JP6426530B2 - Treatment of latent tuberculosis - Google Patents

Description

  The present invention relates to the use of compounds of formula (Ia) or (Ib) for the treatment of latent tuberculosis.

Background Mycobacterium tuberculosis of the invention (Mycobacterium tuberculosis) results in more than death 2 millions a year, is the number one cause of death in people infected with HIV ¹ (Non-Patent Document 1). In spite of decades of TB control programs, asymptomatic but nearly 2 billion people are infected with M. tuberculosis. About 10% of these humans are at risk of developing active TB during their lifetime ² (Non-patent Document 2). The TB epidemic is fueled by fire due to TB infections in HIV patients and an increase in multidrug resistant TB strains (MDR-TB). The reactivation of latent TB is a high risk factor for disease disorders, ¹ causing 32% of deaths in HIV infected patients (Non-Patent Document 1). In order to control TB epidemics, what is needed is to find new drugs that can kill dormant or latent bacilli. Dormant TB can be reactivated by several factors, such as suppression of host immunity by the use of immunosuppressants such as antibodies against tumor necrosis factor alpha or interferon-gamma, to cause disease. For HIV-positive patients, the only preventative treatment available for latent TB is rifampicin, a 2-3 month regimen of pyrazinamide ^3,4 (Non Patent Literature 3, Non Patent Literature 4). The efficacy of treatment regimens is still unclear, and in an environment of limited resources, the length of treatment is an important constraint. Thus, there is a strong need to identify new drugs that can act as chemopreventive agents for patients carrying latent TB bacilli. Tubercle bacilli enter healthy humans by inhalation; they are phagocytosed by pulmonary alveolar macrophages. This leads to a strong immune response and the formation of granulomas consisting of macrophages infected with Mycobacterium tuberculosis surrounded by T cells. After six to eight weeks, the host's immune response causes the death of infected cells by necrosis and the peripheral deposition of cheese-like material with some extracellular bacilli surrounded by layers of macrophages, epithelioid cells and lymphoid tissue ⁵ (Non-patent document 5). In healthy humans, most of the mycobacteria are killed in these environments, but a small proportion of bacilli still survive and appear to be non-replicating, in a metabolic state, anti-such as isoniazid. it is resistant to killing by the TB drug ⁶ (non-Patent Document 6). These bacilli can remain in the altered physiological environment without showing the clinical symptoms of the disease even during human life. However, at 10%, these latent bacilli can reactivate and cause disease. One hypothesis for the emergence of these persisting bacteria is the pathophysiological environment at human foci, namely the reduction in oxygen tension, nutrient restriction and acidic pH ⁷ (Non-patent Document 7). These factors these bacteria, the major anti - ⁷ have been considered to be phenotypically resistant to mycobacterial agents (Non-Patent Document 7).

  U.S. Pat. No. 5,958,015 describes substituted quinoline derivatives useful for the treatment of mycobacterial disease. Said document discloses the antimycobacterial properties of substituted quinoline derivatives against sensitive sensitive Mycobacterium strain but does not describe their activity against latent, dormant, persistent mycobacteria.

WO 2004/011436 pamphlet

Corbett, E., et al. L. et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch. Inern. Med 163, 2003, 1009-1021. Dye, C.I. , Scheele, S .; , Dolin, P .; , Pathania, V., et al. & Raviglione, M. C. Consensus statement. Global burden of tuberculosis: estimated incidence incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282, 1999, 677-686. Am J Respir. Crit Care Med 161, 2000, S221-S247. Halsey, N .; A. et al. Chose, Randomized trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis of HIV-1 infection. Lancet 351, 1998, 786-792. Mitchison, D .; A. & Coates, A. R. Predictive in vitro models of the stabilization activity of anti-tuberculosis drugs. Curr. Pharm. Des 10, 2004, 3285-3295. Karakousis, P. et al. C. et al. By Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis in artificial artificial granulomas in mice. J Exp. Med. 200, 2004, 647-657. Gomez, J.J. E. & McKinney, J.J. D. , M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. (Edinb.) 84, 2004, 29-44.

  This time, we have found that the compounds of the patent document 1, in particular the compounds of the formulas (Ia) and (Ib) as defined below, have sterility; are effective in killing dormant mycobacteria, in particular Mycobacterium tuberculosis, as a result It has been found that it can be used for the treatment of latent TB. So they will greatly strengthen the arsenal to fight TB.

Figure legends Figure 1: Dormant M. cellus assayed by luciferase count. Effects of various agents on M. bovis (RLU: relative luminescence unit) (bacteria were suspended in drug free medium for 5 days after 7 days of anaerobic life).
Figure 2A): Dormant M. Effects of various agents on bovis (CFU: colony forming units) (reporting CFU determined 2 days after anaerobic life).
Figure 2B): Dormant M. Effects of various agents on bovis (CFU: colony forming units) (report CFU determined 5 days after anaerobic life).
Figure 3: Effects of various agents on dormant Mycobacterium tuberculosis (Wayne model).

Thus, the present invention relates to the use of a compound of formula (Ia) or (Ib) for the preparation of a medicament for the treatment of latent TB, wherein the compound of formula (Ia) or (Ib) is

[In the formula,
R ¹ 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, mercapto, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino or a compound of the formula

In which Y is CH ₂ , O, S, NH or N-alkyl;
R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;
q is an integer equal to zero, 1, 2, 3 or 4;
R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; or R ⁴ and R ⁵ together with N containing them, optionally alkyl, halo, haloalkyl, Hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl which can be substituted with pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl Form a group selected from the group of 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Door can be;
R ⁶ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two vicinal R ⁶ groups together And the formula -CH = CH-CH = CH-
Can form a divalent group of
r is an integer equal to 1, 2, 3, 4 or 5;
R ⁷ is hydrogen, alkyl, Ar or Het;
R ⁸ is hydrogen or alkyl;
R ⁹ is oxo; or R ⁸ and R ⁹ together form a group NN—CH = CH—;
Alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or 1 to 6 A saturated cyclic hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 4 carbon atoms; wherein each carbon atom is optionally halo, hydroxy, Can be substituted with alkyloxy or oxo;
Ar is an homocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl, and each homocyclic ring can be optionally substituted by 1, 2 or 3 substituents, and each substituent is 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 And
Het is a monocyclic heterocyclic ring selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, imidazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1,1] 3] a bicyclic heterocycle selected from the group of dioxolyl; each monocyclic and bicyclic heterocycle is optionally selected from the group of halo, hydroxy, alkyl, alkyloxy or Ar-carbonyl , It can be substituted by 2 or 3 substituents;
Halo is a substituent selected from the group of fluoro, chloro, bromo and iodo; and haloalkyl is one to six of which one or more carbon atoms are substituted with one or more halo-atoms. Or a linear saturated or branched hydrocarbon group having 3 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms]
Its pharmaceutically acceptable acid or base addition salt, its N-oxide, its tautomer or its stereochemical isomer.

  The invention also relates to a method of treating a patient, including a human having latent TB, comprising administering to the patient a therapeutically effective amount of a compound according to the invention.

The compounds according to formulas (Ia) and (Ib) are for example the tautomeric equivalents (tautomeric) of the compounds according to formula (Ia) according to formula (Ia) according to formula (Ib) with R ⁹ equal to oxo with R ² equal to hydroxy They are mutually related in that they are equivalent (keto-enol tautomerism).

  In the framework of the present application, alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom Can be optionally substituted with halo, hydroxy, alkyloxy or oxo. Preferably, alkyl is methyl, ethyl or cyclohexylmethyl.

  Within the framework of the present application, Ar is an homocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each of which may be optionally substituted by 1, 2 or 3 substituents, each The substituents are independently hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl It is chosen from the group. Preferably, Ar is naphthyl or phenyl which may optionally be substituted by 1 or 2 halo substituents, respectively.

