom chosen from O, S or N; R'represents a hydrogen atom or halogen; m is 2, or 3 and n is 0, 1 or 2; Y represents a group CHR or CROH, wherein R represents a hydrogen atom; Z represents a CHgroup and, in this case, n is equal to 0 or 1, or alternatively Z represents an oxygen atom, in this case, n is equal to 2; Rrepresents a radical –COR, wherein R represents a hydrogen atom or (C-C)-alkyl; Rrepresents radical alk-R°, in which alk represents (C-C)-alkylene radical and R°represents phenoxy group, phenylthio group, phenylamino group, 5- or 6-membered heteroarylthio group comprising S or N as a heteroatom; R°represents -CR'=CR'-R', where R'represents phenyl, R'and R'represents hydrogen atoms or R°represents –C≡C-R, where Rrepresents phenyl, wherein said phenyl radicals are substituted by 2-3 halogen atoms; in their enantiomeric or diastereoisomeric forms or mixtures thereof, and, as well as their salts. The invention also relates to a method for preparing compounds of general formula (I) use thereof as medicaments for the treatment of bacterial infection as a pharmaceutical composition.

Description

The present invention relates to derivatives of 4-substituted quinolines of the general formula (I)

which are active as antimicrobial agents.

The invention also relates to a method and intermediates for their preparation and pharmaceutical compositions containing them.

The international patent applications SHO 99/37635 and SHO 00/43383 describe antimicrobial

K.1, in particular, is _(C1-C6) alkoxy;

K ₂ means a hydrogen atom;

K ₃ is in position 2 or 3 and means (C ₁ -C ₆ ) alkyl, which may optionally be substituted with 1-3 substituents selected from thiol, halogen, alkylthio group, trifluoromethyl, carboxy group, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxy optionally substituted with alkyl;

K ₄ means a —CH ₂ —K ₅ group in which K _{5 is} selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaroyl;

N is 0-2;

M is 1 or 2; and

A and B, in particular, mean oxygen, sulfur, sulfinyl, sulfonyl, ΝΚ ₁₁ , SK ₆ K ₇ , where K ₆ and K ₇ mean H, thiol, alkylthio group, halogen, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxy group, amino group; and

Ζ ₁ -Ζ ₅ mean N or SK _1A .

Other applications, in particular SHO 00/21952, SHO 00/21948, SHO 01/07432, SHO 01/07433, SHO 03/010138, and SHO 02/40474 or SHO 02/072572, describe other derivatives of 4-quinolylpropylpiperidines, substituted, in particular at position 3 or disubstituted at position 4, active in the same region. European Patent Application 30044 also describes related derivatives active in the cardiovascular region. To date, not a single derivative of this kind has been described whose piperidine ring is modified as in the derivatives of formula (I) above.

It has now been found, and this constitutes an object of the present invention, that the compounds of general formula (I) in which

X ₁ , X ₂ , X ₃ , X ₄ and X ₅ take values, respectively, from> С-К ' ₁ to>С-К'₅;

^K 1 is a (C ₁ -C ₁₀ ) alkyloxy group;

K ' ₁ , K' ₂ and K ' ₄ mean a hydrogen atom;

K ′ ₃ means phenyl or a 5- or 6-membered heterocycle, which optionally may contain another heteroatom selected from O, 8 or Ν;

K ′ ₅ represents a hydrogen or halogen atom;

t is 2;

η is 0, 1 or 2;

Υ means a group of SNK or SKON, and K means a hydrogen atom;

Ζ means a CH2 group, in which case η is 0 or 1, or Ζ is an oxygen atom, and in this case η is 2;

K ₂ is a —CO ₂ K radical, where K is a hydrogen atom or (C ₁ -C ₆ ) alkyl;

K ₃ means a1k-K ° ₃ radical, in which a1k means (C ₁ -C ₁₀ ) alkylene radical and K ° ₃ means a phenoxy group, phenylthio group, phenylamino group, a 5- or 6-membered heteroarylthio group containing 8 or качестве as a heteroatom; or K ° ₃ means -SK'b = SK ' _s -K' _a , where K ' _a means phenyl, K'b and K' _s

- 1 010403 mean hydrogen atoms; or Κ ° ₃ means -C ^ C-E ₃ . where Κι is phenyl, wherein said phenyl radicals are substituted with 2-3 halogen atoms;

in their enantiomeric or diastereoisomeric forms or in the form of mixtures of these forms and / or. if it is possible. in syn- or antiform or as a mixture thereof. and their salts are very potent antibacterial agents.

Of the compounds of general formula (I), the invention is an object. in particular. any of the compounds. having the following names:

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3-hydroxy (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine 3-carboxylic acid;

1- [2- (2.5-difluorophenylsulfanyl) ethyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3carboxylic acid;

1- [2- (2.5-difluorophenyloxy) ethyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1- [2- (thiophen-2-ylsulfanyl) ethyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] azetidine-3-carboxylic acid;

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3-hydroxy (3-fluoro-6-methoxyquinolin-4-yl) propyl] azetidine3-carboxylic acid;

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3- (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1 - [(E) -3- (2.5-difluorophenyl) allyl] -3- [3-hydroxy (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine3-carboxylic acid;

1- [2- (2.5-difluorophenylsulfanyl) ethyl] -3- [3- (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3carboxylic acid;

1- [2- (2.5-difluorophenyloxy) ethyl] -3- [3- (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1- [2- (thiophen-2-ylsulfanyl) ethyl] -3- [3- (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid;

1 - [(2E) -3- (2.5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] 3-pyrrolidinecarboxylic acid;

3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1 - [(2E) -3- (2.5-difluorophenyl) -2-propenyl] 3-pyrrolidinecarboxylic acid;

1- [3- (2.5-difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid;

1- [2 - [(2.5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid;

in its enantiomeric or diastereoisomeric forms or in the form of mixtures of these forms and / or. if it is possible. in syn- or antiform or as a mixture thereof. as well as its salts.

According to the invention, the products of general formula (I) can be obtained by condensation of a K ₃ chain with a 4-substituted quinoline derivative of general formula (II)

in which X ₁ . X ₂ . X ₃ . X4. X ₅ . Κ ₁ . Κ ₂ . Υ. Ζ. m and η have the above meanings. wherein K ₂ is protected. when it includes a carboxy group.

then. if necessary. removal of the protective group from the carboxy group. if necessary. the separation of enantiomeric or diastereoisomeric forms and / or. if necessary. syn - or antiforms and. if necessary. turning the resulting product into a salt.

The condensation reaction of the K ₃ chain with a heterocyclic nitrogen atom is carried out. predominantly. acting by a derivative of the general formula (On)

K3-X (Pa) in which K ₃ has the above meaning and X represents a halogen atom. methylsulfonyl. trifluoromethylsulfonyl or p-toluenesulfonyl. in anhydrous. preferably inert. environment. in an organic solvent. such as amide (e.g. dimethylformamide). ketone (e.g. acetone) or nitrile (e.g. acetonitrile). in the presence of a base. such as a nitrogen-containing organic base

- 2 010403 (for example, triethylamine) or an inorganic base (for example, alkali metal carbonate, such as potassium carbonate), at a temperature of from 20 ° C to the boiling point of the solvent under reflux. The nitrogen atom of the pyrrolidine ring of the derivative of general formula (II) is optionally protected according to a conventional method compatible with the rest of the molecule or reaction; protection is carried out, for example, with a protective radical selected from tert-butoxycarbonyl and benzyloxycarbonyl, and this nitrogen atom is released before the condensation reaction with a derivative of the formula (11a), in particular, acid hydrolysis. Preferably, a derivative of the general formula (11a) is used, wherein X is a chlorine, bromine or iodine atom.

The conditions under which a condensation reaction between the derivatives of the general formulas (II) and (11a) can be carried out is also described in the international application \ ¥ O 02/40474.

When B ₃ means the radical -a1k-K ° ₃ , in which K ° ₃ represents the group -ί.Ά .'- Ρ, ι. in which Κ, ι has the above meaning, the alkynyl halide of the formula HC ^ C-a1k-X is intermediate condensed, then the corresponding radical Щ is condensed with the alkine thus obtained.

When B ₃ means a1k-K ° ₃ radical, in which a1k means alkyl and K ° ₃ means a phenoxy group, phenylthio group, phenylamino group, heteroaryloxy group, heteroarylthio group or heteroarylamino group, the chain can also be constructed by first condensing the chain HO-a1k-X, in which X means a halogen atom, preferably iodine, under the conditions described above for the reaction of a product of general formula (Pa), then, if necessary, converting the hydroxyalkyl chain to a haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl chain and, ec, acting under alkaline conditions an aromatic derivative of structure ° K ₃ ° K or H ₃ H _2.

The conversion of the hydroxylated chain to a haloalkyl or p-toluenesulfonyl chain is carried out by conventional methods of halogenation or sulfonylation, in particular by the action of a halogenating agent, such as thionyl chloride, halogen-containing phosphorus derivatives (for example, trichloride or phosphorus tribromide) or a sulfonylating agent, such as, for example, methanesulfonyl toluenesulfonyl chloride or trifluoromethanesulfonic anhydride. The reaction is carried out in an organic solvent, such as a chlorine-containing solvent (for example, dichloromethane or chloroform), at a temperature of 0-60 ° C. In some cases, it may be preferable to work in the presence of a base such as pyridine or triethylamine.

The reaction of the aromatic derivative B ₃ H or B ₃ H _{2 is} advantageously carried out as described above for exposure to a derivative of the general formula (Pa) in an organic solvent such as an amide (e.g. dimethylformamide), ketone (e.g. acetone), nitrile (e.g. acetonitrile), in the presence of a base, such as an organic nitrogen-containing base (e.g. triethylamine) or an inorganic base (e.g. an alkali metal carbonate, such as potassium carbonate), at a temperature of from 20 ° C to the boiling temperature of the reaction medium with the opposite m condenser. It may be preferable to work in the presence of potassium iodide.

You can still work in ether (such as tetrahydrofuran) under dehydration conditions in the presence of, for example, diisopropylcarbodiimide and triphenylphosphine.

Of course, if the B ₃ radicals include a carboxy group or an amino group as substituents, then the latter are pre-protected, then released after the reaction. They work in accordance with methods well known to those skilled in the art, in particular according to the methods described by Τ.ν. Szhepe and R.S.M. \ νιιΐ5 Pt0e1111e Sgirz ίη Ogdashs 8n1ez1z (2nd edition), A. ^ eu -! n1gzs1epse RiPsiop (1991), or Ms Osh1e Rt1esPuye Sgirz Рη Ogdashs Szes1z3ztu.

The protected carboxyl radical, which is included in _B2 , can be selected from readily hydrolyzable esters. Examples include methyl, benzyl, tert-butyl esters or phenylpropyl or allyl esters. If necessary, the protection of the carboxyl radical is carried out simultaneously with the reaction.

If necessary, the protection of the amino group is carried out using conventional protective radicals indicated in the above links.

The introduction and removal of these protective radicals is carried out in accordance with methods known to those skilled in the art.

According to the invention, derivatives of the general formula (I) in which _B2 is hydroxymethyl or hydroxyethyl can be prepared by the action of a corresponding reducing agent on a derivative in which _B2 means a carboxy group or carboxymethyl or a protected carboxy group or protected carboxymethyl. Perhaps the existing keto group should then be intermediate protected. Also according to the invention, products of the general formula (I) in which B ₂ is carboxymethyl or carboxyethyl can also be obtained from derivatives in which B ₂ is hydroxymethyl or hydroxyethyl, by acting on it with a halogenating or tosylating agent, then a cyanating agent, and finally hydrolysis of nitrile.

The reduction of the protected carboxy group can be carried out by conventional methods which do not affect the rest of the molecule, in particular by the action of a hydride (e.g. lithium aluminum hydride or diisobutyl aluminum hydride) in a solvent such as an ether (e.g. tet

- 3 010403 ragidrofuran), at a temperature of 20-60 ° C. Perhaps the keto group present is intermediate protected, then the protection is removed according to classical methods known to those skilled in the art, in particular via cyclic or non-cyclic acetal.

The reduction of the free carboxy group can also be carried out by methods well known to the person skilled in the art, for example, hydrogenation in the presence of a rhodium or ruthenium catalyst, exposure to sodium borohydride in the presence of a Lewis acid or lithium aluminum hydride in ether. Preferably, in this case, the keto group is also intermediate protected.

The conversion of the hydroxymethyl or hydroxyethyl radical to a carboxymethyl or carboxyethyl radical is carried out by conventional methods that do not affect the rest of the molecule, in particular by the action of a halogenating agent, such as, for example, thionyl chloride, or trichloride, or phosphorus tribromide, or tosylating agent, then alkali metal cyanide, for example, potassium cyanide or sodium cyanide, to obtain the corresponding cyanomethyl derivative, followed by hydrolysis of nitrile.

Halogenation can be carried out in a chlorine-containing solvent (such as, for example, dichloromethane or chloroform), at a temperature from 0 ° C to the boiling point of the solvent under reflux.

According to the invention, products of the general formula (II) in which Υ is a CHK group are obtained by the condensation reaction of a heteroaromatic derivative of the general formula (III)

On1

in which Κι, Χι, X ₂ , X3, X ₄ and X ₅ have the above meanings and H1 is a halogen atom with a derivative of the general formula (IV)

in which P means a protective group and Κ, Ζ, t, η and K ₂ have the above meanings or K ₂ means a protected radical, if K ₂ means or includes a carboxyl group, followed by removal of the protective groups and / or subsequent conversion, by subsequent operations, substituents of the thus obtained aromatic bicycles of general formula (II) to obtain a derivative containing the expected radical Κι, Κ'ι, Κ ' ₂ , K' ₃ , Κ ' ₄ , Κ' ₅ , and, if necessary, followed by removal of the protective radical or protective radicals still available in the molecule.

P may be any protecting group for a nitrogen atom compatible with the reaction (for example, tert-butyloxycarbonyl, benzyloxycarbonyl). Protecting groups for carboxyl groups are selected from conventional groups, the introduction and removal of which do not affect the rest of the molecule, in particular those mentioned in the above links.

The reaction can also be carried out by sequentially acting on a derivative of the general formula (II) with organoborane (such as, for example, 9-borabicyclo [3.3.1] nonane) in a solvent such as ether (e.g. tetrahydrofuran, dioxane), at a temperature of -20 to 20 ° C, then a bicyclic derivative of the general formula (III), in which H1 is a chlorine atom or preferably a bromine or iodine atom, by analogy with the methods described 8i / ir1 e! A1., Riga apb Arr1. SN., 57, 1749 (1985). The reaction is usually carried out in the presence of a palladium salt (for example, diphenylphosphinoferrocene palladium) and a base, such as potassium phosphate, at a temperature of from 20 ° C. to the boiling point of the solvent under reflux.

According to the invention, products of the general formula (II) in which Υ is an SCOH group can be obtained by oxidation in an alkaline medium of the corresponding derivative, in which Υ is an SNK group. The oxidation is carried out with oxygen, preferably in an inert solvent, such as dimethyl sulfoxide, in the presence of tert-butanol and a base such as potassium or sodium tert-butylate, at a temperature of 0-100 ° C.

Derivatives of the general formula (II) in which Υ means a CKP or CP ₂ group can be obtained by fluorination, respectively, starting from a derivative in which Υ means a CKHN group and a derivative in which Υ means carbonyl. The reaction is carried out in the presence of sulfur fluoride (e.g.

- 4,010,403 measures, in the presence of sulfur aminotrifluoride (such as sulfur diethylaminotrifluoride (Gc1ga11ss1gop. 44, 2875 (1988)), sulfur bis (2-methoxyethyl) aminotrifluoride (Oeohoyiog®), sulfur morpholinotrifluoride) or, alternatively, in the presence of tetrafluoride sulfur (1. Ogd. Syet., 40, 3808 (1975)). The fluorination reaction can also be carried out using a fluorinating agent such as hexafluoropropyl diethylamine (Japanese Patent 2039546) or No. (chloro-2-trifluoro-1,1,2-ethyl) diethylamine.

They work in an organic solvent such as a chlorine-containing solvent (e.g. dichloromethane, dichloroethane, chloroform) or in ether (e.g. tetrahydrofuran, dioxane) at a temperature of from -78 to 40 ° C (preferably from 0 to 30 ° C). Preferably, they are operated in an inert environment (in particular in an atmosphere of argon or nitrogen).

Derivatives of the general formula (II) in which Υ means a carbonyl group can be obtained by oxidation of the corresponding derivative of the general formula (II) in which Υ means a group CHOH. This oxidation is carried out, for example, using potassium permanganate, if necessary, in a sodium hydroxide solution (for example, a 3N sodium hydroxide solution) at a temperature of from -20 to 20 ° C, or by acting with 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 of from -60 to 20 ° C, by analogy with the method described Ώ. to \\ ehp e! A1., I. Ogd. Siet., 44, 4148 (1979).

These derivatives can also be obtained by the condensation reaction of a lithium-containing derivative at position 4 of a heteroaromatic derivative of the general formula (III ')

in which K. ₁ , Χι, X ₂ , X ₃ , X ₄ and X ₅ have the above meanings, with a derivative of the general formula (IV ')

in which P, K ₂ , t and η have the meaning indicated in the case of formula (IV) and a1c means alkyl with 1-4 carbon atoms, preferably methyl, followed by removal of the protective groups and / or followed by conversion, by subsequent operation, of substituents thus obtained aromatic bicycles of General formula (II) to obtain a derivative containing the expected radical Κι, Κ'ι, Κ ' ₂ , Κ' ₃ , Κ ' ₄ , Κ' ₅ , and, if necessary, with the subsequent removal of the protective radical / protective radicals still present in the molecule.

The lithium derivative at position 4 of the derivative of formula (III ′) is prepared using a strong lithium-containing base, such as butyllithium, sec-butyl lithium, or preferably lithium diisopropylamide, in a solvent such as ether, for example tetrahydrofuran, at a temperature of from -78 to -40 ° FROM. The condensation reaction of this lithium-containing derivative with an ester of the formula (IV ') is carried out in the same solvent at a temperature of from -78 to 0 ° C.

A derivative of formula (III ') can be obtained by the method described in international patent application \ XO 02/40474.

A derivative of the general formula (II) in which Υ means a group of SKIN ₂ can be obtained from the corresponding CHOH derivative, which is converted into its tosylated derivative, which is affected by ammonia. Work in an inert solvent such as Ν, Ν-dimethylformamide or dimethyl sulfoxide, and preferably under pressure (2-20 atm), at a temperature of from 20 to 100 ° C.

The tosyloxy derivative is obtained from a product of general formula (II), in which Υ stands for SCOH, acting with tosyl chloride in pyridine, at a temperature of from -10 to 20 ° C.

In international patent application \\ 'O 02/40474 describes methods for preparing compounds with different values Κι, X _s X _2, X _3, X ₄ and X ₅ in the derivatives of general formulas (II) and (III) and a derivative of general HA1 formulas (III).

Derivatives of the general formula (IV) can be obtained by a condensation reaction of a derivative of the general formula (V)

- 5 010403 in which η and P have the above meaning and K ₂ has the meaning indicated in the case of the general formula (IV) or (IV '), with the product of the general formula (VI)

Na1- (CH ₂ ) _W _1-CH = SNK (VI) in which Na1 is a halogen atom, preferably bromine, and m and K have the above meaning. They work preferably in the presence of a strong base, in particular an alkali metal amide, for example lithium bis (trimethylsilyl) amide, or an organolithium compound, for example butyl lithium, in an organic solvent, which can be, in particular, an ether such as tetrahydrofuran or dioxane.

In the case where m = 1, a derivative of the general formula (V), such as the above, with a dibromoethane type product of the general formula (VI ') is preferably introduced into the condensation reaction

VgCH ₂ -CNCbg (VI ') in which K has the above meaning, then hydrogen bromide is removed from the resulting product in a manner known to the skilled person. You can, for example, refer to the method described by K.A. Whips e! A1., Ogdashs Rgeragayopz Rgoseyige Shegpaiopak, 31 (1), 99-106 (1999).

Other methods for obtaining derivatives of the general formula (IV) are described in international application ^ O 02/40474. They work based on the corresponding nitrogen-containing heterocyclic derivative.

Examples are given below in the experimental part. The intermediate derivatives of the general formulas (II) and (IV) obtained during the implementation of the method according to the invention are new and on this basis form part of the invention.

Derivatives of formula (V) are generally known (for example, European patent 405506 or international application ^ O 00/37458 can be mentioned by reference), and some are commercially available. Their preparation is presented below in the experimental part.

