EA010601B1 - Quinoline derivatives as antibacterial agents - Google Patents

Abstract

The present invention relates to the use of a compound for the manufacture of a medicament for the treatment of a bacterial infection said compound being a compound of Formulaa pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or N-oxide form thereof, Ris hydrogen, halo, polyhaloCalkyl, Calkyl, Ar or Net; p is 1, 2 or 3; Ris Calkyloxy, Calkyloxy Calkyloxy or Calkylthio; Ris Ar, Het or Het; or Rand Rmay be taken together including the N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings optionally being substituted with Calkyl, halo, polyhalo Calkyl, hydroxy, hydroxy Calkyl, Calkyloxy, amino, mono- or di(Calkyl)amino, Calkylthio, Calkyloxy Calkyl, Calkylthio Calkyl or pyrimidinyl; Ris hydrogen, halo, polyhalo Calkyl, Calkyl, Calkyloxy, Calkylthio or two vicinal radicals of formula –CH=CH=-CH=CH-; r is 1 or 2; Ris hydrogen, Calkyl, Ar, Het or Net; provided that the bacterial infection is other than a Mycobacterial infection.

Description

The present invention relates to the use of quinoline derivatives for the manufacture of a medicament for the treatment of a bacterial infection.

The current problem is resistance to first-line antibiotic agents. Some important examples include penicillin-resistant 8! Ger! Ossossi5 resistant, vancomycin-resistant enterococci, methicillin-resistant 8! Gerossossi5 igeeik, multi-resistant salmonella.

Resistance to antibiotic agents is a serious problem. Infections caused by resistant germs are not treatable, which leads to a prolonged illness and a higher risk of death. Failures in treatment also lead to longer periods of infectivity, which increases the number of infected people in society and, thus, exposing the general population to the risk of getting the infection with a resistant strain. Hospitals are a critical component of the antimicrobial resistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged use of antimicrobial agents and cross-infection led to infections with highly resistant bacterial pathogens.

Antimicrobial self-medication is another major contributor to resistance. Antimicrobial self-medication may be unnecessary, often inadequately dosed, or may not contain adequate amounts of the active drug.

Patient adherence to recommended treatment is another major problem. Patients forget to take treatment, interrupt their treatment when they begin to feel better, or may not be able to afford the full course of treatment, resulting in an ideal environment for the adaptation of microbes, and not their destruction.

Due to the emerging resistance to many antibiotics, doctors resist infections for which there is no effective therapy. The morbidity, mortality and cost aspects of such infectious diseases are raising costs for the health care system.

Thus, there is a great need for new compounds for treating bacterial infections, especially for treating infections caused by resistant strains.

In \ νϋ 2004/011436, substituted quinoline derivatives are described which have activity against mycobacteria, in particular against Mycobacterium viridis biloba. One particular compound of these substituted quinoline derivatives is described in Zaeps (2005), 307, 223-227.

It has now been found that the quinoline derivatives described in νθ 2004/011436 also show activity against bacteria other than mycobacteria.

Thus, the present invention relates to the use of a compound for the manufacture of a medicament for the treatment of a bacterial infection, said compound being a compound of the formula

its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric or Ν-oxide form, where

V ¹ represents hydrogen, halogen, poligaloS1 _-6 alkyl, C1 _-6 alkyl, Ar or He !;

p is an integer equal to 1 or 2;

B ² represents _C1-6 alkyloxy, _C1-6 alkyloxy _C1-6 alkyloxy or _C1-6 alkylthio;

In ³ represents Ar, Not! Or no! ¹ ;

B ⁴ and B ⁵ are each independently hydrogen, C _1-6 alkyl or benzyl, or

B ⁴ and B ⁵ together with the Ν atom to which they are attached can form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may optionally be substituted with C _1-6 alkyl, halo, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkylthioC _1-6 alkyl or pyrimidinyl;

B ⁶ represents hydrogen, halogen, polyhaloC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio or two vicinal radicals B ⁶ can be taken together with the formation of a divalent radical of the formula —CH═CH -CH = CH-;

- 1 010601 g is an integer equal to 1 or 2;

K ⁷ represents hydrogen, C _1-6 alkyl, Ar, He! Or no! ¹ ;

Ar is a homocyclic radical selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocyclic radical may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halogen, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, polyhaloC _1-6 alkyloxy, C _1-6 alkyloxyC _1-6 alkyl, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C 1-6 alkyl) aminocarbonyl;

Not! represents a monocyclic heterocycle selected from the group of фен-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridine; each monocyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halogen, hydroxy, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, C _{1 -6} alkyloxyC _1-6 alkyl or Ar-C (= O) -;

Not! ¹ is a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxynyl or benzoyl;

each bicyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from the group halogen, hydroxy, C1-6alkyl, poligaloS1-6alkila, gidroksiS1 _-6 alkyl, C1 _-6 alkyloxy, C1 _-6 alkyl or alkiloksiS1 _-6 Ar-C (= O) -;

provided that the bacterial infection is other than the mycobacterial infection.

The present invention also relates to a method for treating a bacterial infection in a mammal, in particular a warm-blooded mammal, more particularly a human, comprising administering an effective amount of a compound of the invention to a mammal.

As used herein before or hereafter, the term “C _1-6 alkyl” as a group or part of a group means straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like.

As used here before or after, the term “(= O)” forms a carbonyl moiety upon attachment to a carbon atom.

The term "halogen" is common to fluorine, chlorine, bromine and iodine. The term “polyhaloC1-6alkyl” as used here before or after as a group or part of a group means mono- or polyhalo-substituted C _1-6 alkyl, for example methyl with one or more fluorine atoms, for example dichloromethyl or trifluoromethyl, 1,1-difluoroethyl, etc. P. In the case where more than one halogen atom is attached to an alkyl group in the definition of polyhaloC _1-6 alkyl, they may be the same or different.

It is believed that the definition of Not! Or no! ¹ or when K ⁴ and K ⁵ are taken together, includes all possible isomeric forms of heterocycles, for example, pyrrolyl contains 1H-pyrrolyl and 2H-pyrrolyl.

Ah, no! Or no! ¹ listed in the definitions of substituents of compounds of formula (I) (see, for example, K ³ ), indicated here before or after, can be attached to the rest of the molecule of formula (I) through any carbon atom or heteroatom that is suitable, if not specially agreed. So, for example, when Not! is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

Lines drawn from substituents into ring systems mean that the bond can be attached to any of the suitable ring atoms.

When two K ⁶ vicinal radicals are taken together with the formation of a divalent radical of the formula —CH═CH — CH═CH═CH—, this means that the two K ⁶ vicinal radicals form, together with the phenyl ring to which they are attached, naphthyl.

For therapeutic use, salts of the compounds of formula (I) are salts in which the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

It is intended that the pharmaceutically acceptable addition salts indicated herein before or after include therapeutically active forms of non-toxic acid addition salts which the compounds of formula (I) are capable of forming. The latter can conveniently be obtained by treating the base form with such suitable acids as inorganic acids, for example, hydrohalic acids, for example, hydrochloric acid, hydrobromic acid and the like; sulphuric acid; Nitric acid; phosphoric acid, etc., or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form may

- 2 010601 to be converted by treatment with alkali into the form of a free base.

The compounds of formula (I) containing acidic protons can be converted into their therapeutically active forms of non-toxic metal salts or addition salts with amines by treatment with suitable organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like; salts with organic bases, for example salts with primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine and the four isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylidine piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, метил-methyl-E-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol, hydrabamine; and salts with amino acids, such as, for example, arginine, lysine, and the like. Conversely, the salt form can be converted by treatment with an acid into the free acid form.

The term “addition salt” also includes hydrates and solvent addition forms which the compounds of formula (I) are capable of forming. Examples of such forms are, for example, hydrates, alcoholates, etc.

It is understood that the Ν-oxide forms of the present compounds include compounds of formula (I) in which one or more tertiary nitrogen atoms are oxidized to the so-called Ν-oxide.

The compounds of formula (I) can be converted into the corresponding окс-oxide forms according to procedures known in the art for converting the trivalent nitrogen atom into its Ν-oxide form. Said Ν-oxidation reaction is usually carried out by reacting a material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxyacids such as, for example, benzenepercarboxylic acid or halogen-substituted benzenepercarboxylic acid, for example 3-chlorobenzenepercarboxylic acid; peroxoalkanoic acids, for example peroxoacetic acid; alkyl hydroperoxides, for example tert-butyl hydroperoxide. Suitable solvents are, for example, water; lower alcohols, for example ethanol and the like; hydrocarbons, for example toluene; ketones, for example 2-butanone; halogenated hydrocarbons, for example dichloromethane, and mixtures of such solvents.

It should be understood that some compounds of formula (I) and their окс-oxides or addition salts may contain one or more centers of chirality and may exist in the form of stereochemically isomeric forms.