  In the framework of the present application, Het is a single ring selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. A heterocyclic group; or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] A bicyclic heterocycle selected from the group of dioxynyl or benzo [1,3] dioxolyl; each monocyclic and bicyclic heterocycle optionally being halo, hydroxy, alkyl, alkyloxy or Ar-carbonyl It can be substituted with 1, 2 or 3 substituents selected from the group. Preferably, Het is thienyl.

Within the framework of the present application, halo is a substituent selected from the group of fluoro, chloro, bromo and iodo, and haloalkyl is substituted by one or more halo atoms and one or more carbon atoms. Linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Preferably, halo is bromo, fluoro or chloro, preferably, haloalkyl is polyhaloC C _1-6 alkyl, it is mono - or polyhalo substituted C _1-6 alkyl, for example one or more fluoro atoms Are defined as methyl having for example difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl and the like. If more than one halogen atoms are attached to one alkyl group within the definition of polyhaloC _1-6 alkyl, they may be the same or different.

In the definition of Het, or when R ⁴ and R ⁵ are taken together, it is intended to include all the possible isomers of the heterocycle, eg pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

Ar or Het (see for example R ³ ) mentioned in the definition of substituents of compounds of formula (Ia) or (Ib) mentioned above or below refers to any ring carbon unless otherwise stated Alternatively, it may be attached to the remainder of the molecule of formula (Ia) or (Ib), optionally via a heteroatom. Thus, for example, when Het is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

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

When two vicinal R ⁶ groups are taken together to form a divalent group of the formula -CH = CH-CH = CH-, this is a phenyl group to which two vicinal R ⁶ groups are attached. Together with the ring is meant to form naphthyl.

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

  The pharmaceutically acceptable addition salts mentioned above or below comprise the form of therapeutically active non-toxic acid addition salts which the compounds of formula (Ia) or (Ib) can form. It shall be. The latter is in the form of an inorganic acid such as a hydrohalic acid such as hydrochloric acid, hydrobromic acid etc .; sulfuric acid; nitric acid; phosphoric acid etc .; or organic acids such as acetic acid, Acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, It can be easily obtained by treatment with a suitable acid such as benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like. Conversely, the salt form can be converted to the free base form by treatment with an alkali.

  Compounds of formula (Ia) or (Ib) containing an acidic proton can be converted to their therapeutically active non-toxic metal or amine addition salt form by treatment with suitable organic and inorganic bases . Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts etc., organic bases such as primary, secondary and tertiary aliphatics And salts with aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, 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-propanedio Le, hydrabamine salts, and for example, arginine, comprise salts with amino acids such as lysine. Conversely, the salt form can be converted to the free acid form by treatment with an acid.

  The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (Ia) or (Ib) are able to form. Examples of such forms are eg hydrates, alcoholates etc.

  Some of the compounds of formulas (Ia) and (Ib) and some of the intermediate compounds routinely have at least two stereogenic centers in their structure, which leads to at least four stereochemically different structures it can.

  The term “stereochemically isomeric forms” as used hereinbefore or hereinafter refers to compounds of formulas (Ia) and (Ib) and their N-oxides, addition salts or physiologically functional derivatives. Define all possible stereoisomers that can be possessed. Unless otherwise stated or indicated, the chemical designation of the compound denotes the mixture of all diastereomers of the underlying molecular structure and all possible stereochemically isomeric forms containing the enantiomers. In particular, stereogenic centers can have the R- or S-configuration; substituents on divalent cyclic (partially) saturated groups can have either cis- or trans-configuration. Compounds that contain a double bond may have an E (entgegen) or Z (zusammen) -stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to those skilled in the art. Stereochemically isomeric forms of the compounds of formulas (Ia) and (Ib) are expressly intended to be embraced within the scope of the present invention.

  According to the CAS nomenclature agreement, if there are two known stereogenic centers of known absolute configuration in one molecule, the lowest numbered chiral center, R or S descriptor at the reference center (descriptor) ) Is specified (based on the Cahn-Ingold-Prelog ranking rule). The configuration of the second stereogenic center is indicated using the relative descriptive characters [R *, R *] or [R *, S *], where R * is always defined as the reference center, [R *] , R *] indicate centers having the same chirality, and [R *, S *] indicate centers of chirality that are not the same. For example, if the lowest numbered chiral center in the molecule has the S configuration and the second center is R, the stereodescription is defined as S- [R *, S *]. When "alpha" and "beta" are used: The position of the highest priority substituent on the asymmetric carbon atom in the ring system with the lowest ring number is optionally and always always determined by the ring system "alpha" of the average plane It is in the position. The position of the highest preferred substituent on another asymmetric carbon atom in the ring system relative to the position of the highest preferred substituent on the reference atom is if it is on the same side of the average plane determined by the ring system Is called "α", or "β" if it is on the other side of the mean plane determined by the ring system.

  Where a particular stereoisomer is indicated, this is substantially free of the other isomer, ie less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably 5%. It is meant to be associated with less than, more preferably less than 2% and most preferably less than 1% of other isomers. Thus, if a compound of formula (I) is defined as, for example, (.alpha.S, .beta.R), this means that the compound is substantially free of the (.alpha.R, .beta.S) isomer.

  The compounds of formulas (Ia) and (Ib) can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from one another according to resolution methods known in the art. Racemates of the formulas (Ia) and (Ib) can be converted into the corresponding diastereomeric salt forms by reaction with suitable chiral acids. The forms of the diastereomeric salts are subsequently separated, for example by selective or fractional crystallization, and alkali liberates the enantiomers therefrom. Another method of separating the enantiomeric forms of the compounds of formulas (Ia) and (Ib) involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These methods will advantageously use enantiomerically pure starting materials.

  Tautomers of the compounds of the formulas (Ia) and (Ib) comprise, for example, the compounds of the formulas (Ia) and (Ib) in which the enol group is converted to a keto group (keto-enol tautomerism) I assume.

The N-oxide forms of the compounds according to formulas (Ia) and (Ib) may be one or several third
It is intended to comprise the compounds of the formulas (Ia) and (Ib) in which the class nitrogen atom is oxidized to the so-called N-oxide.

  Compounds of formulas (Ia) and (Ib) can be converted to the corresponding N-oxide forms according to methods known in the art for converting trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting materials of formulas (Ia) and (Ib) with suitable organic or inorganic peroxides. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides are peroxyacids, such as benzene carboperoxo. Acids or halo-substituted benzene carboperoxo acids such as 3-chlorobenzene carboperoxo acids, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides such as t. It can comprise butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

  The invention also comprises derivatized compounds of the pharmacologically active compounds according to the invention (commonly called "prodrugs"), which decompose in vivo to give the compounds according to the invention. Prodrugs are usually (but not necessarily) of lower potency at the target receptor than the compounds that they degrade. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or ineffective. For example, the desired compound may be only slightly soluble, it may not be transported well across mucosal epithelia, or it may have an undesirably short plasma half life. Further discussion of prodrugs can be found in Stella, V. et al. J. et al. , "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176 and Drugs, 29, 1985, pp. It can be found at 455-473.

The prodrug forms of the pharmacologically active compounds according to the invention generally comprise compounds according to formulas (Ia) and (Ib) which have an esterified or amidated acid group, a pharmaceutically acceptable acid or base thereof Addition salts, their stereochemical isomers, their tautomers and their N-oxide forms. Included among such esterified acid groups are groups of the formula -COOR ^x , where R ^x is C _1-6 alkyl, phenyl, benzyl or the following groups:

It is one of the Amidated groups include groups of the formula -CONR ^y R ^z , where R ^y is H, C _1-6 alkyl, phenyl or benzyl and R ^z is -OH, H, C _1-6 Alkyl, phenyl or benzyl.

