BG109179A - Chinoline derivatives as antibacterial means - Google Patents

Abstract

The invention relaters to the use of a compound for the production of a medicament for the treatment of bacterial infections, pharmaceutical acceptable acid or basic connection salt of said compound, to its stereochemical isomeric form or its N-oxide form. The compound has the formula wherein R1 is hydrogen, polyhalo-C1-6alkyl, Ar or Het; p has the value of 1 or 2; R2 is C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy or C1-6alkylthio; R3 is Ar, Het or Het1; R4 and R5 are individually and independently hydrogen, C1-6alkyl or benzyl; or R4 and R5 taken together and including N to which they are attached can form a radical selected from the group of pyrolidinyl, 2-pyrolinyl, 3-pyrolinyl, pyrolyl, imidazolidinyl, pyrazole idinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, triazolyl, piperidinyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of the said rings optionally can be substituted by C1-6 alkyl, halogen, polyhaloC1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6alkyloxy, amino, mono-or di(C1-6 alkyl)amino, C1-6alkylthio, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl; R6 is hydrogen, halogen, polyhaloC1-6alkyl,C1-6alkyl, C1-6alkyloxy, C1-6alkylthio; or two adjacent radicals R6 taken together form a two-valent radical with formula -CH=CH-CH=CH-; r has the value 1 or 2; R7 is hydrogen, C1-6 alkyl, Ar, Het orHet1. The invention also relates to different ones from the mycobacterial.

Description

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

BACKGROUND OF THE INVENTION

Resistance to older and cheaper antibiotic agents has suddenly become a problem. Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, polyresistant salmonella.

© The effects of antibiotic resistance are serious. Infections caused by resistant germs do not respond to treatment, leading to prolonged illness and a higher risk of death. Failure to treat also leads to long periods of infection that increase the number of infected people moving into society, thereby exposing the general population to the risk of contracting resistant strains. Hospitals are a critical component in the worldwide problem of antimicrobial resistance. The combination of highly susceptible patients, the intensive and prolonged use of antimicrobials and cross-contamination lead to infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials and other agents is a major contributing factor to resistance. Self-medicated antimicrobials may be unnecessary, often under-dosed, or may not contain the required amount of medicine.

Another major problem is the patient's disagreement with the recommended treatment. Patients forget to take the medicine, interrupt treatment when they feel better or cannot afford the full course, thus creating the ideal environment for the germs to adapt rather than be destroyed.

Due to the emergence of multiple antibiotic resistance, doctors are facing infections for which there is no effective therapy. The morbidity, mortality and financial costs of such infections require increased care for healthcare systems worldwide.

Therefore, there is a great need for new compounds for the treatment of bacterial infections, and more specifically for the treatment of infections caused by resistant strains.

WO 2004/011436 discloses substituted quinoline derivatives having activity against Mycobacteria, especially against Mycobacterium tuberculosis. One particular compound of these substituted quinoline derivatives is described in Science (2005), 307, 223-227.

It has now been found that the quinoline derivatives described in

WO 2004/011436, have activity against bacteria other than Mycobacteria.

SUMMARY OF THE INVENTION

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

a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or a # -oxide form thereof, wherein

R ¹ is hydrogen, halogen, polyhaloC 1-4 alkyl, C 1-4 alkyl, Ar or Het;

p is an integer equal to 1 or 2;

A

R is C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxy or

Salkalkylthio;

R ³ is Ar, Het or Het ¹ ;

R ⁴ h R ⁵ are each hydrogen, C ^1-4 alkyl or benzyl; or

R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, imidazolyl pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl each

R ⁷

Ar is said rings may be optionally substituted by C 1-6 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 alkylthioC1. ₆ alkyl or pyrimidinyl;

R ⁶ is hydrogen, halogen, polyhaloSvalkyl, Sbalkyl,

Salkyloxy, Svalalkylthio; or two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-;

is an integer equal to 1 or 2;

is hydrogen, C1-6alkyl, Ar, Het or Het ¹ ;

a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle optionally substituted by 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halogen, cyano, nitro, amino, mono- or di (C 1 -alkyl) amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy C _1-6 alkyl, C 1-3. ₆ alkyloxy, polihaloSyvalkiloksi, Sybalkil oksiSybalkil, carboxyl, C ₆ alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (Syb ^_ alkyl) aminocarbonyl;

Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl and pyrazinyl; each monocyclic heterocycle may optionally be substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halogen, hydroxy, C]. ₆ alkyl, polyhaloalkyl, hydroxyC1]. ₆ alkyl, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl or Ar-C (= O) -;

Het ¹ is a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo; each bicyclic heterocycle may be optionally substituted by 1, 2 or 3 substituents, each substituent independently selected from the group of halogen, hydroxy, C1-3alkyl, polyhaloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyl or Ar-C (= C 1 -C (= O) ) -;

provided that the bacterial infection is different from the mycobacterial infection.

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

As used hereinafter, C 1-6 alkyl, as a group or part of a group, means straight or branched chain saturated hydrocarbon radicals containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl , hexyl, 2-methylbutyl and the like.

As used hereinafter, the term (= 0) when attached to a carbon atom is a carbonyl moiety.

The term halo is the generic name for fluoro, chloro, bromo and iodo. As used hereinbefore, polyhaloC1-6alkyl as a group or part of a group means mono- or polychalosubstituted C 1]. ₆ alkyl, for example methyl with one or more fluorine atoms, for example difluoromethyl or trifluoromethyl, 1,1-difluoroethyl and the like. If more than one halogen atom is attached to the alkyl group in the definition of polyhaloC1-6alkyl, they may be the same or different.

In the definition of Het or Het 'or when R ⁴ and R ⁵ are taken together, account is taken of the participation of all possible isomeric forms of heterocycles, for example pyrrolyl includes 1Hpyrrolyl and 2H-pyrrolyl.

Ar, Het or Het ¹ cited in the definitions of the substituents of the compounds of formula (I) (see for example R ³ ), as mentioned hereinafter, may, unless otherwise stated, be attached to the remainder of the molecule with formula (I) at each ring carbon or heteroatom, as appropriate. For example, when Het is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

The lines coming out of the substituents in the ring systems mean that the bond can be at any suitable ring atom.

When two adjacent radicals R ⁶ are taken together to form a divalent radical of formula -CH = CH-CH = CH-, it means that the two adjacent radicals R ⁶ form together with the phenyl ring to which they are attached naphthyl.

Salts of compounds of formula (I) for therapeutic use are those in which the amphoteric ion is pharmaceutically acceptable. However, salts of acids and bases that are pharmaceutically unacceptable may also be used, for example in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are within the scope of the present invention.

The pharmaceutically acceptable addition salts, as referred to hereinafter, are intended to include the therapeutically active non-toxic forms of the acid addition salts which the compounds of formula (I) can form. The latter can be conveniently obtained by treating the basic form with suitable acids, such as inorganic acids, for example, hydrohalic acids, for example hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid, etc .; or organic acids, for example, acetic, propane, hydroxyacetic, 2hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-

1,2,3-Propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzene-sulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like. Conversely, when treated with bases, the salt can be converted to the free base form.

Compounds of formula (I) containing acidic protons can be converted to their therapeutically active non-toxic metal or amine addition salts by treatment with suitable organic or inorganic bases. Suitable basic salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium salts, etc., salts with organic bases, for example primary, secondary and tertiary aliphatic and aromatic amines such as methylamine , propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine isoquinolin, benzathine, A-methyl-D-glucamine, 2-amino-2 (hydroxymethyl) -1,3-propanediol, hidrabamininovite salts, and salts with amino acids such as arginine, lysine and the like. Conversely, salts can be converted to free acids by acid treatment.

The term addition salt also includes the hydrate and solvate attachment forms which the compounds of formula (I) may form. Examples of such forms are, for example, hydrates, alcoholates, and the like.

The V-oxide forms of the present compounds include the compounds of formula (I), wherein one or more tertiary nitrogen atoms are oxidized to the so-called N-oxide.