The term “stereochemically isomeric forms”, used here before or after, means all possible stereoisomeric forms that the compounds of formula (I) and their окс-oxides, addition salts or physiologically functional derivatives may possess. Unless otherwise indicated or indicated, the chemical name of the compounds means a mixture of all possible stereochemically isomeric forms, and these mixtures contain all diastereomers and enantiomers of the main molecular structure. In particular, stereogenic centers may have a B- or 8-configuration; substituents on divalent cyclic (partially) saturated radicals can have either a cis or trans configuration. Compounds containing double bonds may have the stereochemistry E (in the opposite direction) or Ζ (in one direction) of the specified double bond. The terms “cis, trans, B, 8, E, and Ζ” are well known to those skilled in the art. Undoubtedly, it is understood that the stereochemically isomeric forms of the compounds of formula (I) are included within the scope of this invention.

According to the standards of the CA8 nomenclature, when two stereogenic centers of known absolute configuration are present in the molecule, the designation B or 8 is intended (based on the Kahn-Ingolz-Prelog sequence rule) for the lowest-number chiral center, the reference center. The configuration of the second stereogenic center is indicated using the relative designations [B *, B *] or [B *, 8 *], where B * is always defined as a reference center and [B *, B *] means centers with the same chirality and [ B *, 8 *] means centers of different chirality. For example, if the chiral center with the lowest number in the molecule has an 8-configuration and the second center is B, the stereometry should be indicated as 8- [B *, 8 *]. If α- and β-positions are used, the position of the substituent with the highest priority on the asymmetric carbon atom in the cyclic system having the lowest ring number is conditionally always in the α-position of the midplane defined by the cyclic system. The position of the substituent with the highest priority on another asymmetric carbon atom in the cyclic system relative to the position of the substituent with the highest priority on the reference atom is denoted by α if it is on the same side of the midplane defined by the cyclic system, or β if it is on another side of the middle plane defined by the cyclic system.

When a specific stereoisomeric form is indicated, this means that said form is substantially free of another form, i.e. associated with less than 50%, preferably

- 3 010601 with less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably less than 1% of the other isomers). So, when the compound of formula (I), for example, is indicated as (αδ, βΡ), this means that the compound essentially does not contain the isomer (αΚ, βδ).

The compounds of formula (I) can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from each other by separation procedures known in the art. The racemic compounds of formula (I) can be converted into the corresponding forms of diastereomeric salts by reaction with a suitable chiral acid. These forms of diastereomeric salts are then separated, for example, by selective or fractional crystallization, and the enantiomers are isolated from them by alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, said compound can be synthesized by stereospecific methods of preparation. These methods should suitably use enantiomerically pure starting materials.

The invention also includes derivatives (usually called "prodrugs") of the pharmacologically active compounds of the invention, which cleave ίη νίνο to form compounds of the invention. Prodrugs usually (but not always) have lower activity at the target receptor than the compounds into which they are converted. Prodrugs are especially useful when the desired compound has chemical or physical properties that make its administration difficult or ineffective. For example, the desired compound may only be poorly soluble, it may be poorly tolerated through the mucous epithelium, or may have an undesirably short half-life in plasma. Further discussion of prodrugs can be found in 81e11a, UD. e! A1., Rgobgidk, Aegis Eeyuegu ZuChep. 1985, p. 112-176, apb Egidk, 1985, 29, p. 455-473.

The prodrug forms of the pharmaceutically active compounds of the invention are usually derivatives of any of the compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their tautomeric and Ν-oxide forms having an acid group that is esterified or amidated . Such esterified acid groups include groups of the formula -SOOR * in which R ^x represents C1 _-6 alkyl, phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula ^ ΟΝΚΉ ^Ζ in which P ^y represents H, C1-6 alkyl, phenyl or benzyl and Ρ ^Ζ represents —OH, H, C1-6 alkyl, phenyl or benzyl.

Compounds of the invention having an amino group can be converted into derivatives by reaction with a ketone or aldehyde such as formaldehyde to form a Mannich base. Such a base will be hydrolyzed by first order kinetics in an aqueous solution.

It is understood that the term “compounds of formula (I)” as used herein also includes their окс-oxide forms, their addition salts, or their stereochemically isomeric forms. Of particular interest are those compounds of formula (I) which are stereochemically pure.

A first interesting embodiment of the present invention relates to a compound of formula Da)

its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric or Ν-oxide form.

A second interesting embodiment of the present invention relates to a compound of formula D-b)

- 4 010601

its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric or Ν-oxide form.

A third embodiment of interest are compounds of formula (I) or any subgroup thereof, as hereinbefore indicated as an embodiment of interest, wherein B ¹ is hydrogen, halogen, C1 _is balkyl, Ar or He !; preferably hydrogen, halogen, optionally substituted phenyl or He !; more preferably hydrogen, halogen, optionally substituted phenyl, optionally substituted furanyl or pyridinyl; even more preferably hydrogen, halogen or optionally substituted phenyl; most preferably halogen, such as, for example, bromine or chlorine, in particular bromine.

A fourth embodiment of interest are compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ¹ is halogen, polyhaloC _1-6 alkyl, Ar or He !; preferably halogen, Ar or Not !; more preferably halogen, optionally substituted phenyl or He !; even more preferably halogen, phenyl, optionally substituted furanyl or pyridinyl.

A fifth embodiment of interest are compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ² is C _1-6 alkyloxy or C _1-6 alkylthio, in particular methoxy or methylthio; preferably C _1-6 alkyloxy, more preferably methoxy.

A sixth embodiment of interest are compounds of formula (I), or any subgroup thereof, as indicated hereinbefore, as an embodiment of interest, wherein B ³ is Ar or He !, or where B ³ is Ar or He! ¹ ; preferably B ³ is Ar; more preferably optionally substituted phenyl or optionally substituted naphthyl; even more preferably phenyl, optionally substituted with halogen or C _1-6 alkyloxy, or naphthyl, optionally substituted with halogen or C _1-6 alkyloxy, most preferably phenyl, optionally substituted with 1 or 2 halogen atoms, in particular fluorine, or naphthyl, in particular 1 naphthyl.

A seventh embodiment of interest are compounds of formula (I), or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ⁴ and B ⁵ are each independently hydrogen or C 1-6 alkyl or B ⁴ and In ^5, together with the атом-atom to which they are attached, they can form a radical selected from pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolinyl, pyridini la, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with _C1-6 alkyl, halogen, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkylthioC _1-6 alkyl or pyrimidinyl; more preferably B ⁴ is C 1-6 alkyl and B ⁵ is hydrogen or C 1-6 alkyl or B ⁴ and B ^5, together with the атом-atom to which they are attached, can form a radical selected from pyrrolidinyl, 2-pyrrolinyl, 3- pyrrolynyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazinyl, triazinyl C1-6al keel, halogen, polyhaloC1-6alkyl, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxy, amino, mono- or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; even more preferably, B ⁴ is C 1-6 alkyl and B ⁵ is hydrogen or C 1-6 alkyl, or B ⁴ and B ⁵ together with the атом-atom to which they are attached can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl , triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with _C1-6 alkyl, halogen, polyhaloC _1-6 alkyl, hydroxy, hydroxy, hydroxy -6 alkyloxy, amino, mono- or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxy C1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; most preferably, B ⁴ is C 1-6 alkyl, in particular methyl or ethyl, more particularly methyl, and B ⁵ is hydrogen or C 1-6 alkyl, in particular methyl or ethyl, more particularly methyl.

- 5 010601

An eighth embodiment of interest are compounds of formula (I), or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ⁴ and B ⁵ are each independently hydrogen, C 1-6 alkyl or benzyl; preferably B ⁴ and B ⁵ are each independently hydrogen or C 1-6 alkyl; more preferably B ⁴ is C 1-6 alkyl and B ⁵ is hydrogen or C 1-6 alkyl, most preferably B ⁴ and B ⁵ are C _1-6 alkyl, in particular methyl or ethyl, more particularly methyl.

A ninth embodiment of interest is a compound of formula (I), or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ⁴ and B ⁵ together with the Ν-atom to which they are attached can form a radical, selected from pyrrolidinyl, 2-pyrrolinyl, 3-pyrroinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrazinyl, pyrazinyl, pyridinyl , morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with C1-6alkyl, halogen, polyhaloC1-6alkyl, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxy, amino, mono- or di (C1-6alkyl) amino, C1- 6alkylthio, C1-6alkyloxy C1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; preferably B ⁴ and B ⁵ together with the Ν-atom to which they are attached can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and each of these rings may optionally be substituted with _C1-6 alkyl, halogen, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono- or di ( _C1-6 alkyl) amino, C1 -6alkylthio, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimi dinyl; more preferably B ⁴ and B ⁵ together with the Ν-atom to which they are attached can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with C1-6alkyl, halogen, polyhaloC1-6alkyl, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxy, amino, mono- or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxy C1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; even more preferably B ⁴ and B ^5, together with the Ν-atom to which they are attached, can form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with C1- 6alkyl, halogen, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _1-6 alkyloxy _1-6 alkyl; C _1-6 alkylthioC _1-6 alkyl or pyrimidinyl; most preferably B ⁴ and B ^5, together with the Ν to which they are attached, form imidazolyl.

Substituents on the ring system, where B ⁴ and B ⁵ are taken together, are preferably selected from C _1-6 alkyl, halo, polyhaloC _1-6 alkyl, hydroxy, C _1-6 alkyloxy, C _1-6 alkylthio, and pyrimidinyl; more preferably, the substituents are selected from C _1-6 alkyl or pyrimidinyl.

