MXPA05013412A - 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 formula (I):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or a N-oxide form thereof, wherein R1 is hydrogen, halo, polyhaloCi.6alkyl, C1-6alkyl, Ar or Het;p is an integer equal to 1 or 2;R2 is C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy or C1-6alkylthio;R3 is Ar, Het or Het1;R4and R5 each independently are hydrogen, C1-6alkyl or benzyl;or R4 and R5 together and including the N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrroIinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-irnidazolinyl, 2-pyrazolinyl, imidazolyil, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may optionally be substituted with C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxy, amino, mono- or di(C1-6alkyl)aminos C1-6alkylthio, C1-6alkylosyC1-6alkyl, C1-6alkylthioC1-6alkyl or pyrimidinyl;R6 is hydrogen, halo, polyhaloC1-6alkyl, C1-6alkyil, C1-6alkyloxy, C1-6alkylthio;ortwo vicinal R6 radicals may be taken together to form a bivalent radical of formula CH=CH-CH=CH-;r is an integer equal to 1 or 2;R7 is hydrogen, C1-6alkyl, Ar, Het or Het1;provided that the bacterial infection is other than a Mycobacterial infection.

Description

Quinoline derivatives as antibacterial agents DESCRIPTIVE MEMORY The present invention relates to the use of quinoline derivatives for the manufacture of a medicament for the treatment of a bacterial infection. Resistance to first-line antibiotic agents is an emerging problem. Some important examples include Streptococcus pneumoniae resistant to penicillin, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multi-resistant salmonellas. The consequences of resistance to antibiotic agents are severe. Infections caused by resistant microbes do not respond to treatment, resulting in prolonged illness and increased risk of death. Treatment failures also lead to longer periods of impact, which increases the numbers of infected people moving in the community and thus exposing the general population to the risk of contracting a resistant strain infection. Hospitals are a critical component of the problem of antimicrobial resistance throughout the world. The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross infection has resulted in infections with highly resistant bacterial pathogens. Self-medication with antimicrobial agents is another important factor that contributes to resistance. Self-medicated antimicrobials may be unnecessary, are often dosed inadequately, or may not contain adequate amounts of active drug. Compliance by the patient with recommended treatment is another main problem. Patients forget to take the medication, stop their treatment when they begin to feel better, or may not be able to afford a full treatment, thus creating an ideal environment for the microbes to adapt rather than being liquidated. Due to the emerging resistance to multiple antibiotics, physicians are confronted with infections for which there is no effective therapy. The morbidity, mortality and financial costs of such infections place an increasing burden on health systems throughout the world. Therefore, there is a great need to provide new compounds to treat bacterial infections, especially for the treatment of infections caused by resistant strains. WO 2004/011436 discloses substituted quinoline derivatives having activity against Mycobacteria, in particular against Mycobacterium tuberculosis. A particular compound of these substituted quinoline derivatives is described in Science (2005), 307, 223-227. It has been found that the quinoline derivatives described in WO 2004/011436 also show activity against bacteria other than Mycobacteria. Accordingly, 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 formula its pharmaceutically acceptable acid or base addition salt, its stereochemically isomeric form or its N-oxide form, where R is hydrogen, halo, polyhaloalkylC6-6, alkylC-? - 6, Ar or Het; p is an integer equal to 1 or 2; R 2 is C 1-6 -alkyloxy, C 1-4 alkyloxy-C 1-7 alkyloxy-C 1 -alkyloxy; R3 is Ar, Het or Het1; R 4 and R 5 each independently is hydrogen, C 1 -C 6 alkyl or benzyl; or R4 and R5 together and including the N 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 can be optionally substituted with C 1 -C 5 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, hydroxyalkyl C - 6, alkyloxy C 5. -6, amino, mono- or di (alkylC? -6) amino, alkylthioC?? 6, alkyloxyC? -alkylC? .6, or pyrimidinyl; R6 is hydrogen, halo, polyhaloalkylC6, alkylC6-6, alkyloxyC6-6, alkylthioC6-, or two proximal R6 radicals can be taken together to form a bivalent radical of formula -CH = CH -CH = CH-; r is an integer equal to 1 or 2, R7 is hydrogen, alkylC-? - 6, Ar, Het or Het1; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amine, mono- or di (alkylic) amino, alkylod-6, polyhaloalkylC- ? -6, hydroxyalkyl? -6-, alkyloxyC? -6, polyhaloalkyloxyC? -6, alkyloxyC? -6alkylC? -6, carboxyl, alkyloxyCi-bicarbonyl, aminocarbonyl, morpholinyl and mono- or di (alk? IC? - 6) aminocarbonyl; Het is a monocyclic heterocycle selected from the group of? / - phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazo lyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; each monocyclic heterocycle may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, hydroxy, alkylC6, polyhaloalkylC6, hydroxyalkylC6, alkyloxyC6, alkyl. ¡Lox¡C? -6alqu¡loC? .. 6 or Ar-C (= 0) -; Het1 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 or benzo [1,3] dioxolyl; each bicyclic heterocycle can be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, hydroxy, C-? -6 alkyl, polyhaloalkylC? -6, hydroxyalkylC? -6, akyloxyC? -6 , alkyloxyC-i. 6alkylC1-6 or Ar-C (= 0) -; as long as the bacterial infection is different from a Mycobacterial infection. The present invention also relates to a method for the treatment of a bacterial infection in a mammal, in particular a warm-blooded mammal, more in particular a human being, which comprises administering an effective amount of a compound of the invention to the mammal. As used hereinbefore or in the following alkyl C? -6 as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having between 1 and 6 carbon atoms such as methyl, ethyl, propyl, 1-Methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like. As used above or below, the term (= 0) forms a carbonyl moiety when attached to a carbon atom. The term halo is generic for fluorine, chlorine, bromine and iodine. As used above or in the following, polyhaloalkylC-j.6 as a group or part of a group is defined as mono- or polyhalo-substituted C ?_6 alkyl, eg, methyl with one or more carbon atoms. fluorine, for example, difluoromethyl or trifluoromethyl, 1,1-difluoromethyl and the like. In the case where more than one halogen atom is adhered to an alkyl group within the definition of polyhaloalkylC6, they may be identical or different. In the definition of Het or Het1, or when R4 and R5 are taken together, we want to include all possible isomeric forms of the heterocycles, for example, pyrrolyl comprises 1 / - pyrrolyl and 2f / -pyrrolyl. The Ar, Het or Het1 listed in the definitions of the substituents of the compounds of formula (I) (see for example R3) as mentioned above or in the following may be attached to the remainder of the molecule of formula ( I) through any carbon or ring heteroatom as appropriate, if not specified otherwise. Thus, for example, when Het is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like. The lines drawn from the substituents to the ring systems indicate that the bond can be attached to any of the ring atoms suitable. When two nearby R6 radicals are taken together to form a bivalent radical of formula -CH = CH-CH = CH-, this means that the two adjacent R6 radicals together with the phenyl ring to which a naphthyl are attached are formed. For therapeutic use, the salts of the compounds of formula (I) are those where the counterion is pharmaceutically acceptable. However, salts of acids and bases which are not pharmaceutically acceptable may also be useful, 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. The pharmaceutically acceptable addition salts as mentioned above or below are intended to comprise the forms of non-toxic therapeutically active acid addition salts which the compounds of formula (I) are capable of forming. The latter can be conveniently obtained by treating the base form with appropriate acids such as inorganic acids, for example, hydrohalic acids, for example, hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1, 2,3-propane-tricarboxylic acid, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexansulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid and similar acids. Conversely, the salt form can be converted by alkali treatment into the free base form. The compounds of formula (I) containing acidic protons can be converted into their non-toxic, therapeutically active metal or amine addition salt forms by treatment with appropriate organic or inorganic bases. Suitable base salt forms include, for example, the ammonium salts, the alkali metal and the alkaline earth metal salts, for example, the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example , aliphatic and aromatic amines, primary, secondary and tertiary such as methylamine, ethylamine, propylamine, isopropylamine, the four isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine , triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted by acid treatment to the free acid form. The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are capable of forming. Examples of such forms are, for example, hydrates, alcoholates and the like. The N-oxide forms of the present compounds are intended to comprise 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 following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can be carried out generally by reacting the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; Suitable organic peroxides may comprise peroxyacids, such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, for example 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example peroxoacetic acid, alkylhydroperoxides, for example r.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 will be appreciated that some of the compounds of formula (I) and their N-oxides or addition salts may contain one or more centers of chirality and exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used in the foregoing or in the following defines all possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts or physiologically functional derivatives may possess . Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. In particular, the stereogénicos centers can have the configuration R or S; the substituents on bivalent (partially) saturated cyclic radicals can have either the cis or trans configuration. Compounds that span double bonds can have a stereochemistry E (entgegen) or Z (zusammen) in said double bond. Stereochemically isomeric forms of the compounds of formula (I) should obviously be embraced within the scope of this invention. Following the conventions of the CAS nomenclature, when two stereogénicos centers of known absolute configuration are present in a molecule, a descriptor R or S (based on the Cahn-Ingold-Prelog sequence rule) is assigned to the chiral center with the most number low, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R *, R *] or [R *, S *], where R * is always specified as the reference center and [R *, R * \ indicates centers with the same chirality and [R *, S *] indicates different chirality centers. For example, if the chiral center with the lowest number in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S- [R * S *]. If "<" and "®" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest number of rings, is arbitrarily always in the "<" position of the median plane determined by the ring system. The position of the highest priority substituent on the asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is referred to as "<" if it is on the same side of the plane means determined by the ring system, or "®", if it is on the other side of the median plane determined by the ring system. The terms "erythro" and "treo" can also be used as relative stereochemical descriptors. When a molecule carries two asymmetric carbons, there are 4 stereoisomers of the molecule. These isomers can be grouped into two pairs of two enantiomers. A difference between these two pairs can be made using the erythro and treo notation (originally used for Sugar). The two asymmetric carbon atoms in the side chain of the present compounds, indicated by * in the structure that appears later, are determinants for the stereochemistry of the molecules. The relative configuration of the molecules is indicated as erythro if the groups, after being classified according to priority rules (Cahn, Ingold, Prelog rules), go in the same direction when viewed in Newman projection. The relative configuration of the molecules is indicated as treo if the groups, after being classified according to priority rules (Cahn, Ingold, Prelog rules), go in the opposite direction when they are observed in the Newman projection.