The compounds of formula (I) can be converted to the corresponding N-oxide forms by known methods for the conversion of trivalent nitrogen to its V-oxide form.

Said V-oxidation reactions are generally carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali and alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as benzenecarboperoxy acid or halogen-substituted benzenecarboperoxy acid, for example 3-chlorobenzenecarboperoxy acid, peroxoalkanoic acids, e.g.

I peroxoacetic acid, alkyl hydroperoxides, for example tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol, etc., hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

It can be appreciated that some of the compounds of formula (I) and their TV oxides or addition salts may contain one or more chiral centers and exist as stereochemical isomeric forms.

The term stereochemical isomeric forms, as used hereinafter, means all the possible stereoisomeric forms that may have the compounds of formula (I) and their TV oxides, addition salts or physiologically functional derivatives. Unless otherwise mentioned or indicated, the chemical name of the compounds means the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. In particular, stereogenic centers may have an R or S configuration; the substituents on divalent cyclic (partially) saturated radicals may have either a cis- or titration-configuration. Compounds containing double bonds may have E (entergenic) or Z (tosamine) stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are known to those skilled in the art.

It is envisaged to encompass the stereochemical isomeric forms of the compounds of formula (I) within the scope of the invention.

Following the conventional CAS nomenclature (CAS =

Chemical Abstracts Cervices) when two stereogenic centers of known molecular configuration are involved in a molecule, the parameter R or S is specified (based on the Cahn-Ingold Prelog Sequence Rule) for the chiral center with the smallest number - the reference center. The configuration of the second stereogenic center is indicated using relative parameters [7? * 7? *] Or [7? *, S '*], where R * is always specified as the reference center and [7? * 7? *] means centers with the same chirality, a [/? * £ *] means centers with different chirality. For example, if the chiral center with the smallest number in the molecule has 5 configurations and the second center is R, the stereo parameter will be defined as S- [7? *, S *]. If a and β are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the smallest number in the ring is preferably always in the a position relative to the median plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the highest priority position of the reference atom is referred to as a if it is on the same side of the median plane defined by the ring system or as β, if it is on the other side of the median plane defined by the ring system.

When a particular stereoisomeric form is indicated, it means that said form is practically free, i.e. it is mixed with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably less of 1% of the other isomer (s). Thus, when a compound of formula (I) is, for example, specified as (aS, βΚ), this means that the compound is practically free of the (aR, PS) isomer.

The compounds of formula (I) can be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another by known separation methods. The racemic compounds of formula (I) can be converted to the corresponding diastereomeric salts by reaction with a suitable chiral acid. Said diastereomeric salts are subsequently separated, for example, by selective or fractional recrystallization and the enantiomers are liberated by means of bases. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves chiral stationary phase liquid chromatography. Said pure stereochemically isomeric forms may also be prepared from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific. If a specific stereoisomer is sought, it is preferred that said compound be synthesized by stereospecific methods of preparation. These methods preferably use enantiomerically pure starting materials.

The invention also includes derivatives (commonly referred to as precursors) of the pharmacologically active compounds of the invention that are degraded in vivo to give the compounds of the invention. Typically (but not always) precursors have lower target receptor activity than the compounds to which they are degraded. Precursors are particularly useful when the desired compound has chemical and physical properties that make its administration difficult and ineffective. For example, the desired compound may be poorly soluble, may be poorly transported through the mucosal epithelium, or may have an undesirable short plasma half-life. Further discussions on precursors can be found in Stella, V.J. et al, Prodrugs, Drug Delivei Systems, 1985, pp. 112-176 and Drugs, 1985, 29, pp. 455473.

The precursor forms of the pharmacologically active compounds of the invention are generally compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their tautomeric forms, and their A-oxide forms having an acidic group that is esterified or amidated . Such esterified groups include the groups of formula -COOR ^X , where R ^x is C ;. ₆ alkyl, phenyl, benzyl or one of the following groups:

The amidated groups include groups of the formula -CONR ^y R ^z , wherein R ^y is H, C 1-6 alkyl, phenyl or benzyl, and R ^z is -OH, H, C 1-6 alkyl, phenyl or benzyl.

Compounds of the invention containing an amino group may be derivatized with a ketone or aldehyde, such as formaldehyde, forming a manic base. This base is hydrolyzed in aqueous solution in a first order reaction.

As used herein, the term compounds of formula (I) include their # -oxide forms, their addition salts, or their stereochemically isomeric forms. Of particular interest are those compounds of formula (I) which are stereochemically pure.

The first embodiment of the present invention relates to a compound of formula (1-a)

R ⁴

(1-a) its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric form or its A-oxide form.

A second embodiment of the present invention relates to a compound of formula (I-b)

a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an A-oxide form thereof.

A third embodiment is the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ¹ represents hydrogen, halogen, C _1-6 alkyl, Ar or Het; preferably hydrogen, halogen, optionally substituted phenyl or Het; more preferably hydrogen, halogen, optionally substituted phenyl, optionally substituted furanyl or pyridinyl; more preferably hydrogen, halogen or optionally substituted phenyl; most preferably halogen, such as bromine or chloro, especially bromine.

A fourth embodiment is the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ¹ is halogen, polyhaloC 1-6 alkyl, Ar or Het; preferably halogen, Ar or Het; more preferably halogen, optionally substituted phenyl, or Het; more preferably halogen, phenyl, optionally substituted furanyl or pyridinyl.

A fifth embodiment is the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ² is C]. ₆ alkyloxy or C1-4alkylthio, in particular methoxy or methylthio; preferably C 1-6 alkyloxy; more preferably methoxy.

The sixth embodiment of interest are the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ³ is Ar or Het or where R ³ and Ar or Het ¹ ; preferably R ³ is Ar; more preferably optionally substituted phenyl or optionally substituted naphthyl; more preferably phenyl optionally substituted with halogen or C1-6alkyloxy or naphthyl optionally substituted with halogen or C1-6alkyloxy; most preferably phenyl optionally substituted with 1 or 2 halogens, in particular fluoro or naphthyl, in particular 1-naphthyl.

A seventh interest embodiment is the compounds of formula (I) or any subgroup thereof previously mentioned as an interesting embodiment, wherein R ⁴ is R ⁵ are each independently hydrogen or Svalkyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, imidazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which rings may be optionally substituted by C 1-6 alkyl, halogen, polyhaloC 1-6 alkyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, (C 1-6 alkyl) amino, C 1-6 alkyl O S1.6alkiloksiS1.balkil, C byalkiltioCj alkyl or pyrimidinyl; more preferably R ⁴ is Sweet and R ⁵ and hydrogen or C 1-6 alkyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, imidazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which rings may be optionally substituted by C 1-6 alkyl, halogen, polyhaloC 1-6 alkyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, ) amino, Sbalkilt oh SybalkiloksiSybalkil, SrbyalkiltioS1. ₆ alkyl or pyrimidinyl; more preferably R ⁴ is C 1-6 alkyl and R ⁵ is hydrogen or C 1-4 alkyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, triazinyl, triazinyl, triazinyl thiomorpholinyl, each of which may optionally be substituted by C 1-6 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 1-4 alkylthio, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylthioC 1. ₆ alkyl or pyrimidinyl; most preferably R ⁴ and C 1-6 alkyl, in particular methyl or ethyl, in particular methyl, and R ⁵ is hydrogen or C 1-6 alkyl, in particular methyl or ethyl, more preferably methyl.

Eight of interest embodiment are the compounds of formula (I) or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ⁴ and R ⁵ are each independently hydrogen, C 1-6 alkyl or benzyl; preferably R ⁴ and R ⁵ are each hydrogen or C 1-6 alkyl; more preferably R ⁴ is C 1-6 alkyl and R ⁵ is hydrogen or C 1-6 alkyl; most preferably R ⁴ and R ⁵ are C 1-6 alkyl, in particular methyl or ethyl, in particular methyl.