The compounds according to the invention having an amino group can be derivatized with ketones or aldehydes, for example formaldehyde, to form a Mannich base. The base will be hydrolyzed in aqueous solution with first order kinetics.

  Whenever used herein, the term "compounds of formula (Ia) or (Ib)" refers to their pharmaceutically acceptable acid or base addition salts, their N-oxide forms, their It is also intended to include tautomers or their stereochemical isomers. Of particular interest are compounds of the formula (Ia) or (Ib) that are stereochemically pure.

The first interesting aspect of the present invention is
R ¹ is hydrogen, halo, cyano, Ar, Het, alkyl and alkyloxy;
p is an integer equal to 1, 2, 3 or 4; in particular 1 or 2;
R ² is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or formula

Of which Y is O;
R ³ is alkyl, Ar, Ar-alkyl or Het;
q is an integer equal to zero, 1, 2 or 3;
R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; or, R ⁴ and R ⁵ together and including N to which they are attached, pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, Groups selected from the group of piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl can be formed, and each ring system can be optionally substituted with alkyl or pyrimidinyl;
Whether R ⁶ is hydrogen, halo or alkyl; or two vicinal R ⁶ groups together form the formula —CH = CH—CH = CH—
Can form a divalent group of
r is an integer equal to 1;
R ⁷ is hydrogen;
R ⁸ is hydrogen or alkyl;
Whether R ⁹ is oxo; or R ⁸ and R ⁹ together form a group NN—CH = CH—;
Is alkyl a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or 1 to 6 A saturated cyclic hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 20 carbon atoms, wherein each carbon atom is optionally halo or hydroxy Can be substituted;
Ar is an homocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl, and each homocyclic ring may be optionally substituted by 1, 2 or 3 substituents, and each substituent is Independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;
Whether Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or benzothienyl, 2,3-dihydrobenzo [1,4] dioxynyl or benzo A bicyclic heterocycle selected from the group of [1,3] dioxolyl; each monocyclic and bicyclic heterocycle optionally substituted with 1, 2 or 3 alkyl or Ar-carbonyl substituents And the above defined use of the compounds of formula (Ia) or (Ib), wherein halo is a substituent selected from the group of fluoro, chloro and bromo.

In a second interesting aspect, a sub-group of compounds of formula (Ia) or (Ib) or any of those mentioned above as an interesting aspect is that R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy; Preferred are compounds according to formulas (Ia) and (Ib) wherein R ¹ is halo; more preferably R ¹ is bromo.

In a third interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect have formula (Ia) in which p is equal to 1 and R ¹ is different from hydrogen And a compound according to (Ib).

In a fourth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect is where R ² is hydrogen, alkyloxy or alkylthio; preferably R ² Is an alkyloxy, in particular a C _1-4 alkyloxy; more preferably compounds according to formulas (Ia) and (Ib), wherein R ² is methyloxy.

C _1-4 alkyl is a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In a fifth interesting embodiment, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting embodiment is optionally substituted for R ³ respectively with 1 or 2 substituents. Which may be naphthyl, phenyl or thienyl, whose substituents are preferably halo or haloalkyl, most preferably halo; preferably R ³ is each optionally substituted by halo, preferably 3-fluoro more preferably R ³ is naphthyl or phenyl; that in certain naphthyl or phenyl can and most preferably a compound wherein R ³ according to formula (Ia) and (Ib) naphthyl.

  In a sixth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect, have q equal to zero, one or two; preferably q equal to one Compounds according to the formulas (Ia) and (Ib) which are equivalent.

In a seventh interesting aspect, the compounds of the formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect is provided that R ⁴ and R ⁵ are each independently hydrogen or alkyl, in particular hydrogen Or a compound according to formulas (Ia) and (Ib) which is C _1-4 alkyl, more particularly C _1-4 alkyl; preferably hydrogen, methyl or ethyl; most preferably methyl.

C _1-4 alkyl is a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In an eighth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect is a compound wherein R ⁴ and R ⁵ are together and to which they are attached And optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl or alkylthioalkyl, preferably substituted with alkyl, most preferably substituted with methyl or ethyl Compounds according to formulas (Ia) and (Ib) which form a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl.

In a ninth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect is where R ⁶ is hydrogen, alkyl or halo; preferably R ⁶ is Compounds according to formulas (Ia) and (Ib) which are hydrogen.

  In a tenth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned above as an interesting aspect, is in accordance with formulas (Ia) and (Ib), wherein r is 1 or 2. It is a compound.

In an eleventh interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned in the interesting aspect above, R ⁷ is hydrogen or methyl; preferably R ⁷ is hydrogen It is a compound according to a certain formula (Ia) and (Ib).

In a twelfth interesting aspect, in the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned in the interesting aspect above, R ⁸ is alkyl, preferably only for the compounds according to formula (Ib) Compounds according to formulas (Ia) and (Ib) which are methyl and R ⁹ is oxygen.

  In a thirteenth interesting aspect, the compounds of formula (Ia) or (Ib) or any subgroup thereof as mentioned in the interesting aspect above is a compound according to formula (Ia), a pharmaceutically acceptable compound thereof Compounds according to formulas (Ia) and (Ib) which are the acid or base addition salts obtained, their N-oxides, their tautomers or their stereochemical isomers.

An interesting group of compounds is that R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy; p = 1; R ² is hydrogen, alkyloxy or alkylthio; R ³ is optionally halo and haloalkyl respectively Naphthyl, phenyl or thienyl which can be substituted by one or two substituents selected from the group: q = 0, 1, 2 or 3; R ⁴ and R ⁵ are each independently hydrogen Or R ⁴ and R ⁵ together and including N to which they are attached form a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl; R ⁶ There hydrogen, alkyl or halo; r is equal to 1, and the compounds according to formula (Ia) R ⁷ is hydrogen, it may be a pharmaceutically acceptable Or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomers or the N- oxide form.

Preferably, in the compounds of formulas (Ia) and (Ib) or any subgroup thereof as mentioned in the interesting embodiments above, the term “alkyl” denotes C _1-6 alkyl, wherein C _1-6 Alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-methyl-ethyl, pentyl, hexyl and the like.

Preferably, the compound is:
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (3,5-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-Bromo-2-methoxy-quinoline corresponding to 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol -3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,5-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,3-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (2-fluoro-phenyl) -1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-p-tolyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-methylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (3-fluoro-phenyl) -1-phenyl-butan-2-ol; and o 1- (6 -Bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-phenyl-1-phenyl-butan-2-ol;
They are selected from their pharmaceutically acceptable acid or base addition salts, their N-oxides, their tautomers or their stereochemical isomers.

Even more preferably, the compound is o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,3-difluoro-phenyl) -4-dimethylamino-1-phenyl-butane-2 -All;
o 1- (6-Bromo-2-methoxy-quinoline corresponding to 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol -3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol; or their pharmaceutically acceptable acid or base addition salts, their N-oxides , Their tautomers or their stereochemical isomers.

  Another interesting group of compounds are the following: compounds 12, 71, 174, 75, 172 and 79 described below in Tables 1 to 6, in particular compounds 12, 71, 174 and 75, more particularly compounds 12, 71 and 174, their pharmaceutically acceptable acid or base addition salts, their N-oxides, their tautomers or their stereochemical isomers.