Instead of erythro and threo, the terms "without" and "anti" can also be used as stereo relative descriptors for the two pairs of two enantiomers. To determine whether a molecule is syn or anti, the main chain of the molecule is drawn in the common zigzag mode. If the two main substituents (the substituents are classified according to their priority (Cahn Ingold Prelog rules)) are on the same side of the plane defined by the main chain, the stereochemistry is indicated as sin. If the two main substituents are on the opposite side of the plane defined by the main chain, the stereochemistry is indicated as anti. The stereo descriptors cis, trans, E, Z, R, S, erythro, threo, sin, anti are well known to one skilled in the art. Reference is also made to J.Am.Chem.Soc., 1982, 104, 5521-5523, which is incorporated by reference in the present invention. When a specific stereoisomeric form is indicated, this means that said form is substantially free, ie, it is associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, preferably less than 2% and most preferably less than 1% of the one or more other isomer (s). Thus, when a compound of the formula (I) is for example specified as (aS, ßR), this means that the compound is substantially free of the isomer (aR, βS). The compounds of formula (I) can be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other following resolution procedures known in the art. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral fixed phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction stereospecifically occurs. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The invention also comprises derivative compounds (generally called "prodrugs") of the pharmacologically active compounds according to the invention, which are degraded in vivo to provide the compounds according to the invention. Prodrugs are generally (though not always) of lower potency in the target receptor than the compounds to which they are degraded. Prodrugs are particularly useful when the desired compound has chemical or physical properties that render its administration difficult or ineffective. For example, the desired compound may be only poorly soluble, may be poorly transported through the mucosal epithelium, or may have an undesirably short plasma half-life. For more information about prodrugs refer to Stella, V. J. et al., "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.

The prodrug forms of the pharmacologically active compounds according to the invention will generally be compounds according to formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their tautomeric forms and their N-forms. -oxide, which have an acid group which is esterified or amidated. Included in such groups are esterified acids to the groups of the formula -COORx, where R x is a C 1 -C 6 alkyl, phenyl, benzyl or one of the following groups: The amidated groups include groups of the formula - CONRyRz, where Ry is H, alkylC? --6, phenyl or benzyl and Rz is -OH, H, alkylC? 6, phenyl or benzyl. The compounds according to the invention having an amino group can be derivatized with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This base will be hydrolyzed with first order kinetics in aqueous solution. Whenever used in the present invention, the term "compounds of formula (I)" is intended to also include their forms of N-oxide, its addition salts or its stereochemically isomeric forms.