The ninth of interest embodiment are the compounds of formula (I) or any subgroup thereof, previously mentioned as an interesting embodiment, where R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl , 2pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyridinyl, pyrimidinyl Even ualno be substituted with Sybalkil, halogen, polyhaloC, hydroxy, hydroxyC, Syvalkiloksi, amino, mono- or di (S1.balkil) amino, Sybalkiltio, SybalkiloksiSybalkil, SybalkiltioSybalkil or pyrimidinyl; preferably R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazinyl, triazinyl, triazinyl and thiomorpholinyl, each of which may optionally be substituted by Cl. 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 R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which may optionally have is substituted by C 1-6 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 R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which rings may be optionally substituted with C 1-6 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 1-4 alkylthio, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylthioC 1-4 alkyl or pyrimidinyl; most preferably R ⁴ and R ⁵ taken together and including the N to which they are attached form imidazolyl.

Preferably, the substituents in the ring system, when R ⁴ and R ⁵ are taken together, are selected from C 1-6 alkyl, halogen, polychaloC 1. ₆ alkyl, hydroxy, C1]. ₆ alkyloxy, C 1-6 alkylthio and pyrimidinyl; more preferably the substituents are selected from C 1-6 alkyl or pyrimidinyl.

The ten embodiments are the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ⁶ is hydrogen, halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl; or two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-; preferably R ⁶ is hydrogen, halogen, polyhaloC 1-6 alkyl or C 1-6 alkyl; more preferably R ⁶ is hydrogen, halogen, or sweet; more preferably R ⁶ is hydrogen or halogen; most preferably R ⁶ is hydrogen.

The eleven of interest embodiment are the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein R ⁷ is hydrogen.

The twelve of interest embodiment are the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, wherein r is an integer equal to 1.

The thirteen of interest embodiment are the compounds of formula (I) or any subgroup thereof previously mentioned as an interesting embodiment, wherein p is an integer equal to 1.

The fourteenth of interest embodiment are the compounds of formula (I) or any subgroup thereof previously mentioned as an interesting embodiment, provided that when one R ¹ is Cl. ₆ alkyl, then p is an integer equal to 2, and the other R ¹ substituent is selected from halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl, Ar or Het.

The fifteenth of interest embodiment are the compounds of formula (I) or any subgroup thereof previously mentioned as an interesting embodiment, where the compound is different from (aS, pK) -6-bromo-a- [2- (dimethylamino) ethyl] -219 methoxy-α-1-naphthalenyl-t-phenyl-3-quinolinethanol, its pharmaceutically acceptable acid or base addition salt or its A-oxide form.

The sixteenth embodiment of interest is the use of a compound of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, for the manufacture of a medicament for the treatment of infection by a gram-positive and / or gram-negative bacterium.

The seventeenth embodiment of interest is the use of a compound of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, for the manufacture of a medicament for treating a Gram-positive bacterial infection.

The eighteenth of interest embodiment is the use of the compounds of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, for the manufacture of a medicament for treating a Gram-negative bacterial infection.

The twenty embodiment of interest is the use of a compound of formula (I), or any subgroup thereof, previously mentioned as an interesting embodiment, for the manufacture of a medicament for treating a bacterial infection, wherein the compound of formula (I) has 1C ₉₀ <15 μΙ / ml against at least one bacterium, in particular a gram-positive bacterium, preferably 1C ₉ o <10 μΙ / ml, more preferably 1C ₉₀ <5 μΙ / ml; value of 1C ₉ o is determined as described below.

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

a) R ¹ is hydrogen; Salkyl; halogen, in particular bromine or chloro; phenyl; furanyl optionally substituted by hydroxyC 1-6 alkyl; or pyridyl;

b) R ² is C 1-6 alkyloxy, in particular methoxy or ethoxy; C1-6 alkylthio, in particular methylthio; or C1-4 alkyloxy;

c) R ³ is phenyl optionally substituted by 1 or 2 halogens, preferably fluoro; naphthyl optionally substituted with 1 or 2 halogens or C]. ₆ alkyloxy; thienyl; piperidinyl substituted with ArC (= O); 2,3-dihydrobenzo [1,4] dioxinyl; benzo [1,3] dioxolyl; or acenaphthyl;

d) R ⁴ and R ⁵ are each independently hydrogen; C 1-6 alkyl; benzyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from imidazolyl; pyrazinyl substituted with C 1-6 alkyl; piperazinyl substituted with Sweet l; piperazinyl substituted with pyrimidinyl; piperidinyl; thiomorpholinyl; morpholinyl; pyrrolidinyl; or triazolyl;

e) R ⁶ is hydrogen; halogen, in particular chloro or bromo; C 1-6 alkyl; or two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-;

f) R ⁷ is hydrogen.

Most preferred compounds of the present invention are compounds 50, 206, 31, 26, 27, 32, 33, 109, 39, 44, 41, compounds A, E and F, their pharmaceutically acceptable acid or base addition salt, or their A- oxide form.

The present invention also relates to a compound selected from

-4 ·

R ¹ R ² R ³ R ⁶ Stereochemistry 3-Pyridyl OCH3 3,5- difluorophenyl N. (A) 2-furanyl OCH3 1-naphthyl N. (IN) Br OCH3 N. (A) Br OCH3 phenyl N. (B2) Br OCH3 phenyl N. (B1)

a pharmaceutically acceptable acid or base addition salt or A-oxide form thereof.

The present invention also relates to a compound selected from

R ³ L Stereochemistry 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (IN) 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (A)

2,4-difluorophenyl B [(CH ₂ CH ₃ ) (CH ₂ phenyl) (IN) phenyl NH (CH ₃ ) (IN)

a pharmaceutically acceptable acid or base addition salt thereof or a Y-oxide form thereof.

The compounds of formula (I) can be prepared according to the methods described in WO 2004/011436, incorporated herein by reference.

In general, the compounds of the invention can be prepared by a series of steps, each of which is known to one skilled in the art.

In particular, the 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):

Scheme 1

using BuLi in a mixture of diisopropylamine and tetrahydrofuran, wherein all substituents are defined as in formula (I). The reaction rate can be increased with stirring. It is appropriate to carry out the reaction at a temperature in the range of -20 to -70 ° C.

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

Scheme 2

wherein all substituents are defined as in formula (I). Reaction scheme (2) includes step (a) in which a suitably substituted aniline is reacted with the corresponding acyl chloride, such as 3-phenylpropionyl chloride, 3-fluorobenzene propionyl chloride or p-chlorobenzene-propionyl chloride, in the presence of a suitable base, in the presence of a suitable base. a reaction inert solvent such as methylene chloride or ethylenedichloride. It is appropriate to carry out the reaction at a temperature in the range between room temperature and the reflux temperature of the solvent. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl 3) in the presence of Ν, мети dimethylformamide (Vilsmeier-Haack formulation, followed by cyclization). It is appropriate to carry out the reaction at a temperature in the interval between room temperature and

the boiling point of the solvent. In the next step (c), a specific R-group is introduced, where R is, for example, a C 1-6 alkyloxy or C 1-6 alkylthio radical, by reacting the intermediate obtained in step (b) with a compound XX-C 1-6 alkyl, where X is S or O.

The intermediates of formula (II-b) can be prepared according to the following reaction scheme (3), where in the first step (a) substituted indole-2,3-dione is reacted with substituted 3-phenylpropionaldehyde in the presence of a suitable base as sodium hydroxide (Pfitzinger reaction) and then in the next step (b) the carboxylic acid compound is decarboxylated at high temperature in the presence of a suitable inert solvent such as diphenylether.

Scheme 3 .on

Ν '(P-b)

Obviously, in the preceding and subsequent reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methods known in the art, such as extraction, crystallization and chromatography. It is also clear

that reaction products which exist in more than one enantiomeric form can be isolated from their mixture by known methods, in particular preparative chromatography, for example as preparative HPLC. Typically, compounds of formula (I) are separated into their isomeric forms.

