MXPA06008313A - Substituted quinolines and their use as mycobacterial inhibitors - Google Patents

Abstract

The present invention relates to novel substituted quinoline derivatives according to the general formula (Ia) or the general formula (Ib) salts, quaternary amines, stereochemically isomeric forms, tautomeric forms and N --oxide forms thereof, wherein R1 is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl;p is 1, 2, 3 or 4;R2 is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di(alkyl)amino or a radical of formula (Ic);R3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;R4 is hydrogen, alkyl or benzyl;R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl;or two vicinal R5 radicals may be taken together to form together with the phenyl ring to which they are attached a naphthyl;r is 1, 2, 3, 4 or 5;R6 is hydrogen, alkyl, Ar or Het R7 is hydrogen or alkyl;R8 is oxo;or R7 and R8 taken together form the radical - CH=CH-N=;Z is CH2 or C(=O). The claimed compounds are useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as M. tuberculosis, M. bovis, M. avium, M. smegmatis and M. marinum. Also claimed is a pharmaceutical composition containing a compound of the present invention, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of mycobacterial diseases and a process for preparing the claimed compounds.

Description

FR, GB, GR, HU, IE, IS, 1T, LT, LU, MC, NL, PL, PT, RO, Published: SE, YES, SK, TR), OAPI (BF, BJ, CF, CG, Cl , CM, GA, GN, - with intemational search report GQ, GW, ML, MR, NE, SN, TD, TG). (48) Date of publication of this corrected version: 11 May 2006 Declarations under Rule 4.17: - as to applicants' entitlement to apply for and be granulated to (15) Information about Correction: patent (Rule 4? 7 (ii)) 2006 - as to the applicaní 's entitlemenl to claim the priority of the former application (Rule 4.17 (iii)) - of inventorship (Rule 4.17 (iv)) no ofeach regular issue of the PCT Gazetle.

SUBSTITUTED CHINOLINES AND THEIR USE AS MYCOBACTERIAL INHIBITORS The present invention describes novel substituted quinoline derivatives useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium (M.) tuberculosis, M. bovis, M. avium and M. marinum.

BACKGROUND OF THE INVENTION Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a worldwide distribution. Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die of tuberculosis annually. In the last decade, TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, incidences of TB will increase by 41% in the next twenty years. Fifty years after the introduction of effective chemotherapy, TB continues after AIDS, as the infectious cause that leads to adult mortality in the world. The complication of epidemic TB is the emergence of a multidrug-resistant strain of strains and the deadly symbiosis with HIV. People who are HIV positive and are infected with TB are 30 times more likely to develop active TB than people who are HIV negative and TB is responsible for the death of one in three people with HIV / AIDS worldwide. All existing tuberculosis treatment methods involve the combination of multiple agents. For example, the regimen recommended by the Public Health Service of E.U.A. it is a combination of soniazid, rifampicin and pyrazinamide for 2 months, followed by isoniazid and rifampin only for an additional four months. These drugs are continued for an additional seven months in patients infected with HIV. For patients infected with multidrug resistant strains of M. tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies. There is no single agent that is effective in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of therapy lasting less than six months. There is a high medical need for new drugs that improve current treatment by allowing regimens that help the patient and satisfy the provider. Shorter regimes and those that require less supervision are the best way to achieve this. Most of the benefit of treatment comes in the first 2 months, during the intensive phase, or bactericidal when four drugs are provided together; the bacterial load is largely reduced, and patients become non-infectious. The continuation phase, or sterilization, is required for 4 to 6 months to eliminate persistent bacilli and to minimize the risk of recidivism. A potent sterilization drug that shortens treatment to 2 months or less would be extremely beneficial. Also needed are drugs that help acceptance by requiring less intensive supervision. Obviously, a compound that reduces both the total length of the treatment and the frequency of drug administration could provide the greatest benefit. The complication of epidemic TB is the incidence of increased strains resistant to multiple drugs or MDR-TB. Up to four percent of all global cases are considered MDR-TB, those resistant to the most effective drugs of the standard of four drugs, isoniazid and rifampin. MDR-TB is lethal when it is not treated and can not be adequately treated through standard therapy, so treatment requires up to 2 years of "second-line" drugs. These drugs are sometimes toxic, expensive and marginally effective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with strains of MDR-TB. There is a high medical need for a new drug with a new mechanism of action, which is likely to demonstrate activity against MDR strains. The term "drug resistant" as used before or after is a term well understood by the person with experience in microbiology. A drug-resistant Mycobacterium is a Mycobacterium that is not more susceptible to at least one previously effective drug; who has developed the ability to resist the antibiotic attack of at least one previously effective drug. A drug-resistant strain can transmit that ability to resist its progeny. Such resistance may be due to random genetic mutations in the bacterial cell that alter its sensitivity to a single drug or to different drugs. MDR tuberculosis is a specific form of drug-resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are currently the two most rful anti-TB drugs. The purpose of the present invention is to provide novel compounds, in particular substituted quinoline derivatives which have the property of inhibiting the growth of mycobacteria including the drug resistant or multidrug resistant mycobacteria, and therefore useful for the treatment of diseases mycobacteria, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium, M. smegmatis and M. marinum. Substituted quinolines are already described in US 5,965,572 (United States of America) for the treatment of antibiotic resistant infections and in WO 00/34265 for inhibiting the growth of bacterial microorganisms. None of these publications describes the substituted quinoline derivatives according to our invention.

BRIEF DESCRIPTION OF THE INVENTION The present invention describes novel substituted quinoline derivatives according to formula (la) and (Ib) the pharmaceutically acceptable basic or acid addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, tautomeric forms thereof and the N-oxide forms thereof, wherein: R1 is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; p is an integer equal to 1, 2, 3 or 4; R2 is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, t ^ H ^? mono or di (alkyl) amino or a radical of the formula i wherein Y is CH2, and -? O, S, NH or N-alkyl; R3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which they are attached a naphthyl; r is an integer equal to 1, 2, 3, 4 or 5; and R6 is hydrogen, alkyl, Ar or Het; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; Z is CH2 or C (= 0); alkyl is a straight or branched saturated hydrocarbon radical having 1 to 6 carbon atoms; or is a saturated hydrocarbon radical cyclic having 3 to 6 carbon atoms; or is a hydrocarbon radical saturated cyclic having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo, hydroxy, alkyloxy or oxo; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or 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 monocyclic and bicyclic heterocycle may be optionally substituted on a carbon atom with 1, 2 or 3 substituents selected from the group halo, hydroxy, alkyl or alkyloxy; Halo is a substituent selected from the group of fluorine, chlorine, bromine and iodine and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halo atoms.

The compounds according to formula (la) and (Ib) are interrelated in that, for example, a compound according to formula (Ib), with R8 equal to oxo is the tautomeric equivalent of a compound according to the formula (la) with R2 equal to hydroxy (keto-enol tautomerism).