It is understood that derivatives of the general formulas (I) and (II) can exist in enantiomeric or diastereoisomeric forms or in a syn- or antiform, which are obviously intended to be within the scope of the present invention. These forms can be separated by conventional methods known to the skilled person, in particular by chiral chromatography or high performance liquid chromatography (HPLC).

Derivatives of the general formula (I) can be purified, if necessary, by physical methods, such as crystallization or chromatography.

Derivatives of the general formula (I), if necessary, can be converted into addition salts of acids or bases using known methods. Keep in mind that these additive salts of acids or bases are also included in the scope of the present invention.

Examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids (e.g. hydrochlorides, hydrobromides, sulfates, nitrates or phosphates) or with organic acids (e.g. succinates, fumarates, tartrates, acetates, propionates, maleates, citrates , methanesulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates, isethionates, naphthyl sulfonates or camphorsulfonates), or with substituted derivatives of these acids.

Derivatives of the general formula (I) containing a carboxy group can be converted into metal salts or addition salts of nitrogen-containing bases according to known methods. Salts can be prepared by the action of a metal (for example, an alkali or alkaline earth metal), ammonia or amine as a base on the product of the invention in an appropriate solvent such as alcohol, ether or water, or by reaction with an organic acid salt. The resulting salt precipitates after optional concentration of the solution, it is separated by filtration, decantation or lyophilization. Examples of pharmaceutically acceptable salts include, in particular, salts with alkali metals (sodium, potassium, lithium) or alkaline-earth metals (magnesium, calcium), ammonium salt, salts of nitrogen-containing bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, Ν, Ν-dimethylethanolamine, benzylamine, dicyclohexylamine, Ν-benzyl-b-phenethylamine, Ν, Ν'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, lysine.

Derivatives of the general formula (I) according to the invention are particularly active antibacterial agents.

The following is a study of their activity.

a) Activity ίη νίΐΓΟ.

To determine the minimum inhibitory concentrations (S.M.P.) expressed in μg / ml, the dilution method in agar medium was used in accordance with the recommendations of NCC ^ 8.

The activity of the compounds according to examples 1-4 are presented in the table below.

- 6 010403

Gram-positive bacterium, CM1 in mcg / ml, 24 hours 5. igeeiz ΙΡ8203, sensitive <0.015-4 3. aigeis AZ 5155 resistant to me ticillin <0.015-4 3. rpeishoptae 6254-01, resistant to MBS _B <0.015-4 E. Gaesa From ATCC 29212 resistant to vancomycin 0.25-32 Gram-negative bacterium, SIT μg / ml, 48 hours I. SabaggNaiz ΙΡΑ 151, sensitive <0.12-2 N. tpETiepge 87169, sensitive 1-> 64

The Ιη νΐίΓΟ compounds according to the invention are therefore highly active against both gram-positive bacteria and gram-negative bacteria.

b) Activity ΐη νίνο.

Some derivatives have been found to be active against experimental infections of 81 aryuosossiidae ΙΡ 8203 in mice in doses ranging from 5 to 50 mg / kg when administered subcutaneously or orally.

c) The products of the invention are of particular interest due to their low toxicity. None of the products showed toxicity at a dose of 50 mg / kg when administered to mice subcutaneously or orally (2 doses per day).

These properties make the above products and their salts of pharmaceutically acceptable acids and bases suitable for use as medicines in the treatment of treatment-sensitive microbial diseases provoked by gram-positive bacteria, and in particular in the treatment of staphylococcal infections, such as staphylococcal sepsis, malignant staphylococcal infections face or skin, pyoderma, septic or purulent wounds, carbuncles, phlegmon, erysipelas, acute ordinary or post-influenza staphylococcal diseases, bronchopneumonia, pulmonary suppuration, as well as in the treatment of streptococcal or enterococcal lesions.

These products can also be used as medicines in the treatment of respiratory infections of the upper and lower respiratory tract caused by gram-negative bacteria, such as Naeshora L1 from shpien / ae and Mogache11a salagia11z.

Therefore, the object of the present invention as medicines and especially medicines intended for the treatment of bacterial infections in humans or animals, are compounds of General formula (Ι), such as the above, as well as their pharmaceutically acceptable salts, and in particular preferred compounds, indicated above.

The present invention also relates to pharmaceutical compositions comprising at least one 4-substituted quinoline derivative according to the invention, if necessary, in salt form, in pure form or in association with one or more compatible and pharmaceutically acceptable diluents or additives.

Compositions according to the invention can be used orally, parenterally, locally, rectally or in the form of aerosols.

As solid compositions for oral administration, tablets, pills, gelatine capsules, powders and granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents or additives such as sucrose, lactose or starch. These compositions may include substances other than diluents, for example, a lubricant, such as magnesium stearate, or a protective coating intended for controlled release.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions may also include substances other than diluents, for example wetting, sweetening or flavoring agents.

Compositions for parenteral administration may be sterile solutions or emulsions. As a solvent or excipient, you can use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic esters for injection, for example ethyl oleate. These compositions may also contain additives, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.

Sterilization can be carried out in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be obtained in the form of solid sterile compositions that can be dissolved at the time of use in sterile water

- 7 010403 or any other sterile medium for injection.

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 principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions which are soluble at the time of use in sterile pyrogen-free water, in serum or any other pharmaceutically acceptable excipient. For use in the form of dry aerosols intended directly for inhalation, the active principle is finely ground and combined with a water-soluble diluent or solid excipient with a particle size distribution of 30-80 microns, such as, for example, dextran, mannitol or lactose.

In human therapy, the novel 4-substituted quinoline derivatives of the invention are particularly suitable for the treatment of infections of bacterial origin. Doses depend on the desired effect and duration of treatment. The doctor determines the dosage that he considers the most appropriate for the treatment, depending on the age, weight, severity of the infection and other factors that characterize the subject being treated. Typically, doses are from 750 mg to 3 g of the active product in 2 or 3 doses per day, orally or from 400 mg to 1.2 g intravenously for an adult.

The following examples illustrate the compositions according to the invention.

a) In the usual way receive a liquid composition intended for parenteral use, which includes (K5) -1 - [(E) -3- (2,5-Difluorophenyl) allyl] -3- [3 - (3-fluoro-6 -methoxyquinolin-4-yl) propyl] pyrrolidin-3-carboxylic acid 1 g

Glucose (sufficient amount) up to 2.5%

Sodium hydroxide (sufficient amount) to pH 4-4.5

Pure water for injection (sufficient amount) up to 20 ml

B) In the usual way receive a liquid composition intended for use parenterally, which includes

2- [3- (3-Fluoro-6-methoxyquinolin-4-yl) propyl] -4- [2- (2,5-difluorophenylsulfanyl) ethyl] morpholine-2-carboxylic acid Glucose

Sodium hydroxide

Clean water for injection

500 mg (sufficient amount) to 5% (sufficient amount) to pH 4-4.5 (sufficient amount) to 50 ml

The following examples illustrate the invention.

Example 1. (. + -.) - 1 - [(2E) -3- (2,5-Difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] 3-pyrrolidinecarboxylic acid.

To 1.25 g (2.336 mmol) methyl - (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro- 6methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate in the form of a solution in 25 cm ^{3 of} dioxane at a temperature of about 20 ° C. add 14.2 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 16 hours at the boil under reflux, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue which is treated with 40 cm ^{3 of} acetonitrile. After stirring for 0.5 h at a temperature of about 0 ° C, the suspended orange solid is filtered off, washed 2 times with 7 cm ^{3 of} acetonitrile, then dissolved in 55 cm ^{3 of} water. The aqueous phase is then acidified with 1N. hydrochloric acid to a pH close to 6-7, then extracted 2 times with 20 cm ^{3 of} dichloromethane. The organic phases are combined, washed 2 times with 10 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.55 g (. + -.) - 1 - [(2E ) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid as a yellow solid, melting at a temperature of 77 ° C.

^! H-NMR spectrum (300 MHz, (SP ₃ ) ₂ 8O-b ₆ , δ in ppm), 1.59 (m, 4H); 1.81 (m, 2H); 2.25 (m, 1H); 2.38 (brd, 1 = 9 Hz, 1H); 2.57 (m, 1H); 2.96 (br.s.d, 1 = 9 Hz, 1H); 3.07 (br t, 1 = 7.5 Hz, 2H); 3.21 (br.s.d, 1 = 6 Hz, 2H); 3.94 (s, 3H); 6.47 (d, 1 = 16 and 6 Hz, 1H); 6.61 (brd, 1 = 16 Hz, 1H); 7.12 (m, 1H); 7.24 (decoupled t, 1 = 9.5 and 4.5 Hz, 1H); 7.35 (d, 1 = 3 Hz, 1H); 7.39 (dd, 1 = 9 and 3 Hz, 1H); 7.50 (m, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

Mass spectrum (1C) (chemical ionization): w / x = 485 (MH ⁺ ).

Example 2. Methyl - (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4- quinolinyl) propyl] -3-pyrrolidine carboxylate.

To 2.171 g (5.67 mmol) of methyl - (. + -.) Dihydrochloride - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylate in the form of a solution in 150 cm ^{3 of} acetonitrile at at a temperature of about 20 ° C and in an argon atmosphere add 3.92 g of potassium carbonate, 1.03 g of potassium iodide, then a freshly prepared solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (7 , 34 mmol) in dichloromethane. After stirring

- 8 010403 for 20 hours at the boil under reflux, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), obtaining a residue which is treated with 200 cm ^{3 of} dichloromethane, washed 3 times with 100 cm ^{3 of} water, then with 75 cm ³ aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 2.6 g of an orange oil, which was purified by flash chromatography [eluent: cyclohexane / ethyl acetate (1: 1 by volume)] . After concentration of the fractions under reduced pressure, 1.45 g of methyl - (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3- fluoro6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate as a yellow oil.

Ή-NMR spectrum (300 MHz, (ΟΌ ₃ ) ₂ 8Θ-ά ₆ , δ in ppm): 1.40-1.70 (m, 3H); 1.81 (m, 2H); 2.26 (m, 1H); 2.36 (d, 1 = 9.5 Hz, 1H); 2.40-2.65 (m, 2H); 2.95 (d, 1 = 9.5 Hz, 1H); 3.06 (br t, 1 = 7.5 Hz, 2H); 3.18 (d, 1 = 6 Hz, 2H); 3.53 (s, 3H); 3.95 (s, 3H); 6.45 (d, 1 = 16.5 and 6 Hz, 1H); 6.60 (brd, 1 = 16.5 Hz, 1H); 7.12 (m, 1H); 7.23 (unbound t, 1 = 9.5 and 4.5 Hz, 1H); 7.34 (d, 1 = 3 Hz, 1H); 7.39 (dd, 1 = 9 and 3 Hz, 1H); 7.49 (ddd, 1 = 9.5-6 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

Mass spectrum (1E) (electron impact): w / x = 498 (M ⁺ ); 439 (M-CO ² CH 3+); 153 (C9H ₇ E ₂ ⁺ ).

A solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (7.34 mmol) in dichloromethane can be prepared as follows.

To 1.25 g (7.34 mmol) of 2,5-difluorocinnamic alcohol in the form of a solution in 130 cm ^{3 of} dichloromethane at a temperature of about 20 ° C and in an argon atmosphere, a solution of 0.66 cm ³ (9.07 mmol) of thionyl chloride and 1.08 g (9.07 mmol) of benztriazole in 70 cm of dichloromethane. After stirring for 10 min, the reaction mixture was filtered through a No. 3 porous glass filter and the solid residue was washed 2 times with 20 cm ^{3 of} dichloromethane. The filtrate is washed 3 times with 75 cm ^{3 of} water. The organic phase is dried over anhydrous magnesium sulfate and filtered, obtaining a solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (7.34 mmol), which is immediately used in the next step.

Methyl dihydrochloride - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate can be prepared as follows.

K 2.9 g (6.495 mmol) of 1- (1,1-dimethylethyl) - and (3-methyl) - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl ) propyl] -1,3-pyrrolidinedicarboxylate in the form of a solution in 20 cm ^{3 of} methanol at a temperature of about 20 ° C add 8.117 cm ³ 4N. a solution of hydrogen chloride in dioxane. After stirring for 4 hours at a temperature of about 20 ° C, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 2.38 g of methyl dihydrochloride - (. + -.) - 3- [3- (3-fluoro) -6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate as a yellow solid.

Mass spectrum (1E): w //. 346 (M ⁺ ); 315 (M-OCH ₃ ^+); 304 (M-C-ND); 204 (C-POCHT ').

1- (1,1-Dimethylethyl) - and (3-methyl) - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1,3-pyrrolidinedicarboxylate can be obtained as follows.

To 24.84 cm ³ (12.42 mmol) of a solution of 9-ΒΒΝ (9-borabicyclo [3.3.1] nonane), 0.5 M tetrahydrofuran at a temperature of about 0 ° C in an argon atmosphere, a solution of 2.23 g ( 8.279 mmol) of 1- (1,1-dimethylethyl) - and (3-methyl) - (. + -.) - 3- (2-propenyl) -1,3-pyrrolidinedicarboxylate in 30 cm ^{3 of} tetrahydrofuran. After heating the reaction mixture to a temperature of about 20 ° C, then stirring for 3 hours at a temperature of about 20 ° C, 2.509 g (8.279 mmol) of 3-fluoro-4-iodo-6-methoxyquinoline are added successively as a suspension in 70 cm ^{3 of} tetrahydrofuran then 5.27 g (24.84 mmol) of potassium phosphate and 0.182 g (0.248 mmol) of P6C1 ₂ 6pp pp (1,1'-bis (diphenylphosphino) ferrocenyl palladium dichloride). After stirring for 16 hours at reflux temperature, the reaction mixture was cooled, then filtered through celite. Celite is washed 3 times with 25 cm ^{3 of} tetrahydrofuran. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated with 100 cm ^{3 of} dichloromethane, washed 3 times with 40 cm ^{3 of} water, then with 50 cm ^{3 of an} aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 5.7 g of an orange oil, which was purified by flash chromatography [eluent: cyclohexane / ethyl acetate (7: 3 by volume)] . After concentration of the fractions under reduced pressure, 2.9 g of 1- (1,1-dimethylethyl) - and (3-methyl) - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) are obtained ) propyl] -1,3-pyrrolidinedicarboxylate as a yellow oil.

Mass spectrum (1E): 111 // 446 (\ G); 390 (M-C ₄ H ₈ ⁺ ); 345 (390-CO ² H ⁺ ); 204 (C12H _P OHR ⁺ ).

3-Fluoro-4-iodo-6-methoxyquinoline can be obtained by the method described in international patent application \ UO 02/40474.

1- (1,1-Dimethylethyl) - and (3-methyl) - (. + -.) - 3- (2-propenyl) -1,3-pyrrolidinedicarboxylate can be prepared as follows.

To 2.55 g (11.12 mmol) of 1- (1,1-dimethylethyl) - and (3-methyl) -1,3-pyrrolidinedicarboxylate in the form of a solution in 30 cm ^{3 of} tetrahydrofuran at a temperature of about -78 ° C and in an argon atmosphere, 12.23 cm ³ (12.23 mmol) of lithium bis (trimethylsilyl) amide are added dropwise in the form of a 1M solution in tetrahydrofuran. After stirring for 0.25 hours at a temperature of about -78 ° C, 1.486 cm ³ (16.68 mmol) of allyl bromide is added, then it is kept for 1.5 hours to raise the temperature from -78 ° C to a temperature of about 20 ° C. The reaction medium is then hydrolyzed with 10 cm ³ 1N. hydrochloric acid, then concentrated to three quarters under reduced pressure (2.7 kPa). The concentrate is treated with 50 cm ³ ethyl

- 9 010403 acetate. The organic phase is decanted, washed successively with 15 cm ³ 1N. hydrochloric acid, 20 cm ^{3 of} water and 2 times 20 cm ^{3 of an} aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 2.5 g of a yellow oil, which is purified by flash chromatography [eluent: cyclohexane / ethyl acetate (7: 3 by volume)]. After concentration of the fractions under reduced pressure, 2.23 g of 1- (1,1-dimethylethyl) - and (3-methyl) - (. + -.) - 3- (2-propenyl) -1,3-pyrrolidinedicarboxylate are obtained as a colorless oil .

Mass spectrum (1C): ιιι / ζ.287 (ΜΝΗ ₄ ⁺ ), 270 (MH ⁺ ), 231 (ΜΝΗ4 ⁺ -Ο4Η ₈ ).

1- (1,1-Dimethylethyl) - and (3-methyl) -1,3-pyrrolidinedicarboxylate can be prepared as follows.

To 2.5 g (19.36 mmol) of methyl 3-pyrrolidine carboxylate in the form of a solution in 50 cm ^{3 of} dichloromethane at a temperature of about 20 ° C and under argon atmosphere, 3 cm ^{3 of} triethylamine are successively added, followed by 4.649 g of di-tert-butyl dicarbonate as a solution in 30 cm ^{3 of} dichloromethane. After stirring for 20 hours at a temperature of about 20 ° C, the reaction mixture is washed sequentially 3 times with 50 cm ^{3 of} water and 50 cm ^{3 of an} aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.08 g of a colorless oil, which was purified by flash chromatography [eluent: cyclohexane / ethyl acetate (6: 4 by volume)] . After concentration of the fractions under reduced pressure, 2.55 g of 1- (1,1-dimethylethyl) - and (3-methyl) -1,3-pyrrolidinedicarboxylate are obtained as a colorless oil.

Mass spectrum (1C): vιι / ζ. 247 (ΜΝΗ ₄ ⁺ ), 230 (MH ⁺ ), 191 (ΜΝΗ4ΑζΗ8), 174 (MH ⁺ -C4H ₈ ).

Methyl - (. + -.) - 3-pyrrolidinecarboxylate can be prepared as follows.

To 5 g (22.8 mmol) of methyl - (. + -.) - 1- (phenylmethyl) -3-pyrrolidinecarboxylate in the form of a solution in 100 cm ^{3 of} methanol at a temperature of about 20 ° C, 0.704 g of 10 are added successively in an argon atmosphere % palladium-on-charcoal (Pb / C), then 11.5 g of ammonium formate. After stirring for 3 hours at reflux temperature, the reaction mixture was filtered through celite. Celite is washed 3 times with 20 cm ^{3 of} methanol. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 2.5 g of methyl - (. + -.) - 3-pyrrolidine carboxylate as a colorless oil.

Mass spectrum (1C): t / x = 130 (ΜΗ ⁺ ).

Methyl - (. + -.) - 1- (phenylmethyl) 3-pyrrolidinecarboxylate can be prepared as follows.

To 9.496 g (110.3 mmol) of methyl acrylate and 32.37 g (115.8 mmol) of butoximethyl-no-trimethylsilylmethylbenzylamine (Akita dipole) in the form of a solution in 350 cm ^{3 of} dichloromethane at a temperature of about 20 ° C and dropwise in an argon atmosphere 0.213 cm ³ (2.788 mmol) of trifluoroacetic acid are added. The reaction is very exothermic; after stirring for 4 hours at a temperature of about 20 ° C., 15 g of potassium carbonate are added. After stirring for 15 minutes at a temperature of about 20 ° C, the reaction mixture is washed successively with 3 times 150 cm ^{3 of} water and 150 cm ^{3 of an} aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 26 g of a yellow oil, which was purified by flash chromatography [eluent: cyclohexane / ethyl acetate (gradient from 7: 3 to 6: 4 by volume)]. After concentration of the fractions under reduced pressure, 24.5 g of methyl - (. + -.) - 1- (phenylmethyl) 3-pyrrolidinecarboxylate are obtained in the form of a yellow oil.

Mass spectrum (ΙΕ): ιιι / ζ.219 (Μ ³ ), 188 (X1-S1Sh '). 142 (Μ-Ο ^ ⁴ ), 128 (Μ-ΟΙ '!.

No. Butoxymethyl-No.trimethylsilylmethylbenzylamine (dipole Λκ1ιί \ νη) can be obtained by the method described by Tegao Υ., Ko1ak1 Η., 1ta1 Ν., Leita K., Szet. Ryagt. Vi. 11, 33, 896 (1985).

Example 3. Enantiomer A 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3 - pyrrolidine carboxylic acid.