The intermediates of formula (III) are compounds which are either commercially available or can be prepared according to conventional reaction products known in the art. For example, intermediates of formula (III-a) in which R ³ is Ar, substituted with s substituents R ¹⁰ , wherein each R 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, polyhalo-C 1-6 alkyl, C 1-6 alkyloxy, poly halo C 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C 1-6 alkyl) aminocarbonyl, and 0-carbonyl, and 0-carbonyl; , 1, 2 or 3 can be prepared according to the following reaction scheme (4):

Scheme 4

(a) • Cl ----->

(lll-a)

Reaction scheme (4) includes step (a) in which suitably substituted Ar, especially suitably substituted phenyl, is reacted with Friedel-Craft with a corresponding acyl chloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride in the presence of a suitable Lewis an acid such as AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl ₂ and a suitable inert solvent such as methylene chloride or ethylenedichloride. It is appropriate to carry out the reaction at a temperature in the range between room temperature and the reflux temperature of the solvent. In the next step (b), an amino group (-NR4R5) is introduced by reacting the intermediate obtained in step (a) with a primary or secondary amine.

Typically, bacterial pathogens are classified as either gram-positive or gram-negative pathogens. Antibiotic compounds active against both Gram-positive and Gram-negative pathogens are considered to have a broad spectrum of action. The compounds of the present invention are referred to as gram-positive and / or gram-negative bacterial pathogens. In particular, the present compounds are active to at least one gram-positive bacterium, preferably to several gram-positive bacteria, more preferably to 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, including staphylococci, such as S. aureus; enterococci, such as E. faecalis; streptococci, for example S. pneumoniae, S. mutans, S. pyogens; bacilli, for example Bacillus subtilis; Listeria, for example Listeria monocytogenes; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; Pseudomonas, for example Pseudomonas aeruginosa; and Escherichia, for example E. coli. Gram-positive pathogens, such as staphylococci, enterococci, and streptococci, are particularly important because they develop resistant strains, which once emerged, are difficult to treat and difficult to eradicate in a hospital setting, for example. Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae, and polyresistant Enterococcus faecium.

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

The compounds of the present invention are particularly active against Staphylococcus aureus, including resistant Staphylococcus aureus, such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae.

In particular, the compounds of the present invention are active against those bacteria whose vitality depends on the proper functioning of FIFO ATP synthase. Without being bound by any theory, the activity of the present compounds is believed to lie in the inhibition of FIFO ATP synthase, particularly in the inhibition of the F0 complex of FIFO ATP synthase, in particular in the inhibition of the subunit with the F0 complex of FIFO ATP synthase, which results in the destruction of bacteria by depleting the cellular ATP levels of the bacteria.

When it is said so far or further that the compounds can treat a bacterial infection, it is meant that the compounds can treat the infection from one or more bacterial strains.

When a bacterial infection is so far or hereafter said to be different from a mycobacterial infection, it is meant that the bacterial infection is different from an infection by one or more mycobacteria.

The exact dosage and frequency of administration of the present compounds, as known to one skilled in the art, depends on the particular compound of formula (I) used, the exact condition being treated, the severity of the condition being treated, the age, the weight, sex, diet, time of administration, and general physical condition of the individual patient, the route of administration, and other medicines the patient may take. Furthermore, it is clear that the effective daily amount may be reduced or increased depending on the response of the individual being treated and / or at the discretion of the physician 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. The compounds and compositions containing the compounds can be administered topically, locally or systemically. Systemic administration includes any method of administration of the compound to body tissues, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. The specific dosage of the antibacterial agent administered as well as the duration of treatment may, if necessary, be specified.

Bacterial infections that can be treated with the present compounds include, for example, central nervous system infections, external ear infections, middle ear infections such as acute medial otitis, cranial sinus infections, eye infections, oral infections such as infections of the teeth, gums and mucous membranes, infections of the upper respiratory tract, infections of the lower respiratory tract, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin infections and skin structures, bacterial endocarditis, burns, antibacterial surgical prophylaxis, and antibacterial prophylaxis in immunosuppressed patients, such as cancer patients with chemotherapy or organ transplant patients.

Due to 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 combat bacterial infections.

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

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

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

For its administration, the present pharmaceutical composition may be in various pharmaceutical forms. Suitable compositions may be cited for all compositions used for systemically administered drugs. For the preparation of the pharmaceutical compositions of this invention, an effective amount of the individual compounds, optionally in the form of an addition salt, is mixed as an active ingredient in a homogeneous mixture with a pharmaceutically acceptable carrier, which carrier may have a wide variety of forms depending on the desired preparation. . These pharmaceutical compositions are desirably in unit dosage form, suitable in particular for oral administration or parenteral injection. For example, in the preparation of compositions in oral dosage form, any conventional pharmaceutical medium, such as water, glycols, oils, alcohols, and the like, may be used 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 of administration, tablets and capsules represent the most preferred oral unit dosage form, naturally using solid pharmaceutical carriers. For parenteral compositions, the carrier typically contains sterile water for the most part, but other ingredients may be included, for example, to aid solubility. For example, injectable solutions may be prepared in which the carrier includes saline, glucose solution or a mixture of saline and glucose solution. For example, injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. Also included are solid preparations that can be converted to liquid shortly before use.

Depending on the route of administration, the pharmaceutical composition preferably contains from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of the active ingredients and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight of the pharmaceutically acceptable carrier. all percentages being based on the total weight of the composition.

The weight / weight ratios of the compound of formula (I) and (b), the other antibacterial agent (s) when given in combination, can be determined by one of ordinary skill in the art. Said ratio and exact dosage and frequency of administration, as known to one of ordinary skill in the art, depend on the exact condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, and the general physical condition of the individual patient, the route of administration, and other medicines the patient may take. Furthermore, it is clear that the effective daily amount may be reduced or increased depending on the response of the individual being treated and / or at the discretion of the physician prescribing the compounds of the present invention.

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

The pharmaceutical composition may further comprise a variety of other known ingredients 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 colorant.

It is particularly advisable to formulate the above pharmaceutical compositions in unit dosage form for easy administration and uniform dosage. A unit dosage form as used herein refers to physical discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient, calculated to give the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including graphite or film-coated tablets), capsules, pills, powders, patches, suppositories, injectable solutions or suspensions and other similar and separate multiples thereof. The daily dose of the compound of the invention naturally varies with the compound used, the route of administration, the treatment desired, and the bacterial disease indicated.

Other antibacterial agents that can be combined with the compounds of formula (I) are known in the art antibacterial agents. These other antibacterial agents include antibiotics of the β-lactam group such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semi-synthetic cephalosporins, cephamicins, 1-oxacephemes, clavulanic acids, penemas, carbapenems, monocarbins, monocarbins, monocarbins; tetracyclines, anhydrotetracyclines, anthracyclines;

aminoglycosides; nucleosides such as A-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides such as 12 membered ring macrolides, 14 membered ring macrolides,

16-membered ring macrolides; ansamycin; peptides such as bleomycin, gramicidins, polymyxins, bacitracins, large-ring peptide antibiotics containing lactone bonds, actinomycin, amphomycin, capreomycin, dystamycin, enduracidin, mycamycin, neocarcinostatin, stendomycin, viomycin; cycloheximide; cycloserine; variotin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycin; fumagiline; monensins; pyrrolitrin; phosphomycin; fusidic acid; D- (phydroxyphenyl) glycine; D-phenylglycine; united.

Certain antibiotics that may be combined with the present compounds of formula (I) are, for example, benzylpenicillin (potassium, procaine, benzatin), phenoxymethylpenicillin (potassium), pheneticillin potassium, propicillin, carbenzylin (disodium, phenylnatrium, indanylcincyl) disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, meslocillin, piperacillin sodium, amoxicillin, cyclacillin, hectacillin, sulbactam sodium, thalampicillin hydrochlorcic, cefalexin cefacolin cefacolin cefadroxil cefadirin cefapirin sodium cefacetril cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin, cefmetazole, cefotethan, latamoxef, clavulanic acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride, demethylchlortetracycline, metetetracycline n, doxycycline, rolitetracycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamitsinsulfat, bekanamitsin, tobramycin, gentamycin sulfate, dibekacin, amikacin, mikronomitsin, ribostamycin, neomycine sulphate, paromomitsinsulfat, streptomycin sulfate, dihydrostreptomycin, destomitsin A, hygromycin B, apramycin, sisomicin, netilmitsinsulfat , spectinomycin hydrochloride, astromycin sulfate, validamycin, casugamycin, polyoxin, blasticidin S, erythromycin, erythromycinestolate, oleandomycin phosphate, tracetyloleandomycin, kitamycin, g samicin, tiromycin, butyricin, butyric acid monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, trichomycin, mitramycin, lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavophospholipol, cycloserine, pecilocin, griseofulvin, chloramphenicol loramfenikolpalmitat, mitomycin C, pirolnitrin, fosfomycin, fusidic acid, bikozamitsin, tiamulin, sikanin.