A tenth embodiment of interest are compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ⁶ is hydrogen, halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl, or two vicinal radicals B ⁶ are taken together with the formation of a divalent radical of the formula —CH═CH — CH — CH═CH—; preferably B ⁶ is hydrogen, halogen, poligaloS1-6alkil or C ₁ - ₆ alkyl; more preferably B ⁶ is hydrogen, halogen or C 1-6 alkyl; even more preferably, B ⁶ is hydrogen or halogen; most preferably B ⁶ is hydrogen.

An eleventh embodiment of interest is a compound of formula (I), or any subgroup thereof, as described hereinbefore, as an embodiment of interest, wherein B ⁷ is hydrogen.

A twelfth embodiment of interest is a compound of formula (I) or any subgroup thereof, as indicated hereinbefore, as an embodiment of interest, where r is an integer of 1.

The thirteenth interesting embodiment is the compounds of formula (I) or any subgroup thereof, as indicated hereinbefore, as an interesting embodiment, where p is an integer of 1.

The fourteenth, interesting embodiment, are compounds of formula (I) or any subgroup thereof, as indicated hereinabove, provided that when one B ¹ is C1-6 alkyl, then p is an integer of 2 and the other substituent B ¹ selected from halogen, polyhaloC _1-6 alkyl, C _1-6 alkyl, Ar or He !.

A fifteenth interesting embodiment is the compounds of formula (I) or any subgroup thereof, as indicated hereinbefore, as an interesting embodiment, wherein the compound is not (a8, 3B) -6-bromo-a- [2- ( dimethylamino) ethyl] -2-methoxy-a-1naphthalenyl-b-phenyl-3-quinolinethanol, its pharmaceutically acceptable acid or base addition salt, or its Ν-oxide form.

- 6 010601

A sixteenth embodiment of interest is the use of compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an embodiment of interest for the manufacture of a medicament for the treatment of an infection caused by a gram-positive and / or gram-negative bacterium.

A seventeenth interesting embodiment is the use of compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an interesting embodiment for the manufacture of a medicament for the treatment of an infection caused by a gram-positive bacterium.

An eighteenth interesting embodiment is the use of compounds of formula (I) or any subgroup thereof, as described hereinbefore, as an interesting embodiment for the manufacture of a medicament for the treatment of an infection caused by a gram-negative bacterium.

A nineteenth interesting embodiment is the use of compounds of formula (I) or any subgroup thereof, as indicated hereinbefore, as an interesting embodiment for the manufacture of a medicament for treating a bacterial infection, wherein the compound of formula (I) has Κ / ,, ΑΕδ μl / ml against at least one bacterium, in particular a gram-positive bacterium, preferably Κ / ,, ΑίΟ μl / ml, more preferably Λ _9ο <5 μl / ml, the Yudo value being determined as described hereinafter.

Also of interest are the compounds of the present invention are those compounds of formula (I) to which one or more, preferably all of the following definitions apply:

a) K. ¹ represents hydrogen; C _1-6 alkyl; halogen, in particular bromine or chlorine; phenyl; furanyl optionally substituted with hydroxyC _1-6 alkyl; or pyridyl;

b) K ² represents C _1-6 alkyloxy, in particular methoxy or ethoxy; C _1-6 alkylthio, in particular methylthio; or C _1-6 alkyloxyC _1-6 alkyloxy;

c) K ³ represents phenyl optionally substituted with 1 or 2 halogen atoms, in particular fluorine; naphthyl, optionally substituted by 1 or 2 halogen atoms or C ₁ - ₆ alkyloxy; thienyl; piperidinyl substituted with Ar-C (= O); 2,3-dihydrobenzo [1,4] dioxinyl; benzo [1,3] dioxolyl or acenaphthyl;

b) K ⁴ and K ⁵ are each independently hydrogen; C1-6alkyl; benzyl; or K ⁴ and K ^5, together with the atom Ν to which they are attached, can form a radical selected from imidazolyl; pyrazinyl substituted with C1-6alkyl; pyrazinyl substituted with C _1-6 alkyl; piperazinyl substituted with pyrimidinyl; piperidinyl; thiomorpholinyl; morpholinyl; pyrrolidinyl or triazolyl;

e) K ⁶ represents hydrogen; halogen, in particular chlorine or bromine; C _1-6 alkyl; or two K ⁶ vicinal radicals can be taken together with the formation of a divalent radical of the formula —CH═CH — CH═CH—;

1) K ⁷ represents hydrogen.

The most preferred compounds of the present invention are compound 50, 206, 31, 26, 27, 32, 33, 109, 39, 44, 41, compounds A, E and E, their pharmaceutically acceptable acid or base addition salts or their Ν- oxide forms.

The present invention also relates to a compound selected from

to ¹ IN* IN? Stereochemistry 3-pyridyl OCH 3,5-difluorophenyl n (BUT) 2-furanyl OCH 1-naphthyl n (IN) Vg OCH ₃ f n (BUT) Vg OCH Phenyl N (AT 2) Vg OCH ₃ Phenyl n (IN 1)

its pharmaceutically acceptable acid or base addition salt or its его-oxide form.

- 7 010601

The present invention also relates to a compound selected from

TO* B Stereochemistry and melting points 2,4-difluorophenyl MH (CH ₂ CH ₃ ) (IN) 2,4-difluorophenyl ΝΗ (ΟΗ ₂ ΟΗ ₃ ) (BUT) 2,4-difluorophenyl ЩСНгСНз) (СН ₂ phenyl) (IN) phenyl Eun (SNz) (IN)

its pharmaceutically acceptable acid or base addition salt or its его-oxide form.

Compounds of formula (I) can be prepared by the methods described in νΟ 2004/011436, which is incorporated herein by reference. In general, the compounds of the invention can be prepared by a sequence of steps, each of which is known to one skilled in the art.

In particular, compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) according to the following reaction scheme (1):

using C&I in a mixture of diisopropylamine and tetrahydrofuran, where all the symbols have the meanings indicated as in formula (I).

Stirring may increase the reaction rate. The reaction can be conveniently carried out at a temperature between -20 and -70 ° C.

The starting materials and intermediates of formula (II) and (III) are compounds that are either commercially available or can be prepared by conventional reaction procedures commonly known in the art. For example, intermediates of formula (P-a) can be prepared by the following reaction scheme (2):

where all the symbols have the meanings indicated as in formula (I).

Reaction Scheme (2) comprises step (a) in which a suitably substituted aniline is reacted with a suitable acyl chloride, such as 2-phenylpropionyl chloride, 3-fluorobenzenepropionyl chloride or p-chlorobenzenepropionyl chloride, in the presence of a suitable base, such as triethylamine, and an inert solvent under the reaction conditions, such as methylene chloride or ethylene dichloride. The reaction can be conveniently carried out at a temperature, finding

- 01 010601 between room temperature and reflux temperature. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POC1 ₃ ) in the presence of Ν, Ν-dimethylformamide (formation by the Vilsmeier-Haack reaction followed by cyclization). The reaction can conveniently be carried out at a temperature between room temperature and reflux temperature. In the next step (c), a specific B ² group, where K ² is, for example, C1 _- balkyloxy or C _1-6 alkylthio radical, is introduced by reacting the intermediate obtained in step (b) with the compound H — X — C _{1 -6} alkyl, where X is 8 or O.

Intermediates of the formula (b) can be prepared according to the following reaction scheme (3), wherein in the first step (a), the substituted indole-2,3-dione is reacted with the substituted 3-phenylpropionic aldehyde in the presence of a suitable base, such as sodium hydroxide (Pfitzinger reaction), after which the carboxylic acid in the next step (b) is decarboxylated at high temperature in the presence of a suitable solvent inert under the reaction conditions, such as diphenyl ether.

Scheme 3

(N-b)

Obviously, in the above and subsequent reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified by methodologies commonly known in the art, such as extraction, crystallization and chromatography. It is further apparent that reaction products that exist in more than one enantiomeric form can be isolated from their reaction mixture by known methods, in particular preparative chromatography, such as preparative HPLC. The compounds of formula (I) can usually be separated into their isomeric forms.

Intermediates of formula (ΙΙΙ) are compounds that are either commercially available or that can be prepared by conventional reaction procedures commonly known in the art. For example, intermediates of formula (S-a) in which K ³ is Ar substituted with K ¹⁰ substituents, where each K ^{10 is} independently selected from the group of hydroxy, halogen, cyano, nitro, amino, mono or di (C _{1- 6} alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy, polyhaloC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C _1-6 alkyl) aminocarbonyl, and 8 is an integer equal to zero, 1, 2 or 3, can be obtained by the following reaction scheme (4):

Scheme 4

(II1-9)

Reaction scheme (4) comprises step (a) in which suitably substituted Ar, in particular suitably substituted phenyl, is reacted by the Friedel-Crafts reaction with a suitable acyl chloride, such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride, in the presence of a suitable acid Lewis, such as, for example, A1C1 ₃ , ETC1 ₃ , 8pC1 ₄ , T1C1 ₄ or Ζηί, 'Κ and a suitable solvent inert under the reaction conditions, such as methylene chloride or ethylene dichloride. The reaction can conveniently be carried out at a temperature between room temperature and reflux temperature. In the next step (b), the amino group (-ΝΚ ₄ Κ ₅ ) is introduced by reacting the intermediate obtained in step (a) with a primary or secondary amine.