To 0.0693 g (0.139 mmol) of enantiomer A (levorotatory) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate in the form of a solution in 3 cm ^{3 of} dioxane at a temperature of about 20 ° C. add 1.17 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 48 hours at the boil under reflux, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue, which was treated with 5 cm ^{3 of} water and 5 cm ^{3 of} dichloromethane. The aqueous phase is acidified with 5n. hydrochloric acid, then 1n. hydrochloric acid to a pH of about 7. The organic phase is decanted, then the aqueous phase is concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.067 g of a residue, which is purified by flash chromatography [eluent: dichloromethane / methanol / acetonitrile (60:20: 20 by volume)]. After concentration of the fractions under reduced pressure, 0.059 g of a beige solid is obtained, which is treated with 5 cm ^{3 of} water and 5 cm ^{3 of} dichloromethane. The pH of the aqueous phase is adjusted to 7 with 0.01N. an aqueous solution of sodium hydroxide. The aqueous phase is extracted 2 times with 5 cm ^{3 of} dichloromethane. The organic phases are combined, washed with 5 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.04 g of enantiomer A 1 - [(2E) -3- (2,5difluorophenyl ) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a beige solid, melting at a temperature of 76- 80 ° C.

[a] _c ²⁰ = + 7.3 ° ± 0.4 ° [dichloromethane (c = 0.5), 589 nm].

- 10 010403

Ή-NMR spectrum (300 MHz, ((Ό _; )); 8Ο- ±. Δ in ppm): 1.66 (m, 4H); 1.79 (m, 2H); 2.24 (m , 1H); 2.35 (d, 1 = 9 Hz, 1H); 2.40-2.60 (m, 1H); 2.94 (d, 1 = 9 Hz, 1H); 3.06 (br .t, 1 = 7 Hz, 2H), 3.19 (d, 1 = 6 Hz, 2H); 3.95 (s, 3H); 6.48 (d, 1 = 16 and 6 Hz, 1H); 6.61 (brd, 1 = 16 Hz, 1H); 7.14 (m, 1H); 7.25 (unbound t, 1 = 9.5 and 5 Hz, 1H); 7.307.45 (m, 2H); 7.51 (ddd, 1 = 9.5-6 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.69 (s, 1H).

Mass spectrum (1E): 111 // 484 (M '); 439 (M-CO ₂ H ⁺ ); 153 (sevd).

Enantiomer A (levorotatory) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylate can be obtained as described further in examples 5 and 6.

Example 4. Enantiomer B 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

To 0.0675 g (0.135 mmol) of enantiomer B (dextrorotatory) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate in the form of a solution in 3 cm ^{3 of} dioxane at a temperature of about 20 ° C. add 1.137 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 48 hours at the boil under reflux, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue, which was treated with 2 cm ^{3 of} water and 5 cm ^{3 of} dichloromethane. The aqueous phase is acidified with 1N. hydrochloric acid, then 0.1 n. hydrochloric acid to a pH of about 7. The aqueous phase is extracted 2 times with 5 cm ^{3 of} dichloromethane. The organic phases are combined, washed with 5 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.035 g of enantiomer B 1 - [(2E) -3- (2,5-difluorophenyl ) -

2- propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a beige solid, melting at a temperature of 80-84 ° FROM.

| α | ι / ° = -7.7 ° ± 0.4 ° [dichloromethane (c = 0.5), 589 nm].

Ή-NMR spectrum (300 MHz, (CO ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.58 (m, 4H); 1.80 (m, 2H); 2.25 (m, 1H); 2.36 (br.s.d, 1 = 9 Hz, 1H); 2.45-2.65 (m, 1H); 2.93 (br.s; d; 1 = 9 Hz, 1H); 3.07 (br t, 1 = 7 Hz, 2H); 3.18 (d, 1 = 6 Hz, 2H); 3.94 (s, 3H); 6.47 (d, 1 = 16 and 6 Hz, 1H); 6.61 (brd, 1 = 16 Hz, 1H); 7.12 (m, 1H); 7.24 (decoupled t, 1 = 9.5 and 4.5 Hz, 1H); 7.35 (m, 1H); 7.38 (dd, 1 = 9 and 3 Hz, 1H); 7.50 (ddd, 1 = 9.5-6 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.69 (br s, 1H).

Mass spectrum (ΙΕ): 111 // 484 (M '); 439 (M-CO ₂ H ⁺ ); 153 (C ₉ H ₇ E ₂ ⁺ ).

Enantiomer B (dextrorotatory) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylate can be prepared as described below.

Examples 5 and 6. Enantiomers A (levorotatory) and B (dextrorotatory) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3 - (3-fluoro-6 -methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate (absolute configuration not determined).

Methyl - (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl ] -

3- pyrrolidinecarboxylate (0.155 g) is introduced into a column with a diameter of 80 cm and a length of 35 cm containing 1200 g of the stationary chiral phase СЫта1рак АО ТМ with a particle size fraction of 20 μm. Elution is carried out using the mobile phase [heptane / 2-propanol / methanol (92: 5: 3 by volume)] with a flow rate of 120 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm. Enantiomer A (levorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.069 g of a colorless oil.

Mass spectrum (1E): 111 // 498 (M ⁺ ); 439 (M-CO ² CH 3+); 153 (C9H ₇ E ₂ ⁺ ).

[a] _c ²⁰ = -11.6 ° + 0.4 ° [methanol (c = 0.5), 589 nm].

Enantiomer B (dextrorotatory), the absolute configuration of which is not defined, eluting in the second place, isolated, then concentrated in vacuo, getting 0,067 g of a colorless oil.

Mass spectrum (1E): tA = 498 (M ⁺ ); 439 (M-CO ² CH 3+); 153 (C9H ₇ E ₂ ⁺ ).

[a] _c ²⁰ = + 11.5 ° ± 0.4 ° [methanol (c = 0.5), 589 nm]. Methyl - (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl ] 3-pyrrolidinecarboxylate can be obtained as described in example 2.

Example 7. Enantiomer A 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid (absolute configuration not defined).

A solution of 0.21 g of the enantiomer A methyl-4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2- morpholine carboxylate in a mixture of 10 cm ^{3 of} 1,4-dioxane, 10 cm ^{3 of} methanol and 1.18 cm ^{3 of} 5N. The sodium hydroxide solution is maintained at a temperature of about 80 ° C with stirring and in an inert atmosphere for 12 hours. After cooling to a temperature of about 20 ° C, the reaction medium is evaporated under reduced pressure (2 kPa; 45 ° C) to obtain a whitish film. The residue is treated with 25 cm ^{3 of} dichloromethane and 10 cm ^{3 of} distilled water, then neutralized with 1.2 cm ³ 5N. of hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30 ° C. The resulting residue was purified by silica gel column chromatography (particle size 70-200 μm; diameter 2 cm), eluting with a mixture of chloroformmethanol-28% ammonium hydroxide solution (12: 3: 0.5 by volume) and collecting fractions of 10 cm ³ . The fractions containing the target product are combined, then evaporated according to the above conditions

- 11,010,403 viyam. 0.18 g of enantiomer A of 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid is obtained in the form of a white solid.

¹ H-NMR spectrum (300 MHz, (SI ₃ ) ₂ 8O-b ₆ with the addition of a few drops ΟΌ ₃ ΟΘΘΌ-ά ₄ , δ in ppm): 1.451.90 (m, 4H); 2.04 (d, 1 = 11 Hz, 1H); 2.12 (br t, 1 = 11 Hz, 1H); 2.40-2.60 (m, 2H); 2.63 (br.s.d, 1 = 11 Hz, 1H); 2.95-3.05 (m, 2H); 3.04 (t, 1 = 7.5 Hz, 2H); 3.12 (d, 1 = 11 Hz, 1H); 3.52 (very broad d, 1 = 11 Hz, 1H); 3.77 (br t, 1 = 11 Hz, 1H); 3.85 (s, 3H); 7.20 (m, 1H); 7.30-7.50 (m, 2H); 7.50-7.60 (m, 2H); 8.08 (d, 1 = 9 Hz, 1H); 8.73 (br s, 1H).

[a] _s ²⁰ = -12.7 ° + 0.6 ° [methanol, s = 0.5%].

Example 8. Enantiomer B 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholincarboxylic acid (absolute configuration not defined).

A solution of 0.22 g of enantiomer B methyl-4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2- morpholine carboxylate in a mixture of 10 cm ^{3 of} 1,4-dioxane, 10 cm ^{3 of} methanol and 1.23 cm ^{3 of} 5N. The sodium hydroxide solution is maintained at a temperature of about 80 ° C with stirring and in an inert atmosphere for 12 hours. After cooling to a temperature of about 20 ° C, the reaction medium is evaporated under reduced pressure (2 kPa; 45 ° C) to obtain a whitish film. The residue is treated with 25 cm ^{3 of} dichloromethane and 10 cm ^{3 of} distilled water, then neutralized with 1.2 cm ³ 5N. hydrochloric acid and extracted with 25 cm ^{3 of} diethyl ether. The organic phase is dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30 ° C. The resulting residue was purified by silica gel column chromatography (particle size 70-200 μm; diameter 2 cm), eluting with a mixture of chloroform-methanol-28% ammonium hydroxide solution (12: 3: 0.5 by volume) and collecting 10 cm fractions ³ . The fractions containing the target product are combined, then evaporated according to the above conditions. Obtain 0.2 g of the enantiomer of B 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid as solid white.

'H-NMR spectrum (300 MHz, (CO ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.50-1.85 (m, 4H); 1.96 (d, 1 = 11 Hz, 1H); 2.08 (br t, 1 = 11 Hz, 1H); 2.45-2.55 (m, 2H); 2.60 (br.s.d, 1 = 11 Hz, 1H); 3.07 (m, 2H); 3.10 (t, 1 = 7.5 Hz, 2H); 3.10-3.20 (m, 2H); 3.54 (very broad d, 1 = 11 Hz, 1H); 3.91 (br t, 1 = 11 Hz, 1H); 3.98 (s, 3H); 7.07 (m, 1H); 7.20-7.35 (m, 2H); 7.35-7.45 (m, 2H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (s, 1H).

[a] _s ²⁰ = + 16.0 ° ± 0.5 ° [methanol, s = 0.5%].

Enantiomers A and B methyl 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinocarboxylate.

A mixture of 0.7 g of methyl - (. + -.) - 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylate (racemic mixture of enantiomers A and B), 0.59 g of 2 - [(2-bromoethyl) thio] -1,4-difluorobenzene, 0.32 g of potassium iodide and 1.33 g of potassium carbonate in 45 cm ^{3 of} acetonitrile are heated with stirring and in an inert atmosphere for 20 hours at a temperature of 75 ° C. After cooling to a temperature of about 20 ° C., the reaction mixture was filtered and the insoluble part was washed 2 times with 10 cm ^{3 of} acetonitrile. The filtrate was evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The evaporation residue is treated with 50 cm ^{3 of} distilled water and 100 cm ^{3 of} ethyl acetate. The organic phase is washed 3 times with 30 cm ^{3 of} distilled water and 2 times with 50 cm ^{3 of an} aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated according to the above conditions. The resulting oil was purified by silica gel column chromatography (particle size 70-200 μm; diameter 2.5 cm), eluting with dichloromethane-ethyl acetate (90:10 by volume) and collecting 10 cm ³ fractions. The fractions containing the desired product are combined, then evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.52 g of methyl - (. + -.) - 4- [2 - [(2,5-difluorophenyl) thio] ethyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) is obtained propyl] -2-morpholinocarboxylate in the form of a thick, colorless oil (racemic mixture of enantiomers A and B).

'H-NMR spectrum (300 MHz, (CO ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 2.01 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H), 2.50-2.60 (m, 2H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.06 (m, 2H); 3.10 (t, 1 = 7 Hz, 2H); 3.17 (brd, 1 = 11 Hz, 1H); 3.59 (s, 3H); 3.64 (very broad d, 1 = 7 Hz, 1H); 3.81 (unbound t, 1 = 11 and 3 Hz, 1H); 3.97 (s, 3H); 7.65 (m, 1H); 7.20-7.35 (m, 2H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H);

7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

1 - [(2-Bromethyl) thio] -2,5-difluorobenzene is prepared according to the method described in international patent application UO 02/40474.

Based on the racemic mixture of the enantiomers A and B obtained above, each enantiomer is isolated by HPLC.

The separation of the 2 enantiomers A and B is carried out on the basis of 0.52 g of the mixture A and B described above using the stationary phase CGlare1 М TM C18 (particle size fraction 20 μm; column with a diameter of 80 mm and a length of 350 mm; the mass of the stationary phase is 1200 g) ; the mobile phase is formed by a mixture of heptane-ethanol-triethylamine (95: 05: 0.05 by volume) with a flow rate of 110 cm ³ per minute and the wavelength of the UV detector is fixed at 265 nm.

Fractions containing the first enantiomer (enantiomer A), eluting primarily, levorotatory, are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C,

- 12 010403 obtaining 0.224 g of a colorless oil.

The fractions containing the second enantiomer (enantiomer B), eluted second, dextrorotatory, are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C, yielding 0.236 g of a colorless oil.

Enantiomer A.

¹ H-NMR spectrum (300 MHz, (ΟΌ ₃ ) ₂ 8Θ-ά ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 2.01 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H); 2.50-2.60 (m, 2H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.05 (m, 2H); 3.10 (t, 1 = 7 Hz, 2H); 3.17 (brd, 1 = 11 Hz, 1H); 3.59 (s, 3H); 3.64 (very broad d, 1 = 11 Hz, 1H); 3.81 (unbound t, 1 = 11 and 3 Hz, 1H); 3.97 (s, 3H); 7.05 (m, 1H); 7.20-7.35 (m, 2H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H);

7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

[a] _c ²⁰ = -17.5 ° ± ... [dimethyl sulfoxide, c = 0.6%].

Enantiomer B.

'H-NMR spectrum (300 MHz, (ΟΌ ₃ ) ₂ 8Θ-ά ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 2.01 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H); 2.50-2.60 (m, 2H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.06 (m, 2H); 3.10 (t, 1 = 7 Hz, 2H); 3.17 (brd, 1 = 11 Hz, 1H); 3.59 (s, 3H); 3.64 (very broad d, 1 = 7 Hz, 1H); 3.81 (unbound t, 1 = 11 and 3 Hz, 1H); 3.97 (s, 3H); 7.05 (m, 1H); 7.20-7.35 (m, 2H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H);

7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

^{. | (/ | ι,:} ° = + 24.1 ° ± 0.9 ° [ DMSO, c = 0.5%].

Methyl - (. + -.) - 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinocarboxylate.

To the solution, 3.2 g of 4- (1,1-dimethylethyl) - and (2-methyl) - (. + -.) - 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2,4-morpholindicarboxylate in 70 cm ^{3 of} dioxane add 17.3 cm ³ 4N. a solution of hydrogen chloride in dioxane, then kept under stirring for 16 hours at a temperature of 20 ° C. The reaction medium is then evaporated under reduced pressure (45 ° C; 5 kPa). The residue is treated with 30 cm ^{3 of} ethyl acetate and 20 cm ^{3 of} distilled water, then neutralized with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered, and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 40 ° C. The obtained residue was purified by silica gel column chromatography (granulometry 70-200 μm; diameter 2.5 cm), eluting with a dichloromethane-methanol mixture (95: 5 by volume) and collecting 10 cm ³ fractions. The fractions containing the target product are combined, then evaporated according to the above conditions. 1.8 g of methyl - (. + -.) - 2 [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylate are obtained in the form of a thick brown oil.

¹ H-NMR spectrum (300 MHz, (ΟΌ ₃ ) ₂ δΟ-ά ₆ , δ in ppm): 1.35-1.60 (m, 1H); 1.69 (m, 3H); 2.55-2.70 (m, 1H); 3.04 (m, 2H); 3.19 (m, 2H); 3.30-3.35 (m, 1H); 3.55 (very broad d, 1 = 11 Hz, 1H); 3.60 (s, 3H); 3.70 (m, 1H); 3.97 (s, 3H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

4- (1,1-Dimethylethyl) - and (2-methyl) - (. + -.) - 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2,4-morpholindicarboxylate .

To a solution of 3.9 g of 4- (1,1-dimethylethyl) - and (2-methyl) - (. + -.) - 2- (2-propenyl) -2,4-morpholindicarboxylate in 40 cm ^{3 of} tetrahydrofuran with stirring in an inert atmosphere and after cooling to a temperature of −10 ° C., 32 cm ^{3 of a} 0.5M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran are added dropwise. The mixture was then brought to a temperature of about 20 ° C, while stirring was continued for another 4 hours. 4.35 g of 4-iodo-3-chloro-6-methoxyquinoline was added over 45 minutes as a solution in 30 cm ^{3 of} tetrahydrofuran, then 260 mg of diphenylphosphinoferrocene palladium chloride and finally 7.54 g of potassium phosphate. The reaction mixture was refluxed for 15 hours, then filtered while hot through a sintered glass filter. The filtrate is treated 4 times with 20 cm ^{3 of} ethyl acetate and concentrated to dryness under reduced pressure (40 ° C; 5 kPa). The residue is treated with 250 cm ^{3 of} ethyl acetate and 200 cm ^{3 of} water. The organic phase is decanted, washed 3 times with 50 cm ^{3 of} distilled water and 2 times 100 cm ^{3 of an} aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, then concentrated under reduced pressure (45 ° C; 5 kPa). The residue was purified by chromatography on a silica gel column (particle size 70-200 microns; diameter 2.8 cm), eluting with dichloromethane then dichloromethane-ethyl acetate (90:10 by volume) and collecting fractions of 200 cm ^3. The fractions containing the product are combined, then concentrated under reduced pressure (40 ° C; 5 kPa). 3.22 g of 4- (1,1-dimethylethyl) - and (2-methyl) - (. + -.) - 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] - 2,4 morpholindicarboxylate in the form of a viscous yellow oil.

¹ H-NMR spectrum (300 MHz, (CO ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.35-1.85 (m, 4H); 1.38 (s, 9H); 2.85-3.05 (m, 1H); 3.07 (m, 2H); 3.61 (s, 3H); 3.67 (m, 4H); 3.97 (s, 3H); 4.17 (d, 1 = 13.5 Hz, 1H); 7.35-7.45 (m, 2H); 7.97 (d, 1 = 9 Hz, 1H); 8.69 (br s, 1H).

4- (1,1-Dimethylethyl) - and (2-methyl) - (. + -.) - 2- (2-propenyl) -2,4-morpholindicarboxylate.

To a solution of 3.7 cm ^{3 of} diisopropylamine in 50 cm ^{3 of} tetrahydrofuran, while stirring in an inert atmosphere and after cooling to -70 ° C., a 15 cm ^{3 of a} 1.6 M solution of butyl lithium in hexane is added dropwise. The mixture was stirred at the same temperature for 70 minutes. A solution of 5 g of 4- (1,1-dimethylethyl) - and (2-methyl) -2,4-morpholindicarboxylate in 40 cm ^{3 is} added dropwise over 40 minutes

- 13 010403 tetrahydrofuran. The mixture was stirred at the same temperature for 40 minutes. A solution of 3.2 g of allyl bromide in 10 cm ^{3 of} tetrahydrofuran is added dropwise over 25 minutes. The mixture was stirred at the same temperature for 70 minutes. The mixture is then brought to a temperature of about 20 ° C. while stirring was continued for another 2 hours. 15 cm ^{3 of a} saturated solution of ammonium chloride was added dropwise. The temperature is increased to 25 ° C. The organic phase is decanted. washed 1 time with 50 cm ^{3 of} distilled water and 2 times 100 cm ^{3 of an} aqueous saturated solution of sodium chloride. dried over magnesium sulfate. filtered. then concentrated under reduced pressure (45 ° C; 5 kPa). The residue was purified by silica gel column chromatography (granulometry 70-200 μm; diameter 2.8 cm). eluting with dichloromethane and collecting 50 ^cm3 fractions. Fractions. containing the product. combine. then concentrated under reduced pressure (45 ° C; 5 kPa). Obtain 3.5 g of 4- (1.1-dimethylethyl) - and (2-methyl) - (. + -.) -

2- (2-propenyl) -2.4-morpholindicarboxylate as a colorless oil.

¹ H-NMR spectrum (300 MHz. (CO ₃ ) ₂ 8O-b _6. Δ in ppm): 1.40 (s. 9H); 2.38 (d. 1 = 7.5 Hz. 2H); 2.80-3.05 (m, 2H); 3.55-3.80 (m. 3H); 3.66 (s. 3H); 4.20 (d. 1 = 13 Hz. 1H); 5.00-5.20 (m. 2H); 5.70 (m, 1H).

4- (1.1-Dimethylethyl) - and (2-methyl) - (. + -.) - 2.4-morpholindicarboxylate.