Of special 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 (I-a) its pharmaceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxidq form: A second interesting embodiment of the present invention relates to a compound of formula (1-b) its pharmaceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxide form. A third interesting embodiment is the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment where R 1 represents hydrogen, halo, C 1-6 alkyl, Ar or Het; preferably hydrogen, halo, optionally substituted phenyl or Het; more preferably hydrogen, halo, optionally substituted phenyl, optionally substituted furanyl, or pyridinyl; even more preferably hydrogen, halo or optionally substituted phenyl; most preferably halo, such as, for example, bromine or chlorine, in particular bromine. A fourth interesting mode are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment where R 1 is halo, polyhaloC 1-6 alkyl, Ar or Het; preferably halo, Ar or Het; more preferably halo, optionally substituted phenyl, or Het; even more preferably halo, phenyl, optionally substituted furanyl, or pyridinyl; most preferably halo or phenyl. A fifth interesting modality is the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment wherein R 2 is C 1-6 alkyloxy or alkylthioCi-β, in particular methoxy or methylthio; preferably C6-C6 alkyloxy; more preferably methoxy. A sixth interesting modality are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality where R3 is Ar or Het or where R3 is Ar or Het1; preferably R3 is Ar; more preferably optionally substituted phenyl or optionally substituted naphthyl; even more preferably phenyl optionally substituted with halo or alkyloxyd-6, or naphthyl optionally substituted with halo or C 1-6 alkyloxy; more preferably phenyl optionally substituted with 1 or 2 halo, in particular fluorine, or naphthyl, in particular 1-naphthyl or 2-naphthyl. An interesting seventh embodiment are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment wherein R 4 and R 5 each independently is hydrogen or C 1-6 alkyl; or R4 and R5 together and including the N to which they are ated can form a radical selected from the pyrrolidinyl group, 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 one of said rings may be optionally substituted with C 1 -C 6 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, hydroxyalkylC 6, alkyloxyCi. 6, amino, mono- or alkylthiod-β, alkyloxyCi-βalkylC-i-e, alkylthioC?-6alkylC1-6 or pyrimidinyl; more preferably R 4 is C 1-6 alkyl and R 5 is hydrogen or C 1-6 alkyl; or R4 and R5 together and including the N 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 be optionally substituted with aCycloC-? - 6, halo, polyhaloalkylC-? - 6, hydroxy, hydroxyCi-β, alkyloxyCi . 6, amino, mono- or di (alkylC6-) amino, alkylthioC1-6, alkyloxyCi-βalkylCi-β, alkylC 6? -6alkylC-? 6 or pyrimidinyl; even more preferably R4 is alkylod.Get 6 and R5 is hydrogen or C6-alkyl; or R4 and R5 toer and including the N 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 said rings may be optionally substituted with C alquilo-C alquiloalkyl, halo, polyhaloalkylC?-6, hydroxy, hydroxyalknoCi-e, C alquilo--6alkyloxy, amino, mono- or di (alkylC ?.6) amine, alkylthioC?-6 C 1-4 alkyloxy C 1-4 alkyl, C 1-6 alkyloxy or pyrimidinyl; more preferably R 4 is C 1-6 alkyl, in particular methyl or ethyl, more in particular methyl, and R 5 is hydrogen or C 1-6 alkyl, in particular methyl or ethyl, more in particular methyl. An eighth interesting modality are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment wherein R4 and R5 each independently is hydrogen, C- or C6alkyl or benzyl; preferably R4 and R5 each is independently hydrogen or alkylod-β; more preferably R 4 is alkylC-i-β and R 5 is hydrogen or C 1 -C 6 alkyl; most preferably R 4 and R 5 are C 1-6 alkyl, in particular methyl or ethyl, more in particular methyl. An interesting ninth embodiment are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality where R4 and R5 toer and including the N to which they are attached can form a radical selected from the pyrrolidinyl group , 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, midazolidinyl, pyrazolidinyl, 2-midazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each one of said rings may be optionally substituted with C 1 -C 6 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, C 1 -C 6 hydroxyalkyl, C 1 alkyloxy. 6, amino, mono- or di (alkylC? -6) amino, alkylthioC? -6, alkyloxyC? -6alkylC? -6, alkylthioC ?, 6alkylC? -6 or pyrimidinyl; preferably R4 and R5 toer and including the N to which they are attached can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, piridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morphplinyl and thiomorpholinyl, each of said rings may be optionally substituted with aIquiCo-C6, halo, polyhaloCiCiCi-6, hydroxy, hydroxyCiCiCi, pCiCi. 6, amino, mono- or alkylthioCi-β, alkyloxyC?-6alkylC?-6, alkyltioCi-ealkylC-i-e or pyrimidinyl; more preferably R4 and R5 toer and including the N 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 said rings can optionally be substituted with alkylodi 6, halo, polyhaloalkylC? -6, hydroxy, hydroxyalkylC? -6, amino, mono- or di (alkylC? -6) amino, alkylthioCi. 6, C 1-6 alkyloxy-6alkylC? -6, alkylthioC-i-βalkylC-i-e or pyrimidinyl; even more preferably R 4 and R 5 toer and including the N to which they are attached can form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of said rings can be optionally substituted with C 1 -C 6 alkyl, halo, polyhaloalkylC? -6, hydroxy, hydroxyalkylC? -6, alkyloxyC? -6, amino, mono- or di (alkylC1-6) amino, alkylthioC? -6, alkyloxyCi-ß-alkylCi-β, alkylthioC? _6alkylC? -6 or pyrimidinyl; most preferably R4 and R5 toer 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 toer, are selected from C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, hydroxy, C 1-7 alkyloxy, C 1-6 alkylthio and pyrimidinyl; more preferably the substituents are selected from C6-C6 alkyl or pyrimidinyl. An interesting tenth embodiment are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting embodiment where R6 is hydrogen, halo, polyhaloalkylC-? - 6 or alkylC-? - 6; or two proximal radicals R6 can be taken together to form a bivalent radical of formula -CH = CH-CH = CH-; preferably R 6 is hydrogen, halo, polyhaloC 1-6 alkyl or C 1-6 alkyl; more preferably R6 is hydrogen, halo or C6-6alkyl, "even more preferably R6 is hydrogen or halo, most preferably R6 is hydrogen.An eleventh interesting mode are the compounds of formula (I) or any subgroup thereof. the aforementioned as an interesting embodiment where R7 is hydrogen.A twelfth interesting modality are the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality where r is an integer equal to 1. An interesting thirteenth modality is the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality where p is an integer equal to 1. A fourteenth interesting modality are the compounds of formula ( I) or any subgroup thereof as mentioned above as an interesting modality as long as an R1 is alq uiloC -? - 6 then p is an integer equal to 2 and the other substituent R1 is selected from halo, polyhaloalkylC? -6, alkylC? -6, Ar or Het. An interesting fifteenth embodiment is the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality where the compound is other than (aS, ßR) -6-bromo-a- [2- ( dimethylamino) ethyl] -2-methoxy-a-1-naphthalenyl-β-phenyl-3-quinolinetanol, its pharmaceutically acceptable acid or base addition salt or its N-oxide form. A sixteenth interesting modality is the use of a compound of formula (I) or any subgroup thereof as mentioned above as an interesting modality for the manufacture of a medicament for the treatment of an infection with a gram-positive bacterium and / or gram-negative.