  Another chemical name for 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol is 6-bromo -[Alpha]-[2- (Dimethylamino) ethyl] -2-methoxy- [alpha] -1-naphthalenyl- [beta] -phenyl-3-quinolineethanol. The compound can also be shown as follows:

Most preferably, the compound is one of the following:
6-Bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol, its pharmaceutically acceptable acid or base addition salts, N-oxide or stereochemical isomer thereof; or 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or pharmaceutical thereof Acceptable acid addition salts; or 6-bromo-.alpha .- [2- (dimethylamino) ethyl] -2-methoxy-.alpha.-1-naphthalenyl-.beta.-phenyl-3-quinolineethanol or its stereochemical isomerism Or 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or N-oxide forms of (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol and (αR, , ΒS) -6-Bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or their pharmaceutically acceptable acid addition Salts or mixtures of their stereochemically isomeric forms, in particular racemic mixtures; ie compound 14 (diastereoisomer A); or (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl]- 2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol, ie compound 12 or a pharmaceutically acceptable acid addition salt thereof; or (αS, βR) 6-bromo-.alpha.-[2-(dimethylamino) ethyl] -2-methoxy-.alpha.-1-naphthalenyl -β- phenyl-3-quinolineethanol, i.e. compound 12.

  Most preferably, the compound is (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol, which is It corresponds to (1R, 2S) -1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol. The compound can also be shown as follows:

  The compounds of formula (Ia) and (Ib) can be prepared according to the method 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 skilled worker.

  In particular, compounds according to formula (Ia) can be obtained by reacting an intermediate compound of formula (II) with an intermediate compound of formula (III) according to the following reaction scheme (1) using BuLi in a mixture of diisopropylamine and tetrahydrofuran Can be manufactured:

Here all variables are defined as in formula (Ia). Stirring can increase the reaction rate. The reaction can be conveniently carried out at a temperature in the range of -20 to -70 ° C.

  The compounds of formula (Ib) can be synthesized using the same reaction method.

  Starting materials and intermediate compounds of the formulas (II) and (III) are compounds which are commercially available or can be prepared according to the usual reaction methods generally known in the art. For example, an intermediate compound of formula (II-a) can be prepared according to the following reaction scheme (2):

Here all variables are defined as in formula (Ia). Reaction scheme (2) comprises step (a), and in step (a), in the presence of a suitable base such as triethylamine and a suitable solvent inert to the reaction such as methylene chloride or ethylene dichloride, The appropriately substituted aniline is reacted with a suitable acyl chloride, such as 3-phenylpropionyl chloride, 3-fluorobenzenepropionyl chloride or p-chlorobenzenepropionyl chloride. The reaction can be conveniently carried out at a temperature ranging from room temperature to reflux temperature. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl ₃ ) 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 the next step (c), R ² is for example C _1-6 by reacting the intermediate compound obtained in step (b) with a compound H—X—C _1-6 alkyl wherein X is S or O. Introduce specific R ^2- groups which are alkyloxy or C _1-6 alkylthio groups.

  Intermediate compounds according to formula (II-b) can be prepared according to the following reaction scheme (3), wherein in the first reaction step (a) the substituted indole-2,3-dione is sodium hydroxide. Reaction with a substituted 3-phenylpropionaldehyde in the presence of a suitable base (Pfitzinger reaction) and then in the next step (b) the carboxylic acid compound in the presence of a suitable solvent inert to reactions such as diphenyl ether Decarboxylates at high temperature.

  In the reactions mentioned above and below, it is clear that the reaction product can be isolated from the reaction medium and further purified if necessary according to methods generally known in the art such as extraction, crystallization and chromatography. It is further apparent that reaction products present in more than one enantiomeric form can be isolated from their mixtures by known methods, in particular by preparative chromatography, such as preparative HPLC. Typically, compounds of formula (I) can be separated into their isomers.

The intermediate compounds of formula (III) are compounds which are commercially available or can be prepared according to the usual reaction methods generally known in the art. For example R ³ is Ar substituted with s substituents R ¹⁰ where each R ¹⁰ is independently hydroxy, halo, cyano, nitro, amino, mono- or di (C _1-6 alkyl) amino C _1-6 alkyl, polyhalo C _1-6 alkyl, C _1-6 alkyloxy, polyhalo C _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di (C Intermediate compounds of the formula (III-a) selected from the group of _1-6 alkyl) aminocarbonyl and s is an integer equal to zero, 1, 2 or 3 can be prepared according to the following reaction scheme (4) it can:

Reaction scheme (4) comprises step (a) and suitable Lewis acids such as AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl ₂ in step (a) and suitable solvents inert to the reaction Acyl chloride, for example 3-chloropropionyl chloride or 4-chlorobutyryl chloride, which is suitable, for example, in the presence of methylene chloride or ethylene dichloride and which is suitably substituted Ar, in particular suitably substituted phenyl, by the Friedel-Craft reaction. React with. The reaction can be conveniently carried out at a temperature ranging from room temperature to reflux temperature. In the next step (b), the intermediate compound obtained in step (a) is reacted with a primary or secondary amine to introduce an amino group (-NR ₄ R ₅ ).

  For the interpretation of the invention, the latent TB, the resting TB or the surviving TB are the same.

  As already described above, the compounds of the formulas (Ia) and (Ib) can be used for the treatment of latent TB. The exact dosage of the compound and the frequency of administration will depend on the particular compound of formulas (Ia) and (Ib) being used, the particular condition being treated, as is well known to those skilled in the art. It depends on the severity of the condition, the age, weight, sex, diet, time of administration and general physical condition of the particular patient, the mode of administration and other medications that the patient may be taking. Furthermore, it is clear that the effective daily dose can be reduced or increased depending on the response of the patient being treated and / or on the evaluation of the prescribing compound of the invention .

  The compounds of the present invention can be administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.

  The pharmaceutical composition can have various pharmaceutical forms for administration purposes. Suitable compositions can include all compositions commonly used to administer drugs systemically. For the preparation of pharmaceutical compositions, the active ingredient effective amount of the particular compound, which may optionally be in the form of an addition salt, is combined in an intimate mixture with a pharmaceutically acceptable carrier, The carrier may take a wide variety of forms depending on the form of preparation desired for administration. Desirably, these pharmaceutical compositions are in unitary dosage forms suitable, particularly, for administration orally or by parenteral injection. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical media, for example, oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, water, glycols, oils Alternatively, in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugars, kaolin, diluents, lubricants, binders, disintegrants and the like can be used. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. In the case of parenteral compositions, the carrier usually comprises sterile water, at least to a large extent, but may, for example, comprise other ingredients to aid solubility. For example, an injectable solution can be prepared 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 appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted to liquid form preparations shortly before use.

  Depending on the mode of administration, the pharmaceutical composition is preferably 0.05 to 99% by weight, more preferably 0.1 to 70% by weight of active ingredient and 1 to 99.95% by weight, more preferably Comprising 30 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total composition.

  The pharmaceutical composition further comprises various other ingredients known in the art such as lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavors or colorants. It can be contained.

  It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as a single dose, each unit having a predetermined amount of active ingredient calculated to produce the desired therapeutic effect. Together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including engraved or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and the like, as well as their pluralities separated. is there. The daily dosage of the compounds according to the invention will of course vary with the compound employed, the mode of administration, the desired treatment and the mycobacterial disease to which it is applied. In general, however, satisfactory results will be obtained if the compounds according to the invention are administered at daily dosages not exceeding 1 or 2 grams per kg of body weight, for example in the range of 10 to 50 mg.

EXPERIMENTAL PART As already mentioned above, the compounds of the formulas (Ia) and (Ib) and their preparation are described in WO 2004/011436, the contents of which are hereby incorporated by reference. The contents of

  The absolute stereochemical configuration of one or more stereogenic carbon atoms therein of some compounds was not experimentally determined. In such cases, the first isolated stereochemical isomer is referred to as "A", the second as "B" and no further mention of the actual stereochemical configuration. However, one skilled in the art can clearly characterize the "A" and "B" isomers using methods known in the art such as, for example, X-ray diffraction.