In general, bacterial pathogens can be classified as either gram-positive or gram-negative pathogens. Antibiotic compounds with activity against both gram-positive and gram-negative pathogens are usually considered as having a wide spectrum of activity. The compounds of the present invention are considered as active against gram-positive

- 9 010601 ny and / or gram-negative bacterial pathogens. In particular, the present compounds are active against at least one gram-positive bacteria, preferably against several gram-positive bacteria, more preferably against one or more gram-positive bacteria and / or one or more gram-negative bacteria.

The present compounds have bactericidal or bacteriostatic activity.

Examples of gram-positive and gram-negative aerobic and anaerobic bacteria include staphylococci, for example Z. aigeik; enterococci, for example E. Gaesike; streptococci, for example, Z. rpeitoshae, 8.ti1ap5. Z. ruodepk; bacilli, for example VasShik kyyyk; Lepa, for example, Lepa toposu Judepek; hemophilic bacteria, for example NlpPiepha; Mogaha11a, for example M. sakggyayk; Rkeibotopack, for example Rkeibotopack aegidshock; and Exxepsia, for example E.eoH. Gram-positive pathogens, such as staphylococci, enterococci and streptococci, are especially important due to the development of resistant strains, which are both difficult to treat and difficult to eliminate, for example, from the hospital environment after they are detected. Examples of such strains are methicillin-resistant 81ap11u1ossoss8 igeeik (MK.8A), methicillin-resistant, staphylococcus coagulase negative (ΜΚΟΝδ), penicillin-resistant 81erossossiens and resistant to many medicinal products.

The compounds of the present invention also exhibit activity against resistant bacterial strains.

The compounds of the present invention are especially active against 8! Aryyosossi8 aigeyik, including resistant 81yryosossi8 aigeyik, such as, for example, methicillin-resistant 8!

In particular, the compounds of the present invention are active against those bacteria whose viability depends on the proper activity of ATP synthase E1E0. Without being bound by any theory, it is believed that the activity of the present compounds is the inhibition of E1E0 ATP synthase, in particular the inhibition of the E0 complex of ATP synthase E1E0, more specifically the inhibition of the subunit from the E0 complex of ATP synthase E1E0, which leads to the destruction of bacteria by depleting cellular levels of ATP bacteria.

Whenever the text here before or after indicates that the compounds can treat a bacterial infectious disease, this means that the compounds can treat an infectious disease with one or more bacterial strains.

Whenever it is indicated here before or after that a bacterial infection is other than a mycobacterial infection, it means that a bacterial infection is different than an infection with one or more mycobacteria.

The exact dosage and frequency of administration of the present compounds depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, nutrition, time of administration and general physical condition of the particular patient, the method of administration, and another drug therapy that an individual can take, which is well known to one skilled in the art. In addition, it is obvious that the effective daily amount can be reduced or increased depending on the response of the subject being treated and / or depending on the assessment of the doctor prescribing the compounds of the present invention.

The compound of the present invention may be administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier. Compounds and compositions containing these compounds may be administered by such routes as local, local or systemic routes of administration. Systemic use includes any method of administering a compound to body tissues, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. If necessary, you can adjust the specific dose of the antibacterial agent that you want to enter, as well as the duration of treatment.

Bacterial infections that can be treated with the present compounds include, for example, central nervous system infections, outer ear infections, middle ear infections such as acute middle ear infections, cranial sinus infections, eye infections, oral infections such as tooth infections , gums and mucous membranes, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, sepsis, bone and cartilage infections, infections skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunodepressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.

Given the fact that the compounds of formula (I) are active against gram-positive and / or gram-negative bacteria, the present compounds can be combined with other antibacterial agents to effectively fight bacterial infections.

Thus, the present invention also relates to a combination of (a) a compound of formula (I) and (b) of one or more other antibacterial agents, provided that one or more

- 10 010601 other antibacterial agents are other than antimycobacterial agents.

The present invention also relates to a combination of (a) a compound of formula (I) and (b) of one or more other antibacterial agents, provided that one or more other antibacterial agents are other than antimycobacterial agents for use as a medicine.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of (a) a compound of formula (I) and (b) one or more other antibacterial agents, provided that one or more other antibacterial agents are other than antimycobacterial agents, also included in the present invention.

The present invention also relates to the use of a combination or pharmaceutical composition as described above for the treatment of a bacterial infection.

The present pharmaceutical composition may take various pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly used for systemically administered drugs can be mentioned here. To obtain the pharmaceutical compositions of this invention, an effective amount of the specific compounds, optionally in the form of an addition salt, is mixed as an active ingredient to form a intimate mixture with a pharmaceutically acceptable carrier, the carrier may take various forms depending on the form of preparation required for administration. These pharmaceutical compositions are desirable in unit dosage form suitable, in particular, for administration by oral or parenteral injection. For example, in preparing the composition in oral dosage form, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols, and the like. in the case of oral liquid preparations, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, and the like. in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most suitable oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually contains sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.

Depending on the method of administration, the pharmaceutical composition will preferably contain from 0.05 to 99 wt.%, More preferably from 0.1 to 70 wt.% Of the active ingredient and from 1 to 99.95 wt.%, More preferably from 30 to 99 , 9 wt.% Pharmaceutically acceptable carrier, and all percentages are based on the total weight of the composition.

The mass to mass ratio (a) of the compound of formula (I) and (b) of the other antibacterial agent (s), when given in combination, can be determined by one skilled in the art. The indicated ratio and the exact dosage and frequency of administration depends on the particular compound of formula (I) and the other antibacterial agent (s) used, the particular condition being treated, the severity of the condition being treated, age, weight, gender, nutrition, time of administration and general physical condition a particular patient, method of administration, as well as other drug therapy that the individual may take, which is well known to one skilled in the art. In addition, it is obvious that the effective daily amount can be reduced or increased depending on the response of the subject being treated and / or depending on the assessment of the doctor prescribing the compounds of the present invention.

The compounds of formula (I) and one or more other antibacterial agents may be combined as a single preparation or may be formulated as separate preparations so that they can be administered simultaneously, individually or sequentially. Thus, the present invention also relates to a product containing (a) a compound of formula (I) and (b) one or more other antibacterial agents, provided that one or more other antibacterial agents are other than antimycobacterial agents, in the form of a combined a drug for simultaneous, separate or sequential use in the treatment of bacterial infection.

The pharmaceutical composition may further comprise various other ingredients known in the art, for example, a lubricant, a stabilizing agent, a buffering agent, an emulsifying agent, a viscosity regulating agent, a surfactant, a preservative, a flavoring agent or a coloring agent.

Particularly suitable is the manufacture of the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dose. Unit dosage

- 11 010601 the form used here refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient, determined to cause the desired therapeutic effect in association with the desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets with notches or coatings), capsules, pills, sachets of powders, cachets, suppositories, injectable solutions or suspensions, and the like. and their segregated multiple doses. The daily dose of the compound of the invention will, of course, vary depending on the compound used, the route of administration, the treatment required and the particular bacterial disease.

Other antibacterial agents that can be combined with compounds of formula (I) are also known in the art. Other antibacterial agents include antibiotics of the β-lactam group, such as natural penicillins, semisynthetic penicillins, natural cephalosporins, semisynthetic cephalosporins, cefamycins, 1-oxacephemes, clavulanic acids, penems, carbapenems, monocardins; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as Ν-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin 8; macrolides, such as macrolides with a 12-membered ring, macrolides with a 14-membered ring, macrolides with a 16-membered ring; ansamycins; peptides such as bleomycin, gramicidins, polymyxins, bacitracins, large-ring peptide antibiotics containing lactone bonds, actinomycins, amphomycin, capreomycin, distamycin, enduracidins, mycomycin, neocarcinostatin, stentomycin, biomycin, b; cycloheximide; cycloserine; variotin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycin; fumagillin; monensins; pyrrolnitrin; fosfomycin; fusidic acid; O- (p-hydroxyphenyl) glycine; Ό-phenylglycine; enedins.