A seventeenth interesting modality is the use of a compound of formula (I) or any subgroup thereof as mentioned above as an interesting modality for the manufacture of a medicament for the treatment of an infection with a gram-positive bacterium. An eighteenth interesting mode is the use of the compounds of formula (I) or any subgroup thereof as mentioned above as an interesting modality for the manufacture of a medicament for the treatment of an infection with a gram-negative bacterium. A nineteenth interesting mode is the use of a compound of formula (I) or any subgroup thereof as mentioned above as an interesting modality for the manufacture of a medicament for the treatment of a bacterial infection wherein the compound of formula ( I) has an IC90 < 15 μl / ml against at least one bacterium, in particular a gram-positive bacterium, preferably an ICgo < 10 μl / ml, more preferably an IC90 < 5 μl / ml; the value of IC90 being determined as described below. Also interesting compounds of the present invention are those compounds of formula (I) wherein one or more, preferably all, of the following definitions apply: a) R1 is hydrogen; Ci-β alkyl; halo, in particular bromine or chlorine; phenyl; furanyl optionally substituted with hydroxyalkyl Ci-β; or pyridylo; b) R 2 is C 1-6 alkyloxy, in particular methoxy or ethoxy; alkylthioC -? - 6, in particular methylthio; or C 1-6 alkyloxyC? -6alkyloxy; c) R3 is phenyl optionally substituted with 1 or 2 halo, in particular fluorine or chlorine; naphthyl optionally substituted with 1 or 2 halo or alkyloxyC-i-β; thienyl; piperidinyl substituted with Ar-C (= 0); 2,3-dihydrobenzo [1,4] dioxinyl; benzo [1,3] dioxolyl: or acenaphthyl; d) R4 and R5 are each independently hydrogen; Ci-β alkyl; benzyl; or R4 and R5 together and including the N to which they are attached can form a radical selected from imidazolyl; pyrazinyl substituted with C 1 -C 6 alkyl; piperazinyl substituted with C 1 -C 6 alkyl; piperazinyl substituted with pyrimidinyl; piperidinyl; thiomorpholinyl; morpholinyl; pyrrolidinyl; or triazolyl; e) R6 is hydrogen; halo, in particular chlorine, fluorine or bromine; C-i-ß alkyl; or two proximal radicals R6 can be taken together to form a bivalent radical of formula -CH = CH-CH = CH-; f) R7 is hydrogen. Preferred compounds of the present invention are compounds 50, 206, 31, 26, 27, 32, 33, 109, 39, 44, 41, compound A, E and F, their pharmaceutically acceptable acid or base addition salt or their N-oxide form. Another group of preferred compounds are the compounds defined in claim 24, ie, compounds 36, 46, 206, 31, 26, 33, 13, 39, 44, Compound A, E and F, their acid addition salt or pharmaceutically acceptable base or its N-oxide form. The present invention also relates to a compound according to claim 29, ie the compounds A, B, C, D, E, F, G, H, I, their pharmaceutically acceptable acid or base addition salt or its N-oxide form. The compounds of formula (I) can be prepared according to the methods described in WO 2004/011436, which is incorporated herein by reference. In general, the compounds according to the invention can be prepared by a succession of steps, each of which is known to the person skilled in the art. In particular, the compounds according to formula (I) can be prepared by reacting an intermediate compound of formula (II) with an intermediate compound of formula (III) according to the following reaction scheme (1): SCHEME 1 (lll) (») Using BuLi in a mixture of diisopropylamine and tetrahydrofuran, and where all the variables are defined with in the formula (I) Agitation can increase the speed of the reaction. The reaction it can be carried out conveniently at a temperature ranging between -20 and -70 ° C.

The starting materials and intermediates of formula (II) and (III) are compounds that are commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, the compounds intermediates of formula (ll-a) can be prepared in accordance with following reaction scheme (2): SCHEME 2 (ll-a) where all the variables are defined as in the formula (I). The reaction scheme (2) comprises step (a) in which an appropriately substituted aniline is reacted with an appropriate acylchloride such as 3-phenylpropionyl chloride, 3-fluorobenzenepropanoyl chloride or p-chlorobenzenepropanoyl chloride, in the presence of a suitable base, such as triethylamine and a solvent inert to the suitable reaction such as methylene chloride or ethylene dichloride. The reaction can be conveniently carried out at a temperature ranging from room temperature to reflux temperature. In a next step (b) the adduct obtained in step (a) is reacted with phosphoryl chloride (POCI3) in the presence of N, N-dimethylformamide (Vilsmeier-Haack formylation followed by cyclization). The reaction can be conveniently carried out at a temperature ranging from room temperature to reflux temperature. In a next step (c) a specific R2 group, where R2 is for example an alkyloxyC-α-6 radical or alkylthioC-α-6, is introduced by reacting the intermediate compound obtained in step (b) with an HX-alkyl compound ??? C6 where X is S or O. It is evident that in the above and in the following reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to generally known methodologies. the technique, such as extraction, crystallization and chromatography. It is also evident that reaction products that exist in more than one enantiomeric form can be isolated from their mixture by known techniques, in particular preparative chromatography such as preparative HPLC. Typically, the compounds of formula (I) can be separated into their isomeric forms. Intermediate compounds of formula (III) are compounds that are commercially available or that can be prepared according to conventional general reaction procedures known in the art. For example, the intermediate compounds of formula (III-a) in which R3 is Ar substituted with s substituents R10, wherein each R10 is independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or di (alkylic) ? -6) amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-4 alkyloxy. 6, polyhaloalkyloxyC? -6, carboxyl, alkyloxyC? -carbonyl, aminocarbonyl, morpholinyl and mono- or di (alkylC? 6) aminocarbonyl and s is an integer equal to zero, 1, 2 or 3, can be prepared according to the following reaction scheme (3): SCHEME 3 (lll-a) The reaction scheme (3) comprises step (a) in which a Ar suitably substituted, in particular an appropriately substituted phenyl, is reacted by Friedel-Craft reaction with an appropriate acylchloride such as 3-chloropropionyl chloride, in the presence of a suitable Lewis acid, such as for example AICI3, FeC, SnCl , TiCU or ZnCl2 and a solvent inert to the suitable reaction, such as methylene chloride or ethylene dichloride. The reaction can be conveniently carried out at a temperature ranging from room temperature to reflux temperature. In a next step (b) an amino group (-NR4R5) is introduced by reacting the intermediate compound obtained in step (a) with HNR4R5. In general, bacterial pathogens can be classified as gram-positive or gram-negative pathogens. Antibiotic compounds with activity against gram-positive and gram-negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are considered active against gram-positive and / or gram-negative bacterial pathogens. In particular, the present compounds are active against at least one gram-positive bacteria, preferably against various gram-positive bacteria, more preferably against one or more gram-positive bacteria and / or gram-negative bacteria. The present compounds have bactericidal or bacteriostatic activity. Examples of aerobic and anaerobic gram-positive and gram-negative bacteria include Staphylococci, for example S. aureus; Enterococci, for example 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, for example Staphylococci, Enterococci and Streptococci are particularly important due to the development of resistant strains which are difficult to treat and difficult to eradicate from, for example, a hospital environment once they are established.

Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), Streptococcus pneumoniae resistant to penicillin and Enterococcus faecium with multiple resistance. The compounds of the present invention also show activity against resistant bacterial strains. The compounds of the present invention are especially active against Staphylococcus aureus, including resistant Staphylococcus aureus such as for example methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae. In particular, the compounds of the present invention are active on those bacteria of which the viability depends on the proper functioning of the F1 F0 ATP synthase. Without being limited to any theory, it is described that the activity of the present compounds lies in the inhibition of F1F0 ATP synthase, in particular the inhibition of the FO complex of the F1F0 ATP synthase, more in particular the inhibition of the c subunit of the FO complex. of F1F0 ATP synthase, which leads to killing the bacteria by depleting the cellular ATP levels of the bacteria. Whenever used in the above or in the following, that the compounds can treat a bacterial infection means that the compounds can treat an infection with one or more bacterial strains. Whenever it is used in the above or in what follows, that the bacterial infection is different from Mycobacterial infection means that the bacterial infection is other than an infection with one or more Mycobacterial strains. The exact dose and frequency of administration of the present compounds depends on the particular compound of formula (I) used, treating the particular condition, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the patient in particular, the mode of administration as well as other medications that the individual may be taking, as is well known to those skilled in the art. Additionally, it is evident that the effective daily amount may be decreased or increased depending on the response of the treated subject and / or depending on the evaluation of the prescribing physician of the compounds of the present invention. The compound of the present invention may be administered in pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier. The compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically. Systemic application includes any method for introducing the compound into body tissues, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The specific dosage of antibacterial to be administered, as well as the duration of the treatment, can be adjusted as necessary. Bacterial infections which can be treated by the present compounds include, for example, infections of the central nervous system, infections of the outer ear, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial surgery prophylaxis, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving chemotherapy for cancer, or patients with organ transplants. 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 in order to effectively fight bacterial infections. Accordingly, 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 one or more other antibacterial agents are not antimycobacterial agents. The present invention also refers to a combination of (a) a compound of formula (I), and (b) one or more other antibacterial agents provided that one or more other antibacterial agents are not antimycobacterial agents, to be used as a medicament. 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 do not are antimycobacterial agents, also found within the present invention.