DETAILED DESCRIPTION OF THE INVENTION In the structure of this application, alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo, hydroxy, alkyloxy or oxo. Preferably, alkyl is methyl, ethyl or cyclohexylmethyl. In the structure of this application, Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl. Preferably, Ar is naphthyl or phenyl, each optionally substituted with 1 or 2 halo substituents.

In the structure of this application, Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or 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 monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom with 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl or alkyloxy. Preferably, Het is thienyl or furanyl or pyridyl, more preferably Het is furanyl. In the structure of this application, halo is a substituent selected from the group of fluorine, chlorine, bromine and iodine and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halo atoms. Preferably, halo is bromine, fluorine or chlorine and preferably, haloalkyl is trifluoromethyl. Each time it is used thereafter, the term "compounds of formula (Ia) or (Ib)" is primarily to also include their N-oxide forms, their salts, their quaternary amines, their tautomeric forms and their stereochemically isomeric forms. Of special interest are those compounds of formula (la) or (Ib) which are stereochemically pure.

An interesting embodiment of the present invention describes those compounds of formula (Ia) or (Ib), the pharmaceutically acceptable basic or acid addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof, wherein Z is CH2; R1 is hydrogen, halo, halo, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; p is an integer equal to 1, 2, 3 or 4; R 2 is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino or a radical of the formula 1, "" "" | wherein Y is CH2, O, S, NH or N-alkyl; R3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which they are attached a naphthyl; r is an integer equal to 1, 2, 3, 4 or 5; and R6 is hydrogen, alkyl, Ar or Het; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo, hydroxy, alkyloxy or oxo; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl; furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or 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 monocyclic and bicyclic heterocycle may be optionally substituted on a carbon atom with 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl or alkyloxy; Halo is a substituent selected from the group of fluorine, chlorine, bromine and iodine and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halo atoms. Preferably, R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl. Preferably, the invention describes compounds of the formula (la) or (Ib) wherein: R 1 is hydrogen, halo, cyano, Ar, Het, alkyl, and alkyloxy; p is an integer equal to 1, 2, 3, or 4; R2 is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or a radical of the formula where Y is O; R3 is alkyl, Ar, Ar-alkyl or Het; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo or alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which they are attached a naphthyl; r is an integer equal to 1; and R6 is hydrogen; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo or hydroxy; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from the group of benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1,3] dioxolyl; each monocyclic and bicyclic heterocycle may be optionally substituted on a carbon atom with 1, 2 or 3 alkyl substituents; and halo is a substituent selected from the group of fluorine, chlorine and bromine. For the compounds according to either formula (la) or (Ib), preferably, R 1 is hydrogen, halo, Ar, Het, alkyl or alkyloxy. More preferably, R1 is halo. More preferably, R1 is bromine. Preferably, p is equal to 1. Preferably, R 2 is hydrogen, alkyloxy or alkylthio. More preferably, R2 is alkyloxy. More preferably, R2 is methyloxy. Preferably, R3 is naphthyl, phenyl or Het, each optionally substituted with 1 or 2 substituents, these substituents preferably being a halo or haloalkyl, more preferably being a halo. More preferably, R3 is naphthyl or phenyl. More preferably, R3 is naphthyl. Preferably, R 4 is hydrogen or alkyl, more preferably alkyl, such as methyl or ethyl. More preferably R4 is methyl. Preferably, R5 is hydrogen, alkyl or halo. More preferably, R5 is hydrogen. Preferably r is 1 or 2. Preferably, R6 is hydrogen or methyl. More preferably, R6 is hydrogen. Preferably Z is CH2. Preferably, Z is C (= 0). For compounds according to formula (Ib) only, preferably, R7 is alkyl, preferably methyl, and R8 is oxygen. An interesting group of compounds are the compounds of the formula (Ia), the pharmaceutically acceptable basic or acid addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. An interesting group of compounds are those compounds according to formula (Ia), the pharmaceutically acceptable basic or acid addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms of the and the N-oxide forms thereof, wherein R 1 is hydrogen, halo, Ar, Het, alkyl or alkyloxy; p = 1; R2 is hydrogen, alkyloxy or alkylthio; R3 is naphthyl, phenyl or Het, each optionally substituted with 1 or 2 substituents selected from the group of halo and haloalkyl; R 4 is hydrogen or alkyl; R5 is hydrogen, alkyl or halo; r is equal to 1 and R6 is hydrogen. An interesting group of compounds are those compounds according to formula (la) wherein R 1 is hydrogen, halo, for example, bromine; alkyl, for example, methyl; or Het, for example furanyl; R2 is alkyloxy, for example, methyloxy; R3 is naphthyl, phenyl or Het, each optionally substituted with halo, for example, phenyl optionally substituted with halo, naphthyl or furanyl; R 4 is alkyl, for example, methyl or ethyl; R5 is hydrogen or halo, for example, chloro; R6 is hydrogen; Z is CH2 or C (= 0). The pharmaceutically acceptable acid addition salts are defined to comprise the therapeutically active non-toxic acid addition salt forms which the compounds according to either formula (Ia) or (Ib) are capable of forming. Said acid addition salts can be obtained by treating the basic form of the compounds according to either formula (Ia) or (Ib) with suitable acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicyclic acid, p-aminosalicylic acid and pamico acid. Compounds according to either formula (Ia) or formula (Ib) containing acidic protons can also be converted into their therapeutically active non-toxic base addition salt forms by treatment with the appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular, lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, for example, benzathine, N-methyl-D-glucamine, hibramine salts, and salts with amino acids, for example arginine and lysine. Conversely, such basic or acid addition salt forms can be converted to the free forms by treatment with the appropriate base or acid. The term "addition salt" as used in the structure of this application also comprises solvates which compounds according to either formula (Ia) or (Ib) as well as salts thereof, are capable of forming. Said solvates are, for example, hydrates and alcohol. The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of the formula (la) or (Ib) are capable of forming by reaction between a basic nitrogen of a compound of the formula (cf. ) or (Ib) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, for example, methyloduro or becyliodide. Other reagents with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. The term "stereochemically isomeric forms" as used herein defines all possible isomeric forms that compounds of either formula (Ia) or (Ib) 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 the diastereomers and enantiomers of the basic molecular structure. More in particular, stereogénicos centers can have the configuration R- or S-; the substituents on the saturated (partially) cyclic bivalent radicals can have either the cis- or trans- configuration. The stereochemically isomeric forms of the compounds of either formula (la) or (Ib) are obviously intended to be accepted within the scope of this invention. Following the conventions of the CAS nomenclatureWhen 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 a lower number to 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 the centers with the same chirality and [R *, S *] indicates centers of non-similar chirality. 