Tables 1 to 4 list compounds of formula (I) according to the present invention.

Some compounds have not been experimentally determined by the absolute stereochemical configuration of the stereogenic carbon atom (s). In these cases, the stereochemical isomeric form, which is isolated first, is referred to as A and the second as B, without further citing the actual stereochemical configuration. However, said A and B isomeric forms can be unambiguously characterized by one of ordinary skill in the art, using methods known in the art, for example, by X-ray diffraction.

In case A and B are stereoisomeric mixtures, they can be further separated, whereby the corresponding isolated first fractions are denoted A1 and B1, respectively, and the latter with A2 B2 respectively, without further citing the actual stereochemical configuration. However, said Al, A2 and B1, B2 isomeric forms can be unequivocally characterized by one of ordinary skill in the art, using methods known in the art, for example, by X-ray diffraction.

The present compounds are numbered in accordance with the compounds of WO 2004/011436 and can be prepared according to the methods described in WO 2004/011436. "Etc. No. ”in the tables below refers to the example numbers in WO 2004/011436, indicating according to which method the compounds can be prepared.

The additional compounds are indicated by letters.

Compounds A, B and C were prepared according to the methods described in WO 2004/011436. The diagram below shows the course of synthesis of compounds A, B and C. Examples Nos. A8, A9, B12 and B13 correspond to the methods of WO 2004/011436.

Compound C, which is a diastereoisomer (B), is isolated from the diastereoisomer mixture as follows:

The residue (5.4 g) obtained according to the procedure of B12 was purified by column chromatography on silica gel (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 the diastereoisomer (B), and compound B, which is the diastereoisomer (A), were isolated from the mixture of diastereoisomers as follows: The residue (1.7 g) obtained according to the procedure of Example B13 was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH4OH; 98/2 / 0.1). Two fractions were collected and the solvent was evaporated. The fractions were recrystallized individually in diisopropyl ether to give 0.31 g of compound B (diastereoisomer A) (yield: 27%) and 0.52 g of compound A (diastereoisomer B) (yield: 45%).

Compound D was prepared according to the methods described in

WO 2004/011436. The diagram below shows the course of synthesis of compound D. Examples numbers A9, B12 and B13 correspond to the methods of WO 2004/011436.

Compound D, which is the diastereoisomer (B), is isolated from the mixture of diastereoisomers as follows:

The residue (1.2 g) obtained according to the procedure of Example B13 was purified by silica gel column chromatography (eluent: CH2Cl2 / CH3OH / NH4OH; 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 D (diastereoisomer B) (yield: 10%).

Compounds E and F were prepared by separating compound 4 (diastereoisomer B) from WO 2004/011436 into its enantiomers by the following method: The final compound 4 (2.5 g) was separated into its enantiomers by column chromatography (eluent: hexane / ethanol 99.95 / 0.05; column: CHIRACEL OD). Two pure fractions were collected and the solvents were evaporated. Yield: 0.5 g of compound E (enantiomer B1) (melting point 180 ° C) and 0.12 g of compound F (enantiomer B2) (melting point 175 ° C).

Compound G was prepared as follows:

Mixture of compound 115 (prepared according to B15 of WO 2004/011436) (0.00028 mol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.00055 mol), Pd [P (Ph ₃ )] ₄ (0.00003 mol) and Na ₂ CO ₃ 2M (0.0011 mol) in dimethoxyethane (4 ml) was 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 pm). The pure fractions were collected and the solvent was evaporated. Yield: 0.09 g of compound G (60%) (mp 201 ° C).

Compound H was prepared as follows:

Mixture of compound 15 (prepared according to B7 of WO 2004/011436) (0.0009 mol), 2-furanboric acid (0.0018 mol), Pd [P (Ph ₃ )] ₄ (0.00009 mol) and Na ₂ CO ₃ 2M (0.0036 mol) ) in dimethoxyethane (10 ml) was stirred at 90 ° C for 6 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 (0.57 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 99/1 / 0.1; 10 pm). The pure fractions were collected and the solvent was evaporated to give 0.23 g of residue.

The fraction was recrystallized from diisopropyl ether / acetonitrile. The precipitate was filtered off and dried. Yield: 0.071 g of compound H (15%) (mp 215 ° C).

Compound I was prepared according to the methods described in WO 2004/011436. The diagram below shows the course of synthesis of compound J. Examples Nos. A10 and B1 correspond to the methods of WO 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), HCl / iPrOH (1 ml) and ethanol (100 ml) was stirred and heated. at reflux for 48 hours. The solvent was evaporated. The residue was mixed with H ₂ O / HCl 3N / CH ₂ C1 ₂ . The aqueous layer was basified and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2CI2CH3OH / NH4OH 95/5 / 0.2; 15-40 pm). The pure fractions were collected and the solvent Yield: 4.9 g of intermediate J (48%).

n-BuLi 1.6M (0.0102 mol) was added dropwise at -20 ° C to a solution of diisopropylamine (0.0091 mol) in tetrahydrofuran (15 ml) in a stream of N ₂ . The mixture was 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 J (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 EtOAc. 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 / NH 4 OH 99/1 / 0.2; 15-40 pm). Two fractions were collected and the solvent was evaporated. Yield: 0.96 g Fl, 0.72 g F2. Fl is recrystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.87 g of compound J (17%).

Table 1:

No. No. Etc. No R ¹ R ² R ³ R ⁶ Stereochemistry and mp 41 B1 N. OSN ₃ phenyl N. (IN); 160 ° C 206 Q7 Br OSN ₃ 1-naphthyl F (B); 213 ° C 31 B1 C1 OSN ₃ phenyl N. (IN); 181 ° C 26 B1 phenyl OSN ₃ phenyl n (A); 174 ° C 27 B1 phenyl OSN ₃ phenyl n (IN); 192 ° C 32 B1 Br OCH3 phenyl n (A); 208 ° C 33 B1 Br OCH3 phenyl n (IN); 196 ° C 109 Q9 Br OCH3 3-fluorophenyl n (A2); 156 ° C 39 Q9 Br OCH3 3-fluorophenyl n (IN); 207 ° C

36 Bl Br OCH3 phenyl C1 (A); 197 ° C 14 B7 Br OCH3 1-naphthyl N. (A); 210 ° C 15 B7 Br OCH3 1-naphthyl N. (IN); 244 ° C 46 Q7 Br OCH3 2-naphthyl N. (IN); 162 ° C 4 Bl Br OCH3 phenyl N. (IN); 190 ° C 174 Q9 B- OCH3 3-fluorophenyl N. (A); 159 ° C 24 Bl Br OCH3 3-thienyl N. (A); 162 ° C 5 B2 Br OCH ₂ CH3 phenyl N. (A); 162 ° C 38 Q9 Br OCH3 3-fluorophenyl N. (A); 198 ° C 69 B1 Br OCH3 2-fluorophenyl N. (A); butter 70 B1 Br OCH3 2-fluorophenyl N. (IN); butter 16 B1 Br OCH3 4-chlorophenyl N. (A); 200 ° C 17 B1 Br OCH3 4-chlorophenyl N. (IN); 190 ° C 67 Q8 Br OCH3 2,5-difluorophenyl N. (A); 60 ° C 116 Q15 Br OCH3 3,5-difluorophenyl N. (IN); 224 ° C 159 Q8 Br OCH3 2,5-difluorophenyl N. (A1); 208 ° C 160 Q8 Br OCH3 2,5-difluorophenyl N. (A2); 167 ° C 113 B14 Br OCH3 2,3-difluorophenyl N. (A); 128 ° C 196 Q15 Br OCH3 3,4-difluorophenyl N. (IN); 184 ° C 76 B1 Br OCH3 X » N. (IN); 130 ° C 84 B1 phenyl OCH3 1-naphthyl N. (A); 248 ° C 45 Q7 Br OSN ₃ 2-naphthyl n (A); 262 ° C 77 B1 Br OCH3 CO., LTD n (A); 202 ° C 78 B1 Br OCH3 CO., LTD n (IN); 202 ° C 165 Q9 Br ° х 3-fluorophenyl n (IN); butter 72 B1 Br OCH3 1-naphthyl CH3 (IN); 178 ° C 212 Q7 OCH3 1-naphthyl n (IN); 220 ° C 163 Q7 Br OCH3 6-methoxy-2-naphthyl n (IN); 206 ° C