  Where "A" and "B" are stereoisomer mixtures, they can be further separated, whereby the respective first fractions isolated thereby are referred to as "A1" and "B1" respectively, the second Are referred to as "A2" and "B2", respectively, and no further mention of the actual stereochemical configuration. However, one skilled in the art can clearly characterize the "A1, A2" and "B1, B2" isomers using methods known in the art, such as X-ray diffraction, for example. .

  The compounds (see Tables 1 to 6) can be numbered according to the compounds of WO 2004/011436 and can be prepared according to the methods described in WO 2004/011436. . The example numbers in the following table refer to the example numbers of WO 2004/011436 and indicate that the compounds can be prepared according to the method.

  In particular, the preparation of compounds 12, 13, 12a, 13a, 14 and 15 is described in detail below.

Production of intermediate compounds
Example A1
Production of Intermediate Compound 1

At room temperature benzene propanoyl chloride (0.488 mol) was added dropwise to a solution of Et ₃ N (70 ml) and CH ₂ Cl ₂ (700 ml) solution of 4-bromo benzenamine (0.407 mol), the mixture at room temperature And stirred overnight. The mixture was poured out into water and concentrated NH ₄ OH and extracted with CH ₂ Cl ₂ . The organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is crystallized from diethyl ether. The residue (119.67 g) was taken up in CH ₂ Cl ₂ and washed with HCl 1N. The organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated. Yield: 107.67 g of intermediate compound 1.

Example A2
Production of Intermediate Compound 2

The reaction was performed twice. Was added dropwise to POCl ₃ N in (1.225 mol) of 10 ° C., N-dimethylformamide (DMF) (0.525 mol). Intermediate compound 1 (prepared according to A1) (0.175 mol) was then added at room temperature. The mixture was stirred at 80 ° C. overnight, poured out on ice and extracted with CH ₂ Cl ₂ . The organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of intermediate compound 2 (67%).

Example A3
Production of Intermediate Compound 3

And the mixture stirred overnight methanol CH ₃ ONa (30%) in (222.32Ml) and methanol (prepared according to A2) of intermediate compound 2 in (776 ml) (0.233 mol) was and refluxed, then on ice Pour out and extract with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / cyclohexane 20/80 and then 100/0; 20-45 [mu] m) was purified by. The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate compound 3 as a white powder (yield = 33%; melting point 84 ° C.).

Final compound 12,13,12A, 13a, 14 and 15 produced <br/> final compound 12,13,12A of, 13a, 14 and 15 produced

To a solution of N- (1-methylethyl) -2-propanamine (0.05 mol) in tetrahydrofuran (THF) (80 ml), nBuLi 1.6 M (0.05 mol) at −20 ° C. under a stream of N ₂ Was added slowly. The mixture was stirred at -20 ° C for 15 minutes and then cooled to -70 ° C. A solution of intermediate compound 3 (prepared according to A3 above) (0.046 mol) in THF (150 ml) was added slowly. The mixture was stirred at -70 ° C for 30 minutes. A solution of 0.055 mol 3- (dimethylamino) -1- (1-naphthyl) -1-propanone in THF (120 ml) was added slowly. The mixture was stirred at -70 <0> C for 3 hours, hydrolyzed at -30 <0> C with ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (29 g) was purified by column chromatography over silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH; 15~35μm; 99.5 / 0.5 / 0.1) was purified by. Two fractions were collected and the solvent was evaporated to give 3 g of fraction 1 and 4.4 g of fraction 2. Fractions 1 and 2 were crystallized separately from DIPE. The precipitate is filtered off, dried and 2.2 g of diastereoisomer A final compound 14 (yield: 9%; mp 210 ° C.) as a white solid, and 4 g of diastereoisomer B final compound 15 (Yield: 16%; mp 244 ° C.) was obtained as a white solid. Diastereoisomer A (final compound 14) was purified by chiral chromatography on silica gel (chiralpack AD) (eluent: hexane / EtOH; 99.95 / 0.05) to obtain the corresponding enantiomers. Two fractions were collected and the solvent was evaporated. Yield: 0.233 g of enantiomer A1 (final compound 12) as a white solid (melting point 118 ° C., [α] _D ²⁰ =
−166.98 ^° (c = 0.505 g / 100 ml in DMF) and 0.287 g of the enantiomer A2 as a white solid (final compound 13) (melting point 120 ° C., [α] _D ²⁰ = + 167.60 ^o (c = 0.472 g / 100 ml in DMF)). Enantiomer A1 was crystallized from EtOH to give a white solid: mp 184 ° C., [α] _D ²⁰ = −188.71 ^° (c = 0.621 g / 100 ml in DMF). Crystallization of enantiomer A2 from EtOH gave a solid with a melting point of 175 ° C.

0.2 g of diastereoisomer B (final compound 15) is purified by chiral chromatography on silica gel (chiralpack AD) (eluent: EtOH / iPrOH / N-ethyl-ethanamine; 50/50 / 0.1) did. Two fractions were collected and the solvent was evaporated. Yield: 78.2 mg of enantiomer B1 and 78.8 mg of enantiomer B2. Enantiomer B1 column chromatography over silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH; 15~40μm; 99/1 / 0.1) was purified by. One fraction was collected and the solvent was evaporated. Yield: enantiomers of 57 mg B1 (final compound ^{_{12a) ([α] D 20}} = -42.56 o (0.336g / 100ml in c = DMF)). Enantiomer B2 column chromatography over silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH; 15~40μm; 99/1 / 0.1) was purified by. One fraction was collected and the solvent was evaporated. Yield: enantiomers of 53 mg B2 (final compound ^{_{13a) ([α] D 20}} = + 43.55 o (c = 0.349g / 100ml in DMF)).

  Tables 1-6 list compounds of formulas (Ia) and (Ib).

A. Study of the effect of final compound 12 on killing of dormant Mycobacterium bovis Bacterial strains and culture medium Mycobacterium bovis BCG was obtained from Tibotec Virco (TB0087- (Belgium). Plasmid pSMT1 M. bovis BCG (a kind gift from Dr. Kris Huygen at Pasteur Institute, Brussels, ⁸ ) expressing the luciferase gene above, Meddlebrook 7 H9 medium (Difco, BD 2713 ¹⁰ ) with 0.05% Tween-80 (Sigma). In the log phase for a period of 3 to 4 days before the start of the experiment.

  For the preparation of the growth medium: 4.7 g of Middlebrook powder is dissolved in 895 ml of distilled water, 5 ml of glycerol, 200 μl of Tween 80 are added and autoclaved at 121 ° C. for 15 minutes. Once cooled to 45 ° C., aseptically add 100 ml of Middlebrook OADC enrichment medium to the medium. Store at 4 ° C for up to 1 month. All media are pre-incubated for 2 days at 37 ° C. and checked for contamination. A strain M. which expresses a luciferase gene. For Bovis BCG (BCG-pSMT1), add 50 μg / ml hygromycin.

I. Study dormancy assay with Mycobacterium bovis BCG 500 μl of Mycobacterium bovis BCG stock strain was added to 100 ml of Middlebrook 7H9 broth with complement in 250 ml of sterile Duran bottle with magnetic stir bar . Incubation was carried out at 37 ° C. for 7 days on a magnetic stirrer (500 rpm). Aliquots of 5 ml of log phase cultures (OD _{600 nm} = 0.5-0.8) were transferred into 15 ml screw capped falcon tubes. The various agents were added to individual tubes at a final concentration of 10 μg / ml. After drug addition, all tubes were loosely closed and placed in an anaerobic jar (BBL). Anaerobic gas generation envelopes were used to obtain anaerobic conditions in the jar, and anaerobic strips were used to monitor anaerobic conditions. The addition of the individual agents and the initiation of the anaerobic life in the jar took place very rapidly as described previously ⁹ . The jars were incubated at 37 ° C. for 7 days.