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 could be specified as S- [R *, S *]. If "a" and "ß" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number is arbitrarily always in the "a" position of the plane means determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system in relation to the position of the highest priority substituent on the reference atom is termed "ce", if it is on the same side of the plane means determined by the ring system, or "ß", if it is on the other side of the median plane determined by the ring system. The compounds of either formula (la) or (Ib) and some of the intermediates invariably have at least two stereogenic centers in their structure which can carry at least 4 stereochemically different structures. Compounds of either formula (la) or (Ib) as prepared in the methods described above can be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another following well-known resolution procedures. The racemic compounds of either formula (la) or (Ib) can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said 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 either formula (la) or (Ib) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, providing that the reaction occurs stereospecifically. 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 tautomeric forms of the compounds of either formula (la) or (Ib) refer to that they comprise those compounds of either formula (la) or (Ib) wherein, for example, an enol group becomes a keto group (tautomerism keto-enol). The N-oxide forms of the compounds according to either formula (la) or (Ib) are mainly to comprise those compounds of either formula (la) or (Ib) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides where the nitrogen of the amine radical is oxidized. The invention also comprises derivative compounds (usually called "pro-drugs") of the pharmacologically active compounds according to the invention, which are degraded in vivo to produce the compounds according to the invention Pro-drugs are usually (but not always ) of lower potency in the target receptor than the compounds to which they are degraded Pro-drugs are particularly useful when the desired compound has chemical and physical properties that make its admtration difficult or inefficient., 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. Further discussion on the pro-drugs can be found in Stella, V. J. et al., "Pro-drugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473. The pro-drug forms of the pharmacologically active compounds according to the invention will generally be compounds according to either the formula (Ia) or (Ib), the pharmaceutically acceptable basic or acid addition salts thereof, the forms stereochemically isomeric thereof, the tautomeric forms thereof and the N-oxide forms thereof, which have an acid group which is esterified or amidated. Included in such esterified acid groups are the groups of the formula -COORx, wherein Rx is a C6 alkyl, phenyl, benzyl or one of the following groups: The amidated groups include groups of the formula -CONR and Rz, wherein Ry is H, C 1-6 alkyl, phenyl or benzyl and Rz is -OH, H, C? -6 alkyl, 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 hydrolyze with the first order kinetic parameters in aqueous solution. The compounds according to the invention surprisingly have been shown to be suitable for the treatment of microbacterial diseases, particularly those diseases caused by pathogenic mycobacteria, including drug-resistant and multi-drug resistant mycobacteria, such as Mycobacterium tuberculosis, M. bovis, M. avium, M. smegmatis and M. marinum. The present invention thus also discloses compounds of either formula (la) or (Ib) as defined above, the pharmaceutically acceptable basic or acid addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms of them and the N-oxide forms thereof, for use as a medicine. The invention also describes a composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to the invention. The compounds according to the invention can be formulated in various pharmaceutical forms for administration purposes. As suitable compositions herein, mention may be made of all the compositions usually employed for drugs of routine administration. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of addition salt, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, the carrier can take a wide variety of dependent forms in the form of preparation desired for administration. These pharmaceutical compositions are desirable in a unit dosage form suitable, in particular, for administration orally or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media can be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions. , serums, 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 ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For perenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, can be prepared in which the carrier comprises saline, glucose solution or a mixture of saline and glucose. Injectable suspensions can also be prepared in which case the appropriate liquid carriers, suspending agents and the like can be employed. Also included are solid form preparations which are intended to be converted, briefly before use, into liquid form preparations. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of the active ingredient of the formula (la) or (Ib), and from 1 to 99.95% by weight , more preferably from 30 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages are based on the total composition. The pharmaceutical composition may additionally contain several other ingredients known in the art., for example, a lubricant, stabilizing agent, pH regulating agent, emulsifying agent, viscosity regulating agent, surfactant, preservative, aromatic substance or dye. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for easy administration and uniformity of dosage. The unit dosage form as used herein 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 unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. 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 mycobacterial disease. However, in general, satisfactory results will be obtained when the compound according to the invention is administered in a daily dose not exceeding 1 gram, for example, in the range of 10 to 50 mg / kg of body weight. In addition, the present invention also discloses the use of a compound of either formula (Ia) or (Ib), the pharmaceutically acceptable basic or acid addition salts thereof, the stereochemically isomeric forms thereof, tautomeric forms thereof and the N-oxide forms thereof, as well as any of the aforementioned pharmaceutical compositions thereof for the manufacture of a medicament for the prevention or treatment of mycobacterial diseases. Accordingly, in other aspects, the invention provides a method of treating a patient suffering from, or at risk of, a mycobacterial disease, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition in accordance to the invention. The compounds of the present invention can be combined with one or more other anti-mycobacterial agents. Therefore, the present invention also describes a combination of (a) a compound of formula (la) or (Ib) and (b) one or more other anti-mycobacterial agents. The present invention also describes a combination of (a) a compound of formula (la) or (Ib) and (b) one or more other anti-mycobacterial agents for use as a medicine.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, an active ingredient, a therapeutically effective amount of (a) a compound of the formula (Ia) or (Ib) and (b) one or more other anti-mycobacterial agents are also included by the present invention. The other mycobacterial agents which can be combined with the compounds of the formula (la) or (Ib) are, for example, rifampin (= rifampin); isoniazid, pyrazinamide; amikacin; ethionamide; moxifloxacin, ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; quinolones / fluoroquinolones such as for example ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as, for example, clarithromycin, clofazimine, amoxicillin with clavulanic acid; rifamycins; rifabutin; rifapentine. Preferably, the present compounds of the formula (la) or (Ib) are combined with rifapentine and moxifloxacin.