To a solution of 10 g of 4- (1.1-dimethylethyl) -2.4-morpholindicarboxylate in 200 cm ^{3 of} acetonitrile, 13.5 cm ^{3 of} iodomethane are added under stirring in an inert atmosphere and at a temperature of about 20 ° C. then 7 g of cesium carbonate. The mixture was stirred at the same temperature for 24 hours. The mixture was then filtered through celite and the filtrate was concentrated to dryness under reduced pressure (45 ° C; 5 kPa). The residue is treated with 250 cm ^{3 of} dichloromethane and 200 cm ^{3 of} water. The organic phase is decanted. washed 3 times with 50 cm ^{3 of} distilled water and 2 times with 100 cm ^{3 of an} aqueous saturated sodium chloride solution. dried over magnesium sulfate. filtered. then concentrated under reduced pressure (35 ° C; 5 kPa). 5 g of 4- (1.1-dimethylethyl) - and (2-methyl) - (. + -.) - 2.4-morpholindicarboxylate are obtained in the form of a viscous yellow oil. which slowly crystallizes. The melting point is 68 ° C.

'H-NMR spectrum (300 MHz. (SE ₃ ) ₂ 8O-b ₆ at a temperature of 37 ° C. δ in ppm): 1.45 (s. 9H); 3.18 (dd isolated. 1 = 13.5-9 and 3 Hz. 1H); 3.28 (dd. 1 = 13.5 and 8 Hz. 1H); 3.53 (m, 2H); 3.71 (s. 3H); 3.80 (dd. 1 = 13.5 and 3 Hz. 1H); 3.89 (d. 1 = 11 and 4 Hz. 1H); 4.17 (dd. 1 = 8 and 3 Hz. 1H).

Example 9. Enantiomer A of 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid (absolute configuration not defined).

Solution 0.21 g of enantiomer A methyl 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -2-morpholincarboxylate in a mixture of 10 cm ³ 1.4-dioxane. 10 cm ^{3 of} methanol and 1.22 cm ³ 5n. The sodium hydroxide solution is maintained at a temperature of about 80 ° C with stirring and in an inert atmosphere for 12 hours. After cooling to a temperature of about 20 ° C, the reaction medium is evaporated under reduced pressure (2 kPa; 45 ° C). getting a whitish film. The residue is treated with 25 cm ^{3 of} dichloromethane and 10 cm ^{3 of} distilled water. then neutralize 1.23 cm ³ 5N. of hydrochloric acid. The organic phase is dried over magnesium sulfate. filtered. then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30 ° C. The resulting residue was purified by silica gel column chromatography (particle size distribution 70-200 μm; diameter 2 cm). eluting with a mixture of chloroform-methanol-28% solution of ammonium hydroxide (12: 3: 0.5 by volume) and collecting fractions of 10 cm ³ . Fractions. containing the target product. combine. then evaporated according to the above conditions. 0.13 g of enantiomer A of 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid is obtained as a yellow lacquer.

'H-NMR spectrum (300 MHz. (C1) _; ) _; 8O-s1. „Δ in ppm): 1.45-1.60 (m. 1H); 1.65-1.90 (m, 3H); 1.95 (d. 1 = 11 Hz. 1H); 2.09 (untied t. 1 = 11 and 3.5 Hz. 1H); 2.63 (br.s. 1 = 11 Hz. 1H); 2.95-3.15 (m, 4H); 3.17 (brd 1 = 11 Hz. 1H); 3.63 (very broad d.d. 1 = 11 Hz. 1H); 3.90 (very broad dd. 1 = 11 Hz. 1H); 3.96 (s. 3H); 6.41 (d. 1 = 7 and 16.5 Hz. 1H); 6.62 (brd 1 = 16.5 Hz. 1H); 7.13 (m. 1H); 7.24 (decoupled t. 1 = 10 and 4.5 Hz. 1H); 7.39 (m. 2H); 7.48 (m, 1H); 7.96 (d. 1 = 10 Hz. 1H); 8.68 (s. 1H).

[a] _with ²⁰ = -12.6 ° ± 0.7 ° [methanol. c = 0.5%].

Example 10. Enantiomer of B 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinecarboxylic acid (absolute configuration not defined).

A solution of 0.21 g of enantiomer B of methyl 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -2-morpholinocarboxylate in a mixture of 10 cm ³ 1.4-dioxane. 10 cm ^{3 of} methanol and 1.22 cm ³ 5n. The sodium hydroxide solution is maintained at a temperature of about 80 ° C with stirring and in an inert atmosphere for 12 hours. After cooling to a temperature of about 20 ° C, the reaction medium is evaporated under reduced pressure (2 kPa; 45 ° C). getting a whitish film. The residue is treated with 25 cm ^{3 of} dichloromethane and 10 cm ^{3 of} distilled water. then neutralize 1.2 cm ³ 5N. of hydrochloric acid. The organic phase is dried over magnesium sulfate. filtered. then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30 ° C. The resulting residue was purified by silica gel column chromatography (particle size distribution 70-200 μm; diameter 2 cm). eluting with a mixture of chloroform-methanol-28% solution of ammonium hydroxide (12: 3: 0.5 by volume) and collecting fractions of 10 cm ³ . Fractions. containing the target product. combine. then evaporated according to the above conditions. Obtain 0.14 g of enantiomer B 4- [3- (2.5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4-chi

- 14 010403 nolinyl) propyl] -2-morpholincarboxylic acid in the form of a thick orange oil.

Ή-NMR spectrum (300 MHz, (SE ₃ ) ₂ 8О-а ₆ , δ in ppm): 1.45-1.60 (m, 1Н); 1.65-1.85 (m, 3H); 1.95 (d, 1 = 11 Hz, 1H); 2.09 (decoupled t, 1 = 11 and 2.5 Hz, 1H); 2.62 (br.s.d, 1 = 11 Hz, 1H); 2.95-3.15 (m, 4H); 3.17 (brd, 1 = 11 Hz, 1H); 3.62 (br.s.d, 1 = 11 Hz, 1H); 3.91 (very brt, 1 = 11 Hz, 1H); 3.96 (s, 3H); 6.40 (d, 1 = 16 and 7 Hz, 1H); 6.62 (brd, 1 = 16 Hz, 1H); 7.13 (m, 1H); 7.24 (decoupled t, 1 = 10 and 5 Hz, 1H); 7.39 (m, 2H); 7.48 (m, 1H); 7.96 (d, 1 = 10 Hz, 1H); 8.68 (br s, 1H).

| α | ι / ° = + 12.4 ° ± 0.6 ° [methanol, c = 0.5%].

Preparation of the enantiomers A and B of methyl 4- [3- (2,5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy4-quinolinyl) propyl] -2-morpholinecarboxylate.

To 0.7 g of 2,5-difluorocinnamic alcohol dissolved in 90 cm ^{3 of} chloroform, with stirring in an inert atmosphere and at a temperature of about 23 ° C, a solution of 0.62 g of benzonitrile and 0.62 g of thionyl chloride in 30 cm ^{3 is} added dropwise. chloroform. The mixture was then stirred at the same temperature for 2 hours. The reaction mixture was treated with 75 cm ^{3 of} saturated sodium bicarbonate solution, then 75 cm ^{3 of} distilled water, and finally dried over magnesium sulfate to give a yellow solution 8. This solution 8 is added to a mixture of 1.1 g of methyl 2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2morpholine carboxylate, 0.5 g of potassium iodide and 2.1 g of potassium carbonate in 150 cm ³ acetonitrile, after which the whole mass is heated with stirring and in an inert atmosphere for 20 hours at a temperature of about 75 ° C. After cooling to a temperature of about 20 ° C., the reaction medium is filtered and the insoluble part is washed 2 times with 10 cm ^{3 of} acetonitrile. The filtrate was evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The evaporation residue is treated with 50 cm ^{3 of} distilled water and 100 cm ^{3 of} ethyl acetate. The organic phase is washed 3 times with 30 cm ^{3 of} distilled water and 2 times 50 cm ^{3 with an} aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under the above conditions. The resulting oil was purified by silica gel column chromatography (particle size 70-200 μm; diameter 2.5 cm), eluting with a dichloromethane-ethyl acetate mixture (80:20 by volume) and collecting 10 cm ³ fractions. The fractions containing the target product are combined, then evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.48 g of methyl 4- [3- (2,5-difluorophenyl) -2-propenyl] -2- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -2-morpholinocarboxylate is obtained in the form of a gum-like brown substances (racemic mixture of enantiomers A and B).

Ή-NMR spectrum (300 MHz, (SE ₃ ) ₂ 8О-а ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 1.99 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.05 (m, 2H); 3.05-3.15 (m, 2H); 3.18 (br.s.d, 1 = 11 Hz, 1H); 3.61 (s, 3H); 3.67 (very broad d, 1 = 11 Hz, 1H); 3.83 (decoupled t, 1 = 11 and 2.5 Hz, 1H);

3.96 (s, 3H); 6.39 (d, 1 = 16.5 and 7 Hz, 1H); 6.61 (brd, 1 = 16.5 Hz, 1H); 7.13 (m, 1H); 7.24 (decoupled t, 1 = 10 and 5 Hz, 1H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H); 7.49 (m, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (br s, 1H).

Based on the racemic mixture of the enantiomers A and B obtained above, each enantiomer is isolated by HPLC.

The separation of the 2 enantiomers A and B is carried out on the basis of 0.52 g of the above mixture A and B, using the stationary phase CGaee1 OE TM C18 (particle size fraction 20 μm; column with a diameter of 80 mm and a length of 350 mm; the mass of the stationary phase is 1200 g) ; the mobile phase is formed by a mixture of heptane / methanol / propanol (95:01:04 by volume) with a flow rate of 100 cm ³ per minute, and the wavelength of the UV detector is fixed at 254 nm.

Fractions containing the first enantiomer, the first eluted (called enantiomer A), levorotatory, are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C, obtaining 0.217 g of a colorless oil.

Fractions containing a second enantiomer, second eluted (called enantiomer B), dextrorotatory, are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. to obtain 0.212 g of a colorless oil.

Enantiomer A.

Ή-NMR spectrum (300 MHz, (SE ₃ ) ₂ 8О-а ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 1.99 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.05 (m, 2H); 3.05-3.15 (m, 2H); 3.18 (d, 1 = 11 Hz, 1H); 3.61 (s, 3H); 3.67 (very broad d, 1 = 11 Hz, 1H); 3.83 (decoupled t, 1 = 11 and 2.5 Hz, 1H); 3.96 (s, 3H); 6.39 (d, 1 = 16 and 6.5 Hz, 1H); 6.61 (brd, 1 = 16 Hz, 1H); 7.13 (m, 1H); 7.24 (decoupled t, 1 = 10 and 4.5 Hz, 1H.); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H); 7.49 (m, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (s, 1H).

Enantiomer B.

Ή-NMR spectrum (300 MHz, (SE ₃ ) ₂ 8О-а ₆ , δ in ppm): 1.40-1.60 (m, 1H); 1.73 (m, 3H); 1.99 (d, 1 = 11 Hz, 1H); 2.12 (decoupled t, 1 = 11 and 3.5 Hz, 1H); 2.64 (br.s.d, 1 = 11 Hz, 1H); 3.05 (m, 2H); 3.05-3.15 (m, 2H); 3.18 (br.s.d, 1 = 11 Hz, 1H); 3.61 (s, 3H); 3.67 (very broad d, 1 = 11 Hz, 1H); 3.83 (decoupled t, 1 = 11 and 2.5 Hz, 1H);

3.96 (s, 3H); 6.39 (d, 1 = 16 and 7 Hz, 1H); 6.61 (brd, 1 = 16 Hz, 1H); 7.13 (m, 1H); 7.24 (decoupled t, 1 = 10 and 5 Hz, 1H); 7.36 (d, 1 = 3 Hz, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H); 7.49 (m, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.68 (s, 1H).

Example 11. 1 - [(2E) -3 - (2,5-Difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -

3-azetidinecarboxylic acid.

K 614 mg (1.267 mmol) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4

- 15 010403 quinolinyl) propyl] -3-azetidine carboxylate in the form of a solution in 20 cm ^{3 of} dioxane at a temperature of about 20 ° C. add 5 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 1.5 hours at the boil under reflux, another 6 cm ^{3 of} 5N are added. an aqueous solution of sodium hydroxide and refluxed for another 3 hours; the reaction medium is cooled and 4.5 cm ^{3 of} 37% hydrochloric acid is added, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue which is flash chromatographed on a 200 cm ³ column ^of finely divided silica [eluent: solvent gradient dichloromethane-methanol-28% solution of ammonium hydroxide (from 100: 0: 0 to 72: 24: 4 by volume)]. The fractions containing the product are combined and evaporated to dryness (2.7 kPa). The residue (530 mg) was treated with 10 cm ^{3 of} dichloromethane diluted with 25 cm ^{3 of} diethyl ether to obtain 445 mg of 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [ 3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3-azetidinecarboxylic acid as a pinkish solid, melting at a temperature of 211 ° C.

¹ H-NMR spectrum (300 MHz, (SP ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.60 (m, 2H); 1.99 (m, 2H); 2.95-3.55 (m, 2H); 3.09 (d, 1 = 7 Hz, 2H); 3.19 (brd, 1 = 5.5 Hz, 2H); 3.37 (d, 1 = 7 Hz, 2H); 3.96 (s, 3H); 6.35 (d, 1 = 16.5 and 5.5 Hz, 1H); 6.57 (brd, 1 = 16.5 Hz, 1H); 7.13 (m, 1H); 7.25 (decoupled t, 1 = 9.5 and 5 Hz, 1H); 7.35-7.45 (m, 2H); 7.49 (ddd, 1 = 9.5-6 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.70 (br s, 1H).

Mass spectrum of DS): t / h = 471 (M + H) ⁺ (peak of molecular ion).

Methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-azetidinecarboxylate may be obtained as described in example 12.

Example 12. Methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- azetidine carboxylate.

To 1.18 g (2.91 mmol) of methyl 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-azetidinecarboxylate dihydrochloride at a temperature of about 20 ° C. and under an argon atmosphere, 2 g of potassium carbonate, 0.531 g of potassium iodide, then a freshly prepared solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (3.8 mmol) in 70 cm ^{3 of} acetonitrile. After stirring for 3 hours at reflux temperature, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue that was treated with 100 cm ^{3 of} water, extracted 6 times with 100 cm ^{3 of} dichloromethane, concentrated to dryness under reduced pressure (2.7 kPa) to give 1.546 g of a brown oil, which was purified by flash chromatography using 240 ml of finely divided silica [eluent: cyclohexane / ethyl acetate gradient (50:50 to 40:60 by volume)]. After concentration of the fractions under reduced pressure, 0.799 g of methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl is obtained ] -3-azetidinecarboxylate as a yellow oil.

'H-NMR spectrum (300 MHz, (SP ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.57 (m, 2H); 2.00 (m, 2H); 3.00-3.15 (m, 2H); 3.10 (d, 1 = 7.5 Hz, 2H); 3.17 (br.s.d, 1 = 6 Hz, 2H); 3.38 (d, 1 = 6 Hz, 2H); 3.60 (s, 3H); 3.96 (s, 3H); 6.35 (d, 1 = 16.5 and 6 Hz, 1H); 6.55 (brd, 1 = 16.5 Hz, 1H); 7.12 (m, 1H); 7.24 (unbound t, 1 = 9.5 and 5 Hz, 1H); 7.30-7.45 (m, 2H); 7.48 (ddd, 1 = 9.5-6 and 3 Hz, 1H); 7.96 (d, 1 = 9 Hz, 1H); 8.70 (d, 1 = 1 Hz, 1H).

Mass spectrum (GE): t / x = 484 (M ⁴ ); t / x = 191 (peak molecular ion).

A solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (3.8 mmol) in acetonitrile can be prepared as follows.

To 0.646 g (3.8 mmol) of 2,5-difluorocinnamic alcohol in the form of a solution in 40 cm ^{3 of} dichloromethane at a temperature of about 20 ° C and in an argon atmosphere add a solution of 0.34 cm ³ (4.66 mmol) of thionyl chloride and 0.555 g (4.66 mmol) of benzotriazole in 40 cm ^{3 of} dichloromethane. After stirring for 10 minutes, the reaction mixture was filtered through a No. 3 porous glass filter, and the solid residue was washed 3 times with 10 cm ^{3 of} dichloromethane. The filtrate is washed 3 times with 30 cm ^{3 of} water. The organic phase was dried over magnesium sulfate and filtered to give a solution of 2 - [(1E) -3-chloro-1-propenyl] -1,4-difluorobenzene (3.8 mmol), which was then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 20 ° C, before dissolving in acetonitrile.

Methyl 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-azetidinecarboxylate dihydrochloride can be prepared as follows.

To 1.325 g (3.06 mmol) of 1- (1,1-dimethylethyl) - and (3-methyl) -3- [3- (fluoro-6-methoxy-4-quinolinyl) propyl] 1,3-azetidinedicarboxylate in the form of a solution in 10 cm ^{3 of} methanol at a temperature of about 20 ° C add 10 cm ³ 4N. a solution of hydrogen chloride in dioxane. After stirring for 4 hours at a temperature of about 20 ° C., the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.19 g of methyl 3- [3- (3-fluoro-6-methoxy-4- dihydrochloride) quinolinyl) propyl] -3-azetidine carboxylate in the form of a pale yellow meringue.

Mass spectrum DE): t / h = 332 (M ⁴ ); t / x = 304. 204 (peak molecular ion) and 191.

1- (1,1-Dimethylethyl) - and (3-methyl) -3- [3- (fluoro-6-methoxy-4-quinolinyl) propyl] -1,3-azetidinedicarboxylate can be prepared as follows.

To 12 cm ³ (6 mmol) of a solution of 9-ΒΒΝ (9-borabicyclo [3.3.1] nonane), 0.5 M tetrahydrofuran at a temperature of about 3 ° C and a solution of 1.021 g (4 mmol) 1- are added in argon atmosphere (1,1-dimethylethyl) - and (3methyl) -3- (2-propenyl) -1,3-azetidinedicarboxylate in 15 cm ^{3 of} tetrahydrofuran. After heating the reaction

- 16 010403 mixture to a temperature of about 20 ° C, then 2.34 g (4.4 mmol) of 3-fluoro-4-iodo-6-methoxyquinoline are added in succession as a suspension for 3 hours at a temperature of about 20 ° C. in 35 cm ^{3 of} tetrahydrofuran, then 2.55 g (12 mmol) of potassium phosphate and 0.09 g (0.123 mmol) of RbSTbrrG (1,1'bis (diphenylphosphino) ferrocenyl palladium dichloride). After stirring for 19 hours at reflux temperature, the reaction mixture was cooled, then filtered through a sintered glass filter, which was washed extensively with tetrahydrofuran and ethyl acetate. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.09 g of a black oil, which was purified by flash chromatography using 300 cm ^{3 of} finely divided silica [eluent: cyclohexane / ethyl acetate gradient (75:25 to 60 -40 by volume)]. After concentration of the fractions under reduced pressure, 1.344 g of 1- (1,1-dimethylethyl) - and (3-methyl) -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -1,3-azetidinedicarboxylate are obtained in the form of yellow oil.

Mass spectrum (1C): w / x = 433 (M + H) ⁺ (peak molecular ion).

1- (1,1-Dimethylethyl) - and (3-methyl) -3- (2-propenyl) -1,3-azetidinedicarboxylate can be prepared as follows.

To 3.609 g (16.73 mmol) of 1- (1,1-dimethylethyl) - and (3-methyl) -1,3-azetidinedicarboxylate in the form of a solution in 40 cm ^{3 of} tetrahydrofuran at a temperature of about -78 ° C and in argon atmosphere 20 cm ³ (20 mmol) of lithium bis (trimethylsilyl) amide are added dropwise in the form of a 1M solution in tetrahydrofuran. After stirring for 10 min at a temperature of about -78 ° C, 2.2 cm ³ (25.4 mmol) of allyl bromide are added, then they are kept for raising the temperature from -78 to about 20 ° C, at which they are stirred for another 17 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated with 50 cm ^{3 of} water, then extracted 3 times with 50 cm ^{3 of} ethyl acetate, dried over anhydrous magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.525 g of a yellow oil, which is purified by flash chromatography [eluent: gradient cyclohexane-ethyl acetate (90:10 to 80:20 by volume)]. After concentration of the fractions under reduced pressure, 2.75 g of 1- (1,1-dimethylethyl) - and (3-methyl) -3- (2-propenyl) -1,3-azetidinedicarboxylate are obtained as a colorless oil.