Specific antibiotics that can be combined with the present compounds of formula (I) are, for example, benzylpenicillin (potassium, procaine, benzathine), phenoxymethylpenicillin (potassium), phenethicillin potassium, propicillin, carbenicillin (disodium, phenyl sodium, indilinicillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, fluloxacillin, ampicillin, meslocillin, piperacillin sodium, amoxicillin, cyclacillin, hectacillin, sulbactam sodium, thalampicillin hydrochloride id, bacampicillin hydrochloride, pivecillinam, cyfalexin, cefaclor, cefaloglycine, cefadroxil, cefradine sodium, cefroxadine sodium, cefacetri sodium, cefsulodin sodium, cefalfamide, cefeferfin cefeferfin cefeferfin cefeferfin cefefridin sodium, cefmenoxide hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin, cefmetazole, cefotetan, latamoxef, clavulanic acid, imipenem, aetreon, tetracycline, chlortetracycline hydrochloride, dimeti chlortetracycline, oxytetracycline, metacycline, doxycycline, rolytetracycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, becanamycin, tobramycin, gentamicin sulfate, dicericinomycidomycin, micromecinomycrinomycin, micronomycin , hygromycin B, apramycin, sisomycin, netilmicin sulfate, spectinomycin hydrochloride, astromycin sulfate, validamycin, casugamycin, polyoxin, blasticidin 8, erythromycin, erythromycin estolate, oleandomycin phosphate, triacetyloleandomycin, kitazamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramycidin 8, polymyxin B, bacitracin, colistin sulfate, colistomycinomycin enviomycin, vancomycin, actinomycin Ό, neocarcinostatin, bestatin, pepstatin, monensin, lazalocide, salinomycin, amphotericin B, nystatin, natamycin, trichomycin, mitramycin, lincomycin, clindamycin, clindamycin palmititis hydrochloride, flavofosfolipol, cycloserine, petsilotsin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin, fosfomycin, fusidic acid, bikozamitsin, tiamulin, sikkanin.

In the table. 1-4 lists the compounds of formula (I) of the present invention.

The absolute stereochemical configuration of the stereogenic carbon atom (s) of some compounds has not been experimentally determined. In some cases, the stereochemically isomeric form, which was isolated first, is designated as A, and the second as B without further reference to the actual stereochemical configuration. However, these isomeric forms A and B can be unambiguously characterized by a person skilled in the art using methods known in the art, for example, X-ray diffraction.

In the case where A and B are stereoisomeric mixtures, they can then be separated, whereby the extracted first corresponding fraction is designated A1, respectively B1, and the second as A2, respectively B2, without further reference to the actual stereochemical configuration. However, these isomeric forms A1, A2 and B1, B2 can be unambiguously characterized by a person skilled in the art using methods known in the art, for example, X-ray diffraction.

- 12 010601

These compounds are numbered in accordance with compounds XVO 2004/011436 and can be obtained by the methods described in νθ 2004/011436. The number of examples in the following tables refers to the number of examples νθ 2004/011436, which respectively indicate which procedure compounds can be obtained.

Additional compounds are indicated by letters.

Compounds A, B, and C were prepared according to the procedures described in νθ 2004/011436. The diagram below indicates the synthesis route of compound A, B and C. The numbers of examples A8, A9, B12 and B13 correspond to the procedures νθ 2004/011436

Compound C, which is a diastereoisomer (B), was isolated from a mixture of diastereoisomers as follows. The residue (5.4 g) obtained by Procedure B12 was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / cyclohexane, 60/40). Two fractions were collected and the solvent was evaporated. The second fraction was crystallized from diisopropyl ether to give 0.83 g of compound C (diastereoisomer B) (yield: 13%).

Compound A, which is diastereoisomer B, and compound B, which is diastereoisomer (A), were isolated from a mixture of diastereoisomers as follows. The residue (1.7 g) obtained by the procedure of Example B13 was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / HH ₄ OH, 98/2 / 0.1). Two fractions were collected and the solvent was evaporated. The fractions were crystallized separately from diisopropyl ether, yielding 0.31 g of compound B (diastereoisomer A) (yield: 27%) and 0.52 g of compound A (diastereoisomer B) (yield: 45%).

Compound Ό was prepared according to the procedures described in νθ 2004/011436. The diagram below indicates the synthesis route for compound Ό. The numbers of examples A9, B12 and B13 correspond to the procedures νθ 2004/011436

Compound Ό, which is a diastereoisomer (B), was isolated from a mixture of diastereomers as follows.

The residue (1.2 g) obtained by the procedure of Example B13 was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / HH ₄ OH, 95/5 / 0.5). Two fractions were collected and the solvent was evaporated. The second fraction was crystallized from diisopropyl ether to give 0.08 g of compound Ό (diastereoisomer B) (yield: 10%).

Compounds E and E were obtained by separation of compound 4 (diastereoisomer B) VO 2004/011436 into its enantiomers by the following procedure.

- 13 010601

The final compound 4 (2.5 g) was separated into its enantiomers by column chromatography (eluent: hexane / ethanol, 99.95 / 0.05; column: COMBINE ΟΌ). Two pure fractions were collected and their solvents were evaporated.

Yield: 0.5 g of compound E (enantiomer B1) (mp 180 ° C) and 0.12 g of compound P (enantiomer B2) (mp 175 ° C).

Compound 6 is prepared as follows.

A mixture of compound 115 (obtained in accordance with B15 \ UO 2004/011436) (0.00028 mol), a cyclic ester of 1,3-propanediol and pyridine-3-boronic acid (0,00055 mol), Pb [P (PP ₃ ) ] ₄ (0.00003 mol) and 2 M NaCl ₃ , (0.0011 mol) in dimethoxyethane (4 ml) are stirred at 90 ° C for 1.5 hours, then poured into H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH, 95/5; 5 μm). Pure fractions were collected and the solvent was evaporated.

Yield: 0.09 g of compound 6 (60%) (mp. 201 ° C).

Compound H is prepared as follows.

A mixture of compound 15 (obtained according to B7 \ UO 2004/011436) (0.0009 mol), 2-furanboronic acid (0.0018 mol), Pb [P (PP ₃ )] ₄ (0.00009 mol) and 2 M No. bC'O ₃ , (0.0036 mol) in dimethoxyethane (10 ml) was stirred at 90 ° C for 6 hours, then poured into H2O and extracted with CH2C12. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.57 g) was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / IN ₄ OH, 99/1 / 0.1; 10 μm). Pure fractions were collected and the solvent was evaporated, yielding 0.23 g of a residue. This fraction is crystallized from a mixture of diisopropyl ether / acetonitrile. The precipitate was filtered off and dried.

Yield: 0.071 g of compound H (15%) (mp. 215 ° C).

Compounds I were prepared according to the procedures described in XVO 2004/011436. The following scheme indicates the synthesis route of compound I. The numbers of Examples A10 and B1 correspond to procedures VΟ 2004/011436

A mixture of commercially available 5-acetyl-1,2-dihydroacenaphthylene (0.0407 mol) and dimethylamine hydrochloride (0.0858 mol) in paraformaldehyde (37% in water, 4 ml), HC1 / 1PgOH (1 ml) and ethanol (100 ml) was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was dissolved in a mixture of H2O / 3n. HC1 / CH2C12. The aqueous layer was made basic and extracted with CH2C12. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ ΟH / NH ₄ ΟH, 95/5 / 0.2; 15-40 μm). Pure fractions were collected and the solvent was evaporated. Yield: 4.9 g of intermediate I (48%).

1.6 M H-BCCY (0.0102 mol) was added dropwise at −20 ° C. to a solution of diisopropylamine (0.0091 mol) in tetrahydrofuran (15 ml) in a Ν ₂ stream. The mixture is stirred at -20 ° C for 20 minutes, then cooled to -70 ° C. A solution of intermediate 3 (0.0091 mol) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at −70 ° C. for 2 hours. A solution of intermediate I (0.01 mol) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred at -70 ° C for 3 hours, poured into ice water and extracted with HU Ac. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (6.5 g) was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / IN ₄ OH, 99/1 / 0.2; 15-40 μm). Two fractions were collected and the solvent was evaporated.

Yield: 0.96 g P1, 0.72 g P2. P1 is crystallized from diethyl ether. The precipitate was filtered and dried. Yield: 0.87 g of compound I (17%).

- 14 010601

Table 1

Connection No. No. at measure K ¹ I? to" TO* Stereochemistry and melting points 41 IN 1 N DOS phenyl N (IN); 16O’s twenty" 87 Vg main 1-naphthyl R (ВМЗ’С 31 IN 1 but DOS phenyl n (IN); 181Ό 26 IN 1 phenyl wasp. phenyl n (BUT); 174 * C 27 IN 1 phenyl DOS phenyl n (B): 192 * C 32 IN 1 Vg 5CH, phenyl n (A); 208'C 33 ΒΙ Vg 5CH, phenyl n (IN); 196Ό 109 AT 9 Vg BAS 3-fluorophenyl n (A2); 156 ° C 39 AT 9 Vg DOS 3-fluorophenyl n (IN); 207 ° C 36 IN 1 Vg DOS phenyl α (BUT); 197’s 14 AT 7 Vg DOS 1-naphthyl n (BUT); 210 * C fifteen AT 7 Vg Ook 1-naphthyl n (IN); 244’s 46 AT 7 Vg DOS 2-naphthyl n (IN); 162 ° C 4 IN 1 Vg. . main phenyl n (IN); 19О‘С 174 AT 9 (? .. main 3-fluorophenyl n (BUT); 1594: 24 IN 1 Vg DOS 3-thienyl n (BUT); 162’s 5 AT 2 Tue OCHAS, phenyl n (BUT); 162 ° C 33 AT 9 Tue DOS 3-fluorophenyl n (BUT); 198 ° C