73 Bl Nr OCH3 1-naphthyl C1 (B); 174 ° C 201 Bl Nr OCH ₃ ~ ^with uh N. (A); 214 ° C 30 Bl Cl OCH3 phenyl N. (A); 170 ° C 21 Bl Nr OCH3 2-thienyl N. (IN); 176 ° C 25 Bl Nr OCH3 3-thienyl N. (IN); 160 ° C 20 Bl Nr OCH3 2-thienyl N. (A); 96 ° C 6 B2 Nr OCH ₂ CH ₃ phenyl N. (IN); 74 ° C 108 B9 Nr OCH3 3-fluorophenyl N. (A1); 160 ° C 37 Bl Nr OCH3 phenyl C1 (IN); 221 ° C 13 B7 Nr OCH3 1-naphthyl N. (A2); 120 ° C 130 B7 Nr OCH3 5-bromo-2-naphthyl N. (IN); 220 ° C Mr 3-Pyridyl OCH3 3,5-difluo orophenyl N. (A); 201 ° C Η 2-furanyl OCH3 1-naphthyl N. (B); 215 ° C I Nr OCH3 1 W ⁴ N. (A); > 260 ° C F Bl Nr OCH3 phenyl N. (B2); 175 ° C Well Bl Nr OCH3 phenyl N. (B1); 180 ° C

Table 2:

With No Etc. No R ¹ R ² R ³ R ⁴ R ⁵ Phys. data (salt / melt) and stereochemistry 44 Q4 Br OCH3 phenyl N. N. (A); 190 ° C 19 B1 Br OSN ₃ phenyl CH ₂ CH ₃ CH ₂ CH ₃ ethanedioate (2: 3), (B); 150 ° C 18 B1 Br OCH3 phenyl CH ₂ CH ₃ CH ₂ CH ₃ ethanedioate (2: 3); (A); 230 ° C

Table 3:

No. No. Etc. No R ³ L Stereochemistry, etc. 50 B1 phenyl 1-imidazolyl (IN); 230 ° C 137 Q7 2-naphthyl 4-methylpyrazinyl (IN); 232 ° C 154 Q7 6-bromo-2-naphthyl 4-methylpiperazinyl (IN); 254 ° C 49 B1 phenyl 1-imidazolyl (A); 216 ° C 136 Q7 2-naphthyl 4-methylpyrazinyl (A); 188 ° C 48 B1 phenyl 1-piperidinyl (IN); 210 ° C 55 B1 phenyl thiomorpholinyl (A); butter 171 Q7 2-naphthyl 1-pyrrolidinyl (B); 218 ° C 129 B1 2-naphthyl 1-piperidinyl (IN); 212 ° C 149 Q7 1-naphthyl 4-methylpyrazinyl (IN); 232 ° C 166 Q7 6-bromo-2-naphthyl 1-piperidinyl (B); 218 ° C 151 Q7 3-bromo-1-naphthyl 4-methylpiperazinyl (A); 178 ° C 53 B1 phenyl 1- (1,2,4-triazolyl) (A); 180 ° C 47 B1 phenyl 1-piperidinyl (A); 190 ° C 51 B1 phenyl 1- (4-methyl) piperazinyl (A); 150 ° C 170 Q7 2-naphthyl 1-pyrrolidinyl (A); 238 ° C 128 B1 2-naphthyl 1-piperidinyl (A); 254 ° C 145 Q7 1-naphthyl 1-piperidinyl (A); 212 ° C 139 Q7 2-naphthyl morpholinyl (A); 258 ° C 140 Q7 2-naphthyl morpholinyl (B); 214 ° C 155 Q7 6-bromo-2-naphthyl 1-piperidinyl (A); 224 ° C A B13 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (IN) IN B13 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (A) p B12 2,4-difluorophenyl T4 (CH ₂ CH ₃ ) (CH ₂ phenyl) (IN) D B13 phenyl NH (CH ₃ ) (IN); 197 ° C

209 Q7 2-naphthyl (IN); 198 ° C 58 Q6 phenyl \ /. p-o (A); 208 ° C 11 Q6 phenyl K. Fr. (IN); 208 ° C

Table 4:

No. No. Etc. No R ¹ R ³ R ⁶ Stereochemistry, etc. a b p d 215 Q9 N. Br CH ₃ N. 3-fluorophenyl N. (A); 197 ° C 226 Q7 N. Br CH3 N. 1-naphthyl N. (B); 2O8 ° C 229 Q7 N. dream ₃ CH3 N. 1-naphthyl N. (A); 238OC 227 Q15 N. Br CH3 N. 3,5-difluorophenyl N. (A); 195 ° C 223 Q7 N. Br N. n 1-naphthyl Fr. 3 4 (IN); 205 ° C

Analytical methods

The mass of some compounds was recorded by LCMS (liquid chromatography by mass spectrometry). The method used is described below. The data are summarized in Table 5.

LCMS method

LCMS analysis was performed (positive ionization ionization, scanning from 100 to 900 amu) on a Kromasil Cl8 column (Interchim, Montlucon, FR; 5 pm, 4.6 x 150 mm) at a flow rate of 1 ml / minute. 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 achieve a 100% A gradient over 1 minute to 100% B for 4 minutes, 100% B for 5 minutes to 100% A for 3 minutes, and equilibration with 100% A for 2 minutes.

Table 5: LCMS start peak

Compound No LCMS start peak (MH ⁺ ) A 541 IN 541 P 631

Pharmacological examples

Preparation of bacterial suspensions for sensitivity testing:

The bacteria used in this study were grown in flasks containing 100 ml Mueller-Hinton broth (Becton Dickinson - cat. No. 275730) in sterile deionized water with shaking at 37 ° C overnight. Stock solutions (0.5 ml / tube) were stored at -70 ° C until used. Bacteria were titrated in microtiter plates to determine TCID50, where TLC ₅₀ represented the dilution, which gave an increase in bacterial growth in 50% of the inoculated cultures.

Typically, an inoculation rate of about 100 TSO ₅₀ is used for sensitivity studies.

Antibacterial susceptibility test: determination of ICgo

Analysis in microtiter plates

Flat-bottomed sterile 96-well plastic microtiter plates were filled with 180 μΐ of sterile deionized water, with the addition of 0.25% BSA. Subsequently, stock solutions (7.8 x final test concentration) of the compounds in a volume of 45 μΐ were added to column 2. Sterile five-fold dilutions (45 μΐ in 180 μΐ) were made directly into the microtiter plates of column 2 to reach column 11. The untreated control samples with (column 1) and without (column 12) inoculum were included in each plate. Depending on the type of bacteria, rows A to H, except column 12, were added approximately 10 to 60 CFU per well of bacterial inoculum (100 TCID50) in a volume of 100 μΐ in 2.8x Mueller-Hinton broth. The same volume of inoculum broth was added in rows A to H of column 12. The cultures were incubated at 37 ° C for 24 hours in a normal atmosphere (open air incubator and continuous ventilation). At the end of the incubation, one day after the inoculation, the bacterial growth was quantified fluorometrically. To this end, resorcinol (0.6 mg / ml) in a volume of 20 μΐ was added to each well 3 h after inoculation and the plates were again incubated overnight. The change in color from blue to pink indicates bacterial growth. Fluorescence was recorded with a computer-controlled fluorometer (Cytofluor Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percent inhibition of growth achieved with the compounds was calculated by standard methods. IC90 (expressed in μ / ml) was defined as 90% bacterial growth inhibition concentration. The results are shown in Table 6.