General preparation The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to persons with experience. The compounds of the formula (la) or (Ib) wherein Z is CH 2, said compounds are represented by the formula (la-1) and (lb-1), can be prepared by reacting an intermediate of the formula (II). a) and (ll-b) with paraformaldehyde in a suitable solvent, such as for example toluene. («-a) íla-1) The compounds of the formula (la) and (Ib) wherein Z is C (= O), said compounds are represented by the formula (la-2) and (lb-2), can be prepared by reacting an intermediate of formula (III-a) and (III-b) wherein Wi represents a suitable leaving group, such as for example imidazole, alkoxy groups, for example methoxy, with a suitable base, such such as for example sodium hydride, potassium tertiobutylate, in a suitable solvent, such as for example tetrahydrofuran, diethyl ether, dioxane.

(III-a) (Ia-2) In the above reactions, the compound obtained of the formula (Ia) or (Ib) can be isolated, and, if necessary, purified according to the methodologies generally known in the art. techniques such as, for example, extraction, crystallization, distillation, trituration and chromatography. In the case that the compound of formula (la) or (Ib) is separated by crystallization, it can be isolated by filtration. Otherwise, crystallization may be caused by the addition of a suitable solvent, such as for example water; acetonitrile; an alcohol, such as, for example, methanol, ethanol; and combinations of said solvents. Alternatively, the reaction mixture can also be evaporated to dryness, followed by purification of the residue by chromatography (e.g., reverse phase HPLC, flash chromatography and the like). The reaction mixture can also be purified by chromatography without prior evaporation of the solvent. The compound of the formula (Ia) or (Ib) can also be isolated by evaporation of the solvent followed by re-crystallization in an appropriate solvent, such as for example; Water; acetonitrile; an alcohol, such as for example methanol; and combinations of said solvents. Those skilled in the art will recognize which method should be used, which solvent is the most appropriate to use or belong to routine experimentation to find the most suitable isolation method. The compounds of the formula (la) or (Ib) can also be prepared by converting the compounds of the formula (la) or (Ib) into one another according to the well-known group of transformation reactions. The compounds of the formula (la) or (Ib) can be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen to its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting material of the formula (Ia) or (Ib) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metals, for example, sodium peroxide, potassium peroxide.; suitable organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or substituted halobenzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkane acids, for example, peroxoacetic acid alkylhydroperoxides, for example, t-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 said solvents. The compounds of the formula (la) or (Ib) wherein R 4 is alkyl, can be converted to a suitable quaternary amine by reaction with a suitable quaternizing agent, such as, for example, an optionally substituted alkylhalide, for example ICH 3 in the presence of a suitable solvent, such as for example acetone. Some of the compounds of the formula (I) and some of the intermediates in the present invention may consist of a mixture of stereochemically isomeric forms. The pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of the procedures known in the art. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, for example, countercurrent distribution, liquid chromatography and the like. Enantiomers can be obtained from racemic mixtures first by converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, for example liquid chromatography and similar methods; and finally by converting said separated diastereomeric salts or compounds into the corresponding enantiomers. The pure stereochemically isomeric forms can be obtained from stereochemically isomeric forms of the appropriate intermediates and starting materials, causing the intervening reactions to occur stereospecifically. An alternative way of separating the enantiomeric forms of the compounds of the formula (I) and the intermediates involves liquid chromatography, in particular liquid chromatography using the chiral stationary phase. It is understood that in the above or following preparations, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography. Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to well-known procedures. The intermediates of the formula (ll-a) and (ll-b) can be prepared by reacting an intermediate of the formula (IV-a) or (IV-b) with a suitable deprotection agent, such as for example chloroformate of 1-chloroethyl, in a suitable solvent, such as for example 1,2-dichloroethane and a suitable alcohol, such as for example methanol and the like.

(IV-0) (ll-b) Intermediates of the formula (ll-a) or (ll-b) can also be prepared by reacting an intermediate of the formula (IV-a) or (IV-b) with ammonium formate in the presence of palladium or carbon vegetable and in the presence of a suitable solvent, such as for example an alcohol, for example, methanol. The intermediates of the formula (IV-a) or (IV-b) wherein R1 is halo, can lose said halo substituent during their transformation to intermediates of the formula (ll-a) or (ll-b). The intermediates of the formula (IV-a) and (IV-b) can be prepared by reacting an intermediate of the formula (Va) and (Vb) with an intermediate of the formula (VI) in the presence of a reducing agent suitable, such as for example n-BuLi, in the presence of a suitable base, such as for example, NN-diisopropylamine, and in the presence of a suitable solvent, such as for example tetrahydrofuran.

The intermediates of the formula (IV-a) or (IV-b) wherein R1 represents Het and p is 1, said intermediates are represented by the formula (IV-a-1) or (IV-b-1) can be prepared by reacting an intermediate of the formula (IV-a) or (IV-b) wherein R1 represents halo, said intermediates are represented by the formula (IV-a-2) or (IV-b-2), with a intermediate of the formula (VII) in the presence of a suitable catalyst, such as for example Pd (PPh3) 4, a suitable base, such as for example K2C03 and a suitable solvent, such as for example dimethylether and a suitable alcohol, such like for example methanol and the like.

(IV-!> 2> (IV-t> -1) The intermediates of the formula (III-a) or (III-B) can be prepared by reacting an intermediate of the formula (II-a). ) or (ll-b) with an intermediate of the formula (VIII) wherein W1- (C = 0) represents the group that has been introduced and R represents the rest of the intermediate, such as for example 1,1'-carbonylbis -1H-imidazole, methylchloroformate or ethylchloroformate, in the presence of a suitable solvent, such as for example tetrahydrofuran.

Intermediates of the formula (V-a) or (V-b) are compounds that are commercially available or that can be prepared according to conventional reaction procedures generally known in the art. For example, the intermediates of the formula (V-a-1) can be prepared according to the following reaction scheme (1): SCHEME 1 fV-a-l) where all the variables are defined as in the formula (la) and (Ib). The reaction scheme (1) comprises step (a) in which an appropriately substituted aniline is reacted with an appropriate acyl chloride such as 3-phenylpropionyl chloride, 3-fluorobenzenepropionyl chloride or p-chlorobenzenepropionyl chloride, in the presence of a suitable base, such as triethylamine and a solvent inert to the suitable reaction, such as a methylene chloride or an ethylene dichloride. The reaction can conveniently be carried out at a temperature ranging between room temperature and reflux temperature. In a next step (b) the adduct obtained in step (a) is reacted with phosphoryl chloride (POCI3) in the presence of a suitable solvent, such as for example N, N-dimethylformamide (Vilsmeier-Haack formylation followed by cyclization). The reaction can be conveniently carried out at a temperature ranging between room temperature and reflux temperature. In a next step (c) a specific R2 group, wherein R2 is an alkyloxy or alkylthio radical is introduced by reacting the intermediate obtained in step (b) with a compound -X-Alk, wherein X = S or O and Alk is an alkyl group as defined in formula (la) and (Ib), such as for example sodium methanolate, in the presence of a suitable solvent, such as for example an alcohol, for example methanol. The intermediates according to the formula (Va-2) can be prepared according to the following reaction scheme (2), wherein in a first step (a) a substituted indole-2,3-dione is reacted with a substituted phenylpropionaldehyde in the presence of a suitable base such as sodium hydroxide (Pfitzinger reaction), after which the carboxylic acid compound in a next step (b) is decarboxylated at a high temperature in the presence of a solvent inert to the suitable reaction such as diphenylether.

SCHEME 2 (V-a-2) 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 methodologies generally known in the art, such as as extraction, crystallization and chromatography. It is also evident that the 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. Usually, the compounds of the formula (la) and (Ib) can be separated into their isomeric forms. The intermediates of the formula (VI) are compounds that are either commercially available or that can be prepared according to conventional reaction procedures generally known in the art. For example, the intermediate compounds of the formula (VI) can be prepared according to the following reaction scheme (3): SCHEME 3 The reaction scheme (3) comprises the step (a) in which R > 3 ?, for example a phenyl, naphthyl het appropriately substituted, is reacted by the Friedel-Craft reaction with an appropriate acyl chloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride, in the presence of a Lewis acid suitable, such as AICI3, FeCl3, SnCl4, TiCl4 or ZnCl2 and optionally a solvent inert to the suitable reaction, such as methylene chloride or ethylene dichloride. The reaction can conveniently be carried out at a temperature ranging between room temperature and reflux temperature. In a next step (b) an amino group (-NR4 (CH2-C6H5) is introduced by reacting the intermediate obtained in step (a) with a primary or secondary amine, in the presence of a suitable solvent, such as for example acetonitrile, and optionally in the presence of a suitable base, such as for example K2C03 The following examples illustrate the present invention without being limited thereto.