- 15 010601

69 IN! Vg axis. 2-fluorophenyl AND (BUT); oil 70 IN 1 Vg DOS 2-fluorophenyl n CB): oil. sixteen IN 1 Vg DOS 4-chlorophenyl n CA); 200 * C 17 IN 1 Vg DOS 4-chlorophenyl n (IN); 190 * C 67 AT 8 Vg main 2,5-difluorophenyl n ίΔΐ "Ό 116 B15 Vg main 3,5-difluorophenyl n (IN); 224 = C 159 AT 8 Vg DOS 2,5-difluorophenyl n (A1); 208 ^r C 160 AT 8 Vg DOS 2,5-difluorophenyl n (A2); 167’s 113 BX4 Vg main 2,3-difluorophenyl n (BUT); 128 ° C 196 B15 Vg main 3,4-difluorophenyl n (IN); 184’s 76 IN 1 Tue main t " n (IN); 130 “C 84 IN 1 phenyl OSN 1-naphthyl n (A): 248 ° C 45 AT 7 Vg DOS 2-naphthyl n (A); 262 ° C 77 IN 1 Tue OSNe With n (BUT); 202 ° C 78 IN 1 Vg 00¾ n (IN); 202 * C 165 AT 9 Tue / Z-fluorophenyl n ®U, oil 72 IN 1 Vg DOS 1-naphthyl sn (B): 178 ° C 212 AT 7 "Ts? -. DOS 1-naphthyl n (B); 220 ”C 163 AT 7 Tue DOS 5-metho xi-2-naphthyl n (B); 20b “C 73 IN 1 Vg DOS 1-naphthyl but (IN); 174 * C 201 IN 1 Tue DOS -o ^ n (A); 214 “C thirty 21 C1 main phenyl n (BUT); 170-s 21 IN 1 Vg DOS 2-thienyl n (IN); 176Ό 25 IN 1 Tue DOS? 3-thienyl n (IN); 160C twenty ΒΙ Vg DOS 2-thienyl and (A); 96 “C 6 Hh. Tue DOS phenyl n (B): 74 * C 108 AT 9 Vg main Z-fluorophenyl n 1 (A1); 160 * 0 | 37 Β1 Vg DOS phenyl C1 (B): 22GS thirteen AT 7 Vg 00¾ 1-naphthyl n (A2); 120 ° C 130 AT 7 Vg DOS 5-bromo-2-naphthyl n ®); 220 * C about 3-lire went main 3,5-difluorophenyl to (A); 201’C Η 2-furanyl main 1-naphthyl n ®); 215 * C I Tue main n (A);> 260 * C R Vg Tue DOS phenyl and (B2): G75 ° C E ΒΙ Tue DOS phenyl n ®1); 180 ° C

- 16 010601

table 2

Connection No. Example No. K. ¹ K ¹ IN? I* to' Physical data (salt melting points) and stereochemistry 44 AT 4 Vg DOS phenyl n n CA); 190 * C sixteen IN 1 Tue main phenyl SNGSNe sn / sc ethanedioate 0: 3), (B); 150 * 0 eighteen IN 1 Tue smallpox phenyl SNsN, CH ₂ CH, ethanedioate 0 = 3); (BUT); 230 ° C

Table 3

Connection No. Example No. b Stereochemistry and flame points fifty IN 1 phenyl 1-imidazolyl CB); 230 * 0 137 AT 7 2-naphthyl 4-methylpyrazinyl (B); 232 * C 154 AT 7 6-bromo-2-naphthyl 4-methylpiperazinyl CB); 254 * 0 49 IN 1 phenyl 1-imidazolyl (BUT); 216 * 0 136 AT 7 2-naphthyl 4-methylpyrazinyl (BUT); 188 ° C 4B IN 1 phenyl 1-piperidinyl CB); 210 * 0 55 IN 1 phenyl thiomorpholinyl (BUT); oil 171 AT 7 2-naphthyl 1-pyrrolidinyl (IN); 218 * 0 129 IN 1 2-naphthyl 1-liperidinyl (B); 212 ° C 149 AT 7 1-naphthyl 4-methylpyrazinyl (IN); 232 * 0 166 AT 7 6-bromo-2-naphthyl 1-piperidinyl (B); 218 * C 151 AT 7 3-bromo-1-naphthyl 4-methylpiperazinyl CA); 178 * C 53 ΒΙ phenyl 1- (1,2,4-triazolyl) (BUT); 18042 47 IN 1 phenyl 1-piperidinyl (Α); 190Ό 51 IN 1 phenyl 1 - (4-methyl) piperazine il (BUT); 150 “C 170 AT 7 2-naphthyl 1-pyrrolidinyl CA); 238 * 0 128 IN 1 2-naphthyl 1-piperidinyl (BUT); 254Ό 145 AT 7 1-naphthyl 1-piperidinyl (A); 212 * C 139 AT 7 2-naphthyl morpholinyl CA); 258 * 0 140 AT 7 2-naphthyl morpholinyl (IN); 214 * 0 155 AT 7 6-bromo-2-naphthyl 1-piperidinyl (BUT); 224 * 0 BUT B13 2,4-difluorophenyl YZHSN1SNY ®) - IN 2,4-difluorophenyl FALSE,) ™ 1

- 17 010601

from AT 12 2,4-difluorophenyl MCCNaSTcXCH ^ phenyl) .. υ B13 phenyl ΝΗ (Οίι) (IN); 197 ° C twenty? AT 7 2-naphthyl (IN); 198 ° C 58 Wb phenyl about (A); 208’s eleven Wb phenyl to about Yes); 208’s

Table 4

<

Connection No. Example No. TO* to? Th ⁸ Stereochemistry and melting points & b FROM <1 215 AT 9 n Vg sv and 3-fluorophenyl IN (BUT); 197-C 226 AT 7 and Tue n 1-naphthyl n (B); 208 ° C 229 AT 7 and CH sn. n 1-naphthyl and (A); 238 * C 227 B15 n Vg sn and 3,5-difluorophenyl n (BUT); 195 ° C 223 AT 7 n Vg and n 1-naphthyl about 3 4 (IN); 205-C

Analytical methods.

The mass of some compounds was recorded by LC-MS (liquid chromatography-mass spectrometry). The method used is described below. The data are collected in table. 5.

The method of LC-MS.

LC-MS analysis was performed (positive ionization by electrospray, scanning mode from 100 to 900 atomic mass units) on a KgotakP C18 column (ShegsYt, Mopbisop, BK; 5 μm, 4.6x150 mm) with a flow rate of 1 ml / min. Two mobile phases (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) were used to establish a gradient condition from 100% A in during 1 min to 100% B in 4 min, 100% B in 5 min to 100% A in 3 min and again establish equilibrium with 100% A for 2 min.

Table 5

LC-MS molecular peak

Pharmacological examples.

Obtaining bacterial suspensions for sensitivity testing.

The bacteria used in this study were grown overnight in flasks with

- 18 010601 holding 100 ml of Mie11eg-NT1op broth (Weight1op ΩίοΚιηδοη - catalog No. 275730) in sterile deionized water, with shaking at 37 ° C. Stock solutions (0.5 ml / tube) were stored at −70 ° C. before use. Bacterial titrations were performed in microtiter plates for the determination of TSSH ₅₀ , where TSS ₅ ,. is a dilution that causes bacterial growth in 50% of inoculated cultures. In general, a seed dilution level of approximately 100 TSP _{50 was} used for sensitivity tests.

Antibacterial susceptibility test: determination of Ή ₉₀ .

Analysis in microtiter plates.

Sterile 96-well plastic flat bottom microtiter plates were filled with 180 μl of sterile deionized water supplemented with 0.25% B 8A. Then, stock solutions (7.8 x final test concentration) of the compounds were added in volumes of 45 μl to column 2 of the plate. Five serial dilutions (45 μl in 180 μl) were carried out directly in microtiter plates from column 2 to column 11. Untreated control samples with seed (column 1) and without it (column 12) were included in each microtiter plate. Depending on the type of bacteria, approximately 10-60 CEI per well of inoculum bacteria (100 TSH ₅₀ ) in a volume of 100 μl in 2.8x medium of Mie11eg-Ht1op broth was added to rows A to H, except for the column

12. The same volume of broth medium without inoculum was added to column 12 in rows A to N. The cultures were incubated at 37 ° C for 24 hours in a normal atmosphere (incubator with an open valve for air and continuous ventilation). At the end of incubation, the day after inoculation, bacterial growth was quantified by fluorometry. Therefore, resazurin (0.6 mg / ml) was added in a volume of 20 μl to all wells 3 hours after inoculation and the plates were again incubated overnight. A color change from blue to pink indicates bacterial growth. The fluorescence was read in a computer-controlled fluorometer (Cy1Diog Vyukeagsk) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The growth inhibition in% achieved by the compounds was calculated by standard methods. Ι ^ ₀ (expressed in μg / ml) was defined as a 90% inhibitory concentration for bacterial growth. The results are shown in table. 6.

The method of cultivation in agar.

Values ΜΙί. ' ₉₉ (the minimum concentration to obtain 99% inhibition of bacterial growth) can be determined by carrying out the standard method of agar dilution according to the standards * ^ *, in which the medium used includes Mie11eg-Ht1op agar (* C11hc1a1aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 2005). Dilution test methods for bacteria that grow under aerobic conditions: accepted standard sixth edition).