Mass spectrum (1C): w / x = 256 (M + H) ⁺ ; ιη / ζ = 273 (Μ + ΝΉ ₄ ⁺ ) (peak of the molecular ion).

1- (1,1-Dimethylethyl) - and (3-methyl) -1,3-azetidinedicarboxylate can be prepared as follows.

To a solution of 3.513 g (17.46 mmol) of 1- (1,1-dimethylethyl) 1,3-azetidinedicarboxylic acid ester in the form of a solution in 30 cm ^{3 of} methanol, 0.9 cm ³ (0.9 mmol) of a 1 M solution of tetrabutylammonium fluoride is added ; it is cooled to a temperature of about 5 ° C and 10 cm ³ (20 mmol) of a 2M solution of trimethylsilyldiazomethane in hexane is poured over 5 minutes, then, after 30 minutes, another 15 cm ³ (30 mmol) of a 2M solution of trimethylsilyldiazomethane in hexane is added. After decolorization, the solvents were evaporated under reduced pressure (2.7 kPa) to obtain 4.205 g of a brown liquid, which was purified by flash chromatography using 320 ml of finely divided silica [eluent: cyclohexane / ethyl acetate (80:20 by volume)]. After concentration of the fractions under reduced pressure, 3.456 g of 1 (1,1-dimethylethyl) - and (3-methyl) -1,3-azetidinedicarboxylate are obtained as a colorless oil.

Mass spectrum (1C): ιη / ζ = 216 (M + H) ⁺ , ιη / ζ = 233 (Μ + NH ₄ ) ⁺ (peak of the molecular ion).

Example 13. Sodium salt of 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] 3-azetidinecarboxylic acid.

The procedure of Example 11 was followed, but starting from 512.4 mg (1.08 mmol) of methyl 3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl ] -3-azetidinecarboxylate, 20 cm ^{3 of} dioxane and 10 cm ^{3 of} 5N. an aqueous solution of sodium hydroxide, and refluxed for 1.5 hours. Cool, then add 5 cm ^{3 of} hydrochloric acid, then an aqueous solution of ammonium hydroxide to achieve a pH> 8. After that, the solvents are evaporated under reduced pressure (2.7 kPa) not to dryness. It is treated with 20 cm ^{3 of} water and left to stand, after which it is filtered off, washed with water and diethyl ether. Thus, 473 mg of the 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-azetidinecarboxylic acid sodium salt is obtained in the form of a white powder melting at a temperature of 67 ° C.

^! H-NMR spectrum (300 MHz, (SP ₃ ) ₂ 8O-b ₆ , δ in ppm): 1.57 (m, 2H); 1.96 (m, 2H); 2.57 (br t, 1 = 7 Hz, 2H); 2.74 (br t, 1 = 7 Hz, 2H); 2.95-3.10 (m, 2H); 3.05 (br.s.d, 1 = 7 Hz, 2H); 3.32 (brd, 1 = 7 Hz, 2H); 3.97 (s, 3H); 7.04 (dd, 1 = 5.5 and 3.5 Hz, 1H); 7.17 (brd, 1 = 3.5 Hz, 1H); 7.38 (m, 1H); 7.40 (dd, 1 = 9 and 3 Hz, 1H); 7.60 (brd, 1 = 5.5 Hz, 1H); 7.97 (d, 1 = 9 Hz, 1H); 8.70 (br s, 1H).

Mass spectrum (1E): ιη / ζ = 460 (M ⁺ ), ιη / ζ = 331 (peak of a molecular ion).

Example 14

Methyl 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] - 1- [2- (2-thienylthio) ethyl] -3-azetidinecarboxylate can be prepared as follows.

To a solution of 508 mg (1.35 mmol) methyl-3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- (2-hydroxyethyl] -3-azetidinecarboxylate, 314 mg (2, 7 mmol) of 2-thiophentiol and 708 mg (2.7 mmol) of triphenylphosphine in 5 cm ^{3 of} tetrahydrofuran at a temperature of about 20 ° C. add 0.53 cm ³ (2.7 mmol) of diisopropylcarbodiimide in 5 cm ^{3 of} tetrahydrofuran and kept under stirring in for 22 hours at a temperature of about 20 ° C.

- 17 010403

After that, 30 cm ^{3 of} diethyl ether are added to the reaction medium and extracted 2 times with 30 cm ^{3 of} water, to which 0.5 cm ^{3 of} concentrated methanesulfonic acid is added, then 1 time with 30 cm ^{3 of} water. These combined aqueous acidic phases are washed with 30 cm ^{3 of} diethyl ether, then alkalinized to pH>11; extracted 5 times with 50 cm ^{3 of} dichloromethane, and then evaporated to dryness under reduced pressure (2.7 kPa). The residue (693 mg) was purified by flash chromatography using 150 cm ^{3 of} finely divided silica [eluent: cyclohexane / ethyl acetate (1: 1 by volume)]. After concentration of the fractions under reduced pressure, 340 mg of methyl-3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-azetidinecarboxylate is obtained in the form of an almost colorless oils.

^! H-NMR spectrum (300 MHz, (0Ό ₃ ) ₂ 8Ο-ά ₆ , δ in ppm): 1.53 (m, 2H); 1.97 (m, 2H); 2.56 (t, 1 = 7 Hz, 2H); 2.74 (t, 1 = 7 Hz, 2H); 3.00-3.15 (m, 2H); 3.06 (d, 1 = 7 Hz, 2H); 3.33 (d, 1 = 7 Hz, 2H); 3.59 (s, 3H); 3.97 (s, 3H); 7.04 (dd, 1 = 5.5 and 3.5 Hz, 1H), 7.17 (dd, 1 = 3.5 and 1 Hz, 1H), 7.37 (br.s, 1 = 3 Hz , 1H); 7.41 (brd, 1 = 9 and 3 Hz, 1H); 7.60 (dd, 1 = 5.5 and 1 Hz, 1H); 7.97 (d, 1 = 9 Hz, 1H); 8.70 (d, 1 = 1 Hz, 1H).

Mass spectrum (ΙΕ): w / x = 474 (MC, w / x = 345 (peak of the molecular ion).

Methyl 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- (2-hydroxyethyl) -3-azetidinecarboxylate can be prepared as follows.

To a solution of 2.57 g (6.347 mmol) of methyl 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] 3-azetidinecarboxylate dihydrochloride and 0.75 cm ³ (9.6 mmol) 2- 3.51 g (24.4 mmol) of potassium carbonate are added to 100 cm ^{3 of} acetonitrile of iodoethanol and stirred for 20 hours at a temperature of about 20 ° C, then refluxed for 1.25 hours and the solvents are evaporated off under reduced pressure . The residue is treated with 100 cm ^{3 of} water and extracted 3 times with 100 cm ^{3 of} dichloromethane, which is then evaporated under reduced pressure (2.7 kPa). Obtain 2.88 g of pink oil, which is purified by flash chromatography using 300 ml of finely divided silica [eluent: gradient dichloromethane-methanol-28% solution of ammonium hydroxide (from 100: 0: 0 to 86: 12: 2 each volumes)]. After concentration of the fractions under reduced pressure, 1.748 g of methyl 3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -1- (2-hydroxyethyl) -3-azetidinecarboxylate are obtained in the form of a pink oil.

Mass spectrum (ΙΕ): w / x = 376 (M '); w / x = 345 (peak molecular ion).

Example 15. Sodium salt (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,5-difluorophenyl) - 2-propenyl] -3-pyrrolidinecarboxylic acid.

Following the procedure described in example 1, but starting from 4-bromo-3-chloro-6-methoxyquinoline (which can be obtained by the method described in international patent application AO 2002/40474-A2), a sodium salt is obtained (. + - .) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid in the form of a solid, melting at a temperature of 77 ° C.

Mass spectrum (ΙΕ): t / h = 500 M '; t / x = 153 C ₉ H ₇ B ₂ ⁺ (peak molecular ion).

IR Spectrum (KBr): 2936, 1621, 1504, 1491, 1230, 1117, 831, 743 and 728 cm ^-1 .

Example 16. The sodium salt of (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid.

Following the procedure described in example 1, but starting from 4-bromo-6-methoxyquinoline, the sodium salt of (. + -.) - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] is obtained -3- [3- (6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid as a solid, melting at a temperature of 109-112 ° C.

Mass spectrum (1C): t / x = 467 MH ⁺ (peak molecular ion).

IR Spectrum (KBr): 2941, 1621, 1591, 1509, 1490, 1242, 1228, 1031 845 and 728 cm ^-1 .

Example 17. Enantiomer A (levorotatory) 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2thienylthio) ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) .

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio ) ethyl] -3-pyrrolidinecarboxylate, the enantiomer A (levorotatory) 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3 - is obtained pyrrolidinecarboxylic acid (absolute configuration not defined) in the form of a white solid, melting at a temperature of 160 ° C.

| α | ι / ° = -36.3 ° ± 0.8 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2937, 1620, 1508, 1228, 1031, 847, 832, 809, 785, 708 and 452 cm ^-1 .

Mass spectrum (ΙΕ): t / x = 474 (M ⁺ ); 345 (M = C ₅ H ₅ 8 ₂ ) ⁺ peak molecular ion.

Methyl - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-pyrrolidinecarboxylate can be obtained, as described in example 2, but starting from 2 - [(2-bromoethyl) thio] thiophene. A yellow oil is obtained.

Mass spectrum (ΙΕ): t / x = 488 (M ³ ).

2 - [(2-Bromethyl) thio] thiophene can be obtained by the method described in international patent application AO 2002/40474-A2.

Example 18. Enantiomer B (dextrorotatory) 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2thienylthio) ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) .

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio ) ethyl] -3-pyrrolidinecarboxylate, enantiomer B is obtained (right)

- 18 010403 reducing) 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-pyrrolidinecarboxylic acids (absolute configuration not determined) in as a white solid, melting at a temperature of 172 ° C.

[a] _c ²⁰ = + 36.3 ° ± 0.8 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2937, 1620, 1508, 1228, 1031, 847, 832, 809, 785, 708 and 452 cm ^-1 .

Mass spectrum (W): w / h = 474 (M ³ ); 345 (M = C ₅ H ₅ § ₂ ) ⁺ peak molecular ion.

Example 19. Enantiomer A (dextrorotatory) of sodium salt 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3 [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl-1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3 [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) of the sodium salt of 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl is obtained ] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid.

[a] _c ²⁰ = + 15.3 ° ± 0.8 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2934, 1620, 1509, 1483, 1361, 1230, 1187, 1030, 909, 831 and 757 cm ^-1 .

Mass spectrum (K '): w / x = 505 (MH) ⁺ peak of the molecular ion.

Methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylate can be obtained following the procedure of Example 2, but starting from 2 - [(2-bromoethyl) thio] 1,4-difluorobenzene. A pale yellow oil is obtained.

Mass spectrum (ΣΕ): t / x = 518 (M ⁺ ).

2 - [(2-Bromoethyl) thio] -1,4-difluorobenzene can be obtained according to the method described in international patent application AO 2002/40474-A2.

Example 20. Enantiomer B (levorotatory) of the sodium salt of 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3 [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (levorotatory) of the sodium salt of 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6) is obtained -methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid.

[a] _c ²⁰ = -17.5 ° ± 0.7 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2934, 1620, 1509, 1483, 1361, 1230, 1187, 1030, 909, 831 and 757 cm ^-1 .

Mass spectrum (I '): t / x = 505 (MH) ⁺ peak of the molecular ion.

Example 21. Enantiomer A (levorotatory) 1- [2- (2,6-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2- (2,6-difluorophenoxy) ethyl] -

3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (levorotatory) 1- [2- (2,6-difluorophenoxy) ethyl] -3- [3 - (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white lacquer.

[a] _c ²⁰ = -18.9 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (CC1 ₄ ): 2929, 1621, 1507, 1499, 1477, 1292, 1231, 1031, 1008, 908 and 832 cm ^-1 .

Mass spectrum (I '): t / x = 489 (MH) ⁺ peak molecular ion.

Methyl - (. + -.) - 1- [2- (2,6-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate may be obtained by following the procedure of example 2, but starting from 2- (2-bromoethoxy) -1,3 difluorobenzene. A yellow oil is obtained.

Mass spectrum (ΣΕ): t / x = 502 (M ⁺ ).

2- (2-Bromoethoxy) -1,3-difluorobenzene can be obtained according to the method described in international patent application AO 2002/40474.

Example 22. Enantiomer B (dextrorotatory) 1- [2- (2,6-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2- (2,6-difluorophenoxy) ethyl] -

3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (dextrorotatory) 1- [2- (2,6-difluorophenoxy) ethyl] -3- [3 - (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white lacquer.

[a] _c ²⁰ = + 18.3 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (CC1 ₄ ): 2929, 1621, 1507, 1499, 1477, 1292, 1231, 1031, 1008, 908 and 832 cm ^-1 .

Mass spectrum (I '): t / x = 489 (MH) ⁺ peak molecular ion.

Example 23. Enantiomer A 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

To 0.49 g (0.987 mmol) of enantiomer A methyl-1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6

- 19 010403 methoxy-4-quinolinyl) propyl] -3-pyrrolidine carboxylate in the form of a solution in 30 cm ^{3 of} dioxane at a temperature of about 20 ° C. 8.3 cm ^{3 of} 5N are added. an aqueous solution of sodium hydroxide. After stirring for 16 hours at the boil under reflux, the reaction medium is concentrated under reduced pressure (2.7 kPa), then 75 cm ^{3 of} distilled water are treated. The clear yellow solution is then acidified to a pH of 5 to 20 cm ³ 2N. hydrochloric acid, then extracted with 75 cm ^{3 of} dichloromethane, then 2 times 50 cm ^{3 of} dichloromethane. The organic phases are decanted, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.29 g of a residue, which is triturated with 5 cm ^{3 of} diisopropyl ether, and then dried. This operation is repeated 2 times. Obtain 0.28 g of enantiomer A of 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute not defined) in the form of a cream-colored solid.

Mass spectrum (W): t / h = 482 (M ³ ); t / x = 151 (C ₉ H ₅ E ₂ ⁺ ) peak molecular ion.

IR Spectrum (KBr): 2943, 1621, 1509, 1496, 1231, 1170, 1031, 830, 767 and 595 cm ^-1 . [a] _c ²⁰ = -37.5 ° ± 1 ° [dichloromethane (c = 0.3), 589 nm].

The enantiomer A of methyl 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate can be prepared as follows way.

A solution of 1.68 g of methyl - (. + -.) - 1- (2-propynyl) -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate (racemate), 75 mg of copper diiodide, 0.67 g of 2,5-difluorobromobenzene and 0.24 g of tetrakistriphenylphosphine in 17 cm ^{3 of} triethylamine are heated at 80 ° C for 1 h, then stirred at room temperature for 16 h. The reaction mixture is diluted with using 100 cm ^{3 of} ethyl acetate, then filtered, the organic phase is washed 3 times with 50 cm ^{3 of} distilled water, then extracted with 100 cm ³ 2N. of hydrochloric acid. The aqueous phase is adjusted to pH 8-9 by the addition of potassium carbonate, then extracted 3 times with 100 cm ^{3 of} ethyl acetate. The organic phases are combined, washed with 50 cm ^{3 of} distilled water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.83 g of a thick brown oil, which is purified by flash chromatography [eluent: cyclohexane-ethyl acetate (1: 1 by volume)]. After concentration of the fractions under reduced pressure, 1.46 g of a pale yellow thick oil are obtained.

Separation of chiral HPLC of the two enantiomers A and B methyl-1- [3- (2,5-difluorophenyl) -2-propynyl] -

3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate is carried out according to the procedure described in examples 5 and 6.

For enantiomer A: [a] _c ²⁰ = -21.4 ° ± 0.5 ° [methanol (c = 0.5), 589 nm]; mass spectrum (ΣΕ): t / x = 496 (M ³ ). For enantiomer B: [a] _c ²⁰ = + 19.2 ° ± 0.7 ° [methanol (c = 0.5), 589 nm]; mass spectrum (ΣΕ): t / x = 496 (M ³ ). Methyl - (. + -.) - 1- (2-propynyl) -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylate (racemate) can be prepared as follows.

To a solution of 6.23 g of methyl - (. + -.) Dihydrochloride - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate in 62 cm ^{3 of} dimethylformamide dropwise at room temperature 6.7 cm ^{3 of} triethylamine are added, then 2.4 cm ^{3 of} propargyl bromide are added dropwise. The solution was stirred at room temperature for 1 h, then the reaction mixture was poured onto 180 g of crushed ice and 300 cm ^{3 of} distilled water. The aqueous phase is extracted 3 times with 350 cm ^{3 of} diethyl ether, the organic phases are combined, washed with 350 cm ^{3 of} distilled water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.2 g of an orange oil.

Mass spectrum (ΣΕ): t / x = 384 (M ³ ).

Example 24. Enantiomer of 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from enantiomer B, methyl-1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl ) propyl] -3-pyrrolidinecarboxylate give the enantiomer B 1- [3- (2,5-difluorophenyl) -2-propinyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3 -pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (ΣΕ): t / x = 482 (M ³ ); t / x = 151 (C ₉ H ₅ E ₂ ⁺ ) peak molecular ion.

IR Spectrum (KBr): 2943, 1621, 1509, 1496, 1231, 1170, 1031, 830, 767 and 595 cm ^-1 . [a] _c ²⁰ = + 24.7 ° + 0.7 ° [methanol (c = 0.3), 589 nm].

Example 25. Enantiomer A 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2Ε) -3- (2,5-difluorophenyl) -2-propenyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] - 1 - [(2Ε) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylate, the enantiomer A 3 - [3 - (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2Ε) -3- is obtained (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid as a solid.

Mass spectrum (ΣΕ): t / x = 500 (M ³ ); t / x = 153 (C ₉ H ₇ E ₂ ⁺ ) peak of the molecular ion.

IR Spectrum (KBr): 2965, 2936, 1621, 1591, 1504, 1491, 1423, 1230, 1117, 831, 743 and 728 cm ^-1 . | (/. | v / ° = -7.4 ° ± 0.6 ° [dichloromethane (c = 0.5), 589 nm]. Methyl - (. + -.) - 3- [3- (3-chloro-6- methoxy-4-quinolinyl) propyl] -1 - [(2Ε) -3- (2,5-difluorophenyl) -2-propenyl]

- 20 010403

3-pyrrolidinecarboxylate was prepared according to the method described in Example 1, but starting from 4-bromo-3-chloro-6-methoxyquinoline.

Mass spectrum (W): t / x = 515 (M ').

Example 26. Enantiomer B 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl - (.'-.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylate, the enantiomer B 3- [3 - (3-chloro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3 - is obtained (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid as a solid.

Mass spectrum (GE): t / x = 500 (M '); t / x = 153 (C ₉ H ₇ E ₂ ⁺ ) peak of the molecular ion.

IR Spectrum (KBr): 2965, 2936, 1621, 1591, 1504, 1491, 1423, 1230, 1117, 831, 743 and 728 cm ^-1 .

[a] _c ²⁰ = + 5.5 ° ± 0.5 ° [dichloromethane (c = 0.5), 589 nm].

Example 27. Enantiomer A 1- [3- (2,6-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,6-difluorobromobenzene, the enantiomer A 1- [3- (2,6-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) is obtained methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (W): t / x = 482 (M ⁺ ); t / x = 151 (C ₉ H ₅ E ₂ ⁺ ) peak molecular ion.

IR Spectrum (KBr): 2941, 1707, 1622, 1509, 1469, 1231, 1145, 1030, 1004, 830, 785 and 719 cm ^-1 .

[a] _c ²⁰ = -31 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

Example 28. Enantiomer B 1- [3- (2,6-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,6-difluorobromobenzene, the enantiomer B 1- [3- (2,6-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (W): t / x = 482 (M ⁺ ); t / x = 151 (C ₉ H ₅ E ₂ ⁺ ) peak molecular ion.

IR Spectrum (KBr): 2941, 1707, 1622, 1509, 1469, 1231, 1145, 1030, 1004, 830, 785 and 719 cm ^-1 .

[a] _c ²⁰ = + 31.7 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Example 29. Enantiomer A (levorotatory) 1- [2- (2,5-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2- (2,5-difluorophenoxy) ethyl] 3- [3- (3-fluoro-6-methoxy-4- quinolinyl) propyl] -3-pyrrolidine carboxylate, the enantiomer A (levorotatory) 1- [2- (2,5-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] is obtained] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) in the form of a white meringue.