CFU Assay After 7 days of anaerobic life, dormant cultures were collected by low speed centrifugation (2000 rpm for 10 minutes). The cells were washed twice with 7H9 medium to remove drug and resuspended in drug-free medium. CFU of treated and untreated cultures were determined by plating on day 0, 2 and 5 to assess bactericidal activity.

II. M. expressing the luciferase gene on plasmid pSMT1. Study Dormant Assay with Bovis BCG 500 μl of Mycobacterium bovis BCG luciferase (pSMT1) stock bacteria were added to 100 ml of Middlebrook 7H9 broth with complement in sterile 250 ml Duran bin with magnetic stir bar. Incubation was carried out at 37 ° C. for 7 days on a magnetic stirrer (500 rpm). Aliquots of 5 ml of log phase cultures (OD _{600 nm} = 0.5-0.8) were transferred into 15 ml screw-cap Falcon tubes. The various agents were added to individual tubes at a final concentration of 10 μg / ml. After drug addition, all tubes were loosely closed and placed in the anaerobic jar (BBL) ⁹ very quickly as previously described. An anaerobic gas generation shroud was used to obtain anaerobic conditions in the jar and an anaerobic strip was used to monitor anaerobic conditions. The jars were incubated at 37 ° C. for 7 days.

Luciferase Assay After 7 days of anaerobic life, dormant cultures were collected by low speed centrifugation (2000 rpm for 10 minutes). The cells were washed twice with 7H9 medium to remove drug and resuspended in drug-free medium. After washing, 250 μl of resting M. Bovis BCG luciferase (pSMT1) was added to 5 different microplates (0-5 days). All samples were diluted in culture medium (5-fold dilution) in microplates and reincubated at 37 ° C. for up to 0-5 days. 40 μl of sample and dilutions were added to 140 μl PBS. 20 μl of luciferase substrate (1% n-decyl aldehyde in ethanol) was added. Luminescence was measured for 10 seconds daily (0 to 5 days) to follow the growth of viable bacteria (using Luminoskan Ascent Labsystems with injectors).

Results and Discussion In vitro diapause models of diapause have been developed based on Wayne's method for the formation of diapause bacteria by oxygen depletion ^9,10 . In Wayne's model, as the mycobacteria settle to the bottom of the flask, they form an oxygen gradient, resulting in an anaerobic condition at the bottom of the flask. This transition to low oxygen concentrations causes mycobacteria to become quiescent, leading to the upregulated expression of several genes, including isocytotolyase and glycine dehydrogenase. These enzymes are responsible for the production of energy in the absence of oxygen, and the terminal electron acceptors are nitrates, sulfates etc. compared to molecular oxygen in aerobic respiration. The energy of the reduced substrate produces an electron chemical gradient.

In this experiment, the application of Wayne's model was used in an experimental setup involving the use of gaspak anaerobic jars that deplete oxygen in the room by chemical reactions ⁹ . Attach a lid containing the catalyst to the gas packer. A gaspack foil wrap containing hydrogen and a substance that produces CO ₂ is placed in a jar with bacterial culture. Open the cover and pipette 10 ml of tap water into it. When the jar is closed (the lid is tightened tightly), the generated hydrogen combines with the oxygen and forms water through the mediation of the catalyst. This gradually depletes the oxygen present in the chamber, thus creating an oxygen gradient. In addition, the indicator strip in the jar contains methylene blue, which turns colorless in the absence of oxygen. A change in color in the indicator strip indicates that adequate atmospheric conditions have been achieved.

For rapid analysis of the effect of compounds on dormant bacteria, the luciferase construct was used to transform M. coli. Bovis BCG was used. M. Bovis BCG was used in previous experiments as a surrogate to mimic dormancy in whole mycobacteria and specifically in Mycobacterium tuberculosis ^11,12 . Luciferase reporter strain has been very often used to assess the viability of bacteria ^13,14. E. Using the reporter plasmid pSMT1, a shuttle vector containing the E. coli and mycobacterial origins of replication, M. pylori was used. Transform Bovis BCG ⁸ . The luminescent genes (lux A and B) from Vibro harvryi are under the control of the BCG hsp60 promoter and produce light in the presence of ATP or flavin mononucleotide (FMNH ₂ ). Dead cells can not produce these cofactors, thus corresponding to a decrease in luminescence.

The activity of final compound 12 as well as the activity of other agents, including metronidazole and isoniazid, were analyzed in this diapause assay. Dormant bacteria are not killed by isoniazid and are to some extent resistant to rifampicin, but susceptible to killing by metronidazole, an antibiotic for anaerobic pathogens ^15,16 . Isoniazid acts as an initial bactericidal agent and its activity is limited to the killing of replicating bacilli, but has no significant sterilizing activity against dormant bacilli ¹⁷ .

After 7 days of anaerobic life, the bacteria were suspended in drug free medium for 5 days and the effect of various compounds on bacterial viability was assessed by luciferase counts. As shown in FIG. 1, isoniazid has no effect on these dormant bacteria, and these bacteria have almost similar growth characteristics compared to the standard and do not have the dormant or non-replicating state of the culture bacilli. Indicated. In contrast, metronidazole was apparently effective in killing dormant bacilli over a period of time, with a 2 log ₁₀ reduction compared to the standard. The final compound 12 affects the survival of the dormant bacteria in a concentration dependent manner. At final compound 12 at 10 μg / ml concentration, there was an approximately 4-log ₁₀ reduction in bacterial survival as compared to the untreated standard. At 0.1 and 1 μg / ml of compound, the kill of the corresponding dormant bacteria was approximately 0.5 log ₁₀ and 2 log ₁₀ , respectively.

Bacterial counts were also measured on 7H10 plates to correlate the effect of final compound 12 on bacterial killing by relative luminescence units (RLU / ml) against colony forming units (CFU / ml). After plating 2 day and 4 day samples on 7H10 plates, similar ratios of RLU units to CFU counts were observed. The decrease in CFU counts compared to the counts of untreated standards is approximately 4, 2.3 and 0 at 2 days of viability at 10 μg / ml, 1 μg / ml and 0.1 μg / ml of final compound 12, respectively. .5 log ₁₀ and 5 days were shown to decrease approximately 6, 4.7 and 1.1 log ₁₀ . Figure 2 (A and B) reports CFU data. A close relationship between luminescence and CFU was observed during the various stages of the experiment. Interestingly, there is a marked decrease in RLUs compared to CFU counts at time 0, mainly because of the very low concentration of ATP in these cells, which is characteristic of the metabolic state of dormant bacilli It is shown that ⁸ .

  The final activity of Compound 12 on dormant (non-proliferative) mycobacteria is a very important finding, which is to fight against tuberculosis by eradicating disease in patients at risk of developing TB. For it will help.

B. Study of the effect of final compound 12 on killing of quiescent Mycobacterium tuberculosis according to the Wayne Dormant Model * Bacterial strains and culture medium Mycobacterium tuberculosis (H37 RV) was cultured in Middlebrook's medium with 0.05% Tween .

For the preparation of Middlebrook 7H9 broth (1X) (BD 271310) with supplements: Dissolve 4.7 g of Middlebrook powder in 895 ml of distilled water, add 5 ml of glycerol, 200 μl of Tween 80, 15 at 121 ° C. Autoclave for a minute. 100ml Middlebrook when cooled to 45 ° C
Aseptically add OADC enrichment medium (BD 211886) to the medium. Store at 4 ° C for up to 1 month. All media are pre-incubated for 2 days at 37 ° C. and checked for contamination.
* Wayne L. G. et al. By; Infection and Immunity 64 (6), 1996, 2062-2069.