Tests for death depending on time.

The bactericidal or bacteriostatic activity of the compounds can be determined by analysis for death depending on time using the method of microdilution of the broth ^ Ζυ ^ π ^, C.E. e! a1. W ίΙΐΌ ίΙΐΌ Д Д Д о о И 100 I-100592 apb I-100766, poee1 okhoNbtope apnas1epa1 adpK Aptugo. Adep18 Sketo1keg. 40, 839-845 (1996)). In the analysis for death, depending on the time, 81arcosossi§ igeeik and methicillin-resistant 8.aigei§ (MK8A), the initial inoculated doses of 8.aiguig§ and MK8A are 10 ⁶ CEI / ml in the Mie11eg Hsh1op broth. Antimicrobial compounds are used at a concentration of 0.1 to 10 times higher than MK (i.e., Yudo, determined by analysis in a microtiter plate). Wells that do not receive an antibacterial agent form a culture growth control. Tablets containing the microorganism and test compounds are incubated at 37 ° C. After 0, 4, 24, and 48 hours of incubation, the samples were removed to determine the content of viable microorganisms by serial dilution (from 10 ^-1 to 10 ^-6 ) in sterile PB8 and plated on Mie11g Hsh1op agar (200 μl). The plates are incubated at 37 ° C for 24 hours and the number of colonies is determined. Death curves can be constructed by applying 1ode ₁₀ CEI per ml depending on time. The bactericidal effect is usually defined as 3-1 ° ₁ 10 a decrease in the number of SEI per ml compared with untreated seed. The potential effect of drug transfer is eliminated by serial dilution and colony counting at the largest dilution used for plating.

Determination of cellular ATP levels.

To determine the change in the total concentration of cellular ATP (using ATP Lyu1it1pexepse KP, Koske), the analyzes were carried out by culturing the initial culture of 8. igee§ (ATCC 29213) in 100 ml Mie11eg Htop flasks and incubating in a shaker incubator for 24 hours at 37 ° C ( 300 rpm). An OI of ₄₀₅ nm was measured and SEI / ml was calculated. Cultures are diluted to 1x10 ⁶ SEI / ml (final concentration for measuring ATP: 1x10 ⁵ SEI / 100 μl per well), test compound is added in an amount of 0.1-10 times the amount of MK. ' (i.e., ΙΟ ₉₀ , as determined by microtiter plate assay). These tubes are incubated for 0, 30 and 60 minutes at 300 rpm at 37 ° C. Use 0.6 ml of bacterial suspension from snap-cap tubes and add to the new 2 ml Eppendorf tubes. Add 0.6 ml of cell lysis reagent (Koske kit), mix with swirl at maximum speed and incubate for 5 min at room temperature. Cool on ice. Allow the luminometer to warm up to 30 ° C (Litshokkap Axep! Lakkuk

- 19 010601

1ssh8 with an injector). Fill one column (= 6 wells) with 100 μl of the same sample. Add 100 μl of luciferase reagent to each well using an injection system. Measure luminescence for 1 s.

Table 6

The values of GSed (μg / ml) determined by analysis in microtiter tablet

1C 90 (mcg / ml) Connection No. Β8Ό ECO EPA EPA ίΜΟ RAE serpent 6ΡΝ 5ΡΥ 8TA THIS 8TA THIS 43635 25922 14506 29212 49594 27853 33402 6305 8668 43300 25923 29213 SHETN BUT nineteen/ 1,1 YU/ 10.8 12.1 60 10/ 10/ 23L 21.0 26 / 26 / 10/ 41 17 / R 22 / 25 / 22 / 206 12/ 31 10/ 4.6 4.1 Yul yul 5/ one/ 11L 44 7.6 7 / 26 Yul 4/ 4 (5 2.0 eleven/ 5/ eleven/ 8/ 27 Yul 8 (9 12/ E 12.7 n / a 7.1 10.1 10.1 5.7 5.1 12.7 32 11.7 4/ 4.6 yud 4/ 13.1 4/ 136 9 £ DZD. 33 UD 11.7 4.6 2 / 11.7 YU/ 5/ 2 / 5/ 13.1 103 11.7 9.3 11.7 13.1 thirteen/ 13.1 10.4 39 10/ 4.7 yud lg 5/ 1.9 13.1 UD 137 21 / 23.8 θΉ- 21 / 36 24.1 4/ IN/ 4/ 3 / 2.7 0 / 4/ 14 11.1 nine/ 5/ 2L 5/ 12D 6 / 2 / 5.6 nine/ 14/ fifteen 24.8 24.8 5L 2 / 12.4 12/ 6 / 2 / 5/ 46 6L 2.8 ? / B / 2 / 0 / 5/ 164 10/ 27D 27.4 27.4 13.8 24 / 4 12.7 174 10/ 175 10/ 12/ 24 10/ 5 ΐ <Μ 38 UD 69 10,4 10/ 13.1 70 10/ 13.1 49 YU/ 10/ thirteen/ 10/ 5 $ eleven/ 136 Yul Yul nineteen/ nineteen one?/ 215 19.7 6 13 (6 10/ Yul sixteen thirteen/ 17 Yul 0 / 67 10 (8 10/ 116 YU/ 110 10/ thirteen/ 111 yul 113 10.8 thirteen/ 196 yul

- 20 010601

in 8/ n thirteen/ thirteen/ 48 10/ 10/ 10/ thirteen/ 13.7 78 P/ eleven/ 84 11.0 eleven/ 7 / eleven/ 45 11.1 12/ 77 eleven/ 14/ 78 115 eleven/ eleven/ 55 0 / 165 14.3 14/ eleven/ 72 9.0 14/ eleven/ 226 14/ 212 eleven/ 171 eleven/ 163 14.7 73 eleven/ 14/ 129 eleven/ 1 $ / eleven/ 149 12/ 201 12/ 12/ 12/ 12.3 FROM fifteen/ eighteen 1?, 3 135 0.7 165 sixteen/ 151 fifteen/ 154 thirty 10.3 10/ nine/ 10.3 5/ 10/ ABOUT 4/ 229 22.5 5,0 21 eleven/ 4.6 eleven/ 12.8 12.8 25 11.6 11l 11.5 12.6 4.1 12.8 twenty 2.6 6 eleven/ eleven/ 11.6 4.6 thirteen/ 4/ 108 13.1 53 5.9 37 12.1

B8I 43639 means BASHIK 8bb! Wk (ATCC 43639); ECO 25922 means ExNepsia Co11 (ATCC 25922); EEA 14506 means En! Egossossik Kaesenk (ATCC 14506); EEA 29212 means En! Egossossik Kaesenk (ATCC 29212); LMO 49594 means L1k! Epa toposuYudepek (ATCC 49594); PAE 27853 means Rkeibotopac aegidshock (ATCC 27853); 8MI 33402 means 81her! Ossosik Ti! Apk (ATCC 33402); 8ΡΝ 6305 means 8! Ger! Ossossik rpeitoshae (ATCC 6305); 8ΡΥ 8668 means 81ger! Ossossik ruodek (ATCC 8668); 8TA 43300 means 81aBy1ossossik igeeik (ATCC 43300); 8TA 25923 means 81arNu1ososspk igeeik (ATCC 25923); 8TA 29213 means 81 arEy1ossossik igeeik (ATCC 29213); 8TA KMETN stands for methicillin-resistant 81arNu1osospk igeeik (MK8A) (clinical isolate from the University of Antwerp). ATCC stands for American Type Culture Collection.

Claims (38)