[a] _c ²⁰ = -17.5 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2930, 1709, 1622, 1514, 1231, 1205, 1159, 1029, 832 and 793 cm ^-1 .

Mass spectrum (K. '): t / x = 489 (MH ⁺ ); peak molecular ion.

Methyl - (. + -.) - 1- [2- (2,5-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate may be obtained according to the procedure described in example 2, but starting from 2- (2 bromoethoxy) -1,4-difluorobenzene. A yellow oil is obtained.

Mass spectrum (W): t / x = 502 (M ⁺ ).

2- (2-Bromoethoxy) -1,4-difluorobenzene can be obtained according to the method described in international patent application VO 2002/40474-A2.

Example 30. Enantiomer B (dextrorotatory) 1- [2- (2,5-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2- (2,5-difluorophenoxy) ethyl] 3- [3- (3-fluoro-6-methoxy-4- quinolinyl) propyl] -3-pyrrolidine carboxylate, the enantiomer B (dextrorotatory) 1 - [2- (2,5-difluorophenoxy) ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] is obtained] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a white solid, melting at a temperature of 157 ° C.

[a] _c ²⁰ = + 22.6 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2930, 1709, 1622, 1514, 1231, 1205, 1159, 1029, 832 and 793 cm ^-1 .

Mass spectrum (W): t / h = 488 (M ⁺ ); 345 (MC ₇ H ₅ OE ₂ ) ⁺ (peak molecular ion).

Example 31. Enantiomer A (dextrorotatory) of the sodium salt of 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio ) ethyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) of the sodium salt of 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] - 3-pyrrolidinecarboxylic acid (absolute configuration not determined) in the form of a white solid, melting at a temperature in the range from 265 to 270 ° C.

- 21 010403 | α | ι / ° = + 7.1 ° ± 0.6 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2952, 2815, 1621, 1558, 1506, 1412, 1229, 1125, 1028, 828, 744 and 705 cm ^-1 .

Mass spectrum (E8) (electron sputter ionization): w / x = 491 (MH) ⁺ peak molecular ion. Methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3pyrrolidinecarboxylate can be prepared according to the procedure, described in example 2, but starting from 3chloro-4-bromo-6-methoxyquinoline and 2 - [(2-bromoethyl) thio] thiophene. A colorless oil is obtained.

Mass spectrum (1E): t / x = 504 (M ').

3-Chloro-4-bromo-6-methoxyquinoline can be obtained as described in international patent application UO 2002/40474-A2.

Example 32. Enantiomer B (levorotatory) of the sodium salt of 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio ) ethyl] -3-pyrrolidinecarboxylate, the enantiomer B (levorotatory) of the sodium salt of 3- [3 - (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2- (2-thienylthio) ethyl] - 3-pyrrolidinecarboxylic acid (absolute configuration not defined) in the form of a white solid, melting at a temperature in the range from 269 to 271 ° C.

[a] _c ²⁰ = -3.3 ° ± 0.5 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2952, 2815, 1621, 1558, 1506, 1412, 1229, 1125, 1028, 828, 744 and 705 cm ^-1 .

Mass spectrum (E8): t / x = 491 (MH) ⁺ peak molecular ion.

Example 33. Enantiomer A (dextrorotatory) 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2,5difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylic acid ( absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2, 5-difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2.5 -difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a white solid, melting at a temperature of 146 ° C.

[a] _c ²⁰ = + 25.8 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR spectrum (CH ₂ Cl ₂ ): 2940, 1732, 1622, 1504, 1484, 1230, 1188, 1119 and 834 cm ^-1 .

Mass spectrum (1C): t / x = 521 (MH) ⁺ peak of the molecular ion.

Methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- pyrrolidinecarboxylate can be obtained according to the procedure described in example 2, but starting from 3chloro-4-bromo-6-methoxyquinoline and 2 - [(2-bromoethyl) thio] -1,4-difluorobenzene. Get ocher color oil.

Mass spectrum (1E): t / x = 534 (M ').

Example 34. Enantiomer B (levorotatory) 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2,5difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylic acid ( absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2, 5-difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylate, the enantiomer B (levorotatory) 3- [3- (3-chloro-6-methoxy-4-quinolinyl) propyl] -1- [2 - [(2.5 -difluorophenyl) thio] ethyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a white solid, melting at a temperature of 146 ° C.

[a] _c ²⁰ = -20.4 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2953, 1707, 1620, 1504, 1483, 1231, 1188, 1118, 829 and 744 cm ^-1 .

Mass spectrum (1C): t / x = 521 (MH) ⁺ peak of the molecular ion.

Example 35. Enantiomer A 1 - [(2E) -3- (2,5-dichlorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -1,4-dichlorobenzene, the enantiomer A 1 - [(2E) -3- (2,5- dichlorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1E): t / x = 516 M '; t / x = 481 (M-C1) ⁺ peak molecular ion.

IR Spectrum (KBr): 2938, 1709, 1621, 1508, 1464, 1360, 1230, 1097, 1030, 969, 830, 811 and 785 cm ^-1 .

[a] _c ²⁰ = -21.2 ° ± 0.6 ° [methanol (c = 0.5), 589 nm].

Example 36. Enantiomer B 1 - [(2E) -3- (2,5-dichlorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -1,4-dichlorobenzene, the enantiomer B 1 - [(2E) -3- (2,5- dichlorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid melting at a temperature of 102 ° C .

Mass spectrum (1E): t / x = 516 M '; t / x = 481 (M-C1) ⁺ peak molecular ion.

IR Spectrum (KBr): 2938, 1709, 1621, 1508, 1464, 1360, 1230, 1097, 1030, 969, 830, 811 and 785 cm ^-1 .

- 22 010403 [a] _with ²⁰ = + 22 ° [methanol (c = 0.5), 589 nm].

Example 37. Enantiomer A of the sodium salt 1 - [(2E) -3- (3,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] - 3-pyrrolidinecarboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -3,5-difluorobenzene, the enantiomer A of the sodium salt 1 - [(2E) -3- (3, 5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1E): t / x = 484 M '; w / x = 153 (C ₉ H ₇ P ₂ ^{) +} peak molecular ion.

IR Spectrum (KBr): 2928, 1706, 1621, 1591, 1509, 1469, 1322, 1231, 1119, 1030, 984 and 831 cm ^-1 .

| (/. | ιΓ ° = -25.6 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Example 38. Enantiomer B 1 - [(2E) -3- (3,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -3,5-difluorobenzene, the enantiomer B 1 - [(2E) -3- (3,5- difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1E): t / x = 484 M ⁺ ; w / x = 153 (C ₉ H ₇ P ₂ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2928, 1706, 1621, 1591, 1509, 1469, 1322, 1231, 1119, 1030, 984 and 831 cm ^-1 . [a] _c ²⁰ = + 28.2 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Example 39. Enantiomer A 1- [3- (5-chloro-2-fluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2-fluoro-5-chloro-bromobenzene, the enantiomer A 1- [3- (5-chloro-2-fluorophenyl) -2-propynyl] -3- [3- (3- fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1C): w / x = 499 MN ⁺ peak of the molecular ion.

IR Spectrum (CC1 ₄ ): 2936, 1704, 1622, 1508, 1487, 1469, 1259, 1232, 1218 and 832 cm ^-1 . [a] _c ²⁰ = -27.3 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Example 40. Enantiomer B 1- [3- (5-chloro-2-fluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2-fluoro-5-chloro-bromobenzene, the enantiomer B 1- [3- (5-chloro-2-fluorophenyl) -2-propynyl] -3- [3- (3- fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1C): w / x = 499 MN ⁺ peak of the molecular ion.

IR Spectrum (KBr): 2942, 1707, 1621, 1509, 1486, 1469, 1260, 1231, 1145, 1085, 1030 and 830 cm ^-1 . [a] _c ²⁰ = + 29.6 ° ± 1 ° [methanol (c = 0.5), 589 nm].

Example 41. Enantiomer A of 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,6difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic hydrochloride acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -2,6-difluorobenzene, enantiomer A of 3- [3- (3-fluoro-6-methoxy hydrochloride) is obtained -4-quinolinyl) propyl] -1 - [(2E) -3- (2,6difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid melting at a temperature of 96 ° C.

Mass spectrum (1E): w / x = 484 M '; w / x = 153 (C ₉ H ₇ P ₂ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2942, 2459, 1715, 1621, 1509, 1468, 1361, 1266, 1232, 990, 830 and 782 cm ^-1 . [a] _c ²⁰ = -22.3 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Example 42. Enantiomer B 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (2,6-difluorophenyl) -2-propenyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from 2 - ((2E) -3-chloro-2-propenyl) -2,6-difluorobenzene, the enantiomer B 3- [3- (3-fluoro-6-methoxy- 4-quinolinyl) propyl] -1 - [(2E) -3- (2,6-difluorophenyl) 2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid melting at 88 ° C.

Mass spectrum (1C): w / x = 485 MH ⁺ peak molecular ion.

IR Spectrum (KBr): 2941, 1710, 1621, 1508, 1467, 1360, 1266, 1231, 1144, 989, 830 and 782 cm ^-1 . [a] _c ²⁰ = + 23.7 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

Example 43. Enantiomer A 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [3- (3,4,5-trifluorophenyl) -

2-propynyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

Following the procedure described in Example 23, but starting from 3,4,5-trifluorobromobenzene, the enantiomer A 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [3- (3 , 4,5-trifluorophenyl) -2-propynyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1E): t / h = 500 M ⁺ ; t / x = 169 (C ₉ H ₄ P ₃ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2944, 1709, 1621, 1612, 1528, 1429, 1232, 1048, 858 and 830 cm ^-1 . [a] _c ²⁰ = -17.5 ° ± 0.5 ° [methanol (c = 0.5), 589 nm].

- 23 010403

Example 44. Enantiomer B 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [3- (3.4.5-trifluorophenyl) 2-propynyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

Following the technique. described in example 23. but starting from 3.4.5-trifluorobromobenzene. the enantiomer of B 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1- [3- (3.4.5-trifluorophenyl) -2-propynyl] -3-pyrrolidinecarboxylic acid (absolute configuration is not defined) as a solid.

Mass spectrum (ΣΕ): t / x = 500 M '; t / x = 169 (C ₉ H ₄ E ₃ ) ⁺ peak molecular ion.

IR spectrum (KBr): 2944. 1709. 1621. 1612. 1528. 1429. 1232. 1048. 858 and 830 cm ^-1 .

[a] _c ²⁰ = + 16.8 ° ± 0.6 ° [methanol (c = 0.5). 589 nm].

Example 45. Enantiomer A 1 - [(2E) -3- (5-chloro-2-fluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the technique. described in Example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -2-fluoro-5-chlorobenzene. get enantiomer A 1 - [(2E) -3- (5-chloro-2-fluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid.

Mass spectrum (TS): t / x = 501 MN ⁺ peak molecular ion.

IR spectrum (CC1 ₄ ): 2936.1707. 1621. 1508. 1482. 1231. 1033. 972. 832 and 649 cm ^-1 .

[a] _c ²⁰ = -17.4 ° ± 0.6 ° [methanol (c = 0.5). 589 nm].

Example 46. Enantiomer B 1 - [(2E) -3- (5-chloro-2-fluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the technique. described in Example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -2-fluoro-5-chlorobenzene. get enantiomer of B 1 - [(2E) -3- (5-chloro-2-fluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid.

Mass spectrum (ΣΕ): t / x = 500 M ⁺ . t / x = 169 (C ₉ H ₇ C1E) ⁺ peak molecular ion.

IR spectrum (CC1 ₄ ): 2936.1707. 1621. 1508. 1482. 1231. 1033. 972. 832 and 649 cm ^-1 .

[a] _c ²⁰ = + 18.3 ° ± 0.6 ° [methanol (c = 0.5). 589 nm].

Example 47. Enantiomer A 1 - [(2E) -3- (2.3-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the technique. described in example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -2.3-difluorobenzene. get enantiomer A 1 - [(2E) -3- (2.3-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid.

Mass spectrum (TS): t / x = 485 MN ⁺ peak molecular ion.

IR spectrum (CC1 ₄ ): 2936. 1706. 1622. 1508. 1484. 1264. 1231. 1032. 973. 832 and 713 cm ^-1 .

[a] _c ²⁰ = -21.1 ° ± 0.6 ° [methanol (c = 0.5). 589 nm].

Example 48. Enantiomer B 1 - [(2E) -3- (2.3-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the technique. described in example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -2.3-difluorobenzene. get enantiomer B 1 - [(2E) -3- (2.3-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid.

Mass spectrum DE): t / h = 484 M ⁺ peak molecular ion; t / x = 153 (C ₉ H ₇ E ₂ ) ⁺ .

IR spectrum (CC1 ₄ ): 2936. 1706. 1622. 1508. 1484. 1264. 1231. 1032. 973. 832 and 713 cm ^-1 .

[a] _c ²⁰ = + 21.5 ° ± 0.7 ° [methanol (c = 0.5). 589 nm].

Example 49. Enantiomer A 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (3.4.5-trifluorophenyl) -2-propenyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the technique. described in Example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -3.4.5-trifluorobenzene. get enantiomer A 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (3.4.5-trifluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid. melting at a temperature of 110 ° C.

Mass spectrum DE): t / h = 502 M '; t / x = 171 (C ₉ H ₆ E ₃ ) ⁺ peak molecular ion.

IR spectrum (KBr): 2940. 1620. 1529. 1509. 1442. 1359. 1232. 1042. 970. 831 and 790 cm ^-1 .

[a] _c ²⁰ = + 28.1 ° ± 0.8 ° [methanol (c = 0.5). 589 nm].

Example 50. Enantiomer B 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (3.4.5-trifluorophenyl) -2-propenyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the technique. described in Example 3. but starting from 2 - ((2E) -3-chloro-2-propenyl) -3.4.5-trifluorobenzene. get the enantiomer of 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1 - [(2E) -3- (3.4.5-trifluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a solid. melting at a temperature of 148 ° C.

Mass spectrum DE): t / h = 502 M '; t / x = 171 (C ₉ H ₆ E ₃ ) ⁺ peak molecular ion.

IR spectrum (KBr): 2940. 1620. 1529. 1509. 1442. 1359. 1232. 1042. 970. 831 and 790 cm ^-1 .

- 24 010403 [α] π ²⁰ = -19.4 ° ± 0.6 ° [methanol (c = 0.5), 589 nm].

Example 51. Enantiomer A of 1- [3- (2,3-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,3-difluorobromobenzene, the enantiomer A 1 - [3 - (2,3-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1C): t / x = 483 MH ⁺ peak molecular ion.

IR Spectrum (KBr): 2941, 1706, 1621, 1584, 1509, 1489, 1473, 1231, 1146, 1030, 831, 784 and 716 cm ^-1 . [a] _c ²⁰ = -25.1 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Example 52. Enantiomer B 1- [3- (2,3-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,3-difluorobromobenzene, the enantiomer B 1- [3- (2,3-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (ΙΕ): t / x = 482 M '; w / x = 151 (C ₉ H ₅ E ₂ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2941, 1706, 1621, 1584, 1509, 1489, 1473, 1231, 1146, 1030, 831, 784 and 716 cm ^-1 . [a] _c ²⁰ = + 27.2 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Example 53. Enantiomer A 1- [3- (3,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 3,5-difluorobromobenzene, the enantiomer A 1- [3- (3,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (ΙΕ): t / h = 482 M ⁺ ; w / x = 151 (C ₉ H ₅ E ₂ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2937, 1708, 1619, 1586, 1509, 1470, 1430, 1231, 1122, 1030, 990, 857, 831 and 672 cm ^-1 . [a] _c ²⁰ = -19.4 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

Example 54. Enantiomer B 1- [3- (3,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 3,5-difluorobromobenzene, the enantiomer B 1- [3- (3,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (ΙΕ): w / x = 482 M ⁺ ; w / x = 151 (C ₉ H ₅ E ₂ ) ⁺ peak molecular ion.

IR Spectrum (KBr): 2937, 1708, 1619, 1586, 1509, 1470, 1430, 1231, 1122, 1030, 990, 857, 831 and 672 cm ^-1 . [a] _c ²⁰ = + 27.7 ° ± 1 ° [methanol (c = 0.5), 589 nm].

Example 55. Enantiomer A of 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,5-dichlorobromobenzene, the enantiomer A 1- [3- (2,5-difluorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1C): w / x = 515 MH ⁺ peak of the molecular ion.

IR Spectrum (KBr): 2928, 1709, 1621, 1509, 1468, 1231, 1096, 1031, 830, 786 and 600 cm ^-1 . [a] _c ²⁰ = -22.5 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Example 56. Enantiomer B 1- [3- (2,5-dichlorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined).

Following the procedure described in example 23, but starting from 2,5-dichlorobromobenzene, the enantiomer B 1- [3- (2,5-dichlorophenyl) -2-propynyl] -3- [3- (3-fluoro-6-) methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a solid.

Mass spectrum (1C): w / x = 515 MH ⁺ ; W / H = 287 (C1 ₇ H ₂₀ N ₂ OE) ⁺ peak molecular ion.

IR Spectrum (KBr): 2928, 1709, 1621, 1509, 1468, 1231, 1096, 1031, 830, 786 and 600 cm ^-1 . [a] _c ²⁰ = + 27.5 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Example 57. Enantiomer A (dextrorotatory) 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid, melting at a temperature of 106 ° C.

[a] _c ²⁰ = + 29.1 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2940, 1704, 1621, 1606, 1509, 1463, 1233, 1144, 990, 830 and 785 cm ^-1 .

Mass spectrum (ΙΕ): t / x = 504 (M '); 345 (M-C ₇ H ₅ E ₂ 8) ⁺ peak molecular ion.

Methyl - (. + -.) - 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidinecarboxylate can be obtained according to the procedure described in example 2, but starting from 2 - [(2

25 010403 bromoethyl) thio] -1,3-difluorobenzene. A pale yellow oil is obtained.

Mass spectrum (1E): w / x = 518 (M ').

2 - [(2-Bromethyl) thio] -1,3-difluorobenzene can be obtained by the method described in international patent application AO 2002/40474-A2.

Example 58. Enantiomer B (levorotatory) 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (levorotatory) 1- [2 - [(2,6-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid (absolute configuration not defined) in the form of a white solid, melting at a temperature of 86 ° C.

[a] _c ²⁰ = -29.3 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2940, 1704, 1621, 1606, 1509, 1463, 1233, 1144, 990, 830 and 785 cm ^-1 .

Mass spectrum (1C): t / x = 505 (MH ⁺ ) peak of the molecular ion.

Example 59. Enantiomer A (dextrorotatory) 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid, melting at a temperature of 79 ° C.

[a] _c ²⁰ = + 22.3 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2939, 1706, 1621, 1569, 1509, 1450, 1362, 1230, 1141, 1095, 1034, 830, 806 and 575 cm ^-1 . Mass spectrum (E8): t / x = 537 (MH ⁺ ) peak of the molecular ion.

Methyl - (. + -.) - 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylate can be obtained according to the procedure described in example 2, but starting from 2 - [(2 bromoethyl) thio] -1,4-dichlorobenzene. A pale yellow oil is obtained.

Mass spectrum (1E): t / x = 550 (M ⁺ ).

2 - [(2-Bromoethyl) thio] -1,4-dichlorobenzene can be obtained by the method described in international patent application AO 2002/40474-A2.

Example 60. Enantiomer B (levorotatory) 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (levorotatory) 1- [2 - [(2,5-dichlorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid, melting at a temperature of 67 ° C.

[a] _c ²⁰ = -22.6 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2939, 1706, 1621, 1569, 1509, 1450, 1362, 1230, 1141, 1095, 1034, 830, 806 and 575 cm ^-1 .

Mass spectrum (1C): tA = 537 (MH ⁺ ) peak of the molecular ion.

Examples 61 and 62. Diastereoisomers A (dextrorotatory) and C (levorotatory) of sodium salt

1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3pyrrolidinecarboxylic acid (absolute configuration not defined).

1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] 3-pyrrolidinecarboxylic acid ( a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in an amount of 0.370 g is introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of a fixed chiral phase of CH1KOV1OT1C TM particle size fraction of 10 μm. Elution is carried out using the mobile phase [H ₂ O-tetrahydrofuran-triethylamine-acetic acid (80: 15: 0.15: 0.05 by volume)] with a flow rate of 100 ml / min, detection is carried out using a UV detector at a wavelength 254 nm.

Diastereoisomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.150 g of a white powder. This powder is then purified using the same column, eluting with the mobile phase [methanol-triethylamine-acetic acid (100: 0.05: 0.05)] at a flow rate of 100 ml / min. Diastereoisomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo, getting 0,060 g of white meringue.