Agar dilution method

The MIC90 values (the minimum concentration to obtain 99% inhibition of bacterial growth) can be determined by performing the standard agar dilution method according to NCCLS * standards, in which the medium used is Mueller-Hinton agar.

* Institute for Clinical Laboratory Standards. 2005. Dilution Methods Antimicrobial Sensitivity Tests for Aerobic Growing Bacteria; approved standard sixth edition.

Destruction time analysis

The bactericidal or bacteriostatic activity of the compounds can be determined by the time of destruction using the broth microarray method *. In the analysis of the destruction time of Staphylococcus aureus and methicillin-resistant S. aureus (MRS A), the starting inoculum of S. aurues and MRS A was 10 ⁶ CFU / ml in Mueller Hinton broth. The antibacterial compounds were used at a concentration of 0.1 to 10 times the concentration of MIC (i.e., IC90 as determined in the microtiter plate assay). Wells that do not receive an antibacterial agent are controls for the growth of the crop. Plates containing the microorganism and the test compounds were incubated at 37 ° C. After 0, 4, 24 and 48 hours of incubation, the samples were separated to determine viable bacteria by serial dilution (10 ' ¹ to 10' ⁶ ) in sterile PBS and placing (200 μΐ) on Mueller Hinton agar. The plates were incubated at 37 ° C for 24 hours and the number of colonies was determined. Destruction curves can be constructed by plotting logioCFU per ml over time. The bactericidal effect is usually defined as a 3-logio reduction in the number of CFU per ml relative to untreated inoculum. The potential effect of drug delivery is eliminated by serial dilutions and colony counts at the highest dilution used.

* Zurenko, G.E. et al. In vitro activities of U-100592 and U-100766, novel oxaazolidinone antibacterial agents. Antimicrob. Agents Chemother. 40, 839-845 (1996).

Determination of cellular ATP levels

To analyze the change in total cellular concentration of ATP (using ATP 10 bioluminescent kit, Roche), assays were performed by culturing stock solution S ', aureus (ATCC29213) in 100 ml Mueller Hinton flasks and incubating in shaker incubator for 24 hours at 37 ° C (300 rpm). Measure OD ₄₀ 5 nm and calculate CFU / ml. The cultures were diluted to 1 x 10 ⁶ CFU / ml (final ATP measurement concentration: 1 x 10 ⁵ CFU / 100 μΐ per well) and the test compound added at a concentration of 0.1 to 10 times the MIC concentration (i.e. IC90, as determined in the microtiter plate assay). These tubes were incubated for 0, 30 and 60 minutes at 300 rpm and 37 ° C. Use 0.6 ml of bacterial suspension from the sealed tubes and place in new 2 ml Eppendorf tubes. 0.6 ml of cell lysis reagent (Roche kit) was added, vortexed at maximum crucible and incubated for 5 minutes at room temperature. Cool on ice. The luminometer was allowed to warm to 30 ° C (Luminoskan Ascent Labsystems with injector). Fill one column (= 6 wells) with 100 pm of the same sample. Using the injector system, 100 µl luciferase reagent was added to each well. Luminescence is measured in 1 sec.

Table 6: IC90 values (pg / ml) determined by microtiter plate analysis.

IC90 (pq / ml) With No BSU ESO EFA EFA LMO RAE SMU SPN SPY STA STA STA STA 43639 25922 14506 29212 49594 27853 33402 6305 8668 43300 25923 29213 RMETH A 10.8 1.1 10.8 10.8 12.1 50 10.5 10.5 23.6 21.0 26.5 26.5 10.5 41 17.0 F 22.6 25.3 22.6 206 12.8 31 10.3 4.6 4.1 10.3 10.3 5.2 1.8 11.6 44 7.6 7.6 26 10.0 4.5 4.5 2.0 11.3 5.6 2.5 11.3 8.9 27 10.0 8.9 12.6 Well 12.7 11.3 7.1 10.1 10.1 5.7 5.1 12.7 32 11.7 4.6 4.6 10.4 4.6 13.1 4.6 13.1 9.3 13.1 33 10.4 11.7 4.6 2.3 11.7 10.4 5.9 2.6 5.9 13.1 109 11.7 9.3 11.7 13.1 13.1 13.1 10.4 39 10.4 4.7 10.4 11.7 5.9 1.9 13.1 10.4 137 21.2 23.8 8.4 21.2 36 24.1 4.8 5.4 4.8 3.8 2.7 0.4 4.8 14 11.1 9.9 5.0 2.5 5.0 12.4 6.2 2.8 5.6 9.9 14.0 15 24.8 24.8 5.0 2.5 12.4 12.4 6.2 2.2 5.0 46 5.0 2.8 5.0 5.6 2.8 0.6 5.6 154 10.9 27.4 27.4 27.4 13.8 24.5 4 12.7

i

174 10.2 175 10.2 12.8 24 10.2 5 10.4 38 10.4 69 10.4 10.4 13.1 70 10.4 13.1 49 10.5 10.5 13.3 10.5 5.9 11.8 136 10.6 10.6 10.6 19 13.4 215 10.7 Mr 13.6 10.8 10.8 16 13.6 17 10.8 0.5 67 10.8 13.6 116 10.8 110 10.8 13.6 111 10.8 113 10.8 13.6 196 10.8 B 8.6 H 13.6 13.6 48 10.9 10.9 10.9 13.7 13.7 76 11.0 11.0 84 11.0 11.0 7.0 11.0 45 11.1 12.4 77 11.2 14.2 78 11.2 11.2 11.2 55 0.6 165 14.3 14.3 11.3 72 9.0 14.3 11.4 226 14.3 212 11.4 171 11.6 163 14.7 73 11.8 14.8 129 11.9 15.0 11.9

149 12.2 201 12.3 12.3 12.3 12.3 C 15.9 18 13.3 13.3 0.7 165 16.9 151 15.4 15.4 30 10.3 10.3 9.2 10.3 5.2 10.3 D 4.9 229 22.5 5.0 21 11.5 4.6 11.5 12.8 12.8 25 11.5 11.5 11.5 12.8 4.1 12.8 20 2.6 6 11.6 11.6 11.6 4.6 13.0 4.6 108 13.1 53 5.9 37 12.1 47 6.9 227 5.0 13 11.1 11.1 8.8 11.1 2.2 3.5 2.8 8.8 11.1 11.1 51 28.1 25.0 25.0 5.6 I 11.6 170 26.0 128 9.4 145 23.7 9.4 139 18.9 26.7 140 9.5 223 5.4 13.6 5.4 130 10.1 155 26.9 209 15.1 58 5.9 8.3 11 11.7 10.4 11.7

BSU 43639 means Bacillus subtilis (ATCC43639); ECO

25922 means Escherichia coli (ATCC25922); EFA 14506 means Enterococcus faecalis (ATCC14506); EFA 29212 means

Enterococcus faecalis (ATCC29212); LMO 49594 means Listeria monocytogenes (ATCC49594); PAE 27853 means Pseudomonas aeruginosa (ATCC27853); SMU 33402 means Streptococcus mutans (ATCC33402); SPN 6305 means Streptococcus pneumoniae (ATCC6305); SPY 8668 means Streptococcus pyogens (ATCC8668); STA 43300 means Staphylococcus aureus (ATCC43300); STA 25923 means Staphylococcus aureus (ATCC25923); STA 29213 means Staphylococcus aureus (ATCC29213); STA RMETH stands for Staphylococcus aureus (MRSA) (isolated clinically from the University of Antwerp). ATCC stands for American Cell Culture Type.