Experimental part Of some compounds the absolute stereochemical configuration of the stereogenic carbon atom (s) in that respect is not determined experimentally. In those cases the stereochemically isomeric form that is first isolated is designated as "A" and the second as "B", without further reference to the current stereochemical configuration. However, said "A" and "B" isomeric forms can be unambiguously characterized by a person skilled in the art, using methods known in the art such as, for example, X-ray diffraction. The isolation method is described with detail later. For some of the intermediates and some of the final compounds, the stereochemical configurations are indicated in the structures.

These configurations are relative configurations that indicate that the interested groups are located on the same or opposite plane of the molecule (* ^ ^^ f = same plane; ^ '% - opposite plane) * R means that the chiral center is absolute R or Absolute S * S means that the chiral center is absolute R or absolute S.

Experimental part After, the term "P.f." means melting point, "THF" means tetrahydrofuran, "EtOAc" means ethyl acetate, "MeOH" means methanol, "DME" means dimethyl ether, "DIPE" means diisopropyl ether, "DMF" means N, N-dimethylformamide, "Et3N" means triethylamine, "Pd (PPh3) 4" means tetrakis (triphenylphosphine) palladium, "CDI" means 1,1-carbonylbis-1 H-medazole.

A. Preparation of intermediates EXAMPLE A1 Preparation of intermediate 1 Intermediate 1 Benzenepropanoyl chloride (0.488 mol) is added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture is stirred at room temperature all the night. The mixture is poured into water and concentrated NH 4 OH, and extracted with CH 2 Cl 2. The organic layer is dried (MgSO), filtered and the solvent is evaporated. The residue is crystallized from diethyl ether. The residue (119.67 g) is taken up in CH2Cl2 and washed with 1N HCl. Dry the organic layer (MgSO4), filter and evaporate the solvent. Yield: 107.67 g of intermediate 1.

EXAMPLE A2 Preparation of intermediate 2 Intermediate 2 The reaction is carried out twice. POCI3 (1.225 mol) is added dropwise at 10 ° C for DMF (0.525 mol). Then intermediate 1 (0.175 mol) is added at room temperature. The mixture is stirred overnight at 80 ° C, poured into ice and extracted with CH2Cl2. The organic layer is dried (MgSO 4), filtered, and the solvent is evaporated, yield 77.62 g (67%) of intermediate 2. The product is used without further purification.

EXAMPLE A3 Preparation of intermediate 3 Intermediate 3 A mixture of intermediate 2 (0.233 mol) in CH3ONa (30%) in MeOH (222.32 ml) and MeOH (776 ml) are stirred and refluxed overnight, then poured into ice and extracted with CH2Cl2. The organic layer is separated, dried (MgSO 4), filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / cyclohexane 20/80 and then 100/0, 20-45 μm ). The pure fractions are collected and the solvent is evaporated. Yield: 25 g (33%) of intermediate 3 (P.f .: 84 ° C).

EXAMPLE A4 a) Preparation of intermediates 4 and 5 Intermediate 4 Intermediate 5 A mixture of aluminum chloride (34.3 g, 0.257 mol) and 3-chloropropanoyl chloride (29.7 g, 0.234 mol) in 1,2-dichloromethane (150 ml) is stirred at 0 ° C. A solution of naphthalene (30 g, 0.234 mol) in 1,2-dichloroethane (50 ml) is added. The mixture is stirred at 5 ° C for 2 hours and poured into ice water. The organic layer is separated, dried (MgSO 4), filtered, and the solvent is evaporated. The residue (56 g) is purified by column chromatography on silica gel (eluent: cyclohexane / CH 2 Cl 2: 60/40, 20-45 μm). Two fractions are collected and the solvent is evaporated to yield intermediate 4 (31 g, 61%) as an oil. The second fraction (14 g) is taken in DIPE to yield intermediate 5 (8.2 g, 16%, M.p .: 68 ° C) as a pale yellow solid.

The following intermediate is prepared according to the previous procedure: b) Preparation of intermediate 6 Intermediate 6 Aluminum chloride (0.3 mol) is carefully added to 1,3-difluorobenzene (0.26 mol) and this is heated with vigorous stirring to 50 ° C. 3-Chloropropanoyl chloride (0.26 mol) is added dropwise over a period of 15 minutes at 40 ° C (cooled on ice) and the mixture is stirred at 50 ° C. The mixture is poured into water (250 ml), ice (250 g) and HCl (25 ml) and stirred for 20 minutes. The formed precipitate is filtered and extracted with CH2CL2 and water. Yield: 40 g of intermediate 6 (75%).

EXAMPLE A5 a) Preparation of intermediate 7 Intermediate 7 A mixture of intermediate 4 (3 g, 0.0137 mol), N-benzylmethylamine (2 ml, 0.0150 mol) in acetonitrile (100 ml) is stirred at 80 ° C for 2 hours. Water is added at room temperature. The mixture is extracted with CH2Cl2. The organic layer is separated and dried (MgSO 4), filtered, and the solvent is evaporated. The residue (6 g) is purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH: 97/3, 20-45 μm) to produce an oil. Yield: 4.2 g of intermediate 7. The following intermediate is prepared according to the previous procedure: b) Preparation of intermediate 8 Intermediate 8 A mixture of intermediate 6 (0.015 mol), N-ethylbenzenemethanamine (0.016 mol) and K2C03 (0.016 mol) in acetonitrile (30 ml) is stirred at 70 ° C for 2 hours, poured into H20 and extracted with CH2Cl2. . The organic layer is separated, dried (MgSO), filtered, and the solvent is evaporated. Yield: 4 g of intermediate 8 (88%).