[a] _c ²⁰ = + 54.5 ° ± 1.2 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3428, 2959, 1622, 1591, 1509, 1491, 1429, 1355, 1231, 1148, 1029, 975, 830 and 728 cm ^-1 .

Mass spectrum (E8): t / x = 501 (MH) ⁺ .

Diastereoisomer C (levorotatory), the absolute configuration of which is not defined, eluting secondarily, is isolated, then concentrated in vacuo to obtain 0.080 g of white meringue.

- 26 010403 [α] _Β ²⁰ = -24.6 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3415, 2955, 1622, 1591, 1509, 1491, 1429, 1355, 1231, 1199, 1030, 975, 830 and 728 cm ^-1 . Mass spectrum (E8): ιη / ζ = 501 (ΜΗ) ⁺ .

1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -

3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) can be obtained according to the procedure described in examples 64 and 65, but starting from enantiomer A 1- (1,1-dimethylethyl) - and (3-methyl) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1,3-pyrrolidinedicarboxylate (absolute configuration not determined); get yellow oil.

Mass spectrum (ΙΕ): ιη / ζ = 500 (Μ ⁴ ).

Examples 63 and 64. Diastereoisomers B (levorotatory) and Ό (dextrorotatory) of 1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6) sodium salt -methoxy-4-quinolinyl) -3-hydroxypropyl] -3pyrrolidinecarboxylic acid (absolute configuration not determined).

Following the procedure described in examples 61 and 62, but starting from the sodium salt of 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3 - (3-fluoro-6-methoxy -4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration), the following is obtained.

Diastereoisomer B (levorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo, obtaining 0.130 g of white meringue.

[a] _c ²⁰ = -53.1 ° ± 1.0 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3414, 2938, 1622, 1591, 1509, 1491, 1429, 1354, 1230, 1198, 1029, 974, 830 and 728 cm ^-1 . Mass spectrum (E8): ιη / ζ = 501 (ΜΗ) ⁺ .

Diastereoisomer Ό (dextrorotatory), the absolute configuration of which is not defined, eluting in the second place, is isolated, then concentrated in vacuo, getting 0,100 g of white meringue.

[a] _c ²⁰ = + 24.8 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3397, 2958, 1622, 1591, 1509, 1491, 1429, 1355, 1230, 1199, 1029, 975, 831 and 728 cm ^-1 . Mass spectrum (E8): ιη / ζ = 501 (ΜΗ) ⁺ .

Sodium salt of 1 - [(2E) -3 - (2,5-difluorophenyl) -2-propenyl] -3- [3 - (3-fluoro-6-methoxy-4-quinolinyl) -3hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) can be obtained as follows.

To 0.56 g (1.088 mmol) methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) - 3-hydroxypropyl] -3-pyrrolidinecarboxylate (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in the form of a solution in 120 cm ^{3 of} dioxane at a temperature of about 20 ° C add 9.14 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 16 hours at the boil under reflux, the reaction mixture was cooled, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue which was treated with 50 cm ^{3 of} water. The pH is adjusted to about 7 by the addition of 1N. of hydrochloric acid. The aqueous phase was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 7 g of a residue, which was treated with 50 cm ^{3 of} methanol. Suspended No. 1C1 is filtered off. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.2 g of a pale yellow solid, which was purified by flash chromatography [eluent: dichloromethane-methanol (80:20 by volume) + 0.5% ΝΗ ₄ ΟΗ]. After concentration of the fractions under reduced pressure, 0.464 g of 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3 fluoro-6-methoxy-4-quinolinyl) - sodium salt is obtained 3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in the form of a pale yellow meringue.

Mass spectrum (1E): ιη / ζ = 522 (Μ ').

Methyl-1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3- pyrrolidine carboxylate (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) can be obtained as described in examples 71 and 72, but starting from enantiomer B 1 (1,1-dimethylethyl) - and methyl-3- [3- (3-fluoro -6-methoxy-4-quinolinyl) propyl] - 1,3-pyrrolidinedicarboxylate (absolute configuration not determined); get yellow oil, which hardens.

Mass spectrum (1E): ιη / ζ = 500 (Μ ').

Enantiomers A and B of 1- (1,1-dimethylethyl) - and methyl-3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1,3 pyrrolidinedicarboxylate (absolute configuration not determined) can be obtained in the following way.

2.55 g of 1- (1,1-dimethylethyl) - and methyl - (. + -.) - 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -1,3-pyrrolidinedicarboxylate injected into the column with a diameter of 8 cm and a length of 30 cm, containing 1200 g of the stationary chiral phase HUIEEK 88, 88 ΤΜ particle size fraction of 10 μm. Elution is carried out using the mobile phase [heptane / methyl tert-butyl ether / ethanol / triethylamine (76: 20: 2: 2: 0.1 by volume] with a flow rate of 140 ml / min; detection is carried out using a UV detector with a length of waves of 254 nm.

Enantiomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 1.15 g of a colorless oil.

- 27 010403 [α] _Β ²⁰ = + 23.6 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

Mass spectrum (ΙΕ): ιιιΖ / 460 (M ⁺ ); 359 (M-C5H9O2) ⁺ ; 57 (C4H ₉ ⁺ ).

Enantiomer B (levorotatory), the absolute configuration of which is not defined, eluting secondarily, is isolated, then concentrated in vacuo to obtain 1.25 g of a colorless oil.

[a] _c ²⁰ = -21.4 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Mass spectrum (ΙΕ): ιιιΖ / 460 (M ⁴ ); 359 (M-C5H9O2) ⁺ ; 57 (C4H ₉ ⁺ ).

Example 65. Enantiomer A (levorotatory) of the sodium salt 1- [3 - [(2,5-difluorophenyl) thio] propyl] 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [3 - [(2,5-difluorophenyl) thio] propyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (levorotatory) of the sodium salt of 1- [3 - [(2,5-difluorophenyl) thio] propyl] -3- [3- (3-fluoro-6) is obtained -methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not defined) as a white solid, melting at a temperature in the range from 110 to 113 ° C.

[a] _c ²⁰ = -17.8 ° ± 0.6 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2955, 1620, 1509, 1483, 1230, 1188, 1032, 908, 825, 810, 785 and 757 cm ^-1 .

Mass spectrum (1C): w / x = 519 (MH ⁺ ) peak of the molecular ion.

Methyl - (. + -.) - 1- [3 - [(2,5-difluorophenyl) thio] propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylate may be obtained according to the procedure described in example 2, but starting from 2 [(3-bromopropyl) thio] -1,4-difluorobenzene. An orange oil is obtained.

Mass spectrum (ΙΕ): w / x = 532 (M ³ ).

2 - [(3-Bromopropyl) thio] -1,4-difluorobenzene can be obtained by the method described in international patent application AO 2002/40474-A2.

Example 66. Enantiomer B (dextrorotatory) of sodium salt 1- [3 - [(2,5-difluorophenyl) thio] propyl] 3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3- pyrrolidine carboxylic acid (absolute configuration not determined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [3 - [(2,5-difluorophenyl) thio] propyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (dextrorotatory) of the sodium salt of 1- [3 - [(2,5-difluorophenyl) thio] propyl] -3- [3- (3-fluoro-6) is obtained -methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid, melting at a temperature in the range from 121 to 123 ° C.

[a] _c ²⁰ = + 18.8 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 2955, 1620, 1509, 1483, 1230, 1188, 1032, 908, 825, 810, 785 and 757 cm ^-1 .

Mass spectrum (Ε8): w / x = 519 (MH ⁺ ) peak of the molecular ion.

Example 67. 1- [2 - [(2-Pyridinyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined) .

Following the procedures described in examples 1 and 2, but starting from 2 - [(2-bromoethyl) thio] pyridine, an orange oil is obtained.

Mass spectrum (Ε8): t / x = 470 (MH ⁺ ) peak of the molecular ion.

2 - [(2-Bromoethyl) thio] pyridine can be obtained by the method described in international patent application AO 2002/40474-A2.

Example 68. Enantiomer A (dextrorotatory) 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer A (dextrorotatory) 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid.

[a] _c ²⁰ = + 28.5 ° ± 0.7 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2929, 1635, 1621, 1531, 1510, 1231, 1187, 1030, 830 and 786 cm ^-1 .

Mass spectrum (Ε8): t / x = 488 (MH ⁺ ) peak of the molecular ion.

Methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3pyrrolidinecarboxylate may be obtained as follows.

To 1.9 g (2.77 mmol) methyl-1- [2 - [(2,5-difluorophenyl) - [(2-nitrophenyl) sulfonyl] amino] ethyl] -3- [3- (3 fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate as a solution in 60 cm ^{3 of} dimethylformamide at a temperature of about 20 ° C and 1.65 cm ^{3 of} 1,8-diazabicyclo [5.4.0] undec- 7-ena (ΌΒυ) and 1.16 cm ³ mercaptoethanol. After stirring for 5 hours at a temperature of about 20 ° C, the reaction mixture was poured into 600 cm ^{3 of} water, then extracted 4 times with 200 cm ^{3 of} dichloromethane. The organic phases are combined, washed with 200 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.67 g of a yellow oil, which is purified by flash chromatography [eluent: dichloromethane-methanol (95: 5 by volume)]. After

- 28 010403 concentration of the fractions under reduced pressure gives 1.58 g of a yellow oil, which is again purified by flash chromatography [eluent: dichloromethane-ethyl acetate (9: 1 by volume)]. After concentration of the fractions under reduced pressure, 0.76 g of methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate as a pale yellow oil.

Mass spectrum (ΙΕ): t / x = 501 (M ⁴ ).

Methyl-1- [2 - [(2,5-difluorophenyl) - [(2-nitrophenyl) sulfonyl] amino] ethyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) propyl] -3- pyrrolidine carboxylate can be obtained according to the procedure described in example 2, but starting from M- (2-bromoethyl) -Y- (2,5-difluorophenyl) -2-nitrobenzenesulfonamide. A pale yellow oil is obtained.

Mass spectrum (1C): w / x = 687 (MH ⁺ ).

M- (2-Bromoethyl) -Y- (2,5-difluorophenyl) -2-nitrobenzenesulfonamide can be obtained by the method described in international patent application UO 2002/40474-A2.

Example 69. Enantiomer B (dextrorotatory) 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acids (absolute configuration is not defined).

Following the procedure described in example 3, but starting from methyl - (. + -.) - 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6- methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylate, the enantiomer B (dextrorotatory) 1- [2 - [(2,5-difluorophenyl) amino] ethyl] -3- [3- (3-fluoro-6-methoxy) is obtained -4-quinolinyl) propyl] -3pyrrolidinecarboxylic acid (absolute configuration not determined) as a white solid.

| (/. | ιΡ ° = -40.5 ° ± 0.9 ° [dichloromethane (c = 0.5), 589 nm].

IR Spectrum (KBr): 2929, 1635, 1621, 1531, 1510, 1231, 1187, 1030, 830 and 786 cm ^-1 .

Mass spectrum (Ε8): w / x = 488 (MH ⁺ ) peak of the molecular ion.

Examples 70 and 71. Diastereoisomers A (dextrorotatory) and C (levorotatory) 3- [3- (3-chloro-6methoxy-4-quinolinyl) -3-hydroxypropyl] - 1 - [(2E) -3- (2,5 -difluorophenyl) -2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

3- [3- (3-Chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -

3-pyrrolidine carboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in the amount of 0.367 g is introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of the stationary chiral phase of CH1KOV1OT1C TM particle size fraction of 10 μm. Elution is carried out using the mobile phase [H2O-tetrahydrofuran-triethylamine-acetic acid (80: 15: 0.1: 0.1 by volume)] with a flow rate of 90 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Diastereoisomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.161 g of a colorless oil.

[a] _c ²⁰ = + 63.7 ° ± 1.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (CH ₂ Cl ₂ ): 3593, 1718, 1621, 1503, 1491, 1421, 1355, 1231, 1185, 1117, 1068, 1036, 975 and 835 cm ^-1 . Mass spectrum (E8): w / x = 517 (MH) ⁺ .

Diastereoisomer C (levorotatory), the absolute configuration of which has not been determined, eluting in the second place, is isolated, then concentrated in vacuo to give 0.0137 g of a colorless oil.

[a] _c ²⁰ = negative sign in methanol [methanol (c = 0.5), 589 nm].

IR Spectrum (CH ₂ Cl ₂ ): 3587, 1723, 1621, 1503, 1491, 1421, 1355, 1231, 1117, 975, 897 and 836 cm ^-1 .

Mass spectrum (E8): w / x = 517 (MH) ⁺ .

3- [3- (3-Chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1- [3 - (2,5-difluorophenyl) -2-propenyl] -3 pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers A and With an unknown absolute configuration) can be obtained as follows.

To 0.51 g (1.165 mmol) of 3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3pyrrolidinecarboxylic acid dihydrochloride (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) as a solution 0.354 g of triethylamine, 0.74 g of sodium triacetoxyborohydride and a solution of 0.294 g of (E) -3- (2,5-difluorophenyl) propenal are added in 25 cm ^{3 of} dichloromethane at a temperature of about 20 ° C and in an argon atmosphere. After stirring for 2 hours at a temperature of about 20 ° C., the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.82 g of a residue, which was purified by flash chromatography [eluent: chloroform-methanol-28% aqueous IN ₄ OH solution (12: 2.25: 0.38 by volume)]. After concentration of the fractions under reduced pressure, 0.42 g of 3- [3- (3-chloro-6methoxy-4-quinolinyl) -3-hydroxypropyl] -1- [3- (2,5-difluorophenyl) -2-propenyl] is obtained -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) as a yellow oil.

Mass spectrum (1E): w / x = 516 (M ⁺ ).

3- [3- (3-Chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid dihydrochloride (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) can be obtained as follows.

- 29 010403

To 0.604 g (1.3 mmol) of 1,1-dimethylethyl-3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3pyrrolidinedicarboxylate (mixture of 2 diastereoisomers A and C of unspecified absolute configuration ) in the form of a solution in 20 cm ^{3 of} dioxane at a temperature of about 20 ° C add 16 cm ³ 4N. a solution of hydrogen chloride in dioxane. After stirring for 48 hours at a temperature of about 20 ° C., the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.64 g of a yellow solid, which was triturated with 10 cm ^{3 of} diethyl ether. After filtering off, the solid is washed with 10 cm ^{3 of} diethyl ether, then dried under reduced pressure (2.7 kPa) to obtain 0.6 g of 3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3- dihydrochloride hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) as a yellow solid.

Mass spectrum (1E): ιη / ζ = 437 (M ').

1- (1,1 - Dimethylethyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] - 1,3-pyrrolidinedicarboxylate (mixture of 2 diastereoisomers A and C of unspecified absolute configuration) can be obtained as follows.

Into a solution of 2.3 g (5.12 mmol) of enantiomer A 1- (1,1-dimethylethyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1, 3-pyrrolidinedicarboxylate (absolute configuration not determined) in 185 cm ^{3 of} dimethyl sulfoxide at a temperature of about 20 ° C. Oxygen is bubbled for 20 minutes until saturation. 1.32 g (11.78 mmol) of potassium tert-butylate are then added as a solution in 84 ml of tert-butanol. Oxygen is again bubbled for 5 hours. The reaction mixture is cooled to a temperature of about 0 ° C. 540 cm ^{3 of} water are added dropwise, maintaining the temperature at about 20 ° C, the pH is adjusted to 5-6 by adding 1.5 cm ^{3 of} acetic acid, after which 250 cm ^{3 of} water are added. The reaction mixture was extracted 4 times with 250 cm ^{3 of} dichloromethane. The organic phases are combined, washed with 250 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.14 g of a yellow oil, which is treated with 40 cm ^{3 of} diethyl ether. The ether phase is washed 2 times with 20 cm ^{3 of} water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 1.27 g of 1- (1,1-dimethylethyl) -3- [3 - (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1,3-pyrrolidinedicarboxylate (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in the form of a pale yellow meringue.

Mass spectrum (1E): ιη / ζ = 464 (M ').

Enantiomer A 1- (1,1-dimethylethyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1,3 pyrrolidinedicarboxylate (absolute configuration not determined) can be obtained as follows .

K 2.78 g (6 mmol) of enantiomer A 1- (1,1-dimethylethyl) - and (3-methyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl ] -1,3-pyrrolidinedicarboxylate (absolute configuration not determined) in the form of a solution in 230 cm ^{3 of} dioxane at a temperature of about 20 ° C add 50 cm ³ 5N. an aqueous solution of sodium hydroxide. After stirring for 18 hours at the boil under reflux, the reaction mixture was cooled, then concentrated to dryness under reduced pressure (2.7 kPa) to obtain a residue, which was treated with 700 cm ^{3 of} water. The pH is adjusted to about 4 by the addition of citric acid. After 4 hours at a temperature of about 20 ° C, the suspension is filtered, the solid is washed 3 times with 50 cm ^{3 of} diisopropyl ether, then dried under reduced pressure (2.7 kPa) at a temperature of about 43 ° C to obtain 2.3 g enantiomer A of 1- (1,1-dimethylethyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] - 1,3-pyrrolidinedicarboxylate (absolute configuration not determined) as a solid white matter.

Mass spectrum (1E): ιη / ζ = 448 (M ').

Enantiomers A and B of 1- (1,1-dimethylethyl) - and (3-methyl) -3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1,3-pyrrolidinedicarboxylate (absolute configuration not defined) can be obtained as follows.

1- (1,1-Dimethylethyl) - and (3-methyl) - (. + -.) - 3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1, 2. Pyrrolidine dicarboxylate in an amount of 2.55 g is introduced into a column with a diameter of 6 cm and a length of 30 cm, containing 800 g of the stationary chiral phase of PHNEK O1, 88 TM particle size fraction of 10 μm. Elution is carried out using the mobile phase [heptane / methyl tert-butyl ether / methanol / isopropanol / triethylamine (74: 20: 1: 4: 0.1 by volume)] with a flow rate of 120 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Enantiomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.46 g of a colorless oil.

Mass spectrum (1E): μ / ζ = 462 (M '); 361 (M-C ₅ H ₉ O ₂ ) ⁺ , 57 (C ₄ H ₉ ⁺ ).

[a] _c ²⁰ = + 18.8 ° ± 0.6 ° [methanol (c = 0.5), 589 nm].

Enantiomer B (levorotatory), the absolute configuration of which is not defined, eluting secondarily, is isolated, then concentrated in vacuo to give 0.217 g of a colorless oil.

[a] _c ²⁰ = -18.4 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

Mass spectrum (E8): μ / ζ = 462 (M '); 361 (M-C ₅ H ₉ O ₂ ) ⁺ , 57 (C ₄ H ₉ ⁺ ).

- 30 010403

Examples 72 and 73. Diastereoisomers B (levorotatory) and Ό (dextrorotatory) 3- [3- (3-chloro-6methoxy-4-quinolinyl) -3-hydroxypropyl] -1- [3- (2,5-difluorophenyl) - 2-propenyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

Following the procedure described in examples 70 and 71, but starting from 3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1- [3- (2,5-difluorophenyl) - 2-propenyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers Β and Ό of unknown absolute configuration), the following is obtained.

Diastereoisomer B (levorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.192 g of a colorless oil.

[a] _c ²⁰ = -68.3 ° ± 0.9 ° [methanol (c = 0.5), 589 nm];

[a] _c ²⁰ = -48.3 ° ± 0.9 ° [dimethyl sulfoxide (c = 0.5), 589 nm].

IR spectrum (KBr): 3431, 1621, 1503, 1491, 1231, 1117, 977 and 728 cm ^-1 .

Mass spectrum (E8): t / x = 517 (MH) ⁺ .

Diastereoisomer Ό (dextrorotatory), the absolute configuration of which is not defined, eluted in the second place, is isolated, then concentrated in vacuo, getting 0.198 g of a colorless oil.

[a] _c ²⁰ = + 11.8 ° ± 0.8 ° [dimethyl sulfoxide (c = 0.5), 589 nm].

IR Spectrum (KBr): 3401, 1715, 1621, 1503, 1491, 1456, 1231, 1116, 973, 832 and 728 cm ^-1 .

Mass spectrum (E8): t / x = 517 (MH) ⁺ .

3- [3- (3-Chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] - 1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -

3- pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers B and Ό of an unknown absolute configuration) can be obtained as described in examples 71 and 72, but starting from enantiomer B 1 (1,1-dimethylethyl) - and (3-methyl) -3- [3- (3-Chloro-6-methoxy-4-quinolinyl) propyl] - 1,3-pyrrolidinecarboxylate (absolute configuration not determined); get a beige meringue.