The present invention also relates to the use of a combination or pharmaceutical composition as defined above for the treatment of a bacterial infection, in particular a bacterial infection that is not a Mycobacterial infection. The present pharmaceutical composition can have various pharmaceutical forms for administration purposes. Suitable compositions are all the compositions generally used for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compounds, optionally in the form of addition salt, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in a unit dosage form suitable, in particular, for oral administration or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed 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, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral unit dosage forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier generally comprises sterile water, at least in large part, although other ingredients may be included, for example, to aid solubility. Injectable solutions can be prepared, for example, in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be employed. Also included are preparations in solid form which are intended to be converted, before use, into liquid form preparations. Depending on the mode of administration, the pharmaceutical composition preferably comprises between 0.05 and 99% by weight, more preferably between 0.1 and 70% by weight of the active ingredients, and, between 1 and 99.95% by weight, more preferably between 30 and 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total composition. The weight to weight ratio of the compound of formula (I) and (b) the one or more other antibacterial agents when provided as a combination can be determined by the person skilled in the art. Said relationship and the exact dose and frequency of administration depends on the particular compound of formula (I) and on the other antibacterial agents used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration and general physical condition of the patient in particular, the mode of administration as well as other medication that the individual is taking, as is well known to the person skilled in the art. Additionally, it is evident that the effective daily amount may be reduced or increased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The compounds of formula (I) and one or more other antibacterial agents can be combined in a single preparation or can be formulated into separate preparations so that they can be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product that contains (a) a compound of formula (I), and (b) one or more other antibacterial agents provided that one or more other antibacterial agents are not antimycobacterial agents, such as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection. The pharmaceutical composition may further contain various different ingredients known in the art, for example, a lubricant, stabilizing agent, pH regulating agent, emulsifying agent, viscosity regulating agent, surfactant, preservative, flavoring or coloring. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form as used in the present invention refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such type of unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and their segregated multiples. The daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the desired treatment and the indicated bacterial disease. The other antibacterial agents which can be combined with the compounds of formula (I) are antibacterial agents known in the art. The other antibacterial agents comprise antibiotics of the β-lactam group such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semisynthetic cephalosporins, cefamycins, 1-oxacephems, clavulanic acids, pened, carbapenems, nocardicines, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycins; peptides such as bleomycins, gramicidins, polymyxins, bacitracins, large ring peptide antibiotics containing lactone ligations, actinomycins, ampomycin, capreomycin, distamycin, enduracidins, mikamycin, neocarzinostatin, stendomicin, viomycin, virginiamycin; cycloheximide; cycloserine; variotin; sarkomycin A; novobiocin; griseofulvin; Chloramphenic !; mitomycins; fumagillin; monensins; pyrrolnitrine; fosfomycin; fusidic acid; D- (p-hydroxyphenyl) glycine; D-phenylglycine; enediinas. Specific antibiotics which can be combined with the present compounds of formula (I) are for example benzylpenicillin (potassium, procaine, benzathine), phenoxymethylpenicillin (potassium), potassium feneticilin, propicillin, carbenicillin (disodium, phenylsodium, indanyl sodium), sulbenicillin, ticarcillin. disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, cyclacillin, hectacillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillin, cephalexin, cefaclor, cephaglycine, cefadroxil, cephradine , cefroxadine, cephapirin sodium, cephalothin sodium, cefacetril sodium, cefsulodin sodium, cephaloridin, cefatrixine, cefoperazone sodium, cefamandole, hydrochloride vefotiam, cefazolin sodium, ceftizoxime sodium, cefotaxime sodium, cefmenoxime hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin, cefme tazol, cefotetan, latamoxef, clavulanic acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride, demethylclortetracycline, oxytetracycline, metacycline, doxycycline, rolitetracycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, bekanamycin, tobramycin, gentamicin sulfate , dibekacin, amikacin, micronomycin, ribostamycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, disomycin A, hygromycin B, apramycin, sisomycin, netilmicin sulfate, spectinomycin hydrochloride, astromycin sulfate, validamycin, kasugamycin, polyoxin , blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, traceyloleandomycin, kitasamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin, colistin sulfate, sodium colistinmethane sulfonate , in ramycin, mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin, actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, tricomycin, mitramycin, lincomycin, clindamycin, clindamycin hydrochloride palmitate , flavophospholipol, cycloserine, pecillin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrine, fosfomycin, fusidic acid, bicozamycin, tiamulin, siccanin. Tables 1 to 4 show the compounds of formula (I) according to the present invention. Of some compounds the absolute stereochemical configuration of the stereogenic carbon atoms in them was not determined experimentally. In those cases, the stereochemically isomeric form which was first isolated is designated as "A" and the second as "B", without further reference to the actual stereochemical configuration. However, said "A" and "B" isomeric forms can be unambiguously characterized by one skilled in the art, using methods known in the art such as, for example, X-ray diffraction. In the case where "A" and "B" are stereoisomeric mixtures, they can be further separated so that the first isolated respective fractions are designated "A1" respectively "B1" and the second one as "A2" respectively "B2", without further reference to the actual stereochemical configuration. However, said isomeric forms "A1, A2" and "B1, B2" can be unambiguously characterized by one skilled in the art, using methods known in the art such as, for example, X-ray diffraction. in the foregoing or in what follows, a compound is designated "A" or "B" which means that the compound is a mixture of two enantiomers. Whenever in what follows and in the foregoing, a compound is designated as "A1", "A2", "B1" or "B2" this means that the compound is an enantiomer. The relative configuration of the present compounds indicated by erythro and threo was determined by NMR, carried out in a Bruker Avance 400 MHz apparatus (the samples were dissolved in CDCI3), comparing the chemical deviations of a maximum of protons between the different stereoisomers or by 2D NOESY; -LCMS carried out on a Applied Biosystems API100 single quadrupole mass spectrometer. Samples were dissolved in a mixture of acetonitrile / methanol and injected in the Flow Injection Analysis mode and analyzed in positive electrospray using a 40V ungrouping potential. The erythro / threo designation was based on the ionic peak [MH +] corresponding to the loss of methanol (which is the result of fragmentation at the electrospray source). When the ion is produced, it is larger in the spectrum of threo compound than in the spectrum of erythro compound. 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. The No. of Example in the tables that appear later refers to the numbers of Examples of the document WO 2004/011436 that indicates according to which procedure the compounds can be prepared. Additional compounds are indicated by letters. Compounds A, B and C were prepared according to the procedures described in WO 2004/011436. The scheme given below indicates the synthesis route of the compounds A, B and C. The numbers of examples A8, A9, B12 and B13 correspond to the procedures of WO 2004/011436.