EXAMPLE A6 a) Preparation of intermediate 9 Intermediate 9 Add n-butyl lithium (0.0075 mol) at -20 ° C to a solution of diisopropylamine (0.0075 mol) in THF (50 ml). The mixture is cooled to -70 ° C. Intermediate 3 (0.0062 mol) is added. The mixture is stirred at -70 ° C for 1 hour and 30 minutes. Intermediate 7 (0.0075 mol) is added. The mixture is stirred for 1 hour and 30 minutes. H20 is added. The mixture is extracted with CH2Cl2. The organic layer is separated, dried (MgSO), filtered, and the solvent is evaporated. The residue (3 g) is purified by column chromatography on silica gel (eluent: 90/10 cyclohexane / EtOAc, 15-40 μm). The pure fractions are collected and the solvent is evaporated. Yield: 1.5 g of a mixture of two diastereoisomers (38%), that is, intermediate 9. The following intermediate is prepared according to the above procedure: b) Preparation of intermediate 10 Intermediate 10 n-Butyl lithium (0.0075 mol) is added at -20 ° C to a solution of diisopropylamine (0.0075 mol) in THF (50 ml). The mixture was cooled to -70 ° C. Intermediate 3 (0.0061 mol) is added. The mixture is stirred at -70 ° C for one hour and 30 minutes. 4- [Methyl (phenylmethyl) amino] -1-phenyl-1-butanone (0.0073 mol) is added. The mixture is stirred for 1 hour and 30 minutes. H20 is added. The mixture is extracted with CH2Cl2. The organic layer is separated, dried (MgSO), filtered, and the solvent is evaporated. The residue (4.9 g) is purified by column chromatography on silica gel (eluent: 100% CH 2 Cl 2, 15-40 μm). The pure fractions are collected and the solvent is evaporated, yield: 1.43 g of an intermediate 10 (40%, mixture of diastereoisomers: 60/40). The following intermediates are prepared according to the previous procedure: c) Preparation of intermediates 11 and 12 Intermediate 11 (day A) and Intermediate 12 (day B) n-Butyl lithium (0.0075 mol) is added at -20 ° C to a solution of diisopropylamine (0.0075 mol) in THF (50 ml). The mixture is cooled to -70 ° C. Intermediate 3 (0.0084 mol) is added. The mixture is stirred at -70 ° C for 1 hour and 30 minutes. Intermediate 8 (0.0099 mol) is added. The mixture is stirred for 1 hour and 30 minutes. H20 is added. The mixture is extracted with CH2Cl2.

The organic layer is separated, dried (MgSO 4), filtered, and the solvent is evaporated. The residue (5.4 g) is purified by column chromatography on silica gel (eluent: CH2Cl2 / cyclohexane 60/40, 15-40 μm). HE collect two fractions and the solvent evaporates. Yield: 0.95 g of intermediate 11 as diastereoisomer A (15%, P.f .: 171 ° C) and 0.83 g of intermediate 12 as diastereomer B (13%, MH +: 631).

EXAMPLE A7 Preparation of intermediate 17 Intermediate 17 Intermediate 9 (1.58 mmol), 2-furanboronic acid (2.69 mmol), Pd (PPh3) 4 (0.158 mmol), DME (30 mL), MeOH (10 mL) and K2C03 (1.6 mL) are heated under microwave (300W, 68 ° C) for 10 minutes. The mixture is cooled, poured into water and extracted with EtOAc. The organic layer is separated, dried (MgSO), filtered, and the solvent is evaporated. The residue (1.4 g) is purified by column chromatography over silica gel (eluent: 90/10 cyclohexane / EtOAc, 15-40 μm). The pure fractions are collected and the solvent is evaporated. Yield: 0.47 g of intermediate 17 as a mixture of diastereomers (60/40) (41%).

EXAMPLE A8 a-1) Preparation of intermediates 13 and 14 Intermediate 13 (diastereoisomer A) Intermediate 14 (diastereomer B) 1-Chloroethyl chloroformate (15 ml) is added at room temperature to a mixture of intermediate 9 (0.0023 mol) in 1,2-dichloroethane (30 ml). The mixture is stirred at 80 ° C for 1 hour. The solvent is evaporated. MeOH (15 ml) is added. The mixture is stirred and heated to reflux for 30 minutes. The solvent is evaporated. The residue (*) (1.49 g) is purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH / NH 4 OH 97/3 / 0.1, 15-40 μm). Two fractions are collected and the solvent is evaporated. The first residue (0.23 g) is crystallized from DIPE. The precipitate is filtered and dried, yield: 0.168 g (13%) of intermediate 13 (diastereomer A) (Mp .: 204 ° C). The second residue (0.32 g) is crystallized from DIPE. The precipitate is filtered and dried. Yield: 0.298 g (23%) of intermediate 14 (diastereomer B) (P.f .: 225 ° C).

The following intermediates are prepared according to the above procedure: The purification of the resulting residue (*) is indicated for each intermediate separately. a-2) Preparation of intermediates 15 and 16 Intermediate 15 Intermediate Intermediate 13 (diastereoisomer A) (0.9 g) was purified by chiral chromatography on silica gel (eluent: 100% ethanol). Two fractions are collected and the solvent is evaporated. Yield: 0.420 g of intermediate 15 (enantiomer A1) (P.f .: 161 ° C, MH +: 541) and 0.397 g of intermediate 16 (enantiomer A2) (P.f .: 158 ° C, MH +: 541). a-3) Preparation of intermediates 44 and 45 Intermediate 44 Intermediate 45 A mixture of intermediate 43 (prepared according to A6.a) (1.5 g, 2.62 mol), ammonium formate (0.83 g, 0.013 mol) and palladium on charcoal (10%, 1.5 g) in methanol (30 ml) is heated under reflux for 1 hour. The mixture is cooled and filtered on a short pad of Celite. Water is added. Extract the organic layer with ethyl acetate, separate, dry (MgSO 4), filter, and evaporate the solvent. The residue (1.3 g) is purified by column chromatography on silica gel (eluent: MeOH / AcNH: 60/40, kromasil C? 8, 5 μm). The pure fractions are collected and the solvent is evaporated producing two fractions. Yield: 0.14 g of intermediate 44 as diastereoisomer A (12%) and 0.26 g of intermediate 45 as diastereomer B (22%).

EXAMPLE A9 Preparation of intermediate 18 Intermediate 18 A mixture of intermediate 39 (prepared according to Example A8.a-1) (0.0002 mol) and CDI (0.0003 mol) in THF (7 ml) is stirred and heated at reflux for 2 hours, poured into H20. and extracted with CH2Cl2. The organic layer is separated, dried (MgSO), filtered, and the solvent is evaporated.

Yield: 0.15 g of intermediate 18 (diastereoisomer A) (84%).

B. Preparation of the compounds EXAMPLE B1 Preparation of compound 1 Compound 1 A mixture of intermediate 13 (prepared according to Example A8.a-1) (0.00009 mol) and paraformaldehyde (0.0001 mol) in toluene (5 ml) is stirred at 80 ° C. The mixture is evaporated. The residue is purified (*) by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 99/1, 15-40 μm). The pure fractions are collected and the solvent is evaporated. Yield: 0.025 g of compound 1 (diastereomer A) (49%, M.p .: 12 ° C). The following compounds are prepared according to the above procedure. The purification of the residue (*) is indicated if it is different from the purification described above.

EXAMPLE B2 Preparation of compound 2 Compound 2 A mixture of intermediate 37 (diastereomer A prepared according to example A8.a-1) (0.00009 mol) and paraformaldehyde (0.0001 mol) in toluene (5 ml) is stirred at 80 ° C. The mixture is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2 / MeOH 99/1; 15-40 μm). The pure fractions are collected and the solvent is evaporated. The residue is crystallized (0.06 g, 92%) from DIPE. The precipitate is filtered and dried. Yield: 0.026 g of compound 2 (diastereoisomer A) (40%, P.f .: 201 ° C).