Mass spectrum DE): t / x = 516 (M ⁴ ).

Examples 74 and 75. Diastereoisomers A (dextrorotatory) and C (levorotatory) 1- [3- (2,5-difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3 -hydroxypropyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

1- [3- (2,5-Difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers A and C unknown absolute configuration) in an amount of 230 g is introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of a stationary chiral phase of SCHKOVYUIS TM with a granulometry of 10 μm. Elution is carried out using the mobile phase [H ₂ O-tetrahydrofuran-triethylamine-acetic acid (80: 20: 0.1: 0.1 by volume)] with a flow rate of 100 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Diastereoisomer A (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo to obtain 0.072 g of white meringue.

[a] _c ²⁰ = + 48.9 ° ± 1.0 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3414, 2927, 2856, 1715, 1622, 1598, 1497, 1427, 1355, 1263, 1231, 1198, 1142, 1030, 831, 813 and 789 cm ^-1 .

Mass spectrum (TE): t // = 502 (M ⁴ ); 361 (M-C8H7P2) ⁺ ; 343 (361-H2O) ⁺ .

Diastereoisomer C (levorotatory), the absolute configuration of which is not defined, eluting in the second place, is isolated, then concentrated in vacuo, getting 0,052 g of white meringue.

[a] _c ²⁰ = -24.0 ° ± 0.8 ° [methanol (c = 0.5), 589 nm].

IR (KBr): 3420, 2958, 1717, 1622, 1598, 1497, 1427, 1355, 1263, 1231, 1198, 1142, 1031, 831, 812 and 789 cm ^-1 .

Mass spectrum DE): t //. 502 (M ⁴ ); 361 (M-C8H7P2) ⁺ ; 343 (361-H2O) ⁺ .

1- [3- (2,5-Difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers A and C unknown absolute configuration) can be obtained as follows.

To 0.03 g of 10% palladium-on-charcoal at room temperature and in an argon atmosphere add 25 cm ^{3 of} methanol and 0.3 g (0.6 mmol) 1 - [(2E) -3- (2.5 -difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereomers A and C of an unknown absolute configuration). The reaction medium is purged with argon 5 times, then hydrogenated with hydrogen pressure of 2 bar at room temperature for 24 hours. The catalyst is filtered off on Celite, celite is washed 3 times with 25 cm ^{3 of} methanol, then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) yielding 0.26 g of 1- [3- (2,5-difluorophenyl) -2-propyl] -3- [3- (3-fluoro-6-methoxy-

4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers A and C of an unknown absolute configuration) as a yellow lacquer.

Mass spectrum DE): t / h = 502 (M ⁴ ).

Examples 76 and 77. Diastereoisomers B (levorotatory) and Ό (dextrorotatory) 1- [3- (2,5-difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3 -hydroxypropyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

1- [3- (2,5-Difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrro

- 31 010403 lidine carboxylic acid (a mixture of 2 diastereoisomers B and Ό of unknown absolute configuration) in an amount of 0.600 g is introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of a stationary chiral phase of CH1KOV1OT1C TM particle size fraction of 10 μm. Elution is carried out using the mobile phase [H2O-tetrahydrofuran-triethylamine-acetic acid (80: 20: 0.1: 0.1 by volume)] with a flow rate of 100 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Diastereoisomer Ό (levorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo, then crystallized in the presence of water to obtain 0.472 g of a white powder.

[a] _with ^2C1 = negative sign in dimethyl sulfoxide [dimethyl sulfoxide (c = 0.5), 589 nm].

IR Spectrum (KBr): 3431, 2950, 1622, 1510, 1497, 1459, 1427, 1355, 1266, 1242, 1230, 1187, 1144, 1080, 1031, 832 and 817 cm ^-1 .

Mass spectrum (1E): 111 //. 502 (M ⁺ ); 361 (M-C8H7E2) ⁺ ; 343 (361-H2O) ⁺ .

Diastereoisomer Ό (dextrorotatory), the absolute configuration of which is not defined, eluting in the second place, is isolated, then concentrated in vacuo, then crystallized in the presence of water, getting 0.113 g of a white powder.

[a] _c ²⁰ = positive sign in dimethyl sulfoxide [dimethyl sulfoxide (c = 0.5), 589 nm].

IR Spectrum (KBr): 3418, 2953, 1622, 1593, 1509, 1497, 1467, 1427, 1384, 1355, 1266, 1231, 1197, 1142, 1069, 831 and 813 cm ^-1 .

Mass spectrum (1E): 111 //. 502 (M ⁺ ); 361 (M-C8H7E2) ⁺ ; 343 (361-H2O) ⁺ .

1- [3 - (2,5-Difluorophenyl) propyl] -3- [3 - (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers B and Ό unknown absolute configuration) can be obtained as follows.

To 0.15 g of 10% palladium-on-charcoal at room temperature and in an argon atmosphere, 125 cm ^{3 of} methanol and 1.5 g (3 mmol) of 1 - [(2E) -3- (2,5-difluorophenyl) are added ) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers B and Ό of unknown absolute configuration). The reaction medium is purged with argon 5 times, then hydrogenated at 2 bar hydrogen pressure at room temperature for 24 hours. The catalyst is filtered off on Celite, the celite is washed 3 times with 100 cm ^{3 of} methanol, then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) yielding 1.31 g of 1- [3- (2,5-difluorophenyl) -2-propyl] -3- [3- (3-fluoro-6methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers B and Ό of an unknown absolute configuration) in the form of a beige meringue.

Mass spectrum (1E): w / x = 502 (M ⁺ ).

Examples 78 and 79. Diastereoisomers A (levorotatory) and C (dextrorotatory) 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl ) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

1- [2 - [(2,5-Difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers A and C of an unknown absolute configuration) in an amount of 0.170 g are introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of the stationary chiral phase CH1KOV1OT1C TM with a particle size of 10 μm. Elution is carried out using the mobile phase [H ₂ O-tetrahydrsfuran-triethylamine-acetic acid (80: 20: 0.1: 0.1 by volume)] with a flow rate of 100 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Diastereoisomer A (levorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo, then crystallized in the presence of water, obtaining 0.057 g of white meringue.

[a] _c ²⁰ = -45.6 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

IR spectrum (KBr): 3415, 1717, 1622, 1509, 1484, 1355, 1262, 1231, 1187, 1082, 1060, 1030, 908, 830,

804 and 757 cm ^-1 .

Mass spectrum (1C): t // = 521 (MH) ⁺ ; 503 (MH ⁺ —H ₂ O).

Diastereoisomer C (dextrorotatory), the absolute configuration of which is not defined, eluting secondarily, is isolated, then concentrated in vacuo, then crystallized in the presence of water, getting 0.059 g of white meringue.

[a] _c ²⁰ = + 19.9 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR (KBr): 3409, 1716, 1622, 1509, 1484, 1355, 1262, 1231, 1188, 1081, 1060, 1030, 908, 830,

805 and 757 cm ^-1 .

Mass spectrum (1C): t // = 521 (MH) ⁺ ; 503 (MH ⁺ —H ₂ O).

1- [2 - [(2,5-Difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers A and C of an unknown absolute configuration) can be obtained as described in Examples 70 and 71, but starting from the enantiomer B 1- [2 - [(2,5difluorophenyl) thio] ethyl] -3- [3- (3-fluoro -6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarbono

- 32 010403 howling acid; a beige solid is obtained.

Mass spectrum (ΙΕ): t / 7 = 520 (M ⁺ ).

Examples 80 and 81. Diastereoisomer B (dextrorotatory) and Ό (levorotatory) 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl ) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (absolute configuration not determined).

1- [2 - [(2,5-Difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid (mixture of 2 diastereoisomers B and Ό of an unknown absolute configuration) in an amount of 0.100 g is introduced into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of a stationary chiral phase of CH1KOV1OT1C TM particle size fraction of 10 μm. Elution is carried out using the mobile phase [H ₂ O-tetrahydrofuran-triethylamine-acetic acid (80: 20: 0.1: 0.1 by volume)] with a flow rate of 100 ml / min; detection is carried out using a UV detector at a wavelength of 254 nm.

Diastereoisomer B (dextrorotatory), the absolute configuration of which is not defined, eluting first, is isolated, then concentrated in vacuo, then crystallized in the presence of water, obtaining 0.057 g of white meringue.

[α] _ο ²⁰ = + 42.3 ° ± 0.9 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3414, 1717, 1622, 1509, 1484, 1356, 1261, 1231, 1188, 1082, 1060, 1027, 908, 861, 805 and 757 cm ^-1 .

Mass spectrum (ΙΕ): m ^ = 520 (M) ⁺ ; 361 (M-S7H58G2) ⁺ ; 343 (361-H2O) ⁺ .

Diastereoisomer Ό (levorotatory), the absolute configuration of which is not defined, eluting in the second place, is isolated, then concentrated in vacuo, then crystallized in the presence of water, getting 0.059 g of white meringue.

[α] _ο ²⁰ = -20.5 ° ± 0.7 ° [methanol (c = 0.5), 589 nm].

IR Spectrum (KBr): 3414, 1717, 1622, 1509, 1484, 1355, 1261, 1231, 1188, 1082, 1028, 908, 804 and 757 cm ^-1 .

Mass spectrum (1C): m ^ = 520 (M) ⁺ ; 361 (M-S7H58G2) ⁺ ; 343 (361-H2O) ⁺ .

1- [2 - [(2,5-Difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) propyl] -3-pyrrolidinecarboxylic acid (a mixture of 2 diastereoisomers B and Ό unknown absolute configuration) can be obtained as described in examples 70 and 71, but starting from the enantiomer A 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro- 6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3-pyrrolidinecarboxylic acid; a beige solid is obtained.

Mass spectrum (ΙΕ): t / 7 = 520 (M ⁺ ).

Claims (14)

CLAIM 1. A derivative of 4-substituted quinoline, characterized in that it corresponds to the general formula (Ι) Υ < ^CH 0p - ( ^CH g) _t N-- ' ^K 2 in which X !, X ₂ , X ₃ , X4 and X ₅ take values, respectively, from>C-C' ₁ to> C-C '₅; TO! means (C1-C1 ₀ ) alkyloxy; Κ'ι, K ' ₂ , K' ₃ and K ' ₄ means a hydrogen atom; To ' ₅ means a hydrogen atom or halogen; t is 2; η is 0, 1 or 2; Υ means a group of SNK or SCON, and K means a hydrogen atom; Ζ means a CH ₂ group, in which case η is 0 or 1, or Ζ means an oxygen atom, and in this case η is 2; K ₂ means a radical —CO ₂ K, and K means a hydrogen atom or (C 1 -C ₆ ) alkyl; K ₃ means akk-K ° ₃ radical, in which ak means (C1-C0 ₀ ) alkylene radical and K ° ₃ means a phenoxy group, phenylthio group, phenylamino group, 5- or 6-membered heteroarylthio group, containing 8 or Ν as a heteroatom; or K ° ₃ means -SC ' _b = CK' _with -K ' _a , where K' _a means phenyl, K ' _b and K' _s mean hydrogen atoms, or K ° ₃ means -C ^ C-Cz, where it means phenyl , moreover, these phenyl radicals are substituted by 2-3 halogen atoms; in its enantiomeric or diastereoisomeric forms, or as mixtures of these forms, and / or, if carried - 33 010403 can be, in syn- or anti-form, or in the form of their mixtures, as well as its salts. 2. A derivative of general formula (I) according to claim 1, characterized in that X ₁ , X ₂ , X ₃ , X ₄ and X ₅ have the meanings indicated in item 1; TO! means (C1-C _{! 0} ) alkyloxy; K'1, K'2 and K'4 mean a hydrogen atom; K'5 means a hydrogen atom or halogen, Υ means the radical CH ₂ , CHOH; η has the meaning specified in claim 1; Ζ means a CH ₂ group and η is 0 or 1, or Ζ is an oxygen atom, and in this case η is 2; K ₂ means a radical —CO ₂ K, and K means a hydrogen atom or (C 1 -C ₆ ) alkyl; and K ₃ means akk-K ° ₃ radical, in which ak means (C1-C0 ₀ ) alkylene radical and K ° ₃ means a phenoxy group, phenylthio group, phenylamino group, heteroarylthio group as defined in claim 1; or K ° ₃ means -SC ' _b = CK' _with -K ' _a , where K' _a means phenyl and where K ' _b and K' _c mean hydrogen atoms; or K ° ₃ means -C ^ C-K * where Κι means phenyl, bearing in mind that the above-mentioned phenyl radicals are possibly substituted, as discussed in item 1; in its enantiomeric or diastereoisomeric forms, or as mixtures of these forms, and / or, if possible, in syn- or antiform, or as mixtures thereof, as well as its salt. 3. A derivative of general formula (I) according to claim 1, characterized in that X1, X ₂ , X ₃ , X ₄ and X ₅ mean, respectively, from> C-K \ to> C-C '₅; K1 means (C1-C1 ₀ ) alkyloxy; K'1, R _'2 and R' ₄ represent a hydrogen atom; K'5 means a hydrogen atom or halogen, Υ means the radical CH2, CHOH; η has the meaning specified in claim 1; Ζ means CH2 group and η is 0 or 1, or Ζ means oxygen atom, and in this case η is 2; K ₂ has the meaning indicated in paragraph 2; and K ₃ means the radical a1k-K ° ₃ , in which a1k means (C1-C1 ₀ ) alkylene radical and K ° ₃ means a phenoxy group, a phenylthio group, a heteroarylthio group as defined in claim 1; or By means -rm ° ₃ '= CR _{b' c} -R _'a wherein R' _a is phenyl, and wherein R _'b and R' _c are hydrogen atoms; or K ° ₃ means the radical-C = C-K * in which K ₄ means phenyl; bearing in mind that the aforementioned phenyl radicals are possibly substituted, as discussed in paragraph 1; in its enantiomeric or diastereoisomeric forms, or as mixtures of these forms, and / or, if possible, in syn- or antiform, or as mixtures thereof, as well as its salt. 4. A derivative of general formula (I) according to claim 1, selected from those having the following names: 1 - [(E) -3- (2,5-difluorophenyl) propenyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1 - [(Ε) -3- (2,5-difluorophenyl) propenyl] -3- [3-hydroxy (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1- [2- (2,5-difluorophenylsulfanyl) ethyl] -3- [3 - (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1- [2- (2,5-difluorophenoxy) ethyl] -3- [3 - (3-fluoro-6-methoxy-quinolin-4-yl) propyl] pyrrolidin-3 carboxylic acid; 1- [2- (2-thienylthio) ethyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1 - [(E) -3- (2,5-difluorophenyl) propenyl] -3- [3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] azetidine-3carboxylic acid; 1 - [(Ε) -3- (2,5-difluorophenyl) propenyl] -3- [3- (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1 - [(Ε) -3- (2,5-difluorophenyl) propenyl] -3- [3-hydroxy (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1- [2- (2,5-difluorophenylsulfanyl) ethyl] -3- [3- (3-chloro-6-methoxy-quinolin-4-yl) propyl] pyrrolidine-3-carboxylic acid; 1- [2- (thiophen-2-ylsulfanyl) ethyl] -3- [3 - (3-chloro-6-methoxyquinolin-4-yl) propyl] pyrrolidine-3 carboxylic acid; 1 - [(2Ε) -3- (2,5-difluorophenyl) -2-propenyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] 3-pyrrolidinecarboxylic acid; 3- [3- (3-chloro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -1 - [(2Ε) -3- (2,5-difluorophenyl) -2-propenyl] 3-pyrrolidinecarboxylic acid; 1- [3- (2,5-difluorophenyl) propyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3 pyrrolidinecarboxylic acid; 1- [2 - [(2,5-difluorophenyl) thio] ethyl] -3- [3- (3-fluoro-6-methoxy-4-quinolinyl) -3-hydroxypropyl] -3 - 34 010403 pyrrolidinecarboxylic acid; in its enantiomeric or diastereoisomeric forms, or as mixtures of these forms, and / or, if necessary, in syn- or anti-form, or as mixtures thereof, as well as its salt. 5. The method of obtaining derivatives of general formula (I) specified in claim 1, characterized in that the chain K ₃ , as defined in claim 1, is introduced into a condensation reaction with a 4-substituted quinoline derivative of general formula (II) in which X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , K ₁ , K ₂ , Υ, Ζ, t and n have the meanings indicated in item 1, and K ₂ is protected by methyl, benzyl, tert-butyl, phenylpropyl or propenyl, when it contains a carboxy group, then, if necessary, remove the protective group from the carboxy group, if necessary, separate the enantiomeric or diastereoisomeric forms and / or , If necessary, sinili antiform and, if necessary, converting the product obtained into a salt. 6. The method according to claim 5, characterized in that the condensation reaction of the chain K ₃ with a heterocyclic nitrogen atom is carried out, acting derivative of the general formula (PA) K ₃ -X (Pa) in which K ₃ has the meaning indicated in claim 1 and X represents a halogen atom, methylsulfonyl, trifluoromethylsulfonyl or p-toluenesulfonyl. 7. The method according to any of paragraphs.5 and 6, characterized in that when K ₃ means the radical -a1k-K ° ₃ , in which a1k means (C1 _- 1 ₀ ) alkyl and K ° ₃ means the radical -C = C -Ka, in which it has the meaning indicated in claim 1, the reaction is carried out by condensation of an alkynyl halide of the formula HC = C-a1k-X, in which a1k has the above value and X represents a halogen atom, then replacing the chain with the appropriate radical K _a . 8. The method according to any of paragraphs.5 and 6, characterized in that when K ₃ means the radical -a1k-K ° ₃ , in which a1k means (C1 _- w) alkyl and K ° ₃ means a phenoxy group, phenylthio group, phenylamino group or the heteroarylthio group is reacted by chain design, first condensing the HOa1k-X chain, in which X means a halogen atom, then either turning the resulting hydroxyalkyl chain into a haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl chain, and finally, acting in an alkaline medium with an aromatic derivative of the K ° structure 3N silt K ° 3H2, or directly the action Vuia aromatic derivatives in the conditions of the dehydration. 9. The method according to claim 5, characterized in that the derivatives of general formula (II), in which Υ means a group of SNA, are obtained by the condensation reaction of a heteroaromatic derivative of general formula (III) Na1 in which K _1, X 1, X _2, X _3, X ₄ and X ₅ are _as defined in claim 1 and na1 represents a halogen atom, with a derivative of general formula (IV) wherein P is a protecting group selected from tert butoxycarbonyl or benzyloxycarbonyl, and K, Ζ, t, n, and K ₂ have the meanings indicated in item 1, followed by removal of the protective groups and / or subsequent transformation, by subsequent operation, thus obtained substituents of the aromatic bicycle of general formula (II) to obtain a derivative containing the expected radical R _1, R _'1, R' _2, R _'3, R' _4, R _'5, and, in cases e necessary, followed by removal of the protective radical or protective radicals still present in the molecule. 10. The method according to claim 9, characterized in that the derivatives of general formula (IV), in which K, Ζ, P, K ₂ and p have the values indicated in paragraph 9 and m is 2, are obtained by a condensation reaction with a derivative - 35 010403 of the formula (V) in which η, Ζ and K ₂ have the meanings indicated in paragraph 1 and P has the meaning indicated in paragraph 10, of the product of general formula (VI) H1- (CH ₂ ) t_1-CH = CHK (VI) in which H1 means a halogen atom and m and K have the meanings indicated in item 1. 11. Derivatives of the general formula (II) in which Χι, X ₂ , X ₃ , X ₄ , X ₅ , Κι, K ₂ , Υ, Ζ, t and η have the meanings indicated in item 1, and K ₂ is protected by methyl, benzyl, t-butyl, phenylpropyl or propenyl when it contains a carboxy group. 12. Derivatives of general formula (IV) in which P represents a protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl; t is 2; η is 0, 1 or 2; K represents a hydrogen atom or (C1- _C6 ) alkyl; Ζ means a CH ₂ group, in which case η is 0 or 1, or Ζ means an oxygen atom, and in this case η is 2; and K ₂ has the values indicated in paragraph 1. 13. The use of derivatives according to any one of claims 1 to 4 of general formula (I), such as indicated in claim 1, as medicaments for the treatment of bacterial infections. 14. A pharmaceutical composition for the treatment of bacterial infections, characterized in that it contains at least one derivative according to claim 1, in a pure state or as an association with one or more compatible and pharmaceutically acceptable diluents and / or additives.