Claims (32)

Patent Claims Use of a compound for the manufacture of a medicament for treating a bacterial infection, said compound being a compound of formula (D its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric form or its A-oxide form, wherein R ¹ is hydrogen, halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl, Ar or Het; p is an integer equal to 1 or 2; R is C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxy or Salkalkylthio; R ³ is Ar, Het or Het ¹ ; R ⁴ and R ⁵ are each hydrogen, C 1-6 alkyl or benzyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, imidazolyl pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may be optionally substituted by C1-6alkyl, halogeno, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl or di (C]. _6alkyl) amino, Sybal kiltio, SbalkyloxyC]. ₆ alkyl, C 1-6 alkylthioC 1-6 alkyl or pyrimidinyl; R ⁶ is hydrogen, halogen, polyhaloC1-6alkyl, C1-6alkyl, - C1. ₆ alkyloxy, C1-6alkylthio; or © two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-; Mr is an integer equal to 1 or 2; R ⁷ is hydrogen, C1. ₆ alkyl, Ar, Het or Het ¹ ; Ah is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle may be optionally substituted by 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; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; each monocyclic heterocycle may optionally be substituted by 1, 2 or 3 the substituent, each substituent is 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) -; Het ¹ is a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo; each bicyclic heterocycle may optionally be substituted by 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, Cl. ₆ alkyloxy, C _1-6 alkyloxyC 1-4 alkyl or Ar-C (= O) -; provided that the bacterial infection is different from the mycobacterial infection. Use according to claim 1, wherein the compound is other than (aS, pK) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-N-phenyl-3-quinolinethanol, its a pharmaceutically acceptable acid or base addition salt or its A-oxide form. Use according to claim 1 or 2, wherein the compound of formula (I) is a compound having the following formula its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric form or its A-oxide form. Use according to any one of the preceding claims, wherein the compound of formula (I) or (N-a) is a compound having the following formula its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric form or its A-oxide form. Use according to any one of the preceding claims, wherein R ¹ is hydrogen, halogen, optionally substituted phenyl or Het. The use according to claim 5, wherein R ¹ is hydrogen, halogen or optionally substituted phenyl. Use according to claim 6, wherein R ¹ is halogen. 8. Use according to any of the foregoing claims, wherein R is C 1-6 alkyloxy or C 1-4. ₆ alkylthio. Use according to any one of the preceding claims, wherein R ³ is Ar or Het. Use according to any one of claims 1 to 8, wherein R ³ is Ar or Het ¹ . Use according to claim 9 or 10, wherein R ³ is Ar. The use of claim 11, wherein R ³ is optionally substituted phenyl or optionally substituted naphthyl. Use according to any one of the preceding claims, wherein R ⁴ and R ⁵ are each hydrogen, C 1-4 alkyl or benzyl. The use according to claim 13, wherein R ⁴ and R ⁵ are each hydrogen or C 1-6 alkyl. The use according to any one of claims 1 to 12, wherein R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl imidazolinyl, pyrazolinyl, pyrazolinyl, pyrrolidone , hydroxy, hydroxyS lkil, Sybalkiloksi, amino, mono- or di (Sybalkil) amino, C1. ₆ alkylthio, C1. ₆ alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl. The use according to claim 15, wherein R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl , pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may be optionally substituted by C1. ₆ alkyl, halogen, polyhaloC 1-6 alkyl, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkyloxy, amino, I ......... mono- or di (C1-6alkyl) amino, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl. Use according to any one of the preceding claims, wherein R ⁶ is hydrogen, halogen, polyhaloC 1-6 alkyl, Cl. ₆ alkyl; or two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-. The use of claim 17, wherein R ⁶ is hydrogen or halogen. Use according to any one of the preceding claims, wherein R ⁷ is hydrogen. The use according to any one of the preceding claims, wherein r is an integer equal to 1. Use according to any one of the preceding claims, wherein p is an integer equal to 1. Use according to claim 1, provided that when one R ¹ is C 1-6 alkyl, then p is an integer equal to 2 and the other substituent R ¹ is selected from halogen, polyhaloC 1-6 alkyl, C 1-6 alkyl, Ar or Het. © Use according to any one of the preceding claims, wherein the bacterial infection is an infection by a Gram-positive bacterium. The use of claim 1, wherein R ¹ is hydrogen; C 1-6 alkyl; halogen; phenyl; furanyl optionally substituted by hydroxyC1-6alkyl; or pyridyl; R ² is C 1-6 alkyloxy; C1. ₆ alkylthio; or C1-4 alkyloxy; R is phenyl optionally substituted by 1 or 2 halogens; naphthyl optionally substituted with 1 or 2 halogens or C 1-6 alkyloxy; thienyl; piperidinyl substituted with Ar-C (= O) -; 2,3-dihydrobenzo [1,4] dioxinyl; benzo [1,3] dioxolyl; or acenaphthyl; R ⁴ and R ⁵ are each independently hydrogen; C _1-6 alkyl; benzyl; or R ⁴ and R ⁵ taken together and including N to which they are attached may form a radical selected from imidazolyl; pyrazinyl substituted with C1-4alkyl; piperazinyl substituted with C 1-6 alkyl; piperazinyl substituted with pyrimidinyl; piperidinyl; thiomorpholinyl; morpholinyl; pyrrolidinyl; or triazolyl; R ⁶ is hydrogen; halogen; Salkyl; or two adjacent radicals R ⁶ taken together form a divalent radical of formula -CH = CH-CH = CH-; R ⁷ is hydrogen. The use of claim 1, wherein the compound of formula (I) is selected from R ³ L Stereochemistry phenyl 1-imidazolyl (IN) 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (A) a pharmaceutically acceptable acid or base addition salt thereof or a TV oxide form thereof. The use of claim 1, wherein the compound of formula (I) is selected from R ¹ R ² R ³ R ⁶ Stereochemistry N. OSN ₃ phenyl N. (IN Br OCH3 1-naphthyl F (IN) C1 OCH3 phenyl N. (IN) phenyl OCH3 phenyl N. (A) phenyl OCH3 phenyl N. (IN) Br SCH ₃ phenyl N. (A) Br SCH ₃ phenyl N. (IN) Br OCH3 3-fluorophenyl N. (A2) Br OCH3 3-fluorophenyl N. (IN) Br OCH3 phenyl C1 (B2) Br OCH3 phenyl n (B1) a pharmaceutically acceptable acid or base addition salt thereof or a TV oxide form thereof. The use of claim 1, wherein the compound of formula (I) is R ¹ R ² R ³ R ⁴ R ⁵ Stereochemistry Br OCH3 phenyl N. N. (A) a pharmaceutically acceptable acid or base addition salt thereof or a / V-oxide form thereof. A combination of (a) a compound of formula (I) as defined in any one of claims 1 to 27, and (b) one or more antibacterial agents, provided that these one or more other antibacterial agents are other than antimycobacterial agents . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of (a) a compound of formula (I) as defined in any one of claims 1 to 27, and (b) one or more antibacterial agents, provided that these one or more antibacterial agents are other than antimycobacterial agents. Use of a combination according to claim 28 or a pharmaceutical composition according to claim 29 for the treatment of a bacterial infection. A preparation comprising (a) a compound of formula (I) as defined in any one of claims 1 to 27, and (b) one or more antibacterial agents, provided that these one or more antibacterial agents are other than antimycobacterial agents , in the form of a combination preparation for simultaneous, separate or sequential administration in the treatment of bacterial infection. 32. Compound selected from Τ OH rV WG CHj LA xJL R ³ R ¹ R ² R ³ R ⁶ Stereochemistry 3-Pyridyl OSN ₃ 3,5-difluorophenyl N. (A) 2-furanyl OCH3 1-naphthyl N. (IN) Br OSN ₃ * H · (A) Br OCH3 phenyl N. (B2) Br OSN ₃ phenyl N. (B1) a pharmaceutically acceptable acid or base addition salt thereof or a V-oxide form thereof. R ³ L Stereochemistry 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (IN) 2,4-difluorophenyl NH (CH ₂ CH ₃ ) (A) 2,4-difluorophenyl M (CH ₂ CH ₃ ) (CH ₂ phenyl) (IN) phenyl NH (CH ₃ ) (IN) a pharmaceutically acceptable acid or base addition salt thereof or a V-oxide form thereof.