EXAMPLE B3 Preparation of compound 3 Compound 3 A mixture of intermediate 30 (diastereomer B prepared according to Example A8.a-1) (0.00009 mol) and paraformaldehyde (0.0001 mol) in toluene (5 ml) is stirred at 80 ° C. The mixture is evaporated. The residue is purified by column chromatography over silica gel (eluent: CH2Cl2 / MeOH 99/1; 15-40 μm). The pure fractions are collected and the solvent is evaporated. The residue is crystallized (0.11 g, 100%) from diethyl ether. The precipitate is filtered and dried. Yield: 0.033 g of compound 3 (diastereomer B) (33%, P.f .: 189 ° C).

EXAMPLE B4 Preparation of compound 4 Compound 4 A mixture of compound 7 (diastereomer A prepared according to example B1) (0.1 mmol) and iodomethane (0.1 mmol) in acetone (2 ml) is stirred at room temperature for 2.5 hours. The precipitate is filtered, washed with acetone and dried. Yield: 0.031 g of compound 4 as a hydroiodide (diastereomer A) (48%, M.p .: 211 ° C). The following compound is prepared according to the previous procedure: EXAMPLE B5 Preparation of compound 5 Compound 5 Sodium hydride (0.011 g) is added at 0 ° C to a mixture of intermediate 18 (prepared according to Example A9) (0.0001 mol) in THF (10 ml) under N2 flow. The mixture is stirred at 0 ° C for 30 minutes, poured into H2O and extracted with EtOAc. The organic layer is separated, dried (MgSO 4), filtered, and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: 80/20 cyclohexane / EtOAc, 15-40 μm). The pure fractions are collected and the solvent is evaporated. The residue is crystallized (0.09 g, 67%) from DIPE. The precipitate is filtered and dried.

Yield: 0.034 g of compound 5 (diastereomer A) (M.p .: 192 ° C). The following compound is prepared according to the previous procedure: EXAMPLE B6 Preparation of compound 20 Compound 20 A mixture of intermediate 44 (diastereomer A prepared according to example A8a-3) (0.12 g, 0.298 mmol) and formaldehyde (0.358 mmol) in toluene (5 ml) is stirred at 80 ° C for 2 hours. Water is added at room temperature and the organic layer is extracted with ethyl acetate, separated, dried (MgSO 4), filtered, and the solvent is evaporated. The residue (0.13 g) is purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH: 99/1 / 0.1, 10 μm). The pure fractions are collected and the solvent is evaporated. Yield: 0.075 g of compound 20 (diastereomer A) (61% MH +: 415). The following compound is prepared according to the previous procedure but without column chromatography: C. Analytical methods The mass of the compounds is recorded with LCMS (liquid chromatography mass spectrometry). Three methods are used that are described later. The data is collected in Table 1 below.

LCMS method 1 LCMS analyzes (positive mode electrophoresis ionization, scanning mode 100 to 900 amu) are carried out on a Kromasil C18 column (Interchim, Montlu? On, FR; 5 μm, 4.6 x 150 mm) with a flow rate of 1 ml / minute. Two mobile phases are used (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 ml / l), mobile phase B: 100% acetonitrile) to run a condition of gradient of 100% A for 1 minute at 100% B in 4 minutes, 100% B for 5 minutes at 100% A in 3 minutes, and rebalances with 100% A for 2 minutes.

LCMS method 2 The LCMS analyzes are carried out (electro-spray ionization in both positive and negative (pulsed) scan mode of 100 to 1000 amu) on a Kromasil C18 column (Interchim, Montlu? On, FR; 3.5 μm, 4. 6 x 100 mm) with a flow rate of 0.8 ml / minute. Two mobile phases are used (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml / l), mobile phase B: 100% acetonitrile) to run a condition of gradient of 100% A for 1 minute at 100% B in 4 minutes, 100% B at a flow rate of 1.2 ml / minute for 4 minutes at 100% A at 0.8 ml / minute in 3 minutes, and rebalances with 100% of A for 1.5 minutes.

LCMS method 3 The LCMS analyzes (electro-spraying ionization in both positive and negative (pulsed) scanning mode from 100 to 1000 amu) are carried out on a Sunfire C18 column (Waters, Millford USA; 3.5 μm, 4.6 x 100 mm) with a flow rate of 0.8 ml / minute. Two mobile phases are used (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml / l), mobile phase B: 100% acetonitrile) to run a condition of gradient of 100% A for 1 minute at 100% B in 4 minutes, 100% B at a flow rate of 1.2 ml / minute for 4 minutes at 100% A at 0.8 ml / minute in 3 minutes, and rebalances with 100% of A for 1.5 minutes.

LCMS method 4 LCMS analyzes are carried out (electro-spraying ionization in both positive and negative (pulsed) scanning mode from 100 to 1000 amu) on a Sunfire C18 column (Waters, Millford USA; 3.5 μm, 4.6 x 100 mm) with a flow rate of 0.8 ml / minute. Two mobile phases are used (mobile phase A: 25% 6.5 mM ammonium acetate + 50% acetonitrile + 25% formic acid (2 ml / l), mobile phase B: 100% acetonitrile) to run a condition of gradient of 100% A for 1 minute at 100% B in 4 minutes, 100% B at a flow rate of 1.2 ml / minute for 4 minutes at 100% A at 0.8 ml / minute in 3 minutes, and rebalances with 100% of A for 1.5 minutes.

TABLE 1 Main LCMS peak D. Pharmacological examples D.1. In vitro method to test compounds against M tuberculosis. 96-well sterile plastic microtiter plates are filled, flat bottom, with 100 μl of Middlebrook broth medium (1x). Subsequently, the stock solutions (10 x final test concentration) of the compounds are added in volumes of 25 μl to a series of duplicate wells in column 2 in order to allow evaluation of their effects on bacterial growth. Five-fold serial dilutions are made directly on the microtiter plates of column 2 through 11 using an adapted robotic system (Zymark Corp., Hopkinton, MA). Pipette tips are changed after 3 dilutions to minimize pipetting errors with higher hydrophobic compounds. Control samples not treated with (column 1) and without (column 2) inoculum are included in each microtiter plate. Approximately 5000 CFU per well of Mycobacterium tuberculosis (strain H37RV), in a volume of 100 μl in Middlebrook broth medium (1x), are added to rows A to H, except in column 12. The same volume of broth medium no inoculum is added to column 12 in row A to H. Cultures are incubated at 37 ° C for 7 days in a humidified atmosphere (incubator with open air valve and continuous ventilation). One day before the end of the incubation, six days after the inoculation, Resazurin (1: 5) is added to all the wells in a volume of 20 μl and the plates are incubated for another 24 hours at 37 ° C. On day 7 bacterial growth is quantified fluorometrically. Fluorescence is read on a computer-controlled fluorometer (Spectramax Gemini EM, Molecular Devices) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percentage of inhibition of growth achieved by the compounds is calculated according to standard methods, and the MIC data (which represent IC90 expressed in microgram / ml) are calculated.