The present intermediate 1 was prepared in the same way as intermediate 12 of WO 2004/011436, ie, according to Example A8 of WO 2004/011436, although starting from 1,3-difluorobenzene. Yield: 57% of the present intermediate 1. The present intermediate 2 was prepared in the same way as intermediate 14 of WO 2004/011436, ie, according to Example A9 of WO 2004/011436, although starting from the present intermediary 1 and reacting it with N-ethylbenzylamine. Yield: 88% of the present intermediate 2. Compound C was prepared in the following manner: the present intermediate 2 was reacted with the intermediate compound 3 of WO 2004/011436 in the same way as described in the Example B12 of WO 2004/011436. The residue (5.4 g) obtained according to the procedure of B12, which is a mixture of diastereoisomers, was purified by column chromatography on silica gel (eluent: CH2Cl2 / Cyclohexane: 60/40). Two fractions were collected and the solvent was evaporated. The second fraction was crystallized from diisopropyl ether to give 0.83g of compound C (diastereomer B) (yield: 13%). Compounds A and B were prepared in the following manner: The residue obtained in the synthesis of compound C was reacted with 1-chloroethyl-chloroformate in the same manner as described in Example B13 of WO 2004/011436. The residue (1.7g) obtained according to the procedure of Example B13, which is a mixture of diastereoisomers, 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 crystallized separately from diisopropyl ether yielding 0.31 g of compound B (diastereomer A) (yield: 27%) and 0.52 g of compound A (diastereomer B) (yield: 45%). Compound D was prepared according to the procedures described in WO 2004/011436. The scheme that follows indicates the synthesis route of compound D. The numbers of examples A9, B12 and B13 correspond to the procedures of WO 2004/011436.

The present intermediate 3 was prepared in the same way as intermediate 14 of WO 2004/011436, ie, according to Example A9 of WO 2004/011436, although starting from 3-chloropropiophenone. Yield: 98% of the present intermediate 3. Compound J was prepared in the following manner: the present intermediate 3 was reacted with the intermediate compound 3 of WO 2004/011436 in the same way as that described in Example B12 of WO 2004/011436 . The residue obtained (4.9 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2). A fraction was collected and the solvent was evaporated. Yield: 1.43g of compound J, which is a mixture of diastereoisomers. Compound D was prepared in the following manner: Compound J was reacted with 1-chloroethyl-formate in the same manner as described in Example B13 of WO 2004/011436. The residue (1.2g) obtained according to the procedure of Example B13 was purified by column chromatography on silica gel (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 yielding 0.08g of compound D (diastereomer B) (yield ^ 0 %) - Compounds E and F were prepared by separating compound 4 (diastereoisomer B) of WO 2004/011436 in its enantiomers by the following procedure: Final compound 4 of WO 2004/011436 (2.5g) was separated into its enantiomers by column chromatography (eluent: hexane / ethanol 99.95 / 0.05; : CHIRACEL OD). 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 F (enantiomer B2) (mp 175 ° C). Compound G was prepared as follows: A mixture of compound 115 of WO 2004/011436 (prepared according to B15 of WO 2004/011436) (0.00028 mol), cyclic ester of 1,3-propanediol of pyridin-3-boronic acid (0.00055 mol), Pd [P (Ph3)] 4 (0.00003 mol) and 2N Na2CO3 (0.0011 mol) in dimethoxyethane (4 ml) was stirred at 90 ° C. C for 1.5 hours, then poured into H20 and extracted with CH2Cl2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5; 5μm). 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: A mixture of compound 15 of WO 2004/011436 (prepared according to B7 of WO 2004/011436) (0.0009 mol), 2-furanboronic acid (0.0018 mol), Pd [P ( Ph3)] 4 (0.00009 mol) and Na2C03 2M (0.0036 mol) in dimethoxyethane (10 ml) was stirred at 90 ° C for 6 hours, then poured into H20 and extracted with CH2CI2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.57g) was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH30H / NH40H 99/1 / 0.1, 10μm). The pure fractions were collected and the solvent was evaporated, yielding 0.23 g of residue. This fraction was crystallized from diisopropyl ether / acetonitrile. The precipitate was filtered and dried. Yield: 0.071 g of compound H (15%) (mp 215 ° C). Compound I was prepared according to the procedures described in WO 2004/011436. The scheme that follows indicates the synthesis route of compound I. The numbers of examples A10 and B1 correspond to the procedures 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, 4ml), HCI / iPrOH (1ml) and ethanol (100ml) it was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was taken up in H2O / 3N HCI / CH2Cl2. The aqueous layer was basified and extracted with GH2C! 2. The organic layer was separated, dried (MgSO 4), filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.2, 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 4.9 g of intermediate 4 (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) under N2 flow. The mixture was stirred at -20 ° C for 20 minutes, then cooled to -70 ° C. A solution of intermediate compound 3 of WO 2004/011436 (0.0091 mol) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -70 ° C for 2 hours. A solution of the present intermediate 4 (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 column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 99/1 / 0.2, 15-40 μm). Two fractions were collected and the solvent was evaporated. Performance: 0.96g F1, 0.72g F2. F1 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.87 g of compound I (17%). TABLE 1 TABLE 2 TABLE 3 TABLE 4 TABLE 4 Analytical methods The mass of some compounds was registered with LCMS (liquid chromatography mass spectrometry) (mass spectrometry by liquid chromatography). The method used is described below. The data is shown in table 5 below.

LCMS Method The LCMS analysis was carried out (electrospray ionization in positive mode, scanning mode 100 to 900 amu) on a Kromasil C18 column (Interchim, Montlucon, FR, 5 μm, 4.6 x 150 mm) with a flow rate of 1 ml / minute. Two mobile phases were used (mobile phase A: 30% ammonium acetate 6.5mM + 40% acetonitrile + 30% formic acid (2ml / l), mobile phase B: 100% acetonitrile) for a gradient condition of 100% A during 1 minute at 100% B in 4 minutes, 100% B for 5 minutes at 100% A in 3 minutes, and rebalanced with 100% A for 2 minutes.

TABLE 5 Initial LCMS peak PHARMACOLOGICAL EXAMPLES Preparation of bacterial suspensions for susceptibility tests: The bacteria used in this study were grown overnight in flasks containing 100 ml of Mueller-Hinton Culture Broth (Becton Dickinson-cat. No. 275730) in sterile deionized water, with shaking, at 37 ° C. Base products (0.5 ml / tube) were stored at -70 ° C until used. The bacterial titrations were carried out in microtitre plates to detect TCID 0, where the TCID50 represents the dilution that gives rise to bacterial growth in 50% of the inoculated cultures. In general, an inoculum level of approximately 100 TCID50 was used for susceptibility testing.