Study dormancy assay with Mycobacterium tuberculosis (H37RV) 1000 μl of Mycobacterium tuberculosis stock strain (previous culture) was added to 100 ml of Middlebrook 7H9 broth with complement in 250 ml of sterile Duran bottle with magnetic stir bar . Incubation was carried out at 37 ° C. for 7 days on a magnetic stirrer (500 rpm). An aliquot of 17 ml of log phase culture (calculated OD _600nm = 0.01) was transferred into a 25 ml tube. The tube was tightly closed with a cap with a rubber septum and incubated on a magnetic stir plate to produce anaerobic deprivation by oxygen depletion. Stirring in the tube was performed with an 8 mm Teflon stir bar. The tubes were incubated at 37 ° C. for 22 days in an incubator on a magnetic stir plate (120 rpm) until anaerobic living (methylene blue (1.5 mg / liter) turns colorless). After 14 days, various agents (final concentrations of 100, 10, 1 and 0.1 μg / ml) were added to the individual tubes. Metronidazole was added as a standard for killing dormant bacteria (added at start). Isoniazid was added as a standard to show that it has no effect on the growth and viability of dormant bacteria.

CFU Assay After 22 days, cultures were harvested by low speed centrifugation (2000 rpm for 10 minutes). Cells were washed twice in drug free medium and cells were resuspended in drug free medium and incubated. By plating after anaerobic life, the reduction in CFU compared to untreated standard cultures was determined to assess bactericidal activity.

Results and Discussion:
Using the Wayne dormancy model, the effect of final compound 12 on dormant bacteria is shown (see FIG. 3). As already indicated above, it is an in vitro oxygen depletion model, which initiates a dormancy response in bacteria ^18-23 . In the Wayne model, bacterial cultures are subjected to gradual oxygen depletion by incubation in a sealed closed tube. With the slow transition of the aerobic growth bacteria to the anaerobic state, the culture can be more adapted to and survive the anaerobic life by moving downward to the anaerobic state. The Wayne model is a well-characterized in vitro model for dormancy.

In the final compound 12 at a concentration of 10 μg / ml, a more than 2 log ₁₀ reduction of dormant bacteria was observed, as was also seen with moxifloxacin and rifampicin. While isoniazid has no effect on dormant bacteria, the standard compound metranidazole showed excellent efficacy.

Reference list 1. Corbett, E., et al. L. et al. , The growing burden
of tuberculosis: global trends and interactions with the HIV epidemic. Arch. Inern. Med 163, 2003, 1009-1021.
2. Dye, C.I. , Scheele, S .; , Dolin, P .; , Pathania, V., et al. & Raviglione, M. C. Consensus statement. Global burden of tuberculosis: estimated incidence incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282, 1999, 677-686.
3. Targeted tuberculin test and treatment of latent tuberculosis infection. The official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is American Thoracic Society (ATS) and Centers for Disease Control
and Prevention (CDC) joint statement. This statement has been endorsed by the Council of the Infectious Diseases Society of America (IDSA), September 1999 and by the Department of this Statement. Am J Respir. Crit Care Med 161, 2000, S221-S247.
4. Halsey, N .; A. et al. Chose, Randomized trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis of HIV-1 infection. Lancet 351, 1998, 786-792.
5. Mitchison, D .; A. & Coates, A. R. Predictive in vitro models of the stabilization activity of anti-tuberculosis drugs. Curr. Pharm. Des 10, 2004, 3285-3295.
6. Karakousis, P. et al. C. et al. By Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis in artificial artificial granulomas in mice. J Exp. Med. 200, 2004, 647-657.
7. Gomez, J.J. E. & McKinney, J.J. D. , M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. (Edinb.) 84, 2004, 29-44.
8. Snewin, V. A. et al. By, Assessment of immunity to mycobacterial infection with luciferase reporter constructs. Infect. Immun. 67, 1999, 4586-4593.
9. Stover, C .; K. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis, Nature 405, 2000, 962-966.
10. Wayne, L .; G. , Synchronized replication of Mycobacterium tuberculosis. Infect. Immun. 17, 1977, 528-530.
11. Boon, C .; & Dick, T. By Mycobacterium bovis
BCG response regulator essential for hypoxic dormancy. J. Bacteriol. 184, 2002, 6760-6767.
12. Hutter, B .; & Dick, T. Up-regulation of narX, encoding a putative 'fused nitrate reductase' in anaerobic dormant Mycobacterium bovis BCG. FEMS Microbiol. Lett. 178, 1999, 63-69.
13. Andrew, P .; W. & Roberts, I .; S. , Construction of a bioluminescent mycobacterium and
its use for assay of antimycobacterial agents. J Clin. Microbiol. 31, 1993, 2251-2254.
14. Hickey, M .; J. et al. , Luciferase in vivo
expression technology: use of recombinant mycobacterial reporter strains to evaluate antimycobacterial activity in mice.
Antimicrob. Agents Chemother. 40, 1996, 400-407.
15. Wayne, L .; G. & Sramek, H. A. , Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 38, 1994, 2054-2058.
16. Wayne, L .; G. Author, Dormancy of Mycobacterium
tuberculosis and latency of disease. Eur. J Clin Microbiol. Infect. Dis 13, 1994, 908-914.
17. Lalande, V. , Truffot-Pernot, C.I. Paccaly-Moulin, A., et al. Grosset, J. et al. & Ji, B. , Powerful bacteria activity of sparfloxacin (AT-4140) against Mycobacterium tuberculosis in mice. Antimicrob. Agents Chemother. 37, 1993, 407-413.
18. Zhang, Y .; , Persistent and dormant tubercle bacilli and latent tuberculosis. Front Biosci. 9, 2004, 1136-1156.
19. Boon, C .; & Dick, T. By Mycobacterium bovis
BCG response regulator essential for hypoxic dormancy. J Bacteriol. 184, 2002, 6760-6767.
20. Peh, H. L. , Toh, A., et al. Murugasu-Oei, B., et al. & Dick, T. In vitro activities of mitomycin C against growing and hypoxic dormant tubercle bacilli. Antimicrob. Agents Chemother. 45, 2001, 2403-2404.
21. Hutter, B .; & Dick, T. By, Increased alanine
Dehydrogenase activity during dormancy in Mycobacterium smegmatis. FEMS Microbiol. Lett. 167, 1998, 7-11.
22. Wayne, L .; G. & Hayes, L. G. By An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two
stages of nonreplicating persistence. Infect. Immun. 64, 1996, 2062-2069.
23. Antia, R., et al. , Koella, J., et al. C. & Perrot, V. , Models of the within-host dynamics of persistent mycobacterial infections. Proc. Biol. Sci. 263, 1996, 257-263.

Dormant M. coli assayed by luciferase count. FIG. 6 is a graph showing the effects of various agents on bovis. Dormant M. FIG. 6 is a graph showing the effects of various agents on bovis. Dormant M. FIG. 6 is a graph showing the effects of various agents on bovis. FIG. 6 is a graph showing the effects of various agents on dormant Mycobacterium tuberculosis.

  The main features and aspects of the present invention are listed below.