D.2. In vitro method to test compounds for antibacterial activity against strain M. Smegmatis TACC607. Plain sterile 96-well plastic microtiter plates are filled with 180 μl of sterile deionized water, supplemented with 25% BSA. Subsequently, the stock solutions (7.8 x final test concentration) of the compounds are added in 45 μl volumes to a series of duplicate wells in column 2 so as to allow evaluation of their effects on bacterial growth. Five-fold serial dilutions (45 μl in 180 μl) are made directly on the microtiter plates of column 2 to 11 using an adapted robotic system (Zymark Corp., Hopkinton, MA). Pipette tips are changed after 3 dilutions to minimize pipetting errors with higher hydrophobic compounds. Control samples not treated with (column 1) and without (column 2) inoculum are included in each microtiter plate. Approximately 250 CFU per bacterial inoculum well, in a volume of 100 μl in 2.8 x medium Mueller-Hinton broth, are added to rows A to H, except in column 12. The same volume of broth medium without inoculum is added to column 12 in row A to H. Cultures are incubated at 37 ° C for 48 hours in a humidified atmosphere with 5% C02 (incubator with open air valve and continuous ventilation). At the end of the incubation, two days after the inoculation, the bacterial growth is quantified fluorometrically. Then Blue Alamar (10x) is added to all the wells in a volume of 20 μm and the plates are incubated for another 2 hours at 50 ° C. The fluorescence is read on a computer-controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm (gain 30). The% inhibition of growth achieved by the compounds according to standard methods is calculated. The plC50 is defined as 50% of the inhibitory concentration for bacterial growth. The results are shown in table 2.

TABLE 2 Results of in vitro scanning of the compounds according to the invention for M. smegmatis (pICgo).

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound formula or the pharmaceutically acceptable basic or acid addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, tautomeric forms thereof and the N-oxide forms thereof, wherein: R1 is hydrogen, halo, haloalkyl, cyano , hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; p is an integer equal to 1, 2, 3 or 4; R 2 is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino or a radical of the formula f 1 'wherein Y is CH 2, O, S, NH or N-alkyl; R3 is U? alkyl, Ar, Ar-alkyl, Het or Het-alkyl; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which they are attached a naphthyl; r is an integer equal to 1, 2, 3, 4 or 5; and R6 is hydrogen, alkyl, Ar or Het; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; Z is CH2 or C (= 0); alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo, hydroxy, alkyloxy or oxo; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or 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 monocyclic and bicyclic heterocycle may be optionally substituted on a carbon atom with 1, 2 or 3 substituents selected from the group halo, hydroxy, alkyl or alkyloxy; Halo is a substituent selected from the group of fluorine, chlorine, bromine and iodine and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halo atoms.

2. The compound according to claim 1, further characterized in that Z is CH2.

3. The compound according to any of the preceding claims, further characterized in that R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl.

4. The compound according to claim 1 or 2, further characterized in that R1 is hydrogen, halo, cyano, Ar, Het, alkyl, and alkyloxy; p is an integer equal to 1, 2, 3, or 4; R 2 is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or a radical of the formula f I wherein Cast; R3 is alkyl, Ar, Ar-alkyl or Het; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo or alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which they are attached a naphthyl; r is an integer equal to 1; and R6 is hydrogen; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo or hydroxy; Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl; Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from the group of benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1,3] dioxolyl; each monocyclic and bicyclic heterocycle may be optionally substituted on a carbon atom with 1, 2 or 3 alkyl substituents; and halo is a substituent selected from the group of fluorine, chlorine and bromine.

5. The compound according to any of the preceding claims, further characterized in that the compound is a compound of formula (la) and wherein R1 is hydrogen, halo, Ar, Het, alkyl or alkyloxy; p = 1; R2 is hydrogen, alkyloxy or alkylthio; R3 is naphthyl, phenyl or Het, each optionally substituted with 1 or 2 substituents selected from the group of halo and haloalkyl; R 4 is hydrogen or alkyl; R5 is hydrogen, alkyl or halo; r is equal to 1 and R6 is hydrogen.

6. The compound according to any one of claims 1, 3, 4 or 5, further characterized in that the compound is a compound according to formula (Ia) wherein R1 is hydrogen, halo, alkyl, or Het; R2 is alkyloxy; R3 is naphthyl, phenyl or Het, each optionally substituted with halo; R4 is alkyl; R5 is hydrogen or halo; Rd is hydrogen; Z is CH2 or C (= 0).

7. A compound that is degraded in vivo to produce a compound according to any of the preceding claims.

8. The compound according to any of the preceding claims for use as a medicine.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as defined in any of claims 1 to 6.

10. The use of a compound in accordance with any of claims 1 to 6 or a composition according to claim 9 for the manufacture of a medicament for the treatment of mycobacterial diseases.

11. A process for the preparation of a compound according to claim 1, characterized by a) reacting an intermediate of the formula (ll-a) and (ll-b) with formaldehyde in a suitable solvent (ll-a) (la-1) with R > 1 a ^ D R8, p and r as defined in claim 1; b) reacting an intermediate of formula (III-a) and (III-b) with a suitable base in a suitable solvent, («-a) íla-1) 0W > ) (lb-1) with R1 to R8, p and r as defined in claim 1 Wi representing a suitable leaving group; or if desired, converting the compounds of the formula (la) or (Ib) into each other of the following transformations known in the art, and further, if desired, converting the compounds of the formula (Ia) or (Ib) ), in a therapeutically active non-toxic acid addition salt by treatment with an acid, or in a non-toxic therapeutically active basic addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the basic addition salt into the free acid by acid treatment; and, if desired, preparing the stereochemically isomeric forms, quaternary amines, tautomeric forms or N-oxide forms thereof. SUMMARY OF THE INVENTION The present invention describes novel substituted quinoline derivatives according to formula (Ia) or general formula (Ib) salts, quaternary amines, stereochemically isomeric forms, tautomeric forms and N-oxide forms thereof, wherein R 1 is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar- alkyl or di (Ar) alkyl; p is a 1, 2, 3 or 4; R 2 is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino or a radical of the formula (le); R3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; R 4 is hydrogen, alkyl or benzyl; R5 is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two adjacent R5 radicals can be taken together to form together with the phenyl ring to which a naphthyl is attached; r is 1, 2, 3, 4 or 5; R6 is hydrogen, alkyl, Ar or Het; R7 is hydrogen or alkyl; R8 is oxo; or R7 and R8 together form the radical -CH = CH-N =; Z is CH2 or C (= 0); the claimed compounds are useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as M. tuberculosis, M. bovis, M. avium and M. marinum; Also claimed is a pharmaceutical composition containing a compound of the present invention, the use of the compounds or compositions claimed for the manufacture of a medicament for the treatment of mycobacterial diseases and a process for the preparation of the claimed compounds. 31 B P06 / 802F