Antibacterial Susceptibility Tests: determination of ICgg Microtiter plate assay Sterile, 96-well, flat-bottom plastic microtitre plates were loaded with 180 μl. of sterile deionized water, supplemented with 0.25% BSA. Subsequently, initial solutions (7.8 x final assay concentration) of the compounds were added in 45 μl of volumes in column 2. Five-fold serial dilutions (45 μl in 180 μl) were prepared directly on the microtiter plates of column 2 to reach column 11. Control samples not treated with (column 1) and without (column 12) inoculum were included in each microtiter plate. Depending on the type of bacteria, approximately 10 to 60 CFU per well of bacteria inoculum (100 TCID50), in a volume of 100 μl in medium of Mueller-Hinton 2.8x broth, was added to rows A - H, except for column 12. The same volume of broth medium without inoculum was added to column 12 in row A-H. Cultures were incubated at 37 ° C for 24 hours under a normal atmosphere (incubator with open air valve and continuous ventilation). At the end of the incubation, one day after the inoculation, the bacterial growth was quantified fluorometrically. Therefore, resazurin (0.6 mg / ml) in a volume of 20 μl was added to all wells 3 hours after inoculation, and the plates were re-incubated overnight. A color change from blue to pink indicated the growth of bacteria. Fluorescence was read on a computer-controlled fluorometer (Cytofluor Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The% growth inhibition achieved by the compounds was calculated according to conventional methods. The lCg0 (expressed in μg / ml) was defined as 90% inhibitory concentration for bacterial growth. The results are shown in table 6. Dilution method with agar The MIC99 values (the minimum concentration to obtain a 99% inhibition of bacterial growth) can be determined by carrying out the conventional agar dilution method according to NCCLS standards * where the medium used includes Mueller-Hinton agar. * Institute of clinical laboratory standards (Clinical laboratory standard institute). 2005. Methods for susceptibility testing Antimicrobial dilution for bacteria growing Aerobically: approved pattern - sixth edition (Methods for dilution Antimicrobial susceptibility tests for bacteria that grows Aerobically: approved standard -sixth edition) Elimination time assays The bactericidal or bacteriostatic activity of the compounds can be determined in an elimination time trial using the microdilution method in broth culture *. In an elimination time trial in Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), the starting inoculum of S. aurues and MRSA is 106 CFU / ml in Muller Hinton broth. The antibacterial compounds are used at the concentration of 0.1 to 10 times the MIC (ie, the IC90 as determined in the microtiter plate assay). Wells that did not receive an antibacterial agent constitute the control of crop growth. The plates containing the microorganism and the test compounds are incubated at 37 ° C. After 0, 4, 24, and 48 hours of incubation, the samples are removed for determination of viable counts by serial dilution (10"1 to 10" 6) in sterile PBS and plate placement (200 μl) in Mueller Hinton agar. . The plates are incubated at 37 ° C for 24 hours and the number of colonies is determined. The elimination curves can be constructed by plotting the log-ioCFU for each ml against time. A bactericidal effect is commonly defined as the decrease of 3-log-? Or in the amount of CFU per ml compared to the untreated inoculum. The potential remnant effect of the drugs is eliminated by serial dilutions and colony count at the highest dilution used for plaque placement. * Zurenko, G.E. et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother. 40, 839-845 (1996).

Determination of cellular ATP levels In order to analyze the change in cellular ATP concentration (using ATP bioluminescence kit, Roche), trials were carried out by growing an initial culture of S. aureus (ATCC29213) in Mueller Hinton flasks. of 100 ml and incubated in a shaker-incubator for 24 hours at 37 ° C (300 rpm). The OD405 nm was measured and the CFU / ml was calculated. The cultures were diluted to 1 x 10 6 CFU / ml (final concentration for ATP measurement: 1 x 10 5 CFU / 100 μl per well) and test compound was added to 0.1 to 10 times the MIC (i.e. determined in microtiter plate assay). These tubes were incubated for 0, 30 and 60 minutes at 300 rpm and 37 ° C. 0.6 ml of bacterial suspension of the rapid opening cap tubes was used and added to new 2 ml eppendorf tubes. 0.6 ml of cell lysis reagent (Roche Kit) was added, vortexed at maximum speed and incubated for 5 minutes at room temperature. They cooled on ice. The luminometer was allowed to warm up to 30 ° C (Luminoskan Ascent Labsystems with injector). A column (= 6 wells) was loaded with 100 μl of the same sample. 100 μl of Luciferase reagent was added to each well using the injector system. The luminescence was measured for 1 sec.

TABLE 6 IC30 values fμg / ml) determined according to the microtiter plate assay.

BSU 43639 means Bacillus subtilis (ATCC43639); ECO 25922 means Escherichia coli (ATCC25922); EFA 14506 means Enterococcus faecalis (ATCC14506); EFA 29212 stands for Enterococcus faecalis (ATCC29212); LMO 49594 stands for Listeria monocytogenes (ATCC49594); PAE 27853 stands for Pseudomonas aeruginosa (ATCC27853); SMU 33402 stands for Streptococcus mutans (ATCC33402); SPN 6305 means Streptococcus pneumoniae (ATCC6305); SPY 8668 means Streptococcus pyogens (ATCC8668); STA 43300 stands for Staphylococcus aureus (ATCC43300); STA 25923 stands for Staphylococcus aureus (ATCC25923); STA 29213 stands for Staphylococcus aureus (ATCC29213); STA RMETH stands for methicillin-resistant Staphylococcus aureus (MRSA) (a clinical isolate from the University of Antwerp).

ATCC means tissue culture of the American type ("American type tissue culture"). Having thus specially described and determined the nature of the present invention and the manner in which it is to be put into practice, it is declared to claim as property and exclusive right what is contained in the following claims.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound for the manufacture of a medicament for the treatment of a bacterial infection, said compound being a compound of formula its pharmaceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxide form, where R1 is hydrogen, halo, polyhaloalkylC-α-6, alkylC-α-6, Ar or Het; p is an integer equal to 1 or 2; R 2 is C 1-4 -alkyloxy, C 1-6 alkyloxy-C 1-6 alkyloxy or C 1-6 alkylthio; R3 is Ar, Het or Het1; R 4 and R 5 each independently is hydrogen, C 1-6 alkyl or benzyl; or R4 and R5 together and including the N to which they are attached can form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazoIinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl , piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may be optionally substituted with Ci-β alkyl, halo, polyhaloalkylC?-6, hydroxy, hydroxyalkylC ?6, alkyloxyC?-6 , amino, mono- or di (alkylC? -6) amino, alkylthioC? -6, alkyloxyC? _6alkylC? -6, alkylthioCi-ealkylCi-e or pyrimidinyl; R6 is hydrogen, halo, polyhaloalkyl-t-6, C1-6alkyl, alkyloxyC-? -6, alkylthioC6-6; or two proximal radicals R6 can be taken together to form a bivalent radical of formula -CH = CH-CH = CH-; r is an integer equal to 1 or 2; R7 is hydrogen, alkylC, Ar, Het or Het1; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle may be optionally substituted with 1, 2 or 3-substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or di (alkylC? -6) amino, C 1-6 alkyl, polyhaloalkylC? -6, hydroxyalkylC-i-β, C 1-6 alkyloxy, polyhaloalkyloxy C? -6, C 1-6 alkyl? 6alkyl? 6-carboxyl, C 1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (alkyIC? -6) 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 be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, hydroxy, alkylC ?6, polyhaloCalkylC - ?6, hydroxyalkylC? -6, alkyloxyC? -6, alkyloxyCi-ealkylCi-e or Ar-C (= O) -; Het1 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 or benzo [1,3] dioxolyl; each bicyclic heterocycle may be optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, hydroxy, C 1-6 alkyl, polyhaloalkyl C? -6) hydroxyalkyl C? -6, alkyloxyC? -6, alkyloxyCi-p.alkylCi -e or Ar-C (= 0) -; as long as the bacterial infection is not a Mycobacterial infection; and provided that the compound is not (aS, ßR) -6-bromo-a- [2- (dimethylamino) ethyl] -2-methoxy-a-1-naphthalenyl-β-phenyl-3-quinolinetanol, its salt of pharmaceutically acceptable acid or base addition or its N-oxide form.