1.
Use of a compound of formula (Ia) or (Ib) for the manufacture of a medicament for the treatment of latent TB, wherein the compound of formula (Ia) or (Ib) is
[In the formula,
R ¹ 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, mercapto, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di (alkyl) amino or a compound of the formula
In which Y is CH ₂ , O, S, NH or N-alkyl;
R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;
q is an integer equal to zero, 1, 2, 3 or 4;
R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; or R ⁴ and R ⁵ together with N containing them, optionally alkyl, halo, haloalkyl, Hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl which can be substituted with pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl Form a group selected from the group of 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Door can be;
R ⁶ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or two vicinal R ⁶ groups together And the formula -CH = CH-CH = CH-
Can form a divalent group of
r is an integer equal to 1, 2, 3, 4 or 5;
R ⁷ is hydrogen, alkyl, Ar or Het;
R ⁸ is hydrogen or alkyl;
R ⁹ is oxo; or R ⁸ and R ⁹ together form a group NN—CH = CH—;
Alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or 1 A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 6 to 6 carbon atoms, wherein each carbon atom is optionally Can be substituted with halo, hydroxy, alkyloxy or oxo;
Ar is an homocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl, and each homocyclic ring can be optionally substituted by 1, 2 or 3 substituents, and each substituent is 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 And
Het is a monocyclic heterocyclic ring selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, imidazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1,1] 3] a bicyclic heterocycle selected from the group of dioxolyl; each monocyclic and bicyclic heterocycle is optionally selected from the group of halo, hydroxy, alkyl, alkyloxy or Ar-carbonyl , It can be substituted by 2 or 3 substituents;
Halo is a substituent selected from the group of fluoro, chloro, bromo and iodo; and haloalkyl is one to six of which one or more carbon atoms are substituted with one or more halo-atoms. Or a linear or branched saturated hydrocarbon group having 3 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms]
Use which is its pharmaceutically acceptable acid or base addition salt, its N-oxide, its tautomer or its stereochemical isomer.

2.
R ¹ is hydrogen, halo, cyano, Ar, Het, alkyl and alkyloxy;
p is an integer equal to 1 or 2;
R ² is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or formula
Of which Y is O;
R ³ is alkyl, Ar, Ar-alkyl or Het;
q is an integer equal to zero, 1, 2 or 3;
R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; or, R ⁴ and R ⁵ together and including N to which they are attached, pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, Groups selected from the group of piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl can be formed, and each ring system can be optionally substituted with alkyl or pyrimidinyl;
Whether R ⁶ is hydrogen, halo or alkyl; or two vicinal R ⁶ groups together form the formula —CH = CH—CH = CH—
Can form a divalent group of
r is an integer equal to 1;
R ⁷ is hydrogen;
R ⁸ is hydrogen or alkyl;
Whether R ⁹ is oxo; or R ⁸ and R ⁹ together form a group NN—CH = CH—;
Whether the alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or 1 A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 6 to 6 carbon atoms, wherein each carbon atom is optionally Can be substituted with halo or hydroxy;
Ar is an homocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl, and each homocyclic ring may be optionally substituted by 1, 2 or 3 substituents, and each substituent is Independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;
Whether Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or benzothienyl, 2,3-dihydrobenzo [1,4] dioxynyl or benzo A bicyclic heterocycle selected from the group of [1,3] dioxolyl; each monocyclic and bicyclic heterocycle optionally substituted with 1, 2 or 3 alkyl or Ar-carbonyl substituents And halo is a substituent selected from the group of fluoro, chloro and bromo. Use according to.

3.
In formula (Ia) or (Ib), R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy. Or 2. Use according to.

4.
R ¹ is halo3. Use according to.

5.
In formula (Ia) or (Ib), p is equal to 1. ~ 4. Use according to any one of.

6.
In formula (Ia) or (Ib), R ² is hydrogen, alkyloxy or alkylthio. To 5. Use according to any one of.

7.
R ² is alkyloxy6. Use according to.

8.
In formulas (Ia) or (Ib), R ³ is naphthyl, phenyl or thienyl which may optionally be substituted by one or two substituents, each optionally selected from the group of halo and haloalkyl. ~ 7. Use according to any one of.

9.
8. R ³ is naphthyl Use according to.

10.
In formula (Ia) or (Ib), q is equal to 1. ~ 9. Use according to any one of.

11.
In the formula (Ia) or (Ib), R ⁴ and R ⁵ are each independently hydrogen or alkyl, or R ⁴ and R ⁵ together and including N to which they are bound, imidazolyl, Form a group selected from the group of triazolyl, piperidinyl, piperazinyl and thiomorpholinyl. To 10. Use according to any one of.

12.
11. In the formula (Ia) or (Ib), R ⁴ and R ⁵ are each independently hydrogen or alkyl. Use according to.

13.
12. R ⁴ and R ⁵ are C _1-4 alkyl 12. Use according to.

14.
In formula (Ia) or (Ib), R ⁶ is hydrogen, alkyl or halo. To 13. Use according to any one of.

15.
13. R ⁶ is hydrogen 13. Use according to.

16.
In formula (Ia) or (Ib), r is equal to 1. -15. Use according to any one of.

17.
In the formula (Ia) or (Ib), R ⁷ is hydrogen. To 16. Use according to any one of.

18.
In formula (Ia) or (Ib), R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy; p = 1; R ² is hydrogen, alkyloxy or alkylthio; R ³ is optionally Naphthyl, phenyl or thienyl which can be substituted by one or two substituents selected from the group of halo and haloalkyl; q = 0, 1, 2 or 3; R ⁴ and R ⁵ are each Independently hydrogen or alkyl, or R ⁴ and R ⁵ together and including N to which they are bound, form a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl R ⁶ is hydrogen, alkyl or halo; r is equal to 1 and R ⁷ is hydrogen Use according to.

19.
The compound is:
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (3,5-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,5-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,3-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (2-fluoro-phenyl) -1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-p-tolyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-methylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol;
o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (3-fluoro-phenyl) -1-phenyl-butan-2-ol; and o 1- (6 -Bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2-phenyl-1-phenyl-butan-2-ol;
It is characterized in that it is selected from the group consisting of their pharmaceutically acceptable acid or base addition salts, their N-oxides, their tautomers or their stereochemical isomers. Use according to.

20.
The compound is 1- (6-bromo-2-methoxy-quinolin-3-yl) -2- (2,3-difluoro-phenyl) -4-dimethylamino-1-phenyl-butan-2-ol;
o 1- (6-Bromo-2-methoxy-quinoline corresponding to 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol -3-yl) -4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol; or their pharmaceutically acceptable acid or base addition salts, their N-oxides 19. their selected from the group consisting of their tautomers or their stereochemical isomers; Use according to.

21.
The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol, its pharmaceutically acceptable acid or base addition salt , Its N-oxide or its stereochemical isomer. Use according to.

22.
The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or a pharmaceutically acceptable acid addition salt thereof 21. Use according to.

23.
21. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or a stereochemical isomer thereof 21. Use according to.

24.
21. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or its N-oxide form 21. Use according to.

25.
The compound is (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or pharmaceutically acceptable thereof 21. An acid addition salt to be obtained Use according to.

26.
25. The compound is (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol 25. Use according to.

Claims (6)

The following formula
6-Bromo-.alpha .- [2- (dimethylamino) ethyl] -2-methoxy-.alpha.-1-naphthalenyl-.beta.-phenyl-3-quinolineethanol with or having a pharmaceutically acceptable acid or base thereof A pharmaceutical composition for killing dormant Mycobacterium tuberculosis , comprising a compound selected from the group consisting of addition salts, their N-oxides or their stereochemical isomers. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or a pharmaceutically acceptable acid addition salt thereof The pharmaceutical composition according to claim 1. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or a stereochemically isomeric form thereof. Pharmaceutical composition as described. The compound according to claim 1, wherein the compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or its N-oxide form. Pharmaceutical composition. The compound has the following formula
Or (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or The pharmaceutical composition according to claim 1, which is a pharmaceutically acceptable acid addition salt. 6. The compound according to claim 5, wherein the compound is (.alpha.S, .beta.R) -6-bromo-.alpha .- [2- (dimethylamino) ethyl] -2-methoxy-.alpha.-1-naphthalenyl-.beta.-phenyl-3-quinolineethanol. Pharmaceutical composition.