CLAIM 1. The use of a compound for the manufacture of a medicament for the treatment of a bacterial infection, the compound being a compound of the formula, its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric or Ν-oxide form, where B ¹ represents hydrogen, halogen, polyhaloC _1-6 alkyl, C _1-6 alkyl, Ar or He !; p is an integer equal to 1 or 2; V ² is C _1-6 alkyloxy, C _1-6 alkyloxyC _1-6 alkyloxy or C _1-6 alkylthio; In ³ represents Ar, Not! Or no! ¹ ; B ⁴ and B ⁵ are each independently hydrogen, C 1-6 alkyl or benzyl, or B ⁴ and B ⁵ together with the Ν atom to which they are attached can form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may optionally be substituted with C1-6alkyl, halo, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono - or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxy C1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; B ⁶ represents hydrogen, halogen, polyhaloC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio or two vicinal radicals B ⁶ can be taken together with the formation of a divalent radical of the formula —CH═CH -CH = CH-; g is an integer equal to 1 or 2; B ⁷ represents hydrogen, C _1-6 alkyl, Ar, He! Or no! ¹ ; Ar is a homocyclic radical selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocyclic radical may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halogen, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, polyhaloC _1-6 alkyloxy, C _1-6 alkyloxyC _1-6 alkyl, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C 1-6 alkyl) aminocarbonyl; Not! represents a monocyclic heterocycle selected from the group of фен-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridine; each monocyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halogen, hydroxy, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, C _{1 -6} alkyloxyC _1-6 alkyl or Ar-C (= O) -; Not! ¹ is a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl dioxolyl [benzo]; each bicyclic heterocycle may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halogen, hydroxy, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, C _{1 -6} alkyloxyC _1-6 alkyl or Ar-C (= O) -; provided that the bacterial infection is other than the mycobacterial infection. 2. The use according to claim 1, where the compound is other than (a8, 3B) -6-bromo-a- [2 (dimethylamino) ethyl] -2-methoxy-a-1-naphthalene-b-phenyl-3- quinolinethanol, its pharmaceutically acceptable acid or base addition salt, or its Ν-oxide form. - 22 010601 3. The use according to claim 1 or 2, where the compound of formula (I) is a compound having the following formula: its pharmaceutically acceptable acid or base addition salt; its stereochemically isomeric or Ν-oxide form. 4. The use according to any one of the preceding paragraphs, where the compound of formula (I) or (Ha) is a compound having the following formula: its pharmaceutically acceptable acid or base addition salt; its stereochemically isomeric or Ν-oxide form. 5. The use according to any one of the preceding paragraphs, where I ¹ represents hydrogen, halogen, optionally substituted phenyl or He !. 6. The use according to claim 5, where I ¹ represents hydrogen, halogen or optionally substituted phenyl. 7. The use according to claim 6, where I ¹ represents a halogen. 8. The use according to any one of the preceding paragraphs, where ^II is _C1-6 alkyloxy or _C1-6 alkylthio. 9. The use according to any one of the preceding paragraphs, where I ³ represents Ar or Not !. 10. The use according to any one of claims 1 to 8, where I ³ represents Ar or He! ¹ . 11. The use according to claim 9 or 10, where I ³ represents Ar. 12. The use of claim 11, wherein R ³ is optionally substituted phenyl or optionally substituted naphthyl. 13. Use according to any one of the preceding claims, wherein I ⁴ and I ⁵ are each independently hydrogen, C1 _-6 alkyl or benzyl. 14. The application of item 13, where I ⁴ and I ⁵ represent, each independently, hydrogen or C1-6 alkyl. 15. The use according to any one of claims 1 to 12, where I ⁴ and I ⁵ together with the atom Ν to which they are attached, can form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl , 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may optionally be substituted by C1 _-6 alkyl, halogen, polyhalo _C1-6 alkyl, hydroxy, hydroxyC 1 _-6 alkyl, C1 _-6 alkyloxy, amino, mono- or di (C1 _-6 alkyl) amino, C1 _-6 alkylthio, C1 _-6 alkiloksiS1 _-6 alkyl, C1 _-6 alkiltioS1 _-6 alkyl or pyrimidinyl. 16. The application of clause 15, where I ⁴ and I ⁵ together with the atom Ν to which they are attached, can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl , triazinyl, morpholinyl and thiomorpholinyl, each of these rings may optionally be substituted with C _1-6 alkyl, halogen, polyhaloC _1-6 alkyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkyloxy, amino, mono or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxy C1-6alkyl, C1-6alkylthioC1-6alkyl and pyrimidinyl. 17. The use according to any one of the preceding paragraphs, where I ⁶ represents hydrogen, halogen, polyhaloC _1-6 alkyl, C _1-6 alkyl or two vicinal radicals I ⁶ are taken together with the formation of a divalent radical of the formula -CH = CH-CH = CH -. 18. The application of clause 17, where I ⁶ represents hydrogen or halogen. - 23 010601 19. The use according to any one of the preceding paragraphs, where K ⁷ represents hydrogen. 20. The use according to any one of the preceding paragraphs, where r is an integer equal to 1. 21. The use according to any one of the preceding paragraphs, where p is an integer equal to 1. 22. The use according to claim 1, provided that when one K ¹ is C1-6 alkyl, then p is an integer equal to 2, and the other Deputy K ^{1 is} selected from halogen, polyhalo _C1-6 alkyl, _C1-6 alkyl , Ar or Not !. 23. The use according to any one of the preceding paragraphs, where the bacterial infection is an infection caused by a gram-positive bacterium. 24. The use according to claim 1, where K ¹ represents hydrogen; C1-6alkyl; halogen; phenyl; furanyl optionally substituted with hydroxyC1-6alkyl; or pyridyl; K ² represents C1-6 alkyloxy; C1-6alkylthio or C1-6alkyloxy C1-6alkyloxy; K ³ represents phenyl optionally substituted with 1 or 2 halogen atoms; naphthyl optionally substituted with 1 or 2 halogen atoms or C 1-6 alkyloxy; thienyl; piperidinyl substituted with Ar-C (= O) -; 2,3-dihydrobenzo [1,4] dioxinyl; benzo [1,3] dioxolyl or acenaphthyl; K ⁴ and K ⁵ are each independently hydrogen; C! -6 alkyl; benzyl or K ⁴ and K ⁵ together with the atom Ν to which they are attached can form a radical selected from imidazolyl; pyrazinyl substituted with _C1-6 alkyl; piperazinyl substituted with C1-6alkyl; piperazinyl substituted with pyrimidinyl; piperidinyl; thiomorpholinyl; morpholinyl; pyrrolidinyl or triazolyl; K ⁶ represents hydrogen; halogen; C 1-6 alkyl or two vicinal K ⁶ radicals can be taken together to form a divalent radical of the formula —CH═CH — CH — CH═CH—; K ⁷ represents hydrogen. 25. The use according to claim 1, where the compound of formula (I) is selected from K ³ B Stereochemistry phenyl 1-imidazolyl (IN) 2,4-difluorophenyl MN (CH ₂ CH ₃ ) (IN) its pharmaceutically acceptable acid or base addition salt or its его-oxide form. 26. The use according to claim 1, where the compound of formula (I) is selected from K ¹ K ² In ³ At ⁶ Stereochemistry n OCH phenyl N (IN) Vg OCH ₃ 1-naphthyl B (IN) C1 OCH ₃ phenyl N (IN) phenyl OCH ₃ phenyl n (BUT) phenyl OCH phenyl n (IN) Vg 8CH ₃ phenyl n (BUT) Vg ZSNz phenyl n (IN) Vg OCH 3-fluorophenyl n (A2) Vg OCH 3-fluorophenyl n (IN) Vg OCH phenyl n (AT 2) Vg OCH phenyl n (IN 1) - 24 010601 its pharmaceutically acceptable acid or base addition salt or its Ν-oxide form. 27. The use according to claim 1, where the compound of formula (I) is selected from K ¹ In ² In ³ At ⁴ at ⁵ Stereochemistry Vg OCH ₃ phenyl n n (BUT) its pharmaceutically acceptable acid or base addition salt or its его-oxide form. 28. The combination (a) of a compound of formula (I) according to any one of claims 1 to 27 and (b) of one or more other antibacterial agents for treating a bacterial infection, provided that one or more other antibacterial agents are other than antimycobacterial agents. 29. A pharmaceutical composition for treating a bacterial infection, comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of (a) a compound of formula (I) according to any one of claims 1 to 27 and (b) one or more other antibacterial agents, provided that one or more other antibacterial agents are other than antimycobacterial agents. 30. The use of the combination of claim 28 for treating a bacterial infection. 31. The use of the pharmaceutical composition according to clause 29 for the treatment of bacterial infections. 32. A product for the treatment of bacterial infection, containing (a) a compound of formula (I) according to any one of claims 1 to 27 and (b) one or more other antibacterial agents, provided that one or more other antibacterial agents are other than antimycobacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of bacterial infections. 33. A compound selected from In ¹ In ² In ³ At ⁶ Stereochemistry 3-pyridyl OCH ₃ 3,5-difluorophenyl N (BUT) 2-furanyl OCH ₃ 1-naphthyl n (IN) Vg OCH f n (BUT) Vg OCH ₃ Phenyl n (AT 2) Vg OCH Phenyl n (IN 1) its pharmaceutically acceptable acid or base addition salt or its его-oxide form. 34. A compound selected from - 25 010601 K ³ B Stereochemistry and melting points 2,4-difluorophenyl CN (CH ₂ CH ₃ ) (IN) 2,4-difluorophenyl ΝΗ (ΟΗ ₂ ΟΗ ₃ ) (BUT) 2,4-difluorophenyl S (CH ₂ CH ₃ ) (CH ₂ -phenyl) (IN) phenyl ΝΗ (ΟΗ ₃ ) (IN) its pharmaceutically acceptable acid or base addition salt or its его-oxide form. 35. The use according to any one of claims 1 to 27, 30 and 31, wherein the bacterial infection is an infection associated with staphylococci, enterococci or streptococci. 36. The use according to any one of claims 1 to 27, 30 and 31, wherein the bacterial infection is an infection associated with methicillin-resistant 81 aryu1ossoss5 aigeik (MK8A), methicillin-resistant, coagulase-negative staphylococci (ΜΕΟΝΞ). penicillin-resistant 81gerosossi5 rieitoshe or resistant to many drugs 37. The use according to any one of claims 1 to 27, 30 and 31, wherein the bacterial infection is an infection associated with 81 aryosossi5 aigeyik or 81er1osossi5 ariel. 38. The use according to any one of claims 1 to 27, 30 and 31, where the bacterial infection is an infection associated with 81 aryuosossi5 aigeyik.