2. The use claimed in claim 1, wherein the compound of formula (I) is a compound having the following formula its pharmaceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxide form.

3. The use claimed in any of the preceding claims wherein the compound of formula (I) or (Ia) is a compound having the following formula its pharmaceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxide form.

4. The use claimed in any of the preceding claims, wherein R1 is hydrogen, halo, optionally substituted phenyl, or Het.

5. The use claimed in claim 4, wherein R1 is hydrogen, halo or optionally substituted phenyl.

6. The use claimed in claim 5, wherein R1 is halo.

7. The use claimed in any of the preceding claims, wherein R2 is Ci-βalkyloxy or alkylthioC-γ-6.

8. The use claimed in any of the preceding claims, wherein R3 is Ar or Het.

9. The use claimed in any of claims 1 to 7, wherein R3 is Ar or Het1.

10. The use claimed in claim 8 or 9, wherein R3 is Ar. 1 - . 1 - The use claimed in claim 10, wherein R 3 is optionally substituted phenyl or optionally substituted naphthyl. 12. The use claimed in any of the preceding claims, wherein R4 and R5 each independently is hydrogen, C6_6alkyl or benzyl. 13. The use claimed in claim 12, wherein R4 and R5 each independently is hydrogen or alkyiC? 6. 14. The use claimed in any of claims 1 to 11, wherein R4 and R5 together and including the N to which they are attached can form a radical selected from the group of pyrrolidinyl, 2-pyrrolinium, 3-pyrrolinyl, pyrrolyl , imidazolidinyl, pyrazolidinyl, 2-imidazoinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may be optionally substituted with C-alkyl t-β, halo, polyhaloalkylCi.6, hydroxy, hydroxyalkylC-? 6, alkyloxyC-? - 6, amino, mono- or di (alkylC? .6) amino, alkylthioCi-β, alkyloxyC? -6alkylC? 6, AcylthioCi-ßalkylCi-β or pyrimidinyl. 15. The use claimed in claim 14, wherein R4 and R5 together and including the N to which they are attached can form a radical selected from the group of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinium, pyridazinyl , pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings can be optionally substituted with C 1 -C 6 alkyl, halo, polyhaloalkyl C 6, hydroxy, C 6 hydroxyalkyl, C 6 alkyloxy, amino, mono- or alkylthioC? -6, C 1-6 alkyloxyC 6 alkyl, 6 alkylthioC 6 alkyl, or 6 pyrimidinyl. 16. The use claimed in any of the preceding claims, wherein R6 is hydrogen, halo, polyhaloalkylC-α-6, or C alquilo-C --alkyl; or two proximal R6 radicals can be taken together to form a bivalent radical of formula -CH = CH-CH = CH-. 17. The use claimed in claim 16, wherein R6 is hydrogen or halo. 18. The use claimed in any of the preceding claims, wherein R7 is hydrogen. 19. The use claimed in any of the preceding claims, wherein r is an integer equal to 1. 20. The use claimed in any of claims 1, 4 to 19, wherein p is a integer equal to 1. 21.- The use claimed in any of the claims 1, 2, 4 to 19 so long as one R1 is C1-6alkyl, then p is an integer equal to 2 and the other substituent R1 is selected from halo, polyhaloalkylC? -6, alkylC? -6, Ar or Het. 22. The use claimed in any of the preceding claims, wherein the bacterial infection is an infection with a gram-positive bacterium. 23. The use claimed in claim 1, wherein R1 is hydrogen; alkyl Ci-e; halo; phenyl; furanyl optionally substituted with hydroxyalkyl Ci-β; or pyridyl; R 2 is C 1-7 alkyloxy, C 1-6 alkylthio, or C 1-6 alkyloxyC 1-6 cycloxy; R 3 is phenyl optionally substituted with 1 or 2 halo; naphthyl optionally substituted with 1 or 2 halo or C 1-7 alkyloxy; thienyl; substituted piperidinyl; with Ar-C (= 0) -, 2,3-dihydrobenzo [1,4] dioxinyl, benzo [1,3] dioxolyl, or acenaphthyl, R4 and R5 are each independently hydrogen, Ci-β alkyl benzyl, or R4 and R5 together and including the N to which they are attached can form a radical selected from imidazolyl, pyrazinyl substituted with Ci-β alkyl, piperazinyl substituted with C1-6 alkyl, piperazinyl substituted with pyrimidinyl, piperidinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, or triazolyl; is hydrogen, halo, C 1-6 alkyl, or two proximal R 6 radicals can be taken together to form a bivalent radical of the formula -CH = CH-CH = CH-; R 7 is hydrogen. claims in claim 1, wherein the compound of formula (I) is selected from the following com posts its paceutically acceptable acid or base addition salt or its N-oxide form. 25. A combination of (a) a compound of formula (I) as defined in any of claims 1 to 24, and (b) one or more other antibacterial agents provided that one or more other antibacterial agents are not antimycobacterial agents. 26. A paceutical composition comprising a paceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of (a) a compound of formula (I) as defined in any of claims 1 to 24, and (b) ) one or more different antibacterial agents provided that one or more different antibacterial agents are not antimycobacterial agents. 27. The use of a combination as claimed in claim 25 or a paceutical composition as claimed in claim 26 for the treatment of a bacterial infection. 28.- A product that contains (a) a. compound of formula (I) as defined in any one of claims 1 to 24, and (b) one or more other antibacterial agents provided that one or more other antibacterial agents are not antimycobacterial agents, as a combined preparation for the use simultaneous, separate or sequential in the treatment of a bacterial infection. 29. A compound of formula (I), wherein the compound is selected from the following compounds to the addition of paceutically acceptable acid or base or its N-oxide form. SUMMARY OF THE INVENTION 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 formula its paceutically acceptable addition or base salt, its stereochemically isomeric form or its N-oxide form, where R1 is hydrogen, halo, polyhaloalkylC? -6, alkylC? -6, 'Ar or Het; p is an integer equal to 1 or 2; R2 is C 1-6 alkyloxy, C 1-6 alkyloxy-6alkyloxyC? -6 or alkylthioC? -6; R3 is Ar, Het or Het1; R 4 and R 5 each independently is hydrogen, C 1 -C 6 alkyl or benzyl; or R4 and R5 together and including the N 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 be optionally substituted with alkyiC? -6, halo, polyhaloalkylC? -6, hydroxy, hydroxyalkylC-i-β, alkyloxyC ? -6, amino, mono- or di (alkylC? -6) amino, alkylthioC? -6, alkylthioCi-βalkylC-i. 6 or pyrimidinyl; R 6 is hydrogen, halo, polyhaloC 1-6 alkyl, C 1-6 alkyl, alkyloxyd-6, alkylthioCi-β; or two proximal radicals R6 can be taken together to form a bivalent radical of formula -CH = CH-CH = CH-; r is an integer equal to 1 or 2; R7 is hydrogen, C ^ alkyl, Ar, Het or Het1; as long as the bacterial infection is not a Mycobacterial infection. MARVAL P05 / 2053